Synlett 2019; 30(15): 1791-1794
DOI: 10.1055/s-0039-1690147
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 1,3,4-Thiadiazolo[2′,3′:2,3]imidazo[4,5-b]indoles

Behzad Jafari
a   Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   Email: peter.langer@uni-rostock.de
,
Sayfidin Safarov
a   Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   Email: peter.langer@uni-rostock.de
b   Institute of Chemistry, Tajikistan Academy of Sciences, ul. Aini 299, Dushanbe, 734063, Tajikistan
,
Muattar Khalikova
a   Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   Email: peter.langer@uni-rostock.de
b   Institute of Chemistry, Tajikistan Academy of Sciences, ul. Aini 299, Dushanbe, 734063, Tajikistan
,
Peter Ehlers
a   Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   Email: peter.langer@uni-rostock.de
,
Peter Langer
a   Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany   Email: peter.langer@uni-rostock.de
c   Leibniz Institut für Katalyse an der Universität Rostock e.V. (LIKAT), Albert-Einstein-Str. 29a, 18059 Rostock, Germany
› Author Affiliations
Further Information

Publication History

Received: 24 June 2017

Accepted after revision: 22 July 2019

Publication Date:
09 August 2019 (online)


Abstract

Hitherto unknown thiadiazolo[2′,3′:2,3]imidazo[4,5-b]indoles were synthesized for the first time by base-mediated cyclocondensation, bromination, and subsequent cyclization by two-fold Buchwald–Hartwig reactions.

Supporting Information

 
  • References and Notes

    • 1a Gadad AK, Mahajanshetti CS, Nimbalkar S, Raichurkar A. Eur. J. Med. Chem. 2000; 35: 853
    • 1b Ramprasad J, Nayak N, Dalimba U, Yogeeswari P, Sriram D, Peethambar SK, Achur R, Kumar HS. S. Eur. J. Med. Chem. 2015; 95: 49
    • 1c Ibraheem H, Al-Majedy Y, Al-Amiery A. Syst. Rev. Pharm. 2018; 9: 36
  • 2 Alwan WS, Karpoormath R, Palkar MB, Patel HM, Rane RA, Shaikh MS, Kajee A, Mlisana KP. Eur. J. Med. Chem. 2015; 95: 514
    • 3a Kolavi G, Hegde V, Khazi IA. Tetrahedron Lett. 2006; 47: 2811
    • 3b Hegde VS, Kolavi GD, Lamani RS, Khazi IA. M. J. Sulfur Chem. 2006; 27: 553
    • 4a Gadad AK, Palkar MB, Anand K, Noolvi MN, Boreddy TS, Wagwade J. J. Bioorg. Med. Chem. 2008; 16: 276
    • 4b Cristina A, Leonte D, Vlase L, Bencze LC, Imre S, Marc G, Apan B, Mogosan C, Zaharia V. Molecules 2018; 23: 2425
    • 5a Elkis Y, Cohen M, Yaffe E, Satmary-Tusk S, Feldman T, Hikri E, Nyska A, Feiglin A, Ofran Y, Shpungin S, Nir U. Nat. Commun. 2017; 8: 940
    • 5b Kumar R, Bua S, Ram S, De Prete S, Capaso C, Supuran CT, Sharma PK. Bioorg. Med. Chem. 2017; 25: 1286
    • 5c Patel HM, Sing B, Bhardwaj V, Palkar M, Shaikh MS, Rane R, Alwan WS, Gadad AK, Noolvi MN, Karpoormath R. Eur. J. Med. Chem. 2015; 93: 599
    • 5d Kamal A, Rao AV. S, Reddy TS, Polepalli S, Shaik SP, Bagul C, Vishnuvardhan MV. P. S, Jain N. Med. Chem. Commun. 2015; 6: 1842
    • 6a Temple KJ, Duvernay MT, Young SE, Wen W, Wu W, Maeng JG, Blobaum AL, Stauffer SR, Hamm HE, Lindsley CW. J. Med. Chem. 2016; 59: 7690
    • 6b Chen P, Ren S, Song H, Chen C, Chen F, Xu Q, Kong Y, Sun H. Bioorg. Med. Chem. 2019; 27: 116
  • 7 Khazi IA. M, Gadad AK, Lamani RS, Bhongade BA. Tetrahedron 2011; 67: 3289 ; and references cited therein
    • 8a Copin C, Henry N, Buron F, Routier S. Eur. J. Org. Chem. 2012; 3079
    • 8b Copin C, Massip S, Léger J.-M, Jarry C, Buron F, Routier S. Eur. J. Org. Chem. 2015; 6932
    • 8c Copin C, Buron F, Routier S. Eur. J. Org. Chem. 2016; 1958
    • 8d Copin C, Henry N, Buron F, Routier S. Synlett 2016; 27: 1091
    • 9a Janke J, Ehlers P, Villinger A, Langer P. Synlett 2019; 30: 817
    • 9b Do HH, Janke J, Amirjanyan A, Ghochikyan T, Flader A, Villinger A, Ehlers P, Lochbrunner S, Surkus A.-E, Langer P. Org. Biomol. Chem. 2018; 16: 6543
    • 9c Salman GA, Janke S, Pham NN, Ehlers P, Langer P. Tetrahedron 2018; 74: 1024 ; and references cited therein
    • 10a Jafari B, Rashid F, Safarov S, Ospanov M, Yelibayeva N, Abilov ZA, Turmukhanova MZ, Kalugin SN, Ehlers P, Umar MI, Zaib S, Iqbal J, Langer P. ChemistrySelect 2018; 3: 12213
    • 10b Jafari B, Ospanov M, Yelibayeva N, Ejaz SA, Khan SU, Amjad ST, Safarov S, Abilov ZA, Turmukhanova MZ, Kalugin SN, Ehlers P, Lecka J, Sévigny J, Iqbal J, Langer P. Eur. J. Med. Chem. 2018; 144: 116
    • 10c Jafari B, Yelibayeva N, Ospanov M, Ejaz SA, Afzal S, Khan SU, Abilov ZA, Turmukhanova MZ, Kalugin SN, Safarov S, Lecka J, Sévigny J, Raman Q, Ehlers P, Iqbal J, Langer P. RSC Adv. 2016; 6: 107556
    • 10d Jafari B, Jalil S, Zaib S, Safarov S, Khalikova M, Ospanov M, Yelibayeva N, Abilov ZA, Turmukhanova MZ, Kalugin SN, Ehlers P, Iqbal J, Langer P. ChemistrySelect 2019; 4: 7284
  • 11 Safarov S, Rahmon R, Kukaniev MA, Schollmeyer D, Karpuk E, Meier H. J. Heterocycl. Chem. 2008; 45: 299
  • 12 General Procedure A for the Synthesis of 6-(2-Bromophenyl)-2-ethyl-imidazo[2,1-b]-1,3,4-thiadiazole (3) 2-Amino-5-ethyl-1,3,4-thiadiazole (1.70 g, 13 mmol) and 2,2′-dibromoacetophenone (1.88 g, 6.8 mmol) were dissolved in n-butanol (50 mL). Afterwards, the reaction mixture was heated to reflux for 8 h. After cooling to room temperature, the crude compound was purified by flash column chromatography on silica gel (ethyl acetate/heptane).
  • 13 6-(2-Bromophenyl)-2-ethyl-imidazo[2,1-b]-1,3,4-thiadiazole (3) According to procedure A, product 3 (1.76 g, 84%) was isolated as a brownish solid; mp 110–112 °C. IR (ATR): ν = 3140 (w), 3069 (w), 2962 (w), 2869 (w), 1688 (m), 1608 (m), 1520 (s), 1445 (m), 1376 (m), 1261 (m), 1182 (s), 1015 (s), 938 (w), 853 (s), 759 (s) cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.39 (s, 1 H, CHAr), 8.01 (dd, 3 J = 7.9 Hz, 4 J = 1.9 Hz, 1 H, CHAr), 7.63 (dd, 3 J = 7.9 Hz, 4 J = 1.5 Hz, 1 H, CHAr), 7.34–7.39 (m, 1 H, CHAr), 7.10–7.16 (m, 1 H, CHAr), 3.01 (q, 3 J = 7.45 Hz, 2 H, CH2), 1.43 (t, 3 J = 7.53 Hz, 3 H, CH3). 13C NMR (75 MHz, CDCl3): δ = 166.3 (CAr), 144.6 (CAr), 143.3 (CAr), 134.5 (CAr), 133.9 (CHAr), 130.9 (CHAr), 128.7 (CHAr), 127.7 (CHAr), 121.0 (CAr), 113.4 (CHAr), 25.9 (CH2), 13.1 (CH3). MS (EI, 70 ev): m/z = 309 (77) [M]+, 307 (77) [M]+, 227 (29), 277 (40), 225 (28), 183 (32), 181 (32), 173 (52), 146 (100), 120 (5), 114 (7), 102 (41). HRMS: m/z calcd for C12H10N3 81BrS: 308.97529; found: 308.97518. HRMS: m/z calcd for C12H10N3BrS: 306.97773; found: 306.97720.
  • 14 General Procedure B for the Synthesis of 5-Bromo-6-(2-bromophenyl)-2-ethyl-imidazo[2,1-b]-1,3,4-thiadiazole (4) 6-(2-Bromophenyl)-2-ethyl-imidazo[2,1-b]-1,3,4-thiadiazole (3; 1.40 g, 3.6 mmol) dissolved in acetic acid (15 mL) and bromine (0.26 mL) dissolved in acetic acid (1.5 mL) were added dropwise at ambient temperature over 15 min. The reaction was vigorously stirred for 75 min. A saturated aqueous solution of NaOAc (410 mg, 5 mmol) was slowly added with cooling, the precipitate formed was collected by filtration, and the crude compound was purified by flash column chromatography on silica gel (ethyl acetate/heptane).
  • 15 5-Bromo-6-(2-bromophenyl)-2-ethyl-imidazo[2,1-b]-1,3,4-thiadiazole (4) According to procedure B, product 4 (1.35 g, 76%) was isolated as a yellow solid; mp 109–110 °C. IR (ATR): ν = 2979 (w), 2934 (w), 2915 (w), 1594 (w), 1524 (m), 1467 (s), 1426 (m), 1322 (m), 1284 (w), 1106 (s), 1044 (s), 977 (s), 754 (s), 724 (s), 669 (m), 638 (s) cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.69 (d, 3 J = 8.1 Hz, 1 H, CHAr), 7.47 (d, 3 J = 7.5 Hz, 1 H, CHAr), 7.38 (d, 3 J = 7.3 Hz, 1 H, CHAr), 7.28 (d, 3 J = 7.7 Hz, 1 H, CHAr), 3.09 (q, 3 J = 7.5 Hz, 2 H, CH2), 1.46 (t, 3 J = 7.8 Hz, 3 H, CH3). 13C NMR (62 MHz, DMSO): δ = 168.0 (CAr), 143.4 (CAr), 142.2 (CAr), 133.7 (CAr), 132.8 (CHAr), 132.4 (CHAr), 130.6 (CHAr), 127.5 (CHAr), 123.1 (CAr), 94.8 (CAr), 25.0 (CH2), 12.8 (CH3). MS (EI, 70 ev): m/z = 389 (35) [M]+, 387 (66) [M]+, 385 (33) [M]+, 253 (100), 251 (98), 226 (9), 201 (6), 172 (16), 151 (15), 149 (14), 146 (15), 128 (16), 120 (28), 102 (17). HRMS: m/z calcd for C12H9N3Br2S: 384.88784; found: 384.88737. HRMS: m/z calcd for C12H9N3Br81BrS: 386.88580; found: 386.88539. HRMS: m/z calcd for C12H9N3 81Br2S: 384.88375; found: 388.88329.
  • 16 General Procedure C for the Synthesis of 2-Ethyl-5-(substituted)-5H-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-b]indole 5a–g 5-Bromo-6-(2-bromophenyl)-2-ethyl-imidazo[2,1-b]-1,3,4-thiadiazole (4, 100 mg, 0.275 mmol), aniline derivative (0.412 mmol), Pd2(dba)3 (0.025 mmol), XantPhos (0.0750 mmol), NaOt-Bu (0.750 mmol) were heated in dry xylene (2 mL) at 150 °C for 24 h. After cooling to room temperature, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The crude compound was purified by flash column chromatography on silica gel (ethyl acetate/heptane).
  • 17 2-Ethyl-5-(p-tolyl)-5H-[1,3,4]thiadiazolo[2′,3′:2,3]-imidazo[4,5-b]indole (5a) According to procedure C, using p-toluidine, product 5a (73 mg, 84%) was isolated as a brown solid; mp 187–188 °C. IR (ATR): ν = 3034 (w), 2980 (w), 2939 (w), 2872 (w), 1606 (m), 1537 (m), 1513 (s), 1436 (m), 1380 (m), 1259 (s), 1186 (m), 1081 (w), 970 (w), 888 (w), 797 (s), 749 (m), 736 (s) cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.96–8.01 (m, 1 H, CHAr), 7.60–7.63 (m, 1 H, CHAr), 7.55 (d, 3 J = 8.4 Hz, 2 H, CHAr), 7.38 (d, 3 J = 8.5 Hz, 2 H, CHAr), 7.26–7.30 (m, 2 H, CHAr), 3.01 (q, 3 J = 7.6 Hz, 2 H, CH2), 2.47 (s, 3 H, CH3), 1.41 (t, 3 J = 7.6 Hz, 3 H, CH3). 13C NMR (75 MHz, CDCl3): δ = 164.5 (CAr), 144.0 (CAr), 138.7 (CAr), 136.9 (CAr), 134.1 (CAr), 131.3 (CAr), 130.3 (CHAr), 125.0 (CHAr), 122.8 (CHAr), 121.3 (CHAr), 120.3 (CAr), 119.3 (CAr), 118.6 (CHAr), 111.4 (CHAr), 26.0 (CH2), 21.4 (CH3), 13.3 (CH3). MS (EI, 70 ev): m/z = 332 (93) [M]+, 278 (10), 277 (40), 276 (100), 263 (9), 262 (50), 250 (5), 219 (36), 166 (8), 138 (26), 102 (12). HRMS: m/z calcd for C19H16N4S: 332.10902; found: 332.10875.