Bond Alkynylation Research Articles

Stoichiometric and Catalytic Lithium Nickelate-Mediated C-F Bond Alkynylation of Fluoroarenes.

Low-valent nickelates have recently been shown to be key intermediates that facilitate challenging cross-coupling reactions under mild conditions. Expanding the synthetic potential of these heterobimetallic complexes, herein we report the success of trilithium nickelate Li3(TMEDA)3Ni(C≡C-Ph)3 in promoting stoichiometric C-F activation of assorted aryl fluorides furnishing novel mixed Li/Ni(0) or Li/Ni(II) species depending on the substrate and conditions employed. These stoichiometric successes can be upgraded to catalytic regimes to enable the atom-efficient alkynylation of aryl fluorides and polyfluoroarenes with lithium acetylides and precatalyst Ni(COD)2, which operates without the intervention of external ligands, Cu cocatalysts, or additives.

Unlocking Regiodivergence in PdII- and RhIII-Mediated Site-Selective C-H Bond Alkynylation of Imidazopyridines.

An efficient PdII- and RhIII-controlled site-selective C-H bond alkynylation of imidazopyridines using (bromoethynyl)triisopropylsilane is disclosed. The divergent methodology allows straightforward access to a wide range of products alkynylated at the C3 and ortho positions. This strategy is suggestive of a practical platform that can be suitable for late-stage diversification and may assist in the design of more selective and complementary catalytic systems.

Transition-Metal Free Radical-Mediated C—H Bond Alkynylation and Allylation of Ethers, Aldehydes and Amides

Transition-Metal Free Radical-Mediated C—H Bond Alkynylation and Allylation of Ethers, Aldehydes and Amides

Cascade Reaction to Selectively Synthesize Multifunctional Indole Derivatives by IrIII -Catalyzed C-H Activation.

An effective and condition-controlled way to synthesize with high selectivity a variety of functionalized indoles with potent biological properties has been developed. Notably, 2,4-dialkynyl indole products were obtained by direct double C-H bond alkynylation, whereas alkynyl at the C4 position could convert to carbonyl to generate 2-alkynyl-3,4-diacetyl indoles fast and effectively. Additionally, a one-pot relay catalytic reaction led to 2,5-di-alkynyl-3,4-diacetyl indoles when using a carbonyl group as the directing group and by controlling the type and quantity of additives. A possible mechanism was proposed based on many studies including deuterium-exchange experiments, the necessary conditions of product conversion, and the effect of water on the reaction.

Room-temperature C-H bond alkynylation by merging cobalt and photocatalysts.

A new protocol is developed for the mono- and bis-ortho-C-H alkynylation of easily accessible benzamide derivatives using alkynyl bromides at room temperature by merging cobalt and photocatalysts. The diverse reactivity of various alkynyl bromides towards the C-H alkynylation and competing C-H/N-H bond annulation reactions has been demonstrated to give the corresponding products in good yields with excellent functional group tolerance.

Palladium-catalyzed defluorinative alkynylation of polyfluoroalkyl ketones with alkynes for the synthesis of fluorinated fused furans

A Pd-catalyzed C–F bond alkynylation of polyfluoroalkyl ketones with terminal alkynes for the synthesis of fluoroalkylated fused furans was developed.

Regio‐Divergent C—H Alkynylation with Janus Directing Strategy via Ir(III) Catalysis

Summary of main observation and conclusionDirecting strategy has been extensively exploited to maintain activity and selectivity for the rapid access to functionalized molecules and pharmaceutical targets. However, ‘one‐to‐one’ activation model was usually achieved through traditional directing strategy. Herein, we achieved ‘one‐to‐two’ activation model by slight modification of simple and practical ketoxime and amide functionality. With judicious choice of directing groups, Csp3—H and Csp2—H bond alkynylation reaction, and more significantly, dehydrogenative Csp3—H alkynylation, were realized, enabling the regio‐divergent late‐stage modifications of pharmaceuticals.

Stereoselective Palladium-Catalyzed C-F Bond Alkynylation of Tetrasubstituted gem-Difluoroalkenes.

A stereoselective Pd(PPh3 )4 -catalyzed C-F bond alkynylation of tetrasubstituted gem-difluoroalkenes with terminal alkynes has been developed. This method gives access to a great variety of conjugated monofluoroenynes bearing a tetrasubstituted alkene moiety with well-defined stereochemistry. Chelation-assisted oxidative addition of Pd to the C-F bond is proposed to account for the high level of stereocontrol. An X-ray crystal structure of a key monofluorovinyl PdII intermediate has been obtained for the first time as evidence for the proposed mechanism.

Stereoselective Palladium‐Catalyzed C−F Bond Alkynylation of Tetrasubstituted gem‐Difluoroalkenes

AbstractA stereoselective Pd(PPh3)4‐catalyzed C−F bond alkynylation of tetrasubstituted gem‐difluoroalkenes with terminal alkynes has been developed. This method gives access to a great variety of conjugated monofluoroenynes bearing a tetrasubstituted alkene moiety with well‐defined stereochemistry. Chelation‐assisted oxidative addition of Pd to the C−F bond is proposed to account for the high level of stereocontrol. An X‐ray crystal structure of a key monofluorovinyl PdII intermediate has been obtained for the first time as evidence for the proposed mechanism.

Rhodium(III)‐Catalyzed Alkynylation of 4‐Arylphthalazin‐1(2H)‐one Scaffolds via C‐H Bond Activation

Selective C–H bond alkynylation toward modular access to material and pharmaceutical molecules is of great desire in modern organic synthesis. Disclosed herein is rhodium(III)‐catalyzed selective C–H bond mono‐/bialkynylation of 4‐aryl phthalazin‐1(2H)‐one was developed. The silver salt AgSbF6 are demonstrated to play a vital role in promoting the bialkynylation reactions. The present alkynylation strategy is simple, efficient, and features high functional group tolerance and broad substrate scope under an air atmosphere. Additionally, 6‐aryl pyridazin‐3(2H)‐one scaffold is amenable to the selective monoalkynylation and sequential bialkynylation, respectively.

Rh-Catalyzed aldehydic C-H alkynylation and annulation.

Novel Rh-catalyzed aldehydic C-H bond alkynylation and annulation for the in situ synthesis of chromones and aurones are described. It involves the sequential aldehyde C-H bond alkynylation of salicylaldehyde with in situ generated 1-bromoalkyne from 1,1-dibromoalkene followed by annulation. This protocol shows good functional group tolerance including aryl, alkenyl, alkyl and heteroaryl-1,1-dibromoalkenes. The steric/electronic effect was demonstrated during the base-mediated in situ cyclization of o-hydroxyynones to generate aurones.

Rhodium-catalyzed direct C-H bond alkynylation of aryl sulfonamides with bromoalkynes.

Herein we report a novel rhodium-catalyzed ortho-mono-alkynylation of aryl sulfonamides. The reactions of N-tosylacetamides with triisopropylsilyl (TIPS)-substituted bromoalkyne are catalyzed by a [(Cp*RhCl2)2] complex without cyclization, forming ortho-(1-alkynyl) benzenesulfonamides. While triethylsilyl or trimethylsilyl (TES or TMS)-substituted bromoalkyne was also amenable to the alkynylation, affording six-membered benzosultams via the alkynylation/intramolecular cyclization cascade reaction. The present protocol displays high functional group tolerance and broad substrate scope under an air atmosphere in good to high yields. Mechanistic studies indicate that the reaction proceeds by a turnover limiting C-H activation step and a plausible mechanism was proposed.

Mechanism of Nickel(II)-Catalyzed C(2)–H Alkynylation of Indoles with Alkynyl Bromide

The nickel system (THF)2NiBr2/phen has recently been shown as an efficient catalyst for the C–H bond alkynylation of diverse heteroarenes with (triisopropylsilyl)alkynyl bromide via monodentate chelation assistance. Herein, we report an extensive mechanistic investigation for the direct alkynylation of indoles involving the well-defined nickel catalyst, which features a coordinative insertion pathway of alkynyl bromide with the Ni(II) catalyst. Catalytic relevant nickel complexes, (phen)NiCl2 (5), (phen)2NiCl2 (6) and [(phen)3Ni]·NiCl4 (7) were isolated, and the complexes 6 and 7 were structurally characterized. Well-defined complexes were as competent as the in situ generated catalyst system (THF)2NiBr2/phen for the alkynylation of indoles. Various controlled studies and reactivity experiments were performed to understand the probable pathway for the alkynylation reaction. Kinetics analysis highlights that the complex (phen)NiX2 acts as a precatalyst, and the involvement of substrate indole and LiOtBu ar...

A Copper‐ and Phosphine‐Free Nickel(II)‐Catalyzed Method for C−H Bond Alkynylation of Benzothiazoles and Related Azoles

AbstractA phosphine‐free nickel(II)‐catalyzed method for the C(2)−H bond alkynylation of (benzo)thiazoles, (benz)imidazoles, and oxazoles is described. Well‐defined and air‐stable (Phen)NiCl2 catalyst efficiently catalyzes the coupling of diverse azoles with alkynyl bromides without the use of a copper co‐catalyst, and the method tolerates synthetically important functional groups. Preliminary mechanistic studies on this NiII‐catalyzed alkynylation emphasize the homogeneous nature of the catalyst, and rule out a radical manifold for the reaction. The synthetic utility of this Ni‐catalyzed method is demonstrated by further functionalizing the alkynylated benzothiazoles to 3‐methyl‐2‐(alkynyl)benzo[d]thiazolium salts that are known DNA cleaving agents.

Rhodium-Catalyzed C-O Bond Alkynylation of Aryl Carbamates with Propargyl Alcohols.

The rhodium-catalyzed alkynylation of aryl carbamates with propargyl alcohols is described. This methodology can provide aryl acetylenes from aryl carbamates via C-O bond activation. The use of propargyl alcohols as alkynylating agents allows the use of a variety of functional groups that are incompatible with organometallic nucleophiles. This reaction also serves to broaden the utility of a carbamate moiety as a convertible ortho directing group.

Regioselective C-H Bond Alkynylation of Carbonyl Compounds through Ir(III) Catalysis.

Selective C-H bond alkynylation toward modular access to material and pharmaceutical molecules is of great desire in modern organic synthesis. Reported herein is Ir(III)-catalyzed regioselective C-H alkynylation of ketones and esters, which is generally applicable for the rapid construction of molecular complexity. This protocol provides a complementary process for conventional alkyne synthesis. Further functionalization of carbonyl-derived material molecules and pharmaceuticals demonstrates the potential synthetic utility of this methodology.

C–S Bond Alkynylation of Diaryl Sulfoxides with Terminal Alkynes by Means of a Palladium–NHC Catalyst

Sonogashira–Hagihara-type alkynylation of diaryl sulfoxides with unactivated terminal alkynes has been developed. With a combination of a palladium–NHC catalyst and LiOtBu as a base, a series of diaryl sulfoxides were converted into the alkynylated products via C–S bond cleavage.

C–H Bond Alkynylation of Heteroarenes

C–H Bond Alkynylation of Heteroarenes

A General Nickel-Catalyzed Method for C-H Bond Alkynylation of Heteroarenes Through Chelation Assistance.

A general nickel-catalyzed method for the alkynylation of heteroarenes through monodentate chelation assistance is described. Many heterocycles, including indoles, pyrroles, imidazoles, and pyrazole, efficiently coupled with (triisopropylsilyl)alkynyl bromide, and synthetically important functional groups, such as halides, ether, nitrile, and nitro, are tolerated. Synthetic applicability of this Ni-catalyzed method is demonstrated by the removal of the triisopropylsilyl group and further functionalization to triazolyl, benzofuranyl, and alkynyl arene derivatives. Preliminary mechanistic investigations of the alkynylation of indole suggest that the reaction proceeds through kinetically relevant C-H activation and follows a two-electron redox pathway. A catalytically relevant Ni species, namely, [(Phen)3 Ni]NiBr4 (PheN=1,10-phenanthroline), was isolated and structurally characterized.

Expedient Cobalt-Catalyzed C-H Alkynylation of (Enantiopure) Benzylamines.

A unified strategy for cobalt-catalyzed ortho-C-H bond alkynylation of benzylamines is reported. Simple, commercially available CoBr2 was used as a cobalt source. The developed alkynylation strategy is robust and efficient and has a broad substrate scope including 1°, 2°, and 3° benzylamines. The mechanistic study shows that C-H bond cleavage is reversible, and the kinetic study illustrates that the rate of reaction depends solely on the catalyst.