CuH-Catalyzed Conjugate Addition-intermolecular Aldol Addition Domino Reaction

Copper hydride, typically [CuH(PPh3)]6, has been used in conjugate addition ofα,β-unsaturated carbonyl compounds selectively. It has also been used to catalyze conjugateaddition of silanes to α,β-unsaturated carbonyls. The products, reduction of the carbon-carbondouble bond in the α,β-unsaturated carbonyl compounds can be obtained via the workup ofthe enolate intermediates or hydrolysis of the enol ethers formed. Instead of being treated withwater, the enolate can react with other functional groups directly, and consequently, a dominoreaction proceeds. This results in simplifying the operation, minimizing the separationprocedures, and improving efficiency and yield. In spite that domino reactions based onCuH-catalyzed conjugate reduction have been reported, much attention is focused on theintramolecular domino reaction. On the other side, the intermolecular alternative is relativelyunexplored, and the control of stereoselectivities of intermolecular is more challenging thanthat of intramolecular reactions. In addition, it is one of the core research fields in catalysis tofind new efficiently catalytic reactions.Studied in this paper are domino reactions initiallized by CuH-catalyzed conjugatereduction of unsaturated carbonyls. Conjugate reduction-intermolecular aldol addition dominoreactions among acrylate or crotonate, ketone and silane can be accomplished in the presenceof CuH generated from a copper complex and a silane. Different phosphine ligands were usedto stablize the CuH and adjust its reactivity as well as reaction selectivity. UsingCuH-DPEphos catalyst, high yields of the domino products could be achieved with moderatediastereoselectivity (d.r.<66/34, anti/syn) when methyl acrylate or crotonate was used andporfoming the reaction at room temperature. The diastereoselectivity could be improved viautilization of lower reaction temperature, bulky unsaturated ester and Xantphos as the ligand.Reaction of t-butyl acrylate with substituted acetophenone at-30℃using CuH derived fromCuF(PPh3)3·2MeOH and Xantphos gave d.r. up to96/4(anti/syn), which represents thehighest d.r. value for this kind of reaction. Forty three β-hydroxy carboxylates, including35new compounds, have been obtained via this kind of reaction.A new kind of domino reaction, CuH-catalyzed conjugate reduction-aldoladdition-lactonization reaction, has been discovered. The three-step reaction proceeds among(substituted) acetophenone, dimethyl maleate and a silane in the presence of CuH, yieldinglactones bearing a β-ester group. Higher yields could be obtained under the catalysis of CuH-DPEphos or CuH-Xantphos than those using CuH-DPE or CuH-DPP. The configurationof the unsatured diester is important to the reaction. While maleate is reactive to the reaction,fumarate is latent. Very low conversion of fumarate is observed. On the other hand, itaconateis highly reactive. The stereoselectivity of the domino reaction using maleate or itaconate asthe CuH acceptor is affected by substituted carbonyls in some sense. Moderatediastereoselectivties are obtained for most reactions. In addition to aromatic ketones, alphaticketones can participate in the domino reaction. The asymmetric version of the three-stepdomino has been also studied. Ee values up70.2%have been achieved using chiral BINAPligand. Twenty four lactonates, nineteen unreported in literature, have been obtained and fullycharacterized.The method of three-step domino reaction revealed in this work provides an efficientway for the synthesis of complex molecules with β-ester-γ-lactone moiety and relatedcompounds.