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Summer 1968
PREPARATION AND SOME REACTIONS OF 3-ARYLTROPIDINES AND 3-ARYLTROPANOLS
CHARLES RAYMOND ELLEFSON
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Recommended Citation ELLEFSON, CHARLES RAYMOND, "PREPARATION AND SOME REACTIONS OF 3-ARYLTROPIDINES AND 3-ARYLTROPANOLS" (1968). Doctoral Dissertations. 884. https://scholars.unh.edu/dissertation/884
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ELLEFSON, Charles Raymond, 1942- PREPARATION AND SOME REACTIONS OF 3-ARYLTROPIDINES AND 3-ARYLTR0PAN0LS.
University of New Hampshire, Ph.D., 1968 Chemistry, organic
University Microfilms, Inc., Ann Arbor, Michigan
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. PREPARATION AND SOME REACTIONS OF
3-ARYLTROPIDINES AND 3-ARYLTROPANOLS
BY
CHARLES RAYMOND ELLEFSON
B. A. , Concordia College, 1964
A THESIS
Submitted to the University of New Hampshire
In Partial Fulfillment of
The Requirements for the Degree of
Doctor of Philosophy
Graduate School
Department of Chemistry -
August, 1968
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/ v m J h / $ . W U r r v v o rv *
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Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGEMENTS
The author expresses his appreciation to Dr. Robert E. Lyle
for providing and directing the research problem and thanks him for
his understanding and encouragement throughout the development of
this thesis problem. He wculd also like to express appreciation to
Dr. James D. Morrison for helping in the preparation of the thesis.
Special thanks are given to Dr. Helmut M. Haendler for pre
paring the X-ray powder patterns, to Dr. Edward White V and Miss
Ta-Yuen Li for running the mass spectra, and to Mr. Ingo Hartmann
for his efforts in doing the elemental analyses.
The author expresses his appreciation to the University of New
Hampshire for providing the UNH Fellowship which enabled this con
tinuation of his education. He would also like to express his apprecia
tion to Dr. Alexander R. Amell and the Faculty and Staff cf the
Department of Chemistry for the kindness expressed during his four
years working with them.
The author also expresses a special thanks to Miss Anne Kohl
for her assistance in the preparation of this manuscript.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. This thesis is dedicated to my parents.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLE OF CONTENTS
LIST OF TABLES ...... viii
LIST OF FIGURES...... ix
I. INTRODUCTION...... 1
IL RESULTS AND DISCUSSION...... 9
1. The Preparation of 3-Aryltropines ...... 11
2. The Preparation of 3-Aryltropidines ...... 18
3. The Isolation and Characterization of the Two Diastereo- meric Hydrobromide Salts of 3-Phenyltropidine ...... 26
4. The Conformational Preference of the N-Methyl Substituent in Cyclic Tertiary Methyl Amines ...... 35
a. Other Unsaturated Tropane Systems ...... 35 b. Saturated Tropane Systems ...... 37 c. 2, 6-Dimethylpiperidine Hydrohalides ...... 38
5. Attempted Preparations of 3-Phenyltropane-2, 3-oxide ...... 51
a. Attempts to Produce 2-Bromo-3-phenyltropine: The Preparation of 4-Bromo-3-phenyltropine Hydro brom ide ...... 52 b. Attempted Peracid Oxidation of 3-Phenyltropidine ...... 54
6. Reactions of 4-Bromo-3-phenyitropidine Hydrobromide ...... 55
7. Hydroboration of 3-Aryltropidines ...... 58
8. Attempted Oxidations of 3-Phenyl-2- a-tropanol ...... 63
9. Preparation of 3-Aryl-2- a -tropanyl Acetates ...... 64
10. Demethylation Reactions of Tropane Compounds ...... 66
a. The Reaction of 3-Pheny'ltropine with Cyanogen Bromide. 66 b. The Reaction of 3-Phenyltropidine with Phenylchloro- fo rm a te ...... 68
v
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. IH EXPERIMENTAL...... 69
1. G eneral ...... 69
2. Preparation of 3-Phenyltropine ...... 70
3. Dehydration of 3-Phenyltropine ...... 71
4. Preparation of 3-Phenyltropidine ...... 71
5. Purification of the Isomers of 3-Phenyltropidine Hydrobromide ...... 72
6. Conversion of the 3-Phenyltropidine Hydrobromide Isomers to the Free A m in e ...... 74
7. Evidence for Exchange of the Ammonium Proton in 3- Phenyltropidine Hydrobromides ...... 75
8. Attempted Resolution of 3-Phenyltropidine * ...... 76
9. Preparation and Reactions of 4-Bromo-3-phenyltropidine Hydrobromide ...... 77
a. The Reaction of a -3-Phenyltropidine Hydrobromide with Bromine in Water .77 ...... 77 b. The Reaction of (3 -3-Phenyltropidine Hydrobromide with Bromine in W ater ...... 78 c. Bromination of 3-Phenyltropidine Hydrobromide in Glacial Acetic Acid ...... 79 d. The Reaction of 3-Phenyltropidine Hydrobromide with N-Bromosuccinimide ...... 80 e. The Reaction of 4-Bromo-3-Phenyltropidine Hydro bromide with Sodium Hydroxide ...... 81 f. The Reaction of 4-Bromo-3-Phenyltropidine Hydro bromide with Sodium Cyanide ...... 82.
10. The P reparation of 3 -A ry ltro p in e s ...... 82
11. Preparation of 3-Aryltropidines ...... H8
12. Preparation of 3-Ary'ltropidine Hydrobromides ...... 90
13. Preparation of Cyclic Tertiary Methyl Amine Hydrohalides. .94
14. Hydroboration-Oxidation of 3-Aryltropidines ...... 97
15. Attempted Equilibration of 3-Pheny'l-2 -a -tropanol ...... 101
16. Attempted Oxidations of 3-Phenyl-2- a-tropanol ...... 102
v i
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 17. Preparation of Acetates of3-Aryl-2- a-tropanols ...... 102
18. Demethylation Reactions of Tropane Compounds ...... 105
a. The von Braun Cyanogen Bromide Degradation of 3- Phenyltropine ...... 105 b. Reaction of 3-Phenyltropidine with Phenylchloro- fo r m a te ...... 107
IV. SUMMARY...... 108
BIBLIOGRAPHY...... 110
APPENDIX ...... 116
BIOGRAPHICAL DATA...... 181
v ii
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF TABLES
I 3-Aryltropines (2) ...... 12
II 3-Aryltropidines (3) ...... 19
III NMR Comparisons of 3-Aryltropidines (3) ...... 21
IV Mass Spectral Comparisons of 3-Aryltropidines (3) ...... 25
V Nuclear Magnetic Resonance Analysis of 3-Aryltropidine Hydrobromides ...... 36
VI Conformational Preferences in Some Cyclic Tertiary Methylamine Salts ...... 38
VII The Hydroboration of 3-Aryltropidines (3) ...... 99
VIH 3-Aryl-2- a -tropanyl Acetates...... 103
v iii
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF FIGURES
I The Proton Magnetic Resonance Spectra of the Diastereomeric Isomers of 3-Phenyltropidine Hydrobromide (20) and a Mixture of the Two Isomers ...... 27
II X-ray Powder Patterns of the Two Isomeric 3-Phenyltropidine Hydrobromides (20a and 20b) ...... 30
IH Conformational Equilibria in Some Tertiary Cyclic Amines 49
ix
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. INTRODUCTION
Synthetic organic chemistry has devoted considerable effort
toward the synthesis of naturally occurring compounds and their
analogs that might be useful as medicinal agents. Two naturally
occurring systems that have provided the basis for such research are
the morphinans and the tropanes. Roth of these systems have led to
analogs that have shown activity as analgesics. Therefore, it has been
a goal of synthetic organic chemists to produce potent, non-habit-
forming drugs of low toxicity modeled after them.
OH 1
One aspect of this research in organic medicinal chemistry has
been directed toward the identification of the portion of the structure
of the natural product that was responsible for the pharmacological
activity and elimination of the portion causing the undesirable responses
that were associated with many of the naturally occurring compounds.
For example, morphine (i_), the most potent agent known for the relief
of pain, has lim ited application because of its addicting qualities and
respiratory depressive after-effects. Therefore, it became desirable
to produce compounds that have analgesic activity sim ilar to morphine
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but that do not have the undesirable side-effects.
The potential contribution of synthetic organic chemistry to chemo
therapy was clearly shown by Eisleb-*- in 1939 by the synthesis of the
ethyl ester of l-methyl-4-phenylpiperidine-4-carboxylic acid (ii),
(Demerol, pethidine, or meperidine), which was shown by Schaumann^ 3 to be spasmolytic and the most potent synthetic analgesic known at
that time. In general, the effects of ii were sim ilar to morphine (i).
The side-effects were sim ilar and it, too, produced addiction. From
studies by Schaumann^ on the structure-activity relationships of
piperidine derivatives came the conclusion that the 1-methyl-4-phenyl-pi
peridine moiety was essential for the activity in morphine and its
analogs.
‘C 02E t
Following the suggestion of Schaumann many derivatives of 4-
phenylpiperidine were prepared as potential analgesics^ and many of
these compounds showed promising activity. One very important lead
was obtained by the discovery that esters of 1-m ethyl-4-phenyl-4-
piperidinol showed analgesic activity. This demonstrated that the
position to which the phenyl group was attached did not have to have
three additional carbon substituents to show activity. Thus the search
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for analgesics expanded to the "reverse esters", i.e. the piperidine
moiety became the alcoholic portion of the ester. 4-Phenyl-4-hydroxy -
1-methylpiperidine propionate had only about 1/7 the analgetic activity
of morphine , but the introduction of a methyl group into the 3-position
in the piperidine ring produced a drug with an effect 5. 5 times that of
morphine. ^ This compound, alphaprodine (iii) minimized the effect of
respiratory depression but was classified as a narcotic because of the
Q liability of addiction.
■OCOEt •—CHq
c h 3
The activity of derivatives of ethanol amines (choline derivatives,
epinepherine, etc.) led to the exploration of the activity of 3-piperidinol
derivatives. Whereas the 4-phenyl-4-piperidinol derivatives produced
analgesia the 3-piperidinols were potent as central nervous system
stimulants; however, the therapeutic use of these derivatives for this
activity was lim ited for they were found to be potent psychotropic 9 agents as w ell.
Stereochemical considerations are important in determining which
projected drugs w ill have potency. In a recent study of a series of 2-
aralkyl-3-piperidinols it was found that' when two of the most active
compounds were resolved, one optical isomer only was prim arily re- 1 n sponsible for the activity. x In the 4-phenylpiperidinols this effect was
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. apparent when betaprodine, in which the phenyl and methyl groups are
cjgllc , de^ wag very potent although the isomer in which these two
groups were trans(alphaprodine) (iii) was not as active. Ha, b The
stereochemical relationship of reactor-receptor sites in biological
and pharmacological reactions has received increasing attention in
the past year, and particularly significant is the application of con
formational analysis to this question. 12,13 Qasyl^, jor example,
has suggested that the conformational preference of the aromatic
ring in 4-phenylpiperidines may be an important consideration in
their activity relationships.
Another important naturally occurring series of compounds that
have been of much interest to organic medicinal chemists is the family
of tropane alkaloids. 15 They are important as antispasmodics for
which the necessary action of drugs is the inhibition of smooth muscle
spasms. Drugs having such properties are exemplified by atropine
(iv ) and analogous esters of amino alcohols. 1®
E 3 ^
OCOCH(CH„OH)Ph
IV
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A large number and variety of derivatives of atropine (iv) have
been synthesized and tested for parasympatholytic activity. The
tropane alkaloid, scopolamine (v), for example, has been used in
combination with morphine as a preoperative preparation by many 19 anesthetists. Most of the early analogs of iv were amino esters
of substituted acetic acids in which the amino moiety was replaced
by other less complex amino alcohols. ^0 With the synthesis^ and
commercial availability of 3-tropinone it became possible to make
a wide variety of new compounds containing the tropane nucleus. ^3
Some of the typical physiological activities of tropane bases have been op compiled by Fodor.
The tropane nucleus has provided organic chemists an oppor
tunity to revise nature by molecular modification. ^ ^ Cocaine (vi)
exhibits topical anesthetic activity but has no local infiltration value
as an anesthetic. Dissection of the cocaine structure, however, has
led to the synthesis of the anesthetic, procaine (vii) the hydro
chloride of vii is commonly known as Novocaine. Application of
molecular modifications to atropine (iv) and scopolamine (v) has em
erged into important drugs of simple structure which are useful as
antispasmodics and antiulcer, antidiarreal, and antiparkinsonism
agents^ as well as central nervous system stimulants. ^2 Synthetic
studies of compounds having the tropane nucleus have received
lim ited investigation in comparison with the piperidines.
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cQ C H -C 0 2
v
C02(CH2)2N(C2H 5)2
COgCHg
By combining the structural features of the tropane ring system,
the hydroxy amines, and 4-phenylpiperidines into a single structure,
a high probability for pharmacological activity should result. Thus a
series of 3 -a ry ltro p a n o ls and th e ir de riva tive s qualified as an im
portant class of compounds to prepare and explore for pharmacolog
ical activity. These compounds would combine the 4-phenylpiperidine
structure, which was shown to be necessary in the activity of morphine
(i), and the rigid structure of the tropane bases which is probably
desirable to provide the conformational features best suited for high
potency as medicinal agents.
These compounds would be of value in evaluating the conforma
tional requirements of receptor sites. The enormous amount of
research that has been concerned with the stereochemical assignments
and absolute configurations of the naturally occurring tropane alkaloids
presents a background for making assignments in new compounds. ^ ^
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The structural rigidity of the tropane nucleus provides predictable
steric features which would aid in the determination of the stereo
chemistry of the products. Therefore, any differences in activity
could be related to stereochemical effects.
The purpose of this research, therefore, was to synthesize
various 3-aryl-2 and 3-tropanols. Since it has been shown that esters
of the amino alcohols are more active than the parent compound ,
esters of selected derivatives were prepared. The stereochemistry
of the products was of particular interest since it is such an important
aspect in the activity of synthetic drugs.
The-study would include a consideration of the stereochemical
course of reactions of tropane derivatives and provide valuable infor
mation about the reaction pathways and conformational preferences in
the tropane ring system. The ethano bridge holds two syn axial groups
on the a-side of the ring providing a model for studying steric effects
produced by such groupings. In a monocyclic system this diaxial con
figuration would be too high in energy to mahe such a conformation
favorable. The tropane bicyclic system makes it possible to study
the stereochemical control of addition to carbonyl and double bond
functions in close proxim ity to 1,3-diaxial constituents.
The nitrogen and its substituent are in an unusual environment
since the equatorial conformation of the substituent can bring it close
enough to the ethano bridge to experience unfavorable non-bonded
interactions. By studying the stereochemistry and conformational
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. preference of the salts of these derivatives the magnitude of such inter
actions could be evaluated and compared with other analogous systems.
A convenient method for the measurement of conformational equilibria
results because the configuration of the substituent at the nitrogen can
be inverted without bond breaking or ring conversion.
This thesis reports the results of these experimental endeavors.
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RESULTS AND DISCUSSION
It has been shown that esters having a tertiary amino function
two and three carbons removed from the carbinol carbon have local
anesthetic, analgesic, spasmolytic, and hallucinogenic activity. The
activity has been altered by using acyclic, cyclic, and bicyc'lic
skeletons with various substitution patterns. Phenyl substituents have
been shown to intensify or vary this activity as well. The research
described in this thesis was initiated to evaluate various approaches
to the synthesis of esters having the amino function as part of a phenyl-
tropane ring system. This effort concentrated on the preparation of
several 3-aryl-2 and 3-tropano'ls. Several pathways were evaluated
(see p. 10) and these w ill be outlined here in a preview of the dis
cussion and then considered separately in detail throughout the
discussion.
The preparative approaches which were successful for the
synthesis of various piperidino'l derivatives offered an analogous
route to these compounds from the available 3-tropanone (tropinone,
I). The method of choice for the preparation of the 3-ary'ltropines
(2) (the term tropine refers to tropan-3-ol) was the reaction of aryl-
lithium reagents with tropinone (1). Dehydration of these tropines
produced 3-aryltropidines (3) which were used as intermediates to other
tropanols. The synthesis of 3-phenyltropidine (3, Ar = phenyl) by Of? these steps had been reported. u
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Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 11
The hydroboration of 3 provided a possible method for preparing
several of the 2- and 3-tropanols (8). The study of this reaction with
3-aryltropidines (_3) also furnished information about the reactivity
and direction of approach of this reducing agent in cyclic substituted
styrene systems. Another route to several different tropanols was
through the intermediate, 3-aryltropan-2, 3-oxide (5), which might be
obtained from 3 via the bromohydrin (4) or by the peroxyacid oxidation
of the 3-aryltropidine (3). A variety of tropanols and diols could be
prepared by opening this epoxide with acids, nucleophiles, and reduc
ing agents. Finally, allylic bromination of 3 to produce 4-bromo-3-
phenyltropidine (6) would provide a method for the preparation of the
allylic alcohols (7) by nucleophilic displacement of bromide.
The Preparation of 3-Aryltropines
The reaction of aryllithium reagents with tropinone (1) was found
to be a facile method for the preparation of 3-aryltropines (2) in yields
of about 60% to 90% (see Table 1). The preparation using the Grignard
reagent was less successful.
Two methods were employed for the preparation of the lithium
reagents. The phenyllithium and p-tolyllithium reagents, were pre
pared by the direct reaction of the corresponding bromide with lithium 26 metal. The method of Cope and D'Addieco was used for these prepa
rations. A metal-halogen exchange reaction was used for the prepara
tion of the p-chlorophenyl, p-trifluoromethylphenyl, and p-anisyl
lithium reagents. It was found that exchange of the respective bromides
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1 I— CO , __ A1 A5 A9 A7 A8 Appendix IR , F ig u re , __ B7 BIO B l l Appendix NMR, Figure (%) 7 ■57 y ie ld mp (°C) 161-162 76 B1 168. 5-170 162-164 158. 5-161 53 194-195. 5 89 B8 A6 217. 5-219. 5 73 B9 TABLE 1: 3-Aryltropines (2) - A r phenyl 2-methoxy-5- methylphenyl p -to ly l p -a n isyl pheny'l p-trrfluoro- bromophenyl 9 11 p-chloro- 14 10 13 12 Compound
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 13
with n-butyllithium was a much more satisfactory method for pre
paring these reagents than was the direct reaction of the halide with
lithium metal even though the preparation of these organometallics 91 by this method has been reported.
The reagents were prepared by adding a solution of the aryl 28 bromide in anhydrous ether to a commercial solution of n-butyl-
lithium in hexane. The yields of these tropines were generally as
good or better than using the reagent prepared from lithium metal,
and the work-up of the reaction mixture was cleaner and easier since
there was no excess lithium metal to destroy.
The preparation of the p-anisyllithium by metal-halogen ex
change produced another organometallic, 2-methoxy-5-bromophenyl-
lithium, as a by-product. This resulted from the metalation of the
aromatic ring rather than the desired metai-halogen exchange. The
product resulting from this reagent, 3-(2-methoxy-5-bromophenyl)-
tropine (14), amounted to 12% of the total product. This was in
agreement with the amount of metalation that has been observed in
other preparations of this reagent. ^
It was of interest that the reaction of the aryllithium reagent
with tropinone (1) gave only one isomer of the 3-aryltropine (2). In
all cases this product appeared to be the alpha isomer, which was
the configuration that had been reported for 3-phenyltropine (9). ^
(The alpha side of the tropane system is defined as the side anti
to the methylamino bridge while the beta side is syn to the bridge). 30
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This structural assignment was based on several factors. First,
it would be expected that the approach of the organometallic reagent
from the alpha side would be hindered by the axial ethano bridge.
Secondly, a boat form of the 6 membered ring has been shown to pre
dominate when there was a 3- a -phenyl substituent in a tropane
system. ^ If the beta isomer had formed it w mid be expected to exist
in a non-chair conformation because of the severe, unfavorable inter
action of the axial aromatic ring with the syn-axial, ethano bridge. The
beta isomer in a non-chair conformation would be expected to show some
intramolecular hydrogen bonding which would be detected by the concen
tration-independent absorption band at a frequency lower than 3600 cm'-*- oq in the infrared spectrum; however, no such absorption was observed.
Third, the dehydration of these compounds occurred very easily. This
suggested that the hydroxyl group is ideally situated for a trans diaxial
elimination of water as would be the case if it were alpha and axial.
The stereospecificity of the organolithium addition suggested that
the endo side of the carbonyl of tropinone (1) was sterically hindered
from approach by the attacking species. This effect has also been
noticed by others in reactions of tropane bases in the reduction of
tropanone with lithium aluminum hydride^? 33? attempts to 34 oxidize beta tropanols. In all of these cases the results indicated
attack of the reagent from the less hindered, beta side of the molecule.
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The results of this research showed that this is an important consid
eration in predicting the reactivity and course of reactions of func
tional groups in the tropane ring system.
In the case of the preparation of 3-phenyltropine (9) several
attempts were made to try to improve the yield of the reaction although possible to increase the yield to greater than 76%, however. This maximum lim it of yield indicated that a competitive reaction was occurring and that 24% of the tropinone (1) was undergoing reaction by an enolization process. The enolate would resist reaction with the organolithium reagent, and on hydrolysis would be converted to 1. It was usually possible to recover about 12% of 1. The product from the reactions of other ary'llithium reagents with tropinone (_1) was also the 3-aryltropine (2). The tropinone was not recovered from these reactions; however, the trend in yield (see Table I) suggested that enolization was occurring. The yields of 2 increased from about 60% (p-tolyl (10) and p-anisyl (_13)) to 90% p-chlorophenyl (_11). A relationship between basicity and amount of enolization seemed apparent since the stronger the base was the less 3-aryltropine (2) that was produced. The reaction of the Grignard reagent with tropinone (_1) was of no value for the preparation of 3-aryltropines (2) and was worthwhile only for comparison with the reaction with lithium reagents. Several attempts were made to obtain a product from the reaction of p-chloropheny'l- Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 16 magnesium bromide with _1. In only one tria l wasaiy 3-p-chloro- phenyltropine (11) isolated and this was in only 5% yield. The Grignard reagent had definitely formed for all of the magnesium had undergone reaction and the reaction mixture gave a positive qualita tive te st^ for the presence of a Grignard reagent. Difficulty with the reaction of phenylmagnesium bromide with pa tropinone had been reported previously. It v/as suggested that the Grignard reagent formed a complex with the basic nitrogen for com plexes of tertiary amines with Grignard reagents have been reported. W ith tropinone (_1) this could have the effect of preventing reaction. With either the magnesium complex or the N- methyl group shielding the carbonyl group from the beta side and the ethano bridge prevent ing approach of the Grignard reagent from the alpha side the net effect would be failure of an addition reaction. The system could give a reaction by enolization, however, and this would have the effect of destroying the Grignard reagent and leading to recovered tropinone (1). The nuclear magnetic resonance spectra for the 3-aryltropines (2) were consistent with their assignment. The main differences with change in substitution in the aryl group were observed in the 7-8 ppm region. The para-disubstituted aromatic rings all showed clear AgBg patterns. The coupling between the adjacent protons was nearly constant for all of the compounds with J = 8-9 Hz. The chemical shift differences, however, varied considerably with changes in the Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 17 para substituent on the phenyl group. The AS values^ progressed from p-methoxy (13). AS a b = 34. 7 Hz; p -m e th yl (10), 19. 4 Hz; p-chloro (11), ^ P“trifluoromethyl (12), A6 =8. 4 Hz. Compounds JLO and 13 were observed in deutero- chloroform solution and compounds HL and 12 were run in deuterium oxide with one drop of concentrated sulfuric acid added to effect solution. The differences in chemical shift were consistent with an assign ment of the lower field protons as those nearer the carbinol carbon for the compounds with ihe p-methoxyl (13), p-methyl (10), and p-chloro (11) substituents and nearer the p-substituent on the aromatic ring in the p-trifluorom ethyl analog (12) by comparison with the known effects of these substituents. ^8 The chemical shift differences are summarized in the representation of the diagram below. 34.7 o c h 3 19.4 CH. 3 12. 5 Cl c f 3 7.9 7 .7 7. 5 7.3 7. 1 6.9 6(ppm) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 18 A plot of log Afor these aromatic protons against a+ 89 substituent constants gave good agreement with a straight line. This correlation may only have been fortuitous as its significance was not known. The Preparation of 3-Aryltropidines (3) Dehydration of 3-phenyltropine (9) had previously been achieved 26 by a laborious process using thionyl chloride. The dehydration should proceed easily since the conformation is favorable for the transition state for elimination by a trans diaxial arrangement. The ease of dehydration would also be facilitated by stabilization of the transition state by the phenyl substituent and steric acceleration could result from removal of the unfavorable non-bonded interaction of the axial hydroxyl group with the axial ethano bridge upon elimination. The dehydrations were carried out easily using 40% hydrobromic acid and the product from 9, 3-phenyltropidine hydrobromide (20), which precipitated after the reaction was isolated in quantitative yield. The other 3-aryltropines (2) underwent dehydration about as readily as 3-pheny'ltropine (9). The only other product which precipitated from the reaction medium as the hydrobromide was 3-p-anisyltropidine hydro bromide (24). A ll of the reaction mixtures were made alkaline and the free amines were isolated for identification (see Table II). Nuclear magnetic resonance spectra of these 3-aryltropidines (3) showed the resonance signal for the vinylic proton as a doublet. The position of the doublet progressed downfield as the proton was deshielded Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. without prohibited reproduction Further owner. copyright the of permission with Reproduced TABLE II: 3-Ary'ltropidines (3) O CO C ^ P K CD ^ K § £ , P l, C T H • r &1 Pi p fH CD h Pj ~ „ M -a o ■d K r—H *d • H • r < O O P CD p . p o PJ o i 3 CO o T>co C- D L CO S T ^ T—1O-T d ffl < t D L K d — P i I s 1 ll <—< „ Oc - c~ CO CD CD co O L CO m rH < 1 1 0 D L D L O W co « 1 i co CO DC-CO - C CD D I o H s CD T CO o LD t ^ by p-substituents of increasing electron withdrawing ability. The chemical shift of the phenyl derivative, however, fell out of order and had the highest field signal for the vinylic proton. The separation of the peaks of the doublet, due to coupling with the bridgehead proton, was between 5. 4 and 6 Hz for all compounds. These nmr data are summarized in Table III. Mass spectral analysis of the 3-aryltropidines (3) was also consistent with the structural assignment. An interpretation of the fragmentation patterns was worked out by analogy with examples that have been reported for other tropane alkaloids. ^ The molecular ion probably was formed by the loss of one electron from the nitrogen to form species a since nitrogen stabilizes a positive charge more 4? than any other part of the molecule. One of the most important patterns for fragmentation of amines is the homo'lytic cleavage of one of the g-bonds. This could occur in several ways in the tropidines. The most significant for these compounds seemed to be cleavage of the 1-7 bond of the molecular ion to give b. Two pathways could be followed from b to the most abundant fragment (m/e = 170 for phenyl (15)) of the spectrum, the 100% fragment. The fir s t^ ’ ^ of these involved the transfer of the hydrogen at C-4 to C-7 to give c. Homolytic cleavage of the 5-6 bond with loss of ethyl radical would then produce the N-m ethyl-4-arylpyridinium ion, d, which was the 100% fragment for all of the 3-ary'ltropidines. A second cleavage pathway from b probably consisted of the cleavage of the 5-6 bond Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. without prohibited reproduction Further owner. copyright the of permission with Reproduced TABLE III: NMR Comparisons of 3-Ary'ltropidines (3) Jo Jo '—I a & ft •'- directly from this fragment with loss of ethylene to produce f. Now loss of the 4-hydrogen could also lead to the main fragment d. 7 -e M e-N : 6 3 It was necessary to predict both of these pathways leading from fragment b because of the presence of fragments in the mass spectra of these compounds that appeared at equivalent weights other than whole numbers. These fragment ions could only be explained as dicationic species. The di-cation produced from the 100% fragment, resulting from the loss of an electron from the pi-system of the aryl ring, was fragment e. The loss of an electron from the aryl ring in fragment f_ would produce g. The fragment e from 3-phenyltropidine (15) occurred at m /e = 85. 5. CH. a liLZ* be-N+ // M e-N + M e-N+ \ = d ( 100 %) -e -e V M e-N + M e -N + g e Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 23 Other pathways of cleavage of the molecular ion leave the pyrro lidine ring intact with the g -cleavage occurring in the piperidine ring. Two fragments that appear to be the same as were observed from the fragmentation of tropane alkaloids are k and n. 41 Homo'lysis of the 4-5 bond in a would lead to the fragment represented by the resonance forms h and i_. Migration of the hydrogen from C -l to C-2 generates which can produce k, m/e = 96, by homolytic cleavage of the 2-3 linkage. In all of the samples studied another peak appeared at m /e = 94 which might be explained as a consequence of fragment k losing hydrogen to produce the pseudo-aromatic system 1_ or its isomer, N-methylpyridinium ion, m. The production of frag ment n from h would involve the transfer of the C-7 hydrogen to C-4 and subsequent cleavage of the 2-3 bond. a - i & 6 _ R <------» -R h 1H-*C2 k (m /e=96) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 24 A ll tropane alkaloids exhibit a peak at m/e==42. A suggested representation for this fragment is HC ItCHg. This would involve multiple bond ruptures; the overall process being favorable because of the high stability of this ion. 41 N tC H , r ^ + h = H NTCHg 3 n (m /e =82) R R These fragmentation assignments seemed to be consistent with known electronic effects of the para substituents in these compounds. It was notable that the pyrrolidine fragments increased as the electron withdrawing ability of the substituent increases. Also, the di-cationic fragments decreased in intensity in the same manner. The trifluoro- methyl substituent would be less able to stabilize a positive charge on the aromatic ring and, therefore, it would be expected that fragmenta tion routes requiring positive charges on the aromatic ring would make lesser contributions. This was observed with these compounds. A summary of the mass spectral data of the 3-aryltropidines is included in Table IV. The graphic representations of the spectra are found in Figures C-2, 5, 6, 7 and C-8 in the Appendix. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. without prohibited reproduction Further owner. copyright the of permission with Reproduced TABLE IV : Mass Spectral Comparison of 3-Aryltropidines (3) ‘Ml Ml ! - P4 -t-> SI CD| oil U s 1 I 5R eR eR eR ^1 P 01 01 h 1 m /e m /e m /e m /e m /e m/e % 02 96 (XI CO LO CO LO K CO LO LO X - i i 1 199 1 171 2. 5 170 100 85 5. 2 4.0 94 82 2.9 CO CO 96 CO r-H LO CO O H h-. X - CO 213 1 185 92. 5 1.8 184 100 92 4.5 94 7.5 82 3.3 *9 •w L O O CO o o LO CO CO CO \ 1—1 o- —i CO 229 201 4.4 200 100 100 96 94 • 82 3.3 t-H o CO CO CO 1— CO CO o CO LO o 02 X 00 CO o - i 1 1 233 205 1 2. 2 204 100 102 8. 5 96 94 82 4 .3 96 CO CO CS] LO CO O P X T—1 - CO h f 267 239 238 100 119 7.7 94 13.9 5.0 26 The Isolation and Characterization of The Two Piastereomeric Hydrobromide Salts of 3-Phenyltropidine (20)44 While investigating the properties of 3-phenyltropidine (115) it was found that the two stereoisomeric ammonium salts of lj5, which differ only in the configuration of the ammonium nitrogen, could be isolated. This and work by S i m m o n s ^on macrobicyclic diamines represented the firs t time that such isomers had been found to be stable in solution at room temperature. 44 Dehydration of 3-phenyltropine (9) was accomplished with 40% hydrobromic acid and the product was allowed to crystallize from the reaction medium to give a -3-phenyltropidine hydrobromide (20a), (see Figure I). The base, 3-phenyltropidine (15), was prepared from this salt and conversion to the known hydrochloride^and methiodide^® showed it to be identical with the base that had been reported. The reaction of this base (15) with hydrogen bromide in anhydrous ether caused the precipitation of another 3-pheny'ltropidine hydrobromide, the $-isomer (20b). The non-identity of the a - and 3 -forms of 3-phenyltropidine hydrobromide (20) was clearly evident from analysis by the x-ray powder patterns and by proton magnetic resonance and infrared spectra. Other properties of the two salts including mass spectra and ultraviolet spectra were nearly identical. The purification of the isomers could not be achieved by conven tional recrystallizations because this caused conversion to an equilibrium mixture of the two isomers. Purification could be accomplished by Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 27 recrystallization if the temperature of the solution was never allowed to rise above room temperature. By dissolving the salt in alcohol at room temperature and then cooling the solution in a Dry Ice-acetone bath to effect crystallization, purification was accomplished. Correct analyses were obtained for each isomer through this procedure. FIGURE I: The Proton Magnetic Resonance Spectra of the Diastereo- meric Isomers of 3-Phenyltropidine Hydrobromide (20) and a Mixture of the Two Isomers. * HBf 2 0 Q. p-*-Ph#ftr«r»pWtM HBf in ) 0.30 ~77Yr.„A ru-^ n J 1 .0 50 3010 • i l 7.0 «4> 5.0 1.0 -- U E i* CHjN- ph ; 9 OH 2 Og ,OH* 007.0 to 3.0 ♦This figure has been reproduced from reference 44, with per mission of the Editor. The assignments of the structures are the same as those in that reference, however, evidence will be presented later in the discussion that may dispute these assignments. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 28 The proton magnetic resonance analysis was the most valuable tool for identifying and distinguishing the two isomers. The spectra (Figure I) showed that the chemical shifts for the N-methyl and vinylic protons were different for the two isomers while the remainder of the spectra were very similar. The a -3-phenyltropidine hydro bromide (20a) indicated a singlet for the N-methyl at 3. 02 ppm and a doublet for the vinylic proton (J =6Hz) at 6. 48 ppm. The 3 -isomer (20b) showed a singlet at 2. 96 ppm for the N-methyl substituent and a doublet for the vinylic proton at 6. 30 ppm (J = 6 Hz). A mixture of the isomers showed all of these signals. The infrared spectra of the two isomers also showed some distinct differences (see Figure A3, Appendix). There were signifi cant differences in the N-H stretching absorption region (2500-2800 cm "l) and in part (900-1300 cm_l) of the fingerprint and aromatic hydrogen (out-of-plane deformation)(650-800 cm_l) regions. Infrared spectroscopy was most useful in showing that proton exchange occurred in aqueous solutions of the salts at room temperature. Recovery of either salt from deuterium oxide solution gave absorption bands not present in the original salts in the 1900-2100 cm"'*' region caused by if-D stretching vibrations. The general shape of these absorption bands was sim ilar in appearance to those of the iJ-H absorptions. These new IvT-D absorptions were accompanied by decreases in the intensity of absorption in the ifr-H region. These observations are shown in Figure A3, Appendix. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 29 These data showed that in the deuterium oxide solutions of the salts (20a and 20b) used in the pmr studies, exchange of i^T-H for ifr-D was occurring. Since the N-methyl substituent retained its conforma tional and configurational integrity over long periods of time in these solutions it can be concluded that the proton exchange occurred at a rate faster than the inversion of the nitrogen configuration. Further studies with the pmr solutions substantiated this. When either one of the two isomers was heated in the deuterium oxide solu tion an equilibration to a mixture of the isomers was immediately achieved. However, if the solution of the pure isomer was saturated with anhydrous hydrogen bromide no equilibration was observed. These solutions were heated on a steam bath for up to 0. 5 hr and still no equilibration occurred, i. e ., only one singlet for the N-methyl group and one doublet for the vinylic proton were observed. In pure deuterium oxide solutions equilibration occurred immediately when the solution was placed in a steam bath. In the acidic solutions in deuterium oxide an exchange of deuterium for the vinylic proton did take place, for the vinyl signal disappeared after heating a short period of time. This exchange probably occurred by the formation of the phenyl carbonium ion (A). Evidence that this ion formed was obtained by inducing optical activity into 3-phenyltropidine (15) by heating it with d-10-camphor sulfonic acid. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 30 H H H Me (A) Other evidence for the non-identity of the 3-phenyltropidine hydrobromide salts (20a and 20b) was'found in the x-ray powder patterns. This procedure gave distinctly different patterns for each of the two isomers and it could be concluded that they definitely were not the same compound. These data are summarized in Figure II. FIGURE II: X-ray Powder Patterns of the Two Isomeric 3- Phenyltropidine Hydrobromides (20a and 20b). A B A: a-3-Phenyltropidine Hydrobromide (20). B: p-3-Phenyltropidine Hydrobromide (20). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 31 The evidence above has shown that the a - and & -3-phenyl- tropidine hydrobromides (20a and 20b) are unique compounds. An important necessity remained and that was to show that they do indeed have the same skeletal structure. The ultraviolet spectra of the two isomeric hydrobromides were essentially the same with absorption maxima at 216. 2, 247. 9 and 290 nm. These spectra are sim ilar to and consistent with other a , £- disubsti- 47 tuted styrene systems. Thus the same conjugated it -system was present in both compounds. Mass spectral analysis also was consistent with an assignment of the same basic ring structure for the two isomers (see Figures C-l, 3, and 4, Appendix). The mass spectra of the a - and 6 -isomers or the equilibrium mixture were identical and showed the loss of hydrogen bromide in the inlet system. The molecular ion peak was at m /e = 199 and the strongest peak in each spectrum was at m/e= 170 which was probably due to 1-methyl-4- phenylpyridinium ion. These spectra were also identical with the spectrum of 3-phenyltropidine (15) (Figure C-2, Appendix) which indeed suggested the loss of hydrogen bromide before fragmentation. An assignment of some of the fragments can be found with other 3-aryltropidines in Table IV. Either of the isomeric hydrobromides or the equilibrium mixture was converted to the same amine, 3-phenyltropidine (15), as evidenced by identical infrared and pmr spectra. The purified amine (15) was recovered in 75-85% yield. Since the equilibrium mixture was about a 50:50 mixture of the two forms, no one component should be re covered in greater than 50% yield. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 32 Even though pmr spectroscopy was used to show the structural non-identity of the two hydrobromides (20a and 20b), it can also be used to suggest that they have the same skeletal structure. The interconversion of the isomers occurred very slowly at room temper ature in solution in deuterium oxide but within a few minutes at 50°. A variable temperature study revealed that the two N-methyl resonance signals for the two isomers began to coalesce at about 100° showing that the rate of interconversion was comparable with the pmr time scale. When this solution was allowed to cool to room temperature the spectrum of the equilibrium mixture was observed. If a structural change were occurring in this procedure, i. e ., the two isomers did not have the same ring skeleton, it would have been expected that the new spectrum would be different from that of the equilibrium mixture or that a rather strange reversible reaction was taking place. In summary, the conclusions about the two 3-phenyltropidine hydrobromides (20a and 20b) are: 1) Analysis by nmr and infrared spectroscopy and the x-ray powder patterns prove that the a- and 3 -isomers are indeed different compounds. 2) Because of the sim ilarity of the ultraviolet spectra the two isomers must contain the same type of ^ -electron system. 3) The two isomers must contain the same skeleton or undergo a very unusual rearrangement. Evidence for this was that the same base was formed from either isomer under thermal decomposition Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 33 conditions (identical mass spectra). Isolation of the free amine in basic media also produced the same amine from either isomer. Carbonium ions are very often intermediates In rearrangements of unsaturated systems of this type. Thus a rearrangement of 3- phenyltropidine (_15) during salt formation or in heating a solution of the salt would probably occur by a carbonium ion mechanism. The decrease in the rate of equilibration between the two isomers in highly acidic media is opposite to that to be expected for a carbonium ion rearrangement and also argues against the possibility of skeletal isomers. The evidence repudiates attempts to explain the isomerism by differences in the skeletal arrangement of the compounds. 4) The most satisfactory explanation for the existence of the two isomers was one based on stereoisomeric differences as outlined in Figure I. The stability of these isomers (20a and 20b) in aqueous medium was indeed exceptional and shows potential for a contribution to hetero cyclic conformational analysis. ^8 The inversion at the nitrogen in a free tertiary amine such as tropane was sufficiently rapid to prevent detection of the two diastereomeric configurations by nuclear magnetic 49 resonance spectroscopy. The rate of inversion of a protonated nitrogen was decreased sufficiently to permit observation of the two signals for the nitrogen substituent. This has been observed for many tertiary methyl amines in acidic media. ^ However, since the protonation was reversible the two isomeric ammonium salts had not Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 34 previously been isolated. It had seemed that the protonation-deproto nation process was slower than the inversion at the nitrogen and, therefore, the isolation of one of the diastereomers was prevented. Recently Simmons and Park^5 have shown that the conformational isomers of macrobicyclic diamines with bridgehead nitrogen atoms, such as 1, 10-diazabicyclo [8. 8. 8 ]hexacosane bishydroch'loride could be isolated and showed a definite stability in aqueous media. The isolation of the two diastereomeric hydrobromide salts of 3-phenyl tropidine (20) along with the data presented by Simmons and Park established that the protonation-deprotonation of these amines was actually faster than the inversion of the nitrogen. The consequence of these findings could have a valuable effect on future studies of heterocyclic conformational analysis. An N- substituted conformationally rigid piperidine, for example, could be used as a model for studies of non-bonded interactions with axial substituents in the 3- and 5-positions. The ammonium salts of such compounds would be ideal for studying the conformational equilibrium because it would not be necessary to break the bond between the sub stituent and the nitrogen or to invert the ring to achieve an equilibrium m ix tu re . It was, therefore, necessary to evaluate the extent to which this type of analysis could be useful. The following studies were carried out to show that the behavior of the two 3-phenyltropidine ammonium salts (20a and 20b) was not a unique phenomenon. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 35 The Conformational Preference of the N-Methyl Substituent in Cyclic Tertiary Methyl Amines Three general types of compounds were employed to determine the generality of the behavior found in the stereoisomeric forms of 3- phenyltropidine hydrobromide (20). The compounds that were studied were other unsaturated tropane systems, some saturated tropanes, and some 2, 6-disubstituted piperidines. They w ill be discussed separately and the combined conclusions drawn from the experimental data in each case w ill be summarized at the end of this section. 1) Other Unsaturated Tropane Systems The preparation of four more 3-aryltropidines (16, 17, 18 and 19) was presented in an earlier section, p. 18 The hydrobromides were prepared by treating the amine in anhydrous ether with anhydrous hydrogen bromide. A summary of the pmr spectral data for these compounds is found in Table V. The behavior of these compounds (.16, 17, 18 and 19) was con sistent with that found for the unsubstituted phenyl derivative (15). A ll of the hydrobromides, with the exception of the p-trifluorom ethyl- pheny'ltropidine hydrobromide (23), which first formed an oil, showed a predominance of the higher field isomer of the N-methy'l substituent when they were prepared in anhydrous ether (see Figures B-16 - B-21, Appendix). Besides the a-3-phenyltropidine hydrobromide (20a) the only other salt that crystallized out of the dehydration reaction medium was the p-anisyltropidine hydrobromide (24). Because of its low Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. without prohibited reproduction Further owner. copyright the of permission with Reproduced TABLE V : Nuclear Magnetic Resonance Analysis of 3-Aryltropidine Hydrobromides. K O CO CO 3 o < .o!V? w w (-5 ^ -i-> +-> si CD s S C N ? CD Cl) >? I < < S 5 _ K M rcs O P M o a o 3 S=i o a a N to a a N <1 i h col CO* co’ co’ CO LO w o o 1—I LO lO CO CO CO CO CO u 2 0 CO O 0 d cdcd 1 CO CO 3 0 col CO 05 o w 03 cdcd CO ^ LO CO CO LO id CO 0 CO CO* CO CO CO - COC- 1 CO CO col l ° CO CO cd CO CO d co’cd 03 O cd cd CO o LO O L 03C- K I CO col COI d co’cd CO CD CO 03 O cdcd LO CO i—i O 0 1—1 CO LO 1 col CO| d cd cd i—I CO cd CD* Co’ 03 C— 03 O [A CO 0 LO LO 1 CO 36 37 solubility in deuterium oxide, this salt (24) had to be heated to effect solution before the pmr spectrum could be observed. However, a predominance of the lower field isomer was observed in the pmr spectrum if it was run immediately after solution was effected (see Figure B-20, Appendix). This also corresponded to the isomer that was formed by the dehydration of 3-phenyltropine (9) which was the alpha isomer. Heating the solutions of these salts always produced approximately a 50:50 mixture of the isomers as shown by their pmr spectra. The unsubstituted tropidine (£5) was found to behave in the same manner in a nmr analysis of the salts (see Figures B-22 and B-23, Appendix). On preparing the hydrobromide (26) of 25 in anhydrous ether, the high field isomer was produced. Heating solutions of this isomer produced a mixture of isomers. However, in this instance a 50 :50 mixture was not produced. The pmr spectrum showed that in this compound the equilibrium mixture contained about 62% of the higher field methyl conformer. These data are included in Table VI. 2) Saturated Tropane Systems Studies by G. L. Closs^b of the deuterochlorides of tropanes in deuterium oxide solution showed that the lower field methyl in these compounds predominated to a much greater extent than in the tropidines. The ratios for the lower field methyl signal to the higher field signal in saturated tropanes were 10-20:1. It was shown, however, that a 6- or 7- 3 - substituent produced a 1:1 mixture of the two isomers, Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 38 e. g ., benzoylscopo'line deuterochloride and 2, 2, 4, 4 -te tra d e u te rio - te'loidinone deuteriochloride (see Table VI). 3) 2, 6-Dimethylpiperidine Hydrohalides Studies here and elsewhere^ have shown that in a compound such as 1, 2 ,6- trim ethyl piperidine hydrochloride (28) the N-methyl substit uent does not always prefer the equatorial conformation but can be isolated as this one isomer. The pmr spectra of this compound and of 1 ,2 ,4 , 6-tetramethylpiperidine hydrobromide (30) show that the equilibrium favors the equatorial conformation by a ratio of about 7 :3 (see Figures B-24 - B-27, Appendix). TABLE VI: Conformational Preferences in Some Cyclic Tertiary Methylamine Salts 6 N -C H 3 A6 Conform . Compound (ppm) (Hz) P ref. Ref. * Unsaturated Tropane Tropidine-HBr 2.98 5 38% a 2.90 ...62% Saturated Tropanes Tropane-D Cl 7 15:1 b Pseudotropine-DCl 8 9. 5:1 b Tropine-DCl 5 15:1 b Atropine-D Cl 6 20:1 b Benzoylscopoline-DCl 3 1:1 b 2,2,4,4-Tetradeuterio- 5 1:1 b te'loidinone*DCl Piperidines 1,2,6-Trimethylpiperidine-HCl 2.88 15 70% e a, c 2.62 30% a 1 ,2 ,4 , 6-Tetramethylpiperidine- 2. 87 16 70% e a HC'l 2.60 30% a *(a) this work; (b) ref. 49b; (c) ref. 51. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 39 51 It was reported that these salts exist in only one conformation in the solid state, and that the rapid equilibration led to the mixture observed in the pmr spectrum. The two conformations do co-exist in the solid state, however. If the pure isomer formed by precipi tation of the salt in anhydrous ether was analyzed it showed only one isomer to be present. The deuterium oxide solution was observed several times over a period of 0. 5 hr and this isomer kept its conformational integrity. If, however, the solution was heated an immediate equilibration began to take place. This indicated that the isomers did hold their original conformation in solution over long periods of time or until they were heated. It was also observed that some samples, when submitted to pmr studies, immediately showed two N-methyl absorptions indicating a mixture of the isomers. It can be concluded that both of the isomers were present in the solid state, since the isomers would not have equilibrated in the time re quired to run the spectrum. It was previously suggested^ that the higher field methyl signal in the mixture of a- andg -3-phenyltropidine hydrobromides (20) was due to the methyl group being in the axial position. This assignment was made by analogy with the pinenes in which the higher field signal was assigned to the methyl that was nearer the double bond and probably in its shielding cone. However, closer examination in the heterocyclic systems indicated that other considerations may be im portant before an assignment can be established. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 40 (0.856 ) :h 3 (1.63 s) (1.75 5) (1.27 6) ( A6 = 9 Hz) ( A6 =25 Hz) Pinane a -Pinene Other reports^®a’ k havs suggested that the N-methyl signal at the lower field resonance corresponds to the equatorial methyl isomer in acidic solutions of 1,2, 6-trim ethylpiperidine^a and in saturated tropane derivatives. These are in agreement with assignments in the cyclohexane series in which equatorial methyl signals are generally at about 0. 5 ppm lower field than a corresponding axial methyl group. 52 Experiments with the hydrohalide salts of 1, 2, 6- trim ethylpiperidine (28) and 1, 2, 4, 6-tetramethylpiperidine (30) were in agreement with this conclusion. With these compounds the equil ibrium in deuterium oxide showed a predominance of the lower field isomer in the pmr spectra (see Table VI). A consideration of non bonded interactions suggested that the most populous isomer would have the N-methy'l group in an equatorial position. Since the lower field signal for the N-methyl was more intense it probably belonged to the equatorial methyl (see Figures B-24 - B-27, Appendix). The separation of the two N-methyl signals ( A 6 ) was about 15 Hz. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 41 These analogies do not follow as clearly for the tropane deriva tives, however. Examination of Tables V and VI shows that the separation of the two N-methyi signals (3-8 Hz) in saturated tropane compounds is quite small as compared to the saturated piperidine derivatives ( A 6 15 Hz). This difference may be because the equatorial N-methyl in tropanes is situated over a pyrrolidine ring which might have an induced diamagnetic current sim ilar to a piperi dine ring. Thus in the isomers the equatorial and axial N-methyl groups are in more nearly equivalent environments. No data are available concerning the relative shielding abilities of a pyrrolidine ring compared to a piperidine ring so quantitative comparisons could not be made. When the structural assignments for the two stereoisomers of 3-phenyltropidine hydrobromide (20a and 20b) were firs t reported^ (see Figure I), the N-methyl assignments were based on analogy with known systems. These assignments were in agreement with the carbocyclic analog, a-pinene, see diagram p. 40 . The assignment of the resonance at higher field to the axial methyl group was in agree ment with the assignments in the other tropanes and structurally biased piperidines in which the higher field signal was assigned to the axial conformer. It seemed that the double bond should have a shielding effect on the methyl in an axial configuration. Indeed, measurements made on Dreiding models led to the conclusion that the axial N-methyl substituent would be in the shielding cone of the double bond. Any Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 42 group within 55° of the axis perpendicular to the plane of the double bond should be in the shielding area. ^ A ll three of the methyl hydrogens on the axial methyl substituent fall in this area in the model structure. This would lead to the prediction that the signal for the axial substituent would be at higher field. Mechanistic considerations also argued for assignment of the low field signal to the equatorial methyl conformation. The lower field isomer was the isomer that was formed stereospecifically from the dehydration of 3-phenyltropine (9) in aqueous hydrogen bromide. The most plausible mechanism for such a stereospecific reaction was one in which the nitrogen participated in the dehydration as suggested in the scheme below. -Ph H B r ■Ph O ■Ph (20a, ?) OH 2 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 43 These considerations suggested an assignment as outlined in Figure I. These assignments were based on the phenyltropidines only and further study indicated that consideration of these assign ments might show them wrong. The firs t inconsistency was evident on further comparison of the pinenes with the tropidines. The difference in the chemical shifts of the methyl signals in pinane were 9 Hz but the presence of the double bond in a-pinene caused the difference to increase to 25 Hz. In comparing the saturated tropane ( A 6 = 5-7 Hz) with the un saturated tropidines ( A5 = 2-7 Hz) the change is insignificant if not negative. Eased on a-pinene the A 6 for the tropidines should have been at least 20 Hz. This suggested that perhaps other considerations were important before the structures of the isomeric 3-phenyltropi- dine hydrobromides ( 20a and 20b) could be assigned. Examination of the data in Table V showed that the chemical shift differences for the isomeric N-methyl substituents increased as the electron-withdrawing character of the para-substituent on the aromatic ring increased. This could be consistent with an assignment of the lower., field signal to the axial methyl group. In that case the electron-releasing p-methoxy'l substituent on the ring would have in creased the electron density of the double bond and increased the shielding of the axial N-methyl and shifted the lower field axial signal to higher field. This would have the effect of bringing the two methyl signals closer together in the pmr spectrum and that was observed Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 44 ( AS = 2. 5 Hz). As the para-substituent became less electron- releasing and finally became electron-withdrawing the 6A values would be expected to increase as the axial methyl signal went to a lower field. This was observed in progressing to the p-trifluoromethyl analog (AS = 6. 8 Hz). A different approach, however, could use the same data to assign the lower field methyl signal to the equatorial isomer of the N- methyl. This would result if a ir-hydrogen bond between the ammonium proton and the double bond was important. In this case the only isomer which could accommodate the tt -bonding was the equatorial conforma tion of the N-methyl substituent as suggested below. In this case an assignment of the axial methyl conformer as the higher field isomer was assumed. The position of the lower field equatorial isomer would be affected more by the changes in the para-substituent. The electron- releasing p-methoxy substituent would increase the basicity of the double bond and thereby increase the strength of the ir-bond of the proton with the double bond. The net effect of this would be a decrease in the positive charge on the nitrogen as the ir -system would be supporting part of the charge. A decrease in charge on the nitrogen would bring the equatorial methyl substituent to a higher field resonance ( AS = 2. 5 Hz for p-OCHg). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 45 -R R = -OCHg, -CHg, -H -C l, - c f 3 An electron-attracting substituent like trifluoromethy'l on the other hand, would not facilitate it- bond formation. This effect would place more of the positive charge on the nitrogen thereby de creasing the electron density at the nitrogen and the methyl signal would, therefore, appear at lower field ( A6 = 6. 8 for p-CFg). Both of these rationales for the data from chemical shift differ ences were based on the basicity of the double bond. The two effects that have been described are opposed to one another and it was not known which one would be greater. The conclusions from these data, therefore, are tenuous and an unequivocal assignment could not be made directly from it. The assignment of the higher field signal to the equatorial methyl' group in the tropidine hydrobromides also allowed these data to be in agreement with studies into the direction of protonation in the prepara tion of the salts. When either 1, 2, 6-trimethylpiperidine or 1, 2, 4, 6- tetramethylpiperidine were treated with hydrogen bromide in anhydrous ether the product contained only one isomer of the salt. This corres ponded to the methyl group at lower field strength and has been assigned to the equatorial isomer. If care was taken to keep the solutions very Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 46 anhydrous the formation of the hydrobromides of tropidine (25), 3- pheny'ltropidine (1_5) and 3-p-toly'ltropidine (16) formed stereospecifi- caily one isomer, this isomer being the higher field isomer. If the same mechanism of reaction was occurring in all of these reactions it was necessary to assign this isomer to the one in which the methyl group is equatorial. In these reactions the proton would be approach ing from the axial direction. This has been found to be the direction 54 of protonation of conformationally biased 1-methylpiperidines and in the quaternization of tropanes with no 2- or 4-alpha substituents. 55 When the hydrobromides of the p-anisyl (19), p-trifluoromethylphenyl (18) and p-chlorophenyl (17) tropidines were prepared an oil usually formed initially before crystallization occurred. When these salts were analyzed by pmr spectroscopy a mixture of the two isomers was detected. It was assumed that an equilibration between the two isomers occurred while the salts were in the liquid phase. These compounds did, however, show a predominance of the higher field isomer. Solvent also seemed to have an effect in the direction of protona tion for these hydrobromides. The dehydration of 3-phenyltropine (9) in 40% hydrobromic acid produced only the a - isomer of 3-phenyltro pidine (20a). The dehydration of 3-p-anisyltropine (13) also produced a salt (24) that precipitated out of the reaction medium and showed a predominance of the lower field isomer after the solution had been heated to effect solution. Recrystallization of 3-phenyltropidine hydro Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 47 bromide (20) from 40% hydrobromic acid also produced the a -isomer. Preparation of the salt in anhydrous ether gave the 3 -isom er but, if wet ether was used a mixture of the isomers was obtained. The data presented in this section show that there is no clear cut basis for making structural assignments for the a - and 3 -3-pheny'l- tropidine hydrobromides (20a and 20b). It has been shown that the assignment is more complicated than assigning the configurations of the nitrogen substituents in saturated tropanes and the piperidine analogs. The presence of the double bond in the tropidines provides a basis for increasing the shielding of either the axial (by direct effect) or equatorial (via hydrogen bonding) methyls. Since there is no basis for determining the relative magnitude of these effects, their relative importance cannot be evaluated and a configurational assignment was not possible. The relative contributions of the ring current effect of the pyrro lidine ring as compared with the piperidine ring also seemed important. Data concerning the induced diamagnetic currents in these rings was not available so this contribution still remained an unknown. It seems that an answer to the question of structural identification of the isomers of tropidines w ill have to come from the preparation of compounds in which the equilibrium composition of the two conformation al isomers w ill not be a 50: 50 mixture. Such a compound would have groups in the beta configuration attached to the ethano bridge. This should force the equilibrium to favor the axial conformer and a Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 48 clearer distinction should become available. The composition of the conformational equilibrium found for each of these compounds (see Figure III) provides a basis for speculation about non-bonded interactions in them. In an unsubstituted 1-methyl- piperidine there was, of course, only one isomer observed and this was the conformer with the equatorial methyl group. 49a However, when cis methyl groups were substituted in the 2- and 6-positions, thereby freezing the ring conformation with these two groups in equa torial relationships, about 30% of the N-methyl substituent was found to be in the axial conformation in an equilibrated solution of the hydro bromide (Case 1). The apparent reason for this was the unfavorable non-bonded interaction that existed between an equatorial N-methyl and the two methyl groups on the adjacent carbons. Relative to the unfavorable interaction caused by the axial interference between the N-methyl and the syn-axial hydrogens this 1, 2, 6-trim ethyl interference was large enough to cause the N-methyl in the axial position to be of comparable stability. The tropanes (Case 2) have an analogous 2, 6- disubstituted piper idine ring; however, the ethano bridge is frozen rigidly in the diaxial positions. The interference to a N-methyl substituent in the equatorial conformation is provided by the two equatorial hydrogens on the adjacent carbons and the hydrogens on the ethano bridge. The two axial hydrogens in the piperidine ring provided sufficient unfavorable non-bonded interference (relative to the equatorial interferences) to Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 49 FIGURE III: Conformational Equilibria in Some Tertiary Cyclic Amines. H H3 30 Case 1 70 c h 3 CH. H Case 2 10-20 H Case 3 HO. HO HO HO Case 4 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 50 make the axial N-methyl highly unfavorable and the equatorial confor mation preferred. As in the 1-methylpiperidines, the experimental evidence for this was the 10- 20:1 observed ratio favoring the equa- 49b torial conformer in the conformational equilibria (see Table VI). This situation can be changed, however, by putting substituents in the beta configuration on the ethano bridge. Case 3 illustrates this with telloidinone which has a 1:1 ratio of the two conformers at equilibrium. The axial conformation can be favored by removing a syn-axial interaction as was observed with the 3-aryltropidines (3) (Case 4). In these compounds the removal of interference to an axial N-methyl effected the conformational equilibrium. The removal of one of the axial hydrogens in the piperidine ring by the introduction of a double bond instead of adding unfavorable non-bonding interactions as in Case 3 resulted in a 50:50 equilibrium mixture. The result was that with the 3-aryltropidines the two conformers had the same free energy (Figures B-2 and B-16 - B-21, Appendix). The equilibrium composition of the two isomers did not change on changing the p-substituent in the aromatic ring, for all 3- aryltropidine hydrobromides showed an equilibrium composition of equal amounts of each of the isomers. The equilibrium composition of such compounds could also be used to assign the stereochemical arrangement of a substituent in a novel system such as 4-bromo-3-phenyltropidine hydrobromide (31). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 51 Because the coupling constant for the CBr-H with the bridgehead proton was small as predicted for either configuration, additional data were necessary. Under equilibrating conditions 31 existed pre dominantly as one conformer. On this basis it might be assumed that the bromine was in an axial orientation since in this configura tion the N-methyl would be expected to exist only in the equatorial conformation. If the bromine had been equatorial both configurations of the N-methyl should have been detected. These results are in agreement with the conformational assignment made for the corres- 56 ponding l-methyl-3-bromo-4-phenyl-1, 2, 3, 6-tetrahydropiperidine. In tropidine hydrobromide (26), having no 3-aryl substituent, the conformational equilibrium contained 62% of one isomer and 38% of the other. If the major isomer had the methyl axial then this change reflects a small but definite steric interaction between the 3-aryl group and the axial N-methyl in 26. On the other hand, if the major isomer had the N-methyl equatorial this probably reflects a dipole-dipole interaction which has been ignored in the discussion above. Attempted Preparations of 3-Phenyltropane-2, 3-oxide (_5) A pathway to several 2- and 3-tropanols could easily be seen through the intermediate 3-phenyltropane-2,3-oxide (5). Even though attempts to prepare 5 were unsuccessful, the information obtained in these experiments was beneficial. Two approaches to the preparation of 5 w ere employed. One was through the b rom o hydrin (4) and the Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. other was by direct oxidation of the double bond. 1) Attempts to Produce 2-Bromo-3-phenyltropine (5): The Preparation of 4-Bromo-3-phenyltropidine Hydrobromide (31) The reaction of 1-methyl-4-phenyl-1,2, 5, 6-tetrahydropyridine hydrobromide with bromine and water provided a method for preparing the bromohydrin which was then converted to the epoxide. ^ T his route seemed to be the method of choice in preparing 5. The reaction - of.3-phenyltropidine hydrobromide (20) with bromine in water, however, did not produce the desired bromohydrin (4). An alternate method^ using glacial acetic acid as solvent for the bromination of _20 to form the dibromide gave the identical product as that from the reaction of 20 with bromine in water. This product remained unchanged when boiled in water indicating that it was not the dibromide which should have been converted to the bromohydrin. This same product was also formed when _20 was treated with N-bromosuccinimide in water/chloroform. The structure of this bromination product was assigned as 4- bromo-3-phenyltropidine hydrobromide (31) on the basis of its spectro scopic properties. The absence of absorption in the 3200 cnT^ region of the infrared spectrum eliminated the possibility of a hydroxyl group being present. The nmr spectrum gave clearly defined doublets at the appropriate chemical shifts for a vinylic proton (6. 48 ppm, J= 6 Hz) and a CBr-H (5. 62 ppm, J = 1. 5 Hz). The remainder of the spectrum was consistent with the structure 31. The ultraviolet absorption Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 53 spectrum showed absorption clearly related to the styry'l system of 3-phenyltropidine. Finally, the elemental analysis was consistent with a structure having the composition of 4-bromo-3-pheny'ltropidine hydrobromide (31). The 4-bromo substituent was suggested to be in the beta configuration (see page 50). This configuration would also be predicted on mechanistic grounds. The reaction differences of 3-phenyltropidine hydrobromide (20) as compared with the tetrahydropyridine hydrobromide would be anticipated from a consideration of the mechanistic pathway. The reaction would be initiated by the attack of the bromonium ion at the 2-position along an axial pathway to form the resonance stabilized phenyl carbonium ion. This intermediate could be converted to a stable product as outlined below. •H B r / •HBr •H B r '+ \ C C r •HBr •HBr -Ph OH Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 54 Reaction of the solvent with the carbonium ion would produce the desired alcohol (4). Because of the steric interference between the ethano bridge and the approaching water molecule the transition state 59 for this pathway may be unfavorable. In view of this, and also in view of the stability of the unsaturated product, it seemed that ab straction of the 3-axial-proton by water or by the nitrogen which is already present in the molecule to yield the styryl system would be favored. Because of the tt -overlap possible in the styrene system this product would have resonance stabilization which should also favor its formation. 2) Attempted Peracid Oxidation of 3-Pheny'ltropidine (15) The failure to obtain 3-phenyltropane-2,3-oxide (5) via the bromohydrin (4) required the consideration of the synthesis of 5 by peroxy acid epoxidation of 3-phenyltropidine (15). Related epoxida- tions were reported in the synthesis of scopolamine®® and the epoxide 1 from tropidine (25). The reaction of 3-phenyltropidine (15) with peroxytrifluoroacetic acid following the procedure of Fodor gave back unreacted 1_5. The failure of this reaction appeared to result from the same interference to formation of an sp^ carbon at the 3-position as was observed with the bromination reactions. Fodor's epoxidations produced the beta-epoxides, i. e. with the epoxide syn to the N-methyl bridge, which resulted by approach of the peracid from the least hindered side of the molecule. The transition state for such a reaction with 3-phenyltropidine (15), however, would Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 55 require the phenyl at the 3-position to approach the ethano bridge as O the carbon at C-3 became sp hybridized. This transition state would be very unfavorable and would have a high energy, therefore, pre venting the reaction from occurring. h 3C The alternate pathway for the formation of the epoxide, approach of the reagent from the alpha side, would also be unfavorable due to non-bonded repulsion between the approaching reagent and the ethano bridge. Since this mode of attack does not occur in other reactions it would not be expected in this case. Sim ilar behavior has been ob served in other systems such as 1, 2,2, 6, 6- pentamethy 1-4-phenyl- 1, 2, 3, 6-tetrahydropyridine. ^ Reactions of 4-Bromo-3-phenyltropidine Hydrobromide (31) The ally'lic bromide (31) formed by the reaction of bromine with 3-phenyltropidine hydrobromide (20) provided a possible intermediate for the preparation of several 4-substituted 3-phenyltropidines. The halide of the allylic system would be expected to undergo facile nucleo- philic displacement to form the corresponding alcohol on hydrolysis in aqueous acid or base and the nitrile with cyanide ion. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 56 The reaction of 31 with bases gave mixtures of compounds in each case. The reaction with cyanide ion in ethanol gave an oily product which no longer contained halogen. Infrared spectroscopy showed the presence of cyano functions for two bands were observed at 2230 and 2250 cm"-*-. These two absorptions suggested that a m ix ture of the 4-cyano and 2-cyano-3-phenyltropidine was formed. These products were not characterized. The preparation of 4-hydroxy-3-phenyltropidine (7) was attempted through the reaction of 31 with sodium hydroxide. The nucleophilic displacement of bromide resulted in an oil that was shown by glc analysis to be a mixture of at least four components. An infrared spectrum of this crude oil indicated the presence of hydroxylic (3 400 cm"**) and carbonyl (1670 cm- **-) groups. A crude ultraviolet spectrum indicated a possible phenone-type structure or an a,8 -unsaturated carbonyl function with maxima at 314, 280 and 243 nm with relative extinctions of 0.17:1:1. The formation of a red-orange 2, 4-dinitro- phenylhydrazone further confirmed the presence of a conjugated ketonic function. The pmr spectrum showed a signal at 6- 6. 5 ppm indicative of vinylic hydrogen. All attempts to isolate the components of this oil were unsuccessful. Some speculation can be made about the composition of the oil, however. The allylic alcohol (7) almost certainly was one of the products and probably represented the major component. The free amine, 4-bromo-3-phenyltropidine may have been another component Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 57 for the product mixture caused a skin irritation comparable to that «p produced by mustard-like compounds. It was more difficult to postulate as to the identity of the carbonyl containing constituent. Two possibilities considered for the structure of this compound are presented below. One (a) could result from the air oxidation of the ally'lic alcohol. No explanation can be given for the other product (b) at the present time (if it were the right assignment). Other possibilities were that the carbonyl constituent comes from an impurity in the ally lie bromide hydro bromide (31). Such a possibility would be a bromohydrin in which the bromine and hydroxyl were not in a trans-diaxial relationship. These compounds are known to produce ketones when they were reacted with base. ^ However, the intensity of the absorption in the infrared spectrum indicated that it cannot be an impurity in only trace amounts. An elemental analysis, it seemed, would have to vary from theoretical by a considerable amount if this amount of product were to come from an impurity (especially if the impurity were a dibromo or hydroxybromo derivative). a b Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 58 Hydroboration of 3-Aryltropidines (3) Since 1956 when it was firs t reported that olefins were converted to organo-boranes by reaction with diborane, this process has become important for preparing intermediates in the synthesis of a wide variety of compounds. 64 it was the hydroboration procedure that was considered best for the preparation of the 3-aryl-2-tropanols. Hydro boration was known to proceed through a cis - addition of borane (BHg) to a double bond in an anti-Markownikoff orientation. This would result in a product with the boron bonded to the less substituted carbon. Oxidation of the organo-borane intermediate with basic hydrogen per oxide would yield an alcohol with the hydroxy function in the same stereochemical position as the boron had occupied. A particularly important consideration in reactions using borane was the finding that this reaction was very susceptible to steric influ ences. The reaction had also been found to be sensitive to electronic effects but to a lesser extent than to steric effects. The steric and electronic effects are demonstrated in a general manner by the examples that are given below. 9H3 Ph 3 9 H3 ch3ch2-c=ch2 CH3-C=CHCH3 T \ 1% 99% 2% 98% 2% 98% Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 59 Hydroboration was used as a means of producing the four isomeric 2- and 3-tropanols. ^ Previously these alcohols had been prepared by the reductions of the corresponding 2- and 3-tropa- nones. ^ The synthetic route to the 2-tropanols was difficult due op to the problem in preparing 2-tropanone. The hydroboration- oxidation procedure allowed all of these alcohols to be synthesized from tropidine (25). R R It was obvious in the hydroboration of tropidine (25) that the preferred addition was from the alpha side of the molecule for 93% of the product corresponded to alpha tropanols. This was opposite to the direction of approach from that of other reagents on reaction with tropane derivatives. 33,34 Thus the reduction of tropinone (_!) by chemical reagents usually occurred from the beta sid e ^j 33, 66^ but the direction of addition of the reducing agent was reversed when the quaternary salt of the amine was used as the substrate. ^3 The reactions which gave products resulting from approach of the reagent from the alpha side were assumed to be directed by interference of the nitrogen substituent to attack of the reactant from the beta side. Thus, the only reaction pathway available was from the alpha side. In the case of tropidine (25) the immediate formation of the amine- borane required that the -BH3 or -CH3 be in an axial orientation on the nitrogen relative to the piperidine ring and interfere with reaction at the double bond from the alpha side. Such amine-boranes were shown to be intermediates by isolation if only one equivalent of borane fib was used. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 60 Considering these steric influences it was, therefore, expected that the hydroboration of 3-phenyltropidine (15) would give the alpha isomer of the 2-tropanol. With styrene systems it had been shown that the aromatic ring could help stabilize the transition state with the boron at the benzylic position even though this might be the more sub stituted carbon. This electron effect is illustrated by the results summarized below. 9 H3 C—CH 'CH— CH t t tr . 100% 85% 15% C H = C H f CH t t 20% 80% C=:CH / h 3c \ 72% (isolated) CH=CH0 CH =CH9 CH—CH9 t t ^ T t t 9% 91% 18% 82% 35% 65% Examination of all the previously reported results suggested that the major product from the hydroboration of 3-aryltropidines (3) would be the 3-aryl-2- a -tropano'l with some 3-aryltropine as a by product. The results of the hydroboration-oxidation of 3-phenyl tropidine (15), 3-p-chlorophenyltropidine (17), and 3-p-anisyltropidine (19) agreed with this speculation. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 61 The major product in each of the hydroborations was the 3-aryl- 2- a-tropanol. The integrations of the pmr spectra of the hydrobora tion products were examined carefully and it was found that the inte gration of the signal assigned to the C-2 hydrogen corresponded to less than one proton. This suggested that a second product was present. Thin layer chromatographic analysis of the products from the hydro boration of the three 3-aryltropidines showed a contaminant in each. The two products from the reaction mixture were never completely separated. The second, minor product was identified by isolation by column chromatography for the case of the hydroboration of 3-phenyl tropidine (15). The later fractions of the chromatography contained only the second product in small amounts. Comparisons of this product with an authentic sample of 3-phenyltropine (9) by infrared spectroscopy, mixture melting point, and thin layer chromatography, allowed assignment of its structure. These data were consistent with as assignment of 3-phenyltropine (9) as the minor product. It was assumed that this isomer was also the minor product in each of the other hydroboration reactions. Quantitative analysis of the isolated mixture of the two tropanols from the hydroboration of each of the 3-aryltropidines was of limited accuracy. An estimate of the ratio of the two products could be made by analysis of the integration of the pmr spectra. The intensity of the signal for the four aromatic protons provided a value for the total amount of tropanols and comparison with the signal for the single Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 62 carbinol or hydroxy lie proton of the 2- tropanols provided an estimate of the composition of the mixture. The trend in the ratio of the 2- a- tropanol to the 3-tropano'l in the isolated products was sim ilar to that observed for the p-substituted styrenes (see p. 60), but the substituent effect was not as pronounced as in these systems. Hydroboration of 3-p-anisyltropidine (19) gave a product that contained about 80% of the 2- a -isom er (34); 3-phenyltropidine (15) produced about 75% of the 2- a -isom er (32); and 3-p-chlorophenyltropidine (17) gave closer to 70% of the 2- a -isomer (33). The pmr spectra are found in Figures B-22 - B-24, Appendix. The major product from the hydroboration of 3-phenyltropidine (15) was identified as 3-phenyl-2- a_tropanol by infrared and pmr spectroscopy. High-dilution infrared spectra (10"^ M) showed no evidence for intramolecular hydrogen bonding thus requiring that the hydroxylic function be in the alpha configuration. Proton magnetic resonance spectra showed signals which were consistent with a beta configuration for the proton at the 2-position. These signals for 3- phenyl-2- a-tropanol (32) occurred as a pair of doublets at 3. 79 ppm. The coupling constant for the carbinol proton at the 2-position with the axial proton at C-3 was 10 Hz, and the carbinol proton showed a second, smaller coupling of 3 Hz with the bridgehead proton. By consideration of the Karp'lus^ correlations these coupling constants corresponded to an assignment of the 2-proton as axial and the hydroxyl function alpha or equatorial. The pmr spectrum for the Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 63 3-p-chloropheny'l-2- a -tropanol (33) showed a sim ilar pattern with a coupling of the axial protons at C-2 and C-3 of 10 Hz and a smaller coupling of 4 Hz for the 2-proton with the bridgehead hydrogen. The resonance signal for the 2-hydrogen in the p-anisyl derivative (34) was obscured by the signal of the methyl of the methoxyl substituent and, therefore, could not be analyzed as were the others. It is probable that the reaction proceeded by the same stereochemical course with all the compounds. Attempted Oxidations of 3-Phenyl-2- a -Tropanol (32) 3-Aryl-2-tropanones would provide interesting intermediates for the synthesis of 3-aryl-2-substituted-2-tropanols, 3-aryl- 3 -2- tropanols, and 3-aryl-3-substituted-2-tropanones. These derivatives would be of interest for conformational studies as well as being potential pharmaceutical agents. It seemed that a useful synthesis of these tropanones would be by the oxidation of the 3-aryl-2- a - tropanols. Several attempts to cause the oxidation of 3-phenyl-2- a - tropanol (32), however, were unsuccessful. The starting alcohol (32) was recovered unchanged in substantial yields when subjected to such oxidizing conditions as Jones' reagent, potassium dichromate in con centrated sulfuric acid using acetone, water, or ether as the solvent, and t-butylhypochlorite. This striking resistance to oxidation has been observed in other tropane systems. Attempts to oxidize 2- 3 -tropanol^, tropan-6- 3 - ol®®, and 6- 3 - hy dr oxy tro p in one 1^ were also unsuccessful. Compar ison with cyclohexanols, however, leads to the prediction that 2- 3 - Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. tropanols should be oxidized more readily than 2- a -isomers. Cyclohexanols having axial hydroxyl groups are oxidized 3-6 times faster than the equatorial isomers. ^ The inert nature of 3-phenyl-2- a - tropanol (32) probably re sulted from a combination of factors. The hydroxyl group is shielded from reaction with t-butylhypochlorite or to form an ester with chromic acid by the adjacent phenyl substituent. Therefore, the formation of an intermediate necessary to achieve oxidation may be inhibited. The carbinol hydrogen is also hindered from easy reaction by being in the axial conformation and since the nitrogen is probably complexed with the oxidizing agent it is further shielded from reaction. Preparation of 3-Aryl-2- g-tropanyi Acetates The primary objective in the preparation of the tropanols was to prepare derivatives that would be screened for pharmacological activity. It has been found that esters provide excellent derivatives of alcohols for screening since these derivatives often exhibit greater activity. Thus the preparation of esters of the 3-aryl-2- a-tropanols was attem pted. The greatest psychotomimetic activity of amino alcohols is ex hibited by the benzylic acid esters. These are usually prepared by an alcoho'lysis reaction of methyl benzilate with the anion of the amino alcohol. With the 3-ary'l-2- a -tropanols the anion was prepared by reaction of the amino alcohol with sodium hydride in hexane or diglyme. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 65 The oxygen of the alcohol of the 2- a -tropanols, however, was too hindered for approach of the carbonyl of the methyl benzilate and trans-esterification was not achieved. The propionates of the 4-aryl-4-piperihinols are the active esters of the analgesic series. Therefore, the preparations of the acetates and propionates of the 3-aryl-2- a-tropanols were attempted by reac tion of the alcohols with the acid halides and anhydrides. These reac tions also failed, probably due to the steric crowding of the alcohol. A convenient method for the preparation of the acetates was by 7? the treatment of the 3-aryl-2- a-tropanol with ketene. This reac tion was carried out by passing freshly generated ketene, prepared by the thermal decomposition of acetone, through an ether solution of the amino alcohol. An acid-base work-up of the reaction solution produced the 3-aryl-2- a-tropanyl acetates in crude yields of approximately 75%. The structures of the acetates were confirmed by elemental analysis and were consistent with the infrared and pmr spectra. The pmr spectrum of 3-p-anisyl-2- a -tropanyl acetate (37) also helped to confirm the structure of the alcohol (34). In the pmr spectrum of 3-p- anisyl-2- a-tropanol (34) the signal for the carbinol proton was under that for the methoxyl absorption and, therefore, accurate coupling values could not be determined. The formation of the acetate shifted the signal for the carbinol proton to lower field and showed a double doublet with a large coupling of 10 Hz and a smaller coupling of 4 Hz Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 66 which was consistent with an assignment of an axial carbinol proton. D erne thy lation Reactions of Tropane Compounds Demethylation of the tropane molecule was studied with cyanogen bromide and phenylchloroformate. The reaction could serve as a method for substituting groups other than methyl on the nitrogen. Changes in the pharmacological properties and the stereochemical preferences of groups other then methyl in the ammonium salts could then be investigated. The study also provided an opportunity for evaluating the cleavage reactions with cyanogen bromide (von Braun reaction"^) and with phenylchloroformate. Both methods were successful in removing the methyl group. 1) The Reaction of 3-Phenyltropine (9) with Cyanogen Bromide no The von Braun cyanogen bromide reaction' ° has shown general applicability with almost any tertiary amine. The reaction of cyanogen bromide with a tertiary amine proceeds to yield an alkyl bromide and a disubstituted cyanamide. Tropane^ and cocaine^ are reported to undergo reaction with cyanogen bromide predominantly to give de methylation. The ethyl ester of anhydroecgonine, however, did not demethylate on reaction with cyanogen bromide because extensive ring cleavage occurred. ^5 This difference in reactivity was due to the presence of the unsaturation which made the bridgehead position allylic and susceptible to reaction. The reaction of 3-phenyltropine (9) with cyanogen bromide in benzene proceeded to give two products. The major product (51%) was the result of the expected demethylation, N-cyano-3-phenylnor- Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 67 tropine (38). The minor product (9%) resulted from ring opening at the bridgehead carbon to yield l-phenyl-3-bromo-6-(N-cyanomethyl- amino)-cyc’loheptanol (39). The reaction proceeded to give the best yields when a solution of the amine in benzene was added all at once to a solution of cyanogen bromide in benzene. This seemed to de crease the amount of 3-phenyltropine methylbromide that resulted from the reaction of the methyl bromide liberated by the demethylation process with 9. Both compounds (38) and (39) gave infrared absorptions at 2200 cm'^- which confirmed the incorporation of the cyano group into the molecule (see Figures A 20 and A 22, Appendix). The pmr spectra were also consistent with structures 38 and 39 (see Figures B 34 and B 35, Appendix). The mass spectrum of N-cyano-3-phenylnortropine (38) gave a molecular ion peak at m/e = 210 which probably resulted from loss of water in the inlet system. Another peak (m/e =181, 30. 7%) was most likely the N-cyano-4-phenylpyridinium ion which could result by loss of the ethano bridge and two hydrogens from the molecular ion fragment. The major fragment (m/e = 170, 100%) has not been identified. (A possibility may be the radical-ion formed by the loss of CN£ from the molecular ion peak. This would eventually lead to the phenyltropylium ion which is indicated by a peak of 5. 5% at m/e = 167). The mass spectrum of 1-phenyl-3-bromo-6-(N-cyanomethyl- amino)-cycloheptanol (39) was more complex and has not been charac Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 68 terized. The molecular ion peak (m/e =224, 2. 0%) presumably re sulted from the loss of hydrogen bromide and water from the starting alcohol in the inlet system. Loss of HgCNCN from this fragment could give the fragment at m/e = 169 which corresponds to a 99. 4% peak. Other peaks at m/e = 94, 100% and m/e = 96, 91. 2% have not been assigned. Graphical representations of these mass spectra are found in figures C-9 and C-10, Appendix. 2) The Reaction of 3-Phenyltropidine (15) with Phenylchloro fo rm a te The reaction of tertiary methyl amines with phenylchloroformate has been shown to be a convenient method for the demethylation of amines. This reaction has been reported to give a 66% yield of demethylated tropane and 90% of nortropinone. Reaction of phenylchloroformate with 3-pheny'ltropidine (15) in dry methylene chloride resulted in a 39% yield of N-carbophenoxy-3- phenylnortropidine (40). The structure was confirmed by elemental analysis and by infrared and pmr spectroscopy. The pmr spectrum showed the disappearance of the N-methyl signal that was present in the tropidine and the appearance of signals corresponding to five protons in the aromatic region. The infrared spectrum had a strong carbonyl absorption at 1715 cm“l. There was no evidence for a second product of ring cleavage being formed. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 69 EXPERIMENTAL G eneral Melting Points. Melting points were determined using a Mel- temp apparatus and are uncorrected. Infrared Absorption Spectra. The infrared spectra were deter mined using a Perkin-Elmer Model 137B Infracord spectrophotometer equipped with sodium chloride optics or a Perkin-Elm er Model 337 grating infrared spectrophotometer. The spectra of liquids were determined as film s and the spectra of solids were run as double m ulls in Halocarbon oil from 4000 cm- -*- to 1350 cm"-*- and in Nujol from 1350 cm- -*- to 650 cm'*-. The spectra reproduced in the Appendix were all determined using the Perkin-Elm er Model 137B except for Figure A -3 which was determined with the Perkin-Elm er Model 337. Ultraviolet Absorption Spectra. The ultraviolet absorption spectra were determined using a Cary Model 15 recording spectro photometer. Nuclear Magnetic Resonance Spectra. The nuclear magnetic resonance spectra were determined using a Varian Model A-60 Spectrom eter. The chemical shift data are reported as s values in ppm from TMS. The solvent and standard used are reported with the other analytical data for each compound in the experimental section. The integrations were determined by dividing the total integration by the Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 70 theoretical number of protons and each absorption region was then determined using this calculated value for a proton. A ll protons gave values within 0. 2 of theoretical. Mass Spectra. The mass spectra were determined using a Perkin-Elmer RMU-6E Direct Inlet Mass Spectrometer. The intens ities are reported relative to the .more intense base peak, which is given a value of 100%. Elemental Analysis. Elemental analyses were determined by W eiler and Strauss Microanalytical Laboratories, Oxford, England; by M-H-W Laboratories, Garden City, Michigan; or with an F and M Model 180 carbon, hydrogen, and nitrogen analyzer. The m icro analyses determined by W eiler and Strauss are indicated by ANALYSES (WS); those determined by M-H-W by ANALYSES (MHW); and those determined using the F and M are indicated by ANALYSES (FM). Preparation of 3-Phenyltropine (9) The reaction of tropinone (1) with phenyllithium following the procedure of Cope and D'Addieco’^® gave a 76% yield of 3-phenyltropine (9), mp 158-161°, which after recrystallization from hexane melted at 161-162°. ANALYSIS (W S): Calcd fo r C14H NO: C, 77. 36; H, 8. 82; N, 6.45. Found: C, 77. 07; H, 8.69; N, 6.19. UV SPECTRUM: a ?_tOH a 0Q p. ) 236.5 (1.75), 242.1 (1.92). 1"‘~ 1 ' 1 Illctii. 247. 3 (2. 07), 251. 3 (2. 25), 257. 5 (2. 31), 260. 2 sh (2.17), 263. 6 (2.18) and 266. 8 nm (1. 96). IR SPECTRUM : See Figure A -l, Appendix. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 71 NMR SPECTRUM: See Figure B-l, Appendix: (TMS, DCC13) 7 .1 0 -7 . 70 (m , 5H); 3.19 (um, 2H); 2. 48 (s, 1H); 2. 23 (s, 3H) and 1. 55- 2 .6 2 ppm (u, 8H). Dehydration of 3-Phenyltropine (9) A mixture of 22. 58 g (0.104 mole) of 3-phenyltropine (9) and 90 m l of 40% hydrobromic acid in a 250 m l beaker was heated on a hot plate until all of the solid had dissolved. The beaker was removed from the heat and the solution was allowed to cool to room temperature. The crystals that formed overnight were removed by filtration, and dried under reduced pressure in a vacuum desiccator to give a nearly quantitative yield (29.19 g, 0.104 mole) of 3-phenyltropidine hydro bromide (20), mp 135-141°. Recrystallization from isopropano'l raised the melting point to 179-181°. ANALYSIS (WS): Calcd for C14H18BrN: C, 60. 00; H, 6. 49; N, 5.00. Found: C, 60.22; H, 6. 28;* N, 5.31. Preparation of 3-Phenyltropidine (15) A solution of 6. 85 g (0. 024 mole) of crude 3-phenyltropidine hydro bromide (20) in water was treated with potassium carbonate until it was saturated. The mixture was extracted with several portions of ether and the combined ether extracts were dried over anhydrous potassium carbo nate. Removal of the ether by distillation yielded 3. 68 g (0. 018 mole) of liquid amine (75%). The amine (15) was further purified by distillation and the fraction bp 150-151° (10 mm) was collected. Derivatives of _15 were the methiodide, mp 256-257. 5° (lit. mp 260-261°)^, Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 72 hydrochloride, mp 231-233° (lit. mp 230-233°)^, picrate, mp 151- 1 ?A0, and the methy'lbromide, mp 273-277°. UV SPECTRUM: A hex^e q e) 249.1 (4. 09) and 291 nm max * (2.90). IR SPECTRUM: See Figure A 2, Appendix. NMR SPECTRUM: See Figure B 2, Appendix: (TMS, neat) 7. 09 (m , 5H); 5.99 (d, 1H, J = 5. 4 Hz); 3. 07 (urn, 2H); 2.14 (s, 3H) and 1.19-2. 80 ppm (u, 6H). MASS SPECTRUM: See Figure C 2, Appendix. Purification of the Isomers of 3-Phenyltropidine Hydrobromide (20) a) a -3-Phenyltropidine Hydrobromide (20a): The crude reaction product from the dehydration of 3-phenyltropine (9) consisted of only the cc-isomer (20a). This was purified by dissolving it in absolute ethanol at room temperature and cooling the solution in a Dry Ice- acetone bath for several hours. The precipitate was collected by filtration to give pure a-3-phenyltropidine hydrobromide (20a), mp 179. 5-181°. ANALYSIS (F M ): Calcd fo r C14H 18B rN : C, 60. 00; H, 6.49; N, 5.00. Found: C, 60.01; H, 6.31; N, 5.03. UV SPECTRUM: x Et0H (log e ) 216.2 (4.01), 247.9 (4.11) ------max and 290. 3 nm (2. 39). IR SPECTRUM: See Figure A 3, Appendix. NMR SPECTRUM: See Figure B 3, Appendix: (TMSPSA, D20) 7.48 (s, 5H); 6. 48 (d, 1H, J= 6Hz); 4.29 (urn, 2H); 3.02 (s, 3H) and 1.48-3.72 ppm (u, 6H). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 73 MASS SPECTRUM: See Figure C 4, Appendix. b) B-3-Phenyltropidine Hydrobromide (20b): A solution of 11.15 g (0. 056 mole) of 3-phenyltropidine (15) in 100 ml of anhydrous ether was treated with 100 m l of anhydrous ether that had been satura ted with anhydrous hydrogen bromide. The solid that formed was removed by filtration and anhydrous hydrogen bromide was bubbled into the filtrate until precipitation was complete. The combined solids yielded 14. 9 g (0. 053 m ole, 94. 6%) of 3 -3 -p h e n yltro p id in e h yd ro bromide (20b) that was virtually free of the a - isomer (20a) as indi cated by nmr analysis. Recrystallization by dissolving some of this salt in absolute ethanol at room temperature and cooling the solution in a Dry Ice-acetone bath produced an analytical sample of 20b, mp 180-182°. ANALYSIS (F M ): Calcd fo r C14H18B rN : C, 60. 00; H, 6.49; N, 5.00. Found: C, 60.19; H, 6.69; N, 5.06. UV SPECTRUM: X EtOH (log e ) 216. 2 (4. 07), 247.1 (4. 17) and 290. 0 nm (2. 40). IR SPECTRUM: See Figure A 3, Appendix. NMR SPECTRUM: See Figure B 4, Appendix: (TMSPSA, D20) 7. 57 (s, 5H); 6. 30 (d, 1H, J = 6 Hz); 4. 31 (urn, 2H); 2. 96 (s, 3H) and 1. 52-3. 39 ppm (u, 7H). MASS SPECTRUM : See F ig u re C 3, Appendix. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 74 c) Mixture of a- and b-3-Phenyltropidine Hydrobromides (20a and 20b): A mixture of the two isomers (20a and 20b) was ob tained by recrysta'llization of either of the pure a - (20a) or g - (20b) isomers from isopropanol, mp 179-181°. A typical mixture obtained in this manner contained 53% of 20a and 47% of 20b as calcu lated by nuclear magnetic resonance analysis. ANALYSIS (FM): Calcd for C ^H ^B rN : C, 60.00; H, 6. 49; N, 5.00. Found: C, 60.25; H, 6.21; N, 5.15. UV SPECTRUM: A EtOH (log e ) 216. 2 (3. 97), 247. 9 (4. 02), r iX leLX and 290. 2 nm (2. 22). IR SPECTRUM: The infrared spectrum showed essentially a combination of the absorptions of the (20a) and (20b) isomers, (see Figure C 3, Appendix). NMR SPECTRUM: See Figure B 5, Appendix: (TMSPSA, DsO) 7.48 (s); [6.48 (d, J = 5. 7 Hz), 6. 30 (d, J = 5.9 Hz), A6 =11.2 HzJ ; 4. 39 (urn); [3. 03 (s), 2. 93 (s), as = 6. 2 Hz ] and 1. 55-3. 72 ppm (u). It was determined by pmr analysis that heating a deuterium oxide solution of ether pure isomer in steam or boiling water produced an approximately 50:50 equilibrium mixture of isomers. MASS SPECTRUM: See Figure C 1, Appendix. Conversion of the 3-Phenyl tropidine Hydrobromide Isomers (20a and 20b) to the Free Amine (15) The amine salt was dissolved in water and the solution was satur ated with potassium carbonate. The resulting mixture was extracted Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 75 with three portions of ether. The combined ether extracts were dried over anhydrous potassium carbonate. Removal of the ether and volatile im purities by heating under reduced pressure on a rotary evaporator yielded the liquid amine. Infrared and nuclear magnetic resonance spectra of all three samples of amine showed them to be identical. The results were as follows : Isomer g used (moles) yield _15 g (moles) percent yield alpha (20a) 6. 85 (0. 024) 3. 68 (0. 018) 75 beta (20b) 0. 907 (0. 0032) 0. 557 (0. 0029) 90 mixture (20) 1. 216 (0. 0043) 0. 685 (0. 0034) 79 Evidence for Exchange of the Ammonium Proton in 3-Phenyltropidine Hydrobromides (20a and 20b) A solution of a small amount of the a -isomer of 3-phenyltro pidine hydrobromide (20a) in deuterium oxide was allowed to evaporate to dryness on a watch glass. The solid residue was ground to a powder and washed with a few drops of cold acetone. An infrared spectrum (see Figure A 3, Appendix) showed that some exchange of deuterium for hydrogen had taken place. The evidence for this was the appearance of new absorption bands at 2000 cm“ ^ which were not present in the starting sample. An equivalent decrease in absorption was observed + -i in the N-H absorption region (2550 cm ). The same procedure was followed for a sample of the g -isomer (20b). The results in this case were sim ilar but a significantly greater amount of exchange was observed (Figure A -3, Appendix). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 76 If a sample of the mixture of isomers was heated in 40% hydro- bromic acid and recrystallization allowed, the product which was recovered in only about 50% yield was the low field ( a ) isomer (20a). »■ Since 20a was known to recrystallize from 40% hydrobromic acid (as evidenced by this being the only product from the dehydration of 3- phenyltropine (9) in this medium), this suggested there was no inversion of the nitrogen. Further evidence for this was found in nuclear magnetic resonance studies. If a solution of one of the pure isomers in deuterium oxide was saturated with anhydrous hydrogen bromide and heated in a boiling water bath for several minutes to 0. 5 hr, no equilibration to the other isomer occurred as evidenced by the fact that only a single methyl signal and one doublet for the vinylic proton were observed. However, some exchange of deuterium for the vinylic proton was indicated by a decreased in the strength of the signal for this proton. Attempted Resolution of 3-Phenyltropidine (15) A solution of 0. 95 g (0. 0048 mole) of 3-phenyltropidine (15) and 2. 33 g (0. 0096 m ole) of d -10-cam phor sulfonic acid in 15 m l of 95% ethanol was placed in a 25 ml flask equipped with a magnetic stirrer and a condenser. The reaction mixture was heated under reflux for 48 hrs. After concentrating the reaction mixture to a thick oil, it was dissolved in water and the solution was made basic with potassium carbonate. The organic layer that separated was dissolved in ether and the aqueous layer was extracted three times with 15 ml portions Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 77 of ether. The combined ether extracts were dried over anhydrous magnesium sulfate. Removal of the ether gave 0. 63 g (66%) of material, the infrared spectrum of which was identical with that of the starting amine (15). Crude rotation measurements using a Franz Schmidt and Haensch polarimeter were made on a solution that was approximately 0. 49 g of 3-phenyltropidine (15) in 5 ml of ethanol, or 9. 80 g per 100 m l of solution. Polarimeter readings Solvent readings (with sample) 0 .8 0 ° 0. 50° 0.80 0. 53 0. 79 0. 64 0.82 0. 63 0. 77 0. 53 avg 0. 56° 0.77 0. 76 0. 75 avg 0. 79° A crude ORD curve was also run and an increase in the rotation was observed with a decrease in wavelength. Preparation and Reactions of 4-Brom o-3-phenyl tropidine Hydrobromide (29) The Reaction of a-3-Phenyltropidine Hydrobromide (20a) with Bromine in Water A solution of 4. 43 g (0. 0158 mole) of crude a -3-phenyltropidine hydrobromide (20a) in 100 ml of water was placed in a 250 ml flask equipped with a stirring bar and an addition funnel. A solution of 2. 55 g of bromine and 2. 44 g of sodium bromide in 100 m l of water was added dropwise over a period of one hour. The solution was concen- Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 78 trated under reduced pressure until a precipitate began to form. The crystals (4.28 g, 0.0119 mole, 75%), mp 207. 5-209°, were collected and recrystallized from ethanol and water to give an analytical sample of 4-bromo-3-phenyltropidine hydrobromide (31), mp 213-215°d. ANALYSIS (W S): Calcd fo r C ^ H ^ B r g N : C, 46. 82; H, 4. 78; N, 3.90. Found: C, 47. 08; H, 4.73; N, 4.02. UV SPECTRUM: AEt0H (log e) 245. 9 nm (3. 99). ------max IR SPECTRUM: See Figure A-4, Appendix. NMR SPECTRUM: See Figure E -6, Appendix: (TMSPSA, DsO) 7. 55 (m, 5H); 6. 48 (d, J = 6 Hz, 1H); 5. 62 (d, J = 1. 5 Hz, 1H); 4. 51 (um, 2H); 3.08 (s, 3H); and 1.78-3.23 ppm (u, 4H). After concentrating the mother liquor to about 25 m l and cooling the solution, an additional amount of white solid (0. 36 g) was collected. This solid on heating underwent a transition from white to yellow and back to white at 179-182° and then melted at 200. 5-203° with decompo sition. Structural identification was not completed. The compound probably contained an hydroxyl group for the infrared spectrum showed absorption in the 3200-3300 cm"^ region. IR SPECTRUM: (halocarbon, nujol) 3251, m; 1500, w; 1490, m; 1455, m; 1430, m; 1375, s; 854, m ; 778, s; and 695 cm “ ^, s. The Reaction of p -3-Phenyltropidine Hydrobromide (20b) with Bromine in Water A solution of 3. 67 g (0. 013 mole) of 3 -3-phenyltropidine hydro bromide (20b) in 100 m l of water was placed in a 250 m l flask equipped with a magnetic stirring bar and an addition funnel. A solution of 2.1 g Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 79 of brom ine and 1. 60 g of sodium brom ide in 100 m l of w a te r was added dropwise over a period of 45 minutes. A small amount of sodium bi sulfite was added at this time to help bring the small amount of orange tar that had formed into solution. The mixture was stirred until everything had dissolved. The reaction mixture was then concentrated to about 60 m l and cooled in an ice bath. The white crystalline solid, mp 216. 5-219°d, was collected and weighed 3. 27 g (0. 0091 mole, 70%). This compound was shown to be 4-bromo-3-phenyltropidine hydrobromide (31) by comparison of an infrared spectrum with an authentic sample. The solution that remained was evaporated to dryness and water (10 ml) was added to dissolve the inorganic salts. The oily substance that remained was crystallized by rubbing it on a porous plate to yield 0. 66 g of crude 31, mp 199°d. Bromination of 3-Phenyltropidine Hydrobromide (20) in Glacial Acetic A cid A solution containing 14. 87 g (0. 053 mole) of 3-phenyltropidine hydrobromide (20) in 750 m l of glacial acetic acid was placed in a 2-1- three-necked flask equipped with a stirre r and an addition funnel. A solution of 8. 80 g (0. 055 mole) of bromine in 100 ml of glacial acetic acid was added over a period of one hour. The reaction solution was stirred at room temperature for an additional four hours. The glacial acetic acid was removed under reduced pressure at 45-55°. The red oil that remained was crystallized by adding acetone that had been freshly distilled from potassium permanganate and potassium carbonate. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 80 This produced 14. 47 g (75. 5%) of 4-bromo-3-phenyltropidine hydro bromide (31), mp 215. 5-216°. This sample was shown to be 31 by comparison of its infrared and ultraviolet spectra with those of an authentic sample. Two reactions were run on this product to show that it was not the dibromo derivative. A solution of 2. 97 g of 29 in 10 ml of glacial acetic acid was heated over steam for 45 min. After removal of the acetic acid and the addition of acetone to effect crystallization unchanged starting material 31 was obtained. This material was heated with 10 ml of water with stirring at reflux for one hour. Isolation of the salt again showed that it remained unchanged. If the product of the reaction of 20 with bromine in glacial acetic acid had been the dibromide, these reac tions should have effected the loss of H B r^ to produce 31 and the dis placement of bromide by hydroxyl^ to produce the bromohydrin (4) respectively (see Discussion, p. 52 ). The Reaction of 3-Phenyltropidine Hydrobromide (20) with N-Bromo- succinimide A suspension of 4.17 g of N-bromosuecinimide in 10 ml of water was added to a solution of 6. 38 g (0. 023 mole) of 3-phenyltropidine hydrobromide (20) in 25 ml of water. An orange oil immediately separated. Chloroform (15ml) was added and after three hours the water layer was separated. The organic layer was washed with water. The combined water layers were washed with ether and the water was rem oved under reduced pressure to y ie ld 3. 22 g (0. 0089 m ole, 38%) of 4-bromo-3-phenyltropidine hydrobromide (31). This product was Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 81 identical to the product from the other bromination reactions. The Reaction of 4-Bromo-3-phenyltropidine Hydrobromide (31) with Sodium Hydroxide When a sample of 4-bromo-3-phenyltropidine hydrobromide (31) was treated with sodium hydroxide in water an oil separated. This oil was extracted into ether and the ether solution dried over anhydrous potassium carbonate. Removal of the ether left an oil that was not fully characterized. However, the following data are available: 1) Infrared analysis showed the presence of both hydroxyl and carbonyl (1670 cm"-'-) functions. 2) An ultraviolet spectrum indicated a possible phenone-type structure. It was impossible to obtain a quantitative ultraviolet spectrum since no constituent of the product was ever isolated in pure form; however, absorption maxima did appear at 314, 280 and 243 nm. 3) The pmr spectrum showed signals in the vinylic absorption region (6- 6. 5 ppm). 4) Vapor phase chromatographic analysis of the oil indicated that there were at least four components. 5) Some of the crude oil was dissolved in methanol and added to a saturated solution of 2,4-dinitrophenylhydrazine in 2 _N hydro chloric acid. After recrystallization of the product from methanol a red-orange derivative, mp 135-140, was recovered. The discussion of some possible structural assignments for the products of this reaction are given on page 57. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 82 The Reaction of 4-Bromo-3-phenyltropidine Hydrobromide (31) with Sodium Cyanide A solution of 1. 01 g (0. 0028 mole) of 4-bromo-3-phenyltropidine hydrobromide (31) in 30 ml of ethanol was heated to 60° to keep the solid salt in solution. A solution of 0. 42 g (0. 0096 mole) of sodium cyanide in 50 m l of ethanol was added and the reaction mixture was maintained in a hood at 60-65° for three hours. The solvent was re moved under reduced pressure. The solid that remained was washed with three 25 m l portions of ether and these combined ether portions were dried over anhydrous magnesium sulfate. Removal of the ether afforded 0. 64 g of a brown oil. The oil showed two weak cyano ab sorptions (about 2500 cm"^) in the infrared spectrum. A Beilstein test for the presence of halogen was negative. Attempts to prepare derivatives, such as the hydrobromide salt, resulted in oils as products. The Preparation of 3-Aryltropines (2) The Preparation of 3-p-Tolyltropine (10) A 500 ml three-necked flask was equipped with a mechanical stirrer, a condenser fitted with a drying tube, and a pressure- equalizing addition funnel fitted with a gas inlet. The apparatus was flame dried and flushed with nitrogen. A solution of 18. 29 g (0.107 mole) of p-bromotoluene in 75 m l of anhydrous ether was added drop- wise over a period of one hour to a mixture of 1. 53 g (0. 220 mole) of lithium wire in 75 ml of anhydrous ether. The reaction mixture was Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 83 then heated under reflux for an additional 1. 5 hrs. After allowing the flask and its contents to cool to room temperature, a solution of 6.17 g (0. 044 mole) of tropinone (1) in 70 ml of anhydrous ether was added over 0. 5 hr and the reaction mixture was heated under reflux for 2 hr. The reaction flask was cooled in an ice-water bath and 70 m l of 5% hydrochloric acid were added. Concentrated hydrochloric acid was then added until the solution was acidic. The reaction mixture was stirred at room temperature until all the excess lithium was des troyed. The ether layer was decanted and extracted with three 50 ml portions of 5% hydrochloric acid. These extracts were combined with the aqueous reaction solution and were washed with two portions of ether. This aqueous acidic solution was then saturated with potassium carbonate and extracted with three 100 ml portions of ether. The combined ether extracts were dried over anhydrous magnesium sulfate. Removal of the ether gave 7. 49 g of crude product. This was boiled with 50 ml of hexane, cooled in an ice bath, and recollected by filtra tion to yield 5. 70 g (0. 025 mole, 56. 8%) of 3-p-tolyltropine (10), mp 163-164. 5°. An analytical sample, mp 168. 5-170°, was prepared by recrystallization from benzene. ANALYSIS (F M ): Calcd fo r C15H 21N O : C, 77. 85; H, 9.17; N, 6.06. Found: C, 77.77; H, 9.61; N, 6.00. IR SPECTRUM: See Figure A -5, Appendix. NMR SPECTRUM: See Figure B-7, Appendix: (TMS, DCClg) 7.26 (q, 4H); 3.17 (urn, 2H); 2.30 (s, 3H); 2.23 (s, 3H); and 1. 50-2. 58 ppm (u, 9H including 0-H at 2. 47 ppm). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 84 The Preparation of 3-p-Chlorophenyltropine (11) An apparatus sim ilar to the one used for the preparation of 10 was flame dried and flushed with nitrogen. A solution of 30. 66 g (0.149 mole) of p-bromoch'lorobenzene in 250 ml of anhydrous ether was added over ten minutes to a solution of 140 ml of a 1. 6 IT solution of n-butyl- lith iu m ^ in hexane and 100 ml of anhydrous ether. The reaction solu tion was stirred at reflux temperature for an additional 0. 5 hr. After cooling the reaction to room temperature a solution of 20. 67 g (0.149 mole) of tropin one (1) in 200 m l of anhydrous ether was added over 0. 5 hr. The reaction mixture was stirred and heated under reflux for 3 hrs. After cooling to room temperature, 100 ml of ice water were added over 1 hr with vigorous stirring with stirring continued at room temperature for 2 hr. The solid that had separated was re moved by filtration, washed with several portions of cold hexane and dried to yield 27. 35 g of 3-p-chlorophenyltropine (11), mp 191-196°. The ether layer was decanted and the water layer was extracted several times with ether. The combined ether portions were washed with two 50 m l portions of water and then dried over anhydrous potassium carbonate. Removal of the ether followed by washing the solid with cold hexane gave 6. 05 g more of 3-p-chlorophenyltropine (11), mp 192-195°. The total product, 33. 40 g (0.133 mole), corres ponds to an 89. 2% y ie ld of 11. An analytical sam ple of 11, mp 194- 195. 5°, was prepared by recrystallization from benzene. ANALYSIS (FM): Calcd for C14H18NC10: C, 66. 78; H, 7. 22; N, 5.56. Found: C, 67.20; H, 7.42; N, 5.69. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 85 NMR SPECTRUM: See Figure B -8, Appendix: (TMSPSA, D20 /H 2S04) 7. 42 (q, 4H); 3. 95 (um, 2H); 2. 80 (s, 3H); and 1. 84-3. 01 ppm (u, 8H). The Preparation of 3-p-Trifluoromethylphenyltropine (12) An apparatus sim ilar to the one used for the preparation of 10 was flame dried and flushed with nitrogen. A solution of 9. 00 g (0. 040 mole) of p-bromo-a, a, a-benzotrifluoride in 50 ml of anhydrous ether was added to a solution of 25 m l of 1. 6 N_ n-butyllithium in hexane^® in 50 m l of anhydrous ether and the reaction solution was refluxed for 20 minutes. The reaction mixture immediately became a bright yellow and turned to an orange color. The reaction mixture was cooled to room temperature and a solution of 5. 08 g (0. 040 mole) of tropinone (1) in 60 ml of anhydrous ether was added over 10 min and then heated under reflux for an additional hour. After cooling the reaction mixture to room temperature, 30 ml of water were added followed by stirring for 1 hr at room temperature. The solid that formed was removed by filtration and dried to yield 7. 57 g of crude product. The ether solution was separated from the water and the water layer was extracted several times with ether. The combined ether portions were washed with water and then dried over anhydrous potassium carbonate. Removal of the ether gave 2.13 g more of crude product. The combined products were washed in boiling hexane and after cooling the mixture, the solid was removed by filtration to yield 8.19 g (0. 029 mole) (72. 5%) of 3-p-trifluoromethylphenyltropine Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 86 (12), mp 216. 5-219°. Recrystallization from benzene produced an a n a lytica l sam ple of 12, m p 217. 5-219. 5 . ANALYSIS (FM): Calcd for C^H^FgNO : C, 63.14; H, 6.37; N, 4.91. Found: C, 63.36; H, 6. 42; N, 4.95. IR SPECTRUM : See F ig ure A - 7, Appendix. NMR SPECTRUM: See Figrre B-9, Appendix: (TMSPSA, D20/H 2S04) 7. 80 (q, 4H); 4.12 (urn, 2H); 3. 02 (s, 3H); and 1. 85-3.19 ppm (u, 8H). The Preparation of 3-p-Anisyltropine (13) and 3-(2-Methoxy-5-bromo- ph enyl)-tro pine (14) A flame dried apparatus consisting of a 500 ml three-necked flask equipped with a mechanical stirrer, a condenser fitted with a drying tube, and a pressure-equalizing addition funnel connected with a nitrogen inlet was flushed with dried nitrogen. A solution of 25 ml of 1. 6 M n-butyllithium (0. 040 moles) in hexane ^ and 25 m l of an hydrous ether was placed in the flask which was cooled in an ice bath. A solution of 7. 48 g (0. 040 mole) of p-bromoanisole in 50 m l of anhy drous ether was added and then the reaction mixture was heated under reflux for 20 min. After cooling the reaction mixture to room tempera tu re , a solution of 5. 08 g (0. 036 m ole) of tropinone (1) in 60 m l of anhydrous ether was added and the reaction mixture was heated under reflux for 1. 5 hr. Again the reaction mixture was cooled to room temperature and 30 m l of water were added with stirring continued for an additional 0. 5 hr. The white precipitate was removed by filtration Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 87 and dried to yield 3. 85 g of crude product. The combined ether layer and two ether extractions of the water layer were dried over anhydrous potassium carbonate. Removal of the ether gave 5. 69 g more of crude product. The combined products were boiled in 100 ml of hexane. After cooling, the solid that remained was removed by filtration to yield 4. 81 g (0. 019 mole, 53.4%) of 3-p-anisyltropine (13), mp 156. 5- 159°. An analytical sample of _13, mp 158. 5-161°, was prepared by recrystallization from benzene. ANALYSIS (FM ): Calcd for C15H21NO2: C, 72. 83; H, 8. 57; N , 5.66. Found: C, 72. 30; H, 8. 50; N, 5.71. IR SPECTRUM : See F ig u re A - 8, Appendix. NMR SPECTRUM: See Figure B -10, Appendix: (TMS, DCCI3) 7.16 (q, 4H); 3. 78 (s, 3H); 3.19 (urn, 2H); 2. 28 (s, 3H); and 1. 55-2. 59 ppm (u, 9H). When the hexane wash was left standing overnight, 0. 85 g of crystals, mp 154-158°, formed. Recrystallization of these from isopropanol-water produced an analytical sample of 3-(2-methoxy-5- bromophenyR-tropine (14), mp 162-164°. ANALYSIS (F M ): Calcd fo r C i5H 20BrN O 2 : C, 55. 21; H, 6.19; N, 4.29. Found: C, 55.26; H, 6.07; N, 4.35. IR SPECTRUM: See Figure A -9, Appendix. NMR SPECTRUM: See Figure B -11, Appendix: (TMS, DCCI3) 7. 49 (d, J2> 4= 2. 5 Hz); 7. 29 (dd, 1H, J4j 5 = 8. 5 Hz, J4j 2 = 2. 5 Hz); 6. 73 (d, 1H, J5>4 = 8. 5 Hz); A<5 4> 5 calcd = 13. 9 Hz3?; 3. 83 (s, 3H); 3. 20 (um, 2H); 2. 33 (s, 3H); and 1. 69-2. 83 ppm (u, 9H). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 88 Preparation of 3-Aryltropidlnes The following procedure was used for the preparation of all of the 3-aryTtropidines. A mixture of the 3-aryltropine and 40% hydro- bromic acid (approximately 5 ml of acid per gram of amine) was heated in a beaker until all of the solid had dissolved. After allowing the reaction mixture to stand at room temperature overnight it was made alkaline with potassium carbonate. The amine was isolated by extracting the resulting mixture with several portions of ether and the combined ether extracts were dried over anhydrous potassium carbonate. Removal of the ether under reduced pressure on a steam bath gave the product. The Preparation of 3-p-To'lyltropidine (16) The reaction of 3. 09 g (0. 013 mole) of 3-p-tolyltropine (10) with 13 m l of 40% hydrobromic acid produced 2. 66 g (0. 012 mole, 93%) of 3-p-to'lyltropidine (16), mp 52. 5-54°. ANALYSIS (FM): Calcd for C15HigN: C, 84.44; H, 9.00; N, 6.57. Found: C, 84.61; H, 8.87; N, 6.63. IR SPECTRUM: See Figure A -10, Appendix. NMR SPECTRUM: See Figure B-12, Appendix: (TMS, DCClg) 7.15 (q, 4H); 6.17 (d, 1H, J = 6 Hz); 3. 36 (um, 2H); 2.35 (s, 3H); 2.28 (s, 3H); and 1.42-3.07 ppm (u, 6H). MASS SPEC TR U M : See F ig u re C -5, Appendix. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 89 The Preparation of 3-p-Chlorophenyltropidine (17) Dehydration of 2. 05 g (0. 0081 mole) of 3-p-chlorophenyltropine (11) with 10 ml of 40% hydrobromic acid produced, after recrystalliza tion from hexane, 1. 65 g (0. 0071 mole, 87. 7%) of 3-p-chlorophenyl- tropidine (17), mp 95-97. 5°. An analytical sample, mp 97. 5-100°, was prepared by recrystallization from heptane. ANALYSIS (FM ): Calcd for C i4H16C'lN: C, 71. 93; H, 6. 91; N, 5.99. Found: C, 71.94; H, 6.86; N, 6.06. IR SPECTRUM: See Figure A -ll, Appendix. NMR SPECTRUM: See Figure B -13, Appendix: (TMS, DCClg) 7. 24 (s, 4H); 6. 20 (d, 1H, J= 5. 5 Hz); 3. 36 (urn, 2H); 2. 36 (s, 3H); and 1. 42-3. 07 ppm (u, 6H). MASS SPEC TR U M : See F ig u re C -7, Appendix. The Preparation of 3-p-TrifIuoromethy'lphenyltropidine (18) The reaction of 1. 62 g (0. 0057 mole) of 3-p-trifluoromethylphenyl- tropine (12) with 7 m l of 40% hydrobromic acid produced 1. 38 g (0. 0051 mole, 89.5%) of 3-p-trifluoromethylphenyltropidine (18), mp 73-76°. Recrystallization from hexane produced an analytical sample of 18, m p 74-76°. ANALYSIS (F M ): Calcd fo r C i5H 16F 3N: C, 67. 39; H, 6. 05; N, 5.24. Found: C, 67. 76; H, 5.96; N, 5.32. IR SPECTRUM: See Figure A -12, Appendix. NMR SPECTRUM: See Figure B-14, Appendix: (TMS, DCC13) 7. 51 (s, 4H); 6. 37 (d, 1H, J = 5. 5 Hz); 3. 43 (urn, 2H); 2. 41 (s, 3H); and 1. 42-3.15 ppm (u, 6H). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 90 MASS SPECTRUM: See Figure C-8, Appendix. The Preparation of 3-p-An.isy'ltropidine (19) Dehydration of 1. 44 g (0.0058 mole) of 3-p-anisyltropine (13) in 6 m l of 40% hydrobromic acid produced 1. 20 g (0.0052 mole, 89. 6%) of crude 3-p-anisyltropidine (19), mp 77. 5-81°. An analytical sample, mp 85-87°, was produced by recrystallization from hexane. The sample for the mass spectrum was purified on a Florisil column using chloroform as the eluent. ANALYSIS (F M ): Calcd fo r C15H19N O : C, 78. 55; H, 8. 37; N , 6.11. Found: C, 78. 45; H, 8. 40; N, 6.18. IR SPECTRUM : See F ig u re A - 13, Appendix. NMR SPECTRUM: See Figure B-15, Appendix: (TMS, DCClg) 7. 05 (q, 4H); 6.12 (d, 1H, J = 6 Hz); 3. 71 (s, 3H); 3. 34 (urn, 2H); 2.37 (s, 3H); and 1.37-3.06 ppm (u, 6H). MASS SPECTRUM: See Figure C-6, Appendix. Preparation of 3-Aryltropidine Hydrobromides The 3-aryltropidine hydrobromides were prepared by dissolving the 3-aryltropidine in anhydrous ether and adding a solution of anhy drous hydrogen bromide in anhydrous ether until precipitation was complete. The crude salts were dried under reduced pressure in a vacuum desiccator. Analytical samples were prepared by recrystal lization from isopropanol. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 91 3-p-Tolyltropidine Hydrobromide (21) The crude salt (21) from the above procedure had a melting point of 207-209° and after recrystallization from isopropanol melted at 207. 5-208. 5°. ANALYSIS (FM): Calcd for C15H2oBrN: C, 61. 22; H, 6. 86; N, 4.76. Found: C, 61. 24; H, 6. 88; N, 5.01. UV SPECTRUM: X EtOH (ioa e ) 218. 7 (3. 98); 253. 4 (4.18); ------max and 292. 8 nm (2. 61). NMR SPECTRA: See Figures B-16 and B-17, Appendix: (TMSPSA DgO) Sample B-16 was formed by precipitation from ether and shows a predominance of the higher field isomer (it was at times possible to prepare this isomer in nearly pure form if much care was taken in keeping the reaction conditions anhydrous). Sample B-17 is the result of heating a sample such as B-16 in a steam bath. Assignments are made from Spectrum B-17: 7.15 (m, 4H); [ 6. 45 (d, J = 6 Hz), 6.23 (d, J = 6 Hz), 1H, A6 = 11. 5 Hz] ; 4. 30 (urn, 2H); [3. 02 (s), 2. 93 (s), A6 = 5. 9 Hz, 3H] ; [2. 37 (s), 2. 32 (s), A6 =2. 2 Hz, 3H] ; and 1. 70-3. 68 ppm (u, 6H). 3-p-Chloropheny'ltropidine Hydrobromide (22) The crude salt prepared by the reaction of 3-p-chlorophenyltro- pidine (17) with hydrogen bromide in ether melted at 200. 5-202°, and after recrystallization from isopropanol, melted at 203. 5-205°. ANALYSIS (F M ): Calcd fo r C14H 17B rC lN : C, 53. 26; H, 5. 76; N, 4.44. Found: C, 52.96; H, 5.40; N, 4.55. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 92 UV SPECTRUM: X _Et0_H Qocr e ) 2. 21 (4. 20* 218. 6 (3. 98); IT1 SIX 253. 4 (4. 27); 284. 6 (3.14); and 293. 6 nm (2. 60). NMR SPECTRUM: See Figure B-18, Appendix: (TMSPSA, DgO) 7.22-7.63 (m, 4H); [ 6. 50 (d, J= 6 Hz), 6.31 (d, J= 6 Hz), A6 = 11. 5 Hz, 1H ]; 4. 30 (um, 2H); [ 3. 01 (s), 2. 93 (s), A6 = 4. 8 Hz, 3 H ]; and 1. 66-3. 65 ppm (u, 6H). This spectrum showed a predominance of the higher field isomer. A 50:50 mixture can be observed by heating this sample on a steam bath. 3-p-Trifluoromethylphenyltropidine Hydrobromide (23) The crude product, mp 172-174°, from the reaction of 3-p- trifluoromethylphenyltropidine (18) with hydrogen bromide in anhydrous ether was initially an oil which crystallized on drying under reduced pressure in a vacuum desiccator. The analytical sample of 23, mp 183. 5-186. 5, was prepared by recrystallization from isopropano'l. ANALYSIS (FM): Calcd for C i5H17ErF3N: C, 51. 73; H, 4. 93; N, 4.02. Found: C, 51.57; H, 4.85; N, 4.14. UV SPECTRUM: \EtOH q e) 209. 0 (4.06); 215. 5 (3. 85); ------max and 250.1 nm (4.10). NMR SPECTRUM: See Figure B -19, Appendix: (TMSPSA, DsO) 7. 72 (d, 4H, J =3 Hz); [ 6. 70 (d, J = 6 H z), 6. 49 (d, J = 5. 5 Hz), A5 =12 Hz, 1H] ; 4. 50 (um, 2H); [3. 21 (s), 3 .1 0 (s), A6 = 6 .8 H z, 3H] ; and 1. 92-3. 88 ppm (u, 6H). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 93 3-p-Anisyltropidine Hydrobromide (24) The analytical sample of 3-p-anisyltropidine hydrobromide (24) mp 217-219°, was prepared by the above method. ANALYSIS (F M ): Calcd fo r C i5H 2oB rN O : C, 58. 06; H, 6. 51; N, 4.52. Found: C, 57.74; H, 6.62; N, 4.61. UV SPECTRUM: \ EtOH (ion e) 215. 0 (4. 09: 262. 7 (4. 20): max and 299. 0 nm (3. 23). NMR SPECTRUM: See Figure B-20, Appendix: (TMSPSA, DgO) The assignments are given for Figure B-21. Of these four 3-aryltropidine hydrobromides this was the only one that crystallized from the dehydration medium in the same manner as did 3-phenyltropidine hydrobromide (20 a ). A beaker containing 2. 94 g (0. 0119 mole) of 3-p-anisyltropine (13) and 10 ml of 40% hydrobromic acid was heated until all of the amine had dissolved. The beaker was then allowed to stand until crystals had formed (about two days). The crystals were removed by filtration and then dried under reduced pressure in a vacuum desiccator to yield 2. 99 g (0. 0096 mole, 81%) of 3-p-anisyltropidine hydrobromide (24), mp 213. 5-216°. Nuclear magnetic resonance analysis showed this sample to predominate in the opposite isomer to that isolated by forming the hydrobromide in anhydrous ether. It was necessary to warm the solutions of 3-p-anisyltropidine hydrobromide (24) in the nmr tubes in order to achieve solution. This may have caused some equilibration of isomers. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. NMR SPECTRUM: See Figure B-21, Appendix: (TMSPSA, D 2 0 ) 7. 30 (q, 4H ); [6. 42 (d, J = 6 Hz), 6. 25 (d, J = 6 Hz), AS = 11 H z, 1H3; 4. 32 (um, 2H); [3 . 93 (s), 3.90 (s), AS =2 Hz, 3H ]; [ 3. 05 (s), 3. 01 (s), AS = 2. 5 Hz, 3H 3; and 1. 68-3. 76 ppm (u, 6H). Preparation of Cyclic Tertiary Methyl Amine Hydrohalides The Preparation of Tropidine Hydrobromide (26) The procedure of A. Ladenberg^ was followed for the prepara tion of tro pidin e (25). In a 250 m l fla s k , 12 g of acetic acid were added to 25 g of tropine. After cooling the mixture, 46 g of concen trated sulfuric acid were added slowly. The reaction mixture was heated at 160-175° for 7. 5 hr. After cooling the reaction mixture it was diluted with 200 m l of cold water and then a solution of 50 g of sodium hydroxide in 80 ml of water was added slowly with cooling to keep the temperature below 20°. The reaction mixture was ex tracted with several portions of ether totaling 1-1. The combined ether extracts were dried over anhydrous potassium carbonate and the ether was removed to yield a liquid amine product. The product was dissolved in anhydrous ether and treated with anhydrous hydrogen bromide until precipitation was complete. Tropidine hydrobromide (26), 10. 46 g, was collected by filtration. Recrystallization from cyc'lohexanol-hexane followed by washing with ethyl acetate produced an analytical sample of 26, mp 230°d. ANALYSIS (F M ): Calcd fo r C8H 14B rN : C, 47. 07; H, 6. 93; N, 6. 86. Found: C, 47. 39; H, 6.96; N, 6. 88. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 95 NMR SPECTRA: See Figures B-22 and B-23, Appendix: (TMSPSA, DgO) Figure B-22 is the sample produced from the above procedure. Figure B-23 is the equilibrium product. Assignments are made from Figure B-23: 5.96 (um, 2H); 4.12 (um, 2H); [2.97 (s), 2. 90 (s), A<5 = 5 Hz, 3H ]; and 3. 29-1. 74 ppm (u, 6H). The Preparation of 1, 2, 4, 6-Tetramethylpiperidine Hydrobromide (30) F o rm ic acid (13 g of 90%) was added w ith cooling to 12. 7 g (0. 10 mole) of 2,4,6-trimethylpiperidine (29) in a 100 ml flask equipped with a gas exit and a magnetic stirrer. To this solution were added 10 g of a 37% formaldehyde solution (0.12 mole) and the reaction solution was stirred at room temperature overnight (or until gas was no longer evolved). The gas exit was replaced by a condenser and the reaction mixture was heated under reflux on a steam bath for 4 hr. After cooling the solution to room temperature, 11 ml of concentrated hydrochloric acid were added. The excess formaldehyde solution and form ic acid were removed under reduced pressure on a rotary evaporator. The residue was dissolved in water and the amine pro duced upon making the solution basic with 25% sodium hydroxide was isolated by extracting the solution with ether. The ether extracts were dried over anhydrous potassium carbonate followed by removal of the ether to yield an oil. The oil was distilled under aspirator pressure (15 mm) to yield 8. 96 g (0. 64 mole, 64%) of the methylated amine, 1,2,4, 6-tetramethylpiperidine, as the combination of distilla tion fractions: (1), bp 120-130°, 5.16 g; (2), bp 130-140°, 3.10 g; and (3), bp>140°, 0.70 g. The starting material, 2,4, 6-trimethy'l- Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 96 piperidine (29) distilled below 123° under sim ilar conditions. Infrared analysis showed no evidence for any secondary amine in the distilled product. An analytical sample of 1,2, 4, 6-tetramethylpiperidine hydrobromide (30), mp 194-198°, was prepared by treating a solution of the distilled amine in anhydrous ether with a solution of anhydrous hydrogen bromide in anhydrous ether and recrystallization of the solid from ethanol. ANALYSIS (FM): Calcd for CgH20BrN : C, 48. 64; H, 9. 09; N, 6.30. Found: C, 48. 77; H, 9.16; N, 6.51. NMR SPECTRA: See Figures B-24 and B-25, Appendix: (TMSPSA, D20) Figure B-24 is from a sample produced by formation of the salt (30) in anhydrous ether. Figure B-25 is the result of equilibrating the sample by heating it in a steam bath. Assignments are fro m F ig u re B -2 5 : 3. 30 (um, 2H); [2. 87 (s), 2. 60 (s), A6 = 16 Hz, 3H ]; [ 1. 40 (d, J= 6. 5 Hz), 1. 30 (d, J= 6. 5 Hz), A6 = 5. 5 Hz, 6H] ; [ 0. 95 (d, J= 6 Hz), 0. 92 (d, J = 5. 5 Hz), A6 = 2. 3 Hz, 3H] ; and 0. 80-2.16 ppm (u, 5H). The Preparation of 1,2, 6-Trimethylpiperidine Hydrobromide (28) A quantity of cis-2, 6-dimethylpiperidine hydrochloride (27) was prepared and recrystallized twice from methanol to a melting point of 292. 5-295. 5°('lit. mp 286-292°) which corresponds to the melting point of the cis isomer. The hydrochloride (27) was then reconverted to the amine. The Eschwei'ler-Clarke^ reaction was used as in the previous procedure. Formic acid, 51 g of 90%, was added to 22. 3 g (0.19 mole) of the amine. The resulting solution was treated with 41 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 97 g of a 37% formaldehyde solution. The reaction mixture was stirred until gas no longer evolved and was then heated under reflux on a steam bath for 4 hr. After this period 25 g of concentrated hydro chloric acid were added and the solution was evaporated to near dryness. The solid that remained was recrysta'llized from 95% ethanol to yieM 7. 3 g of cis-1, 2, 6-trimethylpiperidine hydrochloride (0. 045 mole, 23.7%), mp 272-274°. This compound was character ized by reconversion to the amine followed by reaction with anhydrous hydrogen bromide. Recrystallization of the solid from 95% ethanol produced an analytical sample of 1, 2, 6-trimethylpiperidine hydro bromide (28), mp 280-281° (lit. ^9 mp 268-269°). ANALYSIS (FM): Calcd for C8H18BrN: C, 46.15; H, 8. 73; N, 6.73. Found: C, 46. 31; H, 8.98; N, 6.91. NMR SPECTRA: See Figures B-26 and B-27, Appendix: (TMSPSA, DgO) Figure B-26 was determined from a sample of 28 produced by the above method. Figure B-27 shows this sample after equilibrium was reached by heating this solution on a steam bath. Assignments are made from Figure B-27: 3. 22 (um, 2H); [2. 88 (s), 2.6 2 (s), A6 =15 Hz, 3H]; [ 1. 39 (d, J = 6. 5 Hz), 1.30 (d, J = 6. 5 Hz), A5 = 5. 5 Hz, 6H]; and 1.18-2.15 ppm (u, 6H). Hydroboration-Oxidation of 3-Ary'ltropidines (3) The following general procedure was employed for the hydrobor ation of 3-phenyltropidine (15), 3-p-chlorophenyltropidine (17), and 3- p-anisyltropidine (jL9). A solution of 1. 0 M BHg (in excess of two equivalents) in tetrahydrofuran was added to a solution of the 3-aryl- Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 98 tropidine (3) in anhydrous tetrahydrofuran in a three-necked flask equipped with a thermometer, a condenser fitted with a drying tube, and a magnetic stirrer. The solutions were stirred at room tempera ture for 4 hr and then were heated under reflux for an additional 4 hr. After the reaction mixture had cooled to room temperature, water was added cautiously until all of the excess borane had been destroyed. The reaction solution was made basic with 6 N_ sodium hydroxide and then 30% hydrogen peroxide was added slowly with care being taken to keep the reaction temperature under 60°. This solution was then heated under reflux for 2 hr. Concentrated hydrochloric acid was added until the reaction solution was acidic and the reaction mixture was heated at reflux for 1 h r.. The reaction mixture was concentrated to dryness under reduced pressure on a rotary evaporator. The solid that remained was dissolved in water and the solution was saturated with potassium carbonate. The alkaline solution was extracted with several portions of ether. The combined ether extracts were dried over anhydrous potassium carbonate. Removal of the ether produced white solids that were immediately recrystal'lized from ethanol/water. Table VII gives the quantitative data on the three 3-aryltropidines that were reacted in this manner. It was difficult to determine the composition of the product from infrared and nuclear magnetic resonance analysis. Thin layer chroma tography on Eastman silica gel plates using chloroform/ethanol (50/50, v/v) as the solvent showed that there were two compounds. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CD CD 120-122 100-102 147. 5-154 75 73 64 6.71 13.45 g g 8 rec. EtOH/H20 % mp + TT r j3 R 8 15 10 8.23 h 2o 2 m l 30% OH 15 m l 6 N NaOH 150 100 10 BHg/hexane m l 1. 0 N HgC TABLE VII: The Hydroboration of 3-Aryltropidines (3) 0.087 250 20 0. 036 0.051 m oles 3 60 100 100 17. 40/ g 3 used/ m l THF 11. 96/ This product represents a mixture of 3-aryl-2 and 3-tropanols. -R -H -OCHg 8 .2 6 / -C l a Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 100 These components were isolated and identified from the hydroboration- oxidation of 3-pheny'ltropidine QJ5) and it was assumed that the same two isomers were formed in the hydroborations in each of the other 3-aryltropidines (17 and 19). The major component of the reaction of (15) was 3-phenyl-2- tropanol (32) which was identified by nmr analysis. The minor constit uent was found to be 3-phenyltropine (9). This (9) was isolated by submitting the reaction mixture to a F lo risil column using 95% ethanol/chloroform (50/50, v/v) as the eluent. The early fractions were a mixture of 9 and _32, but the later fractions contained only 3- phenyltropine (9). It was identified by comparison with an authentic sample by infrared spectroscopy, thin layer chromatography, and mixture melting point. Analytical data for the three hydroboration-oxidation products are given below: 1) 3-Phenyl-2- a -tropanol (32) and 3-Phenyltropine (9) ANALYSIS (F M ): Calcd fo r C 14H 19N O : C, 77. 36; H, 8. 82; N, 6.45. Found: C, 77. 55; H, 9.00; N, 6.30. UV SPECTRUM: X Et0H (log e) 237. 2 (1. 82); 242. 4 (1. 97); m ax 247. 3 (2.12); 251. 9 (2. 24); 257. 7 (2. 32); 260. 4, sh (2. 24); 263. 7 (2. 20); and 267. 4 nm (2. 08). IR SPECTRUM: See Figure A -14, Appendix. NMR SPECTRUM: See Figure B-28, Appendix: (TMS, DCC'lg) 7.00-7. 51 (m, Ar); 4. 84 (s, -OH); 3. 80 (dd, J = 10 Hz, J = 5 Hz, -CH_-OH); 2. 99 (um); and 2. 00 ppm (s, -N-CHg). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 101 2) 3-p-Ch'lorophenyI-2- a -tropanol (33) and 3-p-Clilorophenyl- tropine (11) ANALYSIS (FM ): Calcd far C14H18C1N0: C, 66. 78; H, 7.22; N, 5.56. Found: C, 66.92; H, 7.17; N, 5.58. IR SPECTRUM: See Figure A -15, Appendix. NMR SPECTRUM: See Figure B-29, Appendix: (TMS, DCCig) 7.13-7. 58 (m, -Ar); 3. 96 (s, -OH); 3. 79 (dd, J = 10 Hz, J = 4 Hz, -CH_-OH); 3. 06 (um); and 2.13 ppm (s, -N-CHg). 3) 3-p-Anisyl-2- a -tropanol (34) and 3-p-Anisy'ltropine (13) ANALYSIS (FM): Calcd for C ^H ^N O g: C, 72. 83; H, 8. 57; N, 5.66. Found: C, 72. 81; H, 8. 52; N, 5.57. IR SPECTRUM: See Figure A -16, Appendix. NMR SPECTRUM: See Figure B-30, Appendix: (TMS, DCC1S) 6. 67-7. 33 (m, -Ar); 3. 72 (s, -O-CH3); 3.63 (s, -OH); 3.06 (um); and 2.15 ppm (s, -N-CHg). Attempted Equilibration of 3-Phenyl-2- a -tropanol (30) The method of Bell and Archer^b was Used. A solution of sodium-3-pentoxide was prepared by dissolving 0. 90 g of sodium metal in 1. 5 ml of 3-pentanol in a 10 m l flask equipped with a condenser and a magnetic stirrer. To this solution were added 0. 267 g (0. 00123 mole) of 3-pheny'l-2- a-tropanol (32) in 1. 0 m l of anhydrous toluene and 0. 024 g (0. 000126 mole) of 9-fluorenone (10 mole percent) and the mixture was stirred under reflux for 46 hr. After 20 hr an additional amount of each solvent was added as some solid was Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 102 separating above the surface of the liquid in the flask. After allowing the reaction mixture to cool to room temperature, 1 ml of water was added. The organic layer was separated. The aqueous layer was made basic with potassium carbonate and extracted with ether. The combined organic portions were then dried over anhydrous magnesium sulfate. An ether solution of hydrogen chloride was added to the dried ether solution of product. The precipitate that formed, mp 223-226°, was converted to the amine. Analysis of the amine by infrared spec troscopy and vapor phase chromatography showed it to be identical with the starting material. An infrared spectrum determined in carbon tetrachloride showed no intramolecular hydrogen bonding at high dilution. Attempted Oxidations of 3-Phenyl-2- a-tropanol (32) Several attempts were made to oxidize 3-phenyl-2- a -tropanol (32) with different oxidizing agents. A ll attempts were unsuccessful and starting material was recovered. The oxidizing agents (with % recovery) included Jones reagent (77%), potassium dichromate in concentrated sulfuric acid (90%) with ether or water as solvent, N- bromosuccinimide, and t-butylhypochlorite. Preparation of Acetates of 3-Aryl-2- g-tropanols The same procedure was employed for the preparation of each of the 3-aryl-2- a-tropany'l acetates (35, _36, and 37). The 3-ary'l-2 -a tropanol that had been produced by the hydroboration procedure was dissolved in about 70-100 ml of anhydrous ether and freshly generated Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1 O CO U— c mp (°C) 61-64 88-92 R 36 35 yie ld p u rifie d OCOCHg P u rifie d g B 1. 45b 1. 07d 61b 2 .16d yie ld H3C' B 76 75 crude yield h 2c = c = o a R 1. 1. 82 g B ■OH TABLE VIII: 3-A ryl-2- a -tropanyl Acetates A moles crude yield' 0.0092 0.0106 2. 32 0.0207 4. 50 75 used g A 5.12 2.01 2. 67 33 No. 34 H3C- A purification. Purification and crystallization were achieved by several recrystallizations from petroleum ether (65-75°). -R ~ -H 32 -C l -OCHg a) From the procedure described. b) Calculatedc) by distillation Isolatedd) and characterized These (0. 01 yieldsmm) of areas 1. 50 theg low ofhydrobromide, becausethe crude a considerable product mp to 236. amountyield5-239°. of 1. the20 g productof purified was lost ester in finding(61%). a method of Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 104 ketene was passed through the solution for 2. 5-3 hr. The resulting solution was extracted with three portions of 5% hydrochloric acid. The combined aqueous acidic portions were made basic with potassium carbonate and the amine that separated was removed by extraction of the mixture with ether. After drying the ether extracts over anhy drous potassium carbonate, the ether was removed to yield the crude ester. The crude product was washed with several portions of petroleum ether (65-75°) and the combined washes were dried over anhydrous magnesium sulfate. Removal of the petroleum ether yielded the 3-aryl-2- a-tropanylacetate (crude yield). The esters were purified by distillation or recrystallization. The data are summarized in Table VIII. The analytical data on the 3-a ryl-2- a -tropanylacetates are as follows: 1) 3-Phenyl-2- a-tropanyl Acetate Hydrobromide (35) ANALYSIS (FM): Calcd for C16H22BrN02: C, 56. 47; H, 6.53; N, 4.12. Found: C, 56.38; H, 6.63; N, 4.14. IR SPECTRUM: See Figure A -17, Appendix. NMR SPECTRUM: See Figure B-31, Appendix: (TMSPSA, D20) 7. 42 (u, 5H); 5. 54 (dd, J = 11 Hz, J =4 Hz, 1H); 4.15 (um, 2H); 3. 02 (s, 3H); 1. 90 (s, 3H); and 1. 71-2. 69 ppm (u, 7H). 2) 3-p-Chlorophenyl-2- a -tropanyl Acetate (36) ANALYSIS (FM): Calcd for Cie^oClNOg: C, 65. 40; H, 6. 87; N, 4.77. Found: C, 65.56; H, 6.77; N, 4.66. IR SPECTRUM: See Figure A -18, Appendix. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 105 NMR SPECTRUM: See Figure B-32, Appendix: (TMS, DCCI3) 7.19 (s, 4H); 5. 06 (dd, J = 10 Hz, J= 4 Hz, 1H); 3. 24 (um, 2H); 2.31 (s, 3H); 1.84 (s, 3H); and 1.48-3.90 ppm (u, 7H). 3) 3-p-Anisyl-2- g -tropanyl Acetate (37) ANALYSIS (FM): Calcd for C17H23N03: C, 70. 55; H,- 8.03; N, 4.84. Found: C, 70.56; H, 7.92; N, 4.77. IR SPECTRUM: See Figure A -19, Appendix. NMR SPECTRUM: See Figure E-33, Appendix: (TMS, DCCI3) 6. 95 (q, 4H); 5. 03 (dd, J = 10 Hz, J= 4 Hz, 1H); 3. 71 (s, 3H); 3. 20 (um , 2H); 2. 31 (s, 3H);1. 80 (s, 3H); and 1. 40-2. 86 (u, 7H). Demethylation Reactions of Tropane Compounds The von Braun Cyanogen Bromide Degradation of 3-Phenyitropine (9) A warm ed solution of 13. 32 g (0. 06 m ole) of 3-phenyltropine (9) in 200 m l of anhydrous benzene was added all at once to a solution of 17. 0 g (0. 16 moie) of cyanogen bromide in 150 m i of anhydrous benzene in a 1-1. flask equipped with a magnetic stirrer and a condenser. After an additional 200 ml of anhydrous benzene were added and the reaction solution was heated under reflux with stirring for 4. 5 hr, the reaction mixture was then stirred at room temperature overnight. The solid that formed was removed by filtration and yielded 1. 93 g of 3-phenyl tropine methylbromide, identified by infrared spectroscopy. The filtrate was extracted with three 100 ml portions of 5% sodium hydroxide. The benzene solution was then evaporated to dryness and the solid that Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 106 remained was recrystallized from ethano'l/water. This yielded 11. 62 g of crude product. A second portion of crystals from the recrystalliza tion gave 1. 83 g of another product which gave a positive Beilstein test for halide. Two more recrystallizations from ethanol/water of this second product yielded an analytical sample of l-phenyl-3-bromo-6-(N-cyano- methylamino)-cycloheptanol (39), mp 94-98°. ANALYSIS (F M ): Calcd fo r C15H19B rN 20 : C, 55. 73; H, 5.94; N, 8.67. Found: C, 55. 70; H, 6.05; N, 8.78. IR SPECTBUM: See Figure A-20, Appendix. NMR SPECTRUM: See Figure B-34, Appendix: (TMS, DCClg) 7.36 (u, 5H); 4.28 (um, 1H); 3.39 (s, 1H); 2.73 (s, 3H); and 1.57-3.56 ppm (u, 9H). MASS SPECTRUM: See Figure C-10, Appendix. Recrystallization of the original 11. 62 g of crude product from 95% ethanol yielded 7. 09 g (50. 6%) of N-cyano-3-phenylnortropine (38) and 2. 5 g of a mixture of the two products. An analytical sample of 38, mp 181. 5-184°, was prepared by another recrystallization from 95% ethanol. ANALYSIS (F M ): Calcd fo r C14H 16N20 : C, 73. 64; H, 7. 08; N, 12.27. Found: C, 73.73; H, 7.23; N, 12.42. IR SPECTRUM : See F ig u re A -21, Appendix. NMR SPECTRUM: See Figure B-35, Appendix: (TMS, DCC'lg) 7. 28-7. 68 (um, 5H); 3. 99 (um, 2H); and 1. 68-2. 75 ppm (u, 9H). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 107 MASS SPECTRUM: See Figure C-9, Appendix. Reaction of 3-Phenyltropidine (3J3) with Phenylch'loroformate A solution of 4. 0 g (0. 02 mole) of 3-phenyl tropidine (15) in 10 ml of dry methylene chloride was cooled in an ice bath and a solution of 3. 0 g (0. 019 mole) of phenylchloroformate in 10 ml of dry methylene chloride was added rapidly. The reaction mixture was stirred in the ice bath for 20 min and then overnight at room temperature. The reaction mixture was heated on a steam bath for 1 hr, and then was washed successively with two 10 ml portions each of 4 N sodium hydroxide, 10% hydrochloric acid, and water. The organic portion was dried over anhydrous potassium carbonate. Removal of the solvent yielded 4. 7 g of crude oil which eventually crystallized at room temper ature. Fractional crystallization of the solid from petroleum ether (bp 65-75°) produced 2. 36 g (0. 0077 mole, 39%) of N-carbophenoxy- 3-phenylnortropidine (40), mp 87. 5-90°; an analytical sample melted at 88-89. 5°. ANALYSIS (MHW): Calcd for C20HigNO2: C, 78. 65; H, 6. 38. Found: C, 78.76; H, 6.35. IR SPECTRUM: See Figure A-22, Appendix. NMR SPECTRUM: See Figure B-36, Appendix: (TMS, DCClg) 6. 98-7. 48 (m , 10H); 6. 42 (d, J = 6 Hz, 1H); 4. 68 (um, 2H); 2. 93-3. 45 (u, 1H); and 1. 50-2. 45 ppm (u, 5H). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 108 SUMMARY 1) The reaction of aryllithium reagents with tropinone gave good yields of the 3-aryltropine. Only one isomer was formed in the reaction, presumably because of steric interference to formation of the g - tropanol. 2) Dehydration of 3-aryltropines in 40% hydrobromic acid gave the 3-aryltropidines. The mass spectra of several p-substituted 3- aryltropidines are discussed. 3) Closer examination of the ammonium salts of 3-phenyltropidine showed that they existed as stereoisomeric hydrobromides which could be isolated and characterized as unique compounds. The stability of the isomers in aqueous medium indicated that the rate of nitrogen inversion in conformationally rigid cyclic ammonium salts is slower than the rate of exchange of the ammonium proton. The electronic nature of the p-substituent of the aromatic ring influenced the position of the N-methyl signal in the pmr spectra. The stereochemistry of the salts could not be assigned, however, since analogies with other bicyclic systems were not consistent with behavior of the 3-aryltro pidines. Other parameters such as relative ring current magnitudes in the piperidine and pyrrolidine rings, pi-hydrogen bonding, and electronic nature of the unsaturated system seemed important in determining the chemical shifts of the methyl substituents. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 109 4) Attempts to brominate the double bond of 3-phenyltropidine resulted in aLLylic bromination. Again steric factors seemed to be the determining factor in the reaction. Behavior of this 4-bromo-3-phenyl tropidine on reaction with bases was unexpected as an unidentified ketone was formed on reaction with sodium hydroxide. 5) Hydroboration of the 3-aryltropidines produced a mixture of two products. The major product in each case was the 3-aryl-2- a - tropanol and the minor component was the 3-aryltropine. Electronic effects of the p-substituent of the aromatic ring were only of moderate influence in determining product ratios. 6) Esters of the 3-aryl-2- a- tropanols were readily prepared by reaction with ketene. Other more standard preparations of the esters were unsuccessful. Steric interference to the approach of the acid to the tropanol was suggested as the reason for the resistance to reaction with methylbenzilate, acetic anhydride, and propionic anhydride. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 110 BIBLIOGRAPHY 1. (a) O. Eis'leb and O. Schaumann, Deutsch. Med. Schschr., 65, 967 (1939); (b) O. Eisleb, Ber. Deutsch. Chem. Ges. , B74, 1433 (1941). 2. 0. Schaumann, Arch. Exp. Pathol, u. Pharmako'l. , 196, 109 (1940). 3. J. Hellerbach, O. Schnider, H. Besendorf, and B. 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Archer, ibid. , 80, 6147 (1958); (b) indem., 82, 4642 (1960). 33. H. O. House, H. C. Muller, C. G. Pitt, and P. P. Wickham, J. Org. Chem., 28, 2407 (1963), and references cited therein. 34. W. A. M. Davies, J. B. Jones, and A. R. Pinder, J. Chem. Soc., 3504 (1960). 35. (a) H. Gilman and F. Schulze, J. Am. Chem. Soc., 47, 2002 (1925); (b) H. Gilman and L. L. Heck, ib id ., 52, 4949 (1930). 36. M. S. Kharasch and O. Reinmuth, "Grignard Reactions of Non- Metallic Substances", Prentice-Hall, Inc., New York, 1954, pp. 142 & 156. 37. L. M. Jackman, "Applications of Nuclear Magnetic Resonance Spectroscopy in Organic Chemistry", Pergamon Press, New York, 1959, p. 89. 38. J. A. Pople, W. G. Schneider and H. J. Bernstein, "High-Resolution Nuclear Magnetic Resonance", McGraw-Hill Book Company, Inc. , New Y o rk, 1959, p. 258 ff. 39. J. Hine, "Physical Organic Chemistry", McGraw-Hill Book Company, In c ., New Y o rk , 1962, p. 90. 40. H. Budzikiewicz, C. Djerassi and D. H. Williams, "Structural Elucidation of Natural Products by Mass Spectrometry", Vol. I: Alkaloids, Holden-Day, Inc., San Francisco, 1964, pp. 218-219. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 113 41. H. Budzikiewicz, C. Djerassi and D. H. Williams, "Interpretation of Mass Spectra of Organic Compounds", Holden-Day, Inc. , San Francisco, 1964, pp. 92-97. 42. K. Bieman, "Mass Spectrometry", McGraw-Hill Book Company, In c ., New Y o rk, 1962, p. 87. 43. R. M. Silverstein and G. C. Bass'ler, "Spectrometric Identification of Organic Compounds", John Wiley and Sons, Inc., New York, 1964, p. 15. 44. R. E. Lyle and C. R. Ellefson, J. Am. Chem. Soc. , 89, 4563 (1967). 45. (a) H. E. Simmons and C. H. Park, J. Am. Chem. Soc., 90, 2428 (1968); (b) ibid. , 90, 2429 (1969); (c) ibid. , 90, 2431 (1968). 46. M. R. Bell and S. Archer, J. Am. Chem. Soc. , 82, 4638 (1960). 47. For example, 1-phenylcyclohexene: R. B. Carlin and H. P. Landerl, J. Am. Chem. Soc., _75, 3969 (1953). See also H. M. Hershenson, "Ultraviolet and Visible Absorption Spectra, Indices", Academic Press, Inc., New York, 1956. 48. For a review see F. G. Riddell, "Heterocyclic Conformational Analysis", Quart. Revs., 21, 364 (1967). 49. (a) J. C. N. M a and E. W. W arnoff, Can. J. C hem ., 43, 1849 (1965); (b) G. L. Gloss, J. Am. Chem. Soc., 81, 5456 (1959); (c) D. L. Griffith and J. D. Roberts, ibid. , 87, 4089 (1965). 50. R. W. H orobin, J. McKenna and J. M. McKenna, Tetrahedron S uppi., 7, 35 (1966). 51. Y. Kawazoe, M. Tsuda and M. Ohnishi, Chem. Pharm. Bull. (Tokyo), 15, 51 (1967). 52. (a) J. R. Dyer, "Applications of Absorption Spectroscopy of Organic Compounds", Prentice-Hall, Inc., Englewood Cliffs, N. J. , 1965, p. 82; (b) J. A. Pople, W. G. Schneider and H. J. B ern stein, "High Resolution Nuclear Magnetic Resonance", McGraw-Hill Book Company, Inc., New York, 1959, p. 183. 53. B. Franzus, W. C. Baird, Jr., N. F. Chamberlain, T. Hines and E. I. Snyder, J. Am. Chem. Soc., 90, 3721 (1968). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 114 54. H. O. House, B. A. T e rfe rtil'le r and C. G. P itt, J. O rg. C he m ., 31, 1073 (1966). 55. G. Fodor, J. D. Medina and N. M. Mandava, Chem. Commun. (London), 581 (1968). 56. R. E. Lyle and W. E. Krueger, J. Org. Chem., 32, 3613 (1967). 57. R. E. Lyle and W. E. Krueger, ibid. , 30, 394 (1965). 58. C. J. Schmidle and R. C. Mansfield, J. Am. Chem. Soc., 78, 425 (1956). 59. G. S. Hammond, ibid. , 77, 334 (1955). 60. G. Fodor, J. Toth, P. Dobo, G. Hanzso and I. Vincze, Chem. & Ind. (London), 764 (1956). 61. D. E. Ayer, G. Buchi, P. Reynolds-Warnhoff and D. M. White, J. Am. Chem. Soc., 80, 6146 (1958). 62. "The Merck Index", P. G. Stecher, ed., Merck and Co. , Inc. , Rahway, N. J. , 1960, see M u stard Gas, p. 697 fo r effects. 63. D. Y. Curtin and R. J. Harder, J. Am. Chem. Soc. , 82, 2357 (1960). 64. H. C. Brown, "Hydroboration", W. A. Benjamin, Inc., New York, 1962. 65. C. K. Spicer, Ph. D. Thesis, University of New Hampshire, 1966. 66. R. Mizra, Nature, 170, 630 (1952). 67. M. Karp'lus, J. Chem. Phys., 30, 11 (1959). 68. J. B. Jones and A. R. Pinder, J. Chem. Soc., 615 (1959). 69. J. Meinwald and O. L. Chapman, J. Am. Chem. Soc., 80, 633 (1958). 70. E. L. Elie'l, N. L. Allinger, S. J. Angyal and G. A. Morrison, " Conformational Analysis", Interscience Publishers, New York, 1967, p. 81 ff. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 115 71. (a) S. B. Kadin and J. G. Cannon, J. Org. Chem., 27, 240 (1962); (b) F. P. Doyle, M. D. Mehta, R. Ward, J. Bainbridge and D. M. Brown, J. Med. Chem., 8, 571 (1965). 72. For a review see R. N. Lacy in "Advances in Organic Chemistry, Methods and Results, Vol. IT", R. A. Raphael, E. C. Taylor and H. Wynberg, eds., Interscience Publishers, Inc. , New York, 1960, p. 213. 73. For a review see H. A. Hageman in "Organic Reactions, Vol. VII", R. Adams, ed., John Wiley and Sons, Inc., New York, 1953, p. 198. 74. J. von Braun, B er., 44, 1252 (1911). 75. J. von Braun and E. Muller, B er., 51, 235 (1918). 76. J. D. Hobson and J. G. McCluskey, J. Chem. Soc., 2 015 (1967). 77. A. Ladenburg, Ann. Chem., 217, 74 (1883). 78. H. T. Clarke, H. B. Gillespie and S. Z. Weisshaus, J. Am. Chem. S oc., 55, 4571 (1933). 79. R. Lukes and J. Jizba, Chem. Listy., 46, 622 (1952), cf. C. A ., 47, 9326f (1953). 80. W. E. Krueger, Ph.D. Thesis, University of New Hampshire, 1966. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 116 APPENDIX Page Part A Infrared Spectra ...... 117 Part B NMR Spectra ...... 140 Part C Mass Spectra ...... 176 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 118 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 119 o o ITS O o o CO o o LO t>> CO CO K Q A-3 A-3 3-Phenyltropidine Hydrobromides (20a and 20b) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 120 O LTD CO O O CO 0 LO 01 u -Q O o O 03 o C"3 o CN3LO A-3 A-3 3-Phenyltropidine Hydrobromides (20a and 20b) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 121 WLUli 11 I f f»rt ni! ■•it}'-; t“1:; A -4 4-Bromo-3-phenyltropidine Hydrobromide (31) ! mt * f r ♦ i 1 \ Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1 2 2 A -5 A -5 3-p-Tolyltropine (10) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 123 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 124 : ini;; :i;; i;; ■ r 11 f n n "nr:'; rniiiii ijllijii CM | CCD • ftrH O -<-> ■ I c 0) jg >» CD s O u 0 3 •r-H E-i1 f t I oo c- i <5 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 125 111. ::!! iiHhj!: Hi •••• t:t;r( r : “ : us i " i :!|!t m m - *11 * t ! hit ill: col CCD ' III! • r—I ’! lliiil a 0 u -4-> rH w • cr4 • !! h!! i! < 1 p, I oo COI C Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 126 q - nr,on TinTITr m A -9 A -9 3-(2-Methoxy-5-bromopheny'l)-tropine (14) niimiii) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1- ■ • j i "“ JZ— \ 10 10 3-p-To'lyltropidine (16) A- Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 128 A -11 A -11 3-p-Chlorophenyltropidine (17) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 129 Him !!! !: ■ ii !:! 1; i 21 o f t o 11 i 111! i i i i •; j i‘ :1r ';' i; ■ ■; ',::;•;j;y: ! HMiltn >> c cu ft f t •—>» i ft a P o l-H 0 ililiii ■Hilli!1 _p ' i .... •r"S■H I ! ; 1 i " ' 5-4 1 f t I CO CO 1—I iiiaiiiiiiiiiii I Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. A -13 A -13 3-p-Amsyltropidine (19) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 9 - 131 U v :.u: a -tropanol (32) A - 14 A - 14 3-Phony 1-2- Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 133 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. A-18 A-18 3-p-Ch'lorophenyl-2-a -tropanyl acetate (36) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 136 o cd ei o i c \ CD -*-> cci (D O a >» c kJ a 0 u ■ 1 o e o i o (N) c\ I 1>> m • Cr—i <■ a i CQ o 03T-1 o I 00 < Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 137 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 136 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. - A-22 A-22 N-Carbophenoxy-3-phenylnortropidine (40) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 140 A. a.- n •n 3-Phenyltropine (9) co Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 141 D. m co B-2 B-2 3-Phenyltropidine (15) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 142 Ol O- lO 00 B-3 B-3 a -3-Phenyltropidine Hydrobromide (20.a) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 143 n m o 00 B-4 B-4 f3c-3-Phenyltropidine Hydrobromide (20b) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 144 a. - - and p -3-Pheny'ltropidine Hydrobromide (20a and 20b) oo Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 145 cc 3romo-3-phonyltropicline Hydrobromide (31) ;q i ^ Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 146 B-7 B-7 3-p-Toly'ltropine (10) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 147 Q. ■O 00 B-8 B-8 3-p-Chlorophenyltropine (11) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 148 m CO CO B-9 B-9 3-p-Trifluoromethylphenyltropine (12) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 149 n m -10 -10 3-p-Anisy'ltropine (13) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 150 r> ■o K oo B-ll 3-(2-Methoxy-5-bromophenyl)-tropine (14) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 151 D_' CO -12 3-p-Telyltropidine (16) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 152 CO oo B-13 B-13 3-p-Chlorophenyltropidine (17) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 153 n m CO 00 B-14 B-14 3-p-Trifluoromethylphenyltropidine (18) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 154 «o GO B-15 B-15 3-p-AnisyItropidine (19) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 155 a.' w ■n oo B-16 B-16 3-p-Tolyltropidine Hydrobromide (21) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 156 n w oo B-17 B-17 3-p-Tolyltropidine Hydrobromide (21) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 157 n oo B-18 B-18 3-p-Chlorophenyltropidine Hydrobromide (22) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 158 a . o. m CO to B-19 B-19 3-p-Trifluoromethylphenyltropidine Hydrobromide (23) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 159 Q. 00 B-20 B-20 3-p-Anisy'ltropidine Hydrobromide (24) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 160 Q. IO 00 B-21 B-21 3-p-Anisyltropidine Hydrobromide (24) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 161 w 00 B-22 B-22 Tropidine Hydjobromide (26) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1 6 2 ’ a . n oo B-23 B-23 Tropidine Hydrobromide (26) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 163 0 rc» •i—9 i O •9 r -i >> t- H I—' 0 0 & >> 0 0 cC 0 Eh l CO '0*' cvT c\) t P Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 164 I CM O w -Tetramethy'lpiperidine Hydrobromide (30) 6 B-25 B-25 1, 2, 4, Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 165 la j W ! -26 -26 6-TrimethylpipericUne 2, 1, Hydrobrornide (28) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 166 s w -Trimethylpiper.idine Hydrobromide (28) 6 B-27 B-27 1, 2 , Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 167 n M a -tropanol (32) 00 B-28 B-28 3 -P h e n yl-2- Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 168 U> -29 -29 3-p-ChlorophenyI-2- a -tropano (33) 1 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 169 B. CO B-30 B-30 3-p-AnisyI-2- a -tropanol (34) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 170 a . a.' B-31 B-31 3-Phenyl-2-a -tropanyl acetate Hydrobromide (35) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 171 c.a . .■s m o l Q B-32 B-32 3-p-Chlorophenyl-2-a -tropanyl acetate (36) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 172 to o a -tropanyl acetate (37) 00 B-33 B-33 3-p-Anisy'l-2- Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 173 a. co B-34 B-34 l-Phenyl-3-bromo-6-(N-cyanomethylamino)-cycloheptanol (39) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1 7 4 B-35 B-35 N- Cyano-3-phenylnortropine (38) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1 7 5 CO B-36 B-36 N-Carbophenoxynor-3-phenyltropidine (40) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. without prohibited reproduction Further owner. copyright the of permission with Reproduced C-l a - and P-3-PheAy'ltropidine Hydrobromides (20a and 20b) 176 C-2 3-Pheny'ltropidine (20) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. without prohibited reproduction Further owner. copyright the of permission with Reproduced C-3 p-3-Phenyltropidine Hydrobromide (20b) 7 7 1 C-4 a-3-Phenyltropidine Hydrobromide (20a) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. without prohibited reproduction Further owner. copyright the of permission with Reproduced C-5 3-p-Tolyltropidine (16) o O o o CO 0 0 © ID SI 8 7 1 C-6 3-p-Anisy'ltropidine (19) 1 7 9 3-p-Trifluoromethylphenyltropidine (18) -8 C efs SI Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1 8 0 o CM o cn o o o © col001 0 c o • rf H t o su> > CD f t 1 CO I o o in >> O i £ CDI o o o o o oo U C-10 l-Phenyl-3-bromo-6-(N-cyanomethylamino)-cyc'loheptanol (39) ■ffll ^ Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. BIOGRAPHICAL DATA Name: Charles R. Ellefson Date of Birth: September 14, 1942 Place of Birth: Dawson, Minnesota Secondary Education: Yankton High School Yankton, South Dakota Collegiate Education: Concordia College Moorhead, Minnesota Publications: "The Isolation and Characterization of Two Diastereomeric Ammonium Salts Differing Only ir; Nitrogen Configuration", with R. E. Lyle, J. Am. Chem. Soc. , 89, 4563 (1967). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.