2025-12-30 東京大学
図1：不均一系触媒カラムフロー反応のイメージ
＜関連情報＞
殺菌剤テトラコナゾールの連続フロー合成：アルドール縮合における前例のない選択性とインライン200MHz 1 H NMRによる機構解明 Continuous-Flow Synthesis of the Fungicide Tetraconazole: Unprecedented Selectivity in Aldol Condensation and Mechanistic Insights via In-Line 200 MHz 1H NMR
Masahiro Sasaya,Haruro Ishitani,and Shu̅ Kobayashi
JACS Au Published December 29, 2025
DOI:https://doi.org/10.1021/jacsau.5c01462
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 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.
