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Enantiospecific preparation of alkyl phenyl chlorides, bromides and acetates via sulfuranes

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posted on 2020-10-22, 14:58 authored by Daniele Canestrari

Chapter 1

This chapter offers an extensive introduction about alkyl halides, an important class of intermediates in organic chemistry and biologically active compounds in nature and drug discovery. In particular, we have reviewed their physical and chemical properties, their methods of synthesis, highlighting the stereoselective procedures of their preparation and the relevant limitations. Finally, a brief overview about the organocatalytic reactions involved in the stereospecific carbon-sulfur bond formation was discussed in order to present the methods of synthesis of enantiopure sulfides, which were key substrates used in this experimental work.

Chapter 2

A novel chlorination reaction of readily available secondary and tertiary alkyl phenyl sulfides using (dichloroiodo)benzene (PhICl2) was developed and reported. This mild and rapid nucleophilic chlorination is extended to sulfa-Michael derived sulfides, affording elimination-sensitive β-chloro carbonyl compounds in good to high yields. The chlorination of enantioenriched benzylic sulfides to the corresponding inverted chlorides proceeds with high stereoselectivity, providing a formal entry into enantioenriched chloro-Michael adducts. Enantiopure chlorides can be involved as suitable intermediates for the synthesis of top-selling drugs, such as dapoxetine. A mechanism implying the formation of a dichloro-λ4-sulfurane intermediate is proposed.

Chapter 3

A novel nucleophilic substitution approach to synthetically important alkyl bromides was described and reported. Using molecular bromine (Br2), readily available secondary benzyl and tertiary alkyl phenyl sulfides are converted into the corresponding bromides under exceptionally mild, acid- and base-free

reaction conditions. This simple transformation allows the isolation of elimination sensitive benzylic β-bromo carbonyl compounds in mostly high yields and purities. Remarkably, protic functionalities, such as carboxylic acids, are tolerated. The bromination of enantioenriched benzylic β-sulfido esters to the corresponding inverted bromides proceeds with high stereoselectivities, approaching complete enantiospecificity at –40 °C. Significantly, the reported benzylic β-bromo esters can be stored without racemisation for prolonged periods at –20 °C. Their synthetic potential was demonstrated by their one-pot derivatisation into a highly enantiopure -azido alcohol. NMR studies revealed an initial formation of a sulfide-bromine adduct, which in turn is in an equilibrium with a postulated dibromosulfurane intermediate that undergoes C–Br bond formation.

Chapter 4

A new visible-light catalysed desulfurative acetoxylation of easy accessible alkyl phenyl sulfides was herein reported and developed in Prof. Shibata’s research group in Nagoya Institute of Technology (NITech), Japan. Using PhI(OAc)2/I2 as oxidant system, this mild and green method provides activated benzylic acetates and β-acetoxy esters in moderate to very high yields. Preliminary investigations on enantiomerically enriched β-sulfido esters exhibit poor stereoselectivity under standard reaction conditions, suggesting a possible mechanism via nucleophilic displacement in a SN2 fashion rather than a photocatalytic radical pattern


Irish Research Council


First Supervisor

Prof. Mauro F. A. Adamo


A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2019.

Published Citation

Canestrari D. Enantiospecific preparation of alkyl phenyl chlorides, bromides and acetates via sulfuranes [PhD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2019.

Degree Name

Doctor of Philosophy (PhD)

Date of award



  • Doctor of Philosophy (PhD)