THE COMPETITIVE ACYLATION AND SULPHONYLATION OF

AMINES

A thesis submitted by

SHAHRZAD TOGHRAIE

for the

DEGREE OF DOCTOR OF PHILOSOPHY,

UNIVERSITY OF LONDON,

DEPARTMENT OF CHEMISTRY

IMPERIAL COLLEGE

LONDON SW7 2AY. JULY, 1980.

CONTENTS

PAGE:

ACKNOWLEDGEMENTS

2

ABSTRACT

3

LITERATURE REVIEW - INTRODUCTION

5

CHAPTER I. Alicyclic Compounds Containing the Acyl-X Bond. 6

CHAPTER II. Acyl Heterocyclic Compounds

23

CHAPTER III. Masked Acylating Reagents

42

RESULTS AND DISCUSSION

51

EXPERIMENTAL

86

REFERENCES

147

PUBLICATIONS

ACKNOW1EDGEMENTS

I wish to thank:

Dr. A.G.M. Barrett for his unceasing help, guidance and

enthusiasm throughout the course of this work.

Professor C.W. Rees for the privilege of working

in his department.

The technical assistance of the various service staff.

My colleagues in the Hofmann and Heilbron laboratories for

their help and friendship.

My husband for his patience and understanding.

My parents for their constant support and encouragement

Miss M. Shanahan for the typing of this thesis.

2

ABSTRACT

Acylating reagents used for the conversion of amines

into amides are reviewed. Emphasis is given to alicyclic,

heterocyclic and masked reagents.

The influence of crown ethers on the selective acylation

of mixtures of amines is described. In general, in competition

experiments the order of reactivity of two amines was reversed

in the presence of 18-crown-6. This phenomenon resulted from

selective host guest complexation. Such dynamic protection has

been applied in the differentiation between a primary and a

secondary amine, a linear and an a-branched primary amino

function and between an axial and an equatorial amine. Such

studies are relevant to the design of alternatives to classical

group protection.

3

To Ahmad and my Parents. vwvvnrt,

INTRODUCTION

Novel Reagents for the Acylation of Amines.

The conversion of an amine into an amide is classically

carried out using acyl halides, anhydrides, or esters.1

Examples are legion. However, in the extension of synthetic

methodology new acylating reagents have been devised to overcome

problems in amide preparations. Such problems include the

design of reagents selective for one amine function in a

polyfunctional molecule or reagents that do not undergo

epimerisation a to the acyl function. The suppression of

racemisation is of paramount importance in peptide bond formation.

Novel acylating species can be conveniently classified as

follows:

1) Alicyclic compounds containing the acyl-X bond.

2) Acyl heterocyclic compounds.

3) Masked acylating reagents.

5

6

CHAPTER I

1) Alicyclic Compounds Containing the Acyl-X Bond.

The preparation of amides using simple acyl chlorides, esters

and anhydrides is amply reviewed elsewhere1 and will be herein

excluded. Mixed anhydrides have been known for over a century

since the work of Gerhart2 and Chiozza.3 The reactions of a sodium,

silver, or triethylammonium carboxylate with an acyl chloride or

sulphonate are convenient methods of preparation. Behal4'5 and

Authenreith6 studied the reaction of mixed anhydrides with amines.

These anhydrides are very useful mild reagents for the acylation

of amines. In general, amines react by attack at the most

electrophilic carbonyl. Mixed anhydrides derived from a carboxylic

acid and a carbonic or sulphonic acid are alternative reagents.

Overberger and Sarlo7 reported that the mixed carboxylic-sulphonic

anhydride system was especially useful in that attack occured

solely at the carbonyl function; sulphonation did not occur.

Acetic formic anhydride, which was readily prepared by

warming acetic anhydride with formic acid, reacted with amines (e.g., 1)

selectively at the formyl group and provided an excellent method for the

preparation of formamides (2).8 These in turn were readily

dehydrated giving rise to isonitriles (3) (Scheme 1).

7

HCONH

C-N

HCO2 CO CH3

T Sc!

(2) (3)

SCHEME 1

The selective N-acylation of D-glucosamine (4) using a

series of mixed anhydrides has been studied.9 In general, attack

occurred at the more electrophilic carbonyl (Table 1) giving

amides (5).

(4)

(5)

TABLE 1

Amides (5) Formed by the Acylation of Glucosamine (4) with Mixed

Anhydrides

Mixed Anhydride % (5)

CH3C0.0.COPh 69

CH3(CH2)14CO.O.000H3 63

CH3(CH2)12CO.O.COPh 86

CH3(CH2)14CO.O.CO(CH2)6CH3 79

CH3(CH2)4C0.0.000H3 50

INCH2C0.0.COPh 65

8

The mixed anhydrides of acetic acid with dichloroacetic,

trichloroacetic, a- and (i-chloropropionic, and 'y-chlorobutanoic

acids have been prepared and have been found to be useful for

acylating amines.10 The ratio of acetylation to chloroacylation,

using these reagents, was found to depend upon the nature of

the solvent.

An example which clearly illustrates the ubiquitous importance

of both leaving group ability and protonation in determining the

reactivity of RCOX was provided by the acylation reactions using

unsymmetrical carboxylic anhydrides.11 In aqueous media the

reaction of haloacetic acid anhydrides with chloroanilines gave

the amide of the weaker acid, the acetanilide derivative, as

the major product. In aprotic media, on the other hand, the amide

of the stronger acid was preferentially formed (Scheme 2).

1) CHC€2C0.0.0OCH3 + RC6H4NH2

Rc6H4NH.co.CH3

2) CHCi2C0.0.000H3 + RC6H4NH2

'----)RC 6H 4 NH.CO.CHC? 2

SCHEME 2

+ 0 aqueous > RC6H4NH2—C-0.000HCe2 media

CH3

0 + ~

aprotic RC6H4NH2—C-0.CO.CH3 media

CHC$2

9

The product compositions formed in the acylation of aniline

with acetic chloroacetic anhydride in different solvents are

tabulated (Table 2).

TABLE 2

Effect of Solvent of the Reaction Between Aniline and Acetic

Chloroacetic Anhydride.

Entry Solvent Mole Fraction Acetanilide Formed

1 Benzene .14

2 Benzene-Acetone (80:20) .21

3 Benzene-Acetone (50:50) .26

4 Acetone .38

5 Acetone-Water (98:2) .43

6 Acetone-Water (80:20) .69

7 Acetone-Water .72

Dichloroacetanilide and acetanilide were formed via the respective

tetrahedral intermediates (Scheme 2). Clearly in a non-polar solvent

the ratio of amides was controlled by the relative electrophilicities

of the two carbonyl functions; thus the dichloroamide predominated.

10

11

In a more polar system, solvation would stabilise the intermediates,

ensure a later transition state, and thus favour the expulsion of

the better leaving group thus giving acetanilide as the principle

product.

Mixed anhydrides of carboxylic acids with carbonic acids (8)

are conveniently prepared by the reaction of an alkyl chloroformate (7)

with a sodium or triethylammonium carboxylate (6). These reagents

usually undergo selective aminolysis at the acyl carbonyl function

giving amides (9) (Scheme 3).

R'CO2 + R20.000e ---mai R'CO.0.00.0R2 3 4 R R NH ) R'CONR3R6

(6) (7) (8) (9)

SCHEME 3

Such mixed anhydrides (8) are very useful reagents in peptide

synthesis.12 Anhydrides derived from carboxylic and carbamic acids

(10) are alternative less reactive reagents. 13

R'C0.O.CONR2R3

(10)

Bicyclo[2.2.2}octane-l-carboxylic acid (11) reacted with ethyl

chloroformate in chloroform to yield the mixed anhydride (12). This

reacted with aniline to give the expected anilide (13) in good yield.14

E t OCOCI PhNH2

CO2H CO.O•CO.OE t

(12)

CONHPh

(13)

Ben zy loxycarbonylaminoacetoxycarbonyloxyethane (14) reacted with

aniline to give the expected glycinanilide derivative (15) in

65% yield.15

PhCH2OCONHCH2C0.0.CO.OEt

PhNH2 > PhCH2OCONHCH2CONHPh

(14) (15)

Reagent (14) was prepared in situ using triethylamine and ethyl

chloroformate.

Surprisingly, benzoyloxycarbonyloxyethane (16) reacted with

N-methylaniline to give the carbamate (17),16 presumably the benzoyl

carbonyl was insufficiently electrophilic. The reaction was found

to be general17 with the ratio of amide: carbamate formed decreasing

with an increase in steric hindra.Wce at the amine nitrogen.

Carbonate formation was also a predominant pathway in the reaction

of amines with t-butylcarbonyloxycarbonyloxyalkanes (18). In

general, non sterically hindered alkylcarbonyloxycarbonyloxyalkanes

and amines give amides. As a side reaction the decomposition of

anhydride (16) giving benzoic anhydride, diethyl carbonate and a

carbon dioxide has been observed with some amines including

diphenylamine.

PhCO.0.00.0Et

MeNHPh EtO.CO.N(Me)Ph

(16) (17)

—H-- C0.0.CO.OR

12

(18)

Mixed anhydrides of carboxylic acids with inorganic oxyacids

are good reagents for the acylation of amines. For example, the

addition of the N,N-dimethylformamide-sulphur trioxide complex to

an alkali metal carboxylate gave an acyl sulphate (19) which

was readily aminolysed (Scheme 4).18

2 3 _ R1CO2 + S03 —) R1CO2S03

R R NH) R1C0NR2R3 + HSO4

(19)

SCHEME 4

Carboxylic sulphonic anhydrides (20) were also prepared by the

reaction of a sulphonic anhydride with a carboxylic acid,19 by the

treatment of a silver carboxylate with an arenesulphonyl chloride,20

by the reaction of an arenesulphonyl chloride with a carboxylic acid

in pyridine,21 or by the oxidation of a arenesulphinic acid with a

diacyl peroxide.22 These mixed anhydrides (20) are very reactive

acylating reagents. Thus, for example, the addition of aniline to

a solution of benzoyl benzenesulphonate (21) gave benzanilide (22)

(Scheme 5) . R1CO.OSO2R2

(20)

PhCO 2 PhS02Cf). PhCO.0.S02Ph PhNH24 PhCONHPh

(21) (22)

SCHEME 5

Gunatilaka and Sotheeswaran23 described a convenient preparation

of hindered esters derived from testosterone and 19-norethisterone

using acyl benzenesulphonates.

13

For example the reaction of testosterone (23) with 3,3-dimethyl-

butanoyl benzenesulphonate (25) gave the steroid ester (24) in

72% yield. OR

14

ButC H2 CO2SO2Ph

(23) R = H

(24) R = COCH2Bu t

(25)

As expected cyclic sulphonic carboxylic anhydrides were found to

react with amines by attack at the carbonyl function (Scheme 6) 24

O C\

p + RNH 2 S /

62

CONHR

503H

SCHEME 6

The trifluoromethanesulphonyl (trifyl) group is the most powerful

electron-withdrawing group known. This effect has been applied in

a series of synthetic transformations.25 Triflation of nitrogen greatly

enhances the potential ofa.function to act as a stabilised anionic

leaving group [CF3S02NH2, pKa 5.8]. Thus, acylating reagents, (e.g.,

26 and 27) may be prepared from secondary amides or acyl halides

(Scheme 7).

15

COPh PhCH2NHCOPh a) NaH or 1 PhCH2N\

SO2CF3 Bu Li

b) (CF3S02)29 (26)

PhCOC? PhNHSO2CF3 Et3N

Ph > PhCON

-SO2CF3

(27)

SCHEME 7

Such acylating reagents (e.g., 26 and 27) were crystalline

substances, less reactive than acid chloride but they reacted

cleanly in high yield with modestly basic nucleophiles, e.g.,

benzylamine and reagent (27) gave N-benzylbenzamide. N-Acetyl-

N-phenyltriflamide proved to be far more efficacious for the

N-acetylation of substituted pyrroles than N-acetyl-imidazole

or other common acetylating agents. The analogous reagent,

N,N-ditriflylaniline (28) showed unexpected selectivity of reaction

with amines. Reaction of aniline, benzylamine or piperidine with

reagent (28) in triethylamine gave good yields of the corresponding

triflamides (29) but N-methyl- or N-ethylaniline were recovered

unchanged.26 The discrimination showed by this reagent could

be useful in the separation of primary and secondary aromatic amines

especially since the triflyl group is readily cleaved off.27

PhN(SO2CF3)2 + R1R2NH • ) R1R2NSO2CF3

(28) (29)

16

!-Ary1su1pheny1oxazo1idine-2,5-dione derivatives (e.g., 31)

have been used as acy1ating reagent~ in peptide synthesis (Scheme 8).28

CO 2 , ,

> + '

H3N-- C-H I

C OC/ 2 Me )

I . CH2. Ph

(30)

~N02.

VSCI

ONOl.

I =:(CH.2Ph

NO ~ S-N RNHl. OC 2. I ) I ' o~o 0 ---C-O-2.~ ~ SN HCH(CONHR)CH2,PH

(31)

SCHEME 8

These have the advantage of suppressing polymerisation encountered

when the parent heterocyc1es (e.g., 30) react with nuc1eophi1es. 29

In the course of a search for novel routes to prepare

thiourea derivatives the reaction of anhydride (32)30 with primary

and secondary amines was examined. Benzoy1ation was observed

instead of the expected thiocarbamoy1ation (Scheme 9).

PhCOC(

+

(33)

SCHEME 9

17

The base-soluble by-product (33) was easily removed. The reaction

has been applied to a range of aliphatic and aromatic amines and

amino D.68 derivatives. Thus, compound (32) was a very effective

benzoylating reagent. Its use at elevated temperatures was

precluded by decomposition with the elimination of carbon disulphide.31

Thiol esters are very useful acylating agents for amines which

have advantages over their oxygen analogues. In spite of the

ever-increasing interest in acyl-coenzyme A and its involvement

in biosyntliesis,there has not been developed a general, direct,

mild and selective method to prepare thiol esters which is applicable

to sensitive, complex organic substances. Thiol esters may be

prepared directly from carboxylic acids (Scheme 10).32 The use of

DCC often has the disadvantage of difficult work-up procedures.

R'—COOH + B(SR2) 3

R'—COOH + R2—SH + (PNC'2) 3

R'—COOH + R2—SH +

reflux, solvent

100°C, pyridine, 20 min

N=C=N 25°C, 16h

0 R'--C"

---) \S R 2

SCHEME 10

The reaction of 2-nitrophenylthiocyanate with cyclohexanecarboxylic

acid in the presence of tri-n-butylphosphine provided an 80% yield

of the thiolester (34).33

0

0---ICs N O1

(34)

PI, 0 CH3CO.S--N

Br

0 PI,

CH3CO. S—N

Br 0 l

18

Alternative, less general, preparative methods using

trithio-orthoesters (35)34 or using alkynyl sulphides (36)35 have

been described (Scheme 11).

RC (S Me) 3

(35)

SR2

+ RIC =CS RZ --~

(36)

SCHEME 11

0

Thiol esters were found to function as good acylating agents

for amines, when mixed with an oxidising agent in dichloromethane

solution. Thiol esters and N-bromosuccinimide appeared to form a

sulphurane as the reactive intermediate (Scheme 12).

~(0

CH3C0.SPh CH2Cez

0

CH3 . C. NHPh + PhSN\

` Pes?

0 lT 0

SCHEME 12

The structure of the intermediate was not certain, but the absorptions

in the PMR spectrum due to the succinimide hydrogens (d 2.79) were

consistent with the sulphurane structure, not the ion pair.36

Acyclic mixed carboxylic phosphoric anhydrides are good

acylating reagents.37 They, however, suffer from the drawback

of instability towards heat and hydrolytic conditions. The use

of the cyclic mixed anhydrides (37) obtained from 2,2-dimethyl-

propane-1,3-diol offer an attractive alternative. The position

of the attack of a nucleophile on the anhydride (37) was controlled

by the steric environment around the phosphoryl centre. Treatment

of 1,4-diamino-2,6-dibromobenzene (38) in pyridine with the

phosphate (37) gave the amide (39) in 87% yield.38

Br

H,N N }-{ x-0 O 2 + ~ il ---~ HzN ~ N H C O P{, CJ» OCOCGH5 Br

(39)

The mixed anhydride (37) exclusively acylates diverse aromatic amines;

phosphoramidates (40) were not detected. Since 2,4,6- tribromoaniline

failed to react with phosphate (37) such reagents,with suitable

)C0, P

P ci \NHAr

(40)

modification, may be suitable for selective polyamine functionalisation.

Simple phosphate derivatives (41 and 42) have found use in peptide (43)

synthesis39 (Scheme 13). The preparation of amides from amines

and carboxylic acids in polyphosphoric acid proceed via the conjugate

acid of intermediate (41).

19

(38) (37)

R'CO.OP03 + R2NH2 --> R'CONHR2

(41)

Et02C.CH(R')NH2 [(Et0)2P0]z0

> Et02C.CH(R')NHPO.(OEt)2

(42)

R2CONHCH(R3)CO2H Et02CCH(R')NHCOCH(R3)NHCOR2

(43)

SCHEME 13

a-Acylaminoacyl dichlorophosphates (43) have been conveniently

prepared using phosphorus oxychloride and converted into amides

(Scheme 14). 40

CbzoNHCH2CO2H POC$3

? CbzoNHCH2CO.OPOC$2 Et3N

(43)

NHzCH2COzMe~ CbzoNHCH2CONHCH2CO2Me

Cbzo = C6H5CH2000-

SCHEME 14

The preparation of amides by the aminolysis of simple esters

has been adequately described elsewhere.' Of note,however, was the

use of the more electrophilic vinyl and aryl esters. Representative

examples41-48

are provided in Scheme 15. Clearly such esters are

highly versatile reagents. For a given acyl function variation

the electrophilicity and hence selectivity may be easily achieved.

0—CHO

20

in

(a)

NH3

NH2(CH2) 3CH- / CO2

CO; ) HCONH(CH2) 3CH\

NH3

NO,

(b)

OAc

NH / NAc

21

NH,. N

(c) PhCO 2H DCC PhCH2C0.0.0=NR / > PhCH2CONH \\N

NHR

(d) PhCO2H Et zNC-CH PhCO.O. C=CH2 PhNH z PhCONHPh

NEt 2

(e)

4-02NC6H4NH2 NHAc

N"OAc

(n NC OAc HOCH2CH2NH2

HOCH2CH2NHAc

(g) SO2CH=C_CH2 PhCO2 SO2CH2C=C H2 OCOPh

Et02CCH2NH2 Et02CCH2NHCOPh

OMe

(h) PhCO2H HC-COMe) PhCO2 C PhCH2NH2 )PhCH2NHCOPh

Hg2+ CH2

SCHEME 15

22

2-Acyloxytetrahydropyran derivatives were found to be good

acylating reagents for amines; the by-product tetrahydropyran-2-ol

was innocuous. 49

The carbyne complexes (44) were readily prepared from the

reaction of an alkyl trichloroacetate with dicobalt octacarbonyl

in THF.50 In concentrated sulphuric acid the derived acylium

cation (45) or an equivalent was formed. This was isolated as a

hexafluorophosphate salt or converted into a range of amides

(Scheme 16). SCHEME 16

R'CO2R2 H2S0° ) RICO+ —) RICO+PF6

(44) (45)

PhCH2CH2NH2 > R'CONHCH2CH2Ph

T C

RI = (OC)3Cō '''''' Co(C0)3 R2 = H, Me, Et, Mea, Si, etc.

C (C0)3

Simple acylium cations have been prepared and converted into

amides. Their reactivity is too great to permit their use in

selective acylation reaction (Scheme 17).51

PhCOF SbF5

) PhCO+SbF6 t AgSbF6

PhNH2

PhCONHPh

SCHEME 17

PhCOC€

23

CHAPTER II

CHAPTER II

ACYL HETEROCYCLIC COMPOUNDS

Two heterocyclic systems have been used to activate a

carboxylic acid for amide preparation. Firstly, heterocyclic

esters or thioesters (46) have found wide application when the

heterocyclic alcohol or thiol is a good leaving group. Alternatively,

ring acylated heterocycles (47) are good acyl transfer

reagents when the departing group is stabilised, e.g., by

aromaticity.

RCO.X - heterocyclic ring

(46) X= 0, S

/--1 RCO.N heterocyclic ring

-.J

(47)

24

The acylation of an amino group by an amide

represents a transamidation and should be formulated,

therefore,as an equilibrium (Scheme 18).

O R II iR i R —C —N + NH

2R RCO—NH—R -f -HN , R- 2 NR

SCHEME 18

All the reagents of class (47) have a nitrogen-containing

heterocyclic ring system as amide component. Staab has reported

a review on these acylating species. These compounds can be

classified in order of their rates of hydrolysis. Pyrazolides

(48), imidazolides (49), 1,2,4-triazolides (50) and

tetrazolides (51) belong to this class of compound (Scheme 19).

/N- R• C O.N\

(48)

/--= -N R -CO' N

(49)

IN=N R•C0.NN _I

(51)

/N-

R • CO•N I \=.N

(50)

SCHEME 19

25

Imidazolides (49) and analogues have been studied by

Staab et al.52-58

They can be synthesized from the commercially

available imidazole (52), purine (53), benzimidazole (54), and

6-methyl purine (55) with an acid anhydride. N-Acetylimidazole

(56) was first prepared from the reaction between imidazole (52)

and isopropenyl acetate.

H N---1

N/~ N c_i LN 1 N)

H (52) (53)

H (54)

(52 )

(55)

. 'OAc

AcN N U

(56) H2 S 04

26

N-Trifluoro- and trichloroacetylimidazole have been shown

to be good acylating agents for the preparation of amides

(Scheme 20).59

PhNH2 (_ 4~)~ RCONHPh ( R = CF3 90% ) R = CCf 3 90%

SCHEME 20

This reaction was applicable to a wide range of primary and

secondary aliphatic and aromatic amines.

An interesting acylimidazole is 1,1'-carbonyldi-imidazole (57)

which was prepared by the reaction of phosgene with imidazole

or 1-trimethylsilylimidazole in dry benzene. This was found to

be a good carbonyl transfer reagent and a valuable source of

other acylimidazoles (Scheme 21).

N----7\ ~" N

RCO2 H ± N-CO-N i -- (48)+ CO2

-i- (52)

27

(57)

SCHEME 21

These acylimidazoles reacted readily with amines to give amides.

28

Amino acids (58) were readily acylated in the presence of

aqueous sodium hydroxide at room temperature with 1-acyl-3-methyl-

imidazolium chloride (59). The reagent (59) was obtained from

N-methylimidazole and the acid chloride (Scheme 22).60 Typical

yields are tabulated (Table 3).

O R2 II Q I _

R-C -N` jN-CH3 CI ± H2N-CH-0O2

(59) (58)

O I I

> R1 —C - NH- CH -COOH

R 2

SCHEME 22

Table 3

Amides Produced from Aminoacids (58) and the Acylimidazolium Salts (59).

R1 R2 Yield

CH3 H 90

C2H5 H 47

C6H5 H 85

C6H13 H 100

C6H5 -CH2OH 35

CH3 i-C4H9 88

29

Reagent (59) was also applicable to the acylation of simple

amines. Similar reagents including bis-salts (60) and (61)

have the same ability for the acylation of amines and amino acids.

O I H3 CH2 -C -N jN-CH3

2C1 C_N N-CH3

l 1 0

CH -C 2

11 l 0

(60)

Triazolides (50) have been prepared by the reaction of

1-trimethylsilyl-1,2,4-triazoline (62) with an acid chloride.

The precursor (62) was found to be conveniently available from

the trimethylsilylation of 1,2,4-triazoline (63) with hexamethyl-

disilazane (Scheme 23).

2C!

TMS

TMS2NH j N RCOC/

~ I N 50)

( 6 3) (62)

SCHEME 23

The acylation of 3-amino-1,2,4-trizole (64) with N-acyl-

imidazoles (49) surprisingly gave 2-acyl-3-amino-1,2,4-triazoles

(65) only,61 but previous methods using acyl halides or

anhydrides have produced mixtures of acylated and diacylated

derivatives (Scheme 24).

H

N I IN IL -}- (a s ) >

NH2

2 N-COR - (51)

NH2

(64) SCHEME 24

(65)

N,N'-Carbonyldi-S-triazole (66) has been shown to be a

useful peptide bond forming reagent.62 It has advantages over

other reagents which include a low degree of racemization and

applicability in DMF, an excellent solvent for both small and

large peptides (Scheme 25).

0 ' R

I + RCO N H-CHCO2H N

(66)

30

RCONH-CH-C -NA N\ -j- C 02 + II 0 LN

R ' NH2C H ~C0 R R

2

HN -W

RCONH-C H- C- NH - 1 H-CO2R •0 R.

SCHEME 25

It must be stressed that the reactivity of the acyl

nitrogen heterocycles so far described resulted from the

stability of the expelled parent heterocyclic conjugate base.

As an alternative to aromatic stabilisation N-acylpyrrolidones

(67) have been used to prepare the peptide bond. In this

case the good leaving group was the pyrrolidone anion. Thus,

the DL-alanine derivative (67) reacted with DL-alanine

methyl ester (68) to give the expected dipeptide (69) in 89%

yield.63

O

CH3 —CH —CO- N NHTs C H3

(67) ,CH3CHCONHCHCO2Me

NH Ts HH\1CH(CH3)COOCH3 (69)

(68)

As alternatives to the N-acyl-heterocycles (47) a number

of N-hydroxysuccinimide esters of acylamino acids have been

synthesized. These esters were found to be very good acylating

agents and were useful in peptide synthesis. 0-acylhydroxylamine

derivatives(70) are generally more useful than the analogous

esters of N-hydroxyphthalimide (71).

O

RCO O

O O

(70) (71)

31

The use of preformed esters of N-hydroxysuccinimide (70)

in peptide synthesis had been proposed earlier and favourable

results obtained in racemization tests.64 N-Hydroxysuccinimide

(72) is an " a-effect" nucleophile and was found to react very

rapidly with 0-acylisourea derivatives (73). Subsequent reaction

of the resulting ester (70) with the amino component was also

rapid, probably because of the formation of the hydrogen bonded

intermediate (74) (Scheme 26).65

0

NC6Hi/ RCOOC ± NOH "NHC6H11

(73) (72)

RNH2 0

0\ --N ) RC NH

R /

R I (74) H SCHEME 26

3-(Succinimidoxy)•-4,5-benzoisothiazole-1,1-dioxide (75) is a

useful reagent to convert carboxylic acids to their N-hydroxy-

succinimide esters (70). Micheel and Lorenz66 reported the

synthesis of peptides by using such 1,2-benzoisothiazol-3(2H)-one-

1,1-dioxide derivatives, first in 1963. Such saccharin derivatives

have good crystalline properties.67 Hettler67 found that

3-chloro-4,5 -benzoisothiazole-1,l-dioxide (76) was also effective

32

(70)

(76) (75) 0

(72) ET3N MeCN 0

Cl 0 C 2S NN

33

for the esterification of carboxylic acids. N-hydroxysuccinimide

(72) was found to be a good reagent to prepare activated esters

with minimum racemization in peptide synthesis. 3-(Succinimidoxy)-

1,2-benzoisothiazole-1,l-dioxide (75) was prepared as described

in Scheme (27).

SCHEME 27

To check its reactivity, reagent (75) was allowed to react with

benzoic acid in acetonitrile using triethylamine, to give the

N-benzoyloxysuccinimide (70, R = Ph) in 87% yield. In a

similar manner, the alanine derivative (77) was obtained in 80%

yield (Scheme 28).

O

(75) RCO2 H Et3N, McCN > R C 02N

r. t.

(77)

BocNHCH(CH3)

SCHEME 28

From these results, it was suggested that reagent (75) was

useful to convert carboxylic acids to their N-hydroxysuccinimide

esters (70). The reagent has been used to synthesise dipeptides

without racemization using benzyloxycarbonyl and t-butyloxy-

carbonyl-N-protection.

N(Benzyloxycarbonyloxy)succinimide (78) was found to be

a very reactive acylating reagent. For the selective 1-N-

acylation of aminocyclitol antibiotics, the method of transition

metal chelation proved useful. Quick acylation of the unbound

amino group(s) occurred. For example the treatment of kanamycin

A (79) with zinc acetate and N-(benzyloxycarbonyloxy)succinimide

(78) gave the 3,6'-bis-N-(benzyloxycarbonyl)kanamycin A (80),

O O

P hCH 2OCO•N

(7 8) a tris-N-(benzyloxycarbonyl)kanamycin A and a tetrakis-N-(benzyloxy-

carbonyl)kanamycin A (Scheme 29).68

34

HO

H2N

3

( 79)

(82)

IZn (OA c)2 .2H2Q ; (78)

HO

HO OH 0

H2N N HC bz .

(so)

SCHEME 29

Nefkens and Tesser69'70 have prepared hydroxyphthalimido

esters (81) from N-benzyloxycarbonyl-amino acids and N-hydroxy-

phthalimide (82) via the carbodiimide method.70

35

CH2OH HO 0 H2N

O R

N—OCOCHNHCbz

(81)

These activated esters (81) reacted with amino acid esters (83)

at 0°C within a few seconds to form dipeptide derivative (84) in

yield of 40-80% (Scheme 30).

R' R R'

(81) + H2N—CH—COOR" ) Cbz —NH—CH—CONH—CH—COOR"

(83) (84)

+ (82)

SCHEME 30

N-Succinimidyl diphenylphosphate (86), which was prepared

by the reaction of diphenylphosphoryl chloride (85) with

N-hydroxysuccinimide (72) under the conditions of the

Schotten-Baumann reaction, was useful for the preparation of

active esters and peptides instead of DCC (Scheme 31).

Ph O O O 0‘\

P-Cl t(72) Ph0 u y P-ON

Ph 0 PKY ~ī (85) (86) 0

SCHEME 31

Peptides were prepared by direct synthesis, for example, ethyl

glycinate (87)and Cbz valine (88) were treated with reagent (86)

to give the peptide (89) (Scheme 32).71

R R R R

36

NH2CHCOOR' + R"--NHIHCOOH (86) 1 R'! NHCHCONHCHCOOR'

Et3N

(87) (88) (89)

+ PhO _ +

P---0 Et3NH

PhO II 0

= CH3, C2H5

\R" = PhCH2OCO-

SCHEME 32

37

Uncatalysed reactions of 1-piperidyl esters (90) with

highly nucleophilic amines such as benzylamine was found to

be unexpectedly rapid for an ester of such a weakly acidic

hydroxy-compound. The rapidity of reaction was due to stabilisation

of the intermediate by hydrogen-bonding (Scheme 33). Subsequent

elimination occurred via the transfer of a proton to the

piperidyl-nitrogen.72

0 / )

RCON -t RN H2 \ (90)

O -> R-- C-O-N;

RNH

RCONHR + O-NH

SCHEME 32

The electrophilic attack of acyl halides on 2-ethoxypyridine-

1-oxide (91) was shown to be an exothermic reaction which gave

l-acyloxy-2(1H)-pyridones (92)(Scheme 34).73

/~ RC OC! ~N I 1 ,~

C1

\N . O C 2H 5 \~i~0 C 2H s ~ I 0 O- COR

(91)

''."--N/4p (92) I OC OR

SCHEME 34

O

N-C H—C_Cl

0 CH2

93)

94)

2NC H2COOC2H5

The high reactivity of compound (92) was applied to the

construction of peptide units. For example, reaction of acid

chloride (93) with reagent (91) afforded the activated ester

(94) which was readily condensed with glycine ethyl ester to

give an optically active phthaloyl-L-phenylalanylglycine ethyl

ester (95) (Scheme 35).

38

O II

N-C H-C-NHC H 2COOC2H5

i

( 95) SCHEME 35

Sulphonates of strongly acidic N-hydroxy compounds,

for example, 6-chloro-1(4-chlorophenylsulphonyloxy)benzotria-

zole (96k) have been used as excellent coupling reagents for

amide bond formation. The coupling reagents, listed in Table 4,

were prepared from the N-hydroxyheterocycle, arene- or alkane-

sulphonyl chloride, and base. The reactivity of each sulphonate

(96) for amide bond formation increased with a decrease in the

pks of the parent N-hydroxy compound and of the sulphonic acid.74

Clearly fine control of reactivity should be available.

(96)

39

40

Table 4. Preparation of Su1phonates (96)

RI X Base Yield % - --

a Me H NaOH 99

b Bun H Et3N 97

c CH2-{ ~ H NaOH 47

cl K )-CI H Et3N 99

e K) H NaOH 70

f Me N0 2 (6) NaOH 72

g K-) N0 2 (6) Et3N 53

h Me Ct(6) Et3N 83

i CH2-< ) Ct(6) NaOH 57

j ~-<) Me ct(6) Et3N 78

k }Q-CI ct(6) NaOH 91

_ t + McS02S Et3NH

Based on a consideration of the reactivity, stability

and accessibility, 6-chloro-1-(4-chlorophenylsulphonyloxy)-

benzotriazole (96k) was finally chosen as the most useful

member of the series.

Amides have been prepared by two procedures using the

sulphonates of acidic N-hydroxy compounds. Firstly, via

activation of a carbonyl component with the reagent (96a)

prior to the addition of an amine component, or secondly, via

the addition of the carbonyl and the amine components

simultaneously (Scheme 36).75

41

(96 a) MeCOSH Et 3N

OCOMe

McCO NH Ph

(97 )

(96a) MeCOSH ~(97) + McCONHPh + McS02S • Et3NH H2NPh

E t3N

SCHEME 36

42

CHAPTER III

CHAPTER III

MASKED ACYLATING REAGENTS

Masked acylating regents that have been used to prepare

amides include ketene derivatives, orthoesters, electrophilic

ketones and carbon monoxide.

Ketenes are good acylating agents and have been prepared

by the pyrolytic decomposition of acetic anhydride,76 glyceryl

triacetate,77 acetone,78 and other ketones,79 and by the action

of zinc or triphenylphosphine on e-haloacyl halides.80 The

more recent work on pyrolytic methods usually involved either

the use of hot metallic filaments or of metallic oxide catalysts.81

Pyrolysis of diketene82 provides an alternative synthesis of

ketene (50%) (Scheme 37).

43

jO

440 2 C H2=C=O H2C

SCHEME 37

Ketenes convert amines into amides in high yield. The reaction

involves initial nucleophilic attack of the amine on the carbonyl

function83,84 (Scheme 38).

A /CI-7-C= O

NH2

[c=_5 =0 ]..DHC—C=0

NH2R + NH2R / NHR

SCHEME 38

An important method to prepare amides from ketenes is the

Arndt-Eistert reaction, which an acyl halide is converted into

a diazo ketene; treatment with a silver(I) catalyst and an

amine gives the homologous amide85 (Scheme 39).

R' COC? CH2N2--.j R' COCHN 2 A ± -> R' CH=C=O

z R~ R'CH2CONHR2

Scheme 39

The reaction rate with ketene has been shown to be a function

of the dissociation constant of the base. Whereas aliphatic

secondary amines react readily, aromatic secondary amines react

slowly. Diphenylamine in ether at 0°C reacted slowly with

ketene to give N-N-diphenylacetamide in only 33% yield.86 With

substituted ketenes, Staudinger87 observed a higher reaction rate

with amines, than with alcohols. Diphenylketene, for example,

reacted with aniline in concentrated solution or without diluent to

give diphenylacetanilide (98) with almost explosive violence.

44

Ph2CHCONHPh

(98)

Monochloroamine gave chloroacetamide with ketene in good yield.

Dibromoamine reacted in an unexpected fashion with ketenes to

give N,l-dibromoacetamide derivatives in low yield88 (Scheme 40).

R\ R 0

C=C=O + NH2C€ —~ \CC$—C—NH2 R/ R///

(70-75%)

R\ H

C=C=0 + NHBr 2 --) \CBr— —NHBr

R/ H'/

(18%)

Scheme 40

The reaction of aziridines (100) with bis-[trifluoro-

methyl]ketene (99) in ether gave N-(3,3,3-trifluoro-2-trifluoro-

methylpropanoyl)aziridines (101) in good yield.89 Compound

(101, R = CH3) upon heating in heptane isomerised to give

amide (102) in 90% yield (Scheme 41).

F3C\ R F3C R

C=C=0 + NHH r--- R _~ \CH—CO=N~

F3C/ ` F3C/

(99) (100) (101)

R=H 80% yield

R=CH3 60% yield

F3C

CH—00—NH—CHZ—NE i =CHZ /

F3C CH3

Scheme 41 (102)

45

d CF3 CO2 2 H+ McC(CH OH) > 3 Xylene O O 106)

Bergmann and Stern90 were able to effect the N-acetylation of

amino acids by passing ketene into an alkaline solution of the

acid at room temperature (Scheme 42).

46

C H2-C=0 CH2~ HCO2 .

NH2 H2O

r.t.

CH2 1

HCO2H

NHCOCH3

Scheme 42

Orthoesters, for example (103-106) are available via

imidate hydrochlorides, acyloxonium salts, keten acetals, or,

rarely,directly,from carboxylic acids91 (Scheme 43).

+ 2

a R1CN + RZOH H~~ 7 R1(R20)C=NH2C? R2OH R1C(0R2)3

(103)

111 = H, alkyl or aryl; R2 = alkyl or acyl

RONa ) OR (104)

0 OR

b

R

BF4

C (105)

Scheme 43

C C 13 C O C C13 -~- Hexane

The acylation of amines with orthoesters is complex. The

reaction of orthoesters with aromatic amines gave imidic esters

(107).92 With mineral acid these were rearranged giving

amides (108) (Scheme 44).

47

ArNH2 + R'C(OR2) 3 —4 ArN=C R1

H2SO4 ArN—COR1 `OR2 12

(107) (108)

R1 = H, Me, Et, etc. R2 = alkyl or aryl

SCHEME 44

Electrophilic ketones are good acylating agents for amines,

providing one of the alkyl functions is a good leaving group.

Ketones containing the trichforomethyl group, such as hexachloro-

acetone were found to react with amines in hexane to yield their

trichloroacetyl derivatives (Scheme 45).

NH2 NHCOCI3

SCHEME 45

The reaction was general for primary aromatic and primary and

secondary aliphatic amines; yields of amides were good to

oxcellent.93 Hexachforoacetone has been used in peptide synthesis,

CHC13

under essentially neutral conditions without interference

from free carboxyl groups (Scheme 46).94

R2

Ce 3C . CO . CC? 3 + H 2N—CH—CO—N—CH—COOH

R1 R3

0 R2 0 I

Ce 3C . C—NH—CH—CO—N—CH—COOH

I I R1 R3

DMSO —__.). 25°C, 12-24 h.

SCHEME 46

N-Trifluoroacetyl derivatives of amino acid and peptides (109)

have been conveniently prepared under mild and neutral conditions

by reaction of amine (110) with 1,1,1-trichloro-trifluoroacetone.95

Concomitant cleavage of peptide bonds was not observed as in

the case when trifluoroacetic anhydride was used as the acylating

reagent (Scheme 47).

R-CH-C -}- C13C-C-CF3 > R-CH-C NH2 X 0 25~ HN \X

(110)

C —CF It 3 0

SCHEME 47 (109)

48

O DMSO O

(112)

HO NH2 I l CCI3COCHCl2

CHCHCH2OH 0

49

Unsymmetrical trihalomethyl ketones are less frequently used

as acylating reagents but have been shown to be valuable in the

synthesis of chloroamphenicol (111), in which the amino group in

intermediate (112) was selectively acylated by treatment with

pentachloroacetone to give the final product (111) (Scheme 48).96

OH OH

/".N HCCC12

CHCHCH2OH

SCHEME 48

Finally, reactions of 2-nitrocyclohexanone (113) with diamines and

ammonia, respectively gave the ring opening amide products (114 and

115).97

NO2

NH3 94% >O2N (CH2)5CONH2

(114)

NO2 (CH2) CO

(113) H2N-(C H2)~ NH2

`02N (CH2)5C NH(CH2)n—NH I I 0

n=0,2,6 (115)

SCHEME 49

Carbon monoxide has been used to acylate primary and secondary

amines in the presence of sodium methoxide and cobalt octacarbonyl

to give formamides. Tertiary alkylamines when similarly treated

suffered loss of one of the substituents giving dialkylformamides

(Scheme 50).

50

R1R2NH + CO HCONR'R2

Bun3N + CO --j BuZ11NCH0

PhNEt2 + CO -- PhNCOEt 1 Et

SCHEME 50

Allylamine has been reacted with carbon monoxide to give

pyrrolidone (Scheme 51).

CO= (C0)8 CH2-CHCH2NH2 + CO

SCHEME 51

Presumably the reaction proceeded via a cobalt-hydroxycarbene

complex (e.g., 116).98

/NMe2

Ln Co=C \ OH

(116)

(L = ligand, e.g., CO).

51

DISCUSSION

DISCUSSION

A common problem associated with the synthesis and selective

transformations of organic molecules is the differentiation

between two similar functions in the same molecule. Such selection

is relevant to peptide, polynucleotide, carbohydrate, etc., and

general synthetic organic chemistry. Classically, the problem

was solved by the masking or blocking of the functions in a

molecule that must be taken through a series of synthetic

operations unscathed. Thus, functional group protection has

enjoyed unrivalled use.

There are three basic requirements for the ideal protecting

group. It must be introduced under mild selective conditions in 100%

yield, it must be stable to all the required synthetic transformations

and it must be remova ble at the required time in 100% yield under

mild specific conditions. Added attractions of certain protecting

groups are the ability to confer easy crystallisability, to increase

solubility in organic solvents, or to improve chromatographic

behaviour, etc. Few protecting groups completely meet all these strict

criteria. In addition, each time a group protection is used, two

extra steps are added to a synthetic scheme: this is highly undesirable.

The range of protecting groups is enormous, choice may be dictated by

fashion.

52

NH2 SH H,% /

CO2H

(117)

).(O N

1

CO2 Me (118)

53

Group protection falls into two classes. Firstly, simple

protection in which a function is just blocked from reaction.

This is illustrated by the protection of the amino, carboxyl, and

hydroxyl functions, etc., in polypeptide chemistry. Sedondly, group

protection may, as well as conferring inertness as required, be

pivotal to controlling key steps in a synthesis. Woodward's

cephalosporin C synthesis clearly illustrates this class. The

starting material L-cysteine (117) was elegantly protected as the

1,3-thiazolidine (118). This, as well as blocking undesirable

electrophilic functionalisation at nitrogen or sulphur, permitted

stereochemical control in the amination steps (118-4119) and

facililated the 5-lactam cyclisation (119—X120)99 (Scheme 52).

x O X )(o

Nii

N S s~ N

c i H H,, CO2Me N H2 NH

0 (119) (120)

SCHEME 52

a X— B

X

2

+ (A)

(B)

54

Clearly, this second type of protection is exquisite. But simple

protection: what alternatives are there?

We considered that in a general molecule (121) containing

two similar functions, xl and x2 then selective transformation

should be possible using dynamic protection. If two equilibria are

set up between a species (A) and substrate (121) then the ratio of

the two equilibrium constants K1 and K2 will have a profound effect

on the relative proportions of products (122 and 123) formed when

reagent (B) is added [where (122) and (123) are the two products

formed by selective transformation at function x2 and xl respectively]

(Scheme 53). Thus, dynamic protection, if possible, would be more

attractive than classical simple protection in that two steps

(protection and deprotection) are eliminated.

3

K

X

4 2 K

X -( B~ X t--=

1X--(B)

• (122) (123)

SCHEME 53

O

NOCOOCH2Ph

0 (125)

OH CH2NHCO2CH2Ph

CH2OH HO 0

H2N

OH OH

Zn (OAC) 2.2H 20

HO OH

55

There are a• few examples of dynamic protection already in

the literature. For example, the aminocyclitol antibiotics such

as kanamycin A have been selectively acylated by using

transition metal chelation. This method was based on the temporary

protection of suitably disposed amino-hydroxy group as a metal

chelates and rapid acylation of the unbound amino group(s).

Treatment of kanamycin A (124) with zinc acetate dihydrate and

N-(benzyloxycarbonyloxy)succinimide (125), gave 3,6'-bis-N-(benzyl-

oxycarbonyl)kanamycin A (126) as the major product, (Scheme 54),100

3

(124)

0

(128)

O NHCO2CH2 Ph

SCHEME 54

NH2 HO O.

HO

Treatment of kanamycin A (124) with a free base and

copper(II) acetate hydrate in THF with 4-nitrophenyl acetate gave

6'-N-acetylkanamycin A (128) in 82% yield, (Scheme 55),101

56

NH 2

OH O._

HO

HaN

OH ,OAc

U, 'Cu~`•Cu - OAc

(127)

SCHEME 55

Nagabhushan, et al.,102

described the selective N-acetylation of

sisumycin, gentamycins, and kanamycin A via chelation of vicinal

or non-vicinal (1 and 2" ) amino-alcohol units.

In a heterogenous example of dynamic protection Risbood and

Ruthven claimed that styrene was selectively brominated in the

presence of cyclohexene using bromine and 5A molecular sieves.103

The selection resulted from preferential adsorption of styrene

and bromine into the zeolite cavities. Clearly, both zeolites

and clathrates are worthy of further application.

Crown ethers are macrocyclic host molecules containing a

range of heteroatom substituents and a cavity into which guest

cations can be accommodated.104

Since Pedersen's first report on

their complexation chemistry, the macrocyclic polyethers have

become recognised as important selective complexing agents for

alkali and alkali earth metal cations. In the complexation by

crown ethers there are several important parameters:

(1) The stability of the complex.

(2) The changes in the crown ether conformation on complexation.

(3) The relationship between the size of the host cavity and guest

molecule.

(4) The rates of complexation and 105

P decomplexation.

0 18-Crown-6 has a cavity of about 2.7 A, which is ideally

suitable for the accommodation of a potassium ion guest.104

Thus,

potassium salts may be dissolved in non-polar organic solvents.

57

O O OMe

(___,_C* /0 Me

58

Excellent reviews of the behaviour of such solution are available,104

the high reactivity of naked anions,106

purple benzene", 107

and potassium-l8-crown-6 as a reducing agent108 are worthy of

note.

18-Crown-6 has been shown to form stable complexes with

primary alkylammonium salts. C.P.K. models show that the high

stability results from the formation of three linear hydrogen

bonds and three 0...NH interactions (129).

Typical stability constants (K in M) for complexes of crown

ethers with t-butylammonium thiocyanate in chloroform at 24°C

are listed (Scheme 56).109

2 1 .3x10 6

3 x10

59

/■.-Th 0 0■

0-' J 3 6

1.7 x10 5•13 x 10

SCHEME 56

The stability constants were conveniently measured in a

two phase water-chloroform system using an nmr method. Clearly,

both by variation in the ring size and heteroatom substitution.

it is possible to design host molecules specific for certain

guests. The chiral recognition of 2-amino esters by crownsbased

on, dinaphthy1110

or carbohydrate units111

are most worthy of note.

Clearly, 18-crown-6 should be of application in the dynamic

protection of amines. A molecule containing two amino functions

should be able, in the presence of a proton source and 18-crown-6

to reversibly form two distinct 1:1 guest:host complexes. Thus,

on the addition of an electrophile, dynamic protection should

dramatically alter the nature of the product mixture.formed. If a

molecule contains two amino functions which dramatically differ

in their ability to be complexed by 18-crown-6 and a proton source,

then it must be expected that selective electrophilic functionalisation

of the less complexed substituent would be observed.

C.P.K. models indicate that although the methylammonium

cation is readily complexed by 18-crown-6, the dimethylammonium

cation is not. This results from a reduction in hydrogen bonding

and destabilisation by steric congestion (Scheme 57).

Sc heme 57

60

Thus, it may be expected that an alkylammonium salt would be

selectively complexed in the presence of a dialkylammonium salt.

In addition, it is predicted that in a competition experiment for

limited electrophile the dialkylammonium salt, as its conjugate

base, would be selectively functionalised in the presence of

an alkylammonium salt.

Recently, Barrett and Lana112

have described model experiments

that indicate that 18-crown-6 is indeed able to bring about amine

dynamic protection. As model systems the acylation of benzylamine

and N-alkyl-N-benzylamine mixtures were examined. In each case,

a dramatic increase in the ratio of secondary: primary acylation

was achieved in the presence of 18-crown-6. In a typical experiment

trifluoroacetic anhydride and subsequently, over 10 minutes,

triethylamine (1 mole each) were added to a solution of 18-crown-6,

benzylamine and N-benzyl-N-ethylammonium chloride (1 mmoleeach) in

chloroform (1 ml). Chromatography gave N-benzyl- and N-benzyl-N-

ethyltrifluoroacetamides (98%, 0.21 : 0.79). Without crown ether,

the amide ratio was primary: secondary 4:1. The results obtained

by these authors are tabulated (Table 5).

Thus, dynamic protection permits easy differentiation between

a primary and secondary amine function.

Clearly, in order to extend the utility of dynamic protection,

a more comprehensive study of the reaction is required. Variation

in the crown ether used, in the nature of the electrophile and

61

62

Table 5

TABLE

Entry No. Amine salt 18-Crown-6

(equiv.) % Amides Secondary amides,

(mat fractions) (I) N-Benzyl-N-methylammonium chloride 0 93 0 42 (2) „ 1 75 ().82 (3) „ •• 2 68(55)" 0 97 (4) N-Benzyl-N-ethylammonium chloride 0 99(66)d 0 20 (5) 11 11 /1 1 98 0 79 (6) •, , 2 85(75)e 41.971 (7) N-Benzyl-N-isopropylammonium chloride 0 94 0 06 (8) ,• ,• ,. 1 93 0.41 (9) •• 11 2 99(6:3)^ 0.63

(10) NN-Dibenzylammoniuin chloride 0 (14)e (54)1 0.21 (11) ., „ 1 (62)6 (29)1 0 60 (12) •, ,. 2 (86)e 1 .0 (13) N-Benzyl-N-mcthylammonium toluene-4-sulphonate` 0 90(57)d 0.24 (14) ,. .. „ 1 86 0.85 (15) ., ,• „ 2 85 3 0 98 (16) „ •, 0 100 0.67 (17) •• •• „ 1 9•t 0.93 (18) 2 913(80)^ 30.98 (19) •• „ •. 0 76 (3.86 (20) „ ,. 1 92 30.98 (21) 2 94 30.98

S \cylating agent: entries 1 --15, (C172C0),0; entries 16 -18, Ac20; entries 19--21, PhC0C1. b With the exception of entries 10, 11. and 12, ratios were estimated by n.m.r. spectroscopy (-}_0.0.2). All new compounds gave the expected microanalytical and spectral data. e Secondary amide isolated by distillation. a Primary amide isolated by crystallisation from toluene and cyclohexane, e Secondary amide isolated by chromatography on Merck Kieselgel H. 1 I'rimary amide isolated as in d. a Entries 13-21 carried out on 1 mmol scale using chloroform (10 ml). ^ Secondary amide isolated by recrystallisation from diethyl ether and cyclohexane.

structure of the amines were chosen for more detailed attention.

In addition. to 18-crown-6, dibenz-18-crown-6 (130),

dicyclohexyl-18-crown-6-(131) and N-benzyl-monoaza-18-crown-6

(132) were examined. Condensation of catechol with

di(2-chloroethyl)-ether under basic conditions gave dibenz-

18-crown-6 (130) (Scheme 58),113

Hydrogenation of crown (130) using ruthenium on alumina

gave dicyclohexyl-18-crown-6 (131)114 as a mixture of

the cis-syn-cis and cis-anti-cis isomers,115 (Scheme 59).

(130)

O + CI Cl

63

KO H

nBuOH

) A

SCHEME 58

H / Ō/ 0 H

cr

0 013 H

/ ` / H

(1 3 0 H2 (7o atm)

Ru—A120 3 >

nB uOH,100 0

H d ~b 0 u

H o 0 o H

SCHEME 59

/\/ \/ \O ` + Ts O

HO

Ph

H N

The reaction was conveniently followed by the UV spectrum in

addition to hydrogen uptake.

N-Benzyl-monoaza-18-crown-6 (132) was prepared using the

route preliminarily described by Gokel.116

Thus, condensation

of the ditosylate (133) with N-benzyldiethanolamine (134)117 under

basic conditions gave the expected crown ether (132)(Scheme 60).

The product, most conveniently isolated by distillation and

chromatography, was identical with an authentic microanalytically

pure sample.118

Tsō

64

(133) (134)

Ph

N NaOH

to3 (132)

SCHEME 60

Lana's112 work should be extended considerably if crown

ethers were able to distinguish between two primary amines.

This would be of considerable importance in peptide and

aminoglycoside methodology. This we set out to examine. At

the start of this work variation in the stability constant for

18-crown-6 complexes with substituted ammonium ions had not been

established. Recently, however, Izatt, et al.,119 have shown

that the stability of alkylammonium salt complexes decreased

with a-branching. The stability constants were determined in

methanol- at 25°C by a calorimetric method. Selected results are

tabulated (Table 6).

TABLE 6

Stability Constants for 18-Crown-6 Complexes with Substituted

Ammonium Iodides at 25°C in Methanol.

Substituted ammonium

iodide

log K

NH4 4.27 + 0.02

NeNH3 4.25 + 0.04

McCH2NH3 3.99 + 0.03

McCH2CH2NH3 3.97 + 0.07

Me2CHNH3 3.56 + 0.03

Me3CNH3 2.90 + 0.03

Me2NH3 1.76 + 0.02

Me3NH+ Complexation of.

low exothermicity

65

66

In order to exploit the difference in stability in competition

experiments between benzylamine and benzhydrylamine (135a)

were examined. Refluxing benzophenone with hydroxylammonium

chloride and triethylamine gave the oxime (83%). Subsequent

reduction with zinc dust and ammonium acetate gave benzhydryl-

amine (135a) (85%). In all the competition experiments one of

the amines was employed as the toluene-4-sulphonate salt. Clearly

for complexation to take place one equivalent of acid was

required; toluene-4-sulphonate salts were found to be in general,

non-hydrated and non-hygroscopic and thus very convenient.

Reaction of benzhydrylamine (135a) with toluene-4-sulphonic acid

in methanol gave the analytically pure salt (76%). Reference

samples of N-benzyl (136a) and N-benzhydryl (135b) toluene-4-

sulphonamides were prepared by reaction of the amines with

toluene-4-sulphonyl chloride in triethylamine. In each of the

competition experiments, reference samples of both amine

derivatives were prepared (see experimental). All toluene-4-

sulphonate salts and amine derivatives were fully characterised

by spectral data and microanalysis or by comparison with

literature data (see experimental).

Benzhydrylammonium toluene-4-sulphonate, benzylamine

and 18-crown-6 (1 mtuole each) were dissolved in dry dichloro-

methane (5 ml) to give a crystal clear solution. Toluene-

4-sulphonyl chloride (1 equivalent) was added, followed by

triethylamine (1 mmol) over five minutes. After 48 h the

toluene-4-sulphonyl chloride was completely consumed.

Chromatography gave N-benzhydryltoluene-4-sulphonamide (135b)

(30%) and N-benzyltoluene-4-sulphonamide (136a) (67%). In

the blank experiment the reaction was repeated without crown

ether. This time the solution, before the addition of

toluene-4-sulphonyl chloride, was hazy. Chromatography gave

N-benzhydryltoluene-4-sulphonamide (135b) (4%) and N-benzyl-

toluene-4-sulphonamide (136a) (91%). When the reaction was

repeated using two equivalents of 18-crown-6, the two sulphonamides

(135b) (44%) and (136a) (47%) were isolated. Thus, as the

amount of 18-crown-6 was increased the ratio of more hindered

(135b) to less hindered (136a) sulphonamide formed was

increased. Although exclusive formation of sulphonamide

(135b) was not achieved the variation in reaction was fully

constant with Izatt's measurements.119

Ph

67

Ph NHR Ph/NNHR

(135)

(136)

a; R = H

b; R = Ts

c; R = SO2

a; R = Ts

b; R = SO2 /

\ /

The partial success in the dynamic protection of

benzhydrylamine (135a) in the presence of benzylamine

followed from the anticipated lower stability of complex

(137a) relative to (137b).

./0..H, 4 H.A ■., N:

R1H 1oi ō

(137)

a; R = Ph2CH

b; R = PhCH2

We expected that an increase in steric congestion in the

crown unit would destabilise complex (137a) more than (137b)

thus improving the dynamic protection. The competition

experiment between benzhydrylamine (135a) and benzylamine was

repeated in the presence of dicyclohexyl-18-crown-6 (131).

With one and two equivalents, the sulphonamides (135b) (59, 71%

respectively) and (136a) (29, 27% respectively) were formed.

Clearly the more hindered dicyclohexyl-18-crown-6 (131) was

more advantageous. The naphthalene-l-sulphonylation of mixtures

of benzhydrylamine (135a) and benzylamine also varied

68

with 18-crown-6. However, the ratio of sulphonamides (135c

and 136b) did not vary dramatically with 18-crown-6 (13:87-

31:69). The more difficult differentiation between 1-phenyl-

ethylamine (138a) and benzylamine'wasalso examined. In a

competition experiment without crown ether, both N-(1-phenyl-

ethyl)toluene-4-sulphonamide (138b) (10%) and N-benzyltoluene-

4-sulphonamide (136a) (85%) were formed. With 18-crown-6

(1 and 2 equivalents) the respective yields were (138b) (22, 22%)

and (136a)(71, 76%).

Ph NHR

(138)

a; R = H

b; R = Ts

It was of much interest to prepare and study the use of

a hindered crown ether in the differentiation between benzhydryl-

amine (135a) or 1-phenylethylamine (138a) and benzylamine.

Tetramethyl-l8-crown-6 (139) was chosen for study. This crown

should be available via Scheme 61.

69

),

/

HO HO

/0 r0 O

I L-01 O

Ph Ph

o\

\OH HO/

PhO CI (14(3)

Na H

Pd/C

70

(139)

SCHEME 61

a; X= 0

b; X = NOH

2-Benzyloxyethanol120 on reaction with thionyl chloride and

N,N-dimethylaniline was converted into the known 2-benzyl-

oxyethyl chloride (140). Attempted condensation between

chloride (140) and pinacol (141) under diverse basic conditions

gave only intractable mixtures. The route was abandoned.

Competition experiments between 9-aminofluorene (142a)

and benzylamine were also abandoned. 9-Aminofluorene (142a)

(83%) was prepared by reduction of oxime (143b) with lithium

aluminium hydride. The derived toluene-4-sulphonate salt

(142b) could not be obtained microanalytically pure and amine

(142a) did not react clearly with toluene-4-sulphonyl chloride

etc.

71

(142)

(143)

a; R = NH2 +

b; R = NH3Ts0

In competition experiments between a secondary and a

primary amine, Lana studied acylating but not sulphonylating

reagents in detail. In an extension of this work, competition

experiments between benzylamine and N-alkylbenzylamines with

several electrophiles were studied (Table 7 and experimental).

In each case it can be seen that the more hindered amide

was favoured by dynamic protection; the phenomenon is

general. Of particular note (entry 30) was the predominance

of formation of the secondary amide in a competition experiment

between benzylamine and N-benzyl-iso-propylamine. In the

presence of N-benzyl-mono-aza-l8-crown-6 (132) 62% of the

very hindered N-benzyl-N-iso-propyltoluene-4-sulphonamide

was formed.

(144)

a; X = C€

b; X = NHCH 2Ph

c; X = N(Me)CH2Ph

N-Methylaniline was selectively tosylated in the presence of

aniline or benzoylated in the presence of benzylamine using model

dynamic protection (Table 8). However, in a competition experiment

between benzylamine and n-butylamine no significant variation with

crown ether was observed.

72

TABLE 7

Competition Experiments Between Benzylamine and N-Alkylbenzylamines

Entry N-alkylbenzylamine as toluene-4- sulphonate salt

Equivalent 18-crown-6a

Electrophile Temperature Rate of Et3N addition

% Amine derivative

Mole fraction secondary amine derivative b

1 PhCH2NHMe 0 TsCe Room temp. 5 min 94 0.97

2 1* " 97 1.0

3 2* " 97 1.0

4 " 0 " " II

9 0 0.97

5 " 1* 94 0.97

6 II 2* " " " 94 1.0

7 u 0 McS02Ce " " 88 0.52

8 u 1* u " " 97 1.0

9 2* It II 11 94 1.0

10 " 0 4-02NC6H4OCOPh " " 98 0

11 " 1* " " " 98 0.15

12 " 2* " 98 0.67

TABLE 7 (cont.)

Entry

.

N-Alkylbenzylamine as toluene-4- sulphonate salt

Equivalent 18-crown-6a

_

Electrophile Temperature

,

Rate of Et3N addition

% Amine derivative

Mole fraction secondary amine derivativeb

13 PhCH2NHMe 0 144a room temp. 5 min 98 0

14 I, 1* 11 ft " 95 0.33

15 If 2* If 11 11 99 0.50

16

17

PhCH2NHiso

Pr 11

0

1*

TSC$ II

" It

" it

100

98

< 0.02

0.31

18 It 2* It 99 0.46

19 It 2* " " 89 0.47

20 it 2* It " 2 hr 92 0.51

21 " 2* It " 12 hr 92 0.57

22 u 2* 48 hr 94 0.56

23 " , 2* " It 1 week 96 0.60

24 2* 40° 12 hr 98 0.02

25 11 2* I t 0° 12 hr 99 0.16

26 " 2* " -18° 12 hr incomplete in 2 months

TABLE 7 (cont)

T

Entry N-Alkylbenzylamine Equivalent Electrophile Temperature Rate of Et3N 7, Amine Mole fraction as toluene-4- sulphonate salt

18-crown-6a addition derivative secondary amine derivativeb

27 PhCH2NHiso

Pr 0 TsC$ room temp. 5 min 98 0

28 II 1* It 97 0.55

29 II 2* " 97 0.62

30 " 2* It 1 week 95 0.65

31 " 0 McSO2C$ " 5 min 100 0

32 11 1* It " I' 77 0.48

33 " 2* " " " 91 0.52

34 0 4-02NC6HAOCOPh ft 0

35 " 1* " " " 92 traces

36 it 2* " 94 traces

•

TABLE 7 (cont.)

Entry N-Alkylbenzylamine as toluene-4- sulphonate salt

Equivalent 18-crown-6a

-

Electrophile Temperature Rate of Et3N addition

% Amine derivative

Mole fraction secondary mine derivative

37 PhCH2NHCH2Ph 0 TsCe room temp. 5 min 89 0.30

38 It 1* tt It II

90 0.62

39 " 2* " It 100 0.80

40 It 2* " " 12 hr 84 0.84

41 II 2* Ac20 " 5 min 95 0.96

42 PhCH2NHtBu 2* TsC$ 1' 5 min 99 traces

a Reactionsdesignated (*) were completely homogeneous during the reactions. All other reaction solutions were hazy although

the amount of undissolved material was small. Reactions (4,5 and 6) were carried out using dibenz-18-crown-6 (130) whereas

reactions (27, 28, 29 and 30) utilised N-benzyl-mono-az-l8-crown-6 (132).

b The ratios of ,amides were estimated by nmr spectroscopy by comparison with reference compounds.

TABLE 8

Competition Experiments Between Two Amines

Entry Amine I Amine II as toluene- 4-sulphonate salt

Equivalent. 18-crown-6a

Electrophile % Amine derivative

Mole Fraction amine II derivative

1 nBuNH 2 PhCH2CH2NH2 0 PhCOCi 85 0.46

2 " it 1* " 62 0.48

3 " " 2* II 72 0.50

4 PhNH2 PhNHMe 0* TSC$ 84 0.54

5 It It 1* 'T 84 0.80

6 " " 2* It 88 0.96

7 PhCH2NH2 PhNHMe 0* PhCOC$ 97 0.73

8 " 1* " 96 0.78

9 2* 94 0.89

a,b see footnotes Table 7.

78

The ring electrophilic substitution of aniline iS a very

facile process compared with the anilinium cation. Since anilinium

cations are complexed by 18-crown-6, it was of interest to

examine the substitution of aniline and derivatives in the presence

of 18-crown-6 and a proton source. As a model reaction, a

competition reaction between aniline and N-methylaniline was

examined. It was anticipated that in the presence of a proton

source and 18-crown-6, N-methylaniline would be preferentially

substituted. When anilinium toluene-4-sulphonate (145a) and

N-methylanilinium toluene-4-sulphonate (145b) were reacted with

bromine (3 equivalents) in the presence of 18-crown-6 (2 equivalents)

three products were obtained. By comparisons with authentic

samples, these were assigned as 2,4,6-tribromoaniline (146a)

(34%), N-methyl-2,4,6-tribromoaniline (146b) (11%), and

4-bromoaniline (147) (37%). Without crown ether, the products

identified were 2,4-dibromo-N-methylaniline (148b) (28%), 2,4-di-

bromoaniline (148a)(6%) and 4-bromoaniline (147) (1%). Using

excess crown ether((5.0 equivalents), 2,4-dibromo-N-methylaniline

(148b) (14%), N-methyl-2,4,6-tribromoaniline (146b) (8%), and

4-bromoaniline (147) (24%) were formed. Thus, although the

addition of 18-crown-6 brought about a variation in bromination,

the reaction was preparatively useless and was abandoned.

79

+ - R N H,.Tso RNH

Br

(145)

(146)

a; R = H a; R= H

b; R = Me b; R = Me

NH2 RNH

Br

(148)

a; R = H

b; R = Me

Br

(147)

In general, the results in this thesis and Lana's results

show that the regioselectivity of both acylation and sulphonyl-

ation of a diamine (or model mixture of two amines) is reversed

on dynamic protection. We were interested in extending the

reaction to conformationally rigid systems. We anticipated

that an axial amine would be less nucleophilic than an

equatorial amine. However, dynamic protection would _reverse

the reactivity and favour axial substitution. Thus competition

experiment between the axial 3a-amino-(149a) and equatorial

3R-amino-(149b)-5a-cholestanes were carried out. Using

standard procedures 5a-cholestan-30-ol (149c) was converted into

5a-cholestan-3-one (150a)121

and then to oxime (150b).122

Reduction of oxime (150b) with lithium aluminium hydride in THF

gave a mixture of 3a- and 3R-amino-5a-cholestanes (149a and b),123

These were conveniently separated after acetylation with acetic

anhydride and triethylamine. Chromatography of the amide

mixture on Kieselgel H gave the less polar 3a-amide (149d) (59%1

and the more polar 313-amide (149e) (38%). Both were identified by

microanalysis and comparison with literature data for the

m.p.'s and [a]r) values123 (see experimental). In addition, as

expected,124

the nmr spectra were highly informative. The C-3

proton was observed at S 4.2 (WH 15 Hz) in the 3a-amide (149d)

and at 6 3.8 (WH 30 Hz) in the 313-amide (149e). The pure

3a-(149a) and 30-(149b) amines were prepared by hydrolyses

using ethanolic hydrochloric acid at reflux. (Scheme 62).

80

(149)

a; R1 = H, R2 = NH2 f; R1 = H, R2 = NHTs

b; R1 = NH2, R2 = H g; R1 = NHTs, R2 = H

c; R1 = OH, R2 = H

h; R1 = H, R2 = NHCOCF3

d; R1 = H, R2 = NHAc i; R1 = NHCOCF3, R2 = H

e; R1 = NHAc, R2 = H

j; R1 = N(Ac) 2, R2 = H

(150)

a; X=0

b; X = NHOH

(149c) K2Cr20'

IT- (150a)

+ -

NH30H C$ (150b)

H2SO4 NaOAc

H20, PhH THF, EtOH, A

LiA$H4 b) + (149e)

THF, A (149a,

Ac20

Et20

) (149d)

1) HC?, EtOH, A

1) HC?,

EtOH A

2) NaOH 2) NaOH

(149a) (149b)

81

SCHEME 62

82

Reference samples of 3a-(149f) and 30-(149g)-toluene-4-

sulphonylamino-5a-cholestanes were prepared using toluene-4-

sulphonyl chloride and triethylamine. Both were obtained

micro analytically pure and fully characterised spectroscopically.

Again, the WH

values for the 3-protons were in full agreement

for assignment of configuration [(149f) S 3.5 (1H, m, WH, 16 Hz,

with D20 gave WH 8Hz, 30-H); (149g) S 3.05 (1H, m, WH 28 Hz, with

D20 gave WH 22Hz, 3a-H)]. The 3a-amine (149a) with trifluoro-

acetic anhydride and triethylamine gave the expected trifluoro-

acetamide (149h). All spectral data [especially S 3.8 (1H, m

WH 18 Hz, 30-H)] and microanalysis were in full agreement with

the expected structure (149h). Reaction of the 30-amine (149b)

with trifluoroacetic anhydride and triethylamine gave a

crystalline solid m.p. 150-152°C. Although spectral data +

[especially Mie 483 (M)] were in agreement with formulation as

the 30-trifluoroacetamide (1491) the compound could not be

obtained microanalytically pure, even after repeated crystallisation.

Competition experiments between 3a-amino-(149a) and

30-amino-(149b)-5a-cholestanes were carried out as follows.

Trifluoroacetic acid and acetic anhydride (0.5 mole each)

were added in sequence to amines (149a and b) (0.5 mmole each)

in dry chloroform (10 ml). To the resulting clear solution was

added triethylamine (0.5 mole) over five minutes. After 24 h

chromatography gave amides (149d) (12%) and (149e) (71%).

Clearly, as expected, the predominant product was the equatorial

83

0-amide. When the reaction was repeated in the presence

of 18-crown-6 (1 or 2 equivalents) the 3a-(149d) (40, 59%) and

30-(149e) (45, 22%) were formed respectively. Thus, in the

presence of excess crown ether dynamic protection favoured the

formation of the more hindered amide (149d) although not to

the exclusion of the 30-product (149e). However, using N-benzyl

mono-aza-18-crown-6 (1 or 2 equivalents) (132) instead of

18-crown-6 a curious result was observed. A new product

(C31H33NO2) was formed in both reactions, neither 3-amides

(149d or e) were formed. On reaction with benzylamine the

unknown product gave amide (149e) and N-benzylacetamide (tic).

Thus the,new compound was the 30-diacylamine (149j). Presumably,

the N-benzyl-mono-aza-18-crown-6 (132) was functioning as an acetyl

transfer catalyst. Exclusive 0-substitution was intriguing.

Competitive toluene-4-sulphonylation of amine (149a and b)

mixtures was also studied (Table 9). Again, it is apparent

that dynamic protection favoured selective a-substitution even

though this was via the more hindered pathway. Using

N-benzyl--mono-aza-18-crown-6 (132) the 3a-toluene-4-sulphonamide

(149f) was the exclusive product. Thus dynamic protection should

be of immense importance in the differentiation between two

conformationally different primary amino-functions.

84

The trifluoroacetylation of mixtures of amines (149a and b)

was also examined. Without crown ether the ratio of 3a: 3R-

trifluoroacetamides (149h:i) was 16:9. With crown ether (1 or

2 equivalents) the respective ratios were 4:1 and 41:9. The

high yield of the a-amide (149h) without crown ether was puzzling.

In a series of blank experiments monitored by tic, it was

shown that transacylation was unimportant. Mixtures of

amine (149a or b) and amide (149i or h) did not appreciably

exchange even in the presence of 18-crown-6 or trifluoroacetic

acid. In general, the reactions giving the trifluoroacetamides

(149h and i) were irreproducible. Lana attributed this to the

fragmentation of 18-crown-6 by trifluoractic anhydride on

prolonged reactions,125

In addition., failure to prepare amide

(1491) analytically pure, was an added complication.

Dynamic protection has been shown to be widely applicable

in model systems. Differentiation between a secondary and a

primary amine, an a-branched primary and a linear primary amine,

or an axial and an equatorial primary amine are all clearly

synthetically useful.

Table 9

Competitive toluene-4-sulphonylation of mixtures of amines

(149a and b) in the presence of 18-crown-6.

Entry Crown Ether (equivalent)

% Yield (149f and g)

Ratio (149f):(149g)

1 - 96 13:37

2 18-crown (1) 88 47:53

3 " (2) 88 70:30

4 dicyclohexyl- 18-crown-6 (131) (1) 87 13:12

5 " (2) 85 37:13

6 N-benzyl-mono aza-18-crown- 6 (132) (1) 84 1:0

7 " (2) 87 1:0

85

86

EXPERIMENTAL

EXPERIMENTAL

M.P.'s were determined on a Kofler hot stage and are un-

corrected. Optical rotations were recorded on chloroform

.solutions. I.r, spectra were recorded using a Perkin Elmer

257 grating spectrophotometer. Unless stated to the contrary,

nmr spectra were recorded as deuteriocholoroform solutions

using a Varian T60 or Perkin Elmer R32 instrument. Ultraviolet

spectra were recorded on ethanol solutions on a Unicam SP 800B

spectrophotometer. All solvents were dried and redistilled

prior to use. Merck Kieselgel H or 60 was used for column

chromatography under a positive pressure. T.l.c. was carried

out on commercial Merck F254 plates either foil or glass

backed; whilst p.l.c. used 1 mm films of Keiselgel GF254.

Organic solutions were dried over sodium sulphate and

evaporated under reduced pressure. During the competition

experiments homogeneity during complete reaction is designated

by * (See Tables 10-32).

87

88

Preparation of Dibenz-18-crown-6 (130): Sodium hydroxide pellets

(40.4 g, 1.01 moles) were added to a solution of catechol (110 g,

1 mole) in n-butanol (650 ml). The mixture was brought to reflux

and a solution of bis-[2-chloroethyl]ether (74.4 g, 0.5 mole)

in n-butanol (50 ml) was added dropwise with stirring over 2 h.

After an additional hour the solution was cooled to 90°C and

sodium hydroxide (40.4 g, 1.01 moles) was added. After a further

0.5 h at reflux, a solution of the dichloroether (as above)

was again added and the resulting mixture refluxed for 16 h. The

solution was acidified with concentrated hydrochloric acid (100 ml).

The butanol was removed by distillation, and the crown was

obtained by precipitation with acetone. Recrystallisation from

acetonitrile gave dibenz-18-crown-6 (130) (108 g, 30%) as white

needles, m.p., 166-168°C (lit.113

164°C ), vmax (nujol) 1590,

1510, 1450, 1250, 1230, 1130, 990, 930, 770, and 740 cm-1;

d(CDC€3) 4.1 (16 H, m, CH2) and 6.9 (8 H, s, aryl-H); m/e 360 (M),

180, 163, 136 and 121; (Found: C, 66.64; H, 6.71. Calculated for

C20H2406: C, 66.65; H, 6.71%).

Preparation of Dicyclohexy1-18-crown-6 (131): Dibenz-l8-crown-6

(1300 (12.5 g, 0.03 mole) in iso-butanol (50 ml), and 5% ruthenium

on alumina (1.25 g) was hydrogenated at 100°C under a 70 atm

pressure. When the ultraviolet spectrum of an aliquot was

transparent at 250 nm, the catalyst was filtered off, and the solvent

89

evaporated to give the crude product (13 g) which solidified on

standing. A solution of crude product in petroleum 40-60°C and

dichloromethane (1:1) (50 ml) was filtered through a column of

Brockman neutral I alumina (eluant dichloromethane). Evaporation

of the solvent gave a mixture of the diastereoisomeric cis- anti-

cis-, and cis- syn- cis- dicyclohexyl-l8-crown-6 (131) as white

prisms (7.8 g, 70%), m.p., 41-50°C (lit.114 38-54°C), 'max

(nujol)

3460, 1450, 1350, 1110 broad s, 1000, and 970 cm-1; d(CDC$3)

0.9-2.2 (16 H, m), and 3.68 (20 H, s, OCH2).

Preparation of N-Benzyldiethanolamine (134): Diethanolamine (105 g,

1 mole) was dissolved in tetrahydrofuran (200 ml) and benzyl

bromide (171 g, 1.0 equiv.) was slowly added (exothermic reaction).

An aqueous solution (100 ml) of sodium hydroxide (40 g, 1.0 equiv.)

was added,und the mixture refluxed overnight. The solvent was

evaporated, and the solid residue dissolved in fresh tetrahydrofuran

(200 ml) and the solid filtered off. The solvent was evaporated and

the residue was redistilled to give the product (62 g, 32%),

b.p., 156-157°C/0.9 mm (lit.117

189-91°C/760 mm), Vmax (neat)

3330, 2870, 1608, 1455, 1055, 875, 730, and 700 cm-1; d(CDC$3)

2.63 (4 H, t, J = 5 Hz, N-CH2), 3.18 (2 H, s, OH), 3.58 (4 H, t,

J = 5 Hz, 0-CH2), 3,66 (2 H, s, PhCH2), and 7,2 (5 H, s, aryl-H).

90

Preparation of 1,11-Bis-(toluene-4-sulphonyloxy)-3,6,9-trioxa-

undecane (133): Tetraethylene glycol (194 g, 1 mole) was dissolved

in pyridine (200 ml) and toluene-4-sulphonyl chloride (381 g, 2.0

equiv.) was added slowly. The mixture was stirred overnight.

The pyridine was distilled off and the liquid residue was

poured into water and extracted with dichloromethane (500 ml).

The solvent was evaporated and the residue chromatographed on

Kieselgel 60 (100 g) to give (eluant dichloromethane) the title

compound (133) (165 g, 33%), as a crude oil, (lit.126

very high

boiling syrup), vmax

(neat) 3440, 1640, 1585, 1440, 1350,

1300, 1110 broad s, 740, 708, and 650 cm-1 ; S(CDC$3) 2.32

(6 H, s, aryl-Me2), 3.84 (16 H, broad s, 8 x CH2), and 7,30

(8 H, m, aryl-H).

Preparation of N-Benzyl-monoaza-18-crown-6 (132)1 :8 N-benzyldiethanol-

amine (134) (61.6 g) was dissolved in dry tetrahydrofuran (2 L) under

nitrogen, and sodium hydride (22.8 g, 3.0 equiv.) was added to the

solution. The solution was stirred overnight to provide the

dianion. 1,11-Bis-(toluene-4-sulphonyloxy)-3,6,9-trioxaundecane

(133) (165 g) was added in dry tetrahydrofuran (1 L) to the dianion

and the solution was stirred for one week at room temperature.

Water (5G ml) was added to the solution and the solvent was

evaporated off, The liquid residue was extracted with chloroform

(300 ml) and washed with water (2 x). Evaporation of the solvent

and redistillation gave the crude product crown ether (132) (55 g,

499), b.p., 185-220°C/0.1 mm, vmax

(neat) 3450, 3060, 2870, 1625, 1500,

1458, 1355, 1300, 1250, 930, 735 and 700 cm-1; S(CDC$3) 2.79 (2 H,

t, J = 5 Hz, N-CH2), 3.65 (24 H, s, 0-CH2, N-CHZ) and 7.26 (5 H,

s, aryl-H) .

91

Preparation of 2-Benzyloxyethanol: Potassium hydroxide (78.2 g,

2 moles) was dissolved in ethane-1,2-diol (310 g, 5 moles). After

distilling a small amount of water from the solution, benzyl

chloride (252 g, 2 moles) was added over 2 h keeping the

temperature about 90°C. When the addition was complete, the

temperature was increased to 130°C and kept at 130°C for 2 h.

The mixture was cooled and diluted with water (1 L), the insoluble

oily product was extracted with diethyl ether (1.5 L). The

solvent was evaporated off and the liquid residue distilled to give

2-benzyloxyethanol(62%) as an oil, b.p., 140-145°C/20 mm (lit.127

131°C/13 mm); vmax

(neat) 3340, 2900, 1650, 1455 and 1080 cm-1:

d(CDCt3) 3.60 (4 H, broad s, 0-CH2), 4.50 (2 H, s, aryl-CH2),

4.8 (1 H, broad s, OH), and 7.25 (5 H, s, aryl-H); m/e 152 (M),

107 and 91.

Preparation of 2-Benzyloxyethyl Chloride (140): A mixture of

2-benzyloxyethanol (8 g) and N,N-dimethylaniline (6.5 g) was

treated below 30°C with thionyl chloride (7.25 g) in chloroform

(10 m1). The mixture was heated on a steam-bath for 30 mins. and

poured into dilute hydrochloric acid (100 ml). The oil was

extracted with chloroform (2 x) and the extract washed with dilute

hydrochloric acid and water and distilled to give the title chloride

(140) (77%), b.p., 65-70°C/1 mm (lit,12O 124°C/20 mm); S(CDC$3)

3.63 (4 H, m, 0-CH2, C€-CH2), 4.58 (2 H, s, CH2•), and 7.35 (5 H, s,

aryl-H).

92

Preparation of Benzophenone Oxime: Benzophenone (10 g) was dissolved

in ethanol (100 ml), and hydroxylammonium chloride (3.6 g, 2.0 equiv.),a►id

triethylamine (5.8 g, 1.0 equiv.) were added in the usual way.

Recrystallisation from ethanol gave benzophenone oxime (8.96 g,

83%) as white needles, m.p., 140-142°C (lit.128 141-142°C); S(CDCe3)

7.58 (m) .

Preparation of Benzhydrylamine (135a): Benzophenone oxime (2 g)

was dissolved in ammonium hydroxide (conc. 20 ml) and ethanol

(20 ml). Ammonium acetate (840 mg, 1.0 equiv.) and zinc dust

(1 g, 1.0 equiv.) were added to the solution in the usual way.

Benzhydrylamine (135a) (1.53 g, 76%) was obtained as an oil,

b.p., 192-193°C/0.5 mm (lit.129 288°C/760 mm); "max

(neat) 3220,

3015, 2850, 1590, 1480, 1450, 1310, 1025,870, and 740 cm-1;

S(CDC€3) 1.6 (2 H, s, NH2), 5.1 (1 H, s, CH), and 7.3 (10 H, m, aryl-H).

Preparation of 9-Hydroxyiminofluorene (143b): Fluorenone (143a)

(10 g) was dissolved in ethanol and tetrahydrofuran (1:1) (100 ml).

Hydroxylammonium chloride (7.6 g) and sodium acetate (15 g) were

added to this solution and the mixture was heated to reflux for

24 h to complete reaction. The solvent was evaporated off and

the solid residue recrystallised from ethanol to give 9-hydroxy-

iminofluorene (143b) (10.7 g, 99%) as an orange crystalline solid,

m.p., 197-198°C, (lit.130 198°C), vmax (nujol) 3150, 1610, 1450,

1000, 935, 780, and 730 cm-1; S(CDC€3) 7,8 (9 H, m, aryl-H and OH).

93

Preparation of 9-Aminofluorene (142a): 9-Hydroxyiminofluorene

(143b) (8 g) was dissolved in tetrahydrofuran (100 ml) and lithium

aluminium hydride (3.9 g, 3.0 equiv.) was added to this solution.

The mixture was heated to reflux for 48 h. Saturated aqueous

sodium sulphate (5 ml) was added to destroy the excess of hydride,

the mixture was filtered and the solid washed with hot THF.

Evaporation of THF solution gave 9-aminofluorene (142a) (6.12 g,

76%) as yellow needles, m.p., 64-66°C (lit.131 62-63°C), "max (CHC'3)

3260, 2870, 1645, 1615, 1605, 1450, 1340, 1150, 1100, 1060, 890, and

865 cm-1 , d(CDC$3) 7.0-8.0 (m, aryl-H and NH2, CH).

Preparation of p-Nitrophenyl Benzoate: p-Nitrophenol (3.5 g) and

benzoyl chloride (3.1 g) were heated until hydrogen chloride was

no longer evolved; the mixture was poured into boiling glacial

acetic acid and then into water. The solid was filtered off and

recrystallised from water to give p-nitrophenyl benzoate (4.27 g,

70%), as needles, m.p., 143-145°C (lit,132 142-142.5°C);

Amax (nujol)

1740, 1620, 1595, 1518, 1350, 1315, 1265, 1205, 1060, 885, 845 and

805 cm-1 ; d(CDC?3) 8,4-8.0 (4 H, m, aryl-H) and 7,7-7,2 (5 H,

m, aryl-H); m/e 243 (M), 139, 105 and 77.

Preparation of Benzhydrylammonium Toluene-4-Sulphonate: Benzhydrylamine

(135a) (5 g) was added to a solution of toluene-4-sulphonic acid

(5,8 g, 1.0 equiv.) in hot methanol (6 ml), The solution was cooled

and diethyl ether (50 ml) added to precipitate the salt. Recrystallisation

94

from methanol gave benzhydrylammonium toluene-4-sulphonate (8.1 g,

84%) as white needles, m.p., 240-241°C, vmax (nujol) 3500-2500 br,

1580, 1100br, 1000, 800, 730 and 670 cm-1

; S(CDC€3) 2.38 (3 H, s,

CH3), 5.4 (1 H, s, CH), and 7.4 (17 H, m, aryl-H and NH3); (Found:

C, 67.45; H, 5.98; N, 3.90. C20H21NO3S requires: C, 67.58;

H, 5.95; N, 3.94%).

Preparation of 1-Phenylethylammonium Toluene-4-Sulphonate: 1-Phenyl-

ethylamine (138a) (318 mg) was added to a solution of toluene-4-

sulphonic acid (0.5 g, 1.0 equiv.) in hot methanol (2 ml). The

solution was cooled and diethyl ether (50 ml) added to precipitate

the salt. Recrystallisation from methanol gave 1-phenylethylammonium

toluene-4-sulphonate (658 mg,89 as white plates, m.p. 98-100°C,

v max

(nujol) 1535, 1205, 1170, 1030, 1005, and 680 cm-1; 6(CDC?3)1.28

(3H,d,J = 6Hz, CH3), 2.3 (3 H, s, CH3) and 7.41 (12 H, m, aryl-H and

NH3); (Found: C, 61.17; H, 6.47; N, 4.69. C15H19NO3S requires: C, 61.41;

H, 6.52; N, 4.77%).

Preparation of N-Benzylmethylammonium Toluene-4-Sulphonate: Toluene-

4-sulphonic acid (20 g) was dissolved in hot methanol (25 ml) and

N-methylbenzylamine (12.7 g, 1.0 equiv.) added. The solution was

cooled and diethyl ether (100 ml) added to precipitate the salt.

Recrystallisation from methanol gave N-benzylmethylammonium toluene-

4-sulphonate (24.9 g, 81%) as white needles, m.p., 154-1560 C,vmax (nujol),

1620, 1450, 1370, 1220, 1160, 1120, 1030, 1010, 810,_740, 700, and

680 cm-1; S(CDCe3) 2.31 and 2.46 (6 H,2s , 2 x Me), 4.08 (2 H, s, CH2)

and 7.1-7.9 (11 H, m, aryl-H and NH2), (Found: C, 61.40; H, 6.51;

N, 4.84. C13H19NO3S requires: C, 61.41; H, 6.52; N, 4.77%).

95

Preparation of N-Benzyl-iso-propylammonium Toluene-4-sulphonate:

Toluene-4-sulphonic acid (20 g) was dissolved in hot methanol

(25 ml) and N-benzyl-iso-propylamine (14.9 g, 1.0 equiv.) was

added to the solution, on cooling diethyl ether (100 ml) was

added to precipitate the salt. Recrystallisation from methanol

and diethyl ether gave N-benzyl-iso-propylammonium toluene-4-

sulphonate (30.7 g, 96%) as white needles, m.p., 119-120.5°C;

vmax

(nujol) 2580, 2440, 1610, 1450, 1390, 1230, 1160, 1120, 1030,

1005, 810, 780, 700 and 680 cm-1 ; d(CDC$3) 1.3 (6 H, d, J = 7 Hz,

2 x Me), 2.4 (3 H, s, aryl-CH3), 3.1 (1 H, m, Me2CH), 4.15

(2 H, t, J = 6 Hz, aryl-CH2), and 7.5 (11 H, m, aryl-H, and NH2);

(Found: C, 63.51; H, 7.25; N, 4.32%.C17H23NO3S requires:

C, 63.52; H, 7.21; N, 4.35%).

Preparation of Dibenzylammonium Toluene-4-sulphonate: Toluene-4-

sulphonic acid (10 g) was dissolved in hot methanol (12 ml) and

dibenzylamine (10.3 g, 1.0 equiv.) added. The solution was cooled

and diethyl ether (100 ml) added to the solution to precipitate

the salt. Recrystallisation from methanol gave dibenzylammonium

toluene-4-sulphonate (13 g, 67%) as white needles, m.p., 161-162°C,

vmax

(nujol) 3200-2300 br, 1625, 1525, 1450, 1300, 1270, 1220,

1030, 1005, 815, 760, 690, and 680 cm-1 ; 6(CDC(3) 2.4 (3 H, s, CH3),

4.35 (4 H, s, 2 x CH2) and 7.40 (16 H, m, aryl-H, and NH2);

(Found: C, 68.46; H, 6.34; N, 3.83. C21H23NO3S requires: C, 68.26;

H, 6.27; N, 3.79%).

96

Preparation of N-Methylanilinium Toluene-4-sulphonate: N-methyl-

aniline (10.8 g, 0.1 mole) was added to a solution of toluene-4-

sulphonic acid (22 g, 1.0 equiv.) in hot methanol (20 ml).

The solution was cooled and diethyl ether (100 ml) added to

precipitate the salt. Recrystallisation from methanol and diethyl

ether gave N-methylanilinium toluene-4-sulphonate (27.8 g, 99%)

as a greenish crystalline solid, m.p., 134°C (lit.133

133-135°C),

vmax

(nujol) 2660, 1585, 1490, 1450, 1370, 1005, 810 and 610 cm-1.

Preparation of 9-Fluorenylammonium Toluene-4-sulphonate (142b):

9-Aminofluorene (142a) (6.8 g) was added to a solution of toluene-

4-sulphonic acid (7 g, 1.0 equiv.) in hot methanol (8 ml). The

solution was cooled and diethyl ether (50 ml) added to precipitate

the salt. Recrystallisation from ethanol gave an impure solid

possibly 9-fluorenylammonium toluene-4-sulphonate (142b) (7.9 g) as

orange needles, m.p., 255-257°C, vmax

(nujol)3000-2200 br,

1440, 1120 br, 890, 855, 795, 725, and 670 cm-1; d(CDCe3 and

CF3CO2H) 2.4 (3 H, s, CH3), and 7.0-8.0 (15 H, m, aryl-H, CH and

NH3); (Found: C, 66.88; H, 5.12,and N, 3,42%).

Preparation of Benzhydryltoluene-4-sulphonamide (135b): Benzhydryl-

amine (135a) (366 mg, 2 moles) was dissolved in dry triethylamine

(5 ml) and toluene-4-sulphonyl chloride (381 mg, 1.0 equiv.) was

added to the solution which was stirred for 72 h. The mixture

was worked up by evaporating the solvent and washing the solid

residue with water. Recrystallisation from methanol gave N-benz-

hydryltoluene-4-sulphonamide (135b) (539 mg, 80%) as a white

97

crystalline solid, m.p., 154-155°C, vmax

(nujol) 3250, 1600, 1500,

1455, 1380, 1320, 1160, 1090, 1060, 945, 810, 750, and 700 cm-1;

6(CDC€3) 2.38 (3 H, s, CH3), 5.5 (1 H, m, NH), and 7.38 (15 H, m,

aryl-H and N-CH); m/e M (absent), 260, 182, 180, 167, 155, 152,

104, 91 and 77; (Found: C, 70.99; H, 5.60; N, 4.04. C20H19NO2S

requires: C, 71.18; H, 5.67; N, 4.14%).

Preparation of N-Benzyltoluene-4-sulphonamide (136a): Benzylamine

(214 mg, 2 moles) was dissolved in dry triethylamine (5 ml) and

toluene-4-sulphonyl chloride (381 mg, 1.0 equiv.) was added. The

solution was stirred for 24 h and was worked up by evaporating

the solvent and washing the solid residue with water (3 x) to remove

triethylammonium chloride. Recrystallisation from ethanol gave

N-benzyltoluene-4-sulphonamide (136a) (364 mg, 70%) as needles,

m-p-, 118-120 °C (lit.134 116°C);

vmax (nujol) 3275, 1600, 1425,

1325, 1165, 1060, 875, 810 and 740 cm-1; 6(CDC$3) 2.42 (3 H, s aryl-

CH3), 4.12 (2 H, d, J = 6Hz, N-CH2), 4.9 (1 H, broad m, NH), 7.06

(5 H, s, aryl-H) and 7.32 and 7.76 (4 H, ABq, J = 8 Hz, aryl-H);m/e

261 (M),196, 182, 157, 155, 139, 106, and 91.

Preparation of N-(1-Phenylethyl)toluene-4-sulphonamide (138b);

1-Phenylethylamine (138a) (266 mg) was dissolved in dry triethylamine

(5 ml) and toluene-4-sulphonyl chloride (381 mg, 1.0 eqiv.) was

added. The solution was stirred for 24 h and was worked up by

evaporating the solvent and washing the solid residue with water,

to remove triethylammonium chloride. Recrystallisation of the

insoluble residue from methanol gave N-(1-phenylethyl)toluene-4-

sulphonamide (138b) (506 mg, 84%) as white needles, m.p., 80-81°C,

98

6(CDC€3) 1.25 (3 H, d, J = 6 Hz, CH3) 2.3 (3 H, s, aryl-CH3),

4.45 (1 H, m, CH-N), and 7.0-7.8 (10 H, m, aryl-H, NH); m/e

275 (M); (Found: C, 65.54; H, 6.25; N, 5.07. C15H17NO2S requires;

C, 65.42; H, 6.22; N, 5.08%).

Preparation of N-Benzyl-N-methyltoluene-4-sulphonamide: N-Benzyl-

methylamine (242 mg, 2 moles) was dissolved in triethylamine (5 ml)

and toluene-4-sulphonyl chloride (381 mg, 1.0 equiv.) was added.

The solution was stirred for 24 h to complete reaction. Solvent

was evaporated off and the residue in dichloromethane washed with

water (3 x) to remove triethylammonium chloride. Evaporation of

the solvent gave the crude sulphonamide (374 mg, 68%) as white

needles, m.p., 90-92°C (lit.135 94.4-94.8°C)vmax (nujol) 1590,

1490, 1450, 1340, 1160, 1110, 970, 930, 910, 820, 770, 725, 700,

and 650 cm-1

; S(CDC€3) 2.44 and 2.55 (6 H, 2s, 2 x Me), 4.17

(2 H, s, CH2), 7.3 (5 H, s, aryl-H), and 7.35 and 7.7 (4 H, ABq,

J = 8Hz, aryl-H); m/e 275 (M), 198, 155, 120 and 91.

Preparation of N-Benzyl-N-iso-propyltoluene-4-sulphonamide: N-Benzyl-

iso-propylamine (298 mg, 2 mmoles) was dissolved in dry triethylamine

(5 ml) and toluene-4-sulphonyl chloride (381 mg, 1.0 equiv.) was

added. The solution was stirred for 48 h and was evaporated. The

solid residue in dichloromethane (20 ml) was washed with water (3 x)

to remove triethylammonium chloride. Evaporation of the dried organic

extract gave the crude sulphonamide (412 mg, 68%). Recrystallisation

99

from methanol gave N-benzyl-iso-propyltoluene-4-sulphonamide as

white needles, m.p., 98-99°C;vmax (nujol) 2580, 1610, 1450,

1390, 1255, 1150, 1000, and 750 cm -1 ; S(CDC$3) 0.93 (6 H, d,

J = 7Hz, CHMe2), 2.4 (3 H, s, aryl-CH3), 4.1 (1 H, m, CHMe2),

4.38 (2 H, s, aryl-CH2), and 7.2-7.8 (9 H, m, aryl-H); (Found:

C, 67.11; H, 7.03; N, 4.57. C17H21NO2S requires C, 67.30; H, 6.98;

N, 4.62%).

Preparation of N,N-Dibenzyltoluene-4-sulphonamide: Toluene-4-sulphonyl

chloride (190 mg, 1 mmol) was added to a solution of dibenzylamine

(197 mg) in triethylamine (5 ml). The solution was stirred for

24 h and worked up by evaporating off the solvent and washing the

solid residue with water to remove triethylammonium chloride.

Recrystallisation from methanol gave N,N-dibenzyltoluene-4-sulphonamide

(301 mg, 86%) as a white crystalline solid, m.p., 77-77.5°C;

vmax (nujol) 1430, 1300, 1125, 1095, 920, 890, 805, 780, 725, and

690 cm-1

; S(CDCe3) 2.42 (3 H, s, aryl-CH3), 4.28 (4 H, s, aryl-CH2),

and 7.1-7.9 (14 H, m, aryl-H); m/e. 351 (M), 274, 260, 259, 224, 196

168, 125 and 91; (Found: C, 71.61; H, 6.10; N, 3.98, C21H21NO2S

requires C, 71.77; H, 6.02; N, 3.99%).

Preparation of N-Methyl-N-toluene-4-sulphonylaniline: Toluene-4-

sulphonyl chloride (381 mg, 2 mmoles) was added to a solution

of N-methylaniline (214 mg, 1.0 equiv,) in dry triethylamine (5 ml).

The solution was stirred for 48 h at room temperature and worked up

by evaporating off the solvent and washing the solid residue with

water. Recrystallisation from methanol gave N-methyl-N-toluene-4-

100

sulphonylaniline (469 mg, 90%) as white needles, m.p., 88-89°C

(lit.136 90-92 °C); vmax

(nujol) 1580, 1450, 1340, 1160, 1150, 1060,

865, 810, 770, 710, 695, and 650 cm 1; S(CDC$3) 2.35 (3 H, s, aryl-CH3),

3.18 (3 H, s, N-CH3), and 7.0-7.8 (9 H, m, aryl-H).

Preparation of N-Toluene-4-sulphonylaniline: Toluene-4-sulphonyl

chloride (381 mg, 2 mmoles) was added to a solution of aniline

(186 mg, 1.0 equiv.) in triethylamine (5 ml) in the usual way.

Recrystallisation from methanol gave the sulphonamide as white

needles (469 mg, 95%), m.p., 104-105°C (lit.136 104°C);

'max (CHC$3)

3260, 2925, and 1600 cm-l; S(CDC$3) 2.28 (3 H, s, aryl-CH3),

and 6.6-7.8 (10 H, m, aryl-H and NH).

Preparation of N-Benzylmethanesulphonamide: Benzylamine (214 mg,

2 mmoles) was dissolved in triethylamine (5 ml) and methane-

sulphonyl chloride (228 mg, 1.0 equiv.) was added. The solution

was stirred for 24 h. The solvent was evaporated off and the

solid residue washed with water to remove triethylammonium chloride.

Recrystallisation of the residual solid from methanol gave the

title compound as white needles, (270 mg, 73%), m.p., 66-68°C (lit.137a

65°C); d(CDC$3) 2.75 (3 H, s, S-CH3), 4.2 (2 H, s, aryl-CH 2), 4.8

(1 H, s, NH) , and 7.35 (5 H, m, aryl-H) , m!e M (absent) , 182, 105

and 77.

Preparation of N-Benzyl-N-methyl methanesulphonamide: N-Benzyl-

methylamine, (398 mg) was dissolved in triethylamine (5 ml) and

methanesulphonyl chloride (228 mg, 1.0 equiv.) was added to the

solution. After 24 h at room temperature the mixture was worked

up by evaporating off the solvent. The solid residue was washed

with water to remove triethylammonium chloride. Recrystallisation

from methanol gave the title compound (242 mg, 37%) as a white

crystalline solid, m.p., 33-34°C (lit.137b 34°C), 6(CDC€3) 2.72. and 2.80 (6H,

2s, 2 x Me), 4.25 (2 H, s, CH2), and 7.33 (5 H, s, aryl-H), mfe

199 (M) .

Preparation of N-Benzyl-N-iso-propylmethanesulphonamide: N-Benzyl-

iso-propylamine (298 mg, 2 moles) was dissolved in triethylamine

(5 ml) and methane sulnhonyl chloride (228. mg, 1.0 equiv.) was

added. The solution was stirred for 24 h and was worked up by

evaporating the solvent and washing the solid residue with water,

to remove triethylammonium chloride. Recrystallisation from

methanol gave N-benzyl-N-iso-propylmethanesulphonamide (304 mg, 67%)

as white needles, m.p., 55-56°C;vmax

(nujol) 1290, 1120, 1020,

965, 920, 840, 760, 725, and 700 cm-1; 6(CDC€3) 1.2 (6 H, d, J = 6 Hz,

CHMe2), 2.8 (3 H, s, aryl-CH3), 4,18 (1 H, br m, CHMe2), 4.4 (2 H,

s, CH2), and 7.4 (5 H, m, aryl-H);m/e 227 (M), 212, 147, 132,

and 91; (Found: C, 58.00; H, 7.58; N, 6,11. C11H17NO2S requires

C, 58.12; H, 7.54; N, 6.16%).

101

102

Preparation of N-Benzhydrylnaphthalene-l-sulphonamide (135c):

Benzhydrylamine (135a) (366 mg, 2 moles) was dissolved in dry

triethylamine (5 ml) and naphthalene-l-sulphonyl chloride (452 mg,

1.0 equiv.) was added. The solution was stirred for 24 h to

complete reaction . Solvent was evaporated off and the solid residue

washed with water to remove triethylammonium chloride. Recrystallisation

of the insoluble residue from ethanol gave N-benzhydrylnaphthalene-

1-sulphonamide (135c) (674 mg, 90%) as white needles, m.p., 176-176,5°C,

Vmax (nujol) 3240, 1580, 1490, 1450, 1320, 1150, 1130, 1070, 1050,

1025, 955, 870, 820, 755, 740, 700, and 680 cm-1 ; d(CDC$3)

7.2 (10 H, s, Ph) and 8.0 (7 H, m, aryl-H); rule 373 (M), 296, 182,

167, 127 and 77; (Found: C, 73.75; H, 5.07; N, 3.62. C231119NO2S

requires: C, 73.96; H, 5.13; N, 3.75%).

Preparation of N-Benzylnaphthalene-l-sulphonamide (136b): Benzylamine

(214 mg, 2 mmoles) was dissolved in dry triethylamine (5 ml)

and naphthalene-l-sulphonyl chloride (452 mg, 1.0 equiv.) added

to the solution. After 24 h at room temperature the mixture was

worked up by evaporating off the solvent. The solid residue was

washed with water to remove triethylammonium chloride. Recrystallisation

of the solid residue from methanol gave N-benzylnaphthalene-1-

sulphonamide (136b) (526 mg, 88%), as white needles, m.p., 122-123,5°C;

'max (nujol) 3240, 1580, 1500, 1310, 1155, 1125, 1065, 900, 860,

825, 815, 750, 725, 700, 655, 640, and 615 cm-1; d(CDCC3) 4.2 (2 H,

d, J = 7 Hz, aryl-CH2), 5.0 (1 H, br, m, NH), 7.25 (5 H, s, Ph),

and 7.5-8.5 (7 H, m, aryl-H); mfe 297 (M); (Found; C, 68.45; H, 5.07;

N, 4.67. C17H15NO2S requires: C, 68.66; H, 5.09; N, 4.71%).

103

Preparation of N-Benzylbenzamide: Benzylamine (214 mg, 2 mmoles),

was dissolved in dry triethylamine (5 ml) and p-nitrophenyl benzoate

(486 mg, 1.0 equiv.) was added. The solution was stirred for 48 h

at room temperature and worked up as above to give N-benzylbenzamide

(350 mg, 83%) after recrystallisation from methanol, m.p., 103-

105°C (lit.138

105°C), vmax (nujol) 3360, and 1635 cm-1; 6(CdC?3)

4.60 (2 H, d, J = 6 Hz, CH2) and 7.2-8.0 (11 H, m, aryl-H and NH); +

m/e 211 (M), and 105.

Preparation of N-Benzyl-N-methylbenzamide: N-Benzylmethylamine

(242 mg, 2 mmoles) was dissolved in dry triethylamine (5 ml) and

p-nitrophenyl benzoate (248 mg, 1.0 equiv.) was added to the

solution. After 48 h at room temperature the mixture was worked up

by evaporating off the solvent. The solid residue was washed with

water and extracted with dichloromethane. Evaporation of the organic

phase gave the title compound (261 mg, 58%), m.p., -48°C 0

p g p g, p., 46-48 C (lit. 44 C);

vmax (CHC?3) 3060, 3040, 2925, 1635, 1500, 1450, 1400, 1338, 1290, 1265,

1110, 1070, 1030, 790, 720 and 700 cm-1; S(CDC'3) 2.9 (3 H, s, N-CH3)

and 7.35 (10 H, m, aryl-H).

Preparation of N-Benzyl-N-iso-propylbenzamide: N-Benzyl-iso-propylamine

(298 mg, 2 mmoles) was dissolved in triethylamine (5 ml) and benzoyl

chloride (281 mg, 1.0 equiv.) was added. The solution was stirred for

24 h. The solvent was evaporated off and the liquid residue in

dichloromethane washed with water (3 x). Evaporation of the organic

phase gave N-benzyl-N-iso-propylbenzamide (270 mg, 53%) as an oil,

vmax

(neat), 3040, 2925, 1630, 1500, 1440, 1420, 1345, 1600 and

200 cm-1.

104

S(CDCe3) 1.2 (6 H, d, J = 6 Hz, CHMe2), 4.26 (1 H, br m, CHMe2),

4.7 (2 H, s, CH2) and 7.43 (10 H, m, aryl-H); (Found : C, 80.66;

H, 7.85; N, 5.70. C17119N0 requires: C, 80.60; H, 7.56; N, 5.52%).

Preparation of N-(2-Phenylethyl)benzamide: 2-Phenylethylamine (242 mg,

2 mmoles) was dissolved in triethylamine (5 ml) and benzoyl chloride

(281 mg, 1.0 equiv.) was added. The solution was stirred for 48 h,

and the solvent was evaporated off. The solid residue was washed

with water (3 x) to remove triethylammonium chloride. Recrystallisation

of the insoluble material from methanol gave N-(2-phenylethyl)

benzamide (371 mg, 82%) as white needles, m.p., 115°C (lit.140

116-

117°C), vmax

(nujol) 3340, 1640, and 1455 cm-1; S(CDCe3) 2.95

(2 H, t, J = 7 Hz, aryl-CH2), 3.8 (2 H, q, J = 7 Hz, N-CH2), 6.42 (1 H,

broad m, NH), and 7.3-8.1 (10 H, m, aryl-H); m/e 225 (M), 105 and 77.

Preparation of N-n-butylbenzamide: n-Butylamine (146 mg, 2 mmoles)

was dissolved in dry triethylamine (5 ml) and benzoyl chloride

(280 mg, 1.0 equiv.) added. The solution was stirred for 24 h.

The solvent was evaporated off and the liquid residue in dichloro-

methane washed with water (3 x). Evaporation of the organic phase

gave N-n-butylbenzamide (208 mg, 59%) as an oil (lit.141 182-184°C/12mm),

vmax (neat) 3280, 2060, 2920, 2860, 1625, 1300 and 1150 cm 1;

S(CDCe3) 0.9 (3 H, t, J = 6 Hz, CH3), 1.5 (4 H, m, 2 x CH2), 3.5

(2 H, q, J'= 6 Hz, N-CH2), and 7.5 and 8.0 (6 H, m, aryl-H, NH);

m/e 177 (M), 162, 148, 134, 105, 86 and 77.

105

Preparation of N-Benzylacetamide: Benzylamine (214 mg, 2 mmoles) was

dissolved in dry triethylamine (5 ml) and acetic anhydride (204 mg,

1.0 equiv.) was added to the solution. After 48 h at room temperature

the mixture was worked up by evaporating off the solvent. The solid

residue was washed with water and extracted with dichloromethane.

Evaporation of the organic phase gave N-benzykaCeramide (149 mg, 50%)

as a white crystalline solid, m.p., 58-60°C (litl42 61-62.°C), vmax

(CDCt3) 3450, 3330, 2920, 1670, 1490, 1370, 1230 br, 1080, and 970 cm-1;

6(CDCt3) 1.8 (3 H, s, Ac), 4,22, (2 H, d, J = 6 Hz, CH2) and 7.23 +

(5 H, s, aryl-H); m/e 149 (M), 106, and 91.

Preparation of N,N-Dibenzylacetamide: Dibenzylamine (394 mg, 2 mmoles)

was dissolved in triethylamine (5 ml) and acetic anhydride (204 mg, 1.0

equiv.) was added. The solution was stirred for 48 h and

worked up by evaporating off the solvent and the residue in

dichloromethane, washed with water (3 x). Evaporation of the solvent

gave N,N-dibenzylacetamide (191 mg, 40%) as an oil, b.p., 121°C/0.5 mm

(lit.143

194-195°C/3 mm; vmax (neat) 3040, 3900, 1645, 1598, 1420,

1360, 1240, 980, 730, and 700 cm-l; S(CDCt3) 2.2 (3 H, s, Ac), 4.55

(4 H, 2s, 2 x CH2) and 7.33 (10 H, s, aryl-H); m/e 245 (impurity), +

239 (M), 195, 148, 106 and 91.

Preparation of N-Benzyladamantane-l-carboxamide (144b): Benzylamine

(214 mg, 2 mmoles) was dissolved in triethylamine (5 ml) and

adamantane-l-carbonyl chloride (397 mg, 1.0 equiv.) was added. The

solution was stirred for 24 h. The solvent was evaporated off and

106

the solid residue washed with water (3 x). Recrystallisation of

the insoluble material from methanol gave N-benzyladamantane-l-

carboxamide (144b) (352 mg, 66%) as white needles, m.p., 170-171°C,

vmax (nujol) 3340, 1635, 1530, 1460, 1415, 1380, 1000, 718, and

692 cm-1, d(CDC$3) 1.82 (15 H, m), 4.5 (2 H, d, J = 6 Hz, N-CH 2),

6.08 (1 H, broad m, NH), and 7.4 (5 H, s, aryl-H); (Found: C, 80.13;

H, 8.68; N, 5.32. C18H 23 ND requires C, 80.25; H, 8.60; N, 5.20%).

Preparation of N-Benzyl-N-methyladamantane-l-carboxamide (144c):

N-Benzylmethylamine (214 mg, 2 mmoles) was dissolved in dry

triethylamine (5 ml) and adamantane-l-carbonyl chloride (397 mg,

1.0 equiv.) was added. The solution was stirred for 24 h and

worked up by evaporating off the solvent and the solid residue

was washed with water (3 x). Recrystallisation of the insoluble

material from ethanol gave N-benzyl-N-•methyladamantane-l-carboxamide

(144c) (297 mg, 53%) as white needles, m,p., 74-75.5°C,'max

(nujol)

1615, 1500, 1455, 1380, 1255, 1230, 1180, 1100, 1060, 970, 945,

815, 800, 740, 722, 717, 696, and 665 cm-1; 6(CDC(3) 1.5-2,5 (15 H, m)

2.98 (3 H, s, Ac), 4.72 (2 H, s, N-CH 2), and 7.27 (5 H, s, aryl-H);

(Found: C, 80.46; H, 8.92; N, 5.17. C19H25N0 requires: C, 80.52;

H, 8.90; N, 4.94%).

107

Selective Toluene-4-Sulphonylation of Benzhydrylamine (135a) in

the Presence of Benzylamine, Using 18-Crown-6:

a) Benzhydrylammonium toluene-4-sulphonate (355 mg, 1 mmole) was

added to dry dichloromethane (5 ml) and benzylamine (109 p€, 107 mg,

1 mmole) was added to this solution. Toluene-4-sulphonyl chloride

(190.5 mg, 1.0 equiv.) was added, followed by the addition of

triethylamine (139 p$, 101 mg, 1.0 equiv.) over 5 mins. The mixture

was stirred for 72 h. After complete reaction (tic) the mixture was

directly chromatographed on Kieselgel H (10 g), (eluant petroluem

40-60°C) to give N-benzhydryltoluene-4-sulphonamide (135b) (13 mg, 4%)

and N-benzyltciluene-4-sulphonamide (136a) (238 mg, 91%) both as pure

crystalline solids.

b) The reaction was repeated with the addition of 18-crown-6

(264 mg, 1.0 equiv.) before the toluene-4-sulphonyl chloride.

The pure sulphonamides were separated by chromatography on

Kieselgel H (10 g).

c) The reaction was repeated in the presence of 18-crown-6 (528 mg,

2.0 equiv.) before toluene-4-sulphonyl chloride. Both reactions

with 18-crown-6 were homogeneous. The results are tabulated (Table

10) .

Table 10

r Experiment Equivalent 18-crown-6

Total weight of sulphonamides

Mole fraction Ph2CHNHT6 (135b) .

, Overall Yield

a 0 243 mg 0.04 95

b* 1 278 mg 0.30 97

c* 2 260 mg 0.44 91

108

Selective Toluene-4-sulphonylation of Benzhydrylamine (135a)

in the Presence of Benzylamine Using Dicyclohexyl-18-Crown-6 (131):

a) Benzhydrylammonium toluene-4-sulphonate (355 mg, 1 mmole) was

added to dry dichloromethane (5 ml) followed by benzylamine (109 pe,

107 mg, 1 mmole). Dicyclohexyl-18-crown-6 (372 mg, 1.0 equiv.)

added to the solution, followed by the addition of toluene-4-sulphonyl

chloride (190.5 mg, 1.0 equiv.) and finally triethylamine (139 u?,

101 mg, 1.0 equiv.) over 5 mins. The solution was stirred for 48 h.

The mixture was •directly chromatographed on Kieselgel H (10 g),

(eluant petroluem 40-60°C) to give N-benzyltoluene-4-sulphonamide

(136a) (104 mg, 40%) and N-benzhydryltoluene-4-sulphonamide (135b)

(195 mg, 56%) both as pure crystalline solids.

b) The reaction was repeated in the presence of dicyclohexyl-18-

crown-6 (131) (744 mg, 2.0 equiv.) before the toluene-4-sulphonyl

chloride. Both reactions were homogeneoi . The results are

tabulated (Table 11).

Table 11

Experiment Equivalent Dicyclo. hexyl-18- crown-6

Total weight of sulphonamides

Mole fraction PhCH(Ph)- NHTs (135b)

Overall yield

(131)

a* 1 299 mg 0.59 96

b* 2 307 mg 0.71 98

Selective Naphthalene-l-sulphonylation of Benzhydrylamine (135a)

in the Presence of Benzylamine Using 18-Crown-6:

a) Benzhydrylammonium toluene-4-sulphonate (355 mg, 1 mole)

and benzylamine (109 p€, 107 mg, 1 mole) were added in

sequence to chloroform (10 ml). Naphthalene-l-sulphonyl

chloride (226 mg, 1.0 equiv.) was added to the solution,

followed by the addition of triethylamine (139 u$ , 101 mg, 1.0

equiv.) over 5 mins. After 5 h stirring at room temperature,

chromatography on Kieselgel H (10 g), (eluant petroleum ether

40-60°C) gave N-benzylnaphthalene-l-sulphonamide (136b) (188 mg,

63%) and N-benzhydrylnaphthalene-l-sulphonamide (135c) (34 mg,

9%) both as pure crystalline solids.

b) and c): The reaction was repeated in the presence of 18-crown-6

[264 mg, 1.0 equiv. (b), and 528 mg, 2.0 equiv, (c)] before the

addition of naphthalene-l-sulphonyl chloride. The pure sulphonamides

were separated by chromatography on Kieselgel H. Both reactions

with 18-crown-6 were homogeneous. The results are tabulated (Table 12).

Table 12

Experiment Equivalent 18-crown-6

Total weight of sulphonamides

Mole fraction PhCH(Ph)-

NHSOzC1oH7

Overall yield

(135c)

a 0 222 mg 0.15 72

b* 1 237 mg 0.16 77

c* 2 220 mg 0,38 68

109

110

Selective Toluene-4-sulphonylation of 1-Phenylethylamine (138a) in

the Presence of Benzylamine, Using 18-Crown-6:

a) 1-Phenylethylammonium toluene-4-sulphonate (293 mg, 1 mmole)

was added to dry dichloromethane (5 ml) and benzylamine (109 u€,

107 mg, 1 mmole) was added to this solution. Toluene-4-sulphonyl

chloride (190.5 mg, 1.0 equiv.) was added in portions to the

mixture, followed by the addition of triethylamine (139 ud, 101 mg,

1.0 equiv.) over 5 mins. The solution was stirred for 24 h to

complete reaction. The reaction mixture was chromatographed on

Kieselgel 60 (25 g); elution with dichloromethane (500 ml) gave

a mixture of sulphonamides [PhCH(Me)NHTs] (138b) and (PhCH 2NHTs)

(136a) (248 mg).

b) The reaction was repeated with the addition of 18-crown-6

(264 mg, 1.0 equiv.) before the toluene-4-sulphonyl chloride.

The mixture of the two sulphonamides (138b, 136a) (245 mg) was

obtained by identical chromatogrpahy,

c) The reaction was repeated in the presence of 18-crown-6 (528 mg,

2.0 equiv.) Both reactions with 18-crown-6 were homogeneous.

The results are tabulated (Table 13).

Table 13

Experiment Equivalent 18-crown-6

Total weight of sulphonamides

Mole Fraction PhCH(Me)N-HTs (138a)

Overall Yield

a 0 248 mg 0.10 95

b* 1 245 mg 0.22 93

c* 2 257 mg 0.22 98

Attempted Selective Toluene-4-sulphonylation of 9-Aminofluorene

(142a) in the Presence of Benzylamine, Using 18-Crown-6:

a) 9-Fluorenammonium toluene-4-sulphonate (142b) (353 mg, 1 mmole)

was added to dry chloroform (10 ml) and benzylamine (109 pe, 107 mg,

1 mmole) was added to this solution. Toluene-4-sulphonyl chloride

(190.5 mg, 1.0 equiv.) was added in portions to the mixture, followed

by the addition of triethylamine (139 u$, 101 mg, 1,0 equiv.) over

5 mins. The solution was stirred for 72 h. Thin layer chromatography

showed decomposition giving an intractable mixture.

b) and c): The reaction was repeated with the addition of 18-crown-6

[264 mg, 1.0 equiv. (b), and 528 mg, 2,0 equiv. (c)] before the toluene-

4-sulphonyl chloride, Again decomposition gave diverse products;

the reactions were abandoned,

111

Selective Toluene-4-sulphonylation of N-Benzylmethylamine in the

Presence of Benzylamine, Using 18-Crown-6:

a) N-Benzylmethylammonium toluene-4-sulphonate (293 mg, 1 mmole) was

added to dry chloroform (10 ml) and benzylamine (109 p€, 107 mg,

1 mmol) was added to this cloudy solution. Toluene-4-sulphonyl

chloride (190.5 mg, 1.0 equiv.) was added in portions to the

mixture, followed by the addition of triethylamine (139 p$, 101 mg,

1.0 equiv.) over 5 mins. The solution was stirred for 24 h to

complete reaction. The reaction mixture was chromatographed on

Kieselgel 60 (25 g); elution with dichloromethane (500 ml) gave the

product amides (257 mg) which were isolated by evaporation. The

nmr spectrum of the product indicated a mixture of N-benzyltoluene-

4-sulphonamide and N-benzyl-N--methyltoluene-4-sulphonamides

b) The reaction was repeated with the addition of 18-crown-6

(264 mg, 1.0 equiv.) before the addition of toluene-4-sulphonyl

chloride. The pure secondary sulphonamide (267 mg) was obtained

by identical chromatography. N-Benzyltoluene-4-sulphonamide was not

detected.

c) The reaction was repeated in the presence of 18-crown-6 (528 mg,

2.0 equiv.). Both reactions with 18-crown-6 were 'homogeneous. The

results are tabulated (Table 14),

112

Table 14

Experiment Equivalent 18-crown-6

Total weight of sulphonamides

Mole fraction PhCH2N(Me)-Ts

Overall Yield

a 0 257 mg 0.97 94

b* 1 267 mg 1.0 97

c* 2 268 mg 1.0 97

Selective Toluene-4-sulphonylation of N-Benzylmethylamine in the

Presence of Benzylamine, Using Dibenz-18-Crown-6 (130):

a) N-Benzylmethylammonium toluene-4-sulphonate (293 mg, 1 mole)

was dissolved in dry chloroform (10 ml) and benzylamine (109 pi,

107 mg, 1 mole) was added to this cloudy solution. Toluene-4-

sulphonyl chloride (190.5 mg, 1.0 equiv.) was added, followed

by triethylamine (139 p$, 101 mg, 1.0 equiv.) over 5 mins. The

mixture was stirred for 24 h. After complete reaction the mixture

was directly chromatographed on Kieselgel 60 (25 g) to give a

mixture of the sulphonamides (PhCH2NHTs) and (PhCH2NMeTs) (245 mg)

(0.03: 0.97) .

b) and c): The reaction was repeated with the addition of dibenz-18-

crown-6 (130) [360 mg, 1.0 equiv. (b) and 720mg, 2.0 equiv. (c)]

before the toluene-4-sulphonyl chloride. Again the ratio of

sulphonamides were determined by nmr spectroscopy (Table 15),

113

Table 15

Experiment Equivalent Dibenz-18- crown-6

Total weight of sulphonamides

Mole fraction PhCH2N(Me)- Is

Overall Yield

(130)

a 0 245 mg 0.97 90

b* 1 257 mg 0.97 94

c* 2 259 mg 1.0 94

Selective Methanesulphonylation of N-Benzylmethylamine in the

Presence of Benzylamine, Using 18-Crown-6:

a) N-Benzylmethylammonium toluene-4-sulphonate (293 mg, 1 mmole)

was dissolved in dry dichloromethane (5 ml) and benzylamine (109 pf,

107 mg, 1 mmole) was added to the solution. Methanasulphonyl chloride

(77 u?, 114 mg, 1.0 equiv.) was added to the solution followed by

the addition of triethylamine (139 U$, 101 mg, 1.0 equiv.') over

5 mins. The solution was stirred for 24 h to complete reaction.Tie

nix}ure was chromatographed on Kieselgel 60 (25 g); elution with

dichloromethane (500 ml) gave the product sulphonamides (168 mg)

on evaporation. The nmr spectrum indicated a mixture of N-benzyl-

N-methylmethane sulphonamide and N-benzylmethanesulphonamide (13:12).

114

b) The reaction was repeated with the addition of 18-crown-6

(264 mg, 1.0 equiv.) before the addition of methanesulphonyl

chloride. The nmr spectrum of the product only showed the

formation of N-benzylmethylmethane sulphonamide (194 mg, 97%)

after chromatography on Kieselgel 60 (25 g).

c) The reaction was repeated in the presence of 18-crown-6 (528 mg,

2.0 equiv.). Both reactions with 18-crown-6 were homogeneous. These

results are tabulated (Table 16).

Table 16

Experiment Equivalent 18-crown-6

Total weight of methane- sulphonamides

Mole fraction PhCH2NMe-SO 2Me

Overall Yield

a

i

0 168 mg 0.52 88

b* 1 194 mg 1.0 97

c*. 2 188 mg 1.0 94

Selective Benzoylation of N-Benzylmethylamine in the Presence of

Benzylamine Using p-Nitrophenyl Benzoate and 18-Crown-6:

a) N-Benzylmethylammonium toluene-4-sulphonate (293 mg, 1 mmole)

was dissolved in dry dichloromethane (5 ml) and benzylamine (109 p€,

107 mg, 1 mmole) was added. p-Nitrophenyl benzoate (243 mg, 1.0 equiv.)

115

was added to the cloudy solution, followed by the addition of

triethylamine (139 u?, 101 mg, 1.0 equiv.) over 5 mins. After

one week at room temperature chromatography on Kieselgel 60

(25 g) (eluant dichloromethane) gave N-benzylbenzamide (207 mg,

97%). The secondary amide was not detected.

b) and c): The reaction was repeated with the addition of

18-crown-6 [264 mg, 1.0 equiv. (b), and 528 mg, 2.0 equiv. (c)],

before the p-nitrophenyl benzoate. The results are tabulated

(Table 17).

Table 17

Experiment Equivalent 18-crown-6

Total weight of benzamides

Mole fraction PhCON(Me)-CH2Ph

0

0.15

,. I

Overall Yield

98

98

98

a 0 207 mg

b* 1 209 mg

c* 2 215 mg 0.67

Selective Acylation of N-Benzylmethylamine in the Presence of

Benzylamine, Using Adamantane-l-Carbonyl Chloride (144a) and

18-Crown-6:

a) N-Benzylmethylammonium toluene-4-sulphonate (293 mg, 1 mmole) was

added to dry dichloromethane (5 ml) and benzylamine (109 p€, 107 mg,

1 mmole) was added. Adamantane-1-carbonyl chloride (144a) (194 mg,

1.0 equiv.) was added to the solution, followed by the addition of

116

triethylamine (139 u?, 101 mg, 1.0 equiv.) over 5 mins. The

solution was stirred for one week. Chromatography on Kieselgel

60 (25 g) gave N-benzyladamantane-l-carboxamide (144b) (262 mg,

97%) containing only traces of the secondary amide (144c).

b) The reaction was repeated with the addition of 18-crown-6

(264 mg, 1.0 equiv.) before adamantane-l-carbonyl chloride (144a).

The ratio of carboxamides were determined by nmr spectroscopy in

the usual way.

c) The reaction was repeated in the presence of 18-crown-6 (528 mg,

2.0 equiv.). Both reactions with 18-crown-6 were homogenous.

The results are tabulated (Table 18).

Table 18.

Experiment Equivalent Total weight 18-crown-6 ' of carbox-

amides

Mole fraction C1oH15C0N-(Me)CH 2Ph (144c)

Overall Yield

a 0 262 mg 0 98

b* 1 261 mg 0.33 95

c* 2 269 mg 0.55 99

117

Selective Toluene-4-sulphonylation of N-Benzyl-iso-propylamine

in the Presence of Benzylamine, Using 18-Crown-6:

a) N-Benzyl-iso-propylammonium toluene-4-sulphonate (321 mg,

1 mmole) was dissolved in dry dichloromethane (5 ml) and benzylamine

(109 p€, 107 mg, 1 mmole) was added. The solution was stirred and

toluene-4-sulphonyl chloride (190.5 mg, 1.0 equiv.) added in

portions followed by triethylamine (139 u€, 101 mg, 1.0 equiv.) over

5 mins. The mixture was stirred for 48 h. Chromatography on

Kieselgel 60 (25 g) gave (eluant dichloromethane) pure N-benzyl-

toluene-4-sulphonamide (260 mg, 100%); the secondary sulphonamide

was not detected.

b) and c): The reaction was repeated with the addition of

18-crown-6 [264 mg, 1.0 quiv. (b) or 528 mg, 2.0 equiv, (c)] before

the addition of toluene-4-sulphonyl chloride, The ratio of

sulphonamides [PhCH 2NHTs and PhCH 2N(Ts)CHMe 2) were determined by

nmr spectroscopy.

d), e), f), g), h), i), j), k'), 1), m), n): The reaction was

repeated using 18-crown-6 (2,0 equiv,) when triethylamine in

dichloromethane (5 ml) was added over 5 Thins [reaction (d) ],

2h [reaction (e)], 12 h [reaction (f)], 48 h [reaction (g)], or

one week [reaction (h)]. Reaction (f) was repeated at reflux

(reaction (i)], 0°C [reaction (j)] or -18°C [reaction (k)], or

by using toluene-4-sulphonyl chloride (0.1 equiv,) [reaction (1)],

(0.5 equiv.) [reaction (m)), or (0.4 equiv.) and no triethylamine

[reaction (n)]. The yields and mole fraction of N-benzyl-N-iso-

propyl-toluene-4-sulphonamide formed are tabulated (Table 19):

118

Table 19

Experiment Equivalent 18-crown-6

Total weight of sulphon- amides

Mole fraction PhCH2N(CHMe)2Tw

Overall Yield

a 0 260 mg < 0.02 100

b* 1 269 mg 0.31 98

c* 2 270 mg 0.46 99

d* 2 249 mg 0.47 89

e* 2 260 mg 0.51 92

f* 2 262 mg 0.57 92

g* 2 267 mg 0.56 94

h* 2 261 mg 0.60 96

i* 2 260 mg 0.02 98

1* 2 265 mg 0.16 99'

k* 2 incomplete reaction in 2 months

1* 2 25 mg 0 96t

m* 2 130 mg 0 1001

n* 2 104 mg 0.08 1001

Yields based on toluene-4-sulphonyl chloride used.

119

Selective Toluene-4-sulphonylation of N-Benzyl-N-iso-propylamine

in the Presence of Benzylamine, Using N-Benzyl-monoaza-18-Crown-6

(132) :

a) N-Benzyl-iso-propylammonium toluene-4-sulphonate (321 mg,

1 mole) was added to dry dichloromethane (5 ml). Benzylamine

(109 p$, 107 mg, 1 mole) was added to this solution. Toluene-4-

sulphonyl chloride (190.5 mg, 1.0 equiv.) was added in portions

to the mixture, followed by the addition of triethylamine (139 pt,

101 mg, 1.0 equiv.) over 5 mins. The solution was stirred for

48 h to complete reaction. The mixture was chromatographed on

Kieselgel 60 (25 g); elution with dichloromethane (500 ml) gave

pure N-benzyltoluene-4-sulphonamide (255 mg, 98%) as the only

product.

b) and c): The reaction was repeated with the addition of N-benzyl-

monoaza-18-crown-6 (132) (353 mg, 1.0 equiv, (b), or 706 mg, 2.0 equiv.

(c)] before toluene-4-sulphonyl chloride. The mixtures of the two

sulphonamides were obtained by identical chromatography.

d) Reaction(c) was repeated. However, triethylamine in dichloro-

methane (5 ml) was added over one week. The results are tabulated

(Table 20).

120

Table 20

Experiment Equivalent N-benzyl- monoaza- 18-crown-6 (132)

Total weight of sulphonamides

Mole fraction PhCH2N-(CHMe2)Ts

Overall Yield

a 0 255 mg 0 98

b* 1 276 mg 0.55 97

c* 2 278 mg 0.62 97

d* 2 277 mg 0.65 95

Selective Methanesulphonylation of N-Benzyl-N-iso-propylamine

in the Presence of Benzylamine,'Using 18-Crown-6:

a) N-Benzyl-N-iso-propylammonium toluene-4-sulphonate (321 mg,

1 mmole) was dissolved in dry dichloromethane (5 ml) and benzyl-

amine (109 p$, 107 mg, 1 mmole) was added to the solution. Methane-

sulphonyl chloride (77 pC, 114 mg, 1.0 equiv.) was added, followed

by the addition of triethylamine (139 u?, 101 mg, 1,0 equiv.) over 5

mins. The mixture was stirred for 24 h, and was directly chromatographed

on Kieselgel 60 (25 g), (eluant dichloromethane) to give pure

N-benzylmethanesulphonamide (185 mg, 100%).

121

122

b) and c): The reaction was repeated with the addition of 18-crown-6

[264 mg, 1.0 equiv. (b), and 528 mg, 2.0 equiv. (c)] before the

methanesulphonyl chloride. Again the ratio of sulphonamides were

determined by nmr spectroscopy (Table 21):

Table 21

Experiment Equivalent 18-crown-6

Total weight of methane- sulphonamides

Mole fraction PhCH2N(CH-Mc2)SO2Me

Overall Yield

a 0 185 mg 0 100

b* 1 157 mg 0.48 77

c* 2 220 mg 0.52 91

Selective Benzoylation of N-Benzyl-iso-propylamine in the Presence

of p-Nitrophenyl Benzoate, Using 18-Crown-6:

a) N-Benzyl-iso-propylammonium toluene-4-sulphonate (321 mg,

lmmole) was dissolved in dry dichloromethane (5 ml), and benzylamine

(109 p$, 107 mg, 1 mole) was added. p-Nitrophenyl benzoate

(243 mg, 1.0 equiv.) was added to the mixture, followed by the

addition of triethylamine (139 1e, 101 mg, 1.0 equiv.) over 5 mins.

After three days at room temperature, chromatography on Kieselgel

60 (25 g) gave (eluant dichloromethane) N-benzylbenzamide (203 mg,

96%) .

123

b) and c): The reaction was repeated with the addition of

18-crown-6 [264 mg, 1.0 equiv. (b), and 528 mg, 2.0 equiv. (c)]

before the p-nitrophenyl benzoate. Chromatography gave N-benzyl-

benzamide [(b) (195 mg, 92%) and (c)(198 mg, 94%)]; in neither case

were significant amounts of N-benzyl-N-iso-propylbenzamide formed

(nmr).

Selective Toluene-4-sulphonylation of Dibenzylamine in the Presence

of Benzylamine, Using 18-Crown-6:

a) N,N-Dibenzylammonium toluene-4-sulphonate (369 mg, 1 mole)

was added to dry dichloromethane (5 ml) and benzylamine (109 p$,

107 mg, 1 mole) was added to this solution. Toluene-4-sulphonyl

chloride (190.5 mg, 1.0 equiv.) was added, followed by the addition

of triethylamine (139 u?, 101 mg, 1.0 equiv.) over 5 mins. The

solution was stirred for 24 h. After complete reaction, the mixture

was directly chromatographed on Kieselgel H (10 g), (eluant

petroleum ether 40-60°C) to give N-benzyltoluene-4-sulphonamide

(182 mg, 68%) and N,N-dibenzyltoluene-4-sulphonamide (82 mg, 21%)

both as pure crystalline solids.

b) and c): The reaction was repeated with the addition of 18-crown-6

[264 mg, 1.0 equiv. (b), and 528 mg, 2.0 equiv. (c)] before the

toluene-4-sulphonyl chloride. The ratios of sulphonamides were

determined after separation as (a) [reaction (c)] or by nmr

spectroscopy after chromatography on Kieselgel 60 [reaction (b)].

d) The reaction was repeated, using 18-crown-6 (2 equiv.) and

triethylamine in dichloromethane (5 ml) was added over 12 h.

The ratio of sulphonamides were determined by nmr spectroscopy

after chromatography on Kieselgel 60 (eluant dichloromethane).

Results are tabulated (Table 22):

Table 22

Experiment Equivalent 18-crown-6

Total weight of sulphonamides

Mole fraction (PhCH2)2,

NTc

r

Overall Yield

a 0 264 mg 0.30 89

b* 1. 285 mg 0.62 90

c* 2 331 mg 0.80 100

d* 2 280 mg 0.84 84 J

Selective Acetylation of N,N-Dibenzylamine in the Presence of

Benzylamine, Using 18-Crown-6:

a) N,N-Dibenzylammonium toluene-4-sulphonate (369 mg, 1 :mole)

was dissolved in dry chloroform (10 ml) and benzylamine (109 ut,

107 mg, 1 mole) was added. The solution was stirred at room

temperature and 18-crown-6 (528 mg, 2.0 equiv.) added to the

124

solution, followed by the addition of acetic anhydride (94 PQ,

100 mg, 1.0 equiv.) and finally triethylamine (139 ue, 101 mg,

1.0 equiv.). The solution was stirred for 12 h to complete

reaction. Chromatography on Kieselgel 60 (25 g) gave (eluant

dichloromethane) a mixture of the acetamides [PhCH2NHCOCH3 and

(PhCH2)2NCOCH3] (210 mg, 95%). The ratio was determined by nmr

spectroscopy (Table 23):

Table 23

Experiment Equivalent 18-crown-6

Total weight of acetamides

Mole fraction (PhCH2)2-NCOCH3

Overall Yield

a 2 210 mg 0.96 95

Selective Toluene-4-sulphonylation of N-Benzyl-t-butylamine in

the Presence of Benzylamine, Using 18-Crown-6:

a) N-Benzyl-t-butylammonium toluene-4-sulphonate (335 mg,

1 mmole) and benzylamine (109 p?, 107 mg, 1 mmole) were added in

sequence to dry chloroform (10 ml). Then 18-crown-6 (528 mg,

2 equiv.) was added to this solution, followed by the addition

of toluene-4-sulphonyl chloride (190.5 mg, 1.0 equiv.) and triethyl-

amine (139 ue, 101 mg, 1.0 equiv.) over 5 mins. After 72h at room

temperature, the mixture was directly chromatographed on Kieselgel 60

(25 g), (eluant dichloromethane) to give N-benzyltoluene-4-sulphonamide

(259 mg, 99%) contaminated by traces of N-benzyl-N-t-butyltoluene-

4-sulphonamide.

125

Selective Benzoylation of 2-Phenylethylamine in the Presence of

n-Butylamine, Using 18-Crown-6:

a) 2-Phenylethylammonium toluene-4-sulphonate (293 mg, 1 mmole)

was added to dry dichloromethane (10 ml) and n-butylamine (99 u$,

79 mg, 1 mmole) was added to this cloudy solution. Benzoyl

chloride (116 ue, 140.5 mg, 1.0 equiv.) was added, followed by the

addition of triethylamine'(139 p$, 101 mg, 1.0 equiv.) over 5 mins.

The solution was stirred for 72 h. Chromatography on Kieselgel 60

(25 g) gave, on elution with dichloromethane (500 ml), the product

amides (170 mg, 857) which were isolated by evaporation. The nmr

spectrum of the product indicated a mixture of N-(2-Phenylethyl)benzamide

and n-butylbenzamide (9:11).

b) and c): The reaction was repeated with the addition of

18-crown-6 [264 mg, 1.0 equiv. (b), and 528 mg, 2,0 equiv. (c)]

before the addition of benzoyl chloride. The mixtures of the two

benzamides (125 mg) were separated by identical chromatography.

Both the reactions with 18-crown-6 were homogeneous. The results

are tabulated (Table 24):

Table 24

Experiment Equivalent 18-crown-6

Total weight of benzamides

Mole fraction of PhCH2-CH2NHCOPh

Overall Yield

a 0 170 mg 0.46 85

b* 1 125 mg 0.48 62

c* 2 146 mg 0.50 72

126

Selective Toluene-4-Sulphonylation of N-Methylaniline in the

Presence of Aniline, Using 18-Crown-6:

a) N-Methylanilinium toluene-4-sulphonate (279 mg, 1 mmole) was

dissolved in dichloromethane (5 ml) and aniline (91 pC, 93 mg,

1 mole) was added. Toluene-4-sulphonyl chloride (190.5 mg,

1.0 equiv.) was added to the solution, followed by the addition of

triethylamine (139 u$, 101 mg, 1.0 equiv.) over 5 mins. The

solution was stirred for 48 h. Chromatography on Kieselgel 60

(25 g) gave a mixture of sulphonamides [PhN(Me)Ts, and PhNHTs

(225 mg) ].

b) and c): The reaction was repeated with the addition of

18-crown-6 [264 mg, 1.0 equiv. (b), and 528 mg, 2.0 equv. (c)]

before toluene-4-sulphonyl chloride. The ratio of sulphonorn des

were determined by nmr spectroscopy (Table 25):

Table 25

Experiment

I

Equivalent 18-crown-6

Total weight of sulphonamides

Mole fraction PhN(Me)Th.

Overall Yield

a 0 225 mg 0.54 84

b* 1 218 mg 0.80 84

c'k 2 228 mg 0.96 88

127

Selective Benzoylation of N-Methylaniline in the Presence of

Benzylamine,Using Benzoyl Chloride and 18-Crown-6:

a) N-Methylanilinium toluene-4-sulphonate (279 mg, 1 mmole )

was dissolved in dry dichloromethane (5 ml) and benzylamine

(109 ue, 107 mg, 1 mmole) was added to the solution. Benzoyl

chloride (116 we, 140.5 mg, 1.0 equiv.)was added, followed by

triethylamine (139 lit, 101 mg, 1.0 equiv.). The solution

was stirred at room temperature for 48 h. Chromatography on

Kieselgel 60 (25 g)(eluant dichloromethane) gave a mixture of

benzamides [PhCH2NHCOPh, and PhN(Me)COPh] (205 mg, 97%).

The ratio (19:81) was determined by nmr spectroscopy.

b) The reaction was repeated with the addition of 18-crown-6

(264 mg, 1.0 equiv.) before the addition of benzoyl chloride. The

mixture of the two benzamides (202 mg) was obtained by identical

chromatography.

c) The reaction was repeated in the presence of 18-crown-6 (528 mg,

2.0 equiv.). Both reactions with 18-crown-6 were homogeneous. The

results are tabulated (Table 26):

Table 26

Experiment Equivalent 18-crown-6

Total weight of benzamides

Mole -' fraction PhN(Me)QOPh

Overall Yield

a 0 205 mg 0.73 97

b* 1 202 mg 0.78 96

c* 2 198 mg 0.89 94

128

129

Preparation of 2,4,6-Tribromo-aniline: Aniline (5 g) was dissolved

in acetic acid (20 g) and bromine (26.2 g, 3.0 equiv.) in acetic

acid (50 ml) was added to the solution, whilst stirring and

cooling. The mixture was poured into water, the solid filtered

off and washed with water (2 x). Recrystallisation from methanol

gave 2,4,6-tribromo-aniline (1.459,8.2%) as needles, m.p., 119-120°C

(lit.144

120-122°C), Umax

(nujol) 3280, 1620, 1450, 1380, 1050, 840 and

700 cm-1; S(CDC?3) 4.63 (2 H, s, NH2) and 7.62 (2 H, s, aryl-H);

m/e 333, 331, 329, 327 (M), 305, 303, 301, 299, 352, 250, 248, 225,

223, 221, 171, 170, 169, 168, and 90.

Preparation of N-Methyl-2,4,6-tribromo-aniline: N-Methylaniline (5 g)

was dissolved in acetic acid (20 g), and bromine (22.8 g, 3.0 equiv.)

in acetic acid (50 ml) added to the solution, whilst stirring and

cooling. When complete, the mixture was poured into water, and the

mixture extracted with dichloromethane (200 ml). Evaporation gave

the N-methyl-2,4,6-tribromo-aniline (771 mg, 4.8 %) as needles,

m.p., 34-36°C (lit.14539oC) ; U

max (nujol) 3275, 1620, 1450, and

1370 cm-1; d(CDC€3) 3.0 (3 H, d, J = 6 Hz, N-Me) 3.98 (1 H, br m,

NH), and 7.65 (2 H, s, aryl-H); m/e 347, 345, 343, 341 (M), 265,

263, 261, 251, 249 and 247.

Bromination of N-Methylaniline and Aniline in the Presence of

18-Crown-6:

a) Anilinium toluene-4-sulphonate (145a) (265 mg, 1 mmole) and

N-methylanilinium toluene-4-sulphonate (145b) (279 mg, 1 mmole)

were added to dry dichloromethane(20 ml). The mixture was cooled

130

to 0°C, and bromine (480 mg, 3.0 equiv.) in dichloromethane (5 ml)

added to the solution. After 24 h at room temperature, triethyl-

amine (202 mg, 2.0 equiv.) was added. Chromatography on Kieselgel H

(10 g) gave on elution with petroleum ether 40-60° ; 2,4-dibromo-

N-methylaniline (148b) (74.2 mg, 28%), m.p., 48-50°C (lit.145

48°C);

vmax (nujol) 3390, 1575, 1450, 1370, 1350, 1280, and 795 cm 1;

S (CDC$3) 2.82 (3 H, s, N-CH3) , 4.4 (1 H, br m, NH) , 6.48 (1 H, d,

J = 8 Hz, 6-H), 7.3 (1 H, dd, J = 8 Hz, 5 H), and 7.6 (1 H, d,

J = 2 Hz, 3 H); m/e 267, 265, 263 (M), 185, and 183;

2,4-dibromo-aniline (148a) (15 mg, 6%) m.p., 79.5-80°C (lit.146

79-80°C),

vmax (nujol) 3390, 3280, 1610, 1450, 1370, 1280, 860, 835, 805 and

720 cm 1; S(CDC€3) 4.06 (2 H, s, NH2), 6.78 (1 H, d, J = 8 Hz, 6-H),

7.3 (1 H, dd, J = 8 Hz, 5-H), and 7.7 (1 H, d, J = 2 Hz, 3-H); m/e

253, 251, 249 (M) and 223;and 4-bromoaniline (147)(2.5 mg, 1%),

m.p., 66-67°C (lit.147 66°C), vmax (nujol) 3360, 1580, 1300, and

805 cm-1 ; S(CDC€3) 3.65 (2 H, s, NH2) 6.63 (2 H, d, J = 8 Hz,

2 x CH) and 7.3 (2 H, d, J = 8 Hz, 2 x CH); m/e 173, 171 (M), 92,

and 65; all as pure crystalline solids.

b) The reaction was repeated with the addition of 18-crown-6

(528 mg, 2.0 equiv.) before the bromine. Chromatography on

Kieselgel H (10 g), (eluant petroleum 40-60°), gave 2,4,6-tribromo-

aniline (146 a) (110 mg, 34%); N-methyl-2,4,6-tribromo-aniline

(146b) (38 mg, 11%); and 4-bromo-aniline (147) (64 mg, 37%) all as

pure crystalline solids.

c) The reaction was repeated in the presence of 18-crown-6

(1.32 g, 5.0 equiv.) added before the bromine. Chromatography

on Kieselgel H (10 g) (eluant petroleum 40-60°) gave

2,4-dibromo-N-methylaniline (148b) (38 mg, 14%); N-methyl-2,4,6-

tribromo-aniline (146b) (26 mg, 8%) and 4-bromoaniline (147)

(42 mg, 24%) all as pure crystalline solids.

Preparation of 5a-Cholestan-3-one (150a): A solution of 5a-cholestan-

30-ol (149c) (5 g) in benzene (50 ml) was added with cooling to a

solution of sodium dichromate (6.8 g) and concentrated sulphuric

acid (9 ml) in water (30 ml). After stirring for 6 h at 25-30°C,

the benzene layer was separated and washed with water (2 x 10 ml),

5% aqueous potassium hydroxide (20 ml) and with water (2 x 10 ml).

Evaporation of the organic phase gave 5a-cholestan-3-one (150a)

(4.05 g, 81%) as white needles from methanol, m.p., 129-130°C

(lit.121

128-129 °C), [a]D° + 42° (C = 0.1) (lit.121 + 42.5),

vmax (nujol) 1715 cm

-1.

Preparation of 3-Hydroxyimino-5a-Cholestane (150b): 5a-Cholestan-3-

one (150a) (1 g) was dissolved in tetrahydrofuran and ethanol (1:1)

(50 ml). Hydroxylammonium chloride (0.36 g, 2.0 equiv.) and sodium

acetate (0.42 g, 2.0 equiv.) were added to this solution and the

mixture was heated to reflux for 24 h to complete reaction. The

solvent was evaporated off and the solid residue leached with and

recrystallised from dichloromethane to give 3-hydroxyimino-5a-

cholestane (150b) (720 mg, 70%) as white plates, m.p., 194-196°C

131

132

(lit,122

196°C}, [a]D° + 37 (C = 0.1) (lit. 122 + 38); vmax (nujol)

3350, 1650, 1450, 1370, 1045, and 880 cm-1; m/e 401 (M), 385,

370, 356, 246, 230, and 69.

Preparation of 3a-Amino-5a-Cholestane (149a)and 30-Amino-5a-

Cholestane (149b): 3-Hydroxyimino-5a-cholestane (I50b) (1 g)

was dissolved in dry tetrahydrofuran (10 ml) and lithium aluminium

hydride (0.8 g, 10.0 *equiv.) was added. The mixture was heated to

reflux for 48 h. Saturated aqueous sodium sulphate (5 ml) was

added to destroy the excess of lithium aluminium hydride. The

mixture was filtered and the solid washed with hot THF.

Evaporation of the THF solution gave a crude mixture of 3a-amino-

5a-cholestane (149a) and 3R-amino-5a-cholestane (149b) (985 mg).

Acetic anhydride (2 ml) was added to the mixture of the two amines in

diethyl ether (15 ml), followed by the addition of triethylamine

(5 ml), Evaporation gave a mixture of 3a-acetamido-5a-cholestane

(149d) and 30-acetamido-5a-cholestane (149e) (970 mg, 89%).

Chromatography on Kieselgel H (10 g), (eluant petroleum 40-60°) gave

3a-acetamido-5a-cholestane (149d) (572 mg, 59%) from methanol as

white needles , m.p., 217-218°C (lit.I23

218°C), [a]2O + 36° D

(C = 0.1)(lit.123

+ 36); vmax

(nujol) 3280, 1640, 1560, and

720 cm-l; 6(CDC$3) 0.65 (3 H, s, 13-Me), 0.72, 0.74, 0.87, 0.95

(methyl peaks), 0.92 (3 H, s, 10-Me), 2.02 (3 H, s, OAc), 4.2

(1 H, m, WH 15 Hz, 3R-H), and 5.95 (1 H, m, NH), m/e 429 (M), 370,

355, and 215; (Found: C, 80.91; H, 12.04; N, 3.22. Calc. for

C29H31N0; C,81.10; H, 12.00; N, 3.26%) and 3R-acetamido-5a-

133

cholestane (149e) (374 mg, 38%) as white needles, m.p., 245-6°C

(lit.121

245-256°C) [a]D° + 12.5 (C = 0.1) (lit.121 + 12);

vmax(nujol) 3280, 1640, 1560, and 1290 cm-1; S(CDCe3) 0.62

(3 H, s, 13-Me) 0.78, 0.83, 0.87, 0.93 (methyl peaks), 0.90 (3 H, s,

10-Me), 1.95 (3 H, s, OAc), 3.8 (1 H, m, WH 30 Hz, 3a-H) and

5.62 (1 H, m, NH), m/e 429 (M), 414, 370, and 355; (Found: C, 81.20;

H, 12.13; N, 3.26. Calc. for C29H51N0: C, 81.10; H, 12.00;

N, 3.26%). 30-Acetamido-5a-cholestane (149e) was heated under reflux:

in ethanol (210 ml) and concentrated hydrochloric acid (140 ml)

for 24 h. The solvent was evaporated off and the solid residue

basified with 50% sodium hydroxide solution (5 ml) and extracted

with diethyl ether. Evaporation gave 30-amino-5a-cholestane (149b)

(72 mg, 21%) as colourless needles from methanol, m.p., 117-121°C

(lit.121 118°C), [a]D° + 29 (C = 0.1) (lit.

121 + 29); vmax

(nujol)

3250, and 1635; S(CDC$3) 0.65 (3 H, s, 13-Me), 0.95 (3 H, s, 10-Me),

and 3.68 (1 H, s, CH); We 387 (M) 370, and 257. 3a-Acetamido-5a-

cholestane (149d ) (250 mg)was heated under reflux in ethanol (210 ml)

and concentrated hydrochloric acid (140 ml) for 24 h. The mixture

was worked up in the usual way. Recrystallisation from ethanol gave

3a-amino-5a-cholestane (149a) (117 mg, 52%) as white needles, m.p.,

87-88°C (lit.123

87-88°C), [a]D° + 27 (C = 0.1) (lit.123

+ 27);

vmax (nujol) 3250, and 1120 cm-1 ; S(CDCe3) 0.65 (3 H, s, 13-Me),

0.80 (9 H, s, side chain methyls) 0.95 (3 H, s, 10-Me) and 3.65

(1 H, s, CH); m/e 387 (M) 370, 355 and 351.

Preparation of 3R-Acetamido-5a-cholestane (149e): 30-Amino-5a-

cholestane (149b) (1 g) was dissolved in triethylamine (5 ml) and

acetic anhydride (0.3 g, 1.0 equiv.) was added. The solution

was stirred for 10 mins and was evaporated to dryness. The solid

residue was washed with water, and recrystallised from ethanol

to give the title compound (149e) (880 mg, 80%) identical with

the previous material.

Preparation of 3a-Acetamido-5a-cholestane (149d): 3a-Amino-5a-

cholestane (149a) (1 g) was dissolved in dry triethylamine (5 ml)

and acetic anhydride (0.3 g, 1,0 equiv.) was added to the solution.

After 10 mins at room temperature, usual work up and recrystallisation

from ethanol gave 3a-acetamido-5a-cholestane (781 mg, 71%) (149d)

as white needles identical with the previous sample.

Preparation of N-(5a-Cholestan-3a-yl)toluene-4-sulphonamide (149f):

3a-Amino-5a-cholestane (149a) (387 mg, 1 mole) was dissolved in

dry triethylamine (5 ml) and toluene-4-sulphonyl chloride (190.5 mg,

1.0 equiv.) was added. The solution was stirred for 24 h and

evaporated to dryness. The solid residue was washed with water

to remove triethylammonium chloride. Recrystallisation of the

insoluble residue from ethanol gave the title compound (149f) (486 mg,

90%) as white needles, m.p., 186-187°C; [a]D° + 32 (C = 0.1);

vmax (nujol) 3300, 1600, 1150 and 820 cm-1 ; 6(CDC$3) 0.62 (3 H, s,

13-Me) 0.70, 0.82 (methyl peaks) 0.90 (3 H, s, 10-Me), 2.42 (3 H, s,

aryl-Me), 3.5 (1 H, m, WH 16 Hz, with D20 gives WH 8HZ, 38-H), 5.08

(1 H, m, exch D20, NH), 7.35, aid 8.83 (4 H, ABq, J = 8Hz, aryl-H);

m/e 541, 386, 370, 355, 321, 293, 265, 167 and 149;(Found: C, 75.65;

H, 10.49; N, 2.58. C34H55NO2S requires: C, 75.37; H, 10.23;

N, 2.60%).

134

135

Preparation of N-(5a-Cholestan-313-yl)toluene-4-sulphonamide (149g):

30-Amino-5a-cholestane (149b) (774 mg, 2 moles) was dissolved in

triethylamine (5 ml) and toluene-4-sulphonyl chloride (381 mg,

1.0 equiv.) added. The solution was stirred for 24 h and worked

up in the usual way. Recrystallisation from ethanol gave the

title compound (149g) (519 mg, 48%) as white needles, m.p., 219.5-

221°C, [a]D° + 15 (C = 0.1); vmax (nujol) 3275, 1600, 1330, 1160,

1093, 910, 816 and 670 cm-1

; S(CDCQ3), 0.62 (3 H, s, 13-Me), 0.70,

0.81 (methyl peaks), 0.89 (3 H, s, 10-Me), 2.42 (3 H, s, aryl-Me),

3.05 (1 H, m, WH 28 Hz with D20 gives WH 22 Hz, 3a-H), 4.64

(1 H, m, exch D20, NH) 7.33, and 7.81 (4 H, ABq, J = 8 Hz, aryl-H);

m/e 541 (M), 526, 401, 386, 370, 335, 331, and 215; (Found: C, 75.13,

H, 10.42; N, 2.55. C34H55NO2S requires: C, 75.37; H, 10.23;

N, 2.60%).

Preparation of 3R-Trifluoroacetamido-5a-cholestane (149i): 30-Amino-

5a-cholestane (149b) (387 mg, 1 mmole) was dissolved in triethylamine

(5 ml) and trifluoroacetic anhydride (210 mg, 1.0 equiv.) was

added. The solution was stirred for 48 h to complete reaction.

The solvent was evaporated off and the solid residue washed with

water and recrystallised from methanol to give 30-trifluoracetamido-

5a-cholestane (149i) (120 mg, 25%) as a white crystalline solid, m.p.,

150-152°C, [a]D° + 11 (C = 0.1); 'umax (nujol) 3280, 1735, 1700, 1570,

1210, 1190 and 1160 cm 1;

S(CDCe3) 0.65 (3 H, s, 13-Me), 0.82,

0.86, 1.0 (methyl peaks) and 0.90 (3 H, s, 10-Me); m/e 483(M), 370,

355, 343, 328 and 215.

136

Preparation of 3a-Trifluoroacetamido-5a-cholestane (149h): 3a-Amino-

5a-cholestane (149a) (387 mg, 1 mmole) was dissolved in dry

triethylamine(5 ml) and trifluoroacetic anhydride (210 mg, 1.0 equiv.)

was added. The solution was stirred for 48 h. The mixture was

worked up in the usual way. Recrystallisation from methanol

gave 3a-trifluoroacetamido-5a-cholestane (149h) (153 mg, 32%) as

a white powder, m.p., 140-141°C, [a] ° + 29.5 (C = 0.1); vmax (nujol)

3290, 3100, 1735, 1700, 1560, 1280, 1210, 1190, and 1160 cm-1;

d(CDC€3) 0.64 (3 H, s, 13-Me), 0.82, 0.88, 0.93 (methyl peaks),

0.90 (3 H, s, 10-Me) 3.8 (1 H, m, WH 18 Hz, 30-H) and 6.15 (1 H,

m, NH); m/e 483 (M), 468, 370, 355, 343, 329, and 215; (Found:

C, 72.01; H, 10.20; N, 2.87. C29H4 F3N0 requires: C, 71.99; H, 10.01;

N, 2.89%).

Selective Acetylation of 3a-Amino-5a-cholestane (149a) in the Presence

of 30-Amino-5a-cholestane (149b), Using 18-Crown-6:

a) 3a-Amino-5a-cholestane (149a) (193.5 mg, 0.5 mmole) and 30-amino-

5a-cholestane (149b) (193.5 mg, 0.5 mmole) were added to dry chloroform

(10 ml), and trifluoroacetic acid (39 pt, 1.0 equiv.) was added.

Acetic anhydride (47 p?, 1.0 equiv.) was added to the solution,

followed by the addition of triethylamine (69.5 pf, 1.0 equiv.)

over 5 rains. The solution was stirred for 24 h, when chromatography

on Kieselgel H (10 g) gave (eluant petroleum 40-60°) 3a-acetamido-

5a-cholestane (149d) (22.5 mg, 10%) and 30-acetamido-5a-cholestane (149e)

(162 mg, 75%) both as pure crystalline solids, identical with

authentic samples.

b) and c): The reaction was repeated with the addition of

18-crown-6 [132 mg, 1.0 equiv. (b) and 264 mg, 2.0 equiv. (c)]

before the addition of acetic anhydride. In both cases, the

amides were separated by chromatography. The results are tabulated

(Table 27). All reactions were homogenous.

Table 27

Experiment Equivalent 18-crown-6

Total weight of acetamides

Mole fraction of 3a-acet-amide (1494)

Overall Yield

a* 0 184.5 mg 0.12 83

b* 1 187.3 mg 0.40 85

81 c* 2 178.5 mg 0.59

Selective Acetylation of 3a-Amino-5a-cholestane (149a) in the Presence

of 30-Amino-5a-cholestane (149b) Using N-Benzyl-monoaza-l8-Crown-6 (132):

a) 3a-Amino-5a-cholestane (149a) (193.5 mg, 0.5 mole) and

30-amino-5a-cholestane (149b) (193.5 mg, 0.5 mmol) were dissolved in

dry dichloromethane (10 ml) and trifluoroacetic acid .(39 pi, 1.0 equiv.)

was added. N-Benzyl--monoaza-18-crown-6 (132) (176 mg, 1,0 equiv.)

137

138

and acetic anhydride (47 p$, 1.0 equiv.) were added in sequence to

this solution, followed by the addition of triethylamine (69.5 u',

1.0 equiv.) over 5 mins. The solution was stirred for 48 h.

Chromatography on Kieselgel H (10 g) gave 3R-(N-acetylacetamido)-

5a-cholestane (149j) (171 mg, 72%) as white needles from methanol

m.p., 105-106°C; [a]D° + 7 (C = 0.1); d(CDC$3) 0.65 (3 H, s, 13-Me),

0.95 (3 H, s, 10-Me) and 2.18 (6 H, s, 2 x Me); mie 443 (M-28),

386, 371, 246, 231,

C31H53NO2 requires:

and 217;

C, 78.92;

(Found: C, 78.63; H, 11.47;

H, 11.32; N, 2.96%).

N, 3.06.

b) The reaction was repeated, using N-benzyl-monoaza-l8-crown-6

(132) (353 mg, 2.0 equiv.). Chromatography on Kieselgel H (10 g)

gave 33-(N-acetylacetamido)-5a-cholestane (149j) (173 mg, 73%).

Determination of the Stereochemistry of 3R-(N-Acetylacetamido)-

5a-cholestane (149j): The acetylacetamide derivative (149j)

(140 mg) was dissolved in dichloromethane (5 ml), benzylamine

(31.8 mg, 1.0 equiv.) and triethylamine (30 mg, 1.0 equiv.) were

added in sequence. After 48 h at room temperature the solvent was

evaporated off and the solid residue washed with water. Recrystallisation

from methanol gave 313-acetamido-5a-cholestane (149e) (102 mg, 73%)

identical (tic) with an authentic sample.

139

Selective Toluene-4-sulphonylation of 3a-Amino-5a-cholestane (149a)

in the Presence of 3R-Amino-5a-cholestane (149b) Using 18-Crown-6:

a) 3a-Amino-5a-cholestane (149a) (193.5 mg, 0.5 mmole) and 36-amino-

5a-cholestane (149b) (193.5 mg, 0.5 mmole) were dissolved in dry

chloroform (10 ml) and trifluoroaceticacid (39 ue, 1.0 equiv.)

was added. Toluene-4-sulphonyl chloride (95 mg, 1.0 equiv.)

followed by triethylamine (69.5 p?, 1.0 equiv.) over 5 mins were

added to the solution. The mixture was stirred for 72 h when

chromatography on Kieselgel H (10 g) (eluant with petroleum 40-60°)

gave N-(5a-cholestane-3a-yl)toluene-4-sulphonamide (149f) (67 mg,

25%) and N-(5a-cholestane-313-yl)toluene-4-sulphonamide (149g) (193 mg,

70%) both as pure crystalline solids, identical with authentic

samples.

b) and c): The reaction was repeatedwith the addition of 18-crown-6

[132 mg, 1.0 equiv. (b) or 264 mg, 2.0 equiv. (c)] before toluene-4-

sulphonyl chloride. The results are tabulated (Table 28). All reactions

were homogenous..

Table 28

Experiment Equivalent 18-crown-6

Total weight of sulphon- amides

Mole fraction of 3a-sulphon.-amide (149f)

Overall yield

96 a*

l

• 0 260 mg 0.26 .

b* 1 239 mg 0.47 88

c* 2 238 mg 0.70 88

140

Selective Toluene-4-sulphonylation of 3a-Amino-5a-cholestane (149a)

in the Presence of 30-Amino-5a-cholestane (149b) Using Dicyclohexyl-

18-Crown-6 (131) :

a) 3a-Amino-5a-cholestane (149a) (193.5 mg, 0.5 mmole) and

3R-amino-5a-cholestane (149b) (193.5 mg, 0.5 mmol) were dissolved

in dry dichloromethane (5 ml) and trifluoroacetic acid (39 pt, 1.0 equiv.)

was added. Dicyclohexyl-18-crown-6 (131) (186 mg, 1.0 equiv.)

and toluene-4-sulphonyl chloride (95 mg, 1.0 equiv.) were added

in sequence to the solution, followed by the addition of

triethylamine (69.5 pt, 1.0 equiv.) over 5 mins. The solution

was stirred for 32 h, when chromatography on Kieselgel H (10 g)

gave N-(5a-cholestan-3a-yl)toluene-4-sulphonamide (149f) (124 mg, 46%)

and N-(5a-cholestane-313-yl)toluene-4-sulphonamide (149 g) (111 mg,

41%) both as pure crystalline solids identical with authentic material.

b) The reaction was repeated, using dicyclohexyl-18-crown-6

(372 mg, 2.0 equiv.), results are tabulated (Table 29).

Table 29

Experiment

a*

Equivalent Dicyclohex- y1-18-crown 6 (131)

Total weight of sulphon- amides

Mole fraction of 3a-sulphon-amides (149f)

Overall Yield

0 235 mg 0.52 87

b* 1 231 mg 0.74 85

141

Selective Toluene-4-sulphonylation of 3a-Amino-5a-cholestane (149a)

in the Presence of 30-Amino-5a-cholestane (149b) Using N-Benzyl-

monoaza-18-Crown-6 (132):

a) 3a-Amino-5a-cholestane (149a) (193.5 mg, 0.5 mmole), 35-amino-

5a-cholestane (149b) (193.5 mg, 0.5 mmole) and trifluoroacetic

acid (39 p$, 0.5 mmole) were dissolved in dichloromethane (5 ml).

N-Benzyl-monoaza-18-crown-6 (132) (176.5 mg,.1.0 egi,iv.) and

toluene-4-sulphonyl chloride (95 mg, 1.0 equiv.) were added in

sequence to the solution, followed by the addition of triethylamine

(69.5 p€, 1.0 equiv.) over 5 mins. The solution was stirred for

72 h at room temperature. Chromatography on Kieselgel H (10 g)

gave only N-(5a-cholestan -3a-yl)toluene-4-sulphonamide (149f)

(228 mg, 84%)as a white crystalline solid identical with authentic

material

b) The reaction was repeated using N-benzyl-monoaza-18-crown-6

(132) (353 mg, 2.0 equiv.); results are tabulated (Table 30).

Table 30

Experiment Equivalent N-Benzyl- monoaza-l8- crown-6 (132)

r -

Total weight of sulphon- amides

Mole fraction 3a-sulphon-' amide .

Overall Yield

a* 1 •

228 mg 1.0 84

b* 2 235 mg 1.0 87

142

Selective Trifluoroacetylation'of3a-Amino-5a-cholestane (149a) in the

Presence of 30-Amino-5a-cholestane (149b) Using 18-Crown-6:

a) 3a-Amino-5a-cholestane (149a) (193.5 mg, 0.5 mmole) and 30-amino-

5a-cholestane (149b) (193.5 mg, 0.5 mmole) were dissolved in dry

chloroform (10 ml) and dry trifluoroacetic acid (39 pd, 1.0 equiv.)

added. Trifluoroacetic anhydride (69,5 pe, 1.0 equiv.) was added to

the solution, followed by the addition of triethylamine (69.5 pi,

1.0 equiv.) over 5 mins. The solution was stirred for 48 h,when

chromatography on Kieselgel H (10 g) (eluant petroleum 40-60°)

gave 3a-trifluoroacetamido-5a-cholestane (149h) (127 mg, 53%) and

3R-trifluoroacetamido-5a-cholestane (149i) (71 mg, 29%),both as

crystalline solids, identical with authentic materials.

b) The reaction was repeated with the addition of 18-crown-6 (132 mg,

1.0 equiv.) before the trifluoroacetic anhydride.

c) The reaction was repeated in the presence of 18-crown-6 (264 mg,

2.0 equiv.). The results are tabulated (Table 31).

Table 31

,

Experiment Equivalent 18-crown-6

Total weight of trifluoro- acetamides

Mole fraction of 3a-amide

- .

Overall Yield

a* 0 198 mg 0.64 82

b* 1 190 mg 0.80 79

c* 2 197 mg 0.82 1

82

Blank Reactions for the Trifluoroacetylation Studies.

a) 3a-Trifluoroacetamido-5a-cholestane (149h) (111 mg) was dissolved

in dichloromethane (5 ml) and 30-amino-5a-cholestane (149b) (96.7 mg)

was added.

b) The reaction was repeated with the addition of 18-crown-6

(132 mg, 2.0 equiv.) before the addition of 33-amino-5a-cholestane

(149b).

c) Reaction(a) was repeated with the addition of trifluoroacetic

acid (19.5 u?, 1.0 equiv.) before the 30-amino-5a-cholestane

(149b) .

d) Reaction(b) was repeated with trifluoroacetic acid (19.5 iQ,

1.0 equiv,) before the 18-crown-6.

e) 3S-Trif1uoroacetamido-5a-cholestane (1491) (111 mg) was

dissolved in dry dichloromethane (5 ml) and 3a-amino-5a-cholestane

(149a) (96.7 mg) was added.

f) Reaction(e) was repeated with the addition of 18-crown-6 (132 mg,

2,0 equiv,) before 3a-amino-5a-cholestane (149a).

g) Reaction(e) was repeated with trifluoroacetic acid (19.5 u$, 1.0 equiv.)

added before 3a-amino-5a-cholestane (149a).

143

144

h) Reaction(f) was repeated with the addition of trifluoroacetic

acid (19.5 we, 1.0 equiv.) before the 18-crown-6.

In each of the reactions(a) to(h) no transtrifluoroacetylation

was observed after 48 h at room temperature (tic, silica,

dichloromethane).

Selective Trifluoroacetylation of 30-Amino-5a-cholestane (149b) in

the Presence of 3a-Amino-5a-cholestane (149a) Using 18-Crown-6:

a) 3a-Amino-5a-cholestane (149a) (193.5 mg, 0.5 mmole) and 313-amino-

5a-cholestane (149b) (193.5 mg, 0.5 mmole) were dissolved in dry

dichloromethane (5 ml) and trifluoroacetic acid (39 pC, 0.5 mmole)

was added. Trifluoroacetic anhydride (69 pf, 1.0 equiv.) was rapidly

added, followed by the addition of triethylamine (69.5 u$, 1.0 equiv.)

over 3 h. The solution was stirred for 48 h, when chromatography

on Kieselgel H (10 g) (eluant petroleum 40-60°) gave 313-trifluoro-

acetamido-5a-cholestane (149i) (108 mg, 45%) and 3a-trifluoro-

acetamido-5a-cholestane (149h) (72 mg, 30%) both as pure crystalline

solids.

b) The reaction was repeated with the addition of 18-crown-6

(264 mg, 2.0 equiv.) before the addition of trifluoroacetic

anhydride. Chromatography on Kieselgel H (10 g) gave 30-trifluoro-

acetamido-5a-cholestane (149i) (170 mg, 71%) as the only product.

145

c) 3a-Amino-5a-cholestane (149a) (193.5 mg, 0.5 mmole) and

313-amino-5a-cholestane (149b) (193.5 mg, 0.5 mmole) were dissolved

in dry dichloromethane (5 ml) and trifluoroacetic acid (39 pe,

0.5 mmole) was added. Trifluoroacetic anhydride (69 p€,i.o ejv;1.1•)

was added rapidly. The solution was stirred for 48 h at room

temperature. Chromatography on Kieselgel H (10 g) gave 3Q-trifluoro-

acetamido-5a-cholestane (1491) (111 mg, 46%) and 3a-trifluoro-

acetamido-5a-cholestane (149h) (99 mg, 41%) both as pure crystalline

solids.

d) The reaction was repeated in the presence of 18-crown-6

(264 mg, 2.0 equiv.) before the addition of trifluoroacetic anhydride.

Chromatography on Kieselgel H (10 g) gave 3R-trifluoroacetamido-5a-

cholestane (149i) (159 mg, 66%), a. the only product.

e) 3a-Amino-5a-cholestane (149h) (193.5 mg, 0.5 mmole) and

30-amino-5a-cholestane (1491) (193.5 mg, 0.5 mmole) were dissolved

in dry dichloromethane (5 ml) and trifluoroacetic acid (39 p$,

1.0 equiv.) was added . Trifluoroacetic anhydride (69 pr, 1.0 equiv.)

was added over 3 h, followed by the addition of triethylamine

(69.7 p$, 1,0 equiv.) over 3 h. The solution was stirred for

48 h at room temperature. Chromatography on Kieselgel H (10 g)

gave 30-trifluoroacetamido-5a-cholestane (1491) (125 mg, 52%)

and 3a-trifluoroacetamido-5a-cholestane (149h) (31 mg, 13%).

146

f) The reaction was repeated in the presence of 18-crown-6

(264 mg, 2.0 equiv.) before the addition of trifluoroacetic

anhydride. Chromatography on Kieselgel H (10 g) gave 3L3-trifluoro-

acetamido-5a-cholestane (149i) (163 mg, 68%) as the only

product, results are tabulated (Table 32).

Table 32.

Experiment Equivalent 18-crown-6

Total weight of acetamides

Mole fraction of 3a-tri-fluoroacet-amide (149h)

Overall Yield

a* 0 180 mg 0.40 75

b* 2 170 mg 0 71

c* 0 210 mg 0.47 87

d* 2 159 mg 0 66

e* 0 156 mg 0.20 65

f* 2 163 mg 0 68

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Dynamic Protection of Amines using 18-Crown-6

By ANTHONY G. M. BARRETT,* J. CARLOS A. LANA, and SHAHRZAD TOGRAIE

(Department of Chemistry, Imperial College, London SW7 2AY)

Reprinted from the Journal of The Chemical Society Chemical Communications 1980

300 J.C.S. CHEM. COMM., 1980

Dynamic Protection of Amines using 18-Crown-6

By ANTHONY G. M. BARRETT,* J. CARLOS A. LANA, and SHAHRZAD TOGRAIE (Department of Chemistry, Imperial College, London SW7 2AV)

Summary The regioselectivity of diamine monoacylation has been controlled by selective complexation with 18-crown-6 and a proton source.

RECENTLY we reported a convenient method for the selective acylation of secondary amines in the presence of primary amines.' 18-Crown-6 forms complexes with alkylammonium salts via three hydrogen bonds and pole-dipole interactions in the 2.7 A cavity.- We expected that rapid selective complexation of one (or more) ammonium function(s) in a polyamine substrate should permit selective functionalisation of uncomplexed sites. Since dialkyl-ammonium salts form less stable complexes owing to a reduction in hydrogen bonding, selective acylation of a secondary amino function in the presence of a primary is possible.

selective monobenzoylation of ethylenediamine and homo-logues was also improved in the presence of 18-crown-6.

The decrease in stability of crown-primary alkylammon-ium salt complexes with increasing steric congestion3 should permit the selective acylation of a hindered primary amine in the presence of a non-hindered function. Such selection is relevant to aminoglycoside chemistry. As model systems, competition in the acylation and toluene-4-sulph-onylation of mixtures of benzylamine and benzhvdrylamine or 3x-(axial) and 3s-(equatorial) amino-5x-cholestanes4 were studied (Table 2). Without crown ether the less hindered (benzyl- or Sfl- respectively) amine was principally functionalised. In the presence of 18-crown-6 the ratio of hindered : non hindered amides was increased. Consistent with sterically selective complexation' dicyclohexyl 18-crown-6 (entries 10, 11) was superior to 18-crown-6. In the

TABLE 1. Selective acylation of diamines RNH[CH_]„NH_.

Percentage yields of products RN ('1 s) [CH„ 1„-

NHCOAr U•2

traces traces

4 1 0.5 u

Entry 1

3

Equiv. of 18-crown-6

(lb 1 2

RN(Ts) [CH2]„- NHTs

30 12

traces

RN(COAr) [CH,]„ - NHTs

16 63 79

4 (Ib 40 5 1 12 51 6 2 6 lil 7 2 (f 69 8 ob 43 8 9 1 29 56

10 2 4 76 11 (Ib 40 12 1 11 41 13 2 5 79 14 Ob 42 15 1 18 49 16 2 5 64 17 Ob 37 (1 18 lb 15 31 19 2b 9 32

RN (COAr) [Cl-3_]„-N HCOAr

37

15 42 11 s

22 27 17

34 26 10 47 23 24 45 29 32

a R = Mc (entries 1-7) and H (8-19) ; Ar = Ph (1-3, 7-19) and C6H4-4-NO. (4-6) ; n = 2 (1-6, 8-10), 3 (7, 11-13), 4 (14-16) and 8 (17-19). Typically benzoyl chloride and triethylamine were added in sequence to N-methylethylenediammonium di(toluene-4-sulphonate) and 18-crown-6 (1 mmol each) in dichloromethane (10 ml). When reactions were complete (t.l.c.) toluene-4-sulphonyl chloride (1 mmol), triethylamine (4 mmol), and an excess of potassium chloride were added. Yields refer to pure compounds isolated by direct chromatography on Merck Iiieselgel H. b Heterogeneous reactions. It must be assumed that the high yield of RN-(iOAr)[CH2]„NHCOAr in the blank reactions followed in part from the low solubility of the RNH:+[CH:]„NH3+2TsO- salts. How, ever, the increase in the yield of RN(COAr) [CHZ]„NHTs with increase in crown ether from 1 to 2 equiv. is consistent only with selective complexation.

Herein we report dramatic improvements in diamine monoacylation using dynamic protection (Table 1). For example the reaction of N-methylethylenediamine with benzoyl and toluene-4-sulphonyl chlorides in sequencet gave N-benzoyl-N-methyl-N'-toluene-4-sulphonylethylene-diamine (16%). In the presence of 18-crown-6 the yield was increased to 79%. Surprisingly (entries 8-19) the

steroid examples exclusive axial substitution was observed in the presence of N-benzylmono-aza-18-crown-6.5

The advantage of the aza-crown was emphasised by competition experiments between benzylamine and N-benz-yl-iso-propylamine. Since the rate of tosylation of the latter was slow, a 02% yield of N-benzyl-N-isopropyl-toluene-4-sulphonamide was only obtained when the

t The diamine was used as its di-toluene-4-sulphonate and, to facilitate chromatographic separation, after acylation remaining aminb functions were toluene-4-sulphonylated.

J.C.S. CHEM. COMM., 1980

Equiv of Entry crown ether

TABLE 2. Selective acylation and sulphonylation of amines&

Amine Ammonium salt % Amidesb

301

Hindered amideb mol fraction

1 0° PhCH,NH, Ph1CHNH,+TsO- 96 0.61 2 1 ++ ,, 85 0.78 3 2 +. ++ 79 1.00 4 0° If IS 93 0.31 5 1 ++ +I 92 0.47 6 2 If +I 95 0.52 7 00 +l 95 0.04 8 1 „ ++ 97 0.30 9 2 ,. .. 91 0.44

10 1 If Si 98 0.59 11 2 PP II 98 0.71 12 00 PhCH5NH2 PhCH,Pr'NH=+TsO- 100 .0.02 13 1 ,. ,, 98 0.31 14 2 ,, 99 0.46 15 2 ,, 96 0.80 16 1 II If 97 0.55 17 2 21 II 97 0.62 18 2 If II 95 0.65 19 0 3/3- : 3a-Amino-5E-cholestanes: CF3CO5H 1:1 :1 83 0.12 20 1 If 85 0.40 21 2 „ 81 0.59 22 0 If 98 0.26 23 1 „ 88 0.47 24 2 1P 88 0.70 25 1 ,' 84 1.0 28 2 .. 87 1.0

a Reactions were carried out using 18-crown-6 (entries 2, 3, 5, 6, 8, 9, 13-15, 20, 21, 23, and 24), dicyclohexyl-18-crown-6 (Fluka AG) (10, 11), and N-benzylmono-aza-18-crown-6 (16-18, 25, 26) with (CF3CO)10 (1-3), PhCOC1 (4-6), TsC1 (7-18, 22-26), or Ac,0 (19-21) as electrophile. b The ratios of amides were determined by n.m.r. spectroscopy (± 0.02) (entries 12-18); all other ratios refer to pure isolated compounds. Typically toluene-4-sulphonyl chloride and then, over 5 min, triethylamine (1 mmol each) were added to a solution prepared from 18-crown-6, benzylamine, and benzhydrylammonium toluene-4-sulphonate (1 mmol each) in dichloromethane (10 ml) [or (entries 19-26) from 3a- and 3s-amino-5a-cholestanes and CF,CO'H (1:1 ; 1)]. Chromatography on Merck Kieselgel H gave N-benzyl (0.68 mmol) and N-benzhydryl- (0.29 mmol) toluene-4-sulphonamides. In entries 15 and 18 the triethylamine was added over 1 week. a Heterogeneous reactions.

triethylamine was added slowly (1 week rather than 5 min) after the toluene-4-sulphonyl chloride (Table 2, entry 18).

Clearly dynamic protection provides a more convenient simple alternative to classical protection group methodo-logies.

We thank Capes, Brasilia, Brazil for financial support (to J.C.A.L.) and Dr. S. J. Abbott for helpful discussions.

(Received, 8th January 1980; Corn. 014.)

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