Synthesis and characterization of new thiadiazole derivatives bearing a pyrazole moiety

Article abstract of DOI:10.1080/10426507.2017.1345905

A series of thidiazole derivatives (4, 7) from pyrazole-3-carboxylic acid chloride (2) and pyrazole-3,4- dicarboxylic acid chloride derivatives (6) were synthesized and characterized. The structures of the new compounds were confirmed byelemental analysis

Full text of DOI:10.1080/10426507.2017.1345905

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis and characterization of new thiadiazole
derivatives bearing a pyrazole moiety
Mustafa Saçmacı, Çiler Arslaner & Ertan Şahin
To cite this article: Mustafa Saçmacı, Çiler Arslaner & Ertan Şahin (2017): Synthesis and
characterization of new thiadiazole derivatives bearing a pyrazole moiety, Phosphorus, Sulfur, and
Silicon and the Related Elements, DOI: 10.1080/10426507.2017.1345905
To link to this article: http://dx.doi.org/10.1080/10426507.2017.1345905
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Synthesis and characterization of new thiadiazole derivatives bearing a pyrazole moiety
Mustafa Saçmacıa, Çiler Arslanera, Ertan Şahinb
aDepartment of Chemistry, Faculty of Arts and Sciences, Bozok University, Yozgat, Turkey
bDepartment of Chemistry,Faculty of Sciences, Ataturk University, Erzurum, Turkey
Corresponding author email: msacmaci@hotmail.com
ABSTRACT
A series of thidiazole derivatives (4, 7) from pyrazole-3-carboxylic acid chloride (2) and
pyrazole-3,4-dicarboxylic acid chloride derivatives (6) were synthesized and characterized. The
13
structures of the new compounds were confirmed byelemental analysis, NMR (1H and C) and
IR spectra. The molecular and crystal structure of 4-benzoyl-N-[5-(methylthio)-1,3,4-thiadiazol-
2-yl]-1,5-di-phenyl-1H-pyrazole-3-carboxamide(4d)was determined by single crystal X-ray
diffraction method.
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KEYWORDS
Thiadiazole;pyrazole; X-ray structure
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Introduction
Recently, thiadiazole derivatives have received significant attention and have been increasingly
investigated due to their diverse range of biological properties. They exhibit, for example, anti-
microbial,1,2anti-bacterial,3 anticancer,4 anti-inflammatory,5,6 carbonic anhydrase inhibiting
effect,7 antanxiety, anti-depressant,8 anti-oxidant properties.9Five membered heterocyclic
compounds exhibit a variety of biological activities, amongst them 2,5-disubstituted 1,3,4-
thiadiazoles are associated with diverse biological activities probably by virtue of = N-C-S-
group.10In addition, some thiadiazole derivatives are pharmacologically active substances such as
acetazolamide, methazolamide, sulfamethazole drugs and the derivatives of these drugs exhibit
other activities, including anticonvulsant and selective cerebral vasodilation, as well as the
anticipated inhibition of carbonic anhydrase.11
In continuation to our interest in the chemical and pharmacological properties of thiadiazole
derivatives, we reported a facile synthetic strategy for preparation of some new thiadiazole
derivatives linked to a pyrazole moiety.
Resultsanddiscussion
Various 2-amino-1,3,4-thiadiazoles (3) were reacted with pyrazole carboxylic acid mono
and dichloride derivatives (2, 6) to give the corresponding new thiadiazole derivatives (4, 7)as
described in Schemes 1-2. In order to synthesize the mono and dithidiazole compounds (4, 7),
firstly carboxyl group of pyrazol carboxylic acids (1, 5) were activated by thionyl chloride12-
14and then 2-amino-1,3,4-thiadiazole derivatives (3) with activated pyrazole carboxylic acid
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mono and dichloride (2, 6) were reacted in dry acetonitrile by refluxing. The target compounds
(4, 7) were obtained in moderate yields.
The structures of the reaction products were characterized from analytical and spectoscopy
data (elemental analysis, IR, 1H, 13C NMR and also X-ray diffraction method for compound 4d).
There are different carbonyl groups features in each ofthe compounds4 and 7, each of them with
a different electronic environment. So, the IR and NMR spectra provide excellent evidence of
their structures. For instance, the absorption bands observed at 1675 and 1663, 1668, 1658 cm1
1
for 4d and 7a belong to benzoyl and amide carbonyl groups, respectively. The H NMR spectra
of 4d and 7a forN-H proton signals were observed at 10.65 and12.01 ppm.The 13C NMR spectra
of 4d and 7a for carbonyl carbons signalswere observed at 191.0, 157.6 and 160.9, 158.6
ppm.Other characteristic peaks appeared at expected regions (see Experimental for details).
Experimental section
Melting points are uncorrected and recorded on Electrothermal 9200 digital melting point
apparatus. Microanalyses were performed on a Leco-932 CHNS-O Elemental Analyser. IR
spectra (in the range of 400-4000 cm1 region) of the molecules were recorded by Perkin-Elmer
Spectrometer with a resolution of 4 cm1 at room temperature using ATR techniques. 1H and 13C
NMR spectra were recorded on a Bruker Avance model using Si(CH3)4 as a reference in CDCl3
and DMSO-d6 at 400 MHz, respectively. The reactions were followed by TLC using DC
Alufolien Kieselgel 60 F254 Merck and Camag TLC lamp (254/366 nm). Solvents and all other
chemical reagents were purchased from Merck, Sigma, Aldrich and Fluka and used directly
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without further purification. The Supplemental Materials file contains sample H, 13C NMR and
IR spectra of products 4 and 7 (Figures S 1 -- S 44).
General procedure for the synthesis of compound 4 derivatives
Previously,
4-benzoyl-1,5-diphenyl-1H-pyrazole-3-carbonyl-chloride
(2),
ethyl-3-
(chlorocarbonyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (2) and 1,5-diphenyl-1H-pyrazole-3,4-
di carbonyl-dichloride (6) were prepared according to the published methods.12-14
To a stirred solution of compound (2)or(6) in acetonitrile (10 mL) was added the solution of
2-amino-1,3,4-thidiazole derivatives (3) in acetonitrile (5 mL) dropwise.The mixture were
refluxed for 4-5 h. Later, the solvent was evaporated under reduced pressure to give an oily
residue which was triturated with anhydrous diethylether and finally recrystallized from the
indicated solvents.
4-Benzoyl-1,5-diphenyl-N-1,3,4-thiadiazol-2-yl-1H-pyrazole-3-carboxamide (4a)
Compound 4a wassynthesized from 2 (0.38 g, 1.0 mmol) and 3a (0.10 g, 1.0 mmol) according to
the general procedure. The crude product was purified by recrystallization from ethanol. Yield:
78%; m.p.: 168-169C. IR (ATR, cm1): 3330 (N-H), 1682, 1667(C = O), 1596 (C = C), 1496 (C
1
= N), 1210 (C = S). H NMR (400 MHz, CDCl3): δ (ppm) = 10.81 (s, 1H, N-H), 7.85-7.14 (m,
15H, Ar-H). 13C NMR (100 MHz, CDCl3): δ (ppm) = 191.4, 159.9 (C = O), 157.9, 157.8, 147.9,
144.6, 142.3, 138.4, 137.2, 133.6, 129.7, 129.6, 129.6, 129.2, 128.9, 128.6, 128.4, 127.4, 125.2,
122.6, (C = C). Anal. calcd. for C25H17N5O2S (451 g/mol): C, 66.50; H, 3.80; N, 15.51, S, 7.10.
Found: C, 66.81; H, 3.96; N, 15.65, S, 6.90.
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4-Benzoyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-1,5-di-phenyl-1H-pyrazole-3-carboxamide
(4b)
Compound 4b wassynthesized from 2 (0.38 g, 1.0 mmol) and 3b (0.12 g, 1.0 mmol) according to
the general procedure. The crude product was purified by recrystallization from ethanol. Yield:
81%; m.p.: 230-231C. IR (ATR, cm1): 3140 (N-H), 1687, 1663(C = O), 1593 (C = C), 1495 (C
1
= N), 1234 (C = S). H NMR (400 MHz, CDCl3): δ (ppm) = 10.81 (s, 1H, N-H), 7.85-7.14 (m,
13
15H, Ar-H), 2.66 (s, 3H, CH3). C NMR (100 MHz, CDCl3): δ (ppm) = 191.1, 160.6 (C = O),
158.0, 157.7, 144.4, 142.5, 138.5, 137.3, 133.5, 129.7, 129.6, 129.5, 129.1, 128.8, 128.6, 128.4,
127.5, 125.1, 122.6 (C = C), 15.3 (CH3). Anal. calcd. for C26H19N5O2S (465 g/mol): C, 67.08; H,
4.11; N, 15.04, S, 6.89. Found: C, 66.90; H, 4.05; N, 14.90, S, 6.70.
4-Benzoyl-N-(5-ethyl-1,3,4-thiadiazol-2-yl)-1,5-diphenyl-1H-pyrazole-3-carboxamide (4c)
Compound 4c wassynthesized from 2 (0.38 g, 1.0 mmol) and 3c (0.13 g, 1.0 mmol) according to
the general procedure. The crude product was purified by recrystallization from ethanol. Yield:
75%; m.p.: 235-236C. IR (ATR, cm1): 3137 (N-H), 1677, 1660(C = O), 1595 (C = C), 1498 (C
1
= N), 1196 (C = S). H NMR (400 MHz, CDCl3): δ (ppm) = 10.64 (s, 1H, N-H), 7.86-7.15 (m,
13
15H, Ar-H), 3.07-3.01 (q, 2H, CH2), 1.40-1.36 (t, 3H, CH3). C NMR (100 MHz, CDCl3): δ
(ppm) = 191.1, 167.4 (C = O), 157.6, 157.6, 144.4, 142.5, 138.5, 137.3, 133.5, 129.6, 129.6,
129.2 128.9, 128.7, 128.4, 127.5, 125.1, 122.7, (C = C), 25.3 (CH2), 14.0 (CH3). Anal. calcd. for
C27H21N5O2S (479 g/mol): C,67.62; H, 4.41; N, 14.60, S, 6.69. Found: C, 67.45; H, 4.20; N,
14.25, S, 6.50.
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4-Benzoyl-N-[5-(methylthio)-1,3,4-thiadiazol-2-yl]-1,5-di-phenyl-1H-pyrazole-3-carbox-
amide (4d)
Compound 4d wassynthesized from 2 (0.38 g, 1 mmol) and 3d (0.15 g, 1 mmol) according to the
general procedure. The crude product was purified by recrystallization from ethanol. Yield: 70%;
m.p.: 183-184C. IR (ATR, cm1): 3120 (N-H), 1675, 1663(C = O), 1593 (C = C), 1499 (C = N),
1190 (C = S). 1H NMR (400 MHz, CDCl3): δ (ppm) = 10.65 (s, 1H, NH), 7.85-7.15 (m, 15H, Ar-
13
H), 2.72 (t, 3H, SCH3). C NMR (100 MHz, CDCl3): δ (ppm) = 191.0, 157.7 (C = O), 144.6,
142.3, 138.5, 137.3, 133.5, 129.7, 129.6, 129.6, 129.2, 128.9 128.7, 128.4, 127.4, 125.2, 122.6,
(C = C), 16.3 (SCH3). Anal. calcd. for C26H19N5O2S2 (497 g/mol): C, 62.76; H, 3.85; N, 14.07, S,
12.89. Found: C, 62.50; H, 3.70; N, 13.90, S, 12.65.
4-Benzoyl-N-[5-(ethylthio)-1,3,4-thiadiazol-2-yl]-1,5-di-phenyl-1H-pyrazole-3-carbox-
amide (4e)
Compound 4e wassynthesized from 2 (0.38 g, 1.0 mmol) and 3e (0.16g, 1.0 mmol) according to
the general procedure. The crude product was purified by recrystallization from ethanol. Yield:
55%; m.p.: 169-170C. IR (ATR, cm1): 3133 (N-H), 1682, 1659(C = O), 1598 (C = C), 1495 (C
1
= N), 1192 (C = S). H NMR (400 MHz, CDCl3): δ (ppm) = 10.64 (s, 1H, N-H), 7.85-7.15 (m,
15H, Ar-H), 3.26-3.21 (q, 2H, SCH2), 1,45-1.41 (t, 3H, SCH2CH3). 13C NMR (100 MHz,
CDCl3): δ (ppm) = 191.1, 161.0 (C = O), 157.8, 157.6, 144.5, 142.3, 138.4, 137.3, 133.5, 129.7,
129.6, 129.6 129.2, 128.6, 128.4,127.4, 125.2, 122.6, (C = C), 28.7 (SCH2), 14.7 (SCH2CH3).
Anal. calcd. for C27H21N5O2S2 (511 g/mol): C, 63.38; H, 4.14; N, 13.69; S, 12.54. Found: C,
63.15; H, 4.05; N, 13.50, S, 12.35.
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Ethyl-1,5-diphenyl-3-[(1,3,4-thiadiazol-2-yl-amino)-carbonyl]-1H-pyrazole-4-carboxy-late
(4f)
Compound 4f wassynthesized from 2 (0.35 g, 1.0 mmol) and 3a (0.10 g, 1.0 mmol) according to
the general procedure. The crude product was purified by recrystallization from i-propanol.
Yield: 60%; m.p.: 176-177C. IR (ATR, cm1): 3146 (N-H), 1682, 1667(C = O), 1596 (C = C),
1
1494 (C = N), 1178 (C = S). H NMR (400 MHz, CDCl3): δ (ppm) = 13.09 (s, 1H, NH), 8.91-
7.26 (m, 11H, Ar-H), 4.26-4.21 (q, 2H, OCH2CH3), 1,02-0.99 (t, 3H, OCH2CH3). 13C NMR (100
MHz, CDCl3): δ (ppm) = 165.1, 160.1 (C = O), 157.8, 148.2, 143.9, 138.3, 130.1, 129.6, 128.6,
128.6, 128.2, 125.5 (C = C), 62.0 (OCH2CH3), 13.4 (OCH2CH3). Anal. calcd. for C21H17N5O3S
(419 g/mol): C, 60.13; H, 4.09; N, 16.70,;S, 7.64. Found: C, 59.95; H, 3.90; N, 16.50, S, 7.50.
Ethyl-3-{[(5-methyl-1,3,4-thiadiazol-2-yl)-amino]-carbonyl}-1,5-diphenyl-1H-pyrazole-4-
carboxylate (4g)
Compound 4g wassynthesized from 2 (0.35 g, 1.0 mmol) and 3b (0.12 g, 1.0 mmol) according to
the general procedure. The crude product was purified by recrystallization from ethanol. Yield:
65%; m.p.: 168-169C. IR (ATR, cm1): 3167 (N-H), 1723, 1710(C = O), 1594 (C = C), 1500 (C
1
= N), 1166 (C = S). H NMR (400 MHz, CDCl3): δ (ppm) = 12.73 (s, 1H, NH), 7.42-7.25 (m,
10H, Ar-H), 4.24-4.19 (q, 2H, OCH2CH3), 2,74 (s, 3H, C2H2N2SCH3), 1.02-0.99(t, 3H,
OCH2CH3). 13C NMR (100 MHz, CDCl3): δ (ppm) = 164.5, 160.8 (C = O), 158.4, 157.6, 147.5,
138.3, 130.1, 129.5, 128.9, 128.8, 128.6, 128.2, 125.5, 113.4 (C = C), 61.9 (OCH2CH3), 15.3
(SCH3), 13.4 (OCH2CH3). Anal. calcd. for C22H19N5O3S (433 g/mol): C, 60.96; H, 4.42; N,
16.16; S, 7.40. Found: C, 60.76; H, 4.20; N, 15.95, S, 7.20.
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Ethyl-3-{[(5-ethyl-1,3,4-thiadiazol-2-yl)-amino]-carbonyl}-1,5-diphenyl-1H-pyrazole-4-
carboxylate (4h)
Compound 4h wassynthesized from 2 (0.35 g, 1.0 mmol) and 3c (0.13 g, 1.0 mmol) according to
the general procedure. The crude product was purified by recrystallization from i-propanol.
Yield: 72%; m.p.: 155-156C. IR (ATR, cm1): 3246 (N-H), 1680, 1668(C = O), 1595 (C = C),
1494 (C = N), 1179 (C = S). 1H NMR (400 MHz, CDCl3): δ (ppm) = 12.66 (s, 1H, N-H), 7.45-
7.21 (m, 10H, Ar-H), 4.28-4.16 (q, 2H, OCH2CH3), 2,74 (s, 3H, C2H2N2SCH3), 1.02-0.99 (t, 3H,
OCH2CH3). 13C NMR (100 MHz, CDCl3): δ (ppm) = 164.5, 160.8 (C = O), 158.4, 157.6, 147.5,
138.3, 130.1, 129.5, 128.9, 128.8, 128.6, 128.2, 125.5, 113.4 (C = C), 61.9 (OCH2CH3), 23.6
(SCH2), 14.2 (SCH3), 13.4. Anal. calcd.for C23H21N5O3S (447 g/mol): C, 61.73; H, 4.73; N,
15.65; S, 7.17. Found: C, 61.50; H, 4.50; N, 15.30; S, 6.95.
Ethyl-3-({[5-(methylthio)-1,3,4-thiadiazol-2-yl]-amino}-carbonyl)-1,5-diphenyl-1H-
pyrazole-4-carboxylate (4i)
Compound 4i wassynthesized from 2 (0.35 g, 1.0 mmol) and 3d (0.15g, 1.0 mmol) according to
the general procedure. The crude product was purified by recrystallization from methanol. Yield:
66%;m.p.: 160-161C. IR (ATR, cm1): 3100 (N-H), 1682, 1659(C = O), 1595 (C = C), 1498 (C
1
= N), 1184 (C = S). H NMR (400 MHz, CDCl3): δ (ppm) = 12.80 (s, 1H, NH), 7.42-7.25 (m,
10H, Ar-H), 4.25-4.20 (q, 2H, OCH2CH3), 2.72 (s, 1H, SCH3), 1.03-0.99 (t, 3H, OCH2CH3). 13C
NMR (100 MHz, CDCl3): δ (ppm) = 164.5, 162.2 (C = O), 158.1, 157.6, 147.6, 143.8, 138.3,
130.1, 129.6, 128.9, 128.9, 128.6, 128.2, 125.5, 113.4 (C = C), 62.0 (OCH2CH3), 16.3 (SCH3),
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13.4 (OCH2CH3). Anal. calcd. for C22H19N5O3S2 (465 g/mol): C, 56.76; H, 4.11; N, 15.04; S,
13.78. Found: C, 56.58; H, 3.99; N, 14.91; S, 13.58.
Ethyl-3-({[5-(ethylthio)-1,3,4-thiadiazol-2-yl]-amino}-carbonyl)-1,5-diphenyl-1H-pyrazole-
4-carboxylate (4j)
Compound 4j wassynthesized from 2 (0.35 g, 1.0 mmol) and 3e (0.16 g, 1.0 mmol) according to
the general procedure. The crude product was purified by recrystallization from i-propanol.
Yield: 61%; m.p.: 140-141C. IR (ATR, cm1): 3132 (N-H), 1680, 1666(C = O), 1594 (C = C),
1
1492 (C = N), 1178 (C = S). H NMR (400 MHz, CDCl3): δ (ppm) = 12.82 (s, 1H, NH), 7.44-
7.25 (m, 10H, Ar-H), 4.24-4.19 (q, 2H, OCH2CH3), 3,33-3.27 (q, 2H, SCH2CH3), 1.49-1.45 (t,
13
3H, OCH2CH3), 1.02-0.99 (t, 3H, SCH2CH3). C NMR (100 MHz, CDCl3): δ (ppm) = 164.5,
160.9 (C = O), 158.4, 157.6, 147.6, 143.8, 138.3, 130.1, 129.6, 128.9, 128.9, 128.6, 128.2, 125.5,
113.4 (C = C), 62.0 (OCH2CH3), 28.7 (SCH2CH3), 14.7 (OCH2CH3), 13.4 (SCH2CH3). Anal.
calcd. for C23H21N5O3S2 (479 g/mol): C, 57.60; H, 4.41; N, 14.60; S, 13.37. Found: C, 57.48; H,
4.30; N, 14.45; S, 13.10.
General procedure for the synthesis of compound 7 derivatives
A mixture of pyrazole carboxylic acid dichloride (6) (1.0 mmol), and the appropriate 2-
amino-1,3,4-thiadiazole derivatives 3 (4.0 mmol) was heated under reflux condition in freshly
distilled acetonitrile (25 mL) for 5 h. The solvent was evaporated in vacuo and residue was
washed with water. The precipitated crude product was filtered and crystallized from the
appropriate solvent.
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1,5-Diphenyl-N,N'-di-1,3,4-thiadiazol-2-yl-1H-pyrazole-3,4-dicarboxamide (7a)
Compound 7a wassynthesized from 6 (0.34 g, 1.0 mmol) and 3a (0.10 g, 1.0 mmol) according to
the general procedure. The crude product was purified by recrystallization from methanol. Yield:
63%; m.p.: 289-290 C. IR (ATR, cm1): 3379, 3233 (N-H), 1668, 1658(C = O), 1594 (C = C),
1497 (C = N), 1186 (C = S). 1H NMR (400 MHz, CDCl3): δ (ppm) = 12.01 (br., 1H, N-H), 8.99-
13
7.26 (m, 10H, Ar-H). C NMR (100 MHz, CDCl3): δ (ppm) = 160.9, 158.6 (C = O), 158.2,
150.9, 148.8, 147.9, 139.8, 137.9, 130.3, 130.0, 129.3, 129.1, 128.5, 127.5, 125.3, 115.6 (C = C),
62.0 (OCH2Me), 28.7 (SCH2Me), 14.7 (OCH2CH3), 13.4 (SCH2CH3). Anal. calcd. for
C21H14N8O2S2 (474 g/mol): C, 53.15; H, 2.97; N, 23.61; S, 13.52. Found: C, 52.95; H, 2.90; N,
23.50; S, 13.30.
N,N'-bis(5-methyl-1,3,4-thiadiazol-2-yl)-1,5-di-phenyl-1H-pyrazole-3,4-dicarboxamide (7b)
Compound 7b wassynthesized from 6 (0.34 g, 1.0 mmol) and 3b (0.12 g, 1.0 mmol) according to
the general procedure. The crude product was purified by recrystallization from methanol. Yield:
77%; m.p.: 261-262 C. IR (ATR, cm1): 3147 (N-H), 3075(N-H), 1671, 1660(C = O), 1563 (C
= C), 1489 (C = N), 1189 (C = S). 1H NMR (400 MHz, CDCl3): δ (ppm) = 13.80, 10.95 (br., 2H,
N-H), 7.47-7.19 (m, 10H, Ar-H), 2.78, 2.68 (s, 6H, CH3). 13C NMR (100 MHz, CDCl3): δ (ppm)
= 161.7, 160.5 (C = O), 160.3, 158.1, 150.9, 139.9, 137.9, 130.4, 129.9, 129.3, 129.1, 128.4,
128.1, 125.4, 115.7, (C = C), 15.5, 15.3 (CH3). Anal. calcd. for C23H18N8O2S2 (502 g/mol): C,
54.97; H, 3.61; N, 22.30; S, 12.76. Found: C, 54.80; H, 3.50; N, 22.10; S, 12.50.
N,N'-bis(5-ethyl-1,3,4-thiadiazol-2-yl)-1,5-di-phenyl-1H-pyrazole-3,4-dicarboxamide (7c)
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Compound 7c wassynthesized from 6 (0.34 g, 1.0 mmol) and 3c (0.13 g, 1.0 mmol) according to
the general procedure. The crude product was purified by recrystallization from acetic acid.
Yield: 57%; m.p.: 236-237 C. IR (ATR, cm1): 3191 (N-H), 3075 (N-H), 1671, 1647(C = O),
1612 (C = C), 1495 (C = N), 1222 (C = S). 1H NMR (400 MHz, CDCl3): δ (ppm) = 13.80, 11.29
13
(br, 2H, N-H), 7.47-7.18 (m, 10H, Ar-H), 3.13-3.01 (q, 2H, CH2), 1.47-1.35 (t, 6H, CH3). C
NMR (100 MHz, CDCl3): δ (ppm) = δ 168.2, 167.0 (C = O), 160.6, 158.4, 158.2, 157.6, 150.6,
140.1, 137.9, 130.4, 129.8, 129.2, 129.0, 128.3, 128.1, 125.4, 115.8 (C = C), 29.6, 23.6 (CH2),
14.1, 14.0 (CH3). Anal. calcd. for C25H22N8O2S2 (530 g/mol): C, 56.59; H, 4.18; N, 21.12; S,
12.09. Found: C, 56.45; H, 4.05; N, 20.95; S, 11.91.
N,N'-bis[5-(methylthio)-1,3,4-thiadiazol-2-yl]-1,5-di-phenyl-1H-pyrazole-3,4-dicarbox-
amide (7d)
Compound 7d wassynthesized from 6 (0.34 g, 1.0 mmol) and 3d (0.15 g, 1.0 mmol) according to
the general procedure. The crude product was purifiedby recrystallization from acetic acid.
Yield: 47%; m.p.: 264-265 C. IR (ATR, cm1): 3386, 3152 (N-H), 1677, 1656(C = O), 1594 (C
1
= N)-1495 (C = C), 1186 (C = S). H NMR (400 MHz, CDCl3): δ (ppm) = 7.48-7.24 (m, 10H,
13
Ar-H), 2.84, 2.74 (s, 3H, SCH3). C NMR (100 MHz, CDCl3): δ (ppm) = δ 161.0, 160.2 (C =
O), 157.6, 157.5, 144.5, 142.3, 138.5, 137.3, 133.5, 129.7, 129.6, 129.5129.2, 128.9, 128.6,
128.4, 127.4, 125.2, 122.6 (C = C), 14.2, 14.1 (CH3). Anal. calcd. for C23H18N8O2S4 (566 g/mol):
C, 48.75; H, 3.20; N, 19.77; S, 22.63. Found: C, 48.55; H, 2.95; N, 19.55; S, 22.50.
N,N'-bis[5-(ethylthio)-1,3,4-thiadiazol-2-yl]-1,5-diphenyl-1H-pyrazole-3,4-dicarbox-amide
(7e)
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Compound 7e wassynthesized from 6 (0.34 g, 1.0 mmol) and 3e (0.16 g, 1.0 mmol) according to
the general procedure. The crude product was purified by recrystallization from acetic acid.
Yield: 55%; m.p.: 220-221C. IR (ATR, cm1): 3340, 3140 (NH), 1675, 1657(C = O), 1605 (C =
1
C), 1491 (C = N), 1178 (C = S). H NMR (400 MHz, CDCl3): δ (ppm) = 12.26 (br, 2H, N-H),
7.48-7.25 (m, 10H, Ar-H), 3.35-3.20 (q, 2H, CH2), 1.51-1.41 (t, 6H, CH3). 13C NMR (100 MHz,
CDCl3): δ (ppm) = δ 176.1, 162.5 (C = O), 160.7, 160.4, 158.7, 157.9, 150.6, 139.9, 137.9,
130.3, 129.9, 129.2, 129.0, 128.4, 128.0, 125.3, 115.6 (C = C), 28.7, 28.7 (CH2), 14.7, 14.6
(CH3). Anal. calcd. for C25H22N8O2S2 (594 g/mol): C, 50.49; H, 3.73; N, 18.84; S, 21.57. Found:
C, 50.35; H, 3.51; N, 18.69; S, 21.45.
X-ray Crystallography
For the crystal structure determination, single-crystals of molecule 4d was used for data
collection on a four-circle Rigaku R-AXIS RAPID-S diffractometer (equipped with a two-
dimensional area IP detector). Graphite-monochromated Mo-Kα radiation ( = 0.71073 Å)and
oscillation scans technique with w = 5 for one image were used for data collection. The lattice
parameters were determined by the least-squares methods on the basis of all reflections with F2>
2(F2). Integration of the intensities, correction for Lorentz and polarization effects and cell
refinement was performed using Crystal Clear (Rigaku/MSC Inc. 2005) software.15The
structures were solved by direct methods using SHELXS-97 and refined by a full-matrix least-
squares procedure using the program SHELXL-97.16_ENREF_22H atoms were positioned
geometrically and refined using a riding model. The final difference Fourier maps showed no
peaks of chemical significance.
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The crystal structure of the molecule 4d with the atom labeling and the dimeric structure are
shown in Fig. 1. The crystallographic data and structural refinement details for compound 4d is
given in Table 1. Compound 4d crystallizes in the triclinic P-1 space group with two molecules
per unit cell. The bond lengths of pyrazole C-N, N-N vary from 1.345(3) Å to 1.378(3) Å and
shorter than the corresponding single bond distances. This fact suggests multiple bond order and
confers aromaticity to the ring. The aromatic groups attached to the pyrazole ring are twisted
considerably due to the steric hindrance.
Deviation of the bond angle from 120° in the 1,3,4-thiadiazole ring is a common feature in
five-membered rings. Thiadiazole bond distances are as follows; S1-C24 1.728(3) Å, S1-C25
1.733(3) Å, N4-N5 1.392(3) Å, N4-C24 1300(3) Å and N4-C24 1.290(3) Å. C-N and C-S bond
in thiadiazole ring involves carbon atom with sp2 hybridization. The values found for bond
angles and lengths are similar to those reported in related compounds.17,18 The dihedral angle
between the thiadiazole and the phenyl rings is found to be 38.3°. Ring planarity and π-electron
delocalization lead to the conclusion that the thiadiazole ring is aromatic in the studied
compound. Selected bond lengths and angles are presented in Table S 1
In the solid state, the compound 4d is stabilized via effective intra-molecular N3-H∙∙∙N4
bonding, which leads to the formation of dimeric structure. Along with that C13-H∙∙∙O1 [D∙∙∙A =
3.510(3) Å] and C4-H∙∙∙O1 [D∙∙∙A = 3.446(3) Å] interactions have a contribution in the formation
of a stable structure.
Crystallographic data that were deposited in CSD under CCDC-1473635 registration number
contain the supplementary crystallographic data for this letter. These data can be obtained free of
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charge
from
the
Cambridge
Crystallographic
Data
Centre
(CCDC)
via
www.ccdc.cam.ac.uk/data_request/cif and are available free of charge upon request to CCDC, 12
Union Road, Cambridge, UK (fax: +441223 336033, e-mail: deposit@ccdc.cam.ac.uk).
Acknowledgements
The authors would like to express their gratitude to the Research Fund of Bozok University
(Project Number: FBE/ T-177)
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References
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Sci.2008, 70,672-677.
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Org. Med. Chem.Lett. 2005, 15, 4488-4492.
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115-124.
7. Nadeem, S.; Priya, A.; Waquar, A.; Pandeya, S. and Shamsher, M. J. Chem. Pharm. Res.
2009, 1, 19-30.
8. Cleici, F.; Pocar, D.; Guido, M.; Loch, A.; Perlini, V. and Brufani, M. J. Med. Chem. 2001,
44, 931-936.
9. Martinez, A.; Alonso, D.; Castro, A.; Aran, J.; Cardelus, I. and Banos, E. Arch. Pharm. 1999,
332, 191-194.
10. Oruc, E.; Rollas, S.; Kandemirli, F.; Shvets, N. and Dimoglo, A. J. Med. Chem. 2004, 47,
6760-6767.
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11. Masereel, B.; Rolin, S.; Abbate, F.; Scozzafava, A.; Supuran, C.T. J. Med. Chem. 2002,45,
312-320.
12. Akcamur, Y.; Sener, A.; Ipekoglu, A. M.; Kollenz, G. J.Het. Chem.1997, 34, 221-224.
13. Sener, A.; Tozlu, I.; Genc, H.; Bildirici, I.; Arisoy, K. J. Het. Chem.2007, 44, 1077-1081.
14. Kasimogullari, R.; Seckin Arslan, B. J. Het. Chem.2010, 47, 1040-1048.
15. Rigaku/MSC, Inc., 9009 New Trails Drive, The Woodlands, TX 77381.
16. Sheldrick, G.H. SHELXS97 and SHELXL97. [Program for Crystal Structure Solution and
Refiniment], University of Göttingen, Germany, 1997.
17. Wang, H.; Gaob, Y.; and Wang, W. Acta Cryst. 2010, E66, o3085.
18.Fun, H. K.; Chantrapromma, S.; Chandrakantha, B.; Isloord, A. M.; and Shetty, P.Acta
Cryst.2011,E67, o163.
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Table 1: Crystal Structure and Data Refinement Parameters
Compound
4d
Empirical Formula
Formula Weight
Crystal System / Space Group
a / Å
C26H19N5O2S2
497.6
Triclinic / P-1
8.3579(7)
9.3663(8)
16.0222(13)
89.334(3)
87.245(3)
76.627(3)
1218.84(9)
2
b / Å
c / Å
 / °
β / °
γ / °
V / Å3
Z
D calc (g/cm3)
μ (mm1)
1.36
0.252
Crystal size (mm)
Color / Shape
Temp (K)
0.10  0.11  0.13
-
293(2)
Theta range for collection
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness of fit on F2
3.2-28.3
57430
6062
4377/0/317
1.515
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Final R indices [I > 2σ(I)]
R indices (all data)
0.0429
0.124
Largest difference peak/hole
0.327 / -0.326
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Figure 1. Up: Crystalstructureof the molecule 4d. Thermal ellipsoids are drawn at the 40%
probability level. Down: Dimeric structure with intra-molecular H-bonding geometry. Hydrogen
bonds are drawn as dashed lines. Selected bond lengths [Å]: N1-N2 1.345(2), N4-N5 1.392(2),
S1-C24 1.728(2), S2-C25 2.743(2),O2-C23 1.218(2), N3-H…N4 2.976(2).
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Scheme 1.The synthetic route of mono thiadiazoles
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Scheme 2. Synthetic pathways for the preparation of dithiadiazole derivatives
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