Optimizing Amine‐Mediated Alkyne–Allene Isomerization to Improve Benzannulation Cascades: Synergy between Theory and Experiments

Abstract

A synergy between theory and experiments leads to a milder protocol for base‐mediated high‐temperature benzannulation of alkynylpyridine substrates. Computational analysis identifies mechanistic and energetic nuances in the previously postulated 1,3‐proton transfer isomerization which results in replacement of DBU with a bicyclic guanidine, 1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene (TBD). We have also outlined the general stereoelectronic and geometric hurdles for the design of 1,3‐proton transfer catalysts. Considerable reductions in time, temperature, and equivalents of base underscore the potential of computational analysis to impact experimental design in the laboratory.