The Vilsmeier–Haack Reaction

Abstract

The classical Vilsmeier-Haack reaction1,2 involves electrophilic substitution of a suitable carbon nucleophile with a chloromethyleneiminium salt, for example salt (1). Suitable carbon nucleophiles are generally electron-rich aromatic compounds such as N.N′-dimethylaniline (2), alkene derivatives such as styrene (3) or activated methyl or methylene compounds such as 2,4,6-trinitrotoluene (4; Scheme 1). These compounds (2–4) react with salt (1) giving, after loss of hydrogen chloride, the corresponding iminium salts (5–7). Hydrolysis of iminium salt (5) affords aldehyde derivative (8) and this transformation (ArH → ArCHO) is the well-known Vilsmeier-Haack formylation reaction. Hydrolysis of iminium salt (6) similarly yields the formylated product (9). Compounds that possess activated methyl or methylene groups such as 2,4,6-trinitrotoluene (4) react with salt (1) giving iminium salts like (7). Proton loss from iminium salt (7) affords the enamine derivative (10), which can participate in a further electrophilic substitution reaction with salt (1) giving vinylamidinium salt (11). Hydrolysis of this salt (11) yields the malondialdehyde derivative