Functionalization of C(sp ³ )–H bonds using a transient directing group

Abstract

Proximity-driven metalation has been extensively exploited to achieve reactivity and selectivity in C–H bond activation. Despite the substantial improvement in developing more efficient and practical directing groups, their stoichiometric installation and removal limit efficiency and often applicability as well. Herein, we report the development of an amino acid reagent that reversibly reacts with aldehydes and ketones in situ via imine formation to serve as a transient directing group for activation of inert C–H bonds. Arylation of a wide range of aldehydes and ketones at the β- or γ-positions proceeds in the presence of a Pd catalyst and a catalytic amount of amino acid. The feasibility of achieving enantioselective C–H activation reactions using a chiral amino acid as the transient directing group is also demonstrated.

Controlling Pd(iv) reductive elimination pathways enables Pd(ii)-catalysed enantioselective C(sp3)−H fluorination

“…Interestingly, the opposite absolute configuration of these two products was observed, indicating the involvement of two distinct reaction pathways. The configuration of 3a is consistent with our previous arylation reaction 28 , suggesting that fluorination proceeds through a classic inner-sphere reductive elimination process with retention of stereochemistry, while 2a is formed through an S N 2-type mechanism to achieve inversion of stereochemistry. To further support this mechanistic hypothesis, we conducted a series of experiments to rule out the possibility of 2a and 3a forming through an identical mechanism from two different diastereomeric palladacycles.…”

“…We have recently developed a Pd(II)-catalyzed enantioselective C(sp 3 )–H arylation using a chiral amino acid transient directing group 28 . This finding led us to investigate the feasibility of developing a new chiral transient directing group to enable an enantioselective C(sp 3 )–H fluorination.…”

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

“…6b). On the basis of the above observed results and the previous reports 25,37 , a plausible catalytic cycle of this reaction is proposed (Fig. 6).…”

“…Furthermore, the primary amines with a cyclic alkyl group reacted smoothly in this catalytic system (2j and 2k). Although many successful examples for functionalizing unactivated secondary sp 3 C−H bonds have been reported with the installation of a mono-or bidentate directing group on the substrates [5][6][7][8][9][10][11][12][13][14][15] , direct functionalization of these bonds remains a great challenge with carbonyl compounds using a transient directing group 37 and free aliphatic amines 23,30,31 , presumably due to the inherent steric hindrance. In this catalytic system, substrate 1l with cyclic methylene C−H bonds provided the γ-arylated product 2l in 23% yield, while arylation of noncyclic secondary C−H bonds was not realized.…”

Selective oxidation of aliphatic C–H bonds in alkylphenols by a chemomimetic biocatalytic system

“…However, a number of problems are persistently associated with the chemical oxidation of aliphatic C-H bonds in alkylphenols: (i) the requirement of protection/deprotection of the phenolic hydroxyl group under reaction conditions that are distinct from those for oxidation complicates the synthetic process; (ii) it is difficult to delicately control the extent of oxidations (i.e., alcohol vs. aldehyde/ketone vs. carboxylic acid); (iii) the oxidation of an aromatic C-H bond may sometimes occur when using strong oxidants; (iv) the regio-and stereoselective oxidation of an unactivated sp 3 C-H bond (in alkylphenols) remains a central challenge despite recent advances in combined use of specialized directing groups with transition metal catalysts (9)(10)(11) and in biomimetic supramolecular assemblies (12)(13)(14); and (v) chemical oxidants could be associated with significant environmental concerns (2,3). Given these issues, oxidative enzymes with inherent catalytic selectivity and reduced environmental impact may be developed into alternative catalysts for selective oxidation of organic compounds including alkylphenols (15)(16)(17)(18).…”