Synthesis of new 4-amino-5-(1,4-benzodioxan-2-yl)-4H-1,2,4-triazole-3-thiol derivatives

Article abstract of DOI:10.1134/S1070428017030198

Acylation and cyclization reactions of 4-amino-5-(1,4-benzodioxan-2-yl)-4H-1,2,4-triazole-3-thiol were studied. Acylation of the title compound with substituted benzoyl chlorides gave the corresponding amides, whereas its reactions with substituted benzoic acids in the presence of POCl3 were accompanied by cyclization with formation of triazolothiadiazoles containing a 1,4-benzodioxane substituent. 4-Amino-5-(1,4-benzodioxan-2-yl)-4H-1,2,4-triazole-3-thiol reacted with substituted benzaldehydes to afford the corresponding Schiff bases, and its alkylation with chloroacetic acid in ethanol in the presence of sodium acetate gave S-ethoxycarbonylmethyl derivative.

Full text of DOI:10.1134/S1070428017030198

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 3, pp. 428–432. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © A.S. Avakyan, S.O. Vartanyan, A.B. Sargsyan, 2017, published in Zhurnal Organicheskoi Khimii, 2017, Vol. 53, No. 3,
pp. 427–431.
Synthesis of New 4-Amino-5-(1,4-benzodioxan-2-yl)-
4H-1,2,4-triazole-3-thiol Derivatives
A. S. Avakyan,* S. O. Vartanyan, and A. B. Sargsyan
Mndzhoyan Institute of Fine Organic Chemistry, Scientific Technological Center of Organic
and Pharmaceutical Chemistry, National Academy of Sciences of Armenia,
pr. Azatutyan 26, Yerevan, 0014 Armenia
*e-mail: avagal@mail.ru
Received November 9, 2016
Abstract—Acylation and cyclization reactions of 4-amino-5-(1,4-benzodioxan-2-yl)-4H-1,2,4-triazole-3-thiol
were studied. Acylation of the title compound with substituted benzoyl chlorides gave the corresponding
amides, whereas its reactions with substituted benzoic acids in the presence of POCl3 were accompanied by
cyclization with formation of triazolothiadiazoles containing a 1,4-benzodioxane substituent. 4-Amino-5-(1,4-
benzodioxan-2-yl)-4H-1,2,4-triazole-3-thiol reacted with substituted benzaldehydes to afford the corresponding
Schiff bases, and its alkylation with chloroacetic acid in ethanol in the presence of sodium acetate gave
S-ethoxycarbonylmethyl derivative.
DOI: 10.1134/S1070428017030198
Both synthetic and naturally occurring 1,4-benzo-
dioxane derivatives attract strong interest as potential
pharmacologically active compounds, in particular
those exhibiting antihepatotoxic, adrenergic blocking,
anti-inflammatory, and other activities [1–3]. Bihetero-
cycles containing both 1,4-benzodioxane and a five-
membered nitrogen, oxygen, or sulfur heterocycle
were found to act as adrenolytics, antioxidants, hypo-
glycemic, antitumor, antihypoxic, and burn treatment
agents, antidotes, and radioprotectors [4–7].
able and promising, and the synthesis and study of
chemical and biological properties of substituted
1,2,4-triazoles constitute an important field of modern
heterocyclic chemistry [8–10]. 1,2,4-Triazole ring is
a structural fragment of many medicines, e.g.,
alprazolam (anxiolytic), ribavirin (antiviral drug),
fluconazole and itraconazole (antifungal agents), and
rizatriptan (5-HT1 receptor agonist used to treat
migraine headaches).
The present work was aimed at studying the
chemical properties of 4-amino-5-(1,4-benzodioxan-2-
yl)-4H-1,2,4-triazole-3-thiol (1) which was synthesized
by us previously [11]. Various transformations of com-
Search for new biologically active compounds in
the series of 1,4-benzodioxane derivatives containing
a trisubstituted 1,2,4-triazole ring seems quite reason-
Scheme 1.
N
N
S
O
O
23°C
N
Ph
NHBz
N
N
N
N
N
SH
S
O
O
O
O
PhCH2Cl
BzCl
4
N
N
Ph
NH2
NH2
N
O
O
S
170°C
1
3
N
N
Ph
5a
428

SYNTHESIS OF NEW 4-AMINO-5-(1,4-BENZODIOXAN-2-YL)-4H-1,2,4-TRIAZOLE-3-THIOL
429
Scheme 2.
N
N
N
N
S
S
O
O
O
O
170°C
N
N
5a
Ph
Ph
–PhCH2Cl, –H2O
NH2
N
O
Cl
H
HO
Ph
Cl
Ph
3
Scheme 3.
ArCOOH, POCl3
N
N
N
N
N
N
SH
Ar
SH
O
O
O
O
S
POCl3
ArCOCl
N
N
HN
N
N
NH2
Ar
O
O
O
1
2a–2c
5a–5e
2, Ar = Ph (a), 4-MeOC6H4 (b), 2,4-(MeO)2C6H3 (c); 5, Ar = Ph (a), 4-ClC6H4 (b), 4-BrC6H4 (c), 4-MeOC6H4 (d), 4-EtOC6H4 (e).
pound 1 afforded new bi- and triheterocyclic 1,4-ben-
zodioxane derivatives which may be promising as bio-
logically active compounds.
ditions at 20–23°C (20–22 h). Raising the temperature
to 170°C led to the formation of triazolothiadiazole
5a which was identified by IR and H NMR spectra.
1
Presumably, the cyclization involved simultaneous
elimination of the benzyl group as shown in Scheme 2.
The presence of amino and thiol functionalities in
the vicinal positions of molecule 1 implies the pos-
sibility of alkylation, acylation, and cyclization. The
alkylation of 1 with various arylalkyl chlorides was
described in [11]. We studied acylation of 1 with sub-
stituted benzoyl chlorides; however, the corresponding
amides were formed in low yields despite variation of
the solvent (acetone, benzene, dioxane, DMF) and
basic reagent (pyridine, triethylamine). We succeeded
in synthesizing target amides 2a–2c in 37–40% yield
by carrying out the reactions in anhydrous dioxane in
the presence of pyridine. In order to exclude the effect
of the SH group on the acylation process, compound 1
was converted to S-benzyl derivative 3 (Scheme 1).
However, the reaction of 3 with benzoyl chloride in
different solvents led to the formation of mixtures of
products which were difficult to separate.
Taking into account published data on antifungal,
antimicrobial, anti-inflammatory, and antitumor activ-
ities of triazolothiadiazoles with various aryl and
hetaryl substituents [12, 13], we synthesized analogous
derivatives containing a 1,4-benzodioxane substituent.
Triheterocyclic compounds 5a–5e were prepared in
high yield by heating amino thiol 1 with substituted
benzoic acids in the presence of phosphoryl chloride
(Scheme 3). Triazolothiadiazoles 5a and 5c were also
synthesized from benzamides 2a and 2c.
Amino thiol 1 was also brought into reactions with
substituted benzaldehydes with a view to obtaining
partially hydrogenated triazolothiadiazoles [14]. How-
ever, instead of the expected cyclization products, we
isolated the corresponding Schiff bases 6a and 6b
(Scheme 4) whose structure was proved by IR and
1H and 13C NMR spectra.
The corresponding amide 4 was isolated only when
the reaction was carried out under solvent-free con-
Scheme 4.
N
N
N
N
N
N
ClCH2COOH
AcONa, EtOH
ArCHO
SH
SH
S
O
O
O
O
O
O
O
N
N
N
N
NH2
NH2
OEt
Ar
6a, 6b
1
7
6, Ar = Ph (a), 3-O2NC6H4 (b).
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AVAKYAN et al.
430
Farghaly et al. [15] described the synthesis of anti-
N-[3-(1,4-Benzodioxan-2-yl)-5-sulfanyl-4H-1,2,4-
triazol-4-yl]-4-methoxybenzamide (2b). Yield 38%,
mp 250–251°C, Rf 0.49. IR spectrum, ν, cm–1: 3238
viral triazolothiadiazinones from substituted 4-amino-
3-sulfanyl-1,2,4-triazoles. We tried to obtain analogous
compounds with a 1,4-benzodioxane fragment by
reaction of 1 with chloroacetic acid in ethanol in the
presence of sodium acetate, but the product was ester 7
(yield 72%).
1
(NH), 1678 (C=O), 1603, 1577 (C=Carom). H NMR
spectrum, δ, ppm: 3.87 s (3H, OCH3), 4.42 d.d (1H,
OCH2, J = 11.7, 6.1 Hz), 4.46 d.d (1H, OCH2, J = 11.7,
2.9 Hz), 5.20 d.d (1H, OCH, J = 6.1, 2.9 Hz), 6.76–
6.85 m (4H, C6H4), 6.97–7.02 m (2H, m-H), 7.98–
8.03 m (2H, o-H), 11.56 s (1H, NH), 13.95 s (1H, SH).
Found, %: C 56.57; H 4.51; N 14.32. C18H16N4O4S.
Calculated, %: C 56.24; H 4.20; N 14.57.
The structure and purity of the isolated compounds
were confirmed by spectral data and TLC. Preliminary
pharmacological screening revealed a weak antibacte-
rial activity of compounds 2b, 4, 5b, and 6b.
N-[3-(1,4-Benzodioxan-2-yl)-5-sulfanyl-4H-1,2,4-
triazol-4-yl]-2,4-dimethoxybenzamide (2c). Yield
37%, mp 241–243°C, Rf 0.35. IR spectrum, ν, cm–1:
EXPERIMENTAL
The IR spectra were recorded on a Nicolet Avatar
330 FT-IR spectrometer from samples dispersed in
1
3246 (NH), 1682 (C=O), 1593 (C=Carom). H NMR
spectrum, δ, ppm: 3.88 s (3H, OCH3), 4.01 s (3H,
OCH3), 4.41 d.d (1H, OCH2, J = 11.6, 6.1 Hz),
4.45 d.d (1H, OCH2, J = 11.6, 2.8 Hz), 5.20 d.d (1H,
OCH, J = 6.1, 2.8 Hz), 6.60–6.64 m (2H, m-H), 6.77–
6.85 m (4H, C6H4), 7.94 d (1H, o-H, J = 9.3 Hz),
10.63 s (1H, NH), 13.89 br.s (1H, SH). 13C NMR spec-
trum, δC, ppm: 55.1 and 55.6 (OMe), 64.0 (CH2), 65.5
(OCH), 98.0 (CH), 105.7 (CH) 111.5, 116.6 (CH),
121.0 (CH), 121.1 (CH), 133.1 (CH), 142.0, 142.4,
147.4, 159.3, 163.4, 164.0, 167.5. Found, %: C 55.39;
H 4.54; N 13.61. C19H18N4O5S. Calculated, %:
C 55.06; H 4.38; N 13.52.
1
mineral oil. The H NMR spectra were recorded on
a Varian Mercury-300 instrument at 300 MHz using
DMSO-d6 as solvent and tetramethylsilane as internal
standard. The melting points were measured on
a Boetius micro hot stage. The progress of reactions
and the purity of products were monitored by TLC on
Silufol UV-254 plates using benzene–acetone (3:1) as
eluent; spots were visualized by treatment with iodine
vapor.
Thiol 1 and amine 3 were synthesized according to
the procedure described in [11].
Compounds 2a–2c (general procedure). A solution
of 4 mmol of substituted benzoyl chloride in 20 mL of
anhydrous dioxane was slowly added with stirring to
a mixture of 1.0 g (4 mmol) of amino thiol 1 and 0.3 g
(4 mmol) of pyridine in 30 mL of anhydrous dioxane,
and the mixture was refluxed for 10–12 h. After
cooling, the mixture was poured into 200 mL of cold
water and left overnight. The precipitate was filtered
off, washed with water, and dried. The product was
treated with 10 mL of ethanol, the undissolved material
was filtered off, the solvent was distilled off from
the filtrate, and the residue was recrystallized from
anhydrous ethanol.
N-[(3-Benzylsulfanyl)-5-(1,4-benzodioxan-2-yl)-
4H-1,2,4-triazol-4-yl]benzamide (4). A mixture of
1.7 g (5 mmol) of amine 3 and 1.05 g (7.5 mmol) of
benzoyl chloride was stirred for 20–22 h at 20–23°C.
The mixture was diluted with 15 mL of anhydrous
diethyl ether, and the precipitate was filtered off, dried,
and recrystallized from ethanol. Yield 62%, mp 182–
183°C, Rf 0.56. IR spectrum, ν, cm–1: 3201 (NH), 1692
1
(C=O), 1597 (C=N), 1548, 1493 (C=Carom). H NMR
spectrum, δ, ppm: 4.40 s (2H, CH2S), 4.50 d.d (1H,
OCH2, J = 11.7, 6.2 Hz), 4.54 d.d (1H, OCH2, J = 11.7,
2.9 Hz), 5.21 d.d (1H, OCH, J = 6.2, 2.9 Hz), 6.75–
6.84 m (4H, C6H4), 7.20–7.61 m (8H) and 8.02 m (2H)
(Harom), 11.92 s (1H, NH). Found, %: C 65.07; H 4.42;
N 12.89. C24H20N4O3S. Calculated, %: C 64.85;
H 4.54; N 12.60.
N-[3-(1,4-Benzodioxan-2-yl)-5-sulfanyl-4H-1,2,4-
triazol-4-yl]benzamide (2a). Yield 40%, mp 275–
277°C, Rf 0.41. IR spectrum, ν, cm–1: 3242 (NH), 1686
1
(C=O), 1593 (C=Carom). H NMR spectrum, δ, ppm:
Triazolothiadiazoles 5a–5e (general procedures).
a. A mixture of 1.0 g (4 mmol) of amino thiol 1,
4 mmol of substituted benzoic acid, and 20 mL of
phosphoryl chloride was refluxed for 5 h. The mixture
was cooled, poured onto 100 g of finely crushed ice,
and made alkaline (pH 8) by adding a solution of
potassium hydroxide. The precipitate was filtered off,
4.44 d.d (1H, OCH2, J = 11.8, 6.0 Hz), 4.48 d.d (1H,
OCH2, J = 11.8, 2.9 Hz), 5.23 d.d (1H, OCH, J = 6.0,
2.9 Hz), 6.76–6.85 m (4H, C6H4), 7.47–7.54 m (2H,
m-H), 7.56–7.62 m (1H, p-H), 8.02–8.06 m (2H, o-H),
11.75 s (1H, NH), 13.97 s (1H, SH). Found, %:
C 57.44; H 4.10; N 15.62. C17H14N4O3S. Calculated,
%: C 57.62; H 3.98; N 15.81.
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SYNTHESIS OF NEW 4-AMINO-5-(1,4-BENZODIOXAN-2-YL)-4H-1,2,4-TRIAZOLE-3-THIOL
431
1
thoroughly washed with water, dried, and recrystal-
lized from ethanol.
1606 (C=N), 1576, 1496 (C=Carom). H NMR spec-
trum, δ, ppm: 3.90 s (3H, OCH3), 4.63–4.76 m (2H,
OCH2), 5.74 d.d (1H, OCH, J = 6.9, 2.7 Hz), 6.81–
6.93 m (4H, C6H4), 7.02–7.08 m and 7.87–7.89 m
(2H each, C6H4OCH3). Found, %: C 59.32; H 3.61;
N 15.45. C18H14N4O3S. Calculated, %: C 59.01;
H 3.85; N 15.29.
b. A mixture of 4 mmol of amide 2a or 2c and
30 mL of phosphoryl chloride was refluxed for 3 h.
Excess phosphoryl chloride was distilled off, the
residue was treated with 100 mL of ice water under
stirring, the mixture was made alkaline by adding
potassium hydroxide, and the precipitate was filtered
off, washed with water, dried, and recrystallized from
ethanol.
3-(1,4-Benzodioxan-2-yl)-6-(4-ethoxyphenyl)-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (5e). Yield
67%, mp 145–147°C, Rf 0.43. IR spectrum, ν, cm–1:
1
1610 (C=N), 1580, 1500 (C=Carom). H NMR spec-
c. A mixture of 1.4 g (4 mmol) of amine 3 and 1.1 g
(8 mmol) of benzoyl chloride was stirred for 30 min at
170°C. The mixture was cooled and diluted with
diethyl ether, and the precipitate was filtered off,
washed with acetone, dried, and recrystallized from
ethanol.
trum, δ, ppm: 1.44 t (3H, CH3, J = 6.9 Hz), 4.14 q (2H,
OCH2CH3, J = 6.9 Hz), 4.68 d.d (1H, OCH2, J = 11.7,
2.9 Hz), 4.72 d.d (1H, OCH2, J = 11.7, 7.1 Hz),
5.74 d.d (1H, OCH, J = 7.1, 2.9 Hz), 6.81–6.93 m
(4H, C6H4), 7.00–7.06 m and 7.82–7.88 m (2H each,
C6H4OEt). Found, %: C 60.33; H 3.96; N 14.85.
C19H16N4O3S. Calculated, %: C 59.99; H 4.24;
N 14.73.
3-(1,4-Benzodioxan-2-yl)-6-phenyl[1,2,4]triazolo-
[3,4-b][1,3,4]thiadiazole (5a). Yield 67% (a), 57% (b),
49% (c); mp 240–241°C, Rf 0.48. IR spectrum, ν, cm–1:
1
4-(Benzylideneamino)-5-(1,4-benzodioxan-2-yl)-
4H-1,2,4-triazole-3-thiol (6a). A mixture of 1.0 g
(4 mmol) of amino thiol 1 and 0.5 g (4.7 mmol) of
freshly distilled benzaldehyde in 15 mL of DMF was
refluxed for 14–15 h. The mixture was cooled and
poured into 100 mL of ice water, and the precipitate
was filtered off, washed with hot benzene, and recrys-
tallized from ethanol. Yield 56%, mp 210–212°C,
Rf 0.51. IR spectrum, ν, cm–1: 1597 (C=N), 1581, 1495
1588 (C=N), 1514, 1490 (C=Carom). H NMR spec-
trum, δ, ppm: 4.69 d.d (1H, OCH2, J = 11.6, 3.2 Hz),
4.73 d.d (1H, OCH2, J = 11.6, 7.2 Hz), 5.77 d.d (1H,
OCH, J = 7.2, 3.2 Hz), 6.83–6.92 m (4H, C6H4), 7.54–
7.65 m (3H) and 7.92–7.96 m (2H) (C6H5). Found, %:
C 61.10; H 3.87; N 16.93. C17H12N4O2S. Calculated,
%: C 60.70; H 3.60; N 16.66.
3-(1,4-Benzodioxan-2-yl)-6-(4-chlorophenyl)-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (5b). Yield
65%, mp 172–173°C, Rf 0.43. IR spectrum, ν, cm–1:
1
(C=Carom). H NMR spectrum, δ, ppm: 4.49 d.d (1H,
OCH2, J = 11.6, 6.7 Hz), 4.56 d.d (1H, OCH2, J = 11.6,
2.7 Hz), 5.57 d.d (1H, OCH, J = 6.7, 2.7 Hz), 6.77–
6.90 m (4H, C6H4), 7.45–7.57 m (3H) and 7.86–7.91 m
(2H) (C6H5), 10.40 s (1H, N=CH), 14.03 br.s (1H, SH).
Found, %: C 60.71; H 4.38; N 16.82. C17H14N4O2S.
Calculated, %: C 60.34; H 4.17; N 16.56.
1
1592 (C=N), 1495 (C=Carom). H NMR spectrum, δ,
ppm: 4.68 d.d (1H, OCH2, J = 11.6, 3.2 Hz), 4.72 d.d
(1H, OCH2, J = 11.6, 7.1 Hz), 5.77 d.d (1H, OCH, J =
7.1, 3.2 Hz), 6.81–6.92 m (4H, C6H4), 7.55–7.60 m
and 7.93–7.98 m (2H each, C6H4Cl). Found, %:
C 55.32; H 3.18; N 15.52. C17H11ClN4O2S. Calculated,
%: C 55.06; H 2.99; N 15.11.
5-(1,4-Benzodioxan-2-yl)-4-[(3-nitrobenzylidene)-
amino]-4H-1,2,4-triazole-3-thiol (6b) was synthe-
sized in a similar way from 3-nitrobenzaldehyde. Yield
54%, mp 243–245°C, Rf 0.48. IR spectrum, ν, cm–1:
3-(1,4-Benzodioxan-2-yl)-6-(4-bromophenyl)-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (5c). Yield
65% (a), 54% (b), mp 205–207°C, Rf 0.34. IR spec-
trum, ν, cm–1: 1595 (C=N), 1571, 1510 (C=Carom).
1H NMR spectrum, δ, ppm: 4.68 d.d (1H, OCH2, J =
11.7, 3.1 Hz), 4.72 d.d (1H, OCH2, J = 11.7, 6.8 Hz),
5.78 d.d (1H, OCH, J = 6.8, 3.1 Hz), 6.82–6.92 m
(4H, C6H4), 7.70–7.76 m and 7.86–7.92 m (2H each,
C6H4Br). Found, %: C 49.43; H 2.77; N 13.88.
C17H11BrN4O2S. Calculated, %: C 49.17; H 2.67;
N 13.49.
1
1637 (C=N), 1582, 1529 (C=Carom). H NMR spec-
trum, ν, ppm: 4.49 d.d (1H, OCH2, J = 11.6, 6.7 Hz),
4.56 d.d (1H, OCH2, J = 11.6, 2.8 Hz), 5.65 d.d (1H,
OCH, J = 6.7, 2.8 Hz), 6.77–6.88 m (4H, C6H4),
7.78 d.d (1H, 5-H, J = 8.2, 7.8 Hz), 8.32 d.d.d (1H, J =
7.8, 1.5, 1.0 Hz) and 8.37 d.d.d (1H, J = 8.2, 2.3,
1.0 Hz) (4-H, 6-H), 8.69 d.d (1H, 2-H, J = 2.3, 1.5 Hz),
10.64 s (1H, N=CH), 14.12 br.s (1H, SH). 13C NMR
spectrum, δC, ppm: 63.9 (OCH2), 65.2 (OCH), 116.7
(2C, CH), 121.1 (CH), 121.2 (CH), 122.7 (CH), 125.8
(CH), 130.0 (CH), 133.8 (CH), 134.0, 142.0, 142.4,
146.0, 148.1, 158.0 (N=CH), 161.2, 162.2. Found, %:
3-(1,4-Benzodioxan-2-yl)-6-(4-methoxyphenyl)-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (5d). Yield
69%, mp 182–183°C, Rf 0.40. IR spectrum, ν, cm–1:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 3 2017

AVAKYAN et al.
432
4. Habibullah, K., Khan, S., Ahsan, M.J., and Ahmed, B.,
C 53.48; H 3.75; N 18.49. C17H13N5O4S. Calculated,
%: C 53.26; H 3.42; N 18.27.
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Ethyl 2-[4-amino-5-(1,4-benzodioxan-2-yl)-4H-
1,2,4-triazol-3-ylsulfanyl]acetate (7). A mixture of
1.0 g (4 mmol) of amino thiol 1, 0.4 g (4 mmol) of
chloroacetic acid, and 0.3 g (4 mmol) of sodium
acetate in 20 mL of anhydrous ethanol was refluxed for
10 h. The mixture was cooled and poured into 100 mL
of cold water, and the precipitate was filtered off,
washed with water, dried, and recrystallized from
ethanol. Yield 72%, mp 90–92°C, Rf 0.57. IR spec-
trum, ν, cm–1: 3346, 3273 (NH2), 1731 (C=O), 1625
1
(C=N), 1591, 1493 (C=Carom). H NMR spectrum, δ,
ppm: 1.29 t (3H, CH3, J = 7.1 Hz), 4.00 s (2H, SCH2),
4.18 q (2H, OCH2CH3, J = 7.1 Hz), 4.48 d.d (1H,
OCH2, J = 11.5, 7.8 Hz), 4.54 d.d (1H, OCH2, J = 11.5,
2.6 Hz), 5.45 d.d (1H, OCH, J = 7.8, 2.6 Hz), 5.95 s
(2H, NH2), 6.78–6.92 m (4H, C6H4). Found, %:
C 50.26; H 4.55; N 16.94. C14H16N4O4S. Calculated,
%: C 49.99; H 4.79; N 16.66.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 3 2017