Imines in Stille‐Type Cross‐Coupling Reactions: A Multicomponent Synthesis of α‐Substituted Amides

Abstract

An alternative to nucleophilic chemistry for the construction of α‐substituted amides and amine derivatives from imines is provided by the Stille‐type coupling of imines with organotin reagents and acid chlorides (see scheme). This Pd‐catalyzed reaction is suitable for components with a range of functional groups and has been extended into a four‐component‐coupling reaction with carbon monoxide. dba=dibenzylideneacetone, RT=room temperature.

Metal‐Catalyzed One‐Step Synthesis: Towards Direct Alternatives to Multistep Heterocycle and Amino Acid Derivative Formation

“…As a result of this rapid oxidative addition, selective carbon-carbon bond formation occurs even in the presence of classic Stille coupling partners, such as aryl iodides, and under mild conditions (ambient temperature cross coupling without added ligands). [30] In addition to palladium, copper(I) salts, such as CuI, can also catalyze this reaction, and do so with an even greater diversity of organotin reagents. [39] The latter likely occurs through a mechanism different than in Scheme 4, involving an initial transmetalation to create an organocopper intermediate, which reacts with the in situ generated N-acyl iminium salt.…”

“…(10)]. [30] This reaction provides an unusual route to use multiply bonded electrophiles (i.e., imines) in a palladium-catalyzed cross-coupling reaction. In general, while cross-coupling rewww.chemeurj.org actions have become an important method to construct carbon-carbon bonds with RÀX electrophiles, [38] one traditional limitation of this process is its inability to mediate similar bond formation with multiply bonded substrates.…”

“…This is clearly observed in control experiments, in which the reaction of in situ generated iminium salts with [Pd 2 -A C H T U N G T R E N N U N G (dba) 3 ] forms to 2 in near quantitative yield. [30] Overall, this series of steps provides a method to convert imines into a reduced a-palladated amide (imine reduction). Kinetic studies show that this oxidative addition step is at least partially rate determining in the catalytic formation of münchnones.…”

“…(6)]. [30] Interestingly, initial attempts to perform this reaction under the conditions used to form münchnones [e.g., Eq. (3)] yielded only traces of pyrrole.…”

Metal‐Catalyzed Multicomponent Reactions

“…The same method allows the synthesis of N-carbamateprotected propargylamines [149]. a-Substituted amides 161 may also be prepared under palladium catalysis by substituting alkynes for vinyltin (Scheme 8.71) [150]. A remarkable modular approach to polyfunctionalized pyrroles has also been developed by Arndtsen.…”