Sulphide as a leaving group: highly stereoselective bromination of alkyl phenyl sulphides.

Daniele Canestrari,John O'Brien,Lorenza Ghisu,Mauro F A Adamo,Ilaria Biancofiore,Hasim Ibrahim,Caterina Cioffi,Stefano Lancianesi,Manuel Ruether

doi:10.1039/c9sc03560e

Daniele Canestrari, John O'Brien + Show 7 more

Open Access

https://doi.org/10.1039/c9sc03560e

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Abstract

A conceptionally novel nucleophilic substitution approach to synthetically important alkyl bromides is presented. Using molecular bromine (Br2), readily available secondary benzyl and tertiary alkyl phenyl sulphides 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 and nitrile compounds in mostly high yields and purities. Remarkably, protic functionalities such as acids and alcohols are tolerated. Enantioenriched benzylic β-sulphido esters, readily prepared by asymmetric sulpha-Michael addition, produce the corresponding inverted bromides 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 the one-pot preparation of γ-azido alcohol (S)-5 in 90% ee. NMR studies revealed an initial formation of a sulphide bromine adduct, which in turn is in equilibrium with a postulated dibromosulphurane intermediate that undergoes C-Br bond formation.

Highlights

Alkyl bromides are versatile and extensively utilised synthetic intermediates, constitute precursors for a wide range of C–C1 and C–heteroatom[2] bond forming reactions, and are motifs found in biologically active natural products.[3]
Numerous methods have been developed for their preparation,[4] with protocols relying on the nucleophilic substitution of alkyl alcohols with bromide ions remaining the most widely applied and studied.[5,6]
Temperature, methods of generation, isolation and structural analysis,[13] it has been suggested that the reaction could, via an equilibrium, generate tetrahedral sulphur(II) molecular complexes A (MCs), trigonal pyramidal sulphur(IV) bromosulphonium bromides B or trigonal bipyramidal (TB) sulphur(IV) dibromosulphurane adducts C (Scheme 1c).[13,14]

Summary

Introduction

Alkyl bromides are versatile and extensively utilised synthetic intermediates, constitute precursors for a wide range of C–C1 and C–heteroatom[2] bond forming reactions, and are motifs found in biologically active natural products.[3]. Using conditions from entry 2 in Table 1 we proceeded to examine the scope of our bromination with various b-sulphido carbonyl compounds, which generally gave good to excellent yields of the corresponding bromide products (Table 2, 4a–4p).

Results

Conclusion