Mechanistic Insights into the B(C6F5)3-Initiated Aldehyde-Aniline-Alkyne Reaction to Form Substituted Quinolines

Article abstract of DOI:10.1021/acs.organomet.7b00174

A substoichiometric quantity of the Lewis acid B(C₆F₅)₃ is sufficient to initiate the aldehyde-amine-alkyne reaction, in a one-pot methodology that enables the synthesis of a range of functionalized quinolines. Optimization studies revealed that key requirements for the high-yielding tricomponent reaction initiated by B(C₆F₅)₃ at raised temperatures include an excess of the in situ generated imine (which acts as a hydrogen acceptor) and an alkyne substituent able to stabilize positive charge buildup during the cyclization. Mechanistic experiments revealed that under these conditions B(C₆F₅)₃ is acting as a Lewis acid-assisted Br?nsted acid, with H₂O-B(C₆F₅)₃ being the key species enabling catalytic quinoline formation. This was indicated by deuterium labeling studies and the observation that the cyclization of N-(3-phenylpropargyl)aniline using B(C₆F₅)₃ under anhydrous conditions afforded the zwitterion [(N-H-3-B(C₆F₅)₃-4-Ph-quinolinium], which does not undergo protodeboronation to release B(C₆F₅)₃ and the quinoline product under a range of conditions. Finally, a brief substrate scope exploration demonstrated that this is an operationally simple and effective methodology for the production of functionalized quinolines.