the reaction. An elegant new protocol of generating a “CN”
unit was developed by Chang and his co-workers using
DMF and ammonia7a or ammonium iodide7b as “CN”
source via palladium-catalyzed or copper-mediated reac-
tions. Recently, Jiao et al. demonstrated a novel Pd- cata-
lyzed direct cyanation of indoles and benzofurans through
CÀH functionalization employing DMF as both reagent
and solvent.8 Alternatively, DMSO could also be applied in
the cyanation reaction instead of DMF.9
N-(2-pyrimidyl)indole14 (1a) with tert-butyl isocyanide in
the presence of Pd(OAc)2 (5 mol %) in toluene using Cu-
(OAc)2 as oxidant. Intriguingly, the 2-cyano substituted
indole 2a was produced in 12% yield after reacting for 24 h
at 120 °C under air (entry 1, Table S1; see the Supporting
Information). An extensive screening concerning solvents,
copper resources, atmosphere and temperature revealed that
the use of Cu(TFA)2 as oxidant in DMF at 130 °C under
atmospheric oxygen turned out to be the best choice and
resulted in 92% yield. Decreased yield could be afforded
without using palladium catalyst (entry 13), and trace
amount of 2-cyanoindole product was detected in the absence
of Cu(TFA)2 (entry 14) or t-BuNC (entry 15), which in-
dicated that both the Cu(II) and isocyanide were crucial to
proceed this cyanation reaction.
Scheme 1. Different Sources of “CN” in Cyanation Reactions
With the optimized reaction conditions in hand, we then
extended the reaction with a range of substrates. As
illustrated in Scheme 2, this reaction was compatible with
functionalized N-pyrimidyl substituted indoles bearing
substitutionsatC3-,C5-orC6-position(2bÀ2e,Scheme2),
and afforded 2-cyanoindoles in good to excellent yields
with high regioselectivity. N-Pyrimidyl indoles containing
both electron-donating (2b and 2e) and electron-withdrawing
groups (2c and 2d) afforded 2-cyanated products predomi-
nately. Indoles with electron-donating groups usually gave
better yields than those with electron-withdrawing groups.
For substrate having a bromo substitution, the yield turned
out to be lower (2d), the reason may be due to the competitive
reactions at the reactive bromine. For those substrates with
phenyl group substituted at pyrimidine ring, 2-cyanoindoles
could be furnished in good yields (2f and 2g). It should be
noted that 1-(4-phenylpyrimidin-2-yl)-1H-indole (1f), which
has two potential cyanation positions, gave exclusive product
Isonitriles are uniquely versatile intermediates in organic
synthesis because of their structural and reactive properties
and have proven themselves to be powerful C1 building
blocks toward a variety of desirable molecules.10 Sustain-
ability contribution of isonitriles has been widely recognized
in the multicomponent Passerini and Ugi reactions.10c,11
Recently, several examples have been reported via metal-
catalyzed intermolecular isonitrile insertion reaction by
means of CÀH bond activation.12 However, employing
readily available isonitrile as a successful source of “CN”
unit has not yet been disclosed. Herein, we report a novel
palladium-catalyzed regioselective cyanation of heteroarenes
through CÀH bond functionalization using tert-butyl iso-
cyanide as “CN” source (Scheme 1). To our knowledge, this
approach represents the first example for highly regioselec-
tive CÀH cyanation using isonitrile as crucial “CN” source.
To determine the feasibility of chelation effect of
a pyrimidyl group in the CÀH bond cyanation reac-
tion,13 we initially examined the reaction by exploring
Scheme 2. 2-Cyanation of Substituted Indolesa,b
(7) (a) Kim, J.; Chang, S. J. Am. Chem. Soc. 2010, 132, 10272.
(b) Kim, J.; Choi, J.; Shin, K.; Chang, S. J. Am. Chem. Soc. 2012, 134, 2528.
(8) Ding, S.; Jiao, N. J. Am. Chem. Soc. 2011, 133, 12374.
(9) Ren, X.; Chen, J.; Chen, F.; Cheng, J. Chem. Commun. 2011, 47,
6725.
(10) For reviews, see: (a) Lygin, A. V.; de Meijere, A. Angew. Chem.,
Int. Ed. 2010, 49, 9094. (b) Tobisu, M.; Chatani, N. Chem. Lett. 2011, 40,
330. (c) Wilson, R. M.; Stockdill, J. L.; Wu, X.; Li, X.; Vadola, P. A.;
Park, P. K.; Wang, P.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2012,
51, 2834.
(11) For recent reviews of MCRs involving isonitriles, see: (a) El
Kaim, L.; Grimaud, L. Tetrahedron 2009, 65, 2153. (b) Gulevich, A. V.;
Zhdanko, A. G.; Orru, R. V. A.; Nenajdenko, V. G. Chem. Rev. 2010,
110, 5235. (c) Sadjadi, S.; Heravi, M. M. Tetrahedron 2011, 67, 2707.
(12) (a) Tobisu, M.; Imoto, S.; Ito, S.; Chatani, N. J. Org. Chem.
2010, 75, 4835. (b) Wang, Y.; Wang, H.; Peng, J.; Zhu, Q. Org. Lett.
2011, 13, 4604. (c) Zhu, C.; Xie, W.; Falck, J. R. Chem.;Eur. J. 2011, 17,
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(13) (a) Song, B.; Zheng, X.; Mo, J.; Xu, B. Adv. Synth. Catal. 2010,
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(c) Zheng, X.; Song, B.; Li, G.; Liu, B.; Deng, H.; Xu, B. Tetrahedron
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a Reaction conditions: 1aÀm (0.3 mmol), t-BuNC (3.0 equiv), Pd-
(OAc)2 (5 mol %), Cu(TFA)2 (3.0 equiv), DMF (1.5 mL) under O2
balloon at 130 °C. b Isolated yield.
B
Org. Lett., Vol. XX, No. XX, XXXX