Vilsmeier-Haack reaction solvents

Acylthiophenes. Manufacturing methods introducing the carboxaldehyde group into the 2- or 5-positions of thiophene and alkylthiophenes utilise the Vilsmeier-Haack reaction. To synthesize 2-thiophenecarboxaldehyde (Table 5), a controlled addition of phosphoms oxychloride to thiophene in /V, /V- dim ethyl form am i de is carried out, causing the temperature to rise. Completion of the reaction is followed by an aqueous quench, neutralization, and solvent extraction to isolate the product. 

Solvents for the Vilsmeier-Haack reaction include DMF (the most common), POCI3 and chlorinated alkanes such as dichloromethane, chloroform and tetrachloromethane. The choice of solvent and conditions is often an important consideration in Vilsmeier-Haack reactions when both mono- and di-sub-stituted products can be formed. 

A variation of the Vilsmeier-Haack reaction uses a formamide such as 211 with benzene (or another aromatic compound) to give the aromatic aldehyde (benzaldehyde) and the amine precursor to the formamide (N-methylaniline in this case). A solvent-free Vilsmeier reaction has been reported using microwave irradiation on silica gel. 39... 

Gupta et al. reported that the Vilsmeier-Haack cyclisation of acetanilides 20 using supported reagents and microwave-irradiation in solvent-free conditions is rapid and efficient. Reaction yields are good, although only a few activated derivatives have been investigated. 

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