Synthesis of 3-Iodomethyl Sultams

Abstract

A method for the synthesis of iodomethyl-substituted five-membered sultams has been developed. The sultams were synthesized by intramolecular iodoamination of alkenyl sulfamides. The method allows synthesis of N- and C-substituted sultams. NH-Sultams were prepared by acidic cleavage of the corresponding tert-butyl sultams that are readily available. Varying the length of alkenyl substituent at sulfamide it was shown that only five- and six-membered sultams could be prepared by this method. Neither four- nor seven-membered sultams were detected. The simple practical procedure and available starting materials make the variously substituted sultams readily available.

Key words

sultam - iodoamination - sulfamide - iodine - cyclization

• References and Notes

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• 46 General Procedure for the Synthesis of Iodomethyl Sultams To a solution of the corresponding sulfamide (5 mmol, 1 equiv) in acetonitrile (20 mL) was added sodium bicarbonate (7.5 mmol, 1.5 equiv), then iodine (15 mmol, 3 equiv), and the reaction mixture was stirred overnight. To the reaction mixture, water (20 mL) was added with stirring. Sodium metabisulfite was added portionwise to the stirring reaction mixture until the disappearance of the brown color of iodine. The reaction mixture was extracted with chloroform (3 × 30 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and evaporated to dryness. The crude sultam was purified by flash chromatography (hexane/dichloromethane 9:1 to dichloromethane). General Procedure D: Cleavage of the tert-Butyl Group in Sultams 2d,f,h To a solution of the corresponding sultam (2 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at 35 °C for 4 h, and the reaction mixture was evaporated to dryness. The residue was purified by column chromatography (dichlormethane/tert-butyl methyl ether 9:1 to tert-butyl methyl ether).
• 47 Analytical Data for 2-(tert-Butyl)-3-(iodomethyl)isothiazolidine 1,1-Dioxide (2d) Procedure C was applied, starting from 1d. Yield 1.53 g, 96%; yellowish crystals; mp 121–123 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.86–3.73 (m, 1 H), 3.33–3.13 (m, 3 H), 3.12–3.02 (m, 1 H), 2.48–2.42 (m, 2 H) 1.42 (s, 9 H). ¹³C NMR (125 MHz, CDCl₃): δ = 57.9, 57.8, 47.1, 28.6, 24.8, 9.3. GC-MS (EI): m/z (%) = 317 (1), 302 (100), 176 (59), 134 (50), 120 (62). Anal. Calcd: C, 30.29; H, 5.08; N, 4.42. Found: C, 30.05; H, 5.37; N, 4.31.
• 48 Analytical Data for 3-(Iodomethyl)isothiazolidine 1,1-Dioxide (2a) Procedure D was applied, starting from sultam 2d. Yield 1.16 g, 89%; yellow powder; mp 74–76 °C. ¹H NMR (500 MHz, CDCl₃): δ = 4.89 (br s, 1 H, NH), 3.85–3.73 (m, 1 H), 3.38–3.22 (m, 3 H), 3.19–3.09 (m, 1 H), 2.74–2.58 (m, 1 H), 2.22–2.10 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 54.8, 48.6, 29.4, 9.2. MS: m/z (%) = 262 [M + H]⁺ (100). Anal. Calcd: C, 18.40; H, 3.09; N, 5.36. Found: C, 18.63; H, 2.87; N, 5.58.