From allylic alcohols to aldols through a new nickel-mediated tandem reaction: synthetic and mechanistic studies

Nickel hydride type complexes have been successfully developed as catalysts for the tandem isomerization-aldolization reaction of allylic alcohols with aldehydes. Optimization of the reaction conditions has shown that a cocatalyst, such as MgBr2, has a very positive effect on the kinetics of the reaction and in the yields of aldols. Under such optimized conditions {[NiHCl(dppe)] + MgBr(2) at 3-5 mol %)}, this reaction affords the aldols in good to excellent yields. It is a full-atom-economy-type reaction that occurs under mild conditions. Furthermore, it has a broad scope for the allylic alcohols and it is compatible with a wide range of aldehydes, including very bulky derivatives. The reaction is completely regioselective, but it exhibits a low stereoselectivity, except for allylic alcohols with a bulky substituent at the carbinol center. The use of chiral nonracemic catalysts was not successful, affording only racemic compounds. However, it was possible to use asymmetric synthesis for the preparation of optically active aldols. Various mechanistic studies have been performed using, for instance, a deuterated alcohol or a deuterated catalyst. They gave strong support to a mechanism involving first a transition-metal-mediated isomerization of the allylic alcohol into the free enol, followed by the addition of the latter intermediate onto the aldehyde in an "hydroxyl-carbonyl-ene" type reaction. These results confirm that allylic alcohols can be considered as new and useful partners in the development of the aldol reaction.     

Nickel‐Catalyzed Allylic Alkylation with Diarylmethane Pronucleophiles: Reaction Development and Mechanistic Insights

Palladium‐catalyzed allylic substitution reactions are among the most efficient methods to construct C?C bonds between sp³‐hybridized carbon atoms. In contrast, much less work has been done with nickel catalysts, perhaps because of the different mechanisms of the allylic substitution reactions. Palladium catalysts generally undergo substitution by a “soft”‐nucleophile pathway, wherein the nucleophile attacks the allyl group externally. Nickel catalysts are usually paired with “hard” nucleophiles, which attack the metal before C?C bond formation. Introduced herein is a rare nickel‐based catalyst which promotes substitution with diarylmethane pronucleophiles by the soft‐nucleophile pathway. Preliminary studies on the asymmetric allylic alkylation are promising.     

Asymmetric Allylic Alkylation of β‐Ketoesters with Allylic Alcohols by a Nickel/Diphosphine Catalyst

Asymmetric allylic alkylation of β‐ketoesters with allylic alcohols catalyzed by [Ni(cod)₂]/(S)‐H₈‐BINAP was found to be a superior synthetic protocol for constructing quaternary chiral centers at the α‐position of β‐ketoesters. The reaction proceeded in high yield and with high enantioselectivity using various β‐ketoesters and allylic alcohols, without any additional activators. The versatility of this methodology for accessing useful and enantioenriched products was demonstrated.     

Pentacoordinated Carboxylate π‐Allyl Nickel Complexes as Key Intermediates for the Ni‐Catalyzed Direct Amination of Allylic Alcohols

Direct amination of allylic alcohols with primary and secondary amines catalyzed by a system made of [Ni(1,5‐cyclooctadiene)₂] and 1,1′‐bis(diphenylphosphino)ferrocene was effectively enhanced by adding nBu₄NOAc and molecular sieves, affording the corresponding allyl amines in high yield with high monoallylation selectivity for primary amines and high regioselectivity for monosubstituted allylic alcohols. Such remarkable additive effects of nBu₄NOAc were elucidated by isolating and characterizing some nickel complexes, manifesting the key role of a charge neutral pentacoordinated η³‐allyl acetate complex in the present system, in contrast to usual cationic tetracoordinated complexes earlier reported in allylic substitution reactions.     

Nickel‐Catalyzed Allylmethylation of Alkynes with Allylic Alcohols and AlMe3: Facile Access to Skipped Dienes and Trienes

We present herein an unprecedented allylative dicarbofunctionalization of alkynes with allylic alcohols. This simple catalytic procedure utilizes commercially available Ni(COD)₂, triphenylphosphine, and inexpensive reagents, and delivers valuable skipped dienes and trienes with an all‐carbon tetrasubstituted alkene unit in a highly stereoselective fashion. Preliminary mechanistic studies support the reaction pathway of allylnickelation followed by transmetalation in this dicarbofunctionalization of alkynes.     

Cover Picture: The Chemistry of Escapin: Identification and Quantification of the Components in the Complex Mixture Generated by an L‐Amino Acid Oxidase in the Defensive Secretion of the Sea Snail Aplysia californica (Chem. Eur. J. 7/2009)

Defensive chemicals such as the ink secretion of this marine gastropod mollusk—the sea hares Aplysia californica—are released following attacks from predators for protection. One might expect these secretions to be complex mixtures of products, given that they must work against a diversity of predators. In their Full Paper on page 1597 ff. , C. D. Derby et al. describe some of the chemical complexity of the ink of sea hares attributable to the enzyme “escapin”. Escapin is an L ‐amino acid oxidase that oxidatively deaminates its major substrate, L ‐lysine, to produce an equilibrium mixture of the molecules shown in this image. Photograph from Genny Anderson (Santa Barbara City College).