Br?nsted acid-catalyzed simple and efficient synthesis of 1,2,4-triazoles and 1,2,4-oxadiazoles using 2,2,2-trichloroethyl imidates in PEG

Article abstract of DOI:10.1016/j.tetlet.2013.10.147

A facile and highly efficient synthesis of 3,4,5-trisubstituted 1,2,4-triazoles and 3,5-disubstituted 1,2,4-oxadiazoles from 2,2,2-trichloroethyl imidates using PEG as a solvent and employing PTSA as the catalyst under mild conditions is described.

Full text of DOI:10.1016/j.tetlet.2013.10.147

Tetrahedron Letters 55 (2014) 177–179
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Brønsted acid-catalyzed simple and efficient synthesis of 1,2,4-
triazoles and 1,2,4-oxadiazoles using 2,2,2-trichloroethyl imidates
in PEG
Mangarao Nakka, Mahaboob Basha Gajula, Ramu Tadikonda, Srinuvasarao Rayavarapu,
⇑
Prasanthi Sarakula, Siddaiah Vidavalur
Department of Organic Chemistry & FDW, Andhra University, Visakhapatnam 530003, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and highly efficient synthesis of 3,4,5-trisubstituted 1,2,4-triazoles and 3,5-disubstituted 1,2,4-
oxadiazoles from 2,2,2-trichloroethyl imidates using PEG as a solvent and employing PTSA as the catalyst
under mild conditions is described.
Received 18 September 2013
Revised 25 October 2013
Accepted 29 October 2013
Available online 6 November 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Polyethylene glycol
1,2,4-Triazole
1,2,4-Oxadiazole
2,2,2-Trichloro ethyl imidate
p-Toluene sulfonic acid
The study of heterocyclic systems such as triazoles and oxadiaz-
oles is known to have considerable development due to their
varied effects in diverse domains. In general, 1,2,4-triazoles and
1,2,4-oxadiazoles have been attracting attention over the last dec-
ade due to their biological activities such as anti-inflammatory,1
antibacterial,2 antitumor,3 and antiviral.4 In the view of greater
medical significance, a number of synthetic routes have been
developed for the synthesis of 3,4,5-trisubstituted 1,2,4-triazoles
and 3,5-disubstituted 1,2,4-oxadiazoles. Generally, synthesis of
these heterocyclic compounds is carried out by a two-step method.
Initially carboxylic acids couple with amidrazones or amidoximes
followed by cyclodehydration in the next step to afford corre-
sponding 1,2,4-triazoles5 or 1,2,4-oxadiazoles,6 respectively. More-
over, these heterocyclic compounds were also synthesized in one
pot directly from corresponding amidrazones and amidoximes
using anhydrides.7 However, these protocols suffered from the
limitation of harsh conditions, tedious synthetic procedures, and
unsatisfactory yields. Therefore, developing a mild and more
general procedure to access 1,2,4-triazoles and 1,2,4-oxadiazoles
is still highly desirable.
selenoamides, and 2-substituted pyrimidine-4-(3H)-ones, and also
conversion of pyrimidine into pyridine. Depending on the nature of
the amine nucleophile, the imidates can react either as the
free-base or the hydrochloride salt. Based on their successful use
as electrophiles, we considered additional applications for these
reagents and recognized that nitrogen could serve as a second leav-
ing group in the form of protonated ammonia under acidic
conditions.
Recently, polyethylene glycol (PEG) is found to be an interesting
eco-friendly solvent system in synthetic organic chemistry9 with
unique properties such as nontoxic, inexpensive, and nonionic
NH2
N
R
NH
R1
N
N
1
R2
R
N
PTSA, PEG, 80 °C
R1
3a-3j
NH
R2
O
CCl3
Imidates8 are easily prepared by reaction of a nitrile and ethanol
in the presence of HCl. These compounds have been used as
reagents for the preparation of s-triazines, diazirines, selenoesters,
OH
N
O
2
N
R3
PTSA, PEG, 80 °C
NH2
R2
4
R3
N
5a-5j
⇑
Corresponding author. Tel.: +91 8912544683; fax: +91 8912544682.
E-mail address: sidduchem@gmail.com (V. Siddaiah).
Scheme 1. Preparation of 3,4,5-trisubstituted 1,2,4-triazoles and 3,5-disubstituted
1,2,4-oxadiazoles.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.147

178
N. Mangarao et al. / Tetrahedron Letters 55 (2014) 177–179
liquid solvent of low volatility. PEG is a biologically acceptable
polymer which has been used extensively in drug delivery and in
bioconjugates as tools for diagnostics.10
was studied by varying the amount of PTSA using PEG as solvent
(Table 1). It was found that 40 mol % of PTSA was sufficient to carry
out this reaction smoothly (Table 1, entry7). The effect of temper-
ature on reaction rate as well as on yields of products was also
investigated. Faster reactions occurred on increasing the tempera-
ture but the product yields were not satisfactory (Table 1, entries 9
and 10). Progress of the reaction was monitored by TLC analysis
(using EtOAc/hexane as eluents).
Further, we screened a variety of solvents, and examined their
effect on reaction times and yields (Table 2). Thus, aprotic solvents
like toluene, dioxane gave no positive effects, whereas protic sol-
vents like isopropyl alcohol (IPA) or polyethylene glycol (PEG) im-
proved the yield and declined the reaction time. However, PEG had
superior solvent effects for this reaction and was therefore used for
all subsequent reactions (Table 2, entries 6–8).
To explore the generality and scope of the method, the opti-
mized reaction conditions (amidrazone (1) (1.7 mmol), 2,2,2-tri-
chloroethyl imidate (2) (1.8 mmol), PEG (5 mL), and PTSA
(40 mol %) at 80 °C) were applied to various structurally diverse
amidrazones and 2,2,2-trichloroethyl imidates (Table 3). From
the results detailed in Table 3, we can discern that this reaction tol-
erates a wide scope of amidrazone derivatives with either electron-
donating or electron-withdrawing substituents on the aryl residue
and 2,2,2-trichloroethyl imidates with aryl or alkyl substituents.
In continuation of our studies11 in developing inexpensive and
environmentally benign methodologies for the synthesis of bioac-
tive molecules, herein, we report a novel and direct synthesis of
3,4,5-trisubstituted 1,2,4-triazoles and 3,5-disubstituted 1,2,4-oxa-
diazoles from 2,2,2-trichloroethyl imidates using PEG as a solvent
and employing PTSA as the catalyst (Scheme 1).
In order to investigate the reaction conditions for the synthesis
of 3,4,5-trisubstituted 1,2,4-triazoles, we have chosen the reaction
of amidrazone, 2,2,2-trichloroethyl imidate in PEG as a model reac-
tion. Thus, amidrazone (1a) (1.7 mmol) was treated with 2,2,2-tri-
chloroethyl imidate (2a) (1.8 mmol) in PEG (5 mL) at 80 °C without
any catalyst. The product was obtained in very low yield after pro-
longed time. Therefore, our efforts were focused on the search for a
suitable catalyst. Initially, acetic acid (20 mol %) was chosen as a
catalyst to carry out this reaction. As a result, long reaction times
with poor yields were observed. Use of trifluoroacetic acid
(20 mol %) as a catalyst gave satisfactory yield (Table 1, entry 2).
Encouraged by these results, we turned our attention to various
Brønsted acids; these were screened in our model reaction (Ta-
ble 1). Finally, we found that PTSA showed high catalytic activity
in terms of reaction time as well as yield of the product. The effect
of amount of catalyst on the conversion and rate of the reaction
Table 3
Synthesis of various 3,4,5-trisubstituted 1,2,4-triazoles from the corresponding
amidrazones and 2,2,2-trichloroethyl imidates12
Table 1
NH2
Effect of various catalysts in the synthesis of 3a
N
N
N
NH
PTSA
R2
NH2
R
N
N
N
R
NH
R1
N
NH
R2
O
CCl3
PEG, 80°C
Catalyst
R1
Ph
3a
Ph
Ph
1a
NH
Ph
N
Ph
Ph
O
CCl3
1
3
2
PEG, t °C
2a
Entry
R
R1
R2
Product
Yielda (%)
1
2
3
4
5
6
7
8
9
10
Ph
Ph
Ph
Ph
Ph
4-MePh
4-OMePh
4-OMePh
4-OMePh
4-ClPh
3a
3b
3c
3d
3e
3f
3g
3h
3i
86
84
86
85
88
86
88
83
81
80
Entry
Catalyst (mol %)
Temp (°C)
Time (min)
Yielda (%)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-BrPh
3-ClPh
3-ClPh
Ph
4-BrPh
4-MePh
4-BrPh
4-ClPh
Ph
1
2
3
4
5
6
7
8
9
10
AA (20)
TFA (20)
BSA (20)
Sulphanilic acid (20)
PTSA (20)
PTSA (30)
PTSA (40)
PTSA (50)
PTSA (40)
80
80
80
80
80
80
80
80
100
120
32
28
25
22
18
11
9
9
7
7
36
56
59
61
86
86
86
86
52
46
Et
Cyclohexyl
3j
a
Isolated yield after column chromatography.
PTSA (40)
AA-acetic acid, TFA-trifluoroacetic acid, BSA-benzene sulfonic acid, PTSA p-toluene
sulfonic acid.
a
Isolated yield after column chromatography.
Table 4
Synthesis of various 3,5-disubstituted 1,2,4-oxadiazoles from the corresponding
amidoximes and 2,2,2-trichloroethyl imidates12
OH
NH
Table 2
N
O
N
PTSA
Effect of various solvents in the synthesis of 3a
R2
R2
O
CCl3
R3
NH2
R3
N
PEG, 80 °C
NH2
N
N
N
NH
4
2
5
PTSA
Ph
3a
Ph
Ph
NH
Ph
N
Ph
Ph
O
CCl3
solvent, 80 °C
Entry
R3
R2
Product
Yielda (%)
1a
2a
1
2
3
4
5
6
7
8
9
10
Ph
Ph
4-Me Ph
Ph
2-Py
2-Py
Ph
Ph
2-Py
Ph
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
92
91
91
89
91
89
92
90
92
89
4-MePh
4-MePh
4-ClPh
Ph
2-Py
Me
Entry
Solvent
Time (min)
Yielda (%)
1
2
3
4
5
6
7
Toluene
1,4-Dioxane
Acetonitrile
IPA
PEG 200
PEG 300
PEG 400
21
22
22
23
9
58
61
60
76
86
86
86
Et
Et
9
9
Cyclohexyl
5j
a
a
Isolated yield after column chromatography.
Isolated yield after column chromatography.

N. Mangarao et al. / Tetrahedron Letters 55 (2014) 177–179
179
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2,2,2-trichloroethyl imidates. This method was found to be quite
general (amidoxime (4) (1.7 mmol), 2,2,2-trichloroethyl imidate
(2) (1.8 mmol), PEG (5 mL), and PTSA (40 mol %) at 80 °C) and
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In conclusion, we have developed a simple, efficient, and eco-
friendly convenient general method for the synthesis of 1,2,4-tria-
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using PEG as a solvent and employing PTSA as the catalyst under
mild conditions. This method provided structurally diverse 1,2,4-
triazoles and 1,2,4-oxadiazoles in excellent yields. 1,2,4-triazoles
and 1,2,4-oxadiazoles derivatives are biologically and pharmaceu-
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The authors thank the Department of Science and Technology
(DST), New Delhi for financial assistance (through a project SR/
FT/CS-052/2008) and UGC, New Delhi for the award of JRF to the
authors N.M. and T.R.
Supplementary data
12. General experimental procedure for the synthesis of 3 and 5: A mixture of 2,2,2-
trichloroethyl imidate (1.8 mmol), amidrazone (1.7 mmol) or amidoxime
(1.7 mmol), PEG-400 (5 mL), and PTSA (1.0 mmol) was heated to 80 °C for
9 min. After completion of the reaction as monitored by TLC, reaction mixture
was cooled to room temperature, aqueous Na2CO3 solution (10 mL) was added
and extracted with ethyl acetate (2 Â 15 mL). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated under reduced pressure
to yield 3 or 5 which was purified by silica gel column chromatography using
EtOAc/hexane (5:5) as eluents.
Supplementary data associated (general experimental proce-
dure and spectral analysis data) with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
10.147.
References and notes
3,4,5-Triphenyl-4H-1,2,4-triazole (3a): Mp: 287–289 °C; 1H NMR (400 MHz,
CDCl3): d = 7.40–7.33 (m, 6H). 7.30–7.19 (m, 7H), 7.06–7.09 (m, 2H); 13C NMR
(100 MHz, CDCl3): d = 154.8, 135.2, 129.9, 129.5, 128.8, 128.8, 128.3, 127.8,
126.9; LCMS: m/z = 298 [M+1]+. Anal. Calcd for C20H15N3: C, 80.78; H, 5.08; N,
14.13. Found: C, 80.72; H, 5.11; N, 14.11.
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CDCl3): d = 7.49–7.56 (m, 6H), 8.18–8.20 (m, 4H); 13C NMR (100 MHz,
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