Cascade Reaction of Enyne-Amides with Sulfur-Ylides for the Synthesis of Indole-Tethered 5-Oxaspiro[2.4]hept-6-ene Derivatives.

An unexpected cascade reaction of enyne-amides with sulfur-ylides has been developed. This cascade reaction involves cycloisomerization, dearomatic cyclopropanation, ring-opening rearomatization, and subsequent cyclopropanation, differing from the common [2 + n] cyclization of enyne-amides. A variety of (spirocyclopropane)dihydrofuran derivatives have been efficiently and conveniently synthesized in a single vessel, exhibiting excellent diastereoselectivity and good functional group tolerance.

Pd-Catalyzed 1,4-Difluoromethylative Functionalization of 1,3-Dienes Using Freon-22.

We report a visible-light-driven, palladium-catalyzed 1,4-difluoromethylative functionalization of conjugated dienes using chlorodifluoromethane (ClCFH, Freon-22) as a cost-effective difluoromethyl source. The excited palladium catalyst efficiently reduces the C-Cl bond, which generates a CFH radical, followed by regioselective S2' substitution to afford 1,4-difunctionalized products. This versatile, redox-neutral method accommodates diverse nucleophiles and exhibits broad functional group compatibility, making it suitable for late-stage functionalization in drug discovery and offering a direct route to difluoromethylated molecules.

Selective 1,4-syn-Addition to Cyclic 1,3-Dienes via Hybrid Palladium Catalysis.

1,4-cis-Disubstituted cyclic compounds play a pivotal role in pharmaceutical development, offering enhanced potency and bioavailability. However, their stereoselective and modular synthesis remains a long-standing challenge. Here, we report an innovative strategy for accessing these structures via mild conditions employing cyclic 1,3-dienes/alkyl(aryl)halides and amines.

Hybrid Palladium-Catalyzed Intramolecular Carboamination of Conjugated Dienes: Synthesis of Functionalized Pyrrolidines via Selective Trifluoromethylarene Defluorination.

The incorporation of difluoromethylene groups into aza-heterocycles represents a compelling yet underexplored avenue in contemporary chemical research. In this study, we unveil a hybrid palladium-catalyzed intramolecular gem-difluoroalkylamination of conjugated dienes, providing a versatile approach to the synthesis of diverse functionalized pyrrolidines. Noteworthy features include mild reaction conditions and a remarkable tolerance toward various functional groups.

Substrate-directed divergent annulations of sulfur ylides: synthesis of functionalized bispirocyclopentane and bispirocyclopropane derivatives.

Herein, an efficient, substrate-directed divergent [2 + 3]/[2 + 1] annulation of tetra-substituted oxa-dienes and allylic sulfur ylides has been successfully developed. Under precise annulation regulation, a series of functionalized bispirocyclopentane and bispirocyclopropane derivatives were synthesized in a highly stereoselective and economical manner (up to 95% yield, >20 : 1 dr or >20 : 1 /). This protocol offers the advantages of mild conditions, high chemo-, regio- and diastereoselectivity and broad substrate compatibility.

Recent advances in [4 + 4] annulation of conjugated heterodienes with 1,4-dipolar species for the synthesis of eight-membered heterocycles.

Numerous eight-membered heterocycles are of significance in biological chemistry, the pharmaceutical industry, agrochemistry, and materials science. However, the assembly of eight-membered heterocycles is usually challenging due to the unfavorable enthalpic and entropic barriers of the transition states during the ring formation. Tremendous efforts have been devoted to the development of synthetic routes to eight-membered heterocycles.

Highly Diastereoselective One-Pot Synthesis of 4,5-Dihydrofuro[2,3-]azocin-6-one Derivatives through Cyclization/[4+4] Annulation Reactions.

A variety of 4,5-dihydrofuro[2,3-]azocin-6-one derivatives were expediently assembled through Au(I)-catalyzed cyclization and 2-(-butyl)-1,1,3,3-tetramethylguanidine (BTMG)-mediated [4+4] annulation reactions of enyne-amides and ynones. The reactions exhibit high efficiency with excellent regio- and diastereoselectivity. A broad spectrum of substrates was utilized.

Modular synthesis of unsaturated aza-heterocycles via copper catalyzed multicomponent cascade reaction.

The unsaturated aza-heterocycles such as tetrahydropyridines pose significant applications in both drug discovery and development. However, the methods to construct polyfunctionalized tetrahydropyridines are still limited. Herein, we report a modular synthesis of tetrahydropyridines via copper catalyzed multicomponent radical cascade reaction.

Late-Stage Modification of Drugs via Alkene Formal Insertion into Benzylic C-F Bond.

C-F insertion of carbon-atom units is underdeveloped although it poses significant potential applications in both drug discovery and development. Herein, we report a photocatalytic protocol for late-stage modification of trifluoromethyl aromatic drugs involving formal insertion of abundant alkene feedstocks into a benzylic C-F bond selectively. This redox-neutral transformation features mild conditions and extraordinary functional group tolerance.

Atroposelective Access to 1,3-Oxazepine-Containing Bridged Biaryls via Carbene-Catalyzed Desymmetrization of Imines.

We disclose herein an atroposelective synthesis of novel bridged biaryls containing medium-sized rings via N-heterocyclic carbene organocatalysis. The reaction starts with addition of the carbene catalyst to the aminophenol-derived aldimine substrate. Subsequent oxidation and intramolecular desymmetrization lead to the formation of 1,3-oxazepine-containing bridged biaryls in good yields and excellent enantioselectivities.

Metal-Free [5 + 1] Cycloaddition-Aromatization of Benzotriazoles and Sulfur Ylides to Construct 1,2,4-Benzotriazines.

Reported herein is a novel [5 + 1] cycloaddition-aromatization of benzotriazoles and sulfur ylides to efficiently construct 1,2,4-benzotriazine derivates with good yield. This new protocol does not employ any transition metal reagent and enables the cycloaddition by cleavage of the N-N single bond. The use of inexpensive and readily available starting materials, a broad substrate scope, mild reaction conditions, metal-free, and versatile functionalization of the 1,2,4-benzotriazines make this strategy more attractive.

Photocatalytic difluoromethylarylation of unactivated alkenes a (hetero)aryl neophyl-like radical migration.

Photoredox-catalyzed addition of the difluoromethylradical to unactivated alkenes has been found to trigger neophyl-like aryl and heteroaryl migrations which allowed the construction of a diverse series of difluoromethyl ketones. The reaction featured mild reaction conditions and broad substrate scope.

Difluoromethylarylation of α,β-unsaturated amides a photocatalytic radical smiles rearrangement.

A photocatalytic Smiles rearrangement, triggered by radical difluoromethylation of conjugated arylsulfonylated amides, was developed to construct both β-difluoromethyl amide and heterocyclic scaffolds selectively. This transformation features mild conditions and broad substrate scope. More importantly, the chemoselectivity of the intermediate amidyl radical could be altered completely by simply changing the light source, along with addition of water to the reaction mixture.

Synthesis of Furo[2,3-][1,4]diazepin-3-one Derivatives through Tandem Cyclization/[4 + 3] Annulation Reactions.

A variety of furo[2,3-][1,4]diazepin-3-one derivatives were facilely synthesized through one-pot tandem cyclization/[4 + 3] annulation reactions between enynamides and α-bromohydroxamates. The reactions proceeded efficiently at room temperature, and various functional groups were well tolerated. The obtained furo[2,3-][1,4]diazepin-3(2)-ones containing a 7-membered dinitrogen-fused ring might be of biological and medicinal value.

Decatungstate Catalyzed Synthesis of Trifluoromethylthioesters from Aldehydes via a Radical Process.

Here we report a mild and general method for the trifluoromethylthiolation of aldehydes using -trifluoromethylthiosaccharin as the CFS radical source and sodium decatungstate (NaDT) as the photocatalyst. This reaction proceeds via hydrogen atom abstraction by photoactivated DT and features good functional groups and substrate tolerance. Generally, electron-rich aldehydes demonstrate better reactivity than electron-deficient ones and good selectivity is observed for the trifluoromethylthiolation of aldehydic C-H bonds over tertiary and benzylic C-H bonds.

Highly enantioselective tandem cycloisomerization/Diels-Alder reaction of 2-(1-alkynyl)-2-alken-1-ones and enals: dual catalysis with platinum and amines.

Herein, we disclosed a highly efficient strategy of enantioselective synthesis of 2,3-furan-fused carbocycles bearing three-contiguous stereocenters. This transformation is catalyzed by dual catalysis of PtCl4/chiral amines via tandem dehydrogenative annulation/Diels-Alder reaction of 2-(1-alkynyl)-2-alken-1-ones and enals. The in situ generation of the furan-based ortho-quinodimethane intermediates and the iminium activation of enals are crucial to this transformation.

Transition-Metal-Free α Csp -H Cyanation of Sulfonamides.

This report describes the site-selective α-functionalization of sulfonylamide derivatives through the in-situ generation of imine intermediates. The N-F sulfonylamides, which could facilitate the elimination to generate imines, are coupled with TBACN to efficiently and mildly afford α-amino cyanides. Comparing with Strecker reaction, this transformation offers a complementary strategy to efficiently construct α-amino cyanides from direct α C-H functionalization of sulfonylamindes.

Carbene-Catalyzed Activation of Remote Nitrogen Atoms of (Benz)imidazole-Derived Aldimines for Enantioselective Synthesis of Heterocycles.

A new mode of carbene-catalyzed heteroatom activation and asymmetric reactions is disclosed. The reaction starts with addition of a carbene catalyst to a (benz)imidazole-derived aldimine substrate. Subsequent oxidation and proton transfer lead to the formation of a catalyst-bound triaza-diene as the key intermediate, in which the nitrogen atom at a site remote to the catalyst-substrate bond is activated.

Carbene-Catalyzed Enantioselective Aldol Reaction: Post-Aldol Stereochemistry Control and Formation of Quaternary Stereogenic Centers.

The dominated approaches for asymmetric aldol reactions have primarily focused on the aldol carbon-carbon bond-forming events. Here we postulate and develop a new catalytic strategy that seeks to modulate the reaction thermodynamics and control the product enantioselectivities via post-aldol processes. Specifically, an NHC catalyst is used to activate a masked enolate substrate (vinyl carbonate) to promote the aldol reaction in a non-enantioselective manner.

Carbene-Catalyzed Reaction of Indolyl Methylenemalononitriles and Enals for Access to Complex Tetrahydrocarbazoles.

A carbene-catalyzed enantioselective cascade reaction of substituted methylenemalononitriles and α-bromoenals is disclosed. Key steps of this cascade process include a formal [4 + 2] cycloaddition, aldol reaction, and intramolecular lactonization. Our reaction offers streamlined and highly stereoselective access to complex tetrahydrocarbazole derivatives, with simultaneous formation of four chemical bonds and four chiral centers.

One-pot synthesis of 2-azolylimidazole derivatives through a domino addition/A coupling/cyclization process under copper catalysis.

A novel one-pot approach for the synthesis of multi-substituted 2-imidazolylimidazoles, 2-pyrazolylimidazoles and 2-indazolylimidazoles was developed through a domino addition/A3 coupling/cyclization process under copper catalysis. A variety of aminoethyl- or hydroxylethyl-tethered 2-azolylimidazole derivatives were conveniently and efficiently assembled in one pot using N-propargylcarbodiimides, azoles, paraformaldehyde and secondary amines as starting materials. The products containing an o-iodoaryl group could be further converted to imidazo[1,2-c]imidazo[1,2-a]quinazoline derivatives through a copper-catalyzed intramolecular C-H arylation.

Gold and Carbene Relay Catalytic Enantioselective Cycloisomerization/Cyclization Reactions of Ynamides and Enals.

The combined use of gold as transition metal catalyst and N-heterocyclic carbene (NHC) as organic catalyst in the same solution for relay catalytic reactions was disclosed. The ynamide substrate was activated by gold catalyst to form unsaturated ketimine intermediate that subsequently reacted with the enals (via azolium enolate intermediate generated with NHC) effectively to form bicyclic lactam products with excellent diastereo- and enantio-selectivities. The gold and NHC coordination and dissociation can be dynamic and tunable events, and thus allow the co-existence of both active metal and carbene organic catalysts in appreciable concentrations, for the dual catalytic reaction to proceed.

Hydrodehalogenation of Aryl Halides through Direct Electrolysis.

A catalyst- and metal-free electrochemical hydrodehalogenation of aryl halides is disclosed. Our reaction by a flexible protocol is operated in an undivided cell equipped with an inexpensive graphite rod anode and cathode. Trialkylamines nBu N/Et N behave as effective reductants and hydrogen atom donors for this electrochemical reductive reaction.

Access to All-Carbon Spirocycles through a Carbene and Thiourea Cocatalytic Desymmetrization Cascade Reaction.

A new catalytic approach for rapid asymmetric access to spirocycles is disclosed. The reaction involves a carbene- and thiourea-cocatalyzed desymmetrization process with the simultaneous installation of a spirocyclic core. The use of a thiourea cocatalyst is critical to turn on this reaction, as no product was formed in the absence of a thiourea.

Sulfinate and Carbene Co-catalyzed Rauhut-Currier Reaction for Enantioselective Access to Azepino[1,2-a]indoles.

A carbene and sulfinate co-catalyzed intermolecular Rauhut-Currier reaction between enals and nitrovinyl indoles is disclosed. The carbene catalyst activates the enal and the sulfinate co-catalyst activates the nitrovinyl indole. Both activation processes are realized via the formation of covalent bonds between the catalysts and substrates to generate catalyst-bound intermediates.