Starch-sulfuric acid (SSA) as catalyst for a one-pot synthesis of 1,5-diaryl-1H-pyrazoles

Article abstract of DOI:10.1002/hlca.201200621

Protocols with starch-sulfuric acid (SSA) as reusable catalyst for the synthesis of aryl-1H-pyrazoles are described. SSA acted as an efficient and environmentally friendly catalyst for the regioselective condensation of Baylis-Hillman adducts 1 with phenylhydrazine hydrochloride leading to the new 1,5-diaryl-1H-pyrazole 2a-2e in excellent yields (Scheme and Table 1). Copyright

Full text of DOI:10.1002/hlca.201200621

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Helvetica Chimica Acta – Vol. 96 (2013)
StarchꢀSulfuric Acid (SSA) as Catalyst for a One-Pot Synthesis of 1,5-Diaryl-
1H-pyrazoles
by Farhad Hatamjafari
Department of Chemistry, Faculty of Science, Islamic Azad University-Tonekabon Branch, Tonekabon,
Iran (e-mail: hatamjafari@yahoo.com)
Protocols with starchꢀsulfuric acid (SSA) as reusable catalyst for the synthesis of aryl-1H-pyrazoles
are described. SSA acted as an efficient and environmentally friendly catalyst for the regioselective
condensation of BaylisꢀHillman adducts 1 with phenylhydrazine hydrochloride leading to the new 1,5-
diaryl-1H-pyrazole 2a – 2e in excellent yields (Scheme and Table 1).
Introduction. – Starchꢀsulfuric acid (SSA) is one of the cheap and heterogeneous
biopolymer catalysts, that we designed and used in the synthesis of aryl-1H-pyrazoles. It
can be easily separated, reused, and does not pollute the environment. Cellulose-
sulfuric acid has been used previously as catalyst [4 – 7]. Aryl-1H-pyrazole derivatives
belong to an important class of compounds exhibiting a wide range of biological
activities as pharmaceuticals, agrochemicals, anti-inflammatories, antivirals, and
antibacterials [8 – 13]. As part of our ongoing research on heterocyclic compounds
containing N-atom [14], we report herein starchꢀsulfuric acid (SSA) as a new catalyst
for the one-pot synthesis of 1,5-diaryl-1H-pyrazole derivatives 2 by condensation of
BaylisꢀHillman adducts 1 and phenylhydrazine (Scheme).
Scheme Condensation of BaylisꢀHillman Adducts 1 and Phenylhydrazine
Results and Discussion. – The BaylisꢀHillman adducts 1 were prepared by the
reaction of methyl or ethyl vinyl ketone and benzaldehydes [15]. For the synthesis of
the 1,5-diaryl-1H-pyrazole derivatives 2, the reaction of a BaylisꢀHillman adduct 1 and
phenylhydrazine hydrochloride in 1,2-dicloroethane was used (Scheme). The reactions
were complete after almost 1 h at 808 on starchꢀsulfuric acid (SSA) as solid support
and gave 2a – 2e in yields > 90% (Table 1).
Table 2 shows the optimization for the synthesis of 3-ethyl-4-methyl-5-(2-nitro-
phenyl)-1-phenyl-1H-pyrazole (2b) from 1b. Surprisingly, a significant improvement
was observed and the yield of 2b substantially increased to 97% after stirring; the
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Table 1. Three-Component Synthesis of Some 1,5-Diaryl-1H-pyrazoles 2 from BaylisꢀHillman Adducts
1a)
Entry
R
Ar
Product
Yield [%]
1
2
3
4
5
Me
Et
Et
Et
Et
Ph
2a
2b
2c
2d
2e
91
97
95
93
90
2-O2NꢀC6H4
4-O2NꢀC6H4
3-ClꢀC6H4
4-ClꢀC6H4
a) Conditions: 1 (1 mmol), phenylhydrazine hydrochloride (1 mmol), and SSA (0.05 g) in 1,2-
dichloroethane (5 ml), at 808 for ca. 1 h.
mixture was stirred for only 1 h (Table 1, Entry 2). With this optimistic result in hand,
we investigated the best reaction conditions by using different amounts of SSA (0.05 g
of SSA was sufficient to catalyze the reaction effectively, Table 2) and solvents such as
H2O, MeOH, EtOH, MeCN, THF, and 1,2-dichloroethane. Only the latter gave
excellent yields of 2b. We also tested the reaction at different temperatures and
established that the best temperature was 808.
Table 2. Optimizing the Reaction Conditions for 2ba)
SSA [g]
Time [h]
Yield [%]
0.00
0.02
0.05
0.10
0.12
5
2
1
2
2
45
85
91
76
69
a) Conditions: 1b (1 mmol) and phenylhydrazine hydrochloride (1 mmol) in 1,2-dichloroethane (5 ml)
at 808.
Conclusions. – We demonstrated the efficiency of starchꢀsulfuric acid (SSA) as
catalyst for the synthesis of 1,5-diaryl-1H-pyrazoles 2 from BaylisꢀHillman adducts 1
and phenylhydrazine hydrochloride in 1,2-dicloroethane giving good to excellent yields.
SSA is superior to previously reported heterogeneous catalysts in view of its recovery,
efficiency, nontoxicity, cheapness, and environmentally friendly behavior: It gives high
yields and is reusable and, therefore, ideal for industrial applications.
We gratefully acknowledge the financial support from the Research Council of Tonekabon Branch
Islamic Azad University.
Experimental Part
General. All chemicals were obtained from Merck or Fluka and used without further purification.
TLC: silica gel SILG/UV 254 plates. IR Spectra: Shimadzu-IR-470 spectrophotometer; ˜n in cmꢀ1. 1H- and
13C-NMR Spectra: Bruker-500-DRX-Avance instrument; at 500 and 125 MHz, resp.; d in ppm rel. to
Me4Si as internal standard, J in Hz. MS: Finnigan-MAT 8430 mass spectrometer; ionization potential

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Helvetica Chimica Acta – Vol. 96 (2013)
70 eV; in m/z. Element analyses (C, H, N): Carlo-Erba-EA-1108 analyzer carried out with a Perkin-
Elmer-240c analyzer.
StarchꢀSulfuric Acid (SSA). To a magnetically stirred mixture of starch (1.0 g) in CH2Cl2 (20 ml),
chlorosulfuric acid (ClSO3H; 0.2 g, 1.8 mmol) was added dropwise at 08 during 30 min, while HCl gas was
removed from the reaction vessel immediately. After the addition was complete, the mixture was stirred
for 2 h at 08. The mixture was then filtered, washed with EtOH (30 ml), and dried at r.t.: starchꢀsulfuric
acid. White powder.
Compounds 2a – 2e: General Procedure. A mixture of SSA (0.05 g), BaylisꢀHillman adduct 1
(1 mmol), and phenylhydrazine hydrochloride (1 mmol) in 1,2-dichloroethane (5 ml) was heated at 808
until the reaction was complete (ca. 1 h; TLC monitoring). The mixture was diluted with CH2Cl2 and
washed with H2O, the org. layer dried (MgSO4), the solvent evaporated, and the residue purified by
column chromatography (silica gel; hexane/AcOEt 8 :2): 1H-pyrazoles 2a – 2e.
3,4-Dimethyl-1,5-diphenyl-1H-pyrazole (2a): Orange oil. IR: 3056, 2974, 1603, 1593, 1495. 1H-NMR
(500 MHz, CDCl3): 1.36 (t, J ¼ 7.6, 3 H); 1.94 (s, 3 H); 2.75 (q, J ¼ 7.6, 2 H); 7.21 – 7.26 (m, 5 H); 7.34 (dd,
J ¼ 7.6, 1.4, 1 H); 7.55 (dt, J ¼ 8.1, 1.4, 1 H); 7.62 (dt, J ¼ 7.5, 1.3, 1 H); 7.98 (dd, J ¼ 8.1, 1.2, 1 H). 13C-NMR
(125 MHz, CDCl3): 154.4; 149.6; 140.2; 136.1; 133.5; 133.4; 130.0; 129.3; 127.2; 126.7; 125.0; 124.5; 115.3;
20.6; 13.8; 8.5. MS: 248 (Mþ). Anal. calc. for C17H16N2: C 82.22, H 6.49, N 11.28; found: C 82.04, H 6.35, N
11.20.
3-Ethyl-4-methyl-5-(2-nitrophenyl)-1-phenyl-1H-pyrazole (2b): Orange oil. IR: 3052, 2970, 2965,
1
2920, 1607, 1552, 1487, 1351, 1455, 900, 750. H-NMR (500 MHz, CDCl3): 1.38 (t, J ¼ 7.5, 3 H); 1.95 (s,
3 H); 2.70 (q, J ¼ 7.5, 2 H); 7.20 – 7.26 (m, 5 H); 7.33 (dd, J ¼ 7.5, 1.5, 1 H); 7.58 (dt, J ¼ 8.5, 1.5, 1 H); 7.65
(dt, J ¼ 7.5, 1.3, 1 H); 8.00 (dd, J ¼ 8.5, 1.3, 1 H). 13C-NMR (125 MHz, CDCl3): 156.4; 148.2; 141.2; 135.7;
132.2; 135.5; 132.0; 129.7; 128.0; 127.4; 125.5; 124.5; 116.8; 21.8; 14.2; 8.8. MS: 307 (Mþ). Anal. calc. for
C18H17N3O2: C 70.34, H 5.58, N 13.67; found: C 70.25, H 5.48, N 13.53.
3-Ethyl-4-methyl-5-(4-nitrophenyl)-1-phenyl-1H-pyrazole (2c): Orange oil. IR: 3055, 2972, 2920,
2821, 1590, 1456, 1519, 1340, 750. 1H-NMR (500 MHz, CDCl3): 1.34 (t, J ¼ 7.2, 3 H); 2.12 (s, 3 H); 2.79 (q,
J ¼ 7.2, 2 H); 7.20 (dd, J ¼ 8.5, 1.3, 2 H); 7.30 – 7.38 (m, 3 H); 7.40 (d, J ¼ 8.5, 2 H); 8.30 (d, J ¼ 8.5, 2 H).
13C-NMR (125 MHz, CDCl3): 158.0; 148.0; 143.5; 140.8; 135.5; 132.1; 129.2; 128.8; 127.0; 125.9; 120.2;
23.8; 14.5; 8.9. MS: 307 (Mþ). Anal. calc. for C18H17N3O2: C 70.34, H 5.58, N 13.67; found: C 70.18, H 5.42,
N 13.56.
5-(3-Chlorophenyl)-3-ethyl-4-methyl-1-phenyl-1H-pyrazole (2d): Orange oil. IR: 3054, 2962, 2855,
1590, 1568, 1490, 1055, 920, 850, 747, 690. 1H-NMR (500 MHz, CDCl3): 1.41 (t, J ¼ 7.5, 3 H); 2.40 (s, 3 H);
2.90 (q, J ¼ 7.5, 2 H); 7.30 (dt, J ¼ 7.5, 1.2, 1 H); 7.25 – 7.35 (m, 8 H). 13C-NMR (125 MHz, CDCl3): 158.0;
144.1; 142.2; 137.7; 138.8; 135.5; 132.1; 129.5; 128.8; 128.1; 127.1; 126.0; 115.6; 21.1; 13.5; 9.1. MS: 296
(Mþ). Anal. calc. for C18H17ClN2: C 72.84, H 5.77, N 9.44; found: C 72.69, H 5.61, N 9.35.
5-(4-Chlorophenyl)-3-ethyl-4-methyl-1-phenyl-1H-pyrazole (2e): Orange oil. IR: 3055, 2964, 2916,
2873, 1605, 1509, 1455, 1732, 763. 1H-NMR (500 MHz, CDCl3): 1.38 (t, J ¼ 7.5, 3 H); 2.13 (s, 3 H); 2.81 (q,
J ¼ 7.5, 2 H); 7.14 (d, J ¼ 7.0, 2 H); 7.20 – 7.26 (m, 3 H); 7.31 (m, 2 H); 7.35 (d, J ¼ 7.0, 2 H). 13C-NMR
(125 MHz, CDCl3): 158.5; 152.3; 145.4; 138.3; 135.6; 131.4; 128.3; 126.5; 125.5; 124.8; 118.5; 21.0; 13.1;
9.0. MS: 296 (Mþ). Anal. calc. for C18H17ClN2: C 72.84, H 5.77, N 9.44; found: C 72.78, H 5.66, N 9.29.
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Received November 23, 2012