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.

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

Transition-metal-catalyzed cross-coupling reactions have been well-established as indispensable tools in modern organic synthesis. One of the major research goals in cross-coupling area is expanding the scope of the coupling partners. In the past decade, diazo compounds (or their precursors N-tosylhydrazones) have emerged as nucleophilic cross-coupling partners in C–C single bond or C═C double bond formations in transition-metal-catalyzed reactions. This type of coupling reaction involves the following general steps. First, the organometallic species is generated by various processes, including oxidative addition, transmetalation, cyclization, C–C bond cleavage, and C–H bond activation. Subsequently, the organometallic species reacts with the diazo substrate to generate metal carbene intermediate, which undergoes rapid migratory insertion to form a C–C bond. The new organometallic species generated from migratory insertion may undergo various transformations. This type of carbene-based coupling has proven...

Transition-Metal-Catalyzed Cross-Couplings through Carbene Migratory Insertion

An Overview on Ynamines
Alkynes represent one of the most important and versatile building blocks in organic synthesis. Heteroatom-substituted alkynes, which can be considered as subgroups of alkynes, have also been vastly utilized in developing synthetic methods. In particular, ynamines [1-amino-alkynes or N-alkynyl amines] became the most valuable subgroup of alkynes after the establishment of their practical synthesis in the 1960's. The first attempt at preparation of an ynamine was reported by Bode1,2 in 1892. While well-characterized ynamines were reported in 19583 and 1960,4 a practical synthesis was not achieved until the effort led by Viehe5 in 1963 in addition to other subsequent works. In the ensuing twenty years, the synthetic significance of ynamines in organic and organometallic chemistry was firmly established by the work of many creative synthetic chemists. These elegant pioneer works have been informatively and carefully reviewed by Viehe in 19676 and 1969;7 Ficini in 1976;8 Pitacco and Valentin9 in 1979; Collard-Motte and Janousek10 in 1986; Himbert11 in 1993; and most recently by us12,13 and Katritzky14.





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The synthetic eminence of ynamines is well merited because of the predicable regioselectivity in their transformations as shown by the generalization in Scheme i, and more importantly, because they are inherently highly reactive. However, this latter attribute is also the source of the limitation that has seriously hampered the development of ynamine chemistry, thereby shortening the period of its prominence in synthesis. Ynamines are very sensitive toward hydrolysis, as protonation of the electron-rich alkynyl motif affords reactive keteniminium intermediates, which upon trapping with water leads to simple amides in a rather expensive manner (Scheme i). This hydrolytic instability has caused much difficulty in the experimental preparation and general handling of ynamines, and more detrimentally, rendered ynamine chemistry inaccessible.




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Scheme i



Consequently, the synthetic utility of ynamines has suffered a dramatic decline during the last thirty years.15 The most glaring limitations have been in the development of intramolecular and stereoselective reactions.7–14 The only reported intramolecular reaction of ynamines was Genet and Kahn's acid catalyzed addition of a hydroxyl group to an ynamine [i→ii in Scheme ii] in 1980,16 and although clever, it constitutes a hydrolytic process.






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Scheme ii



Besides Reinhoudt's17 sole account in 1987 reporting hetero-[4 + 2] cycloadditions of chiral ynamine iii with nitroalkenes that led to cycloadducts iv in modest de, the only other notable studies were reported ten years later by Fischer18 showcasing [2 + 2] cycloadditions of chiral ynamides v and vi with vinylidene chromium carbene complexes, and another three years later by Pericas19 in their Pauson-Khand cycloadditions using chiral ynamines vii.

Ynamides: A Modern Functional Group For The New Millennium

(Pentamethylcyclopentadienyl)rhodium (RhCp*)-catalyzed CH transformations have emerged as a prosperous field in CH bond activation. Recent advances in this area have significantly focused on the development of new strategies for CC and Cheteroatom bond formation that are characterized by the novel reactivity of the RhCp* catalyst to undergo formal SN-type reactions with electrophilic substrates. This review is intended to give an overview on this rather new class of RhCp*-catalyzed CH transformations, covering recent CC and Cheteroatom bond-forming reactions. The nature of the reaction partner in these CH functionalization reactions serves as a guideline throughout this article and, combined with selected descriptions of mechanistic proposals, should emphasize general characteristics of transformations within this novel reaction class.

Formal SN‐Type Reactions in Rhodium(III)‐Catalyzed CH Bond Activation

Multisubstituted isoquinoline and pyridine N-oxides have been prepared by Rh(III)-catalyzed cyclization of oximes and diazo compounds via aryl and vinylic C–H activation. This intermolecular annulation involving tandem C–H activation, cyclization, and condensation steps proceeds under mild conditions, obviates the need for oxidants, releases N2 and H2O as the byproducts, and displays a broad substituent scope.

Rh(III)-catalyzed synthesis of multisubstituted isoquinoline and pyridine N-oxides from oximes and diazo compounds.

Rh(III)-Catalyzed intramolecular redox-neutral cyclization of alkenes via C–H activation

Pd-catalyzed domino reactions have been shown to stitch together chemical groups to form more complex scaffolds. Now these methods are used in a diversity-oriented synthesis approach to make intricate natural product–like structures using simple sugars as starting materials.

Domino access to highly substituted chromans and isochromans from carbohydrates

The cooperative catalysis by palladium and triphenylborane effects the intramolecular oxycyanation of alkenes through the cleavage of O-CN bonds and the subsequent insertion of double bonds. The use of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) as a ligand for palladium is essential for allowing the transformation to proceed with high chemo- and regioselectivity. Variously substituted dihydrobenzofurans with both a tetra-substituted carbon and cyano functionality are accessed by the newly developed methodology.

Dennis C. Koester

Papers

Rh(III)-catalyzed synthesis of multisubstituted isoquinoline and pyridine N-oxides from oximes and diazo compounds.

Rh(III)-Catalyzed intramolecular redox-neutral cyclization of alkenes via C–H activation

Domino access to highly substituted chromans and isochromans from carbohydrates

Intramolecular oxycyanation of alkenes by cooperative Pd/BPh3 catalysis.

Flexible Synthesis of 2‐Deoxy‐C‐Glycosides and (1→2)‐, (1→3)‐, and (1→4)‐Linked C‐Glycosides