Syntheses of some novel and symmetrical bis(4-amino-4H-1,2,4-triazole-3- thiols)

Article abstract of DOI:10.1080/17415993.2012.721367

A series of bis(4-amino-4H-1,2,4-triazole-3-thiols) 3a-e were prepared by condensation reactions of 2,2-(phenylmethylene)bis(sulfanediyl)diacetic acids 2a-e with thiocarbohydrazide. The starting diacid 2a-e was prepared by reactions of aromatic aldehydes

Full text of DOI:10.1080/17415993.2012.721367

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Syntheses of some novel and
symmetrical bis(4-amino-4H-1,2,4-
triazole-3-thiols)
Sattar Ebrahimi a & Masoomeh Sayadi a
a Department of Chemistry, Malayer Branch, Islamic Azad
University, Malayer, Iran
Version of record first published: 18 Sep 2012.
To cite this article: Sattar Ebrahimi & Masoomeh Sayadi (2012): Syntheses of some novel
and symmetrical bis(4-amino-4H-1,2,4-triazole-3-thiols), Journal of Sulfur Chemistry,
DOI:10.1080/17415993.2012.721367
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Journal of Sulfur Chemistry
iFirst, 2012, 1–6
Syntheses of some novel and symmetrical
bis(4-amino-4H-1,2,4-triazole-3-thiols)
Sattar Ebrahimi* and Masoomeh Sayadi
Department of Chemistry, Malayer Branch, Islamic Azad University, Malayer, Iran
(Received 6 July 2012; final version received 13 August 2012)
A series of bis(4-amino-4H-1,2,4-triazole-3-thiols) 3a–e were prepared by condensation reactions of
2,2ꢀ-(phenylmethylene)bis(sulfanediyl)diacetic acids 2a–e with thiocarbohydrazide. The starting diacid
2a–e was prepared by reactions of aromatic aldehydes 1a–e with 2-mercaptoacetic acid. The structures
of these newly synthesized compounds are characterized by elemental analysis, and infrared and NMR
spectroscopy.
N
SH
NH2
NH2
SH
N
N
N
R
S
S
R
CHO
1a–e
3a–e
N
N
Keywords: bis(4-amino-4H-1,2,4-triazole-3-thiol); thiocarbohydrazide; 1,2,4-triazole; thioacetal; thio-
glycolic acid
1. Introduction
The 1,2,4-triazole system has been known to be an important recognition element in biologically
active molecules. This moiety was also found in potent agonist or antagonist receptor ligands
(1, 2). 1,2,4-Triazole derivatives have been used as mimics (3, 4) or isosteres (5) of the amide
bond in attempts to increase bioavailability of the parent bioactive molecules. They have also
been incorporated into peptides as surrogate for cis amide bonds (6).
Differentapproacheshavebeenreportedforthepreparationof4-amino-1,2,4-triazole-3-thioles.
4-Amino-4H-1,2,4-triazole-3-thioles were prepared by reacting carboxylic acids (7), carboxylic
*Corresponding author. Email: seyonesi@iau-malayer.ac.ir, seyonesi@gmail.com
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2012 Taylor & Francis
http://dx.doi.org/10.1080/17415993.2012.721367
http://www.tandfonline.com

2
S. Ebrahimi and M. Sayadi
acid hydrazides (8) and 1,3,4-oxadiazol-5-thioles (9). The amino and thiol groups are ready-
made nucleophilic centers for the synthesis of condensed nitrogen and sulfur heterocyclic rings,
for example, triazolothiadiazoles (10–13), triazolothiadiazines (14, 15), macrocycles (16–18) and
triazolothiadiazepines (19).
As part of our ongoing studies on the synthesis of triazole derivatives, we report here the
synthesis of some novel symmetrical bis(4-amino-4H-1,2,4-triazole-3-thiols).
2. Results and discussion
The synthesis of compounds 2a–e and 3a–e are outlined in Schemes 1 and 2. Firstly, 2,2ꢀ-
(arylmethylene)bis(sulfanediyl)diacetic acids were synthesized. The reaction of various substi-
tuted benzaldehyde and thioglycolic acid using l-proline as an organocatalyst at 70◦C under
solvent-free conditions afforded the corresponding compounds 2a–e as shown in Scheme1. The
expected compounds were obtained in excellent yields.
COOH
S
S
R
R
L
-proline
CHO
+
HSCH2COOH
solvent free
COOH
1a–e
2a–e
Scheme 1. Synthesis of compound 2a–e.
N
N
SH
NH2
NH2
SH
N
N
COOH
S
S
S
S
S
R
R
Fusion
15min
+
H2N
N
N NH2
H
H
COOH
2a–e
3a–e
N
N
Scheme 2. Synthesis of the bis-aminotriazole 3a–e.
1H NMR spectra of all synthesized compounds reveal a singlet signal in the region
−
−
δ = 5.25–5.86 ppm attributed to the resonance of the methine proton (S CH S). The
appearance of the infrared (IR) absorptions and 13C NMR signals due to the carbonyl
groups of the synthesized compounds 2a–e, clearly confirmed the formation of 2,2ꢀ-
(arylmethylene)bis(sulfanediyl)diacetic acids.
Compounds 2a–e were used as key intermediates for the synthesis of novel bis(4-amino-4H-
1,2,4-triazole-3-thiol) derivatives. Thus, the novel bis-triazole compounds 3a–e were prepared
by heating compounds 2a–e with two equivalents of carbonothioic dihydrazide in an oil bath at
150◦C (Scheme 2). The expected compounds were obtained in reasonable yields as reported in
Table 1.
The structures of new compounds 3a–e were identi?ed by NMR, IR and elemental analyses.
The IR spectrum of the compounds 2a–e showed two absorption bands, at 1700 and 2500–
3500 cm−1 due to C O and OH groups, respectively, which were absent in the IR spectra of
=
the bis-aminotriazole 3a–e. Similarly, the 1H NMR spectrum of compounds 2a–e showed broad

Journal of Sulfur Chemistry
3
Table 1. Synthesis of compounds 2a–e and 3a–e.
Entry
R
Time (min)
Yields (%)
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
H
15
15
12
10
10
15
15
15
15
15
>99
>99
>99
>99
>99
65
70
85
87
85
4-Methyl
4-Chloro
3-Nitro
4-Nitro
H
4-Methyl
4-Chloro
3-Nitro
4-Nitro
singlets at δ ∼ 12.60, attributed to the OH groups, which disappeared upon formation of the bis-
aminotriazole 3a–e. The appearance of the IR absorptions and 1H NMR signals due to the NH2 and
SH groups of synthesized compounds 3a–e, clearly confirmed the formation of bis-aminotriazoles.
3. Conclusion
In conclusion, we have described a rapid and highly efficient method for the synthesis of a new
series of symmetrical bis-aminotriazoles. This protocol is characterized by a rapid reaction rate,
short reaction time, good yield and simple purification. Our ongoing efforts for the synthesis of
other compounds starting from intermediate 2 and 3 will be reported elsewhere.
4. Experimental
4.1. General
Melting points were determined using an electrothermal digital apparatus and are uncorrected.
Purity of the compounds 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 the Bruker 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.
4.2. General procedure for the synthesis of compounds 2a–e
Aldehydes 1a–e (5 mmol), thioglycolic acid (12 mmol) and l-proline (5% mol) were mixed and
the resulting mixture was magnetically stirred at 70◦C. After completion (controlled by TLC), the
reaction mixture was slowly poured into crushed ice, with constant stirring. The solid that was
separated was filtered and washed with water. The compound so obtained was dried to give the
pure products 2a–e.
4.2.1. 2,2ꢀ-(phenylmethylene)bis(sulfanediyl)diacetic acid (2a, Table 1)
mp 133–134◦C, IR (KBr): (υ, cm−1) = 2520–3420 (OH), 1701 (C O), 1201 (C O); H NMR
1
=
−
(DMSO-d6, δ, ppm): 12.71 (br, 2H, 2 OH), 7.33–7.39 (br, 5H, Harom.), 5.28 (s, 1H, CH), 3.40 (d,

4
S. Ebrahimi and M. Sayadi
2H, CH2, J = 15.4 Hz), 3.23 (d, 2H, CH2, J = 15.4 Hz); Calcd. for C12H14O4S2: C, 48.51; H,
4.44; S, 23.55. Found: C, 48.39; H, 7.35; S, 23.43.
4.2.2. 2,2ꢀ-(p-Tolylmethylene)bis(sulfanediyl)diacetic acid (2b, Table 1)
mp 133–134◦C, IR (KBr): (υ, cm−1) = 2450–3430 (OH), 1702 (C O), 1190 (C O); H NMR
1
=
−
(DMSO-d6, δ, ppm): 12.60 (br, 2H, 2 OH), 7.28 (d, 2H, Harom., J = 7.7 Hz), 7.17 (d, 2H, Harom.
,
J = 7.7 Hz), 5.25 (s, 1H, CH), 3.37 (d, 2H, CH2, J = 15.3 Hz), 3.23 (d, 2H, CH2, J = 15.3 Hz);
Calcd. for C12H14O4S2: C, 50.33; H, 4.93; S, 22.39. Found: C, 50.21; H, 4.89; S, 22.29.
4.2.3. 2,2ꢀ-((4-Chlorophenyl)methylene)bis(sulfanediyl)diacetic acid (2c, Table 1)
1
mp 152–154◦C, IR (KBr): (υ, cm−1) = 2500–3450 (OH), 1700 (C O), 1185 (C O); H NMR
(DMSO-d6, δ, ppm): 12.26 (br, 2H, 2 OH), 7.41 (s, 4H, Harom.), 5.30 (s, 1H, CH), 3.40 (d, 2H,
CH2, J = 15.4 Hz), 3.25 (d, 2H, CH2, J = 15.4 Hz); Calcd. for C11H11ClO4S2: C, 43.07; H, 3.61;
S, 20.90. Found: C, 42.98; H, 3.58; S, 20.84.
=
−
4.2.4. 2,2ꢀ-((3-Nitrophenyl)methylene)bis(sulfanediyl)diacetic acid (2d, Table 1)
mp 120–121◦C, IR (KBr): (υ, cm−1) = 2500–3430 (OH), 1705 (C O), 1532, 1321 (NO2), 1191
=
1
−
(C O); H NMR (DMSO-d6, δ, ppm): 12.63 (br, 2H, 2 OH), 7.94 (d, 1H, Harom., J = 7.7 Hz),
7.76–7.83 (m, 2H, Harom.), 7.58 (d, 1H, Harom., J = 7.1 Hz), 5.86 (s, 1H, CH), 3.46 (d, 2H, CH2,
J = 15.3 Hz), 3.30 (d, 2H, CH2, J = 15.3 Hz); Calcd. for C11H11NO6S2: C, 41.63; H, 3.49; N,
4.41; S, 20.21. Found: C, 41.48; H, 3.42; N, 4.21; S, 20.09.
4.2.5. 2,2ꢀ-((4-Nitrophenyl)methylene)bis(sulfanediyl)diacetic acid (2e, Table 1)
mp 165–168◦C, IR (KBr): (υ, cm−1) = 2500–3400 (OH), 1706 (C O), 1520, 1320 (NO2), 1199
=
1
−
(C O); H NMR (DMSO-d6, δ, ppm): 12.74 (br, 2H, 2 OH), 8.23 (d, 2H, Harom., J = 8.2 Hz),
7.67 (d, 2H, Harom., J = 8.3 Hz), 5.45 (s, 1H, CH), 3.45 (d, 2H, CH2, J = 15.5 Hz), 3.31 (d, 2H,
CH2, J = 15.5 Hz); Calcd. for C11H11NO6S2: C, 41.63; H, 3.49; N, 4.41; S, 20.21. Found: C,
41.55; H, 3.45; N, 4.48; S, 20.14.
4.3. General procedure for the synthesis of bis-aminotriazole 3a–e
A mixture of thiocarbohydrazide (20 mmol) and diacid 2a–e (10 mmol) was fused at 150◦C in an
oil bath for 15 min.After cooling, the reaction mixture was triturated with ethanol. The compound
so obtained was dried and crystallized from ethanol to give the pure products 3a–e.
4.3.1. 5,5ꢀ-(Phenylmethylene)bis(sulfanediyl)bis(methylene)bis(4-amino-4H-1,2,4-triazole-3-
thiol) (3a, Table 1)
mp 232–233◦C, IR (KBr): (υ, cm−1) = 3290, 3150 (NH2), 2771 (SH) 1610 (C N), 1493 (CH2);
=
1H NMR (DMSO-d6, δ, ppm): 13.25 (s, 2H, 2 SH), 7.32–7.40 (m, 5H, Harom.), 5.52 (s, 4H, 2 NH2),
5.37 (s, 1H, CH), 3.92 (d, 2H, CH2, J = 14.5 Hz), 3.70 (d, 2H, CH2, J = 14.4 Hz); 13C NMR
(DMSO-d6, δ, ppm): 25.3, 53.2, 124.6, 128.1, 128.7, 129.1, 150.1, 166.8; Calcd. for C13H16N8S4:
C, 37.84; H, 3.91; N, 27.16; S, 31.09. Found: C, 37.69; H, 3.85; N, 26.98; S, 30.96.

Journal of Sulfur Chemistry
5
4.3.2. 5,5ꢀ-(p-Tolylmethylene)bis(sulfanediyl)bis(methylene)bis(4-amino-4H-1,2,4-
triazole-3-thiol) (3b, Table 1)
mp 246–247◦C, IR (KBr): (υ, cm−1) = 3317, 3170 (NH2), 2764 (SH) 1614 (C N), 1485 (CH2);
1H NMR (DMSO-d6, δ, ppm): 13.40 (s, 2H, 2 SH), 7.29 (d, 2H, Harom. J = 7.2 Hz), 7.14 (d, 2H,
Harom. J = 7.1 Hz), 5.51 (s, 4H, 2 NH2), 5.33 (s, 1H, CH), 3.68 (d, 2H, CH2, J = 14.9 Hz), 3.68
(d, 2H, CH2, J = 14.9), 2.27 (s, 3H, CH3); 13C NMR (DMSO-d6, δ, ppm): 21.2, 25.3, 53.0, 128.0,
129.6, 136.18, 138.1, 150.1, 166.8. C14H18N8S4: C, 39.42; H, 4.25; N, 26.27; S, 30.07. Found:
C, 39.21; H, 4.15; N, 26.08; S, 29.93.
=
4.3.3. 5,5ꢀ-((4-Chlorophenyl)methylene)bis(sulfanediyl)bis(methylene)bis(4-amino-4H-1,2,4-
triazole-3-thiol) (3c, Table 1):
mp 247–278◦C, IR (KBr): (υ, cm−1) = 3321, 3191 (NH2), 2774 (SH) 1602 (C N), 1490 (CH2);
=
1H NMR (DMSO-d6, δ, ppm): 13.45 (s, 2H, 2 SH), 7.40 (br, 4H, Harom.), 5.51 (s, 4H, 2 NH2),
5.38 (s, 1H, CH), 3.89 (br, 2H, CH2), 3.74 (br, 2H, CH2); 13C NMR (DMSO-d6, δ, ppm): 25.4,
52.4, 129.0, 130.0, 133.2, 138.3, 150.0, 166.8; C13H15ClN8S4: C, 34.93; H, 3.38; N, 25.07; S,
28.69. Found: C, 34.68; H, 3.26; N, 24.82; S, 28.51.
4.3.4. 5,5ꢀ-((3-Nitrophenyl)methylene)bis(sulfanediyl)bis(methylene)bis(4-amino-4H-1,2,4-
triazole-3-thiol) (3d, Table 1)
mp 227–229◦C, IR (KBr): (υ, cm−1) = 3281, 3164 (NH2), 2756 (SH) 1606 (C N), 1520, 1321
=
(NO2), 1495 (CH2); 1H NMR (DMSO-d6, δ, ppm): 13.50 (s, 2H, 2 SH), 8.23 (s, 1H, Harom.), 8.13
(s, 1H, Harom.), 7.85 (s, 1H, Harom.), 7.61 (s, 1H, Harom.), 5.58 (s, 1H, CH), 5.50 (s, 4H, 2 NH2), 5.33
(s, 1H, CH), 3.98 (d, 2H, CH2, J = 14.2 Hz), 3.80 (d, 2H, CH2, J = 14.1 Hz); 13C NMR (DMSO-
d6, δ, ppm): 25.6, 52.2, 122.8, 123.6, 130.6, 134.7, 141.6, 148.0, 149.8, 166.8; C13H15N9O2S4:
C, 34.12; H, 3.30; N, 27.55; S, 28.03. Found: C, 33.86; H, 3.19; N, 27.74; S, 27.82.
4.3.5. 5,5ꢀ-((4-Nitrophenyl)methylene)bis(sulfanediyl)bis(methylene)bis(4-amino-4H-1,2,4-
triazole-3-thiol) (3e, Table 1)
mp 241–242◦C, IR (KBr): (υ, cm−1) = 3292, 3171 (NH2), 2770 (SH) 1600 (C N), 1520, 1321
=
(NO2); 1H NMR (DMSO-d6, δ, ppm): 13.52 (s, 2H, 2 SH), 8.15 (d, 2H, Harom. J = 5.2 Hz), 7.65
(d, 2H, Harom. J = 5.0 Hz), 5.51 (s, 5H, 2 NH2, 1CH), 3.98 (d, 2H, CH2, J = 14.0 Hz), 3.80 (d,
2H, CH2, J = 14.1 Hz); 13C NMR (DMSO-d6, δ, ppm): 21.2, 25.3, 53.0, 128.0, 129.6, 136.18,
138.1, 150.1, 166.8; C13H15N9O2S4: C, 34.12; H, 3.30; N, 27.55; S, 28.03. Found: C, 33.93; H,
3.21; N, 27.37; S, 27.90.
Acknowledgements
We are thankful to the Malayer Branch, Islamic Azad University for their financial support.
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