Palladium-catalyzed C–N Cross Coupling Of Chiral Sulfinamides And Aryl Halides

Nitrogen-contained organic compounds are widespread on the earth, most ofwhich have important physiological activity of medicinal value and industrial value.Organic synthesis is a very important way to obtain nitrogen-contained organiccompounds. Up to date, the C-N cross-coupling reaction has been very extensiveinvestigated, the recently developed Buchwald-Hartwig coupling reaction is animprovement of great significance to the C-N cross-coupling reaction, and is animportant method to realize the amination of aromatics to obtain aryl amines.There have already been varieties of synthetic methods to produce chiral N-alkyl-alkylsulfinamides, however, chiral N-aryl-alkylsulfinamide is short of universal,effective, convenient synthetic methods. The C-N cross-coupling of chiral pure, cheapand readily available chiral tert-butanesulfinamide and aryl-halides is an idealsynthesis method to get chiral N-aryl sulfinamide. We attempted some existedmethods, and only extreme low yields or even no desired products were obtained. Byaccident, we discovered that when a little of water was added to the reaction, the C-Ncoupling reaction of chiral tert-butanesulfinamide and aryl-halides can be performedsmoothly to gain high yield of C-N coupling product.In order to obtain the best reaction conditions by the reference standard ofchemical yields after isolation, we selected bromobenzene and (R)-tert-butylsulfinamide as substrate for the coupling reaction, then respectively investigated thefactors including the loading of catalyst, type and dosage of ligand, reaction duration,temperature, type and dosage of base, solvent and the content of water which werethought to affect the efficiency of the reaction. Finally, got the optimal reactionconditions:1mol%Pd2(dba)3as the palladium source catalyst,5mol%tBu-XPhosas the ligand,2eq. NaOH as the base,6mL toluene with5%water as the solvent,temperature was90oC and duration was20hours.With the obtained optimal reaction conditions, we then investigated the cross-coupling reaction of tert-butanesulfinamide and bromobenzene,4-bromotoluene,2- bromotoluene,3-bromotoluene,3-methoxy phenyl bromide,4-Bromobenzoic acid,4-nitrobromobenzene,4-Bromoacetophenone,4-fluorophenyl bromide,4-bromobiphenyl,2-Bromonaphthalene,1-Bromonaphthalene, iodobenzene,Chlorobenzene,4-chloronitrobenzene,3-chloronitrobenzene,2-Bromopyridine,respectively. The coupling of aryl bromides with tert-butanesulfinamide carried outbetter than that of aryl chlorides and iodobenzene. And aryl bromides with electron-withdrawing group afforded higher yields than that with electron-donating groups.The cross-coupling reactions of p-toluenesulfinamide with bromobenzene,4-bromotoluene,4-nitrobromobenzene, and4-bromoacetophenone were alsoinvestigated under the similar reaction conditions respectively. It was observed that4-nitrobromobenzene and4-bromoacetophenone did not react with p-toluenesulfinamide, and the yields of bromophenyl and4-bromotoluene with p-toluenesulfinamide were moderate. All compounds were characterized by1H NMR,13C NMR, ESI-MS and IR spectroscopy.The paper also described the application of N-phenyl-tert-Butyl sulfinamide. N-Aryl tert-butanesulfinamides were readily derived into other compounds. N-methylation and N-allylation of (R)-N-phenyl tert-butanesulfinamide were smoothlyperformed with sodium hydride as a base to give N-methyl-N-phenyl tert-butanesulfinamide and N-allyl-N-phenyl tert-butanesulfinamide, which laid afoundation for further applications of the N-phenyl-tert-butyl sulfonamide.