AcOH-mediated dichloroimination of indoles using chloramine-B: A facile access to 2,3-functionalized indolines

Article abstract of DOI:10.1039/c4ob01179a

A new and mild method for the efficient synthesis of 3,3-dichloro-2-sulfonyliminoindolines via AcOH-mediated dichloroimination of indoles using chloramine-B is presented. Application of this method to the efficient construction of pyrrolidinoindoles and N-C3 linked pyrrolidinoindolines is demonstrated.

Full text of DOI:10.1039/c4ob01179a

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Biomolecular Chemistry
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AcOH-mediated dichloroimination of indoles
using chloramine-B: a facile access to
2,3-functionalized indolines†
Cite this: Org. Biomol. Chem., 2014,
12, 7494
Received 6th June 2014,
Accepted 12th August 2014
Xiaozu Liu, Qinghong Hu, Zeli Yuan* and Peijun Liu*
DOI: 10.1039/c4ob01179a
www.rsc.org/obc
A new and mild method for the efficient synthesis of 3,3-dichloro-
2-sulfonyliminoindolines via AcOH-mediated dichloroimination
of indoles using chloramine-B is presented. Application of this
method to the efficient construction of pyrrolidinoindoles and
N–C3 linked pyrrolidinoindolines is demonstrated.
The indole moiety is present in numerous natural products
possessing interesting biological activities1 and represents a
privileged element for synthetic pharmaceuticals.2 Direct
indole functionalization has received considerable attention
from organic and medicinal chemists due to its practicality
and atom-economy, and is an efficient approach toward the
synthesis of indole derivatives.3 While considerable efforts
have been made for the direct C–C bond formation of
indoles,4 there are only limited reports for the direct C–N bond
derivatization,5 especially for the direct C-2 amination of
indoles. Recently, Li and co-workers developed a copper-
catalyzed regioselective amidation of 1-methylindoles with
acetanilide derivatives.6 Subsequently, several methods for the
direct C–N bond formation of indoles at the C2 position have
been documented,7 i.e. palladium/copper-catalyzed regioselective
amination of indoles with chlorosulfonamides,7a and
I2-mediated regioselective C-2 amination of indoles with
morpholine,7b N-tosylbenzenamines,7c azoles,7d or anilines.7e
However, all these methods only afforded aminated indole
derivatives. No approach toward the direct imination of
indoles has been documented. Recently, Che and co-workers
realized this transformation via a ruthenium porphyrin cata-
lyzed diimination of indoles with aryl azides as the nitrene
source (Scheme 1, eqn (1)).8 As an alternative, metal-free
methods have become very important from the economical
and environmental point of view. However, the development of
a facile and metal-free method for this transformation remains
Scheme 1 Intermolecular C–H imination of indoles.
a synthetic challenge. Herein, we would like to describe a
novel AcOH-mediated dichloroimination of indoles using
chloramine-B under mild conditions (Scheme 1, eqn (2)). This
protocol provides a facile access to various 3,3-dichloro-2-
sulfonyliminoindolines which could be further converted to
isatin analogs and 2-amino-substituted indoles. Furthermore,
it also provides an efficient way for the construction of pyrroli-
dinoindoles and N–C3 linked pyrrolidinoindolines.
Our studies were commenced with 1-methylindole 1a and
chloramine-B as the model substrates. The reaction para-
meters, including Brønsted acids, solvents and equivalents of
chloramine-B, were investigated. The results are shown in
Table 1. In an initial attempt, the reaction of indole 1a
(1.0 mmol) with chloramine-B (2.0 mmol) was performed in
acetonitrile at 0 °C without any additive, no reaction took
place (Table 1, entry 1). Since the cleavage of the N–Cl bond
may be facilitated under acidic conditions, several acids
including HCl/diethyl ether, trifluoroacetic acid, p-toluene-
sulfonic acid (PTSA) and acetic acid were investigated. The
reaction proceeded smoothly in the presence of acetic acid, and
the desired compound 2a, confirmed by 1H NMR, 13C NMR
and HRMS analyses, was obtained as the major product in
44% yield (Table 1, entry 5). Other acids led to poor yields of
2a (Table 1, entries 2–4). To our delight, when the ratio of
indole 1a to chloramine-B was changed from 1 : 2 to 1 : 3, the
yield was increased to 92% (Table 1, entry 6). Shifting the
solvent system to other solvents, no improvements were
observed under the same conditions (Table 1, entries 7 and 8).
Pharmacy School, Zunyi Medical University, Zunyi 563000, P.R. China.
E-mail: pjliu@zmc.edu.cn, zlyuan@zmc.edu.cn; Fax: +86-852-8609343;
Tel: +86-852-8608579
†Electronic supplementary information (ESI) available. CCDC 1006093. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ob01179a
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Table 1 Optimization of the reaction conditionsa
Table 2 Scope of dichloroimination of indolesa,b
Chloramine-B
(equiv.)
Yieldb
(%)
Entry
Brønsted acid
Solvent
1
2
3
4
5
6
7
8
2.0
2.0
2.0
2.0
2.0
3.0
3.0
3.0
—
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeOH
1,4-Dioxane
n.r.
Trace
9
17
44
92
Trace
59
1 N HCl in ether
CF3CO2H
PTSA
AcOH
AcOH
AcOH
AcOH
a Reaction conditions: 1a (1.0 mmol), chloramine-B and the indicated
Brønsted acid (5.0 equiv.) were stirred in the indicated solvent
(10.0 mL) at 0 °C for 0.5 h. b Isolated yield.
Thus, the optimized reaction conditions include the use of 5.0
equiv. of acetic acid and 3.0 equiv. of chloramine-B as the
amine and chlorine source in acetonitrile at 0 °C.
With the optimized conditions in hand, we began to investi-
gate the generality of this established transformation (Table 2).
A wide range of indoles reacted with chloramine-B or chlor-
amine-T smoothly to afford the desired products in moderate
to excellent yields. The protecting groups for N-protection,
including methyl, benzyl and allyl (Table 2, 2a–2c, 2g–2i, 2p
and 2q), were well tolerated. Indoles bearing electron-with-
drawing substituents at the C5 or C6 position were also suit-
able substrates, affording the desired products in good yields
(Table 2, 2g–2j, 2l–2n, 2p and 2q). The structure of 2i was
further confirmed by single-crystal X-ray analysis9 (Fig. 1). In
contrast, introduction of electron-donating substituents such
as methyl and methoxy at the C5 position of the indole
decreased the yields of the corresponding products (Table 2, 2f
and 2k). Substrates bearing substituents at the C4 position
only afforded moderate yields (Table 2, 2d and 2e). It was note-
worthy that 1,3-dimethylindole 1r gave the highest yield. These
results implied that the electronic effect or the position of sub-
stituents had a great influence on the yields of the corres-
ponding products. In addition, chloramine-T as the amine and
chlorine source was also investigated to give moderate yields
(Table 2, 2s).
a Standard conditions:
1 (1.0 mmol), 3 (3.0 mmol) and AcOH
(5.0 mmol) in acetonitrile (10.0 mL) were stirred for 0.5 h at 0 °C.
b Isolated yield. c 1,3-Dimethyl-1H-indole as the substrate.
A possible mechanism for the reaction is illustrated in
Scheme 2.7c,g The reaction of N-substituted indole with
N-chlorobenzenesulfonamide, generated in situ from chlor-
amine-B and AcOH, led to the formation of A. A subsequent
elimination of HCl molecules gave B. The next step involved a
chlorination of B to give C. Further transformation of C via a
dearomatization led to the formation of the cation D, followed
by removal of a proton to provide the final product 2a.
Fig. 1 X-ray crystal structure of compound 2i.
chosen as substrates for further transformations (Scheme 3).
In the presence of acetic acid, 2a was converted to the isatin
analog 4 or 5 in good yields under different reaction con-
ditions. As a class of important molecules, isatin and its
derivatives exhibit rich biological activities.10–12 In addition,
isatins are often used as versatile building blocks in organic
synthesis and medicinal chemistry.13 Meanwhile, treating 2n
With these encouraging results in hand, we set to examine
the synthetic applications of these 2,3-functionalized indo-
lines. 3,3-Dichloro-2-sulfonyliminoindolines 2a and 2n were
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been realized through an acid hydrolysis or
a NaBH4
reduction. Furthermore, application of this reaction to the syn-
thesis of N–C3 linked pyrrolidinoindolines and pyrrolidino-
indoles may provide a facile way for the total synthesis of an
indole alkaloid, psychotrimine.
Acknowledgements
Scheme 2 Proposed mechanism.
We are grateful for the financial support from the Natural
Science Foundation of the Guizhou Provincial Department of
Education (KY[2012]078) and the International Cooperation
Project of the Guizhou Provincial Department of Science and
Technology (G[2013]7036).
Notes and references
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synthesis of a series of 3,3-dichloro-2-sulfonyliminoindolines.
This reaction features mild conditions, short reaction time,
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