A Green Mechanochemical Synthesis of New 3,5-Dimethyl-4-(arylsulfanyl)pyrazoles

Article abstract of DOI:10.1002/jhet.2528

A small series of new 3,5-dimethyl-4-(arylsulfanyl)pyrazoles have been synthesized in good to excellent yields by a grinding-induced, sequential one-pot three-component reaction, of an equimolar mixture of 3-chloro-2,4-pentanedione, differently substitute

Full text of DOI:10.1002/jhet.2528

Month 2015
A Green Mechanochemical Synthesis of New 3,5-Dimethyl-
4-(arylsulfanyl)pyrazoles
*
Aamer Saeed and Pervaiz Ali Channar
Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan
*
E-mail: asaeed@qau.edu.pk
Received May 26, 2015
DOI 10.1002/jhet.2528
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
A small series of new 3,5-dimethyl-4-(arylsulfanyl)pyrazoles have been synthesized in good to excellent
yields by a grinding-induced, sequential one-pot three-component reaction, of an equimolar mixture of 3-
chloro-2,4-pentanedione, differently substituted thiophenols, and hydrazine hydrate in the presence of piper-
idine under solvent-free conditions.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
positive and gram negative bacteria [6]. In addition, some
mercaptoheterocyclic compounds were converted into cor-
responding acylated hydrazines via acetates. The acylated
hydrazines on reaction with ketene dithioacetal derivatives
afforded the sulphur bridged pyrazoles [7].
Motivated by the aforesaid facts concerning the scarcity
of sulfur containing pyrazoles systems coupled with our
synthetic and biological experience in the field of heterocy-
cles [8], herein, we report a mechanochemical method
for synthesis of title compounds. The grinding-induced
method not only reduces the time of reaction from several
hours to a few minutes but also improves the yields com-
pared with that of conventional conditions.
Pyrazoles are amongst the best known heterocycles hav-
ing two nitrogens at adjacent positions and found to have a
diversity of applications in the pharmaceutical and agro-
chemical industries. Pyrazoles constitute the central core
of some well-known drugs like celecoxib, a COX-2 selec-
tive nonsteroidal anti-inflammatory drug; oxymetazoline, a
selective alpha-1 and partial alpha-2 agonist topical decon-
gestant; butazoline; metamizole, an ampyrone sulfonate
analgesic, antispasmodic and antipyretic marketed as no-
valgin; apixaban, an anticoagulant and a direct factor Xa
inhibitor; and fipronil, a broad-spectrum insecticide and
rimonabant, anorectic anti-obesity drug. Moreover, these
are versatile building blocks towards the synthesis of a
number of other heterocyclic systems. In view of the fact
that a number of books and reviews are available for syn-
thesis and applications of pyrazoles [1–3], there is hardly
any need to cite the literature in this connection. However,
it is motivating to note that despite the very common
occurrence of pyrazole scaffold, a survey of literature indi-
cates only handful reports of sulfur containing pyrazoles.
The sulfur containing pyrazole derivatives as blood sugar
level-lowering agents had long been patented [4]. Some
1-(2,4-dinitrophenyl)-3-aryl-4-(arylsulfonyl)-1H-pyrazoles
were prepared by the Vilsmeier reaction of hydrazones un-
der microwave irradiation. The requisite hydrazones were
themselves obtained from 2,4-dinitrophenylhydrazine and
substituted aryl sulfides [5]. Another report describes the
synthesis of pyrazoles by the reaction of the carbanions of
1-aryl-2-(phenylsulphonyl)ethanone with different hydrazonyl
halides under ultrasonic conditions. These were shown
to exhibit strong antibacterial activity against both gram
RESULTS AND DISCUSSION
The synthetic strategy adopted for the synthesis of the
target compounds is depicted in Scheme 1.
Accordingly, an intimate equimolar mixture of 3-chloro-
2,4-pentanedione and suitably substituted thiophenols was
homogenized in a glass mortar and pestle, in the presence
of catalytic amount of piperidine. The mixture was ground
further for 5–10min to afford a semisolid. An equimolar
amount of hydrazine hydrate was added, and the grinding
was continued for further 10–15min [9]. The progress of
the reaction was monitored by TLC using n-hexane ethyl
acetate (8:2). On completion, the reaction mixture was
diluted with ethyl acetate and filtered; the filtrate was con-
centrated and recrystallized from ethanol to afford pure
products in yields shown in Table 1.
The products were characterized on the basis of their
FTIR, 1H NMR, mass spectroscopic and microelemental an-
alytical data. The stretchings at 3160 (NH), 528 (C=N), 1597
© 2015 HeteroCorporation

A. Saeed and P. A. Channar
Vol 000
Scheme 1. Synthetic route to new 3,5-dimethyl-4-(arylsulfanyl)pyrazoles. [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
Table 1
shortening of reaction time, effortless separation, and the
Physical data of 3,5-dimethyl-4-(arylsulfanyl)pyrazoles (4a–j).
eco-friendliness. The bioevaluation of the compounds is pres-
ently in progress and will be reported in due course.
Time
(min)
Yield
(%)
Entry
R
Melting point °C
EXPERIMENTAL
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
CH3
Oil
95
13
11
15
10
11
10
15
10–15
15–17
10
75
78
81
79
80
83
72
74
88
87
Melting points were recorded using a digital Gallenkamp
(SANYO, Moriguchi, Japan) model MPD BM 3.5 appara-
tus and are uncorrected. 1H NMR spectra were determined
as CDCl3 solutions at 300MHz using a Bruker AM-300
spectrophotometer (Billerica, MA, USA). FT IR spectra
were recorded using Bio-Rad Excalibur FTS 3000 MX
spectrophotometer (Madison, WI), Mass Spectra (EI,
70eV) on a GC-MS instrument. The reactions were carried
out in glass mortar and pestle.
3,4-di (CH3)2
3-CH3O
4-CH3O
3,4-di (CH3O)2
4-Cl
4-Br
4-NO2
2-naphthyl
108
Oil
Oil
115
130
80
Oil
122
4j
General procedure for the preparation of 3,5-dimethyl-
Scheme 2. Mechanistic pathway to 4-(arylsulfanyl)pyrazoles. [Color figure
can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
4-(arylsulfanyl)pyrazoles (4a–j).
A mixture of the
appropriate thiophenol (1mmol), 3-chloro-2,4-pentaned
ione (1mmol), and a catalytic amount of piperidine was
ground in a glass mortar and pestle at room temperature.
After grinding for 5–10min, hydrazine hydrate (1mmol)
was added, and the grinding was continued for further
10min. The progress of the reaction was monitored by
TLC using n-hexane ethyl acetate (8:2). On completion, the
reaction mixture was diluted with ethyl acetate and filtered
to remove salts, and the filtrate was concentrated. Recrystal
lization from ethanol afforded pure products (4a–j).
(C=C), and 780 (C–S) cmÀ1 were noted in the FTIR spectra
of pyrazoles. In H NMR spectra, the typical sharp singlets
1
were noticed at δ 9.34 for NH at δ 2.42 and 2.32 ppm because
of CH3 protons besides those in the range δ 7.31–7.83 for the
aromatic protons, indicating the successful linkage of aryl
through sulfur bridge. 13C NMR spectra displayed the signal
at δ 156.5 (C=N), 136.1 (C=C), 108.6 (C–S), and 9.6 (CH3)
ppm, in addition to those of aromatic carbons.
Mechanistically, it is likely that first 3-(arylthio)pentane-
2,4-dione is formed as an intermediate, which undergoes
usual cyclization with hydrazine to afford the target
pyrazoles (Scheme 2).
3,5-Dimethyl-4-phenylsulfanyl-1H-pyrazole (4a).
Colorless
oil; FTIR (KBr): 3128 (sp2CH), 2936 (sp3CH), 1578
(C=N), 1608 (C=C), 693 (C–S) cmÀ1 1H NMR
;
(300 MHz, CDCl3): δ 9.4 (s, 1H, NH), 7.1 (m, 1H, ArH),
(m, 2H, ArH), 7.0 (dd, 2H, J= 1.2, Hz, ArH), 2.3 (s, 6H,
CH3); 13C NMR (75 MHz, CDCl3): δ 148.4 (C=N), 147.5
(C=C), 133.5, 130.3, 127.5 (Ar–C), 108 (C–S), 10.5
(CH3). Anal. Calcd. for C11H12N2S: C, 64.67; H, 5.92;
N, 13.71; S, 15.70. Found: C, 64.65; H, 5.93; N, 13.74;
S, 15.68. Calcd. (204.29). Found: 204.
CONCLUSION
3,5-Dimethyl-4-p-tolylsulfanyl-1H-pyrazole (4b).
Yellow
solid; FTIR (KBr): 3129 (sp2CH), 2939 (sp3CH), 1568
An efficient, rapid, one-pot method for the preparation of
sulfur containing pyrazoles by a domino multicomponent re-
action is described. The outstanding features include crucial
1
(C=N), 1608 (C=C), 735 (C–S) cmÀ1; H NMR (300 MHz,
CDCl3): δ 9.3 (s, 1H, NH), 7.2 (d, J= 7.5Hz, 2H, ArH), 6.8
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
New 3,5-Dimethyl-4-(arylsulfanyl)pyrazoles
4-(4-Chlorophenylsulfanyl)-3,5-dimethyl-1H-pyrazole (4g). Light
(d, J=7.5Hz, 2H, ArH), 2.4 (s, 1H, CH3), 2.3 (s, 3H, CH3),
2.4 (s, 3H, CH3); 13C NMR (75MHz, CDCl3): δ 152.1
(C=N), 146.5 (C=C), 136.6, 132.6, 131.6, 130.4 (Ar–C), 109
(C–S), 22.1, 11.1, 9.5 (CH3). Anal. Calcd. for C12H14N2S:
C, 66.02; H, 6.46; N, 12.83; S, 14.69. Found: C, 66.01;
H, 6.45; N, 12.84; S, 14.70. Calcd. (218.09). Found: 218.
4-(3,4-Dimethylphenylsulfanyl)-3,5-dimethyl-1H-pyrazole
yellow; FTIR (KBr): 3115 (sp2CH), 2955 (sp3CH), 1569
(C=N), 1595–1495 (C=C), 727 (C–S) cmÀ1 1H NMR
;
(300MHz, CDCl3): δ 9.6 (s, 1H, NH), 7.2 (d, J=9.1Hz,
2H, ArH), 6.7 (d, J=9.1Hz, 2H, ArH), 2.4 (s, 1H, CH3),
2.3 (s, 3H, CH3); 13C NMR (75MHz, CDCl3): δ 155.8
(C=N), 146.9 (C=C), 137.6, 134, 129.4, 129.2 (Ar–C),
110.4 (C–S), 11.1, 9.7 (CH3). Anal. Calcd. for
C11H11ClN2S: C, 55.34; H, 4.64; N, 11.73; S, 13.43.
Found: C, 55.32; H, 4.66; N, 11.71; S, 13.45. Calcd.
(4c).
Light yellow solid; FTIR (KBr): 3125 (sp2CH),
2935 (sp3CH), 1577 (C=N), 1605 (C=C), 757 (C–S)
1
cmÀ1; H NMR (300MHz, CDCl3): δ 9.4 (s, 1H, NH),
6.7 (d, J=8.7Hz, 1H, ArH), 6.6 (d, J=2.8Hz, 1H, ArH),
6.3 (dd, J=8.7Hz, 2.8Hz, 1H, ArH), 2.8 (s, 3H, CH3),
2.6 (s, 3H, CH3), 2.4 (s, 3H, CH3), 2.4 (s, 3H, CH3); 13C
NMR (75MHz, CDCl3): δ 152.1 (C=N), 148.6 (C=C),
145.6, 145.7, 145.6, 132.9, 129.9, 127.9 (Ar–C), 107.3,
108 (C–S), 20.5, 23.5, 10.1, 8.5 (CH3). Anal. Calcd. for
C13H16N2S: C, 67.20; H, 6.94; N, 12.06; S, 13.80. Found:
C, 67.18; H, 6.92; N, 12.09; S, 13.81. Calcd. (232.10).
(238.03). Found: 238.
4-(4-Bromophenylsulfanyl)-3,5-dimethyl-1H-pyrazole (4h). Yellow
solid, yield 40%, mp 80°C; FTIR (KBr): 3117 (sp2CH),
2955 (sp3CH), 1569 (C=N), 1595 (C=C), 695 (C–S) cmÀ1
;
1H NMR (300MHz, CDCl3): δ 9.5 (s, 1H, NH), 7.5 (d,
J=7.5Hz, 2H, ArH), 6.7 (d, J=7.3Hz, 2H, ArH), 2.4 (s,
1H, CH3), 2.7 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): δ
154.8 (C=N), 144.91 (C=C), 137.63, 134.5, 132.4, 130.4
(Ar–C), 110.4 (C–S), 11.1, 9.50 (CH3). Anal. Calcd. for
C11H11BrN2S: C, 46.65; H, 3.92; N, 9.89; S, 11.32. Found:
C, 46.63; H, 3.94; N, 9.91; S, 11.30. Calcd. (281.98).
Found: 232.
4-(3-Methoxyphenylsulfanyl)-3,5-dimethyl-1H-pyrazole
(4d). Colourless oil; FTIR (KBr): 3127 (sp2CH), 2936
1
(sp3CH), 1577 (C=N), 1605(C=C), 733 (C–S) cmÀ1; H
Found: 281.
NMR (300 MHz, CDCl3): δ 9.3 (s, 1H, NH), 6.51–6.5 (m,
3H, ArH), 6.8–6.9 (m, 1H, ArH), 3.4 (s, 1H, OCH3), 2.4
(s, 3H, CH3), 2.3 (s, 3H, CH3); 13C NMR (75MHz,
CDCl3): δ 163.5 (O–Ar), 147.5 (C=N), 145.6 (C=C), 135.3,
130.5, 125.5, 116.5, 113.3 (Ar–C), 107.3 (C–S), 56.5
(OCH3), 11.0, 9.5 (CH3). Anal. Calcd. for C12H14N2OS:
C, 61.51; H, 6.02; N, 11.96; S, 13.68. Found: C, 61.49;
H, 6.04; N, 11.95; S, 13.69. Calcd. (234.08). Found: 234.
4-(4-Methoxyphenylsulfanyl)-3,5-dimethyl-1H-pyrazole
3,5-Dimethyl-4-(4-nitrophenylsulfanyl)-1H-pyrazole (4i). Pink
oil, yield 58%; FTIR (KBr): 3115 (sp2CH), 2955
(sp3CH), 1569 (C=N), 1595 (C=C), 738 (C–S) cmÀ1
;
1H NMR (300 MHz, CDCl3): δ 9.33 (s, 1H, NH), 8.0
(d, J = 7.5 Hz, 2H, ArH), 7.1 (d, J = 7.3 Hz, 2H), 2.4 (s,
1H, CH3), 2.2 (s, 3H, CH3); 13C NMR (75 MHz,
CDCl3): δ 155.8 (C=N), 147.9 (C=C), 146.6, 142.6,
134.2, 123.5 (Ar–C), 107.4 (C–S), 10.1, 8.5 (CH3).
Anal. Calcd. for C11H11N3O2S; C, 53.00; H, 4.45; N,
16.86; S, 12.86. Found: C, 53.02; H, 4.43; N, 11.95;
(4e).
Colour less oil; FTIR (KBr): 3126 (sp2CH), 2937
(sp3CH), 1576 (C=N), 1605 (C=C), 695 (C–S) cmÀ1; H
NMR (300MHz, CDCl3): δ 9.28 (s, 1H, NH), 7.3 (d,
J=7.5Hz, 2H, ArH), 6.7 (d, J= 7.5Hz, 2H, ArH), 3.4 (s,
1H, OCH3), 2.3 (s, 3H, CH3), 2.2 (s, 3H, CH3); 13C NMR
(75MHz, CDCl3): δ 158.5 (O–Ar), 152.1 (C=N), 144.6
(C=C), 138.6, 135.4, 135.2, 128.9, 121.3 (Ar–C), 106.3
(C–S), 61.1 (OCH3), 10.1, 8.5 (CH3). Anal. Calcd. for
C12H14N2OS: C, 61.51; H, 6.02; N, 11.96; S, 13.68.
Found: C, 61.50; H, 6.03; N, 11.95; S, 13.69. Calcd.
(234.08). Found: 234.
1
S, 13.69. Calcd. (234.08). Found: 234.
3,5-Dimethyl-4-(naphthalen-2-ylsulfanyl)-1H-pyrazole (4j). Light
pink solid; FTIR (KBr): 3160 (NH), 3057 (sp2CH), 2917
1
(sp3CH), 1528 (C=N), 1597 (C=C), 777 (C–S) cmÀ1; H
NMR (300MHz, CDCl3): δ 9.3 (s, 1H, NH), 7.8–7.7
(m, 2H), 7.7 (qd, J=7.5, 1.4Hz, 2H, ArH), 7.5–7.3 (m, 3H,
ArH), 2.4 (S, 6H); 13C NMR (75MHz, CDCl3): δ 156.5
(C=N), 136.1 (C=C), 134.3, 129.8, 129.6, 127.7, 126.9,
126.6, 124.2, 117.6 (Ar–C), 108.6 (C–S), 9.6 (CH3). Anal.
Calcd. for C15H14N2S: C, 70.83; H, 5.55; N, 11.01; S,
12.61. Found: C, 70.81; H, 5.56; N, 11.03; S, 12.60. Calcd.
(254.09). Found: 254.
4-(3,4-Dimethoxyphenylsulfanyl)-3,5-dimethyl-1H-pyrazole
(4f).
Yellow solid; FTIR (KBr): 3125 (sp2CH), 2935
(sp3CH), 1577 (C=N), 1602 (C=C), 722 (C–S) cmÀ1; H
NMR (300MHz, CDCl3): δ 9.3 (s, 1H, NH), 6.8 (d,
J=8.7Hz, 1H, ArH), 6.6 (d, J=2.8Hz, 1H, ArH), 6.3
(dd, J=8.7Hz, 2.8Hz, 1H, ArH), 3.8 (s, 3H, OCH3), 3.9
(s, 3H, OCH3), 2.4 (s, 3H, CH3), 2.3 (s, 3H, CH3); 13C
NMR (75MHz, CDCl3): δ 155.5 (O–Ar), 152.1 (C=N),
148.6 (C=C), 147.6, 135.7, 130.6, 122.9 (Ar–C), 109.3
(C–S), 56.5 (OCH3), 53.5 (OCH3), 10.1, 8.5 (CH3). Anal.
Calcd. for C13H16N2O2S: C, 59.07; H, 6.10; N, 10.60; S,
12.13. Found: C, 59.05; H, 6.12; N, 10.59; S, 12.14.
Calcd. (264.09). Found: 264.
1
REFERENCES AND NOTES
[1] Ajay Kumar, K.; Jayaroopa, P. Int J of PharmTech Res 2013, 5,
1473.
[2] Jamwal, A.; Javed, A.; Bhardwaj, V. J Pharm BioSci 2013, 3,
114.
[3] Aggarwal, R.; Kumar, V.; Kumar, R.; Shiv, P. S. J Org Chem 7
2011, 179.
[4] Album, H. E.; Chester, W.; Grant, N. H.; Wood, W.; Fletcher, H.
Sulfur containing pyrazole derivatives United States Patent, 3,350,407
Oct 31.1967.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Saeed and P. A. Channar
Vol 000
[5] Manikannan, R.; Venkatesan, R.; Muthusubramanian S. Ind J
Chem 50B 2011, 1611.
[6] Mohan, S.; Ananthan, S.; Murugan, K. R. Int J Pharm Sci Res
2010, 1, 391.
[7] Tamer, S. S.; Naglaa, M. Ultrason Sonochem 2009,
16, 237.
[8] Saeed, A.; Shabbir, S.; Flörke, U. J Heterocyclic Chem 2014,
52, 1357; J. Heterocyclic Chem 2015, 52, 846; Saeed, A.; Mahesar, P. A.
Tetrahedron 2014, 70, 1401; Zaib, S.; Saeed, A.; Stolte, K.; Flörke, U.;
Shahid, M.; Iqbal, J. J Med Chem 2014, 78, 140; Ashraf, Z.; Saeed, A.;
Nadeem, H. RSC Adv 2014, 4, 53842.
[9] Kumar, A.; Sharma, S. Green Chem 2011, 13, 2017.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet