Electrochemically enabled synthesis of substituted isoxazolines

  • Samuel David Lee Holman

Student thesis: Doctoral Thesis


Synthetic electroorganic chemistry has recently become an attractive method for the preparation of many organic molecules.1 With the introduction of enabling technologies, such as IKA’s ElectraSyn 2.0, synthetic electrochemistry can be applied in a standardised way, allowing reproducible procedures. -- The study presented herein explores the electrochemical synthesis of substituted isoxazolines, using an inexpensive, environmentally benign mediator. Isoxazolines can be found in many natural products, as well as pharmaceutical and agricultural compounds. Traditionally, isoxazolines have been prepared using 1,3-dipolar cycloaddition reactions between nitrile oxides and dipolarophiles; other methods, such as transition metal-catalysed ring closures, have also been reported. However, nitrile oxides, with the exception of sterically encumbered aromatic nitrile oxides, are reactive and rapidly form dimers. In-situ preparations of these highly reactive species have been developed, though these often require toxic and/or expensive reagents, such as electrophilic halogenating agents and strong oxidants. There have been very few reports of more benign and environmentally friendly procedures, with alternative approaches which address these issues desirable. -- The electrochemically enabled synthesis of substituted isoxazolines has been realised, with a substrates scope of 45 examples that were isolated in up to 86% yield. Of particular note, previously elusive alkyl derived aldoximes have been successfully electrolysed under the optimised conditions, furnishing the desired products in moderate to good yields. Furthermore, green metrics were obtained that showed that this electrochemical procedure has a smaller impact on the environment when compared with other non-electrochemical methods. -- Building on previous work by Shono, it is envisioned that an electrochemical oxidation of a halide anion and subsequent combination with an aldoxime, followed by further oxidation and deprotonation by conjugate base, could generate a nitrile oxide. This nitrile oxide could participate in a 1,3-dipolar cycloaddition reaction with a dipolarophile to fashion a substituted isoxazoline. The reaction pathway was probed using both in-situ IR monitoring (using the commercially available ReactIR experimental set up) and 1H NMR. IR reaction profiling revealed pseudo-zero order reaction kinetics, as expected of a surface-mediated reaction. 1H NMR profiling of the electrochemical reaction between para-substituted benzaldehyde oximes and tertbutyl acrylate allowed Hammett and Swain-Lupton analyses to be performed. These analyses gave an inverted V-shaped plot that is indicative of change in rate-limiting step, consistent with a 1,3-dipolar cycloaddition reaction of ambiphilic nitrile oxide dipoles, as the change in rate-limiting step is attributed to the change in interacting frontier molecular orbitals. These NMR profiles may suggest that underlying physical phenomena may be responsible for the inverted V-shape of the Hammett and SwainLupton analyses. -- [See thesis for illustration] -- Additionally, the batch electrochemical reaction was successfully adapted into a flow procedure. These early results have allowed the isolation of the desired isoxazoline in 49% yield, showing great promise. Further work needs to be conducted as full consumption of starting material after a first-pass through the electrochemical cell has not been achieved to date.
Date of Award1 Jun 2020
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsUniversity of Strathclyde
SupervisorMarc Reid (Supervisor) & Nick Tomkinson (Supervisor)

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