Efficient C-7 or C-3/C-7 Direct Arylation of Tri- or Disubstituted Imidazo[1,2-b]pyrazoles

Abstract

A novel and efficient method of C-7 direct arylation of the imidazo[1,2-b]pyrazole core, never described to date, is presented in this paper. Series of electron-rich or electron-poor aryl and heteroaryl groups were easily introduced. The corresponding products were obtained in moderate to excellent yields thanks to this ­pallado-catalyzed and microwave-assisted process. A one-pot ­double C-3 and C-7 direct coupling is also reported.

Key words

C–C coupling - arylation - fused-ring systems - microwave chemistry - palladium

• References and Notes

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• 15 General Procedure A; C-7 Direct Arylation of the Imidazo[1,2-b]pyrazoles 1–5: A microwave vial containing a stirring bar was loaded with imidazo[1,2-b]pyrazole 1–5 in 1,4-dioxane, (hetero)aryl bromide or chloride (2.0 equiv), tricyclohexylphosphine tetrafluoroborate (0.20 equiv) and cesium carbonate (2.0 equiv). The tube was evacuated and backfilled with dry argon twice. Palladium acetate (0.10 equiv) was added and the mixture was submitted to microwave irradiation with stirring at 160 °C for 4 h. It was then cooled to r.t., and 1,4-dioxane was removed under reduced pressure. The residue was purified by flash chromatography to provide the desired products 1a–5b. 2-(4-Methoxyphenyl)-1-methyl-6-phenyl-3-(4-tolyl)-7-[4-(trifluoromethyl)phenyl]-1H-imidazo[1,2-b]pyrazole (1b): The reaction was carried out as described in general procedure A using imidazo[1,2-b]pyrazole 1 (100 mg, 0.254 mmol), palladium acetate (5.7 mg, 0.0254 mmol), tricyclohexylphosphine tetrafluoroborate (18.7 mg, 0.0508 mmol), cesium carbonate (142 mg, 0.508 mmol) and 4-bromobenzotrifluoride (114 mg, 72 μL, 0.508 mmol) in 1,4-dioxane (2 mL). Standard workup followed by flash chromatography (CH₂Cl₂–petroleum ether, 1:1) yielded 1b as a pale yellow solid (123 mg, 90%); mp 226–228 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.71 (d, J = 8.1 Hz, 2 H, H_Ar), 7.58 (d, J = 8.4 Hz, 2 H, H_Ar), 7.53 (d, J = 7.9 Hz, 2 H, H_Ar), 7.47 (d, J = 8.1 Hz, 2 H, H_Ar), 7.33 (d, J = 8.5 Hz, 2 H, H_Ar), 7.25–7.29 (m, 3 H, H_Ar), 7.12 (d, J = 8.1 Hz, 2 H, H_Ar), 7.00 (d, J = 8.5 Hz, 2 H, H_Ar), 3.88 (s, 3 H, OMe), 3.30 (s, 3 H, NMe), 2.32 (s, 3 H, Me). ¹³C NMR (101 MHz, CDCl₃): δ = 160.31 (C_q), 152.26 (C_q), 140.07 (C_q), 137.17 (C_q), 136.82 (C_q), 134.27 (C_q), 132.46 (CH_Ar), 130.97 (CH_Ar), 129.19 (C_q), 129.03 (CH_Ar), 128.87 (CH_Ar), 128.18 (CH_Ar), 127.87 (² J _C–F = 33.0 Hz, C_q), 127.42 (CH_Ar), 127.14 (CH_Ar), 125.63 (C_q), 125.14 (³ J _C–F = 3.72 Hz, CH_Ar), 124.41 (¹ J _C–F = 273 Hz, C_q), 121.13 (C_q), 118.42 (C_q), 114.64 (CH_Ar), 94.33 (C_q), 55.34 (OMe), 31.73 (NMe), 21.29 (Me). IR (neat): 1603, 1322, 1118, 1066, 838, 697 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for C₃₃H₂₇F₃N₃O: 538.21007; found: 538.21007. HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₃H₂₇F₃N₃O: 560.19202; found: 560.19113. General Procedure B; One-Pot C-3 and C-7 Direct Arylation of Imidazo[1,2-b]pyrazole 6: A microwave vial containing a stirring bar was loaded with imidazo[1,2-b]pyrazole 6 in 1,4-dioxane, (hetero)aryl bromide (3.0 equiv), tricyclohexylphosphine tetrafluoroborate (0.20 equiv) and cesium carbonate (4.0 equiv). The tube was evacuated and back-filled with dry argon twice. Palladium acetate (0.10 equiv) was added and the mixture was submitted to microwave irradiation with stirring at 160 °C for 4 h. It was then cooled to r.t., and 1,4-dioxane was removed under reduced pressure. The residue was purified by flash chromatography to provide the desired products 1a, 6a and 6b. 2-(4-Methoxyphenyl)-1-methyl-6-phenyl-3,7-bis[4-(trifluoromethyl)phenyl]-1H-imidazo[1,2-b]pyrazole (6a): The reaction was carried out as described in general procedure B using imidazo[1,2-b]pyrazole 6 (100 mg, 0.329 mmol), palladium acetate (8.04 mg, 0.0329 mmol), tricyclohexylphosphine tetrafluoroborate (24.0 mg, 0.0658 mmol), caesium carbonate (369 mg, 1.32 mmol) and 4-bromobenzotrifluoride (222 mg, 138 μL, 0.987 mmol) in 1,4-dioxane (2 mL). Standard workup followed by flash chromatography (CH₂Cl₂–petroleum ether, 3:7) yielded 6a as a white solid (151 mg, 78%); mp 220–222 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.01 (d, J = 8.4 Hz, 2 H, H_Ar), 7.47–7.64 (m, 8 H, H_Ar), 7.29–7.41 (m, 5 H, H_Ar), 7.07 (d, J = 8.4 Hz, 2 H, H_Ar), 3.92 (s, 3 H, OMe), 3.33 (s, 3 H, NCH₃). ¹³C NMR (101 MHz, CDCl₃): δ = 160.76 (C_q), 152.49 (C_q), 140.08 (C_q), 136.81 (C_q), 133.96 (C_q), 132.34 (CH_Ar), 132.28 (C_q), 131.09 (C_q), 131.05 (CH_Ar), 128.78 (CH_Ar), 128.37 (² J _C–F = 32.6 Hz, C_q), 128.27 (CH_Ar), 128.20 (² J _C–F = 32.8 Hz, C_q), 127.64 (CH_Ar), 126.73 (CH_Ar), 125.25 (³ J _C–F = 3.70 Hz, 2 × CH_Ar), 124.36 (¹ J _C–F = 273 Hz, C_q), 124.18 (¹ J _C–F = 273 Hz, C_q), 120.39 (C_q), 117.03 (C_q), 114.99 (CH_Ar), 94.65 (C_q), 55.39 (OMe), 31.74 (NMe). IR (neat): 1613, 1320, 1249, 1162, 1103, 1076, 1064, 1016, 834 cm^–1. HRMS (ESI): m/z [M + H] calcd for C₃₃H₂₄F₆N₃O: 592.18181; found: 592.18163.