Computer-aided reaction design. Development of a new facile procedure to synthesize 2-mercapto-3-alkoxycarboxylate on the basis of ab initio molecular orbital calculations

This paper describes a new facial procedure to substitute a tosyloxy group in 2-(tosyloxy)alkanoate with SH- to yield 2-mercaptoalkanoate on the basis of ab initio MO calculations. Combination of substrate and solvent effects can control both reactivity and selectivity of reaction for 2-(tosyloxy)-3 -alkoxycarboxylic acid which gave 2-mercapto-3-alkoxycarboxylic acid in goo d yield while its ethyl ester gave cr,P-unsaturated carboxylate ester as a main product. The difference of carboxylate moiety in the substrate causes remarkable change in reactivity and selectivity. To clarify origin of the d ifference, ab initio MO calculations in the gas phase and in DMF have been carried out. The solvent effect was considered at RHF/6-31+G* with the IPCM -SCRF model. It was confirmed that the substrate with an ester fragment pre fers the E1cB to the S(N)2 mechanism. In the transition state of the S(N)2 mechanism with a carboxylate ion fragment, the nucleophile SH- locates far from the reaction center due to the electrostatic repulsion between the COO - fragment and SH-. This repulsion causes high activation barrier in the ga s phase while polar solvent can reduce the barrier height. Therefore, react ion conditions can control reactivity of carboxylic acid. On the basis of a nalysis of the MO calculations, subsequent experiments were designed for a new dianion system to synthesize 2-pyrimidinylthio carboxylic acid from 2-t osyloxy carboxylate. We succeeded in developing a new facile method that th e two reactions for thioether carried out in a one-pot procedure in excelle nt yield.