Synthesis of 3-acylindoles via decarboxylative cross-coupling reaction of free (NH) indoles with α-oxocarboxylic acids

Article abstract of DOI:10.1016/j.cclet.2013.10.004

A convenient and general method for acylation of free (NH) indoles via palladium-catalyzed decarboxylative cross-coupling reaction was developed. This process provided a useful method for the preparation of diverse 3-acylindoles in high yields utilizing a reaction with readily accessible reactants under mild conditions.

Full text of DOI:10.1016/j.cclet.2013.10.004

Chinese Chemical Letters 25 (2014) 90–92
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Synthesis of 3-acylindoles via decarboxylative cross-coupling reaction
of free (N–H) indoles with -oxocarboxylic acids
a
*
Li-Jun Gu , Ji-Yan Liu, Li-Zhu Zhang, Yong Xiong, Rui Wang
Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan University of Nationalities,
Kunming 650500, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A convenient and general method for acylation of free (N–H) indoles via palladium-catalyzed
decarboxylative cross-coupling reaction was developed. This process provided a useful method for the
preparation of diverse 3-acylindoles in high yields utilizing a reaction with readily accessible reactants
under mild conditions.
Received 1 July 2013
Received in revised form 20 September 2013
Accepted 24 September 2013
Available online 12 November 2013
ß 2013 Li-Jun Gu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords:
3-Acylindoles
Decarboxylative acylation
a
-Oxocarboxylic acids
1. Introduction
alternative efficient methods has encouraged the development of
new methods for the synthesis of 3-acylindoles. In 2011, Su and co-
The indole ring system represents one class of the most abundant
and ubiquitous heterocycles in nature. Owing to their structural
diversity and remarkable biological functions, the synthesis and
transformation of indoles has been and continues to be a topic of
research interest for syntheticorganic chemists [1–3]. 3-Acylindoles
are versatile intermediates in the syntheses of a wide range of indole
derivatives since their carbonyl groups can readily undergo a variety
of transformations such as C–C and C–N coupling reactions and
reductions [4–6]. Thus, the synthesis of 3-acylindoles has gained
considerable attention. Traditionally, the common method for the
preparation of 3-acylindoles is the Friedel–Crafts reaction (Scheme
1a) [7–9]. The other significant approaches include the Vilsmeier–
Haack type reaction [10], and Grignard reactions [11]. Other
methods involve nitrilium salts with dialkyl carbenium ions and
pyridinium salts. Under the acidic conditions of Friedel–Crafts
reactions, indole polymerization readily occurs. Vilsmeier–Haack
acylindolesuse unacceptableamountsofenvironmentallyunfriend-
ly POCl3. The reactions of indole salts with acyl chlorides cannot
tolerate the functional group sensitivities to strong nucleophiles
because Grignard reagents are used in these reactions. The existing
methods often involve uncommonly used acylated reagents or
unbenign reaction conditions. As a consequence, the demand for
workers reported a convenient and general method for formylation
and acylation of free (N–H) indoles via Ru- or Fe-catalyzed oxidative
coupling using anilines as the carbonyl source (Scheme 1b) [1].
Recently, Song and Wang independently reported the synthesis
of 3-acylindoles through palladium-catalyzed addition of indoles to
nitriles (Scheme 1c) [12,13].
Palladium-catalyzed decarboxylative cross-coupling reactions
using simple carboxylic acids as coupling partners have emerged
as a new type of C–C bond formation reaction [14–16]. In these
reactions, using readily available and stable carboxylic acids
instead of organometallic reagents enabled the decarboxylative
cross-coupling reactions to proceed with good selectivities and
tolerance of functional groups. In 2008, Goossen first reported the
synthesis of unsymmetrical diaryl ketone using
a-oxocarboxylic
acid salts as acyl anion equivalents through palladium-catalyzed
decarboxylative cross-coupling [17]. Later, Ge described elegant
studies on Pd-catalyzed decarboxylative ortho-acylation of acet-
anilides and phenylpyridines with
a-oxocarboxylic acids via C–H
bond activation [18]. Thereupon, we envision that an efficient and
general Pd-catalyzed decarboxylative cross-coupling reaction to
synthesize 3-acylindoles would be more intriguing than the
existing protocols. As part of our ongoing research program
on transition-metal-catalyzed reactions [19–21], we herein
describe a new strategy to construct 3-acylindoles that relies on
palladium-catalyzed decarboxylative acylation of free (N–H)
indoles (Scheme 1d) [22,23].
* Corresponding author.
E-mail address: gulijun2005@126.com (L.-J. Gu).
1001-8417/$ – see front matter ß 2013 Li-Jun Gu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.10.004

L.-J. Gu et al. / Chinese Chemical Letters 25 (2014) 90–92
91
O
Previous work
R
filtered. Solvents were evaporated under reduced pressure. The
residue was purified by flash column chromatography with
hexane/ethyl acetate to give the corresponding product 3.
(5,6-Dimethyl-1H-indol-3-yl)(phenyl)methanone (3af): Gray
R'
Lewis acid
a
+
R'COCl
ArNH
R
N
H
N
H
solid; Mp 192–194 8C; IR (KBr, cmÀ1):
1104; 1H NMR (400 MHz, DMSO-d6):
7.82–7.79 (m, 2H), 7.49–7.43 (m, 3H), 7.23 (s, 1H), 2.33 (s, 3H), 2.31
(s, 3H); 13C NMR (100 MHz, DMSO-d6):
189.5, 137.8, 137.3, 136.2,
v
d
max 3109, 2921, 1724, 1521,
8.23 (s, 1H), 7.92 (s, 1H),
O
R'
Ru or Fe
TBHP
R'
R
+
R
R
b
d
N
N
H
H
133.0, 132.3, 129.4, 128.6, 127.5, 120.8, 117.4, 113.4, 110.7, 20.5
20.3; HRMS (ESI) calcd. for C17H16NO (M+H)+ (m/z): 250.1227,
found: 250.1231.
O
R'
Pd
R
c
N
CR'
O
+
3. Results and discussion
N
H
N
H
Our initial study started from the coupling of indole 2a with
phenylglyoxylic acid 1a using O2 as the oxidant, Pd(TFA)2 as the
catalyst in the presence of I2, K2CO3 and N,N-dimethylformamide
(DMF) at 45 8C for 12 h. To our delight, the desired product 3aa was
obtained in 43% yield (entry 1, Table 1). It was found that Pd(OAc)2
was superior to other Pd sources (entries 1–4, Table 1). Further
studies indicated that the presence of iodine could promote the
efficiency of this transformation (entry 5, Table 1). It was found
that Cs2CO3 was superior to other bases (entries 4 and 6–8,
Table 1). The influence of solvent on the reaction efficiency was
also significant; when N-methylpyrrolidone (NMP) was chosen as
the solvent, the yield was enhanced to 82% (entries 8–13, Table 1).
This work
R
O
R'
Pd(OAc) 2,O 2
Cs2CO3, I2
OH
+
d
R'
R
N
H
N
O
H
Scheme 1. Existing routes and our strategy to 3-acylindoles.
2. Experimental
Reagents were obtained commercially and used as received.
Solvents were purified and dried by standard methods. The
melting points were determined on an XT-4 micro melting point
apparatus and uncorrected. IR spectra were recorded on an
EQUINOX-55 spectrometer on a KBr matrix. NMR spectra were
recorded on an INOVA-400 NMR instrument at room temperature
using TMS as internal standard. Coupling constants (J) were
With the optimized conditions in hand,
oxocarboxylic acids 1 were investigated, as shown in Table 2.
Both electron-donating and electron-withdrawing -oxocar-
a series of a-
a
boxylic acids could be successfully converted to the corresponding
3-acylindoles in good yields. In addition, a high level of tolerance
by functional groups was observed, and the efficiency of the
reaction was not affected in the presence of halide, ether, and nitro
group. Furthermore, substituents at different positions on the
arene group (para, meta, and ortho positions) did not affect the
measured in Hz. Chemical shift values (d) are given in ppm. High
Resolution mass spectrometer (HRMS) spectra were recorded on a
Bruker micrOTOF-Q II analyzer. A 200–300 mesh silica gel was
used for column chromatography.
Representative procedure for the synthesis of 3-acylindoles (3):
A 10 mL oven-dried Schlenk tube was charged with phenyl-
glyoxylic acid 1a (49.5 mg, 0.33 mmol), indole 2a (35.1 mg,
0.3 mmol), I2 (164.5 mg, 0.65 mmol), Pd(OAc)2 (10 mol%, 6.7 mg,
0.03 mmol), Cs2CO3 (292 mg, 0.9 mmol). The tube was evacuated
and filled with O2 (this procedure was repeated three times). Then
NMP (1.5 mL) were added with a syringe under a counter flow of
O2. The tube was sealed with a screw cap. The reaction was stirred
at 45 8C for 12 h, and was then allowed to cool to ambient
temperature. The mixture was added 20 mL EtOAc, and filtered,
washed with water. The organic layers were dried over Na2SO4 and
reaction efficiency. It is noteworthy that halo-substituted a-
oxocarboxylic acids were tolerated well, thus leading to halo-
substituted products, which could be used for further transforma-
tions (entries 2 and 3, Table 2). Subsequently 2-thienylglyoxylic
acid was used in this reaction, affording the corresponding
products in good yields (entry 7, Table 2). Gratifyingly, aliphatic
a-oxocarboxylic acids were also compatible in this reaction, giving
the desired product in 71% yield (entries 8 and 9, Table 2).
To expand the scope of this direct acylation reaction further, we
next investigated the decarboxylative coupling of phenylglyoxylic
Table 2
Palladium-catalyzed decarboxylative acylation of a
-oxocarboxylic acids 1 with 2a.a
Table 1
Palladium-catalyzed decarboxylative acylation of free (N–H) indoles.a
Entry
Pd(II)
Base
Solvent
Yield (%)b
1
2
Pd(TFA)2
PdCl2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
K3PO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMAc
THF
43
26
36
57
16
44
62
77
58
NDd
23
82
ND
3
Pd(dba)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
4
5c
6
Entry
1
R1
3
Yield (%)b
7
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
Ph
3aa
3ba
3ca
3da
3ea
3fa
82
76
73
80
79
77
81
71
74
8
4-ClC6H4
3-BrC6H4
4-NO2C6H4
2-MeC6H4
4-OMeC6H4
2-Thienyl
t-Bu
9
10
11
12
13
DCM
NMP
Diglyme
1g
1h
1i
3ga
3ha
3ia
a
Reaction conditions: 1a (0.33 mmol), 2a (0.3 mmol), PdX2, (10% mol), I2
(0.65 mmol), Base (0.9 mmol), solvent (3 mL), O2 (1 atm), 45 8C, 12 h.
Me
b
a
Yield of isolated product.
Reaction conditions: 1 (0.33 mmol), 2a (0.3 mmol), Pd(OAc)2, (0.03 mmol), I2
(0.65 mmol), Cs2CO3 (0.9 mmol), NMP (3 mL), O2 (1 atm), 45 8C, 12 h.
c
Without I2.
d
b
ND, not determined.
Yield of isolated product.

92
L.-J. Gu et al. / Chinese Chemical Letters 25 (2014) 90–92
Table 3
provided a useful method for the preparation of diverse 3-
Palladium-catalyzed decarboxylative acylation of a
-oxocarboxylic acids 1a with 2.a
acylindoles in high yields from readily accessible reactants under
mild reaction conditions. This protocol offers several advantages
including use of readily accessible carboxylic acids, a simple
procedure, generality, which enhances its potential in future
applications.
Acknowledgment
Entry
2
R2
3
Yield (%)b
We are grateful for the financial support from the State Ethnic
Affairs Commission (No. 12YNZ005).
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
H
3aa
3ab
3ac
3ad
3ae
3af
82
84
81
75
62
88
7-Me
5-OMe
5-F
5-NO2
5,6-di-Me
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In summary, we have developed a convenient and general
method for acylation of free (N–H) indoles via a palladium-
catalyzed decarboxylative cross-coupling reaction. This process