Chan-Lam Amination of Benzylic Secondary and Tertiary Boronic Esters

Abstract

The Cu-catalysed coupling of arylboronic acids with amines, known as the Chan-Lam reaction, is used widely to prepare aryl amines. In contrast, alkyl variants of this reaction, while highly desirable, are underdeveloped. Herein, we report a Chan-Lam coupling reaction of benzylic boronic esters with primary and secondary anilines to form valuable alkyl amine products. Both secondary and tertiary boronic esters can be used as coupling partners, with mono-alkylation of the aniline occurring selectively. This is a rare example of a transition metal-mediated transformation of a tertiary alkylboron reagent. The method is operationally simple and tolerates a broad range of functional groups. Initial investigation into the reaction mechanism suggests that transmetallation from B to Cu occurs through a single electron, rather than a two-electron process.

Chan–Lam Amination of Secondary and Tertiary Benzylic Boronic Esters

“…This complements a recent report of Cu-catalyzed decarboxylative amination of benzylic carboxylic acids which was proposed to occur through a Chan−Lam type mechanism. 11,12 As part of the ongoing investigation into Cu-catalyzed oxidative transformations of boronic esters, 13 we explored the reaction of boronic ester 1 with aniline 2a in the presence of Cu(OAc) 2 and Cs 2 CO 3 (see Table 1). 14 Heating these reagents in a mixture of MeOH and pyridine at 50 °C under air gave amine 3a, alongside oxidation products 4 and 5 which are consistent with our previous observations.…”

A unified synthetic strategy to introduce heteroatoms via electrochemical functionalization of alkyl organoboron reagents

“…Indeed, basic reactivity has been noted, and organoboron compounds could be utilized to generate reactive carbocation intermediates under oxidative conditions in both a chemical and electrochemical manner. [35][36][37] However, attempts to explore the synthetic feasibility of this strategy are still in their infancy because of the limitations enforced by the reaction parameters, such as the unfavorable stoichiometry of the reaction partners and/or harsh conditions. In addition, there is no systematic assessment of the system to scrutinize the formation of the reactive intermediate.…”

“…Subsequently, the reactivity scope of weaker oxygen-based nucleophiles, carboxylic acids, was assessed to afford hindered esters. Various aliphatic and aromatic carboxylic acids could conveniently be introduced to the C(sp 3 )-center of the organoboron reagent to furnish sterically congested ester products (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39). Notably, carboxylic acids that are vulnerable to oxidation under other electrochemical oxidation conditions could be utilized as reaction partners without competitive generation of reactive species (25-31, 39).…”

“…Notably, carboxylic acids that are vulnerable to oxidation under other electrochemical oxidation conditions could be utilized as reaction partners without competitive generation of reactive species (25-31, 39). 46 Moreover, highly reactive ,-unsaturated carbonyl systems (34)(35) and biomedically important heterocycles (36)(37)(38)(39) were tolerated. Remarkably, in the case of mandelic acid, which contains a hydroxyl group, the generated alkyl carbocation selectively reacted with the carboxylic acid moiety (29).…”