Hydrazides of 4-aryl(hetaryl)-2-oxopyrrolidine-3-carboxylic acids: Synthesis and structure

Article abstract of DOI:10.1134/S1070428016110129

Proceeding from reactions of methyl 4-aryl(hetaryl)-2-oxopyrrolidine-3-caroxylates with hydrazine and phenylhydrazine a series of hydrazides of the corresponding 2-oxopyrrolidine-3-carboxylic acids was obtained combining in the molecule a lactam ring and carbohydrazide groups. Phenylhydrazides of 2-oxopyrrolidine-3-carboxylic acids possess the Z-configuration.

Full text of DOI:10.1134/S1070428016110129

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 11, pp. 1616–1624. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © N.V. Gorodnicheva, E.S. Ostroglyadov, O.S. Vasil’eva, V.V. Pelipko, V.V. Gurzhii, V.M. Berestovitskaya, E.S. Lipina, 2016,
published in Zhurnal Organicheskoi Khimii, 2016, Vol. 52, No. 11, pp. 1622–1630.
Hydrazides of 4-Aryl(hetaryl)-2-oxopyrrolidine-3-carboxylic
Acids: Synthesis and Structure
N. V. Gorodnichevaa,* E. S. Ostroglyadova, O. S. Vasil’evaa, V. V. Pelipkoa,
V. V. Gurzhiib, V. M. Berestovitskayaa, and E. S. Lipinaa
a Herzen Russian State Pedagogical University, nab. r. Moiki, 48, St. Petersburg, 191186 Russia
*e-mail: kohrgpu@yandex.ru
b St. Petersburg State University, St. Petersburg, 199034 Russia
Received June 22, 2016
Abstract—Proceeding from reactions of methyl 4-aryl(hetaryl)-2-oxopyrrolidine-3-caroxylates with hydrazine
and phenylhydrazine a series of hydrazides of the corresponding 2-oxopyrrolidine-3-carboxylic acids was
obtained combining in the molecule a lactam ring and carbohydrazide groups. Phenylhydrazides of 2-
oxopyrrolidine-3-carboxylic acids possess the Z-configuration.
DOI: 10.1134/S1070428016110129
The great interest attracted by derivatives of 2-
oxopyrrolidine is due to their considerable applied
importance. The lactam ring is known to be the key
pharmacophore group in the structure of nootropic
drugs used in the medical practice, racetams
(piracetam, carphedon, oxiracetam, levetiracetam, etc.)
[1–9]. At the same time the replacement of the
carbamoyl residue for a carbohydrazide group in the
carphedon molecule (phenyl analog of piracetam)
supplies it with pronounced antidepressant, anxiolytic,
and nootropic properties [10,1 1].
relatively readily form the corresponding hydrazides
15–17, 19–22, and 26 in good yields (up to 77%).
Hydrazide 15 was obtained before in reaction of ester
1 with hydrazine hydrate, but under other conditions,
namely, in ethanol solution under microwave
irradiation [16, 17].
Yet the formation of hydrazides 18, 23–25, 27, and
28 in the reaction of esters 4, 9–11, 13, and 14 with
hydrazine hydrate required more rigid conditions: Two
hour heating of the reaction mixture at 95°С with sub-
sequent keeping for 20 h at 18–20°С. Compounds 18,
23–25, 27, and 28 were isolated in yields up to 74%.
Therefore the substituted 2-oxopyrrolidines
containing at the C3 atom of the lactam ring the
carbohydrazide groups are of definite interest as
promising biologically active compounds. 2-
Oxopyrrolidine-3-caroxylates may be regarded as
convenient precursors in the synthesis of such
substances since their hydrazinolysis is a targeted way
to the preparation of new piracetam analogs.
The differences in the chemical behavior of esters
1–14 were observed as well in the reactions with phe-
nylhydrazine. For instance, phenylhydrazides 29–35
were successfully obtained in the reaction of esters 1–3,
5, 9, and 11–13 with phenylhydrazine after 10 min
heating of the reagents mixture at 170°С followed by
keeping at 18–20°С for 20 h. However we failed to
bring into the reaction with phenylhydrazine indole-con-
taining 2-oxopyrrolidinecaroxylates 6–8 and 10 eviden-
tly due to the high sterical loading of the molecules.
We examined the chemical behavior of 4-aryl-(het-
aryl)-2-oxopyrrolidine-3-caroxylates 1–14 in the reac-
tions with hydrazine and phenylhydrazine. Initial esters
1–14 were synthesized along procedures [12–15].
The structure of all synthesized compounds 15–36
was confirmed by combination of the methods of IR
and 1Н, 13C {1H} NMR spectroscopy and X-ray
diffraction (XRD) analysis (by an example of
hydrazide 36).
The successful outcome of these reactions
essentially depends on their conditions. For instance,
esters 1–3, 5–8, and 12 react with hydrazine hydrate in
relatively mild conditions: At 18–20°С over 20 h they
1616

HYDRAZIDES OF 4-ARYL(HETARYL)-2-OXOPYRROLIDINE-3-CARBOXYLIC ACIDS:...
1617
CON6HNH2
R2
H2NNH2 H2O
2
a: 18_20oC, 20 h;
b: 95oC, 2 h, then
18_20oC, 20 h
1
R1
O
N
R2
COOMe
O
H
a: 15_17, 19_22, 26,
b: 18, 23_25, 27, 28
R1
N
H
CON6HN7HPh
R2
1_14
H2NNHPh
170oC, 10 min;
18_20oC, 20 h
R1
O
N
H
29_36
R1 = H, R2 = Ph (1, 15, 29), 4-MeOC6H4 (2, 16, 30), 4-MeC6H4 (3, 17, 31), 4-ClC6H4 (4, 18),
Bn
H
H
Me
N
N
N
N
(7, 21),
(5, 19, 32),
(6, 20),
Me (8, 22),
Me
Bn
N
N
(11, 25, 34),
(12, 26, 35),
Me
Me
(10, 24),
(9, 23, 33),
O
N
N
N
N
N
R1 = Ph, R2 =
(14, 28).
(13, 27, 36);
Me
Me
IR spectra of hydrazides 15–28 and phenylhyd-
razides 29–36 are alike. For instance, in the IR
spectrum of compound 36 in the region of carbonyl
absorption strong broadened bands are observed with
the frequencies 1712 and 1662 cm–1 belonging to the
stretching vibrations of lactam and hydrazide С=O
groups respectively. In the high frequency region a
broadened band appears (3270–3185 cm–1) resulting
H3C
N1H
N2H
N
6
7
CONHNHC6H5
N
6
CONHNH2
H3C
4
3
2
5
4
3
1
N
H
O
2
5
NCH3
CH3
C3H
1
O
N
δ, ppm
9.96
7.84
H
Ph
Ph
NH2
C3H
C4H
N1H
C5H2
Bza
N7H
C4H
C5H2
N1H
8.0
N6H
9.0
N6H
10.0
9.0
8.0
7.0
6.0
5.0
δ, ppm
δ, ppm
7.0
6.0
5.0
4.0
Fig. 1. 1Н NMR spectrum of 4-(4-methylphenyl)-2-
oxopyrrolidine-3-carboxylic acid hydrazide 17 in
DMSO-d6.
Fig. 2. Н NMR spectrum of 4-(1-methylbenzimidazol-2-
yl)-2-oxopyrrolidine-3-carboxylic acid phenylhydrazide 36
in DMSO-d6.
1
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 11 2016

GORODNICHEVA et al.
methyl protons of the benzimidazole ring is observed
1618
C5H''
C4H
C3H
C5H'
60.0
0
δ,
upfield (3.76 ppm). The protons of the carbohydrazide
fragment are present downfield as two doublets: 9.96
(N6H, 3J 2.1 Hz), 7.84 ppm (N7H, 3J 2.1 Hz).
ppm
C4H/C4
Such substituted hydrazides are known to exist as
Z- or E-conformers [18, 19], since in the amide group
C(=O)NH due to its ability to form mesomeric
structures certain barrier appears against the rotation
around the nitrogen-carbon bond.
C4
40.0
50.0
C5H'/C5
C5H''/C5
C5
N
CONHNHC6H5
N
N7HPh
N6
H3C
O
H
O
4
3
H'
5
2
C3H/C3
1
C3
N6
R
O
R
N
H
H''
N7HPh
H
0 0.40.8
4.6
4.2
3.8
δ, ppm
O
O
N
N
H
Fig. 3. Fragment of H-13C HMQC spectrum of hydrazide
36 in DMSO-d6.
1
H
E
Z
The chemical shifts of the NH proton of the
carbohydrazide function (9.96 ppm) and of the
carbonyl carbon atom (168.43 ppm) evidence the Z-
conformation of compound 36, namely, the oxygen
atom of the carbonyl group and the NHPh fragment are
located in the cis-position with respect to the C–N
bond. This conclusion is based on the close data for
structures containing analogous blocks with trans (E)
and cis (Z) conformations [20, 21]. In particular,
carbon signals of the carbonyl group are observed at
~168 (Z) and ~173 (E) ppm; the downfield shift of the
latter is due to the possibility of the formation of
intramolecular hydrogen bond between the oxygen and
hydrogen atoms of the hydrazide group [20]. Since the
from superposition of the stretching vibrations of NH
groups of the lactam and the hydrazide function.
1Н NMR spectrum of each specimen of the
hydrazides series 15–28 and phenylhydrazides 29–36
contains a single set of proton signals corresponding to
structural fragments thus indicating their diastereo
1
uniformity (Figs. 1, 2). For example, in the Н NMR
spectrum of hydrazide 17 according to the signals
multiplicity the doublet at 3.22 ppm (3J3,4 10.4 Hz)
belongs to the methine proton H3, and the proton Н4
3
gives rise to the quartet at 3.84 ppm (3J3,4 10.4, J4,5'
3
9.3, J4,5'' 8.4 Hz). Methylene protons appear as two
triplets: Н5' at 3.13 ppm (3J4,5' 9.3, 2J5',5'' 9.3 Hz) and H5''
2
at 3.56 ppm (3J4,5'' 8.4, J5',5'' 9.3 Hz). In the weak field
1
data of Н and 13C NMR spectra of substance 36 are
of this spectrum signals of proton H1 of the pyrrolidine
ring (7.92 ppm) and of the phenyl substituent (7.07–
7.12 ppm) are present. The protons of the hydrazide
fragment appear as singlets: NH2 group at 4.25 ppm,
NH more downfield (9.18 ppm).
well consistent with those of all phenylhydrazides 29–
35 it is possible to conclude with a high probability
that the result obtained for compound 36 is valid for all
the series of substances.
1
The analysis of Н NMR spectra of hydrazides 15–
1
In the Н NMR spectra of phenylhydrazides 29–36
28 and phenylhydrazides 29–36 shows that the values
3J3,4 8.9–10.7 Hz of protons H3,4 of 2-oxopyrrolidine
ring indicate their trans-position and are in a good
agreement with the data published on trans-2-
oxopyrrolidinecarboxylic esters [22].
differences in the signals of the protons of the hydrazide
function are regularly observed. For instance, in the
spectrum of phenylhydrazide 36 (Fig. 2) a doublet is
present from the proton H3 (3.94 ppm, 3J3,34 9.2 Hz) and
3
a quartet from the proton Н4 (4.40 ppm, J3,4 9.2, J4,5'
To prove the validity of assignment of signals in 1Н
and 13С NMR spectra of compounds 15–36 we
registered 2D heteronuclear correlation NMR spectra
1Н-13С HMQC and НMВС for hydrazides 17 and 20
and phenylhydrazides 32 and 36. For example, in the
3
8.8, J4,5'' 8.8 Hz). Methylene protons are present as
2
two triplets: Н5' at 3.52 ppm (3J4,5' 8.8, J5',5'' 9.1 Hz),
H5'' at 3.83 ppm (3J4,5'' 8.8, 2J5',5'' 8.8 Hz). The downfield
part of the spec-trum contains the signals of the H1 of
the lactam ring (8.17 ppm) and multiplets belonging to
protons of phe-nyl (6.61–7.09 ppm) and benzimidazole
(7.24–7.63 ppm) substituents. The singlet from the
1
correlation spectrum H-13C HMQC of phenylhydra-
zide 36 (Fig. 3) a coupling is observed between the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 11 2016

HYDRAZIDES OF 4-ARYL(HETARYL)-2-OXOPYRROLIDINE-3-CARBOXYLIC ACIDS:...
1619
С26
H
N7
O
N
С25
С10
С9
С11
С12
N6
N
H
O24
С20
Me
С21
С22
O
С8
N
С13
N14
H
С19
С18
N7H
N6HC(O)
N7
0.1
С23
0
С6
Co
N7H/Co
С14
С4
С5
δ,
ppm
N16
N17
С3
С15
N
6
7
CONHNHC6H5
N
130.0
O15
H3C
4
3
С2
N1
2
N7H/Cu
5
Cu
1
O
O2
N
H
150.0
170.0
Fig. 5. General arrangement of hydrazide 36 molecule with
a solvate ethanol in the crystal represented with thermal
ellipsoids of 50% probability.
N6H
10.0
C(O)
0 0.3 0.6
δ, ppm
9.0
8.0
1
Fig. 4. Fragment of H-13C HMBC spectrum of hydrazide
36 in DMSO-d6.
and 32. The application of the 2D heteronuclear
correlation NMR spectroscopy 1Н-13С HMQC to
compounds 17, 20, 32, and 36 made it possible to
assign all the signals of protons bound to atoms C3–5 of
the 2-oxopyrrolidine ring for the total series of
obtained hydrazides 15–36.
proton Н3 (3.94 ppm) and the atom С3 (52.16 ppm),
between the proton Н4 (4.40 ppm) and atom С4
(35.92 ppm), protons Н5',5'' (3.52 and 3.83 ppm) and
atom С5 (45.06 ppm). Similar correlations appear also
The validity of the signals assignment of the
carbonyl carbon atoms and the protons of NH group of
in the spectra Н-13С HMQC of compounds 17, 20,
1
N16'
N7'
O24
H16'
N1
H1
H16
N16
N7
H24
O15'
O15
H1'
N1'
Fig. 6. Fragment of hydrazide 36 structure. Combination into a three-dimentional scaffold occurs due to H-bonds (dotted lines)
between contiguous molecules of hydrazide 36 and ethanol molecule.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 11 2016

GORODNICHEVA et al.
1620
2-oxopyrrolidine rings and the hydrazide function of
Compounds synthesized present an independent
interest as promising biologically active compounds;
they also may be regarded as initial reagents for the
synthesis of new derivatives of 2-oxopyrrolidine.
1
compounds 15–36 was proved by registering Н-13С
{1H} НMВС spectra for derivatives 17, 20, 32, and 36.
1
For example, in the Н-13С {1H} НMВС spectrum of
phenylhydrazide 36 (Fig. 4) a correlation was observed
between the proton of the N1H group (8.17 ppm) of
lactam and the atom С2 (172.36 ppm) of the 2-
oxopyrrolidine ring, of the proton N6H (9.96 ppm) and
the carbon atom (169.44 ppm) of the hydrazide
function, of the proton N7H (7.84 ppm) of the
hydrazide function and the ipso- (149.39 ppm) and
ortho- (112.69 ppm) carbon atoms of the benzene ring.
EXPERIMENTAL
Spectral characteristics and elemental analysis data
of synthesized compounds were measured using the
equipment of the Center of joint usage of the chemical
faculty of the Herzen State Pedagogical University.
XRD analysis was performed using the equipment of
the Resource Center of Saint-Petersburg State
University “X-ray diffraction investigation methods.”
1Н, 1H-13C {1H} HMQC and HMBC NMR
spectra were registered on a spectrometer Jeol
ECX400A at operating frequencies 399.78 (1Н) and
100.52 (13С) MHz in dimethyl sulfoxide-d6 using the
residual signal of the nondeuterated solvent as an
internal reference. IR spectra were taken on a Fourier
spectrophotometer Shimadzu IRPrestige-21 from
pellets with KBr. Elemental analysis of substances
synthesized was carried out on an analyzer EuroVector
EA 3000 (CHN Dual mode). Melting points were
measured on a device PTP(M).
Thus the similar character of spectra of the total
series of synthesized hydrazides as well as the
phenylhydrazides series, and also the analysis of the
1Н-13С {1H} HMQC and НMВС spectra of compounds
17, 20, 32, and 36 made it possible to reliably interpret
1
the Н and С13{1H} NMR spectra of the whole series
of prepared hydrazides 15–28 and phenylhydrazides
29–36 and to show authentically that in their molecules
the substituents at the atoms C3,4 are located in the
trans-position.
The spatial arrangement of obtained substances 15–
36 was subjected to XRD analysis by an example of
hydrazide 36 (Figs. 5, 6). Compound 36 crystallized as
racemate. Two asymmetric centers (atoms C3,4)
possess relative configurations 3R and 4S. The five-
membered ring possesses an envelope conformation, in
the molecule 36 the fragment С5N1С2С3 is planar
within 0.004 Å, the deviation of the atom С4 from this
plane is 0.561(2) Å. The distribution of bond lengths at
the atoms N1 and N16 indicates the conjugation of the
unshared electron pairs on nitrogen atoms and the С=О
bonds: bonds N1–C2 [1.3420(12) Å] and C15–N16
[1.3331(11) Å] are notably shortened as compared
with those in the acetanilide PhNHCOMe molecule
[1.43(1) Å] [23]. The substituents at the atoms C3,4 are
located on different sides of the plane of the lactam
ring: torsion angle C15C3C4C6 77.5(1)°, respectively,
protons at these atoms have a transoid location. The
carbonyl oxygen atom and the substituent NHC6H5 of
the hydrazide fragment are situated practically in the
same plane with respect to the amide bond C15–N16:
torsion angle is O15C15N16N17 4.05(14)° corresponding
to the Z-conformation. The crystals of compound 36
are stabilized with intermolecular hydrogen bonds
N1H···O15, N16H···N7 forming a three-dimensional
scaffold. A solvate molecule of ethanol is present in
the crystal and forms a hydrogen bond C2H5OH···O15
(Fig. 6).
The XRD experiment for compound 36 was
performed on a diffractometer Bruker Kappa Apex II
Duo (MoKα, λ 0.71073 Å) using programs of data
collection and processing APEX2 [24]. The extinction
was taken into consideration applying the program
package SADABS [25]. The solving and refining of
the structure using the least squares method was
carried out by SHELXS program [26] implemented in
OLEX2 software [27]. The positions and thermal
parameters of nonhydrogen atoms were refined in an
anisotropic approximation. The positions of hydrogen
atoms were revealed from the difference electron
density, the thermal parameters of hydrogen atom were
refined in the rider model. The crystallographic
parameters of the structure refinement of compound 36
at 150(2) K are as follows: C19H19N5O2·C2H5OH,
crystal size 0.24 × 0.17 × 0.11 mm3, M 395.46, tricli-
nic crystal system, space group P1, a 9.9831(18), b
10.7902(19), c 11.233(2) Å; β 63.943(3), γ 69.852(4)°;
V 1012.8(3) Å3, Z 2, dcalc 1.297 g/cm3, μ 0.089 mm–1.
Measured reflections 19065, independent reflections
5798 (Rint 0.0598), observed reflections with |Fo| ≥ 4σF
5037, R1 0.0401, wR2 0.1121, parameter of refinement
1.055. Maximum unaccounted electron density –0.230,
0.382 e/Å3. The complete information on the studied
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 11 2016

HYDRAZIDES OF 4-ARYL(HETARYL)-2-OXOPYRROLIDINE-3-CARBOXYLIC ACIDS:...
1621
structure is deposited in the Cambridge
Crystallographic Data Center (CCDC 1476906).
NH2), 1693, 1664 (С=О, CON). 1Н NMR spectrum, δ,
3
2
ppm: 3.24 t (1H, H5', J4,5' 9.2, J5',5'' 9.2 Hz), 3.30 d
3
3
2
(1H, H3, J3,4 10.1 Hz), 3.69 t (1H, H5'', J4,5'' 8.6, J5',5''
2-Oxo-4-phenylpyrrolidine-3-carbocylic acid
hydrazide (15). A solution of 1.2 g (6 mmol) of ester
1 in 2.33 mL of hydrazine hydrate was stirred for 20 h
at 18–20°C. The separated crystalline precipitate was
filtered off and dried. Yield 1.09 g (83%), mp 114–
116°С (from methanol) {120°С (from methanol)
[16]}. IR spectrum, ν, cm–1: 3480–3258 (NH, NH2),
9.2 Hz), 4.11 q (1H, H4, J3,4 10.1, J4,5' 9.2, J4,5''
3
3
3
8.6 Hz), 4.24 d (2H, NH2, 3JNH–NH 3.4 Hz), 6.94–7.46 m
(5Hindole), 7.95 s (1H, N1H), 9.18 d (1H, N6H, JNH–NH
3
3.4 Hz), 10.90 s (1H, NHindole). Found, %: N 21.96,
21.80. C13H14N4O2. Calculated, %: N 21.69.
4-(1-Methylindol-3-yl)-2-oxopyrrolidine-3-car-
boxylic acid hydrazide (20). Yield 83%, mp 190–
192°С (from methanol). IR spectrum, ν, cm–1: 3447–
1
1708, 1670 (С=О, CON). Н NMR spectrum, δ, ppm:
3.16 t (1H, H5', 3J4,5' 9.1, 2J5',5'' 9.1 Hz), 3.26 d (1H, H3,
1
3
2
3J3,4 10.4 Hz), 3.59 t (1H, H5'', J4,5'' 9.1, J5',5'' 9.1 Hz),
3.89 q (1H, H4, 3J3,4 10.4, 3J4,5' 9.1, 3J4,5'' 9.1 Hz), 4.26 s
(2H, NH2), 7.18–7.30 m (5Harom), 7.96 s (1H, N1H),
9.18 s (1H, N6H). Found, %: N 19.41, 19.42.
C11H13N3O2. Calculated, %: N 19.17.
3131 (NH, NH2), 1712, 1662 (С=О, CON). Н NMR
3
2
spectrum, δ, ppm: 3.24 t (1H, H5', J4,5' 9.1, J5',5''
9.1 Hz), 3.26 d (1H, H3, 3J3,4 10.4 Hz), 3.66 t (1H, H5'',
3J4,5'' 9.1, 2J5',5'' 9.1 Hz), 3.69 s (NCH3), 4.11 q (1H, H4,
3
3
3J3,4 10.4, J4,5' 9.1, J4,5'' 9.1 Hz), 4.23 s (2H, NH2),
6.98–7.47 m (5Hindole), 7.95 s (1H, N1H), 9.15 s (1H,
N6H). 13С{1H} NMR spectrum, δ, ppm: 32.87 (CH3),
36.00 (C4), 46.81 (C5), 54.15 (C3), 168.72 (C6), 173.66
(C2); 110.27, 114.03, 119.29, 119.50, 121.89, 126.77,
127.11, 137.43 (Carom). Found, %: N 18.31, 18.28.
C14H16N4O2·2Н2О. Calculated, %: N 18.17.
Esters 16, 17, 19–22, and 26 were obtained
similarly.
4-(4-Methoxyphenyl)-2-oxopyrrolidine-3-carbo-
xylic acid hydrazide (16). Yield 71%, mp 174–176°С
(from methanol). IR spectrum, ν, cm–1: 3332–3119
1
(NH, NH2), 1715, 1656 (С=О, CON). Н NMR spec-
4-(1-Benzylindol-3-yl)-2-oxopyrrolidine-3-carbo-
xylic acid hydrazide (21). Yield 69%, mp 233–235°С
(from methanol). IR spectrum, ν, cm–1: 3333–3126
(NH, NH2), 1706, 1664 (С=О, CON). 1Н NMR
spectrum, δ, ppm: 3.29 t (1H, H5', 3J4,5' 9.1, 2J5',5'' 9.1 Hz),
3.27 d (1H, H3, 3J3,4 10.0 Hz), 3.69 t (1H, H5'', 3J4,5'' 9.1,
3
2
trum, δ, ppm: 3.11 t (1H, H5', J4,5' 9.3, J5',5'' 9.3 Hz),
3.20 d (1H, H3, 3J3,4 10.4 Hz), 3.52 t (1H, H5'', 3J4,5'' 8.5,
2J5',5'' 9.3 Hz), 3.68 s (3H, OCH3), 3.83 q (1H, H4, J3,4
3
3
3
10.4, J4,5' 9.3, J4,5'' 8.5 Hz), 4.25 s (2H, NH2), 6.84–
7.15 m (4Harom), 7.92 s (1H, N1H), 9.15 s (1H, N6H).
Found, %: C 57.88, 57.90; H 5.93, 5.96; N 17.00,
17.02. C12H15N3O3. Calculated, %: C 57.82; H 6.07; N
16.86.
3
2J5',5'' 9.1 Hz), 4.13 q (1H, H4, J3,4 10.0, 3J4,5' 9.1, 3J42,5''
9.1 Hz), 4.25 s (2H, NH22), 5.29 d (1H, CH2, J
16.8 Hz), 5.35 d (1H, CH2, J 16.8 Hz), 6.95–7.52 m
(5Hindole), 7.97 s (1H, N1H), 9.16 s (1H, N6H). Found,
%: С 69.11, 69.02; Н 5.64, 5.68; N 15.93, 15.96.
C20H22N4O2. Calculated, %: C 68.95; H 5.79; N 16.08.
4-(4-Methylphenyl)-2-oxopyrrolidine-3-carbo-
xylic acid hydrazide (17). Yield 84%, mp 185–187°С
(from methanol). IR spectrum, ν, cm–1: 3448–3149
(NH, NH2), 1710, 1666 (С=О, CON). 1Н NMR
spectrum, δ, ppm: 2.22 s (3H, CH3), 3.13 t (1H, H5',
4-(2-Methylindol-3-yl)-2-oxopyrrolidine-3-
carboxylic acid hydrazide (22). Yield 63%, mp 99–
101°С (from methanol). IR spectrum, ν, cm–1: 3354–
2
3
3J4,5' 9.3, J5',5'' 9.3 Hz), 3.22 d (1H, H3, J3,4 10.4 Hz),
3.56 t (1H, H5'', 3J4,5'' 8.4, 2J5',5'' 9.3 Hz), 3.84 q (1H, H4,
1
3114 (NH, NH2), 1699, 1673 (С=О, CON). Н NMR
3J3,4 10.4, J4,5' 9.3, J4,5'' 8.4 Hz), 4.25 s (2H, NH2),
7.07–7.12 m (4Harom), 7.92 s (1H, N1H), 9.18 s (1H,
N6H). 13С{1H} NMR spectrum, δ, ppm: 21.12 (CH3),
43.66 (C4), 47.40 (C5), 54.13 (C3), 168.26 (C6), 173.39
(C2); 127.61, 129.63, 136.53, 138.15 (Carom). Found,
%: C 57.44, 57.46; H 6.56, 6.55; N 16.64, 16.32.
C12H15N3O2·Н2О. Calculated, %: C 57.36; H 6.82; N
16.72.
3
3
spectrum, δ, ppm: 2.26 s (3H, СH3), 3.31 m (1H, H5'),
3
3.42 d (1H, H3, J3,4 10.1 Hz), 3.46 m (1H, H5''), 4.15
m (1H, H4, 3J3,4 10.1 Hz), 4.18 s (2H, NH2), 6.89–7.41
m (4Hindole), 8.00 s (1H, N1H), 9.03 s (1H, N6H), 10.79
s (1H, NHindole). Found, %: С 61.25, 61.18; Н 5.71,
5.75; N 20.31, 20.19. C14H16N4O2. Calculated, %: C
61.75; H 5.92; N 20.58.
2-Oxo-4-(furan-2-yl)pyrrolidine-3-carboxylic
acid hydrazide (26). Yield 70%, mp 146–148°С (from
methanol). IR spectrum, ν, cm–1: 3328–3289 (NH,
NH2), 1695, 1658 (С=О, CON). 1Н NMR spectrum, δ,
4-(Indol-3-yl)-2-oxopyrrolidine-3-carboxylic acid
hydrazide (19). Yield 61%, mp 87–89°С (from
methanol). IR spectrum, ν, cm–1: 3391–3118 (NH,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 11 2016

GORODNICHEVA et al.
ppm: 3.26 t (1H, H5', J4,5' 9.1, J5',5'' 9.1 Hz), 3.36 d
1622
3
2
2-Oxo-4-(pyridin-3-yl)pyrrolidine-3-carboxylic
acid hydrazide (25). Yield 60%, mp 154–156°С (from
methanol). IR spectrum, ν, cm–1: 3205–3133 (NH,
NH2), 1707, 1671 (С=О, CON). 1Н NMR spectrum, δ,
ppm: 3.20 t (1H, H5', 3J4,5' 9.3, 2J5',5'' 9.3 Hz), 3.30 d (1H,
H3, 3J3,4 10.4 Hz), 3.63 t (1H, H5'', 3J4,5'' 8.4, 2J5',5'' 9.3 Hz),
3.94 q (1H, H4, 3J3,4 10.4, 3J4,5' 9.3, 3J4,5'' 8.4 Hz), 4.32 s
(2H, NH2), 7.22–7.34 m (4HPy), 7.99 s (1H, N1H), 9.21
s (1H, N6H). Found, %: N 25.28, 25.19. C10H12N4O2.
Calculated, %: N 25.46.
(1H, H3, J3,4 9.6 Hz), 3.61 t (1H, H5'', J4,5'' 8.6, J5',5''
3
3
2
9.1 Hz), 3.98 q (1H, H4, J3,4 9.6, J4,5' 9.1, J4,5''
8.6 Hz), 4.33 s (2H, NH2), 6.24 m (1HFu), 6.39 m
(1HFu), 7.58 m (1HFu), 8.01 s (1H, N1H), 9.27 s (1H,
N6H). Found, %: С 51.63, 51.76; Н 5.29, 5.34; N
20.21, 20.19. C9H11N4O3. Calculated, %: C 51.68; H
5.26; N 20.10.
3
3
3
2-Oxo-4-(4-chlorophenyl)pyrrolidine-3-carbo-
xylic acid hydrazide (18). A solution of 1.52 g
(6 mmol) of reagent 4 in 2.33 mL of hydrazine hydrate
was stirred for 2 h at 95°С and 20 h at 18–20°C. The
separated crystals were filtered off and dried. Yield
0.94 g (62%), mp 193–196°С (from methanol). IR
spectrum, ν, cm–1: 3349–3243 (NH, NH2), 1731, 1657
4-(1-Methylbenzimidazol-2-yl)-2-oxopyrrolidine-
3-carboxylic acid hydrazide (27). Yield 61%, mp
223–225°С (from methanol). IR spectrum, ν, cm–1:
1
3360–3315 (NH, NH2), 1702, 1644 (С=О, CON). Н
NMR spectrum, δ, ppm: 3.38 t (1H, H5', 3J4,5' 9.0, 2J5',5''
3
9.0 Hz), 3.69 d (1H, H3, J3,4 8.9 Hz), 3.53 t (1H, H5'',
1
(С=О, CON). Н NMR spectrum, δ, ppm: 3.15 t (1H,
3J4,5'' 9.0, 2J5',5'' 9.0 Hz), 3.75 s (3H, NCH3), 4.37 q (1H,
H5', J4,5' 9.3, J5',5'' 9.3 Hz), 3.23 d (1H, H3, J3,4
3
2
3
3
3
3
H4, J3,4 8.9, J4,5' 9.0, J4,5'' 9.0 Hz), 4.36 s (2H, NH2),
7.21–7.59 m (4H, Hbenzimidazole), 7.92 s (1H, N1H), 9.34
s (1H, N6H). Found, %: C 57.01, 56.91; H 5.61, 5.58;
N 25.60, 25.53. C13H15N5O2. Calculated, %: C 57.14;
H 5.50; N 25.64.
10.4 Hz), 3.58 t (1H, H5'', J4,5'' 8.5, 2J5',5'' 9.3 Hz), 3.89
3
q (1H, H4, 3J3,4 10.4, 3J4,5' 9.3, 3J4,5'' 8.5 Hz), 4.26 s (2H,
NH2), 7.27–7.35 m (4Harom), 7.96 s (1H, N1H), 9.16 s
(1H, N6H). Found, %: C 52.23, 52.11; H 4.59, 4.66; N
16.76, 16.63. C11H12ClN3O2. Calculated, %: C 52.08;
H 4.77; N 16.56.
4-(1-Methylbenzimidazol-2-yl)-2-oxo-5-phenyl-
pyrrolidine-3-carboxylic acid hydrazide (28). Yield
59%, mp 230–232°С (from methanol). IR spectrum, ν,
cm–1: 3325–3237 (NH, NH2), 1703, 1644 (С=О,
Hydrazides 23–25, 27, and 28 were obtained
similarly.
1
CON). Н NMR spectrum, δ, ppm: 5.31 d (1H, H5',
4-(1,2-Dimethylindole-3-yl)-2-oxo-pyrrolidine-3-
carboxylic acid hydrazide (23). Yield 68%, mp 215–
219°С (from methanol). IR spectrum, ν, cm–1: 3427–
3
3J4,5' 8.6 Hz), 4.31 d (1H, H3, J3,4 9.1 Hz), 3.70 s (3H,
3
3
NCH3), 4.70 t (1H, H4, J3,4 9.1, J4,5' 8.6 Hz), 4.95 s
1
3121 (NH, NH2), 1692, 1660 (С=О, CON). Н NMR
(2H, NH2), 6.97–7.02 (5Harom), 7.08–7.35
m
spectrum, δ, ppm: 2.29 s (3H, CH3), 3.45 m (1H, H5'),
(4Hbenzimidazole), 8.59 s (1H, N1H), 9.63 s (1H, N6H).
Found, %: C 65.07, 65.11; H 5.51, 5.51; N 20.15,
20.21. C19H19N5O2. Calculated, %: C 65.33; H 5.44; N
20.06.
3.47 d (1H, H3, J3,4 9.2 Hz), 3.47 m (1H, H5''), 3.59 s
3
(NCH3), 4.22 m (1H, H4, J3,4 9.2 Hz), 4.19 s (2H,
3
NH2), 6.95–7.39 m (4Hindole), 8.01 s (1H, N1H), 9.03 s
(1H, N6H). Found, %: С 62.58, 62.83; Н 6.17, 6.23; N
19.71, 19.83. C15H18N4O2. Calculated, %: C 62.92; H
6.34; N 19.57.
2-Oxo-4-phenylpyrrolidine-3-carboxylic acid
phenylhydrazide (29). A solution of 1.2 g (6 mmol)
of ester
1
in 4.72 mL of freshly distilled
4-(1-Benzyl-2-methylindole-3-yl)-2-oxopyrro-
lidine-3-carboxylic acid hydrazide (24). Yield 74%,
mp 199–204°С (from methanol). IR spectrum, ν, cm–1:
phenylhydrazine was stirred for 10 min at heating on a
glycerol bath (170°С), cooled to 18–20°C, and was
stirred for 20 h. The separated crystals were filtered off
and dried. Yield 0.96 g (54%), mp 200–202°С (from
methanol). IR spectrum, ν, cm–1: 3301–3136 (NH,
NH2), 1701, 1663 (С=О, CON). 1Н NMR spectrum, δ,
1
3322–3241 (NH, NH2), 1704, 1650 (С=О, CON). Н
NMR spectrum, δ, ppm: 2.25 s (3H, CH3), 3.50 m (1H,
3
H5'), 3.46 d (1H, H3, J3,4 9.8 Hz), 3.50 m (1H, H5''),
4.22 m (1H, H4, 3J3,4 9.8 Hz), 4.19 d (2H, NH2, 3JNH–NH
3
2
ppm: 3.26 t (1H, H5', J4,5' 10.3, J5',5'' 10.3 Hz), 3.45 d
2
3
3
2
(1H, H3, J3,4 10.7 Hz), 3.61 t (1H, H5'', J4,5'' 8.4, J5',5''
2.6 Hz), 5.32 d (1H, CH2, J 17.1 Hz), 5.38 d (1H,
2
10.3 Hz), 3.93 q (1H, H4, J3,4 10.7, J4,5' 10.3, J4,5''
3
3
3
CH2, J 17.1 Hz), 6.94–7.43 m (4Hindole.), 8.02 s (1H,
3
N1H), 9.04 d (1H, N6H, JNH–NH 2.6 Hz). Found, %: C
8.4 Hz), 6.61–7.04 m (5Harom), 7.25–7.35 m (5Harom),
3
7.80 d (1H, N7H, JNH–NH 2.6 Hz), 8.03 s (1H, N1H),
69.70, 69.78; H 6.14, 6.13; N 15.31, 15.36.
C21H22N4O2. Calculated, %: C 69.61; H 6.08; N 15.47.
3
9.77 d (1H, N6H, JNH–NH 2.6 Hz). Found, %: С 68.98,
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HYDRAZIDES OF 4-ARYL(HETARYL)-2-OXOPYRROLIDINE-3-CARBOXYLIC ACIDS:...
1623
69.03; Н 5.59, 5.61; N 14.36, 14.39. C17H17N3O2.
Calculated, %: C 69.14; H 5.80; N 14.23.
mp 220–224°С (from methanol). IR spectrum, ν, cm–1:
3309–3264 (NH, NH2), 1690, 1660 (С=О, CON). Н
1
NMR spectrum, δ, ppm: 2.28 s (3H, CH3), 3.49 m (1H,
Hydrazides 30–36 were obtained similarly.
3
H5'), 3.63 d (1H, H3, J3,4 9.8 Hz), 3.51 m (1H, H5''),
3.63 s (3H, NCH3), 4.21 q (1H, H4, 3J3,4 9.8 Hz), 6.63–
4-(4-Methoxyphenyl)-2-oxopyrrolidine-3-carbo-
xylic acid phenylhydrazide (30). Yield 70%, mp 210°С
(from methanol). IR spectrum, ν, cm–1: 3301–3136
7.05 m (5Harom), 6.98–7.44 m (4Hindole), 7.71 d (1H,
3
N7H, JNH–NH 2.1 Hz), 8.08 s (1H, N1H), 9.61 d (1H,
1
3
N6H, JNH–NH 2.1 Hz). Found, %: С 69.51, 69.38; Н
(NH, NH2), 1701, 1663 (С=О, CON). Н NMR spec-
3
2
trum, δ, ppm: 3.22 t (1H, H5', J4,5' 9.3, J5',5'' 9.3 Hz),
5.98, 5.95; N 15.46, 15.36. C21H22N4O2. Calculated,
%: C 69.59; H 6.12; N 15.46.
3.38 d (1H, H3, 3J3,4 10.7 Hz), 3.56 t (1H, H5'', 3J4,5'' 8.4,
2J5',5'' 9.3 Hz), 3.71 s (3H, OCH3), 3.86 q (1H, H4, J3,4
3
4-(Pyridin-3-yl)-2-oxopyrrolidine-3-carboxylic
acid phenylhydrazide (34). Yield 43%, mp 188–190°С
(from methanol). IR spectrum, ν, cm–1: 3301–3134
10.7, 3J4,5' 9.3, 3J4,5'' 8.4 Hz), 6.60–6.90 m (5Harom), 7.03–
7.20 m (4Harom), 7.79 d (1H, N7H, JNH–NH 2.4 Hz),
3
7.99 s(1H, N1H), 9.73 d (1H, N6H, JNH–NH 2.4 Hz).
3
1
(NH, NH2), 1700, 1663 (С=О, CON). Н NMR spec-
Found, %: С 66.77, 66.25; Н 5.73, 5.68; N 13.12,
13.05. C18H19N3O3. Calculated, %: C 66.45; H 5.89; N
12.91.
3
2
trum, δ, ppm: 3.30 t (1H, H5', J4,5' 9.3, J5',5'' 9.3 Hz),
3.48 d (1H, H3, 3J3,4 10.7 Hz), 3.65 t (1H, H5'', 3J4,5'' 8.5,
3
2J5',5'' 9.3 Hz), 3.97 q (1H, H4, J3,4 10.7, 3J4,5' 9.3, 3J4,5''
4-(4-Methylphenyl)-2-oxopyrrolidine-3-carbo-
xylic acid phenylhydrazide (31). Yield 77%, mp 240°С
(from methanol). IR spectrum, ν, cm–1: 3354–3130
(NH, NH2), 1700, 1658 (С=О, CON). 1Н NMR
spectrum, δ, ppm: 2.26 s (3H, CH3), 3.23 t (1H, H5',
8.5 Hz), 6.61–7.08 m (5Harom), 7.26–7.38 m (4HPy),
3
7.84 d (1H, N7H, JNH–NH 2.2 Hz), 8.08 s (1H, N1H),
3
9.81 d (1H, N6H, JNH–NH 2.2 Hz). 13С{1H} NMR
spectrum, δ, ppm: 44.15 (C4), 47.10 (C5), 54.36 (C3),
168.90 (C6), 173.02 (C2); 112.07, 112.70, 114.66,
118.82, 119.10, 119.39, 121.81, 122.52, 126.81,
129.02, 137.08, 149.37 (Carom). Found, %: С 64.91,
64.89; Н 5.42. C16H16N4O2. Calculated, %: C 64.87; H
5.41.
2
3
3J4,5' 9.3, J5',5'' 9.3 Hz), 3.40 d (1H, H3, J3,4 10.7 Hz),
3.58 t (1H, H5'', 3J4,5'' 8.4, 2J5',5'' 9.3 Hz), 3.88 q (1H, H4,
3J3,4 10.7, 3J4,5' 9.3, 3J4,5'' 8.4 Hz), 6.61–7.04 m (5Harom),
7.12–7.18 m (4Harom), 7.79 d (1H, N7H, 3JNH–NH 2.4 Hz),
3
8.01 s (1H, N1H), 9.75 d (1H, N6H, JNH–NH 2.4 Hz).
2-Oxo-4-(furan-2-yl)pyrrolidine-3-carboxylic
acid phenylhydrazide (35). Yield 70%, mp 174–175°С
(from methanol). IR spectrum, ν, cm–1: 3235–3114
Found, %: С 70.06, 69.93; Н 5.63, 5.96; N 13.77,
13.78. C18H19N3O2. Calculated, %: C 69.88; H 6.19; N
13.58.
1
(NH, NH2), 1718, 1655 (С=О, CON). Н NMR spec-
3
2
trum, δ, ppm: 3.31 t (1H, H5', J4,5' 9.2, J5',5'' 9.2 Hz),
4-(Indol-3-yl)-2-oxopyrrolidine-3-carboxylic acid
phenylhydrazide (32). Yield 36%, mp 241–242°С
(from methanol). IR spectrum, ν, cm–1: 3424–3205
3.45 d (1H, H3, 3J3,4 10.0 Hz), 3.63 t (1H, H5'', 3J4,5'' 8.7,
3
2J5',5'' 9.2 Hz), 4.03 q (1H, H4, J3,4 10.0, 3J4,5' 9.2, 3J4,5''
1
(NH, NH2), 1719, 1651 (С=О, CON). Н NMR spec-
8.7 Hz), 6.64–7.15 m (5Harom), 6.30 m (1HFu), 6.44 m
3
2
trum, δ, ppm: 3.33 t (1H, H5', J4,5' 9.1, J5',5'' 9.1 Hz),
3
(1HFu), 7.63 m (1HFu), 7.90 d (1H, N7H, JNH–NH
3.48 d (1H, H3, 3J3,4 10.2 Hz), 3.69 t (1H, H5'', 3J4,5'' 9.1,
3
2.4 Hz), 8.10 s (1H, N1H), 9.89 d (1H, N6H, JNH–NH
3
2J5',5'' 9.1 Hz), 4.16 q (1H, H4, J3,4 10.2, 3J4,5' 9.1, 3J4,5''
2.4 Hz). Found, %: С 63.04, 63.28; Н 5.34, 5.37; N
14.70, 14.82. C15H15N3O3. Calculated, %: C 63.16; H
5.26; N 14.74.
9.1 Hz), 6.61–6.99 m (5Harom), 6.97–7.51 m (5H,
3
H
indole), 7.77 d (1H, N7H, JNH–NH 1.8 Hz), 8.02 s (1H,
N1H), 9.74 d (1H, N6H, JNH–NH 1.8 Hz), 10.96 s (1H,
NHindole). 13С{1H} NMR spectrum, δ, ppm: 36.00 (C4),
46.87 (C5), 54.32 (C3), 169.44 (C6), 173.49 (C2);
112.07, 112.70, 114.66, 118.82, 119.10, 119.39,
121.81, 122.52, 126.81, 129.02, 137.08, 149.37
(Carom). Found, %: С 68.11, 68.09; Н 5.23, 5.24; N
16.73, 16.81. C19H18N4O2. Calculated, %: C 68.25; H
5.43; N 16.76.
3
4-(1-Methylbenzimidazol-2-yl)-2-oxopyrrolidine-
3-carboxylic acid phenylhydrazide (36). Yield 62%,
mp 242–244°С (from ethanol). IR spectrum, ν, cm–1:
1
3270–3185 (NH, NH2), 1712, 1662 (С=О, CON). Н
NMR spectrum, δ, ppm: 3.52 t (1H, H5', 3J4,5' 8.8, 2J5',5''
3
8.8 Hz), 3.76 s (3H, CH3), 3.94 d (1H, H3, J3,4
9.2 Hz), 3.83 t (1H, H5'', 3J4,53'' 8.8, 2J5',5'' 8.8 Hz), 4.40 q
3
3
(1H, H4, J3,4 9.2, J4,5' 8.8, J4,5'' 8.8 Hz), 6.61–7.09 m
4-(1,2-Dimethylindol-3-yl)-2-oxopyrrolidine-3-
carboxylic acid phenylhydrazide (33). Yield 32%,
(5Harom), 7.24–7.63 m (4H, Hbenzimidazole), 7.84 d (1H,
3
N7H, JNH–NH 2.1 Hz), 8.17 s (1H, N1H), 9.96 d (1H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 11 2016

GORODNICHEVA et al.
1624
3
N6H, JNH–NH 2.1 Hz). 13С{1H} NMR spectrum, δ,
ppm: 30.15 (CH3), 35.92 (C4), 45.06 (C5), 52.62 (C3),
168.43 (C6), 172.36 (C2); 110.66, 112.69, 118.96,
119.16, 122.20, 122.63, 129.11, 136.62, 142.38,
149.39, 154.62 (Carom). Found, %: С 65.24, 65.09; Н
5.52, 5.51; N 19.98, 19.93. C19H19N5O2. Calculated,
%: C 65.33; H 5.44; N 20.06.
va, V.V., RF Patent no. 2437659, 2010; Chem. Abstr.,
2012, vol. 156, no. 92452.
11. Berestovitskaya, V.M., Vasileva, O.S., Petrov, V.I.,
Tjurenkov, I.N., Bagmetova, V.V., and Ostroglyadov, E.S.,
RF Patent no. 2440981, 2010; Chem. Abstr., 2012, vol. 156,
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The study was carried out under the financial
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