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Benzothiophenes are valuable heterocycles that are widely used in medicines, agrochemicals, and materials science. Herein, we report a general method for the synthesis of enantioenriched 2,3-disubstituted benzothiophenes via a transition-metal-free C2-alkylation of benzothiophenes with boronic esters. The reactions utilize benzothiophene S -oxides in lithiation–borylations to generate intermediate arylboronate complexes, and subsequent Tf 2 O-promoted S−O bond cleavage to trigger a Pummerer-type 1,2-metalate shift, which gives the coupled products with complete enantiospecificity. Primary, secondary and tertiary alkyl boronic esters and aryl boronic esters are successfully coupled with a range of C3-substituted benzothiophenes. Importantly, this transformation does not require the use of C3 directing groups, therefore it overcomes a major limitation of previously developed transition-metal-mediated C2 alkylations of benzothiophenes.

Generality in analytical chemistry can be manifested in impactful platforms that can streamline modern organic synthesis and biopharmaceutical processes. We herein introduce a hybrid separation technique named Dual-Gradient Unified Chromatography (DGUC), which is built upon an automated dynamic modulation of CO

Amino phosphonates exhibit potent inhibitory activity for a wide range of biological processes due to their specific structural and electronic properties, making them important in a plethora of applications, including as enzyme inhibitors, herbicides, antiviral, antibacterial, and antifungal agents. While the traditional synthesis of α-amino phosphonates has relied on the multicomponent Kabachnik-Fields reaction, we herein describe a novel and facile conversion of activated derivatives of α-amino acids directly to their respective α-amino phosphonate counterparts via a decarboxylative radical–polar crossover process enabled by the use of visible-light organophotocatalysis. The novel method shows broad applicability across a range of natural and synthetic amino acids, operates under mild conditions, and has been demonstrated to successfully achieve the late-stage functionalization of drug molecules.

The reaction of bicyclo[1.1.0]butyl pinacol boronic ester (BCB‐Bpin) with nucleophiles has been studied. Unlike BCBs bearing electron‐withdrawing groups, which react with nucleophiles at the β‐position, BCB‐Bpin reacts with a diverse set of heteroatom (O, S, N)‐centred nucleophiles exclusively at the α‐position. Aliphatic alcohols, phenols, carboxylic acids, thiols and sulfonamides were found to be competent nucleophiles, providing ready access to α‐heteroatom‐substituted cyclobutyl boronic esters. In contrast, sterically hindered bis‐sulfonamides and related nucleophiles reacted with BCB‐Bpin at the β’‐position leading to cyclopropanes with high trans‐selectivity. The origin of selectivity is discussed.

The synthetically versatile pinacol boronic ester group (Bpin) is generally thought of as a bulky moiety because of the two adjacent quaternary sp3 -hydribized carbon atoms in its diol backbone. However, recent diastereoselective reactions reported in the literature have cast doubt on this perception. Reported herein is a detailed experimental and computational analysis of Bpin and structurally related boronic esters which allows determination of three different steric parameters for the Bpin group: the A-value, ligand cone angle, and percent buried volume. All three parameters suggest that the Bpin moiety is remarkably small, with the planarity of the oxygen-boron-oxygen motif playing an important role in minimising steric interactions. Of the three steric parameters, percent buried volume provides the best correlation between steric size and diastereoselectivity in a Diels-Alder reaction.

1,2-Bis-boronic esters are useful synthetic intermediates particularly as the two boronic esters can be selectively functionalized. Usually, the less hindered primary boronic ester reacts, but herein, we report a coupling reaction that enables the reversal of this selectivity. This is achieved through the formation of a boronate complex with an electron-rich aryllithium which, in the presence of an electron-deficient aryl nitrile, leads to the formation of an electron donor-acceptor complex. Following visible-light photoinduced electron transfer, a primary radical is generated which isomerizes to the more stable secondary radical before radical–radical coupling with the arene radical–anion, giving β-aryl primary boronic ester products. The reactions proceed under catalyst-free conditions. This method also allows stereodivergent coupling of cyclic cis -1,2-bis-boronic esters to provide trans -substituted products, complementing the selectivity observed in the Suzuki-Miyaura reaction.

Stereogenic trifluoromethyl-substituted carbon centers are highly sought-after moieties in pharmaceutical and agrochemical discovery. Here, we show that lithiation–borylation reactions of 2-trifluoromethyl oxirane give densely functionalized and highly versatile trifluoromethyl-substituted α-tertiary boronic esters. The intermediate boronate complexes undergo the desired 1,2-rearrangement of the carbon-based group with complete retentive stereospecificity, a process that was only observed in non-polar solvents in the presence of TESOTf. Although the trifluoromethyl group adversely affects subsequent transformations of the α-boryl group, Zweifel olefinations provide trifluoromethyl-bearing quaternary stereocenters substituted with alkenes, alkynes and ketones.

The identification of spiro N-heterocycles as scaffolds that display structural novelty, three-dimensionality, beneficial physicochemical properties, and enable the controlled spatial disposition of substituents has led to a surge of interest in utilizing these compounds in drug discovery programs. Herein, we report the strain-release-driven Friedel-Crafts spirocyclization of azabicyclo[1.1.0]butane-tethered (hetero)aryls for the synthesis of a unique library of azetidine spiro-tetralins. The reaction was discovered to proceed through an unexpected interrupted Friedel-Crafts mechanism, generating a highly complex azabicyclo[2.1.1]hexane scaffold. This dearomatized intermediate, formed exclusively as a single diastereomer, can be subsequently converted to the Friedel-Crafts product upon electrophilic activation of the tertiary amine, or trapped as a Diels-Alder adduct in one-pot. The rapid assembly of molecular complexity demonstrated in these reactions highlights the potential of the strain-release-driven spirocyclization strategy to be utilized in the synthesis of medicinally relevant scaffolds.

Alkenyl boronic esters are important reagents in organic synthesis. Herein, we report that these valuable products can be accessed by the homologation of boronic esters with lithiated epoxysilanes. Aliphatic and electron-rich aromatic boronic esters provided vinylidene boronic esters in moderate to high yields, while electron-deficient aromatic and vinyl boronic esters were found to give the corresponding vinyl silane products. Through DFT calculations, this divergence in mechanistic pathway has been rationalized by considering the stabilization of negative charge in the C-Si and C-B bond breaking transition states. This vinylidene homologation was used in a short six-step stereoselective synthesis of the proposed structure of machillene, however, synthetic and reported data were found to be inconsistent.

A new strategy for the coupling of a broad scope of electronically diverse aromatics to boronic esters is reported. The coupling sequence, which relies on the directed ortho-lithiation of chromium arene complexes followed by boronate formation and oxidation, occurs with complete ortho-selectivity and enantiospecificity to give the coupling products in excellent yields and with high functional group tolerance. An intermediate chromium arene boronate complex was characterized by X-ray, NMR, and IR experiments to elucidate the reaction mechanism.