HETEROCYCLES

Paper | Regular issue | Vol. 87, No. 5, 2013, pp. 1059-1074
Received, 13th March, 2013, Accepted, 2nd April, 2013, Published online, 10th April, 2013.
DOI: 10.3987/COM-13-12703

■ Synthesis and Characterization of 4-Substituted 1-(4-Halogenophenyl)pyrrolidin-2-ones with Azole and Azine Moieties

Rita Vaickelioniene, Vytautas Mickevicius,* and Gema Mikulskiene

Department of Organic Chemistry, Kaunas University of Technology, Radvilėnų pl. 19, Kaunas LT-50254, Lithuania

Abstract

4-Substituted 1-(4-fluoro- and 4-chlorophenyl)pyrrolidin-2-ones containing azole, oxadiazole, triazole, and triazine fragments have been synthesized, and the characterization of the obtained products is presented. The study compounds have been analyzed by elemental analysis, and the NMR, IR, MS techniques. The 1H/13C 2D (HETCOR), APT (13C) NMR methods, and molecular modeling (MM2) were used for structure elucidation in more complicated cases.

INTRODUCTION
Many azoles containing one or several heteroatoms in the molecule are known as biologically active compounds with a lot of practical properties: they are anti-tumour CDK inhibitors,1 show antituberculous,2 antifungal,3-5 antimicrobial and antifungal,4 antifungal and antiparasitic,5 antibacterial6 effects may be used as crop protectors,7 dyes8 and in other fields of industry e.g., as catalysts of the polymerization process,9 corrosion inhibitors.10 A number of 1,3,4-oxadiazoles have been described in numerous publications in relation to their practical application. The 1,3,4-oxadiazole core is an important pharmacophore in agricultural science, and compounds bearing this moiety often display antifungal, herbicidal,11 anticandidal,12 insecticidal13,14 effects. Some material applications of 1,3,4-oxadiazole derivatives lie in the fields of photosensitizers15 and liquid crystals.16,17 1,2,4-Triazoles and triazines have attracted particular attention due to the wide range of their biological properties such as antibacterial, antifungal,18-20 anticancer–antitumour,21 cyclooxygenase and 5-lipoxygenase inhibiting,22 antidepressant23 effects and as agrochemi­cals24,25 which treat and control various diseases.
As a continuation of our interest in the synthesis of new azole derivatives,26-29 we decided to synthesize the title compounds for the future evaluation of their biological activity. Therefore efforts have been made to investigate the structural features30-43 of compounds containing heteroatoms.

RESULTS AND DISCUSSION
The pathway of synthesis of the new 1,4-disubstituted pyrrolidinone derivatives possesing numerous prominent pharmacologically active structural fragments is shown in Scheme 1 (3–11) and in Scheme 2 (12–16).
The structure of all newly synthesized compounds has been confirmed by elemental analysis, mass spectrometry, IR, and investigated in detail by 1H, 13C NMR spectroscopy. The 1H and 13C NMR spectral data are presented in the Experimental section. Carbon atoms of the pyrrolidinone ring are marked arbitrarily according to the numbering given in Scheme 1.
For the synthesis of oxadiazole and triazole derivatives, the hydrazides 1a,b, obtained by the method described in,44 were heated with carbon disulfide in 2-propanol in the presence of potassium hydroxide. Upon refluxing, the formed potassium dithiocarbazates 2a,b were dissolved in water, and acidifying the reaction mixture with diluted hydrochloric acid to pH 1 gave 1-(4-halogenophenyl)-4-(4,5-dihydro-5-thioxo-1,3,4-oxadiazol-2-yl)pyrrolidin-2-ones 3a,b. The formation of the oxadiazolethione ring in compounds 3a,b was proven by signals at ~164 ppm (O-C=N) and ~178 ppm (C=S) in 13C NMR spectra, and by the broad singlet, centered at ~14 ppm (NH) in 1H NMR spectra. A characteristic absorption band of the NH group of compound 3a was observed at 3106 cm-1 in the IR spectrum. The absorption bands at 1683 cm-1, 1482 cm-1 and 1329 cm-1 were ascribed to the C=O group of the pyrrolidinone ring, the C=N group of the oxadiazole cycle and the C=S group, respectively.
It should be noted that such compounds as 3–10 in DMSO-d6 solutions can exist in thiole and thione tautomeric forms.36-41 In the light of the above-mentioned works, the simultaneous presence of thione and thiole tautomers in the DMSO-d6 solution may be assumed. The theoretical chemical shift for hydrogen bonded to N is 14.35 ppm, the thiole tautomer SH proton chemical shift being 4.12 ppm, and these data were in satisfactory agreement with experimental data: 14.05 ppm (NH) and 3.37 ppm (SH).39 The observed value (~14 ppm) of the chemical shift of the NH/SH proton for the study compounds 3–10 represents the averaged value of all existing NH/SH proton states. Considering the above-mentioned chemical shift values, the thione form may be concluded to be dominant.

The corresponding aminotriazoles 4a,b were obtained by heating potassium dithiocarbazates 2a,b with hydrazine hydrate. Another way of synthesizing aminotriazoles 4a,b is heating the corresponding 1,3,4-oxadiazoles 3a,b with hydrazine hydrate in ethanol.45
The resonances at ~152.5 ppm (N-C=N) and at ~167 ppm (C=S) in 13C NMR spectra as well as the resonances at ~5.5 ppm (NH2) and at ~13.6 ppm (NH/SH) in 1H NMR spectra revealed the formation of 5-membered triazole derivatives 4a,b. The existence of a 5-membered heterocycle, containing three nitrogen atoms, also confirmed by absorption bands in the interval of 3279−2941, and at about 1680, 1495 and 1315 cm-1, were attributed to the NH, NH2, C=O, C=N and C=S, respectively, in IR spectra.
The condensation of aminotriazoles 4a,b with aromatic aldehydes (benzaldehyde, 4-chlorobenzaldehyde, and 4-methoxybenzaldehyde) were carried out, and the corresponding Schiff bases 5a, 6a and 7−9b were obtained. Due to the above-mentioned condensation reaction, the resonances of protons of the NH2 group (~5.5 ppm) disappeared in 1H NMR spectra of compounds 5a, 6a and 7−9b. Characteristic changes of the chemical shift of the resonances of the 5-membered heterocycle moiety were observed because of the changed influence of the substituent at C-N-CS. In this case, the C=S atom resonated at ~162 ppm, and the N-C=N atom at ~151 ppm in 13C NMR spectra. Additional spectral lines were observed in the aromatic region and were assigned to the carbon atoms of the other benzene ring and azomethine group. The value of the latter chemical shifts depends on the nature of the substituent in the benzene ring and was manifested in the range ~160–163 ppm. The 1H NMR spectra of compounds 5a, 6a and 7−9b showed characteristic resonances at ~14 ppm (NH/SH), at ~10 ppm attributed to the azomethine group proton and the multiplet of the benzene ring, integrated for 8 (6a, 8b, 9b) or 9 (5a, 7b) protons. The NMR spectra of mentioned compounds revealed the absence of geometric isomers. Considering all the above facts, the structure of compounds 5a, 6a and 7−9b certainly exists.
During reactions of 4-amino-1,2,4-triazoles 4a,b with 2,5-hexanedione, performed in the refluxing 2-propanol in the presence of a catalytic amount of hydrochloric acid, the N-substituted pyrrole derivatives 10a,b were synthesized. The formation of a 2,5-dimethylpyrrole ring included into the 10a,b composition is displayed by the double intensity resonances of CH at ~106 ppm, =C at 127.5 ppm, and CH3 at ~11 ppm in 13C NMR spectra, and singlets at ~2 ppm (CH3), 6 ppm (=CH), ~14 ppm (NH) in 1H NMR spectra. The NCSNH and NC=N carbons of the 1,2,4-triazole ring in comparison with compounds 4a,b are found to be ~0.5 ppm deshielded and shielded, respectively, in 13C NMR spectra.
The 1-(4-chlorophenyl)-N-(2,5-dimethyl-1H-pyrrol-1-yl)-5-oxopyrrolidine-3-carboxamide (11b) was obtained by condensation of hydrazide 1b with 2,5-hexanedione in refluxing ethanol in the presence of a catalytic amount of glacial acetic acid. The 1H and 13C NMR spectral patterns of the 2,5-dimethylpyrrole ring moiety of compound 11b are similar to this of compound 10b. No rotamers were observed in the NMR spectra of compound 11b in DMSO-d6 solution despite the fact that the presence of the amide group caused isomer formation. Characteristic absorption band at 3275 cm-1 (NH) and sharp band at 1685 cm-1 (C=O) in the IR spectrum of derivative 11b also confirm its structure.
Refluxing of above-mentioned hydrazides 1a,b in the excess of triethyl orthoformate, in the presence of p-toluenesulfonic acid, gave 2-substituted oxadiazoles 13a,b. The observed resonances at ~155 ppm (O-CH=N), at ~166.5 ppm (O-C=N) in 13C NMR spectra and at ~9.2 ppm (O-CH=N) in 1H NMR spectra, confirmed the successful formation of a oxadiazole ring. The shortening of the reaction time to 5 minutes allowed us to isolate the hydrazone-type intermediates 12a,b containing amide, azomethine, and ether fragments. The presence of the mentioned above fragments determine the specific features of compounds 12a,b. The NMR spectra of compounds 12a,b exhibited four sets of resonances, therefore four different spatial states may exist in the DMSO-d6 solution.27

Condensation of hydrazides 1a,b with ethyl acetoacetate gave 3-[2-[[5-oxo-1-phenyl­pyrrolidin-3-yl]carbonyl]hydrazinylidene]butanoates 14a,b. The NMR spectra of compounds 14a,b are complicated due to additional sets of resonances. The origin of such resonances is determined by isomers of different spatial structure. This fact was revealed from the optimized molecular models of each isomer. It should be noted that the molecules of the study compounds in the solutions apparently were in the dynamic equilibrium characterized by the equilibrium portion of each structure.
NMR did not provide conclusive information about separate conformations of the molecules studied, but gave a time averaged spectral view from all of the structures existing in the solution. Two sets of resonances observed in 13C NMR spectra may be attributed to E (7.15 kJ/mol)/Z (9.46 kJ/mol) rotamers. More sensitive 1H NMR spectra showed two intensively and four less intensively resolved resonances in the CH3 and NH spectral regions. The analysis of isomer composition was not the aim of the present study. Taking into account the facts mentioned above, we may conclude that compounds 14a,b were synthesized.
Investigation of the reactions of hydrazides 1a,b with itaconic acid has revealed that they as primary amines form compounds containing a fragment of γ-amino acid, which undergoes a closure of 5-membered pyrrolidinone cycle already during the reaction, and compounds with two pyrrolidine rings 15a,b were obtained. The presence of two pyrrolidinone rings and four carbonyl groups in the molecules of the study compounds made the NMR spectra of 15a,b intricate for interpretation. Nevertheless the NMR spectra of compounds 15a,b were elucidated and their resonances were unambiguously assigned on the basis of general considerations of NMR properties, spectral data of structurally related compounds, and the computer molecular modeling. Molecules of 15a,b compounds can exist as a mixture of E/Z rotamers through the amide bond. Experimental NMR data exhibited only one isomer in the DMSO-d6 solution. The information derived from MM2 calculations allowed us to conclude that 15a compound existed as Z rotamer (total sterical energy for rotamer – E (31.31 kJ/mol) and for Z one (17.92 kJ/mol)).
The chemical shift values of resonances of pyrrolidinone rings and carbonyl group carbons have been paralleled with the Extended Hückel partial charges computed for each atom of Z isomer of compounds 15a,b. The carbons of the pyrrolidinone ring II were found to be more shielded than those of the ring I, whereas, in the sequence of carbonyl group carbons, the CONH group carbon was the most shielded and COOH carbon – the least shielded. Compound 15b was used in agriculture technology investigating the influence on the yield and quality of oilseed rape (Brassica napus L.).46 It was established that 1-(4-chlorophenyl)-5-oxopyrrolidine-3-carboxylic acid (15b) increased the average seed yield, but this compound could be more suitable in B. napus cultivation for specifical technical (non-food) purposes because it deteriorated all characteristics which are important for B. napus suitability for food industry: the level of linolenic acid exceeded that of linoleic acid, and the levels of erucic acid and glucosinolates were strongly increased. Compound 15b also increased the fibre level in the seeds.
In the final stage of this work, the 4-(5,6-diphenyl-1,2,4-triazin-3-yl)-1-phenylpyrrolidin-2-ones 16a,b were synthesized from carbohydrazides 1a,b by three-component reaction. The expected structure of compounds 16a,b indicated resonances at ~167 ppm (N=C-N) and ~156 ppm (N-C=C-N); additional resonances of two benzene rings in 13C NMR spectra and the aromatic multiplets integrated to 14 protons in 1H NMR spectra confirmed the formation of compounds 16a,b.
The study compounds 3–16 have a fluorine atom (compounds a) and a chlorine atom (compounds b) at the p-position of the benzene ring. Because of the specific magnetic properties of the fluorine atom, a spin–spin coupling was observed in the 1H and 13C NMR spectra.26 The doublets of the aromatic resonances in the 1H NMR spectra overlapped and were insufficiently informative, whereas F-13C coupling doublets were resolved properly in the 13C NMR spectra.

CONCLUSIONS
A variety of 4-substituted 1-(4-halogenophenyl)pyrrolidin-2-ones containing azole and azine fragments can be synthesized from 1-(4-halogenophenyl)-5-oxopyrrolidine-3-carbohydrazides by the condensation reactions or by modification of the obtained compounds. All structures of the new compounds desribed here were in agreement with the synthetic, analytical, and spectroscopic values. The molecular modeling provided further comprehension of structural features of compounds 14a,b and 15a,b.

EXPERIMENTAL
The starting materials and solvents were obtained from Sigma-Aldrich Chemie GmbH (Germany) and Fluka (Switzerland) and were used without further purification. The methods used to follow the reactions were TLC and NMR. The NMR spectra were recorded on a Varian Unity Inova (300 MHz) spectrometer (Varian, Inc., USA). Samples were prepared using DMSO-d6 as a solvent. Chemical shifts are expressed as δ, ppm relative to TMS. IR spectra (ν, cm-1) were recorded on a Perkin Elmer BX FT–IR spectrometer (Perkin Elmer Inc., USA) using KBr tablets. Mass spectra were obtained on a Waters ZQ 2000 spectrometer (Waters, Germany) using the atmospheric pressure chemical ionization (APCI) mode and operating at 25 V. Elemental analyses were performed on a CE-440 elemental analyzer (Exeter Analytical Inc., USA). Melting points were determined on a B-540 Melting Point Analyzer (Büchi Corporation, USA) and are uncorrected. TLC was performed using Merck, Silica gel 60 F254 (Kieselgel 60 F254) silica gel plates.
The molecular modeling of the study compounds was carried out using Chem3D Ultra 9.0 (Licence Cambridge Software Package, Serial number: 031 406391 4800).
1-(4-Fluorophenyl)-4-(4,5-dihydro-5-thioxo-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (3a): A mixture of the hydrazide 1a (5 mmol), potassium hydroxide (0.67 g, 12 mmol), carbon disulfide (0.57 g, 7.5 mmol) and 2-propanol (30 mL) was refluxed for 8 h, cooled down to room temperature, diluted with water (20 mL) and acidified with diluted hydrochloric acid (1 : 1) to pH 1. The precipitate was filtered off, washed with water, dried and crystallized from iPrOH to give 3a (1.16 g, 83%); a white solid; mp 162–163 °C (iPrOH); IR 3106, 2958 (NH), 1683 (C=O), 1512, 1482 (C=N), 1329 (C=S) cm-1; 1H NMR (300 MHz, DMSO-d6) δ 2.79−3.02 (2H, m, CH2CO), 3.92–4.00 (1H, m, CH), 4.05–4.24 (2H, m, CH2N), 7.18−7.27 (2Harom, m, 3,5-CH), 7.63−7.70 (2Harom, m, 2,6-CH), 14.43 (1H, br. s, NNHCS); 13C NMR (75 MHz, DMSO-d6): δ 27.9 (C-4′), 34.9 (C-3′), 50.1 (C-5′), 115.3 (2JC-F = 22.2 Hz, d, C-3,5), 121.7 (3JC-F = 7.9 Hz, d, C-2,6), 135.3 (C-1), 158.7 (1JC-F = 241.5 Hz, d, C-4), 163.9 (O-C=N), 170.9 (C-2′), 178.0 (O-CS-N). MS m/z 280 ([M+H]+ 100). Anal. Calcd for C12H10FN3O2S: C, 51.61; H, 3.61; N, 15.05. Found: C, 51.71; H, 3.47; N, 15.16.
1-(4-Chlorophenyl)-4-(4,5-dihydro-5-thioxo-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (3b): (1.14 g, 77%); a white solid. The melting point and spectral data correspond to those given in ref.47
General Procedure for the Synthesis of 4-(4-Amino-4,5-dihydro-5-thioxo-1H-1,2,4-triazol-3-yl)-1-phenylpyrrolidin-2-ones 4a,b. Method A. A mixture of the corresponding hydrazide 1 (30 mmol), potassium hydroxide (4.04 g, 72 mmol), carbon disulfide (3.42 g, 45 mmol) and 2-propanol (65 mL) was refluxed for 5 h, cooled down to 15 °C, and diethyl ether (45 mL) was poured into the reaction mixture. The precipitate was filtered off, washed with diethyl ether (3 x 50 mL) and dried. A mixture of the obtained dry solid, hydrazine hydrate (4.38 mL, 90 mmol) and water (10 mL) was refluxed for 5 h (until the orange colour of the mixture turned to green), then the mixture was cooled down to room temperature, diluted with water (25 mL) and neutralized with 3N hydrochloric acid to pH 7. The precipitate of the obtained compound was filtered off, washed with water, dried, and crystallized from EtOH to give 4a (4.84 g, 55%) and 4b (4.37 g, 47%).
4-(4-Amino-4,5-dihydro-5-thioxo-1H-1,2,4-triazol-3-yl)-1-(4-fluorophenyl)pyrrolidin-2-one (4a): a white solid; mp 220–221 °C (EtOH); IR 3279, 3120 (NH, NH2), 1689 (C=O), 1510, 1492 (C=N), 1319 (C=S) cm-1; 1H NMR (300 MHz, DMSO-d6) δ 2.81−3.01 (2H, m, CH2CO), 3.82−3.94 (1H, m, CH), 4.05–4.24 (2H, m, CH2N), 5.57 (2H, s, NH2), 7.19−7.26 (2Harom, m, 3,5-CH), 7.62−7.67 (2Harom, m, 2,6-CH), 13.63 (1H, br. s, NNHCS); 13C NMR (75 MHz, DMSO-d6) δ 27.3 (C-4′), 35.1 (C-3′), 50.6 (C-5′), 115.3 (2JC-F = 22.2 Hz, d, C-3,5), 121.6 (3JC-F = 8.1 Hz, d, C-2,6), 135.5 (C-1), 152.6 (N-C=N), 158.5 (1JC-F = 241.2 Hz, d, C-4), 167.3 (N-CS-N), 171.6 (C-2′); MS m/z (%): 294 ([M+H]+ 100). Anal. Calcd for C12H12FN5OS: C, 49.14; H, 4.12; N, 23.88. Found: C, 49.26; H, 4.24; N, 23.64.
4-(4-Amino-4,5-dihydro-5-thioxo-1H-1,2,4-triazol-3-yl)-1-(4-chlorophenyl)pyrrolidin-2-one (4b): a white solid; mp 255–256 °C (EtOH); IR 3104, 3046 (NH, NH2), 1670 (C=O), 1497 (C=N), 1314 (C=S) cm-1; 1H NMR (300 MHz, DMSO-d6) δ 2.77−3.01 (2H, m, CH2CO), 3.80–3.90 (1H, m, CH), 4.04–4.24 (2H, m, CH2N), 5.57 (2H, s, NH2), 7.40−7.71 (4Harom, m, 4CH), 13.63 (1H, br. s, NNHCS); 13C NMR (75 MHz, DMSO-d6) δ 27.1 (C-4′), 35.2 (C-3′), 50.3 (C-5′), 120.9 (C-2,6), 127.8 (C-4), 128.5 (C-3,5), 137.9 (C-1), 152.4 (N-C=N), 167.2 (N-CS-N), 171.5 (C-2′); MS m/z 310 ([M+H]+ 100), 312 ([M+2+H]+ 40). Anal. Calcd for C12H12ClN5OS: C, 46.53; H, 3.90; N, 22.61. Found: C, 46.63; H, 3.91; N, 22.65.
Method B. Compounds 4a,b were synthesized by the method described in ref.45
4-(4-Amino-4,5-dihydro-5-thioxo-1H-1,2,4-triazol-3-yl)-1-(4-fluorophenyl)pyrrolidin-2-one (4a): (4.58 g, 52%); a white solid. The melting point and spectral data correspond to those given in Method A.
4-(4-Amino-4,5-dihydro-5-thioxo-1H-1,2,4-triazol-3-yl)-1-(4-chlorophenyl)pyrrolidin-2-one (4b): (3.90 g, 42%); a white powder. The melting point and spectral data correspond to those given in Method A.
General Procedure for the Synthesis of 1-(4-Halogenophenyl)-4-[4-[(phenylmethyli­dene)amino]-4,5-dihydro-5-thioxo-1H-1,2,4-triazol-3-yl]pyrrolidin-2-ones 5–9. A mixture of the corresponding aminotriazole 4 (2 mmol), benzaldehyde, 4-chlorobenzaldehyde or 4-methoxybenzaldehyde (4 mmol), EtOH (8 mL) and hydrochloric acid (2 drops) was refluxed for 8 h, and then cooled down. The precipitate of the obtained compounds was filtered off, washed with EtOH, dried and crystallized from iPrOH (5a, 6a) and a mixture of 1,4-dioxane and water (7–9b) to give 5a (0.42 g, 55%), 6a (0.72 g, 86%), 7b (0.60 g, 75%), 8b (0.72 g, 83%), and 9b (0.84 g, 98%).
1-(4-Fluorophenyl)-4-[4-[(phenylmethylidene)amino]-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]pyrrolidin-2-one (5a): a white solid; mp 219–220 °C (iPrOH); IR 3128 (NH), 1672 (C=O), 1510, 1496 (C=N), 1273 (C=S) cm-1; 1H NMR (300 MHz, DMSO-d6) δ 2.85−3.04 (2H, m, CH2CO), 3.99−4.26 (3H, m, CH + CH2N), 7.17–7.90 (9Harom, m, 9CH), 10.12 (1H, s, CH=N), 13.93 (1H, s, NNHCS); 13C NMR (75 MHz, DMSO-d6): δ 27.3 (C-4′), 35.2 (C-3′), 50.5 (C-5′), 115.3 (2JC-F = 22.2 Hz, d, C-3,5), 121.7 (3JC-F = 7.8 Hz, d, C-2,6), 128.6 (C-3″,5″), 129.1 (C-2″,6″), 132.1 (C-1″), 132.7 (C-4″), 135.4 (C-1), 151.4 (N-C=N), 158.6 (1JC-F = 241.9 Hz, d, C-4), 162.0, (N-CS-N), 162.8 (N=CH), 171.4 (C-2′); MS m/z 382 ([M+H]+ 100). Anal. Calcd for C19H16FN5OS: C, 59.83; H, 4.23; N, 18.36. Found: C, 59.86; H, 4.49; N, 18.21.
4-[4-[[(4-Chlorophenyl)methylidene]amino]-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]-1-(4-fluoro-phenyl)pyrrolidin-2-one (6a): a yellow solid; mp 234–235 °C (iPrOH); IR 3160 (NH), 1669 (C=O), 1509, 1491 (C=N), 1275 (C=S) cm-1; 1H NMR (300 MHz, DMSO-d6) δ 2.84−3.04 (2H, m, CH2CO), 3.99−4.26 (m, 3H, CH + CH2N), 7.17–7.93 (8Harom, m, 8CH), 10.19 (1H, s, CH=N), 13.96 (1H, s, NNHCS); 13C NMR (75 MHz, DMSO-d6) δ 27.3 (C-4′), 35.2 (C-3′), 50.5 (C-5′), 115.3 (d, 2JC-F = 22.2 Hz, C-3,5), 121.7 (d, 3JC-F = 7.8 Hz, C-2,6), 129.3 (C-3″,5″), 130.2 (C-2″,6″), 131.0 (C-1″), 135.4 (C-1), 137.3 (C-4″), 151.5 (N-C=N), 158.6 (d, 1JC-F = 241.6 Hz, C-4), 161.1 (N=CH), 162,0 (N-CS-N), 171.4 (C-2′); MS m/z 417 ([M+H]+ 100), 419 ([M+2+H]+ 40). Anal. Calcd for C19H15ClFN5OS: C, 54.87; H, 3.64; N, 16.84. Found: C, 55.01; H, 3.82; N, 16.77.
1-(4-Chlorophenyl)-4-[4-[[phenylmethylidene]amino]-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]pyrrolidin-2-one (7b): a white solid; mp 212–213 °C (1,4-dioxane and water); IR 3103 (NH), 1662 (C=O), 1500, 1473 (2C=N), 1274 (C=S) cm-1; 1H NMR (300 MHz, DMSO-d6) δ 2.87−3.05 (2H, m, CH2CO), 4.00−4.10 (1H, m, CH), 4.08–4.27 (2H, m, CH2N), 7.40–7.90 (9Harom, m, 9CH), 10.12 (1H, s, CH=N), 13.96 (1H, s, NNHCS); 13C NMR (75 MHz, DMSO-d6) δ 26.8 (C-4′), 35.0 (C-3′), 49.9 (C-5′), 120.7 (C-2,6), 127.5 (C-4), 128.2 (C-2″,6″), 128.3 (C-3,5), 128.8 (C-3″,5″), 131.8 (C-1″), 132.3 (C-4″), 138.1 (C-1), 151.0 (N-C=N), 162.4 (N-CS-N + N=CH), 171.4 (C-2′); MS m/z 398 ([M+H]+ 100), 400 ([M+2+H]+ 40). Anal. Calcd for C19H16ClN5OS: C, 57.35; H, 4.05; N, 17.60. Found: C, 57.40; H, 4.06; N, 17.53.
4-[4-[[(4-Chlorophenyl)methylidene]amino]-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]-1-(4-chlorophenyl)pyrrolidin-2-one (8b): a white solid; mp 218–219 °C (1,4-dioxane and water); IR 3114 (NH), 1662 (C=O), 1500, 1489 (2C=N), 1309 (C=S) cm-1; 1H NMR (300 MHz, DMSO-d6) δ 2.85−3.05 (2H, m, CH2CO), 4.00−4.11 (1H, m, CH), 4.07–4.26 (2H, m, CH2N), 7.00–7.90 (8Harom, m, 8CH), 10.19 (1H, s, CH=N), 13.99 (1H, s, NNHCS); 13C NMR (75 MHz, DMSO-d6) δ 27.1 (C-4′), 35.3 (C-3′), 50.1 (C-5′), 121.0 (C-2,6), 127.7 (C-4), 128.4 (C-3,5), 129.2 (C-3″,5″), 130.2 (C-1″), 131.0 (C-2″,6″), 137.2 (C-4″), 137.8 (C-1), 151.3 (N-C=N), 161.0 (N=CH), 162.0 (N-CS-N), 171.7 (C-2′); MS m/z 432 ([M+H]+ 70), 434 ([M+2+H]+ 40). Anal. Calcd for C19H15Cl2N5OS: C, 52.78; H, 3.50; N, 16.20. Found: C, 52.59; H, 3.52; N, 16.17.
1-(4-Chlorophenyl)-4-[4-[[(4-methoxyphenyl)methylidene]amino]-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]pyrrolidin-2-one (9b): a white solid; mp 217–218 °C (1,4-dioxane and water); IR 3094 (NH), 1657 (C=O), 1497, 1467 (2C=N), 1325 (C=S) cm-1; 1H NMR (300 MHz, DMSO-d6) δ 2.85−3.02 (2H, m, CH2CO), 3.80 (3H, s, OCH3), 3.99−4.09 (1H, m, CH), 4.07–4.28 (2H, m, CH2N), 7.09−7.99 (8Harom, m, 8CH), 9.88 (1H, s, N=CH). 13.90 (1H, br. s, NNHCS); 13C NMR (75 MHz, DMSO-d6) δ 27.2 (C-4′), 35.2 (C-3′), 50.1 (C-5′), 55.5 (CH3), 114.6 (C-3″,5″), 121.0 (C-2,6), 124.4 (C-1″), 127.8 (C-4), 128.5 (C-3,5), 130.6 (C-2″,6″), 137.8 (C-1), 151.1 (N-C=N), 161.9 (N-CS-N) 162.8 (N=CH), 163.2 (C-4″), 171.7 (C-2′); MS m/z 428 ([M+H]+ 100), 430 ([M+2+H]+ 40). Anal. Calcd for C20H18ClN5O2S: C, 56.14; H, 4.24; N, 16.37. Found: C, 55.98; H, 4.25; N, 16.31.
General Procedure for the Synthesis of 4-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-4,5-dihydro-5-thioxo-1H-1,2,4-triazol-3-yl]-1-phenylpyrrolidin-2-ones 10a,b. A mixture of the corresponding aminotriazole 4 (1.5 mmol), 2,5-hexanedione (0.26 g, 2.25 mmol), concentrated hydrochloric acid (6 drops) and iPrOH (50 mL) was refluxed for 7 h, the solvent was separated under reduced pressure, and the residue diluted with water (30 mL). The precipitate was filtered off, washed with water, dried, and crystallized from iPrOH (10a) or 1,4-dioxane (10b) to give 10a (0.48 g, 87%) and 10b (0.52 g, 89%).
1-(4-Fluorophenyl)-4-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-4,5-dihydro-5-thioxo-1H-1,2,4-triazol-3-yl]pyrrolidin-2-one (10a): a white solid; mp 215–216 °C (iPrOH); IR 3122 (NH), 1671 (C=O), 1509, 1474 (C=N), 1324 (C=S) cm-1; 1H NMR (300 MHz, DMSO-d6) δ 1.98 (6H, s, CCH3), 2.47−2.55 (0.5(1H), m, CH2CO), 2.75−2.83 (0.5(1H), m, CH2CO), 3.47−3.58 (1H, m, CH), 3.85−3.88 (0.5(1H), m, CH2N), 4.06−4.11 (0.5(1H), m, CH2N), 5.92 (2H, s, CH=), 7.18–7.24 (2Harom, m, 3,5-CH), 7.56–7.61 (4Harom, m, 2,6-CH), 14.23 (1H, s, NNHCS); 13C NMR (75 MHz, DMSO-d6) δ 10.9, 11.0 (CCH3), 27.4 (C-4′), 35.2 (C-3′), 50.1 (C-5′), 105.8 (CH=), 115.4 (2JC-F = 22.3 Hz, d, C-3,5), 121.8 (3JC-F = 7.8 Hz, d, C-2,6), 127.4, 127.5 (CCH3), 135.2 (C-1), 151.9 (N-C=N), 158.7 (1JC-F = 241.6 Hz, d, C-4), 167.7 (N-CS-N), 170.67 (C-2′); MS m/z 372 ([M+H]+ 100). Anal. Calcd for C18H18FN5OS: C, 58.21; H, 4.88; N, 18.85. Found: C, 57.99; H, 5.05; N, 18.75.
1-(4-Chlorophenyl)-4-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-4,5-dihydro-5-thioxo-1H-1,2,4-triazol-3-yl]pyrrolidin-2-one (10b): a white solid; mp 177–178 °C (1,4-dioxane); IR 3106 (NH), 1708 (C=O), 1495 (C=N), 1322 (C=S) cm-1; 1H NMR (300 MHz, DMSO-d6) δ 1.97 (6H, s, CCH3), 2.50−2.83 (2H, m, CH2CO), 3.50−3.59 (1H, m, CH), 3.87−4.12 (2H, m, CH2N), 5.92 (2H, s, CH=), 7.40-7.64 (4Harom, m, 4CH), 14.25 (1H, s, NNHCS); 13C NMR (75 MHz, DMSO-d6) δ 11.2 (CCH3), 27.6 (C-4′), 35.6 (C-3′), 50.0 (C-5′), 106.0 (CH=), 121.3 (C-2,6), 127.6 (CCH3), 127.7 (C-4), 128.8 (C-3,5), 137.9 (C-1), 152.0 (N-C=N), 167.9 (N-CS-N), 171.1 (C-2′); MS m/z 388 ([M+H]+ 50), 410 ([M+Na]+ 100). Anal. Calcd for C18H18ClN5OS: C, 55.74; H, 4.68; N, 18.06. Found: C, 55.94; H, 4.68; N, 18.13.
1-(4-Chlorophenyl)-N-(2,5-dimethyl-1H-pyrrol-1-yl)-5-oxopyrrolidine-3-carboxamide (11b). A mixture of the hydrazide 1b (1.19 g, 5 mmol), 2,5-hexanedione (0.86 g, 7.5 mmol), glacial acetic acid (1 mL) and EtOH (35 mL) was refluxed for 16 h, the solvent was separated under reduced pressure, the residue diluted with water (50 mL), and the solution was heated to a gentle boil. Upon cooling of the reaction mixture, the precipitate was filtered off, washed with water, dried and crystallized from EtOH to give 11b (1.54 g, 93%). A white solid; mp 161–162 °C (EtOH); IR 3275 (NH), 1705, 1685 (2C=O) cm-1; 1H NMR (300 MHz, DMSO-d6) δ 2.03 (6H, s, CCH3), 2.75−2.97 (2H, m, CH2CO), 3.50−3.63 (1H, m, CH), 3.97−4.20 (2H, m, CH2N), 5.68 (2H, s, CH=), 7.42–7.79 (4Harom, m, 4CH), 10.95 (1H, s, CONH); 13C NMR (75 MHz, DMSO-d6) δ 11.4 (CCH3), 34.47 (C-4′), 36.1 (C-3′), 50.8 (C-5′), 103.6 (CH=), 121.4 (C-2,6), 127.2 (CCH3), 128.4 (C-4), 129.1 (C-3,5), 138.4 (C-1), 172.2, 172.1 (C-2′ + CONH); MS m/z 332 ([M+H]+ 100), 334 ([M+2+H]+ 40). Anal. Calcd for C17H18ClN3O2: C, 61.54; H, 5.47; N, 12,66. Found: C, 61.66; H, 5.40; N, 12.62.
General Procedure for the Synthesis of Ethyl [(5-oxo-1-phenylpyrrolidin-3-yl)carbonyl]­hydrazonoformates 12a,b. A mixture of the corresponding hydrazide 1 (5 mmol) and triethyl orthoformate (10 mL) was heated to boiling, and then cooled down. The precipitate was filtered off, washed with ether, dried, and crystallized from iPrOH to give 12a (1.07 g, 73%) and 12b (1.28 g, 83%).
Ethyl [[1-(4-fluorophenyl)-5-oxopyrrolidin-3-yl]carbonyl]hydrazonoformate (12a): a white solid; mp 153–154 °C (iPrOH); IR 3201 (NH), 1695, 1664, 1617 (C=O), 1510, 1478, 1460 (C=N) cm-1; 1H NMR (300 MHz, DMSO-d6) δ 1.24, 1.26, 1.29 (3H, J = 7.1 Hz, 3t, CH3), 2.57–2.80 (2H, m, CH2CO), 3.16–4.21 (5H, m, CH + OCH2CH3 + CH2N), 6.86, 6.91 ((0.6)1H, 2s, CH=N), 7.17–7.23 (2Harom, m, 3,5-CH), 7.65–7.69 (2Harom, m, 2,6-CH), 7.94, 8.22 ((0.4) 1H, 2s, CH=N), 10.06, 10.55, 10.76, 10.79 ((0.20 : 0.48 : 0.10 : 0.22)1H, 4s, CONH); 13C NMR (75 MHz, DMSO-d6) δ 14.1, 15.3, 15.5 (OCH2CH3), 32.5, 34.1, 34.6, 34.6, 34.8, 35.6, 35.7 (C-4′,3′), 50.1, 50.3, 50.8, 51.0 (C-5‘), 62.5, 62.5, 67.1 (OCH2CH3), 115.3 (2JC-F = 22.3 Hz, d, C-3,5), 121.3 (3JC-F = 7.8 Hz, d, C-2,6), 135.6 (C-1), 143.2, 145.4, 155.4 (CH=N), 158.4 (1JC-F = 240.8 Hz, d, C-4), 167.9, 168.4, 171.9, 172.0, 172.0, 172.5 (CONH + C-2′); MS m/z 294 ([M+H]+ 100). Anal. Calcd for C14H16FN3O3: C, 57.33; H, 5.50; N, 14.33. Found: C, 57.54; H, 5.66; N, 14.18.
Ethyl [(1-(4-chlorophenyl)-5-oxopyrrolidin-3-yl)carbonyl]hydrazonoformate (12b): a white solid; mp 167–168 °C (iPrOH); IR 3211 (NH), 1696, 1664 (2C=O), 1495 (C=N) cm-1; 1H NMR (300 MHz, DMSO-d6) δ 1.24, 1.26, 1.29 (3H, J = 7.1 Hz, 3t, CH3), 2.58–2.82 (2H, m, CH2CO), 3.15–4.21 (5H, m, CH + CH2N + OCH2CH3), 6.86, 6.91 ( (0.6)1H, 2s, CH=N), 7.39–7.45 (2Harom, m, 3,5-CH), 7.67–7.73 (2H, m, 2,6-CH), 7.94, 8.22 (2s, (0.4) 1H, CH=N), 10.07, 10.56, 10.77, 10.80 ((0.18 : 0.46 : 0.13 : 0.23)1H, 4s, CONH); 13C NMR (75 MHz, DMSO-d6) δ 14.2, 15.3, 15.5 (OCH2CH3), 32.4, 34.0, 34.6, 34.7, 34.9, 35.7, 35.8 (C-4′,3′), 49.9, 50.1, 50.6, 50.7 (C-5′), 62.5, 62.5, 67.2, 67.1 (OCH2CH3), 120.8 (C-2,6), 127.7 (C-4), 128.5 (C-3,5), 138.1 (C-1), 143.2, 145.5, 149.6, 155.4 (CH=N), 167.8, 168.4, 172.0, 172.2, 172.3, 172.4, 172.5 (CONH + C-2′); MS m/z 310 ([M+H]+ 40), 332 ([M+Na]+ 100). Anal. Calcd for C14H16ClN3O3: C, 54.29; H, 5.21; N, 13.57. Found: C, 54.09; H, 5.20; N, 13.53.
General Procedure for the Synthesis of 4-(1,3,4-Oxadiazol-2-yl)-1-phenylpyrrolidin-2-ones 13a,b. A mixture of the corresponding hydrazide 1 (5 mmol), triethyl orthoformate (5.93 g, 40 mmol) and p-toluenesulfonic acid (0.19 g, 1 mmol) was refluxed for 20 h, cooled down, the precipitate was filtered off, washed with hexane, dried, and crystallized from iPrOH to give 13a (0.52 g, 42%) and 13b (0.62 g, 47%).
1-(4-Fluorophenyl)-4-(1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (13a): a white solid; mp 158–159 °C (iPrOH); IR 1705 (C=O), 1603, 1588 (C=N) cm-1; 1H NMR (300 MHz, DMSO-d6) δ 2.84−3.10 (2H, m, CH2CO), 4.09−4.33 (3H, m, CH + CH2N), 7.19–7.27 (2Harom, m, 3,5-CH), 7.64–7.71 (2H, m, 2,6-CH), 9.24 (1H, s, O-CH=N); 13C NMR (75 MHz, DMSO-d6) δ 27.6 (C-4′), 35.8 (C-3′), 50.8 (C-5′), 115.3 (2JC-F = 22.3 Hz, d, C-3,5), 121.7 (3JC-F = 7.9 Hz, d, C-2,6), 135.1 (C-1), 154.9 (O-CH=N), 158.6 (1JC-F = 241.4 Hz, d, C-4), 166.4 (OC=N-N), 171.1 (C-2′); MS m/z 248 ([M+H]+ 100). Anal. Calcd for C12H10FN3O2: C, 58.30; H, 4.08; N, 17.00. Found: C, 58.55; H, 4.24; N, 16.84.
1-(4-Chlorophenyl)-4-(1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (13b). White powder, mp 106–107 °C (iPrOH). IR 1703 (C=O), 1494, 1484 (C=N) cm-1. 1H NMR (300 MHz, DMSO-d6) δ 2.90−3.10 (2H, m, CH2CO), 4.00−4.21 (2H, m, CH2N), 4.23–4.37 (1H, m, CH), 7.40–7.71 (4Harom, m, 4CH), 9.24 (1H, s, O-CH=N). 13C NMR (75 MHz, DMSO-d6): δ 27.8 (C-4′), 36.1 (C-3′), 50.8 (C-5′), 121.3 (C-2,6), 128.3 (C-4), 128.8 (C-3,5), 138.0 (C-1), 155.1 (O-CH=N), 166.5 (OC=N-N), 171.6 (C-2′). MS m/z (I, %): 265 ([M+H]+ 100), 267 ([M+2+H]+ 35). Anal. Calcd for C12H10ClN3O2: C, 54.66; H, 3.82; N, 15.94%. Found: C, 54.89; H, 3.83; N, 15.99.
General Procedure for the Synthesis of Ethyl 3-[2-[[5-oxo-1-phenylpyrrolidin-3-yl]carbonyl]hydrazinylidene]butanoates 14a,b. A mixture of the corresponding hydrazide 1 (5 mmol), EAA (1.11 g, 8.5 mmol), EtOH (20 mL) and glacial acetic acid (1 mL) was refluxed for 4 h, cooled down, the precipitate was filtered off, washed with EtOH, dried and crystallized from EtOH to give 14a (1.00 g, 57%) and 14b (1.04 g, 57%).
Ethyl 3-[2-[[1-(4-fluorophenyl)-5-oxopyrrolidin-3-yl]carbonyl]hydrazinylidene]butanoate (14a): a white solid; mp 136–137 °C (EtOH); IR 3188 (NH), 1735, 1693, 1662 (3C=O) cm-1; 1H NMR (300 MHz, DMSO-d6) δ 1.10−1.23 (2H, m, OCH2CH3), 1.80, 1.92, 1.95, 1.96, 1.97, 2.16 (2H, 6s, =CCH3), 2.57–2.86 (2H, m, CH2CO), 3.24–3.53 (2H, m, =CCH2-C + H2O), 3.81–4.15 (5H, m, CH2N + CH + OCH2CH3), 7.18–7.25 (2Harom, m, 3,5-H), 7.63–7.71 (2Harom, m, 2,6-CH), 10.05, 10.20, 10.40, 10.49, 10.58, 10.66 (1H, 6s, CONH); 13C NMR (75 MHz, DMSO-d6) δ 14.0 (OCH2CH3), 16.4, 16.8 (CH3C=), 33.3, 34.3, 34.7, 35.6 (C-4′ + C-3′), 43.9, 44.0 (=CCH2CO), 50.2, 50.9 (C-5′), 60.4, 60,5 (OCH2CH3), 115.3 (2JC-F = 22.4 Hz, d, C-3,5), 121.4, 121.5 (3JC-F = 8.3 Hz, 3JC-F = 10.5 Hz, d, C-2,6), 135.6 (C-1), 147.8, 151.8 (N=CCH3), 158.5 (1JC-F = 241.5 Hz, d, C-4), 162.2 (CH2COOCH2CH3), 168.0, 169.0, 169.5, 169.6, 172.0, 173.7 (CONH + C-2′); MS m/z 350 ([M+H]+ 100). Anal. Calcd for C17H20FN3O4: C, 58.45; H, 5.77; N, 12.03. Found: C, 58.46; H, 5.90; N, 11.91.
Ethyl 3-[2-[[1-(4-chlorophenyl)-5-oxopyrrolidin-3-yl]carbonyl]hydrazinylidene]butanoate (14b): a white solid; mp 138–139 °C (EtOH); IR 3205 (NH), 1733, 1706, 1674 (3C=O) cm-1; 1H NMR (300 MHz, DMSO-d6) δ 1.10−1.23 (2H, m, OCH2CH3), 1.80, 1.92, 1.95, 1.96, 1.97, 2.15 (2H, 6s, =CCH3), 2.63–2.88 (2H, m, CH2CO), 3.25–3.53 (2H, m, =CCH2-C + H2O), 3.81–4.15 (5H, m, CH2N + CH + OCH2CH3), 7.41–7.44 (2Harom, m, 3,5-CH), 7.67–7.72 (2Harom, m, 2,6-CH), 10.05, 10.22, 10.40, 10.49, 10.58, 10.66 (1H, 6s, CONH); 13C NMR (75 MHz, DMSO-d6) δ 14.0 (OCH2CH3), 16.5, 16.8 (CH3C=), 33.2, 33.7, 34.2, 34.8, 35.6, 35.8 (C-4′ + C-3′), 43.9, 44.0 (=CCH2CO), 49.9, 50.4, 50.7 (C-5′), 60.4, 60.8 (OCH2CH3), 120.9, 120.9 (C-2,6), 127.7, 127.9 (C-4), 128.6 (C-3,5), 138.0, 138.01 (C-1), 147.8, 151.9 (N=CCH3), 162.2 (CH2COOCH2CH3), 167.6, 168.0, 168.01, 169.5, 169.6, 171.4, 172.0, 172.3, 172.3, 173.7 (CONH + C-2′); MS m/z 367 ([M+H]+ 100), 369 ([M+2+H]+ 40). Anal. Calcd for C17H20ClN3O4: C, 55.82; H, 5.51; N, 11.49. Found: C, 55.75; H, 5.73; N, 11.32.
General Procedure for the Synthesis of 5-Oxo-1-[[(5-oxo-1-phenylpyrrolidin-3-yl)carbonyl]amino]pyrrolidine-3-carboxylic acids 15a,b. A mixture of correspon­ding hydrazide 1 (5 mmol), itaconic acid (0.78 g, 6 mmol) and 10 mL of water was refluxed for 12 h, cooled down, the precipitate was filtered off, washed with water, dried, and crystallized from iPrOH (15a) or water (15b) to give 15a (1.20 g, 69%).
1-[[[1-(4-Fluorophenyl)-5-oxopyrrolidin-3-yl]carbonyl]amino]-5-oxopyrrolidine-3-carboxylic acid (15a): a white solid; mp 210–211 °C (iPrOH); IR 3273 (NH), 3027 (OH), 1729, 1702, 1677, 1601 (C=O) cm-1; 1H NMR (300 MHz, DMSO-d6) δ 2.45−2.84 (4H, m, CH2CO (II) + CH2CO (I)), 3.24–3.34 (2H, m, CH (II) + CH (I)), 3.57–3.72 (2H, m, CH2N (II)), 3.84–4.07 (2H, m, CH2N (I)), 7.19–7.24 (2Harom, m, 3,5-CH), 7.64–7.68 (2Harom, m, 2,6-CH), 10.38 (1H, s, CONH), 11.99 (1H, br. s, COOH); 13C NMR (75 MHz, DMSO-d6) δ 31.3 (C-4″ (II)), 33.6 (C-4′ (I)), 34.1 (C-3″(II)), 35.2 (C-3′(I)), 49.6 (C-5″(II)), 50.5 (C-5′ (I), 115.3 (2JC-F = 22.2 Hz, d, C-3,5), 121.6 (3JC-F = 8.0 Hz, d, C-2,6), 135.5 (C-1), 158.5 (1JC-F = 240.9 Hz, d, C-4), 170.9 (CONH), 171.4 (C-2″ (II)), 171.6 (C-2′ (I)), 174.0 (COOH); MS m/z 350 ([M+H]+ 100). Anal. Calcd for C16H16FN3O5: C, 55.01; H, 4.62; N, 12.03. Found: C, 55.22; H, 4.72; N, 11.91.
1-[[[1-(4-Chlorophenyl)-5-oxopyrrolidin-3-yl]carbonyl]amino]-5-oxopyrrolidine-3-carboxylic acid (15b): a white powder; yield 1.39 g (76%); mp 150–151 °C (water). Melting point and spectral data correspond to those given in ref.42
General Procedure for the Synthesis of 4-(5,6-diphenyl-1,2,4-triazin-3-yl)-1-phenylpyrrolidin-2-ones 16a,b. A mixture of corresponding hydrazide 1 (5 mmol), 1,2-diphenylethane-1,2-dione (1.05 g, 5 mmol), ammonium acetate (3.85 g, 50 mmol) and 20 mL of glacial acetic acid was refluxed for 9 h, cooled down and diluted with water (30 mL). The formed crystalline-oily precipitate was washed with hot water (2 × 20 mL), the residue was dissolved in 15 mL of iPrOH, the solution was filtered off, and the solvent was separated under reduced pressure. The residue of formed crystalline substance after the cooling was recrystallized from iPrOH to give 16a (1.25 g, 61%) and 16b (1.39 g, 65%).
4-(5,6-Diphenyl-1,2,4-triazin-3-yl)-1-(4-fluorophenyl)pyrrolidin-2-one (16a): a yellow solid; mp 175–176 °C (iPrOH); IR 1695 (C=O), 1509, 1479 (C=N) cm-1; 1H NMR (300 MHz, DMSO-d6) δ 3.05−3.20 (2H, m, CH2CO), 4.24−4.46 (3H, m, CH2N + CH), 7.19−7.27 (2Harom, m, 3,5-CH), 7.35−7.53 (10Harom, m, (2″- 6″) + (2′′′- 6′′′)CH), 7.71 –7.77 (2Harom, m, 2,6-CH); 13C NMR (75 MHz, DMSO-d6) δ 36.9 (C-4′), 37.1 (C-3′), 52.4 (C-5′), 115.3 (2JC-F = 22.2 Hz, d, C-3,5), 121.6 (3JC-F = 8.0 Hz, d, C-2,6), 128.4, 128.5 (C-3″, 5″+ C-3′′′,5′′′), 129.3 (C-2″,6″ or C-2′′′,6′′′), 129.5 (C-4″ or C-4′′′), 129.7 (C-2′′′,6′′′ or C-2″,6″), 130.7 (C-4′′′ or C-4″), 135.3, 135.4 (C-1″ + C-1′′′), 135.7 (C-1), 156.0, 156.1 (N-C=C-N), 158.5 (1JC-F = 240.9 Hz, d, C-4), 166.8 (N=C-N), 172.1 (C-2′); MS m/z 411 ([M+H]+ 100). Anal. Calcd for C25H19FN4O: C, 73.16; H, 4.67; N, 13.65. Found: C, 72.95; H, 4.79; N, 13.66.
4-(5,6-Diphenyl-1,2,4-triazin-3-yl)-1-(4-chlorophenyl)pyrrolidin-2-one (16b): a yellow solid; mp 203–204 °C (iPrOH); IR 1698 (C=O), 1491, 1478 (C=N) cm-1; 1H NMR (300 MHz, DMSO-d6) δ 3.09−3.16 (2H, br. m, CH2CO), 4.24−4.46 (3H, br. m, + CH2N + CH), 7.34–7.77 (14Harom, m, 14CH); 13C NMR (75 MHz, DMSO-d6) δ 36.8 (C-4′), 37.2 (C-3′), 52.1 (C-5′), 121.0 (C-2,6), 127.8 (C-4), 128.4 (C-3,5), 128.5, 128.6 (C-3″,5″ or C-3′′′,5′′′), 129.3 (C-2″,6″ or C-2′′′,6′′′), 129.5 (C-4″ or C-4′′′), 129.7 (C-2′′′,6′′′ or C-2″,6″), 130.7 (C-4′′′ or C-4″), 135.3, 135.4 (C-1″ + C-1′′′), 138.2 (C-1), 155.9, 156.1 (N-C=C-N), 166.7 (N=C-N), 172.4 (C-2′); MS m/z 428[M+H]+ 100), 430([M+2H]+ 35. Anal. Calcd for C25H19ClN4O: C, 70.34; H, 4.49; N, 13.12. Found: C, 70.65; H, 4.58; N, 13.21.

References

1. R. Lin, G. Chiu, Y. Yu, P. J. Connolly, S. Li, Y. Lu, M. Adams, A. R. Fuentes-Pesquera, S. L. Emanuel, and L. M. Greenberger, Bioorg. Med. Chem. Lett., 2007, 17, 4557. CrossRef
2. S. K. Arora, N. Sinha, S. Jain, R. S. Upadhayaya, G. Jana, S. Ajay, and R. K. Sinha, U. S. Patent 7763602, 2010.
3. M. S. A. El-Gaby, A. M. Gaber, A. A. Atalla, and K. Abd Al-Wahab, Farmaco, 2002, 57, 613. CrossRef
4. R. Vaickelionienė, V. Mickevičius, G. Mikulskienė, M. Stasevych, O. Komarovska-Porokhnyavets, and V. Novikov, Res. Chem. Intermed., 2011, 37, 1009. CrossRef
5. H. S. El-Kashef, T. I. El-Emary, M. Gasquet, P. Timon-David, J. Maldonado, and P. Vanelle, Pharmazie, 2000, 55, 572.
6. M. V. Stasevych, V. G. Chervetsova, m. Yu. Plotnikov, M. O. Platonov, S. I. Sabat, R. Ya. Musyanovych, and V. P. Novikov, Ukrainica Bioorganica Acta, 2006, 2, 33.
7. H. Walter, Z. Naturforsch., 2008, 63b, 351.
8. M. M. M. Raposo, A. M. R. C. Sousa, A. M. C. Fonseca, and G. Kirsch, Mater. Sci. Forum, 2006, 514-516, 103. CrossRef
9. J. Cook, I. Shulman, and J. J. Bielak, U. S. Patent 6984602, 2006.
10. O. Krima, M. Bouachrineb, B. Hammouti, A. Elidrissia, and M. Hamidib, Port. Electrochim. Acta, 2008, 26, 283. CrossRef
11. Z. Liu, G. Yang, and X. Qin, J. Chem. Technol. Biot., 2001, 76, 1154. CrossRef
12. Z. A. Kaplancikli, Molecules, 2011, 16, 7662. CrossRef
13. X. Qian and R. Zhang, J. Chem. Technol. Biotechnol., 1996, 67, 124. CrossRef
14. R. E. Wheeler and W. F. King, U. S. Patent US4213973, 1980.
15. E. Schinzel, T. Martini, and W. Spatzeier, Probst, (Hoechst AG), Ger. Offen. 3126464, 1983/1981 (Chem. Abstr., 1983, 98, 199 850).
16. A. Hetzheim, C. Wasner, J. Werner, H. Kresse, and C. Tschierske, Liq. Cryst., 1999, 26, 885. CrossRef
17. D. Girdziunaite, C. Tschierske, E. Novotna, H. Horst Kresse, and A. Hetzheim, Liq. Cryst., 1991, 10, 397. CrossRef
18. V. Mickevičius, V. Intaitė, A. Voskienė, K. Kantminienė, M. Stasevych, O. Komarovska-Porokhnyavets, and V. Novikov, Heterocycles, 2010, 81, 649. CrossRef
19. N. Upmanyu, S. Kumar, M.-D. Kharya, K. Shah, and P. Mishra, Acta Pol. Pharm. – Drug. Res., 2011, 68, 213.
20. S. Ozkirimli, A. T. Idli, M. Kiraz, and Y. Yegenoglu, Arch. Pharm. Res., 2005, 28, 1213. CrossRef
21. B. S. Holla, B. Veerendra, M. K. Shivananda, and B. Poojary, Eur. J. Med. Chem., 2003, 38, 759. CrossRef
22. D. H. Boschelli, D. T. Connor, D. A. Bornemeier, R. D. Dyer, J. A. Kennedy, P. J. Kuipers, G. C. Okonkwo, D. J. Schrier, and C. D. Wright, J. Med. Chem., 1993, 36, 1802. CrossRef
23. J. M. Kane, M. W. Dudley, S. M. Sorensen, and F. P. Miller, J. Med. Chem., 1988, 31, 1253. CrossRef
24. V. J. Ram and A. J. Vlietinck, J. Heterocycl. Chem., 1988, 25, 253. CrossRef
25. G. Heubach, K. Bauer, and H. Bieringer, U. S. Patent 4 639 266, 1987.
26. V. Mickevičius, R. Vaickelionienė, I. Jonuškienė, G. Mikulskienė, and K. Kantminienė, Monatsh. Chem., 2009, 140, 1513. CrossRef
27. V. Intaitė, A. Voskienė, R. Vaickelionienė, G. Mikulskienė, and V. Mickevičius, Chemija, 2012, 23, 52.
28. K. Brokaite, V. Mickevicius, and G. Mikulskiene, ARKIVOC, 2006, (ii), 61.
29. K. Anusevičius, V. Mickevičius, and G. Mikulskienė, Chemija, 2010, 21, 127.
30. A. Kudelko and W. Zieliński, Heterocycles, 2010, 81, 883. CrossRef
31. M. Koparir, A. Cętin, and A. Cansiz, Molecules, 2005, 10, 475. CrossRef
32. K. Rutkauskas, I. Tumosienė, G. Mikulskienė, K. Kantminienė, and Z. J. Beresnevičius, Chemija, 2011, 22, 238.
33. M. Amir, I. Ahsan, W. Akhter, S. A. Khan, and I. Ali, Indian J. Chem., 2011, 50B, 207.
34. T. Plech, M. Wujec, B. Kapron, U. Kosikowska, and A. Malm, Heteroat. Chem., 2011, 22, 737. CrossRef
35. N. Trotsko, J. Król, A. Siwek, M. Wujec, U. Kosikowska, and A. Malm, Heteroat. Chem., 2012, 23, 117. CrossRef
36. L. I. Socea, T. V. Apostol, G. Şarament, Ş. F. Bărbuceanu, C. Draghici, and M. Dinu, J. Serb. Chem. Soc., 2012, 77, 1.
37. O. D. Cretu, S. F. Barbuceanu, G. Sarament, and C. Draghici, J. Serb. Chem. Soc., 2010, 75, 1463.
38. E. S. H. El Ashry, A. A. Kassem, H. Abdel-Hamid, F. F. Lous, Sh. A. N. Khattab, and M. R. Aouad, ARKIVOC, 2006, xiv, 119.
39. A. Piŕnău, V. Chiş, L. Szabo, O. Cozar, M. Vasilescu, O. Oniga,R. and A. Varga, J. Mol. Struct., 2009, 924-926, 361.
40. S. Karakuş, U. Çoruh, B. Barlas-Durgun, E. M. Vázquez-López, S. Őzbaş-Turan, J. Akbuğa, and S. Rollas, Marmara Pharm. J., 2010, 14, 84.
41. B. S. Holla, C. S. Prasanna, B. Poojary, M. Ashok, K. S. Rao, and K. Shridhara, Z. Naturforsch., 2006, 61b, 334.
42. V. Mickevicius, Z. I. Beresnevicius, M. Mickevicius, and B. Sapijanskaite, Chem. Heterocycl. Compd., 2005, 41, 932. CrossRef
43. A. S. Abd El-All, A. A. Magd-El-Din, S. A. Osman, H. A. Yosef, and T. S. Hafez, Aust. J. Basic Appl. Sci., 2011, 5, 1335.
44. R. Vaickelioniene and V. Mickevicius, Chem. Heterocycl. Compd., 2006, 6, 753. CrossRef
45. A. R. Farghaly, N. Haider, and D. H. Lee, J. Heterocycl. Chem., 2012, 49, 799. CrossRef
46. D. Žiaukienė, I. Jonuškienė, V. Mickevičius, and N. Burbulis, Cheminė technologija, 2009, 4, 5.
47. V. Mickevicius, R. Vaickelioniene, and B. Sapijanskaite, Chem. Heterocycl. Compd., 2009, 45, 215. CrossRef