Microwave-assisted synthesis of 4-oxo-2-butenoic acids by aldol-condensation of glyoxylic acid

Abstract

A new method for the synthesis of 4-oxo-2-butenoic acids is described by aldol condensation with methyl ketones. Substrate dependent conditions are rationalised mechanistically with quantum mechanically derived molecular orbital energies.

Build–Couple–Transform: A Paradigm for Lead-like Library Synthesis with Scaffold Diversity

“…For those carboxylic acids ( 2 ) not commercially available, the α,β-unsaturated system was accessed via an aldol condensation between the appropriate methylketone 3 and glyoxylic acid 4 using microwave conditions with pyrrolidinium acetate or p -toluenesulfonic acid ( Scheme 3 a). 21 Alternatively, electron rich arenes directly underwent Friedel–Crafts acylation with maleic anhydride 5 to generate carboxylic acids 2 in moderate yields ( Scheme 3 b).…”

“…R f = 0.65 (80% EtOAc in PE); mp = 180–182 °C; UV λ max (EtOH/nm) 287.2, 223.6, 200.0; FTIR (cm –1 ) ν 2840 (b, m, O–H acid), 1699 (s, CO acid), 1661 (s, CO ketone), 1592 (s, CC alkene), 1511 (s, CC aromatic), 1420 (s, O–H acid); 1 H NMR (chloroform- d , 500 MHz) δ 3.90 (3H, s), 6.88 (1H, d, J = 15.5 Hz), 6.97–7.02 (2H, m), 7.97–8.05 (3H, m); 13 C NMR (chloroform- d , 126 MHz) δ 55.77, 114.39, 129.6, 130.61, 131.55, 138.77, 164.57, 169.84, 187.48; MS­(ES+) m / z 207.2. Data are in accordance with ref .…”

“…R f = 0.32 (5% MeOH in DCM); mp = 113–115 °C; UV λ max (EtOH/nm) 330.8, 219.8; FTIR (cm –1 ) ν 3062 (b, m, O–H acid), 2922 (s, C–H alkane), 2851 (s, C–H alkane), 1660 (s, CO acid), 1427 (s, O–H acid); 1 H NMR (methanol- d 4 , 500 MHz) δ 1.05–1.21 (5H, m), 1.51–1.67 (5H, m), 2.50 (1H, tt, J = 10.7, 3.4 Hz), 6.42 (1H, d, J = 15.9 Hz), 6.91 (1H, d, J = 15.9 Hz); 13 C NMR (methanol- d 4 , 126 MHz) δ 26.49, 29.31, 50.35, 132.21, 139.56, 168.50, 204.38; MS­(ES+) m / z 183.1 [M + H] + ; HRMS calcd for C 10 H 14 O 3 [M – H] − 181.0870, found 181.0870. Data are in accordance with ref .…”

“…R f = 0.12 (10% MeOH in DCM); mp = 134–140 °C; UV λ max (EtOH/nm) 256.4; FTIR (cm –1 ) ν 3063 (b, m, O–H acid), 2231 (w, CN); 1 H NMR (methanol- d 4 , 500 MHz) δ 6.83 (1H, d, J = 15.6 Hz), 7.91 (1H, d, J = 15.6 Hz), 7.93 (2H, d, J = 8.4 Hz), 8.17 (2H, d, J = 8.4 Hz); 13 C NMR (methanol- d 4 , 126 MHz) δ 117.86, 118.87, 130.43, 133.93, 135.05, 136.84, 141.19, 168.23, 190.30; MS (ES+) m / z = 201.1 [M – H] − ; HRMS calcd for C 11 H 7 NO 3 200.0348 [M + H] + , found 200.0363. Data in accordance with ref .…”

“…General Procedure 19 (21). A solution of ketoenamide 1 (1.0 equiv) and K 2 CO 3 (2.0 equiv) was dissolved in 1 mL of H 2 O/dioxane 4:1 (0.08 M).…”