Anion-Mediated, Stereospecific Synthesis of Secondary and Tertiary Cyclopropylboronates from Chiral Epoxides and gem-Diborylalkanes.

We report a transition-metal-free deborylative cyclization approach to synthesize enantioenriched secondary and tertiary cyclopropylboronates using γ-phosphate-containing gem-diborylalkanes derived from chiral epoxides and gem-diborylalkanes. Our method enables the synthesis of a broad range of enantioenriched secondary and tertiary cyclopropylboronates in good yields with excellent stereospecificity. We demonstrate the versatility of our approach by performing a gram-scale reaction. We also show that the enantioenriched tertiary cyclopropylboronates can be transformed into a wide array of enantioenriched cyclopropane derivatives in a stereospecific boron-group transformation.

Iridium-Catalyzed Chemo-, Diastereo-, and Enantioselective Allyl-Allyl Coupling: Accessing All Four Stereoisomers of (E)-1-Boryl-Substituted 1,5-Dienes by Chirality Pairing.

Here, we report a highly chemo-, diastereo-, and enantioselective allyl-allyl coupling between branched allyl alcohols and α-silyl-substituted allylboronate esters, catalyzed by a chiral iridium complex. The α-silyl-substituted allylboronate esters can be chemoselectively coupled with allyl electrophiles, affording a diverse set of enantioenriched (E)-1-boryl-substituted 1,5-dienes in good yields, with excellent stereoselectivity. By permuting the chiral iridium catalysts and the substrates, we efficiently and selectively obtained all four stereoisomers bearing two consecutive chiral centers. Mechanistic studies via density functional theory calculations revealed the origins of the diastereo- and chemoselectivities, indicating the pivotal roles of the steric interaction, the ß-silicon effect, and a rapid desilylation process. Additional synthetic modifications for preparing a variety of enantioenriched compounds containing contiguous chiral centers are also included.

Stereoselective Access to Tetra- and Tri-Substituted Fluoro- and Chloro-Borylalkenes via Boron-Wittig Reaction.

Reported herein is the efficient synthesis of tetra- and tri-substituted (Z)-fluoro- and (Z)-chloro-borylalkenes by the Boron-Wittig reaction of ketones and aldehydes with bench-top stable halo-diborylmethanes. The substrate scope is broad and the Boron-Wittig reaction proceeds from a diverse range of ketones and aldehydes including biologically relevant molecules with fluoro- or chloro-diborylmethanes, providing tetra- and tri-substituted (Z)-fluoro- and (Z)-chloro-borylalkenes in good yields with high stereoselectivity. The utilities of the obtained (Z)-fluoro- and (Z)-chloro-borylalkenes are highlighted by further modifications to afford fluoroalkene derivatives or all-carbon substituted alkene.

Diborylmethyl Group as a Transformable Building Block for the Diversification of Nitrogen-Containing Molecules.

The development of new approaches to installing diverse carbon fragments to a nitrogen atom has attracted considerable attention in chemical science. While numerous strategies have been devised to forge C(sp3 )-N bonds, one conceptually powerful and straightforward approach is to insert a transformable sp3 -carbon unit onto a nitrogen atom for modular diversification. Here we describe the successful synthesis of halo-diborylmethanes and their applications to the preparation of nitrogen-substituted diborylmethanes through their homologative coupling with a variety of nitrogen nucleophiles including biologically relevant molecules. This process exhibits a remarkably broad substrate scope, and the usefulness of the obtained compounds is demonstrated by the modular diversification of the diborylmethyl group to access various nitrogen-containing molecules.

Defluorinative C-C Bond-Forming Reaction of Trifluoromethyl Alkenes with gem-(Diborylalkyl)lithiums.

We report the transition-metal-free defluorinative C-C bond-forming reaction of trifluoromethyl alkenes with gem-(diborylalkyl)lithiums. This synthetic strategy provides access to a variety of 4,4-difluoro homoallylic diboronate esters, which serve as versatile intermediates in the efficient preparation of valuable gem-difluoroalkene derivatives. Further synthetic modifications are conducted to demonstrate the synthetic utility of the obtained 4,4-difluoro homoallylic diboronate esters.

Catalytic Chemo- and Enantioselective Transformations of gem-Diborylalkanes and (Diborylmethyl)metallic Species.

Chemo- and stereoselective transformations of polyborylalkanes are powerful and efficient methods to access optically active molecules with greater complexity and diversity through programmed synthetic design. Among the various polyborylalkanes, gem-diborylalkanes have attracted much attention in organic chemistry as versatile synthetic handles. The notable advantage of gem-diborylalkanes lies in their ability to generate two key intermediates, α-borylalkyl anions and (gem-diborylalkyl) anions. These two different intermediates can be applied to various enantioselective reactions to rapidly access a diverse set of enantioenriched organoboron compounds, which can be further manipulated to generate various chiral molecule libraries via stereospecific C(sp3)-B bond transformations.In this Account, we summarize our recent contributions to the development of catalytic chemo- and stereoselective reactions using gem-diborylalkanes as versatile nucleophiles, which can be categorized as follows: (1) copper-catalyzed enantioselective coupling of gem-diborylalkanes with electrophiles and (2) the design and synthesis of (diborylmethyl)metallic species and their applications to enantioselective reactions. Since Shibata and Endo reported the Pd-catalyzed chemoselective Suzuki-Miyaura cross-coupling of gem-diborylalkanes with organohalides in 2014, Morken and Hall subsequently developed the first enantioselective analogous reactions using TADDOL-derived chiral phosphoramidite as the supporting ligand of a palladium catalyst. This discovery sparked interest in the catalytic enantioselective coupling of gem-diborylalkanes with electrophiles. Our initial studies focused on generating chiral (α-borylmethyl)copper species by enantiotopic-group-selective transmetalation of gem-diborylalkanes with chiral copper complexes and their reactions with various aldimines and ketimines to afford syn-ß-aminoboronate esters with excellent enantio- and diastereoselectivity. Moreover, we developed the enantioselective allylation of gem-diborylalkanes that proceeded by reaction of in situ-generated chiral (α-borylalkyl)copper and allyl bromides. Mechanistic investigations revealed that the enantiotopic-group-selective transmetalation between gem-diborylalkanes and the chiral copper complex occurred through the open transition state rather than the closed transition state, thereby effectively generating chiral (α-borylmethyl)copper species. We also utilized (diborylmethyl)metallic species such as (diborylmethyl)silanes and (diborylmethyl)zinc halides in catalytic enantioselective reactions. We succeeded in developing the enantiotopic-group-selective cross-coupling of (diborylmethyl)silanes with aryl iodides to afford enantioenriched benzylic 1,1-silylboronate esters, which could be used for further consecutive stereospecific transformations to afford various enantioenriched molecules. In addition, we synthesized (diborylmethyl)zinc halides for the first time by the transmetalation of isolated (diborylmethyl)lithium and zinc(II) halides and their utilization to the synthesis of enantioenriched gem-diborylalkanes bearing a chiral center at the ß-position via an iridium-catalyzed enantioselective allylic substitution process. In addition to our research efforts, we also include key contributions by other research groups. We hope that this Account will draw the attention of the synthetic community to gem-diboryl compounds and provide guiding principles for the future development of catalytic enantioselective reactions using gem-diboryl compounds.

Advances in transition metal-free deborylative transformations of gem-diborylalkanes.

Carbanions serve as key intermediates in a variety of chemical transformations. Particularly, α-borylcarbanions have received considerable attention in recent years because of their peculiar properties, including the ability of boron atom resonance to stabilise the adjacent negatively charged carbon atom. This feature article summarises recent progress in the synthetic utilisation of α-borylcarbanions, including carbon-carbon bond formation with alkyl halides, alkenes, N-heteroarenes, and carbonyls. Carbon-boron bond formation in organohalides mediated by α-borylcarbanions is also summarised.

Copper-Catalyzed Enantiotopic-Group-Selective Allylation of gem-Diborylalkanes.

We report a copper-catalyzed enatiotopic-group-selective allylation of gem-diborylalkanes with allyl bromides. The combination of copper(I) bromide and H8-BINOL derived phosphoramidite ligand proved to be the most effective catalytic system to provide various enantioenriched homoallylic boronate esters, containing a boron-substituted stereogenic center that is solely derived from gem-diborylalkanes, in good yields with high enantiomeric ratios under mild conditions. Experimental and theoretical studies have been conducted to elucidate the reaction mechanism, revealing how the enatiotopic-group-selective transmetalation of gem-diborylalkanes with chiral copper complex occurs to generate chiral α-borylalkyl-copper species for the first time. Additional synthetic applications to the synthesis of various chiral building blocks are also included.

Cobalt-Catalyzed Defluorosilylation of Aryl Fluorides via Grignard Reagent Formation.

Transition-metal-catalyzed transformations of the carbon-fluorine bond not only tackle an interesting problem of challenging bond activation but also offer new synthetic strategies where the relatively inert C-F bond is converted to versatile functional groups. Herein we report a practical cobalt-catalyzed silylation of aryl fluorides that uses a cheap electrophilic silicon source with magnesium. This method is compatible with various silicon sources and can be operated under aerobic conditions. Mechanistic studies support the in situ formation of a Grignard reagent, which is captured by the electrophilic silicon source.

ZnMe2-Mediated, Direct Alkylation of Electron-Deficient N-Heteroarenes with 1,1-Diborylalkanes: Scope and Mechanism.

The regioselective, direct alkylation of electron-deficient N-heteroarenes is, in principle, a powerful and efficient way of accessing alkylated N-heteroarenes that are important core structures of many biologically active compounds and pharmaceutical agents. Herein, we report a ZnMe2-promoted, direct C2- or C4-selective primary and secondary alkylation of pyridines and quinolines using 1,1-diborylalkanes as alkylation sources. While substituted pyridines and quinolines exclusively afford C2-alkylated products, simple pyridine delivers C4-alkylated pyridine with excellent regioselectivity. The reaction scope is remarkably broad, and a range of C2- or C4-alkylated electron-deficient N-heteroarenes are obtained in good yields. Experimental and computational mechanistic studies imply that ZnMe2 serves not only as an activator of 1,1-diborylalkanes to generate (α-borylalkyl)methylalkoxy zincate, which acts as a Lewis acid to bind to the nitrogen atom of the heterocycles and controls the regioselectivity, but also as an oxidant for rearomatizing the dihydro-N-heteroarene intermediates to release the product.

Facile Synthesis of α-Boryl-Substituted Allylboronate Esters Using Stable Bis[(pinacolato)boryl]methylzinc Reagents.

Reported herein is the utilization of bis[(pinacolato)boryl]methylzinc halides, whose structures are characterized via single-crystal X-ray analysis, as solid storable reagents for copper-catalyzed coupling with vinyliodonum salts. The reaction proceeds under mild conditions and shows broad scope with respect to vinyliodonium salts, affording various α-boryl-substituted allylboronate esters in good yields. Synthetic applications of the obtained products are also demonstrated.

Highly Mesoporous Metal-Organic Frameworks as Synergistic Multimodal Catalytic Platforms for Divergent Cascade Reactions.

Rational engineering and assimilation of diverse chemo- and biocatalytic functionalities in a single nanostructure is highly desired for efficient multistep chemical reactions but has so far remained elusive. Here, we design and synthesize multimodal catalytic nanoreactors (MCNRs) based on a mesoporous metal-organic framework (MOF). The MCNRs consist of customizable metal nanocrystals and stably anchored enzymes in the mesopores, as well as coordinatively unsaturated cationic metal MOF nodes, all within a single nanoreactor space. The highly intimate and diverse catalytic mesoporous microenvironments and facile accessibility to the active site in the MCNR enables the cooperative and synergistic participation from different chemo- and biocatalytic components. This was shown by one-pot multistep cascade reactions involving a heterogeneous catalytic nitroaldol reaction followed by a [Pd/lipase]-catalyzed chemoenzymatic dynamic kinetic resolution to yield optically pure (>99 % ee) nitroalcohol derivatives in quantitative yields.

Palladium-Catalyzed Chemoselective Negishi Cross-Coupling of Bis[(pinacolato)boryl]methylzinc Halides with Aryl (Pseudo)Halides.

We describe a palladium-catalyzed chemoselective Negishi cross-coupling of a bis[(pinacolato)boryl]methylzinc halide with aryl (pseudo)halides. This reaction affords an array of benzylic 1,1-diboronate esters, which can serve as useful synthetic handles for further transformations. The developed coupling reaction is compatible with various functional groups and can be easily scaled up. The coupling of bis[(pinacolato)boryl]methylzinc halides with pharmaceuticals and the subsequent late-stage manipulations demonstrate the power of the developed protocol.

Generation and Application of (Diborylmethyl)zinc(II) Species: Access to Enantioenriched gem-Diborylalkanes by an Asymmetric Allylic Substitution.

We report the successful generation of (diborylmethyl)zinc(II) species by transmetallation beteween isolable (diborylmethyl)lithium and zinc(II) halide (X=Br, Cl) and their application in the synthesis of enantioenriched gem-diborylalkanes bearing a stereogenic center at the ß-position of the diboryl groups by an asymmetric allylic substitution reaction. The reaction has a broad substrate scope, and various enantioenriched gem-diborylalkanes can be obtained in good yields with excellent enantioselectivity. Further elaboration of the enantioenriched gem-diborylalkanes provides access to a diverse set of valuable chiral building blocks.

Confined Nucleation and Growth of PdO Nanocrystals in a Seed-Free Solution inside Hollow Nanoreactor.

This paper reports a novel and adaptable hollow nanoreactor system containing a solution of cucurbituril (CB) inside a silica nanoparticle (CB@h-SiO2) which enables the nucleation and formation of nanocrystals (NCs) to be confined at the seed-free interior solution inside the cavity. The above nanospace confinement strategy restricted the volume of medium available for NC formation to the solution inside the cavity to a few tens of nanometers in size and allowed homogeneous NC nucleation to be examined. Harboring of CB@h-SiO2 in a Pd2+ complex solution confined the nucleation and formation of PdO NCs to the well-isolated nanosized cavity protected by the silica nanoshell, allowing the convoluted formation of clustered PdO NCs to be thoroughly examined. The corresponding temporal investigation indicated that PdO NC clusters evolved via a distinct pathway combining dendritic growth on early nucleated seed NCs and attachment of small intermediate clusters. In addition, the explored strategy was used to fabricate a recyclable nanocatalyst system for selective catalytic oxidation of cinammyl alcohols, featuring a cavity-included Fe3O4/PdO nanocomposite.

Diastereo- and Enantioselective Synthesis of ß-Aminoboronate Esters by Copper(I)-Catalyzed 1,2-Addition of 1,1-Bis[(pinacolato)boryl]alkanes to Imines.

Reported herein is an efficient copper(I)-catalytic system for the diastereo- and enantioselective 1,2-addition of 1,1-bis[(pinacolato)boryl]alkanes to protected imines to afford synthetically valuable enantioenriched ß-aminoboron compounds bearing contiguous stereogenic centers. The reaction exhibits a broad scope with respect to protected imines and 1,1-bis[(pinacolato)boryl]alkanes, thus providing ß-aminoboronate esters with excellent diastereo- and enantioselectivity. The synthetic utility of the obtained ß-aminoboronate ester was also demonstrated.

Chemo- and Stereoselective Crotylation of Aldehydes and Cyclic Aldimines with Allylic gem-Diboronate Ester.

We report a highly chemo- and stereoselective crotylation of aldehydes and cyclic aldimines with allylic-gem-diboronate ester as a new type of organoboron reagent. The allylic-gem-diboronate ester undergoes the crotylation with aldehydes and cyclic aldimines in excellent stereoselectivity, forming anti-5,6-disubstituted oxaborinin-2-ols or (E)-δ-boryl-anti-homoallylic amines in high efficiency. The reaction shows a wide range of substrate scope and excellent functional group tolerance. The synthetic applications of the obtained products, including stereospecific C-C, C-O, and C-Cl bond formation, are also demonstrated.

Spontaneous Pt Deposition on Defective Surfaces of In2O3 Nanocrystals Confined within Cavities of Hollow Silica Nanoshells: Pt Catalyst-Modified ITO Electrode with Enhanced ECL Performance.

Although the deposition of metallic domains on a preformed semiconductor nanocrystal provides an effective pathway to access diverse hybrid nanocrystals with synergistic metal/semiconductor heterojunction interface, those reactions that take place on the surface of semiconductor nanoscrystals have not been investigated thoroughly, because of the impediments caused by the surface-capping organic surfactants. By exploiting the interfacial reactions occurring between the solution and nanoparticles confined with the cavities of hollow nanoparticles, we propose a novel nanospace-confined strategy for assessing the innate reactivity of surfaces of inorganic semiconductor nanoparticles. This strategy was adopted to investigate the newly discovered process of spontaneous Pt deposition on In2O3 nanocrystals. Through an in-depth examination involving varying key reaction parameters, the Pt deposition process was identified to be templated by the defective In2O3 surface via a unique redox process involving the oxygen vacancies in the In2O3 lattice, whose density can be controlled by high-temperature annealing. The product of the Pt-deposition reaction inside the hollow silica nanoparticle, bearing In2O3-supported Pt catalysts inside the cavity protected by a porous silica shell, was proved to be an effective nanoreactor system which selectively and sustainably catalyzed the reduction reaction of small-sized aromatic nitro-compounds. Moreover, the surfactant-free and electroless Pt deposition protocol, which was devised based on the surface chemistry of the In2O3 nanoparticles, was successfully employed to fabricate Pt-catalyst-modified ITO electrodes with enhanced electrogenerated chemiluminescece (ECL) performance.

Base-promoted, deborylative secondary alkylation of N-heteroaromatic N-oxides with internal gem-bis[(pinacolato)boryl]alkanes: a facile derivatization of 2,2'-bipyridyl analogues.

A base-promoted, secondary alkylation of N-heteroaromatic N-oxides using internal gem-bis[(pinacolato)boryl]alkanes as alkylation reagents is reported. The reaction exhibits a broad scope, providing deoxygenated secondary alkylated N-heteroaromatic compounds with high efficiency. The usefulness of the developed protocol is evidenced by the sequential direct alkylation of 2,2'-bipyridine-N-oxide.

Chemoselective Coupling of 1,1-Bis[(pinacolato)boryl]alkanes for the Transition-Metal-Free Borylation of Aryl and Vinyl Halides: A Combined Experimental and Theoretical Investigation.

A new transition-metal-free borylation of aryl and vinyl halides using 1,1-bis[(pinacolato)boryl]alkanes as boron sources is described. In this transformation one of the boron groups from 1,1-bis[(pinacolato)boryl]alkanes is selectively transferred to aryl and vinyl halides in the presence of sodium tert-butoxide as the only activator to form organoboronate esters. Under the developed borylation conditions, a broad range of organohalides are borylated with excellent chemoselectivity and functional group compatibility, thus offering a rare example of a transition-metal-free borylation protocol. Experimental and theoretical studies have been performed to elucidate the reaction mechanism, revealing the unusual formation of Lewis acid/base adduct between organohalides and α-borylcarbanion, generated in situ from the reaction of 1,1-bis[(pinacolato)boryl]alkanes with an alkoxide base, to facilitate the borylation reactions.