Homologation Reaction by Ketene Dithioacetalization

A Horner-Emmons reagent, diethyl (1,3-dithian-2-yl)phosphonate (1), reacts with aldehydes and ketones to afford the ketene dithioacetals. After deprotection, followed by hydrolysis or alkolysis, the intermediate ketenes can be converted to the corresponding homologous carboxylic acids or esters in good yields. The one-carbon homologation reaction is an important transformation in organic synthesis.

Typical Procedure:
To a solution of (1,3-dithian-2-yl)phosphonate (0.371 g, 1.45 mmol) in THF (15 mL) at -78 °C is added n-BuLi (0.9 mL, 1.45 mmol, 1.6 M in hexane), and the mixture is stirred for 1 hour. The aldehyde (0.240 g, 1.32 mmol) in THF (5 mL) is added while stirring for 15 minutes. The cooling bath is removed, and stirring is continued for 30 minutes. The reaction mixture is quenched with NH₄Cl solution (5 mL) extracted with ether (50 mL), and the organic layer is concentrated and purified by silica gel chromatography (2% EtOAc in hexanes) to afford the ketene dithioacetal as a pale yellow oil (0.276g, 73%). The obtained ketene dithioacetal (0.220 g, 0.77 mmol) is dissolved in a methanolic solution of CuSO₄ (30 mL, 0.2 M) and heated at 65 °C for 2.5 hours. After concentration, the residue is diluted with EtOAc (40 mL) and water (5 mL). The organic layer is concentrated and purified by column (3% EtOAc in hexanes) to give the desired one-carbon homologated methyl ester (0.150 g, 85%) as a colorless viscous oil.