Stereoselectivity Inversion by Water Addition in the −SO ₃ H‐catalyzed Tandem Prins‐Ritter Reaction for Synthesis of 4‐amidotetrahydropyran Derivatives

A range of heterogeneous ‐SO₃H functionalized catalysts including carbon and halloysite nanotubes, commercial K10 clay, Amberlyst‐15 etc. was investigated for the first time using as a model the Prins‐Ritter reaction of (−)‐isopulegol with benzaldehyde and acetonitrile producing 4‐amido derivatives of octahydro‐2H‐chromenes (as (S)‐ and (R)‐diastereomers). A strong effect of water addition prior the reaction on the overall selectivity and the ratio of isomers in the case of heterogeneous and homogeneous (p‐toluenesulfonic acid) catalysis was found for the first time. The yield of the (R)‐diastereomer sharply increased with increasing amount of added water, while the S‐isomer prevailed with a minimum amount of added water. Experimental results and DFT calculations clearly indicate a kinetic control for R‐amide formation. Typically synthesis of 4‐amidooctahydro‐2H‐chromenes requires subzero temperatures and toxic catalysts, which were avoided in the current work. Nevertheless, the yield of the desired products (up to 83 %) at 30 °C after water addition exceeded the values reported previously. Thus, adding water is a simple and a very effective method for controlling both the yield and stereoselectivity of the Prins‐Ritter reaction products under mild conditions.