Stereoselectivity Inversion by Water Addition in the −SO3H‐catalyzed Tandem Prins‐Ritter Reaction for Synthesis of 4‐amidotetrahydropyran Derivatives

Abstract A range of heterogeneous ‐SO 3 H 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‐2 H ‐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‐2 H ‐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.