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

• Published in: RSC advances Vol. 11; no. 48; pp. 3229 - 3236
• Main Authors: Uguen, Mélanie, Gai, Conghao, Sprenger, Lukas J, Liu, Hang, Leach, Andrew G, Waring, Michael J
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 05.10.2021; The Royal Society of Chemistry
• Subjects: Acetic acid; Acids; Aldehydes; Chemical synthesis; Chemistry; Condensates; Glyoxylic acid; Substrates
• ISSN: 2046-2069; 2046-2069
• DOI: 10.1039/d1ra05539a

4-Oxobutenoic acids are useful as biologically active species and as versatile intermediates for further derivatisation. Currently, routes to their synthesis can be problematic and lack generality. Reaction conditions for the synthesis of 4-oxo-2-butenoic acid by microwave-assisted aldol-condensation between methyl ketone derivatives and glyoxylic acid have been developed. They provide the desired products in moderate to excellent yields for a wide range of substrates, by applying a simple procedure to accessible starting materials. The investigation revealed different conditions are required depending on the nature of the methylketone substituent, with aryl derivatives proceeding best using tosic acid and aliphatic substrates reacting best with pyrrolidine and acetic acid. This substituent effect is rationalised by frontier orbital calculations. Overall, this work provides methods for synthesis of 4-oxo-butenoic acids across a broad range of substrates. 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.