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 degrees 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. (C) 2014 Elsevier B.V. All rights reserved.
Are Carboxylic Esters Really Refractory to DAST? On the Fluorination of -Hydroxyesters with DAST.
LEPRI, SUSAN;BUONERBA, FEDERICA;GORACCI, LAURA;RUZZICONI, Renzo
2015
Abstract
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 degrees 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. (C) 2014 Elsevier B.V. All rights reserved.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
