JACS: asymmetric synthesis of sulfimide -- arylation of sulfimide

Sulfimides are hexavalent sulfur compounds containing one oxygen atom, one nitrogen atom and two carbon substituents When two carbon substituents are different, the sulfur atom becomes the chiral center Chiral sulfimides have unique properties, such as good solubility in polar solvents At the same time, sulfimide is also a potential bioelectrophore in pharmaceutical chemistry, and the stereochemistry of sulfur atom has a great influence on biological activity Therefore, the development of new methods for stereoselective synthesis of chiral sulfimides is of great significance for accelerating the study of new bioactive molecules (source: J am Chem SOC.) the synthesis of chiral sulfimides mainly includes the following methods (Figure 2): 1) stereospecific transfer reaction of nitrogen; 2) stereospecific oxidation of chiral sulfimides; 3) kinetic resolution strategy; 4) desymmetry strategy; 5) Keiji maruoka The alkylation of chiral Sulfinamide developed by the research group Recently, the Keiji maruoka group of Kyoto University, Japan, has realized the Cu catalyzed arylation of chiral sulfimides and synthesized a series of chiral sulfimides It is worth noting that although nitrogen atom is more nucleophilic, the reaction has excellent sulfur atom selectivity After being treated with acid or alkali, the product of arylation can form chiral aryl sulfonamides, which can be further arylated or alkylated, providing a modular method for the synthesis of chiral sulfonamides Relevant research results were published in J am Chem SOC (DOI: 10.1021 / JACS 9b11298) (source: J am Chem SOC.) the author first used t-butylsulphonamide-1 as template substrate for condition optimization (Table 1) By optimizing the reaction conditions of protecting group, solvent, alkali and reactant equivalent on N, the author determined the optimal reaction conditions as follows: Cui as metal salt, pH 2 IOTF as arylation reagent, dicyclohexylmethylamine as alkali, DMSO as solvent, 4 Å molecular sieve as additive, substrate reacted at 60 ℃ for 24 hours, and finally the target product was obtained in 94% yield It is worth mentioning that the product is sulfonimide with tert butyl substitution, which is unstable under strong alkaline condition Therefore, the use of weak base and highly electrophilic arylation reagents is very important for the success of the reaction (source: J am Chem SOC.) determined the optimal reaction conditions, and then the author inspected the generality of the reaction (Table 2) Firstly, the substrate range of diaryldionium salt was investigated The substrate with power supply group can get the product in good yield, but the yield of symmetrical diaryldionium salt with electric absorption group is low (30% - 43%), while the yield of asymmetric diaryldionium salt can get medium to high, which may be due to the formation of unreacted electron donor acceptor (EDA) by amine or sulfamide ）Complex When there are substituents in the ortho or meta position of diaryldionium salt, the target product can be obtained in medium yield In addition, α, β - unsaturated sulfimide can also be obtained by this method It is important that in these reactions, the chirality of the raw materials remains unchanged and there is no racemization process When the scale reaction of 6 mmol is adopted, the product can also be obtained in 82% yield (source: J am Chem SOC.) then, the author used acid or alkaline conditions to remove the tert butyl of the product, and the generated Sulfinamide chirality can remain unchanged As the reaction and the corresponding alkyl removal process have the ability of chiral retention, the author then used the chiral Sulfinamide as the raw material to realize the chiral synthesis of sulfimide compounds (Table 3) In addition, the reaction has good functional group tolerance, and trifluoromethyl, ester group, alkyl halide, aryl group and Trifluoromethoxy group are all compatible with the reaction conditions Then, the chiral diarylsulphonimides were synthesized by using tert butylsulphonamide, S-arylation, de tert butyl and re arylation In addition, the protective group on N can be removed by LiAlH 4, which increases the practicability of the reaction (source: J am Chem SOC.) finally, in order to illustrate the application value of the reaction, the author realized the asymmetric synthesis of Vioxx Ⓡ analogues (scheme 5) by using this reaction (source: J am Chem SOC.) Summary: Keiji maruoka group has developed Cu catalyzed arylation of chiral Sulfinamide and synthesized a series of sulfimide compounds In addition, diarylsulphonimides can be synthesized by S-arylation, dealkylation and re arylation.