Recyclization of 1,3,4-oxadiazoles and bis-1,3,4-oxadiazoles into 1,2,4-triazole derivatives. Synthesis of 5-unsubstituted 1,2,4-triazoles

Article abstract of DOI:10.1007/s10593-005-0240-2

Efficient methods have been developed for obtaining precursors of stable carbenes, viz. 5-unsubstituted 3,4-diaryl-1,2,4-triazoles and 3,3′- or 4,4′-bridge linked bis-1,2,4-triazoles, by the recyclization of 5-unsubstituted 1,3,4-oxadiazoles or p-phenylen

Full text of DOI:10.1007/s10593-005-0240-2

Chemistry of Heterocyclic Compounds, Vol. 41, No. 7, 2005
RECYCLIZATION OF 1,3,4-OXADIAZOLES
AND BIS-1,3,4-OXADIAZOLES INTO
1,2,4-TRIAZOLE DERIVATIVES. SYNTHESIS OF
5-UNSUBSTITUTED 1,2,4-TRIAZOLES
N. I. Korotkikh, A. V. Kiselev, A. V. Knishevitsky, G. F. Raenko, T. M. Pekhtereva,
and O. P. Shvaika
Efficient methods have been developed for obtaining precursors of stable carbenes, viz. 5-unsubstituted
3,4-diaryl-1,2,4-triazoles and 3,3'- or 4,4'-bridge linked bis-1,2,4-triazoles, by the recyclization of
5-unsubstituted 1,3,4-oxadiazoles or p-phenylenebis-1,3,4-oxadiazole with anilines or aromatic
diamines in the presence of trifluoroacetic acid or with aniline hydrochlorides in pyridine.
Keywords: 3,4-diaryl-1,2,4-triazoles, precursors of stable carbenes, 1,3,4-oxadiazoles, 3,3'- and
4,4'-bridge linked bis-1,2,4-triazoles, recyclization reaction.
One of the most important methods of obtaining the 1,2,4-triazole system is based on recyclization
reactions of 1,3,4-oxadiazoles under the action of amines and hydrazines [1, 2]. These conversions are used for
obtaining both monotriazoles and polytriazoles [2]. Recyclization in a series of individual aliphatic derivatives,
particularly 2,5-dimethyl-1,3,4-oxadiazole, with amines (taking place at 110°C) has been known for a fairly long
time [3]. Recyclization of aromatic derivatives, such as 2,5-diaryl-1,3,4-oxadiazoles, also gives triazoles, but are
effected under more forcing conditions (150-200°C) [4]. However the latter process, according to our data, is
accompanied by the formation of significant quantities of colored material which hinders the isolation of
individual substances. In [5, 6] the recyclization is described of 2,5-dialkyl-1,3,4-oxadiazoles with hydrazines
leading to derivatives of 4-amino-1,2,4-triazoles. It proceeds well with unsubstituted hydrazine even at room
temperature, with monoalkylhydrazines with significantly more difficulty, on boiling in an excess of reactant,
and leads to a low yield of 4-alkylamino-1,2,4-triazoles.
Among the numerous variants of recyclization, the reaction of 5-unsubstituted oxadiazoles has not been
studied, and might give 5-unsubstituted 1,2,4-triazoles, important precursors in the synthesis of stable carbenes
of the 1,2,4-triazole series (their salts act as precursors). The reaction was not used for the synthesis of
bistriazole systems, including those unsubstituted in positions 3 or 5.
In connection with the development of the chemistry of stable carbenes it seemed of interest to
synthesize 3-unsubstituted triazoles and the triazolium system. A method of obtaining triazolium salts is known,
which consists of the conversion of amides with phosphorus oxychloride into the corresponding imidoyl
chlorides, reaction of the latter with 1-substituted formhydrazides and cyclization of the condensation products
__________________________________________________________________________________________
L.M. Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of
Ukraine, Donetsk 83114; e-mail: korotkikh@infou.donetsk.ua, nkorotkikh@ua.fm. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 7, pp. 1026-1032, July, 2005. Original article submitted August 26, 2003;
revision submitted October 15, 2003.
866
0009-3122/05/4107-0866©2005 Springer Science+Business Media, Inc.

with acetic anhydride [7]. But in this synthesis good yields (58-84%) of the desired salts were achieved in only
three cases, in the others, particularly in the synthesis of bisazolium systems, extremely moderate or low yields
of salts (11-41%) were obtained. Data are not presented in this paper on the possibility of synthesizing neutral
triazoles and conjugated bistriazole systems.
Our problem is the development of a means of recyclizing 1,3,4-oxadiazoles which should be useful for
obtaining triazole precursors of stable carbenes, 5-unsubstituted 1,2,4-triazoles, particularly conjugated
1,2,4-triazoles, and would not lead to the formation of colored material.
To solve this problem initially the effect of acid additives on the yield of triazoles was studied in the
example of the reaction of model compound 2-phenyl-1,3,4-oxadiazole (1a) with aniline 2a.
R1 NH2
N
N
2a–d
N
N
R
R
CF3COOH
O
N
R1
o-dichlorobenzene
1a,b
3a–f
1 а R = H, b R = Br; 3 a-d R =H; e,f R = Br; 2, 3 a R1 = Ph, b R1 = C6H4Br-p,
c R1 = C6H4Me-p; d R1 = α-С10Н7; 3 e R1 = Ph, f R1 = C6H4Br-p
On carrying out the reaction of oxadiazole 1a with some aniline salts 2a (hydrochloride, hydrobromide)
without solvent the process is accompanied by sublimation of the aniline salt, which does not enable a yield of
triazole 3a greater than 30-40% to be achieved. The application of high-boiling aromatic solvents such as
1,2,4-triethylbenzene, without acid components makes an increase in the yield of triazole 3a to 50% possible,
but as in the melt colored material was obtained. Under the same conditions sublimation was also observed with
aniline hydrochloride, as also on carrying out the process in the more polar o-dichlorobenzene (µ 2.50 D). We
note that the use of high boiling aprotic solvents (DMF, N-methylpyrrolidone) leads to the formation of a
significant amount of unidentified byproducts.
In order to prevent sublimation of the reactant in the process of recyclizing compound 1a in aromatic
solvents, in place of aniline hydrohalides we used aniline trifluoroacetate, which was prepared in situ from
aniline and trifluoroacetic acid. Heating the mixture at 190°C in o-dichlorobenzene gives a high yield (95%) of
3,4-diphenyl-1,2,4-triazole (3a). In this reaction the favorable action on the yield and purity of triazole 3a proves
to be both the acid catalyst and the use of o-dichloro-benzene, as a result of probably, the adequate polarity of
the solvent and the azeotropic mode of removing water during the process.
This procedure was used for the synthesis of other derivatives of 3,4-diaryl-1,2,4-triazole 3b-f and also
gave mainly good results (Table 1, 52-77% yields). In the majority of cases significant formation of colored
contaminants did not occur. However in the case of the synthesis of naphthyltriazole 3d the formation of colored
material was observed, probably with the participation of the naphthyl group which is very inclined to
combination reactions, and leads to a reduction in the yield of triazole to 36%.
It was interesting to extend the method to the preparation of 3,3'- and 4,4'-bridge linked bistriazoles,
precursors of triazole biscarbenes. On interacting oxadiazole 1a with p-phenylenediamine hydrochloride in the
presence of 2 equiv. sodium acetate in o-dichlorobenzene 4,4'-p-phenylenebis-1,2,4-triazole 4a was obtained in
56% yield. The analogous procedure with m-phenylenediamine dihydrochloride gave only 24% bistriazole 4b.
Carrying out the same recyclization process with 1a and m-phenylenediamine base in the presence of an
equivalent amount of trifluoroacetic acid in dichlorobenzene increased the yield of bistriazole 4b to 54%.
867

N
N
H2NXNH2 . HCl, NaOAc
N
N
N
X
N
N
O
or H2NXNH2,
N
o-dichlorobenzene
1a
4a,b
4 а Х = p-C6H4; b Х = m-C6H4
To obtain 3,3'-bridge linked bis-1,2,4-triazoles recyclization was carried out of p-phenylenebis-1,3,4-
oxadiazole 5a and tetramethylenebis-1,3,4-oxadiazole 5b with aniline and p-bromoaniline respectively. Reaction
of oxadiazole 5a proceeds extremely smoothly and gives bistriazole 6a in high yield (95%). The yield of
bistriazole 6b was significantly less (27%) from the reaction of the aliphatic derivative 5b. The reason for the
reduction may be side reactions linked with the kinetic lability of alkyl-substituted azoles compared with the
phenyl analogs [8].
N
N
N
N
N
N
N
N
RNH2
X
X
CF3COOH
o-dichlorobenzene
N
R
O
N
R
O
5a,b
6a,b
6 a R = Ph, b R = p-BrC6H4; 5, 6 а Х = p-C6H4, b Х = (CH2)4
In spite of the fact that the method using trifluoroacetic acid is fairly convenient, it is not the only route
to optimization of the conditions for this recyclization. The use of amine hydrochlorides and pyridine, which is
taken in stoichiometric amount or in excess to the amine, also makes possible carrying out this process
efficiently. On boiling a mixture of oxadiazole 1a and aniline hydrochloride 2a in a 3-4-fold excess of pyridine
for 30 min the yield of triazole 3a reaches 57%. Carrying out the reaction in o-dichlorobenzene in the presence
of a stoichiometric amount of pyridine enables the yield of triazole 3a to rise to almost 100 %. This result is
probably caused by the efficient removal under the reaction conditions of water, the presence of which in the
reaction mixture causes hydrolysis of the 2-unsubstituted oxadiazole.
Carrying out the recyclization of oxadiazoles under the action of amines on heating (180-190°C) in high
boiling solvents, in o-dichlorobenzene in particular, under conditions of catalysis with trifluoroacetic acid or the
analogous recyclization with amine salts in the presence of pyridine gives the best yields of 3-unsubstituted
1,2,4-triazoles.
1
In the H NMR spectra of all the compounds investigated (Table 2) signals were detected for the
aromatic CHN protons at 8.3-9.0 and for the benzene ring protons at 7.1-8.4 ppm. It is interesting that the signals
of the CHN protons for bistriazoles 4a,b and 6a were displaced substantially towards low field in relation to the
analogous monotriazole signal in the spectra of compounds 3a-f (by 0.4-0.6 ppm), which probably indicates the
presence of conjugation of the thiazole and phenylene nuclei in the bistriazole molecules, even for the m-
substituted bistriazole 4b (8.83 against 8.93 ppm for the para analog 4a). Almost the same as in the 4,4'-linked
bistriazoles 4a,b, but seemingly more marked, conjugation is observed in the 3,3'-linked compound 6a (8.97
ppm). Confirmation of this conclusion may also be the fact that the effect of the unconjugated triazole nuclei on
the chemical shift of the signals of the CHN group proton in the spectrum of compound 6b is insignificant and
the
signal
is
observed
at
8.17
ppm.
The
latter
is
even
somewhat
displaced
868

TABLE 1. Characteristics of Compounds 3-6
Found, %
Calculated, %
mp, °C
(solvent for
recrystallization)
——————
Com-
pound
Empirical
formula
Yield,
%
Rf
С
Н
Вr
N
3а
3b
3c
3d
3e
3f
С14Н11N3
76.3
76.0
5.0
5.0
—
12.1
12.0
155-157
(2-propanol)
0.75
0.70
0.68
0.62
0.75
0.58
0.41
0.56
0.85
95
60
57
36
52
77
56
54
95
С14Н10ВrN3
С15Н13N3
56.2
56.0
3.2
3.4
26.7
26.6
14.2
14.0
214-216
(DMF)
76.4
76.6
5.8
5.6
—
17.9
17.9
151
(DMF)
160-163
(benzene–hexane, 1:1)
С18Н13N3
79.9
79.7
4.6
4.8
—
15.8
15.5
С14Н10ВrN3
С14Н9Вr2N3
С22Н16N6
56.1
56.0
3.4
3.4
26.8
26.6
14.1
14.0
160-161
(DMF)
44.3
44.4
2.4
2.4
42.0
42.2
11.2
11.1
225-226
(DMF)
332-334
4а
4b
5a
72.8
72.5
4.4
4.4
—
—
—
—
23.2
23.1
(methanol)
С22Н16N6
72.4
72.5
4.5
4.4
23.4
23.1
221-223
(methanol)
С10Н6N4O2
56.0
56.1
2.8
2.8
26.0
26.2
240-241
(o-dichlorobenzene)
6a
6b
C22H16N6
72.6
72.5
47.7
47.8
4.6
4.4
3.5
3.6
23.0
23.1
16.7
16.7
0.65
0.65
95
27
>300 (DMF)
C20H18Br2N6
32.1
31.8
325-326
(DMF)
towards high field in relation to the CHN signal of diaryl-substituted monotriazoles 3a-f (8.3-8.4 ppm), probably
due to the electron-donating action of the alkylene chain in the absence of conjugation of the triazole nuclei with
one another. In the spectrum of bisoxadiazole 5 the signal of the CHN group proton is at substantially lower field
(9.40) than in bistriazoles 4a,f and 6a (8.83-8.97 ppm) which is caused by the higher acceptor action of the
oxygen atoms in the 5a molecule than of the nitrogen atoms in structures 4 and 6.
TABLE 2. 1H NMR Spectra of the Synthesized Compounds 3-6
Com-
pound
Chemical shifts, δ, ppm. (J, Hz)
3а
3b
3c
7.28 (5Н, m, Ar); 7.47 (5H, m, Ar); 8.34 (1H, s, CHN)
7.16 (2H, d, 3J = 8.6, Ar); 7.43 (5H, m, Ar); 7.63 (2H, d, 3J = 8.6, Ar); 8.35 (1H, s, CHN)
2.43 (1H, s, СН3С); 7.11 (2H, d, 3J = 8.6, Ar); 7.30 (5H, m, Ar); 7.47 (2H, d, 3J = 8.6, Ar);
8.31 (1H, s, CHN)
3d
7.20 (3Н, m, Ar); 7.43 (4Н, m, Ar); 7.55 (3Н, m, Ar); 8.02 (2Н, m, Ar);
8.36 (1Н, s, CHN)
3e
3f
7.28 (4Н, m, Ar); 7.48 (5Н, m, Ar); 8.32 (1Н, s, CHN)
7.13 (2Н, d, 3J = 8.6, Ar); 7.31 (2Н, d, 3J = 8.6, Ar); 7.49 (2Н, d, 3J = 8.6, Ar);
7.63 (2Н, d, 3J = 8.6, Ar); 8.31 (1Н, s, CHN)
4а
4b
5a
5b
6а
6b
7.41-7.55 (14H, m, Ar); 8.93 (1H, s, СHN)
7.44 (14Н, m, Ar); 8.83 (1Н, s, СHN)
8.23 (4Н, m, СН arom.); 9.40 (2Н, s, СНО)
2.44 (4H, m, β-CH2), 2.88 (4H, m, α-CH2), 8.80 (c, CHO)
7.50 (14Н, m, СН arom.); 8.97 (2Н, s, СНN)
1.77 (4Н, m, СН2С); 2.69 (4Н, m, СН2С); 7.18 (4Н, d, J = 8.4, CHN);
7.68 (4Н, d, J = 8.4, CHN); 8.17 (2Н, s, СНN)
869

EXPERIMENTAL
The 1H NMR spectra were recorded on a Varian Gemini 200 spectrometer (200 MHz), internal standard
was TMS. The purity of substances was assessed by TLC on Silufol silica gel, eluent was chloroform–methanol,
10:1.
3,4-Diaryl-1,2,4-triazoles 3a-f (General Method Using Trifluoroacetic Acid). A. Trifluoroacetic acid
(10 mmol) and o-dichlorobenzene (1-2 ml) were added to a mixture of 2-aryl-1,3,4-oxadiazole (10 mmol) and
aromatic amine (10 mmol), and the mixture was heated at 190°C for 10 h. The resulting solution was washed
with hexane (20 ml) and the resinous or crystalline substance was treated with a 20% solution of sodium
carbonate (1.59 g, 15 mmol). The solid was filtered off, washed with water, and recrystallized from the
appropriate solvent (Table 1).
3,4-Diphenyl-1,2,4-triazole (3a) (Method Using Aniline Hydrochloride and Pyridine). B. A mixture
of compound 1 (1.46 g, 10 mmol), aniline hydrochloride (1.29 g, 10 mmol), and pyridine (4 ml) was refluxed for
6 h. The excess of pyridine was distilled off, and the residue rubbed with 20% sodium carbonate solution
(10 ml). The solid was filtered off and dried. Yield of crude triazole 3a 2.2 g (100%). There was no depression
of melting point with a sample of compound 3a obtained by method A.
1,4-Bis(3-phenyl-1,2,4-triazol-4-yl)benzene (4a). A mixture of oxadiazole 1a (2.92 g, 20 mmol),
p-phenylenediamine dihydrochloride (1.81 g, 10 mmol), sodium acetate (1.64 g, 20 mmol), and
o-dichlorobenzene (1.5 ml) was refluxed for 3 h 30 min. The reaction mixture was cooled, the solid rubbed with
hexane (20 ml), the solid filtered off, and washed with hexane. A solution of sodium hydroxide (0.8 g, 20 mmol)
in methanol (10 ml) was added to the residue, which was rubbed, the solid filtered off, washed with water to
neutral reaction, and dried. Yield 2.03 g (56%).
1,3-Bis(3-phenyl-1,2,4-triazol-4-yl)benzene (4b). A mixture of oxadiazole 1a (3.47 g, 23.8 mmol),
m-phenylenediamine (1.28 g, 11.9 mmol), trifluoroacetic acid (1.82 ml, 23.8 mmol), and o-dichlorobenzene
(2.5 ml) was refluxed for 4 h 30 min. The reaction mixture was cooled, the solid was rubbed with petroleum
ether (40 ml), then filtered off, washed with petroleum ether, dried, and rubbed with methanol (15 ml) cooled to
-10°C. The solid was filtered off, washed with methanol, and dried. Yield 2.32 g (54%).
Compounds 5a,b were obtained by the general approach described in [9], starting from the appropriate
dihydrazides of dicarboxylic acids and an excess of ethyl orthoformate. Compound 5a, in the pure state, and 5b,
1
as the crude product with a content of the main product of 60-70% (according to data of H NMR spectra,
Table 2), were used to obtain bistriazole 6b without further purification.
1,4-Bis(4-phenyl-1,2,4-triazol-3-yl)benzene (6a). A mixture of compound 5a (5 g, 23.4 mmol), aniline
(4.25 ml, 46.7 mmol), trifluoroacetic acid (3.47 ml, 93.5 mmol), and o-dichlorobenzene (5 ml) was heated at
190°C for 14 h. The reaction mixture was washed with petroleum ether (20 ml), the solvent decanted, and the
crystalline residue rubbed with an aqueous solution of sodium carbonate (5.3 g, 50 mmol). The crystalline
powder of 6a was washed with water to neutral reaction, filtered off, washed with petroleum ether, and dried.
Yield 8.1 g (95%).
1,4-Bis(4-bromophenyl-1,2,4-triazol-3-yl)butane (6b) was obtained analogously to bistriazole 6a,
starting from 70% crude compound 5b (2.86 g, 10.3 mmol) (synthesized by the general method for obtaining
oxadiazoles [9]), 4-bromoaniline (3.55 g, 20.6 mmol), trifluoroacetic acid (1.58 ml, 20.6 mmol), and
o-dichlorobenzene (3 ml). The mixture was heated for 10 h, then rubbed with petroleum ether (2 × 10 ml). The
ether was decanted, toluene (10 ml) and 20% aqueous sodium carbonate solution (10 ml) were added, and the
mixture stirred for 15 min. The solid was filtered off, and washed with petroleum ether. Yield of compound 6b
1.4 g (27%).
The work was carried out with the financial support of the Ministry of Education and Science and the
Ukraine State Fund for Fundamental Investigations (Grant No. 03.07/00215).
870

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