Ruthenium‐Catalyzed α‐(Hetero)Arylation of Saturated Cyclic Amines: Reaction Scope and Mechanism

Abstract

Transition-metal-catalyzed sp(3) C-H activation has emerged as a powerful approach to functionalize saturated cyclic amines. Our group recently disclosed a direct catalytic arylation reaction of piperidines at the α position to the nitrogen atom. 1-(Pyridin-2-yl)piperidine could be smoothly α-arylated if treated with an arylboronic ester in the presence of a catalytic amount of [Ru3(CO)12] and one equivalent of 3-ethyl-3-pentanol. A systematic study on the substrate and reagent scope of this transformation is disclosed in this paper. The effect of substitution on both the piperidine ring and the arylboronic ester has been investigated. Smaller (pyrrolidine) and larger (azepane) saturated ring systems, as well as benzoannulated derivatives, were found to be compatible substrates with the α-arylation protocol. The successful use of a variety of heteroarylboronic esters as coupling partners further proved the power of this direct functionalization method. Mechanistic studies have allowed for a better understanding of the catalytic cycle of this remarkable transformation featuring an unprecedented direct transmetalation on a Ru(II)-H species.

Direct Arylation of α‐Amino C(sp3)‐H Bonds by Convergent Paired Electrolysis

“…[1] An ideal method to construct the building blocks is the direct cross-coupling of aryl compounds and amines. [2][3][4] Among the existing methods, transition-metal catalysis or stoichiometric oxidants are utilized to active the inert a-amino sp 3 CÀHb onds.I n2 011, MacMillan and co-workers disclosed abreakthrough method involving photoredox-catalyzed a-amino C À Ha rylation for the construction of benzylic amines from readily available tertiary amines and cyanoaromatics. [2a] Inspired by this pioneering work, highly efficient photoredox catalysis methods were successively developed for diverse CÀHb ond arylation reactions.…”

Directed Ruthenium‐Catalyzed C(sp3)H α‐Alkylation of Cyclic Amines Using Dioxolane‐Protected Alkenones

“…The piperidine derivatives possessing a C‐3 trifluoromethyl ( 3d ), phenyl ( 3e ) or methoxymethyl ( 3f ) substituent all underwent smooth monoalkylation at the sterically less hindered α‐position, with the resulting 2,5‐disubstituted piperidines ( 4d–f ) being isolated in 63–75% yield. Regioselective monofunctionalization of C‐3 substituted piperidines was also observed in our previously developed direct arylation protocol and therefore seems to be substrate controlled (sterics) and independent of the reagents used 3i. For the 2,5‐disubstituted piperidines ( 4d – f ) resulting from this regioselective monoalkylation, the cis‐ diastereoisomer was observed to be the major reaction product, in contrast to what was observed for the 2,6‐disubstituted piperidines ( 4b , c ), where the trans ‐isomer was predominant.…”

“…This is not surprising when one considers the inherently lower reactivity of six‐membered rings versus their five‐membered counterparts 7. In the past years, our laboratory has developed a direct Ru‐catalyzed CH activation8 protocol for the C‐2 arylation3g,i and alkylation3h of substituted piperidines. The protocols have proved to be general, as justified by their applicability to other cyclic amine substrates.…”

Recent Advances in C–H Bond Functionalization with Ruthenium-Based Catalysts

“…Arylation Involving Decarboxylative and sp 3 C-H Bond FunctionalizationIn 2006, Sames's research group demonstrated the direct arylation of cyclic amines, especially pyrrolidines involving an sp 3 C-H bond functionalization, using ruthenium(0) catalyst, [Ru 3 (CO) 12 ] and aryl boronic acid as arylating reagents[94]. In subsequent years, Peschiulli et al performed a similararylation of a saturated cyclic amine with aryl boronic esters in the presence of [Ru 3 (CO) 12 ][95]. Following this early discovery, Mihovilovic and co-workers have shown that a ruthenium(II) catalyst could efficiently activate the sp 3 C-H bond of benzylic amine[96].…”