Synthesis and monoamine transporter binding properties of 2,3-diaryltropanes

Article abstract of DOI:10.1021/jm0582423

Synthetic procedures were developed for the synthesis of 2β,3β- and 2α,3α-diaryltropanes. These compounds are analogues of the 3-aryltropane-2β-carboxylic acid methyl ester class of monoamine uptake inhibitors, where the 2β-carbomethoxy group has been rep

Full text of DOI:10.1021/jm0582423

J. Med. Chem. 2005, 48, 7437-7444
7437
Synthesis and Monoamine Transporter Binding Properties of
2,3-Diaryltropanes
Sharadsrikar V. Kotturi, Songchun Jiang, An-Chih Chang, Philip Abraham, Herna´n A. Navarro,
Michael J. Kuhar, and F. Ivy Carroll*
Center for Organic and Medicinal Chemistry, Research Triangle Institute, P.O. Box 12194,
Research Triangle Park, North Carolina 27709
Received June 17, 2005
Synthetic procedures were developed for the synthesis of 2â,3â- and 2R,3R-diaryltropanes. These
compounds are analogues of the 3-aryltropane-2â-carboxylic acid methyl ester class of
monoamine uptake inhibitors, where the 2â-carbomethoxy group has been replaced by an aryl
group. The compounds were evaluated for inhibition of radioligand binding at the dopamine,
norepinephrine, and serotonin transporters (DAT, NET, and 5-HTT, respectively). The results
showed that the replacement of the 2â-carbomethoxy group in the 3-aryltropane class with a
2â-aryl group led to compounds possessing very similar monoamine transporter binding
properties. However, the 2â,3â-diaryltropanes tended to be more potent at the DAT and more
selective for the DAT relative to the NET and 5-HTT. One of the most interesting compounds
was 3â-(4-methylphenyl)-2â-(4-methylphenyl)tropane (3d), which showed an IC50 of 1.23 nM
at the DAT with 289- and 185-fold selectivity for the DAT relative to the NET and 5-HTT. The
2R,3R-diaryltropanes were much less potent at all three transporters than 2â,3â-diaryltro-
panes.
Cocaine (1) addiction is a significant socioeconomic
problem of our times. Evidence of cocaine addiction
being a disease of the brain with specific neurobiological
characteristics1,2 necessitates development of effective
therapies to treat cocaine addiction. Cocaine has been
shown to block the reuptake of dopamine (DA), seroto-
nin (5-HT), and norepinephrine (NE) as well as to exert
effects on the cholinergic, muscarinic, and σ receptors
and sodium channels.3,4 Results from animal studies
suggest that the dopamine transporter (DAT) is a key
target (receptor) for cocaine regarding the reinforcing
effects of the drug.3,4 Thus, compounds selective for the
DAT relative to the norepinephrine transporter (NET)
and serotonin transporter (5-HTT) are of particular
interest as potential pharmacotherapies to treat cocaine
addiction. A number of studies have been directed
toward the characterization of the binding site on the
DAT with the hope that the information would aid in
the discovery of potential pharmacotherapies for treat-
ing cocaine addiction.3,5-8 Many of these studies have
been directed toward the 3-phenyltropane class of
compounds where 3â-phenyltropane-2â-carboxylic acid
methyl ester (2a, WIN 35,065-2) served as the lead
compound. In this study, we describe the syntheses of
2â,3â- and 2R,3R-diaryltropanes (3a-g and 4a-f, re-
spectively) and report that some analogues show high
Chemistry
potency for the DAT combined with high selectivity
relative to the NET and 5-HTT. These compounds can
be viewed as structures where the 2â-carbomethoxy
group present in 2a has been replaced by a phenyl or
substituted phenyl ring. Preliminary results from some
of these studies have been reported.9
The syntheses of compounds 3a-g and 4a-f, starting
with the appropriate 2,3-diaryltrop-2-enes (5a-g), are
shown in Scheme 1. Catalytic reduction of 5a or 5b in
methanol using 5% palladium on carbon gave exclu-
sively the 2R,3R-diaryltropanes 4a and 4b, respectively.
No reduction conditions were found that would directly
convert 5a or 5b to the 2â,3â-diaryltropanes 3a and 3b,
respectively. Fortunately, we found that catalytic reduc-
* To whom correspondence should be addressed. Telephone: 919-
541-6679. Fax: 919-541-8868. E-mail: fic@rti.org.
10.1021/jm0582423 CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/21/2005

7438 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23
Kotturi et al.
Scheme 1a
a Reagents: (a) C6H5OCOCl, CH2Cl2, NaHCO3; (b) H2, Pd/C, CH3OH; (c) LiAlH4, (C2H5)2O; (d) chromatography separation.
Scheme 2a
a Reagents: (a) (CF3SO2)2NC6H4, NaN[Si(CH3)3]2, THF; (b) p-XC6H4B(OH)2, Pd[P(C6H5)3]4, CsF, DEM; (c) (i) 0.5 N KOH followed by 1
N HCl, (ii) (C6H5O)2PON3, (C2H5)3N, toluene; (d) C2H5OH, reflux 8 h; (e) reflux with 19% HCl for 1 h; (f) aryl MgBr, (C2H5)2O; (g)
concentrated HBr, reflux, 15 min; (h) (CF3SO2)2NC6H4, NaN[Si(CH3)3]2, THF.
tion of the N-phenoxycarbonyl-protected analogues 6a-
g, followed by lithium aluminum hydride reduction to
convert the urethane to the N-methyl group, gave a
mixture of the 2â,3â- and 2R,3R-isomers 3 and 4, which
could be readily separated by chromatography. The
urethanes 6a-g were obtained by N-demethylation of
5a-g with phenyl chloroformate. The relative stereo-
chemistry of each compound was determined by analy-
(trimethylsilyl)amide afforded the triflate 8. Reaction
of 8 with phenyl- or 4-methylphenylboronic acid in
refluxing diethoxymethane (DEM) using tetrakis(triph-
enylphosphine)palladium(0) as catalyst followed by
chromatographic purification gave 3-phenyl- or 3-(4-
methylphenyl)-2-tropenes 9a or 9b in 88% and 89%
yields, respectively. Hydrolysis of 9a and 9b with 0.5
N potassium hydroxide solution followed by acidification
to pH 6 gave the corresponding carboxylic acid, which
was treated with diphenylphosphoryl azide in toluene
containing triethylamine. The resulting intermediate
isocyanate 10a or 10b was refluxed in ethanol to afford
the corresponding urethane, which was hydrolyzed with
19% hydrochloride acid to give the desired (R)-2-
1
ses of the H NMR spectra.
The 2,3-diaryltrop-2-enes (5a-g) needed to prepare
3a-h and 4a-g were synthesized starting with 2-car-
bomethoxy-3-tropinone (7) as outlined in Scheme 2.10,11
The addition of N-phenyltrifluoromethanesulfonamide
to a tetrahydrofuran solution of 7 containing sodium bis-

2,3-Diaryltropanes
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23 7439
Table 1. Monoamine Transporter Binding Properties of 2,3-Diaryltropanes
IC50, nM (Ki, nM)
DAT
NET
5-HTT
compd
X
Y
Z
isomer structure [3H]WIN 35,428
[3H]Nisoxetine
[3H]paroxetine
cocaine
2aa
2ba
14a
3a
89.1
3300 (1990)
920 ( 70 (550 ( 44)
60 ( 1 (36 ( 1)
1050 (45)
H
2â,3â
2â,3â
2R,3R
2â,3â
2R,3R
2â,3â
2R,3R
2â,3â
2R,3R
2â,3â
2R,3R
2â,3â
2R,3R
2â,3â
2R,3R
2â,3â
A
A
A
B
B
B
B
B
B
B
B
B
B
B
B
B
23 ( 5
1960 ( 61 (178 ( 6)
CH3
CH3
H
1.7 ( 0.3
23.4 ( 4.2
12.6 ( 1.9
690 ( 37
1.96 ( 0.08
430 ( 59
22.4 ( 5.5
540 ( 57
1.35 ( 0.34
340 ( 9
1.23 ( 0.13
238 ( 32
23.3 ( 0.8
980 ( 48
0.90 ( 0.12
240 ( 27 (23 ( 3)
>2000
21000 ( 3300 (1900 ( 300)
41000 ( 5300 (3700 ( 481)
1100 ( 83 (100 ( 7)
16000 ( 3700 (1500 ( 340)
45000 ( 9500 (4100 ( 860)
11000 ( 2600 (1000 ( 240)
1010 ( 20 (250 ( 5)
10000 ( 1100 (910 ( 100)
1669 ( 167 (410 ( 41)
1530 ( 255 (376 ( 63)
13700 ( 7100 (1250 ( 646)
H
H
H
H
H
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
3850 ( 1270 (1930 ( 63)
920 ( 150 (550 ( 89)
1040 ( 41 (626 ( 24)
480 ( 86 (280 ( 51)
4850 ( 72 (2920 ( 43)
6100 ( 1100 (3700 ( 640)
4700 ( 200 (2800 ( 120)
780 ( 84 (390 ( 42)
13000 ( (7800 (
282 ( 44 (191 ( 22)
NT
10000 ( 1400 (6000 ( 840)
78000 ( 2800 (46000 ( 16000) 16200 ( 1700 (1470 ( 154)
132 ( 25 (61 ( 13)
4a
H
3b
CH3
CH3
H
4b
3c
4c
H
3d
4d
3e
CH3 CH3
CH3 CH3
CH3 CH3O
CH3 CH3O
4e
3f
CH3 CH3O CH3O
CH3 CH3O CH3O
CH3
4f
3g
F
H
100 ( 6.0 (25 ( 2)
a Taken from ref 12.
tropinone 11a or 11b in 62% and 55% yields, respec-
tively, from 7. Addition of the appropriate arylmagne-
sium bromide to 11a or 11b gives the addition products
12a-c, which were dehydrated with concentrated hy-
drobromic acid to yield the 2,3-diaryltropenes 5a-c.
Tropenes 5d-g as well as 5a were prepared by convert-
ing 11a and 11b to triflates 13a and 13b using N-
phenyltrifluoromethanesulfonamide and sodium bis-
(trimethylsilyl)amide. Reaction of 13a or 13b with the
appropriate boronic acid in diethoxymethane using
tetrakis(triphenylphosphine)palladium(0) gave the de-
sired tropenes 5a and 5d-g.
present in 2a and other 3â-aryl substituted analogues
with a carboxamido, heterocyclic, olefinic, keto, or alkyl
group has very little effect on binding affinity at the
DAT.5 In the present study, we report the effect of
replacing the 2â-carbomethoxy group with various aryl
groups. Replacement of the 2â-carbomethoxy group of
2a with a 3â-phenyl group to give 3a results in an
essential 2-fold increase in binding affinity (12.6 vs 23
nM IC50). In the case of the 3â-(4′-methylphenyl)
analogue 2b, replacing the 2â-carbomethoxy group with
a 2â-phenyl ring had almost no effect on binding affinity
(1.96 vs 1.7 nM IC50). The addition of a 4-methyl group
to 2a to give 3c or the addition of 4-methyl, 4-methoxy,
or 4-fluoro group to 3b to give 3d, 3e, and 3g, respec-
tively, had very little effect on binding affinity to the
DAT. The most potent compound was the 4-fluoro
analogue 3g, which possessed a 0.9 nM IC50 value at
the DAT. Results for the 2R,3R analogues were quite
different from those of the 2â,3â analogues. For ex-
ample, replacement of the 2R-carbomethoxy group in the
2R,3R compound 14 with a 3R-phenyl group to give 4b
results in an 18-fold loss in binding affinity at the DAT
(430 vs 23.4 nM IC50). The IC50 values for the 2R,3R-
(4-methylphenyl)tropanes (4b-f) ranged from 340 to
980 nM. The 2R,3R-diphenyl analogue 4a possessed an
IC50 of 690 nM. None of the compounds evaluated have
appreciable affinity at the 5-HTT and NET. In fact,
compounds 3b, 3d, and 3e with IC50 values of 1.96, 1.35,
and 1.23 nM, respectively, at the DAT, with Ki values
of 280, 390, and 191 nM at the NET and 100, 250, and
410 nM at the 5-HTT, respectively, are selective for the
DAT relative to the NET and 5-HTT. Thus, even though
the replacement of the carbomethoxy group of the
3-phenyltropanes 2a,b with a 2â-aryl group to give
3a-g had only a small effect on binding to the DAT,
the overall effects of binding at the DAT, NET, and
5-HTT resulted in compounds with increased potency
at the DAT and selectivity at the DAT relative to the
Biology
The IC50 values for the inhibition of radioligand
binding at the dopamine, serotonin, and norepinephrine
transporters for 3a-g and 4a-f are listed in Table 1.
For comparison, the previously reported IC50 values for
cocaine (1), 2a, 2b (RTI-32), and 3R-(4-methylphenyl)-
tropane-2R-carboxylic acid methyl ester (14) are also
listed.12 The binding affinities at the dopamine, sero-
tonin, and norepinephrine transporters were deter-
mined via competitive binding assays using previously
reported procedures.13,14
Results and Discussion
Studies from our laboratory as well as from others
have shown that replacing the 2â-carbomethoxy group

7440 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23
Kotturi et al.
boronic acid (2.30 g, 11 mmol), Pd(PPh3)4 (0.52 g, 0.045 mmol),
and cesium fluoride (3.0 g, 33.0 mmol) in DEM (30 mL) was
stirred at 60 °C for 2 h. The solvent was evaporated, and the
reaction mixture was diluted with ether (200 mL). The
resulting solid was separated by filtration, and the solvent was
evaporated. The dark oil was purified by flash column chro-
matography (SiO2, 5% Et3N in EtOAc) to give 9b as a light-
yellow oil (3.61 g, 89%): [R]23D -72.5° (c 3.68, CHCl3); 1H NMR
(CDCl3) δ 7.13-7.09 (m, 2H), 7.03-7.00 (m, 2H), 3.83 (m, 1H),
3.48 (s, 3H), 3.33 (m, 1H), 2.73 (dd, J ) 4.7, 18.8 Hz, 1H), 2.43
(s, 3H), 2.33 (s, 3H), 2.23-2.10 (m, 2H), 2.09-1.90 (m, 2H),
1.63 (m, 1H); 13C NMR (CDCl3) δ 168.4, 143.3, 138.0, 136.9,
130.0, 128.5, 126.5, 60.2, 57.2, 57.1, 37.2, 35.7, 34.1, 30.0, 21.0.
Anal. (C17H21NO2) C, H, N.
(R)-3-Phenyl-2-tropinone (11a). Methyl ester 9a (2.06 g,
8.01 mmol) was heated to reflux in KOH solution (0.5 N, 32
mL). After 30 min, the mixture was acidified to pH 6 using
HCl solution (1 N). After removal of solvents, the resulting
residue was extracted with absolute EtOH (3 × 40 mL).
Evaporation of EtOH gave the acid as a white solid. The acid
was stirred with diphenylphosphoryl azide (2.64 g, 9.61 mmol)
and Et3N (3.35 mL, 24.03 mmol) in toluene (25 mL) at room
temperature. After 30 min, the reaction mixture was main-
tained at 90 °C for another 30 min and then heated to reflux
briefly. Absolute EtOH (10 mL) was added, and the reaction
mixture was refluxed for 8 h. The residue obtained after
removal of solvents was refluxed in 19% HCl solution (10 mL)
for 1 h, basified to pH >9 with 6 N NaOH solution, and
extracted with CH2Cl2 (4 × 50 mL). The CH2Cl2 extracts were
washed with H2O (10 mL) and brine (10 mL) and dried (Na2-
SO4), and the solvents were removed. The resulting dark oil
was purified by flash column chromatography (SiO2, 5-10%
MeOH in EtOAc/Et3N, 90:0.5) to give 11a as a white solid (1.06
g, 62%): mp 104.0-105.5 °C; [R]24D +29.8° (c 0.63, CHCl3); 1H
NMR (CDCl3) δ 7.36-7.22 (m, 3H), 7.17-7.13 (m, 2H), 3.59
(dd, J ) 8.1, 11.8 Hz, 1H), 3.46 (m, 2H), 2.46 (s, 3H), 2.44-
2.20 (m, 3H), 2.12 (m, 1H), 2.00-1.80 (m, 2H); 13C NMR
(CDCl3) δ 208.4, 138.3, 129.0, 128.5, 127.0, 71.8, 50.2, 49.3,
40.2, 37.9, 26.6. Anal. (C14H17NO) C, H, N.
NET and 5-HTT. The high potency and DAT selectivity
of the 2â,3â-aryltropanes increase interest in this class
of compounds as potential pharmacotherapies for co-
caine addiction.
In summary, we developed procedures for the syn-
thesis of 2â,3â-diaryltropanes. The compounds can be
viewed as analogues of 2a and 2b where the 2â-
carbomethoxy group has been replaced by a substituted
phenyl ring. The compounds having the 2â-aryl group
tended to be more potent at the DAT than the corre-
sponding 2â-carbomethoxy analogues and more selective
relative to binding at the NET and 5-HTT. The 2â-(4-
methylphenyl)-3â-(4-methylphenyl)tropane (3d) was the
most potent and selective analogue.
Experimental Section
Commercial reagents and solvents were used as received.
All reactions were run under dry N2 in oven-dried glassware.
The HCl (1 M), NaOH (6 M), Na2CO3 (saturated), NH4Cl
(saturated), and NaCl (saturated) used in various procedures
refer to aqueous solutions. All organic solvents used, unless
otherwise mentioned, were either distilled before use or were
purchased anhydrous and used directly. Reactions were moni-
tored by TLC on silica gel GF plates (0.25 µm film thickness).
Preparative separations were performed using flash column
chromatography on silica gel (grade 62, 60-200 mesh) and
PTLC on 20 cm × 20 cm silica gel GF plates; band elution
was monitored using a hand-held UV lamp. Optical rotations
were measured on an AutoPol III polarimeter, purchased from
Rudolf Research. Elemental analyses were performed by
Atlantic Microlab, Norcross, GA. Melting points were uncor-
rected. 1H NMR and 13C NMR spectra were measured in CDCl3
at 300, 250, 62.5, and 75 MHz, respectively, and were
referenced to internal (CH3)4Si, as the free bases.
(R)-2-Carbomethoxy-3-tropinone 3-Triflate (8). To a
solution of (R)-(+)-2-carbomethoxy-3-tropinone (7, 7.08 g, 36
mmol) in dry THF (200 mL) at -78 °C was added dropwise
NaN(TMS)2 (1 M solution in THF, 43 mL) in 10 min. The
mixture was stirred for 30 min, the mixture was allowed to
warm to 0 °C, and N-phenyltrifluoromethanesulfonamide (15.4
g, 43 mmol) was added portionwise in 10 min. The reaction
mixture was stirred at 0 °C for 1 h and then at room
temperature for 4 h. After removal of the solvents, the residue
was taken up with water (50 mL) and extracted with EtOAc
(4 × 100 mL). The EtOAc extracts were washed with brine
(20 mL), dried (Na2SO4), and evaporated. The crude product
was purified by flash column chromatography on SiO2, using
EtOAc followed by 5% Et3N in EtOAc as eluent to afford 8 as
an amber oil (10.94 g, 92%): [R]23D +9.86° (c 7.25, CHCl3); 1H
NMR (CDCl3) δ 3.94 (d, J ) 4.9 Hz, 1H), 3.82 (s, 3H), 3.43 (m,
1H), 2.85 (dd, J ) 4.6, 18.7 Hz, 1H), 2.40 (s, 3H), 2.25-2.10
(m, 2H), 2.05-1.93 (m, 2H), 1.61 (m, 1H); 13C NMR (CDCl3) δ
163.7, 149.0, 125.2, 118.2 (q, J ) 317.8 Hz), 60.0, 57.4, 52.0,
34.8, 34.6, 33.0, 30.0. Anal. (C11H14F3NO5S) C, H, N.
(R)-2-Carbomethoxy-3-phenyl-2-tropene (9a). A mix-
ture of compound 8 (3.29 g, 10 mmol), phenylboronic acid (1.46
g, 12 mmol), Pd(PPh3)4 (0.035 g, 0.30 mmol), and cesium
fluoride (3.34 g, 22 mmol) in DEM (20 mL) was stirred at 60
°C for 2 h. The reaction mixture was diluted with ether (200
mL), and the resulting solid was separated by filtration. The
ether extracts were washed with H2O (10 mL), dried (Na2SO4),
and evaporated. The resulting dark oil was purified by flash
column chromatography (SiO2, 5% Et3N in EtOAc) to give 9a
as a light-yellow oil (2.27 g, 88%): [R]26D -61.4° (c 2.87, CHCl3);
1H NMR (CDCl3) δ 7.36-7.24 (m, 3H), 7.15-7.11 (m, 2H), 3.87
(d, J ) 5.3 Hz, 1H), 3.47 (s, 3H), 3.36 (m, 1H), 2.77 (dd, J )
4.8, 18.9 Hz, 1H), 2.46 (s, 3H), 2.30-2.10 (m, 2H), 2.10-1.94
(m, 2H), 1.66 (m, 1H); 13C NMR (CDCl3) δ 143.6, 141.1, 130.4,
127.9, 127.3, 126.6, 60.2, 57.4, 51.2, 37.4, 35.9, 34.2, 30.1. Anal.
(C16H19NO) C, H, N.
(R)-3-(4-Methylphenyl)-2-tropanone (11b). Methyl ester
9b (1.42 g, 5.24 mmol) was heated to reflux in KOH solution
(0.5 N, 21 mL). After 30 min, the mixture was acidified to pH
6 using HCl solution (1 N). After removal of solvents, the
resulting residue was extracted with absolute EtOH (3 × 40
mL). The solvent was evaporated to produce the acid as a white
solid. The acid was stirred with diphenylphosphoryl azide (1.73
g, 6.29 mmol) and Et3N (2.2 mL, 15.7 mmol) in toluene (20
mL) at room temperature. After 30 min, the reaction mixture
was maintained at 90 °C for another 30 min and then heated
to reflux briefly. Absolute EtOH (10 mL) was added, and the
reaction mixture was refluxed for 10 h. The residue obtained
after removal of solvents was refluxed in 19% HCl solution
(10 mL) for 1 h, basified to pH >9 with 6 N NaOH solution,
and extracted with CH2Cl2 (4 × 50 mL). The CH2Cl2 extracts
were washed with H2O (10 mL) and brine (10 mL) and dried
(Na2SO4), and the solvents were removed. The resulting dark
oil was purified by flash column chromatography (SiO2, 5-10%
MeOH in EtOAc/Et3N, 90:0.5) to give 11b as a white solid (0.65
1
g, 55%): mp 100-101.5 °C; [R]24 +20.2° (c 0.59, CHCl3); H
D
NMR (CDCl3) δ 7.12 (m, 2H), 7.02 (m, 2H), 3.53 (dd, J ) 8.1,
11.8 Hz, 1H), 3.42 (m, 2H), 2.47 (s, 3H), 2.40-2.15 (m, 3H),
2.30 (s, 3H), 2.07 (m, 1H), 1.85 (2H); 13C NMR (CDCl3) δ 208.3,
136.3, 135.2, 129.0, 128.7, 71.7, 60.0, 48.7, 40.0, 37.8, 26.4, 20.9.
Anal. (C15H19NO) C, H, N.
(R)-2,3-Diphenyl-2-tropinol (12a). To a solution of ketone
11a (1.45 g, 6.75 mmol) in ethyl ether (35 mL) was added
phenylmagnesium bromide solution (3 M in ether, 6.75 mL)
at room temperature. The reaction mixture was stirred at room
temperature for 11 h and diluted with ether (100 mL), and
the reaction was quenched with H2O (50 mL). The aqueous
layer was extracted with ether (3 × 50 mL). The ether extracts
were washed with H2O (10 mL) and dried (Na2SO4), and the
solvents were removed. The resulting residue was purified by
flash column chromatography (SiO2, hexane/EtOAc followed
(R)-2-Carbomethoxy-3-(4-methylphenyl)-2-tropene (9b).
A mixture of compound 8 (4.95 g, 15 mmol), 4-methylphenyl-

2,3-Diaryltropanes
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23 7441
by EtOAc, then 5% MeOH in EtOAc/Et3N, 99.5:0.5) to give
the desired alcohol 12a as a white solid (0.67 g, 34%) (92%
based on recovered ketone) (0.908 g, 63%): mp 92.5-94.0 °C;
[R]23D -137.3° (c 0.555, CHCl3); 1H NMR (CDCl3) δ 7.75-7.64
(m, 2H), 7.20-7.10 (m, 6H), 6.95-6.90 (m, 2H), 3.43 (m, 1H),
3.27 (m, 1H), 3.15 (dd, J ) 5.3, 13.7 Hz, 1H), 2.50 (m, 1H),
2.41 (s, 3H), 2.35-2.00 (m, 3H), 1.89 (s, 1H), 1.82 (m, 1H), 1.67
(ddd, J ) 3.1, 5.3, 13.0 Hz, 1H); 13C NMR (CDCl3) δ 144.8,
139.9, 129.6, 128.4, 127.2, 126.7, 126.3, 126.2, 76.2, 72.9, 61.4,
46.2, 41.5, 36.6, 25.2, 22.1.
6.99 (m, 2H), 6.89 (m, 4H), 3.64 (d, J ) 5.7 Hz, 1H), 3.43 (m,
1H), 2.76 (dd, J ) 4.4, 18.0 Hz, 1H), 2.57 (s, 3H), 2.21 (s, 3H),
2.33-1.94 (m, 4H), 1.74 (m, 1H); 13C NMR (CDCl3) δ 141.3,
138.0, 137.9, 135.7, 129.8, 129.2, 128.6; 128.4, 127.8, 126.0,
65.1, 58.1, 35.95, 35.97, 33.4, 30.2, 21.0.
3-Phenyl-2-(4-methylphenyl)tropene (5c). The 12c (0.52
g, 1.67 mmol) was refluxed in concentrated HBr (4 mL) for 15
min. HBr was evaporated. The residue was taken up by
saturated NaHCO3 and extracted with EtOAc (15 mL × 4).
EtOAc was washed with brine (10 mL), dried over Na2SO4,
and evaporated to give a brownish oil. Purification of crude
by flash column chromatography (SiO2, 5% Et3N in EtOAc)
afforded 5c as a clear oil: [R]23D -224.5° (c 0.955, CHCl3); 1H
NMR (CDCl3) δ 7.32-6.86 (m, 9H), 3.61 (d, J ) 5.6 Hz, 1H),
3.41 (t, J ) 6.3 Hz, 1H), 2.75 (dd, J ) 17.3 Hz, 1H), 2.55 (s,
3H), 2.23 (s, 3H), 2.17-1.93 (m, 4H), 1.74 (m, 1H); 13C NMR
(CDCl3) δ 141.5, 138.5, 138.3, 135.7, 129.6, 129.1, 128.8, 128.6,
127.7, 126.1, 65.2, 58.2, 36.2, 33.6, 30.4, 21.1.
(R)-3-(4-Methylphenyl)-2-phenyl-2-tropinol (12b). To a
solution of ketone 11b (0.84 g, 3.67 mmol) in ethyl ether (25
mL) was added phenylmagnesium bromide solution (3 M in
ether, 3.67 mL) at room temperature. The reaction mixture
was stirred at room temperature for 11 h and diluted with
ether (100 mL), and the reaction was quenched with H2O (50
mL). The aqueous layer was extracted with ether (3 × 50 mL).
The ether extracts were washed with H2O (10 mL) and dried
(Na2SO4), and the solvents were removed. The resulting
residue was purified by flash column chromatography (SiO2,
hexane/EtOAc followed by EtOAc, then 5% MeOH in EtOAc/
Et3N, 99.5:0.5) to give the desired alcohol 12b as a white solid
(R)-3-Phenyl-2-tropinone 2-Triflate (13a). A solution of
NaN(TMS)2 was added slowly (5 min) to the ketone 11a in
THF (20 mL) at -78 °C. The reaction mixture was stirred at
room temperature for 30 min, then warmed to 0 °C. N-
Phenyltrifluoromethanesulfonamide (0.826 g) was added in
one portion. The reaction mixture was stirred for 1 h at 0 °C
and then at room temperature for 22 h. The reaction was
quenched with H2O (15 mL) and extracted with EtOAc (3 ×
20 mL). The EtOAc extracts were washed with brine (10 mL)
and dried (MgSO4). Removal of the solvents gave an amber
oil, which was purified by column chromatography (SiO2,
EtOAc then MeOH/EtOAc/Et3N, 5:94:1) to afford 13a as a
(0.47 g, 42%, 89%) based on recovered ketone (0.448 g, 53%):
1
mp 156.0-157.4 °C; [R]23 -163° (c 0.655, CHCl3); H NMR
D
(CDCl3) δ 7.75-7.71 (m, 2H), 7.14-7.08 (m, 3H), 6.88 (d, J =
8.0 Hz, 2H), 6.74 (d, J = 8.0 Hz, 2H), 3.36 (m, 1H), 3.22 (m,
1H), 3.03 (dd, J ) 5.4, 13.7 Hz, 1H), 2.41 (m, 1H), 2.33 (s, 3H),
2.26-2.00 (m, 3H), 2.22 (s, 3H), 1.77 (s, 1H), 1.74 (m, 1H), 1.58
(ddd, J ) 3.1, 5.4, 13.0 Hz, 1H); 13C NMR (CDCl3) δ 145.0,
136.8, 135.8, 129.5, 128.5, 128.1, 126.8, 126.3, 76.3, 73.0, 61.6,
46.1, 41.6, 37.0, 25.4, 22.1, 20.9. Anal. (C21H25NO) C, H, N.
light-yellow oil (250 mg, 34%): [R]23 +16.7° (c 2.43, CHCl3);
D
1H NMR (CDCl3) δ 7.41-7.26 (m, 5H), 3.50 (d, J ) 4.8 Hz,
1H), 3.47 (t, J ) 5.5 Hz, 1H), 2.96 (dd, J ) 4.5, 17.8 Hz, 1H),
2.55 (s, 3H), 2.27-2.17 (m, 3H), 2.10 (d, J ) 17.6 Hz, 1H),
1.67 (m, 1H); 13C NMR (CDCl3) δ 144.9, 135.0, 128.2, 128.0,
127.6, 125.8, 118.0 (q, J ) 318.2 Hz), 61.4, 56.5, 35.2, 34.6,
33.9, 30.1.
(R)-3-Phenyl-2-(4′-methylphenyl)-2-tropinol (12c). To a
solution of 11a (860 mg, 4 mmol) in ether (30 mL) at -30 °C
was added dropwise a solution of 4-methylphenylmagnesium
bromide (1 m, 8 mL) under N2 in 5 min. The mixture was
stirred at -30 °C for 1 h, then warmed to 0 °C. The mixture
was diluted with ether (100 mL), and the reaction was
quenched with H2O (50 mL). The aqueous layer was extracted
further with ether (50 mL × 3). Ether layers were combined,
washed with H2O (10 mL), dried over Na2SO4, and evaporated.
The crude residue was purified by flash column chromatog-
raphy (SiO2, hexane/EtOAc, 2:1, then EtOAc, then 2% Et3N
in EtOAc) to afford 12c (0.78 g, 63%) and starting material
(0.20 g, 23%): [R]25D -140.5° (c 0.22, CHCl3); 1H NMR (CDCl3)
δ 7.56 (d, J ) 8.4 Hz, 2H), 7.08 (m, 3H), 6.89 (m, 4H), 3.35 (m,
1H), 3.21 (d, J ) 6.4 Hz, 1H), 3.07 (dd, J ) 5.3, 13.5 Hz, 1H),
2.43 (m, 1H), 2.33 (s, 3H), 2.24 (s, 3H), 2.20-2.00 (m, 2H),
1.79-1.67 (m, 2H), 1.55 (m, 2H); 13C NMR (CDCl3) δ 153.7,
141.8, 140.0, 135.6, 129.6, 129.0, 128.3, 127.4, 127.2, 126.1,
115.1, 73.1, 61.4, 46.1, 41.5, 36.6, 25.2, 22.1, 20.8.
2,3-Diphenyl-2-tropene (5a). Alcohol 12a (631 mg, 2.15
mmol) was refluxed in concentrated HBr (5 mL) for 15 min.
The residue obtained after removal of solvents was taken up
in saturated NaHCO3 (10 mL) and extracted with EtOAc (4 ×
15 mL). The EtOAc extracts were washed with brine (10 mL),
dried (Na2SO4), and evaporated to give a yellow oil (580 mg,
98%), which was pure enough for the next step. Purification
by flash column chromatography (5% Et3N in EtOAc) gave 5a
as a clear oil: [R]23D -277.6° (c 0.75, CHCl3); 1H NMR (CDCl3)
δ 7.17-7.05 (m, 6H), 7.02-6.96 (m, 4H), 3.75 (d, J ) 5.8 Hz,
1H), 3.54 (m, 1H), 2.83 (dd, J ) 4.4, 18.2 Hz, 1H), 2.64 (s, 3H),
2.40-2.11 (m, 3H), 2.05 (m, 1H), 1.80 (m, 1H); 13C NMR
(CDCl3) δ 140.7, 140.5, 137.7, 130.3, 129.2, 128.7, 128.0, 127.8,
126.4, 65.1, 58.3, 36.0, 35.8, 33.3, 30.0. Anal. (C20H21NO) C,
H, N.
2,3-Diphenyl-2-tropene (5a) from 13a. A mixture of
triflate 13a (95 mg, 0.27 mmol), phenylboronic acid (40 mg,
0.32 mmol), Pd(PPh3)4 (9 mg), and cesium fluoride (90 mg, 0.59
mmol) in DEM (8 mL) was refluxed for 1 h. The solvent was
removed, and the resulting residue was purified by flash
column chromatography (SiO2, 2.5% Et3N in EtOAc) to give
5a as a clear oil (55 mg, 74%). The 1H NMR spectrum was
identical to the compound prepared from 12a.
(R)-3-(4-Methylphenyl)-2-tropinone 2-Triflate (13b). To
a well-stirred hexane-washed suspension of 0.13 g (5.41 mmol)
of NaH in THF at -78 °C was added 1.00 g (4.36 mmol) of 8b
in 20 mL of THF over 10 min, and the mixture was stirred for
15 min. The mixture was then warmed to room temperature
and stirred for 30 min, and 4.65 g (13.0 mmol) of N-phenyl-
trifluoromethanesulfonamide was added in one portion. The
mixture was stirred at room temperature for 2 h. Concentra-
tion of the mixture, followed by extraction with ether, resulted
in a heavy brown oil, which was purified by column chroma-
tography using hexanes with increasing concentrations of
EtOAc and Et3N to yield 0.93 g (59%) of 6 as a thick red oil
that had the following properties: [R]23D +18.2° (c 0.60, CHCl3);
1H NMR (CDCl3) δ 7.18 (s, 4H), 3.50 (d, J ) 4.8 Hz, 1H), 3.33
(t, J ) 5.5 Hz, 1H), 2.96 (dd, J ) 17.8, 4.5 Hz, 1H), 2.54 (s,
3H), 2.34 (s, 3H), 2.27-2.17 (m, 3H), 2.10 (d, J ) 17.6 Hz,
1H), 1.67 (m, 1H); 13C NMR (CDCl3) δ 144.0, 137.3, 131.4,
128.5, 128.3, 128.1, 126.9, 125.0, 119.5, 115.2, 60.8, 59.4, 56.0,
39.5, 37.2, 34.6, 34.1, 33.3, 29.5, 25.9, 20.4. Anal. (C16H18F3-
NO3S) C, H, N.
3-(4-Methylphenyl)-2-phenyl-2-tropene (5b). Alcohol 12b
(331 mg, 1.07 mmol) was refluxed in concentrated HBr (3 mL)
for 15 min. The reaction mixture was basified to pH >9 using
6 N NaOH and extracted with CH2Cl2 (4 × 15 mL). The CH2-
Cl2 extracts were washed with brine (10 mL), dried (Na2SO4),
and evaporated. The resulting solid was purified by flash
column chromatography (SiO2, 20% MeOH in EtOAc/Et3N, 80:
0.5) to give 5b as a colorless oil (251 mg, 81%): [R]23D -254.1°
(c 13.84, CHCl3); 1H NMR (CDCl3) δ 7.17-7.05 (m, 3H), 7.05-
Synthesis of 5d-g. Compounds 5d-g were synthesized
from triflate 13b using conditions analogous to that described
for the synthesis of 5a from triflate 13a.
2,3-Di(4-methylphenyl-2-tropene (5d). Yellow oil, 320 mg
1
(84%); [R]23 -72.2° (c 3.75, CHCl3); H NMR (CDCl3) δ 6.90
D
(m, 8H), 3.60 (d, J ) 5.7 Hz, 1H), 3.40 (t, J ) 5.8 Hz, 1H),
2.73 (dd, J ) 18.7, 4.6 Hz, 1H), 2.55 (s, 3H), 2.26 (s, 3H), 2.24
(s, 3H), 2.20-2.00 (m, 3H), 1.97 (dt, J ) 11.6, 2.8 Hz, 1H),

7442 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23
Kotturi et al.
1.74 (m, 1H); 13C NMR (CDCl3) δ 138.5, 138.3, 138.0, 135.6,
129.3, 129.1, 128.6, 128.5, 128.4, 65.2, 58.1, 36.2, 33.5, 30.7,
21.1, 21.0.
3-(4-Methylphenyl)-2-(4-methoxyphenyl)-2-tropene (5e).
White semisolid, 380 mg (96%); [R]23D -234.0° (c 1.00, CHCl3);
1H NMR (CDCl3) δ 6.92 (m, 6H), 6.70 (d, J ) 8.5 Hz, 2H), 3.74
(s, 3H), 3.60 (d, J ) 6.0 Hz, 1H), 3.40 (t, J ) 6.0 Hz, 1H), 2.73
(dd, J ) 18.0, 4.5 Hz, 1H), 2.25 (s, 3H), 2.20-2.00 (m, 3H),
1.96 (dt, J ) 9.5, 3.0 Hz, 1H), 1.73 (m, 1H); 13C NMR δ 157.9,
139.0, 137.8, 135.6, 133.9, 130.3, 129.1, 128.7, 128.5, 113.3,
65.2, 58.2, 55.0, 36.6, 36.3, 33.5, 30.3, 21.0.
) 14.7 Hz, 1H), 4.64 (d, J ) 18.5 Hz, 1H), 3.08 (t, J ) 17.2,
1H), 2.50-2.30 (m, 2H), 2.25 (s, 3H), 2.24 (s, 3H), 2.20-1.80
(m, 3H); 13C NMR (CDCl3) δ 152.7, 151.3, 141.0, 140.5, 137.8,
136.8, 136.6, 136.2, 136.0, 129.6, 129.2, 128.7, 128.5, 125.2,
121.8, 121.7, 59.3, 58.9, 53.7, 53.4, 40.0, 38.8, 34.2, 33.3, 30.5,
29.8, 21.1, 21.0.
(R)-N-Phenoxycarbonyl-2-(4-methoxyphenyl)-3-(4-me-
thylphenyl)-2-tropene (6e). Compound 6e was prepared
using a procedure similar to that described for 6a. The
compound was obtained as a white semisolid: 380 mg (85%);
[R]23D -330.0° (c 0.25, CHCl3); 1H NMR (CDCl3) δ 7.40 (m, 2H),
7.30-7.15 (m, 4H), 7.09 (m, 2H), 6.96 (m, 4H), 6.80-6.70 (m,
3H), 4.92 (dd, J ) 16.0, 4.3 Hz, 1H), 4.70 (m, 1H), 3.75 (s, 3H),
3.12 (dt, J ) 16.5, 3.5 Hz, 1H), 2.60-2.40 (m, 2H), 2.29 (s,
3H), 2.20-1.90 (m, 3H); 13C NMR (CDCl3) δ 158.2, 156.2, 152.7,
151.3, 140.5, 140.0, 137.7, 136.0, 132.0, 131.8, 130.8, 130.5,
130.3, 129.3, 129.2, 128.7, 128.6, 125.2, 121.8, 121.6, 119.8,
115.5, 113.5, 113.4, 59.3, 58.9, 55.0, 53.6, 53.4, 39.9, 38.8, 34.2,
33.3, 30.5, 29.8, 21.0.
(R)-N-Phenoxycarbonyl-2-(2,3-dimethoxyphenyl-3)-4-
methylphenyl-2-tropene (6f). Compound 6f was prepared
using a procedure similar to that described for 6a. The
compound was obtained as a white semisolid: 1.34 g (90%);
[R]23D -270.7° (c 1.10, CHCl3); 1H NMR (CDCl3) δ 7.34 (m, 2H),
7.16 (m, 3H), 6.92 (m, 4H), 6.72 (m, 2H), 6.54 (d, J ) 19.3 Hz,
1H), 4.91 (dd, J ) 17.2, 4.2 Hz, 1H), 4.65 (m, 1H), 3.80 (s, 3H),
3.58 (s, 3H), 3.49 (s, 3H), 3.09 (t, J ) 17.2 Hz, 1H), 2.53-2.30
(m, 2H), 2.24 (s, 3H), 2.20-1.90 (m, 3H); 13C NMR (CDCl3) δ
152.7, 151.2, 148.1, 147.7, 140.6, 140.3, 137.9, 136.0, 132.1,
131.9, 130.5, 129.4, 129.2, 128.5, 125.1, 121.7, 121.6, 121.0,
113.2, 110.5, 59.0, 58.6, 55.6, 55.4, 53.5, 53.4, 39.9, 38.8, 34.3,
33.4, 30.5, 29.8, 20.9.
3-(Methylphenyl)-2-(2,3-dimethoxyphenyl)-2-tropene
(5f). Light-yellow oil, 1.15 g (97%); [R]23 -189.1° (c 2.17,
D
1
CHCl3); H NMR δ (CDCl3) 6.92 (m, 4H), 6.71 (d, J ) 8.3 Hz,
1H), 6.65 (dd, J ) 8.4, 1.7 Hz, 1H), 6.41 (d, J ) 1.7 Hz, 1H),
3.82 (s, 3H), 3.65 (d, J ) 5.7 Hz, 1H), 3.54 (s, 3H), 3.42 (t, J )
5.7 Hz, 1H), 2.76 (dd, J ) 17.6, 4.3 Hz, 1H), 2.54 (s, 3H), 2.34
(s, 3H), 2.20-2.10 (m, 3H), 1.97 (dt, J ) 8.7, 2.5 Hz, 1H), 1.75
(m, 1H); 13C NMR (CDCl3) δ 147.9, 147.3, 138.7, 137.8, 135.6,
133.8, 129.4, 128.5, 128.4, 120.8, 113.4, 110.5, 64.9, 58.2, 55.6,
55.4, 36.5, 33.5, 30.1, 20.9.
3-(4-Methylphenyl)-2-(4-fluorophenyl)-2-tropene (5g).
White semisolid, 365 mg (90%); [R]23D -125.2° (c 2.35, CHCl3);
1H NMR (CDCl3) δ 6.97-6.92 (m, 4H), 6.88-6.82 (m, 4H), 3.57
(d, J ) 6.0 Hz, 1H), 3.41 (t, J ) 5.5 Hz, 1H), 2.74 (dd, J )
18.0, 4.0 Hz, 1H), 2.55 (s, 3H), 2.24 (s, 3H), 2.24 (s, 3H), 2.23
(m, 1H), 2.18-2.08 (m, 2H), 1.97 (dt, J ) 9.5, 3.0 Hz, 1H), 1.74
(m, 1H); 13C NMR (CDCl3) δ 163.1, 159.2, 137.9, 137.3, 137.2,
137.1, 135.7, 130.6, 130.5, 130.1, 128.5, 128.4, 114.8, 114.5,
65.1, 58.0, 36.1, 33.3, 30.1, 20.9.
(R)-N-Phenoxycarbonyl-2,3-diphenyl-2-tropene (6a). A
mixture of diphenyltropene 5a (220 mg, 0.80 mmol), phenyl
chloroformate (0.40 mL, 0.32 mmol), and NaHCO3 (402 mg,
4.8 mmol) in dry CH2Cl2 was stirred at room temperature.
After 16 h, the reaction was quenched with saturated NaHCO3
(10 mL). The aqueous layer was separated and extracted
further with EtOAc (3 × 20 mL). The EtOAc extracts were
washed with H2O (10 mL) and dried (Na2SO4). The residue
obtained after removal of solvents was purified by flash column
chromatography (SiO2, 20% ether in hexane) to give 6a as a
white solid (286 mg, 94%): [R]23D -337.8° (c 0.97, CHCl3); 1H
NMR (CDCl3, 250 MHz) δ 7.39-6.97 (m, 15H), 4.89 (d, J )
13.1 Hz, 1H), 4.62 (m, 1H), 3.13 (t, J ) 13.6 Hz, 1H), 2.55-
2.37 (m, 2H), 2.17-1.97 (m, 3H); 13C NMR (CDCl3) δ 152.8,
151.3, 141.6, 141.1, 140.6, 139.6, 139.4, 131.4, 130.3, 129.7,
129.34, 129.26, 128.9, 128.1, 128.0, 127.8, 126.7, 126.5, 125.2,
121.7, 121.6, 119.9, 115.3, 59.2, 59.0, 53.6, 53.4, 39.9, 38.8, 34.3,
30.6, 29.8.
(R)-N-Phenoxycarbonyl-2-(4-fluorophenyl)-3-(4-meth-
ylphenyl)-2-tropene (6g). Compound 6g was prepared using
a procedure similar to that described for 6a. The compound
was obtained as a thick colorless oil: 320 mg (95%); [R]23
D
-298° (c 0.20, CHCl3); 1H NMR (CDCl3) δ: 7.38 (m, 2H), 7.20-
7.10 (m, 3H), 7.08 (m, 2 H), 6.98-6.70 (m, 6 H), 4.90 (dd, J )
16.0, 4.3 Hz, 1 H), 4.70 (m, 1 H), 3.20 (dt, J ) 16.0, 4.0 Hz, 1
H), 2.60-2.30 (m, 2 H), 2.20 (s, 3 H), 2.19-1.90 (m, 3 H); 13C
NMR (CDCl3) δ: 163.1, 159.2, 152.8, 152.0, 147.9, 147.3, 140.5,
140.0, 138.5, 137.7, 136.0, 132.0, 131.8, 129.4, 128.7, 128.2,
120.9, 114.8, 114.0, 113.5, 113.0, 65.0, 57.5, 35.5, 33.3, 30.0,
20.9.
2â,3â- and 2r,3r-Diphenyltropanes (3a and 4a). A
mixture of carbamate alkene 6a (216 mg, 0.56 mmol) and 5%
Pd/C (215 mg) in MeOH (5 mL) was hydrogenated at room
temperature under 50 psi. After 4 days, the solvent was
evaporated to give the reduced carbamate as a clear oil (221
mg). The carbamate (156 mg, 0.407 mmol) and LAH (77 mg,
2.03 mmol) were refluxed in ether (15 mL) under N2 for 3 h,
and the reaction mixture was diluted with ether (50 mL). The
reaction was quenched with H2O (0.5 mL). The reaction
mixture was stirred with Celite (1 g) and Na2SO4 (2.0 g) and
filtered. Removal of the solvent produced a clear oil (130 mg).
Purification by flash column chromatography (SiO2, MeOH/
CH2Cl2/Et3N, 5:95:0.5) afforded 3a as a white solid (39 mg,
35%) and 4a (46 mg, 41%) as a clear oil. The free bases were
converted to the HCl salt using HCl/ether (1 M).
(R)-N-Phenoxycarbonyl-2-phenyl-3-(4-methylphenyl)-
2-tropene (6b). Compound 6b was prepared using a proce-
dure similar to that described for 6a. The compound was
obtained as a white semisolid: 296 mg (95%); [R]23 -279.0°
D
(c 0.935, CHCl3); 1H NMR (CDCl3) δ 7.40-7.30 (m, 2H), 7.32-
7.10 (m, 7H), 7.00-6.70 (m, 5H), 4.90 (m,1H), 4.70 (m, 1H),
3.09 (m, 1H), 2.50-2.30 (m, 2H), 2.23 (s, 3H), 2.10-1.90 (m,
3H); 13C NMR (CDCl3) δ 152.7, 151.2, 141.2, 140.6, 139.8,
139.6, 137.5, 136.0, 131.1, 130.0, 129.7, 129.3, 129.2, 128.7,
128.5, 128.0, 127.9, 126.6, 125.2, 121.7, 121.6, 59.2, 58.9, 53.6,
53.3, 39.9, 38.7, 34.2, 33.3, 30.6, 29.7, 20.6.
2â,3â-3a‚HCl: mp 240 °C (dec); [R]24 -21.8° (c 0.17, CH3-
(R)-N-Phenoxycarbonyl-2-(4-methylphenyl)-3-phenyl-
2-tropene (6c). Compound 6c was prepared using a procedure
similar to that described for 6a. The compound was obtained
D
OH); 1H NMR (free base, CDCl3) δ 7.26-6.95 (m, 9H), 3.99
(m, 1H), 3.82 (m, 1H), 3.54 (m, 1H), 3.31 (m, 1H), 2.64 (m,
1H), 2.37 (s, 3H), 2.14-1.91 (m, 2H), 1.90-1.78 (m, 2H), 1.46
(m, 1H); 13C NMR (free base, CDCl3) δ 144.0, 142.7, 128.4,
128.3, 127.9, 127.2, 125.5, 124.8, 64.3, 60.4, 49.4, 40.7, 37.1,
36.9, 27.3, 22.6. Anal. (C20H24ClN‚0.25H2O) C, H, N.
as a white semisolid: 495 mg (75%); [R]23 -327.9° (c 1.06,
D
CHCl3); 1H NMR (CDCl3) δ 7.40-7.30 (m, 2H), 7.25-7.00 (m,
6H), 7.04-6.90 (m, 6H), 4.90 (m, 1H), 4.70 (m, 1H), 3.10 (m,
1H), 2.53-2.30 (m, 2H), 2.23 (s, 3H), 2.15-1.80 (m, 3H); 13C
NMR (CDCl3) δ 152.8, 151.3, 141.5, 141.0, 140.8, 136.4, 130.9,
129.3, 128.9, 127.8, 126.4, 125.2, 121.8, 59.3, 58.9, 53.7, 53.4,
40.0, 38.8, 34.3, 33.4, 30.7, 29.8, 21.1.
2r,3r-4a‚HCl: mp 233.4-235 °C; [R]23D +8.33° (c 0.12, CH3-
1
OH); H NMR (free base, CDCl3) δ 7.40-7.36 (m, 2H), 7.08-
6.98 (m, 6H), 6.89-6.86 (m, 2H), 3.45-3.29 (m, 3H), 2.92 (m,
1H), 2.45 (t, J ) 12.7 Hz, 1H), 2.27 (s, 3H), 2.27-2.21 (m, 2H),
1.82 (m, 2H), 1.69 (m, 1H); 13C NMR (free base, CDCl3) δ 142.9,
142.4, 130.6, 127.9, 127.6, 127.1, 125.5, 125.4, 67.8, 62.0, 53.1,
41.9, 37.2, 35.0, 27.3, 25.0. Anal. (C20H24ClN‚0.5H2O) C, H,
N.
(R)-N-Phenoxycarbonyl-2,3-di-(4-methylphenyl)-2-tro-
pene (6d). Compound 6d was prepared using a procedure
similar to that described for 6a. The compound was obtained
as a colorless heavy oil; [R]23D -310.0° (c 2.55, CHCl3); 1H NMR
(CDCl3) δ 7.35 (m, 2H), 7.17 (m, 3H), 6.92 (m, 8H), 4.87 (d, J

2,3-Diaryltropanes
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23 7443
(R)-3â-(Methylphenyl)-2â-phenyltropane (3b) and (R)-
3r-(Methylphenyl)-2r-phenyltropane (4b). A mixture of
carbamate alkene 6b (296 mg, 0.75 mmol) and 10% Pd/C (150
mg) in MeOH (10 mL) was hydrogenated at room temperature
under 50 psi. After 3 days, more catalyst (500 mg) was added,
and the reduction was continued for an additional 4 days. The
catalyst was separated by filtration and washed with ether
(100 mL). The solvent was evaporated to give the carbamates,
which were separated by flash column chromatography (SiO2,
30% EtOAc in hexane) to give the 2R,3R-isomer 4b (86 mg,
30%) and the 2â,3â-isomer 3b (88 mg, 30%).
127.2, 124.7, 64.4, 60.4, 49.0, 40.7, 37.1, 36.8, 27.3, 22.5, 20.9.
Anal. (C21H26ClN‚1.0H2O) C, H, N.
2â,3â- and 2r,3r-Di(4-methylphenyl)tropane (3d and
4d). Compounds 3d and 4d were prepared by a procedure
similar to that described for 3a and 4a. From 158 mg (0.39
mmol) of 6d, 33 mg (28%) and 44 mg (38%) of 3d and 4d were
obtained.
2â,3â‚4d‚HCl: mp 233-244 °C (dec); [R]24 -9.3° (c, 0.22,
D
CH3OH); 1H NMR (free base CDCl3) δ 7.26 (d, J ) 8.1 Hz,
2H), 6.86 (m, 4H), 6.75 (d, J ) 8.1 Hz, 2H), 3.38 (m, 1H), 3.25
(m, 2H), 2.85 (dd, J ) 2.5, 6.5 Hz, 1H), 2.31 (m 3H), 2.22 (s,
3H), 2.21 (s, 3H), 2.19 (s, 3H), 1.76 (m, 2H), 1.62 (m, 1H); 13C
NMR (free base, CDCl3) δ 141.1, 139.8, 134.8, 134.0, 128.7,
128.4, 128.3, 64.4, 60.6, 49.9, 40.7, 37.3, 36.6, 27.0, 22.7, 20.9,
20.8. Anal. (C22H28ClN‚0.5H2O) C, H, N.
2r,3r-Isomer: 1H NMR (CDCl3) δ 7.40-6.76 (m, 14H),
4.84-4.50 (m, 2H), 4.20 (m, 1H′), 3.64 (m, 1H), 2.80 (m, 1H),
2.19 (s, 3H), 2.20-1.50 (m, 5H).
2â,3â-Isomer: 1H NMR (CDCl3) δ 7.30-7.00 (m, 8H), 6.95-
6.85 (m, 4H), 6.65 (m, 2H), 4.82 (m, 1H), 4.70 (m, 1H), 3.64
(m, 1H), 3.26 (m, 1H), 2.70 (m, 1H), 2.11 (s, 3H), 2.26-2.00
(m, 3H), 1.93 (m, 2H).
2r,3r‚4d‚HCl: mp 218 °C (dec); [R]23D -10.5° (c, 0.19, CH3-
OH); 1H NMR (free base CDCl3) δ 6.96 (m, 4H), 6.94-6.82 (m,
4H), 3.90 (dd, J ) 5.0, 7.9 Hz, 1H), 3.76 (dd, J ) 7.2, 13.5 Hz,
1H), 3.51 (m, 1H), 3.27 (m, 1H), 2.59 (pent. J ) 6.8 Hz, 1H),
2.35 (s, 3H), 2.25 (s, 3H), 2.18 (s, 3H), 2.10 (m, 1H), 1.97 (m,
1H), 1.84 (m, 2H), 1.43 (m, 1H); 13C NMR (free base, CDCl3) δ
140.3, 140.0, 134.7, 134.6, 130.5, 128.3, 127.9, 127.8, 68.1, 62.0,
52.8, 42.0, 37.0, 36.0, 27.3, 25.1, 21.0, 20.8. Anal. (C22H28ClN‚
0.75H2O) C, H, N.
The 2R,3R-carbamate (86 mg, 0.22 mmol) and LAH (42 mg,
1.10 mmol) were refluxed in ether (20 mL) under N2 for 3 h,
the reaction mixture was diluted with ether (50 mL), and the
reaction was quenched with H2O (0.5 mL). The reaction
mixture was stirred with Celite (1 g) and Na2SO4 (2.0 g),
filtered, and washed with ether. Removal of the solvent and
purification of the residue by flash column chromatography
(SiO2, 5% Et3N in EtOAc) afforded 4b (50 mg, 79%) as a clear
oil. The amine was converted to the HCl salt as a white solid
3â-(4-Methoxyphenyl)-2â-(4-methylphenyl)tropane (3e)
and 3r-(4-Methoxyphenyl)-2r-(4-methylphenyl)tropane
(4e). Compounds 3e and 4e were prepared using a procedure
similar to that described for 3a and 4a. From 239 mg (0.56
mmol) of 6e, 32 mg (18%) and 35 mg (19%) of the 3R and 4e
were obtained.
using HCl/ether: mp 226.0-227.5 °C; [R]24 +5.24° (c 0.21,
D
CH3OH); 1H NMR (free base, CDCl3) δ 7.20-7.06 (m, 5H), 6.86
(dd, J ) 8.2, 19.9 Hz, 4H), 3.93 (m, 1H), 3.79 (m, 1H), 3.54 (m,
1H), 3.29 (m, 1H), 2.61 (m, 1H), 2.36 (m, 3H), 2.17 (s, 3H),
2.10 (m, 1H), 2.05-1.75 (m, 3H), 1.44 (m, 1H); 13C NMR (free
base, CDCl3) δ 142.9, 140.9, 134.0, 128.3, 128.1, 127.9, 125.4,
64.2, 60.5, 49.2, 40.7, 37.3, 36.6, 26.9, 22.7, 20.7. Anal. (C21H26-
ClN‚0.25H2O) C, H, N.
2â,3â‚3e‚HCl: mp 218-220 °C; [R]23 -20.6° (c 1.00, CH3-
D
1
OH); H NMR (free base, CDCl3) δ 7.32 (d, J ) 8.8 Hz, 2H),
6.86 (d, J ) 8.0 Hz, 2H), 6.73 (d, J ) 8.0 Hz, 2H), 6.60 (d, J )
8.0 Hz, 2H), 3.71 (s, 3H), 3.37-3.19 (m, 3H), 2.83 (m, 1H), 2.27
(s, 3H), 2.19 (s, 3H), 2.18-2.10 (m, 3H), 1.74 (m, 2H), 1.60 (m,
1H); 13C NMR δ 157.4, 140.3, 135.3, 134.8, 131.6, 128.3, 127.9,
112.3, 68.0, 62.0, 55.0, 52.4, 42.0, 37.2, 35.5, 27.3, 25.0, 20.9.
Anal. (C22H28ClN‚0.25H2O) C, H, N.
The 2â,3â-carbamate (88 mg, 0.221 mmol) and LAH (42 mg,
1.10 mmol) were refluxed in ether (20 mL) under N2 for 3 h,
the reaction mixture was diluted with ether (50 mL), and the
reaction was quenched with H2O (0.5 mL). The reaction
mixture was stirred with Celite (1 g) and Na2SO4 (2.0 g) and
filtered. Removal of the solvent and purification of the residue
by flash column chromatography (SiO2, MeOH:CH2Cl2/Et3N,
3:97:0.5) afforded 3b as a white solid (39 mg, 35%). The amine
was converted to the HCl salt as a white solid using HCl/ether
(1 M): mp 228 °C (dec); [R]23D -17.1° (c 0.21, CH3OH); 1H NMR
(free base, CDCl3) δ 7.41-7.37 (m, 2H), 7.10-7.00 (m, 3H),
6.80 (dd, J ) 8.0, 17.9 Hz, 4H), 3.41-3.24 (m, 3H), 2.90 (m,
1H), 2.38 (m, 1H), 2.24 (s, 3H), 2.18 (s, 3H), 2.30-2.00 (m, 2H),
1.80 (m, 2H), 1.64 (m, 2H); 13C NMR (free base, CDCl3) δ 143.0,
140.0, 134.8, 130.7, 128.3, 127.8, 127.0, 125.4, 67.8, 62.0, 53.2,
42.0, 37.0, 35.5, 27.3, 25.1, 20.9. Anal. (C21H26ClN‚1.5H2O) C,
H, N.
2r,3r‚4e‚HCl: mp 151-153 °C; [R]23 -13.0° (c 0.13, CH3-
D
1
OH); H NMR (free base, CDCl3) δ 6.97 (d, J ) 8.3 Hz, 2H),
6.91 (m, 4H), 6.71 (d, J ) 8.3 Hz, 2H), 3.89 (m, 1H), 3.73 (m,
4H), 3.48 (m, 1H), 3.28 (m, 1H), 2.59 (m, 1H), 2.35 (s, 3H),
2.19 (s, 3H), 2.11-1.96 (m, 2H), 1.82 (m, 2H), 1.46 (m, 1H);
13C NMR (CDCl3) δ 157.3, 141.0, 135.0, 134.0, 129.1, 128.3,
128.0, 113.3, 64.5, 60.5, 55.0, 48.6, 40.7, 37.0, 36.6, 27.1, 22.5,
20.7. Anal. (C22H28ClNO‚0.2H2O) C, H, N.
3â-(4′-Methylphenyl)-2â-(3,4-dimethoxyphenyl)tro-
pane (3f) and 3r-(4-Methylphenyl)-2â-(3,4-dimethoxyphe-
nyl)tropane (4f). Compounds 3f and 4f were prepared using
a procedure similar to that described for 3a and 4a. From 312
mg (0.69 mmol) of 6f, 73 mg (31%) and 83 mg (35%) of 3f and
4f were obtained.
2â,3â-3f‚HCl: mp 144-146 °C (dec); [R]23 -1.6 ° (c 0.19,
D
3â-Phenyl-2â-(4-methylphenyl)tropane (3c) and 3r-
Phenyl-2r-(4-methylphenyl)tropane (4c). Compounds 3c
and 4c were prepared using a procedure similar to that
described for 3a and 4a. From 305 mg (0.77 mmol) of 6c, 76
(34%) and 82 mg (36%) of the 2R,3R- and 2â,3â-isomers were
obtained.
1
CH3OH); H NMR (free base, CDCl3) δ 7.06 (dd, J ) 1.9, 83
Hz, 1H), 6.97 (d, J ) 1.9 Hz, 1H), 6.86 (d, J ) 7.9 Hz, 2H),
6.71 (d, J ) 7.9 Hz, 2H), 6.58 (d, J ) 8.3 Hz, 1H), 3.79 (s, 3H),
3.63 (s, 3H), 3.37 (m, 2H), 3.25 (m, 1H), 2.76 (dd, J ) 2.4, 6.6
Hz, 1H), 2.35-2.05 (m, 3H), 2.27 (s, 3H), 2.19 (s, 3H), 1.77
(m, 2H), 1.57 (m, 1H); 13C NMR (free base, CDCl3) δ 147.2,
146.6, 140.2, 135.6, 134.8, 128.2, 128.0, 122.5, 114.5, 109.7,
67.6, 61.9, 55.5, 55.4, 52.3, 41.8, 37.5, 35.4, 27.3, 24.9, 20.8.
Anal. (C23H30ClNO‚0.25H2O) C, H, N.
2â,3â-3c‚HCl: mp 230-232 °C (dec); [R]24 -25.0° (c 0.28,
D
CH3OH); 1H NMR (free base CDCl3) δ 7.26 (m, 2H), 7.08-
6.95 (m, 3H), 6.90-6.80 (m, 4H), 3.40-3.24 (m, 3H), 2.86 (dd,
J ) 2.2, 6.6, Hz, 1H), 2.36 (dt, J ) 2.7, 1.29 Hz, 1H), 2.23 (s,
3H), 2.19 (s, 3H), 2.10-2.00 (m, 2H), 1.84-1.70 (m, 2H), 1.64
(dt, J ) 4.1, 12.6 Hz, 1H); 13C NMR (free base, CDCl3) δ 143.3,
139.8, 134.7, 130.4, 128.0, 127.8, 127.5, 125.4, 67.9, 61.93, 52.9,
42.0, 37.4, 35.2, 27.3, 25.1, 20.9. Anal. (C21H26ClN‚1.25H2O):
C, H, N.
2r,3r-4f‚HCl: mp 132-134 °C (dec); [R]23 -20.0° (c 0.13,
D
CH3OH); 1H NMR (free base, CDCl3) δ 6.94-6.84 (m, 4H), 6.69
(d, J ) 8.3 Hz, 1H), 6.61 (dd, J ) 1.7, 8.3 Hz, 1H), 6.48 (d, J
) 1.7 Hz, 1H), 3.91 (m, 1H), 3.81 (s, 3H), 3.73 (m, 1H), 3.67 (s,
3H), 3.46 (t, J ) 5.5 Hz, 1H), 3.30 (t, J ) 6.0 Hz, 1H), 2.61 (m,
1H) 2.36 (s, 3H), 2.19 (s, 3H), 2.05 (dd, J ) 5.8, 11.7 Hz, 2H),
1.08 (m, 2H), 1.53 (m, 1H); 13C NMR (free base, CDCl3) δ 148.1,
146.7, 141.0, 135.4, 134.1, 128.6, 128.5, 128.2, 128.0, 120.4,
112.1, 110.6, 64.7, 60.4, 55.6, 55.4, 49.0, 40.7, 36.7, 36.5, 27.5,
22.3, 20.7. Anal. (C23H30ClNO2‚H2O) C, H, N.
2r,3r‚4c‚HCl: mp 224-225 °C (dec); [R]24 -6.84° (c 0.19,
D
CH3OH); 1H NMR (free base CDCl3) δ 7.03-6.85 (m, 9H), 3.96
(dd, J ) 8.0, 5.1 Hz, 1H), 3.79 (dd, J ) 7.7, 14.0 Hz, 1H), 3.50
(m, 1H), 3.28 (m, 1H), 2.62 (m, 1H), 2.35 (s, 3H), 2.22 (s, 3H),
2.21-1.90 (m, 2H), 1.89-1.77 (m, 2H), 1.43 (m, 1H); 13C NMR
(free base, CDCl3) δ 144.1, 139.5, 134.7, 128.6, 128.4, 128.1,
2â-(4-Fluorophenyl)-3â-(4-methylphenyl)tropane (3g).
Compound 3g was prepared by a procedure similar to that

7444 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23
described for 3a. In this case, it was necessary to prepare the
Kotturi et al.
(5) Carroll, F. I.; Lewin, A. H.; Mascarella, S. W. Dopamine
Transporter Uptake Blockers: Structure-Activity Relationships.
Neurotransmitter Transporters: Structure, Function, and Regu-
lation, 2nd ed.; Humana Press: Totowa, NJ, 2001; pp 381-432.
(6) Carroll, F. I. 2002 Medicinal Chemistry Division Award Ad-
dress: monoamine transporters and opioid receptors. Targets
for addiction therapy. J. Med. Chem. 2003, 46, 1775-1794.
(7) Newman, A. H. Novel pharmacotherapies for cocaine abuse
1997-2000. Expert Opin. Ther. Pat. 2000, 10, 1095-1122.
(8) Dutta, A. K.; Zhang, S.; Kolhatkar, R.; Reith, M. E. Dopamine
transporter as target for drug development of cocaine depen-
dence medications. Eur. J. Pharmacol. 2003, 479, 93-106.
(9) Jiang, S.; Chang, A.-C.; Abraham, P.; Kuhar, M. J.; Carroll, F.
I. Synthesis and transporter binding properties of (R)-2â,3â- and
(R)-2R,3R-diaryltropanes. Bioorg. Med. Chem. Lett. 1998, 8,
3689-3692.
(10) Clarke, R. L.; Daum, S. J.; Gambino, A. J.; Aceto, M. D.; Pearl,
J.; Levitt, M.; Cumiskey, W. R.; Bogado, E. F. Compounds
affecting the central nervous system. 3â-Phenyltropane-2-car-
boxylic esters and analogs. J. Med. Chem. 1973, 16, 1260-1267.
(11) Findlay, S. P. Concerning 2-carbomethoxytropinone. J. Org.
Chem. 1957, 22, 1385-1394.
(12) Carroll, F. I.; Runyon, S. P.; Abraham, P.; Navarro, H.; Kuhar,
M. J.; Pollard, G. T.; Howard, J. L. Monoamine transporter
binding, locomotor activity, and drug discrimination properties
of 3-(4-substituted-phenyl)tropane-2-carboxylic acid methyl ester
isomers. J. Med. Chem. 2004, 47, 6401-6409.
tartarate salt 2â,3â-4f‚CH3C6H4SO3: mp 174-177 °C; [R]23
D
-17.0° (c 0.13, CH3OH); 1H NMR (free base, CDCl3) δ 7.37
(dd, J ) 5.8, 2.1 Hz, 2H), 6.85 (d, J ) 7.9 Hz, 2H), 6.71 (d, J
) 8.3 Hz, 6H), 6.85 (d, J ) 7.9 Hz, 2H), 6.71 (d, J ) 8.3 Hz,
4H), 3.38-3.23 (m, 3H), 2.83 (m, 2H), 2.23 (s, 3H), 2.19 (s, 3H),
2.35-2.06 (m, 4H), 1.79 (m, 3H), 1.60 (m, 2H); 13C NMR
(CDCl3) δ 162.8, 159.5, 139.9, 138.6, 135.0, 132.0, 131.9, 128.4,
127.9, 120.9, 113.8, 113.5, 67.7, 62.0, 52.4, 42.0, 37.0, 35.2, 27.3,
25.0, 20.9. Anal. (C28H32FNO3S‚1.75H2O) C, H, N.
(R)-2R,3R-Diphenyltropane (4a). A mixture of alkene 6a
(61 mg, 0.21 mmol) and Pd/C (5%) in CH3OH (3 mL) was
hydrogenated under H2 (50 psi). After 8 days, the catalyst was
removed by filtration. The residue obtained after removal of
solvent was purified by flash column chromatography (SiO2,
10% CH3OH in CH2Cl2/Et3N (99.5/0.5) to give the starting
material (22 mg, 36%) and the 2R,3R-isomer 4a as a clear oil
(19 mg, 31%).
Acknowledgment. This research was supported by
the National Institute on Drug Abuse, Grant DA05477.
Supporting Information Available: Results from el-
emental analysis. This material is available free of charge via
the Internet at http://pubs.acs.org.
(13) Carroll, F. I.; Gray, J. L.; Abraham, P.; Kuzemko, M. A.; Lewin,
A. H.; Boja, J. W.; Kuhar, M. J. 3-Aryl-2-(3′-substituted-1′,2′,4′-
oxadiazol-5′-yl)tropane analogues of cocaine: Affinities at the
cocaine binding site at the dopamine, serotonin, and norepi-
nephrine transporters. J. Med. Chem. 1993, 36, 2886-2890.
(14) Carroll, F. I.; Kotian, P.; Dehghani, A.; Gray, J. L.; Kuzemko,
M. A.; Parham, K. A.; Abraham, P.; Lewin, A. H.; Boja, J. W.;
Kuhar, M. J. Cocaine and 3â-(4′-substituted phenyl)tropane-2â-
carboxylic acid ester and amide analogues. New high-affinity
and selective compounds for the dopamine transporter. J. Med.
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