Directing effects of tethered alkenes in nickel-catalyzed coupling reactions of 1,6-enynes and aldehydes

Nickel-catalyzed reductive coupling reactions of aldehydes and 1,6-enynes proceed in excellent regioselectivity in the absence of a phosphine, and the use of a monodentate phosphine additive leads to the formation of the opposite regioisomer with equally high selectivity. Both products are the result of the same fundamental mechanism, with the inversion of regioselectivity being the result of stereospecific ligand substitution at the metal center.     

Enantioselective and regioselective nickel-catalyzed multicomponent coupling of chiral allenes, aromatic aldehydes, and silanes

A detailed account of the development of a recently developed, nickel-catalyzed multicomponent coupling of chiral allenes, aromatic aldehydes, and silanes is described. The axial chirality of the allene is transferred completely to the product, a trisubstituted Z-allylic alcohol protected as a silyl ether. A very high preference for sp rather than sp² coupling is observed, and differentially substituted allenes undergo highly site-selective coupling. These transformations represent the first enantioselective multi-component coupling processes of allenes.     

Mechanistic study of nickel-catalyzed ynal reductive cyclizations through kinetic analysis

The mechanism of nickel-catalyzed, silane-mediated reductive cyclization of ynals has been evaluated. The cyclizations are first-order in [Ni] and [ynal] and zeroth-order in [silane]. These results, in combination with the lack of rapid silane consumption upon reaction initiation, are inconsistent with mechanisms involving reaction initiation by oxidative addition of Ni(0) to the silane. Silane consumption occurs only when both the alkyne and aldehyde are present. Mechanisms involving rate-determining oxidative cyclization to a metallacycle followed by rapid reaction with the silane are consistent with the data obtained.     

Palladium-catalyzed tandem cyclization/Suzuki coupling of 1,6-enynes

[reaction: see text] A Pd(0)-catalyzed 1,6-enyne cyclization-arylation cascade reaction was effected via pi-allylpalladium intermediate formation and subsequent Suzuki coupling to give cyclic products with stereodefined exocyclic double bonds.     

Ligand-dependent scope and divergent mechanistic behavior in nickel-catalyzed reductive couplings of aldehydes and alkynes

A new procedure for catalytic reductive coupling of aldehydes and alkynes has been developed. The procedure uses Ni(COD)2 with an imidazolium carbene ligand as the catalyst and triethylsilane as the reducing agent. A crossover deuterium-labeling experiment illustrated that variants involving trialkyl phosphines and imidazolium carbene ligands with a nickel catalyst proceed by different mechanisms.     

Mechanistic and stereochemical aspects of the asymmetric cyclocarbonylation of 1,6-enynes with rhodium catalysts

NMR and kinetic investigations of the cyclocarbonylation of 1,6-enynes with cationic rhodium(i) catalysts, modified with atropisomeric diphosphines, disprove the involvement of carbonyl species for 1,6-enyne activation; low-temperature catalysis, with molecular sieves as the carbon monoxide reservoir, is highly enantioselective (ee up to 97%).     

Highly regioselective, catalytic asymmetric reductive coupling of 1,3-enynes and ketones

[reaction: see text] Highly regioselective, catalytic asymmetric reductive coupling reactions of 1,3-enynes and ketones have been achieved using catalytic amounts of Ni(cod)(2) and a P-chiral, monodentate ferrocenyl phosphine ligand. These couplings represent the first examples of catalytic, intermolecular reductive coupling of alkynes and ketones, enantioselective or otherwise, and afford synthetically useful 1,3-dienes possessing a quaternary carbinol stereogenic center in up to 70% ee.     

cis-chloropalladation of 1,6-enynes

A PdCl(2)-catalyzed cis-chloropalladation-cyclization reaction of various 1,6-enyne substrates was developed. This Pd-catalyzed enyne cyclization reaction represents a new route for the synthesis of stereodefined alpha-halomethylene-gamma-butyrolactones, lactams, tetrahydrofurans, and cyclopentanes. A mechanism involving a neighboring coordination group is proposed to explain the experiment results.     

Highly enantioselective and regioselective nickel-catalyzed coupling of allenes, aldehydes, and silanes

A complex derived from Ni(cod)2 and NHC-IPr catalyzes a three-component coupling reaction involving allenes, aldehydes, and organosilanes and transfers the axial chirality of the allene to a stereogenic center in the product with very high fidelity. An unexpected regioselectivity is observed; favored are allylic rather than homoallylic alcohol derivatives, corresponding to the unusual process of coupling two electrophilic atoms: the allene sp and aldehyde carbon atoms. In all cases, high enantioselectivity, high Z/E selectivity, and, with differentially substituted allenes, high site selectivity are observed. This transformation represents the first enantioselective multicomponent coupling process of allenes.     

Nickel-catalyzed reductive coupling of unactivated alkyl bromides and aliphatic aldehydes

A mild, convenient coupling of aliphatic aldehydes and unactivated alkyl bromides has been developed. The catalytic system features the use of a common Ni(ii) precatalyst and a readily available bioxazoline ligand and affords silyl-protected secondary alcohols. The reaction is operationally simple, utilizing Mn as a stoichiometric reductant, and tolerates a wide range of functional groups. The use of 1,5-hexadiene as an additive is an important reaction parameter that provides significant benefits in yield optimizations. Initial mechanistic experiments support a mechanism featuring an alpha-silyloxy Ni species that undergoes formal oxidative addition to the alkyl bromide via a reductive cross-coupling pathway.

Aliphatic aldehydes and alkyl bromides are reductively coupled using nickel catalysis. A BiOX ligand and 1,5-hexadiene paired with a silyl chloride and Mn as the terminal reductant are important features of the process.     

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.     

Hydrogen-mediated C-C bond formation: catalytic regio- and stereoselective reductive condensation of alpha-keto aldehydes and 1,3-enynes

Hydrogenation of 1,3-enynes in the presence of alpha-keto aldehydes using cationic Rh(I) catalysts enables regio- and stereoselective reductive coupling to the acetylenic terminus of the enyne to afford (E)-2-hydroxy-3,5-dien-1-one products. Reductive condensation of 1-phenyl but-3-en-1-yne 1a with phenyl glyoxal 2a performed under an atmosphere of D(2) provides the product of mono-deuteration, (E)-2-hydroxy-3-deuterio-3,5-dien-1-one deuterio-3a, in 85% yield. Competition experiments involving catalytic hydrogenation of phenyl glyoxal in the presence of equimolar quantities of 1,4-diphenylbutadiene and 1,4-diphenylbut-3-en-1-yne 10a, as well as 1,4-diphenylbut-3-en-1-yne 10a and 1,4-diphenylbutadiyne, are chemoselective for coupling to the more highly unsaturated partner, suggesting a preequilibrium involving precoordination and exchange of the pi-unsaturated pronucleophiles with the catalyst prior to C-C bond formation, as well as a preference for coordination of the most pi-acidic reacting partner, as explained by the Dewar-Chatt-Duncanson model for alkyne coordination.     

An extension of nickel-catalyzed reductive coupling between tertiary alkyl halides with allylic carbonates

The nickel catalyzed reductive coupling of allylic carbonates with chloro-cyclotryptamine analogs to construct sterically congested all C(sp³) quaternary centers has been achieved with emphasis on the substrate scope. And the using of dienyl methyleneyl carbonates coupling with a variety of tertiary alkyl halides furnished the dienylated products improved the reaction's applicability.     

Hydroxyl-directed cyclizations of 1,6-enynes

The palladium-catalyzed, hydroxyl-directed cyclization reactions of 1,6-enynes provide a highly diastereoselective process for the syntheses of stereochemically defined cyclopentanes. Consistently high levels of cis-selectivity are possible using homopropargyl alcohols in contrast to the corresponding propargyl alcohols. Hydroborylative enyne cyclizations coupled with this directing group effect provide a useful method for the syntheses of multifaceted compounds bearing all carbon quaternary centers.     

Photomediated reductive coupling of nitroarenes with aldehydes for amide synthesis

In view of the widespread significance of amide functional groups in organic synthesis and pharmaceutical studies, an efficient and practical synthetic protocol that avoids the use of stoichiometric activating reagents or metallic reductants is highly desirable. A straight-forward pathway to access amides from abundant chemical feedstock would offer a strategic advantage in the synthesis of complex amides. We herein disclose a direct reductive amidation reaction using readily available aldehydes and nitroarenes enabled by photo-mediated hydrogen atom transfer catalysis. It avoids the use of metallic reductants and production of toxic chemical waste. While aldehydes represent a classic class of electrophilic synthons, the corresponding nucleophilic acyl radicals could be directly accessed by photo hydrogen atom transfer catalysis, enabling polarity inversion. Our method provides an orthogonal strategy to conventional amide couplings, tolerating nucleophilic substituents such as free alcohols and sensitive functional groups to amines such as carbonyl or formyl groups. The synthetic utilization of this reductive amidation is demonstrated by the late-stage modification of complex biologically active molecules and direct access of drug molecules leflunomide and lidocaine.

In view of the widespread significance of amide functional groups in organic synthesis and pharmaceutical studies, an efficient and practical synthetic protocol that avoids the use of stoichiometric activating reagents or metallic reductants is highly desirable.     

Regioselective reductive coupling of alkynes and aldehydes leading to allylic alcohols

Treatment of a mixture of a terminal alkyne and an aldehyde with CrCl(2) and a catalytic amount of NiCl(2) and triphenylphosphine in the presence of water in DMF at 25 degrees C gives a 1,2-disubstituted allylic alcohol regioselectively.     

Rhodium-catalyzed reductive cyclization of 1,6-diynes and 1,6-enynes mediated by hydrogen: catalytic C-C bond formation via capture of hydrogenation intermediates

Catalytic hydrogenation of carbon-, nitrogen- and oxygen-tethered 1,6-diynes 1a-9a and 1,6-enynes 10a-18a using cationic Rh(I) precatalysts at ambient temperature and pressure enables reductive carbocyclization to afford 1,2-dialkylidene cyclopentanes 1b-9b and monoalkylidene cyclopentanes 10b-18b, respectively, in good to excellent yields and as single alkene stereoisomers. Notably, the 1,3-diene and alkene containing cyclization products 1b-9b and 10b-18b are not subject to over-reduction under the conditions of catalytic hydrogenation in which they are formed. Reductive cyclization 1,6-diyne 1a and 1,6-enyne 10a performed under an atmosphere of D(2) provides the carbocyclization products deuterio-1b and deuterio-10b, respectively, which incorporate two deuterium atoms. The collective data are consistent with a catalytic mechanism involving heterolytic activation of elemental hydrogen (H(2) + Rh(+)X(-) --> Rh-H + HX) followed by Rh(I)-mediated oxidative cyclization of the 1,6-diyne or 1,6-enyne substrates to afford (hydrido)Rh(III)-based metallocyclopentadiene and metallocyclopentene intermediates, respectively. These transformations represent the first examples of metal-catalyzed reductive carbocyclization mediated by hydrogen.     

Palladium-catalyzed tandem cyclization/Suzuki coupling of 1,6-enynes: reaction scope and mechanism

A palldium(0)-catalyzed tandem cyclization/Suzuki coupling reaction of various 1,6-enyne substrates was developed. This Pd-catalyzed enyne cyclization reaction represents a new process for the synthesis of stereodefined alpha-arylmethylene-gamma-butyrolactones, lactams, multifunctional tetrahydrofurans, pyrrolidines, and cyclopentanes. The mechanism of the reaction was studied by the employment of different enyne isomers and boronic acids; a pi-allyl palladium intermediate was suggested to explain the formation of the cyclic products. The stereochemistry of this reaction can be well explained by a chairlike transition state.