Continuous-Flow Synthesis of the Fungicide Tetraconazole: Unprecedented Selectivity in Aldol Condensation and Mechanistic Insights via In-Line 200 MHz 1H NMR.

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 condensationa 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 1H 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 LiBH4. 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.