Advances in the stereoselective synthesis of antifungal agents and ...

Chapter 4 97NCO 2 HNCO 2 H(±)34c(-)-(S)-34cCH 2 N 2MeOHNNCO 2 MeCO 2 Me(±)36(-)-(S)-36Scheme 4.3: Esterification of (±)-34c and (-)-(S)-34c.Since the dimethyl ester (-)-(S)-36 showed an e.e. of only 40 % e.e. itwas concluded that the intermediate diacid (-)-(S)-34c racemized during thedecarboxylation process. The dimethyl esters (±)-36 and (-)-(S)-36 wereanalyzed again by 1 H-NMR in presence of shift reagents in order todetermine the enantiomeric excess.4.3. Mitsunobu reaction with 4-(5)-ethyl imidazolecarboxylate 37.With the aim of avoiding the drastic conditions required in thehydrolysis and decarboxylation sequence of 4,5-dicyanoimidazolederivatives the use of another substituted imidazole was investigated.4.3.1. Synthesis of 4-(5)-ethyl imidazole carboxylate 37.The synthesis of 4-(5) - ethyl imidazole carboxylate 37 was reported atthe end of the last century 3 without any experimental conditions or physicalconstants.The synthesis involved the acetylation of ethyl glycine ester usingacetyl chloride in presence of triethyl amine leading in quantitave yield to theacetyl glycine ethyl ester 38. α−alkylation of 38 with ethyl formiate in drybenzene and sodium ethoxide as base led to the intermediate 39 which wasnot purified or characterized. The reaction mixture appeared as a white solidafter 24h at 0°C. The crude product was dissolved in water and acidifiedwith hydrochloric acid and cyclized to 2-mercapto-4(5)-ethylimidazolecarboxylate 40 using KCNS. Finally 40 was desulfurated by