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

Chapter 4 92was 1:1, TLC analysis showed an almost complete comsumption of thestarting material. However it was impossible to obtain higher chemical yieldsthan 55% after purification by flash chromatography. An unknown sideproduct was detected by NMR analysis, inseparable from the reducedDEAD:Entry R1 R2 Config.(ee%)T (°C) Productyield %Config.prod. (ee%)A Et Ph R (99) 25 (-)-33e(55) S (41)B Et Ph R (99) 25 (-)-33e(32) S (43)C Et Ph R (99) -15 (-)-33e (4) S (45)Table 4.2: Reaction mechanism for (+)-(R)-31e.5) Diaryl methanoles (+)-27a, (+)-27b, (+)-27c (entries 12, 14, 16,Tab. 4.1) and the 2-benzo[b]furane-2,4 dichlorophenyl methanol (+)-27m(entry 19 tab 4.1) led to racemic products because of a completely S N 1reaction mechanism. These reactions were performed using both anequimolar or excess ratio (4:1) of reagents and substrate. Under the latterconditions a quantitative yield of the corresponding alkylate 4,5dicyanoimidazole derivative with diaryl methanoles (+)-3a, (+)-3g, (+)-3ewas obtained.The use of different phosphines such as n-tributyl phosphine or p-methoxytriphenyl phosphine did not show any advantages as compared tothe more common triphenyl phosphine. Identical results were obtained inusing either diisopropyldiazodicarboxylate DIAD or ADDP [(1,1'-azodicarbonyl) dipepiridine)] instead of DEAD.On the basis of these results it was clear that the Mitsunobu reactionwas not a preferred methodology to obtain our target compounds inenantiopure form. Nevertheless it can be considered an alternative synthesisof the final products in racemic form.4.1.1 N-Alkyl-4,5-dicyanoimidazoles 33c-e,g-i,m: determinationof enatiomeric excess.The determination of the enantiomeric excess in the Mitsunobureaction products 33c-e,g-i,m was one of the major problems in thesynthetic efforts. These products do not contain functional groups such as