Molecular syntheses largely rely on time‐ and labour‐intensive prefunctionalization strategies. In contrast, C−H activation represents an increasingly powerful approach that avoids lengthy syntheses of prefunctionalized substrates, with great potential for drug discovery, the pharmaceutical industry, material sciences, and crop protection, among others. The enantioselective functionalization of omnipresent C−H bonds has emerged as a transformative tool for the step‐ and atom‐economical generation of chiral molecular complexity. However, this rapidly growing research area remains dominated by noble transition metals, prominently featuring toxic palladium, iridium and rhodium catalysts. Indeed, despite significant achievements, the use of inexpensive and sustainable 3d metals in asymmetric C−H activations is still clearly in its infancy. Herein, we discuss the remarkable recent progress in enantioselective transformations via organometallic C−H activation by 3d base metals up to April 2019.

Asymmetric pallada‐electrocatalyzed C−H olefinations were achieved through the synergistic cooperation with transient directing groups. The electrochemical, atroposelective C−H activations were realized with high position‐, diastereo‐, and enantio‐control under mild reaction conditions to obtain highly enantiomerically‐enriched biaryls and fluorinated N−C axially chiral scaffolds. Our strategy provided expedient access to, among others, novel chiral BINOLs, dicarboxylic acids and helicenes of value to asymmetric catalysis. Mechanistic studies by experiments and computation provided key insights into the catalyst's mode of action.

The enantioselective cobalt(III)-catalyzed C À H alkylation was achieved through the design of an ovel chiral acid. The cobalt(III)-catalyzed enantioselective CÀHa ctivation was characterized by high position-, regio-and enantiocontrol under exceedingly mild reaction conditions.T hereby, the robust cooperative cobalt(III) catalysis proved tolerant of valuable electrophilic functional groups,i ncluding hydroxyl, bromo,a nd iodo substituents.M echanistic studies revealed ac onsiderable additive effect on kinetics and on an egative non-linear-effect.The activation of otherwise inert C À Hbonds has emerged as at ransformative tool in molecular sciences, [1] with notable applications to material sciences [2] and pharmaceutical industries. [3] While major progress was predominantly realized with precious transition metals,r ecent focus has shifted to less expensive,e arth abundant 3d metals. [4] In this context, highvalent pentamethylcyclopentadienyl cobalt(III) complexes [5] were identified as particularly powerful C À Ha ctivation catalysts. [6][7][8][9][10] Thef ull control of selectivity is paramount to achieving synthetically meaningful CÀHf unctionalization. [11] However,inthe scenario of enantioselective CÀHactivation, progress was thus far primarily limited to noble 4d and 5d transition metals,s uch as palladium, [12] rhodium, [13] and iridium. [14] In sharp contrast, enantioselective C À Ht ransformations by late 3d transition metals have largely been accomplished with superstoichiometric amounts of reactive Grignard reagents, [15,16] which leads to undesired byproducts, and, more importantly,l imits considerably the robustness in terms of functional group tolerance.B ased on our recent mechanistic findings on base-assisted internal electrophilic substitution (BIES)-C À Hm etalations, [17] we became intrigued to the development of unprecedented enantioselective cobalt(III)-catalyzed CÀHa ctivation, on which we wish to report herein (Figure 1). Salient features of our findings include (a) first asymmetric Cp*Co III -catalyzed C À H activation, (b) robust functional group tolerance,(c) detailed mechanistic insights into cooperative catalysis by experiment and computation and (d) the de-novo design of ah ighly selective chiral carboxylic acid scaffold.We initiated our studies by probing various Brønsted acids for the envisioned asymmetric C À Ha lkylation of indole 1a (Table 1, and Table S-1 in the Supporting Information). [18] Thus,N -protected amino acids L1-L4 (entries 3-6) provided the product 3aa with only poor levels of enantiocontrol. Decreasing the L2 loading led to al ower efficacya nd only as light improvement of the enantioselectivity (entry 7). Interestingly,t he well-established BINOL-based Brønsted acids L5-L7 failed entirely in the enantioselective C À H alkylations (entry 8), reflecting the challenging nature of the asymmetric cobalt catalysis.Gratefully, [19] the newly designed C 2 -symmetric carboxylic acid L8 delivered the desired product 3aa with an enantiomeric ratio of 93:7, [20] albeit wi...

A unique C–H allylation has been discovered with unbiased aliphatic olefins. An intimate M–L affiliation between a high-valent cobalt catalyst and amino-quinoline derived benzamides has been found to be crucial for this unprecedented selectivity. An exemplary set of aliphatic olefins, high yields coupled with excellent regio- and stereoselectivity, and wide functional group tolerances are noteworthy. In addition, a catalytically competent organometallic Co­(III) species has been identified through X-ray crystallography. This study is expected to facilitate new synthetic designs toward unconventional allylic selectivity with aliphatic olefins.

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

Synthetically meaningful isoindolones were accessed by cupraelectro-catalyzed C–H activation with electricity as terminal oxidant. Thus, a versatile, inexpensive, and nontoxic Cu­(OAc)2 catalyst enabled broadly applicable C–H/N–H functionalizations on electron-rich and electron-deficient benzamides with distinct functional group tolerance and resource-economy. Detailed mechanistic studies provided strong support for a C–H alkynylation mechanism through fast C–H metalation, which likewise set the stage for cupraelectro-catalyzed C–H/C–C functionalizations in a decarboxylative fashion.

Inexpensive cobalt‐catalyzed oxidative C−H functionalization has emerged as a powerful tool for the construction of C−C and C−Het bonds, which offers unique potential for transformative applications to modern organic synthesis. In the early stage, these transformations typically required stoichiometric and toxic transition metals as sacrificial oxidants; thus, the formation of metal‐containing waste was inevitable. In contrast, naturally abundant molecular O2 has more recently been successfully employed as a green oxidant in cobalt catalysis, thus considerably improving the sustainability of such transformations. Recently, a significant momentum was gained by the use of electricity as a sustainable and environmentally benign redox reagent in cobalt‐catalyzed C−H functionalization, thereby preventing the consumption of cost‐intensive chemicals while at the same time addressing the considerable safety hazards related to the use of molecular oxygen in combination with flammable organic solvents. Considering the unparalleled potential of the aforementioned approaches for sustainable green synthesis, this Review summarizes the recent progress in cobalt‐catalyzed oxidative C−H activation until early 2020.