Silica-Supported Glyoxylic Acid: A Traceless, Green Approach to the Groebke–Blackburn–Bienymé Reaction

Abstract

The first example of a formaldehyde equivalent covalently immobilized onto a silica surface is presented in a prototypical regioselective Groebke–Blackburn–Bienymé (GBB) reaction to afford 2-unsubstituted-3-aminoimidazo[1,2-a]heterocycles. The presence of a solid support facilitates the reaction without a solvent under microwave irradiation in good yields.

Key words

silica-supported glyoxylic acid - isocyanide - multicomponent reactions - solventless

• References and Notes

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• 17 Preparation of Glyoxyloyl Chloride (GA-Cl) Glyoxylic acid monohydrate (4.0 g, 44 mmol) was dissolved in excess SOCl₂ (12 mL, 164 mmol), and the mixture was heated to reflux for 48 h. Excess SOCl₂ was then removed under reduced pressure to furnish glyoxaloyl chloride as gum in 92% yield (3.7 g). Preparation of Si-Glyoxylate (Si-GA) Activated silica (15 g) was suspended in MeCN (30 mL), and glyoxyloyl chloride (3.7 g, 40 mmol) was added. The reaction mixture was cooled in an ice-bath at 0–5 °C, and NaH (1.2 g, 50 mmol) was added portionwise. The reaction mixture was warmed to r.t. and stirred for 12 h. After this time, the solvent was removed under reduced pressure, and the solid was washed with MeOH and dried to obtain 12 g of Si-GA. Further analysis of the Si-GA via complexation with DNPH and analysis with HPLC indicated an incorporation of 0.6 mmol/g. The supported reagent was stored at r.t. in a desiccator. One-Pot Reaction Procedure for the GBB Reaction Si-GA (1, 1.7 g, 1.0 mmol), 2-aminoazine 2a–e (1.0 mmol) and isonitrile 3a–c (1.2 mmol) were mixed in CH₂Cl₂ (1 mL), and then the solvent was removed under reduced pressure. The residue was irradiated for 5 min under MW irradiation. After completion of the reaction (TLC), CH₂Cl₂ was added to the solid and the mixture filtered. The solvent was removed under reduced pressure, and the residue was purified either by recrystallization or by column chromatography. N-tert-Butyl-6-methylimidazo[1,2-a]pyridin-3-amine (4a) Yield 74%; colorless crystals; mp 91–93 °C. IR (4000–600 cm^–1): ν_max = 3272, 2971, 1551, 1360, 1335, 800 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.16 (s, 9 H), 2.30 (s, 3 H), 2.68 (s, 1 H), 6.93 (d,J= 9.1 Hz, 1 H), 7.24 (s, 1 H), 7.38 (d, J = 9.14 Hz, 1 H), 7.95 (s, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 18.4, 29.6, 53.8, 116.8, 120.6, 120.9, 126.7, 128.6, 141.9 ppm. ESI-HRMS: m/z calcd for C₁₂H₁₇N₃: 204.1495 [M + H]⁺; found: 204.1511 [M + H]⁺. N-(2,6-Dimethylphenyl)-6-methylimidazo[1,2-a]pyridin-3-amine (4c) Yield 75%; colorless crystals; mp 156–158 °C. IR (4000–600 cm^–1): ν_max = 3237, 2881, 2363, 1659, 1414, 1383, 1227, 780, 710, 645 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.06 (s, 6 H), 2.34 (s, 3 H), 4.99 (br s, 1 H), 6.89 (t, 1 H, J = 8.2 Hz), 7.00 (m, 4 H), 7.44 (d, 1 H, J = 10.2 Hz), 7.89 (s, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 18.1, 18.5, 117.2, 119.7, 122.0, 122.9, 124.4, 126.8, 129.1, 129.2, 141.0, 141.3 ppm. ESI-HRMS: m/z calcd for C₁₆H₁₇N₃: 252.1495 [M + H]⁺; found: 252.1508 [M + H]⁺. N-(2,6-Dimethylphenyl)imidazo[1,2-a]pyrazin-3-amine (4d) Yield 63%; orange crystals; mp 145–147 °C. IR (4000–600 cm^–1): ν_max = 3286, 2940, 1544, 1475, 1314, 1055, 791, 769 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.93 (s, 6 H), 4.35 (br s, 1 H), 6.64 (s, 1 H), 6.86 (m, 1 H), 6.95 (d, 2 H, J = 7.4 Hz), 7.71 (d, 1 H, J = 4.7 Hz), 8.13 (d, 1 H, J= 6.5 Hz), 8.74 (s, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 18.2, 115.4, 124.9, 126.4, 127.5, 131.4, 136.5, 138.7, 141.9, 142.0 ppm. ESI-HRMS: m/z calcd for C₁₆H₁₇N₃: 239.1291 [M + H]⁺, 261.1110 [M + Na]⁺; found: 239.1299 [M + H]⁺, 261.1116 [M + Na]⁺. N-(2,6-Dimethylphenyl)-7-methylimidazo[1,2-a]pyridin-3-amine (4e) Yield 69%; yellowish viscous liquid. IR (4000–600 cm^–1): ν_max = 3231, 2360, 1644, 1561, 1414 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.02 (s, 3 H), 2.19 (s, 6 H), 5.37 (br s, 1 H), 6.86 (t, 1 H, J = 8.2 Hz), 6.98 (m, 1 H), 7.63 (m, 1 H), 7.95 (s, 1 H), 8.02 (d, 1 H, J = 6.9 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 18.1, 21.4, 110.7, 114.7, 121.9, 121.2, 129.2, 141.7, 151.9, 157.3, 162.7 ppm. ESI-HRMS: m/z calcd for C₁₆H₁₇N₃: 252.1495 [M + H]⁺; found: 252.1484 [M + H]⁺. N-(2,6-Dimethylphenyl)-5-methylimidazo[1,2-a]pyridin-3-amine (4g) Yield 65%; reddish viscous liquid. IR (4000–600 cm^–1): ν_max = 3248, 2924, 2854, 1639, 1559, 1509, 1289, 1145, 1035, 772, 733 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.04 (s, 6 H), 2.94 (s, 3 H), 5.17 (br s, 1 H), 6.44 (m, 2 H), 6.84 (t, 2 H, J = 7.3 Hz), 7.28 (t, 1 H, J = 7.3 Hz), 7.32 (s, 1 H), 7.35 (s, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 18.5, 20.4, 113.5, 116.3, 122.3, 123.9, 127.1, 128.0, 135.8, 138.5, 142.6, 143.9 ppm. ESI-HRMS: m/z calcd for C₁₆H₁₇N₃: 252.1495 [M + H]⁺; found: 252.1488 [M + H]⁺. N-tert-Butyl-7-methylimidazo[1,2-a]pyridin-3-amine (4h) Yield 69%; yellow viscous liquid. IR (4000–600 cm^–1): ν_max = 3240, 2924, 2854, 1639, 1559, 1471, 1145 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.29 (s, 9 H), 2.23 (s, 3 H), 4.49 (br s, 1), 6.40 (d, 1 H, J = 5.8 Hz), 6.55 (s, 1 H), 6.84 (m, 1 H), 7.68 (d, 1 H, J = 6.0 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 20.5, 28.7, 52.1, 110.5, 113.1, 116.6, 124.1, 125.3, 152.0, 155.3 ppm. ESI-HRMS: m/z calcd for C₁₂H₁₇N₃: 204.1495 [M + H]⁺; found: 204.1507 [M + H]⁺.
• 18 Sharma A, Li H.-Y. Synlett 2011; 1407