Reactions of 2-[Lithio(trimethylsilyl)methyl]-2H-tetrazoles: Synthesis of 2-[1-(Trimethylsilyl)alkyl]-2H-tetrazoles and (2H-Tetrazol-2-yl)acetates

Abstract

The reaction of 2-[(trimethylsilyl)methyl]-2H-tetrazoles with various alkyl halides and carbonates using n-butyllithium or lithium diisopropylamide (LDA) gave 2-[1-(trimethylsilyl)alkyl]-2H-tetrazoles and (2H-tetrazol-2-yl)acetates as useful synthons of modified tetrazoles.

Key words

tetrazoles - synthetic methods - lithiation - synthons

• References and Notes

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• 16 Reaction of 2-[2-(Trimethylsilyl)alkyl]-2H-tetrazoles with Alkyl Halides; Typical Procedure for 5-Phenyl-2-[1-(trimethylsilyl)ethyl]-2H-tetrazole (2a):A solution of 1 (0.50 mmol) in anhydrous THF (1 mL) was cooled to –78 °C under an argon atmosphere. n-BuLi (1.6 M in n-hexane, 0.55 mmol) was added to the suspension dropwise over 30 min, and the mixture was stirred further for 1 h. Iodomethane (0.55 mmol) was added to the mixture, which was stirred at –78 °C for 2 h. After quenching with HCl, the reaction mixture was extracted with EtOAc. The organic layer was washed with H₂O, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford 2a (90%) as a colorless oil.¹H NMR (CDCl₃): δ = 0.15 [s, 9 H, (CH₃)₃Si], 1.71 (d, J = 7.6 Hz, 3 H, CH₃), 4.52 (q, J = 5.6 Hz, 1 H, CH), 7.42–7.53 (m, 3 H, ArH), 8.12–8.20 (m, 2 H, ArH); ¹³C NMR (CDCl₃): δ = –3.50, 16.23, 51.86, 126.73, 127.90, 128.82, 130.00, 164.49; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₉N₄Si: 247.1379; found: 247.1353.
• 17 Preparation of Acetates and Ketones; Typical Procedure for Methyl (5-Phenyl-2H-tetrazol-2-yl)acetate (3b): A mixture of 1 (0.50 mmol) and dimethyl carbonate (0.55 mmol) in anhydrous THF (1 mL) was cooled to –78 °C under an argon atmosphere. LDA (1.1 M in n-hexane–THF, 1.05 mmol) was added to the suspension dropwise over 60 min. After stirring for 2 h at –78 °C, HCl (1.0 M, 3 mL) was added to the mixture. The mixture was allowed to reach r.t., and stirred for 30 min. The reaction mixture was extracted with EtOAc and the organic layer was washed with H₂O, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford 3b (88%) as a white solid.Mp 97–98 °C (n-hexane–CHCl₃) (Lit.¹⁴ 93–94 °C); IR (ATR): 1756 cm^–1; ¹H NMR (CDCl₃): δ = 3.83 (s, 3 H, COOCH₃), 5.48 (s, 2 H, CH₂), 7.47–7.53 (m, 3 H, ArH), 8.13–8.20 (m, 2 H, ArH); ¹³C NMR (CDCl₃): δ = 53.23, 53.31, 127.01, 127.04, 128.93, 130.56, 165.53, 165.71; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₀H₁₁N₄O₂: 219.0882; found: 219.0872.
• 18 Multicomponent Reaction of 2-[1-(Trimethylsilyl)methyl]-2H-tetrazole; Typical Procedure for Dimethyl 2-(5-Phenyl-2H-tetrazol-2-yl)malonate (4a): A mixture of 1 (0.50 mmol) and dimethyl carbonate (0.55 mmol) in anhydrous THF (1 mL) was cooled to –78 °C under an argon atmosphere. LDA (1.1 M in n-hexane–THF, 1.05 mmol) was added to the suspension dropwise over 30 min. After stirring for 30 min, methyl chloroformate (1.05 mmol) was added to the mixture. The mixture allowed to reach 10 °C slowly, and stirred overnight. After quenching with HCl, the reaction mixture was extracted with EtOAc and the organic layer was washed with H₂O, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford 4a (51%) as a colorless oil.IR (ATR): 1752 cm^–1; ¹H NMR (CDCl₃): δ = 3.91 (s, 6 H, COOCH₃), 6.37 (s, 1 H, CH), 7.47–7.51 (m, 3 H, ArH), 8.16–8.22 (m, 2 H, ArH); ¹³C NMR (CDCl₃): δ = 54.13, 66.61, 126.73, 127.14, 128.87, 130.70, 162.51, 165.69; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₃N₄O₂: 277.0937; found: 277.0927.