Synthetic Approach Toward Heterocyclic Hybrids of [1,2,4]Triazolo[3,4- b ][1,3,4]thiadiazines

Article abstract of DOI:10.1055/s-0036-1591991

The synthesis of novel heterocyclic [1,2,4]triazolo[3,4- b ][1,3,4]thiadiazine hybrids by a bimolecular reaction of 2-(4-amino-5-mercapto-4 H -[1,2,4]triazol-3-yl)phenol with an aromatic or heterocyclic α-bromoacetyl derivatives is described. This synthetic procedure starts from an unprotected phenol.

Full text of DOI:10.1055/s-0036-1591991

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
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6
©
Georg Thieme Verlag Stuttgart · New York
2018, 29, A–C
letter
A
en
Synlett
N. Lechani et al.
Letter
Synthetic Approach Toward Heterocyclic Hybrids of [1,2,4]Triazo-
lo[3,4-b][1,3,4]thiadiazines
Nawel Lechania,b
Maamar Hamdi*a
Baya Kheddis-Boutemeura
Oualid Talhi*c,d
Yacine Laichic
Khaldoun Bacharic
S
O
N
SH
Br
N
HO
CO2Me
N
N
O
N
N
OH
N
NH2
O
R
OH
HO
R1
Unprotected
phenol
Artur M. S. Silva*d
0
0
0
0
0-
0
0
3
2-
8
6
1
8-
2
8
6
OH
OH
a
N
Laboratoire de Chimie Organique Appliquée, Faculté de Chimie,
Université des Sciences et de la Technologie Houari Boumediène BP
N
S
N
Heterocyclic hybrids
examples
Yield 50–72%
N
5
R2
N
OH
O
N
32, El-Alia Bab-Ezzouar, 16111 Alger, Algeria
N
O
S
prhamdi@gmail.com
Département de Chimie, Faculté des Sciences, Université Saad
Dahleb, Blida, Algeria
Centre de Recherche Scientifique et Technique en Analyses Physico-
Chimiques, BP 384, Bou-Ismail, 42004 Tipaza, Algeria
QOPNA and Department of Chemistry, University of Aveiro, 3810-
N
b
c
d
193 Aveiro, Portugal
oualid.talhi@ua.pt
artur.silva@ua.pt
3
Received: 10.03.2018
Accepted: 24.03.2018
Published online: 23.04.2018
DOI: 10.1055/s-0036-1591991; Art ID: st-2018-d0157-l
and antioxidant agents. In the past few years, our group
has devoted considerable efforts to exploring the valuable
4
anticancer activities of coumarins and pyran-2-ones.
Syntheses of 3,6-disubstituted [1,2,4]triazolo[3,4-
b][1,3,4]thiadiazine derivatives by condensing 3-(alkyl or
aryl)-4-amino-5-mercapto-1,2,4-triazoles with α-halocar-
bonyl compounds has been reported. In the present work,
we describe a synthetic protocol for constructing the het-
Abstract The synthesis of novel heterocyclic [1,2,4]triazolo[3,4-
b][1,3,4]thiadiazine hybrids by a bimolecular reaction of 2-(4-amino-5-
mercapto-4H-[1,2,4]triazol-3-yl)phenol with an aromatic or heterocy-
clic α-bromoacetyl derivatives is described. This synthetic procedure
starts from an unprotected phenol.
5
erocyclic [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine hybrids
Key words triazolothiadiazines, triazolylphenol, bromomethyl ketones,
polycycles, heterocycles, cyclization
3a–e bearing aryl, dehydroacetic acid (DHA), or coumarin
moieties. The main reaction is a bimolecular condensation
of 2-(4-amino-5-mercapto-4H-[1,2,4]triazol-3-yl)phenol
(1) with aromatic or heterocyclic α-bromoacetyl derivatives
2a–e (Scheme 1).
The structural combination of heterocycles with various
types and numbers of heteroatoms has been intensively
used in molecular engineering to generate a significant di-
versity of fused heterocycles, usually bearing nitrogen ring
junctions. These so-called ‘heterocyclic hybrids’ are de-
signed for specific biological or technological applications.
In this context, the [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine
fused system, which combines nitrogen and sulfur atoms in
a unique scaffold, has proved to be useful in biological and
agricultural areas, such systems being employed as antimi-
crobial, antibacterial, antifungal, herbicidal, or anthelmintic
OH
N
N
N
N
O
AcOH/EtOH
reflux 2 h
SH
N
NH2
Br
N
+
N
R
OH
S
R
1
2a–e
3a–e
OH
OH
R =
1
O
O
HO
O
O
3
H C
O
O
agents. In pharmaceutical applications, these structures
a
b
c
d
e
have been reported to present a broad spectrum of proper-
ties, including antitubercular, diuretic, and hypoglycemic
Scheme 1 Synthetic pathway for the formation of [1,2,4]triazolo[3,4-
b][1,3,4]thiadiazine hybrids 3a–e
2
activities. In the other hand, coumarins and pyran-2-ones
form a class of oxygen-containing heterocyclic compounds
that play key roles in biological and physiological systems.
Synthetic coumarin derivatives constitute one of the most
widely used groups of anti-HIV, antiviral, antiinflammatory,
The key starting compound (4-amino-5-mercapto-4H-
1,2,4-triazol-3-yl)phenol (1) was prepared from 2-hydroxy-
benzohydrazide (5), obtained by the reaction of methyl 2-
hydroxybenzoate (4) with hydrazine hydrate in methanol
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–C

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Synlett
N. Lechani et al.
Letter
(
Scheme 2). Compound 5 was then treated with an equi-
O
H+
O
molar mixture of potassium hydroxide and carbon disulfide
to afford potassium 2-(2-hydroxybenzoyl)hydrazinecarba-
Br
R
N
N
N
OH
N
OH
S
OH
N
R
N
dithionate (6), which gave phenol 1 upon treatment with
SH
H
N
H2N
N
an excess of hydrazine (see Supporting Information).6
H
HO
N
N
NH2
S
R
OH
OH
OH
NH2NH2
KOH
CS2
S K
- +
H
H
OMe
N
N
MW, reflux
NH2
N
S
OH
OH
H
O
O
O
– H2O
– H+
4
5
6
N
N
N
N
H
N
NH2NH2
MW, reflux
H
N
N
N
O
SH
R
S
H
S
N
R
NH2
Scheme 4 Proposed mechanism for the formation of substituted
1,2,4]triazolo[3,4-b][1,3,4]thiadiazines 3a–e
OH
[
1
Scheme 2 Synthesis of (4-amino-5-sulfonyl-4H-1,2,4-triazol-3-yl)phenol 1.
All the new structures 3a–e were characterized by
means of 1D- and 2D-NMR spectroscopy (see Supplemen-
1
In parallel, 3-(bromoacetyl)coumarins 2a and 2b were
prepared from the corresponding salicylaldehydes 7a and
tary Information). As a representative example, the H NMR
spectrum of the hybrid of coumarin with triazolo[3,4-
b][1,3,4]thiadiazine 3b showed four characteristic singlets,
including those of the labile protons 7-OH and 2′′-OH at δ =
11.33 and 10.23 ppm, respectively. The vinylic C=CH group
of the pyran-2-one ring was observed at δ = 8.77 ppm, fol-
7b by Knoevenagel condensation with ethyl acetoacetate
followed by α-bromination of the resulting 3-acetylcouma-
rins 8a and 8b, respectively (Scheme 3; see Supplementary
9
7
Information). A similar strategy was used to prepare the 3-
(bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one
2c
lowed by the methylene group CH of the thiadiazine at δ =
2
and 3-bromoacetophenones 2d and 2e by brominating the
corresponding ketones (see Supplementary Information).7
With the functionalized triazole 1 and the α-bromoace-
tyl synthons 2a–e in hand, we went on to develop the syn-
thesis of a novel series of the aryl-, pyran-2-one-, or couma-
rin-substituted [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine hy-
brids 3a–e (Scheme 1), which incorporate three important
heterocyclic pharmacophores. We propose a mechanistic
pathway based on sequential (consecutive or simultaneous)
thianucleophilic substitution of the α-bromoacetyl moiety
and imine formation (Scheme 4). Experimentally, moder-
ate-to-good yields (50–72%) were obtained, and the pure
5.00 ppm. With help of HSQC spectroscopy, all the proton-
ated carbons could be assigned, particularly the peaks at δ =
43.9 ppm, assigned to the C-7′ methylene carbon, and at δ =
149.9 ppm, assigned to the C-4 vinylic carbon. In 3b, the ten
different quaternary carbons were assigned by examination
of HMBC connectivities (Figure 1). Aromatic carbons C-2′′
(δ = 156.5 ppm) and C-7 (δ = 165.4 ppm) were localized by
means of HMBC correlations with protons 2′′-OH and 7-OH,
respectively. Among the functional carbons, three different
imine C=N groups could be distinguished through the
cross-correlations observed between H-6′′ and C-3′ (δ =
164.9 ppm) and between H-7′ and C-8′a (δ = 163.3 ppm). In
addition, the hybrid junction C-3 (δ = 117.9)–C6′ (δ = 189.9)
was identified by considering the connectivity between H-
4 and C-3 and H-7′, and between H-4 and C-6′, respectively.
The carbonyl carbon of the pyran-2-one was assigned to the
resonance at δ = 159.6 ppm; this was confirmed by HMBC
8
products 2a–e were isolated by filtration. This process is
general and efficient without byproduct formation; the pu-
rity of the resulting compounds 2a–e was verified by HPLC.
O
O
O
O
piperidine
CHO
Br
Br2
EtOH
R
OH
a R = H
OEt
R
O
AcOH
R
O
O
O
8
a,b
7
7
2a,b
b R = OH
OH
O
OH
O
O
AcOH
reflux
R =
H3C
+
Br2
Br
R
CH3
R
O
2c–e
2c
2d
2e
Scheme 3 Synthesis of aryl and pyran-2-one α-bromoacetyl derivatives 2a–e
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–C

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Synlett
N. Lechani et al.
Letter
correlations with H-4 and H-8 of the coumarin ring. Thus,
by in-depth analyses of the HMBC NMR spectra, all struc-
tures of compounds 3a–e were confirmed.
B. Lab. Anim. Res. 2011, 27, 259. (e) Yun, E.-S.; Park, S.-S.; Shin,
H.-C.; Choi, Y.-H.; Kim, W.-J.; Moon, S.-K. Toxicol. In Vitro 2011,
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W.-C.; Wang, S.-Y.; Sung, P.-J.; Kuo, Y.-H. J. Agric. Food Chem.
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O
H
6
"
N
2012, 60, 1673.
H
3'
N 1'
N
(4) (a) Talhi, O.; Schnekenburger, M.; Panning, J.; Pinto, D. G. C. A.;
Fernandes, J. A.; Almeida Paz, F.; Jacob, C.; Diederich, M.; Silva,
A. M. S. Bioorg. Med. Chem. 2014, 22, 3008. (b) Talhi, O.;
Abdeldjebar, H.; Belmiloud, Y.; Hassaine, R.; Taibi, N.; Válega,
M.; Paz, F. A. A.; Brahimi, M.; Bachari, K.; Silva, A. M. S. New
J. Chem. 2017, 41, 10790. (c) Bouhenna, M. M.; Orlikova, B.;
Talhi, O.; Schram, B.; Pinto, D. C. G. A.; Taibi, N.; Bachari, K.;
Diederich, M.; Silva, A. M. S.; Mameri, N. Anticancer Res. 2017,
H
5
H
O
N 5'
8'a
4
a
S
H
3
2
7'
H
H
O
7
8a
O
H
Figure 1 HMBC correlations observed in the spectrum of compound 3a–e
37, 5225. (d) Lee, J.-Y.; Talhi, O.; Jang, D.; Cerella, C.; Gaigneaux,
A.; Kim, K.-W.; Lee, J. W.; Dicato, M.; Bachari, K.; Han, B. W.; Silva,
A. M. S.; Orlikova, B.; Diederich, M. Cancer Lett. 2018, 416, 94.
5) (a) El-Dawy, M. A.; Amohsen, M. E. O.; Ismail, A. M.; Hazaa, A. A.
B. J. Pharm. Sci. 1983, 72, 45. (b) Rao, V. R.; Kumar, V. R.;
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257.
In conclusion, a simple synthesis of heterocyclic and ar-
omatic hybrids of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines is
disclosed. The reported approach provides such advantages
as short reaction times, good yields, and simple workup.
The resulting highly functionalized hybrids contain up to
three types of oxygen-, nitrogen-, and sulfur-based hetero-
cycles.
(
(6) (a) Lakshman, A. B.; Gupta, R. L. Asian J. Chem. 2009, 21, 86.
b) Lechani, N.; Hamdi, M.; Aklil, F.; Khabouche, S.; Benali Bai-
tich, O.; Kheffache, D.; Moussi, S.; Ouamerali, O. Eur. J. Chem.
013, 4, 285.
(
2
Funding Information
(7) (a) Patil, R. D.; Joshi, G.; Adimurthy, S.; Ranu, B. C. Tetrahedron
Lett. 2009, 50, 2529. (b) Hikem-Oukacha, D.; Hamdi, M.; Silva, A.
M. S.; Rachedi, Y. J. Heterocycl. Chem. 2011, 48, 63. (c) Ngoy, B.
P.; Šebej, P.; Šolomek, T.; Lim, B. H.; Pastierik, T.; Park, B. S.;
Givens, R. S.; Heger, D.; Klán, P. Photochem. Photobiol. Sci. 2012,
11, 1465. (d) Benali Baitich, O.; Lechani, N.; Hamdi, M.; Aklil, F.;
Khabouche, S.; Kheffache, D.; Moussi, S.; Ouamerali, O. Eur.
J. Chem. 2013, 4, 285. (e) Ben Mohamed, S.; Rachedi, Y.; Hamdi,
M.; Le Bideau, F.; Dejean, C.; Dumas, F. Eur. J. Org. Chem. 2016,
2016, 2628.
Thanks are due to the University of Aveiro and FCT/MEC for financial
support to the QOPNA research project (FCT UID/QUI/00062/2013), fi-
nanced by national funds and, when appropriate, co-financed by FED-
ER under the PT2020 Partnership Agreement. Thanks are also due to
the Portuguese NMR Network. We would also like to thank FCT/MEC
and the General Directorate for Scientific Research and Technological
Development – DGRSDT of Algeria and the Agence Thématique de Re-
cherche en Sciences et Technologie ATRST for approving the co-fi-
nanced bilateral project PT-DZ/0005.
)(
(8) [1,2,4]Triazolo[3,4-b][1,3,4]thiadiazines 3a–e; General Proce-
dure
Equimolar amounts of the appropriate α-bromoacetyl deriva-
tive 2a–e (1.0 mmol) and triazolylphenol 1 (0.2 g; 1.0 mmol)
were dissolved in absolute EtOH (10 mL) containing a catalytic
amount of AcOH (1 mL), and the mixture was heated for 2 h,
then cooled to r.t. The resulting solid was collected by filtration
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591991.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
and washed with EtOH and Et O to give the pure product.
2
(
9) 7-Hydroxy-3-[3-(2-hydroxyphenyl)-7H-[1,2,4]triazolo[3,4-
References and Notes
b][1,3,4]thiadiazin-6-yl]-2H-chromen-2-one (3b)
C
19H12N O S. Green solid; yield: 0.23 g (60%); mp 239–241 °C.
4 4
(
1) (a) Molina, P.; Alajarin, M.; Pérez de Vega, M. J.; de la Concep-
1
H NMR (400 MHz, DMSO-d ): δ = 5.00 (s, 2 H, H-7′), 6.80 (d,
J = 2.2 Hz, 1 H, H-8), 6.89 (dd, J = 8.6, 2.2 Hz, 1 H, H-6), 6.93–7.01
6
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1
1
7
8
H, H-4′′), 7.71 (dd, J = 7.8, 1.7 Hz, 1 H, H-6′′), 7.85 (d, J = 8.6 Hz,
H, H-5), 8.77 (s, 1 H, H-4), 10.23 (s, 1 H, 2′′-OH), 11.33 (s, 1 H,
(
13
-OH). C NMR (100 MHz, DMSO-d ): δ = 44.0 (C-7′), 102.4 (C-
), 110.0 (C-1′′), 111.4 (C-4a), 115.1 (C-6), 117.7 (C-3′′), 117.9
6
5235. (b) Hester, J. B.; Ludens, J. H.; Emmert, D. E.; West, B. E.
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(C-3), 120.1 (C-5′′), 129.3 (C-6′′), 133.6 and 133.7 (C-4′′ and C-
5
8
), 149.9 (C-4), 156.5 (C-2′′), 158.0 (C-8a), 159.6 (C-2), 163.3 (C-
′a), 164.9 (C-3′, C=N), 165.4 (C-7), 189.9 (C-6′, C=N). HRMS-
(
+
+
ESI : m/z [M + H] calcd for C19H13N O S: 393.0658; found:
4
4
393.0677.
(d) Lee, C.-R.; Shin, E.-J.; Kim, H.-C.; Choi, Y.-S.; Shin, T.; Wie, M.-
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–C