2-Aroylindoles from o-bromochalcones via Cu(i)-catalyzed SNAr with an azide and intramolecular nitrene C-H insertion

Article abstract of DOI:10.1039/c4cc02501f

A simple procedure for the synthesis of 2-aroylindole derivatives comprising a one-pot CuI-catalyzed S_NAr reaction of o-bromochalcones with sodium azide and subsequent intramolecular cyclization through nitrene C-H insertion has been developed. This protocol is also applicable with the 2′-bromocinnamates giving the indole-2-carboxylates. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02501f

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2-Aroylindoles from o-bromochalcones via
Cu(I)-catalyzed SNAr with an azide and
intramolecular nitrene C–H insertion†
Cite this: Chem. Commun., 2014,
50, 7790
Received 4th April 2014,
Accepted 14th May 2014
Yogesh Goriya and Chepuri V. Ramana*
DOI: 10.1039/c4cc02501f
www.rsc.org/chemcomm
A simple procedure for the synthesis of 2-aroylindole derivatives com-
prising a one-pot CuI-catalyzed SNAr reaction of o-bromochalcones with
sodium azide and subsequent intramolecular cyclization through nitrene
C–H insertion has been developed. This protocol is also applicable with
the 20-bromocinnamates giving the indole-2-carboxylates.
Indole is one of the most commonly encountered heterocyclic units
in a wide range of bioactive molecules.1 The early disclosure of its
constitution/structure in dealing with the synthesis of indigo, ‘‘indole
synthesis’’, has witnessed a constant progress in its research during
the last two centuries and has bagged several named reactions.2,3
Indole derivatives having a carbonyl functional group at C2 are
important building blocks for natural product/pharmacologically
Fig. 1 Metal-catalyzed cyclization of azidostyrene derivatives.
active compound synthesis, in particular C2–aroyl indole derivatives.4 Driver and co-workers have recently reported intramolecular
The C2–aroyl indole derivatives without any N- or C3 substituent have C–H amination from either side via a Rh-catalyzed decomposition
been identified as potent small molecular modulators for diverse of a-azidoacrylates or aryl azides leading to indole derivatives.10
biological targets such as cell surface receptors (receptor tyrosine Our group has been working on the Cu-catalyzed SNAr of aryl
kinase), nuclear receptor proteins, cyclooxygenase and histone halides with azide and the trapping of the intermediate azide
deacetylases and have also proven to be important in controlling either for cycloaddition or cyclization.11 Given the current interest
the polymerization of tubulin.5 The examination of these derivatives in 2-aroylindole synthesis, we speculated on the possibility of a
across a wide range of biological targets was, in particular, possible one-pot [Cu]-catalysed synthesis of 2-aroylindoles from easily
because of their ready availability and because of the development of accessible o-bromochalcones (Fig. 1).12,13
reliable protocols for their synthesis.6–9
Initial experiments with simple a-bromochalcone 1a under the
The deoxygenation of b-substituted-o-nitrostyrenes with P(OEt)3, previously established conditions [20 mol% of each of CuSO4ꢀ5H2O,
trivially known as the ‘‘Cadogan–Sundberg indole synthesis’’ is one sodium ascorbate and L-proline, 1.5 equivalents of K2CO3 and NaN3
of the early methods in this direction, despite the fact that it afforded in DMSO at 80 1C for 15 h]11b gave a mixture of the required
2-ethoxycarbonyl- and 2-acylindoles in very poor yields.7 The involve- 2-benzoylindole (2a, 47%), along with the 2-phenylquinoline
ment of a singlet nitrene and its insertion across the C–H bond of (3a, 39%). Having obtained the first promising results, we next
the olefin unit is a generally accepted mechanism in these nitro- focussed on the optimization of the reaction conditions. As
reduction processes.8 Replacing the nitro with an azide as a nitrene shown in Table 1, among the various copper sources employed,
surrogate has not seen much success when the reactions are CuI was found to be the best for the present transformation.13a
conducted under standard pyrolysis or photolysis conditions.9 The outcome of the required 2-aroylindole increased by switching
the solvent from DMSO, DMA to NMP (Table 1, entries 2–4).
Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune-411008,
While the presence of Na-ascorbate is not essential, the presence
of the base K2CO3 (4.0 equivalents) is required (Table 1 entry 8).
However, other bases such as Cs2CO3 and Na2CO3 did not show
India. E-mail: vr.chepuri@ncl.res.in; Fax: +91 20 2590 2629;
Tel: +91 20 2590 2578
† Electronic Supplementary Information (ESI) available: Experimental proce-
any improvement in the yield (Table 1, entries 9 and 10).
Reducing the concentration of the ligand L-proline from 100 mol%
dures, characterization data, NMR, and MS spectral of all new compounds. See
DOI: 10.1039/c4cc02501f
7790 | Chem. Commun., 2014, 50, 7790--7792
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Table 1 Optimization of reaction conditiona
Sr. No Catalyst Solvent Base Yield (2a)b,c,d (%) Yield (3)b,c,d
1
2
3
4
5
6
7
8
CuSO4
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
DMSO
DMSO
DMA
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
1.5
1.5
1.5
1.5
—
2.0
3.0
4.0
1.5e
3.0 f
1.5
4.0
3.0
4.0
3.0
4.0
47e
56
62
69
47
39%e
41%
38%
Scheme 2 Reagents and conditions: (a) CuI (20 mol%), L-proline (20 mol%),
K2CO3 (4.0 eq.) in NMP at 100 1C, for 15 h; (b) CuI (20 mol%), NMP at 100 1C
for 15 h; (c) NMP at 100 1C for 15 h; (d) same as condition (a) along with NaN3
(1.5 eq.).
26%
13% (39%)h
20%
80
81
5% (4%)
3%
51%
86
9
49 f
72g
52e
87
10
11
12
13
14
15
16
CuI
CuSO4
CuI
27%
5% (27%)e
1%
These experiments revealed that the carboxylate group can be a
suitable alternative for the aroyl group. The suitability of the
C3-substituted o-bromocinnamates (prepared by the two-carbon
Wittig homologation of the corresponding ketones) as substrates
has been examined next. As shown in Scheme 2. The one-pot
SNAr-cyclization reaction of o-bromocinnamates 4c–4e having
respectively, the methyl, butyl, or phenyl group at C3 proceeded
smoothly to afford the corresponding indole-2-carboxylates
5c–5e in good yields (Scheme 2).
CuI
75
84
54
ND
7% (17%)
— (4%)
24% (21%)
ND
CuCl
Cu2O
—
a
Reaction condition: o-bromochalcone (1a, 1 eq.), NaN3 (1.5 eq.), CuI
(20 mol%), L-proline (0.2 eq.), K2CO3 (4.0 eq.) in NMP at 100 1C for 15 h.
b
c
L-Proline (1.0 eq.) was used for entries 2–11. Yield based on GC.
d
e
f
Isolated yield. (20 mol%) Na-ascorbate was used. Cs2CO3 used as a
g
h
base. K2CO3 use as base. Parenthesis indicate (%) starting intact.
To understand the course of the reaction, control experiments
were conducted with the 2-azidochalcone 6 and with the bromo-
chalcone 1u having a methyl group in place of the hydrogen atom
to be abstracted. As shown in Scheme 3, the treatment of
2-azidochalcone 6 with CuI under optimized conditions resulted
in a mixture of indole 2a and quinolone 3a derivatives. A similar
result was obtained when the reaction was conducted only with
20 mol% CuI and without any other additive. On the other hand,
when 6 was heated alone in NMP, it gave exclusively indole in
39% yield. However, the reaction of the o-bromochalcone 1u with
a C2–methyl substituent under standard conditions resulted in
the formation of a mixture of quinolone 3u and the aniline
derivative 8. These results clearly indicate that while the involvement
of a nitrene-intermediate essentially leads to indole formation, when
the copper salt is present, the yields are better, indicating the
possible involvement of a copper–nitrenoid species. However, the
reduction of the aryl azide seems to be a competing process at high
azide concentrations (Table 2).
to 20 mol% did not show any effect on the reaction efficiency
(Table 1, entry 12).
The generality of the current reaction has been examined
first by selecting the substrates where the nature of substituent next
to the carbonyl has been varied from aromatic to heteroaromatic,
cycloalkyl and alkyl groups. The reactions with other aromatic/
heterocyclic rings like naphthyl, furyl, pyrrol, pyridine, benzofuran
and benzothiophene gave the desired products in moderate to good
yields. However, when the aryl ring was replaced by an alkyl or
cyclopropyl group, the yields were seen to decrease. Next, the scope
of the present reaction was further extended by employing
2-bromochalcones having different substituents on both the phenyl
rings. The substituents on the bromoaryl ring do not have much
influence on the reaction outcome. On the other hand, with
substrates having the electron donating group on the aryl ring next
to the carbonyl, the reaction yields are moderate (Scheme 1).
To look at the compatibility of an ester group, the o-bromo-
cinnamate and the 2-bromo-5-methoxy cinnamate have been
subjected to the current reaction and the corresponding
indoles 5a and 5b respectively were obtained in good yields.
With the available information in hand and considering the
previous reports,14 we propose the following tentative mechanism.
Earlier it has been shown that the [Cu] is required for the SNAr with
Scheme 1 Cu(I)-catalyzed synthesis of indole-2-carboxylates.
Scheme 3 Plausible catalytic cycle.
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Table 2 Scope of the [Cu]-catalyzed 2-aroyl indole synthesis
Notes and references
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azide and that the decomposition of the azide takes place after the aryl
azide formation.13,14c,15 There exist two possibilities for the subsequent
C–N bond formation.8,16 A step-wise process involving an initial C–N
bond formation and subsequent C–H bond cleavage,8,10a,16 or a
concerted process10a,13a with simultaneous breaking of the C–H bond
and the formation of the C–N bond. Considering the fact that the
reacting olefin in the present case is electron deficient and that the
chalcone 1u having a 2-methyl substituent did not provide any indole
derivative (the formation of which is expected due to the migration
of the methyl group if it is a step-wise process)10a we propose that
a concerted process is operating in the present case, having
Cu-participation in both the steps (Scheme 3).
In conclusion, a simple catalytic protocol for the preparation
of 2-aroylindoles from 2-bromochalcones has been developed.
This Cu-catalyzed process involves a set of three reactions –
(i) SNAr with azide and (ii) conversion of azide to nitrene; and
(iii) intramolecular insertion of nitrene across the C–H bond –
with the net formation of two new C–N bonds.
The authors would like to acknowledge CSIR (India) for
providing the financial support for this project under the
ORIGIN program of 12FYP (CSC0108) and the research
fellowship to YG.
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7792 | Chem. Commun., 2014, 50, 7790--7792
This journal is ©The Royal Society of Chemistry 2014