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

Chapter 4 91benzo[b]furane (entries 17-19 Tab 4.1), the reaction led to very lowconversions (5/10%). The starting material was always recovered also whenthe reaction time was very long (>24 hours) and a large excess of reagentswas used (molar ratio reagents / substrate 5/1).3) The reaction showed pure S N 2 mechanism with secondary aliphaticalcohols. Enantiomerically pure aliphatic alcohols (-)-(R)-31c, (+)-(S)-31c,(-)-(R)-31d (entries 4,5 and 7 Table 4.1) gave the corresponding 1-alkyl-4,5-dicyano imidazoles (+)-(S)-33c,(-)-(R)-33c and (+)-(S)-33d as singleenantiomers ( 97/98% e.e.) with medium to good chemical yields. Themolar ratio between substrate and reagents was always 1:1. In these casesthe reaction conditions were not further optimized towards higher chemicalyields.4) The reaction had a mixed S N 2-S N 1 mechanism with the benzylicsecondary alcohol (+)-(R)-31e (entry 9 tab 4.1). The resulting product (-)-(S)-33e showed an enantiomeric excess of 41% e.e.. Thus more than 50%of the enantiomeric excess of the corresponding starting material was lost.In order to establish whether the racemization process occured due toreaction conditions or due to the inherent "mixed" mechanism threedifferent experiments were perfomed:A) Reverse addition of reagents:In this experiment the betaine complex between DEAD and triphenylphosphine was preformed at -20°C in dry THF in absence of alcohol and4,5-dicyanoimidazole. Then the last two reagents in dry THF were added tothe reaction mixture. After 20 hours, the temperature was raised to roomtemperature for 8 hours. Following this procedure the enantiomeric excessof the product was not increased.B) Shorter reaction time:The reaction was carried out for a short time (10') and immediatelyinterrupted. The resulting chemical yield was lower than in the normalexperiment, however the enantiomeric excess was identical.C) Lower temperature:An experiment as described under B was carried out at a lowertemperature. At -25°C the reaction did not occur, at -15°C the chemicalyield was decreased to 4%. The enantiomeric excess was identical to thoseobtained in the other experiments.The results of these three experiments are summarized in Table 4.2.The substrate was always (+)-(R)-31e, the molar ratio substrate / reagent