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Synthesis of O-tert-Butyl-N,N-disubstituted Hydroxylamines by N-O Bond Formation

Jarvis Hill and David Crich*

*Department of Chemistry, University of Georgia, 140 Cedar Street, Athens, Georgia 30602, United States, Email:

J. Hill, D. Crich, Org. Lett., 2021, 23, 6337-6341.

DOI: 10.1021/acs.orglett.1c02215

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The reaction of magnesium amides with tert-butyl 2,6-dimethyl perbenzoate in tetrahydrofuran at 0 C provides O-tert-Butyl-N,N-disubstituted hydroxylamines by direct N-O bond formation with a broad functional group tolerance. A reaction mechanism is presented to account for the observed reactivity.

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General Procedure for the Synthesis of O‐tert‐butyl‐N,N‐disubstituted hydroxylamines

To a stirred solution of amine (0.75‐1.0 mmol, 2.5 eq.) in 0.75‐1.0 mL anhydrous THF under an argon atmosphere at 0 C was added EtMgBr (3 M in diethyl ether) (0.6‐0.8 mmol, 2.0 eq.) and the solution was stirred for 15 min. After such time, perester (0.3‐0.4 mmol, 1.0 eq.) was added dropwise as a solution in 0.75‐1.0 mL anhydrous THF (0.2 M total) to the stirred magnesium amide solution. The solution was stirred for an additional 15 min (30 min total reaction time) at 0 C, after which, the solution was diluted with EtOAc (10 mL) and washed with NaHCO3 (1 x, 10 mL) followed by brine (1 x, 10 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated in vacuo. Flash column chromatography on silica (EtOAc:Hexanes) of the crude material afforded the title O‐tert‐butyl‐N,N‐disubstituted hydroxylamines.

Note on magnesium amide formation: while we have not encountered any issues generating the corresponding magnesium amides, caution should be exercised on larger scales as ethane gas is rapidly evolved upon deprotonation.

Key Words


ID: J54-Y2021