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DOI: 10.1039/C3CC47174H
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For recent reviews on aerobic C−H functionalization: (a) Shi, Z.;
Zhang, C.; Tanga, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3381; (b)
Campbell, A. N.; Stahl, S. S. Acc. Chem. Res. 2012, 45, 851.
For bioinspired Cuꢀcatalyzed oxidations: P. Gamez, P. G. Aubel, W.
L. Driessen, J. Reedijk, Chem. Soc. Rev. 2001, 30, 376.
For reviews on Cuꢀcatalyzed aerobic C−H functionalization: (a) A. E.
Wendlandt, A. M. Suess and S. S. Stahl, Angew. Chem. Int. Ed. 2011,
50, 11062; (b) S. E. Allen, R. R. Walvoord, R. PadillaꢀSalinas and M.
C. Kozlowski, Chem. Rev. 2013, 113, 6234.
For selected recent examples: (a) T. Xiong, Y. Li, X. Bi, Y. Lv and
Q. Zhang, Angew. Chem. Int. Ed. 2011, 50, 7140; (f) K. Hirano and
M. Miura, Chem. Commun. 2012, 48, 10704.
X. Chen, X.ꢀS. Hao, C. E. Goodhue and J.ꢀQ. Yu, J. Am. Chem. Soc.
2006, 128, 6790.
(a) G. Brasche and S. L. Buchwald, Angew. Chem. Int. Ed. 2008, 47,
1932; (b) S. Ueda and H. Nagasawa, Angew. Chem. Int. Ed. 2008, 47,
6411; (c) B.ꢀX. Tang, R.ꢀJ. Song, C.ꢀY. Wu, Y. Liu, M.ꢀB. Zhou, W.ꢀ
T. Wei, G.ꢀB. Deng, D.ꢀL. Yin and J.ꢀH. Li, J. Am. Chem. Soc. 2010,
132, 8900.
Examples of nonꢀaerobic Cuꢀcatalyzed C−H functionalization: (a) H.
A. Duong, R. E. Gilligan, M. L. Cooke, R. J. Phipps and M. J. Gaunt,
Angew. Chem. Int. Ed. 2011, 50, 463; (b) M. Nishino, K. Hirano, T.
Satoh and M. Miura, Angew. Chem. Int. Ed. 2013, 52, 4457; (c) L. D.
Tran, J. Roane, O. Daugulis, Angew. Chem. Int. Ed. 2013, 52, 6043.
Notably, smooth diꢀoꢀchlorination was observed in anilines
with the two oꢀpositions unsubstituted (Scheme 5).21
45
50
55
60
65
70
75
80
85
90
95
4
5
Scheme 5 Diꢀoꢀchlorination.
6
5
The lack of NCSꢀchlorination of 1 in the presence of radical
scavengers such as TEMPO or Galvinoxyl (1.0 equiv)
suggested that a SET pathway might operate.22 Finally, both
Pyꢀ and Pyrꢀbased directing groups could be removed under
mild conditions to generate the free NH2ꢀanilines (31 and 32,
10 Scheme 6). The versatility of the halogenated products as
building blocks was illustrated in the conversion of the
derivative 3-Br into the functionalized indoles 33 and 34.23
7
8
9
10 For Cuꢀcatalyzed C−H functionalization via SET process: (a) C.
Zhang, C. Tanga and N. Jiao, Chem. Soc. Rev. 2012, 41, 3464. For
the divergence organometallic/SET CuIIꢀcatalyzed aerobic C−H
oxidation of Nꢀ(8ꢀquinolyl)benzamide: (b) A. M. Suess, M. Z. Ertem,
C. J. Cramer and S. S. Stahl, J. Am. Chem. Soc. 2013, 135, 9797.
11 For reviews on C−H halogenation: (a) A. Podgoršek, M. Zupan and J.
Iskra, Angew. Chem. Int. Ed. 2009, 48, 8424; (b) A. Vigalok and A.
W. Kaspi, Top. Organomet. Chem. 2010, 31, 19. For Pdꢀcatalyzed oꢀ
halogenation of anilines: (c) D. Kalyani, A. R. Dick, W. Q. Anani
and M. S. Sanford, Org. Lett. 2006, 8, 2523; (d) X. Wan, Z. Ma, B.
Li, K. Zhang, S. Cao, S. Zhang and Z. Shi, J. Am. Chem. Soc. 2006,
128, 7416; (e) R. B. Bedford, M. F. Haddow, C. J. Mitchell and R. L.
Webster, Angew. Chem. Int. Ed. 2011, 50, 5524.
12 For pꢀselective Cuꢀcatalyzed halogenation: (a) L. Menini, J. C. da
Cruz Santos, E. V. Gusevskaya, Adv. Synth. Catal. 2008, 350, 2052;
(b) L. Yang, Z. Lub and S. S. Stahl, Chem. Commun. 2009, 6460.
13 W. Wang, C. Pan, F. Chen and J. Cheng, Chem. Commun. 2011, 47,
3978.
14 S. Mo, Y. Zhu and Z. Shen, Org. Biomol. Chem. 2013, 11, 2756.
15 For reviews on removable directing groups: (a) G. Rousseau and B.
Breit, Angew. Chem. Int. Ed. 2011, 50, 2450. (b) C. Wang and Y.
Huang, Synlett 2013, 24, 145. See also: (c) S. R. Neufeldt and M. S.
Sanford, Acc. Chem. Res. 2012, 45, 936.
Scheme 6 Deprotection and synthetic applications.
15 In summary, a highly regioselective NꢀSO2Pyꢀdirected Cuꢀ
catalyzed oꢀC−H monohalogenation of anilines leading to o-
Cl and oꢀBr aniline derivatives has been developed. The
directing 2ꢀpyridylsulfonyl and 2ꢀpyrimidylsulfonyl groups
can be easily cleaved in the final products.
20 Acknowledgements
This work was supported by the Spanish Government
(MINECO, CTQ2009ꢀ07791; CTQ2012ꢀ35790), and Madrid
regional government (AVANCAT, S2009/PPQꢀ1634). N.R. and
B.U. thank the MICINN for a Ramón y Cajal contract and a
25 predoctoral fellowship. N.R. thanks the Marie Curie
Foundation (CIG: CHAASꢀ304085) and B.U. thanks the MC
for a contract. We thank Lim Jia Hui for optimization studies.
16 (a) A. GarcíaꢀRubia, B. Urones, R. Gómez Arrayás and J. C.
Carretero, Angew. Chem. Int. Ed. 2011, 50, 10927; (b) N. Rodríguez,
J. A. RomeroꢀRevilla, M. A. FernándezꢀIbáñez and J. C. Carretero,
Chem. Sci. 2013, 4, 175 (c) B. Urones, R. Gómez Arrayás and J. C.
Carretero, Org. Lett. 2013, 15, 2110. For pioneering work on the use
of SO2Py directing group: (d) T. Llamas, R. Gómez Arrayás and J. C.
Carretero, Adv. Synth. Catal. 2004, 346, 1651; (e) P. Mauleón and J.
C. Carretero, Org. Lett. 2004, 6, 3195; (f) H. Han, I. Bae, E. J. Yoo,
J. Lee, Y. Do and S. Chang, Org. Lett. 2004, 6, 4109.
Notes and references
Departamento de Química Orgánica, Universidad Autónoma de Madrid,
100 17 O2 proved to be important for reactivity and regiocontrol (see ESI).
18 See, for instance: P. Thansandote, D. G. Hulcoop, M. Langer and M.
Lautens, J. Org. Chem. 2009, 74, 1673.
† Electronic Supplementary Information (ESI) available: [experimental
procedures and characterization data of new compounds and copies of
NMR spectra]. See DOI: 10.1039/b000000x/
19 Reported electrophilic NBSꢀbromination of mꢀsubstituted anilines
favors pꢀbromination, see: S. Bartoli, A. Cipollone, A. Squarcia, A.
Madami and D. Fattori, Synthesis 2009, 1305.
20 A. V. Gulevich, F. S. Melkonyan, D. Sarkar and V. Gevorgyan, J.
Am. Chem. Soc. 2012, 134, 5528.
105
35
40
1
(a) S. S. Stahl, Science 2005, 309, 1824; (b) K. M.Gligorich and M.
S. Sigman, Angew. Chem. Int. Ed. 2006, 45, 6612; (c) T. Newhouse
and P. S. Baran, Angew. Chem. Int. Ed. 2011, 50, 3362.
21 Mixtures of o/pꢀhalogenated products were observed in the case of
substrates unsubstituted at pꢀposition.
2
(a) C. S. Yeung and V. M. Dong, Chem. Rev. 2011, 111, 1215; (b) P.
B. Arockiam, C. Bruneau and P. H. Dixneuf, Chem. Rev. 2012, 112,
5879; (c) J. Yamaguchi, A. D. Yamaguchi and K. Itami, Angew.
Chem. Int. Ed. 2012, 51, 8960; (d) J. J. Mousseau and A. B. Charette,
Acc. Chem. Res. 2013, 46, 412; (e) J. WencelꢀDelord and F. Glorius,
Nature Chem. 2013, 5, 369.
110 22 Additional mechanistic studies (see ESI) also supported a SET path.
For a related Cuꢀcatalyzed o-azidation of anilines, see: C. Tang and
N. Jiao, J. Am. Chem. Soc. 2012, 134, 18924.
23 B. Z. Lu, H. –X. Wei, Y. Zhang, W. Zhao, M. Dufour, G. Li, V.
Farina and C. H. Senanayake, J. Org. Chem. 2013, 78, 4558.
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