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

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.

Key words

solvent free - grinding - regioselective substitution - in situ bromination - atom economy

• References and Notes

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• 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 (2a–d; 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.
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• 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.