Ni-catalyzed cross-coupling between aryl alkyl ethers (ArOR) and Grignard reagents (RMgBr), known since 1979, proceeds under mild conditions in many cases. Although the reaction routes of various synthetic protocols involving transition-metal-catalyzed C-O bond activation have been elucidated, the mechanism of this etheric Kumada-Tamao-Curriu reaction remains enigmatic. This is because oxidative addition of inert etheric C-O to Ni(0) is thermodynamically and kinetically unfavorable, making it hard to explain the observed high reactivity of ether toward Ni catalysts. In this work, we used DFT calculations to identify a plausible reaction pathway by the Ni(0)-ate complex, which enables smooth C-O bond cleavage and R-group transfer with reasonable activation barriers; this mechanism also accounts for the ineffectiveness of Pd catalysts. These results throw new light on both C-O activation and cross-coupling, and should be valuable for further rational development of the methodologies.

Multicomponent reactions (MCRs), in which three or more molecules react in one pot and generate products containing almost all atoms of the reactant molecules, have been developed extensively as tools to achieve highly atom-, step-, and energy-economic organic syntheses.[1] The Passerini reaction, which is formally a three-component reaction involving a carboxylic acid, an aldehyde (or ketone), and an isocyanide to generate an a-acyloxycarboxamide, is the most fundamental MCR involving isocyanides.[1a,c, 2] A conventional mechanism of this reaction is shown in Scheme 1, [1a, 2i] where the reaction takes place efficiently at or below room temperature, in apolar solvent, and with high concentration of reactants. Here we present a quantum chemical study of all possible pathways among three reactant molecules of the Passerini reaction using a new theoretical approach for finding transition states (TSs) and propose the most probable pathway without prejudice for presumed pathways or mechanisms.Advances in quantum chemical calculation methods have enabled accurate and efficient theoretical elucidations of mechanisms, kinetics, and dynamics of many chemical reactions.[3] The intrinsic reaction coordinate (IRC) [4] is an idealized reaction path on quantum chemical potentialenergy surfaces (PESs) and has been calculated to elucidate detailed pathways and mechanisms of various chemical reactions. Despite the growing interest in MCRs and the advances in theoretical methods, detailed theoretical studies of full mechanisms of MCRs have been rather scarce. This is in part because of difficulties in guessing structures of TSs that involve extensive bond rearrangements and partly because of the existence of many possible association pathways. Most of previous theoretical studies for MCRs (and also for other complex reactions) have examined only a few of pathways, which are assumed rather arbitrarily on the basis of intuition and experience. Although there have been considerable efforts to develop methods to locate many TSs automatically and systematically, [5] their applications to associative reactions of type A + B!X have not been very successful. Lack of systematic methods for reactions of type A + B!X has been serious, not only in analysis and prediction of MCRs, but also for many other organic reactions in which often two or more reagents including reactant(s) and catalyst(s) are mixed together and many complex reactions may be taking place simultaneously.Recently, we proposed a new approach for finding all reaction pathways (with or without TSs) for reactions of type A + B!X in an efficient and systematic way, [6] which we call the artificial force induced reaction (AFIR) method. To illustrate this method, let us consider an association reaction between two atoms A and B for which the PES E(r AB ) as a function of A À B distance r AB looks like Figure 1 a and the product structure X is not known. From the reactants, it is usually difficult to guess reasonable structures of TS or X. Now consider a potential curve F(r AB...

Cross-coupling is a fundamental reaction in the synthesis of functional molecules, and has been widely applied, for example, to phenols, anilines, alcohols, amines and their derivatives. Here we report the Ni-catalysed Stille cross-coupling reaction of quaternary ammonium salts via C–N bond cleavage. Aryl/alkyl-trimethylammonium salts [Ar/R–NMe3]+ react smoothly with arylstannanes in 1:1 molar ratio in the presence of a catalytic amount of commercially available Ni(cod)2 and imidazole ligand together with 3.0 equivalents of CsF, affording the corresponding biaryl with broad functional group compatibility. The reaction pathway, including C–N bond cleavage step, is proposed based on the experimental and computational findings, as well as isolation and single-crystal X-ray diffraction analysis of Ni-containing intermediates. This reaction should be widely applicable for transformation of amines/quaternary ammonium salts into multi-aromatics.

Deprotonative directed ortho cupration of aromatic/heteroaromatic C-H bond and subsequent oxidation with t-BuOOH furnished functionalized phenols in high yields with high regio- and chemoselectivity. DFT calculations revealed that this hydroxylation reaction proceeds via a copper (I → III → I) redox mechanism. Application of this reaction to aromatic C-H amination using BnONH2 efficiently afforded the corresponding primary anilines. These reactions show broad scope and good functional group compatibility. Catalytic versions of these transformations are also demonstrated.