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Scheme 2 Ni‐catalyzed chlorination of Aryl C(sp )–H bonds.
China (2015CB856600), the NSFC (2142220D6O, 2I:11400.1201379/0C,62C1C20702822026D)
and the Fundamental Research Funds for the Central Universities
As shown in Table 3, a variety of heterocycles including thiophenes
2p–2r, 3v, 3p), pyridines (2s, 2t, 3u), and benzothiophene (3w), were
all tolerated under identical reaction conditions. Notably, 2‐
Fluoroisonicotinamide 1s, 2‐bromoisonicotinamide 1t, and 2‐
choloroisonicotinamide 1u reacted at less sterically hindered 6‐
position.
(
(
2015XZZX004‐03) is gratefully acknowledged.
Notes and references
Table 3 Ni‐catalyzed halogenation of heteroaryl C(sp )–H bonda
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For reviews, see: (a) A. de Meijere and F. Diederich,
Metal‐Catalyzed Cross‐Coupling Reactions, Wiley‐VCH
Verlag GmbH & Co. KGaA, Weinheim, Germany, 2004; (b)
J. Hassan, M. Se′vignon, C. Gozzi, E. Schulz and M.
Lemaire, Chem. Rev., 2002, 102, 1359; (c) A. F. Littkeand
G. C. Fu, Angew. Chem., Int. Ed., 2002, 41, 4176; (d) J. P.
Corbetand G. Mignani, Chem. Rev., 2006, 106, 2651; (e)
L. X. Yin and J. Liebscher, Chem. Rev., 2007, 107, 133; (f)
X. F.Wu, Chem. Eur. J. 2015, 21, 12252.
P.B.D.De La Mare, Electrophilic Halogenation, Cambridge
University Press, New York, 1976.
H. H. Hodgson, Chem. Rev., 1947, 40, 251.
For a review on an ortho‐lithiation approach, see: V.
Snieckus, Chem. Rev., 1990, 90, 879.
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For selected reviews on transition‐metal‐catalyzed C–H
functionalization, see: (a) O. Daugulis, H.‐Q. Do and D.
Shabashov, Acc. Chem. Res., 2009, 42, 1074; (b) X. Chen,
K. M. Engle, D.‐H. Wang and J.‐Q. Yu, Angew. Chem., Int.
Ed., 2009, 48, 5094; (c) R. Giri, B.‐F. Shi, K. M. Engle, N.
Maugel and J.‐Q. Yu, Chem. Soc. Rev., 2009, 38, 3242;(d)
T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110
,
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147;(e) D. A. Colby, R. G. Bergman and J. A. Ellman,
Chem. Rev., 2010,110, 624; (f) J. Wencel‐Delord, T. Droge,
F. Liu and F. Glorius, Chem. Soc. Rev., 2011, 40, 4740; (g)
P. B. Arockiam, C. Bruneau and P. H. Dixneuf, Chem. Rev.
012, 112, 5879; (h) L. Ackermann, Acc. Chem. Res., 2014,
47, 281; (i) M. Zhang, Y. Zhang, X. Jie, H. Zhao, G. Li and
W. Su, Org. Chem. Front. 2014, , 843; (k) Z. Chen, B.
Wang, J. Zhang, W. Yu, Z. Liu and Y. Zhang, Org. Chem.
Front. 2015, , 1107.
For a recent review on C–H halogenation, see: G. Liao
and B.‐F. Shi, Acta Chim. Sinica, 2015, 73, 1283.
For selected examples of palladium‐catalyzed direct
halogenation of C–H bonds, see: (a) A. R. Dick, K. L. Hull
and M. S. Sanford, J. Am. Chem. Soc., 2004, 126, 2300; (b)
R. Giri, X. Chen and J.‐Q. Yu, Angew. Chem., Int. Ed., 2005,
,
2
To prove both practically and effectiveness of this method, gram‐
scale reaction of 1e was carried out with using as little as 5 mol%
nickel catalyst. The desired product 2e was obtained in 56% isolated
yield (Scheme 3A). It was worth noting that the PIP directing group
can be easily removed under acidic conditions with excellent yields as
shown in Scheme 3B.
1
2
6
7
4
4
, 2112; (c) X. B. Wan, Z. X. Ma, B. J. Li, K. Y. Zhang, S. K.
Cao, S. W. Zhang and Z.‐J. Shi, J. Am. Chem. Soc., 2006,
28, 7416; (d) T. S. Mei, R. Giri, N. Maugel and J.‐Q. Yu,
Angew. Chem., Int. Ed., 2008,47, 5215; (e) X. Zhao, E.
Dimitrijevicand V. M. Dong, J. Am. Chem. Soc., 2009, 131
466; (f) F. Kakiuchi, T. Kochi, H. Mutsutani, N. Kobayashi,
1
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S. Urano, M. Sato, S. Nishiyama and T. Tanabe, J. Am.
Chem. Soc., 2009, 131, 11310;(g) R. B. Bedford, M. F.
Haddow, C. J. Mitchell and R. L. Webster, Angew. Chem.,
Int. Ed., 2011, 50, 5524; (h) B. Song, X. Zheng, J. Moand
B. Xu, Adv. Synth. Catal., 2010, 352, 329; (i) X.‐C. Wang,
Y. Hu, S. Bonacorsi, Y. Hong, R. Burrell and J.‐Q. Yu, J. Am.
Chem. Soc.2013, 135, 10326; (j) D. Sarkar, F. S.
Melkonyan, A. V. Gulevich and V. Gevorgyan, Angew.
Chem., Int. Ed., 2013, 52, 10800; (k) D. Gao, Q. Gu and S.‐
Scheme 3 Gram‐scale reaction of 1e using reduced loading of Ni(OTf)
and removal of the PIP group
2
L. You, ACS Catal., 2014,
J.‐Q. Yu, Science, 2014, 346, 451; (m) Q. Zhang, F. Yang
and Y. Wu, Org. Chem. Front., 2014, , 694.
4, 2741; (l) L. Chu, K.‐J. Xiao and
In summary, we have developed the first nickel‐catalyzed ortho‐C–
H halogenation of (hetero)arenes using simple, inexpensive and
readily available lithium halides (LiX, X=Br, I, Cl) as halogen source. The
reaction features a broad substrate scope, high functional group
tolerance, compatibility with numerous heterocycles, and gram‐scale
synthesis, just providing a practical protocol to prepare a broad range
of functionalized (hetero)aryl halides.
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For selected examples of rhodium‐catalyzed direct
halogenation of C–H bonds, see: (a) N. Schroder, J.
Wencel‐Delord and F. Glorius, J. Am. Chem. Soc., 2012,
1
34, 8298; (b) N. Kuhl, N. Schroder and F. Glorius, Org.
Lett., 2013, 15, 3860; (c) H. Hwang, J. Kim, J. Jeong and S.
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