Abstract
Continuous manufacturing offers a sustainable and flexible approach for fine chemical production, yet its application to complex agrochemicals like tetraconazole remains largely unexplored. Herein, we report the first continuous-flow synthesis of the fungicide tetraconazole, addressing the challenging catalytic synthesis of α-aryl acrylates. We demonstrate that a packed-bed flow reactor, equipped with a newly designed heterogeneous base catalyst, achieves unprecedented selectivity in the dehydrative aldol condensationa transformation that previously suffered from poor conversion and yielded different major products under batch conditions. This key reaction proceeds with high efficiency and selectivity for the first time in a continuous-flow system, resulting in the desired acrylate product (7). Kinetic analysis, supported by in situ monitoring using a high-temperature superconductor (HTS) portable 200 MHz (1)H NMR spectrometer with an in-line cell, reveals that this flow-induced selectivity is not merely due to enhanced mixing but stems from an accelerated interconversion equilibrium between crucial intermediates, effectively enabling a direct elimination pathway that bypasses the typically slow dehydration step. This robust catalytic strategy was successfully integrated into a three-step sequential and continuous-flow process for the synthesis of the tetraconazole precursor, combining the catalytic dehydrative aldol condensation, the catalytic 1,4-addition of triazoles, and a flow ester reduction using LiBH(4). Crucially, the integration of the water-containing upstream process with the moisture-sensitive reduction was achieved via an efficient in-line liquid-liquid extraction module. This work provides an impactful example of applying sophisticated reactor engineering and mechanistic insight into transform a historically nonselective batch reaction into a high-yielding (up to 74% overall) and fully integrated continuous manufacturing method for a complex pesticide.