Synthesis and receptor binding properties of 2β-alkynyl and 2β-(1,2,3-triazol)substituted 3β-(substituted phenyl)tropane derivatives

Article abstract of DOI:10.1016/j.bmc.2008.04.008

A series of 2β-alkynyl and 2β-(1,2,3-triazol)substituted 3β-(substituted phenyl)tropanes were synthesized and evaluated for affinities at dopamine, serotonin, and norepinephrine membrane transporters using competitive radioligand binding assays. All teste

Full text of DOI:10.1016/j.bmc.2008.04.008

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 5529–5535
Synthesis and receptor binding properties of 2b-alkynyl
and 2b-(1,2,3-triazol)substituted 3b-(substituted
phenyl)tropane derivatives
*
´
Chunyang Jin, Hernan A. Navarro and F. Ivy Carroll
Organic and Medicinal Chemistry, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, USA
Received 6 March 2008; revised 3 April 2008; accepted 4 April 2008
Available online 10 April 2008
Abstract—A series of 2b-alkynyl and 2b-(1,2,3-triazol)substituted 3b-(substituted phenyl)tropanes were synthesized and evaluated
for affinities at dopamine, serotonin, and norepinephrine membrane transporters using competitive radioligand binding assays. All
tested compounds were found to exhibit nanomolar or subnanomolar affinity for the dopamine transporter (DAT). One of the most
potent and selective compounds in the series was 3b-(4-chlorophenyl)-2b-(4-nitrophenylethynyl)tropane (10c) that possessed an IC50
value of 0.9 nM at the DAT and Ki values of 230 nM and 620 nM at the norepinephrine transporter (NET) and serotonin trans-
porter (5-HTT), respectively.
ꢀ 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Cocaine (1, Fig. 1) is one of the most powerful central
nervous system (CNS) stimulants with reinforcing prop-
erties. While cocaine blocks the presynaptic reuptake of
dopamine (DA), serotonin (5-HT), and norepinephrine
(NE), numerous studies have strongly supported the
hypothesis that the dopamine transporter (DAT) is
highly significant in cocaine abuse regarding its reinforc-
ing effects.1–5 Although other targets may be important
to addiction (metabotropic and iontropic glutamate
receptors, GABA)6–8 animal behavioral and clinical
finding suggest that the DAT is still an important tar-
get.9–14 Structure–activity relationship (SAR) studies of
a number of different classes of DAT inhibitors with
the goal of the development of pharmacotherapies to
treat cocaine addiction have been reported.12,15–18 One
of the most studied classes of DAT inhibitors are the
Figure 1. Structures of compounds 1, 2a–c, and 3.
3-phenyltropanes.12,15,19,20 The lead compound was 3b-
phenyltropane-2b-carboxylic acid methyl ester (2a,
WIN 35,065-2).21,22 A large part of our SAR studies
have been directed toward modification of the 40-methyl
Most of the studies were directed toward changes in the
and 40-chloro analogs 2b,c.12
C(2)-position of 2a–c. SAR studies have revealed that a
variety of functional groups and substituents are well
tolerated at this position without loss of high-affinity
for monoamine transporters. In early studies, we
showed that a variety of 2b-esters and amides had
high-affinity for the DAT, in some cases, with consider-
ably reduced affinity at the 5-HTT and NET.12 SAR
Keywords: Monoamine transporters; 3-Phenyltropanes; Alkynes; 1,2,3-
Triazoles; Cocaine; Addiction.
*
Corresponding author. Tel.: +1 919 541 6679; fax: +1 919 541
8868; e-mail: fic@rti.org
0968-0896/$ - see front matter ꢀ 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.04.008

5530
C. Jin et al. / Bioorg. Med. Chem. 16 (2008) 5529–5535
studies from other groups and us also revealed that large
lipophilic groups on the 2b-position, including alkyl,
alkenyl and aryl substituents retained high DAT binding
affinity.12,23–25 In addition, exchange of the 2b-carbome-
thoxy group with bioisosteric heterocyclic groups led to
analogs with high-affinity and selectivity for the DAT.
One of the most studied compounds in this series is
the DAT selective 3-phenyltropane analog, RTI-336
(3). RTI-336 is currently in advanced preclinical devel-
opment.10–12
has high potency and good selectivity for the DAT rela-
tive to the 5-HTT and NET.
2. Chemistry
The synthesis of 2b-alkynyl-3b-(substituted phenyl)tro-
pane analogs 9a,b and 10a–d starting with anhydroecg-
onine methyl ester (4) is outlined in Scheme 1. The
1,4-addition of 4 with the appropriate Grignard reagent
at ꢀ45 ꢁC in ethyl ether followed by trifluoroacetic acid
(TFA) led to the corresponding 3b-aryl substituted com-
pounds 2b,c.26 Lithium aluminum hydride (LiAlH4)
reduction of the 2b-ester group of 2b,c afforded alcohols
5a,b. Swern oxidation of 5a,b provided aldehydes 6a,b.
The aldehydes 6a,b were not stable and underwent
epimerization at the C(2)-position during silica gel
chromatography. Therefore, crude 6a,b, used without
purification, were treated with carbon tetrabromide, tri-
phenylphosphine, and zinc to give the 2b-isomers 7a,b in
the order of 54–56% yield as well as the minor 2a-iso-
mers 8a,b in 1.7% and 1.4% yield, respectively, after col-
umn chromatography. With the C(2)-position no longer
susceptible to epimerization, 7a,b were treated with 2
equivalents of butyl lithium to afford 2b-ethynyltro-
Despite extensive efforts directed toward the develop-
ment of a pharmacotherapy for cocaine abuse, at pres-
ent no clinically approved drugs are available. In order
to gain a better understanding of the molecular
mechanisms of cocaine actions in the brain and find
highly potent and selective monoamine uptake inhibi-
tors, we have continued the investigation on modifica-
tion of 2a. The present study was undertaken to
further explore the SAR of 2-substituents of the 3b-phe-
nyltropanes. In this paper, we describe the synthesis and
monoamine transporter binding properties of several
2b-alkynyl and 2b-(1,2,3-triazol)substituted 3b-(substi-
tuted phenyl)tropane derivatives, and report that 3b-
(4-chlorophenyl)-2b-(4-nitrophenylethynyl)tropane (10c)
Scheme 1. Reagents and conditions: (a) Grignard reagent, ꢀ45 ꢁC, 2 h, then ꢀ78 ꢁC, TFA; (b) LiAlH4 THF, room temperature; (c) Swern oxidation;
(d) CBr4, PPh3, Zn, CH2Cl2, room temperature; (e) BuLi, THF, ꢀ78 ꢁC to room temperature; (f) ArI, Pd(PPh3)4, CuI, benzene–Et3N, 40 ꢁC.

C. Jin et al. / Bioorg. Med. Chem. 16 (2008) 5529–5535
5531
Recently, the copper(I)-catalyzed 1,2,3-triazole forma-
tion from terminal alkynes and azides, also known as
the ‘click reaction’, has found growing applications in
drug discovery due to the favorable physicochemical
properties of triazole, which can readily associate with
biological targets through hydrogen bonding and dipole
interactions.27,28 Accordingly, 2b-(1,2,3-triazol)substi-
tuted tropanes 11 and 12 were synthesized by treatment
of 9b with 1-(2-azidoethyl)piperidine or benzylazide in
the presence of copper sulfate and sodium ascorbate
(Scheme 2).
Scheme 2. Reagents and conditions: (a) azide, CuSO4, sodium
ascorbate, tBuOH-H2O, room temperature.
3. Biology
panes 9a,b exclusively. Sonogashira coupling of ethyne
9a or 9b with iodobenzene using tetrakis(triphenylphos-
phine)palladium(0), and copper(I) iodide in 1:1 mixture
of benzene-triethylamine gave 2b-phenylethynyltro-
panes 10a and 10b, respectively. Finally, coupling of
9b with 1-iodo-4-nitrobenzene or 4-iodoaniline fur-
nished 10c and 10d. The relative stereochemistry of each
The binding affinities for the target compounds at the
DAT, NET, and 5-HTT were determined via competi-
tive binding assays using the previously reported proce-
dures.29,30 The final concentration of radioligands in the
assays was 0.5 nM [3H]WIN35,428 for the DAT, 0.5 nM
[3H]nisoxetine for the NET, and 0.2 nM [3H]paroxetine
for the 5-HTT. The results of the binding studies, along
with binding data of cocaine and 2a10 for comparison
are listed in Table 1. Since the NET and 5-HTT have
only one binding site, Ki values were calculated for inhi-
bition of binding at these two transporters.
1
compound was determined by H NMR spectral analy-
sis, particularly with the aid of coupling constants of
C(2)–H and C(3)–H. The vicinal couplings of
J2eq,3ax = 5.4–5.7 Hz and J2ax,3ax = 11.5–11.9 Hz for the
2b- and 2a-substituents, respectively, are in good agree-
ment with stereochemical assignments.
Table 1. Monoamine transporter binding potencies for 2b-substituted 3b-(substituted phenyl)tropane derivatives
Compounda
clogP
Structure
X
Y
R
DAT, IC50 (nM)
[3H]WIN35,428
NET, Kid (nM)
[3H]nisoxetine
5-HTT, Kid (nM)
[3H]paroxetine
d
Cocaineb
2a
7a
89.1
23
1990
556
95
182
—
—
A
A
Ac
Ac
B
—
—
—
5.21
5.35
5.21
5.35
3.40
3.53
5.87
6.01
5.74
4.73
CH3
Cl
0.23 0.05
0.32 0.05
3.6 1.1
1.4 0.2
3.4 0.6
3.5 0.3
39 10
7
7b
8a
2
CH3
Cl
55
49
2
2
252 13
76
54 15
18
730 190
81
620 150
19
8b
9a
9
CH3
Cl
11
3
150 20
75 13
9b
B
3.6 0.4
0.8 0.3
0.8 0.2
0.9 0.2
2.2 0.5
2
10a
10b
10c
10d
C
CH3
Cl
H
31
14
1
2
C
H
4
C
Cl
Cl
NO2
NH2
230 20
50
C
3
3
11
3.89
D
Cl
8
1
430 50
138 11
161 27
NCH2CH2
12
4.25
D
Cl
C6H5CH2
47 12
2560 130
a All compounds were tested as the HCl salt.
b Data taken from Ref. 9.
c 2a-Stereoisomer.
d All values are means standard error of three or four experiments performed in triplicate.

5532
C. Jin et al. / Bioorg. Med. Chem. 16 (2008) 5529–5535
4. Results and discussion
was observed between the 2b-substituents and the
monoamine selectivity. 3b-(4-Chlorophenyl)-2b-(4-
nitrophenylethynyl)tropane (10c) with an IC50 value of
0.9 nM at the DAT and Ki values of 230 nM at the
NET and 620 nM at the 5-HTT, respectively, was one
of the most potent and selective compounds for the
DAT relative to the NET and 5-HTT in the series.
One of the most interesting features of the SAR of 3-
phenyltropane analogs for the DAT is that exchanging
the 2b-ester group in WIN 35,065-2, with amide, ether,
heterocyclic, keto, alkyl, alkenyl, or aryl substituents
at the C(2)-position provides compounds with equal or
greater affinity than that of WIN 35,065-2 at the
DAT.12 Although the DAT tolerates ligands having a
broad variety of 2b-substituents with little change in
the affinity of the ligand, the nature of the substituents
has a profound effect on the monoamine selectivity. In
order to gain additional information on the structural
requirements for high-affinity and good selectivity at
the C(2)-position, we designed and synthesized a new
series of 2-substituted 3b-(substituted phenyl)tropane
derivatives.
In summary, several novel 3b-(substituted phenyl)tro-
panes with various 2b-alkynyl and 2b-(1,2,3-triazol)
substituents were synthesized and evaluated for their
monoamine transporter binding affinities. All the tested
compounds demonstrated higher potency at the DAT
than cocaine and were more selective relative to binding
at the NET and 5-HTT. One of the most potent and
selective compounds in the series, 3b-(4-chlorophenyl)-
2b-(4-nitrophenylethynyl)tropane (10c) had an IC50 va-
lue of 0.9 nM at the DAT and was 256- and 689-fold
selective for the DAT over the NET and 5-HTT, respec-
tively. These 2b-substituted tropanes are promising
leads for further investigation of highly potent and selec-
tive monoamine inhibitors.
All the compounds possessed high affinities at the DAT
with nanomolar or subnanomolar IC50 values ranging
from 0.23 nM to 47 nM. No correlation was observed
between the DAT binding affinities with the calculated
partition coefficients (clogP) of the compounds. Gener-
ally, the 3b-(4-chlorophenyl) substituted tropanes except
7b were equal or more potent than the compounds with
a 3b-(4-methylphenyl) substitution. The 2a-isomers 8a
and 8b were approximately 16- and 4-fold less potent
than the corresponding 2b-isomers 7a and 7b, respec-
tively. This was consistent with the previous findings
that exchange of the 2b-substituent in the tropane deriv-
atives with the 2a moiety decreased the relative binding
affinity for the DAT.31
5. Experimental
Melting points were determined using a MEL-TEMP II
capillary melting point apparatus and are uncorrected.
Nuclear magnetic resonance (1H NMR and 13C NMR)
spectra were obtained on a Bruker Avance DPX-
300 MHz NMR spectrometer. Chemical shifts are re-
ported in parts per million (ppm) with reference to inter-
nal solvent. Mass spectra (MS) were run on a Perkin-
Elmer SCIEX API 150 EX mass spectrometer outfitted
with ESI (turbospray) source or on a Hewlett Packard
5989A instrument by electron impact. Elemental analy-
sis was performed by Atlantic Microlab Inc., Atlanta,
GA. Optical rotations were measured on an AutoPol
III polarimeter, purchased from Rudolf Research. Ana-
lytical thin-layer chromatography (TLC) was carried
out using EMD silica gel 60 F254 TLC plates. TLC visu-
alization was achieved with a UV lamp or in an iodine
chamber. Flash column chromatography was done on
a CombiFlash Companion system using Isco prepacked
Among the tested 2b-substituted tropanes, the 2b-di-
bromovinyltropanes 7a and 7b possessed the highest po-
tency at the DAT with IC50 values of 0.23 nM and
0.32 nM, respectively. Replacement of the vinyl group
with the ethynyl substitution afforded 9a and 9b with de-
creased affinities at the DAT (11 nM vs 0.23 nM and
3.6 nM vs 0.32 nM IC50). It is interesting to note that
attachment of a phenyl group to the end of the ethyne
group gave 10a and 10b, which regained the binding
affinity by 4- to 14-fold, respectively. In addition, replac-
ing the phenylethynyl group at the C(2)-position of the
3b-(4-chlorophenyl) analogue 10b (IC50 = 0.8 nM) with
the 4-nitrophenylethynyl substitution to give 10c had
no effect on binding affinity (IC50 = 0.9 nM). However,
the addition of a 4-amino group to 10b resulted in
approximately 3-fold loss of binding affinity at the
DAT. These findings support previous reports that a
large pocket is present in the DAT binding site occupied
by the 2b-substituent.12 The lipophilic interactions as
well as the possible p-interactions between the 2b-sub-
stituents and the binding site may play an important role
for the high affinity of these ligands. Finally, as analogs
of the reported 2b-heterocyclic tropanes, the 2b-(1,2,3-
triazol)substituted tropane derivatives 11 and 12 also
possessed high-affinity at the DAT with IC50 values of
8 nM and 47 nM, respectively.
˚
silica gel columns or using EM Science silica gel 60 A
(230–400 mesh). Unless otherwise stated, reagent-grade
chemicals were obtained from commercial sources and
were used without further purification. All moisture-
and air-sensitive reactions and reagent transfers were
carried out under dry nitrogen.
5.1. 3b-(4-Methylphenyl)-2b-hydroxymethyltropane (5a)
To a stirred solution of 2b26 (11.4 g, 0.04 mol) in anhy-
drous THF (100 mL) at 0 ꢁC under nitrogen was added
LiAlH4 (3.04 g, 0.080 mol). After stirring at room tem-
perature for 2 h, the reaction was quenched by slow
addition of H2O (20 mL). The organic layer was sepa-
rated and the aqueous layer was extracted with EtOAc
(3 · 30 mL). The combined organic phases were washed
with brine (3 · 50 mL), and dried (Na2SO4). Removal of
the solvent under reduced pressure afforded crude 5a
In terms of monoamine selectivity, all the compounds
exhibited lower binding affinities at the NET and 5-
HTT relative to the DAT. However, no correlation
1
(9.60 g, 98%) as a white solid: mp 78–80 ꢁC; H NMR

C. Jin et al. / Bioorg. Med. Chem. 16 (2008) 5529–5535
5533
20
D
(CDCl3) d 7.25 (d, J = 8.1 Hz, 2 H), 7.12 (d, J = 8.1 Hz,
2H), 3.75 (dd, J = 10.8, 2.1 Hz, 1H), 3.51–3.45 (m, 1H),
3.39 (dd, J = 10.8, 2.1 Hz, 1H), 3.37–3.29 (m, 1H). 3.05
(ddd, J = 12.9, 5.7, 5.7 Hz, 1H), 2.51 (ddd, J = 12.9,
12.9, 3.0 Hz, 1H), 2.32 (s, 3H), 2.27 (s, 3H), 2.26–2.04
(m, 2H), 1.82–1.57 (m, 3H), 1.52–1.43 (m, 1H); MS
(ESI) m/z 246.4 (M+1). The desired compound was used
in the next step without further purification.
to the hydrochloride salt: mp 241 ꢁC (dec); ½aꢁ ꢀ41.67ꢁ
(c 0.24, CH3OH); Anal. Calcd for C17H21Br2NÆH-
ClÆ0.75H2O: C, 45.46; H, 5.27; N, 3.12. Found: C,
45.32; H, 5.35; N, 3.01.
1
Compound 8a: white solid; mp 115–117 ꢁC; H NMR
(CDCl3) d 7.07 (s, 4H), 6.09 (d, J = 9.1 Hz, 1H), 3.30–
3.16 (m, 2H), 3.03 (ddd, J = 11.5, 2.6, 9.1 Hz, 1H),
2.60 (ddd, J = 11.5, 11.7, 5.4 Hz, 1H), 2.39 (s, 3H),
2.30 (s, 3H), 2.20–1.94 (m, 2H), 1.87 (ddd, J = 11.7,
11.7, 2.4 Hz, 1H), 1.77–1.54 (m, 3H); 13C NMR
(75 MHz; CDCl3) d 140.1, 140.0, 136.2, 129.4, 127.7,
89.9, 64.4, 61.4, 49.7, 40.4, 39.9, 39.7, 26.4, 23.7, 21.2;
5.2. 3b-(4-Chlorophenyl)-2b-hydroxymethyltropane (5b)
The procedure for 5a was followed using 10.0 g
(0.034 mol) of 2c26 to give 8.90 g (99%) of 5b as a white
1
solid: mp 82–84 ꢁC; H NMR (CDCl3) d 7.38–7.25 (m,
MS (ESI) m/z 400.3 (M+1). The free base was converted
20
D
4H), 3.75 (dd, J = 11.1, 2.1 Hz, 1H), 3.50–3.42 (m,
1H), 3.38–3.28 (m, 2H), 3.12–3.00 (m, 1H), 2.49 (ddd,
J = 12.9, 12.9, 3.2 Hz, 1H), 2.27 (s, 3H), 2.26–2.04 (m,
2H), 1.80–1.57 (m, 3H), 1.50–1.44 (m, 1H); MS (ESI)
m/z 266.3 (M+1). The desired compound was used in
the next step without further purification.
to the hydrochloride salt: mp 210 ꢁC (dec); ½aꢁ +23.53ꢁ
(c 0.26, CH3OH); Anal. Calcd for C17H21Br2NÆH-
ClÆ0.25H2O: C, 46.39; H, 5.15; N, 3.18. Found: C,
46.21; H, 5.36; N, 3.11.
5.4. 3b-(4-Chlorophenyl)-2b-(2,2-dibromovinyl)tropane
(7b) and 3b-(4-chlorophenyl)-2a-(2,2-dibromovinyl)tro-
pane (8b)
5.3. 3b-(4-Methylphenyl)-2b-(2,2-dibromovinyl)tropane
(7a) and 3b-(4-methylphenyl)-2a-(2,2-dibromovinyl)tro-
pane (8a)
The procedure for 7a and 8a was followed using 5.30 g
(0.02 mol) of 5b to give 4.53 g (54%) of 2b-isomer 7b
and 0.12 g (1.4%) of 2a-isomer 8b. Compound 7b: white
To a stirred solution of oxalyl chloride (2 M solution,
16.5 mL, 33.0 mmol) in anhydrous CH2Cl2 (100 mL)
at ꢀ78 ꢁC under nitrogen was added anhydrous DMSO
(4.68 mL, 66.0 mmol). After stirring for 15 min, a solu-
tion of 5a (5.40 g, 22.0 mmol) in anhydrous CH2Cl2
(100 mL) was added and the reaction mixture was stir-
red at ꢀ78 ꢁC for another 30 min. TEA (18.4 mL,
132 mmol) was then added and the reaction mixture
was warmed to room temperature and stirred for 2 h.
The reaction was quenched by addition of H2O
(10 mL). The organic layer was separated and washed
with NH4Cl (3 · 50 mL), brine (50 mL) and dried
(Na2SO4). Removal of the solvent under reduced pres-
sure afforded aldehyde 6a (5.42 g) as an oil, which was
used in the next step without further purification.
1
solid; mp 88–90 ꢁC; H NMR (CDCl3) d 7.30–7.20 (m,
2H), 7.10–7.03 (m, 2H), 6.70 (d, J = 9.5 Hz, 1H), 3.32–
3.26 (m, 1H), 3.18–3.10 (m, 1H), 3.07 (ddd, J = 12.9,
5.6, 5.4 Hz, 1H), 2.62 (ddd, J = 5.6, 3.3, 9.5 Hz, 1H),
2.22 (s, 3H), 2.20–2.02 (m, 3H), 1.80–1.57 (m, 3H); 13C
NMR (75 MHz; CDCl3) d 140.5, 139.2, 132.0, 129.3,
128.2, 88.2, 65.9, 62.1, 51.3, 42.1, 36.0, 35.0, 26.6, 25.2;
MS (ESI) m/z 420.3 (M+1). The free base was converted
20
D
to the hydrochloride salt: mp 235 ꢁC (dec); ½aꢁ ꢀ34.9ꢁ
(c 0.22, CH3OH); Anal. Calcd for C16H18Br2ClNÆHCl:
C, 42.14; H, 4.20; N, 3.07. Found: C, 42.27; H, 4.21;
N, 3.14.
Compound 8b: oil; 1H NMR (CDCl3) d 7.25 (d,
J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 6.07 (d,
J = 9.4 Hz, 1H), 3.30–3.16 (m, 2H), 3.00 (ddd,
J = 11.9, 2.4, 9.4 Hz, 1H), 2.61 (ddd, J = 11.9, 12.2,
5.4 Hz, 1H), 2.39 (s, 3H), 2.20–1.94 (m, 2H), 1.85
(ddd, J = 12.2, 12.6, 2.4 Hz, 1H), 1.77–1.53 (m, 3H);
13C NMR (75 MHz; CDCl3) d 141.7, 139.4, 132.4,
129.3, 128.8, 90.4, 64.5, 61.4, 50.1, 40.3, 40.1, 39.6,
26.3, 23.7; MS (ESI) m/z 420.5 (M+1). The free base
To a stirred solution of CBr4 (14.6 g, 0.044 mol) in anhy-
drous CH2Cl2 (165 mL) at 0 ꢁC under nitrogen was
added PPh3 (11.5 g, 0.044 mol) followed by zinc dust
(2.88 g, 0.044 mol). After stirring at room temperature
for 16 h, the reaction mixture was cooled to 0 ꢁC and
a solution of aldehyde 6a (5.42 g) was added. The reac-
tion mixture was stirred at room temperature for 1 h
and filtered through a short pad of Celite. The filtrate
was washed with brine (3 · 50 mL), dried (Na2SO4),
and concentrated under reduced pressure. Flash column
chromatography on silica gel (300 g) using 0 ! 30%
ether in hexanes with 5% TEA afforded 2b-isomer 7a
(4.94 g, 56%) and 2a-isomer 8a (0.15 g, 1.7%). Com-
was converted to the hydrochloride salt: mp 140 ꢁC (fu-
20
D
sion); ½aꢁ +26.1ꢁ (c 0.23, CH3OH); Anal. Calcd for
C16H18Br2ClNÆHCl: C, 42.14; H, 4.20; N, 3.07. Found:
C, 42.27; H, 3.97; N, 3.02.
5.5. 3b-(4-Methylphenyl)-2b-ethynyltropane (9a)
1
pound 7a: white solid; mp 48–50 ꢁC; H NMR (CDCl3)
d 7.08 (d, J = 8.1 Hz, 2H), 7.01 (d, J = 8.1 Hz, 2H), 6.70
(d, J = 9.4 Hz, 1H), 3.35–3.26 (m, 1H), 2.19–2.13 (m,
1H), 3.07 (ddd, J = 12.6, 5.7, 5.7 Hz, 1H), 2.64 (ddd,
J = 5.7, 3.5, 9.4 Hz, 1H), 2.31 (s, 3H), 2.22 (s, 3H),
2.21–2.01 (m, 3H), 1.80–1.58 (m, 3H); 13C NMR
(75 MHz; CDCl3) d 139.8, 138.9, 135.8, 129.0, 127.8,
87.7, 66.1, 62.4, 51.5, 42.2, 35.9, 35.1, 26.6, 25.2, 21.2;
MS (ESI) m/z 400.2 (M+1). The free base was converted
To a stirred solution of 7a (400 mg, 1.00 mmol) in anhy-
drous THF (10 mL) at ꢀ78 ꢁC under nitrogen was
added BuLi (1.6 M solution, 1.31 mL, 2.10 mmol). After
stirring at ꢀ78 ꢁC for 1 h, the reaction mixture was
warmed to room temperature and the stirring was con-
tinued for another 1 h. The reaction mixture was
quenched by addition of saturated NH4Cl. The organic
layer was separated and the aqueous layer was extracted

5534
C. Jin et al. / Bioorg. Med. Chem. 16 (2008) 5529–5535
with EtOAc (3· 30 mL). The combined organic phases
were washed with brine (3· 30 mL), dried (Na2SO4),
and concentrated under reduced pressure. Flash column
chromatography on silica gel (12 g Isco prepacked col-
umn) using 0 ! 5% ether in hexanes with 5% TEA affor-
5.8. 3b-(4-Chlorophenyl)-2b-(phenylethynyl)tropane (10b)
The procedure for 10a was followed using 78.0 mg
(0.30 mmol) of 9b and 0.13 mL (1.20 mmol) of iodoben-
zene to give 70.0 mg (70%) of 10b as an oil: H NMR
1
1
ded 9a (130 mg, 54%) as an oil: H NMR (CDCl3) d
(CDCl3) d 7.29 (s, 5H), 7.20 (m, 4H), 3.50–3.40 (m,
1H), 3.39–3.30 (m, 1H), 3.07 (ddd, J = 12.9, 5.4,
5.4 Hz, 1H), 2.92–2.84 (m, 1H), 2.37 (s, 3H), 2.35–2.05
(m, 3H), 1.78–1.53 (m, 3H); 13C NMR (75 MHz;
CDCl3) d 141.5, 132.4, 131.8, 130.0, 128.2, 127.5,
124.2, 90.6, 84.2, 66.5, 61.8, 42.3, 42.0, 36.6, 35.1, 26.5,
7.22–7.08 (m, 4H), 3.38–3.28 (m, 2H), 2.97 (ddd,
J = 12.9, 5.4, 5.4 Hz, 1H), 2.73–2.67 (m, 1H), 2.40–
2.00 (m, 10H), 1.76–1.51 (m, 3H); 13C NMR (75 MHz;
CDCl3) d 139.4, 136.0, 128.8, 128.1, 84.8, 71.6, 66.7,
61.9, 42.3, 41.6, 35.9, 35.1, 26.1, 25.2, 21.2; MS (ESI)
m/z 240.4 (M+1). The free base was converted to the
25.4; MS (ESI) m/z 336.5 (M+1). The free base was con-
20
D
20
D
hydrochloride salt: mp 210 ꢁC (dec); ½aꢁ ꢀ114.2ꢁ (c
verted to the hydrochloride salt: mp 234 ꢁC (dec); ½aꢁ
0.28, CH3OH); Anal. Calcd for C17H21NÆHClÆ0.25H2O:
C, 72.84; H, 8.09; N, 5.00. Found: C, 72.66; H, 8.08; N,
4.99.
ꢀ228.1ꢁ (c 0.21, CH3OH); Anal. Calcd for
C22H22ClNÆHClÆ0.5H2O: C, 69.29; H, 6.34; N, 3.67.
Found: C, 69.65; H, 6.12; N, 3.73.
5.6. 3b-(4-Chlorophenyl)-2b-ethynyltropane (9b)
5.9. 3b-(4-Chlorophenyl)-2b-(4-nitrophenylethynyl)tro-
pane (10c)
The procedure for 9a was followed using 650 mg
(1.55 mmol) of 7b to give 260 mg (65%) of 9b as a white
solid: mp 123–125 ꢁC; H NMR (CDCl3) d 7.32–7.18
(m, 4H), 3.40–3.30 (m, 2H), 2.98 (ddd, J = 12.9, 5.4,
5.4 Hz, 1H), 2.72–2.65 (m, 1H), 2.33 (s, 3H), 2.30–2.00
(m, 4H), 1.78–1.53 (m, 3H); 13C NMR (75 MHz; CDCl3)
d 141.0, 132.3, 129.7, 128.2, 84.4, 71.9, 66.6, 61.8, 42.3,
41.5, 35.9, 35.1, 26.1, 25.2; MS (ESI) m/z 260.4 (M+1).
The procedure for 10a was followed using 78.0 mg
(0.30 mmol) of 9b and 299 mg (1.20 mmol) of 1-iodo-4-
nitrobenzene to give 110 mg (96%) of 10c as a white solid:
mp 62–64 ꢁC; H NMR (CDCl3) d 8.12–8.02 (m, 2H),
7.40–7.23 (m, 6H), 3.50–3.41 (m, 1H), 3.40–3.30 (m,
1H), 3.12 (ddd, J = 12.6, 5.4, 5.4 Hz, 1H), 2.98–2.90 (m,
1H), 2.36 (s, 3H), 2.32–2.05 (m, 3H), 1.80–1.54 (m, 3H);
13C NMR (75 MHz; CDCl3) d 146.6, 141.1, 132.5,
132.4, 131.3, 129.7, 128.3, 123.4, 97.0, 82.7, 66.3, 61.8,
42.7, 42.1, 36.3, 35.1, 26.3, 25.3; MS (ESI) m/z 381.6
1
1
The free base was converted to the hydrochloride salt:
20
D
mp 145 ꢁC (fusion); ½aꢁ ꢀ106.3ꢁ (c 0.26, CH3OH); Anal.
Calcd for C16H18ClNÆHClÆ1.25H2O: C, 60.29; H, 6.80; N,
4.39. Found: C, 60.37; H, 6.89; N, 4.27.
(M+1). The free base was converted to the hydrochloride
20
salt: mp 115–117 ꢁC; ½aꢁD ꢀ265.3ꢁ (c 0.23, CH3OH);
5.7. 3b-(4-Methylphenyl)-2b-(phenylethynyl)tropane
(10a)
Anal. Calcd for C22H21ClN2O2ÆHClÆ0.25H2O: C, 62.64;
H, 5.38; N, 6.64. Found: C, 62.44; H, 5.31; N, 6.49.
To a stirred mixture of 9a (40.0 mg, 0.17 mmol), CuI
(3.18 mg, 0.017 mmol), and Pd(PPh3)4 (6.00 mg,
0.005 mmol) in 1:1 mixture of benzene–TEA (5 mL) at
room temperature under nitrogen was added iodoben-
zene (0.075 mL, 0.67 mmol). The reaction mixture was
stirred at 40 ꢁC for 1 h. After cooling to room tempera-
ture, the reaction mixture was diluted with EtOAc
(50 mL), washed with NH4Cl (10 mL), brine
(3 · 30 mL), and concentrated under reduced pressure.
The resultant residue was partitioned between ether
(10 mL) and 6 N HCl (10 mL). The aqueous layer was
separated, basified to pH 11 with NH4OH and extracted
with EtOAc (3· 30 mL). The combined EtOAc extracts
were washed with brine (3· 30 mL), dried (Na2SO4), and
concentrated under reduced pressure. Flash column
chromatography on silica gel (12 g Isco prepacked col-
umn) using 2% TEA in hexanes afforded 10a (45.0 mg,
86%) as an oil: 1H NMR (CDCl3) d 7.34–7.08 (m,
9H), 3.47–3.40 (m, 1H), 3.39–3.30 (m, 1H), 3.06 (ddd,
J = 12.9, 5.4, 5.4 Hz, 1H), 2.93–2.87 (m, 1H), 2.42–
2.03 (m, 9H), 1.80–1.54 (m, 3H); 13C NMR (75 MHz;
CDCl3) d 139.8, 136.1, 131.8, 128.8, 128.5, 128.0,
127.3, 124.6, 91.2, 83.9, 66.6, 61.9, 42.5, 42.1, 36.8,
35.3, 26.5, 25.4, 21.2; MS (ESI) m/z 316.5 (M+1). The
5.10. 3b-(4-Chlorophenyl)-2b-(4-aminophenylethynyl)tro-
pane (10d)
The procedure for 10a was followed using 78.0 mg
(0.30 mmol) of 9b and 263 mg (1.20 mmol) of 4-iodoan-
iline to give 65.0 mg (62%) of 10d as a white solid: mp
1
188–190 ꢁC; H NMR (CDCl3) d 7.27 (s, 4H), 7.01 (d,
J = 6.0 Hz, 2H), 6.50 (d, J = 6.0 Hz, 2H), 3.64 (br s,
2H), 3.45–3.38 (m, 1H), 3.38–3.30 (m, 1H), 3.02 (ddd,
J = 12.6, 5.4, 5.4 Hz, 1H), 2.88–2.81 (m, 1H), 2.37 (s,
3H), 2.32–2.03 (m, 3H), 1.80–1.53 (m, 3H); 13C NMR
(75 MHz; CDCl3) d 146.0, 141.6, 132.9, 132.2, 130.0,
128.2, 114.7, 113.9, 87.9, 84.5, 66.6, 61.8, 42.2, 42.0,
36.7, 35.1, 26.5, 25.4; MS (ESI) m/z 351.3 (M+1). The
free base was converted to the hydrochloride salt: mp
20
D
240 ꢁC (dec); ½aꢁ ꢀ199.2ꢁ (c 0.26, CH3OH); Anal.
Calcd for C22H23ClN2Æ2HClÆ1.25 H2O: C, 59.20; H,
6.21; N, 6.28. Found: C, 59.57; H, 6.11; N, 6.05.
5.11. 3b-(4-Chlorophenyl)-2b-[1-(2-piperidin-1-yl)ethyl-
1H-[1,2,3]triazol-4-yl]tropane (11)
To a stirred suspension of 9b (130 mg, 0.50 mmol) and 1-
(2-azidoethyl)-piperidine (77.1 mg, 0.50 mmol) in 1:1
mixture of tBuOH-H2O (4 mL) at room temperature un-
der nitrogen was added a freshly prepared 1 M sodium
ascorbate solution (0.50 mL, 0.50 mmol) followed by
0.3 M CuSO4 solution (0.167 mL, 0.05 mmol). After stir-
free base was converted to the hydrochloride salt: mp
20
D
228 ꢁC (dec); ½aꢁ ꢀ229.0ꢁ (c 0.25, CH3OH); Anal.
Calcd for C23H25NÆHClÆ0.25H2O: C, 77.51; H, 7.49;
N, 3.93. Found: C, 77.30; H, 7.45; N, 3.92.

C. Jin et al. / Bioorg. Med. Chem. 16 (2008) 5529–5535
5535
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ring for 10 h, the reaction mixture was diluted with EtOAc
(50 mL), washed with brine (3· 30 mL) and dried
(Na2SO4). The solvent was concentrated under reduced
pressure. Flash column chromatography on silica gel
(12 g Isco prepacked column) using 0 ! 10% ether in hex-
anes with 5% TEA afforded 11 (135 mg, 65%) as a white
solid: mp 250 ꢁC (dec); 1H NMR (CDCl3) d 7.77 (s, 1H),
7.02–6.92 (m, 2H), 6.83–6.73 (m, 2H), 4.37–4.16 (m,
2H), 3.34–3.09 (m, 4H), 2.60 (t, J = 6.0 Hz, 2H), 2.40–
2.21 (m, 4H), 2.20–1.92 (m, 6H), 1.80–1.30 (m, 9H); 13C
NMR (75 MHz; CDCl3) d 147.4, 141.2, 131.6, 129.1,
128.0, 124.1, 66.8, 61.8, 58.6, 54.5, 47.7, 45.7, 42.2, 35.6,
35.0, 26.3, 26.2, 25.2, 24.3; MS (EI) m/z 414.2 (M+). The
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free base was converted to the hydrochloride salt: mp
20
D
145 ꢁC (fusion); ½aꢁ ꢀ66.0ꢁ (c 0.24, CH3OH); Anal.
Calcd for C23H32ClN5Æ2HClÆ1.5H2O: C, 53.75; H, 7.26;
N, 13.63. Found: C, 54.13; H, 7.21; N, 13.27.
5.12. 3b-(4-Chlorophenyl)-2b-(1-benzyl-1H-[1,2,3]triazol-
4-yl)tropane (12)
The procedure for 11 was followed using 130 mg
(0.50 mmol) of 9b and 0.066 mL (0.50 mmol) of benzy-
lazide to give 155 mg (79%) of 12 as a white solid:
118–119 ꢁC; 1H NMR (CDCl3) d 7.63 (s, 1H), 7.40–
7.27 (m, 3H), 7.10–6.95 (m, 4H), 6.77 (d, J = 8.4 Hz,
2H), 5.55 (d, J = 15.0 Hz, 1H), 5.31 (d, J = 15.0 Hz,
1H), 3.46–3.40 (m, 1H), 3.32–3.18 (m, 3H), 2.30–1.93
(m, 6H), 1.88–1.53 (m, 3H); 13C NMR (75 MHz;
CDCl3) d 148.3, 141.1, 135.9, 131.7, 129.0, 128.9,
128.4, 128.1, 127.3, 123.6, 66.7, 61.8, 53.7, 46.0, 42.2,
35.4, 34.9, 26.3, 25.2; MS (EI) m/z 393.2 (M+). The free
base was converted to the hydrochloride salt: mp 118 ꢁC
20
(fusion); ½aꢁ ꢀ110.9ꢁ (c 0.23, CH3OH); Anal. Calcd for
D
C23H25ClN4ÆHClÆ0.75H2O: C, 62.37; H, 6.26; N, 12.65.
Found: C, 62.44; H, 6.29; N, 12.53.
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Acknowledgment
This research was supported by the National Institute
on Drug Abuse, Grant No. DA05477.
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