Synthesis and characterization of 4-substituted 1-(4-halogenophenyl) pyrrolidin-2-ones with azole and azine moieties

Article abstract of DOI:10.3987/COM-13-12703

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

Full text of DOI:10.3987/COM-13-12703

HETEROCYCLES, Vol. 87, No. 5, 2013, pp. 1059 - 1074. © 2013 The Japan Institute of Heterocyclic Chemistry
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,1 Vytautas Mickevicius,1* and Gema Mikulskiene2
1Department of Organic Chemistry, Faculty of Chemical Technology,
Kaunas University of Technology, Radvilenu pl. 19, 50254 Kaunas, Lithuania
2Department of the Biochemistry of Xenobiotics, Vilnius University
Institute of Biochemistry, Mokslininku Str. 12, LT-08662, Vilnius, Lithuania;
E-mail: Vytautas.Mickevicius@ktu.lt
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,
1
MS techniques. The H/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.

Scheme 1. Synthesis of 4-substituted 1-(4-halogenophenyl)pyrrolidin-2-ones 311
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
13
The resonances at ~152.5 ppm (N-C=N) and at ~167 ppm (C=S) in C NMR spectra as well as the
1
resonances at ~5.5 ppm (NH2) and at ~13.6 ppm (NH/SH) in H 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-
13
1
CH=N), at ~166.5 ppm (O-C=N) in C NMR spectra and at ~9.2 ppm (O-CH=N) in H 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

Scheme 2. Synthesis of 4-substituted 1-(4-halogenophenyl)pyrrolidin-2-ones 1216
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
13
resonances observed in C 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
1
spin–spin coupling was observed in the H and 13C NMR spectra.26 The doublets of the aromatic
1
resonances in the H 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 , ppm relative to TMS. IR spectra (, 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
1
(iPrOH); IR 3106, 2958 (NH), 1683 (C=O), 1512, 1482 (C=N), 1329 (C=S) cm-1; H NMR (300 MHz,
DMSO-d6)  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
13
(2Harom, m, 3,5-CH), 7.637.70 (2Harom, m, 2,6-CH), 14.43 (1H, br. s, NNHCS); C NMR (75 MHz,
DMSO-d6):  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
1
(C=S) cm-1; H NMR (300 MHz, DMSO-d6)  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-
13
CH), 13.63 (1H, br. s, NNHCS); C NMR (75 MHz, DMSO-d6)  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)
1
cm-1; H NMR (300 MHz, DMSO-d6)  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)  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
(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,
(4b):

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
1
(C=S) cm-1; H NMR (300 MHz, DMSO-d6)  2.853.04 (2H, m, CH2CO), 3.994.26 (3H, m, CH +
13
CH2N), 7.17–7.90 (9Harom, m, 9CH), 10.12 (1H, s, CH=N), 13.93 (1H, s, NNHCS); C NMR (75 MHz,
DMSO-d6):  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),
1
1509, 1491 (C=N), 1275 (C=S) cm-1; H NMR (300 MHz, DMSO-d6)  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)  27.3 (C-4′), 35.2 (C-3′), 50.5 (C-5′), 115.3 (d, 2JC-F = 22.2 Hz,
3
C-3,5), 121.7 (d, JC-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),
1
137.3 (C-4″), 151.5 (N-C=N), 158.6 (d, JC-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,
1
1473 (2C=N), 1274 (C=S) cm-1; H NMR (300 MHz, DMSO-d6)  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)  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-chloro-
phenyl)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)  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,
13
CH=N), 13.99 (1H, s, NNHCS); C NMR (75 MHz, DMSO-d6)  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
1
(NH), 1657 (C=O), 1497, 1467 (2C=N), 1325 (C=S) cm-1; H NMR (300 MHz, DMSO-d6)  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)  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)  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),
13
14.23 (1H, s, NNHCS); C NMR (75 MHz, DMSO-d6)  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)  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,
13
4CH), 14.25 (1H, s, NNHCS); C NMR (75 MHz, DMSO-d6)  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)  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)  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
1
153–154 C (iPrOH); IR 3201 (NH), 1695, 1664, 1617 (C=O), 1510, 1478, 1460 (C=N) cm-1; H NMR
(300 MHz, DMSO-d6)  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 :
13
0.10 : 0.22)1H, 4s, CONH); C NMR (75 MHz, DMSO-d6)  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;
1
mp 167–168 C (iPrOH); IR 3211 (NH), 1696, 1664 (2C=O), 1495 (C=N) cm-1; H NMR (300 MHz,
DMSO-d6)  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 :
13
0.23)1H, 4s, CONH); C NMR (75 MHz, DMSO-d6)  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
1
(iPrOH); IR 1705 (C=O), 1603, 1588 (C=N) cm-1; H NMR (300 MHz, DMSO-d6)  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)  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
1
(iPrOH). IR 1703 (C=O), 1494, 1484 (C=N) cm-1. H NMR (300 MHz, DMSO-d6)  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):  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)  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)  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
=
3
22.4 Hz, d, C-3,5), 121.4, 121.5 (3JC-F = 8.3 Hz, JC-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)  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
13
(1H, 6s, CONH); C NMR (75 MHz, DMSO-d6)  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)carbo-
nyl]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)  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,
13
3,5-CH), 7.64–7.68 (2Harom, m, 2,6-CH), 10.38 (1H, s, CONH), 11.99 (1H, br. s, COOH); C NMR (75
MHz, DMSO-d6)  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–
1
176 C (iPrOH); IR 1695 (C=O), 1509, 1479 (C=N) cm-1; H NMR (300 MHz, DMSO-d6)  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,
13
(2″- 6″) + (2′′′- 6′′′)CH), 7.71 –7.77 (2Harom, m, 2,6-CH); C NMR (75 MHz, DMSO-d6)  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–
1
204 C (iPrOH); IR 1698 (C=O), 1491, 1478 (C=N) cm-1; H NMR (300 MHz, DMSO-d6)  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)  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.
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