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.

Selectivity control in hydroarylation-based C-H alkylation has been dominated by steric interactions. A conceptually distinct strategy that exploits the programmed switch in the C-H activation mechanism by means of cobalt catalysis is presented, which sets the stage for convenient C-H alkylations with unactivated alkenes. Detailed mechanistic studies provide compelling evidence for a programmable switch in the C-H activation mechanism from a linear-selective ligand-to-ligand hydrogen transfer to a branched-selective base-assisted internal electrophilic-type substitution.

Acylated amino acid ligands enabled ruthenium(II)-catalyzed C-H functionalizations with excellent levels of meta-selectivity. The outstanding catalytic activity of the ruthenium(II) complexes derived from monoprotected amino acids (MPAA) set the stage for the first ruthenium-catalyzed meta-functionalizations with removable directing groups. Thereby, meta-alkylated anilines could be accessed, which are difficult to prepare by other means of direct aniline functionalizations. The robust nature of the versatile ruthenium(II)-MPAA was reflected by challenging remote C-H transformations with tertiary alkyl halides on aniline derivatives as well as on pyridyl-, pyrimidyl-, and pyrazolyl-substituted arenes. Detailed mechanistic studies provided strong support for an initial reversible C-H ruthenation, followed by a SET-type C-Hal activation through homolytic bond cleavage. Kinetic analyses confirmed this hypothesis through an unusual second-order dependence of the reaction rate on the ruthenium catalyst concentration. Overall, this report highlights the exceptional catalytic activity of ruthenium complexes derived from acylated amino acids, which should prove instrumental for C-H activation chemistry beyond remote functionalization.

Cationic cobalt complexes enable unprecedented cobalt-catalyzed C-H/C-C functionalizations with unique selectivity features. The versatile cobalt catalyst proved broadly applicable, enabled efficient C-H/C-C cleavage at room temperature, and delivered Z-alkenes with excellent diastereocontrol.

Well-defined ruthenium(II) phosphinous acid (PA) complexes enabled chemo-, site-, and diastereoselective C-H functionalization of arenes and alkenes with ample scope. The outstanding catalytic activity was reflected by catalyst loadings as low as 0.75 mol %, and the most step-economical access reported to date to angiotensin II receptor antagonist blockbuster drugs. Mechanistic studies indicated a kinetically relevant C-X cleavage by a single-electron transfer (SET)-type elementary process, and provided evidence for a PA-assisted C-H ruthenation step.

C–F/C–H functionalizations proved to be viable within a versatile manganese­(I) catalysis manifold. Thus, a wealth of fluorinated alkenes were employed in C–F/C–H functionalizations through facile C–H activation. The robust nature of the manganese­(I) catalysis regime was among others reflected by the first C–F/C–H activation with perfluoroalkenes as well as racemization-free C–H functionalizations on imines, amino acids, and peptides.

Sustainable, cobalt-catalyst enabled, synthetically significant CÀF/CÀHf unctionalizations were achieved with an ample substrate scope at an ambientt emperature of 25 8C, thereby delivering perfluoroallylated heteroarenes. Detailed experimental and computational mechanistic studies on the CÀF/CÀHf unctionalizations provided strong support for af acile CÀFcleavage.CÀHf unctionalizations have been recognized asi ncreasingly viable tools for molecular synthesis, [1] with applications in material sciences, [2] as well as the agrochemical and pharmaceutical industries.[3] As ignificant advance was recently made by Loh, Li, Wang,a nd Ackermann, in whichC ÀHa ctivation chemistry was merged with challenging CÀFf unctionalizations within aC ÀF/CÀHa ctivation manifold, [4] thereby providing access to selectively fluorinated molecules.[5] Despite these undisputed advances, catalytic CÀF/CÀHf unctionalizations continue to be scarce, and are limited to elevated reaction temperatures and/or strongly nucleophilic hydroxide bases, which considerably compromise chemoselectivity.I nc ontrast, within our program on sustainable CÀHf unctionalizations, [6] we have now developed af irst room-temperature CÀF/CÀHf unctionalization using earth-abundant cobalt catalysis, [7][8][9] with the weak base K 2 CO 3 under exceedingly mild reaction conditions (Figure 1). Notable features of our findings include (i)C ÀF/CÀH functionalizations at room temperature withm ild carbonate bases, (ii)first cobalt-catalyzed CÀF/CÀHa llylations with perfluoroalkyl alkenes, (iii)C ÀF/CÀHf unctionalizations with cobalt loadings as low as 0.25 mol %, and (iv) detailed mechanistic insights into the working mode of CÀF/CÀHf unctionalization by cobalt catalysis.We initiated our studies by probing the effect exertedbydifferent solvents and weak bases on the unprecedented cobaltcatalyzed CÀF/CÀHf unctionalization of indole 1a with perfluoroalkylalkene 2a (Table 1and Ta ble S1 in the Supporting Information). Indeed, the desired CÀF/CÀHt ransformation provedv iable,p articularly when using TFE as the most effective solvent( entries 1-4). Amongavariety of weak bases, K 2 CO 3 turned out to be optimal (entries 4-14). Notably,t he

Manganese-catalyzed CH functionalization reactions of ketimines set the stage for the expedient synthesis of cis-β-amino acid esters through site- and regioselective alkene annulations. The organometallic CH activation occurred efficiently with high functional group tolerance, delivering densely functionalized β-amino acid derivatives with ample scope.