Facile regiospecific synthesis of 2,3-disubstituted indoles from isatins

Article abstract of DOI:10.1039/c4cc04555f

A facile regiospecific synthesis of 2,3-disubstituted indoles from isatins has been developed. Nucleophilic addition of Grignard reagents to commercially available isatins, followed by reduction with borane, afforded an array of structurally diverse 2,3-disubstituted indoles in moderate to good yields. The method described herein represents a novel and very simple approach to synthesize various 2,3-disubstituted indoles, extremely important structural motifs in the pharmaceutical industry and medicinal chemistry. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc04555f

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Facile regiospecific synthesis of 2,3-disubstituted
indoles from isatins†
Cite this: Chem. Commun., 2014,
50, 9469
Xiaowei Dou, Weijun Yao, Shan Wen and Yixin Lu*
Received 16th June 2014,
Accepted 4th July 2014
DOI: 10.1039/c4cc04555f
www.rsc.org/chemcomm
A facile regiospecific synthesis of 2,3-disubstituted indoles from isatins
has been developed. Nucleophilic addition of Grignard reagents to
commercially available isatins, followed by reduction with borane,
afforded an array of structurally diverse 2,3-disubstituted indoles in
moderate to good yields. The method described herein represents a
novel and very simple approach to synthesize various 2,3-disubstituted
indoles, extremely important structural motifs in the pharmaceutical
industry and medicinal chemistry.
Indole represents one of the most important structural units of
natural products and pharmaceutical agents,1 and continuous
efforts have been devoted to the efficient synthesis of indole
structures over the past century.2 Fisher indole synthesis,
although discovered more than 100 years ago, still remains
one of the most widely used methods.3 Many transition metal-
based approaches have emerged over the past few decades,
including Larock aniline–alkyne cyclizations,4 C–H activation
strategies,5 and cross-dehydrogenative coupling methods,6
among others (Scheme 1). Despite the aforementioned impressive
progress, straightforward and efficient methods without employing
a transition metal are still highly desired. Given the importance of
2,3-disubstituted indoles in biological sciences and medicinal
chemistry (Fig. 1),7 we set out to design an efficient method to
access such structural motifs. The vast majority of known methods
rely on the annulation of a five-membered ring to an existing
benzene ring for the construction of the indole core, and synthesis
of specific precursors containing the right functionalities can
pose huge synthetic problems. Moreover, formation of mixed
regioisomers at the 2- and 3-positions is often problematic in the
above approaches. In our design, we set the following criteria for
Scheme 1 Common methods for indole synthesis.
Fig. 1 Selected bioactive compounds containing
indole moiety.
a 2,3-disubstituted
starting materials to ensure an efficient indole synthesis: (1) ready precursors, and (4) easy functionalization to allow access to
availability, (2) the existing fused ring structures, (3) latent indole different 2,3-substituted indoles. Commercially available isatins
seem to be excellent candidates fulfilling all the above requirements.
Nucleophilic additions to the carbonyl groups at 2- and 3-positions
could yield 2,3-disubstituted intermediates. Moreover, the carbonyl
groups at 2- and 3-positions of isatins have different electrophilic
Department of Chemistry and Medicinal Chemistry Program, Life Sciences Institute,
National University of Singapore, 3 Science Drive 3, Republic of Singapore 117543.
E-mail: chmlyx@nus.edu.sg
properties, and thus careful differentiation of these groups is
expected to make selective functionalizations possible, thus
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc04555f
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Scheme 2 Synthesis of 2,3-disubstituted indoles from isatins.
Table 1 Investigating the synthesis of 2,3-disubstituted indoles from isatinsa
c
Entry
R
X
Y
Z/h
Yieldb [%]
2 : 20
1
2
3
4
5
6
7
8
H
5
5
5
5
5
5
5
5
5
5
4
3
7
7
7
7
5
3
3
3
2
4
2
1
2
2
2
2
2
2
3
4
3
3
3
3
40
Trace
68
77
68
56
86
86
71
o1 : 25
n.d.
15 : 1
10 : 1
12 : 1
425 : 1
425 : 1
425 : 1
425 : 1
20 : 1
425 : 1
425 : 1
Boc
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Scheme 3 Substrate scope for synthesis of symmetric 2,3-disubstituted-
indoles.
2 equivalents of borane, the desired 2,3-disubstituted indoles
were formed in high yields (entry 11).9
9
By utilizing the above optimal reaction conditions, we pre-
pared a number of symmetric 2,3-disubstituted indoles from
isatins (Scheme 3). Various alkyl and aryl substituents were
easily installed at the 2- and 3-positions with employment of
different Grignard reagents10 (2a–2f). Furthermore, indole core
structures could also be varied if different isatins were utilized
as starting materials (2g and 2h).
10
11
12
88
86
63
a
Reactions were performed with 1a (0.2 mmol), MeMgBr (x eq., 3.0 M in
Et2O), BH3-SMe2 ( y equiv., 2.0 M in THF) in THF (1.0 mL), 0 1C to reflux.
b
c
Combined isolated yield of 2 and 20. Determined by 1H NMR analysis.
Our next goal was to regiospecifically synthesize 2,3-disub-
introducing different substituents at 2- and 3-positions. Finally, stituted indoles bearing different substituents. This is a for-
using a suitable reduction protocol,8 various 2,3-disubstituted midable synthetic task, and previous literature efforts only met
indoles can be readily created (Scheme 2).
with limited success.11 We reasoned that this challenging
We first tested the feasibility of forming indoles from isatins, regioselectivity issue may be easily addressed via stepwise
installing the same substituent at the 2- and 3-positions. The functionalization of the indole precursor, taking advantage of
methyl group was introduced via a methyl Grignard reagent, and the difference in electrophilicity of the 2- and 3-carbonyl groups
subsequent reduction with borane yielded the indole products of isatins. Treatment of N-benzyl isatins with the Grignard
(Table 1). We initially employed 5 equivalents of the Grignard reagent at low temperature yielded 3-hydroxy-3-substituted
reagent as well as a large excess of borane (7 eq.) to ensure high oxindole substrates 3,12 which were then subjected to the
conversion of the reaction. When unprotected isatin (1a) was second functionalization at the 2-carbonyl position. The reac-
used, only a 3-monosubstituted indole product (2a-10) was tion was conducted in the presence of 4 equivalents of the
obtained in low yield, (entry 1). When Boc-protected isatin (3a) Grignard reagent and 2 equivalents of borane, and the results
was used, the desired indole product was virtually not formed are summarized in Scheme 4. 2,3-Disubstituted indoles with
(entry 2). Switching the N-protection to an alkyl group proved to different substitution patterns were easily prepared, including:
be effective, and the desired 2,3-disubstituted indole was 2-alkyl-3-alkyl (4a–4d), 2-aryl-3-alkyl (4e–4h), 2-alkyl-3-aryl
obtained in high yield when N-methyl or N-benzyl isatin was (4i–4l), and 2-aryl-3-aryl (4m–4p) substituents. Moreover, differ-
used for the reaction (entries 3 and 4). However, it was observed ent indole cores could be obtained if different isatins were
that 3-monosubstituted indole was also formed during the utilized as the starting materials (4q–4t). All the products were
reaction, which could not be easily separated from the desired readily prepared, within a few hours, in moderate to good
disubstituted product via chromatographic separation. We rea- chemical yields. It is noteworthy that our method allowed
soned that varying the molar equivalence of the Grignard reagent convenient preparation of 2,3-disubstituted indoles in a regio-
and borane might be the key to solving this problem. Therefore, specific manner, even though the substituents may have
further optimizations were carried out. When the amount of great similarity both sterically and electronically. For instance,
borane was reduced to 3 equivalents, the 2,3-disubstituted 2-methyl-3-ethyl-indole 4a and 2-ethyl-3-methyl-indole 4b were
indole 2a was obtained as the sole product in moderate yield prepared in high yields, both as a pure regioisomer, as opposed
(entry 6). The chemical yield was easily improved to 86% to the formation of mixed isomers reported in the literature.13
with slightly increased reaction time (entries 7 and 8). Further The 2,3-disubstituted indoles could also be synthesized via a
experimentations revealed the best reaction conditions; in the one-pot protocol. Isatin 1a was treated with different Grignard
presence of
4 equivalents of the Grignard reagent and reagents in a stepwise fashion, the phenyl group was first
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Scheme 6 Proposed reaction pathway.
be converted into LY311727 using the procedures described in
the literature (Scheme 5).
Unprotected indole products could be easily obtained after
the N-debenzylation reaction. The benzyl group of 4o could be
readily removed by treating it with potassium tert-butoxide and
oxygen in DMSO/THF at room temperature, and the corres-
ponding unprotected indole 10 was obtained in high yield
(eqn (2)).15
(2)
A plausible reaction pathway is illustrated in Scheme 6.
Treatment of isatin 1a with a Grignard reagent yields inter-
mediate A. Excess Grignard reagent leads to the formation of
intermediate B. Upon the elimination of OMgBrꢀ, iminium
intermediate C is generated, which is further reduced to indo-
line intermediate D. The final indole product 4 is then gener-
ated upon subsequent elimination of Mg(OH)Br.
In summary, we have successfully developed a novel method
for regiospecific preparation of 2,3-disubstituted indoles. Our
method makes use of commercially available isatins as starting
materials, and employs readily available Grignard reagents as
nucleophilic partners and borane as a convenient reducing
agent. Stepwise functionalization of the 2- and 3-carbonyl
groups of isatins is the key to the introduction of different
substituents regiospecifically at the 2- and 3-positions of the
indole products. Extension of the approach described here to
the synthesis of other important heterocyclic compounds is
ongoing in our laboratory.
Scheme 4 Regiospecific synthesis of 2,3-disubstituted-indoles bearing
different substituents.
introduced into the 3-position, followed by 2-carbonyl functional-
ization with another Grignard reagent. Finally, the desired product
was obtained upon borane reduction (eqn (1)).
(1)
The synthetic value of our method was demonstrated by
preparing LY311727, the first potent and selective s-PLA2
inhibitor.7b 3-Hydroxy oxindole substrate 6 was easily derived
from isatin 5 (see the ESI† for details). Treatment of 6 with
ethylmagnesium bromide led to the formation of indoline 7,
instead of the corresponding indole intermediate. Indole 8 was
obtained via a mesylation–elimination reaction.14 Removal of
the silyl protection afforded the key intermediate 9, which can
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