Self-Catalyzed One-Pot Four-Component Green Synthesis of 2-Amino-6-[1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl]-4-phenyl-4H-pyran-3,5-dicarbonitriles

Article abstract of DOI:10.1134/S1070428019120212

The title compounds were synthesized in good yields by one-pot four-component condensation of phthaloyl dichloride, ethyl cyanoacetohydrazide, malononitrile, and substituted benzaldehydes in boiling ethanol for 1–2 h. The reaction involves in situ generat

Full text of DOI:10.1134/S1070428019120212

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 12, pp. 1936–1939. © Pleiades Publishing, Ltd., 2019.
Self-Catalyzed One-Pot Four-Component Green Synthesis
of 2-Amino-6-[1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl]-
4-phenyl-4H-pyran-3,5-dicarbonitriles
P. Karunakara, b and C. N. S. S. P. Kumarb*
a GVK Biosciences Private Limited, Chemistry Services IDA Nacharam, Hyderabad, Telangana, 500076 India
b Division of Chemistry, Department of Sciences and Humanities, Vignan’s Foundation for Science,
Technology & Research University, Vadlamudi, Guntur, Andhra Pradesh, 522213 India
*e-mail: padurikarunakar123@gmail.com
Received June 8, 2019; revised October 15, 2019; accepted October 23, 2019
Abstract—The title compounds were synthesized in good yields by one-pot four-component condensation
of phthaloyl dichloride, ethyl cyanoacetohydrazide, malononitrile, and substituted benzaldehydes in boiling
ethanol for 1–2 h. The reaction involves in situ generation of hydrogen chloride in the first step, which catalyzes
further addition, dehydration, and cyclization steps. The procedure is advantageous due to easy workup, short
reaction times, good yields, the use of ethanol as a green solvent, and no external catalyst is needed.
Keywords: Green one-pot synthesis, ethanol, hydrochloric acid, phthaloyl dichloride, 2-amino-6-[1,4-dioxo-
3,4-dihydrophthalazin-2(1H)-yl]-4-phenyl-4H-pyran-3,5-dicarbonitriles.
DOI: 10.1134/S1070428019120212
Multi component reactions have been known for
over 100 years [1]. They play an efficient role in
modern and combinatorial chemistry because of their
potential to prepare structurally diverse small drug-like
molecules, as well as heterocyclic compounds, in a few
steps with a high degree of atom economy [2–4].
Nitrogen heterocycles are abundant in nature, and their
applications to biologically active pharmaceutical
ingredients, agrochemicals, and functional materials
are becoming more and more important. In particular,
heterocyclic compounds containing an endocyclic
hydrazine moiety have received considerable attention
because of their pharmacological properties and clinical
applications [5–7].
Kumar et al. [8] previously described a one-pot
three-component condensation of 3-[1,4-dioxo-3,4-
dihydrophthalazin-2(1H)-yl]-3-oxopropanenitrile (1)
with aromatic aldehydes 2 and malononitrile 3 (or ethyl
Scheme 1.
NH2
CN
Ar
O
O
O
O
O
O
CN
L
N
EtOH, -proline, r.t.
N
+
ArCHO
+
NC
CN
NH
80–85%
NH
CN
1
2a 2f
–
3
4a 4f
–
O
O
AcOH, r.t.
CN
1
+
O
H2N
N
H
O
5
Ar = Ph (a), 4-MeC6H4 (b), MeOC6H4 (c), 4-O2NC6H4 (d), 2-MeC6H4 (e), 4-ClC6H4 (f).
1936

SELF-CATALYZED ONE-POT FOUR-COMPONENT GREEN SYNTHESIS
1937
Scheme 2.
O
O
EtOH, reflux, 1–2 h
Cl
Cl
4a–4f
+
+
ArCHO
+
NC
H2N
CN
CN
N
H
O
6
5
2a–2f
3
Scheme 3.
O
O
O
O
O
N
H+
H2C(CN)2
N
ArCHO
–H2O
N
Ar
5
6
4
+
–2HCl
NH
NH
CN
O
1
7
cyanoacetate) catalyzed by L-proline in ethanol, which
afforded 2-amino-4-aryl-6-[1,4-dioxo-3,4-dihydro-
phthalazin-2(1H)-yl]-4H-pyran-3,5-dicarbonitriles 4 in
up to 85% yield (Scheme 1). For this reaction, com-
pound 1 was preliminarily synthesized from phthalic
anhydride and 2-cyanoacetohydrazide (5).
Compounds 4 could also be obtained via a tandem
process. For this purpose, a mixture of 5 and 6 in
ethanol was heated at 60–65°C for 30 min to form
intermediate 1. After completion of the reaction, alde-
Table 1. Four-component condensation of phthaloyl di-
chloride (6), 2-cyanoacetohydrazide (5), benzaldehyde (2a),
and malononitrile (3) in different solventsa
Herein, we report the synthesis of the same com-
pounds via self-catalyzed one-pot four-component con-
densation of phthaloyl dichloride 6, hydrazide 5, benz-
aldehydes 2a–2f, and malononitrile 3, where hydrogen
chloride liberated in the first step catalyzed the subse-
quent transformations, so that no external catalyst was
required.
Solvent
Reaction time, h
Yield of 4a,b %
EtOH
MeOH
DMF
2.5
3
80
75
65
62
49
49
50
3
DMSO
MeCN
THF
3
Initially, the effects of solvent (ethanol, methanol,
acetonitrile, THF; Table 1) and temperature (room
temperature, 40°C, 60°C, reflux; Table 2) on the yield
of 4a in the model reaction with benzaldehyde (2a)
were studied. The best result (85% yield) was achieved
using ethanol as solvent under reflux for 1 h. Then,
other substituted benzaldehydes 2b–2f containing both
electron-withdrawing and electron-donating substit-
uents were reacted under the optimized conditions to
afford 4b–4f in 80–87% yield (Scheme 2, Table 3).
3.5
3.5
3
CHCl3
a
The reactions were carried out with equimolar amounts of the
reactants (1 mmol) at room temperature using 20 mL of solvent.
Isolated yield.
b
Table 2. Four-component condensation of phthaloyl di-
chloride (6), 2-cyanoacetohydrazide (5), benzaldehyde (2a),
and malononitrile (3) in ethanol at different temperaturesa
Obviously, 3-[1,4-dioxo-3,4-dihydrophthalazin-
2(1H)-yl]-3-oxopropanenitrile (1) is formed as inter-
mediate via nucleophilic addition of ethyl hydrazide 2
to phthaloyl dichloride 6, which is accompanied by
liberation of hydrogen chloride. The latter activates
both methylene group of 1 and aldehyde group of 2 to
promote Knoevenagel type condensation with the
formation of intermediate 7 which is likely to have E
configuration for steric reasons. Finally, the Michael
type addition of malononitrile (3) to heterodiene 7,
followed by cyclization, yields product 4 (Scheme 3).
Temperature, °C
Reaction time, h
Yield of 4a,b %
20–25
40
2.5
2
85
80
85
85
60
1.5
1
Reflux
a
The reactions were carried out with equimolar amounts of the
reactants (1 mmol) using 20 mL of ethanol.
Isolated yield.
b
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 12 2019

KARUNAKAR, KUMAR
1938
Table 3. One-pot three- and four-component syntheses of compounds 4a–4f
Three-component synthesis [8]
Four-component synthesis (this work)
Comp. no.
Ar
reaction time, h yield,a %
mp, °C [8]
reaction time, h
yield, %
mp, °C
4a
Ph
1
85
83
80
85
82
80
138–140
180–182
140–142
160–162
180–182
178–180
1
85
87
83
80
86
82
139–141
181–182
141–143
162–163
181–183
178–180
4b
4-MeC6H4
4-MeOC6H4
4-O2NC6H4
2-MeC6H4
4-ClC6H4
1
1
4c
1
1
4d
1.5
1.5
1.5
1
4e
4f
1.5
2
a
Crude product.
hyde 2 was added to the reaction mixture which was
maintained at the same temperature for 30 min; as
a result, intermediate 7 was obtained (TLC). Malono-
nitrile (3) was then added, and the mixture was heated
again for 60 min to afford target compound 4.
Compounds 4a–4f were identified by comparing their
zide (5, 1 mmol), aromatic aldehyde 2a–2f (1 mmol),
and malononitrile (3, 1 mmol) in ethanol (20 mL) was
refluxed for 1.0–2.0 h. The progress of the reaction was
monitored by TLC. After completion of the reaction,
the mixture was poured into cold water (60 mL), and
the precipitate was filtered off, washed with 1 M so-
dium bicarbonate solution (3 × 50 mL) and water
(50 mL), and dried at 50–55°C for 10–12 h. The yields,
reaction times, and melting points of compounds 4a–4f
are given in Table 3. The products had identical melting
points and spectroscopic characteristics with those
described in [8].
1
melting points and spectral characteristics (IR, H and
13C NMR, and mass spectra) with those reported in [8]
(Table 3).
In summary, we have successfully adapted a simple
one-pot green procedure for the synthesis of 2-amino-
4-aryl-6-[1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl]-
4H-pyran-3,5-dicarbonitriles via four-component con-
densation. The procedure is advantageous due to easy
workup, short reaction times, good yields, and the use
of ethanol as a green solvent. Furthermore, it is superior
to the three-component synthesis reported previously
[8] since it involves one step less, does not require
external catalyst, and ensures comparable or higher
yields in the same (or shorter time).
ACKNOWLEDGMENTS
The authors are thankful to GVK Biosciences Private
Limited (IDA Nacharam, Hyderabad, Telangana, India) and
Division of Chemistry, Department of Sciences and
Humanities, Vignan’s Foundation for Science, Technology &
Research University (Vadlamudi, Guntur, Andhra Pradesh,
India) for providing facilities to perform this study.
EXPERIMENTAL
CONFLICT OF INTERESTS
No conflict of interest is declared by the authors.
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