Koji Kubota

Over the past decade, photoredox catalysis has harnessed light energy to accelerate bond-forming reactions. We postulated that a complementary method for the redox-activation of small organic molecules in response to applied mechanical energy could be developed through the piezoelectric effect. Here, we report that agitation of piezoelectric materials via ball milling reduces aryl diazonium salts. This mechanoredox system can be applied to arylation and borylation reactions under mechanochemical

A borylative exo-cyclization of alkenyl halides has been reported. The reaction includes the regioselective addition of a borylcopper(I) intermediate to unactivated terminal alkenes, followed by the intramolecular substitution of the resulting alkylcopper(I) moiety for the halide leaving groups. Experimental and theoretical investigations of the reaction mechanism have also been described. This reaction provides a new method for the synthesis of alkylboronates containing strained cycloalkyl stru

Conventional organic synthesis generally relies on the use of liquid organic solvents to dissolve the reactants. Therefore, reactions of sparingly soluble or insoluble substrates are challenging and often ineffective. The development of a solvent-independent solid-state approach that overcomes this longstanding solubility issue would provide innovative synthetic solutions and access to new areas of chemical space. Here, we report extremely fast and highly efficient solid-state palladium-catalyze

The application of piezoelectricity for the generation of trifluoromethyl (CF₃ ) radicals is reported together with the development of a method for the mechanochemical C-H trifluoromethylation of aromatic compounds. As compared to conventional solution-based approaches, this mechanoredox C-H trifluoromethylation enables cleaner and more sustainable access to a wide range of trifluoromethylated N-heterocycles and peptides, which are important structural motifs in modern drug discovery.

Palladium-catalyzed cross-coupling reactions are one of the most powerful and versatile methods to synthesize a wide range of complex functionalized molecules. However, the development of solid-state cross-coupling reactions remains extremely limited. Here, we report a rational strategy that provides a general entry to palladium-catalyzed Buchwald-Hartwig cross-coupling reactions in the solid state. The key finding of this study is that olefin additives can act as efficient molecular dispersants

We have developed a novel approach for the synthesis of enantioenriched 3-boryl-tetrahydropyridines via the Cu(I)-catalyzed regio-, diastereo-, and enantioselective protoborylation of 1,2-dihydropyridines, which were obtained by the partial reduction of the pyridine derivatives. This dearomatization/enantioselective borylation stepwise strategy provides facile access to chiral piperidines together with the stereospecific transformation of a stereogenic C-B bond from readily available starting ma

The Suzuki-Miyaura cross-coupling reaction is one of the most reliable methods for the construction of carbon-carbon bonds in solution. However, examples for the corresponding solid-state cross-coupling reactions remain scarce. Herein, we report the first broadly applicable mechanochemical protocol for a solid-state palladium-catalyzed organoboron cross-coupling reaction using an olefin additive. Compared to previous studies, the newly developed protocol shows a substantially broadened substrate

The enantioselective borylative dearomatization of a heteroaromatic compound has been achieved using a copper(I) catalyst and a diboron reagent. This reaction involves the regio- and enantioselective addition of active borylcopper(I) species to indole-2-carboxylates, followed by the diastereoselective protonation of the resulting copper(I) enolate to give the corresponding chiral indolines, which bear consecutive stereogenic centers.

This review describes recent advances in direct borylation reactions of organic halides, including both transition-metal-catalyzed and metal-free methods. Since the pioneering work on palladium-catalyzed boryl substitution of aryl halides with a diboron compound reported by Miyaura and co-workers in 1995, various catalytic systems for the borylation of aryl, alkneyl, and alkyl halides have been developed to give a wide range of organoboronate esters that cannot be synthesized using conventional

Palladium-catalyzed Suzuki-Miyaura cross-coupling reactions of liquid, unbiased dibromoarenes under mechanochemical conditions selectively afford the monoarylated products. The lower reactivity of the crystalline monoarylated products relative to the liquid starting materials should be attributed predominantly to the low diffusion efficiency of the former in the reaction mixture, which results in a selective monoarylation. The present study sheds light on a novel approach using <i>in situ</i> ph

A new method for cysteine-lysine cross-linking in peptides and proteins using palladium oxidative addition complexes is presented. First, a biarylphosphine-supported palladium reagent is used to transfer an aryl group bearing an O-phenyl carbamate substituent to a cysteine residue. Next, this carbamate undergoes chemoselective acyl substitution by a proximal lysine to form a cross-link. The linkage so formed is stable toward acid, base, oxygen, and external thiol nucleophiles. This method was ap

Organic reactions that employ moisture- and/or oxygen-sensitive reagents or intermediates usually involve the use of glove-box or Schlenk-line techniques as well as dry and degassed solvents. Unfortunately, these requirements may greatly reduce the utility of the targeted organic molecules. Herein, we demonstrate that solvent-free mechanochemical synthetic techniques allow using highly oxygen-sensitive palladium(0) species in air for the stoichiometric oxidative addition of aryl halides. The low

The first catalytic enantioselective nucleophilic borylation of a C═O double bond has been achieved. A series of aldehydes reacted with a diboron reagent in the presence of a copper(I)/DTBM-SEGPHOS complex catalyst using MeOH as a proton source to give the corresponding optically active α-alkoxyorganoboronate esters with excellent enantioselectivities. Furthermore, the products could be readily converted to the corresponding functionalized chiral alcohol derivatives through stereospecific C-C bo

Sonogashira coupling represents an indispensable tool for the preparation of organic materials that contain C(sp)-C(sp²) bonds. Improving the efficiency and generality of this methodology has long been an important research subject in materials science. Here, we show that a high-temperature ball-milling technique enables the highly efficient palladium-catalyzed Sonogashira coupling of solid aryl halides that bear large polyaromatic structures including sparingly soluble substrates and