A New Synthetic Study on Medium Sized Oxacycles using the Baylis-Hillman Adducts

Abstract

In this thesis, several new synthetic approaches to medium sized oxacycles (oxepine and oxocine derivatives) using the Baylis-Hillman (BH) adducts were disclosed. Medium-sized oxacycles (oxepine and oxocine) are of current interest due to their occurrence in natural products and important pharmacological applications. Hence, we have developed new synthetic methods for oxepine and oxocine derivatives from Baylis-Hillman adducts which useful in the heterocycle synthesis. At first, a simple synthesis of several methyl 2-oxo-2,3-dihydro-benzo[b]oxepine-4-carboxylates from Baylis-Hillman adducts of O-benzyl protected 2-hydroxybenzaldehydes has been described through the acetylation, cyanation, debenzylation, as well as acid assited Pinner cyclization. Secondly, a new method for the synthesis of dimethyl 2,3-dihydrobenzo[b]-oxepine-2,4-dicarboxylates and methyl 2-(2-carbomethoxybenzo[b]furan-3-yl)-propanoates by an intramolecular conjugate displacement (ICD) reaction of acetates of Baylis-Hillman adducts of methyl (2-formylphenoxy)acetates has been developed. Dihydrobenzo[b]oxepines were produced in a Cs2CO3-THF system and benzo[b]-furans were given in a Cs2CO3-DMF system, respectively. Thirdly, a new method for the synthesis of methyl 1-carbomethoxymethyl-2-methoxy-2,4-dihydro-3(1H)-benzoxocin-5-carboxylates from the BH adducts of iodobenzaldehydes was developed through a process of acetylation, rearrangement, hydrolysis, and palladium-catalyzed Heck reaction with 2,5-dimethoxy-2,5-dihydrofuran. Lactonization of 1-carbomethoxymethyl-3(1H)-benzoxocin derivatives occurred to yield methyl 1,3a,5,11b-tetrahydrofuro[3,2-a][3]benzoxocin-2(1H)-6-carboxylates on exposure to excess trifluoroacetic acid. Finally, we have successfully elaborated a new synthetic method for methyl 7H-dibenz[b,g]oxocin-6-carboxylates by Friedel–Crafts reaction of readily available bromides of Baylis–Hillman adducts with aluminum chloride. The structures of new compounds were established on the basis of 1H NMR, 13C NMR, IR, GC/Mass, EA and HRMS spectroscopic data.