The synthesis of 1,5-diaryl-4-arylthiopyrrolidin-2-ones by arylsulfenylation of styryl acetic acid N-arylamides

The role of the electrophilic intramolecular cyclization (EIC) reaction of unsaturated carboxylic acid amides has been described for the design of arylthio-containing lactams and lactones. In order to identify the effect of the styryl moiety on regioselectivity of the electrophilic intramolecular cyclization process styryl acetic acid amides with electron-donating substituents in para-position of the styryl moiety have been studied. It has been found that these compounds react with phenyl and p-tolylsulfenylchlorides in nitromethane in the presence of lithium perchlorate as a “doping additive” to form 1,5-diaryl-4-arylthiopyrrolidin-2-ones with the yield of 60-66%. It is most likely that the reaction found includes the formation of the episulfonium cation stabilized by the perchlorate-anion followed by 5-endo-cyclization onto the nitrogen atom of the amide group. The structure of the compounds synthesized has been confirmed by their spectral parameters. In particular, the IR-spectra contain strong absorption bands C=O at 1703-1703 cm-1, and 1H NMR-spectra of the compounds obtained are characterized by two protons multiple shifts of the H3 pyrrolidine ring at 2.52-2.64 and 3.08-3.22 ppm, respectively, H4 proton multiple shifts at 3.61-3.76 ppm and H5 at 4.99-5.09 ppm. Formation of the pyrrolidine ring as a result of cyclization has been reliably proven by 13C NMR-spectra with the typical signals of carbon atoms: C3 (37 ppm), C4 (48 ppm), C5 (69 ppm) and C2 (172 ppm).

The role of the electrophilic intramolecular cyclization (EIC) reaction of unsaturated carboxylic acid amides has been described for the design of arylthio-containing lactams and lactones. In order to identify the effect of the styryl moiety on regioselectivity of the electrophilic intramolecular cyclization process styryl acetic acid amides with electron-donating substituents in para-position of the styryl moiety have been studied. It has been found that these compounds react with phenyl and p-tolylsulfenylchlorides in nitromethane in the presence of lithium perchlorate as a "doping additive" to form 1,5-diaryl-4-arylthiopyrrolidin-2-ones with the yield of 60-66%. It is most likely that the reaction found includes the formation of the episulfonium cation stabilized by the perchlorate-anion followed by 5-endo-cyclization onto the nitrogen atom of the amide group. The structure of the compounds synthesized has been confirmed by their spectral parameters. In particular, the IR-spectra contain strong absorption bands C=O at 1703-1703 cm - Formation of the pyrrolidine ring as a result of cyclization has been reliably proven by 13 C NMR-spectra with the typical signals of carbon atoms: C 3 (37 ppm), C 4 (48 ppm), C 5 (69 ppm) and C 2 (172 ppm).

4-Thio-functionalized γ-lactams (pyrrolidine-2-ones)
are important building blocks in the synthesis of carbapenems -β-lactam antibiotics with a wide spectrum of action. Obtaining compounds of this type described in literature is based on multistage transformations of methyl aspargate [1] or dimethyl 3-hydroxyglutarate [2]. Taking into consideration the biological and synthetic potential of pyrrolidine-2-one compounds [3][4][5][6] the problem of developing effective ways to obtain new derivatives, in particular, suitable to various modifications of arylsulfanyl groups is urgent today. The results of our previous studies indicate that the electrophilic intramolecular cyclization of unsaturated carboxylic acids amides using arylsulfenyl chlorides is a convenient method for designing arylthio-containing lactam and lactone compounds [7][8][9]. The electrophilic intramolecular cyclization reaction of styryl acetic acid amides containing substituents of a different electronic nature in the amide moiety shows the possibility of formation of benzazepin-2-one, lactam and lactone products [10,11]. It seemed quite reasonable to study the effect of electron-donating groups in the aryl ring of the alkenyl moiety on regioselectivity of this process. Thanks to this purpose, a number of styryl acetic acid amides 1a-d containing electron-donating substituents (Me, i-Pr, or tert-Bu) in p-position of the aryl ring have been synthesized. It has been determined that these anilides react with phenyl-or p-tolyl sulfenyl chlorides 2a,b in nitromethane in the presence of an equimolar amount of lithium perchlorate as a "doping additive" [11,12] to form 1,5-diaryl-4-arylthiopyrrolidin-2-ones 3a-f in a good (60-66%) yield. The results obtained indicate regioselectivity of the intramolecular cyclization on the nitrogen atom of the amide moiety. It is logical to assume that the process is implemented under the scheme, which contains the predominant formation of the episulfonium intermediate A stabilized by the perchlorate-anion followed by 5-endo-cyclization onto the nitrogen atom of the amide group. It should be noted that electron-donating aryl substituents better stabilize intermediate A and create favourable conditions for a nitrogen atom to attack a soft episulfonium cation (Scheme).
The structures of compounds 3a-f have been confirmed by spectral data. In particular, IR-spectra contain the intense absorption band of C=O groups in 1703-1705 cm -1 . In 1 H NMR-spectra of two protons the multiple shifts of the H 3 pyrrolidine ring were observed at 2.52-2.64 and 3.08-3.22 ppm, respectively, and H 4 proton multiple shifts at 3.61-3.76 ppm and H 5 at 4.99-5.09 ppm. Formation of the pyrrolidine ring as a result of cyclization has been reliably proven by 13 C NMR-spectra with the typical signals of carbon atoms: С 3 (37 ppm), С 4 (48 ppm), С 5 (69 ppm), С 2 (172 ppm).

Experimental Part
IR-spectra were recorded on a Vertex 70 spectrophotometer in KBr tablets. 1 H and 13 С NMR-spectra were registered on a Varian VXR-400 spectrometer (399.97 and 125.74 MHz, respectively); TMC was used as an internal standard. HPLC-MS measurements were performed on an Agilent 1100\DAD\HSD\VLG 119562 instrument.
The general method for the synthesis of 1,5-aryl-4-arylthiopyrrolidin-2-ones 3a-f. To the mixture of 2 mmol of amide 1а-1d and 2 mmol of lithium perchlorate in 10 mL of nitromethane add dropwise the solution of 2 mmol of arylsulfenyl chloride 2а-2b in 6 mL of nitromethane while stirring at room temperature. Stir the reaction mixture for 10 h and evaporate under vacuum. Crystallize the solid residue from ethanol.