Pyrrolidine and Piperidine Formation via Copper(II) Carboxylate-Promoted Intramolecular Carboamination of Unactivated Olefins:  Diastereoselectivity and Mechanism

Abstract

An expanded substrate scope and in-depth analysis of the reaction mechanism of the copper(II) carboxylate-promoted intramolecular carboamination of unactivated alkenes is described. This method provides access to N-functionalized pyrrolidines and piperidines. Both aromatic and aliphatic gamma- and delta-alkenyl N-arylsulfonamides undergo the oxidative cyclization reaction efficiently. N-Benzoyl-2-allylaniline also underwent the oxidative cyclization. The terminal olefin substrates examined were more reactive than those with internal olefins, and the latter terminated in elimination rather than carbon-carbon bond formation. The efficiency of the reaction was enhanced by the use of more organic soluble copper(II) carboxylate salts, copper(II) neodecanoate in particular. The reaction times were reduced by the use of microwave heating. High levels of diastereoselectivity were observed in the synthesis of 2,5-disubstituted pyrrolidines, wherein the cis substitution pattern predominates. The mechanism of the reaction is discussed in the context of the observed reactivity and in comparison to analogous reactions promoted by other reagents and conditions. Our evidence supports a mechanism wherein the N-C bond is formed via intramolecular syn aminocupration and the C-C bond is formed via intramolecular addition of a primary carbon radical to an aromatic ring.

6‐Azabicyclo[3.2.1]octanes via Copper‐Catalyzed Enantioselective Alkene Carboamination

“…The level and direction of regioselectivity is consistent with addition of a carbon radical to the arene (e.g. path b, Scheme 1) [6b,c,8] as electrophilic aromatic substitution would be expected to favor the less hindered para product 6g . [9] …”

“…[6a] The new N-C bond is thought to be set by an enantioselective aminocupration step. Subsequent C-Cu(II) bond homolysis is thought to occur, forming intermediate A .…”

Synthesis of Saturated Heterocycles via Metal-Catalyzed Alkene Hydroamination or Hydroalkoxylation Reactions

“…The ability to form hydroamination products using this catalyst system was initially observed during studies on alkene carboamination reactions [77]. Following elegant mechanistic work, the authors proposed a mechanism that proceeds via a radical pathway involving initial cis-aminocupration of the substrate 89 to afford 91, followed by Cu-C bond homolysis to afford a carbon radical 92 that undergoes either H-atom abstraction to form a hydroamination product 93 or intramolecular coupling with the arylsulfonyl group to form the carboamination product 94 (Scheme 39).…”

Cu‐Catalyzed Heterocycle Synthesis

“…Chemler and coworkers developed a number of equivalent copper-promoted reactions that involve the intermolecular addition of amines to olefins to the synthesis of N-heterocycles via carboamination [51][52][53][54] and deamination [55,56].…”