Carbene Coupling Research Articles

Rapid (Deuterio)difluoromethylation of Heteroatoms using R‐22 Gas: A Demonstration of Flow Chemistry in Suppressing Intrinsic Reaction Pathways

The exploration and use of deuteriodifluoromethyl heteroatom groups (X‐CF2D) has been limited by persistent challenges, including the unavailability of CF2D precursor reagents, as well as safety, scalability, and environmental concerns associated with conventional batch‐mode syntheses. In this study, we report the use of atom‐efficient and cost‐effective R‐22 gas (ClCF2H) in continuous flow for the rapid installation of CF2H and CF2D groups on heteroatom centers. However, the intrinsic nucleophilic substitution between heteroatom anions and ClCF2H decreases the deuterium incorporation levels. Notably, a judiciously designed continuous flow system proves to suppress the previously unavoidable SN2 reaction and allows for the selective carbene coupling to generate X‐CF2D products with high deuterium incorporation levels up to 96%. Our continuous flow systems provide a broad scope of X‐CF2H and X‐CF2D products (X = S, O, N) within a short residence time of 5 minutes and scalability is also demonstrated.

Visible-Light-Mediated gem-Difunctionalization of Diazo Compounds with Vinyl Sulfoxonium Ylides and Thiols

AbstractA visible-light-induced multicomponent reaction of vinyl sulfoxonium ylide, thiol, and diazo ester to generate tertiary sulfide is described. The present diastereoselective gem-difunctionalization of the diazo ester can be achieved under mild conditions, as it does not require any additives, catalysts, or transition metals and is tolerant of air and moisture. Due to more nucleophilicity, vinyl sulfoxonium ylide undergoes S–H insertion with thiols to generate an allyl sulfide intermediate. Simultaneously, diazo ester undergoes photolysis to generate a carbene intermediate. Subsequently, the coupling of carbene and allyl sulfide intermediates generates sulfonium ylide, which undergoes Doyle–Kirmse rearrangement to generate tertiary sulfide scaffolds.

Palladium-catalyzed asymmetric carbene coupling en route to inherently chiral heptagon-containing polyarenes.

Developing facile and direct synthesis routes for enantioselective construction of cyclic π-conjugated molecules is crucial. However, originate chirality from the distorted structure around heptagon-containing polyarenes is largely overlooked, the enantioselective construction of all-carbon heptagon-containing polyarenes remains a challenge. Herein, we present a highly enantioselective synthesis route for fabricating all carbon heptagon-containing polyarenes via palladium-catalyzed carbene-based cross-coupling of benzyl bromides and N-arylsulfonylhydrazones. A wide range of nonplanar, saddle-shaped tribenzocycloheptene derivatives are efficiently prepared in high yields with excellent enantioselectivities using this approach. In addition, stereochemical stability experiments show that these saddle-shaped tribenzocycloheptene derivatives have high inversion barriers.

Catalytic and Base-free Suzuki-type α-Arylation of Cyclic 1,3-Dicarbonyls via a Cyclic Iodonium Ylide Strategy.

To date, it remains challenging to achieve a general and catalytic α-arylation of cyclic 1,3-dicarbonyls, particularly ubiquitous heteroaromatic ones. In most cases, the preparation of their medically significant arylated derivatives requires multistep synthetic sequences. Herein, we introduce a new, convenient strategy involving the conversion of cyclic 1,3-dicarbonyls to cyclic iodonium ylides (CIYs), followed by rhodium-catalyzed α-arylation with arylboronic reagents via carbene coupling. This approach is mild, operationally simple, base-free, biocompatible, and exhibits broad substrate scope (>100 examples), especially with respect to various heteroaromatic 1,3-dicarbonyls and ortho-substituted or base-sensitive arylboronic acids. Importantly, owing to the excellent compatibility with various arylboronic acids or boronate esters (ArBpin, ArBneop, or ArBF3K), this method allows the late-stage installation of heterocyclic 1,3-dicarbonyl motifs in highly complex settings. The utility of this transformation is further demonstrated through significantly simplifying the synthesis of several bioactive molecules and natural products.

Catalytic and Base‐free Suzuki‐type α‐Arylation of Cyclic 1,3‐Dicarbonyls via a Cyclic Iodonium Ylide Strategy

AbstractTo date, it remains challenging to achieve a general and catalytic α‐arylation of cyclic 1,3‐dicarbonyls, particularly ubiquitous heteroaromatic ones. In most cases, the preparation of their medically significant arylated derivatives requires multistep synthetic sequences. Herein, we introduce a new, convenient strategy involving the conversion of cyclic 1,3‐dicarbonyls to cyclic iodonium ylides (CIYs), followed by rhodium‐catalyzed α‐arylation with arylboronic reagents via carbene coupling. This approach is mild, operationally simple, base‐free, biocompatible, and exhibits broad substrate scope (>100 examples), especially with respect to various heteroaromatic 1,3‐dicarbonyls and ortho‐substituted or base‐sensitive arylboronic acids. Importantly, owing to the excellent compatibility with various arylboronic acids or boronate esters (ArBpin, ArBneop, or ArBF3K), this method allows the late‐stage installation of heterocyclic 1,3‐dicarbonyl motifs in highly complex settings. The utility of this transformation is further demonstrated through significantly simplifying the synthesis of several bioactive molecules and natural products.

Photoelectrothermocatalytic reduction of CO2 to glycol via CdIn2S4-N/C hollow heterostructure mimicking plant cell

A series of novel semiconductor composites of CdIn2S4-N/C, in which CdIn2S4 is grown on hollow nitrogen-doped carbon spheres to mimic plant cells, were designed and applied to photoelectrothermocatalytic reduction of CO2. Our results reveal that the unique hollow structure and photothermal properties of N/C contribute to excellent performance of catalyst in CO2 reduction. Specifically, the optimal catalyst of CdIn2S4-N/C-2–800 demonstrates an outstanding catalytic activity with a formation rate of 168.5 µM h−1 cm−2 for carbon-based products and an electron selectivity for C2 products of 66.9 %. DFT calculations demonstrate that pyridine N and pyrrole N can reduce the energy barrier during CO2 reduction. Two important species of *=C=O and OC-COH* were detected by operando IR spectra and suggested to be key intermediates to C2 products via a carbene (*=C=O) coupling mechanism. CdIn2S4-N/C provides thermoelectrons and active sites like in the membrane of plant to enhance the probability of C-C coupling.

Oxidation-induced coupling reactions of bi(metallacycloprop-1-ene) complexes.

The feasibility of coupling of two carbene ligands of biscarbene complexes LnM(CR2)2 to form alkene complexes LnM(η2-R2CCR2) was predicted theoretically as early as 1982. However, until now, there appear still no reports on carbene coupling reactions of well-defined biscarbene complexes. This work reports oxidation-induced coupling reactions of bi(metallacycloprop-1-ene) complexes to give η4-butadiene complexes, a unique example of coupling of two carbene ligands of biscarbene complexes.

Alkylsulfonylation of alkenes involving copper carbene coupling: access to alkyl–alkyl sulfones

A novel alkyl radical-initiated alkylsulfonylation of alkenes involving copper carbene coupling is developed for the synthesis of various alkyl–alkyl sulfones by employing potassium metabisulphite (K2S2O5) as a connector.

Enantioselective Photochemical Carbene Insertion into C–C and C–H Bonds of 1,3-Diketones by a Guanidine-Amide Organocatalyst

A visible-light-induced enantioselective free carbene transfer reaction of α-diazoesters with 1,3-diketones is established by utilizing a chiral bifunctional guanidine-amide organocatalyst. Selective insertion of free carbene into the C–C or C–H bonds of 1,3-diketone could be achieved with α-diazoesters bearing different steric hindrances. The transformations enable the preparation of a series of 1,4-diketones with a quaternary carbon chiral center or chiral 2-substituted-1,3-diketones in good enantioselectivities. On the basis of the control experiments and DFT calculation, a stepwise triplet free carbene coupling pathway is suggested. A possible reaction mechanism is proposed to explain the origin of high enantioselectivities via hydrogen-bonds and electrostatic interactions of the catalyst.

Synthesis of Olefins by Formal Carbene Coupling

AbstractIn this review, the coupling of two carbene precursors for the synthesis of alkenes is surveyed. The key to selective carbene coupling is the difference in the rate of carbene generation between the two carbene precursors. This strategy requires judicious selection between two carbene precursors as well as fine‐tuning of reaction conditions to obtain the desired chemo‐ and stereoselectivity. These couplings were carried out in the presence and absence of a metal catalyst. The present review describes inter‐ and intramolecular coupling of diazo compounds and cross‐coupling between diazo and non‐diazo compounds.magnified image

Palladium-catalyzed carbene coupling polymerization: synthesis of E-poly(arylene vinylene)s.

The Pd-catalyzed carbene coupling reaction of N-tosylhydrazones and benzyl bromides has been developed into a polymerization process for the first time, providing an efficient method for the synthesis of poly(arylene vinylene)s (PAVs). This method affords PAVs bearing E-vinylene units predominantly. It can also introduce a CF3 group on each vinylene carbon atom in the polymer main chain. The polymerization has a broad scope and the resultant polymers exhibit interesting optical properties and good thermal stabilities.

Palladium-Catalyzed Carbene Coupling Reactions of Cyclobutanone N-Sulfonylhydrazones.

Described herein are the palladium-catalyzed cross-coupling reactions of cyclobutanone-derived N-sulfonylhydrazones with aryl or benzyl halides, suggesting that the metal carbene process and β-hydride elimination can smoothly occur in strained ring systems. Structurally diversified products including cyclobutenes, methylenecyclobutanes, and conjugated dienes are selectively afforded in good to excellent yields. Preliminary success in asymmetric carbene coupling reactions in strained ring systems has been achieved, providing a promising route for the synthesis of enantioenriched four-membered-ring molecules.

Marine furanocembranoids-inspired macrocycles enabled by Pd-catalyzed unactivated C(sp3)-H olefination mediated by donor/donor carbenes

Biomimetic modularization and function-oriented synthesis of structurally diversified natural product-like macrocycles in a step-economical fashion is highly desirable. Inspired by marine furanocembranoids, herein, we synthesize diverse alkenes substituted furan-embedded macrolactams via a modular biomimetic assembly strategy. The success of this assembly is the development of crucial Pd-catalyzed carbene coupling between ene-yne-ketones as donor/donor carbene precursors and unactivated Csp3‒H bonds which represents a great challenge in organic synthesis. Notably, this method not only obviates the use of unstable, explosive, and toxic diazo compounds, but also can be amenable to allenyl ketones carbene precursors. DFT calculations demonstrate that a formal 1,4-Pd shift could be involved in the mechanism. Moreover, the collected furanocembranoids-like macrolactams show significant anti-inflammatory activities against TNF-α, IL-6, and IL-1β and the cytotoxicity is comparable to Dexamethasone.

Pd‐Catalyzed Cascade Metallo‐Ene Cyclization/Metallo‐Carbene Coupling of Allenamides

AbstractA highly efficient palladium‐catalyzed cascade metallo‐ene/metallo‐carbene coupling reaction was developed to produce 2,3‐dihydropyrrole derivatives in high yields. In this transformation, two new Csp3−Csp2 and Csp2−Csp2 bonds were constructed in one‐pot. The alkene was one of the most easily functionalized groups, making it possible for these molecules to be transformed into more complex molecules. More importantly, the final product possessed an attractive 1,3,8‐trienes scaffold, which was difficult to be synthesized.

Ru(II)Porphyrinate-based molecular nanoreactor for carbene insertion reactions and quantitative formation of rotaxanes by active-metal-template syntheses

Selectivity in N–H and S–H carbene insertion reactions promoted by Ru(II)porphyrinates currently requires slow addition of the diazo precursor and large excess of the primary amine and thiol substrates in the reaction medium. Such conditions are necessary to avoid the undesirable carbene coupling and/or multiple carbene insertions. Here, the authors demonstrate that the synergy between the steric shielding provided by a Ru(II)porphyrinate-based macrocycle with a relatively small central cavity and the kinetic stabilization of otherwise labile coordinative bonds, warranted by formation of the mechanical bond, enables single carbene insertions to occur with quantitative efficiency and perfect selectivity even in the presence of a large excess of the diazo precursor and stoichiometric amounts of the primary amine and thiol substrates. As the Ru(II)porphyrinate-based macrocycle bears a confining nanospace and alters the product distribution of the carbene insertion reactions when compared to that of its acyclic version, the former therefore functions as a nanoreactor.

Oxidation, Coordination, and Nickel-Mediated Deconstruction of a Highly Electron-Rich Diboron Analogue of 1,3,5-Hexatriene.

The reductive coupling of an N‐heterocyclic carbene (NHC) stabilized (dibromo)vinylborane yields a 1,2‐divinyldiborene, which, although isoelectronic to a 1,3,5‐triene, displays no extended π conjugation because of twisting of the C2B2C2 chain. While this divinyldiborene coordinates to copper(I) and platinum(0) in an η2‐B2 and η4‐C2B2 fashion, respectively, it undergoes a complex rearrangement to an η4‐1,3‐diborete upon complexation with nickel(0).

Transition-Metal-Catalyzed Cross-Coupling with Ketones or Aldehydes via N-Tosylhydrazones.

Ketones and aldehydes play central roles in organic synthesis. There are numerous broadly used reactions that are related to the carbonyl reactivity, such as Grignard reactions, Wittig reactions, aldol reactions, and so on. In addition, the formation of enol triflates is a classic protocol that enables the ketones to be applied in transition-metal-catalyzed cross-coupling reactions, in which case the ketones are considered as the precursors of alkenyl electrophiles in the C-C bond-forming transformations. In the past decade, a new type of ketone- or aldehyde-based C-C bond-forming transformations has emerged. In this type of reactions, the ketones or aldehydes are first converted to their corresponding N-tosylhydrazones, which are employed as reaction partners in various transition-metal-catalyzed carbene-based cross-coupling reactions. The N-tosylhydrazone-based carbene couplings significantly enhance the potential of ketones and aldehydes in modern organic synthesis. This Perspective aims to give an overview of carbene coupling reactions with N-tosylhydrazones from the viewpoint of exploring new potentials of ketones and aldehydes in organic synthesis.

Trapping of a Borirane Intermediate in the Reductive Coupling of an Arylborane to a Diborene.

The reductive coupling of a N-heterocyclic carbene (NHC)-stabilized aryldibromoborane yields a mixture of trans- and cis-diborenes in which the aryl groups are coplanar with the diborene core. Under dilute reduction conditions two diastereomers of a borirane-borane intermediate are isolated, which upon further reduction give rise to the aforementioned diborene mixture. DFT calculations suggest a mechanism proceeding via nucleophilic attack of a dicoordinate borylene intermediate on the aryl ring and subsequent intramolecular B-B bond formation.

Palladium-catalyzed cross-coupling reaction of sulfoxonium ylides and benzyl bromides by carbene migratory insertion.

A palladium-catalyzed cross-coupling reaction of sulfoxonium ylides and benzyl bromides has been developed, which has potential safety advantages over previous carbene coupling reactions using either diazo compounds or their in situ precursors. This reaction affords polysubstituted olefins, and features good substrate tolerance and is suitable for late-stage modification of biologically active molecules. Pd-carbene migratory insertion is supposed to be involved in this coupling reaction.

Cross coupling of sulfonyl radicals with silver-based carbenes: a simple approach to β-carbonyl arylsulfones.

A coupling reaction between sulfonyl radicals and silver-based carbenes has been well established. This simple radical-carbene coupling (RCC) process provided an efficient approach to a variety of β-carbonyl arylsulfones from sodium arylsulfinates and diazo compounds, and was characterized by wide substrate scope, easy scale-up, simple manipulation, accessible starting materials, and mild reaction conditions.