Coupling with Thiols

Figure 5.11 NPIA is one of the shortest heterobifunctional reagents. It reacts with amine-containing molecules through its p-nitrophenyl ester end to produce amide bonds. The iodoacetyl group then can be used to couple with thiol compounds to give stable thioether linkages.

The oxidative reactions of this sequence are catalyzed by the microsomal P-450 system [69, 70, 71]. A P-450 system from rat liver can also oxidize morphine [72]. One product of this oxidation is morphinone, a highly toxic electrophile that couples with thiol groups. The latter reaction may deplete glutathione and in other ways may account for the hepatotoxicity of morphine [73, 74]. The demethylation of codeine to morphine probably accounts for the analgesic action of codeine, and people with a defect in this demethylating system probably get no analgesia from codeine [75, 76]. Rats, too, show strain differences in the ability to demethylate codeine to morphine [77]. Quinidine, quinine, or sparteine inhibit the conversion of codeine to morphine, presumably by inhibiting the P-450 enzyme [71, 78]. While O-demethylation converts codeine to morphine, N-demethylation also occurs and produces norcodeine [79]. 

Group 9 Metal-Catalyzed Cross-Coupling with Thiols. 49... 

In 2013, Liu et al. [147] reported the application of MnCl2 for the arylation of aryl and alkyl thiols with aryl iodides. The specific conditions that were used were MnClj (20 mol%), and phen ligand (20 mol%) with CSjCOj (1.5 equiv) in toluene or dioxane at 148 °C for 48 h. Good to excellent yields of the arylthiols were obtained, and good functional group tolerance, enabling steric2illy hindered iodides to couple with thiols, was evident. 

Oxidation of thiol 287 with air in glyme gave disulfide 288, which on intramolecular oxidative coupling with A,)V-dibromoisocyanurate formed macrocycle 289 in 42% yield (Scheme 188) (99MI3). 

The coupling of thiols with aryl halides has been recently reported using Ni(NHC)2 complexes [171]. After screening different pre-catalysts, compound 28 showed the best behaviour in terms of activity and substrate scope, allowing the coupling of electron rich and poor aryl bromides with aryl or alkyl thiols (Scheme 6.52). 

The use of tetraoctylammonium salt as phase transfer reagent has been introduced by Brust [199] for the preparation of gold colloids in the size domain of 1-3 nm. This one-step method consists of a two-phase reduction coupled with ion extraction and self-assembly using mono-layers of alkane thiols. The two-phase redox reaction controls the growth of the metallic nuclei via the simultaneous attachment of self-assembled thiol monolayers on the growing clusters. The overall reaction is summarized in Equation (5). 

Several palladium catalysts for formation of aryl sulfides from aryl halides have been investigated more recently. A combination of Pd2(dba)3 and DPEphos catalyzed the formation of a broad range of diaryl sulfides in the presence of 1 mol.% palladium and NaO-t-Bu base in toluene solvent.12,rThe highest yields of alkyl aryl sulfides were obtained from aryl triflates and n-butyl thiol catalyzed by a combination of palladium acetate and BINAP. However, these reactions contained 10 mol.% catalyst, were long, and required deactivated aryl triflates. A combination of Pd2(dba)3 and DPPF catalyzed the coupling of thiols with resin-bound aryl halides.121... 

Although not directly analogous to the coupling of thiols with aryl halides, the reaction of thiourea with an aryl halide in the presence of palladium catalyst, nevertheless, can be used to generate a thiophenol from an aryl halide after hydrolysis (Equation (39)).129 This process occurred in greater than 90% yield with a variety of simple aryl halides ... 

Figure 1.121 Sodium tetrathionate reacts with thiols to form reactive sulfenylthiosulfate intermediates. Another sulfhydryl-containing molecule may couple to this active group to create a disulfide linkage.

SAMSA-fluorescein, 5- [2(and 3)-5-(acetylmercapto)-succinoyl]amino fluorescein, is a fluorescent probe containing a protected sulfhydryl group. In its protected state, the compound is unre-active. The acetyl-protecting group can be removed by treatment with dilute NaOH at pH 10.0 (Figure 9.9). The resulting free sulfhydryl derivative can be used to label thiol-reactive crosslinkers or to couple with sulfhydryl residues on proteins and other molecules. After activating... 

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