Breslow-type intermediates

A mechanistic rationale for the observed cw-selectivity has been proposed based on preorganisation of the Breslow-type intermediate and imine through hydrogen bonding 253, with an aza-benzoin oxy-Cope process proposed. Reaction via a boat transition state delivers the observed cw-stereochemistry of the product (Scheme 12.57). Related work by Nair and co-workers (using enones 42 in place of a,P-unsaturated sulfonylimines 251, see Section 12.2.2) generates P-lactones 43 with fran -ring substituents, while the P-lactam products 252 possess a cw-stereo-chemical relationship. 

You and co-workers have demonstrated a further application of NHCs in the kinetic resolution of formyl p-lactams ( )-265 [103]. Upon treatment with a chiral NHC, the Breslow-type intermediate is formed, followed by ring-opening of the P-lactam moiety, with subsequent trapping of the acylazolium intermediate leading to the enantio-enriched succinimide product 266 and resolved formyl P-lactam (which is reduced to its alcohol 267). The authors note that when R" = H, the products undergo racemisation readily, and this is a possible explanation for the lower levels of enantioselectivity observed in the succinimide products 266 (Scheme 12.60). 

The observed stereoselectivity of the reaction might be explained by transition state 18, as shown in Figure 9.5. The Si-face of the assumed Breslow-type intermediate would be shielded by the tert-butyl group of the bicyclic catalyst, thus limiting any attack to the. Re-face of the hydroxy enamine. Furthermore, the substituents of the enol moiety might cause a pre-orientation of the approaching... 

The reactivity of peculiar Breslow intermediates (146) has been explored. Interestingly enough, (146) have been found to evolve towards tertiary alcohols (147) via a Claisen-like rearrangement. This example is a bit apart in this section because the related process involves a Breslow-type intermediate but is not NHC catalysed. 

Breslow-type intermediates and their exploitation in organic synthesis continue to attract much attention from the organic chemistry community. 

The ability of A -heterocyclic carbenes to activate a,p-unsaturated carbonyl compounds via the formation of the corresponding Breslow intermediate, which plays the role of a homoenolate nucleophile, has also been applied to a cascade process involving a formal intramolecular Michael reaction/oxidation/ lactonization, leading to the formation of complex tricyclic carbon frameworks starting from a bifunctional substrate containing an enone and an a,p-unsa-turated aldehyde side chain linked to each other via a benzene tether (Scheme 7.82). The reaction involved a complex multistep mechanism which started with the activation of the enal by the catalyst, forming the Breslow intermediate, which subsequently underwent intramolecular Michael reaction and next the generated enol-type intermediate reacted intramolecularly with the... 

The number of synthetic methodologies exploiting Breslow-type species as key intermediates has continued to grow exponentially since the start of this decade. 

The Bode group disclosed NHC-catalyzed highly enantioselective annulations of a,P,P -trisubstituted enals with cyclic sulfonylimines. Mechanistically, it is proposed that the combination of enal and free NHC leads to the formation of the Breslow intermediate, which is oxidized to form the key a,p-unsaturated acyl azolium. Tautomerization between the imine and the enamine occurs readily in the presence of base, and the enamine is intercepted by the key a,p-unsaturated acyl azolium to form a hemiaminal which further engages in a Stork-Hickmott-Stille-type annulation via a tight-ion-pair/aza-Claisen type transition state. Lactam formation follows the protonation of enolate and brings about catalyst turnover to complete the catalytic cycle (Scheme 7.113). 

NHCs catalyse an intramolecular Stetter reaction of methyl 4-(2-formylphenoxy)-2-butenoate in toluene to yield a chromanone. A B3LYP/6-3IG study identified the formation of the Breslow intermediate as the rate-determining step, followed by a Michael-type addition, which is the stereoselectivity-determining step. 

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