1,3-Dipolar [3+3] Cycloaddition of 1,4-Benzodiazepinone-Based Nitrones with α-Halohydroxamates for Diastereoselective Synthesis of Novel d-Edge Heterocycle-Fused 1,4-Benzodiazepinones

Abstract

Promoted by K₂CO₃ (2.0 equiv), the 1,3-dipolar [3+3] cy­cloaddition between 1, 4-benzodiazepinone-based nitrones and α-halohydroxamates processed smoothly under the mild reaction conditions and delivered structurally novel and complex cis- or trans-configured d-edge heterocycle-fused 1,4-benzodiazepinones in up to >99% isolated yield with >20:1 dr. The relative configuration of the title chemical entities was clearly identified with the use of single-crystal X-ray structure analysis. The reaction mechanism was assumed to interpret the diastereoselective production of the obtained cis- or trans-configured d-edge heterocycle-fused 1,4-benzodiazepinones.

Key words

1,3-dipolar [3+3] cycloaddition - 1,4-benzodiazepinone-based nitrone - α-halohydroxamate - diastereoselectivity - heterocycle-fused 1,4-benzodiazepinone

Publication History

Received: 27 July 2021

Accepted after revision: 09 September 2021

Accepted Manuscript online:
09 September 2021

Article published online:
01 October 2021

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• 11 Typical Procedure and Characterization Data for 3db A mixture of 1,4-benzodiazepinone-based nitrones 1d (1.0 equiv, 0.1 mmol), α-halohydroxamates 2b (2.0 equiv, 0.2 mmol), and K₂CO₃ (2.0 equiv, 0.2 mmol) in TFE (2.0 mL) was stirred at room temperature for 0.5–1 h until 1,4-benzodiazepinone-based nitrones were consumed completely indicated by TLC plate. The reaction mixture was concentrated under reduced pressure, and the crude products were purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 4:1 to 7:1) to afford product cis- 3db, 94% yield; mp 227.0–227.2 °C. ¹H NMR (400 MHz, CDCl₃): δ = 4.43 (d, J = 8 Hz, 1 H), 7.67 (d, J = 2 Hz, 1 H), 7.63 (td, J = 7.2, 1.2 Hz, 1 H), 7.59–7.55 (m, 3 H), 7.46–7.42 (m, 1 H), 7.38 (dd, J = 8.4, 2.4 Hz 1 H), 7.35–7.30 (m, 4 H), 7.28–7.26 (m, 4 H), 7.15–7.03 (m, 6 H), 5.76 (s, 1 H), 5.05 (d, J = 8.4 Hz, 1 H), 4.45 (d, J = 15.6 Hz, 1 H), 4.27 (d, J = 2 Hz, 1 H), 3.53 (d, J = 16 Hz, 1 H), 3.47 (d, J = 11.2 Hz, 1 H), 3.03 (d, J = 8.4 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 164.9, 163.9, 140.0, 137.1, 135.9, 134.0, 132.8, 132.5, 132.2, 131.9, 130.7, 130.6, 130.2, 130.1, 129.8, 129.5, 128.9, 128.8, 128.7, 128.5, 128.2, 127.9, 127.5, 126.7, 124.7, 123.7, 90.1, 82.1, 58.9, 53.1 ppm. HRMS (ESI): m/z calcd for C₃₇H₂₉BrClN₃O₄ [M + H]⁺: 694.1108; found: 694.1103.
• 12 CCDC 2046001 (trans-3dg) and CCDC 2106234 (cis-3cd) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Center via www. ccdc.cam.ac.uk/structures

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