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

Chapter 5 115to avoid this side reaction trimethyl silyl acetylene (TMSA) was used togenerate the stable nucleophile lithium trimethyl silyl acetylide. For thisTMSA in dry THF was cooled to -75°C and n-butyllithium was addeddropwise, leading to lithium trimethyl silyl acetylide. The reactionmixture was then cannulated dropwise into a solution of the aryl aldehydein dry THF at -78°C to form the desired 1-aryl-2-propyn-3-trimethylsilyl-1-ols (±)-59a-g (Scheme 5.2).RH1)H SiMe 3nBuLidry THF -78 0 CRSiMe 3O2) dry THF -78/0 0 COH(±)-59 a-gScheme 5.2: Synthesis of 1-aryl-2-propyn-3-trimethylsilyl -1-ols (±)-59a-g.These reactions gave very good chemical yields with seven arylaldehydes as reported in table 5.1.Entry R aldehyde T °C Product Yield %1 H -15 (±)-59a 98.52 4Me -78 / 0 (±)-59b 97.03 4F -78 / 0 (±)-59c 98.04 4Cl -78 / -15 (±)-59d 96.05 4CN -78 (±)-59e 87.06 4NO2 -78 (±)-59f 49.07 3,4 OMe -15 (±)-59g 96.0Table 5.1: Reaction conditions and chemical yields for the synthesis of (±)-59a-f.It is interesting that for the first four compounds (±)-59a-e (entries1-4) the reactions were so clean that purifications were unnecessary. Forcompounds (±)-59e-f, (entries 5,6), it was necessary to keep thetemperature very low (-78°C). Raising the temperature to -15°C causedcomplete degradation of both the starting material and the product. It wasimpossible to recover the materials. Under these conditions, the cyanogroup does not react with the lithium reagent. This procedure led to thedesired ethynyl carbinoles in very good yield with the exception of the