Straightforward Synthesis of Halopyridine Aldehydes via Diaminomethylation.

A novel two-step method for formylation of fluoropyridines with silylformamidine Me SiC(=NMe)NMe (1) under catalyst-free conditions was developed. A series of all possible 18 fluoropyridines featuring one to four fluorine atoms were subjected to the reaction with 1 existing in equilibrium with its carbenic form Me NC(:)N(Me)SiMe (1'). Among them, 12 fluoropyridines were shown to react via C-H insertion. The reaction proceeded either at β- or γ-positions affording the corresponding aminals. The more fluorine atoms in pyridines, the easier the reaction proceeded. We also hypothesized that the pyridines in which the fluorine was substituted by other halogens would react in a similar manner. To test the hypothesis, a set of 3,5-disubstituted pyridines with various combination of halogen atoms was prepared. 3,5-Difluoropyridine was taken as a compound for comparison. All the pyridines in the series also reacted likewise. In most cases, hydrolysis of the aminals afforded the corresponding aldehydes. As DFT calculations indicate, the reaction mechanism includes deprotonation of pyridine by 1' as a strong base and the following rearrangement of the formed tight ionic pair to the final product. An alternative reaction pathway involving addition of 1' to the pyridine carbon with the following hydrogen transfer via a three-membered transition state structure required much higher activation energy.