Pd-catalysed flow Tsuji–Trost allylation of phenols: continuous-flow, extraction-free synthesis of esmolol via allylation, epoxidation, and aminolysis

Abstract

We report a method for the continuous flow Tsuji–Trost allylation of phenols using a heterogeneous Pd/PNP-PS catalyst and allyl methyl carbonate that does not require the use of aryl halides or bases. This base-free protocol enables the efficient conversion of various phenols into allyl aryl ethers without post-reaction purification. The resulting reaction solution then directly undergoes a titanium-silicate-1-zeolite-catalysed epoxidation step using H₂O₂, followed by Nb₂O₅-catalysed aminolysis with isopropylamine to afford 3-amino-1,3-propanediol derivatives. The integration of these three catalytic steps under continuous-flow conditions enables the synthesis of esmolol, a cardioselective β₁-adrenergic receptor antagonist, in high yield and purity without an extraction step. Further, the final crystallization of esmolol hydrochloride is achieved without chromatographic purification. The overall process is a sustainable and scalable strategy for the synthesis of fine chemicals and pharmaceuticals, highlighting the potential of continuous-flow methodologies in modern chemical manufacturing.