Catalytic transformation of ubiquitous C–H bonds into valuable C–N bonds offers an efficient synthetic approach to construct N-functionalized molecules. Over the last few decades, transition metal catalysis has been repeatedly proven to be a powerful tool for the direct conversion of cheap hydrocarbons to synthetically versatile amino-containing compounds. This Review comprehensively highlights recent advances in intra- and intermolecular C–H amination reactions utilizing late transition metal-based catalysts. Initial discovery, mechanistic study, and additional applications were categorized on the basis of the mechanistic scaffolds and types of reactions. Reactivity and selectivity of novel systems are discussed in three sections, with each being defined by a proposed working mode.

Transition Metal-Catalyzed C–H Amination: Scope, Mechanism, and Applications

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.

Transition metal-catalyzed direct functionalization of C–H bonds is one of the key emerging strategies that is currently attracting tremendous attention with the aim to provide alternative environmentally friendly and efficient ways for the construction of C–C and C–hetero bonds. In particular, the strategy involving regioselective C–H activation assisted by various functional groups shows high potential, and significant achievements have been made in both the development of novel reactions and the mechanistic study. In this review, we attempt to give an overview of the development of utilizing the functionalities as directing groups. The discussion is directed towards the use of different functional groups as directing groups for the construction of C–C and C–hetero bonds via C–H activation using various transition metal catalysts. The synthetic applications and mechanistic features of these transformations will be discussed, and the review is organized on the basis of the type of directing groups and the type of bond being formed or the catalyst.

Transition metal-catalyzed C–H bond functionalizations by the use of diverse directing groups

The present review is devoted to summarizing the recent advances (2015-2017) in the field of metal-catalysed group-directed C-H functionalisation In order to clearly showcase the molecular diversity that can now be accessed by means of directed C-H functionalisation, the whole is organized following the directing groups installed on a substrate Its aim is to be a comprehensive reference work, where a specific directing group can be easily found, together with the transformations which have been carried out with it Hence, the primary format of this review is schemes accompanied with a concise explanatory text, in which the directing groups are ordered in sections according to their chemical structure The schemes feature typical substrates used, the products obtained as well as the required reaction conditions Importantly, each example is commented on with respect to the most important positive features and drawbacks, on aspects such as selectivity, substrate scope, reaction conditions, directing group removal, and greenness The targeted readership are both experts in the field of C-H functionalisation chemistry (to provide a comprehensive overview of the progress made in the last years) and, even more so, all organic chemists who want to introduce the C-H functionalisation way of thinking for a design of straightforward, efficient and step-economic synthetic routes towards molecules of interest to them Accordingly, this review should be of particular interest also for scientists from industrial R&D sector Hence, the overall goal of this review is to promote the application of C-H functionalisation reactions outside the research groups dedicated to method development and establishing it as a valuable reaction archetype in contemporary R&D, comparable to the role cross-coupling reactions play to date

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A comprehensive overview of directing groups applied in metal-catalysed C-H functionalisation chemistry.

Research and industrial interest in radical C–H activation/radical cross-coupling chemistry has continuously grown over the past few decades. These reactions offer fascinating and unconventional approaches toward connecting molecular fragments with high atom- and step-economy that are often complementary to traditional methods. Success in this area of research was made possible through the development of photocatalysis and first-row transition metal catalysis along with the use of peroxides as radical initiators. This Review provides a brief and concise overview of the current status and latest methodologies using radicals or radical cations as key intermediates produced via radical C–H activation. This Review includes radical addition, radical cascade cyclization, radical/radical cross-coupling, coupling of radicals with M–R groups, and coupling of radical cations with nucleophiles (Nu).

Recent Advances in Radical C-H Activation/Radical Cross-Coupling.

α-Amino acids (αAA) are one of the most useful chiral building blocks for synthesis. There are numerous general strategies that have commonly been used for αAA synthesis, many of which employ de novo synthesis focused on enantioselective bond construction around the Cα center and others that consider conversion of existing αAA precursors carrying suitable functional groups on side chains (e.g., serine and aspartic acid). Despite significant advances in synthetic methodology, the efficient synthesis of enantiopure αAAs carrying complex side chains, as seen in numerous peptide natural products, remains challenging. Complementary to these "conventional" strategies, a strategy based on the selective functionalization of side chain C-H bonds, particularly sp(3) hybridized C-H bonds, of various readily available αAA precursors may provide a more straightforward and broadly applicable means for the synthesis and transformation of αAAs. However, many hurdles related to the low reactivity of C(sp(3))-H bonds and the difficulty of controlling selectivity must be overcome to realize the potential of C-H functionalization chemistry in this synthetic application. Over the past few years, we have carried out a systematic investigation of palladium-catalyzed bidentate auxiliary-directed C-H functionalization reactions for αAA substrates. Our strategies utilize two different types of amide-linked auxiliary groups, attached at the N or C terminus of αAA substrates, to exert complementary regio- and stereocontrol on C-H functionalization reactions through palladacycle intermediates. A variety of αAA precursors can undergo multiple modes of C(sp(3))-H functionalization, including arylation, alkenylation, alkynylation, alkylation, alkoxylation, and intramolecular aminations, at the β, γ, and even δ positions to form new αAA products with diverse structures. In addition to transforming αAAs at previously unreachable positions, these palladium-catalyzed C-H functionalization strategies enable new retrosynthetic logic for the synthesis of many basic αAAs from a common alanine precursor. This approach reduces the synthetic difficulty for many αAAs by bypassing the requirement for stereocontrol at Cα and relies on straightforward and convergent single-bond coupling transformations at the β-methyl position of alanine to access a wide range of β-monosubstituted αAAs. Moreover, these β-monosubstituted αAAs can undergo further C-H functionalization at the β-methylene position to generate various β-branched αAAs in a stereoselective and programmable fashion. These new strategies offer readily applicable methods for synthesis of challenging αAAs and may facilitate the efficient total synthesis of complex peptide natural products.

Syntheses and Transformations of α-Amino Acids via Palladium-Catalyzed Auxiliary-Directed sp3 C–H Functionalization

A photoredox-mediated Minisci C–H alkylation reaction of N-heteroarenes with alkyl boronic acids is reported. A broad range of primary and secondary alkyl groups can be efficiently incorporated into various N-heteroarenes using [Ru(bpy)3]Cl2 as photocatalyst and acetoxybenziodoxole as oxidant under mild conditions. The reaction exhibits excellent substrate scope and functional group tolerance, and offers a broadly applicable method for late-stage functionalization of complex substrates. Mechanistic experiments and computational studies suggest that an intramolecularly stabilized ortho-iodobenzoyloxy radical intermediate might play a key role in this reaction system.

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Photoredox-mediated Minisci C–H alkylation of N-heteroarenes using boronic acids and hypervalent iodine

Halogen-Bond-Promoted Photoactivation of Perfluoroalkyl Iodides: A Photochemical Protocol for Perfluoroalkylation Reactions

New methods capable of effecting cyclization, and forming novel three-dimensional structures while maintaining favourable physicochemical properties are needed to facilitate the development of cyclic peptide-based drugs that can engage challenging biological targets, such as protein-protein interactions. Here, we report a highly efficient and generally applicable strategy for constructing new types of peptide macrocycles using palladium-catalysed intramolecular C(sp3)-H arylation reactions. Easily accessible linear peptide precursors of simple and versatile design can be selectively cyclized at the side chains of either aromatic or modified non-aromatic amino acid units to form various cyclophane-braced peptide cycles. This strategy provides a powerful tool to address the long-standing challenge of size- and composition-dependence in peptide macrocyclization, and generates novel peptide macrocycles with uniquely buttressed backbones and distinct loop-type three-dimensional structures. Preliminary cell proliferation screening of the pilot library revealed a potent lead compound with selective cytotoxicity toward proliferative Myc-dependent cancer cell lines.

A general strategy for synthesis of cyclophane-braced peptide macrocycles via palladium-catalysed intramolecular sp 3 C-H arylation

We report a method for the monoselective alkylation of ortho-C–H bonds of N-quinolyl benzamides with both primary and secondary alkyl halides under palladium catalysis. With promotion by NaHCO3 and (BnO)2PO2H or (PhO)2PO2H, symmetric benzamide substrates can be selectively ortho-alkylated to give either mono- or dialkylated products by simply adjusting the amount of NaHCO3 applied. The use of phosphate notably improves the alkylation yield, although it may not be directly involved in C–H palladation or the subsequent functionalization step. Kinetic isotope effect studies indicate that C–H palladation is not the rate-limiting step. Examination of the reactions of an isolated palladacycle intermediate with both cis- and trans-4-methylcyclohexyl iodides revealed surprising stereoretentive couplings of these alkyl iodides. This evidence strongly suggests that the functionalization of the palladacycle with secondary alkyl iodides proceeds via a rarely precedented concerted oxidative addition pathway.

Gang He

Papers

Syntheses and Transformations of α-Amino Acids via Palladium-Catalyzed Auxiliary-Directed sp3 C–H Functionalization

Photoredox-mediated Minisci C–H alkylation of N-heteroarenes using boronic acids and hypervalent iodine

Halogen-Bond-Promoted Photoactivation of Perfluoroalkyl Iodides: A Photochemical Protocol for Perfluoroalkylation Reactions

A general strategy for synthesis of cyclophane-braced peptide macrocycles via palladium-catalysed intramolecular sp 3 C-H arylation

Pd-Catalyzed Monoselective ortho-C–H Alkylation of N-Quinolyl Benzamides: Evidence for Stereoretentive Coupling of Secondary Alkyl Iodides