Synthesis 2019; 51(20): 3859-3864
DOI: 10.1055/s-0037-1611895
© Georg Thieme Verlag Stuttgart · New York

Aryl Ketone Mediated Photoinduced Radical Coupling for the Alkylation­ of Benzazoles Employing Saturated Heterocyclic Compounds­

Shin Kamijo
Graduate School of Sciences and Technology for Innovation, Yamaguchi University, Yamaguchi 753-8512, Japan   eMail:
Kaori Kamijo
Toshihiro Murafuji
› Institutsangaben
This research was supported by a research grant from the Astellas Foundation for Research on Metabolic Disorders, a program of the YU Project for Formation of the Core Research Center, and the Japan Society for the Promotion of Science (JSPS, KAKENHI Grant Number JP18K05107).
Weitere Informationen


Received: 12. Mai 2019

Accepted after revision: 01. Juli 2019

31. Juli 2019 (online)


An aryl ketone mediated synthesis of 2-alkylated benzazoles was achieved via radical coupling under photoirradiation starting from saturated heterocycles and 2-sulfonylated benzazoles, such as benzothiazoles, benzoxazole, and benzimidazole. Heterocyclic compounds, including a cyclic ether, azacycles, and tetrahydrothiophene, were applicable, and the benzazole unit was site-selectively installed at the carbon center proximal to the heteroatom. The present transformation takes place at ambient temperature under neutral reaction conditions without the aid of any metallic catalysts or reagents.

Supporting Information

  • References

  • 1 For the general chemistry of benzazoles, see: Joule JA, Mills K. Heterocyclic Chemistry . Blackwell Science; Oxford: 2000. Chap. 23, 449-460

    • For representative reviews, see:
    • 2a Noël S, Cadet S, Gras E, Hureau C. Chem. Soc. Rev. 2013; 42: 7747
    • 2b Horton DA, Bourne GT, Smythe ML. Chem. Rev. 2003; 103: 893
  • 3 For an example, see: Castet F, Rodriguez V, Pozzo J.-L, Ducasse L, Plaquet A, Champagne B. Acc. Chem. Res. 2013; 46: 2656

    • For representative reports on metal-catalyzed coupling reactions for the derivatization of benzazoles, see:
    • 5a Li JJ, Gribble GW. Palladium in Heterocyclic Chemistry . Pergamon; Oxford: 2000. Chaps. 7 and 8, 297-334
    • 5b Liu C, Yuan J, Gao M, Tang S, Li W, Shi R, Lei A. Chem. Rev. 2015; 115: 12138
    • 5c Muto K, Yamaguchi J, Itami K. J. Am. Chem. Soc. 2012; 134: 169
    • 5d Yamada S, Murakami K, Itami K. Org. Lett. 2016; 18: 2415
    • 5e Shi Q, Zhang S, Zhang J, Oswald VF, Amassian A, Marder SR, Blakey SB. J. Am. Chem. Soc. 2016; 138: 3946
    • 5f Iwasaki M, Topolovčan N, Hu H, Nishimura Y, Gagnot G, Na nakorn R, Yuvacharaskul R, Nakajima K, Nishihara Y. Org. Lett. 2016; 18: 1642

      For metal-catalyzed alkylations of benzazoles, see:
    • 6a Fiorentiono M, Testaferri L, Tiecco M, Troisi L. J. Chem. Soc., Chem. Commun. 1977; 316
    • 6b Colby DA, Bergman RG, Ellman JA. Chem. Rev. 2010; 110: 624
    • 6c Ackermann L, Punji B, Song W. Adv. Synth. Catal. 2011; 353: 3325
    • 6d Yao T, Hirano K, Satoh T, Miura M. Angew. Chem. Int. Ed. 2012; 51: 775
    • 6e Ren P, Salihu I, Scopelliti R, Hu X. Org. Lett. 2012; 14: 1748
    • 6f Babu KR, Zhu N, Bao H. Org. Lett. 2017; 19: 46
    • 6g Yim JC.-H, Nambo M, Crudden CM. Org. Lett. 2017; 19: 3715

      For other alkylation methods of benzazoles, see:
    • 7a Molander GA, Colombel V, Braz VA. Org. Lett. 2011; 13: 1852
    • 7b He T, Yu L, Zhang L, Wang L, Wang M. Org. Lett. 2011; 13: 5016
    • 7c Xia R, Niu H.-Y, Qu G.-R, Guo H.-M. Org. Lett. 2012; 14: 5546
    • 7d Wang J, Li J, Huang J, Zhu Q. J. Org. Chem. 2016; 81: 3017
    • 7e Ikeda Y, Ueno R, Akai Y, Shirakawa E. Chem. Commun. 2018; 54: 10471
    • 8a Devari S, Shah BA. Chem. Commun. 2016; 52: 1490
    • 8b Zhang Y, Teuscher KB, Ji H. Chem. Sci. 2016; 7: 2111
  • 9 Prier CK, MacMillan DW. C. Chem. Sci. 2014; 5: 4173
  • 10 Lipp A, Lahm G, Opatz T. J. Org. Chem. 2016; 81: 4890

    • For related examples of photoinduced C(sp3)–H functionalizations from our group, see:
    • 11a Kamijo S, Hoshikawa T, Inoue M. Tetrahedron Lett. 2011; 52: 2885
    • 11b Kamijo S, Hoshikawa T, Inoue M. Org. Lett. 2011; 13: 5928
    • 11c Hoshikawa T, Kamijo S, Inoue M. Org. Biomol. Chem. 2013; 11: 164
    • 11d Hoshikawa T, Yoshioka S, Kamijo S, Inoue M. Synthesis 2013; 45: 874
    • 11e Amaoka Y, Nagatomo M, Watanabe M, Tao K, Kamijo S, Inoue M. Chem. Sci. 2014; 5: 4339
    • 11f Kamijo S, Hirota M, Tao K, Watanabe M, Murafuji T. Tetrahedron Lett. 2014; 55: 5551
    • 11g Kamijo S, Tao K, Takao G, Murooka H, Murafuji T. Tetrahedron Lett. 2015; 56: 1904
    • 11h Kamijo S, Watanabe M, Kamijo K, Tao K, Murafuji T. Synthesis 2016; 48: 115
    • 11i Kamijo S, Takao G, Kamijo K, Hirota M, Tao K, Murafuji T. Angew. Chem. Int. Ed. 2016; 55: 9695
    • 11j Kamijo S, Takao G, Kamijo K, Tsuno T, Ishiguro K, Murafuji T. Org. Lett. 2016; 18: 4912
    • 11k Kamijo S, Kamijo K, Maruoka K, Murafuji T. Org. Lett. 2016; 18: 6516
    • 11l Kamijo S, Kamijo K, Murafuji T. J. Org. Chem. 2017; 82: 2664

      For related reports of aryl ketone mediated photoinduced C(sp3)–H functionalizations from other research groups, see:
    • 12a Hoshikawa T, Inoue M. Chem. Sci. 2013; 4: 3118
    • 12b Nagatomo M, Yoshioka S, Inoue M. Chem. Asian J. 2015; 10: 120
    • 12c Xia J.-B, Zhu C, Chen C. J. Am. Chem. Soc. 2013; 135: 17494
    • 12d Kee CW, Chin KF, Wong MW, Tan C.-H. Chem. Commun. 2014; 50: 8211
    • 12e Xia J.-B, Zhu C, Chen C. Chem. Commun. 2014; 50: 11701
    • 12f Cantillo D, de Frutos O, Rincón JA, Mateos C, Kappe CO. J. Org. Chem. 2014; 79: 8486
    • 12g Ota E, Mikame Y, Hirai G, Nishiyama S, Sodeoka M. Synlett 2016; 27: 1128
  • 13 Kamijo S, Tao K, Takao G, Tonoda H, Murafuji T. Org. Lett. 2015; 17: 3326
  • 14 After the coupling, sulfinic acid and/or in situ generated sulfonic acid by disproportionation of sulfinic acid can be formed. These acids should be neutralized with the pyridine part of 4-BzPy, so that neutral conditions were presumably kept during the transformation.
  • 15 No compounds containing a protic NH moiety, such as amide 1e and benzimidazole 6, were examined as a starting substance in ref. 10, reporting a similar photoinduced alkylation of benzazoles under basic conditions. Alkylation at the nitrogen atom might proceed under these basic conditions, which did not take place under the present neutral conditions.
  • 16 Sulfonylated benzoxazole 4 was not so stable as the sulfonyl group at the oxazole moiety was prone to be substituted by water. In this respect, the protocol employing 2-chlorobenzoxazole seemed to be superior for synthesizing alkylated benzoxazoles, as reported in ref. 10.
  • 17 The alkylation of benzothiazole employing ethanol, cyclohexanol, and Boc-protected butylamine, respectively, using 4-BzPy in acetone did not give rise to reasonable yields of the expected products. In the case of cyclohexanol, the formation of cyclohexanone and phenyl(pyridyl)methanol was observed. This result indicates that the photoinduced oxidation of alcohol13 was occurring preferentially to the alkylation of benzothiazole.
  • 18 Compounds 3e and 7 might not be stable when heated as they became colored as they melted.