3+2] cycloaddition reaction between CF3-substituted thiocarbonyl ylides and thioketones: Exploration of regioselectivity and mechanistic aspects using Molecular Electron Density Theory

Abstract

A CF3-containing thiadiazole derivative, TDA1, participates in a domino process initialized with a thermal N2 extrusion experienced at TDA1 within a retro- [3+2] cycloaddition (32CA) reaction to yield CF3-substituted thiocarbonyl ylide TCY3. Then, TYC3 is trapped over the course of a subsequent 32CA reaction toward thioketone TBP4 to generate dithiolane derivative CA5. This domino process was studied through Molecular Electron Density Theory (MEDT) at the B3LYP/6-31G(d) computational level. Exploration of the relative Gibbs free energies obviously indicates that this domino process needs to overcome high barriers justifying why the harsh conditions (100 °C for 24h in toluene) is experimentally requested. In excellent agreement with the experimental findings, an entirely C1–C5 regioselective, polar, and pmr-type 32CA reaction of in situ generated TCY3 toward TBP4 leads to the formation of cycloadduct CA5 as the sole product along a quite irreversible pathway. While the high global electrophilicity ω index of TBP4 together with the high global nucleophilicity N index of TCY3 are responsible for the considerable polar character of the mentioned 32CA reaction, analysis of the electrophilic Pk+ and nucleophilic Pk− Parr functions at the reactive sites of reactants allows to rationalize C1–C5 regioselectivity observed experimentally. In terms of quantum topological analysis of the electron localization function (ELF) over some relevant points located along the IRC profile connecting separate TCY3 and TBP4 to CA5, a non-concerted two-stage one-step molecular mechanism is established for this polar pmr-type 32CA reaction. Such ELF analysis evidently shows that formation of the first C1–C5 and second C3–S4 single bonds is a direct consequence of coupling C1- to –C5 and C3- to –S4 pseudoradical centers, respectively.