B2 Pin2 Research Articles

Enantio- and Regioselective Cascade Hydroboration of Methylenecyclopropanes for Facile Access to Chiral 1,3- and 1,4-Bis(boronates).

Chiral 1, n-bis(boronate) plays a crucial role in organic synthesis and medicinal chemistry. However, their catalytic and asymmetric synthesis has long posed a challenge in terms of operability and accessibility from readily available substrates. The recent discovery of the C═C bond formation through β-C elimination of methylenecyclopropanes (MCP) has provided an exciting opportunity to enhance molecular complexity. In this study, the catalyzed asymmetric cascade hydroboration of MCP is developed. By employing different ligands, various homoallylic boronate intermediate are obtained through the hydroboration ring opening process. Subsequently, the cascade hydroboration with HBpin or B2pin2 resulted in the synthesis of enantioenriched chiral 1,3- and 1,4-bis(boronates) in high yields, accompanied by excellent chemo- and enantioselectivities. The selective transformation of these two distinct C─B bonds also demonstrated their application potential in organic synthesis.

Neutral and Anionic Diboron Compounds Bearing Electron-Precise B-B Bond.

Electron-precise B-B bonded compounds are valuable reagents in organic syntheses, which can be used as key starting material for the synthesis of functionalized organoboranes. Bis(pinacolato)diborane(4) B2 pin2 and its derivatives are among the most studied diboron species. However, their B-B bonds usually need to be activated by transition metal catalysts or bases for further transformations. Recently, many well-designed/reactive electron-precise B-B bonded compounds have been developed, which could facilitate direct reactions with small molecules, unsaturated substrates, and electrophiles. This review highlights the synthesis, structure, and reactivity of neutral and anionic B-B bonded compounds.

Regioselective Iridium-Catalyzed C8-H Borylation of 4-Quinolones via Transient O-Borylated Quinolines.

The quinolone-quinoline tautomerization is harnessed to effect the regioselective C8-borylation of biologically important 4-quinolones by using [Ir(OMe)(cod)]2 as the catalyst precursor, the silica-supported monodentate phosphine Si-SMAP as the ligand, and B2 pin2 as the boron source. Initially, O-borylation of the quinoline tautomer takes place. Critically, the newly formed 4-(pinBO)-quinolines then undergo N-directed selective Ir-catalyzed borylation at C8. Hydrolysis of the OBpin moiety on workup returns the system to the quinolone tautomer. The C8-borylated quinolines were converted to their corresponding potassium trifluoroborate (BF3 K) salts and to their C8-chlorinated quinolone derivatives. The two-step C-H borylation-chlorination reaction sequence resulted in various C8-Cl quinolones in good yields. Conversion to C8-OH-, C8-NH2 -, and C8-Ar-substituted quinolones was also feasible by using this methodology.

Boronyl Borinic Esters: Preparation as B2 pin2 /sec BuLi/TFAA Adducts, Structural Insights and Reactivity in Pd-catalyzed Allylic Borylation.

Novel boronyl borinic ester I was generated by quenching the B2 pin2 /sec BuLi-ate complex with trifluoroacetic acid anhydride (TFAA) via ring-opening in the 1,3,2-dioxaborolane moiety on ate-boron. Detailed NMR studies of the B2 pin2 /sec BuLi-ate complex in solution and in solid state allowed us to assume its oligomeric nature in solids with only ate-boron involved in the oligomerization process. The O-trifluoroacetyl pinacolate residue on borinic ester I initially formed on quenching with TFAA undergoes an unusual intramolecular transesterification with the carbonyl group of trifluoroacetyl forming othroester moiety in a few hours at r. t. to give boronyl borinic ester II. A solution of these reagents I/II was proved to be efficient for borylation of (2-fluoroallyl)pyridinium salts that are highly base sensitive.

Mechanism and Origins of Diastereo- and Regioselectivities of Palladium-Catalyzed Remote Diborylative Cyclization of Dienes via Chain-Walking Strategy.

Density functional theory calculations have been performed to investigate the palladium-catalyzed remote diborylative cyclization of dienes. The computations reveal that the reaction proceeds through a rarely explored Pd(II)/Pd(IV) catalytic cycle, and the formal σ-bond metathesis between the alkylpalladium intermediate and B2 pin2 occurs via the pathway of the B-B oxidative addition/C-B reductive elimination involving the high-valent Pd(IV) species. The diastereoselectivity is determined by the migratory insertion into the Pd-C bond, which is mainly due to the combination of the torsional strain effect, steric repulsion and C-H-O hydrogen-bonding interaction. The steric hindrance around the reacting carbon group in the C-B reductive elimination turns out to be a key factor to provide the driving force of the chain walking of the Pd center to the terminal primary carbon position, enabling the experimentally observed remote regioselectivity.

Ligand-Controlled Regiodivergent Cyanoboration of Internal Allenes by Copper Catalysis.

The first copper-catalyzed regiodivergent cyanoboration of internal allenes with B2 pin2 (bis(pinacolato)diboron) and NCTS (N-cyano-N-phenyl-p-toluenesulfonamide) derivatives is reported. The β,γ- and α,β-cyanoborylated products were synthesized with high regio- and stereo-selectivity. Computational studies revealed that nucleophilic addition of allylcopper or related intermediates on cyanation reagent is the regio- and stereo-determining step, while transmetalation with B2 pin2 is the rate-determining step. The nucleophilic addition step proceeds via inner-sphere mechanism in the CuI /P(o-tol)3 and CuI /Xantphos (P(o-tol)3 =tris(o-methylphenyl)phosphine, Xantphos=4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) catalytic systems and via outer-sphere mechanism in the CuII /Xantphos catalytic system, respectively.

Copper-Catalyzed Borylation of Acyl Chlorides with an Alkoxy Diboron Reagent: A Facile Route to Acylboron Compounds.

Herein, the copper‐catalyzed borylation of readily available acyl chlorides with bis(pinacolato)diboron, (B2pin2) or bis(neopentane glycolato)diboron (B2neop2) is reported, which provides stable potassium acyltrifluoroborates (KATs) in good yields from the acylboronate esters. A variety of functional groups are tolerated under the mild reaction conditions (room temperature) and substrates containing different carbon‐skeletons, such as aryl, heteroaryl and primary, secondary, tertiary alkyl are applicable. Acyl N‐methyliminodiacetic acid (MIDA) boronates can also been accessed by modification of the workup procedures. This process is scalable and also amenable to the late‐stage conversion of carboxylic acid‐containing drugs into their acylboron analogues, which have been challenging to prepare previously. A catalytic mechanism is proposed based on in situ monitoring of the reaction between p‐toluoyl chloride and an NHC‐copper(I) boryl complex as well as the isolation of an unusual lithium acylBpinOBpin compound as a key intermediate.

Metal-Free Reductive Coupling of para-Quinone Methides with 4-Cyanopyridines Enabled by Pyridine-Boryl Radicals: Access to Pyridylated Diarylmethanes with Anti-Cancer Activity.

Reported herein is a streamlined protocol to produce pyridylated diarylmethanes through pyridine-boryl radical induced reductive coupling between para-quinone methides (p-QMs) and 4-cyanopyridines using bis(pinacolato)diboron (B2 pin2 ) as a templated reagent. The metal-free process is characterized by an operationally simple approach, excellent chemoselectivity (1,2- vs. 1,6-selectivity), and a broad substrate scope with good functional group compatibility. The mechanistic studies provided important insights into the reductive cross-coupling process between diarylmethyl radical and pyridine-boryl radical. Moreover, part of the obtained pyridylated diarylmethane products were screened against a panel of cancer cell lines, and 3 v was confirmed to significantly inhibit the proliferation of head and neck squamous cell carcinoma (HNSCC) cells. This method offers a platform for the preparation of new lead compounds with antitumor activity.

Copper-Catalyzed Highly Selective Protoboration of CF3 -Containing 1,3-Dienes.

The copper-catalyzed highly selective protoboration of CF3 -containing conjugated diene with proton source and B2 Pin2 has been developed. This chemistry could suppress the well-known defluorination and provide borated reagents with an intact CF3 -group. Further studies indicated that the functional group tolerance of this chemistry is very well, and the products could be used as versatile precursors for different types of transformations. Importantly, using chiral diphosphine ligand, we have developed the first example for using such starting material to synthesis allylic boron-reagents which bearing a CF3 -containing chiral center. Notably, the reaction mechanism was intensively studied by DFT calculations, which could reveal the reason that defluorination was inhibited.

Electrochemical Hydroboration of Alkynes.

Herein we reported the electrochemical hydroboration of alkynes by using B2Pin2 as the boron source. This unprecedented reaction manifold was applied to a broad range of alkynes, giving the hydroboration products in good to excellent yields without the need of a metal catalyst or a hydride source. This transformation relied on the possible electrochemical oxidation of an in situ formed borate. This anodic oxidation performed in an undivided cell allowed the formation of a putative boryl radical, which reacted on the alkyne.

Four-Component Borocarbonylation of Vinylarenes Enabled by Cooperative Cu/Pd Catalysis: Access to β-Boryl Ketones and β-Boryl Vinyl Esters.

We report here a general four-component synthetic procedure for the preparation of β-boryl ketones and β-boryl vinyl esters. Joint catalyzed by palladium and copper catalysts, borocarbonylative reaction between vinylarenes, aryl halides/triflates, B2 Pin2 , and carbon monoxide proceed successfully. A variety of synthetically useful β-boryl ketones were synthesized in good to high yields by using aryl iodides as the substrates. It is noteworthy that when aryl triflates were applied as the starting materials, β-boryl vinyl esters were synthesized in a similar manner and with broad functional group tolerance. A rational mechanism for this reaction was also proposed.

Asymmetric Synthesis of Silicon-Stereogenic Silanes by Copper-Catalyzed Desymmetrizing Protoboration of Vinylsilanes.

The catalytic asymmetric creation of silanes with silicon stereocenters is a long-sought but underdeveloped topic, and only a handful of examples have been reported. Moreover, the construction of chiral silanes containing (more than) two stereocenters is a more arduous task and remains unexploited. We herein report an unprecedented copper-catalyzed desymmetrizing protoboration of divinyl-substituted silanes with bis(pinacolato)diboron (B2 pin2 ). This method enables the facile preparation of an array of enantiomerically enriched boronate-substituted organosilanes bearing contiguous silicon and carbon stereocenters with exclusive regioselectivity and generally excellent diastereo- and enantioselectivity.

Aminoazanium of DABCO: An Amination Reagent for Alkyl and Aryl Pinacol Boronates.

The aminoazanium of DABCO (H2 N-DABCO) has been developed as a general and practical amination reagent for the direct amination of alkyl and aryl pinacol boronates. This compound is stable and practical for use as a reagent. Various primary, secondary. and tertiary alkyl-Bpin and aryl-Bpin substrates were aminated to give the corresponding amine derivatives. The amination is stereospecific. The anti-Markovnikov hydroamination of olefins was easily achieved by catalytic hydroboration with HBpin and in subsequent situ amination using H2 N-DABCO. Moreover, the combination of 1,2-diboration of olefins, using B2 pin2 , with this amination process achieved the unprecedented 1,2-diamination of olefins. The amination protocol was also successfully extended to aryl pinacol boronates.

Palladium(0)-Catalyzed Directed syn-1,2-Carboboration and -Silylation: Alkene Scope, Applications in Dearomatization, and Stereocontrol by a Chiral Auxiliary.

We report the development of palladium(0)-catalyzed syn-selective 1,2-carboboration and -silylation reactions of alkenes containing cleavable directing groups. With B2 pin2 or PhMe2 Si-Bpin as nucleophiles and aryl/alkenyl triflates as electrophiles, a broad range of mono-, di-, tri- and tetrasubstituted alkenes are compatible in these transformations. We further describe a directed dearomative 1,2-carboboration of electron-rich heteroarenes by employing this approach. Through use of a removable chiral directing group, we demonstrate the viability of achieving stereoinduction in Heck-type alkene 1,2-difunctionalization. This work introduces new avenues to access highly functionalized boronates and silanes with precise regio- and stereocontrol.

Diastereo- and Enantioselective Synthesis of (E)-δ-Boryl-Substituted anti-Homoallylic Alcohols in Two Steps from Terminal Alkynes.

We report the highly diastereo- and enantioselective preparation of (E)-δ-boryl-substituted anti-homoallylic alcohols in two steps from terminal alkynes. This method consists of a cobalt(II)-catalyzed 1,1-diboration reaction of terminal alkynes with B2 pin2 and a palladium(I)-mediated asymmetric allylation reaction of the resulting 1,1-di(boryl)alk-1-enes with aldehydes in the presence of a chiral phosphoric acid. Propyne, which is produced as the byproduct during petroleum refining, could be used as the starting material to construct homoallylic alcohols that are otherwise difficult to synthesize with high stereocontrol.

An Efficient Approach to Regio- and Stereodefined Fully-Substituted Alkenylsilanes by Pd-Catalyzed Allenic C(sp3 )-H Oxidation.

A highly efficient palladium-catalyzed functionalization of allenylsilanes to give regio- and stereodefined fully-substituted alkenylsilanes has been developed. This oxidative coupling reaction showed good functional group compatibility with exclusive regio- and stereoselectivity. The pending olefin on the silyl group was shown to be an indispensable element for the initial allenic C(sp3 )-H bond cleavage, and performs as the directing group to control the overall selectivity. The addition of substoichiometric amounts of Et3 N was found to increase the reaction rate leading to a higher reaction yield. The reaction can be easily scaled up and applied for the late-stage functionalization of natural products and pharmaceutical compounds, including amino acids and steroid derivatives. The newly introduced functional groups include aryl, alkynyl, and boryl groups. The highly strained four-membered ring, silacyclobutene was obtained when B2 pin2 was employed as the coupling partner. Mechanistic studies, including kinetic isotope effects, showed that the allenic C(sp3 )-H bond cleavage is the rate-limiting step.

An Olefinic 1,2‐Boryl‐Migration Enabled by Radical Addition: Construction ofgem‐Bis(boryl)alkanes

A series of in situ formed alkenyl diboronate complexes from alkenyl Grignard reagents (commercially available or prepared from alkenyl bromides and Mg) with B2 Pin2 (bis(pinacolato)diboron) react with diverse alkyl halides by a Ru photocatalyst to give various gem-bis(boryl)alkanes. Alkyl radicals add efficiently to the alkenyl diboronate complexes, and the adduct radical anions undergo radical-polar crossover, specifically, a 1,2-boryl-anion shift from boron to the α-carbon sp2 center. This transformation shows good functional-group compatibility and can serve as a powerful synthetic tool for late-stage functionalization in complex compounds. Measurements of the quantum yield reveal that a radical-chain mechanism is operative in which the alkenyl diboronates acts as reductive quencher for the excited state of the photocatalyst.

The Mechanism of Copper-Catalyzed Trifunctionalization of Terminal Allenes.

A highly selective copper-catalyzed trifunctionalization of allenes has been established based on diborylation/cyanation with bis(pinacolato)diboron (B2 pin2 ) and N-cyano-N-phenyl-p-toluenesulfonamide (NCTS). The Cu-catalyzed trifunctionalization of terminal allenes is composed of three catalytic reactions (first borocupration, electrophilic cyanation, and second borocupration) that provide a densely functionalized product with regio-, chemo- and diastereoselectivity. Allene substrates have multiple reaction-sites, and the selectivities are determined by the suitable interactions (e.g., electronic and steric demands) between the catalyst and substrates. We employed DFT calculations to understand the cascade copper-catalyzed trifunctionalization of terminal allenes, providing densely-functionalized organic molecules with outstanding regio-, chemo- and diastereoselectivity in high yields. The selectivity challenges presented by cumulated π-systems are addressed by systematic computational studies; these give insight to the catalytic multiple-functionalization strategies and explain the high selectivities that we see for these reactions.

Stoichiometric and Catalytic Aryl-Cl Activation and Borylation using NHC-stabilized Nickel(0) Complexes.

NHC-nickel (NHC=N-heterocyclic carbene) complexes are efficient catalysts for the C-Cl bond borylation of aryl chlorides using NaOAc as a base and B2 pin2 (pin=pinacolato) as the boron source. The catalysts [Ni2 (ICy)4 (μ-(η2 :η2 )-COD)] (1, ICy=1,3-dicyclohexylimidazolin-2-ylidene; COD=1,5-cyclooctadiene), [Ni(ICy)2 (η2 -C2 H4 )] (2), and [Ni(ICy)2 (η2 -COE)] (3, COE=cyclooctene) compare well with other nickel catalysts reported previously for aryl-chloride borylation with the advantage that no further ligands had to be added to the reaction. Borylation also proceeded with B2 neop2 (neop=neopentylglycolato) as the boron source. Stoichiometric oxidative addition of different aryl chlorides to complex 1 was highly selective affording trans-[Ni(ICy)2 (Cl)(Ar)] (Ar=4-(F3 C)C6 H4 , 11; 4-(MeO)C6 H4 , 12; C6 H5 , 13; 3,5-F2 C6 H3 , 14).

Rhodium-Catalyzed PIII -Directed ortho-C-H Borylation of Arylphosphines.

Transition-metal-mediated metalation of an aromatic C-H bond that is adjacent to a tertiary phosphine group in arylphosphines via a four-membered chelate ring was first discovered in 1968. Herein, we overcome a long-standing problem with the ortho-C-H activation of arylphosphines in a catalytic fashion. In particular, we developed a rhodium-catalyzed ortho-selective C-H borylation of various commercially available arylphosphines with B2 pin2 through PIII -chelation-assisted C-H activation. This discovery is suggestive of a generic platform that could enable the late-stage modification of readily accessible arylphosphines.