Enal acyl anion

Recently, the Chi group disclosed an NHC-promoted asymmetric inter-molecular cross-aza-benzoin reaction of enals with isatin-derived ketimines to afford chiral quaternary 3-aminooxindoles (18 examples, with up to 76% yield, 96% ee). The chemoselectivity is controlled by the NHC catalysts, with electron-deficient and sterically non-congested carbene catalysts favoring the enal acyl anion reaction pathway and aza-benzoin, allowing convenient access to products of different scaffolds by starting from the same set of readily available substrates (Scheme 7.16). 

The Chi group reported in 2011 the enantioselective Stetter reaction between enals and modified chalcones proceeding through a Michael-type addition of NHC-bound enal acyl anions to the Michael acceptors. The Stetter reaction with p-alkyl enals afforded the Michael addition products with good enantioselectivity and yields (14 examples, up to 93% yield, 94% ee). While P-aryl enals were tested in this reaction, up to moderate yield was achieved. This was because the enolate pathway (giving Diels-Alder products)" dominated, which was difficult to suppress under these reaction conditions (Scheme 7.26). 

Recently, Chi and coworkers disclosed the enantioselective cross-aza benzoin reaction of enals with isatin-derived ketimines, affording the 3-aminooxindoles 29 bearing a quaternary stereogenic centre with high enantioselectivities. The electron-deficient and sterically noncongested car-bene catalyst H2 was shown to favour the pathway of enal acyl anion leading to an aza-benzoin reaction (Scheme 20.14). 

Enals (92) react with modified chalcones (e.g. 93) in an enantioselective Stetter reaction, giving highly functionalized products (94) in ees up to 97%, using chiral NHC catalysis. A Michael-type addition of NHC-bound enal acyl anion to the chalcone is proposed. ... 

Homoenolates generated catalytically with NHCs can also be employed for C-C and C-N bond formation. Bode and Glorias have independently accomplished the diastereoselective synthesis of y-butyrolactones by annulation of enals and aldehydes [121, 122]. Bode and co-workers envisioned that increasing the steric bulk of the acyl anion equivalent would allow reactivity at the homoenolate position. While trying to suppress the competing benzoin and enal dimerization the authors comment on the steric importance of the catalyst. Thiazolium pre-catalyst 173 proved unsuccessful at inducing annulation. A-mesityl substituted imidazolium salt 200 was found to provide up to 87% yield and moderate diastereoselectivities (Scheme 34). 

The proposed catalytic cycle is shown in Scheme 35 and begins with the imida-zolylidene carbene adding to the enal. Proton transfer provides acyl anion equivalent XLVII, which may be drawn as its homoenolate resonance form XLVIII. Addition of the homoenolate to aldehyde followed by tautomerization affords L the precursor for lactonization and regeneration of the carbene. 

Addition of acyl anion equivalents (propenal d reagents) to ketones provides general access to a -hy-droxy enones. In an application of this method to pentaimulation, the trimethylsilyl- or ethoxyethyl-pro-tected cyanohydrins of a, -enals were used." The derived tertiary acetates undergo elimination (p-TsOH/benzene) to the divinyl ketones which cyclize in the acidic reaction medium (equation 25)." In some cases the a -hydroxy or a -silyloxy enones underwent cyclization but in much lower yields. Substitution in the ring and on the double bonds is compatible. 

Previously unreported yn-diastereoselectivity in the synthesis of 6-niuoesters (94) from enals (95) and nitroalkenes (96) has been achieved, using an NHC (97, reminiscent of dialkylprolinol TMS ether) designed to avoid the established acyl anion/Stetter pathway and favour the homoenolate route.The method has been further exploited in a mild and elegant one-pot synthesis of 6-lactams (98) from similar starters. 

An innovative stereoselective synthesis of A-acylhydrazones via an unprecedented A-heterocyclic carbene-catalysed addition of aldehydes to diazo compounds has been presented. Enals exclusively afforded A-acylhydrazones, in yields up to 91% (Scheme 13). The observed regioselectivity was traced back to the reaction of the viny-logous Breslow intermediate via the acyl anion pathway over competing homoenolate, enol, and acyl azolium pathways. This unusual reaction profile was studied based on DFT calculations, which revealed that the reaction is under orbital control, rather than being ruled by charge. 

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