A Concise Approach Toward Tetrazolyl-Substituted Benzazocines via a Novel Isocyanide-Based Multicomponent Reaction

Abstract

The synthesis of pharmacologically relevant isoquinoline-tetrazoles and benzazocine-tetrazoles via sequential azido-Ugi and alkyne-induced ring-expansion reactions starting from cotarnine chloride are reported. A one-pot, multicomponent reaction protocol toward the ring-expanded product is also described.

Key words

alkaloids - multicomponent reaction - domino reaction - ring expansion - alkynes

• References and Notes

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• 12 Isoquinoline-Tetrazoles 4a–i; General Procedure Cotarnine chloride (2) (1 mmol), isonitrile 3 (1.2 mmol) and NaN₃ (1.2 mmol) were dissolved in H₂O–MeOH (1:5, 5 mL), and the mixture was stirred at r.t. for 18–24 h (TLC monitoring). Products 4a,b were isolated using flash chromatography (EtOAc–hexanes, from 1:50 to 1:10). Products 4c–i precipitated from the reaction mixtures and were removed by filtration, washed with cold MeOH (15 mL) and dried in air. 5-(1-Cyclohexyl-1H-tetrazol-5-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline (4а) Yield: 189 mg (51%); colorless powder; mp 147–149 °C (EtOAc–hexanes); reaction time = 19 h.¹H NMR (600 MHz, DMSO-d ₆): δ = 1.18–1.33 (m, 2 H), 1.37–1.47 (m, 1 H), 1.60–1.71 (m, 2 H), 1.72–1.79 (m, 2 H), 1.79–1.87 (m, 2 H), 1.91–1.97 (m, 1 H), 2.21 (s, 3 H), 2.56 (dt, J = 4.8, 11.7 Hz, 1 H), 2.64 (dt, J = 4.8, 16.5 Hz, 1 H), 2.79–2.86 (m, 1 H), 2.90–2.96 (m, 1 H), 3.50 (s, 3 H), 4.51–4.59 (m, 1 H), 5.18 (s, 1 H), 5.90 (d, J = 9.6 Hz, 2 H), 6.50 (s, 1 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ = 25.1, 25.2, 25.3, 26.8, 33.1, 33.2, 42.2, 46.8, 52.7, 57.1, 59.3, 101.4, 103.3, 118.2, 129.5, 134.5, 139.9, 148.8, 154.6. HRMS (MALDI): m/z [M + Na]⁺ calcd for C₁₉H₂₅N₅O₃Na: 394.1849; found: 394.1861. Azocines 5; General Procedure DMAD, methyl propiolate or acetyl acetylene (1.2 mmol) was added to a solution of derivative 4a,c (1 mmol) in TFE (10 mL). The mixture was stirred for 4–8 hours at 35 °C (TLC monitoring). The solvent was evaporated under reduced pressure and the residue was crystallized from EtOAc–hexane to give the corresponding benzazocine-tetrazole 5a–d. Methyl 10-(1-Benzyl-1H-tetrazol-5-yl)-11-methoxy-7-methyl-5,6,7,10-tetrahydro[1,3]dioxolo[4′,5′:4,5]benzo-[1,2-d]azocine-9-carboxylate (5a) Yield: 350 mg (75%), pale brown solid; mp 116–118 °С; reaction time = 8 h. ¹H NMR (400 MHz, CDCl₃): δ = 2.74 (dt, J = 5.5, 16.5 Hz, 1 H), 2.80 (s, 3 H), 2.80–2.88 (m, 1 H), 2.49 (dt, J = 5.5, 15.1 Hz, 1 H), 3.68 (s, 3 H), 3.78 (s, 3 H), 3.96–4.08 (m, 1 H), 5.42 (AB, J = 15.6 Hz, 2 H), 5.90 (s, 2 H), 6.25 (s, 1 H), 6.86 (s, 1 H), 7.00–7.44 (m, 2 H), 7.21–7.29 (m, 3 H), 7.33 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 29.9, 35.2, 45.3, 50.6, 51.6, 52.4, 60.2, 92.9, 101.3, 105.8, 121.8, 127.2 (2 С), 128.1, 128.6 (2 С), 132.9, 134.3, 136.2, 141.3, 148.1, 154.2, 159.3, 169.7. HRMS (MALDI): m/z [M + Na]⁺ calcd for C₂₄H₂₅N₅O₅Na: 486.1747; found: 486.1758.