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Mild Generation and Novel Reactivity of Nitroso Compounds

  • Author(s): Frazier, Charles Patrick
  • Advisor(s): Read de Alaniz, Javier
  • et al.
Abstract

The development of efficient methods for the formation of carbon-nitrogen bonds is of great interest in organic chemistry. While traditional approaches to C-N bond formation are well developed and have found widespread use, approaches utilizing an electrophilic source of nitrogen are vastly underdeveloped. Although a number of electrophilic sources of nitrogen have been developed, the efforts of our research have centered on the use of nitrosocarbonyl compounds. Due to their high reactivity, nitrosocarbonyl intermediates can only be generated in situ and are classically obtained from the oxidation of hydroxamic acid derivatives using periodate salts. However, this in situ oxidation protocol, which is commonly used in the hetero-Diels-Alder (HDA) reaction, is incompatible with the other reactions because the initially formed adduct is highly susceptible to decomposition. While this has significantly limited the development of chemistry utilizing nitrosocarbonyl compounds, we postulated that if the oxidation conditions were mild enough to circumvent product decomposition, nitrosocarbonyls could be utilized in a wide variety of C-N bond-forming reactions.

Recently, we reported the first example of the aerobic generation of nitrosoformate intermediates for use in the nitroso ene reaction. The aerobic oxidation method, which relies on the use of catalytic amounts of CuCl (5 mol %) and uses air as the terminal oxidant, proved mild enough to avoid decomposition of the ene adducts, affording the allylic hydroxylamines in up to quantitative yields. Additionally, the oxidation protocol is highly general for a wide variety of N-substituted hydroxylamines; the Diels-Alder reaction can be carried out in up to quantitative yields employing an array of nitroso compounds. Moreover, by switching to photoredox conditions using Ru(bpy)3Cl2, the nitrosocarbonyl intermediates can be efficiently generated with temporal and spatial control.

As proposed, the mild oxidation conditions allowed the expansion of nitrosocarbonyl chemistry into new areas, such as the nitroso aldol reaction. Through the synergistic combination of our aerobic oxidation with known Lewis acid activation of beta-ketoesters, the alpha-amination and alpha-oxygenation of carbonyl compounds was achieved for the first time using nitrosocarbonyl compounds. All of the reactions are operationally simple to perform, utilize reagent grade solvents and air as the terminal oxidant, and the only byproduct is water.

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