Synthesis of Substituted Pyridines via Formal (3+3) Cycloaddition of Enamines with Unsaturated Aldehydes and Ketones

Abstract

An organocatalyzed, formal (3+3) cycloaddition reaction is described for the practical synthesis of substituted pyridines. Starting from readily available enamines and enal/ynal/enone substrates, the protocol affords tri- or tetrasubstituted pyridine scaffolds bearing various functional groups. This method was demonstrated on a 50 g scale, enabling the synthesis of 2-isopropyl-4-methylpyridin-3-amine, a raw material used for the manufacture of sotorasib. Mechanistic analysis using two-dimensional nuclear magnetic resonance (NMR) spectrometry revealed the transformation proceeds through the reversible formation of a stable reaction off-cycle species that precedes pyridine formation. In situ reaction progress kinetic analysis and control NMR studies were employed to better understand the role of FeCl3 and pyrrolidine hydrochloride in promoting the reaction.

Thioarylation of 6‐Amino‐2,3,6‐trideoxy‐d‐manno‐oct‐2‐ulosonic Acid (IminoKdo): Access to 3,6‐Disubstituted Picolinates and Mechanistic Insights

“…[18] Due to the medicinal significance of the pyridine scaffold, substantial efforts have been dedicated to developing methodologies for synthesizing functionalized pyridines. Such approaches encompass the preparation of pyridines through multicomponent synthesis, [19] cycloaddition reactions, [20] and cross-coupling chemistry. [21] However, limits in chiral resolution, [22] low reactivity, [23] and poor regioselectivity [24] still make the functionalization of the pyridine ring a strategic synthetic challenge.…”