Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA.
Molecules. 2023 Apr 15;28(8):3497. doi: 10.3390/molecules28083497.
Phosphonic acids represent one of the most important categories of organophosphorus compounds, with myriad examples found in chemical biology, medicine, materials, and other domains. Phosphonic acids are rapidly and conveniently prepared from their simple dialkyl esters by silyldealkylation with bromotrimethylsilane (BTMS), followed by desilylation upon contact with water or methanol. Introduced originally by McKenna, the BTMS route to phosphonic acids has long been a favored method due to its convenience, high yields, very mild conditions, and chemoselectivity. We systematically investigated microwave irradiation as a means to accelerate the BTMS silyldealkylations (MW-BTMS) of a series of dialkyl methylphosphonates with respect to solvent polarity (ACN, dioxane, neat BTMS, DMF, and sulfolane), alkyl group (Me, Et, and iPr), electron-withdrawing P-substitution, and phosphonate-carboxylate triester chemoselectivity. Control reactions were performed using conventional heating. We also applied MW-BTMS to the preparation of three acyclic nucleoside phosphonates (ANPs, an important class of antiviral and anticancer drugs), which were reported to undergo partial nucleoside degradation under MW hydrolysis with HCl at 130-140 °C (MW-HCl, a proposed alternative to BTMS). In all cases, MW-BTMS dramatically accelerated quantitative silyldealkylation compared to BTMS with conventional heating and was highly chemoselective, confirming it to be an important enhancement of the conventional BTMS method with significant advantages over the MW-HCl method.
膦酸是有机磷化合物最重要的类别之一，在化学生物学、医学、材料学等领域都有大量实例。膦酸可以通过三甲基溴硅烷（BTMS）的硅烷基脱烷基化作用，从其简单的二烷基酯快速简便地制备，然后与水或甲醇接触进行脱硅。这种方法最初是由 McKenna 引入的，BTMS 路线制备膦酸由于其简便、高产率、非常温和的条件和化学选择性，长期以来一直是一种受欢迎的方法。我们系统地研究了微波辐射作为一种加速一系列二烷基甲基膦酸酯与溶剂极性（ACN、二氧六环、纯 BTMS、DMF 和环丁砜）、烷基（Me、Et 和 iPr）、吸电子 P 取代和膦酸酯-羧酸三酯化学选择性的 BTMS 硅烷基脱烷基化（MW-BTMS）的方法。控制反应使用常规加热进行。我们还将 MW-BTMS 应用于三种无环核苷膦酸酯（ANPs，一类重要的抗病毒和抗癌药物）的制备，据报道，在 130-140°C 下用 HCl 进行 MW 水解时（MW-HCl，BTMS 的替代方法），它们会发生部分核苷降解。在所有情况下，与常规加热的 BTMS 相比，MW-BTMS 都大大加速了定量的硅烷基脱烷基化，并且具有高度的化学选择性，这证实了它是对传统 BTMS 方法的重要改进，与 MW-HCl 方法相比具有显著优势。
