CHU ET AL.
3 of 4
TABLE 2 Synthesis of 3‐cyanoindoles by palladium(II)‐catalyzed C─H
reaction tube at 130 °C for 2 h. After completion of the reac-
tion, monitored using TLC, the resulting mixture was then
quenched with brine (5 ml). The mixture was extracted with
ethyl acetate (3 × 15 ml), and the combined organic layer was
dried with sodium sulfate. Next, the organic phase was filtered
and evaporated under reduced pressure. The residue was puri-
fied using TLC to afford the product.
activation of indolesa
Entry
Indole 1
Product 2
2a
Time (h)
Yield (%)b
1
2
93
4
| CONCLUSIONS
We have described an efficient method for the trans‐PdCl2
(NH2CH2COOH)2‐catalyzed cyanation at the 3‐position of
indole C─H bond using safe, commercially available and
nontoxic K4[Fe(CN)6] as the cyanide source. Facile and
efficient synthesis of free (N─H)‐3‐cyanoindoles, which are
known to be crucial scaffolds of biologically active com-
pounds, is an advantage of this protocol. Further insight into
the synthetic applications for natural products and bioactive
compounds is under investigation.
2
3
2b
2c
4
6
74
85
4
5
6
2d
2e
2f
5
2
6
85
78
98
ACKNOWLEDGMENTS
This research was financially supported by the National
Natural Science Foundation of China (no. 21363026) and
the Scientific and Technological Landing Project of Higher
Education of Jiangxi Province (no. KJLD13091).
REFERENCES
7
8
2g
2h
18
4
60
78
[1] a) A. J. Kochanowska‐Karamyan, M. T. Hamann, Chem. Rev. 2010, 110,
4489; b) D. Crich, A. Banerjee, Acc. Chem. Res. 2007, 40, 151; c) G. R.
Humphrey, J. T. Kuethe, Chem. Rev. 2006, 106, 2875; d) S. Cacchi,
G. Fabrizi, Chem. Rev. 2005, 105, 2873; e) N. K. Kaushik, N. Kaushik,
P. Attri, N. Kumar, C. H. Kim, A. K. Verma, E. H. Choi, Molecules 2013,
18, 6620; f) A. Ndagijimana, X. Wang, G. Pan, F. Zhang, H. Feng,
O. Olaleye, Fitoterapia 2013, 86, 35; g) M. Ishikura, T. Abe, T. Choshib,
S. Hibinob, Nat. Prod. Rep. 2013, 30, 694.
[2] a) J. B. Chen, B. Liu, D. F. Liu, S. Liu, J. Cheng, Adv. Synth. Catal. 2012,
354, 2438; b) J. L. Peng, L. Y. Liu, Z. W. Hu, Z. B. Huang, Q. Zhu, Chem.
Commun. 2012, 48, 3772; c) K. Ebrahim, H. Hamed, D. Ali, Tetrahedron
2013, 69, 5193.
9
2i
24
24
24
trace
trace
trace
[3] a) M. T. G. Dhar, Z. Shen, H. H. Gu, P. Chen, D. Norris, S. H. Watterson,
S. K. Ballentine, C. A. Fleener, K. A. Rouleau, J. C. Barrish, R. Townsend,
D. L. Hollenbaugh, E. J. Iwanowicz, Bioorg. Med. Chem. Lett. 2003, 13,
3557; b) B. Jiang, X. Gu, Bioorg. Med. Chem. 2000, 8, 363; c) D. Kumar,
M. K. Narayanam, K. H. Chang, K. Shah, Chem. Biol. Drug Des. 2011,
77, 182; d) G. Zedda, G. Simbula, M. Begala, M. Pibiri, C. Floris, M. Casu,
L. Casu, G. Tocco, Arch. Pharm. 2012, 345, 195; e) S. Wu, L. Wang,
W. Guo, X. Liu, J. Liu, X. Wei, B. Fang, J. Med. Chem. 2011, 54, 2668.
10
11
2j
2k
aReaction conditions: indole 1 (0.5 mmol), K4[Fe(CN)6] (0.25 mmol), trans‐
PdCl2(NH2CH2COOH)2 (12 mol%), Cu(OAc)2 (3.0 equiv.), DMSO (5 ml), under
air, 130 °C.
[4] a) R. C. Larock, Comprehensive Organic Transformations: A Guide to Func-
tional Group Preparations, Wiley‐VCH, New York 1989; b) Z. Rappoport,
Chemistry of the Cyano Group, John Wiley, London 1970 121;
c) C. W. Liskey, X. Liao, J. F. Hartwig, J. Am. Chem. Soc. 2010, 132, 11389.
bIsolated yield.
[5] a) A. Khorshidi, Chin. Chem. Lett. 2012, 23, 903; b) Y. Yang, Y. Zhang,
J. Wang, Org. Lett. 2011, 13, 5608; c) K. Yoshida, J. Chem. Soc., Chem.
Commun. 1978, 1108; d) G. Yan, C. Kuang, Y. Zhang, J. Wang, Org. Lett.
2010, 12, 1052; e) L. Zhang, Q. Wen, J. Jin, C. Wang, P. Lu, Y. Wang,
Tetrahedron 2013, 69, 4236; f) H. Togo, S. Ushijima, M. Miyamoto,
Tetrahedron 2012, 68, 4588; g) S. Ushijima, H. Togo, Synlett 2010, 1067;
h) P. Anbarasan, T. Schareina, M. Beller, Chem. Soc. Rev. 2011, 40, 5049;
i) G. P. Ellis, T. M. Romnry‐Alexander, Chem. Rev. 1987, 87, 779;
j) G. Yan, J. Yu, L. Zhang, Chin. J. Org. Chem. 2012, 32, 294; k)
P. Anbarasan, H. Neumann, M. Beller, Angew. Chem. Int. Ed. 2011, 50,
3.2 | General procedure for synthesis of 3‐cyanoindoles
Under air, a mixture of 2‐methyl‐1H‐indole (1a; 0.0663 g,
0.5 mmol), K4[Fe(CN)6] (0.1071 g, 0.25 mmol), Cu(OAc)2
(0.2909 g, 1.5 mmol), trans‐PdCl2(NH2CH2COOH)2
(0.0198 g, 0.06 mmol) and DMSO (5 ml) was stirred in a