Synthesis of trans‐Disubstituted Alkenes by Cobalt‐Catalyzed Reductive Coupling of Terminal Alkynes with Activated Alkenes

A cobalt‐catalyzed reductive coupling of terminal alkynes, RC?CH, with activated alkenes, R′CH?CH₂, in the presence of zinc and water to give functionalized trans‐disubstituted alkenes, RCH?CHCH₂CH₂R′, is described. A variety of aromatic terminal alkynes underwent reductive coupling with activated alkenes including enones, acrylates, acrylonitrile, and vinyl sulfones in the presence of a CoCl₂/P(OMe)₃/Zn catalyst system to afford 1,2‐trans‐disubstituted alkenes with high regio‐ and stereoselectivity. Similarly, aliphatic terminal alkynes also efficiently participated in the coupling reaction with acrylates, enones, and vinyl sulfone, in the presence of the CoCl₂/P(OPh)₃/Zn system providing a mixture of 1,2‐trans‐ and 1,1‐disubstituted functionalized terminal alkene products in high yields. The scope of the reaction was also extended by the coupling of 1,3‐enynes and acetylene gas with alkenes. Furthermore, a phosphine‐free cobalt‐catalyzed reductive coupling of terminal alkynes with enones, affording 1,2‐trans‐disubstituted alkenes as the major products in a high regioisomeric ratio, is demonstrated. In the reactions, less expensive and air‐stable cobalt complexes, a mild reducing agent (Zn) and a simple hydrogen source (water) were used. A possible reaction mechanism involving a cobaltacyclopentene as the key intermediate is proposed.     

Cobalt‐Catalyzed,Aminoquinoline‐Directed C(sp2)H Bond Alkenylation by Alkynes

A method for cobalt‐catalyzed, aminoquinoline‐ and picolinamide‐directed C(sp²)? H bond alkenylation by alkynes was developed. The method shows excellent functional‐group tolerance and both internal and terminal alkynes are competent substrates for the coupling. The reaction employs a Co(OAc)₂?4 H₂O catalyst, Mn(OAc)₂ co‐catalyst, and oxygen (from air) as a terminal oxidant.     

Nitrimines as Reagents for Metal‐Free Formal C(sp2)–C(sp2) Cross‐Coupling Reactions

Nitrimines are employed as powerful reagents for metal‐free formal C(sp²)–C(sp²) cross‐coupling reactions. The new chemical process is tolerant of a wide array of nitrimine and heterocyclic coupling partners giving rise to the corresponding di‐ or trisubstituted alkenes, typically in high yield and with high stereoselectivity. This method is ideal for the metal‐free construction of heterocycle‐containing drug targets, such as phenprocoumon.     

Cobalt‐Catalyzed,Aminoquinoline‐Directed C(sp2)?H Bond Alkenylation by Alkynes

A method for cobalt‐catalyzed, aminoquinoline‐ and picolinamide‐directed C(sp²) H bond alkenylation by alkynes was developed. The method shows excellent functional‐group tolerance and both internal and terminal alkynes are competent substrates for the coupling. The reaction employs a Co(OAc)₂⋅4 H₂O catalyst, Mn(OAc)₂ co‐catalyst, and oxygen (from air) as a terminal oxidant.     

Investigation of Alkyne Regioselectivity in the Ni‐Catalyzed Benzannulation of Cyclobutenones

A Ni‐catalyzed benzannulation reaction of cyclobutenones and alkynes provides a rapid synthesis of heavily substituted phenols. The regioselectivity of this reaction can be modulated by variation of substituents on the alkyne. Though the incorporation of Lewis basic donors provides modest selectivities, the use of aryl substituents can provide high levels of regiocontrol. Finally, alkynylboronates derived from alkyl‐substituted acetylenes provide both high yields and regioselectivities. This study suggests that alkynes bearing one sp²‐ and one sp³‐based substituent can undergo benzannulation with high levels of regiocontrol whereby the sp³‐based group is incorporated ortho‐to the phenolic OH.     

Zinc‐Catalyzed Dehydrogenative Cross‐Coupling of Terminal Alkynes with Aldehydes: Access to Ynones

Because of the lack of redox ability, zinc has seldom been used as a catalyst in dehydrogenative cross‐coupling reactions. Herein, a novel zinc‐catalyzed dehydrogenative C(sp²)? H/C(sp)? H cross‐coupling of terminal alkynes with aldehydes was developed, and provides a simple way to access ynones from readily available materials under mild reaction conditions. Good reaction selectivity can be achieved with a 1:1 ratio of terminal alkyne and aldehyde. Various terminal alkynes and aldehydes are suitable in this transformation.     

Selenide‐Catalyzed Stereoselective Construction of Tetrasubstituted Trifluoromethylthiolated Alkenes with Alkynes

The efficient regio‐ and stereoselective construction of tetrasubstituted alkenes is challenging and very important. For this purpose, we have developed an efficient approach to synthesize tetrasubstituted trifluoromethylthiolated alkenes from simple alkynes in excellent regio‐ and stereoselectivities by selenide‐catalyzed multicomponent coupling. Using this method, trifluoromethylthiolated alkenyl triflates and arenes were achieved. In particular, the triflates could be further converted into carbofunctionalized alkenes by palladium‐catalyzed cross‐coupling reactions. Our method provides a new pathway for the construction of trifluoromethylthiolated tricarboalkenes. This work presents the first example of selenide‐catalyzed trifluoromethylthiolation of alkynes and enables the challenging functionalizations of alkynes.     

Cu‐Catalyzed Cross‐Dehydrogenative ortho‐Aminomethylation of Phenols

A highly selective Cu^II‐catalyzed cross‐dehydrogenative ortho‐aminomethylation of phenols with aniline derivatives is described. The corresponding C(sp²)?C(sp³) coupling products were obtained in moderate to excellent yields under mild reaction conditions and with a broad substrate scope. A radical mechanism is proposed.     

2,4‐Dinitrophenol‐Catalyzed α‐C(sp3)−H and C(sp)−H Bond Functionalization of Cyclic Amines and Alkynes: Highly Regio‐/Diastereoselective Synthesis of α‐Alkynyl‐3‐Amino‐2‐Oxindoles

A transition‐metal‐ and oxidant‐free DNP (2,4‐dinitrophenol)‐catalyzed atom‐economical regio‐ and diastereoselective synthesis of monofunctionalized α‐alkynyl‐3‐amino‐2‐oxindole derivatives by C?H bond functionalization of cyclic amines and alkynes with indoline‐2,3‐diones has been developed. This cascade event sequentially involves the reductive amination of indoline‐2,3‐dione by imine formation and cross coupling between C(sp³)?H and C(sp)?H of the cyclic amines and alkynes. This reaction offers an efficient and attractive pathway to different types of α‐alkynyl‐3‐amino‐2‐oxindole derivatives in good yields with a wide tolerance of functional groups. The salient feature of this methodology is that it completely suppresses the homocoupling of alkynes. To the best of our knowledge, this is the first example of a DNP‐catalyzed metal‐free direct C(sp³)?H and C(sp)?H bond functionalization providing biologically active α‐alkynyl‐3‐amino‐2‐oxindole scaffolds.     

Rhodium‐Catalyzed Defluorinative Vinylation of gem‐Difluoroalkenes for the Synthesis of 2‐Fluoro‐1,3‐dienes

Herein, we present a strategy for the formation of 2‐fluoro‐1,3‐diene derivatives via rhodium‐catalyzed direct C(sp²)—C(sp²) cross‐coupling of gem‐difluoroalkenes and acrylamides. By merging Rh(III)‐catalyzed C(sp²)–H bond activation and nucleophilic addition/F‐elimination of gem‐difluoroalkene, an efficient defluorinative vinylation reaction is uncovered, which leads to the generation of 2‐fluoro‐1,3‐dienes in moderate to good yields with excellent stereoselectivity under mild conditions. Preliminary mechanistic study suggests unique effects of fluorine substituents which allow the reactivity profile not observed with the congeners bearing heavier halides.     

Palladium‐Catalyzed One‐Pot Three‐ or Four‐Component Coupling of Aryl Iodides,Alkynes, and Amines through CN Bond Cleavage: Efficient Synthesis of Indole Derivatives

An efficient synthesis of N‐substituted indole derivatives was realized by combining the Pd‐catalyzed one‐pot multicomponent coupling approach with cleavage of the C(sp³)?N bonds. Three or four components of aryl iodides, alkynes, and amines were involved in this coupling process. The cyclopentadiene–phosphine ligand showed high efficiency. A variety of aryl iodides, including cyclic and acyclic tertiary amino aryl iodides, and substituted 1‐bromo‐2‐iodobenzene derivatives could be used. Both symmetric and unsymmetric alkynes substituted with alkyl, aryl, or trimethylsilyl groups could be applied. Cyclic secondary amines such as piperidine, morpholine, 4‐methylpiperidine, 1‐methylpiperazine, 2‐methylpiperidine, and acyclic amines including secondary and primary amines all showed good reactivity. Further application of the resulting indole derivatives was demonstrated by the synthesis of benzosilolo[2,3‐b]indole.     

Photoredox‐Catalyzed Stereoselective Conversion of Alkynes into Tetrasubstituted Trifluoromethylated Alkenes

A regio‐ and stereoselective synthesis of trifluoromethylated alkenes bearing four different substituents has been developed. Stereocontrolled sulfonyloxytrifluoromethylation of unsymmetric internal alkynes with an electrophilic CF₃ reagent, namely the triflate salt of the Yagupol’skii–Umemoto reagent, in the presence of an Ir photoredox catalyst under visible‐light irradiation afforded trifluoromethylalkenyl triflates with well‐predictable stereochemistry resulting from anti addition of the trifluoromethyl and triflate groups. Subsequent palladium‐catalyzed cross‐couplings led to tetrasubstituted trifluoromethylated alkenes in a highly stereoselective manner. The present method is the first example of a facile one‐pot synthesis of tetrasubstituted trifluoromethylated alkenes from simple alkynes.     

An Alkene‐Promoted Borane‐Catalyzed Highly Stereoselective Hydrogenation of Alkynes to Give Z‐ and E‐Alkenes

The stereoselective hydrogenation of alkynes to alkenes is an extremely useful transformation in synthetic chemistry. Despite numerous reports for the synthesis of Z‐alkenes, the hydrogenation of alkynes to give E‐alkenes is still not well resolved. In particular, selective preparation of both Z‐ and E‐alkenes by the same catalytic hydrogenation system using molecular H₂ has rarely been reported. In this paper, a novel strategy of using simple alkenes as promoters for the HB(C₆F₅)₂‐catalyzed metal‐free hydrogenation of alkynes was adopted. Significantly, both Z‐ and E‐alkenes can be furnished by hydrogenation with molecular H₂ in high yields with excellent stereoselectivities. Further experimental and theoretical mechanistic studies suggest that interactions between H and F atoms of the alkene promoter, borane intermediate, and H₂ play an essential role in promoting the hydrogenolysis reaction.     

Expedient Synthesis of Ketones via N‐Heterocyclic Carbene/Nickel‐Catalyzed Redox‐Economical Coupling of Alcohols and Alkynes†

An N‐heterocyclic carbene/nickel‐catalyzed direct coupling of alcohols and internal alkynes to form α‐branched ketones has been developed. This methodology provides a new approach to afford branched ketones, which are difficult to access through the hydroacylation of simple internal alkenes with aldehydes. This redox‐neutral and redox‐economical coupling is free from any oxidative or reductive additives as well as stoichiometric byproducts. These reactions convert both benzylic and aliphatic alcohols and alkynes, two basic feedstock chemicals, into various α‐branched ketones in a single chemical step.     

A Convergent Synthesis of Functionalized Alkenyl Halides through Cobalt(III)‐Catalyzed Three‐Component C−H Bond Addition

A Co^III‐catalyzed three‐component coupling of C(sp²)−H bonds, alkynes, and halogenating agents to give alkenyl halides is reported. This transformation proceeds with high regio‐ and diastereoselectivity, and is effective for a broad range of aryl and alkyl terminal alkynes. Diverse C−H bond partners also exhibit good reactivity for a range of heteroaryl and aryl systems as well as synthetically useful secondary and tertiary amide, urea, and pyrazole directing groups. This multicomponent transformation is also compatible with allenes in place of alkynes to furnish tetrasubstituted alkenyl halides, showcasing the first halo‐arylation of allenes.     

Stereospecific Pd‐Catalyzed Intermolecular C(sp3)–C(sp) Cross‐Coupling of Diarylmethyl Carbonates and Terminal Alkynes Under Base‐Free Conditions

A palladium‐catalyzed intermolecular decarboxylative C(sp³)–C(sp) coupling of diarylmethyl carbonates and terminal alkynes has been developed. The reaction proceeds smoothly under external base‐free conditions to deliver the corresponding alkynylated diarylmethanes with the liberation of CO₂ and MeOH as the sole byproducts. Moreover, enantioenriched diarylmethyl carbonates are stereospecifically converted to optically active cross‐coupling products with inversion of configuration. Thus, the stereospecific palladium catalysis can provide new and unique access to the alkynylated chiral tertiary stereocenters, which are relatively difficult to construct by conventional methods.     

PdII‐Catalyzed Enantioselective C(sp3)–H Arylation of Cyclobutyl Ketones Using a Chiral Transient Directing Group

The use of chiral transient directing groups (TDGs) is a promising approach for developing Pd^II‐catalyzed enantioselective C(sp³)?H activation reactions. However, this strategy is challenging because the stereogenic center on the TDG is often far from the C?H bond, and both TDG covalently attached to the substrate and free TDG are capable of coordinating to Pd^II centers, which can result in a mixture of reactive complexes. We report a Pd^II‐catalyzed enantioselective β‐C(sp³)?H arylation reaction of aliphatic ketones using a chiral TDG. A chiral trisubstituted cyclobutane was efficiently synthesized from a mono‐substituted cyclobutane through sequential C?H arylation reactions, thus demonstrating the utility of this method for accessing structurally complex products from simple starting materials. The use of an electron‐deficient pyridone ligand is crucial for the observed enantioselectivity. Interestingly, employing different silver salts can reverse the enantioselectivity.     

Copper‐Catalyzed Decarboxylative Radical Silylation of Redox‐Active Aliphatic Carboxylic Acid Derivatives

A decarboxylative silylation of aliphatic N ‐hydroxyphthalimide (NHPI) esters using Si−B reagents as silicon pronucleophiles is reported. This C(sp³)−Si cross‐coupling is catalyzed by copper(I) and follows a radical mechanism, even with exclusion of light. Both primary and secondary alkyl groups couple effectively, whereas tertiary alkyl groups are probably too sterically hindered. The functional‐group tolerance is generally excellent, and α‐heteroatom‐substituted substrates also participate well. This enables, for example, the synthesis of α‐silylated amines starting from NHPI esters derived from α‐amino acids. The new method extends the still limited number of C(sp³)−Si cross‐couplings of unactivated alkyl electrophiles.     

Gold‐Catalyzed C(sp3)H/C(sp)H Coupling/Cyclization/Oxidative Alkynylation Sequence: A Powerful Strategy for the Synthesis of 3‐Alkynyl Polysubstituted Furans

In sharp contrast to the gold‐catalyzed reactions of alkynes/allenes with nucleophiles, gold‐catalyzed oxidative cross‐couplings and especially C? H/C? H cross‐coupling have been under represented. By taking advantage of the unique redox property and carbophilic π acidity of gold, this work realizes the first gold‐catalyzed direct C(sp³)? H alkynylation of 1,3‐dicarbonyl compounds with terminal alkynes under mild reaction conditions, with subsequent cyclization and in situ oxidative alkynylation. A variety of terminal alkynes including aryl, heteroaryl, alkenyl, alkynyl, alkyl, and cyclopropyl alkynes all successfully participate in the domino reaction. The protocol offers a simple and region‐defined approach to 3‐alkynyl polysubstituted furans.     

Nickel‐Catalyzed Cyclization of ortho‐Iodoketoximes and ortho‐Iodoketimines with Alkynes: Synthesis of Highly Substituted Isoquinolines and Isoquinolinium Salts

A convenient method for the synthesis of highly substituted isoquinolines and isoquinolinium salts by the nickel‐catalyzed cyclization of ortho‐haloketoximes and ‐ketimines, respectively, with alkynes is described. The reaction of ortho‐haloketoximes and various alkynes in the presence of [Ni(PPh₃)₂Br₂] and zinc powder in a mixture of acetonitrile and tetrahydrofuran at 80 °C for 15 hours gave 1,3,4‐trisubstituted isoquinoline products in moderate to excellent yields and high regioselectivity. The corresponding isoquinoline N‐oxide was found to be the intermediate in the cyclization reaction pathway. In contrast, the reaction of ortho‐haloketimines and alkynes under similar catalytic conditions in tetrahydrofuran at 70 °C for two hours gave 1,2,3,4‐tetrasubstituted isoquinolinium salts in good to excellent yields.