Site-selective C–H arylation of primary aliphatic amines enabled by a catalytic transient directing group

Abstract

Abstract. Transition metal-catalyzed direct C−H bond functionalization of aliphatic amines is of great importance in organic and medicinal chemistry research. While several methods have been developed for the direct sp 3 C−H functionalization of secondary and tertiary aliphatic amines, site-selective functionalization of primary aliphatic amines remains a challenge. Here we report the direct highly siteselective arylation of primary alkylamines via a palladium-catalyzed C−H bond functionalization process on unactivated sp 3 carbons with catalytic glyoxylic acid as a novel, inexpensive, and transient directing group. With this approach, a wide array of γ-arylated primary alkylamines, important structural motifs in organic and medicinal chemistry, were prepared without any protection or deprotection steps.Aliphatic amines are ubiquitously present in pharmaceuticals with a wide range of biological activities 1,2 .

Direct Aryl C−H Amination with Primary Amines Using Organic Photoredox Catalysis

“…[9–12] Significant challenges exist for C–N couplings using aliphatic amines, since many strategies for functionalization of these substrates involve C–C bond construction adjacent to the nitrogen atom. [13–16] Accordingly, C–H amination of arenes with aliphatic amines has been demonstrated only in select examples (Scheme 1). [17] To achieve C–N bond formation, the use of strongly acidic media and prefunctionalized chloroamines, which suffer from limited stability, are often required (Scheme 1a).…”

Palladium‐Catalyzed C(sp3)−H Arylation of Primary Amines Using a Catalytic Alkyl Acetal to Form a Transient Directing Group

“…Very recently, transient directing groups (TDGs) have been applied to the functionalization of C(sp 3 )−H bonds, particularly arylation of aldehyde and ketone substrates via endo ‐imines formed in situ with amine additives . The use of exo ‐imine directing groups for C−H functionalization of primary amines remains rare, with examples using palladium catalysis . In 2016 Dong used stoichiometric 8‐formylquinoline to form an imine which effected arylation with bisaryliodonium salts .…”

Remote, Late-Stage Oxidation of Aliphatic C–H Bonds in Amide-Containing Molecules

“…4 Recently, these catalysts were shown to oxidize remote C—H bonds in the presence of basic amines and electron-poor imides. 5 Electron-rich amines, previously used as directing groups, 6 promoted remote C—H oxidations after protonation by a strong Brønsted acid (HBF 4 ) or complexation with an oxidatively stable Lewis acid (BF 3 ). 5 The electronically deactivated ammonium salts and BF 3 adducts provided strong inductive deactivation of hyperconjugatively activated sites α to nitrogen and promoted remote oxidations of the most electron rich aliphatic C—H bonds.…”