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

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

• 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, CH_Ar), 8.01 (dd, ³ J = 7.9 Hz, ⁴ J = 1.9 Hz, 1 H, CH_Ar), 7.63 (dd, ³ J = 7.9 Hz, ⁴ J = 1.5 Hz, 1 H, CH_Ar), 7.34–7.39 (m, 1 H, CH_Ar), 7.10–7.16 (m, 1 H, CH_Ar), 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 (C_Ar), 144.6 (C_Ar), 143.3 (C_Ar), 134.5 (C_Ar), 133.9 (CH_Ar), 130.9 (CH_Ar), 128.7 (CH_Ar), 127.7 (CH_Ar), 121.0 (C_Ar), 113.4 (CH_Ar), 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, CH_Ar), 7.47 (d, ³ J = 7.5 Hz, 1 H, CH_Ar), 7.38 (d, ³ J = 7.3 Hz, 1 H, CH_Ar), 7.28 (d, ³ J = 7.7 Hz, 1 H, CH_Ar), 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 (C_Ar), 143.4 (C_Ar), 142.2 (C_Ar), 133.7 (C_Ar), 132.8 (CH_Ar), 132.4 (CH_Ar), 130.6 (CH_Ar), 127.5 (CH_Ar), 123.1 (C_Ar), 94.8 (C_Ar), 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, CH_Ar), 7.60–7.63 (m, 1 H, CH_Ar), 7.55 (d, ³ J = 8.4 Hz, 2 H, CH_Ar), 7.38 (d, ³ J = 8.5 Hz, 2 H, CH_Ar), 7.26–7.30 (m, 2 H, CH_Ar), 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 (C_Ar), 144.0 (C_Ar), 138.7 (C_Ar), 136.9 (C_Ar), 134.1 (C_Ar), 131.3 (C_Ar), 130.3 (CH_Ar), 125.0 (CH_Ar), 122.8 (CH_Ar), 121.3 (CH_Ar), 120.3 (C_Ar), 119.3 (C_Ar), 118.6 (CH_Ar), 111.4 (CH_Ar), 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.