High-throughput synthesis of symmetrically 3,5-disubstituted 4-amino-1,2,4-triazoles from aldehydes using microwave

Article abstract of DOI:10.3987/COM-02-9584

Symmetrically 3,5-substituted 4-amino-1,2,4-triazoles are quickly prepared from aromatic aldehydes via nitriles by two-step reactions without any separation under microwave irradiation for each several minutes.

Full text of DOI:10.3987/COM-02-9584

HETEROCYCLES, Vol. 57, No. 11, 2002, pp. 2145 - 2148, Received, 31st July, 2002
HIGH-THROUGHPUT SYNTHESIS OF SYMMETRICALLY
3,5-DISUBSTITUTED 4-AMINO-1,2,4-TRIAZOLES
FROM ALDEHYDES USING MICROWAVE
Hideko Koshima,* Mitsuo Hamada, Makiko Tani, Shunsuke Iwasaki,
and Fumika Sato
Department of Applied Chemistry, Faculty of Engineering, Ehime University,
Matsuyama 790-8577, Japan
Abstract - Symmetrically 3,5-substituted 4-amino-1,2,4-triazoles are quickly
prepared from aromatic aldehydes via nitriles by two-step reactions without any
separation under microwave irradiation for each several minutes.
In rapid synthesis, it is necessary to decrease the reaction time as well as simplify the separation procedures.
Use of microwave heating brings the technical solutions because of dramatic decrease of reaction time.1-3
4-Aminotriazoles are potentially good corrosion inhibitors for metals.4,5 Symmetrically 3,5-disubstituted
4-amino-1,2,4-triazoles (4) are prepared by one-step reaction of aromatic nitriles (2) via dihydrotetrazines
(3) with hydrazine dihydrochloride in the presence of an excess of hydrazine hydrate in ethylene glycol.6
Microwave heating shortens the reaction times from several hours to several minutes.7 Aromatic nitriles (2)
are also quickly prepared by one-step reaction of aldehydes (1) with hydroxylamine hydrochloride in N-
methyl-2-pyrrolidinone (NMP) by microwave heating.8 Many kinds of aldehydes (1) are commercially
available and cheaper than nitriles (2). Hence, if the two microwave-assisted reactions can be successively
combined in a vessel without any separation, more practically useful preparation of 4 from 1 should be
achieved.
MW
H2NNH2•2HCl
H2NNH2•H2O
H
H
MW
NH2OH•HCl
NH2
N
N N
Ar C N
Ar
Ar
Ar CHO
Ar
Ar
HOCH2CH2OH
O
N
N N
N N
1
2
CH3
4
3
In order to optimize the two step reactions, we first examined which kind of solvent should be used for the
transformation of aldehydes (1) to nitriles (2). A mixture of 4-bromobenzaldehyde (1f, 10 mmol) and
hydroxylamine (10 mmol) hydrochloride was submitted to microwave irradiation in several high polar and
high boiling point solvent and ionic solvent (Table 1). The every reaction temperature was measured by
fiber thermometer and regulated to be kept up to around 200 °C by intermittent irradiation. Presence of 5 mL
of NMP and 1,3-dimethyl-2-imidazolidinone gave 4-bromobenzonitrile (2f) in high yields by microwave
irradiation for 3 min (Entries 4 and 5), but ethylene glycol and two ionic solvents in slightly lower yields

(Entries 6-8). In the absence of solvent, the reaction did not proceed even by prolonged irradiation for 45
min because the temperature was not elevated. We selected NMP as the solvent for the first step reaction
from 1 to 2 due to much cheaper than 1,3-dimethyl-2-imidazolidinone. Next, effect of amount of NMP
was examined; presence of 0.5 mL of NMP gave almost constant yields of 91-93% (Entries 1-4). However,
0.5 mL of NMP needed slightly longer irradiation time for 5 min to complete the reaction. Thereafter, 1 mL
of NMP was adopted.
Table 1. Effect of solvents on the transformation of
4-bromobenzaldehyde (1f) to 4-bromobenzonitrile (2f)
Irrad time
(min)
Yield
(%)
Entry
Solvent
(mL)
0.5
1
5
3
3
3
93
91
91
91
1
2
3
4
CH3
N
O
3
5
O
CH3
CH3
90
77
70
5
6
7
5
5
5
3
10
2
N
N
HOCH2CH2OH
CH3
N
+
• Cl–
N
CH2CH3
(n-C4H9)4N+•Br–
5
5
83
8
Table 2 summarizes the results of transformation of various aldehydes (1) to nitriles (2). Substituted
benzaldehydes (1b-g) afforded the corresponding nitriles (2b-g) in high isolated yields of 82-96% by
microwave irradiation for 2-5 min and then filtration of the water slurry of reaction mixtures (Entries 2-7).
Benzonitrile (2a) and 2-thiophenecarbonitrile (2h) were extracted with ethyl acetate because the two nitriles
are liquid at room temperature, giving moderate yields (Entries 1 and 8).
Next, we examined the conditions for the second step reaction of nitriles (2) to 4-amino-1,2,4-triazoles (4).
After the first step reaction of 4-bromobenzaldehyde (1f), hydrazine dihydrochloride (0.75 equiv.) and
hydrazine hydrate (3.0 equiv.) were directly added to the reaction mixture without any separation.
However, transformation from 2f to 3,5-bis(4-bromophenyl)-4-amino-1,2,4-triazole (4f) did not smoothly
proceed by microwave heating because the solution was separated into two layers. Addition of ethylene
glycol (3.0 mL) led to mix the two layers each other into homogeneous solution, and cause complete
transformation to 4f via orange-colored 3,6-bis(4-bromophenyl)-1,2-dihydro-1,2,4,5-tetrazine (3f) by
intermittent irradiation at 160 W for 9 min at around 150 °C. Some water was added to the reaction mixture
and the slurry was filtered off. Recrystallization from ethanol gave 4 f in 67% isolated yield based on initial
1 f (Table 2, Entry 6). Similarly, other aminotriazoles (4) were obtained from the corresponding aldehydes

(1) in moderate yields of 45-63% (Table 2, Entries 1-5, 7 and 8). Dihydrotetrazines (3) did not remained
even in the crude products, easily differentiated from aminotriazoles (4) by 1H NMR spectra. The protons
bound to nitrogens in the molecule 3 appeared at a much lower field (δ, around 9 ppm) than those of 4
(δ, around 6 ppm).
Table 2. Preparation of nitriles and triazoles from aldehydes
Nitrile (2)
Triazole (4)
Entry
Aldehyde
b
Irrad time Yield
Yield
Irrad time
(min)
1
(min)
(%)
(%)
CHO
a
1
2
3
4
a
b
c
d
e
3
65
96
8
10
12
12
45
CHO
3
3
2
5
42
55
58
46
CH3
CHO
CHO
82
83
84
91
CH3O
(CH3)2N
CHO
6
9
5
6
Cl
CHO
CHO
3
67
f
Br
g
7
8
3
3
85
47
8
5
62
63
CH3S
S
a
CHO
h
a
Separated by extraction with ethyl acetate. Others were filtered off.
Isolated yield based on aldehyde.
b
For comparison, after the first step reaction of several aldehydes (1b, 1c, 1e and 1f), the reaction mixture
was once separated by filtration, and then the second step reaction was carried out to afford 4b, 4c, 4e and
4f in 48, 59, 50 and 63% yields, respectively, showing almost comparable yields (42, 55, 46 and 67%) by
successive two-step reactions without any separation (Table 2, Entries 2,3,5, and 6). Finally, conventional
heating was applied to the second step reaction of the nitriles (2b and 2f) separated after the first step
reactions of the aldehydes (1b and 1f). Long reaction times were needed for 7 and 3 hs at 130 °C to
complete the reactions, giving the triazoles (4b and 4 f) in 59 and 72% yields, respectively. In conclusion,
the microwave-assisted two-step synthesis of triazoles (4) from aldehydes (1) dramatically decreases the
reaction times as well as effectuates the separation procedures.
EXPERIMENTAL
1H-NMR spectra were measured on a JEOL JNM-GSX270 spectrometer with tetramethylsilane as an internal

standard. IR spectra were recorded on a JASCO FT/IR-300E spectrophotometer. Melting points were not
corrected. Elemental analysis was carried out with a Yanaco CHN Corder MT-5. All the reagents were
commercially available.
General procedure for preparation by microwave irradiation
A mixture of aromatic aldehyde (10 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol) in N-
methyl-2-pyrrolidinone (NMP, 1.0 mL, 10 mmol) was introduced into a glass test tube and placed in a
domestic microwave oven (2.45 GHz) with a reflux condenser, and irradiated intermittently for 2–5 min (200
W) up to around 200 °C. Without filtration, hydrazine dihydrochloride (0.79 g, 7.5 mmol), hydrazine
monohydrate (1.50 g, 30 mmol), and ethylene glycol (3.0 mL) were added to the reaction mixture, and the
whole was irradiated intermittently for 5-12 min (160 W) at around 160 °C. After cooling, the reaction
mixture was diluted with water (10 mL) and filtered off. The residue was dried and then recrystallized from
ethanol.
3, 5-Bis(4-methylthiophenyl)-4-amino-1,2,4-triazole (4j)
mp 219.8-221.4°C (from EtOH); 1H-NMR (DMSO-d6) δ 7.98 (d, 4H, J = 8.4 Hz), 7.41 (d, 4H, J = 8.4 Hz),
6.26 (s, 2H), 2.54 (s, 6H); IR (KBr) 3352, 3281, 3243 cm–1. Anal. Calcd for C10H8N4S2: C, 58.54; H,
4.88; N, 17.07. Found: C, 58.46; H, 5.06; N, 17.08.
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