Formylation [Synthetic Reagents]

Formyl group-containing compounds are important building blocks in organic synthesis since the formyl group can be transformed to other various functional groups. Aldehydes are the most typical formyl group-containing compound and are widely used as a substrate for carbon-carbon bond forming reactions such as the aldol reaction and the Wittig reaction.^1-2) Also, their oxidation/reduction converts them to the related alcohols and carboxylic acids respectively, while the reductive amination is an efficient functional transformation of the formyl group into amines.^3-5) As above reactions,the formyl group is a versatile precursor of organosynthetic reactions and a number of various formyl group introducing reagents have been developed.
Reagents for the formylation are classified into three types according to their reactivity and substrates: (1) electrophilic aromatic substitution, (2) reaction with carbon nucleophiles, and (3) direct formylation at oxygen or nitrogen atoms.

Vilsmeier reagent is a strong electrophile and formylates electron-rich alkenes and aromatic rings by electrophilic aromatic substitution.⁶⁾ This reagent is widely used and can be prepared by the reaction of DMF or N-methylformanilide with phosphoryl chloride.⁷⁾ The Duff reaction using hexamethylenetetramine is effective to formylate electron-rich aromatic compounds such as phenols and indoles.⁸⁾ Furthermore, the Riecke reaction using dichloromethyl methyl ether is suitable for formylation at the sterically hindered site of substances.⁹⁾

Formyl group-containing compounds can be also synthesized by the reaction of Grignard reagents or organolithium compounds with N,N-disubstituted formamides, orthoformates, N-methoxymethyleneaniline and so on (Bouveault/ Bodroux-Chichibabin aldehyde synthesis).^10,11) In addition, it is known that the direct C-formylation of ketones can be performed by the reaction of related ketone enolates with TFEF.¹²⁾

N-Formylsaccharin, cyanomethyl formate,^13-15) and 1-formyl-1H-benzotriazole work as O/N-formylating reagents, and successfully react with alcohols and amines under mild conditions to afford the desired O/N-formylated compounds. Especially, N-formylsaccharin can be used not only as a formylating reagent but also as a carbon monoxide introducing reagent.