10.1002/ejoc.201800374
European Journal of Organic Chemistry
COMMUNICATION
yields. This approach is a valuable strategy to develop new
arylating agents for the quick preparation of C-2-arylbenzofurans.
Experimental Section
General procedure for the Pd-catalyzed C-2 arylation of benzofurans
A mixture of benzofuran 1 (0.30 mmol), N’-acyl arylhydrazine 2 (0.45
mmol), PdCl2(MeCN)2 (0.045 mmol), and TEMPO (0.90 mmol) in dioxane
(2.0 mL) was stirred at 100 ℃ for 24 h. After completion of the reaction
(indicated by TLC), the mixture was quenched with saturated NaCl
solution and extracted with EtOAc, followed by washing with H2O and
saturated NaCl solution, and finally dried over Na2SO4. The crude
product was purified by flash column chromatography to provide the
corresponding product 3.
Acknowledgements
This work was financially supported by the National Natural
Science Fundation of China (No. 81703356, 81660348,
81560559), the National Science Grand Fundation of Guizhou
Province (No. JZ[2015]2001), the Guizhou High-School
Engineering Research Center for Medicinal Chemistry (KY2014-
219), the Social Development of Technical Supporting Fundation
of Guizhou Province (No. [2016]2819, [2017]2839), the National
Science Fundation of Health and Family planning Commission
of Guizhou Province (gzwjkj2016-1-051) and the Science
Funcation of Guiyang ([20161001]016, [2017]30-28)
Scheme 4. Control experiments.
Based on these experiments and the literature,7a,11a,12,24,25 we
proposed a possible mechanism for the Pd-catalyzed arylation
reaction (Figure 2). N'-Acyl aryhydrazine (A) was oxidized by the
Pd(II) species to give diazene intermediate B. The reductive
Pd(0) coordinated with B to form azo-palladium(II) complex C,
which further coordinated with benzofuran (D) to afford
intermediate E. The migration of the aryl group to the α-carbon
atom of benzofuran gave F. Degeneration of the
organopalladium intermediate F afforded the coupling product G
and regenerated the Pd(0) species, which may be reoxidized to
the Pd(II) species in the presence of TEMPO.
Keywords: Arylation • Palladium • Benzofuran • Arylhydrazines
• Regioselective
[1] a) H. Khanam, Shamsuzzaman, Eur. J. Med. Chem. 2015, 97, 483-504; b)
R. Naik, D. S. Harmalkar, X. Xu, K. Jang, K. Lee, Eur. J. Med. Chem.
2015, 90, 379-393; c) A. Radadiya, A. Shah, Eur. J. Med. Chem. 2015, 97,
356-376.
[2] K. Chand, Rajeshwari, A. Hiremathad, M. Singh, M. A. Santos, R. S. Keri,
Pharmacol. Rep. 2017, 69, 281-295.
[3] C. Salome, V. Narbonne, N. Ribeiro, F. Thuaud, M. Serova, A. de
Gramont, S. Faivre, E. Raymond, L. Desaubry, Eur. J. Med. Chem. 2014,
74, 41-49.
[4] Y. Cheng, M. Ono, H. Kimura, S. Kagawa, R. Nishii, H. Saji, Bioorg. Med.
Chem. Lett. 2010, 20, 6141-6144.
[5] A. Aggarwal, M. K. Parai, N. Shetty, D. Wallis, L. Woolhiser, C. Hastings,
N. K. Dutta, S. Galaviz, R. C. Dhakal, R. Shrestha, S. Wakabayashi, C.
Walpole, D. Matthews, D. Floyd, P. Scullion, J. Riley, O. Epemolu, S.
Norval, T. Snavely, G. T. Robertson, E. J. Rubin, T. R. Ioerger, F. A. Sirgel,
R. van der Merwe, P. D. van Helden, P. Keller, E. C. Bottger, P. C.
Karakousis, A. J. Lenaerts, J. C. Sacchettini, Cell 2017, 170, 249-259.e25.
[6] M. Dixit, B. K. Tripathi, A. K. Tamrakar, A. K. Srivastava, B. Kumar, A. Goel,
Bioorg. Med. Chem. 2007, 15, 727-734.
[7] Selected references: a) H. P. L. Gemoets, I. Kalvet, A. V. Nyuchev, N.
Erdmann, V. Hessel, F. Schoenebeck, T. Noel, Chem. Sci. 2017, 8, 1046-
1055; b) A. Bruneau, K. P. J. Gustafson, N. Yuan, C.-W. Tai, I. Persson, X.
Zou, J.-E. Baeckvall, Chem. - Eur. J. 2017, 23, 12886-12891; c) M. J.
Bosiak, ACS Catal. 2016, 6, 2429-2434; d) H. Fang, L. Guo, Y. Zhang, W.
Yao, Z. Huang, Org. Lett. 2016, 18, 5624-5627; e) D. Yang, Y. Zhu, N.
Yang, Q. Jiang, R. Liu, Adv. Synth. Catal. 2016, 358, 1731-1735; f) S.-C.
Yin, Q. Zhou, X.-Y. Zhao, L.-X. Shao, J. Org. Chem. 2015, 80, 8916-8921;
g) D.-T. D. Tang, K. D. Collins, J. B. Ernst, F. Glorius, Angew. Chem. Int.
Ed. 2014, 53, 1809-1813;
Figure 2. Proposed mechanism.
Conclusions
[8] Selected references: a) A. Zanardi, J. A. Mata, E. Peris, Organometallics
2009, 28, 4335-4339; b) S.-H. Wang, P.-H. Li, L. Yu, L. Wang, Org. Lett.
2011, 13, 5968-5971.
[9] A. Ohta, Y. Akita, T. Ohkuwa, M. Chiba, R. Fukunaga, A. Miyafuji, T.
Nakata, N. Tani, Y. Aoyagi, Heterocycles 1990, 31, 1951-1958.
[10] T. A. Dwight, N. R. Rue, D. Charyk, R. Josselyn, B. DeBoef, Org. Lett.
2007, 9, 3137-3139.
[11] a) S.-D. Yang, C.-L. Sun, Z. Fang, B.-J. Li, Y.-Z. Li, Z.-J. Shi, Angew.
Chem. Int. Ed. 2008, 47, 1473-1476; b) R. Cano, J. M. Perez, D. J.
Ramon, G. P. McGlacken, Tetrahedron 2016, 72, 1043-1050.
[12] L. Loukotova, K. Yuan, H. Doucet, ChemCatChem 2014, 6, 1303-1309.
In summary, we have developed a novel Pd-catalyzed
direct C-2 arylation reaction of benzofurans using N'-acyl
arylhydrazines as the aryl donor. The procedure, using TEMPO
as the oxidant, is quite simple and highly regioselective, and can
be applied to a broad scope of substrates in good to excellent
This article is protected by copyright. All rights reserved.