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

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.