N-(Trimethylsilyl)-2-amino-5-nitrothiazole: An Efficient Reagent for the Direct Synthesis of 2-Amino-5-nitrothiazole-Based Antimicrobial Agents

Abstract

Here we report the synthesis of a novel reagent designed to prepare 2-amino-5-nitrothiazole (ANT) amides and analogues in high yields. N-(Trimethylsilyl)-2-amino-5-nitrothiazole (N-(TMS)-ANT) was prepared in 99% yield via silylation of ANT using 1,1,1,3,3,3-hexamethyldisilazane (HMDS), trimethylsilyl chloride (TMSCl), and catalytic saccharin. N-(TMS)-ANT is a superb reagent for the preparation of ANT amides in excellent yields. Notably, cyclic anhydrides and base-sensitive acyl chlorides can be utilized with N-(TMS)-ANT to furnish ANT amides that are difficult to prepare by previously reported procedures.

Key words

2-amino-5-nitrothiazole - N-silylation - antimicrobials - antiviral - biofilms

Publication History

Received: 26 August 2022

Accepted after revision: 30 September 2022

Article published online:
03 November 2022

• References and Notes

• 1 Rossignol JF. Antiviral Res. 2014; 110: 94
• 2 Ball P. J. Antimicrob. Chemother. 2002; 49: 31
• 3 Mathur H, Rea MC, Cotter PD, Hill C, Ross RP. Gut Pathog. 2016; 8: 20
• 4 Koenig HN, Durling GM, Walsh DJ, Livinghouse T, Stewart PS. Antibiotics 2021; 10: 855
• 5 Ballard TE, Wang X, Olekhnovich I, Koerner T, Seymour C, Hoffman PS, Macdonald TL. Bioorg. Med. Chem. Lett. 2010; 20: 3537
• 6 Ballard TE, Wang X, Olekhnovich I, Koerner T, Seymour C, Salamoun J, Warthan M, Hoffman PS, Macdonald TL. ChemMedChem 2011; 6: 362
• 7 Bruynes CA, Jurriens TK. J. Org. Chem. 1982; 47: 3966
• 8 Wilhelm M, Marquardt FH, Meier K, Schmidt P. Helv. Chim. Acta 1966; 49: 2443
• 9 Preparation of N-(TMS)-ANT (1) A 100 mL round-bottomed flask equipped with a magnetic stirring bar and a polyseal cap was charged with 2-amino-5-nitrothiazole (3.625 g, 25.0 mmol), saccharin (0.169 g, 1.25 mmol), and anhydrous acetonitrile (25 mL). The reactant mixture was blanketed with argon and then trimethylsilyl chloride (1.05 g, 1.225 mL, 9.5 mmol) was added dropwise by syringe with stirring. After stirring for an additional 10 min at 23 °C, 1,1,1,3,3,3-hexamethyldisilazane (1.48 g, 1.91 mL, 9.17 mmol) was added dropwise by syringe. The reactant mixture was stirred for 1 h at 23 °C and then heated at 65 °C with stirring for an additional 1 h. The NH₄Cl precipitate was then filtered, with care being taken to avoid exposure to atmospheric moisture. The NH₄Cl was leached with anhydrous acetonitrile (5 mL), and the solvents were removed in vacuo. A 100 mL recovery flask was used for the final removal of trace solvents and subsequent sublimation under high vacuum (0.01 mmHg 60 °C) furnished the title compound 1 as a yellow/orange crystalline solid (5.4 g, 99%). ¹H NMR (CDCl₃, 500 MHz): δ = 8.08 (1 H, s), 5.30 (1 H, s), 0.39 (9 H, s). ¹³C NMR (CDCl₃, 125 MHz): δ = 169.7, 143.1, 29.9, 0.0. HRMS (ESI): m/z calcd for [C₆H₁₁N₃O₂SSi + H]⁺: 218.0414; found: 218.0425 (mass error Δm = 5 ppm).
• 10 Representative Amidation: Preparation of 5 A 10 mL round-bottomed flask equipped with a magnetic stirring bar and polyseal cap was charged with N-(TMS)-ANT (1, 217 mg, 1.0 mmol), anhydrous dichloromethane (3.0 mL), and blanketed with argon in succession. The mixture was stirred until homogeneous, then crotonoyl chloride (105 mg, 96 μL, 1.0 mmol) was subsequently added by gas-tight syringe, and the reactant mixture was allowed to stir at room temperature for 24 h. The solvent was then removed in vacuo, and the residue was diluted with EtOAc (5 mL) and successively extracted with water (2 × 5 mL), saturated sodium bicarbonate (2 × 5 mL), and brine (2 × 5 mL). The organic layer was then passed through a pad of silica gel and removal of the solvent in vacuo provided the title compound (202 mg, 95%). ¹H NMR (DMSO-d ₆, 500 MHz): δ = 13.13 (1 H, s), 8.65 (1 H, s), 7.10 (1 H, dq, J = 7 Hz), 6.26 (1 H, dq, J = 7, 2 Hz), 1.94 (3 H, dd, J = 7, 2 Hz). ¹³C NMR (DMSO-d ₆, 125 MHz): δ = 164.8, 162.5, 146.6, 143.3, 142.5, 123.0, 18.6. HRMS (ESI): m/z calcd for [C₇H₇N₃O₃S]⁺: 213.0208; found: 213.0146 (mass error Δm = 29 ppm).