Synthesis of 4,5-dihydropyrazolyl-2H-indenediones by aldol condensation of ninhydrin with 1H-pyrazol-5-ol

Article abstract of DOI:10.3184/174751916X14757655073559

A simple and efficient procedure for the synthesis of 2-hydroxy-2-(5-hydroxy-1H-pyrazol-4-yl)-2H-indene-1,3-dione derivatives, proceeding via aldol condensation between ninhydrin and various 3-alkyl-1H-pyrazol-5-ols is described. The syntheses were carried out in ethanol at room temperature and proceeded with short reaction times to give the products with high yields.

Full text of DOI:10.3184/174751916X14757655073559

664 RESEARCH PAPER
VOL. 40 NOVEMBER, 664–666
JOURNAL OF CHEMICAL RESEARCH 2016
Synthesis of 4,5-dihydropyrazolyl-2H-indenediones by aldol condensation of
ninhydrin with 1H-pyrazol-5-ol
Ebrahim Soleimania*, Mina Hariria, Arman Rostamzadehb and Somayeh Ghorbania
aDepartment of Chemistry, Razi University, Kermanshah 67149-67346, Iran
bDepartment of Chemistry, Faculty of Science, Ilam University, Ilam, Iran
A simple and efficient procedure for the synthesis of 2-hydroxy-2-(5-hydroxy-1H-pyrazol-4-yl)-2H-indene-1,3-dione derivatives, proceeding
via aldol condensation between ninhydrin and various 3-alkyl-1H-pyrazol-5-ols is described. The syntheses were carried out in ethanol at
room temperature and proceeded with short reaction times to give the products with high yields.
Keywords: ninhydrin, pyrazolone, indandione, aldol condensation
Ninhydrin (indane-1,2,3-trione), traditionally used for the
analysis of amino acids,1 is known to participate in a number
of chemical reactions, such as aldol and Knoevenagel
condensations, giving rise to the formation of many
1,3-indenediones.2 The 1,3-indanedione grouping is present
in a large variety of natural products and drugs.3 In addition,
these compounds also have a range of biological activities,
such as anticoagulant, antioxidant, antiplatelet aggregation,
As a model reaction, we first investigated the condensation
of ninhydrin 3 and 3-methyl-1H-pyrazol-5-ol (4; R1 = Me,
R2 = H) under various conditions. We first investigated the
model reaction rate in different solvents by measuring the
isolated yield using identical amounts of reactants for a fixed
reaction time of 5 h at room temperature. The desired product
was obtained in polar solvents such as water, ethanol, methanol,
ethyl acetate and acetonitrile, but ethanol afforded the product
in the highest yield. The desired product was not obtained in
a non-polar solvent, such as dichloromethane, toluene and
benzene. This result can be explained by a simple acid-catalysis
mechanism facilitated by the strong hydrogen bond interaction
at the organic–ethanol interface, which stabilises the reaction
intermediate. In addition, it was found that addition of water to
the ethanol solution did not improve the reaction outcome and,
interestingly, when the reaction was performed in pure ethanol,
the corresponding product was obtained in high yield. Next, we
studied the model reaction in ethanol at different temperatures.
The reaction rate did not change as the temperature was
increased. At room temperature, the maximum yield was
obtained in a reaction time of 5 h.
antithrombosis,
antiangina,
antimicrobial,
antifungal,
antiproliferative and antiinflammatory activities.4-6
Among the wide variety of heterocycles that have been
explored for developing potential pharmacologically active
compounds, pyrazolones fused with different heterocycles are
known to possess various chemotherapeutic effects and have
found use as antimicrobial,7,8 antifungal9 and antiviral agents.10
In addition, some fused pyrazolone derivatives have been
reported to induce various antileukemic,11 antitumor12,13 and
antiproliferative14,15 activities. Development of new methods for
the synthesis of pyrazolone derivatives, which will yield subsets
of heterocycles with the potential to serve as templates for new
biologically active molecules, is of great importance.
With optimised conditions established, we then applied the
process to six variously substituted pyrazolones and the results
are summarised in Table 1. In all cases, good yields were
obtained. The structures of the products were established by
spectroscopic methods.
Although we have not experimentally established the reaction
mechanism, a possible explanation is proposed (Scheme 2).
Mechanistically, the active methylene of pyrazolone 4 is
converted into the enolate form in the presence of ethanol,
Results and discussion
In continuation of our interest in the synthesis of heterocyclic16–19
and pyrazolone compounds,20,21 we report the development herein
of the synthesis of 4,5-dihydropyrazolyl-2H-indenediones via an
aldol condensation of ninhydrin 3 and 1H-pyrazol-5-ol 4 in ethanol
at room temperature in high yield (Scheme 1). It should be noted
that the pyrazolones 4 were available by the condensation of β-keto
esters 1 and hydrazine 2 in ethanol for 5 min (Scheme 1).22
O
O
+ R2 NH
NH
2
R1
OEt
1
2
EtOH
r.t., 5 min
R2
O
O
O
O
R1
N
N
OH
OH
OH
EtOH, r.t.
+
R1
O
N
N
R2
3
4
5
HO
Scheme 1
* Correspondent. E-mail: e_soleimanirazi@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2016 665
O
O
O
OH
R1
O
R2
R2
R1
OH
N
N
N
N
+
O
N
R1
N
O
HO
3
R2
4
5
Scheme 2
3
Table 1 Yields of variously substituted pyrazolyl indandiones 5 prepared
from ninhydrin 3 and variously substituted pyrazolones 4 (Scheme 1)a
2.77 (2H, t, JHH = 8.0 Hz, CH3), 6.33 (1H, s, C= C–OH), 7.95–7.98
(4H, m, H–Ar), 9.50 (1H, s, OH), 11.30 (1H, s, NH); 13C NMR (100
MHz, DMSO-d6): δ 14.0 (CH3–propyl), 22.1 (CH2–propyl), 27.4
(CH2–propyl), 75.6 (C–OH), 97.0 (C=C–OH), 123.3 (C–ninhydrin),
136.2 (C–ninhydrin), 140.1 (C–ninhydrin), 142.0 (C=C–OH), 158.5
(C=N), 199.0 (C=O). Anal. calcd for C15H14N2O4: C, 62.93; H, 4.93; N,
9.79; found: C, 62.89; H, 4.92; N, 9.76%.
Entry
R1
Me
Pr
Me
CO2Me
iPr
Me
R2
H
H
Ph
H
H
Products
Yield/%b
91
90
89
85
81
70
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
2-Hydroxy-2-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2H-
indene-1,3-dione (5c): White powder; m.p. 210–212 °C; yield 0.29 g,
(89%); IR (KBr) (vmax cm−1): 3450, 3200, 3100, 1750, 1700, 1600,
2,4-NO2–Ph
aReaction conditions: a solution containing ninhydrin 3 (1.0 mmol) and pyrazolone 4 (1.0
mmol) in ethanol (10 mL) was stirred at room temperature for 5 h.
bIsolated yield.
1
1475; MS m/z: 334 (M+), 319, 257, 229, 173, 161, 132, 85; H NMR
(400 MHz, DMSO-d6): δ 2.46 (3H, s, CH3), 6.60 (1H, s, C=C–OH),
7.10–7.98 (9H, m, H–Ar), 11.70 (1H, s, OH); 13C NMR (100 MHz,
DMSO-d6): δ 11.8 (CH3), 75.2 (C–OH), 118.5 (C=C–OH), 123.3 (C–
ninhydrin), 124.7 (C–Ph), 128.8 (C–Ph), 136.2 (C–ninhydrin), 140.0
(C–ninhydrin), 140.2 (C=C–OH), 152.1 (C–Ph), 160.0 (C=N), 199.0
(C=O). Anal. calcd for C19H14N2O4: C, 68.26; H, 4.22; N, 8.38; found:
C, 68.23; H, 4.22; N, 8.36%.
which then reacts with ninhydrin in an aldol-type addition
reaction to give the product 5 (Scheme 2).
Conclusion
Methyl 4-(2,3-dihydro-2-hydroxy-1,3-dioxo-1H-inden-2-yl)-5-hydroxy-
1H-pyrazole-3-carboxylate (5d): White powder; m.p. 214–216 °C; yield
0.25 g (85%); IR (KBr) (vmax cm−1): 3450, 3400, 1750, 1700, 1600, 1480;
In conclusion, we have developed a new and efficient approach
for the synthesis of a wide range of pyrazolyl indandione
derivatives from the reaction of ninhydrin and pyrazolone in
ethanol at room temperature in high yield. The reaction has
been shown to display good functional group tolerance and is
high yielding, and product isolation is very straightforward.
1
MS m/z: 302 (M+), 273, 271, 202, 161, 144, 85; H NMR (400 MHz,
DMSO-d6): δ 3.66 (3H, s, CH3), 6.38 (1H, s, C=C–OH), 7.94–8.00
(4H, m, H–Ar), 9.70 (1H, s, OH), 11.70 (1H, s, NH); 13C NMR (100
MHz, DMSO-d6): δ 51.7 (OCH3), 75.2 (C–OH), 98.0 (C=C–OH),
123.4 (C–ninhydrin), 136.3 (C–ninhydrin), 140.0 (C–ninhydrin), 141.2
(C=C–OH), 160.0 (C=N), 161.0 (C=O), 198.7 (C=O). Anal. calcd for
C14H10N2O6: C, 55.63; H, 3.33; N, 9.27; found: C, 55.61; H, 3.32; N, 9.30%.
2-Hydroxy-2-(5-hydroxy-3-isopropyl-1H-pyrazol-4-yl)-2H-indene-
1,3-dione (5e): White powder; m.p. 215–217 °C; yield 0.23 g (81%); IR
(KBr) (vmax cm−1): 3550, 3450, 3200, 1750, 1700, 1600, 1500; MS m/z:
286 (M+), 257, 243, 202, 161, 85, 43; 1H NMR (400 MHz, DMSO-d6): δ
1.21 (6H, d, 3JHH = 8.0 Hz, CH3), 3.76 (2H, quin, 3JHH = 8.0 Hz, CH), 6.34
(1H, s, C=C–OH), 7.96–7.97 (4H, m, H–Ar), 9.70 (1H, s, OH), 11.50 (1H,
s, NH);13C NMR (100 MHz, DMSO-d6): δ 22.18 (CH3–isopropyl), 24.70
(CH–isopropyl), 75.7 (C–OH), 98.0 (C=C–OH), 123.3 (C–ninhydrin),
136.1 (C–ninhydrin), 140.10 (C=C–OH), 152.0 (C–ninhydrin), 158.0
(C=N), 198.9 (C=O). Anal. calcd for C15H14N2O4: C, 62.93; H, 4.93; N,
9.79; found: C, 62.95; H, 4.90; N, 9.77%.
2-Hydroxy-2-(5-hydroxy-3-methyl-1-(2,4-dinitrophenyl)-1H-
pyrazol-4-yl)-2H-indene-1,3-dione (5f): White powder; m.p.
219–221 °C; yield 0.29 g (70%); IR (KBr) (vmax cm−1): 3550, 3350, 1750,
1600, 1490; MS m/z: 424 (M+); 1H NMR (400 MHz, DMSO-d6): δ 2.13
(3H, s, CH3), 6.12 (1H, s, C=C–OH), 7.02 (1H, s, H–Ar), 7.65–8.00
(6H, m, H–Ar), 10.20 (1H, s, OH), 10.80 (1H, s, NH); 13C NMR (100
MHz, DMSO-d6): δ 12.1 (CH3), 83.0 (C–OH), 115.0 (C=C–OH),
122.9 (C–Ph), 123.1 (C–ninhydrin), 126.0 (C–Ph), 126.1 (C–Ph),
129.4 (C–Ph), 129.6 (C–Ph), 130.2 (C–Ph), 130.4 (C–ninhydrin), 135.5
(C–ninhydrin), 149.5 (C=C–OH), 160.9, (C=N), 199.0 (C=O). Anal.
calcd for C19H12N4O8: C, 53.78; H, 2.85; N, 13.20; found: C, 53.79; H,
2.86; N, 13.21%.
Experimental
All chemicals were purchased from Fluka, Merck or Aldrich, and
were used without further purification. Melting points and infrared
(IR) spectra of all compounds were measured on an Electrothermal
9100 apparatus and a Ray Leigh Wqf-510 Fourier Transform Infrared
(FTIR) spectrometer, respectively. The 1H NMR and 13C NMR spectra
were obtained on a Bruker-400 Avance instrument using DMSO-d6
as the solvent and tetramethylsilane (TMS) as the internal standard at
400 and 100 MHz, respectively. The mass spectra were recorded on a
Finnigan-MAT 8430 instrument.
Synthesis of pyrazolyl indandione derivatives (5a–f); general procedure
A solution containing ninhydrin (1.0 mmol) and a pyrazolone 4 (1.0 mmol)
in ethanol (10 mL) was stirred at room temperature for 5 h. Then the
solution was diluted with ethanol (10 mL) and stirred in an ice bath for 30
min. The resultant solid was filtered off, washed with cool ethanol (10 mL)
and recrystallised from ethanol to give pure pyrazolyl indandiones.
2-Hydroxy-2-(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-2H-indene-
1,3-dione (5a): White powder; m.p. 210–212 °C; yield 0.23 g (91%);
IR (KBr) (vmax cm−1): 3550, 3450, 3050, 1650, 1600, 1475; MS m/z: 258
1
(M+), 343, 173, 161, 97, 85; H NMR (400 MHz, DMSO-d6): δ 2.35
(3H, s, CH3), 3.54 (2H, brs, OH and NH), 6.42 (1H, s, C=C–OH), 7.97
(4H, m, H–Ar); 13C NMR (100 MHz, DMSO-d6): δ 12.0 (CH3), 76.0
(C–OH), 98.0 (C=C–OH), 123.9 (C–ninhydrin), 136.8 (C–ninhydrin),
140.5 (C–ninhydrin), 141.0 (C=C–OH), 158.2 (C=N), 199.4 (C=O).
Anal. calcd for C13H10N2O4: C, 60.47; H, 3.90; N, 10.85; found: C,
60.44; H, 3.91; N, 10.80%.
2-Hydroxy-2-(5-hydroxy-3-propyl-1H-pyrazol-4-yl)-2H-indene-
1,3-dione (5b): White powder; m.p. 211–213 °C; yield 0.26 g (90%);
IR (KBr) (vmax cm−1): 3450, 3350, 3030, 1770, 1700, 1600, 1550; MS
Acknowledgement
We gratefully acknowledge financial support from the Iran
National Science Foundation (INSF) and the Research Council of
Razi University.
1
m/z: 286 (M+), 257, 243, 202, 144, 125, 85, 43; H NMR (400 MHz,
DMSO-d6): δ 0.92 (3H, t, 3JHH = 8.0 Hz, CH3), 1.66–1.68 (2H, m, CH2),

666 JOURNAL OF CHEMICAL RESEARCH 2016
11 L.C. Chou, L.J. Huang, J.S. Yang, F.Y. Lee, C.M. Teng and S.C. Kuo,
Bioorg. Med. Chem., 2007, 15, 1732.
12 J. Li, Y.F. Zhao, X.L. Zhao, X.Y. Yuan and P. Gong, Arch. Pharm. Chem.
Life Sci., 2006, 339, 593.
Received 26 August 2016; accepted 15 September 2016
Paper 1604283 doi: 10.3184/174751916X14757655073559
Published online: 20 October 2016
13 V. Krystof, D. Moravcova, M. Paprskarova, P. Barbier, V. Peyrot, A.
Hlobilkova, L. Havlicek and M. Strnad, Eur. J. Med. Chem., 2006, 41,
1405.
References
1
2
3
4
5
M.M. Joullie, T.R. Thompson and N.H. Nemeroff, Tetrahedron, 1991, 47,
8791.
M. Chakrabarty, A. Mukherji, S. Arima, Y. Harigaya and G. Pilet,
Montash. Chem., 2009, 140, 189.
J. Jin, Y. Luo, C. Zhou, X. Chen, Q. Wen, P. Lu and Y. Wang, J. Org. Chem.,
2012, 77, 11368.
K.S. Babu, X.-C. Li, M.R. Jacob, Q. Zhang, S.I. Khan, D. Ferreira and A.M.
Clark, J. Med. Chem., 2006, 49, 7877.
14 S. Schenone, O. Bruno, A. Ranise, F. Bondavalli, C. Brullo, P. Fossa, L.
Mosti, G. Menozzi, F. Carraro, A. Naldini, C. Bernini, F. Manettic and M.
Botta, Bioorg. Med. Chem. Lett., 2004, 14, 2511.
15 G. Daidone, D. Raffa, B. Maggio, M.V. Raimondi, F. Plescia and D.
Schillaci, Eur. J. Med. Chem., 2004, 39, 219.
16 E. Soleimani and M. Zainali, J. Org. Chem., 2011, 76, 10306.
17 E. Soleimani, M. Zainali and S. Samadi, Tetrahedron Lett., 2011, 52, 4186.
18 E. Soleimani, M. Zainali, N. Ghasemi and B. Notash, Tetrahedron, 2013,
69, 9832.
19 E. Soleimani, S. Ghorbani and H.R. Ghasempour, Tetrahedron, 2013, 69,
8511.
K. Shinjiro, M. Yasuhiko, M. Notoya, I. Kouhei, K. Ikuko and K. Masayasu,
Jpn J. Pharmacol., 1992, 60, 397.
6
7
H.J. Kabat, Pharmacol., 1994, 80, 160.
B.S. Holla, M. Mahalinga, M.S. Karthikeyan, P.M. Akberali and N.S.
Shetty, Bioorg. Med. Chem., 2006, 14, 2040.
8
A.H. Shamroukh, M.E.A. Zaki, E.M.H. Morsy, F.M. Abdel-Motti and
F.M.E. Abdel-Megeid, Arch. Pharm. Chem. Life Sci., 2007, 345.
E. Akbas and I. Berber, Eur. J. Med. Chem., 2005, 40, 401.
20 E. Soleimani, M. Hariri and P. Saei, C. R. Chimie, 2013, 16, 773.
21 E. Soleimani, S. Ghorbani, M. Taran and A. Sarvari, C. R. Chimie, 2012,
15, 955.
9
10 R.Z. Yan, X.Y. Liu, W.F. Xu, C. Pannecouque, M. Witvrouw and E.
DeClercq, Arch. Pharm. Res., 2006, 29, 957.
22 X.J. Wang, J. Tan and K. Grozinger, Tetrahedron Lett., 2000, 41, 4713.