The mechanism of the Ir(III) and Rh(III)-mediated C-N coupling reaction, which is the key step of catalytic C-H amidation, was investigated in an integrated experimental and computational study. Novel amidating agents containing a 1,4,2-dioxazole moiety allowed for designing a stoichiometric version of the catalytic C-N coupling reaction and giving access to reaction intermediates that reveal details about each step of the reaction. Both DFT and kinetic studies strongly point to a mechanism where the M(III) complex engages the amidating agent via oxidative coupling to form a M(V)-imido intermediate, which then undergoes migratory insertion to afford the final C-N coupled product. For the first time, the stoichiometric versions of the Ir and Rh-mediated amidation reaction were compared systematically to each other. Iridium reacts much faster than rhodium (~ 1100 times at 6.7 °C) with the oxidative coupling being so fast that the activation of the initial Ir(III)-complex becomes rate-limiting. In the case of Rh, the Rh-imido formation step is rate-limiting. These qualitative difference stems from a unique bonding feature of the dioxazole moiety and the relativistic contraction of the Ir(V), which affords much more favorable energetics for the reaction. For the first time, a full molecular orbital analysis is presented to rationalize and explain the electronic features that govern this behavior.

In place of functional groups that impose different inductive effects, we immobilize molecules carrying thiol groups on a gold electrode. By applying different voltages, the properties of the immobilized molecules can be tuned. The base-catalyzed saponification of benzoic esters is fully inhibited by applying a mildly negative voltage of –0.25 volt versus open circuit potential. Furthermore, the rate of a Suzuki-Miyaura cross-coupling reaction can be changed by applying a voltage when the arylhalide substrate is immobilized on a gold electrode. Finally, a two-step carboxylic acid amidation is shown to benefit from a switch in applied voltage between addition of a carbodiimide coupling reagent and introduction of the amine.

While numerous organo(metallic)catalyst systems were documented for dearomative hydroboration of N‐aromatics, alkoxide base catalysts have not been disclosed thus far. Described herein is the first example of alkoxide‐catalyzed hydroboration of N‐heteroaromatics including pyridines, providing a broad range of reduced N‐heterocycles with high efficiency and selectivity. Mechanistic studies revealed an unprecedented counterintuitive dearomatization pathway, in which 1) pyridine‐BH3 adducts undergo a hydride attack by alkoxyborohydrides, 2) in situ generated BH3 serves as a catalytic promoter, and 3) 1,4‐dihydropyridyl borohydride is in a predominant resting state.

Construction of carbon–carbon bonds is one of the most important tools in chemical synthesis. In the previously established cross-coupling reactions, prefunctionalized starting materials were usually employed in the form of aryl or alkyl (pseudo)­halides or their metalated derivatives. However, the direct use of arenes and alkanes via a 2-fold oxidative C–H bond activation strategy to access chemoselective C­(sp2)–C­(sp3) cross-couplings is highly challenging due to the low reactivity of carbon–hydrogen (C–H) bonds and the difficulty in suppressing side reactions such as homocouplings. Herein, we present the new development of a copper-catalyzed cross-dehydrogenative coupling of polyfluoroarenes with alkanes under mild conditions. Relatively weak sp3 C–H bonds at the benzylic or allylic positions, and nonactivated hydrocarbons could be alkylated by the newly developed catalyst system. A moderate-to-high site selectivity was observed among various C–H bonds present in hydrocarbon reactants, including gaseous feedstocks and complex molecules. Mechanistic information was obtained by performing combined experimental and computational studies to reveal that the copper catalyst plays a dual role in activating both alkane sp3 C–H bonds and sp2 polyfluoroarene C–H bonds. It was also suggested that the noncovalent π–π interaction and weak hydrogen bonds formed in situ between the optimal ligand and arene substrates are key to facilitating the current coupling reactions.

The direct amination of C−H bonds with ammonia is a challenge in synthetic chemistry. Herein, we present a copper-mediated approach that enables a chelation-assisted aromatic C−H bond amination using aqueous ammonia. A key strategy was to use soft lowvalent Cu(I) species to avoid the strong coordination of ammonia. Mechanistic investigations suggest that the catalysis is initiated by a facile deprotonation of bound ammonia, and the C−N coupling is achieved by subsequent reductive elimination of the resultant copper−amido intermediate from a Cu(III) intermediate that is readily generated by disproportionation of low-valent copper analogues. This mechanistic postulate was supported by a preliminary kinetic isotope effect study and computations. This new chelation-assisted, copper-mediated C−H bond amination with aqueous ammonia was successfully applied to a broad range of substrates to deliver primary anilines. Moreover, the mild conditions required for this transformation allowed the reaction to operate even under substoichiometric conditions to enable a late-stage application for the preparation of pharmaceutical agents.

Chemical synthesis based on the skeletal variation has been prolifically utilized as an attractive approach for modification of molecular properties. Given the ubiquity of unstrained cyclic amines, the ability to directly alter such motifs would grant an efficient platform to access unique chemical space. Here, we report a highly efficient and practical strategy that enables the selective ring-opening functionalization of unstrained cyclic amines. The use of difluorocarbene leads to a wide variety of multifaceted acyclic architectures, which can be further diversified to a range of distinctive homologative cyclic scaffolds. The virtue of this deconstructive strategy is demonstrated by successful modification of several natural products and pharmaceutical analogues.

β2-Amino carbonyls, an α-substituted β-amino scaffold, hold a prominent place in the development of new pharmaceuticals and peptidomimetics. Herein, we report a highly efficient Rh-catalyzed ring-opening amidation of substituted cyclopropanols, which turned out to serve as a linchpin for the selective synthesis of β2-amino ketones to outcompete the formation of β3-isomers. Instead of the generally accepted rationale to consider steric factors for the β2-selectivity, orbital interaction was elucidated to play a more critical role in the amidative ring-opening of cyclopropanols to generate the key Rh–C intermediate. Subsequent inner-sphere acylnitrene transfer was achieved in excellent efficiency (TON > 5000) by using readily accessible dioxazolones as the amino source to afford β2-amino ketones with broad applicability.

Selective dearomative transformation of readily available N-heteroarenes is a powerful tool accessing useful synthetic building units. Described herein is the NHC-catalyzed 1,2-selective hydroboration of quinolines with high functional group tolerance. Dihydroquinoline products could be isolated as their amide derivatives upon in situ N-protection, thus offering high synthetic utility of the current procedure. Combined experimental and computational studies revealed that the observed regioselectivity can be rationalized by proposing a six-membered transition state that collectively incorporates NHC catalyst, hydroborane reductant, and protonated quinoline substrate.