Ni-catalyzed ligand-controlled divergent and selective synthesis

Scaffold diversity is a key feature of a compound library and plays a pivotal role in its success in biological screening. Therefore,it is highly desirable to develop efficient strategies to rapidly construct structurally distinct and diverse “privileged” molecular scaffolds, thereby giving rise to compound libraries with selective and differing biological activities. This review covers recent efforts in this emerging field of Ni-catalyzed divergent and selective synthesis, and will focus on rea...     

anti-1,2-Diols via Ni-catalyzed reductive coupling of alkynes and alpha-oxyaldehydes

[reaction: see text] Ni-catalyzed reductive coupling of aryl alkynes (1) and enantiomerically enriched alpha-oxyaldehydes (2) afford differentiated anti-1,2-diols (3) with high diastereoselectivity and regioselectivity, despite the fact that the methoxymethyl (MOM) and para-methoxybenzyl (PMB) protective groups typically favor syn-1,2-diol formation in carbonyl addition reactions of this family of aldehydes.     

Selective Ni-catalyzed cross-electrophile coupling of alkynes,fluoroalkyl halides,and vinyl halides

We report a Ni-catalyzed three-component cross-electrophile coupling of alkynes with alkenyl halides and fluoroalkyl halides to generate fluoroalkyl-incorporated 1,3-dienes. This mild and operationally simple protocol is distinguished by its broad substrate scope and excellent chemo-, regio-, and stereo-selectivity, offering a new and organometallic agent-free platform for the construction of fluoroalkyl-incorporated diene motifs. Preliminary mechanistic studies have been conducted to probe the potential reaction pathway.     

Ni-catalyzed intramolecular cycloaddition of methylenecyclopropanes to alkynes

Ni-catalyzed intramolecular cycloaddition of methylenecyclopropanes (MCPs) to arkylalkynes via proximal bond cleavage is reported. The reaction provides a facile route for the preparation of cyclopenta[a]indene derivatives.     

Ni-catalyzed, ZnCl(2)-assisted domino coupling of enones, alkynes, and alkenes

A Ni(0)/ZnCl(2) system effectively promotes the coupling of enones and alkene-tethered alkynes. In the reaction with 1,6-enynes, the oxidative cyclization of Ni(0) species on enones across the alkyne part followed by ZnCl(2)-promoted cleavage generates alkenylnickel intermediates. Subsequent migratory insertion of the tethered alkene occurs with 5-exo-cyclization. When the resulting sigma-alkylnickel intermediates have beta-hydrogen atoms, the reaction terminates by beta-hydrogen elimination to provide cyclopentane derivatives. On the other hand, a sigma-alkylnickel intermediate that does not have beta-hydrogen atoms undergoes the insertion of a second alkene unit to cause a domino effect via a three-fold C-C bond formation process with and without the cleavage of one C-C bond.     

Highly selective catalytic intermolecular reductive coupling of alkynes and aldehydes

Alkynes (internal and terminal) and aldehydes (aromatic and aliphatic) are reductively coupled in a single catalytic reaction to yield di- and trisubstituted allylic alcohols with high stereoselectivity and regioselectivity. In most cases, a 1:1 ratio of alkyne to aldehyde is sufficient for efficient coupling. The yield and regioselectivity are strongly dependent on the phosphine ligand, but the allylic alcohols formed are invariably the products of cis addition to the alkyne.     

Ni-catalyzed addition reaction of allylic selenides to alkynes

Nickel complex catalysts, Ni(cod)₂-2PPh₃ and Ni(cod)₂-dppb systems in particular, catalyze the addition reactions of phenyl allyl selenide to terminal alkynes to regioselectively afford 2-phenylseleno-1-allyl-1-alkenes in good to excellent yields. A mechanism that involves a η³-allyl-nickel complex is proposed on the basis of isolation, crystal structure determination and reactivity study of the complex.     

Propargylamine synthesis by copper-catalyzed oxidative coupling of alkynes and tertiary amine N-oxides

An efficient method for synthesizing N,N-dimethylpropargylamines is described. The synthesis exploited the Cu(II)-catalyzed oxidative alkynylation reaction of trimethylamine N-oxides with alkynes in the absence of external oxidant. Both aromatic and aliphatic alkynes were utilized to achieve the corresponding products in moderate to excellent yields. The reaction conditions tolerated ester, hydroxy, and aldehyde groups.     

Facile synthesis of fluorinated α-imino alkynes by the coupling reaction of imidoyl iodides with terminal alkynes

A series of N-arylbromodifluoroacetimidoyl iodides and 1-alkynes were converted into α-imino alkynes by using Pd(Ph₃)₂Cl₂/CuI as the catalyst under mild conditions. The reaction proceeded smoothly to give the coupling products in good to excellent yields.     

Simple and convenient synthesis of fluoroalkenes via direct coupling of alcohols,alkynes and fluoroboric acid under metal-free conditions

A novel and convenient method for the synthesis of fluoroalkenes from alkynes, alcohols and fluoroboric acid has been developed under mild conditions. The present protocol provides an attractive approach to access various fluoroalkenes from simple and commercially available starting materials without any metal catalyst, ligand or additive.     

Efficient Fe/I2/NaI mediated synthesis of alkenyl iodides through direct coupling of alcohols and alkynes

A new and efficient method for the synthesis of alkenyl iodides through direct coupling of alcohols and alkynes has been developed in the presence of iron powder, I₂, and NaI. This methodology not only provides an attractive approach to alkenyl iodides, but also expands the application of iron in synthetic chemistry.     

One-pot synthesis of polyimides via Ni-catalyzed coupling of bis(chlorophthalimide)s

A one-pot synthesis method for the preparation of polyimides containing biphenyl units was developed via nickel-catalyzed coupling reaction of bis(chlorophthalimide)s which were prepared from chlorophthalic anhydrides and diamines in xylene. The resulting polyimides had inherent viscosities of above 0.60 dL g⁻¹. In the meantime, the copolymerizations from a mixture of three isomeric bis(chlorophthalimide)s gave the polymers with inherent viscosities of 0.36-0.55 g dL⁻¹. The solubility and film formability of the copolymers were better than those of homopolymers from bis(4-chlorophthalimide). The 10% weight loss of these polyimides was between 470 and 531 °C.     

Oxidant-free direct coupling of internal alkynes and 2-alkylpyridine via double C-H activations by alkylhafnium complexes

We have developed a novel oxidant-free direct cross-coupling reaction of 2,6-lutidine and internal alkynes leading to five-membered carbocyclic compounds mediated by nonmetallocene cationic hafnium alkyl complexes. Mechanistic studies of the coupling reaction showed that the reaction begins with C(sp(3))-H bond activation via σ-bond metathesis, after which the coordinatively unsaturated hafnium center mediates further insertion, migration, and β-H elimination reactions to give five-membered carbocycles from readily available substrates.     

Palladium-catalyzed multicomponent coupling of alkynes, imines, and acid chlorides: a direct and modular approach to pyrrole synthesis

A new palladium-catalyzed method to prepare pyrroles directly from three basic building blocks-imines, alkynes, and acid chlorides-is described. This approach provides a straightforward method both to prepare pyrroles in one step and to diversify their structure by simple variation of any of the three starting materials. Mechanistic studies suggest that this process occurs via a complex series of eight individual steps, and this is discussed.     

Copper-, ligand- and solvent-free synthesis of ynones by coupling acid chlorides with terminal alkynes

A general and efficient copper-, ligand- and solvent-free synthesis of ynones by coupling of a wide range of acid chlorides with terminal alkynes catalyzed by palladium(II) acetate at room temperature is reported.     

Base-mediated selective synthesis of diversely substituted N-heterocyclic enamines and enaminones by the hydroamination of alkynes

Regio- and stereoselective alkynylation of various N-heterocycles 1a-l using potassium and cesium salts in DMSO is described. Terminal alkynes 2a-k and internal alkynes 4a-f provided the kinetically stable Z-enamines 3a-l and 5a-i in good to excellent yields using KOH at 120 °C. Addition of heterocyclic amines to 1,3- and 1,4-diethynylbenzene 6a-b provided the mixture of E/Z isomers with KOH; however, with Cs(2)CO(3) selectively Z-isomers 7ab-db were obtained by the hydroamination at one triple bond. This developed methodology also provides an easy and novel access for the synthesis of enaminones 10a-c. The detailed work also supports the formation of cis-isomer by preferential addition of o-haloarylalkynes followed by intramolecular C2 arylation in the copper-catalyzed tandem synthesis of indolo and pyrrolo[2,1-a]isoquinolines.     

Stereodefined construction of trisubstituted alkenes by direct coupling reaction of allylating agents, alkynes, and organoboranes

Tandem reaction: The Pd-catalyzed three-component coupling reaction of an allylic alcohol, terminal alkyne, and organoborane to give (E)-1-substituted 2-alkyl-1,4-pentadienes, involving geminal allylation and alkylation at the acetylenic terminal carbon, is described. Bis-diene undergoes a similar multicomponent coupling reaction with acetylene and organoborane, involving cyclization of bis-π-allylpalladium, to form trans-allyl pentadienyl cyclic and heterocyclic compounds with excellent regio- and stereoselectivities (see scheme).     

Rapid access to t-butylalkylated olefins enabled by Ni-catalyzed intermolecular regio- and trans-selective cross-electrophile t-butylalkylation of alkynes

Among the carbo-difunctionalization of alkynes, the stereoselective dialkylation of alkynes is the most challenging transformation due to associated competitive side reactions and thus remains underdeveloped. Herein, we report the first Ni-catalyzed regio- and trans-selective cross-dialkylation of alkynes with two distinct alkyl bromides to afford olefins with two aliphatic substituents. The reductive conditions circumvent the use of organometallic reagents, enabling the cross-dialkylation process to occur at room temperature from two different alkyl bromides. This operationally simple protocol provides a straightforward and practical access to a wide range of stereodefined dialkylated olefins with broad functional group tolerance from easily available starting materials.

A direct reductive cross-dialkylation of alkynes is achieved to afford trans-dialkylated olefins using two distinct alkyl bromides. The reaction undergoes with exclusive chemo-, regio- and stereoselectivity without the use of organometallic reagents.     

Highly enantioselective direct reductive coupling of conjugated alkynes and alpha-ketoesters via rhodium-catalyzed asymmetric hydrogenation

Catalytic hydrogenation of 1,3-enynes 1a-7a in the presence of ethyl pyruvate and related activated ketones using chirally modified cationic rhodium catalysts results in reductive coupling to afford dienylated alpha-hydroxy esters 1b-7b and 3c-3f with exceptional levels of regio- and enantiocontrol. These studies represent the first highly enantioselective direct catalytic reductive couplings of alkynes to ketones. As illustrated by the conversion of 6b to 6c-6h, the diene containing the side chain of the coupling products is subject to diverse chemo- and regioselective manipulation. Reductive coupling of enyne 6a and ethyl pyruvate using elemental deuterium provides the monodeuterated product deuterio-6b, consistent with a catalytic mechanism involving alkyne-carbonyl oxidative coupling followed by hydrogenolytic cleavage of the resulting oxametallacycle, as corroborated by ESI-MS analysis.     

Ni-catalyzed arylation of alkynes with organoboronic acids and aldehydes to access stereodefined allylic alcohols

A new, efficient and practical method for the three-component arylative coupling of aldehydes, alkynes and arylboronic acids has been developed through nickel catalysis. This transformation provides diverse Z-selective tetrasubstituted allylic alcohols without the use of any aggressive oragnometallic nucleophiles or reductants. Moreover, benzylalcohols are viable coupling partners via oxidation state manipulation and arylative coupling in one single catalytic cycle. This reaction features a direct and flexible approach for the preparation of stereodefined arylated allylic alcohols with broad substrate scope under mild conditions. The utility of this protocol is demonstrated through the synthesis of diverse biologically active molecular derivatives.

A direct, efficient and practical method for the three-component arylative coupling of aldehydes (or the corresponding alcohols), alkynes and arylboronic acids has been developed through nickel catalysis.