A Convenient synthesis of 1,2,3-triazole with glyoxal

Article abstract of DOI:10.1055/s-1998-1678

A new synthetic method of 1,2,3-triazole from glyoxal mono-hydrazone mono-oxime (1a) has been developed. 1a obtained by the thermal disproportionation of glyoxal bis-hydrazone (1b) and glyoxime (1c) was treated with acetic anhydride to give 2-acetyl-1,2,3-triazole, following alcoholysis gave 1,2,3-triazole in high yield.

Full text of DOI:10.1055/s-1998-1678

April 1998
SYNLETT
431
A Convenient Synthesis of 1,2,3-Triazole With Glyoxal
Katsumasa Harada, Mizuho Oda, Akio Matsushita, and Masashi Shirai
Ube Research Laboratory UBE Industries, Ltd., 1978-5 Kogushi, Ube Yamaguchi 755, Japan
Received 9 January 1998
Abstract: A new synthetic method of 1,2,3-triazole from glyoxal mono-
hydrazone mono-oxime (1a) has been developed. 1a obtained by the
thermal disproportionation of glyoxal bis-hydrazone (1b) and glyoxime
(1c) was treated with acetic anhydride to give 2-acetyl-1,2,3-triazole,
following alcoholysis gave 1,2,3-triazole in high yield.
Dichloroacetaldoxime (1e) was prepared according to the method
16
described in the literature
from dichloroacetaldehyde and
hydroxylamine hydrochloride. The reaction of (1e) with hydrazine
hydrate was carried out as follows ; into a solution of excess hydrazine
in methanol, a solution of 1e in methanol was added dropwise at 0 °C
and the reaction mixture was kept at 10 °C for 1 hr. The yield of 1a was
17
around 85 %. As for a much more convenient method, we examined
Although so many kinds of cephalosporin bearing 1,2,3-triazole or its
heterocyclic analogs as a partial structure have been still under active
the reaction of glyoxal with hydroxylamine and hydrazine as shown in
Figure 3.
1
investigation for the search of more active and more safe compounds,
the synthetic method of 1,2,3-triazole has been less studied since 1,2,3-
triazole and also its precursors such as diazo- and azido-derivatives are
2,3
not only thermally unstable but also explosive as reported before.
According to the literature reported, the synthesis of 1,2,3-triazole has
involved the preparation of substituted 1,2,3-triazole and following
Figure 3
desulfurization or decarboxylation of 5- or 4,5-substituted-1,2,3-
4-11
triazoles or reduction of 1-benzyl-1,2,3-triazole.
However, the
This reaction would give a mixture of 1a, 1b, and 1c. In fact, the
reaction of glyoxal with an equimolar mixture of hydrazine and
hydroxylamine initially gave a mixture of 1a, 1b, and 1c in 2:1:1 ratio.
As for ketone derivatives, the reaction results were found to be totally
different from the case of glyoxal, for example, the reaction of 2,3-
butanedione gave mainly α-oximo hydrazone-dimer and the reaction of
benzil gave a mixture of mono-oxime and mono-hydrazone derivatives
by the same reaction conditions. However, unexpectedly, it was found
that the crude mixture of 1a, 1b, and 1c was quantitatively converted to
1a by standing in non-polar solvent or by simply heating in situ at 60
°C. In order to investigate the reaction mechanism for the thermal
disproportionation of 1b and 1c, we tried to make each of 1b and 1c by
explosive property makes every handling troublesome, especially for a
large-scale production of 1,2,3-triazole. Recently we have reported the
synthetic method of 1,2,3-triazole by one-pot reaction of
12
dichloroacetaldehyde tosylhydrazone with ammonia. This reaction
system is both convenient and secure for a large scale production
because dichloroacetaldehyde tosylhydrazone acts as an excellent
precursor of diazo derivatives by treatment with ammonia and
spontaneously cyclizes to 1,2,3-triazole under mild conditions as shown
in Figure 1.
the reaction of glyoxal with hydrazine or hydroxylamine according to
13,14
the method described in the literature.
However, 1c could be
Figure 1
prepared by the reaction of glyoxal with hydroxylamine but 1b could
not be obtained by the reaction of glyoxal with hydrazine in the same
manner described in the literature. The product was unidentified
14
In the course of our investigation for preparation of 1,2,3-triazole we
found another new method starting from glyoxal mono-hydrazone
mono-oxime (1a). The key compound (1a) for the new synthetic method
polymer, indicating the reaction conditions reported were not suitably
applied for the preparation of 1b because the consecutive reaction of 1b
could not be controlled. On the other hand, the reaction of glyoxal with
an equimolar mixture of hydrazine and hydroxylamine gave a mixture
of 1a, 1b, and 1c without unidentified polymeric compounds,
suggesting that 1c once formed may prevent further reaction of 1b.
Polar solvents such as methanol prevent 1b and 1c from the
intermolecular disproportionation.
13
is unknown still now although glyoxal bis-hydrazone (1b) and
14
glyoxime (1c) have been already reported in the literature.
α-Diketones, for example, 2,3-butanedione or benzil could not be
applied for the reaction to make mono-hydrazone mono-oxime
derivatives. These results imply that the stereochemical configuration of
1b and 1c is also effective to the intermolecular disproportionation.
16,18
First of all, we postulated that 1a could be made by the reaction of
glyoxal mono-oxime (1d) with hydrazine hydrate since α-oximo
ketones can be made by the reaction of ketones with nitrosyl chloride.
However glyoxal mono-oxime (1d) could not be prepared by the same
manner and some other attempts on the reaction of vinyl acetate, vinyl
methyl ether, and vinyl chloride with nitrosyl chloride were also
unsuccessful. On the other hand, we found that dichloroacetaldoxime
was an excellent precursor of 1a as shown in Figure 2.
15
According to literature,
triazoles are obtained by cyclization with
loss of water of hydrazone derivatives of α-oximo ketones, for example,
with phosphorus(V) chloride in chloroform or acetic anhydride as
shown below.
Figure 2

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SYNLETT
Therefore, glyoxal mono-hydrazone mono-oxime (1a) was thought to
be a good precursor for the synthesis of 1,2,3-triazole. We examined the
cyclization with loss of water of 1a, with thionyl chloride instead of
phosphorus pentachloride in chloroform or acetic anhydride in some
kinds of solvent. The cyclization with thionyl chloride in the presence of
triethylamine gave 1,2,3-triazole in around 40-45 % of isolated yield by
column chromatography on silica gel. The reaction also gives
cyanoformaldehyde hydrazone (b) as a by-product shown in Figure 4.
derivatives were easily prepared from 1a, 2 under both acidic and basic
conditions as a byproduct.
Isolation of the cyclization product (3b) should be avoided because
decomposition of 3b isolated from the reaction mixture starts at 115.2°C
and also evolution of heat is relatively large observed by differential
scanning calorimeter (DSC), so that 3b needs treating with great care
about isolation but its isolation is avoidable since 3b is easily converted
to TZ by treatment with alcohol. Before treatment of the reaction
mixture with alcohol, the reaction mixture was filtered to remove
glyoxal N,N- diacetyl-bis-hydrazone derived from 1b which was a
contaminant of 2 and the deposited precipitates of sodium carbonate and
sodium acetate at room temperature. Alcoholysis of 3b was carried out
in situ almost quantitatively to give TZ at 55°C for 3 hr. Ethanol was
used as one of the best reagent for alcoholysis.
As a result, we found a new and convenient synthetic method of 1,2,3-
triazole (TZ). However, we found also that the thermal stability of all of
the intermediates in this reaction, 1a, 2, and 3b were thermally unstable
because these compounds decomposed with relatively large evolution of
20
heat observed by differential scanning calorimeter (DSC). Therefore,
Figure 4
synthesis of TZ from glyoxal should be necessary for great care of
handling. The following procedure is found to be the most convenient.
Water is removed by azeotrope with butyl acetate after the reaction of
glyoxal with a mixture of hydrazine hydrate and hydroxylamine
hydrochloride in water at room temperature for 4 hrs. A mixture of 1a,
1b and 1c is soluble in butyl acetate. Precipitated sodium chloride
derived from hydroxylamine hydrochloride was separated by filtration
and then the solution was concentrated to one tenth of the volume. The
deposited precipitates of 1a, 1b and 1c were collected by filtration after
adding toluene. Disproportionation of 1b and 1c including 1a was
conducted in toluene at 50°C for 2 hrs and 60°C for 16 hrs. The
deposited 1a was collected by filtration after cooling at room
temperature. N- Acylation of 1a was conducted with acetic anhydride in
ethyl acetate at the temperature below 30°C for 4 hrs. Solid of 2 was
collected by filtration and 1c was removed as filtrate. O-Acylation and
the following cyclization of 2 were conducted by addition of acetic
anhydride, sodium acetate and sodium carbonate in ethyl acetate at
85°C for 5 hrs. The deposited precipitates of sodium carbonate, sodium
acetate and N,N- bis-acetyl derivative of 1b were removed by filtration.
Alcoholysis of 3b was carried out in situ almost quantitatively to give
TZ at 55 °C for 3 hr. The reaction mixture was concentrated by reduced
pressure. 1,2,3-Triazole (TZ) was isolated by distillation of the residual
oil.
From the mechanistic view point, the production of 1,2,3-triazole (TZ)
from 1a suggests that the reaction proceed via the intermediate (a) as
expected. The intermediate (a) induces the simultaneous cyclization
reaction by addition elimination manner to afford 1,2,3-triazole (TZ).
However, it was found that the chlorine atom as a leaving group was too
reactive to give 1,2,3-triazole mainly since the compound (b) was
unavoidably yielded by elimination manner in the reaction conditions.
The cyclization with acetic anhydride was conducted as shown in Figure
5. In order to cyclized 1a with acetic anhydride to make triazole (TZ),
The selective acylation of the hydroxyl group is necessary but both the
N- and O- acylation should be take place competitively to afford a
complex mixture. Therefore, after several trials we attempted
undergoing the two steps acylation of 1a.
Figure 5
Namely, N- acylation of 1a was carried out with acetic anhydride at
room temperature in ethyl acetate to give glyoxal N-acetylhydrazone
mono-oxime (2) in 93 % yield since this acylation gives us an advantage
to be able to purify 2 after converting the liq. 2 to the crystals from the
reaction mixture. Especially, the removal of the undesired compound 1c
which gives dicyane and hydrogen cyanide is performed in the
Acknowledgements
We gratitude to Mr. Masayuki Asano, Director of Ube Research
Laboratory, UBE Industries Ltd., for his help to perform this work and
also Prof. Naomichi Furukawa at Tsukuba University for his advice.
19
following cyclization reactions.
References and notes
The O-acylation of 2 with acetic anhydride was conducted at 85°C in
ethyl acetate and the following cyclization was achieved by addition of
sodium acetate and sodium carbonate in the reaction mixture. Although
the reaction mixture was still acidic since acetic acid derived from acetic
anhydride was in there, sodium acetate with sodium carbonate was
found to be more effective for the cyclization than sodium acetate only.
From the mechanistic view point, sodium acetate might abstract the
proton on the nitrogen atom of the hydrazone group and the following
cyclization gives 3b by the nucleophilic substitution on the nitrogen
atom of the oxime group. Without sodium carbonate, the yield of
cyanoformaldehyde N- acetylhydrazone which was a by-product was
increased. Those results implied that cyanoformaldehyde hydrazone
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