Remote Hydrogen Bonding between Ligand and Substrate Accelerates C-H Bond Activation and Enables Switchable Site Selectivity.

Transition-metal-catalyzed selective and efficient activation of an inert C-H bond in an organic substrate is of importance for the development of streamlined synthetic methodologies. An attractive approach is the design of a metal catalyst capable of recognizing an organic substrate through noncovalent interactions to control reactivity and selectivity. We report here a spirobipyridine ligand that bears a hydroxy group that recognizes pyridine and quinoline substrates through hydrogen bonding, and in combination with an iridium catalyst enables site-selective C-H borylation.

Recent Advances in Metal-catalyzed Alkylation, Alkenylation and Alkynylation of Indole/indoline Benzenoid Nucleus.

Selective editing of the benzenoid C-H bonds (C4-C7) in indoles/indolines has received great interest because functionalized indoles/indolines are featured in many marketed drugs and natural products. Transition-metal-catalyzed directed C-H functionalization has thus been developed to manipulate the benzenoid core through C-C and C-heteroatom bond formation. This review covers the recent advances in selective C-C bond forming reactions, alkylation, alkenylation and alkynylation, over the benzenoid ring (C4-C7) of indoles/indolines using metal catalysis.

Oxidative C-H/N-H Annulation of Aromatic Amides with Dialkyl Malonates: Access to Isoindolinones and Dihydrobenzoindoles.

A copper-mediated oxidative C-H/N-H annulation of aromatic amides with dialkyl malonates has been presented to afford synthetically valuable dihydrobenzoindoles and isoindolinones. The reaction proceeds through direct oxidative C(sp)-H/C(sp)-H coupling followed by an intramolecular N-H/C(sp)-H dehydrogenative coupling to deliver the target motifs with broad scope and functional group tolerance.

Cp*Co(III)-Catalyzed C-7 C-C Coupling of Indolines with Aziridines: Merging C-H Activation and Ring Opening.

A Cp*Co(III)-catalyzed directing group-assisted C7 C-C coupling of indolines with aziridines has been developed by merging C-H activation and ring opening. The use of cobalt catalyst, detection of a Co(III) intermediate, and late-stage removal of the directing group are important practical features.

Weak Coordination Enabled Switchable C4-Alkenylation and Alkylation of Indoles with Allyl Alcohols.

A weak carbonyl coordination facilitated tunable reactivity between alkenylation and alkylation of indoles at the C4 C-H site is presented using readily accessible allylic alcohols in the presence of Rh catalysis by switching the additives or directing group. Exclusive site selectivity, functional group tolerance, and late-stage modifications are the important practical features.

Weak Coordination-Guided Regioselective Direct Redox-Neutral C4 Allylation of Indoles with Morita-Baylis-Hillman Adducts.

A weak carbonyl coordination-guided regioselective C4 allylation of indoles is demonstrated using the versatile Morita-Baylis-Hillman adduct in the presence of Rh catalysts in a redox-neutral fashion. The substrate scope, functional group diversity, oxidant free character, mechanistic aspects, and synthetic utilities are important practical features.

Cp*Co(III)-Catalyzed Regioselective C2 Amidation of Indoles Using Acyl Azides.

A cobalt-catalyzed C2-selective amidation of indoles using acyl azides has been accomplished. Isotope experiments suggest that C-H activation is reversible. The use of sustainable Co catalysis, functional group diversity, substrate scope, and regioselectivity are the important practical features.

Exploiting Strained Rings in Chelation Guided C-H Functionalization: Integration of C-H Activation with Ring Cleavage.

Strained ring systems are regarded as privileged coupling partners in directed C-H bond functionalization and have emerged as a potential research area in organic synthesis. The inherent ring strain in these systems acts as a driving force, allowing the facile construction of diversified structural scaffolds via integrating C-H activation and ring-scission. The mechanistic underpinnings allows the implementation of a plethora of C-H bonds across plentiful organic substrates, including the less reactive alkyl ones.

Stereospecific Copper(II)-Catalyzed Tandem Ring Opening/Oxidative Alkylation of Donor-Acceptor Cyclopropanes with Hydrazones: Synthesis of Tetrahydropyridazines.

Aerobic copper(II)-catalyzed tandem ring opening and oxidative C-H alkylation of donor-acceptor cyclopropanes with bisaryl hydrazones is accomplished to produce tetrahydropyridazines, in which copper(II) plays dual role as a Lewis acid as well as redox catalyst. The reaction is stereospecific, and optically active cyclopropanes can be reacted with high optical purities (89-98% enantiomeric excess). The substrate scope, functional group tolerance, dual role of the copper(II) catalyst, and the use of air as an oxidant are the important practical features.

Iron-Catalyzed Regioselective Remote C(sp)-H Carboxylation of Naphthyl and Quinoline Amides.

Iron(III)-catalyzed regioselective direct remote C-H carboxylation of naphthyl and quinoline amides was developed using CBr and alcohol. The reaction involves a radical pathway using a coordination activation strategy and single electron transfer process. The use of sustainable iron catalysis, selectivity, and the substrate scope are the important practical features.

Transition-metal-catalyzed site-selective C7-functionalization of indoles: advancement and future prospects.

C7-Decorated indoles are important structural motifs present in a plethora of bioactive and pharmaceutical compounds. Early stage developments for C7 modifications were realized through directed metallation (DOM) and subsequent quenching with suitable electrophiles or by halogenation with Cu(ii) halides. Direct C-7 functionalization of indoles is comparatively difficult compared to functionalization at C-2 and C-3 positions owing to the inherent reactivity of the pyrrole-type ring.

Ru(ii)-Catalyzed C7-acyloxylation of indolines with carboxylic acids.

Ruthenium(ii)-catalyzed site-selective C7-acyloxylation of indolines with carboxylic acids is presented. The substrate scope and functional group tolerance are important practical features. The kinetic isotope studies suggest that C-H bond activation may be the rate-determining step.

Expedient cobalt(ii)-catalyzed site-selective C7-arylation of indolines with arylboronic acids.

Cobalt(ii)-catalyzed pyrimidyl directing group-assisted C7 arylation of indolines with arylboronic acids has been developed using Mn(OAc)·4HO as an oxidant. The use of cobalt(ii)-PCy as a catalyst and broad substrate scope are the important practical features.

Copper(II)-Mediated Chelation-Assisted Regioselective N-Naphthylation of Indoles, Pyrazoles and Pyrrole through Dehydrogenative Cross-Coupling.

A copper-mediated picolinamide directed regioselective cross-coupling of naphthylamines with azoles is developed via C-H functionalization and C-N bond formation. The reaction of indoles leads to the formation of chiral C-N cross-coupled products with functional group tolerance. These reaction conditions can also be extended to the cross-coupling of pyrazole and pyrrole scaffolds.

Stereoselective Copper-Catalyzed Cross-Coupling of Aziridines with Benzimidazoles via Nucleophilic Ring Opening and C(sp)-H Functionalization.

A copper-catalyzed cross-coupling of 2-alkyl-/2-arylaziridines with benzimidazoles is reported. The reactions involve a regiospecific ring opening of aziridines with benzimidazoles to give benzoimidazolylethylamine derivatives that lead to dehydrogenative cross-coupling between C(sp)-H and N-H bonds to produce dihydroimidazobenzimidazoles. Optically active 2-arylaziridines can be stereoinvertivebly cross-coupled with high enantiomeric purities (77-97% ee).