Synthesis and Antimicrobial Screening of Novel Azetidin-2-ones Derived from Pyromellitic Diimide via [2+2]-Cycloaddition Reaction

Article abstract of DOI:10.1134/S1070428019120261

A series of novel 2-azetidinone derivatives have been obtained starting from pyromellitic dianhydride. Pyromellitic dianhydride was converted to pyromellitic diimide using sodium cyanate, and the diimide was alkylated with ethyl chloroacetate. The resulting diester was treated with hydrazine hydrate to obtain dihydrazide which reacted with substituted pyridine-2-carbaldehydes to give the corresponding Schiff bases, and [2+2]-cycloaddition of the latter with chloroacetyl chloride in the presence of triethylamine afforded the target azetidin-2-one derivatives. The newly synthesized compounds showed high antimicrobial activities against some bacterial and fungal strains.

Full text of DOI:10.1134/S1070428019120261

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 12, pp. 1961–1966. © Pleiades Publishing, Ltd., 2019.
Synthesis and Antimicrobial Screening
of Novel Azetidin-2-ones Derived from Pyromellitic Diimide
via [2+2]-Cycloaddition Reaction
A. N. Ayyasha
a
Department of Applied Chemistry, College of Applied Sciences, University of Fallujah, Anbar, Iraq
e-mail: ayyash1982@gmail.com; ahmedn.ayyash@uofallujah.edu.iq
Received July 12, 2019; revised October 13, 2019; accepted October 23, 2019
Abstract—A series of novel 2-azetidinone derivatives have been obtained starting from pyromellitic dian-
hydride. Pyromellitic dianhydride was converted to pyromellitic diimide using sodium cyanate, and the diimide
was alkylated with ethyl chloroacetate. The resulting diester was treated with hydrazine hydrate to obtain
dihydrazide which reacted with substituted pyridine-2-carbaldehydes to give the corresponding Schiff bases,
and [2+2]-cycloaddition of the latter with chloroacetyl chloride in the presence of triethylamine afforded the
target azetidin-2-one derivatives. The newly synthesized compounds showed high antimicrobial activities
against some bacterial and fungal strains.
Keywords: azetidin-2-ones, antimicrobial activity, pyromellitic diimide, pyridine-2-carbaldehyde, [2+2]-cyclo-
addition.
DOI: 10.1134/S1070428019120261
Azetidin-2-ones (β-lactams) constitute an important
class of heterocyclic compounds. β-Lactam moiety is
a structural unit of antibiotics, e.g., penicillin, clavu-
lanic acid, and cephalosporin drugs, which are used
for the treatment of bacterial infections and microbial
diseases [1, 2]. Due to biological activities of azetidin-
tained reacted with excess hydrazine hydrate to give
bis-acetohydrazide 4 in a good yield. The condensa-
tion of 4 with substituted pyridine-2-carbaldehydes
in anhydrous ethanol containing a few drops of glacial
acetic acid as a catalyst under reflux afforded the new
Schiff bases, 2,2′-[(1,3,5,7-tetraoxo-3,5,6,7-tetrahy-
dropyrrolo[3,4-f]isoindole-2,6(1H,3H)-yl)]bis[(E)-N′-
(R-pyridine-2-ylmethylidene)acetohydrazides] 5a–5g.
Finally, the target compounds 6a–6g were synthesized
by [2+2]-cycloaddition of Schiff bases 5a–5g and
chloroacetyl chloride in DMF in the presence of tri-
ethylamine. Presumably, the reaction followed the
imine–ketene mechanism as shown in Scheme 3 [14].
2
-one derivatives such as antibiotic, antimicrobial,
anti-inflammatory, and anticonvulsant [3–7], as well
as their chemical properties as synthetic intermediates
for many biologically active compounds [8], the syn-
thesis and development of new compounds containing
azetidin-2-one fragments has been an important line of
research [9–12].
This article reports the synthesis of some new azeti-
din-2-one derivatives and their antibacterial and anti-
fungal activities. The synthetic strategy is outlined in
Scheme 1. The starting material was 1H,3H-furo-
The structure of the newly synthesized compounds
was confirmed by IR and H and C NMR spectra.
1
13
The IR spectrum of 3 showed a strong absorption band
–
1
at 1698 cm due to stretching vibrations of the ester
1
[
3,4-f][2]benzofuran-1,3,5,7-tetrone (1, pyromellitic
carbonyl group, and its H NMR spectrum displayed
dianhydride) which was converted to pyromellitic di-
imide 2 by treatment with sodium cyanate in DMF
under reflux. A plausible mechanism of this trans-
formation is shown in Scheme 2 [13]. Diimide 2 was
alkylated at the nitrogen atoms with ethyl chloroacetate
in boiling ethanolic potassium hydroxide [11], and
diethyl 2,2′-[1,3,5,7-tetraoxo-5,7-dihydropyrrolo-
signals in the region δ 3.30–2.11 and 4.44 ppm, which
were assigned to the OCH CH and OCCH N protons,
2
3
2
respectively, whereas no NH signal was observed.
Compound 4 was characterized by IR absorption bands
of the primary amino and amide carbonyl groups at
–
1
–1
3433, 3153 cm and 1712, 1641 cm , respectively.
1
The H NMR spectrum of 4 contained a four-proton
[3,4-f]isoindole-2,6(1H,3H)-diyl]diacetate (3) thus ob-
singlet at δ 5.60 ppm for the two hydrazide amino
1
961

1962
AYYASH
Scheme 1.
O
O
O
O
O
O
O
NaOCN, DMF
reflux, 5 h
ClCH
2
COOEt
EtO
KOH/EtOH, reflux, 2–3 h
O
O
HN
NH
N
N
OEt
O
O
O
O
O
O
O
1
2
3
CHO
R
R
N
8
0% N
2
H
4
· H
2
O
O
O
O
O
O
O
N
KOH/EtOH
EtOH/AcOH
reflux, 3 h
HN
N
HN
reflux, 2–3 h
H
2
N
N
NH
NH
2
N
N
N
N
NH
O
O
O
N
O
O
O
R
4
5a–5g
R
Cl
O
O
O
O
2'
3'
ClCH COCl, DMF, Et N
2
3
HN
reflux, 4–5 h
4'
2"
N
N
N
N
N
6"
N
NH
O
O
O
O
Cl
R
6a–6g
5
, 6, R = H (a), 5-Me (b), 6-Me (c), 5-MeO (d), 3-MeO (e), 3-HO (f), 3-Cl (g).
Scheme 2.
O
O
O
O
O
O
O
O
O
·
N
O
N
O–
N
O Na+
O
O
Na+
O
O
O
O
O
O
O
O
O
O
O
O
O
NH
H
2
O
NaOCN
O
N– Na+
O
NH
· · ·
HN
–CO
2
–NaOH
O
O
O
O
O
O
groups, as well as other signals supporting its structure.
The IR and NMR spectra and microanalysis data of
Schiff bases 5a–5g and azetidin-2-one derivatives 6a–
37°C for 24 h, and the plates with fungal cultures
were incubated at 25°C for 72 h. Cefuroxime and
Fluconazole were used as reference antibacterial and
antifungal drugs, respectively. The results of measuring
the inhibition zone diameters (Table 1) indicated good
to excellent activities of the synthesized compounds in
comparison to the standard drugs.
6
g were fully consistent with the assigned structures
(see Experimental).
Compounds 5a–5g and 6a–6g were evaluated for
their antimicrobial activities against some bacterial
strains (gram-positive Staphylococcus Sciuri and gram-
negative Eschrichia coli) and two fungal strains
EXPERIMENTAL
(
Aspergillus flavus and Candida albicans) by the agar
Chemicals and reagents were used as purchased
(from Sigma–Aldrich, BDH, Merck, Fluka) without
further purification. The progress of reactions was
monitored by TLC on pre-coated aluminum plates. The
diffusion method [15]. The tested compounds were
dissolved in DMSO to a concentration of 100 μg/mL.
The plates with bacterial cultures were incubated at
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 12 2019

SYNTHESIS AND ANTIMICROBIAL SCREENING OF NOVEL AZETIDIN-2-ONES
1963
Scheme 3.
Ar
Cl
Ar
X
H
Cl
Cl
Ar
Cl
·
N
N
3
Et N
Cl
N
O
X
O
X
O
O
Ketene
Imine
O
O
O
HN
N
N
N
N
X =
; Ar =
.
NH
R
R
N
O
O O
melting points were measured in open capillaries with
an Electrothermal melting point apparatus and are
uncorrected. The IR spectra were recorded in KBr on
white powder, mp >280°C (decomp.). IR spectrum, ν,
–
1
cm : 3404–3200 (N–H), 3095 (C–H), 1681 (C=O),
1
1604 (C=C), 1244, 1111 (C–N). H NMR spectrum,
1
a Shimadzu 8400s FTIR spectrometer. The H and
δ, ppm: 8.79 s (2H, NH), 7.93–7.20 s (2H, Harom).
13
C NMR spectra were run on a Bruker spectrometer at
Found, %: C 55.52; H 1.85; N 12.92. C H N O . Cal-
1
0
4
2
4
4
00 and 100 MHz, respectively, using DMSO-d as
culated, %: C 55.57; H 1.87; N 12.96.
6
solvent and tetramethylsilane as internal standard.
Microanalysis was performed with a Fison EA 1108
elemental analyzer.
Diethyl 2,2′-(1,3,5,7-tetraoxo-5,7-dihydropyr-
rolo[3,4-f]isoindole-2,6(1H,3H)-diyl)diacetate (3).
A solution of 0.216 g (1 mmol) of 2 and 0.490 g
(4 mmol) of ethyl chloroacetate in 15 mL of anhydrous
ethanol containing 0.112 g (2 mmol) of potassium
hydroxide was refluxed for 2 h. The mixture was
cooled to room temperature, and the precipitate was
filtered off, washed with water, dried, and recrystal-
lized from aqueous ethanol (1:1) [11]. Yield 0.142 g
(66%), pale yellow powder, mp 128–129°C. IR spec-
Pyrrolo[3,4-f]isoindole-1,3,5,7(2H,6H)-tetrone
(2). A solution of 0.436 g (2 mmol) of 1H,3H-furo-
[3,4-f][2]benzofuran-1,3,5,7-tetrone (1) and 0.26 g
(4.0 mmol) of sodium cyanate in 10 mL of DMF was
heated under reflux for 5 h. After cooling to room
temperature, the mixture was poured onto crushed ice,
and the solid product was separated by filtration and
recrystallized from ethanol [13]. Yield 0.344 g (79%),
–
1
trum, ν, cm : 3044–2998 (C–H) 1698 (C=O, ester),
Table 1. Antibacterial and antifungal activities (inhibition zone diameter, mm) of compounds 5a–5g and 6a–6g at a concen-
tration of 100 ꢀg/mL
Bacterial strains
Fungal strains
Compound no.
Staphylococcus sciuri
Escherichia coli
Aspergillus flavus
Candida albicans
5
5
5
5
5
5
5
6
6
6
6
6
6
6
a
b
c
d
e
f
g
a
b
c
d
e
f
10
16
17
20
16
14
14
15
12
17
15
19
20
22
20
11
18
15
17
13
17
12
18
18
23
18
20
19
17
24
22
16
19
20
22
17
16
18
18
23
19
21
20
26
18
16
23
22
17
17
20
14
21
17
22
15
18
21
g
Cefuroxime
Fluconazole
24
28
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 12 2019

1964
AYYASH
1
636 (C=O, lactam), 1592 (C=C), 1247, 1108 (C–N).
1663 (C=O), 1624 (C=N), 1590 (C=C), 1241–1108
1
1
H NMR spectrum, δ, ppm: 2.11 t (6H, CH CH ),
(C–N). H NMR spectrum, δ, ppm: 2.57 s (6H, CH ),
2
3
3
3
.30 t (4H, OCH ), 4.44 s (4H, NCH ), 7.71 m
3.49 s (4H, CH ), 7.41–7.25 m (8H, Harom), 8.75 s (2H,
N=CH), 9.08 s (2H, NH). C NMR spectrum, δC,
2
2
2
1
3
(
2H, Harom). Found, %: C 55.62; H 4.13; N 7.19.
C H N O . Calculated, %: C 55.67; H 4.15; N 7.21.
ppm: 23.2 (CH ), 48.0 (CH N), 122.4–137.2 (Carom),
18
16
2
8
3
2
1
1
55.0–153.3 (C ), 157.8 (CH=N), 163.5 (NC=O),
Py
2
,2′-[1,3,5,7-Tetraoxo-5,7-dihydropyrrolo[3,4-f]-
71.0 (COCH ). Found, %: C 59.41; H 3.93; N 19.82.
2
isoindole-2,6(1H,3H)-diyl]di(acetohydrazide) (4).
A solution of 0.338 g (1 mmol) of 3 and 0.228 g
6 mmol) of 80% hydrazine hydrate in 20 mL of
anhydrous ethanol was refluxed under stirring for
–3 h. The mixture was left to cool overnight, and the
C H N O . Calculated, %: C 59.36; H 3.91; N 19.78.
2
8
22
8
6
(
2,2′-[1,3,5,7-Tetraoxo-5,7-dihydropyrrolo[3,4-f]-
isoindole-2,6(1H,3H)-diyl]bis[(E)-N′-(6-methyl-
pyridin-2-ylmethylidene)acetohydrazide] (5c). Yield
0
2
.255 g (71%), pale yellow crystals, mp 170–172°C.
solid was filtered off, washed with water, dried, and
recrystallized from chloroform. Yield 0.256 g (76%),
brown–yellow powder, mp 125–128°C. IR spectrum, ν,
–
1
IR spectrum, ν, cm : 3405–3229 (N–H), 3070–2990
CH), 1672 (C=O), 1661 (C=N), 1598 (C=C), 1239–
(
1
–1
1110 (C–N). H NMR spectrum, δ, ppm: 3.02 s (6H,
CH ), 3.43 s (4H, CH ), 7.73–7.27 m (8H, Harom),
8
cm : 3433, 3153 (NH , NH), 3063–2955 (C–H), 1712,
2
1
1
641 (C=O), 1572 (C=C), 1244–1058 (C–N). H NMR
spectrum, δ, ppm: 4.18 s (4H, NCH ), 5.60 s (4H,
3
2
1
3
.90 s (2H, N=CH), 10.04 s (2H, NH). C NMR spec-
2
trum, δ , ppm: 21.6 (CH ), 48.5 (CH N), 123.3–138.0
NH ), 7.02–7.99 m (2H, Harom), 8.31 s (2H, NH).
C
3
2
2
(
(
Carom), 155.5–154.1 (C ), 158.0 (CH=N), 163.8
NC=O), 171.6 (COCH ). Found, %: C 59.41; H 3.94;
Found, %: C 46.60; H 3.33; N 23.29. C H N O .
Calculated, %: C 46.67; H 3.36; N 23.33.
Py
1
4
12
6
6
2
N 19.81. C H N O . Calculated, %: C 59.36; H 3.91;
N 19.78.
2
8
22
8
6
2
,2′-[1,3,5,7-Tetraoxo-5,7-dihydropyrrolo[3,4-f]-
isoindole-2,6(1H,3H)-diyl]bis[(E)-N′-(pyridin-2-yl-
methylidene)acetohydrazides] 5a–5g (general proce-
dure). A solution of 2 mmol of the corresponding
substituted pyridine-2-carbaldehyde in 30 mL of anhy-
drous ethanol was added to 0.36 g (1 mmol) of com-
pound 4 and few drops (3–4) of glacial acetic acid. The
mixture was heated under reflux and stirring for 3 h.
After cooling, the solid precipitate was filtered off,
washed with water, dried, and purified by recrystal-
lization from ethanol.
2
,2′-[1,3,5,7-Tetraoxo-5,7-dihydropyrrolo[3,4-f]-
isoindole-2,6(1H,3H)-diyl]bis[(E)-N′-(5-methoxy-
pyridin-2-ylmethylidene)acetohydrazide] (5d). Yield
.237 g (66%), yellow crystals, mp 181–182°C. IR
spectrum, ν, cm : 3385–3188 (N–H), 3095–2971
C–H), 1646 (C=O), 1612 (C=N), 1592 (C=C), 1240–
0
–
1
(
1
1
115 (C–N). H NMR spectrum, δ, ppm: 3.49 s (4H,
CH ), 3.98 s (6H, OCH ), 7.39–7.05 m (8H, Harom),
2
3
1
3
8
.70 s (2H, N=CH), 9.28 s (2H, NH). C NMR
spectrum, δ , ppm: 47.2 (CH N), 57.5 (OCH ), 121.3–
38.0 (Carom), 155.8–152.1 (C ), 157.5 (CH=N), 163.1
NC=O), 171.2 (COCH ). Found, %: C 56.24; H 3.73;
N 18.76. C H N O . Calculated, %: C 56.19; H 3.70;
N 18.72.
C
2
3
2
,2′-[1,3,5,7-Tetraoxo-5,7-dihydropyrrolo[3,4-f]-
1
(
Py
isoindole-2,6(1H,3H)-diyl]bis[(E)-N′-(pyridin-2-yl-
methylidene)acetohydrazide] (5a). Yield 0.19 g
2
2
8
22
8
8
(
53%), yellow crystals, mp 166–167°C. IR spectrum,
–1
ν, cm : 3315–3184 (N–H), 3085–2899 (C–H), 1669
2
,2′-[1,3,5,7-Tetraoxo-5,7-dihydropyrrolo[3,4-f]-
(
C=O), 1638 (C=N), 1594 (C=C), 1238–1108 (C–N).
isoindole-2,6(1H,3H)-diyl]bis[(E)-N′-(3-methoxy-
pyridin-2-ylmethylidene)acetohydrazide] (5e). Yield
.277 g (77%), pale yellow powder, mp 186–189°C.
IR spectrum, ν, cm : 3318–3164 (N–H), 3089–2997
CH), 1671 (C=O), 1644 (C=N), 1594 (C=C), 1238–
108 (C–N). H NMR spectrum, δ, ppm: 3.70 s (4H,
1
H NMR spectrum, δ, ppm: 4.40 s (4H, CH ), 7.62–
2
7
.38 m (12H, Harom, N=CH), 9.37 s (2H, NH).
0
1
3
C NMR spectrum, δ , ppm: 48.0 (CH N), 122.4–
C
2
–1
1
37.2 (Carom), 155.0–153.3 (C ), 157.8 (CH=N), 163.5
Py
(
1
(
NC=O), 171.0 (COCH ). Found, %: C 58.97;
1
2
H 3.38; N 20.84. C H N O . Calculated, %: C 57.99;
2
6
18
8
6
CH ), 4.26 s (6H, OCH ), 7.80–7.02 m (8H, Harom),
2
3
H 3.37; N 20.81.
13
8
.89 s (2H, N=CH), 9.52 s (2H, NH). C NMR
2
,2′-[1,3,5,7-Tetraoxo-5,7-dihydropyrrolo[3,4-f]-
spectrum, δ , ppm: 47.2 (CH N), 58.2 (OCH ), 121.2–
C
2
3
isoindole-2,6(1H,3H)-diyl]bis[(E)-N′-(5-methyl-
pyridin-2-ylmethylidene)acetohydrazide] (5b). Yield
139.0 (Carom), 156.1–152.9 (C ), 157.5 (CH=N),
Py
163.4 (NC=O), 171.3 (COCH ). Found, %: C 56.24;
2
0
.223 g (62%), yellow solid, mp 160–163°C. IR spec-
H 3.74; N 18.77. C H N O . Calculated, %: C 56.19;
H 3.70; N 18.72.
2
8
22
8
8
–1
trum, ν, cm : 3381–3275 (N–H), 3072–2982 (C–H),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 12 2019

SYNTHESIS AND ANTIMICROBIAL SCREENING OF NOVEL AZETIDIN-2-ONES
1965
2
,2′-[1,3,5,7-Tetraoxo-5,7-dihydropyrrolo[3,4-f]-
2,2′-[1,3,5,7-Tetraoxo-5,7-dihydropyrrolo[3,4-f]-
isoindole-2,6(1H,3H)-diyl]bis{N-[(3-chloro-4-(5-
methylpyridin-2-yl)-2-oxoazetidin-1-yl]acetamide}
(6b). Yield 0.34 g (65 %), brown–yellow powder,
mp 202–205°C. IR spectrum, ν, cm : 3403–3285
(N–H), 1735 (C=O, β-lactam), 1671 (C=O, amide),
isoindole-2,6(1H,3H)-diyl]bis[(E)-N′-(3-hydroxy-
pyridin-2-ylmethylidene)acetohydrazide] (5f). Yield
.295 g (82%), dark yellow crystals, mp 203–205°C.
IR spectrum, ν, cm : 3430 (O–H), 3347–3284 (N–H),
097–2992 (C–H), 1660 (C=O), 1634 (C=N), 1599
C=C), 1241–1110 (C–N). H NMR, δ, ppm: 4.32 s
4H, CH ), 4.98 s (2H, OH), 8.59–7.38 m (10H, Harom,
N=CH), 9.25 s (2H, NH). C NMR spectrum, δC,
ppm: 48.0 (CH N), 122.4–137.2 (Carom), 154.9–153.8
0
–
1
–1
3
(
(
1
1649 (C=N), 1595 (C=C), 1240–1080 (C–N), 719
1
(C–Cl). H NMR spectrum, δ, ppm: 2.79 s (6H, CH ),
2
3
1
3
3.90 s (4H, NCH ), 4.89 s (2H, 4′-H), 6.02 d (2H,
2
1
3
3′-H), 7.42–8.93 m (10H, Harom, NH). C NMR spec-
2
4
′
(
C ), 157.8 (CH=N), 163.8 (NC=O), 171.4 (COCH ).
trum, δ , ppm: 21.0 (CH ), 47.1 (CH N), 63.0 (C ),
Py
2
C 3 2
3
′
2″
Found, %: C 54.80; H 3.21; N 19.67. C H N O .
Calculated, %: C 54.74; H 3.18; N 19.64.
64.4 (C ), 120.8–137.0 (C ), 150.2 and 161.5 (C ,
arom
C ), 162.2 (C ), 165.8 (NC=O), 169.5 (COCH ).
26
18
8
8
6
″
2′
2
Found, %: C 53.37; H 3.33; N 15.52. C H Cl N O .
Calculated, %: C 53.42; H 3.36; N 15.57.
2
,2′-[1,3,5,7-Tetraoxo-5,7-dihydropyrrolo[3,4-f]-
32 24
2
8
8
isoindole-2,6(1H,3H)-diyl]bis[(E)-N′-(3-chloropyri-
din-2-ylmethylidene)acetohydrazide] (5g). Yield
.219 g (61%), brown–yellow crystals, mp 169–170°C.
IR spectrum, ν, cm : 3340–3137 (N–H), 3085–2895
C–H), 1680 (C=O), 1644 (C=N), 1591 (C=C), 1248–
108 (C–N), 729 (C–Cl). H NMR spectrum, δ, ppm:
2,2′-[1,3,5,7-Tetraoxo-5,7-dihydropyrrolo[3,4-f]-
isoindole-2,6(1H,3H)-diyl]bis{N-[(3-chloro-4-
(6-methylpyridin-2-yl)-2-oxoazetidin-1-yl]acet-
amide} (6c). Yield 0.362 g (64%), whitish yellow
0
–
1
(
1
1
–1
powder, mp 217–219°C. IR spectrum, ν, cm : 3385–
4
9
1
1
.62 s (4H, CH ), 8.84–7.61 m (10H, Harom, N=CH),
3189 (N–H), 1731 (C=O, β-lactam), 1663 (C=O,
2
1
3
.59 s (2H, NH). C NMR, δ , ppm: 49.2 (CH N),
amide), 1635 (C=N), 1588 (C=C), 1234–1080 (C–N),
C
2
1
20.8–137.2 (Carom), 151.7–151.9 (C ), 156.3 (CH=N),
723 (C–Cl). H NMR spectrum, δ, ppm: 3.08 s (6H,
Py
63.5 (NC=O) 171.0 (COCH ). Found, %: C 51.38;
CH ), 3.90 s (4H, NCH ), 4.89 s (2H, 4′-H), 6.02 d
2
3
2
H 2.63; N 18.40. C H Cl N O . Calculated, %:
(2H, 3′-H), 7.42–8.93 m (10H, Harom, NH). 13C NMR
2
6
16
2
8
6
4′
C 51.42; H 2.66; N 18.45.
,2′-[1,3,5,7-Tetraoxo-5,7-dihydropyrrolo[3,4-f]-
isoindole-2,6(1H,3H)-diyl]bis{N-[(3-chloro-2-oxo-4-
pyridin-2-yl)azetidin-1-yl]acetamides} 6a–6g (gen-
spectrum, δ , ppm: 20.4 (CH ), 47.1 (CH N), 63.0 (C ),
C 3 2
3
′
2″
6
4.4 (C ), 121.6–136.8 (C ), 150.8 and 162.1 (C ,
arom
2
6
″
2′
C ), 162.2 (C ), 165.8 (NC=O), 169.5 (COCH ).
2
Found, %: C 53.39; H 3.34; N 15.53. C H Cl N O .
3
2
24
2
8
8
(
Calculated, %: C 53.42; H 3.36; N 15.57.
eral procedure). A solution of 0.226 g (2 mmol) of
chloroacetyl chloride and 0.203 g (2 mmol) of triethyl-
amine in 20 mL of DMF was added with stirring to
2,2′-[1,3,5,7-Tetraoxo-5,7-dihydropyrrolo[3,4-f]-
isoindole-2,6(1H,3H)-diyl]bis{N-[(3-chloro-4-(5-me-
thoxypyridin-2-yl)-2-oxoazetidin-1-yl]acetamide}
(6d). Yield 0.381 g (71%), whitish yellow powder,
1
mmol of Schiff base 5a–5g. The mixture was re-
fluxed under stirring for 4–5 h, cooled to room tem-
perature, and poured onto ice. The precipitate was
separated by filtration, dried, and recrystallized from
dimethyl sulfoxide.
–
1
mp 234–235°C. IR spectrum, ν, cm : 3385–3189
(NH), 1722 (C=O, β-lactam), 1656 (C=O, amide),
1642 (C=N), 1594 (C=C), 1244–1082 (C–N), 721
1
(
C–Cl). H NMR spectrum, δ, ppm: 3.79 s (6H,
2
,2′-[1,3,5,7-Tetraoxo-5,7-dihydropyrrolo[3,4-f]-
isoindole-2,6(1H,3H)-diyl]bis{N-[(3-chloro-2-oxo-4-
pyridin-2-yl)azetidin-1-yl]acetamide} (6a). Yield
.33 g (55%), whitish yellow powder, mp 221–223°C.
OCH ), 3.95 s (4H, NCH ), 4.61 s (2H, 4′-H), 6.54 d
3
2
(
2H, 3′-H), 7.46–8.22 m (10H, Harom, NH). 13C NMR
spectrum, δ , ppm: 58.0 (OCH ), 47.4 (CH N), 63.0
(
0
C
3
2
4
′
3′
–
1
(C ), 64.4 (C ), 120.8–137.2 (Carom), 149.9 and 160.5
(
IR spectrum, ν, cm : 3343–3188 (N–H), 1724 (C=O,
β-lactam), 1665 (C=O, amide), 1643 (C=N), 1597
2
″
6″
2′
C , C ), 162.2 (C ), 165.8 (NC=O), 169.5 (COCH ).
2
1
Found, %: C 51.10; H 3.20; N 14.88. C H Cl N O .
32 24 2 8 10
(C=C), 1232–1115 (C–N), 721 (C–Cl). H NMR spec-
Calculated, %: C 51.14; H 3.22; N 14.91.
trum, δ, ppm: 4.09 s (4H, NCH ), 4.20 s (2H, 4′-H),
2
5
.48 d (2H, 3′-H), 7.69–7.20 m (12H, Harom, NH).
2,2′-[1,3,5,7-Tetraoxo-5,7-dihydropyrrolo[3,4-f]-
isoindole-2,6(1H,3H)-diyl]bis{N-[(3-chloro-4-(3-
methoxypyridin-2-yl)-2-oxoazetidin-1-yl]acet-
amide} (6e). Yield 0.424 g (73%), pale yellow powder,
mp 230–231°C. IR spectrum, ν, cm : 3380–3128
(N–H), 1705 (C=O, β-lactam), 1666 (C=O,
13
4′
C NMR spectrum, δ , ppm: 47.2 (CH N), 63.0 (C ),
C
2
3′
2″
6
4.5 (C ), 119.8–137.0 (C ), 150.2 and 162.5 (C ,
arom
6
″
2′
C ), 162.2 (C ), 165.8 (NC=O), 169.5 (COCH ).
Found, %: C 52.06; H 2.90; N 16.17. C H Cl N O .
Calculated, %: C 52.11; H 2.92; N 16.21.
2
–
1
3
0
20
2
8
8
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 12 2019

1966
AYYASH
amide), 1634 (C=N), 1598 (C=C), 1240–1082 (C–N),
REFERENCES
1
7
21 (C–Cl). H NMR spectrum, δ, ppm: 3.80 s (6H,
1
2
. Fleming, A., Br. J. Exp. Pathol., 1929, vol. 10, p. 226.
PMCID: PMC2048009
OCH ), 3.71 s (4H, NCH ), 4.03 s (2H, 4′-H), 6.74 d
3
2
1
3
(
2H, 3′-H), 7.29–8.91 m (10H, Harom, NH). C NMR
. Knowles, J.R., Acc. Chem. Res., 1985, vol. 18, p. 97.
https://doi.org/10.1021/ar00112a001
spectrum, δ , ppm: 58.0 (OCH ), 47.4 (CH N), 63.0
C
3
2
4
′
3′
(
(
C ), 64.5 (C ), 121.1–137.4 (Carom), 151.2 and 160.8
C , C ), 162.2 (C ), 165.8 (NC=O), 170.2 (COCH ).
2″
6″
2′
3. Patel, N.B. and Patel, J.C., Arab. J. Chem., 2011, vol. 4,
p. 403.
2
Found, %: C 51.09; H 3.18; N 14.86. C H Cl N O .
3
2
24
2
8
10
https://doi.org/10.1016/j.arabjc.2010.07.005
Calculated, %: C 51.14; H 3.22; N 14.91.
4
. Gurupadayya, B.M., Gopal, M., Padmashaly, B., and
Manohara, Y., Indian J. Pharm. Sci., 2008, vol. 70,
p. 572.
2
,2′-[1,3,5,7-Tetraoxo-5,7-dihydropyrrolo[3,4-f]-
isoindole-2,6(1H,3H)-diyl]bis{N-[(3-chloro-4-(3-hy-
droxypyridin-2-yl)-2-oxoazetidin-1-yl]acetamide}
https://doi.org/10.4103/0250-474X.45393
(
6f). Yield 0.416 g (68%), white powder, mp >275°C
5
. Ishwar, B.K., Mubeen, M., and Kalluraya, B., Indian J.
Heterocycl. Chem., 2003, vol. 13, p. 183.
–
1
(
3
decomp.). IR spectrum, ν, cm : 3452 (O–H), 3383–
205 (N–H), 1704 (C=O, β-lactam), 1665 (C=O,
amide), 1648 (C=N), 1592 (C=C), 1244–1110 (C–N),
6
. Gilani, S.J., Nagarajan, K., Dixit, P.S., Taleuzzaman, M.,
and Khan, S.A., Arab. J. Chem., 2016, vol. 9, p. 1523.
https://doi.org/10.1016/j.arabjc.2012.04.004
1
7
19 (C–Cl). H NMR spectrum, δ, ppm: 3.98 s (4H,
NCH ), 4.03 s (2H, 4′-H), 5.21 s (2H, OH), 5.68 d (2H,
2
7
8
. Mohan, J. and Kumar, A., Indian J. Heterocycl. Chem.,
1
3
3
′-H), 7.98–7.10 m (10H, Harom, NH). C NMR spec-
trum, δ , ppm: 47.4 (CH N), 63.3 (C ), 64.5 (C ),
19.8–137.0 (C ), 151.2 and 160.8 (C , C ), 162.2
C ), 166.0 (NC=O), 170.2 (COCH ). Found, %:
2
003, vol. 12, p. 189.
4
′
3′
C
2
. Halve, A.K., Bhadauria, D., and Dubey, R., Bioorg. Med.
Chem. Lett., 2007, vol. 17, p. 341.
https://doi.org/10.1016/j.bmcl.2006.10.064
2
″
6″
1
(
arom
2
′
2
C 49.78; H 2.76; N 15.44. C H Cl N O . Calculated,
3
0
20
2
8
10
9
. Jin, X., Zheng, C.J., Song, M.X., Wu, Y., and Sun, L.P.,
Eur. J. Med. Chem., 2012, vol. 56, p. 203.
%: C 49.81; H 2.79; N 15.49.
2
,2′-[1,3,5,7-Tetraoxo-5,7-dihydropyrrolo[3,4-f]-
https://doi.org/10.1016/j.emech.2012.08,026
isoindole-2,6(1H,3H)-diyl]bis{N-[(3-chloro-4-(3-
chloropyridin-2-yl)-2-oxoazetidin-1-yl]acetamide}
1
0. Kishore, B. and Brahmeshwari, G., Indian J. Chem.,
Sect. B, 2018, vol. 57, p. 1042.
(
2
(
6g). Yield 0.412 g (57%), yellow solid, mp 236–
37°C. IR spectrum, ν, cm : 3312–3180 (N–H), 1721
1
1. Jaberi, H.R., Fattahi, H., Ahmannasrollahi, A.,
–
1
Yarandpour, M., and Sedaghatizadeh, S., Org. Chem.
Res., 2019, vol. 5, p. 42.
https://doi.org/10.22036/ORG.CHEM.2018.133516.
1150
C=O, β-lactam), 1662 (C=O, amide), 1648 (C=N),
1
1594 (C=C), 1239–1086 (C–N), 717 (C–Cl). H NMR
spectrum, δ, ppm: 4.57 s (4H, NCH ), 4.12 s (2H,
2
4
′-H), 6.08 d (2H, 3′-H), 8.07–7.39 m (10H, Harom,
12. Marri, S., Kakkerla, R., and Krishna, M.P.S., Indian J.
Chem., Sect. B, 2019, vol. 58, p. 381.
13
NH). C NMR spectrum, δ , ppm: 49.6 (CH N), 64.3
C
2
4′
3′
(C ), 64.5 (C ), 119.6–137.8 (Carom), 151.6 and 164.1
13. Nikpour, F., Kazemi, S., and Sheikh, D., Heterocycles,
2006, vol. 68, p. 1559.
2″
6″
2′
(C , C ), 162.2 (C ), 165.4 (NC=O), 169.7 (COCH ).
2
https://doi.org/10.3987/COM-06-10762
Found, %: C 47.34; H 2.35; N 14.71. C H Cl N O .
3
0
18
4
8
8
Calculated, %: C 47.39; H 2.39; N 14.74.
14. Gupta, A. and Halve, A.K., Open Chem. J., 2015,
vol. 2, p. 1.
https://doi.org/10.2174/1874842201502010001
CONFLICT OF INTERESTS
1
5. Arthington-Skaggs, B., Motley, M., and Morrison, C.J.,
The author declares no conflict of interest.
J. Clin. Microbiol., 2000, vol. 38, p. 2254.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 12 2019