Direct carboxamidation of indoles by palladium-catalyzed C-H activation and isocyanide insertion

Article abstract of DOI:10.1039/c2cc30351e

A selective C3 carboxamidation of indoles including free (N-H) ones by palladium-catalyzed sequential C-H activation-isocyanide insertion has been developed. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc30351e

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COMMUNICATION
Direct carboxamidation of indoles by palladium-catalyzed
C–H activation and isocyanide insertionw
Jiangling Peng, Lanying Liu, Ziwei Hu, Jinbo Huang and Qiang Zhu*
Received 16th January 2012, Accepted 17th February 2012
DOI: 10.1039/c2cc30351e
A selective C3 carboxamidation of indoles including free (N–H)
ones by palladium-catalyzed sequential C–H activation–isocyanide
insertion has been developed.
the synthesis of C3 carboxamidated indoles under mild
conditions.
We initiated the study by using N-methylindole 1a and tert-
butylisocyanide 2a (1.2 equiv.) as the substrates. After extensive
screening of reaction parameters (see ESIw for details), the
optimal reaction conditions involving Pd(OAc)2 (10 mol%),
Cu(OAc)2 (1 equiv.), TFA (1.2 equiv.), and H2O (5 equiv.) in
THF (1 mL) at 70 1C were identified (Table 1). The desired
product N-tert-butyl-1-methyl-1H-indole-3-carboxamide 3a
was obtained in excellent yield (94%). Removal of Pd(OAc)2
from the reaction system resulted in complete recovery of the
starting N-methylindole (entry 2, Table 1). Pd(TFA)2 was also
an effective catalyst in this reaction, leading to 3a in 89% yield
(entry 3). Other oxidants such as O2 and AgOAc were much
less efficient, while CuO hampered the reaction completely
(entries 4–6). The catalyst loading can be reduced to 5 mol%
without significant loss of the yield (entry 7). It was intriguing
that a different product, N-acetyl-N-tert-butyl-1-methyl-1H-
indole-3-carboxamide 4a, was obtained in 82% yield at elevated
temperature (90 1C) when TFA and H2O were absent. In
this case, the formation of 3a was significantly suppressed
(entry 8). It is obvious that TFA plays a vital role in directing
the product formation. The structures of 3a and 4a were
Indole and its derivatives are a very important class of
molecules existing widely in natural products and synthetic
pharmaceutical agents with a broad range of bioactivities.
Therefore, continuous efforts have been paid to their synthesis
since more than a century ago, by strategies of either indole
scaffold construction or direct functionalization of existing
indoles.1 Among numerous methods developed, transition-
metal-catalyzed C–H activation2 provides complementary and
advantageous approaches to functionalized indoles, including
regioselective arylation,3 alkenylation,4 alkylation,5 cyanation,6
carbonylation,7 borylation,8 and others.9 To the best of our
knowledge, direct carboxamidation of indoles via transition-
metal-catalyzed C–H activation has not been realized. Indole-
2(3)-carboxamides exhibit remarkable bioactivities10 and also
they serve as useful building blocks for the synthesis of more
complicated indole-containing molecules.11 However, methods
toward their synthesis limit to transformation of prefunctionalized
indoles12 and Friedel–Crafts reaction of indoles with chlorosulfonyl
isocyanate, providing primary indole-3-carboxamides.13
Recently, Jiang and co-workers reported a novel method
for synthesis of aryl and vinyl amides from the corresponding
bromides and isocyanides under palladium catalysis.14 However,
the generation of hazardous halogen-containing waste makes
environmentally benign approaches more attractive. The
synthetic community has witnessed the prosperity in the
research area of transition-metal-catalyzed C–H activation in
the past decade. Among the countless examples of C–H
functionalization, direct carboxamidation of C–H bonds is
still scarce in the literature.15 We herein report a first example
of palladium-catalyzed carboxamidation of indoles including
free (N–H) ones via C–H activation followed by isocyanide
insertion,16 providing a general and efficient method for
Table 1 Optimization of reaction conditions
Yieldb (%)
Entry
Variation from the ‘‘standard conditions’’a
3a
4a
1
None
Without Pd(OAc)2
94
n.d.
89
10
37
n.d.
89
4
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
82
2c
3
Pd(TFA)2, instead of Pd(OAc)2
O2, instead of Cu(OAc)2
AgOAc, instead of Cu(OAc)2
CuO, instead of Cu(OAc)2
Pd(OAc)2 (5 mol%)
4d
5
6
7
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of
Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan
Avenue, Guangzhou 510530, China. E-mail: zhu_qiang@gibh.ac.cn;
Fax: +86 20-3201-5299; Tel: +86 20-3201-5287
w Electronic supplementary information (ESI) available: General
procedures, spectral data and other supplementary information.
CCDC 858032 and 862590. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2cc30351e
8
Without TFA and H2O
a
Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), Pd(OAc)2
(10 mol%), Cu(OAc)2 (1.0 equiv.), TFA (1.2 equiv.), H2O (5 equiv.),
b
c
d
THF (1 mL), 70 1C, 1.5 h. Isolated yield. 30 h. 90 1C.
c
3772 Chem. Commun., 2012, 48, 3772–3774
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Table 2 Synthesis of N-alkyl(aryl)-1H-indole-3-carboxamidesa
Fig. 1 Reactions of C3 or C2 substituted indoles under the standard
a
conditions. AcOH as the solvent, without TFA, 50 1C.
Entry R1
R2
R3
Time/h Product Yield (%)
Table 3 Synthesis of N-acetyl-N-alkyl(aryl)-1H-indole-3-carboxamidesa
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Et
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
1
1.5
1
1
1.5
2
2
2
4
1.5
2
8
8
2
2
1
1
1
1
3b
3c
3d
3e
3f
3g
3h
3i
92
85
88
86
72
94
92
76
66
75
92
95
90
92
78
96
94
83
81
88
65
61
58
95
5-Me
5-OMe
5-OBn
5-OH
5-F
5-Cl
5-Br
5-I
5-CN
5-CHO
5-CO2Me
5-NO2
6-Cl
6-Br
7-Me
7-Et
H
9
3j
3k
3l
10
11b
12b
13b
14
15
16
17
18
19
20
21c
22c
23d
24
Product yield (%)
R1
R2
R3
Time/h
4
3
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
3x
3y
Entry
1
2
3
4
H
H
H
H
H
H
H
H
Me
3
3
8
3
4b, 78
4c, 77
4d, 60
4aa, 45
3b, 12
3c, 13
3d, 8
5-Me
5-OMe
H
3aa, 13
a
Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol), Pd(OAc)2
(10 mol%), Cu(OAc)2 (1.0 equiv.), THF (1.0 mL), 90 1C, 3–8 h, yield
of isolated 4 and 3.
H
H
H
H
H
H
Allyl t-Bu
Bn
H
H
H
H
t-Bu
i-Pr
Cy
2,6-diMePh
1-Ad
1.5
8
8
3
2
and 65% yield, respectively. It is notable that only the
secondary amides 3 are isolated in all of the cases except for
3x, where 17% of the tertiary amide 4x is obtained (entry 23).
Part of the indole substrates is explored under the acid- and
water-free conditions, where tertiary N-acetyl-N-substituted-
1H-indole-3-carboxamides 4 are formed as the major products
(Table 3). Again, free (N–H) indoles and indoles substituted
with Me, and OMe at the C5 position are compatible with the
reaction conditions, leading to the corresponding tertiary
carboxamidation products 4b, 4c, and 4d in 78%, 77%, and
60% yield, respectively (entries 1–3). 2-Methylindole is also
applicable to the reaction, albeit resulting in lower yield (45%)
and higher by-product ratio (13 : 45, entry 4).
a
Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), Pd(OAc)2
(5 mol%), Cu(OAc)2 (1.0 equiv.), TFA (1.2 equiv.), THF (1.0 mL),
b
70 1C, 1–8 h, yield of isolated 3. 2 (1.5 equiv.), Pd(OAc)2 (10 mol%).
c
d
Cu(TFA)2 as oxidant. 50 1C, and 17% of 4x was isolated.
unambiguously confirmed by X-ray diffraction analysis (see
ESIw for details).
With the optimal reaction conditions in hand, the scope of
indoles was investigated first (Table 2). To our delight, free
(N–H) indoles bearing either electron-donating or electron-
withdrawing substituents at different positions are compatible
with the reaction conditions, producing the corresponding
products in good to excellent yields (entries 1–17). For strong
electron-withdrawing group substituted indoles, increasing the
catalyst loading to 10 mol% is required for complete conversion
of the starting indoles (entries 11–13). It is noteworthy that a
variety of functional groups, such as OH, Br, I, CHO, CN,
COOMe, and NO2, are well tolerable, providing opportunities
for further elaboration of the carboxamidated indoles. Other
substrates of N-alkyl substituted indoles besides 1a are also
reactive (entries 18–20), while electron-withdrawing group
protected indoles remain intact even at elevated temperatures.
Other alkyl and aryl isocyanides are also tested. Carboxamidation
of indoles with isopropylisocyanide, cyclohexylisocyanide, or
2,6-dimethylphenylisocyanide produces the corresponding
products in relatively lower yields than tert-butylisocyanide
(entries 21–23). Impressively, sterically hindered 1-adamantyl-
isocyanide reacts with indoles in 95% yield. When the C3 of
indole is blocked with a methyl group, carboxamidation
occurs at C2 (Fig. 1). C2 methyl and phenyl substituted
indoles also react with 2a, furnishing 3aa and 3ab in 88%
To gain insight into the reaction, the tertiary carboxamide 4b
and N-tert-butyl-1H-indole-3-carbaldimine 517 were subjected
to the standard reaction conditions for the synthesis of 3
(1 and 2, Scheme 1). No desired product 3b was formed in
both cases, suggesting that neither 4b nor 5 was the inter-
mediate for 3b. Fully O18 incorporated 3b–O18 was formed in
the presence of H2O18 as additive (3). On the other hand,
stirring of 3b under the identical conditions did not result in
any oxygen exchange between carbonyl oxygen in 3b and
H2O18, indicating that the oxygen atom in 3b originated from
water during the reaction. In contrast, in the reaction of
indoles with 2a in the absence of TFA with H2O18 as additive,
neither of the carbonyl oxygen was O18 labeled, suggesting
that both of the carbonyl oxygen atoms in the tertiary
carboxamide 4b were derived from acetate.
A plausible mechanism for this acid-tuned Pd-catalyzed
carboxamidation of indoles is proposed in Scheme 2. Initial
selective C3 electrophilic palladation of indoles with iso-
cyanide coordinated Pd(II) species yields intermediate A,
followed by migratory insertion of isocyanide. The resulting
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3772–3774 3773

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We are grateful to the National Science Foundation of
China (21072190) for financial support of this work. The
authors also thank Prof. Jinsong Liu for his assistance with
X-ray analysis.
Notes and references
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In conclusion, a novel and selective C3 carboxamidation of
indoles, catalyzed by Pd(OAc)2 with Cu(OAc)2 as the stoichio-
metric oxidant, was developed. The reaction proceeds through
a Pd-catalyzed sequential C–H activation–isocyanide insertion
rather than Lewis acid promoted Friedel–Crafts reaction
followed by oxidation of the imine intermediate. The presence
of acid as additive is crucial for the product formation. In
the presence of TFA and water as additives, diversified
secondary N-alkyl(aryl)-1H-indole-3-carboxamides were formed
in good to excellent yields. Alternatively, when TFA and
water are absent, N-acetyl-N-alkyl-1H-indole-3-carboxamides
were formed as the major products. Free (N–H)-indoles with
diverse functional groups are well tolerable under the reaction
conditions.
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c
3774 Chem. Commun., 2012, 48, 3772–3774
This journal is The Royal Society of Chemistry 2012