Efficient methodology for the synthesis of 3-amino-1,2,4-triazoles

Article abstract of DOI:10.1021/jo9016502

(Chemical Equation Presented) A general and efficient method for the preparation of 3-amino-1,2,4-triazoles has been developed. The desired 3-amino-1,2,4-triazoles (1) were prepared in good overall yield via two convergent routes. The key intermediate wit

Full text of DOI:10.1021/jo9016502

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herbicides,5 and patented as neuropeptide Y receptor
Efficient Methodology for the Synthesis of
3-Amino-1,2,4-triazoles
ligands.6 Aminotriazoles have also been described as potent
CRF1 receptor antagonists,7 as well as inhibitors of methio-
nine aminopeptidase-2.8
€
Romain Noel, Xinyi Song, Rong Jiang,
Numerous methods have been developed for the synthesis
of 1,5-disubstituted 3-amino-1,2,4-triazoles.9 However, few
of these describe direct synthesis of the triazole lacking
substitution at the 5-position. Methods do exist to synthesize
5-amino-substituted analogues which are then diazotized to
remove the amino group, but this is laborious as it requires
an additional step for every analogue synthesized.10 Addi-
tionally, other published routes to 5-unsubstituted triazoles
suffer some disadvantages including the following: (1) not
atom economical,11 (2) low yielding11a,12 and (3) limited
scope with regards to substitution of the 3-amino group13
or in the N-1 position14 (the substituent in this position was
added in an additional step). In some cases, chemistry is
limited to symmetric bisaryl substitution patterns, which
may not find general use.15 In other approaches, there are
only a few examples given. Hence, the breadth and applic-
ability of these methods to synthesize a variety of substituted
(alkyl, aryl, primary or secondary alkyl or aryl amine)
3-amino-1,2,4-triazoles is lacking.11
Michael J. Chalmers, Patrick R. Griffin, and
Theodore M. Kamenecka*
Department of Molecular Therapeutics and Translational
Research Institute, The Scripps Research Institute, Scripps
Florida, 130 Scripps Way No. A2A, Jupiter, Florida 33458
kameneck@scripps.edu
Received August 6, 2009
As part of our medicinal chemistry research program, we
required a robust facile synthesis of 3-aminotriazole deriva-
tives (devoid of C-5 substitution) 1 wherein we could vary the
R1, R2, and R3 groups. Herein we report a convergent and
convenient method for the preparation of these derivatives.
We envisioned that 3-aminotriazole 1 could be obtained
by cyclization of hydrazinecarboximidamide derivative 2
with a formic acid equivalent (Scheme 1). This precursor
could be prepared by two different methods. One route
begins with thiourea 3 and the other with hydrazinecar-
bothioamide 4 wherein the R1/R2/R3 groups are introduced
A general and efficient method for the preparation of
3-amino-1,2,4-triazoles has been developed. The desired
3-amino-1,2,4-triazoles (1) were prepared in good overall
yield via two convergent routes. The key intermediate
within both routes is substituted hydrazinecarboximida-
mide derivative 2.
Triazole heterocycles occupy a central position in modern
heterocyclic chemistry, principally because this heterocyclic
ring is an important recognition element in biologically
active molecules. Consequently new and efficient methods
for the preparation of this important heterocyclic ring system
are of contemporary interest. 3-Amino-1,2,4-triazole and its
derivatives have also been the subject of numerous studies
because of the many reported applications in the fields of
medicinal and agrochemistry. For example, 3-aminotriazole
derivatives are inhibitors of catalase1 and histidine2 bio-
synthesis. Sufotidine bismuth citrate, a complex with an
aminotriazole motif that is a histamine H2-receptor antago-
nist, is used in the treatment of duodenal and gastric ulcera-
tion and other conditions where histamine is a known
mediator.3 3-Aminotriazoles have also been found effective
for the treatment of chronic bronchial asthma,4 used as
(6) Fauchere, J.-L.; Ortuno, J.-C.; Duhault, J.; Boutin, J. A.; Levens, N.
European Patent EP 1044970, 2000.
(7) Lowe, R. F.; Nelson, J.; Dang, T. N.; Crowe, P. D.; Pahuja, A.;
McCarthy, J. R.; Grigoriadis, D. E.; Conlon, P.; Saunders, J.; Chen, C.;
Szabo, T.; Chen, T. K.; Bozigian, H. J. Med. Chem. 2005, 48, 1540–1549.
(8) Marino, J. P.; Fisher, P. W.; Hofmann, G. A.; Kirkpatrick, R. B.;
Janson, C. A.; Johnson, R. K.; Ma, C.; Mattern, M.; Meek, T. D.; Ryan, M.
D.; Schulz, C.; Smith, W. W.; Tew, D. G.; Tomazek, T. A.; Veber, D. F.;
Xiong, W. C.; Yamamoto, Y; Yamashita, K.; Yang, G.; Thompson, S. K.
J. Med. Chem. 2007, 50, 3777–3785.
(9) (a) Temple, C., Jr. In Triazoles 1,2,4; Mongomery, J. A., Ed.; John Wiley
and Sons: New York, 1981; p 130. (b) Polya, J. B. In Comprehensive Heterocyclic
Chemistry; Potts, K. T., Ed.; Pergamon Press: Oxford, UK, 1984; Vol. 5, p 733.
(c) Katritzky, A. R.; Rogovoy, B. V.; Vvedensky, V. Y.; Kovalenko, K.; Steel, P. J.;
Markov, V. I.; Forood, B. Synthesis 2001, 6, 897-893 and references cited
therein. (d) Makara, G. M.; Ma, Y.; Margarida, L. Org. Lett. 2002, 4, 1751-1754
and references cited therein.
(10) Davies, R. J.; Arnost, M. J.; Bemis, G. W.; Forster, C. J.; Grey, R.,
Jr.; Ledford, B.; Marhefka, C.; Messersmith, D.; Pierce, A. C.; Salituro, F.;
Wang, J. International Patent WO 2005013982, 2005.
(11) (a) Miyamoto, Y.; Yamazaki, C. J. Heterocycl. Chem. 1989, 26,
763–767. (b) Miyamoto, Y.; Yamazaki, C. J. Heterocycl. Chem. 1989, 26,
327–332.
(1) Khadir, A.; Verreault, J.; Averill, D. A. Arch. Biochem. Biophys. 1999,
370, 163–175.
(12) Frenna, V.; Vivona, N.; Consiglio, G.; Spinelli, D.; Mezzina, E.
J. Chem. Soc., Perkin Trans. 2 1993, 7, 1339–1343.
(2) Ventura, L.; PerezGonzales, J. A.; Ramon, D. FEMS Microbiol. Lett.
1997, 149, 207–212.
(3) Clitherow, J. W. European Patent EP 367484, 1989.
(4) Naito, Y.; Akahoshi, F.; Takeda, S.; Okada, T.; Kajii, M.; Nishimura,
H.; Sigiura, M.; Fukaya, C.; Kagitani, Y. J. Med. Chem. 1996, 39, 3019–3029.
(5) Hartmann, M.; Bauer, H.-J.; Wermann, K. Biocide Polym. 1985, 195.
(13) (a) El-Gendy, Z.; Abdel-Rahman, R. M.; Abdel-Malik, M. S. Indian J.
Chem., Sect. B 1989, 28B, 6, 479-485. (b) Abdel-Rahman, R. M.; Ghareib, M.
Indian J. Chem., Sect. B 1987, 26B, 5, 496-500
(14) Brenchley, G.; Charrier, J.-D.; Durrant, S.; Knegtel, R.; Ramaya, S.;
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DOI: 10.1021/jo9016502
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Published on Web 09/04/2009
J. Org. Chem. 2009, 74, 7595–7597 7595
2009 American Chemical Society

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SCHEME 1. Retrosynthesis
TABLE 1. Preparation of 1 from 5
SCHEME 2. Synthesis of 3-Amino-1,2,4-triazole from 3a
b
aReaction condition of the first step. Isolated yield over two steps.
cWithout additive. dWith 2.2 equiv of triethylamine.
SCHEME 3. Synthesis of 3-Amino-1,2,4-triazole from 4a
Reagents and conditions: (a) Na2MoO4 2H2O (0.05 equiv), 30% H2O2
3
(5 equiv), NaCl (0.4 equiv), H2O, 0 °C to rt; (b) R1NHNH2 (1 equiv),
without or with triethylamine (2.2 equiv), CH3CN, rt or 80 °C, 1.5 h;
(c) HC(OMe)3, 140 °C, overnight.
just prior to cyclization. This convergent synthesis facilitates
the study of structure-activity relationships for 1 depending
on the starting material 3 or 4. To illustrate the potential
of this approach, we decided to optimize the chemistry
using commercially available derivatives: 1-phenylthiourea
3a (R2 = Ph and R3 = H) and 1-phenyl-3-thiosemicarbazide
4a (R1 = Ph).
Reagents and conditions: (a) Na2MoO4 2H2O (0.05 equiv), 30% H2O2
3
(5 equiv), NaCl (0.4 equiv), H2O, 0 °C to rt; (b) R2R3NH (1 equiv),
pyridine (2.2 equiv), CH3CN, 120 °C, 30 min; (c) HC(OMe)3, 140 °C,
overnight.
Thiourea 3a was converted to the known sulfonic acid 5
following the reported literature procedure (Scheme 2).16
Oxidation of thiourea 3a with hydrogen peroxide in the
presence of sodium molybdate dehydrate gave 5 in excellent
yield.17 The reaction of 5 with a variety of commercially
available aryl- or alkyl-hydrazines afforded intermediates 2a
which when treated with trimethyl orthoformate provided
the desired 3-aminotriazoles 1.
Our initial reaction of 5 with phenylhydrazine at room
temperature (without base) showed good conversion to the
expected compound 2a (R1 = Ph). Because of the aqueous
solubility of this intermediate the crude reaction mixture was
simply concentrated in vacuo, and taken to the next step.
Heating of this intermediate in trimethyl orthoformate at
140 °C for 14 h produced the 3-aminotriazole 1a in 66%
isolated yield (Table 1, entry 1).
temperature, but proceeded more efficiently at 80 °C. With
tert-butylhydrazine hydrochloride (Table 1, entry 5), the first
step did not occurr even at 80 °C and starting material was
recovered. However, the reaction did progress smoothly in
the presence of an external base. Of the different bases tried
(pyridine, 1,4,6-collidine, diisopropylethylamine, cesium
carbonate, sodium hydroxide, triethylamine, and DBU)
triethylamine proved to give the highest overall yields for
the two steps. Base was required in all reactions starting with
hydrazine hydrochloride salts (Table 1, entries 3, 5, and 6).
Other (free base) aliphatic hydrazines (Table 1, entries 7 and
8) reacted smoothly at room temperature without additive to
give the desired product in good yield. Although the yields
are modest in some cases, the two-step one-pot method
provided rapid access to the desired compounds not readily
available via other synthetic methods.
To investigate substitution of the 3-position of triazole 1,
we envisioned an alternative route featuring 1-phenyl-
3-semithiocarbazide 4a as the starting material in place of
1-phenylthiourea 3a (Scheme 3). The synthesis of sulfonic
acid derivative 6 had not been reported in the literature, but
was readily prepared in 93% yield from 4a following the
same procedure described to synthesize 5.17 The reaction of 6
with a variety of commercially available aryl- or alkylamines
led to intermediates 2b which when treated with trimethyl
The same procedure was then applied to the other hydra-
zines in Table 1. In the cases where R1 is a substituted phenyl
ring (Table 1, entries 2 and 3), the 3-aminotriazoles
were obtained with moderate yields. When the reaction
was performed with 2-hydrazinopyridine (Table 1, entry 4),
the conversion of the first step was very slow at room
(16) Maryanoff, C. A.; Stanzione, R. C.; Plampin, J. N.; Mills, J. E. J.
Org. Chem. 1986, 51, 1882–1884.
(17) While crude 5 or 6 could be used directly, better yields were obtained
if 5 or 6 were purified on silica gel.
7596 J. Org. Chem. Vol. 74, No. 19, 2009

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TABLE 2. Preparation of 1 from 6
In conclusion, we have developed an efficient and con-
vergent method to synthesize differently substituted 3-ami-
no-1,2,4-triazoles 1 from readily available starting materials.
To vary the substitution at the N-1 position, the synthesis
of aniline derived sulfonic acid intermediate 5 is followed
by addition of hydrazine and then cyclization. To vary the
3-amino substitutents, the synthesis of sulfonic acid 6 is
followed by amine addition and then cyclization. The yields
are good for the two-step, one-pot protocol and mild enough
to accommodate a range of functional groups. Our ongoing
efforts toward the synthesis of biologically active com-
pounds containing the 3-aminotriazole motif using this
methodology will be reported elsewhere.
Experimental Section
Representative Experimental Procedure for the Preparation
of Compound 1: General Procedure A. A mixture of 5 (240 mg,
1.2 mmol) and phenylhydrazine (108 mg, 1.0 mmol) in anhy-
drous acetonitrile (1 mL) was stirred at room temperature for
1.5 h. The reaction mixture was then concentrated to a solid,
which was added with trimethyl orthoformate (1 mL) and
heated overnight at 140 °C in a sealed tube. The resulting
mixture was cooled to room temperature, filtered through a
short pad of silica gel, and flushed with 20% MeOH in CH2Cl2.
The filtrate was concentrated and purified by preparative HPLC
to provide the desired product 1a (156 mg, 66%) as a solid.
General Procedure B. A mixture of 6 (100 mg, 0.465 mmol),
aniline (37 μL, 0.406 mmol), and pyridine (72 μL, 0.890 mmol) in
anhydrous acetonitrile (470 μL) was stirred at 120 °C for 30 min
in a sealed tube. The reaction mixture was then concentrated.
The residue was diluted with methyl orthoformate (1.2 mL) and
heated overnight at 140 °C in a sealed tube. The resulting
mixture was partitioned between a saturated solution of NaH-
CO3 (5 mL) and EtOAc (3 ꢀ 20 mL). The combined organic
layers were washed with brine (10 mL), dried over anhydrous
MgSO4, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography to provide the desired pro-
duct 1a (41 mg, 43%) as a solid. 1H NMR (DMSO-d6, 400 MHz)
δ 6.83-6.87 (m, 1H), 7.26-7.30 (m, 2H), 7.33-7.37 (m, 1H),
7.52-7.56 (m, 2H), 7.64-7.66 (m, 2H), 7.84-7.87 (m, 2H), 9.07
(s, 1H), 9.44 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 116.0,
118.1, 119.5, 126.6, 128.7, 129.7, 136.9, 140.8, 141.5, 160.8; MS
(ESI) [M þ H]þ 237.19
aIsolated yield over two steps.
orthoformate afforded the desired 3-aminotriazoles 1.
A study was carried out to optimize the reaction conditions.
Treatment of 6 with aniline at 120 °C for 30 min (without
base) gave a very low conversion to intermediate 2b. The
reaction was then tried in the presence of different bases.
When the reaction was performed with DBU, triethylamine,
sodium hydroxide, or cesium carbonate, we noted that the
formation of byproducts was considerably increased in rela-
tion to the conversion to 2b. However, we found that
conversion to 2b was dramatically improved in the presence
of pyridine. We also tried the reactions in different solvents
(DMF, EtOH, CH3CN) with the cleanest conversions occur-
ring in acetonitrile. The cyclization of intermediates 2b was
performed as before at 140 °C for 14 h to afford the desired
products 1 in good yields for the two steps.
As reported in Table 2, the 3-aminotriazoles 1 were
obtained in all cases in good yields. In examples where the
reaction was performed with aniline derivatives (Table 2,
entries 1 and 2), the yields are slightly lower perhaps reflecting
the reduced reactivity of these nucleophiles toward intermedi-
ate 6. It is noteworthy that the reactions are compatible with
primary and secondary amines as well as anilines. Moreover,
the reactions are compatible with several functional groups
such as olefins, acetals, carbamates, and esters.
Acknowledgment. Professor William R. Roush (The
Scripps Research Institute, Scripps Florida) is gratefully
acknowledged for proofreading the manuscript. The efforts
of P.R.G. and M.J.C. were supported by the National
Institutes of Health (NIH) Molecular Library Screening
Center Network (MLSCN) grant U54MH074404 (Hugh
Rosen, Principal Investigator).
Supporting Information Available: Experimental proce-
dures and analytical data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 19, 2009 7597