Construction of Dihydropyrido[2,3-d]pyrimidine Scaffolds via Aza-Claisen Rearrangement Catalyzed by N-Heterocyclic Carbenes

Abstract

N -Heterocyclic carbenes (NHCs) catalyzing aza-Claisen rearrangement of α,β-unsaturated enals with cyclic vinylogous amides under oxidative conditions generating potentially biologically active dihydropyridinone-fused uracils have been developed. This strategy represents a unique NHC-activation-based path with the use of 6-aminouracils as stable α,β-diEWG cyclic vinylogous amides for the efficient synthesis of bicyclic N -unprotected lactams similar to those in many useful drugs.

N-heterocyclic carbene-catalyzed direct enantioselective synthesis of dihydroisoxazolo[5,4-b]pyridin-6-ones

“…Based on our experimental results and previous related works, 10 l ,11 a plausible reaction mechanism was proposed as shown in Scheme 5 with the formation of 3a as the model reaction. The combination of chiral NHC C′ generated from precatalyst C under basic conditions with α-bromoenal 1a leads to the formation of α,β-unsaturated acyl azolium I .…”

“…In 2020, Rafiński and co-workers reported an NHC-catalyzed [3 + 3] cycloaddition of enals with 1,3-disubstituted 6-aminouracils, giving bicyclic dihydropyridinone-fused uracils in good yields, albeit with low enantioselectivities (Scheme 1, b). 11 In this regard, the discovery of novel bis-nucleophiles will likely provide many new opportunities for the chemistry of α,β-unsaturated acyl azoliums.…”

Recent Advances in Catalytic [3,3]-Sigmatropic Rearrangements

“…Lastly, the synthetic utility of the obtained products was clearly demonstrated. One year later, Rafinski's research team applied NHC catalysis to the aza-Claisen rearrangement to construct dihydropyrido [2,3-d]pyrimidine scaffolds (Scheme 14b) [41] The reaction between α,β-unsaturated aldehydes 68 and N-substituted 6-aminouracils 69 yielded the N-unprotected lactam moiety 70 through simultaneous C-C bond formation and amide formation. In this case, all tested NHC salts were reactive for the aza-Claisen rearrangement.…”

Organocatalytic Name Reactions Enabled by NHCs

“…In addition, Bode significantly developed the subject of the possibilities of using acyclic enamines in the aza-Claisen rearrangement [106]. Rafiński and co-workers reported recently the first aza-Claisen reaction of cyclic enamines in the form of 6-amino-uracils [107]. Not much later, Biju showed interesting C2-functionalization of 3-aminobenzofurans via aza-Claisen rearrangement [108].…”

“…Materials 2020, 13, x FOR PEER REVIEW 6 of 29 uracils [107]. Not much later, Biju showed interesting C2-functionalization of 3-aminobenzofurans via aza-Claisen rearrangement [108].…”