One-Pot Sequential Hydroamination Protocol for N-Heterocycle Synthesis: One Method To Access Five Different Classes of Tri- Substituted Pyridines

Tri-substituted pyridines are important scaffolds that can be found in a plethora of commercially available drugs. A one pot general method for the selective synthesis of less explored/ challenging patterns of tri-substituted pyridines is described. Hydroamination of alkynes with commercially available Ntriphenylsilylamine generates N-silylenamines. These in situ generated N-silylenamines, upon reaction with alpha ,beta-unsaturated carbonyl compounds and subsequent oxidation, furnish 25 examples of selectively substituted 2,4,5-, 2,3,4-, 3,4,5-, 2,3,5-, and 2,3,6trisubstituted pyridines in up to 78% yield. The reaction features high functional group compatibility providing an expeditious and general approach for the assembly of selectively substituted trisubstituted pyridine derivatives. The robustness and practicality of the reaction have been demonstrated in a gram-scale reaction.

Automated summary

This paper describes a selective synthesis method for tri-substituted pyridines. The hydroamination of alkynes with commercially available N-triphenylsilylamine generates N-silylenamines, which upon reaction with alpha, beta-unsaturated carbonyl compounds and subsequent oxidation, produces selectively substituted 2,4,5-, 2,3,4-, 3,4,5-, 2,3,5-, and 2,3,6-trisubstituted pyridines in up to 78% yield. The reaction shows high functional group compatibility and provides an efficient and general approach for selectively assembling trisubstituted pyridine derivatives.