Mechanism, Regioselectivity, and the Kinetics of Phosphine‐Catalyzed [3+2] Cycloaddition Reactions of Allenoates and Electron‐Deficient Alkenes

Abstract

With the aid of computations and experiments, the detailed mechanism of the phosphine‐catalyzed [3+2] cycloaddition reactions of allenoates and electron‐deficient alkenes has been investigated. It was found that this reaction includes four consecutive processes: 1) In situ generation of a 1,3‐dipole from allenoate and phosphine, 2) stepwise [3+2] cycloaddition, 3) a water‐catalyzed [1,2]‐hydrogen shift, and 4) elimination of the phosphine catalyst. In situ generation of the 1,3‐dipole is key to all nucleophilic phosphine‐catalyzed reactions. Through a kinetic study we have shown that the generation of the 1,3‐dipole is the rate‐determining step of the phosphine‐catalyzed [3+2] cycloaddition reaction of allenoates and electron‐deficient alkenes. DFT calculations and FMO analysis revealed that an electron‐withdrawing group is required in the allene to ensure the generation of the 1,3‐dipole kinetically and thermodynamically. Atoms‐in‐molecules (AIM) theory was used to analyze the stability of the 1,3‐dipole. The regioselectivity of the [3+2] cycloaddition can be rationalized very well by FMO and AIM theories. Isotopic labeling experiments combined with DFT calculations showed that the commonly accepted intramolecular [1,2]‐proton shift should be corrected to a water‐catalyzed [1,2]‐proton shift. Additional isotopic labeling experiments of the hetero‐[3+2] cycloaddition of allenoates and electron‐deficient imines further support this finding. This investigation has also been extended to the study of the phosphine‐catalyzed [3+2] cycloaddition reaction of alkynoates as the three‐carbon synthon, which showed that the generation of the 1,3‐dipole in this reaction also occurs by a water‐catalyzed process.