Green and Scalable Aldehyde‐Catalyzed Transition Metal‐Free Dehydrative N‐Alkylation of Amides and Amines with Alcohols

Abstract

In contrast to the borrowing hydrogentype N-alkylation reactions, in which alcohols were activated by transition metal-catalyzed anaerobic dehydrogenation, the addition of external aldehydes was accidentally found to be a simple and effective protocol for alcohol activation. This interesting finding subsequently led to an efficient and green, practical and scalable aldehyde-catalyzed transition metal-free dehydrative N-alkylation method for a variety of amides, amines, and alcohols. Mechanistic studies revealed that this reaction most possibly proceeds via a simple but interesting transition metal-free relay race mechanism.

Base‐Mediated Transition‐Metal‐Free Dehydrative C−C and C−N Bond‐Forming Reactions from Alcohols

“…of benzyl alcohols under similar reaction conditions (Scheme ). The formation of dialkylated products was justified by the electron‐rich nature of five‐membered thiazole in comparison to other six‐membered heterocycles, and explained by the mechanism depicted in Scheme …”

“… Proposed MPV‐transition states involved in the TM‐free transfer hydrogenation reactions from alcohols to imines …”

“…These optimal reaction conditions were extended to a variety of amines and alcohols, affording conversions and selectivity that were strongly dependent on the nature of both reactants (Scheme ). The proposed reaction mechanism depicted in Scheme , showed that both PhCHO and N ‐benzylideneaniline are the actual intermediates in the reaction of PhCH 2 OH with PhNH 2 . In fact, the addition of both PhCHO and N ‐benzylideneaniline in the initial reaction mixture improved the reaction rate significantly.…”

Transition‐Metal‐Free Hydrogen Autotransfer: Diastereoselective N‐Alkylation of Amines with Racemic Alcohols

“…Screening of the reaction conditions revealed that both the ketone and base are essential (see Table S1, entries 2-4). This ketone-catalyzed amination appears to be reminiscent of the aldehyde-catalyzed achiral alkylation reactions reported by Xu, [22] Kang,[22b] and co-workers,i nw hich ac atalytic amount of an aldehyde initiates the reaction with the catalysis sustained by aldehyde subsequently generated. This ketone-catalyzed amination appears to be reminiscent of the aldehyde-catalyzed achiral alkylation reactions reported by Xu, [22] Kang,[22b] and co-workers,i nw hich ac atalytic amount of an aldehyde initiates the reaction with the catalysis sustained by aldehyde subsequently generated.…”

“…[22] Thus,t aking the amination of 2a with 1 as an example,the initially-introduced catalytic ketone would react reversibly with 1 to form the imine (R)-17,t he reduction of which by the sodium salt of racemic 2a would then afford the diaseteromerically pure 3a, while releasing one new ketone molecule and the base used in forming the alkoxide from 2a( Figure 6). [22] Thus,t aking the amination of 2a with 1 as an example,the initially-introduced catalytic ketone would react reversibly with 1 to form the imine (R)-17,t he reduction of which by the sodium salt of racemic 2a would then afford the diaseteromerically pure 3a, while releasing one new ketone molecule and the base used in forming the alkoxide from 2a( Figure 6).…”