Preparation and purification of zinc sulfinate reagents for drug discovery

Abstract

SUMMARY The present protocol details the synthesis of zinc bis(alkanesulphinate)s that can be used as general reagents for the formation of radical species. The zinc sulphinates described herein have been generated from the corresponding sulphonyl chlorides by treatment with zinc dust. The products may be used crude, or a simple purification procedure may be performed to minimize incorporation of water and zinc chloride. Elemental analysis has been conducted in order to confirm the purity of the zinc sulphinate reagents; reactions with caffeine have also been carried out to verify the reactivity of each batch that has been synthesized. Although the synthesis of the zinc sulphinate salts generally proceeds within 3 h, workup can take up to 24 h and purification can take up to 3 h. Following the steps in this protocol would enable the user to generate a small toolkit of zinc sulphinate reagents over the course of one week.

Radicals: Reactive Intermediates with Translational Potential

“… 108 , 109 The first reagent of the series, zinc difluoromethanesulfinate, or [CF 2 H–SO 2 ] 2 Zn (dubbed “DFMS”), is an air-stable compound that allowed for C–H to C–CF 2 H transformation ( Figure 4 B). 108 Heteroarene trifluoromethylation was revisited: [CF 3 SO 2 ] 2 Zn (TFMS) was synthesized, and the yield-enhancing zinc effect was observed. 110 Building on this positive effect, a flurry of other zinc bis(fluoroalkane)sulfinate reagents were synthesized (only their chemical acronyms are shown here).…”

“…C–H functionalization using these salts can be carried out in a variety of biologically relevant media (aqueous and aerobic), including cell lysate, oolong tea, and a lactamase buffer ( Figure 4 B)! 108 Such practicality is reminiscent of a “click” reaction and points to the robust nature of these transformations. 113 It is worth noting that sulfinate salts can also participate in desulfinylative cross-couplings with boronic acid derivatives and carboxylic acids.…”

“…Tandem functionalization of dihydroquinine was realized with isopropyl and trifluoromethyl radicals attacking the electrophilic C-2 and nucleophilic C-7 sequentially to yield 61 . 108 Relative contributions of opposing substituents were found to depend on external factors such as solvent and pH—thus, the regiochemical outcome of certain substrates can be fine-tuned through simple variations in reaction conditions. While in an acidic chloroform/water mixture the electrophilic CF 3 radical reacts with 62 selectively at C-4, use of DMSO as solvent elicits “conjugate reactivity” of the ester group and C-5 substitution prevails.…”

Translational tidbits

“…Forrest and Halford said the deal was inspired by the success of Sigma-Adrich's series of zinc-based difluoromethylation compounds from Baran's lab. 1 Those compounds, which came on the market last year, have been widely adopted in medicinal chemistry laboratories in academia and industry as an easy way to fluoridate pharmaceutical leads.…”

Study of the zinc action on the 2-chloroethyl 2-bromo-2-perfluoroalkylethanoates

“…The perfluoroalkyl chains constitute an important source of reagents for these syntheses. These chains have particular chemical [1,2], physical [3][4][5][6] and biological [7][8][9][10] properties. Their introduction into organic molecules gives them particular properties compared to their non-fluorinated homologues [11].…”