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

Abstract

A substoichiometric quantity of the Lewis acid B(C 6 F 5 ) 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(C 6 F 5 ) 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(C 6 F 5 ) 3 is acting as a Lewis acid-assisted Brønsted acid, with H 2 O−B(C 6 F 5 ) 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(C 6 F 5 ) 3 under anhydrous conditions afforded the zwitterion [(N-H-3-B(C 6 F 5 ) 3 -4-Ph-quinolinium], which does not undergo protodeboronation to release B(C 6 F 5 ) 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.

Synthesis of substituted quinolines via B(C6F5)3‐catalyzed aniline‐aldehyde‐pyruvate oxidative annulation

“…Interestingly, a by‐product N ‐(4‐chlorobenzyl)aniline ( 5a ) was also produced in 42% yield. A possible explanation for the formation of 5a is that a transfer hydrogenation process occurred in the oxidation step to form the quinoline where the imine acts as a hydrogen acceptor …”

“…Based on our findings and the related references, a plausible reaction mechanism for the present B(C 6 F 5 ) 3 ‐catalyzed aniline‐aldehyde‐pyruvate annulation reaction is depicted in Scheme . Upon heating, B(C 6 F 5 ) 3 is generated from a Lewis adduct or the hydroxy borate to activate the imine I derived from aniline 1a and aldehyde 2a , which then undergoes nucleophilic…”

“…A possible explanation for the formation of 5a is that a transfer hydrogenation process occurred in the oxidation step to form the quinoline where the imine acts as a hydrogen acceptor. [41] Next, the optimization of the reaction conditions was firstly studied on the ratio of the substrates. As expected, raising the ratio of both 1a and 2a (Table 1, entries 1-3) improved the reaction yield significantly.…”

“…One of the research hotspots is the borane‐catalyzed multicomponent reactions (MCRs). Recently, a remarkable work made by Ingleson and coworkers covered a B(C 6 F 5 ) 3 ‐initiated aldehyde‐aniline‐alkyne reaction, which enabled the synthesis of various functionalized quinolines . However, the high catalyst loading (20 mol %) and the utility of expensive alkynes limited its practicability to some degree.…”

“…Recently, a remarkable work made by Ingleson and coworkers covered a B(C 6 F 5 ) 3 -initiated aldehyde-aniline-alkyne reaction, which enabled the synthesis of various functionalized quinolines. [41] However, the high catalyst loading (20 mol %) and the utility of expensive alkynes limited its practicability to some degree. Very recently, our group have devoted much efforts to B(C 6 F 5 ) 3 -catalyzed MCRs, furnishing versatile 2,4,6-triarylpyridines and bis (indolyl)alkanes in high yields.…”