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SYNLETT0936-52141437-2096
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 404–407
letter
Syn lett
404
Letter
G. M. Shelke et al.
Microwave-Assisted Catalyst-Free Synthesis of Substituted
1,2,4-Triazoles
Ganesh M. Shelkea,b
V. Kameswara Raoa
Mukund Jhab
T. Stan Cameronc
a
Department of Chemistry, Birla Institute of Technology and
Science, Pilani, Rajasthan 333 031, India
[email protected]
b
Department of Biology and Chemistry, Nipissing University,
North Bay, ON P1B 8L7, Canada
c
Department of Chemistry, Dalhousie University, Halifax, NS,
B3H 4R2, Canada
Received: 25.10.2014
Accepted after revision: 16.11.2014
Published online: 07.01.2015
DOI: 10.1055/s-0034-1379734; Art ID: st-2014-d0884-l
Abstract A simple, efficient, and mild method has been developed for
the synthesis of substituted 1,2,4-triazoles from hydrazines and formamide under microwave irradiation. The reaction proceeds smoothly in
the absence of a catalyst and shows excellent functional-group tolerance.
Key words microwave, microwave-assisted organic synthesis, 1,2,4triazoles, aryl hydrazine, formamide
Triazoles constitute an important class of heterocyclic
compounds. Among them 1,2,4-triazoles have received a
great deal of attention due to their wide range of biological
N
activities. Compounds derived from 1,2,4-triazoles have
shown anticancer,1 antifungal,2 antibacterial,3 anti-inflammatory,4 and anticonvulsant5 activities. Several compounds
of therapeutic importance such as anastrozole, fluconazole,
rizatriptan, tebuconazole, and voriconazole contain the
1,2,4-triazole moiety (Figure 1).
Not surprisingly, a large number of synthetic methods
has been reported for the preparation of 1,2,4-triazoles,6 including the reaction of imides with alkyl hydrazines (Einhorn–Brunner reaction),7 reaction of amides or thioamides
with hydrazides (Pellizzari reaction),8 reaction of nitriles
and hydrazonoyl chlorides,9 copper triflate catalyzed reaction between two imidates and ammonium carbonate,10
copper(II) acetate mediated reaction of amines and nitriles,11 p-PTSA-catalyzed reaction of amidrazone and 2,2,2-
N
Cl
N
N
N
NMe2
N
N
N
N
OH
N
N
F
OH
N
H
tebuconazole
(fungicide)
F
rizatriptan
fluconazole
(antimigraine)
N
(antifungal)
N
N
N
N
N
CN
OH
F
F
N
N
CN
anastrozole
(anticancer)
F
voriconazole
(antifungal)
Figure 1 Structure of some bioactive 1,2,4-triazoles
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 404–407
N
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Anil Kumar*a
405
Letter
G. M. Shelke et al.
trichloroethyl imidate,12 reaction between N-acylated amide derivative with hydrazine hydrochlorides in pyridine,13
base-catalyzed reaction between nitriles and hydrazides,14
and N-arylation of 1H-1,2,4-triazole.15 However, these
methods frequently require elevated temperatures with
long reaction time and result in low yields, require expensive reagents, or involve multistep processes.
Microwave-assisted organic synthesis provides an alternative to conventional heating and can lead to significant
reduction in reaction time, minimal side reactions, and improved yields.16 Herein, we report an efficient, straightforward, catalyst-free, one-pot synthesis of 1,2,4-triazoles assisted by microwave irradiation (Scheme 1).
O
R
NHNH2
1a–q
N
H
NH2
2
250 psi, 230 W
10 min
Table 1 Optimization of Reaction Conditions
Entry
Formamide (equiv) Temp (°C)
Time (min)
Yield (%)a
1
2.0
140
10
20
2
2.0
140
30
28
3
2.0
160
10
24
N
4
10.0
160
10
52
R
3a–q
5
15.0
160
10
63
6
20.0
160
10
74
7
25.0
160
10
71
20.0
140
10
69
160 °C, MW
+
N′-phenylacetohydrazide (5a) and N′-phenylbenzohydrazide (5b) were obtained in 54% and 61% yields, respectively,
instead of the desired triazoles (Scheme 2). The structure of
product 5 was assigned based on IR and NMR analysis and
comparison with the literature.19 Furthermore, reaction of
1a with N,N-dimethylformamide did not occur and starting
materials were recovered under these conditions.
N
Scheme 1 Microwave-assisted synthesis of 1,2,4-triazoles
8
Optimization of reaction conditions was carried out by
irradiating a mixture of phenylhydrazine (1a) with two
equivalents of formamide (2) under solvent-free conditions
at 140 °C without catalyst (Table 1, entry 1). Under these
conditions 1-phenyl-1H-1,2,4-triazole (3a) was indeed obtained but in only 20% yield. The yield of 3a was not markedly improved by either increasing the reaction time to 30
minutes or increasing the reaction temperature to 160 °C
(Table 1, entries 2 and 3). However, a significant improvement in the yield was observed by increasing the amount of
formamide to ten equivalents and the temperature to 160
°C (Table 1, entry 4). The best yield of 3a was observed on
irradiating 1a with 20 equivalents of formamide at 160 °C
for 10 minutes (Table 1, entry 6). The increase in the yield
with increasing amount of formamide is in agreement with
earlier reports.17
To explore the generality and substrate scope of the
method, various hydrazines were allowed to react with formamide under the optimized reaction conditions. As
shown in Table 2, we were able to obtain diverse 1,2,4-triazoles 3a–q using various substituted hydrazines 1a–q in
moderate to good yields (54–81%). Aryl hydrazines possessing both electron-donating and electron-withdrawing substituents on the aromatic ring reacted smoothly with formamide to give corresponding triazoles (Table 2, entries 1–
15). Similarly, aliphatic hydrazines, such as tert-butylhydrazine and cyclohexylhydrazine, also gave the corresponding
triazoles 3p and 3q, respectively, in good yields (Table 2, entries 16 and 17).
Next, phenylhydrazine was allowed to react with acetamide (4a) and benzamide (4b) under the optimized reaction conditions. In these cases, transamidation18 products
a
Isolated yield of 1-phenyl-1H-1,2,4-triazole (3a).
Table 2 Substrate Scope for the Synthesis of 1,2,4-Triazoles Using
Microwave Irradiationa,20
R
Product
Yield (%)b
1
Ph
3a
74c
–d
2
4-MeOC6H4
3b
76
88–89
3
2-MeC6H4
3c
75
–d
4
3-MeC6H4
3d
78
–d
5
3,4-Me2C6H3
3e
70
51–52
6
4-t-BuC6H4
3f
68
–d
7
3-FC6H4
3g
66
72–74
8
2-ClC6H4
3h
81
69–70
Entry
Mp (°C)
9
3-ClC6H4
3i
78
94–96
10
4-ClC6H4
3j
76
130–132
11
2,4-Cl2C6H3
3k
68
168–170
12
3,4-Cl2C6H3
3l
79
138–140
13
3-Cl-4-MeC6H3
3m
66
128–129
14
4-BrC6H4
3n
77
146–148
15
4-NCC6H4
3o
64
162–164
16
t-Bu
3p
60e
3q
e
17
C6H10
a
54
–d
66–68
Reaction conditions: 1 (1.0 mmol) and 2 (20 mmol), 160 °C, 10 min.
b
Isolated yield after column chromatography.
c
Used the free form of phenylhydrazine.
d
Liquid.
e
Reaction temperature: 180 °C.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 404–407
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Syn lett
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Letter
G. M. Shelke et al.
References and Notes
O
NHNH2 +
160 °C, MW
R
1a
NHNHCOR
NH2
250 psi, 230 W
10 min
4a,b
5a R = Me, 54%
5b R = Ph, 61%
Scheme 2 Reaction of phenyl hydrazine with acetamide and benzamide
Based on the experimental observations and literature
reports, the probable pathway for the reaction is shown in
Scheme 3. It is believed that initially transamidation of
aryl/alkyl hydrazine 1 results in the formation of formohydrazide 6 that, upon condensation with formamide 2, gives
1,2,4-triazole 3. The presence of a peak at m/z = 192.96 corresponding to molecular formula C11H17N2O+ ion in the ESIMS of the reaction mixture of 1f (R = 4-t-BuC6H4) with formamide along with a molecular ion peak at m/z = 201.96
was an indication of the formation of formohydrazide 6 (R =
4-t-BuC6H4) as an intermediate.
R
NHNH2
MW
1
irradiation
+
HCONH2
2
R
O
HCONH2
2
H
MW
irradiation
NHNH
6
N
N
N
R
3
Scheme 3 Probable reaction pathway
In summary, we have developed a simple, efficient, and
mild method for the synthesis of substituted 1,2,4-triazoles
from substituted hydrazines and formamide under microwave irradiation. The reactions proceed smoothly in the absence of a catalyst and have excellent functional-group tolerance. Short reaction times, excellent yields, and catalystfree conditions are salient features of this method. Reaction
of phenyl hydrazine with acetamide and benzamide under
these conditions resulted in the formation of N′-phenylacetohydrazide and N′-phenylbenzohydrazide, respectively.
Acknowledgment
The authors gratefully acknowledge the financial support provided by
DST-FIST (CSI-174/2008) for purchase of a focused microwave and
FTIR and the Natural Sciences and Engineering Research Council of
Canada (NSERC) to conduct this research. G.S. is thankful to CSIR, New
Delhi for a Senior Research Fellowship.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379734. SuponritIgfmanSuponritIgfman
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(20) Experimental Procedure for the Synthesis of 3a
To a dried microwave tube was added phenylhydrazine (108
mg, 1 mmol) and formamide (0.82 mL, 20 mmol). The tube was
sealed with a plastic microwave septum and then placed into
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 404–407
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Syn lett
407
Letter
G. M. Shelke et al.
the microwave cavity and irradiated at 160 °C, 250 psi, and 230
W for 10 min. After completion of reaction (TLC), the mixture
was cooled to r.t.; distilled H2O (10 mL) was added, and the
mixture extracted with EtOAc (3 × 10 mL). The combined
organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by
silica gel column chromatography using a mixture of n-hexane
and EtOAc as eluent.
Spectroscopic Data for Selected Triazoles
1-o-Tolyl-1H-1,2,4-triazole (3c)
Pale yellow liquid. 1H NMR (300 MHz, CDCl3): δ = 8.20 (s, 1 H),
8.05 (s, 1 H), 7.36–7.19 (m, 4 H), 2.16 (s, 3 H). 13C NMR (75 MHz,
CDCl3): δ = 152.17, 143.80, 136.21, 133.90, 131.55, 129.66,
126.87, 126.06, 17.87.
1-(3-Chlorophenyl)-1H-1,2,4-triazole (3i)
White solid; mp 94–96 °C. 1H NMR (300 MHz, CDCl3): δ = 8.57
(s, 1 H), 8.11 (s, 1 H), 7.74 (s, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.45
(t, J = 7.9 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H). 13C NMR (75 MHz,
CDCl3): δ = 152.83, 140.91, 137.87, 135.65, 130.84, 128.26,
120.35, 117.85.
1-(3-Chloro-4-methylphenyl)-1H-1,2,4-triazole (3m)
Off-white solid; mp 128–129 °C. 1H NMR (300 MHz, CDCl3): δ =
8.53 (s, 1 H), 8.09 (s, 1 H), 7.71 (d, J = 2.2 Hz, 1 H), 7.47 (dd, J =
8.2, 2.2 Hz, 1 H), 7.35 (d, J = 8.3 Hz, 1 H), 2.42 (s, 3 H). 13C NMR
(75 MHz, CDCl3): δ = 152.65, 140.79, 136.24, 135.69, 135.41,
131.78, 120.70, 117.95, 19.70.
1-tert-Butyl-1H-1,2,4-triazole (3p)
Brownish liquid. 1H NMR (300 MHz, CDCl3): δ = 8.16 (s, 1 H),
7.94 (s, 1 H), 1.63 (s, 9 H). 13C NMR (75 MHz, CDCl3): δ = 151.36,
139.77, 58.31, 29.41.
1-Cyclohexyl-1H-1,2,4-triazole (3q)
White solid; mp 66–68 °C. 1H NMR (300 MHz, CDCl3): δ = 8.09
(s, 1 H), 7.93 (s, 1 H), 4.24–4.11 (m, 1 H), 2.22–2.15 (m, 2 H),
1.97–1.86 (m, 2 H), 1.83–1.68 (m, 3 H), 1.52–1.19 (m, 3 H). 13C
NMR (75 MHz, CDCl3): δ = 151.34, 140.73, 59.37, 33.02, 25.12,
25.03.
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