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

Publication History

Received: 25 December 2024

Accepted after revision: 25 March 2025

Accepted Manuscript online:
25 March 2025

Article published online:
17 April 2025

• References and Notes

• 1a Wang H, Zhang X, Li Y, Xu L.-W. Angew. Chem. Int. Ed. 2022; 61: e202210851
• 1b Zuo Y, Gou Z, Quan W, Lin W. Coord. Chem. Rev. 2021; 438: 213887
• 1c Alarcos N, Cohen B, Ziółek M, Douhal A. Chem. Rev. 2017; 117: 13639
• 1d Dasog M, Kehrle J, Rieger B, Veinot JG. C. Angew. Chem. Int. Ed. 2016; 55: 2322
• 1e Chen C, Yi X, Yang K.-F, Li Z, Lai G.-Q, Zhang P. Macromolecules 2023; 56: 10192
• 2a Langkopf E, Schinzer D. Chem. Rev. 1995; 95: 1375
• 2b Zhou C, Wang X, Quan X, Cheng J, Li Z, Maienfisch P. J. Agric. Food Chem. 2022; 70: 11063
• 2c Franz AK, Wilson SO. J. Med. Chem. 2013; 56: 388
• 3a Crance JM, Scaramozzino N, Jouan A, Garin D. Antiviral Res. 2003; 58: 73
• 3b Liu J, Gong Y, Shi J, Hao X, Wang Y, Zhou Y, Hou Y, Liu Y, Ding S, Chen Y. Eur. J. Med. Chem. 2020; 194: 112244
• 3c Kumar JS. D, Majo VJ, Hsiung S.-C, Millak MS, Liu K.-P, Tamir H, Prabhakaran J, Simpson NR, Van Heertum RL, Mann JJ, Parsey RV. J. Med. Chem. 2006; 49: 125
• 4 Shnider BI, Frei EIII, Tuohy JH, Gorman J, Freireich EJ, Brindley CO. Jr, Clements J. Cancer Res. 1960; 20: 28
• 5a Vitaku E, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257
• 5b Duplantier AJ, Dombroski MA, Subramanyam C, Beaulieu AM, Chang S.-P, Gabel CA, Jordan C, Kalgutkar AS, Kraus KG, Labasi JM, Mussari C, Perregaux DG, Shepard R, Taylor TJ, Trevena KA, Whitney-Pickett C, Yoon K. Bioorg. Med. Chem. Lett. 2011; 21: 3708
• 5c Blakemore DC, Castro L, Churcher I, Rees DC, Thomas AW, Wilson DM, Wood A. Nat. Chem. 2018; 10: 383
• 6a Albini A, Pietra S. Heterocyclic N-Oxides . CRC Press; Boca Raton: 1991
• 6b Albini A. Synthesis 1993; 263
• 7a Wójtowicz-Rajchel H, Bednarczyk I, Katrusiak A, Koroniak H. Mendeleev Commun. 2004; 14: 63
• 7b Vincent-Rocan J.-F, Ivanovich RA, Clavette C, Leckett K, Bejjani J, Beauchemin AM. Chem. Sci. 2016; 7: 315
• 8a Sun K, Shi A, Liu Y, Chen X, Xiang P, Wang X, Qu L, Yu B. Chem. Sci. 2022; 13: 5659
• 8b Cheng F, Fan L, Lv Q, Chen X, Yu B. Green Chem. 2023; 25: 7971
• 8c Zhang Z, Cheng F, Ma X, Sun K, Huang X, An J, Peng M, Chen X, Yu B. Green Chem. 2024; 26: 7331
• 9a Ghosh P, Kwon NY, Kim S, Han S, Lee SH, An W, Mishra NK, Han SB, Kim IS. Angew. Chem. Int. Ed. 2021; 60: 191
• 9b Ghosh P, Kwon NY, Byun YN, Mishra K, Park JS, Kim IS. ACS Catal. 2022; 12: 15707
• 10a Zhang H.-Y, Chen J, Lu C.-C, Han Y.-P, Zhang Y, Zhao J. J. Org. Chem. 2021; 86: 11723
• 10b Tan Y, Xuekun W, Han Y.-P, Zhang Y, Zhang H.-Y, Zhao J. J. Org. Chem. 2022; 87: 8551
• 11a Panda SP, Hota SK, Dash R, Roy L, Murarka S. Org. Lett. 2023; 25: 3739
• 11b Meher P, Panda SP, Mahapatra SK, Thombare KR, Roy L, Murarka S. Org. Lett. 2023; 25: 8290
• 12 Huang X.-L, Zhang D.-L, Li Q, Xie Z.-B, Le Z.-G, Zhu Z.-Q. Org. Lett. 2024; 26: 3727
• 13 Pan Y, Zhu Y, Li S, Li G, Ma Z, Qian Y, Huang W. Chem. Commun. 2024; 60: 3665
• 14a Zhang C, He D, Ma Z, Wang M, Zhu Y, Liu Y, Chen J, Guo L, Lv G, Wu Y. J. Org. Chem. 2024; 89: 10112
• 14b Pan C, Chen D, Zeng M, Tian H, Yu J.-T. Eur. J. Org. Chem. 2024; 27: e202301177
• 14c Zhu J, Hong Y, Wang Y, Guo Y, Zhang Y, Ni Z, Li W, Xu J. ACS Catal. 2024; 14: 6247
• 15 Yu Y, You M, Yu J, Kong W, Zhang C, Bai J, Li W, Li T. Adv. Synth. Catal. 2025; 367: e202400857
• 16 Mahato F, Ghosh AK, Hajra A. Chem. Eur. J. 2025; 31: e202403685
• 17a Das KK, Hajra A. Org. Biomol. Chem. 2024; 22: 1034
• 17b Neogi S, Ghosh AK, Mandal S, Ghosh D, Ghosh S, Hajra A. Org. Lett. 2021; 23: 6510
• 17c Neogi S, Bhunya S, Ghosh AK, Sarkar B, Roy L, Hajra A. ACS Catal. 2024; 14: 4510
• 18a Prakash G, Paul N, Oliver GA, Werz DB, Maiti D. Chem. Soc. Rev. 2022; 51: 3123
• 18b Tortajada A, Hevia E. Catal. Sci. Technol. 2023; 13: 4919
• 19a Wang L, Zhu H, Guo S, Cheng J, Yu J.-T. Chem. Commun. 2014; 50: 10864
• 19b Xia D, Li Y, Miao T, Li P, Lei W. Chem. Commun. 2016; 52: 11559
• 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.