Synthesis of 3-[5-methyl-1-(4 -methylphenyl)-1,2,3-triazol-4 -yl]-6-aryl/heteroaryl-substituted-s-triazolo-[3,4-b] -1,3,4-thiadiazoles

Article abstract of DOI:10.1081/SCC-100000183

Several 3-[5-methyl-1-(4-methylphenyl)-1,2,3-triazol-4-yl]-6 -substituted-1,3,4-triazolo[3,4-b]-1,3,4-thiadiazoles have been synthesized and the structures of these compounds were established by elemental analysis. MS, IR, and ¹H NMR spectral data.

Full text of DOI:10.1081/SCC-100000183

This article was downloaded by: [Illinois State University Milner Library]
On: 26 November 2012, At: 05:25
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
SYNTHESIS OF 3-[5-METHYL-1-(4-
METHYLPHENYL)-1,2,3-TRIAZOL-4-YL]-6-ARYL/
HETEROARYL-SUBSTITUTED-S-TRIAZOLO- [3,4-
b]-1,3,4-THIADIAZOLES
Heng-Shan Dong a , Kun Wei a , Qing-Lian Wang a & Bin Quan a
a National Laboratory of Applied Organic Chemistry, Institute of Organic Chemistry,
College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu,
730000, China
Version of record first published: 09 Nov 2006.
To cite this article: Heng-Shan Dong, Kun Wei, Qing-Lian Wang & Bin Quan (2001): SYNTHESIS OF 3-[5-METHYL-1-(4-
METHYLPHENYL)-1,2,3-TRIAZOL-4-YL]-6-ARYL/HETEROARYL-SUBSTITUTED-S-TRIAZOLO- [3,4-b]-1,3,4-THIADIAZOLES,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:1, 81-88
To link to this article: http://dx.doi.org/10.1081/SCC-100000183
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 COMMUNICATIONS, 31(1), 81–88 (2001)
SYNTHESIS OF 3-[5-METHYL-1-
(4-METHYLPHENYL)-1,2,3-TRIAZOL-
4-YL]-6-ARYL/HETEROARYL-
SUBSTITUTED-S-TRIAZOLO-
[3,4-b]-1,3,4-THIADIAZOLES
Heng-Shan Dong,∗ Kun Wei, Qing-Lian Wang,
and Bin Quan
National Laboratory of Applied Organic Chemistry,
Institute of Organic Chemistry, College of Chemistry
and Chemical Engineering, Lanzhou University,
Lanzhou, Gansu 730000, China
ABSTRACT
Several 3-[5-methyl-1-(4-methylphenyl)-1,2,3-triazol-4-yl]-
6-substituted-1,3,4-triazolo[3,4-b]-1,3,4-thiadiazoles have been
synthesized and the structures of these compounds were established
by elemental analysis, MS, IR, and 1H NMR spectral data.
In recent years, fused heterocycles have been found to possess many unique
properties in synthesis and pharmacology. Especially, s-triazolo[3,4-b]-1,3,4-thia-
diazole derivatives have been attracting the attention of chemists and pharmacol-
ogists. Certain compounds having 1,3,4-triazole nucleus have been reported as
fungicidal (1), insecticidal (2), antimicrobial (3), and bactericidal (4). Compounds
∗To whom correspondence should be addressed.
81
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

ORDER
REPRINTS
82
DONG ET AL.
with 1,2,3-triazole nucleus have been reported as antibacterial (5), antifungal (6),
antiviral (7), anti-inflammatory, and analgesic (8). Recently, some new 1,3,4-
triazole derivatives have been synthesized as possible anticonvulsants (9) and
plant growth regulators (10), and 1,2,3-triazole derivatives have been synthesized
to inhibit tumor proliferation, invasion, and metastasis (11). Likewise, the 1,3,4-
thiadiazole nucleus, which incorporates an N-C-S linkage, exhibits a large number
of biological activities (12). 1,3,4-Triazolo[3,4-b]-1,3,4-thiadiazoles are fused het-
erocyclic derivatives showing various biological effects such as antifungal (13),
antibacterial, hypotensive, and CNS depressant activities (14). For this reason,
synthesis of several of the heterocyclic derivatives containing 1,2,3-triazole, 1,3,4-
triazole, and 1,3,4-thiadiazole nuclei is very interesting because there has been no
synthetic study on the title compounds of s-triazolo[3,4-b]-1,3,4-triazole contain-
ing a 1,2,3-triazole cycle in the literature up to now.
The title compounds were prepared according to the following method.
EXPERIMENTAL
All melting points were determined on a Kofler melting point apparatus and
are uncorrected. Mass spectrum was performed on a HP-5988A spectrometer (EI
at 70 eV). IR spectra were obtained in KBr discs using a Nicolet 170SX FT-IR
spectrometer. 1H NMR spectra were recorded at room temperature at 80.13 MHz
on a Bruker FT-AC 80 instrument. Elemental analyses were carried out on a Yanaco
CHN Corder MT-3 analyzer.
Phosphorus oxychloride was redistilled (b.p. 105◦C). 5-Methyl-1-(4-methyl-
phenyl)-1,2,3-triazol-4-carboxylic acid (1) was prepared following methods in the
literature (15) m.p. 182◦–183◦C (Lit. 182◦–183◦C) (16).
Esterification of 5-Methyl-1-(4-methylphenyl)-1,2,3-
triazol-4-carboxylic Acid 1 with Absolute Ethanol
In a 150-mL flask, a mixture of 21.7 g (0.10 mol) of 1, 46 g (59 mL,
1.0 mol) of absolute ethanol and 6 ml of concentrated sulfuric acid was refluxed
gently for 10 h. The mixture was then cooled to room temperature, and refrigerated
for 10–12 h. A white solid was obtained and filtered. The solid was washed with
absolute ethanol and recrystallized from absolute ethanol. The yield of (2) (a white
crystalline solid, m.p. 130–132◦C) was 19.7 g (81%). 1H NMR: δ 7.35 (s, 4H, Ar);
4.34–4.61 (q, 2H, J = 7.0 Hz, -OCH2-); 2.58 (s, 3H, Ar-CH3); 2.47 (s, 3H, -CH3);
1.37–1.54 (t, 3H, J = 7.0 Hz, -CH2CH3).
5-Methyl-1-(4-methylphenyl)-1,2,3-triazol-4-carbonylhydrazine (3) was
prepared from (2) following the procedure method in the literature (17).
A mixture of 0.1 mol of 2 and 0.15 mol (85% hydrazine hydrate) was refluxed
in 200 mL of ethanol for 6 h. The ethanol, water, and excess hydrazine hydrate

ORDER
REPRINTS
1,3,4-THIADIAZOLES
83

ORDER
REPRINTS
84
DONG ET AL.
Table 2. IR Spectral Data of Compounds 6a–j
IR (cm−1) (KBr disc)
3
5
3380, 3200, 3100, 1680, 1620
3290, 2920, 1625, 1565, 1485
6a 3047, 2921, 1614, 1578, 1518, 1446, 1378, 1273, 766, 713
6b 3062, 2920, 1616, 1570, 1518, 1457, 1378, 1277, 805, 720
6c 3025, 2922, 1614, 1592, 1517, 1457, 1373, 1266, 793, 713
6d 3040, 2932, 2836, 1606, 1578, 1516, 1463, 1375, 1268, 709
6e 3010, 2921, 1606, 1520, 1495, 1461, 1376, 1259, 710
6f
3022, 2923, 2857, 1612, 1520, 1454, 1371, 1253, 714
6g 3022, 2918, 1611, 1517, 1460, 1374, 1261, 710
6h 3042, 2904, 1613, 1515, 1449, 1378, 1269, 706
6i
6j
3068, 2921, 2862, 1613, 1515, 1449, 1378, 1269, 719
3068, 2922, 2857, 1611, 1519, 1463, 1381, 1269, 719
Table 3. 1H NMR Spectral Data for Compoundsa
1H NMR (CDCL3-d) δ (ppm), J (Hz)
Compound
3
7.34 (s, 4H, Ar1), 4.80 (broad peak, 3H, N–H), 2.599 (s, 3H, ArCH3),
2.46 (s, 3H, CH3)
5
7.40 (s, 4H, Ar1), 3.6–4.4 (broad, 2H, N–H), 13.46 (s, 1H, SH), 2.57
(s, 3H, ArCH3), 2.50 (s, 3H, CH3)
6a
6b
6c
6d
6e
6f
6g
6h
6i
7.43 (s, 4H, Ar1), 7.48–8.30 (m, 4H, Ar2), 2.50 (s, 3H, CH3), 2.76
(s, 3H, ArCH3)
7.44 (s, 4H, Ar1), 7.49–8.06 (m, 4H, Ar2), 2.50 (s, 3H, CH3), 2.76
(s, 3H, ArCH3)
7.44 (s, 4H, Ar1), 7.51–8.06 (q, 4H, Ar2), 2.50 (s, 3H, CH3), 2.75
(s, 3H, ArCH3)
7.43 (s, 4H, Ar1), 7.06–7.53 (m, 4H, Ar2), 2.50 (s, 3H, CH3), 2.75
(s, 3H, ArCH3), 3.93 (s, 3H, -OCH3)
7.44 (s, 4H, Ar1), 7.00–8.04 (q, 4H, Ar2), 2.50 (s, 3H, CH3), 2.74
(s, 3H, ArCH3), 3.93 (s, 3H, -OCH3)
7.44 (s, 4H, Ar1), 7.47–7.87 (m, 4H, Ar2), 2.50 (s, 3H, CH3), 2.75
(s, 3H, Ar1CH3), 3.07 (s, 3H, Ar2CH3)
7.43 (s, 4H, Ar1), 7.28–7.91 (q, 4H, Ar2), 2.49 (s, 3H, CH3), 2.74
(s, 3H, Ar1CH3), 2.46 (s, 3H, Ar2CH3)
7.44 (s, 4H, Ar1), 7.28–8.89 (m, 7H, Ar2), 2.51 (s, 3H, CH3), 2.79
(s, 3H, ArCH3)
7.42 (s, 8H, Ar1), 2.50 (s, 6H, CH3), 2.77 (s, 3H, Ar2CH3), 2.80
(s, 3H, Ar1, CH3)
6j
7.43 (s, 4H, Ar1), 7.44–7.71 (m, 4H, Ar2), 2.51 (s, 3H, CH3), 2.78
(s, 3H, Ar2CH3), 2.80 (s, 3H, Ar1CH3)
aAll spectra were recorded at 297 K.

ORDER
REPRINTS
1,3,4-THIADIAZOLES
85
Table 4. MS Spectral Data for Compounds 6a–j
M/z (%)
No
M+
6a
407(3)
379(27), 242(12), 213(55), 199(21), 181(9), 170(36), 169(62),
155(45), 111(22), 102(27), 91(92), 77(17), 65(84), 43(100)
379(40), 242(11), 213(70), 199(21), 181(11), 170(42), 169(77),
155(53), 137(22), 111(13), 102(31), 91(100), 77(13), 65(93),
43(10)
379(42), 242(10), 213(62), 199(23), 181(10), 170(36), 169(67),
155(57), 137(27), 111(19), 102(41), 91(100), 77(21), 65(81),
43(34)
6b
6c
407(3)
407(5)
6d
6e
6f
403(11) 375(100), 242(15), 213(80), 199(20), 170(46), 169(76), 151(50),
133(11), 107(4), 103(17), 92(10), 91(77), 77(16), 65(53)
403(6)
375(51), 242(8), 213(45), 199(21), 170(38), 169(60), 151(79),
133(27), 107(4), 103(25), 92(11), 91(100), 77(19), 69(20), 65(85)
387(11) 359(100), 242(15), 213(85), 199(20), 181(12), 170(46), 169(78),
155(11), 135(60), 117(15), 91(91), 77(12), 65(60)
6g
6h
6i
387(4)
359(50), 242(9), 213(44), 199(22), 181(8), 170(33), 169(54),
155(11), 135(52), 117(19), 91(100), 77(12), 65(79)
423(15) 395(79), 242(15), 213(71), 199(29), 171(89), 170(58), 169(96),
153(63), 127(39), 91(100), 77(16), 65(74)
468(3)
440(22), 242(3), 215(3), 213(23), 199(16), 181(6), 170(57), 169(75),
155(13), 91(100), 77(10), 65(70)
6j
488(1)
460(17), 242(6), 223(2), 213(49), 199(24), 181(12), 170(41),
169(73), 155(27), 111(63), 91(92), 77(15), 65(62), 44(100)
were removed in vacuo, and the residual solid recrystallized. It gave 21 g (91%
yield) of product, m.p. 177◦–178◦C (other data shown in Tables 1–4).
1-Amino-2-mercapto-5-[5-methyl-1-(4-methylphenyl)-1,2,3-triazol-4-yl]-
1,3,4-triazole (5) was prepared from (3) via (4) following the method reported
in the literature (18).
Carbon disulfide (0.14 mol) was added dropwise to an ice-cold solution of
potassium hydroxide (0.15 mol) and 3-aryloxyacetic acid hydrazide (0.09 mol) in
150 mL absolute ethanol. The mixture was stirred at room temperature for 14 h.
Dry ether (200 mL) was then added and the separated solid was filtered and washed
with either (2 × 50 mL). The product (4) obtained in nearly quantitative yield was
employed in the next reaction without further purification.
A suspension of (4) (about 0.08 mol) and hydrazine hydrate 85% (0.16 mol)
in 50 mL of water was refluxed while stirring for 4 h. The color of the reaction
mixture changed to green, hydrogen sulphide was evolved, and a homogeneous
solution resulted. On dilution with 850 mL of cold water and acidification with
concentrated HCl, a white solid was precipitated. The product was filtered, washed
with water, and recrystallized from ethanol to give white flake of (5). It gave 18 g
(71% yield) of product, m.p. 189◦–190◦C (see Tables 1–4).

ORDER
REPRINTS
86
DONG ET AL.
General Procedure of Preparation of 3-[5-Methyl-1-
(4-methylphenyl)-1,2,3-triazol-4-yl]-6-substitute-phenyl-
s-triazolo[3,4-b]-1,3,4-thiadiazole Derivatives (6)
A mixture of 1-amino-2-mercapto-5-[5-methyl-1-(4-methylphenyl)-1,2,3-
triazol-4-yl]-1,3,4-triazole (5) (1 mmol), aromatic carboxylic acid (1 mmol) and
POCl3 (5 mL) was heated under reflux for 6 h. The cooled reaction mixture was
poured into ice water and made alkaline by adding potassium hydroxide, then
the resulting solid was filtered. It was recrystallized from ethanol to give the title
compound (6a–j) (see Table 1).
RESULTS AND DISCUSSION
The novel 6-aryl-3-[5-methyl-1-(4-methylphenyl)-1,2,3-triazol-4-yl]-s-
triazolo[3,4-b]-1,3,4-thiadiazoles(6a–j)havebeensynthesizedbythecondensation
of
3-[5-methyl-1-(4-methylphenyl)-1,2,3-triazol-4-yl]-4-amino-5-mercapto-s-
triazolo (5) with various aromatic carboxylic acids in the presence of phosphorus
Scheme 1.

ORDER
REPRINTS
1,3,4-THIADIAZOLES
87
oxychloride. The structure of these compounds was characterized with 1H NMR,
IR, and MS spectroscopy, and results are given in Tables 1, 2, 3 and 4.
IR absorption peaks of 5 at 3270, 3167 and 2578 cm−1 are assigned to
its NH2 and SH groupings. When 5 converted 6, the SH peak disappears but
a new peak characteristic of νc-s-c appeared at 690 cm−1. Like the allied sys-
– ==
– ==
tem, compound 6 shows absorption peaks for N N C and N N N in the re-
gion of 1250–1290 cm−1 and for C N in 1590–1680 cm−1. In the mass spectra
==
of 6, the molecular ion peaks are very weak (relative intensities ∼3–6%) and
all the members of 6 exhibit some important ion peaks at m/z 242 (8–24%),
213 (45–70%), 170 (36–44%). Recently, we have established the crystal struc-
ture of 3-[5-methyl-1-(4-methylphenyl)-1,2,3-triazol-4-yl]-6-(4-methylphenyl)-s-
triazolo[3,4-b]-1,3,4-thiadiazole 6g by x-ray diffraction (the manuscript will
be submitted for revision). The crystal structure of 6g agrees to the structure
(Scheme 1).
ACKNOWLEDGMENTS
The authors wish to acknowledge the support of a NLAOC grant and Doctor
fund.
REFERENCES
1. Hausach, C.; Sachse, B.; Buerstell, H. Ger Offen, 2,826,760 (Chem. Abstr.
1980, 92, 181200h).
2. Tanka, B. Japan Kokai 7495,973 (Chem. Abstr. 1975, 82, 156320h).
3. Griffin, A.D.; Sally, K. EP 119474 (Chem. Abstr. 1986, 106, 98120).
4. Van Reet, G.; Heeres, J. U.S. Patent, 4,160,838 (Chem. Abstr. 1979, 91,
753612).
5. Zhang, Z.Y., Liu, Y.; Yang, S.Y. Pharmaceutica Simica 1991, 26 (11), 809
(Chem. Abstr. 1992, 116, 128807).
6. Abdou, N.A.; Soliman, I.N.; Sier Abou, A.H. Bull Facpharm (Cairo Univ.)
1990, 28 (2), 29 (Chem. Abstr. 1992, 117, 69793).
7. Srivatava, A.J.; Swarup, S.; Saxena, V.K. J. Indian Chem. Soc. 1991, 68 (2),
103.
8. Cooper, K.; Steele, J. EP 329357 (Chem. Abstr. 1990, 112, 76957).
9. Husain, M.I.; Amir Mol, J. Indian Chem. Soc. 1986, 63, 317.
10. Raymond, E.; Raymond, S.; Alan, G.S. GB 2,175,301 (Chem. Abstr. 1987,
107, 134310).

ORDER
REPRINTS
88
DONG ET AL.
11. Kohn, E.C.; Liotta, L.A. U.S. 637145 (Chem. Abstr. 1991, 115, 248099).
12. Omar A Mohsen, M.E.; Aboul Wafa, O. M. J. Heterocycl. Chem. 1986, 23,
1339.
13. Bano, Q.; Tiwari, N.; Giyi, S.; Nizamudolin, Indian J. Chem., 1992, 31B,
714.
14. Zhang, Z.Y.; Chen, X.; Chin. J. Chem. 1992, 10, 59 (Chem. Abstr. 1992, 117,
90216).
15. Khaclem, H.E.L.; Mansour, H.A.R.; Meshreki, M.H. J. Chem. Soc(c). 1968,
1329.
16. Sun, X.W.; Xu, P.F.; Zhang, Z.Y. Mag. Reson. Chem. 1998, 36, 459–460.
17. Yale, H.I.; Losee, K.; Martin, J.; Hervy, H.; Pervy, F.M.; Bernstain, J. J. Amer.
Chem. Soc. 1953, 75, 1933.
18. El-Barbary, A.A.; Fahmy, M.; El-Badawi, M.; El-Bremal, K.; El-Brollosi,
N.R. Revue Roumaine de Chime 1991, 36 (4–7), 619.
Received April 2, 2000

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request
Permission/Reprints Here" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
(AAP) website for guidelines on Fair Use in the Classroom.
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our Website
User Agreement for more details.
Order now!
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081SCC100000183