Synthesis of tertiary arylamines: Lewis acid-catalyzed direct reductive N-alkylation of secondary amines with ketones through an alternative pathway

Abstract

We report herein a highly efficient, tin(ii)/PMHS catalyzed reductive N-alkylation of arylamines with ketones affording tertiary arylamines. A very wide substrate scope was observed for the current catalytic method as all six permutations of ketones/aldehydes/heterocyclic carbonyls and primary/secondary/heterocyclic amines were well tolerated, enabling access to secondary, tertiary and heterocyclic amines. The method is also convenient for the synthesis of N-substituted isoindolinones and phthalazinones via a tandem amination-amidation sequence. Mechanistic investigations revealed a carbocationic pathway instead of an ordinary direct reductive amination pathway.

Lewis‐Acid‐Catalyzed Direct Nucleophilic Substitution Reaction of Alcohols for the Functionalization of Aromatic Amines

“…Some screening outcomes are compiled in Table . Initially, the reaction between a and b was carried under previously developed conditions and surprisingly, reaction resulted in excellent yield of desired amine (Table , entry 1). Further, relatively lower yield of the amine was obtained with less catalyst loading (Table , entry 2).…”

“…To overcome the challenges associated to developed protocols, our group have developed new catalytic approaches for the synthesis of tertiary amines using various alkylating agents such as carbonyls and alkynes via an alternative carbocationic pathway –. During our previous study on the direct reductive N‐alkylation of secondary anilines with carbonyl compounds, we found that initially, the carbonyl compound is reduced to alcohol intermediate.…”

“…Based on our previous strategy, we reacted 4‐methoxybenzylalcohol with N ‐methylaniline under previously optimized reaction conditions . Surprisingly, 95% yield of desired amine was obtained (Scheme a).…”

“…Based on our previous study and results of control experiments, a possible catalytic cycle for the proposed transformation is shown in Scheme . In analogy to pervious reported Sn catalyzed C−N bond forming reactions, initially, the alcohol undergoes silylation in the presence of tin(II) triflate and polymethylhydrosiloxane (PMHS).…”

“…Further, this complex A protonates B to form the benzylic cation ( D ) via desilylation of intermediate C . Next, carbocation D is trapped by various nucleophile such as thiol ( 1 bb ), and N ‐methylaniline ( 2 ) (Scheme c). Further, tin(II) amide attacks the cationic centre of D to form E .…”