Potassium carbonate-mediated efficient and convenient synthesis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1 H)-ones

Article abstract of DOI:10.1080/00397911.2013.879184

Unprecedented cyclization was observed during N-sulfonylation of 3-[1-(phenylhydrazono)-ethyl]-chromen-2-one in pyridine, affording 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones. To avoid use of noxious pyridine, reaction was tried in different basic

Full text of DOI:10.1080/00397911.2013.879184

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Potassium Carbonate–Mediated Efficient
and Convenient Synthesis of 3-Methyl-1-
phenylchromeno[4,3-c]pyrazol-4(1H)-
ones
Jagdeep Grover a , Somendu Kumar Roy a & Sanjay Madhukar Jachak
a
a Department of Natural Products , National Institute of
Pharmaceutical Education and Research , Mohali , Punjab , India
Accepted author version posted online: 18 Mar 2014.Published
online: 29 May 2014.
To cite this article: Jagdeep Grover , Somendu Kumar Roy & Sanjay Madhukar Jachak (2014)
Potassium Carbonate–Mediated Efficient and Convenient Synthesis of 3-Methyl-1-phenylchromeno[4,3-
c]pyrazol-4(1H)-ones, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 44:13, 1914-1923, DOI: 10.1080/00397911.2013.879184
To link to this article: http://dx.doi.org/10.1080/00397911.2013.879184
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Synthetic Communications1, 44: 1914–1923, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.879184
POTASSIUM CARBONATE–MEDIATED EFFICIENT
AND CONVENIENT SYNTHESIS OF 3-METHYL-1-
PHENYLCHROMENO[4,3-c]PYRAZOL-4(1H)-ONES
Jagdeep Grover, Somendu Kumar Roy, and
Sanjay Madhukar Jachak
Department of Natural Products, National Institute of Pharmaceutical
Education and Research, Mohali, Punjab, India
GRAPHICAL ABSTRACT
Abstract Unprecedented cyclization was observed during N-sulfonylation of 3-[1-
(phenylhydrazono)-ethyl]-chromen-2-one in pyridine, affording 3-methyl-1-phenylchro-
meno[4,3-c]pyrazol-4(1H)-ones. To avoid use of noxious pyridine, reaction was tried in
different basic conditions and the best results were obtained with potassium carbonate in
acetone. A wide range of substrates bearing either electron-donating or electron-withdrawing
substituents on phenylhydrazine ring were compatible with the developed methodology.
Rapid access of starting material, 3-acetylcoumarin, excellent yields of products, and
use of environmentally benign base and solvent for the cyclization make this strategy an
efficient and convenient method for synthesis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-
4(1H)-ones.
Keywords Acetone; 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones; potassium
carbonate
Received October 11, 2013.
Address correspondence to Sanjay Madhukar Jachak, Department of Natural Products, National
Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar, Mohali 160062,
Punjab, India. E-mail: sanjayjachak@niper.ac.in
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
1914

EFFICIENT SYNTHESIS OF CHROMENOPYRAZOLES
1915
INTRODUCTION
Pyrazole and its derivatives are well explored as anti-inflammatory,[1,2]
antiviral,[3,4] antimalarial,[5,6] HIV-reverse transcriptase inhibitors,[7,8] antimicro-
bial,[9,10] and antitumor agents.[11,12] In particular, 3-methyl-1-phenylchromeno[4,3-c]
pyrazol-4(1H)-ones are well known for their affinity toward benzodiazepine central
receptor and are used as an intermediate to synthesize immunomodulatory drugs.[13]
In the literature, several methods for the synthesis of chromenopyrazoles have been
reported, such as reaction of arylidenechromones and hydrazine in basic media,[14]
nucleophilic rearrangement of 3-cyano-4-[(o-hydroxy)phenyl]-1-phenyl-3-methylpyr-
azole (path a, Scheme 1),[15] and 3-chromonecarboxylic acids (path b, Scheme 1),[16]
intramolecular conjugate substitution of coumarin hydrazones (path c, Scheme 1),[17]
employing catalysts such as Zn[L-proline]2.[18] However, most of these methods
require the presence of a leaving group (chloro, hydroxyl, and O-tosyl) at C-4 pos-
ition of 3-acetylcoumarin and use of high-boiling solvents, making access to starting
material cumbersome. Other methods using 2-methylchromonecarbonitrile[15] and
3-chromonecarboxylic acids[16] as synthones suffer from the drawback that the prep-
aration of these starting materials requires two to three steps. Recently, a few reports
based on oxidative cyclization of coumarin hydrazones, utilizing catalyst such as cop-
[21]
have been described in the
per acetate,[19] CuO=SBA-15,[20] and Cu (SO3)2CF3
literature (path d, Scheme 1). Yang et al. reported cyclization of coumarin hydra-
zones by air oxidation and catalytic oxidation under solvent-free conditions. How-
ever, the air oxidation and solvent-free conditions required long reaction time for
90–94% conversion (12–25 days, in case of air oxidation and 34 h under solvent-free
Scheme 1. Various methods of preparation of chromenopyrazoles.

1916
J. GROVER, S. K. ROY, AND S. M. JACHAK
conditions). In addition to long reaction time, elevated temperature up to 150 ꢀC is
required under solvent-free conditions that make the overall methodology
inconvenient.[21] Although these methods rule out the requirement of leaving group
at C-4 position of coumarin hydrazones, they suffer from certain drawbacks such as
low to moderate yield of desired compounds, difficulty in separation, and recycling of
homogeneous catalyst. Moreover, in the case of method employing CuO=SBA-15,
special efforts are required for the preparation of catalyst. The approach utilizing
copper catalysts is based on transmetallation followed by conjugate addition of
organocopper reagent. A nucleophilic activation of secondary nitrogen of coumarin
hydrazone to facilitate the cyclization could serve as an alternative approach. We
observed an unexpected cyclization when N-sulfonylation of 2 was attempted in
the presence of methanesulphonyl chloride using pyridine both as a base and a
solvent. The reaction resulted in the formation of 4 instead of 3 (Scheme 2). The
observed cyclization eliminates requirement of a leaving group at C-4 position of
coumarin hydrazone and use of additional metal catalyst, making the overall
synthesis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones simple and
efficient. Also, the use of noxious agent such as POCl3, which is required for the
synthesis of starting material 3-acetyl-4-hydroxycoumarin, as an additional step
could be avoided.[22]
One-pot easy access of starting material and formation of desired chromeno-
pyrazole in good yield along with our desire to find a substitute of noxious pyridine
encouraged us to study the cyclization of 3-[1-(phenylhydrazono)ethyl]chromen-
2-ones. Inspired from the unexpected cyclization of coumarin hydrazones into
their corresponding pyrazoles under basic conditions, herein we report an efficient
and environmentally benign synthesis of chromenopyrazoles utilizing the simple
and economic base potassium carbonate in a less hazardous solvent such as acetone.
To the best of our knowledge, this is the first report on the development of a
methodology based on base-induced nucleophilic activation–cyclization of 3-[1-
(phenylhydrazono)ethyl]chromen-2-ones for the synthesis of chromenopyrazoles.
Scheme 2. Synthesis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-one.

EFFICIENT SYNTHESIS OF CHROMENOPYRAZOLES
1917
RESULTS AND DISCUSSION
3-Acetylcoumarin (1) was synthesized by Knoevenagel condensation of com-
mercially available salicylaldehyde and ethyl acetoacetate.[2] It was then converted
into 3-[1-(phenylhydrazono)-ethyl]-chromen-2-one (2) by treating it with phenylhy-
drazine, followed by reaction with methanesulfonyl chloride in pyridine to form
its N-sulfonyl derivative (3). Unprecedently, it underwent cylization to afford 4
(Scheme 2). The cyclization of 2 in the absence of leaving group at C-4 position
was surprising, as cyclization of this class of compounds is generally reported in
the presence of a leaving group at the C-4 position. A similar experiment was repeated
using pyridine in the absence of methanesulfonyl chloride and it again furnished com-
pound 4. While attempting these reactions, it was observed that 2a cyclized to corre-
sponding pyrazole compound 4a (25–30% yield) under base-free conditions when
kept in chloroform for 2 days at room temperature, which is also witnessed in the
literature.[19,21] So, we hypothesize that rate of cyclization might increase under reflux
conditions of solvent. To substantiate our hypothesis, we performed similar reaction
under reflux conditions of acetone, chloroform, and ethanol. However, it was
observed that reaction did not proceed to completion even after refluxing for 24 h
(Table 1, entry 1). Based on the aforementioned finding, we anticipated that base
could act as a driving force by enhancing the nucleophilicity of secondary nitrogen
of coumarin hydrazone and facilitate aromatization. Thus, to gain more understand-
ing of this reaction and obliterate the limitations of the earlier methods, different
bases and solvents were explored to arrive at the best possible yield (Table 1). The
reaction was attempted using triethylamine and piperidine in place of pyridine, but
poor solubility of compound 2a in these bases necessitates the use of solvent. Chloro-
form was selected as a one of the solvents as it facilitated cyclization under base-free
conditions. In addition, other aprotic (acetone) and protic (ethanol) solvents were
tried. It was observed that organic bases gave products in moderate to poor yields
when ethanol was used as a solvent (Table 1, entries 2–7). The competitive proton
abstraction by the base from ethanol and decrease in the nucleophilicity of secondary
nitrogen due to hydrogen bonding with ethanol may account for the poor yield.
Further, aprotic solvents such as chloroform and acetone were explored and the reac-
tion worked quite well with acetone. This may be due to the fact that acetone is a more
polar aprotic solvent as compared to chloroform. Similar results were obtained in the
case of inorganic bases such as potassium carbonate and sodium carbonate (Table 1,
entries 8 and 9). Strong bases such as NaOH and KOH were found to be ineffective
under all solvent conditions, as substantial decomposition, multitude of side pro-
ducts, or poor yields were obtained (Table 1, entries 10 and 11). Competitive proton
abstraction of olefinic and methyl proton by strong bases may account for formation
of complex reaction mixtures. An excellent yield of desired product was obtained
when the reaction was carried out with potassium carbonate in acetone. Further, to
investigate the effect of amount of base on the reaction completion, different amounts
of potassium carbonate were used. The use of stoichiometric amounts of potassium
carbonate has little impact on reaction time and percentage yield (Table 2, entries 1
and 2). However, with catalytic amount, we obtained comparatively lower yield of
4a, with concomitant longer reaction time (Table 2, entry 3). Therefore, we intended
to use 1 equiv of potassium carbonate to examine the substrate scope under optimized

1918
J. GROVER, S. K. ROY, AND S. M. JACHAK
Table 1. Optimization of various alkaline and solvents conditions for the cyclization of
3-[1-(phenylhydrazono)ethyl]chromen-2-one (2a)a
Entry
1
Base (1 equiv)
None
Solvent
Isolated yield (%)
CHCl3
EtOH
30
20
Acetone
neat
45
85
2
3
Pyridineb
Triethylamine
CHCl3
EtOH
40
25
Acetone
CHCl3
EtOH
65
45
4
5
DMAP
Piperidine
DBU
28
60
Acetone
CHCl3
EtOH
32
18
Acetone
CHCl3
EtOH
69
40
6
30
72
Acetone
CHCl3
EtOH
7
DABCO
K2CO3
Na2CO3
NaOH
KOH
42
28
Acetone
CHCl3
EtOH
75
8
51
32
Acetone
CHCl3
EtOH
97
45
9
22
Acetone
CHCl3
EtOH
83
10
11
No reactionc
No reactionc
No reactionc
No reactionc
No reactionc
No reactionc
Acetone
CHCl3
EtOH
Acetone
aThe reactions were carried out with 2a (0.72 mmol) and base (0.72 mmol) at 50 ꢀC for 24 h.
b2 equiv were used.
cDesired products were not formed.
conditions. As potassium carbonate has gained recognition as favorable environmen-
tally benign alternatives[23,24] and acetone represents class 3 solvent,[25] the present
methodology adds to the development of sustainable chemistry.

EFFICIENT SYNTHESIS OF CHROMENOPYRAZOLES
1919
Table 2. Effect of amounts of potassium carbonate on cyclization of 2a
Entry
Equiv
Time (h)
Isolated yield (%)
1
2
3
1.5
2
16
12
28
92
88
85
0.5
To illustrate the versatility of developed methodology, a variety of phenylhydra-
zines were used as starting materials, and results are depicted in Table 3. Apart from
3-acetylcoumarin, the substrate scope of optimized conditions was also extended to
3-acetyl-7-methoxycoumarin as a starting material. The desired products were formed
in excellent yields in all cases. Almost all substrates containing either electron-
withdrawing or donating groups reacted at nearly the same time (15–18 h) except
for compound 2b, 2e, 2f, and 2o. The short reaction time of 2b and 2e might be
because of easy activation and enhanced nucleophilicity of the nitrogen center due
to strong electron-withdrawing effect of halogen substituents, whereas 2f and 2o took
longer time because of electron-donating substituents, which has a reverse effect. The
observed effect of electronic nature of substituent on the rate of aza-Michael addition
is supported by aza-Michael addition reactions of 4-nitrophthalimide with a,b-
unsaturated ketones, which revealed that activation of Michael donor is enhanced
when substituted with electron-withdrawing groups.[26] The products were isolated
Table 3. Synthesis of various chromenopyrazoles using optimized conditions
Entry
Ar
R
Product
Time (h)
Isolated yield (%)
1
2
C6H5-(2a)
4-CF3-C6H4-(2b)
4-Cl-C6H4-(2c)
4-Br-C6H4-(2d)
2,4-(Cl)2-C6H3-(2e)
2,5-(CH3)2C6H3-(2f)
2-CF3-C6H4-(2g)
4-F-C6H4 (2h)
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
18
10
15
15
10
24
15
14
17
17
15
15
15
15
24
95
90
93
95
90
89
91
92
98
92
96
95
96
90
88
3
4
5
6
7
4g
4h
4i
8
9
C6H5-(2i)
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
10
11
12
13
14
15
2-CF3-C6H4-(2j)
4-CF3-C6H4-(2k)
4-Cl-C6H4-(2l)
4j
4k
4l
4-Br-C6H4-(2m)
4-F-C6H4-(2n)
2,5-(CH3)2C6H3 (2o)
4m
4n
4o

1920
J. GROVER, S. K. ROY, AND S. M. JACHAK
Scheme 3. Plausible mechanism of cyclization.
by employing simple workup such as filtration followed by recrystallization in
methanol. The structural assignments of synthesized compounds were made on the
basis of 1H NMR, 13C NMR, and high-resolution mass spectrometry (HRMS).
Keeping in view these observations and related literature,[19,22] a plausible
mechanism of this reaction is depicted in Scheme 3. First, under a reversible mech-
anism, the substrate 2 undergoes intramolecular Michael addition to give intermedi-
ate 3a. Base plays a catalytic role by deprotonating 3a instead of 2, because the NH
proton of 2 is not acidic enough to be abstracted by weak or mild bases. Because of
resonance stabilization, 2 require strong basic conditions to generate an anion, which
is evidenced from the literature.[27,28] Subsequently, resonance stabilization of 3a to
afford dihydro-pyrazolone intermediate 3b is followed by in situ irreversible oxidative
dehydrogenation by oxygen in the air to furnish final compounds.
EXPERIMENTAL
All the chemicals were procured from Sigma Aldrich (U.S.A.), S.D. Fine
Chemicals, and Alfa Aesar (India). Thin-layer chromatography (TLC) was per-
1
formed on precoated TLC silica-gel 60 F254 plates (Merck, Germany). H NMR
spectra were recorded on Bruker Avance III 400 spectrometer operating at a fre-
quency of 400.13 MHz for protons, and tetramethylsilane (TMS) was used as an
internal standard. Chemical shifts are reported as d values and referenced to CDCl3
(for 1H NMR 7.26 ppm and for 13C NMR 77.00 ppm). HRMS spectra were recorded
on MaXisTM UHR-TOF (Bruker, Singapore). Melting points were determined on a
digital melting-point apparatus (Perfit, India).

EFFICIENT SYNTHESIS OF CHROMENOPYRAZOLES
1921
General Procedure for Synthesis of 3-Methyl-1-phenylchromeno
[4,3-c]pyrazol-4(1H)-ones (4)
The reaction mixture containing 3-acetylcoumarin (3.5 mmol) and various
substituted phenylhydrazines (3.7 mmol) was refluxed in ethanol (10 mL) for 5 h,
and reaction progress was monitored by thin-layer chromatography (TLC). On com-
pletion of the reaction, the solvent was removed from the reaction mixture under
vacuum to afford the corresponding coumarin hydrazones, which were further used
for cyclization without purification. For cyclization, a reaction mixture containing
coumarin hydrazones (1.09 mmol) and potassium carbonate (1.09 mmol) was
refluxed in acetone (5 mL) for 10–24 h. Reaction was monitored by TLC. On com-
pletion, the reaction mixture was filtered and the solvent was removed under reduced
pressure. Finally crystallization was done in methanol to get pure compounds in
excellent yield.
CONCLUSION
In summary, an efficient and novel protocol for the cyclization of 3-[1-(phenyl-
hydrazono)ethyl]-chromen-2-ones into corresponding pyrazoles using potassium
carbonate as catalyst in acetone has been developed. The developed methodology
eliminates the requirement of a leaving group at C-4 position of starting material
3-acetylcoumarin. The nonhazardous experimental conditions, rapid access of start-
ing material, and good yields of desired products made this methodology simple and
economical.
FUNDING
Authors thank the director of NIPER for providing financial assistance and
necessary facilities to carry out this work.
SUPPLEMENTARY DATA
Full experimental detail, mp, 1H NMR, 13C NMR, and HRMS spectra for this
article can be accessed on the publisher’s website.
REFERENCES
1. Selvam, C.; Jachak, S. M.; Thilagavathi, R.; Chakraborti, A. K. Design, synthesis,
biological evaluation, and molecular docking of curcumin analogues as antioxidant,
cyclooxygenase inhibitory, and anti-inflammatory agents. Bioorg. Med. Chem. Lett.
2005, 15, 1793–1797.
2. Khode, S.; Maddi, V.; Aragade, P.; Palkar, M.; Ronad, P. K.; Mamledesai, S.;
Thippeswamy, A. H. M.; Satyanarayana, D. Synthesis and pharmacological evaluation
of a novel series of 5-(substituted) aryl-3-(3-coumarinyl)-1-phenyl-2-pyrazolines as novel
anti-inflammatory and analgesic agents. Eur. J. Med. Chem. 2009, 44, 1682–1688.
3. Goodell, J. R.; Puig-Basagoiti, F.; Forshey, B. M.; Shi, P.-Y.; Ferguson, D. M.
Identification of compounds with anti–West Nile virus activity. J. Med. Chem. 2006,
49, 2127–2137.

1922
J. GROVER, S. K. ROY, AND S. M. JACHAK
4. Ouyang, G.; Cai, X.-J.; Chen, Z.; Song, B.-A.; Bhadury, P. S.; Yang, S.; Jin, L.-H.; Xue,
W.; Hu, D.-Y.; Zeng, S. Synthesis and antiviral activities of pyrazole derivatives contain-
ing an oxime moiety. J. Agric. Food Chem. 2008, 56, 10160–10167.
5. Stein, R. G.; Biel, J. H.; Singh, T. Antimalarials: 4-Substituted 1H-pyrazolo [3,4-b]
quinolines. J. Med. Chem. 1970, 13, 153–155.
6. Mishra, S.; Karmodiya, K.; Surolia, N.; Surolia, A. Synthesis and exploration of
novel curcumin analogues as anti-malarial agents. Bioorg. Med. Chem. Lett. 2008, 16,
2894–2902.
7. Sweeney, Z. K.; Harris, S. F.; Arora, N.; Javanbakht, H.; Li, Y.; Fretland, J.; Davidson, J. P.;
Billedeau, J. R.; Gleason, S. K.; Hirschfeld, D. Design of annulated pyrazoles as inhibitors of
HIV-1 reverse transcriptase II. J. Med. Chem. 2008, 51, 7449–7458.
8. Lynch, C. L.; Hale, J. J.; Budhu, R. J.; Gentry, A. L.; Finke, P. E.; Caldwell, C. G.; Mills,
S. G.; MacCoss, M.; Shen, D.-M.; Chapman, K. T. CCR5 antagonists: 3-(Pyrrolidin-1-yl)
propionic acid analogues with potent anti-HIV activity. Org. Lett. 2003, 5, 2473–2475.
9. Tanitame, A.; Oyamada, Y.; Ofuji, K.; Fujimoto, M.; Iwai, N.; Hiyama, Y.; Suzuki, K.;
Ito, H.; Terauchi, H.; Kawasaki, M. Synthesis and antibacterial activity of a novel series of
potent DNA gyrase inhibitors: Pyrazole derivatives. J. Med. Chem. 2004, 47, 3693–3696.
10. Holla, B. S.; Mahalinga, M.; Karthikeyan, M. S.; Akberali, P. M.; Shetty, N. S. Synthesis
of some novel pyrazolo[3,4-d]pyrimidine derivatives as potential antimicrobial agents.
Bioorg. Med. Chem. Lett. 2006, 14, 2040–2047.
11. Baraldi, P. G.; Balboni, G.; Pavani, M. G.; Spalluto, G.; Tabrizi, M. A.; Clercq, E. D.;
Balzarini, J.; Bando, T.; Sugiyama, H.; Romagnoli, R. Design, synthesis, DNA binding,
and biological evaluation of water-soluble hybrid molecules containing two pyrazole
analogues of the alkylating cyclopropylpyrroloindole (CPI) subunit of the antitumor
agent CC-1065 and polypyrrole minor groove binders. J. Med. Chem. 2001, 44, 2536–
2543.
12. Lin, R.; Chiu, G.; Yu, Y.; Connolly, P. J.; Li, S.; Lu, Y.; Adams, M.; Fuentes-Pesquera,
A. R.; Emanuel, S. L.; Greenberger, L. M. Design, synthesis, and evaluation of 3,4-
disubstituted pyrazole analogues as anti-tumor CDK inhibitors. Bioorg. Med. Chem. Lett.
2007, 17, 4557–4561.
13. Colotta, V.; Cecchi, L.; Filacchioni, G.; Melani, F.; Palazzino, G.; Martini, C.;
Giannaccini, G.; Lucacchini, A. Synthesis, binding studies, and structure–activity rela-
tionships of 1-aryl-and 2-aryl [1] benzopyranopyrazol-4-ones, central benzodiazepine
receptor ligands. J. Med. Chem. 1988, 31, 1–3.
14. Kidwai, M.; Singhal, K.; Rastogi, S. A convenient K2CO3-catalysed regioselective
synthesis for benzopyrano[4,3-c]pyrazoles in aqueous medium. Heterocycles 2007, 71,
569–576.
15. Colotta, V.; Cecchi, L.; Melani, F.; Palazzino, G.; Filacchioni, G. The correct synthesis of
2,3-dihydro-2-aryl-4-r-[1] benzopyrano [4, 3-c] pyrazole-3-ones. Tetrahedron Lett. 1987,
28, 5165–5168.
16. Chantegrel, B.; Nodi, A.-I.; Gelin, S. 4-Oxo-1H-and-2H-[1]benzopyrano[4,3-c]pyrazoles:
Preparation from 4-hydroxycoumarin or 3-chromonecarboxylic acid derivatives. Tetra-
hedron Lett. 1983, 24, 381–384.
17. Stadlbauer, W.; Hojas, G. Ring closure reactions of 3-arylhydrazonoalkyl-quinolin-2-ones
to 1-aryl-pyrazolo [4, 3-c] quinolin-2-ones. J. Heterocycl. Chem. 2004, 41, 681–690.
18. Manvar, A.; Bochiya, P.; Virsodia, V.; Khunt, R.; Shah, A. Microwave-assisted and
Zn[l-proline]2-catalyzed tandem cyclization under solvent-free conditions: Rapid synthesis
of chromeno[4,3-c]pyrazol-4-ones. J. Mol. Catal. A: Chem. 2007, 275, 148–152.
˜
19. Padilla-Martinez, I. I.; Flores-Larios, I. Y.; GarcAa-Baez, E. V.; Gonzalez, J.; Cruz, A.;
˜
MartAnez-Martinez, F. J. X-ray supramolecular structure, NMR spectroscopy, and
synthesis of 3-methyl-1-phenyl-1-H-chromeno[4,3-c]pyrazol-4-ones formed by the

EFFICIENT SYNTHESIS OF CHROMENOPYRAZOLES
1923
unexpected cyclization of 3-[1-(phenyl-hydrazono)ethyl]-chromen-2-ones. Molecules 2011,
16, 915–932.
20. Yang, G.-Y.; Yang, J.-T.; Wang, C.-X.; Fan, S.-F.; Xie, P.-H.; Xu, C.-L.
Microwave-assisted synthesis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1 h)-ones
under solvent-free conditions. Heterocycles 2013, 87, 1337–1347.
21. Yang, G.-Y.; Wang, C.-X.; Fan, S.-F.; Zhao, L.-J.; Wang, D.; Xu, C.-L. Study on the
cyclization methods of 3-[1-(phenyl-hydrazono) ethyl] ethyl]-chromen-2-ones. Synth.
Commun. 2013, 43, 1263–1269.
22. Al-Ayed, A. S. Synthesis of new substituted chromen [4, 3-c] pyrazol-4-ones and their
antioxidant activities. Molecules 2011, 16, 10292–10302.
23. Kidwai, M.; Lal, M.; Mishra, N. K.; Jahan, A. Potassium carbonate as a green catalyst for
Markovnikov addition of azoles to vinyl acetate in PEG. Green Chem. Lett. Rev. 2013, 6,
63–68.
24. Kidwai, M.; Bhatnagar, D.; Chauhana, R. Potassium carbonate–mediated green and
efficient synthesis of imidazo[2,1-b]-1,3,4-thiadiazoles using PEG as solvent. J. Heterocycl.
Chem. 2013, 50, E234–E236.
25. ICH Guideline Q3C (R5) on Impurities: Guideline for Residual Solvents; Geneva:
International Conference on Harmonization, 2005.
26. Ma, S.; Wu, L.; Liu, M.; Xu, X.; Huang, Y.; Yang, Y. Highly enantioselective aza-
Michael addition reactions of 4-nitrophthalimide with a,b-unsaturated ketones. RSC
Adv. 2013, 3, 11498–11501.
27. Brehme, R.; Enders, D.; Fernandez, R.; Lassaletta, J. M. Aldehyde n,n-dialkylhydrazones
as neutral acyl anion equivalents: Umpolung of the imine reactivity. Eur. J. Org. Chem.
2007, 5629–5660.
28. Shawali, A. S.; Parkanyi, C. Hydrazidoyl halides in the synthesis of heterocycles.
J. Heterocycl. Chem. 1980, 17, 833–854.