First example of C-3 alkylation of indoles with activated azetidines catalyzed by indium(III) bromide

Article abstract of DOI:10.1055/s-0028-1087957

Indoles undergo smooth alkylation with N-tosylazetidines in the presence of indium(III) bromide in dichloroethane under mild conditions to produce the corresponding C-3 substituted indole derivatives in good to high yields and with high selectivity. This

Full text of DOI:10.1055/s-0028-1087957

LETTER
727
First Example of C-3 Alkylation of Indoles with Activated Azetidines
Catalyzed by Indium(III) Bromide
C
-3 Alkyl
.
ation of Indo
S
les with
A
ctiv
.
ated
A
zetidin
Y
e
s
adav,* B. V. Subba Reddy, G. Narasimhulu, G. Satheesh
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 22 September 2009
3-yl)propyl-4-methylbenzenesulfonamide (3a) in 80%
Abstract: Indoles undergo smooth alkylation with N-tosylaze-
tidines in the presence of indium(III) bromide in dichloroethane un-
der mild conditions to produce the corresponding C-3 substituted
indole derivatives in good to high yields and with high selectivity.
This is the first report on the alkylation of indoles with activated
azetidines.
yield (Scheme 1).
NHTs
InBr3 (10 mol%)
DCE, reflux
N-Ts
+
N
N
H
H
Key words: indoles, indium(III) bromide, activated azetidine, C-3
3a
1
2
alkylation
Scheme 1
Similarly, N-tosylazetidine reacted smoothly with various
other indoles such as 5-bromo-, 2-methyl-, 7-ethyl-, 5-me-
thyl-, and 2-ethoxycarbonyl derivatives to produce the
corresponding C-3 alkyl indoles (entries 2–6, Table 1).
The indole nucleus is one of the most relevant structures
in medicinal chemistry.1 Substituted indoles are widely
found in nature and are considered as ‘privileged scaf-
folds’ since they are capable of binding to many receptors
with high affinity.2 Therefore, the synthesis and selective
functionalization of indoles have been the focus of active
research over the years.3,4 In particular, 3-substituted in-
doles are important building blocks for the synthesis of
various biologically active molecules. Consequently,
there is a continuing interest in the development of im-
proved methods for the synthesis of 3-substituted in-
doles.5,6 Particular focus is devoted to developing new
methods to couple indoles and pyrroles with various elec-
trophiles such as electron-deficient systems, aziridines,
enol ethers, cyclic acetals, and allylic acetates.5–7 Howev-
er, there have been no previous reports on the C-3 alkyla-
tion of indoles with azetidines.
In addition, N-ethylindole also participated in this reaction
(entry 7, Table 1). This result provided incentive for fur-
ther studies with other substituted azetidines. Interesting-
ly, 2-phenyl-N-tosylazetidine also participated well in this
reaction. For example, treatment of indole (1) with 2-phe-
nyl-N-tosylazetidine (4) in the presence of 10 mol% InBr3
at room temperature gave N-(3-1H-indol-3-yl)-3-phenyl-
propyl)-4-methylbenzenesulfonamide (3h) in 82% yield
(Scheme 2).
Ph
NHTs
InBr3 (10 mol%)
DCE, r.t.
N-Ts
Ph
+
N
H
N
Recently, indium tribromide has received increasing at-
tention as a water-tolerant, green Lewis acid catalyst for
organic synthesis demonstrating highly chemo-, regio-,
and stereoselective results.8 Compared to conventional
Lewis acids, it has advantages of water stability, recycla-
bility, operational simplicity, strong tolerance to oxygen,
and nitrogen-containing substrates and functional groups,
and it can often be used in catalytic amounts.9
H
1
4
3h
Scheme 2
In the case of 2-phenyl-N-tosylazetidine, the correspond-
ing ring-opened product 3h was obtained by preferential
attack of indole at the benzylic position (entries 8–11,
Table 1). Because of the stability of the benzylic carboca-
tion, the ring-opening of azetidine is highly regioselective
(entries 8–11, Table 1). Both electron-rich as well as elec-
tron-deficient indoles reacted effectively with N-tosylaze-
tidines under these reaction conditions. In the absence of
catalyst, the reaction failed to give the desired product.
The products were characterized by NMR and IR spec-
troscopy and mass spectrometry. The advantages of this
procedure include mild conditions as well as convenience
and easy workup. This method is effective even with un-
protected indoles. There was no considerable difference in
Following our interest in catalytic uses of indium tribro-
mide,10,11 we herein report a novel method for the C-3
alkylation of indoles with N-azetidines using a catalytic
amount of InBr3 under mild conditions. We first attempt-
ed the coupling of indole (1) with N-tosylazetidine (2).
The reaction was carried out using 10 mol% anhydrous
InBr3 in dichloroethane, and went to completion in 4.5
hours at reflux temperature giving product N-(3-1H-indol-
SYNLETT 2009, No. 5, pp 0727–0730
x
x.
x
x.
2
0
0
9
Advanced online publication: 26.2.2009
DOI: 10.1055/s-0028-1087957; Art ID: D33408ST
© Georg Thieme Verlag Stuttgart · New York

728
J. S. Yadav et al.
LETTER
Table 1 C-3 Alkylation of Indoles with N-Tosylazetidines
Entry
1
Indole
Azetidine
Producta
Time (h)
4.5
Yield (%)b
NHTs
80
75
80
N-Ts
N
H
N
H
Br
Br
NHTs
2
3
4
6.0
5.0
5.0
N-Ts
N-Ts
N-Ts
N
H
N
H
NHTs
NHTs
N
H
N
H
Me
Me
74
N
H
N
H
Et
Et
Me
Me
NHTs
5
6
4.5
5.5
80
70
N-Ts
N-Ts
N
N
H
H
NHTs
NHTs
N
H
N
H
CO2Et
CO2Et
7
8
4.0
2.0
80
82
N
N
N-Ts
Et
Et
Ph
Ph
NHTs
NHTs
N
H
N-Ts
N
H
Ph
Ph
9
1.5
3.0
2.5
2.0
84
73
74
78
N
H
Me
N-Ts
N
H
Me
Ph
O2N
NC
Br
Ph
O2N
NC
Br
9
NHTs
NHTs
N
H
N-Ts
N
H
Ph
Ph
10
11
N
N-Ts
H
N
H
Ph
Ph
NHTs
N
N-Ts
H
N
H
a Products were characterized by MS, 1H NMR, and IR spectroscopy.
b Yield refers to pure products after chromatography.
yields when comparing protected and unprotected in- sults. No bromination of indole was observed under the
doles. No bisindoles were formed under these conditions. reaction conditions. The effects of various Lewis acids
As solvent, dichloroethane appeared to give the best re- such as InCl3, InBr3, ZrCl4, BiCl3, YbCl3, YCl3, SmCl3,
Synlett 2009, No. 5, 727–730 © Thieme Stuttgart · New York

LETTER
C-3 Alkylation of Indoles with Activated Azetidines
729
A.; Bianchi, G.; Chiarini, M.; Anniballe, G.; Marinelli, F.
Synlett 2004, 6, 944. (e) Yadav, J. S.; Reddy, B. V. S.;
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and CeCl3·7H2O were tested for this conversion. Of these
catalysts, anhydrous InBr3 was found to be the most effec-
tive in terms of conversion. Various metal triflates such as
Bi(OTf)3, In(OTf)3, Sm(OTf)3, Yb(OTf)3, Sc(OTf)3 were
found to be ineffective for this transformation. Various in-
dium(III) reagents such as InBr3, InCl3, In(OTf)3, and
In(ClO4)3 were also screened for this conversion. Of these
catalysts, indium tribromide was found to be most effec-
tive in terms of conversion and selectivity. For example,
treatment of indole (1) with N-tosylazetidine (2) in the
presence of 10 mol% of InBr3 and 10 mol% of InCl3 for
4.5 hours in refluxing dichloroethane afforded 3a in 80%
and 71% yields, respectively. The scope and generality of
this process is illustrated in Table 1.12
(7) (a) Nenajdenko, V. G.; Karpov, A. S.; Balenkova, E. S.
Tetrahedron: Asymmetry 2001, 12, 2517. (b) Yadav, J. S.;
Reddy, B. V. S.; Satheesh, G.; Prabhakar, A.; Kunwar, A. C.
Tetrahedron Lett. 2003, 44, 2221. (c) Yadav, J. S.; Reddy,
B. V. S.; Abraham, S.; Sabitha, G. Tetrahedron Lett. 2002,
43, 1565. (d) Yadav, J. S.; Reddy, B. V. S.; Satheesh, G.
Tetrahedron Lett. 2004, 45, 3673.
(8) (a) Zang, Z. H. Synlett 2005, 711. (b) Sakai, N.; Hirasawa,
M.; Konakahara, T. Tetrahedron Lett. 2005, 46, 6407.
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3375. (c) Harada, S.; Takita, R.; Ohshima, T.; Matsunaga,
S.; Shibasaki, M. Chem. Commun. 2007, 948.
(10) (a) Yadav, J. S.; Reddy, B. V. S.; Rao, K. V.; Raj, K. S.;
Prasad, A. R.; Kumar, S. K.; Kunwar, A. C.; Jayaprakash,
P. J.; Jagannath, B. Angew. Chem. Int. Ed. 2003, 42, 5198.
(b) Yadav, J. S.; Reddy, B. V. S.; Kumar, G. M. Synlett 2001,
1781. (c) Yadav, J. S.; Reddy, B. V. S.; Baishya, G. Synlett
2003, 396. (d) Yadav, J. S.; Reddy, B. V. S.; Swamy, T.
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Tetrahedron Lett. 2003, 44, 6055. (b) Yadav, J. S.; Reddy,
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2003, 2390.
In summary, anhydrous InBr3 has proved to be a useful
and highly efficient catalyst for the C-3 alkylation of in-
doles via ring opening of activated azetidines under mild
conditions. In addition to its simplicity and efficiency, this
method produces 3-alkylindoles in good yields. This
method provides an access to a wide range of potentially
valuable homotriptamine derivatives which will find ex-
tensive applications in organic synthesis.
Acknowledgment
G.N. and G.S. thank CSIR, New Delhi for the award of fellowships.
(12) General Procedure
To a stirred solution of indole (1 mmol) in DCE (3 mL) were
added the N-tosylazetidine (1 mmol) and InBr3 (0.1 mmol).
The resulting mixture was stirred at reflux temperature for
the appropriate time (Table 1).
After complete conversion as indicated by TLC, the solvent
was removed by evaporation, and the residue was diluted
with H2O and extracted with EtOAc (2 × 10 mL). The
combined organic layers were dried over anhyd Na2SO4 and
concentrated in vacuo. The resulting product was purified by
column chromatography on SiO2 (Merck, 100–200 mesh)
using EtOAc–hexane (3:7) as eluent to afford pure 3-alkenyl
indole derivative.
References and Notes
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Tetrahedron Lett. 2007, 48, 4169.
Spectroscopic Data for Selected Products
N-1-[3-(1H-3-indolyl)propyl]-4-methyl-1-benzenesulfon-
amide (3a)
Semisolid. IR (KBr): nmax = 3405, 3054, 2923, 2853, 1598,
1455, 1322, 1156, 1091, 813, 771, 745 cm–1. 1H NMR (200
MHz, CDCl3): d = 1.71–1.85 (m, 2 H), 2.38 (s, 3 H), 2.72 (t,
J = 6.6 Hz, 2 H), 2.94 (q, J = 6.6 Hz, 2 H), 4.74 (br s, 1 H,
NH), 6.85–7.30 (m, 6 H), 7.40 (d, J = 8.0 Hz, 1 H), 7.65 (d,
J = 8.0 Hz, 2 H), 7.88 (br s, 1 H, ArNH). LC-MS: m/z = 351
[M + Na], 169, 139. HRMS: m/z calcd for C18H20N2O2NaS:
351.1143; found: 351.1131.
N-1-[3-(2-Methyl-1H-3-indolyl)propyl]-4-methyl-1-
benzenesulfonamide (3c)
Solid; mp 107–109 °C. IR (KBr): nmax = 3397, 3290, 3054,
2923, 2856, 1596, 1462, 1322, 1156, 1091, 814, 745 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.65–1.72 (m, 2 H), 2.25
(s, 3 H), 2.40 (s, 3 H), 2.65 (t, J = 6.6 Hz, 2 H), 2.87 (q,
J = 6.6 Hz, 2 H), 4.65 (t, J = 6.6 Hz, 1 H), 6.89–7.07 (m, 2
H), 7.10–7.30 (m, 4 H), 7.60 (d, J = 8.0 Hz, 2 H), 7.73 (br s,
1 H, ArNH): LC-MS: m/z = 381 [M + K], 365 [M + Na], 242,
197, 169, 139. HRMS: m/z calcd for C19H22N2O2KS:
381.1039; found: 381.1043.
(6) (a) Campos, K. R.; Woo, J. C. S.; Lee, S.; Tillyer, R. D. Org.
Lett. 2004, 6, 79. (b) Hong, K. B.; Lee, C. W.; Yum, E. K.
Tetrahedron Lett. 2004, 45, 693. (c) Kohling, P.; Schmidt,
A. M.; Eilbracht, P. Org. Lett. 2003, 5, 3213. (d) Arcadi,
Synlett 2009, No. 5, 727–730 © Thieme Stuttgart · New York

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J. S. Yadav et al.
LETTER
N-1-[3-(2-Methyl-1H-3-indolyl)-3-phenylpropyl]-4-
methyl-1-benzenesulfonamide (3i)
Solid: mp 76–78 °C. IR (KBr): nmax = 3380, 3026, 2924,
2855, 1601, 1457, 1323, 1156, 1092, 813, 753 cm–1. 1H
NMR (200 MHz, CDCl3): d = 2.30 (s, 3 H), 2.30–2.35 (m, 2
H), 2.38 (s, 3 H), 2.84 (t, J = 5.2 Hz, 2 H), 4.23 (dd, J = 6.4,
9.4 Hz, 1 H), 4.57 (t, J = 6.0 Hz, 1 H), 6.85–7.24 (m, 10 H),
7.28 (d, J = 7.5 Hz, 1 H), 7.54 (d, J = 8.3 Hz, 2 H), 7.84 (br
s, 1 H, ArNH). LC-MS: m/z = 441 [M + Na], 139, 111.
HRMS: m/z calcd for C25H26N2O2NaS: 441.1612; found:
441.1619.
Synlett 2009, No. 5, 727–730 © Thieme Stuttgart · New York