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Intermolecular [5 + 1]-Cycloaddition between Vinyl Diazo Compounds and tert-Butyl Nitrite to 1,2,3-Triazine 1-Oxides and Their Further Transformation to Isoxazoles

Luca De Angelis, Haifeng Zheng, Matthew T. Perz, Hadi Arman and Michael P. Doyle*

*Department of Chemistry, The University of Texas at San Antonio, San Antonio, Texas 78249, United States, Email:

L. De Angelis, H. Zheng, M. T. Perz, H. Arman, M. P. Doyle, Org. Lett., 2021, 23, 6542-6546.

DOI: 10.1021/acs.orglett.1c02352


1,2,3-Triazine 1-oxides are formed by addition of tert-butyl nitrite to the vinylogous position of vinyl diazo compounds. This formal [5 + 1] cycloaddition occurs under mild conditions with high functional group tolerance and regioselectivity, and can be employed for late-stage functionalization. Upon heating in refluxing chlorobenzene, an extrusion of N2 provides isoxazoles in very high yields.

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proposed mechanism

Formation of 1,2,3-triazine 1-oxide through nitrosyl exchange between tert-butyl nitrite (TBN) and vinyl diazo compounds

In a dry 8-mL tube, tBuONO (1.3 equiv., 0.33 mmol) was added to 3 mL solution containing 20:1 v/v DCM:HFIP, and the vinyl diazo compound (1.0 equiv., 0.25 mmol, 0.1 M in DCM) was added dropwise to the solution over 1-2 minutes. The solution was stirred at room temperature under air for 1 h. The solvent was then removed under reduced pressure, and the residue was purified by flash chromatography (hexane/ethyl acetate = 3/1) to give the desired 1,2,3-triazine 1-N-oxide product.

Thermal decomposition of 1,2,3-triazine 1-oxide to form isoxazoles

A dry 10-mL round bottom flask was equipped with a magnetic stir bar and was charged with 1,2,3-triazine 1-N-oxide (0.2 mmol) and 2.0 mL of PhCl. Equipped with a reflux condenser, the reaction solution was heated to reflux (oil bath). Upon consumption of triazine N-oxide observed by TLC, the reaction solution was cooled to rt, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (hexane/ethyl acetate = 9/1) to give the desired isoxazole product.

Inverse Electron Demand Diels-Alder-Type Heterocycle Syntheses with 1,2,3-Triazine 1-Oxides: Expanded Versatility

S. Biswas, L. De Angelis, G. Rivera, H. Arman, M. P. Doyle, Org. Lett., 2023, 25, 1104-1108.

Synthesis of 1,2,3-Triazine Derivatives by Deoxygenation of 1,2,3-Triazine 1-Oxides

G. Rivera, L. De Angelis, A. Al-Sayyed, S. Biswas, H. Arman, M. P. Doyle, Org. Lett., 2022, 24, 6543-6547.

Key Words

1,2,3-Triazines, Isoxazoles

ID: J54-Y2021