Catalytic enantioselective synthesis of the dopamine D1 antagonist ecopipam

Article abstract of DOI:10.1016/j.tetasy.2012.01.017

A concise asymmetric synthesis of the potent dopamine D1 antagonist, ecopipam, has been accomplished in six steps with 33% overall yield via catalytic enantioselective aziridination and subsequent one-pot Friedel-Crafts cyclization of an in situ generated tethered aziridine with high diastereo- and enantioselectivities.

Full text of DOI:10.1016/j.tetasy.2012.01.017

Tetrahedron: Asymmetry 23 (2012) 151–156
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Catalytic enantioselective synthesis of the dopamine D1 antagonist ecopipam
⇑
Saumen Hajra , Sukanta Bar
Department of Chemistry, Indian Institute Technology Kharagpur, Kharagpur 721302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise asymmetric synthesis of the potent dopamine D1 antagonist, ecopipam, has been accomplished
in six steps with 33% overall yield via catalytic enantioselective aziridination and subsequent one-pot
Friedel–Crafts cyclization of an in situ generated tethered aziridine with high diastereo- and
enantioselectivities.
Received 16 December 2011
Accepted 25 January 2012
Available online 16 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Cl
N
CH3
Me
2,3,4,5-Tetrahydro-1H-3-benzazepines have been the subject of
great interest over the last few decades because of their selective
affinity for the D1 subpopulation of dopamine receptors in the
central nervous system.1 Benzazepine SCH 23390 1a was initially
N
HO
H
HO
developed as
a prototype dopamine D1 receptor antagonist
(Fig. 1).2 Ethylene bridged restricted benzazepine, trans-(ꢀ)-
(6aS,13bR)-11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-5H-ben-
zo[d]naphth[2,l-b]azepin-l2-ol (SCH 39166) was later developed as
a potent dopamine D1 antagonist to treat schizophrenia and other
D1 dependent neurological disorders.3 SCH 39166 1b (ecopipam)
was shown to reduce the craving for addictive substances such as
cocaine, nicotine, alcohol, and so on, in animal models.4 Clinical tri-
als showed that ecopipam 1b reduced the euphoric effects of co-
caine,5 but was not effective in completely treating the addiction.
It also shows sedative and antipsychotic effects, but it was not ap-
proved for medical prescription due to side effects such as depres-
sion and anxiety.6 Ecopipam was further studied as a potential
candidate to enhance and maintain weight loss in obese people.7
It is currently under clinical trial for the treatment of Lesch–Nyhan
syndrome8 and Tourette syndrome.9
Cl
SCH 23390 1a
SCH 39166 1b
(ecopipam)
Figure 1. Benzoazepine dopamine D1 antagonists.
much effort has focused on the asymmetric synthesis. Wu et al. the
first reported chiral-pool based asymmetric synthesis of ecopipam
1b starting from (1S,2S)-2-amino-1-phenyl-1,3-diol in eleven
steps, where one-carbon homologation, amide coupling, double
reduction, and two Friedel–Crafts cyclization reactions were the
key steps.10b A number of strategies starting from either
L-hom-
ophenylalanine or trans-N-alkyl-1-amino-2-hydroxytetralin have
already been reported in the literature.10c,d Among these, the regio-
and stereoselective ring openings of the aziridinium ion, derived
from enantiomerically pure trans-N,N-dialkyl-1-amino-2-hydroxy-
tetralin, by a 3-chloro-4-methoxyphenyl Grignard reagent to form
2-amino-1-aryltetralin are one of the more efficient methods.10c
trans-2-Amino-1-aryltetralin 2, usually prepared in 4–6 steps, is
thus found to be an advanced intermediate for the synthesis of
ecopipam. One convenient and concise strategy for the asymmetric
synthesis of aminotetralin 2 is the stereoselective intramolecular
2. Results and discussion
Due to its importance, several syntheses of ecopipam 1b are
known in the literature.10 The discovery synthesis3a described
the construction of the tetracyclic core structure as a mixture of
cis/trans isomers via Friedel–Crafts cyclization of 2{[2-(3,4-dime-
thoxyphenyl)-ethyl]-methylamino}-1-hydroxytetralin. Separation
of the trans-isomer and late stage resolution provided the enantio-
merically pure SCH 39166. Since these benzoazepine compounds
display a high enantiospecificity toward the dopamine D1 receptor,
Friedel–Crafts type cyclization of tethered chiral aziridine
3
(Scheme 1). Herein, we report the asymmetric synthesis of ecopi-
pam via a catalytic enantioselective one-pot aziridoarylation reac-
tion, which proceeds with high diastereo- and enantioselectivities.
To begin the synthesis of ecopipam, styrene 4 was prepared by
two routes. Wittig reaction of dihydrocinnamaldehyde 5 and
phosphonium salt 6 provided as an E/Z-mixture of compound 4
⇑
Corresponding author. Tel.: +91 3222 283340; fax: +91 3222 255303.
E-mail address: shajra@chem.iitkgp.ernet.in (S. Hajra).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2012.01.017

152
S. Hajra, S. Bar / Tetrahedron: Asymmetry 23 (2012) 151–156
NR1R2
SCH 39166
(ecopipam)
NR1
OMe
OMe
OMe
2
3
4
Cl
Cl
Cl
Scheme 1. Retrosynthesis of SCH 39166.
O
CH2PPh3Br
n-BuLi,
THF, -78 °C
H
85%
OMe
OMe
Cl
6
Cl
E:Z = 1:1
4
5
Scheme 2. Preparation of styrene 4 via a Wittig reaction.
(1:1) in an 85% yield (Scheme 2). Suzuki coupling11 of the in situ
generated vinylborane 8, obtained by heating alkyne 7 with cate-
cholborane, and 4-bromo-1-chloro-2-methoxybenzene 9 exclu-
sively provided trans-alkene trans-4 (Scheme 3).
From our previous studies we found that the Cu(OTf)2 catalyzed
intramolecular Friedel–Crafts type cyclization of an in situ
generated aziridine from the tethered alkene provided trans-2-
amino-1-aryltetralins, where [N-(4-nitrobenzenesulfonyl)imino]-
phenyliodinane, PhINSO2(4-NO2C6H4) [PhINNs] was used as an
efficient nitrenoid source for the aziridination of the tethered al-
kenes.12 Chiral copper complexes prepared from Cu(OTf)2 and the
bis-oxazoline (Box) ligand derived from phenylglycinol was found
to be the more efficient ones.12b
the E/Z mixture of alkene 4. When trans-4 was subjected to the
aziridination reaction under similar reaction conditions, it under-
went smooth aziridination in 1 h and upon further treatment with
an additional 10 mol % Cu(OTf)2 provided aminotetralin 2 within
1 h at rt (entry 2). The use of the trans-alkene provided an im-
proved yield of the reaction (85% yield) with the same enantiose-
lectivity (89% ee). Generally large excess of alkene was used to
ensure complete consumption of the nitrene reagent.12,13 Both
the yield and ee decreased upon lowering the alkene loading (entry
3). Attempts to enrich the ee by crystallization from different sol-
vents were unsuccessful. The reaction of trans-4 under similar con-
ditions using Box ligand ent-10 derived from
produced aminotetralin ent-2 in 92% ee with a high yield (85%) (en-
try 4). It should be noted that - and -phenylglycines were ob-
D-phenylglycinol
With the standard reaction conditions in hand, we started the
synthesis of ecopipam. First, alkene 4 was subjected to an aziridin-
ation reaction in the presence of Cu(OTf)2 (0.13 equiv) and
L
D
tained from different sources; the former showed a slightly lower
enantiomeric purity. Thus, the use of (S)-Box derived from better
(S)-Box-ligand 10 (0.15 equiv) derived from
L
-phenylglycinol and
quality L-phenylglycine might provide aminotetralin 2 with up to
molecular sieves in DCM. This gave aziridine 3 after 3 h at 32 °C
as detected from the 1H NMR of the crude reaction mixture. With-
out isolation of the aziridine, the reaction was continued with an
additional 0.1 equiv of Cu(OTf)2 at rt and in one-pot. This gave
the desired (1R,2S)-N-nosyl-2-amino-1-aryltetralin 2 in a 79% yield
with 89% ee (Table 1, entry 1). It was thought that the use of pure
trans-alkene trans-4 might give a better yield and selectivity than
92% ee. It should be noted that the E/Z (1:1) mixture of styrene 4
upon aziridination and subsequent Friedel–Crafts cyclization
exclusively provided trans-2-amino-1-aryltetralin 2 (dr >99:1)
while the corresponding cis-cyclized product was not detected in
the crude reaction mixture by 1H NMR analysis. This is due to
the dual chemoselectivity of the aziridination and Friedel–Crafts
reactions.12a,b The E/Z ratio of the recovered styrene 4 attained to
Br
OMe
catecolborane
THF, heat
9
(1.1 equiv)
Cl
B
(Ph3P)4Pd (5 mole%))
O
O
7
20% aq Na2CO3
reflux, 12h
OMe
Cl
trans-4
89%
8
E/Z > 99:1
Scheme 3. Synthesis of styrene trans-4 via a Suzuki coupling.

S. Hajra, S. Bar / Tetrahedron: Asymmetry 23 (2012) 151–156
153
Table 1
Catalytic and enantioselective one-pot synthesis of aminotetralin 2a
1. PhINNs (1.0 equiv)
10 (0.15 equiv)
O
O
NHNs
Cu(OTf)2 (0.13 equiv)
4Å MS, CH2Cl2, T, t1
N
N
10
Ph
Ph
2. Cu(OTf)2 (0.1 equiv),
rt, t2
MeO
MeO
Cl
dr: >99:1
T (°C)
2
Cl
4
Entry
Alkene
E/Z ratio
Alkene loading (equiv)
t1 (h)
t2 (h)
Yield of 2d (%)
eee (%)
b
c
1
2
4
1:1
>99:1
>99:1
>99:1
5
5
2.5
5
32
25
25
25
3
1
2
1
2
1
1
1
79
85
71
85
89
89
82
92g
trans-4
trans-4
trans-4
3
4f
a
To a solution of bis(oxazoline)–Cu(II) complex derived from 13 mol % Cu(OTf)2 and 15 mol % bis(oxazoline) ligand 10 and styrene 4 (5 equiv) in CH2Cl2, PhINNs (1.0 equiv)
was added. The suspension was stirred at the specified temperature. After dissolution of all of the nitrenoid reagents, an additional 10 mol % of Cu(OTf)2 was added.
b
Time required for the aziridination reaction.
Time required for the Friedel–Crafts cyclization.
Isolated yields of 2 after column chromatography.
Enantiomeric excess (ee) was determined by HPLC using a chiral column.
Reaction carried out using Box ligand ent-10.
The opposite enantiomer ent-2 was formed.
c
d
e
f
g
1:1.6 from 1:1 that might further support the chemoselectivity at
aziridination step.
refluxed with KF/Al2O3 and BrCH2CH(OMe)2 in acetonitrile,10d but
produced a 1:1 mixture of the desired product 13 along with ester
14 as a by-product. The problem was resolved when the sodium
salt of compound 12, generated by the reaction of NaH (2.4 equiv)
at 0 °C for 1 h in dry THF, was refluxed with BrCH2CH(OMe)2
(3.0 equiv) under an argon atmosphere. After 48 h, compound 13
was obtained in 75% yield. The specific rotation of 13
For the synthesis of ecopipam, N-methylation of aminotetralin
2 was carried out on the sodium salt of compound 2, generated
by the reaction of NaH, with MeI at 0 °C. Within 1 h, it provided
compound 11 in good yield (92%) (Scheme 4). Denosylation of
compound 11 with 4-methoxythiophenol (3.0 equiv) and K2CO3
(3 equiv) in CH3CN/DMSO (49:1) at 32 °C afforded the N-methyla-
minotetralin 12 after 5 h with excellent yield. Compound 12 was
{½a 2D3
¼ þ56:9 (c 1.40, EtOH)} was found to be in good agreement
ꢁ
with the literature data {½a D20
ꢁ
¼ þ63:5 (c 1.49, EtOH)}.10d Construc-
p-MeOC6H4SH (3.0 equiv),
NaH (2.4 equiv),
K2CO3 (3.0 equiv),
MeI (2.4 equiv),
NHNs
NNs
Me
NHMe
CH3CN/DMSO (49:1),
32 °C, 5h
THF, 0 °C to rt, 4h
MeO
MeO
MeO
95%
92%
Cl
11
Cl
Cl
2
12
BrCH2CH(OMe)2(2.4 equiv)
KF/Al2O3, reflux, 24 h
NaH (2.4
equiv),
BrCH2CH(OMe)2
80%
75%
Me
Me
(3.0 equiv)
N
N
THF, reflux, 48 h
OMe
OMe
OMe
13
O
MeO
MeO
Cl
Cl
CH3SO3H, DCM
tBuNH2·BH3
70%
1:1
13
14
Me
Me
N
N
AcOH, 48% HBr, reflux
DMF, AqNaHCO3, filter
85%
HO
MeO
Cl
SCH 39166
15
Cl
Scheme 4. Synthesis of SCH 39166.

154
S. Hajra, S. Bar / Tetrahedron: Asymmetry 23 (2012) 151–156
tion of the azepine core and demethylation would complete the
synthesis. For this purpose, an acid catalyzed cyclization using Me-
SO3H and subsequent one-pot reduction with t-BuNH2ꢂBH3 affor-
ded tetracyclic compound 15 in a 70% yield.10d Finally, the HBr
mediated demethylation of compound 15 in acetic acid at 130 °C
accomplished the synthesis of ecopipam as an HBr salt. Neutraliza-
tion with 5% aq NaHCO3 gave ecopipam 1b as a white solid in
excellent yield. The specific rotation of the synthesized ecopipam
1.5H), 3.86 (s, 1.5H), 2.85–2.75 (m, 2H), 2.69–2.45 (m, 2H); ESI-
MS m/z: 272 [M]+; Anal. Calcd for C17H17ClO: C, 74.86; H, 6.28.
Found: C, 74.98; H, 6.13.
4.1.2. 1-Chloro-2-methoxy-4-(4-phenyl-but-1-enyl)-benzene
trans-4
To a stirred solution of alkyne 7 (2.0 g, 15.38 mmol) in 25 mL
of THF was added catecholborane (4.8 g, 38.46 mmol) slowly over
a period of 5 min under ice cold conditions. Then the reaction
mixture was refluxed for 3 h. The reaction mixture was again
cooled to ice cold conditions and 4-bromo-1-chloro-2-methoxy-
benzene 9 (3.7 g, 16.9 mmol) was added slowly over 1 min, after
which (Ph3P)4Pd (0.93 g, 0.769 mmol) was added to the reaction
mixture. The mixture was allowed to stir at rt for 25 min. The
reaction mixture was recooled to 0 °C, at which point 15.38 mL
of 20% aqueous Na2CO3 solution was added slowly over the reflux
condenser. The reaction mixture was then allowed to reflux for
12 h. Upon completion of the reaction, it was cooled to rt, diluted
with 50 mL of EtOAc and the organic portion was washed with
brine and dried with Na2SO4. Solvent evaporation and column
purification (EtOAc/hexane = 7/93) gave the title alkene trans-4
(3.7 g, 89% yield) as a light yellow liquid. 1H NMR (400 MHz,
CDCl3): d 7.36–7.18 (m, 6H), 6.89 (d, J = 7.2 Hz, 2H), 6.39 (d,
J = 16.0 Hz, 1H), 6.31–6.24 (m, 1H), 3.90 (s, 3H), 2.85–2.80 (m,
2H), 2.59–2.53 (dd, J = 7.2, 15.7, 2H); 13C NMR (CDCl3,
100 MHz): d 154.8, 141.5, 137.7, 130.8, 130.0, 129.5, 128.5 (2C),
128.4 (2C), 125.9, 120.8, 118.9, 109.4, 56.0, 35.7, 34.8; ESI-MS
m/z: 272 [M]+; Anal. Calcd for C17H17ClO: C, 74.86; H, 6.28.
Found: C, 74.96; H, 6.18.
was found to be ½a D24
¼ ꢀ200:9 (c 0.52, DMF), which was in good
ꢁ
agreement with the literature value {[
a
]
D = ꢀ220.8 (c 0.56,
DMF)}.3a The overall yield of this catalytic and enantioselective
synthesis of ecopipam (ꢀ)-SCH 39166 was 33% starting from al-
kene trans-4 in six steps. Similarly, the other enantiomer of ecopi-
pam was successfully synthesized from aminotetralin ent-2. The
specific rotation of (+)-SCH 39166 {½a D24
ꢁ
¼ þ202:8 (c 0.29, DMF)}
matched well with the literature data {[
DMF)}.3a
a]
D = +220.5 (c 0.29,
3. Conclusion
In conclusion, we have achieved a concise asymmetric synthesis
of aminotetralin 2 from alkene trans-4 and also from 4 (E/Z = 1:1)
with diastereo- (>99:1) and enantioselectivity (ee 89%) via cata-
lytic and enantioselective aziridoarylation. Aminotetralin 2 was
transformed to ecopipam in five steps. The overall yield of this syn-
thesis from alkene trans-4 was found to be 33%. We have also syn-
thesized (+)-SCH 39166 from aminotetralin ent-2 prepared via an
aziridoarylation reaction using (R)-Box ligand ent-10.
4. Experimental
4.1. General
4.1.3. (+)-trans-(1R,2S)-N-[1-(4-Chloro-3-methoxy-phenyl)-
1,2,3,4-tetrahydronaphthalen-2-yl]-4-nitro-benzenesulfon-
amide 2
A 10 mL two-necked round bottom flask was charged with (S)-
bis-oxazoline ligand 10 (0.012 g, 0.037 mmol, 0.15 equiv) and
Cu(OTf)2 (0.011 g, 0.032 mmol, 0.13 equiv). Anhydrous DCM
(1.2 mL) was injected and the resulting mixture was stirred for
30 min. To this solution, alkene trans-4 (0.320 g, 1.23 mmol,
5.0 equiv) in 1.2 mL of DCM, PhINNs (0.1 g, 0.247 mmol, 1.0 equiv),
and 0.2 g of powdered molecular sieves (4 Å) were added and the
reaction mixture was allowed to stir at rt under an argon atmo-
sphere for 1 h. Upon dissolution of PhINNs, an additional 0.009 g
of Cu(OTf)2 (0.0247 mmol, 0.10 equiv) was added to the reaction
mixture and it was allowed to stir for another 1 h at rt. The reaction
was quenched by diluting with ethyl acetate (10 mL) and filtering
through a short plug of silica gel. The silica gel was washed with an
additional 10 mL of ethyl acetate. The filtrate was concentrated by
rotary evaporation under reduced pressure. The crude mass was
subjected to purification by flash column chromatography using
20% EtOAc in hexane as an eluent, which provided aminotetralin
2 (0.085 g, 85%). White solid, mp: 180–182 °C. 1H NMR (CDCl3,
200 MHz): d 8.16 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.12–
7.15 (m, 2H), 7.07 (d, J = 8.0 Hz, 1H), 7.01–6.97 (m, 1H), 6.60 (d,
J = 7.6 Hz, 1H), 6.46 (d, J = 8.0 Hz, 1H), 6.27 (s, 1H), 5.02 (d,
J = 7.2 Hz, 1H), 3.83 (d, J = 9.2 Hz, 1H), 3.61 (s, 3H), 3.55–3.58 (m,
1H), 3.03–3.06 (m, 1H), 2.91–2.96 (m, 1H), 2.42–2.38 (m, 1H),
1.88–1.84 (m, 1H); 13C NMR (CDCl3, 100 MHz): d 154.8, 149.6,
145.5, 142.7, 135.9, 135.2, 130.6, 129.9, 128.6, 127.6 (2C), 126.9,
126.3, 123.8 (2C), 122.1, 121.6, 112.0, 57.5, 55.7, 52.2, 29.9, 27.6;
ESI-MS m/z: 473 [M+H]+; Anal. Calcd for C23H21ClN2O5S: C, 58.41;
All reactions were conducted using oven-dried glassware under
an atmosphere of Argon (Ar). Commercial grade reagents were
used without further purification. Solvents were dried and distilled
following the usual protocols. Flash chromatography was carried
out using silica gel (230–400 mesh). TLC was performed on alumi-
num-backed plates coated with Silica gel 60 with F254 indicator.
The 1H NMR spectra were recorded with a 200 and a 400 MHz
instrument and the 13C NMR spectra were recorded with a 50
and a 100 MHz instrument using CDCl3. 1H NMR chemical shifts
are expressed in parts per million (d) relative to CDCl3 (d = 7.26).
13C NMR chemical shifts are expressed in parts per million (d) rel-
ative to the central CDCl3 resonance (d = 77.0). Mass spectra were
obtained under positive electron spray ionization (m/z values are
given). HPLC analyses were done by Chiralpak AD-H (0.46 cm ꢃ
15 cm). Melting points were uncorrected.
4.1.1. 1-Chloro-2-methoxy-4-(4-phenyl-but-1-enyl)-benzene 4
To a stirred suspension of substituted benzyl triphenylphospho-
nium bromide 6 (27.7 g, 55.90 mmol) in dry THF (100 mL) under a
nitrogen atmosphere, n-BuLi in hexane (34.9 mL, 1.6 M in hexane)
was injected dropwise at ꢀ78 °C via a glass syringe and the stirring
was maintained for 30 min. 3-Phenylpropionaldehyde 5 (5.0 g,
37.26 mmol) in dry THF (25 mL) was then slowly added. The reac-
tion mixture was allowed to reach room temperature over 1 h. The
reaction was quenched with aqueous NH4Cl solution and extracted
with diethyl ether (three times). The combined organic layers were
washed with brine, and dried over anhydrous Na2SO4. Flash col-
umn chromatography of the crude mass over silica-gel yielded al-
kene 4 (8.6 g, 85%) as an E/Z-mixture (E/Z = 1:1). 1H NMR (CDCl3,
200 MHz): 7.31–7.18 (m, 6H), 6.88 (d, J = 6.2 Hz, 1H), 6.76 (d,
J = 6.2 Hz, 1H), 6.43–6.18 (m, 1.5H,), 5.80–5.67 (m, 0.5H,), 3.91 (s,
H, 4.41; N, 5.92. Found: C, 58.30; H, 4.52; N, 5.84; ½a D23
¼ þ64:2
ꢁ
(c 0.3, DCM) for 89% ee (HPLC, Daicel Chiralpak AD-H, hexane/i-
propanol = 90/10, 1.0 mL/min, 220 nm, minor 15.1 min and major
18.4 min).

S. Hajra, S. Bar / Tetrahedron: Asymmetry 23 (2012) 151–156
155
4.1.4. (ꢀ)-trans-(1S,2R)-N-[1-(4-Chloro-3-methoxy-phenyl)-
1,2,3,4-tetrahydronaphthalen-2-yl]-4-nitro-benzenesulfon-
amide ent-2
after which it was quenched with a saturated NH4Cl solution and
extracted with ethyl acetate. The organic phase was dried over
Na2SO4 and concentrated under reduced pressure. It was then puri-
fied by flash column chromatography using EtOAc/hexane (1:4) as
eluent to give compound 13 (0.096 g, 75%) as a light yellow liquid.
1H NMR (CDCl3, 200 MHz): d 7.20 (d, J = 7.8 Hz, 1H), 7.07–6.93 (m,
3H), 6.74–6.61 (m, 3H), 4.11–4.01 (m, 2H), 3.81 (s, 3H), 3.18 (s, 3H),
3.10 (s, 3H), 2.94–2.90 (m, 3H), 2.58–2.50 (m, 2H), 2.29 (s, 3H),
2.06–1.98 (m, 1H), 1.76–1.60 (m, 1H); 13C NMR (CDCl3,
100 MHz): d 154.5, 146.4, 139.4, 136.7, 130.4, 129.4, 128.2, 125.5,
122.4, 119.7, 113.5, 103.9, 67.3, 56.5, 56.1 (2C), 54.1, 53.0, 49.3,
37.9, 29.7, 22.5; ESI-MS m/z: 390 [M+H]+; Anal. Calcd for
½
a 2D3
ꢁ
¼ ꢀ66:0 (c 0.3, DCM) for 92% ee (HPLC, Daicel Chiralpak
AD-H, hexane/i-propanol = 90/10, 1.0 mL/min, 220 nm, minor
14.0 min and major 16.7 min).
4.1.5. (+)-trans-(1R,2S)-N-[1-(4-Chloro-3-methoxy-phenyl)-
1,2,3,4-tetrahydronaphthalen-2-yl]-4-nitro-benzenesulfon-
amide 11
To a stirred solution of aminotetralin 2 (0.10 g, 0.21 mmol) in
4 mL of THF, NaH (0.012 g, 0.50 mmol) was added at 0 °C and stir-
red at the same temp for 30 min. Next, MeI (0.072 g, 0.50 mmol)
was added dropwise and the reaction mixture allowed to stir at
rt. After 4 h, upon completion it was quenched with saturated
NH4Cl solution and extracted with ethyl acetate. The organic phase
was dried over Na2SO4 and concentrated. It was then purified by
column chromatography using EtOAc/hexane (1:4) as eluent to
give compound 11 (0.094 g, 92%). White solid, mp: 205 °C. 1H
C
22H28ClNO3: C, 67.77; H, 7.24; N, 3.59. Found: C, 67.56; H, 7.36;
N, 4.31; ½a 2D3
¼ þ56:9 (c 1.40, EtOH).
ꢁ
4.1.10. (ꢀ)-trans-(1S,2R)-1-(4-Chloro-3-methoxyphenyl)-N-(2,2-
dimethoxyethyl)-1,2,3,4-tetrahydro-N-methyl-2-naphthalen-
amine ent-13
½
a 2D3
ꢁ
¼ ꢀ57:2 (c 1.40, DCM).
NMR (CDCl3, 200 MHz):
d 8.14 (d, J = 8.6 Hz, 2H), 7.46 (d,
J = 8.6 Hz, 2H), 7.16–7.12 (m, 3H), 7.04–6.95 (m, 1H), 6.62–6.57
(m, 2H), 6.44 (d, J = 1.6 Hz, 1H), 4.48–4.35 (m, 1H), 4.07 (d,
J = 11.4 Hz, 1H), 3.69 (s, 3H), 3.21–3.12 (m, 1H), 3.06–3.02 (m,
1H), 2.93 (s, 3H), 2.17–2.04 (m, 2H); 13C NMR (CDCl3, 100 MHz):
d 154.9, 149.3, 145.5, 143.2, 137.7, 135.2, 130.0, 129.9, 128.4,
127.6 (2C), 126.6, 126.2, 123.8 (2C), 122.3, 121.4, 112.3, 61.2,
55.8, 48.9, 29.5, 28.5, 28.0; ESI-MS m/z: 487 [M+H]+; Anal. Calcd
for C24H23ClN2O5S: C, 59.19; H, 4.76; N, 5.75. Found: C, 58.98; H,
4.1.11. {[1-(4-Chloro-3-methoxy-phenyl)-1,2,3,4-tetrahydro-
naphthalen-2-yl]-methyl-amino}-acetic acid methyl ester 14
Gummy liquid; 1H NMR (CDCl3, 200 MHz): d 7.20 (d, J = 7.8 Hz,
1H), 7.09–6.90 (m, 3H), 6.70–6.78 (m, 2H), 6.54 (dd, J = 1.6, 8.0 Hz,
1H), 4.09 (d, J = 8.2 Hz, 1H), 3.81 (s, 3H), 3.60 (s, 3H), 3.26 (d,
J = 6.2 Hz, 2H), 3.01–3.10 (m, 1H), 2.94–2.80 (m, 2H), 2.40 (s, 3H),
2.04–1.98 (m, 1H), 1.82–1.63 (m, 1H); 13C NMR (CDCl3,
100 MHz): d 171.9, 154.5, 146.1, 138.3, 136.7, 130.4, 129.5, 128.7,
126.1, 125.9, 122.1, 119.9, 113.4, 65.6, 56.0, 55.4, 51.4, 48.8, 38.5,
28.5, 23.1; ESI-MS m/z: 374 [M+H]+; Anal. Calcd for C21H24ClNO3:
C, 67.46; H, 6.47; N, 3.75. Found: C, 67.56; H, 6.36; N, 3.61.
4.80; N, 5.62; ½a D23
¼ þ24:6 (c 0.3, DCM).
ꢁ
4.1.6. (ꢀ)-trans-(1S,2R)-N-[1-(4-Chloro-3-methoxy-phenyl)-
1,2,3,4-tetrahydronaphthalen-2-yl]-4-nitro-benzenesulfon-
amide ent-11
4.1.12. trans-(–)-(6aS,13bR)-11-Chloro-6,6a,7,8,9,13b-hexa-
hydro-7-methyl-12-methoxy-5H-benzo[d]naphth[2,1-b]-
azepine 15
½
a 2D3
ꢁ
¼ ꢀ24:9 (c 0.3, DCM).
4.1.7. (+)-trans-(1R,2S)-[1-(4-Chloro-3-methoxy-phenyl)-
1,2,3,4-tetrahydronaphthalen-2-yl]-methylamine 12
A solution of CH3SO3H (1.5 g, 15.62 mmol) and 2 mL of DCM
was cooled to ꢀ15 °C, and then a solution of amine 13 (0.10 g,
0.251 mmol) in 4 mL of DCM was added over a 5 min period. After
stirring at 25 °C for 24 h, t-BuNH2ꢂBH3 (0.034 g, 0.37 mmol) was
added, and then after 1 h, a saturated solution of NaHCO3 was
added to neutralize the reaction mixture. The layers were sepa-
rated, and the aqueous layer was extracted twice with 50 mL of
DCM. The combined organic layers were washed with 20 mL of
H2O, dried over anhydrous Na2SO4, and concentrated. Column
purification using 2% methanol in DCM provided the title com-
pound (0.057 g, 70%). White solid, mp: 103–105 °C. 1H NMR
(CDCl3, 200 MHz): d 7.15–7.08 (m, 4H), 6.98–6.95 (m, 1H), 5.85
(s, 1H), 4.74 (d, J = 7.2 Hz, 1H), 3.62–3.50 (m, 1H), 3.45 (s, 3H),
3.23–3.11 (m, 1H), 2.85–2.64 (m, 4H), 2.50 (s, 3H), 2.44–2.36 (m,
1H), 2.01–1.99 (m, 1H), 1.80–1.60 (m, 1H); 13C NMR (CDCl3,
100 MHz): d 153.2, 148.3, 139.6, 137.5, 135.0, 131.3, 130.3, 128.3,
126.3 (2C), 118.9, 111.3, 66.7, 58.3, 56.0, 45.1, 37.6, 32.1, 29.9
(2C); ESI-MS m/z: 328 [M+H]+; Anal. Calcd for C20H22ClNO: C,
73.27; H, 6.76; N, 4.27. Found: C, 73.45; H, 6.81; N, 4.19;
To a stirred solution of methyl protected aminotetralin 11
(0.1 g, 0.205 mmol) in 8 mL of CH3CN/DMSO (49:1) were added
K2CO3 (0.085 g, 0.62 mmol) and p-methoxythiophenol (0.086 g,
0.62 mmol). The reaction mixture was then stirred at rt for 5 h.
Upon completion of the reaction, the mixture was concentrated
under reduced pressure. The crude mass was subjected to column
purification by using 3% methanol in DCM as eluent to give amine
12 (0.059 g, 95%). White solid, mp: 120–122 °C. 1H NMR (CDCl3,
200 MHz): d 7.29 (d, J = 8.2 Hz, 1H), 7.13 (d, J = 4.2 Hz, 2H), 7.08–
6.98 (m, 1H), 6.75–6.65 (m, 3H), 3.97 (d, J = 8.4 Hz, 1H), 3.84 (s,
3H), 3.01–2.86 (m, 3H), 2.41 (s, 3H), 2.30–2.21 (m, 1H), 1.87 (br
s, 1H), 1.79–1.64 (m, 1H); 13C NMR (CDCl3, 100 MHz): d 155.0,
144.2, 137.4, 136.1, 130.2, 130.1, 128.5, 126.2, 126.0, 122.1,
120.7, 113.2, 62.2, 56.1, 51.9, 33.5, 27.3, 25.6; ESI-MS m/z: 302
[M+H]+; Anal. Calcd for C18H20ClNO: C, 71.63; H, 6.68; N, 4.64.
Found: C, 71.49; H, 6.61; N, 4.54; ½a D23
¼ þ46:6 (c 1.00, DCM).
ꢁ
4.1.8. (ꢀ)-trans-(1S,2R)-[1-(4-Chloro-3-methoxy-phenyl)-
1,2,3,4-tetrahydronaphthalen-2-yl]-methylamine ent-12
½
a 2D3
ꢁ
¼ ꢀ170:9 (c 1.00, EtOH).
½
a 2D3
ꢁ
¼ ꢀ47:1 (c 1.00, DCM).
4.1.13. trans-(+)-(6aR,13bS)-11-Chloro-6,6a,7,8,9,13b-hexa-
hydro-7-methyl-12-methoxy-5H-benzo[d]naphth[2,1-b]-
azepine ent-15
4.1.9. (+)-trans-(1R,2S)-1-(4-Chloro-3-methoxyphenyl)-N-(2,2-
dimethoxyethyl)-1,2,3,4-tetrahydro-N-methyl-2- naphthalen-
amine 13
½
a 2D3
ꢁ
¼ þ172:5 (c 1.00, EtOH).
The Na salt of amine 12 (0.1 g, 0.33 mmol) was generated by
treatment with NaH (0.019 g, 0.79 mmol) in 6 mL of THF at 0 °C
4.1.14. trans-(ꢀ)-(6aS,13bR)-11-chloro-6,6a,7,8,9,13b-hexa-
hydro-7-methyl-5H-benzo[d]naphth-[2,l-b]azepin-l2-ol SCH
39166
over
a period of 1 h. Then 3-bromo-1,1-dimethoxypropane
(0.180 g, 0.99 mmol) was added to the reaction mixture at 0 °C
and slowly warmed to rt. The mixture was left for 48 h at reflux,
A mixture of 7 (0.10 g, 0.305 mmol) in 3 mL of 48% HBr and
3 mL of AcOH was heated at 130 °C for 7 h. The volatile materials

156
S. Hajra, S. Bar / Tetrahedron: Asymmetry 23 (2012) 151–156
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Leitz, F. M.; Houser, V. P.; Korduba, C. A. J. Pharmacol. Exp. Ther. 1983, 226, 462–
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3. (a) Berger, J. G.; Chang, W. K.; Clader, J. W.; Hou, D.; Chipkin, R. E.; McPhail, A. T.
J. Med. Chem. 1989, 32, 1913–1921; (b) Sedvall, G.; Farde, L.; Stone-Elander, S.;
Halldin, C. In Neurobiology of Central D-1 Dopamine receptors; Breese, G. R.,
were removed from the reaction mixture until the mixture was
concentrated to about 1 mL. The residue was chilled, and the pre-
cipitated solids were filtered and washed with a small amount of
ice-water. The wet solids were dissolved in 1 mL of DMF by heating
on a water bath. The hot solution was poured slowly into 5 mL of
5% NaHCO3, with stirring. The precipitated solids were filtered
and washed with water and cold ether. After drying under reduced
pressure, the desired product was obtained in an 89% yield
(0.085 g).White solid, mp: 217–219 °C. 1H NMR (CDCl3,
200 MHz): d 7.15–6.98 (m, 5H), 5.98 (s, 1H), 4.73 (d, J = 7.2 Hz,
1H), 3.61–3.48 (m, 1H), 3.22–3.13 (m, 1H), 2.95–2.65 (m, 4H),
2.49 (s, 3H), 2.43–2.33 (m, 1H), 2.04–1.96 (m, 1H), 1.75–1.69 (m,
1H); 13C NMR (CDCl3, 100 MHz): d 149.5, 149.0, 139.5, 137.3,
134.8, 131.0, 128.7, 128.0, 126.3, 126.1, 116.1, 114.5, 66.5, 58.2,
Creese, I., Eds.; Plenum Press: New York, 1991;
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Psychopharmacology (Berlin Ger.) 1995, 121, 309–316; (b) Coffin, V. L.; McHuch,
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Pharmacol. Exp. Ther. 1988, 247, 1093–1102.
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10. (a) Berger, J. G.; Chang, W. K.; Gold, E. H.; Clader, J. W. European Patent
Application 230270, 1987.; (b) Wu, G.; Wong, Y.; Steinman, M.; Tormos, W.;
Schumacher, D. P.; Love, G. M.; Shutts, B. Org. Process Res. Dev. 1997, 1, 359–
364; (c) Draper, R. W.; Hou, D.; Iyer, R.; Lee, G. M.; Liang, J. T.; Mas, J. L.; Tormos,
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1998, 2, 175–185; (d) Draper, R. W.; Hou, D.; Iyer, R.; Lee, G. M.; Liang, J. T.;
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44.6, 37.2, 31.9, 29.7 (2C).;ESI-MS m/z: 314 [M+H]+; {½a D23
¼
ꢁ
ꢀ200:9 (c 0.52, DMF)}.
4.1.15. trans-(+)-(6aR,13bS)-11-chloro-6,6a,7,8,9,13b-hexa-
hydro-7-methyl-5H-benzo[d]naphth-[2,l-b]azepin-l2-ol (+)-
SCH 39166
{½a 2D3
¼ þ202:8 (c 0.29, DMF)}.
ꢁ
Acknowledgements
We thank DST, New Delhi for providing financial support. S.B.
thanks CSIR, New Delhi, for his fellowship. We are also grateful
to the referees for their valuable suggestions.
11. Perner, R. J.; Lee, C.-H.; Jiang, M.; Gu, Y.-G.; DiDomenico, S.; Bayburt, E. K.;
Alexander, K. M.; Kohlhaas, K. L.; Jarvis, M. F.; Kowaluk, E. L.; Bhagwat, S. S.
Bioorg. Med. Chem. Lett. 2005, 15, 2803–2807.
12. (a) Hajra, S.; Maji, B.; Sinha, D.; Bar, S. Tetrahedron Lett. 2008, 49, 4057–4059;
(b) Hajra, S.; Maji, B.; Mal, D. Adv. Synth. Catal. 2009, 351, 859–864.
Corrigendum: Hajra, S.; Maji, B.; Mal, D. Adv. Synth. Catal. 2010, 352, 3112;
(c) Hajra, S.; Sinha, D. J. Org. Chem. 2011, 76, 7334–7340.
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