Aspects of

Organoselenium Chemistry

A thesis presented for the degree of

Doctor of Philosophy

by

Virginia R. Ward

B.Sc. (Hons)

School of Chemistry and Physics

November 2012

TABLE OF CONTENTS

ABSTRACT iii

STATEMENT OF ORIGINALITY v

ACKNOWLEDGEMENTS vi

ABBREVIATIONS vii

1 INTRODUCTION 1

1.1 SELENIUM 1

1.2 ORGANOSELENIUM CHEMISTRY 5

1.2.1 Selenium dioxide 5 1.2.2 Electrophilic Selenium Reagents 7 1.2.3 Nucleophilic Selenium Reagents 15 1.2.4 Radical Chemistry of Organoselenium Compounds 21 1.2.5 The Selenoxide syn-Elimination 26 1.2.5 Biotransformation of Organoselenium Compounds 29

2 THE AMIDOSELENATION OF ALKENES 32

2.1 INTRODUCTION 32

2.2 INVESTIGATION OF THE FORMATION OF THE trans-OXAZOLINE (2.9) 34

2.3 ONE-POT PREPARATION OF -AMIDO SELENIDES 40

2.4 ALTERNATIVE SOLVENTS FOR THE AMIDOSELENATION REACTION 46

2.5 TWO-STEP PREPARATION OF -AMIDO SELENIDES 49

2.6 PREPARATION OF THE trans-OXAZOLINE (2.9) 56

3 CYCLISATION OF -AMIDOALKYL PHENYL SELENIDES 59

3.1 INITIAL ATTEMPTS TO OPTIMISE THE FORMATION OF N-ACYLAZIRIDINES 59

3.2 CYCLISATION OF -AMIDO SELENIDES AT LOW TEMPERATURE 67

3.3 SUMMARY OF RESULTS FROM THE CYCLISATION OF -AMIDO SELENIDES 76

3.4 FACTORS DETERMINING THE FORMATION OF 3- VERSUS 5-MEMBERED RINGS 77

3.5 OCCURRANCE AND UTILITY OF N-ACYLAZIRIDINES 79

4 AMIDOSELENATION via ADDITION OF ‘PHENYLSELENENYL PERCHLORATE’ 83

4.1 INTRODUCTION 83

4.2 PREPARATION OF -(PHENYLSELANYL)CYCLOHEXYL AMIDES 86

4.3 ALTERNATIVES TO THE -AMIDO SUBSTITUENT 88

5 CLOSER EXAMINATION OF A SELENOXIDE AND A SELENONE 92

5.1 PREPARATION OF N-[2-(PHENYLSELENINYL)CYCLOHEXYL]BENZAMIDE

AND N-[2-(PHENYLSELENONYL)CYCLOHEXYL]BENZAMIDE 92

5.2 HYDROGEN-BONDING IN THE SELENIDE (2.5), SELENOXIDE (5.1) AND SELENONE (5.9) 98

5.3 NMR-SCALE OXIDATION OF N-[2-(PHENYLSELANYL)CYCLOHEXYL]BENZAMIDE (2.5) 101

6 PREPARATION AND CYCLISATION OF -HYDROXY SELENIDES 107

6.1 INTRODUCTION 107

6.2 ATTEMPTED ONE-POT PREPARATION OF 2-PHENYLOXETANE 110

6.3 PREPARATION AND ATTEMPTED CYCLISATION OF 3-PHENYL-3-PHENYLSELENOPROPANOL 112

6.3 PREPARATION AND CYCLISATION OF -HYDROXY SELENIDES BEARING A PRIMARY SELENIUM MOIETY 115

6.4 OXETANES IN NATURAL PRODUCTS AND DRUG DESIGN 124

7 EXPERIMENTAL 128

7.1 GENERAL EXPERIMENTAL 128

7.2 WORK DESCRIBED IN CHAPTER 2 131

7.3 WORK DESCRIBED IN CHAPTER 3 160

7.4 WORK DESCRIBED IN CHAPTER 4 182

7.5 WORK DESCRIBED IN CHAPTER 5 187

7.6 WORK DESCRIBED IN CHAPTER 6 196

REFERENCES 212

PUBLICATIONS 230

iii

ABSTRACT

A range of-amidoalkyl phenylselenides were prepared in order to explore their

cyclisation via oxidation of the selenium moiety to the selenone followed by

intramolecular displacement. At first, the -amidoalkyl phenylselenides were

prepared in one-step from the alkenes. However, the one-step preparation was

complicated by side-reactions and a two-step method was found to give clean

reactions and higher yields of a wide range of the desired amido selenides.

Along with the expected oxazolines, isomeric N-acylaziridines were obtained from the

cyclisation reaction. Formation of N-acylaziridines by cyclisation of amides is

unusual, and variation of the conditions was explored in order to optimise this novel

aziridine-forming reaction. It was found that conducting the oxidation reaction at low

temperature favoured the aziridine products. In this way, the aziridines derived from

all prepared -amido selenides were obtained in good to excellent yield. From some

substrates, the aziridine was obtained as the exclusive product.

The low temperature generation of a selenone from the corresponding selenide had

not been reported previously. Experiments were carried out which provided

evidence for the supposition that the intermediate in the cyclisation reaction was the

selenone.

The preparation of -amido selenides was also investigated using silver ion to

sequester the halide of the selenium reagent, rendering the selenium species more

electrophilic and its addition to the alkene to give a seleniranium ion, irreversible.

The seleniranium ion was generated in the presence of nitrile to allow attack by the

iv

weak nitrile nucleophile upon the seleniranium ion, giving a nitrilium ion. With

addition of water to the nitrilium ion, -amido selenides were formed in moderate

yield. Thus, it was shown that the -amido selenides could be prepared without the

use of strong acid. Addition of azide to the nitrilium ion gave a tetrazole, which

demonstrated that this methodology could provide access to selenides substituted at

the -position with groups other than the amido group.

-Benzamidocyclohexyl phenyl selenoxide and -benzamidocyclohexyl phenyl

selenone were prepared, and hydrogen bonding in the two compounds was

examined spectroscopically. An X-ray crystal structure of the selenoxide showed

intermolecular hydrogen bonding between the amide hydrogen and the seleninyl

oxygen, in contrast to proposals in the literature that analogous selenoxides were

stabilised by intramolecular hydrogen bonding in the solid state.

Three -hydroxy selenides were prepared and their low-temperature oxidation and

cyclisation was explored with a view to obtaining the corresponding oxetanes. The

low-temperature procedure did not translate successfully to the cyclisation of -

hydroxy selenides to oxetanes, instead giving complex mixtures. However, with

reference to literature conditions for the preparation of methoxy-substituted oxetanes,

the -hydroxy selenides were cyclised to the corresponding oxetanes by oxidation in

methanol at room temperature, demonstrating that the scope of this method could be

widened to a more generalised preparation of oxetanes.

v

STATEMENT OF ORIGINALITY

I certify that this work contains no material which has been accepted for the award of

any other degree or diploma in any university or other tertiary institution and, to the

best of my knowledge and belief, contains no material previously published or written

by another person, except where due reference has been made in the text. In

addition, I certify that no part of this work will, in the future, be used in a submission

for any other degree or diploma in any university or other tertiary institution without

the prior approval of the University of Adelaide and where applicable, any partner

institution responsible for the joint-award of this degree.

I give consent to this copy of my thesis, when deposited in the University Library,

being made available for loan and photocopying, subject to the provisions of the

Copyright Act 1968.

I also give permission for the digital version of my thesis to be made available on the

web, via the University’s digital research repository, the Library catalogue and also

through web search engines, unless permission has been granted by the University

to restrict access for a period of time.

Virginia Ward November, 2012

vi

ACKNOWLEDGEMENTS

I thank David Ward for giving me the opportunity to work with this intriguing element,

for sagely guiding my experimental endeavours, for generously editing my thesis

chapters, and for being a steadfast presence throughout this long journey.

I have many happy memories of working in Lab 6, thanks to the good company of our

postdocs, Matt Lucas and Pasquale Razzino. Thanks also to Herbert Foo for much

helpful advice and assistance during my brief stay in Lab 3. I wish him a happy and

successful career.

Thanks to the staff of the Chemistry Department, particularly Phil Clements for his

expert assistance in obtaining NMR and mass spectra.

Many thanks to John Bowie and Simon Pyke for overseeing the final stages and

making it possible for me to complete this work.

And thanks to Tricia, Hugh, Vanessa, Edward and Graham, and to my mother for

their encouragement and the constant distractions.

vii

ABBREVIATIONS

General Ac acetate

AIBN azobisisobutyronitrile

Bn benzyl, C6H5CH2

Bu3SnH tri-butyltin hydride

CH2Cl2 dichloromethane

CHCl3 chloroform

de diastereomeric excess

DMF dimethyl formamide

DMSO dimethyl sulfoxide

ee enantiomeric excess

Et2O diethyl ether

EtOAc ethyl acetate

EtOH ethanol

HMPA hexamethylphosphoramide

i-PrOH isopropanol

KOH potassium hydroxide

LDA lithium diisopropylamide

m-CPBA meta-chloroperbenzoic acid

Me methyl, CH3

MeOH methanol

MgSO4 magnesium sulfate

N2 nitrogen

NaBH4 sodium borohydride

NaCl sodium chloride

viii

NaH sodium hydride

NaHCO3 sodium hydrogen carbonate

Nu nucleophile

OTf trifluoromethanesulfonate, triflate

Ph phenyl, C6H5

Pr propyl, C3H7

r.t. room temperature

t-BuOK potassium tertiary-butoxide

TfOH trifluoromethanesulfonic acid, triflic acid

THF tetrahydrofuran

TLC thin layer chromatography

NMR d doublet

Hz hertz

m multiplet

MHz megahertz

ppm parts per million

q quartet

qn quintet

s singlet

sept septet

t triplet

chemical shift

ix

IR br broad

cm-1 wavenumbers (reciprocal centimeters)

KBr potassium bromide pressed disc

s strong

w weak

MS EI electron impact

ESI electrospray

FAB fast atom bombardment

HRMS high resolution mass spectrum

M molecular ion

m/z mass per unit charge

Chapter 1

1

1 INTRODUCTION

1.1 SELENIUM

Selenium was discovered in 1818 by Jöns Jakob Berzelius who observed a powdery

red deposit which precipitated from the burning of sulfur at his sulfuric acid plant in

the Swedish mining town of Fahlun.[1] Upon heating the red powder Berzelius noted

that it gave off a strong odour of decayed radishes.[1] The German chemist Martin

Heinrich Klaproth had observed a similar odour upon heating a sample of tellurium.

Subsequently, Berzelius showed that the tellurium sample must have been

contaminated with a new substance which he named ‘selenium’ after the moon to

recall its association with tellurium which Klaproth had named after the earth.[1]

The sixty-sixth most abundant crustal element, selenium is found principally in

association with the sulfides of chalcophyllic metals, clausthalite (PbSe) being the

most abundant selenium mineral.[2] Elemental selenium has three crystalline

allotropes: two red allotropes of puckered Se8 rings which are transformed with

heating to the more thermodynamically stable grey or black trigonal selenium, which

is made up of helical Sen chains.[3] Industrial uses of selenium include the

vulcanisation of rubber, the decolourisation of glass and, as cadmium selenide, in the

manufacture of ruby-coloured glass.[2] The photoconductive properties of trigonal

selenium formed the basis for its use in the first photocells[2] while the

photoconductive properties of amorphous selenium found application in the

development of xerography.[4-5]

Chapter 1

2

Plants take up inorganic selenium from the soil as selenite or selenate and

incorporate it into organic compounds such as amino acids - particularly

selenomethionine (1.1), selenocysteine (1.2), Se-methylselenocysteine (1.3), -

glutamyl-Se-methylselenocysteine (1.4) - and isoselenocyanates such as (1.5).[6]

Selenium–accumulating plants can take up selenium in higher proportion to the

selenium concentration in the soil. In the selenium-accumulators wheat,[7] brazil

nuts,[8] yeast[9] and mushrooms[6] the major proportion of the absorbed selenium is

incorporated as selenomethionine (1.1). Recognised as an essential amino acid in

1983 and regarded as the ‘nutritional form’ of selenium,[10] selenomethionine (1.1) is

incorporated non-specifically into proteins by the body in place of methionine.

Selenomethionine (1.1) is also converted to selenocysteine (1.2) which has its own

triplet code and is incorporated non-randomly into selenoproteins, and is therefore

considered to be the twenty-first genetically coded amino acid.[11] In garlic, onions,

broccoli and wild leeks, selenium is mainly incorporated into the amino acid Se-

methylselenocysteine[12] (1.3), or its -glutamyl- derivative (1.4), both of which are

metabolised to methylselenol.[8-9, 13]

Chapter 1

3

Selenium was recognised as an essential element in 1957.[14] In areas where the

soil is low in selenium, deficiency of the element manifests as a cardiomyopathic

condition known as ‘Keshan disease’ in humans and nutritional muscular dystrophy

or ‘white muscle disease’ in calves and lambs.[15] Twenty-five mammalian

selenoproteins have been identified.[16] Three whose activity has been elucidated

are glutathione peroxidase, thioredoxin reductase and iodothyronine deiodinase.

Glutathione peroxidase is important for oxidative defense, having a selenium atom at

its active site and acting as a scavenger of hydroperoxides.[17] Thioredoxin

reductase reduces disulfide bonds and the oxidised state of vitamin C and catalyses

the reduction of thioredoxin while iodothyronine deiodinase regulates thyroid

hormone metabolism by converting thyroxine to triiodothyronine.[18]

The anticarcinogenic potential of selenium was first noted almost 100 years ago.[19]

However, research was inhibited by a limited understanding of the safe dosage and

the nature of the most appropriate form to administer. Recent epidemiological

studies indicate an inverse relationship between selenium status and the risk of a

range of cancer types[18] while human and animal trials using selenium

supplementation provide strong indications that selenium plays an important role in

protecting against and reversing the early stages of cancer.[17-19] There is evidence

that it is small selenium-containing metabolites such as methylselenol, rather than

selenium-containing enzymes, which are active in cancer prevention.[12-13, 20-21]

Chapter 1

4

The propensity of selenium (II) organic compounds to undergo oxidation to selenium

(IV) by a variety of oxidants and their subsequent ease of reduction back to the

divalent state affords organoselenium compounds potential as modulators of the

redox environment of cells. Thus, a number of selenium-containing compounds

have been developed and explored for their antioxidant, antitumour and antiinfective

properties and other types of biological activity.[22-23] Selenium-containing

compounds which show high antioxidant activity include the clinically useful

Chapter 1

5

glutathione peroxidase mimetic ebselen (1.6),[24] the related cationic compound

(1.7),[25] which exhibits glutathione peroxidase-like activity in vitro, and the selenium

analogue (1.8) of the body’s most important cell membrane antioxidant, -

tocopherol.[26] The high activity of compound (1.11) as an intracellular redox cycler

was attributed to having more than two redox centres in the molecule and

particularly, the quinone-selenide moiety.[27] This compound (1.11) exhibits

considerable cytotoxicity against tumor lines in cell culture.[27] Activity in cell culture

indicates potential for selenosartans (1.9) as anti-hypertensive agents[28] while

compound (1.10) demonstrates high superoxide anion and hydrogen peroxide

scavenging ability in vitro as well as bactericidal properties and wound healing in

vivo.[29]

1.2 ORGANOSELENIUM CHEMISTRY

Organoselenium chemistry has many parallels with organosulfur chemistry.

However, because of the greater polarisability of its electrons, weaker C-Se bonds

and the greater capacity of selenium for hypervalency, transformations of selenium

compounds and reagents often occur with greater ease and under milder conditions

than those of its chalcogen relative.

1.2.1 SELENIUM DIOXIDE The unique qualities of organoselenium reagents and compounds were poorly

appreciated until the 1970s, prior to which the main selenium reagent with wide

application in organic chemistry was selenium dioxide, utilised for the oxidation of

methyl or methylene groups - to a double bond or aromatic ring.[30-31]

Chapter 1

6

The application of selenium dioxide for the oxidation of aldehydes and ketones to

glyoxals and diketones,[32] and for the transformation of alkenes to allylic alcohols,[33]

was first reported in the 1930s. However, the reaction mechanisms were not

elucidated until forty years later when Sharpless et al. determined that both

oxidations involved a seleninic acid intermediate, (1.12) and (1.13), the first reaction

proceeding via a Pummerer rearrangement[34] and the second by an ene reaction

followed by a [2,3] sigmatropic shift (Scheme 1.1).[35]

Subsequent to these mechanistic studies was the recognition by Sharpless et al. of

the potential of the selenoxide syn-elimination (vide infra) as a powerful method for

the introduction of a double bond.[36] This facile elimination reaction was first noted

in 1970 by Jones, Mundy and Whitehouse.[37] Sharpless et al.[38] proved the syn-

nature of the reaction and showed it to be effective for the conversion of epoxides to

allylic alcohols.[36] The generality of this method for introducing a double bond

combined with the mild conditions under which it proceeds inspired a surge of

interest in organoselenium reagents

Chapter 1

7

1.2.2 ELECTROPHILIC SELENIUM REAGENTS The addition of an electrophilic selenium reagent to an alkene is one of a wide range

of methods for the introduction of a selenium moiety into a molecule. The facile

addition of such reagents to alkenes, first reported in 1958,[39] did not receive much

attention until the 1970s renaissance of organoselenium chemistry. Over the

following two decades, methods were developed for the preparation of -hydroxy,[40-

41] -azido,[40, 42] -alkoxy[42] and -acetoxy selenides[43] from alkenes via addition of

phenylselenenyl halide.

The addition of the pseudohalides phenylselenenyl chloride or bromide to an alkene

gives a -halo selenide in equilibrium with a seleniranium ion. The reaction of the

seleniranium ion with an external nucleophile affords a -substituted selenide. In the

presence of a suitably positioned internal nucleophile, a cyclic product is formed

(Scheme 1.2).

Chapter 1

8

For terminal alkenes, the addition of phenylselenenyl halide at low temperature

generally gives the anti-Markovnikov product which isomerises to the Markovnikov

product, via the seleniranium ion, upon warming.[44-45] Electronic factors

predominate in the reactions of tri- and tetra-substituted alkenes,[45-46] and styrene

and its derivatives,[45, 47-48] from which the Markovnikov adduct is the favoured

product, even at low temperature.

The preference for Markovnikov addition can be overridden where there is an oxygen

atom that can coordinate to the selenium atom of the seleniranium ion

intermediate.[43, 49-52] In the addition of phenylselenenyl chloride to an allylic alcohol

or allylic acetate in aqueous acetonitrile, ‘PhSeOH’ can add with anti-Markovnikov

orientation.[51-52] It has been proposed that coordination of the seleniranium ion to

the hydroxyl or carbonyl oxygen weakens the C-Se bond, promoting nucleophilic

attack at the -carbon.[51-53] In the addition of phenylselenenyl chloride to ,-

unsaturated carbonyl compounds, interaction between the carbonyl oxygen and the

selenium of the seleniranium ion leads to the predominance of the -phenylseleno

regioisomer[54] (Scheme 1.3).

Chapter 1

9

Replacement of the halide with a non-nucleophilic counterion such as

trifluoroacetate,[55] hexafluorophosphate,[56] hexafluoroantimonate[56] or

tetrafluoroborate[57] generates a more electrophilic selenium reagent. These

reagents can be prepared in situ from the phenylselenenyl halide and a silver salt or

by addition of the silver salt to the -halo selenide adduct. The diminished

nucleophilicity of these counterions allows the reaction of the seleniranium ion with

less reactive nucleophiles such as carbamates and cyanamide.[57]

Toshimitsu et al.[58] found that the amidoselenenylation of electron-rich alkenes such

as tri- and tetra-substituted alkenes with phenylselenenyl halide and a nitrile was low-

yielding and attributed this to the stabilisation of the intermediate seleniranium ion by

the electron-donating substituents, reducing its reactivity toward nucleophilic attack.

Amidoselenation of electron-rich alkenes using the 2-pyridylseleno group gave the

desired products in high yield as a result of an increase in the reactivity of the

seleniranium ion.[58] The binary reagent PhSeCl-ZnCl2 facilitates the

chloroselenenylation of electrophilic olefins such as the fumarate diester (1.14),

giving the adduct (1.15) in excellent yield[59] (Scheme 1.4).

Chapter 1

10

Although the seleniranium ion intermediates are not usually observed in addition

reactions of electrophilic selenium, Schmid and Garratt[56] showed that stable

seleniranium salts (1.16) could be generated by the addition of silver

hexafluorophosphate or hexafluoroantimonate to the 4-tolylselenenyl chloride

adducts of ethylene and 2-butene, or by the addition of tolylselenenyl

hexafluorophosphate or hexafluoroantimonate to the alkene. The seleniranium ions

(1.16) were found to be stable at low temperature. Treatment of the seleniranium

ions (1.16) with chloride ion generated the -chloro selenide adducts (1.17) (Scheme

1.5).

Denmark and Edwards[48] observed by NMR the formation of the seleniranium ion

formed from the addition of the methyl ester (1.18) to a solution of phenylselenenyl

hexafluoroantimonate at -70°C.[48] Treatment of the seleniranium ion (1.19) with

tetra-n-butyl ammonium chloride generated the -chloro selenide adduct (1.20) along

with starting material (Scheme 1.6).

Chapter 1

11

Cross-over experiments[48, 60] have shown that the formation of the seleniranium ion

is reversible. Addition of 4-(2-methylphenyl)-3-butenoic acid to a solution of the

phenylselenenyl chloride adduct (1.21) of 4-phenyl-3-butenoic acid led to a mixture of

the addition products (1.21) and (1.22).[48] Reversing the order of addition of the

acids gave the same mixture of products[48] (Scheme 1.7).

NMR analysis[48] of the addition of phenylselenenyl bromide to 4-phenyl-3-butenoic

acid showed that the equilibrium between the adduct and the alkene was affected by

Chapter 1

12

temperature, with the equilibrium shifting toward starting material as the temperature

was increased.[48]

The evolution of chiral electrophilic selenium reagents began with the binaphthyl

diselenide (1.23) described by Tomoda and Iwaoka in 1988.[61]

Methoxyselenenylation of alkenes with this reagent resulted in diastereomeric

excesses of up to 49%.[61] Following this were the reports of C2-symmetric reagents

such as (1.24) developed by Deziel,[62] the diferrocenyl reagent (1.25) prepared by

Uemura et al.,[63] the D-mannose-derived reagent (1.26) designed by Tomoda et al.[64]

and a range of diselenides of type (1.27) synthesised by Wirth et al.[23, 65] Reagents

(1.24), (1.26) and (1.27) share the common feature of a heteroatom that is able to

coordinate to the selenium atom, inducing a conformational rigidity in the molecule.

Chapter 1

13

The stereoselective step in the addition of electrophilic selenium reagents to

unsymmetrical alkenes and trans-alkenes is the formation of a diastereomeric

seleniranium cation.[64, 66] A more electrophilic selenium reagent, achieved by using

a less nucleophilic counterion, is more reactive toward the alkene and allows the

addition to occur at a lower temperature, which contributes to a higher

stereoselectivity as equilibration between the two seleniranium ion diastereomers is

inhibited.[64] Strong interaction between the heteroatom and the selenium atom of

reagents (1.24), (1.26) and (1.27) enhances asymmetric induction by bringing the

chiral source close to the reaction centre[64] and by stabilising the seleniranium ion,

inhibiting equilibration of the two diastereomers.[67] Greater bulkiness and rigidity of

the selenium reagent also contribute to a higher facial selectivity.[64, 67] The nature

of the counterion has also been found to affect yield as well as stereoselectivity.[67]

The electrophilic selenium reagent (1.28) was effective in inducing chirality in the

carboselenenylation of a range of styrene derivatives with heterocyclic aromatic

compounds and electron-rich benzene derivatives (Scheme 1.8).[68]

Chapter 1

14

The carbocycle (1.29) and related structures were prepared in up to 98% ee through

the reaction of the corresponding alkene (e.g. 1.30) with the selenenyl triflate (1.31).

In some cases cyclisation was facilitated by a Lewis acid to shift the equilibrium from

the methoxy selenide toward the reactive seleniranium intermediate (Scheme 1.9).[62]

Chapter 1

15

Stereoselective addition of the electrophilic selenium compound (1.33) was utilised

by Wirth et al.[69] in a synthesis of the lignan (+)-samin (1.32). The reaction of

selenenyl triflate (1.33) with the alkene (1.34) followed by addition of 2,3-butadien-1-

ol gave the lignan (1.32) in 85% ee after radical cyclisation and cleavage of the

TBDMS-group (Scheme 1.10).

Using a chiral electrophilic selenium reagent (1.35) with enhanced rigidity, the

isoquinoline alkaloid (-)-(S)-salsolidine (1.36) was synthesised in 90% ee via

selenocyclisation of carbamate (1.37) followed by removal of the protecting group[67]

(Scheme 1.11).

1.2.3 NUCLEOPHILIC SELENIUM REAGENTS A selenium moiety can be introduced into an organic molecule via nucleophilic attack

by a selenolate anion. Reduction of diselenides or elemental selenium produces

Chapter 1

16

selenolate anions, excellent nucleophiles whose reactivity depends on the conditions

under which they are generated.

The reduction of diphenyl diselenide with sodium borohydride in ethanol gives the

complexed selenolate anion, Na+[PhSeB(OEt)3]-,[70] which will readily displace a

halide or sulfonate[71] or open an epoxide.[36] Its nucleophilicity is improved in a less

protic environment such as when it is generated in dimethyl formamide.[72]

The uncomplexed selenolate anion, RSe-Na+ or RSe-K+ can be generated from

diaryl and dialkyl diselenides by reduction with sodium in THF/HMPA,[73] or with

sodium hydride or potassium hydride respectively in THF or DMF.[74-75] This anion is

a more potent nucleophile than the borane complex Na+[PhSeB(OEt)3]-,[73] and will

cleave an ester or lactone at the carbinol carbon in high yield under mild

conditions.[73, 75-76]

The reduction of diphenyl diselenide with lithium aluminium hydride generates a

selenolate ion having Lewis acid character due to the oxygenophilic nature of the

aluminium.[77] The anion is effective in the ring-opening of oxetanes and oxolanes,

providing access to - and -phenylselenenyl alcohols.[77] Diisobutylaluminium

phenylselenolate (i-Bu2AlSePh) reacts regioselectively with ,-unsaturated acetals,

giving exclusively 1-alkoxy-3-phenylseleno-1-alkenes, and 3-phenylselenoalkanals

after hydrolysis[78] and also exclusively affords 1,1-disubstituted ethenes upon

reaction with terminal acetylenes[79] (Scheme 1.12).

Chapter 1

17

In a biphasic solution of diethyl ether and 10% hydrochloric acid, diphenyl diselenide

can be reduced by zinc dust.[80-81] In the acidic aqueous phase, aziridines can be

activated and undergo ring opening by the selenolate anion. A range of chiral -

seleno amines were obtained from unprotected chiral aziridines in this way[81]

(Scheme 1.13).

A mixture of diorganyl diselenide, tertiary alkyl halide and zinc in dichloromethane

gives the tertiary-substituted organyl selenides in good to excellent yield. This

reaction is selective for tertiary halides; the phenylseleno- group substitutes for the

tertiary bromide of (1.38), leaving the primary bromide intact[82] (Scheme 1.14).

Chapter 1

18

Asymmmetric ring-opening of meso-epoxides with arylselenols to give -

arylselenoalcohols in high ee was achieved with a catalytic amount of the chiral Ti-

Ga-Salen heterometallic system (1.39)[83] (Scheme 1.15). The Lewis acids Ti and Ga

are believed to work synergistically by activating the epoxide through coordination of

the oxygen to the hard Lewis acid titanium while the soft arylselenol is directed to

attack of the epoxide through coordination of selenium to gallium.[83]

-Seleno carbanions, accessed via the characteristic selenium-lithium exchange of

selenoacetals by alkyllithiums, are excellent selenium-containing nucleophiles which

owe their stability to the polarisability of the selenium atom.[84-85] A wide range of -

seleno alkyllithiums is possible by choice of alkyllithium, solvent and reaction

temperature.[86] -Seleno carbanions react with carbonyl compounds to give allylic

alcohols via -hydroxyselenides,[87] and with epoxides to give homoallylic alcohols via

Chapter 1

19

-hydroxy selenides,[88] and provide a path to homologation of oxetanes to

tetrahydrofurans.[89] The unusual nucleophilicity of 2-lithio-2-selenopropanes toward

hindered carbonyl compounds enables the preparation of hydroxy selenides from

hindered ketones such as 2,2,6,6,-tetramethylcyclohexanone and their subsequent

transformation to hindered epoxides and olefins (Scheme 1.16).[90]

-Seleno carbanions are also derived from selenides possessing an -hydrogen via

deprotonation with non-nucleophilic bases, although potential substrates are limited

to those substituted with an anion-stabilising group and the reactions can be slow

and low-yielding.[91] However, deprotonation of polystyrene-supported selenides has

been successfully carried out with LDA or butyllithium.[92-93] After reaction of the

carbanion with an electrophile and transformation of the substrate via the

Chapter 1

20

stereospecific selenoxide syn-elimination the polymer-supported selenide is easily

regenerated for reuse[92-93] (Scheme 1.17).

Complexation of an -seleno alkyllithium with a chiral ligand and trapping of the

diastereomeric complex with an electrophile can lead to enantiomeric enrichment in

the product.[94-96] Thus, in the presence of a bisoxazoline, axially chiral

benzylidenecyclohexanes are produced in good yield and high ee via the

enantioselective reaction of an -seleno carbanion and a cyclohexanone followed by

stereospecific syn-elimination[97] (Scheme 1.18).

Chapter 1

21

1.2.4 RADICAL CHEMISTRY OF ORGANOSELENIUM COMPOUNDS

An organoselenium compound containing divalent selenium is stable to many

conditions and can withstand further manipulation until the selenium moiety is

removed reductively or oxidatively. Reductive cleavage of the selenium moiety can

be achieved with Raney nickel[98] or, more generally, with tributyltin or triphenyltin

hydride, by homolytic substitution at selenium with tributyltin or triphenyltin radical

and abstraction of hydrogen from the tin hydride by the carbon-centred radical

intermediate.[99-100] In the presence of a double or triple bond, a new carbon-carbon

bond can form faster than abstraction of hydrogen from the tin hydride, either inter- or

intramolecularly (Scheme 1.19).

Selenides as radical precursors offer the advantage over the alternative bromides in

being able to withstand attack by a nucleophile to which a bromide would be

vulnerable. For example, selenoesters as precursors of acyl radicals are less

electrophilic, and therefore more stable, than acyl bromides. The acyl radicals

Chapter 1

22

generated from tri-n-butyltin hydride treatment of phenyl selenoesters (1.39) undergo

free radical polycyclisations faster than both hydrogen atom abstraction from the tin

hydride and decarbonylation.[101] Under high dilution conditions, the acyl radicals

generated from selenoesters (1.40) and (1.42) undergo intramolecular addition to the

activated alkenyl group providing the macrocycles (1.41) and (1.43)[102] (Scheme

1.20).

Homolytic substitution at selenium with tributyltin radical is approximately three

orders of magnitude faster than the reaction with a sulfur analogue.[103-104] Thus,

N,Se- and O,Se-acetals are deselenated much more rapidly than desulfurisation of

the corresponding N,S- and O,S-acetals and are effective precursors to -N, and -O

Chapter 1

23

radicals. N,Se- and O,Se-acetals are also preferable to the corresponding -bromo

amides and ethers due to their greater stability.[105-106] Alkoxymethyl radicals such

as (1.44), generated via tributyltin hydride treatment of O,Se-acetals, cyclise to

tetrahydrofurans and tetrahydropyrans in good to excellent yield.[106] The N,Se-

acetal (1.45) is efficiently reduced with Bu3SnH/AIBN or allylated with methyl 2-

[(tributylstannyl)methyl]prop-2-enoate, whereas attempted allylation of the analogous

N,S-acetal gave no reaction[105, 107] (Scheme 1.21).

Photolysis of alkyl phenyl selenides generally favours cleavage of the alkyl C-Se

bond due to its lower bond dissociation energy. The efficiency of this reaction can

be improved through optimisation of the reaction conditions.[108] Photolysis of 1-

naphthyl alkyl selenides in an oxygen atmosphere under conditions optimised with

respect to irradiation wavelength, temperature, substrate concentration and solvent

Chapter 1

24

gives the corresponding carbonyl compounds in excellent yield[109] (Scheme 1.22).

Cleavage of the alkyl C-Se bond is further favoured if the alkyl radical fragment is

stabilised, such as with an active methylene moiety. Thus, photolysis of

phenylselenomalonates in the presence of alkenes or alkynes provides the radical

addition products in high yield[110-111] (Scheme 1.22).

Ogawa et al. have exploited the carbon-radical-capturing ability of diphenyl diselenide

in the four-component coupling of unsaturated compounds leading to

cyclopentanes.[112] In the reaction of diphenyl diselenide with ethyl propiolate, tert-

butyl acrylate and 2-methoxypropene (Scheme 1.23), the phenylseleno radical

produced by irradiation of diphenyl diselenide adds preferentially to the alkyne, giving

a vinyl radical which adds preferentially to the electron-rich alkene, the resulting

intermediate adding to the electron-poor alkene, followed by cyclisation. Reaction of

the carbon radical (1.46) with diphenyl diselenide is faster than polymerisation and

allows formation of cyclopentanes in up to 76% yield. With the use of diphenyl

disulfide, the radical (1.46) is not trapped as readily and polymerised products

predominate.[112]

Chapter 1

25

Homolytic substitution at selenium is an established path to selenium-containing

heterocycles.[113-114] The anti-inflammatory compound ebselen and its analogues[115]

(1.47) were prepared by the reaction of the diselenides (1.49) with t-butyl peroxide or

by irradiation of the PTOC imidate esters (1.48). The selenacycles of the selenium

analogues, (1.50) and (1.51), of the -lactamase inhibitor, sulbactam[116] and

tocopherol[26, 117] were also constructed via homolytic substitution (Scheme 1.24).

Chapter 1

26

1.2.5 THE SELENOXIDE syn-ELIMINATION The selenoxide syn-elimination has the advantage over the analogous sulfoxide

elimination in that it proceeds approximately 1000 times as fast.[118] Divalent

selenium can be oxidised to Se(IV) more readily than the analogous transformation of

a sulfide, and a range of oxidants can be used, e.g. hydrogen peroxide, peracids,

ozone or periodate, as overoxidation to Se(VI) is easily avoided. The selenoxide

syn-elimination provides a mild procedure to prepare enones from ketones,[119]

Chapter 1

27

acetylenes from vinyl selenoxides,[120] and allylic alcohols from epoxides after ring-

opening with a selenolate anion.[36] Protic solvents retard the elimination reaction by

hydrogen-bonding to the selenoxide oxygen, while an electron withdrawing

substituent on selenium will increase the reaction rate[121] and the use of a non-

nucleophilic base inhibits the re-addition of ‘RSeOH’ to the double bond.[121] If there

is a -hydroxyl substituent, the syn-elimination generally occurs regioselectively away

from the oxygen, giving the allylic rather than the vinylic product.[36, 122] If the

selenoxide is allylic, a [2,3]-sigmatropic rearrangement can occur faster than the syn-

elimination to give an allylic selenenate which hydrolyses to an allylic alcohol[36, 123]

(Scheme 1.25).

Unlike optically active sulfoxides, which are stable and separable, optically active

selenoxides are configurationally labile and racemise easily via the hydrate, a

process facilitated by acid catalysis.[124-125] Optically active selenoxides have been

prepared by enantioselective oxidation[126-128] by kinetic resolution,[125, 129] by

deracemisation[130] or by preparing diastereomeric selenoxides by oxidation of a

selenide possessing a chiral substituent,[37, 63, 131] and by resolution of stabilised

selenoxides with an optically active column.[132-134]

Chapter 1

28

Selenoxides (1.52) were kinetically resolved with camphor sulfonamide under

anhydrous conditions.[125] The formation of a dihydrate was sterically inhibited by the

bulky 2,4,6-triisopropylphenyl group, rendering the selenoxides stable with a half-life

of 30 hours in the presence of water (Scheme

1.26).[125] The 2,4,6-triisopropylphenyl group

also contributed kinetic stability to selenoxide

(1.53) which was further stabilized to

racemisation via intramolecular coordination to

the amino group of the 8-dimethylamino-1-

naphthyl substituent.[132]

Stabilisation of the selenoxides (1.54) and (1.55) was attributed to steric and/or

electronic effects[63] but not coordination of Se to N of the chiral ferrocenyl substituent

as x-ray analysis showed no evidence of such an interaction.[131] Syn-elimination

and 2,3-sigmatropic rearrangement occurred with almost no loss of optical purity

furnishing chiral allenecarboxylic esters (1.56) in up to 89% ee[63, 131] and the allylic

alcohol (1.57) in up to 89% ee,[131] respectively (Scheme 1.27).

Chapter 1

29

1.2.5 BIOTRANSFORMATION OF ORGANOSELENIUM COMPOUNDS Concomitant with the development of chiral organoselenium reagents over the past

two decades has been research into the biotransformation of organoselenium

compounds.[135] Excellent yields and stereoselectivity have been reported in the

enzymatic resolution of a range of hydroxy selenides,[135-138] the selenium moiety

being well-tolerated by various lipases.

Incubation of the hydroxy selenides (R,S)-(1.58) with the fungus Aspergillus terreus

led to enantioselective oxidation and biomethylation of one isomer, giving the alcohol

(S)-(1.58) in 50% yield and high ee.[139] Deracemisation of hydroxy selenide (R,S)-

Chapter 1

30

(1.59), also catalysed by A. terreus, afforded the (R)-isomer in 98% yield and 99%

ee[140] (Scheme 1.28).

Selenium-containing chiral amines such as (1.60) were resolved by dynamic kinetic

resolution, giving the amides (1.61) in 74% yield and 99% ee.[141-142] Racemisation

of the amines was catalysed using Pd-BaSO4 with the acylation step catalysed by

Candida antarctica lipase B (CAL-B)[141] (Scheme 1.29).

Chapter 1

31

meta- or para-Organoselenoacetophenones, (1.62) for example, can be reduced to

chiral alcohols (1.63) in high yield and ee after incubation with whole fungal cells[143]

or fresh carrot[144] (Scheme 1.30).

Through the many contributions to the development of organoselenium chemistry

over the last four decades, selenium-mediated transformations now occupy an

established and significant place in organic synthesis.

Chapter 2

32

2 THE AMIDOSELENATION OF ALKENES

2.1 INTRODUCTION

The amidoselenation of alkenes was first described by Toshimitsu et al.[145] in 1981.

In the literature procedure, [145] an alkene is treated with phenylselenenyl halide, a

nitrile and aqueous triflic acid to give a -amidoalkyl phenyl selenide. The

mechanism of this reaction was proposed[145] to be a variation of that of the Ritter

reaction[146] in which amides are formed from a nitrile and a carbonium ion under

strongly acidic conditions.[147] The seleniranium ion (2.1) which is initially formed is

in equilibrium with the haloselenide adduct[145] (2.2). Attack by nitrogen on the

seleniranium ion (2.1) gives an imidoyl halide (2.3) which is then hydrolysed to yield

the amide (2.4) (Scheme 2.1).

In previous work of our research group,[148] the amidoselenation of cyclohexene and

cyclopentene was investigated using two equivalents of phenylselenenyl bromide in

Chapter 2

33

benzonitrile. Under these conditions, the corresponding oxazolines were obtained.

However, assignment of the stereochemistry of the oxazolines was inconclusive.[148]

The cis-fused oxazoline (2.7) could form via oxidation of the initially-formed -

(phenylselanyl)cyclohexyl benzamide (2.5) with the second phenylselenenyl bromide

to give the selenonium ion (2.6) followed by displacement of diphenyl diselenide by

the amide oxygen (Scheme 2.2, Path A). An alternative proposition[148] was that a

trans-fused oxazoline (2.9) could be produced via displacement of diphenyl

diselenide from the selenonium ion (2.6) by bromide, followed by displacement of

bromide from the cis-bromide (2.8) by the amide oxygen (Scheme 2.2, Path B).

Chapter 2

34

Both the cis- and the trans-oxazolines, (2.7) and (2.9), are known compounds.[149-150]

The initial aim of the present work was to investigate whether a trans-oxazoline (2.9)

could be formed in the manner described above.

2.2 INVESTIGATION OF THE FORMATION OF THE trans-OXAZOLINE (2.9)

When cyclohexene was heated with two equivalents of phenylselenenyl bromide and

aqueous triflic acid in benzonitrile at a range of temperatures from 100 to 160°C, only

the cis-oxazoline[149] (2.7) was obtained, in yields of 5-30%. At the higher reaction

temperatures of 140-160°C which, it was proposed,[148] might allow for strain in the

transition state to the trans-oxazoline to be overcome, the yield of the cis-oxazoline

(2.7) was lowest.

The reaction could be investigated by treatment of the ‘intermediate’ amido selenide

with one equivalent of phenylselenenyl bromide. For this it was necessary to

prepare 2-(phenylselanyl)cyclohexyl benzamide (2.5).

The amido selenide[145] (2.5) was obtained in 66% yield from cyclohexene in

benzonitrile heated to 90°C, according to a variation[148] of the literature

amidoselenation procedure.[145] Treatment of 2-(phenylselanyl)cyclohexyl

benzamide (2.5) with phenylselenenyl bromide in benzonitrile at 115°C afforded the

cis-oxazoline (2.7) as a minor product (3%) along with trans-2-

Chapter 2

35

bromocyclohexylbenzamide (2.10, 31%) and cis-2-bromocyclohexylbenzamide (2.8,

10%) (Scheme 2.4). Stereochemistry of the bromide isomers was assigned based

on the ring methine proton coupling constants: a trans-diaxial coupling constant of

10.5 Hz for the trans-bromide (2.10) and a coupling constant of 3.0 Hz for the cis-

isomer (2.8). While the two ring methine protons of the trans-bromide (2.10) occur at

similar frequencies, 4.14 and 4.02, the analogous signals of the cis-bromide (2.8)

are more differentiated. The CHBr proton of (2.8) resonates at 4.49, 0.69 ppm

downfield from the CHN proton signal, a multiplet centred at 4.1, so-assigned to

account for coupling to the NH proton. In a model of the cis-bromide (2.8) in which

steric interactions are minimised, the molecule adopts a conformation with the bulky

amide group equatorial and the bromine axial. Deshielding of the equatorial CHBr

proton can therefore be attributed to the deshielding cone of the cyclohexane ring

carbons as well as the aromatic amide group. Mass spectra of both bromides

provided evidence of the bromine substituent with two weak molecular ions of similar

intensity occurring at m/z 281 and 283. In both spectra, fragmentation led to the

expected peaks at m/z 202, 122 and 105 due to loss of bromine from the molecular

ion, the protonated benzamide ion and the benzoyl cation, C6H5C=O+, respectively.

Spectral data for the cis-bromide (2.8) compared well with that of cis-2-

bromocyclohexylacetamide.[151]

Treatment of 2-(phenylselanyl)cyclohexyl benzamide (2.5) with phenylselenenyl

bromide in dichloromethane at room temperature gave a 3:1 mixture of the cis-

oxazoline (2.7) and the cis-bromide (2.8). When the reaction was conducted in

refluxing acetonitrile the cis-oxazoline (2.7) was again the main product along with

the trans-bromide (2.10) and the cis-bromide (2.8).

Chapter 2

36

With addition of tetraethylammonium bromide to the reaction mixture, the cis-bromide

(2.8) could be made to predominate. At room temperature in dichloromethane an

approximately 60% yield of (2.8) was thus obtained as 75% of the product along with

the cis-oxazoline (2.7) and unreacted amido selenide (2.5) in minor amounts. In

refluxing acetonitrile with addition of tetraethylammonium bromide the cis-bromide

(2.8) also made up over 50% of the product which also included the cis-oxazoline

(2.7) and trans-bromide (2.10). These observations are consistent with reported

results[152] from a procedure in which the selenide is oxidised with molecular chlorine

rather than phenylselenenyl bromide and from a previous study[151] in which

molecular bromine was used as the oxidant. At room temperature and in refluxing

acetonitrile it appears that displacement of diphenyl diselenide by bromide ion to give

the cis-bromide (2.8) competes with displacement by the amide oxygen to give the

cis-oxazoline (2.7). Conducting the reaction in benzonitrile at 115°C may have

provided sufficient energy for the ring-opening of the oxazoline (2.7) by bromide ion

to give the trans-bromide (2.10).

Chapter 2

37

For the purpose of verifying the stereochemistry of the oxazoline products of these

reactions, it was decided to prepare the cis-oxazolines via the established procedure

of Toshimitsu et al.[153] in which excess m-CPBA (2.5-5 equivalents) followed by

potassium hydroxide (7.5-11 equivalents) are added to a solution of the selenide at

room temperature in an alcohol solvent. These conditions were employed by

Toshimitsu et al.[153] in the cyclisation of the 2-pyridylselenoamide (2.11) to the 2-

methyloxazoline (2.12) (Scheme 2.5) and in the generation of three- to six-membered

N-tosyl nitrogen-containing heterocycles (2.13) from N-{(phenylseleno)alkyl}-p-

toluenesulfonamides (2.14) and the pyrrolidine (2.15) from the amidoselenide (2.16)

(Scheme 2.5).

Chapter 2

38

Following the procedure developed by Toshimitsu et al.,[153] the oxidation of 2-

(phenylselanyl)cyclohexyl benzamide (2.5) with 4 equivalents of m-CPBA in

isopropanol followed by addition of 7.5 equivalents of potassium hydroxide, gave only

a 12% yield of the expected cis-oxazoline (2.7) and, unexpectedly, the N-

benzoylaziridine[154] (2.17) which was isolated in a yield of 85% (Scheme 2.6). The

symmetry of this aziridine[154] (2.17) was reflected in the 13C NMR spectrum in which

there appeared only three alkyl signals, at 37.02, 23.87 and 19.93, and in the 1H

NMR spectrum in which the ring methine protons appeared as a narrow multiplet at

2.75. The mass spectrum of (2.17) showed a strong peak at m/z 202 due to M+H

and fragments at m/z 105 and m/z 96 due to the benzoyl cation and loss of the

benzoyl group from the molecular ion respectively. From these investigations it was

concluded from that the trans-oxazoline (2.9) could not be prepared from the reaction

of cyclohexene with two equivalents of phenylselenenyl halide.

Conditions effecting the cyclisation of amides to oxazolines are various and well-

established.[150, 155-162] However, N-acylaziridines are only obtained from amides

Chapter 2

39

under specific conditions. Boschelli[163] obtained the N-acylaziridine (2.18) from

cyclisation of the threo-hydroxybenzamides (2.19) under Mitsunobu conditions while

Wipf and Miller[155, 164] obtained the aziridine (2.20) exclusively via the Mitsunobu-type

treatment of threonine-containing peptide (2.21). The ring-opening of N-acryloyl-2,3-

dimethylaziridine (2.22) with phenylselenolate was carried out by Toshimitsu et al.[165]

for the purpose of obtaining the -(acrylamido)selenide (2.23) (Scheme 2.7).

However, the converse reaction, cyclisation of a -amidoselenide to an N-

acylaziridine, was novel, and an investigation into the scope of this reaction was

embarked upon.

Chapter 2

40

2.3 ONE-POT PREPARATION OF -AMIDO SELENIDES

Investigation of this aziridine-forming reaction necessitated the preparation of a range

of -amido selenide substrates. Following the straightforward preparation of 2-

(phenylselanyl)cyclohexyl benzamide (2.5), using a variation of the literature

procedure[145] developed by Cooper,[148] benzamidoselenation was attempted with the

alkenes cyclopentene, cycloheptene, 1-octene and trans-2-hexene using the same

procedure.

Unlike the reaction with cyclohexene, yields of the -amido selenides (2.24) and

(2.27) derived from cyclopentene and cycloheptene were poor (16% and 2%

respectively), although comparable with the yields of the same compounds obtained

Chapter 2

41

by Cooper.[148] Both the cyclopentyl and cycloheptyl derivatives were characterised

by 1H NMR data showing the three diagnostic signals of the methine ring and NH

protons in the regions expected.[145] Mass spectra in both cases showed a strong

molecular ion and a selenium-containing fragment due to loss of benzamide as well

as a fragment at m/z 188 (2.24) and m/z 216 (2.27) due to loss of C6H5Se from the

parent molecule. Concomitant with amidoselenation of the 5-, 6- and 7-membered

cycloalkenes was the formation of the corresponding cis-oxazolines (2.25, 32%),

(2.7, 6%) and (2.28, 24%). The Ritter products, N-cyclopentylbenzamide[154] (2.26,

4%) and N-cycloheptylbenzamide[166-167] (2.29, 20%) were also produced from the

reactions with cyclopentene and cycloheptene respectively (Scheme 2.8). An

additional by-product from the reaction with cycloheptene was the syn-elimination

product, N-(cyclohept-2-en-1-yl)benzamide (2.30, 2%). N-(cyclohept-2-en-1-

yl)benzamide (2.30) was characterised in the 1H NMR spectrum by the appearance

of two alkene proton peaks at 5.88 and 5.64, an NH proton signal at 6.23 and a

fourth downfield signal at 4.82 due to the allylic CHN proton. The alkene protons

had a coupling constant of 12.3 Hz, within the range expected for alkene protons of a

cycloheptene ring.[168] In the 13C NMR spectrum the alkene carbons appeared at

128.81 and 127.11 while the mass spectrum showed a strong molecular ion at m/z

215.

Following the literature amidoselenation procedure,[145] acetamidoselenation of

cyclohexene afforded an 88% yield of -(phenylselanyl)cyclohexyl acetamide[145]

(2.31) (Scheme 2.9).

Chapter 2

42

Amidoselenation of 1-octene in benzonitrile gave a mixture of the Markovnikov and

anti-Markovnikov products in 59% yield from which the Markovnikov product (2.32)

was isolated by crystallisation. The Markovnikov compound (2.32) was

distinguishable from its regioisomer (2.33) in the 1H NMR spectrum by two doublets

of doublets at 3.29 and 3.22 attributed to the diastereotopic CH2Se protons

coupled to the neighbouring CHN proton (4.8 and 5.4 Hz) and with a geminal

coupling constant of 12.8 Hz. The 1H NMR signals of the diastereotopic CH2N

protons of the regioisomer (2.33) were well differentiated at 3.80 and 3.51 and

appeared as two doublets of doublets of doublets, coupled to the NH proton as well

as the CHSe proton and with a geminal coupling constant of 13.5 Hz. These signals

were downfield from the CHSe multiplet which appeared at 3.41.

Benzamidoselenation of trans-2-hexene gave a poor yield (12%) of the -amido

selenides as a mixture of the Markovnikov and anti-Markovnikov products (2.34) and

(2.35) in a ratio of 47:53 along with the oxazolines (2.36) and (2.37) in a ratio of 52:48

(Scheme 2.10). The slight predominance of the anti-Markovnikov amido selenide

(2.34) over its regioisomer (2.35) could be due to the more facile transformation of

the adduct (2.34) into the oxazoline (2.36) by displacement of PhSeSePh from the

less-hindered carbon.

Chapter 2

43

The two amido selenide isomers (2.34) and (2.35) were distinguishable

spectroscopically by the pattern of their methine signals in the 1H NMR spectrum.

The CHSe signal of the Markovnikov isomer (2.34), appeared as a clearly defined

doublet of quartets at 3.65 while a more complex signal approximating a doublet of

doublets of triplets at 4.33 was attributable to the CHN proton. The CHN signal of

the anti-Markovnikov isomer (2.35) appeared as a twelve-line signal at 4.47,

interpreted as a doublet of doublets of quartets, coupled to the CHSe, NH and methyl

protons, with the CHSe protons resonating as a less complex doublet of doublets of

Chapter 2

44

doublets at 3.56. In the 13C NMR spectra of the Markovnikov isomer (2.34), the

CHN signal resonated at 53.88, downfield from the CHSe signal at 47.51 due to

its more electronegative amide substituent. In contrast, in the 13C spectrum of

(2.35), the signal for the C3 CHSe carbon appeared at 54.97, identifiable by its

distinct CSe satellites, while the signal of the C2 CHN carbon appeared upfield at

48.66, the effect of the position at C3 in the carbon chain overriding the effect of the

more electronegative substituent at C2.

The two oxazoline regioisomers (2.36) and (2.37) were distinguishable in the 1H NMR

spectrum by the doublet of quartets at carbon 2 which occurred at 4.39 due to the

CHO proton in isomer (2.36) and at 3.91 due to the CHN proton in isomer (2.37).

The mass spectra of the two oxazolines also reflected the differences in their

structures: the mass spectrum of isomer (2.36) showed a base peak at m/z 44 which

was attributed to the acetaldehyde fragment, and a prominent peak at m/z 160 due to

loss of C3H7, whereas isomer (2.37) fragmented to give a base peak at m/z 131 due

to loss of C3H7CHO.

The Ritter products (2.26) and (2.29), which had not been reported previously from

the amidoselenation reaction,[145, 148] may have arisen from the addition of H+ and

benzonitrile to the double bond. The ability for (2.26) to be formed in this manner

was confirmed by reacting cyclopentene with aqueous trifluoromethanesulfonic acid

Chapter 2

45

in benzonitrile, giving N-cyclopentylbenzamide[154] (2.26) in 25% yield. Similarly,

cyclohexene gave N-cyclohexylbenzamide[154] (2.38), in 55% yield (Scheme 2.11).

Chapter 2

46

It has been shown that in the addition of a selenenyl halide to an alkene, the alkene

and the haloselenide adduct (2.2) are in equilibrium and can interconvert via the

seleniranium ion (2.1, Scheme 2.1).[48, 60] The direction of the equilibrium is

influenced by the nature of the alkene, the counterion, and the reaction

temperature.[48] It is therefore reasonable to propose that in the amidoselenation

reaction with cyclopentene and cycloheptene, the equilibrium between the alkene

and the seleniranium ion may lie more toward the alkene, than in the reaction with

cyclohexene. The unconsumed cyclopentene (or cycloheptene) is then free to

undergo the Ritter reaction to give the N-cycloalkyl amide (2.26) (or (2.29)) (Scheme

2.12). The unconsumed selenium reagent is available to react with the amido

selenide (2.24) (or (2.27)) to give a phenylselenonium intermediate (2.39) (or (2.40))

which then cyclises to the cis-oxazoline (2.7) (or (2.28)) with loss of diphenyl

diselenide. The syn-elimination product (2.30) from the reaction with cycloheptene

may have been generated by elimination of H+ and diphenyl diselenide from the

selenonium intermediate (2.40).

2.4 ALTERNATIVE SOLVENTS FOR THE AMIDOSELENATION REACTION

In order to verify the stereochemistry of the oxazolines and amidoselenides by X-ray

crystal determination, the preparation of a p-bromobenzamido selenide derived from

p-bromobenzonitrile was undertaken. The amidoselenation reaction could not be

conducted with the nitrile as solvent using the solid p-bromobenzonitrile, and

therefore, a non-nitrile solvent was required. Since previous reactions had been

carried out in refluxing acetonitrile, initial consideration was given to solvents with a

boiling point of at least 82°C, namely dimethylacetamide and toluene. Trial reactions

were conducted using either cyclohexene or cyclopentene and four to five

equivalents of benzonitrile (Table 2.1).

Chapter 2

47

TABLE 2.1

BENZAMIDOSELENATION IN NON-NITRILE SOLVENTSa

alkene solvent

reaction temp (°C)

% isolated yield

amido selenide

hydroxy selenide

N-cycloalkyl benzamide

cis-oxazoline

cyclohexene

dimethyl acetamide 90-95 - 41 - -

toluene 96-115 7 - 17 15

dichloromethane 39.5 67 1 - -

dichloromethane r.t. 90b - - -

chloroform 62 10 20 - -

cyclopentene benzonitrile r.t.-55c 55 - - -

dichloromethane 39.5 10 - 37 - a 5 eq.benzonitrile in solvent specified, 1 eq. TfOH, 5 eq. H2O b Product not isolated c r.t. for 6 days then 55°C for 12 h with additional TfOH

Attempted amidoselenation of cyclohexene in dimethylacetamide at 90–95°C gave

only 2-(phenylseleno)cyclohexanol[169] (2.41) (Scheme 2.13). Transformation

beyond the hydroxy selenide stage requires protonation of the hydroxyl group which

is lost on formation of the seleniranium ion. The dimethylacetamide may have

‘sequestered’ the acid, preventing protonation of the hydroxyl group.

From amidoselenation of cyclohexene in toluene at 96-115°C, N-

cyclohexylbenzamide (2.38, 17%), the cis-oxazoline (2.7, 15%) and the -amido

selenide (2.5, 7%) were obtained.

Chapter 2

48

In refluxing chloroform, a mixture of the hydroxy selenide (2.41) and the -amido

selenide (2.5) was produced, in low yield in a ratio of 2:1. Unsuitability of these non-

polar solvents could be attributed to poor solvation of the charged seleniranium

intermediate and, particularly with toluene, low availability of water to react with the

seleniranium ion as a result of an inhomogeneous reaction mixture.

The reaction with cyclohexene in refluxing dichloromethane was reasonably

successful, giving the -amido selenide (2.5) in 67% yield. However, this success

could not be replicated with cyclopentene, from which a mixture of the -amido

selenide (2.24) and the Ritter product (2.26) were produced, demonstrating

competition between the Ritter reaction with cyclopentene, H+, and benzonitrile and

formation of the seleniranium ion/haloselenide adduct.

At room temperature, the reaction of cyclohexene in dichloromethane gave a 90%

yield of the -amido selenide (2.5) before purification, which indicated that a higher

reaction temperature was not necessary for, and might hinder, the amidoselenation

reaction.

The reaction with cyclopentene in benzonitrile at room temperature gave a 55% yield

of the -amido selenide (2.24). This reaction was monitored by TLC over three

Chapter 2

49

days, after which, TLC analysis showed there to be a mixture of the -amido selenide

(2.24) and the hydroxy selenide[169] (2.42). Further trifluoromethanesulfonic acid was

added and the mixture reacted for a further 3 days and finally heated to 55°C for 12

hours. The subsequent conversion of the hydroxy selenide (2.42) to amido selenide

(2.24) suggested that isolation of the alcohol before treating it with

trifluoromethanesulfonic acid and the nitrile might be a cleaner route to -amido

selenides (Scheme 2.14).

2.5 TWO-STEP PREPARATION OF -AMIDO SELENIDES

Amidoselenation via hydroxyselenation using chloroacetonitrile or bromoproprionitrile

in reagent quantity in dichloromethane at room temperature has been reported by

Toshimitsu et al.[41, 165] Hydroxyselenation[169] of cyclohexene with phenylselenenyl

chloride in an acetonitrile-water mixture gave 2-(phenylseleno)cyclohexanol (2.41) in

high yield. The reaction of the alcohol (2.41) with benzonitrile and

trifluoromethanesulfonic acid in dichloromethane at room temperature for 48 hours

gave the -amido selenide (2.5) in excellent yield with the overall yield higher than for

the one-step amidoselenation of cyclohexene.

Chapter 2

50

This two-step procedure (Scheme 2.15) gave good overall yields of the -benzamido

selenides (2.24) and (2.27) derived from cyclopentene and cycloheptene via the

hydroxy selenides (2.42) and (2.43) and avoided the complication of the oxazoline,

Ritter and syn-elimination by-products. Also using this procedure, a good yield

(77%) of -acetamidocycloheptyl phenyl selenide (2.44) was afforded compared with

the literature yield of 55% for the one-step procedure.[145]

The two-step process was successful in the reaction of 2-(phenylseleno)cyclohexanol

(2.41) using the solid nitrile, p-bromobenzonitrile, with the preparation of 2-

(phenylselanyl)cyclohexyl p-bromobenzamide (2.45) proceeding in 87% yield

(Scheme 2.16). Table 2.2 summarises the results of the one- and two-step

procedures.

Chapter 2

51

TABLE 2.2

PERCENTAGE YIELDS FOR 1-STEP AND 2-STEP AMIDO SELENIDE PREPARATION

alkene nitrile

1-step amido selen- ation

2-step amidoselenation

hydroxy selenide

amido selenide

Yield over two steps

cyclopentene benzonitrile 16 77 76 59

cyclohexene

acetonitrile 88 - - -

benzonitrile 66 89 93 83

p-bromo-benzonitrile - 89 87 77

cycloheptene acetonitrile - 91 85 77

benzonitrile 2 91 57 52

cyclooctene benzonitrile - 69 45 31

trans-2-hexene benzonitrile 12 85 97 82

1-octene benzonitrile 59 71 82 58

p-bromo- benzonitrile - 71 43 31

One-step amidoselenation of cyclooctene was not attempted after the success of the

two-step procedure. Hydroxyselenation to give 2-(phenylseleno)cyclooctanol (2.46)

proceeded in 69% yield; however, only a 45% yield of 2-(phenylselanyl)cyclooctyl

benzamide (2.47) was obtained in the amidoselenation step. Low yields were also

reported by Toshimitsu et al.[169] for the reaction of 2-phenylselenocyclooctanol with

acrylonitrile (39%) and chloroacetonitrile (24%).

Hydroxyselenation of 1-octene gave a mixture of the Markovnikov and anti-

Markovnikov products (2.48) and (2.49) in 71% yield in a ratio of 85:15. The two

Chapter 2

52

hydroxy selenides were isolated by chromatography. Under electrospray conditions,

the high resolution mass spectrum of each isomer showed the expected mass for an

M-OH fragment. In the 1H NMR spectrum of the Markovnikov isomer (2.48), the

methine CHO proton resonated as a multiplet centered at 3.65, with two doublets of

doublets, at 3.15 and 2.89, due to the diastereotopic methylene protons under

selenium. In the 1H NMR spectrum of the anti-Markovnikov compound (2.49), the

signals of the diastereotopic protons under oxygen appeared as two doublets of

doublets, at 3.56 and 3.45, downfield, as expected, from the multiplet at 3.16

due to the proton under selenium.

Chapter 2

53

The amidoselenation step was carried out on the mixture of the hydroxy selenide

regioisomers, (2.48) and (2.49), as the reaction proceeds via a selenonium ion

intermediate, eliminating any advantage conferred by starting with a single

regioisomer. The reaction of the mixture of hydroxy selenides with benzonitrile gave

a mixture of the benzamido selenides (2.32) and (2.33) in a ratio of 95:5. The

Markovnikov adduct (2.32) was isolated from the mixture in 82% yield by

recrystallisation (Scheme 2.17).

Amidoselenation of a mixture of the hydroxy selenides (2.48) and (2.49) derived from

1-octene with three equivalents of p-bromobenzonitrile in dichloromethane gave a

51% yield of a mixture of the Markovnikov and anti-Markovnikov p-bromobenzamido

selenides (2.50) and (2.51), with the Markovnikov isomer predominating (Scheme

2.18) along with a small amount of the oxazoline (2.52) derived from amido selenide

(2.50). 80% of the nitrile was recovered, giving a theoretical yield of 60%, indicating

that the reaction was not very efficient. The 1H NMR spectrum of the Markovnikov

amido selenide (2.50) closely resembled that of the bromine-free compound (2.32) in

showing a three-proton system, with the signals due to the diastereotopic protons

under selenium appearing as two clean strongly-coupled doublets of doublets at

3.30 and 3.20 with vicinal coupling to the multiplet at 4.39 due to the CHN proton.

The anti-Markovnikov isomer (2.51) was not obtained pure but was assigned from its

three-proton system of two distinct signals, at 3.83 and 3.44 due to the CH2N

protons and its CHSe multiplet at 3.38.

Chapter 2

54

Hydroxyselenation of trans-2-hexene gave an 85% yield of the Markovnikov and anti-

Markovnikov products (2.53) and (2.54) in a ratio of 55:45 (Scheme 2.19).

Chromatography partially separated the two alcohols, making it possible to

distinguish the NMR signals of the individual isomers. The doublet of quartets at C2

was diagnostic, and appeared at 3.44 for the CHSe signal of the Markovnikov

isomer (2.53), and at 3.85 for the CHO signal of the anti-Markovnikov isomer (2.54).

The C3 proton signals appeared as doublets of doublets of doublets at 3.62 for the

CHO proton of isomer (2.53) and at 3.37 for the CHSe proton of isomer (2.54). In

the 13C NMR spectrum, carbon-selenium coupling was evident in the CSe signal of

the Markovnikov isomer, at 47.40, and of the anti-Markovnikov isomer, at 57.27.

Further reaction of the mixture of (2.53) and (2.54) gave the amido selenides as a

Chapter 2

55

mixture of the Markovnikov and anti-Markovnikov products (2.34) and (2.35) in a ratio

of 53:47 in 97% yield.

For characterisation purposes, a mixture of the two regioisomers (2.34) and (2.35)

was subjected to chromatography in order to purify them but also in an attempt at

their separation. Although full separation was not achieved, fractions were obtained

that were enriched in one or other regioisomer. From the first-eluted enriched

fraction were obtained large transparent crystals. A crystal structure

determination[170] showed that this material, the anti-Markovnikov isomer (2.35), was

chiral with absolute configuration (2S,3R)-2-(benzamido)-3-(phenylseleno)hexane.

Only two stereoisomers of each regioisomer would be expected as the selenonium

ion intermediate would constrain the stereochemistry of C2 relative to C3. The

racemate appears to have crystallised as a conglomerate,[171] resolving

spontaneously into enantiomorphous crystals. This is a phenomenon which has only

Chapter 2

56

been observed in 5 to 10% of organic racemates[171] and potentially allows for the

mechanical separation of enantiomers.

These explorations of the amidoselenation reaction led to the conclusion that the two-

step procedure with isolation of the hydroxy selenide intermediate was superior to the

one-step procedure, giving higher yields in most cases and simpler product mixtures.

2.6 PREPARATION OF THE trans-OXAZOLINE (2.9)

In 1950 Johnson and Schubert[150] reported the preparation of the trans-oxazoline

(2.9) by the treatment of trans-2-aminocyclohexanol hydrochloride with ethyl

iminobenzoate (2.55) (Scheme 2.20). The identity of the trans-fused product was

verified from the melting point of the known product of its hydrolysis, trans-2-

benzoyloxycyclohexylamine hydrochloride (2.56).

In order to obtain spectral data for the trans-oxazoline (2.9) to distinguish it from the

cis-oxazoline (2.7) and to verify that it had not been produced in the amidoselenation

Chapter 2

57

reaction, the trans-oxazoline (2.9) was prepared, following the literature

procedure,[150] from ethyl iminobenzoate (2.55) and commercially available trans-2-

aminocyclohexanol hydrochloride.

Ethyl iminobenzoate hydrochloride (2.57) was prepared according to the procedure of

MacKenzie et al.[172] in 89% yield from benzonitrile, ethanol and hydrogen chloride.

Deprotonation[173] gave ethyl iminobenzoate (2.55) in 87% yield after Kugelrohr

distillation (Scheme 2.21). From the reaction of ethyl iminobenzoate (2.55) with

trans-2-aminocyclohexanol hydrochloride[150] the trans-oxazoline (2.9) was obtained

(35%). Recrystallisation gave colourless crystals which melted at 78-79.5°C,

comparing well with the literature[150] melting point of 73-77°C for the trans-oxazoline,

and differentiating it from compound (2.7), with its melting point of 42-45°C, in accord

with the literature[150] value of 46-48°C for the cis-oxazoline.

Comparison of the 1H and 13C NMR spectra of the trans- and cis-oxazolines, (2.9)

and (2.7), shows distinct differences. The 1H NMR signals of the CHN and CHO

protons of the trans-oxazoline (2.9) are approximately 0.9 ppm upfield from the

analogous cis-oxazoline signals. In order for the fused ring system to accommodate

the trans-geometry, the trans-oxazoline CHN and CHO protons would occur in the

axial position and would not be affected by the C-C deshielding cone of the

cyclohexyl ring, whereas the cis-oxazoline CHN and CHO protons are more likely to

Chapter 2

58

found within the deshielding cones of the cyclohexyl C-C bonds. The 1H NMR

signals of the trans-oxazoline CHN and CHO protons appear as doublets of doublets

of doublets with coupling constants of 13.8, 11.7 and 3.6 Hz and 13.8, 11.7 and 3.3

Hz respectively. The two sets of trans-diaxial coupling constants is in contrast with

the typical cis coupling constant of 8.1 Hz exhibited by the CHN and CHO protons of

the cis-oxazoline (2.7).

In the 13C NMR spectrum, the CHN and CHO and other alkyl signals of the trans-

oxazoline (2.9) are downfield in comparison with the cis-oxazoline signals.

The assignment of cis-stereochemistry to the product obtained from the reaction of

two equivalents of phenylselenenyl bromide, nitrile and cyclohexene is therefore

strongly supported by these results and spectral data.

Chapter 3

59

3 CYCLISATION OF -AMIDOALKYL PHENYL SELENIDES

3.1 INITIAL ATTEMPTS TO OPTIMISE THE FORMATION OF N-ACYLAZIRIDINES

The conditions used in the oxidation of 2-(phenylselanyl)cyclohexyl benzamide (2.5),

which unexpectedly generated the N-acylaziridine (2.17), provided the starting point

for the investigation of our new method for the generation of

N-acylaziridines. The -(phenylselanyl)alkyl amides, (2.24),

(2.5), (2.27), (2.31), (2.45) and (2.32) were used as the

substrates for the initial investigation. According to the

literature procedure,[153] the -amido selenide was dissolved in isopropanol and

treated with at least three equivalents of m-CPBA, The use of an excess of m-CPBA

as oxidant[174-176] and an alcohol as solvent[174-176] have been shown to be effective

conditions for the oxidation of a selenide to a selenone. An excess of oxidant has

also been shown to facilitate the oxidation of a selenoxide to a selenone, so as to

avoid the selenoxide syn-elimination as a side-reaction.[175]

Chapter 3

60

Using these general conditions,[153] and with variation of some parameters, a clean

reaction giving the aziridine exclusively was not achieved from any of the starting -

amido selenides. Using 10.8 equivalents of hydroxide and 4 equivalents of peracid,

a 95:5 ratio of aziridine (2.17) to oxazoline (2.7) was obtained from 2-

Chapter 3

61

(phenylselanyl)cyclohexyl benzamide (2.5). Increasing the amount of base to 13.5

equivalents did not increase the proportion of aziridine (2.17) in the product.

The reaction of 2-(phenylselanyl)cyclopentyl benzamide (2.24) using 10.5 equivalents

of hydroxide and 3.9 equivalents of peracid gave a 60:40 ratio of aziridine (3.1) to

oxazoline (2.25). With 13.4 equivalents of base the product ratio decreased to 45:55

(Scheme 3.1). Using ethanol in place of isopropanol as solvent also favoured the

oxazoline (2.25), giving a 30:70 ratio of aziridine (3.1) to oxazoline (2.25). The

bridgehead CHN protons of known[154] aziridine (3.1) appeared as a singlet-like peak

at 3.19. Unlike the bridgehead proton signals for the other fused aziridines

prepared (vide infra), the complete coalescence of this signal suggests more rapid

pyramidal inversion at nitrogen (Scheme 3.1).

Increasing the quantity of base from 8 to 10 equivalents in the reaction of 2-

(phenylselanyl)cycloheptyl benzamide (2.27) led to a small increase from 15:85 to

25:75 in the ratio of aziridine (3.2) to oxazoline (2.28) produced (Scheme 3.1).

Lowering the reaction temperature to 0°C decreased the ratio of aziridine (3.2) to

oxazoline (2.28) to 15:85. Carrying out the reaction at 37°C also appeared to favour

the oxazoline, giving a 10:80:10 mixture of aziridine (3.2), oxazoline (2.28) and the

syn-elimination product, N-(cyclohept-2-en-1-yl)benzamide (2.30). In the 1H NMR

spectrum of the aziridine (3.2) the signals of the bridgehead CHN protons appeared

as a narrow multiplet centred at 2.72. The symmetry of the molecule was again

apparent in the 13C spectrum which showed only four alkyl and four aromatic signals

and the carbonyl carbon at 180.0. The oxazoline (2.28) was characterised in the

1H NMR spectrum by a doublet of doublets of doublets at 4.86 and a doublet of

Chapter 3

62

triplets at 4.42, assigned to the CHO and CHN protons. An M+H peak was

apparent in an electrospray high resolution mass spectrum, while in the 13C NMR

spectrum there appeared seven alkyl signals, one at 83.21 and another at 69.83

due to the CHO and CHN carbons respectively.

The bromine substituent of 2-(phenylselanyl)cyclohexyl p-bromobenzamide (2.45)

might be expected to facilitate aziridine-formation by rendering the amide proton

more acidic and thus more easy to deprotonate. However, cyclisation of (2.45) with

4.1 equivalents of peracid and 8.5 equivalents of hydroxide resulted in a mixture of

the aziridine (3.3) and oxazoline (3.4) in a ratio of 60:40 (Scheme 3.1). The NMR

spectra of the bromine-substituted aziridine (3.3) and oxazoline (3.4) differed from the

spectra of the bromine-free analogues (2.17) and (2.7) only in displaying pairs of

aromatic proton signals integrating to two hydrogens and in the aromatic 13C peaks in

which deshielding of the two substituted carbons was evident. In the mass spectrum

of the aziridine (3.3) the bromine substituent was indicated by a molecular ion at m/z

281 and a peak of almost equal intensity at m/z 279. Loss of bromine gave a small

peak at m/z 200. Peaks due to the p-bromobenzoyl cation appeared at m/z 185 and

183 with loss of C=O from this cation giving peaks at m/z 157 and 155. The IR

spectrum showed a C-Br stretch at 1304 cm-1 and an absorption of medium intensity

at 849 cm-1 attributable to the C-H bend of a disubstituted benzene ring.

Chapter 3

63

In previous work of our research group[148] the oxidation of 2-

(phenylselanyl)cyclohexyl acetamide (2.31) under acidic conditions, in which the

number of equivalents of peracid exceeded that of hydroxide, had given the ring-

contracted amide (3.6) and the lactone (3.5). The current study also obtained a

mixture of (3.5), (3.6) and starting material from the reaction of the acetamide (2.31)

with 3.2 equivalents of m-CPBA and 2 equivalents of hydroxide (Scheme 3.2).

1,2-alkyl shifts similar to the contraction to give (3.6) have been reported[176] following

oxidation of cyclic methoxyselenides (3.8) and (3.10) to give the ring-contracted

acetals (3.9) and (3.11) (Scheme 3.3).

Cyclisation of the acyclic amido selenide (2.32) produced no aziridine; from the

reactions both with zero and with 7.8 equivalents of potassium hydroxide, the

oxazoline (3.12) was the sole product (Scheme 3.4). The mass spectrum of (3.12)

showed an M+H peak at m/z 232, fragmentation of the alkyl chain and a peak due to

the benzoyl cation at m/z 105. Six alkyl signals appeared in the 13C NMR spectrum,

with two signals at 72.52 and 66.80 due to the carbons under oxygen and

nitrogen respectively and a signal at 163.29 of the O-C=N carbon. In the 1H NMR

Chapter 3

64

spectrum two distinct signals due to the diastereotopic methylene protons appeared

at 4.48 and 4.03 and flanked a multiplet centred at 4.27 due to the proton under

nitrogen.

Results of these reactions using potassium hydroxide as base could not be replicated

consistently, possibly due to the difficulty in obtaining dry carbonate-free powdered

hydroxide. Precedents for the N-alkylation of amides indicate that N-alkylation will

only occur reliably in preference to O-alkylation if the amide is first deprotonated

using a strong base in an inert solvent.[177] Sodium hydride was therefore

substituted for potassium hydroxide; addition of sodium hydride to isopropanol would

generate the stronger base, isopropoxide ion.

Use of sodium hydride as base gave more consistent results, however, the conditions

which would generate aziridines as the sole products remained elusive except for the

cyclohexene derivatives, 2-(phenylselanyl)cyclohexyl benzamide (2.5) and 2-

(phenylselanyl)cyclohexyl p-bromobenzamide (2.45) from which the aziridines (2.17)

and (3.3) were cleanly produced in the reactions using 3-4.5 equivalents of peracid

and ten and eight equivalents of sodium hydride respectively.

Chapter 3

65

FIGURE 3.1

OXIDATION OF -AMIDO SELENIDES (2.24), (2.5) AND (2.27):

PROPORTION OF AZIRIDINE IN PRODUCT VERSUS EXCESS OF BASEa (KOH OR NaH) USED

a equivalents base minus equivalents m-CPBA

Binary mixtures of the aziridine (3.1) and oxazoline (2.25) were obtained in the

oxidation of the 2-(phenylselanyl)cyclopentyl benzamide (2.24) using sodium hydride

as base. A reaction profile using 3.9 equivalents of m-CPBA and incrementally

increasing the quantity of sodium hydride from two to ten equivalents, confirmed the

dependence of aziridine-formation on the basicity of the reaction medium (Figure

3.1). An excess of about 2.5 equivalents of NaH was optimal, giving the aziridine

(3.1) as just over 50% of the product; with a greater excess of base, the yield of

aziridine (3.1) declined. For the same reaction but with KOH as the base the NaH

data are translated to the right along the x-axis, the weaker hydroxide base being

required in greater excess for an equivalent result. Figure 3.1 also illustrates the

significant difference in response to the same reaction conditions of three

cycloalkylamidoselenides which differ only in the number of ring carbons.

Chapter 3

66

Using 6 to 10 equivalents of sodium hydride as base and about 4 equivalents of m-

CPBA, a predominance of the aziridine (3.2) was achieved consistently in the

oxidation of 2-(phenylselanyl)cycloheptyl benzamide (2.27). Ratios of aziridine (3.2)

to oxazoline (2.28) in the crude product were of the order of 3-4 to 1. However, loss

of product occurred upon purification by chromatography with concomitant generation

of N-(cyclohept-2-en-1-yl)benzamide (2.30), through -elimination of the aziridine[178]

(3.2) (Scheme 3.5).

The acyclic amido selenide, 1-(phenylselanyl)-2-octyl benzamide (2.32), was reacted

with 8.6 equivalents of sodium hydride and 3.9 equivalents of m-CPBA. Though

creating a more strongly basic medium than previous reactions using potassium

hydroxide or no base at all, these conditions again produced no aziridine, only the

oxazoline (3.12), in 87% isolated yield.

The hindered base potassium tert-butoxide proved to be similar in effect to sodium

hydride in the reaction of 2-(phenylselanyl)cyclohexyl benzamide (2.5) giving the

aziridine (2.17) as the sole product and in the reaction of 2-(phenylselanyl)cyclopentyl

benzamide (2.24), which using this base gave a 51:49 mixture of the aziridine (3.1)

and oxazoline (2.25), essentially identical to the result using sodium hydride.

Chapter 3

67

3.2 CYCLISATION OF -AMIDO SELENIDES AT LOW TEMPERATURE

With the resurgence of interest in organoselenium chemistry in the 1970s came new

approaches to overcoming the well-known[179] difficulties in generating selenones.

Shimizu, Ando and Kuwajima[174] reported that m-CPBA was an effective oxidant for

the conversion of vinyl selenides to selenones and that methanol or t-butanol as

solvent were preferable to dichloromethane in facilitating the oxidation of the

selenoxide. The work of Krief et al.[175] showed that use of a peracid in

dichloromethane at 20°C was effective in the generation of a range of dialkyl and

alkyl phenyl selenones. Krief et al.[175] also noted that potassium permanganate as

the oxidant provided the advantage that the by-products of oxidation were inorganic

and could be removed in the aqueous layer. Uemura et al.[176] found methanol to be

preferable to dichloromethane and other alcohols as with this solvent the rate of

oxidation of the selenoxide to the selenone increased. Toshimitsu et al.[153]

recommended ethanol or 2-propanol rather than methanol to avoid formation of

methyl meta-chlorobenzoate by esterification of m-CBA. Other oxidants such as

peroxides and periodate have been found to be ineffective in the oxidation of

selenium beyond the +IV oxidation state in organic compounds.[175-176]

The conditions developed by Toshimitsu et al.[153] were those followed up to this point

of the present investigation. Variation of these conditions above room temperature

offered no improvement in the yield of aziridine. There appears to be no reference in

the literature to attempts to produce a selenone below 0°C except by Paetzold and

Bochman[180] who reported the preparation of dialkyl selenones by ozonisation of the

corresponding selenoxides at -10°C. However, the indication[180] that generation of a

selenone at temperatures below 0°C may be possible was encouraging, and

Chapter 3

68

therefore an investigation into the possibility of the preparation of aziridines at low

temperature was undertaken.

Thus, 2-(phenylselanyl)cyclopentyl benzamide (2.24) was treated with 3.2

equivalents of m-CPBA and 6 equivalents of potassium tert-butoxide in

tetrahydrofuran at –6°C, giving the surprising result of a 73% yield of the aziridine

(3.1) with minor amounts of the oxazoline (2.25) and syn-elimination product, N-

(cyclopent-2-ene-1-yl)benzamide[154] (3.13) (Scheme 3.6). When the reaction was

carried out at –60°C, cyclisation proceeded cleanly to the aziridine (3.1) which was

isolated in a yield of 75%.

Chapter 3

69

The subsequent oxidations at –60°C in tetrahydrofuran, with potassium tert-butoxide

as base, of 2-(phenylselanyl)cyclohexyl, -cycloheptyl and -cyclooctyl benzamides,

(2.5), (2.27) and (2.47), 2-(phenylselanyl)cyclohexyl and -cycloheptyl acetamides,

(2.31) and (2.44), and 2-(phenylselanyl)cyclohexyl p-bromobenzamide (2.45) also

gave the corresponding bicyclic aziridines (2.17), (3.2), (3.16), (3.14), (3.15), (3.3) as

the sole products in good to excellent yield (Scheme 3.7, Table 3.1).

TABLE 3.1

PRODUCTS FROM THE REACTION OF 2-AMIDOALKYL PHENYL SELENIDES

WITH M-CPBA UNDER BASIC CONDITIONS

selenide producta yielda productb yieldb

(ratio) % (ratio) % 2.32 3.12 87 3.17,3.12 73

(74:26) 2.50 - 3.18,2.52 72

(61:39)

2.34,2.35 - 3.19, 2.36,2.37 83

(90:5:5) 2.24 3.1,2.25 87 3.1 75

(55:45) 2.5 2.17,2.7 97 2.17 83

(88:12) 2.45 3.3 70 3.3 94 2.31 - 3.14 66 2.27 3.2,2.28 76 3.2 81

(74:12)c 2.44 - 3.15 67 2.47 - 3.16 87

a 4 eq. m-CPBA, 6-8 eq. NaH or t-BuOK in i-PrOH, r.t. b 3.3 eq. m-CPBA, 4.5-9 eq. t-BuOK in THF, -60°C

The 1H NMR spectrum of the aziridine[149] (3.14) displayed a narrow multiplet at

2.56 due to the bridgehead CHN protons and an isolated methyl signal at 2.11.

The 13C spectrum showed only four alkyl signals and a carbonyl signal at 183.66.

The bridgehead proton signal of aziridine (3.15) also appeared as a narrow multiplet

Chapter 3

70

centred at 2.61 in the 1H NMR spectrum. The mass spectrum showing a very

weak molecular ion at m/z 153 and the base peak being at m/z 110, due to loss of

the acetyl group.

In the 1H NMR spectrum of the aziridine[154] (3.16), the bridgehead proton signals

occurred as a narrow multiplet at 2.52. This compound (3.16) exhibited a simple

13C spectrum showing four aryl and four alkyl signals and the carbonyl carbon signal

at 179.71. The mass spectrum showed a weak molecular ion at m/z 229, a peak

at m/z 201 due to loss of ethylene with a base peak at m/z 124 corresponding to loss

of the benzoyl group.

In contrast to the results from reactions conducted at room temperature on 1-

(phenylselanyl)-2-octyl benzamide (2.32), in which only the oxazoline (3.12) was

produced, the low temperature cyclisation of this amidoselenide gave a 3:1 mixture of

the aziridine (3.17) and oxazoline (3.12). The reaction of 1-(phenylselanyl)-2-octyl p-

bromobenzamide (2.50) under the low temperature conditions also gave a 3:1

mixture of the aziridine (3.18) to oxazoline (2.52) (Scheme 3.8). The bromine-

substituted aziridine (3.18) and oxazoline (2.52) were again only distinguishable from

the unsubstituted aziridine (3.17) and oxazoline (3.12) in their NMR spectra by the

Chapter 3

71

pattern of aromatic proton and carbon signals.

The 1H NMR spectra of (3.18) and (2.52) showed

two sets of aromatic protons, each integrating to

two hydrogens, while in the 13C spectrum the

substituted aromatic carbon signals were shifted

upfield as expected for a bromine-substituted

benzene ring. The diastereotopic ring protons of

aziridines (3.17) and (3.18), with signals at 2.49 and 2.19 for (3.17) and 2.50

and 2.19 for (3.18), are coupled to the vicinal proton, Hc, with coupling constants of

3.6 Hz and 6 Hz respectively. Given an HaCCHc, dihedral angle approaching 120°

and a small HbCCHc dihedral angle, the 3Jac value would be expected to be smaller

than the 3Jbc value, in accord with the Karplus correlation.[181-182] Therefore, a trans-

and cis-relationship to Hc were assigned to the proton (Ha) with signal at 2.49 (

2.50) and the proton (Hb) with signal at 2.19 respectively.

Chapter 3

72

Cyclisation of an approximately 50:50 mixture of 2-(phenylselanyl)-3-hexyl

benzamide (2.34) and 3-(phenylselanyl)-2-hexyl benzamide (2.35) under the low

temperature oxidation conditions gave a mixture that was 90% aziridine (3.19) and

5% of each of the two oxazolines, (2.36) and (2.37), and an isolated yield of aziridine

(3.19) of 69% (Scheme 3.9).

As a result of the stereoselectivity of the amidoselenation of trans-2-hexene and the

cyclisation reaction, aziridine (3.19) was formed as a pair of enantiomers with

configuration (R,S) and (S,R). This aziridine was isolated as a colourless oil. The

13C NMR spectrum showed six clean alkyl and four aryl signals and the carbonyl

signal at 177.92. In the 1H NMR spectrum the C2 CHN proton appeared as a

doublet of quartets at 2.59 coupled to the methyl group with a coupling constant of

5.7 Hz, the methyl group signal appearing as a doublet at 1.19. The C3 CHN

proton appeared as a doublet of doublets of doublets at 2.44 with a coupling

constant of 3.3 Hz to the C2 CHN proton. The mass spectrum showed a moderately

strong molecular ion at m/z 203 with fragmentation of the alkyl chain giving peaks at

m/z 188, 174 and 160. The familiar peak for the benzoyl cation appeared at m/z 105

and a peak at m/z 98 was attributed to loss of the benzoyl group from the molecular

ion.

While there is evidence that the N-acylaziridine nitrogen in crystalline samples has

considerable pyramidal character,[183] there is nevertheless sufficient sp2 character in

such compounds in solution to render the barrier to inversion of nitrogen very low.[184]

Early NMR studies[185-186] of the barrier to inversion of N-acylaziridines were unable to

observe any decoalescence at low temperature. No decoalescence of the aziridine

Chapter 3

73

ring proton signal of N-acetylaziridine was observed at –160°C on a 60MHz

spectrometer.[186] Boggs and Gerig[185] observed no decoalescence in N-

benzoylaziridine at –155°C and attributed this to the significant contribution of the

structure in which the lone-pair electrons are delocalised, so that the NCO system is

in the same plane as the three-membered ring, thereby lowering the barrier to

inversion.

Of the N-acylaziridines prepared in the present study, only the cyclopentene

derivative (3.1) displayed a singlet for the bridgehead protons. The analogous

protons of the other fused aziridines appeared as narrow multiplets in 1H spectra

recorded at room temperature on a 300MHz spectrometer, suggesting that

thermodynamic data of such compounds may now be obtainable.

In order to determine that the intermediate was the selenone and not the selenoxide,

the low-temperature reaction was carried out with only sufficient m-CPBA to oxidise

the selenide to the selenoxide. Under these conditions, 2-(phenylselanyl)cyclopentyl

Chapter 3

74

benzamide (2.24) and 2-(phenylselanyl)cycloheptyl benzamide (2.27) were expected

to be transformed into N-(cyclopent-2-ene-1-yl)benzamide[154] (3.13) and N-

(cyclohept-2-ene-1-yl)benzamide (2.30), via the syn-elimination of the respective

selenoxides. These starting materials, (2.24) and (2.27), were chosen because the

selenoxide syn-elimination of five- and seven-membered ring selenoxides is known to

be facile;[121, 145] six-membered ring selenoxides are known to be very slow to

undergo the syn-elimination.[121, 145] The products from this treatment of the five-

membered ring amido selenide (2.24) were the expected N-(cyclopent-2-ene-1-

yl)benzamide (3.13) along with the starting amido selenide (2.24) and the aziridine

(3.1) in a ratio of 55:30:15. The slight excess of peracid would account for the

aziridine (3.1) produced, via the selenone. Similar treatment of the seven-

membered ring amido selenide (2.27) with 1.05 equivalents of m-CPBA gave N-

(cyclohept-2-ene-1-yl)benzamide (2.30 ,58%) along with some starting amido

selenide (2.27, 13%) (Scheme 3.10). The starting material in these reactions was

presumably regenerated from the selenoxide under the reductive workup conditions.

To determine that the low temperature, and not the solvent or base, was the main

factor influencing the direction of the reaction, 2-(phenylselanyl)cycloheptyl

benzamide (2.27) was oxidised in tetrahydrofuran with 3.2-3.3 equivalents of m-

CPBA and 6 equivalents of potassium tert-butoxide as base at –15°C and at 0°C.

Chapter 3

75

Mixtures of the aziridine (3.2) and N-(cyclohept-2-ene-1-yl)benzamide (2.30) were

produced, the latter more favoured with the higher temperature (Scheme 3.11). The

syn-elimination product (2.30) was not observed in reactions carried out at –60°C,

suggesting that at higher temperatures the syn-elimination pathway is competitive

with oxidation of the selenoxide. At room temperature and at 0°C in isopropanol, the

syn-elimination product (2.30) only occurred in trace quantities, probably as a result

of the inhibitory effects of (i) strong hydrogen bonds between the solvent and the

selenoxide[121] and (ii) formation of the selenoxide hydrate as a result of water

present in the reaction mixture.[121]

Aziridines are known to undergo isomerization to oxazolines with acid-catalysis[187] or

in the presence of a nucleophile.[178] To determine if the reaction conditions were

affecting the product ratios, the aziridine (2.17) was (i) refluxed with silica in

dichloromethane and (ii) stirred with m-CPBA in ethanol. No change occurred at all

when the aziridine (2.17) was refluxed with silica in dichloromethane. A minor

amount of isomerization to the cis-oxazoline (2.7) was observed after treatment of the

aziridine (2.17) with m-CPBA. However, the amount was not sufficient to account for

the oxazoline formed from oxidation of the amido selenide (2.5).

2-(Phenylselanyl)cyclohexyl benzamide (2.5) was treated with 10 equivalents of

potassium hydroxide in 2-propanol to confirm that base alone could not induce

cyclisation. After stirring for 5 hours, a 1H NMR spectrum showed no new product

and after work up, 80% of the starting material was recovered.

Chapter 3

76

3.3 SUMMARY OF RESULTS FROM THE CYCLISATION OF -AMIDO SELENIDES

The results of this study of the reaction of a range of -amido selenides with an

oxidising agent under basic conditions, showed that three products could arise – the

aziridine, oxazoline and the selenoxide syn-elimination product – in combinations

depending on the reaction conditions.

Conditions favouring the aziridine were a strongly basic medium, a non-polar, aprotic

solvent and low temperature. The requirement for strongly basic conditions is

consistent with the general principle that N-alkylation of amides requires prior

deprotonation of the amide with a strong base[177] while a non-polar, aprotic solvent

would be expected to enhance the nucleophilicity of the amide anion. With

cyclisation to the aziridine occurring at low temperature, the aziridine would appear to

be the kinetic product under strongly basic conditions, deprotonation of the amide

lowering the activation energy of the transition state.

The syn-elimination reaction of susceptible substrates, e.g. 2-benzamidocycloheptyl

and 2-benzamidocyclopentyl phenyl selenides, was inhibited under the conditions

which favoured the aziridine. Under non-polar, aprotic conditions the selenoxide

oxygen would not be solvated, which would facilitate the elimination reaction.

However, the low temperature may not provide sufficient energy to overcome the

syn-elimination activation energy.

Cyclisation to the oxazoline was favoured at a higher temperature, in a protic solvent

and a weakly basic reaction medium. A higher temperature appears to be

necessary to overcome the activation energy of the transition state to the oxazoline.

Chapter 3

77

Although the higher temperature would allow the selenoxide syn-elimination to

compete with cyclisation to the oxazoline, this effect would be countered by a protic

solvent which would inhibit the elimination reaction. In the formation of oxazolines

from N-2-bromoethylbenzamides, Heine[156] found a 2- to 4-fold rate acceleration

where the aromatic ring was para-substituted with electron-withdrawing groups and

concluded that deprotonation occurred either prior to, or concomitantly with,

cyclisation to the oxazoline. Cyclisation of the acyclic amido selenides (2.32) and

(2.50) to the oxazolines with no base and with an excess of base showed that the

oxazolines could form either from the neutral amide or the amide anion, which is

consistent with Heine’s[156] conclusion.

While the cyclic amido selenides cyclised exclusively to aziridines under the low-

temperature conditions, mixtures of aziridine and oxazoline resulted from similar

treatment of the acyclic amido selenides (2.32), (2.50) and (2.34) and (2.35). This

suggests that deprotonation of the amide may be necessary for the internal N-

alkylation of these acyclic amidoselenides, but does not determine the course of the

cyclisation. 1-(Phenylselanyl)-2-octyl benzamide (2.32) and 1-(phenylselanyl)-2-

octyl p-bromobenzamide (2.50) gave the same product ratio of aziridine to oxazoline,

indicating that any stabilisation of the amide anion due to the p-bromo group did not

affect the direction of cyclisation.

3.4 FACTORS DETERMINING THE FORMATION OF 3- VERSUS 5-MEMBERED RINGS

Although there may be no specific data for the ring strain of the aziridines and

oxazolines of the present study, nevertheless it is apparent by comparison of the ring

strain of cyclopropane (27.5 kcal/mol[188]), aziridine (26.7 kcal/mol[189], 27.7

kcal/mol[189]), cyclopentane (6.2 kcal/mol[188]) and cyclopentene (4.1 kcal/mol[188]) that

Chapter 3

78

the aziridines would be considerably more strained than the corresponding

oxazolines. As well as having less bond angle strain than a three-membered

ring,[188] and a double bond, which would reduce torsional strain,[188] the oxazoline

ring has two heteroatoms which would also be expected to reduce the non-bonded

interactions.[190] An acyl substituent on nitrogen would be expected to increase the

angle strain through greater sp2 character of the aziridine nitrogen.

Despite their high ring strain, three-membered rings often display surprisingly high

rates of formation in comparison to larger, less strained rings.[191] One explanation

for this phenomenon is that there is less loss of entropy upon formation of a three-

membered ring compared with that of a larger ring. Illuminati and Mandolini[192]

demonstrated that the loss of entropy upon formation of a three-membered lactone

was low compared with less strained five- or six-membered lactones (although this

interpretation has been disputed[193]). The fast rate of formation of the three-

membered, compared with the five-membered, lactones was therefore attributed to

compensation of the ring strain through reduced loss of entropy upon formation of the

transition state.[192]

Differences in loss of entropy upon cyclisation could explain the differences in the

results for the acyclic amido selenides compared with the relatively rigid

cycloalkylamido selenides of the present study. The acyclic amido selenides

possess a greater number of degrees of freedom than the cycloalkyl substrates.

The difference in the loss of entropy upon cyclisation of the acyclic amido selenides

to the three- versus the five-membered ring would therefore be relatively less than

the same comparison for the cyclic amido selenides.

Chapter 3

79

3.5 OCCURRANCE AND UTILITY OF N-ACYLAZIRIDINES

Aziridines are useful intermediates in organic synthesis and can be regarded as

‘spring-loaded rings’[194] which readily undergo ring-opening reactions with C, O, N, S,

Se and halogen nucleophiles.[195-197] The ring-opening of aziridines generally

proceeds more readily if the ring is activated by incorporation of an electron-

withdrawing group on the ring nitrogen.[195] Activation of an aziridine ring with an N-

acyl group can accelerate the rate of ring-opening by up to 1018, through stabilisation

of the amide anion and increased ring strain due to the sp2 character of the

nitrogen.[198]

Unlike the epoxide ring, the aziridine ring is not particularly common in natural

products. Some notable aziridine-containing natural compounds are the mitomycins

and azinomycins, some of which were discovered and characterised in the late

1950s.[199] These compounds possess antitumor and antibiotic properties, with the

aziridine ring playing a key role in their mode of action through DNA alkylation.[199]

Desymmetrization of meso-aziridines is an effective and reliable way to obtain

enantiomerically pure -substituted amines. In recent years a number of catalysts

have been developed which enable the catalytic desymmetrization of meso-aziridines

in high yield and ee.[200] Some examples of the catalysts which can be used in the

ring opening of N-acylaziridines are the chiral guanidine (3.20), for ring-opening with

thiols,[201] VAPOL-hydrogen phosphate (3.21), for azide[202] and selenium[203]

nucleophiles and the chiral dimeric yttrium complex (3.22), which catalyses ring

opening with azide and cyanide nucleophiles.[204] Ring-opening of meso-N-

acylaziridines with malonates under the catalysis of the heterobimetallic La(O-

Chapter 3

80

iPr)3/Yb(Otf)3/Schiff base (3.23) produces -amino acids in up to 99% yield and

>99.5% ee.[205]

Lewis acid catalysed ring-opening of an N-acylaziridine is the penultimate step in a

number of syntheses[206-209] of the anti-influenza drug Tamiflu (3.24), while catalytic

desymmetrization of a meso-N-acylaziridine under the catalysis of the yttrium

complex with the chiral ligand (3.25) is a key step in the Tamiflu synthesis developed

by Shibasaki and co-workers (Scheme 3.12).[206-207]

Chapter 3

81

N-acylaziridines are usually prepared by acylation of the corresponding N-H

aziridine.[178, 183, 185, 210-211] Methods of preparing N-H aziridines encompass addition

of a nitrene or equivalent to a double bond, addition of a carbene or equivalent to an

imine or cyclisation of an aminoalcohol or equivalent.[212] Methods involving addition

reactions are often low in stereocontrol and require harsh conditions.[212] In contrast,

the formation of -amidoselenides has been shown to be trans-stereospecific,[145]

while cyclisation of tosylamino phenyl selenides to N-tosyl-pyrrolidines[213] and -

alkylamino phenyl selenides to aziridines[214] has been shown to proceed with

inversion. The generation of N-acylaziridines via cyclisation of -amido selenides

therefore provides an alternative approach to the preparation of these useful

synthons.

Chapter 3

82

Recent advances in the development of chiral electrophilic selenium reagents have

led to the preparation of heterocycles in high optical purity.[215] Tiecco et al.[216] have

prepared diastereomeric 2-amidoalkyl camphorselenides which were separated and

cyclised to the enantiopure oxazolines via activation of the seleno-moiety with

phenylselenenyl triflate. These developments suggest that there is potential for the

methodology developed in the present study to be extended to the preparation of

chiral N-acylaziridines.

Chapter 4

83

4 AMIDOSELENATION VIA ADDITION OF ‘PHENYLSELENENYL

PERCHLORATE’

4.1 INTRODUCTION

In the one-pot amidoselenation reaction of alkenes with phenylselenenyl halide and

nitrile,[145] the halide ion remaining after the formation of the seleniranium ion can

lead to undesired side-reactions. For example, Toshimitsu et al.[165] found that the

one-pot preparation of 1-(acrylamido)-2-(phenylseleno)cyclohexane (4.1) from

cyclohexene and phenylselenenyl chloride in acrylonitrile was complicated by the

further reaction of the desired product (4.1) with hydrogen chloride which added to

the carbon-carbon double bond, giving the chloroamide (4.2) (Scheme 4.1).

Conducting the amidoselenation reaction in two steps with isolation of the

hydroxyselenide intermediate avoided this side-reaction and gave the acrylamido

selenide (4.1) in high yield.[165]

In the addition of a selenenyl halide to a double bond, the presence of the halide ion

can drive the equilibrium between the alkene and the seleniranium ion to the left,

resulting in lower yields.[217] The formation of N-cycloalkyl amides in the

amidoselenation reaction (Chapter 2) was attributed to the reversal of the formation

of the seleniranium ion, facilitated by the presence of the chloride ion (Scheme 4.2).

Chapter 4

84

Conducting the reaction in two steps with isolation of the hydroxy selenide avoided

this side-reaction also.

It was of interest to prepare -amido selenides from their essential components -

alkene, nitrile, selenenyl halide and hydroxide ion - without the use of strong acid, via

a path which does not involve the hydroxy selenide intermediate. Sequestration of

the halide ion after addition of a selenenyl halide to a double bond has led to the

formation of stable seleniranium salts, such as the seleniranium

hexafluorophosphates and hexafluoroantimonates (4.3) prepared by Schmid and

Garratt[56] (Scheme 4.3), and can increase the reactivity of the seleniranium ion as

well as increase product yield.[66, 218]

Chapter 4

85

Through addition of silver tetrafluoroborate to a mixture of alkene, phenylselenenyl

chloride and ethyl carbamate, sequestration of the chloride nucleophile allowed the

reaction of the seleniranium ion (4.4) with the weakly nucleophilic carbamate, leading

to the formation of 2-(phenylseleno)alkylcarbamates (4.5, Scheme 4.4).[57]

In a reaction analogous to the amidoselenation of alkenes, Hassner et al.[219]

prepared -bromoalkyl amides (4.6) via attack on a bromonium ion (4.7) by nitrile

followed by hydrolysis (Scheme 4.5). To avoid competition between the bromide ion

(produced in the formation of the bromonium ion (4.7)) and the nitrile in nucleophilic

attack upon (4.7), silver perchlorate was added to sequester the bromide ion.

Introduction of hydroxide to the mixture containing the nitrilium ion (4.8) led to the

successful bromoamidation of a range of alkenes.[219] Addition of azide instead of

hydroxide gave the -bromotetrazoles (4.9) (Scheme 4.5).

Chapter 4

86

4.2 PREPARATION OF -(PHENYLSELANYL)CYCLOHEXYL AMIDES

These precedents[56-57, 219] for the formation and reactions of seleniranium and

nitrilium ions suggested that conducting the amidoselenation reaction with

sequestration of the halide ion might be a way to prepare a -amido selenide and by-

pass the formation of the hydroxy selenide intermediate. Addition of silver

perchlorate to a solution of cyclohexene, phenylselenenyl bromide and nitrile would

remove the bromide ion from solution and expose the seleniranium ion (4.10) to

attack by nitrile (Scheme 4.6). An equilibrium mixture of the seleniranium and

nitrilium ions (4.10) and (4.11) would result; addition of hydroxide to this mixture

would lead to either or both the hydroxy selenide (2.41) by reaction with (4.10) or the

acetamide (2.31) by reaction with (4.11) (Scheme 4.6). The direction of this

Chapter 4

87

equilibrium would depend on the nucleophilicity of the nitrile and relative stabilities of

the nitrilium and seleniranium ions.

In the first attempt at this reaction, silver perchlorate was added to a dry

dichloromethane solution of cyclohexene, acetonitrile and phenylselenenyl chloride,

giving an immediate precipitate of silver chloride. Slow introduction of aqueous

sodium hydroxide to the stirred suspension gave only the hydroxy selenide (2.41), in

56% yield. In the second attempt, using phenylselenenyl bromide instead of the

chloride, 1.5 equivalents of water in acetonitrile was slowly added after precipitation

of the silver salt, affording 2-(phenylselanyl)cyclohexyl acetamide (2.31) in 57%

isolated yield, a result comparable with the 60% yield of -bromocyclohexyl

acetamide (4.9, R=Me) obtained by Hassner et al.[219] The hydroxy selenide (2.41)

was also isolated in 15% yield under the latter conditions (Scheme 4.6). The greater

success with addition of water rather than hydroxide to the mixture of the nitrilium and

seleniranium ions (4.10) and (4.11) could be due to an irreversible reaction of (4.10)

Chapter 4

88

with hydroxide to give the hydroxy selenide (2.41) unlike its

reaction with water which would be reversible.

Using benzonitrile in place of acetonitrile, introduction of a

mixture of water in nitrile to the reaction mixture was not

possible for the reason of immiscibility. Slow addition of

water to the seleniranium ion-nitrilium ion equilibrium generated from cyclohexene,

phenylselenenyl bromide and silver perchlorate gave only a 33% yield of 2-

(phenylselanyl)cyclohexyl benzamide (2.5). The lower yield may be a reflection of

the lower nucleophilicity of benzonitrile compared with acetonitrile.[220-221]

4.3 ALTERNATIVES TO THE -AMIDO SUBSTITUENT

Addition of azide anion to the mixture containing the nitrilium ion could potentially

give the phenylseleno- analogues of the -bromotetrazoles (4.9) prepared by

Hassner et al.[219] With the aim of preparing such a phenylselenotetrazole, sodium

azide was introduced to a mixture of cyclohexene, phenylselenenyl bromide,

acetonitrile and silver perchlorate in dichloromethane, giving a complex mixture from

which 2-(phenylselanyl)cyclohexyl acetamide (2.31) was isolated in 24% yield along

with a product whose spectral data were consistent with the tetrazole (4.12) (Scheme

4.7).

Chapter 4

89

A mass corresponding to the expected MH+ mass for the tetrazole (4.12) was

obtained in a high resolution mass spectrum. A peak at m/z 322, attributable to the

molecular ion of the tetrazole (4.12), was shown in a low resolution

spectrum along with a selenium-containing fragment at m/z 238

consistent with the loss of 1H-5-methyl-tetrazole (4.13) from the

molecular ion.

The cyclohexyl methine peaks in the 1H NMR spectrum of the tetrazole (4.12)

occurred as doublets of doublets of doublets at 4.16 and 3.67 with a trans-diaxial

coupling constant of 11.4 Hz. Compared with the analogous acetamide (2.31), these

peaks were downfield, due to the electron-withdrawing nature of the tetrazole ring.

The methyl singlet appeared at 2.57, deshielded by the tetrazole ring current, while

in the 13C NMR spectrum, a carbon signal corresponding to the amidine carbon, N-

C=N, occurred at 150.99. These 1H and 13C NMR signals were consistent with the

spectra of other 1,5-disubstituted tetrazoles.[222-223]

A second attempt at this reaction

gave a viscous brown oil from

which trituration and

recrystallisation led to the isolation

of a product with spectral

characteristics similar but not

identical to those of the tetrazole (4.12). In the 1H NMR spectrum, the cyclohexyl

methine protons resonated at 4.53 and 3.55 with a trans-diaxial coupling constant

of 11.7 Hz. These protons each integrated to 2 hydrogens compared with the 3

Chapter 4

90

hydrogens of the methyl singlet, suggesting a double addition. X-ray analysis[224] of

the crystals showed the product to be the ‘meso’ tetrazolium perchlorate (4.14). The

downfield shifts, compared with the tetrazole, of both the CHN proton signal and the

methyl singlet at 3.51 could therefore be attributed to further deshielding by the

positively charged tetrazolium ring.

Over weeks in solution, decomposition of an NMR sample of the tetrazolium salt

(4.14) occurred to give the tetrazole (4.12), as indicated by NMR analysis.

The tetrazolium salt (4.14) had resulted from a reaction mixture which was slightly

deficient in azide which suggests stoichiometry as the reason for the double addition.

Yields of both the tetrazole (4.12) and tetrazolium perchlorate (4.14) were poor (14%

and 9% respectively), probably at least partly due to the difficulty in their isolation.

Using a modification of the carbamatoselenation procedure of Francisco et al.,[57]

namely substituting silver perchlorate for the silver tetrafluoroborate specified in the

literature procedure, 2-(phenylselanyl)cyclohexyl carbamate (4.15) was obtained in

82% yield (Scheme 4.7). The ethoxy group was evident in the 1H NMR spectrum,

the quartet appearing at 4.20 and the triplet at 1.25. The peak due to the CHSe

proton occurred at 3.06 as a doublet of doublets of doublets with a trans-diaxial

coupling constant of 10.8 Hz. The signal due to the CHN proton was a less well-

defined multiplet at 3.50. The mass spectrum gave a molecular ion at m/z 327 and

further fragments at m/z 281, 238 and 170 corresponding to loss of CH3CH2O.,

NH2CO2CH2CH3 and C6H5Se. respectively from the molecular ion.

Chapter 4

91

This examination of the amidoselenation reaction of cyclohexene, with sequestration

of the halide ion, showed these conditions to be capable of producing reasonable

yields of -amido selenides. The cost and hygroscopicity of the silver reagent limit

the utility of the method, although it could be useful if the particular target were a -

phenylselenoalkyl tetrazole. Further work on this reaction could involve exploring

the effect of low temperature on the stability of, or equilibrium between, the nitrilium

and seleniranium ions.

Chapter 5

92

5 CLOSER EXAMINATION OF A SELENOXIDE AND A SELENONE

5.1 PREPARATION OF N-[2-(PHENYLSELENINYL)CYCLOHEXYL]BENZAMIDE

AND N-[2-(PHENYLSELENONYL)CYCLOHEXYL]BENZAMIDE

In the cyclisation of -amidoselenides, the intermediate selenoxides and selenones

were not observed among the reaction products. It was expected that isolation of

these oxidised intermediates would be difficult due to the thermal instability of

selenoxides[1] and the vulnerability of the selenonyl group to

nucleophiles.[175]

However, it was possible that the selenoxide (5.1) might be

relatively stable for two reasons. Firstly, cyclohexyl

selenoxides are more reluctant than other cycloalkyl

selenoxides to undergo the syn-elimination reaction. For example, the half-life of

phenylseleninyl cyclohexane (5.2) is 364 times that of phenylseleninyl cyclopentane

(5.3) (Scheme 5.1).[121] This has been attributed, at least partly, to unfavourable

dihedral angles in the transition state.[121]

Chapter 5

93

Secondly, the selenoxide (5.1) could be stabilised by an intramolecular hydrogen

bond between the NH hydrogen and the SeO oxygen. Spectroscopic evidence has

been cited[145] for the existence of such a bond in 2-acetylamido- and 2-(n-

propyl)amido- cyclohexyl phenyl selenoxides, (5.4) and (5.5), which do not readily

undergo the elimination reaction to yield allyl amides. These selenoxides exhibit

deshielding of the NH proton in the NMR spectrum, and in the IR spectrum, show an

increase in the carbonyl stretching frequency and a lowering of the NH stretching

frequency in comparison with the selenide.[145] An intramolecular hydrogen bond is

also believed to be the reason for the unusual stability of the 2-

(phenylseleninyl)cyclohexanols (5.6)[225] and (5.7).[226]

Indeed, in the oxidation of 2-(phenylselanyl)cyclohexyl benzamide (2.5) as described

in Chapter 3, the syn-elimination product was not observed, despite the occurrence

of the respective syn-elimination product from the oxidation of both 2-

(phenylselanyl)cyclopentyl benzamide (2.24) and 2-(phenylselanyl)cycloheptyl

benzamide (2.27). It was therefore of interest to prepare the selenoxide (5.1) to see

if it exhibited the same hydrogen-bonding properties as other cyclohexyl selenoxides

and whether an intramolecular hydrogen bond would be present in the crystalline

state.

Chapter 5

94

2-(Phenylseleninyl)cyclohexyl benzamide (5.1) was obtained in 96% yield by

oxidation of the amido selenide (2.5) with 1.1 equivalents of m-CPBA in

dichloromethane at room temperature. While the amido selenide (2.5) has two

asymmetric carbons, the trans-addition of the amidoselenation reaction constrains

the number of stereoisomers to one pair of enantiomers.[145] Three chirality centres

are present in the selenoxide - the two methine ring carbons and the selenium atom –

so that four stereoisomers of the selenoxide, R,R,SSe-(5.1), S,S,SSe-(5.1), R,R,RSe-

(5.1), S,S,RSe-(5.1) would be expected. However, inversion at selenium can

transform one stereoisomer into a diastereomer with the same configuration at the

ring carbons, but the opposite configuration at selenium. The 1H NMR spectrum of

2-(phenylseleninyl)cyclohexyl benzamide (5.1) showed a single, poorly-resolved peak

due to the methine protons, indicating rapid inversion at selenium between

diastereomeric isomers.[124] Recrystallisation of the selenoxide by slow infusion of

ethyl acetate into a methanol solution gave colourless needles which X-ray analysis

revealed to be crystals of R,R,SSe-(5.1) with the unit cell comprised of two

conformational isomers, both having configuration S at selenium and configuration R

at both the CHN and CHSe carbons.[227] The enantiomer, S,S,RSe-(5.1), with

configuration R at selenium and configuration S at both chiral carbons was

presumably also present in the crystal. SeO-HN intermolecular hydrogen bonds

were exhibited in the crystal but no intramolecular hydrogen bonds were evident.[227]

The crystalline selenoxide enantiomers R,R,SSe-(5.1) and S,S,RSe-(5.1), are

assumed to be the thermodynamically-favoured isomers, inversion at selenium via

the hydrate being facilitated by the methanol and/or water present in the

recrystallisation medium.[124, 228]

Chapter 5

95

In a 1H NMR spectrum of a solution of these crystals, the CHN peak appeared as a

doublet of doublets of doublets of doublets at 3.60 with coupling constant of 4.8 Hz

to the NH proton which resonated at 8.10 and with a trans-diaxial coupling of 11.1

Hz to the CHSe peak which appeared as a doublet of doublets of doublets at 3.39.

Over several hours, inversion at selenium occurred in the NMR sample of (5.1), to

give a mixture of all four stereoisomers, R,R,SSe-(5.1), S,S,SSe-(5.1), R,R,RSe-(5.1)

and S,S,RSe-(5.1). Well-defined peaks due to the CHN and CHSe methine protons

of the isomers R,R,RSe-(5.1) and S,S,RSe-(5.1) appeared at 4.04 and 3.14

respectively. Assuming an intramolecular hydrogen bond analogous with the

structures of (5.4) through (5.7),[145, 225-226] then the CHN proton at 3.60 of isomers

R,R,SSe-(5.1) and S,S,SSe-(5.1) is shielded relative to the corresponding proton in the

selenide (2.5) ( 3.96) due to its 1,3 relationship to the benzene ring of the selenium

moiety. The CHSe proton at 3.39 is deshielded compared with the analogous

proton in the selenide at 3.15 due to its trans-1,2 position with respect to this

benzene ring as well as the electron-withdrawing effect of the selenoxide group.

A model of the isomers R,R,RSe-(5.1) and S,S,RSe-(5.1) incorporating an

intramolecular hydrogen bond shows that the CHSe proton (at 3.14) is now cis

relative to the benzene ring and hence more shielded than in the selenide, while the

Chapter 5

96

CHN proton is unaffected and resonates at a similar frequency to the corresponding

proton in the selenide.

A 77Se NMR spectrum of a mixture of the four selenoxide stereoisomers (5.1)

exhibited resonances at 872.8 and 843.7, in the region expected for

selenoxides.[229] Duddeck et al.[230] reported two peaks in the 77Se NMR spectra of

monosubstituted cyclohexyl phenyl selenides and selenoxides and attributed these to

the equatorial and axial conformers. However, as compound (5.1) contained two

large vicinal groups, it can be assumed that the conformer with both substituents

equatorial would be of lower energy with a high barrier to inversion. It is therefore

proposed that the two sets of signals in the 77Se and 1H NMR spectra are due to the

two enantiomeric pairs of selenoxides R,R,SSe-(5.1), S,S,SSe-(5.1) and R,R,RSe-(5.1),

S,S,RSe-(5.1).

The crystalline selenoxide isomers (5.1) exhibited a strong absorption at 814 cm-1 in

the IR spectrum (KBr disc), characteristic of the selenoxide SeO stretch[231] and in the

mass spectrum, a molecular ion at m/z 375. The selenoxide crystals were stable

indefinitely at room temperature.

Oxidation of 2-(phenylselanyl)cyclohexyl benzamide (2.5) with 3 equivalents of m-

CPBA in tetrahydrofuran gave a white precipitate which was collected and washed

with cold tetrahydrofuran to remove m-CBA and excess m-CPBA. A 1H NMR

spectrum of this product showed two cyclohexyl methine signals at 4.16 and 3.97

coupled to each other with a trans-diaxial coupling constant of 11.4 Hz, the signal at

3.97 also being coupled (6.6 Hz) to the NH signal at 7.31. The substantial

electron-withdrawing effect of the selenonyl moiety resulted in a downfield shift of the

Chapter 5

97

CHSe signal of 0.77 and 1.02 ppm compared with the selenoxide isomers (5.1) and a

shift of 1.01 ppm compared with the selenide (2.5). Consequently, and in contrast

to the selenide and selenoxide, the CHSe 1H resonance of the selenone (5.8) was

further downfield than the CHN signal. A high resolution mass spectrum obtained

under electrospray conditions showed a satisfactory MH+ peak, while a low resolution

mass spectrum showed an MH+ peak at m/z 392 and a peak at m/z 376 due to loss

of oxygen from the MH+ ion. In the IR spectrum, the product (5.8) exhibited two

strong absorptions at 935 cm-1 and 879 cm-1, characteristic of the selenone

asymmetric and symmetric O=Se=O stretches respectively.[231]

A solution of the product (5.8) in tetrahydrofuran, with a few drops of dichloromethane

added to aid dissolution, was washed with 30% sodium hydroxide solution, resulting

in a mixture of the aziridine (2.17) and cis-oxazoline (2.7) in a ratio of 7:3 (Scheme

5.2). The high proportion of aziridine produced was further support that in the

isolated compound the selenium atom was oxidised to the +VI oxidation state since

treatment of the selenoxide (5.1) with base would be expected to give either no

reaction or the syn-elimination product. If the product (5.8) was further along the path

to an oxazoline, then treatment with base would be expected to give predominantly

the cis-oxazoline (2.7).

Chapter 5

98

Recrystallisation of the selenone (5.8) from tetrahydrofuran/hexane gave fine

colourless needles which were stable under nitrogen at –15°C, but decomposed

when stored at room temperature.

5.2 HYDROGEN-BONDING IN THE SELENIDE (2.5), SELENOXIDE (5.1) AND SELENONE (5.9)

Spectroscopic indicators of the extent of hydrogen bonding in the three compounds -

selenide (2.5), selenoxide (5.1) and selenone (5.8) - are shown in Table 5.1. 1H

NMR spectra were recorded as 0.005 M solutions in deuterochloroform; IR spectra

of KBr discs of the oxidised species and nujol mulls of the selenide and selenoxide

were compared with spectra of dilute solutions in chloroform and/or dichloromethane.

TABLE 5.1

HYDROGEN BOND INDICATORS IN THE SELENIDE (2.5), SELENOXIDE(5.1) AND SELENONE (5.8)

R

NMRA

(ppm) IR (solid)

(cm-1) IR (solution)B

(cm-1)

NH NH CO SeO SeO2 NH CO SeO SeO2

SePh 6.13 nujol 3319

s br 1631 CHCl3 3691 1655

Se(O)Ph 8.07

KBr 3230

s br 1655 814

CH2Cl2

3431

3257 w br

1661 826 809

nujol 3223 s br 1654 814

Se(O2)Ph 7.19 KBr 3309

s br 1657 935

879

CHCl3 3688 1664 933 881

CH2Cl2 3684 1666 935 880

A 1H NMR, 0.005M in CDCl3 B 0.001M in CHCl3, 0.002M in CH2Cl2

Chapter 5

99

Expected intermolecular hydrogen bonding in the solid selenide (2.5) is indicated by

a difference of 24 cm-1 between the frequency of the selenide carbonyl stretch in the

solid state (1631 cm-1) and in dilute solution (1655 cm-1) along with a strong

intermolecular NH stretch at 3319 cm-1 in the spectrum of the solid which becomes a

discrete free NH stretch at 3691cm-1 in the spectrum of the solution. The NH signal

at 6.13 in the 1H NMR spectrum of the selenide (2.5) is consistent with the absence

of intramolecular hydrogen bonding.

The X-ray structure of the selenoxide (5.1) shows an intermolecular hydrogen bond

between the Se=O oxygen and the amide hydrogen. If this is the case, then the

SeO stretch at 814 cm-1 in both the KBr disc and nujol mull infrared spectra of the

selenoxide could be interpreted as characteristic of the intermolecularly hydrogen

bonded SeO. The solution infrared spectrum of the selenoxide (5.1) appeared to

show two SeO stretches, at 826 and 809 cm-1. These two bands could represent the

free SeO and intramolecularly hydrogen bonded SeO stretches respectively. The

sharp (3431 cm-1) and broad (3257 cm-1) NH stretches in the dichloromethane

solution of the selenoxide are consistent with this interpretation. Intramolecular

hydrogen bonding in the solution of the selenoxide (5.1) is also supported by the

downfield resonance ( 8.07) of the NH proton in the 1H NMR spectrum.

Some intramolecular hydrogen bonding in the selenone (5.8) is suggested by the

somewhat downfield signal of the NH proton at 7.19. However, this is in contrast

with the sharp NH stretches and the absence of any broad NH stretch in the solution

infrared spectra, which suggest that no intramolecular hydrogen bonding of the NH

hydrogen is occurring in the selenone in dilute solution. The absence of any

Chapter 5

100

significant difference in the frequencies of the SeO symmetric and asymmetric

stretches in the spectrum of the solid compared with the analogous stretches in the

chloroform and dichloromethane solution spectra also do not support the involvement

of the SeO2 group in hydrogen bonding. The less polar selenone selenium-oxygen

bond would be expected to result in weaker hydrogen bonding to the group if it

occurred.[232-233] The effect this would have on the Se=O stretching frequencies

may therefore not be significant.

The slight increase in the carbonyl stretching frequencies of the selenoxide (5.1) and

selenone (5.8) on going from the solid state to the solution is perhaps indicative of

some bonding, other than hydrogen bonding, to the carbonyl group in the solid.

In the dilute chloroform solution infrared spectra of (5.8), evidence of intramolecular

hydrogen bonding between the NH proton and an oxygen on selenium may be

masked by hydrogen bonding between the Se-O oxygen and solvent,[233] and

therefore, this data provides no conclusive evidence regarding such intramolecular

hydrogen bonding. Unfortunately, the selenoxide was not soluble in the less polar,

non-hydrogen-bonding solvent carbon tetrachloride, which may have provided more

conclusive evidence of intramolecular hydrogen bonding.[233] Dichloromethane, less

polar and less hydrogen-bonding than chloroform, was chosen as a compromise.

The solid IR spectra of the KBr discs of the selenoxide (5.1) and selenone (5.8) may

also not be a valid reflection of the bonding in the crystal due to mechanochemical

changes which may occur in the preparation of a KBr disc.[234]

Chapter 5

101

5.3 NMR-SCALE OXIDATION OF N-[2-(PHENYLSELANYL)CYCLOHEXYL]BENZAMIDE (2.5)

It was of interest to follow the course of the oxidation of the selenide using NMR to

observe the transformation of the selenide to the selenoxide and then to the

selenone, and to observe the subsequent decomposition of the selenone. 2-

(Phenylselanyl)cyclohexyl benzamide (2.5) was chosen as the subject of NMR

studies of the oxidation reaction due to the stability of its selenoxide (5.1).

The oxidation reaction was observed by 1H NMR at room temperature in two

experiments: one in methylene chloride-d2 (CD2Cl2) and the other in tetrahydrofuran-

d8 (THF-d8) containing a small amount CD2Cl2 to aid dissolution. The experiments

were carried out at approximately the same concentration as the preparatory-scale

oxidation reactions.

FIGURE 5.1

OXIDATION OF 2-(PHENYLSELANYL)CYCLOHEXYL BENZAMIDE IN CD2CL2:

PROPORTION (%) OF COMPOUNDS (5.1), (5.8) AND (5.9) IN PRODUCT VERSUS REACTION TIME (t)

Chapter 5

102

In CD2Cl2, the oxidation reaction was followed by 1H NMR with six spectra recorded

at approximately six minute intervals and then one spectrum recorded at 90 minutes’

reaction time (Figure 5.1).

Spectrum 1, at approximately 6 minutes, showed that all of the starting material had

been consumed, most of the product being the selenoxide together with a small

amount of the selenone. After 12 minutes, there appeared two broad signals at

5.05 and 4.51, apparently due to a product of decomposition of the selenone (5.8).

The subsequent spectra showed a steady diminution of the selenoxide signals, an

increase in the concentration of the selenone which peaked at 24 minutes’ reaction

time before decreasing, and finally, predominance of the decomposition product.

The two diagnostic signals of the decomposition product were shifted further

downfield with each spectrum and finally appeared as a multiplet at 5.48 and a

doublet of doublets of doublets at 4.80. This product was assigned the structure of

the oxazolinium ion (5.9). As confirmation of this assignment, a 1H NMR sample of

the cis-oxazoline (2.7) in CDCl3 was shaken with two drops of concentrated HCl.

Protonation of the oxazoline resulted in a downfield shift of the methine CHN and

CHO protons to 5.46 and 4.79 respectively, almost identical with the signals of the

product obtained in the NMR-scale oxidation of the selenide (Scheme 5.3). Slight

differences in chemical shift could be attributed to a different solvent (CDCl3 versus

Chapter 5

103

CD2Cl2) and/or a different counterion (chloride versus m-chlorobenzoate). Bannard,

Gibson and Parkkari[235] observed similar downfield shifts for the methine resonances

in the 1H NMR spectrum of 2-methyl-cis-cyclohexanooxazoline hydrochloride

compared with the spectrum of the free oxazoline. It is proposed that the gradual

downfield shift of the decomposition product signals is due to the initial transformation

of the selenone (5.8) to the cis-oxazoline (2.7) which exchanges protons with the

weak acid m-CBA present in the reaction mixture, resulting in broad signals in the

NMR spectrum. As the reaction progresses, more m-CBA becomes available to

protonate the oxazoline until finally all of the oxazoline has been protonated and the

signals appear sharp and in accord with those of the oxazoline hydrochloride. The

NMR sample of the reaction mixture containing the oxazolinium ion (5.9) was washed

with dilute sodium hydroxide solution to give a product with a 1H NMR spectrum

identical to that of the free oxazoline (2.7) (Scheme 5.3).

FIGURE 5.2

OXIDATION OF 2-(PHENYLSELANYL)CYCLOHEXYL BENZAMIDE (2.5) IN THF-d8:

PROPORTION (%) OF COMPOUNDS (5.1), (5.8) AND (5.9) IN PRODUCT VERSUS REACTION TIME (t)

Chapter 5

104

The oxidation of the selenide was followed by 1H NMR in THF-d8, with a small

amount of CD2Cl2 added to aid dissolution. Nine spectra were recorded, eight at

intervals of approximately 6 minutes, then one after 40 hours’ reaction time (Figure

5.2).

After 6 minutes all of the selenide (2.5) had been consumed and the spectrum

showed a mixture of the selenoxide (5.1) and the selenone (5.8) in a ratio of

approximately 4 to 1. After 18 minutes, the selenone was the predominant product

and weak signals due to the oxazolinium ion were evident. After 36 minutes the

selenoxides (5.1) had been consumed and the selenone (5.8) and oxazolinium (5.9)

ion made up the product in a ratio of approximately 95 to 5. The transformation of

selenone (5.8) to oxazolinium ion (5.9) is slow in tetrahydrofuran and even after 48

minutes the selenone (5.8) still made up approximately 90% of the product.

Inversion at selenium is also inhibited in this solvent as predominantly one selenoxide

isomer was observed by NMR. A spectrum recorded after 40 hours’ reaction time

showed the oxazolinium ion (5.9) along with other unidentified minor products. Basic

workup of the sample gave the cis-oxazoline (2.7) along with small amounts of

unidentified products.

Due to the parameters involved with 77Se NMR, namely the high concentration and

lengthy time required to attain a spectrum, it was not possible to follow the oxidation

reaction using this technique. However, a reaction mixture of the selenide (2.5) and

4.8 equivalents of m-CPBA in THF at approximately sixteen times the preparatory

concentration was prepared in an NMR tube. A spectrum was recorded at –60°C;

after 570 transients a signal at 1010 attributed to the selenone[229] (5.8) and two

Chapter 5

105

selenoxide signals,[229] at 859.5 and 843.9, were observed. This spectrum was

an average of the reaction up to that point and therefore the relative concentration of

the products could not be determined. The difference in -value of one of the

selenoxide peaks compared with the selenoxide spectrum conducted in CDCl3 may

be due to solvent, temperature or concentration effects.

At the higher concentration required to run the 77Se NMR experiment, the selenone

(5.8) precipitated out of solution as a white solid. A 1H NMR spectrum of the

precipitate in deuterochloroform showed two well-defined peaks at 4.15 and 3.96,

identical with those of the isolated selenone (5.9), together with a minor amount of

the cis-oxazoline (2.7). The cis-oxazoline (2.7) may have formed in the original

reaction mixture or during collection and dissolution of the precipitate. A spectrum

recorded of this deuterochloroform sample after 18 hours showed that the selenone

(5.8) had been cleanly and completely transformed into the cis-oxazoline (2.7).

2-(Phenylseleninyl)cyclohexyl benzamide (5.1) was found to be as stable as

structurally-similar previously-reported cyclohexyl selenoxides.[145, 225-226] However,

contrary to proposals in the literature,[145, 226] X-ray analysis showed hydrogen

bonding in the crystalline selenoxide (5.1) to be intermolecular rather than

intramolecular. NMR and IR data suggest that an intramolecular hydrogen bond

may be important for stability of the selenoxide in solution.

2-(Phenylselenonyl)cyclohexyl benzamide (5.8) was found to be a surprisingly stable

compound both as a solid and in solution in tetrahydrofuran. Comparison of the

Chapter 5

106

course of the reaction in CD2Cl2 and THF-d8 showed that the selenone (5.8) forms

more rapidly in tetrahydrofuran and decomposes much more slowly in this solvent.

Monitoring of the oxidation reaction by 1H NMR in the absence of base suggested

that, in both polar and non-polar solvent, the selenone (5.8) decomposed to the cis-

oxazoline (2.7) which was then protonated by acid present in the reaction mixture to

give the oxazolinium ion (5.9). This is supported by the observation that isolation of

the selenone (5.8) from m-CBA and dissolution in deuterochloroform resulted in

cyclisation to the cis-oxazoline (2.7) with no intermediate or further transformation to

the oxazolinium ion (5.9).

Results from the current work have clearly shown that base is not necessary in the

cyclisation of -selenonyl amide to the oxazoline, although Heine[156] has reported

that base is involved in the rate-determining step in the cyclisation of -bromo amides

to oxazolines. Heine[156] suggested that deprotonation of a -bromo amide may

occur concomitantly with cyclisation to the oxazoline. If deprotonation occurs

concomitantly with cyclisation of the selenone (5.8) to the cis-oxazoline (2.7) then an

intramolecular hydrogen bond could facilitate the transformation (Scheme 5.4).

Chapter 6

107

6 PREPARATION AND CYCLISATION OF -HYDROXY SELENIDES

6.1 INTRODUCTION

Although the parent oxetane has been known since 1878,[236] there are relatively few

synthetic approaches to oxetanes. The Paterno-Büchi reaction[237-239] affords

oxetanes from the photocycloaddition of a carbonyl compound and an alkene

(equation 1). The reaction can proceed with regio- and facial selectivity depending

on the choice of the carbonyl and alkene substrates.[237-239] Enantiomerically pure

oxetanes have been prepared from the photocycloaddition of enantiomerically pure

silyl enol ethers to aromatic aldehydes[240-241] (equation 2).

The intramolecular Williamson ether synthesis furnishes oxetanes from the base-

induced cyclisation of 1,3-halohydrins and related substrates (equation 3). The

cyclisation of optically active substrates can provide access to optically active

oxetanes. For example, optically pure 2,2-substituted oxetanes were prepared via

optically active 1,3-chlorohydrin intermediates, generated by enantioselective

reduction of -halogenoketones[242] (equation 4).

Chapter 6

108

Biggs[243] developed a method of generating oxetane by thermal decomposition of the

tributyltin derivative of a 1,3-bromoacetate, itself derived from corresponding 1,3-diol

(equation 5). This method avoids the use of strong base required for cyclisation of -

substituted alcohols and provided oxetane in a yield of 40%.

Chapter 6

109

Using the methylene transfer reagent, dimethyloxosulfonium methylide, a ketone can

be transformed to an oxetane via the corresponding epoxide[244] (equation 6). Using

this sulfur ylide in concert with a chiral heterobimetallic catalyst, enantioselectivity

was amplified over the two steps, giving 2,2-disubstituted oxetanes in up to >99.5%

ee[245] (equation 7).

Oxetanes have been prepared from selenium-containing precursors by

selenocyclisation of unsaturated substrates. For example,

phenylselenoetherification of 2,4-dimethyl-1,4-pentadiene using N-

phenylselenenylsuccinimide gave bis(phenylseleno)-oxetane[246] (equation 8);

selenocyclisation of a 2-ene-1,5-diol with N-phenylselenenylphthalimide, provided the

two oxetanes[247] (equation 9). Displacement of the selenonyl group affords 3-

alkoxyoxetanes after conjugate addition of an alkoxide to a 3-

hydroxyvinylselenone[174, 248] (equation 10).

Chapter 6

110

6.2 ATTEMPTED ONE-POT PREPARATION OF 2-PHENYLOXETANE

It was thus of interest to investigate the utility of the selenonyl group and in particular,

our methodology for aziridine-formation from -amidoselenides, for the preparation of

oxetanes.

In theory, an oxetane could simply be formed by cyclisation of a -hydroxyselenone in

a one-pot preparation involving the ring-opening of an epoxide with an -metallo-alkyl

selenone to give an alkoxyselenone which might then cyclise in situ with loss of the

selenonyl moiety (Scheme 6.1).

The deprotonation of methyl phenyl selenone and addition of the anion to an

aldehyde in the expectation of forming a -hydroxyselenone was explored by

Saez.[249] Using LDA or LiHMDS as the base, Saez unexpectedly produced an

epoxide as a result of in situ displacement of the selenonyl group by the alkoxide ion

(Scheme 6.2).

Chapter 6

111

With a view to adapting this method of Saez[249] for the preparation of an oxetane

from the reaction of an -lithio selenone with an epoxide, methyl phenyl selenide[74]

(6.1) was prepared in 81% isolated yield by sodium hydride reduction of diphenyl

diselenide[75] and treatment of the resulting sodium phenylselenolate with methyl

iodide (Scheme 6.3).[74] Oxidation with m-CPBA gave methyl phenyl selenone[249]

(6.2) in 41% recrystallised yield. Although an attempt to replicate Saez’ result by

metallation of methyl phenyl selenone with LDA and reaction with benzaldehyde did

not result in the production of styrene oxide, when the reaction was conducted using

potassium tert-butoxide as the base, styrene oxide was obtained in low yield. The

subsequent attempt to prepare 2-phenyloxetane (6.3) by deprotonation of methyl

phenyl selenone with potassium tert-butoxide and reaction of the anion with styrene

oxide was, however, unsuccessful; methyl phenyl selenone and styrene oxide were

recovered from the reaction (Scheme 6.3).

While the attack of -lithio selenoxides on aldehydes and ketones has been

reported[250] in the production of -hydroxy selenides, there are no reports of the

Chapter 6

112

opening of epoxides with -lithio selenoxides to give -hydroxy selenoxides, which

would be useful intermediates on the path to oxetanes. Adapting a procedure

described by Reich[250] for the reaction of -lithio selenoxides with aldehydes and

ketones, oxidation of methyl phenyl selenide (6.1) to the selenoxide (6.4) with m-

CPBA, in situ deprotonation with LDA and introduction of styrene oxide to the mixture

at –78°C gave no reaction, with recovery of the styrene oxide (Scheme 6.4).

6.3 PREPARATION AND ATTEMPTED CYCLISATION OF 3-PHENYL-3-PHENYLSELENOPROPANOL

An alternative approach to the preparation of -hydroxy selenides could be the

addition of phenyl selenol to an ,-unsaturated aldehyde or ketone, such as

cinnamaldehyde, followed by reduction of the carbonyl group.

Sodium phenylselenolate was prepared by sodium hydride reduction of diphenyl

diselenide.[75] Introduction of cinnamaldehyde to the sodium phenylselenolate

suspension gave 3-phenyl-3-phenylselenopropanal (6.5) in approximately 80% crude

yield. Chromatography resulted in the decomposition of some of this product as was

evident from the appearance of a yellow band of diphenyl diselenide during elution of

the propanal (6.5) (Scheme 6.5). Decomposition of the propanal (6.5) during

chromatography had been observed previously in our research group[251-252] and

could occur via the elimination of phenyl selenol followed by its oxidation to diphenyl

diselenide. The isolated yield of 3-phenyl-3-phenylselenopropanal (6.5) was

Chapter 6

113

approximately 51%, contaminated with cinnamaldehyde and diphenyl diselenide.

The mass spectrum of 3-phenyl-3-phenylselenopropanal (6.5) showed a selenium-

containing molecular ion at m/z 290 and in the 1H NMR spectrum, two doublets of

doublets of doublets at 3.27 and 3.12 with a geminal coupling constant of 17.4 Hz

attributed to the diastereotopic methylene protons. These signals also showed

coupling to the benzylic proton whose signal appeared at 4.81, and to a triplet at

9.69 due to the aldehydic proton.

Sodium borohydride reduction of the impure aldehyde gave the -hydroxy selenide,

3-phenyl-3-phenylseleno-1-propanol (6.6), in 56% isolated yield (Scheme 6.5).

Assignment of this structure was supported by a molecular ion at m/z 292 in the

mass spectrum with fragments due to loss of C6H5Se at m/z 135 and further loss of

water at m/z 117. In the 1H NMR spectrum, two distinct doublets of triplets at 3.72

and 3.59 with a geminal coupling constant of 10.8 Hz were attributed to the

diastereotopic protons under oxygen. Signals due to the second diastereotopic

methylene protons, vicinal to the benzylic proton, appeared as a doublet of doublets

Chapter 6

114

of doublets at 2.29 with coupling constants of 6.0 and 6.3 Hz to the vicinal

methylene protons and of 7.8 Hz to the benzylic proton, the triplet due to which

appeared at 4.44. Also produced was cinnamyl alcohol, (6.7) through reduction of

the cinnamaldehyde present in the starting material. A third product exhibited two

triplets at 3.65 and 2.69 and a multiplet at 1.87 in the 1H NMR spectrum,

consistent with its being 3-phenyl-1-propanol (6.8) (Scheme 6.5). Further reduction

of the cinnamaldehyde double bond to give this product (6.8) is plausible as sodium

borohydride reduction of a double bond is known to occur where the double bond is

conjugated with a carbonyl group and is especially facile in a cinnamyl system.[256-257]

Attempted cyclisation of 3-phenyl-3-phenylseleno-1-propanol (6.6) under the

conditions developed for the preparation of aziridines, namely, oxidation with m-

CPBA at -78°C in THF solution, addition of 5 equivalents of potassium tert-butoxide

and warming to room temperature, gave a mixture, the 1H NMR spectrum of which

showed no indication of the expected triplet at ~ 5.9 of 2-phenyloxetane[258-259] (6.3)

(Scheme 6.6). Previous workers[251-252] in this research group had made attempts to

cyclise 3-phenyl-3-phenylseleno-1-propanol (6.6) to the oxetane; a range of reaction

conditions had been explored, including oxidation with (i) m-CPBA, (ii) H2O2 with acid

catalysis, (iii) oxone in a medium buffered at pH 11 and (iv) oxone in a medium

buffered at pH 8. However, no evidence had been observed for the formation of the

oxetane under any of the conditions used. For this reason, further attempts to

cyclise 3-phenyl-3-phenylseleno-1-propanol (6.6) were not pursued in the present

work. Competition between elimination and oxidation of the seleninyl group,

competition between the displacement and elimination of the selenonyl group, and

Chapter 6

115

hindrance of the secondary carbon by the bulky phenyl and phenylseleno groups

could all contribute to the reluctance of this molecule to cyclise to an oxetane.

6.3 PREPARATION AND CYCLISATION OF -HYDROXY SELENIDES BEARING A PRIMARY

SELENIUM MOIETY

Efforts were directed toward the possibility that a -hydroxy selenide bearing a

primary seleno group and a secondary hydroxyl group would be a more viable

oxetane-precursor. These -hydroxy selenides could be prepared by the ring-

opening of an epoxide with phenylselenomethyllithium.[86]

Bis(phenylseleno)methane (6.9) was prepared in 94% isolated yield by sodium

hydride reduction of diphenyl diselenide[75] and the reaction of the resulting sodium

phenylselenolate with methylene iodide.[74, 260] Selenium-metal exchange was

effected by treatment of the selenoacetal with n-butyllithium,[86] giving

phenylselenomethyllithium (6.10). Addition of HMPA and a solution of styrene oxide

in THF to the mixture gave the -hydroxy selenide, 1-phenyl-3-phenylseleno-1-

propanol[261] (6.11, 44%), along with the expected by-product n-butyl phenyl selenide

(6.12, 62%). HMPA is added to this reaction mixture to inhibit the decomposition of

phenylselenomethyllithium (6.10) to lithium phenylselenolate.[86, 89] However, also

Chapter 6

116

obtained was an 18% yield of 1-phenyl-2-phenylselenoethanol[136] (6.13), resulting

from the reaction of styrene oxide with lithium phenylselenolate (Scheme 6.7).

The mass spectrum of 1-phenyl-3-phenylseleno-1-propanol[261] (6.11) showed a

strong molecular ion at m/z 292 with a selenium-containing fragment at m/z 185

attributed to PhSeCHCH2+

, and a signal at m/z 107 attributed to C6H5CH2O+. In the

1H NMR spectrum, two doublets of doublets of triplets, at 2.18 and 2.0, with a

geminal coupling constant of 14.1 Hz, were assigned to the diastereotopic methylene

protons at C2. These protons were coupled to the benzylic proton whose signal

appeared at 4.83, and to the methylene protons under selenium, which resonated

as a triplet at 2.98.

An attempt to cyclise 1-phenyl-3-phenylseleno-1-propanol (6.11) to 2-phenyloxetane

(6.3), under the conditions which produced the aziridine from a -amido selenide,

gave a complex mixture whose 1H NMR spectrum showed no evidence of the

oxetane[258-259]. A second attempt at this reaction, varying the method by carrying

out the oxidation at ambient temperature and then cooling the mixture to –78°C

Chapter 6

117

before addition of base, gave predominantly 1-phenyl-1,3-propanediol[262-263] (6.14),

which was isolated in 23% yield (Scheme 6.8).

Efforts were directed to determine whether the conditions described by Kuwajima,

Shimizu and Ando[174, 248] for the preparation of 3-methoxyoxetanes (equation 10)

would be generally conducive to the cyclisation of -hydroxy selenides to oxetanes.

This procedure[174, 248] uses methanol as the solvent, which has been shown to

optimise the rate of oxidation of a number of selenoxides to the respective

selenones.[176] Thus, 1-phenyl-3-phenylseleno-1-propanol (6.11) was oxidised with

three equivalents of m-CPBA in methanol at room temperature for 30 minutes.

Aqueous sodium hydroxide was added and the reaction allowed to continue for 18

hours, resulting in a mixture of 2-phenyloxetane[258-259] (6.3) and 3-methoxy-1-phenyl-

1-propanol[262] (6.15) in a ratio of 2:1, along with 1-phenyl-1,3-propanediol[262-263]

(6.14). Chromatography of the mixture isolated 2-phenyloxetane[258-259] (6.3, 20%)

and 3-methoxy-1-phenyl-1-propanol[262] (6.15, 12%) (Scheme 6.8). The five ring

protons of 2-phenyloxetane (6.3) appeared as five distinct signals in the 1H NMR

spectrum: a triplet at 5.82, due to the -proton, and two pairs of signals - at 4.84

and 4.67, and at 3.03 and 2.67 - due to the - and - diastereotopic methylene

protons respectively.

The -hydroxy selenide (6.11) was oxidised with 2.5 equivalents of m-CPBA in

methanol but without the addition of hydroxide; 3-methoxy-1-phenyl-1-propanol[262]

(6.15) was obtained in 41% yield as the predominant product, with no evidence of the

oxetane in 1H NMR spectrum, indicating that the cyclisation reaction could not

proceed in the absence of base.

Chapter 6

118

A further two -hydroxy selenides, 1-phenylseleno-3-undecanol (6.17) and 4-

phenylseleno-1-phenyl-2-butanol (6.18), were prepared by the ring-opening of an

epoxide with phenylselenomethyllithium (6.10). 1-Phenylseleno-3-undecanol (6.17)

was isolated in 24% yield along with the -hydroxy selenide,1-phenylseleno-2-

decanol[264] (6.19, 14%) from the reaction of the phenylselenomethyllithium (6.10)

and 1,2-epoxydecane (Scheme 6.9). The expected eleven alkyl signals were

evident in the 13C NMR spectrum of the -hydroxy selenide (6.17). Both the low and

high resolution mass spectra showed a molecular ion, and a prominent fragment due

to loss of OH. In the 1H NMR spectrum, the CHO proton appeared as a multiplet

centered at 3.72, while signals due to the diastereotopic methylene protons under

selenium were almost coincident and appeared as a multiplet centered at ~ 3.01

which was not further elucidated. The signals due to the diastereotopic methylene

protons at C2 were also almost coincident and appeared as a complex multiplet

centered at 2.83.

Chapter 6

119

The -hydroxy selenide[264] (6.19) exhibited a strong molecular ion at m/z 314 with a

peak at m/z 297 due to loss of OH and a prominent selenium-containing peak at m/z

172 assigned to PhSeCH3+. The 13C spectrum showed ten alkyl carbons while the

1H NMR spectrum gave three diagnostic signals: two distinct doublets of doublets at

3.15 and 2.88 due to the diastereotopic protons under selenium, coupled to the

CHO proton which resonated at 3.67.

The oxidation of 1-phenylseleno-3-undecanol (6.17) under the conditions described

by Shimizu, Ando and Kuwajima[174, 248] gave a mixture of 2-octyloxetane[265] (6.20)

and 1-methoxy-3-undecanol (6.21), each in a yield of about 30%, estimated from the

1H NMR integrations in a spectrum of the crude product (Scheme 6.10). Purification

by chromatography resulted in very small yields, perhaps due to the volatility of both

compounds. The oxetane (6.20) exhibited five distinct alkyl signals in the 1H NMR

spectrum, corresponding to the five ring protons. Two doublets of doublets of

doublets, at 4.66 and 4.50, with a geminal coupling of 5.7 Hz, were attributed to

the diastereotopic -methylene ring protons. Signals due to the diastereotopic -

methylene ring protons appeared at 2.64 and 2.35 with a germinal coupling

constant of 10.8 Hz, and were coupled to the -methine proton which resonated at

4.82. Two poorly-resolved multiplets, at 1.78 and 1.66, corresponded to the

diastereotopic methylene protons of the alkyl chain.

Chapter 6

120

In the 1H NMR spectrum of 1-methoxy-3-undecanol (6.21), two doublets of doublets

of doublets at 3.78 and 3.63, with a germinal coupling constant of 9.3 Hz, were

assigned to the diastereotopic methylene protons at C1. The neighbouring

diastereotopic methylene protons at C2 appeared as a multiplet at 1.73. A

multiplet at 3.78 and a singlet at 3.36 were assigned to the methine CHO and the

methoxy protons respectively. A D2O shake resulted in greater resolution of the

CHOH multiplet at 3.78, supporting the assignment of this structure rather than of

the isomeric 3-methoxy-1-undecanol. Three of the twelve signals in the 13C

spectrum of (6.21) resonated downfield ( 71.83, 71.57 and 58.90) corresponding to

the three carbons attached to oxygen. A high resolution mass spectrum showed a

molecular ion, with the base peak at m/z 185.1901, due to loss of OH.

The ring-opening of 2-benzyloxirane with phenylselenomethyllithium (6.10) gave the

-hydroxy selenide, 4-phenylseleno-1-phenyl-2-butanol (6.18, 13%), along with the -

hydroxy selenide, 3-phenylseleno-1-phenyl-2-propanol[266] (6.22, 2%). Also

produced was 4,4-bis(phenylseleno)-1-phenyl-2-butanol (6.23, 14%) (Scheme 6.11).

In the mass spectrum, the -hydroxy selenide (6.18) gave a molecular ion at m/z 306

and a fragment at m/z 213 due to loss of C7H9. In the 1H NMR spectrum, the

diastereotopic methylene protons under selenium resonated as two doublets of

triplets at 3.15 and 3.05, with a geminal coupling constant of 12.3 Hz. Signals of

Chapter 6

121

the benzylic diastereotopic methylene protons appeared as doublets of doublets at

2.85 and 2.72 with a geminal coupling constant of 13.5 Hz. A poorly resolved

multiplet at 4.02 was assigned to the CHO proton. The third pair of diastereotopic

methylene protons at C2 resonated as a complex multiplet at 1.95. The -hydroxy

selenide (6.22) was characterised by three alkyl signals in the 13C NMR spectrum

and three corresponding sets of alkyl signals in the 1H NMR spectrum. A 16-line

signal centred at 3.93 in the 1H NMR spectrum was assigned to the CHO proton.

This signal was coupled to the diastereotopic methylene protons under selenium

which resonated as two doublets of doublets at 3.13 and 2.93, and to a doublet of

doublets at 2.93 which was attributed to the benzylic diastereotopic methylene

protons The mass spectrum of the selenoacetal (6.23) showed a molecular ion at

m/z 462 and fragment at m/z 187 due to loss of the phenylseleno group and water.

In the 13C NMR spectrum, C-Se coupling was apparent for two aromatic signals, at

134.83 and 134.33. The 1H NMR spectrum showed a one-hydrogen multiplet at

4.25 which was assigned to the CHO proton, and a doublet of doublets at 4.71,

assigned to the proton under the two selenium atoms. The benzylic diastereotopic

methylene protons resonated as two doublets of doublets at 2.70 and 2.66 while

two doublets of doublets of doublets, at 2.14 and 2.05, were attributed to the

remaining diastereotopic methylene protons at C2. Strong bands at 1069, 1022 and

1000 cm-1 in the infrared spectrum of the selenoacetal (6.23) were consistent with

similar absorptions in the infrared spectrum of bis(phenylseleno)methane (6.9), and

also the expected absorptions of an acetal or ketal,[267] and could be attributed to C-

Se stretching.

Chapter 6

122

-Hydroxyalkylselenoacetals analogous with compound (6.23) have arisen in the

work of Krief et al.[86] from the reactions of bis(phenylseleno)methane and 1,1-

bis(phenylseleno)ethane with alkehydes and ketones. Krief et al.[86] proposed that

these products are generated via the metallation of the selenoacetal by the

selenoalkyllithium (Scheme 6.12).

The reaction[174, 248] of 1-phenyl-4-phenylseleno-2-butanol (6.18) with m-CPBA in

methanol followed by addition of aqueous sodium hydroxide gave a complex mixture

from which 2-benzyloxetane[268] (6.24) and 4-methoxy-1-phenyl-2-butanol (6.25) were

isolated in yields of 10% and 15% respectively (Scheme 6.13). 2-Benzyloxetane[268]

Chapter 6

123

(6.24) was characterised by four alkyl carbon signals in the 13C NMR spectrum and

seven distinct alkyl signals in the 1H NMR spectrum, each integrating to one

hydrogen. The apparent quintet due to the CHO proton resonated at 5.04, while

the signals of the CH2O protons appeared as distinct doublets of doublets of doublets

at 4.65 and 4.48 with a geminal coupling constant of 5.7 Hz. Signals due to the

benzylic methylene protons appeared as two strongly coupled doublets of doublets at

3.09 and 2.98, with a geminal coupling constant of 13.8 Hz. Two distinct, but

more complex, signals at 2.63 and 2.44 were assigned to the remaining

diastereotopic methylene protons.

4-Methoxy-1-phenyl-2-butanol (6.25) gave an M+H peak in the mass spectrum, with

prominent fragment at m/z 162 due to loss of water, and a fragment at m/z 131 due

to an additional loss of OCH3. The 13C spectrum of (6.25) showed five alkyl signals

while five sets of alkyl protons were also apparent in the 1H NMR spectrum. A three-

hydrogen singlet at 3.34 was evidence of an methoxy group. The CHO methine

proton appeared as a poorly resolved pentuplet, while the diastereotopic methylene

protons - to the methoxy group appeared as two distinct doublets of doublets of

doublets at 3.62 and 3.52. Two doublets of doublets at 2.81 and 2.76 were

assigned to the benzylic diastereotopic methylene protons. The remaining multiplet

centred at 1.73 was assigned to the remaining methylene protons.

Chapter 6

124

These preliminary investigations demonstrated that oxetanes may be prepared from

-hydroxy selenides via a variation of the literature procedure.[174, 248] Future work

would involve optimising the yield by exploring the parameters of reaction time and

temperature and the use of a less nucleophilic solvent.

6.4 OXETANES IN NATURAL PRODUCTS AND DRUG DESIGN

In natural product investigations, the discovery of an oxetane ring is often regarded

as unusual or unique in a family of compounds. Some recent examples include the

limonoid (6.26), isolated from the leaves and twigs of Melia toosendan,[269] the

sesquiterpene dimer (6.27), containing a hemiacetal oxetane, isolated from the

leaves of Xylopia aromatica,[270] the macrolactin (6.28), isolated from the fermentation

broth of a marine Bacillus sp. and found to exhibit antibacterial activity,[271] and the

herbicidal and bacteriocidal Oxetin (6.29), obtained from the culture filtrate of a

Streptomyces sp.[272] The diterpenoid (6.30), isolated from the leaves and twigs of

Trigonostemon chinensis,[273] and Mitrephorone A (6.31), isolated from Mitrephora

glabra,[274] both display anticancer activity.[273-274] Oxetanocin A (6.32), isolated from

the fermentation broth of Bacillus megaterium, attracted considerable interest as it

was shown to inhibit the in vitro replication of HIV.[275-278]

Chapter 6

125

Chapter 6

126

The oxetane moiety is not unusual among the taxane compounds found in the Yew

trees of the genus Taxus. Of the approximately 550 taxanes isolated from species

of this genus, more than one-quarter contain an oxetane ring.[279] Taxol (6.33),

which was isolated from T. brevifolia in the late 1960s, is currently used in cancer

chemotherapy. The role of the oxetane ring in the bioactivity of Taxol is believed to

be two-fold: firstly, in contributing to the conformational rigidity of the four-ring

scaffold and secondly, as a hydrogen-bond acceptor in the tubulin protein binding

pocket.[280]

Despite having similar ring strain to oxiranes, oxetanes are not quite as susceptible

toward acid-catalysed ring-opening,[281-282] and in the absence of acid catalysis, are

considerably less reactive than oxiranes toward nucleophiles.[282-284] 3-Substituted

oxetanes are particularly resistant to nucleophilic attack, as substitution results in

lower ring-strain[285] and ring-opening would lead to unfavourable non-bonding

interactions. Oxetanes have the highest affinity for hydrogen-bonding among the

common cyclic ethers,[286] and comparable or greater hydrogen-bonding ability than

carbonyl compounds, with the exception of amides.[287-289]

Chapter 6

127

These physicochemical properties make the oxetane unit an attractive component for

incorporation into a drug molecule.[290-292] An oxetane moiety can be incorporated

into a drug to ‘block’ a reactive methylene group or to introduce conformational

constraint, without increasing the lipophilicity of the molecule.[290-292] The oxetane

unit is thus a structural alternative to a gem-dimethyl group which has the

disadvantage of increasing the lipophilicity of the drug, thereby exposing it to

enzymatic degradation.[290, 292] The oxetane unit also provides the polarity and

comparable hydrogen bonding ability of a carbonyl group, but without the carbonyl

group’s inherent reactivity.[290, 292] The oxetane moiety can thus be regarded as a

‘bioisostere’ of both a gem-dimethyl group and a carbonyl group.[293]

Morpholine (6.34) is incorporated

into a number of drugs in order to

increase their aqueous solubility

but has the disadvantage that it is

susceptible to oxidative metabolic

attack.[294] The spirocyclic oxetane (6.35) has been proposed as a viable substitute

for morpholine, and has been shown to be stable at pH 1-10 and resistant to

oxidative degradation.[294]

Recent studies in medicinal chemistry suggest that oxetanes will find extensive

application in drug design in the future.[290-292] As synthetic approaches to oxetanes

are few, further exploration of the use of the selenonyl group in the synthesis of

oxetanes, with the mild conditions required for its displacement, could therefore be a

worthwhile endeavour.

Experimental 7.1

128

7 EXPERIMENTAL

7.1 GENERAL EXPERIMENTAL

All solvents were redistilled prior to use. Tetrahydrofuran (THF) was distilled from

sodium wire and sodium benzophenone under a nitrogen atmosphere immediately

prior to use. Sodium hydride was used as a 60% dispersion in oil. meta-

Chloroperbenzoic acid was recrystallised from dichloromethane and was 80% pure

as determined by iodometric titration. Other reagents were purified according to

standard procedures.[295]

Flash chromatography was carried out with Merck Kieselgel 60 (230-400 mesh).

Thin layer chromatography (TLC) was performed on MERCK aluminium-backed silica

gel 60 F254 plates. TLC plates were visualised with UV light at 254 nm or using an

ammonium molybdate dip.

1H and 13C NMR spectra were obtained using either Varian Gemini 2000

Spectrometers (1H: 199.954, 13C: 50.283 MHz and 1H: 300.145, 13C: 75.479 MHz) or

a Varian INOVA Spectrometer (1H: 599.842, 13C: 150.842 MHz). Unless otherwise

stated, spectra were recorded as solutions in deuterochloroform at 25°C. Chemical

shifts () are reported in parts per million (ppm), relative to an internal standard of

tetramethylsilane (0 ppm) for 1H spectra, an internal standard of chloroform (77.0

ppm) for 13C spectra and an external standard of diphenyl diselenide (463 ppm) for

77Se spectra. Hydrogen multiplicities are abbreviated as s (singlet), d (doublet), t

(triplet), q (quartet), qn (quintuplet), m (multiplet).

Experimental 7.1

129

Infrared spectra were recorded on an ATI Mattson Genesis FT IR spectrometer or a

Perkin-Elmer 1720X FT IR spectrometer or a Perkin-Elmer Spectrum 100 ATR FT IR

spectrometer. Liquids were recorded as liquid films, solids as nujol mulls between

sodium chloride plates or as dispersions in pressed potassium bromide discs.

Solution spectra were obtained using a 0.5 mm path-length solution cell with sodium

chloride windows.

Electron impact (EI) mass spectra were recorded with a VG ZAB 2HF mass

spectrometer operating at 70 eV or a Shimadzu mass spectrometer at the University

of Adelaide. Electrospray (ESI) mass spectra were recorded with a Finnigan LCQ

mass spectrometer at the University of Adelaide. Electron impact high resolution

mass spectra (EI HRMS) were recorded on a Kratos Concept ISQ mass

spectrometer at the University of Tasmania. Electrospray high resolution mass

spectra (ESI HRMS) were recorded with an LTQ Orbitrap XL ETD spectrometer at

the University of Adelaide. Elemental analyses were performed at the University of

Otago, New Zealand.

Melting points were determined using a Kofler hot stage apparatus fitted with a

Reichert microscope and are uncorrected.

X-ray crystal structures were determined by Dr Edward Tiekink at the University of

Adelaide or by Professor Allan White at the University of Western Australia.

Unless otherwise stated, ratios of products were estimated from the integration of

peaks in the 1H NMR spectrum. The peaks used for -amidoselenides, -

Experimental 7.1

130

bromoamides, aziridines and cis-oxazolines were the protons under the two vicinal

substituents of the ring or chain, and for the syn-elimination products, the two alkene

protons and the proton under the amide group.

Data is described for each compound in the Experimental for the chapter in which it

first appears. Upon each occurrence thereafter the page containing the data is cited.

In subsequent preparations of the same compound, the compound was identified by

its accordance with spectra of a previous sample(s).

Experimental 7.2

131

7.2 WORK DESCRIBED IN CHAPTER 2

Amidoselenation of cyclohexene with 2 equivalents phenylselenenyl bromide

Procedure 7.2A: To a solution of cyclohexene in benzonitrile was added

phenylselenenyl bromide followed by aqueous TfOH. The mixture was stirred at the

specified bath temperature for 1 h then allowed to cool to r.t. Saturated aqueous

NaHCO3 (10 mL) was added and the products were extracted with CHCl3 (2 x 25

mL). The combined organic layers were washed with saturated aqueous NaCl (10

mL), dried (MgSO4), and the solvent evaporated at reduced pressure.

(i) reaction at 100°C

Following Procedure 7.2A, a mixture of cyclohexene (92 mg, 1.1 mmol) and

phenylselenenyl bromide (465 mg, 1.97 mmol) in benzonitrile (5.5 mL), TfOH (0.09

mL, 1 mmol) and water (0.09 mL, 5 mmol) was stirred at 97-107°C.

Chromatography (CHCl3/hexane 15:85 to remove diphenyl diselenide then

EtOAc/hexane 50:50) gave a fraction (93 mg) which contained the cis-oxazoline[149-

150] (2.7, data: page 137) and the selenide (2.5, data: page 137) in a ratio of 80:20 as

estimated from integration of peaks in the 1H NMR spectrum.

(ii) reaction at 120°C

Following Procedure 7.2A, a mixture of cyclohexene (120 mg, 1.46 mmol) and

phenylselenenyl bromide (706 mg, 2.99 mmol) in benzonitrile (8 mL), TfOH (0.13 mL,

1.5 mmol) and water (0.13 mL, 7.2 mmol) was stirred at 120°C. Chromatography

(CHCl3/hexane 20:80 to remove diphenyl diselenide, then EtOAc/hexane 50:50) gave

the cis-oxazoline[149-150] (2.7, data: page 137) as a pale brown gum (88 mg, 30%).

Experimental 7.2

132

(iii) reaction at 150°C

Following Procedure 7.2A, a mixture of cyclohexene (92 mg, 1.1 mmol) and

phenylselenenyl bromide (499 mg, 2.12 mmol) in benzonitrile (6 mL), TfOH (0.09 mL,

1 mmol) and water (0.09 mL, 5 mmol) was stirred at 146-151°C. Chromatography

(CHCl3/hexane 15:85 to remove diphenyl diselenide then EtOAc/hexane 30:70) gave

the cis-oxazoline[149-150] (2.7, data: page 137) as a brown gum (33 mg, 15%).

(iv) reaction at 160°C

Following Procedure 7.2A, a mixture of cyclohexene (128 mg, 1.56 mmol) and

phenylselenenyl bromide (769 mg, 3.26 mmol) in benzonitrile (6 mL), TfOH (0.14 ml,

1.6 mmol) and water (0.14 mL, 8.0 mmol) was stirred at 160°C. Chromatography

(EtOAc/hexane, gradient of 25:75 to 40:60) gave diphenyl diselenide followed by the

cis- oxazoline[149-150] (2.7, data: page 137) as a brown oil (15 mg, 5%).

Reaction of trans-2-benzamidocyclohexyl phenyl selenide (2.5) with

phenylselenenyl bromide

(i) reaction in benzonitrile at 115°C

A mixture of the amido selenide (2.5, 161 mg, 0.448 mmol) and phenylselenenyl

bromide (120 mg, 0.509 mmol) in benzonitrile (5.5 mL) was stirred at a bath

temperature of 115°C for 4 h. The mixture was allowed to cool and the solvent was

evaporated at reduced pressure. Chromatography (EtOAc/hexane 40:60) gave

trans-2-bromocyclohexyl benzamide (2.10) which crystallised from the eluting solvent

as white crystals (39 mg, 31%), m.p.152-154°C. Found: C, 55.17; H, 5.40; N, 5.03.

C13H16NOBr requires C, 55.33; H, 5.72; N, 4.96%. max: 3228, 3080, 1635, 1574,

1342, 1194, 706 cm-1. 1H NMR: 7.81-7.77, m, 2H, ArH; 7.54 - 7.41, m, 3H, ArH;

6.20, d, J 6.0 Hz, 1H, NH; 4.14, ddt, J 3.6, 7.8, 10.5 Hz, 1H, CHN; 4.02, ddd, J 4.2,

Experimental 7.2

133

10.5, 11.1 Hz, 1H, CHBr; 2.48 - 2.32, m, 2H; 2.04-1.91, m, 1H; 1.81-1.76, m, 2H;

1.58-1.29, m, 3H. 13C NMR: 167.06, C=O; 134.85, 131.46, 128.59, 126.96, all Ar;

55.83, CHN; 55.25, CHBr; 37.17, 33.29, 26.55, 24.35. MS: m/z 281 (M+, 79Br), 202

(M+-Br), 122 (C6H5CONH3+), 105 (C6H5CO+), 77 (C6H5

+). Further elution gave cis-2-

bromocyclohexyl benzamide (2.8, 13 mg, 10%). Recrystallisation from EtOAc gave

(2.8) as white crystals, m.p. 150.5-152°C. EI HRMS: 281.0409 C13H16NO79Br

requires 281.0416. max: 3324, 2943, 1633, 1525, 1489, 1447, 1313, 1296, 1282,

1263, 1244, 1103, 824, 799, 718, 691, 657 cm-1. 1H NMR: 7.80-7.76, m, 2H, ArH;

7.54-7.42, m, 3H, ArH; 6.33, d, J 6.9 Hz, 1H, NH; 4.79, m, 1H, CHBr; 4.16-4.07, m,

1H, CHN; 2.25-2.18, m, 1H; 2.06-1.94, m, 1H; 1.86-1.67, m, 4H; 1.61-1.43, m, 2H.

13C NMR: 166.63, C=O; 134.58, 131.85, 128.85, 127.17, all Ar; 61.39, CHBr; 50.89,

CHN; 34.01; 28.06; 24.79; 19.99. MS: m/z 281 (M+, 79Br), 202 (M+-Br), 122

(C6H5CONH3+), 105 (C6H5CO+), 77 (C6H5

+). Further elution gave the cis-

oxazoline[149] (2.7, 3 mg, 3%, data: page 137).

(ii) reaction in CH2Cl2 at r.t.

To a solution of the amido selenide (2.5, 71 mg, 0.20 mmol) in CH2Cl2 (5 mL) was

added phenylselenenyl bromide (57 mg, 0.24 mmol) and the mixture was stirred at

r.t. for 48 h. An aliquot of the mixture was taken and the solvent evaporated at

reduced pressure. 1H NMR analysis showed a substantial amount of unreacted

amido selenide (2.5) and therefore, a further portion of phenylselenenyl bromide (26

mg, 0.11 mmol) was added and the mixture was stirred a further 44 h. The mixture

was diluted with CH2Cl2 then washed with saturated aqueous NaHCO3 and saturated

aqueous NaCl and dried (MgSO4), and the solvent removed at reduced pressure to

give a pale brown oil (114 mg). 1H NMR analysis showed this product to be a

Experimental 7.2

134

mixture of the cis-oxazoline[149] (2.7, data: page 137), the cis-bromide (2.8, data:

page 133) and the amido selenide (2.5) in a ratio of 75:20:5.

(iii) reaction in refluxing CH3CN

A solution of the amido selenide (2.5, 72 mg, 0.20 mmol) and phenylselenenyl

bromide (74 mg, 0.31 mmol) in CH3CN (8 mL) was refluxed for 3 h, then cooled and

diluted with CH2Cl2 (25 mL). The mixture was washed with saturated aqueous

NaHCO3 (10 mL) and saturated aqueous NaCl (10 mL) and dried (Na2SO4) and the

solvent evaporated at reduced pressure to give a yellow solid (110 mg). 1H NMR

analysis showed the product to be a mixture of cis-oxazoline[149] (2.7, data: page

137), the trans-bromide (2.10, data: page 132) and the cis-bromide (2.8, data: page

133) in a ratio of 60:25:15.

(iv) in CH2Cl2 with addition of Et4NBr

To a solution of the amido selenide (2.5, 68 mg, 0.19 mmol) in CH2Cl2 (5 mL) was

added phenylselenenyl bromide (73 mg, 0.31 mmol) followed by Et4NBr (66 mg, 0.31

mmol) and the mixture was stirred at r.t. for 4 d. The mixture was diluted with

CH2Cl2, washed with saturated aqueous NaHCO3 and saturated aqueous NaCl and

dried (MgSO4) and the solvent evaporated at reduced pressure to give a yellow solid

(93 mg). 1H NMR analysis showed the product to be a mixture of the cis-bromide

(2.8), the cis-oxazoline[149] (2.7, data: page 137) and the amido selenide (2.5) in a

ratio of 75:15:10. Chromatography (EtOAc/hexane, gradient of 5:95 to 15:85) gave

a fraction (34 mg) containing the cis-bromide (2.8) and the amido selenide (2.5) in a

ratio of 90:10. Recrystallisation of this mixture from EtOAc gave the cis-bromide

(2.8, data: page 133) as white crystals, m.p. 150.5-152°C. Further elution gave the

cis-oxazoline[149] (2.7, 4 mg, 10%).

Experimental 7.2

135

(v) in refluxing CH3CN with addition of Et4NBr

A solution of the amido selenide (2.5, 71 mg, 0.20 mmol), phenylselenenyl bromide

(69 mg, 0.29 mmol) and Et4NBr (63 mg, 0.30 mmol) in CH3CN (8 mL) was refluxed

for 3 h, then cooled and diluted with CH2Cl2 (20 mL). The mixture was washed with

saturated aqueous NaHCO3 (10 mL) and saturated aqueous NaCl (10 mL) and dried

(Na2SO4) and the solvent evaporated at reduced pressure to give a yellow solid (108

mg). 1H NMR analysis showed the product to be a mixture of the cis-bromide (2.8,

data: page 133), the cis-oxazoline[149] (2.7, data: page 137), the trans-bromide (2.10,

data: page 132) and the amido selenide (2.5) in a ratio of 50:20:15:15.

Oxidation of 2-amidoalkyl phenyl selenide with m-CPBA and with KOH as base

To a stirred solution of the amido selenide (2.5, 151 mg, 0.421 mmol) in i-PrOH (20

mL) was added powdered KOH (178 mg, 3.17 mmol) followed by m-CPBA (362 mg,

80%, 1.68 mmol) and the mixture was stirred at r.t. for 1 h. Aqueous Na2S2O3 (0.5

M, 15 mL) and saturated aqueous NaHCO3 (10 mL) were added and the products

were extracted with CHCl3 (2 x 25 mL). The combined organic extracts were dried

(Na2SO4) and the solvent evaporated at reduced pressure. Chromatography

(EtOAc/hexane, gradient of 10:90 to 30:70) gave 7-benzoyl-7-

azabicyclo[4.1.0]heptane[154] (2.17) as a white solid (72 mg, 85%), which crystallised

from the eluting solvent as white crystals, m.p. 79.5-80.5°C (lit.[154] m.p. 77°C).

max(Nujol) 3059, 3008, 2951, 1716, 1666, 1630, 1599, 1577, 1547, 1450, 1410,

1336, 1311, 1294, 1263, 1230, 1186, 1119, 1072, 754, 737, 708, 627 cm-1. 1H

NMR: 8.00-7.97, m, 2H, ArH; 7.56-7.51, m, 1H, ArH; 7.47-7.41, m, 2H, ArH; 2.76-

2.75, m, 2H, CHN; 2.12-2.03, m, 2H; 1.95-1.85, m, 2H; 1.62-1.50, m, 2H; 1.41-1.29,

m, 2H. 13C NMR: 180.25, C=O; 133.77, 132.45, 129.11, 128.35, all Ar; 37.02,

Experimental 7.2

136

23.87, 19.93. MS: m/z 202 (M++H), 105 (PhCO+), 96 (M+-PhCO), 77 (C6H5+).

Further elution gave the cis-oxazoline[149] (2.7, data: page 137) as a pale yellow gum

(10 mg, 12%)

One-Step Amidoselenation[145, 148]

Procedure 7.2B: To a solution of the alkene in nitrile was added phenylselenenyl

chloride followed by a solution of TfOH in water. The mixture was stirred at the

temperature and for the time specified, then cooled to r.t. Saturated aqueous

NaHCO3 (10 mL) was added and the products were extracted with CHCl3 (2 x 25

mL). The combined organic extracts were washed with saturated aqueous NaCl (10

mL), dried (MgSO4), and the solvent was evaporated at reduced pressure. The

crude product was purified by chromatography.

(a) trans-2-(Phenylselanyl)cyclohexyl acetamide (2.31)

Following Procedure 7.2B, a mixture of cyclohexene (0.506 mL, 5.00 mmol) and

phenylselenenyl chloride (958 mg, 5.00 mmol) in CH3CN (28 mL) and TfOH (0.44

mL, 5.0 mmol) in water (0.45 mL, 25 mmol) was refluxed for 2 h. Chromatography

(gradient of EtOAc/hexane 60:40 to EtOAc/hexane/MeOH 60:30:10) gave 2-

(phenylseleno)cyclohexanol[169] (2.41) as a brown oil (7 mg, 1%). max (neat) 3429,

3070, 3055, 2931, 2856, 1577, 1477, 1446, 1437, 1381, 1356, 1271, 1255, 1186,

1113, 1065, 1036, 1022, 957, 741, 694 cm-1. 1H NMR: 7.61-7.58, m, 2H, ArH;

7.34-7.26, m, 3H, ArH; 3.33, dt, J 4.2, 9.9 Hz, 1H, CHO; 2.94, s, 1H, OH; 2.90, ddd,

3.9, 9.9, 12.1 Hz, 1H, CHSe; 2.21-2.12, m, 2H; 1.76-1.70, m, 1H; 1.65-1.60, m, 1H;

1.44-1.17, m, 4H; 13C NMR (200 MHz): 136.08, 129.01, 128.11, 126.72, all Ar;

72.24, CHO; 53.48, CHSe; 33.82, 33.31, 26.75, 24.36. 77Se NMR: 333.43. MS:

m/z 256 (M+), 239, (M+-OH), 158 (C6H5SeH+), 99 (M+-C6H5Se), 81 (C6H9+). Further

Experimental 7.2

137

elution gave the title compound[145] which crystallised from the eluting solvent as fine

white needles (1.298 g, 88%), m.p. 153-155°C (lit.[145] m.p. 149-150°C). EI HRMS:

297.0628 C14H19NOSe requires 297.0633. max (Nujol) 3307, 1643, 1543, 1317,

1178, 1113, 976, 744, 692, 598 cm-1. 1H NMR: 7.59-7.30, m, 2H, ArH; 7.30-7.26,

m, 3H, ArH; 5.43, d, J 7.5 Hz, 1H, NH; 3.81, ddt, J 4.2, 7.5, 11.1 Hz, 1H, CHN; 3.01,

dt, J 3.9, 11.1 Hz, CHSe; 2.21-2.10, m, 2H; 1.90, s, 3H, CH3; 1.70-1.47, m, 3H; 1.42-

1.11, m, 3H. 13C NMR: 169.20, C=O; 135.36, 129.02, 128.27, 127.75, all Ar;

53.32, CHN; 47.94, CHSe; 34.05, 33.81, 26.65, 24.57, 23.40. MS: m/z 297 (M+),

238 (M+-NH2COCH3), 157 (C6H5Se+), 140 (M+-C6H5Se), 98 (C6H12N+), 81 (C6H9+).

(b) trans-2-(Phenylselanyl)cyclohexyl benzamide (2.5)

Following Procedure 7.2B, a mixture of cyclohexene (239 mg, 2.91 mmol) and

phenylselenenyl chloride (617 mg, 3.22 mmol) in benzonitrile (15 mL) and TfOH (0.26

mL, 2.9 mmol) in water (0.26 mL, 14 mmol) was stirred at a bath temperature of

100°C for 1 h. Chromatography (CHCl3/hexane 15:85 to remove diphenyl

diselenide, then EtOAc/hexane 50:50) gave the title compound[145] which crystallised

from the eluting solvent as colourless needles (691 mg, 66%), m.p. 143-144°C (lit.[145]

m.p. 133-134°C). max (Nujol) 3319, 1631, 1577, 1539, 1327, 1178, 741, 694, 665

cm-1. 1H NMR: 7.69-7.66, m, 2H, ArH; 7.58-7.54, m, 2H, ArH; 7.51-7.50, m, 1H,

ArH; 7.49-7.38, m, 2H, ArH; 7.25-7.21, m, 3H, ArH; 6.16, d, J 7.5 Hz, 1H, NH; 3.96,

ddt, J 3.6, 7.5, 11.1 Hz, 1H, CHN; 3.15, dt, J 3.9, 11.1 Hz, 1H, CHSe; 2.39-2.33, m,

1H; 2.26-2.19, m, 1H; 1.76-1.68, m, 1H; 1.64-1.55, m, 1H; 1.50-1.20, m, 4H. 13C

NMR: 166.69, C=O; 135.41, 134.89, 131.25, 129.08, 128.46, 128.07, 127.77,

126.89, all Ar; 53.91, CHN; 48.06, CHSe; 34.04, 26.80, 24.61. MS: m/z 359 (M+),

238 (M+-C6H5CONH2), 202 (M+-C6H5Se), 158 (C6H5SeH+), 122 (C6H5CONH3+), 105

(C6H5CO+), 81 (C6H9+), 77 (C6H5

+). Further elution gave cis-3a,4,5,6,7,7a-

Experimental 7.2

138

hexahydro-2-phenylbenzoxazole[149] (2.7) as a pale yellow gum (37 mg, 6%) which

was recrystallised from hexane to give colourless crystals, m.p. 42-45°C (lit.[149] m.p.

47-48°C). max 3313, 3274, 1720, 1637, 1577, 1543, 1346, 1275, 1176, 1151, 1111,

1066, 1026, 976, 903, 775, 696 cm-1. 1H NMR: 7.99-7.95, m, 2H, ArH; 7.51-7.37,

m, 3H, ArH; 4.68, dt, J 5.1, 8.1 Hz, 1H, CHO; 4.13, ddd, J 6.0, 6.6, 8.1 Hz, 1H, CHN;

1.97-1.78, m, 2H; 1.69-1.38, m, 4H. 13C NMR: 164.27, C=N; 131.16, 128.24,

126.92, all Ar; 78.86, CHO; 63.54, CHN; 27.66, 26.22, 19.78, 19.07. MS: m/z 202

(MH+), 122 (C6H5CONH3+), 105 (C6H5CO+), 77 (C6H5

+).

(c) trans-2-(Phenylselanyl)cyclopentyl benzamide (2.24)

Following Procedure 7.2B, a mixture of cyclopentene (342 mg, 5.02 mmol) and

phenylselenenyl chloride (1.18g, 3.22 mmol) in benzonitrile (15 mL) and TfOH (0.45

mL, 5.1 mmol) in water (0.45 mL, 25 mmol) was stirred at a bath temperature of 100-

105°C for 1 h. Chromatography (EtOAc/hexane 40:60) gave the title compound

which crystallised from the eluting solvent as colourless needles (275 mg, 16%),

m.p.121.5-123.5°C. C18H19NOSe requires: C 62.79, H 5.56, N 4.07. Found: C 62.89,

H 5.51, N 4.14. EI HRMS: 345.0634 C18H19NOSe requires 345.0633. max (Nujol)

3273, 2854, 1631, 1549, 1358, 1323, 1296, 1221, 1182, 1070, 737, 692 cm-1. 1H

NMR: 7.63-7.59, m, 4H, ArH; 7.47-7.44, m, 1H, ArH; 7.40-7.35, m, 2H, ArH; 7.27-

7.22, m, 3H, ArH; 6.10, br d, J 6.0 Hz, 1H, NH; 4.31, qn, J 7.5 Hz, 1H, CHN; 3.44, dt,

J 7.5, 8.1 Hz, 1H, CHSe; 2.35-2.22, m, 2H; 1.81-1.72, m, 3H; 1.55-1.48, m, 1H. 13C

NMR: 167.31, C=O; 134.98, 134.59, 131.38, 129.12, 128.73, 128.45, 127.70,

126.88, all Ar; 58.06, CHN; 46.82, CHSe; 31.74, 31.56, 22.06. MS: m/z 345 (M+),

224 (M+-C6H5CONH2), 188 (M+-C6H5Se), 105 (C6H5CO+), 77 (C6H5+). Further elution

gave a fraction (99 mg) containing a mixture of trans-2-(phenylselanyl)cyclopentyl

benzamide (2.24) and N-cyclopentylbenzamide[154] (2.26) in a ratio of 1:1, as

Experimental 7.2

139

estimated from integrations in the 1H NMR spectrum (data for (2.26): page 143).

Further elution gave cis-4,5,6,6a-tetrahydro-2-phenyl-3aH-cyclopentoxazole[149]

(2.25) (296 mg, 32%) as a brown oil. max 3410, 3282, 3060, 2960, 2870, 1649,

1579, 1495, 1450, 1354, 1323, 1296, 1257, 1201, 1095, 1065, 1024, 947, 781, 696

cm-1. 1H NMR: 7.94-7.90, m, 2H, ArH; 7.49-7.37, m, 3H, ArH; 5.11, dd, J 5.7, 7.2

Hz, 1H, CHO; 4.73, t, J 7.2 Hz, 1H, CHN; 2.12-1.99, m, 2H; 1.81-1.25, m, 4H. 13C

NMR: 163.81, C=N; 131.09, 128.23, 127.84, all Ar; 84.70, CHO; 71.80, CHN;

34.64, 33.85, 22.12. MS: m/z 187 (M+), 158 (M-C2H5+), 130 (M-C3H5O+), 104

(C6H5CNH+), 77 (C6H5+).

(d) trans-N-2-(Phenylselanyl)cycloheptyl benzamide (2.27)

Following Procedure 7.2B, a mixture of cycloheptene (491 mg, 5.11 mmol) and

phenylselenenyl chloride (1.196 g, 6.24 mmol) in benzonitrile (19 mL) and TfOH (0.45

mL, 5.1 mmol) in water (0.45 mL, 25 mmol) was stirred at a bath temperature of 96-

110°C for 20 h. Chromatography (EtOAc/hexane 25:75) gave a fraction (145 mg)

containing the title compound (2.27; data: page 152), the cis-oxazoline, cis-

4,5,6,7,8,8a-hexahydro-2-phenyl-3aH-cycloheptoxazole (2.28), N-cycloheptyl

benzamide[166-167] (2.29), and the syn-elimination product, N-(cyclohept-2-en-1-

yl)benzamide (2.30; data: page 180), in a ratio of 20:25:40:15. Simultaneous

equations translate these ratios into the following approximate yields, respectively:

2%: 3%: 5%: 2%. Further elution gave a fraction from which N-

cycloheptylbenzamide[166-167] (2.29) was isolated as a pale brown solid (163 mg,

15%) by trituration and crystallization from CH2Cl2/hexane, m.p. 126-130°C (lit.[167]

m.p. 127-129°C). 1H NMR: 7.76-7.30, m, 2H, ArH; 7.51 -7.39, m, 3H, ArH; 6.08, br

d, J 9.6 Hz, 1H, NH; 4.19-4.15, m, 1H, CHN; 2.08-2.00, m, 2H; 1.67-1.48, m, 10H.

13C NMR: 166.28, C=O; 136.20, 131.10, 128.44, 126.74, all Ar; 50.83, CHN; 35.17,

Experimental 7.2

140

28.02, 24.15. MS: m/z 217 (M+), 121 (C6H5CONH2+), 105 (C6H5CO+). The mother

liquor contained mainly the cis-oxazoline, cis-4,5,6,7,8,8a-hexahydro-2-phenyl-3aH-

cycloheptoxazole (2.28) (222 mg, 21%). ESI HRMS: 216.13793 C14H17NO+H

requires 216.13883. max 3240, 2925, 2857, 1637, 1625, 1576, 1555, 1489, 1461,

1445, 1327, 1269, 1075, 1054, 888, 803 cm-1. 1H NMR: 7.97-7.93, m, 2H, ArH;

7.50 - 7.37, m, 3H, ArH; 4.86, ddd, J 6.0, 6.9, 10.2 Hz, 1H, CHO; 4.42, ddd, J 3.6,

9.6, 10.2 Hz, 1H, CHN; 2.08 - 1.36, m, 10H. 13C NMR: 162.31, C=N; 131.04,

128.49, 128.21, 128.16, all Ar; 83.21, CHO; 69.83, CHN; 31.57, 30.91, 30.88, 26.06,

24.33. MS: m/z 215 (M+), 105 (C6H5CO+).

(e) 1-(Phenylselanyl)-2-octyl benzamide (2.32)

Following Procedure 7.2B, a mixture of 1-octene (0.471 mL, 3.00 mmol) and

phenylselenenyl chloride (578 mg, 3.02 mmol) in benzonitrile (18 mL) and TfOH

(0.270 mL, 3.05 mmol) in water (0.27 mL, 15 mmol) was stirred at a bath temperature

of 105°C for 2 h. Chromatography (CH2Cl2/hexane 15:85 then a gradient of

EtOAc/hexane 5:95 to 50:50) gave slightly impure 1-(phenylselanyl)-2-octyl

benzamide (2.32) as an orange oil (692 mg, 59%). Recrystallisation from

CH2Cl2/hexane gave the title compound as fine white needles, m.p. 69.5-71.5°C. EI

HRMS: 389.1258 C21H27NOSe requires 389.1259. max (KBr) 3296, 3059, 2953,

2927, 2850, 1628, 1603, 1577, 1537, 1491, 1477, 1466, 1437, 1421, 1412, 1375,

1350, 1321, 1302, 1281, 1072, 1022, 733, 698, 688, 667 cm-1. 1H NMR: 7.59-7.53,

m, 4H, ArH; 7.50-7.44, m, 1H, ArH; 7.40-7.34, m, 2H, ArH; 7.27-7.24, m, 1H, ArH;

7.23-7.19, m, 2H, ArH; 6.14, d, J 8.7 Hz, 1H, NH; 4.43-4.37, m, 1H, CHN; 3.29, dd, J

5.4, 12.9 Hz, 1H, CHaHbSe; 3.22, dd, J 4.8, 12.9 Hz, 1H, CHaHbSe; 1.71-1-61, m, 2H;

1.36-1.24, m, 8H; 0.86, t, J 6.9 Hz, 3H, CH3. 13C NMR: 166.84, C=O; 132.70,

131.29, 130.09, 129.24, 128.51, 128.42, 127.06, 126.80, all Ar; 49.58, CHN; 34.55;

Experimental 7.2

141

33.88, CHSe; 31.64, 29.04, 26.01, 22.52, 13.97. MS: m/z 389 (M+), 268 (M-

C6H5CONH+), 232 (M-C6H5Se+), 127 (C8H17N+), 105 (C6H5CO+), 77 (C6H5+). The

mother liquor contained a mixture of the title compound (2.32) and a second

compound which was identified as the regioisomer, 2-(phenylselanyl)-1-octyl

benzamide (2.33), on the basis of the following signals: 1H NMR: 6.69, br s, 1H,

NH; 3.80, ddd, J 4.2, 6.3, 13.5 Hz, 1H, CHaHbNH; 3.51, ddd, J 5.1, 8.1, 13.5 Hz, 1H,

CHaHbNH; 3.41, m, 1H, CHSe.

(f) 2-(Phenylselanyl)-3-hexyl benzamide (2.34) and 3-(Phenylselanyl)-2-hexyl benzamide (2.35)

Following Procedure 7.2B, a mixture of trans-2-hexene (0.629 mL, 5.00 mmol) and

phenylselenenyl chloride (994 mg, 5.19 mmol) in benzonitrile (20 mL) and TfOH (0.44

mL, 5.0 mmol) in water (0.44 mL, 24 mmol) was stirred at a bath temperature of 90°C

for 1.5 hours. Chromatography (CH2Cl2/hexane 20:80 to remove diphenyldiselenide

then a gradient of Et2O/hexane 5:95 to 50:50) gave a fraction that was predominantly

trans-4-methyl-2-phenyl-5-propyl-4,5-dihydro-1,3-oxazole (2.37) as a yellow oil (56

mg, 6%). max (neat) 3062, 3032, 2960, 2929, 2872, 1720, 1649, 1603, 1579, 1533,

1495, 1450, 1375, 1340, 1319, 1296, 1273, 1244, 1113, 1082, 1065, 1053, 1026,

877, 781, 696 cm-1. 1H NMR: 7.95-7.92, m, 2H, ArH; 7.49-7.37, m, 3H, ArH; 4.39,

qn, J 6.3 Hz, 1H, CHO; 3.77, q, J 6.3 Hz, 1H, CHN; 1.73-1.66, m, 2H; 1.58-1.39, m,

5H; 1.41, d, J 6.3 Hz, 3H, CH(O)CH3; 0.98, t, J 7.2 Hz, 3H, CH2CH3. 13C NMR:

162.40, C=N; 130.96, 128.23, 128.12, 128.08, all Ar; 81.14, CHO; 73.36, CHN;

37.78, 20.92, 18.87, 14.01. MS: m/z 203 (M+), 160 (M+-C3H7), 130 (M+-CH3CHO-

C2H5), 105 (C6H5CO+), 77 (C6H5+), 44 (CH3CHO+). Further elution gave a fraction

(A) containing a mixture of the two oxazoline isomers (2.36) and (2.37) and the title

compounds (2.34) and (2.35) followed by a fraction (B) containing a mixture of the

Experimental 7.2

142

title compounds and the oxazoline (2.36). Fraction (A) was further chromatographed

(EtOH/CH2Cl2 1:99) to give a mixture of the title compounds as a yellow oil (76 mg,

4%). max (Nujol) 3371, 1637 cm-1. 2-(Phenylselanyl)-3-hexyl benzamide (2.34) 1H

NMR: 7.60-7.57, m, 2H, ArH; 7.55-7.52, m, 2H, ArH; 7.48-7.45, m, 1H, ArH; 7.41-

7.35, m, 2H, ArH; 7.22-7.17, m, 3H, ArH; 6.23, d, J 9.3 Hz, 1H, NH; 4.33, ddt, J 3.6,

9.3, 9.9 Hz, 1H, CHN; 3.65, dq, J 3.6, 7.2, Hz, 1H, CHSe; 1.75-1.36, m, 4H; 1.57, d, J

7.2 Hz, 3H, CHCH3; 0.95, t, J 7.2 Hz, 3H, CH2CH3. 13C NMR: 166.94, C=O; 134.54,

134.13, 131.35, 129.52, 129.22, 128.47, 127.48, 126.80, all Ar; 53.88, CHN; 47.51,

CHSe; 33.24, 20.09, 19.52, 13.97. 3-(Phenylselanyl)-2-hexyl benzamide (2.35) 1H

NMR: 7.54-7.50, m, 2H, ArH; 7.48-7.41, m, 3H, ArH; 7.37-7.29, m, 2H, ArH; 7.19-

7.15, m, 3H, ArH; 6.48, d, J 8.7 Hz, 1H, NH; 4.47, ddq, J 3.3, 6.6, 8.7 Hz, 1H, CHN;

3.56, ddd, J 3.3, 6.9, 7.5 Hz, 1H, CHSe; 1.79-1.64, m, 2H; 1.63-1.46, m, 2H; 1.26, d,

J 6.6 Hz, 3H, CHCH3; 0.95, t, J 7.2 Hz, 3H, CH2CH3. 13C NMR: 166.25, C=O;

136.89, 133.55, 131.26, 129.76, 129.33, 128.37, 127.27, 126.75, all Ar; 54.97, CHSe;

48.66, CHN; 36.62, 21.44, 15.52, 13.78. Further elution gave a fraction which was

mainly the oxazoline (2.37) as a yellow oil (60 mg, 6%) followed by a fraction which

was mainly trans-5-methyl-2-phenyl-4-propyl-4,5-dihydro-1,3-oxazole (2.36) as a

yellow oil (40 mg, 4%). max (neat) 3060, 3032, 2960, 2931, 2872, 1720, 1643,

1603, 1579, 1537, 1493, 1450, 1375, 1342, 1321, 1302, 1269, 1176, 1157, 1113,

1078, 1063, 1026, 953, 928, 891, 837, 781, 741, 696 cm-1. 1H NMR: 7.95-7.93, m,

2H, ArH; 7.49-7.37, m, 3H, ArH; 4.19, dt, J 5.1, 7.2 Hz, 1H, CHO; 3.91, dq, J 6.9, 6.9

Hz, 1H, CHN; 1.95-1.44, m, 4H; 1.34, d, J 6.9 Hz, 3H, CH(N)CH3; 0.99, t, J 7.2 Hz,

3H, CH2CH3. 13C NMR: 162.64, C=N; 131.01, 128.27, 128.14, 128.08, all Ar;

86.62, CHO; 67.21, CHN; 36.95, 21.44, 18.45, 13.87. MS: m/z 203 (M+), 188 (M+–

CH3), 174 (M+-C2H5), 160 (M+-C3H7), 131 (M+-C3H7CHO), 104 (C6H5CNH+), 103

Experimental 7.2

143

(C6H5CN+), 77 (C6H5+). Chromatography (acetone/CH2Cl2 5:95) of fraction (B) gave

a mixture of the title compounds as a yellow oil (141 mg, 8%) followed by a fraction

which was mainly the oxazoline (2.36) as a yellow oil (93 mg, 9%).

N-Cyclohexylbenzamide (2.38)

To a stirred solution of cyclohexene (205 mg, 2.49 mmol) in benzonitrile (10 mL) was

added a solution of TfOH (0.22 mL, 2.5 mmol) in water (0.22 mL, 12 mmol) and the

mixture was stirred at a bath temperature of 120°C for 1 h. Saturated aqueous

NaHCO3 (10 mL) was added and the mixture was extracted with CHCl3. The

combined organic extracts were washed with saturated aqueous NaCl (10 mL), dried

(MgSO4), and the solvent removed under reduced pressure. Chromatography

(EtOAc/hexane 50:50) gave the title compound[296-297] as a white solid (280 mg,

55%), m.p. 154-156°C (lit.[297] m.p. 152–154°C). max (Nujol) 3330, 3236, 3074,

1639, 1562, 11331, 700 cm-1. 1H NMR(200 MHz): 7.78-7.73, m, 2H, ArH; 7.50-

7.38, m, 3H, ArH; 5.95, m, 1H, NH; 3.99, m, 1H, CHN; 2.07-2.00, m, 2H; 1.79-1.14,

m, 8H. 13C NMR: 166.58, C=O; 135.16, 131.19, 128.49, 126.78, all Ar; 48.65,

CHN; 33.25, 25.59, 24.89. MS: m/z 203 (M+), 122 (C6H5CONH3+), 105 (C6H5CO+),

77 (C6H5+).

N-Cyclopentylbenzamide (2.26)

To a solution of cyclopentene (207 mg, 3.04 mmol) in benzonitrile (10 mL) was added

a solution of TfOH (0.26 mL, 2.9 mmol) in water (0.26 mL, 14 mmol) and the mixture

was stirred at a bath temperature of 100°C for 2 h. Saturated aqueous NaHCO3 (10

mL) was added and the products extracted with CHCl3. The combined organic

extracts were washed with saturated aqueous NaCl (10 mL), dried (MgSO4), and the

Experimental 7.2

144

solvent removed under reduced pressure. Chromatography (EtOAc/hexane 50:50)

gave the title compound[154, 167] as a white solid (146 mg, 25%), m.p. 162-164°C

(lit.[167] m.p. 156-157°C). max (Nujol) 3290, 1628, 1545, 1315, 1184, 1076, 1028,

931, 890, 804, 696 cm-1

. 1H NMR: 7.77-7.32, m, 2H, ArH; 7.50-7.27, m, 3H, ArH;

6.26, br s, 1H, NH; 4.39, dqn, J 6.9, 6.9 Hz, 1H, CHN; 2.13-2.02, m, 2H; 1.76-1.57,

m, 4H; 1.55-1.43, m, 2H. 13C NMR: 167.12, C=O; 134.93, 131.12, 128.39, 126.79

all Ar; 51.64, 33.13, 23.77. MS: m/z 189 (M+), 122 (C6H5CONH3+), 105 (C6H5CO+),

77 (C6H5+).

Amidoselenation in non-nitrile solvents

(a) Reaction of cyclohexene

(i) in dimethyl acetamide

To a solution of phenylselenenyl chloride (284 mg, 1.48 mmol) and benzonitrile (770

mg, 7.47 mmol) in dimethyl acetamide (7 mL) was added cyclohexene (134 mg, 1.63

mmol) followed by TfOH (0.13 mL, 1.5 mmol) in water (0.13 mL, 7.2 mmol). The

mixture was stirred at a bath temperature of 90-95°C for 1 h, then cooled, diluted with

saturated aqueous NaHCO3 (10 mL), extracted with CHCl3 (2 x 30 mL), washed with

saturated aqueous NaCl (10 mL) and dried (NaSO4). Evaporation of the solvent at

reduced pressure and chromatography (CHCl3/hexane 15:85 to remove diphenyl

diselenide, then EtOAc/hexane 20:80) gave 2-(phenylseleno)cyclohexanol (2.41) as

a red oil (172 mg, 41%, data: page 136).

(ii) in toluene

To a solution of cyclohexene (97 mg, 1.2 mmol) and benzonitrile (513 mg, 4.97

mmol) in toluene (1 mL) was added phenylselenenyl chloride (228 mg, 1.19 mmol) in

toluene (5.5 mL) followed by TfOH (0.09 mL, 1 mmol) in water (0.09 mL, 5 mmol).

Experimental 7.2

145

The mixture was stirred at a bath temperature of 96-115°C for 80 min and then

allowed to cool to room temperature. Saturated aqueous NaHCO3 (10 mL) was

added and the products were extracted with CHCl3 (2 x 25 mL). The combined

organic extracts were washed with saturated aqueous NaCl (10 mL), dried (MgSO4),

and the solvent evaporated at reduced pressure. Chromatography of the residue

gave a fraction (70 mg) containing 2-(phenylselanyl)cyclohexyl benzamide (2.5) and

N-cyclohexylbenzamide[296-297] (2.38) in a ratio of 1:2.5. Simultaneous equations

translate these ratios into the approximate yields, respectively: 7% and 17%.

Further elution gave the cis-oxazoline (2.7, 37 mg, 15%, data: page 137).

(iii) in CHCl3 at reflux

A solution of phenylselenenyl chloride (280 mg, 1.46 mmol) in CHCl3 (4.5 mL)

followed by benzonitrile (0.75 mL, 7.3 mmol) were added to a solution of cyclohexene

(148 mL, 1.46 mmol) in CHCl3 (4 mL) at 0°C. The solution was warmed to r.t. and

stirred for 30 min. A solution of TfOH (0.13 mL, 1.5 mmol) in water (0.13 mL, 7.2

mmol) was added and the mixture was refluxed for 2h. Saturated aqueous NaHCO3

(15 mL) was added and the aqueous layer extracted with CHCl3 (3 x 20 mL). The

combined organic layers were washed with saturated aqueous NaCl (15 mL) and

dried (MgSO4) and the solvent removed at reduced pressure to give a brown oil.

Chromatography (CHCl3/hexane 15:85 then a gradient of EtOAc/hexane 5:95 to

50:50) gave 2-(phenylseleno)cyclohexanol (2.41) as a red oil (74 mg, 20%, data:

page 136). Further elution gave a fraction which was predominantly 2-

(phenylselanyl)cyclohexyl benzamide (2.5) as a pale brown oil (50 mg, 10%), data:

page 137).

Experimental 7.2

146

(iv) in CH2Cl2 at reflux

A solution of phenylselenenyl chloride (281 mg, 1.47 mmol) in CH2Cl2 (4.5 mL)

followed by benzonitrile (0.75 mL, 7.3 mmol) were added to a solution of cyclohexene

(0.148 mL, 1.46 mmol) in CH2Cl2 (4 mL) at 0°C. The solution was warmed to r.t. and

a solution of TfOH (0.13 mL, 1.5 mmol) in water (0.13 mL, 7.2 mmol) was added and

the mixture was refluxed for 2h. Saturated aqueous NaHCO3 (15 mL) was added

and the aqueous layer extracted with CHCl3 (3 x 15 mL). The combined organic

layers were washed with saturated aqueous NaCl (15 mL) and dried (MgSO4) and

the solvent removed at reduced pressure to give a yellow solid. Chromatography

(CHCl3/hexane 15:85 then a gradient of EtOAc/hexane 5:95 to 60:40) gave 2-

(phenylseleno)cyclohexanol (2.41) as a brown liquid (5 mg, 1%, data: page 136).

Further elution gave 2-(phenylselanyl)cyclohexyl benzamide (2.5) as a white solid

(349 mg, 67%, data: page 137).

(v) in CH2Cl2 at r.t.

Cyclohexene (0.034 mL, 0.34 mmol) was added to a solution of phenylselenenyl

chloride (70 mg, 0.37 mmol) in CH2Cl2 (1 mL). Benzonitrile (0.17 mL, 1.7 mmol) and

TfOH (0.05 mL, 0.57 mmol) in water (0.015 mL, 0.83 mmol) were added and the

mixture was stirred at r.t. for 24 h. After 24 h TLC analysis showed that the hydroxy

selenide had formed but that the amido selenide was still only a minor product and 1

drop TfOH was added. Stirring was continued for a further 3 d at which point TLC

analysis showed the main product to be the amido selenide. Saturated aqueous

NaHCO3 (10 mL) was added and the aqueous layer extracted with CH2Cl2 (2 x 20

mL). The combined organic layers were washed with saturated aqueous NaCl (10

mL) and dried (MgSO4) and the solvent removed at reduced pressure to give a

Experimental 7.2

147

yellow oil which 1H NMR analysis showed to be predominantly 2-

(phenylselanyl)cyclohexyl benzamide (2.5) (113 mg, 90%, data: page 137).

(b) Reaction of cyclopentene

(i) in CH2Cl2 at reflux

A solution of phenylselenenyl chloride (290 mg, 1.51 mmol) in CH2Cl2 (3 mL)

followed by benzonitrile (0.75 mL, 7.3 mmol) were added to a solution of

cyclopentene (0.13 mL, 1.5 mmol) in CH2Cl2 (5.5 mL) at 0°C. The solution was

warmed to r.t. and a solution of TfOH (0.13 mL, 1.5 mmol) in water (0.03 mL, 1.7

mmol) was added and the mixture was refluxed for 2h. Saturated aqueous NaHCO3

(15 mL) was added and the aqueous layer extracted with CHCl3 (3 x 20 mL). The

combined organic layers were washed with saturated aqueous NaCl (15 mL) and

dried (MgSO4), and the solvent removed at reduced pressure to give a yellow solid.

Chromatography (EtOAc/hexane 25:75 to 50:50) gave a fraction (65 mg) containing a

mixture of 2-(phenylselanyl)cyclopentyl benzamide (2.24) and N-cyclopentyl

benzamide (2.26) in a ratio of 2:1. Further elution gave N-cyclopentyl benzamide

(2.26) (90 mg, 32%, data: page 143).

(ii) in benzonitrile at r.t. then 55°C

Cyclopentene (0.09 mL, 1.0 mmol) and water (0.09 mL, 5.0 mmol) were added to a

solution of phenylselenenyl chloride (197 mg, 1.02 mmol) in benzonitrile (3 mL). The

solution was stirred at r.t. for 3 d. TLC analysis showed the formation of the hydroxy

selenide and further TfOH (0.09 mL, 1.02 mmol) was added and the mixture was

stirred a further 3 d. TLC analysis showed that the reaction had not gone to

completion and a further 3 drops TfOH were added and the mixture stirred for 5 h at

a bath temperature of 55°C. TLC analysis showed that the reaction was still not

complete and a further 3 drops TfOH was added and the mixture was stirred 7 h at

Experimental 7.2

148

bath temperature 55°C. The mixture was cooled and saturated aqueous NaHCO3

(10 mL) was added and the aqueous layer extracted with CH2Cl2 (3 x 15 mL). The

combined organic layers were dried (MgSO4) and the solvent removed at reduced

pressure to give a yellow solid. Chromatography (CHCl3/hexane 15:85 then a

gradient of EtOAc/hexane 5:95 to 30:70) gave 2-(phenylselanyl)cyclopentyl

benzamide (2.24) (192 mg, 55%, data: page 138).

Hydroxyselenation

Procedure 7.2C:[169] Phenylselenenyl chloride was added to a solution of the

alkene in acetonitrile followed by water and the solution was stirred at room

temperature for 48 h. Saturated aqueous NaHCO3 (15 mL) was added and the

products were extracted with CH2Cl2 (3 x 20 mL). The combined organic layers

were washed with saturated aqueous NaCl (15 mL) and dried (Na2SO4) and the

solvent removed under reduced pressure. The crude product was purified by

column chromatography (CHCl3/hexane 15:85 to remove diphenyl diselenide

followed by a gradient of EtOAc/hexane 5:95 to 50:50).

(a) trans-2-(Phenylseleno)cyclopentanol (2.42)

Following Procedure 7.2C, a mixture of cyclopentene (0.44 mL, 5.0 mmol),

phenylselenenyl chloride (960 mg, 5.01 mmol) and water (3 mL) in acetonitrile (15

mL) gave the title compound as a pale yellow oil (927 mg, 77 %). max (neat) 3377,

3070, 3057, 2958, 2870, 1579, 1477, 1437, 1336, 1302, 1196, 1120, 1093, 1070,

1034, 978, 843, 737, 692, 669 cm-1. 1H NMR: 7.59-7.55, m, 2H, ArH; 7.30-7.25, m,

3H, ArH; 4.15, dd, J 4.8, 11.3 Hz, 1H, CHO; 3.40, ddd, J 1.3, 5.7, 11.3 Hz, 1H, CHSe;

2.30-2.23, m, 1H; 2.10, br s, 1H, OH; 2.10-2.01, m, 1H; 1.86-1.56, m, 4H; 13C NMR:

134.09, 129.33, 129.02, 127.37, all Ar; 78.95, CHO; 49.70, JCSe 264 Hz, CHSe;

Experimental 7.2

149

32.83, 31.07, 22.00. 77Se NMR: 349.68; MS: m/z 242 (M+), 225 (M+-OH), 158

(C6H5SeH+), 85 (M+-C6H5Se), 77 (C6H5+), 67 (C5H7

+).

(b) trans-2-(Phenylseleno)cyclohexanol (2.41)

Following Procedure 7.2C, a mixture of cyclohexene (0.75 mL, 7.4 mmol),

phenylselenenyl chloride (1.42 g, 7.42 mmol) and water (5 mL) in acetonitrile (22 mL)

gave the title compound as a pale yellow oil (1.68 g, 89%, data: page 136)

(c) trans-2-(Phenylseleno)cycloheptanol (2.43)

Following Procedure 7.2C, a mixture of cycloheptene (0.93 mL, 8.0 mmol),

phenylselenenyl chloride (1.54 g, 8.04 mmol) and water (4.8 mL) in acetonitrile (24

mL) gave the title compound as a pale yellow oil (1.96 g, 91%). max (neat) 3433,

3070, 3055, 2926, 2858, 1577, 1477, 1456, 1437, 1385, 1265, 1211, 1072, 1022,

999, 739, 692, 671 cm-1. 1H NMR: 7.60-7.58, m, 2H, ArH; 7.33-7.25, m, 3H, ArH;

3.58, ddt, J 1.5, 3.6, 9.6 Hz, 1H, CHO; 3.10, dt, J 3.3, 9.6 Hz, 1H, CHSe; 2.82, br s,

1H, OH; 2.25-2.17, m, 1H; 2.04-1.95, m, 1H; 1.73-1.54, m, 5H; 1.52-1.37, m, 3H. 13C

NMR: 135.27, 135.21, 128.94, 127.82, all Ar; 74.97, CHO; 56.08, JCSe 239 Hz,

CHSe; 33.56, 32.51, 27.19, 26.48, 21.67. MS: m/z 270 (M+), 158 (C6H5SeH+), 113

(M+-C6H5Se), 95 (C7H11+), 78 (C6H6

+), 77 (C6H5+), 67 (C5H7

+), 55 (C4H7+).

(d) trans-2-(Phenylseleno)cyclooctanol (2.46)

Following Procedure 7.2C, a mixture of cyclooctene (0.977 mL, 7.52 mmol),

phenylselenenyl chloride (1.44 g, 7.52 mmol) and water (4.5 mL) in acetonitrile (23

mL) gave the title compound as a pale yellow oil (1.46 g, 69%). max(neat) 3454,

3070, 3055, 2924, 2854, 1577, 1475, 1464, 1439, 1387, 1354, 1329, 1302, 1271,

1228, 1113, 1072, 1041, 1022, 999, 968, 739, 692, 669 cm-1. 1H NMR: 7.61-7.58,

m, 2H, ArH; 7.33-7.27, m, 3H, ArH; 3.70, ddd, J 3.0, 5.7, 9.9 Hz, 1H, CHO; 3.32, ddd,

J 2.7, 8.7, 9.9 Hz, 1H, CHSe; 2.90, br s, 1H, OH; 2.30-2.22, m, 1H; 1.93-1.85, m, 2H;

Experimental 7.2

150

1.82-1.40, m, 9H. 13C NMR: 135.39, 135.33, 129.04, 127.91, all Ar; 73.67, CHO;

55.38, JCSe 236 Hz, CHSe; 31.95, 31.70, 26.78, 26.73, 25.32, 23.58. 77Se NMR:

368.22. MS: m/z 284 (M+), 158 (C6H5SeH+), 127 (M+-C6H5Se), 109 (C8H13+).

(e) R,S- and S,R-2-(Phenylseleno)-3-hexanol (2.53) and R,S- and S,R-3-(Phenylseleno)-2-hexanol (2.54) Following Procedure 7.2C, a mixture of trans-2-hexene (0.629 mL, 5.00 mmol),

phenylselenenyl chloride (993 mg, 5.18 mmol) and water (3 mL) in acetonitrile (15

mL) gave a mixture of the title compounds, the Markovnikov and anti-Markovnikov

hydroxy selenides (2.53) and (2.54), in a ratio of 55:45 as a yellow oil (1.214 g).

Chromatography (CH2Cl2/hexane 15:85 to remove diphenyldiselenide then a gradient

of EtOAc/hexane 5:95 to 25:75) gave a fraction containing the Markovnikov and anti-

Markovnikov isomers (2.53) and (2.54) in a ratio of 66:34 as a yellow oil (868 mg,

67%). Further elution gave a fraction containing (2.53) and (2.54) in a ratio of 17:83

as a colourless oil (227 mg, 18%). max (neat mixture of (2.53) and (2.54)) 3438

cm-1, br, OH str. MS (mixture of (2.53) and (2.54)): m/z 258 (M+), 213 (M+-C2H5O,

(2.54)), 186 (M+-C4H8O, (2.53)), 158 (C6H5SeH+), 101 (M+-C6H5Se), 78 (C6H6+), 77

(C6H5+), 55 (C4H7

+) 45 (C2H5O+), 43 (C3H7+). NMR data of compound (2.53): 1H

NMR: 7.60-7.54, m, 2H, ArH; 7.30-7.25, m, 3H, ArH; 3.62, ddd, J 3.0, 3.6, 8.7 Hz,

1H, CHO; 3.44, dq, J 3.0, 7.2 Hz, 1H, CHSe; 2.27, br s, 1H, OH; 1.74-1.59, m, 2H;

1.55-1.26, m, 2H; 1.39, d, J 7.2 Hz, 3H, CH(Se)CH3; 0.88, t, J 6.9 Hz, 3H, CH2CH3.

13C NMR: 134.64, 129.08, 127.66, 127.46, all Ar; 72.45, CHO; 47.40, JCSe 239 Hz,

CHSe; 35.76, 19.29, 14.90, 13.85. NMR data of compound (2.54): 1H NMR: 7.61-

7.55, m, 2H, ArH; 7.29-7.23, m, 3H, ArH; 3.85, dq, J 3.6, 6.3 Hz, 1H, CHO; 3.27, ddd,

J 3.6, 4.5, 9.3 Hz, 1H, CHSe; 2.48, br s, 1H, OH; 1.74-1.59, m, 2H; 1.55-1.26, m, 2H;

1.20, d, J 6.3 Hz, 3H, CH(O)CH3; 0.92, t, J 6.9 Hz, 3H, CH2CH3. 13C NMR: 134.26,

Experimental 7.2

151

129.52, 128.96, 127.31, all Ar; 68.84, CHO; 57.27, JCSe 252 Hz, CHSe; 33.21, 21.45,

19.72, 13.71.

(f) 1-(Phenylseleno)-2-octanol (2.48) and 2-(phenylseleno)-1-octanol (2.49)

Following Procedure 7.2C, a mixture of 1-octene (0.81 mL, 5.2 mmol),

phenylselenenyl chloride (1.00 g, 5.23 mmol) and water (3 mL) in acetonitrile (15 mL)

gave a mixture of the title compounds, the Markovnikov and anti-Markovnikov

hydroxy selenides (2.48) and (2.49), in a ratio of 85:15 as a yellow oil.

Chromatography (EtOAc/hexane 15:85) gave 1-(phenylseleno)-2-octanol (2.48) as a

yellow oil (291 mg, 51%). ESI HRMS: 269.07989 C14H22OSe-OH requires

269.08084. max (neat) 3402, 2954, 2927, 2856, 1579, 1477, 1466, 1437, 1072,

1022, 737, 690 cm-1. 1H NMR: 7.55-7.51, m, 2H, ArH; 7.28-7.24, m, 3H, ArH;

3.69-3.62, m, 1H, CHO; 3.15, dd, J 3.6, 12.6 Hz, 1H, CHaHbSe; 2.89, dd, J 8.7, 12.6

Hz, 1H, CHaHbSe; 2.43, br s, 1H, OH; 1.56-1.26, m, 10H; 0.87, t, J 6.8 Hz, 3H, CH3.

13C NMR: 132.91, 129.37, 129.12, 127.16, all Ar; 69.81, CHO; 37.16, CHSe; 36.53,

31.67, 29.17, 25.70, 22.51, 14.01. MS: m/z 286 (M+), 201 (M+-C6H13), 183 (M+-

C6H13-H2O), 172 (C6H5SeCH3+), 157 (C6H5Se+), 129 (M+-C6H5Se), 77 (C6H5

+), 69

(C5H9+), 55 (C4H7

+). Further elution gave a fraction containing both regioisomers,

(2.48) and (2.49), as a yellow oil (750 mg, 20%) followed by 2-(phenylseleno)-1-

octanol (2.49) as a yellow oil (6 mg, 0.4%). ESI HRMS: 269.07993 C14H22OSe-OH

requires 269.08084. 1H NMR: 7.51-7.45, m, 2H, ArH; 7.25-7.17, m, 3H, ArH; 3.56,

dd, J 5.1, 11.4 Hz, 1H, CHaHbO; 3.45, dd, J 6.6, 11.4, 1H, CHaHbO; 3.16, m, 1H,

CHSe; 1.90, br s, 1H, OH; 1.61-1.19, m, 10H; 0.81, t, J 6.9 Hz, 3H, CH3. 13C NMR:

135.43, 133.17, 129.08, 127.94, all Ar; 64.22, CHO; 50.63, CHSe; 31.66, 31.58,

28.99, 27.76, 22.58, 14.05. MS: m/z 286 (M+), 255 (M-CH2OH), 201 (M+-C6H13), 183

(M+-C6H13-H2O), 156 (C6H4Se+), 129 (M+-C6H5Se), 111 (C8H15+).

Experimental 7.2

152

Amidoselenation of -hydroxy selenides

Procedure 7.2D:[165] To a solution of the hydroxy selenide in CH2Cl2 was added the

nitrile followed by a solution of TfOH in water. The mixture was stirred for

approximately 48 h as specified, treated with saturated aqueous NaHCO3 (15 mL),

and the products were extracted with CH2Cl2 (3 x 20 mL). The combined organic

layers were washed with saturated aqueous NaCl (15 mL), dried (Na2SO4), and the

solvent removed under reduced pressure. Chromatography (CHCl3/hexane 15:85 to

remove diphenyl diselenide followed by a gradient of EtOAc/hexane 5:95 to 50:50)

gave the 2-amidoalkyl phenyl selenide.

(a) trans-2-(phenylselanyl)cyclopentyl benzamide (2.24)

Following Procedure 7.2D, but with a reaction time of 41 h, the reaction of trans-2-

(phenylseleno)cyclopentanol (2.42) (667 mg, 2.77 mmol), benzonitrile (2.0 mL, 20

mmol), TfOH (0.26 mL, 2.9 mmol) and water (0.2 mL, 10 mmol) in CH2Cl2 (2.6 mL)

gave the title compound as a white solid (726 mg, 76%, data: page 138).

(b) trans-2-(Phenylselanyl)cyclohexyl benzamide (2.5)

Following Procedure 7.2D, but with a reaction time of 22 h, the reaction of trans-2-

(phenylseleno)cyclohexanol (2.41) (4.12 g, 16.2 mmol), benzonitrile (13 mL, 130

mmol), TfOH (1.43 mL, 16.2 mmol) and water (0.29 mL, 16 mmol) in CH2Cl2 (11 mL)

gave the title compound as a white solid (5.382 g, 93%, data: page 137).

(c) trans-N-2-(Phenylselanyl)cycloheptyl benzamide (2.27)

Following Procedure 7.2D the reaction of trans-2-(phenylseleno)cycloheptanol (2.43)

(1.91 g, 7.09 mmol), benzonitrile (7.0 mL, 75 mmol), TfOH (0.63 mL, 7.1 mmol) and

water (0.13 mL, 7.2 mmol) in CH2Cl2 (5 mL) gave the title compound as a white solid

which, after chromatography, crystallised from the eluting solvent as colourless

crystals (1.498 g, 57%), m.p. 148-150.5°C. EI HRMS: 373.0947 C20H23NOSe

Experimental 7.2

153

requires 373.0947. max (Nujol) 3311, 1631, 1577, 1529, 1323, 1186, 737, 694 cm-1.

1H NMR: 7.71-7.68, m, 2H, ArH; 7.62-7.58, m, 3H, ArH; 7.56-7.38, m, 2H, ArH;

7.30-7.23, m, 3H, ArH; 6.29, br d, J 7.5 Hz, 1H, NH; 4.22, ddd, J 3.3, 7.5, 9.6 Hz, 1H,

CHN; 3.39, ddd, J 3.3, 8.4, 9.6 Hz, 1H, CHSe; 2.19-2.06, m, 2H; 1.94-1.46, m, 8H.

13C NMR: 166.45, C=O; 134.88, 134.73, 131.27, 129.30, 129.11, 128.46, 127.58,

126.86, all Ar; 56.05, CHN; 50.50, CHSe; 33.64, 33.08, 27.79, 26.35, 23.66. MS: m/z

371 (M+-H2), 251 (M-H-C6H5CONH2+), 216 (M-C6H5Se+), 158 (C6H5SeH+), 122

(C6H5CONH3+), 105 (C6H5CO+), 77 (C6H5

+)

(d) trans-N-2-(phenylselanyl)cyclooctyl benzamide (2.47)

To a solution of trans-2-(phenylseleno)cyclooctanol (2.46) (906 mg, 3.20 mmol) in

benzonitrile (4 mL, 40 mmol), cooled to 0°C, was added dropwise a solution of TfOH

(0.32 mL, 3.6 mmol) in water (0.064 mL, 3.6 mmol). The mixture was allowed to

warm to r.t. and stirred for 49 h followed by work-up according to Procedure 7.2D.

Evaporation of the CH2Cl2 under reduced pressure gave a yellow benzonitrile

solution from which crystallised a white solid which was collected, washed with cold

Et2O and recrystallised from acetonitrile to give the title compound as white needles

(293 mg, 24%), m.p. 133-136°C. The remaining benzonitrile was distilled from the

mother liquor at low pressure and the residue chromatographed (a gradient of

EtOAc/hexane 12:88 to 50:50) to give the title compound which crystallised from the

eluting solvent as white needles (258 mg, 21%). EI HRMS: 387.1099 C21H25NOSe

requires 387.1102. max (Nujol) 3327, 1631, 1577, 1531, 1323, 1232, 1161, 1078,

741, 719, 694, 663, 606 cm-1. 1H NMR: 7.67-7.63, m, 2H, ArH; 7.55-7.36, m, 5H,

ArH; 7.26-7.21, m, 3H, ArH; 6.26, d, J 7.2 Hz, 1H, NH; 4.33, ddt, J 3.0, 7.2, 10.8 Hz,

1H, CHN; 3.53, ddd, J 2.7, 7.2, 10.8 Hz, 1H, CHSe; 2.27- 2.22, m, 1H; 2.02-1.50, m,

13H. 13C NMR: 166.48, C=O; 134.78, 134.73, 131.22, 129.59, 129.15, 128.42,

Experimental 7.2

154

127.57, 126.86, all Ar; 55.00, CHN; 50.01, CHSe; 32.56, 31.17, 26.51, 26.22, 25.73,

25.21. MS: m/z 387 (M+), 266 (M+-C6H5CONH2), 230 (M+-C6H5Se), 157 (C6H5Se+),

122 (C6H5CONH3+), 109 (C8H13

+), 105 (C6H5CO+), 77 (C6H5+).

(e) trans-N-[2-(phenyselanyl)cyclohexyl]acetamide[145] (2.44)

To a solution of 2-(phenylseleno)cycloheptanol (2.43) (915 mg, 3.40 mmol) in CH3CN

(20 mL) was added a solution of TfOH (0.3 mL, 3 mmol) in water (0.06 mL, 3 mmol)

and the solution was stirred at r.t. for 50 h. The mixture was diluted with CH2Cl2 (30

mL) and worked up according to Procedure 7.2D to give a yellow solid (1.16 g).

Chromatography (gradient of EtOAc/hexane 25:75 to 100:0) gave the title compound

as a pale yellow solid (902 mg, 85%) which was recrystallised from ethyl acetate to

afford white crystals, m.p. 113.5-115°C (lit.[298] m.p. 107-108°C). EI HRMS:

311.0787 C15H21NOSe requires 311.0789. max (Nujol) 3298, 3070, 1635, 1539,

1315, 1184, 953, 742, 694, 604 cm-1. 1H NMR: 7.58-7.55, m, 2H, ArH; 7.30-7.26,

m, 3H, ArH; 5.68, d, J 7.2 Hz, 1H, NH; 4.06, ddt, J 3.6, 7.8, 9.3 Hz, 1H, CHN; 3.24,

ddd, J 3.3, 8.7, 9.3 Hz, 1H, CHSe; 2.12-2.04, m, 1H; 1.90, s, 3H, CH3; 1.97-1.43, m,

10H. 13C NMR: 169.30, C=O; 134.92, 129.85, 129.35, 127.82, all Ar; 55.87, CHN;

50.67, CHSe; 33.95, 32.94, 28.20, 26.70, 23.83, 23.70. MS: m/z 311 (M+), 252 (M+-

NHCOCH3-H), 157 (C6H5Se+), 154 (M+-C6H5Se), 112 (C7H14N+), 95 (C7H11+), 77

(C6H5+).

(f) trans-N-2-(phenylselanyl)cyclohexyl p-bromobenzamide (2.45)

Following Procedure 7.2D the reaction of trans-2-(phenylseleno)cyclohexanol (2.41)

(58 mg, 0.23 mmol), 4-bromobenzonitrile (123 mg, 0.676 mmol), TfOH (0.02 mL, 0.2

mmol) and water (0.01 mL, 0.6 mmol) ) in CH2Cl2 (1 mL) and chromatography

(CHCl3/hexane 15:85 then a gradient of EtOAc/hexane 5:95 to 100:0) gave 4-

bromobenzonitrile as a white solid (67 mg, 54% recovery) followed by the title

Experimental 7.2

155

compound as a white solid which, after chromatography, crystallised from the eluting

solvent as colourless crystals (86 mg, 87%), m.p. 154-157.5°C. max (Nujol) 3338,

1633, 1591, 1537, 1327, 1186, 1012, 839, 757, 742, 692 cm-1. 1H NMR: 7.55-7.47,

m, 4H, ArH; 7.29-7.21, m, 5H, ArH; 6.06, br d, J 7.2 Hz, 1H, NH; 3.95, dddd, J 3.6,

7.2, 10.5, 11.1 Hz, 1H, CHN; 3.14, dt, J 3.9, 11.1 Hz, CHSe; 2.36-2.32, m, 1H; 2.26-

2.22, m, 1H; 1.76-1.56, m, 3H; 1.49-1.19, m, 3H. 13C NMR: 165.70, C=O; 135.25,

135.52, 131.65, 129.17, 128.53, 128.07, 127.83, 125.95, all Ar; 54.27, 47.94, 34.08,

33.96, 26.81, 24.61. MS: m/z 438 (M+-H, 81Br), 436 (M+-H, 79Br), 282 (M+-C6H5Se,

81Br), 280 (M+-C6H5Se, 79Br), 238 (M+-BrC6H4CONH2), 202 (BrC6H4CONH3+, 81Br),

200 (BrC6H4CONH3+, 79Br), 185 (BrC6H4CO+, 81Br), 183 (BrC6H4CO+, 79Br), 157

(C6H5Se+), 104 (C6H4CO+), 81 (C6H9+).

(g) S,R- and R,S-2-(phenylselanyl)-3-hexyl benzamide (2.34) and S,R- and R,S-3-

(phenylselanyl)-2-hexyl benzamide (2.35)

To a solution of a 17:83 mixture of 2-(phenylseleno)-3-hexanol (2.53) and 3-

(phenylseleno)-2-hexanol (2.54) (226 mg, 0.879 mmol) in benzonitrile (3 mL) was

added a solution of TfOH (0.08 mL, 0.9 mmol) in water (0.02 mL, 1 mmol) and the

mixture was stirred at r.t. for 48 h. The mixture was diluted with CH2Cl2 and worked

up according to Procedure 7.2D to give a yellow oil (662 mg). Chromatography

(CH2Cl2/hexane 15:85 then a gradient of EtOAc/hexane 5:95 to 30:70) gave a 53:47

mixture of the title compounds as a pale yellow solid (306 mg, 97%). Further

chromatography (gradient of Et2O/hexane 10:90 to 50:50) gave fractions enriched in

one or other isomer. Solvent was evaporated slowly from the first amido selenide-

containing fraction, giving 2-benzamido-3-(phenylseleno)hexane (2.35) as colourless

plates, m.p. 76-78.5°C. ESI HRMS: 362.10136 C19H23NOSe+H requires 362.10176.

max: 3321, 2938, 1633, 1578, 1523, 1489, 1447, 1296, 1076, 1022, 800, 736, 719,

Experimental 7.2

156

690 cm-1. MS: m/z 361 (M+), 240 (M+-C6H5CONH2), 204 (M-C6H5Se+). The

structure of (2.35) was confirmed by an X-ray structure determination.[170]

(h) 1-(phenylselanyl)-2-octyl benzamide (2.32) and 2-(phenylselanyl)-1-octyl benzamide (2.33) To a solution of a mixture of 1-(phenylseleno)-2-octanol (2.48) and 2-(phenylseleno)-

1-octanol (2.49) (801 mg, 2.80 mmol) in benzonitrile (3 mL) was added a solution of

TfOH (0.25 mL, 2.8 mmol) in water (0.05 mL, 3 mmol) and the solution was stirred at

r.t. for 48 h. The mixture was diluted with CH2Cl2 and worked up according to

Procedure 7.2D to give a yellow oil (1.377 g). Chromatography (CH2Cl2/hexane

15:85 then a gradient of EtOAc/hexane 5:95 to 30:70) gave a mixture of the title

compounds (2.32) and (2.33) in a ratio of 9:1 as pale pink solid (1.119 g, 103%).

Recrystallisation from dichloromethane/hexane afforded the title compound (2.32) as

a pale yellow solid (892 mg, 82%, data: page 140).

(i) N-[1-(phenylselanyl)-2-octyl] p-bromobenzamide (2.50) and N-[2-(phenylselanyl)-1-octyl] p-bromobenzamide (2.51) Following Procedure 7.2D the reaction of a mixture of 1-(phenylseleno)-2-octanol

(2.48) and 2-(phenylseleno)-1-octanol (2.49) (360 mg, 1.26 mmol), p-

bromobenzonitrile (734 mg, 4.03 mmol), TfOH (0.120 mL, 1.36 mmol) and water

(0.03 mL, 2 mmol) in dichloromethane (10 mL) and chromatography (gradient of

CH2Cl2/hexane 50:50 to 100:0) gave p-bromobenzonitrile as a colourless solid (589

mg, 80% recovery). Further elution gave a mixture of the title compounds (2.50) and

(2.51) and the oxazoline (2.52) (data: page 176) in a ratio of 2.5:0.1:0.25 as a yellow

solid (125 mg, 21%) followed by a fraction containing a mixture of the title

compounds (2.50) and (2.51) in a ratio of 2.5:1 as a yellow solid (178 mg, 30%)

which was recrystallised from EtOAc to give the title compound, N-[1-(phenylselanyl)-

2-octyl] p-bromobenzamide (2.50), as colourless needles, m.p. 103–105.5°C. ESI

Experimental 7.2

157

HRMS: 468.04291 C21H26NOSeBr+H requires 468.04358. max (Nujol) 3346, 2953,

1630, 1591, 1525, 1414, 1296, 1070, 1012, 843, 758, 735, 692 cm-1. 1H NMR:

7.55-7.47, m, 4H, ArH; 7.40-7.37, m, 2H, ArH; 7.23-7.19, m, 3H, ArH; 6.06, d, J 8.4

Hz, 1H, NH; 4.44-4.33, m, 1H, CHN; 3.29, dd, J 4.5, 13.2 Hz, CHaHbSe; 3.20, dd, J,

5.1, 13.2 Hz, CHaHbSe; 1.70-1.60, m, 4H; 1.30-1.24, m, 6H; 0.86, t, J 6.6 Hz, 3H,

CH3. 13C NMR: 165.86, C=O; 133.27, 132.62, 131.63, 129.96, 129.34, 128.42,

127.16, 125.99, all Ar; 49.68, 34.45, 33.66, 31.65, 29.03, 26.01, 22.54, 14.04. MS:

m/z 469 (M+, 81Br), 467 (M+, 79Br), 312 (M+-C6H5Se, 81Br), 310 (M+-C6H5Se, 79Br), 268

(M+-BrC6H4CONH2), 185 (BrC6H4CO+, 81Br), 183 (BrC6H4CO+, 79Br), 157 (C6H5Se+),

104 (C6H4CO+), 91 (C7H7+). N-[2-(phenylselanyl)-1-octyl] p-bromobenzamide (2.51)

was identified from the following 1H NMR signals in a spectrum of the mixture of

(2.50) and (2.51): 6.55, br s, 1H, NH; 3.83, ddd, J 3.6, 6.6, 13.5 Hz, 1H, CHaHbNH;

3.44, ddd, J 4.8, 8.4, 13.5 Hz, CHaHbNH; 3.41-3.35, m, 1H, CHSe.

Preparation of trans-3a,4,5,6,7,7a-hexahydro-2-phenylbenzoxazole (2.9)

Ethyl iminobenzoate hydrochloride (2.57)[172, 299]

Benzonitrile (7.5 ml, 73 mmol) and absolute ethanol (5.0 ml, 86 mmol) were placed in

a quick-fit test tube and the solution was cooled to 0°C. Hydrogen chloride was

bubbled through the solution for about 1.5 h. The reaction mixture was securely

stoppered and kept at 5°C. After 4 d the mixture was almost completely crystalline.

After a further 15 d the crystals were collected, washed once with dry ether, and the

residual solvent evaporated under reduced pressure over KOH to give the title

compound[299] (12.07 g, 89%) which was stored over KOH and not purified further.

1H NMR: 8.41-8.37, m, 2H, ArH; 7.75-7.68, m, 1H, ArH; 7.61-7.54, m, 2H, ArH;

4.94, q, J 6.6 Hz, 2H, CH2; 1.63, t, J 6.6 Hz, CH3.

Experimental 7.2

158

Ethyl iminobenzoate (2.55)[173]

Ethyl iminobenzoate hydrochloride (2.57, 10.011 g, 53.9 mmol) was added in

portions to a stirred mixture of aqueous KOH (42 ml, 2M, 84 mmol) and CH2Cl2 (105

ml) cooled externally with ice. The layers were separated and the organic layer was

washed with water (2 x 30 ml) and dried (MgSO4) and the solvent was evaporated

under reduced pressure. Kugelrohr distillation (b.p. 40°C/0.1mm, lit.[299] b.p. 56-

60°C/0.6mm) gave the title compound[299] (6.986 g, 87%) as a colourless oil. max

(neat): 3332, 3299, 3061, 2983, 2939, 2900, 1635, 1579, 1478, 1449, 1399, 1373,

1331, 1298, 1169, 1078, 1029, 1020, 999, 873, 828, 783, 696, 677 cm-1. 1H NMR:

7.76-7.74, m, 2H, ArH; 7.47-7.38, m, 3H, ArH; 4.33, q, J 7.2 Hz, 2H, CH2; 1.43, t, J

7.2 Hz, 3H, CH3. 13C NMR: 167.76, C=N; 132.97, 130.70, 128.35, 126.61, all Ar;

61.72, CH2; 14.15, CH3. MS: m/z 149 (M+), 122 (C6H5CONH3+), 121 (C6H5CONH2

+),

105 (C6H5CO+), 77 (C6H5+).

trans-3a,4,5,6,7,7a-Hexahydro-2-phenylbenzoxazole (2.9)[150]

d,l-trans-2-Aminocyclohexanol (683 mg, 4.50 mmol) was added to a solution of ethyl

iminobenzoate (2.55, 838 mg, 5.62 mmol) in dry ethylene dichloride (45 ml) and the

mixture was refluxed for 24 h. After cooling, the mixture was filtered to remove

suspended salt and the filtrate was concentrated under reduced pressure. Kugelrohr

distillation (130°C/15 mm) recovered ethyl iminobenzoate as a colourless liquid,

leaving a pale brown solid containing the oxazoline, imine and benzamide in a ratio of

35:40:25 together with small amounts of unidentified products. Chromatography

(Et2O/hexane 70:30) gave the oxazoline contaminated with imine as a white solid

(319mg, 35%). Further evaporation of imine under reduced pressure gave the trans-

oxazoline (2.9) as a white solid, m.p. 64-67°C. Recrystallisation from MeOH/Et2O

Experimental 7.2

159

gave the title compound as white crystals, m.p. 78-79.5°C [lit.[150] m.p. 73-77°C].

max (KBr) 2934, 2859, 1622, 1600, 1575, 1492, 1448, 1358, 1334, 1318, 1291, 1255,

1230, 1145, 1103, 1086, 1067, 1048, 1013, 927, 890, 870, 779, 697, 553 cm-1. 1H

NMR: 8.00-7.97, m, 2H, ArH; 7.51-7.38, m, 3H, ArH; 3.76, ddd, J 3.6, 11.7, 13.8

Hz, 1H, CHO; 3.25, ddd, J 3.3, 11.7, 13.8 Hz, 1H, CHN, 2.45-2.38, m, 2H; 1.97-1.84,

m, 2H; 1.78, ddd, J 4.2, 12.0, 24.0 Hz, 1H; 1.54, ddd, J 3.3, 12.0, 23.7 Hz, 1H; 1.43-

1.34, m, 2H. 13C NMR: 165.96, C=N; 131.36, 131.11, 128.29, 128.02, all Ar;

87.02, CHO; 71.49, CHN; 30.50, 29.65, 25.06, 24.34. MS: m/z 201 (M+), 172 (M+-

CHO), 158 (M+-CH2CO), 130 (M+-C3H7CO), 117 (M+-C5H8O), 105 (C6H5CO+), 104

(C6H5CNH+), 77 (C6H5+).

Experimental 7.3

160

7.3 WORK DESCRIBED IN CHAPTER 3

Oxidation of 2-amidoalkyl phenyl selenide with KOH as base

Procedure 7.3A: To a stirred solution of the selenide in i-PrOH was added powdered

KOH followed by m-CPBA and the suspension was stirred at r.t. for 1-2 h. Aqueous

Na2S2O3 (0.5 M, 15 mL) and saturated aqueous NaHCO3 (10 mL) were added and

the products were extracted with CHCl3 (2 x 25 mL). The combined organic extracts

were dried (MgSO4) and the solvent evaporated at reduced pressure.

(a) Reaction of trans-2-(phenylselanyl)cyclohexyl benzamide (2.5)

(i) with 4 equivalents of potassium hydroxide

Following Procedure 7.3A, the reaction of the amido selenide (2.5, 100 mg, 0.280

mmol) with KOH (63 mg, 1.1 mmol) and m-CPBA (194 mg, 0.899 mmol) in i-PrOH

(20 mL) followed by chromatography (EtOAc/hexane 25:75 to 80:20) gave the

aziridine[154] (2.17, trace, data: page 135). Further elution gave the amido selenide

(2.5) as a colourless oil (13 mg, 13%). Further elution gave the cis-oxazoline[149]

(2.7, data: page 137) as a pale yellow gum (28 mg, 50%).

(ii) with 10.8 equivalents of potassium hydroxide

Following Procedure 7.3A, the reaction of the amido selenide (2.5, 60 mg, 0.17

mmol) with KOH (102 mg, 1.81 mmol) and m-CPBA (147 mg, 0.681 mmol) in i-PrOH

(11 ml) gave a semi-solid (31 mg, 93%), being a mixture of the aziridine[154] (2.17,

data: page 135) and the cis-oxazoline[149] (2.7, data: page 137) in a ratio of 95:5.

(iii) with 13.5 equivalents of potassium hydroxide

Following Procedure 7.3A, the reaction of the amido selenide (2.5, 60 mg, 0.17

mmol) with potassium hydroxide (129 mg, 2.30 mmol) and m-CPBA (144 mg, 0.668

mmol) in i-PrOH (11 mL) gave a mixture (23 mg, 68%) of the aziridine[154] (2.17,

data: page 135) and the cis-oxazoline[149] (2.7, data: page 137) in a ratio of 95:5.

Experimental 7.3

161

(b) Reaction of trans-2-(phenylselanyl)cyclopentyl benzamide (2.24)

(i) with 4 equivalents of potassium hydroxide

Following Procedure 7.3A, the reaction of the amido selenide (2.24, 81 mg, 0.23

mmol) with KOH (52 mg, 0.93 mmol) and m-CPBA (203 mg, 0.941 mmol) in i-PrOH

(15 mL) followed by chromatography (EtOAc/hexane 25:75 to 50:50) gave the

aziridine[154] (3.1,1 mg, 2%, data: page 166) as a brown oil. Further elution gave the

amido selenide (2.24, 10 mg, 13%, data: page 138) as a white solid, then the cis-

oxazoline (2.25, data: page 139) as a brown oil (23 mg, 52%).

(ii) with 7.5 equivalents of potassium hydroxide

Following Procedure 7.3A, the reaction of the amido selenide (2.24, 60 mg, 0.18

mmol) with KOH (74 mg, 1.3 mmol) and m-CPBA (151 mg, 0.700 mmol) in i-PrOH

(11 mL) gave a mixture of the aziridine[154] (3.1, data: page 166) and the cis-

oxazoline (2.25) in a ratio of 25:75. Chromatography (EtOAc/hexane 45:55) gave

the aziridine[154] (3.1, 4 mg, 12%, data: page 166). Further elution gave the cis-

oxazoline (2.25, 10 mg, 31%, data: page 139).

(iii) with 10.5 equivalents of potassium hydroxide

Following Procedure 7.3A, the reaction of the amido selenide (2.24, 60 mg, 0.18

mmol) with KOH (106 mg, 1.88 mmol) and m-CPBA (151 mg, 0.700 mmol) in i-PrOH

(11 ml) gave a mixture (28 mg, 87%) of the aziridine[154] (3.1, data: page 166) and

the cis-oxazoline (2.25, data: page 139) in a ratio of 60:40.

(iv) with 13.4 equivalents of potassium hydroxide

Following Procedure 7.3A, the reaction of the amido selenide (2.24, 60 mg, 0.18

mmol) with KOH (136 mg, 2.42 mmol) and m-CPBA (151 mg, 0.700 mmol) in i-PrOH

(11 mL) gave a mixture (31 mg, 96%) of the aziridine[154] (3.1, data: page 166) and

the cis-oxazoline (2.25, data: page 139) in a ratio of 45:55.

Experimental 7.3

162

(v) in ethanol with 11 equivalents of potassium hydroxide

Following Procedure 7.3A but with EtOH rather than i-PrOH as solvent, the reaction

of the amido selenide (2.24, 60 mg, 0.17 mmol) with KOH (103 mg, 1.84 mmol) and

m-CPBA (212 mg, 0.983 mmol) in EtOH (9.5 mL) gave a mixture (31 mg, 96%) of the

aziridine[154] (3.1, data: page 166) and the cis-oxazoline (2.25, data: page 139) in a

ratio of 30:70.

(c) Reaction of 1-(phenylselanyl)-2-octyl benzamide (2.32)

(i) with 0 equivalents of potassium hydroxide

Following Procedure 7.3A but with no KOH, the reaction of the amido selenide (2.32,

101 mg, 0.260 mmol) and m-CPBA (102 mg, 0.473 mmol) in i-PrOH (10 mL) followed

by chromatography (EtOAc/hexane 15:85 to 30:70) gave 4-(n-hexyl)-2-phenyl-4,5-

dihydro-oxazole (3.12) as a pale yellow oil (27 mg, 45%). ESI HRMS: 232.16936

C15H21NO+H requires 232.16959. max 2955, 2926, 2856, 1650, 1450, 1356, 1270,

1080, 1061, 1025, 970, 779 cm-1. 1H NMR: 7.96-7.93, m, 2H, ArH; 7.47-7.37, m,

3H, ArH; 4.48, dd, J 9.3, 8.1 Hz, 1H, CHHO; 4.27, m, 1H, CHN; 4.03, dd, J 8.1, 7.8

Hz, CHHO; 1.79-1.71, m, 1H; 1.57-1.29, m, 8H; 0.89, t, J 6.9 Hz, 3H, CH3. 13C

NMR: 163.29, C=N; 131.07, 128.27, 128.18, 127.97, all Ar; 72.52, CHO; 66.80,

CHN; 35.94, 31.69, 29.24, 25.82, 22.53, 13.97. MS: m/z 232 (M++H), 202 (M+-

C2H5), 188 (M+-C3H7), 174 (M+-C4H9), 161 (M+-C5H10), 146 (M+-C6H13), 122

(C6H5CONH2+), 105 (C6H5CO+), 91 (C7H7

+), 77 (C6H5+). Further elution gave the

selenide (2.32, trace, data: page 140)).

(ii) with 7.8 equivalents of potassium hydroxide

Following Procedure 7.3A, the reaction of the amido selenide (2.32, 120 mg, 0.310

mmol) with KOH (136 mg, 2.42 mmol) and m-CPBA (265 mg, 1.23 mmol) in i-PrOH

Experimental 7.3

163

(12 mL) gave a yellow oil whose 1H NMR spectrum showed to be a mixture with the

oxazoline (3.12, data: page 162) as the predominant product.

(d) Reaction of trans-2-(phenylselanyl)cyclohexyl acetamide (2.31)

Following Procedure 7.3A, the reaction of the acetamide (2.31, 100 mg, 0.338 mmol)

with KOH (38 mg, 0.67 mmol) and m-CPBA (234 mg, 1.08 mmol) in i-PrOH (10 mL)

followed by chromatography (EtOAc/hexane 60:40) gave 6-acetamidehexano-6-

lactone (3.5, 10 mg, 17%) as a pale yellow oil. 1H NMR: 5.33, dd, J 3.6, 6.3 Hz,

1H, CH(O)N; 2.65, m, 1H, CHaHbC(O)O; 2.55, m, 1H, CHaHbC(O)O; 2.09, s, CH3;

2.08-1.55, m, 6H. Further elution gave N-(1-isopropoxy-1-cyclopentyl)acetamide

(3.6) as a pale yellow oil (6 mg, 9%). 1H NMR: 5.71, d, J 8.4 Hz, 1H, NH; 5.06, dd,

J 8.4, 9.3 Hz, 1H, CH(O)N; 3.78, sept, J 6.3 Hz, 1H, CH(CH3)2; 2.01, s, 3H,

C(O)CH3; 2.07-1.96, m, 1H, CHCH(O)N; 1.81-1.67, m, 2H; 1.63-1.50, m, 4H; 1.48-

1.25, m, 2H; 1.15, d, J 6.3 Hz, 3H, CH(CH3)CH3; 1.12, d, J 6.3 Hz, 3H, CH(CH3)CH3.

(e) Reaction of 2-(phenylselanyl)cyclohexyl p-bromobenzamide (2.45)

Following Procedure 7.3A but stirring for 16 h at r.t., the reaction of the selenide

(2.45, 80 mg, 0.18 mmol) with KOH (87 mg, 1.6 mmol) and m-CPBA (159 mg, 0.737

mmol) in i-PrOH (10 mL) gave a yellow solid (64 mg) as a mixture of the cis-

oxazoline (3.4, data: page 170) and the aziridine (3.3, data: page 173) in a ratio of

60:40.

(f) Reaction of trans-N-2-(phenylselanyl)cycloheptyl benzamide (2.27)

(i) with 6 equivalents of potassium hydroxide

Following Procedure 7.3A, the reaction of the amido selenide (2.27, 149 mg, 0.400

mmol) with KOH (136 mg, 2.42 mmol) and m-CPBA (278 mg, 1.29 mmol) in i-PrOH

(14 mL) gave a yellow solid (98 mg) which 1H NMR analysis showed to be a mixture

Experimental 7.3

164

of the aziridine (3.2, data: page 168), the cis-oxazoline (2.28, data: page 140) and the

syn-elimination product (2.30, data: page 180) in a ratio of 10:50:40.

(ii) with 8 equivalents of potassium hydroxide

Following Procedure 7.3A, the reaction of the amido selenide (2.27) (100 mg, 0.269

mmol) with KOH (121 mg, 2.16 mmol) and m-CPBA (187 mg, 0.867 mmol) in i-PrOH

(15 mL) gave a yellow solid (92 mg) which 1H NMR analysis showed to be a mixture

of the aziridine (3.2, data: page 168) and the cis-oxazoline (2.28, data: page 140) in a

ratio of 15:85 along with a trace of the syn-elimination product (2.30, data: page 180).

(iii) with 10 equivalents of potassium hydroxide

Following Procedure 7.3A, the reaction of the amido selenide (2.27) (150 mg, 0.403

mmol) with KOH (224 mg, 3.99 mmol) and m-CPBA (278 mg, 1.29 mmol) in i-PrOH

(14 mL) gave a pale brown oil (66 mg, 76%) which 1H NMR analysis showed to be a

mixture of the aziridine (3.2, data: page 168) and the cis-oxazoline (2.28, data: page

140) in a ratio of 25:75.

(iv) with 8 equivalents of potassium hydroxide at 0°C

Following Procedure 7.3A but carrying out the reaction at 0°C, the reaction of the

amido selenide (2.27) (150 mg, 0.403 mmol) with KOH (181 mg, 3.22 mmol) and m-

CPBA (280 mg, 1.30 mmol) in i-PrOH (15 mL) gave a mixture of the aziridine (3.2,

data: page 168) and the cis-oxazoline (2.28, data: page 140) in a ratio of 15:85.

(v) with 9 equivalents of potassium hydroxide at 37°C

Following Procedure 7.3A but carrying out the reaction at 37°C, the reaction of the

amido selenide (2.27) (52 mg, 0.14 mmol) with KOH (71 mg, 1.3 mmol) and m-CPBA

(121 mg, 0.561 mmol) in i-PrOH (7.5 mL) gave a pale yellow oil (31 mg) which 1H

NMR analysis showed to be a mixture of the aziridine (3.2, data: page 168), the cis-

Experimental 7.3

165

oxazoline (2.28, data: page 140) and the syn-elimination product (2.30, data: page

180) in a ratio of 10:80:10.

Oxidation of 2-amidoalkyl phenyl selenide with NaH as base

Procedure 7.3B: NaH (60% suspension in oil) was added with stirring to dry i-PrOH

under a N2 atmosphere. To the resulting i-PrONa/i-PrOH mixture was added the

selenide and stirring was continued until the selenide had dissolved. A solution of

m-CPBA in i-PrOH was added and the resulting mixture was stirred a further 1.5-2h.

Aqueous Na2S2O3 (0.5 M, 15 mL) and saturated aqueous NaHCO3 (10 mL) were

added and the products were extracted with CHCl3 (2 x 25 mL). The combined

organic extracts were washed with saturated aqueous NaCl, dried (MgSO4) and the

solvent evaporated at reduced pressure.

(a) Reaction of trans-2-(phenylselanyl)cyclopentyl benzamide (2.24)

(i) with 2 equivalents of sodium hydride

Following Procedure 7.3B, the reaction of the amido selenide (2.24, 74 mg, 0.22

mmol) with NaH (18 mg, 60%, 0.45 mmol) and m-CPBA (186 mg, 0.862 mmol) in i-

PrOH (12 mL) gave a mixture (54 mg) of the aziridine[154] (3.1, data: page 166) and

the cis-oxazoline (2.25, data: page 139) in a ratio of 2:98.

(ii) with 4 equivalents of sodium hydride

Following Procedure 7.3B, the reaction of the amido selenide (2.24, 74 mg, 0.22

mmol) with NaH (35 mg, 60%, 0.88 mmol) and m-CPBA (185 mg, 0.858 mmol) in i-

PrOH (12 mL) gave a mixture (69 mg) of the aziridine[154] (3.1, data: page 166) and

the cis-oxazoline (2.25, data: page 139) in a ratio of 25:75.

Experimental 7.3

166

(iii) with 6 equivalents of sodium hydride

Following Procedure 7.3B, the reaction of the amido selenide (2.24, 71 mg, 0.21

mmol) with NaH (49 mg, 60%, 1.2 mmol) and m-CPBA (179 mg, 0.830 mmol) in i-

PrOH (12.5 mL) gave a mixture (63 mg) of the aziridine[154] (3.1, data: page 166) and

the cis-oxazoline (2.25, data: page 139) in a ratio of 40:60.

(iv) with 8 equivalents of sodium hydride

Following Procedure 7.3B, the reaction of the amido selenide (2.24, 71 mg, 0.21

mmol) with NaH (65 mg, 60%, 1.6 mmol) and m-CPBA (176 mg, 0.816 mmol) in i-

PrOH (12.5 mL) gave a mixture (66 mg) of the aziridine[154] (3.1, data: page 166) and

the cis-oxazoline (2.25, data: page 139) in a ratio of 55:45.

(v) with 10 equivalents of sodium hydride

Following Procedure 7.3B, the reaction of the amido selenide (2.24, 75 mg, 0.22

mmol) with NaH (88 mg, 60%, 2.2 mmol) and m-CPBA (186 mg, 0.862 mmol) in i-

PrOH (12.5 mL) gave a mixture (70 mg) of the aziridine[154] (3.1, data: page 166) and

the cis-oxazoline (2.25, data: page 139) in a ratio of 50:50.

(vi) with 8 equivalents of sodium hydride at 0°C

Following Procedure 7.3B but with the flask placed in ice, the reaction of the amido

selenide (2.24, 75 mg, 0.22 mmol) with NaH (70 mg, 60%, 1.7 mmol) and m-CPBA

(183 mg, 0.848 mmol) in i-PrOH (12 mL) gave a mixture (66 mg) of the aziridine[154]

(3.1) and the cis-oxazoline (2.25) in a ratio of 45:55 as estimated from integrations of

1H NMR signals. Chromatography (EtOAc/hexane 25:75) gave 6-benzoyl-6-

azabicyclo[3.1.0]hexane[154] (3.1) as a colourless oil (10 mg, 24%). max (KBr) 3035,

2966, 2956, 2924, 2850, 1664, 1643, 1595, 1577, 1450, 1433, 1414, 1390, 1348,

1319, 1288, 1221, 1107, 1076, 1012, 941, 808, 733, 694 cm-1. 1H NMR: 7.99-

7.95, m, 2H, ArH; 7.55-7.50, m, 1H, ArH; 7.46-7.40, m, 2H, ArH; 3.19, s, 2H, CHN;

Experimental 7.3

167

2.13, dd, J 12.6, 8.0 Hz, 2H; 1.71-1.62, m, 3H; 1.43-1.35, m, 1H. 13C NMR:

178.06, C=O; 133.76, 132.29, 128.78, 128.30, all Ar; 43.68, CHN; 27.01, 19.58 MS:

m/z 187 (M+), 105 (C6H5CO+), 77 (C6H5+), 55 (C4H7

+). Further elution gave the cis-

oxazoline (2.25, data: page 139) as a pale yellow oil (14 mg, 34%).

(b) Reaction of trans-2-(phenylselanyl)cyclohexyl benzamide (2.5)

(i) with 4 equivalents of sodium hydride

Following Procedure 7.3B, the reaction of the amido selenide (2.5, 100 mg, 0.279

mmol) with NaH (49 mg, 60%, 1.2 mmol) and m-CPBA (194 mg, 0.899 mmol) in i-

PrOH (16 mL) gave a mixture (76 mg) containing the aziridine[154] (2.17, data: page

135) and the cis-oxazoline[149] (2.7, data: page 137) in a ratio of 20:80.

(ii) with 6 equivalents of sodium hydride

Following Procedure 7.3B, reaction of the amido selenide (2.5, 100 mg, 0.279 mmol)

with NaH (72 mg, 60%, 1.8 mmol) and m-CPBA (193 mg, 0.895 mmol) in i-PrOH (15

mL) gave a mixture (36 mg) containing the aziridine[154] (2.17, data: page 135) and

the cis-oxazoline (2.7, data: page 137) in a ratio of 80:20.

(iii) with 10 equivalents of sodium hydride

Following Procedure 7.3B, the reaction of the amido selenide (2.5, 79 mg, 0.22

mmol) with NaH (88 mg, 60%, 2.2 mmol) and m-CPBA (204 mg, 0.946 mmol) in i-

PrOH (12 mL) gave a mixture (66 mg) of the aziridine[154] (2.17) in an approximate

ratio of 90:10 with other products including the amido selenide (2.5).

Chromatography (EtOAc/hexane 15:85) gave the aziridine[154] (2.17, data: page 135)

as a white solid (26 mg, 59%). Further elution gave a mixture (3.3 mg) containing

the amido selenide (2.5) and the cis-oxazoline (2.7, data: page 137) in a ratio of 15:1.

Experimental 7.3

168

(c) Reaction of trans-N-2-(phenylselanyl)cycloheptyl benzamide (2.27)

(i) with 6 equivalents of sodium hydride

Following Procedure 7.3B, the reaction of the amido selenide (2.27) (83 mg, 0.22

mmol) with NaH (54 mg, 60%, 1.4 mmol) and m-CPBA (180 mg, 0.834 mmol) in i-

PrOH (12.5 mL) gave a mixture (36 mg) containing the aziridine (3.2), the cis-

oxazoline (2.28) and the syn-elimination product (2.30) in a ratio of 70:25:5.

Chromatography (EtOAc/hexane gradient of 15:85 to 50:50) gave the 8-benzoyl-8-

azabicyclo[5.1.0]octane (3.2) as a pale yellow oil (16 mg, 35%). Crystallisation from

CH2Cl2/hexane gave white, star-like crystals, m.p. 104.5-106.5°C. ESI HRMS:

216.13884 C14H17NO+H requires 216.13829. max 3301, 2924, 1672, 1544, 1450,

1428, 1313, 1296, 1259, 1175, 1133, 1091, 1071, 1022, 740, 668 cm-1. 1H NMR:

7.98-7.95, m, 2H, ArH; 7.56-7.51, m, 1H, ArH; 7.47-7.42, m, 2H, ArH; 2.73-2.71, m,

2H, CHN; 2.12-1.93, m, 4H; 1.71-1.57, m, 5H; 1.30-1.26, m, 1H. 13C NMR:

179.99, C=O; 133.54, 132.32, 128.93, 128.27 all Ar; 41.83, CHN; 31.40, 29.05,

25.40. MS: m/z 215 (M+), 110 (M+-C6H5CO), 105 (C6H5CO+), 77 (C6H5+).

Further elution gave a mixture (8 mg, 17%) of the cis-oxazoline (2.28, data: page

140) and the syn-elimination product (2.30, data: page 180) in a ratio of 55:45.

(ii) with 8 equivalents of sodium hydride

Following Procedure 7.3B, the reaction of the amido selenide (2.27) (82 mg, 0.22

mmol) with NaH (72 mg, 60%, 1.8 mmol) and m-CPBA (185 mg, 0.858 mmol) in i-

PrOH (12.5 mL) gave a mixture (74 mg) containing the aziridine (3.2), the cis-

oxazoline (2.28) and the syn-elimination product (2.30) in a ratio of 75:15:10 as

estimated from integrations of 1H NMR signals. Chromatography (EtOAc/hexane

15:85) gave the aziridine (3.2, data: page 168) as a colourless oil (25 mg, 53%).

Experimental 7.3

169

Further elution gave a mixture (15 mg) containing the cis-oxazoline (2.28, data: page

140) and the syn-elimination product (2.30, data: page 180) in a ratio of 40:60.

(iii) with 10 equivalents of sodium hydride

Following Procedure 7.3B, the reaction of the amido selenide (2.27) (79 mg, 0.21

mmol) with NaH (88 mg, 60%, 2.2 mmol) and m-CPBA (187 mg, 0.867 mmol) in i-

PrOH (12 mL) gave a mixture (86 mg) containing the aziridine (3.2), the cis-oxazoline

(2.28), the syn-elimination product (2.30) and the amido selenide (2.27) in a ratio of

70:20:10:10 as estimated from integrations of 1H NMR signals. Chromatography

(CHCl3/hexane to remove diphenyl diselenide then EtOAc/hexane 5:95 to 25:75)

gave the aziridine (3.2, data: page 168) as a pale yellow oil (21 mg, 46%). Further

elution gave a mixture (13 mg) containing the cis-oxazoline (2.28, data: page 140)

the syn-elimination product (2.30, data: page 180) and the selenide (2.27, data: page

152) in a ratio of 45:35:20.

(d) Reaction of 1-(phenylselanyl)-2-octyl benzamide (2.32)

(i) with 8.6 equivalents of sodium hydride

Following Procedure 7.3B, the reaction of the amido selenide (2.32, 85 mg, 0.22

mmol) with NaH (75 mg, 60%, 1.9 mmol) and m-CPBA (186 mg, 0.862 mmol) in i-

PrOH (12 mL) gave a pale yellow oil (72 mg). Chromatography (EtOAc/hexane

15:85) gave the oxazoline (3.12, 44 mg, 87%, data: page 162) as a pale yellow oil.

(e) Reaction of 2-(phenylselanyl)cyclohexyl p-bromobenzamide (2.45)

(i) with 4 equivalents of sodium hydride

Following Procedure 7.3B, the reaction of the amido selenide (2.45, 94 mg, 0.22

mmol) with NaH (38 mg, 60%, 0.95 mmol) and m-CPBA (185 mg, 0.858 mmol) in i-

PrOH (12 mL) gave a pale yellow solid containing the aziridine (3.3) and cis-

oxazoline (3.4, data: page 170) in a ratio of 1:3 as estimated from integrations of 1H

Experimental 7.3

170

NMR signals. Chromatography (EtOAc/hexane gradient of 15:85 to 45:55) gave the

aziridine (3.3, data: page 173) as a white solid (12 mg, 20%). Further elution gave

cis-3a,4,5,6,7,7a-hexahydro-2-(4’-bromophenyl)benzoxazole (3.4) as a pale yellow

solid (40 mg, 67%). Recrystallisation from EtOAc/hexane gave white crystals, m.p.

46-47°C. ESI HRMS: 298.04329 C13H14NOBr+H3O requires 298.04426. max 2940,

1645, 1591, 1486, 1401, 1346, 1264, 1071, 1011, 979, 916, 832, 728, 673 cm-1. 1H

NMR: 7.85-7.80, m, 2H, ArH; 7.57-7.52, m, 2H, ArH; 4.69, dt, J 5.4, 8.1 Hz, 1H,

CHO; 4.12, dt, J 6.3, 8.1 Hz, 1H, CHN; 1.93-1.83, m, 2H; 1.64-1.51, m, 2H; 1.46-

1.37, m, 2H; 1.27-1.19, m, 2H. 13C NMR: 163.48, C=O; 131.53, 131.52, 129.62,

125.81, all Ar; 79.09, CHO; 63.62, CHN; 27.65, 26.20, 19.79, 19.06.

(ii) with 6 equivalents of sodium hydride

Following Procedure 7.3B, the reaction of the amido selenide (2.45, 82 mg, 0.19

mmol) with NaH (48 mg, 60%, 1.2 mmol) and m-CPBA (158 mg, 0.732 mmol) in i-

PrOH (12.5 mL) gave the aziridine (3.3) in a clean reaction. Chromatography

(CHCl3/hexane 15:85 to remove diphenyl diselenide then EtOAc/hexane 15:85 to

25:75) gave the aziridine (3.3, data: page 173) as a colourless solid (37 mg, 70%).

Oxidation of 2-amidoalkyl phenyl selenide with t-BuOK as base

Procedure 7.3C: To dry i-PrOH under a N2 atmosphere was added with stirring t-

BuOK and stirring was continued until the salt had dissolved. The selenide was

added and the mixture was stirred until the solid had dissolved. m-CPBA was added

and the resulting mixture was stirred a further 1.5 h. Aqueous Na2S2O3 (0.5 M, 15

mL) and saturated aqueous NaHCO3 (10 mL) were added and the products were

extracted with CHCl3 (3 x 20 mL). The combined organic extracts were washed with

saturated aqueous NaCl (10 mL), dried (MgSO4) and the solvent was evaporated at

reduced pressure.

Experimental 7.3

171

(a) Reaction of trans-2-(phenylselanyl)cyclopentyl benzamide (2.24)

Following Procedure 7.3C, the reaction of the amido selenide (2.24, 78 mg, 0.23

mmol) with t-BuOK (204 mg, 1.82 mmol) and m-CPBA (195 mg, 0.904 mmol) in i-

PrOH (12 mL) gave a mixture of the aziridine (3.1) and the cis-oxazoline (2.25) in a

ratio of 51:49. Chromatography (EtOAc/hexane 25:75) gave the aziridine[154] (3.1,

data: page 166) as a pale yellow oil (18 mg, 42%). Further elution gave the cis-

oxazoline (2.25, data: page 139) as a pale yellow oil (15 mg, 35%).

(b) Reaction of trans-2-(phenylselanyl)cyclohexyl benzamide (2.5)

Following Procedure 7.3C, the reaction of the amido selenide (2.5, 80 mg, 0.22

mmol) with t-BuOK (199 mg, 1.8 mmol) and m-CPBA (199 mg, 0.923 mmol) in i-

PrOH (12 mL) gave a colourless oil (49 mg) whose 1H NMR spectrum showed it to

contain the aziridine[154] (2.17) along with traces of other products. Chromatography

(EtOAc/hexane 20:80 to 45:55) gave the aziridine[154] (2.17, data: page 135) as a

pale yellow solid (38 mg, 85%).

Oxidation of trans-2-(phenylselanyl)cyclopentyl benzamide (2.24) with t-BuOK

as base at –6°C

The amido selenide (2.24, 76 mg, 0.22 mmol) was dissolved in THF (15 mL) and the

solution was cooled in an ice-salt bath at –6°C. A solution of m-CPBA (152 mg,

80%, 0.705 mmol) in THF (10 mL) was added dropwise to the cooled solution. The

mixture was stirred for 20 min by which time the bath temperature had risen to –3°C.

t-BuOK (148 mg, 1.32 mmol) was added and the resulting suspension was stirred 2 h

by which time the bath temperature was 15°C. Aqueous Na2S2O3 (0.5 M, 15 mL)

and saturated aqueous NaHCO3 (20 mL) were added and the products were

extracted with CH2Cl2 (2 x 25 mL). The combined organic extracts were washed with

Experimental 7.3

172

saturated aqueous NaCl (10 mL), dried (MgSO4) and the solvent evaporated at

reduced pressure to give a yellow oil (44 mg). Chromatography (EtOAc/hexane

20:80 to 30:70) gave the aziridine[154] (3.1, data: page 166) as a pale yellow oil (30

mg, 73%). Further elution gave a mixture (2 mg) of the cis-oxazoline (2.25, data:

page 139) and syn-elimination product[154] (3.13, data: page 178) in a ratio of 55:45

as a pale yellow oil.

Oxidation and cyclisation of 2-amidoalkyl phenyl selenide at low temperature

Procedure 7.3E: The selenide was dissolved in dry THF (20 mL) and the flask was

placed in a dry ice/acetone bath cooled to a bath temperature of between -60°C and

-70°C. A solution of m-CPBA in dry THF (20 mL) was added dropwise to the cooled

solution and the mixture was stirred for 1h with the bath temperature below –60°C.

t-BuOK was added in one portion and the resulting mixture was stirred for a further

1h. The flask was removed from the cooling bath and allowed to warm over 0.5-1h.

Aqueous Na2S2O3 (0.5 M, 15 mL) and saturated aqueous NaHCO3 (10 mL) were

added and the aqueous phase was extracted with Et2O (30 mL). The organic extract

was washed with aqueous NaOH (10%, 10 mL) and saturated aqueous NaCl (10 mL)

and dried (MgSO4) and the solvent evaporated at reduced pressure.

(a) 7-Acetyl-7-azabicyclo[4.1.0]heptane (3.14)

Following Procedure 7.3E, the reaction of 2-(phenylselanyl)cyclohexyl acetamide

(2.31, 250 mg, 0.844 mmol), m-CPBA (594 mg, 2.75 mmol) and t-BuOK (571 mg,

5.09 mmol) gave a pale yellow oil (119 mg) containing the aziridine (3.14).

Chromatography (Et2O/CH2Cl2 gradient of 0:100 to 10:90) gave the title

compound[149] as a colourless oil (77 mg, 66%). max (KBr) 2934, 2857, 1657, 1553,

1449, 1413, 1373, 1303, 1248, 1221, 1075, 1043 cm-1. 1H NMR: 2.63-2.32, m, 2H,

Experimental 7.3

173

CHN; 2.11, s, 3H, CH3; 1.90, m, 2H; 1.85, m, 2H; 1.50-1.38, m, 2H; 1.32-1.23, m, 2H.

13C NMR: 183.66, C=O; 35.82, 23.77, 23.41, 19.81.

(b) 7-Benzoyl-7-azabicyclo[4.1.0]heptane (2.17)

Following Procedure 7.3E, the reaction of trans-2-(phenylselanyl)cyclohexyl

benzamide (2.5, 152 mg, 0.424 mmol) with m-CPBA (290 mg, 1.34 mmol) and t-

BuOK (284 mg, 75%, 1.90 mmol) gave a pale yellow liquid (88 mg) containing the

aziridine[154] (2.17, data: page 135). Chromatography (EtOAc/hexane 20:80)

afforded the title compound as a pale yellow solid (71 mg, 83%), which crystallised

from the eluting solvent to give white crystals, m.p. 79.5–80.5 °C (lit.[154] m.p. 77°C).

(c) 6-Benzoyl-6-azabicyclo[3.1.0]hexane (3.1)

Following Procedure 7.3E, the reaction of trans-2-(phenylselanyl)cyclopentyl

benzamide (2.24, 144 mg, 0.418 mmol) with m-CPBA (291 mg, 1.35 mmol) and t-

BuOK (282 mg, 75%, 1.88 mmol) gave a pale yellow oil (67 mg) containing the

aziridine[154] (3.1, data: page 166) and a trace of the cis-oxazoline (2.25, data: page

139). Chromatography (EtOAc/hexane 20:80) afforded the title compound as a

colourless oil (59 mg, 75%).

(d) 7-(4’-Bromobenzoyl)-7-azabicyclo[4.1.0]heptane (3.3)

Following Procedure 7.3E, the reaction of 2-(phenylselanyl)cyclohexyl p-

bromobenzamide (2.45, 95 mg, 0.22 mmol) with m-CPBA (151 mg, 0.700 mmol) and

t-BuOK (146 mg, 75%, 0.976 mmol) gave a pale yellow solid (82 mg) containing the

aziridine (3.3). Chromatography (CH2Cl2/hexane 15:85 to remove diphenyl

diselenide then EtOAc/hexane, gradient of 5:95 to 50:50) afforded the title compound

which crystallised from the eluting solvent as white crystals (57 mg, 94%), m.p. 110–

113°C. EI HRMS: 279.0247 C13H14NOBr requires 279.0259. max (KBr) 2947,

2933, 2860, 1662, 1587, 1568, 1481, 1441, 1412, 1396, 1371, 1344, 1304, 1252,

Experimental 7.3

174

1232, 1171, 1117, 1084, 1070, 1009, 849, 762 cm-1. 1H NMR: 7.87-7.82, m, 2H,

ArH; 7.61-7.57, m, 2H, ArH; 2.76-2.75, m, 2H, CHN; 2.10-2.00, m, 2H; 1.96-1.88, m,

2H; 1.59-1.50, m, 2H; 1.41-1.32, m, 2H. 13C NMR: 179.14, C=O; 132.53, 131.58,

130.51, 127.35, all Ar; 37.23, CHN; 23.81, 19.90. MS: m/z 281 (M+, 81Br), 279 (M+,

79Br), 278 (M+-1, 79Br), 200 (M+-Br), 185 (BrC6H4CO+, 81Br), 183 (BrC6H4CO+, 79Br),

157 (BrC6H4+, 81Br), 155 (BrC6H4

+, 79Br), 96 (C6H10N+), 69 (C5H9+), 55 (C4H7

+), 41

(C3H5+).

(e) 8-Benzoyl-8-azabicyclo[5.1.0]octane (3.2)

Following Procedure 7.3E, the reaction of trans-2-benzamidocycloheptyl phenyl

amido selenide (2.27) (81 mg, 0.22 mmol) with m-CPBA (156 mg, 0.723 mmol) and t-

BuOK (148 mg, 75%, 0.989 mmol) gave a pale yellow oil (38 mg) containing the

aziridine (3.2) and traces of other products. Chromatography (EtOAc/hexane 20:80)

afforded the title compound as a pale yellow solid (38 mg, 81%, data: page 168).

(f) 9-Benzoyl-9-azabicyclo[6.1.0]nonane (3.16)

Following Procedure 7.3E, the reaction of trans-2-(phenylselanyl)cyclooctyl

benzamide (2.47, 85 mg, 0.22 mmol) with m-CPBA (154 mg, 0.714 mmol) and t-

BuOK (149 mg, 75%, 0.998 mmol) gave a pale yellow solid (49 mg) containing the

aziridine (3.16) and traces of other products. Chromatography (EtOAc/hexane

20:80) afforded the title compound as a pale yellow solid (44 mg, 87%).

Recrystallisation from Et2O/hexane gave white crystals, m.p. 52.5-54.5°C (lit.[154]

m.p. 72.5°C) 1H NMR: 8.00-7.96, m, 2H, ArH; 7.56-7.51, m, 1H, ArH; 7.47-7.41,

m, 2H, ArH; 2.54-2.50, m, 2H, CHN; 2.34-2.28, m, 2H; 1.71-1.43, m, 10H. 13C NMR:

179.71, C=N; 133.67, 132.35, 129.02, 128.23, all Ar; 41.50, CHN; 26.70, 26.39,

26.36. MS: m/z 229 (M+), 228 (M+-H), 201 (M+-C2H4), 124 (M+-C6H5CO), 105

(C6H5CO+), 97 (C7H13+), 77 (C6H5

+).

Experimental 7.3

175

(g) 8-Acetyl-8-azabicyclo[5.1.0]octane (3.15)

Following Procedure 7.3E, the reaction of trans-2-acetamidocycloheptyl phenyl

selenide (2.44, 101 mg, 0.325 mmol) with m-CPBA (229 mg, 1.06 mmol) and t-BuOK

(211 mg, 1.88 mmol) gave a yellow oil which was chromatographed (EtOAc/hexane,

gradient 15:85 to 30:70) to afford the title compound as a colourless oil (33 mg, 67%).

EI HRMS 153.1151 C9H15NO requires 153.1154. max (neat) 2925, 2851, 1694,

1455, 1442, 1365, 1299, 1245, 1224, 733 cm-1. 1H NMR: 2.62-2.60, m, 2H, CHN;

2.10, s, 3H, CH3; 2.01-1.83, m, 4H; 1.63-1.43, m, 4H; 1.25-1.19, m, 2H. 13C NMR:

183.83, C=O; 40.80, CHN; 31.25, CH3; 28.82, 25.19, 23.39. MS: m/z 153 (M+),

110 (M+-CH3CO), 96 (C7H12+).

(h) N-benzoyl-2-methyl-3-(n-propyl)aziridine (3.19)

Following Procedure 7.3E, the reaction of a mixture of 3-(phenylselanyl)-2-hexyl

benzamide (2.35) and 2-(phenylselanyl)-3-hexyl benzamide (2.34) (100 mg, 0.277

mmol) with m-CPBA (236 mg, 1.09 mmol) and t-BuOK (248 mg, 2.21 mmol) gave

yellow oil (54 mg) containing the aziridine (3.19) and oxazolines, (2.36) and (2.37), in

a ratio of 90:5:5. Chromatography (EtOH/CH2Cl2, gradient of 0.75:99.25 to 5:95)

afforded the title compound as a colourless oil (39 mg, 69%). ESI HRMS:

204.13862 C13H17NO+H requires 204.13829. max (neat) 3062, 3030, 2962, 2931,

2873, 1668, 1601, 1581, 1531, 1491, 1450, 1383, 1340, 1323, 1271, 1225, 1174,

1151, 1122, 1095, 1070, 1026, 725, 702 cm-1. 1H NMR: 8.02-7.99, m, 2H, ArH;

7.56-7.51, m, 1H, ArH; 7.47-7.41, m, 2H, ArH; 2.59, dq, J 3.3, 5.7 Hz, 1H, CH3CHN;

2.44, ddd, J 3.3, 5.1, 7.5 Hz, 1H, CH2CHN; 1.73-1.62, m, 1H; 1.53-1.40, m, 2H; 1.32-

1.23, m, 1H; 1.19, d, J 5.7 Hz, 3H, CHCH3; 0.95, t, J 7.2 Hz, 3H, CH2CH3. 13C NMR:

177.92, C=O; 134.59, 132.27, 128.82, 128.27, all Ar; 44.26, CH3CHN; 40.52,

CH2CHN; 33.48, 20.37, 16.63, 13.69. MS: m/z 203 (M+), 188 (M+-CH3), 174 (M+-

Experimental 7.3

176

CH2CH3), 160 (M+-(CH2)2CH3), 105 (PhCO+), 98 (M+-PhCO), 77 (C6H5+), 56 (C4H8

+).

Further elution gave a fraction containing the oxazoline (2.36, data: page 142) and

unidentified products as a colourless oil (6 mg, 10%). Further elution gave the

oxazoline (2.37, data: page 141) as a colourless oil (2 mg, 4%).

(i) N-(4’-Bromobenzoyl)-2-(n-hexyl)aziridine (3.18)

Following Procedure 7.3E, the reaction of N-[2-(phenylselanyl)-1-octyl] p-

bromobenzamide (2.50, 66 mg, 0.14 mmol) with m-CPBA (98 mg, 0.45 mmol) and t-

BuOK (97 mg, 75%, 0.65 mmol) gave a pale yellow liquid which was

chromatographed (hexane/CH2Cl2, gradient of 10:90 to 0:100) to afford the title

compound as a pale yellow oil (19 mg, 44%). ESI HRMS: 310.07956

C15H20NOBr+H requires 310.08010. max 2955, 2927, 2856, 1675, 1587, 1466,

1397, 1311, 1226, 1171, 1089, 1069, 1011, 848, 764 cm-1. 1H NMR: 7.91-7.87, m,

2H, ArH; 7.61-7.58, m, 2H, ArH; 2.56-2.53, m, 1H, CHN; 2.49, d, J 6.0 Hz, 1H,

CHHN; 2.19, d, J 3.6 Hz, CHHN; 1.86-1.78, m, 1H; 1.44-1.26, m, 9H; 0.89, t, J 6.6

Hz, 3H, CH3. 13C NMR: 178.37, C=O; 132.39, 131.65, 130.55, 127.55, all Ar;

38.80, 32.07, 31.67, 31.66, 28.90, 26.42, 22.49, 13.97. MS: m/z 309 (M+), 280 (M+-

C2H5), 239 (M+-C5H10), 224 (M+-C6H13), 183 (BrC6H4CO+), 155 (BrC6H4+), 126

(C8H16N+). Further elution afforded 4-(n-hexyl)-2-(4’-bromophenyl)-4,5-dihydro-

oxazole (2.52) as a pale yellow oil (12 mg, 28%). ESI HRMS: 310.07990

C15H20NOBr+H requires 310.08010. max 2952, 2922, 2853, 1721, 1638, 1592,

1484, 1463, 1398, 1366, 1318, 1291, 1274, 1263, 1077, 1056, 975, 835, 756, 729,

677 cm-1. 1H NMR: 7.84-7.79, m, 2H, ArH; 7.55-7.52, m, 2H, ArH; 4.48, dd, J 8.1,

9.3 Hz, 1H, CHHO; 4.31-4.21, m, 1H, CHN; 4.03, dd, J 7.8, 8.1 Hz, CHHO; 1.79-

1.71, m, 1H; 1.61-1.26, m, 9H; 0.89, t, J 6.9 Hz, CH3. 13C NMR: 162.57, C=N;

131.51, 129.75, 126.91, 125.79, all Ar; 72.74, CHO; 66.91, CHN; 35.88, 31.70, 29.23,

Experimental 7.3

177

25.83, 22.54, 14.00. MS: m/z 309 (M+), 280 (M+-CHO, M+-C2H5), 239 (M+-C5H10),

224 (M+-C6H13), 183 (BrC6H4CO+), 155 (BrC6H4+).

(j) N-benzoyl-2-(n-hexyl)aziridine (3.17)

Following Procedure 7.3E, the reaction of 1-(phenylselanyl)-2-octyl benzamide (2.32,

110 mg, 0.283 mmol) with m-CPBA (238 mg, 1.10 mmol) and t-BuOK (273 mg, 2.43

mmol) gave a pale yellow liquid (51 mg) being a mixture of the title compound and

the isomeric oxazoline in a ratio of 75:25, as estimated by 1H NMR signals.

Chromatography (hexane/CH2Cl2, gradient of 10:90 to 5:95) afforded the title

compound as a pale yellow oil (36 mg, 56%). EI HRMS: 231.1623 C15H21NO

requires 231.1624. max (KBr) 2956, 2929, 2856, 1678, 1601, 1581, 1466, 1450,

1406, 1317, 1300, 1230, 723, 710 cm-1. 1H NMR: 8.05-8.01, m, 2H, ArH; 7.58–

7.52, m, 1H, ArH; 7.48–7.42, m, 2H, ArH; 2.58–2.49, m, 1H, CHN; 2.50, d, J 6.0 Hz,

1H, CHHN; 2.19, d, 3.6 Hz, 1H, CHHN; 1.89–1.81, m, 1H; 1.48–1.29, m, 9H; 0.86, t,

J 6.9 Hz, 3H, CH3. 13C NMR: 179.31, C=O; 133.52, 132.52, 129.05, 128.32, all Ar;

38.63, 32.14, 31.69, 31.58, 28.94, 26.44, 22.51, 13.99. MS: m/z 232 (M++H), 216

(M+-CH3), 202 (M+-C2H5), 188 (M+-C3H7), 174 (M+-C4H9), 161 (M+-C5H10), 146 (M+-

C6H13), 126 (M+-C6H5 CO), 105 (C6H5CO+), 77 (C6H5+). Further elution afforded the

oxazoline (3.12, data: page 162) as a pale yellow oil (11mg, 17%).

Oxidation of trans-2-(phenylselanyl)cyclopentyl benzamide (2.24)

with 1.1 equivalents of m-CPBA

Following procedure 7.3E, the reaction of the amido selenide (2.24, 77 mg, 0.22

mmol) with m-CPBA (53 mg, 0.25 mmol) and t-BuOK (80 mg, 0.71 mmol) gave a

yellow oil (33 mg) as a mixture of the aziridine[154] (3.1), the amido selenide (2.24)

and the syn-elimination product (3.13) in a ratio of 15:30:55. Chromatography

Experimental 7.3

178

(CH2Cl2/hexane 15:85 to remove diphenyl diselenide then EtOAc/hexane gradient of

5:95 to 50:50) gave the aziridine[154] (3.1, data: page 166) as a yellow solid (trace).

Further elution gave the cis-oxazoline (2.25, data: page 139) as a pale yellow oil (2

mg, 4%). Further elution gave the amido selenide (2.24, 4 mg, 5%, data: page 138)

as a pale brown solid. Further elution gave N-(cyclopent-2-en-1-yl)benzamide[154]

(3.13) as a yellow solid (12 mg, 29%). Recrystallisation from CH2Cl2/hexane gave

pale yellow crystals, m.p. 121-123°C (lit.[154] m.p. 123°C). max 3293, 3059, 2926,

2852, 1627, 1603, 1578, 1534, 1491, 1454, 1338, 1285, 1263, 1057, 916, 806 cm-1.

1H NMR: 7.77-7.75, m, 2H, ArH; 7.51-7.37, m, 3H, ArH; 6.12, br s, 1H, NH; 6.00,

ddd, J 2.1, 3.9, 5.7 Hz, 1H, CHCHN; 5.77, ddd, J 2.1, 4.2, 5.7 Hz, 1H, CH2CH:CH;

5.24-5.14, m, 1H, CHN; 2.53-2.29, m, 2H; 1.79-1.63, m, 2H. 13C NMR(600MHz):

166.84, C=O; 135.13, CH2CH; 134.74, 131.35, both Ar; 131.05, CHNCH; 128.53,

126.86, both Ar; 56.10, CHN; 31.58, 31.23.

Oxidation of 2-(phenylselanyl)cycloheptyl benzamide (2.27)

with 1.1 equivalents of m-CPBA

Following procedure 7.3E, the reaction of the amido selenide (2.27) (82 mg, 0.22

mmol) with m-CPBA (50 mg, 0.23 mmol) and t-BuOK (73 mg, 0.65 mmol) gave a

yellow solid (52 mg) as a mixture of the starting material and syn-elimination product

(2.30) in a ratio of 80:20.

Oxidation of trans-N-2-(phenylselanyl)cycloheptyl benzamide (2.27) with excess m-CPBA at –15°C

The amido selenide (2.27) (81 mg, 0.22 mmol) was dissolved in THF (12.5 mL) and

the solution was cooled in an ice-salt bath to –15°C. A solution of m-CPBA (152 mg,

0.705 mmol) in THF (10 mL) was added dropwise to the cooled solution. The

Experimental 7.3

179

mixture was stirred for 1 h, the bath temperature being maintained between –15 and

–9°C. t-BuOK (149 mg, 1.33 mmol) was added and the resulting suspension was

stirred 1 h by which time the bath temperature was 7°C. Aqueous Na2S2O3 (0.5 M,

15 mL) and saturated aqueous NaHCO3 (15 mL) were added and the aqueous phase

extracted with Et2O (3 x 20 mL). The combined organic extracts were washed with

saturated aqueous NaHCO3 (4 x 10 mL) followed by saturated aqueous NaCl (15

mL), dried (MgSO4) and the solvent evaporated at reduced pressure to give a pale

yellow liquid (43 mg) estimated to be a mixture of the aziridine (3.2) and the syn-

elimination product (2.30) in a ratio of 75:25 from integrations of 1H NMR signals.

Chromatography (EtOAc/hexane 20:80 to 50:50) gave the aziridine (3.2, data: page

168) as a yellow oil (28 mg, 59%). Further elution gave the syn-elimination product

(2.30, data: page 180) as a pale yellow solid (9 mg, 19%).

Oxidation of trans-N-2-(phenylselanyl)cycloheptyl benzamide (2.27)

with excess m-CPBA at 0°C

The amido selenide (2.27) (83 mg, 0.22 mmol) was dissolved in THF (12.5 mL) and

the solution was cooled in an ice bath to 0°C. A solution of m-CPBA (155 mg, 0.719

mmol) in THF (10 mL) was added to the cooled solution. The mixture was stirred for

1 h, the bath temperature being maintained at 0°C. t-BuOK (150 mg, 1.33 mmol)

was added and the resulting suspension was stirred 1 h by which time the bath

temperature was 4°C. The flask was removed from the cooling bath and the mixture

was stirred a further 15 min. Aqueous Na2S2O3 (0.5 M, 15 mL) and saturated

aqueous NaHCO3 (15 mL) were added and the aqueous phase extracted with Et2O

(3 x 20 mL). The combined organic extracts were washed with saturated aqueous

NaHCO3 (4 x 10 mL) followed by saturated aqueous NaCl (15 mL), dried (MgSO4)

Experimental 7.3

180

and the solvent evaporated at reduced pressure to give a pale yellow solid (43 mg)

as a mixture of the aziridine (3.2) and the syn-elimination product (2.30) in a ratio of

1:9 as estimated from integrations of 1H NMR signals. Chromatography

(EtOAc/hexane 20:80 to 45:55) gave the aziridine (3.2, data: page 168) as a pale

yellow oil (3 mg, 6%). Further elution gave N-(cyclohept-2-en-1-yl)benzamide (2.30)

as a pale yellow solid (29 mg, 61%). Recrystallisation from CH2Cl2/hexane gave

white crystals, m.p. 122-124°C. EI HRMS: found 215.1309 C14H17NO requires

215.1311. max 3291, 2927, 1628, 1602, 1578, 1541, 1491, 1332, 1309, 1278, 1261,

719, 692, 680, 663 cm-1. 1H NMR: 7.79-7.75, m, 2H, ArH; 7.53-7.40, m, 3H, ArH;

6.23, m, 1H, NH; 5.88, dddd, J 2.1, 5.4, 6.6, 12.3 Hz, 1H, CH2CHCH; 5.64, ddd, J

2.1, 2.4, 12.3 Hz, 1H, CH2CHCH; 4.82, m, 1H, CHN; 2.24-2.17, m, 2H; 1.97-1.89, m,

2H; 1.83-1.62, m, 3H; 1.49-1.39, m, 1H. 13C NMR: 166.68, C=O; 135.18, 134.78,

132.90, 131.59, all Ar; 128.81, CH2CHCH; 127.11, CH2CHCH; 51.15, CHN; 34.24,

CH2CHCH; 28.84, 27.77, 27.10. MS: m/z 215 (M+), 122(C6H5CONH3+), 105

(C6H5CO+), 94 (C7H10+); 77 (C6H5

+).

Attempted isomerisation of aziridine (2.17) to cis-oxazoline (2.7)

(i) stirring with silica

The aziridine (2.17, 32 mg, 0.16 mmol) was stirred with silica in CH2Cl2 at r.t. for 24 h

at which time TLC analysis indicated no change in the reaction mixture. The mixture

was then refluxed for 30 min at which time TLC analysis again showed no new

product. The mixture was filtered and the solvent removed at reduced pressure to

give the aziridine[154] (2.17, data: page 135).

Experimental 7.3

181

(ii) with m-CPBA

The aziridine (2.17, 5 mg, 0.025 mmol) was stirred in EtOH (3 mL) at r.t. for 1.75 h

after which time no new product was observed by TLC analysis. m-CPBA (10.9 mg,

0.06 mmol) was added and the mixture stirred for a further 1.75 h. Aqueous

Na2S2O3 (0.5 M, 5 mL) and saturated aqueous NaHCO3 were added and the mixture

was extracted with CHCl3. The combined organic layers were dried (MgSO4) and the

solvent removed at reduced pressure. 1H NMR analysis of the product showed the

aziridine[154] (2.17, data: page 135) as the predominant product along with a small

amount of the cis-oxazoline (2.7, data: page 137) and other products in minor

amounts which were not identified.

Attempt to cyclise trans-2-(phenylselanyl)cyclohexyl benzamide (2.5) by

treatment with hydroxide

The amido selenide (2.5, 30 mg, 0.08 mmol) was stirred with KOH (47 mg, 0.8 mmol)

in i-PrOH (5.5 mL) at r.t. for 5 h. The mixture was acidified with dropwise addition of

HCl (0.1 M), then extracted with CHCl3 (2 x 20 mL). The combined organic layers

were dried (MgSO4) and the solvent removed at reduced pressure to give the amido

selenide (2.5, 24 mg, 80%).

Experimental 7.4

182

7.4 WORK DESCRIBED IN CHAPTER 4

Attempted acetamidoselenation of cyclohexene

Phenylselenenyl chloride (213 mg, 1.11 mmol) was added to a solution of

cyclohexene (95 L, 0.94 mmol) in dry acetonitrile (5 mL) and the mixture was cooled

to 0°C under N2. To the resulting yellow solution was added silver perchlorate (216

mg, 1.04 mmol), giving a white precipitate. The mixture was stirred at 0°C for 10 min

and to it was added aqueous KOH (0.5 mL) and stirring was continued for a further

10 min at 0°C. The mixture was diluted with Et2O (40 mL) and decanted. The Et2O

layer was washed with water (10 mL), dried (MgSO4) and the solvent evaporated at

reduced pressure to give a yellow oil (208 mg). Chromatography (CHCl3/hexane

15:85 then a gradient of EtOAc/hexane 5:95 to 60:40) gave 2-

(phenylseleno)cyclohexanol[169] (2.41) as a pale red oil (135 mg, 56%) which was

identified by comparison of its 1H NMR spectrum with that of (2.41) prepared

previously (see page 136).

N-[2-(Phenylselanyl)cyclohexyl]acetamide (2.31)

To a solution of cyclohexene (100 L, 0.987 mmol) in acetonitrile (4 mL) under N2

was added phenylselenenyl bromide (231 mg, 0.979 mmol) and the mixture was

cooled to 0°C. To it was added silver perchlorate (221 mg. 1.07 mmol) and the

mixture was stirred for 5 min. A solution of water (2 drops) in acetonitrile (2 mL) was

added over 50 min followed by a solution of water (3 drops) in acetonitrile (0.5 mL)

added over 15 min. The mixture was diluted with CH2Cl2 (40 mL) and the CH2Cl2

layer was decanted from the precipitated silver salts, washed with water (10 mL),

dried (MgSO4) and the solvent evaporated at reduced pressure. Chromatography

Experimental 7.4

183

(CHCl3/hexane 15:85 then a gradient of EtOAc/hexane 5:95 to 75:25)) gave 2-

(phenylseleno)cyclohexanol[169] (2.41) as a red oil (39 mg, 15%) which was identified

by comparison of its 1H NMR spectrum with that of (2.41) prepared previously (see

page 136). Further elution gave the title compound[145] as a white solid (166 mg,

57%) which was identified by comparison of its 1H NMR spectrum with that of (2.31)

prepared previously (see page 136).

trans-N-[2-(Phenylselanyl)cyclohexyl]benzamide (2.5)

To a solution of cyclohexene (100 L, 0.987 mmol) in benzonitrile (4 mL) under N2

was added phenylselenenyl bromide (262 mg, 1.11 mmol) and the mixture was

cooled to 5°C. To it was added silver perchlorate (228 mg, 1.10 mmol) and the

mixture was stirred for 10 min. Water (2 drops) was added dropwise and the mixture

was stirred for a further 50 min, then diluted with CHCl3 (35 mL). The mixture was

filtered to remove the precipitated silver salts and the organic layer was washed with

water (10 mL), dried (MgSO4) and the solvent evaporated at reduced pressure.

Chromatography (CHCl3/hexane 15:85 then a gradient of EtOAc/hexane 5:95 to

50:50) gave the title compound[145] as a pale pink solid (118 mg, 33%) which was

identified by comparison of its 1H NMR spectrum with that of (2.5) prepared

previously (see page 137).

5-Methyl-1-[trans-2-(phenylselanyl)cyclohexyl]-1H-tetrazole (4.12)

Cyclohexene (101 L, 0.997 mmol) was added to a solution of phenylselenenyl

bromide (238 mg, 1.01 mmol) in acetonitrile (4 mL) under N2 and the mixture was

cooled to 0°C, and to it was added silver perchlorate (209 mg, 1.01 mmol), giving a

white precipitate. To the suspension was added, with stirring, sodium azide (64 mg,

Experimental 7.4

184

0.98 mmol) over 20 min. The mixture was stirred at 0°C for 1.5 h, then diluted with

CH2Cl2 (40 mL), and decanted, leaving a residue of white silver salts. The CH2Cl2

layer was washed with water (7 mL) and dried (MgSO4) and the solvent evaporated

under reduced pressure to give a yellow oil (251 mg). Chromatography

(EtOAc/hexane 80:20) gave the title compound as a red oil (45 mg, 14%) which was

crystallised from CH2Cl2/Et2O as colourless crystals, m.p. 97-98°C. ESI HRMS:

323.07686 C14H18N4Se+H requires 323.07694. max (CHCl3) 3013, 2944, 2862,

1667 (C=N), 1524, 1477, 1450, 1438, 1404, 1226 (C-N), 1118, 1091, 1022, 794 cm-1.

1H NMR: 7.29-7.17, m, 5H, ArH; 4.16, dt, J 4.5, 11.4 Hz, 1H, CHN; 3.67, dt, J 4.2,

11.4 Hz, 1H, CHSe; 2.58, s, 3H, CH3; 2.48-2.43, m, 1H; 2.16-1.93, m, 2H; 1.86-1.82,

m, 1H; 1.74-1.60, m, 2H; 1.55-1.20, m, 2H. 13C NMR: 150.99, C=N; 135.30,

134.81, 129.03, 128.15, all Ar; 62.69, 47.55, 34.46, 34.01, 26.32, 24.86, 9.26. MS:

m/z 322 (M+), 238 (M+-CH3CN4H), 157 (C6H5Se+). Further elution gave a 2-

(phenylselanyl)cyclohexyl acetamide [145] (2.31) as a white solid (72 mg, 24%) which

was identified by comparison of its 1H NMR spectrum with that of (2.31) prepared

previously (see page 136). Further elution gave an orange-red solid which appeared

by 1H NMR to be a complex mixture and was not further purified.

5-Methyl-1,4-di[2-(phenylselanyl)cyclohexyl]-4H-1,2,3,4-tetraazol-1-ium

perchlorate (4.14)

Phenylselenenyl bromide (295 mg, 1.16 mmol) was added to a solution of

cyclohexene (118 L, 1.16 mmol) in acetonitrile (10 mL) under N2. After a few

minutes the mixture was still orange due to unreacted phenylselenenyl bromide, and

two more drops of cyclohexene were added. The mixture immediately became a

very pale orange and was cooled to 0°C, and to it was added silver perchlorate (241

Experimental 7.4

185

mg, 1.16 mmol), and the mixture was stirred for 10 min. Sodium azide (60 mg, 0.92

mmol) was added over 5 min and the resulting mixture was stirred for 80 min then

filtered through a bed of celite and the solvent was evaporated under reduced

pressure to give a viscous orange oil. The oil was dissolved in CHCl3 (30 mL) and

washed with water (10 mL) and saturated aqueous NaCl (10 mL) and the solvent was

evaporated under reduced pressure to give a viscous brown oil. Trituration with

Et2O/CH2Cl2 and recrystallisation from CH2Cl2/hexane gave the title compound as

pale brown crystals (34mg, 9%). This structure was confirmed by an X-ray structure

determination.[224] 1H NMR: 7.39-7.20, m, 10H, ArH; 4.53, dt, J 4.2, 11.7 Hz, 2H,

CHN; 3.55, dt, J 4.2, 11.7 Hz, 2H, CHSe; 3.12, s, 3H, CH3; 2.76-2.70, m, 2H; 2.43-

2.38, m, 2H; 2.18-1.98, m, 4H; 1.85-1.71, m, 4H; 1.57-1.41, m, 4H. 13C NMR:

151.50, C=N; 135.18, 129.47, 128.74, 126.27, all Ar; 65.77, CHN; 47.09, CHSe;

34.90, 32.88, 26.23, 24.46, 10.67. MS: m/z 322 (M+-C6H10SeC6H5); 238

(C6H9SeC6H5+).

trans-Ethyl[2-(phenylselanyl)cyclohexyl]carbamate (4.15)

Following a variation of the procedure of Francisco et al.,[57] to a mixture of ethyl

carbamate (4.75 g, 53.3 mmol), cyclohexene (0.138 mL, 1.36 mmol) and silver

perchlorate (334 mg, 1.61 mmol) in dry CH2Cl2 (45 mL) under N2 and protected from

light with aluminium foil, was added dropwise with stirring a solution of

phenylselenenyl chloride (290 mg, 1.51 mmol) in dry CH2Cl2 (10 mL) over

approximately 25 min. The resultant mixture was stirred 1 h at r.t., then poured into

10% KOH solution and filtered through a bed of celite. The aqueous layer was

extracted with Et2O (40 mL) and the combined organic layers washed with water (10

mL) and saturated aqueous NaCl (10 mL), dried (Na2SO4) and concentrated at

Experimental 7.4

186

reduced pressure to give a pale brown solid (4.3 g). The product was dissolved in

CH2Cl2 and absorbed onto silica (approximately 10 g) and the solvent evaporated.

Chromatography (EtOAc/hexane 25:75) gave the title compound as a pale pink solid

(365 mg, 82%) which was recrystallised from EtOAc to give colourless needles, m.p.

94.5-96.5°C. EI HRMS: 327.0738 C15H21NO2Se requires 327.0738. max(nujol)

3330, 3068, 3052, 1685, 1533, 1475, 1311, 1230, 1041 cm-1. 1H NMR: 7.61-7.57,

m, 2H, ArH; 7.32-7.24, m, 3H, ArH; 4.77, d, J 6.0Hz, 1H, NH; 4.12, q, J 7.2 Hz, 2H,

OCH2; 3.54-3.46, m, 1H, CHN; 3.01, ddd, J 3.9, 10.8, 10.8 Hz, 1H, CHSe; 2.21-2.07,

m, 2H; 1.69-1.48, m, 3H; 1.41-1.16, m, 3H; 1.25, t, J 7.2 Hz, 3H, CH3. 13C NMR:

155.86, C(=O)O; 135.63, 128.92, 128.00, 127.76, all Ar; 60.73, OCH2; 54.26, CHN;

48.40, CHSe; 33.99, 33.73, 26.36, 24.46; 14.62, CH3. MS: m/z 327 (M+), 281 (M+-

OC2H5), 238 (M+-NH2CO2Et), 170 (M+-C6H5Se), 81 (C6H9+). Further elution gave

ethyl carbamate as colourless crystals (3.64g, 77% recovery).

Experimental 7.5

187

7.5 WORK DESCRIBED IN CHAPTER 5

N-[2-(Phenylseleninyl)cyclohexyl]benzamide (5.1)

m-CPBA (127 mg, 0.59 mmol) was added to a solution of the amido selenide (2.5)

(199 mg, 0.555 mmol) in CH2Cl2 (10 mL) and the solution was stirred at r.t. for 70

min. The solution was diluted with CH2Cl2 (10 mL) and washed with aqueous NaOH

(10%, 3 x 15 mL) and saturated aqueous NaCl (10 mL), dried (MgSO4) and the

solvent was evaporated at reduced pressure to give the title compound as a white

solid (200 mg, 96%). Recrystallisation from MeOH/EtOAc gave the pure selenoxide

(5.1) as colourless needles, m.p. 137–138.5°C. An X-ray crystal determination

confirmed the crystals to be a mixture of R,R,SSe-(5.1) and its enantiomer S,S,RSe-

(5.1).[300] max (KBr): 3411, 3230, 3051, 2935, 2858, 1655, 1603, 1577, 1533, 1491,

1443, 1321, 1294, 814 (Se=O), 741, 698 cm-1. 1H NMR: 8.10, d, J 4.8 Hz, 1H,

NH; 7.95-7.91, m, 2H, ArH; 7.58-7.43, m, 8H, ArH; 3.60, dddd, J 4.2, 4.8, 10.8, 11.1

Hz, 1H, CHN; 3.39, ddd, J 3.6, 11.1, 12.3 Hz, 1H, CHSe; 2.45-2.40, m, 1H; 1.98-

1.93, m, 1H; 1.88-1.84, m, 1H; 1.75-1.25, m, 5H. 77Se NMR: (CDCl3/CD3OD, 2:3)

887.7; (THF/CD3OD, 2:3) 872.8, 843.7; diastereomeric mixture. Mass spectrum

m/z 375 (M+), 358 (M+-OH), 254 (M+-C6H5CONH2), 216 (M+-C4H8-H2), 200 (M+-

C6H5SeO–H2), 173 (C6H5SeO+), 157 (C6H5Se+), 122 (C6H5CONH2++H), 105

(C6H5CO+), 77 (C6H5+).

The NMR sample of R,R,SSe-(5.1) and S,S,RSe-(5.1) was allowed to stand for 24 h

after which time epimerisation at selenium had occurred to give a 1:1 mixture of

R,R,SSe-(5.1) and S,S,RSe-(5.1) and their diastereomers R,R,RSe-(5.1) and S,S,SSe-

(5.1). Data for the mixture of R,R,RSe-(5.1) and S,S,SSe-(5.1): 1H NMR: 8.85, d, J

8.1 Hz, 1H, NH; 8.00-7.88, m, 2H, ArH; 7.63-7.28, m, 8H, ArH; 4.04, dddd, J 3.9, 8.1,

Experimental 7.5

188

11,7, 12.3 Hz, 1H, CHN; 3.14, ddd, J 3.9, 10.8, 11.7 Hz, 1H, CHSe; 2.19-2.15, m, 1H;

1.92-1.87, m, 1H; 1.79-1.43, m, 3H; 1.32-0.85, m, 2H; 0.73-0.60, m, 1H.

N-[2-(Phenylselenonyl)cyclohexyl]benzamide (5.8)

m-CPBA (446 mg, 2.07 mmol) was added to a solution of the amido selenide (2.5)

(248 mg, 0.692 mmol) in dry THF (20 mL) and the solution was stirred under N2 at r.t.

for 2 h. At this time a white solid had precipitated from the mixture. This was

collected by Büchner filtration and washed with cold THF. Recrystallisation of a

sample from THF/hexane gave fine colourless needles (m.p. 99-101°C) which

noticeably coloured upon standing at r.t. ESI HRMS: 392.07610 C10H21NO3Se+H

requires 392.07594. max (KBr): 3462, 3057, 2937, 2858, 1657, 1637, 1603, 1579,

1541, 1491, 1444, 1321, 1292, 1066, 935 (as, O=Se=O), 879 (s, O=Se=O), 746,

700, 687, 671 cm-1. 1H NMR: 7.86-7.81, m, 4H, ArH; 7.64-7.59, m, 1H, ArH; 7.55-

7.49, m, 3H, ArH; 7.44-7.40, m, 2H, ArH; 7.31, d, J 6.6Hz, 1H, NH; 4.16, ddd, J 3.9,

11.4, 12.6 Hz, 1H, CHSe; 3.97, dddd, J 4.2, 6.6, 11.4, 11.4 Hz, 1H, CHN; 2.59-2.55,

m, 1H; 2.44-2.40, m, 1H; 1.96-1.72, m, 2H; 1.67-1.55, m, 2H; 1.45-1.34, m, 2H. ESI

MS: m/z 391.7 (MH+), 375.8 (MH+-O), 202.1 (M+-C6H5SeO2)

Cyclisation of 2-(phenylselenonyl)cyclohexyl benzamide (5.8)

The selenone (5.8) (14 mg, 0.036 mmol) was dissolved in dry THF (5 mL) containing

a few drops of CH2Cl2 to facilitate dissolution. The solution was immediately washed

with aqueous NaOH (30%, 15 mL), the layers were separated and the aqueous layer

was extracted with CH2Cl2 (2 x 10 mL). The combined organic layers were dried

(MgSO4) and the solvent evaporated at reduced pressure to give a pale brown oil

which 1H NMR analysis showed to be a mixture of the aziridine (2.17) and the

oxazoline (2.7) in a ratio of 7:3 (5 mg, 69%).

Experimental 7.5

189

Solution spectra of dilute solutions of (2.5), (5.1) and (5.8)

Solution spectra in CHCl3 were obtained from 4 scans over the range 4000 to 600

cm-1. The spectrum of the selenoxide (5.1) in CH2Cl2 was obtained from 20 scans

per spectrum in three spectra, over the ranges 4000 to 3000, 1700 to 1600 and 900

to 800 cm-1. The spectrum of the selenone (5.8) in CH2Cl2 was obtained from 20

scans per spectrum in three spectra, over the ranges 4000 to 3000, 1700 to 1600

and 1000 to 800 cm-1.

(i) N-[2-(Phenylselanyl)cyclohexyl]benzamide (2.5) (see also Experimental 7.2)

max (0.001M in CHCl3): 3433 (sh), 3013, 1655, 1516, 1486 cm-1. 1H NMR (0.005M

in CDCl3): 7.69-7.65, m, 2H, ArH; 7.57-7.54, m, 2H, ArH; 7.51-7.37, m, 4H, ArH;

7.31-7.22, m, 2H, ArH; 6.13, d, J 7.5 Hz, 1H, NH; 3.92, dddd, J 3.6, 7.5, 10.8, 10.8

Hz, 1H, CHN; 3.15, ddd, J 3.6, 10.8, 11.7 Hz, 1H, CHSe; 2.38-2.34, m, 1H; 2.24-

2.20, m, 1H; 1.76-1.64, m, 2H; 1.49-1.25, m, 4H.

(ii) N-[2-(Phenylseleninyl)cyclohexyl]benzamide (5.1)

max (0.001M in CHCl3): 3694 (sh), 1658, 1602, 1547, 1536, 1485, 1233, 1212, 814

(Se=O) cm-1. max (0.002M in CH2Cl2): 3431 (sh, NH), 3257 (br w, NH), 1661 (C=O),

826 (Se=O), 809 (Se=O) cm-1. max (nujol): 3223 (str, br), 2953, 2921, 1653, 1532,

1462, 1377, 1320, 1291, 814 (Se=O), 740, 699 cm-1. 1H NMR (0.005M in CDCl3):

8.07, d, J 4.8 Hz, 1H, NH; 7.94-7.91, m, 2H, ArH; 7.57-7.42, m, 8H, ArH; 3.57, dddd,

J 4.2, 4.8, 10.8, 11.1 Hz, 1H, CHN; 3.36, ddd, J 3.6, 11.1, 12.3 Hz, 1H, CHSe; 2.46-

2.42, m, 1H; 2.00-1.96, m, 1H; 1.95-1.84, m, 1H; 1.75-1.71, m, 1H; 1.62-1.27, m, 4H.

(iii) N-[2-(Phenylselenonyl)cyclohexyl]benzamide (5.8)

max (0.001M in CHCl3): 3690 (sh), 1656, 1602, 1276, 1116, 936 (as O=Se=O), 888,

868 (s O=Se=O) cm-1. max (0.002M in CH2Cl2): 3684 (sh, NH), 1666 (C=O), 935

(as O=Se=O), 880 (s O=Se=O) cm-1. 1H NMR (0.005M in CDCl3): 7.85-7.81, m,

Experimental 7.5

190

4H, ArH; 7.65-7.59, m, 1H, ArH; 7.57-7.49, m, 3H, ArH; 7.46-7.41, m, 2H, ArH; 7.19,

d, J 6.6 Hz, 1H, NH; 4.16, ddd, J 3.6, 10.8, 12.6 Hz, 1H, CHSe; 3.93, dddd, J 4.5,

6.6, 10.8, 10.8 Hz; 1H, CHN; 2.59-2.55, m, 1H; 2.48-2.44, m, 1H; 2.00-1.96, m, 1H;

1.77-1.52, m, 3H; 1.43-1.37, m, 2H.

7.5.2 NMR-Scale oxidation of 2-(phenylselanyl)cyclohexyl benzamide (2.5)

(i) 1H NMR in CD2Cl2

The amido selenide (2.5) (12 mg, 0.033 mmol) and m-CPBA (29 mg, 0.13 mmol)

were dissolved in CD2Cl2 (1.5 mL). 0.7 mL of this solution was transferred to an

NMR tube. Six 1H NMR spectra of 40 transients were recorded at 6 min intervals

followed by one spectrum recorded at 90 minutes’ reaction time. In the seven

spectra, the three compounds – selenoxide (5.1), selenone (5.8) and oxazolinium salt

(5.9) – were identified from their methine proton signals which appeared in the NMR

spectra as follows:

(a) N-[2-(Phenylseleninyl)cyclohexyl]benzamide, R,R,SSe-(5.1) and S,S,RSe-(5.1)

1H NMR: 3.99-3.89, m, 1H, CHN; 3.83-3.76, m, 1H, CHSe.

(b) N-[2-(Phenylseleninyl)cyclohexyl]benzamide, R,R,RSe-(5.1) and S,S,SSe-(5.1)

1H NMR: 4.22-4.10, m, 1H, CHN; 3.62-3.54, m, 1H, CHSe.

(c) N-[2-(Phenylselenonyl)cyclohexyl]benzamide (5.8)

1H NMR: 4.39, ddd, J 4.2, 11.4, 12.9 Hz, 1H, CHSe; 4.14, dddd, J 4.2, 7.2, 11.4,

11.4 Hz, 1H, CHN.

(d) cis-3a,4,5,6,7,7a-hexahydro-2-phenylbenzoxazole m-CBA salt (5.9)

1H NMR: 5.48, m,1H, CHO; 4.80, ddd, J 6.3, 6.6, 8.4 Hz, 1H, CHN.

Experimental 7.5

191

The proportion of each of the three products - (5.1), (5.8) and (5.9) – at each stage of

the reaction was calculated from the ratios of the integration of these methine signals

(Table 7.5.1).

TABLE 7.5.1

NMR-SCALE OXIDATION OF 2-(PHENYLSELANYL)CYCLOHEXYL BENZAMIDE (2.5) IN CD2CL2

spectrum reaction

time (min)

proportion of product (%) selenoxide

(5.1) selenone

(5.8) oxazolinium ion

(5.9)

1 6 91 9 0

2 12 58 29 11

3 18 47 36 17

4 24 37 39 25

5 30 30 37 33

6 36 26 33 41

7 90 0 0 100

After 90 minutes, the NMR sample was diluted with CH2Cl2 and washed with dilute

aqueous NaHCO3 followed by dilute aqueous NaOH. The organic layer was dried

(MgSO4) and the solvent evaporated at reduced pressure to give a colourless oil

which 1H NMR analysis showed to be a mixture with the oxazoline (2.7) as the main

product.

Experimental 7.5

192

(ii) 1H NMR in THF-d8

The amido selenide (2.5) (12 mg, 0.033 mmol) and m-CPBA (30 mg, 0.14 mmol)

were dissolved in CD2Cl2 ( ~0.3 mL) and THF-d8 (1 mL). 0.7 mL of this solution was

transferred to an transferred to an NMR tube. Eight 1H NMR spectra of 40 transients

were acquired at 6 min intervals, followed by one spectrum at 40 hours’ reaction time.

The three compounds – selenoxide (5.1), selenone (5.8) and oxazolinium salt (5.9) –

were identified from their methine proton signals which appeared in the NMR spectra

as follows:

(a) N-[2-(Phenylseleninyl)cyclohexyl]benzamide (5.1)

1H NMR: 4.06-3.93, m, 1H, CHN; 3.38-3.30, m, 1H, CHSe.

b) N-[2-(Phenylselenonyl)cyclohexyl]benzamide (5.8)

1H NMR: 4.19, ddd, J 3.9, 11.4, 12.9 Hz, 1H, CHSe; 4.05, dddd, J 4.1, 7.2, 11.4,

11.4 Hz, 1H, CHN.

(c) cis-3a,4,5,6,7,7a-hexahydro-2-phenylbenzoxazole m-CBA salt (5.9)

1H NMR: 5.41, ddd, J 4.5, 4.8, 8.4 Hz, 1H, CHO; 4.78, ddd, J 6.3, 6.6, 8.4 Hz, 1H,

CHN.

The proportion of each of the three products - (5.1), (5.8) and (5.9) – at each stage of

the reaction was calculated from the ratios of the integration of these methine signals

(Table 7.5.2).

Experimental 7.5

193

TABLE 7.5.2

NMR-SCALE OXIDATION OF 2-(PHENYLSELANYL)CYCLOHEXYL BENZAMIDE (2.5) IN d8-THF

spectrum reaction

time (min)

proportion of product (%) selenoxide

(5.1) selenone

(5.8) oxazolinium ion

(5.9)

1 6 83 17 0

2 12 79 21 0

3 18 37 60 3

4 24 15 81 4

5 30 7 89 4

6 36 0 96 4

7 42 0 95 5

8 48 0 93 7

9 2400 0 1 99

After 40 h, the NMR sample was diluted with CH2Cl2 and washed with dilute aqueous

NaOH. The organic layer was dried (MgSO4) and the solvent evaporated at reduced

pressure to give a mixture in which the oxazoline (2.7) was the predominant product.

cis-3a,4,5,6,7,7a-hexahydro-2-phenylbenzoxazole hydrochloride (5.10)

An NMR sample of the oxazoline (2.7) in CDCl3 was shaken with two drops of

concentrated HCl. The methine signals of the hydrochloride were compared with the

product (5.9) from the NMR-scale oxidations of the selenide (2.5):

Experimental 7.5

194

cis-3a,4,5,6,7,7a-hexahydro-2-phenylbenzoxazole (2.7)

1H NMR: 4.68, ddd, J 5.1, 5.7, 8.1 Hz, 1H, CHO; 4.13, ddd, J 6.0, 6.6, 8.1 Hz, 1H,

CHN.

cis-3a,4,5,6,7,7a-hexahydro-2-phenylbenzoxazolinium hydrochloride (5.10)

1H NMR: 5.46, ddd, J 4.4, 4.8, 8.8 Hz, 1H, CHO; 4.79, ddd, J 5.8, 5.8, 8.8 Hz, 1H,

CHN.

(iii) 77Se NMR in THF-d8 at low temperature

A solution of the amido selenide (2.5) (50 mg, 0.14 mmol) in dry THF (0.7 mL) was

added to a solution of m-CPBA (144 mg, 0.67 mmol) in dry THF (0.5 mL) at r.t. 0.7

mL of this solution was used to prepare an NMR sample which was placed in the

probe which had been cooled to –30°C. The probe was further cooled to –60°C. A

spectrum was acquired at this temperature over 2 hours, spectra being recorded at

intervals of 20-30 minutes. Two signals were constant for the first 80 minutes: 77Se

NMR 1010.31, 843.86 while one signal drifted from 859.16 (30 min) to 859.24

(45 min) to 859.51 (50-80 min) to 859.59 (95-120 min). The probe was warmed

to –40°C and a spectrum acquired over 30 minutes at this temperature, 77Se NMR

860.03. The probe was then warmed to above 0°C and the sample was removed.

A white solid had precipitated from the NMR sample solution. The precipitate was

collected, giving a white solid (4 mg), which 1H NMR analysis showed to be

predominantly the selenone (5.8) with the oxazoline (2.7) as the minor product. The

precipitate was dissolved in CH2Cl2 (6 mL) and washed with aqueous NaOH (20%, 6

mL). The organic layer was dried (MgSO4) and the solvent evaporated at reduced

pressure to give a 3:1 mixture of the aziridine (2.17) and oxazoline (2.7) as a

colourless oil (2 mg, 97% from 4 mg selenone). Evaporation of the filtrate gave a

white solid which was dissolved in CDCl3 containing a few drops of CD3OD to

Experimental 7.5

195

facilitate dissolution. A 1H NMR spectrum showed essentially only aromatic signals,

consistent with the spectrum of a mixture of m-CPBA and m-CBA.

Experimental 7.6

196

7.6 WORK DESCRIBED IN CHAPTER 6

Methyl phenyl selenide[74-75] (6.1)

A solution of diphenyl diselenide (1.00 g, 3.21 mmol) in THF (10 mL) was added to a

suspension of sodium hydride (249 mg, 8.30 mmol) in THF (10 mL) under N2. The

resulting mixture was refluxed for 1 h 40 min, then cooled to r.t., and to it was added

methyl iodide (0.33 mL, 5.3 mmol) and the mixture was stirred at r.t. for 41 h. The

mixture was diluted with Et2O (20 mL) and washed with half-saturated aqueous NaCl

(15 mL). The aqueous layer was extracted with Et2O (2 x 15 mL) and the combined

organic layers were washed with saturated aqueous NaCl (10 mL) and dried

(Na2SO4). Evaporation of the solvent at reduced pressure gave a yellow oil (0.9728

g) which was purified by Kugelrohr distillation (50°C/0.1 mm) to give the title

compound[74, 301] as a pale yellow oil (738 mg, 81%). 1H NMR: 7.44-7.41, m, 2H,

ArH; 7.29-7.19, m, 3H, ArH; 2.35, s, JSeH 11.1 Hz, 3H, CH3. 13C NMR: 131.79,

130.41, 128.97, 126.07, all Ar; 7.17, Jcse 253 Hz, CH3. MS: m/z 172 (M+), 157 (M+-

CH3), 91 (C7H7+), 77 (C6H5

+).

Methyl phenyl selenone[249] (6.2)

A solution of methyl phenyl selenide (413 mg, 2.41 mmol) in CH2Cl2 was cooled to

0°C and to it was added m-CPBA (1.296 g, 6.08 mmol) and the resulting mixture was

stirred for 23 h, then allowed to warm to r.t. The mixture was then cooled to 0°C and

the precipitated m-CBA was removed by filtration. The yellow filtrate was washed

with aqueous NaOH (0.75 M, 10 mL) and saturated aqueous NaCl (10 mL), and dried

(Na2SO4), and the solvent was removed at reduced pressure to give a colourless

solid (399 mg). Recrystallisation from ethyl acetate gave the title compound[249] as

Experimental 7.6

197

colourless crystals (199 mg, 41%), m.p. 110-114°C (lit.[249] m.p. 130.5-131°C). 1H

NMR: 8.04-8.01, m, 2H, ArH; 7.78-7.65, m, 3H, ArH; 3.31, s, JSeH 8.1 Hz, 3H, CH3.

13C NMR: 142.65, 134.36, 130.31, 126.49, all Ar; 44.26, CH3.

One-pot preparation of styrene oxide

(i) Reaction of benzaldehyde and -lithiomethylphenylselenone[249]

A solution of LDA in THF was prepared by the addition of n-butyllithium (140 L, 1.85

M, 0.259 mmol) to a solution of diisopropylamine (38 L, 0.27 mmol) in THF (3 mL) at

0°C under N2.[3] The LDA solution was then cooled to -78°C. A solution of methyl

phenyl selenone (51 mg, 0.25 mmol) and benzaldehyde (35 L, 0.34 mmol) in THF

(5 mL) was cooled to –78°C and to it was added the LDA solution via cannula. The

resulting mixture was stirred for 15 min at -78°C, and to it was added a solution of

acetic acid (30 L, 0.52 mmol) in THF (0.5 mL). The mixture was stirred a further 55

min, while being allowed to warm to r.t., and then was diluted with CH2Cl2 (15 mL).

The reaction mixture was washed with a mixture of aqueous HCl (10%, 2 mL) and

saturated aqueous NaCl (2 mL), then washed with saturated aqueous NaHCO3 (3

mL) followed by saturated aqueous NaCl (3 mL) and dried (Na2SO4). Evaporation of

the solvent at reduced pressure gave a yellow oil (52 mg). NMR analysis showed

the oil to be a complex mixture with none of the expected peaks for styrene oxide [302]

apparent.

(ii) Reaction of benzaldehyde and potassium phenylselenonylmethylate

A solution of methyl phenyl selenone (29 mg, 0.14 mmol) and benzaldehyde (15 L,

0.15 mmol) in THF (7 mL) was cooled to -60°C and to it was added t-BuOK (40 mg,

0.36 mmol) and the mixture was stirred for 1.5 h, then allowed to warm to r.t. The

Experimental 7.6

198

mixture was quenched with water (10 mL) and the layers were separated. The

aqueous layer was extracted with CH2Cl2 (2 x 15 mL) and the combined organic

layers were washed with saturated aqueous NaCl (10 mL) and dried (Na2SO4).

Evaporation of the solvent at reduced pressure gave a partly-solid product (4 mg)

which NMR analysis showed to be a mixture of styrene oxide[302] and methyl phenyl

selenone in a ratio of 6:1.

Attempted one-pot preparation of 2-phenyloxetane via the reaction of styrene

oxide with potassium phenylselenonylmethylate

A solution of methyl phenyl selenone (42 mg, 0.21 mmol) and styrene oxide (52 mg,

0.43 mmol) in THF (12 mL) was cooled to 0°C and to it was added t-BuOK (46 mg,

0.41 mmol). The mixture was stirred for 50 min, the flask was removed from the ice

bath, and the mixture was diluted with water (10 mL). The layers were separated,

the aqueous layer was extracted with CH2Cl2 (15 mL), and the combined organic

layers were washed with saturated aqueous NaCl (10 mL) and dried (Na2SO4).

Evaporation of the solvent at reduced pressure gave a yellow solid (21 mg) which

NMR analysis showed to be a mixture containing methyl phenyl selenone and

styrene oxide in a ratio of 2.4:1 with none of the expected peaks for 2-

phenyloxetane[302] apparent.

Attempted preparation[250] of 1-phenyl-3-phenylseleninyl-1-propanol

A solution of LDA in THF was prepared[119] by the addition of n-butyllithium (2.1 mL,

1.5 M, 3.2 mmol) to a solution of diisopropylamine (445 L, 3.18 mmol) in THF (0.6

mL) at -78°C under N2. The solution was allowed to warm to 0°C and was kept at

this temperature under N2 until needed. To a solution of methyl phenyl selenide

Experimental 7.6

199

(260 mg, 1.52 mmol) in THF (3 mL) at -70°C was added a solution of m-CPBA (277

mg, 1.61 mmol) in THF (1.5 mL). The mixture was stirred for 30 min, then cooled to

–78°C, and to it was added the LDA solution followed by styrene oxide (175 L, 1.54

mmol). Stirring was continued for 20 min, then water (0.5 mL) containing a few

drops of acetic acid was added followed by Et2O (10 mL). The layers were separated

and the organic layer was washed with half-saturated aqueous NaCl (15 mL) and the

aqueous layer was extracted with Et2O (15 mL). The combined organic layers were

washed with saturated aqueous NaCl and dried (Na2SO4) and the solvent was

evaporated at reduced pressure to give slightly impure styrene oxide[302] (196 mg,

106%) which was identified from its IR and 1H NMR spectra. max (neat): 3085, 3052,

3037, 2989, 2912, 1726, 1496, 1479, 1454, 1390, 1292, 1258, 1202, 1128, 1074,

1027, 985, 877, 812, 759, 700 cm-1. 1H NMR: 7.38-7.25, m, 5H, ArH; 3.87, dd, J

2.6, 4.1 Hz, CHO; 3.15, dd, J 4.1, 5.6 Hz, 1H, CHH; 2.81, dd, J 2.6, 5.6 Hz, 1H, CHH.

3-Phenyl-3-phenylselenopropanal (6.5)

A solution of diphenyl diselenide (500 mg, 1.60 mmol) in THF (15 mL) was added to

a suspension of NaH (128 mg, 4.27 mmol) under N2, and the mixture was refluxed for

24 h and then cooled in ice. Cinnamaldehyde ( 0.61 mL, 4.8 mmol) was added and

the mixture was stirred for 2 h. Acetic acid (0.28 mL, 4.9 mmol) was added and this

mixture was stirred for 24 h, then poured into saturated aqueous NaHCO3 (10 mL).

The layers were separated and the aqueous layer was extracted with Et2O (30 mL).

The combined organic layers were washed with saturated aqueous NaCl (10 mL),

dried (Na2SO4) and the solvent evaporated at reduced pressure to give an orange oil

(1.044 g). Chromatography (CH2Cl2/hexane 3:2) gave the title compound (approx.

50%) contaminated with diphenyl diselenide and cinnamaldehyde as a yellow oil (580

Experimental 7.6

200

mg). From integration of the signals in the 1H NMR spectrum, the ratio of the title

compound to cinnamaldehyde in the product was estimated as 4:1. Decomposition

of the selenide during chromatography was evident from the appearance of a yellow

band (diphenyl diselenide) coincident with elution of the selenide. Data for (6.5):

max(neat) 3058, 3029, 2822, 2726, 1721,1577, 1494, 1475, 1452, 1437, 1066, 1021,

1000 cm-1. 1H NMR: 9.69, t, J 1.5 Hz, CHO; 7.67-7.61, m, 2H, ArH; 7.51-7.40, m,

2H, ArH; 7.34-7.22, m, 6H, ArH; 4.81, dd, J 7.2, 8.4 Hz, CHSe; 3.27, ddd, J 1.5, 8.4,

17.4 Hz, 1H, CHaHb; 3.12, ddd, J 1.5, 7.2, 17.4 Hz, 1H, CHaHb. 13C NMR: 199.68,

C=O; 136.00, 131.50, 129.12, 128.99, 128.50, 127.67, 127.47, 127.36, all Ar; 49.22,

CH2; 40.38, CSe. MS: m/z 290 (M+), 157 (C6H5Se+), 133 (M-C6H5Se+), 105

(C6H5CH2CH2+), 77 (C6H5

+).

3-Phenyl-3-phenylseleno-1-propanol (6.6)

To a solution of impure 3-phenyl-3-phenylseleno-1-propanal (6.5) (contaminated with

cinnamaldehyde and diphenyl diselenide) (366 mg, ~0.98 mmol in (6.5)) in EtOH (15

mL) was added NaBH4 (68 mg, 1.8 mmol) in three portions over 10 min. The

mixture was stirred at r.t. under N2 for 1 h, then diluted with water (5 mL). 10%

aqueous HCl was added dropwise until no further H2 evolution was observed. The

mixture was extracted with Et2O (2 x 15 mL) and the combined organic layers were

washed with saturated aqueous NaCl, dried (Na2SO4) and the solvent evaporated at

reduced pressure to give a yellow oil (350 mg). Chromatography (Et2O/hexane

60:40) gave the title compound as a pale yellow oil (103 mg, 36%). HRMS: 292.0366

C15H16OSe requires 292.0367. max (neat): 3575, 3359, 3059, 3028, 2935, 2879,

1577, 1493, 1475, 1452, 1437, 1155, 1041, 1022, 739, 694 cm-1. 1H NMR: 7.40-

7.38, m, 2H, ArH; 7.29-7.16, m, 8H, ArH; 4.44, t, J 7.8 Hz, 1H, CHSe; 3.72, dt, J 6.0,

10.8 Hz, 1H, CHaHbO; 3.59, dt, J 6.3, 10.8 Hz, 1H, CHaHbO; 2.29, ddd, J 6.0, 6.3, 7.8

Experimental 7.6

201

Hz, 2H, CHCH2. 13C NMR: 135.49, 131.53, 129.17, 128.82, 128.39, 127.88, 127.69,

127.04, all Ar; 61.10, CHSe; 44.85, CH2O; 38.65, CHCH2. MS: m/z 292 (M+), 157

(C6H5Se+), 135 (M+-C6H5Se), 117 (M+-C6H5Se-H2O), 105 (C8H9+), 91 (C7H7

+), 77

(C6H5+). Further elution gave a fraction containing a mixture which was

chromatographed (EtOAc/hexane 45:55) to give the title compound (55 mg, 20%) as

a pale yellow oil. Further elution gave a fraction (48 mg) containing a mixture of the

title compound (6.6), cinnamyl alcohol[253-254] (6.7) and 3-phenyl-1-propanol[255] (6.8)

in a ratio of 2:5:3. Further elution gave a fraction (6 mg) containing a mixture of

cinnamyl alcohol[253-254] (6.7) and 3-phenyl-1-propanol[255] (6.8) in a ratio of 1:1. 1H

NMR: 7.41-7.19, m, 10H, ArH; 6.62, dd, J 1.5, 15.9 Hz, 1H, CCH (6.7); 6.37, dt, J

5.7, 15.9 Hz, 1H, CCHCH (6.7); 4.33, dd, J 1.5, 5.7 Hz, 2H, CH2O (6.7); 3.68, t, J 6.3

Hz, 2H, CH2O (6.8); 2.69, t, J 7.8 Hz, CCH2 (6.8); 1.90, tt, J 6.3, 7.8 Hz, CH2CH2CH2

(6.8); 1.60-1.50, br s ,2H ,OH (6.7 and 6.8).

Bis(phenylseleno)methane[75, 260] (6.9)

A solution of diphenyl diselenide (1.000 g, 3.20 mmol) in THF (10 mL) was added via

cannula to a suspension of NaH (257 mg, 8.57 mmol) in THF (10 mL) under N2. The

mixture was refluxed for 100 min, then cooled to r.t. and to it was added methylene

iodide (335 L, 4.16 mmol). The resulting mixture was stirred for 19 h, then diluted

with Et2O (20 mL) and washed with half-saturated aqueous NaCl (15 mL). The

aqueous layer was extracted with Et2O (2 x 15 mL) and the combined organic layers

were washed with saturated aqueous NaCl (10 mL) and dried (Na2SO4) and the

solvent was removed at reduced pressure to give a yellow oil (1.125 g). Kugelrohr

distillation (150-160°C/0.2mm, lit.[260] b.p. 138°C/0.1mm) gave the title compound[91,

260] as a pale yellow oil (977 mg, 94%). max (neat): 3069, 3055, 3014, 2997, 2915,

Experimental 7.6

202

2852, 1578, 1477, 1453, 1437, 1378, 1299, 1133, 1070, 1022, 999, 733, 690, 670

cm-1. 1H NMR: 7.56-7.50, m, 4H, ArH; 7.31-7.25, m, 6H, ArH; 4.22, s, 2H, CH2. 13C

NMR: 132.99, 130.79, 129.08, 127.49, all Ar; 20.97, CH2. MS: m/z 328 (M+), 171

(M+-C6H5Se), 91 (C7H7+).

Styrene oxide (6.11)[303]

To a solution of styrene (1.0447 g, 100 mmol) in CH2Cl2 (100 mL) was added pH 8

phosphate buffer solution (0.1M, 100 mL) and the solution was cooled to 0°C. To

the solution was added m-CPBA (2.459 g, 100 mmol) in small portions over 10 min.

The flask was removed from the cooling bath and the reaction mixture was stirred for

4 h, then cooled again to 0°C and to it was added m-CPBA (2.494 g, 100 mmol) in

small portions over 20 min. The flask was again removed from the cooling bath and

stirring was continued for 3 h. Saturated aqueous Na2S2O3 (15 mL) was added and

the mixture was stirred 5 min. The layers were separated and the organic layer was

washed with Na2S2O3 (15 mL), then with half-saturated aqueous NaCl (20 mL), and

dried (Na2SO4), and the solvent was evaporated at reduced pressure to give the title

compound[302] as a colourless oil (0.9728 g, 81%). max (neat): 3085, 3052, 3037,

2989, 2912, 1726, 1496, 1479, 1454, 1390, 1292, 1258, 1202, 1128, 1074, 1027,

985, 877, 812, 759, 700 cm-1. 1H NMR: 7.38-7.25, m, 5H, ArH; 3.87, dd, J 2.6, 4.1

Hz, CHO; 3.15, dd, J 4.1, 5.6 Hz, 1H, CHH; 2.81, dd, J 2.6, 5.6 Hz, 1H, CHH.

Preparation of -hydroxy selenides via the reaction of an epoxide

with -phenylselenomethyllithium[86, 88, 252]

Procedure 7.6A: A solution of bis(phenylseleno)methane (6.9) in THF was cooled

to –78°C and to it was added n-butyllithium. The solution was stirred for 1 h and to

it was added HMPA followed by a solution of the epoxide in THF. The mixture was

Experimental 7.6

203

stirred at –78°C for 2 h and then removed from the cooling bath and stirred a

further 1.5 h. The flask was placed in ice and the reaction was quenched with

dropwise addition of saturated aqueous NH4Cl (5 mL). A further portion of saturated

aqueous NH4Cl (15 mL) was added, followed by water (10 mL). The mixture was

extracted with Et2O (2 x 20 mL) and the combined organic layers were washed with

saturated aqueous NaCl (10 mL) and dried (Na2SO4), and the solvent evaporated at

reduced pressure.

1-Phenyl-3-phenylseleno-1-propanol (6.11)

Following Procedure 7.6A, a mixture of bis(phenylseleno)methane (6.9) (1.00 g, 3.07

mmol) and n-butyllithium (1.6 M in hexane, 2.5 mL, 4.0 mmol) in THF (10 mL), stirred

for 1 h, followed by addition of HMPA (0.54 mL, 3.1 mmol) and a solution of styrene

oxide (561 mg, 4.67 mmol) in THF (5 mL) and stirred for 2 h after removal from the

cooling bath, gave a pale yellow oil (1.4317 g). Chromatography

(CH2Cl2/hexane/EtOH 68:30:2) gave n-butyl phenyl selenide[304] (6.13) as a yellow oil

(406 mg, 62%). max (neat): 3071, 3058, 2959, 2928, 2871, 2859, 1579, 1476, 1463,

1437, 1378, 1296, 1258, 1199, 1073, 1022, 999, 900, 734, 690, 670 cm-1. 1H

NMR:7.50-7.46, m, 2H, ArH; 7.29-7.22, m, 3H, ArH; 2.92, t, J 7.5 Hz, 2H, CH2Se;

1.68, tq, J 7.5, 7.5 Hz, 2H, CH3CH2; 1.43, qn, J 7.5 Hz, CH3CH2CH2; 0.91, t, 7.5 Hz,

3H, CH3. 13C NMR(200 MHz): 132.37, 129.30, 128.84, 126.56, all Ar; 32.24, 27.61,

22.92, 13.52. MS: m/z 214 (M+), 158 (C6H5SeH+), 78 (C6H6+), 77 (C6H5

+). Further

elution gave 1-phenyl-2-(phenylseleno)-ethanol[136] (6.13) as a pale yellow oil (155

mg, 18%). 1H NMR:7.60-7.52, m, 2H, ArH; 7.38-7.20, m, 8H, ArH; 4.75, dd, J 3.9,

9.3 Hz, 1H, CHOH; 3.31, dd, J 3.9, 12.6 Hz, 1H, CHaHbSe; 3.14, dd, J 9.3, 12.6 Hz,

1H CHaHbSe; 2.80, br s, 1H, OH. 13C NMR(200 MHz): 142.48, 133.07, 129.21,

Experimental 7.6

204

129.06, 128.49, 127.87, 127.34, 125.77 all Ar; 72.23, CHO; 38.20, CHSe. Further

elution gave the title compound[261] as a pale yellow oil (389 mg, 44%). max (neat):

3390, 3059, 3029, 2935, 2874, 1578, 1493, 1477, 1453, 1437, 1392, 1359, 1328,

1301, 1248, 1203, 1184, 1054, 1023, 1001, 912, 896, 763, 735, 700, 670, 649 cm-1.

1H NMR: 7.49-7.46, m, 2H, ArH; 7.37-7.22, m, 8H, ArH; 4.83, dd J 5.1, 7.8 Hz, 1H,

CHO; 2.98, dd, J 7.2, 7.8 Hz, 2H, CH2Se; 2.18, ddt, J 7.2, 7.8, 14.1 Hz, 1H,

CHCHaHbCH2; 2.05, ddt, J 5.1, 7.8, 14.1 Hz, 1H, CHCHaHbCH2, 1.95, br s, 1H, OH.

13C NMR: 143.93, 132.54, 129.95, 129.07, 128.54, 127.73, 126.84, 125.80, all Ar;

73.84, CHO; 39.02, CHSe; 23.80. MS: m/z 292 (M+), 275 (M+-OH), 185 (M+-

C6H5CH2O), 157 (C6H5Se+), 134 (M+-C6H5SeH), 117 (C9H9+), 107 (C6H5CH2O+),

77(C6H5+).

1-Phenyl-4-phenylseleno-2-butanol (6.18)

Following Procedure 7.6A, a mixture of bis(phenylseleno)methane (6.9) (880 mg,

2.69 mmol) and n-butyllithium (2.45 M in hexane, 1.44 mL, 3.53 mmol) in THF (10

mL), stirred for 70 min, followed by addition of HMPA (0.47 mL, 2.7 mmol) and a

solution of 2-benzyloxirane (540 L, 4.10 mmol) in THF (5 mL) and stirred for 6 h

after removal from the cooling bath, gave a yellow oil (596 mg). Kugelrohr distillation

(25-100°C/0.2mm) gave a fraction containing a mixture of n-butyl phenyl selenide

(6.12), HMPA and 2-benzyloxirane as a colourless oil. The residue, a yellow oil

(0.5045 g), was chromatographed (CH2Cl2) to give 1-phenyl-4,4-bis(phenylseleno)-2-

butanol (6.23) as a pale yellow oil (173 mg, 14%). EI HRMS: 461.9998 C22H22OSe2

requires 462.0002. max (neat): 3555 (sharp, OH), 3435 (broad, OH), 3057, 3026,

2931, 1578, 1494, 1476, 1437, 1069, 1022, 1000, 739, 691, 669 cm-1. 1H NMR:

7.59-7.52, m, 4H, ArH; 7.47-7.19, m, 9H, ArH; 7.17-7.13, m, 2H, ArH; 4.71, dd, J 4.8,

Experimental 7.6

205

9.3 Hz, 1H, CH(Se)Se; 4.25, m, 1H, CHO; 2.70, dd, J 5.4, 13.5 Hz, 1H, CCHaHb;

2.66, dd, J 7.5, 13.5 Hz, 1H, CCHaHb; 2.14, ddd, J 4.8, 9.0, 14.7 Hz, 1H,

CHCHaHbCH; 2.05, ddd, J 3.3, 9.3, 14.7 Hz, 1H, CHCHaHbCH; 1.75, d, J 3.0 Hz, 1H,

OH. 13C NMR(200 MHz): 137.78, 134.83, JCSe 36.4 Hz; 134.33, JCSe 38.0 Hz;

130.39, 129.31, 129.26, 129.00, 128.93, 128.49, 128.04, 127.84, 126.46, all Ar;

71.00, 43.81, 43.57, 39.78. MS: m/z 462 (M+); 287 (M+-C6H5Se-H2O); 185

(C6H5SeCH2CH2+); 147 (M+-C6H5Se- C6H5Se-H); 129 (C10H9

+); 103 (C8H7+); 91

(C7H7+); 77 (C6H5

+). Further elution gave a fraction containing a mixture as a yellow

oil (192 mg) which was chromatographed (hexane/CH2Cl2/EtOH 30:69:1) to give 1-

phenyl-3-phenylseleno-2-propanol[266] (6.22) as a yellow oil (19 mg, 2%). ESI

HRMS: 275.0333 C12H26O2-OH requires 275.0339. max (neat): 3426 (br, OH), 3060,

3028, 2923, 2849, 1671, 1650, 1579, 1478, 1451, 1437, 1428, 1314, 1297, 1260,

1071, 1022, 736, 691 cm-1. 1H NMR: 7.53-7.44, m, 2H, ArH; 7.34-7.15, m, 8H,

ArH; 3.98-3.88, m, 1H, CHO; 3.13, dd, J 4.0, 12.8 Hz, 1H, CHaHbSe; 2.93, dd, J 8.0,

12.8 Hz, 1H, CHaHbSe; 2.87, d, J 6.8 Hz, 2H, C6H5CH2; 2.35, br s, OH. 13C NMR:

137.79, 132.86, 129.38, 129.20, 128.53, 127.24, 126.60, all Ar; 71.03, CO; 42.90,

35.88. One of the aromatic carbon signals did not appear in the spectrum. MS: m/z

292 (M+); 201 (M+-C7H7); 183 (M+-C7H7-H2O); 157 (C6H5Se+); 117 (M+-C6H5Se-H2O).

Further elution gave the title compound as a pale yellow oil (109 mg, 13%). 1H

NMR: 7.56-7.50, m, 2H, ArH; 7.39-7.19, m, 8H, ArH; 4.05-3.98, m, 1H, CHO; 3.15,

dt, J 7.2, 12.3 Hz, 1H, CHaHbSe; 3.05, dt, J 7.5, 12.3 Hz, 1H, CHaHbSe; 2.85, dd, J

4.2, 13.5 Hz, 1H, CCHaHbCH; 2.72, dd, J 8.1, 13.5 Hz, 1H, CCHaHbCH; 1.99-1.92, m,

2H, CHCH2CH2Se; 1.64, br s, 1H, OH. MS: m/z 306 (M+); 213 (M+-C7H7Se-H2); 157

(C6H5Se+); 91 (C7H7+).

Experimental 7.6

206

1-Phenylseleno-3-undecanol (6.17)

Following Procedure 7.6A, a mixture of bis(phenylseleno)methane (6.9) (864 mg,

2.65 mmol) and n-butyllithium (2.5 M in hexane, 1.27 mL, 3.18 mmol), stirred for 45

min, followed by addition of 1,2-epoxydecane (740 L, 3.98 mmol) and HMPA (0.47

mL, 2.7 mmol), and stirred for 2 h after removal from cooling bath, gave a yellow oil

(1.421 g). Kugelrohr distillation (25-100°C/0.2 mm) gave a fraction containing a

mixture of n-butyl phenyl selenide, 1,2-epoxydecane and HMPA as a colourless oil.

The residue was chromatographed ((hexane/CH2Cl2/EtOH, 30:69:1) to give 1-

phenylseleno-2-decanol[264] (6.19) as a yellow oil (119 mg, 14%). max (neat): 3373,

2953, 2926, 2854, 1579, 1477, 1466, 1437, 1408, 1385, 1072, 1022, 1001, 737, 690

cm-1. 1H NMR: 7.56-7.50, m, 2H, ArH; 7.32-7.24, m, 3H, ArH; 3.66, dddd, J 3.3,

5.1, 6.9, 8.7 Hz, 1H, CHO; 3.15, dd, J 3.3, 12.6 Hz, 1H, CHaHbSe; 2.88, dd, J 8.7,

12.6 Hz, 1H, CHaHbSe; 2.36, br s, 1H, OH; 1.56-1.44, m, 2H, CH2CHO; 1.43-1.25, m,

12H; 0.87, t, J 6.6 Hz, 3H, CH3. 13C NMR: 132.99, 129.15, 129.05, 127.21, all Ar;

69.87, CH2O; 37.25; 36.59, CH2Se; 31.80; 29.53; 29.44; 29.18; 25.75; 22.60; 14.04.

MS: m/z 314 (M+), 297 (M+-OH), 172 (C6H5SeCH3+). Further elution gave the title

compound as a pale yellow solid (210 mg, 24%) which was recrystallised from

hexane to give colourless plates, m.p. 47-49.5°C. ESI HRMS: 329.1373

C17H28OSe+H requires 329.1378. max (neat): 3392, 2954, 2918, 2899, 2872, 2848,

1579, 1477, 1470, 1437, 1402, 1342, 1257, 1078, 1055, 1034, 1022, 899, 729, 690

cm-1. 1H NMR: 7.55-7.48, m, 2H, ArH; 7.32-7.26, m, 3H, ArH; 3.75-3.69, m, 1H,

CHO; 3.11-2.94, m, 2H, CH2Se; 1.88-1.78, m, 2H, CHCH2CH2Se; 1.55-1.26, m, 16H;

0.88, t, J 6.6 Hz, 3H, CH3. 13C NMR: 132.58, 132.55, 129.02, 126.78, all Ar; 71.55,

CH2O; 37.42, CH2Se; 31.82; 29.56; 29.50; 29.19; 25.52; 25.27; 24.12; 22.60; 14.02.

Experimental 7.6

207

MS: m/z 328 (M+); 311 (M+-OH); 185 (C6H5CH2CH2+); 171 (M+-C6H5; C6H5SeCH2

+);

158 (M+-C6H5SeCH2; C6H5SeH+); 141 (C9H17O+); 57 (C3H5O+); 43 (C2H3O+).

Cyclisation of -hydroxy selenides

Attempted cyclisation of 1-Phenyl-3-phenylseleno-1-propanol (6.11)

(i) in THF at low temperature

Following Procedure 7.3E, the reaction of 1-phenyl-3-phenylseleno-1-propanol (6.11)

(62 mg, 0.21 mmol), m-CPBA (207 mg, 70%, 0.84 mmol) and t-BuOK (202 mg, 1.80

mmol) gave a negligible yield of a pale yellow oil. NMR analysis showed the product

to be a complex mixture which was not purified further.

(ii) in THF at r.t.

To a solution of 1-phenyl-3-phenylseleno-1-propanol (6.11) (40 mg, 0.14 mmol) in

THF (15 mL) was added m-CPBA (100 mg, 70%, 0.41 mmol) and the mixture was

stirred at r.t. for 3 d. The mixture was then cooled to -78°C and to it was added t-

BuOK (140 mg, 1.25 mmol) and the mixture was removed from the cooling bath and

stirred for 2.5 h. The reaction was quenched with aqueous Na2S2O3 (0.5 M, 8 mL)

and the mixture was diluted with Et2O (15 mL). The layers were separated and the

organic layer was washed with aqueous NaOH (10%, 10 mL) followed by saturated

aqueous NaCl (10 mL), and dried (Na2SO4). Evaporation of the solvent at reduced

pressure gave a pale yellow oil (20 mg). Chromatography (EtOAc/hexane 60:40 to

80:20) gave 1-phenyl-1,3-propanediol[262-263] (6.14) as a colourless oil (5 mg, 23%).

1H NMR: 7.39-7.34, m, 3H, ArH; 7.33-7.27, m, 2H, ArH; 4.97, dd, J 3.6, 8.7 Hz, 1H,

CHO; 3.87, dd, J 5.1, 5.7 Hz, 2H, CH2O; 2.87, br s, 1H, OH; 2.42, br s, 1H, OH;

2.07-1.90, m, 2H, CCHaHbC. 13C NMR: 144.29, 128.50, 127.58, 125.61, all Ar;

Experimental 7.6

208

74.33, CHOH; 61.44, CH2OH; 40.50. Further elution gave a fraction which NMR

analysis showed to be complex mixture which was not purified further.

2-Phenyloxetane[169] (6.3)

A solution of 1-phenyl-3-phenylseleno-1-propanol (6.11) (102 mg, 0.350 mmol) and

m-CPBA (150 mg, 0.87 mmol) in methanol (3 mL) was stirred at r.t. for 30 min.

Aqueous NaOH (1 M, 1.75 mL, 1.75 mmol) was added and the solution was stirred a

further 18 h. Half-saturated aqueous NaCl (10 mL) was added and the aqueous

layer was extracted with Et2O (2 x 20 mL). The combined organic layers were

washed with saturated aqueous NaCl (10 mL) and dried (Na2SO4), and the solvent

was evaporated at reduced pressure to give a colourless oil (26 mg).

Chromatography (hexane/EtOAc, 9:1 to 7:3) gave the title compound[258-259] as a

colourless oil (9 mg, 20%). 1H NMR: 7.47-7.27, m, 5H, ArH; 5.82, t, J 7.5 Hz, 1H,

CHO; 4.84, ddd, J 5.7, 7.8, 8.1 Hz, CHaHbO; 4.67, ddd, J 5.4, 5.7, 9.3 Hz, 1H,

CHaHbO; 3.03, dddd, J 5.4, 7.5, 8.1, 11.1 Hz, 1H, CHCHaHb; 2.67, dddd, J 7.5, 7.8,

9.3, 11.1 Hz, 1H, CHCHaHb. Further elution gave 3-methoxy-1-phenyl-1-

propanol[262] (6.15) as a colourless oil (7 mg, 12%). 1H NMR: 7.39-7.33, m, 3H,

ArH; 7.29-7.25, m, 2H, ArH; 4.92, dd, J 3.9, 8.1 Hz, 1H, CHO; 3.62-3.53, m, 2H,

CHaHbO; 3.38, s, 3H, CH3; 3.30, br s, 1H, OH; 2.08-1.93, m, 2H, CCHaHbC. 13C

NMR: 144.39, 128.33, 127.26, 125.65, all Ar; 73.56, COH; 71.18, CH3; 58.89,

CH2OH; 38.53. Further elution gave 1-phenyl-1,3-propanediol[262-263] (6.14) as a

brown oil (trace). 1H NMR: 7.39-7.34, m, 3H, ArH; 7.33-7.27, m, 2H, ArH; 4.97,

dd, J 3.6, 8.7 Hz, 1H, CHO; 3.87, t, J 5.4 Hz, 2H, CH2O; 2.87, br s, 1H, OH; 2.42, br

s, 1H, OH; 2.07-1.90, m, 2H, CCHaHbC. 13C NMR: 144.29, 128.50, 127.58, 125.61,

all Ar; 74.33, CHOH; 61.44, CH2OH; 40.50.

Experimental 7.6

209

3-Methoxy-1-phenyl-1-propanol[262] (6.15)

A solution of 1-phenyl-3-phenylseleno-1-propanol (6.11) (55 mg, 0.19 mmol) and m-

CPBA (83 mg, 0.48 mmol) in methanol (5 mL) was stirred at r.t. for 4 d after which

the solvent was evaporated to give a pale yellow solid. The product was dissolved in

Et2O (15 mL) and washed with aqueous NaOH (10%, 8 mL) followed by saturated

aqueous NaCl (8 mL) and dried (Na2SO4). Evaporation of the solvent at reduced

pressure gave a yellow oil (35 mg) which was chromatographed (hexane/EtOAc,

75:25) to give the title compound, 3-methoxy-1-phenyl-1-propanol,[262] (6.15) as a

pale yellow oil (13 mg, 41%) whose 1H NMR spectrum was in accord with the

spectrum of (6.15) previously obtained.

2-Benzyloxetane[174] (6.24)

A solution of 1-phenyl-4-phenylseleno-2-butanol (6.18) (91 mg, 0.30 mmol) and m-

CPBA (129 mg, 0.748 mmol) in methanol (3 mL) was stirred at r.t. for 1 h. Aqueous

NaOH (1 M, 1.5 mL, 1.5 mmol) was added and the solution was stirred a further 17 h.

Half-saturated aqueous NaCl (10 mL) was added and the mixture was extracted with

Et2O (2 x 20 mL). The combined organic layers were washed with saturated

aqueous NaCl (10 mL) and dried (Na2SO4), and the solvent was evaporated at

reduced pressure to give a colourless oil (42 mg). Chromatography (hexane/EtOAc

3:1) gave the title compound[268] as a colourless oil (4.6 mg, 10%). 1H NMR: 7.33-

7.20, m, 5H, ArH; 5.04, dddd, J 6.3, 6.6, 6.9, 7.2 Hz, 1H, CHO; 4.65, ddd, J 5.7, 7.5,

8.1 Hz, 1H, CHaHbO; 4.48, ddd, J 5.7, 6.0, 9.0 Hz, 1H, CHaHbO; 3.09, dd, J 6.3, 13.8

Hz, 1H, C6H5CHaHb; 2.98, dd, J 6.6, 13.8 Hz, 1H, C6H5CHaHb; 2.63, dddd, J 6.0, 7.2,

8.4, 10.8 Hz, 1H, CHCHaHbCH2; 2.44, dddd, 6.9, 7.5, 9.0, 10.8 Hz, 1H,

CHCHaHbCH2. 13C NMR: 137.04, 129.19, 128.36, 126.38, all Ar; 82.61, CHO;

Experimental 7.6

210

67.89, CH2O; 44.00, C6H5CH2; 27.13. MS: m/z 148.1 (M+), 131.1 (M+-OH), 117.1

(M+-CH2OH), 105.1, (M+-C2H3O), 91.1 (C7H7+), 77 (C6H6

+), 65.1 (C5H5+), 57.0

(C3H5O+), 43.0 (C2H3O+). Further elution gave 1-phenyl-4-methoxy-2-butanol (6.25)

as a pale yellow oil (8 mg, 15%). max (KBr): 3438 (br, OH), 2924, 1496, 1454, 1385,

1339, 1191, 1118, 1086, 1029, 746, 701 cm-1. 1H NMR: 7.33-7.19, m, 5H, ArH;

4.02, qn, J 6.9 Hz, 1H, CHO; 3.62, ddd, J 5.1, 5.4, 9.3 Hz; 1H, CHaHbOMe; 3.52, ddd,

J 6.6, 7.5, 9.3 Hz, 1H, CHaHbOMe; 3.34, s, 3H, OCH3; 2.87, br s, 1H, OH; 2.81, dd, J

7.2, 13.5 Hz, 1H, CHaHbCH; 2.76, dd, J 6.0, 13.5 Hz, 1H, CCHaHbCH; 1.76-1.70, m,

2H, CHCH2CH2. 13C NMR: 138.55, 129.40, 128.39, 126.29, all Ar; 72.11, CHO;

71.39, CH2O; 58.82, OCH3; 43.99, C6H5CH2; 35.67. MS: m/z 181 (M+), 162 (M+-

H2O), 147 (M+-H2O-CH3), 131 (M+-H2O-OCH3), 117 (C6H5CHCHCH2+), 103 (C8H7

+),

91 (C7H7+), 89 (C4H9O2

+), 45 (CH2OCH3+).

2-Octyloxetane[174] (6.20)

A solution of 1-phenylseleno-3-undecanol (6.17) (103 mg, 0.315 mmol) and m-CPBA

(137 mg, 0.794 mmol) in methanol (3 mL) was stirred at r.t. for 30 min. Aqueous

NaOH (1 M, 1.6 mL, 1.6 mmol) was added and the mixture was stirred a further 43 h.

Half-saturated aqueous NaCl (10 mL) was added and the mixture was extracted with

Et2O (2 x 20 mL). The combined organic layers were washed with saturated

aqueous NaCl (10 mL) and dried (Na2SO4), and the solvent was evaporated at

reduced pressure to give a colourless oil (42 mg). 1H NMR analysis showed the

product to be predominantly a mixture of 2-octyloxetane (6.20) and 1-methoxy-3-

undecanol (6.21) in a ratio of 1:1. Chromatography (hexane/EtOAc 9:1) gave the

title compound[265] as a colourless oil (trace). ESI HRMS: 171.1743 C11H22O+H

requires 171.1749. 1H NMR: 4.82, qn, J 6.9 Hz, 1H, CHO; 4.66, ddd, J 5.7, 7.5,

Experimental 7.6

211

8.4 Hz, 1H, CHaHbO; 4.50, ddd, J 5.7, 5.7, 9.0 Hz, 1H, CHaHbO; 2.64, dddd, J 5.7,

6.9, 8.4, 10.8 Hz, 1H, CHCHaHbCH2O; 2.35, dddd, J 6.9, 7.5, 9.0, 10.8 Hz, 1H,

CHCHaHbCH2O; 1.83-1.76, m, 1H, CH2CH2CHaHbCHO; 1.68-1.58, m, 1H,

CH2CH2CHaHbCHO; 1.4-1.1, m, 12H; 0.88, t, 6.9 Hz, 3H, CH3. Further elution gave

a fraction containing a complex mixture (12 mg). Further elution gave 1-methoxy-3-

undecanol (6.21) as a pale yellow oil (trace). ESI HRMS: 203.2006 C12H26O2+H

requires 203.2006. max (neat): 3433 (broad, OH), 2924, 2854, 1460, 1380, 1187,

1118, 1029, 965, 721 cm-1. 1H NMR: 3.78, m, 1H, CHO; 3.63, ddd, J 5.1, 5.1, 9.3

Hz, 1H, CHaHbO; 3.55, ddd, J 5.4, 7.2, 9.3 Hz, 1H, CHaHbO; 3.36, s, 3H, OCH3;

1.73-1.63, m, 2H, CHCHaHbCH2O; 1.62-1.26, m, 15H; 0.88, t, J 6.6 Hz, 3H, CH2CH3.

13C NMR: 71.83, CH2O; 71.57, CHO; 58.90, CH3O; 37.49, 36.28, 31.88, 29.69,

29.58, 29.27, 25.60, 22.66, 14.10, CH(OH)CH2CH2O. MS: m/z 185 (M+-H), 169 (M+-

H2O), 155 (M+-CH3O), 141 (C10H21), 124 (M+-C2H5O-OH).

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230

PUBLICATIONS

Synthesis of N-acylaziridines from -amido selenides. Virginia R. Ward,

Matthew A. Cooper, A. David Ward, Journal of the Chemical Society, Perkin

Transactions 1, 2001, 944-945.

The Synthesis of N-Benzoyl Aziridines from -Benzamidoalkyl Phenyl

Selenides. Virginia R. Ward, Matthew A. Cooper and A. David Ward, Phosphorus,

Sulfur and Silicon, 2001, 172, 195-201.

Crystal Structure of N1-[2-(phenylseleninyl)cyclohexyl]benzamide,

C19H21NO2Se. Ward, A. D.; Ward, V. R.; Tiekink, E. R. T., Zeitschrift für

Kristallographie – New Crystal Structures, 2001, 216(4) 555-557.

Crystal Structure of 5-methyl-1,4-di[2-(phenylselanyl)cyclohexyl]-4H-1,2,3,4-

tetraazol-1-ium perchlorate, [(C6H5SeC6H10)2CH3CN4]ClO4. Ward, A. D.;

Ward, V. R.; Tiekink, E. R. T., Zeitschrift für Kristallographie – New Crystal

Structures, 2001, 216(4) 551-552.

PERKIN 1lncorporati ng Acta Chemi ca Scandi navica

W6*s'{e t&a*

{*Kv&p##rwffir&*s *f *fux* &sa#&affi.{

An internation"l journal

of organic and

bioorganic chemistry

ruffiffiffi^w?.&w

RSO(www.rsc.org lperkin 1 ROYAL SOCIETY OF CHEMISTRY

Synthesis of l/-acylaziridines from F-amido selenides

Virginia R. Ward,* Matthew A. Cooper and A. David Ward

Department of Chemistry, Adelaide (Jniversity, Adelaide, Australia 5005

Received 15th March 2001, Accepted 16th March 2001First published as an Advance Article on the web 30th March 2001

MCPBA under

ErnPnzand 8 with

Product D Yield'(ratio) (%)

6a,7a (74 :26:) 73

6b,7b (61 : 39) 726c,7c (83 : I l)" 83

rlo==CZ.-lCz

The low temperature oxidation of p-amido selenides withMCPBA affords the corresponding B-amido selenones.In situ treatment of the selenones with I(OtBu givesN-acylaziridines in good to excellent yield.

Aziridines are valuable compounds due to the regio- and stereo-controlled ring-opening reactions which are central to theirchemistry.t ,A/-Acylaziridines are of particular value in such

reactions as substitution at the nitrogen atom with an electron-withdrawing group enhances the susceptibility of the aziridinering to open.l-3

.n/-Acylaziridines are usually prepared by acylation of theunsubstituted aziridine.ou The alternative approach, via cyclis-ation of B-substituted amides, often forms oxazolines,t-tt as a

result of ring-closure by oxygen rather than by nitrogen, andonly rarely produces an aziridine.a Krook and Millert2 have

shown that cyclisation of the mesylate I can be directed to give

the oxazoline 2 under weakly basic conditions (potassiumbicarbonate in hot dichloroethane) and the aziridine 3 and

Table I Products lrom the reaction of 5basic conditions

Product o

Selenide (ratio)Yield "(%,)

5a 7a5b5c8a8b8c8d8e

8f8g

87

9a,10a (il : a9) 179b 859c 70

9e,10e (14 :12)' 55

9a9b9c9d

7583

9466

9e 8l9f 6799 87

o 4 eq. MCPBA, 6-8 eq. NaH or tBuOK in iPrOH, RT. t 3.3 eq.

MCPBA,4.5-9 eq. tBuOK in THtr, -60 "C. " Some of the correspond-ing elimination product was also lormed.

o

,.A*H

! ,oMsi

,rNHoBzo'

1

oAr4

N

R1

oA*T]

R2 'R3

7

Phse. NHcoRl f;o*tHLni tRr R24n3

B-lactam 4 under strongly basic conditions (potassium tert-butoxide (tBuOK) in tetrahydrofuran (THF)), thus demonstrat-ing that cyclisation of amides to aziridines requires generationof the amide anion prior to alkylation, ?s does //-alkylationof amides in general.t3 B-Hydroxy amides of threo-stereo-chemistry, such as threonine-containing peptides, have been

found to give aziridines under Mitsunobu conditions in whichthe reduced diisopropyl azodicarboxylate anion is believed toact as the base. t4-17 The same treatment of allo-threoninederivatives, however, leads to oxazolines.15

Toshimitsuls cyclized B-amido selenide 5a to the oxazolineTain 84o/o yield through its oxidation to the selenone with MCPBAin methanol in the absence of base. We report herein that thecyclisation of B-amido selenides under strongly basic con-ditions at low temperature can be directed predominantly toaziridine formation and that where the alkyl group is cyclic,azindines are formed as the exclusive products.

Initially the cycloalkyl phenyl selenides were oxidised underconditions similar to those used by Toshimitsu,rs with an excess

of MCPBA in isopropanol (propan -2-ol) in the presence ofpotassium hydroxide (KOH). Thus the reaction of selenide 8b

using 1.5 equivalents of KOH and 3 equivalents of MCPBAgave the oxazoline in94'Yuyield. However, withT .5 equivalents ofbase the aziridine was afforded in 73% yield. Investigation of

944 J. Chem. Soc., Perkin Trans. 1,2001 ,944-945

a Rl = C6H5i R2 = H,H; R3 = CoHrg

b R1 = pBr-C6Ha; R2 - H,H; R3 = CoHrs

c approx. 1:1 mixture of

R1 = CsHs; R2 = CHr' R3 = C3H7 and

R1 = C6H5i R2 = C3H7i R3 = CHs

the oxidation of other cyclic benzamido selenides confirmedthat neutral or acidic conditions favoured the oxazoline with an

excess of base giving the azindine as the predominant product.The use of sodium hydride (NaH) or tBuOK instead of KOHimproved the ratio of aziridine to oxazoline, presumably due togeneration of the stronger base, isopropoxide ion (Table 1, con-ditions a). However, except with the cyclohexanebenzamides 8b

and 8c, we were unable to effect a clean transformation to theazindines. Oxidation of acyclic selenoamide 5a under these

conditions gave the oxazoline in 8J'Y,, yield, a replication ofToshimitsu's result. r8

The work of Krook and Miller tt suggested that cyclisation tothe aziridine might be more favoured by the use of an aproticsolvent such as THF at a lower temperature. We were unawareof any precedent for the generation of selenones at temper-atures below zero degrees; neither did we know of any reportsof the generation of selenones with MCPBA in solvents otherthan alcohols or dichloromethane. Indeed, we have found theoxidation of other selenides to be 50 to 60 times slower in THFthan in alcohols and we expected the reaction at low tem-perature in THF to be very slow, if it proceeded at all. We were

therefore surprised to find that oxidation of the cyclic amidoselenides for one hour at -60'C in THF followed by additionof tBuOK and allowing the mixture to warm to ca.0 'C over 1

hour, afforded the aziridines as the exclusive products, often inexcellent yield (Table 1, conditions b).le The acyclic compounds

DOI: 10.1039/b102468j

o

*A"frE/ \ srAN--H 7l*oazo< A'NHOBz

34

This journal is O The Royal Society of Chemistry 2001

SePh

,,,NHCOR

a n=3,R=CoHsb n=4,R=CoHsc n=4,R-pBr-CoH+d n=4,R=CHse n=5,R=COHsI n=5,R=CHgI 11 = 6, R = COHS

9

,t]-o..(cQA,(h*

N-COR

2 tr. A. Davis, H. Liu and G. V. Reddy, Tetrahedron Lett., 1996, 37 ,

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18 A. Toshimitsu, C. Hirosawa, S. Tanimoto and S. tlemura, Tetra-hedron Lett., 1992,33, 4017 .

19In a typical procedure, to a solution ol the selenide 8d (250 mg,

0.84 mmol) in tetrahydroluran (20 ml) cooled to -60 "C was addeddropwise, with stirring, a solution of MCPBA (594 nlg, 80Y,,,

2.7 5 mmol) in tetrahydrofuran (20 ml) and the mixture was stirred at

-60 "C for t h. Potassium tert-butoxide (571 mg, 5.1 mmol) was

added and the resulting mixture stirred for a lurther I h. Aqueoussodium thiosullate (0.5 M, I 5 ml) and saturated aq. sodiumbicarbonate (10 ml) were added and the aqueous phase extractedwith diethyl ether (30 ml). The organic extract was washed with 10%,

aq. sodium hydroxide (10 ml) and saturated aq. sodium chloride(10 ml) and dried (MgSOo) and the solvent evaporated at reducedpressure. Chromatography using a gradient of 0 to 10'2, diethyl etherin dichloromethane as eluent gave the aziridine 9d as a clear liquid(77 mg,66%,,).

20 A. Krief, W. Dumont, J. N. Denis, G. Evrard and B. Norberg,J. Chent Soc., Chem. Commurz., 1985,569.

2l A. Toshimitsu, T. Aoai, H. Owada, S. Llemura and M. Okano,J. Chent. Soc., Chem. Contntun, 1980, 412.

22 A. Toshimitsu, G. Hayashi, K. Terao and S. Uen-rura, J. Chem. Soc.,

Perkin Trans. l, 1986, 343.23 M. Hayashi, K.Ono, H. Hoshimi and N. Oguni, Telraltedron, 1996,

52,l81l .

24 Z. da Zhang and R" Scheffold, Helv" Chim. Acta, 1993, 76,2602.

10

GNHcoc6H511

5a-c also predominantly formed the corresponding aziridines6a-c under these conditions.

The oxidation of 8e with 1 equivalent of MCPBA (sufficientto give the selenoxide) and 3 equivalents of tBuOK with otherparameters constant gave the selenoxide syn-elimination productll (5S%) and starting material (13'/,,). This confirmed thatthe intermediate was the selenone and not the selenoxide. Inaddition, the ttSe NMR spectrum of a mixture of 8b andMCPBA in THF at -60 "C showed a peak atld l0l0, consistentwith the presence of a selenone.2o

When the reaction was conducted on 8e at higher temper-atures (- l5 oC, 0'C) aziridine formation decreased with a con-comitant increase in the s-t,rz-elimination product 11. At bothtemperatures only traces of oxazoline were observed. These

results indicate that although it may have little effect on themode of cyclisation, the low temperature is necessary to ensure

that the selenoxide is sufficiently long-lived to enable its furtheroxidation to the selenone.

The B-amido selenides were prepared via establishedprocedures in two steps from the corresponding alkenes,27'22

with overall yields of aziridine from the starting alkene at least

comparable to, and in one case a six-fold improvement oil,yields reported using other method s.23'24 Thus our method-ology represents an efficient and mild alternative route to//-acylaziridines.

References

1 D. Tanner, Angew. Chem.,Int. Ed" Eng\.,1994,33,599.

Chem. Soc., Perkin Trans. 1,2001 ,944-945 945

Ward, V.R., Cooper, M.A. and Ward, A.D. (2001) The Synthesis of N-Benzoyl Aziridines from β-Benzamidoalkyl Phenyl Selenides. Phosphorus, Sulfur, and Silicon and the Related Elements, v. 172 (1), pp. 195-201,

May 2001

NOTE: This publication is included in the print copy of the thesis

held in the University of Adelaide Library.

It is also available online to authorised users at:

http://dx.doi.org/10.1080/10426500108046651

A.D. Ward, V.R. Ward and E.R.T. Tiekink (2001) Crystal structure of 5-methyl-1,4 di[2-phenylselanyl)cyclohexyl]-4H-1,2,3,4-tetraazol-1-ium perchlorate, [(C6H5SeC6H10)2CH3CN4]CIO4 Zeitschrift fur Kristallographie - New Crystal Structures, v. 216, pp. 551-552, 2001

A NOTE:

This publication is included in the print copy of the thesis held in the University of Adelaide Library.

A.D. Ward, V.R. Ward and E.R.T. Tiekink (2001) Crystal structure of N1-[2-(phenylseleninyl)cyclohexyl]benzamide, C19H21NO2Se Zeitschrift fur Kristallographie - New Crystal Structures, v. 216, pp. 555-557, 2001

A NOTE:

This publication is included in the print copy of the thesis held in the University of Adelaide Library.