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

C-H Functionalization of amines is a prominent challenge due to the strong complexation of amines to transition metal catalysts, and therefore typically requires derivatization at nitrogen with a directing group. Transient directing groups (TDGs) permit C-H functionalization in a single operation, without needing these additional steps for directing group installation and removal. Here we report a palladium catalyzed γ-C-H arylation of amines using catalytic amounts of alkyl acetals as transient activators (e.g. commercially available (2,2-dimethoxyethoxy)benzene). This simple additive enables arylation of amines with a wide range of aryl iodides. Key structural features of the novel TDG are examined, demonstrating an important role for the masked carbonyl and ether functionalities. Detailed kinetic (RPKA) and mechanistic investigations determine the order in all reagents, and identify cyclopalladation as the turnover limiting step. Finally, the discovery of an unprecedented off-cycle free-amine directed ϵ-cyclopalladation of the arylation product is reported.

Transient imines as 'next generation' directing groups for the catalytic functionalisation of C-H bonds in a single operation.

C-H functionalisation promises a paradigm shift in synthetic planning. However, the additional steps often required to install and remove directing groups currently detract from the efficiency. The strategy of reversible installation of a directing group via an imine linkage has recently emerged, with the imine formed and hydrolysed in situ. Such transient directing groups can promote transition metal catalysed functionalisation of unactivated C-H bonds of aldehydes, ketones and amines. This approach removes additional steps usually required for covalent directing groups and can use catalytic quantities of the imine forming component. This review updates the rapidly developing field of transient directing groups for C-H functionalisation on sp2 and sp3 carbon centres, to form new C-C and C-X bonds. We focus on the structures of the transient directing groups as mono or bidentate coordinating groups for various metal catalysts.

Methylene C(sp3)-H ß,ß'-Diarylation of Cyclohexanecarbaldehydes Promoted by a Transient Directing Group and Pyridone Ligand.

A hindered ß-amino amide transient directing group effects di-trans-arylation of cyclohexanecarbaldehydes. The amide N-substituents are shown to affect yield and can enhance the rate of arylation compared with the α-amino acid. Addition of a pyridone ligand further enhanced reactivity. The reaction is successful for a range of aryl iodides, and various substituted cyclohexane carboxaldehydes, providing functionalized products from simple feedstocks. A mechanism is proposed evoking a transient enamine.

Intramolecular palladium(ii)/(iv) catalysed C(sp3)-H arylation of tertiary aldehydes using a transient imine directing group.

Palladium catalysed ß-C(sp3)-H activation of tertiary aldehydes using a transient imine directing group enables intramolecular arylation to form substituted indane-aldehydes. A simple amine bearing a methyl ether (2-methoxyethan-1-amine) is the optimal TDG to promote C-H activation and reaction with an unactivated proximal C-Br bond. Substituent effects are studied in the preparation of various derivatives. Preliminary mechanistic studies identify a reversible C-H activation, product inhibition and suggest that oxidative addition is the turnover limiting step.

Highly Chemoselective NH- and O-Transfer to Thiols Using Hypervalent Iodine Reagents: Synthesis of Sulfonimidates and Sulfonamides.

Aryl thiols can be selectively converted to sulfonimidates or sulfonamides with three new S-X connections being made selectively in one pot. Using hypervalent iodine reagents in the presence of ammonium carbamate, NH- and O-groups are transferred under mild and practical conditions. Reducing the loading of ammonium carbamate changed the product distribution, converting the sulfonimidate to the sulfonamide. Studies into the possible intermediate species are presented, suggesting that multiple pathways may be possible via sulfinate esters, or related intermediates, with each species forming the same products.

Catalytic meta-selective C-H functionalization to construct quaternary carbon centres.

A catalytic meta-selective C-H functionalization of 2-phenylpyridines using a range of tertiary halides is described. The protocol is simple to perform and uses commercially available reagents to construct challenging quaternary carbon centres in a regioselective manner. Preliminary studies suggest the C-H functionalization proceeds through a radical process directed via a remote σ-activation.