Are carboxylic esters really refractory to DAST? On the fluorination of α-hydroxyesters with DAST

•A new approach to α,α-difluoro-β-hydroxyethers from 2-alkyl-2-hydroxyesters.•Advanced synthesis of nucleus and side-chain fluorinated indole derivatives.•Unexpected DAST-promoted cyclization of indole-based esters to spiroindolines.

Diethyl 2-alkyl-2-hydroxymalonates react with DAST almost exclusively at the ester carbonyl giving a mixture of ethyl 2-(ethoxydifluoromethyl)-2-hydroxyalkanoates, 1,1-bis(ethoxydifluoromethyl)alkan-1-ols when administered at room temperature in dichloromethane. The reaction was exploited in the synthesis of nucleus- and side-chain polyfluorinated indoles. The fluorination of substituted diethyl 2-[(1-tert-butoxycarbonylindol-3-yl)methyl]-2-hydroxymalonates with DAST gave a mixture of ethyl 2-(ethoxydifluoromethyl)-2-hydroxy-3-(1-tert-butoxycarbonylindol-3-yl)propionate, diastereomeric 1′-tert-butoxycarbonyl-2′-hydroxy-2,2-diethoxycarbonylspiro(cyclopropane-1,3′-indoline) and only traces of 1,1-bis(ethoxydifluoromethyl)-2-(1-tert-butoxycarbonylindol-3-yl)ethanol. The composition of these mixtures changes depending on the reaction conditions. Regioselectively substituted ethyl 2-hydroxy-2-[(1-tert-butoxycarbonylindol-3-yl)methyl]-3,3,3-trifluoropropionate reacts with DAST at 0 °C in dichloromethane giving satisfactory yields of the corresponding 1-ethoxy-2-[(1-tert-butoxycarbonylindol-3-yl)methyl]-1,1,3,3,3-pentafluoropropan-2-ols as the exclusive reaction products. In the same reaction conditions, ethyl 3-(1-tert-butoxycarbonylindol-3-yl)-2-hydroxypropionate mainly provides 1′-tert-butoxycarbonyl-2′-hydroxy-2,2-diethoxycarbonylspiro(cyclopropane-1,3′-indoline) together with the “normal” fluorination product ethyl 3-(1-tert-butoxycarbonylindol-3-yl)-2-fluoropropionate. A plausible mechanism of this process is proposed in the following.

Graphical abstractDAST reacts with dialkyl 2-alkyl-2-hydroxymalonates giving mainly α,α-difluoroethers and tetrafluorinated diethers. Indole derived dialkyl 2-hydroxymalonates and alkyl 3,3,3-trifluorpyruvates give polyfluorinated indole-based ethers.Figure optionsDownload full-size imageDownload as PowerPoint slide