A simple and efficient procedure for synthesis of symmetrical bis(4-amino-4H-1,2,4-triazole-5-thiols)

Article abstract of DOI:10.1515/hc-2012-0127

A series of bis(1,2,4-triazole-3-thiols) 3a-d were prepared by condensation reactions of arylbis(carboxymethylthio)methanes 2a-d with thiocarbohydrazide. The starting diacids 2a-d were prepared by reactions of aromatic aldehydes 1a-d with thioglycolic aci

Full text of DOI:10.1515/hc-2012-0127

ꢁꢁꢁꢂ
DOI 10.1515/hc-2012-0127ꢀ ꢀHeterocycl. Commun. 2013; 19(1): 65–67
Sattar Ebrahimi*
A simple and efficient procedure for synthesis
of symmetrical bis(4-amino-4H-1,2,4-triazole-
5-thiols)
Abstract: A series of bis(1,2,4-triazole-3-thiols) 3a–d
were prepared by condensation reactions of aryl-
Results and discussion
bis(carboxymethylthio)methanes 2a–d with thiocarbo-
The synthesis of compounds 2a–d and 3a–d is outlined in
hydrazide. The starting diacids 2a–d were prepared by
Scheme 1. The substrates 2a–d were obtained by reaction
reactions of aromatic aldehydes 1a–d with thioglycolic
of various substituted benzaldehydes and thioglycolic
acid. The structures of these newly synthesized com-
acid using L-proline as an organocatalyst at 70°C under
pounds are characterized by elemental analysis, IR, and
solvent-free conditions. The desired compounds were
NMR spectroscopy.
obtained in excellent yields.
1
The H NMR spectra showed a singlet signal in the
Keywords: 4-amino-4H-1,2,4-triazole-3-thiol; thioacetal;
region of 5.18–5.88 ppm attributed to the resonance of the
thiocarbohydrazide.
methine proton (S-CH-S). The IR absorptions and 13C NMR
signals due to the presence of carbonyl groups clearly con-
*Corresponding author: Sattar Ebrahimi, Department of Chemistry,
Malayer Branch, Islamic Azad University, Malayer, Iran,
e-mail: seyonesi@gmail.com
firmed the formation of products 2a–d.
The final bis-triazole derivatives 3a–d were prepared
by heating compounds 2a–d with two equivalents of
thiocarbohydrazide in an oil bath at 150°C. These com-
pounds were obtained in reasonable yields. The struc-
tures of new compounds 3a–d were supported by NMR
and IR spectra, and elemental analyses. The IR spectrum
of compounds 2a–d showed two absorption bands, at
2500–3500 cm-1 and 1700 cm-1, due to OH and C=O groups,
respectively, that are absent in the IR spectra of products
3a–d. Similarly, the 1H NMR spectrum of compounds
2a–d showed a broad singlet peak at δ ∼12.60 ppm for
the COOH groups, which disappear upon the formation
of bis(aminotriazole) derivatives 3a–d. The correspond-
ing IR absorptions and 1H NMR signals for the SH and NH2
groups in compounds 3a–d clearly confirm the formation
of the bis(aminotriazole) system.
Introduction
The 1,2,4-triazole system is an important recognition
element in many biologically active molecules includ-
ing 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 surrogates
for cis amide bonds [6]. A variety of approaches have been
reported for the preparation 4-amino-1,2,4-triazol-3-thi-
oles including the reactions of carboxylic acids [7] and
1,3,4-oxadiazol-5-thiones [8]. The amino and thiol groups
are nucleophilic centers for the synthesis of condensed
nitrogen and sulfur heterocyclic systems, such as triazolo-
thiadiazoles [9–12], triazolothiadiazines [13, 14], macro-
cycles [15–17], and triazolothiadiazepines [18]. As part of
our ongoing studies on the synthesis of triazole deriva-
tives, we report here the synthesis of novel symmetrical
bis(4-amino-4H-1,2,4-triazole-3-thiols).
Conclusion
A rapid and highly efficient method for the synthe-
sis of a new series of symmetrical bis(aminotriazoles)
is described. This protocol is characterized by a short
reaction time, good to excellent yield, and simple
purification.
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66ꢀ
ꢀS. Ebrahimi: Synthesis of symmetrical bis(4-amino-4H-1,2,4-triazole-5-thiols)
S
COOH
H2N
N
H
N
H
NH2
S
S
L-proline
HSCH2COOH
Ar
2a-d
Ar CHO
+
neat, 70oC
neat, 150oC
15 min
1a-d
COOH
N
SH
N
N
N
NH2
S
a:
c:
b:
Ar = 4-MeOC6H4
Ar = 4-HOC6H4
Ar = 2-NO2C6H4
Ar
d: Ar =
Me
S
NH2
SH
S
N
3a-d
N
Scheme 1ꢀ
J = 15 Hz), 3.30 (d, 2H, J = 15 Hz). Anal. Calcd for: C11H11NO6S2: C, 41.63;
H, 3.49; N, 4.41; S, 20.21. Found: C, 41.50; H, 3.42; N, 4.37; S, 20.14.
Experimental
Melting points were determined using an electrothermal digital ap-
paratus and are uncorrected. Purity of the compounds were checked
by thin layer chromatography (TLC) using EtOH/n-hexane (1:1, v/v)
as an eluent. IR spectra were recorded on a Galaxy series FT-IR 5000
spectrophotometer using KBr discs. NMR spectra were recorded in
5-Methyl-2-thienyl-bis(carboxymethylthio)methane (2d)ꢀReac-
tiontime20min;yield85%;mp96–98°C;IR:2425–3417,1704,1203cm-1;
1H NMR: δ 12.71 (br, 2H), 6.88 (s, 1H), 6.63 (s, 1H), 5.52 (s, 1H), 3.45
(d, 2H, J = 15 Hz), 3.29 (d, 2H, J = 15 Hz), 2.39 (s, 3H); 13C NMR: δ 15.5,
34.5, 48.6, 125.2, 127.1, 140.6, 140.7, 171.1. Anal. Calcd for C10H12O4S3: C,
41.08; H, 4.14; S, 32.90. Found: C, 40.95; H, 4.08; S, 32.78.
1
DMSO-d6 on a Bruker spectrophotometer (300 MHz for H NMR and
75 MHz for 13C NMR). Elemental analyses were performed on a Vario
EL III elemental analyzer.
General procedure for synthesis
of bis(aminotriazoles) 3a–d
General procedure for preparation
of compounds 2a–d
A mixture of an aldehyde 1a–d (5 mmol), thioglycolic acid (12 mmol),
and L-proline (5% mol) was magnetically stirred at 70°C. Afer com-
pletion of the reaction (monitored by TLC), the mixture was poured
slowly onto crushed ice with stirring. The resultant precipitate of
2a–d was filtered, washed with water, and dried.
A
mixture of diacid 2a–d (10 mmol) and thiocarbohydrazide
(20 mmol) was fused at 150°C in an oil bath for 15 min. Afer cooling,
the reaction mixture was triturated with ethanol. The precipitate was
dried and crystallized from ethanol to give pure product 3a–d.
4-Hydroxyphenyl-bis[(4-amino-5-mercapto-4H-1,2,4-triazol-3-
yl)methylthio]methane (3a)ꢀReaction time 15 min; yield 80%; mp
228–230°C; IR: 3285, 3142, 2752, 1605, 1490 cm-1; H NMR: δ 13.38 (s,
1
2H), 9.56 (s, 1H), 7.18 (d, 2H, J = 7.6 Hz), 6.75 (d, 2H, J = 7.6 Hz), 5.50
4-Hydroxyphenyl-bis(carboxymethylthio)methane (2a)ꢀReac-
tion time 15 min; yield 99%; mp 160–161°C (lit mp 155–156°C; [19]);
IR: 2540–3430, 1700, 1200 cm-1; 1H NMR: δ 12.63 (br, 2H), 9.59 (s, 1H),
7.19 (d, 2H, J = 7.7 Hz), 6.73 (d, 2H, J = 7.7 Hz), 5.18 (s, 1H), 3.35 (d, 2H J =
15 Hz), 3.18 (d, 2H, J = 15 Hz); 13C NMR: δ 34.4, 52.8, 115.7, 129.3, 129.4,
157.7, 171.3. Anal. Calcd for C11H12O5S2: C, 45.82; H, 4.19; S, 22.24. Found:
C, 45.70; H, 4.14; S, 22.16.
(s, 4H), 5.21 (s, 1H), 3.85 (d, 2H, J = 14 Hz), 3.66 (d, 2H, J = 14 Hz); 13
C
NMR: δ 25.2, 52.8, 115.8, 129.1, 129.6, 150.0, 157.7, 166.5. Anal. Calcd for
C13H16N8OS4: C, 36.43; H, 3.76; N, 26.15; S, 29.93. Found: C, 36.21; H,
3.65; N, 26.02; S, 29.76.
4-Methoxyphenyl-bis[(4-amino-5-mercapto-4H-1,2,4-triazol-3-
yl)methylthio]methane (3b)ꢀReaction time 15 min; yield 77%; mp
215–218°C; reaction time 15 min; yield 99%; mp 160–161°C; IR: 3245,
3150, 2761, 1600 cm-1; 1H NMR: δ 13.35 (s, 2H), 7.31 (d, 2H, J = 8.0 Hz),
6.92 (d, 2H, J = 8 Hz), 5.52 (s, 4H), 5.23 (s, 1H), 3.82 (d, 2H, J = 14 Hz),
3.65 (d, 2H, J = 14 Hz); 13C NMR: δ 25.3, 52.7, 55.7, 114.4, 129.3, 130.9,
149.9, 161.0, 166.8. Anal. Calcd for C14H18N8OS4: C, 37.99; H, 4.10; N,
25.32; S, 28.98. Found: C, 37.75; H, 3.99; N, 25.17; S, 28.83.
4-Methoxyphenyl-bis(carboxymethylthio)methane (2b)ꢀReac-
tion time 15 min; yield 99%; mp 122–123°C (lit mp 121.5–122.5°C; [20]);
IR: 2520–3400, 1705, 1205, 1185 cm-1; 1H NMR: δ 12.60 (br, 2H), 7.31 (d,
2H, J = 8.4 Hz), 6.73 (d, 2H, J = 8.4 Hz), 5.24 (s, 1H), 3.75 (s, 3H), 3.37
(d, 2H, J = 15 Hz), 3.20 (d, 2H, J = 15 Hz). Anal. Calcd for C12H14O5S2: C,
47.67; H, 4.67; S, 21.21. Found: C, 47.59; H, 4.63; S, 21.15.
2-Nitrophenyl-bis[(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)
methylthio]methane (3c)ꢀReaction time 15 min; yield 80%; mp
2-Nitrophenyl-bis(carboxymethylthio)methane (2c)ꢀReaction
time 15 min; yield 99%; mp 124°C (lit mp 122–123°C; [21]); IR: 2500–
3385, 1711, 1532, 1362, 1201 cm-1; H NMR: δ 12.65 (br, 2H), 7.93 (m, 208–210°C; IR: 3268, 3162, 2770, 1612, 1550, 1325 cm-1; 1H NMR: δ 13.45
1H), 7.81 (m, 1H), 7.74 (m, 1H), 7.53 (m, 1H), 5.88 (s, 1H), 3.47 (d, 2H, (s, 2H), 7.93 (d, 1H J = 7.9 Hz), 7.74–7.82 (m, 2H), 7.56 (m, 1H), 5.86
1
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ꢂꢁꢁꢁ
S. Ebrahimi: Synthesis of symmetrical bis(4-amino-4H-1,2,4-triazole-5-thiols)ꢀ
ꢀ67
(s, 1H), 5.54 (s, 4H), 4.00 (d, 2H, J = 14 Hz), 3.73 (d, 2H, J = 14 Hz); 2.41 (s, 3H); 13C NMR: δ 15.6, 25.4, 48.8, 125.2, 127.0, 140.5, 140.7, 150.0,
13C NMR: δ 25.7, 52.5, 125.6, 127.9, 128.2, 130.2, 131.6, 135.3, 147.6, 149.8, 166.3. Anal. Calcd for C12H16N8S5: C, 33.31; H, 3.73; N, 25.90; S, 37.06.
166.9. Anal. Calcd for C13H15N9O2S4: C, 34.12; H, 3.30; N, 27.55; S, 28.03. Found: C, 33.15; H, 3.65; N, 25.81; S, 37.19.
Found: C, 33.91; H, 3.22; N, 27.42; S, 27.89.
Acknowledgment: I am thankful to Malayer Branch,
5-Methyl-2-thienyl-bis[(4-amino-4H-1,2,4-triazol-3-yl)methylthio]
Islamic Azad University for financial support.
methane (3d)ꢀReaction time 15 min; yield 68%; mp 180–183°C; IR:
1
3381, 3153, 2760, 1599 cm-1; H NMR: δ 13.41 (s, 2H), 6.87 (s, 1H), 6.65
Received August 16, 2012; accepted September 10, 2012; previously
published online January 9, 2013
(s, 1H), 5.52 (m, 5H), 3.88 (d, 2H, J = 14 Hz), 3.68 (d, 2H, J = 14 Hz),
References
[1] Jenkins, S. M.; Wadsworth, H. J.; Bromidge, S.; Orlek, B. S.;
Wyman, P. A.; Riley, G. J.; Hawkins, J. Substituent variation in
azabicyclic triazole- and tetrazole-based muscarinic receptor
ligands. J. Med. Chem. 1992, 35, 2392–2406.
[2] Chen, C.; Dagnino, R.; Huang, C. Q.; McCarthy, J. R.;
Grigoriadis, D. E. 1-Alkyl-3-amino-5-aryl-1H-[1,2,4]triazoles:
novel synthesis via cyclization of N-acyl-S-methylisothioureas
with alkylhydrazines and their potent corticotropin-releasing
factor-1 (CRF1) receptor antagonist activities. Bioorg. Med.
Chem. Lett. 2001, 11, 3165–3168.
[3] Tully, W. R.; Gardner, C. R.; Gillepsie, R. J.; Westwood, R.
2-(Oxadiazolyl)- and 2-(thiazolyl)imidazo[1,2-a]pyrimidines as
agonists and inverse agonists at benzodiazepine receptors.
J. Med. Chem. 1991, 34, 2060–2067.
[4] Burrell, G.; Evans, J. M.; Hadley, M. S.; Hicks, F.; Stemp,
G. Benzopyran potassium channel activators related to
cromakalim – heterocyclic amide replacements at position.
Bioorg. Med. Chem. Lett. 1994, 4, 1285–1290.
[5] Boyd, S. A.; Fung, A. K. L.; Baker, W. R.; Mantei, R. A.;
Stein, H. H.; Cohen, J.; Barlow, J. L.; Klinghofer, V.;
[11] Foroughifar, N.; Mobinikhaledi, A.; Ebrahimi, S.; Kamali, M.;
Kazemi, M. A simple and efficient procedure for synthesis of
optically active 1,2-bis(s-triazolo)bis(s-triazolo[3,4-b][1,3,4]
thiadiazole-3-yl) alkane derivatives containing L-amino acid
moieties. J. Sulfur Chem. 2011, 32, 593–598.
[12] Foroughifar, N.; Ebrahimi, S.; Mobinikhaledi, A.; Mozafari, R.
An efficient and convenient protocol for the synthesis
of optically active 1,2,4-triazolo-[3,4-b]-[1,3,4]-thiadiazole,
1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives
having L-amino acid moieties. S. Afr. J. Chem. 2012,
65, 1–4.
[13] Subrahmanya Bhat, K.; Poojary, B.; Jagadeesh Prasad,
D.; Naik, P.; Shivarama Holla, B. Synthesis and antitumor
activity studies of some new fused 1,2,4-triazole derivatives
carrying 2,4-dichloro-5-fluorophenyl moiety. Eur. J. Med. Chem.
2009, 44, 5066–5070.
[14] Foroughifar, N.; Mobinikhaledi, A.; Ebrahimi, S. An
efficient and convenient protocol for the synthesis of novel
1,2,4-triazolo[3,4-b][1,3,4]thiadiazines. Synthetic Commun.
2010, 40, 2421–2428.
Wessale, J. L.; Verburg, K. M.; et al. Nonpeptide renin inhibitors [15] Foroughifar, N.; Mobinikhaledi, A.; Ebrahimi, S.; Moghanian,
with good intraduodenal bioavailability and efficacy in dog. J.
Med. Chem. 1994, 37, 2991–3007.
H.; Bodaghi Fard, M. A.; Kalhor, M. Synthesis of a new class of
azathia crown macrocycles containing two 1,2,4-triazole or two
1,3,4-thiadiazole rings as subunits. Tetrahedron Lett. 2009, 50,
836–839.
[6] Duncia, J. V.; Santela, J. B., III; Higley, A.; Van Atten, M. K.;
Weber, P. C.; Alexander, R. S.; Kettner, C. A.; Pruitt, J. R.; Liauw,
A. Y.; Quan, M. L.; et al. Pyrazoles, 1,2,4-triazoles, and tetrazoles
as surrogates for cis-amide bonds in boronate ester thrombin
inhibitors. Bioorg. Med. Chem. Lett. 1998, 8, 775–780.
[7] Ghorab, M. M.; El-Sharief, A. M. Sh.; Ammar, Y. A.; Mohamed,
Sh. I. Synthesis and radiation stability of novel biologically
active sulfur compounds derived from 1,2-bis(4-amino-5-
mercapto-s-triazol-3-yl)ethane. Il Farmaco 2000, 55, 354–361.
[8] Chen, X.; Liu, R.; Xu, Y.; Zou G. Tunable protic ionic
liquids as solvent-catalysts for improved synthesis of
multiply substituted 1,2,4-triazoles from oxadiazoles and
organoamines. Tetrahedron 2012, 68, 4813–4819.
[16] Foroughifar, N.; Mobinikhaledi, A.; Ebrahimi, S. Synthesis of a
novel class of aza crown macrocycles and lariat crown ethers
containing two 1,2,4-triazole rings as subunits. Synthesis
2009, 15, 2557–2560.
[17] Ebrahimi, S.; Moghanian H. Synthesis of new aza crown
macrocycles and lariat ethers. Heterocycl. Commun. 2012, 18,
29–31.
[18] Almajan, G. L.; Barbuceanu, S. F.; Saramet, I.; Draghici C. New
6-amino-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines and [1,2,4]
triazolo[3,4-b] [1,3,4]thiadiazin-6-ones: synthesis, character-
ization and antibacterial activity evaluation. Eur. J. Med. Chem.
2010, 45, 3191–3195.
[19] Kishimoto, Y.; Akabori, Y.; Horiguchi, T. (Methylene)dithio-
diacetic acid derivatives. I. Antimicrobial and antiprotozoal
activity 1. Yakugaku Zasshi 1958, 78, 447–450.
[20] Ritter, J. J.; Lover, M. J. Mercaptocarboxylic acids as reagents
for the identification of carbonyl compound. J. Am. Chem. Soc.
1952, 74, 5576–5577.
[21] Stoner, G. G.; Dougherty, G. The use of bunte salts in
synthesis. II. The preparation of derivatives of mercapto
aliphatic acids. J. Am. Chem. Soc. 1941, 63, 987–988.
[9] Foroughifar, N.; Mobinikhaledi, A.; Ebrahimi, S.; Bodaghi
Fard, M. A.; Moghanian, M. A simple and efficient procedure
for synthesis of optically active 1,2,4-triazolo-[3,4-b]-1,3,4-
thiadiazole derivatives containing L-amino acid moieties.
J. Chin. Chem. Soc. 2009, 56, 1043–1047.
[10] Foroughifar, N.; Ebrahimi, S.; Mobinikhaledi, A.; Mozafari R. An
efficient and convenient protocol for the synthesis of optically
active [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives
containing L-amino acid moieties. Heterocycl. Commun. 2011,
17, 211–214.
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