A [4+3] Cycloaddition Reaction of Aza-ortho-quinone Methides with C,N-Cyclic Azomethine Imines for Synthesis of 1,2,4-Triazepines

Abstract

The base-induced formal [4+3] cycloaddition reaction of C,N-cyclic azomethine imines with aza-ortho-quinone methides, generated in situ, is reported. This protocol provided an efficient method for the synthesis of biologically important 1,2,4-triazepine derivatives, with a wide substrate scope and excellent functional-group tolerance, and it gives moderate to excellent yields under mild conditions. Several of the derivatives exhibited in vitro antitumor activities against the A2780 cell line in a screening of the cancer cell lines HCT-116, H2228, and A2780 by an MTT assay.

Key words

azaquinone methides - cyclic azomethine imines - [4+3] cycloaddition­ - triazepines - anticancer drugs

Publication History

Received: 08 July 2021

Accepted after revision: 12 August 2021

Accepted Manuscript online:
12 August 2021

Article published online:
24 August 2021

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• 23 1,2,4-Triazepines 3aa–ra; General Procedure A 25 mL Schlenk flask was charged with the appropriate C,N-cyclic azomethine imine 1 (0.2 mmol), K₂CO₃ (0.4 mmol), DCM (3 mL), and the [o-(chloromethyl)aryl]sulfonamide 2 (0.2 mmol). The mixture was stirred vigorously at r.t. for 2–6 h until the arylsulfonamide 2 was completely consumed. The solvent was then removed under reduced pressure and the crude product was purified by flash column chromatography.
• 24 8,14-Ditosyl-8,9,14,14a-tetrahydroquinazolino[4,3-b][1,3,4]benzotriazepine (3aa) White solid; yield: 105 mg (91%); mp 188.4–190.2 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 7.81 (d, J = 8.2 Hz, 2 H), 7.59–7.55 (m, 1 H), 7.52 (d, J = 8.1 Hz, 2 H), 7.42–7.37 (m, 6 H), 7.36–7.34 (m, 2 H), 7.31–7.27 (m, 1 H), 6.92 (dd, J = 6.0, 2.9 Hz, 1 H), 6.79 (s, 1 H), 6.73 (d, J = 7.8 Hz, 1 H), 6.26 (s, 1 H), 4.62 (d, J = 12.6 Hz, 1 H), 3.98 (d, J = 12.5 Hz, 1 H), 2.44 (s, 3 H), 2.40 (s, 3 H). ¹³C NMR (151 MHz, DMSO-d ₆): δ = 148.58, 145.73, 144.65, 138.63, 136.36, 133.81, 133.70, 132.64, 132.31, 131.76, 130.83, 130.59, 130.43, 130.41, 130.39, 128.40, 127.87, 127.37, 127.34, 125.68, 122.25, 72.49, 52.43, 21.53, 21.48. HRMS (ESI/Q-TOF): m/z [M + H]⁺ calcd for C₂₉H₂₇N₄O₄S₂: 559.1468, found: 559.1471; [M + Na]⁺ calcd for C₂₉H₂₆N₄NaO₄S₂: 581.1288; found: 581.1308.