2-Bromo-1-(1H-pyrazol-4-yl)ethanone: Versatile precursors for novel mono-, bis- and poly{6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines}

Article abstract of DOI:10.1016/j.tet.2015.12.024

A simple synthesis of novel mono-, bis- and poly{6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines} is reported. The formation of the target compounds was achieved by the reaction of 2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone with the appropriate aminotriazolethiol or by the reaction of 6-pyrazolyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-3-thiol with the appropriate di- and poly(bromo) compounds. The structures of the newly synthesized compounds were established by spectroscopy and elemental analyses.

Full text of DOI:10.1016/j.tet.2015.12.024

Tetrahedron xxx (2015) 1e8
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
2
-Bromo-1-(1H-pyrazol-4-yl)ethanone: versatile precursors for
novel mono-, bis- and poly{6-(1H-pyrazol-4-yl)-[1,2,4]triazolo
3,4-b][1,3,4]thiadiazines}
[
Mostafa E. Salem, Ahmed F. Darweesh, Ahmad M. Farag, Ahmed H. M. Elwahy *
Chemistry Department, Faculty of Science, Cairo University, Giza, 12613, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple synthesis of novel mono-, bis- and poly{6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thia-
Received 30 October 2015
Received in revised form 25 November 2015
Accepted 10 December 2015
Available online xxx
diazines} is reported. The formation of the target compounds was achieved by the reaction of 2-bromo-
1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone with the appropriate aminotriazolethiol or by the
reaction of 6-pyrazolyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-3-thiol with the appropriate di- and
poly(bromo) compounds. The structures of the newly synthesized compounds were established by
spectroscopy and elemental analyses.
Keywords:
Cyclocondensation
Alkylation
Ó 2015 Elsevier Ltd. All rights reserved.
Triazolothiadiazine
Pyrazole
1
. Introduction
anticancer25e28 and as antimicrobial agents.29 Along with these
activities, some bis-heterocyclic derivatives also exhibited potent
antialzheimer and antiprion activity.
3
0
Pyrazole derivatives are an important class of heterocyclic
compound for being key substructures in a variety of compounds
with important biological properties. They are known to possess
a wide spectrum of activities such as antimicrobial,
flammatory,
In addition, bis-heterocyclic compounds separated by a carbon
chain or other functional group have also been recently reported as
1
2,3
31
antiin-
corrosion inhibitors.
4,5
antiparasitic, antidepressant, antiviral,8 antifun-
6
7
Furthermore, over recent years there have been an increasing
9
10,11
32
gal, and antitumour activities.
Moreover, the pyrazole nucleus
number of reports of so-called ‘multi-armed’ molecules. For ex-
represent the core unit in a variety of drugs such as celecobix
(
ample, benzene cores appended by six flexible arms, each termi-
Celebrex),12 sildenafil (Viagra), and rimonabant (Acomplia).
13
14
nated by an anionic group, have recently been shown to form
3
2a,b
Moreover, much attention has been paid over the past decade
micelles in aqueous solution.
Multi-armed molecules, in which
for the synthesis of 1,2,4-triazoles and their heterocyclic fused an-
alogues, triazolothiadiazines, for their therapeutically importance.
They are reported to possess a wide spread of medical applications
such as antibacterial, antifungal, anticancer, antitumour, anticon-
vulsant, anti-inflammatory, antimicrobial activity and analgesic
properties.1
a combination of an aromatic core and aromatic side chains find
3
2q
uses as discotic liquid crystals.
Some multi-armed derivatives
with arms containing donor atoms have been utilized as metal ion
3
3
ligands. Multi-armed compounds have also been used as building
3
4
units for dendrimers. Some conjugated multi-armed compounds
5e19
35,36
exhibit interesting properties in materials science.
In addition, compounds including bis-heterocyclic moieties
were encountered in many bioactive natural products. Recent
reports showed that among libraries of derivatized heterocycles,
Motivated by these findings, we report herein on the synthesis
of some novel mono-, bis- and poly heterocyclic compounds in-
corporating a combination of pyrazole and [1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazine pharmacophores for the first time. The combi-
nation of two pharmacophores into a single molecular skeleton is
a well-established approach for designing more potent drugs with
significant increase in activity.
2
0
the most active library compounds have a bis-heterocyclic
structure.2
1e24
Bis-heterocycles in which two bioactive heterocy-
cles are tethered via a flexible linker were reported to be
The strategy used for the synthesis of the target {6-(1H-pyrazol-
4
-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine} depends mainly on
*
Corresponding author. Tel.: þ20 1000294190; fax: þ20 2 35727556;
the initial formation of 2-bromo-1-(5-methyl-1-phenyl-1H-
e-mail address: aelwahy@hotmail.com (A.H.M. Elwahy).
http://dx.doi.org/10.1016/j.tet.2015.12.024
0
040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Salem, M. E.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.12.024

2
M.E. Salem et al. / Tetrahedron xxx (2015) 1e8
pyrazol-4-yl)ethanone (5) as a key intermediate and subsequent
reaction with the appropriate aminotriazolethiol. The amino and
mercapto groups in these compounds serve thereby as readily ac-
cessible nucleophilic centres for the preparation of N-bridged
heterocycles.
2
. Results and discussion
The desired 2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)
ethanone (5) was synthesized by the reaction of phenylhydrazine
with ((dimethylamino)methylene)pentane-2,4-dione (3), obtained
upon treatment of acetylacetone with dimethylformamide dime-
thylacetal (DMFDMA), to give 1-phenyl-5-methyl-4-acetypyrazole
3
7
(
4) followed by bromination upon treatment with Br
2
in AcOH
Scheme 4. Synthesis of bis(6-pyrazolyl-s-triazolo[3,4-b][1,3,4]thiadiazines) linked to
ethyl or butyl spacer.
38
to give 5 (Scheme 1).
The bis(triazoles) 9aed can be obtained by a one-step reaction
between aliphatic dicarboxylic acids and two molar equivalents of
thiocarbohydrazide at the melting temperature for 30 min
4
0
according to the method described by Xu et al.
The reaction pathway is assumed to involve S-alkylation to give
the corresponding bis(aminotriazole) intermediates, followed by
intramolecular cyclocondensation to give 10. The proposed mech-
anism was confirmed by the possible isolation of the corresponding
bis(triazolyl)bis(sulfanediyl)bis(1H-pyrazol-4-yl)ethanone 11b and
Scheme 1. Synthesis of 2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone.
Thus, reaction of 5 with 4-amino-3-mercapto-1,2,4-triazole
derivatives 6a,b39 in refluxing ethanol in the presence of a few
drops of triethylamine as catalyst, afforded the novel pyrazolyl(5,6-
dihydro-s-triazolo[3,4-b]thiadiazines) 8a and 8b in 70 and 75%
yields, respectively, via initial formation of 2-(4-amino-5-methyl-
11d upon treatment of 9b,d with two equivalents of 5 in refluxing
EtOH containing a few drops of triethylamine. The latter com-
pounds underwent cyclocondensation in refluxing acetic acid to
give 10b and 10d, respectively (Scheme 4). Compounds 10b,d can
also be alternatively obtained in 79, 80% yield in a one step reaction
of 9b,d with 5 in refluxing acetic acid containing sodium acetate.
The same methodology was extended to the preparation of
bis(s-triazolo[3,4-b][1,3,4]thiadiazines) 14 in which the pyrazolyl-
triazolothiadiazine is linked to a benzene core via an alkyl linkage
4
H-1,2,4-triazol-3-ylthio)-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)
ethanone, followed by cyclocondensation in refluxing acetic acid
Scheme 2).
(
0
as depicted in Scheme 4. Thus, treatment of 5,5 -(1,4-
phenylenebis(methylene))bis(4-amino-4H-1,2,4-triazole-3-thiol)
12 with two equivalents of 5 in refluxing EtOH containing a few
drops of triethylamine afforded the corresponding bis(amino-
triazoles) 13. The latter compound underwent cyclocondensation
in refluxing acetic acid to give 14 (Scheme 5). Compound 12 was
Scheme 2. Synthesis of pyrazolyl(5,6-dihydro-s-triazolo[3,4-b]thiadiazines).
0
obtained by the reaction of one mole of 2,2 -(1,4-phenylene)diac-
In continuation of this work, we also describe simple and effi-
cient routes for the synthesis of novel bis(6-pyrazolyl-s-triazolo
3,4-b][1,3,4]thiadiazines) 10aed in which the pyrazolyl-
etic acid with two moles of thiocarbohydrazide under fusion
41
conditions.
[
triazolothiadiazine is linked to the alkyl spacer through the triazole
ring (Schemes 3 and 4).
Scheme 3. Synthesis of bis(6-pyrazolyl-s-triazolo[3,4-b][1,3,4]thiadiazines) linked to
methylene or propylene spacer.
The synthetic approach used for the synthesis of the target bis-
compounds 10a,c includes the initial formation of the appropriate
bis(4-amino-5-mercapto-1,2,4-triazol-3-yl)alkanes 9a,c as pre-
cursors, which upon treatment with two equivalents of 5 in
refluxing EtOH, containing few drops of triethylamine, afforded the
corresponding bis(6-pyrazolyl triazolothiadiazines) 10a and 10c in
Scheme 5. Synthesis of bis(6-pyrazolyl-s-triazolo[3,4-b][1,3,4]thiadiazines) linked to
xylyl spacer.
We also studied the synthesis of novel twofold branched pyr-
azolyltriazolothiadiazines 18aec which are linked to an alkyl
spacer via a thioether group as outlined in Scheme 6.
73 and 70% yields, respectively.
Please cite this article in press as: Salem, M. E.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.12.024

M.E. Salem et al. / Tetrahedron xxx (2015) 1e8
3
Encouraged by the above results, our study was extended to
expand the scope of this reaction to prepare novel three-, four-, and
sixfold branched pyrazolyltriazolothiadiazines, which are linked to
a benzene core via sulfanylmethylene spacers (Scheme 8).
Scheme 6. Synthesis of bis(6-pyrazolyl-s-triazolo[3,4-b][1,3,4]thiadiazines) linked to
alkyl spacer via thioether group.
The two possible approaches, Path A and Path B for 19aec, are
given in Scheme 6. In the case of Path-A, 6-pyrazolyl-7H-[1,2,4]
triazolo[3,4-b][1,3,4]thiadiazine-3-thiol (16) has been synthesized
in the first step in 88% yield, upon treatment of 4-amino-4H-1,2,4-
triazole-3,5-dithiol (15) with one equivalent of 5 in refluxing EtOH
containing triethylamine. Twofold substitution of the appropriate
dibromoalkane 17aec with two equivalents of 16 in refluxing EtOH
containing KOH afforded 19aec in 70e76% yields. Alternatively,
this can also be achieved via Path-B, where the desired bis(sulfa-
nediyl)bis(4-amino-4H-1,2,4-triazole-3-thiols) 18aec were ob-
tained by twofold substitution of the appropriate dibromoalkane
1
7aec with two equivalents of 4-amino-4H-1,2,4-triazole-3,5-
42
43
dithiol (15) in refluxing EtOH containing KOH. Subsequent re-
action of 18aec with 5 in refluxing ethanol-DMF mixture in the
presence of a few drops of triethylamine as a catalyst afforded
19aec in 74e80% yields.
The same methodology described in Path A was extended to the
preparation of bis(pyrazolyltriazolothiadiazines) 21aec in which
the pyrazolyltriazolothiadiazines are linked to a benzene core via
sulfanylmethylene spacers. Thus, twofold substitution of the ap-
propriate bis(bromomethyl)benzene 20aec with two equivalents
of 16 under similar conditions afforded 21a, 21b and 21c in 65, 73
and 78% yields, respectively (Scheme 7).
Scheme 8. Synthesis of poly(pyrazolyltriazolothiadiazines) linked to a benzene core
via sulfanyl-methylene spacers.
The synthetic utility of 16 as building blocks for novel 1,3,5-tris-
and
1,2,4,5-tetrakis(6-pyrazolyl-7H-[1,2,4]triazolo-[3,4-b][1,3,4]
thiadiazines) 23 and 25 was investigated (Scheme 8). Thus, three-
and fourfold substitution of tris(bromomethyl)benzene 22 and
tetrakis(bromomethyl)-benzene 24 with three and four equivalents
of
6-pyrazolyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-3-thiol
(16) in refluxing EtOH/DMF mixture containing KOH afforded 23
and 25 in 66 and 63% yields, respectively. The same methodology
can be extended to the preparation of 1,2,3,4,5,6-hexakis((6-(5-
methyl-1-phenyl-1H-pyrazol-4-yl)-7H-[1,2,4]triazolo[3,4-b]
Scheme 7. Synthesis of bis(6-pyrazolyl-s-triazolo[3,4-b][1,3,4]thiadiazines) linked to
xylyl spacer via thioether group.
[1,3,4]-thiadiazin-3-ylthio)methyl)benzene (27). Thus, sixfold sub-
stitution of hexakis(bromomethyl)benzene 26 with six equivalents
of 16 under similar conditions afforded 27 in 60% yield (Scheme 8).
The structures of the new synthesized compounds were con-
firmed by IR, NMR, mass spectra and elemental analysis. The
symmetry of compounds 23, 25 and 27 are manifested by a single
All compounds were characterized by their elemental analysis,
IR, H NMR and mass spectra. The spectral data agree with the
proposed structures. Thus, the disappearance of NH stretching
2
bands in the IR spectra of triazolothiadiazines, together with the
disappearance of the characteristic peaks belonging to primary
amine in their 1H NMR spectra are evidences for the cyclo-
condensation of 2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)
ethanone with the corresponding bis-aminotriazoles. In addition,
1
set of signals characteristic of the equivalent SCH
groups in the H NMR spectra.
2
and 5-methyl
1
3. Conclusion
2
the presence of SCH protons, resonated at d 4.42e4.61 ppm as
singlet signals integrating four protons, clearly indicated that ring
closure reaction occurred. All other protons were seen at the ex-
pected chemical shifts and integral values.
We have developed a simple method for the preparation of 2-
bromo-1-(1H-pyrazol-4-yl)ethanone and studied its synthetic
utility as building blocks for novel mono-, bis- and poly{6-(1H-
Please cite this article in press as: Salem, M. E.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.12.024

4
M.E. Salem et al. / Tetrahedron xxx (2015) 1e8
pyrazol-4-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine}. Full charac-
terization of these compounds is reported. The new synthesized
compounds are interesting both in their own right as unusual
molecules, and for their promising pharmacological and biological
activities. They offer an advantage of their easy synthesis in a sim-
ple one step or two step procedure from inexpensive starting ma-
terials. Our current studies are directed to examine the inclusion
behaviour of the new compounds as well as to extend the scope of
this method to cover additional multi-armed heterocyclic
compounds.
4.3.1. 6-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-7H-[1,2,4]triazolo-
[3,4-b][1,3,4]thiadiazine (8a). (1.03 g, 70%) as a creamy crystal, mp
ꢀ
160e162 C; [Found: C, 56.59; H, 4.11; N, 28.20; S, 10.65. C14
H
12
N
6
S
requires C, 56.74; H, 4.08; N, 28.36; S,10.82%];
n
max (Neat film) 3135,
ꢁ1
3079, 1632,1584,1450 cm
;
d
H
(300 MHz, DMSO) 2.59 (s, 3H, CH ),
3
4.34 (s, 2H, H-6 thiadiazine), 7.52e7.59 (m, 5H, aromatic), 8.26
(s, 1H, H-3 pyrazole), 9.07 (s, 1H, H-3 triazole); m/z (EI, 70 eV) 296
þ
(100, M ), 196 (15.3), 183 (13.8), 118 (47.7), 104 (14.3), 77 (46.9%).
4.3.2. 6-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-3-phenyl-7H-[1,2,4]
triazolo[3,4-b][1,3,4]thiadiazine (8b). (1.39 g, 75%) as a colourless
ꢀ
crystal, mp 228e230 C; [Found: C, 64.39; H, 4.11; N, 22.20; S, 8.55.
4
4
. Experimental section
C
20
H
16
N
6
S requires C, 64.50; H, 4.33; N, 22.56; S, 8.61%];
n
max (Neat
(300 MHz, DMSO) 2.58
), 3.93 (s, 2H, H-6 thiadiazine), 7.43e7.98 (m, 10H, aro-
matic), 8.09 (s, 1H, H-3 pyrazole), (75 MHz, DMSO) 13.1, 23.7,
14.9, 125.4, 126.0, 127.8, 128.5, 128.7, 129.2, 130.0, 138.3, 140.2,
ꢁ
1
film) 3055, 2924, 1628, 1551, 1457 cm
s, 3H, CH
; d
H
.1. Materials and methods
(
3
d
C
Melting points were determined in open glass capillaries with
1
1
a Gallenkamp apparatus. Elemental analyses were carried out at the
Microanalytical Center of Cairo University, Giza, Egypt. The infrared
spectra were recorded as potassium bromide disks on a Pye Unicam
SP 3-300 and Shimaduz FTIR 8101 PC infrared spectrophotometer.
NMR spectra were recorded with a Varian Mercury VXR-300 NMR
þ
41.2, 142.1, 151.3, 152.1; m/z (EI, 70 eV) 372 (100, M ), 196 (19.2),
83 (15.5), 128 (10.0), 118 (26.8), 103 (42.1), 77 (36.3%).
1
4
7
.4. Synthesis of bis(6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-
H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl)alkane 10a,c
1
13
spectrometer at 300 MHz ( H NMR) and at 75 MHz ( C NMR). Mass
spectra (EI) were obtained at 70 eV with a type Shimadzu GCMQP
A mixture of 2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)
1000 EX spectrometer. Analytical thin-layer chromatography was
ethanone (5) (5.58 g, 20 mmol) and the appropriate bis(4-amino-5-
mercapto-1,2,4-triazol-3-yl)alkane 9a or 9c (10 mmol) was dis-
solved in ethanol (30 mL), TEA (2 mL) was added, and the reaction
mixture was refluxed for 7e9 h then left to cool. The solid product
was filtered off and recrystallized from EtOH/DMF to afford the title
compounds 10a,c.
performed using pre-coated silica gel 60,778 plates (Fluka), and the
spots were visualized with UV light at 254 nm.
4
3
7
.2. Synthesis of 2-(4-amino-5-substituted-4H-1,2,4-triazol-
-ylthio)-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethanone
a,b
4
.4.1. Bis(6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-7H-[1,2,4]-triazolo
A mixture of 2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)
ethanone (5) (2.79 g, 10 mmol) and the appropriate 5-substituted-
-amino-4H-1,2,4-triazole-3-thiol 6a or 6b (10 mmol) were dis-
solved in ethanol (20 mL), TEA (1 mL) was added and the reaction
mixture was refluxed for 5e7 h. The reaction mixture then left to
cool, the solid product was filtered off to afford the title compounds
[3,4-b][1,3,4]thiadiazin-3-yl)methane (10a). (4.40 g, 73%) as
ꢀ
a brown powder, mp<300 C; [Found: C, 57.30; H, 4.04; N, 27.71; S,
4
1
0.38. C29
max (Neat film) 3099, 2966, 1664, 1555, 1464 cm
DMSO) 2.50 (s, 6H, CH ), 4.29 (s, 2H, CH ), 4.55 (s, 4H, H-6 thia-
24 12 2
H N S requires C, 57.60; H, 4.00; N, 27.80; S, 10.61%];
ꢁ1
n
H
; d (300 MHz,
3
2
diazine), 7.47e7.58 (m, 10H, aromatic), 8.24 (s, 2H, H-3 pyrazole);
m/z (EI, 70 eV) 604 (10.4, M ), 557 (10.7), 479 (11.2), 379 (12.5), 296
þ
7
a,b.
(
(
13.1), 256 (15.1), 199 (18.8), 182 (39.3), 128 (46.6), 118 (32.5), 96
47.4), 77 (95.6), 64 (100%).
4
1
.2.1. 2-(4-Amino-4H-1,2,4-triazol-3-ylthio)-1-(5-methyl-1-phenyl-
H-pyrazol-4-yl)ethanone (7a). (2.35 g, 75%) as a white powder, mp
ꢀ
133e135 C; [Found: C, 53.19; H, 4.32; N, 26.62; S, 10.33.
4
.4.2. 1,3-Bis(6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-7H-[1,2,4]tri-
14 14 6 max
C H N OS requires C, 53.49; H, 4.49; N, 26.73; S, 10.20%]; n
azolo[3,4-b][1,3,4]thiadiazin-3-yl)propane (10c). (4.42 g, 70%) as
a pale yellow powder, mp 118e122 C; [Found: C, 58.53; H, 4.34; N,
ꢁ
1
(
Neat film) 3429, 3337, 1660, 1402, 935 cm
;
d
H
(300 MHz, DMSO)
ꢀ
2
5
.51 (s, 3H, CH
3
), 4.65 (s, 2H, CH
2
), 6.12 (s, 2H, NH ), 7.52e7.58 (m,
2
2
1
(
4
6.35; S, 10.22. C31
0.13%]; max (Neat film) 3102, 2966, 1653, 1548, 1462 cm
300 MHz, DMSO) 2.19e2.22 (m, 2H, CH ), 2.51 (s, 6H, CH ), 2.97 (t,
H, CH2, J ¼ 6.9 Hz), 4.25 (s, 4H, H-6 thiadiazine), 7.5e7.59 (m, 10H,
aromatic), 8.24 (s, 2H, H-3 pyrazole); (75 MHz, DMSO) 13.1, 23.3,
3.6, 23.8, 114.9, 125.3, 128.7, 129.2, 129.6, 138.3, 139.7, 140.1, 140.9,
28 12 2
H N S requires C, 58.84; H, 4.46; N, 26.56; S,
ꢁ1
H, aromatic), 8.38 (s, 1H, H-3 pyrazole), 8.44 (s, 1H, H-3 triazole).
n
; d
H
2
3
4
1
.2.2. 2-(4-Amino-5-phenyl-4H-1,2,4-triazol-3-ylthio)-1-(5-methyl-
-phenyl-1H-pyrazol-4-yl)ethanone (7b). (3.00 g, 77%) as a white
d
C
ꢀ
powder, mp 190e192 C; [Found: C, 61.19; H, 4.46; N, 21.40; S, 8.03.
C
2
þ
H
20 18
N
6
OS requires C, 61.52; H, 4.65; N, 21.52; S, 8.21%];
n
max (Neat
) 2.54 (s,
1
2
(
50.9; m/z (EI, 70 eV) 632 (2.7, M ), 557 (3.0), 424 (8.4), 379 (21.0),
55 (19.1), 191 (24.4), 159 (40.4), 128 (62.8), 118 (52.8), 96 (40.6), 77
56.1), 64 (100%).
ꢁ1
film) 3435, 3330,1669,1503, 764 cm
H, CH ), 4.56 (s, 2H, CH
aromatic), 8.09 (s, 1H, H-3 pyrazole).
;
d
H
(300 MHz, CDCl
3
3
3
2 2
), 5.37 (s, 2H, NH ), 7.36e7.51 (m, 10H,
4.5. Synthesis of bis(6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-
4
.3. Synthesis of 3-substituted-6-(5-methyl-1-phenyl-1H-pyr-
7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl)alkane 10b,d
azol-4-yl)-7H-[1,2,4]triazolo [3,4-b][1,3,4]thiadiazine 8a,b
0 0
A. 2,2 -(5,5 -(Ethane-1,2-diyl)bis(4-amino-4H-
4.5.1. Procedure
2
-(4-Amino-5-substituted-4H-1,2,4-triazol-3-ylthio)-1-(5-
1,2,4-triazole-5,3-diyl))bis(sulfanediyl)bis(1-(5-methyl-1-phenyl-
0
0
methyl-1-phenyl-1H-pyrazol-4-yl)ethanone 7a,b (5 mmol) was
cyclized to thiadiazine ring when refluxed in acetic acid (10 mL) for
h then left to cool; few drops of water were added. The solid
product was filtered off and recrystallized from ethyl acetate for 8a,
and ethanol for 8b.
1H-pyrazol-4-yl)ethanone) 11b or 2,2 -(5,5 -(butane-1,4-diyl)bis(4-
amino-4H-1,2,4-triazole-5,3-diyl))bis(sulfanediyl)bis(1-(5-methyl-
1-phenyl-1H-pyrazol-4-yl)ethanone) 11d was cyclized to thiadia-
zine ring when refluxed in acetic acid (10 mL) for 2 h. The reaction
mixture then left to cool; few drops of water were added. The
2
Please cite this article in press as: Salem, M. E.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.12.024

M.E. Salem et al. / Tetrahedron xxx (2015) 1e8
5
formed solid product was filtered off and recrystallized from EtOH/
DMF to afford 10b,d.
4H, CH
(s, 4H, NH
2
), 2.50 (s, 6H, CH
3
), 2.71 (br, 4H, CH
2
), 4.61 (s, 4H, CH
2
), 5.91
2
), 7.51e7.58 (s, 10H, aromatic), 8.37 (s, 2H, H-3 pyrazole).
4
1
.5.2. Procedure B. A mixture of 2-bromo-1-(5-methyl-1-phenyl-
H-pyrazol-4-yl)ethanone (5) (5.58 g, 20 mmol) and the appro-
0
0
4
1
.7. 2,2 -(5,5 -(1,4-phenylenebis(methylene))bis(4-amino-4H-
,2,4-triazole-5,3 diyl))bis(sulfanediyl)bis(1-(5-methyl-1-
phenyl-1H-pyrazol-4-yl)ethanone) (13)
priate bis(4-amino-5-mercapto-1,2,4-triazol-3-yl)alkane 9b or 9d
10 mmol) was dissolved in acetic acid (10 mL), sodium acetate (2 g)
(
was added, and the reaction mixture was refluxed for 4e5 h. The
reaction mixture then left to cool, the solid product was filtered off
and recrystallized from EtOH/DMF to afford 10b,d.
A mixture of 2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)
0
ethanone
(5)
(5.58
g,
20
mmol)
and
5,5 -(1,4-
phenylenebis(methylene))bis(4-amino-4H-1,2,4-triazole-3-thiol)
12) (3.34 g, 10 mmol) was dissolved in ethanol (30 mL), TEA (2 mL)
was added and the reaction mixture was refluxed for 7e9 h. The
(
4.5.3. 1,2-Bis(6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-7H-[1,2,4]-tri-
azolo[3,4-b][1,3,4]thiadiazin-3-yl)ethane (10b). ((A) 4.44 g, 72%; (B)
reaction mixture was then left to cool and the solid product was
ꢀ
4
.88 g, 79%) as a white powder, mp 256e258 C; [Found: C, 58.19;
filtered off to afford 13 (5.03 g, 69%) as a creamy solid, mp
H, 4.15; N, 27.20; S, 10.38. C30
7.17; S, 10.36%]; max (Neat film) 3107, 2989, 1659, 1551, 1458 cm
(300 MHz, DMSO) 2.55 (s, 6H, CH ), 3.2 (s, 4H, CH ), 4.22 (s, 4H,
26
H N
12
S
2
requires C, 58.23; H, 4.24; N,
ꢀ
1
C
(
2
62e164 C; [Found: C, 59.11; H, 4.52; N, 22.89; S, 8.58.
ꢁ1
2
n
;
36
H
34
N
12
O
2
S
2
requires C, 59.16; H, 4.69; N, 23.00; S, 8.77%];
n
max
d
H
3
2
ꢁ1
Neat film) 3447, 3328, 1663, 1540, 876 cm
.49 (s, 6H, CH ), 4.03 (s, 4H, CH
NH ), 7.2e7.55 (m, 14H, aromatic), 8.36 (s, 2H, H-3 pyrazole); m/z
;
d
H
(300 MHz, DMSO)
H-6 thiadiazine), 7.4e7.57 (m, 10H, aromatic), 8.25 (s, 2H, H-3
3
2
), 4.61 (s, 4H, CH
2
), 5.91 (s, 4H,
þ
pyrazole); m/z (EI, 70 eV) 618 (3.7, M ), 473 (11.8), 424 (17.3), 379
2
(
(
32.2), 317 (38.0), 239 (39.6), 198 (19.6), 183 (71.9), 155 (42.1), 128
62.0), 118 (95.2), 96 (35.7), 77 (99.6), 64 (100%).
þ
(
(
(
EI, 70 eV) 730 (1.7, M ), 657 (1.5), 594 (1.5), 415 (1.7), 372 (1.4), 301
1.6), 213 (1.7), 185 (3.9), 130 (1.7), 95 (2.1), 80 (100), 79 (10.8), 64
27.1%).
4.5.4. 1,4-Bis(6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-7H-[1,2,4]-tri-
azolo[3,4-b][1,3,4]thiadiazin-3-yl)butane (10d). ((A) 4.84 g, 75%; (B)
4
.8. 1,4-Bis((6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-7H-[1,2,4]-
ꢀ
5
.16 g, 80%) as a creamy powder, mp 186e190 C; [Found: C, 59.19;
triazolo[3,4-b][1,3,4]thiadiazin-3-yl)methyl)benzene (14)
H, 4.54; N, 25.90; S, 9.88. C32
5.99; S, 9.92%]; max (Neat film) 3064, 2912, 1645, 1551, 1462 cm
(300 MHz, DMSO) 1.82 (br, 4H, CH ), 2.52 (s, 6H, CH ), 2.87 (br,
30 12 2
H N S requires C, 59.42; H, 4.68; N,
ꢁ1
2
n
;
A solution of 13 (0.730 g, 1 mmol) in acetic acid (10 mL) was
heated under reflux for 2 h. The solid obtained upon cooling and
dilution with few drops of water was filtered off and recrystallized
d
H
2
3
4
H, CH
2
), 4.26 (s, 4H, H-6 thiadiazine), 7.53 (s, 10H, aromatic), 8.25
þ
(s, 2H, H-3 pyrazole); m/z (EI, 70 eV) 646 (32.5, M ), 629 (28.3), 579
(28.6), 510 (26.1), 427 (31.8), 363 (31.2), 296 (34.3), 200 (33.4), 183
(65.6), 155 (42.0), 129 (36.9), 118 (45.2), 80 (84.3), 77 (67.5), 64
(100%).
from ethanol to afford 14 (0.451 g, 65%) as a creamy solid, mp
ꢀ
198e200 C; [Found: C, 62.19; H, 4.11; N, 24.25; S, 9.08. C36
H
30
N
12
S
2
requires C, 62.23; H, 4.35; N, 24.19; S, 9.23%];
n
max (Neat film) 3175,
ꢁ
1
2918, 1660, 1540, 1455 cm
;
d
H
(300 MHz, DMSO) 2.37 (s, 6H, CH ),
3
4
.18 (s, 4H, CH
2
), 4.23 (s, 4H, H-6 thiadiazine), 7.18e7.57 (m, 14H,
0
0
4
4
.6. Synthesis of 2,2 -(5,5 -(ethane-1,2-diyl)bis(4-amino-4H-1,2,-
þ
aromatic), 8.22 (s, 2H, H-3 pyrazole); m/z (EI, 70 eV) 694 (5.1, M ),
-triazole-5,3-diyl))bis(sulfanediyl)bis(1-(5-methyl-1-phenyl-1-
570 (5.5), 444 (5.3), 379 (11.3), 296 (9.8), 239 (13.6), 183 (42.5), 159
0
0
H-pyrazol-4-yl)ethanone) (11b) and 2,2 -(5,5 -(butane-1,4-diyl)-
bis(4-amino-4H-1,2,4-triazole-5,3-diyl))bis(sulfanediyl)-bis(1-(5-
methyl-1-phenyl-1H-pyrazol-4-yl)ethanone) (11d)
(46.3), 128 (60.5), 118 (34.0), 77 (52.9), 64 (100%).
4.9. 6-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-7H-[1,2,4]tri-
azolo-[3,4-b][1,3,4]-thiadiazine-3-thiol (16)
A mixture of 2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)
ethanone (5) (5.58 g, 20 mmol) and the appropriate bis(4-amino-5-
mercapto-1,2,4-triazol-3-yl)alkane 9b or 9d (10 mmol) was dis-
solved in ethanol (30 mL), TEA (2 mL) was added. The reaction
mixture was refluxed for 7e9 h then left to cool. The solid product
was filtered off to afford the title compounds 11b and 11d.
A mixture of 2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)
ethanone (5) (2.79 g, 10 mmol) and 4-amino-4H-1,2,4-triazole-3,5-
dithiol (15) (1.48 g, 10 mmol) was dissolved in ethanol (30 mL), TEA
(1 mL) was added and the reaction mixture was refluxed for 3e5 h
then left to cool. The solid product was filtered off and recrystal-
lized from EtOH/DMF to afford 16 (2.88 g, 88%) as a pale yellow
0 0
.6.1. 2,2 -(5,5 -(Ethane-1,2-diyl)bis(4-amino-4H-1,2,4-triazole-5,3-
4
ꢀ
solid, mp 298e300 C; [Found: C, 51.08; H, 3.45; N, 25.47; S, 19.45.
diyl))bis(sulfanediyl)bis(1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)
ethanone) (11b). (5.23 g, 80%) as a pale yellow powder, mp
14 12 6 2 max
C H N S requires C, 51.20; H, 3.68; N, 25.59; S, 19.53%]; n
ꢁ1
ꢀ
(Neat film) 3131, 2978, 2426, 1631, 1544, 1454 cm
DMSO) 2.68 (s, 3H, CH ), 4.31 (s, 2H, H-6 thiadiazine), 7.52e7.58 (m,
5H, aromatic), 8.25 (s, 1H, H-3 pyrazole) 13.8 (s, 1H, SH);
; d (300 MHz,
2
C
(
(
CH
38e240 C; [Found: C, 54.96; H, 4.53; N, 25.43; S, 9.65.
requires C, 55.03; H, 4.62; N, 25.67; S, 9.79%];
H
30
H
30
N
12
O
2
S
2
n
max
3
Neat film) 3432, 3351, 3066, 2968, 1662, 1551, 1456 cm 1;
ꢁ
d
H
d
C
(75 MHz, DMSO) 13.1, 23.3, 115.0, 125.3, 128.6, 129.2, 138.5, 139.7,
300 MHz, DMSO) 2.50 (s, 6H, CH
), 6.03 (s, 4H, NH ), 7.51e7.58 (m, 10H, aromatic), 8.38 (s, 2H, H-
pyrazole); (75 MHz, DMSO) 11.9, 15.9, 21.0, 119.0, 125.3, 128.7,
38.0,139.0,141.9,142.9,150.9,155.4,188.4; m/z (EI, 70 eV) 654 (4.2,
3 2
), 3.10 (s, 4H, CH ), 4.63 (s, 4H,
þ
140.5, 140.8, 151.4, 164.7; m/z (EI, 70 eV) 328 (100, M ), 295 (10.6),
2
2
228 (6.8), 184 (24.6), 118 (38.9), 77 (62.0%).
3
1
d
C
þ
M ), 473 (4.1), 429 (4.3), 384 (4.5), 300 (4.7), 197 (5.7), 149 (6.3), 121
4.10. Synthesis of bis(6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-
7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-ylthio)alkane
(
4.8), 111 (5.1), 80 (100%).
19aec
0 0
.6.2. 2,2 -(5,5 -(Butane-1,4-diyl)bis(4-amino-4H-1,2,4-triazole-5,3-
4
diyl))bis(sulfanediyl)bis(1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)
ethanone) (11d). (5.79 g, 85%) as a white powder, mp 148e150 C;
4.10.1. Procedure A. To a solution of KOH (0.112 g, 2 mmol) in EtOH
(20 mL) was added the 6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-
7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-3-thiol (16) (0.65 g,
2 mmol). The resulting mixture was refluxed for 2e3 h with the
appropriate di-bromo alkane 17aec (1 mmol). The reaction mixture
ꢀ
34 12 2 2
[Found: C, 56.12; H, 5.21; N, 24.39; S, 9.52. C32H N O S requires
C, 56.29; H, 5.02; N, 24.62; S, 9.39%];
n
max (Neat film) 3415, 3337,
ꢁ1
3
010, 2898, 1664, 1543, 1449 cm
;
d
H
(300 MHz, DMSO) 1.74 (br,
Please cite this article in press as: Salem, M. E.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.12.024

6
M.E. Salem et al. / Tetrahedron xxx (2015) 1e8
then left to cool and the solid product was filtered off and recrys-
tallized from EtOH/DMF to give 19aec.
C, 56.72; H, 4.21; N, 22.36; S, 16.73. C36
H, 3.98; N, 22.15; S, 16.90%]; max (Neat film) 3102, 2967, 1639, 1548,
(300 MHz, DMSO) 2.56 (s, 6H, CH ), 4.29 (s, 4H, H-6
30 12 4
H N S requires C, 56.97;
n
ꢁ1
1453 cm
;
d
H
3
4
(
2
.10.2. Procedure B. To a solution of KOH (1.12 g, 20 mmol) in EtOH
20 mL), 4-amino-4H-1,2,4-triazole-3,5-dithiol (15) (2.96 g,
0 mmol) was added. The resulting mixture was refluxed for 2e3 h
thiadiazine), 4.61 (s, 4H, CH
2H, H-3 pyrazole); m/z (EI, 70 eV) 758 (0.7, M ), 369 (3.9), 328
(100), 270 (8.0), 196 (14.3), 184 (20.1), 118 (60.5), 77 (38.1%).
2
), 7.22e7.57 (m, 14H, aromatic), 8.23 (s,
þ
with the appropriate di bromo alkane 17aec (10 mmol) then left to
cool. The solid product was filtered off and recrystallized from
EtOH/DMF to afford the appropriate 5,5 -(alkane-1,4-diylbis(sulfa-
nediyl))bis(4-amino-4H-1,2,4-triazole-3-thiol) 18aec. To a mixture
of the appropriate bis(4-amino-4H-1,2,4-triazole-3-thiol) 18aec
4.11.2. 1,3-Bis((6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-7H-[1,2,4]
triazolo[3,4-b][1,3,4]thiadiazin-3-ylthio)methyl)benzene
(21b). (0.553 g, 73%) as a white crystal, mp 240e242 C; [Found:
0
ꢀ
C, 56.72; H, 3.81; N, 22.06; S, 16.68. C36
H, 3.98; N, 22.15; S, 16.90%]; max (Neat film) 3059, 2973, 1644,
(300 MHz, DMSO) 2.57 (s, 6H, CH ), 4.31 (s,
30 12 4
H N S requires C, 56.97;
(
10 mmol) in ethanol (30 mL), 2-bromo-1-(5-methyl-1-phenyl-1H-
n
ꢁ1
pyrazol-4-yl)ethanone (5) (5.58 g, 20 mmol) and TEA (2 mL) were
added. The reaction mixture was refluxed for 2e3 h then left to cool
and the solid product was filtered off and recrystallized from EtOH/
DMF to afford 19aec.
1548, 1453 cm
;
d
H
3
4H, H-6 thiadiazine), 4.42 (s, 4H, CH
matic), 8.26 (s, 2H, H-3 pyrazole); m/z (EI, 70 eV) 758 (1.4, M ),
2
), 7.25e7.55 (m, 14H, aro-
þ
454 (2.2), 328 (100), 296 (15.7), 239 (17.5), 184 (39.2), 118 (61.1),
77 (97.6%).
4.10.3. 1,2-Bis(6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-7H-[1,2,4]tri-
azolo[3,4-b][1,3,4]thiadiazin-3-ylthio)ethane (19a). ((A) 0.477 g,
4.11.3. 1,4-Bis((6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-7H-[1,2,4]
triazolo[3,4-b][1,3,4]thiadiazin-3-ylthio)methyl)benzene
(21c). (0.591 g, 78%) as a white crystal, mp 258e260 C; [Found:
ꢀ
7
5
3
0%; (B) 5.04 g, 74%) as a white powder, mp 272e274 C; [Found: C,
ꢀ
2.56; H, 3.64; N, 24.84; S, 18.59. C30
.84; N, 24.61; S, 18.78%]; max (Neat film) 3104, 2992, 1642, 1551,
(300 MHz, DMSO) 2.55 (s, 6H, CH ), 3.57 (s, 4H, CH ),
H
26
N
12
S
4
requires C, 52.77; H,
n
C, 57.12; H, 4.07; N, 22.06; S, 17.02. C36
H, 3.98; N, 22.15; S, 16.90]; max (Neat film) 3080, 2961, 1633, 1549,
(300 MHz, DMSO) 2.56 (s, 6H, CH ), 4.31 (s, 4H, H-6
thiadiazine), 4.42 (s, 4H, CH ), 7.35e7.55 (m, 14H, aromatic), 8.25
(s, 2H, H-3 pyrazole); (75 MHz, DMSO) 13.0, 24.2, 34.3, 114.6,
30 12 4
H N S requires C, 56.97;
ꢁ1
1
4
2
3
458 cm
;
d
H
3
2
n
ꢁ1
.34 (s, 4H, H-6 thiadiazine), 7.51e7.53 (m, 10H, aromatic), 8.26 (s,
1454 cm
;
d
H
3
þ
H, H-3 pyrazole); m/z (EI, 70 eV) 682 (1.8, M ), 589 (1.9), 447 (1.8),
2
56 (17.5), 328 (100), 295 (22.6), 184 (29.9), 155 (16.7), 128 (18.8),
d
C
118 (87.7), 77 (65.0%).
125.3, 128.7, 129.0, 129.3, 136.4, 138.3, 140.4, 141.0, 148.9, 151.3; m/
z (EI, 70 eV) 758 (8.9, M ), 737 (10.3), 623 (10.7), 547 (10.3), 443
þ
4
.10.4. 1,3-Bis(6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-7H-[1,2,4]tri-
(10.5), 358 (17.0), 328 (91.1), 296 (24.5), 183 (48.1), 118 (93.4), 77
(100%).
azolo[3,4-b][1,3,4]thiadiazin-3-ylthio)propane (19b). ((A) 0.528 g,
ꢀ
76%; (B) 5.35 g, 77%) as an orange powder, mp 235e237 C; [Found:
C, 53.65; H, 4.01; N, 24.22; S, 18.23. C31
H, 4.05; N, 24.12; S,18.40%]; max (Neat film) 3060, 2969,1648,1548,
(300 MHz, DMSO) 2.19e2.25 (m, 2H, CH ), 2.6 (s, 6H,
), 3.30e3.35 (m, 4H, CH ), 4.33 (s, 4H, H-6 thiadiazine),
H
28
N
12
S
4
requires C, 53.43;
4.12. Synthesis of 1,3,5-tris((6-(5-methyl-1-phenyl-1H-pyr-
azol-4-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-ylthio)
methyl)benzene (23)
n
ꢁ1
1
CH
454 cm
;
d
H
2
3
2
7
.51e7.54 (m, 10H, aromatic), 8.26 (s, 2H, H-3 pyrazole); m/z (EI,
To a solution of KOH (0.168 g, 3 mmol) in EtOH (25 mL) was
added the 6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-7H-[1,2,4]tri-
azolo[3,4-b][1,3,4] thiadiazine-3-thiol (16) (0.984 g, 3 mmol). The
resulting mixture was refluxed for 2e3 h with 1,3,5-tris(-
bromomethyl)benzene (22) (0.356 g, 1 mmol). The reaction mix-
ture was then left to cool and the solid product was filtered off and
recrystallized from DMF to afford 23 (0.724 g, 66%) as a creamy
þ
7
0 eV) 696 (0.6, M ), 369 (3.9), 328 (98.6), 296 (22.9),184 (30.0),118
(
73.1), 77 (100%).
4.10.5. 1,4-Bis(6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-7H-[1,2,4]tri-
azolo[3,4-b][1,3,4]thiadiazin-3-ylthio)butane (19c). ((A) 0.532 g,
7
ꢀ
5%; (B) 5.68 g, 80%) as a yellow powder, mp 238e240 C; [Found:
ꢀ
C, 54.01; H, 4.33; N, 23.91; S,17.93. C32
.25; N, 23.64; S, 18.04%]; max (Neat film) 3083, 2992, 1631, 1549,
(300 MHz, DMSO) 1.86 (br, 4H, CH ), 2.58 (s, 6H,
), 3.25 (br, 4H, CH ), 4.33 (s, 4H, H-6 thiadiazine), 7.51e7.55 (m,
(75 MHz, DMSO) 13.0,
4.2, 28.0, 30.1, 114.7, 125.3, 128.6, 129.2, 138.3, 140.3, 141.0, 141.3,
30
H N
12
S
4
requires C, 54.06; H,
powder, mp 210e212 C; [Found: C, 55.63; H, 3.67; N, 22.84; S,
4
n
17.42. C51
H
42
N
18
S
6
requires C, 55.72; H, 3.85; N, 22.93; S, 17.50%];
ꢁ
1
ꢁ1
1455 cm
;
d
H
2
n
max (Neat film) 3100, 2971, 1664, 1548, 1453 cm
DMSO) 2.55 (s, 9H, CH
CH ), 7.37e7.54 (m, 18H, aromatic), 8.25 (s, 3H, H-3 pyrazole);
H
; d (300 MHz,
3
), 4.3 (s, 6H, H-6 thiadiazine), 4.39 (s, 6H,
CH
3
2
10H, aromatic), 8.26 (s, 2H, H-3 pyrazole);
d
C
2
d
C
2
(75 MHz, DMSO) 13.1, 24.3, 34.4, 114.6, 125.3, 128.6, 129.2, 137.6,
138.3, 140.4, 141.0, 141.6, 148.8, 151.3.
þ
149.4, 151.2; m/z (EI, 70 eV) 710 (1.5, M ), 351 (2.0), 328 (100), 295
(
12.9), 196 (19.8), 184 (31.6), 118 (50.0), 77 (62.2%).
4.13. 1,2,4,5-Tetrakis((6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-
4
.11. Synthesis of bis((6-(5-methyl-1-phenyl-1H-pyrazol-4-
7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-ylthio)methyl)-
yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-ylthio)methyl)-
benzene 21aec
benzene (25)
To a solution of KOH (0.224 g, 4 mmol) in EtOH (25 mL) was
added the 6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-7H-[1,2,4]tri-
azolo[3,4-b][1,3,4] thiadiazine-3-thiol (16) (1.312 g, 4 mmol). The
resulting mixture was refluxed for 2e3 h with 1,2,4,5-tetrakis(-
bromomethyl)benzene (24) (0.449 g, 1 mmol). The reaction mix-
ture was then left to cool and the solid product was filtered off and
recrystallized from DMF to afford 25 (0.905 g, 63%) as an orange
To a solution of KOH (0.112 g, 2 mmol) in EtOH (20 mL) was
added the 6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-7H-[1,2,4]tri-
azolo[3,4-b][1,3,4] thiadiazine-3-thiol (16) (0.65 g, 2 mmol). The
resulting mixture was refluxed for 2e3 h with the appropriate
bis(bromomethyl)benzene 20aec (1 mmol). The reaction mixture
then left to cool, the solid product was filtered off and recrystallized
from DMF to afford 21aec.
ꢀ
powder, mp 262e264 C; [Found: C, 55.13; H, 3.72; N, 23.29; S,
1
7.77. C66
film) 3057, 2967, 1662, 1547, 1451 cm
12H, CH ), 4.28 (s, 8H, H-6 thiadiazine), 4.54 (s, 8H, CH
(m, 22H, aromatic), 8.22 (s, 4H, H-3 pyrazole); NMR (75 MHz,
H
54
N
24
S
8
: C, 55.06; H, 3.78; N, 23.35; S, 17.82%];
n
max (Neat
(300 MHz, DMSO) 2.5 (s,
), 7.47e7.49
ꢁ1
4.11.1. 1,2-Bis((6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-7H-[1,2,4]tri-
; d
H
azolo[3,4-b][1, 3,4]thiadiazin-3-ylthio)methyl)benzene
3
2
ꢀ
(
21a). (0.492 g, 65%) as an orange crystal, mp 173e175 C; [Found:
d
C
Please cite this article in press as: Salem, M. E.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.12.024

M.E. Salem et al. / Tetrahedron xxx (2015) 1e8
7
DMSO) 13.1, 24.3, 31.9, 114.6, 125.2, 128.6, 129.2, 135.1, 138.2, 140.3,
41.0, 141.7, 148.6, 151.3.
14. Seltzmann, H. H.; Carroll, F. I.; Burgess, J. P.; Wyrick, C. D.; Burch, D. F. J. Chem.
Soc. Chem. Commun. 1995, 1549e1550.
1
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Med. Chem. 2005, 40, 607e613; (b) Walczak, K.; Gondela, A.; Suwinski, J. Eur. J.
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A.; Denkova, P. Eur. J. Med. Chem. 2009, 44, 63e69.
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4
.14. 1,2,3,4,5,6-Hexakis((6-(5-methyl-1-phenyl-1H-pyrazol-4-
yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-ylthio)methyl)
benzene (27)
1
6
057e6059; (c) Amir, M.; Shikha, K. Eur. J. Med. Chem. 2004, 39, 535e545.
To a solution of KOH (0.336 g, 6 mmol) in EtOH (25 mL) was
added the 6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-7H-[1,2,4]tri-
azolo[3,4-b][1,3,4] thiadiazine-3-thiol (16) (1.968 g, 6 mmol). The
resulting mixture was refluxed for 2e3 h with 1,2,3,4,5,6-hex-
akis(bromomethyl)benzene (26) (0.635 g, 1 mmol). The reaction
mixture was then left to cool and the solid product was filtered off
1
7. (a) Karegoudar, P.; Prasad, D. J.; Ashok, M.; Mahalinga, M.; Poojary, B.; Holla,
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4528e4538.
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and recrystallized from DMF to afford the title compound 27 (1.27 g,
ꢀ
6
3
2
0%) as an orange powder, mp 288e290 C; [Found: C, 54.13; H,
1
156e1162.
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3.78; S, 18.14%]; max (Neat film) 2962, 2920, 1631, 1549,
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thiadiazine), 4.77 (s, 12H, CH ), 7.41e7.56 (m, 30H, aromatic), 8.18
78 36
H N S12 requires C, 54.37; H, 3.71; N,
(
n
Chem. 2006, 41, 657e663; (c) El-Shehrya, M. F.; Abu-Hashem, A. A.; El-Telbani,
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ꢁ
1
1452 cm
;
d
H
3
6
2
20. Murru, S.; Nefzi, A. ACS Comb. Sci. 2014, 16, 39e45.
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2
2
(
s, 6H, H-3 pyrazole).
2
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J.; Kupchinsky, S.; Ahlijanian, M. K.; Tate, B.; Menniti, F. S.; Kelly, K.; Peterson, M.
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Acknowledgements
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4. Soural, M.; Bouillon, I.; Krch nꢀ ꢁa k, V. J. Comb. Chem. 2008, 10, 923e933.
2
Professor A.H.M.E. and Dr. A.F.D. gratefully acknowledge the
Alexander von Humboldt Foundation for a research fellowship.
5. Thurston, D. E.; Bose, D. S.; Thompson, A. S.; Howard, P. W.; Leoni, A.; Croker, S.
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Supplementary data
2004, 47, 5244e5250.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.12.024.
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