One-Pot Four Component Synthesis of 3-Amino-1-(1H-indol-2-yl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine Derivatives Mediated by [DBUH][OAc]

Article abstract of DOI:10.1134/S1070363218090219

One-pot, four component, green, and efficient synthesis of 3-amino-1-(5-nitro-1H-indol-2-yl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine derivatives by reaction of phthalic anhydride with hydrazine hydrate, 5-nitro-1H-indole-3-carboxaldehyde–indole-3-carboxaldehydes and malononitrile–ethyl cyanoacetate in the presence of [DBUH][OAc] at 60–65°C is developed. The method is characterized by short reaction time, high yields, and purity of products formed.

Full text of DOI:10.1134/S1070363218090219

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 9, pp. 1892–1898. © Pleiades Publishing, Ltd., 2018.
One-Pot Four Component Synthesis
of 3-Amino-1-(1H-indol-2-yl)-5,10-dioxo-5,10-dihydro-
1H-pyrazolo[1,2-b]phthalazine Derivatives Mediated
by [DBUH][OAc]1
G. Jeevan Raghavendraa* and V. Siddaiaha
a Department of Organic Chemistry, Foods, Drug and Water, College of Science and Technology,
Andhra University, Visakhapatnam, Andhra Pradesh, 530003 India
*e-mail: jeevan.gutala@gmail.com
Received July 5, 2018
Abstract―One-pot, four component, green, and efficient synthesis of 3-amino-1-(5-nitro-1H-indol-2-yl)-5,10-
dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine derivatives by reaction of phthalic anhydride with
hydrazine hydrate, 5-nitro-1H-indole-3-carboxaldehyde–indole-3-carboxaldehydes and malononitrile–ethyl
cyanoacetate in the presence of [DBUH][OAc] at 60–65°C is developed. The method is characterized by short
reaction time, high yields, and purity of products formed.
Keywords: [DBUH][OAc], green synthesis, one-pot reaction
DOI: 10.1134/S1070363218090219
INTRODUCTION
range of organic and inorganic compounds. By
modification of cations and/or anions, the properties of
ILs can be turned in many ways for various
applications in organic synthesis [13–17]. DBU is a
strong organic base and has been extensively applied
in the base-induced reactions with excellent catalytic
activity. However, separation of DBU from a reaction
mixture is generally difficult. DBU-based ILs (DBU-
ILs) overcome this drawback and exhibit the basicity
similar to that of DBU accompanied by the general
features of ILs [18].
Phthalazines are heterocycles that possess multiple
biological activities such as antimicrobial [1],
anticonvulsant [2], antifungal [3], anticancer [4], and
anti-inflammatory [5]. Therefore, a number of methods
of synthesis of phthalazine derivatives [6, 7] has been
developed. Recently, synthesis of 1-aryl-1H-pyrazolo-
[1,2-b]phthalazine-5,10-diones by one-pot, three com-
ponent condensation of phthalhydrazide with
malononitrile–ethyl cyanoacetate and benzaldehydes
was reported [8–10]. 1-Aryl-1H-pyrazolo[1,2-b]phtha-
lazine-5,10-diones were synthesized in a four com-
ponent process of phthalic anhydride with hydrazine,
malononitrile/ethyl cyanoacetate and benzaldehydes
using basic ionic liquids, such as 1,8-diazabicyclo-
[5.4.0]-undec-7-en-8-ium acetate [11], pyrrolidinium
acetate [11] and TEA as a catalyst under ultrasound-
sonication [12].
Based on the above, we report herein synthesis of
3-amino-1-(5-nitro/chloro-1H-indol-2-yl)-5,10-dioxo-
5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine deriva-
tives by reaction of phthalic anhydride with hydrazine
hydrate, indole-3-carboxaldehydes and malononitrile/
ethyl cyanoacetate in the presence of [DBUH][OAc] at
60–65°C.
RESULTS AND DISCUSSION
Ionic liquids (ILs) have attracted close attention due
to their distinctive properties such as negligible vapour
pressure, high thermal stability, wide liquid
temperature range, easy recyclability, excellent
chemical stability, and strong solvent power for a wide
Initial optimization of the one-pot four component
reaction started with the reaction of phthalic anhydride
1 with hydrazine hydrate 2 in-situ and formation of
phthalhydrazide as an intermediate in the presence of
the ionic liquid. Addition of 5-nitroindole-3-car-
boxaldehyde 3a and malononitrile 4a to the above
1 The text was submitted by the authors in English.
1892

ONE-POT FOUR COMPONENT SYNTHESIS
1893
Scheme 1. Synthesis of 3-amino-1-(1H-indol-2-yl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine derivatives 5a–5h.
NH2
R
.
NH2 H2O
Y
N
R
2
O
N
O
[DBUH][OAc]
N
N
X
60−65oC, 30-40 min
O
H
Y
O
NH2
O
O
CN
1
3
5
X
Y = NO2 (3a, 5a, 5e), H (3b–3d, 5b–5d, 5f–5h), R = H (3a, 3b, 5a, 5b, 5e, 5f), CH3 (3c, 5c, 5g), C2H5 (3d, 5d, 5h), X = CN
(5a–5d), COOEt (5e, 5f–5h).
reaction mixture in the presence of different ionic
liquids ([DBUH][OAc], [bmim][Br] or [bmim][OH] )
at room temperature led to formation of 3-amino-1-(5-
nitro-1H-indol-2-yl)-5,10-dioxo-5,10-dihydro-1H-
pyrazolo[1,2-b]phthalazine-2-carbonitrile 5a. This
process was used in the following studies as a simple
model method (see Table 1).
This newly developed synthetic method was
successfully extended to malononitrile, indole-3-
carboxaldehyde 3b and its N-methyl and N-ethyl
derivatives 3c, 3d (Table 2).
The plausible mechanism of the process can be
presented as follows (Scheme 2). In the first step,
formation of phthalhydrazide X1 is achieved by nucleo-
philic addition of hydrazine hydrate 2 to phthalic
anhydride 1, which is followed by dehydration. The
second step involves formation of heterodiene Y1 by
the standard Knoevenagel condensation of indole-3-
Following optimization of the process was carried
out by using different ratio of the reagents in the range
of temperature 20–80°C over various reaction time
(Table 1). This approach allowed to work out the most
favorable conditions of the synthesis (Scheme 1) that
were the one-pot reaction of compound 1 (1 equiv.)
with compounds 2 (1 equiv.), 3a (1 equiv.) and 4a
(1 equiv.) in the presence of [DBUH][OAc] as a
medium (5 equiv.), the reaction time 30 min and
temperature range 60-65°C. These led to the highest
yield (85%) of the product 3-amino-1-(5-nitro-1H-
indol-2-yl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-
b]phthalazine-2-carbonitrile 5a (see Table 1).
carboxaldehyde
3
with malononitrile or ethyl
cyanoacetate 4. In the third step, the Michael-type
addition of phthalhydrazide X1 to the heterodiene Y1
leads to formation of the intermediate iminomethylene
derivative which undergoes cyclisation affording 5.
EXPERIMENTAL
Melting points were determined in open capillary
tubes. TLCs were carried out on silica gel G and
visualized by iodine vapour or under UV light. IR
1
The structure of 5a has been elucidated from H
and 13C NMR, IR, and Mass spectroscopic data.
Table 1. Effects of ionic liquids and the reaction conditions upon the yield of the compound 5a
Temprature,
°C
Time, Yield of
Temprature, Time, Yield of
[Ionic liquid]/equiv.
[Ionic liquid/ equiv.
min
120
240
180
90
5a, %
°C
60
80
60
60
min
5a, %
[DBUH][OAc]/5
[bmim][Br]/5
Room temperature
Room temperature
Room temperature
40
65
[DBUH][OAc]/5
[DBUH][OAc]/5
[DBUH][OAc]/2
[DBUH][OAc]/10
30
85
60
30
60
[bmim][OH]/5
[DBUH][OAc]/5
55
90
70
75
30
80
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 9 2018

1894
JEEVAN RAGHAVENDRA, SIDDAIAH
Scheme 2. Plausible mechanism for 3-amino-1-(1H-indol-2-yl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine
derivatives 5.
Step 1
O
O
O
O
H
H
N
OH
N
NH
NH
H2N
.
O
NH2 H2O
−H2O
H
O
2
O
X1
1
O
Step 2
H
Y
N
H
OH
Y
3
R
X
[DBUH][OAc]
Y
X
NC
4
X
X
−H2O
NC
NC
NC
H
N
R
N
R
Y1
Step 3
Y
Y
R
R
O
N
N
H
O
Y
O
X
NH
NH
X
N
N
NH
X
NC
N
O
H
N
R
N
NH
O
X1
O
Y1
Y
R
N
O
N
X
N
NH2
O
5
spectra were recorded on a Perkin Elmer 1000 spectro-
(1) (10 mM) and hydrazine hydrate (2) (10 mM) were
added to [DBUH][OAc] (50 mM) and heated for
10 min at 60–65°C to form phthalhydrazide as an
intermediate. Then, to this reaction mixture were
added 5-nitroindole-3-carboxaldehydes (3a) (10 mM)
and malanonitrile/ethylcyano acetate (4) (10 mM). The
reaction mixture was heated for 20–35 min until no
starting materials could be detected by TLC. Upon
completion of the process, cold water was added and
1
photometer in KBr pellets. H and 13C NMR spectra
were recorded in DMSO-d6 using TMS as an internal
standard at 400 MHz operating frequency. Mass spectra
were measured on an Agilent-LCMS instrument.
General procedure of synthesis of 3-amino-1-(1H-
indol-2-yl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo-
[1,2-b]phthalazine derivatives (5). Phthalic anhydride
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 9 2018

ONE-POT FOUR COMPONENT SYNTHESIS
Table 2. Synthesis data for compounds 5a–5h
1895
Comp.
no.
Yield,
%
Reagents
Product
Time, min
30 30
5a
1
2
3a
3a
30
H
(R = H, Y = NO2) (R = H, Y = NO2)
NO2
N
O
O
N
CN
NH2
N
H
5b
1
2
3b
4a
40
82
(R = H, Y = H)
(X = CN)
N
O
N
CN
NH2
N
O
5c
1
2
3c
4a
(X = CN)
45
78
H3C
O
(R = CH3,
Y = H)
N
N
CN
N
NH2
O
5d
1
2
3d
4a
C2H5
40
81
(R = C2H5,
Y = H)
(X = CN)
N
O
N
N
CN
NH2
O
O
H
5e
1
2
3a
(R = H,
Y = NO2)
4b (X = COOEt)
30
83
NO2
N
N
N
COOEt
NH2
O
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 9 2018

1896
JEEVAN RAGHAVENDRA, SIDDAIAH
Table 2. (Contd.)
Comp.
no.
Reagents
Product
Time, min Yield, %
H
5f
1
2
3b
4b (X = COOEt)
45
82
N
(R = H, Y = H)
O
O
N
COOEt
NH2
N
H3C
5g
1
2
3c
4b (X = COOEt)
45
82
N
(R = CH3,
Y = H)
O
N
COOEt
NH2
N
O
C2H5
5h
1
2
3d
4b (X=COOEt)
40
81
(R = C2H5,
Y = H)
N
O
O
N
N
COOEt
NH2
thevsolid residue was filtered off. The corresponding
product 5 was recrystallized from ethanol.
115.9, 119.2, 122.9, 123.9, 127.3, 134.6, 135.8, 138.4,
144.6, 145.8, 161.0, 164.5. MS: m/z: 356 [M + H]+.
3-Amino-1-(5-nitro-1H-indol-2-yl)-5,10-dioxo-
5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine-2-carbo-
nitrile (5a). mp >220°C. IR spectrum, ν, cm–1: 3116–
3440 br.m (NH), 2218 s (CN), 1669 s (CO, amide),
1686 s (CO, amide). 1H NMR spectrum, δ, ppm: 5.67 s
(1H, CH), 7.26–8.68 m (10H, Ar-H, NH2), δ 11.87 s
(1H, NH). 13C NMR spectrum, δ, ppm: 61.5, 69.1,
110.6, 111.5, 115.8, 115.9, 119.2, 122.9, 123.6, 127.6,
134.6, 135.6, 138.4, 144.6, 145.8, 161.6, 164.5. MS:
m/z: 400 [M + H]+.
3-Amino-1-(1-methyl-1H-indol-2-yl)-5,10-dioxo-
5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine-2-carbo-
nitrile (5c). mp >220°C. IR spectrum, ν, cm–1: 2213 s
(CN), 1668 s (CO, amide), 1682 s (CO, amide). 1H
NMR spectrum, δ, ppm: 2.20 s (3H, CH3), 5.30 s (1H,
CH), 7.21–8.68 m (11H, Ar-H, NH2). 13C NMR
spectrum, δ, ppm: 23.4, 60.1, 68.1, 111.3, 111.4,
114.8, 118.1, 122.9, 123.6, 127.4, 133.5, 134.7, 138.3,
144.2, 145.9, 161.4, 164.4. MS: m/z: 370 [M + H]+.
3-Amino-1-(1-ethyl-1H-indol-2-yl)-5,10-dioxo-
5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine-2-carbo-
nitrile (5d). mp >220°C. IR spectrum, ν, cm–1: 2216 s
(CN), 1663 s (CO, amide), 1678 s (CO, amide). 1H
NMR spectrum, δ, ppm: 1.81 t (3H, CH3) 2.22 q (2H,
CH2), 5.26 s (1H, CH), 7.21–8.94 m (11H, Ar-H,
NH2). 13C NMR spectrum, δ, ppm: 19.2, 23.2, 60.4,
68.5, 111.2, 111.5, 114.2, 118.2, 122.4, 123.2, 127.1,
3-Amino-1-(1H-indol-2-yl)-5,10-dioxo-5,10-dihyd-
ro-1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile (5b).
mp >220°C. IR spectrum, ν, cm–1: 3116–3440 br.m
(NH), 2218 s (CN), 1669 s (CO, amide), 1686 s (CO,
amide). 1H NMR spectrum, δ, ppm: 5.67 s (1H, CH),
7.26–8.68 m (11H, Ar-H, NH2), δ 11.87 s (1H, NH).
13C NMR spectrum, δ, ppm: 61.0, 69.0, 110.1, 111.5,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 9 2018

ONE-POT FOUR COMPONENT SYNTHESIS
1897
133.0, 134.3, 138.2, 144.0, 145.2, 161.5, 164.9. MS:
hydro-1H-pyrazolo[1,2-b]phthalazine derivatives has
been developed by the reaction of phthalic anhydride
with hydrazine hydrate, indole-3-carboxaldehydes and
malononitrile/ethyl cyanoacetate in the presence of
[DBUH][OAc] at 60–65°C. This one-pot process is
characterized by short reaction time, high yields and
purity of products isolated.
m/z: 384 [M + H]+.
Ethyl-3-amino-1-(5-nitro-1H-indol-2-yl)-5,10-di-
oxo-5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine-2-
carboxylate (5e). mp >220°C. IR spectrum, ν, cm–1:
3076–3360 m (NH), 2297 s (CN), 1660 s (CO, amide),
1666 s (CO, amide). 1H NMR spectrum, δ, ppm: 1.32 t
(3H, CH3), 4.46 q (2H, CH2), 6.02 s (1H, CH), 7.20–
8.69 m (10H, Ar-H, NH2), 11.79 s (1H, NH). 13C NMR
spectrum, δ, ppm: 14.0, 61.9, 69.1, 74.0, 110.6, 111.1,
115.8, 115.9, 119.1, 122.9, 123.6, 127.1, 134.6, 135.7,
140.6, 143.7, 151.6, 155.6. MS: m/z: 402 [M + H]+.
ACKNOWLEDGMENTS
Authors are very thankful to the authorities of the
Department of Organic Chemistry, Foods, Drug and
Water, College of Science and Technology, Andhra
University, Visakhapatnam 530003, Andhra Pradesh,
INDIA for constant support.
Ethyl-3-amino-1-(1H-indol-2-yl)-5,10-dioxo-5,10-
dihydro-1H-pyrazolo[1,2-b]phthalazine-2-carbo-
xylate (5f). mp >220°C. IR spectrum, ν, cm–1: 3112–
3453 m (NH), 2204 s (CN), 1668 s (CO, amide), 1672
s (CO, amide). 1H NMR spectrum, δ, ppm: 1.24 t (3H,
CH3), 4.18 q (2H, CH2), 5.42 s (1H, CH), 7.22–8.68 m
(11H, Ar-H, NH2), 11.78 s (1H, NH). 13C NMR
spectrum, δ, ppm: 15.3, 55.2, 60.5, 68.1, 110.3, 111.4,
115.0, 117.2, 122.0, 123.5, 127.2, 133.0, 134.9, 137.3,
142.5, 144.5, 150.1, 156.4. MS, m/z: 403 [M + H]+.
CONFLICT OF INTERESTS
No conflict of interests was declared by the authors.
REFERENCES
1. El-Sakka, S.S., Soliman, A.H., and Imam, A.M.,
Afinidad, 2009, vol. 66, p. 167. https://core.ac.uk/
download/pdf/39152404.pdf
Ethyl-3-amino-1-(1-methyl-1H-indol-2-yl)-5,10-
dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine-
2-carboxylate (5g). mp >220°C. IR spectrum, ν, cm–1:
2213 s (CN), 1664 s (CO, amide), 1683 s (CO, amide).
1H NMR spectrum, δ, ppm: 1.12 t (3H, CH3), 2.24 s
(3H, CH3), 4.00 q (2H, CH2), 5.42 s (1H, CH), 7.22–
8.64 m (11H, Ar-H, NH2). 13C NMR spectrum, δ, ppm:
15.3, 22.5, 56.3, 61.4, 67.0, 111.4, 113.5, 114.7, 118.0,
122.0, 122.7, 125.0, 132.4, 134.6, 138.0, 144.1, 143.5,
152.2, 153.5. MS: m/z: 417 [M + H]+.
2. Zhang, L., Guan, L.P., Sun, X.Y., Wei, C.X., Chai, K.Y.,
and Quan, Z.S., Chem. Bio. Drug. Design, 2009,
vol. 73, p. 313. doi 10.1111/j.1747-0285.2009.00776.x
3. Ryu, C.-K., Park, R.-E., Ma, M.-Y., and Nho, J.-H.,
Bioorg. Med. Chem. Lett., 2007, vol. 17, p. 2577. doi
10.1016/j.bmcl.2007.02.003
4. Li, J., Zhao, Y.F., Yuan, X.Y., Xu, J.X., and Gong, P.,
Molecules, 2006, vol. 11, p. 574.doi 10.3390/11070574
5. (a) Sinkkonen, J., Ovcharenko, V., Zelenin, K.N.,
Bezhan, I.P., Chakchir, B.A., Al-Assar, F., and Pihlaja, K.,
Eur. J. Org. Chem, 2002, p. 2046. doi 10.1002/1099-
0690(200207)2002:13<2046::AID-EJOC2046>
Ethyl-3-amino-1-(1-ethyl-1H-indol-2-yl)-5,10-
dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine-
2-carboxylate (5h). mp >220°C. IR spectrum, ν, cm–1:
2215 s (CN), 1666 s (CO, amide), 1673 s (CO, amide).
1H NMR spectrum, δ, ppm: 1.18 t (3H, CH3), 1.69 t
(3H, CH3) 2.39 q (2H, CH2), 4.15 q (2H, CH2), 5.26 s
(1H, CH), 7.22–8.93 m (11H, Ar-H, NH2). 13C NMR
spectrum, δ, ppm: 15.2, 19.4, 23.6, 54.3, 60.2, 68.4,
111.5, 111.7, 114.0, 118.1, 122.3, 124.1, 126.8, 133.4,
134.9, 138.1, 144.2, 145.5, 151.6, 154.6. MS: m/z: 431
[M + H]+.
3.0.CO;2-C
(b) Reddy, Y.D., Narayana, B.S.,
Reddy, Ch.V.R., and Dubey, P.K., Synth. Commun.,
2014, vol. 44, p. 3037. doi 10.1080/00397911.2014.928326
6. Ghahremanzadeh, R., Ahadi, S., Sayyafi, M., and
Bazgir, A., Tetrahedron Lett., 2008, vol. 49, p. 4479.
doi 10.1016/j.tetlet.2008.05.063
7. Li, J., Zhao, Y.F., Yuan, X.Y., Xu, J.X., and Gong, P.,
Molecules, 2006, vol. 11, p. 574. doi 10.3390/11070574
8. Ghahremanzadeh, R., Shakibaei, G.I., and Bazgir, A.,
Synlet, 2008, vol. 8, p.1129. doi 10.1055/s-2008-
1072716
CONCLUSIONS
9. Nabid, M.R., Tabatabaie, S.J., Gahremanzadeh, R., and
Bazgir, A., Ultrason. Sonochem., 2010, vol. 17, p. 159.
doi 10.1016/j.ultsonch.2009.06.012
In summary, a novel method of synthesis of
3-amino-1-(5-nitro-1H-indol-2-yl)-5,10-dioxo-5,10-di-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 9 2018

1898
JEEVAN RAGHAVENDRA, SIDDAIAH
10. Raghuvanshi, D.S. and Singh, K.N. Tetrahedron Lett.,
2011, vol. 52, p. 5702. doi 10.1016/j.tetlet.2011.08.111
11. Shaterian, H.R. and Mohammadnia, M., J. Mol Liquids,
2012, vol. 173, p. 55. doi 10.1016/j.molliq.2012.06.007
41:8<1290::AID-ANIE1290>3.0.CO;2-Y
15. Dupont, J., de Souza, R.F., and Suarez, P.A.Z., Chem.
Rev., 2002, vol. 102, p. 3667. doi 10.1021/cr010338r
16. Song, C.E., Oh, C.R., Roh, E.J., and Choo, D.J., Chem.
Commun, 2000, p. 1743. doi 10.1039/B004645K
12. Liu, L.-P., Lu, J.-M., and Shi, M., Org. Lett. 2007,
vol. 9, p. 1303. doi 10.1021/ol070178r
17. Yan, N., Yuan, Y.A., Dykeman, R., Kou, Y.A., and
Dyson, P.J., Angew. Chem. Int. Ed., 2010, vol. 49,
p. 5549. doi 10.1002/ange.201001531
18. Bo, Y., Hongye, Z., Yanfei, Z., Sha, C., Jilei, X.,
Leiduan, H., and Zhimin, L., ACS Catal., 2013, vol. 3,
p. 2076. doi 10.1021/cs400256j
13. Zhao, D.B., Fei, Z.F., Geldbach, T.J., Scopelliti, R., and
Dyson, P.J., J. Am. Chem. Soc., 2004, vol. 126,
p. 15876. doi 10.1021/ja0463482
14. Herrmann, W.A., Angew. Chem., Int. Ed., 2002, vol. 41,
p. 1290. doi 10.1002/1521-3773(20020415)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 9 2018