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Updated: Jun 21, 2025

A Direct, Regioselective and Atom-Economical Synthesis of 3-Aroyl-N-hydroxy-5-nitroindoles by Cycloaddition of 4-Nitronitrosobenzene with Alkynones

A Direct, Regioselective and Atom-Economical Synthesis of 3-Aroyl-N-hydroxy-5-nitroindoles by Cycloaddition of 4-Nitronitrosobenzene with Alkynones

Published on: January 21, 2020

Energetic Aspects and Molecular Mechanism of 3-Nitro-substituted 2-Isoxazolines Formation via Nitrile N-Oxide [3+2]

Ewa Dresler¹, Aneta Wróblewska², Radomir Jasiński³

¹Łukasiewicz Research Network-Institute of Heavy Organic Synthesis "Blachownia", Energetyków 9, 47-225 Kędzierzyn-Koźle, Poland.

Molecules (Basel, Switzerland)

|July 13, 2024

Abstract:

Regioselectivity and the molecular mechanism of the [3+2] cycloaddition reaction between nitro-substituted formonitrile N-oxide 1 and electron-rich alkenes were explored on the basis of the wb97xd/6-311+G(d) (PCM) quantum chemical calculations. It was established that the thermodynamic factors allow for the formation of stable cycloadducts along all considered models. The analysis of the kinetic parameters of the main processes show that all [3+2] cycloadditions should be realized with full regioselectivity. In all cases, the formation of 5-substituted 3-nitro-2-isoxazolidines is clearly preferred. It is interesting that regiodirection is not determined by the local electrophile/nucleophile interactions but by steric effects. From a mechanistic point of view, all considered reactions should be treated as polar, one-step reactions. All attempts to locate the hypothetical zwitterionic intermediates along the cycloaddition paths were, however, not successful.

Keywords:

Gibbs free energy of activation Gibbs free energy of reaction [3+2] cycloaddition isoxazolines

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