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.     

Nickel-catalyzed coupling of terminal allenes, aldehydes, and silanes

The development of a nickel-catalyzed coupling of terminal allenes, aldehydes, and silanes is described. This transformation selectively provides 1,1-disubstituted allylic alcohols, protected as a silyl ether. The choice of the reducing agent is essential for achieving selectivity in this coupling process. A trialkylphosphine (Cyp₃P) and an N-heterocyclic carbene (IPr) are complementary in this reaction.     

Highly regioselective and stereoselective allylation of aldehydes via palladium-catalyzed in situ hydrostannylation of allenes

[reaction: see text] Highly regio- and stereoselective allylation of aldehydes by allenes proceeds smoothly in aqueous/organic media in the presence of PdCl(2)(PPh(3))(2), HCl, and SnCl(2). The reaction likely occurs via hydrostannylation of allenes and allylation of aldehydes by the in situ generated allyltrichlorotins to afford the final products.     

Highly enantioselective nickel-catalyzed hydrovinylation with chiral phosphoramidite ligands

Readily available chiral phosphoramidites are a promising class of ligands for nickel-catalyzed asymmetric hydrovinylation of vinyl arenes. Cooperative effects are operative when ligands with more than one element of chirality are used. Choosing the proper stereochemistry in each part of the modular ligand system leads to high chemoselectivities and excellent enantioselectivities up to 94%. Moreover, the catalysts derived from these ligands proved extremely efficient and remarkably robust performing up to 8300 catalytic turnovers at an initial turnover frequency beyond 1000 h-1. The large potential for structural variation and their straightforward synthesis make the phosphoramidites currently the best lead structure for catalyst development in this field.     

Cobalt- and nickel-catalyzed regio- and stereoselective reductive coupling of alkynes, allenes, and alkenes with alkenes

Transition-metal-catalyzed coupling of two different C-C pi components through a metallacycle intermediate is a highly atom economical method to construct C-C bonds in organic synthesis. The metal-catalyzed coupling of an alkene and alkyne generally gives an Alder-ene or reductive coupling product. In this article, we focus on the cobalt- and nickel-catalyzed reductive coupling of alkynes, allenes, and alkenes with alkenes. These reductive coupling reactions provide convenient methods for the synthesis of various alkenes, dienes, functionalized alkanes, lactones, lactams, and cyclic alcohols in a highly regio- and stereoselective manner. A chemselective formation of metallacyclopentene intermediate from the two different C-C pi components and a low-valence metal species plays a key role for the high regio- and stereoselectivity of the catalytic reaction.     

Highly regioselective synthesis of trisubstituted allenes via lithiation of 1-aryl-3-alkylpropadiene, subsequent transmetalation, and Pd-catalyzed Negishi coupling reaction

A novel methodology for the synthesis of trisubstituted allenes is reported. Lithiation of 1-aryl-3-alkylpropadienes and subsequent transmetalation with zinc bromide followed by Pd-catalyzed Negishi coupling reactions with halides afforded the corresponding trisubstituted allenes in a highly regioselective fashion with moderate to excellent yields. A plausible regioselective lithiation mechanism was proposed on the basis of deuterium labeling experiments.     

Highly regioselective palladium/copper-catalysed cross-coupling reactions of terminal alkynes and allenes

The Pd/Cu-catalysed cross-coupling reaction of heterocyclic terminal alkynes and allene/allenyl heterocycles affords novel trisubstituted en-ynes in good yield.     

Mechanistic implications of nickel-catalyzed reductive coupling of aldehydes and chiral 1,6-enynes

[reaction: see text]. A study of nickel-catalyzed reductive coupling reactions of aldehydes and chiral 1,6-enynes has provided evidence for three distinct mechanistic pathways that govern regioselectivity in this transformation. In the absence of a phosphine additive, high regioselectivity and high diastereoselectivity are obtained as a direct result of coordination of both the alkyne and the olefin to the metal center during the C-C bond-forming step.     

Highly enantioselective fluoromalonate addition to α,β-unsaturated aldehydes

A highly enantioselective organocatalytic fluoromalonate addition to α,β-unsaturated aldehydes is reported. The reaction is catalyzed by simple and commercially available secondary amines, affording the corresponding 1,4-adducts with high yields and enantioselectivities.     

Highly enantioselective and regioselective substitution of Morita-Baylis-Hillman carbonates with nitroalkanes

A highly enantioselective and regioselective substitution reaction of the Morita-Baylis-Hillman (MBH) carbonates with nitroalkanes catalyzed by a quinidine-derived tertiary amine-thiourea catalyst has been developed. The described method, which is different from most organocatalytic allylic substitutions of the MBH adducts to date, represents a novel approach to regioselectively functionalize the MBH adducts.     

Nickel-catalyzed enantioselective three-component coupling of bis-1,3-dienes, aldehydes, and dimethylzinc

Nickel-catalyzed three-component coupling of bis-1,3-dienes, aldehyde, and dimethylzinc was investigated. In the presence of catalytic amounts of Ni(acac)2 and PPh3, bis-1,3-dienes smoothly react with an aldehyde and dimethylzinc via intramolecular cyclodimerization of bis-1,3-diene moiety. The reaction proceeds through formation of a cyclic bis-allylnickel complex, insertion of an aldehyde, and addition of dimethylzinc to the resulting oxanickellacycle intermediate. An enantioselective coupling was also achieved by the use of a chiral monodentate phosphine ligand, H-MOP.     

Highly enantioselective alpha-aminoxylation of aldehydes and ketones in ionic liquids

As the first example for the synthesis of optically active alpha-hydroxyaldehydes and alpha-hydroxyketones in ionic liquids, we applied RTILs into L-proline catalyzed direct enantioselective alpha-aminoxylation of both aldehydes and ketones successfully. This protocol features a number of advantages, such as recycling of green solvents and chiral organocatalyst, high yields, excellent enantioselectivities, short reaction times, and broad substrate scope.     

Highly regioselective palladium-catalyzed annulation reactions of heteroatom-substituted allenes for synthesis of condensed heterocycles

We have developed a highly regioselective synthesis of heterocycles via palladium-catalyzed annulation reaction of heteroatom-substituted allenes. Various aryl halides were reacted and one regioisomer was observed exclusively in all reactions. In addition, subsequent functionalizations of annulated products were carried out using alkyl metal reagents, and the introduction of alkyl moieties was accomplished.     

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.     

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.     

Highly enantioselective phenylacetylene additions to both aliphatic and aromatic aldehydes

The readily available and inexpensive BINOL in combination with Ti(O(i)Pr)(4) is found to catalyze the reaction of an alkynylzinc reagent with various types of aldehydes including aliphatic aldehydes, aromatic aldehydes, and other alpha,beta-unsaturated aldehydes to generate chiral propargyl alcohols with 91-99% ee at room temperature. No previous chiral catalysts have exhibited such a broad scope of enantioselectivity with respect to the type of aldehydes for this reaction. [reaction: see text]