Main-Group-Catalyzed Reductive Alkylation of Multiply Substituted Amines with Aldehydes Using H₂

Abstract

Given the growing demand for green and sustainable chemical processes, the catalytic reductive alkylation of amines with main-group catalysts of low toxicity and molecular hydrogen as the reductant would be an ideal method to functionalize amines. However, such a process remains challenging. Herein, a novel reductive alkylation system using H is presented, which proceeds via a tandem reaction that involves the B(2,6-ClCH)( p-HCF)-catalyzed formation of an imine and the subsequent hydrogenation of this imine catalyzed by a frustrated Lewis pair (FLP). This reductive alkylation reaction generates HO as the sole byproduct and directly functionalizes amines that bear a remarkably wide range of substituents including carboxyl, hydroxyl, additional amino, primary amide, and primary sulfonamide groups. The synthesis of isoindolinones and aminophthalic anhydrides has also been achieved by a one-pot process that consists of a combination of the present reductive alkylation with an intramolecular amidation and intramolecular dehydration reactions, respectively. The reaction showed a zeroth-order and a first-order dependence on the concentration of an imine intermediate and B(2,6-ClCH)( p-HCF), respectively. In addition, the reaction progress was significantly affected by the concentration of H. These results suggest a possible mechanism in which the heterolysis of H is facilitated by the FLP comprising THF and B(2,6-ClCH)( p-HCF).

Computational Investigation of the Mechanism of FLP Catalyzed H2Activation and Lewis Base Assisted Proton Transfer

“…Several protocols are adopted to install alkyl groups on the amine nitrogen, including reductive alkylation using carbon dioxide and carboxylic/carbonic acid derivatives, transition metal catalysed N‐nucleophilic substitution to alcohols, hydrogen borrowing methodology by heterogeneous catalysis, late‐transition and non‐precious metal catalysed hydroamination and hydroamidation processes etc [11] . However, the recent focus on green, sustainable and low‐toxic catalytic processes have highlighted novel alkylation of amines employing H 2 as a reducing agent and readily available Lewis acidic triarylboranes as catalyst [12] . In fact, tris(pentafluorophenyl)borane have lately been employed as an effective Lewis acid catalyst for a variety of synthetic conversions [13] .…”

“…In a recent experimental effort, Ogoshi and others have shown that triarylborane, B(2,6‐Cl 2 C 6 H 3 )( p ‐HC 6 F 4 ) 2 ( BAr 3 ), catalyses the condensation of aniline ( An ) and benzaldehyde ( Bz ) in presence of molecular H 2 to synthesize the desired N ‐phenylbenzylamine ( Am ) with the intermediacy of N ‐benzylideneaniline ( Im ) (Scheme 1) in THF solvent [12] . Interestingly, this strategy has widespread applications and broader substrate scope, like in the alkylation of amino acids and their derivatives [12] . Furthermore, utilization of H 2 as the reductant offers generation of H 2 O as the sole by‐product, in congruence to the “greenness” of this reaction.…”

B(C6F5)3-catalyzed dehydrogenative cyclization of N-tosylhydrazones and anilines via a Lewis adduct: a combined experimental and computational investigation

“…Tris(pentauorophenyl)borane has recently emerged as a powerful Lewis acid catalyst. [1][2][3] The strong Lewis acidity 2,3 at the boron center allows us to establish a wide range of organic transformations via C-B, [4][5][6] C-C, [7][8][9][10] C-N, 11,12 C-O 13,14 and C-Si [15][16][17][18] bond formations. Pioneered by Stephan and Erker, B(C 6 F 5 ) 3 has gained popularity in frustrated Lewis pair (FLP) chemistry which encompasses widespread applications in organic reactions.…”

Readily Available Primary Aminoboranes as Powerful Reagents for Aldimine Synthesis

“…[2] Additionally, only seven reports described reactions involving their secondary counterparts (R 2 NBR 2 ). [2][3][4][5][6] Herein we report that primary aminoboranes are powerful tools for the mild and chemoselective preparation of aldimines, [7][8][9] especially those hard to access with previous methods. [10] We hypothesized that primary aminoboranes should be sufficiently Lewis acidic to react with aldehydes to afford unstable hemi-aminals B;t he latter would eliminate boronic acid giving access to aldimines C (Scheme 1).…”

“…Using our optimized conditions [1:1 ratio of aminoborane to aldehyde in C 6 D 6 (1.1m)a t2 5 8 8C],w ee xamined the substrate scope (Scheme 2). With respect to the substituents on nitrogen this methodology is readily applicable to avariety of amines featuring different steric and electronic properties (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13), and even to hydrazines (14). Although aminoboranes derived from very electron poor anilines (7,8)e xhibit lower conversions this is circumvented by using 2equivalents of the corresponding aminoborane.W ith respect to aldehydes,t he reaction is widely applicable to both alkyl-and aryl-aldehydes (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”