A Cu(I)-catalyzed interrupted click reaction, using N-chlorophthalimide as electrophilic chlorine source, enabling the facile synthesis of 1,4,5-trisubstituted 5-chloro-1,2,3-triazoles in one step from readily available terminal alkynes and azides is reported. This approach allowed complete control of regioselectivities with a broad substrate scope. Furthermore, a novel epoxidation was developed using 5-chloro-triazole as substrate, which could be further applied in various organic transformations.

Abstract

5-Halo-1,2,3-triazoles are important scaffolds in organic chemistry, but current click reactions cannot produce 1,4,5-trisubstituted 5-chloro-1,2,3-triazoles in a simple way. Herein, we disclosed a Cu(I)-catalyzed interrupted click reaction, using N-chlorophthalimide as an electrophilic chlorine source, enabling the facile synthesis of 1,4,5-trisubstituted 5-chloro-1,2,3-triazoles in one step from readily available terminal alkynes and azides. Complete control of regioselectivities with a broad substrate scope was accomplished by this approach. Furthermore, a novel epoxidation was developed using 5-chloro-triazole as substrate, which could be further applied in various organic transformations.

This concise protocol provided easy access to the α-CF₃ tertiary alkyl ethers, alcohol and fluorides with good yields and excellent functional group tolerance. In addition, the four-component “SO₂” insertion reaction also worked efficiently to produce the α-CF₃, β-sulfonyl ethers in moderate to good yields. A radical-polar crossover coupling pathway was proposed for the C−O bond formation.

Abstract

Metal-free, visible light-induced difunctionalizations of α-CF₃ styrenes with aryl diazonium salts and various hetero nucleophiles (ROH, H₂O, N₃ ⁻ and F⁻) are described. This concise protocol provided easy access to the α-CF₃ tertiary alkyl ethers, alcohol and fluorides with good yields and excellent functional group tolerance. In addition, the four-component “SO₂” insertion reaction also worked efficiently to produce the α-CF₃, β-sulfonyl ethers in moderate to good yields. A radical-polar crossover coupling pathway was proposed for the C−O bond formation.

Metal-free deformylative/dehalogenative carbonylation, Michael addition of β-bromovinyl aldehydes for the synthesis of δ-oxo esters and vinyl ethers have been reported. Nucleophilic and organo-catalytic behaviour of DBU is explored and the regeneration of the parent starting material from the vinyl ether is also highlighted.

Abstract

Herein we have disclosed metal-free 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU)-catalyzed protocol for the deformylative/dehalogenative carbonylation and Michael addition of β-bromovinyl aldehydes with acrylates and carbonylation followed by etherification with benzyl bromides to synthesize δ-oxo esters and vinyl ethers respectively in good yields under an open atmosphere with broad substrate scope. Regeneration of starting material from vinyl ethers, organo-catalytic and nucleophilic behavior of DBU is also discussed.

Benzo-fused five-membered N/O/S heterocyclic compounds, such as indole, benzofuran, and benzothiophene, possessing a single heteroatom, have important applications in medicinal chemistry, agrochemistry, and material chemistry. Metal-catalyzed reactions are well-established synthetic pathways for the formation of C-X bonds, enabling the direct synthesis of heterocycles. This approach offers advantages over traditional methods, such as fewer steps, increased atom economy, low catalyst loading, regioselectivity, and stereoselectivity. Due to their widespread uses in the pharmaceutical industry, the formation of C-N, C-O, and C-S bonds has gained significant attention. This article focusses on the metal-catalysed synthesis and corresponding mechanistic approaches for N/O/S heterocycles, particularly indole, benzofuran, and benzothiophene, reviewing the progress of the past five years and discussing unexplored future opportunities.

Dibenzofuran and its derivatives are ubiquitous and important medicinal and natural products. Many contain electron-donating substituents. Herein, we report a Pd-catalysed C−H functionalisation protocol that works with electron-rich arenes. We use tetrabutylammonium acetate (NBu₄OAc), which we suspect can act as base and ligand, rendering this protocol a simple and efficient route to dibenzofurans.

Abstract

Dibenzofuran and its derivatives are ubiquitous and important medicinal and natural products. Many contain electron-rich aryl rings. Forming the key intramolecular Ar−Ar bond using traditional cross-coupling is difficult. The C−H functionalisation (C−H activation) approach is, in principle, far more useful. However, we previously found that the well-established conditions, which promote C−H functionalisation through Concerted Metalation-Deprotonation (CMD), proved unsatisfactory. Herein, we report a Pd-catalysed C−H functionalisation protocol that works with electron-rich arenes. We use tetrabutylammonium acetate (NBu₄OAc), which we suspect can act as base, ligand and solvent, rendering this protocol a simple and efficient route to electron-rich dibenzofurans.

Tau be or not tau be. A variety of fluorescent thiophene-vinylene-based ligands was synthesized. Ligands with specific chemical composition displayed selectivity towards distinct protein aggregates in tissue sections with Alzheimer's disease pathology and distinct heterocyclic moieties governed the selectivity of the ligand towards Aβ or tau pathology. We foresee that these findings will aid in designing ligands towards disease-associated protein aggregates.

Abstract

Distinct aggregated proteins are correlated with numerous neurodegenerative diseases and the development of ligands that selectively detect these pathological hallmarks is vital. Recently, the synthesis of thiophene-based optical ligands, denoted bi-thiophene-vinyl-benzothiazoles (bTVBTs), that could be utilized for selective assignment of tau pathology in brain tissue with Alzheimer's disease (AD) pathology, was reported. Herein, we investigate the ability of these ligands to selectively distinguish tau deposits from aggregated amyloid-β (Aβ), the second AD associated pathological hallmark, when replacing the terminal thiophene moiety with other heterocyclic motifs. The selectivity for tau pathology was reduced when introducing specific heterocyclic motifs, verifying that specific molecular interactions between the ligands and the aggregates are necessary for selective detection of tau deposits. In addition, ligands having certain heterocyclic moieties attached to the central thiophene-vinylene building block displayed selectivity to aggregated Aβ pathology. Our findings provide chemical insights for the development of ligands that can distinguish between aggregated proteinaceous species consisting of different proteins and might also aid in creating novel agents for clinical imaging of tau pathology in AD.

In this work, we explore how adding a catalytic amount of an NC-type ligand improves ketone-directed ortho C−H arylation, whereas a full equivalent shuts down the transformation. Increased catalytic activity stems from the formation of a cyclometallated complex containing the NC-type ligand to provide an intermediate which accelerates the ortho-arylation of the ketone substrate.

Abstract

Herein, we report a ruthenium-catalyzed ketone directed ortho-arylation wherein the addition of a bidentate NC-type ligand, most effectively 2-(o-tolyl) pyridine, significantly enhances the C−H arylation reaction. Various aryl-alkyl ketones, including cyclic, aliphatic, and heterocyclic ones, are competent substrates, and arylboronic acid esters were used as aryl sources. However, substitution with OMe and CF₃ in the aromatic ring of the ketone substrates is not tolerated, while such residues on the benzoic ester are possible. Notably, this study provides valuable insights into ketone-directed ortho arylation in the presence of 2-(o-tolyl) pyridine and adds additional options for catalyst and ligand optimization in ruthenium-catalyzed C−H functionalization.

In this work, we have described an efficient protocol for the photoinduced defluorocarboxylation of α-trifluoromethylstyrene using formate as the CO₂ radical anion precursor, which successfully yields a wide variety of gem-difluorovinylacetic acids with excellent functional group tolerance.

Abstract

Herein, we report an efficient protocol in which formate is used as a precursor of the CO₂ radical anion for the photoinduced defluorocarboxylation of α-trifluoromethylstyrene. A wide range of gem-difluorovinylacetic acids bearing a variety of functional groups were successfully obtained in the absence of metal catalysts. The synthetic value of this protocol was highlighted by successful gram-scale synthesis and late-stage modification for complex biologically active molecules. This protocol provides a complementary method that extends the range of currently available methodologies for accessing the structurally versatile gem-difluoroalkenes.

N-heterocyclic olefin (NHO) is known as a highly electron-donative ligand, but its application to metal catalysts has rarely been studied. In this study, a well-defined NHO ligated-Pd catalyst was developed. N-substituents on NHO ligand affected the catalytic performance, and the addition of a phosphine co-ligand, in particular [2-(MeO)C₆H₄]₃P was effective to enhance the activity.

Abstract

N-heterocyclic olefin (NHO) is known as a highly electron-donative ligand, but its application to metal catalysts has rarely been studied. In this study, we synthesized 2-methyleneimidazolidine ligands equipped with a bicyclic frameworks with the goal of developing a NHO-ligated Pd catalyst. These synthesized [(NHO)PdCl(μ-Cl)]₂ complexes had a phosphine co-ligand that proved effective as a catalyst for Suzuki-Miyaura coupling at ambient temperature. By optimizing the N-substituents of NHO ligands and a phosphine co-ligand, we developed a [(NHO)Pd{[2-(CH₃O)C₆H₄]₃P}Cl₂] complex as a catalyst that shows good catalytic activity.

Newly developed rigid-featured chiral Fu-2NO ligands possesses two pyrroloimidazolone-based N-oxides as non-flat chiral walls, and afforded the opportunity for fine-tuning the ligand's electronic and conformational properties by judicious choice of the substituent in the nonligating nitrogen atom.

Abstract

To expand the chemical space of chiral N-oxides and chiral furan-containing ligands, herein we designed and synthesized a new class of rigid-featured tertiary amine-derived C₂ -symmetric chiral furan-N,N′-dioxide (Fu-2NO) ligands from optically pure l-prolinamides/hydroxylprolinamides in operationally simple two steps and up to 57 % overall yield. The newly developed rigid-featured chiral Fu-2NO ligands possesses two pyrroloimidazolone-based N-oxides as non-flat chiral walls, and afforded the opportunity for fine-tuning the ligand electronic and conformational properties by judicious choice of the substituent in the nonligating nitrogen atom. More importantly, The Fu-2NO ligands can tolerate air and moisture such that no special handling is needed for their storage, and can be applied in the Ni(II)-catalyzed asymmetric Friedel-Crafts alkylation reaction of indole.