A one-pot stereoselective synthesis of trans-1-aryl-2-aminotetralins from 2-arylethyl styrenes

Article abstract of DOI:10.1016/j.tetlet.2008.04.056

An efficient stereoselective synthesis of trans-1-aryl-2-aminotetralins has been achieved via Cu(OTf)₂ catalyzed one-pot aziridination and regioselective intramolecular arylation of in situ generated aziridines from 2-arylethyl styrenes and PhINSO₂(4-NO₂C₆H₄) [PhINNs]. Reaction of a mixture of E/Z-styrenes (≤85:15) provided trans-N-protected-1-aryl-2-aminotetralins with high diastereoselectivity (dr > 95:5), which are important synthons for many artificial pharmaceuticals.

Full text of DOI:10.1016/j.tetlet.2008.04.056

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Tetrahedron Letters 49 (2008) 4057–4059
A one-pot stereoselective synthesis of trans-1-aryl-
2-aminotetralins from 2-arylethyl styrenes
Saumen Hajra *, Biswajit Maji, Debarshi Sinha, Sukanta Bar
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Received 25 January 2008; revised 5 April 2008; accepted 10 April 2008
Available online 12 April 2008
Abstract
An efficient stereoselective synthesis of trans-1-aryl-2-aminotetralins has been achieved via Cu(OTf)2 catalyzed one-pot aziridination
and regioselective intramolecular arylation of in situ generated aziridines from 2-arylethyl styrenes and PhINSO2(4-NO2C6H4)
[PhINNs]. Reaction of a mixture of E/Z-styrenes (685:15) provided trans-N-protected-1-aryl-2-aminotetralins with high diastereoselec-
tivity (dr > 95:5), which are important synthons for many artificial pharmaceuticals.
Ó 2008 Elsevier Ltd. All rights reserved.
RO
RO
HO
HO
1-Aryl-2-aminotetralin 1 is the key precursor to many
biologically active compounds, in particular, artificial
pharmaceuticals such as dihydrexidine, A-86929 and
Sch39166.1–3 Concise stereoselective synthesis of trans-tetr-
alin 1 is, therefore, highly desirable in organic and medici-
nal chemistry. A straightforward synthetic approach
towards 1 is the stereoselective intramolecular arylation
of tethered aziridines (Scheme 1). In contrast to the exten-
sive study on aziridine ring opening with a number of
nucleophiles,4 intramolecular electrophilic arylation with
tethered aziridines has not been explored.5 Our efforts6
towards electrophilic arylation with alkenes via reactive
intermediates led us to investigate this chemistry. Herein,
we report our preliminary results on the stereoselective
one-pot synthesis of trans-1-aryl-2-aminotetralins via
Cu(OTf)2 catalyzed intramolecular arylation of in situ gen-
erated aziridines.
NMe
NH
NH
HO
S
Cl
Sch 39166
Dihydrexidine
R = H: A-86929
R = Ac: ABT-431
Z
Z
Z
NHR
NR
Ar
1
Ar
2
Ar
3
Scheme 1.
Cu(OAc)2 catalyzed reactions with PhINTs as a nitrenoid
source produced traces of products after 12 h (entries 2,
4 and 6). In the case of PhINNs, the CuCl catalyzed reac-
tion afforded exclusively aziridine 2a, no cyclized product
1a was obtained even after a prolonged reaction time (entry
3). With CuCl2 and Cu(OAc)2 as catalysts, mixtures of 1a
and 2a were obtained (entries 5 and 7). The Cu(OTf)2 cata-
lyzed reactions both with PhINTs and with PhINNs pro-
vided directly 1a in 40% and 56% yields, respectively
(entries 8 and 9). The catalytic reaction of 3a with PhINNs
to produce 1a was found to be better in CH2Cl2(56%) com-
pared to dichloroethane (51%), benzene (41%) and aceto-
nitrile (45%), and there was no reaction in THF, DMF
Cu(I) and Cu(II) are excellent catalysts for the aziridin-
ation of alkenes with PhINSO2Ar.4 Thus, we began our
studies on the reactions of 2-phenylethyl styrene 3a with
PhINSO2(4-MeC6H4)
[PhINTs]
and
PhINSO2(4-
NO2C6H4) [PhINNs] in the presence of commonly avail-
able Cu-catalysts (Table 1). The CuCl, CuCl2 and
*
Corresponding author. Tel.: +91 3222 283340; fax: +91 3222 255303.
E-mail address: shajra@chem.iitkgp.ernet.in (S. Hajra).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.056

4058
S. Hajra et al. / Tetrahedron Letters 49 (2008) 4057–4059
Table 1
Table 2
Screening of copper catalysts for the intramolecular arylation and in situ
generation of aziridine of 3aa
Cu(OTf)2 catalyzed one-pot synthesis of N-protected 1-aryl-2-
aminotetralinsa
Entry
Substrate (E:Z)b
t (h)
Product
Yieldc (%)
PhINSO2Ar (1.0 equiv)
CuLn (0.1 equiv)
NHSO2Ar
+
NSO2Ar
4Å MS, DCM, 25 °C
NHNs
NHNs
1
8
56
3a
(75:25)
1a
3a
2a
1a
Entry
CuLn
Nitrogen
source
t (h) Yieldb 2a Yieldb 1a
(%)
(%)
1
2
3
4
5
6
7
8
9
a
None
CuCl
CuCl
PhINTs/PhINNs 12
NR
Traces
51
2
3
4
5
6
61
80
68
78
1b
3b
(63:37)
PhINTs
PhINNs
PhINTs
PhINNs
PhINTs
PhINNs
PhINTs
PhINNs
12
12
12
12
12
12
10
8
—
—
Me
Me
CuCl2
CuCl2
Cu(OAc)2
Cu(OAc)2
Cu(OTf)2
Cu(OTf)2
Traces
20
Traces
18
—
—
Traces
30
Traces
12
40
NHNs
3
1c
3c
(75:25)
56
OMe
OMe
˚
A suspended solution of 3a (5 equiv), PhINSO2Ar (1.0 equiv), 4 A MS
(0.2 g/mmol of 3a) and CuLn(0.1 equiv) in CH2Cl2 was stirred at 25 °C.
b
Isolated yield after column chromatography.
MeO
MeO
NHNs
4
3d
1d
1e
(75:25)
and MeOH. Traces of product 1a were observed in chloro-
form. Thus, when a suspended solution of 3a (E/Z 75:25;
5.0 equiv), PhINNs (1.0 equiv) and 4 A MS in CH2Cl2
Me
Me
˚
was treated with Cu(OTf)2 (0.1 equiv) at 25 °C, trans-1-
phenyl-2-aminotetralin 1a was obtained in 8 h with >95:5
diastereoselectivity in 56% yield. 1H NMR spectral analysis
of the crude reaction mixture revealed the formation of
traces (6%) of the cis-aziridine cis-2a, but no cis-cyclized
product cis-1a was observed. It appears that both the cis-
styrene and the cis-aziridine might be less reactive than
the corresponding trans-isomer. To examine this pure cis-
alkene cis-3a reacted with PhINNs under the same reaction
conditions. After 3 h, the formation of cis-aziridine cis-2a
was detected by 1H NMR, but no cyclized product (Scheme
2) and 42% of cis-2a was isolated after 8 h. When the same
reaction was continued with an additional amount of
Cu(OTf)2 (0.5 equiv), a non-separable mixture of unidenti-
fied compounds was formed. It is worth mentioning that
when pure 2a, obtained from the reaction in Table 1, entry
3, was treated with Cu(OTf)2 (0.1 equiv), the cyclized prod-
uct 1a was produced in 2 h in quantitative yield.
MeO
MeO
MeO
NHNs
NHNs
5
3e
(67:33)
Cl
Cl
MeO
6d
2.5
58
1f
3f
(85:15)
OMe
OMe
a
˚
A suspended solution of substrate 3 (5 equiv), PhINNs (1.0 equiv), 4 A
MS (0.2 g/mmol of 3) and Cu(OTf)2(0.1 equiv) in CH2Cl2 was stirred at
25 °C.
b
Synthesis of styrenes 3a–f is described in the Supplementary data.
c
Isolated yield after column chromatography.
Reaction was carried out at 0 °C.
d
minor product when the reaction was stopped after 4 h.
The reactivity of3b was comparable with 3a and afforded
the desired product 3b in 61% yield under the same reaction
conditions (entry 2). Substrates 3c–e having electron-rich
aromatic rings at either end of the alkene chain underwent
fast reactions and gave good yields of 1c–e (entries 3–5).
The more electron-rich substrate 3f gave a clean reaction
at 0 °C affording a moderate yield of 1f (entry 6). Unlike
3a, no intermediate aziridines 2c–f and cis-2c–f were
Next, we investigated the scope of the catalytic method
for the synthesis of N-protected 1-aryl-2-aminotetralins
(Table 2).7,8 Substrate 3a smoothly underwent Cu(OTf)2
catalyzed intramolecular arylation of the tethered in situ
generated aziridine with PhINNs and afforded product 1a
in 56% yield (entry 1). The formation of aziridine interme-
1
diate 2a was detected by H NMR and was isolated as a
Cu(OTf)2 (0.1 equiv)
PhINNs (1.0 equiv)
X
NHNs
DCM, 4Å MS, 25 °C
NsN
cis-2a
cis-3a
cis-1a
Scheme 2.

S. Hajra et al. / Tetrahedron Letters 49 (2008) 4057–4059
4059
Michaelides, M. R.; Hong, Y.; DiDomenico, S., Jr.; Asin, K. E.;
Britton, D. R.; Lin, C. W.; Williams, M.; Shiosaki, K. J. Med. Chem.
1995, 38, 3445–3447.
K2CO3
,
SH
MeO
NH2
NHNs
MeCN:DMSO (49:1), rt
81%
3. (a) Ehrlich, P. P.; Ralston, J. W.; Michaelides, M. R. J. Org. Chem.
1997, 62, 2782–2785; (b) Yamashita, M.; Yamada, K.-I.; Tomioka, K.
J. Am. Chem. Soc. 2004, 126, 1954–1955; (c) Yamashita, M.; Yamada,
K.-I.; Tomioka, K. . Tetrahedron 2004, 60, 4237–4242.
4. (a) Pearson, W. H.; Lian, B. W.; Bergmeier, S. C. In Comprehensive
Heterocyclic Chemistry II, 2nd ed.; Padwa, A., Ed.; Pergamon:
Oxford, 1996; Vol. 1A, pp 1–60; (b) Lokanatha Rai, K. M.; Hassner,
A. In Comprehensive Heterocyclic Chemistry II, 2nd ed.; Padwa, A.,
Ed.; Pergamon: Oxford, 1996; Vol. 1A, pp 61–96. For a recent review
on ring opening of aziridines, see: (c) Hu, X. E. Tetrahedron 2004, 60,
2701–2743.
5. Intra- and intermolecular aziridne ring opening with p-nucleophiles:
(a) Bergmeier, S. C.; Katz, S.; Huang, J.; McPherson, H.; Donoghue,
P. J.; Reed, Damon D. D. Tetrahedron Lett. 2004, 45, 5011–5014; (b)
Bera, M.; Roy, S. Tetrahedron Lett. 2007, 48, 7144–7146; (c) Yadav, J.
S.; Reddy, B. V. S.; Rao, R. S.; Veerendhar, G.; Nagaiah, K.
Tetrahedron Lett. 2001, 42, 8067–8070.
6. (a) Hajra, S.; Maji, B.; Bar, S. Org. Lett. 2007, 9, 2783–2786; (b)
Hajra, S.; Maji, B.; Karmakar, A. Tetrahedron Lett. 2005, 46, 8599–
8603.
1c
4c
OMe
OMe
Scheme 3.
detected for the reaction of substrates 3c–f. It should be
noted that the reaction was judged to be complete as soon
as all the nitrenoid reagents had dissolved in the reaction
medium. Allowing the reactions to proceed further resulted
in the formation of more by-products. In all the cases,
PhINNs was used as a limiting reagent (1.0 equiv) with
an excess of styrene 3 (5 equiv) to ensure complete con-
sumption of aziridine reagent. If substrate 3 was used as
the limiting reagent, that is, 1.0 equiv of 3 and 1.2 equiv
of PhINNs, the yield was reduced to almost half and also
the generation of undesired by-products increased.
Deprotection of the amide9 of 1 followed by Pictet–
Spengler cyclization would provide the important hexa-
hydrobenzo[a]phenanthridine. As an example, compound
1c was treated with 4-methoxythiophenol and K2CO3 in
CH3CN/DMSO (49:1) at rt, to produce trans-1-(4-
methoxyphenyl)-2-aminotetralin 4c10 in 81% yield in 3 h
(Scheme 3).
In summary, we have developed an efficient one-pot
protocol for the stereoselective synthesis of trans-1-aryl-2-
aminotetralins from 2-arylethyl styrenes via Cu(II) cata-
lyzed aziridination and subsequent regio- and stereoselec-
tive intramolecular arylation of the in situ generated
aziridine. The combination of Cu(OTf)2 as a catalyst and
PhINNs as a nitrene source was found to be superior for
the reaction.
7. General procedure : To a well-stirred suspended solution of PhINNs
(0.1 g, 0.25 mmol), 2-phenylethyl styrene 3a (0.26 g, 1.23 mmol) and
˚
4 A MS (0.25 g) in dry DCM (4 ml), Cu(OTf)2 (0.009 g, 0.025 mmol)
was added and the heterogeneous reaction mixture was stirred at
room temperature for 8 h under an argon atmosphere. On comple-
tion, the reaction was quenched with water and extracted with Et2O
(3 Â 10 ml). The combined organic layer was washed with brine and
dried over Na2SO4. After removal of the solvents under reduced
pressure, the crude mass was subjected to purification by flash column
chromatography using pet-ether (60–80)/EtOAc to obtain pure
4-nitro-N-(1-phenyl-1,2,3,4-tetrahydronaphthalen-2-yl)-benzenesulfo-
namide 1a (0.056 g, 56% yield) as a white solid.
8. All the compounds listed in Table 2 were characterized by 1H and 13
C
NMR spectroscopy. The following are the representative spectral
data of 1a and 1c.4-Nitro-N-(1-phenyl-1,2,3,4-tetrahydronaphthalen-
2-yl)-benzenesulfonamide (1a): White solid. Mp 171–173 °C. 1H
NMR (CDCl3, 400 MHz): d 8.12 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.8
Hz, 2H), 7.20–7.04 (m, 5H), 7.00 (m, 1H), 6.83 (d, J = 7.0 Hz, 2H),
6.61 (d, J = 7.6 Hz, 1H), 4.76 (d, J = 7.2 Hz, 1H), 3.85 (d, J = 8.4 Hz,
1H), 3.68–3.57 (m, 1H), 3.15–2.98 (m, 1H), 2.90 (m, 1H), 2.45–2.30
(m, 1H), 1.91–1.78 (m, 1H). 13C NMR (CDCl3, 100 MHz): d 149.5,
145.7, 142.7, 136.2, 135.4, 130.4, 129.0 (2C), 128.6 (2C), 127.8 (2C),
127.0, 126.7 (2C), 126.3, 124.1 (2C), 57.3, 52.0, 28.9, 27.1. HRMS (EI)
calcd for C23H20N2O4S, 431.1041 m/z (M+Na)+; found, 431.1042
m/z.N-[1-(4-Methoxy-phenyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-4-
nitro-benzenesulfonamide (1c): White solid. Mp 120–122 °C. 1H
NMR (CDCl3, 400 MHz): d 8.13 (d, J = 8.8 Hz, 2H), 7.67 (d,
J = 8.8 Hz, 2H), 7.13 (m, 2H), 7.00 (m, 1H), 6.73 (d, J = 8.4 Hz,
2H), 6.62 (d,J = 7.6 Hz, 1H), 6.58 (d, J = 8.4 Hz, 2H), 4.75 (d,
J = 7.2 Hz, 1H), 3.77 (d, J = 8.4 Hz, 1H), 3.73 (s, 3H), 3.65–3.48 (m,
1H), 3.12–2.95 (m, 1H), 2.92 (m, 1H), 2.46–2.35 (m, 1H), 1.90–1.78
(m, 1H). 13C NMR (CDCl3, 100 MHz): d 158.6, 149.5, 145.8, 136.7,
135.3, 134.5, 130.3, 129.8 (2C), 128.5, 127.9 (2C), 126.2, 125.9, 123.9
(2C), 113.8 (2C), 57.7, 55.0, 51.3, 29.4, 22.6. HRMS (EI) calcd for
Acknowledgements
We thank DST, New Delhi, for providing financial sup-
port. B.M. thanks UGC, New Delhi; D.S. and S.B. thank
CSIR, New Delhi, for their fellowships, respectively.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.04.056.
References and notes
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23H22N2O5S, 461.1147 m/z (M+Na)+; found, 461.1147m/z.
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