C–H activation has surfaced as an increasingly powerful tool for molecular sciences, with notable applications to material sciences, crop protection, drug discovery, and pharmaceutical industries, among others. Despite major advances, the vast majority of these C–H functionalizations required precious 4d or 5d transition metal catalysts. Given the cost-effective and sustainable nature of earth-abundant first row transition metals, the development of less toxic, inexpensive 3d metal catalysts for C–H activation has gained considerable recent momentum as a significantly more environmentally-benign and economically-attractive alternative. Herein, we provide a comprehensive overview on first row transition metal catalysts for C–H activation until summer 2018.

3d Transition Metals for C-H Activation.

This Review summarizes the advancements in Pd-catalyzed C(sp3)–H activation via various redox manifolds, including Pd(0)/Pd(II), Pd(II)/Pd(IV), and Pd(II)/Pd(0). While few examples have been reported in the activation of alkane C–H bonds, many C(sp3)–H activation/C–C and C–heteroatom bond forming reactions have been developed by the use of directing group strategies to control regioselectivity and build structural patterns for synthetic chemistry. A number of mono- and bidentate ligands have also proven to be effective for accelerating C(sp3)–H activation directed by weakly coordinating auxiliaries, which provides great opportunities to control reactivity and selectivity (including enantioselectivity) in Pd-catalyzed C–H functionalization reactions.

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Palladium-Catalyzed Transformations of Alkyl C-H Bonds.

Alkylation reactions represent an important organic transformation to form C–C bonds. In addition to conventional approaches with alkyl halides or sulfonates as alkylating agents, the use of unactivated olefins for alkylations has become attractive from both cost and sustainability viewpoints. This Review summarizes transition-metal-catalyzed alkylations of various carbon–hydrogen bonds (addition of C–H bonds across olefins) using regular olefins or 1,3-dienes up to May 2016. According to the mode of activation, the Review is divided into two sections: alkylation via C–H activation and alkylation via olefin activation.

Transition-Metal-Catalyzed C–H Alkylation Using Alkenes

The development of new methods for the direct functionalization of unactivated C–H bonds is ushering in a paradigm shift in the field of retrosynthetic analysis. In particular, the catalytic enantioselective functionalization of C–H bonds represents a highly atom- and step-economic approach toward the generation of structural complexity. However, as a result of their ubiquity and low reactivity, controlling both the chemo- and stereoselectivity of such processes constitutes a significant challenge. Herein we comprehensively review all asymmetric transition-metal-catalyzed methodologies that are believed to proceed via an inner-sphere-type mechanism, with an emphasis on the nature of stereochemistry generation. Our analysis serves to document the considerable and rapid progress within in the field, while also highlighting limitations of current methods.

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Catalytic Enantioselective Transformations Involving C-H Bond Cleavage by Transition-Metal Complexes.

In recent years, the transition-metal catalyzed three-component coupling of an aldehyde, an alkyne and an amine, commonly called A3-coupling, has been established as a convenient and general approach towards propargylamines. Furthermore, the A3-coupling has found a broad application as a key step in the construction of various nitrogen-containing heterocycles, biologically active compounds and natural products. Several interesting modifications of the A3-coupling as well as different tandem reactions involving A3-coupling have been developed. This tutorial review aims to highlight the current achievements in the field of A3-couplings and related transformations.

A walk around the A3-coupling

Chiral trivalent phosphorus species are the dominant class of ligands and the key controlling element in asymmetric homogeneous transition-metal catalysis. Here, novel chiral diaminophosphine oxide ligands are described. The arising catalyst system with nickel(0) and trimethylaluminum efficiently activates formamide C–H bonds under mild conditions providing pyrrolidones via intramolecular hydrocarbamoylation in a highly enantioselective manner with as little as 0.25% mol catalyst loading. Mechanistically, the secondary phosphine oxides behave as bridging ligands for the nickel center and the Lewis acidic organoaluminum center to give a heterobimetallic catalyst with superior reactivity.

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Diaminophosphine Oxide Ligand Enabled Asymmetric Nickel-Catalyzed Hydrocarbamoylations of Alkenes

The 1,6-annulated 2-pyridone motif is found in many biologically active compounds and its close relation to the indolizidine and quinolizidine alkaloid core makes it an attractive building block. A nickel-catalyzed CH functionalization of 2-pyridones and subsequent cyclization affords 1,6-annulated 2-pyridones by selective intramolecular olefin hydroarylation. The switch between the exo- and endo-cyclization modes is controlled by two complementary sets of ligands. Irrespective of the ring size, the regioselectivity during the cyclization is under full catalyst control. Simple cyclooctadiene promotes an exo-selective cyclization, whereas a bulky N-heterocyclic carbene ligand results in an endo-selective mode. The method was further applied in the synthesis of the lupin alkaloid cytisine.

Ligand-controlled regiodivergent nickel-catalyzed annulation of pyridones.

Efficient synthesis of the 3-benzazepine framework via intramolecular Heck reductive cyclization.

Taddol-based phosphoramidite ligands enable enantioselective palladium(0)-catalyzed C–H arylation of cyclopropanes. The cyclized products are obtained in high yields and enantioselectivities. The reported method provides efficient access to a broad range of synthetically attractive cyclopropyl containing dihydroquinolones and dihydroisoquinolones as well as allows for an efficient enantioselective construction of the 7-membered ring of the cyclopropyl indolobenzazepine core of BMS-791325.

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Enantioselective palladium(0)-catalyzed intramolecular cyclopropane functionalization: access to dihydroquinolones, dihydroisoquinolones and the BMS-791325 ring system

Pavel A. Donets

Papers

Diaminophosphine Oxide Ligand Enabled Asymmetric Nickel-Catalyzed Hydrocarbamoylations of Alkenes

Ligand-controlled regiodivergent nickel-catalyzed annulation of pyridones.

Efficient synthesis of the 3-benzazepine framework via intramolecular Heck reductive cyclization.

Enantioselective palladium(0)-catalyzed intramolecular cyclopropane functionalization: access to dihydroquinolones, dihydroisoquinolones and the BMS-791325 ring system

Efficient Synthesis of the Indoloazocine Framework via Intramolecular Alkyne Carbocyclization