Synthesis of 1-acyl- and 1-arylsulfonyl derivatives of 3,5-diamino-1,2,4- triazole

Article abstract of DOI:10.1007/s11167-005-0390-0

Acylation of 3,5-diamino-1,2,4-triazole with anhydrides and chlorides of alkane- and arenecarboxylic acids and arenesulfonyl chlorides in aqueous solutions and under phase-transfer catalysis was studied.

Full text of DOI:10.1007/s11167-005-0390-0

Russian Journal of Applied Chemistry, Vol. 78, No. 5, 2005, pp. 776 780. Translated from Zhurnal Prikladnoi Khimii, Vol. 78, No. 5,
2005, pp. 790 795.
Original Russian Text Copyright
2005 by Chernyshev, Gaidukova, Zemlyakov, Taranushich.
ORGANIC SYNTHESIS
AND INDUSTRIAL ORGANIC CHEMISTRY
Synthesis of 1-Acyl- and 1-Arylsulfonyl Derivatives
of 3,5-Diamino-1,2,4-triazole
V. M. Chernyshev, G. V. Gaidukova, N. D. Zemlyakov, and V. A. Taranushich
South Russian State Technical University, Novocherkassk, Rostov oblast, Russia
Received August 20, 2004; in final form, February 2005
Abstract Acylation of 3,5-diamino-1,2,4-triazole with anhydrides and chlorides of alkane- and arenecarbox-
ylic acids and arenesulfonyl chlorides in aqueous solutions and under phase-transfer catalysis was studied.
Acyl, aroyl, and arenesulfonyl derivatives of 3,5-
diamino-1,2,4-triazoles are used as intermediates
for preparing nitro and azido derivatives of 1,2,4-tri-
azoles [1 3], and also drugs and herbicides [4 7]. The
most general route to acyl derivatives of 3,5-diamino-
1,2,4-triazole is acylation of 3,5-diamino-1,2,4-tria-
zole I, which can yield mono-, di-, and triacetyl deriv-
atives depending on the reaction conditions [1, 4, 8
10]. However, triazole I is expensive, despite the fact
that it is prepared from available substances: dicyano-
diamide II and hydrazine [11]. The high cost of I is
due to its difficult isolation from reaction mixtures.
Our previous studies [12, 13] showed that some deriv-
atives of I can be prepared from dicyanodiamide and
hydrazine without isolation of I.
tion gave hydrochloride of I in 92 97% yield (deter-
mined according to [14]), with NH Cl as by-product.
4
Initially we studied acylation of the reaction mix-
tures with acetic anhydride, since 1-acetyl-3,5-diami-
no-1,2,4-triazole III is widely used as a reagent for
preparing various 1,2,4-triazole derivatives, and,
among the existing routes to III, the most convenient
is acylation of I with acetic anhydride in aqueous
solution [1].
Since triazole I occurs in the reaction mixture in
the protonated form (pH 2 3), which does not react
with acylating agents, the mixture should be prelimi-
narily alkalized to convert the salt of I into the free
base. However, for the acylation to be selective, am-
monia should remain in the salt form. According to
+
+
published data, for the equilibrium I H
I + H
In this study we developed a procedure for prepar-
ing 1-acyl-, 1-aroyl-, and 1-arenesulfonyl-3,5-diami-
no-1,2,4-triazoles by acylation of products of the reac-
tion of nitrile II with hydrazine without isolation of I:
+
+
pK = 4.43 [15], and for NH
NH + H , pK =
a
4
3 a
9.27 [16]. Hence, pH 6.4 7.3 is an optimum at which
+
the salt I H is virtually fully deprotonated but am-
monia remains in the salt form. As bases in acylation
with acetic anhydride, we used NaOH, Na CO ,
N
N
N
H2 N
2
3
H2N
.
N
HCl
NaHCO , and sodium acetate.
3
+ 2HCl
H2 N
+ N2 H4
N
NH2
At the equimolar ratio of I and base (pH 4.6 8.4),
the major product of the reaction with acetic anhy-
dride is III; its yield is virtually independent of par-
ticular base. Other acyl derivatives of I were not
detected in the reaction mixtures. With sodium carbo-
nate, hydrocarbonate, or acetate taken in excess, the
reaction selectivity and yield of III remain unchanged.
With excess NaOH (pH > 10), the yield of III de-
creases to 10 15%, because of the hydrolysis of am-
monium chloride and competing reaction of the more
nucleophilic ammonia with acetic anhydride:
NH2
II
I
N
R,
(1)
N
RX
+ NH4Cl
N
Base
NH2
III X
where R = Ac (III), EtCO (IV), PrCO (V), BuCO
(VI), PhCO (VII), PhSO (VIII), p-MeC H SO
2
2
6
4
(IX), p-ClC H SO (X).
6
4
2
The reaction mixtures for acylation were prepared
by a modified procedure from [11] involving the reac-
tion of II with hydrazine hydrate and HCl. This reac-
Ac O
2
NH4Cl + NaOH
NH3 + NaCl
AcNH2 + AcOH.
(2)
1070-4272/05/7805-0776 2005 Pleiades Publishing, Inc.

SYNTHESIS OF 1-ACYL- AND 1-ARYLSULFONYL DERIVATIVES
777
Free ammonia can also cause ammonolysis of the
target product:
Table 1. Yield of III at 20 C and pH 4.6 8.4
Molar ratio
Molar ratio
Yield, %
Yield, %
I : Ac2O
I : Ac2O
III + NH3
I + AcNH2.
(3)
1 : 1.0
1 : 1.1
1 : 1.25
62
71
78
1 : 1.5
1 : 1.75
1 : 2.0
80
80
75
As the molar ratio I : Ac O is changed from 1 : 1
to 1 : (1.25 1.5), the yield of III increases from 62 71
2
to 78 80% (Table 1); larger excess of Ac O does not
2
cause a further increase in the yield of III.
Table 2. Yield of III at the molar ratio I: Na2CO3 : Ac2O =
1: 1: 1.25
It is noteworthy that heating does not appreciably
affect the selectivity of acylation with acetic anhydride
and the yield of the target product (Table 2). In con-
trast to the majority of N-acyl azole derivatives, com-
pound III shows enhanced resistance to hydrolysis,
which may be due to the electron-donor effect of the
3,5-amino groups.
T,
C
Yield, %
T,
50
70
90
C
Yield, %
0
79
78
77
77
72
68
30
40
Thus, it is advisable to perform acylation with ace-
tic anhydride at the molar ratio I : base : Ac O =
2
Apparently, the rate of formation of VII is compar-
able with the rate of its subsequent acylation with
benzoyl chloride into XI. We failed to prepare VII
selectively even at a twofold excess of I relative to
benzoyl chloride. This may be due to the fact that
benzoyl chloride and compound I occur in different
phases. Benzoyl chloride is poorly soluble in water,
whereas triazole I is very well soluble; therefore,
compound VII is mainly formed at the phase bound-
ary. After being formed, compound VII dissolves in
benzoyl chloride and undergoes further acylation.
1 : (1 1.2) : 1.25. As in the range 0 50 C the acyla-
tion selectivity varies insignificantly, all the steps can
be performed at the same temperature as one-pot syn-
thesis. The use of NaOH is not appropriate, because
excess NaOH can cause hydrolysis of NH Cl and
4
decrease the reaction selectivity because of competing
ammonolysis of the acylating agent.
Compounds IV VII were prepared under similar
conditions using appropriate anhydrides (Table 3).
Compound VII is isolated from the reaction mixture
together with benzoic acid. Benzoic acid can be readi-
ly removed by recrystallization from ethanol; yield of
purified compound VII 35 40%.
The reaction with benzenesulfonyl chloride under
the same conditions yielded compound VIII but was
very slow; the yield of the target product did not
exceed 35% in 72 h. Crystalline p-toluenesulfonyl
chloride and p-chlorobenzenesulfonyl chloride under
the same conditions gave IX and X; their yield in
3 days did not exceed 10%, and the major isolated
compounds were unchanged arenesulfonyl chlorides.
With carboxylic acid chlorides and arenesulfonyl
chlorides as acylating agents, it is necessary to intro-
duce an additional amount of a base to bind the re-
leased HCl. Acylation with aliphatic acyl chlorides
resulted only in their hydrolysis. Acylation with ben-
zoyl chloride, which is more resistant to hydrolysis, at
20 C in the presence of sodium acetate gave a mixture
of products consisting, according to liquid chromatog-
raphy, of 14% VII, 42% 5-amino-3-benzamido-1-ben-
zoyl-1,2,4-triazole XI, and 44% benzoic acid. Com-
pound XI is apparently formed by acylation of VII:
We suggested that the selectivity of acylation with
carboxylic acid chlorides and arenesulfonyl chlorides
could be increased by converting triazole I into the
anion and performing the reaction with phase-transfer
catalysis. The anion should be considerably more
nucleophilic and reactive as compared to the neutral
O
N
molecule. For equilibrium (5), pK = 12.12 in water
a
H2 N
N
at 20 C [17]. Hence, at pH > 14.12, compound I in
Ph
water occurs in the anionic form:
N
NH2
VII
N
N
H2 N
H2 N
O
H+ .
+
NH
N
Ph
(5)
O
N
N
PhCOCl
AcONa
N
HN
.
NH2
NH2
(4)
N
Ph
To provide the required basicity, no less than 3 mol
of NaOH per mole of II should be added to the reac-
N
NH2
XI
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 78 No. 5 2005

778
CHERNYSHEV et al.
Table 3. Synthesis conditions, yields, and properties of acylation products III XII (molar ratio I : acylating agent = 1: 1)
Found, %
Yield, %
(synthesis
proce-
Molar
ratio
I : base
Com-
pound
T,
C
,
h
Acylating agent Base
mp,1
C
Formula
Calculated, %
dure)
C
H
N
34.00 5.07 49.59
34.04 5.00 49.62
III
IV
V
AcCl
NaOH 1 : 1.22
5
0.5
1.0
28 (b) 228 (dec.)3
C4H7N5O
C5H9N5O
C6H11N5O
38.75 5.83 45.18
38.65 5.85 45.34
(EtCO)2O
NaOAc 1 : 1.25 20
75 (a)
166 167
112 113
42.80 6.52 41.41
42.60 6.55 41.39
(PrCO)2O
PrCOCl
NaOAc 1 : 1.25 20
1.0
0.5
70 (a)
29 (b)
NaOH 1 : 1.22
5
45.93 7.20 38.25
45.89 7.15 38.22
VI
(BuCO)2O
NaOAc 1 : 1.25 20
1.0
75 (a)
123 124
154 156
C7H13N5O
C9H9N5O
53.26 4.39 34.50
53.32 4.46 34.40
VII
(PhCO)2O
NaOAc 1 : 1.25 45
NaOAc 1 : 2.25 20
1.0
47 (a)4
PhCOCl
PhCOCl
PhCOCl
2.0
0.5
0.5
8 (a)4
58 (b)
52 (b)
NaOH 1 : 1.02
NaOH 1 : 1.22
5
5
40.84 3.80 29.20
40.16 3.79 29.27
VIII
IX
X
PhSO2Cl
PhSO2Cl
NaOAc 1 : 2.25 20
NaOH 1 : 1.22
72
35 (a)
70 (b)
222 2245
216 217
213 215
C8H9N5O2S
C9H11N5O2S
C8H8ClN5O2S
C16H13lN5O2
C9H9N5O
5
0.5
43.00 4.38 27.20
42.68 4.38 27.65
p-MeC6H4SO2Cl NaOAc 1 : 2.25 20
p-MeC6H4SO2Cl NaOH 1 : 1.22
72
10 (a)
60 (b)
5
0.5
35.21 2.89 25.66
35.11 2.95 25.59
p-ClC6H4SO2Cl NaOAc 1 : 2.25 20
p-ClC6H4SO2Cl NaOH 1 : 1.22
72
9 (a)
5
0.5
50 (b)
65.66 4.18 23.00
62.53 4.26 22.79
XI
PhCOCl
PhCOCl
NaOAc 1 : 2.25 20
72
41 (a)4 198 (dec.)
15 (b)4
NaOH 1 : 1.02
5
5
0.5
46.00 7.24 37.60
45.89 7.15 38.22
XII
PhCOCl
NaOH 1 : 1.22
0.5
12 (b)
310 312
1
2
Compounds III VII and XI were crystallized from ethanol; VIII X and XII, from ethanol DMF. Additional 2 mol of NaOH was
3
4
5
introduced per mole of II.
mp 228 230 C [9].
According to liquid chromatography.
mp 225 C [18].
tion mixture [see scheme (1)]. Since NH Cl is fully
hydrolysis of XI:
4
hydrolyzed under these conditions, the released am-
monia was removed by boiling the reaction mixture.
The subsequent acylation with acetyl and butyryl
chlorides in a CH Cl water mixture in the presence
of benzyltriethylammonium chloride yielded only
1-acyl derivatives III and V, and the reaction with
benzoyl chloride, along with the major product VII,
yielded also XI or 5-amino-3-benzamido-1,2,4-triazole
XII depending on the molar ratio I : NaOH (Table 3,
method b). Compound XII is apparently formed by
O
Ph
O
Ph
O
N
N
OH
H O
N
N
N
H
NH .
NH2
2
2
H
2
Ph
N
N
NH2
XII
XI
(6)
In particular, at an equimolar ratio of triazole I
to NaOH, compound XI was isolated in 15% yield
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SYNTHESIS OF 1-ACYL- AND 1-ARYLSULFONYL DERIVATIVES
779
(Table 3), and compound XII was not detected. At
a 20% excess of alkali, compound XI was absent in
the reaction products, and compound XII was isolated
from the aqueous phase in 12% yield. Hence, com-
pound VII formed under the conditions of phase-
transfer catalysis is subsequently slowly acylated to
dibenzoyl derivative XI, which is hydrolyzed to prod-
uct XII with excess alkali. Probably, the hydrolysis of
XI is promoted by an acidic proton of the benzoyl-
amino group, responsible for the dissociation of XI in
an alkali solution with the dissolution of XI in the
aqueous phase and its subsequent hydrolysis.
tons, a signal at 7.32 7.55 ppm for acyl derivatives
III VII and at 6.90 6.97 ppm for arenesulfonyl
derivatives VIII X. The spectrum of XI does not
contain the 3-NH signal but contains a singlet of
2
the amide proton at 10.67 ppm; the 5-NH signal is
2
shifted downfield relative to VII owing to the elec-
tron-withdrawing effect of the additional benzoyl
group. According to the NMR spectrum, compound
XII in DMSO occurs in the form of tautomers A
(major) and B:
O
O
Ph
Ph
H
N
N
N
H
N
H
The low yields of the acetyl (III) and butyryl (V)
derivatives and the lack of acylamino derivatives in
the reaction products may be due to the high rate of
hydrolysis of aliphatic acyl chlorides.
H
N
N
.
N
N
NH2
NH2
B
A
Acylation of I under the phase-transfer conditions
is also an efficient route to 1-arenesulfonyl-3,5-diami-
no-1,2,4-triazoles. Under these conditions, from ap-
propriate arenesulfonyl chlorides, we prepared com-
pounds VIII X in 50 70% yields (Table 3). The
main substance content in the crude products was no
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian
Unity-300 spectrometer (300 MHz) in DMSO-d ,
6
internal reference TMS. The IR spectra were recorded
on a Specord IR-75 spectrometer from mulls in miner-
al oil. The UV spectra (aqueous solutions) were taken
on an SF-26 spectrophotometer. High-performance
liquid chromatography was performed on a Milikhrom
chromatograph equipped with a UV detector and
a 60 3-mm column (sorbent Silasorb C , 5 m,
mobile phase methanol, elution rate 5 l min , detec-
tion at 230 nm).
1
less than 90% according to the H NMR data.
The composition and structure of the compounds
synthesized were confirmed by elemental analysis
1
(Table 3) and by IR, UV, and H NMR spectroscopy.
18
In the IR spectra of acyl derivatives III VII and
XI, the stretching vibration bands of the carbonyl
group bonded to the nitrogen atom of the triazole ring
1
1
1-Acyl- and 1-arenesulfonyl-3,5-diamino-1,2,4-
triazoles III X and 5-amino-3-benzamido-1-benzo-
yl-1,2,4-triazole XI. (a) To 0.0333 mol of hydrazine
hydrate (55% solution), we added dropwise with stir-
ring at a temperature not exceeding 50 C 0.0666 mol
of HCl (30% solution) and 0.0333 mol of II over a
period of 10 15 min; the mixture was heated for 1 h
at 50 C. Then the required amount of a base was
added, and the acylating agent was added dropwise
with stirring at the required temperature (Tables 1 3).
The mixture was stirred for a period indicated in
Table 3; the precipitate was filtered off, washed with
are manifested at 1680 1710 cm , whereas the vibra-
tion frequencies of the amide carbonyl group in
1
XI and XII are lower: 1650 1660 cm . The spectra
of arenesulfonyl chlorides VIII X contain a strong
1
absorption band at 1150 1160 cm , which was as-
signed to the symmetric vibrations of the SO group.
2
The UV spectra of III VII are similar to the spec-
tra of 5-amino-1-acyl-1,2,4-triazoles reported in [9]
and exhibit two maxima at 217 230 and 273 290 nm.
The spectra of 1-arenesulfonyl-3,5-diamino-1,2,4-tri-
azoles VIII X are also characterized by two maxima
in the ranges 220 234 and 261 269 mn. The UV
spectrum of 5-amino-3-benzamido-1,2,4-triazole XII
differs from that of isomeric 1-benzoyl-3,5-diamino-
1,2,4-triazole VII by the absence of the long-wave
maximum at about 290 nm and the presence of a
shoulder at about 253 nm; this is consistent with the
data for 3-R-5-acylamino-1,2,4-triazoles [9].
1
water, dried, and analyzed by H NMR and HPLC.
1
The precipitates of III VI, according to H NMR,
contained no less than 90% main substance, and com-
pound VII, according to HPLC, contained 50% ben-
zoic acid. Compounds III VII were purified by re-
crystallization from ethanol. To separate mixtures
from acylation with benzoyl chloride, the precipitate
was dissolved in 60 ml of boiling ethanol, and the
solution was cooled. The precipitate of XI was filtered
off, recrystallized, and analyzed. The mother liquor
after the separation of XI was evaporated to a volume
The NMR spectra of 1-acyl- and 1-arenesulfonyl-
3,5-diamino-1,2,4-triazoles III X contain two singlets
from protons of amino groups. The 3-NH protons
2
give a signal at 5.36 5.65 ppm, and the 5-NH pro-
2
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 78 No. 5 2005

780
CHERNYSHEV et al.
of 15 ml and cooled; the precipitate of VII was re-
crystallized and analyzed. Compounds VIII X were
washed with chloroform to separate unchanged arene-
sulfonyl chloride, recrystallized, and analyzed.
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3
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2
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prepared by method b at the molar ratio I : NaOH =
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