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Sustainable Catalytic C-H Bond Functionalization

Final Report Summary - CATCHFUN (Sustainable Catalytic C-H Bond Functionalization)

The ERC Starting Grant project “Sustainable Catalytic C-H Bond Functionalization” at the Georg-August-University Göttingen set the stage for ruthenium(II)-catalyzed functionalizations of C(sp3)–H bonds by carboxylate assistance. Ruthenium(II) biscarboxylates further enabled unprecedented hydroarylations of unactivated alkenes (Angew. Chem. Int. Ed. 2013, 52, 3977-3980), oxygenations of arenes by assistance of weakly-coordinating directing groups (Angew. Chem. Int. Ed. 2014, 53, 11285-11288) and decarboxylative functionalizations (Angew. Chem. Int. Ed. 2016, 55, 6929). Furthermore, novel bidentate directing groups have been developed, which among others allowed for the functionalization of unactivated alkanes by C(sp3)–H activation (Angew. Chem. Int. Ed. 2014, 53, 3868). Interestingly, modular 1,2,3-triazoles enabled iron-catalyzed C–H arylations with broad scope. The novel triazole-based bidentate auxiliary is easily accessible in a modular fashion and allowed for user-friendly iron-catalyzed C(sp2)–H functionalizations of arenes and alkenes with excellent chemo- and diastereoselectivities (Chem. Commun. 2017, 53, 6460; Angew. Chem. Int. Ed. 2016, 55, 1484). The versatile iron catalyst also proved applicable for challenging C(sp3)–H functionalizations. Direct C–H alkylations with achieved through bidentate chelation-assistance with a versatile nickel catalysts (Angew. Chem. Int. Ed. 2014, 53, 2477-2480) as well as mono-dentate anilines (Chem. Commun. 2017, 53, 9113; Angew. Chem. Int. Ed. 2016, 55, 3153). On a different note, the nickel catalysis could also be developed for allene transformations without directing groups (Angew. Chem. Int. Ed. 2017, 56, DOI:10.1002/anie.201709087). Furthermore, low-valent cobalt catalysts showed high catalytic activity in the direct alkenylation (Angew. Chem. Int. Ed. 2015, 54, 6352-6355) and alkylation (Chem. Eur. J. 2013, 19, 10605-10610) of arenes, bearing major potential for the envisioned perfluoroalkylation reactions. As to photoredox catalysis, we have developed the unprecedented photo-induced copper-catalyzed C–H activation, which enabled C–H arylations and chalcogenations at room temperature (Chem. Commun. 2017, 53, 5906; Angew. Chem. Int. Ed. 2016, 55, 4759). A broadly applicable nickel catalyst allowed for C–H alkylations of unactivated arenes with challenging primary and secondary alkyl halides. Importantly, the high catalytic efficacy of the nickel catalyst set the stage for direct secondary alkylations of indoles as well as C–H trifluoroethylations with ample scope (Angew. Chem. Int. Ed. 2014, 53, 2477-2480). Moreover, we have devised methods for challenging C–H/C–F by cobalt (Chem. Eur. J. 2017, 23, 12145) and manganese (ACS Catal. 2017, 7, 4209) catalysis for the synthesis of specifically fluorinated compounds. Additionally, we have introduced removable directing groups for ruthenium(II)-catalyzed C–H functionalizations (Chem. Eur. J. 2015, 20, 1790-1794). Moreover, we have shown that a ruthenium(II)-catalyzed phthalide synthesis could be performed in an aerobic fashion (Angew. Chem. Int. Ed. 2015, 54, 5513-5517). Mechanistic studies unraveled the key importance of acetic acid for the crucial reoxidation of ruthenium(0) by molecular oxygen, which proved instrumental for oxidative aerobic alkenylations with molecular oxygen as the sole oxidant (Angew. Chem. Int. Ed. 2016, 55, 264). Also, cobalt oxidase catalysis could be established for C–H activations in terms of alkyne annulations (Chem. Eur. J. 2016, 22, 6759). Ruthenium catalysts enabled C–H bond functionalizations on arenes with challenging secondary alkyl halides with excellent levels of unusual meta-selectivity (J. Am. Chem. Soc. 2013, 135, 5877-5884), including a heterogeneous system (Angew. Chem. Int. Ed. 2017, 56, 1557). Particularly, ruthenium(II) biscarboxylate complexes proved to be the key to success for these direct alkylations (Nature Commun. 2017, 8, 15430; Angew. Chem. Int. Ed. 2017, 56, 2045). The direct alkylations occurred under mild reaction conditions with ample scope, and tolerated valuable functional groups. Detailed mechanistic studies were performed, including various competition experiments as well as reactions with isotopically labeled substrates. These studies provided strong support for an initial reversible cyclometalation (J. Am. Chem. Soc. 2015, 137, 13894). Independently prepared cycloruthenated complexes were found to be catalytically active provided that a carboxylate ligand was present, thereby highlighting the key importance of carboxylate assistance for effective meta-selective C–H bond alkylations. Carboxylate assistance also proved instrumental for the development of para-selective ruthenium(II)-catalyzed hydroxylations of arenes (Org. Lett. 2013, 15, 3484-3486). Asymmetric C–H transformations were accomplished through the design of a novel N-heterocyclic carbene ligand. Thereby, asymmetric C–H alkylations were accomplished by earth abundant iron catalysis (Angew. Chem. Int. Ed. 2017, 56, 14197).