2-[4-(Het)aryl-2-oxopyrrolidin-1-yl]acetohydrazides: synthesis, structures, and reactions with carbonyl compounds

Article abstract of DOI:10.1007/s11172-020-2861-0

2-[4-(Het)aryl-2-oxopyrrolidin-1-yl]acetohydrazides, structural analogs of piracetam, were synthesized by the condensation of 2-[4-(het)aryl-2-oxopyrrolidin-1-yl]acetates with hydrazine hydrate and phenylhydrazine. New [N′-alkyl(hetaryl)idene]-4-(het)aryl-2-oxopyrrolidin-1-ylacetohydrazides were synthesized by the reaction of 2-[4-(het)aryl-2-oxopyrrolidin-1-yl]-acetohydrazides with aromatic aldehydes, acetone, and acetophenone.

Full text of DOI:10.1007/s11172-020-2861-0

Russian Chemical Bulletin, International Edition, Vol. 69, No. 5, pp. 996—1008, May, 2020
996
2-[4-(Het)aryl-2-oxopyrrolidin-1-yl]acetohydrazides:
synthesis, structures, and reactions with carbonyl compounds
N. V. Gorodnicheva,a O. S. Vasil´eva,a E. S. Ostroglyadov,a R. I. Baichurin,a S. V. Makarenko,a
F. A. Karamov,b O. A. Lodochnikova,c and I. A. Litvinovb,c
аHerzen State Pedagogical University of Russia,
48 nab. Moika, 191186 St. Petersburg, Russian Federation.
E-mail: kohrgpu@yandex.ru
bKazan National Research Technological University named after A. N. Tupolev (KAI),
10 ul. K. Marksa, 420111 Kazan, Russian Federation
cA. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of the Russian Academy of Sciences,
8 ul. Akad. Arbuzova, 420088 Kazan, Russian Federation.
E-mail: litvinov@iopc.ru
2-[4-(Het)aryl-2-oxopyrrolidin-1-yl]acetohydrazides, structural analogs of piracetam, were
synthesized by the condensation of 2-[4-(het)aryl-2-oxopyrrolidin-1-yl]acetates with hydrazine
hydrate and phenylhydrazine. New [N´-alkyl(hetaryl)idene]-4-(het)aryl-2-oxopyrrolidin-1-
ylacetohydrazides were synthesized by the reaction of 2-[4-(het)aryl-2-oxopyrrolidin-1-yl]-
acetohydrazides with aromatic aldehydes, acetone, and acetophenone.
Key words: racetams, 2-pyrrolidone, 2-pyrrolidonecarbohydrazides, hydrazides, hydrazones,
rotamers, molecular structure, X-ray diffraction.
1-Carbamoylmethyl-2-pyrrolidone (piracetam) and
its structural analogs, which are active substances of
racetams marketed as nootropic drugs, are the most well-
known 2-pyrrolidone derivatives.1—4
idene moieties, apart from hetaryl substituents on the
lactam ring, is of great interest. 1-Alkoxycarbonylmethyl-
4-(het)aryl-2-pyrrolidones are convenient precursors in
the synthesis of these compounds because their hydr-
azinolysis and reactions of acetohydrazides with carbonyl
compounds provide an approach to the synthesis of new
piracetam analogs, [4-(het)aryl-2-oxopyrrolidin-1-yl]-
acetohydrazides and N´-alkyl(hetaryl)idene carbohydr-
azides. An analysis of the literature11—14 shows that the
data on the methods for the synthesis and properties of
(2-oxopyrrolidin-1-yl)acetohydrazides are scarce and
mainly concern the procedures for the preparation of new
piracetam derivatives.
This study is a continuation of our research on the
development of efficient methods for the synthesis of new
pharmacologically active substances of a series of structur-
ally modified piracetam analogs containing both the lactam
ring and carbohydrazide moieties.15,16 Here we studied
the reactions of ethyl 2-[4-(het)aryl-2-oxopyrrolidin-1-
yl]acetates 1a—i with hydrazine hydrate and phenyl-
hydrazine. Compounds 1a—i were synthesized by a pro-
cedure reported previously.17
Pharmacological properties and applications of more
than a dozen piracetam-like racetams containing an
acetamide moiety, e.g., phenotropil (phenylpiracetam,
carphedon), oxiracetam, levetiracetam, etc., were studied
in detail. It is worth noting that the nature of substitu-
ents in the acetamide moiety has a great effect on the
character and degree of the pharmacological activity
of these compounds.5 For example, piracetam is used
as a nootropic drug; its analog levetiracetam [(S)-(2-
oxopyrrolidin-1-yl)butanamide] is an antiepileptic drug;6,7
the replacement of the amide group in the carphe-
don molecule (the phenyl analog of piracetam) by the
carbazoyl group results in the appearance of strong antide-
pressant and anxiolytic activity, apart from nootropic
properties.8
Active substances of a number of pain-relieving, anti-
pyretic, antibacterial, and other medications contain, apart
from heterocycles, hydrazide functions or alkyl(hetaryl)-
idene moieties. For example, isonicotinic acid hydrazide
(isoniazid) and its derivatives (phthivazid, saluzid) are
known antituberculosis drugs.2,9,10
It was shown that the reactions of esters 1a—i with
hydrazine hydrate under rather mild conditions (the stor-
age of the reaction mixture at 18—20 C for 20 h) proceed
smoothly to produce the corresponding carbohydrazides
2a—i in good yields (40—90%); hydrazide 2a was charac-
terized previously8,11 (Scheme 1).
Therefore, the synthesis of analogs of piracetam-like
racetams, which are promising biologically active sub-
stances containing carbohydrazide functions or alkyl(aryl)-
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 0996—1008, May, 2020.
1066-5285/20/6905-0996 © 2020 Springer Science+Business Media LLC

Pyrrolidone acetohydrazides
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 5, May, 2020
997
Scheme 1
Thus, the reactions of compounds 2a,c,d with 3-pyri-
dinecarbaldehyde, benzaldehyde and its 4-chloro- and
4-methoxy-substituted derivatives performed on heating
under reflux in ethanol over 10 min produced the corre-
sponding N´-(het)arylmethylideneacetohydrazides 4a—l
in good yields (up to 89%). Meanwhile, the reactions of
compounds 2a,c,d with acetone required more severe
conditions. The reactions of these compounds were carried
out under reflux in an excess of acetone (1 : 30) for 1 h to
prepare N´-isopropylideneacetohydrazides 5a—c in yields
of up to 85%.
The reactions of hydrazides 2a,c,d with acetophenone
were investigated to optimize the reaction conditions. The
heating of carbohydrazides 2a,c,d with an equimolar
amount of acetophenone in ethanol under reflux for 3 h
resulted in the formation of [N´-(1-phenylethylidene)]-
acetohydrazides 6a,b in 69—71% yields only in the reac-
tions with carbohydrazides 2a,c, respectively (method A).
The reaction of hydrazide 2d with acetophenone required
an increase in the time of refluxing up to 9 h (method B)
and produced compound 6c in 65% yield (Scheme 2).
All synthesized compounds 2—6 are stable colorless
crystalline solids with distinct melting points. Their struc-
tures were confirmed by IR spectroscopy, 1H and 13C{1H}
NMR spectroscopy, 1H—13C HMQC, 1H—13C HMBC,
and 1H—1H NOESY experiments, and X-ray diffraction.
1, 2
a
R
Ph
1, 2
R
f
g
h
i
1-Bn-indol-3-yl
b
4-MeC6H4
4-ClC6H4
4-MeOC6H4
1-Me-indol-3-yl
1,2-(Me)2-indol-3-yl
1- R´C(O)CH2-indol-3-yl
1-R´C(O)CH2-2-Me-indol-3-yl
c
d
e
R´ = EtO (1h,i), H2NNH (2h,i)
3: R = 4-MeC6H4 (a), 4-ClC6H4 (b), 4-MeOC6H4 (c)
Reagents: i. H2NNH2•H2O; ii. H2NNHPh.
It should be noted that both ester groups of compounds
1h,i underwent hydrazinolysis giving dihydrazides 2h,i in
yields of up to 48%.
Scheme 2
NHNC(O)CH
C(O)NHNH
X = H (h), Me (i)
The reactions of esters 1b—d with phenylhydrazine
were accomplished under similar conditions to prepare
phenylhydrazides 3a—c. The reactions of indole-contain-
ing esters 1e—i with phenylhydrazine under these and
more severe conditions (heating at 170 C for 10 min,
heating under reflux for 4 h in p-xylene) did not bring
the success, as the expected phenylhydrazides were not
produced.
Compounds 2a—i and 3a—c are of interest as potential
biologically active compounds. Besides, hydrazides 2a—i
can be used in reactions with carbonyl compounds to
synthesize new piracetam analogs, [N´-alkyl(hetaryl)-
idene]-4-(het)aryl-2-oxopyrrolidin-1-ylacetohydrazides.
R = Ph (2a, 5a, 6a), 4-ClC6H4 (2c, 5b, 6b), 4-MeOC6H4 (2d, 5c, 6c)
4
a
b
c
d
e
f
R
Ph
Ph
Ph
Ph
R´
Ph
4
g
h
i
R
R´
4-ClC6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4 4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3-C5H4N
Ph
4-ClC6H4
4-MeOC6H4
3-C5H4N
Ph
j
4-ClC6H4
4-ClC6H4
4-ClC6H4
k
l
4-ClC6H4
3-C5H4N
Reagents: i. R´CHO, EtOH; ii. MeCOMe; iii. MeCOPh, EtOH.

Gorodnicheva et al.
998
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 5, May, 2020
Table 1. IR spectra* of compounds 2a—i and 3a—c
which indicates that they are diastereomerically pure
compounds (Tables 3 and 4). The 1H NMR spectra of
compounds 2a—i show proton signals of the pyrrolidone
ring, (het)aryl substituents, and the side chain along with
proton signals of the hydrazide moiety (see Table 3). It is
known that substituted amides can exist as (E´) or (Z´)
conformers due to hindered rotation about the (O)C—NH
bond. Generally, the conformation of these compounds
is determined from the chemical shifts of C=O carbon
atoms: δC  168 for the (Z´) conformer and δC  173 for
the (E´) conformer.15,18,19
Compound
IR, /cm–1
2a
3305 (NH); 3200 (NH2);
1670 br (C=O);
2b
2c
2d
2e
2f
3320 (NH); 3209 (NH2);
1680, 1651 (C=O)
3316 (NH); 3207 (NH2);
1680, 1647 (C=O)
3325 (NH); 3208 (NH2);
1680, 1652 (C=O)
3335 (NH); 3221 (NH2);
1709, 1647 (C=O);
The fact that the carbonyl carbon atom C(7) of hydra-
zides 2a—i gives signals at δ 167.44—167.63 is indicative
of the (Z´) conformation, i.e., the C=O oxygen atom and
the NH2 group are cis to the C—N bond.
3339 (NH); 3263 (NH2);
1672, 1655 (C=O)
2g
2h
2i
3302 (NH); 3278 (NH2);
1688, 1666 (C=O)
3301 (NH); 3119 (NH2);
1701, 1658 (C=O)
3384 (NH); 3210 (NH2);
1671, 1627 (C=O)
The assignment of the carbon signals of C(2)=O groups
of the lactam ring and the hydrazide function at the C(7)
atom of compounds 2a—i and the signals of hydrazide NH
1
protons was confirmed by H—13C HMBC experiments
for compounds 2a,c,d,f. Thus, the 1H—13C HMBC NMR
spectrum of compound 2d shows cross-peaks between the
C(3)H2 protons (δH 2.32, δH 2.61) and the C(4) (δC 36.50)
and C(2) atoms (δC 173.95), between the C(6)H2 (δH 3.78,
δH 3.83) and H(8) protons (δH 9.15) and the C(7) atom
(δC 167.48). Similar correlations are observed for the whole
series of compounds 2a,c,f. Since the 1H and 13C{1H}
NMR spectra of compounds 2a,c,d,f are in good agree-
ment with those of hydrazides 2a—i, it can be assumed
with a high degree of certainty that all these compounds
exist as (Z´) conformers in a solution in DMSO-d6.
It should be noted that there are differences in the
appearance the proton and carbon signals in the 1H
and 13C{1H} NMR spectra of compounds 3—6. Thus, the
1H and 13C{1H} NMR spectra of compounds 3—6 (see
3a
3b
3c
3232 (NH); 1684, 1662 (C=O)
3230 (NH); 1686, 1665 (C=O)
3300, 3244 (NH); 1689, 1665 (C=O)
* The IR spectra were recorded as KBr pellets.
The IR spectra of hydrazides 2a—i, phenylhydrazides
3a—c, and N´-alkyl(hetaryl)ideneacetohydrazides 4a—l,
5a—c, and 6a—c show stretching bands of all functional
groups (Tables 1 and 2). These characteristics have simi-
lar values and are in good agreement with each other (see
Tables 1 and 2).
The 1H and 13C{1H} NMR spectra of hydrazides 2a—i
contain one set of proton signals of all structural units,
Table 2. IR spectra* of compounds 4a—l, 5a—c, and 6a—c
Com-
pound
IR, /cm–1
Com-
pound
IR, /cm–1
Com-
pound
IR, /cm–1
4a
4b
4c
4d
4e
4f
3205, 3112 (NH); 1698, 1661
br (C=O, C=N**)
3213, 3129 (NH); 1698, 1659
br (C=O, C=N**)
3198, 3132 (NH); 1694, 1675
br (C=O, C=N**)
3205, 3090 (NH); 1699, 1666
(C=O); 1647 (C=N)
3205, 3105 (NH); 1697, 1666
br (C=O, C=N**)
3213, 3105 (NH); 1701, 1662
br (C=O, C=N**)
5a
5b
5c
6a
6b
6c
3332, 3209, 3062 (NH); 1700, 1675
br (C=O, C=N**)
3433, 3213, 3051 (NH); 1697, 1674
br (C=O, C=N**)
3437, 3208, 3108 (NH); 1689, 1672
br (C=O, C=N**)
3446, 3194, 3086 (NH); 1692, 1674
br (C=O, C=N**)
3436, 3190, 3085 (NH); 1690, 1672
br (C=O, C=N**)
3436, 3211, 3087 (NH); 1695 br
(C=O, C=N**)
4g
4h
4i
3201, 3101 (NH); 1697, 1662
br (C=O, C=N**)
3468, 3212, 3128 (NH);
1701 br (C=O, C=N**)
3180, 3060 (NH); 1693, 1672
br (C=O, C=N**)
3443, 3214, 3152 (NH); 1698,
1667 (C=O); 1658 (C=N)
3205, 3119 (NH); 1696, 1666
(C=O); 1649 (C=N)
3189, 3062 (NH); 1689, 1675 br
(C=O, C=N**)
4j
4k
4l
* The IR spectra were recorded as KBr pellets.
** In the IR spectra of compounds 4a—c, 4e—i, 4l, 5a—c, and 6a—c, a broadened absorption band with a maximum at 1701—1655 cm–1
is due to overlapping of absorption bands of the lactam carbonyl group and the C=N bond.

Pyrrolidone acetohydrazides
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 5, May, 2020
999
Table 3. 1H NMR spectra* of compounds 2a—i and 3a—c
Com-
pound
 (J/Hz)
R;
[Ph]
H´(3) (dd),
H(3) (dd)
H(4) (m) H´(5) (m),
H´(6) (d), H(6) (d)
H(8) (s)
[H(9) (s)]
H(5) (m)
[NCH2]
2a
2b
2c
2d
2e
2f
7.20—7.30 (m)
2.36 (1 H, J = 8.7,
J = 16.4);
2.66 (1 H, J = 9.0,
J = 16.4)
2.33 ( 1 H, J = 8.7,
J = 16.4);
2.62 (1 H, J = 8.9,
J = 16.4)
2.34 (1 H, J = 8.5,
J = 16.5);
2.66 (1 H, J = 8.9,
J = 16.5)
2.32 (1 H, J = 8.9,
J = 16.4);
2.61 (1 H, J = 9.0,
J = 16.4)
2.43 (1 H, J = 8.0,
J = 16.2);
2.70 (1 H, J = 8.2,
J = 16.2)
2.47 (1H, J = 8.0,
J = 16.3);
2.72 (1 H, J = 8.4,
J = 16.3)
3.50—3.56 3.36, 3.70
3.48—3.55 3.32, 3.67
3.55—3.62 3.34, 3.70
3.48—3.55 3.31, 3.69
3.73—3.80 3.45, 3.78
3.77—3.82 3.48, 3.79
3.79 (1 H, J = 16.2);
3.84 (1 H, J = 16.2)
9.15
[4.22]
7.07—7.19 (m);
2.23 (s, 3 Н, Me)
3.78 (1 H, J = 16.3);
3.83 (1 H, J = 16.3)
9.13
[4.21]
7.26—7.39 (m)
3.78 (1 H, J = 16.2);
3.84 (1 H, J = 16.2)
9.15
[4.22]
6.82—7.24 (m);
3.68 (s, 3 Н, OMe)
3.78 (1 H, J = 16.2);
3.83 (1 H, J = 16.2)
9.15
[4.23]
6.94—7.57 (m);
3.69 (s, 3 Н, NMe)
3.81—3.88 (m, 2 Н)
9.13
[4.21]
6.95—7.59 (m);
5.30 (d, 1 Н, J = 16.3);
5.34 (d, 1 Н, J = 16.3),
[7.14—7.30 (m)]
3.83 (1 H, J = 16.0);
3.87 (1 H, J = 16.0);
5.30 (1 H, J = 16.5);
5.35 (1 H, J = 16.5)
3.82 (1 H, J = 16.3);
3.92 (1 H, J = 16.3)
9.14
[4.24]
2g
2h
2i
6.90—7.53 (m);
2.50—2.58 (m, 2 Н) 3.62—3.69 3.56, 3.84
9.14
[4.23]
3.59 (s, 3 Н, NMe);
2.33 (s, 3 Н, 2-Me)
6.95—7.56 (m)
2.44 (1 H, J = 8.2,
J = 16.3); 2.71 (1 H,
J = 8.2, J = 16.3)
3.43—3.50 3.72—3.81
3.81 (1 H, J = 16.2);
3.86 (1 H, J = 16.2)
[4.66 (s, 2 H)]
3.77—3.98 (m, 2 Н)
[4.66 (s, 2 H)]
9.14, 9.35
[4.25
(4 Н)]
9.15, 9.38
[4.25
(4 Н)]
6.87—7.60 (m);
2.32 (s, 3 Н, 2-Me)
2.50—2.62 (m, 2 Н) 3.87—3.95 3.57—3.68
3a
7.05—7.21 (m);
2.23 (s, 3 Н, Me);
[6.63—7.21 (m)]
2.26—2.40 (m, 2 Н); 3.46—3.60 3.29—3.43,
2.59—2.70 (m, 2 Н)
3.90—4.10
3.89—4.10
3.88—4.09
E´: 9.26, [7.93]
Z´: 9.79 (d, 1 H,
J = 2.4);
[7.73 (d, 1 H,
J = 2.4)]
E´: 9.26, [7.93]
Z´: 9.80 (d, 1 H,
J = 2.4);
[7.73 (d, 1 H,
J = 2.4)]
3.63—3.78
3b
3c
7.30—7.38 (m);
[6.63—7.21 (m)]
2.25—2.40 (m, 2 Н); 3.52—3.66 3.28—3.43,
2.62—2.73 (m, 2 Н) 3.68—3.80
6.82—7.25 (m),
3.68 (s, 3 Н, OMe)
[6.63—7.25 (m)]
2.23—2.38 (m, 2 Н), 3.46—3.58 3.30—3.40,
2.57—2.68 (m, 2 Н) 3.64—3.75
E´: 9.25, [7.93]
Z´: 9.79 (d, 1 H,
J = 2.4);
[7.73 (d, 1 H,
J = 2.4)]
* The 1H NMR spectra were recorded in DMSO-d6 (isomer ratio (Z´) : (E´) = 5 : 1 (3a—c)).
Tables 3—7) show double sets of proton and carbon signals
of all structural units, which attests to the existence of
these compounds as a mixture of (E´) and (Z´) conform-
ers (with respect to the (O)C—NH bond) in DMSO-d6.
For example, the 13C{1H} NMR spectrum of com-
pound 3c contains carbon signals of C=O groups at δC
172.65 and 168.19, which should be assigned to the C(7)
atoms of the (E´) and (Z´) conformers, respectively. This

Gorodnicheva et al.
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Russ. Chem. Bull., Int. Ed., Vol. 69, No. 5, May, 2020
Table 4. 13C{1H} NMR spectra* of compounds 2a—i
Com-
pound

C(2)
С(3)
С(4)
С(5)
С(6)
С(7)
C(Me)
C(R) [C(Ph)]
2a
2b
2c
2d
2e
173.83
173.87
173.66
173.95
174.35
38.69
38.73
38.57
38.88
37.74
37.14
36.80
36.53
36.50
28.90
54.82
54.90
54.63
55.07
53.87
44.35
44.35
44.33
44.33
44.28
167.46
167.46
167.44
167.48
167.51
—
21.13
–
55.59
30.05
127.17, 127.49, 129.11, 143.43
127.36, 129.64, 136.18, 140.35
129.02, 129.48, 131.73, 142.52
114.45, 128.53, 135.22, 158.50
110.73, 116.05, 119.27, 119.46,
121.98, 127.17, 127.52, 136.82
110.85, 116.15, 119.31, 119.54,
122.04, 127.24, 127.59, 136.95
[49.52, 126.08, 127.86, 129.06, 138.80]
109.89, 110.65, 118.78, 119.00,
120.75, 125.71, 134.16, 137.16
47.86, 110.59, 115.87, 119.37,
121.97, 126.64, 127.11, 137.40, 167.28
44.83, 110.00, 111.07, 118.82, 119.29,
120.87, 125.96, 134.45, 137.28, 167.55
2f
174.17
37.81
29.17
54.15
44.37
167.56
—
2g
2h
2i
174.45
174.18
174.42
37.57
37.79
37.46
28.51
29.10
28.49
53.51
54.05
53.40
44.25
44.36
44.25
167.63 10.56,
29.85
167.55
—
167.62
10.62
* The 13C{1H} NMR spectra were recorded in DMSO-d6.
Table 5. 13C{1H} NMR spectra* of compounds 3a—c
Com-
pound

E´/Z´
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(Me)
C(R)
3a
3b
3c
Z´
E´
Z´
E´
Z´
E´
174.03
173.95
173.80
173.70
174.06
173.99
38.73
38.84
38.58
38.67
38.86
38.96
36.86
36.73
36.56
36.42
36.54
36.40
55.07
54.84
54.79
54.54
55.23
54.99
44.43
43.10
44.41
43.10
44.41
43.06
168.17
172.63
168.15
172.61
168.19
172.65
21.15
21.15
—
112.58—149.66
112.58—149.66
112.57—149.64
112.57—149.64
112.57—158.52
112.57—158.52
—
55.57
55.57
* The 13C{1H} NMR spectra were recorded in DMSO-d6.
Table 6. 1H NMR spectra* of compounds 4a—l, 5a—c, and 6a—c
Com-
pound
E/Z
 (J/Hz)
R;
[R´]
H´(3) (dd),
H(3) (dd)
H(4)
(m)
H´(5) (m),
H(5) (m)
H´(6) (d),
H(6) (d)
H(8)
(s)
H(10) (s)
[Me (s)]
4a
4b
4c
E´E
Z´E
E´E
Z´E
E´E
7.17—7.34 (m);
[7.37—7.67 (m)]
2.37 (2 H, J = 8.4,
J = 16.6);
3.54—3.64
3.54—3.64
3.54—3.64
3.54—3.64
3.54—3.64
3.42—3.47,
3.76—3.83
4.39 (1 H,
J = 17.6);
4.45 (1 H,
J = 17.6)
3.99 (1 H,
J = 16.5);
4.04 (1 H,
J = 16.5)
4.38 (1 H,
J = 17.7);
4.44 (1 H,
J = 17.7)
3.98 (1H,
J = 16.5);
4.03 (1 H,
J = 16.5)
4.36 (1 H,
J = 17.7);
4.42 (1H,
J = 17.7)
11.55
11.55
11.59
11.59
11.39
7.97
8.18
7.95
8.17
7.90
2.72 (2 H, J = 9.0,
J = 16.6)
7.17—7.34 (m);
[7.37—7.67 (m)]
2.37 (2 H, J = 8.4,
J = 16.6);
3.42—3.47,
3.76—3.83
2.72 (2 H, J = 9.0,
J = 16.6)
7.18—7.36 (m);
[7.43—7.70 (m)]
2.36 (2 H, J = 8.2,
J = 16.6);
3.38—3.45,
3.76—3.82
2.71 (2 H, J = 9.0,
J = 16.6)
7.18—7.36 (m);
[7.43—7.70 (m)]
2.36 (2 H, J = 8.2,
J = 16.6);
3.38—3.45,
3.76—3.82
2.71 (2 H, J = 9.0,
J = 16.6)
7.16—7.36 (m);
[6.93—7.61 (m);
3.79 (s, 3 Н OMe)]
2.37 (2 H, J = 8.4,
J = 16.6);
3.40—3.47,
3.76—3.83
2.71 (2 H, J = 9.0,
J = 16.6)
(to be continued)

Pyrrolidone acetohydrazides
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 5, May, 2020
1001
Table 6 (continued)
Com-
pound
E/Z
 (J/Hz)
R;
[R´]
H´(3) (dd),
H(3) (dd)
H(4)
(m)
H´(5) (m),
H(5) (m)
H´(6) (d),
H(6) (d)
H(8)
(s)
H(10) (s)
[Me (s)]
4c
4d
Z´E
E´E
7.16—7.36 (m);
[6.95—7.64 (m);
3.76 (s, 3 Н OMe)]
2.37 (2 H, J = 8.4,
J = 16.6);
3.54—3.64
3.40—3.47,
3.76—3.83
3.95 (1 H,
J = 16.4);
4.00 (1 H,
11.37
8.11
2.71 (2 H, J = 9.0,
J = 16.6)
2.37 (2 H, J = 8.4,
J = 16.6);
2.72 (2 H, J = 9.0,
J = 16.6)
2.37 (2 H, J = 8.4,
J = 16.6);
2.72 (2 H, J = 9.0,
J = 16.6)
2.35 (2 H, J = 8.0,
J = 16.6);
2.72 (2 H, J = 9.0,
J = 16.6)
2.35 (2 H, J = 8.0,
J = 16.6);
2.72 (2 H, J = 9.0,
J = 16.6)
2.34 (2 H, J = 8.1,
J = 16.6);
2.72 (2 H, J = 9.1,
J = 16.6)
2.34 (2 H, J = 8.1,
J = 16.6);
2.72 (2 H, J = 9.1,
J = 16.6)
2.34 (2 H, J = 8.1,
J = 16.6);
2.72 (2 H, J = 9.1,
J = 16.6)
2.34 (2 H, J = 8.1,
J = 16.6);
2.72 (2 H, J = 9.1,
J = 16.6)
2.35 (2 H, J = 8.1,
J = 16.7);
2.72 (2 H, J = 9.1,
J = 16.7)
2.35 (2 H, J = 8.1,
J = 16.7);
2.72 (2 H, J = 9.1,
J = 16.7)
2.33 (2 H, J = 8.5,
J = 16.6);
2.67 (2 H, J = 9.0,
J = 16.6)
2.33 (2 H, J = 8.5,
J = 16.6);
J = 16.4)
4.41 (1 H,
J = 17.7);
4.46 (1 H,
J = 17.7)
4.00 (1 H,
J = 16.3);
4.06 (1 H,
J = 16.3)
4.39 (1 H,
J = 17.7);
4.45 (1 H,
J = 17.7)
3.98 (1 H,
J = 16.5);
4.04 (1 H,
J = 16.5)
4.38 (1 H,
J = 17.7);
4.44 (1 H,
J = 17.7)
3.97 (1 H,
J = 16.7);
4.02 (1 H,
J = 16.7)
4.35(1 H,
J = 17.6);
4.41 (1 H,
J = 17.6)
3.95 (1 H,
J = 16.3);
4.01 (1 H,
J = 16.3)
4.40 (1 H,
J = 17.7);
4.46 (1 H,
J = 17.7)
3.98 (1 H,
J = 16.5);
4.04 (1 H,
J = 16.5)
4.38 (1 H,
J = 17.7);
4.44 (1 H,
J = 17.7)
3.98 (1 H,
J = 16.5);
4.03 (1 H,
J = 16.5)
7.15—7.36 (m);
[7.39—8.82 (m)]
3.54—3.64
3.40—3.47,
3.76—3.83
11.69
7.99
8.24
7.97
8.18
7.95
8.17
7.90
8.11
8.00
8.23
7.97
8.19
Z´E
E´E
Z´E
E´E
Z´E
E´E
Z´E
E´E
Z´E
E´E
Z´E
7.15—7.36 (m);
[7.39—8.82 (m)]
3.54—3.64
3.55—3.65
3.55—3.65
3.56—3.66
3.56—3.66
3.55—3.66
3.55—3.66
3.56—3.66
3.56—3.66
3.45—3.58
3.45—3.58
3.40—3.47,
3.76—3.83
11.69
11.54
11.54
11.59
11.59
11.40
11.40
11.69
11.69
11.54
11.53
4e
7.30—7.38 (m);
[7.36—7.67 (m)]
3.38—3.43,
3.75—3.82
7.30—7.38 (m);
[7.36—7.67 (m)]
3.38—3.43,
3.75—3.82
4f
7.31—7.38 (m);
[7.43—7.69 (m)]
3.37—3.44,
3.76—3.83
7.31—7.38 (m);
[7.43—7.69 (m)]
3.37—3.44,
3.76—3.83
4g
4h
4i
7.31—7.38 (m);
[6.93—7.61 (m);
3.78 (s, 3 Н OMe)]
3.37—3.43,
3.76—3.83
7.31—7.38 (m);
[6.95—7.63 (m);
3.75 (s, 3 Н OMe)]
3.37—3.43,
3.76—3.83
7.32—7.38 (m);
[7.40—8.82 (m)]
3.37—3.44,
3.76—3.82
7.32—7.38 (m);
[7.40—8.82 (m)]
3.37—3.44,
3.76—3.82
6.84—7.24 (m);
3.69 (s, 3 Н OMe)
[7.36—7.68 (m)]
3.36—3.42,
3.71—3.78
6.81—7.19 (all m);
3.68 (s, 3 Н OMe)
[7.36— 7.68 (all m)] 2.67 (2 H, J = 9.0,
J = 16.6)
3.36—3.42,
3.71—3.78
(to be continued)

Gorodnicheva et al.
1002
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 5, May, 2020
Table 6 (continued)
Com-
pound
E/Z
 (J/Hz)
R;
[R´]
H´(3) (dd),
H(3) (dd)
H(4)
(m)
H´(5) (m),
H(5) (m)
H´(6) (d),
H(6) (d)
H(8)
(s)
H(10) (s)
[Me (s)]
4j
E´E
Z´E
6.83—7.25 (m);
3.69 (s, 3 Н OMe)
[7.43—7.70 (m)]
2.33 (2 H, J = 8.5,
J = 16.6),
2.67 (2 H, J = 9.0,
J = 16.6)
2.33 (2 H, J = 8.5,
J = 16.6),
3.47—3.58
3.47—3.58
3.47—3.58
3.35—3.42,
3.70—3.77
4.38 (1 H,
J = 17.7);
4.43 (1 H,
J = 17.7)
3.97 (1 H,
J = 16.6);
4.02 (1 H,
J = 16.6)
4.35 (1 H,
J = 17.7);
4.41 (1 H,
J = 17.7)
3.95 (1 H,
J = 16.4);
3.99 (1 H,
J = 16.4)
4.39 (1 H,
J = 17.7);
4.44 (1 H,
J = 17.7)
3.98 (1 H,
J = 16.6);
4.03 (1 H,
J = 16.6)
4.23 (1 H,
J = 18.4);
4.29 (1 H,
J = 18.4)
3.95 (1 H,
J = 16.4);
4.03 (1 H,
J = 16.4)
4.21 (1 H,
J = 18.6);
4.26 (1 H,
J = 18.6)
3.93 (1 H,
J = 16.2);
4.01 (1 H,
J = 16.2)
4.16—4.31
(m, 2 H)
11.59
7.95
6.83—7.25 (m);
3.69 (s, 3 Н OMe)
[7.43—7.70 (m)]
3.35—3.42,
3.70—3.77
11.59
8.17
2.67 (2 H, J = 9.0,
J = 16.6)
4k
4l
E´E
Z´E
E´E
Z´E
E´
6.83—7.24 (m);
2.33 (2 H, J = 8.5,
J = 16.7);
3.35—3.41,
3.70—3.77
11.40
11.38
11.70
7.90
8.12
7.99
8.23
3.68 (s, 3 Н OMe)
[6.93—7.61 (m);
3.78 (s, 3 Н OMe)]
6.83—7.24 (m);
2.67 (2 H, J = 9.0,
J = 16.7)
3.68 (s, 3 Н OMe)
[6.93—7.61 (m);
3.75 (s, 3 Н OMe)]
6.83—7.24 (m);
2.33 (2 H, J = 8.5,
J = 16.5);
3.46—3.58
3.51—3.63
3.52—3.64
3.45—3.58
3.54—3.65
3.35—3.42,
3.70—3.77
3.69 (s, 3 Н OMe)
[7.40—8.82 (all m)] 2.67 (2 H, J = 9.0,
J = 16.5)
6.83—7.24 (m);
3.68 (s, 3 Н OMe)
[7.40—8.82 (m)]
5a
5b
5c
6a
7.16—7.33 (m)
2.35(2 H, J = 8.4,
J = 16.5);
2.70 (2 H, J = 9.1,
J = 16.5)
3.36—3.45,
3.71—3.80
10.30
10.15
10.29
10.13
10.30
10.15
10.79
10.55
[1.82,
1.88]
Z´
[1.82,
1.89]
E´
7.27—7.40 (m)
2.32 (2 H, J = 8.1,
J = 16.5);
2.69 (2 H, J = 9.2,
J = 16.5)
3.32—3.42,
3.70—3.79
[1.81,
1.88]
Z´
E´
6.77—730 (m);
3.69 (s, 3 Н OMe)
2.32 (2 H, J = 8.6,
J = 16.4);
2.65 (2 H, J = 8.9,
J = 16.4)
3.31—3.41,
3.65—3.76
[1.82,
1.88]
Z´
3.94 (1 H,
J = 16.4);
4.02 (1 H,
J = 16.4)
4.41—4.48
(m, 2 H)
[1.82,
1.89]
E´E
Z´E
7.18—7.35 (m);
[7.34—7.79 (m)]
2.38 (2 H, J = 8.3,
J = 16.6);
3.40—3.47,
3.77—3.84
[2.22]
[2.25]
2.72 (2 H, J = 9.0,
J = 16.6)
2.37 (2 H, J = 8.6,
J = 16.5);
4.07 (1 H,
J = 16.5);
4.16 (1 H,
J = 16.5)
2.72 (2 H, J = 9.0,
J = 16.5)
(to be continued)

Pyrrolidone acetohydrazides
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 5, May, 2020
1003
Table 6 (continued)
Com-
pound
E/Z
 (J/Hz)
R;
[R´]
H´(3) (dd),
H(3) (dd)
H(4)
(m)
H´(5) (m),
H(5) (m)
H´(6) (d),
H(6) (d)
H(8)
(s)
H(10) (s)
[Me (s)]
6b
6c
E´E
Z´E
7.32—7.45 (m);
[7.32—7.90 (m)]
2.35 (2 H, J = 8.0,
J = 16.6);
3.55—3.66
3.37—3.42,
3.77—3.84
4.40—4.48
(m, 2 H)
10.77
[2.21]
2.73 (2 H, J = 9.1,
J = 16.6)
4.07 (1 H,
J = 16.5);
4.16 (1 H,
J = 16.5)
4.40—4.49
(m, 2 H)
10.54
[2.24]
E´E
Z´E
6.82—7.26 (m);
3.69 (s, 3 Н OMe)
[7.33—7.91 (m)]
2.34 (2 H, J = 8.5,
J = 16.5);
2.68 (2 H, J = 9.0,
J = 16.5)
3.47—3.58
3.37—3.43,
3.74—3.80
10.78
10.54
[2.22]
[2.25]
4.07 (1 H,
J = 16.8);
4.16 (1 H,
J = 16.8)
* The 1H NMR spectra were recorded in DMSO-d6 (isomer ratio (Z´E) : (E´E) = 1 : 3 (4a—l); (Z´) : (E´) = 1 : 2 (5a—c); (Z´E) : (E´E) =
= 1 : 3 (6a—c)).
Table 7. 13C{1H} NMR spectra* of compounds 4a—l, 5a—c, and 6a—c
Com-
pound
E/Z

С(2)
С(3)
С(4)
С(5)
С(6)
C(7)
C(10)
C(Me)
—
С(R, R´)
4a
E´E
Z´E
174.06
38.77
37.18
54.96
44.07
169.71
164.83
144.22
127.19, 127.35, 127.46,
127.61, 129.14, 129.35,
130.45, 130.63, 134.53,
134.67, 143.53, 143.61
174.02
38.69
37.12
54.96
44.68
147.52
—
4b
E´E
Z´E
174.03
174.03
38.74
38.66
37.15
37.15
54.93
54.93
44.05
44.67
169.77
164.91
142.91
146.20
—
—
127.18, 127.45, 129.00,
129.13, 129.23, 129.43,
130.56, 133.50, 133.63,
134.87, 135.07, 143.52,
143.62
4c
4d
E´E
Z´E
173.99
173.97
38.77
38.69
37.17
37.11
54.94
55.92
44.04
44.66
169.43
164.51
144.09
147.43
55.83
—
114.84, 114.93, 127.17,
127.46, 128.93, 129.14,
129.19, 143.56, 143.63,
161.02, 161.22
124.44, 124.48, 127.18,
127.44, 129.13, 130.48,
130.61, 133.88, 133.97,
143.51, 143.60, 148.99,
149.28, 151.04, 151.25
E´E
Z´E
174.06
174.06
38.74
38.66
37.17
37.17
54.94
54.94
44.09
44.69
169.87
165.04
141.45
144.86
—
—
4e
4f
E´E
Z´E
173.87
173.84
38.65
38.56
36.53
36.53
54.74
54.74
44.05
44.66
169.68
164.81
144.25
147.54
—
—
127.35, 127.60, 129.04,
129.33, 129.40, 130.45,
130.63, 131.76, 134.53,
134.66, 142.61, 142.70
129.04, 129.23, 129.40,
129.61, 130.55, 131.75,
133.49, 133.64, 134.89,
135.07, 142.61, 142.72
E´E
Z´E
173.86
173.83
38.63
38.54
36.51
36.51
54.73
54.73
44.04
44.65
169.75
164.89
142.95
146.23
—
—
4g
E´E
Z´E
173.83
173.80
38.66
38.58
36.52
36.47
54.74
54.70
44.02
44.64
169.41
164.50
144.13
147.44
55.82
55.91
114.84, 114.93, 127.14,
127.19, 129.04, 129.19,
129.40, 130.51, 131.73,
142.64, 142.73, 161.23,
161.38
(to be continued)

Gorodnicheva et al.
1004
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 5, May, 2020
Table 7 (continued)
Com-
pound
E/Z

С(2)
С(3)
С(4)
С(5)
С(6)
C(7)
C(10)
C(Me)
—
С(R, R´)
4h
E´E
Z´E
173.88
38.62
36.51
54.74
44.06
169.85
164.99
141.48
124.46, 124.51, 129.05,
129.42, 130.47, 130.60,
131.75, 133.91, 133.98,
142.62, 142.72, 148.98,
149.27, 151.05, 151.26
173.88
38.54
36.51
54.74
44.64
144.85
—
4i
E´E
Z´E
174.13
174.10
38.94
38.86
36.52
36.47
55.19
55.19
44.04
44.67
169.72
164.84
144.20
147.51
55.56
55.56
114.41, 114.49, 127.35,
127.61, 128.47, 128.91,
129.35, 129.44, 130.45,
130.63, 134.55, 135.13,
135.32, 135.39, 158.49,
158.52
4j
E´E
Z´E
174.13
174.09
38.92
38.85
36.50
36.47
55.18
55.18
44.03
44.64
169.79
164.88
142.90
146.19
55.57
55.57
114.49, 128.47, 129.00,
129.23, 129.42, 130.55,
133.50, 133.62, 134.86,
135.05, 135.30, 135.39,
158.52
4k
4l
E´E
Z´E
174.09
174.06
38.94
38.88
36.51
36.45
55.19
55.19
44.01
44.64
169.45
164.53
144.07
147.40
55.57, 55.89 114.49, 114.84, 114.91,
127.10, 128.47, 128.93,
55.57, 55.82 129.19, 130.51, 135.33,
135.40, 158.52, 161.04,
161.21
E´E
Z´E
174.15
174.15
38.90
38.85
36.50
36.50
55.19
55.19
44.05
44.64
169.88
165.04
141.43
144.81
55.57
55.57
114.42, 114.49, 124.47,
128.47, 130.49, 133.89,
133.98, 135.30, 135.39,
148.99, 149.27, 151.05,
151.26, 158.52
5a
E´
Z´
173.95
173.89
38.77
38.77
37.17
37.07
54.90
54.90
44.26
44.40
169.72
164.52
151.74
156.53
17.52, 25.69 127.16, 127.46, 129.12,
143.63
18.12, 25.46 127.16, 127.46, 129.12,
143.63
5b
5c
E´
Z´
E´
173.74
173.69
174.04
38.67
38.62
38.94
36.48
36.42
36.50
54.69
54.69
55.15
44.24
44.36
44.22
169.69
164.47
169.73
151.79
156.58
151.74
17.54, 25.68 129.02, 129.43, 131.71,
18.12, 25.47
142.77
17.54, 25.69, 114.46, 128.48, 135.40,
55.55
18.12, 25.48,
55.55
158.50
Z´
173.98
174.04
174.04
173.85
38.94
38.79
38.79
38.68
36.40
37.16
37.16
36.50
55.15
54.95
54.95
54.74
44.35
44.55
44.55
44.53
164.53
170.54
165.31
170.51
156.49
148.70
152.55
148.75
6a
E´E
Z´E
E´E
14.04
126.58, 126.85, 127.18,
127.48, 128.86, 128.92,
129.14, 129.68, 138.50,
143.66
126.58, 126.85, 128.91,
129.04, 129.42, 129.67,
131.73, 138.50, 142.79
14.74
14.03
14.73
6b
6c
Z´E
E´E
173.85
174.12
38.68
38.96
36.50
36.52
54.74
55.19
44.53
44.53
165.28
170.54
152.61
148.68
14.02, 55.57 114.49, 126.57, 126.85,
128.48, 128.85, 128.91,
14.72, 55.57 129.66, 135.44, 138.51,
158.52
Z´E
174.12
38.96
36.52
55.19
44.53
165.32
152.53
* The 13C{1H} NMR spectra were recorded in DMSO-d6.
** The signals of both isomers coincide with each other.
1
is in good agreement with the values for related structures
published in the literature.15,18 The 13C{1H} NMR spectra
of all compounds 3—6 show similar patterns of signals for
the C(7) atoms.
The H NMR spectra of compounds 3—6 existing as
(Z´) and (E´) conformers contain signals of hydrazide NH
protons, apart from signals of H(3), H(4), and H(5) of the
pyrrolidone ring and the side-chain H(6) atom (see Tables 3

Pyrrolidone acetohydrazides
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 5, May, 2020
1005
1
and 6). The H NMR spectra of compounds 4a—l show
proton signals of the lactam ring, the side chain, and NH
groups along with singlets of H(10) of the arylidene moiety
(see Table 6).
in DMSO-d6. Meanwhile, the presence of two identical
substituents at the C=N bond in compounds 5a—c excludes
the possibility of the formation of geometric isomers.
Hence, these compounds exist as a mixture of (Z´) and
(E´) conformers in DMSO-d6.
It should be noted that a comparison of the integrated
intensities of proton signals in the 1H NMR spectra of
compounds 3—6 allowed the determination of the (Z´) to
(E´) isomer ratio in a mixture in DMSO-d6 as (Z´) : (E´) =
= 5 : 1 (3a—c), 1 : 3 (4a—l, 6a—c), and 1 : 2 (5a—c).
The validity of the interpretation of the 1H and 13C{1H}
NMR spectra of compounds 3—6 was confirmed by
1H—13C HMQC, 1H—13C HMBC, and 1H—1H NOESY
experiments for compounds 3c, 4a—l, 5a, 5b, 6a, and 6c.
An analysis of the 1H—13C HMQC and 1H—13C HMBC
spectra made it possible to reliably assign the hydrazide
NH protons, the H(3), H(4), and H(5) protons of the
pyrrolidone ring, and the side-chain C(6)H2 proton to the
carbons atoms C(3), C(4), C(5), and C(6) and also the
signals of the carbon atoms C(7) and C(2) of C=O groups
and the C(10) atoms of the azomethine moiety for all
compounds 3—6.
The structure of one of the synthesized compounds
(compound 4d) was determined by X-ray diffraction (Fig. 1).
According to the X-ray diffraction data, compound 4d
crystallizes as a crystal hydrate (the 4d : water ratio is 4 : 1).
The asymmetric unit of the crystal structure comprises
two independent molecules (A and B) and a water mol-
ecule, which occupies a special position on a twofold axis.
The molecule B is disordered over two positions. The
C(12)B, N(1)B, C(3)B÷C(11)B atoms were refined with
an occupancy of 0.587; the C(12)C, N(1)C, C(3)C÷C(11)
C atoms, with an occupancy of 0.413. The relative con-
figurations of the chiral centers C(4) in the molecules A
and B is S*, and the configuration is R* in the disordered
fragment C, but the crystal hydrate is a racemate (true
racemate) since the crystal is centrosymmetric. The five-
membered rings of the independent molecules A and B,
including the disordered fragment C, adopt the C(4)-
envelope conformation, with the C(4) atom deviating from
the C(3)C(2)N(1)C(5) plane. The geometric parameters
of these rings are equal within experimental error. In the
disordered molecules B and C, the C(4) atom deviates
from the C(3)C(2)N(1)C(5) plane in opposite directions
(by 0.8 and 0.7 Å in the molecules B and C), which cor-
responds to the S* and R* configurations of the chiral
centers C(4) in the molecules B and C, respectively.
In all three molecules (A, B, and C), the hydrazide
moieties have a planar zigzag Z´E conformation.
The 1H—1H NOESY spectra of compounds 4d and 6d
have nuclear Overhauser effect cross-peaks between the azo-
methine protons H(8) and H(10) (compound 4d) and bet-
ween the H(8) proton and the CH3 protons (compound 6d)
of the (Z´) and (E´) conformers. This is indicative of the close
spatial proximity of these protons and is indirect evidence
of their E configuration (with respect to the C=N(9) bond).
Similar correlations are observed in the 1H—1H NOESY
spectra of compounds 4a—c, 4e—i, and 6a—c.
Apparently, carbohydrazides 4 and 6 exist as a mixture
of (Z´E) and (E´E) isomers in different ratios in a solution
N(19B)
C(18B)
C(17B)
C(20B)
C(16B)
C(21B)
C(22B)
N(14B)
N(15B)
C(13B)
O(2A)
C(2A)
C(3A)
O(13B)
O(1A)
C(7A)
C(4A)
N(1A)
C(12B)
C(6A)
C(21A)
C(20A)
N(1B)
C(8A)
C(22A)
C(16)
C(5A)
C(12A)
C(13A)
O(13A)
C(9A)
C(5B)
N(15A)
C(2B)
C(11A)
N(19A)
C(18A)
C(10A)
C(4B)
O(2B)
C(7B)
C(8B)
C(17A)
N(14A)
C(3B)
C(6B)
C(9B)
C(11B)
C(10B)
Fig. 1. Geometry of the molecules in the asymmetric unit of the crystal structure of 4d. The disordered atoms of the molecule B
(fragment C) are omitted for clarity. Thermal displacement ellipsoids are drawn at the 50% probability level.

Gorodnicheva et al.
1006
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 5, May, 2020
O(2B)
H(14B)
N(14B)
O(2A)
O(1A)
H(14A)
N(14A)
N(14A)
H(14A)
Fig. 2. Hydrogen bond network in the crystal of 4d. Independent molecules A form hydrogen bonds only with the molecules A through
water molecules; the molecules B form hydrogen bonds only with the molecules B and C (the disordered fragment C is omitted
for clarity).
The crystal structure of compound 4d is stabilized by
classical hydrogen bonds. In the crystal of compound 4d,
the molecules A form hydrogen bonds only with the mol-
ecules A and water molecules of crystallization (double
zigzag chains), while the molecules B form hydrogen bonds
only with the molecule B (simple chains) (Fig. 2).
It should be noted that both the double zigzag chains,
composed of the molecules A and water molecules, and
the simple chains, which include the enantiomeric mol-
ecules B and C, are heterochiral.
Experimental
The spectroscopic and elemental analysis data for the syn-
thesized products were obtained using equipment of the Center
for Collective Use at the Faculty of Chemistry of the Herzen
State Pedagogical University of Russia.
The 1H, 13C{1H}, 1H—13C HMQC, 1H—13C HMBC,
1H—1H NOESY NMR spectra were measured on a JEOL
ECX400A spectrometer operating at 399.78 (1H) and 100.525
MHz (13C) in DMSO-d6 using residual signals of the nondeuter-
ated solvent as the internal standard. The IR spectra were re-
corded on a Shimadzu IR Prestige-21 FT-IR spectrometer as
KBr pellets. Elemental analysis was performed on a EuroVector
EA 3000 analyzer (CHN Dual mode). The melting points were
measured on a PTP (M) melting-point apparatus.
In conclusion, we synthesized new representatives of
the modified piracetam molecule, namely, 2-[4-(het)aryl-
2-oxopyrrolidin-1-yl]acetohydrazides. Preparatively con-
venient methods were developed for the synthesis of N´-
alkyl(hetaryl)idene-2-[4-(het)aryl-2-oxopyrrolidin-1-yl]-
acetohydrazides based on these acetohydrazides.
Starting ethyl 2-[4-(het)aryl-2-oxopyrrolidin-1-yl]acetates
1a—i were synthesized by a known procedure.17
2-(4-Phenyl-2-oxopyrrolidin-1-yl)acetohydrazide (2a). Hydr-
azine hydrate (4.86 mL, 0.1 mol) was added portionwise with
vigorous stirring to ethyl 2-[4-phenyl-2-oxopyrrolidin-1-yl]-
acetate (1a) (2.47 g, 0.01 mol), the temperature being maintained
at 0—5 C. The reaction mixture was vigorously stirred for 20 h at
18—20 C. The crystalline product was filtered off. Yield 1.82 g (78%),
m.p. 152—154 C (propan-2-ol). Found (%): C, 61.97; H, 6.50;
N, 18.02. C12H15N3O2. Calculated (%): C, 61.80; H, 6.44; N, 18.03.
Compounds 2b—i were synthesized in a similar way.
2-[4-(4-Methylphenyl)-2-oxopyrrolidin-1-yl]acetohydrazide
(2b) was synthesized from ester 1b. Yield 61%, m.p. 97—99 C
(propan-2-ol). Found (%): C, 63.26; H, 6.71; N, 17.05.
C13H17N3O2. Calculated (%): C, 63.14; H, 6.93; N, 16.99.
The structures of the new compounds were character-
ized and established by IR spectroscopy, 1H and 13C{1H}
NMR spectroscopy (using 1H—13C HMQC, 1H—13
C
HMBC, and 1H—1H NOESY experiments), and X-ray
diffraction. It was shown that the comparative chemical
shifts of the C=O carbon atoms of the carbohydrazide
moiety can be used as an analytical criterion to decide
whether substituted hydrazides have the (E´) or (Z´)
conformation. Compounds 2—6 can be used to synthesize
new 2-pyrrolidone derivatives. They are also of interest as
promising biologically active compounds.

Pyrrolidone acetohydrazides
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 5, May, 2020
1007
2-[4-(4-Chlorophenyl)-2-oxopyrrolidin-1-yl]acetohydrazide
(2c) was synthesized from ester 1c. Yield 70%, m.p. 102—104 C
(propan-2-ol). Found (%): C, 50.89; H, 4.81; N, 15.42.
C12H14N3O2Cl. Calculated (%): C, 50.84; H, 5.27; N, 15.70.
2-[4-(4-Methoxyphenyl)-2-oxopyrrolidin-1-yl]acetohydr-
azide (2d) was synthesized from ester 1d. Yield 76%, m.p.
123—125 C (propan-2-ol). Found (%): C, 59.33; H, 6.47; N, 16.03.
C13H17N3O3. Calculated (%): C, 59.31; H, 6.46; N, 15.97.
2-[4-(1-Methylindol-3-yl)-2-oxopyrrolidin-1-yl]acetohydr-
azide (2e) was synthesized from ester 1e. Yield 40%, m.p.
105—107 C (propan-2-ol). Found (%): N, 19.18. C15H18N4O2.
Calculated (%): N, 19.57.
2-[4-(1-Benzylindol-3-yl)-2-oxopyrrolidin-1-yl]acetohydr-
azide (2f) was synthesized from ester 1f. Yield 66%, m.p. 132—
135 C (propan-2-ol). Found (%): C, 69.55; H, 5.94; N, 15.44.
C21H22N4O2. Calculated (%): C, 69.59; H, 6.12; N, 15.46.
2-[4-(1,2-Dimethylindol-3-yl)-2-oxopyrrolidin-1-yl]aceto-
hydrazide (2g) was synthesized from ester 1g. Yield 45%, m.p.
194—196 C (propan-2-ol). Found (%): C, 63.87; H, 6.53; N, 18.89.
C16H20N4O2. Calculated (%): C, 63.98; H, 6.71; N, 18.65.
2-{4-[1-(2-Hydrazino-2-oxoethyl)indol-3-yl]-2-oxopyrro-
lidin-1-yl}acetohydrazide (2h) was synthesized from diester 1h.
Yield 41%, m.p. 201—203C (propan-2-ol). Found (%): C, 54.95;
H, 5.64; N, 24.28. C16H20N6O3. Calculated (%): C, 55.80;
H, 5.85; N, 24.40.
2-{4-[1-(2-Hydrazino-2-oxoethyl)-2-methylindol-3-yl]-2-
oxopyrrolidin-1-yl}acetohydrazide (2i) was synthesized from
diester 1i. Yield 48%, m.p. 150—152C (propan-2-ol). Found (%):
N, 23.87. C17H22N6O3. Calculated (%): N, 23.45.
2-[4-(4-Methylphenyl)-2-oxopyrrolidin-1-yl]-N´-phenyl-
acetohydrazide (3a). A mixture of ethyl 2-[4-(4-methylphenyl)-
2-oxopyrrolidin-1-yl]acetate (1b) (1.57 g, 0.006 mol) and
freshly distilled phenylhydrazine (1.77 mL, 0.018 mol) was vig-
orously stirred for 20 h. The crystalline product was filtered off.
Yield 1.00 g (52%), m.p. 182—184 C (propan-2-ol). Found (%):
C, 70.64; H, 6.38; N, 13.08. C19H21N3O2. Calculated (%):
C, 70.57; H, 6.55; N, 12.99.
hydrazide 2a and 4-methoxybenzaldehyde. Yield 71%, m.p.
154—156 C (methanol). Found (%): N, 12.19. C20H21N3O3.
Calculated (%): N, 11.96.
2-(4-Phenyl-2-oxopyrrolidin-1-yl)-N´-[(E)-(pyridin-3-yl)
methylidene]acetohydrazide (4d) was synthesized from hydrazide
2a and 3-pyridinecarbaldehyde. Yield 62%, m.p. 157—159 C
(methanol). Found (%): N, 17.07. C18H18N4O2. Calculated (%):
N, 17.38.
2-[4-(4-Chlorophenyl)-2-oxopyrrolidin-1-yl]-N´-[(E)-phenyl-
methylidene]acetohydrazide (4e) was synthesized from hydrazide
2c and benzaldehyde. Yield 75%, m.p. 153—155 C (methanol).
Found (%): N, 11.58. C19H18N3O2Cl. Calculated (%): N, 11.81.
2-[4-(4-Chlorophenyl)-2-oxopyrrolidin-1-yl]-N´-[(E)-(4-
chlorophenyl)methylidene]acetohydrazide (4f) was synthesized
from hydrazide 2c and 4-chlorobenzaldehyde. Yield 78%, m.p.
147—149 C (methanol). Found (%): N, 10.37. C19H17N3O2Cl2.
Calculated (%): N, 10.77.
2-[4-(4-Chlorophenyl)-2-oxopyrrolidin-1-yl]-N´-[(E)-(4-
methoxyphenyl)methylidene]acetohydrazide (4g) was synthesized
from hydrazide 2c and 4-methoxybenzaldehyde. Yield 84%, m.p.
144—146 C (methanol). Found (%): C, 62.54; H, 5.15; N, 10.58.
C20H20N3O3Cl. Calculated (%): C, 62.26; H, 5.22; N, 10.89.
2-[4-(4-Chlorophenyl)-2-oxopyrrolidin-1-yl]-N´-[(E)-(pyr-
idin-3-yl)methylidene]acetohydrazide (4h) was synthesized from
hydrazide 2c and 3-pyridinecarbaldehyde. Yield 68%, m.p.
83—85 C (methanol). Found (%): N, 15.21. C18H17N4O2Cl.
Calculated (%): N, 15.70.
2-[4-(4-Methoxyphenyl)-2-oxopyrrolidin-1-yl]-N´-[(E)-
phenylmethylidene]acetohydrazide (4i) was synthesized from
hydrazide 2d and benzaldehyde. Yield 70%, m.p. 181—183 C
(methanol). Found (%): C, 68.28; H, 6.02; N, 11.91. C20H21N3O3.
Calculated (%): C, 68.36; H, 6.02; N, 11.96.
N´-[(E)-(4-Chlorophenyl)methylidene]-2-[4-(4-methoxy-
phenyl)-2-oxopyrrolidin-1-yl]acetohydrazide (4j) was synthesized
from hydrazide 2d and 4-chlorobenzaldehyde. Yield 76%, m.p.
146—148 C (methanol). Found (%): N, 10.88. C20H20N3O3Cl.
Calculated (%): N, 10.89.
Compounds 3b and 3c were synthesized in a similar way.
2-[4-(4-Chlorophenyl)-2-oxopyrrolidin-1-yl]-N´-phenyl-
acetohydrazide (3b) was synthesized from ester 1c. Yield 50%,
m.p. 172—174 C (propan-2-ol). Found (%): C, 62.84; H, 5.25;
N, 12.10. C18H18ClN3O2. Calculated (%): C, 62.88; H, 5.28;
N, 12.22.
2-[4-(4-Methoxyphenyl)-2-oxopyrrolidin-1-yl]-N´-[(E)-(4-
methoxyphenyl)methylidene]acetohydrazide (4k) was synthesized
from hydrazide 2d and 4-methoxybenzaldehyde. Yield 86%, m.p.
162—164 C (methanol). Found (%): C, 66.42; H, 5.97; N, 10.72.
C21H23N3O4. Calculated (%): C, 66.13; H, 6.08; N, 11.02.
2-[4-(4-Methoxyphenyl)-2-oxopyrrolidin-1-yl]-N´-[(E)-
(pyridin-3-yl)methylidene]acetohydrazide (4l) was synthesized
from hydrazide 2d and 3-pyridinecarbaldehyde. Yield 76%, m.p.
144—146 C (methanol). Found (%): N, 15.71. C19H20N4O3.
Calculated (%): N, 15.91.
2-(4-Phenyl-2-oxopyrrolidin-1-yl)-N´-isopropylideneaceto-
hydrazide (5a). A solution of 2-[4-phenyl-2-oxopyrrolidin-1-yl]-
acetohydrazide (2a) (1.17 g, 0.005 mol) in acetone (11 mL) was
refluxed for 1 h and then cooled. The crystalline product was
filtered off and dried in air. Yield 1.17 g (85%), m.p. 150—152 C
(methanol). Found (%): C, 65.43; H, 6.97; N, 15.63. C15H19N3O2.
Calculated (%): C, 65.91; H, 7.01; N, 15.37.
Compounds 5b and 5c were synthesized in a similar way.
2-[4-(4-Chlorophenyl)-2-oxopyrrolidin-1-yl]-N´-isopropyl-
ideneacetohydrazide (5b) was synthesized from hydrazide 2c.
Yield 71%, m.p. 123—125 C (acetone). Found (%): N, 13.22.
C15H18N3O2Cl. Calculated (%): N, 13.65.
2-[4-(4-Methoxyphenyl)-2-oxopyrrolidin-1-yl]-N´-isoprop-
ylideacetohydrazide (5c) was synthesized from hydrazide 2d. Yield
73%, m.p. 156—158 C (methanol). Found (%): C, 63.18;
2-[4-(4-Methoxyphenyl)-2-oxopyrrolidin-1-yl]-N´-phenyl-
acetohydrazide (3c) was synthesized from ester 1d. Yield 61%,
m.p. 170—172 C (propan-2-ol). Found (%): C, 67.14; H, 6.20;
N, 12.34. C19H21N3O3. Calculated (%): C, 67.24, H, 6.24; N, 12.38.
2-(4-Phenyl-2-oxopyrrolidin-1-yl)-N´-[(E)-phenylmethyl-
idene]acetohydrazide (4a). A mixture of 2-[4-phenyl-2-oxopyr-
rolidin-1-yl]acetohydrazide (2a) (0.58 g, 0.0025 mol) and
benzaldehyde (0.38 mL, 0.0037 mol) in ethanol (8 mL) was
refluxed for 10 min and then cooled to room temperature. The
crystalline product was filtered off. Yield 0.65 g (81%), m.p.
160—162 C (methanol). Found (%): N, 12.73. C19H19N3O2.
Calculated (%): N, 13.08.
Compounds 4b—l were synthesized in a similar way.
N´-[(E)-(4-Chlorophenyl)methylidene]-2-(4-phenyl-2-oxo-
pyrrolidin-1-yl)acetohydrazide (4b) was synthesized from hydrazide
2a and 4-chlorobenzaldehyde. Yield 89%, m.p. 163—165 C (meth-
anol). Found (%): N, 11.43. C19H18N3O2Cl. Calculated (%): N, 11.81.
N´-[(E)-(4-Methoxyphenyl)methylidene]-2-(4-phenyl-2-
oxopyrrolidin-1-yl)acetohydrazide (4c) was synthesized from

Gorodnicheva et al.
1008
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 5, May, 2020
H, 6.97; N, 13.76. C16H21N3O3. Calculated (%): C, 63.35;
H, 6.98; N, 13.85.
converged to R = 0.1164, wR2 = 0.1959 based on all reflec-
tions, R = 0.0631, wR2 = 0.1619 based on unique reflections,
GOOF = 0.969, 530 refined parameters.
2-(4-Phenyl-2-oxopyrrolidin-1-yl)-N´-[(1E)-1-phenylethyl-
idene]acetohydrazide (6a). A mixture of 2-[4-phenyl-2-oxopyr-
rolidin-1-yl]acetohydrazide (2a) (0.58 g, 0.0025 mol) and ace-
tophenone (0.29 mL, 0.0025 mol) in ethanol (10 mL) was refluxed
for 3 h. The crystalline product was filtered off and dried in air.
Yield 0.58 g (69%), m.p. 193—195 C (methanol). Found (%):
C, 71.44; H, 6.39; N, 12.64. C20H21N3O2. Calculated (%):
C, 71.62; H, 6.31; N, 12.53.
Crystallographic data were deposited with the Cambridge
Crystallographic Data Centre (http://www.ccdc.cam.ac.uk;
CCDC 1957188).
References
Compound 6b was synthesized in a similar way.
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C, 65.12; H, 5.51; N, 11.21. C20H20N3O2Cl. Calculated (%):
C, 64.95; H, 5.45; N, 11.36.
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1-phenylethylidene]acetohydrazide (6c). A mixture of 2-[4-(4-meth-
oxyphenyl)-2-oxopyrrolidin-1-yl]acetohydrazide (2d) (0.66 g,
0.0025 mol) and acetophenone (0.29 mL, 0.0025 mol) in ethanol
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and dried in air. Yield 0.59 g (65%), m.p. 158—160 C (methanol).
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Ostrovskaya, A. P. Skoldinov, Pharm. Chem. J., 1983, 17, 858.
15. N. V. Gorodnicheva, E. S. Ostroglyadov, O. S. Vasil´eva, V.
V. Pelipko, V. V. Gurzhii, V. M. Berestovitskaya, E. S. Lipina,
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16. O. S. Vasil´eva, B. M. Berestovitskaya, I. N. Tyurenkov,
E. S. Ostroglyadov, V. N. Perfilova, N. V. Gorodnicheva, A. I.
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Aleksandrova, Russ. J. Gen. Chem., 2018, 88, 1374.
18. K. Brokaite, V. Mickevicius, G. Mikulskiene, Chem. Hetero-
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20. G. M. Sheldrick, SADABS. Bruker AXS Inc., Madison,
USA, 1997.
Crystals of compound 4d suitable for X-ray diffraction were
obtained by the crystallization from methanol. The crystals
of compound 4d (crystal hydrate) (4(C18H18N4O2)•H2O,
M = 1307.47, one water molecule per four molecules 4d) are
colorless, prismatic, monoclinic, m.p. 157—159 C, at 100 K
a = 52.952(4) Å, b = 8.8432(6) Å, c = 14.3272(10) Å,
β = 105.433(4), V = 6467.0(8) Å3, Z = 2 (two independent
molecules, A and B; a water molecule occupies a special position
on a twofold axis), space group C2/c, dcalc = 1.343 g cm–3
,
μ = 0.09 mm–1, F(000) = 2760, 2 θmax < 56. A total of 70439
measured reflections (Rint = 0.114), 7795 of which are unique;
the number of observed reflections with I > 2σ(I) is 4705. An
absorption correction was applied with the SADABS program.20
The structure was solved by direct methods using the
SHELXT-2018/2 program package21 and refined by the full-
matrix least-squares method based on F2 using the
SHELXL-2018/3 program package.22 The disorder of the pyr-
rolidone ring with the attached phenyl substituent in the inde-
pendent molecule B was revealed based on the sizes of the
displacement ellipsoids and the presence of strong peaks in dif-
ference electron density maps. The refinement of the occupancies
of the disordered fragments gave 0.587 for B and 0.413 for C. All
calculations were performed using the WinGX-2014.1 program
package.23 Nonhydrogen atoms were refined with anisotropic
displacement parameters. The hydrogen atoms at the carbon
atoms were positioned geometrically and refined isotropically
using a riding model. The H(1) atoms at the nitrogen atoms N(1)
and hydrogens of the water molecules were found in difference
electron density maps and refined isotropically. The refinement
21. G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Adv.,
2015, 71, 3.
22. G. M. Sheldrick, Acta Crystallogr., Sect. C: Struct. Chem.,
2015, 71, 3.
23. L. J. Farrugia, J. Appl. Cryst., 2012, 45, 849.
Received November 1, 2019;
in revised form December 23, 2019;
accepted January 13, 2020