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Optimizing Amine‐Mediated Alkyne–Allene Isomerization to Improve Benzannulation Cascades: Synergy between Theory and Experiments
Author(s) -
dos Passos Gomes Gabriel,
Morrison Alec E.,
Dudley Gregory B.,
Alabugin Igor V.
Publication year - 2019
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201801052
Subject(s) - chemistry , isomerization , allene , alkyne , computational chemistry , bicyclic molecule , guanidine , base (topology) , catalysis , combinatorial chemistry , amine gas treating , superbase , organic chemistry , mathematical analysis , mathematics
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.