Studies on a One-Pot Synthesis of Pyridooxazocine Bicycles from Homonicotinic Acid Esters and Aminoalcohols

Indianapolis, IN

In the context of phantasmidine synthesis we sought to prepare a series of pyridofurans related to the parent alkaloid starting from 2,6-dichlorohomonicotinic acid. Direct coupling of the acid with aminoalcohols using DCC or EDC were only modestly successful. Thionyl chloride (SOCl₂) conversion of the precursor acid to the corresponding acid chloride and subsequent reaction with the aminoalcohol were more successful. However a milder and cleaner process turned out to be conversion to the methyl ester and base-promoted transamidation with the aminoalcohol in methanol solution. Given that the subsequent step would be S_NAr displacement of halide, we chose to examine direct synthesis of the bicycle from the methyl ester in one pot. We examined a variety of alkalai metal bases, CsCO₃ being the most effective thus far. However, ring closure failed on repeated attempts with production of a variety of undidentified products. Reactions using 2-fluoro-6-chlorohomonicotinic acid were also complicated by effective competition of solvent for displacement of the halogen, which we ascribe to an unfavorable trans to cis amide isomerization required for ring closure. We are currently investigating non-nuclephilic solvents for this transformation. Our results to date will be discussed.