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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
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Publikationsverlauf

Received: 24. Juni 2017

Accepted after revision: 22. Juli 2019

Publikationsdatum:
09. August 2019 (online)

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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.

Key words

Buchwald–Hartwig reaction - cyclizations - imidazothiazoles - palladium

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0039-1690147.
  • Supporting Information
 

  • References and Notes

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  • 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.