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Development of Regio-, Chemo- and Enantiospecific Halogenations via Hypervalent Sulfur(IV) and their Application to the Sustainable Synthesis of Enantioenriched Bromides and Fluorides

thesis
posted on 24.06.2021, 11:09 by Francesco Alletto
This PhD thesis describes the use of hypervalent sulfur(IV) for the development of new synthetic methodologies to prepare much sought alkyl bromides and fluorides.
In order to frame the context of the work and rationalise the results obtained we present, in the first chapter of this thesis, a literature review of sulfur(IV) and (VI) hypervalent compounds detailing their preparation and application in organic synthesis.
In the second chapter of this thesis, we describe a novel procedure to prepare alkyl fluorides in up to 77% isolated yields and 35% enantiomeric excess. The reaction made use of electrophilic fluorinating reagent N-fluorobenzenesulfonimide (NFSI) to achieve desulfurative fluorination of alkyl sulfides under mild conditions and in short (10-120 minutes) reaction times. Moreover, the presence of hypervalent sulfur(IV) intermediates was observed via NMR analysis.
In the third chapter of this thesis, we report other means to achieve enantioselective desulfurative fluorination of chiral thia-Michael derived alkyl sulfides. Though no conditions suitable for the production of highly enantioenriched alkyl fluorides have been found, three different sets of fluorinating conditions have been identified for the efficient production of thia-Michael derived alkyl fluorides in excellent isolated yields (up to 92% yield) and short reaction times. Moreover, an unexpected and unprecedented methodology to form carbon–carbon bonds has been discovered.
In the fourth and final chapter of the thesis, we present the first example of an on-water enantiospecific synthesis of alkyl bromides. This procedure allowed the conversion of secondary activated alkyl sulfides to benzylic alkyl bromides, in 80-99% isolated yields and excellent enantioselectivity (up to 92% ee; 94% es). The conditions identified required no temperature control, made use of no solvent and did not employ liquid-liquid organic extraction on a multigram-scale.

History

First Supervisor

Prof. Mauro F. A. Adamo

Second Supervisor

Dr. Robert Williams

Comments

Submitted for the Award of Doctor of Philosophy to the Royal College of Surgeons in Ireland, 2021.

Published Citation

Alletto F. Development of Regio-, Chemo- and Enantiospecific Halogenations via Hypervalent Sulfur(IV) and their Application to the Sustainable Synthesis of Enantioenriched Bromides and Fluorides [PhD Thesis] Dublin: Royal College of Surgeons in Ireland; 2021

Degree Name

Doctor of Philosophy (PhD)

Date of award

31/05/2021

Programme

  • Doctor of Philosophy (PhD)

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