Mechanochemical Synthesis and Isomerization of N-Substituted Indole-3-carboxaldehyde Oximes †.

Matej Baláž,Zuzana Kudličková,Ján Imrich,Nina Daneu,Ľudmila Balážová,Mária Vilková

doi:10.3390/molecules24183347

Abstract

Performing solution-phase oximation reactions with hydroxylamine hydrochloride (NH2OH·HCl) carries significant risk, especially in aqueous solutions. In the present study, four N-substituted indole-3-carboxaldehyde oximes were prepared from the corresponding aldehydes by solvent-free reaction with NH2OH·HCl and a base (NaOH or Na2CO3) using a mechanochemical approach, thus minimizing the possible risk. In all cases, the conversion to oximes was almost complete. The focus of this work is on 1-methoxyindole-3-carboxaldehyde oxime, a key intermediate in the production of indole phytoalexins with useful antimicrobial properties. Under optimized conditions, it was possible to reach almost 95% yield after 20 min of milling. Moreover, for the products containing electron-donating substituents (-CH3, -OCH3), the isomerization from the oxime anti to syn isomer under acidic conditions was discovered. For the 1-methoxy analog, the acidic isomerization of pure isomers in solution resulted in the formation of anti isomer, whereas the prevalence of syn isomer was observed in solid state. From NMR data the syn and anti structures of produced oximes were elucidated. This work shows an interesting and possibly scalable alternative to classical synthesis and underlines environmentally friendly and sustainable character of mechanochemistry.

Highlights

Aldoximes are a fundamental class of compounds employed for purification, protection, and characterization of aldehydes [1]
The product containing nearly pure syn isomer can be synthesized for the 1-methoxy analog after the solvent-free milling of the reagents for 20 min in a tungsten carbide milling vessel at 500 rpm
When the residual hydroxylamine hydrochloride is not immediately washed out after the mechanochemical process, the anti oxime is nearly completely transformed into the syn isomer within three days

Summary

Introduction

Aldoximes are a fundamental class of compounds employed for purification, protection, and characterization of aldehydes [1]. They are important precursors for various nitrogen-based organic compounds including amines [2], nitriles [3], and nitro compounds [4]. The solvent-free solid-state reactions for oxime synthesis are gaining popularity [7,8,9,10,11,12,13,14,15,16,17]. Among various solvent-free solid-state approaches, the addition of extra energy via microwave irradiation [18,19] or Molecules 2019, 24, 3347; doi:10.3390/molecules24183347 www.mdpi.com/journal/molecules

Methods

Discussion

Conclusion