Experimental study on the microreactor-assisted synthesis of phosphinic chlorides with varying steric hindrance

Abstract

An efficient and catalyst-free method for the preparation of optically active and racemic mono-substituted t-butyl phosphinic chlorides ^tBuRP(O)Cl under flow conditions was reported. A variety of mono t-butyl substituted phosphinic chlorides were obtained using this protocol starting from the corresponding phosphine oxide and one equivalent of carbon tetrachloride (CAUTION: hepatotoxic) with reasonable residence times (25–125 min) and excellent conversions (up to 99%). The asymmetric reaction conducted in a glass microreactor chip with an internal volume of 250 μL leads to the corresponding chloride with 96% enantiomeric excess. It is significant that the protocol works effectively when the phosphine oxide has one bulky group such as t-butyl, which prevent the formation of undesired products. The steric hindrance is proven to be important for the stabilization of the P–Cl products. The key results were compared with the results obtained in batch conditions and it can be concluded that the flow method provides a sustainable, efficient alternative to the existing methods for the preparation of phosphinic chlorides. The isolation of the reaction products is straightforward because of the lack of any additives and the high purity of the obtained products. The results of the asymmetric reaction and the computational studies suggest that the reaction occurs through a mechanism involving a pentacoordinated phosphorus TS, with the apical positions occupied by the incoming CCl₃⁻ nucleophile and the t-butyl group.