Pyrrole-2-carbaldehyde Vilsmeier-Haack reaction

The Vilsmeier-Haack reaction (herein, Vilsmeier reaction ) provides an effective method for the formylation of aromatic systems. The combination of phosphoryl chloride with V-methylaniline or dimethylformamide generates an iminium phosphorus derivative or chloro-iminium cation that is the active electrophile in an electrophilic substitution reaction. The resulting substitution product is an iminium salt 1, which is hydrolyzed on workup with alkali to give the carbaldehyde product 2 (Scheme l).1,2 The method is particularly useful with activated arenes or electron-rich heterocycles, such as pyrroles, furans, thiophenes, and indoles. We had a special interest in the preparation of indole-7-carbal-dehydes, namely, their properties as isosteres of salicylaldehyde. Thus, we became involved in a wide-ranging investigation of 4,6-dimethoxy-... 

As is the case with pyrroles, C-alkylation of indoles results in mixtures of products. Formylation and acylation, however, occur more readily. The Vilsmeier-Haack reaction furnishes indole-3-carbaldehyde heating with acetic anhydride produces 3-acetylindole. In the Houben-Hoesch acylation, substitution takes place in the 3-position. 

Alkylation of pyrroles proves to be problematic because the usual Lewis acid catalysts initiate polymerization. The Vilsmeier-Haack formylation, however, leads to the formation of pyrrole-2-carbaldehyde in good yield. The Houben-Hoesch acylation (reaction with nitriles in the presence of hydrogen chloride) provides 2-acylpyrroles ... 

Formylation of N-vinylpyrroles proceeds under conditions of the Vilsmeier-Haack classical reaction (dimethylformamide (DMF)/POCl3, 1,2-dichloroethane, reflux) to afford mixtures of N-vinyl- and NH-pyrrole-2-carbaldehydes in low yields. For example, from N-vinyl-4,5,6,7-tetrahydroindole, a mixture of the expected N-vinyl-4,5,6,7-tetrahydroindole-2-carbaldehyde and 4,5,6,7-tetrahydroindole-2-carbalde-hyde is formed ( 1 1) (Scheme 2.131) [87]. 

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