Mechanistic insights into the B(C6F5)3-initiated aldehyde-aniline-alkyne reaction to form substituted quinolines

Sub-stoichiometric quantities 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 tri-component reaction initiated by B(C₆F₅)₃ at raised temperatures include an excess of the in-situ generated imine (which acts as hydrogen acceptor) and an alkyne substituent able to stabilize positive charge build up during the cyclization. Mechanistic experiments revealed that under these conditions B(C₆F₅)₃ is acting as a Lewis acid assisted Brønsted acid, with H₂O-B(C₆F₅)₃ the key species enabling catalytic quinoline formation. This was indicated by deuterium labelling studies and the observation that the cyclization of N-(3-phenyl-propargyl)aniline using B(C₆F₅)₃ under anhydrous conditions afforded the zwitterion [(N-H-3-B(C⁶F⁵)³-4-Ph-quinolinium] that 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.