Applications Of α,β-epoxy Ketones In The Construction Of Some Heterocyclic Skeletons

a,(3-Epoxy ketones are not only the structural unit of many natural products and drugs, but also the significant and widely used intermediates in organic synthesis. This dissertation aimed to develop effective methods for construction of valuable heterocyclic skeletons, which includes three parts:1. The application ofα,β-epoxy ketones in the construction of 3-substituted quinolines3-Substituted quinolines exhibit a wide variety of pharmacological and biological activities. In this dissertation we have developed a novel Friedlander-type reaction for synthesize of 3-aryl quinolines with 3-oxo-2,3-diarylpropionaldehydes and 2-amino arylaldehydes as raw materials. Meanwhile,3-oxo-2,3-diarylpropionaldehydes were prepared from diphenyl substitutedα,β-epoxy ketones by Meinwald rearrangement, which needed no separation and directly reacted with 2-aminobenzaldehydes to produce 3-aryl quinolines in one-pot reaction.(1) We developed a novel one pot, two-step Friedlander-type reaction to produce 3-aryl quinolines by acid-catalysed condensation of 3-oxo-2,3-diaryl-propionaldehydes with 2-aminobenzaldehydes. An enaminone intermediate was produced in the reaction which underwent a base-catalysed intramolecular ring closure to afford the corresponding target product. Under the optimized reaction conditions, most of the substituted substrates gave moderate yields. Among them, a strong electron-withdrawing group (p-O2NC6H4) substituted substrate gave the best yield of 88%.(2) A preliminary mechanism of this novel one pot, two-step synthesis has been explored with the proofs of isolation of the enaminone intermediate and the eliminated benzoic acid in this reaction.(3) A new method for synthesis of 3-aryl quinolines by one-pot Meinwald-Friedlander reaction with diphenyl substitutedα,β-epoxy ketones as starting material was also developed. Meinwald rearrangement of diphenyl substituted α,β-epoxy ketones was catalyzed by trifluoromethanesulfonic acid, and the product was processed directly, without isolation and purification, in the up-mentioned novel Friedlander-type reaction. The final product,3-aryl quinolines, was obtained successfully by the one-pot reaction. Under the optimized reaction conditions, most of the substrates afforded the corresponding 3-aryl quinoline derivatives with moderate to good yields.2. The preliminary study on the application ofα,β-epoxy ketones in the synthesis of 3-formylbenzofuran derivativesBenzofuran is the basic skeleton of many natural products and drugs, and 2-aryl-3-formylbenzofuran is very important in the synthesis of pharmaceuticals, but their synthetic method has rarely been reported. In this dissertation we developed a new method for synthesize of 2-aryl-3-formylbenzofurans by Meinwald rearrangement of 2-methoxylated diphenylα,β-epoxy ketones followed by a Lewis acid-catalysed intramolecular ring closure.(1) A rapid Meinwald rearrangement of 2,3-Epoxy-3-(2’-methoxyphenyl)-1-phenylacetone was catalyzed by BF3 which followed by an intramolecular ring closure under boron tribromide catalysis to afford the major product 2-phenyl-3-formylbenzofuran, in the meantime, an isomer 3-benzoylbenzofuran was also produced. The alteration of catalyst loading, reaction temperature and solvent was studied, and under the optimized reaction conditions, the selectivity for the main product was up to 90%.(2) Different substituted substrates were assayed under the optimized conditions. The results showed that all the substrates can proceed successfully, and among them, electron-withdrawing group substituted substrates gave better yields. The highest isolated yield was up to 81% with the selectivity of 94%.3. High effective preparation of chiral 1,3-diaryl-α,β-epoxy ketones by one-pot reaction and the preliminary exploration of their application in synthesis of chiral dihydroflavonols(1) We developed an efficient one-pot, two-step (Claisen-Schmidt condensation (CSC)-asymmetric epoxidation catalyzed by imidazolium-modified poly(L-leucine) [3-apmim]Cl-PLL) method for preparation of chiralα,β-epoxy ketones from benzaldehydes and acetophenones in heterogeneous solvent reaction system. Most of the aromatic aldehydes and acetophenones bearing substituents with various electronic (both electronic rich and deficient) and steric properties at different (meta-and para-) positions on the aromatic rings underwent the one-pot CSC-asymmetric epoxidation smoothly to afford the corresponding substituted chiral 1,3-diaryl-α,β-epoxy ketones in moderate to good yields (55%-75%) and excellent ees (up to 98%ee). The poly(amino acid) catalyst [3-apmim]Cl-PLL can be easily recovered and recycled for ten times without losing its catalytic efficiency in terms of both enantioselectivity and yield.(2) An efficient one-pot CSC-asymmetric epoxidation catalyzed by [3-apmim]Cl-PLL for preparation of chiralα,β-epoxy ketones from benzaldehydes and acetophenones in homogeneous solvent reaction system was also developed. Many substituted substrates gave satisfied yields and ees, and the highest yield was up to 89% with 97%ee. The yields in homogenous solvent reaction system are significantly higher (up to 22% higher) than those in the heterogeneous solvent one with no or slight enantioselectivity decreasing.(3) The transformation reaction of chiral 1,3-diaryl-α,β-epoxy ketones to chiral dihydroflavonols was preliminarily explored. Although isolation of the product from the reactant was not really easy,1H NMR spectra showed the correct structure and the conversion of 81%. This provides valuable information for the one-pot preparation of chiral dihydroflavonols from benzaldehydes and acetophenones.