Synlett 2019; 30(10): 1246-1252
DOI: 10.1055/s-0037-1611827
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 3-Halo-7-azaindoles through a 5-endo-dig Electrophilic Cyclization Reaction

Aimee Philips
,
Christopher Cunningham
,
Kajal Naran
,
Tanay Kesharwani*
Department of Chemistry, University of West Florida, Pensacola, FL 32514, USA   eMail: tkesharwani@uwf.edu
› Institutsangaben
We are grateful to Research Corporation for Science Advancement for a Cottrell College Science Award (ID 23248). Authors are also thankful for support provided by the University of West Florida (UWF), UWF’s Office of Research and Sponsored Programs and Office of Undergraduate Research. Our research is also supported by the National Institute of General Medical Sciences of the National Institutes of Health under grant number 1T34GM110517-01. The content is solely the responsibility of the authors and it does not necessarily represent the official views of the National Institutes of Health.
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Publikationsverlauf

Received: 16. April 2019

Accepted after revision: 24. April 2019

Publikationsdatum:
20. Mai 2019 (online)


Abstract

Biologically useful 7-azaindoles were synthesized by electrophilic cyclization of 3-alkynyl-N,N-dimethylpyridine-2-amines with molecular iodine. By this simple atom-economical approach under ambient reaction conditions, a library of interesting 3-iodo-7-azaindoles were synthesized in high yields. To synthesize the corresponding 3-bromo- and 3-chloro-7-azaindoles, an environmentally benign copper-mediated cyclization was employed, with inexpensive, nontoxic, and noncorrosive sodium chloride and sodium bromide as the sources of chlorine and bromine, respectively.

Supporting Information

 
  • References and Notes

    • 1a Kim J.-S, Shin-ya K, Furihata K, Hayakawa Y, Seto H. Tetrahedron Lett. 1997; 38: 3431
    • 1b Miyake FY, Yakushijin K, Horne DA. Angew. Chem. Int. Ed. 2005; 44: 3280
    • 1c Delfourne E. Tetrahedron Lett. 2011; 52: 6560
    • 1d Blinov K, Elyashberg M, Martirosian ER, Molodtsov SG, Williams AJ, Tackie AN, Sharaf MM. H, Schiff PL. Jr, Crouch RC, Martin GE, Hadden CE, Guido JE, Mills KA. Magn. Reson. Chem. 2003; 41: 577
    • 1e Hugon B, Anizon F, Bailly C, Golsteyn RM, Pierré A, Léonce S, Hickman J, Pfeiffer B, Prudhomme M. Bioorg. Med. Chem. 2007; 15: 5965
    • 2a Mérour J.-Y, Joseph B. Curr. Org. Chem. 2001; 5: 471
    • 2b Song J, Reeves J, Gallou F, Tan Z, Yee N, Senanayake C. Chem. Soc. Rev. 2007; 36: 1120
  • 3 Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, Chang Z, Woolsey J. Nucleic Acids Res. 2006; 34: D668
    • 4a Štarha P, Trávníček Z, Popa A, Popa I, Muchová T, Brabec V. J. Inorg. Biochem. 2012; 115: 57
    • 4b Singh U, Chashoo G, Khan SU, Mahajan P, Nargotra A, Mahajan G, Singh A, Sharma A, Mintoo MJ, Guru SK, Aruri H, Thatikonda T, Sahu P, Chibber P, Kumar V, Mir SA, Bharate SS, Madishetti S, Nandi U, Singh G, Mondhe DM, Bhushan S, Malik F, Mignani S, Vishwakarma RA, Singh PP. J. Med. Chem. 2017; 60: 9470
  • 5 Verbiscar AJ. J. Med. Chem. 1972; 15: 149
  • 6 Meenakshi K, Gopal N, Sarangapani M, Anusha T. World J. Pharm. Pharm. Sci. 2014; 3: 671
  • 7 Marminon C, Pierre A, Pfeiffer B, Pérez V, Léonce V, Léonce S, Joubert A, Baily C, Renard P, Hickman J, Prudhomme M. J. Med. Chem. 2003; 46: 609
  • 8 De Filippis V, De Boni S, De Dea E, Dalzoppo D, Grandi C, Fontana A. Protein Sci. 2004; 13: 1489
  • 9 Saify Z, Sultana N, Mushtaq N, Hasan N. Int. J. Biochem. Res. Rev. 2014; 4: 624
    • 10a Leboho T, van Vuuren S, Michael J, de Koning C. Org. Biomol. Chem. 2014; 12: 307
    • 10b Saify Z, Nisa M, Moazzam SM, Khanum M, Haider S. Pak. J. Sci. Ind. Res. 2009; 52: 1
  • 11 Silvestri R, De Martino G, La Regina G, Artico M, Massa S, Vargiu L, Mura M, Loi AG, Marceddu T, La Colla P. J. Med. Chem. 2003; 46: 2482
    • 12a Bandarage UK, Clark MP, Perola E, Gao H, Jacobs MD, Tsai A, Gillespie J, Kennedy JM, Maltais F, Ledeboer MW, Davies I, Gu W, Byrn RA, Addae KN, Bennett H, Leeman JR, Jones SM, O’Brien C, Memmott C, Bennani Y, Charifson PS. ACS Med. Chem. Lett. 2017; 8: 261
    • 12b Boyd MJ, Bandarage UK, Bennett H, Byrn RR, Davies I, Gu W, Jacobs M, Ledeboer MW, Ledford B, Leeman JR, Perola E, Wang T, Bennani Y, Clark MP, Charifson PS. Bioorg. Med. Chem. Lett. 2015; 25: 1990
    • 13a Mérour J.-Y, Buron F, Plé K, Bonnet P, Routier S. Molecules 2014; 19: 19935
    • 13b Walker SR, Czyz ML, Morris JC. Org. Lett. 2014; 16: 708
    • 14a Barl NM, Sansiaume-Dagousset E, Karaghiosoff K, Knochel P. Angew. Chem. Int. Ed. 2013; 52: 10093
    • 14b Harcken C, Ward Y, Thomson D, Riether D. Synlett 2005; 3121
    • 15a Zhao S.-B, Cui Q, Wang S. Organometallics 2010; 29: 998
    • 15b Black HT, Yee N, Zems Y, Perepichka DF. Chem. Eur. J. 2016; 22: 17251
    • 15c Sun H, Xiao L, Xie Q, Shao L. Synthesis 2017; 49: 4845
    • 15d Gala E, Cordoba M, Izquierdo ML, Alvarez-Builla J. ARKIVOC 2014; (v): 319
    • 16a D’Attoma J, Cozien G, Brun PL, Robin Y, Bostyn S, Buron F, Routier S. ChemistrySelect 2016; 1: 338
    • 16b Maddox SM, Nalbandian CJ, Smith DE, Gustafson JL. Org. Lett. 2015; 17: 1042
    • 16c Yan J, Ni T, Yan F. Tetrahedron Lett. 2015; 56: 1096
    • 16d Song S, Sun X, Li X, Yuan Y, Jiao N. Org. Lett. 2015; 17: 2886
  • 17 Amjad M, Knight DW. Tetrahedron Lett. 2004; 45: 539
  • 18 Lessing T, Müller TJ. J. Synlett 2017; 28: 1743
  • 19 Hernandes MZ, Cavalcanti SM. T, Moreira DR. M, Filgueira de Azevedo WJr, Lima AC. Curr. Drug Targets 2010; 11: 303
    • 20a Godoi B, Schumacher RF, Zeni G. Chem. Rev. 2011; 111: 2937
    • 20b Mphahlele MJ. Molecules 2009; 14: 4814
    • 20c Gabriele B, Mancuso R, Larock RC. Curr. Org. Chem. 2014; 18: 341
    • 21a Kim S, Dahal N, Kesharwani T. Tetrahedron Lett. 2013; 54: 4373
    • 21b Kesharwani T, Kornman C, Tonnaer A, Hayes A, Kim S, Dahal N, Romero R, Royappa A. Tetrahedron 2018; 74: 2973
    • 21c Kesharwani T, Giraudy K, Jordan M, Olaitan AD. Tetrahedron Lett. 2017; 58: 638
  • 22 Sonogashira K. J. Organomet. Chem. 2002; 653: 46-49
  • 24 Kannaboina P, Anilkumar K, Aravinda S, Vishwakarma RA, Das P. Org. Lett. 2013; 15: 5718
  • 25 Halocyclization Reaction; General Procedures Method A. To a 6-dram vial containing the starting alkyne (0.3 mmol) was added CH2Cl2 (4.0 mL). I2 (2.0 equiv) was then added, and the mixture was stirred at r.t. for 24 h. The reaction mixture was finally purified by column chromatography (silica gel, hexanes–EtOAc). Method B. To a 6-dram vial containing the starting alkyne (0.3 mmol) was added 95% EtOH (4.0 mL). The appropriate sodium halide (5.0 equiv) and CuSO4·5 H2O (5.0 equiv) were added, and the mixture was stirred at r.t. for 48 h. The mixture was finally purified by column chromatography (silica gel, hexanes–EtOAc). 3-Iodo-1-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine (20a) Yellow-brown solid; yield: 93 mg (93%); mp 86–89 °C. 1H NMR (400 MHz, CDCl3): δ = 3.80 (s, 3 H), 7.17 (dd, J = 7.6, 4.4 Hz, 1 H), 7.48–7.54 (m, 5 H), 7.76 (dd, J = 8.0, 1.2 Hz, 1 H), 8.37 (dd, J = 4.4, 1.2 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 30.56, 56.49, 116.93, 123.69, 128.55, 128.70, 128.97, 129.16, 129.26, 130.69, 131.16, 142.16, 143.98, 148.73. Other characterization data agreed with the previously reported values (See ref. 26).
  • 26 Fang Y.-Q, Yuen J, Lautens M. J. Org. Chem. 2007; 72: 5152