Selective Methylation of NH-Containing Heterocycles and Sulfonamides Using N,N-Dimethylformamide Dimethylacetal Based on Calculated pK _a Measurements

Abstract

The use of N,N-dimethylformamide dimethylacetal (DMF-DMA) as a suitable methylating agent for the methylation of NH-containing groups and heterocycles has been investigated. Use of ReactArray and calculated pK _a measurements have allowed additional helpful information to be collated to determine optimum reaction conditions for a variety of substrates.

Key words

methylation - N,N-dimethylformamide dimethylacetal - heterocycles - sulfonamides - pK _a

• References and Notes

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• 10 General Procedure: To a stirred solution of substrate in dry DMF was added DMF-DMA (5 equiv) in one portion at r.t. The resulting mixture was heated at a temperature (60–120 °C) based on calculated pK _a (Table 2) for approximately 18 h and allowed to cool to r.t. The reaction mixture was evaporated to dryness and purified by flash silica chromatography. 2-Methyl-4-phenyl-1,2,4-triazol-3-one (4) Temp 70 °C; yield 78%; white solid; MS (ES⁺): m/z [M + H]⁺ = 176.33; HPLC: t _R= 1.02 min. ¹H NMR (700 MHz, DMSO): δ = 8.43 (s, 1 H), 7.67 (dt, J = 8.7, 1.7 Hz, 2 H), 7.48–7.52 (m, 2 H), 7.35–7.38 (m, 1 H), 3.38 (s, 3 H). ¹³C NMR (176 MHz, DMSO): δ = 151.31, 134.59, 134.11, 129.32, 127.00, 121.48, 32.10. 3-Bromo-N,N-dimethyl-benzenesulfonamide (8) Temp 80 °C; yield 92%; white solid; HRMS: m/z [M + H]⁺ calcd for C₈H₁₀BrNO₂S: 263.96939; found: 263.96875. ¹H NMR (400 MHz, CDCl₃): δ = 7.86 (t, J = 1.8 Hz, 1 H), 7.62–7.69 (m, 2 H), 7.35 (t, J = 7.9 Hz, 1 H), 2.67 (s, 6 H). 1-Methyl-3-phenyl-1H-pyrrolo[2,3-c]pyridine (11) Temp 100 °C; yield 73%; beige solid; MS (ES⁺): m/z [M + H]⁺ = 209.41. HPLC: t _R = 2.13 min. ¹H NMR (400 MHz, DMSO): δ = 8.90 (s, 1 H), 8.23 (d, J = 5.6 Hz, 1 H), 7.95 (s, 1 H), 7.83 (dd, J = 5.6, 1.0 Hz, 1 H), 7.69 (dd, J = 8.3, 1.2 Hz, 2 H), 7.46 (t, J = 7.8 Hz, 2 H), 7.27 (t, J = 7.4 Hz, 1 H), 3.97 (s, 3 H). ¹³C NMR (101 MHz, DMSO, 30 °C): δ = 138.71, 134.37, 134.12, 133.72, 131.18, 129.26, 128.87, 126.21, 125.70, 114.23, 113.58, 32.79. 1-Methyl-3-phenylindole (13) Temp 120 °C; yield 87%; colorless gum; HRMS: m/z [M + H]⁺ calcd for C₁₅H₁₃N: 207.1048; found: 207.1027. ¹H NMR (400 MHz, DMSO): δ = 7.88 (d, J = 8.0 Hz, 1 H), 7.64–7.7 (m, 3 H), 7.50 (d, J = 8.2 Hz, 1 H), 7.40–7.47 (m, 2 H), 7.20–7.27 (m, 2 H), 7.11–7.17 (m, 1 H), 3.85 (s, 3 H).