Synthesis of Silylated Azauracil 1-Oxides by Metal-Free Direct Silylation

Abstract

A direct C–H silylation strategy is reported for synthesizing silylated derivatives of azauracil 1-oxide in a simple and environmentally benign way under metal-free conditions using triphenylsilane as a silyl precursor and TBHP as an oxidant. This methodology is useful for late-stage modification of various bioactive molecules, such as ibuprofen and gemfibrozil. A mechanistic investigation suggested that the reaction proceeds through a radical pathway.

Key words

metal-free reaction - silylation - azauracil oxides - late-stage functionalization - medicinal chemistry

Publikationsverlauf

Eingereicht: 25. Dezember 2024

Angenommen nach Revision: 25. März 2025

Accepted Manuscript online:
25. März 2025

Artikel online veröffentlicht:
17. April 2025

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• 20 2-Ethyl-4-(4-nitrobenzyl)-6-(triphenylsilyl)-1,2,4-triazine-3,5(2H,4H)-dione 1-Oxide (3a); Typical Procedure A mixture of azauracil derivative 1a (0.25 mmol, 1 equiv) and Ph₃SiH (2; 0.5 mmol, 2 equiv) in MeCN (2 mL) in an oven-dried reaction tube was degassed and purged with N₂ three times. TBHP (1.15 mmol, 3 equiv) was then added dropwise under N₂, and the resulting mixture was stirred for 12 h at 80 °C. When the reaction was complete, the mixture was extracted with EtOAc. The organic phase was dried (Na₂SO₄) and concentrated in vacuum, and the crude residue was purified by column chromatography [silica gel, PE–EtOAc (85:15)] to give a white solid; yield: 111 mg (81%); mp 185–186 °C; R_f = 0.50 (PE–EtOAc, 80:20). ¹H NMR (400 MHz, CDCl₃): δ = 8.16 (d, J = 8.8 Hz, 2 H), 7.63–7.58 (m, 6 H), 7.57 (d, J = 8.8 Hz, 2 H), 7.47–7.43 (m, 3 H), 7.40–7.36 (m, 6 H), 5.12 (s, 2 H), 4.25–4.20 (m, 2 H), 1.20 (t, J = 6.8 Hz, 3 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 158.7, 148.1, 147.7, 142.8, 136.1, 135.0, 131.7, 130.2, 127.9, 123.8, 121.3, 43.7, 39.3, 12.7. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₃₀H₂₇N₄O₅Si: 551.1746; found: 551.1752.