Introduction

Amino acids, their derivatives, and products of their cyclization play an important role in the synthesis of biologically active compounds such as pharmaceuticals, protecting agents for field plants, and growth regulators.

Organic hydrazine compounds have been widely used as synthetic starting materials to construct various nitrogen-containing heterocycles. Hydrazides of carboxylic acids are used for the synthesis of hydrazones [1], pyrroles [2], pyrazoles [2], oxadiazoles [3–5], thiadiazoles [4, 6–8], and triazoles [3, 8]. Several of these compounds have analgesic, antitubercular, antidepressive, anticonvulsive, antitumor, and bactericidal activity.

Information about the structural features of these compounds can be obtained by use of the methods of NMR spectroscopic analysis [9]. Computer molecular modeling has provided insight into the structural basis of the title compounds [10]. Fluorine and trifluoromethyl groups attached to the benzene ring determine characteristic spin–spin splitting patterns and chemical shift effects [9]. The coupling constants between F–H and F–C nuclei are sensitive to the electronic effects of the substituents of the benzene ring [9–20]. The separate structural fragments of the study compounds have been widely investigated [21–40].

Signal doubling in the NMR spectra discloses the presence of rotamers or higher aggregates [9, 21, 22]. 1H and 13C NMR spectral data and the results of the MM2 and AM1 methods of modeling [10] have been used to elucidate the structures of the compounds in terms of s-cis/s-trans conformations and (Z)/(E) configurations [26–33]. The objectives of this work were the synthesis of 1-(3-(fluoromethyl and trifluoromethyl)phenyl)-5-oxopyrrolidine-3-carboxylic acid derivatives and investigation of their structures as a continuation of our earlier studies [34, 35].

Results and discussion

In this work, methyl 1-(3-fluorophenyl)-5-oxopyrrolidine-3-carboxylate (2a) and methyl 5-oxo-1-(3-(trifluoromethyl)phenyl)pyrrolidine-3-carboxylate (2b) were synthesized by esterification of carboxylic acids 1a and 1b with excess methanol under reflux in the presence of a catalytic amount of sulfuric acid. Reaction of esters 2a and 2b with hydrazine hydrate in 2-propanol under reflux gave 5-oxopyrrolidine-3-carbohydrazides 3a and 3b, which crystallized from the reaction mixture after cooling (Scheme 1). 1H NMR spectra are most suitable for confirmation of the structures of 3a and 3b. The narrow singlets at ~3.69 ppm characteristic of COOCH3 protons of 2a and 2b are absent in the 1H NMR spectra of 3a and 3b. The broadened singlets at ~4.31 ppm assigned to the protons of the NH2 group and signals at ~9.30 ppm assigned to protons of the CONH fragment of 3a and 3b prove the presence of the CONHNH2 group in these compounds. IR spectra of these hydrazides showed NHNH2 absorption at 3,313–3,284  cm−1.

The structure of hydrazides 3a and 3b was also verified by their reaction with carbonyl compounds. Condensation of compounds 3 with aromatic aldehydes gave N′-benzylidene-1-(3-substituted phenyl)-5-oxopyrrolidine-3-carbohydrazides 4–10. The reaction was carried out under reflux in 2-propanol or 1,4-dioxane.

Detailed analysis of the 1H and 13C NMR spectra of hydrazones 4–10 having different substitution patterns in the benzene ring was carried out. Considerable interest was focused on the ability to reveal the geometrical isomers originating from the azomethine group and on rotamer formation because of the restricted rotation of the amide group. NMR did not yield conclusive information about the conformations mentioned above, consequently molecular modeling data were also used. The total steric energies were obtained for all models of the available isomers of 4–10 using MM2 and AM1 methods. The dominant isomers were ascertained by comparison of the variations of tendencies of the obtained total steric energy values and distribution of the intensities of NH signals in the 1H NMR spectra. The results of comparison led us to conclude that s-cis/(Z) and s-trans/(E) (s-cis and s-trans—amide rotamers, (Z) and (E)—azomethine geometrical isomers) isomers are favored in DMSO-d6 solutions of 4–10.

The presence of isomers was noticeable in the 1H and 13C NMR spectra for atoms separated by few bonds from the center of isomerism. The most informative signals for study of the isomers of 4–10 were NH group singlets which resonated at ~11.64 and ~11.70 ppm with the intensity ratio of 0.7:0.3, indicating the existence of s-cis/s-trans rotamers. The resonances of the N=CH fragments and CH groups of the pyrrolidinone ring with the same intensity ratio also showed the presence of the isomers. The 13C NMR spectra of 4–10 exhibited double sets of resonances of CO, N=CH, pyrrolidinone ring carbons, and even some carbons (C-1, 2, 6) of the N-phenyl ring, because of restricted rotation around the CO–NH bond. The decay of the differences of the corresponding averaged chemical shifts of 4.97 ppm, 3.36 ppm (CO, N=CH), 1.97 ppm (C-3′), 0.73 ppm (C-4′), 0.48 ppm (C-2′), and 0.18 ppm (C-5′) demonstrates with certainty the presence of the center of isomerism. Such decay was not observed for the differences of the chemical shifts for carbons (C-1, 2, 6) of the N-phenyl ring.

Reaction of carbohydrazydes 3a and 3b with acetone under reflux was facile and provided the corresponding N′-isopropylidene hydrazides 11a and 11b. The formation of s-cis/s-trans rotamers in the ratio 0.5:0.5 was observed in the NMR spectra of 11a and 11b. The magnetic nonequivalence observed for both of the methyl groups is caused by the presence of the lone pair of the nitrogen atom in the azomethine group.

Reaction of carbohydrazides with β and γ diketones usually provides cyclic compounds. Condensation of hydrazides 3a and 3b with 2,4-pentanedione in 2-propanol in the presence of a catalytic amount of hydrochloric acid resulted in the formation of 1-substituted 4-((3,5-dimethylpyrazol-1-yl)carbonyl)pyrrolidin-2-ones 12a and 12b. The 13C NMR spectra of these compounds exhibited three resonances at ~111.62, ~143.90, and ~152.17 ppm assigned to the pyrazole ring. The protons of CH and CH3 groups resonated in the expected region of the 1H NMR spectra and thus also confirmed the presence of the pyrazole moiety. The characteristic spin–spin coupling (4 J = 0.6 Hz) between CH and CH3 (CH=CCH 3 ) groups was observed.

Condensation of hydrazides 3a and 3b with 2,5-hexanedione in 2-propanol in the presence of a catalytic amount of acetic acid resulted in the formation of N-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(3-substituted phenyl)-5-oxopyrrolidine-3-carboxamides 13a and 13b. When hydrochloric acid was used as catalyst, the reaction mixture darkened and resinification occurred. The NMR spectra of 13a and 13b displayed the characteristic signals of the suggested structures. The intense singlets at 2.00 and 5.65 ppm (a and b) attributed to CH3 and CH groups of the pyrrole ring were present in the 1H NMR spectra. The double intensity resonances at ~10.91, ~103.06 and ~126.68 ppm in the 13C NMR spectra pointed to the existence of the pyrrole ring. Despite the presence of the amide fragment, only the s-cis isomer with traces of the s-trans isomer were observed in the 1H and 13C NMR spectra of 13a and 13b in DMSO-d6 solutions. The specific conformational behavior of rotation around the CO–NH bond was investigated using molecular modeling techniques. The rotation barriers computed for the model 13a were 117.50 kJ/mol (s-cis) and 62.37 kJ/mol (s-trans) and those for 13b were 174.18 kJ/mol (s-cis) and 64.16 kJ/mol (s-trans). This allowed the conclusion that rotation around the CO–NH bond is highly restricted by the voluminous 2,5-dimethylpyrrole ring.

Monosubstituted oxadiazole derivatives can be obtained directly from acid hydrazides and ethyl orthoformate. 1,3,4-Oxadiazoles 14a and 14b were synthesized by heating hydrazides 3a and 3b under reflux in excess ethyl orthoformate. Formation of the five-membered oxadiazole ring was confirmed by the presence of a singlet (CH=N) at 9.25 ppm (a and b) in the 1H NMR spectra and the resonances at ~154.97 and ~166.33 ppm, attributed to N=CH and N=C groups, in the 13C NMR spectra. Hydrazinocarbonyl compounds also undergo reaction quite easily with carbon disulfide in the presence of potassium hydroxide. 1-Aryl-4-(4,5-dihydro-5-thioxo-1,3,4-oxadiazol-2-yl)pyrrolidin-2-ones 15a and 15b were synthesized from hydrazides 3a and 3b by the method described in literature [4]. Formation of the five-membered oxadiazole ring was confirmed by the presence of an NH singlet at ~14.50 ppm in the 1H NMR spectra and the resonances at 163.77 and 178.02 ppm (a and b), ascribed to N=C and N-CS groups, in the 13C NMR spectra.

The study compounds have F (compounds a) or a CF3 group (compounds b) at the m position of the benzene ring. Because of the specific magnetic properties of the fluorine atom, spin–spin coupling (up to four bonds) was observed in the 1H and 13C NMR spectra. The splittings arising from the fluorine or trifluoromethyl group complicate analysis of the aromatic region of the NMR spectra. The multiplets of the aromatic resonances in the 1H NMR spectra overlap and are insufficiently informative, whereas in the 13C NMR spectra the multiplets are resolved. In the 13C NMR spectra of compounds a atom C-3 resonated as a doublet centered at ~162.00 ppm with 1 J ~241.8 Hz and in the spectra of compounds b the C atom of the CF3 group resonated as a quartet centered at ~121.84 ppm with 1 J ~272.0 Hz. 2 J values were different for C-2 (~26.5 Hz) and C-4 (~21.1 Hz), and 3 J values were different for C-1 (~10.9 Hz) and C-5 (~9.3 Hz) atoms in compounds a. These J values can be rationalized in terms of the substituent effects. The quartets of C-3 for all compounds b were centered at ~129.50 ppm with a 2 J value of ~31.8 Hz. It was noticed that 3 J was fully resolved only for 12b–15b: its value for C-2 atoms centered at ~115.76 ppm was ~3.8 Hz and that for C-4 atoms centered at ~120.46 ppm was ~3.5 Hz. These multiplets for compounds 4b and 9b were not resolved because of the small 3 J values. For the rest of the b-type compounds 3 J values were measured only for C-2 atoms, whereas the resonances assigned to C-4 atoms were broadened and not resolved properly.

In conclusion, we have shown that fluorine-containing 1-aryl-5-oxopyrrolidine-3-carbohydrazides can be used as starting compounds in the synthesis of various hydrazones and azoles, which can have biological activity. The spectral and molecular modeling data were thoroughly analyzed to elucidate the structure and features of the synthesized compounds.

Experimental

The 1H and 13C NMR spectra were recorded on a Varian Unity Inova (300 MHz) spectrometer operating in Fourier transform mode with TMS as a internal standard. IR spectra were recorded on a Perkin–Elmer Spectrum BX FT-IR (KBr pellet) spectrometer. Mass spectra were obtained on a Waters ZQ 2000 spectrometer. Elemental analysis (C, H, N) was performed on an Elemental Analyzer CE-440, and results were found to be in good agreement (±0.2%) with calculated values. Melting points were determined on the Auto probe analyzer APA 1. Silica gel plates (Silufol UV-254) were used for analytical purposes.

Methyl 1-(3-fluorophenyl)-5-oxopyrrolidine-3-carboxylate (2a, C12H12FNO3)

A mixture of 33.5 g 1-(3-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (1a, 0.15 mol), 36.5 cm3 methanol (0.90 mol), and 3 cm3 sulfuric acid was stirred at reflux for 6 h, unreacted methanol was removed under reduced pressure, and 150 cm3 10% Na2CO3 solution was added. The mixture was boiled then cooled. The crude product was isolated by filtration, washed with water, and dried. M.p.: 89–90 °C (from n-hexane to toluene); yield 99%; IR (KBr): \( \bar{\nu } \) = 1,738 (C=O), 1,695 (C=O), 1,229 (OCH3) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.70–2.89 (m, 2H, CH2CO), 3.42–3.52 (m, 1H, CH), 3.68 (s, 3H, OCH3), 3.96–4.12 (m, 2H, NCH2), 6.94–7.68 (m, 4H, Har) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 34.70 (C-3′), 35.03 (C-4′), 49.64 (C-2′), 52.13 (OCH3), 106.20 (d, 2 J C-F = 26.5 Hz, C-2), 110.52 (d, 2 J C-F = 21.1 Hz, C-4), 114.76 (br s, C-6), 130.30 (d, 3 J C-F = 9.3 Hz, C-5), 140.57 (d, 3 J C-F = 10.9 Hz, C-1), 162.00 (d, 1 J C-F = 241.8 Hz, C-3), 171.96 (CONH), 172.93 (C-5′) ppm; MS (ESI, 20 eV): m/z (%) = 238 ([M + H]+, 100).

Methyl 5-oxo-1-(3-(trifluoromethyl)phenyl)pyrrolidine-3-carboxylate (2b, C13H12F3NO3)

A mixture of 54.6 g 5-oxo-1-(3-(trifluoromethyl)phenyl)pyrrolidine-3-carboxylic acid (1b, 0.20 mol), 48.6 cm3 methanol (1.20 mol), and 3 cm3 sulfuric acid was stirred at reflux for 6 h, unreacted methanol was removed under reduced pressure, and 150 cm3 10% Na2CO3 solution was added. The mixture was boiled and cooled. The product was extracted with diethyl ether (3 × 150 cm3), the combined organic layers were dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give resin residue 2b in 70.9% yield. It was used for the synthesis of 3b. R f = 0.48 (acetone:n-hexane, 1:1); 1H NMR (300 MHz, CDCl3): δ = 2.75–2.86 (m, 2H, CH2CO), 3.28–3.39 (m, 1H, CH), 3.70 (s, 3H, OCH3), 3.96–4.09 (m, 2H, NCH2), 7.36–7.87 (m, 3H, Har) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 35.02 (C-3′), 35.19 (C-4′), 49.68 (C-2′), 52.20 (OCH3), 115.85 (q, 3 J C–F = 3.1 Hz, C-2), 120.72 (br s, C-4), 122.33 (C-6), 121.84 (q, 1 J C–F = 272.0 Hz, CF3), 129.12 (C-5), 130.68 (q, 2 J C-F = 33.2 Hz, C-3), 139.52 (C-1), 171.57 (CONH), 172.35 (C-5′) ppm.

General procedure for preparation of 5-oxopyrrolidine-3-carbohydrazides 3a and 3b

A mixture of 47.45 g 2a or 57.45 g 2b (0.20 mol), 29.3 cm3 hydrazine hydrate (0.60 mol), and 75 cm3 2-propanol was heated under reflux for 1 h and cooled. Crystalline material 3 was isolated by filtration and purified.

1-(3-Fluorophenyl)-5-oxopyrrolidine-3-carbohydrazide (3a, C11H12FN3O2)

M.p.: 204–205 °C (from 2-propanol); yield 87.7%; IR (KBr): \( \bar{\nu } \) = 3,313 (NH), 3,170 (NH2), 1,682 (C=O), 1,635 (C=O) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.59–2.78 (m, 2H, CH2CO), 3.11–3.21 (m, 1H, CH), 3.81–4.02 (m, 2H, NCH2), 4.30 (s, 2H, NH2), 6.93–7.69 (m, 4H, Har), 9.30 (s, 1H, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 33.90 (C-3′), 35.89 (C-4′), 50.68 (C-2′), 106.11 (d, 2 J C-F = 26.3 Hz, C-2), 110.44 (d, 2 J C-F = 21.0 Hz, C-4), 114.68 (br s, C-6), 130.35 (d, 3 J C-F = 9.4 Hz, C-5), 140.75 (d, 3 J C-F = 10.9 Hz, C-1), 162.03 (d, 1 J C-F = 241.7 Hz, C-3), 171.43 (CONH), 172.93 (C-5′) ppm; MS (ESI, 20 eV): m/z (%) = 238 ([M + H]+, 100).

5-Oxo-1-(3-(trifluoromethyl)phenyl)pyrrolidine-3-carbohydrazide (3b, C12H12F3N3O2)

M.p.: 165–166 °C (from ethanol); yield 57.4%; IR (KBr): \( \bar{\nu } \) = 3,323 (NH), 3,284 (NH2), 1,687 (C=O), 1,637 (C=O) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.63–2.70 (m, 2H, CH2CO), 3.16–3.31 (m, 1H, CH), 3.91–4.12 (m, 2H, CH2N), 4.33 (s, 2H, NH2), 7.50–8.21 (m, 4H, Har), 9.32 (s, 1H, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 33.63 (C-3′), 35.42 (C-4′), 50.21 (C-2′), 115.09 (q, 3 J C-F = 3.0 Hz, C-2), 119.88 (br s, C-4), 122.24 (C-6), 123.84 (q, 1 J C-F = 272.2 Hz, CF3), 129.02 (q, 2 J C-F = 31.5 Hz, C-3), 129.63 (C-5), 139.42 (C-1), 171.01 (CONH), 172.42 (C-5′) ppm; MS (ESI, 20 eV): m/z (%) = 288 ([M + H]+, 100).

General procedure for preparation of N’-benzylidene-5-oxopyrrolidine-3-carbohydrazides 4a–10a

A mixture of the appropriate benzaldehyde (7.5 mmol), 1.19 g 5-oxopyrrolidine-3-carbohydrazide 3a (5.0 mmol), and 10 cm3 1,4-dioxane was heated under reflux for 3 h. After cooling the product was isolated by filtration, washed with 2-propanol, and dried.

N′-Benzylidene-1-(3-fluorophenyl)-5-oxopyrrolidine-3-carbohydrazide (4a, C18H16FN3O2)

M.p.: 182–183 °C (from 1,4-dioxane); yield 83.7%; IR (KBr): \( \bar{\nu } \) = 3,068 (NH), 2,966 (N=CH), 1,696 (C=O), 1,677 (C=O) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.72–2.92 (m, 2H, CH2CO), 3.30–3.41 (m, 0.3(1H), s-cis, CH), 3.96–4.19 (m, 0.7(1H), s-trans, CH + 2H, NCH2), 6.93–7.73 (m, 9H, Har), 8.04, 8.22 (2s, (0.7/0.3)(1H), s-cis/s-trans, N=CH), 11.62, 11.67 (2s, (0.7/03)(1H), s-cis/s-trans, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 32.37, 34.33 (s-cis/s-trans, C-3′), 34.75, 35.47 (s-cis/s-trans, C-4′), 49.71, 50.18 (s-cis/s-trans, C-2′), 106.15 (d, 2 J C-F = 26.4 Hz, s-cis, C-2), 106.25 (d, 2 J C-F = 26.5 Hz, s-trans, C-2), 110.48 (d, 2 J C-F = 21.0 Hz, C-4), 114.82 (br s, C-6), 126.92, 127.10 (C-2″, C-6″), 128.83 (C-3″, C-5″), 129.92, 130.14 (C-4″), 130.35 (d, 3 J C-F = 9.5 Hz, C-5), 134.11 (C-1″), 140.73 (d, 3 J C-F = 10.4 Hz, s-cis, C-1), 140.80 (d, 3 J C-F = 10.8 Hz, s-trans, C-1), 143.37, 147.09 (s-cis/s-trans, N=CH), 162.08 (d, 1 J C-F = 241.4 Hz, C-3), 168.59 (s-cis, CONH) 172.40, 172.60 (s-cis/s-trans, C-5′), 173.46 (s-trans, CONH) ppm; MS (ESI, 20 eV): m/z (%) = 326 ([M + H]+, 100).

N′-(4-Fluorobenzylidene)-1-(3-fluorophenyl)-5-oxopyrrolidine-3-carbohydrazide (5a, C18H15F2N3O2)

M.p.: 213–214 °C (from 1,4-dioxane); yield 90.9%; IR (KBr): \( \bar{\nu } \) = 3,124 (NH), 2,971 (N=CH), 1,688 (C=O), 1,679 (C=O) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.71–2.93 (m, 2H, CH2CO), 3.29–3.41 (m, 0.3(1H), s-cis, CH), 3.92–4.21 (m, 0.7(1H), s-trans, CH + 2H, NCH2), 6.92–7.74 (m, 8H, Har), 8.03, 8.23 (2s, (0.7/0.3)(1H), s-cis/s-trans, N=CH), 11.62, 11.69 (2s, (0.7/0.3)(1H), s-cis/s-trans, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 32.62, 34.60 (s-cis/s-trans, C-3′), 35.02, 35.76 (s-cis/s-trans, C-4′), 49.99, 50.46 (s-cis/s-trans, C-2′), 106.17, 106.26 (2d, 2 J C-F = 26.5 Hz, s-cis/s-trans, C-2), 110.50 (d, 2 J C-F = 20.7 Hz, C-4), 114.86 (br s, C-6), 115.89 (d, 2 J C-F = 22.0 Hz, C-3″, C-5″), 129.12 (d, 3 J C-F = 8.5 Hz, s-cis, C-2″, C-6″), 129.29 (d, 3 J C-F = 9.2 Hz, s-trans, C-2″, C-6″), 130.36 (d, 3 J C-F = 9.4 Hz, C-5), 130.75 (d, 4 J C-F = 2.0 Hz, C-1″), 140.74 (d, 3 J C-F = 10.7 Hz, s-cis, C-1), 140.80 (d, 3 J C-F = 10.9 Hz, s-trans, C-1), 142.60, 145.98 (s-cis/s-trans, N=CH), 162.09 (d, 1 J C-F = 241.7 Hz, C-3), 163.01 (d, 1 J C-F = 247.7 Hz, C-4″), 168.63 (s-cis, CONH), 172.42, 172.61 (s-cis/s-trans, C-5′), 173.46 (s-trans, CONH) ppm; MS (ESI, 20 eV): m/z (%) = 344 ([M + H]+, 100).

N′-(4-Chlorobenzylidene)-1-(3-fluorophenyl)-5-oxopyrrolidine-3-carbohydrazide (6a, C18H15ClFN3O2)

M.p.: 225–226 °C (from 1,4-dioxane); yield 83.6%; IR (KBr): \( \bar{\nu } \) = 3,130 (NH), 2,970 (N=CH), 1,681 (2×C=O) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.71–2.92 (m, 2H, CH2CO), 3.30–3.41 (m, 0.3(1H), s-cis, CH), 3.95–4.18 (m, 0.7(1H), s-trans, CH + 2H, NCH2), 6.93-7.76 (m, 8H, Har), 8.03, 8.21 (2s, (0.7/0.3)(1H), s-cis/s-trans, N=CH), 11.68, 11.73 (2s, (0.7/0.3)(1H), s-cis/s-trans, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 32.68, 34.67 (s-cis/s-trans, C-3′), 35.07, 35.80 (s-cis/s-trans, C-4′), 50.02, 50.48 (s-cis/s-trans, C-2′), 106.16, 106.25 (2d, 2 J C-F = 26.5 Hz, (s-cis/s-trans, C-2), 110.49 (d, 2 J C-F = 20.8 Hz, C-4), 114.76, 114.84 (2 br s, s-cis/s-trans, C-6), 128.58, 128.73 (C-2″, C-6″), 129.91 (C-3″, C-5″), 130.34 (d, 3 J C-F = 9.2 Hz, C-5), 133.07 (C-1″), 134.35, 134.58 (C-4″), 140.72 (d, 3 J C-F = 10.2 Hz, s-cis, C-1), 140.78 (d, 3 J C-F = 11.3 Hz, s-trans, C-1), 142.46, 145.77 (s-cis/s-trans, N=CH), 162.08 (d, 1 J C-F = 241.6 Hz, C-3), 168.70 (s-cis, CONH), 172.38, 172.56 (s-cis/s-trans, C-5′), 173.52 (s-trans, CONH) ppm; MS (ESI, 20 eV): m/z (%) = 360 (M+, 100), 362 ([M + H + 1]+, 33).

N′-(4-Bromobenzylidene)-1-(3-fluorophenyl)-5-oxopyrrolidine-3-carbohydrazide (7a, C18H15BrFN3O2)

M.p.: 223–224 °C (from 1,4-dioxane); yield 83.1%; IR (KBr): \( \bar{\nu } \) = 3,132 (NH), 2,966 (N=CH), 1,690 (C=O), 1,670 (C=O), 514 (C–Br) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.71–2.92 (m, 2H, CH2CO), 3.30–3.40 (m, 0.3(1H), s-cis, CH), 3.95–4.18 (m, 0.7(1H), s-trans, CH + 2H, NCH2), 6.93–7.73 (m, 8H, Har), 8.01, 8.19 (2s, (0.7/0.3)(1H), s-cis/s-trans, N=CH), 11.68, 11.75 (2s, (0.7/0.3)(1H), s-cis/s-trans, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 32.68, 34.67 (s-cis/s-trans, C-3′), 35.08, 35.80 (s-cis/s-trans, C-4′), 50.02, 50.48 (s-cis/s-trans, C-2′), 106.16 (d, 2 J C-F = 26.8 Hz, s-cis, C-2), 106.25 (d, 2 J C-F = 26.3 Hz, s-trans, C-2), 110.50 (d, 2 J C-F = 21.1 Hz, C-4), 114.76, 114.86 (2 br s, cis/s-trans, C-6), 123.14, 123.41 (C-4″), 128.82, 128.93 (C-2″, C-6″), 30.36 (d, 3 J C-F = 9.0 Hz, C-5), 131.82 (C-3″, C-5″), 133.41 (C-1″), 140.74 (d, 3 J C-F = 11.4 Hz, s-cis, C-1), 140.79 (d, 3 J C-F = 10.6 Hz, s-trans, C-1), 142.57, 145.85 (s-cis/s-trans, N=CH), 162.09 (d, 1 J C-F = 241.5 Hz, C-3), 168.70 (s-cis, CONH), 172.38, 172.57 (s-cis/s-trans, C-5′), 173.52 (s-trans, CONH) ppm; MS (ESI, 20 eV): m/z (%) = 404 (M+, 95), 406 ([M + H + 1]+, 100).

N′-(4-(Dimethylamino)benzylidene)-1-(3-fluorophenyl)-5-oxopyrrolidine-3-carbohydrazide (8a, C20H21FN4O2)

M.p.: 229–230 °C (from 1,4-dioxane); yield 68.7%; IR (KBr): \( \bar{\nu } \) = 3,084 (NH), 2,955 (N=CH), 1,690 (C=O), 1,664 (C=O), 1,613 (N(CH3)2) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.72–2.93 (m, 2H, CH2CO), 2.96 (s, 6H, N(CH3)2), 3.29–3.41 (m, 0.3(1H), s-cis, CH), 3.96–4.22 (m, 0.7(1H), s-trans, CH + 2H, NCH2), 6.71–7.74 (m, 8H, Har), 7.90, 8.06 (2s, (0.7/0.3)(1H), s-cis/s-trans, N=CH), 11.33, 11.38 (2s, (0.7/0.3)(1H), s-cis/s-trans, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 32.63, 34.55 (s-cis/s-trans, C-3′), 35.05, 35.84 (s-cis/s-trans, C-4′), 50.09, 50.59 (s-cis/s-trans, C-2′), 39.78 (N(CH3)2), 106.13, 106.22 (d, 2 J C-F = 26.3 Hz, s-cis/s-trans, C-2), 110.46 (d, 2 J C-F = 21.0 Hz, C-4), 111.79 (C-3″, C-5″), 114.80 (br s, C-6), 121.31, 121.48 (C-1″), 128.18, 128.44 (C-2″, C-6″), 130.36 (d, 3 J C-F = 9.5 Hz, C-5), 140.77 (d, 3 J C-F = 11.4 Hz, s-cis, C-1), 140.83 (d, 3 J C-F = 10.6 Hz, s-trans, C-1), 144.51, 147.86 (s-cis/s-trans, N=CH), 151.36, 151.53 (C-4″), 162.08 (d, 1 J C-F = 241.3 Hz, C-3), 167.94 (s-cis, CONH), 172.51, 172.71 (s-cis/s-trans, C-5′), 172.81 (s-trans, CONH) ppm; MS (ESI, 20 eV): m/z (%) = 369 ([M + H]+, 100).

1-(3-Fluorophenyl)-N′-(4-methoxybenzylidene)-5-oxopyrrolidine-3-carbohydrazide (9a, C19H18FN3O3)

M.p.: 197–198 °C (from 1,4-dioxane); yield 85.6%; IR (KBr): \( \bar{\nu } \) = 3,240 (NH), 3,087 (N=CH), 1,674 (C=O), 1,655 (C=O), 1,252 (OCH3) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.69–2.91 (m, 2H, CH2CO), 3.29–3.39 (m, 0.3(1H), s-cis, CH), 3.79, 3.80 (2s, 3H, s-cis/s-trans, OCH3), 3.93–4.18 (m, 0.7(1H), s-trans, CH + 2H, NCH2), 6.93–7.76 (m, 8H, Har), 8.03, 8.22 (2s, (0.7/0.3)(1H), s-cis/s-trans, N=CH), 11.68, 11.73 (2s, (0.7/0.3)(1H), s-cis/s-trans, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 32.63, 34.58 (s-cis/s-trans, C-3′), 35.04, 35.79 (s-cis/s-trans, C-4′), 50.04, 50.52 (s-cis/s-trans, C-2′), 55.23 (OCH3), 106.07, 106.19 (d, 2 J C-F = 26.4 Hz, s-cis/s-trans, C-2), 110.42 (d, 2 J C-F  = 21.0 Hz, C-4), 114.25 (C-3″, 5″), 114.75 (br s, C-6), 126.58, 126.65 (C-1″), 128.44, 128.66 (C-2″, 6″), 130.30 (d, 3 J C-F = 9.2 Hz, C-5), 140.69, 140.76 (2d, 3 J C-F = 10.6 Hz, s-cis/s-trans, C-1), 143.53, 146.91 (s-cis/s-trans, N=CH), 160.42, 160.81 (C-4″), 162.12 (d, 1 J C-F = 241.3 Hz, C-3), 168.27 (s-cis, CONH), 172.38, 172.59 (s-cis/s-trans, C-5′), 173.13 (s-trans, CONH) ppm; MS (ESI, 20 eV): m/z (%) = 356 ([M + H]+, 100).

1-(3-Fluorophenyl)-N′-(4-nitrobenzylidene)-5-oxopyrrolidine-3-carbohydrazide (10a, C18H15FN4O4)

M.p.: 231–232 °C (from 1,4-dioxane); yield 88.6%; IR (KBr): \( \bar{\nu } \) = 3,130 (NH), 2,976 (N=CH), 1,691 (C=O), 1,660 (C=O), 1,531 and 1,342 (NO2) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.70–2.91 (m, 2H, CH2CO), 3.28–3.39 (m, 0.3(1H), s-cis, CH), 3.92–4.20 (m, 0.7(1H), s-trans, CH + 2H, NCH2), 6.92–8.31 (m, 9H, Har + N=CH), 11.90, 11.98 (2s, (0.7/0.3)(1H), s-cis/s-trans, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 32.73, 34.75 (s-cis/s-trans, C-3′), 35.06, 35.78 (s-cis/s-trans, C-4′), 49.95, 50.41 (s-cis/s-trans, C-2′), 106.17 (d, 2 J C-F = 26.7 Hz, s-cis, C-2), 106.21 (d, 2 J C-F = 26.2 Hz, s-trans, C-2), 110.51 (d, 2 J C-F = 20.8 Hz, C-4), 114.84 (br s, C-6), 124.01 (C-3″, C-5″), 127.86, 128.01 (C-2″, C-6″), 130.35 (d, 3 J C-F = 9.5 Hz, C-5), 141.41 (C-1″), 140.72 (d, 3 J C-F = 11.1 Hz, s-cis, C-1), 140.76 (d, 3 J C-F = 10.5 Hz, s-trans, C-1), 141.42, 144.63 (s-cis/s-trans, N=CH), 147.69, 147.85 (C-4″), 162.09 (d, 1 J C-F = 241.5 Hz, C-3), 169.08 (s-cis, CONH), 172.32, 172.50 (s-cis/s-trans, C-5′), 173.86 (s-trans, CONH) ppm; MS (ESI, 20 eV): m/z (%) = 371 ([M + H]+, 50).

General procedure for preparation of N′-benzylidene-5-oxopyrrolidine-3-carbohydrazides 4b–10b

A mixture of the appropriate benzaldehyde (7.5 mmol), 1.44 g 5-oxopyrrolidine-3-carbohydrazide 3b (5.0 mmol), and 10 cm3 1,4-dioxane was heated under reflux for 3 h. After cooling, the crude product was isolated by filtration and washed with 2-propanol.

N′-Benzylidene-5-oxo-1-(3-(trifluoromethyl)phenyl)-pyrrolidine-3-carbohydrazide (4b, C19H16F3N3O2)

M.p.: 196–197 °C (from 1,4-dioxane); yield 64.0%; IR (KBr): \( \bar{\nu } \) = 3,134 (NH), 2,979 (N=CH), 1,688 (2×C=O) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.71–2.95 (m, 2H, CH2CO), 3.29–3.41 (m, 0.3(1H), s-cis, CH), 4.02–4.25 (m, 0.7(1H), s-trans, CH + 2H, NCH2), 7.04–8.22 (m, 9H, Har + 1H, N=CH), 11.62, 11.67 (2s, (0.7/0.3)(1H), s-cis/s-trans, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 32.78, 34.73 (s-cis/s-trans, C-3′), 34.98 (C-4′), 49.92, 50.38 (s-cis/s-trans, C-2′), 115.66 (br s, C-2), 120.32 (br s, C-4), 122.78 (C-6), 123.67 (q, 1 J C-F = 272.3 Hz, CF3), 126.89, 127.07 (C-2″, C-6″), 128.81 (C-3″, C-5″), 128.81 (C-5), 129.76 (q, 2 J C-F = 33.0 Hz, C-3), 130.02 (C-4″), 134.09 (C-1″), 139.82 (C-1), 143.73, 147.08 (s-cis/s-trans, N=CH), 168.50 (s-cis, CONH), 172.81, 172.93 (s-cis/s-trans, C-5′), 173.93 (s-trans, CONH) ppm; MS (ESI, 20 eV): m/z (%) = 376 ([M + H]+, 100).

N′-(4-Fluorobenzylidene)-5-oxo-1-(3-(trifluoromethyl)-phenyl)pyrrolidine-3-carbohydrazide (5b, C19H15F4N3O2)

M.p.: 221–222 °C (from 1,4-dioxane); yield 99.7%; IR (KBr): \( \bar{\nu } \) = 3,128 (NH), 2,968 (N=CH), 1,687 (C=O), 1,678 (C=O) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.74–2.95 (m, 2H, CH2CO), 3.33–3.43 (m, 0.3(1H), s-cis, CH), 4.02–4.24 (m, 0.7(1H), s-trans, CH + 2H, NCH2), 7.23–8.23 (m, 8H, Har + 1H, N=CH), 11.62, 11.67 (2s, (0.7/0.3)(1H), s-cis/s-trans, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 32.79, 34.76 (s-cis/s-trans, C-3′), 35.02, 35.72 (s-cis/s-trans, C-4′), 49.95, 50.43 (s-cis/s-trans, C-2′), 115.67 (q, 3 J C-F = 3.1 Hz, C-2), 115.87 (C-3″, C-5″), 120.29 (br s, C-4), 122.65, 122.74 (s-cis/s-trans, C-6), 124.09 (q, 1 J C-F = 272.4 Hz, CF3), 129.11 (d, 3 J C-F = 8.9 Hz, s-cis, C-2″, C-6″), 129.28 (d, 3 J C-F = 9.1 Hz, s-trans, C-2″, C-6″), 130.77 (C-5), 129.81 (q, 2 J C-F = 29.0 Hz, C-3), 130.76 (br s, C-1″), 139.80 (br s, C-1), 142.55, 145.84 (s-cis/s-trans, N=CH), 163.01 (d, 1 J C-F = 247.3 Hz, s-cis, C-4″), 163.16 (d, 1 J C-F = 248.4 Hz, s-trans, C-4″), 168.60 (s-cis, CONH), 172.56, 172.75 (s-cis/s-trans, C-5′), 173.56 (s-trans, CONH) ppm; MS (ESI, 20 eV): m/z (%) = 394 ([M + H]+, 100).

N′-(4-Chlorobenzylidene)-5-oxo-1-(3-(trifluoromethyl)phenyl)pyrrolidine-3-carbohydrazide (6b, C19H15ClF3N3O2)

M.p.: 238–239 °C (from 1,4-dioxane); yield 95.7%; IR (KBr): \( \bar{\nu } \) = 3,132 (NH), 3,201 (N=CH), 1,688 (C=O), 1,667 (C=O) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.74–2.95 (m, 2H, CH2CO), 3.32–3.23 (m, 0.3(1H), s-cis, CH), 4.02–4.23 (m, 0.7(1H), s-trans, CH + 2H, NCH2), 7.40–8.22 (m, 8H, Har + 1H, N=CH), 11.66, 11.73 (2s, (0.7/0.3)(1H), s-cis/s-trans, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 32.74, 34.73 (s-cis/s-trans, C-3′), 34.97, 35.63 (s-cis/s-trans, C-4′), 49.88, 50.36 (s-cis/s-trans, C-2′), 115.51 (q, 3 J C-F = 4.2 Hz, s-cis, C-2), 115.61 (q, 3 J C-F = 3.8 Hz, s-trans, C-2), 120.26 (br s, C-4), 122.63, 122.73 (s-cis/s-trans, C-6), 124.01 (q, 1 J C-F = 272.4 Hz, CF3), 128.54, 128.69 (C-2″, C-6″), 129.36 (d, 2 J C-F = 31.7 Hz, C-3), 129.95 (C-3″, C-5″), 133.05 (C-1″), 134.32, 134.56 (C-4″), 139.74, 139.79 (C-1), 142.46, 145.77 (s-cis/s-trans, N=CH), 168.59 (s-cis, CONH), 172.57, 172.75 (s-cis/s-trans, C-5′), 173.45 (s-trans, CONH) ppm; MS (ESI, 20 eV): m/z (%) = 410 ([M + H]+, 100), 412 ([M + H + 1]+, 33).

N′-(4-Bromobenzylidene)-5-oxo-1-(3-(trifluoromethyl)-phenyl)pyrrolidine-3-carbohydrazide (7b, C19H15BrF3N3O2)

M.p.: 200–201 °C (from 2-propanol); yield 91.5%; IR (KBr): \( \bar{\nu } \) = 3,136 (NH), 2,978 (N=CH), 1,687 (C=O), 1,664 (C=O), 693 (C–Br) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.72–2.94 (m, 2H, CH2CO), 3.31–3.43 (m, 0.3(1H), s-cis, CH), 4.01–4.23 (m, 0.7(1H), s-trans, CH + 2H, CH2N), 7.47–8.21 (m, 8H, Har + 1H, N=CH), 11.67, 11.73 (2s, (0.7/0.3)(1H), s-cis/s-trans, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 32.74, 34.73 (s-cis/s-trans, C-3′), 34.97, 35.63 (s-cis/s-trans, C-4′), 49.88, 50.35 (s-cis/s-trans, C-2′), 115.51 (q, 3 J C-F = 4.3 Hz, s-cis, C-2), 115.61 (q, 3 J C-F = 3.8 Hz, s-trans, C-2), 120.22 (br s, C-4), 122.65, 122.74 (s-cis/s-trans, C-6), 123.09, 123.35 (C-4″), 124.04 (q, 1 J C-F = 272.5 Hz, CF3), 128.78, 128.92 (C-2″, C-6″), 129.35 (q, 2 J C-F = 31.8 Hz, C-3), 129.97 (C-5), 131.78 (C-3″, C-5″), 133.38 (C-1″), 139.79 (C-1), 142.55, 145.84 (s-cis/s-trans, N=CH), 168.60 (s-cis, CONH), 172.56, 172,75 (s-cis/s-trans, C-5′), 173.46 (s-trans, CONH) ppm; MS (ESI, 20 eV): m/z (%) = 454 (M+, 97.5), 456 ([M + H + 1]+, 100).

N′-(4-(Dimethylamino)benzylidene)-5-oxo-1-(3-(trifluoromethyl)phenyl)pyrrolidine-3-carbohydrazide (8b, C21H21F3N4O2)

M.p.: 238–239 °C (from 1,4-dioxane); yield 91.0%; IR (KBr): \( \bar{\nu } \) = 3,246 (NH), 2,931 (N=CH), 1,690 (C=O), 1,657 (C=O), 1,603 (N(CH3)2) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.81–2.96 (m, 2H, CH2CO), 2.97, 2.98 (2s, 6H, N(CH3)2), 3.31–3.43 (m, 0.3(1H), s-cis, CH), 4.13–4.25 (m, 0.7(1H), s-trans, CH + 2H, NCH2), 6.72–8.31 (m, 8H, Har + 1H, N=CH), 11.33, 11.37 (2s, (0.7/0.3)(1H), s-cis/s-trans, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 32.78, 34.68 (s-cis/s-trans, C-3′), 39.78 (N(CH3)2), 35.02, 35.75 (s-cis/s-trans, C-4′), 50.01, 50.52 (s-cis/s-trans, C-2′), 111.75 (C-3″, C-5″), 115.56 (q, 3 J C-F = 3.7 Hz, s-cis, C-2), 115.59 (q, 3 J C-F = 3.5 Hz, s-trans, C-2), 120.22 (br s, C-4), 121.30, 121.46 (C-1″), 122.62, 122.69 (s-cis/s-trans, C-6), 124.05 (q, 1 J C-F = 272.5 Hz, CF3), 128.13, 128.39 (C-2″, C-6″), 129.35 (q, 2 J C-F = 31.9 Hz, C-3), 129.97 (C-5), 139.77, 139.84 (s-cis/s-trans, C-1), 144.49, 147.88 (s-cis/s-trans, N=CH), 151.35, 151.51 (C-4″), 167.83 (s-cis, CONH), 172.73, 172.89 (s-cis/s-trans, C-5′), 173.73 (s-trans, CONH) ppm; MS (ESI, 20 eV): m/z (%) = 419 ([M + H]+, 100).

N′-(4-Methoxybenzylidene)-5-oxo-1-(3-(trifluoromethyl)-phenyl)pyrrolidine-3-carbohydrazide (9b, C20H18F3N3O3)

M.p.: 164–165 °C (from 2-propanol); yield 94.8%; IR (KBr): \( \bar{\nu } \) = 3,211 (NH), 2,961 (N=CH), 1,688 (C=O), 1,678 (C=O), 1,607 (OCH3) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.73–2.93 (m, 2H, CH2CO), 3.30–3.41 (m, 0.3(1H), s-cis, CH), 3.78, 3.79 (2s, 3H, s-cis/s-trans, OCH3), 4.01–4.23 (m, 0.7(1H), s-trans, CH + 2H, NCH2), 6.96–8.23 (m, 8H, Har + 1H, N=CH), 11.50, 11.56 (2s, (0.7/0.3)(1H), s-cis/s-trans, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 32.74, 34.68 (s-cis/s-trans, C-3′), 34.97, 35.69 (s-cis/s-trans, C-4′), 49.93, 50.43 (s-cis/s-trans, C-2′), 55.21 (OCH3), 114.24 (C-3″, C-5″), 115.59 (br s, C-2), 120.18 (br s, C-4), 122.57 (C-5), 122.57 (C-6), 124.47 (q, 1 J C-F = 272.6 Hz, CF3), 126.66 (C-1″), 128.44 (C-2″, C-6″), 128.44 (C-5), 129.94 (C-3), 139.79 (C-1), 143.55, 146.91 (s-cis/s-trans, N=CH), 160.62, 160.81 (C-4″), 168.21 (s-cis, CONH), 172.64, 172.83 (s-cis/s-trans, C-5′), 173.09 (s-trans, CONH) ppm; MS (ESI, 20 eV): m/z (%) = 406 ([M + H]+, 100).

N′-(4-Nitrobenzylidene)-5-oxo-1-(3-(trifluoromethyl)-phenyl)pyrrolidine-3-carbohydrazide (10b, C19H15F3N4O4)

M.p.: 233–234 °C (from 1,4-dioxane); yield 97.5%; IR (KBr): \( \bar{\nu } \) = 3,204 (NH), 2,976 (N=CH), 1,689 (C=O), 1,657 (C=O), 1,529 and 1,345 (NO2) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.78–2.97 (m, 2H, CH2CO), 3.30–3.46 (m, 0.3(1H), s-cis, CH), 4.04–4.26 (m, 0.7(1H), s-trans, CH + 2H, NCH2), 7.48–8.43 (m, 8H, Har + 1H, N=CH), 11.90, 11.96 (2s, (0.7/0.3)(1H), s-cis/s-trans, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 32.78, 34.79 (s-cis/s-trans, C-3′), 34.93, 35.05 (s-cis/s-trans, C-4′), 49.82, 50.23 (s-cis/s-trans, C-2′), 115.61 (q, 3 J C-F = 4.3 Hz, C-2), 120.32 (br s, C-4), 122.68, 122.80 (s-cis/s-trans, C-6), 123.72 (q″ 1 J C-F = 272.4 Hz, CF3), 123.99, 124.04 (C-3″, C-5″), 127.88, 128.01 (C-2″, C-6″), 129.37 (q, 2 J C-F = 31.6 Hz, C-3), 129.99 (C-5), 139.70 (C-1), 140.38, 140.43 (C-1″), 141.42, 144.42 (s-cis/s-trans, N=CH), 147.73, 147.88 (C-4″), 168.97 (s-cis, CONH), 172.70 (C-5′), 173.81 (s-trans, CONH) ppm; MS (ESI, 20 eV): m/z (%) = 421 ([M + H]+, 100).

General procedure for preparation of N′-isopropylidene-5-oxopyrrolidine-3-carbohydrazides 11a and 11b

A mixture of the appropriate hydrazide 3 (5.0 mmol) and 30 cm3 acetone was heated under reflux for 3 h. When acetone was removed under reduced pressure the product crystallized.

1-(3-Fluorophenyl)-N′-isopropylidene-5-oxopyrrolidine-3-carbohydrazide (11a, C14H16FN3O2)

M.p.: 167–168 °C (from 1,4-dioxane); yield 76.5%; IR (KBr): \( \bar{\nu } \) = 3,237 (NH), 1,694 (C=O), 1,657 (C=O) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 1.87, 1.88 (2s, (0.5/0.5)(3H), (Z)/s-cis/s-trans, CH3), 1.93 (s, 3H, (E)/s-cis/s-trans, CH3), 2.63–2.83 (m, 2H, CH2CO), 3.36–3.49 (m, 0.5(1H), s-cis, CH), 3.86–4.12 (m, 0.5(1H), s-trans, CH + 2H, NCH2), 6.91–7.70 (m, 4H, Har), 10.25, 10.34 (2s, (0.5/0.5)(1H), s-cis/s-trans, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 17.16, 17.65 ((Z)/s-cis/s-trans, CH3), 24.97, 25.27 ((E)/s-cis/s-trans, CH3), 32.79, 34.14 (s-cis/s-trans, C-3′), 35.14, 36.00 (s-cis/s-trans, C-4′), 50.17, 50.83 (s-cis/s-trans, C-2′), 106.09 (d, 2 J C-F = 26.3 Hz, s-cis, C-2), 106.21 (d, 2 J C-F = 26.4 Hz, s-trans, C-2), 110.43 (d, 2 J C-F = 21.1 Hz, C-4), 114.70, 114.80 (s-cis/s-trans, C-6), 130.33 (d, 3 J C-F = 9.5 Hz, C-5), 140.70 (d, 3 J C-F = 10.7 Hz, s-cis, C-1), 140.77 (d, 3 J C-F = 10.9 Hz, s-trans, C-1), 151.35, 156.25 (s-cis/s-trans, C=N), 162.07 (d, 1 J C-F = 241.7 Hz, C-3), 168.53 (s-cis, CONH), 172.60, 172.69 (s-cis/s-trans, C-5′), 173.56 (s-trans, CONH) ppm; MS (ESI, 20 eV): m/z (%) = 278 ([M + H]+, 100).

N′-Isopropylidene-5-oxo-1-(3-(trifluoromethyl)-phenyl)pyrrolidine-3-carbohydrazide (11b, C15H16F3N3O2)

M.p.: 127–128 °C (from ethanol); yield 34.3%; IR (KBr): \( \bar{\nu } \) = 3,266 (NH), 1,690 (C=O), 1,658 (C=O, N=C(CH3)2) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 1.87, 1.88 (2s, (0.5/0.5)(3H), (Z)/s-cis/s-trans, CH3), 1.94 (s, 3H, (E)/s-cis/s-trans, CH3), 2.65–2.85 (m, 2H, CH2CO), 3.39–3.51 (m, 0.5(1H), s-cis, CH), 3.90–4.17 (m, 0.5(1H), s-trans, CH + 2H, NCH2), 7.48–8.20 (m, 4H, Har), 10.23, 10.34 (2s, (0.5/0.5)(1H), s-cis/s-trans, NH) ppm; MS (ESI, 20 eV): m/z (%) = 328 ([M + H]+, 100).

General procedure for preparation of 4-((3,5-dimethyl-1H-pyrazol-1-yl)carbonyl)pyrrolidin-2-ones 12a and 12b

A mixture of 1.19 g appropriate hydrazide 3 (5.0 mmol), 1.5 g 2,4-pentanedione (15.0 mmol), 15  cm3 2-propanol, and 0.5 cm3 hydrochloric acid was heated under reflux for 5 h, then cooled. The precipitate 12 was isolated by filtration and washed with 2-propanol.

4-((3,5-Dimethyl-1H-pyrazol-1-yl)carbonyl)-1-(3-fluorophenyl)pyrrolidin-2-one (12a, C16H16FN3O2)

M.p.: 133–134 °C (from 2-propanol); yield 59.8%; IR (KBr): \( \bar{\nu } \) = 1,716 (C=O), 1,703 (C=O), 1,395 (2×CH3) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.21 (s, 3H, CHCCH 3 ), 2.48 (d, 3H, 4 J = 0.6 Hz, HC = CCH 3 ), 2.81–2.98 (m, 2H, CH2CO), 4.01–4.24 (m, 2H, NCH2), 4.41–4.53 (m, 1H, CH), 6.23 (q, 1H, 4 J = 0.6 Hz, HC = CCH3), 6.94–7.70 (m, 4H, Har) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 13.59 (CHCCH 3 ), 14.06 (HC = CCH 3 ), 35.23 (C-3′ + C-4′), 50.11 (C-2′), 106.32 (d, 2 J C-F = 26.3 Hz, C-2), 110.60 (d, 2 J C-F = 21.1 Hz, C-4), 111.63 (HC = CCH3), 114.80 (br s, C-6), 130.36 (d, 3 J C-F = 9.4 Hz, C-5), 140.61 (d, 3 J C-F = 10.9 Hz, C-1), 143.90 (HC = CCH3), 152.18 (CHCCH3), 162.05 (d, 1 J C-F = 241.7 Hz, C-3), 172.07 (C-5′), 172.50 (C=O) ppm.

4-((3,5-Dimethyl-1H-pyrazol-1-yl)carbonyl)-1-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one (12b, C17H16F3N3O2)

M.p.: 165–166 °C (from 2-propanol); yield 31.8%; IR (KBr): \( \bar{\nu } \) = 1,723 (C=O), 1,712 (C=O), 1,382 (2×CH3) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.21 (s, 3H, CHCCH 3 ), 2.49 (d, 3H, J = 0.6 Hz, HC = CCH 3 ), 2.88 (dd, 1H, J = 6.9 Hz, J = 17.3 Hz, CH2CO), 2.95 (dd, 1H, J = 9.1 Hz, J = 17.3 Hz, CH2CO), 4.11 (dd, 1H, J = 5.5 Hz, J = 10.0 Hz, CH2N), 4.27 (dd, 1H, J = 8.9 Hz, J = 10.0 Hz, CH2N), 4.51 (dddd, 1H, J = 5.5 Hz, J = 6.9 Hz, J = 8.9 Hz, J = 9.1 Hz, CH), 6.23 (q, 1H, J = 0.6 Hz, HC=CCH3), 7.49–8.18 (m, 4H, Har) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 13.55 (CHCCH 3 ), 13.94 (HC=CCH 3 ), 35.08 (C-3′), 35.27 (C-4′), 50.00 (C-2′), 111.60 (HC=CCH3), 115.71 (q, 3 J C-F = 4.0 Hz, C-2), 120.36 (q, 3 J C-F = 3.8 Hz, C-4), 122.88, 122.22 ((Z)/(E), C-6), 123.22 (q, J C-F = 272.5 Hz, CF3), 129.36 (q, 2 J C-F = 31.8 Hz, C-3), 129.97 (C-5), 139.64 (C-1), 143.89 (HC=CCH3), 152.16 (CHCCH3), 172.27 (C-5′), 172.43 (CO) ppm.

N-(2,5-Dimethyl-1H-pyrrol-1-yl)-1-(3-fluorophenyl)-5-oxopyrrolidine-3-carboxamide (13a, C17H18FN3O2)

A mixture of 1.19 g 3a (5.0 mmol), 1.17 cm3 2,5-hexanedione (10 mmol), 20 cm3 2-propanol, and 1 cm3 acetic acid was heated under reflux for 6 h. After cooling, the precipitate of 13a was isolated by filtration, and washed with a small amount of 2-propanol then diethyl ether.

M.p.: 176–177 °C (from 2-propanol); yield 64.8%; IR (KBr): \( \bar{\nu } \) = 3,280 (NH), 1,693 (C=O), 1,671 (C=O) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.00 (s, 6H, 2CH3), 2.72–2.98 (m, 2H, CH2CO), 3.36–3.53 (m, 1H, CH), 3.96–4.18 (m, 2H, NCH2), 5.65 (s, 2H, CH-CH), 6.95–7.72 (m, 4H, Har), 10.94 (s, 1H, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 10.94 (2CH3), 33.91 (C-3′), 35.81 (C-4′), 50.33 (C-2′), 103.08 (2 CH3C=CH), 106.17 (d, 2 J C-F = 26.8 Hz, C-2), 110.57 (d, 2 J C-F = 21.1 Hz, C-4), 114.82, 114.90 (s-cis/s-trans, C-6), 126.66 (2 CH3 C=CH), 130.30 (d, 3 J C-F = 9.7 Hz, C-5), 140.55 (d, 3 J C-F = 10.5 Hz, C-1), 162.08 (d, 1 J C-F = 242.1 Hz, C-3), 171.76 (C-5′), 172.07 (CONH) ppm; MS (ESI, 20 eV): m/z (%) = 316 ([M + H]+, 100).

N-(2,5-Dimethyl-1H-pyrrol-1-yl)-5-oxo-1-(3-(trifluoromethyl)phenyl)pyrrolidine-3-carboxamide (13b, C18H18F3N3O2)

A mixture of 1.44 g 3b (5.0 mmol), 1.17 cm3 2,5-hexanedione (10.0 mmol), 20 cm3 2-propanol, and 1 cm3 acetic acid was heated under reflux for 3 h. Solvent was removed under reduced pressure and the crude product obtained was boiled in 100 cm3 water, isolated by filtration while hot, washed with water, and dried.

M.p.: 168–169 °C (from n-hexane to toluene); yield 64.1%; IR (KBr): \( \bar{\nu } \) = 3,267 (NH), 1,713 (C=O), 1,673 (C=O), 1,340 (2×CH3) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.00 (s, 6H, 2CH3), 2.74–3.00 (m, 2H, CH2CO), 3.37–3.55 (m, 1H, CH), 4.03–4.24 (m, 2H, NCH2), 5.65 (s, 2H, CH-CH), 7.49–8.22 (m, 4H, Har), 10.95 (s, 1H, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 10.89, 10.92 (2CH3), 33.98 (C-3′), 35.73 (C-4′), 50.15 (C-2′), 103.04 (2 CH3C=CH), 115.58 (q, 3 J C-F = 3.8 Hz, C-2), 120.30 (q, 3 J C-F = 3.7 Hz, C-4), 122.71 (C-6), 123.96 (q, J C-F = 272.4 Hz, CF3), 126.69 (2 CH3 C=CH), 129.36 (q, 2 J C-F = 31.7 Hz, C-3), 129.98 (C-5), 139.65 (C-1), 171.68 (C-5′), 172.26 (CONH) ppm; MS (ESI, 20 eV): m/z (%) = 366 ([M + H]+, 100).

General procedure for preparation of oxadiazolylpyrrolidin-2-ones 14a and 14b

A mixture of the appropriate hydrazide 3 (5.0 mmol), 13.34 g triethyl orthoformate (90.0 mmol), and 0.1 g toluenesulfonic acid was heated under reflux for 7 h, cooled, and diluted with 50 cm3 n-hexane. The crystalline product 14 obtained was isolated by filtration and dried.

1-(3-Fluorophenyl)-4-(1,3,4-oxadiazol-2-yl)pyrrolidin-2-one (14a, C12H10FN3O2)

M.p.: 112–113 °C (from 2-propanol); yield 81.0%; IR (KBr): \( \bar{\nu } \) = 1,689 (C=O) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.88–3.13 (m, 2H, CH2CO), 4.09–4.35 (m, 1H, CH + 2H, NCH2), 6.96–7.68 (m, 4H, Har), 9.25 (s, 1H, N=CH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 27.52 (C-3′), 36.07 (C-4′), 50.60 (C-2′), 106.43 (d, 2 J C-F = 26.4 Hz, C-2), 110.75 (d, 2 J C-F = 21.1 Hz, C-4), 115.02 (d, 4 J C-F = 1.8 Hz, C-6), 130.40 (d, 3 J C-F = 9.4 Hz, C-5), 140.52 (d, 3 J C-F = 10.8 Hz, C-1), 154.97 (N=CH), 162.06 (d, 1 J C-F = 241.6 Hz, C-3), 166.34 (N=C), 171.34 (C-5′) ppm; MS (ESI, 20 eV): m/z (%) = 248 ([M + H]+, 100).

4-(1,3,4-Oxadiazol-2-yl)-1-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one (14b, C13H10F3N3O2)

M.p.: 95–96 °C (from 2-propanol); yield 56.6%; 1H NMR (300 MHz, DMSO-d6): δ = 2.90–3.15 (m, 2H, CH2CO), 4.10–4.22 (m, 1H, CH + 2H, CH2N), 7.50–8.16 (m, 4H, Har), 9.25 (br s, 1H, N=CH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 27.53 (C-3′), 35.90 (C-4′), 50.45 (C-2′), 115.86 (q, 3 J C-F = 3.7 Hz, C-2), 120.58 (q, 3 J C-F = 3.6 Hz, C-4), 123.01 (C-6), 124.04 (q, 1 J C-F = 272.7 Hz, CF3), 129.44 (q, 2 J C-F = 33.0 Hz, C-3), 130.04 (C-5), 139.58 (C-1), 154.98 (CH=N), 166.31 (C=N), 171.90 (C-5′) ppm; MS (ESI, 20 eV): m/z (%) = 298 ([M + H]+, 100).

General procedure for preparation of 4-(4,5-dihydro-5-thioxo-1,3,4-oxadiazol-2-yl)pyrrolidin-2-ones 15a and 15b

A mixture of 1.19 g 3a or 1.44 g 3b (5.0 mmol), 0.38 g carbon disulfide (5.0 mmol), 25 cm3 2-propanol, and 0.28 g 80% potassium hydroxide (5.0 mmol) was heated under reflux for 20 h. After evaporation, the residue was dissolved in water and acidified with hydrochloric acid. The crystalline product 15 obtained was isolated by filtration, washed with water, and dried.

4-(4,5-Dihydro-5-thioxo-1,3,4-oxadiazol-2-yl)-1-(3-fluorophenyl)pyrrolidin-2-one (15a, C12H10FN3O2S)

M.p.: 178–179 °C (from 2-propanol); yield 93.2%; IR (KBr): \( \bar{\nu } \) = 3,118 (NH), 1,688 (C=O) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.83–3.06 (m, 2H, CH2CO), 3.91–4.01 (m, 1H, CH), 4.07–4.26 (m, 2H, NCH2), 6.96–7.66 (m, 4H, Har), 14.48 (s, 1H, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 27.80 (C-3′), 35.22 (C-4′), 49.86 (C-2′), 106.46 (d, 2 J C-F = 26.3 Hz, C-2), 110.77 (d, 2 J C-F = 21.1 Hz, C-4), 115.05 (br s, C-6), 130.39 (d, 3 J C-F = 9.4 Hz, C-5), 140.47 (d, 3 J C-F = 10.8 Hz, C-1), 162.05 (d, 1 J C-F = 242.2 Hz, C-3), 163.77 (OC=N), 171.34 (C-5′), 178.02 (C=S) ppm; MS (ESI, 20 eV): m/z (%) = 280 ([M + H]+, 100).

4-(4,5-Dihydro-5-thioxo-1,3,4-oxadiazol-2-yl)-1-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one (15b, C13H10F3N3O2S)

M.p.: 166–167 °C (from 2-propanol); yield 93.6%; IR (KBr): \( \bar{\nu } \) = 3,097 (NH), 1685 (C=O) cm−1; 1H NMR (300 MHz, DMSO-d6): δ = 2.84–3.08 (m, 2H, CH2CO), 3.93–4.03 (m, 1H, CH), 4.14–4.32 (m, 2H, NCH2), 7.50–8.14 (m, 4H, Har), 14.54 (s, 1H, NH) ppm; 13C NMR (75.4 MHz, DMSO-d6): δ = 27.82 (C-3′), 35.04 (C-4′), 49.72 (C-2′), 115.88 (q, 3 J C-F = 3.7 Hz, C-2), 120.58 (q, 3 J C-F = 3.0 Hz, C-4), 124.04 (q, 1 J C-F = 272.0 Hz, CF3), 123.03 (C-6), 129.01 (q, 2 J C-F = 31.5 Hz, C-3), 130.05 (C-5), 139.55 (C-1), 163.77 (OC=N), 171.71 (C-5′), 178.02 (C=S) ppm; MS (ESI, 20 eV): m/z (%) = 330 ([M + H]+, 100).

Scheme 1
scheme 1

 

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