Synthesis of indatraline using a Suzuki cross-coupling reaction and a chemoselective hydrogenation: A versatile approach

Article abstract of DOI:10.1055/s-2003-40868

Indatraline and its derivatives can be obtained in five steps from indanone by using a Suzuki cross-coupling reaction and a chemoselective hydrogenation catalyzed by Wilkinson's catalyst.

Full text of DOI:10.1055/s-2003-40868

LETTER
1515
Synthesis of Indatraline Using a Suzuki Cross-Coupling Reaction and a
Chemoselective Hydrogenation: A Versatile Approach
S
ynthesis
a
of Indatrali
n
ne ine Cossy,* Damien Belotti, Aude Maguer
Laboratoire de Chimie Organique, associé au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Fax +33(1)40794660; E-mail: janine.cossy@espci.fr
Received 16 April 2003
relies on two key steps, a Suzuki cross-coupling reaction
which employs commercially available boronic acids,14
and a chemoselective hydrogenation performed in the
presence of Wilkinson’s catalyst.
Abstract: Indatraline and its derivatives can be obtained in five
steps from indanone by using a Suzuki cross-coupling reaction and
a chemoselective hydrogenation catalyzed by Wilkinson’s catalyst.
Key words: indatraline, indanone, Suzuki reaction, hydrogenation,
Wilkinson’s catalyst
The first step is the transformation of indanone (2) to the
3-bromoindenone (3) in a one-pot sequence.15 Indanone
(2) was illuminated with a light bulb (75 Watts, visible
light) in the presence of N-bromosuccinimide (2.1 equiv)
and a catalytic amount of AIBN in refluxing CCl4.16 After
2 hours, triethylamine (3.5 equiv) was added at 0 °C and
the reaction mixture was stirred at room temperature for
12 hours. This process provided 3-bromoindenone (3) in
99% yield. The transformation of 3 to 3-arylated indenone
4 was obtained by using a Suzuki cross-coupling reac-
tion.17 When 3 was treated with 3,4-dichlorophenyl-
boronic acid (1.1 equiv) and with a catalytic amount of
palladium tetrakistriphenylphosphine [Pd(PPh3)4, 0.05
equiv] in the presence of an aqueous saturated solution of
Na2CO3 (3.0 equiv) in a degassed mixture of THF/EtOH
(5/1) at room temperature for 1.5 days, compound 4 was
isolated in 90% yield.18 Chloride is certainly one of the
most reducible atoms in transition metal-catalyzed hydro-
genation processes19 and, as a result, selective hydrogena-
tion of the enone 4 in the presence of chloride atoms was
delicate. However, chlorotris(triphenylphosphine)rhodi-
um(I) catalyst (Wilkinson’s catalyst, 0.04 equiv) in THF/
t-BuOH (1/1)20,21 showed good chemoselectivity, and hy-
drogenation of 4 under one atmosphere of hydrogen for 15
hours led to the known precursor of indatraline,8,9,13 ke-
tone 5, in 81% yield. Ketone 5 was obtained in three steps
in 72% yield.
The abuse of stimulants, such as methamphetamine and
amphetamine, is a national and international1 public
health problem,2 and a considerable number of adverse
effects3 derive from that abuse including the increased
transmission of hepatitis and HIV/AIDS.4,5 For this rea-
son, selective dopamine reuptake inhibitors are currently
being evaluated for their potential as substitution medica-
tions to treat cocaine and methamphetamine abuse.6,7 In-
danamines were found to have potencies as dopamine
(DA) reuptake blockers8 and it has been reported that in-
datraline 1 (LU 19-005) (Figure 1) is a potent psychoac-
tive compound with high binding and inhibitory affinity
for neuronal monoamine reuptake sites including the
dopamine (DA) transporter and the serotonin (5-HT)
transporter.9,10 Studies on monkeys indicate that indatra-
line reduces cocaine self-administration11 and that the (+)-
(1R,3S) enantiomer is twenty times more efficient than the
(–)-(1S,3R) enantiomer.12
NHMe·HCl
Cl
Reduction of 5 with NaBH4 (2.0 equiv, –5 °C to r.t.) in a
mixture of THF/H2O (10/1) gave a mixture of the cis and
trans alcohols 6 and 6¢ in quantitative yield and in a ratio
of 97/3 in favour of the cis-isomer. After separation of the
isomers,22 the cis-isomer 6 was treated with triethylamine
(4.0 equiv) in THF, and mesyl chloride was added (2.0
equiv, –15 °C to 0 °C) followed by a large excess of a
10% benzenic solution of methylamine. Slow warming of
the reaction mixture to room temperature gave the free
amine of indatraline as a pale yellow oil. Treatment of this
oil with HCl in diethyl ether gave the salt as a pale yellow
solid, which after recrystallization from ethyl EtOAc/
EtOH (20/1) afforded indatraline (1)9,13 in 65% yield for
the three-step sequence (Scheme 1).
Cl
Indatraline 1
Figure 1
Several syntheses of indatraline have been reported, one
of which is enantioselective and is related to the synthesis
of (+)-indatraline,13 while the others are racemic and have
relied on classical resolution or chiral HPLC techniques to
obtain enantiomerically pure material.8,9 Here, we would
like to report a short synthesis of racemic indatraline that
Synlett 2003, No. 10, Print: 05 08 2003.
Art Id.1437-2096,E;2003,0,10,1515,1517,ftx,en;G08403ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1516
J. Cossy et al.
LETTER
O
O
1) NBS, cat. AIBN, hν
O
O
Z
B(OH)2
CCl4, reflux, 2 h
2) Et3N, 0 °C to r.t., 12 h
99%
cat. Pd(PPh3)4
Na2CO3/H2O
THF/EtOH, r.t.
1.5 day
Br
2
3
Br
3
Z = F : 7a, 78%
Z = CN: 7b, 63%
Cl
Cl
B(OH)2
Z
90%
cat. Pd(PPh3)4
Na2CO3/H2O
THF/EtOH, r.t.
1.5 day
H2
cat. RhCl(PPh3)3
THF/t-BuOH, r.t.
15 h
O
O
H2
O
cat. RhCl(PPh3)3
Indatraline analogues
THF/t-BuOH, r.t.,15 h
81%
5
4
Z = F : 8a, 60%
Z = CN: 8b, 73%
Cl
Cl
Cl
Cl
NaBH4/H2O
Z
Scheme 2
THF, 0 °C to r.t., 3 h
100%
dr = 97/3
OH
ClH.NHMe
1) MsCl, Et3N
THF, –15 °C to 0 °C, 1 h
References
6' +
2) MeNH2/PhH,
0 °C to r.t., 24 h
3) HCl/Et2O
65%
(1) Topp, L.; Hando, J.; Dillon, P.; Roche, A.; Solowij, N. Drug
Alcohol Dependence 1999, 55, 105.
(2) Crome, H. B. Drug Alcohol Dependence 1999, 55, 247.
(3) Yui, K.; Goto, K.; Ikemoto, D.; Ishigoro, T. Drug Alcohol
Dependence 2000, 58, 67.
6
1
Cl
Cl
Cl
Cl
(4) Hoffman, J. A.; Klein, H.; Eber, M.; Crosby, H. Drug
Alcohol Dependence 2000, 58, 227.
Scheme 1
(5) Sorensen, J. L.; Copeland, A. L. Drug Alcohol Dependence
2000, 59, 17.
(6) Baumann, M. H.; Char, G. U.; deCosta, B. R.; Rice, K. C.;
Rothman, R. B. J. Pharmacol. Exp. Ther. 1994, 271, 1216.
(7) Villemagne, V.; Rothman, R. B.; Yokoi, F.; Rice, K. C.;
Matecka, D.; Clough, D. J.; Dannals, R. F. Synapse 1999, 32,
44.
(8) (a) Gu, X. H.; Yu, H.; Jacobson, A. E.; Rothman, R. B.;
Dersch, C. M.; George, C.; Flippen-Anderson, J. L.; Rice, K.
C. J. Med. Chem. 2000, 43, 4868. (b) Froimowitz, M.; Wu,
K.-M.; Moussa, A.; Haidar, R. M.; Jurayj, J.; George, C.;
Gardner, E. L. J. Med. Chem. 2000, 43, 4981.
(9) Bogeso, K. P.; Christensen, A. V.; Hyttel, J.; Liljefors, T. J.
Med. Chem. 1985, 28, 1817.
(10) Hyttel, J.; Larsen, J. J. J. Neurochem. 1985, 44, 1615.
(11) Negus, S. S.; Brandt, M. R.; Mello, N. K. J. Pharmacol. Exp.
Ther. 1999, 291, 60.
(12) Rosenzweig-Lipson, S.; Bergman, J.; Spealman, R. D.;
Madras, B. K. Psychopharmacology 1992, 107, 186.
(13) Davies, H. M. L.; Gregg, T. M. Tetrahedron Lett. 2002, 43,
4951.
(14) 3-Arylindan-1-ones have been synthesized from 3-bromo-
indenone and pinacol boronate esters, which have to be
prepared from the corresponding boronic acids: Clark, W.
M.; Kassick, A. J.; Plotkin, M. A.; Eldridge, A. M.; Lantos,
I. Org. Lett. 1999, 1, 1839.
Furthermore, 3-aryl-1-aminoindane in which the aryl
group is substituted with functional groups sensitive to
hydrogenation conditions, such as a fluorine or a cyano
group, can be prepared. 3-(4-Fluorophenyl)indenone (8a)
and 3-(4-cyanophenyl)indanone (8b) were prepared from
3-bromoindenone (3). When 3-bromoindenone (3) was
treated under the Suzuki conditions [Pd(PPh3)4, Na2CO3/
H2O, THF/EtOH, r.t., 1.5 days) with 4-fluorophenyl-
boronic acid and 4-cyanophenylboronic acid, compounds
7a (78% yield) and 7b (63% yield) were isolated. After
hydrogenation of 7a and 7b with Wilkinson’s catalyst
(1 atm, 15 h), compounds 8a23 (60% yield) and 8b24 (73%
yield) were respectively obtained (Scheme 2).
The synthesis of indatraline and the precursors of its ana-
logues, such as 8a and 8b, demonstrates the versatility of
our synthetic scheme. By combining the availability of
arylboronic acids, which are used in the Suzuki cross-
coupling reaction, with the chemoselectivity of the
Wilkinson’s hydrogenation, a great variety of 3-aryl-1-
aminoindane derivatives can be prepared and tested for
biological activity.
(15) Heffner, R. J.; Joullié, M. Synth. Commun. 1991, 21, 2231.
(16) The reaction was performed on 5–10g of indanone.
(17) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
Synlett 2003, No. 10, 1515–1517 © Thieme Stuttgart · New York

LETTER
Synthesis of Indatraline
1517
(18) Typical Experiment for the Suzuki Reaction: A solution
of the b-bromoindenone 3 (4.18 g, 20 mmol) and 3,4-
dichlorophenyl-boronic acid (4.2 g, 22 mmol) in THF (100
mL) containing absolute EtOH (20 mL) and H2O (20 mL)
was degased with argon for 20 min. Na2CO3 (6.36 g, 60
mmol) and Pd(PPh3)4 (1.16 g, 1 mmol) were added to this
solution. The resulting mixture was vigourously stirred at r.t.
for 1.5 d under an argon atmosphere and then diluted with
CH2Cl2 (250 mL). The reaction mixture was washed with
H2O (2 × 100 mL) and the aqueous layer extracted with
CH2Cl2 (100 mL). The combined organic layers were dried
over MgSO4 and filtered. The solvent was removed in vacuo
and the residue was purified by flash column
chromatography on silica gel (90/10 petroleum ether/
EtOAc) to provide b-arylindenone 5 as a colorless solid
(0.74 g, 81% yield): Mp 113–115 °C. IR: 1710 cm–1.
1H NMR (CDCl3): d = 7.82 (d, J = 7.7 Hz, 1 H), 7.61 (td,
J = 7.5, 1.2 Hz, 1 H), 7.45 (t, J = 7.4 Hz, 1 H), 7.38 (d,
J = 8.3 Hz, 1 H), 7.30–7.20 (2 H), 6.96 (dd, J = 8.3, 2.1 Hz,
1 H), 4.55 (dd, J = 8.1, 3.8 Hz, 1 H), 3.23 (dd, J = 19.2, 8.1
Hz, 1 H), 2.62 (dd, J = 19.2, 3.8 Hz, 1 H). 13C NMR
(CDCl3): d = 204.8 (C), 156.4 (C), 143.9 (C), 136.7 (C),
135.3 (CH), 132.9 (C), 131.1 (C), 130.9 (CH), 129.6 (CH),
128.3 (CH), 126.9 (CH), 126.6 (CH), 123.6 (CH), 46.4
(CH2), 43.5 (CH). MS (EI): m/z (rel. int.) = 276 (100) [M+],
241 (77), 212 (25), 178 (60).
chromatography on silica gel (60/40 petroleum ether/
CH2Cl2) to give the b-arylindenone 4 as a yellow solid (4.95
g, 90% yield): Mp 148–150 °C. IR: 1700 cm–1. 1H NMR
(CDCl3): d = 7.74 (d, J = 2.0 Hz, 1 H), 7.63–7.25 (6 H), 6.01
(s, 1 H). 13C NMR (CDCl3): d = 121.2 (CH), 123.1 (CH),
123.9 (CH), 126.6 (CH), 129.1 (CH), 129.6 (CH), 131.1
(CH), 131.9 (C), 132.9 (C), 133.1 (CH), 133.4 (C), 134.6
(C), 143.3 (C), 160.1 (C), 196.3 (C). MS (EI): m/z
(22) Separated by flash chromatography on silica gel (70/30
petroleum ether/EtOAc).
(23) Compound 8a: Mp 116–118 °C. IR 1710 cm–1. 1H NMR
(CDCl3): d = 7.81 (d, J = 7.6 Hz, 1 H), 7.59 (td, J = 7.5, 1.1
Hz, 1 H), 7.43 (t, J = 7.4 Hz, 1 H), 7.25 (dd, J = 7.6, 0.8 Hz,
1 H), 7.14–6.93 (4 H), 4.57 (dd, J = 8.0, 3.8 Hz, 1 H), 3.23
(dd, J = 19.3, 8.1 Hz, 1 H), 2.64 (dd, J = 19.3, 3.9 Hz, 1 H).
13C NMR (CDCl3): d = 205.5 (C), 161.8 (d, J = 245 Hz,
CF), 157.6 (C), 139.4 (C), 136.7 (C), 135.1 (CH), 129.1
(CH), 129.0 (CH), 128.0 (CH), 126.7 (CH), 123.4 (CH),
115.9 (CH), 115.6 (CH), 46.9 (CH2), 43.7 (CH). MS (EI):
m/z (rel. int.) = 226 (100) [M+], 197 (30), 183 (28).
(24) Compound 8b: Mp 108–110 °C. IR: 2230, 1710 cm–1. 1H
NMR (CDCl3): d = 7.83 (d, J = 7.7 Hz, 1 H), 7.67–7.56 (3
H), 7.47 (t, J = 7.5 Hz, 1 H), 7.30–7.20 (3 H), 4.67 (dd,
J = 8.1, 3.8 Hz, 1 H), 3.27 (dd, J = 19.2, 8.2 Hz, 1 H), 2.64
(dd, J = 19.2, 3.8 Hz, 1 H). 13C NMR (CDCl3): d = 204.5 (C),
156.2 (C), 149.1 (C), 136.7 (C), 135.3 (CH), 132.7 (2 CH),
128.4 (3 CH), 126.6 (CH), 123.7 (CH), 118.5 (C), 111.0 (C),
46.2 (CH2), 44.3 (CH). MS (EI) m/z (rel. int.) = 233 (100)
[M+], 204 (30), 190 (22).
(rel. int.) = 274 (86) [M+], 239 (100), 211 (28), 176 (73).
(19) Rylander, P. N. Catalytic Hydrogenation in Organic
Syntheses; Academic Press: New York, 1979, 114.
(20) Jourdant, A.; Gonzalez-Zamora, E.; Zhu, J. J. Org. Chem.
2002, 67, 3163.
(21) Typical Experiment for the Wilkinson Hydrogenation:
(PPh3)3RhCl (0.122 g, 0.132 mmol) was added to a solution
of b-arylindenone 4 (0.91 g, 3.3 mmol) in THF/t-BuOH
(1/1, 24 mL) under an argon atmosphere. The resulting
solution was saturated with hydrogen and stirred under one
atmosphere of hydrogen overnight at r.t. The reaction
mixture was filtered through a short pad of alumina and
washed thoroughly with EtOAc. The solvent was removed in
vacuo and the residue was purified by flash column
Synlett 2003, No. 10, 1515–1517 © Thieme Stuttgart · New York