Highly Efficient Separation of BTEX via Amide Naphthotube Cavity-Confined Tandem C/N-H···π Interactions.

The separation of BTEX [benzene, toluene, ethylbenzene (EB), and xylene isomers] poses a huge challenge in the industry, attributed to their similar structures and physical properties. Supramolecular compounds show great promise for hydrocarbon separation. Herein, we designed two pairs of endo-functionalized amide naphthotubes with methyl and benzyl side chains, which were first employed as chromatographic separation materials and exhibited high shape-selectivity for BTEX. In particular, the amide naphthotubes with methyl side chains provided complete separation toward BTEX and anti-3a showed high selectivity for the p-xylene over other isomers with αPX/OX = 9.34, αPX/MX = 5.50, and αPX/EB = 4.30. The mechanism of BTEX separation originates from the synergistic effect of specially confined tandem N-H···π and C-H···π interactions toward aromatic compounds. The findings of this research show promise for practical applications in efficiently separating crucial aromatic isomers.

Palladium-Catalyzed Enantioselective Multicomponent Cross-Coupling of Trisubstituted Olefins.

The development of a catalytic method for stereogenic carbon center formation holds immense significance in organic synthesis. Transition-metal-catalyzed cross-coupling reaction has been regarded as a straightforward and efficient tool for stereoselectively forging C-C bond. Nevertheless, the creation of acyclic all-carbon quaternary-containing vicinal stereocenters remains notoriously challenging within the domain of cross-coupling chemistry despite their prominence in various bioactive small molecules. Herein, we describe a palladium-catalyzed asymmetric multicomponent cross-coupling of trisubstituted alkene with aryl diazonium salts and arylboronic acids to realize the formation of tertiary-quaternary carbon centers with high regio-, distereo-, and enantioselectivity. Specifically, the precise manipulation of the stereoconfiguration of trisubstituted alkenes enables the divergent stereoselective cross-coupling reaction, thus allowing for the facile construction of all four enantiomers. Harnessing the ligand-swap strategy involving a chiral bisoxazoline and an achiral fumarate individually accelerates the enantioselective migratory insertion and reductive elimination step in the cross-coupling process, as supported by density functional theory (DFT) calculations, thus obviating the requirement for a neighboring directing group within the internal olefin skeleton.

Enantioselective Ni-Catalyzed 1,2-Borylalkynylation of Unactivated Alkenes.

Enantioselective three-component difunctionalization of alkenes with boron reagents represents an attractive strategy for assembling three-dimensional chiral organoboron compounds. However, regio- and enantiocontrol comprise the pivot challenges in these transformations, which predominantly require the use of activated conjugated alkenes. Herein, by utilizing various carbonyl directing groups, including amides, sulfinamides, ketones, and esters, we succeed in realizing a nickel-catalyzed 1,2-borylalkynylation of unactivated alkenes to enable the simultaneous incorporation of a boron entity and an sp-fragment across the double bond. The products contain boryl, alkynyl, and carbonyl functional groups with orthogonal synthetic reactivities, offering three handles for further derivatization to access valuable intermediates. The utility of this ligand-enabled asymmetric protocol has been highlighted through the late-stage decoration of drug-relevant molecules.

Pd-catalyzed asymmetric Larock reaction for the atroposelective synthesis of N─N chiral indoles.

Atropisomeric indoles defined by a N─N axis are an important class of heterocycles in synthetic and medicinal chemistry and material sciences. However, they remain heavily underexplored due to limited synthetic methods and challenging stereocontrol over the short N─N bonds. Here, we report highly atroposelective access to N─N axially chiral indoles via the asymmetric Larock reaction. This protocol leveraged the powerful role of chiral phosphoramidite ligand to attenuate the common ligand dissociation in the original Larock reaction, forming N─N chiral indoles with excellent functional group tolerance and high enantioselectivity via palladium-catalyzed intermolecular annulation between readily available o-iodoaniline and alkynes. The multifunctionality in the prepared chiral indoles allowed diverse post-coupling synthetic transformations, affording a broad array of functionalized chiral indoles. Experimental and computational studies have been conducted to explore the reaction mechanism, elucidating the enantio-determining and rate-limiting steps.

Diastereo- and Enantioselective Synthesis of Tetracyclic Cycloheptanols through (4+3) Annulation via C-C/C-H Activation Cascade.

Transition metal-catalyzed annulations of four-membered rings via C-C activation are powerful tools to construct complex fused and bridged ring systems. Despite significant progress in (4+1), (4+2) and (4+4) annulations, the (4+3) annulation remains unexplored. Herein, we develop an asymmetric Rh-catalyzed intramolecular (4+3) annulation of α-arylalkene-tethered benzocyclobutenols for the synthesis of dihydrofuran-annulated dibenzocycloheptanols with two discontinuous chiral carbon centers via a C-C and C-H activation cascade. The reaction features excellent diastereo- and enantioselectivities and 100 % atom economy, and is applicable to late-stage modification of complex molecules.

Rhodium-Catalyzed Enantioselective Formal [4+1] Cyclization of Benzyl Alcohols and Benzaldimines: Facile Access to Silicon-Stereogenic Heterocycles.

The carbon-to-silicon switch in formation of bioactive sila-heterocycles with a silicon-stereogenic center has garnered significant interest in drug discovery. However, metal-catalyzed synthesis of such scaffolds is still in its infancy. Herein, a rhodium-catalyzed enantioselective formal [4+1] cyclization of benzyl alcohols and benzaldimines has been realized by enantioselective difunctionalization of a secondary silane reagent, affording chiral-at-silicon cyclic silyl ethers and sila-isoindolines, respectively. Mechanistic studies reveal a dual role of the rhodium-hydride catalyst. The coupling system proceeds via rhodium-catalyzed enantio-determining dehydrogenative OH silylation of the benzyl alcohol or hydrosilylation of the imine to give an enantioenriched silyl ether or silazane intermediate, respectively. The same rhodium catalyst also enables subsequent intramolecular cyclative C-H silylation directed by the pendent Si-H group. Experimental and DFT studies have been conducted to explore the mechanism of the OH bond silylation of benzyl alcohol, where the Si-O reductive elimination from a Rh(III) hydride intermediate has been established as the enantiodetermining step.

Sustainable production of triazoles from lignin major motifs.

An efficiently catalyzed synthesis of pharmaceutically relevant 1,2,3-trazoles from renewable resources is highly desirable. However, due to incompatible catalysis conditions, this endeavor remained challenging so far. Herein, a practical access protocol to 1,2,3-triazoles, starting from lignin phenolic ß-O-4 with γ-OH group utilizing a vanadium-based catalyst is presented. A broad substrate scope reaching up to 97 % yield of 1,2,3-triazoles are obtained. The reaction pathway includes selective cleavage of double C-O bonds, cycloaddition, and dehydrogenation. Mechanistic studies and density-functional theory (DFT) calculations suggest that the V-based complex acts as a bifunctional catalyst for both selective C-O bonds cleavage and dehydrogenation. This synthetic pathway has been applied for the synthesis of pharmacological and biological active carbohydrate derivatives starting from biomass components as feedstock, enabling a potential sustainable route to triazolyl carbohydrate derivatives, which paves the way for lignin-based heterocyclic aromatics in the pharmaceutical applications.

Nickel/Photoredox Dual-Catalyzed Regiodivergent Aminoalkylation of Unactivated Alkyl Halides.

A mild and regiodivergent aminoalkylation of unactivated alkyl halides is disclosed via a dual photoredox/nickel catalysis. Bipyridyl-type ligands without an ortho-substituent control the site-selective coupling at the original position, while ortho-disubstituted ligands tune the site-selectivity at a remote, unprefunctionalized position. Mechanistic studies combined with DFT calculations give insight into the mechanism and the origins of the ligand-controlled regioselectivity. Notably, this redox-neutral, regiodivergent alkyl-alkyl coupling features mild conditions, broad substrate scope for both alkyl coupling partners, and excellent site-selectivity and offers a straightforward way for α-alkylation of tertiary amines to synthesize structurally diverse alkylamines and value-added amino acid derivatives.

Stereoselective Photoredox Catalyzed (3+3) Dipolar Cycloaddition of Nitrone with Aryl Cyclopropane.

By resorting to the principle of remote activation, we herein demonstrate the first photoredox catalyzed (3+3) dipolar cycloaddition of nitrones with aryl cyclopropanes. Key to the fidelity of the reaction resides in a facile manner of substrate activation by single-electron transfer (SET) oxidation with photoredox catalysis, and the reaction takes place through a stepwise cascade encompassing a three-electron-type nucleophilic substitution triggered cyclopropane ring-opening and a diastereoselective 6-endo-trig radical cyclization manifold. The reaction proceeds under mild conditions with excellent regio- and stereoselectivity, nicely complementing the well-developed Lewis acid catalyzed cycloaddition of donor-acceptor cyclopropanes. Other merits of the protocol include wide scope of aryl cyclopropanes with diversified substitution patterns and good functional-group compatibility. A mechanism involving an aryl radical cation promoted remote activation mode was also proposed and supported by mechanistic experiments.

Towards bioresource-based aggregation-induced emission luminogens from lignin ß-O-4 motifs as renewable resources.

One-pot synthesis of heterocyclic aromatics with good optical properties from phenolic ß-O-4 lignin segments is of high importance to meet high value added biorefinery demands. However, executing this process remains a huge challenge due to the incompatible reaction conditions of the depolymerization of lignin ß-O-4 segments containing γ-OH functionalities and bioresource-based aggregation-induced emission luminogens (BioAIEgens) formation with the desired properties. In this work, benzannulation reactions starting from lignin ß-O-4 moieties with 3-alkenylated indoles catalyzed by vanadium-based complexes have been successfully developed, affording a wide range of functionalized carbazoles with up to 92% yield. Experiments and density functional theory calculations suggest that the reaction pathway involves the selective cleavage of double C-O bonds/Diels-Alder cycloaddition/dehydrogenative aromatization. Photophysical investigations show that these carbazole products represent a class of BioAIEgens with twisted intramolecular charge transfer. Distinctions of emission behavior were revealed based on unique acceptor-donor-acceptor-type molecular conformations as well as molecular packings. This work features lignin ß-O-4 motifs with γ-OH functionalities as renewable substrates, without the need to apply external oxidant/reductant systems. Here, we show a concise and sustainable route to functional carbazoles with AIE properties, building a bridge between lignin and BioAIE materials.

Rhodium-catalyzed enantioselective and diastereodivergent access to diaxially chiral heterocycles.

N-N axially chiral biaryls represent a rarely explored class of atropisomers. Reported herein is construction of diverse classes of diaxially chiral biaryls containing N-N and C-N/C-C diaxes in distal positions in excellent enantioselectivity and diastereoselectivity. The N-N chiral axis in the products provides a handle toward solvent-driven diastereodivergence, as has been realized in the coupling of a large scope of benzamides and sterically hindered alkynes, affording diaxes in complementary diastereoselectivity. The diastereodivergence has been elucidated by computational studies which revealed that the hexafluoroisopropanol (HFIP) solvent molecule participated in an unusual manner as a solvent as well as a ligand and switched the sequence of two competing elementary steps, resulting in switch of the stereoselectivity of the alkyne insertion and inversion of the configuration of the C-C axis. Further cleavage of the N-directing group in the diaxial chiral products transforms the diastereodivergence to enantiodivergence.

Rhodium-catalyzed annulative approach to N-N axially chiral biaryls via C-H activation and dynamic kinetic transformation.

N-N axially chiral biaryls represent a rarely explored class of atropisomeric compounds. We hereby report rhodium-catalyzed enantioselective [4 + 2] oxidative annulation of internal alkynes with benzamides bearing two classes of N-N directing groups. The coupling occurs under mild conditions via NH and CH annulation through the dynamic kinetic transformation of the directing group and is highly enantioselective with good functional tolerance. Computational studies of a coupling system at the DFT level has been conducted, and the alkyne insertion was identified as the enantio-determining as well as the turnover-limiting step.

Sigma-Bond Metathesis as an Unusual Asymmetric Induction Step in Rhodium-Catalyzed Enantiodivergent Synthesis of C-N Axially Chiral Biaryls.

Mechanistic understanding of asymmetric induction plays a crucial role in designing new catalytic asymmetric reactions. Reported herein is atroposelective access to C-N axially chiral isoquinolones via rhodium-catalyzed C-H activation of N-alkoxy benzamides and annulation with imidoyl sulfoxonium ylides. The coupling system proceeded with excellent functional group tolerance, and different conditions were identified to afford one or the other enantiomeric product each in excellent enantioselectivity for a representative class of the sulfoxonium ylide reagent, thus making both enantiomers readily available using the same catalyst. Experimental and computational studies revealed a pathway of C-H alkylation and enantio-determining formal nucleophilic substitution-C-N cyclization that is mediated by the rhodium catalyst via σ-bond metathesis as the asymmetric induction mechanism. Computational studies indicated that the solvent-dependent enatiodivergence originated from different levels of σ-bond metathesis mediated by neutral versus cationic rhodium species.

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.

Ni-catalyzed benzylic ß-C(sp3)-H bond activation of formamides.

The development of transition metal-catalyzed ß-C-H bond activation via highly-strained 4-membered metallacycles has been a formidable task. So far, only scarce examples have been reported to undergo ß-C-H bond activation via 4-membered metallacycles, and all of them rely on precious metals. In contrast, earth-abundant and inexpensive 3d transition metal-catalyzed ß-C-H bond activation via 4-membered metallacycles still remains an elusive challenge. Herein, we report a phosphine oxide-ligated Ni-Al bimetallic catalyst to activate secondary benzylic C(sp3)-H bonds of formamides via 4-membered nickelacycles, providing a series of α,ß-unsaturated γ-lactams in up to 97% yield.

Enantioselective C2-H Alkylation of Pyridines with 1,3-Dienes via Ni-Al Bimetallic Catalysis.

A chiral phosphine oxide-ligated Ni-Al bimetallic catalyst was used to realize an enantioselective C2-H alkylation of pyridines without the need of a C2-block. A wide range of pyridines, including unsubstituted pyridine, C3, C4, and C2-substituted pyridines, and even complex pyridine-containing bioactive molecules are well compatible with the reaction, providing up to 81% yield and up to 97% ee.

Nickel-Catalyzed Cross-Coupling of Acyl Chloride with Racemic α-Trifluoromethyl Bromide to Access Chiral α-Trifluoromethyl Ketones.

The nickel-catalyzed reductive cross-coupling reaction of acyl chloride with racemic secondary α-trifluoromethyl bromide has been developed. By this chemistry, a series of structurally interesting chiral α-CF3 carbonyl compounds could be accessed with great enantioselectivity and good functional group tolerance. The study of late-stage transformation indicated that this chemistry could be used as the robust method to prepare products that contain a bioactive motif. Furthermore, the importance of the α-trifluoromethyl group to this reaction has been illustrated by control experiments.

Mechanism and Origins of Enantioselectivity of Cobalt-Catalyzed Intermolecular Hydroarylation/Cyclization of 1,6-Enynes with N-Pyridylindoles.

Density functional theory calculations were performed to investigate the cobalt-catalyzed intermolecular hydroarylation/cyclization of 1,6-enynes with N-pyridylindoles. The computations reveal that the reaction begins with the oxidative cyclization of 1,6-enyne to afford the five-membered cobaltacycle, from which the metal-assisted σ-bond metathesis/C-C reductive elimination led to the final hydroarylation/cyclization product. The initial oxidative cyclization constitutes the rate-determining step of the overall reaction. The steric repulsion and π···π interaction were found to play a crucial role in dictating the experimentally observed enantioselectivity.

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.

Computational and Experimental Study of Turbo-Organomagnesium Amide Reagents: Cubane Aggregates as Reactive Intermediates in Pummerer Coupling.

The dynamic equilibria of organomagnesium reagents are known to be very complex, and the relative reactivity of their components is poorly understood. Herein, a combination of DFT calculations and kinetic experiments is employed to investigate the detailed reaction mechanism of the Pummerer coupling between sulfoxides and turbo-organomagnesium amides. Among the various aggregates studied, unprecedented heterometallic open cubane structures are demonstrated to yield favorable barriers through a concerted anion-anion coupling/ S-O cleavage step. Beyond a structural curiosity, these results introduce open cubane organometallics as key reactive intermediates in turbo-organomagnesium amide mixtures.