Unexpected formation of highly functionalized dihydropyrans via addition-cyclization reactions between dimethyl oxoglutaconate and α,β-unsaturated hydrazones

Abstract

The condensation between dienophiles and α,β-unsaturated hydrazone azadienes was previously reported to afford piperidines. During an attempt to adapt this reaction to the preparation of piperidine-based conformationally-restricted analogs of glutamate, it was discovered that the electrophile, dimethyl oxoglutaconate (DOG) led to highly substituted dihydropyrans in 20–50% yield. The unexpected pyran product likely results from an initial 1,4-addition of the hydrazone to the oxoglutaconate followed by intramolecular cyclization of the resultant enolate oxygen to the α,β-unsaturated iminium ion. Further manipulations afford substituted tetrahydropyran 6-methamino-2,4-dicarboxylic acids.

Chemistry of α-Oxoesters: A Powerful Tool for the Synthesis of Heterocycles

“…Reactions were completed in 24 h, and the corresponding dihydropyrans 816 were obtained in 20−54% yields, via intermediate 815 (Scheme 255). 376 Sequential aldol reaction of ketene diethylacetal with α-oxoesters was developed for the synthesis of 4,4,6,6-tetraethoxytetrahydro-2H-pyran-2-carboxylates 820. Reactions were catalyzed with in situ generated chiral bisoxazolinecopper(II) complex VII-2-Cu (20 mol %), and performed using 3 equiv of ketene diethylacetal in anhydrous Et 2 O at −15 to −78°C under an atmosphere of N 2 , overnight, to afford 820 in 55−80% yields, with 53−93% ee.…”

“…Reactions were completed in 24 h, and the corresponding dihydropyrans 816 were obtained in 20−54% yields, via intermediate 815 (Scheme 255). 376 Sequential aldol reaction of ketene diethylacetal with αoxoesters was developed for the synthesis of 4,4,6,6tetraethoxytetrahydro-2H-pyran-2-carboxylates 820. Reactions were catalyzed with in situ generated chiral bisoxazolinecopper(II) complex VII-2-Cu (20 mol %), and performed using 3 equiv of ketene diethylacetal in anhydrous Et Yang and Shi 378 developed the synthesis of 5,6-dihydropyran-2-ones 823 via TMSOTf-mediated reaction of cyclopropyl aryl ketones with α-oxoesters in DCE at 60 °C for 12 h. Reactions were performed using 1 equiv of TMSOTf to afford 5,6-dihydropyran-2-ones 823 in 35−97% yields.…”

“…Conjugate addition-cyclization reaction between dimethyl oxoglutaconate and α,β-unsaturated hydrazones (1.1 equiv) was carried out in CH 3 CN at room temperature to prepare highly substituted dihydropyrans 816 . Reactions were completed in 24 h, and the corresponding dihydropyrans 816 were obtained in 20–54% yields, via intermediate 815 (Scheme ) …”

Inverse-Electron-Demand oxa-Diels–Alder Reactions of α-Keto-β,γ-unsaturated Esters and α,β-Unsaturated Hydrazones

“…In this context, we recently reported inverse-electron-demand Diels–Alder reaction of α-pyrone with α,β-unsaturated hydrazone using this approach . As an extension of that work, we planned to apply the carbonyl umpolung strategy to inverse-electron-demand oxa-Diels–Alder reaction of enones as oxa-dienes with α,β-unsaturated hydrazones as electron-rich dienophiles (Scheme , bottom) . Herein, we report the inverse-electron-demand oxa-Diels–Alder reaction of α-keto-β,γ-unsaturated esters by using α,β-unsaturated hydrazones for the synthesis of highly functionalized dihydropyrans, as well as indirect synthesis of their formyl derivatives by dehydrazonation of the cycloadduct.…”