Synthesis of tetrazole containing 1,2,3-thiadiazole derivatives via U-4CR and their anti-TMV activity

Article abstract of DOI:10.1016/j.cclet.2013.05.026

A series of novel tetrazole containing 1,2,3-thiadiazole derivatives were designed and synthesized via Ugi reaction. Their structures were confirmed by melting points, IR, ¹H NMR, and HRMS (ESI). Preliminary bioassay indicated that most target

Full text of DOI:10.1016/j.cclet.2013.05.026

G Model
CCLET-2616; No. of Pages 4
Chinese Chemical Letters xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Synthesis of tetrazole containing 1,2,3-thiadiazole derivatives via U-4CR and
their anti-TMV activity
b
b
b
Shou-Xin Wang a,b,1, Zhen Fang b,1, Zhi-Jin Fan b, , Dun Wang , Yue-Dong Li , Xiao-Tian Ji ,
*
Xue-Wen Hua b, Yun Huang c, Tatiana A. Kalinina d, Vasiliy A. Bakulev d, Yury Yu. Morzherin c
a School of Basic Sciences, Jining Medical University, Jining 272067, China
b State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
c Department of Plant Pathology, Sichuan Agricultural University, Chengdu 611130, China
d The Ural Federal University Named after the First President of Russia B.N. Yeltsin, Yeltsin UrFU, 620002 Ekaterinburg, Russia
A R T I C L E I N F O
A B S T R A C T
Article history:
A series of novel tetrazole containing 1,2,3-thiadiazole derivatives were designed and synthesized via
Ugi reaction. Their structures were confirmed by melting points, IR, 1H NMR, and HRMS (ESI).
Preliminary bioassay indicated that most target compounds exhibited very good direct anti-TMV activity
Received 7 April 2013
Received in revised form 25 April 2013
Accepted 7 May 2013
Available online xxx
at 100
mg/mL, which was equal to or higher than that of ribavirin. Among them, compounds 4b, 4c and 4i
also showed equivalent protection effect to ribavirin in vivo at 100
m
g/mL.
ß 2013 Zhi-Jin Fan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords:
1,2,3-Thiadiazole
Tetrazole
Anti-TMV activity
Ugi reaction
1. Introduction
tools to achieve highly atom-, step-, and energy-economic organic
synthesis [19]. Among the MCRs, the Ugi four-component conden-
1,2,3-Thiadiazoles and tetrazoles are important heterocyclic
compounds, both present wide spectrum of biological
sation reaction (U-4CR) features many applications in organic
syntheses and medicinal chemistry [20,21]. The classical U-4CR
between amine, aldehyde, carboxylic acid and isocyanide affords
peptidic structures in high diversity. The Ugi-tetrazole synthesis is a
variation of the classical Ugi-reaction where azidotrimethylsilane
(TMSN3) is employed as an acid component [22] and this synthetic
strategy has been applied to the synthesis of various 1,5-
disubstituted tetrazoles [23,24]. To develop novel candidate
pesticides with diverse biological activities, tetrazole moiety was
introduced into 1,2,3-thiadizole, and a series of novel tetrazole
containing 1,2,3-thiadiazole derivatives were designed and synthe-
sized via U-4CR. Their antivirus activities against tobacco mosaic
virus (TMV) were also evaluated.
a
activities. 1,2,3-Thiadiazoles have antitumor [1], antiviral [2],
fungicidal [3,4], antibacterial [5] and insecticidal [6] activities.
Successful commercialization of some 1,2,3-thiadiazoles such as
tiadinil (TDL) [7] and acibenzolar-S-methyl (BTH) [8] as elicitors
accelerated the studies of their synthesis and systemic acquired
resistance (SAR). [9–11] Tetrazoles and their derivatives have
been reported as antibacterial [12], antiviral [13], herbicidal [14],
anti-inflammatory [15] antitumor [16], analgesic [17], and anti-
proliferative [18] agents. There are many reports about each of the
twoheterocyclics,butthecombinationof1,2,3-thiadiazoleringwith
tetrazole ring in one molecule is seldom reported both in chemistry
and their biological activity studies.
Multicomponent reactions (MCRs), in which three or more
reactants in one pot generate products containing almost all atoms
of the reactant molecules, have been developed extensively as
2. Experimental
Melting points of all compounds were determined on an X-4
binocular microscope (Gongyi Technical Instrument Co., Henan,
China), and the thermometer was not corrected. Proton NMR
spectra were obtained using a Bruker AVANCE-400 MHz spec-
* Corresponding author.
trometer, and chemical shift values (d) were reported as parts per
E-mail addresses: fanzj@nankai.edu.cn (Z.-J. Fan),
million (ppm) with deuteron chloroform (CDCl3) as the solvent
and tetramethylsilane (TMS) as the internal standard. High
5787huangyun@sina.com (Y. Huang).
1
These authors contributed equally to this work.
1001-8417/$ – see front matter ß 2013 Zhi-Jin Fan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.05.026
Please cite this article in press as: S.-X. Wang, et al., Synthesis of tetrazole containing 1,2,3-thiadiazole derivatives via U-4CR and their
anti-TMV activity, Chin. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.05.026

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CCLET-2616; No. of Pages 4
2
S.-X. Wang et al. / Chinese Chemical Letters xxx (2013) xxx–xxx
R
CH3
NH
CH3
N
N
CH3
CH3
N
a
N
N
b
c
S
N
N
N
N
CHO
CH2OH
CO2C2H5
S
N
S
S
N
N
1
2
3
4a-4m
R
R
R
R
propyl
tert-butyl
cyclobutyl
cyclopentyl
cyclohexyl
4-chlorophenyl
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
isopropyl
cyclopropyl
cyclopropylmethyl
2-fluorophenyl
3-chlorophenyl
4-ethylphenyl
3-fluoro-4-methylphenyl
Scheme 1. General synthetic route of the target compounds 4a–4m. Reagents and conditions: (a) NaBH4 (2.0 equiv.), EtOH, 0 8C for 1 h, r.t. for 6 h; (b) pyridinium
chlorochromate (2.0 equiv.), CH2Cl2, r.t. for 8 h; (c) (i) R-NH2 (1.0 equiv.), CH3OH, r.t. for 0.5–1 h; (ii) cyclohexyl isocyanide (1.2 equiv.), TMSN3 (1.5 equiv.), r.t. for 12–24 h.
resolution mass spectrometry (HRMS) data were obtained on an
FTICR-MS Varian 7.0T FTICR-MS instrument. All the reagents
were obtained commercially and used after further purification.
Column chromatography purification was carried out by using
silica gel.
3. Results and discussion
The synthesis route of the target compounds was outlined in
Scheme 1. The starting material, ethyl 4-methyl-1,2,3-thiadiazole-
5-carboxylate 1, was prepared according to Ref. [9]. Cyclohexyl
isocyanide was synthesized according to Ref. [4]. The intermediate
(4-methyl-1,2,3-thiadiazol-5-yl)methanol 2 was obtained in high
yields by reduction of 1 with NaBH4 at 0 8C to room temperature.
Treatment of a intermediate 2 with pyridinium chlorochromate at
room temperature produced 4-methyl-1,2,3-thiadiazole-5-carbal-
dehyde 3 in 86% yields. The target compounds 4a–4m were
obtained by the U-4CR of 3 with substituted amines, cyclohexyl
isocyanide and TMSN3 in methanol in moderate yields, which were
white or pale yellow solid after column chromatography purifica-
tion.
General procedure for synthesis of compounds 4a–4m
(Scheme 1): 4-Methyl-1,2,3-thiadiazole-5-carbaldehyde
3
(0.21 g, 1.6 mmol) and substituted amine (1.6 mmol) were stirred
in 8 mL methanol at room temperature. The imine was pre-
condensated for 0.5–1 h and then cyclohexyl isocyanide (0.21 g,
1.9 mmol) and TMSN3 (0.28 g, 2.4 mmol) were added. The
reaction mixture was stirred for 12–24 h at room temperature
until the reaction was completed (indicated by TLC). Then the
organic solvent was evaporated in vacuo. The crude products were
purified by a silica gel column using ethyl acetate/petroleum ether
(1:2–1:3 (v/v), 60–90 8C) as an eluent to give 4a–4m as white or
pale yellow solids in moderate yields.
Direct anti-TMV activity of target compounds 4a–4m was
conducted by half leaf juice robbing methods according to Ref.
[25]. Protection effect against TMV in vivo was evaluated on N.
tabacum L. leaves [4]. Healthy fresh tobacco plants at the six-leaf
stage were selected for the tests. The compound solution was
smeared on the whole leaves, and then the leaves were dried in the
greenhouse. After 12 h, TMV at a concentration of 5.88 ꢀ 10ꢁ2 mg/
mL was inoculated on the upper three leaves using the
conventional juice robbing method, and the solvent was smeared
on the lower three leaves as a control. The local lesion numbers
were then recorded 2–3 days after inoculation. For each
compound, three repetitions were conducted. All compounds
The structures of the target compounds synthesized herein
were fully characterized by melting points, 1H NMR, IR, and HRMS
(ESI) [26]. In the IR spectra of compounds 4a–4m, strong
absorptions at about 3300 cmꢁ1 were detected, due to the
secondary amino group. In the 1H NMR spectra, CH3 of 1,2,3-
thiadizole were observed at
signal at about 4.80 due to the NH proton coupled with the
aromatic proton at about 7.00 as seen for compounds 4i–4m; as
d 2.57–2.66. Furthermore, a doublet
d
d
for compounds 4a–4h, the NH proton doublet was not always
clearly detected because of overlapping with the aliphatic protons.
The HRMS (ESI) spectral data of all compounds are in good
agreement with theoretical data.
The results of direct anti-TMV activity and protection effect of
all target compounds were listed in Table 1. As shown in the data,
were tested at concentrations of 100
m
g/mL. Ribavirin and
most compounds have very good anti-TMV activity at 100 mg/mL,
ningnanmycin were used as positive control at the same time.
The activity data of protection effect against TMV was calculated
by the following equation:
which were equal to or higher than that of the positive control
ribavirin. Among them, compound 4l showed excellent anti-TMV
activity with inhibition activity of 48.73%, which was higher than
that of ninamycin. Besides possessing good direct anti-TMV
activity, compounds 4b, 4c and 4i also presented very good
CK ꢁ A
Y ¼
ꢀ 100%
CK
protection effect in vivo at 100
mg/mL, which were equivalent to
where Y is the antivirus inhibition ratio (%), CK is the average
number of viral inflammations on the control leaves in vivo, and A
is the average number of viral inflammations on the target
compound treated leaves in vivo.
the positive control ribavirin. After a structural comparison, it was
very clear that the whole molecular structure played an important
role in anti-TMV activity rather than one moiety in the molecule.
Our results indicate that the combination of 1,2,3-thiadiazole ring
Table 1
Direct antivirus activity and protection effect in vivo against TMV of target compounds at 100 mg/mL.
Compd.
Anti-TMV (%)
Protection (%)
Compd.
Anti-TMV (%)
Protection (%)
Compd.
Anti-TMV (%)
Protection (%)
4a
4b
4c
4d
4e
29.58
36.49
33.75
32.17
44.25
12.60
36.59
37.81
30.90
9.76
4f
4g
4h
4i
22.14
29.72
33.23
40.04
23.01
12.60
6.91
4k
37.60
48.73
41.57
33.23
47.63
12.41
4.47
4l
21.14
39.02
8.95
4m
22.36
36.52
40.43
Ribavirin
Ninamycin
4j
Please cite this article in press as: S.-X. Wang, et al., Synthesis of tetrazole containing 1,2,3-thiadiazole derivatives via U-4CR and their
anti-TMV activity, Chin. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.05.026

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3
[15] M. Bertinaria, M.A. Shaikh, C. Buccellati, et al., Designing multitarget anti-inflam-
matory agents: chemical modulation of the lumiracoxib structure toward dual
with tetrazole ring in one molecule can improve their biological
activities. This provides us with useful clues for further research of
finding novel leading structures possessing good antivirus activity
based on the structure reported in this paper.
thromboxane antagonists-COX-2 inhibitors, ChemMedChem
1660.
7 (2012) 1647–
[16] R. Romagnoli, P.G. Baraldi, M.K. Salvador, et al., Synthesis and evaluation of 1,5-
disubstituted tetrazoles as rigid analogues of combretastatin A-4 with potent
antiproliferative and antitumor activity, J. Med. Chem. 55 (2012) 475–488.
[17] C. Tre´cant, A. Dlubala, P. George, et al., Synthesis and biological evaluation of
analogues of M6G, Eur. J. Med. Chem. 46 (2011) 4035–4041.
4. Conclusion
[18] A.S. Gundugola, K.L. Chandra, E.M. Perchellet, et al., Synthesis and antiprolifera-
tive evaluation of 5-oxo and 5-thio derivatives of 1,4-diaryl tetrazoles, Bioorg.
Med. Chem. Lett. 20 (2010) 3920–3924.
[19] S. Maeda, S. Komagawa, M. Uchiyama, K. Morokuma, Finding reaction pathways
for multicomponent reactions: the passerini reaction is a four-component reac-
tion, Angew. Chem. Int. Ed. 50 (2011) 644–649.
[20] W.H. Wang, X.M. Zou, X. Zhang, Y.Q. Fu, P. Xu, Solid-phase synthesis of PNA
monomer by Ugi four-component condensation, Chin. Chem. Lett. 16 (2005) 585–
588.
[21] S.S. Van Berkel, B.G.M. Bo¨gels, M.A. Wijdeven, B. Westermann, F.P.J.T. Rutjes,
Recent advances in asymmetric isocyanide-based multicomponent reactions, Eur.
J. Org. Chem. (2012) 3543–3559.
In summary, a series of novel tetrazole containing 1,2,3-
thiadiazole derivatives were synthesized via a simplified Ugi-
tetrazole reaction and easily purified. The bioassay tests indicated
that most target compounds have higher anti-TMV activity than
that of ribavirin did at 100
showed equivalent protection effect to ribavirin in vivo at 100
m
g/mL. Compounds 4b, 4c and 4i also
g/
m
mL. These studies indicate that the newly synthesized tetrazole
containing 1,2,3-thiadiazole derivatives possessed good potential
bioactivities, and were worthy of further study in pesticide
development.
[22] C. Kalinski, M. Umkehrer, S. Gonnard, et al., A new and versatile Ugi/SNAr
synthesis of fused 4,5-dihydrotetrazolo[1,5-a] quinoxalines, Tetrahedron Lett.
47 (2006) 2041–2044.
[23] T. Zhao, A. Boltjes, E. Herdtweck, A. Do¨mling, Tritylamine as an ammonia surro-
gate in the ugi tetrazole synthesis, Org. Lett. 15 (2013) 639–641.
Acknowledgments
[24] F. Medda, C. Hulme, A facile and rapid route for the synthesis of novel 1,5-
substituted tetrazole hydantoins and thiohydantoins via a TMSN3-Ugi/RNCX
cyclization, Tetrahedron Lett. 53 (2012) 5593–5596.
[25] D.K. Yuan, D.Q. Zhang, R.X. Li, D.Q. Wang, X.L. Yang, Synthesis and anti-TMV
activity of novel N-(pyrimidin-5-yl)-N0-phenylureas, Chin. Chem. Lett. 22 (2011)
18–20.
This study was funded in part by the NSF of Tianjin (No.
10JCZDJC17500), the National Key Project for Basic Research (No.
2010CB126105) and National Key Technology Research and
Development Program (No. 2011BAE06B02) and the Foundation
of Achievements Transformation and Application of Tianjin
Agricultural Science and Technology (No. 201002250), Tianjin
Key Technology Research and Development Program (No.
11ZCGYNC00100), The Commonweal Specialized Research Fund
of China Agriculture (Nos. nyhyzx3-21, 201103016 and
201003029).
[26] Selected characteristic data for the target compounds. 4a: White solid; yield 59%;
mp 75–76 8C; 1H NMR (400 MHz, CDCl3): d 0.93 (t, 3H, J = 7.6 Hz, propyl-CH3),
1.26–2.07 (m, 13H, propyl-CH2, 10cyclohexyl-H, NH), 2.45-2.62 (m, 2H, propyl-
CH2), 2.65 (s, 3H, thiadiazole-CH3), 4.58–4.66 (m, 1H, cyclobutyl-CH), 5.76 (s, 1H,
CH). HRMS: Calcd. for C14H23N7S (M+Na)+: 344.1628, Found: 344.1630; IR (KBr
pellet press, cmꢁ1): v3325, 2951, 2863, 1495, 1450, 1229, 1106, 1009, 809, 759.
4b: White solid; yield 47%; mp 96-97 8C; 1H NMR (400 MHz, CDCl3):d 1.13 (t, 6H,
J = 6.0 Hz, 2 isopropyl-CH3), 1.26–2.07 (m, 11H, 10 cyclohexyl-H, NH), 2.63 (s, 3H,
thiadiazole-CH3), 2.64–2.71 (m, 1H, isopropyl-CH), 4.54–4.62 (m, 1H, cyclobutyl-
CH), 5.83 (s, 1H, CH). HRMS: Calcd. for C14H23N7S (M+Na)+: 344.1628, Found:
344.1626; IR (KBr pellet press, cmꢁ1): v 3276, 2934, 2857, 1501, 1451, 1241, 1126,
1009, 832. 4c: White solid; yield 51%; mp 96–97 8C; 1H NMR (400 MHz, CDCl3):
(0.43-0.54 (m, 4H, cyclopropyl-H), 1.33–2.05 (m, 11H, cyclohexyl-H, NH), 2.58 (s,
1H, cyclopropyl-CH), 2.66 (s, 3H, thiadiazole-CH3), 4.27–4.35 (m, 1H, cyclohexyl-
CH), 5.58 (s, 1H, CH). HRMS: Calcd. for C14H21N7S (M+H)+: 320.1652, Found:
320.1657; IR (KBr pellet press, cm-1): n 3268, 2938, 2856, 1501, 1446, 1239, 1162,
1022, 801, 680. 4d: White solid; yield 53%; mp 88–89 8C; 1H NMR (400 MHz,
CDCl3): d 1.31–2.17 (m, 17H, 5 cyclopropyl-H, 10 cyclohexyl-H, CH2), 2.63 (s, 3H,
thiadiazole-CH3), 3.13 (s, 1H, NH), 4.53–4.60 (m, 1H, cyclohexyl-H), 5.72 (s, 1H,
CH). HRMS: Calcd. for C15H23N7S (M+Na)+: 356.1628, Found: 356.1623; IR (KBr
pellet press, cmꢁ1): v3265, 2941, 2856, 1501, 1466, 1241, 1151, 1009, 810. 4e:
White solid; yield 57%; mp 119–120 8C; 1H NMR (400 MHz, CDCl3): d 1.10 (s, 9H,
3t-butyl-CH3), 1.26–2.07 (m, 11H, 10 cyclohexyl-H, NH), 2.57 (s, 3H, thiadiazole-
CH3), 4.37–4.45 (m, 1H, cyclohexyl-CH), 5.84 (s, 1H, CH). HRMS: Calcd. for
References
[1] R. Tripathy, A. Ghose, J. Singh, et al., 1,2,3-Thiadiazole substituted pyrazolones as
potent KDR/VEGFR-2 kinase inhibitors, Bioorg. Med. Chem. Lett. 17 (2007) 1793–
1798.
[2] W.L. Dong, Z.X. Liu, X.H. Liu, Z.M. Li, W.G. Zhao, Synthesis and antiviral activity of
new acrylamide derivatives containing 1,2,3-thiadiazole as inhibitors of hepatitis
B virus replication, Eur. J. Med. Chem. 45 (2010) 1919–1926.
[3] Z.J. Fan, Z.K. Yang, H.K. Zhang, et al., Synthesis, crystal structure, and biological
activity
of
4-methyl-1,2,3-thiadiazole-
containing
1,2,4-triazolo[3,4-
b][1,3,4]thiadiazoles, J. Agric. Food Chem. 58 (2010) 2630–2636.
[4] X. Zuo, N. Mi, Z.J. Fan, et al., Synthesis of 4-methyl-1, 2,3-thiadiazole derivatives
via Ugi reaction and their biological activities, J. Agric. Food Chem. 58 (2010)
2755–2762.
[5] V. Padmavathi, K. Mahesh, A.V. Nagendra Mohan, A. Padmaja, Synthesis and
bioassay of oxazolyl/thiazolyl selenadiazoles, thiadiazoles and diazaphospholes,
Chem. Pharm. Bull. 57 (2009) 561–566.
[6] H. Wang, Z.K. Yang, Z.J. Fan, et al., Synthesis and insecticidal activity of N-tert-
butyl-N,N0-diacylhydrazines containing 1,2,3-thiadiazoles, J. Agric. Food Chem.
59 (2011) 628–634.
C
15H25N7S (M+Na)+: 358.1784, Found: 358.1787; IR (KBr pellet press, cm-1):
v3327, 2938, 2865, 1453, 1231, 1103, 1076, 861, 741. 4f: White solid; yield
60%; mp 87–88 8C; 1H NMR (400 MHz, CDCl3):d 1.26–2.17 (m, 17H, 6 cyclobutyl-
H, 10 cyclohexyl-H, NH), 2.63 (s, 3H, thiadiazole-CH3), 3.11–3.14 (m, 1H, cyclo-
butyl-CH), 4.49–4.56 (m, 1H, cyclohexyl-CH), 5.70 (s, 1H, CH). HRMS: Calcd. for
C
15H23N7S (M+Na)+: 356.1628, Found: 356.1629; IR (KBr pellet press, cmꢁ1):
v3264, 2941, 2856, 1501, 1451, 1241, 1150, 1105, 1009, 809, 759. 4g: White solid;
yield 58%; mp 122-123 8C; 1H NMR (400 MHz, CDCl3):d 1.32–2.00 (m, 19H, 8
cyclopentyl-H, 10 cyclohexyl-H, NH), 2.63 (s, 3H, thiadiazole-CH3), 2.89–2.95 (m,
1H, cyclopentyl-CH), 4.53–4.60 (m, 1H, cyclohexyl-CH), 5.72 (s, 1H, CH). HRMS:
Calcd. for C16H25N7S (MꢁH)ꢁ: 346.1819, Found: 346.1814; IR (KBr pellet press,
cmꢁ1): v3271, 2938, 2857, 1499, 1449, 1236, 1087, 1005, 844, 732. 4h: White
solid; yield 47%; mp 98–99 8C; 1H NMR (400 MHz, CDCl3):d 1.11–2.05 (m, 21H, 20
cyclohexyl-H, NH), 2.30–2.32 (m, 1H, cyclohexyl-CH), 2.62 (s, 3H, thiadiazole-
CH3), 4.56–4.64 (m, 1H, cyclohexyl-H), 5.90 (s, 1H, CH). HRMS: Calcd. for
[7] M. Yasuda, M. Kusajima, M. Nakajima, et al., Thiadiazole carboxylic acid moiety of
tiadinil, SV-03, induces systemic acquired resistance in tobacco without salicylic
acid accumulation, J. Pestic. Sci. 31 (2006) 329–334.
[8] Z.J. Fan, Y.W. Ai, J.Y. Chen, et al., Preparation of BTH standard and HPLC analysis of
Bion 50%WG, J. Sichuan Normal Univ. (Nat. Sci.) 28 (2005) 608–610.
[9] Z.J. Fan, Z.G. Shi, H.K. Zhang, et al., Synthesis and biological activity evaluation of
1,2,3-thiadiazole derivatives as potential elicitors with highly systemic acquired
resistance, J. Agric. Food Chem. 57 (2009) 4279–4286.
[10] Q.S. Du, W.P. Zhu, Z.J. Zhao, X.H. Qian, Y.F. Xu, Novel benzo-1,2,3-thiadiazole-7-
carboxylate derivatives as plant activators and the development of their agricul-
tural applications, J. Agric. Food Chem. 60 (2012) 346–353.
[11] W.T. Mao, H. Zhao, Z.J. Fan, et al.,A.B. Vasiliy, Synthesis and bioactivity of N-tert-
butyl-N0-acyl-5-methyl-1,2,3-thiadiazole-4-carbohydrazides, Chin. Chem. Lett.
23 (2012) 1233–1236.
[12] S.D. Diwakar, S.S. Bhagwat, M.S. Shingare, C.H. Gill, Substituted 3-((Z)-2-(4-
nitrophenyl)-2-(1H-tetrazol-5-yl) vinyl)-4H-chromen-4-ones as novel anti-
MRSA agents: synthesis, SAR, and in-vitro assessment, Bioorg. Med. Chem. Lett.
18 (2008) 4678–4681.
[13] K.S. Yeung, Z. Qiu, Z. Yang, et al., Inhibitors of HIV-1 attachment. Part 9. An
assessment of oral prodrug approaches to improve the plasma exposure of a
tetrazole-containing derivative, Bioorg. Med. Chem. Lett. 23 (2013) 209–212.
[14] Y.P. Luo, Q. Gong, Q. Chen, G.F. Yang, Synthesis and herbicidal activities of
tetrazolinone derivatives containing oxime ether, Chin. J. Org. Chem. 28 (2008)
1561–1565.
C
17H27N7S (MꢁH)ꢁ: 360.1976, Found: 360.1973; IR (KBr pellet press, cmꢁ1):
v3286, 2927, 2850, 1451, 1236, 1106, 1012, 824, 686. 4i: White solid; yield 55%;
mp 96–97 8C; 1H NMR (400 MHz, CDCl3):d 1.26–1.99 (m, 10H, cyclohexyl-H), 2.65
(s, 3H, thiadiazole-CH3), 4.35–4.41 (m, 1H, cyclohexyl-H), 4.72 (d, 1H, J = 8.0 Hz,
NH), 6.32 (d, 1H, J = 8.0 Hz, CH), 6.66–7.09 (m, 4H, Ph-H). HRMS: Calcd. for
C
17H20FN7S (M+H)+: 374.1558, Found: 374.1555; IR (KBr pellet press, cmꢁ1):
v3401, 2936, 2860, 1620, 1527, 1453, 1251, 1191, 1057, 738. 4j: Pale yellow solid;
yield 50%; mp 115–116 8C; 1H NMR (400 MHz, CDCl3):d 1.26–1.99 (m, 10H, 10
cyclohexyl-H), 2.66 (s, 3H, thiadiazole-CH3), 4.27–4.33 (m, 1H, cyclohexyl-CH),
5.09 (d, 1H, J = 6.0 Hz, NH), 6.23 (d, 1H, J = 7.6 Hz, CH), 6.56 (d, 1H, J = 8.4 Hz, Ph-
H), 6.70 (s, 1H, Ph-H), 6.85 (d, 1H, J = 8.4 Hz, Ph-H), 7.12 (t, 1H, J = 8.0 Hz, Ph-H).
HRMS: Calcd. for C17H20ClN7S (MꢁH)ꢁ: 388.1117, Found: 388.1112; IR (KBr pellet
press, cmꢁ1): v3410, 2937, 2861, 1598, 1484, 1446, 1272, 1158, 1012, 845, 759.
4k: Pale yellow solid; yield 46%; mp 152–153 8C; 1H NMR (400 MHz, CDCl3):d
1.26–2.01 (m, 10H, 10 cyclohexyl-H), 2.66 (s, 3H, thiadiazole-CH3), 4.25–4.32 (m,
Please cite this article in press as: S.-X. Wang, et al., Synthesis of tetrazole containing 1,2,3-thiadiazole derivatives via U-4CR and their
anti-TMV activity, Chin. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.05.026

G Model
CCLET-2616; No. of Pages 4
4
S.-X. Wang et al. / Chinese Chemical Letters xxx (2013) xxx–xxx
1H, cyclohexyl-CH), 4.80 (d, 1H, J = 7.2 Hz, NH), 6.20 (d, 1H, J = 7.2 Hz, CH), 6.63 (d,
2H, J = 8.8 Hz, Ph-H), 7.18 (d, 2H, J = 8.4 Hz, Ph-H). HRMS: Calcd. for C17H20ClN7S
(MꢁH)ꢁ: 388.1117, Found: 388.1119; IR (KBr pellet press, cmꢁ1): v3285, 2944,
2856, 1598, 1497, 1442, 1296, 1245, 1103, 1011, 837. 4l: White solid; yield 45%;
mp 149–150 (oC; 1H NMR (400 MHz, CDCl3):d 1.17 (t, 3H, J = 7.6 Hz, ethyl-CH3),
1.24-2.00 (m, 10H, 10 cyclohexyl-H), 2.50 (q, 2H, J = 15.2 Hz, ethyl-CH2), 2.63 (s,
3H, thiadiazole-CH3), 4.27-4.34 (m, 1H, cyclohexyl-CH), 4.41 (d, 1H, J = 5.2 Hz,
NH), 6.18 (d, 1H, J = 8.0 Hz, CH), 6.63 (d, 2H, J = 8.4 Hz, Ph-H), 7.05 (d, 2H,,
J = 8.4 Hz, Ph-H). HRMS: Calcd. for C19H25N7S (M+Na)+: 406.1784, Found:
406.1783; IR (KBr pellet press, cmꢁ1): v3419, 2935, 2862, 1616, 1523, 1446,
1281, 1102, 818, 756. 4m: White solid; yield 48%; mp 143–144 (C; 1H NMR
(400 MHz, CDCl3): d 1.27-2.00 (m, 10H, cyclohexyl-H), 2.15 (s, 3H, Ph-CH3), 2.65
(s, 3H, thiadiazole-CH3), 4.29-4.34 (m, 1H, cyclohexyl-CH), 4.75 (d, 1H, J = 7.6 Hz,
NH), 6.19 (d, 1H, J = 7.6 Hz, CH), 6.36-6.41 (m, 2H, PhH), 7.00 (t, 1H, J = 8.4 Hz,
PhH). HRMS: Calcd. for C18H22FN7S (MꢁH)ꢁ: 386.1569, Found: 386.1571; IR (KBr
pellet press, cmꢁ1): v3285, 2927, 2849, 1496, 1450, 1236, 1133, 1012, 824, 686.
Please cite this article in press as: S.-X. Wang, et al., Synthesis of tetrazole containing 1,2,3-thiadiazole derivatives via U-4CR and their
anti-TMV activity, Chin. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.05.026