37? - UNT Digital Library/67531/metadc...135 generated at 0° in the Presence of HMPA 155 42....

REACTIONS OF ANIONS OF CYCLIC OXIMES,

OXIME ETHERS, AND CHIRAL IMINES

DISSERTATION

Presented to the Graduate Council of the

North Texas State University in Partial

Fulfillment of the Requirements

For the Degree of

Doctor of Philosophy

By

John R. Maloney, M.S.

Denton, Texas

August, 1980

37? A',-'

( / A f U # i L:

Maloney, John R., Reactions of Anions of Cyclic Oximes,

Oxime Ethers, and Chiral Imines. Doctor of Philosophy

(Chemistry), August, 1980, 177 pp., 6 tables, 58 illus-

trations, bibliography, 73 titles.

The purpose of this investigation is to examine

reactions of anions of oximes, oxime ethers and imines

with acylating agents and other electrophiles. It is also

an attempt to utilize the phenomenon of geometrical

enantiomeric isomerism, in which absolute configuration

is determined by double bond geometry, and the concept of

regiospecific anion formation, also determined by double

bond geometry, for stereospecific synthesis of tropinone

derivatives.

The dianion of 4-t-butylcyclohexanone oxime was reacted

with alkylating agents such as methyl chloroformate. Only

starting material was recovered from the reaction mixture

after hydrolysis. Similar results were obtained when the

dianion was reacted with other electrophiles.

The anion of 4-t-butylcyclohexanone O-methyl oxime

was reacted with acid anhydrides, alkyl chloroformates and

dimethyl carbonate. In all cases nitrogen acylation was

the principle reaction. Only in the case of reaction of the

oxime ether anion with methyl chloroformate was any carbon

acylation product isolated, and it was the minor product.

The imine of tropinone was prepared with a chiral

amine, a-methylbenzyl amine, to produce a mixture of

diastereomers due to geometrical enantiomeric isomerism of

the imine. Nuclear magnetic resonance spectroscopy could

not be used to determine the isomer ratio, even in the

presence of shift reagents. The formation of the anion with

lithium diisopropyl amide, methylation with methyl iodide,

and hydrolysis gave a chiral product. The imine from

(-)-a-methylbenzylamine gave about 5% enantiomeric excess

of (-)-l-R-2-methyltropinone. The absolute configuration

and the optical purity of the 2-methyltropinone was

determined by conversion to N-ethoxycarbonyl-2a-methyl-

tropinone and comparison with an authentic sample prepared

from (-)-cocaine. Since the anion reaction has been shown

to be regiospecific, the asymmetric induction was determined

by the kinetic isomer distribution of the imine only.

TABLE OF CONTENTS

Page

LIST OF TABLES i x

LIST OF ILLUSTRATIONS x

Chapter

I. INTRODUCTION 1

Alkylation of Ketone Derivatives and Structurally Related Compounds

II. EXPERIMENTAL 23

Preparation of Reagents Oxidation of Tropine (3-Tropanol (122)) Preparation of (-)-Menthone (133) Synthesis of (+)-Tropinone Oxime (58,59) Attempted Determination of the Optical

Purity of 3-Tropinone Oxime (58,59) with R-(+)-a-Methoxy-a-Trifluoromethylphenylacetic Acid (MPTA) (61)

Attempted Resolution of Tropinone Oxime (58,59) with (-)-Dibenzoyl L-Tartaric Acid

Preparation of 4-t-Butylcyclohexanone Oxime Sodium Salt (63)

Preparation of Cholesteryl p-Toluene Sulfonate (64)

Preparation of Cholesteryl Iodide (65) Attempted Preparation of 4-t-Butyl-

cyclohexanone of Cholesteryl Ether from Cholesteryl p-Toluene-sulfonate (64) in Absolute Ethanol

Attempted Preparation of 4-t-Butylcyclo-hexanone O-Cholesteryl Ether from Cholesteryl Iodide (65) in Absolute Ethanol

Attempted Preparation of 4-t-Butylcyclo-hexanone Oxime O-Cholesterol Ether from Cholesteryl p-Toluenesulfonate (64) in Hexamethylphosphoramide (HMPA) or Dimethylsulfoxide (DMSO)

i n

Attempted Preparation of 4-t-Butylcyclo-hexanone Oxime O-Cholesterol Ether from Cholesteryl Iodide (65) in HMPA or DMSO

Preparation of (+)-10-Camphorsulfonyl Chloride (68)

Preparation of 4-t-Butylcyclohexanone Oxime O-Cholesteryl Ester (67)

Preparation of 4-t-Butylcyclohexanone Oxime 0-(+)-10-Camphorsulfonate (9)

Preparation of 3-Tropinone Oxime Hydrochloride 0-(+)-10-Camphor-sulfonate

Procedure for Attempted Alkylation of 4-t-Bucylcyclohexanone Oxime (38)

Oxidation of Cyclohexanone Oxime (38) with PCC

Oxidation of 3-Methylcyclohexanone Oxime (77) with PCC

Oxidation of Cyclopentanone Oxime (78) with PCC

Oxidation of Acetophenone Oxime (78) with PCC

Oxidation of Benzaldoxime (80) with PCC

Attempted Oxidation of 4-t-Butylcyclo-hexanone O-Methyl Oxime (5) with PCC

Attempted Acylation of 4-t-Butylcyclo-hexanone Oxime (38)

Acylation of 4-t-Butylcyclohexanone 0-Methyl Oxime (5) with Methyl Chloroformate. Formation of Methyl N-Methoxy-N-4-t-Butyl-cyclohexenylcarbamate (85) and 2-Carbomethoxy-4-t-Butylcyclo-hexanone 0-Methyl Oxime (86)

Acylation of 4-t-Butylcyclohexanone O-Methyl Oxime (5) with Dimethyl Carbonate. Formation of Methyl N-Methoxy-N-4-t-Butylcyclohexenyl-carbamate (85)

Thermal Decomposition of Methyl N-Methoxy-N-Cyclohexenylcarbamate (85). Formation of Methyl N-4-t-Butylcyclo-hexenylcarbamate (101)

IV

Hydrolysis of Methyl N-4-t-Butyl-cyclohexenylcarbamate (106). Formation of 4-t-Butylcyclo-hexanone (38) and Methyl Carbamate

Acylation of 4-t-Butylcyclohexanone O-Methyl Oxime (5) with Acetic Anhydride (87). Formation of N-Methoxy-N-4-t-Butylcyclo-hexenylacetamide (88)

Thermal Decomposition of N-Methoxy-N-4-t-Butylcyclohexenylacetamide (88). Formation of N-4-t-Butylcyclohexenylacetamide (119)

Alkylation of N-4-t-Butylcyclohexenyl-carbamate (85). Formation of N-Methyl-N-4-t-Butylcyclohexenyl-carbamate (121)

Acylation of 4-t-Butylcyclohexanone O-Methyl Oxime (5) with Propionic Anhydride (89). Formation of N-Methoxy-N-4-t-Butylcyclohexenyl-propionamide (90)

Thermal Decomposition of N-Methoxy-N-4-t-Butylcyclohexenylpropionamide (90). Formation of N-4-t-Butyl-cyclohexenylpropionamide (120) and Formaldehyde

Preparation of (-)-Menthone Oxime (134) Preparation of (-)-3-p-Menthylamine

(129) Attempted Preparation of Tropinone

N-(-)-3-p-Menthylimine (129) Preparation of Tropinone N-(-)-a-

Phenethylimine (135) Attempted Determination of Diastereomer

Ratio of Tropinone N-(-)-a-Phen-ethylimine by NMR with Eu(fod)3

Alkylation of Tropinone N-(-)-a-Phenethylimine (135) . Formation of 2-Methyltropinone N-(-)-a-Phenethylimine (137)

Alkylation of Tropinone N-(-)-a-Phen-ethylimine (135). Formation of 2-Methyltropinone N-(-)-a-Phen-ethylimine (137) at Higher Temperatures

v

Page

Alkylation of Tropinone N-(-)-a-Phenethylimine (135). Formation of 2-Methyltropinone N-(-)-a-Phenethylimine (137) Using HMPA

Alkylation of Tropinone N-(-)-a-Phenethylimine (135). Formation of 2-Methyltropinone N-(-)-a-Phenethylimine (137) Using TMEDA

Preparation of Tropinone N-(+)-a-Phenethylimine (136)

Alkylation of Tropinone N-(+)-a-Phenethylimine (136). Formation of 2-Methyltropinone N-(+)-a-Phenethylimine (138) at 0

Alkylation of Tropinone N-(+)-a-Phenethylimine (136). Formation of 2-Methyltropinone N-(+)-a-Phenethylimine (138) Using HMPA

General Procedure for Hydrolysis of 2-Methyltropinone N-a-Phenethyl-imines (137) or (138) with 10% HC1

Isolation of 2-Methyltropinone (139) Yield of 2-Methyltropinone (139)

from 137 or 138 Attempted Determination of Optical

Purity of 2-Methyltropinone (139) via a Chiral Shift Reagent

Preparation of N-Ethoxycarboxyl-2-a-Methyl-3-Tropinone (146)

Yields of N-Ethoxycarboxyl-2a-Methyl-3-Tropinone (146)

Chapter Bibliography

III. RESULTS AND DISCUSSION 55

Oximes Attempted Resolution of Geometrical

Enantiomeric Oximes Reaction of Oxime Dianions with

Electrophiles Oxidation Deoximation with Pyridin-

ium Chlorochromate

V I

Page

Oxime Ethers Introduction Choice of Base Acylation Reactions Thermal Decomposition of N-Methoxy

Amides and Carbamates from N-Acylation of Oxime Ether Anions

Asymmetric Induction in the Alkylation of N-a-Phenethylimines of Tropinone

Chiral Imines Asymmetric Induction in the Alkyla-

tion of Conformational^ Flexible Molecules

Chiral Imines of Tropinone: Formation of Diastereomers from Geometrical Enantiomers

Preparation of Diastereomeric Imines: Attempted Formation of Tropinone N-(-)-3-p-Menthylamine

Preparation of Tropinone N-a-Phenethyl-imines (135,136)

Alkylation of Tropinone N-a-Phenethyl-imines (135) or (136)

Attempted Determination of Diastereomer Ratio

Hydrolysis of 2-Methyltropinone-N-a-Phenethylimines (137) or (138)

Separation of 2-Methyltropinone and a-Methylbenzylamine

Attempted Determination of the Optical Purity of 2-Methyltropinone (139) by NMR

Optical Purity and Absolute Configuration of N-Ethoxycarbonyl-2-a-Methyl-3-Tropinone

Optical Purity Determinations via Rotation and Circular Dichrosim Data

Determination of the Absolute Configura-tion of the Enantiomer Formed in Excess

Conclusions Chapter Bibliography

APPENDICES. 118

Appendix A Appendix B Appendix C

vii

Page

BIBLIOGRAPHY 173

Vlll

LIST OF TABLES

Table Page

I. Resolution of (+)-Tropinone Oxime (58,59) Via Recrystallization of (+)-10-Camphorsulfonate Salt 57

II. Deoximations with Pyridinium Chloro-

chromate (75) 66

III. N-Acylation of Oxime Ether Anions 73

IV. Thermal Decomposition of N-Acyl Enamines . . 83 V. Asymmetric Induction Data of Fraser for

Alkylation of Cyclohexanone N-a-Phenethylimine (127) 91

VI. Optical Purity and Absolute Configuration of N-Ethoxycarbonyl-2a-Methyl-3-Tropinone (146) 109

IX

LIST OF ILLUSTRATIONS

Figure Page

1. Steric course of imine alkylation as proposed by Meyers 89

2. NMR spectrum of Tropinone-N-a-Phenethyl-imine (135) 96

3. Circular dichroism spectra of Tropinone-N-(-)-a-Phenethylimine (135) and Tropinone-N-(+)-a-Phenethylimine (136) 98

4. NMR spectrum of 2-Methyltropinone-N-a-Phenethylimine (137) 101

5. Circular dichroism spectra of 2-Methyltropi-none-N-(+)-a-Phenethylimine (138). . . . 102

6. Circular dichroism spectra of (-)-N-Ethoxy-carbonyl-2a-Methyltropinone (146) Obtained from (-)-Cocaine (71); [©]-.«, = -2877 ? . . Ill

7. Compound 67_ 119

8. Compound 69 120

9. Compound 7£ 121

10. Compound £5 122

11. Compound 8j5 123

12. Compound 106 124

13. Compound _88 125



16. Compound 90 128


x

Figure Page

18. Compounds 135, 136 . 130

19. Compounds 137, 138 . 131

20. Compound 139 . . . . . . . 132

21. Compound 146 . 133


23. Compound 69_ 136

24. Compound 8f5 137

25. Compound _86 138




29. Compound 121 . 142

30. Compound 9_0 143


32. Compounds 135/ 136 145

33. Compounds 137, 138 146

34. Compounds 139, 13 6 14 V



37. Salt of 139_ and 61 150


39. Compound 137 formed from the Anion of Imine 135 generated at -78° 153

40. Compound 137 formed from the Anion of Imine 135 generated at 0° 154

XI

Figure Page

41. Compound 137 formed from the Anion of Imine 135 generated at 0° in the Presence of HMPA 155

42. Compound 137 formed from the Anion of Imine 135 generated at 0 in the Presence Of TMEDA 156


44. Compound 138 formed from the Anion of Imine 136 generated at 0° 158

45. Compound 138 formed from the Anion of Imine 136 generated at 0° in the Presence

of HMPA 159

46. Compound 146 from (-)-Cocaine 160

47. Compound 146 (crude) formed from Imine 137 (anion formation at -78°) 161

48. Compound 146 (purified) formed from Imine 137 (anion formation at -78°) . . . . . . 162

49. Compound 146 (crude) formed from Imine 137 (anion formation at 0°) 16 3

50. Compound 146 (purified) formed from Imine 137 (anion formation at 0°) 164

51. Compound 146 (crude) formed from Imine 137 (anion formation at 0° in the Presence of HMPA) 165

52. Compound 146 (purified) formed from Imine 137 (anion formation at 0° in the Presence of HMPA) 166

53. Compound 146 (crude) formed from Imine 137 (anion-formation at 0° in the Presence of TMEDA) 167

54. Compound 146 (purified) formed from Imine 137 (anion formation at 0° in the Presence of TMEDA) . 168

xi I

Figure Page

55. Compound 147 (crude) formed from Imine 138 (anion formation at 0°) . . . . . . . 169

56. Compound 147 (purified) formed from Imine 138 (anion formation at 0°) 170

57. Compound 147 (crude) from the Imine 138 (anion formation at 0° in the Presence of HMPA) 171

58. Compound 147 (purified) from the Imine 138 (anion formation at 0° in the Presence of HMPA) 172

Xlll

CHAPTER I

INTRODUCTION

Many methods have been developed for introducing a

carbon chain at the a-carbon of a ketone. Problems arise,

however, if the ketone is unsymmetrical. There may be

a lack of regiospecific control, since the ketone has two

different a-carbons bearing hydrogens of similar acidity.

Frequently, direct alkylation gives multiple substi-

tution as well. Recently several groups have found that

carbonyl derivatives and structurally related compounds

exhibit total regiospecificity and stereospecificity in

deprotonation and subsequent alkylation reactions. The

regiospecificity and stereospecificty of these reactions

have been utilized in the synthesis of several natural

products. This thesis reports a study of the scope of

these reactions and potential applications for stereo-

specific synthesis.

Alkylation of Ketone Derivatives and Structurally Related Compounds

The barrier to rotation about the double bond of

ketone derivatives leads to two possible stereoisomeric

carbanions. The use of strong bases such as alkyllithium

and sterically hindered lithium amide bases permits

formation of dianions of oximes and tosylhydrazones, and

monoanions of oxime ethers, dialkylhydrazones, and struc-

turally related nitrosamines. The regiochemistry and

stereochemistry of anion formation and alkylation have been

the subject of several recent studies.

Of all the ketone derivatives, oximes have been most

thoroughly studied. It was found by three groups1'2,3 that

the syn dianion is formed exclusively. For example, the

oxime of 2-butanone (1) formed the syn dianion (2) with

n-butyllithium (Scheme l).1 Deprotonation in this case

involves formation of a secondary carbanion (syn) in

preference to the normally favored primary carbanion (anti).

Even under forcing conditions, the reaction fails to

alkylate oximes in which the syn carbon is disubstituted.

Scheme 1

HO \ N II

CH3CH2CCH3

2 n-BuLi LiO \

N

II CH3(jH-CCH3

Li

HO \ N

CH^HCC^

CH.

1) CH3I

2) H-0

Similar results have been obtained in the case of O-methyl

4 5 A

oximes. ' The nmr experiments by Spencer and Leong indi-

cate that the proton syn to the methoxyl group in the

O-methyl oxime of dibenzoyl ketone (4) is preferentially

removed.

In 1976 Fraser and Dhawan investigated the lithiation

and subsequent methylation of several conformationally C

fixed oxime O-methyl ethers. Lyle had previously noted

that the dipolar resonance structures, which contribute

significantly to the overall electronic distribution of

nitrosamines, is isoelectronic with an O-alkyl oxime. +

>N=N-0 vs >N=N-0 ~

The alkylation with methyl iodide of the lithium salt of

4-t-butylcyclohexanone O-methyl oxime (5) in the presence

of hexamethylphosphoramide (HMPA) gave a 94% yield of the

regiospecifically alkylated product (6) (Scheme 2). The

13

homogeneity of the product was demonstrated by C nmr.

Attempts to achieve a second metallation were unsuccessful

unless the syn methylated oxime ether (6) was first

equilibrated by heating to the anti compound (7).

Scheme 2

N.R.

1)LDA, HMPA

2)CH 31

OCH3

1)LDA, HMPA

2)CH3I

CH->I

Using the more complex O-THP oximes, a study has been

£

carried out by Ensley and Lohr , which suggests that the

anti protons are acidic. It was found that a 68:32

mixture of E and Z acetophenone O-THP oximes (9,10) gave

only recovered E isomer when the anion formed with LDA was

quenched with methanol (Scheme 3). None of the Z isomer

was detected.

Scheme 3

OTHP THPO

OTHP

H2Li

32%

THPO

CH2Li

11 12

Further work demonstrated that step a (Scheme 3) is

fast compared to a step a' and that equilibration of E

and Z_ anions (step b) is rapid and heavily favors the syn

anion. Formation of the syn O-THP oxime anion (11) is both

kinetically and thermodynamically favored. The possibility

of coordination of the THP oxygen with the lithium cation 6

has been suggested to explain this phenomenon.

Ketone tosylhydrazones have been shown to react with

7

alkyllithium reagents to form alkenes (Scheme 4). Since

this initial study, several authors have succeeded in

trapping the vinyl anion intermediates with various electro-O

philes. The case of 2-octanone tosylhydrazones (15,17)

demonstrates that the stereochemistry of the carbon nitrogen Q

double bond controls the regiospecificity of the reaction.

The formation of the hydrazones was shown by ""H nmr spectro-

scopy to give a mixture of 76% of the E isomer (15) with the

toxylamide function syn to the methyl group and 24% of the Z

isomer (17) with the tosylamide function anti to the methyl

group (Scheme 5). Decomposition of the stereoisomeric mix-

ture with LDA in tetramethylethylenediamine (TMEDA) yields a

product mixture of 1-octene (16) and 2-octene (18) in the

ratio of 80:20.

Scheme 4

H Li Ts-N Ts-N N=N

\ \ - R

fj N r >c ^ r ,

CL R / C \

R I R I

H Li

13

- N 2

V

M R^ ^Li / C = C \ <H2° / c = c \ R R1 ~Br R

14

Scheme 5

TSHN

\ jj C H 2 = C H ( C H 2 ) 5 C H 3

C H 3 - C - ( C H 2 ) 5 C H 3

15 16

76% E 80%

NHTs

N || ^ C H 3 C H = C H ( C H 2 ) 4 C H 3

C H 3 C ( C H 2 ) 5 C H 3

17 18

24% Z 20%

The tosylhydrazone dianions may be trapped by alkyl

halides, by aldehydes and ketones to yield B-hydroxyltosyl-

hydrazones (20) and by chloroformates to yield esters (21)

(Scheme 6).^

Scheme 6

N-NHTs

NHTs

21

n-BuLi

THF, -50 C

20

N-NTs

R R2

H

ClC-OR

NHTs

r3 ^4

\ 1) r 3 R4

2) H 20

Corey has recently demonstrated the synthetic utility

of lithiated dimethylhydrazones in the preparation of a

wide variety of functionalized carbonyl derivatives 10 It

was noted that generally metallation of ketone dimethylhydra-

zones occurs very selectively at the less alkylated carbon10a,

and that in the case of cyclohexanone derivatives, axial

methylation is highly favored. Lithiation of the dimethyl-

hydrazone of methyl benzyl ketone (26) and subsequent

methylation gives, after hydrolysis, 3-phenyl-2-butanone

1 0 3.

(27) (Scheme 7) rationalized in terms of the charge

delocalizing capacity of the phenyl substituent.

Scheme 7

/ NMe-

N H

n- C5 Hn C C H3

22

1) LDA 2) Mel

3)10," n-C5HllCCH2CH3

23

24

NSfMe-1) LDA 2) Mel 3)I04"

CH-

25

0

/ NMe-

N

PhCH2-C-CH3

26

1) LDA 2) Mel 3)IO4-

0

Ph-CH-CCHo I 3

CH3

27

In a study of the alkylation of dimethylhydrazones Jung

ana Shaw"'""'" proposed that a proton is removed to give the

syn anion, since only syn 2-butanone dimethylhydrazone (29)

10

was obtained from the alkylation of acetone dimethylhydra-

zone (28) (Scheme 8). Once alkylated, the syn isomer (29)

rearranges on standing to an equilibrium mixture which

consists mainly of the more stable anti isomer (30).

Scheme 8

/ NMe •ie2

N

CH 3 CCH 3

28

Me2N

\ N

C H 3 C C H 2 C H 3

Et2NLi

standing

/ N

II CH 3 CCH 2

Li

NMe,

1) C H 3 I 2 ) H 2 0

V

N / NMe-

C H 3 C C H 2 C H 3

30 29

12

Jung and Shaw later investigated the initial depro-

tonation of dimethylhydrazones and reported a kinetic

preference for initial formation of the anti anion, followed

by rapid isomerization at nitrogen to form the thermo-

dynamically favored syn anion. This explanation has

recently been withdrawn,^ and Bergbreiter and Newcomb^,

utilizing 30% enriched "^CH3-labeled 3-pentanone dimethyl-13

hydrazone (31) and C nmr to observe directly the

11

structure of the intermediate lithio anions, as well as

the products, concluded that the geometry of the C-N

nitrogen lone pair or substituent group has only a small

effect on the site of kinetic deprotonation of dimethyl-

hydrazones with otherwise sterically and electronically

equilivalent acidic protons.

The nitrosamine is electronically similar to ketone

derivatives and has been shown to exist in two geometrically

isomeric forms via contribution of resonance form B.

/? °~ \ // \ + / N-N <—> N=N

A B

Work on nitrosamines clearly established that these

compounds can be metallated on the a-carbon and react with

a variety of electrophiles in good yield.15 in addition,

3 studies by Lyle and Fraser16 indicate that lithiation

occurs exclusively syn to the nitroso group and attack by

electrophiles leads to a product containing an axial substi-

tuent exclusively (Scheme 9). No further alkylation can

occur unless the syn nitrosamine is first converted to

t h e a n t i isomer. The predominant axial proton abstraction

has been verified by deuterium exchange studies."

Scheme 9

12

32

-N n-BuLi II ~ ^ 0 or LDA

ff ,N

N"

CH-

H o

33 LI

Mel

V

35

n-BuLi or LDA

0 V II

N' CH3I

Li 'CH3

34

N-

0 II

CH3 CH3

36 37

13

An explanation for preferred axial alkylation observed

for ketone derivatives and nitrosamines was offered by

Lyle and coworkers3, and the oxime of 4-t-butylcyclohexanone

(38) was used to illustrate that oxime alkylation is sub-

ject to stereoelectronic control. If the oximino system

is part of a six-membered ring, the electrophile approaches

the a-carbon from a direction perpendicular to the plane

of the oximino group (Scheme 10). A conformationally

biased ring such as 4-t-butylcyclohexanone oxime (38)

would give two possible transition states, one chair—like

and one boat-like. Obviously, the former transition state

would be more stable and should determine the configuration

of the majority of the product. The reaction of the dianion

of 4-t-butylcyclohexanone oxime (38) with methyl iodide

gave 2-methyl-4-t-butylcyclohexanone oxime (39) con-

taining an axial methyl group exclusively. These results

are consistent with a stereospecific, stereoelectron-

ically controlled methylation to produce the Z—oxime

trans-2-methyl-4-t-butvlcyclohexanone (39).

Scheme 10

14

38 HO /

,OH N H

The origin of the preferential stabilization of Z

anions is not fully understood. In the case of oximes,1,2'^

dimethylhydrazones^, and tosylhydrazones^, an internally

chelated species involving the lithium cation has been

proposed. Metallocyclic intermediates have been proposed

15

only in systems which bear a 1,4-relationship between a

heteroatom and the carbon-bearing incipient negative

charge. This suggestions has been contested in the case of

4

oxime ethers (Scheme 2). Deprotonation and alkylation of

4-t-butylcyclohexanone O-methyl oxime (5) in the presence

of 15-crown-5~, conditions which should preclude involvement

of the lithium cation in the stereocontrol, gave the same

regiospecificity and stereospecificity of the reaction.

Stabilization of an anion syn to the oxime oxygen may be

due to the symmetry of the orbital of the carbanion which,

like the butadiene dianion, derives stabilization from an

attractive interaction between the termini of the four 5

atom 6ir electron system. This rationale, originally 17

used by Hoffman and Olofson to account for the unusual

stability of cis dihalogens and dialkoxy ethylenes, has

18

been expanded quantitatively by Epiotis. The calculations

show that the stability of the 67r-electron, 4p-orbital

system represented by W-X=Y-Z is greatest with the atoms

Z and W syn.

In the case of the oximes, the course of deprotonation

and alkylation has been definitely established via the use

of geometrical enantiomeric isomerism.^ Geometrical

enantiomerism results from a type of molecular dissymmetry

arising when an unsymmetrically substituted double bond

lies between two similar asymmetric carbon atoms of opposite

configuration (Scheme 11). Lyle and Lyle20 first

16

illustrated this type of isomerism by the successful

resolution of racemic cis-2,6-diphenyl-l-methyl-4-piperi-

done oxime (40, 41). The dextrorotatory oxime (41) was

separated and the absolute configuration established by

21 G. Lyle and Pelosi.

,R A-R

C=0

Scheme 11

:C=X' A R

C=X

Z(+)-l-Methyl-2,6-diphenyl-4-piperidone oxime (41) was

treated with n-butyllithium and alkylated with methyl iodide

to give (Z)-(2R,3R,6S)-1,3-dimethyl-2,6-diphenyl-4-

piperidone oxime (42) (Scheme 12) 19

Scheme 12

N-CH.

N*Noh P h

41

-CH--f

CH3 Ph

-CH-

-CH-

17

That the reaction of anion formation and alkylation

occurred at the syn carbon was demonstrated by determining

the absolute configuration of the (-)-1,3-dimethyl-2,6-

diphenyl-4-piperidones (43, 44) formed by hydrolysis of 42.

22 Reaction of £2 with pyridinium chlorochromate gave a 1:1

mixture of the two epimers (43, 44). This mixture gave

a negative Cotton effect at 296 nm which, by the ketone

23

sector rule , confirmed the absolute configuration to be

(-)-2R,3R,(3S),6S-1,3-dimethyl-2,6-diphenyl-4-piperidone

(43, 44). This series of reactions also provides a

unique approach to stereochemical control of synthesis of

substituted ketones via a chiral oxime.

Fraser and coworkers have recently reported complete

syn selectivity in the alkylation of lithiated ketimines.

The conformationally-fixed ketimine 4-t-butylcyclohexanone

N-isopropylimine (45) undergoes syn-axial alkylation only

(Scheme 13). This axial attack predominates, resulting in

formation of the diaxial derivative (49) if a second

alkylation reaction is attempted. Hydrolysis can be

achieved with partial epimerization to give a mixture

dominant in 2,6-dimethyl-4-t-butylcyclohexanone (53)(both

methyl groups axial). This exclusive axial attack, as has

been rationalized for other ketone derivatives, is probably

the result of stereoelectronic control.

18

Scheme 13

(a) LDA, Mel; (b) LDA, Mel; (c) NH4C1; (d) NH4C1

19

Every reaction of lithiated ketimines yielded the less

stable syn methylation product with extremely high stereo-

selectivity . The observed anti product occurred by inversion

during 13C nmr spectral accumulations. These stereochemical

results are indicative of a large preferential stability

of the syn lithiated imine. The reason for this stability

difference of syn and anti anions is not readily apparent.

Arguments used to account for the syn selectivity of oxime

derivatives, hydrazones and nitrosamines appear inpplicable

to the case of a lithiated ketimine. Chelation cannot

stabilize the syn form, nor would orbital symmetry be

expected to play a significant role, since hyperconjugative

donation of electrons from a C-H or O C bond would be

required to attain a 4 atom, 6tt electron framework.

\ • C=NV R

/ V R+

Fraser recently postulated that the anti anion may

suffer a destabilizing interaction between the lone pair on

24

nitrogen and the pair of n electrons on the a-carbon.

Such a TT repulsive effect has precedent.25

With the exception of the dimethylhydrazones, the

study of ketone derivatives has focused on elucidation of

the theoretical aspects rather than on possible synthetic

applications. Questions such as the origin of preferential

20

stability of Z anions have not been satisfactorily answered

and is a subject of current research by a number of groups.

The reactions of anions of oximes, oxime ethers and

imines have been limited to alkylation with simple alkylating

agents such as methyl iodide. This dissertation is an

investigation of reactions of these anions with acylating

agents and other electrophiles for possible use in the

synthesis of natural products. It is also an attempt to

utilize the phenomenon of geometrical enantiomeric

isomerism, in which absolute configuration is determined

by double bond geometry, and the concept of regiospecific

anion formation, also determined by double bond geometry,

for stereospecific synthesis of tropinone derivatives.

21


1. W. G. Kofran and M. Yeh, J. Org. Chem., 41, 439 (1976).

2. M. E. Jung, P. A. Blair and J. A. Lowe, Tetrahedron Lett., 1439 (1976).

3. R. E. Lyle, J. E. Saavedra, G. G. Lyle, H. M. Fribush, J. L. Marshall, W. L. Lijinsky and G. M. Singer, Tetrahedron Lett., 4431 (1976).

4. T. A. Spencer and C. W. Leong, Tetrahedron Lett., 3889 (1975).

5. R. B. Fraser and K. L. Dhawan, J. Chem. Soc. Chem. Commun., 674 (1976).

6. H. E. Ensley and R. Lohr, Tetrahedron Lett., 1415 (1978).

7 a. R. A. Sheprio and M. J. Heath, J. Am. Chem. Soc., 89, 5734 (1967) .

b. G. Kaufman, F. Cook, H. Schechter, J. Bayless and L. Friedman, J. Am. Chem. Soc., 89, 5734 (1967).

8. R. H. Shapiro, M. F. Lipton, K. J. Kolonko, R. L. Buswell and L. A. Capuano, Tetrahedron Lett., 1811 (1975).

9. K. J. Kolonko and R. H. Shapiro, J. Org. Chem. 43, 1404 (1978) . ' —

10 a. E. J. Corey and D. Enders, Tetrahedron Lett., 3 (1976).

b. E. J. Corey and D. Enders and M. G. Back, Tetrahedron Lett., 7 (1976).

c. E. J. Corey and D. Enders, Tetrahedron Lett., 11 (1976).

c. E. J. Corey and S. Knapp, Tetrahedron Lett., 4687 (1976).

11. M. E. Jung and T. J. Shaw, Tetrahedron Lett., 3305 (1977).

12. M. E. Jung and T. J. Shaw, Tetrahedron Lett., 3305 (1977)

22

13. M. E. Jung, T. J. Shaw, R. B. Fraser, J. Banville and K. Taymaz, Tetrahedron Lett., 4149 (1979).

14. D. E. Bergbreiter and M. Newcomb, Tetrahedron Lett., 4145 (1979).

15 a. D. Seebach and D. Enders, Angew. Chem./ 84, 350 (1972). b. D. Seebach and D. Enders, Angew-Chem., 84, 1186 (1972) c. R. R. Fraser, G. Boussard, I. D. Postescu, J. J.

Whiting, and Y. Y. Wegfield, Canad. J. Chem., 51, 1109 (1973). —

d. J. E. Baldwin, S. E. Branz, R. F. Gomez, P. L. Kraft, A. J. Sinskey and S. R. Tannenbaum, Tetrahedron Lett., 333 (1976).

e. Review: D. Seebach and E. Enders, Angew.Chem., Internat. Ed., 14, 15 (1975).

18

21

22

24

16 a. R. R. Fraser and Y. Y. Wigfield, Tetrahedron Lett 2515 (1971).

b. R. R. Fraser, T. B. Grindley, and S. Possannanti, Canad. J. Chem., 53, 2473 (1975).

c. R. B. Fraser and L. K. Ng, J. Am. Chem. Soc., 98, 5895 (1976) . —

17. R. Hoffman and R. A. Olofson, J. Am. Chem. Soc., 88, 943 (1966). —

N. D. Epiotis, S. Sarkanen, D. Bjorkquist, L. Bjorkquist, and R. Yates, J. Am. Chem. Soc., 96, 4075 (1974). —

19. R. E. Lyle, H. M. Fribush, G. G. Lyle and J. E. Saavedra, J. Org. Chem., 43, 1275 (1978).

20. R. E. Lyle and G. G. Lyle, J. Org. Chem., 24, 1679 (1959). —

G. G. Lyle and E. T. Pelosi, J. Am. Chem. Soc., 88, 5276 (1976). —

J. R. Maloney, R. E. Lyle, J. E. Saavedra, G. G. Lyle, Synthesis, 212 (1978).

23. W. Moffitt, R. B. Woodward, A. Moscowitz, W. Klyne and C. Djerassi, J. Am. Chem. Soc., 83, 401 (1961),

R. B. Fraser, J. Banville, and K. L. Dhawan, J. Am. Chem. Soc., 100, 7999 (1978).

25. W. G. Phillips and R. W. Ratts, J. Org. Chem., 35, 3144 (1970). —

CHAPTER II

EXPERIMENTAL

Infrared spectra (ir) were obtained on a Beckman IR-33

spectrophotometer. The spectra of oils were taken as thin

films between sodium chloride plates or, in the case of

solids, as KBr wafers.

Nuclear magnetic resonance spectra (nmr) were recorded

on a Hitachi Perkin-Elmer Model R-24B in deuteriochloroform.

Chemical shifts are expressed in parts per million down-

field from internal tetramethylsilane (6=0). Preparative

high pressure liquid chromatography (HPLC) was performed

with a Waters Associates Prep LC/System 500 on Silica gel

columns.

Melting points were obtained using a Thomas Hoover

capillary melting point apparatus and are uncorrected.

Optical rotations were obtained using a Beckman

polarimeter and were measured on 1% solutions in CHC13.

Circular dichroism (CD) curves were recorded on a

Jasco J40 A instrument in 0.1 cm cells in hexane.

Elemental analyses were performed by Midwest Microlabs,

Ltd., Indianapolis, Indiana.

23

24

Preparation of Reagents

Tetrahydrofuran was dried and purified by distil-

lation from sodium-potassium alloy under nitrogen prior

to use. Hexamethylphosphoramide (HMPA) was distilled

from calcium hydride or barium oxide under reduced pressure

(water aspirator) and stored over 4A molecular sieves

under an argon blanket. Dimethylcarbonate was

distilled from barium oxide and stored under nitrogen.

Diisopropylamine was distilled from calcium hydride and

stored over 4A molecular sieves under nitrogen, n-

Butyllithium was titrated prior to use by the method

of Kofron and Baclawski."^

Oxidation of Tropine (3-Tropanol (122))

To a solution of 20 g (0.14 m) of tropine (122) in

100 ml of glacial acetic acid was added 13.0 g (0.14 mol)

concentrated sulfuric acid and 53 ml of 0.14 mol Jones

reagent. After 30 min 100 ml of water, 125 g (0.42 mol) of

trisodium citrate dihydrate, and a small piece of amal-

gamated mossy zinc were added. The flask was flushed with

argon and allowed to stir for 15 min. The mixture was made

strongly basic with saturated KOH solution and filtered by

vacuum. The filtrate was extracted with three 100 ml

portions of chloroform. The chloroform extracts were

dried and concentrated, and the residue was subjected to

distillation under reduced pressure to give 13.7 g (70%)

25

of an oil, b.p. 126-127° at 44 mm (lit.13 107-110° at 23 mm)

which solidified on standing was tropanone (123). The solid,

m.p. 39-41° (lit.13, m.p. 39-43.8°) gave spectra (ir,

nmr) and TLC behavior on silica gel identical with authentic

tropanone (123).

Preparation of (-)-Menthone (133)

This compound was prepared essentially according to Q

the procedure of Sanborn. Distillation of 84 g of crude

material gave 66 g (74%) of 133 as a crude oil, b.p. 94-95°/

19 mm (lit.9, b.p. 98-100°/18 mm).

Synthesis of (±)-Tropinone Oxime (58, 59)

2

Following the procedure of Ortega, 200 g (0.15 mol)

of tropinone and 17.5 g (0.25 mol) of hydroxylamine hydro-

chloride were added with stirring to 200 ml of water. To

this solution was added 21.2 g (0.25 mol) of sodium bi-

carbonate in 200 ml of water, and the mixture was stirred

for 72 hours. Anhydrous potatssium carbonate was added

until precipitation of the crude product ceased and

potassium carbonate no longer went into solution. The

mixture was separated by filtration under reduced pressure,

and the solid residue taken up in chloroform. The chloro-

form solution was washed with concentrated K2CC>3 solution,

dried (I^CO^)t and concentrated at reduced pressure to give

20.4 g of a brown solid, m.p. 108-110°. The crude material

was purified by vacuum sublimation, (80°, 0.1 mm) to give

26

19.4 g (84%) of 5!3, 59 as a white solid, m.p. 108-111°

(lit.^ m.p. 108-111°).

Attempted Determination of the Optical Purity of 3-Tropinone Qxime (58_ 59) with (R)-(+)-a-Methoxy-g-Trifluoro-

methylphenylacetic Acid (MTPA) (6ir~

To 20 mg (0.13 mmol) of tropinone oxime (58, 59) in

0.3 ml CDC13 was added 30 mg (0.13 mmol) of (+)-MTPA (61).

The nmr spectrum showed no doubling of the N-methyl resonance

at 62.65 or the O-methyl resonance at 63.45.

Attempted Resolution of a Tropinone Oxime (58, 59)

with (-)-Dibenzoyl L-Tartaric Acid (62)

To 1.0 g (67 mol) of (+)-tropinone oxime (58, 59) in

25 ml of diethyl ether was added a solution of 2.5 g (6.7

mmol of (-)-dibenzoyl-L-tartaric acid (62) in 25 ml of

diethyl ether and a minimum amount of methanol to dissolve

the acid. An oil separated which failed to crystallize

from methanol, 95% ethanol, acetone, ether or hexane.

Preparation of 4-t-Butylcyclohexanone Oxime Sodium Salt (63)

Into a 250 ml 3 neck was placed 10 g (0.06 mol) of

4-t-butylcyclohexanone oxime (38) and 100 ml of hexane. The

flask was flushed with dry nitrogen and after the oxime had

dissolved, 2.5 g of sodium hydride (57% oil dispersion)

was added. The solution was stirred under nitrogen for one

hour until the evolution of gas had ceased. The insoluble

sodium salt was removed quickly by filtration washed with

27

hexane, and the wet filter cake was dried in a vacuum

dessicator. The yield was 10.2 g (89% of a white solid).

The ir spectrum showed no evidence of an OH stretch in the

region 3,000-3,700 cm-1.

Preparation of Cholesteryl p-Toluene Sulfonate (64)

This compound was prepared by the method of Wallis4

in 88% yield and had a melting point of 130-133° (lit.4,

m.p. 131.5-132.5°).

Preparation of Cholesteryl Iodide (65)

This compound was prepared by the method of Benyon5

in 82% yield and had a melting point of 104-109° (lit.5,

m.p. 106.5-107°).

Attempted Preparation of 4-t-Butylcyclohexanone O-Cholesteryl Ether from Cholesteryl

p-Toluenesulfonate (64) in Absolute Ethanol

To 1 g (5.23 mmol) of 4-t-butylcyclohexanone oxime

sodium salt (63) in 50 ml absoluste ethanol was added 2.8

g (5.23 mmol) of cholesteryl tosylate (64), and the solution

was heated under nitrogen for 12 hours. The solvent was

removed by rotary evaporation, and the remaining solid was

shown by TLC (silica gel;hexane/ether 85:15) to be a mix-

ture of starting materials.

28

Attempted Preparation of 4-t-Butylcyclohexanone O-Cholesteryl Ether from Cholesteryl Iodide (65)

in Absolute Ethanol ~

The reaction was carried out in the same manner as

above using 2.6 g (5.23 nrniol) of cholesteryl iodide (65).

After 12 hours, no product had formed as indicated by TLC.

The ir spectrum (nujol) showed the absence of an ether

linkage (1035-1060 cm"1).

Attempted Preparation of 4-t-Butylcyclohexanone Oxime O-Cholesterol Ether from Cholesteryl

p-Toluenesulfonate (64) in Hexamethyl-phosphoramide (HMPA) or Dimethyl-

sulfoxide (DMSO)

The reactions were carried out as above in 50 ml of

dry HMPA or dry DMSO. The reaction mixtures were heated

for 12 hours at 90°C and worked up by pouring into 100 ml

of 10% ammonium chloride and extraction with ether. The

ether extracts were washed with water to remove HMPA or

DMSO and concentrated by rotary evaporation. In each

case, the product was shown by ir and TLC to be a mixture

of the cholesterol derivative (64) or (65) and 4-t-butyl-

cyclohexanone oxime (38).

Attempted Preparation of 4-t-Butylcyclohexanone Oxime O-Cholesteryl Ether from Cholesteryl

Iodide (65) in HMPA or DMSO

The reactions were carried out as above. No reactions

occurred after 12 hours as indicated by TLC of the

recovered product.

29

Preparation of (+)-10-CamphorsuIfonyl Chloride (68)

A 100 ml round bottom flask was equipped with a con-

denser and a drying tube. To this was added 10 g (0.04 mol)

of (+)-10-camphorsulfonic acid and 50 ml of thionyl chloride,

The mixture was heated at reflux for one hour, and the mix-

ture concentrated under reduced pressure to a yellow oil.

To the oil was added 25 ml of ether, and crystallization

occurred on cooling in a dry ice/ethanol bath. The mixture

was filtered by vacuum, washed with a minimum of cold

ether and dried to give 9.5 g (95%) of 68 as white crystals,

m.p. 64-65° (lit.6, m.p. 67-68° ).

Preparation of 4-t-Butylcyclohexanone Oxime O-Cholesteryl Ester (67)

To 5.0 g (0.03 mol) of 4-t-butylcyclohexanone (38)

was added 30 ml of dry pyridine and the mixture stirred in

an ice bath. To this was added 13.3 g (0.03 mol) of

cholesteryl chloroformate (66). The mixture was allowed

to warm to room temperature with stirring over 15 min and

then poured into ice water. The resulting precipitate was

filtered by vacuum, washed with water and dried with a

stream of air. The crude yield was 11.2 g (83%) of 67

as a white solid, m.p. 128-130°. The solid was recrystal-

lized from hexane to give 10.2 g of white solid, m.p.

131-133°. Successive recrystallizations from hexane

resulted in no change in the melting point: ir (Appendix A,

Figure 7); nmr (Appendix B, Figure 22).

30

Preparation of 4-t-Butylcyclohexanone Oxime 0-(+)-10-Camphorsulfonate (69)

To 2.0 g (0.01 mol) of 4-t-butylcyclohexanone oxime

(38) was added 20 ml of dry pyridine and the mixture was

stirred in an ice bath. To this was added 2.96 g (0.01 mol)

of (+)-10-camphorsulfonyl chloride (68) and the mixture

was allowed to warm to room temperature over 15 min. The

mixture was poured into ice water, and the resulting

precipitate was filtered by vacuum, washed with water, and

dried with a stream of air. The crude yield was 3.1 g (88%)

of a white solid, m.p. 85-89°. The material was recrys-

tallized from petroleum ether to give 2.7 g of 6jJ as a white

solid, m.p. 89-91°. Further, recrystallizations resulted

in on change in the melting point: ir (Appendix A, Figure

8) .

Preparation of 3-Tropinone Oxime Hydrochloride 0-(+)-10-Camphorsulfonate (70)

To 6.89 g (0.04 mol) of 3-tropinone oxime (58, 59)

was added 45 ml of dry pyridine and the solution cooled

in an ice bath. To this was added 11.2 g (0.04 mol) (+)-10-

camphorsulfonyl chloride (68). The mixture was stirred

at room temperature for one hour, and the resulting pre-

cipitate was removed by vacuum filtration. The crude

solid was washed with dry pyridine and ether to give 11.0 g

(61%) of 70 as a white solid, m.p. 179° (dec). A 1.6 g

sample was recrystallized from methanol to give 0.6 g of

31

10_, m.p. 186-189° (dec). This material was recrystallized

from methanol to give 0.15 g of 7J3, m.p. 188-190° (dec.);

ir (Appendix A, Figure ); nmr (Appendix B, Figure ).

Procedure for Attempted Alkylation of 4-t-Butylcyclohexanone Oxime (38)

A 100 ml 3-neck flask was flushed with nitrogen and

charged with 50 ml of dry THF. To this was added 1 g (5.9

mmol) of 4-t-butylcyclohexanone oxime (38), the solution

cooled to -78°, and 9.1 ml (11.8 mmol) of 1.3 M n-BuLi

was added. The solution was warmed to 0° for 1 hour and

recooled to -78°. In the case of liquids (triethylortho-

formate, dichloromethane), 5.9 mmol was added via syringe.

Cyanogen iodide (5.9 mmol) was added as a solid, and

formaldehyde was bubbled into the reaction mixture as a

gas after passing through a tube of P2°5- I n e a c h case,

after addition of the electrophile, the solution was

stirred in an ice bath for one hour and hydrolyzed with

20 ml of water. The THF was removed by concentration at

reduced pressure and the resulting aqueous mixture was

extracted with three ml portions of ether. The ether

extracts were combined and dried (K2CQ3) and concentrated

at reduced pressure. The resulting oil was investigated

by TLC (silica gel:hexane/ether 90:10) and found in all

cases to be a mixture of starting materials by comparison

with authentic samples.

32

Oxidation of Cyclohexanone Oxime (38) with PCC

To a rapidly stirring suspension of 6.37 g (30 mmol) of

PCC in 40 ml of methylene chloride was added 1.70 g (15 mmol)

of cyclohexanone oxime (38) in 30 ml of methylene chloride.

The reaction mixture was stirred for 18 hours and poured

into 200 ml of ether. The resulting mixture was filtered

through a pad of Florisil and the solvent was removed by

evaporation at reduced pressure. The resulting green oil

was distilled at reduced pressure to give 0.69 g (47%) of

cyclohexanone, b.p. 155°/760 mm (lit.7, 155°/760 mm).

Oxidation of 3-Methylcyclohexanone Oxime (77) with PCC

The reaction was carried out using the same procedure

as for 3j using 1.9 g (15 mmol) of 3-methylcyclohexanone

oxime (77) and a reaction time of 15 hours workup and

distillation at reduced pressure gave 0.89 g (53%) of 3-

methylcyclohexanone, b.p. 73-74°/20 mm (lit.7, 65°/15 mm).

Oxidation of Cyclopentanone Oxime (78) with PCC


as for 38 using 1.45 g (15 mmol) of cyclopentanone oxime

(78) and a reaction time of 18 hours. Workup and distil-

lation at reduced pressure gave 0.35 g (28%) of cyclopen-

tanone, b.p. 128-129°/760 mm (lit.7 130°/760 mm).

33

Oxidation of Acetophenone Oxime (79) with PCC


as for 3J3 using 2.0 g (15 ramol) of acetophenone oxime (79)

and a reaction time of 15 hours. Workup and distillation at

reduced pressure gave 1.1 g (61%) of acetophenone, b.p.,

60°/0.5 mm (lit.7 79°/10 mm).

Oxidation of Benzaldoxime (80) with PCC


as for .38 using 1.8 g (15 mmol) of benzaldoxime and a

reaction time of 15 hours. Workup and distillation at

reduced pressure gave 0.89 g (56%) of benzaldehyde, b.p.,

70-71°/20 mm (lit.7 62°/10 mm).

Attempted Oxidation of 4-t-Butylcyclohexanone O-Methyl Oxime (5) with PCC


as for 38 using 2.75 g (15 mmol) of 4-t-butylcyclohexanone

0-methyl oxime (5). Workup and distillation gave 2.5 g

(91% recovery) of 5, b.p. 52°/0.05 mm in greater than 98%

purity as shown by G.L.P.C.

Attempted Acylation of 4-t-Butylcyclohexanone Oxime (38)

A flame dried, nitrogen-flushed 100 ml 2-neck flask

was charged with 50 ml of dry THF and 1 g (5.9 mmol) of

4-t-butylcyclohexanone oxime (38). The mixture was cooled

to -78°, and the dianion prepared with 8.1 ml (11.8 mmol)

of 1.46 M n-butyllithium. After one hour at -20°C, the

34

mixture was recooled to -78°C and treated with 0.56 g (5.9

mmol) of methyl chloroformate (81). The mixture was allowed

to warm to 0°C and hydrolyzed with 20 ml of water. THF was

removed by rotary evaporation at 30°C and the mixture was

extracted twice with ether. The ether extracts were dried

(MgSO^) and concentrated at reduced pressure at 30°C to

give 0.95 g of a crude solid, m.p. 134-136°, which was

identical by ir, nmr, and TLC (silica gel:hexane/ether,

90:10) with an authentic sample of 4-t-butylcyclohexanone

oxime (38). The same result was obtained substituting

dimethyl carbonate (84) for methyl chloroformate (81).

Acylation of 4-t-Butylcyclohexanone O-Methyl Oxime (5) with Methyl Chloroformate. Formation of Methyl N-Methoxy-N-4-t-Butylcyclohexenylcarbamate (85) and

2-Carbomethoxy-4-t-Butylcyclohexanone O-Methyl Oxime (86)

A 100 ml 2-neck flask, equipped with a gas inlet tube

and a rubber septum was flame dried, flushed with nitrogen

and charged with 50 ml of dry THF. To this was added 1.0

g (5.46 mmol) of 4-t-butylcyclohexanone 0-methyl ether (5)

and 3.71 g (21.8 mmol) of HMPA. The mixture was cooled to

-78°C and 4.19 ml (5.46 mmol) of 1.3 M n-butyllithium

was added dropwise. The mixture was allowed to stand with

stirring at -78°C for one hour, followed by the rapid

addition of 0.52 g (5.46 mmol) of methyl chloroformate (81).

The reaction mixture was allowed to warm to room temperature

and hydrolyzed with 20 ml of H20. THF was removed by

35

rotary evaporation at 30°C, and the resulting aqeous layer

was extracted with two 20 ml portions of ether. The

ether extracts were combined and washed with three 20 ml

portions of water to remove the HMPA, and the extract was

dried (MgSO^). Concentration of the extract by rotary

evaporation at 30°C gave 1.15 g of light yellow oil. The

nmr spectrum of the crude oil showed it to be a mixture

of 63% of the N-acylated product (85) and 37% of the C-

acylated product (86) by comparison of the integration

values of the multiplets at 6 5.65 and 6 4.15 which result

from the C—1 hydrogen of the N— and C—acylated products,

respectively. An analytical sample of the C—acylated

material (86) was obtained by preparative HPLC: ir

(Appendix A, Figure 11); nmr (Appendix B, Figure 25). nmr:

6 0.85 (s,9H); 1.0-2.40 (m,7H); 6.60 (s,3H); 6.70 (s,3H);

4.15 (m,lH). ir: 1635, 1055 cm"1.

• Calcd for •]_3 23 3* *r ^.70; H, 9.61. Found:

C, 64.41; H, 9.65.

Acylation of 4-t-Butylcyclohexanone O-Methyl Oxime (5) with Dimethyl Carbonate. Formation of Methyl N-Methoxy^N-Jl

t-Buty 1 cyc 1 ohexeny 1 carbamate (85)~

A flame dried, nitrogen—flushed 500 ml 3—neck flask

was charged with 300 ml of dry THF and 19.55 g (0.11 mol)

of HMPA. The mixture was cooled to -78°c and 24.3 ml

(0.035 mol) of 1.46 M n-butyllithium was added, followed by

the dropwise addition of 5 g (0.025 mol) of

36

4-t-butylcyclohexanone O-methyl oxime (5) maintaining the

temperature at -78°C. After one hour at -78°C, 3.19 g

(0.035 mol) of dimethylcarbonate (84) was added, and the

mixture was allowed to warm to room temperature. The

mixture was hydrolyzed with 50 ml of water, and the THF

was removed from the mixture by rotary evaporation at 25°C.

The resulting aqueous layer was extracted with two 30 ml

portions of ether, the combined ether extracts were washed

with three 50 ml portions of water to remove the HMPA, dried

(MgS04), and concentrated by rotary evaporation at 25° to

give 6.6 g of light yellow oil which decomposed slowly at

room temperature with loss of formaldehyde. The material

was chromatographed on Florisil (hexane, ethyl ether 90:10)

to give 6.0 g (91%) of methyl N-methoxy-N-4—t-butylcyclo—

hexenylcarbamate (85) as a clear oil. An analytical sample

was obtained by high pressure liquid chromatography: ir

(Appendix A, Figure 10); nmr (Appendix B, Figure 24). Nmr

(CDC13), 6 0.90 (s, 9H); 1.10-2.5 (m,7H); 3.60 (s,3H);

3.75 (s,3H); 5.65 (m,lH); ir: 1720 cm-1 (vs).

Anal. Calcd for C13H23N03: C, 64.70; H, 9.61. Found:

C, 65.57; H, 10.18.

Thermal Decomposition of Methyl N-Methoxy-N-Cyclohexenyl-carbamate (85). Formation of Methyl N-4-t-Butylcyclo-

hexenylcarbamate (106)

A 50 ml 2-neck flask was equipped with N2 inlet and

a glass outlet leading directly into 30 ml of a standard

37

2,4-dinitrophenylhydrazine solution. Into the flask was

placed 1 g (4.14 mmol) of methyl N-methoxy-N-cyclohexenyl-

carbamate (85). The material was heated in an oil bath

while being swept with nitrogen and at 130° an evolution

of gas and simultaneous precipitation in the 2,4-DNP

solution were noted. Heating was continued for 0.5 hour at

which time there remained 0.83 g (95%) of a yellow oil.

The precipitate was removed by filtration from the 2,4-DNP

solution and weighed 0.65 g (75% of theoretical) and had

a melting point of 158-160°. Two recrystallizations of

the solid from 95% ethanol gave orange crystals, m.p.

166-167° (lit.** 166°), which was undepressed on mixing

with an authentic sample of formaldehyde 2,4-DNP. The

residual oil solidified an addition of a small amount of

hexane, was filtered under reduced pressure and purified

by vacuum sublimation (90°/0.1 mm) to give methyl N-4-t-

butylcyclohexenylcarbamate (106) as white crystals, m.p.

78-80°C; ir (Appendix A, Figure 12); nmr (Appendix B,

Figure 26); nmr: 6 0.9 (s,9H); 1.0-2.5 (m,7H); 3.6 (s,3H);

5.65 (m,IK); 6.0 (broad s,lH); ir: 3300, 1600 cm-1.

Anal. Calcd for C12H21N02: C, 68.21; H, 10.02.

Found: C, 68.45; H, 9.94.

38

Hydrolysis of Methyl N-4-t-Butylcvclohexenvlcarbamafce (106)• Formation of 4-t-Butylcyclohexanone (38)

Methyl Carbamate (10"8)~ ~

To 1.30 g (16.15 mmol) of methyl N-4-t-butylcyclohex-

enyl carbamate (106) was added 20 ml of 20% HCl and the

mixture was allowed to stand with rapid stirring at room

temperature for 20 hours. The reaction mixture was

extracted with two 20 ml of ether, the ether extracts were

dried over K^CO^ and concentrated at room temperature to

give 0.88 g (93%) of an oil which solidified on standing.

This oil was identified as 4-t-butylcyclohexanone (38) by

comparison of ir, nmr, and TLC with that of an authentic

sample. The aqueous acidic phase was neutralized, saturated

with solid K2C03, and extracted with two 20 ml portions of

ether. The ether extracts were dried f.K2C03) and concen-

trated at reduced pressure to give 0.3 g (65%) of an oil

whose ir and nmr were identical with those of an authentic

sample of methyl carbamate (108).

Acylation of 4-t-Butylcyclohexanone Oxime O-Methyl Ether (5) with Acetic Anhydride (87). Formation of

N-Methoxy-N-4-t-Butylcyclohexenylacetamide (88f

A flame dried, nitrogen-flushed 250 ml 3-neck flask was

charged with 150 ml of THF. To this was added 11.7 g

(65.5 mmol) of HMPA, and the mixture was cooled to -78°C.

16.4 ml (21.3 mmol) of 1.3 M n-BuLi was added. The

addition of 30 g (16.4 mmol) of 4-t-butylcyclohexanone 0-

methyl oxime (5) followed the procedures above. The mixture

39

was allowed to warm to -20°C for one hour, and then

recooled to -78°C at which time 2.17 g (21.3 mmol) of

acetic anhydride was added. The mixture was allowed to

warm to 0°C and was hydrolyzed with 50 ml of water. THF

was removed by rotary evaporation at 30°C and the resulting

mixture was extracted with three 50-ml portions of ether.

The ether extracts were washed with three 50 ml portions of

water to remove HMPA and the extracts were dried over

(K2CO3), concentrated by rotary evaporation under reduced

pressure at 30°C to give 4.2 g of a crude oil. On standing

for 12 hours, 0.1 g of a white solid precipitated and was

removed from the oil by filtration under reduced pressure.

The remaining oil was chromatographed on Florisil

(60-100 mesh). Elution with hexane gave 0.35 g of material

which was identical in all respects with starting oxime

ether (5). Elution with hexane/ethyl ether (50:50) pro-

duced 1.9 g (72% based on recovered starting material) of

N-methoxy-N-4-t-butylcyclohexenylacetamide (88) as a

clear oil: ir (Appendix A, Figure 13); nmr (Appendix B,

Figure 27); nmr: 6 0.9 (s,lK); 1.15-2.5 (m,lH); 2.07

(s,3H); 3.6 (s,3H); 5.75 (m,lH); ir: 1680 cm-1.

Anal. Calcd for C13H23N02: C, 69.29; H, 10.29;

Found: C, 68.92; H, 10.05.

40

Thermal Decomposition of N-Methoxy-N-4-t-Butylcyclo-hexenylacetamide (88). Formation of N-4-t-Butyl-

cyclohexenylacetamide (XI9)

Into a 25-ml round bottom flask was placed 0.5 g

(2.39 mmol) of N-methoxy-N-4-t-butylcyclohexenylactamide

(88) and the flask immersed in an oil bath which had been

preheated to 135°C. After about 30 seconds, the rapid

evolution of gas was observed. The remaining oil solidified

on addition of a small amount of hexane. The solid was

collected by filtration under vacuum and recrystallized

from hexane to give 0.40 g (92%) of N-4-t-butylcyclohexenyl-

acetamide (119) as a white solid, m.p. 117-118°.

ir: (Appendix A, Figure 14); nmr (Appendix B, Figure 28).

Ir: 3150 cm "S 1660 cm nmr: 6 0.85 (s,9H);

1.0-2.4 (m,7H); 2.0 (s,3H); 5.85 (m,lH); 7.45 (broad s,

1H) .

Anal. Calcd for C ^ H ^ N O : C, 73.79; H, 10.84. Found:

C, 73.98; H, 10.84.

Alkylation of N-4-t-Butylcyclohexenylcarbamate (85). Formation of N-Methyl-N-4-t-Butylcyclo-

hexenylcarbamate (121J"


was charged with 50 ml of THF. To this was added 2.0 g

(9.5 mmol) of the N-4-t-butylcyclohexenylcarbamate (85)

and 6.78 g (37.8 mmol) of HMPA. The mixture was cooled

to -78°C and 7.3 ml (9.5 mmol) of 1.46 M n-BuLi was added.

The mixture was warmed to -20°C for one hour. After recooling

41

to -78 C, 1.34 g (9.5 mmol) of iodomethane was added.

The mixture was allowed to warm to 0°C and hydrolyzed

with 2 0 ml of water. TEF was removed by rotary evaporation

and the resulting aqueous mixture was extracted with two

50-ml portions of ether. The ether extracts were washed

with three 50-ml portions of water to remove HMPA; the

extracts were dried (I^CO^) and concentrated at reduced

pressure to give 1.9 g of an oil. The oil was distilled

to give 1.8 g (84%) of N-methyl-N-4-t-butylcyclohexenyl-

carbamate (121) as a clear oil; b.p. 82-84°C/0.05 mm; ir

(Appendix A, Figure 15); nmr (Appendix B, Figure 29).

Nmr: 6 0.9 (s,9H); 10.25 (m,7H); 2.98 (s,3H); 3.6

(s,3H); 5.5 (m,1H). Ir: 1710 cm"1.

Anal. Calcd for C 1 3H 2 3N0 2: C, 69.29; H, 10.29.

Found: C, 69.49; H, 10.49.

Acylation of 4-t-Butylcyclohexanone O-Methyl Oxime ill w i t h Propionic Anhdride (89). Formation o£ N-Methoxy-N-4-t-Butylcyclohexenylpropion-

amide (90)


was charged with 100 ml of THF and 11.7 g (65.5 mmol) of

HMPA and the mixture was cooled to -78°C. To this was

added 16.4 ml (21.3 mmol) of 1.3 M n-BuLi followed by

the addition of 3.0 g (16.4 mmol) of 4-t-butylcyclohexanone

O-methyl oxime (5). The mixture was allowed to stir at

-78 C for one hour, followed by the rapid addition of

2.8 g (21.3 mmol) of propionic anhydride (89). The mixture

42

was allowed to warm to 0 C and hydrolyzed with 20 ml of H20,

THF was removed by rotary evaporation at 30°C and the

residue was extracted with three 25 ml portions of water.

The extracts were washed with three 25 ml portions of

water; the extracts were dried (K2CC>3) and concentrated

at reduced pressure at 30°C to give 3.9 g of clear oil.

The oil was chromatographed on 30 g of Florisil, and

elution with hexane gave 0.95 g of an oil identical in all

respects with authentic starting oxime ether (5). Elution

with hexane/ethyl ether (50:50) produced 2.35 g (88%

based on recovered starting material) of N-4-t-butylcyclo-

henenylpropionamide (90) as a clear oil after evaporation

of the solvent; ir (Appendix A, Figure 16); nmr (Appendix

B, Figure 30).

Nmr: 6 0.90 (s,9H); 1.10-2.40 (m,7H); 1.10 (5,3H);

2.33 (q,2H); 3.60 (s,3H); 5.75 (m,lH); ir: 2950, 1680 cm

Anal. Calcd for C14H25N02: C, 70.25; H, 10.53. Found:

C, 69.97; H, 10.31.

43

Thermal Decomposition of N-Methoxy-N-4-t-Butylcyclo-hexenyipropionamide (90). Formation of N-4-t-

Butylcyclohexenylpropionamide (120) and Formaldehyde

A 25 ml round bottom flask containing 0.5 g (2.1 mmol)

of N-methoxy-N-4-t-butylcyclohexenylpropionamide (90) was

immersed in an oil bath preheated to 125°. After approxi-

mately 30 seconds, the rapid evolution of gas was observed.

The remaining oil was taken up in a small amount of hexane

and a solid precipitated on standing overnight. The

solid was collected by suction filtration and recrystallized

from hexane to give 0.35 g (86%) of N-4-t-butylcyclohexenyl-

propionamide (120) as a white solid, m.p. 110-112°; ir

(Appendix A, Figure 17); nmr (Appendix B, Figure 31).

Ir: 3320, 2290, 1680; nmr: 6 0.85 (s,9H); 1.10

(5,3H); 1.1-2.4 (m,7H); 2.13 (q,2H); 5.90 (m,lH); 6.60

(broad s,lH).

Anal. Calcd for C ^ H ^ N O : C, 74.59; H, 11.07. Found:

C, 74.44; H, 10.97.

Preparation of (-)-Menthone Oxime (134)

Into a 1-liter round bottom was placed 66 g (0.43 mol)

of (-)-menthone (133), 500 ml of 95% ethanol and 59.5 g

(0.86 mol) of hydroxylamide hydrochloride. To this was

added a slurry of 72.2 g (0.86 mol) of sodium bicarbonate

in 250 ml of H^O. The mixture was heated at reflux for

three hours and concentrated at reduced pressure to a

volume of approximately 500 ml. The resulting two-phase

44

mixture was placedin a 2-liter separatory funnel and diluted

with 1 liter of H20. The aqueous layer was removed, and

the remaining oil diluted with 30 ml of ether. The ether

solution was washed with 500 ml of H20 and 200 ml of

saturated NaCl. The ether layer was dried (K2CC>3) and

concentrated at reduced pressure to give 80 g of an oil

which solidified on standing overnight. The crude solid,

m.p. 40-43°C, was sublimed at 50°/0.05 mm to give 72.5 g

(99%) of 134 as white crystals, m.p. 42-43° (lit.10,

m.p. 57°C).

Preparation of (-)-3-p-Menthylamine (129)

Following the procedure for the preparation of n-

heptylamine from heptaldoxime 2, the reduction was carried

out on 20.0 g (0.12 mol) of menthone oxime 134 in 240 ml

of absolute ethanol using 30 g of sodium. The amine was

removed by steam distillation and collected in dilute

hydrochloric acid. Evaporation gave 16.1 g (70%) of the

hydrochloride [a]25 -35.7 (5% in water) (lit.14 [a]25 o D D -36.6 ,

5%, in water).

Attempted Preparation of Tropinone N-(-)-3-p-Menthylimine (129)

To 13.8 g (0.072 mol) of 1-menthylamine hydrochloride

in 100 ml H20 was added a concentrated sodium hydroxide

solution until the mixture was basic to litmus. The amine

was extracted into pentane, dried (MgS04), and the solvent

45

removed under reduced pressure. To the resulting oil was

added 5 g (0. 036 iuol) of 3-tropinone and 100 ml of benzene.

The mixture was heated at reflux with azeotropic removal

of water for 48 hours. The mixture was concentrated to a

dark oil which was shown by ir and nmr to be a mixture of

starting materials.

Preparation of Tropinone N-(-)-g-Phenethylimine (135)

A solution of 5.0 g (0.036 mol) of tropinone (1) and

8.7 g (0.072 mol) of (S)-(-)-a-methylbenzylamine (130) in

65 ml of benzene was heated under reflux for 48 hours using

a Dean-Starke trap for azeotropic removal of water. The

solution was concentrated by evaporation to give 9.6 g of

a dark brown oil as residue. The oil was distilled under

reduced pressure, and two fractions were collected. The

first fraction, b.p. 40-50° at 0.01 mm, was shown by ir and

nmr to be unreacted tropinone and a-methylbenzylamine. The

second fraction, b.p. lll-121°/0.01 mm, consisted of 4.7 g

(54%) of 3 as a yellow oil; ir (Appendix A, Figure 18);

nmr (Appendix B, Figure 32); CD (Hexane, 0,0036 g/ml)

(Appendix C, Figure 38). Ce]26g = +794, C©]261 = +781,

[®]240 = "646"

Anal. Calcd for ^2.6^22^2' 79*29; 9.15. Found:

C, 78.95; H, 9.22.

46

Attempted Determination of Diastereomer Ratio of Tropinone N-(-)-a-Phenethylimine by NMR

Eu(fod)I

To 100 mg of L35 in 0.3 ml of CDC13 was added Eu(fod)3

in 5 mg increments. After the addition of 35 ml of shift

reagent, no useful shifts in the nmr spectra were observed.

Alkylation of Tropinone N-(-)-a-Phenethylimine (135). Formation of 2-Methyltropinone N-(-)-a-Phenethylimine (137)

A 500 ml 3-neck flask was flame-dried, flushed with

argon, and charged with 200 ml of THF, and 2.6 g (0.025 mol)

of diisopropylamine was added. The solution was cooled to

-78°C and 20 ml (0.025 mol) of 1.26 M n-BuLi was added over

5 min. The mixture was warmed to 0°C for 15 rnin and

recoiled to -78°C. Addition of 4.7 g (0.019 mol) of (3)

in 20 ml of THF over 10 min was followed by stirring at

-78°C. After 1 hour 3.6 g (0.025 mol) of iodomethane was

added, and the temperature of the solution was maintained

at -78°C for 15 min. The mixture was warmed to 0° and

hydrolyzed with 20 ml of I^O. The solvent was removed by

rotary evaporation, and the resulting aqueous mixture was

extracted twice with 75 ml of ether. The combined ether

extracts were dried (J^CO^) and concentrated at reduced

pressure to give 4.1 g of a yellow oil. The oil distilled

under reduced pressure to give 3.95 g (79%) of 4 as a

yellow oil, b.p. 102—109 /0.01 mm; ir (Appendix A, Figure

19); nmr (Appendix B, Figure 33); CD (Hexane, 0.00385

47

g/ml), (Appendix C, Figure 39); [el268 = +1172; Ce]262 = +892;

C0]245 = ~706'

Anal. Calcd for C 1 ?H 2 4N 2: C, 79.64; H, 9.44. Found:

C, 79.74; H, 9.20.

Alkylation of Tropinone N-(•-)-a-Phenethylimine (135). Formation of 2-Methyltropinone N-(-)-a-Phenethylimine

(137) at Higher Temperatures

The reaction was carried out as described previously

on 4.0 g (0.017 mol) of 135 with the following modification.

The THF solution was maintained at 0° during the addition

of the imine (135) and for 1 hour after the addition was

complete. Prior to the addition of iodomethane, the

mixture was cooled to -78°C. Workup as described previously

gave 4.31 g (99%) of 132 as a yellow oil identical in ir

and nmr with an authentic sample.

CD (Hexane, 0.0036 g/ml): Appendix C, Figure 40;

[0]267 = + 1 1 3 5 ; [e:i261 = + 7 8 5 ; Ce:i235 = ~ 9 8 1 ,

Alkylation of Tropinone N-(-)-a-Phenethylimine (135). Formation of 2-Methyltropinone N-(-)-a-Phenethylimine

(137) Using~HMPA

The reaction was carried out as in the preparation

described previously using 4.0 g (0.017 mol) of 135 with

the following modification. The reaction was carried out

in the presence of 2.96 g (0.017 mol) of HMPA which was

added to the reaction mixture prior to the addition of the

imine 135. The THF solution was maintained at 0° during

the addition of the imine (135) and for 1 hour after the

48

addition was complete. Prior to the addition of iodomethane,

the mixture was cooled to -78°C. After hydrolysis and

extraction with ether, the ether extracts were washed with

three 25 ml portions of water to remove HMPA, the extracts

dried (I^CO^) and concentrated at reduced pressure to

3.9 g (87%) of 137 as a yellow oil identical in ir

and nmr to authentic samples.

CD (Hexane, 0.0045 g/ml): Appendix C, Figure 41.

[® ]266 = + 1 8 8 0 ; C e ]260 = + 1 2 5 3 ' Ce:l244 = " 2 2 2 2 "

Alkylation of Tropinone N-(-)-a-Phenethylimine (135). Formation of 2-Methy1tropinone N-(-)-a-Phene'thy limine

(137) Using TMEDA

The reaction was carried out as described previously

on 4.0 (0.017 mol) of 135 with the following modifications.

The reaction was carried out in the presence of 0.77 g

(0.017 mol) of TMEDA which was added to the reaction

mixture prior to the addition of the imine (135). The

THF solution was maintained at 0° during the addition of

the imine (135), and for one hour after the addition was

complete. Prior to the addition of iodomethane, the mixture

was cooled to -78°C. After hydrolysis and extraction with

ether, the ether extracts were washed with 75 ml portions of

water to remove TMEDA, dried (K2CC>3) and concentrated at

reduced pressure to give 3.97 g (91%) of 137, as a yellow

oil identical in ir and nmr with an authentic sample.

49


C0]267 = +1874'' [0]261 = + 1 2 0 9 ; [e:i244 = " 2 2 0 7*

Preparation of Tropinone N-(+)-a-Phenethylimine (136)

This compound was prepared by the same method as for

135 using 10 g (0.07 mol) of tropinone (123) and 8.7 g

(0.014 mol) of (R)-(+)-a-methylbenzylamine. Workup as

described previously for 135 produced 15.8 g of a crude

oil. The oil was distilled under reduced pressure and two

fractions were collected. The first fraction, b.p. 40-50°/

0.01 mm was shown by ir and nmr to be unreacted tropinone

and (+)-a-methylbenzylamine. The second fraction consisted

of 9.0 g (53%) of 136 as a light yellow oil, b.p. 115-121°/

0.01 mm. This material was identical in ir and nmr to 135

prepared from (-)-a-methylbenzylamine.


[0]267 = " 8 1 0 ; [0]261 = " 8 6 2 ; [0]238 = + 6 1 4*

Alkylation of Tropinone N-(+)-a-Phenethylimine (136). Formation of 2-Methyltropinone N-(+)-a-Phenethylimine

(138) at (F

The reaction was carried out at 0° as described

previously for 135 using 4.0 g of the imine (136). The

yield was 4.2 g (96%) of 138 as a brown oil.


CS]266 = " 1 2 4 4 ; [0]261 = = 1 0 7 9 ; [0]24O = + 1 6 1 9 '

50

Alkylation of Tropinone N-(+)-a-Phenethylimine (136) Formation of 2-Methy1tropinone N-(+)-a-Phenethylimine

(138) Using HMPA ~~

The reaction was carried out at 0° as described

previously for 13j> using a 4.0 g of the imine (136) and

2.96 g of HMPA. The yield was 4.2 g (96%) of 138 as a

brown oil.


[e]266 = " 1 2 9 1 ; Ce]261 = - 1 1 6 7 ; [e]239 = + 1 4 9 1 '

General Procedure for Hydrolysis of 2-Methyltropinone N-g-Phenethylimines (137) or (138)

with 10% HC1

To the crude oil 137 or 138 was added 25 ml of 10%

HC1 and the mixture stirred at room temperature for 12

hours. The acidic solution was cooled in an ice bath and

made basic by the addition of solid K2C03. The basic

mixture was extracted with two 50 ml portions of ether,

the extracts dried (K2C03) and concentrated at reduced

pressure to give brown oils (approximately 4 g) which were

shown by TLC (silica gel, ether), ir and nmr to be a mixture

of 2-methyl tropinone and a-methylbenzylamine; nmr: Appendix A, Figure 34.

Isolation of 2-Methyltropinone (139)

To the reaction mixture obtained from hydrolysis of

137 or 138 (approximately 4 g) was added 30 ml of 10% NaOH.

To this was added 1 g of benzenesulfonyl chloride and the

mixture shaken vigorously for 10 min. This procedure was

51

repeated twice with an additional 2 g of benzenesulfonyl

chloride being added. The mixture was extracted with two

25 ml portions of ether and the extracts concentrated at

reduced pressure to give a brown oil (approximately 4.5 g).

To the oil was added 30 ml of 10% NaOH. The mixture was

treated with three additional 1 g portions of benzene-

sulfonyl chloride and extracted with two 25 ml portions of

ether. The combined organic extracts were extracted with

two 25 ml portions of 10% HCl to remove the amine. The

acidic solution was extracted with 25 ml of ether and

made basic by the slow addition of solid K2CC>3 while stirring

in an ice bath. The basic solution was extracted with

two 25 ml portions of ether, the combined extracts dried

(I^CO^) and concentrated at reduced pressure to give

2-methyltropinone (139) as a brown oil which was purified

by vacuum distillation. Ir: (Appendix A, Figure 20);

nmr (Appendix B, Figure 35).

52

Yields of 2-Methyltropinone (139) front 137 or 138

Reaction

Imine Conditions, Temperature Reagents

Crude Yield

Distilled Product

Boiling Point

137 -78° 1.90 1.78 g 46°/0.05

137 0° 1.83 1.64 g 44 -46°/0.05

137 0° 1 eq HMPA 1.97 1.85 g 44 -46°/0.05mm

137 0° 1 eq TMEDA 2.1 1.95 g 46°/0.05mm

138 0° 1.87 1.45 g 46°/0.05mm

138 0° 1 eq HMPA 1.54 1.3 g 46°/0.05mm

Attempted Determination of Optical Purity of 2-Methyltropinone (139) via a Chiral

Shift Reagent

Into an nmr tube was placed 0.33 ml of a 0.3 M solution

of tri-(3-trifluoromethylhydroxymethylene)-d-camphorato

europium III derivative. To this was added 2—methyltropinone

(139) in 2 yl increments. After the addition of 30 yl,

no splitting of the C-methyl doublet at 6 0.95 or the N-

methyl singlet at 6 2.45 could be observed.

Preparation of N-Ethoxycarboxyl-2-a-Methyl-3-Tropinone (146)

To 2-methyltropinone (139) (1.45-1.85 g) was added 30

ml ethyl chloroformate and the mixture heated at reflux

for 2.5 hours. Excess ethyl chloroformate was removed by

rotary evaporation and the residue was treated with 10

ml of concentrated NH4C1 solution. The mixture was

extracted with ether, the extracts dried (K2CC>3) and

53

concentrated at reduced pressure to give 146 as a yellow

oil. The oil was taken up in ether and filtered through 10

g of Florisil. The ether was removed by concentrated at

reduced pressure to give 146 as a clear oil, identical by

TLC (silica gel, Et20), ir and nmr with an authentic sample

prepared from (-)-cocaine. Ir: (Appendix A, Figure 21);

nmr: (Appendix B, Figure 36); CD (authentic sample, hexane,

0.0058 g/ml): (Appendix C, Figure 8). [Q]307 = -2879.

[a]£5= -24.0.

Yields of N-Ethoxycarbonyl-2a-Methyl-3-Tropinone (146)

Imine

Reaction Conditions, Temperature

Crude Yield (g)

CD App. C

Purified Yield (g)

r I25 D

CD App. C

137 -78° 1.95 Fig 47 1.94 -0.81 Fig 48

137 0° 1.75 Fig 49 1.73 -1.17 Fig 50

137 0° 1 eq HMPA 2.1 Fig 51 2.1 -1.14 Fig 52

137 0° 1 eq TMEDA 2.3 Fig 53 2.25 -1.5 Fig 54

138 0° 1.6 Fig 55 1.6 +0.92 Fig 56

138 0° 1 eq HMPA 1.6 Fig 57 1. 58 + 0.70 Fig 58

54


1. W. G. Kofron and L. E. Baclawski, J. Org. Chem., 41, 1879 (1976). — '

2. G. Ortega, Ph.D. Dissertation, University of Texas, Austin, 1976.

3. H. Singh and B. Razdan, Ind. J. Chem., 6, 568 (1968).

4. E. S. Wallis, E. Fernholz, and F. T. Gephart, J. Am. Chem. Soc. , 59, 137 (1937) .

5. P. Beynon, S. Heilbron and R. Spring, J. Chem. Soc., 910 (1936).

6. S. Smiles and T. P. Hilditch, J. Chem. Soc., 91, 519 (1907). —

7. "Handbook of Chemistry and Physics", 51st edition, Chemical Rubber Co., Cleveland, Ohio, 1970-1971.

8. R. L. Shriner, R. C. Fuson and D. Y. Curtin, "The Systematic Identification of Organic Compounds", John Wiley and Sons, Inc., New York, 1964, p. 320.

9. L. T. Sandborn, "Organic Synthesis", 2nd edition, Collect. Vol. I, John Wiley and Sons, Inc. New York. 1931, p. 340.

10. E. Brinkmann, Ann., 250, 335 (1889).

11. A. C. Cope and E. M. Acton, J. Am. Chem. Soc., 355 (1958)

12. W. H. Lycan, S. V. Puntambeker, C. S. Marvel, "Organic Syntheses", 2nd edition, Collect. Vol. II, John Wiley and Sons, Inc., New York, 1943, p. 318.

13. S. P. Findlay, J. Org. Chem., 21, 1385 (1957).

14. E. S. Rothman and A. R. Day, J. Am. Chem. Soc., 76, 111 (1954). — '

CHAPTER III

RESULTS AND DISCUSSION

Oximes

Attempted Resolution of Geometrical Enantiomeric Oximes

The regio- and stereospecificity of oxime deprotonation

and subsequent reactions of oxime dianions has been clearly

established. In cases where the oximino function (an

unsymmetrically substituted double bond) is centrally

located between two similar asymmetric carbon atoms of

opposite configuration, the molecule is a geometrical

enantiomeric isomer, and there exists a unique opportunity

for stereospecific introduction of an electrophile

onto one of the alpha carbons (Scheme 14). The

stereochemistry will be determined by the stereochemistry

of the carbon-nitrogen double bond formed on oxidation of

the meso precursor below, 2,6-diphenyl-l-methyl-4-piper.idone.

Ph CH3-

Ph

55

56

Scheme 14

CH3-N-Ph

CHo-

CH->-.OH

Ph 41

1) 2nBuLi 2) X-I 3) Pyridinium

chlorochromate

Ph

Ph 40

N

OH

Lyle and Lyle"" provided the first recorded illus-

tration of this type of isomerism by the successful

resolution of racemic cis-2,6-diphenyl-l-methyl-4-piperidone

oxime (40, 41). The dextrorotatory enantiomer (41) was

obtained by successive recrystallizations of the diastereo-

meric salts (54, 55) obtained from the racemic oxime (40, 41)

and (+)-10-camphorsulfonic acid (56). Attempts to obtain

the levorotatory isomer (40) were unsuccessful, although

this could presumably be obtained from the salts of 40 and

41 with (-)-10-camphorsulfonic acid (57).

The literature also reports the resolution of (+)-

tropinone oxime (58, 59)3'4'5 in low yield once again by

fractional crystallization of the diastereomeric salts

(60, 61) of (+)-10-camphorsulfonic acid (56) (Table I).

57

The resolution of tropinone oxime derivatives is significant,

since this ring system is associated with a variety of

pharmacological activities.

TABLE I

RESOLUTION OF (+)-TROPINONE OXIME (58, 59) VIA RECRYSTALLIZATION OF (+)-10-CAMPHORSULFONATE SALT

CH.

^ c h 2 s o 3 h _ i +

60,61

References 3 and 4

8.98 g salt, m.p. 233°C

4.28 g salt

0.32 g salt, m.p. 238°C

base

0.073 g free amine (58)

m.p. 108-109° [a] -21.65

20

D

Reference 5

22.2 g salt

Six recrystallizations

0.8966 g salt, m.p. 241.5

base

0.31 g free amine (58)

, 2 0 m.p. 104-105° [a] -34.11 D

In an attempt to analyze the optical purity of resolved

tropinone oxime (58), Ortega and Delgado5 carried out both

13 proton and C nmr studies using a chiral europium shift

reagent; however, unique N-methyl signals for the

13 diastereomers were not evident. Proton and C nmr studies

58

were also conducted on the camphorsulfonate diastereomers

(60, 61), but in each case only one set of signals was

observed.

The enantiomeric purity of alcohols and amines has been

measured using nmr by studying the esters or amides of (R)-

(+)-a-methoxy-a-trifluoromethylphenylacetic acid (61).6

The salt of this acid and racemic tropinone oxime (58, 59)

was prepared and was soluble in deuterochloroform; however,

the N-methyl and O-methyl resonances of the diastereomers were

not resolved.

Ortega and Delgado~* also attempted resolutions of (+) -

tropinone oxime (58, 59) using salts of (+)-tartaric acid

and (-)-mandelic acid without success. Resolution via the

salt of (+) tropinone oxime (58, 59) and (-)-dibenzoyl-L-

tartaric acid (62) was attempted, but only an oil which

resisted crystallization from various solvents was obtained.

The failure of a successful resolution utilizing diastereo-

meric salts led to a consideration of other methods for

resolution of geometrical enantiomers. Attachment of a

chiral molecule such as a cholesterol moiety to the oxygen

of the oximino formation would produce a pair of

diastereomers which might be separable by fractional

crystallization or chromatographic methods.

One of the oximes chosen for this study and for others

throughout this thesis was 4-t-butylcyclohexanone oxime (38).

This molecule is conformational^ rigid, due to the

59

tejrt butyl substituent and. exists as a pair of enantiomers

by virtue of axial dissymmetry. This type of dissymmetry is

not connected with the presence of asymmetric atoms and is the

same type found in biphenyls, allenes, alkylidenecyclo—

alkanes and spiranes.

The attempted etherifications were conducted by treating

the sodium salt of 4-t-butylcyclohexanone oxime (63) with

various cholesterol derivatives (Scheme 15). Both cholesteryl

p-toluenesulfonate (64) and cholesteryl iodide (65) were heated

with the sodium salt of 51 in absolute ethanol; however,

no reaction was observed. The reactions were also attempted

in hexamethylphosphoramide (HMPA) and dimethylsulfoxide (DMSO)

with only starting materials being isolated after 12 hours

at 90°C. The failure of these reactions is probably due

to steric interactions. C8H17

Na

Scheme 15

C H. 8 17

63 6£ R = p-H3C-C6H5-S03-

65 R = I

60

The failure to obtain chiral oxime ethers led to a

consideration of the use of an ester linkage for attachment

of the chiral function. Cholesteryl chloroformate (66) was

chosen because of its commercial availability. Reaction of

4-t-butylcyclohexanone oxime (38) with 66 in pyridine led

to the cholesteryl oxime ester (67) (Scheme 16).

Scheme 16

38 66 67

This material could be recrystallized from hexane but

no change in the melting point was observed after the first

recrystallization in which > 90% of the compound was

recovered. Separation of the diastereomers was also

attempted by high pressure liquid chromatography on silica

gel, but no evidence of separation was observed. The

reaction of (+)-tropinone oxime (58, 59) with cholesteryl

chloroformate (66) in pyridine produced only a pasty mass

which failed to crystallize from a variety of solvents.

The final attempt to effect resolution consisted in

attachment of a (+)—10—camphorsulfonate group to the oximino

oxygen by reaction of (+)-10-camphorsulfonyl chloride (68)

C8H17

0-C- 0

61

with an oxime in pyridine. These compounds were produced

from both 4-t-butylcyclohexanone oxime (58) and (+)-tropinone

oxime (58, 59) (Scheme 17). In the case of tropinone oxime,

the camphorsulfonate derivative (70) was obtained as the

hydrochloride as evidenced by the nmr spectrum which showed

a shift of the N-methyl from <5 2.3 in tropinone oxime to 6 2.9

/ .OH

38

58, 59

Scheme 17

,so2ci

68

- >

O CH3-,0H

69

CI

The melting point of the 4-t-butylcyclohexanone oxime

(+)-10-camphorsulfonate (69) remained unchanged after the

first two recrystallizations from hexane, in which 86% of

the material was recovered. No change in the ir or nmr

spectra was observed after two recrystallizations.

An attempt was made to recrystallize the tropinone

oxime (+)-10-campho'rsulfonate (70) from a variety of solvents,

62

but only methanol was found to be a suitable recrystallization

solvent. From a 1.6 g sample was obtained only 0.6 g on

recrystallization with a melting point of 186-189°C. A

second recrystallization produced 0.15 g of crystals, m.p.

188-190°C. It is possible that the material from the second

recrystallization was enriched in one enantiomer, but the

yield from recrystallization was too low for this method

to be practical.

Reaction of Oxime Dianions with Electrophiles

Initial investigations of oxime dianions have centered

on the regio- and stereospecificity of their reactions with

simple alkyl halides. No investigation of the synthetic

utility of oxime dianion reactions with other electrophiles

has been made.

The introduction of an acyl group, such as the carbo-

methoxy group, regiospecifically onto one of the a-carbons

of an oxime such as tropinone oxime would provide a useful

intermediate for conversion to natural products related

to (-)-cocaine (71). For this reason the reaction of

4-t-butylcyclohexanone oxime dianion with acylating agents

such as dimethylcarbonate and methyl chloroformate was

investigated. The oxime dianion was generated with two

moles of n-butyllithium, followed by the addition of

dimethylcarbonate or methyl chloroformate.

63

Surprisingly, after hydrolysis with water and workup,

only 4-t-butylcyclohexanone oxime (38) was obtained. The

starting materials were purified and dried repeatedly, but

from each reaction attempt, only starting oxime (38) was

obtained. The electrophile may give reaction at oxygen

to produce a readily hydrolyzable oxime ester.

The oxime dianion failed to react, or failed to produce

a. stable product, on reaction with a variety of other

electrophiles (Scheme 18).

Scheme 18

0 II

C1-C-0CH

Product Isolated

Starting material

/ CH3O-COCH3

I-CN

CH(OEt)

CH2O

Starting material

Starting material

Starting material

Starting material

CH2CI2 Starting material

64

The failure of acylating agents to give electrophilic

substitution led to a consideration of alkylating agents.

Since the tropinone oxime dianion reacted smoothly with

nisthyl iodide, alkylation with a halomethyl ether was

considered. This reaction would produce an ether function

which could be converted to acid derivatives. The chloro-

and bromomethylmethyl ether are suspected carcinogens?

however, the iodomethyl methyl ether (73) was reported by 7

Jung and provided a convenient method of synthesis. It

was so reactive, however, that decomposition occurred prior

to alkylation resulting in a low yield of the desired

product and recovery of starting material.

A partially purified sample of methoxymethylated

tropinone oxime (74) was isolated by column chromatography

and showed a three proton singlet at 6.3.3 in the nmr corre-

sponding to the methoxyl group. This oil decomposed to a

red tar on standing overnight (Scheme 19).

Scheme 19

CH3 - N 1) 2 n-BuLL CH3-

2) I-CH20CH3

58, 59

12 hr Tar

65

Oxidative Deoximation with Pyridinium Chlorochromate

The recovery of the parent aldehyde or ketone from an

oxime derivative has classically involved acid hydrolysis

under suitable conditions which removes the hydroxylamine

from the equilibrium.8 This reduces the utility of oximes

in cases where the parent ketone is acid sensitive. Recent

application of oxidative or reductive methods for removal

of the oximino function^ led to a consideration of pyridinium

chlorochromate (75) as a deoximation reagent.1(^ The results

are shown in Table II.11

0 H ^ r " CrCIO

-H 3 0 " 2 11 ?

R-C-R R-C-R2

The results showed that use of two molar equivalents

of pyridinium chlorochromate gave better yields. The

reaction required greater than 12 hours at room temperature

for maximum yields. Ketoximes were converted to the

corresponding ketones in yields of 50-85%, benzaldoxime (80)

was converted to benzaldehyde without further oxidation,

and oxime ethers were resistant to the reagent providing a

degree of selectivity in the use of substituted imines as

protecting groups for carbonyl compounds.

66

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Oxime Ethers

Introduction

The failure of acylation reactions of oxime dianions

to give carbon substitution suggested the possibility of

directing this reaction to carbon by using the O-alkylated

oxime ether. The availability of methoxylamine and the ease

of reaction of this amine with ketones provides a convenient

method of synthesis.

The alkylation of the mono anion of the oxime is com-

plicated as a synthetic method by the competition of N and

0 alkylation to form the nitrone and oxime ether,

respectively. The method was used by Ortega to prepare

some oxime ethers of the partially resolved geometrical

enantiomers of tropinone.^

The regio- and stereospecificity of the alkylation of

O-methyl oxime ethers were demonstrated by Fraser and

15 Dhawan. They showed that the reaction of the mono lithium

salt of 4-t-butylcyclohexanone O-methyl oxime with methyl

15

iodide gave methylation of the pro Z a-carbon. The

conformationally-biased ring allowed the determination

that the methyl group had entered the axial position in 16

a manner analogous to the oxime as shown by Lyle et al.

7 0

Choice of Base

The anion formation for the alkylation reactions of

oxime ethers has usually been accomplished by the use of

lithium diisopropylamide (LDA). These sterically hindered

bases are preferred over alkyl lithium reagents and should

not give competitive addition to the carbon-nitrogen double

bond. For the study of the acylation, the possibility

exists that the diisopropylamine remaining after proton

abstraction will compete with the lithio anion for reaction

with highly reactive electrophiles such as alkyl chlorofor-

mates. In the initial study of the acylation, the anion was

generated with LDA and the product mixtures from the reactions

with methyl chloroformate (81) clearly showed the presence of

substantial amounts of methyl N,N-diisopropylcarbamate (82)

(Scheme 20). This side product has also been reported from

the reactions of a-lithio alkylnitriles with methyl-

17 chloroformate.

Scheme 20

OCH, / 3

N

. X

2) C1-C0CH,

\ u X ii

a c y l a t e d p r o d u c t s + N-COChL

0

81 82

71

In the case of reactions of oxime ether anions, this

problem was circumvented by finding that n-butyllithium in

the presence of four equivalents of hexamethylphosphoramide

(HMPA) at -78° smoothly deprotonated the oxime ether with

no evidence of addition of the butyl anion to the carbon-

nitrogen double bond. It is possible that the n-butyllithium/

HMPA base system may prove to be a satisfactory substitute

for lithium amide bases in other deprotonation reactions.

The most serious drawback to the use of HMPA is its potential

carcinogenicity. Compounds which could replace HMPA are

being sought, and recently, 1,3-dimethyl-2-imidazolidinone

(83) was suggested as a possible candidate.

0

HoC-N N-CH0 \ /

83

Acylation Reactions

A conformationally biased oxime ether was chosen for

study in order to allow determination of any pertinent

stereochemistry of the acylation. Thus, 4-t-butylcyclo-

hexanone O-methyl oxime (5) was chosen as a model compound.

The oxime ether (5) was smoothly deprotonated with n-butyl-

lithium/HMPA in THF and gave reactions with a variety of

acylating agents. The ir and nmr spectra obtained from

the reaction product of the lithio anion of 5 with dimethyl-

carbonate (84) was inconsistent with the C-acylation.

72

The ir spectrum (Appendix A, Figure 10) showed a broad and

intense carbonyl absorption at 1710 cm-1. The weak, but

characteristic, carbon-nitrogen double bond stretching

vibration at 1650 cm ^ found in oxime ethers was absent.

The nmr spectrum (Appendix B, Figure 24) showed a broad

multiplet for one hydrogen at 6 5.55, which was very

similar in appearance and chemical shift to the vinyl

hydrogen found in both the morpholine enamine and

trimethylsilyl enol ether of 4-t-butylcyclohexanone. The

results of all acylation reactions are summarized in Table

III. With the exception of acylation of the lithio anion

of 5 with methyl chloroformate (81), the products resulted

from the reaction of the acyl group at nitrogen rather than

carbon. Acylation with methyl chloroformate (81) gave,

in addition to the major N-acylated product (85), some

C-acylated material (86). The ir showed a sharp carbonyl

absorption at 1740 cm as well as a weak carbon nitrogen

stretching band at 1640 cm-"'".

The observation of nitrogen acylation in contrast to

C-acylation from the ambident system having terminal

carbon and nitrogen has other analogies in the literature.

The reaction of the anion of indole has been shown to give

alkylation of the 3-position (carbon), even though this

destroys the aromaticity of the heterocycle."'" Acylation

with acetic anhydride (87) under kinetically controlled

conditions, however, gave 1-acylation (nitrogen).6

TABLE III

N-ACYLATION OF OXIME ETHER ANIONS

7 3

N

/ 0 C H 3

1 ) JI B U L I , 4 H M P A

2 ) R - C - X

II

0

0

R C \ / 0 C H 3

N

8 4 X = O C H 3 R = 0 C H 3 8 5 9 1 %

81_ X = C I R = 0 C H 3 8 5 5 5 % 8 6 3 2 %

8 7 X = 0 C C H - , R

II 3

= C H 3 8 8 7 2 %

I I

0

8 9 X = 0 C C H 9 C H Q LI 3

R = C H 2 C H 3 9 0

00

00

74

20

Wittig and Reiff , as part of their investigation of

directed aldol condensations, have investigated reactions

of lithiated Schiff's bases with various electrophiles.

The reaction of the anionized Schiff's base of acetone (91)

with ethyl chloroformate gave a 90% yield of the C-acylated

product (92) and a 5% yield of products resulting from hydro-

lysis of the N-acylated material (93) (Scheme 21). Acylation

of lithium ethylidenecyclohexylamine gave N-acylated material (95)

as the only isolated product (Scheme 21).

Scheme 21

Li

P6Hn N 0 II II

C H 3 - C - C H 2 C O C 2 H 2

92

Nr * / \ -

'C6Hll

CH 3 C - C H 2

90% 91

C I - C O C 2 H 5

0

CH 2 0

V II C-N-COCOHC

/ I 2 5 C H3 c6H11

93

CH.

CH-

H 2 0

0

,C=0 + C G H 1 1 - N H C O C 2 H 5

94 95

75

Li CH2CH-NC6H1]L

96

0

C H CC1 6 5

COOC6H5

CH2=CH-N-C6H11

97 H3O

V C6H5CONHC6H1;L

98

+

Other examples of N-acylation of imines can be found

21

m the recent literature. Ninomiya and coworkers have

shown that the 6-membered heterocyclic enamine system

comparable to indole gives exclusively N-acylation;

however, the anion was not used in this reaction.

Acylation of 3,4-dihydro-6,7-dimethoxy-l-methylisoquinoline

(99) gave acylation at the 2-position with isonicotinoyl

chloride (100) (Scheme 22). Treatment with an

excess of acid chloride led to the spirodihydropyridine

(101).

76

Scheme 22

CI

CH3O

CH30' H N^C2H5^3 CH30

CH,

99

N(C2H5)3

0 100

excess

101

77

Oppolyzer and coworkers22 have prepared N-acyl-N-alkyl-

(aryl)-1-amino-l,3-dienes by N-acylation. These protected

aminobutadiene equivalents were then used in Diels-Alder

reactions (Scheme 23).

Scheme 23

CHO R-NH

102 103

2 3 11 R R -C-Cl

The variation of C and N or C and 0 reactivity in

ambident anions has been the subject of considerable study.

The different reaction paths are affected by many factors

which regulate the relative stability of the two transition

states to the two types of products. Possibly one parameter

which may be of some predictive value in the reaction is

the relative electronegativity of the electrophile. This

would lead to transition states approaching SN- or SN2

conditions as one changes from the highly electrophilic acid

halide to the less reactive alkyl halide. Thus, the bond

lengths in the transition state for C-alkylation would be

shorter than those for N-substitution.

23

78

Thermal Decomposition of N-Methoxy Amides and Carbamates from N-Acylation of Oxime Ether Anions

During the initial attempts to purify the products from

the reaction of the anion of 4-t-butylcyclohexanone O-methyl

ether (5) and dimethyl carbonate (84), an unusual thermal

decomposition reaction was observed. The nmr spectrum for

the N-acylated product (85) contains two singlets at 6 3.75

and 3.60, each integrating for three hydrogens which result

from the methyl group of the carbomethoxy substituent and

from the N-methoxy substituent, respectively (Appendix B,

Figure 24). During manipulations of this compound, which

required heating, the signal at 6 3.60 diminished. On heating

the compound at 130° for several minutes, the signal

disappeared entirely and the evolution of gas was observed.

As the signal at 6 3.60 disappeared, a broad singlet, due

to a single proton which exchanged with D2O appeared at

6 6.00 (Appendix B, Figure 26)- This new product was

isolated, and the mass spectrum of the compound indicated

a loss of thirty mass units which occurred in the thermal

reaction. This corresponded to the loss of formaldehyde

as the gaseous decomposition product. Later this identity

was confirmed by trapping the evolved gas as the 2,4-dinitro-

phenylhydrazone derivative and comparing the solid with

an authentic sample of formaldehyde 2,4-DNP hydrazone (105).

79

The larger fragment of the thermal decomposition was

subjected to hydrolysis with aqueous HC1 and the products were

found to be 4-t-butylcyclohexanone (107) and methyl carbamate

(108). These experiments proved conclusively that the

structure of the original compound from N-acylation of the

lithio anion of 5 was methyl N—methoxy—N~4—t-butylcyclohexenyl

carbamate (85) (Scheme 2 4).

0

V n-ip-r

Scheme 24 C H 3 ( H C - O C H 3

V

0

CH30C^ y0CH3

] 0 % HC1 0 N/ A

C H O O C \ M 6 Nr 107

J CH 3 0CNH 2

108

NH-N = CH,

0

HCH 4 -

NHNH,

.NO,

NO.

06

80

This facile decomposition is probably an intramolecular

process. Consideration of the structures shows that a

Woodward-Hofmann allowed reaction could occur in either of

two ways. The proton transfer from the methoxyl group could

occur to oxygen (path 1) or to carbon (Path 2) (Scheme 25).

Scheme 25

Path 1

Path 2

0 I 2

R-C — Q

N

0 ii RC

85 0

H

?H CH I n 2

R-C. II % 0

N

0 II

RC \ . /

106

0 II CH,

85

81

The product of the reaction was clearly the N-acyl

enamine (106) and not the N-acyl inline (109) as shown by the

spectral data. Although this does not provide unequivocal

evidence for Path 1, it is strongly supporting evidence.

Probably the most significant evidence that Path 1 is the

more probable route comes from the research of Kauffman24,

which has not appeared in the published literature. While

attempting to prepare the cyclic amide (113) by an internal

acylation reaction (Scheme 26), Kauffman found that benzal-

dehyde was produced and the benzyloxy group was lost

(Scheme 2 7). To confirm the course of the reaction, the

stability of N-benzyloxybenzamide (116) was investigated

(Scheme 28). On heating at the boiling point of acetonitrile-

triethylamine, benzyJaldehyde (115) and benzamide (117) were

detected. He did not study the reaction further; however,

it is evident that the reaction observed was comparable to

the decomposition of the N-methoxy-N-4-t-butylcyclohexenyl-

carbamate (85). Since N-benzyloxybenzamide (116) does not

have a carbon-carbon double bond comparable to 85, it is

evident that Path 1 is required for decomposition, and is

thus the probable route for 85. The generality of this

reaction is evident, since not only acylation with carbonate

derivatives but also fatty acid anhydrides gave N-acyl

derivatives and each of these gave loss of formaldehyde on

heating (Table IV). This sequence seems to be a general and

unique method of preparing the unusual N-acyl enamines.

82

Scheme 2 6

PhCH20\ /(CH2)5NH3 CF3C02

N

0 ^C-CH2CH2-C-OPNP

0

111

PNP = p-nitrophenyl base

PhCH90 (CHo)5NH0

0 ^ NSCH2CH2-C-VOPNP

112 V

PhCH, . ( c h

2 ) 2 .

0

NH

'CH2-CH2

113

TABLE IV

THERMAL DECOMPOSITION OF N-ACYL ENAMINES

8 3

0 li

RCv yOCH3

N

A

RCs^ H

N

0 II

+ HCH

8 5 R = OCH- 1 1 8 9 5 %

8 8 R = CH- 1 1 9 9 2 '

9 0 R = CH 2 CH 3 120 86'

Scheme 27

84

" V PNPv^ ||

(CH2)g-NH3CF3C02

CH-

SCH-Ph

-CH- ' C ^ H

PNP +

111

0

^(ch2)5nh3 cf3coo"

ch9 n \ 1

ch2 \ 0 + PhCHO

114 115

Scheme 28

0 I!

Ph-C

CHPh A \v

N I

H

116

O

PhCNH2 + PhCH

117 115

85

In order to investigate further the chemistry of

methyl N-cyclohexenyl carbamate (85), the compound was

treated with n-butyllithium. Proton abstraction from

nitrogen produced a highly resonance-stabilized anion and

reaction with methyl iodide gave exclusive N-alkylation.

The product, isolated from the reaction in 84% yield,

was confirmed as methyl N-methyl-N-cyclohexenylcarbamate

(121) by the presence of a singlet integrating for 3

protons at 6 3.0 with the disappearance of the exchangeable

one proton singlet at 6 6.0 (Scheme 29). These compounds,

therefore, behave quite differently from enamines which

would give C-alkylation under these conditions.

Scheme 29

0 II

CH^OC H N

CH-.0-C'x J N>,

n-BuLi

0 II

CH-.OC N"

ch3i

-CH.

85 121

86

Oxidation of Tropine (3-Tropanol) (122)

In connection with the study of various 3-tropinone

derivatives, over one hundred grams of this expensive

reagent was needed. Since a large quantity of 3-tropanol

(122) was on hand, it was desired to effect transformation

of the amino alcohol (122) to the amino ketone (123) .

The oxidation of amino alcohols to amino ketones is

experimentally difficult for a number of reasons. The

bidentate functionality can form strong complexes with the

metal cation of the oxidizing agent and/or the amino ketone

may oxidize further to give carbon bond cleavage.2^ The

description by Muellar and Depardo26 of a modification of

the Jones oxidation2^ circumvents these problems.

A procedure using Jones reagent in glacial acetic acid

was used for the conversion of tropine (122) to tropinone

(123) (Scheme 30). Normally, addition of base to the reaction

mixture after destruction of excess oxidant would result in

formation of Cr(III) hydroxide, a thick, gelatinous precipi-

tate, difficult, if not impossible, to filter or extract.

To avoid the problem, trisodium citrate was added to the

basic reaction mixture to complex and solubilize Cr(III).

Since Cr(III) does not exchange ligands at a reasonable 2 8

rate, a small amount of zinc was added. The zinc serves

to generate a small amount of Cr(II), which exchanges

ligands quickly. Electron transfer then occurs rapidly to

87

generate complexes Cr(III) and a new Cr(II). Eventually

all the Cr(III) is complexed in a base soluble form.

Using this method, a 70% yield of 3-tropinone (123) was

obtained.

Scheme 30

122

Modified Jones > Oxidation

CH,-

Asymmetric Induction in the Alkylation of N-a-Phenethylimines of Tropinone

5

The work of Ortega and Delgato on the resolution of

tropinone oxime (58, 59) failed to substantially improve

on the method of Singh and Razdan (Table I).3'4 The

resolution, which in both cases consisted of successive

recrystallizations of the (+)-10-camphorsulfonate salt of

tropinone oxime (60, 61), produced only a low yield of

one enantiomer. None of the dextrorotatory enantiomer was

obtained. Attempts to determine the optical purity were 5

unsuccessful , and the absolute configuration of the enan-

tiomer obtained is unknown. For this reason, an alternate route

to the formation of chiral tropinone derivatives via the

resolved oxime was sought.

88

Chiral Imines

Asymmetric Induction in the Alkylation of Chiral Imines of Conformationally Flexible Molecules

The use of chiral imines in asymmetric synthesis has

been limited to conformationally flexible molecules and has

2 9

been elegantly demonstrated by the work of Meyers. Cyclic

ketimines derived from one enantiomer of l-methoxy-2-amino-3-

phenylpropane (124) were transformed to ketones of high

enantiomeric excess (>_80%) , a result attributed to the presence

of a chelatable alkoxy substituent (Figure 1). When the imine

(125) formed from 124 and cyclohexanone (126) is metalated, it

is postulated that the lithium ion becomes coordinated to the

methoxyl oxygen and resulted in two conformers, 1A and IB,

related by a nitrogen inversion. Assuming that the entering

alkyl halid aligns itself so that the halogen is coordinated

to the lithium ion, 1A allows reaction to approach in a less

encumbered area (Figure 1). 30

Recently, it has been demonstrated by Fraser that con-

formationally rigid cyclic ketimines undergo alkylation at the

a-position syn to the substituent on nitrogen. Only axial

alkylation products were obtained. In addition, Fraser31 has

examined stereoselectivity in the methylation of cyclohexanone

N-a-phenethylimine (127). Metalation of 127 would be

expected to product a syn anion, which, when alkylated,

would product two diastereomers 128 and 129 (Scheme 31).

The ratio of formation of the two diastereomers

was determined by obtaining the nmr

89

PhCH

MeO—*• Li

PhCH

V

H-,0

R H H

R

H

(R) (S)

Fig. 1—Steric course of imine alkylation as proposed by Meyers .

90

spectrum of the crude reaction products at -20°C. The

reactions were run under a variety of conditions, and the

diastereomer ratio was found to be affected markedly by the

addition of such compounds as HMPA or TMEDA (Table V).

Scheme 31

2) CH3I

]27 128 129

Imines formed from a-methylbenzylamine possess no

chelatable functionality on the nitrogen substituent,

which is an essential feature of the imine system developed

7 Q

by Meyers. y In spite of this, in the case of reaction in

the presence of MgBr2, there is the potential to produce

ketone of up to 52% optical purity. Fraser proposes a

model which involves an aza-allylic anion with the lithium

atom blocking one face of the molecule. More evidence

will be required for an evaluation of this model.

91

TABLE V

ASYMMETRIC INDUCTION DATA OF FRASER31 FOR OF CYCLOHEXANONE N-a-PHENETHYLIMINE

ALKYLATION (127)

Diastereomer Ratio

Std. Conditions* 2.0

(MgBr2, 1 eq, CH3I) 3.2

(TMEDA, 1 eq, CH3I) 2.5

(HMPA, 1 eq, CH3I) 2.0

((CH 3) 2SO 4) 1.3

(C2H5I) 1.4

(C2H5Br) 2.1

* »< 'Std. Conditions" represents formation of anion using 1.05 eq LDA in THF at 0° for 60 min, followed by addition of alkyl halide at -78°C, a reaction time of 60 min before warming to 0°, removing solvent and examining the spectrum of crude product.

92

+ Li

H

C H _ Y ^ A / c-

T — C ^ / \ / W . — Ph a i R C H 3

Chiral Imines of Tropinone: Formation of Diastereomers from Geometrical Enantiomers

In the case of tropinone oxime (40, 41), the substituent

on nitrogen is achiral and a pair of geometrical enantiomers

results from the destruction of the reflection symmetry of

the parent ketone (123). An analogous situation is the

formation of an imine of tropinone from an achiral primary

amine. If, however, the imine was formed using a chiral

primary amine, then the isomeric forms resulting from

the stereochemistry of the carbon-nitrogen double bond

would be diastereomers (Scheme 32). The regiospecificity

of the alkylation of the anions of these diastereomers

requires that any asymmetric induction observed would reflect

either the ratio of diastereomeric imines of the starting

material or the ratio of diastereomeric imine anions formed

during the reaction, so long as the alkylation reaction is

fast relative to any anion interconversion. By determining

the optical purity and absolute configuration of the

93

2-alkyl 3—tropinones obtained from the hydrolysis of the

alkylated imines, then both the absolute configurations and

relative ratios of the diastereomeric anions prior to

alkylations can be determined as well.

Scheme 32

R R

N NN

R-NH (Achiral)

123 R* - NH~ (Chiralf

|N^ Me

( A ,

Me

Enantiomers

R* R?

X A Me Me

Diastereomers

Preparation of Diastereomeric Imines: Attempted Formation of Tropinone N- (-) -3-p-Merithylamine

For the formation of diastereomeric imines of tropinone

(123), the chiral primary amines, (-)-menthylamine (129) and

(+)-a-methylbenzylamine (130,131), were chosen for study. (-)

Menthol (132) is readily available and was oxidized with

sodium dichromate to give (-)-menthone (133) . 3 2

The ketone (133) was converted

94

to the corresponding oxime (134), which was then reduced by

sodium and ethyl alcohol to the desired amine (129) (Scheme

33). The amine (129) was heated under reflux with 3-tropi-

none (123) for 48 hours, and the product examined by ir.

The absence of any absorption at 1660 cm-"'" (C=N) and the

strong band at 1720 cm"1 (C=0) showed that no imine was

being formed. The most plausible explanation for the lack

of reaction is the severe steric interaction between

the two molecules.

Scheme 33

132

No Reaction 3-Tropinone(123)

129

95

Preparation of Tropinone N-g-Phenethylimines (135, 136)

The commercial availability of both enantiomers of

a-methylbenzylamine made it an attractive candidate for

use in imine formation. The reaction of S-(-)-a-methylbenzyl-

amine (130) (one mole excess) and 3-tropinone (123) was

50-60% complete after heating under reflex for 48 hours.

A reaction time of longer than 48 hours produced substantial

amounts of tar. The nmr spectrum of the distilled imine (135)

showed that a pair of diastereomers had been formed (Figure

2). A doublet of quartets of 6 4.5 was observed for the

methine hydrogen on the nitrogen substituent of each diastereo-

mer. In addition, a doublet of doublets was observed at

5 1.4 for the methyl group of each diastereomer. Only one

N-methyl singlet at 6 2.25 was observed. Unfortunately,

the chemical shift differences between the signals from each

diastereomer were too small to determine the relative ratio

by integration. Visually, one isomer appeared in slight

excess over the other. An attempt to separate the signals

from each diastereomer was also made using an Europium nmr

shift reagent. No significant separation of the signals

was observed. Shift reagents have not, in general, proved

useful in studies of tropinone compounds. The circular

dichroism curve of this mixture gave three absorption

maxima, [©]2gg = +794, [©3261 = + 781 anc^ '-®- 240 = "646

(Figure 3).

96

Fig. 2—NMR spectrum of Tropinone-N-a-Phenethylimine (135).

97

The imine (136) prepared from the reaction of 3-tropinone

(123) and R-(+)-a-methylbenzylamine (136) was synthesized

following the same procedure as for 135. The ir and nmr

spectra for the two imines 135 and 136 were identical. The

circular dichroism curve of this imine (136) was obtained and

compared with the curve for (135) to see if this technique

might be useful for determining the absolute configuration

of the diastereomer formed in excess (Figure 3). In the CD

curve of each imine (135, 136), there are two absorption

maxima which occur between 260 nm and 270 nm. These are

probably due to the weak forbidden ir -> ir* transition of the

aromatic ring on the nitrogen substituent and have little

predictive value in determining the absolute configuration

about the carbon-nitrogen double bond of the diastereomer

present in excess.

Alkylation of Tropinone N-g-Phenethvlimines

(135) or (136)

Metalation of the imines (135, 136), followed by

alkylation with methyl iodide gave good yields of 2-methyl-

tropinone N-a-phenethylimines (137, 138). As indicated 30

by the work of Fraser , the syn-axial alkylation products

obtained probably undergo isomerization on warming producing

a mixture of up to six diastereomers (Scheme 34).

98

2&&i§& 3SS1SH~=

rnrntrHir: PiPiyii

m \hxi~-x\£ *'

iSSBl rr i?S£as:iSr

gfesiia|i|i!|;

^ E S S t e S i

* • • • 1

£rs n *rt lL4H_:xfr-;:; r*tr ~t r:i4 f,

9&=fi U-;tb1,"rr2; - • —4i±~*•tL+T* •T--H-*

Wgg0 ujF:|'np"fa PHjjiKr-PjUHfcSs

135

—' '' -1- +-! •«-*-• Ar j , t. >4-——- -

i g i l l l i p | i i g

lilifilSiliii® iliaililElSlili^ a m l g

-nil

.pr.rtrtn rrifhT t

•~*~i • *•» £-*"$ fi1 Hit?!? itt3fP:; PSf?

M H i l l i S I ^ -•-r "t-H * t «-*~i-*4-* ..** i %Ji* M*-; '•*- r •-»* as®?

#££2* s

^ 1'"

J53j?]jpi3S;

136

Fig. 3—Circular dichroism spectra of Tropinone-N-(-)-a-Phenethylamine (135) and Tropinone-N-(+)-a-Phenethylamine (136).

Scheme 34

99

CHo-

1) LDA 2) CH3I 3) NH4CI

CHo-

*-R

ch3- CH3-N

*R *-R

/ N

/

100

Attempted Determination of Diastereomer Ratio

The nmr spectrum of 137 (Figure 4) indicates the

presence of at least two diastereomers. The signals for

the C-methyl on the tropinone ring occur as two sets of

overlapping doublets at 6 1.1. The overlapping doublets

for the methyl group of the nitrogen are centered at 6 1.4.

The introduction of a methyl group onto the 2 position of

the tropinone ring causes a splitting of the N-methyl signals

at 6 1.15. Once again, no reliable information regarding

the diastereomer ratio could be obtained from the nmr spectra.

The CD spectra of the methylated imines were essentially

identical to those obtained from the imines prior to alky-

lation (Figure 5) .

Hydrolysis of 2-Methvltropinone-N-q-Phenethvlimines

(137) or (138)

The alkylated imines could be smoothly hydrolysed with

10% HC1, but approximately 12 hours were required for complete

reaction. The stability of the imines to hydrolysis is

surprising, especially by comparison with the corresponding

unalkylated compounds 135 and 136, which hydrolyze readily

on exposure to atmospheric moisture. The 2-methyl

derivatives 137 and 138 showed no evidence of hydrolysis

(by ir) even after stirring in water for 12 hours. The

reason for the increased stability on introduction of a

methyl group onto the 2 position of the tropinone moiety

101

Fig. 4—NMR spectrum of 2-Methyltropinone-N-a-Phenethylimine (137).

102

i

i

Fig. 5--Circular dichroism spectra of 2-Methyl-tropinone-N-(+)-a-Phenethylimine (138).

103

must reflect a steric inhibition of water with the

imino carbon.

Separation of 2-Methyltropinone and g-Methylbenzylamine

The hydrolysis of 2-methyltropinone N-a-phenethylimine

(137) produces a 50:50 mixture of 2-methyltropinone (139) and

S-(-)-a-methylbenzylamine (130), which must be separated

prior to any attempt to determine the optical purity of (139).

A variety of TLC systems was investigated, but in all cases

the Rf were sufficiently similar that separation by column

chromatography seemed impractical. Several vacuum distil-

lations were attempted, but the fractions collected were

always shown by nmr analysis to be mixtures of the two

amines.

Separation was attempted by a Hinsburg method for

secondary and tertiary amines. The mixture was treated with

benzenesulfonyl chloride in the presence of base. Initially,

difficulty was encountered finding conditions for complete

conversion of a-methylbenzylamine (130) to its benzene-

sulfonamide (140). Once this conversion was effected,

however, the amines (139) and the sulfonamide (140) could be

smoothly separated by an acid base extraction (Scheme 35).

Once again, an interesting change in physical properties

between 2-methyltropinone (139) and tropinone (123) was

observed. Tropinone (123) is readily water soluble, while

2-methyltropinone (139) was observed as an oil immersible

with water.

Scheme 35

104

R =

CH3CH2OC

CH,-

CH3

V - * ^ P h

ChL Cl-L-Acid-Base

x t r a c t i o n

+ PhCH-CH

PhS02Cl

+ PhCH-CH

V ^2^50C ( 0 ) CI

NH-SOgPh

Attempted Determination of the Optical Purity of 2-Methyltropinone (1391 by NMR

The use of chiral lanthanide shift reagents provides

a simple and direct method for the determination of enantio-

. . 34

m e n c compositions. In the case of 2-methyltropinone

(139), a doublet for the C-methyl group centered at 6 0.95

and the N-methyl singlet at <5 2.45 are the simple peaks

in the spectrum. Both tris[3-(trifluoromethylhydroxymethylene)-

d-camphorate]europium (III) derivative and

105

tris-[3-heptafluorobutyryl)-d-camphorat6] europium (III)

derivative caused large shifts of these signals, but

no splitting into separate signals for each enantiomer

was observed.

Salt formation of the amine (139) and (R)-(+)-a-

methoxy-a-trifluoromethylphenylacetic acid (+)-MTPA) (61)

produced a deuterochloroform soluble salt. The nmr spectrum

(Appendix B, Figure 37) showed a splitting of the C-methyl

doublet at 6 0.95 into a doublet of doublets of roughly

equal intensity. The chemical shift difference was too small

to permit an accurate integration. No splitting of the

N-methyl or O-methyl resonances was observed.

Optical Purity and Absolute Configuration of N-ethoxycarbonyl-2-a-Methyl-3-Tropinone

The failure of a chiral nmr shift reagent to resolve

the spectrum of 2-methyl tropinone for an optical purity

determination led to a consideration of derivatives which

could be compared to authentic samples. The work of Fodor3^

and subsequent work by Clarke36 provided a derivative which

could be used both to determine the optical purity of 2-

methyltropinone (139) obtained from alkylation of imines 135

and 136 and to establish the absolute configuration of

the enantiomer formed in excess.

Fodor described the conversion of natural (-)-cocaine

(71) (of known 1-R configuration) to 2B-methyl-30~tropanol

(146) (Scheme 36).Lithium aluminum hydride reduction

106

Scheme 3 6

CH3-N

CH 2OH

0—C

CK.-H2/Pd

< -CH-3-

9 C 2 H 5 O C C I

143 •

3 Jones oxidation

0

C 2 H 5 O C -

146

SOC1-

C H 2 C I

OMe MeOH

c2H5oc

148

107

of cocaine provided 23-hydroxymethyl-33-tropanol (141) ,

which could be chlorinated selectively to the 28-chloromethyl

derivative (142) . Hydrogenolysis of this material produced

23-methyl-3 3-tropanol (143) (Scheme 36).

Using this compound as starting material, Clarke36

effected demethylation with ethyl chloroformate. The N-

ethoxycaronyl derivative 144 was then oxidized to the

ketone 145, which was epimerized in base to produce an 85:15

mixture of 2a(146) and 23(148) epimer, respectively.

Separation of these compounds gave optically pure (-)-N-

ethoxycarbony1-2a-methy1-3-tropinone (146) of known 1-R

configuration (Scheme 36).

Demethylation of 2-methyltropinone 139 resulting

from alkylation of the tropinone-N-a-phenethylimines (135)

or (136) produced the N-ethoxycarbonyl-2a-methyl-3-tropinone

which was identical by ir, nmr and TLC with an authentic

i 37 sample.

Since the a and 3 epimers have sufficiently different

chromatographic properties to be separable by TLC (silica

36

gel, ether) , a careful search confirmed that the 3 epimer

(axial methyl group) was not present.

The formation of the a epimer almost certainly arises

from an epimerization of the initially formed, axially

substituted product. This isomerization could occur prior

to hydrolysis of the alkylated imine 137 or 138,

during the formation of the benzenesulfonamide (140) of

108

a-methylbenzylamine (Scheme 35), where there is exposure

both to heat and sodium hydroxide, or during the

demethylation reaction. Since the equatorial isomer is the

thermodynamically stable product, exposure to base would

be expected to product almost complete equilibration to the

equatorial epimer.

Optical Purity Determinations via Rotation and Circular Dichroism Data

The optical purity of the 2a-methyl-3-tropinone

obtained by alkylation of chiral imines 135 or 136 was

established in two ways. The first method was by

comparison of the rotation at the wavelength of the sodium

D line with the rotation of the optically pure material

3 6

prepared by Clarke (Table VI). The circular dichroism

also provided quantitative analysis based on a comparison

of the molecular ellipticity [0] of the optically pure

material and the material obtained from alkylation reactions,

since the absorption of left and right circularly polarized

light obeys Beer's Law. In order to determine the relative

amounts of each enantiomer, the following equation should

apply.

^ o b s = fi t 0 ]i + f 2 ^ 2 '

where f^ and f^ are the fractions of each enantiomer.

109

VO O

PH ' —

o H W EH S

O 2 A

D H 0 H o PM & A EH o 1 CJ CO

1

w I

EH >H H O ffi > A EH o W w CO S KL PQ 1 P3 < a <

< I

EH Q CN

13 1 < A

>* t* S3 EH O H & 5 D c PM U

>1 A X c o o ffi H EH EH W PM 1

O A

CN CO o o 00 >iQ i—1 G\ o 00 LO in -P O • « • t * M •H rH 00 00 o 0 KO MH MH

d, u in CJ 0 CN Q H 0 1—1 fd *H O r-» rH s. 0 -P 00 00 kO r- 00 0 1 1 •h fd • • s * • • o -p -p 00 00 CN c & 0 +•> rH O rd

Cl, rH CD O

0 ffi •d EH E 0)

EH rd •H (J) <D LO 00 o CN CJ

M-l rH LO rH Cft 00 O •H H VO-'H i—1 H H H o u 1 1 I 1 + + c fd 00 0 a fd 1 1 P-l CJ CD *H i—i (L) o 00 LO LT) r- <T> tn *d 00 LO H C> CN CJ CO P rH rH •H CJ

1 1 I 1 + + CO 0 U •H d 0 rH •H 0 d) i—1 d CO LO -H fd rH r- CN O fd • CN] QMH -H 00 H H I f ) as r- u 00 i i *H • 6 » 9 • • (DO rH S ?H CD o H rH rH o o XJ 00 o ffi L-J 3 +J 1 1 I f + + -P r-

o ffi

& fd 1

:o %i

w s MH 0 +3 fd

:o %i c CJ 0 0 CD CI •H •H no •H •P -P -P -H o fd 1—1

M i—\ PI

I—I « 1—1 1—i i—i fd TJ 2 £ 1—1 M

i—\ PI

I—I « & CO CO B 0 CD n3 2, 1 I 1 I I 1 U *H ?H 0 tn rH rH rH rH H rH 0 M -H i i 1 1 L—J 1 ! i i 1 1 MH H CO •

>1 (d r-CJ CO ,£ 0) r-0 •P +J g 00 U CJ CD CN

<d CD g CD I <d CO co CO CO CO CO CD MH 0 II

03 CJ c CJ c: C3 U 0 £

II 03 0 0 0 0 0 PA VD G £ •H •H •H *.H *H CD CJ CO 0 0 •P -P •P 01 4J U 0 c: rH •H -H •H •H CT1 •H CD *H •H d1 •H o

•P -P 0 'O TJ CD 'd <D CO -P *H 0 0 -H 00 fi C CI H CJ CJ CJ *H +J U <3 TS 0 0 rH 0 0 0 H 0 fdvo 3 a) c I U U U - U U •H "d +J00 a, as o V, < < 4J fd O •

a, u • • <J • Q • e •H U 0 U

T5 PL| *d H 'd 'd >i O -P -P S -P § +J -P § CJ rQ «d • IM CO CO ffi CO EH CO CO ffi o CD t3 d) c o *d > CN VD t3 d) c CD U o a) c o • & CD II 00 0) *H -H l 1 1 1 + + 'd o CO i—i £=> E -P -P H ,jQ 0 H (D i—i i—i ! ! ! 1 1—1 i—i CO H O ^ i i ^ £ CO CO CO CO P^ PS fd o rQ rH O PQ JH JH 1 1 i 1 1 1 1 1 1 1 i i MH

O g o o MH

CD 1 En A U s •H 6 CU

110

fl + f 2 = 1 f2 = (l-fx)

[0]^ = molecular ellipticity of one enantiomer

C©]2 = molecular ellipticity of other enantiomer

[9], - -ce]2

A simpler way to calculate optical purity is simply to

take the ratio of the observed molecular ellipticity over

the molecular ellipticity of a pure enantiomer

C8]obs x 100 = optical purity.

[0]

In order to avoid any errors in optical purity

measurements resulting from purification of the N-ethoxy-

carbonyl-2a-methyl-3-tropinones (146), the CD was deter-

mined on both crude and purified samples. Table VI shows the

molecular ellipticities obtained, as well as comparison

with optical purities determined by rotation.

Determination of the Absolute Configuration of the Enantiomer Formed in Excess

The circular dichroism curve of the authentic sample

of N-ethoxycarbonyl-2a-methyltropinone (146) of known

1-R configuration obtained from (-)-cocaine showed a

negative cotton effect at 307 nm, [0]=-2878 (Figure 6).

The curve obtained from (146,147) produced via alkylation of

the imine of the tropinone formed from (S)-(-)-a-methyl-

benzylamine (135) also exhibits a negative CD curve

Ill

Fig. 6—Circular dichroism spectra of (-)-N-ethoxy-carbonyl-2a-Methyl Tropinone (146) obtained from (-)-Cocaine (71); [e]306 = -2877.

112

at 307 nm. Although the optical purity is low, this

establishes unequiovcally the absolute configuration of the

enantiomer formed in excess as 1-R (Scheme 37). These

data are further supported by the fact that a positive CD

curve of roughly equal intensity was obtained from 146, 147

obtained by alkylation of the imine (136) formed from

tropinone and S-(+)-a-methylbenzylamine.

Scheme 37

OCH.

C=0

CH„-

O-C-Ph

J l-R-(-)

CHQ H /

X Ph ^ n N

CH.

135

C^H.OC-N CH,-;

l-R-(-)

113

Conclusions

The optical rotation as well as the sign and magnitude

of the circular dichroism curve of N-ethoxycarbonyl-2a-

methyltropinone (146) obtained from alkylation of chiral

imines of tropinone have been related to 146 derived from

natural (-)-cocaine (71), a molecule of known absolute

configuration (1-R) and optical purity. Thus, a method has

been developed for evaluation of the potential for asymmetric

induction in alkylation of imines, formed from a wide variety

of chiral amines, as well as for chiral hydrazones or other

carbonyl derivatives from which the ketone can be regenerated.

The optical purity observed for alkylated products

derived from N-a-methylbenzylimines is low (approximately

3-4%) and is probably a reflection of the diastereomeric

ratio of the starting material. This is supported by the

fact that no significant change in the asymmetric induction

was observed when the reaction was carried out in the presence

of HMPA or TMEDA. These results are not surprising since

one would expect only a small free energy difference between

the two diastereomers. It is possible, however, that the

amount of asymmetric induction can be increased either by

designing structural features into the imine, which would

significantly favor one diastereomer over the other, or by

the use of a new carbonyl derivative (i.e., a chiral hydrazone)

which would form a favorable equilibrium mixture at the

114

anion stage. In the latter case, this could occur in

two ways. If the equilibrium were shifted heavily in

favor of one diastereomer (assuming alkylation is faster

than anion interconversion), the ratio of enantiomers in

the product would reflect the equilibrium. If alkylation

were slower than anion interconversion, and the rates of

alkylation of each diastereomer were competitive, formation

of one alkylated product would be favored.

115


1. R. E. Lyle, H. M. Fribush, G. G. Lyle and J. E. Saavedra, J. Org. Chem., 43, 1275 (1978) .

2. R. E. Lyle and G. G. Lyle, J. Org. Chem. 24, 1679 (1959).

3. H. Singh and B. Razdan, Ind. J. Chem., 6, 568 (1968).

4. H. Singh and B. Razdan, Tetrahedron Lett., 3243 (1966).

5. G. Ortega, Ph.D. Dissertation, University of Texas, Austin, 1976.

6. J. A. Dale, D. L. Dull and H. S. Mosher, J. Org. Chem., 34_, 2543 (1969).

7. M. E. Jung, M. A. Mazurek, and R. M. Lim, Synthesis, 588 (1978).

8. E. B. Hershberg, J. Org. Chem., 13, 542 (1948).

9. E. J. Corey, J. E. Richonan, J. Am. Chem. Soc., 92, 5276 (1970). —

10. E. J. Corey, J. W. Soggs, Tetrahedron Lett., 2647 (1975).

11. J. R. Maloney, R. E. Lyle, J. E. Saavedra, and G. G. Lyle, Synthesis, 212 (1978).

12. Aldrich Catalog Handbook of Organic Chemicals and Biochemicals, Aldrich Chemical Co., Milwaukee, Wisconsin. 1977-1978.

13. Handbook of Chemistry and Physics, 51st edition, Chemical Rubber Co., Cleveland, Ohio, 1970-1971.

14. J. L. Coke, and M. C. Mourning, J. Org. Chem., 32, 4063 (1967). —

15. R. B. Fraser and K. L. Dhawan, J. Chem. Soc. Chem. Commun., 674 (1971).

16. R. E. Lyle, J. E. Saavedra, G. G. Lyle, H. M. Fribush, J. L. Marshall, W. L. Lijinsky, and G. M. Singer, Tetrahedron Lett., 4431 (1976).

17. J. P. Albarella, J. Org. Chem., 42, 2009 (1977).

116

18. Aldrichimica Acta, 12, 84 (1979).

19. R. M. Acheson, An. Introduction to the Chemistry of the Heterocyclic Compounds, 2nd edition, Interscience Publishers, New York, 1967, p. 155.

20. G. Wittig and H. Reiff, Angew. Chem. Internat. Edit. 7, 7 (1968).

21. T. Naits, 0. Miyata, and I. Ninomiya, J. Chem. Soc. Chem. Commun., 517 (1979).

22. W. Oppolyzer, L. Breber and E. Francotte, Tetrahedron Lett., 4537 (1979).

23. W. J. LeNoble, Synthesis, 1 (1970).

24. J. M. Kauffman, Ph.D. Dissertation, Massachusetts Institute of Technology, p. 44, 1963.

25. E. W. Warnhoff and P. Reynolds-Warnhoff, J. Org. Chem., 28, 1431 (1963).

26. R. H. Mueller and R. M. Dipardo, J. Org. Chem., 42, 3210 (1977). —

27. K. Bowden, I. M. Heilbron, E. R. H. Jones and B. C. L. Weedon, J. Chem. Soc., 39 (1946).

28. F. A. Cotton and G. Wilkinson, "Advanced Inorganic Chemistry", 3rd edition, Interscience, New York, N. Y., 1972, pp. 834-838.

29. A. I. Meyers, D. R. Williams, and Melvin Druelinger, J. Am. Chem. Soc., 98, 3032 (1976).

30. R. B. Fraser, J. Banville, and K. L. Dhawan, J. Am. Chem. Soc., 100, 7999 (1978).

31. R. B. Fraser, Fuminori Akiyama and J. Banville, Tetrahedron Lett., 1979, 3929.

32. L. T. Sandborn,"Organic Synthesis", 2nd edition, Collect. Vol. I, John Wiley and Sons, Inc., New York, 1931, p. 340

33. R. L. Shriner, R. C. Fuson and D. Y. Curtin, The Systematic Identification of Organic CompoundsT"John Wiley & Sons, Inc, New York, 1964, p. 119.

34. H. L. Goering, J. N. Eikenberry, G. S. Koermer, C. J. Lattimer, J. Am. Chem. Soc., 96, 1493 (1974).

117

35' 892K<(1954).G' F O d° r a n d T' W S i S Z' H0lV- C h i m' A c t a'

36' 4586*(1978f0 ^ M' L' H e c k l e r' 0r9- Chem., 43,

37* TT,he * u t h o r wishes to thank Dr. R. Clarke, Sterling mthrop Research Institute, Rennselear, New York, for an authentic sample of N-ethoxycarbonyl-2a-methy1-3-tropinone (146).

APPENDIX A: INFRARED SPECTRA

118

jijxf-trtt

0=0

119

NOISSlWSNVai 'iN3D*3«*

120

NOKSfW^NVMI fM3*>V94

mi

121

NOISSlWSNV«i. !N=DlHcl

122

tn *H fa

HOisswsmvai w.uadd

Mi fill

1-=

123

OOl

NOl iSlWSNVl lNS d

124

KO o i—! *3

I CN

&> •H fa

i#£tj

mfm

125

tn •H PL,

KIOICCIWCNVMI

a s mm

126

IT.

8 I I

i—I

•H pLl

MfMOOMIOMWM I ldH"NV1 J

1i

127

•H pLl

NOISSIWSNVai iNRDifld

NOISSIWSNVai lN3D«d o o

mm

5i-3H±J

i M i i m

HH.EH

SBg:f3

128

•? P4

NOtSSlWSNVNl

m

r:f

129

O CM

•Q

8 I I r-

•H

130

KD CO

LO cn I—I

w

1 I I

00

•H P4

nn.

TOR it t i i i i i > , htt Ttit -rl

m

- -

131

00 cn

; ! J

I

jife:4t; Kjt j!

iiit-iht rttnprr :-+4-i H-h

132

NOI?»W<JNV>fl tMCTOI34

h7~

U

4-—i—_I , l I r : J

l~~h 0=0

err - n

NOWIWQMVNI »KJ3-N

4. CM

tP •H P4

133

134

APPENDIX B: NUCLEAR MAGNETIC RESONANCE SPECTRA

135

o=o

CM

-- ro

m

VD

• 00

^ o

136

o=</>—o

o - o

<

ro

U Q. U

in oo

„ i h g .

I CM

- - KD

- - r

--r oo

- - o>

r H

CM

CO

in

KD

CO en o

00

CPt

<£> 00

" 2

. i I

i n CM

tr>

t

tn-«

- <

• • i

\ 2

/ 0=0

O o

ro

O : 1 * ! 4... ^ j

1 cfl • rHi i U l ! Q

- ~o-[ -!• w l

-W~

-&r~

U H —

• d i "<5 •

140

00 oo |

VD

< I I

r (N

P4

o=o

co U Q O oo

a\

. i - ' J - r H

^ " 141

o

2

CN

CO

- - LO

CJ\

* 3

<

I I

,00 CM

< . . t r » VO « " H

• ; ^ Pn

0 0 i—I

O . Q . U

<

o o

; o v . ; . i

143

CM

CO

O <J\

in

o co

CO

ro o

CN

CO

00

o\

'CO-

144

—o-t-

..L ~ •T 1

T ~r

i "r

0=0 <

00 rH u. Q : U

CO

;

l 4. , ro

tn *H

yj i ;

00

r s

I a\

o

145

4- —

148

t

149

o=o

VD

"2

0 1 i 00

tr> •H Pn

150

I—I VD

*2

<J\ CO

O

rd en i I ro

P4

- rH

151

APPENDIX C: CIRCULAR DICHROISM SPECTRA

152

O

E in

0036g/mL (hexane)pu

A (nm)

Fig. 38—Compound 135

153

e CN

CH3N

c = 0.00385g/iaL (hexane)Ph

^ (rati)

F i g . 39—compound 137 formed from the Anion of Imine 135 generated

at -78° .

154

)36g/ml (hex?"VJ>''H

X (nm)

Fig. 40—Compound 137 formed frora the Anion of ttiine 135 generated

at 0°.

155

Eiiliiimiiili'iii!!

0H3N

c = 0.0045g/ml (hexane) Pf,

X (nm)

Fig. 41—Compound 1J7 formed from the Anion of Imine 135 generated at 0° in the Bresence of HMPA.

156

SpiiMI rr-pr i

©wfilfiSi

CH3N

(hexane) \ c = 0.00424g/ml ph

A (nm)

Fig. 42—Compound 137 formed from the Anion of Imine 135 generated at 0° in the Presence of TMEDA.

157

IHI f! nrfffffiFfflFFHHIlUlfltJ U7

CH3N;

£H3

i/ c = 0.00371g/ml (hexane) Ph

A ( n m )

Fig. 43—Compound 136

158

c = 0.00342g/ml (hexane) Ph

!iH!!!!!iii!s X(nm)

Fig. 44—Canpound 138 formed frati the anion of imine 136 generated

at 0°.

159

(hexane) \ c = 0.00561g/mlpu

X (nm)

Fig. 45—Compound 138 formed frcm the anion of imine 136 generated

at 0° in the presence of HMPA

160

(j c = 0.0058g/ml

ch C H 2 O I : N - ^ ^ v - c h 3

x (nm)

Fig. 46—Canpound 146 fraa (-)-cocaine

161

c = 2060g/2iril (hexane)

1 1 1 *

X (nm)

Fig. 47—Compound 146 (crude) formed frcm imine 137 (anion formation

at -78°).

162

c = 0.2083g/2ml (hexane)S

X (nm)

Fig. 48—Compound 146 (purified) formed from imine 137 (anion formation at -78°).

163

ITT!

c = 0.2070g/2ml (hexane)

1 X (nm)

Fig. 49—Ccrnpound 146 (crude) formed frcm imine 137 (anion formation at 0°).

164

tm

I


X (nm) Fig. 50—Compound 146 (purified) formed frcm the imine 137 (anion

formation at 0°).

165

•ffMjaaiffimB

B-3HG c = 0.2080g/2ml

(hexane)

X (nm) Fig. 51—Canpound 146 (crude) formed from imine 137 (anion

formation at 0° in the presence of HMPA).

166

mm

2036g/2ml

•(nm)

Fig 52—Carpound 146 (purified) formed fran the imine 137 (anion formation at 0° in the presence of HMPA).

167

i s s e s e a c = 0.2071g/2ml (hexane)

M

X (rati)

Fig. 53—Compound 146 (crude) formed frcm.the imine 137 (anion formation at 0° presence of TMEDA).

168


•illlllH!:!!:!::!:

A (rim)

Fig. 54—Compound 146 (purified) formed frcm the imine 137 (anion formation at 0° in the presence of TMEDA.) .

169

c = 0.1972g/ (hexane)

tttiUttt

Fig. 55—Compound 147 (crude) formed frcm imine 138 (anion formation at 0°).

170

11

is

c = 0.1978g/2m| (hexane)

Fig. 56—Compound 147 (purified) formed frcm the imine 138

(anion formation at 0°).

171

His

1


mm

Mslrn rf: A (nm)

Fig. 57—Carpound 147 (crude) from the imine 138 (anion formation at 0° in the presence of HMPA)•

172


ml

I

i n

X (rati)

Fig. 58—Carpound 147 (purified) fraa the imine 138 (anion formation at 0° in the presence of HMPA).

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37? - UNT Digital Library/67531/metadc...135 generated at 0° in the Presence of HMPA 155 42....

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Transcript of 37? - UNT Digital Library/67531/metadc...135 generated at 0° in the Presence of HMPA 155 42....