A simple and efficient procedure for the synthesis of optically active s-triazolothiadiazole derivatives

Article abstract of DOI:10.1016/j.cclet.2012.10.014

A series of novel s-triazolothiadiazoles 3a-h were prepared by condensation reaction of substituted amino triazoles 1a-b with N-phethaloyl-l-amino acids 2a-d in the presence of the phosphoroxy chloride (POCl₃) as an anhydrous reagent. The structure of all synthesized compounds was confirmed by IR, ¹H NMR, and ¹³C NMR spectroscopy.

Full text of DOI:10.1016/j.cclet.2012.10.014

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 1335–1338
www.elsevier.com/locate/cclet
A simple and efficient procedure for the synthesis of optically
active s-triazolothiadiazole derivatives
b
c
Sattar Ebrahimi a, , Masoomeh Sayadi , Ghasem Darvishi
*
a Department of Chemistry Malayer Branch, Islamic Azad University, Malayer, Iran
b Young Researchers Club, Malayer Branch, Islamic Azad University, Malayer, Iran
c Department of Chemistry, Markazi Province Education, Arak, Iran
Received 11 July 2012
Available online 16 November 2012
Abstract
A series of novel s-triazolothiadiazoles 3a–h were prepared by condensation reaction of substituted amino triazoles 1a–b with
N-phethaloyl-L-amino acids 2a–d in the presence of the phosphoroxy chloride (POCl3) as an anhydrous reagent. The structure of all
1
synthesized compounds was confirmed by IR, H NMR, and 13C NMR spectroscopy.
# 2012 Sattar Ebrahimi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: s-Triazolothiadiazole; L-Amino acid; 1,2,4-Triazole-3-thiol; Optical activity; Phosphorus oxychloride
In the last few decades, the chemistry of 1,2,4-triazoles and their fused heterocyclic derivatives has received
considerable attention owing to their synthetic and effective biological importance. N-Bridged heterocyclic
compounds derived from 1,2,4-triazoles have found several applications in the field of medicine, agriculture and
industry [1]. 1,3,4-Thiadiazoles display a wide range of biological activities, possibly due to the presence of the
toxophoric N–C–S linkage [2]. They are also known to have applications as pesticides, herbicides, dyes, antibacterial,
fungicidal, antitumor activity and electrochemical properties [3–7]. [1,2,4]-Triazolo-[3,4-b]-[1,3,4]-thiadiazole
derivatives, produced by fusion of the biolibale [1,2,4]-triazole and [1,3,4]-thiadiazole rings, are reported to possess
antibacterial, antifungal, CNS depressant, anticonvulsant and analgesic effects [8]. Preparation of these compounds
have been extensively studied during the past few years and the most convenient and general method for the synthesis
of [1,2,4]-triazolo[3,4-b]-[1,3,4]thiadiazole derivatives involves the reaction of 5-substituted 4-amino-(4H)-1,2,4-
triazole-3-thioles with carboxylic acids [9]. On the basis of these reports and also in continuation of our research
program on the synthesis of heterocyclic compounds containing 1,2,4-triazole and optically active compounds [10–
17], we wish to report the synthesis of some new 3,6-disubstituted 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles containing
L-amino acid moiety, with the hope to improve their biological activities, because chirality is a main factor of the
bioactive molecules and recognition phenomena associated with these molecules.
* Corresponding author.
E-mail addresses: seyonesi@gmail.com, seyonesi@iau-malayer.ac.ir (S. Ebrahimi).
1001-8417/$ – see front matter # 2012 Sattar Ebrahimi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.10.014

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S. Ebrahimi et al. / Chinese Chemical Letters 23 (2012) 1335–1338
1. Experimental
Purity of the compound was checked by thin layer chromatography (TLC) using EtOH/n-hexane (1:1, v/v) as an
eluent. IR spectra were prepared on a galaxy series FT-IR 5000 spectrophotometer using KBr discs. NMR spectra were
recorded on Brucker spectrophotometer (300 MHz) in DMSO-d6 using TMS as an internal standard. C, H, N and S
analyses were performed on a Vario EL III elemental analyzer.
A mixture of amino triazole 1a–b (2 mmol), N-phethaloyl-L-amino acid 2a–d (2 mmol) in POCl3 (10 mL) was
refluxed for 16 h. The reaction mixture slowly was poured into crashed ice with stirring and neutralized with solid
potassium carbonate. The mixture was allowed to stand overnight and the solid separated out was filtered and washed
with cold water. The compound so obtained was dried and giving the pure products 3a–h.
2-(1-(3-(4-Nitrobenzyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)ethyl)isoindoline-1,3-dione (3a): mp: 176–
178 8C; Yield 80%, [a]D À15 (c 0.02, DMSO); IR (KBr, cmÀ1): 3061 (aromatic CH stretch.), 2935 (aliphatic CH
22
stretch.), 1778, 1716 (C O), 1599 (C N); 1H NMR (300 MHz, DMSO-d6): d 8.17 (d, 2H, Harom. J = 8.0 Hz) 7.97 (br,
4H, Harom.), 7.56 (d, 2H, Harom. J = 8.3 Hz), 5.82 (q, 1H, N–CH, J = 6.9 Hz), 4.57 (s, 2H, PhCH2), 1.86 (d, 3H, CH3,
J = 7.0 Hz); 13C NMR (75 MHz, DMSO-d6): d 170.3, 167.3, 154.2, 147.0, 145.7, 143.7, 135.4, 131.6, 130.7, 124.0,
123.9, 46.7, 30.5, 17.0.; Calcd. for: C20H14N6O4S: C, 55.29; H, 3.25; N, 19.35; S, 7.38; Found: C, 55.02; H, 3.16; N,
19.22; S, 7.24.
2-(1-(3-(4-Nitrobenzyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-2-phenylethyl)isoindoline-1,3-dione (3b):
mp: 201–203 8C; Yield 90%, [a]D À27 (c 0.02, DMSO); IR (KBr, cmÀ1): 3063 (aromatic CH stretch.), 2920
22
(aliphatic CH stretch.), 1778, 1718 (C O), 1599 (C N); 1H NMR (300 MHz, DMSO-d6): d 8.11 (d, 2H, J = 7.1 Hz,
Harom.), 7.90 (br, 4H, Harom.), 7.56 (d, 2H, J = 7.0 Hz, Harom.), 7.18–7.33 (m, 3H, Harom.), 6.98–7.14 (m, 2H, Harom.),
6.07 (dd, 1H, J = 9.9, 7.7 Hz, N–CH), 4.56 (s, 2H, PhCH2), 3.72–3.75 (m, 2H, PhCH2); 13C NMR (75 MHz, DMSO-
d6): d 169.7, 167.4, 154.5, 146.9, 145.4, 143.7, 136.1, 135.4, 131.5, 130.6, 129.5, 129.1, 127.3, 124.1, 123.8, 46.8,
36.6, 30.6; Calcd. for: C26H18N6O4S: C, 61.17; H, 3.55; N, 16.46; S, 6.28; Found: C, 61.02; H, 3.49; N, 16.32; S, 6.19.
2-(2-Methyl-1-(3-(4-nitrobenzyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)propyl)isoindoline-1,3-dione (3c):
22
mp: 156–158 8C; Yield 90%, [a]D À35 (c 0.02, DMSO); IR (KBr, cmÀ1): 3065 (aromatic CH stretch.), 2960
(aliphatic CH stretch.), 1782, 1714 (C O), 1599 (C N); 1H NMR (300 MHz, DMSO-d6): d 8.10 (d, 2H, J = 7.0 Hz,
Harom.), 7.83–7.91 (m, 4H, Harom.), 7.56 (d, 2H J = 6.9 Hz, Harom.,), 5.21 (d, 1H, J = 9.9 Hz, N–CH), 4.58 (s, 2H,
PhCH2), 2.88–2.94 (m, 1H, CH(Me)2), 1.06 (d, 3H, J = 6.1 Hz, CH3), 0.92 (d, 3H, J = 6.0 Hz, CH3); 13C NMR
(75 MHz, DMSO-d6): d 169.7, 167.4, 154.3, 146.9, 145.6, 143.7, 135.5, 131.0, 130.7, 124.1, 123.6, 46.8, 30.5, 29.6,
20.0, 19.1; Calcd. for: C22H18N6O4S: C, 57.13; H, 3.92; N, 18.17; S, 6.93; Found: C, 56.98; H, 3.86; N, 18.02; S, 6.83.
2-(3-Methyl-1-(3-(4-nitrobenzyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)butyl)isoindoline-1,3-dione (3d):
22
mp: 130–131 8C; Yield 85%, [a]D À28 (c 0.02, DMSO); IR (KBr, cmÀ1): 3068 (aromatic CH stretch.), 2958
(aliphatic CH stretch.), 1778, 1716 (C O), 1599 (C N); 1H NMR (300 MHz, DMSO-d6): d 8.09 (d, 2H, J = 6.7 Hz,
Harom.), 7.91 (br, 4H, Harom.), 7.56 (d, 2H, J = 7.0 Hz, Harom.), 5.72 (dd, 1H, J = 4.8, 10.1 Hz, N–CH), 4.57 (s, 2H,
PhCH2), 2.41 (br, 1H, CH), 2.05 (m, 1H, CH2), 1.55 (m, 1H, CH2), 0.90 (d, 6H J = 7.1 Hz, 2 CH3,); 13C NMR
(75 MHz, DMSO-d6): d 169.8, 167.5, 154.7, 146.9, 145.5, 143.6, 135.5, 131.3, 130.7, 124.1, 123.9, 49.5, 30.7, 24.9,
23.0, 21.5; Calcd. for: C23H20N6O4S: C, 57.97; H, 4.23; N, 17.64; S, 6.73; Found: C, 57.73; H, 4.16; N, 17.45; S, 6.61.
2-(1-(3-((4-Chlorophenoxy)methyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)ethyl)isoindoline-1,3-dione (3e):
22
mp: 135–137 8C; Yield 80%, [a]D À10 (c 0.02, DMSO); IR (KBr, cmÀ1): 3061 (aromatic CH stretch.), 2935
(aliphatic CH stretch.), 1778, 1716 (C O), 1599 (C N); 1H NMR (300 MHz, DMSO-d6): d 7.74–7.91 (m, 4H, Harom.),
7.30 (d, 2H, J = 8.3 Hz, Harom.), 7.03 (d, 2H, J = 8.3 Hz, Harom.), 5.87 (q, 1H, J = 6.9 Hz, N–CH), 5.50 (s, 2H, OCH2),
1.88 (d, 3H, J = 6.8 Hz, CH3); 13C NMR (75 MHz, DMSO-d6): d 171.0, 167.4, 156.9, 155.1, 144.0, 135.2, 131.7,
129.7, 124.9, 123.5, 117.1, 60.1, 46.7, 17.0; C20H14ClN5O3S: C, 54.61; H, 3.21; N, 15.92; S, 7.29; Found: C, 54.33; H,
3.09; N, 15.72; S, 7.14.
2-(1-(3-((4-Chlorophenoxy)methyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-2-phenylethyl)isoindoline-1,3-
dione (3f): mp: 177–180 8C; Yield 90%, [a]D À30 (c 0.02, DMSO); IR(KBr, cmÀ1): 3063 (aromatic CH stretch.),
22
2920 (aliphatic CH stretch.), 1778, 1718 (C O), 1599 (C N); 1H NMR (300 MHz, DMSO-d6): d 7.75–7.90 (m, 4H,
H
arom.), 7.19–7.32 (m, 4H, Harom.), 6.94–7.13 (m, 5H, Harom.), 6.14 (dd, 1H, J = 10.0, 6.8 Hz, N–CH), 5.54 (s, 2H,
OCH2), 3.74–3.78 (m, 2H, PhCH2); 13C NMR (75 MHz, DMSO-d6): d 170.0, 167.5, 156.6, 155.5, 143.6, 136.1, 135.4,
131.7, 129.7, 129.5, 129.0, 127.5, 124.1, 123.5, 117.3, 59.8, 36.0; C26H18ClN5O3S: C, 60.52; H, 3.52; N, 13.57; S,
6.21; Found: C, 60.31; H, 3.44; N, 13.41; S, 6.38.

S. Ebrahimi et al. / Chinese Chemical Letters 23 (2012) 1335–1338
1337
2-(1-(3-((4-Chlorophenoxy)methyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-3-methylbutyl)isoindoline-
22
1,3-dione (3g): mp: 98–100 8C; Yield 90%, [a]D À33 (c 0.02, DMSO); IR (KBr, cmÀ1): 3065 (aromatic
CH stretch.), 2960 (aliphatic CH stretch.), 1782, 1714 (C O), 1599 (C N); 1H NMR (300 MHz, DMSO-d6): d 7.75–
7.88 (m, 4H, Harom.), 7.26 (d, 2H, J = 7.1 Hz, Harom.), 7.05 (d, 2H, J = 7.8 Hz, Harom.), 5.47 (s, 2H, OCH2), 5.25 (d,
1H, J = 11.0 Hz, N–CH), 2.91–2.95 (m, 1H, CH(Me)2), 1.04 (d, 3H, J = 6.7 Hz, CH3), 0.93 (d, 3H, J = 6.4 Hz, CH3);
13C NMR (75 MHz, DMSO-d6): d 169.7, 167.3, 156.5, 154.9, 143.5, 135.4, 131.5, 129.6, 125.7, 124.0, 117.1, 60.0,
46.7, 29.7, 20.1, 19.3; C22H18ClN5O3S: C, 56.47; H, 3.88; N, 14.97; S, 6.85; Found: C, 56.28; H, 3.81; N, 14.79; S,
6.69.
2-(1-(3-((4-Chlorophenoxy)methyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-4-methylpentyl)isoindoline-1,3-
22
dione (3h): mp: 90–92 8C; Yield 85%, [a]D À24 (c 0.02, DMSO); IR(KBr, cmÀ1): 3068 (aromatic CH stretch.),
2958 (aliphatic CH stretch.), 1778, 1716 (C O), 1599 (C N); 1H NMR (300 MHz, DMSO-d6): d 7.90 (br, 4H, Harom.),
7.28 (d, 2H, J = 8.1 Hz, Harom.), 7.06 (d, 2H, J = 8.1 Hz, Harom.), 5.77 (dd, 1H, J = 4.9, 9.4 Hz, N–CH), 5.50 (s, 2H,
OCH2), 2.47 (br, 1H, CH), 2.05 (br, 1H, CH2), 1.41–1.50 (m, 1H, CH2), 0.90 (d, 6H, 2 CH3, J = 6.8 Hz); 13C NMR
(75 MHz, DMSO-d6): d 170.1, 167.6, 156.8, 155.1, 143.8, 135.5, 131.3, 129.7, 125.8, 124.1, 117.2, 60.0, 49.5, 24.9,
23.1, 21.5; C23H20ClN5O3S: C, 57.32; H, 4.18; N, 14.53; S, 6.65; Found: C, 57.08; H, 4.08; N, 14.40; S, 6.49.
2. Results and discussion
In this present work, a series of 8 new compounds were synthesized. Scheme 1 illustrates the way used for the
preparation of target compounds. Starting materials 1a–b were prepared by the condensation of carbonothiohydrazide
with corresponding substituted acetic acid by employing well known method available in the literature [18]. The
desired N-phethaloyl-L-amino acids 2a–d was prepared according to the literature [19,20].
The resultant 5-substituted 4-amino-(4H)-1,2,4-triazole-3-thioles 1a–b was further converted to 1,2,4-triazolo[3,4-
b]-1,3,4-thiadiazoles 3a–h through one pot reaction by condensation with N-phethaloyl-L-amino acids 2a–d in the
presence of POCl3. Phosphorus oxychloride was necessary for this condensation, which activates the carboxyl group
of amino acids and increases its electrophilicity to enhance the addition of amino triazoles 1a–b to it. This procedure
afforded various triazolothiadiazoles in 80–90% yields.
The structure of newly synthesized compounds was confirmed by recording the IR, 1H NMR and 13C NMR data.
The structure of 3a was confirmed by IR, 1H NMR and 13C NMR. The IR spectrum of 3a exhibited absorption bands at
3041 cmÀ1 due to aromatic CH, 1782 and 1726 cmÀ1 due to C O for imide’s carbonyl groups. Additional support for
the structure of 3a was obtained by recording its 1H NMR spectrum, which exhibited a singlet at d 5.82 due to NCH
proton, three singlets at d 8.17, 7.97 and 7.56, integrating for eight aromatic protons.
The infrared spectra of the triazole 3 showed two absorption bands, at 2730 cmÀ1 and 3203–3317 cmÀ1 due to SH
and NH2 groups which were absent in the IR spectra of the triazolo thiadiazoles 3a–h. Similarly the 1H NMR spectra
of the compounds 3 showed two characteristics absorption (broad singlet at d 5.68) that was attributed to the NH2
group, and another at d 12.95, was assigned to the SH, which were disappeared by the formation of the
triazolothiadiazoles. The absence of these absorptions due to the SH and NH2 groups of triazoles 3 established that all
the triazole had converted to s-triazolothiadiazoles by reacting with the COOH groups of the various N-phethaloyl-L-
amino acids 2a–d.
O
O
N
N
H2N
R
R
N
POCl3
N
+
N
N
N
SH
COOH
Ar
S
O
O
Ar
N
N
1a-b
2a-d
3a-e
3a: R= CH3, Ar= 4-NO2Ph
3b: R= PhCH2, Ar= 4-NO2Ph
3e: R= CH3, Ar= 4-ClPhO
3f: R= PhCH2, Ar= 4-ClPhO
3d: R= (CH3)2CH, Ar= 4-NO2Ph
3d: R= (CH3)2CHCH2, Ar= 4-NO2Ph
3g: R= (CH3)2CH, Ar= 4-ClPhO
3h: R= (CH3)2CHCH2, Ar= 4-ClPhO
Scheme 1. Synthesis of s-triazolothiadiazoles 3a–h.

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S. Ebrahimi et al. / Chinese Chemical Letters 23 (2012) 1335–1338
3. Conclusion
We have been able to synthesize some novel s-triazolothiadiazoles having L-amino acid moiety. This reaction may
be useful for combinational synthesis of type 3 compounds having various R and Ar substitutions with a view to test for
biological activities.
Acknowledgment
We are thankful to Malayer Branch, Islamic Azad University for their financial support.
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