Palladium-catalyzed cyclization of o-alkynyltrifluoroacetanilides followed by isocyanide insertion: Synthesis of 2-substituted 1H-indole-3-carboxamides

Article abstract of DOI:10.1039/c2cc33435f

A base-controlled synthesis of 2-substituted secondary and tertiary 1H-indole-3-carboxamides through PdCl₂-catalyzed cyclization of o-alkynyltrifluoroacetanilides followed by isocyanide insertion has been developed. The reaction proceeds smoothly at ambient temperature using O ₂ in air as the sole oxidant of the palladium catalyst.

Full text of DOI:10.1039/c2cc33435f

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COMMUNICATION
Palladium-catalyzed cyclization of o-alkynyltrifluoroacetanilides
followed by isocyanide insertion: synthesis of 2-substituted
1H-indole-3-carboxamidesw
Ziwei Hu, Dongdong Liang, Jiaji Zhao, Jinbo Huang and Qiang Zhu*
Received 12th May 2012, Accepted 30th May 2012
DOI: 10.1039/c2cc33435f
A base-controlled synthesis of 2-substituted secondary and
tertiary 1H-indole-3-carboxamides through PdCl2-catalyzed
cyclization of o-alkynyltrifluoroacetanilides followed by isocyanide
insertion has been developed. The reaction proceeds smoothly at
ambient temperature using O2 in air as the sole oxidant of the
palladium catalyst.
The indole nucleus is present in a wide range of natural
products and synthetic pharmaceutical agents with varied
bioactivities.1 Consequently, substantial synthetic methods
have been developed for the preparation of indole derivatives
since more than a century ago. Among them, palladium-
catalyzed cyclization of o-alkynylanilides followed by trapping
Scheme 1 Synthesis of C3 carbonylated indoles by palladium-catalyzed
of the resulting s-indolypalladium intermediate with various
nucleophiles has emerged as a powerful and versatile strategy
toward 2,3-disubstituted indoles.2,3 When the reaction is
performed in a carbon monoxide atmosphere, carbonylation
of the indole scaffold at the C3 position will take place through
an s-indolypalladium intermediate upon CO insertion.4 For
example, 2-substitued methyl indole-3-carboxylates were
formed via PdCl2-catalyzed cyclization of o-alkynylmesylanilides
in the presence of CO in methanol by using CuCl2 as a
stoichiometric oxidant (eqn (1), Scheme 1).5 A similar three-
component synthesis of 2-substituted 3-acylindoles was developed
starting from o-alkynyltrifluoroacetanilides, aryl iodides and
carbon monoxide (eqn (2), Scheme 1).6
cyclization of o-alkynylanilides.
cyclization of o-alkynylanilide. The resulting 3-indoimidoyl-
palladium intermediate can be trapped by water and acetate
to produce 2-substituted secondary and tertiary 1H-indole-
3-carboxamides upon tautomerization, respectively (eqn (3),
Scheme 1). Very recently, we have developed a novel method
for the preparation of 2-unsubstituted 3-carboxamidated
indoles through Pd-catalyzed sequential C–H activation and
isocyanide insertion of indoles.11 Herein, we would like to
report an unprecedented and general approach to 2-substituted
secondary and tertiary 1H-indole-3-carboxamides through
Pd-catalyzed cyclization of o-alkynyltrifluoroacetanilides
followed by isocyanide insertion. The current method not only
widens the application of isocyanides in palladium-catalyzed
reactions, but also provides an efficient method for the syn-
thesis of 2-substituted indole-3-carboxamides,12 which exist in
many biologically active molecules.13
Isocyanides have been recognized as versatile building
blocks in Lewis or Brønsted acid-promoted reactions, including
Passerini and Ugi mutlicomponent reactions, complex amide
synthesis and others.7 However, their application in transition
metal-catalyzed imination,8 carboxyamidation9 and amidination10
reactions, acting as isoelectronic equivalents of CO, is rela-
tively undervalued. It is anticipated that when isocyanide
is present instead of CO, isocyanide will insert into the
3-indolylpalladium intermediate following palladium-catalyzed
To test the hypothesis, we commenced the investigation in
DMSO with o-(phenylethynyl)trifluoroacetanilide 1a and tert-
butylisocyanide 2a (1.5 equiv.) as model substrates catalyzed
by PdCl2 (5 mol%) in the presence of K2CO3 (1.0 equiv.) in a
balloon pressure of O2. The expected product, N-tert-butyl-
2-phenyl-1H-indole-3-carboxamide 3aa, was obtained success-
fully in 68% yield at ambient temperature (entry 1, Table 1). It
was notable that the trifluoroacetyl protecting group was
removed simultaneously during the reaction. The carbonyl
oxygen was believed to originate from moisture in the reaction
system, which was confirmed by adding 10 equivalents of H2O18
to the reaction (see ESI for detailsw). Other palladium sources,
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. See
DOI: 10.1039/c2cc33435f
c
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Chem. Commun., 2012, 48, 7371–7373 7371

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Table 1 Optimization of the reaction conditionsa
Table 2 The scope of substrate 1a
Yieldb (%)
Time/ Yield
h
Entry Substrate 1
Product 3
(%)
3aa
4a
Entry Pd source
Base
Oxidant Temp./1C
1
2
3
4
5
6
7
8
1b, R1 = 4-Me, R2 = Ph
1c, R1 = 4-CF3, R2 = Ph
1d, R1 = 4-F, R2 = Ph
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
12
12
12
12
12
48
12
12
12
12
6
12
16
12
16
12
12
24
88
77
88
85
84
69
94
91
82
76b
68b
76
86
79
76
75
88
87
1
2
3
PdCl2
Pd(OAc)2
Pd(TFA)2
K2CO3
K2CO3
K2CO3
O2
O2
O2
O2
O2
O2
Air
—
rt
68
58
51
54
75
N.R.e
67
trace
92
61
—
—
—
—
—
—
—
—
—
—
—
75
86
—
60
60
60
60
rt
1e, R1 = 4-Cl, R2 = Ph
4
Pd(PPh3)2Cl2 K2CO3
1f, R1 = 4-Br, R2 = Ph
5
6
Pd(acac)2
—
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3 Air
Cs2CO3 Air
K3PO4
KOAc
KOAc
—
1g, R1 = 4,6-diMe, R2 = Ph
1h, R1 = H, R2 = 4-CH3C6H4
1i, R1 = H, R2 = 4-MeOC6H4
7
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
rt
rt
8c
9
9
1j, R1 = H, R2 = 4-AcNHC6H4 3ja
rt
rt
10
11
12
13
14
15
16
17
18
1k, R1 = H, R2 = 4-AcC6H4
1l, R1 = H, R2 = 4-MeO2CC6H4 3la
3ka
10
11
12
13d
14
Air
Air
Air
Air
rt
rt
rt
rt
48
—
—
N.R.e
1m, R1 = H, R2 = 4-ClC6H4
1n, R1 = H, R2 = 4-BrC6H4
1o, R1 = H, R2 = 2-ClC6H4
1p, R1 = H, R2 = 3-ClC6H4
1q, R1 = H, R2 = 2-thienyl
1r, R1 = H, R2 = n-butyl
1s, R1 = H, R2 = cyclohexyl
3ma
3na
3oa
3pa
3qa
3ra
3sa
a
All the reactions were carried out at 0.2 mmol scale of 1a, tert-
butylisocyanide 2a (0.3 mmol), palladium catalyst (5 mol%), base
b
(1.0 equiv.) in DMSO (1 mL), in O2 (1 atm) or air for 12 h. Yields of
c
isolated 3aa and 4a. In Ar. 1.2 equiv. of KOAc. N.R. = no
d
e
a
Conditions: 1 (0.2 mmol), tert-butylisonitrile 2a (0.3 mmol), PdCl2
(5 mol%), Na2CO3 (1.0 equiv.), in DMSO (1 mL) under air, rt, yield of
reaction.
b
isolated 3. Reaction conducted at 50 1C.
including Pd(OAc)2, Pd(TFA)2, Pd(PPh3)2Cl2 and Pd(acac)2,
were also effective at elevated temperature (entries 2–5).
A control experiment in the absence of a palladium catalyst
resulted in no product formation at all (entry 6). The reaction
proceeded equally well in air, but it was completely shut down
in an argon atmosphere. To our delight, the yield of 3aa was
improved significantly to 92% by simply changing the base to
Na2CO3 (entry 9). Screening of other bases led to an interesting
finding that N-acetyl-N-tert-butyl-2-phenyl-1H-indole-3-
carboxamide 4a was isolated as a sole product in 75% yield
when KOAc was employed (entries 10–12). The yield of 4a was
improved further to 86% with 1.2 equiv. of KOAc. Neither 3aa
nor 4a were detected when a base additive was absent (entry 14).
Under the optimized conditions, the generality of the reaction
for different o-alkynyltrifluoroacetanilides was investigated first
(Table 2). Gratifyingly, substrates with electron-donating (CH3)
or withdrawing (CF3, F, Cl, Br) substituents on the aniline ring
produced the corresponding products in good to excellent yields
(entries 1–6). A variety of functional groups on the arylalkynyl
moiety, including OMe, NHAc, COCH3, COOMe, Cl and Br,
were compatible with the reaction conditions (entries 7–15).
These functionalities provide handles for further elaboration
of the products. In general, electron-donating substituents on
the aryl ring are more beneficial to the reaction than electron-
withdrawing ones, which need higher reaction temperatures to
drive the reaction to completion. This tendency indicates
that the electron density on the acetylene moiety is essential
for complexation with the palladium catalyst. In addition,
2-heteroaromatic and 2-alkyl substituted N-1H-indole-3-
carboxamides 3qa–3sa were also obtained by following this
methodology.
Table 3 The scope of substrate 2a
Entry
Substrate 2
Product 3
Time/h
Yield (%)
1
2
3
4
5
2b, R = n-butyl
3ab
3ac
3ad
3ae
3af
24
24
30
12
12
51
63
2c, R = isopropyl
2d, R = cyclohexyl
2e, R = 2,6-diMePh
2f, R = adamantyl
61
57b
98c,d
a
Conditions: 1a (0.2 mmol), isocyanide 2 (0.6 mmol), PdCl2 (10 mol%),
Cs2CO3 (1.0 equiv.), in DMSO (1 mL) under air, rt, yield of isolated 3.
b
c
50 1C. PdCl2 (5 mol%), isocyanide 2f (1.5 equiv.) was applied.
Na2CO3 (1.0 equiv.) was employed instead of Cs2CO3.
d
were also applied in this process under modified conditions
(Table 3). However, the corresponding N-1H-indole-
3-carboxamides 3ab–3ae were formed in lower yields than
when employing tert-butylisocyanide as a substrate. It is
notable that sterically hindered 1-adamantylisocyanide was a
feasible coupling partner, leading to the corresponding amide
3ae almost quantitatively.
Finally, some N-acetyl-N-tert-butyl-2-aryl-1H-indole-3-
carboxamides were prepared by applying KOAc as a base
(Table 4). No significant electronic effect on the aniline ring
was observed (4b vs. 4c), while an electron-donating OMe (4e)
on another aryl ring favored the reaction much more than
electron-withdrawing COOMe (4f) and Br (4g).
Isocyanides other than tert-butylisocyanide 2a, such as n-butyl,
isopropyl, cyclohexyl and 2,6-dimethylphenyl isocyanides,
A plausible mechanism involved in the present process is
illustrated in Scheme 2. Initial coordination of isocyanide
c
7372 Chem. Commun., 2012, 48, 7371–7373
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Table 4 Synthesis of tertiary 1H-indole-3-carboxamides 4a
2011, 18, 615; (c) R. Vicente, Org. Biomol. Chem., 2011, 9,
6469; (d) S. Cacchi and G. Fabrizi, Chem. Rev., 2011, 111,
PR215.
3 For selected examples of other transition-metal-catalyzed indole
syntheses, see: (a) M. Nakamura, L. Ilies, S. Otsubo and
E. Nakamura, Angew. Chem., Int. Ed., 2006, 45, 944; (b) Y. Oda,
N. Matsuyama, K. Hirano, T. Satoh and M. Miura, Synthesis,
2012, 1515; (c) N. T. Patil and Y. Yamamoto, Chem. Rev., 2008,
108, 3395.
Entry Substrate 1
Product 4 Time/h Yield (%)
4 A. Brennfuhrer, H. Neumann and M. Beller, Angew. Chem., Int. Ed.,
2009, 48, 4114.
1
2
3
4
5
6
1b, R1 = 4-Me, R2 = H
4b
4c
4d
4e
12
12
18
12
16
18
84
81
73
93
56b
55
1c, R1 = 4-CF3, R2 = H
1f, R1 = 4-Br, R2 = H
1i, R1 = H, R2 = OMe
5 (a) Y. Kondo, F. Shiga, N. Murata, T. Sakamoto and
H. Yamanaka, Tetrahedron, 1994, 50, 11803; (b) Y. Kondo,
T. Sakamoto and H. Yamanaka, Heterocycles, 1989, 29, 1013;
(c) B. Gabriele, L. Veltri, R. Mancuso, G. Salerno and M. Costa,
Eur. J. Org. Chem., 2012, 2549.
6 (a) S. Cacchi, G. Fabrizi and L. M. Parisi, Synthesis, 2004, 1889;
(b) A. Arcadi, S. Cacchi, V. Carnicelli and F. Marinelli, Tetrahedron,
1994, 50, 437; (c) S. V. Damle, D. Semoon and P. H. Lee, J. Org.
Chem., 2003, 68, 7085; (d) B. L. Flynn, E. Hamel and M. K. Jung,
J. Med. Chem., 2002, 45, 2670; (e) S. Cacchi, G. Fabrizi, P. Pace
and F. Marinelli, Synlett, 1999, 620; (f) G. Battistuzzi, S. Cacchi,
G. Fabrizi, F. Marinelli and L. M. Parisi, Org. Lett., 2002, 4,
1355.
1l, R1 = H, R2 = COOMe 4f
1n, R1 = H, R2 = Br
4g
a
Conditions: 1 (0.2 mmol), tert-butylisocyanide 2a (0.3 mmol), PdCl2
(5 mol%), KOAc (1.2 equiv.), DMSO (1 mL), air, rt, yield of isolated
b
4. Reaction conducted at 50 1C.
7 For recent reviews on isocyanide in organic synthesis, see:
(a) R. M. Wilson, J. L. Stockdill, X. Wu, X. Li, P. A. Vadola,
P. K. Park, P. Wang and S. J. Danishefsky, Angew. Chem., Int. Ed.,
2012, 51, 2834; (b) M. Tobisu and N. Chatani, Chem. Lett., 2011,
40, 330; (c) A. V. Lygin and A. de Meijere, Angew. Chem., Int. Ed.,
2010, 49, 9094; (d) A. V. Gulevich, A. G. Zhdanko, R. V. A. Orru
and V. G. Nenajdenko, Chem. Rev., 2010, 110, 5235.
8 M. Tobisu, S. Imoto, S. Ito and N. Chatani, J. Org. Chem., 2010,
75, 4835.
9 (a) H. Jiang, B. Liu, Y. Li, A. Wang and H. Huang, Org. Lett.,
2011, 13, 1028; (b) F. Zhou, K. Ding and Q. Cai, Chem.–Eur. J.,
2011, 17, 12268.
10 (a) C. G. Saluste, R. J. Whitby and M. Furber, Angew. Chem.,
Int. Ed., 2000, 39, 4156; (b) G. V. Baelen, S. Kuijer, L. Rycek,
S. Sergeyev, E. Janssen, F. J. J. de Kanter, B. U. W. Maes,
E. Ruijter and R. V. A. Orru, Chem.–Eur. J., 2011, 17, 15039;
(c) J. Albert, L. D’Andrea, J. Granell, J. Zafrilla, M. Font-Bardia
and X. Solans, J. Organomet. Chem., 2007, 692, 4895; (d) T. Miura,
Y. Nishida, M. Morimoto, M. Yamauchi and M. Murakami,
Org. Lett., 2011, 13, 1429; (e) Y. Wang, H. Wang, J. Peng and
Q. Zhu, Org. Lett., 2011, 13, 4604; (f) T. Vlaar, E. Ruijter,
A. Znabet, E. Janssen, F. J. J. de Kanter, B. U. W. Maes and
R. V. A. Orru, Org. Lett., 2011, 13, 6496; (g) J. Vicente, I. Saura-
Llamas and J.-A. Garcıa-Lopez, Organometallics, 2009, 28, 448;
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48, 3836.
Scheme 2 Proposed reaction mechanism.
ligated Pd(II) with carbon–carbon triple bond triggers intra-
molecular nucleophilic attack of the nitrogen anion across the
triple bond. Isocyanide insertion to the resulting s-indolyl-
palladium intermediate B yields the imidoylpalladium inter-
mediate C followed by reductive elimination. The unstable
imidoylchloride intermediate D undergoes nucleophilic sub-
stitution by water or acetate to give corresponding final
products 3 or 4 via intermediate E upon tautomerization.
Oxidation of concurrently formed Pd(0) by air regenrates the
active Pd(II) species. An alternative direct ligand exchange of
Cl with water or acetate in the intermediate C is also possible.
In summary, we have developed an efficient method for the
construction of 2-substituted 1H-indole-3-carboxamides via
PdCl2-catalyzed cyclization of o-alkynyltrifluoroacetanilides
followed by isocyanide insertion. A variety of 2-substituted
secondary and tertiary 1H-indole-3-carboxamides are formed
selectively by the choice of bases. The reaction proceeds
smoothly at ambient temperature using dioxygen in air as
the sole oxidant for the palladium catalyst.
11 J. Peng, L. Liu, Z. Hu, J. Huang and Q. Zhu, Chem. Commun.,
2012, 48, 3772.
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A. C. Corsioco, A. Corsaro and D. Delmonte, Tetrahedron,
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Chem., 2004, 2, 1070.
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J. L. Fraser, F. C. Galvin, D. R. Hannah, A. F. Haughan,
K. Jenkins, S. R. Mack, W. R. Pitt, A. J. Ratcliffe,
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Notes and references
1 (a) R. J. Sundberg, Indoles, Academic Press, San Diego, 1996;
(b) R. J. Sundberg, in Comprehensive heterocyclic chemistry,
ed. A. R. Katrizky and C. W. Ress, Pergamon, Oxford, 2nd edn,
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2 For recent reviews on palladium-catalyzed indole synthesis:
(a) S. Cacchi, G. Fabrizi and A. Goggiamani, Org. Biomol. Chem.,
2011, 9, 641; (b) S. A. Patil, R. Patil and D. D. Miller, Curr. Med. Chem.,
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 7371–7373 7373