Efficient and convenient synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives mediated by L-proline

Article abstract of DOI:10.1080/00397911.2016.1192650

An efficient, four-component, one-pot condensation reaction of phthalimide or phthalic anhydride, aromatic aldehydes, and ethyl cyanoacetate for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives mediated by L-proline in excellent yields is reported.

Full text of DOI:10.1080/00397911.2016.1192650

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
An Efficient and Convenient Synthesis of 1H-
Pyrazolo [1, 2-b] Phthalazine-5, 10- Dione
Derivatives Mediated by L-Proline
Harendra Nath Roy, Masud Rana, Abu Zafar Al Munsur, Kee-In Lee & Ashis K.
Sarker
To cite this article: Harendra Nath Roy, Masud Rana, Abu Zafar Al Munsur, Kee-In Lee & Ashis
K. Sarker (2016): An Efficient and Convenient Synthesis of 1H-Pyrazolo [1, 2-b] Phthalazine-5,
10- Dione Derivatives Mediated by L-Proline, Synthetic Communications
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1192650
View supplementary material
Accepted author version posted online: 01
Jun 2016.
Published online: 01 Jun 2016.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20
Download by: [University of Cambridge]
Date: 01 June 2016, At: 21:53

An Efficient and Convenient Synthesis of 1H-Pyrazolo [1, 2-b] Phthalazine-5, 10-
Dione Derivatives Mediated by L-Proline
Harendra Nath Roy1, Masud Rana1, Abu Zafar Al Munsur1, Kee-In Lee2, Ashis K.
Sarker3
1Department of Chemistry, University of Rajshahi, Rajshahi, Bangladesh, 2Korea
Research Institute of Chemical Technology (KRICT), Green Chemistry Division,
Yuseong, Daejeon, South Korea, 3Department of Chemistry, Mawlana Bhashani Science
& Technology University, Tangail
Corresponding Author: Harendra Nath Roy, Email: hnroy01@yahoo.com
Abstract
An efficient, four-component, one-pot condensation reaction among phthalimide or
phthalic anhydride, aromatic aldehydes, and ethyl cyanoacetate for the synthesis of 1H-
pyrazolo[1, 2-b]phthalazine-5, 10-dione derivatives mediated by L-proline in excellent
yields is reported.
Graphical Abstract:
KEYWORDS: multicomponent reactions; one-pot synthesis; phthalimide; phthalic
anhydride; ethyl cyanoacetate; pyrazolo[1,2-b]phthalazine-5-dione; organocatalyst.
1

INTRODUCTION
After the discovery of multicomponent reactions (MCRs) in 1850 by Strecker,[1] the
concept has grown substantial interest in organic chemistry because it provides essential
products in a single step by the creation of several new bonds in one pot. In drug
discovery as well as in ‘green chemistry’,[2] MCRs are the chosen strategies due to
convenient synthesis of compounds in a cost and time-effective manner.[3, 4]
Heterocycles containing the pyrazole core are important targets in synthetic and in
medicinal chemistry because this unit is a potential moiety in numerous biologically
active compounds,[5–8] among them viagra 1 & celecoxib 2 are notable. Similarly,
phthalazine containing heterocyclic moiety are of great interest because they show
enough pharmacological and biological activities.[9–12] As an evidence, pyrazolo [1, 2-b]
phthalazine-dione derivatives 4 have been reported as anti-inflammatory, analgesic, anti-
hypoxic and antipyretic agents.[9,10] Moreover, phthalazine derivatives has reported to
possess anticonvulsant, cardiotonic, vasorelaxant, antimicrobial, antifungal, anticancer
and anti-inflammatory activities[13, 14] (Figure 1).
Despite their wide utility range, few methods have been reported for the synthesis of
pyrazolo [1, 2-b] phthalazine-dione.[15] Apparently, some methods suffer from drawbacks
such as relative toxic catalyst, sophisticated reaction arrangements, limited examples etc.
Besides the available methods, the development of new synthetic methods for the
efficient construction of heterocycles containing a phthalazine moiety is therefore an
interesting challenge. Recently, multicomponent reactions of alkyl cyanoacetate, an
2

aldehyde and nucleophilic compounds have attracted a lot to the chemists because the
formation of different condensation products can be expected depending upon the
specific conditions, catalysts and structure of the building blocks.[16–20] To the best of our
knowledge, few multicomponent reactions were conducted by organocatalyst,[21]
especially with L-proline. Our current attempts in screening organocatalyst to
multicomponent reaction envisaged us herein to report the synthesis of 1H-pyrazolo [1,
2-b] phthalazine-5, 10-diones derivatives using L-proline to condense phthalimide /
phthalic anhydride, hydrazine monohydrate, benzaldehyde and ethyl cyanoacetate.
RESULT AND DISCUSSION
As an effort in selecting suitable organocatalyst to multicomponent reaction, initially we
attempted a four-component reaction of phthalimide or phthalic anhydride 5, hydrazine
mono-hydrate 6, ethyl cyanoacetate 7 and bezaldehyde 8 by picolinic acid at the refluxing
temperature of ethanol (Scheme 1). As we know, picolinic acid by its dual nature can
exert organocatalytic activity to some organic transformation and therefore we were
inspired to exploit it in the present reaction. But the use of 2- and 3- picolinic acid over
the reacting components at different reaction conditions did not bring about any
noticeable changes in TLC. From our earlier experiences,[22] later we wished to use L-
cystein to the same reaction and monitored the reaction at different temperatures, solvents
and catalyst loadings (Table 1). Interestingly for a few examples, L-cystein is somewhat
working but the percentage of conversion is not satisfactory. Therefore, we have
undertaken rigorous precautions to make the reaction fruitful by the alteration of reaction
temperatures, solvents and variation of catalyst loadings. But all the efforts went in vain
3

to achieve the target product to a desired level. L-proline is now considered as the
simplest enzymatic catalyst and are exploiting as a versatile organocatalyst in many
enantioselective transformations.[23] Rigid ring structure,[24] easy availability, non toxic
nature and enough durability in air make this tiny molecule significant in synthesizing
different molecules of biologically interest.
Considering the modern ‘paradigm shift’ towards green synthesis, multicomponent
reactions by organocatalysis are heartily welcomed. So, our third attempt is to use L-
proline to the same four component condensation reaction. At the beginning, the reaction
proceeded at a slower rate and incomplete conversion (~ 50 %) was observed even after
48 hrs reflux. Then we thought to use LiCl to the same reaction mixture aiming at to
augment the electrophilicity of aldehyde functionality (Scheme 1) to achieve the
maximum target. Fortunately, our idea turned into got reality and we have achieved
maximum benefits by the addition of LiCl.
Therefore to set the optimistic conditions, reaction of phthalimide or phthalic anhydride
(for 9f-9i) with benzaldehyde, ethyl cyanoacetate and hydrazine mono-hydrate was
performed at different temperatures to various solvents (CH3CN, EtOH and H2O)
without and & with different amount of catalyst (5, 10, 15, 20 mol %, Table 1).
Importantly, at room temperature without and with catalyst reaction does not proceed at
all. But at 35 0C with 5 mol % catalyst loading, reaction proceeded at a very slower rate
and incomplete conversion (10 ~ 25 %) was observed even after 48 hrs heating over the
mentioned solvents. Maximum conversion (~50 %) was noticed at 80 0C in ethanol with
4

by the single use of L- proline (10 mol %). Increment of the amount of catalyst from 15
to 20 mol% failed to afford significant improvement of both the yields and the reaction
time. To our delight improved conversion (~ 93 %) was obtained whenever the solvent
system was altered from ethanol to dual solvent system (ethanol / water; 1:1)
accompanying LiCl (5 mol %) as a co-catalyst.
By this simple technique, reaction time was has surprisingly dropped down to 12 hr with
full conversion (Table 2) of the reactants. To eliminate the ambiguity, LiCl (without L-
proline) was employed to the same reaction but we did not discover any significant
changes in TLC so, LiCl in this reaction is purely acting as a co-catalyst. Moreover, we
also noticed using of excess L-proline (> 10 mol %) did not bring any additional benefits;
on the contrary, it created difficulties to isolate the pure products.
To compare the yields and versatility of the present work, the same reaction was
performed according to a recently published work.[15] Interestingly, a good compatibility
was observed in the results and in some cases better efficacy was discovered. Later, we
wished to make the four-component reaction general and therefore aldehydes with
various groups were reacted. Interestingly, phthalimide and aldehydes with electron
withdrawing groups were providing better yields and required shorter reaction time to
completion. Noticeable electronic and structural effects were observed for the substrates
13-19 and in fact, no condensations were occurred at all. The failure may come from the
negative charge accumulation onto the aldehydic carbon which deters nucleophilic attack,
or the strong hydrogen bond formation possibility between the catalyst and the aldehyde
5

molecules may make the nucleophilic attack difficult. Reaction mechanism by L- proline
is thought to be proceeded by the same fashion as depicted in the literature [25] (Scheme
2).
But in our case, L-Proline due to its -NH functionality forms imine intermediate 2 with
the phthalimide 1 and later it undergoes a nucleophilic attack by the hydrazine and forms
an imino hydrazine 3. This imino hydrazine 3 with the expulsion of -XH2 and catalyst L-
proline forms phthalhydrazide 4 that is also vulnerable to attack by the activated enone 7
formed during Knoevenagel condensation. But before that, phthalhydrazide 4 may form
imine 5 with L-proline and continues the initial condensation by the tandem fashion and
leads to the final product.
As soon as the reaction complete, the resulting products float over the solvent mixture
and by filtration enough pure products were isolated in excellent yields. By this technique
we have synthesized twelve different 1H-pyrazolo [1, 2-b] phthalazine-5, 10-dione
compounds. Some of the products are known in the literatures, so their melting points
were compared with the literature values.[15, 25]
CONCLUSION
In summary, we have developed a one-pot four-component reaction for the synthesis of
pyrazolo [1, 2-b] phthalazine-5, 10-diones derivatives from some available substituted
aldehydes. The novelty of this method has proved by the first time uses of L-proline as
6

organocatalyst to the present multicomponent reaction. As a whole, it is concise, highly
efficient, high yielding, friendly to the environment and inexpensive.
EXPERIMENTAL
General Procedure For The Preparation Of Phthalazine Derivatives (9)
A mixture of phthalimide / phthalic anhydride (147 mg), hydrazine hydrate (50 mg), L-
proline (11 mg, 10 mol %) and LiCl (2 mg, 5 mol %) in ethanol: water (4 mL) was stirred
at 80 0C for 4h with an efficient CaCl2 guard tube over the reaction vessel. Then aromatic
aldehyde, ethyl cyanoacetate (113 mg) were added sequentially to the mixture and it was
again heated (80 0C) till completion of the reaction (monitored by TLC). After
completion, the reaction mixture was allowed to cool to room temperature. A pale yellow
colored product was appeared over the solvent mixture and it was separated by filtration.
Finally, the product was washed with ethanol and for a few cases, recrystallization done
by MeOH and specific rotations were measured for a few pure products (9a, 9f, 9i & 9j).
Spectral Data For Selected Compounds
(9a). Ethyl-3-amino-1-(4-nitrophenyl)-5, 10-dioxo-5, 10-dihydro-1H-pyrazolo [1, 2-b]
phthalazine-2-carboxylate : Pale yellow powder (90 %); mp. 242-244 0C; [α]D25 = -0.71
(c=0.14, pyridine). 1H NMR (500 MHz, CDCl3): δ = 1.02 (3H, brs, -CH3), 4.06-4.04 (2H,
m, -OCH2), 6.32 (1H, s, -CH), 7.61 (2H, d, J = 8 Hz, H-Ar), 7.87-7.89 (2H, m, H-Ar),
8.18 (2H, d, J = 8 Hz, H-Ar), 8.20-8.23(1H, m, H-Ar), 8.35-8.36 (1H, m, H-Ar) ppm. 13C
NMR (500 MHz, CDCl3): δ = 14.1, 59.8, 63.2, 123.6, 127.7, 127.9, 128.5, 128.7, 133.9,
7

135, 145.7, 147.7, 154.1, 157.2 ppm. HRMS calcd for C20H16N4O6: 408.3642, found:
408.3640.
(9f). Ethyl-3-amino-1-(4-chlorophenyl)-5, 10-dioxo-5, 10-dihydro-1H-pyrazolo [1, 2-b]
phthalazine-2-carboxylate
Pale yellow powder (89 %); mp. 275-277 0C; [α]D25 = -2.40 (c = 0.12, pyridine). 1H NMR
(500 MHz, CDCl3): δ = 1.11 (3H, brs, -CH3), 4.08 (2H, q, J = 7 Hz, -OCH2), 6.26 (1H, s,
CH), 7.30 (2H, t, J = 8 Hz, H-Ar), 7.40 (2H, d, J = 8 Hz, H-Ar), 7.86-7.90 (2H, m, H-Ar),
8.27-8.30 (1H, m, H-Ar), 8.35-8.37 (1H, m, H-Ar) ppm. 13C NMR (500 MHz, CDCl3): δ
= 14.2, 59.7, 63.4, 127.7, 127.7, 128.5, 128.6, 129, 129.1, 133.6, 134.07, 134.7, 137.1,
153.7, 157.2 ppm. HRMS calcd for C20H16ClN3O4: 397.8176, found: 397.8174.
(9i). Ethyl-3-amino-1-(3-methoxyphenyl)-5, 10-dioxo-5, 10-dihydro-1H-pyrazolo [1, 2-
b] phthalazine-2-carboxylate
Pale yellow powder (87 %); mp. 256-258 0C; [α]D25 = -1.89 (c = 0.18, pyridine). 1H NMR
(500 MHz, CDCl3): δ = 1.12 (3H, t, J = 7 Hz, -CH3), 3.80 (3H, s, -OMe), 4.09 (2H, q, J =
7 Hz, -OCH2), 6.26 (1H, s, -CH), 6.83 (1H, dd, J = 2, 8, Hz, H-Ar), 6.98 (1H, t, J = 1.8
Hz, H-Ar), 7.05 (1H, d, J = 8 Hz, H-Ar), 7.26 (1H, q, J = 8 Hz, H-Ar), 7.84-7.89 (2H, m,
H-Ar), 8.27-8.30 (1H, m, H-Ar), 8.34-8.37 (1H, m, H-Ar) ppm. 13C NMR (500 MHz,
CDCl3): δ = 14.2, 59.6, 63.9, 82.9, 113.4, 113.5, 120, 127.6, 127.7, 128.6, 129.3, 129.3,
8

133.4, 134.6, 140.3, 134.7, 137.1, 153.8, 157.2, 159.5 ppm. HRMS calcd for C21H19N3O5,
393.3960, Found: 393.3959.
ACKNOWLEDGEMENTS
We gratefully acknowledge to the Department of Chemistry, University of Rajshahi,
Bangladesh for the facility given during our present work and to Green Chemistry
Laboratory, KRICT for the necessary spectral help.
REFERENCES
1.
2.
Strecker, A.; Liebigs Ann. Chem.1850, 75, 27.
Anastas, P. T.; Warner, J. C. 'In Green Chemistry: Theory and Practice; Oxford
University Press: Oxford, UK, 1998; Anastas, P. T.; Williamson, T. 'In Green Chemistry:
Frontiers in Benign Chemical Synthesis and Process, Oxford University Press, Oxford,
UK, 1998.
3.
Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
Kappe, C. O. Acc. Chem. Res. 2000, 33, 879.
4.
5.
Trett, N. K.; Bell, A. S.; Brown, D.; Ellis, P. Bioorg. Med. Chem. Lett. 1996, 6,
1819.
6.
Elguero, J. 'In Comprehensive Heterocyclic Chemistry II,' Vol. 3; Katritzky, A.
R.; Rees, C. W.; Scriven, E. F. Eds. Elsevier Oxford 1996, 1
7. Singh, S. K.; Reddy, P. G.; Rao, S. K.; Lohray, B. B.; Misra, P.; Rajjak, S. A.;
Rao, Y. K.; Venkatewarlu, A. Bioorg. Med. Chem. Lett. 2004, 14, 499.
9

8.
Genin, M. J.; Biles, C.; Keiser, B. J.; Poppe, S. M.; Swaney, S. M.; Tarpley, W.
G.; Yagi, Y.; Romero, D. L. J. Med. Chem. 2000, 43, 1034; O’Hagan, D. J.; Fluorine
Chem. 2010, 131, 1071.
9.
Al’-Assar, F.; Zelenin, K. N.; Lesiovskaya, E. E.; Bezhan, I. P.; Chakchir, B. A.
Pharm. Chem. J. 2002, 36, 598.
10.
11.
12.
Li, J.; Zhao, Y. F.; Yuan, X. Y.; Xu, J. X.; Gong, P. Molecules 2006, 11, 574.
Jain, R. P.; Vederas, J. C. Bioorg. Med. Chem. Lett. 2004, 14, 3655.
Carling, R. W.; Moore, K. W.; Street, L. J.; Wild, D.; Isted, C.; Leeson, P. D.;
Thomas, S.; O’ Conner, D.; Mckernan, R. M.; Quirk, K.; Cook, S.M.; Atack, J. R.;
Waftord, K. A.; Thompson, S. A.; Dawson, G. R.; Ferris P.; Castro, J. L. J. Med. Chem.
2004, 47, 1807.
13.
Grasso, S.; DeSarro, G.; Micale, N.; Zappala, M.; Puia, G.; Baraldi, M.;
Demicheli, C. J. Med. Chem. 2000, 43, 2851; Nomoto, Y.; Obase, H.; Takai, H.;
Teranishi, M.; Nakamura, J.; Kubo, K. Chem. Pharm. Bull. 1990, 38, 2179; Watanabe,
N.; Kabasawa, Y.; Takase, Y.; Matsukura, M.; Miazaki, K.; Ishihara, H.; Kodama, K.;
Adachi, H. J. Med. Chem. 1998, 41, 3367.
14.
Liu, J. N.; Li, J.; Zhang, L.; Song, L. P.; Zhang, M.; Cao, W. G.; Zhu, S. Z.;
Deng, H. G.; Shao, M. Tetrahedron Lett. 2012, 53, 2469; Kim, J. S.; Rhee, H. K.; Park,
H. J.; Lee, S. K.; Lee, C.O.; Park Choo, H.-Y. Bioorg. Med. Chem. 2008, 16, 4545; El-
Sakka, S. S.; Soliman A. H.; Imam, A. M. Afimdad 2009, 66, 167; Ryu,C. K.; Park, R.
E.; Ma, M. Y.; Nho, J. H. Bioorg. Med. Chem. Lett. 2007, 17, 2577.
15.
Ziarani, G. M.; Mohtasham, N. H.; Badiei, A.; Lashgari, N. J. Chin. Chem. Soc.
2014, 61, 990; Shaterian, H. R.; Mohammadnia, M. Res. Chem. Int., 2014, 40, 371;
10

Ghomi, J. S.; Alavi, H. S.; Ziarati, A.; Teymuri, R.; Saberi, M. R. Chin. Chem. Lett.
2014, 25, 401.
16.
17.
Agarwal, A.; Chauhan, P. M. S. Tetrahedron Lett. 2005, 46, 1345.
Wang, X.-S.; Zhang, M.-M.; Jiang, H.; Yao C.-S.; Tu, S.-J. Tetrahedron, Lett.
2007, 63, 4439.
18.
19.
Maggi,R.; Ballini, R.; Sartori, G.; Sartorio, R. Tetrahedron Lett. 2004, 45, 2297.
Magedov,I. V.; Manpadi, M.; Evdokimov, N. M.; Elias, E. M.; Rozhkova, E.;
Ogasavara, M. A.; Bettale, J. D.; Przheval’ski, N. M.; Rogelj S.; Kornienko, A. Bioorg.
Med. Chem. Lett. 2007, 17, 3872.
20.
21.
Wang, X.-S.; Shi, D.-Q.; Wei X.-Y.; Zong, Z.-M. J. Chem. Res. 2004, 679.
Dalko P. I.; Moisan, L. Angew. Chem. Int. Ed. Engl. 2004, 43, 5138; Dalko P. I.;
Moisan, L. Angew. Chem. Int. Ed. Engl. 2001, 41, 3726; Grieco, P. A. 'Organic Synthesis
in Water, Blackie Academic & Profesional, London 1998; Lindström, U. M. Chem. Rev.
2002, 102, 2751; Li,C.-J. Chem. Rev. 2005, 105, 3095; Li C.-J.; Cheng, L. Chem. Soc.
Rev. 2006, 35, 68. Raj, M.; Singh, V. K. Chem. Com., 2009, 6687; For recent examples
on organocatalyzed reaction in water, see: Hayashi,Y.; Sumiya, T.; Takahashi, J.; Gotoh,
H.; Urashima, T.; Shoji, M. Angew. Chem. Int. Ed. 2006, 45, 958; Mase, N.; Nakai, Y.;
Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F. III. J. A. Chem. Soc. 2006,
128, 734.
22.
Roy, H. N.; Pitchaiah, A.; Kim, M. I.; Hwang, T.; Lee, K.-I. RSC Adv. 2013, 3, 3526.
23. Janardhan, B.; Ravibabu, V.; Crooks, P. A.; Rajitha, B. Org. Commun 2012, 5(4),
Roy, H. N.; Rahman, M. M.; Pramanick, P. K. Indian J. Chem. 2013, 52B, 153;
186; An, Z.; Zhang, W.; Shi H.; He, J. J. Cat. 2006, 241, 319; Wang, Y.; Shang, Z. C.;
11

Wu, T. X.; Fan, J. C. Chen, X. J. Mol. Catal. A: Chem. 2006, 253, 212; Karade, N. N.;
Budhewar, V. H.; Shinde, S. V.; Jadhav, W. N. Lett. Org. Chem. 2007, 4, 16; Srinivasan,
M.; Perumal, S.; Selvaraj, S. Arkivoc 2005, xi, 201; Sabitha, G.; Fatima, N.; Reddy E.
V.; Yadav, J. S. Adv. Syn th. Catal. 2005, 347, 1353; Dodda, R.; Zhao, C. G. Synthesis
2006, 19, 3238.
24.
Pandey, A. K.; Naduthambi, D.; K. Thomas, M.; Zondlo, N. J. J. Am. Chem. Soc.
2013, 135, 4333; Mclain, S. E.; Soper, A. K.; Terry, A. E.; Watts, A. J. Phys. Chem. B.
2007, 111, 4568.
25.
Song, S.-H.; Zhong, j.; He, Y.-H.; Guan, Z. Tetrahedron Lett. 2012, 53, 7075;
Nabid, M. R.; Rezaei, S. J. T.; Ghahremanzadeh, R.; Bazgir, A. Ultrasonics Sonochem
2010, 17, 159; Razvi, M.; Ramalingam, T.; Sattur, P. B Indian J. Chem. Sect B: 1989,
28B, 695; Aziz Elassar, A. Z. A.; Elkholy, Y. M.; Elnagdi, M. H. Pharmazie 1996, 51,
714; Raghuvanshi, D. S.; Singh, K. N. Tetrahedron Lett. 2011, 52, 5702.
12

Table 1: Effects of catalysts, solvents & reaction temperature.a
Entry
Catalyst
mol %
Solvent
Temperature (oC)
Time (hour)
yield (%)b
I
Without catalyst
-
CH3CN, EtOH,
H2O
RT, Reflux (80)
RT, Reflux (80)
RT, Reflux (80)
RT
> 48
> 48
> 48
> 48
No
II
2-or 3-picolinic
acid
5, 10, 15, CH3CN, EtOH,
No
20
H2O
III
IV
V
L-cystein
5, 10,
15,20
10
CH3CN, EtOH,
H2O
No
LiCl
CH3CN, EtOH,
H2O
No
LiCl
5~20
5, 10
EtOH
40, 55, 60, Reflux > 48
(80)
30 ~ 32
No
VI
L-proline
EtOH, H2O
RT
35
> 48
VII
VIII
IX
L-proline
5
CH3CN, EtOH
EtOH
> 48
10 ~ 25
~50
L-proline
10
Reflux (80)
Reflux (80)
20~24
18~24
L-proline + LiCl
10 + (~5) EtOH
75
X
L-proline + LiCl 10 + (~5) EtOH : H2O
Reflux (80)
Reflux (80)
Reflux (80)
10~12
10~12
10~12
91
89
88
(1:1)
XI
XII
L-proline + LiCl 15 + (~5) EtOH : H2O
(1:1)
L-proline + LiCl 20 + (~5) EtOH : H2O
(1:1)
aReaction condition: aromatic aldehyde (1.0 mmol), phthalimide (1.0 mmol), hydrazine
hydrate (1.2 mmol), ethyl cyanoacetate (1.0 mmol) and catalyst in solvent.
b Isolated yields.
13

Table 2: Synthesis of 1H-pyrazolo [1, 2-b] phthalazine-5, 10-diones derivatives.a
Entry
1
Substituent on Aldehyde Product
Time (hour) Yield (%)b M. p 0C
4-O2NC6H4-
2-O2NC6H4-
3-O2NC6H4-
C6H5-
9a
9b
9c
9d
9e
9f
10~12
10~12
10~12
10~12
10~12
10~12
10~12
10~12
10~12
10~12
10~12
10~12
> 48
90
87
85
88
87
89
88
90
87
88
89
87
No
No
No
No
No
No
No
242-244
238-241
236-238
245-247
136-138
275-277
238-240
262-264
256-258
199-200
205-207
190-192
2
3
4
5
C10H7-
6
4-ClC6H4-
7
2-ClC6H4-
9g
9h
9i
8
4-CH3OC6H4-
3-CH3OC6H4-
3-BrC6H4-
9
10
11
12
13
14
15
16
17
18
19
9j
4- CH3C6H4-
C7H5O2-
9k
9l
4-HOC6H4-
C6H3C2H2(NH)-
2,4-(OH)2C6H3-
2-OH, 5-BrC6H3-
4-(CH3)2NC6H4-
2-HOC6H4-
C4H3O-
9m
9n
9o
9p
9q
9r
> 48
> 48
> 48
> 48
> 48
9s
> 48
aReaction condition: aromatic aldehyde (1.0 mmol), phthalimide (for coumpounds 9f-9i
phthalic anhydride was used) (1.0 mmol), hydrazine hydrate (1.2 mmol), ethyl
cyanoacetae (1.0 mmol), L-proline (0.1 mmol) and LiCl (0.002 mmol) in ethanol : water
(1:1).
bIsolated yield.
14

Scheme 1: Synthesis of 1H-pyrazolo [1, 2-b] phthalazine-5, 10-diones derivatives
Scheme 2: Tentative mechanistic path way for the formation of substituted phthalazine
derivatives
15