Regioselective single-reactor synthesis of arylsulfonyl derivatives of 3,5-diamino-1,2,4-triazole

Article abstract of DOI:10.1134/S107042721102011X

Arylsulfonylation of 1-acetyl-3,5-diamino-1,2,4-triazole with arylsulfonyl chlorides in pyridine, with the subsequent hydrolysis of the acetyl group, was studied; a new regioselective method for synthesis of N-(5-amino-1H-1,2,4- triazol-3-yl)arylsulfonami

Full text of DOI:10.1134/S107042721102011X

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2011, Vol. 84, No. 2, pp. 230−235. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © V.M. Chernyshov, G.V. Kozlenko, V.A. Taranushich, 2011, published in Zhurnal Prikladnoi Khimii, 2011, Vol. 84, No. 2, pp. 234−239.
ORGANIC SYNTHESIS
AND INDUSTRIAL ORGANIC CHEMISTRY
Regioselective Single-Reactor Synthesis
of Arylsulfonyl Derivatives of 3,5-Diamino-1,2,4-triazole
V. M. Chernyshov, G. V. Kozlenko, and V. A. Taranushich
South-Russian State Technical University (Novocherkassk Polytechnic Institute), Novocherkassk,
Rostov-on-Don oblast, Russia
Received March 23, 2010
Abstract—Arylsulfonylation of 1-acetyl-3,5-diamino-1,2,4-triazole with arylsulfonyl chlorides in pyridine, with
the subsequent hydrolysis of the acetyl group, was studied; a new regioselective method for synthesis of N-(5-
amino-1H-1,2,4-triazol-3-yl)arylsulfonamides was developed.
DOI: 10.1134/S107042721102011X
Arylsulfonyl derivatives of 3,5-diamino-1,2,4-
triazole of general formula I are key starting
substances in syntheses of effective herbicides:
N-([1,2,4]triazolo[1,5-a]pyrimidin-2-yl)- and ([1,2,4]
triazolo[1,5-a][1,3,5]triazin-2-yl)arylsulfonamides [1–
5]. Some representatives of this group of compounds
exhibit anti-HIV and antitumor activity [6]. Methods for
synthesis of compounds I, described until now, include
construction of an aminotriazole fragment bonded to
the arylsulfamide group by reactions of condensation
of N-(arylsulfonyl)-N’-cyanoimidothiocarbamates with
derivatives of hydrazine [1, 2, 4, 5] or S,S-dimethyl-N-
(arylsulfonyl)carbodithioimidates with aminoguanidine
hydrocarbonates [3]. The main disadvantages of these
methods are the high cost of starting substances and
poor yield of target products [4].
A promising method for synthesis of compounds
might become arylsulfonylation of 3,5-diamino-1,2,4-
triazole (DAT). However, the high nucleophilicity of the
endocyclic nitrogen, compared with the exocyclic amino
group, results in that this reaction yields 1-arylsulfonyl-
3,5-diamino-1,2,4-triazoles II, rather than compound I
[7] (Scheme 1).
The goal of our study was to develop a method for
synthesis of compound I from the available 3,5-diamino-
1,2,4-triazole derivatives.
According to published data [8, 9], 1-substituted
3,5-diamino-1,2,4-triazoles are selectively sulfonylated
by arylsulfonyl chlorides at the amino group in position 3
Scheme 1.
230

REGIOSELECTIVE SINGLE-REACTOR SYNTHESIS
231
under heating in acetone in the presence of pyridine. This
suggests that sulfonylation of 3,5-diamino-1,2,4-triazole
having a protective group in position 1 of the triazole
ring upon removal of the protective group will yield
compound I. A suitable compound for arylsulfonylation,
which has an easily removable protective group, might
several minutes. Then the content of compound VI in
the reaction products gradually decreases, so that N-(5-
{[(4-methylphenyl)sulfonyl]amino}-1H-1,2,4-triazol-
3-yl)acetamide (VI) and N-(5-amino-1H-1,2,4-triazol-
3-yl)-4-methylbenzene sulfonamide (VII) become the
main components in 2 h. Thus, the protective acetyl
group precludes endocyclic sulfonylation and the
reaction involves an amino group in position 3 (amino
group in position 5 has a reduced nucleophilicity [8–
10] and, therefore, is not sulfonylated). Compound V
is gradually rearranged into a thermodynamically more
stable isomer VI similarly to other 1-acyl-5-amino-
1,2,4-triazoles [11–13]. Compound VII is presumably
formed via hydrolysis of compound V because of
atmospheric moisture finding its way into the reaction
mixture (Scheme 3).
become
1-acetyl-3,5-diamino-1,2,4-triazole
(III).
Compound III can be easily obtained by single-reactor
synthesis from accessible starting substances: hydrazine
hydrate, N-cyanoguanidine [dicyandiamide (IV)], and
acetic anhydride in accordance with Scheme 2.
Adetailed analysis of the process of arylsulfonylation
of compound III was made for the example of the
reaction with 4-methylbenzenesulfonyl chloride (TsCl).
Attempts to perform arylsulfonylation in acetonitrile–
pyridine mixtures failed because of the poor solubility
of compound III. However, the interaction of compound
III and TsCl in pure boiling pyridine led to fast
dissolution of compound III to give arylsulfonylation
products. An analysis of unpurified reaction products
The structure of compounds V–VII was confirmed
by spectroscopic data and elemental analysis. The
direction of the sulfonylation reaction at the amino
group in position 3 is confirmed by the chemical shift of
protons of the free amino group (7.57 ppm) in compound
V, which is typical of 1-acyl-5-amino-1,2,4-triazoles
(7.2–8.3 ppm in DMSO-d6) [7, 11–13].
1
by H NMR spectroscopy demonstrated that their
composition depends on the synthesis duration (see the
table). First, N-(5-amino-1-acetyl-1H-1,2,4-triazol-3-
yl)-4-methylbenzene sulfonamide (V) is formed during
An alkaline hydrolysis of both the acetyl derivative
Scheme 2.
Scheme 3.
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CHERNYSHOV et al.
Composition of products formed in arylsulfonylation
of 1-acetyl-3,5-diamino-1,2,4-triazole (III) with
4-methylbenzenesulfonyl chloride in pyridine
in the yield, and making it longer, to a poorer purity of
the target product because an admixture of a difficultly
hydrolyzable compound VI is formed.
Using TsCl and arylsulfonyl chlorides VIII–XI,
we obtained arylsulfonyl derivatives VII and XII–
XV in 53–82% yield. We could not obtain ortho- and
para-nitrobenzenesulfonyl derivatives by this method
because strong tarring of the reaction mixture occurred
in sulfonylation and individual substances could not be
eventually recovered from the mixture.
Composition of products, mol %
Synthesis
duration, min
III
V
VI
VII
1
3
27
73
0
0
0
0
0
0
0
0
100
96
66
52
14
0
4
6
0
Thus, we developed a selective single-reactor method
for synthesis of arylsulfonyl derivatives of 3,5-diamino-
1,2,4-triazole. The applicability of the method is limited
to arylsulfonyl chlorides containing no substituents
capable of chemical transformation under synthesis
conditions.
20
40
120
26
33
63
8
15
23
V and acetamide VI leads to the desired product VII
at however, different rates. Compound V is very easily
hydrolyzed when boiled in an aqueous solution of NaOH
for about 5 min at a V : NaOH molar ratio of 1 : 2, with
a nearly quantitative yield of compound VII. However,
hydrolysis of acetamide VI requires a pronounced
excess of the alkali and heating for about 8 h. Therefore,
compound V is a more suitable starting compound for
synthesis of compound VII, than acetamide VI. It was
found that compound V can be conveniently converted
to compound VII without preliminary isolation from the
reaction mixture after sulfonylation of compound III,
i.e., in a single-reactor synthesis (Scheme 4).
EXPERIMENTAL
1H NMR spectra were recorded with a VARIAN
UNITY-300 spectrometer (300 MHz for 1H and 75 MHz
for 13C, solvent DMSO-d6, internal standardTMS). Mass
spectra were obtained with a Finnigan MAT Incos 50
instrument with direct introduction of a sample into the
ionic emission source with an ionization energy of 70 eV.
The elemental analysis was made with a Perkin–Elmer
2400 analyzer. The melting points were determined in
sealed capillaries in a PTP instrument.
1-Acetyl-3,5-diamino-1,2,4-triazole
(III).
To
25 g (0.5 mol) of hydrazine hydrate we added under
vigorous agitation and cooling 121.7 g (1.0 mol) of 30%
hydrochloric acid, making sure that the temperature of
the reaction mixture was not higher than 50°C. Then we
However, to provide a high yield and purity of the
target product, the duration of the first stage of synthesis,
sulfonylation of acetyl derivatives III, must be 3–5 min.
Making the synthesis duration shorter leads to a decrease
Scheme 4.
Ar = 4-MeC6H4 (TsCl) (VII); Ph (VIII), (XII); 4-ClC6H4 (IX), (XIII); 4-MeOC6H4 (X), (XIV); naphthyl-2 (XI), (XV).
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REGIOSELECTIVE SINGLE-REACTOR SYNTHESIS
233
added 42 g (0.5 mol) of N-cyanoguanidine (IV) to the
resulting solution under agitation at a temperature of 40–
50°C in the course of 30 min. The reaction mixture was
kept at 45–50°C for 1 h, and then 100 ml of a 5 M KOH
solution was added dropwise. The resulting mixture
was cooled to 10°C and 63.8 g (0.625 mol) of acetic
anhydride was poured in under vigorous agitation in the
course of 15–25 min, with the temperature maintained
within the range 10–20°C. The mixture was additionally
agitated for 30 min at a temperature of 10°C, and the
resulting precipitate was filtered off, washed with
100 ml of cold water, and dried at 50°C. We obtained
49.4 g (70%) of compound III sufficiently pure for
further syntheses. If necessary, compound III can be
purified by recrystallization from water. The properties
of the product obtained are identical to those described
in [14].
(Irel, %): 295 (9) [M+], 253 (48), 189 (13), 155 (12), 99
(10), 98 (94), 91 (67), 43 (100). Found (%): S 44.51,
N 4.42, N 23.92. C11H13N5O3S. Calculated (%): S 44.74,
N 4.44, N 23.71; M 295.32.
N-(5-{[(4-Methylphenyl)sulfonyl]amino}-1H-
1,2,4-triazol-3-yl)acetamide (VI). A mixture of 1.41 g
(10 mmol) of thoroughly ground compound III, 5 ml
of pyridine, and 1.71 g (9 mmol) of TsCl was boiled
with a reflux under agitation for 2 h and then was
cooled to 20°C and diluted with 15 ml of ethanol. The
resulting precipitate was filtered off, washed with 30 ml
of ethanol, twice recrystallized from DMFA, and dried
in a vacuum at 120°C. We obtained 1.1 g (40%) of
a white crystalline substance, mp 292–293°C. 1H NMR
spectrum, δ, ppm: 2.02 s (3H, CH3), 2.34 s (3H, CH3),
7.34 d (2Harom, J = 8.0 Hz), 7.73 d (2Harom, J = 8.0 Hz),
10.83 s (1H, NH), 11.47 s (1H, NH), 12.87 s (1H, NH).
13C NMR spectrum, δ, ppm: 20.9, 22.7, 125.6, 126.8,
129.3, 137.7, 143.0, 147.6, 168.9. Mass-spectrum, m/z
(Irel, %): 295 (5) [M+], 253 (21), 231 (18), 189 (24),
155 (11), 99 (6), 98 (24), 91 (63), 43 (100). Found (%):
S 44.68, H 4.43, N 23.56. C11H13N5O3S. Calculated
(%): S 44.74, N 4.44, N 23.71; M 295.32.
The effect of the synthesis duration on the yield of
compounds V–VII was studied as follows. A solution of
1.71 g (9 mmol) of TsCl in 5 ml of pyridine was heated to
115°C under vigorous agitation, then 1.41 g (10 mmol)
of thoroughly ground compound III was added, and
time reckoning was started. In the process, the mixture
warmed up to boiling. The reaction mixture was boiled
with a reflux for a required time (see the table) and then
was cooled to 20°C and diluted with 15 ml of cold water.
The resulting precipitate was filtered off, washed with
30 ml of cold water, and dried in a vacuum at 50°C. The
content of compounds V–VII in the products obtained
was determined using 1H NMR spectroscopy.
Synthesis of N-(5-amino-1H-1,2,4-triazol-3-yl-
4-methylbenzenesulfonamide (VII) by hydrolysis of
compounds V and VI. a. A mixture of 1.0 g (3.39 mmol)
of a thoroughly ground compound V, 5 ml of water, and
0.27 g (6.77 mmol) of NaOH was boiled with a reflux
for 5 min and then was neutralized with glacial acetic
acid and cooled to 20°C. The resulting precipitate of
compound VII was filtered off, washed with water, and
dried at 120°C. Yield 0.84 g (98%), light yellow crystals,
mp 314–315°C with decomposition (mp 314–315°C
N-(5-Amino-1-acetyl-1H-1,2,4-triazol-3yl)-4-
methylbenzenesulfonamide (V). A solution of 1.71 g
(9 mmol) of TsCl in 5 ml of pyridine was heated to 115°C
under vigorous agitation and then 1.41 g (10 mmol)
of thoroughly ground compound III was added. The
resulting mixture was boiled with a reflux for 3 min,
cooled to 20°C, and 15 ml of cold water was poured
in. The resulting precipitate was filtered off and washed
successively with 30 ml of water and 20 ml of ethanol.
We obtained 1.7 g (64%) of unpurified compound V,
with the content of the main substance of 95% and more
(according to 1H NMR data). The product was purified
by heating its suspension in ethanol to boiling (3 × 6 ml),
to give 1.22 g (46%) of a white crystalline substance,
1
[3]). H NMR spectrum, δ, ppm: 2.38 s (3H, CH3),
5.82 br.s (2H, NH2), 7.23 d (2Harom, J = 8.1 Hz), 7.67 d
(2Harom, J = 8.1 Hz), 11.27 br.s (1H, NH), 11.64 br.s
(1H, NH). Mass-spectrum, m/z (Irel, %): 253 (24) [M+],
189 (10), 155 (12), 99 (13), 98 (79), 92 (23), 91 (100),
89 (10), 77 (12). Found (%): C 42.63, H 4.40, N 27.68.
C9H11N5O2S. Calculated (%): C 42.68, H 4.38, N 27.65;
M 253.28.
b. A mixture of 0.5 g (1.69 mmol) of a thoroughly
ground compound VI, 3 ml of water, and 0.54 g
(13.5 mmol) of NaOH was boiled with a reflux for 8 h and
then was neutralized with glacial acetic acid and cooled
to 20°C. The resulting precipitate of compound VII
was filtered off, washed with water, and dried at 120°C.
Yield 0.26 g (61%); the properties of the compound
are identical to those of the product synthesized by the
1
mp 290–293°C. H NMR spectrum, δ, ppm: 2.36 s
(6H, 2CH3), 7.37 d (2Harom, J = 8.2 Hz), 7.57 br.s (2H,
NH2), 7.81 d (2Harom, J = 8.2 Hz), 11.24 br.s (1H, NH).
13C NMR spectrum, δ, ppm: 20.9, 22.8, 127.4, 129.2,
137.1, 143.3, 154.2, 156.2, 170.5. Mass-spectrum, m/z
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234
CHERNYSHOV et al.
procedure described above.
108 (29), 107 (82), 99 (31), 98 (82), 92 (58), 78 (14), 77
(82), 43 (100). Found (%): C 40.19, H 4.16, N 25.89.
C9H11N5O3S. Calculated (%): C 40.14, H 4.12, N 26.01;
M 269.28.
General procedure for single-reactor synthesis of
N-(5-amino-1H-1,2,4-triazol-3-yl)arylsulfonamides
VII and XII–XV. A solution of 90 mmol of the
corresponding arylsulfonyl chloride (TsCl, VIII–XI)
in 50 ml of pyridine was heated to 110–115°C under
vigorous agitation and 14.1 g (100 mmol) of thoroughly
ground compound III was added. The mixture was
boiled with a reflux under agitation for 3 min and then
150 ml of a 2M NaOH solution was poured in and the
mixture was boiled for additional 5–8 min. The resulting
solution was neutralized with glacial acetic acid and
cooled to 20°C. The precipitate formed was filtered off,
recrystallized from DMFA, and dried in a vacuum at
120°C. Compounds VII and XII–XV were obtained.
N-(5-Amino-1H-1,2,4-triazol-3-yl)naphthalene-
2-sulfonamide (XV). Yield 23.72 g (82%), yellowish
crystals, mp 305–308°C with decomposition (mp 308–
1
309°C [2]), H NMR spectrum, δ, ppm: 5.85 br.s (2H,
NH2), 7.59–7.66 m (2Harom), 7.80 m (1Harom), 7.97–
8.07 m (3Harom), 8.42 s (1Harom), 11.55 br.s (1H, NH),
11.88 br.s (1H, NH). Mass-spectrum, m/z (Irel, %): 289
(9) [M+], 225 (15), 127 (100), 99 (15), 98 (33). Found
(%): C 49.55, H 3.75, N 24.16. C12H11N5O2S. Calculated
(%): C 49.82, H 3.83, N 24.21; M 289.31.
CONCLUSIONS
N-(5-Amino-1H-1,2,4-triazol-3-yl)-4-methyl-
benzenesulfonamide (VII). Yield 15.23 g (60%), the
properties of the compound are identical to those of the
product obtained by hydrolysis of compound V.
(1) Introduction of an acetyl group into position
1 of the triazole ring can serve as a way to protect
endocyclic nitrogen atoms and amino groups in position
5 of 5-amino-1,2,4-triazoles in reactions involving
arylsulfonyl chlorides.
N-(5-Amino-1H-1,2,4-triazol-3-yl)benzene-
sulfonamide (XII). Yield 14.62 g (61%), white crystals,
mp 293–294°C with decomposition (mp 293–294°C
1
(2) Sulfonylation of 1-acetyl-3,5-diamino-1,2,4-
triazole with arylsulfonyl chlorides in pyridine, followed
by hydrolysis of the acetyl group, enables regioselective
[3]). H NMR spectrum, δ, ppm: 5.83 br.s (2H, NH2),
7.40–7.45 m (3Harom), 7.77–7.80 m (2Harom), 11.29 br.s
(1H, NH), 11.70 br.s (1H, NH). Mass-spectrum, m/z
(Irel, %): 239 (34) [M+], 99 (11), 98 (100), 78 (18), 77
(82). Found (%): C 40.18, H 3.81, N 29.18.
synthesis
arylsulfonamides.
of
N-(5-amino-1H-1,2,4-triazol-3-yl)
C8H9N5O2S. Calculated (%): C 40.16, H 3.79,
N 29.27; M 239.25.
ACKNOWLEDGMENTS
N-(5-Amino-1H-1,2,4-triazol-3-yl)-4-chloro-
benzenesulfonamide (XIII). Yield 14.50 g (53%), light
yellow crystals, mp 305–306°C with decomposition
The study was financially supported by the RF
Federal Agency for Education in the framework of
the Federal Target Program “Scientific and scientific-
pedagogical personnel of the innovative Russia,” State
Contract P302, project NK-109P/2.
1
(mp 299°C [2]). H NMR spectrum, δ, ppm: 5.86 br.s
(2H, NH2), 7.57 d (2Harom, J = 8.5 Hz), 7.78 d (2Harom
,
J = 8.5 Hz), 11.58 br.s (1H, NH), 11.94 br.s (1H, NH).
Mass-spectrum, m/z (Irel, %): 273 (22) [M+], 209 (12),
113 (18), 112 (16), 111 (60), 99 (23), 98 (100), 91
(12), 75 (39). Found (%): C 35.18, H 3.01, N 25.47.
C8H8ClN5O2S. Calculated (%): C 35.11, H 2.95,
N 25.59; M 273.70.
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