Synthesis of 1,2,4-Benzotriazines via Copper(I) Iodide/1H-Pyrrole-2-carboxylic Acid Catalyzed Coupling of o-Haloacetanilides and N-Boc Hydrazine

Abstract

Coupling of o-haloacetanilides and N-Boc hydrazine proceeded at room temperature under the catalysis of CuI/1H-pyrrole-2-carboxylic acid. The coupling products underwent oxidation to afford the azo compounds, which were subjected to deprotection with TFA and in situ cyclization to give 1,2,4-benzotriazines.

Key words

coupling - cyclization - copper - catalysis - 1,2,4-benzotriazine

• References and Notes

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• 17 General Procedure for the Preparation of 9 A Schlenk tube was charged with iodide 7 (0.5 mmol), N-Boc hydrazine (70 mg, 0.53 mmol), CuI (5 mg, 0.025 mmol), 1H-pyrrole-2-carboxylic acid (9 mg, 0.08 mmol), NaI (15 mg, 0.1 mmol), and K₂CO₃ (138 mg, 1.0 mmol), evacuated, and backfilled with argon. DMSO (1.5 mL) was successively added. The reaction mixture was stirred at 25 °C for 24–30 h before oxygen was introduced. After the reaction mixture was stirred at 25 °C for 3–5 h, it was extracted with EtOAc. The combined organic phase was washed with brine and dried over Na₂SO₄. After concentration in vacuo, the residue was purified by column chromatography on silica gel to provide 9. Compound 9a: ¹H NMR (500 MHz, CDCl₃): δ = 9.54 (s, 1 H), 8.70 (dd, J = 8.5, 1.1 Hz, 1 H), 7.74 (dd, J = 8.2, 1.5 Hz, 1 H), 7.54 (ddd, J = 8.6, 7.5, 1.5 Hz, 1 H), 7.09 (ddd, J = 8.4, 7.3, 1.3 Hz, 2 H), 2.41 (t, J = 7.4 Hz, 2 H) 1.80–1.72 (m, 2 H), 1.65 (s, 9 H), 1.00 (t, J = 7.4 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 171.66, 160.23, 138.25, 138.05, 136.01, 123.11, 120.55, 119.36, 84.97, 40.16, 27.85 (3C), 18.75, 13.68. ESI-MS: m/z = 314.2 [M + Na]⁺. ESI-HRMS:m/z calcd for C₁₅H₂₂N₃O₃ ⁺ [M + H]⁺: 292.1656; found: 292.1653. Compound 9k: ¹H NMR (500 MHz, CDCl₃): δ = 11.10 (s, 1 H), 8.83 (dd, J = 8.5, 1.1 Hz, 1 H), 7.95 (dd, J = 8.1, 1.6 Hz, 1 H), 7.71 (dd, J = 3.8, 1.1 Hz, 1 H), 7.62 (dd, J = 7.3, 1.4 Hz, 1 H), 7.59 (dd, J = 5.0, 1.0 Hz, 1 H), 7.22 (ddd, J = 8.3, 7.4, 1.2 Hz, 1 H), 7.14 (dd, J = 5.0, 3.8 Hz, 1 H), 1.71 (s, 9 H). ¹³C NMR (125 MHz, CDCl₃): δ = 160.30, 159.14, 139.74, 138.01, 136.45, 136.30, 131.71, 128.83, 127.88, 125.30, 123.50, 120.31, 84.95, 27.88 (3 C). ESI-MS: m/z = 354.2 [M + Na]⁺. ESI-HRMS:m/z calcd for C₁₆H₁₈N₃O₃S⁺ [M + H]⁺: 332.1063; found: 332.1061.
• 18 Typical Procedure for the Prepration of 10 To a solution of 9 (0.2 mmol) in CH₂Cl₂ (2.0 mL) was added TFA (0.5 mL). The solution was stirred at r.t. for 2 h before aq NaHCO₃ (5 mL) was added. The mixture was extracted with CH₂Cl₂. The organic phase was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel to provide 10. Compound 10a: ¹H NMR (400 MHz, CDCl₃): δ = 8.49 (d, J = 8.4 Hz, 1 H), 7.99 (d, J = 7.9 Hz, 1 H), 7.96–7.90 (m, 1 H), 7.83–7.77 (m, 1 H), 3.35 (t, J = 9.6 Hz, 2 H), 2.08–1.97 (m, 2 H), 1.06 (t, J = 7.4 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 166.45, 146.18, 140.85, 135.25, 129.82, 129.53, 128.51, 39.69, 22.28, 13.92. ESI-MS: m/z = 174.1 [M + H]⁺. ESI-HRMS:m/z calcd for C₁₀H₁₂N₃ ⁺ [M + H]⁺: 174.1026; found: 174.1025. Compound 10h: ¹H NMR (500 MHz, CDCl₃): δ = 8.46 (dd, J = 8.4, 0.7 Hz, 1 H), 8.35 (dd, J = 3.7, 1.1 Hz, 1 H), 8.02–7.97 (m, 1 H), 7.92 (ddd, J = 8.4, 6.8, 1.3 Hz, 1 H), 7.76 (ddd, J = 8.2, 6.8, 1.3 Hz, 1 H), 7.61 (dd, J = 5.0, 1.1 Hz, 1 H), 7.24 (dd, J = 4.9, 3.7 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 157.36, 146.00, 140.87, 140.72, 135.72, 131.31, 130.61, 129.75, 129.70, 128.65, 128.61. ESI-MS: m/z = 214.1 [M + H]⁺. ESI-HRMS:m/z calcd for C₁₁H₈N₃S⁺ [M + H]⁺: 214.0433; found: 214.0432.