Reactions of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides with 1,4-naphthoquinone derivatives and the properties of the obtained products

Article abstract of DOI:10.1007/s11164-011-0306-y

N′-(4-Oxo-1,4-dihydronaphthalen-1-ylidene)-1-phenyl-5-oxopyrrolidine- 3-carbohydrazides and N′-(3-methyl-4-oxo-1,4-dihydronaphthalen-1-ylidene)- 1-phenyl-5-oxopyrrolidine-3-carbohydrazides were synthesized by reactions of 5-oxo-1-phenylpyrrolidine-3-carbo

Full text of DOI:10.1007/s11164-011-0306-y

Res Chem Intermed (2011) 37:1009–1027
DOI 10.1007/s11164-011-0306-y
Reactions of 5-oxo-1-phenylpyrrolidine-3-
carbohydrazides with 1,4-naphthoquinone derivatives
and the properties of the obtained products
•
Rita Vaickelioniene Vytautas Mickevicius
•
_
Gema Mikulskiene Maryna Stasevych
ˇ
•
•
_
Olena Komarovska-Porokhnyavets
Volodymyr Novikov
•
Received: 20 January 2011 / Accepted: 24 March 2011 / Published online: 10 April 2011
Ó Springer Science+Business Media B.V. 2011
Abstract N0-(4-Oxo-1,4-dihydronaphthalen-1-ylidene)-1-phenyl-5-oxopyrrolidine-
3-carbohydrazides and N0-(3-methyl-4-oxo-1,4-dihydronaphthalen-1-ylidene)-1-
phenyl-5-oxopyrrolidine-3-carbohydrazides were synthesized by reactions of
5-oxo-1-phenylpyrrolidine-3-carbohydrazides with 1,4-naphthoquinone or 2-methyl-
1,4-naphthoquinone. The alkylated analogues of the above products were obtained
using ethyl iodide. The interaction of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides
with 2,3-dichloro-1,4-naphthoquinone was followed by formation of N0-(3-
chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-phenyl-5-oxopyrrolidine-3-carbo-
1
hydrazides. All these compounds were characterized using H, 13C NMR, IR and
mass spectra. Some of the new compounds were tested for the antimicrobial and
antifungal activity.
Keywords 5-Oxo-1-phenylpyrrolidine-3-carbohydrazides ꢀ
1,4-Naphthoquinones ꢀ 2,3-Dichloro-1,4-naphthoquinone ꢀ Hydrazone ꢀ
NMR spectroscopy ꢀ Biological activity
_
ˇ
R. Vaickelioniene ꢀ V. Mickevicius (&)
_
Department of Organic Chemistry, Kaunas University of Technology, Radvilenu˛ pl. 19,
50254 Kaunas, Lithuania
e-mail: Vytautas.Mickevicius@ktu.lt
_
G. Mikulskiene
Department of Bioorganic Compounds Chemistry, Vilnius University Institute of Biochemistry,
Mokslininku st. 12, 08662 Vilnius, Lithuania
M. Stasevych ꢀ O. Komarovska-Porokhnyavets ꢀ V. Novikov
Department of Technology of Biologically Active Substances, Pharmacy and Biotechnology,
National University ‘‘Lviv Polytechnic’’, S. Bandery street 12, Lviv, Ukraine
123

_
R. Vaickelioniene et al.
1010
Introduction
Many quinones greatly differing in structure are provided by nature. Large numbers
of substituted quinones have been synthesized recently, and their properties
extensively studied. Special attention has been paid to preparing synthetic
compounds which include aminoquinone moiety in their structure. Naphthoqui-
nones and their various derivatives as a class display many types of biological
activity. They are active against different strains of bacteria and fungi [1–10], show
insecticidal [11, 12], molluscicidal [13], and antiproliferative [4, 14] properties, and
are anticancer agents [15–20]. Furthermore, hydrazones have been demonstrated to
possess many types of biological activity [21].
The present study was directed toward synthesizing novel compounds from
5-oxo-1-phenylpyrrolidine-3-carbohydrazides and 1,4-naphthoquinones and evalu-
ating the biological properties of some of them by testing on several strains of
bacteria and fungi, using diffusion and serial dilution techniques.
The starting compounds, 5-oxo-1-phenylpyrrolidine-3-carbohydrazides 1a–h,
were synthesized according to a standard method by refluxing the corresponding
methyl esters of 5-oxopyrrolidine-3-carboxylic acids with hydrazine hydrate in
2-propanol [22].
The structure of the newly synthesized compounds was investigated using IR and
1H, 13C NMR spectra. The assignment of resonances in the NMR spectra was based
on the chemical shift theory, using previously determined [23] and published [24]
increments of substituents, signal intensity arguments, and multiplicities, and a
comparison with structurally related compounds [20, 25–38]. The DEPT (13C) and
1H/13C 2D (HETCOR) methods were used in some cases.
Results and discussion
The target N0-(4-oxo-1,4-dihydronaphthalen-1-ylidene)-1-phenyl-5-oxopyrrolidine-
3-carbohydrazides (5) and N0-(3-methyl-4-oxo-1,4-dihydronaphthalen-1-ylidene)-1-
phenyl-5-oxopyrrolidine-3-carbohydrazides (6) were prepared by refluxing the
respective carbohydrazides 1 and 1,4-naphthoquinone (2) or 2-methyl-1,4-naphtho-
quinone (3) in 2-propanol in the presence of a catalytic amount of hydrochloric acid
with 37–97% yields as illustrated in Scheme 1. Crystallization of hydrazones 5 and
6 occurred during the reaction. Upon completing the reaction, the crystalline
products were filtered off (from a hot mixture) and washed with 2-propanol.
1
The structures of 5 and 6 were assigned on the basis of their H and 13C NMR
spectra. NMR data showed that, during the reaction of carbohydrazides 1, the amine
functional group interacts with one of the carbonyl groups of 1,4-naphthoquinones
2, 3, resulting in the formation of hydrazones 5, 6. The appearance of two doublets
at 6.7 and 8.2 ppm with J = 10.5 Hz are characteristic of the double bond in the
1
six-membered ring of quinone in H NMR spectra of compounds 5 a–c, e–h. The
presence of benzene ring moiety was proven by a consistent splitting pattern of
H-500, H-600, H-700, and H-800. The 13C NMR spectra of 5 showed only one signal of
the carbonyl group at around 184 ppm of 4-oxo-1,4-dihydronaphthalenylidene
123

Reactions of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides
1011
O
O
5'
3''
4''
O
R
4'
3'
O
2''
R
N
H
N
4a''
1''
N
5''
6''
N
2'
N
8a''
N
O
8''
O
5a-c, e-h
7''
7a, c, d
O
O
C2H5I
O
O
, H+
, H+
O
R
2
N
O
H
O
N
3
N
R
O
O
6a-h
Cl
Cl
N
H
N
NH2
O
O
1a-h
O
4
O
R
Cl
N
H
N
N
H
O
O
8a-h
Scheme 1 Synthetic pathway for compounds 5–8. a R = H; b R = 3-CH3; c R = 4-CH3; d R =
2,5-(CH3)2; e R = 2-CH3-5-Cl; f R = 3-Cl-4-CH3; g R = 4-Br; h R = 4-Cl
moiety. Due to the restricted rotation of the amide group, a splitting of some
resonances was observed. The signals of NH, H-200, H-300, H-800, and H-30 were split
with the intensity ratio 0.8:0.2. The dynamic exchange processes caused by the
CONH group led to the broadening of signals in NMR spectra. In this case, the
resonance of C-100 was observed only as traces at approximately 152 ppm.
1
The structure of 6a–h compounds was mainly substantiated by H NMR spectra.
The patterns of multiplets of the aromatic region were analyzed and assigned to the
corresponding hydrogen atoms. A comparison of the integral intensities of
multiplets confirmed the composition of compounds 6a–h. The broadened singlets
of 4-oxo-1,4-dihydronaphthalenylidene moiety of hydrazones 6 observed in the
interval of 2.07–2.10 ppm, integrated for three protons, the doublets in the interval
of 8.24–8.30 ppm, and the much more broadened singlets varying in the range
8.08–8.13 ppm, each one integrated for a single proton being attributed to the 300-
CH3, H-800 and H-200 hydrogens, respectively. Only the resonance at 11.98 ppm,
assigned to the NH group proton, revealed the presence of a fast exchange process
of amide hydrogen of 6a–h in DMSO-d6 solutions. The above-mentioned
broadening of resonances arises due to the interaction of CONH hydrogen with
electron donating groups. The resonances of C-100 atoms in 13C NMR were greatly
broadened and thus poorly observable in the noise, while the resonances of other
carbonyl groups of 6a–h were situated as expected.
Alkylation products of hydrazones—N-ethylcarbohydrazides 7a, c, d—were
obtained from the corresponding hydrazone 6, ethyl iodide, potassium carbonate,
123

_
R. Vaickelioniene et al.
1012
ethyl methyl ketone, and tetrabuthyl ammonium iodide as a phase-transfer catalyst.
Reactions were carried out at a temperature of 50–55 °C and stirring the mixtures
for 20 h. Purification of the product 7c was performed by crystallization, 7a, d were
purified by the method of column chromatography.
A comparison of NMR spectra of 6b and 7c in DMSO-d6 and CDCl3 reflected
changes in molecular interactions in solutions, caused by solvent properties. The
spectra in CDCl3 solution were characterized by a much finer resolution. The
differences of chemical shifts of the corresponding atoms reveal the intramolecular
interaction between the solute molecules (predominant in CDCl3 solution) and the
intermolecular interaction between the solute and solvent molecules (predominant
in DMSO-d6 solution). The presence of the resonances of the ethyl group and the
absence of signals of the NH group confirmed the formation of compounds 7a, c,
d. The alkylation of the NH group of these compounds makes the molecules more
stabile in DMSO-d6 solution. The signal of C-100 atom appeared at 151.20 ppm in
13C NMR spectra of 7a, c, d compounds. The different spatial location of the N-
ethyl group with respect to adjacent atoms caused the splitting (0.8:0.2) of the
1
signals of 200-CH, 300-CH3 and protons of pyrolidinone moiety in H NMR spectra.
Carbohydrazides 1 react with 2,3-dichloro-1,4-naphthoquinone (4) quite differ-
ently from 1,4-naphthoquinones 2, 3. In this case, N0-(3-chloro-1,4-dioxo-1,4-
dihydronaphthalen-2-yl)-1-phenyl-5-oxopyrrolidine-3-carbohydrazides (8a–h) in
70–92% yields were obtained. Reactions were carried out in dimethyl sulfoxide
at room temperature for 24 h. The NMR spectra of compounds 8a–h are very
complex due to their specific structure. Molecules of these compounds possess two
NH groups capable of much more interactions than the other study compounds. In
spite of the complication arising due to the mentioned NH groups, all fragments of
the study compounds 8a–h were indentified by NMR spectra. Two resonances of the
C=O group of naphthoquinone moiety were observed in the intervals of
175.90–176.41 ppm (C-400) and 178.95–179.11 ppm (C-100) in 13C NMR spectra.
The resonances in the range 111.51–111.56 ppm (C-300) and 144.29–145.53 ppm
(C-200) confirmed the presence of Cl and NHR substituents of naphthoquinone
1
moiety. Several NH resonances in H NMR spectra showed a variety of spatial
structures present in DMSO-d6 solutions.
Assessment of biological properties
Some of synthesized N0-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-phenyl-
5-oxopyrrolidine-3-carbohydrazides (8) were tested for their antibacterial and
antifungal activity against Escherichia coli, Staphylococcus aureus, Mycobacterium
luteum, Candida tenuis, and Aspergillus niger strains by diffusion (Table 1) [39]
and serial dilution techniques (Table 2) [determination of minimal bacteriostatic
concentration (MBSC) and minimal bactericidic concentration (MBCC), minimal
fungistatic concentration (MFSC) and minimal fungicidic concentration (MFCC)]
[40]. Their activity was compared with that of the known antibacterial agent
Vancomycin and the antifungal agent Nystatin.
123

Reactions of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides
1013
Table 1 Antibacterial and fungicidal activity of some of the synthesized compounds determined by
diffusion method
Compound
Concentration (%)
Inhibition diameter of microorganism growth (mm)
E. coli
S. aureus
M. luteum
C. tenuis
A. niger
8a
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.1
0
0
8.0
10.0
10.0
8.0
15.0
11.0
23.0
15.0
0
20.0
18.0
20.0
15.0
0
12.0
13.0
18.0
12.0
0
8b
0
0
8c
0
16.6
0
0
0
0
0
8d
11.0
6.0
0
10.0
9.0
20.0
13.0
23.0
15.0
15.0
12.0
18.0
24.0
20.0
15.0
10.0
20.0
13.3
19.0
12.0
9.0
0
8e
12.0
0
0
0
8f
0
10.0
0
17.6
12.0
20.0
0
Control
14.0
15.0
Diffusion technique
Antimicrobial activity of compounds has been evaluated by diffusion in agar on
solid nutrient medium (nutrient agar—for bacteria; wort agar—for fungi). The disks
(5 mm in diameter) were soaked in solutions of the tested compounds in DMSO
(0.02 mg/mL) and then put on an exponentially growing plated culture. The
microbial loading was 109 cells/mL. The required incubation periods were as
follows: 24 h at 35 °C for bacteria and 48–72 h at 28–30 °C for fungi. The size of
the zone of incubation was measured and compared with a control agent. Control
disk contained Vancomycin (for bacteria) or Nystatin (for fungi) as a standard.
Serial dilution technique
Testing was performed in a flat-bottomed 96-well tissue culture plate. The test
compounds were dissolved in DMSO and solutions within 500–1.9 lg mL-1
concentration range were prepared. The inoculum of bacteria and fungi was
inoculated into a nutrient medium (nutrient meat-extract—for bacteria; wort—for
fungi). The required incubation periods were as follows: 24–72 h at 37 °C for
bacteria and 30 °C for fungi. The results were estimated according to the presence
or absence of microorganism growth.
Data presented in Tables 1 and 2 show that there are substances with
antibacterial and fungicidal action among the study compounds. The test-culture
E. coli appeared to be sensitive only to compound 8d. Its minimal bacteriostatic
concentration was 125 lg mL-1. The S. aureus strain was most sensitive to
compound 8c at a concentration of 0.5%, and the diameter of the inhibition zone
123

_
R. Vaickelioniene et al.
1014
123

Reactions of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides
1015
was 16.6 mm. 8c completely inhibited the growth of bacteria at 125 lg mL-1 when
the test-culture was screened by the serial dilution technique. Other compounds
showed a moderate activity. N0-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-
aryl-5-oxopyrrolidine-3-carbohydrazides 8a–f were more efficient for inhibiting the
growth of the M. luteum bacteria and C. tenuis and A. niger fungi. The diameters of
the inhibition zones were 13.0–23.0, 13.3–24.0 and 12.0–18.0 mm, respectively.
Compounds 8b, 8d, and 8e showed high action against M. luteum at 0.5%
concentration. Antifungal activity against C. tenuis was observed for 8a, 8b, 8d, and
8f at concentration of 0.5% (d = 20–24 mm). Compounds 8c and 8e have no
antifungal activity against A. niger at investigative concentrations. This fungi strain
is sensitive to 8a, 8b, 8d, and 8f at 0.1 and 0.5% concentrations.
The antimicrobial and antifungal activity of the test compounds can be correlated
with their structure. N0-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-(3-meth-
ylphenyl)-5-oxopyrrolidine-3-carbohydrazides containing a substituent at m-posi-
tion in the benzene ring or without it were found to show a more significant
antibacterial and antifungal activity than their analogue containing a substituent in
p-position. The exchange of the methyl group for the chloro substituent showed no
clear influence on the biological activity, while the introduction of a second methyl
group at the 2-position in the benzene ring had a positive effect on the antimicrobial
activity.
Conclusions
The condensation of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides with 1,4-naph-
thoquinone and 2-methyl-1,4-naphthoquinone yielded the corresponding hydrazones,
while similar interactions with 2,3-dichloronaphthoquinone afforded N-substituted
carbohydrazides with naphthoquinone moiety. Among the synthesized N0-(3-chloro-
1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-phenyl-5-oxopyrrolidine-3-carbohydrazides,
compounds with a high antimicrobial activity at low concentrations against
M. luteum bacteria and C. tenuis, A. niger fungi in comparison with control were
identified. N0-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-(3-methylphenyl)-
5-oxopyrrolidine-3-carbohydrazide (8b), N0-(3-chloro-1,4-dioxo-1,4-dihydronaphth-
alen-2-yl)-1-(2,5-dimethylphenyl)-5-oxopyrrolidine-3-carbohydrazide (8d) and
N0-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-(3-chloro-4-methylphenyl)-
5-oxopyrrolidine-3-carbohydrazide (8f) are promising as biologically active
compounds.
Experimental
1
The H and 13C NMR spectra were recorded on a Varian Unity Inova (300 MHz,
75 MHz) spectrometer operating in the Fourier transform mode, using DMSO-d6
and CDCl3 as a solvent and TMS as an internal reference (chemical shifts in d,
ppm). IR spectra (m, cm-1) were recorded on a Perkin Elmer Spectrum BX FT–IR
spectrometer using KBr tablets. Mass spectra were obtained on the Waters ZQ 2000
123

_
R. Vaickelioniene et al.
1016
spectrometer using the atmospheric pressure chemical ionization (APCI) mode and
operating at 20 V. Elemental analyses were performed with a CE-440 elemental
analyser. Melting points were determined with an automatic APA1 melting point
apparatus and are uncorrected.
General procedure for the synthesis of hydrazones 5a–c, e–h
Three drops of concentrated hydrochloric acid were added to a mixture of the
corresponding hydrazide 1 (10 mmol), 1,4-dihydronaphthalene-1,4-dione (2)
(1.58 g, 10 mmol) and 2-propanol (80 mL). The reaction mixture was refluxed
for 4 h and then filtered (hot). Upon completing the reaction, the reaction mixture
was cooled down and the formed crystalline solid was filtered off, washed with
2-propanol and dried.
5-Oxo-N0-(4-oxo-1,4-dihydronaphthalen-1-ylidene)-1-phenylpyrrolidine-3-
carbohydrazide (5a)
Yield 1.9 g (52.5%), m.p. 253–254 °C (from 2-propanol). IR, m: 1599, 1667, 1697
1
(3C=O); 3109, 3178 (NH). H NMR (300 MHz, DMSO-d6), d: 2.82-2.99 (m, 2H,
CH2CO), 3.16-3.76 (m, (0.2)1H, CH), 4.02-4.26 (m, 2H, NCH2), 4.32–4.42 (m,
(0.8)1H, CH), 6.72 (d, J = 10.5 Hz, (0.8)1H, (300-H)), 6.82 (d, J = 10.5 Hz,
(0.2)1H, (300-H)), 7.14 (t, J = 7.4 Hz, 1H, (4-Har)), 7.37 (t, J = 7.9 Hz, 2H, (3,
5-Har)), 7.63 (t, J = 7.7 Hz, 1H, (600-H)), 7.68 (d, J = 8.0 Hz, 2H, (2, 6-Har)), 7.76
(d, J = 7.6 Hz, 1H, (700-H)), 8.01 (d, J = 7.8 Hz, (500-H)), 8.23 (d, J = 10.5 Hz,
1H, (200-H)), 8.35 (d, J = 7.9 Hz, 1H, (800-H)), 11.95 (s, (0.2)1H, NH), 12.29 (s,
(0.8)1H, NH). Found, %: C 70.10, H 4.82. N 12.04. Calculated, %: C 70.18, H 4.77,
N 11.69. C21H17N3O3.
1-(3-Methylphenyl)-5-oxo-N0-(4-oxo-1,4-dihydronaphthalen-1-ylidene)pyrrolidine-
3-carbohydrazide (5b)
Yield 1.4 g (36.9%), m.p. 240–241 °C (from 2-propanol). IR, m: 1604 (N=C), 1645,
1
1676, 1694 (3C=O), 3112, 3173 (NH). H NMR (300 MHz, DMSO-d6), d: 2.29
(s, 3H, (3-CH3)), 2.81–2.98 (m, 2H, CH2CO), 3.59–3.72 (m, (0.2)1H, CH), 4.00–
4.23 (m, 2H, NCH2), 4.29–4.40 (m, (0.8)1H, CH), 6.71 (d, J = 10.5 Hz, (0.8)1H,
(300-H)), 6.81 (d, J = 10.5 Hz, (0.2)1H, (300-H)), 6.95 (d, J = 7.1 Hz, 1H, (6-Har)),
7.21–7.27 (m, 1H, (5-Har)), 7.47–7.51 (m, 2H, (2,4-Har)), 7.62 (t, J = 7.1 Hz, 1H,
(600-H)), 7.75 (t, J = 7.5 Hz, 1H, (700-H)), 8.00 (dd, J = 1.1 Hz, J = 7.8 Hz,
(500-H)), 8.21 (d, J = 10.5 Hz, 1H, 200-H), 8.33 (d, J = 7.7 Hz, 1H, (800-H)), 11.93
(s, (0.2)1H, NH), 12.26 (s, (0.8)1H, NH). 13C NMR (75 MHz, DMSO-d6), d: 21.20
(3-CH3), 32.12 (C-30), 35.02 (C-40), 50.02 (C-20), 116.72 (C-6), 120.04 (C-2),
123.57 (C-300), 124.80 (C-4), 125.41, 127.26 (C-500, C-800), 128.51 (C-5), 129.49
(C-600, C-700), 130.09 (C-4a00), 130.81 (C-200), 133.03 (C-600, C-700), 134.49, 136.33
(C-8a00), 137.96 (C-3), 139.12 (C-1), 171.78 (C-50), 175.61 (CONH), 184.09 (C-400).
MS m/z (I, %): 397 [M ? Na ? H]? (100). Found, %: C 71.08, H 5.19, N 11.36.
Calculated, %: C 70.76, H 5.13, N 11.25. C22H19N3O3.
123

Reactions of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides
1017
1-(4-Methylphenyl)-5-oxo-N0-(4-oxo-1,4-dihydronaphthalen-1-ylidene)pyrrolidine-
3-carbohydrazide (5c)
Yield 1.6 g (43.4%), m.p. 226–227 °C (from 2-propanol). IR, m: 1599 (N=C), 1640,
1
1673, 1687 (3C=O), 3104, 3171 (NH). H NMR (300 MHz, DMSO-d6), d: 2.26 (s,
3H, (4-CH3)), 2.79–2.96 (m, 2H, CH2CO), 3.55–3.67 (m, (0.2)1H, CH), 3.95–4.34
(m, 2H, NCH2 ? (0.8)1H, CH), 4.29–4.40 (m, (0.8)1H, CH), 6.72 (d, J = 10.5 Hz,
1H, (300-H)), 7.16 (d, J = 8.3 Hz, 2H, (3, 5-Har)), 7.55 (d, J = 8.3 Hz, 1H, (2,
6-Har)), 7.49–7.78 (m, 2H, (600, 700-H)), 8.00 (d, J = 7.8 Hz, 1H, (500-H)), 8.20 (d,
J = 10.5 Hz, 1H, (200-H)), 8.32 (d, J = 8.0 Hz, 1H, (800-H)), 11.48 (s, (0.07)1H,
NH), 11.77 (s, (0.26)1H, NH), 12.18 (s, (0.67)1H, NH). Found, %: C 70.41, H 5.26,
N 11.45. Calculated, %: C 70.76, H 5.13, N 11.25. C22H19N3O3.
1-(2-Methyl-5-chlorophenyl)-5-oxo-N0-(4-oxo-1,4-dihydronaphthalen-1-
ylidene)pyrolidine-3-carbohydrazide (5e)
Yield 1.5 g (37.2%), m.p. 222–225 °C (from 2-propanol). IR, m: 1598 (N=C), 1649,
1
1680, 1696 (3C=O), 3111, 3172 (NH). H NMR (300 MHz, DMSO-d6), d: 2.16 (s,
3H, (2-CH3)), 2.72–2.91 (m, 2H, CH2CO), 3.64–4.45 (m, 1H, CH ? 2H, NCH2),
6.68–8.29 (m, 9H, (Har ? 200, 300, 500-800-H)), 11.72, 11.95, 12.22 (3br. s, 1H, NH).
13C NMR (75 MHz, DMSO-d6), d: 17.07 (2-CH3), 33.40 (C-30), 34.41 (C-40), 51.73
(C-20), 123.47 (C-300), 125.40 (C-500, C-800), 126.63 (C-6), 127.26 (C-500, C-800),
127.38 (C-4), 129.48 (C-600, C-700), 130.07, (C-4a00), 130.25 (C-2), 130.76 (C-200),
132.18 (C-5), 132.93 (C-600, C-700), 134.47, 136.21 (C-8a00), 134.70 (C-3), 138.75
(C-1), 171.65 (C-50), 175.62 (CONH), 184.07 (C-400). Found, %: C 64.45, H 4.51, N
10.45. Calculated, %: C 64.79, H 4.45, N 10.30. C22H18ClN3O3.
1-(3-Chloro-4-methylphenyl)-5-oxo-N0-(4-oxo-1,4-dihydronaphthalen-1-
ylidene)pyrolidine-3-carbohydrazide (5f)
Yield 3.2 g (78.7%), m.p. 277–278 °C (from 2-propanol). IR, m: 1602 (N=C), 1645,
1
1673, 1694 (3C=O), 3107, 3170 (NH). H NMR (300 MHz, DMSO-d6), d: 2.28
(s, 3H, (4-CH3)), 2.82–2.99 (m, 2H, CH2CO), 3.60–3.70 (m, (0.2)1H, CH),
4.04–4.22 (m, 2H, NCH2), 4.31–4.41 (m, (0.8)1H, CH), 6.72 (d, J = 10.5 Hz,
(0.8)1H, (300-H)), 6.81 (d, J = 10.5 Hz, (0.2)1H, (300-H)), 7.32 (d, J = 8.4 Hz, 1H,
(5-Har)), 7.47 (dd, J = 2.2 Hz, J = 8.4 Hz, 1H, (6-Har)), 7.63 (t, J = 8.0 Hz, 1H,
(600-H)), 7.75 (t, J = 7.3 Hz, 1H, (700-H)), 7.87 (d, J = 2.2 Hz, 1H, (2-Har)), 8.01
(dd, J = 1.1 Hz, J = 7.8 Hz, (500-H)), 8.22 (d, J = 10.5 Hz, 1H, (200-H)), 8.34 (d,
J = 8.0 Hz, 1H, (800-H)), 11.93 (s, (0.2)1H, NH), 12.26 (s, (0.8)1H, NH). 13C NMR
(75 MHz, DMSO-d6), d: 18.94 (4-CH3), 33.04 (C-30), 34.92 (C-40), 49.85 (C-20),
117.82 (C-6), 119.35 (C-2), 123.59 (C-300), 125.41, 127.28 (C-500, C-800), 129.50
(C-600, C-700), 130.09 (C-4, ?C-4a00), 130.82 (C-200), 131.09 (C-5), 133.03 (C-600,
C-700), 133.11 (C-3), 134.49, 136.38 (C-8a00), 138.21 (C-1), 172.10 (C-50), 175.48
(CONH), 184.09 (C-400). Found, %: C 64.92, H 4.62, N 10.57. Calculated, %: C
64.79, H 4.45, N 10.30. C22H18ClN3O3.
123

_
R. Vaickelioniene et al.
1018
(4-Bromophenyl)-5-oxo-N0-(4-oxo-1,4-dihydronaphthalen-1-ylidene)pyrrolidine-3-
carbohydrazide (5g)
Yield 3.5 g (80.4%), m.p. 242–243 °C (from 2-propanol). IR, m: 1602 (N=C), 1646,
1675, 1694 (3C=O), 3107, 3170 (NH). 1H NMR (300 MHz, DMSO-d6), d:
2.83–2.97 (m, 2H, CH2CO), 3.61–3.75 (m, (0.2)1H, CH), 3.99–4.22 (m, 2H, NCH2),
4.28–4.39 (m, (0.8)1H, CH), 6.69 (d, J = 10.4 Hz, (0.8)1H, (300-H)), 6.79 (d,
J = 10.4 Hz, (0.2)1H, (300-H)), 7.52 (d, J = 8.6 Hz, 2H, (3, 5-Har)), 7.60 (t,
J = 7.5 Hz, 1H, (600-H)), 7.66 (d, J = 8.6 Hz, 2H, 2, 6-Har), 7.73 (t, J = 7.2 Hz,
1H, (700-H)), 7.99 (d, J = 7.6 Hz, 1H, (500-H)), 8.19 (d, J = 10.4 Hz, 1H, (200-H)),
8.30 (d, J = 7.6 Hz, 1H, (800-H)), 11.93 (s, (0.2)1H, NH), 12.27 (s, (0.8)1H, NH).
13C NMR (75 MHz, DMSO-d6), d: 33.03 (C-30), 34.95 (C-40), 49.78 (C-20), 115.94
(C-4), 121.21 (C-2, 6), 123.57 (C-300), 125.39 (C-500), 127.23 (C-800), 129.47 (C-600),
130.08 (C-4a00), 130.82 (C-200), 131.46 (C-3, 5), 133.01 (C-700), 134.45, 136.37
(C-8a00), 138.44 (C-1), 172.12 (C-50), 175.44 (CONH), 184.06 (C-400). Found, %:
C 57.68, H 3.76, N 9.73. Calculated, %: C 57.55, H 3.68, N 9.59. C21H16BrN3O3.
1-(4-Chlorophenyl)-5-oxo-N0-(4-oxo-1,4-dihydronaphthalen-1-ylidene)pyrrolidine-
3-carbohydrazide (5h)
Yield 3.2 g (82.3%), m.p. 244–245 °C (from 2-propanol). IR, m: 1599 (N=C), 1647,
1675, 1694 (3C=O), 3107, 3172 (NH). 1H NMR (300 MHz, DMSO-d6), d: 2.83–2.99
(m, 2H, CH2CO), 3.58–3.71 (m, (0.2)1H, CH), 4.01–4.24 (m, 2H, NCH2), 4.32–4.42
(m, (0.8)1H, CH), 6.72 (d, J = 10.5 Hz, (0.8)1H, (300-H)), 6.82 (d, J = 10.5 Hz,
(0.2)1H, (300-H)), 7.42 (d, J = 8.9 Hz, 2H, (3, 5-Har)), 7.64 (t, J = 8.0 Hz, 1H,
(600-H)), 7.02–7.81 (m, 1H, (700-H) ? 2H, (2, 6-Har)), 8.01 (dd, J = 1.1 Hz,
J = 7.8 Hz, 1H, (500-H)), 8.23 (d, J = 10.5 Hz, 1H, (200-H)), 8.35 (d, J = 7.9 Hz,
1H, (800-H)), 11.94 (s, (0.2)1H, NH), 12.27 (s, (0.08)1H, NH). Found, %: C 64.08,
H 4.16, N 10.62. Calculated, %: C 64.05, H 4.10, N 10.67. C21H16ClN3O3.
General procedure for the synthesis of hydrazones 6a–h
Three drops of concentrated hydrochloric acid were added to a mixture of the
corresponding hydrazide 1 (10 mmol), 2-methyl-1,4-dihydronaphthalene-1,4-dione
(3) (0.86 g, 5 mmol) and 2-propanol (70 mL). The reaction mixture was refluxed
for 19 h and filtered (hot). Upon completing the reaction, the reaction mixture was
cooled down and the formed crystalline solid was isolated by filtration, washed with
2-propanol and dried.
N0-(3-Methyl-4-oxo-1,4-dihydronaphthalen-1-ylidene)-1-phenyl-5-oxopyrrolidine-
3-carbohydrazide (6a)
Yield 3.39 g (88.0%), m.p. 314–315 °C (from the mixture of 2-propanol and
1
dimethylformamide (1:1)). IR, m: 1645, 1675 (C=O), 3073, 3109, 3175 (NH). H
NMR (300 MHz, DMSO-d6), d: 2.10 (s, 3H, (300-CH3)), 2.80–2.98 (m, 2H, CH2CO),
4.04–4.24 (m, 2H, NCH2), 4.33 (br. s, CH), 7.14 (t, J = 7.4 Hz, 1H, (4-Har)), 7.37
123

Reactions of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides
1019
(t, J = 7.9 Hz, 2H, (3, 5-Har)), 7.61 (dt, J = 1.0 Hz, J = 7.8 Hz, 1H, (600-H)), 7.68
(d, J = 8.0 Hz, 2H, (2, 6-Har)), 7.73 (dt, J = 1.0 Hz, J = 7.8 Hz, 1H, (700-H)), 8.02
(dd, J = 1.0 Hz, J = 7.4 Hz, (500-H)), 8.13 (br. s, 1H, (200-H)), 8.30 (d, J = 7.9 Hz,
1H, (800-H)), 11.99 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6), d: 16.61 (300-CH3),
33.12 (C-30), 35.10 (C-40), 50.02 (C-20); 119.44 (C-2, 6), 123.44 (C-200), 124.07
(C-4), 124.12, 125.59 (C-500, C-800), 128.68 (C-3, 5), 129.44 (C-600, C-700), 129.97
(C-4a00), 132.71 (C-600, C-700), 134.53 (C-300), 139.08 (C-8a00), 139.16 (C-1), 171.85
(C-50), 184.21 (C-400). MS m/z (I, %): 374 [M ? H]? (100). Found, %: C 70.95, H
5.32, N 11.47. Calculated, %: C 70.76, H 5.13, N 11.25. C22H19N3O3.
N0-(3-Methyl-4-oxo-1,4-dihydronaphthalen-1-ylidene)-1-(3-methylphenyl)-5-
oxopyrrolidine-3-carbohydrazide (6b)
Yield 3.8 g (98.0%), m.p. 262–263 °C (from the mixture of 2-propanol and
1
dimethylformamide (1:1)). IR, m: 1641, 1674 (C=O), 3079, 3110, 3177 (NH). H
NMR (300 MHz, DMSO-d6), d: 2.09 (s, 3H, (300-CH3)), 2.30 (s, 3H, (3-CH3)),
2.79–2.96 (m, 2H, CH2CO), 4.02–4.21 (m, 2H, NCH2), 4.32 (br. s, CH), 6.95 (d,
J = 7.3 Hz, 1H, (4-Har)), 7.24 (t, J = 8.2 Hz, 1H, (5-Har)), 7.49 (d, J = 6.5 Hz,
1H, (6-Har)), 7.49 (s, 1H, (2-Har)), 7.61 (dt, J = 1.2 Hz, J = 7.8 Hz, 1H, (600-H)),
7.72 (dt, J = 1.4 Hz, J = 7.7 Hz, 1H, (700-H)), 8.02 (dd, J = 1.1 Hz, J = 7.8 Hz,
(500-H)), 8.13 (br. s, 1H, 200-H), 8.29 (d, J = 7.5 Hz, 1H, (800-H)), 11.99 (s, 1H, NH).
1H NMR (300 MHz, CDCl3), d: 2.21 (d, J = 1.2 Hz 3H, (300-CH3)), 2.36 (s, 3H,
(3-CH3)), 3.02–3.17 (m, 2H, CH2CO), 4.17–4.42 (m, 3H, NCH2 ? CH), 7.00 (d,
J = 7.0 Hz, 1H, (4-Har)), 7.26 (t, J = 8.2 Hz, 1H, (5-Har)), 7.41 (d, J = 8.2 Hz,
1H, (6-Har)), 7.46 (s, 1H, (2-Har)), 7.59 (dt, J = 1.3 Hz, J = 7.5 Hz, 1H, (600-H)),
7.67 (dt, J = 1.4 Hz, J = 7.5 Hz, 1H, (700-H)), 7.72 (q, J = 1.2 Hz, 1H, (200-H)),
8.17–8.23 (m, 2H, (500, 800-H)), 10.80 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6),
d: 16.61 (300-CH3), 21.17 (3-CH3), 32.58, 33.16 (C-30), 35.10 (C-40), 50.13 (C-20),
116.71 (C-6), 120.04 (C-2), 123.33 (C-200), 124.12 (C-500, C-800), 124.78 (C-4),
125.59 (C-500, C-800), 128.49 (C-5), 129.43 (C-600, C-700), 129.97 (C-4a00), 132.70
(C-600, C-700), 134.53 (C-300), 137.95 (C-3), 139.07 (C-8a00), 139.12 (C-1), 171.71
(C-50), 175.55 (CONH), 184.20 (C-400). 13C NMR (75 MHz, CDCl3), d: 17.33
(300-CH3), 21.61 (3-CH3), 34.05 (C-30), 35.48 (C-40), 50.32 (C-20), 117.28 (C-6),
120.89 (C-2), 121.41 (C-200), 122.96 (C-500, C-800), 125.91 (C-4), 126.68 (C-500,
C-800), 128.80 (C-5), 130.02 (C-600, C-700), 130.66 (C-4a00), 132.78 (C-600, C-700),
134.15 (C-300), 138.67, 138.90 (C-3), 139.00 (C-8a00), 142.19 (C-1), 171.53 (C-50),
175.26 (CONH). MS m/z (I, %): 388 [M ? H]? (100). Found, %: C 71.57, H 5.68,
N 10.91. Calculated, %: C 71.30, H 5.46, N 10.85. C23H21N3O3.
N0-(3-Methyl-4-oxo-1,4-dihydronaphthalen-1-ylidene)-1-(4-methylphenyl)-5-
oxopyrrolidine-3-carbohydrazide (6c)
Yield 2.6 g (67.0%), m.p. 288–289 °C (from the mixture of 2-propanol and
1
dimethylformamide (1:1)). IR, m: 1643, 1675 (C=O), 3080, 3112, 3177 (NH). H
NMR (300 MHz, DMSO-d6), d: 2.10 (s, 3H, (300-CH3)), 2.27 (s, 3H, (4-CH3)),
2.78–2.95 (m, 2H, CH2CO), 4.01–4.20 (m, 2H, NCH2), 4.30 (br. s, CH), 7.17
123

_
R. Vaickelioniene et al.
1020
(d, J = 8.5 Hz, 2H, (3, 5-Har)), 7.56 (d, J = 8.5 Hz, 2H, (2, 6-Har)), 7.61 (dt,
J = 1.2 Hz, J = 7.8 Hz, 1H, (600-H)), 7.72 (dt, J = 1.4 Hz, J = 7.7 Hz, 1H,
(700-H)), 8.02 (dd, J = 1.1 Hz, J = 7.8 Hz, (500-H)), 8.13 (br. s, 1H, 200-H), 8.30
(d, J = 7.7 Hz, 1H, (800-Har)), 11.97 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6),
d: 16.59 (300-CH3), 20.38 (4-CH3), 33.29 (C-30), 35.08 (C-40), 50.10 (C-20), 119.45
(C-2, 6), 123.32 (C-200), 124.11, 125.58 (C-500, C-800), 129.06 (C-3, 5), 129.42 (C-600,
C-700), 129.96 (C-4a00), 132.69 (C-600, C-700), 133.14 (C-4), 134.53 (C-300), 136.71
(C-1), 139.06 (C-8a00), 171.57 (C-50), 175.39 (CONH), 184.19 (C-400). MS m/z
(I, %): 388 [M ? H]? (100). Found, %: C 71.46, H 5.67, N 11.02. Calculated, %: C
71.30, H 5.46, N 10.85. C23H21N3O3.
N0-(3-Methyl-4-oxo-1,4-dihydronaphthalen-1-ylidene)-1-(2,5-dimethylphenyl)-5-
oxopyrrolidine-3-carbohydrazide (6d)
Yield 3.0 g (75.0%), m.p. 245–246 °C (from the mixture of 2-propanol and
1
dimethylformamide (1:1)). IR, m: 1650, 1703 (C=O), 3138, 3165, 3197 (NH). H
NMR (300 MHz, DMSO-d6), d: 2.07 (s, 3H, (300-CH3)), 2.13 (s, 3H, (2-CH3)), 2.25
(s, 3H, (5-CH3)), 2.71–2.90 (m, 2H, CH2CO), 3.81–4.09 (m, 2H, NCH2), 4.32 (br. s,
CH), 7.03 (d, J = 7.7 Hz, 1H, (4-Har)), 7.05 (s, 1H, (6-Har)), 7.15 (d, J = 7.7 Hz,
1H, (3-Har)), 7.58 (t, J = 6.5 Hz, 1H, (600-H)), 7.70 (t, J = 7.8 Hz, 1H, (700-H)),
7.99 (dd, J = 1.1 Hz, J = 7.8 Hz, (500-H)), 8.08 (br. s, 1H, 200-H), 8.24 (d,
J = 7.9 Hz, 1H, (800-H)), 11.93 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6), d:
16.58 (300-CH3), 17.05 (2-CH3), 20.31 (5-CH3), 33.64 (C-30), 34.28 (C-40), 51.79
(C-20), 123.21 (C-200), 124.06, 125.56 (C-500, C-800), 127.11 (C-6), 128.17 (C-4),
129.36 (C-600, C-700), 129.93 (C-4a00), 130.47 (C-2), 132.19 (C-3), 132.60 (C-600,
C-700), 134.51 (C-300), 135.77 (C-5), 137.19 (C-1), 139.00 (C-8a00), 171.62 (C-50),
175.61, 175.76 (CONH), 184.14 (C-400). MS m/z (I, %): 402 [M ? H]? (100).
Found, %: C 71.98, H 5.99, N 10.63. Calculated, %: C 71.80, H 5.77, N 10.47.
C24H23N3O3.
N0-(3-Methyl-4-oxo-1,4-dihydronaphthalen-1-ylidene)-1-(2-methyl-5-
chlorophenyl)-5-oxopyrrolidine-3-carbohydrazide (6e)
Yield 3.4 g (82.0%), m.p. 270–271 °C (from the mixture of 2-propanol and
dimethylformamide (1:1)). IR, m: 1645, 1679, 1695 (C=O), 3077, 3114, 3185 (NH).
1H NMR (300 MHz, DMSO-d6), d: 2.08 (s, 3H, (300-CH3)), 2.16 (s, 3H, (2-CH3)),
2.73–2.90 (m, 2H, CH2CO), 3.84–4.13 (m, 2H, NCH2), 4.32 (br. s, CH), 7.27–7.33
(m, 2H, (3,4-Har)), 7.39 (d, J = 1.3 Hz, 1H, (6-Har)), 7.60 (t, J = 6.5 Hz, 1H,
(600-H)), 7.72 (t, J = 7.8 Hz, 1H, (700-H)), 8.00 (d, J = 7.7 Hz, (500-H)), 8.11 (br. s,
1H, 200-H), 8.27 (d, J = 7.9 Hz, 1H, (800-H)), 11.96 (s, 1H, NH). 13C NMR
(75 MHz, DMSO-d6), d: 16.66 (300-CH3), 17.08 (2-CH3), 33.53 (C-30), 34.59
(C-40), 51.79 (C-20), 123.29 (C-200), 124.14, 125.63 (C-500, C-800), 126.66 (C-6),
127.42 (C-4), 129.47 (C-600, C-700), 129.98 (C-4a00), 130.26 (C-2), 132.22 (C-5),
132.70 (C-600, C-700), 134.56 (C-300), 134.73 (C-3), 138.78 (C-1), 139.07 (C-8a00),
171.70 (C-50), 175.36 (CONH), 184.22 (C-400). MS m/z (I, %): 422 [M ? H]? (95),
123

Reactions of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides
1021
424 [M ? 2 ? H]? (30). Found, %: C 65.70, H 4.86, N 10.05. Calculated, %:
C 65.48, H 4.78, N 9.96. C23H20ClN3O3.
N0-(3-Methyl-4-oxo-1,4-dihydronaphthalen-1-ylidene)-1-(3-chloro-4-
methylphenyl)-5-oxopyrrolidine-3-carbohydrazide (6f)
Yield 3.5 g (83.0%), m.p. 293–294 °C (from the mixture of 2-propanol and
dimethylformamide (1:1)). IR, m: 1642, 1678, 1691 (C=O), 3079, 3110, 3185 (NH).
1H NMR (300 MHz, DMSO-d6), d: 2.09 (s, 3H, (300-CH3)), 2.28 (s, 3H, (4-CH3)),
2.73–2.97 (m, 2H, CH2CO), 3.98–4.21 (m, 2H, NCH2), 4.30 (br. s, CH), 7.31–7.48
(m, 2H, (5,6-Har)), 7.60 (t, J = 6.5 Hz, 1H, (600-H)), 7.72 (t, J = 7.8 Hz, 1H,
(700-H)), 7.87 (s, 1H, (2-Har)), 8.02 (d, J = 7.7 Hz, (500-H)), 8.12 (br. s, 1H, 200-H),
8.30 (d, J = 7.9 Hz, 1H, (800-H)), 11.98 (s, 1H, NH). MS m/z (I, %): 422 [M ? H]?
(85), 424 [M ? 2 ? H]? (40). Found, %: C 66.33, H 4.92, N 10.39. Calculated, %:
C 65.48, H 4.78, N 9.96. C23H20ClN3O3.
N0-(3-Methyl-4-oxo-1,4-dihydronaphthalen-1-ylidene)-1-(4-bromophenyl)-5-
oxopyrrolidine-3-carbohydrazide (6g)
Yield 4.5 g (99.0%), m.p. 338–339 °C (from the mixture of 2-propanol and
dimethylformamide (1:1)). IR, m: 1644, 1674, 1689 (C=O), 3071, 3107, 3173 (NH).
1H NMR (300 MHz, DMSO-d6), d: 2.08 (s, 3H, (300-CH3)), 2.72–2.98 (m, 2H,
CH2CO), 4.01–4.21 (m, 2H, NCH2), 4.33 (br. s, CH), 7.53–7.74 (m, 6H, 2, 3, 5,
6-Har ? 600, 700-H), 8.01 (d, J = 7.3 Hz, (500-H)), 8.13 (br. s, 1H, 200-H), 8.28 (d,
J = 7.1 Hz, 1H, (800-Har)), 12.04 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6),
d: 16.70 (300-CH3), 33.04 (C-30), 34.98 (C-40), 50.03 (C-20), 115.91 (C-4), 121.21
(C-2, 6), 123.38 (C-200), 124.14, 125.62 (C-500, C-800), 129.45 (C-600, C-700), 129.98
(C-4a00), 131.49 (C-3, 5), 132.74 (C-600, C-700), 134.53 (C-300), 138.47 (C-1), 139.12
(C-8a00), 172.18 (C-50), 175.28 (CONH), 184.22 (C-400). MS m/z (I, %): 452 [M]?
(100). Found, %: C 58.37, H 4.03, N 9.23. Calculated, %: C 58.42, H 4.01, N 9.29.
C22H18BrN3O3.
N0-(3-Methyl-4-oxo-1,4-dihydronaphthalen-1-ylidene)-1-(4-chlorophenyl)-5-
oxopyrrolidine-3-carbohydrazide (6h)
Yield 3.9 g (96.0%), m.p. 335–336 °C (cleavage). IR, m: 1642, 1674, 1688 (C=O),
3073, 3109, 3173 (NH). 1H NMR (300 MHz, DMSO-d6), d: 2.09 (s, 3H, (300-CH3)),
2.72–2.98 (m, 2H, CH2CO), 4.00–4.37 (m, 3H, NCH2 ? CH), 7.42 (d, J = 8.8 Hz,
2H (3, 5-Har)), 7.61 (m, 1H, 600-H), 7.70–7.74 (m, 3H, 700-H ? 2, 6-Har), 8.02
(d, J = 7.6 Hz, (500-H)), 8.12 (br. s, 1H, 200-H), 8.29 (d, J = 7.7 Hz, 1H, (800-H)),
11.97 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6), d: 16.67 (300-CH3), 33.52 (C-30),
35.11 (C-40), 50.01 (C-20), 120.89 (C-2, 6), 123.38 (C-200), 124.14, 125.62 (C-500,
C-800), 127.79 (C-4), 128.57 (C-3, 5), 129.47 (C-600, C-700), 129.98 (C-4a00), 132.74
(C-600, C-700), 134.53 (C-300), 138.06 (C-1), 139.10 (C-8a00), 172.14 (C-50), 175.71
(CONH), 184.22 (C-400). MS m/z (I, %): 430 [M ? Na]? (100). Found, %: C 64.71,
H 4.41, N 10.39. Calculated, %: C 64.79, H 4.45, N 10.30. C22H18ClN3O3.
123

_
R. Vaickelioniene et al.
1022
General procedure for the synthesis of N-alkylated compounds 7a, c, d
A mixture of the corresponding compound 6 (1 mmol), ethyl iodide (20 mL),
potassium carbonate (1.38 g, 10 mmol), ethyl methyl ketone (20 mL) and
tetrabuthyl ammonium iodide (0.2 g, 1 mmol) was heated at 50–55 °C and stirred
for 20 h, then cooled down, the inorganic salts were filtered off and the liquid
fractions were separated under reduced pressure. The solid mass was collected and
purified as follows: N-ethylcarbohydrazide 7c was recrystallized from ethanol,
compounds 7a, d were purified by column chromatography (Silikagel 60). The
eliuent was acetone : hexane (1:1.5).
N-Ethyl-N0-(3-methyl-4-oxo-1,4-dihydronaphthalen-1-yl)-1-phenyl-5-
oxopyrrolidine-3-carbohydrazide (7a)
Yield 0.3 g (85.0%), m.p. 140–141 °C (Rf = 0.86). IR, m: 1649, 1698, 1734 (C=O).
1H NMR (300 MHz, DMSO-d6), d: 1.18 (t, J = 7.0 Hz, 3H, CH2CH3), 2.03 (br. s,
(0.2)3H, (300-CH3)), 2.15 (s, (0.8)3H, (300-CH3)), 2.71–2.92 (m, 2H, CH2CO),
3.88–4.20 (m, 5H, NCH2 ? CH ? CH2CH3), 7.12 (t, J = 7.2 Hz, 1H, (4-Har)),
7.31–7.41 (m. 2H, (3, 5-Har) ? 0.4H(200-H)), 7.55 (s, 0.6H, (200-H)), 7.63
(d, J = 8.3 Hz, 2H, (2, 6-Har)), 7.72 (dt, J = 1.2 Hz, J = 7.4 Hz, 1H, (600-H)),
7.79 (dt, J = 1.2 Hz, J = 7.6 Hz, 1H, (700-H)), 8.06 (d, J = 7.2 Hz, (500-H)), 8.37
(d, J = 7.6 Hz, 1H, (800-H)). 13C NMR (75 MHz, DMSO-d6), d: 12.33 (NCH2CH3),
16.61 (300-CH3), 33.89 (C-30), 35.33 (C-40), 45.99 (NCH2CH3), 50.04 (C-20), 119.47
(C-2, 6), 124.07 (C-4), 124.21, 125.73 (C-500, C-800), 125.89 (C-200), 128.69 (C-3, 5),
130.45 (C-4a00), 130.94, 133.17 (C-600, C-700), 133.88 (C-300), 139.14 (C-1), 141.50
(C-8a00), 151.34 (C-100), 171.85 (C-50), 173.71 (CONH), 184.42 (C-400). MS m/z
(I, %): 402 [M ? H]? (100). Found, %: C 71.93, H 5.83, N 10.39. Calculated, %: C
71.80, H 5.77, N 10.47. C24H23N3O3.
N-Ethyl-N0-(3-methyl-4-oxo-1,4-dihydronaphthalen-1-yl)-1-(4-methylphenyl)-5-
oxopyrolidine-3-carbohydrazide (7c)
Yield 0.4 g (92.0%), m.p. 159–160 °C (from ethanol). IR, m: 1648, 1663, 1692
(C=O). 1H NMR (300 MHz, DMSO-d6), d: 1.18 (t, J = 6.9 Hz, (0.2)3H, CH2CH3),
1.27 (t, J = 6.9 Hz, (0.8)3H, CH2CH3), 2.03 (s, (0.2)3H, (300-CH3)), 2.15 (s,
(0.8)3H, (300-CH3)), 2.25 (s, 3H, (4-CH3)), 2.73–2.96 (m, 2H, CH2CO), 3.87–4.17
(m, 5H, NCH2 ? CH ? CH2CH3), 7.09 (s, (0.2)H, (200-H)), 7.15 (d, J = 8.3 Hz,
2H, (3, 5-Har)), 7.51 (d, J = 8.3 Hz, 2H, (2, 6-H)), 7.55 (s, 0.8H, (200-H), 7.71 (dt,
J = 1.4 Hz, J = 7.5 Hz, 1H, (600-Har)), 7.78 (dt, J = 1.3 Hz, J = 7.7 Hz, 1H, (700-
H)), 8.06 (d, J = 7.5 Hz, (500-H)), 8.36 (d, J = 7.4 Hz, 1H, (800-H)). 1H NMR
(300 MHz, CDCl3), d: 1.30 (t, J = 7.0 Hz, 3H, CH2CH3), 2.23, 2.24 (2 s, 3H, (300-
CH3)), 2.32 (s, (4-Har)), 2.75–2.99 (m, 2H, CH2CO), 2.79 (quin, J = 8.5 Hz, 1H,
CH), 3.90–4.26 (m, 4H, NCH2 ? CH2CH3), 7.16 (d, J = 8.4 Hz, 2H, (3, 5-Har)),
7.28 (q, J = 1.4 Hz, 1H, (200-H)), 7.49 (d, J = 8.4 Hz, 2H, (2, 6-Har)), 7.63–7.73
(m, 2H, (600, 700-H)), 8.19–8.34 (m, 2H, (500, 800-H)). 13C NMR (75 MHz, DMSO-d6),
d: 12.33 (NCH2CH3), 16.61 (300-CH3), 20.41 (4-CH3), 33.89 (C-30), 35.27 (C-40),
123

Reactions of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides
1023
45.98 (NCH2CH3), 50.09 (C-20), 119.46 (C-2, 6), 124.19, 125.71 (C-500, C-800),
125.87 (C-200), 129.07 (C-3, 5), 130.43 (C-4a00), 130.90 (C-600, C-700), 133.14 (C-4),
133.14 (C-600, C-700), 133.88 (C-300), 136.70 (C-1), 141.46 (C-8a00), 151.18 (C-100),
171.54 (C-50), 173.75 (CONH), 184.40 (C-400). MS m/z (I, %): 438 [M ? Na]?
(100). Found, %: C 72.38, H 6.07, N 10.02. Calculated, %: C 72.27, H 6.06, N
10.11. C25H25N3O3.
N-Ethyl-N0-(3-methyl-4-oxo-1,4-dihydronaphthalen-1-yl)-1-(2,5-dimethylphenyl)-5-
oxopyrrolidine-3-carbohydrazide (7d)
1
Yield 0.4 g (84.0%), m.p. 128–129 °C (Rf = 0.80). IR, m: 1650, 1691 (C=O). H
NMR (300 MHz, DMSO-d6), d: 1.18 (t, J = 6.7 Hz, 3H, CH2CH3), 2.08 (s, 3H,
(2-CH3)), 2.13 (s, 3H, (300-CH3)), 2.24 (s, 3H, (4-CH3)), 2.64–2.76 (m, 2H, CH2CO),
3.74–4.12 (m, 5H, NCH2 ? CH ? CH2CH3), 7.00–7.15 (m, 3H, (3, 4, 6-Har)), 7.54
(s, 1H, (200-H)), 7.70–7.82 (m, 2H, (600, 700-H)), 8.06 (dd, J = 1.2 Hz, J = 7.6 Hz,
(500-H)), 8.34 (d, J = 7.9 Hz, 1H, (800-H)). 13C NMR (75 MHz, DMSO-d6), d: 12.27
(NCH2CH3), 16.57 (300-CH3), 17.00 (2-CH3), 20.41 (4-CH3), 33.73 (C-30), 34.60,
35.06 (C-40), 45.98 (NCH2CH3), 51.92 (C-20), 124.11, 125.70 (C-500, C-800), 125.89
(C-200), 127.16 (C-6), 128.17 (C-4), 130.46 (C-2 ? C-4a00), 130.90 (C-600, C-700),
132.21 (C-3), 133.15 (C-600, C-700), 133.89 (C-300), 135.75 (C-5), 137.18 (C-1),
141.45 (C-8a00), 151.12 (C-100), 171.36 (C-50), 173.98 (CONH), 184.39 (C-400). MS
m/z (I, %): 430 [M ? H]? (100). Found, %: C 72.66, H 6.26, N 9.74. Calculated, %:
C 72.71, H 6.34, N 9.78. C26H27N3O3.
General procedure for the synthesis of N0-(3-chloro-1,4-dioxo-1,4-
dihydronaphthalen-2-yl)-1-aryl-5-oxopyrrolidine-3-carbohydrazides (8a–h)
To a solution of the corresponding hydrazide 1 (5 mmol) in dimethyl sulfoxide
(25 mL), 2,3-dichloro-1,4-dihydronaphthalene-1,4-dione (4) (1.14 g, 5 mmol) was
added, and the mixture was stirred for 24 h at room temperature. Upon completing
the reaction, the reaction mixture was diluted with water (25 mL) and stirred for
10–15 min. The formed precipitate was filtered off, washed with water, 2-propanol,
and dried.
N0-(3-Chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-phenyl-5-oxopyrrolidine-3-
carbohydrazide (8a)
Yield 1.6 g (80.0%), m.p. 189–190 °C (from 1,4-dioxane). IR, m: 1688, 1705 (C=O),
1
3174, 3355 (NH). H NMR (300 MHz, DMSO-d6), d: 2.65–2.97 (m, 2H, CH2CO),
3.30–4.26 (m, 2H, NCH2 ? CH), 7.06–8.38 (m, 9H, Har), 9.09, 10.74, 13.67, 13.80
(4 s, 2H, NH). 13C NMR (75 MHz, DMSO-d6), d: 33.83 (C-30), 35.09, 35.35 (C-40),
49.59, 49.88, 50.16 (C-20), 111.53 (C-300), 119.45, 119.57 (C-2, 6), 124.12, 124.020 5
(C-4), 126.19, 126.43, 127.08, 127.39 (C-500, C-800), 128.72 (C-3, 5 ? C-4a ),
130.83, 131.36 (C-600, C-700), 133.31 (C-8a00), 134.66, 134.99, 135.10 (C-600, C-700),
139.12 (C-1), 144.99 (C-200), 171.74, 172.79 (C-50, CONH), 175.90 (C-400), 179.11
123

_
R. Vaickelioniene et al.
1024
(C-100). MS m/z (I, %): 410.3 [M ? H]? (100). Found, %: C 61.21, H 4.17, N 10.00.
Calculated, %: C 61.55, H 3.94, N 10.25. C21H16ClN3O4.
N0-(3-Chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-(3-methylphenyl)-5-
oxopyrrolidine-3-carbohydrazide (8b)
Yield 1.6 g (75.5%), m.p. 151–152 °C (from 1,4-dioxane). IR, m: 1698 (C=O), 3213
1
(NH). H NMR (300 MHz, DMSO-d6), d: 2.30 (s, 3H, (3-Har)), 2.62–3.01 (m, 2H,
CH2CO), 3.35–4.22 (m, 2H, NCH2 ? CH), 6.94–8.39 (m, 8H, Har), 9.07, 10.65,
10.82, 13.60, 13.78 (5 s, 2H, NH). 13C NMR (75 MHz, DMSO-d6), d: 21.16
(4-CH3), 33.85 (C-30), 34.97, 35.14, 35.41 (C-40), 49.86, 50.27 (C-20), 111.52
(C-300), 116.64, 116.76 (C-6), 120.00, 120.14 (C-2), 124.78, 124.86 (C-4), 126.78,
126.36 (C-500, C-800), 127.27 (C-800), 128.47 (C-5), 129.70 (C-4a00), 131.38 (C-600,
C-700), 133.01, 133.07, 133.29 (C-8a00), 134.17, 134.72, 135.03, 135.51 (C-600, C-700),
137.93 (C-3), 138.93, 139.01 (C-1), 144.68, 145.53 (C-200), 170.98, 171.22, 171.38,
171.55 (C-5, CONH), 176.34 (C-400), 178.99 (C-100). Found, %: C 62.57, H 4.69, N
9.81. Calculated, %: C 62.34, H 4.28, N 9.91. C22H18ClN3O4.
N0-(3-Chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-(4-methylphenyl)-5-
oxopyrrolidine-3-carbohydrazide (8c)
Yield 1.7 g (81.3%), m.p. 159–160 °C (from 1,4-dioxane). IR, m: 1671, 1698 (C=O),
3236, 3299 (NH). 1H NMR (300 MHz, DMSO-d6), d: 2.26 (s, 3H, (4-Har)),
2.63–2.85 (m, 2H, CH2CO), 3.30–4.21 (m, 2H, NCH2 ? CH), 7.15–8.38 (m, 8H,
Har), 9.08, 10.71, 13.67, 13.87 (4 s, 2H, NH). 13C NMR (75 MHz, DMSO-d6),
d: 20.42 (4-CH3), 33.35, 33.87 (C-30), 35.16, 35.37 (C-40), 49.99, 50.27 (C-20),
111.53 (C-300), 119.43, 119.88 (C-2, 6), 126.16, 126.42, 127.05 (C-500, C-800),
129.10, 129.22 (C-3, 5), 129.77 (C-4a00), 130.88, 131.43 (C-600, C-700), 133.19 (C-4),
133.33 (C-8a00), 134.63, 135.07 (C-600, C-700), 136.86 (C-1), 144.70 (C-200), 171.08,
171.45 (C-50, CONH), 175.85, 176.41 (C-400), 179.05, 179.03 (C-100). MS m/z (I, %):
446.3 [M ? Na]? (30), 448.4 [M ? 2 ? Na]? (15). Found, %: C 62.59, H 4.56, N
10.03. Calculated, %: C 62.34, H 4.28, N 9.91. C22H18ClN3O4.
N0-(3-Chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-(2,5-dimethylphenyl)-5-
oxopyrrolidine-3-carbohydrazide (8d)
Yield 1.6 g (71.9%), m.p. 188–189 °C (from 1,4-dioxane). IR, m: 1644, 1683 (C=O),
1
3169 (NH). H NMR (300 MHz, DMSO-d6), d: 2.07 (s, 3H, (2-Har)), 2.25 (s, 3H,
(5-Har)), 2.55–2.93 (m, 2H, CH2CO), 3.33–3.44 (m, 1H, CH), 3.67–4.32 (m, 2H,
NCH2), 7.01–8.14 (m, 8H, Har), 9.08, 10.61, 10.81, 13.70 (4 s, 2H, NH). 13C NMR
(75 MHz, DMSO-d6), d: 17.06 (2-CH3), 20.35 (4-CH3), 33.99 (C-30), 34.92 (C-40),
52.06 (C-20), 111.56 (C-300), 126.16, 126.40 (C-500, C-800), 127.08 (C-6), 128.22
(C-4), 129.26, 129.74 (C-4a00), 130.49 (C-2), 131.40 (C-600, C-700), 132.24 (C-3),
133.34 (C-8a00), 134.04, 135.08 (C-600, C-700), 135.79 (C-5), 137.14 (C-1), 144.77
(C-200), 171.23, 171.32 (C-5, CONH), 175.82, 176.37 (C-400), 179.04 (C-100). MS m/z
123

Reactions of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides
1025
(I, %): 460.4 [M ? Na]? (35), 462.3 [M ? 2 ? Na]? (17). Found, %: C 63.41, H
4.57, N 9.56. Calculated, %: C 63.09, H 4.60, N 9.60. C23H20ClN3O4.
N0-(3-Chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-(5-chloro-2-methylphenyl)-
5-oxopyrrolidine-3-carbohydrazide (8e)
Yield 1.8 g (79.2%), m.p. 182–183 °C (from 1,4-dioxane). IR, m: 1678, 1691 (C=O),
3262 (NH). 1H NMR (300 MHz, DMSO-d6), d: 2.28 (s, 3H, (2-Har)), 2.64–2.99 (m,
2H, CH2CO), 3.31–4.30 (m, 2H, NCH2 ? CH), 7.31–8.38 (m, 7H, Har), 9.05, 10.64,
10.81, 13.72 (4 s, 2H, NH). 13C NMR (75 MHz, DMSO-d6), d: 16.97 (2-CH3),
33.83 (C-30), 34.98 (C-40), 51.77 (C-20), 111.54 (C-300), 126.13, 126.24, 126.37
(C-500, C-800), 126.55 (C-6), 127.36 (C-4), 129.75, 129.93 (C-4a), 130.19 (C-2),
131.39 (C-600, C-700), 132.15 (C-5), 133.30 (C-8a), 134.68 (C-3), 135.03 (C-600,
C-700), 138.70 (C-1), 144.74 (C-200), 169.57, 171.14 (CONH), 171.45 (C-50), 176.33
(C-400), 179.01 (C-100). Found, %: C 58.26, H 3.91, N 9.01. Calculated, %: C 57.66,
H 3.74, N 9.17. C22H17Cl2N3O4.
N0-(3-Chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-(3-chloro-4-methylphenyl)-
5-oxopyrrolidine-3-carbohydrazide (8f)
Yield 1.6 g (70.3%), m.p. 204–205 °C (from 1,4-dioxane). IR, m: 1641, 1687 (C=O),
3165 (NH). 1H NMR (300 MHz, DMSO-d6), d: 2.10, 2.14 (2 s, 3H, (4-Har)),
2.56–2.92 (m, 2H, CH2CO), 3.35–4.15 (m, 2H, NCH2 ? CH), 7.23–8.16 (m, 7H,
Har), 9.07, 10.61, 10.82, 13.72 (4 s, 2H, NH). 13C NMR (75 MHz, DMSO-d6),
d: 18.87 (4-CH3), 33.76 (C-30), 35.36 (C-40), 50.06 (C-20), 111.56 (C-300), 117.76
(C-6), 119.39 (C-2), 126.11, 126.34, 127.00 (C-500, C-800), 129.70 (C-4a00), 130.79
(C-5), 131.06 (C-4), 131.37 (C-600, C-700), 133.07 (C-3), 133.28 (C-8a00), 134.58,
135.01 (C-600, C-700), 138.10 (C-1), 144.69 (C-200), 170.89, 171.85 (C-50, CONH),
176.34 (C-400), 178.99 (C-100). Found, %: C 57.44, H 3.92, N 9.12. Calculated %: C
57.66, H 3.74, N 9.17. C22H17Cl2N3O4.
Chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-(4-bromophenyl)-5-
oxopyrrolidine-3-carbohydrazide (8g)
Yield 1.8 g (74.3%), m.p. 150–151 °C (from 1,4-dioxane). IR, m: 1682, 1698 (C=O),
3183 (NH). 1H NMR (300 MHz, DMSO-d6), d: 2.64–3.00 (m, 2H, CH2CO),
3.35–4.22 (m, 2H, NCH2 ? CH), 7.25–8.37 (m, 8H, Har), 9.07, 10.68, 13.70, 13.79,
14.26 (5 s, 2H, NH). 13C NMR (75 MHz, DMSO-d6), d: 33.73 (C-30), 35.43 (C-40),
49.34, 49.51, 50.04 (C-20), 111.51 (C-300), 115.88 (C-4), 121.14, 121.27 (C-2, 6),
126.10, 126.35, 127.00 (C-500, C-800), 129.69 (C-4a00), 131.14 (C-3, 5), 131.43 (C-600,
C-700), 133.27 (C-8a00), 134.58, 135.01 (C-600, C-700), 138.33 (C-1), 144.64 (C-200),
170.85, 171.88 (C-5, CONH), 176.33 (C-400), 178.95 (C-100). Found, %: C 51.65,
H 3.05, N 7.92. Calculated, %: C 51.61, H 3.09, N 8.60. C21H15BrClN3O4.
123

_
R. Vaickelioniene et al.
1026
N0-(3-Chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-(4-chlorophenyl)-5-
oxopyrrolidine-3-carbohydrazide (8h)
Yield 1.7 g (77.5%), m.p. 200–201 °C (from 1,4-dioxane). IR, m: 1681, 1699 (C=O),
1
3233, 3291 (NH). H NMR (300 MHz, DMSO-d6), d: 2.64–2.99 (m, 2H, CH2CO),
3.31–3.41(m, 1H, CH), 3.89–4.24 (m, 2H, NCH2), 7.40–8.11 (m, 8H, Har), 9.08,
10.68, 10.82, 13.67 (4 s, 2H, NH). 13C NMR (75 MHz, DMSO-d6), d: 33.78 (C-30),
35.39 (C-40), 50.14 (C-20), 111.51 (C-300), 120.82 (C-2, 6), 126.15, 126.39, 127.80
(C-500, C-800), 128.57 (C-3, 5), 129.72 (C-4a00), 131.39 (C-600, C-700), 133.32 (C-8a00),
135.05 (C-600, C-700), 137.95 (C-1), 144.65 (C-200), 170.92, 171.93 (C-50, CONH),
176.38 (C-400), 179.01 (C-100). Found, %: C 57.34, H 3.61, N 9.86. Calculated, %: C
56.77,H 3.40, N 9.46. C21H15Cl2N3O4.
Acknowledgment The financial support from the Research Council of Lithuania is gratefully
acknowledged (Project TAP-53/2010).
References
1. M.D. Ball, M.S. Bartlett, M. Shaw, J.W. Smith, M. Nasr, S.R. Meshnick, Antimicrob. Agents
Chemother. 45, 1473 (2001)
2. V.K. Tandon, H.K. Maurya, M.K. Verma, R. Kumar, P.K. Shukla, Eur. J. Med. Chem. 45, 2418
(2010)
3. S.G. Polonik, A.M. Tolkach, N.I. Uvarova, S.I. Stekhova, E.B. Shentsova, M.M. Anisimov, Pharm.
Chem. J. 20, 93 (1986)
4. V.K. Tandon, H.K. Maurya, A. Tripathi, G.B. ShivaKeshava, P.K. Shukla, P. Srivastava, D. Panda,
Eur. J. Med. Chem. 44, 1086 (2009)
5. V.K. Tandon, D.B. Yadav, H.K. Maurya, A.K. Chaturvedi, P.K. Shukla, Bioorg. Med. Chem. Lett.
14, 6120 (2006)
6. V.K. Tandon, D.B. Yadav, R.V. Singh, A.K. Chaturvedic, P.K. Shukla, Bioorg. Med. Chem. Lett. 15,
5324 (2005)
7. V.K. Tandon, D.Y. Ravindra, V. Singh, M. Vaish, A.K. Chaturvedic, P.K. Shukla, Bioorg. Med.
Chem. Lett. 15, 3463 (2005)
8. Ch.-K. Ryu, K. Un Choi, Ju.-Y. Shim, H.-J. You, I.H. Choi, M.J. Chae, Bioorg. Med. Chem. 11, 4003
(2003)
9. Ch.-K. Ryu, H.-J. Kim, Arch. Pharm. Res. 17, 139 (1994)
´
10. G. Errante, G. La Motta, C. Lagana, V. Wittebolle, M.-E. Sarciron, R. Barreta, Eur. J. Med. Chem.
41, 773 (2006)
11. B.P.S. Khambay, D. Batty, M. Cahill, I. Denholm, M. Mead-Briggs, S. Vinall, H.M. Niemeyer,
M.S.J. Simmonds, J. Agric. Food Chem. 47, 770 (1999)
12. N. Jacobsen, L.-E.K. Pedersen, Pestic. Sci. 17, 511 (1986)
13. A. Feitosa dos Santos, P.A.L. Ferraz, A. Ventura Pinto, M. do Carmo, F.R. Pinto, M.O.F. Goulart,
A.E.G. Sant’Ana, Int. J. Parasitol. 30, 1199 (2000)
14. A.E. Shchekotikhin, V.N. Buyanov, M.N. Preobrazhenskaya, Bioorg. Med. Chem. 12, 3923 (2004)
15. B.H. Kim, J. Yoo, S.-H. Park, J.-K. Jung, H. Cho, Y. Chung, Arch. Pharm. Res. 29, 123 (2006)
16. D.P. Bezerra, A.P. Alves, N.M. de Alencar, R.O. Mesquita, M.W. Lima, C. Pessoa, M.O. de Moraes,
J.N. Lopes, N.P. Lopes, L.V. Costa-Lotufo, J. Exp. Ther. Oncol. 7, 113 (2008)
17. V.K. Tandon, R.V. Singh, D.B. Yadav, Bioorg. Med. Chem. Lett. 14, 2901 (2004)
18. S.G. Polonik, N.G. Prokof’eva, I.G. Agafonova, N.I. Uvarova, Pharm. Chem. J. 37, 397 (2003)
19. N. Kongkathip, B. Kongkathip, P. Siripong, Ch. Sangma, S. Luangkamin, M. Niyomdecha, S. Pat-
tanapa, S. Piyaviriyagul, P. Kongsaeree, Bioorg. Med. Chem. 11, 3179 (2003)
´
20. R.A. Tapia, L. Cantuarias, M. Cuellar, J. Villena, J. Braz. Chem. Soc. 20, 999 (2009)
21. S. Rollas, S.G. Kucukguzel, Molecules 12, 1910 (2007)
123

Reactions of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides
1027
22. K. Brokaite, V. Mickevicius, G. Mikulskiene, Arkivoc ii, 61 (2006)
23. K. Brokaite, V. Mickevicius, G. Mikulskiene, Khim. Geterotsikl. Soedin. 9, 1336 (2006)
24. H.O. Kalinowski, S. Berger, S. Braun, in 13C-NMR Spektroskopie (Georg Thieme Verlag, Stuttgart,
New York, 1984), p. 685
´
ˇ
ˇ
` ˇ ˇ
25. Z. Pruckova, A. Klasek, A. Lycka, I. Miksik, A. Ruzicka, Tetrahedron 65, 9103 (2009)
26. M.W. Singh, A. Karmakar, N. Barooah, J.B. Baruah, Beilstein J. Org. Chem. (2007). doi:
10.1186/18605397310
27. W.L. Mosby, R.J. Boyle, J. Org. Chem. (1959). doi:10.1021/jo01085a026
28. T. Win, S. Bittner, Tetrahedron Lett. 46, 3229 (2005)
29. Y.M. Al-Hiari, R. Abu-Dahab, M.M. El-Abadelah, Molecules 13, 2880 (2008)
30. A.P. Neves, C.C. Barbosa, S.J. Greco, M.D. Vargas, L.C. Visentin, C.B. Pinheiro, A.S. Mangrich,
J.P. Barbosa, G.L. da Costa, J. Braz. Chem. Soc. 20, 712 (2009)
31. A.A. Khalil, S. Steyn, N. Castagnoli Jr., Chem. Res. Toxicol. 13, 31 (2000)
32. F.W. Ribeiro, M.C.F.R. Pinto, A.V. Pinto, J. Braz. Chem. Soc. 1, 55 (1990)
33. J.C. Lien, L.J. Huang, C.M. Teng, J.P. Wang, S.C. Kuo, Chem. Pharm. Bull. 50, 672 (2002)
34. A. El-Wareth, A.O. Sarhan, A.M. El-Dean, M.I. Abdel-Monem, Monatsh. Chem. 129, 205 (1998)
35. S. Bittner, C. Meenakshi, G. Temtsin, Tetrahedron 57, 7423 (2001)
36. S.V. Rubashko, T.V. Mikhalina, I.Yu. Bagryanskaya, Yu.V. Gatilov, Russ. Chem. Bull. 43, 1024
(1994)
37. S.W. Lee, C.H. Lee, K.J. Lee, Bull. Korean Chem. Soc. 27, 769 (2006)
38. T. Furumoto, T. Ohara, T. Kubo, Y. Kawanami, H. Fukui, Biosci. Biotechnol. Biochem. 71, 2600
(2007)
39. P.R. Murray, E.J. Baron, M.A. Pfaller, F.C. Tenover, R.H. Yolken, Manual of Clinical Microbiology,
6th edn. (ASM Press, Washington, DC, 1995), pp. 1327–1341
40. National Committee for Clinical Laboratory Standard, Reference method for broth dilution antifungal
susceptibility testing of conidium forming filamentous fungi: proposed standard, Document M38-P
(National Committee for Clinical Laboratory Standard, Wayne, PA, USA, 1998)
123