Synthesis and transporter binding properties of 3β-(4'-alkyl-, 4'- alkenyl-, and 4'-alkynylphenyl)nortropane-2β-carboxylic acid methyl esters: Serotonin transporter selective analogs

Article abstract of DOI:10.1021/jm960409s

New methods for the synthesis of 3β-(4'-alkyl-, 4'-alkenyl-, and 4'- alkynylphenyl)nortropane-2β-carboxylic acid methyl esters 2-4, respectively, were developed. These methods involved coupling of the appropriate organometallic reagents to 3β-(4'-iodophen

Full text of DOI:10.1021/jm960409s

J . Med. Chem. 1996, 39, 4027-4035
4027
Syn th esis a n d Tr a n sp or ter Bin d in g P r op er ties of 3â-(4′-Alk yl-, 4′-a lk en yl-, a n d
4′-a lk yn ylp h en yl)n or tr op a n e-2â-ca r boxylic Acid Meth yl Ester s: Ser oton in
Tr a n sp or ter Selective An a logs
Bruce E. Blough,† Philip Abraham,† Anita H. Lewin,† Michael J . Kuhar,‡ J ohn W. Boja,‡ and F. Ivy Carroll*,†
Chemistry and Life Sciences, Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709, and
Neuroscience Branch, National Institute on Drug Abuse (NIDA) Addiction Research Center, P.O. Box 5180,
Baltimore, Maryland 21224
Received J une 10, 1996X
New methods for the synthesis of 3â-(4′-alkyl-, 4′-alkenyl-, and 4′-alkynylphenyl)nortropane-
2â-carboxylic acid methyl esters 2-4, respectively, were developed. These methods involved
coupling of the appropriate organometallic reagents to 3â-(4′-iodophenyl)tropane-2â-carboxylic
acid methyl ester (6a , RTI-55) or to an N-protected derivative of 6a followed by N-demethylation
or removal of the protecting group. Some analogs were prepared by catalytic reduction of the
alkene and alkyne analogs 3 and 4 or by isomerization of the alkenes 3. The analogs 2-4
were evaluated for inhibition of radioligand binding to the serotonin (5-HT), dopamine (DA),
and norepinephrine (NE) transporters. 3â-(4′-Isopropenyl- and 4′-cis-propenylphenyl)nortro-
pane-2â-carboxylic acid methyl esters (3b,d ), which possessed IC50 values of 0.6 and 1.15 nM,
respectively, were the most potent analogs at the 5-HT transporter, and with NE/5-HT IC50
ratios of 240 and 128 nM, respectively, they were selective for the 5-HT relative to the NE
transporter. Since interaction with the serotonin transporter may modulate the pharmacologi-
cal effects resulting from binding to the dopamine transporter, 3â-(4′-isopropenylphenyl)tropane-
2â-carboxylic acid methyl ester (11b) which has good affinity for both the 5-HT and DA
transporters but low affinity at the NE transporter may be useful for studying this interaction.
In order to understand the mechanism related to the
addictive properties of (-)-cocaine (1a ), it was necessary
to identify the molecular site where this drug interacts
to produce its initial physiological effects. (-)-Cocaine
has several sites of action in the central nervous system
inergic activity have been found not to produce reward
or euphoria. However, some evidence suggests that
inhibition of serotonin reuptake modulates the reinforc-
ing properties of cocaine.10,11 If serotonin synapses on
the cell body of dopamine neurons regulate reward
threshold levels, then cocaine inhibition of serotonin
reuptake could enhance or reduce cocaine-induced ef-
fects in the dopamine system. Even though the impor-
tance of the serotonin transporter in mediating the
neurochemical and behavioral actions of cocaine is now
recognized, the biochemical mechanism of action and
regulation of this transporter is not well understood.
The molecular mechanism of action would be better
understood if cocaine analogs which bind selectively to
the serotonin transporter site were available for phar-
macological studies. In a recent study, we reported that
3â-(4′-ethylphenyl)nortropane-2â-carboxylic acid methyl
ester (2a ) showed higher affinity for the serotonin (5-
HT) transporter than for the dopamine (DA) trans-
porter, which suggested that appropriate modification
of 3â-(substituted phenyl)nortropane-2â-carboxylic acid
methyl esters would lead to compounds potent and
selective for the 5-HT transporter.12 In this study, we
describe the synthesis of several 3â-(4′-alkyl-, 4′-alk-
enyl-, and 4′-alkynylphenyl)nortropane-2â-carboxylic
acid methyl esters 2-4, respectively, and report that
some of the compounds possess good selectivity and
potency for the 5-HT transporter. We also report that
one compound shows good affinity for both the 5-HT and
DA transporters but has low affinity for the norepineph-
rine (NE) transporter.
of rodents and nonhuman primates, as well as in human
brain.1-7 Of these, the dopaminergic pathway has been
implicated in the reinforcing properties of (-)-cocaine.8,9
The current view, termed “the dopamine hypothesis”,
is that the behaviors associated with cocaine addiction
result, to a large extent, not from a direct message
elicited by the binding of (-)-cocaine but rather from
the accumulation of dopamine in the synapse and its
action at one or more of the D1-D5 receptors.8 Research
results from many laboratories have supported this
finding and have led to the view that cocaine binds to
specific recognition sites located on the dopamine trans-
porter of mesolimbocortical neurons thereby preventing
(inhibiting) dopamine reuptake into presynaptic neu-
rons.8
Since cocaine also inhibits serotonin reuptake, the
effects of compounds that interact with serotonin recep-
tors have been evaluated for efficacy against behavioral
effects of cocaine. Serotonin agonists lacking dopam-
Ch em istr y
† Research Triangle Institute.
Some of the 2-4 analogs could be prepared via
N-demethylation of the corresponding 3â-(4′-alkyl, 4′-
‡ NIDA Addiction Research Center.
X Abstract published in Advance ACS Abstracts, September 1, 1996.
S0022-2623(96)00409-8 CCC: $12.00 © 1996 American Chemical Society

4028 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Blough et al.
Sch em e 1
alkenyl, and 4′-alkynylphenyl)tropane-2â-carboxylic acid
methyl esters. However, since the preparation of 3â-
(4′-ethylphenyl)tropane-2â-carboxylic acid methyl esters
via the 1,4-addition of 4-substituted phenylmagnesium
halides to anhydroecgonine methyl ester (5) resulted in
low yields,12 we developed an alternative approach to
synthesize these compounds which relies upon the
palladium-catalyzed coupling of organometallic reagents
to 3â-(4′-iodophenyl)tropane-2â-carboxylic acid methyl
ester (6a , RTI-55). Through the use of both Castro-
presence of a catalytic amount of bis(triphenylphos-
phine)palladium(II) chloride afforded the 4′-vinyl analog
11a . A similar reaction performed with isopropenylzinc
chloride, prepared from isopropenyllithium and zinc
chloride, afforded the isopropenyl analog 11b. Surpris-
ingly, attempts to synthesize the olefins by coupling
tributylvinyltin or tributylisopropenyltin and 6a with
bis(triphenylphosphine)palladium(II) chloride or tetra-
kis(triphenylphosphine)palladium catalyst failed. In-
creasing the temperature from 60 to 110 °C caused
decomposition. A coupling reaction was observed with
tetravinyltin and 6a in refluxing toluene with tetrakis-
(triphenylphosphine)palladium as the catalyst. How-
ever, there was extensive decomposition, and the prod-
uct yield was only 6%. The observed decomposition was
unexpected since allyltributyltin had coupled cleanly in
refluxing toluene with little decomposition of 6a . Ap-
parently, either the palladium intermediate was un-
stable or the vinylstannane reagent and heating caused
decomposition of the tropane ring system.
The ethyl, isopropyl, and n-propyl analogs 12a -c
were synthesized by catalytic hydrogenation of 11a ,b
and 8 with palladium on carbon in ethyl acetate under
60 psi of hydrogen (Scheme 1). The 4′-ethyl has also
been prepared in 8% yield by the addition of 4-ethyl-
phenylmagnesium bromide to 5.12
The 3â-(4′-ethyl-, 4′-isopropyl-, 4′-vinyl-, 4′-allyl-, and
4′-ethynylphenyl)nortropane-2â-carboxylic acid methyl
esters (2a ,c, 3a , and 4a ) were prepared by direct
N-demethylation of the N-methyl compounds. Thus,
reaction of 12a ,b, 11a , and 7b with chloroethyl chloro-
formate (ACE-Cl) in refluxing dichloroethane followed
by reaction in refluxing methanol afforded 2a ,c, 3a , and
4a (Scheme 2).
Stevens
and
Stille-type
palladium-catalyzed
couplings,13-15 we were able to synthesize 3â-(4′-alkyl-,
4′-alkenyl-, and 4′-alkynylphenyl)nortropane-2â-carbox-
ylic acid methyl esters 2-4 as outlined in Scheme 1. In
the case of the 3â-(4′-alkynylphenyl)tropane-2â-carboxy-
lic acid methyl ester derivatives, a Castro-Stevens
coupling of a terminal acetylene with 6a was used
(Scheme 1). Thus, reaction of 6a with trimethylsilyl-
acetylene in the presence of a catalytic amount of
copper(I) iodide and bis(triphenylphosphine)palladium(II)
chloride in degassed diisopropylamine produced 7a .
Removal of the silyl protection group with tetrabutyl-
ammonium fluoride in tetrahydrofuran afforded 7b in
98% yield. In a similar fashion, reaction of 6a with
propyne provided 7c in 73% yield.
The 3â-(4′-allylphenyl)tropane-2â-carboxylic acid meth-
yl ester (8) was synthesized via a Stille16 coupling of
allyltributyltin with 6a using tetrakis(triphenylphos-
phine)palladium as catalyst in refluxing toluene (Scheme
1). Isomerization of the double bond of 8 into conjuga-
tion with the aromatic ring occurred upon standing at
room temperature over 6 months, affording (E)-3â-(4′-
propenylphenyl)tropane-2â-carboxylic acid methyl ester
(9). The isomerization may have been assisted by small
amounts of palladium metal contaminant. The Z analog
10 was prepared by partial reduction of 3â-(4′-propyn-
ylphenyl)tropane-2â-carboxylic acid methyl ester (7c)
using Lindlar’s catalyst and a small amount of quino-
line. The resulting double bond was resistant to further
reduction, and no overreduction was observed, even
under 60 psi of hydrogen.
The remaining 3â-(4′-alkenylphenyl)tropane-2â-car-
boxylic acid methyl ester derivatives were prepared by
utilizing a Stille-type coupling between an alkenylzinc
chloride and 6a . Thus, reaction of 6a and vinylzinc
chloride, generated by the addition of zinc chloride to a
solution of vinylmagnesium bromide in THF, in the
Attempts to remove the N-methyl group from 3â-(4′-
isopropenylphenyl)tropane-2â-carboxylic acid methyl
ester (11b) via ACE-Cl resulted in loss of the isopropen-
yl moiety and decomposition. Since the N-demethyla-
tion had failed and since these reactions sometimes
resulted in lower yields than desired, we investigated

Serotonin Transporter Selective Analogs
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 4029
indicate slight DA selectivity.9,20 In recent years,
structure-activity relationship studies of cocaine ana-
logs (6b, WIN 35,065-2) for binding at monoamine
transporters, particularly at the dopamine transporter,
have been explored,21-24 and some structural modifica-
tions that result in selectivity for the dopamine trans-
porter over the norepinephrine and serotonin transport-
ers have been reported.25-27
Sch em e 2
Early reports showed that replacement of the N-
methyl group by hydrogen in 6b, to give 15b (WIN
35,981), resulted in enhanced affinity for binding at the
5-HT and NE transporters with virtually no change in
binding affinity at the DA transporter, leading to
increased selectivity for the 5-HT and NE transporters
over the DA transporter.1,20 An analogous effect was
observed upon replacement of the N-methyl group in
an alternative route using (2,2,2-trichloroethyl)carbam-
ate (Troc)-protected intermediate N-[(2,2,2-trichloro-
ethyl)carbamoyl]-3â-(4′-iodophenyl)nortropane-2â-car-
boxylic acid methyl ester (13) (Scheme 3). Reaction of
6a with N-2,2,2-trichloroethyl chloroformate (Troc-Cl)
in refluxing dichloroethane afforded 13 in 96% yield.
The isopropenyl analog 14a was then synthesized by
reaction of 13 with isopropenylzinc chloride and bis-
(triphenylphosphine)palladium(II) chloride using condi-
tions similar to those used for the preparation of 11a .
The N-(2,2,2-trichloroethyl)carbamoyl group was also
compatible with the Castro-Stevens coupling reactions
forming 14b. The N-(2,2,2-trichloroethyl)carbamoyl
group was removed using either zinc/acetic acid or 10%
lead oxide-cadmium17 in tetrahydrofuran ammonium
acetate providing the 3â-(4′-substituted phenyl)nortro-
pane-2â-carboxylic acid methyl ester analogs 3b and 4b.
Reduction of 4b using either palladium on carbon or
Lindlar’s catalyst afforded 2b and 3d , respectively.
Isomerization of the allyl group in 14c using rhodium
trichloride in refluxing ethanol followed by removal of
the Troc group afforded 3c. Reaction of 3â-(4′-allylphen-
yl)tropane-2â-carboxylic acid methyl ester (8) with Troc-
Cl in refluxing dichloroethane formed 14c in 72% yield.
The N-(2,2,2-trichloroethyl)carbamoyl group was re-
moved with 10% lead oxide-cadmium as outlined
previously producing 3e.
cocaine (1a ) by hydrogen to give norcocaine (1b), but in
this case, while affinity at NE and 5-HT transporters
was enhanced, it was decreased at the DA trans-
porter.1,12,20 In addition, our examination of the potency
of several 3â-(4′-substituted phenyl)tropane-2â-carbox-
ylic acid esters, 6a ,c-e and 12a , relative to their
nortropane analogs revealed that replacement of the
N-methyl group by hydrogen generally enhances selec-
tivity for 5-HT and NE relative to DA transporters.12
In this study, we also found that changing the N-methyl
group of all of the 3â-(4′-alkyl-, 4′-alkenyl-, and 4′-
alkynylphenyl)tropane-2â-carboxylic acid methyl esters
to hydrogen to afford the nortropane analogs resulted
in increased potency at the 5-HT transporter. It is
interesting that 2-carbon 4′-substituent analogs 2a , 3a ,
and 4a have potency for the DA transporter similar to
their N-methyl derivatives 12a , 11a , and 7b.
As noted in the introduction, the 4′-ethyl analog 2a
showed relatively weak binding to the DA transporter
while having reasonable binding to the 5-HT trans-
porter. In this study, we found that changing the 4′-
substituents to alkyl groups larger than ethyl, such as
the propyl and isopropyl analogs 2b,c, respectively,
resulted in lower affinity for the 5-HT transporter. In
contrast, both two- and three-carbon olefin analogs
showed good affinity for the 5-HT transporter. The 4′-
olefinic substituents (3a -d ), which are in conjugation
with the phenyl ring, all showed IC50 values of less than
2.25 nM at the 5-HT transporter. However, even the
4′-allyl analog 3e, with an IC50 value of 6.2 nM, was
more potent than the n-propyl and isopropyl analogs
2b,c, suggesting that some of the reduction in potency
might be due to steric factors. The nortropane analogs
2-4 were more selective for the 5-HT and NE trans-
porters relative to the DA transporter; however, none
of the analogs were highly selective for the 5-HT
transporter relative to the DA transporter. Neverthe-
less, it is interesting to note that the trans- and cis-4′-
propene analogs 3c,d have similar potencies, but the
cis isomer 3d is 3 times more selective relative to the
NE transporter than the trans isomer 3c. Compound
The structural assignments for key compounds 2c,
3a -e, 4a ,b, 7b ,c, 8, 9, 11a ,b, and 12b,c were based
largely on the method of synthesis and elemental and
1H NMR analyses. The chemical shift and coupling
pattern of the C-2 and C-3 protons were consistent with
previously reported compounds12,18 and with â-stereo-
chemistry. All other distinctive NMR resonances for 2c,
3a -e, 4a ,b, 7b,c, 8, 9, 11a ,b, and 12b,c as well as for
intermediates are given in the Experimental Section.
Biologica l Eva lu a tion
Competitive radioligand binding assays were used to
determine the affinities of target compounds. 5-HT, DA,
and NE transporter binding studies were performed as
previously described18 using [3H]paroxetine, [3H]WIN
35,428, and [3H]nisoxetine in frontal cortex, striati, and
midbrain from rats, respectively. The ratio of IC50
values DA/5-HT and NE/5-HT were used as a measure
of the in vitro selectivity of the compounds for the 5-HT
transporter relative to the DA and NE transporters. The
results of the binding studies are summarized in Table
1 along with the data for cocaine and norcocaine (1a ,b)
for comparison.
Resu lts a n d Discu ssion
Cocaine (1a ) is an inhibitor of the neuronal transport
of norepinephrine, dopamine, and serotonin at roughly
similar concentrations.19 Biochemical binding studies

4030 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Blough et al.
Sch em e 3
Ta ble 1. Comparison of Transporter Binding Potencies for 3â-(4′-Alkyl-, 4′-alkenyl-, and 4′-alkynylphenyl)tropane-2â-carboxylic Acid
Methyl Esters and Their Nortropane Analogsa
IC50 (nM)
5-HT
DA
NE
DA/5-HTb
ratio
NE/5-HTb
ratio
RTI no.
compd
X
R
[3H]paroxetine
[3H]WIN 35,428
[3H]nisoxetine
1a (cocaine)
1045 ( 78c
127 ( 13c
28.4 ( 3.8
8.13 ( 0.30
70.4 ( 4.1
26 ( 1.3
191 ( 9.5
15.1 ( 0.97
9.5 ( 0.8
2.25 ( 0.17
3.13 ( 0.16
0.6 ( 0.06
11.4 ( 0.28
1.3 ( 0.1
89 ( 4.8c
206 ( 29c
55 ( 2
49.9 ( 7.3
68.5 ( 7.1
212 ( 17
597 ( 52
310 ( 21
1.24 ( 0.2
1.73 ( 0.05
14.4 ( 0.30
23 ( 0.9
5.29 ( 0.53
28.6 ( 3.1
15 ( 1.2
31.6 ( 2.2
32.8 ( 3.1
56.5 ( 5.6
1.2 ( 0.1
1.24 ( 0.11
2.37 ( 0.2
6.11 ( 0.67
3298 ( 293c
139 ( 9c
0.09
1.6
1.9
6.1
0.97
8.2
3.1
21
0.13
0.77
4.6
38
0.46
22
2.1
28
1.16
9.1
0.27
0.78
0.15
1.93
3.2
1.1
142
15
56
21
1b
12a
2a
12c
2b
12b
2c
11a
3a
11b
3b
9
83
173
282
364
302
330
359
309
283
357
296
368
304
358
301
369
360
305
281
307
C2H5
C2H5
n-C3H7
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
4030 ( 381
122 ( 12
3920 ( 130
532 ( 8.1
75000 ( 5820
ND
n-C3H7
CH(CH3)2
CH(CH3)2
CHdCH2
392
78 ( 4.1
8.2
6.6
425
240
140
42
395
128
87
15
19
13.7
52
37
CHdCH2
14.9 ( 1.18
1330 ( 333
144 ( 12
C(dCH2)CH3
C(dCH2)CH3
t-CHdCHCH3
t-CHdCHCH3
c-CHdCHCH3
c-CHdCHCH3
CH2CHdCH2
CH2CHdCH2
CtCH
1590 ( 93
54 ( 16
3c
10
3d
8
3e
7b
4a
7.09 ( 0.71
1.15 ( 0.1
28.4 ( 2.4
6.2 ( 0.3
2800 ( 300
147 ( 4.3
2480 ( 229
89.7 ( 9.6
83.2 ( 2.8
21.8 ( 1.0
820 ( 46
CH3
H
CH3
H
4.4 ( 0.4
CtCH
CtCCH3
CtCCH3
1.59 ( 0.2
15.7 ( 1.5
3.16 ( 0.33
7c
4b
116 ( 5.1
a
b
Data are mean ( standard error of three or four experiments performed in triplicate. 5-HT/DA and NE/DA are ratios of IC50 values.
c Reference 9.
3b which is isomeric with 3c,d is both more potent and
more selective for the 5-HT transporter relative to the
NE transporter.
In conclusion, we have developed new methods for the
syntheses of 3â-(substituted phenyl)nortropane-2â-car-
boxylic acid methyl esters. These methods involve
coupling of the appropriate organostannane or zinc
reagent with RTI-55 (6a ) or with an N-(2,2,2-trichloro-
ethyl)carbamoyl (Troc) derivative of 6a followed by
N-demethylation or removal of the Troc protecting
group. 3â-(4′-Isopropenyl- and 4′-cis-propenylphenyl)-
nortropane-2â-carboxylic acid methyl esters (3b ,d )
showed the highest potency and selectivity for the 5-HT
transporter. Since, as pointed out in the introduction
section, some reports suggest that inhibition of serotonin
reuptake modulates the reinforcing properties of co-
caine,10 these compounds may be useful for cocaine
abuse studies. In addition, 3â-(4′-isopropenylphenyl)-

Serotonin Transporter Selective Analogs
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 4031
stirred overnight. The mixture turned dark immediately after
the addition of propyne. The vessel was vented, and the
resulting slurry was concentrated under reduced pressure. The
crude oil was diluted with ethyl acetate and a little triethyl-
amine and filtered through a plug of silica gel. The solution
was concentrated under reduced pressure. The crude yellow
oil was purified by column chromatography on silica gel.
Elution with 3:1 ethyl acetate-hexane with an additional 1%
of triethylamine afforded 0.565 g (73% yield) of 3â-(4′-prop-
nylphenyl)tropane-2â-carboxylic acid methyl ester (7c): 1H
NMR (CDCl3) δ 2.01 (s, 3H, CtCCH3), 7.15 (d, 2H, J ) 8.0
Hz, aryl H), 7.28 (d, 2H, J ) 8.0 Hz, aryl H).
tropane-2â-carboxylic acid methyl ester (11b) with IC50
values of 3.13, 14.4, and 1330 nM for 5-HT, DA, and
NE transporters, respectively, may also be a useful
compound for further investigation.
Exp er im en ta l Section
Proton nuclear magnetic resonance (1H NMR) spectra were
recorded on
a 250 MHz (Bruker AM-250) spectrometer.
Chemical shift data for the proton resonances were reported
in parts per million (δ) relative to internal (CH3)4Si (δ 0.0).
Optical rotations were measured on an AutoPol III polarim-
eter, purchased from Rudolf Research. Elemental analyses
were performed by Atlantic Microlab, Norcross, GA. Analyti-
cal thin-layer chromatography (TLC) was carried out on plates
precoated with silica gel GHLF (250 µm thickness). TLC
visualization was accomplished with a UV lamp. Flash column
chromatography was performed as described by Still.28 All
moisture-sensitive reactions were performed under a positive
pressure of nitrogen maintained by a direct line from a
nitrogen source. The pressurized reactions were performed
in a thick-walled pressure tube purchased from ACE glass.
The hydrogenations were performed by attaching a gauge
assembly to the top of the pressure tube and introducing the
hydrogen from a lecture bottle. The gauge assembly was made
to fit the top of the tube by drilling a hole in the Teflon cap
and threading it for a standard gauge assembly.
The free base was converted to the tartrate salt: mp 137-
139 °C; [R]27 -80.98° (c 0.425, MeOH). Anal. (C23H29
-
D
NO8‚0.5H2O) C, H, N.
3â-(4′-Allylp h en yl)tr op a n e-2â-ca r boxylic Acid Meth yl
Ester (8). To a solution of 150 mg (0.389 mmol) of 3â-(4′-
iodophenyl)tropane-2â-carboxylic acid methyl ester (6a ) in 4
mL of dry toluene under a nitrogen atmosphere was added
0.145 mL (0.467 mmol) of allyltributyltin followed by 60 mg
of tetrakis(triphenylphosphine)palladium. The mixture was
heated to reflux for 12 h, until the solution became dark from
the precipitation of palladium(0). The mixture was concen-
trated under reduced pressure. The dark yellow oil was
dissolved in diethyl ether, and the organic layer was extracted
with 1 M aqueous hydrochloric acid (3×). The combined
aqueous layers were basified with saturated aqueous sodium
carbonate and extracted with methylene chloride (5×). The
combined extract was dried over sodium sulfate, filtered, and
concentrated under reduced pressure. The resulting oil was
purified by flash chromatography on silica gel. Elution with
3:1 ethyl acetate-hexane with 1% additional triethylamine
afforded 0.104 g (89% yield) of 3â-(4′-allylphenyl)tropane-2â-
carboxylic acid methyl ester (8): 1H NMR (CDCl3) δ 3.22 (d,
2H, J ) 6.0 Hz, CH2CH), 5.00 (s, 1H, one of CHdCH2), 5.06
(d, 1H J ) 7.2 Hz, one of CHdCH2), 5.85-6.01 (m, 1H
CHdCH2), 7.08 (d, 2H, J ) 7.4 Hz, aryl H), 7.18 (d, 2H, J )
7.7 Hz, aryl H).
Tetrahydrofuran (THF) was distilled just prior to its use
(sodium benzophenone ketyl). Anhydrous methylene chloride,
toluene, and ethyl acetate were purchased from Aldrich
Chemical Co. Triethylamine and diisopropylamine were
distilled from CaH2 and stored.
3â-(4′-Eth yn ylph en yl)tr opan e-2â-car boxylic Acid Meth -
yl Ester (7b). A solution of 1.08 g (0.0028 mol) of 6a in 28
mL of diisopropylamine in an ACE pressure tube was deaer-
ated by bubbling nitrogen through the mixture for 30 min. To
the stirred solution were added 30 mg (0.14 mmol) of copper-
(I) iodide and 196 mg (0.28 mmol) of bis(triphenylphospine)-
palladium(II) chloride followed by 0.40 mL (2.8 mmol) of
trimethylsilylacetylene. The solution became dark quickly and
solidified. Additional diisopropylamine was added, and the
solution was briefly degassed as before. The vessel was sealed
with a Teflon cap, and the mixture was stirred overnight. The
resulting slurry was concentrated under reduced pressure and
then diluted with ethyl acetate and a little triethylamine and
The free base was converted to the tartrate salt: mp 114-
116 °C; [R]27 -87.3° (c 0.77, MeOH). Anal. (C23H33NO8‚
D
0.25H2O) C, H, N.
(E)-3â-(4′-P r op en ylp h en yl)tr op a n e-2â-ca r boxylic Acid
Meth yl Ester (9). A crude sample of 3â-(4′-allylphenyl)-
tropane-2â-carboxylic acid methyl ester (8) was stored neat
on the bench in light. After 6 months, the olefin had
completely isomerized. The crude material was purified by
flash chromatography on silica gel. Elution with 3:1 ethyl
acetate-hexane with 1% additional triethylamine afforded
0.134 g (100% yield) of (E)-3â-(4′-propenylphenyl)tropane-2â-
carboxylic acid methyl ester (9): 1H NMR (CDCl3) δ 1.77 (d,
3H, J ) 6.3 Hz, CHCH3), 6.08 (dq, 1H, J ) 6.2, 15.7 Hz,
CHCH3), 6.27 (d, 1H, J ) 16 Hz, CHdCHCH3), 7.09 (d, 2H, J
) 8.5 Hz, aryl H), 7.15 (d, 2H, J ) 8.4 Hz, aryl H).
filtered through
a plug of silica gel. The solution was
concentrated under reduced pressure.
To the crude acetylene in 20 mL of tetrahydrofuran at 0 °C
was added 3.60 mL (3.60 mmol) of 1.0 M tetrabutylammonium
fluoride in tetrahydrofuran dropwise. The solution was stirred
for 2 h with warming to room temperature. The solution was
diluted with saturated aqueous sodium bicarbonate, and the
aqueous layer was extracted three times with methylene
chloride. The combined extracts were dried over sodium
sulfate, filtered, and concentrated under reduced pressure. The
crude yellow oil was purified by column chromatography on
silica gel. Elution with 3:1 ethyl acetate-hexane with an
additional 1% of triethylamine afforded 0.766 g (98% yield) of
3â-(4′-ethynylphenyl)tropane-2â-carboxylic acid methyl ester
(7b): 1H NMR (CDCl3) δ 2.77 (s, 1H, CtCH), 6.95 (d, 2H, J )
8.3 Hz, aryl H), 7.14 (d, 2H, J ) 8.0 Hz, aryl H).
The free base was converted to the tartrate salt: mp 142
°C dec; [R]27 -96.5° (c 0.920, MeOH). Anal. (C23H31NO8‚
D
0.5H2O) C, H, N.
(Z)-3â-(4′-P r op en ylp h en yl)tr op a n e-2â-ca r boxylic Acid
Meth yl Ester (10). To a solution of 0.171 g of 3â-(4-
propynylphenyl)tropane-2â-carboxylic acid methyl ester (7c)
in 7.0 mL of benzene in an ACE pressure tube was added 1
small drop of quinoline followed by a catalytic amount of
Lindlar’s catalyst. The gauge assembly was fitted on top, and
the tube was pressurized with 60 psi of hydrogen gas. The
slurry was stirred overnight. The tube was vented, and the
slurry was filtered through a plug of Celite to remove the
catalyst. The solution was concentrated under reduced pres-
sure. The resulting oil was purified by flash chromatography
on silica gel. Elution with 3:1 ethyl acetate-hexane with 1%
additional triethylamine afforded 0.080 g (47% yield) of (Z)-
3â-(4′-propenylphenyl)tropane-2â-carboxylic acid methyl es-
ter: 1H NMR (CDCl3) δ 1.89 (d, 3H, J ) 7.2 Hz, CHCH3), 5.73
(dq, 1H, J ) 7.3, 11.6 Hz, CHCH3), 6.37 (d, 1H, J ) 11.5 Hz,
CHdCHCH3), 7.21 (s, 4H, aryl H).
The free base was converted to the tartrate salt: mp 150
°C dec; [R]27 -75.2° (c 0.105, MeOH). Anal. (C22H27NO8‚
D
1.0H2O) C, H, N.
3â-(4′-P r op yn ylp h en yl)t r op a n e-2â-ca r b oxylic Acid
Meth yl Ester (7c). A solution of 1.0 g (0.0026 mol) of 6a in
13.0 mL of triethylamine in an ACE pressure tube was
deaerated by bubbling nitrogen through the mixture for 30
min. To the stirred solution were added a catalytic amount
of copper(I) iodide and bis(triphenylphospine)palladium(II)
chloride. The gauge assembly was fitted on top, and a lecture
bottle of propyne gas was attached via a tygon hose. The
vessel was evacuated via an aspirator followed by introduction
of the propyne gas. This procedure was repeated three times
to ensure total saturation. The apparatus was then pressur-
ized as much as possible (5 psi) with propyne gas, sealed, and
The free base was converted to the tartrate salt: mp 128-
130 °C; [R]27 -101.7° (c 0.120, MeOH). Anal. (C23H31NO8‚
D
1.25H2O) C, H, N.

4032 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Blough et al.
3â-(4′-Vin ylp h en yl)tr op a n e-2â-ca r boxylic Acid Meth yl
Ester (11a ). To a solution of 7.78 mL (7.78 mmol) of 1.0 M
vinylmagnesium bromide in tetrahydrofuran at -78 °C under
a nitrogen atmosphere was added 19.5 mL of dry tetrahydro-
furan followed by 15.5 mL (7.78 mmol) of 0.5 M zinc chloride
in tetrahydrofuran. The mixture was stirred for 15 min; then
1.5 g (3.89 mmol) of 6a in 5 mL of dry tetrahydrofuran was
added dropwise followed by the additon of 90 mg of bis-
(triphenylphosphine)palladium(II) chloride. The mixture was
stirred overnight with warming to room temperature. The
mixture turned dark soon after reaching room temperature.
The mixture was concentrated under reduced pressure. The
dark yellow oil was dissolved in diethyl ether, and the organic
layer was extracted with 1 M aqueous hydrochloric acid (3×).
The combined aqueous layers were basified with saturated
aqueous sodium carbonate and extracted with methylene
chloride (5×). The combined extracts were dried over sodium
sulfate, filtered, and concentrated under reduced pressure. The
resulting oil was purified by flash chromatography on silica
gel. Elution with 3:1 ethyl acetate-hexane with 1% additional
triethylamine afforded 1.05 g (95% yield) of 3â-(4′-vinylphenyl)-
tropane-2â-carboxylic acid methyl ester (11a): 1H NMR (CDCl3)
δ 5.17 (d, 1H, J ) 10.9 Hz, one of CHdCH2), 5.68 (d, 1H, J )
17.6 Hz, one of CHdCH2), 6.66 (dd, 1H, J ) 10.8, 17.6 Hz
CHdCH2), 7.20 (d, 2H, J ) 8.2 Hz, aryl H), 7.31 (d, 2H, J )
8.2 Hz, aryl H).
H). The NMR spectrum was identical with that of an
authentic sample.12
3â-(4′-Isop r op ylp h en yl)t r op a n e-2â-ca r b oxylic Acid
Meth yl Ester (12b). To a solution of 398 mg (1.33 mmol) of
3â-(4′-isopropenylphenyl)tropane-2â-carboxylic acid methyl
ester (11b) in 2.6 mL of ethanol in an ACE pressure tube was
added a catalytic amount of 5% palladium on carbon (fire
hazard). The gauge assembly was fitted on top, and the tube
was pressurized with 60 psi of hydrogen gas. The slurry was
stirred overnight. The tube was vented, and the slurry was
filtered through a plug of Celite to remove the palladium on
carbon. The solution was concentrated under reduced pres-
sure. The pale yellow oil was then dissolved in 2,2′-dimethoxy-
propane, and a small amount of concentrated hydrochloric acid
was added. After stirring overnight, the mixture was dissloved
in diethyl ether and basified with aqueous sodium bicarbonate.
The aqueous layer was extracted with methylene chloride (5×).
The combined extracts were dried over sodium sulfate, filtered,
and concentrated under reduced pressure. The resulting oil
was purified by flash chromatography on silica gel. Elution
with 3:1 ethyl acetate-hexane with 1% additional triethyl-
amine afforded 0.249 g (63% yield) of 3â-(4′-isopropylphenyl)-
tropane-2â-carboxylic acid methyl ester (12b ): 1H NMR
(CDCl3) δ 1.21 (d, 6H, J ) 6.9 Hz, CH(CH3)2), 7.12 (d, 2H, J )
8.4 Hz, aryl H), 7.19 (d, 2H, J ) 8.4 Hz, aryl H).
The free base was converted to the tartrate salt: mp 130-
131 °C; [R]27 -88.1° (c 0.255, MeOH). Anal. (C23H33NO8) C,
D
The free base was converted to the tartrate salt: mp 129-
131 °C; [R]27 -90.1° (c 0.70, MeOH). Anal. (C22H29NO8‚
H, N.
D
3â-(4′-P r op ylp h en yl)tr op a n e-2â-ca r boxylic Acid Meth -
yl Ester (12c). To a solution of 104 mg (0.347 mmol) of 3â-
(4′-allylphenyl)tropane-2â-carboxylic acid methyl ester (8) in
1 mL of ethyl acetate in an ACE pressure tube was added a
catalytic amount of 10% palladium on carbon (fire hazard).
The gauge assembly was fitted on top, and the tube was
pressurized with 60 psi of hydrogen gas. The slurry was
stirred overnight. The tube was vented, and the slurry was
filtered through a plug of Celite to remove the palladium on
carbon. The solution was concentrated under reduced pres-
sure. The pale yellow oil was then dissolved in 2,2′-dimethoxy-
propane, and a small amount of concentrated hydrochloric acid
was added. After stirring overnight, the mixture was dissloved
in diethyl ether and basified with aqueous sodium bicarbonate.
The aqueous layer was extracted with methylene chloride (5×).
The combined extracts were dried over sodium sulfate, filtered,
and concentrated under reduced pressure. The resulting oil
was purified by flash chromatography on silica gel. Elution
with 3:1 ethyl acetate-hexane with 1% additional triethyl-
amine afforded 74 mg (71% yield) of 3â-(4′-propylphenyl)-
tropane-2â-carboxylic acid methyl ester (12c): 1H NMR (CDCl3)
δ 0.90 (t, 3H, J ) 7.2 Hz, CH2CH3), 2.54 (t, 2H, J ) 7.7 Hz,
CH2CH2CH3), 7.07 (d, 2H, J ) 8.1 Hz, aryl H), 7.16 (d, 2H, J
) 8.1 Hz, aryl H).
0.5H2O) C, H, N.
3â-(4′-Isop r op en ylp h en yl)tr op a n e-2â-ca r boxylic Acid
Meth yl Ester (11b). To a solution of 0.292 mL (3.30 mmol)
of 2-bromopropene in 5 mL of dry tetrahydrofuran at -78 °C
under a nitrogen atmosphere was added 2.1 mL (3.30 mmol)
of 1.6 M n-butyllithium in hexane. The mixture was stirred
for 15 min at -78 °C. To this mixture was added 3.30 mL
(3.30 mmol) of 1 M zinc chloride in diethyl ether, and the
mixture was stirred for an additional 30 min at -78 °C. Then
0.423 g (1.10 mmol) of 6a in 5 mL of dry tetrahydrofuran was
added dropwise followed by the additon of 60 mg of bis-
(triphenylphosphine)palladium(II) chloride. The mixture was
stirred overnight with warming to room temperature. The
mixture turned dark soon after reaching room temperature.
The mixture was concentrated under reduced pressure. The
dark yellow oil was dissolved in diethyl ether, and the organic
layer was extracted with 1 M aqueous hydrochloric acid (3×).
The combined aqueous layers were basified with saturated
aqueous sodium carbonate and extracted with methylene
chloride (5×). The combined extracts were dried over sodium
sulfate, filtered, and concentrated under reduced pressure. The
resulting oil was purified by flash chromatography on silica
gel. Elution with 3:1 ethyl acetate-hexane with 1% additional
triethylamine afforded 0.270 g (84% yield) of 3â-(4′-isopropen-
ylphenyl)tropane-2â-carboxylic acid methyl ester (11b): 1H
NMR (CDCl3) δ 2.11 (s, 3H, CH3CdCH2), 5.02 (s, 1H, one of
CdCH2), 5.33 (s, 1H, one of CdCH2), 7.21 (d, 2H, J ) 8.3 Hz,
aryl H), 7.38 (d, 2H, J ) 8.4 Hz, aryl H).
The free base was converted to the tartrate salt: mp 137-
139 °C; [R]27 -80.8° (c 0.50, MeOH). Anal. (C23H33NO8‚
D
1.0H2O) C, H, N.
Gen er a l P r oced u r e for N-Dem eth yla tion : 3â-(4′-Eth -
ylp h en yl)n or t r op a n e-2â-ca r b oxylic Acid Met h yl E st er
(2a ). To a solution of 156 mg (0.543 mmol) of 3â-(4′-ethylphen-
yl)tropane-2â-carboxylic acid methyl ester (12a ) in 1 mL of dry
1,2-dichloroethane under nitrogen at room temperature was
added 0.175 mL (1.63 mmol) of 1-chloroethyl chloroformate
dropwise. The mixture was refluxed overnight. The solution
was then concentrated under reduced pressure and dissolved
in 5 mL of methanol. This solution was refluxed for 4 h and
cooled. The solution was concentrated under reduced pressure,
and then the mixture was dissolved in diethyl ether and
basified with aqueous sodium bicarbonate. The aqueous layer
was extracted with methylene chloride (5×). The combined
extracts were dried over sodium sulfate, filtered, and concen-
trated under reduced pressure. The resulting oil was purified
by flash chromatography on silica gel. Elution with 3:1 ethyl
acetate-hexane with 2% additional methanol and 1% ad-
ditional triethylamine afforded 0.107 g (72% yield) of 3â-(4′-
ethylphenyl)nortropane-2â-carboxylic acid methyl ester (2a ).
The NMR spectrum was identical with that of an authentic
sample.12
The free base was converted to the tartrate salt: mp 86-
88 °C; [R]27 -87.5° (c 0.480, MeOH). Anal. (C23H31
-
D
NO8‚1.0H2O) C, H, N.
3â-(4′-Eth ylp h en yl)tr op a n e-2â-ca r boxylic Acid Meth yl
Ester (12a ). To a solution of 1.05 g (3.68 mmol) of 3â-(4′-
vinylphenyl)tropane-2â-carboxylic acid methyl ester (11a ) in
12.0 mL of ethyl acetate in an ACE pressure tube was added
0.3 g of 10% palladium on carbon (fire hazard). The gauge
assembly was fitted on top, and the tube was pressurized with
60 psi of hydrogen gas. The slurry was stirred overnight. The
tube was vented, and the slurry was filtered through a plug
of Celite to remove the palladium on carbon. The solution was
concentrated under reduced pressure. The resulting oil was
purified by flash chromatography on silica gel. Elution with
3:1 ethyl acetate-hexane with 1% additional triethylamine
afforded 0.857 g (81% yield) of 3â-(4′-ethylphenyl)tropane-2â-
carboxylic acid methyl ester (12a ): 1H NMR (CDCl3) δ 1.13
(t, 3H, J ) 7.6 Hz, CH2CH3), 2.52 (q, 2H, J ) 7.6 Hz, CH2CH3),
7.02 (d, 2H, J ) 8.0 Hz, aryl H), 7.10 (d, 2H, J ) 8.1 Hz, aryl

Serotonin Transporter Selective Analogs
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 4033
3â-(4′-Isop r op ylp h en yl)n or tr op a n e-2â-ca r boxylic Acid
Meth yl Ester (2c). The procedure for 3â-(4′-ethylphenyl)-
nortropane-2â-carboxylic acid methyl ester (2a ) was followed
with 0.350 g (1.2 mmol) of 3â-(4′-isopropylphenyl)tropane-2â-
carboxylic acid methyl ester (12b) and 0.50 mL (4.65 mmol)
of 1-chloroethyl chloroformate affording 0.0931 g (28% yield)
of 3â-(4′-isopropylphenyl)nortropane-2â-carboxylic acid methyl
ester (2c): 1H NMR (CDCl3) δ 1.22 (d, 6H, J ) 6.9 Hz,
CH(CH3)2), 7.12 (s, 4H, aryl H).
A solution of 0.404 g (0.740 mmol) of 13 in 7.0 mL of
diisopropylamine in an ACE pressure tube was deaerated by
bubbling nitrogen through the mixture for 30 min. To the
stirred solution was added 14 mg (0.074 mmol) of copper(I)
iodide and 104 mg (0.148 mmol) of bis(triphenylphospine)-
palladium(II) chloride. The gauge assembly was fitted on top,
and a lecture bottle of propyne gas was attached via a tygon
hose. The vessel was evacuated via an aspirator followed by
introduction of the propyne gas. This procedure was repeated
three times to ensure total saturation. The apparatus was
then pressurized as much as possible (5 psi) with propyne gas,
sealed, and stirred overnight. The mixture turned green and
then black immediately after the addition of propyne. The
vessel was vented, and the resulting slurry was concentrated
under reduced pressure. The crude oil was diluted with
diethyl ether and filtered through a plug of silica gel washing
with ether. The solution was concentrated under reduced
pressure. The crude yellow oil was purified by column
chromatography on silica gel. Elution with 3:1 hexane-ether
afforded 0.330 g (97% yield) of N-[(2,2,2-trichloroethyl)car-
bamoyl]-3â-(4′-propynylphenyl)nortropane-2â-carboxylic acid
methyl ester (14b).
N-[(2,2,2-Tr ich lor oeth yl)ca r ba m oyl]-3â-(4′-a llylp h en yl-
)n or tr op a n e-2â-ca r boxylic Acid Meth yl Ester (14c). The
procedure for N-[(2,2,2-trichloroethyl)carbamoyl]-3â-(4′-io-
dophenyl)nortropane-2â-carboxylic acid methyl ester (13) was
followed with 487 mg (1.63 mmol) of 8 in 16 mL of dry
dichloroethane and 0.448 mL (3.3 mmol) of 2,2,2-trichloroethyl
chloroformate affording 0.536 g (72% yield) of N-[(2,2,2-
trichloroethyl)carbamoyl]-3â-(4′-allylphenyl)nortropane-2â-car-
boxylic acid methyl ester (14c).
The free base was converted to the tartrate salt: mp 130-
131 °C dec; [R]27 -91.4° (c 0.5, MeOH). Anal. (C22H31NO8‚
D
0.5H2O) C, H, N.
3â-(4′-Vin ylph en yl)n or tr opan e-2â-car boxylic Acid Meth -
yl Ester (3a ). The procedure for 3â-(4′-ethylphenyl)nortro-
pane-2â-carboxylic acid methyl ester (2a ) was followed with
0.110 g (0.385 mmol) of 3â-(4′-vinylphenyl)tropane-2â-carboxy-
lic acid methyl ester (11a ) and 0.166 mL (1.54 mmol) of
1-chloroethyl chloroformate affording 0.0673 g (64% yield) of
3â-(4′-vinylphenyl)nortropane-2â-carboxylic acid methyl ester
(3a ): 1H NMR (CDCl3) δ 5.13 (d, 1H, J ) 10.9 Hz, one of
CHdCH2), 5.63 (d, 1H, J ) 17.7 Hz, one of CHdCH2), 6.61
(dd, 1H, J ) 11.2, 17.8 Hz, CHdCH2), 7.08 (d, 2H, J ) 8.2 Hz,
aryl H), 7.25 (d, 2H, J ) 8.2 Hz, aryl H).
The free base was converted to the tartrate salt: mp 135-
138 °C; [R]27 -99.6° (c 0.255, MeOH). Anal. (C21H27
-
D
NO8‚0.5H2O) C, H, N.
3â-(4′-E t h yn ylp h en yl)n or t r op a n e-2â-ca r b oxylic Acid
Meth yl Ester (4a ). The procedure for 3â-(4′-ethylphenyl)-
nortropane-2â-carboxylic acid methyl ester (2a ) was followed
with 0.110 g (0.390 mmol) of 3â-(4′-ethynylphenyl)tropane-2â-
carboxylic acid methyl ester (7b) and 0.126 mL (1.16 mmol)
of 1-chloroethyl chloroformate affording 0.0284 g (28% yield)
of 3â-(4′-ethynylphenyl)nortropane-2â-carboxylic acid methyl
ester (4a ): 1H NMR (CDCl3) δ 3.05 (s, 1H, acetylenic H), 7.15
(d, 2H, J ) 8.3 Hz, aryl H), 7.42 (d, 2H, J ) 8.3 Hz, aryl H).
The free base was converted to the tartrate salt: mp 148-
3â-(4′-Isop r op en ylp h en yl)n or t r op a n e-2â-ca r b oxylic
Acid Meth yl Ester (3b). To a stirred slurry of N-[(2,2,2-
trichloroethyl)carbamoyl]-3â-(4′-isopropenylphenyl)nortropane-
2â-carboxylic acid methyl ester (14a ) in 7.0 mL of glacial acetic
acid was added 324 mg (0.703 mmol) of activated zinc. The
slurry was stirred overnight and then filtered through a plug
of Celite. The aqueous solution was poured slowly into
saturated aqueous bicarbonate, and additional bicarbonate
was added until basic. The aqueous layer was then extracted
with methylene chloride (5×). The combined extracts were
dried over sodium sulfate, filtered, and concentrated under
reduced pressure. The resulting oil was purified by flash
chromatography on silica gel. Elution with 3:1 ethyl acetate-
hexane with 2% additional methanol and 1% additional
triethylamine afforded 0.128 g (64% yield) of â-(4′-isopropen-
150 °C; [R]27 -71.4° (c 0.070, MeOH). Anal. (C21H25NO8‚
D
0.5H2O) C, H, N.
N-[(2,2,2-Tr ich lor oet h yl)ca r b a m oyl]-3â-(4′-iod op h en -
yl)n or tr op a n e-2â-ca r boxylic Acid Meth yl Ester (13). To
a stirred solution of 1.054 g (2.73 mmol) of 6a in 14 mL of dry
dichloroethane was added 1.13 mL (8.20 mmol) of 2,2,2-
trichloroethyl chloroformate. The solution was refluxed over-
night and cooled to room temperature. The mixture was
diluted with diethyl ether (100 mL). The organic layer was
extracted with 1 M aqueous hydrogen chloride (2x). The
organic layer was dried over sodium sulfate, filtered, and
concentrated under reduced pressure. The crude oil was
purified by flash chromatography on silica gel. Elution with
3:1 hexane-ether afforded 1.425 g (96% yield) of N-[(2,2,2-
trichloroethyl)carbamoyl]-3â-(4′-iodophenyl)nortropane-2â-car-
boxylic acid methyl ester (13).
1H
ylphenyl)nortropane-2â-carboxylic acid methyl ester (3b):
NMR (CDCl3) δ 2.12 (s, 3H, CH3CdCH2), 5.05 (s, 1H, one of
CdCH2), 5.35 (s, 1H, one of CdCH2), 7.15 (d, 2H, J ) 8.4 Hz,
aryl H), 7.39 (d, 2H, J ) 8.3 Hz, aryl H).
The free base was converted to the tartrate salt: mp 103-
106 °C; [R]27 -101.7° (c 0.590, MeOH). Anal. (C22H29NO8‚
D
0.5H2O) C, H, N.
N-[(2,2,2-Tr ich lor oet h yl)ca r b a m oyl-3â-(4′-isop r op en -
ylp h en yl)n or t r op a n e-2â-ca r b oxylic Acid Met h yl E st er
(14a ). To a solution of 0.233 mL (2.62 mmol) of 2-bromopro-
pene in 5 mL of dry tetrahydrofuran at -78 °C under a
nitrogen atmosphere was added 1.64 mL (2.62 mmol) of 1.6
M n-butyllithium in hexane. The mixture was stirred for 15
min at -78 °C. To this mixture was added 5.25 mL (2.62
mmol) of 0.5 M zinc chloride in tetrahydrofuran, and the
mixture was stirred for an additional 30 min with warming
to room temperature. Then 0.478 g (0.875 mmol) of 13 in 5
mL of dry tetrahydrofuran was added dropwise followed by
the additon of 60 mg of bis(triphenylphosphine)palladium(II)
chloride. The mixture was stirred overnight at room temper-
ature. The mixture turned dark soon after reaching room
temperature. The mixture was diluted with saturated aqueous
sodium bicarbonate and extracted with methylene chloride
(5×). The combined extracts were dried over sodium sulfate,
filtered, and concentrated under reduced pressure. The
resulting oil was purified by flash chromatography on silica
gel. Elution with 3:1 hexane-ether afforded 0.380 g (93%
yield) of N-[(2,2,2-trichloroethyl)carbamoyl]-3â-(4′-isopropen-
ylphenyl)nortropane-2â-carboxylic acid methyl ester (14a ).
N-[(2,2,2-Tr ich lor oet h yl)ca r b a m oyl]-3â-(4′-p r op yn yl-
ph en yl)n or tr opan e-2â-car boxylic Acid Meth yl Ester (14b).
3â-(4′-Allylph en yl)n or tr opan e-2â-car boxylic Acid Meth -
yl Ester (3e). To a stirred solution of 128 mg (0.28 mmol) of
N-[(2,2,2-trichloroethyl)carbamoyl]-3â-(4′-allylphenyl)nortro-
pane-2â-carboxylic acid methyl ester (14c) in 1.1 mL of
tetrahydrofuran and 1.1 mL of 1 M aqueous ammonium
acetate was added 0.156 g (1.38 mmol) of 10% PbO/Cd. The
slurry was stirred for 1 h and then filtered through Celite.
The solution was basified with saturated aqueous bicarbonate
and extracted with methylene chloride (5×). The combined
extract was dried over sodium sulfate, filtered, and concen-
trated under reduced pressure. The crude oil was purified by
flash chromatography on silica gel. Elution with 3:1 ethyl
acetate-hexane with 5% additional methanol and 1% ad-
ditional triethylamine afforded 0.0382 g (48% yield) of (E)-3â-
(4′-allylphenyl)nortropane-2â-carboxylic acid methyl ester
(3e): 1H NMR (CDCl3) δ 3.35 (d, 2H, J ) 6.7 Hz, CH2CH),
5.02 (d, 1H J ) 2.7 Hz, one of CHdCH2), 5.07 (s, 1H, one of
CHdCH2), 5.86-6.02 (m, 1H, CHdCH2), 7.11 (s, 4H, aryl H).
The free base was converted to the tartrate salt: mp 111-
113 °C; [R]27 -68.6° (c 0.28, MeOH). Anal. (C22H29NO8‚
D
0.5H2
O) C, H, N.
3â-(4′-P r op yn ylp h en yl)n or tr op a n e-2â-ca r boxylic Acid
Meth yl Ester (4b). The procedure for 3â-(4′-isopropenylphen-

4034 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Blough et al.
yl)nortropane-2â-carboxylic acid methyl ester (3b) was followed
with 0.212 g (0.462 mmol) of N-[(2,2,2-trichloroethyl)carbam-
oyl]-3â-(4′-propynylphenyl)nortropane-2â-carboxylic acid meth-
yl ester (14b) and 0.151 g (2.31 mmol) of activated zinc in 3
mL of glacial acetic acid affording 0.081 g (62% yield) of 3â-
(4′-propynylphenyl)nortropane-2â-carboxylic acid methyl ester
(4b): 1H NMR (CDCl3) δ 1.96 (s, 3H, CCH3), 7.02 (d, 2H, J )
8.2 Hz, aryl H), 7.23 (d, 2H, J ) 8.1 Hz, aryl H).
The free base was converted to the tartrate salt: mp 160-
162 °C; [R]27D -102.4° (c 0.62, MeOH). Anal. (C22H29NO8‚H2O)
C, H, N.
Ack n ow led gm en t. This work was supported in part
by the National Institute on Drug Abuse, Grant No.
DA05477.
The free base was converted to the tartrate salt: mp 168-
170 °C; [R]27 -106.0° (c 0.465, MeOH). Anal. (C22H27NO8‚
Refer en ces
D
0.75H2O) C, H, N.
(1) Madras, B. K.; Fahey, M. A.; Bergman, J .; Canfield, D. R.;
Spealman, R. D. Effects of cocaine and related drugs in nonhu-
man primates. I. [3H]Cocaine binding sites in caudate-putamen.
J . Pharmacol. Exp. Ther. 1989, 251, 131-141.
3â-(4′-P r op ylp h en yl)n or t r op a n e-2â-ca r b oxylic Acid
Meth yl Ester (2b). To a solution of 0.1112 g (0.392 mmol) of
3â-(4′-propynylphenyl)nortropane-2â-carboxylic acid methyl
ester (4b) in 1.0 mL of ethyl acetate in a round-bottom flask
was added 0.1 g of 10% palladium on carbon (fire hazard). The
hydrogen atmosphere was added via a hydrogen-filled balloon,
and the slurry was stirred overnight. The slurry was filtered
through a plug of Celite to remove the palladium on carbon.
The solution was concentrated under reduced pressure. The
resulting oil was purified by flash chromatography on silica
gel. Elution with 3:1 ethyl acetate-hexane with 1% additional
triethylamine afforded 0.082 g (73% yield) of 3â-(4′-propylphen-
yl)nortropane-2â-carboxylic acid methyl ester (2b): 1H NMR
(CDCl3) δ 0.91 (t, 3H, J ) 7 Hz, CH2CH3), 2.54 (t, 2H, J ) 8
Hz, CH2CH2CH3), 7.09 (s, 4H, aryl H).
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The free base was converted to the tartrate salt: mp 138-
140 °C; [R]27 -73.6° (c 0.46, MeOH). Anal. (C22H31NO8‚
D
0.5H2O) C, H, N.
(Z)-3â-(4′-P r op en ylp h en yl)n or t r op a n e-2â-ca r b oxylic
Acid Meth yl Ester (3d ). To a solution of 0.0812 g (0.286
mmol) of 3â-(4′-propynylphenyl)nortropane-2â-carboxylic acid
methyl ester (4b) in 3.0 mL of benzene in an ACE pressure
tube was added 1 small drop (7 µL) of quinoline followed by
183 mg of Lindlar’s catalyst. The gauge assembly was fitted
on top, and the tube was pressurized with 60 psi of hydrogen
gas. The slurry was stirred for 3.5 h. The tube was vented,
and the slurry was filtered through a plug of Celite to remove
the catalyst. The solution was concentrated under reduced
pressure. The resulting oil was purified by flash chromatog-
raphy on silica gel. Elution with 3:1 ethyl acetate-hexane
with 5% additional methanol and 1% additional triethylamine
afforded 0.0612 g (75% yield) of (Z)-3â-(4′-propenylphenyl)-
nortropane-2â-carboxylic acid methyl ester (3d ): 1H NMR
(CDCl3) δ 1.89 (d, 3H, J ) 7.2 Hz, CHCH3), 5.76 (dq, 1H, J )
7.2, 11.6 Hz, CHCH3), 6.38 (d, 1H, J ) 11.5 Hz, CHdCHCH3),
7.15 (d, 2H, J ) 8.3 Hz, aryl H), 7.22 (d, 2H, J ) 8.3 Hz, aryl
H).
The free base was converted to the tartrate salt: mp 107-
108 °C; [R]27 -104.2° (c 0.310, MeOH). Anal. (C22H29NO8‚
D
0.5H2O) C, H, N.
(E)-3â-(4′-P r op en ylp h en yl)n or t r op a n e-2â-ca r b oxylic
Acid Meth yl Ester (3c). To a stirred solution of 0.273 g (0.59
mmol) of N-[(2,2,2-trichloroethyl)carbamoyl]-3â-(4′-allylphen-
yl)nortropane-2â-carboxylic acid methyl ester (14c) in 7.0 mL
of ethanol was added 100 mg of rhodium(III) chloride. The
slurry was heated to reflux overnight and cooled. The slurry
was filtered through a plug of silica gel and concentrated under
reduced pressure affording 0.131 g (48% yield) of crude (E)-
N-[(2,2,2-trichloroethyl)carbamoyl]-3â-(4′-propenylphenyl)nor-
tropane-2â-carboxylic acid methyl ester (14d ).
To the crude carbamate in 1.4 mL of tetrahydrofuran and
1.4 mL of saturated aqueous ammonium acetate was added
0.160 g (1.42 mmol) of 10% PbO/Cd. The slurry was stirred
for 1 h and then filtered through Celite. The solution was
basified with saturated aqueous bicarbonate and extracted
with methylene chloride (5×). The combined extract was dried
over sodium sulfate, filtered, and concentrated under reduced
pressure. The crude oil was purified by flash chromatography
on silica gel. Elution with 3:1 ethyl acetate-hexane with 5%
additional methanol and 1% additional triethylamine afforded
0.0381 g (47% yield) of (E)-3â-(4′-propenylphenyl)nortropane-
2â-carboxylic acid methyl ester (3c): 1H NMR (CDCl3) δ 1.87
(d, 3H, J ) 6.1 Hz, CHCH3), 6.19 (dq, 1H, J ) 6.0, 15.8 Hz,
CHCH3), 6.36 (d, 1H, J ) 16.0 Hz, CHdCHCH3), 7.10 (d, 2H,
J ) 8.3 Hz, aryl H), 7.26 (d, 2H, J ) 8.9 Hz, aryl H).
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