Synthesis of Partially Reduced Imidazo[1,2-a]pyridines through an Unprecedented Base-Mediated (4+2) Cyclization

Abstract

A water-mediated regioselective synthesis of 6,7-diaryl-5-oxo-2,3,5,6-tetrahydroimidazo[1,2-a]pyridine-6-carbonitriles was performed by the reaction of 2-[1-cyano-2,2-bis(methylsulfanyl)vinyl]benzonitrile with 1-aryl-2-(imidazolidin-2-ylidene)ethanones under basic conditions. This reaction involves an unprecedented (4+2) annulation.

Key words

imidazopyridines - ketene aminals - ketene dithioacetals - ­cyclizations

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• 18 7-Aryl-6-(2-cyanophenyl)-5-oxo-2,3,5,6-tetrahydroimidazo[1,2-a]pyridine-6-carbonitriles 5a–i; General Procedure A mixture of the appropriate 1-aryl-2-(imidazolidin-2-ylidene)ethanone 3 (0.5 mmol), 2-[1-cyano-2,2-bis(methylsulfanyl)vinyl]benzonitrile (4; 0.6 mmol), H₂O (0.6 mmol), and NaH (1.0 mmol) in DMSO (3.0 mL) was stirred at r.t. for 8 h. When the reaction was complete, the crude mixture was poured slowly onto ice–water with constant stirring. The mixture was then neutralized with 10% aq HCl. The resulting precipitate was collected by filtration, washed with H₂O, and dried. Products were purified by column chromatography (silica gel, EtOAc). 6-(2-Cyanophenyl)-5-oxo-7-phenyl-2,3,5,6-tetrahydroimidazo[1,2-a]pyridine-6-carbonitrile (5a) Brown solid; yield: 112 mg (66%); mp 130–132 °C. IR (KBr): 2924, 2225, 1606 cm^–1. ¹H NMR (400 MHz, CDCI₃): δ = 4.05–3.90 (m, 2 H, CH₂), 4.10–4.27 (m, 2 H, CH₂), 6.83 (s, 1 H, ArH), 7.13–7.22 (m, 5 H, ArH), 7.33 (t, J = 7.6 Hz, 1 H, ArH), 7.50–7.55 (m, 2 H, ArH), 7.81 (d, J = 7.6 Hz, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 43.5, 54.2, 54.8, 110.1, 115.3, 115.6, 120.1, 127.8, 128.5, 129.4, 129.7, 130.8, 133.3, 134.8, 134.9, 136.5, 144.2, 152.4, 158.7. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₁₅N₄O: 339.1240; found: 339.1238.
• 19 CCDC 1501042 and 1501043 contain the supplementary crystallographic data for compounds 5b and 8b, respectively. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures. 5b: C₂₁H₁₃FN₄O, M = 356.35, triclinic, P-1, a = 8.1557(9) Å, b = 8.6242(8) Å, c = 13.0701(13) Å, α = 109.147(9)°, β= 95.496(8)°, γ = 100.594(8)°, V = 841.50(16) ų, Z = 2, D _calc = 1.406 mg/m³, F(000) = 368, crystal size 0.p220 × 0.200 × 0.180 mm, reflections collected 6662, independent reflections 3844 [R _(int) = 0.0198], Final indices [I> 2σ(I)] R1 = 0.0519, wR2 = 0.0997, R indices (all data) R1 = 0.0854, wR2 = 0.1188, GoF 1.038, Largest difference peak and hole 0.168 and –0.220 e Å–3. 8b: C₂₁H₁₇N₃O₂, M = 343.38, monoclinic, P2_1/c , a = 9.9517(10) Å, b = 23.171(2) Å, c = 7.5232(7) Å, β = 105.529(10)°, V = 1671.4(3) ų, Z = 4, D_calc = 1.365 mg/m³, F(000) = 720, crystal size 0.210 × 0.200 × 0.170 mm, reflections collected 13503, independent reflections 3912 [R _(int) = 0.0663], Final indices [I> 2σ(I)] R1 = 0.0668, wR2 = 0.1530, R indices (all data) R1 = 0.0924, wR2 = 0.1741, GoF 1.078, Largest difference peak and hole 0.368 and –0.248 e Å–3.