Angewandte
Chemie
Synthetic Methods
Hot Paper
Aqueous Titanium Trichloride Promoted Reductive Cyclization of
o-Nitrostyrenes to Indoles: Development and Application to the
Synthesis of Rizatriptan and Aspidospermidine
Shuo Tong, Zhengren Xu, Mathias Mamboury, Qian Wang, and Jieping Zhu*
Abstract: Treatment of o-nitrostyrenes with aqueous TiCl3
solution at room temperature afforded indoles through
a formal reductive C(sp2)–H amination process. A range of
functions such as halides (Cl, Br), carbonyl (ester, carbamate),
cyano, hydroxy, and amino groups were tolerated. From b,b-
disubstituted o-nitrostyrenes, 2,3-disubstituted indoles were
formed by a domino reduction/cyclization/migration process.
Mild conditions, simple experimental procedure, ready acces-
sibility of the starting materials and good to excellent yields
characterize the present transformation. The methodology was
used as a key step in a concise synthesis of rizatriptan and
a formal total synthesis of aspidospermidine.
procedures for this reductive cyclization have been developed
using high-pressure carbon monoxide as a stoichiometric
reductant in the presence of a transition-metal catalyst.[12]
Recently, Driver and co-workers reported an efficient syn-
thesis of 3H-indoles by reductive cyclization of nitrostyrenes
in the presence of Mo(CO)6 and a catalytic amount of
Pd(OAc)2.[13] While o-nitrostyrenes have been recognized to
be ideal precursors for indoles, the potential of this trans-
formation has not been fully exploited because of the
moderate synthetic efficiency and harsh conditions often
associated with the established protocols. In connection with
our ongoing research program, we serendipitously discovered
that aqueous titanous chloride was able to promote the
reductive cyclization of o-nitrostyrenes to indoles in good to
excellent yields.[14] Literature search after our own observa-
tion revealed a single isolated example from the group of
Banwell.[15] We report herein the development and applica-
tions of this novel reductive C(sp2)–H amination process for
the synthesis of indoles. The characteristic features of our
reaction included mild conditions, good to excellent yields,
a wide application scope, and tolerance of functional groups
including the reducible ones.
T
he indole ring system, one of the most important hetero-
cycles, appears as a motif in a large number of bioactive
natural products, pharmaceuticals, and agrochemicals.[1] The
synthesis and functionalization of indoles have attracted
chemists for over a century and remain an active research
area.[2,3] Nitroarenes, due to their widespread availability and
their ease of synthesis,[4] are attractive starting materials for
the preparation of indoles as witnessed by the existence of
a number of named transformations such as Reissert indole
synthesis,[5] Leimgruber–Batcho reaction,[6] Bartoli indole
synthesis,[7] and Cadogan–Sundberg reaction (Scheme 1).[8]
The classic Cadogan–Sundberg conditions involved heat-
ing to reflux a solution of o-nitrostyrenes in neat triethyl
phosphite (b.p. 1568C).[9,10] The yields of the corresponding
indoles are typically moderate because of the concurrent
formation of N-hydroxy-, and N-ethoxyindoles.[11] Alternative
Conditions were surveyed using 1-(2’-nitrophenyl)-cyclo-
hexene (1a) as a test substrate (Table 1). Six equivalents of
titanous chloride were initially employed since this is the
theoretical amount of TiCl3 needed to reduce nitroarenes to
anilines. Performing the reaction in acetone in an ammonium
acetate-buffered solution afforded the tetrahydrocarbazole
2a in 58% yield. Further increasing the amount of TiCl3
Table 1: TiCl3-promoted reductive cyclization of o-nitrostyrenes: optimi-
zation of reaction conditions.[a]
NH4OAc [equiv][b]
2a [%][c]
Scheme 1. Reductive cyclization of o-nitrostyrenes.
Entry
TiCl3 [equiv]
Solvent
1
2
3
4
5
6
6.0
8.0
10.0
4.0
8.0
8.0
8.0
acetone
acetone
acetone
acetone
acetone
acetone
MeCN
33
33
33
33
25
0
58
63
65
32
67
90
90
73
[*] Dr. S. Tong,[+] Dr. Z. Xu,[+] M. Mamboury, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique FØdØrale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
7[d]
8
0
0
8.0
MeOH
[+] These authors contributed equally to this work.
[a] Reaction conditions: 1a (0.2 mmol), TiCl3 (20% solution in 2.0n
HCl), solvent (c=0.2m), RT, 8 h. [b] NH4OAc (2.5n) was used as
a buffer solution. [c] Isolated yield. [d] c=0.4m.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2015, 54, 11809 –11812
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11809