One-Pot Highly Regioselective Synthesis of Indole-Fused Pyridazino[4,5-b][1,4]benzoxazepin-4(3H)-ones by a Smiles Rearrangement

Abstract

A simple and convenient synthesis of indole-fused pyridazino[4,5-b][1,4]benzoxazepin-4(3H)-ones is described. A range of 2-(1H-indol-2-yl)phenols and 4,5-dichloropyridazin-3-ones are compatible with this reaction. A Smiles rearrangement is proposed as a key step in the highly regioselective construction of the products. The easy availability of the starting materials makes this an appealing method in ­organic synthesis.

Key words

indoles - indolopyridazinobenzoxazepinones - regioselectivity - polycyclic heterocycles - Smiles rearrangement

• References and Notes

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• 27 Indolo[1,2-d]pyridazino[4,5-b][1,4]benzoxazepin-9(8H)-ones 3a–r; General Procedure The appropriate 2-(1H-indol-2-yl)phenol 1 (0.30 mmol), 2-tetra­hydropyranylpyridazin-3-one 2 (0.30 mmol), and K₂CO₃ (2.5 equiv.) were successively added to a 10 mL Schlenk tube. DMF (2 mL) was then added from a dropper and the resulting solution was stirred at 80 °C for 3 h. The mixture was cooled to r.t. then extracted with EtOAc (×3). The combined organic phase was washed with brine, dried (Na₂SO₄), and filtered. The solvent was then removed in vacuoto give a crude mixture that was purified by column chromatography (silica gel). 8-(Tetrahydro-2H-pyran-2-yl)indolo[1,2-d]pyridazino[4,5-b][1,4]benzoxazepin-9(8H)-one (3a) Light-yellow solid; yield: 104 mg (90%); mp 122–124 °C. ¹H NMR (500 MHz, CDCl₃): δ = 8.43 (s, 1 H), 7.72–7.70 (m, 2 H), 7.66 (d, J = 8.2 Hz, 1 H), 7.54–7.52 (m, 1 H), 7.40–7.27 (m, 4 H), 6.98 (s, 1 H), 6.15–6.13 (m, 1 H), 4.17–4.14 (m, 1 H), 3.81–3.76 (m, 1 H), 2.23–2.15 (m, 1 H), 2.07–2.04 (m, 1 H), 1.80–1.71 (m, 3 H), 1.60–1.58 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 157.55, 157.02, 144.65, 136.58, 135.94, 133.09, 131.39, 130.48, 129.45, 129.39, 126.36, 123.99, 123.54, 122.82, 122.15, 121.69, 111.56, 105.97, 83.32, 68.98, 28.99, 24.89, 22.83. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₀N₃O₃: 386.1499; found: 386.1491.