Jun 032016
Abstract Image

A novel and convergent approach to tetrasubstituted benzofurans was developed from ortho-bromo aryl fluorides and keto-amides via one-pot SNAr displacement and subsequent Cu(I) catalyzed C–O coupling on the ortho-bromide. The scope of this methodology was demonstrated on several similar substrates.


Concise Cu (I) Catalyzed Synthesis of Substituted Benzofurans via a Tandem SNAr/C–O Coupling Process

Zhiguo J. Song*et al
Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway New Jersey 07065, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00141
Publication Date (Web): May 25, 2016
Copyright © 2016 American Chemical Society
Benzofurans are important building blocks for the synthesis of biologically active compounds in the pharmaceutical industry and compound 3 has been an important intermediate in Merck’s hepatitis C program.(1, 2)

1 as a pale yellow solid (3.1 kg, 86% yield, 98.8% LACP). Mp: > 240 °C.

1H NMR (400 MHz, DMSO-d6)δ 8.54 (d, J = 4.5 Hz, 1H), 8.07 (s, 1H), 8.07–7.94 (m, 3H), 7.42 (t, J = 8.9 Hz, 2H), 3.34 (s, 3H), 3.22 (d, J = 4.1 Hz, 3H), 2.85 (d, J = 4.6 Hz, 3H);13C NMR (100 MHz, DMSO-d6) δ 26.2, 38.2, 112.8, 113.4, 115.9 (d, J = 22 Hz), 119.7, 124.2, 125.2, 128.7, 129.6 (d, J = 8.8 Hz), 136.9, 151.8, 154.4, 162.4, 162.9 (d, J = 247.1 Hz).

19F NMR (376 MHz DMSO-d6) δ 109.9

AHR-FAB-MS calcd for C18H16BrFN2O4S: MH+, 455.2980. Found: 455.0055 (MH+).

  1. (a) Burns, C. J., Del Vecchio, A. M., Bailey, T. R., Kulkarni, B. A., Faitg, T. H., Sherk, S. R., Black-Ledge,C. W., Rys, D. J., Lessen, T. A., Swestock, J., Deng, Y., Nitz, Theodore, J., Reinardt, J. A., Feng, H., andSaha, A. K. Patent WO 2004041201.

    (b) McComas, C. C., Liverton, N. J., Habermann, J., Koch, U.,Narjes, F., Li, P., Peng, X., Soll, R., and Wu, H. WO 2011106929.

    (c) McComas, C. C., Liverton, N. J., Soll,R., Li, P., Peng, X., and Wu, H. WO 2011106986.

    (d) McComas, C. C., Liverton, N. J., Soll, R., Li, P.,Peng, X., Wu, H., Narjes, F., Habermann, J., Koch, U., and Liu, S. WO 2011106992.

    (e) McComas, C. C.,Liverton, N. J., Habermann, J., Koch, U., Narjes, F., Li, P., Peng, X., Soll, R., Wu, H., Palani, A., He, S.,Dai, X., Liu, H., Lai, Z., London, C., Xiao, D., zorn, N., and Nargund, R. WO 2013033971.

  2. He, S.; Li, P.; Dai, X.; McComas, C. C.; Du, C.; Wang, P.; Lai, Z.; Liu, H.; Yin, J.; Bulger, P. G.; Dang, Q.;Xiao, D.; Zorn, N.; Peng, X.; Nargund, R. P.; Palani, A. Tetrahedron Lett. 2014, 55, 22122216, DOI: 10.1016/j.tetlet.2014.02.051

//////Concise Cu (I),  Catalyzed,  Synthesis, Substituted Benzofurans, Tandem SNAr/C–O Coupling Process


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