Alkynyl Halides Research Articles

Nickel-Catalyzed Ligand-Controlled Selective Reductive Cyclization/Cross-Couplings.

ConspectusThe use of quaternary stereocenters during lead candidate optimization continues to grow because of improved physiochemical and pharmacokinetic profiles of compounds with higher sp3 fraction. Pd-catalyzed redox-neutral alkene difunctionalization involving carbopalladation of alkenes followed by nucleophilic-trapping σ-alkyl-palladium intermediates has been developed as an efficient method to construct quaternary stereocenters. However, the low chemoselectivity and air sensitivity of organometallic nucleophiles, as well as their low availability and accessibility, limit the scope of application of this elegant strategy. Recently, Ni-catalyzed reductive cross-coupling has evolved into a privileged strategy to easily construct valuable C(sp3)-C bonds. Despite great progress, the enantioselective coupling of C(sp3) electrophiles still relies on activated or functionalized alkyl precursors, which are often unstable and require multiple steps to prepare. Therefore, Ni-catalyzed reductive difunctionalization of alkenes via selective cyclization/cross-coupling was developed. This strategy not only offers a robust and practical alternative for traditional redox-neutral alkene difunctionalization but also provides strategic complementarity for reductive cross-coupling of activated alkyl electrophiles. In this Account, we summarize the latest results from our laboratory on this topic. These findings mainly include our explorations in modulating the enantioselectivity and cyclization mode of reductive cyclization/cross-couplings.We will first discuss Ni-catalyzed enantioselective reductive cyclization/cross-coupling to construct valuable chiral heterocycles with quaternary stereocenters and focus on the effects of ligands, reductants, and additives and their roles in reductive cross-coupling. A wide range of electrophiles have been explored, including aryl halides, vinyl halides, alkynyl halides, gem-difluoroalkenes, CO2, trifluoromethyl alkenes, and cyano electrophiles. The synthetic potential of this approach has also been demonstrated in the synthesis of biologically active natural products and drug molecules. Second, we will detail how to tune the steric effects of nickel catalysts by modifying bipyridine ligands for regiodivergent cyclization/cross-couplings. Specifically, the use of bidentate ligands favors exo-selective cyclization/cross-coupling, while the use of a carboxylic acid-modified bipyridine ligand permits endo-selective cyclization/cross-coupling. We will also show how to activate the amide substrate by altering the electronic and steric properties of substituents on the nitrogen, thereby enabling the nucleophilic addition of aryl halides to amide carbonyls. Further investigation of ligand properties has led to tunable cyclization/cross-couplings (addition to the amide carbonyl vs 7-endo-cyclization) for the divergent synthesis of pharmacologically important 2-benzazepine frameworks. Finally, we serendipitously discover that modifying the ligands of nickel catalysts and changing the oxidation state of nickel can control the migratory aptitude of different groups, thus providing a switchable skeletal rearrangement strategy. This transformation is of high synthetic value because it represents a conceptually unprecedented new approach to C-C bond activation. Thus, this Account not only summarizes synthetic methods that allow the formation of valuable chiral heterocycles with quaternary stereocenters using a wide variety of electrophiles but also provides insight into the relationship between ligand structure, substrate, and cyclization selectivity.

Simple and efficient nickel-catalyzed cross-coupling reaction of alkenylalanes with alkynyl halides for synthesis of conjugated enynes

A NiCl2(PPh3)2/XantPhos catalyzed synthesis of conjugated enynes by the cross-coupling of terminal alkynyl halides with alkenylaluminum reagents at room temperature in DME solvent was developed under mild reaction conditions. The aryls bearing electron-donating or electron-withdrawing groups in alkynylhalides give the corresponding cross-coupling products conjugated enynes in good to excellent isolated yields up to 97%. This process was simple and easily performed, which provides an efficient method for the synthesis of conjugated enynes derivatives. On the basis of the experimental results, a possible catalytic cycle has been proposed.

Highly efficient synthesis of 1,2-disubstituted acetylenes derivatives from the cross-coupling reactions of 1-bromoalkynes with organotitanium reagents

A Highly efficient route for the synthesis of 1,2-disubstituted acetylene derivatives has been developed by nickel catalyzed cross-couplings of alkynyl halides with aryl titanium reagents under mild conditions. This has given corresponding cross-coupling products good to excellent isolated yields of up to 92 %. The aryls bearing electron-donating or electron-withdrawing groups in either alkynylhalides or aryltitanium substrates gave cross-coupling products good yields. This process was simple and easily performed, which provides an efficient method for the synthesis of 1,2-disubstituted acetylenes derivatives.

Nickel-catalyzed site- and stereoselective reductive alkylalkynylation of alkynes

Nickel-catalyzed site- and stereoselective reductive alkylalkynylation of alkynes

Computational Insights into the Divergent Regioselectivities for Nickel‐Catalyzed Dicarbofunctionalization of Allyl Moiety of N‐Allyl‐2‐aminopyrimidine

AbstractHerein, the origins of organohalide‐dependent regioselectivities for Ni‐catalyzed dicarbofunctionalization of allyl moiety of N‐allyl‐2‐aminopyrimidine were explored by computational studies. When aryl iodides are used for the dicarbofunctionalization, the detailed reaction mechanistic pathway follows the sequential oxidative addition (OA), migratory insertion (MI), β‐H elimination, H‐migration, transmetalation, and reductive elimination (RE) to afford the 1,3‐dicarbofunctionalization products. Due to the presence of chelation of the pyrimidinyl moiety of substrate with Ni, the competitive β‐H elimination leading to the product of Heck reaction is less favourable and thus the regioselective β‐H elimination occurs. The formation of thermodynamically more stable intermediate is the driving force for the subsequent H‐migration. When alkenyl bromides are used, alternative regioselectivity to give 1,2‐dicarbofunctionalization products is obtained and the proposed mechanistic pathway proceeds sequentially via OA, MI, transmetalation, and RE. The main reason accounting for the different regioselectivity between aryl iodides and alkenyl bromides involved in dicarbofunctionalization is revealed. In addition, the reversed 2,1‐regioselectivity achieved by using alkynyl halides in the Ni‐catalyzed dicarbofunctionalization is via sequential steps of OA, transmetalation, MI, and RE. The mechanistic difference that the migratory insertion step is unlikely to occur after OA, which is in contrast to the other two mechanistic pathways, is rationalized.

Visible-Light-Induced Nickel-Catalyzed Cross-Coupling with Alkylzirconocenes from Unactivated Alkenes

Summary Transition-metal-catalyzed cross-coupling reactions between naturally abundant sp3-hybridized carbon centers facilitate access to diverse molecules with complex three-dimensional structures. Organometallic compounds are among one of the most powerful reagents that are broadly used in carbon–carbon bond formations. Although sp2-hybridized organometallic compounds are widely employed in cross-couplings, sp3-hybridized organometallic coupling partners are less developed. Herein, we report visible-light-induced single nickel-catalyzed C(sp3)–C(sp3), C(sp3)–C(sp2), and C(sp3)–C(sp) cross-coupling reactions using alkylzirconocenes, which are easily generated in situ from terminal or internal unactivated alkenes through hydrozirconation and chain walking. This method is mild and applicable for a large range of substrates including primary, secondary, tertiary alkyl, aryl, alkenyl, alkynyl halides, and a variety of alkenes. Mechanistic studies suggest a novel nickel-catalyzed radical cross-coupling pathway, which represents the first visible-light-induced transformation of alkylzirconocenes.

Transition Metal-Catalyzed Reactions of Alkynyl Halides.

Transition metal-catalyzed reactions of alkynyl halides are a versatile means of synthesizing a wide array of products. Their use is of particular interest in cycloaddition reactions and in constructing new carbon-carbon and carbon-heteroatom bonds. Transition metal-catalyzed reactions of alkynyl halides have successfully been used in [4+2], [2+2], [2+2+2] and [3+2] cycloaddition reactions. Many carbon-carbon coupling reactions take advantage of metal-catalyzed reactions of alkynyl halides, including Cadiot-Chodkiewicz, Suzuki-Miyaura, Stille, Kumada-Corriu and Inverse Sonogashira reactions. All the methods of constructing carbon-nitrogen, carbon-oxygen, carbon-phosphorus, carbon-sulfur, carbon-silicon, carbon-selenium and carbon-tellurium bonds employed alkynyl halides. The purpose of this review is to highlight and summarize research conducted in transition metalcatalyzed reactions of alkynyl halides in recent years. The focus will be placed on cycloaddition and coupling reactions, and their scope and applicability to the synthesis of biologically important and industrially relevant compounds will be discussed. It can be seen from the review that the work done on this topic has employed the use of many different transition metal catalysts to perform various cycloadditions, cyclizations, and couplings using alkynyl halides. The reactions involving alkynyl halides were efficient in generating both carbon-carbon and carbonheteroatom bonds. Proposed mechanisms were included to support the understanding of such reactions. Many of these reactions face retention of the halide moiety, allowing additional functionalization of the products, with some new products being inaccessible using their standard alkyne counterparts.

Ni/Photoredox-Dual-Catalyzed Functionalization of 1-Thiosugars.

A general protocol for functionalization of glycosyl thiols has been reported. This protocol is based on a single-electron Ni/photoredox dual-catalyzed cross coupling between 1-thiosugars and a broad range of aryl bromides and iodides as well as alkenyl and alkynyl halides. This base-free method gives access to a series of functionalized thioglycosides in moderate to excellent yields with a perfect control of the anomeric configuration. Moreover, it has been shown that this methodology may be transposed successfully to the continuous-flow photoredox chemistry.

Visible-Light-Induced Nickel-Catalyzed Cross-Coupling with Alkylzirconocenes from Unactivated Alkenes

Transition-metal-catalyzed cross-coupling reactions between naturally abundant sp3-hybridized carbon centers facilitate access to diverse molecules with complex three-dimensional structures. Organometallic compounds are among one of the most powerful reagents that broadly used in carbon–carbon bonds formations. Although sp2-hybridized organometallic compounds are widely used in cross-couplings, sp3-hybridized organometallic coupling partners are less developed. Herein, we report visible-light-induced single nickel-catalyzed C(sp3)–C(sp3), C(sp3)–C(sp2), and C(sp3)–C(sp) cross-coupling reactions using alkylzirconocenes, which are easily generated in situ from terminal or internal unactivated alkenes through hydrozirconation and chain walking. This method is mild and applicable for a large range of substrates including primary, secondary, tertiary alkyl, aryl, alkenyl, alkynyl halides and a variety of alkenes. Mechanistic studies suggest a novel nickel-catalyzed radical cross-coupling pathway, which represents the first visible-light-induced transformation of alkylzirconocenes.

A convenient route to 1,3-diynes using ligand-free Cadiot-Chodkiewicz coupling reaction at room temperature under aerobic conditions

In this study, we report a copper-catalyzed ligand-free Cadiot-Chodkiewicz coupling reaction. No additives or ligands are required for this Cu-catalyzed C(sp)-C(sp) coupling reaction of terminal alkynes with alkynyl halides. The low cost of copper catalyst, excellent yield of the products, suppression of side-products and mild reaction conditions are the major advantages of this protocol.

Synthesis of fluoroalkylated alkynes via visible-light photocatalysis.

Fluoroalkylated alkynes, which are versatile building blocks for the synthesis of various biologically active organofluorine compounds, were synthesized from easily available alkynyl halides and fluoroalkyl halides by visible-light photocatalysis. Addition of fluoroalkyl radicals to alkynes and subsequent dehalogenation selectively yielded fluoroalkylated alkynes.

Recent trends and applications of the Cadiot-Chodkiewicz reaction.

The Cadiot-Chodkiewicz reaction offers an elegant strategy for the formation of 1,3-diynes via Cu-catalyzed cross-coupling of alkynyl halides with terminal alkynes in the presence of an amine. Since both unsymmetrical and symmetrical diacetylenes are of considerable interest due to their pharmaceutical, biological and synthetic applications, novel developments in the field of the Cadiot-Chodkiewicz reaction are of great importance. C(sp)-C(sp) coupling plays a central role in the total synthesis of many natural products and polyynes. This review is devoted to the new protocols and applications of the Cadiot-Chodkiewicz cross-coupling reaction that have been developed recently (2015-2019).

Palladium‐Catalyzed C2‐Selective Alkynylation of Indoles with Bromoalkynes

AbstractThe Pd(II) catalyzed direct C2 alkynylation of indoles bearing N‐2‐pyrimidyl or N‐2‐pyridinyl moiety as a site‐specific directing group was developed with alkynyl halide. A highly regioselective manner can be achieved on a range of indole substrates with excellent functional group tolerance.

Highly efficient synthesis of 1,2-disubstituted acetylenes derivatives from the cross-coupling reactions of 1-bromoalkynes with organoalane reagents

A Highly efficient route for the synthesis of 1,2-disubstituted acetylene derivatives has been developed by palladium catalyzed cross-couplings of alkynyl halides with (hetero)aryl aluminium reagents under mild conditions. This has given corresponding cross-coupling products good to excellent isolated yields of up to 99%. The aryls bearing electron-donating or electron-withdrawing groups in either alkynylhalides or arylaluminum substrates gave cross-coupling products good yields. This process was simple and easily performed, which provides an efficient method for the synthesis of 1,2-disubstituted acetylenes derivatives. On the basis of the experimental results, a possible catalytic cycle has been proposed.

Palladium‐Catalyzed Ring‐Opening of 2‐Alkylidenecyclobutanols: Stereoselective Synthesis of γ,δ‐Unsaturated Ketones by C−C Bond Cleavage

AbstractA facile synthesis of γ,δ‐unsaturated ketones via palladium‐catalyzed ring‐opening of 2‐alkylidenecyclobutanols with organic halides is described. The key step involves − bond cleavage via palladium‐catalyzed β‐carbon elimination. The desired γ,δ‐unsaturated ketones are obtained in good to excellent yields and broad functional group tolerability. Aryl, heteroaryl, benzyl, and alkynyl halides all readily participate to forge tri‐substituted carbon‐carbon double bond in a stereoselective manner.magnified image

Exploration of Ring‐Closing Enyne Metathesis for the Synthesis of ­Azonino[5,4‐b]indoles

AbstractThe use of the ring‐closing enyne metathesis (RCEYM) as a methodology for the synthesis of the azonino[5,4‐b]indole system, featuring the tricyclic substructure of the alkaloids cleavamine and quebrachamine, has been explored. Three series of enyne substrates were studied for their compatibility with the RCEYM reaction. In addition to the usual substrates bearing either a terminal or an internal alkyne, for the first time enynes with an alkynyl halide moiety were also considered. Although the metathesis cyclization allowed for assembly of the azoninoindole nucleus in all three series, an effective catalytic cycle was only noted for internal alkyne substrates. On the basis of the experimental results, the “yne‐then‐ene” pathway seems to be the mechanism at play in these reactions.

Copper-Catalyzed Cross-Coupling of Fluorinated Vinylstannanes with Organic Halides

β-stannylated propenoates 2 bearing a β-trifluoromethyl group, readily available by hydrostannation of 1, undergo copper(I) catalyzed coupling reactions without any palladium catalyst with allyl, benzyl, alkynyl, acyl and aryl halides. The corresponding adducts were obtained in moderate to good yields with a total retention of the double bond configuration. Interestingly, allyl bromides substituted with a stabilizing group did not led to expected coupling products but to the isomerization products 3. Thus, 31 examples are reported with yields up to 89 %. Finally, a mechanistic study was performed in order to confirm the mechanistic proposal.

Ruthenium(ii)-catalyzed C-H functionalizations on benzoic acids with aryl, alkenyl and alkynyl halides by weak-O-coordination.

C-H arylations of weakly coordinating benzoic acids were achieved by versatile ruthenium(ii) catalysis with ample substrate scope. Thus, user-friendly ruthenium(ii) biscarboxylate complexes modified with tricyclohexylphosphine enabled C-H functionalizations with aryl electrophiles. The unique versatility of the ruthenium(ii) catalysis manifold was reflected by facilitating effective C-H activations with aryl, alkenyl and alkynyl halides.

ChemInform Abstract: Stereoretentive Palladium‐Catalyzed Arylation, Alkenylation, and Alkynylation of 1‐Thiosugars and Thiols Using Aminobiphenyl Palladacycle Precatalyst at Room Temperature.

A general and efficient protocol for the palladium-catalyzed functionalization of mono- and polyglycosyl thiols by using the palladacycle precatalyst G3-XantPhos was developed. The CS bond-forming reaction was achieved rapidly at room temperature with various functionalized (hetero)aryl-, alkenyl-, and alkynyl halides. The functional group tolerance on the electrophilic partner is typically high and anomer selectivities of thioglycosides are high in all cases studied. New sulfur nucleophiles such as thiophenols, alkythiols, and thioaminoacids (cysteine) were also successfully coupled to lead to the most general and practical method yet reported for the functionalization of thiols.

Stereoretentive Palladium‐Catalyzed Arylation, Alkenylation, and Alkynylation of 1‐Thiosugars and Thiols Using Aminobiphenyl Palladacycle Precatalyst at Room Temperature

A general and efficient protocol for the palladium-catalyzed functionalization of mono- and polyglycosyl thiols by using the palladacycle precatalyst G3-XantPhos was developed. The C-S bond-forming reaction was achieved rapidly at room temperature with various functionalized (hetero)aryl-, alkenyl-, and alkynyl halides. The functional group tolerance on the electrophilic partner is typically high and anomer selectivities of thioglycosides are high in all cases studied. New sulfur nucleophiles such as thiophenols, alkythiols, and thioaminoacids (cysteine) were also successfully coupled to lead to the most general and practical method yet reported for the functionalization of thiols.