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Cobalt-catalyzed C-H amination via M-nitrenoid species is spiking the interest of the research community. Understanding this process at a molecular level is a challenging task, and here we report a well-defined macrocyclic system featuring a pseudo- O aryl-Co III species that reacts with aliphatic azides to effect intramolecular C-N bond formation. Strikingly, a putative aryl-Co=NR nitrenoid intermediate species is formed and is rapidly trapped by a carboxylate ligand to form a carboxylate masked-nitrene, which functions as a shortcut to stabilize and guide the reaction to productive intramolecular C-N bond formation. On one hand, several intermediate species featuring the C-N bond formed have been isolated and structurally characterized, and the essential role of the carboxylate ligand has been proven. Complementarily, a thorough density functional theory study of the C-N bond formation mechanism explains at the molecular level the key role of the carboxylate-masked nitrene species, which is essential to tame the metastability of the putative aryl-Co III =NR nitrene species to effectively yield the C-N products. The solid molecular mechanistic scheme determined for the C-N bond forming reaction is fully supported by both experimental and computation complementary studies.

Computational studies of the Co-catalyzed remote nitration of 8-aminoquinolinamides have found the mechanism to operate through an unexpected high-spin induced remote radical-coupling., Previously, an unexpected Co-catalysed remote C–H nitration of 8-aminoquinolinamide compounds was developed. This report provided a novel reactivity for Co which was assumed to proceed through the mechanistic pathway already known for analogous Cu-catalysed remote couplings of the same substrates. In order to shed light into this intriguing, and previously unobserved reactivity for Co, a thorough computational study has now been performed, which has allowed for a full understanding of the operative mechanism. This study demonstrates that the Co-catalysed remote coupling does not occur through the previously proposed Single Electron Transfer (SET) mechanism, but actually operates through a high-spin induced remote radical coupling mechanism, through a key intermediate with significant proportion of spin density at the 5- and 7-positions of the aminoquinoline ring. Additionally, new experimental data provides expansion of the synthetic utility of the original nitration procedure towards 1-naphthylpicolinamide which unexpectedly appears to operate via a subtly different mechanism despite having a similar chelate environment.

The formidable challenges of controlling site-selectivity, enantioselectivity, and product chemoselectivity make asymmetric C-H oxidation a generally unsolved problem for nonenzymatic systems. Discrimination between the two enantiotopic C-H bonds of an unactivated methylenic group is particularly demanding and so far unprecedented, given the similarity between their environments and the facile overoxidation of the initially formed hydroxylation product. Here we show that a Mn-catalyzed C-H oxidation directed by carboxylic acids can overcome these challenges to yield γ-lactones in high enantiomeric excess (up to 99%) using hydrogen peroxide as oxidant and a Brønsted acid additive under mild conditions and short reaction times. Coordination of the carboxylic acid group to the bulky Mn complex ensures the rigidity needed for high enantioselectivity and dictates the outstanding γ site-selectivity. When the substrate contains nonequivalent γ-methylenes, the site-selectivity for lactonization can be rationally predicted on the basis of simple C-H activation/deactivation effects exerted by proximal substituents. In addition, discrimination of diastereotopic C-H bonds can be modulated by catalyst design, with no erosion of enantiomeric excess. The potential of this reaction is illustrated in the concise synthesis of a tetrahydroxylated bicyclo[3.3.1]nonane enabled by two key, sequential γ-C-H lactonizations, with the latter that fixes the chirality of five stereogenic centers in one step with 96% ee Support by the Spanish Ministry of Science (PGC2018-101737-B-I00 to M.C. and J.d.C. grant to G.O., FJCI-2016-30243), and Gen-eralitat de Catalunya (ICREA Academia Award to M.C. and 2014SGR 862), and from EU (MSCA-ITN-2015 Action NoNoMeCat, 675020) is acknowledged