Practical Fischer Indolization Using Bench-Stable Arylhydrazine Sulfonate as the Surrogate of Arylhydrazine

Abstract

Fischer indolization using bench-stable sodium arylhydrazine sulfonate as a surrogate of arylhydrazine was developed. The preparation of arylhydrazine sulfonate was also modified by replacing sodium sulfite reductant with Pd-catalyzed hydrogen transfer. The straightforward synthesis of tetrahydrocarbazoles from the corresponding anilines was successfully conducted in a one-pot manner. A practical application of this method was demonstrated in the formal synthesis of pharmaceutical molecules Rizatriptan and Zolmitriptan.

Key words

arylhydrazine sulfonate - desulfonation - Fischer indolization - tryptamine - Rizatriptan - Zolmitriptan

Publication History

Received: 12 September 2023

Accepted after revision: 30 October 2023

Article published online:
30 November 2023

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• 26 General Procedure: Ketone (1.0 mmol, 1.0 equiv) was added dropwise into a solution of sodium arylhydrazine sulfonate (1.0 mmol, 1.0 equiv) in AcOH (5 mL) and the mixture was stirred at 70 °C for 1 hour. The reaction mixture was then cooled to room temperature and diluted with water. The mixture was extracted with ethyl acetate (2 × 50 mL), and the combined organic layer was washed with water and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure and the obtained crude product was purified by silica-gel column chromatography using petroleum ether/EtOAc as eluent.
• 27 Selected analytical data for new compounds: 6-Butyl-2,3,4,9-tetrahydro-1H-carbazole (3c): Purified using petroleum ether/ethyl acetate (100:1, v/v) as eluent. Yield: 0.168 g (74%); yellow solid. ¹H NMR (600 MHz, CDCl₃): δ = 7.57 (s, 1 H), 7.25–7.24 (m, 1 H), 7.18 (d, J = 8.4, 1 H), 6.95 (dd, J = 7.8, 1.2 Hz, 1 H), 2.74–2.67 (m, 6 H), 1.97–1.84 (m, 4 H), 1.70–1.61 (m, 2 H), 1.38–1.34 (m, 2 H), 0.93 (t, J = 7.8 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 134.2, 134.0, 133.6, 128.0, 122.0, 117.0, 109.9, 109.8, 35.9, 34.6, 23.33, 23.30, 23.2, 22.4, 20.9, 14.0. HRMS (ESI): m/z [M + H]⁺ calcd. for C₁₆H₂₁N: 228.1752; found: 228.1754. 6-Phenoxy-2,3,4,9-tetrahydro-1H-carbazole (3d): Purified using petroleum ether/ethyl acetate (95:5, v/v) as eluent. Yield: 0.179 g (68%); white solid. ¹H NMR (600 MHz, CDCl₃): δ = 7.72 (s, 1 H), 7.33–7.27 (m, 3 H), 7.17 (d, J = 2.4 Hz, 1 H), 7.05–7.00 (m, 1 H), 6.99–6.96 (m, 2 H), 6.89 (dd, J = 8.4, 2.4 Hz, 1 H), 2.77–2.74 (m, 2 H), 2.67–2.65 (m, 2 H), 1.99–1.85 (m, 4 H). ¹³C NMR (151 MHz, CDCl₃): δ = 159.7, 149.4, 135.7, 132.6, 129.4, 128.6, 121.6, 117.0, 114.6, 111.1, 110.4, 109.0, 23.3, 23.2, 23.1, 20.9. HRMS (ESI): m/z [M + H]⁺ calcd. for C₁₈H₁₇NO: 264.1388; found: 264.1391. 7-Butoxy-2,3,4,9-tetrahydro-1H-carbazole (3h): Purified using petroleum ether/ethyl acetate (95:5, v/v) as eluent. Yield: 0.163 g (67%); orange solid. ¹H NMR (600 MHz, CDCl₃): δ = 7.54 (s, 1 H), 7.15 (d, J = 8.4 Hz, 1 H), 6.93 (d, J = 2.4 Hz, 1 H), 6.77 (dd, J = 8.4, 2.4 Hz, 1 H), 4.01 (t, J = 6.6 Hz, 2 H), 2.73–2.65 (m, 4 H), 1.95–1.83 (m, 4 H), 1.84–1.74 (m, 2 H), 1.56–1.47 (m, 2 H), 0.98 (t, J = 7.4 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 153.3, 135.0, 130.7, 128.2, 111.2, 110.8, 110.1, 101.6, 68.7, 31.6, 23.4, 23.3, 23.2, 21.0, 19.3, 13.9. HRMS (ESI): m/z [M + H]⁺ calcd. for C₁₆H₂₁NO: 243.1623; found: 243.1626.