Asymmetric synthesis of the dopamine D1 agonist, dihydrexidine

Article abstract of DOI:10.1016/j.tetasy.2011.04.008

A concise asymmetric synthesis of first, high affinity domaine D1 full agonist, dihydrexidine has been accomplished via catalytic enantioselective aziridination and subsequent one-pot Friedel-Crafts cyclization of an in situ generated tethered aziridine w

Full text of DOI:10.1016/j.tetasy.2011.04.008

Tetrahedron: Asymmetry 22 (2011) 775–779
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of the dopamine D1 agonist, dihydrexidine
⇑
Saumen Hajra , Sukanta Bar
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721 302, 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 first, high affinity domaine D1 full agonist, dihydrexidine has been
accomplished via catalytic enantioselective aziridination and subsequent one-pot Friedel–Crafts cycliza-
tion of an in situ generated tethered aziridine with high diastereo- and enantioselectivities.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 21 March 2011
Accepted 8 April 2011
Available online 10 May 2011
1. Introduction
HO
HO
MeO
MeO
Hexahydrobenzophenanthridine is an important structural sub-
unit of various natural products and pharmaceuticals.1,2 For exam-
ple dihydrexidine 1 has been designed and developed as the first
high affinity full efficacy agonist for dopamine D1 receptor.2a,3 This
is in clinical trial for the potential treatment of Parkinson’s disease
and the cognitive deficits of schizophrenia.4 More importantly, this
compound has been found to exhibit a high level of enantiospecific-
ity in their interaction with the D1 receptor. Hence, the develop-
ment of an efficient and concise method for the asymmetric
synthesis of dihydrexidine 1 is highly in demand. There are several
methods for the racemic2a,5 synthesis of dihydrexidine, however,
there are only three asymmetric syntheses of 1, which are known
in the literature.6,7 A general chiral-pool approach for the asymmet-
ric synthesis of hexahydrobenzophenanthridines was developed by
Ehrlich et al. based on the Friedel–Crafts acylation of veratrole from
NH
NHR
2
1
dihydrexidine
MeO
MeO
MeO
MeO
NR
4
3
Scheme 1. Retrosynthesis of dihydrexidine.
(E:Z = 78:22) in good yield. Aldehyde 5 was synthesized from the
corresponding dihydrocinnamyl alcohol using a literature proce-
dure9 (Scheme 2).
costly N-(trifluoroacetyl)-D
-aspartic acid anhydride.6 Tomioka et al.
developed an elegant and impressive general method for the asym-
metric synthesis of dihydrexidine via the enantioselective 1,4-
conjugate addition of an aryllithium to nitroalkenes at ꢀ90 °C using
more than a stoichiometric amount of a chiral ligand, followed by
reduction of the nitro group and cylization.7 It was found that
trans-2-amino-1-aryltetralins 2 is the advanced intermediate for
the synthesis of dihydrexidine. A convenient strategy for this syn-
thesis is an intramolecular Friedel–Crafts type cyclization of the
tethered chiral aziridine 3 (Scheme 1).8 Herein, we report a asym-
metric synthesis of (+)-dihydrexidine 1 via catalytic enantioselec-
tive aziridination and subsequent one-pot Friedel–Crafts type
cyclization with high diastereo- and enantioselectivity.
It was found that copper(II) triflate was an efficient dual cata-
lyst for the aziridination10 of alkenes as well as for the Friedel–
Crafts cyclization of tethered and in situ generated aziridine,
while [N-(p-nitrobenzenesulfonyl)imino]-phenyliodinane, PhIN-
SO2(4-NO2C6H4) [PhINNs] was a successful nitrenoid source for
this purpose.8a Therefore, catalytic enantioselective aziridination
and Friedel–Crafts cyclization of styrene 4 was investigated in
the presence of different bis-oxazoline (Box) ligands mostly
derived from L-amino acids (Table 1). The reaction of 4 (5.0 equiv)
with PhINNs (1.0 equiv) was carried out in the presence of
bis(oxazoline)-copper complexes derived from 0.1 equiv of
Cu(OTf)2 and 0.12 equiv of Box ligand 6a in dichloromethane
(DCM) at rt. Within 1.5 h cyclization was observed to proceed
2. Results and discussion
´
rapidly to exclusively afford trans-2-amino-1-phenyltetralin 2
To commence the synthesis, styrene 4 was prepared from a
Wittig reaction of aldehyde 5 as a mixture of diastereomers
(dr >99:1) with 42% ee in 46% yield (Table 1, entry 1). Under
the similar reaction conditions, other Box-Cu(OTf)2 catalysts
6b–h were investigated. With the sterically demanding tert-butyl
Box ligand 6b, there was no appreciable improvement in ee (47%),
but provided a slightly lower yield (39%) (entry 2).
⇑
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 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.04.008

776
S. Hajra, S. Bar / Tetrahedron: Asymmetry 22 (2011) 775–779
MeO
MeO
phenylglycine, was found to be the best and gave the trans-N-no-
syl-2-amino-1-phenyltetralin 20 in 75% yield with 87% ee (entry
5). The absolute stereochemistry of aminotetralin 20 was assigned
by analogy with the literature report.11,8b,8c It is worth noting that
the E:Z mixture of styrene (78:22) on aziridination and subsequent
Friedel–Crafts cyclization provided exclusively trans-2-amino-1-
phenyltetralin 20 (dr >99:1) and the corresponding cis-cyclized
product was not detected. This is due to the dual chemoselectivity
of the aziridination and Friedel–Crafts reactions.8a,8b
PhCH2PPh3Br (1.2 equiv),
MeO
CHO
n-BuLi (1.2 equiv),
THF, −78 °C,
MeO
90%
5
4
E:Z = 78:22
Scheme 2. Synthesis of alkene 4.
To commence the synthesis of active dihydrexidine, the reac-
tion of styrene 4 was carried out under the same conditions in
the presence of Cu(OTf)2 (0.1 equiv) and (R)-Box-ligand 6e0 derived
Table 1
from
D-phenyl glycine and it gave provided the desired trans-N-no-
Screening of catalysts for the asymmetric aziridination and Friedel–Crafts cyclization
syl-2-amino-1-phenyltetralin
2
in 75% yield with 87% ee
MeO
MeO
PhINNs (1.0 equiv)
6 (0.12 equiv)
(Scheme 3). Recrystallization of compound 2 from methanol at
5 °C crystallized out the minor enantiomer and enhanced the ee
of the mother liquor to >99%ee with 70% recovery yield. The spe-
Cu(OTf)2 (0.10 equiv)
MeO
NHNs
MeO
4Å MS, CH2Cl2, 25 °C
1.5 h
4
cific rotation of pure compound 2 was found to be ½a D28
ꢁ
¼ ꢀ52:0
2´
(c 1.0, CHCl3).
Me
N
Me
R
N
R
Me
N
Me
N
Denosylation of compound 2 with 4-methoxythiophenol and
K2CO3 in CH3CN/DMSO (49:1) afforded aminotetralin 7. Pictet–
Spengler cyclization of aminotetralin 7 under conventional condi-
tions was unsuccessful in giving hexahydrobenzophenanthridine
compound 8.7a Therefore, an attempt was made to synthesize
compound 9 from compound 2 using CH2(OMe)2 and BF3–Et2O.
However, it afforded a non-separable mixture (1:1) of the desired
compound 9 and double alkylation product 10 (Scheme 4).
O
O
O
O
O
O
N
O
O
N
N
N
N
R
Ph
Ph
R
Ph
Ph
6e: R = Me
6f:R = H
6a: R = CHMe2
6b: R = CMe3
6c: R = CH2Ph
6h
6d
6g:R = CH2Ph
Entry
Ligand 6
Yielda (%)
dr (trans:cis)b
eec (%)
1
2
3
4
5
6
7
8
(S)-6a
(S)-6b
(S)-6c
(R)-6d
(S)-6e
(S)-6f
(S)-6g
(S)-6h
46
39
50
51
75
19
46
28
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
42
47
56
48d
87
11
42
21
However, when the sodium salt of compound 2, generated by
the reaction of NaH, was reacted with MOMCl at 0 °C and within
1 h, compound 9 was obtained in excellent yield (Scheme 5). The
Pictet–Spengler type cyclization of compound 9 using TMSOTf
(1.1 equiv) at ꢀ50 °C in DCM led to the formation of the desired
N-nosyl hexahydrobenphenanthridine 11 in 55% yield after 4 h.
The deprotection of the N-nosyl group of compound 11 upon
treatment with 4-methoxythiophenol and K2CO3 in a mixed sol-
vent of CH3CN/DMSO (49:1) at rt gave O-methyldihydrexidine 8
in 92% yield after 2.5 h. The specific rotation of compound 8
a
Isolated yield after column chromatography.
Diastereomeric ratio was measured from the 1H NMR analysis of the crude
reaction mixture.
b
c
Enantiomeric excess was determined by chiral HPLC.
The other enantiomer was formed predominantly.
{½a 2D8
ꢁ
¼ ꢀ217:9 (c 1.1, CHCl3)} was comparable to the literature7b
d
data {½a 2D5
¼ ꢀ222 (c 1.1, CHCl3)}. The BBr3 mediated demethyla-
ꢁ
tion of compound 8 in DCM completed the synthesis of dihydrex-
Improved enantioselectivity (ee 56%) was observed with benzyl
substituted Box-ligand 6c (entry 3). Similar selectivity was also
obtained with Box-ligand 6d, derived from indanol amine (entry
4). The Box-ligand 6e, derived from phenylglycine, provided very
good enantioselectivity and yield (87% ee and 75% yield) (entry
5). However, changing to the unsubstituted Box-ligand 6f, caused
both the yield and the ee to drop to 19% and 11%, respectively
(entry 6). The corresponding gem-dibenzyl ligand 6g showed little
improvement in yield to ee (entry 7). Ligands containing an addi-
tional binding site, such as Py-Box 6h derived from phenylglycine,
also reduced the yield as well as the ee (entry 8). Among all the bis-
oxazoline-Cu catalysts, 6e with a gem-dimethyl derived from
idine as
a
hydrobromide salt, 1ꢂHBr in 95% yield. Finally,
dihydrexidine hydrochloride 1ꢂHCl was obtained by successive
treatment with NaHCO3 and saturated HCl in dry ethanol. The spe-
cific rotation of dihydrexidine hydrochloride 1ꢂHCl {½a D28
¼ þ79:9
ꢁ
(c 0.25, EtOH) was in good agreement with the literature2d data
{½a 2D5
¼ þ83 (c 0.25, EtOH)}.
ꢁ
3. Conclusion
In conclusion, we have accomplished the concise asymmetric
synthesis of (+)-dihydrexdineꢂHCl via
a
one-pot catalytic
MeO
MeO
MeO
MeO
4Å MS, CH2Cl2, 25 °C
PhINNs (1.0 equiv)
Cu(OTf)2 (0.10 equiv),
(R)-6e' (0.12 equiv)
NHNs
O
O
N
N
75%
Ph
Ph
(R)-6e'
2
dr >99:1
87% ee
(E:Z = 78:22)
4
recrystalization
from methanol
at 5 °C
ee: ≥ 99%
70%
Scheme 3. Synthesis of aminotetralin 2.

S. Hajra, S. Bar / Tetrahedron: Asymmetry 22 (2011) 775–779
777
MeO
MeO
MeO
p-MeOC6H4SH
(CH2O)n, acid
(1.2 equiv)
2
X
NH
MeO
NH2
K2CO3 (1.2 equiv)
MeCN:DMSO (49:1), rt
ee: ≥ 99%
8
7
88%
OMe
MeO
MeO
MeO
MeO
2
CH2(OMe)2 (2.0 equiv)
BF3-OEt2, rt, 12h
90%
+
NNs
NNs
OMe
ee: ≥ 99%
OMe
9
10
1:1
Scheme 4. Attempts towards the synthesis of compounds 8 and 9.
MeO
MeO
MeO
MeO
TMSOTf (1.1 equiv)
NaH (1.2 equiv)
MOMCl (2.0 equiv)
MeO
NNs
OMe
NHNs
DCM, −50 °C, 4 h
MeO
NNs
THF, 0 °C
98%
55%
ee: ≥ 99%
9
2
11
MeO
MeO
HO
HO
HO
HO
p-MeOC6H4SH
BBr3
NaHCO3
(1.2 equiv)
( 5.0 equiv)
NH
NH·HBr
NH·HCl
EtOH-HCl
CH2Cl2,
rt, 12 h
K2CO3 (1.2 equiv)
MeCN:DMSO (49:1),
rt, 3 h
72%
95%
92%
1·HBr
1·HCl
8
Scheme 5. Synthesis of dihydrexidine hydrochloride.
enantioselective aziridination and subsequent Friedel–Crafts cycli-
zation with tethered and in situ generated aziridine with high dia-
stereo- and enantioselectivity.
was continued for 20 min. The reaction mixture was re-cooled to
ꢀ78 °C and 3-(3,4-dimethoxyphenyl)-propionaldehyde 5 (5.0 g,
25.0 mmol) in dry THF (25 mL) was slowly added. The reaction
mixture was allowed to reach room temperature. The reaction
was quenched with aqueous NH4Cl solution and extracted with
ether (three times). The combined organic layers were washed
with brine, and dried over anhydrous Na2SO4. Flash column chro-
matography (EtOAc/hexane = 1:9) of the crude mass over silica-
gel yielded alkene 4 (5.9 g, 90%) as a E/Z-mixture (E:Z = 78:22).
1H NMR (CDCl3, 200 MHz): d 7.37–7.15 (m, 5H), 6.86–6.70 (m,
3H), 6.44 (d, J = 11.0 Hz, 0.22H), 6.42 (d, J = 16.0 Hz, 0.78H), 6.30
(m, 0.78H), 5.70 (m, 0.22H), 3.86 (s, 4.68H), 3.85 (s, 0.66H), 3.84
(s, 0.66H), 2.80–2.60 (m, 2.44H), 2.58–2.46 (m, 1.56H). ESI-MS m/
z: 268 (M+).
4. Experimental
4.1. General
All reactions were carried out using oven-dried glassware under
an argon (Ar) atmosphere. Commercial grade reagents were used
without further purification. Solvents were dried and distilled fol-
lowing the usual protocols. Flash chromatography was carried out
using silica gel (230–400 mesh). TLC was performed on aluminum-
backed plates coated with Silica Gel 60 with F254 indicator. The 1
H
NMR spectra were recorded at 200 and 400 MHz and 13C NMR
spectrum were recorded at 50 and 100 MHz using CDCl3 and
CD3OD. 1H NMR chemical shifts are expressed in parts per million
(d) relative to CDCl3 (d = 7.26) and CD3OD (d = 3.31); 13C NMR
chemical shifts are expressed in parts per million (d) relative to
the CDCl3 resonance (d = 77.0) and CD3OD resonance (d = 49.1).
High resolution mass spectra (HRMS) were obtained under positive
electron spray ionization (m/z values are given). HPLC analyses
were done by Chiralpak AD-H column (0.46 cm ꢃ 15 cm). Optical
rotations were measured on a polarimeter.
4.1.2. (1S,2R)-N-(6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydro-
naphthalen-2-yl)-4-nitro-benzenesulfonamide 2
A 10 mL two-necked round bottomed flask was charged with
(R)-bis-oxazoline ligand 6e0 (0.01 g, 0.03 mmol, 0.12 equiv) and
Cu(OTf)2 (0.009 g, 0.025 mmol, 0.1 equiv). Anhydrous DCM (1 mL)
was injected and the resulting mixture was stirred for 30 min. To
this solution, PhINNs (0.1 g, 0.24 mmol, 1.0 equiv), alkene
4
(0.29 g, 1.23 mmol, 5.0 equiv) and 0.2 g of powdered molecular
sieves (4 Å) were added and the reaction mixture was allowed to
stir at 25 °C under an argon atmosphere for 1.5 h. On dissolution
of PhINNs, the reaction was quenched by diluting with ethyl ace-
tate (10 mL) and filtering through a short plug of silica gel. The sil-
ica 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 col-
umn chromatography using EtOAc/hexane (1:4) as an eluent,
4.1.1. 1,2-Dimethoxy-4-(4-phenyl-but-3-enyl)-benzene 4
To a stirred suspension of benzyl triphenylphosphonium bro-
mide (16.7 g, 38.65 mmol) in dry THF (78 mL) under a nitrogen
atmosphere, n-BuLi in hexane (24.2 mL, 1.6 M in hexane) was in-
jected dropwise at ꢀ78 °C via a glass syringe. The temperature
was slowly raised to ꢀ30 °C and at this temperature the stirring

778
S. Hajra, S. Bar / Tetrahedron: Asymmetry 22 (2011) 775–779
which provided aminotetralin 2 (0.084 g, 75%). Mp 63–64 °C. 1H
NMR (CDCl3, 200 MHz): 8.16 (d, J = 8.8 Hz, 2H), 7.74 (d,
allowed to stir for 3 h. Upon completion of the reaction, the solvent
was evaporated under reduced pressure and the crude reaction
mass was subjected to column purification by using 3% MeOH in
DCM as an eluent to give 8 (0.056 g, 92%) as a white solid. Mp
156–157 °C. 1H NMR (CDCl3, 400 MHz): d 7.46 (d, J = 7.2 Hz, 1H),
7.32–7.18 (m, 2H), 7.17 (d, J = 6.8 Hz, 1H), 6.73 (s, 1H), 6.61 (s,
1H), 4.07 (s, 2H), 3.88 (s, 3H), 3.86 (d, J = 9.0 Hz, 1H), 3.77 (s, 3H),
2.96–2.89 (m, 1H), 2.84–2.71 (m, 2H), 2.36 (br s, 1H), 2.25–2.17
(m, 1H), 1.78–1.72 (m, 1H). 13C NMR (CDCl3, 100 MHz): d 147.2,
146.7, 136.7, 136.3, 130.7, 129.9, 128.1, 126.9, 126.2 (2C), 111.9,
d
J = 8.8 Hz, 2H), 7.20–7.06 (m, 3H), 6.90–6.80 (m, 2H), 6.60 (s, 1H),
6.10 (s, 1H), 4.82 (d, J = 7.6 Hz, 1H), 3.85 (s, 3H), 3.78 (d,
J = 7.8 Hz, 1H), 3.64 (m, 1H), 3.56 (s, 3H), 2.98–2.75 (m, 2H),
2.28–2.17 (m, 1H), 1.85–1.70 (m, 1H). 13C NMR (CDCl3,
100 MHz): d 149.6, 148.0, 147.6, 146.0, 142.8, 128.8 (2C), 128.4
(2C), 127.8 (2C), 127.5, 127.3, 127.0, 124.1 (2C), 112.8, 110.8,
57.1, 55.7, 55.7, 51.5, 27.6, 26.1. Before recrystallisation, HPLC
analysis: (chiralcel AD-H, 10% i-PrOH/n-hexane, 1.0 mL/min,
220 nm, tr (major) 23.3 min, tr (minor) 34.0 min); 87% ee. After
one recrystalisation from methanol at 5 °C, HPLC analysis: (chiral-
cel AD-H, 10% i-PrOH/n-hexane, 1.0 mL/min, 220 nm, tr (major)
110.2, 58.6, 56.1, 56.0, 48.4, 44.3, 28.5, 27.4. ½a D28
¼ ꢀ217:9 (c 1.1,
ꢁ
CHCl3) {lit7b
½
a 2D5
ꢁ
¼ ꢀ222 (c 1.1, CHCl3)}. ESI-MS m/z: 296
(M+H)+. HRMS (EI) calcd for C19H21NO2, 296.1651 m/z (M+H)+;
found, 296.1632 m/z.
23.1 min); ee P 99%. ½a D28
¼ ꢀ52:0 (c 1.00, CHCl3). ESI-MS m/z:
ꢁ
469 (MH+). HRMS (EI) calcd for C24H24N2O6S, 491.1253 m/z
(M+Na)+; found, 491.1251 m/z.
4.1.6. (6aR,12bS)-10,11-Dihydroxy-5,6,6a,7,8,12b-
hexahydrobenzo[a]phenanthridine hydrobromide 1ꢂHBr
To a well stirred solution of 8 (0.05 g, 0.169 mmol) taken in
DCM (2 mL) at rt, 5 equiv BBr3 (1 M solution in DCM) were slowly
added and reaction mixture was allowed to stir for 12 h. Upon
completion of the reaction, the mixture was quenched with MeOH
(2 mL) and stirred for 30 min after which the solvent was evapo-
rated to give a crude reaction mixture. Then the crude mass was
scratched and washed with dry ether to get 1ꢂHBr (0.56 g, 95%)
4.1.3. (1S,2R)-N-(6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydro-
naphthalen-2-yl)-N-methoxymethyl-4-nitro-
benzenesulfonamide 9
To a well stirred solution of 2 (0.1 g, 0.214 mmol) taken in THF
(2 mL) at 0 °C, NaH (1.2 equiv) was added and allowed to stir for
30 min under an argon atmosphere. Next, MOMCl (2 equiv) was
slowly added and stirred. After 1.5 h, the reaction was quenched
with saturated NH4Cl solution and extracted with ethyl acetate
and dried over NaSO4. The reaction mixture was subjected to col-
umn purification using 20% EtOAc in hexane as an eluent to obtain
9 (0.108 g, 98%) as a yellow solid. Mp 56–57 °C. 1H NMR (CDCl3,
200 MHz): d 8.03 (d, J = 9.0 Hz, 2H), 7.62 (d, J = 9.0 Hz, 2H), 7.08–
6.90 (m, 3H), 6.88–6.86 (m, 2H), 6.55 (s, 1H), 5.99 (s, 1H), 5.04
(d, J = 11.0 Hz, 1H), 4.69 (d, J = 11.0 Hz, 1H), 4.23 (d, J = 10.2 Hz,
1H), 4.16–4.09 (m, 1H), 3.83 (s, 3H), 3.48 (s, 3H), 3.35 (s, 3H),
3.10–2.95 (m, 1H), 2.88–2.77 (m, 1H), 2.21–2.14 (m, 2H). 13C
NMR (CDCl3, 100 MHz): d 149.7, 147.8, 147.6, 146.5, 143.8, 130.6,
129.4 (2C), 128.5 (2C), 128.4 (2C), 128.0, 126.8, 123.9 (2C), 113.3,
110.9, 76.6, 63.1, 56.03, 55.94, 55.90, 48.9, 30.4, 29.6.
as
a
light yellow solid. Mp 185–186 °C. 1H NMR (CD3OD,
200 MHz): d 7.54–7.38 (m, 4H), 6.81 (s, 1H), 6.67 (s, 1H), 4.45 (s,
2H), 4.22 (d, J = 11.4 Hz, 1H), 3.12–2.72 (m. 3H), 2.42–2.22 (m,
1H), 2.06–1.99 (m, 1H). 13C NMR (CD3OD, 50 MHz): d 145.7,
144.8, 137.7, 131.0, 129.7, 129.5, 129.0, 128.6, 128.1, 126.1,
116.9, 115.6, 59.4, 46.4, 42.4, 28.0, 27.1. ½a D28
¼ þ37:0 (c 0.20,
ꢁ
EtOH). ESI-MS m/z: 268 (MH+). HRMS (EI) calcd for C17H17NO2,
268.1338 m/z (M+H)+; found, 268.1283 m/z.
4.1.7. (6aR,12bS)-10,11-Dihydroxy-5,6,6a,7,8,12b-
hexahydrobenzo[a]phenanthridine hydrochloride 1ꢂHCl2d
At first, 1ꢂHBr (0.05 g, 0.143 mmol) was dissolved in H2O (5 mL)
and the pH was adjusted to 9–10 with NaHCO3 under an Ar atmo-
sphere. The mixture was extracted with CHCl3 and dried over
Na2SO4 to give a pale yellow solid. A solution of this pale yellow so-
lid in EtOH (1 mL) and EtOH–HCl (3 mL) was stirred at rt for 0.5 h
and concentrated. The residue was dried azeotropically with ben-
zene (3 mL) to afford dihydrexidine hydrochloride 1ꢂHCl (0.031 g,
72%) as a pale yellow solid. Mp >120 °C (dec). 1H NMR (CD3OD,
200 MHz): d 7.49–7.34 (m, 4H), 6.76 (s, 1H), 6.62 (s, 1H), 4.40 (s,
2H), 4.16 (d, J = 11.0 Hz, 1H), 3.01–2.75 (m. 3H), 2.35–2.20 (m,
1H), 2.05–1.85 (m, 1H). 13C NMR (CD3OD, 100 MHz): d 145.5,
144.6, 137.5, 130.8, 129.5, 129.3, 128.8, 128.4, 128.0, 125.9,
½
a 2D8
ꢁ
¼ ꢀ36:0 (c 1.00, CHCl3). HRMS (EI) calcd for C26H28N2O7S,
535.1515 m/z (M+Na)+; found, 535.1511 m/z.
4.1.4. (6aR,12bS)-10,11-Dimethoxy-6-(4-nitrobenzenesulfonyl)-
5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine 11
To a well stirred solution of 9 (0.1 g, 0.195 mmol) taken in
4 ml DCM at ꢀ50 °C, 1.1 equiv of TMSOTf was added slowly
and the reaction mixture was allowed to stir for 4 h. Upon com-
pletion, the reaction was quenched with saturated NaHCO3 solu-
tion and extracted with EtOAc and dried over Na2SO4. The
reaction mass was subjected to column purification using 15%
EtOAc in hexane as an eluent to obtain 11 (0.052 g, 55%) as a
yellow solid. Mp 88–89 °C. 1H NMR (CDCl3, 400 MHz): d 8.03
(d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 4.4 Hz,
1H), 7.11 (t, J = 7.6 Hz, 1H), 6.91(t, J = 7.6 Hz, 1H), 6.85 (s, 1H),
6.77 (d, J = 7.2 Hz, 1H), 6.71 (s, 1H), 4.69 (d, J = 16.0 Hz, 1H),
4.53 (d, J = 16.0 Hz, 1H), 4.12 (d, J = 11.6 Hz, 1H), 3.89 (s, 3H),
3.78 (s, 3H), 3.20–3.14 (m, 1H), 3.06–2.99 (m, 1H), 2.90–2.81
116.7, 115.4, 59.2, 46.2, 42.2, 27.8, 26.9. ½a D28
¼ þ79:9 (c 0.25, EtOH)
ꢁ
{lit2d D = +83 (c 0.25, EtOH)}. ESI-MS m/z: 268 (M+H)+. HRMS (EI)
[a]
calcd for C17H17NO2, 268.1338 m/z (M+H)+; found, 268.1283 m/z.
Acknowledgments
We thank DST, New Delhi for providing financial support. S.B.
thanks CSIR, New Delhi, for his fellowship.
(m, 1H), 2.10–2.01 (m, 2H). 13C NMR (CDCl3, 100 MHz):
d
149.7, 148.1, 146.9, 144.0, 138.5, 135.1, 129.7, 128.6 (2C),
127.8, 126.2, 125.8, 124.0, 123.8, 123.7 (2C), 112.6, 112.1, 61.6,
References
56.1, 55.9, 47.7, 43.9, 31.3, 29.4. ½a D28
¼ þ30:2 (c 1.00, CHCl3).
ꢁ
1. (a) Peter, S.; Ruben, I.; Bjorn, K. CNS Drug Rev. 2004, 10, 230–242; (b) Giardina,
W. J.; Williams, M. CNS Drug Rev. 2001, 7, 305–316.
HRMS (EI) calcd for C25H24N2O6S, 503.1253 m/z (M+Na)+; found,
503.1250 m/z.
2. (a) Brewster, W. K.; Nichols, D. E.; Riggs, R. M.; Mottola, D. M.; Lovenberg, T. W.;
Lewis, M. H.; Mailman, R. B. J. Med. Chem. 1990, 33, 1756–1764; (b) Taylor, J. R.;
Lawrence, M. S.; Redmont, D. E.; Elsworth, J. D.; Roth, R. H.; Nochols, D. E.;
Mailman, R. B. Eur. J. Pharmacol. 1991, 199, 389–391; (c) Seiler, M. P.;
Hagenbach, A.; Wüthrich, H.-J.; Marksteun, R. J. Med. Chem. 1991, 34, 303–
307; (d) Knoerzer, T. A.; Nichols, D. E.; Brewster, W. K.; Watts, V. J.; Mottola, D.;
Mailman, R. B. J. Med. Chem. 1994, 37, 2453–2460; (e) Michaelides, M. R.; Hong,
Y., Jr.; DiDomenico, S.; Asin, K. E.; Britton, D. R.; Lin, C. W.; Williams, M.;
Shiosaki, K. J. Med. Chem. 1995, 38, 3445–3447.
4.1.5. (6aR,12bS)-10,11-Dimethoxy-5,6,6a,7,8,12b-
hexahydrobenzo[a]phenanthridine 8
To a well stirred solution of 11 (0.1 g, 0.208 mmol) taken in
2 mL CH3CN/DMSO (49:1) at rt, 1.2 equiv of 4-methoxythiophenol
and 1.2 equiv of K2CO3 were added and the reaction mixture was

S. Hajra, S. Bar / Tetrahedron: Asymmetry 22 (2011) 775–779
779
3. Huang, X.; Lawler, C. P.; Lewis, M. M.; Nichols, D. E.; Mailman, R. B. Int. Rev.
Neurobiol. 2001, 48, 65–139.
8. (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.
doi:10.1002/adsc.201090036; (c) Hajra, S.; Bar, S. Chem. Commun. 2011, 47,
3981–3982.
9. Renaud, J.-L.; Aubert, C.; Malacria, M. Tetrahedron 1999, 55, 5113–5128.
10. (a)Pearson, W. H., Lian, B. W., Bergmeier, S. C., Eds., 2nd ed.Comprehensive
Heterocyclic Chemistry II; Padwa, A., Ed.; Pergamon: Oxford, 1996; Vol. 1A, pp
1–60; (b)Lokanatha Rai, K. M., Hassner, A., Eds., 2nd ed.Comprehensive
Heterocyclic Chemistry II; Padwa, A., Ed.; Pergamon: Oxford, 1996; Vol. 1A,
pp 61–96; For a recent review, see: (c) Hu, X. E. Tetrahedron 2004, 60, 2701–
2743; (d) McCoull, W.; Davis, F. A. Synthesis 2000, 1347–1365; (e) Atkinson, R.
S. Tetrahedron 1999, 55, 1519–1559; (f) Tanner, D. Angew. Chem., Int. Ed. Engl.
1994, 33, 599–619; (g) Krake, H.; Bergmeier, S. C. Tetrahedron 2010, 66, 7337–
7360.
4. (a) George, M. S.; Molnar, C. E.; Grenesko, E. L.; Anderson, B.; Mu, Q.; Johnson,
K.; Nahas, Z.; Knable, M.; Fernandes, P.; Juncos, J.; Huang, X.; Nichols, D. E.;
Mailman, R. B. Schizophr. Res. 2007, 93, 42–50; (b) Goldman-Rakic, P. S.;
Castner, S. A.; Svensson, T. H.; Siever, L. J.; Williams, G. V. Psychopharmacology
(Berl.) 2004, 174, 3–16; (c) Mu, Q.; Johnson, K.; Morgan, P. S.; Grenesko, E. L.;
Molnar, C. E.; Anderson, B.; Nahas, Z.; Kozel, F. A.; Kose, S.; Knable, M.;
Fernandes, P.; Nichols, D. E.; Mailman, R. B.; George, M. S. Schizophr. Res. 2007,
94, 332–341; (d) Nichols, D. E.; Lewis, M. M. Med. Chem. Res. 2004, 13, 105–114.
5. (a) Negash, K.; Nichols, D. E. Tetrahedron Lett. 1996, 37, 6971–6972; (b) Cueva, J.
P.; Nichols, D. E. Synthesis 2009, 715–720.
6. Ehrlich, P. P.; Michaelides, M. R.; McLaughlin, M. M.; Hsaio, C. US 5659037,
1997.
7. (a) Asano, Y.; Yamashita, M.; Nagai, K.; Kuriyama, M.; Yamada, K.-I.; Tomioka,
K. Tetrahedron Lett. 2001, 42, 8493–8495; (b) Yamashita, M.; Yamada, K.-I.;
Tomioka, K. Tetrahedron 2004, 60, 4237–4242.
11. Evans, D. A.; Fad, M. M.; Bilodeau, M. T. J. Am. Chem. Soc. 1994, 116, 2742–
2753.