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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
14. Compound 119 126
15. Compound 121 127
16. Compound 90 128
17. Compound 120 129
x
Figure Page
18. Compounds 135, 136 . 130
19. Compounds 137, 138 . 131
20. Compound 139 . . . . . . . 132
21. Compound 146 . 133
22. Compound £7 135
23. Compound 69_ 136
24. Compound 8f5 137
25. Compound _86 138
26. Compound 106 139
27. Compound £8 140
28. Compound 119 141
29. Compound 121 . 142
30. Compound 9_0 143
31. Compound 120 144
32. Compounds 135/ 136 145
33. Compounds 137, 138 146
34. Compounds 139, 13 6 14 V
35. Compound 139 148
36. Compound 146 149
37. Salt of 139_ and 61 150
38. Compound 135 152
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
43. Compound 136 157
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
Chapter Bibliography
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
The reaction was carried out using the same procedure
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
The reaction was carried out using the same procedure
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
The reaction was carried out using the same procedure
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
The reaction was carried out using the same procedure
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"
A flame dried, nitrogen-flushed 100 ml 2-neck flask
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)
A flame dried, nitrogen-flushed 250 ml 3-neck flask
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
CD (Hexane, 0.00424 g/ml): Appendix C, Figure 42.
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.
CD (Hexane, 0.00371 g/ml): Appendix C, Figure 43.
[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.
CD (Hexane, 0.00342 g/ml): Appendix C, Figure 44.
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.
CD (Hexane, 0.00516 g/ml): Appendix C, Figure 45.
[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
Chapter Bibliography
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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69
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
Chapter Bibliography
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
142
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
c = 0.1977g/2ml (hexane)
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
c = 0.1971g/2ml (hexane)
•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
c = 0.1957g/2ml (hexane)
mm
Mslrn rf: A (nm)
Fig. 57—Carpound 147 (crude) from the imine 138 (anion formation at 0° in the presence of HMPA)•
172
c = 0.2011g/2ml (hexane)
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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