Synthesis and monoamine transporter binding properties of 2β-[3′-(substituted benzyl)isoxazol-5-yl]- and 2β-[3′-methyl-4′-(substituted phenyl)isoxazol-5-yl]-3β-(substituted phenyl)tropanes

Article abstract of DOI:10.1016/j.bmc.2008.05.073

A series of 2β-[3′-(substituted benzyl)isoxazol-5-yl]- and 2β-[3′-methyl-4′-(substituted phenyl)isoxazol-5-yl]-3β-(substituted phenyl)tropanes were prepared and evaluated for affinities at dopamine, serotonin, and norepinephrine transporters using competitive radioligand binding assays. The 2β-[3′-(substituted benzyl)isoxazol-5-yl]-3β-(substituted phenyl)tropanes (3a-h) showed high binding affinities for the dopamine transporter (DAT). The IC₅₀ values ranged from 5.9 to 22 nM. On the other hand, the 2β-[3′-methyl-4′-(substituted phenyl)isoxazol-5-yl]-3β-(substituted phenyl)tropanes (4a-h), with IC₅₀ values ranging from 65 to 173 nM, were approximately 3- to 25-fold less potent than the corresponding 2β-[3′-(substituted benzyl)isoxazol]tropanes. All tested compounds were selective for the DAT relative to the norepinephrine transporter (NET) and serotonin transporter (5-HTT). 3β-(4-Methylphenyl)-2β-[3′-(4-fluorobenzyl)isoxazol-5-yl]tropane (3b) with IC₅₀ of 5.9 nM at the DAT and K_is of 454 and 113 nM at the NET and 5-HTT, respectively, was the most potent and DAT-selective analog. Molecular modeling studies suggested that the rigid conformation of the isoxazole side chain in 4a-h might play an important role on their low DAT binding affinities.

Full text of DOI:10.1016/j.bmc.2008.05.073

Bioorganic & Medicinal Chemistry 16 (2008) 6682–6688
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and monoamine transporter binding properties of 2b-[30-(substituted
benzyl)isoxazol-5-yl]- and 2b-[30-methyl-40-(substituted
phenyl)isoxazol-5-yl]-3b-(substituted phenyl)tropanes
*
Chunyang Jin, Hernán A. Navarro, Kevin Page, F. Ivy Carroll
Organic and Medicinal Chemistry, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, USA
a r t i c l e i n f o
a b s t r a c t
A series of 2b-[30-(substituted benzyl)isoxazol-5-yl]- and 2b-[30-methyl-40-(substituted phenyl)isoxazol-
5-yl]-3b-(substituted phenyl)tropanes were prepared and evaluated for affinities at dopamine, serotonin,
and norepinephrine transporters using competitive radioligand binding assays. The 2b-[30-(substituted
benzyl)isoxazol-5-yl]-3b-(substituted phenyl)tropanes (3a–h) showed high binding affinities for the
dopamine transporter (DAT). The IC50 values ranged from 5.9 to 22 nM. On the other hand, the 2b-[30-
methyl-40-(substituted phenyl)isoxazol-5-yl]-3b-(substituted phenyl)tropanes (4a–h), with IC50 values
ranging from 65 to 173 nM, were approximately 3- to 25-fold less potent than the corresponding 2b-
[30-(substituted benzyl)isoxazol]tropanes. All tested compounds were selective for the DAT relative to
the norepinephrine transporter (NET) and serotonin transporter (5-HTT). 3b-(4-Methylphenyl)-2b-[30-
(4-fluorobenzyl)isoxazol-5-yl]tropane (3b) with IC50 of 5.9 nM at the DAT and Kis of 454 and 113 nM
at the NET and 5-HTT, respectively, was the most potent and DAT-selective analog. Molecular modeling
studies suggested that the rigid conformation of the isoxazole side chain in 4a–h might play an important
role on their low DAT binding affinities.
Article history:
Received 8 May 2008
Revised 28 May 2008
Accepted 29 May 2008
Available online 2 June 2008
Keywords:
Monoamine transporters
3-Phenyltropanes
Isoxazoles
Cocaine
Addiction
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
and selective DAT inhibitors represents one of the promising ap-
proaches in the treatment of cocaine abuse.
Cocaine abuse continues to be a significant medical problem in
the United States. An estimated 2 million Americans currently use
cocaine (past-month) according to the National Survey on Drug
Use and Health (NSDUH).1 In addition to its direct effects, cocaine
abuse has also contributed to the increase of the spread of human
immunodeficiency virus (HIV) infection and drug-resistant tuber-
culosis.2 At present, no effective medication is in clinical use for
the treatment of cocaine abuse. In the central nervous system
(CNS), cocaine (1a, Fig. 1) binds to the dopamine transporter
(DAT), norepinephrine transporter (NET), and serotonin trans-
porter (5-HTT), and inhibits presynaptic reuptake of the respective
neurotransmitters. It also has effects on the cholinergic, musca-
Many research groups have sought to develop the 3-phenyltro-
pane class of DAT inhibitors, with 3b-phenyltropane-2b-carbox-
ylic acid methyl ester (WIN35,065-2, 1b) as the lead
compound.11–19 A large part of our structure–activity relation-
ships (SAR) studies was directed toward modification of the 40-
chloro and 40-methyl analogs 1c,d.16 Over the last several years,
we have synthesized a large number of 3-phenyltropane analogs
and evaluated them for binding at monoamine transporters. We
have shown that a variety of 2b-esters, amides, and heterocyclic
groups possessing either a 40-chloro or 40-methylphenyl group at
the 3b-position had high-affinity for the DAT, in some cases, with
considerably reduced affinity at the NET and 5-HTT.16 One of the
more interesting classes of compounds in the heterocyclic series
is the 2b-[30-(substituted phenyl)isoxazol-5-yl]-3b-(substituted
phenyl)tropanes (2a–h).20 The DAT-selective inhibitor RTI-336
(2e) is currently in advanced preclinical development.21,22 This
study was undertaken to further explore the effect of substituents
on the isoxazole ring of the 3b-phenyltropanes. In this paper, we
describe the synthesis of several 2b-[30-(substituted benzyl)
isoxazol-5-yl]-3b-(substituted phenyl)tropanes (3a–h) and 2b-
[30-methyl-40-(substituted phenyl)isoxazol-5-yl]-3b-(substituted
phenyl)tropanes (4a–h), and report their monoamine transporter
binding properties.
rinic, and
r
receptors and sodium channels.3,4 It is believed that
the DAT is the key recognition site for cocaine, mediating the
behavioural and reinforcing effects that contribute to its abuse lia-
bility.4–8 The dopamine hypothesis of cocaine addiction has re-
ceived further support from molecular biological studies
involving DAT knockout mice and positron emission tomography
(PET).9,10 Accordingly, the discovery and development of potent
* Corresponding author. Tel.: +1 919 541 6679; fax: +1 919 541 8868.
E-mail address: fic@rti.org (F.I. Carroll).
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.05.073

C. Jin et al. / Bioorg. Med. Chem. 16 (2008) 6682–6688
6683
Scheme 1. Reagents and conditions: (a) Grignard reagent, ꢀ45 °C, 2 h, then ꢀ78 °C,
TFA; (b) 1-(4-substituted phenyl)propan-2-one oxime, BuLi, THF, 0–70 °C; (c) 3 N
HCl, THF, reflux.
analogs 3b–h and 4b–h were prepared in the range of 3–43% and
4–18% yields, respectively. The yields obtained along with the ana-
lytical data of target compounds are given in Table 1.
Figure 1. Structures of cocaine (1a) and 3-phenyltropanes.
3. Biology
2. Chemistry
The synthesis of 2b-[30-(substituted benzyl)isoxazol-5-yl]-3b-
(substituted phenyl)tropanes (3a–h) and 2b-[30-methyl-40-(substi-
tuted phenyl)isoxazol-5-yl]-3b-(substituted phenyl)tropanes (4a–h)
starting with anhydroecgonine methyl ester (5) is outlined in
Scheme 1. Briefly, conjugate addition of 5 with the appropriate
Grignard reagent at ꢀ45 °C in ethyl ether followed by trifluroacetic
acid (TFA) yielded 3b-aryltropanes 6a,b.23 Following our previously
reported procedure,20,24 a solution of 6a was added at 0 °C to the
oxime dilithium salt, generated from the oxime of 1-(4-fluoro-
phenyl)propan-2-one with n-butyllithium in tetrahydrofuran
(THF) at room temperature, and the reaction mixture was warmed
to room temperature. After 20 h, the reaction mixture was added
to a 1:1 mixture of 3 N hydrochloric acid and THF, and was refluxed
for 5 h. Column chromatography purification of the crude
product afforded 2b-[30-(4-fluorobenzyl)isoxazol-5-yl]-3b-(4-chlo-
rophenyl)tropane (3a) in 41% yield. Under these conditions, none
of the desired 2b-[30-methyl-40-(4-fluorophenyl)isoxazol-5-yl]-
3b-(4-chlorophenyl)tropane (4a) was obtained. Alternatively,
treatment of the oxime of 1-(4-fluorophenyl)propan-2-one with
n-butyllithium in THF at 70 °C for 30 min followed by addition of
6a and refluxing for 3 h afforded the corresponding mixture of
addition intermediates. Subsequent cyclization in refluxing 3 N
hydrochloric acid and THF furnished a mixture of 3a and 4a, which
were obtained in 4% and 7% yields, respectively, after careful col-
umn chromatography. The low yields of 3a and 4a were due to
the formation of multiple by-products under the reaction condi-
tions. However, none of the by-products was formed in quantities
justifying isolation and identification. The stereochemistry of 3a
and 4a was determined by 1H NMR spectral analysis, particularly
with the aid of coupling constants of C(2)–H and C(3)–H. The vic-
inal couplings of J2eq,3ax = 5.9 Hz and J3ax,4ax = 13.0 Hz for 3a, and
J2eq,3ax = 6.0 Hz and J3ax,4ax = 12.9 Hz for 4a, respectively, are in
good agreement with stereochemical assignments. By employing
the modified reaction conditions, 2b-(substituted isoxazol)tropane
The binding affinities for the target compounds at the DAT, NET,
and 5-HTT were determined via competitive binding assays using
the previously reported procedures.25,26 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, WIN35,065-2,21 and 2a–h20 for comparison are
listed in Table 2. Since the DAT has two binding sites, IC50 values
are reported. The NET and 5-HTT have only one binding site, thus
Ki values were calculated for inhibition of binding at these two
transporters.
4. Results and discussion
SARstudiesfromourlaboratoryas wellasothershaveshownthat
a variety of functional groups and substituents are well tolerated at
the C(2)-position of 3b-phenyltropanes without loss of high-affinity
for the DAT.16,27–29 Results from some of the analogs suggest an elec-
trostatic interaction between the 2b-substituent and the binding
site, whereas results from other analogs are more consistent with a
hydrophobic or steric interaction, which is important for the high
binding potency at the DAT. A possible explanation for the wide
range of substituents that can be accommodated at the C(2)-position
is the existence of more than one binding mode. Although the DAT
tolerates ligands having a broad variety of 2b-substituents with lit-
tle change in the affinity of the ligand, the nature of the substituents
has a profound effect on the monoamine transporter selectivity.16 To
obtain analogs with increased metabolic stability, we have replaced
the metabolically labile 2b-ester group of the 3b-phenyltropanes by
stable bioisosteric heterocyclic groups, which led to several analogs
with high-affinity and selectivity for the DAT.20,24,30,31 Computa-
tional analyses of the electrostatic (molecular electrostatic poten-
tial), hydrophobic (calculated logP), and steric (substituted
volume) properties of these 2b-heterocyclic analogs strongly

6684
C. Jin et al. / Bioorg. Med. Chem. 16 (2008) 6682–6688
Table 1
2b-Isoxazol-3b-(substituted phenyl)tropanes, yields, and analytical data
Compounda
X
Y
Yield (%)
½
a 2D0
ꢁ
(g/100 mL, CH3OH)
Mp (°C)
Molecular formula
24H25Cl2FN2OꢂH2O
C25H28ClFN2Oꢂ1.5H2O
Analysis
3a
3b
3c
3d
3e
3f
3g
3h
4a
4b
4c
4d
4e
4f
Cl
CH3
Cl
CH3
Cl
CH3
Cl
CH3
Cl
CH3
Cl
CH3
Cl
CH3
Cl
F
F
Cl
Cl
CH3
CH3
OCH3
OCH3
F
F
Cl
Cl
CH3
CH3
OCH3
OCH3
4
7
5
3
17
39
33
43
7
18
12
11
9
ꢀ47.7° (0.34)
ꢀ66.6° (0.29)
ꢀ88.3° (0.31)
ꢀ75.4° (0.40)
ꢀ70.0° (0.37)
ꢀ61.9° (0.43)
ꢀ62.4° (0.34)
ꢀ68.7° (0.53)
+22.2° (0.79)
+18.0° (0.25)
+71.4° (0.37)
+51.1° (0.33)
+61.5° (0.35)
+44.7° (0.34)
+69.4° (0.39)
+50.7° (0.28)
192 (dec)
165 (dec)
192 (dec)
180 (dec)
108 (dec)
193 (dec)
178 (dec)
168 (dec)
231 (dec)
208 (dec)
248 (dec)
245 (dec)
248 (dec)
249 (dec)
243 (dec)
238 (dec)
C
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C
24H25Cl3N2Oꢂ0.75H2O
C25H28Cl2N2Oꢂ0.5H2O
C25H28Cl2N2Oꢂ0.5H2O
C26H31ClN2Oꢂ0.75H2O
C25H28Cl2N2O2ꢂ0.75H2O
C26H31ClN2O2ꢂ1.5H2O
C
24H25Cl2FN2OꢂH2O
C25H28ClFN2Oꢂ1.75H2O
C24H25Cl3N2Oꢂ0.25H2O
C25H28Cl2N2Oꢂ1.25H2O
C25H28Cl2N2Oꢂ0.5H2O
C26H31ClN2Oꢂ1.25H2O
C25H28Cl2N2O2ꢂ1.25H2O
C26H31ClN2O2ꢂ1.25H2O
7
7
4
4g
4h
CH3
a
HCl salt used to characterize the compound.
Table 2
Monoamine transporter binding affinities of 2b-isoxazol-3b-(substituted phenyl)tropanes
Compounda
clogP
X
Y
DAT, IC50 (nM)
[3H]WIN35,428
NET, Kib (nM)
5-HTT, Kib (nM)
b
[3H]Nisoxetine
[3H]Paroxetine
Cocainec
89.1
23
1990
556
95
182
WIN35,065-2c
2ad
2bd
2cd
2dd
2ed
2fd
2gd
2hd
3a
3b
3c
3d
3e
3f
3g
3h
4a
4b
4c
4.48
4.34
5.12
4.98
5.01
4.87
4.36
4.23
4.98
4.85
5.53
5.39
5.39
5.26
4.85
4.71
5.09
4.96
5.73
5.60
5.62
5.49
4.98
4.84
Cl
CH3
Cl
CH3
Cl
CH3
Cl
CH3
Cl
CH3
Cl
CH3
Cl
CH3
Cl
CH3
Cl
CH3
Cl
CH3
Cl
CH3
Cl
F
F
Cl
Cl
CH3
CH3
OCH3
OCH3
F
F
Cl
Cl
CH3
CH3
OCH3
OCH3
F
F
Cl
Cl
CH3
CH3
OCH3
OCH3
1.86 0.09
6.45 1.6
6.42 0.46
8.74 1.7
4.09 0.44
13 2.1
1.57 0.1
3.93 0.49
8.6 3.0
5.9 1.5
553 65
552 18
>2000
>2000
1030 24
> 2000
660 19
> 2000
> 2000
> 2000
522 48
>2000
535 16
366 2.9
454 23
455 89
435 40
454 30
677 60
840 70
1100 140
770 40
347 20
357 50
466 40
349 70
788 120
519 20
>2000
72
8
113
8
17.5
1
79 36
85 12
22.2 5.5
22.1 2.8
6.9 2.2
6.1 1.4
42.9
5
89.7 3.5
14.4
1
9.6
5
41.1 11
908 170
>2000
387 130
864 250
297 20
1000 100
1800 300
>2000
111 23
76 12
68.7
4
4d
4e
4f
4g
4h
65.7 22
135 34
173 40
81.6 22
119 16
>2000
>2000
1300 100
CH3
a
All compounds were tested as the HCl salt.
All values are means standard error of three or four experiments performed in duplicate.
Data taken from Ref. 21.
Data taken from Ref. 20.
b
c
d
suggested that electrostatic interactions predominately contributed
to their DAT binding affinities.24
We previously reported that 2b-[30-(substituted phenyl)iso-
xazol-5-yl]-3b-(substituted phenyl)tropanes (2a–h) possessed

C. Jin et al. / Bioorg. Med. Chem. 16 (2008) 6682–6688
6685
high binding affinities (IC50 = 1.57–13 nM) at the DAT with lower
5. Experimental
affinities at the NET and 5-HTT.24 One of the most potent and selec-
tive compounds in the series, RTI-336 (2e), had an IC50 of 4.09 nM
at the DAT and Kis of 1030 nM and 522 nM at the NET and 5-HTT,
respectively, and is currently in advanced preclinical develop-
ment.21,22 In this study, we expanded the 2b-(substituted iso-
xazol)tropanes including 2b-[30-(substituted benzyl)isoxazol]
tropanes 3a–h and 2b-[30-methyl-40-(substituted phenyl)iso-
xazol]tropanes 4a–h to further explore the effect of the substitu-
ents on the isoxazole ring. All of the analogs 3a–h exhibited high
DAT binding affinities similar to the corresponding 2b-[30-(substi-
tuted phenyl)isoxazol]tropanes 2a–h. The IC50 values ranged from
5.9 to 22 nM. On the other hand, the 2b-[30-methyl-40-(substituted
phenyl)isoxazol]tropanes 4a–h, with IC50 values ranging from 65
to 173 nM, were approximately 8- to 60-fold less potent than
2a–h, and 3- to 25-fold less potent than 3a–h. The particular sub-
stituents (F, Cl, CH3, OCH3) on the phenyl group of the isoxazole
moiety appeared to have only a subtle effect on the DAT affinities.
No correlation was observed between the DAT binding affinities
and the calculated logP (clogP) of the compounds. All tested com-
pounds in this study were selective for the DAT relative to the NET
and 5-HTT. However, none of the compounds was as selective as
the corresponding 2b-[30-(substituted phenyl)isoxazol]tropanes
2a–h.
A molecular modeling study was performed to determine
whether conformational differences between 3a–h and 4a–h ac-
count for the observed DAT binding properties. The minimum-en-
ergy conformations (Fig. 2) of 3a and 4a were generated using the
MMFF94 force field in Spartan’06 (Wavefunction, Inc., Irvine, CA).
There were no significant differences in the relative conformations
of the tropane ring and the benzene ring attached at C(3)-position.
However, significant difference in the relative conformations of the
isoxazole ring attached at C(2)-position was revealed by the align-
ment of minimum-energy conformations shown in Figure 2. It is
worthy to note that the isoxazole oxygen atom in 4a is pointed
in an almost opposite direction compared to that in 3a. The two
benzene rings in 4a are proximal, and the resultant steric hin-
drance increases the rigidity of the isoxazole side chain and per-
haps decreases the ability of the ligand to adopt a higher affinity
conformation at the DAT.
Melting points were determined using a MEL-TEMP II capillary
melting point apparatus and are uncorrected. Nuclear magnetic res-
onance (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 internal solvent.
Mass spectra (MS) were obtained by electron impact at 70 eV on a
Hewlett Packard 5989A instrument. Elemental analyses were per-
formed by Atlantic Microlab Inc., Atlanta, GA. Optical rotations were
measured on an AutoPol III polarimeter, purchased from Rudolf Re-
search. Analytical thin-layer chromatography (TLC) was carried out
using EMD silica gel 60 F254 TLC plates. TLC visualization was
achievedwitha UVlamporinaniodinechamber. Flashcolumnchro-
matography was done on a CombiFlash Companion system using
Isco prepacked silica gel columns or using EM Science silica gel
60 Å (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 reac-
tions and reagent transfers were carried out under dry nitrogen.
All compounds described herein were prepared from natural (ꢀ)-
cocaine, and therefore, they all possess the same absolute configura-
tion as (ꢀ)-cocaine.
5.1. 3b-(4-Chlorophenyl)-2b-[30-(4-fluorobenzyl)isoxazol-5-yl]-
tropane (3a)
To a stirred solution of 1-(4-fluorophenyl)propan-2-one (5.00 g,
33.0 mmol) in EtOH (75 mL) at room temperature under nitrogen
was added K2CO3 (12.4 g, 99.0 mmol) followed by hydroxylamine
hydrochloride (4.17 g, 66.0 mmol). After stirring for 5 h, the reac-
tion mixture was filtered through a plug of Celite and the filtrate
was concentrated under reduced pressure. The resultant residue
was dissolved in Et2O (200 mL), washed with brine (3ꢃ 100 mL),
and dried (Na2SO4). Removal of the solvent under reduced pressure
afforded 1-(4-fluorophenyl)propan-2-one oxime (5.40 g) as an oil,
which was used in the next step without further purification.
To a stirred solution of 1-(4-fluorophenyl)propan-2-one oxime
(1.84 g, 11.0 mmol) in anhydrous THF (20 mL) at 0 °C under nitrogen
was added a solution of BuLi in hexanes (1.6 M, 13.7 mL, 22.0 mmol).
The reaction mixture was warmed to room temperature and stirred
for 1 h. A solution of 6a23 (1.07 g, 3.66 mmol) in anhydrous THF
(5 mL) was then added. After stirring at room temperature for
20 h, the reaction was quenched by addition of a 20% NH4Cl aqueous
solution (10 mL). The organic layer was separated and the aqueous
layer was extracted with EtOAc (3ꢃ 50 mL). The combined organic
phases were washed with brine (3ꢃ 50 mL), dried (Na2SO4), and
concentrated under reduced pressure. The resultant residue was
then dissolved in a 1:1 mixture of 3 N HCl aqueous solution and
THF (20 mL), and refluxed for 5 h. After cooling to room temperature,
the mixture was washed with Et2O (3ꢃ 10 mL). The aqueous layer
was made basic with NaHCO3 and extracted with EtOAc (3ꢃ 50
mL). The combined EtOAc extracts were dried (Na2SO4) and concen-
In summary, a new series of 3b-phenyltropanes with various
2b-[30-(substituted benzyl)isoxazol] and 2b-[30-methyl-40-(substi-
tuted phenyl)isoxazol] substituents were synthesized and
evaluated for their monoamine transporter binding affinities. The
2b-[30-(substituted benzyl)isoxazol]tropanes 3a–h exhibited high
affinities (IC50 = 5.9–22 nM) at the DAT, which is similar to that
of the corresponding 2b-[30-(substituted phenyl)isoxazol]tropanes
2a–h. On the other hand, the 2b-[30-methyl-40-(substituted
phenyl)isoxazol]tropanes 4a–h were approximately 3- to 25-fold
less potent than the corresponding 3a–h. Molecular modeling
studies suggested that the conformational properties of the isoxaz-
ole moiety of 3a–h and 4a–h might play an important role on their
DAT binding affinities.
Figure 2. Overlay (center; green: 3a and purple: 4a) of the calculated minimum-energy conformations of 3a (left) and 4a (right) (black, carbon; blue, nitrogen; red, oxygen;
orange, chlorine; and green, fluorine).

6686
C. Jin et al. / Bioorg. Med. Chem. 16 (2008) 6682–6688
trated under reduced pressure. Flash column chromatography of the
crude product on silica gel (40 g Isco prepacked column) using
0 ? 10% Et2O in hexanes with 5% Et3N afforded 3a (610 mg, 41%) as
an oil: 1H NMR (CDCl3) d 7.12–6.90 (m, 6H), 6.88–6.78 (m, 2H), 6.11
(s, 1H), 3.89 (d, J = 15.6 Hz, 1H), 3.80 (d, J = 15.6 Hz, 1H), 3.32–3.12
(m, 4H), 2.30–2.02 (m, 6H), 1.81–1.52 (m, 3H); 1H NMR (300 MHz;
C6D6) d 7.05 (d, J = 8.7 Hz, 2H), 6.80–6.72 (m, 4H), 6.58 (d, J = 8.7 Hz,
2H), 6.11 (s, 1H), 3.67 (d, J = 15.3 Hz, 1H), 3.53 (d, J = 15.3 Hz, 1H),
2.93 (dd, J = 5.9, 2.6 Hz, 1H), 2.88–2.80 (m, 2H), 2.74 (ddd, J = 13.0,
5.9, 5.6 Hz, 1H), 1.91 (ddd, J = 13.0, 12.9, 2.7 Hz, 1H), 1.86 (s, 3H),
1.80–1.60 (m, 2H), 1.30–1.13 (m, 3H); 13C NMR (CDCl3) d 173.2,
162.1, 161.8 (d, JC,F = 243 Hz), 140.3, 133.6 (d, JC,F = 3.2 Hz), 132.1,
130.2 (d, JC,F = 7.9 Hz), 128.8, 128.2, 115.3 (d, JC,F = 21.1 Hz), 103.6,
65.4, 61.6, 46.3, 42.0, 35.4, 34.9, 31.7, 26.4, 25.0; MS (EI) m/z 410
(M+). The free base was converted to the hydrochloride salt: mp
Compound 3b: oil; 1H NMR (CDCl3) d 7.12–6.90 (m, 6H), 6.86–
6.74 (m, 2H), 6.10 (s, 1H), 3.90 (d, J = 15.6 Hz, 1H), 3.80 (d,
J = 15.6 Hz, 1H), 3.35–3.12 (m, 4H), 2.30–2.02 (m, 9H), 1.82–1.52
(m, 3H); 13C NMR (CDCl3) d 173.6, 161.9, 161.7 (d, JC,F = 244 Hz),
138.6, 135.8, 133.8 (d, JC,F = 3.2 Hz), 130.2 (d, JC,F = 7.9 Hz), 128.8,
127.3, 115.3 (d, JC,F = 21.1 Hz), 103.6, 65.5, 61.8, 46.5, 42.0, 35.5,
35.0, 31.7, 26.4, 25.1, 21.1; MS (EI) m/z 390 (M+). The free base
was converted to the hydrochloride salt: mp 165 °C (dec); ½a D20
ꢁ
ꢀ66.6° (c 0.29, CH3OH); Anal. Calcd for C25H28ClFN2Oꢂ1.5H2O: C,
66.14; H, 6.88; N, 6.17. Found: C, 65.74; H, 6.51; N, 6.07.
Compound 4b: oil; 1H NMR (CDCl3) d 7.05–6.84 (m, 6H), 6.69–
6.59 (m, 2H), 3.51–3.43 (m, 1H), 3.23–3.08 (m, 2H), 3.03 (dd,
J = 6.0, 2.1 Hz, 1H), 2.65 (ddd, J = 12.6, 12.6, 2.4 Hz, 1H), 2.35–2.08
(m, 8H), 2.01 (s, 3H), 1.75–1.62 (m, 3H); 13C NMR (75 MHz; CDCl3)
d 169.4, 164.0, 159.2 (d, JC,F = 226 Hz), 139.1, 135.8, 131.5 (d,
JC,F = 8.0 Hz), 128.8, 127.8, 126.8 (d, JC,F = 3.4 Hz), 117.4, 115.5 (d,
JC,F = 21.3 Hz), 66.3, 62.1, 45.7, 42.1, 36.6, 36.1, 26.8, 25.2, 21.1,
10.5; MS (EI) m/z 390 (M+). The free base was converted to the
192 °C (dec);
½
a 2D0
ꢁ
ꢀ47.7° (c 0.34, CH3OH); Anal. Calcd for
C24H25Cl2FN2OꢂH2O: C, 61.94; H, 5.85; N, 6.02. Found: C, 61.95; H,
5.74; N, 5.97.
hydrochloride salt: mp 208 °C (dec); ½a D20
ꢁ
+18.0° (c 0.25, CH3OH);
Anal. Calcd for C25H28ClFN2Oꢂ1.75H2O: C, 65.49; H, 6.92; N, 6.11.
5.2. 3b-(4-Chlorophenyl)-2b-[30-(4-fluorobenzyl)isoxazol-5-yl]-
tropane (3a) and 3b-(4-chlorophenyl)-2b-[30-methyl-40-(4-fluo-
rophenyl)isoxazol-5-yl]tropane (4a)
Found: C, 65.24; H, 6.53; N, 6.03.
5.4. 3b-(4-Chlorophenyl)-2b-[30-(4-chlorobenzyl)isoxazol-5-yl]-
tropane (3c) and 3b-(4-chlorophenyl)-2b-[30-methyl-40-(4-chloro-
phenyl)isoxazol-5-yl]tropane (4c)
To a stirred solution of 1-(4-fluorophenyl)propan-2-one oxime
(1.84 g, 11.0 mmol) in anhydrous THF (20 mL) at 0 °C under nitrogen
was added
a solution of BuLi in hexanes (1.6 M, 13.7 mL,
22.0 mmol). The reaction mixture was warmed to room temperature
over 30 min, and then heated to 70 °C for another 30 min. A solution
of 6a (1.07 g, 3.66 mmol) in anhydrous THF (5 mL) was added. The
resultant mixture was refluxed for 3 h. After cooling to room tem-
perature, the reaction was quenched by addition of a 20% NH4Cl
aqueous solution (10 mL). The organic layer was separated and the
aqueous layer was extracted with EtOAc (3ꢃ 50 mL). The combined
organic phases were washed with brine (3ꢃ 50 mL), dried (Na2SO4),
and concentrated under reduced pressure. The residue was parti-
tioned between Et2O (100 mL) and 2 N HCl (50 mL). The aqueous
layer was separated, made basic with NaHCO3, and extracted with
EtOAc (3ꢃ 50 mL). The combined EtOAc extracts were washed with
brine (3ꢃ 30 mL), dried (Na2SO4), and concentrated under reduced
pressure. The resultant residue was then dissolved in a 1:1 mixture
of 3 N HCl aqueous solution and THF (10 mL), and refluxed for 5 h.
After cooling to room temperature, the mixture was made basic with
NaHCO3 and extracted with EtOAc (3ꢃ 50 mL). The combined EtOAc
extracts were dried (Na2SO4) and concentrated under reduced pres-
sure. Flash column chromatography of the crude product on silica
gel (40 g Isco prepacked column) using 0 ? 10% Et2O in hexanes
with 10% Et3N afforded 3a (55.0 mg, 4%) and 4a (101 mg, 7%).
Compound 4a: oil; 1H NMR (CDCl3) d 7.17–6.88 (m, 6H), 6.77–6.67
(m, 2H), 3.54–3.44 (m, 1H), 3.27–3.08 (m, 2H), 3.04 (dd, J = 6.0, 2.1 Hz,
1H), 2.65 (ddd, J = 12.9, 12.9, 2.7 Hz, 1H), 2.30–2.08 (m, 5H), 2.02 (s,
3H), 1.78-1.62 (m, 3H); 13C NMR (CDCl3) d 168.9, 164.1, 159.3 (d,
JC,F = 221 Hz), 140.8, 132.1, 131.4 (d, JC,F = 8.0 Hz), 129.2, 128.3,
126.6 (d, JC,F = 3.5 Hz), 117.6, 115.8 (d, JC,F = 21.4 Hz), 66.3, 62.0,
45.6, 42.1, 36.4, 35.8, 26.9, 25.2, 10.5; MS (EI) m/z 410 (M+). The free
The procedure for 3a and 4a was followed using 1.07 g
(3.66 mmol) of 6a and 2.02 g (11.0 mmol) of 1-(4-chloro-
phenyl)propan-2-one oxime to give 85.0 mg (5%) of 3c and
180 mg (12%) of 4c.
Compound 3c: oil; 1H NMR (CDCl3) d 7.31–7.22 (m, 2H), 7.14–
7.07 (m, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.11
(s, 1H), 3.90 (d, J = 15.6 Hz, 1H), 3.81 (d, J = 15.6 Hz, 1H), 3.36–
3.14 (m, 4H), 2.30–2.04 (m, 6H), 1.82–1.53 (m, 3H); 13C NMR
(CDCl3) d 173.3, 161.8, 140.3, 136.5, 132.6, 132.2, 130.1, 128.9,
128.7, 128.3, 103.7, 65.5, 61.7, 46.4, 42.1, 35.5, 34.9, 31.9, 26.5,
25.1; MS (EI) m/z 426 (M+). The free base was converted to the
hydrochloride salt: mp 192 °C (dec); ½a D20
ꢀ88.3° (c 0.31, CH3OH);
ꢁ
Anal. Calcd for C24H25Cl3N2Oꢂ0.75H2O: C, 60.39; H, 5.60; N, 5.87.
Found: C, 60.70; H, 5.85; N, 5.62.
Compound 4c: oil; 1H NMR (CDCl3) d 7.35–7.27 (m, 2H), 7.14–
7.05 (m, 2H), 6.91 (d, J = 8.7 Hz, 2H), 6.67 (d, J = 8.7 Hz, 2H),
3.54–3.42 (m, 1H), 3.22–3.08 (m, 2H), 3.04 (dd, J = 6.0, 2.1 Hz,
1H), 2.64 (ddd, J = 12.9, 12.9, 2.7 Hz, 1H), 2.30–2.06 (m, 5H), 2.03
(s, 3H), 1.77–1.63 (m, 3H); 13C NMR (CDCl3) d 169.0, 157.7, 140.7,
133.9, 132.2, 131.0, 129.2, 129.0, 128.3, 117.5, 66.3, 62.0, 45.7,
42.1, 36.4, 35.8, 26.8, 25.2, 10.5; MS (EI) m/z 426 (M+). The free base
was converted to the hydrochloride salt: mp 248 °C (dec); ½a D20
ꢁ
+71.4° (c 0.37, CH3OH); Anal. Calcd for C24H25Cl3N2Oꢂ0.25H2O: C,
61.55; H, 5.49; N, 5.89. Found: C, 61.49; H, 5.75; N, 5.78.
5.5. 3b-(4-Methylphenyl)-2b-[30-(4-chlorobenzyl)isoxazol-5-yl]-
tropane (3d) and 3b-(4-methylphenyl)-2b-[30-methyl-40-(4-chlo-
rophenyl)isoxazol-5-yl]tropane (4d)
base was converted to the hydrochloride salt: mp 231 °C (dec); ½a D20
ꢁ
+22.2° (c 0.79, CH3OH); Anal. Calcd for C24H25Cl2FN2OꢂH2O: C,
The procedure for 3a and 4a was followed using 1.00 g
(3.66 mmol) of 6b and 2.02 g (11.0 mmol) of 1-(4-chloro-
phenyl)propan-2-one oxime to give 40.0 mg (3%) of 3d and
160 mg (11%) of 4d.
61.94; H, 5.85; N, 6.02. Found: C, 61.69; H, 5.85; N, 5.80.
5.3. 3b-(4-Methylphenyl)-2b-[30-(4-fluorobenzyl)isoxazol-5-yl]-
tropane (3b) and 3b-(4-methylphenyl)-2b-[30-methyl-40-(4-fluo-
rophenyl)isoxazol-5-yl]tropane (4b)
Compound 3d: oil; 1H NMR (CDCl3) d 7.31–7.20 (m, 2H), 7.10–
6.77 (m, 6H), 6.10 (s, 1H), 3.91 (d, J = 15.6 Hz, 1H), 3.81 (d,
J = 15.6 Hz, 1H), 3.40–3.17 (m, 4H), 2.40–2.03 (m, 9H), 1.88–1.57
(m, 3H); 13C NMR (CDCl3) d 161.8, 138.6, 136.6, 136.1, 132.5,
131.1, 130.2, 129.0, 128.7, 127.4, 103.8, 65.6, 62.0, 46.5, 42.1,
35.5, 34.9, 31.9, 26.6, 25.1, 21.2; MS (EI) m/z 406 (M+). The free base
The procedure for 3a and 4a was followed using 1.00 g
(3.66 mmol) of 6b23 and 1.84 g (11.0 mmol) of 1-(4-fluoro-
phenyl)propan-2-one oxime to give 105 mg (7%) of 3b and
250 mg (18%) of 4b.
was converted to the hydrochloride salt: mp 180 °C (dec); ½a D20
ꢁ

C. Jin et al. / Bioorg. Med. Chem. 16 (2008) 6682–6688
6687
ꢀ75.4° (c 0.40, CH3OH); Anal. Calcd for C25H28Cl2N2Oꢂ0.5H2O: C,
66.37; H, 6.46; N, 6.19. Found: C, 66.38; H, 6.61; N, 5.87.
45.6, 42.1, 36.4, 36.1, 26.8, 25.2, 21.3, 21.1, 10.6; MS (EI) m/z 386
(M+). The free base was converted to the hydrochloride salt: mp
Compound 4d: oil; 1H NMR (CDCl3) d 7.30–7.23 (m, 2H), 6.95 (d,
J = 8.1 Hz, 2H), 6.86 (d, J = 8.1 Hz, 2H), 6.67–7.57 (m, 2H), 3.53–3.44
(m, 1H), 3.23–3.09 (m, 2H), 3.04 (dd, J = 6.0, 2.0 Hz, 1H), 2.66 (ddd,
J = 12.9, 12.9, 2.7 Hz, 1H), 2.26 (s, 3H), 2.25 (s, 3H), 2.24–2.04 (m,
2H), 2.02 (s, 3H), 1.78–1.63 (m, 3H); 13C NMR (CDCl3) d 169.4,
157.6, 139.0, 136.0, 133.7, 131.2, 129.4, 128.9, 128.8, 127.8,
117.4, 66.3, 62.2, 45.7, 42.1, 36.6, 36.0, 26.9, 25.2, 21.1, 10.6; MS
(EI) m/z 406 (M+). The free base was converted to the hydrochloride
249 °C (dec);
26H31ClN2Oꢂ1.25H2O: C, 70.10; H, 7.58; N, 6.29. Found: C, 70.22;
H, 7.36; N, 6.35.
½
a 2D0
ꢁ
+44.7° (c 0.34, CH3OH); Anal. Calcd for
C
5.8. 3b-(4-Chlorophenyl)-2b-[30-(4-methoxybenzyl)isoxazol-5-yl]-
tropane (3g) and 3b-(4-chlorophenyl)-2b-[30-methyl-40-(4-meth-
oxyphenyl)isoxazol-5-yl]tropane (4g)
salt: mp 245 °C (dec); ½a D20
ꢁ
+51.1° (c 0.33, CH3OH); Anal. Calcd for
25H28Cl2N2Oꢂ1.25H2O: C, 64.45; H, 6.60; N, 6.01. Found: C, 64.50;
The procedure for 3a and 4a was followed using 1.07 g
(3.66 mmol) of 6a and 1.97 g (11.0 mmol) of 1-(4-methoxylphe-
nyl)propan-2-one oxime to give 510 mg (33%) of 3g and 101 mg
(7%) of 4g.
C
H, 6.42; N, 5.92.
5.6. 3b-(4-Chlorophenyl)-2b-[30-(4-methylbenzyl)isoxazol-5-yl]-
tropane (3e) and 3b-(4-chlorophenyl)-2b-[30-methyl-40-(4-meth-
ylphenyl)isoxazol-5-yl]tropane (4e)
Compound 3g: oil; 1H NMR (CDCl3) d 7.14–6.99 (m, 4H), 6.90–
6.80 (m, 4H), 6.10 (s, 1H), 3.89 (d, J = 15.6 Hz, 1H), 3.81 (s, 3H), 3.77
(d, J = 15.6 Hz, 1H), 3.34–3.13 (m, 4H), 2.30–2.05 (m, 6H), 1.83–
1.56 (m, 3H); 13C NMR (CDCl3) d 172.9, 162.6, 158.4, 140.4, 132.1,
130.0, 129.7, 128.9, 128.3, 114.0, 103.8, 65.4, 61.7, 55.4, 46.4, 42.0,
35.5, 35.0, 31.6, 26.5, 25.1; MS (EI) m/z 422 (M+). The free base was
The procedure for 3a and 4a was followed using 1.07 g
(3.66 mmol) of 6a and 1.79 g (11.0 mmol) of 1-(4-methyl-
phenyl)propan-2-one oxime to give 250 mg (17%) of 3e and
130 mg (9%) of 4e.
converted to the hydrochloride salt: mp 178 °C (dec); ½a D20
ꢀ62.4°
ꢁ
(c 0.34, CH3OH); Anal. Calcd for C25H28Cl2N2O2ꢂ0.75H2O: C, 63.49;
H, 6.29; N, 5.92. Found: C, 63.20; H, 6.38; N, 5.78.
Compound 3e: oil; 1H NMR (CDCl3) d 7.16–6.96 (m, 6H), 6.88–
6.79 (m, 2H), 6.13 (s, 1H), 3.91 (d, J = 16.5 Hz, 1H), 3.80 (d,
J = 16.5 Hz, 1H), 3.33–3.13 (m, 4H), 2.34 (s, 3H), 2.30–2.03 (m, 6H),
1.82–1.53 (m, 3H); 13C NMR (CDCl3) d 172.8, 162.3, 140.3, 136.0,
134.8, 132.1, 129.2, 128.9, 128.5, 128.2, 103.8, 65.4, 61.6, 46.3,
41.9, 35.5, 34.9, 32.0, 26.4, 25.0, 21.1; MS (EI) m/z 406 (M+). The free
Compound 4g: white solid; mp 58.0–59.0 °C; 1H NMR (CDCl3) d
7.14–7.08 (m, 2H), 6.95–6.80 (m, 4H), 6.72–6.63 (m, 2H), 3.82 (s,
3H), 3.52–3.42 (m, 1H), 3.24–3.06 (m, 3H), 2.66 (ddd, J = 12.3, 12.3,
2.4 Hz, 1H), 2.25 (s, 3H), 2.24–2.05 (m, 2H), 2.02 (s, 3H), 1.75–1.62
(m, 3H); 13C NMR (CDCl3) d 168.6, 159.2, 158.1, 140.9, 132.0, 130.9,
129.2, 128.2, 122.9, 118.1, 114.2, 66.5, 62.0, 55.4, 45.5, 42.1, 36.3,
35.8, 26.9, 25.2, 10.6; MS (EI) m/z 422 (M+). The free base was con-
base was converted to the hydrochloride salt: mp 108 °C (dec); ½a D20
ꢁ
ꢀ70.0° (c 0.37, CH3OH); Anal. Calcd for C25H28Cl2N2Oꢂ0.5H2O: C,
66.37; H, 6.46; N, 6.19. Found: C, 66.26; H, 6.64; N, 6.04.
verted to the hydrochloride salt: mp 243 °C (dec); ½a D20
ꢁ
+69.4° (c
Compound 4e: oil; 1H NMR (CDCl3) d 7.20–7.03 (m, 4H), 6.93 (d,
J = 8.4 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 3.52–3.44 (m, 1H), 3.27–2.96
(m, 3H), 2.67 (ddd, J = 12.0, 12.0, 2.1 Hz, 1H), 2.36 (s, 3H), 2.32 (s,
3H), 2.26–2.07 (m, 2H), 2.03 (s, 3H), 1.76–1.62 (m, 3H); 13C NMR
(CDCl3) d 168.5, 158.0, 140.8, 137.4, 132.0, 129.5, 129.4, 129.2,
128.2, 127.6, 118.3, 66.4, 62.0, 45.4, 42.1, 36.2, 35.8, 26.8, 25.1,
21.3, 10.6; MS (EI) m/z 406 (M+). The free base was converted to
0.39, CH3OH); Anal. Calcd for C25H28Cl2N2O2ꢂ1.25H2O: C, 62.31; H,
6.38; N, 5.81. Found: C, 62.34; H, 6.42; N, 5.77.
5.9. 3b-(4-Methylphenyl)-2b-[30-(4-methoxybenzyl)isoxazol-5-
yl]tropane (3h) and 3b-(4-methylphenyl)-2b-[30-methyl-40-(4-
methoxyphenyl)isoxazol-5-yl]tropane (4h)
the hydrochloride salt: mp 248 °C (dec); ½a D20
ꢁ
+61.5° (c 0.35,
The procedure for 3a and 4a was followed using 1.00 g
(3.66 mmol) of 6b and 1.97 g (11.0 mmol) of 1-(4-methoxylphe-
nyl)propan-2-one oxime to give 631 mg (43%) of 3h and 52.0 mg
(4%) of 4h.
CH3OH); Anal. Calcd for C25H28Cl2N2Oꢂ0.5H2O: C, 66.37; H, 6.46;
N, 6.19. Found: C, 66.62; H, 6.42; N, 6.07.
5.7. 3b-(4-Methylphenyl)-2b-[30-(4-methylbenzyl)isoxazol-5-yl]-
tropane (3f) and 3b-(4-methylphenyl)-2b-[30-methyl-40-(4-meth-
ylphenyl)isoxazol-5-yl]tropane (4f)
Compound 3h: oil; 1H NMR (CDCl3) d 7.08–6.90 (m, 4H), 6.86–
6.77 (m, 4H), 6.13 (s, 1H), 3.89 (d, J = 15.3 Hz, 1H), 3.80 (s, 3H), 3.79
(d, J = 15.3 Hz, 1H), 3.32–3.10 (m, 4H), 2.30–2.01 (m, 9H), 1.84–
1.53 (m, 3H); 13C NMR (CDCl3) d 173.2, 162.2, 158.2, 138.6, 135.6,
130.0, 129.6, 128.7, 127.3, 113.8, 103.5, 65.3, 61.7, 55.1, 46.4, 41.9,
35.5, 34.9, 31.4, 26.3, 24.9, 21.0; MS (EI) m/z 402 (M+). The free base
The procedure for 3a and 4a was followed using 1.00 g
(3.66 mmol) of 6b and 1.79
g (11.0 mmol) of 1-(4-methyl-
phenyl)propan-2-one oxime to give 550 mg (39%) of 3f and
105 mg (7%) of 4f.
was converted to the hydrochloride salt: mp 168 °C (dec); ½a D20
ꢁ
ꢀ68.7° (c 0.53, CH3OH); Anal. Calcd for C26H31ClN2O2ꢂ1.5H2O: C,
67.01; H, 7.35; N, 6.01. Found: C, 66.72; H, 7.33; N, 5.80.
Compound 3f: oil; 1H NMR (CDCl3) d 7.10 (d, J = 8.1 Hz, 2H), 7.01
(d, J = 8.1 Hz, 2H), 6.95 (d, J = 7.8 Hz, 2H), 6.81 (d, J = 7.8 Hz, 2H),
6.15 (s, 1H), 3.92 (d, J = 15.0 Hz, 1H), 3.81 (d, J = 15.0 Hz, 1H),
3.35–3.13 (m, 4H), 2.33 (s, 3H), 2.30–2.02 (m, 9H), 1.85–1.50 (m,
3H); 13C NMR (CDCl3) d 173.1, 161.9, 138.1, 135.6, 135.4, 134.8,
128.9, 128.6, 128.4, 127.2, 103.4, 65.2, 61.5, 46.3, 41.8, 35.4, 34.8,
31.7, 26.2, 24.8, 20.9, 20.8; MS (EI) m/z 386 (M+). The free base
Compound 4h: oil; 1H NMR (CDCl3) d 7.00–6.76 (m, 6H), 6.66–
6.55 (m, 2H), 3.82 (s, 3H), 3.50–3.40 (m, 1H), 3.20–3.02 (m, 3H),
2.67 (ddd, J = 12.3, 12.3, 2.1 Hz, 1H), 2.24 (s, 6H), 2.21–2.05 (m,
2H), 2.01 (s, 3H), 1.75–1.60 (m, 3H); 13C NMR (CDCl3) d 169.1,
159.1, 158.10, 139.3, 135.8, 131.0, 128.8, 127.8, 123.2, 117.9,
114.0, 66.5, 62.2, 55.4, 45.7, 42.2, 36.5, 36.2, 26.9, 25.2, 21.1,
10.6; MS (EI) m/z 402 (M+). The free base was converted to the
was converted to the hydrochloride salt: mp 193 °C (dec); ½a D20
ꢁ
ꢀ61.9° (c 0.43, CH3OH); Anal. Calcd for C26H31ClN2Oꢂ0.75H2O: C,
71.54; H, 7.50; N, 6.42. Found: C, 71.61; H, 7.37; N, 6.34.
hydrochloride salt: mp 238 ° C (dec); ½a D20
ꢁ
+50.7° (c 0.28, CH3OH);
Anal. Calcd for C26H31ClN2O2ꢂ1.25H2O: C, 67.67; H, 7.32; N, 6.07.
Compound 4f: oil; 1H NMR (CDCl3) d 7.11 (d, J = 7.8 Hz, 2H), 6.94
(d, J = 7.8 Hz, 2H), 6.89 (d, J = 8.1 Hz, 2H), 6.61 (d, J = 8.1 Hz, 2H),
3.50–3.41 (m, 1H), 3.22–3.08 (m, 3H), 2.68 (ddd, J = 12.3, 12.3,
2.1 Hz, 1H), 2.40 (s, 3H), 2.24 (s, 6H), 2.21–2.06 (m, 2H), 2.01 (s,
3H), 1.72–1.60 (m, 3H); 13C NMR (CDCl3) d 169.1, 157.8, 139.2,
137.2, 135.7, 129.6, 129.2, 128.8, 127.9, 127.7, 118.1, 66.5, 62.1,
Found: C, 67.56; H, 7.35; N, 5.96.
Acknowledgment
This research was supported by the National Institute on Drug
Abuse, Grant No. DA05477.

6688
C. Jin et al. / Bioorg. Med. Chem. 16 (2008) 6682–6688
15. Singh, S. Chem. Rev. 2000, 100, 925–1024.
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