Sulfamic acid (H2NSO3H): A low-cost, mild, and efficient catalyst for the synthesis of substituted N-Phenylpyrazoles under solvent-free conditions

Article abstract of DOI:10.1080/00397911.2010.540365

N-Phenylpyrazoles are synthesized by condensing phenylhydrazine and 1,3-diketones in the presence of a catalytic amount of sulfamic acid, a mild and an efficient solid acid catalyst, under solvent-free conditions. This condensation proceeds smoothly in shorter reaction time. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.540365

This article was downloaded by: [University of Illinois Chicago]
On: 15 July 2012, At: 03:53
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Sulfamic Acid (H2NSO3H): A Low-
Cost, Mild, and Efficient Catalyst
for the Synthesis of Substituted N-
Phenylpyrazoles Under Solvent-Free
Conditions
Mohan R. Shetty a & Shriniwas D. Samant a
a Department of Chemistry, Institute of Chemical Technology,
Matunga, Mumbai, India
Accepted author version posted online: 21 Oct 2011. Version of
record first published: 25 Jan 2012
To cite this article: Mohan R. Shetty & Shriniwas D. Samant (2012): Sulfamic Acid (H2NSO3H): A Low-
Cost, Mild, and Efficient Catalyst for the Synthesis of Substituted N-Phenylpyrazoles Under Solvent-
Free Conditions, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 42:10, 1411-1418
To link to this article: http://dx.doi.org/10.1080/00397911.2010.540365
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,

demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 42: 1411–1418, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.540365
SULFAMIC ACID (H2NSO3H): A LOW-COST, MILD, AND
EFFICIENT CATALYST FOR THE SYNTHESIS OF
SUBSTITUTED N-PHENYLPYRAZOLES UNDER
SOLVENT-FREE CONDITIONS
Mohan R. Shetty and Shriniwas D. Samant
Department of Chemistry, Institute of Chemical Technology, Matunga,
Mumbai, India
GRAPHICAL ABSTRACT
Abstract N-Phenylpyrazoles are synthesized by condensing phenylhydrazine and 1,3-dike-
tones in the presence of a catalytic amount of sulfamic acid, a mild and an efficient solid
acid catalyst, under solvent-free conditions. This condensation proceeds smoothly in shorter
reaction time.
Keywords N-Phenylpyrazoles; solid acid catalysis; sulfamic acid
INTRODUCTION
Pyrazoles are an important class of drug intermediates in the pharmaceutical
industry, as the pyrazole core structure is found in numerous biologically active mole-
cules. They possess a number of biological activities such as antimicrobial, antiviral,
antifungal, antitumor, antidepressant, antidiabetic, and anti-inflammatory activi-
ties.[1] Recently, they have been reported as potential atypical antipsychotics.[1] One
of the classic examples is the blockbuster drug Celebrex, which was the first
cyclooxygenase-2 (COX-2) inhibitor approved for the treatment of rheumatism and
osteoarthritis.[2] Many synthetic pyrazoles are dye intermediates. N-Phenylpyrazole
is the basic component of the antiflea and antitick external treatments for cats
and dogs.[3]
Among the various syntheses of pyrazoles, the most convenient is the conden-
sation of 1,3-diketones with hydrazines.[4] However, there are a few other routes that
do not employ the use of 1,3-diketones.[5] Acidic catalysts, such as ion exchange
Received June 29, 2010.
Address correspondence to Shriniwas D. Samant, Department of Chemistry, Institute of Chemical
Technology, N. M. Parekh Road, Matunga, Mumbai 400 019, India. E-mail: samantsd@yahoo.com
1411

1412
M. R. SHETTY AND S. D. SAMANT
Table 1. Reaction of phenylhydrazine and pentane-2,5-dione in the presence of different solid acid
catalysts
Yield of
N-phenylpyrazole (%)
Entry
Catalyst
Time (min)
1
2
Sulfamic acid
Amberlyst-15
H-ZSM
05
05
20
20
30
10
10
10
15
420
91
80
72
73
69
73
78
77
76
45
3
4
Mont-K10
Hb-Zeolite
SiO2-HClO4
SiO2-H2SO4
SiO2-H3PO4
SiO2 -HCl
5
6
7
8
9
10
No catalyst
Note. Reaction conditions: phenylhydrazine (10 mmol, 0.108 g), pentane-2,5-dione (10 mmol, 0.100 g),
catalyst (10 wt% of phenylhydrazine), room temperature (32 ꢀC).
resins, heteropoly acids,[6] SiO2-H2SO4,[7] zeolite,[8] para-toluenesulfonic acid
(p-TSA), and K10[9] have also been used for the synthesis of pyrazole derivatives.
However, supported catalysts have leaching problems. Ion exchange resins are
expensive and require longer reaction times, and the reactions are generally carried
out in organic solvents. Better results are obtained using homogeneous liquid-phase
catalysts; however, these are considerably corrosive and are not environmentally
benign. Herein we report a greener method for the synthesis of N-phenylpyrazoles
by condensation of phenylhydrazines with 1,3-diketones using a low-cost, mild,
and efficient solid acid catalyst: sulfamic acid.
The development of mild, low-cost, and high-performance acid catalysts has
recently attracted much interest. Sulfamic acid (NH2SO3H) is a heterogeneous acid
catalyst in a nonaqueous medium with mild acidity, nonvolatility, and non-
corrosivity. It is inexpensive, insoluble in common organic solvents, and very stable.
However, not much attention has been paid to the use of sulfamic acid as a catalyst
in organic reactions. Earlier, we used sulfamic acid for the Pechmann reaction and to
synthesize bis(1H-indol-3-yl)methanes.[10] With this background, we have used sulfa-
mic acid as a solid acid catalyst for the condensation of phenylhydrazine and
1,3-diketone to prepare N-phenylpyrazoles.
RESULTS AND DISCUSSION
To optimize the reaction conditions, we carried out the condensation of
pentane-2,5-dione with phenylhydrazine.
To study the effect of different heterogeneous catalysts, the reaction was car-
ried out at room temperature in the presence of different solid Brønsted acids and
some silica-supported Brønsted acid catalysts (Table 1). The reaction was catalyzed
by all the catalysts, and sulfamic acid was found to be the best.
The reaction was carried out using different quantities of sulfamic acid
(Table 2). As the catalyst quantity increased, yield of the product increased. Using

SUBSTITUTED N-PHENYLPYRAZOLES
1413
Table 2. Reaction of phenylhydrazine and pentane-2,5-dione in the presence of different quantities of
sulfamic acid
Entry SA (wt% of phenylhydrazine) SA (mol% phenylhydrazine) Yield of N-phenylpyrazole (%)
1
2
3
4
5
50
25
10
5
5
91
89
91
79
73
2.5
1
0.5
0.2
2
Note. Reaction conditions: phenylhydrazine (10 mmol, 0.108 g), pentane-2,5-dione 10 mmol, 0.100 g),
time 5 min, room temperature (32 ꢀC).
10 wt% of phenylhydrazine, the maximum yield of the product was obtained. Hence,
for further reactions, the same quantity of sulfamic acid was used.
The reaction was tried in ethanol at room temperature, when 84% of the pro-
duct was obtained. Thus, the reaction without solvent was found to be the best.
The reaction of phenylhydrazines with different 1,3-dicarbonyl compounds
was carried out under the optimized conditions (Scheme 1, Table 3). The reaction
of phenylhydrazine with symmetrical 1,3-diketones is expected to give only one
N-phenylpyrazole. In the reaction of 1-phenyl-1,3-butanedione (entry 2), only
3-methyl-1,5-diphenylpyrazole (86%) was the isolable product. In literature, in a
K10-catalyzed reaction of 1,3-diketone with phenylhydrazine, a mixture of
3-methyl-1,5-diphenylpyrazole (95%) and 5-methyl-1,3-diphenylpyrazole (5%) has
been reported. The reaction of 2,4-dinitrophenylhydrazine with pentane-2,5-dione
did not give the expected pyrazole, but the reaction stopped at the hydrazone stage,
possibly because of poor nucleophilicity of the second nitrogen atom.[4a] The con-
densation product of phenylhydrazide and benzoylacetone (entry 10) gave the cor-
1
responding hydrazone derivative, which was confirmed by H NMR and infrared
(IR). The reason for the unsuccessful cyclization possibly is the poor nucleophilicity
at the second nitrogen atom. The condensation reaction of phenylhydrazide with
dibenzoyl methane (entry 11) did not give the dehydrated product, which was con-
firmed from the spectral analysis. In the literature, the reaction of phenylhydrazine
with b-keto esters is reported to give pyrazole derivates.[4c] However, the conden-
sation reaction using sulfamic acid gave N-phenylpyrazolone derivative (entry 12).
The known compounds were identified by comparison of reported melting points
in the literature and spectral analysis. The liquid compounds were identified by
spectral analysis.
Scheme 1. Synthesis of N-phenylpyrazoles by the reaction of phenylhydrazines and 1,3-dicarbonyl com-
pounds in the presence of sulphamic acid.

1414

1415

1416
M. R. SHETTY AND S. D. SAMANT
CONCLUSION
We have developed a highly efficient protocol for the synthesis of pyrazoles by
the condensation of phenylhydrazines with 1,3-diketones using a low-cost, mild, and
efficient catalyst, sulfamic acid (solid acid). The reaction takes place in a short time
under solvent-free conditions at ambient temperature.
EXPERIMENTAL
1H NMR spectra were recorded on Bruker 300-MHz and Jeol 60-MHz spec-
trometers. IR spectra were recorded on a Perkin-Elmer Fourier transform (FT)-IR
spectrophotometer. Melting points are uncorrected.
Condensation of Phenylhydrazine and 1,3-Diketone
Phenylhydrazine (10 mmol, 0.108 g), pentane-2,5-dione (10 mmol, 0.100 g), and
catalyst (10wt% of the phenylhydrazine) were added to a 50-mL, single-neck, round-
bottom flask. The flask was equipped with a calcium chloride guard tube. The con-
tents of the flask were stirred on a magnetic stirrer. After completion of the reaction,
the reaction mixture was washed with water to remove the catalyst and then
extracted with diethyl ether (3 ꢁ 6 mL). The organic extract was dried over anhy-
drous sodium sulfate, and the solvent was evaporated in a vacuum. The product
obtained was purified using column chromatography (silica gel: 5% EtOAc–
petroleum ether).
Selected Data
Compound 1a. FT-IR (KBr): 3062, 2981, 2959, 2923, 2866, 1597 (C¼C),
1556, 1500, 1419, 1384, 1131, 1072, 1025, 977, 911, 779, 755, 696, 678, 661,
1
640 cmꢂ1. H NMR (CCl4, 60 MHz) d: 2.28 (s, 6H, 2CH3), 5.98 (s, 1H, CH¼),
7.41 (m, 5H, ArH).
Compound 2a. FT-IR (KBr): 3062, 2924, 2854, 1598, 1551, 1500, 1458, 1413,
1367, 1139, 1084, 1028, 1016, 954, 913, 766, 693, 641 cmꢂ1 1H NMR (CDCl3,
.
300 MHz) d: 2.41 (s, 3H, CH3), 6.32 (s, 1H, CH¼), 7.22–7.31 (m, 10H, ArH).
Compound 3a. FT-IR (KBr): 3121, 3062, 1596, 1546, 1496, 1457, 1484, 1363,
1214 1175, 1066, 1022, 957, 921, 766, 701 cmꢂ1. 1H NMR (CDCl3, 300 MHz) d: 6.85
(s, 1H, CH¼), 7.33–7.96 (m, 15H, ArH).
Compound 7a. FT-IR (KBr): 3048, 2922, 2864, 1609, 1593, 1557, 1495, 1466,
1
1417, 1380, 1364, 1131, 1090, 1023, 976, 857, 788, 696 cmꢂ1. H NMR (CDCl3,
300 MHz) d: 2.29 (s, 6H, 2CH3), 2.27(s, 3H, CH3), 5.96 (s, 1H, CH¼), 7.17–7.26
(d, 4H, ArH).
Compound 8a. FT-IR (KBr): 3066, 2925, 2867, 1604, 1555, 1514, 1416, 1385,
1367, 1289, 1154, 1131, 1094, 1036, 1017, 977, 838, 788, 609 cmꢂ1. 1H NMR (CDCl3,
300 MHz) d: 2.29 (s, 6H, 2CH3), 2.27 (s, 3H, CH3), 5.95 (s, 1H, CH¼), 7.09–7.35 (d,
4H, ArH).

SUBSTITUTED N-PHENYLPYRAZOLES
1417
Compound 10a. FT-IR (KBr): 3232 (NH), 3066, 2836, 1630, 1603, 1554,
1421, 1287, 1131, 1065, 1034, 925, 877, 844, 795, 718.cmꢂ1 1H NMR (CDCl3,
.
300 MHz) d: 2.29 (s, 3H, CH3), 5.98 (s, 1H, CH¼), 7.45–7.91 (m, 10H, ArH),
10.87 (s, 1H, NH), 12.24 (s, 1H, NH).
Compound 11a. FT-IR (KBr): 3455 (OH), 3063, 1637, 1598, 1428, 1415,
1
1337, 1188s, 1069, 923, 860, 795, 759, 718 cmꢂ1. H NMR (DMSO, 300 MHz) d:
3.48–3.67 (d, 2H, CH2), 7.12 (s, 1H OH), 7.27–7.82 (m, 15H, ArH).
ACKNOWLEDGMENT
M. S. is thankful to the University Grants Commission (UGC), New Delhi,
for a fellowship under UGC-SAP.
REFERENCES
1. Polshettiwar, V.; Varma R. S. Greener and rapid access to bio-active hetrocycles: Room-
temperature synthesis of pyrazoles and diazepines in aqeuous medium. Tetrahedron Lett.
2008, 49, 397–400.
2. Reddy, A. R.; Sampath, A.; Reddy, P. P. An improved and scalable process for celecoxib:
A selective cyclooxgenase-2 inhibitor. Org. Process Res. Dev. 2009, 13, 98–101.
3. Jeannin, P. N-Phenylpyrazole based antiflea and antitick external device for cats and dogs.
U.S. Patent 5,885,607, March 23, 1999.
4. (a) Wang, Z.; Qin, H. Solventless syntheses of pyrazole derivatives. Green Chem. 2004, 6,
90–92; (b) Polshettiwar, V.; Varma, R. S. Greener and rapid access to bio-active hetro-
cycles: Room-temperature synthesis of pyrazoles and diazepines in aqeuous medium.
Tetrahedron Lett. 2008, 49, 397–400.
5. (a) Heller, S. T.; Natarajan, S. R. 1,3-Diketones from acid chlorides and ketones: A rapid
and one-pot synthesis of pyrazoles. Org. Lett. 2006, 8, 2675–2678; (b) Mohamed Ahmed,
M. S.; Kobayashi, K.; Mori, A. One-pot construction of pyrazoles and isoxazoles with
palladium-catalyzed four-component coupling. Org. Lett. 2005, 7, 4487–4489; (c) Deng,
X.; Mani, N. S. Base-mediated reaction of hydrazones and nitroolefins with a reversed
regioselectivity: A novel synthesis of 1,3,5-trisubstituted pyrazoles. Org. Lett. 2008, 10,
1307–1310; (d) Deng, X.; Mani, N. S. Regioselective synthesis of 1,3,5-tri- and 1,3,4,5-tet-
rasubstituted pyrazoles from N-arylhydrazones and nitrooeofins. J. Org. Chem. 2008, 73,
2412–2415; (e) Martin, R.; Rivero, M. R.; Buchwald, S. L. Domino Cu-catalyzed C-N
coupling=hydroamidation: A highly efficient synthesis of nitrogen heterocycles. Angew.
Chem. Int. Ed. 2006, 45, 7079–7082.
6. Chen, X.; She, J.; Shang, Z.; Wu, J.; Wu, H.; Zhang, P. Synthesis of pyrazoles, diazepines,
enaminones and enamino esters using 12-tungstophophoric acid as a reusable catalyst in
water. Synthesis 2008, 21, 3478–3486.
7. Chen, X.; She, J.; Shang, Z.; Wu, J.; Zhang, P. Room-temperature synthesis of
pyrazoles, diazepines, b-enaminones, and b-enamino esters using silica-supported sulfuric
acid as a reusable catalyst under solvent-free conditions. Synth. Commun. 2009, 39(6),
947–957.
8. Sreekumar, R.; Padmakumar, R. Simple, efficient, and convenient synthesis of pyroles
and pyrazoles using zeolites. Synth. Commun. 1998, 28(9), 1661–1665.
9. Texier-Boulett, F.; Klein, B.; Hamelin, J. Pyrole and pyrazole ring closure in hetero-
geneous media. Synthesis 1986, 409–411.

1418
M. R. SHETTY AND S. D. SAMANT
10. (a) Singh, P. R.; Singh, D. U.; Samant, S. D. Sulphamic acid: An efficient and cost-effec-
tive acid catalyst for the Pechmannn reaction. Synlett 2004, 11, 1909–1912; (b) Singh, P.
R.; Singh, D. U.; Samant, S. D. Sulphamic acid: A mild, efficient, and cost-effective acid
catalyst for the synthesis of bis(1H-indol-3-yl)methanes. Synth. Commun. 2005, 35(16),
2133–2138.
11. Penicillins: Beecham Group Ltd., GB952283, 1963; Chem. Abstr. 1964, 61, 8315d.
12. Vogel, A. I.; Tatchell, A. R. Vogel’s Textbook of Practical Organic Chemistry, 4th ed.;
ELBS=Longman, UK, 1978; p. 882.