Theoretical Study On Gold-catalyzed Cyclization Of Alkyne Derivatives

In the past few years,a variety of valuable N-containing heterocycles have been synthesized through the gold-catalyzed reactions of alkynes with isoxazoles,benzoisoxazoles and other nitro equivalent reagents.In order to understand the mechanistic details and inherent selectivity of these reactions,three representative cyclization reactions by the experiments were investigated in detail with the aid of DFT calculations.It is anticipated that these computational studies will be informative for designing new related catalytic reaction protocols.1.Density functional theory(DFT)calculations were used to explore the Au(?)-catalyzed selective[4+1]annulations of cyclopropyl-and H-substituted1,4-diyn-3-ols with isoxazole.The results indicated that after the N nucleophilic attack of isoxazole,instead of obtaining the?–hydroxy gold carbene intermediate proposed experimentally,a concerted three-step forward product by isoxazole O-N cleavage,1,2-phenylalkyne shift and the hydroxyl H shift was identified as the key intermediate,for the reaction proceeding either via an Au-assisted C=C double-bond rotation to produce the Z-isomeric enone or via two different Au-assisted C=C rotations to furnish the E-configured enone depending on the substituents used.Further theoretical investigations indicated that the chemoselective step is the nucleophilic cyclization but not the C=C double-bond rotation.The chemoselective preference for the Z-configured product using the cyclopropyl substitutent was attributed to two factors:i)the additional O…H—N hydrogen bonding interaction stabilizes the rate-determining cyclization TS leading to the Z-product,and ii)further Z-E product-isomerization is blocked due to significant structural deformation being involved.In contrast,using the H substituent results in a reversed chemoselectivity with exclusive formation of the E-configured enone,which is closely related to the smaller entropy effects involved.2.Au(?)-catalyzed selective reactions of Et-and ^tBu-substituted propiolates(1a and 1a')with 1,2-benzisoxazole(2a)provide a new strategy for purposefully access to desired bioactive heterocycles.Using DFT calculations,we have systematically investigated the detailed mechanisms and origins of the ester-controlled chemoselectivity.The calculated results indicated that both reactions are initiated by LAu⁺?-coordination,N nucleophilic attack and NTf₂^--assisted stepwise H-shift,generating a nitrilium species,which is identified as a common and requisite intermediate,significantly different from the experimentally proposed6-alkoxy-1,3-oxazin-1-ium intermediate.Starting from the nitrilium intermediate,the newly established nucleophilic cyclization,alkene release,and NTf₂^--assisted stepwise protodeauration provides[4+2]-annulation product P₁,while the nitrilum dissociation,O nucleophilic attack and NTf₂^--assisted stepwise protodeauration generates Michael-type product P₂.Further explorations showed that ^tBu-controlled chemoselectivity of P₁over P₂can be attributed to the energy favorable aromaticity of selective-determining nucleophilic cyclization TS.With substitution of^tBu by Et group,the reversal of chemoselectivity to P₂formation might be closely related to the presence of extremely unstable Et cation in ethylene release TS leading to P₁.3:The gold(?)-catalyzed annulations of alkynes with anthranils were evaluated using DFT calculations.A unified rationale for the Br-migration on?-imino gold(?)-carbene was proposed,from which an unprecedented“N-donation/abstraction substitution”mechanism was established using the substituted anthranils,and direct C-H nucleophilic attack was involved with the unsubstituted anthranils.The controlling factors guiding the site-selectivity were uncovered.These computational studies provide insight for developing new a-imino gold(?)-carbene mediated reactions.