Synlett
DOI: 10.1055/s-0037-1611856
letter
© Georg Thieme Verlag Stuttgart · New York

Hypervalent Iodine Mediated Efficient Solvent-Free Regioselective Halogenation and Thiocyanation of Fused N-Heterocycles

Divakar Reddy Indukuri
a  Flouro & Agrochemicals Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India
b  Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India   Email: manjula@iict.res.in
,
Gal Reddy Potuganti
a  Flouro & Agrochemicals Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India
b  Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India   Email: manjula@iict.res.in
,
Manjula Alla*
a  Flouro & Agrochemicals Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India
b  Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India   Email: manjula@iict.res.in
› Author Affiliations
I.D.R. thanks DST and P.G.R. thanks CSIR, for a fellowship.
Further Information

Publication History

Received: 18 March 2019

Accepted after revision: 16 May 2019

Publication Date:
12 June 2019 (eFirst)

Abstract

A facile, rapid, metal-free regioselective halogenation and thiocyanation of imidazo[1,2-a]pyridine/pyrimidine heterocycles has been achieved under solvent-free reaction conditions. Halogenations and thiocyanation of the heterocycles could be accomplished by simple grinding of reactants and hypervalent iodine reagents with the corresponding alkali metal or ammonium salts. The method has been extrapolated to a cleaner synthesis of brominated imidazo[1,2-a]pyridine/pyrimidine derivatives, starting from the corresponding heterocyclic amines and substituted α-bromoketones, utilising HBr generated in situ as the source of bromine.

Supporting Information

 
  • References and Notes

    • 1a Feng S, Hong D, Wang B, Zheng X, Miao K, Wang L, Yun H, Gao L, Zhao S, Shen HC. ACS Med. Chem. Lett. 2015; 6: 359
    • 1b Gueiffier E, Gueiffier A. Mini-Rev. Med. Chem. 2007; 7: 888
    • 1c Dyminska L. Bioorg. Med. Chem. 2015; 23: 6087
    • 2a Sharma S, Saha B, Sawant D, Kundu B. J. Comb. Chem. 2007; 9: 783
    • 2b Shono H, Ohkawa T, Tomoda H, Mutai T, Araki K. ACS Appl. Mater. Interfaces 2011; 3: 654
    • 3a Stasyuk AJ, Banasiewicz M, Cyranski MK, Gryko DT. J. Org. Chem. 2012; 77: 5552
    • 3b Shao N, Pang G.-X, Yan C.-X, Sci G.-F, Cheng Y. J. Org. Chem. 2011; 76: 7458
    • 3c Douhal A, Amat-Guerri F, Acuna AU. J. Phys. Chem. 1995; 99: 76
    • 3d Douhal A, Amat-Guerri F, Acuna AU. Angew. Chem. Int. Ed. Engl. 1997; 36: 1514
    • 4a Zhang H, Wei Q, Wei S, Qu J, Wang B. Eur. J. Org. Chem. 2016; 3373
    • 4b Bagdi AK, Hajra A. Chem. Rec. 2016; 16: 1868
    • 4c Xiang S, Chen H, Liu Q. Tetrahedron Lett. 2016; 57: 3870
    • 4d Dey A, Singsardar M, Sarkar R, Hajira A. ACS Omega 2018; 3: 3513
    • 4e Li J, Tang J, Wu Y, He Q, Yu Y. RSC Adv. 2018; 8: 5058
    • 4f Rashmi S, Chitrakar R, Rahul K, Ramavatar M, Subbarayappa A. J. Org. Chem. 2019; 84: 792
    • 5a Xuan Q, Song Q. Org. Lett. 2016; 18: 4250
    • 5b Wu W, Ding Y, Xie P, Tang Q, Pittman CU. Jr, Zhou A. Tetrahedron 2017; 73: 2151
    • 5c Ravi C, Reddy NN. K, Pappula V, Samanta S, Adimurthy S. J. Org. Chem. 2016; 81: 9964
    • 5d Jiao J, Xu L, Zheng W, Xiong P, Hu M.-L, Tang R.-Y. Synthesis 2017; 49: 1839
    • 5e Qi Z, Yu S, Li X. J. Org. Chem. 2015; 80: 3471
    • 5f Sun K, Mu S, Liu Z, Feng R, Li Y, Panga K, Zhang B. Org. Biomol. Chem. 2018; 16: 6655
    • 6a Wang S, Huang X, Ge Z, Wang X, Li R. RSC Adv. 2016; 6: 63532
    • 6b Wang Y, Frett B, McConnella N, Li H. Org. Biomol. Chem. 2015; 13: 2958
    • 6c Zhang J.-R, Zhan L.-Z, Wei L, Ning Y.-Y, Zhong X.-L, Lai J.-X, Xu L, Tang R.-Y. Adv. Synth. Catal. 2018; 360: 533
    • 6d Falck JR, Gao S, Prasad RN, Koduru SR. Bioorg. Med. Chem. Lett. 2008; 18: 1768
    • 6e Mitra S, Ghosh M, Mishra S, Hajra A. J. Org. Chem. 2015; 80: 8275
    • 7a Hari DP, Caramenti P, Waser J. Acc. Chem. Res. 2018; 51: 3212
    • 7b Moriyama K, Izumisawa Y, Togo H. J. Org. Chem. 2011; 76: 7249
    • 7c Huang Z.-Z, Yu X.-C, Huang X. Tetrahedron Lett. 2002; 43: 6823
    • 7d Shneider OS, Pisarevsky E, Fristrup P, Szpilman AM. Org. Lett. 2015; 17: 282
    • 7e Daniel M, Blanchard F, Nocquet-Thibault S, Cariou K, Dodd RH. J. Org. Chem. 2015; 80: 10624
    • 7f Zhao Z, Peng Z, Zhao Y, Liu H, Li C, Zhao J. J. Org. Chem. 2017; 82: 11848
    • 7g Shen H, Li J, Liu Q, Pan J, Huang R, Xiong Y. J. Org. Chem. 2015; 80: 7212
    • 8a Gottam H, Vinod KT. J. Org. Chem. 2011; 76: 974
    • 8b Zhang J, Szabó JK, Himo F. ACS Catal. 2017; 7: 1093
    • 8c Kiyokawa K, Yahata S, Kojima T, Minakata S. Org. Lett. 2014; 16: 4646
    • 8d Desjardins S, Andrez J, Canesi S. Org. Lett. 2011; 13: 3406
    • 9a Fang C, Qian W, Bao W. Synlett 2008; 2529
    • 9b Moteki SA, Usui A, Selvakumar S, Zhang T, Maruoka K. Angew. Chem. Int. Ed. 2014; 53: 11060
    • 10a Sun X, Lyu Y, Zhang-Negrerie D, Du Y, Zhao K. Org. Lett. 2013; 15: 6222
    • 10b Yang Y.-D, Azuma A, Tokunaga E, Yamasaki M, Shiro M, Shibata N. J. Am. Chem. Soc. 2013; 135: 8782
    • 10c Mandha SR, Alla M, Bommena VR, Nanubolu JB, Lingala SK, Yarasi S. J. Org. Chem. 2012; 77: 10648
    • 11a Yusubov MS, Wirth T. Org. Lett. 2005; 7: 519
    • 11b Han H, Tsarevsky NV. Chem. Sci. 2014; 5: 4599
    • 11c Ochiai M, Sueda T, Miyamoto K, Kiprof P, Zhdankin VV. Angew. Chem. Int. Ed. 2006; 45: 8203
    • 11d Sajith PK, Suresh CH. Inorg. Chem. 2012; 51: 967
    • 12a Shakoor SM. A, Mandal SK, Sakhuja R. Eur. J. Org. Chem. 2017; 2596
    • 12b Karade NN, Tiwari GB, Shirodkar SG, Dhoot BM. Synth. Commun. 2005; 35: 1197
    • 12c Chen Z, Cao G, Zhang F, Li H, Xu J, Miao M, Ren H. Synlett 2017; 28: 1795
    • 12d Rahaman R, Das S, Barman P. Green Chem. 2018; 20: 141
    • 12e Mondal S, Samanta S, Jana S, Hajra A. J. Org. Chem. 2017; 82: 4504
    • 12f Yagyu T, Takemoto Y, Yoshimura A, Zhdankin VV, Saito A. Org. Lett. 2017; 19: 2506
    • 12g Xu D, Sun W, Xie Y, Liu J, Liu B, Zhou Y, Wu B. J. Org. Chem. 2016; 81: 11081
    • 12h Zhang X, Hou W, Zhang-Negrerie D, Zhao K, Du Y. Org. Lett. 2015; 17: 5252
  • 13 Synthesis of 3-Halo/thiocyanato-2-phenylimidazo[1,2-a]pyridine Derivatives; General Procedure A mixture of 2-phenylimidazo[1,2-a]pyridine (1; 1 mmol), M-X (2ad; 1.5 mmol) and IBD (1.5 mmol) were taken in a mortar and the mixture was ground with a pestle until the solids melted (ca. 15 min). A distinction odour of acetic acid was noted. The progress of the reaction was monitored by TLC and grinding was continued until the starting materials disappeared. The reaction mixture was extracted with ethyl acetate (30 mL) and washed with water (10 mL) to remove remnant inorganic salts. The organic layer was separated and dried over Na2SO4. Solvent was removed in vacuo. The crude product thus obtained was purified by column chromatography for all halogenations (silicon 60–120 mesh; EtOAc/hexane, 5:95). Thiocyanation products could be obtained in pure form without further purification.
  • 14 Synthesis of 3-Bromo-2-phenylimidazo[1,2-a]pyridine/pyrimidine/benzo[d]imidazo[2,1-b]thiazole Derivatives via in Situ Bromination; General Procedure A mixture of heterocyclic hydrobromide (9/11; 1 mmol), and IBD (1.5 mmol) were taken in a mortar and the mixture was ground with a pestle until the solids melted (ca. 15 min). The progress of the reaction was monitored by TLC and grinding was continued until the starting materials disappeared. The solid residue was washed with n-pentane and dried under high vacuum to afford the product
    • 15a Selvakumar S, Kang Q.-K, Arumugam N, Almansour AI, Kumar RS, Maruoka K. Tetrahedron 2017; 73: 5841
    • 15b Zhao F, Sun T, Sun H, Xi G, Sun K. Tetrahedron Lett. 2017; 58: 3132
    • 15c Wang X, Studer A. Acc. Chem. Res. 2017; 50: 1712
    • 15d Wang X, Studer A. Acc. Chem. Res. 2017; 50: 1712
    • 15e Bose DS, Idrees M. J. Org. Chem. 2006; 71: 8261
    • 16a Yoshimura A, Middleton KR, Todora AD, Kastern BJ, Koski SR, Maskaev AV, Zhdankin VV. Org. Lett. 2013; 15: 4010
    • 16b Boye AC, Meyer D, Ingison CK, French AN, Wirth T. Org. Lett. 2003; 5: 2157
    • 17a Tang S.-Z, Zhao W, Chen T, Liu Y, Zhang X.-M, Zhang F.-M. Adv. Synth. Catal. 2017; 359: 4177
    • 17b Akula R, Galligan M, Ibrahim H. Chem. Commun. 2009; 6991
  • 18 Analytical data and copies of spectra of all compounds are given in the Supporting Information. Analytical data of a selection of new compounds are given below. 3-Bromo-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine (3c) Yield: 253 mg (80%); yellow solid; mp 92–94 °C; 1H NMR (500 MHz, CDCl3): δ = 8.08–8.04 (m, 1 H), 8.02 (d, J = 7.0 Hz, 1 H), 7.38 (s, 1 H), 7.03–6.99 (m, 2 H), 6.74 (dd, J = 7.0, 1.5 Hz, 1 H), 3.86 (s, 3 H), 2.42 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 159.57, 145.52, 141.94, 136.15, 129.02, 125.35, 122.96, 115.65, 115.50, 113.81, 89.96, 77.00, 55.24, 21.28. HRMS-ESI: m/z [M + H]+ calcd. for C15H14BrN2O: 317.0284; found: 317.0290. 3-Bromo-7-methyl-2-(p-tolyl)imidazo[1,2-a]pyridine (3l) Yield: 234 mg (78%); white solid; mp 176–178 °C; 1H NMR (400 MHz, CDCl3): δ = 8.00 (dd, J = 7.5, 5.8 Hz, 3 H), 7.37 (s, 1 H), 7.29–7.25 (m, 2 H), 6.70 (dd, J = 7.0, 1.5 Hz, 1 H), 2.40 (s, 6 H). 13C NMR (125 MHz, CDCl3): δ = 145.64, 142.27, 137.95, 136.02, 130.04, 129.08, 127.60, 122.98, 115.81, 115.49, 90.41, 77.00, 21.28. HRMS-ESI: m/z [M + H]+ calcd. for C15H14BrN2: 301.0348; found: 301.0340. 3-Bromo-2-(thiophen-2-yl)imidazo[1,2-a]pyrimidine (3m) Yield: 232 mg (84%); white solid; mp 150–152 °C; 1H NMR (400 MHz, CDCl3): δ = 8.56 (dd, J = 4.0, 1.8 Hz, 1 H), 8.40 (dd, J = 6.8, 1.8 Hz, 1 H), 7.95 (d, J = 3.6 Hz, 1 H), 7.45 (d, J = 5.0 Hz, 1 H), 7.20–7.14 (m, 1 H), 6.99 (dd, J = 6.8, 4.1 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ = 150.23, 147.99, 140.28, 135.12, 131.15, 127.74, 127.28, 126.71, 109.36, 89.31, 77.00. HRMS-ESI: m/z [M + H]+ calcd. for C10H7BrN3S: 279.9543; found: 279.9544. 3-Bromo-2-(3-nitrophenyl)imidazo[1,2-a]pyrimidine (3n) Yield: 214 mg (68%); white solid; mp 224–226 °C; 1H NMR (300 MHz, CDCl3+DMSO): δ = 9.12 (s, 1 H), 8.67 (dd, J = 4.1, 1.9 Hz, 1 H), 8.65–8.57 (m, 2 H), 8.27 (dd, J = 8.2, 1.2 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.15 (dd, J = 6.8, 4.1 Hz, 1 H). 13C NMR (75 MHz, CDCl3+DMSO): δ = 150.36, 147.28, 147.06, 139.91, 133.11, 132.40, 131.32, 128.71, 122.07, 121.29, 109.15, 90.40, 77.00. HRMS-ESI: m/z [M + H]+ calcd. for C12H8BrN4O2: 317.9749; found: 317.9752. 3-Bromo-7-methyl-2-(p-tolyl)imidazo[1,2-a]pyrimidine (3p) Yield: 241 mg (80%); brown solid; mp 180–182 °C; 1H NMR (400 MHz, CDCl3): δ = 8.28 (d, J = 7.0 Hz, 1 H), 8.14–8.10 (m, 2 H), 7.29 (d, J = 8.0 Hz, 2 H), 6.85–6.82 (m, 1 H), 2.66 (s, 3 H), 2.41 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 160.32, 148.05, 143.39, 138.52, 130.58, 129.60, 129.13, 127.73, 110.08, 88.91, 77.00, 24.84, 21.35. HRMS-ESI: m/z [M + H]+ calcd. for C13H11BrN3: 288.0140; found: 288.0136. HRMS-ESI: m/z [M + H]+, calcd. for C14H13BrN3: 302.0293; found: 302.0287. 3-Bromo-2-(4-methoxyphenyl)imidazo[1,2-a]pyrimidine (3q) Yield: 249 mg (82%); white solid; mp 154–156 °C; 1H NMR (400 MHz, CDCl3): δ = 8.57 (dd, J = 4.1, 2.0 Hz, 1 H), 8.45 (dd, J = 6.8, 2.0 Hz, 1 H), 8.22–8.16 (m, 2 H), 7.05–6.96 (m, 3 H), 3.88 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 160.16, 149.79, 148.14, 144.22, 131.18, 129.44, 124.79, 113.95, 109.14, 89.38, 77.00, 55.33. HRMS-ESI: m/z [M + H]+ calcd. for C13H10BrN3O: 304.0086; found: 304.0085. 3-Bromo-7-methoxy-2-(4-methoxyphenyl)benzo[d]imidazo [2,1-b]thiazole (12b) Yield: 251 mg (65%); white solid; mp 206–208 °C; 1H NMR (300 MHz, CDCl3): δ = 8.30 (d, J = 9.1 Hz, 1 H), 7.94 (d, J = 8.8 Hz, 2 H), 7.20 (d, J = 2.4 Hz, 1 H), 7.05–6.92 (m, 3 H), 3.87 (d, J = 4.5 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 159.34, 157.31, 147.08, 143.31, 131.54, 128.46, 127.18, 125.18, 114.26, 113.87, 113.06, 108.54, 90.89, 77.00, 55.88, 55.31. HRMS-ESI: m/z [M + H]+ calcd. for C17H14BrN2O2S: 388.9958; found: 388.9959. 3-Bromo-7-methoxy-2-(p-tolyl)benzo[d]imidazo[2,1-b]thiazole (12c) Yield: 260 mg (70%); pale-pink solid; mp 204–206 °C; 1H NMR (400 MHz, CDCl3): δ = 8.31 (d, J = 9.1 Hz, 1 H), 7.90 (d, J = 8.2 Hz, 2 H), 7.26 (t, J = 4.0 Hz, 2 H), 7.20 (d, J = 2.4 Hz, 1 H), 7.01 (dd, J = 9.0, 2.4 Hz, 1 H), 3.88 (s, 3 H), 2.40 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 157.27, 147.20, 143.74, 137.63, 131.56, 129.96, 129.11, 127.22, 126.99, 114.26, 112.96, 108.54, 91.33, 77.00, 55.86, 21.31. HRMS-ESI: m/z [M + H]+ calcd. for C17H14BrN2OS: 372.9967; found: 372.9954. 3-Chloro-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine (4c) Yield: 155 mg (57%); brown solid; mp 122–124 °C; 1H NMR (400 MHz, CDCl3): δ = 8.09–8.04 (m, 2 H), 7.97 (d, J = 7.0 Hz, 1 H), 7.39 (s, 1 H), 7.03–6.98 (m, 2 H), 6.75 (dd, J = 7.0, 1.5 Hz, 1 H), 3.87 (s, 3 H), 2.43 (d, J = 0.6 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 159.60, 143.98, 139.23, 135.94, 128.75, 125.19, 121.82, 115.80, 115.45, 113.99, 104.16, 55.34, 21.41. HRMS-ESI: m/z [M + H]+ calcd. for C15H14OClN2: 273.0792; found: 273.0789. 3-Iodo-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine (5c) Eluent: hexane/ethyl acetate, 90:10. Yield: 254 mg (70%); white solid; mp 118–120 °C; 1H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 7.0 Hz, 1 H), 8.00 (d, J = 8.7 Hz, 2 H), 7.35 (s, 1 H), 7.01 (d, J = 8.7 Hz, 2 H), 6.73 (d, J = 6.9 Hz, 1 H), 3.86 (s, 3 H), 2.43 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 159.56, 148.23, 147.52, 136.37, 129.59, 126.16, 125.43, 115.71, 115.45, 113.66, 77.00, 57.33, 55.22, 21.19. HRMS-ESI: m/z [M + H]+ calcd. for C15H14IN2O: 365.0146; found: 365.0151. 3-Thiocyanato-2-(p-tolyl)imidazo[1,2-a]pyrimidine (6g) Yield: 223 mg (84%); white solid; mp 208–210 °C; 1H NMR (300 MHz, CDCl3+DMSO): δ = 8.81 (ddd, J = 6.1, 5.5, 1.9 Hz, 2 H), 8.07 (d, J = 8.2 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 7.27 (dd, J = 6.7, 4.3 Hz, 1 H), 2.46 (s, 3 H). 13C NMR (75 MHz, CDCl3+DMSO): δ = 151.94, 138.92, 131.87, 128.45, 127.67, 126.76, 109.65, 77.00, 20.38. HRMS-ESI: m/z [M + H]+ calcd. for C14H11IN4S: 267.0695; found: 267.0699.