Finding optimal chiral ligands for transition-metal-catalyzed asymmetric reactions using trial-and-error methods is often time-consuming and costly, even if the details of the reaction mechanism are already known. Although modern computational analyses allow the prediction of the stereoselectivity, there are only very few examples for the attempted design of chiral ligands using a computational approach for the improvement of the stereoselectivity. Herein, we report a systematic method for the design of chiral ligands for the enantioselective Markovnikov hydroboration of aliphatic terminal alkenes based on a computational and experimental evaluation sequence. We developed a three-hindered-quadrant P-chirogenic bisphosphine ligand that was designed in accordance with the design guidelines derived from this method, which allowed the Markovnikov hydroboration to proceed with high enantioselectivity (up to 99% ee).

The first copper(I)-catalyzed enantioselective borylation of racemic benzyl chlorides has been realized by aq uadrant-by-quadrant structure modulation of QuinoxP*type bisphosphine ligands.T his reaction converts racemic mixtures of secondary benzyl chlorides into the corresponding chiral benzylboronates with high enantioselectivity (up to 92 % ee). The results of mechanistic studies suggest the formation of ab enzylic radical intermediate.T he results of DFT calculations indicate that the optimal bisphosphine-copper(I) catalyst engages in noncovalent interactions that efficiently recognize the radical intermediate,a nd leads to high levels of enantioselectivity. Scheme 1. Copper(I)-catalyzed borylation of alkyl electrophiles.

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 methods. Borylative cyclization of alkyl halides is also discussed.

A new method has been developed for the Markovnikov hydroboration of alkyl-substituted terminal alkenes. Notably, the use of a bulky bisphosphine-copper(i) catalyst system resulted in high regioselectivity to afford secondary alkylboronates from the corresponding terminal alkenes (branch/linear = 92 : 8-97 : 3). This method also exhibited good functional group compatibility.

Abstract:The first enantioselective borylative dearomatization of a heteroaromatic compound has been achieved using a copper(I) catalyst and a diboron reagent. This reaction involves the unprecedented 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 bearing consecutive stereogenic centers.

The first example of the oxidative addition of a C(sp 3 )−F bond in trifluoromethylarenes to a nickel(0) complex is described. A nickel(0) complex that bears two N-heterocyclic carbene (NHC) ligands of low steric demand is able to cleave C(sp 3 )−F bonds of trifluoromethylarenes to afford the corresponding trans-difluorobenzyl nickel(II) fluoride complexes. Isolation and characterization studies suggested that the cleavage of the C(sp 3 )−F bond proceeds via an η 2 -arene nickel(0) complex. Taking advantage of the reactivity of these nickel(II) fluoride complexes, we developed a catalytic hydrodefluorination of trifluoromethylarenes using hydrosilanes. A computational study indicated that the electron-rich nickel(0) center supported by two relatively small NHC ligands cleaves the C(sp 3 )−F bond via a syn-S N 2′ mechanism.

The stereoselective borylative radical cyclization of alkyl halides containing an alkene moiety was developed using a copper(I)/diboron catalyst system. The optimized reaction conditions allowed us to control the chemoselectivity between the allylic substitution and the borylative radical cyclization. The borylation products were subsequently converted to highly functionalized organic compounds by derivatization of the newly formed C-B bond. This borylative radical cyclization offers a novel methodology for the stereoselective synthesis of various heterocyclic compounds.

A stereoselective alkene isomerization and sequential hydroarylation with arylboronic acid using a nickel(0) catalyst has been developed. The bulky monophosphine PAd2(n-Bu) is an effective ligand in these reactions to furnish both various stereo-defined internal alkenes and hydroarylation products (isomerization: up to 98%, E/Z = 98:2; tandem hydroarylation: up to 82%). Mechanistic studies based on experiments and computational calculations suggested that the isomerization proceeds via an intra- or intermolecular hydrogen shift. Furthermore, a concerted multibond recombination with boronic acid-assisted oxidative protometallation of the alkene was found to be a reasonable mechanism for the formation of the alkylnickel­(II) species from the alkene, nickel(0), alcohol, and boronic acid in the hydroarylation.