Bis(α-bromo ketones): Versatile Precursors for Novel Bis(s-triazolo[3,4-b][1,3,4]thiadiazines) and Bis(thiazoles)

Article abstract of DOI:10.1002/jhet.2223

A synthesis of novel bis(s-triazolo[3,4-b][1,3,4]thiadiazines) 4, 5, 6 in which the triazolothiadiazine is linked to the benzene core through the thiadiazine ring via phenoxymethyl spacers was reported. First attempt to synthesize 4, 5, 6 by the reaction of the appropriate bis(acetophenones) with 4-amino-3-mercapto-1,2,4-triazole derivatives using an acidified acetic acid method were unsuccessful. On the other hand, reaction of the corresponding bis(α-bromoketones) with 4-amino-3-mercapto-1,2,4-triazole derivatives afforded 4, 5, 6 in good yields. The reaction pathway is assumed to involve S-alkylation to give bis(aminotriazole) intermediates, followed by intramolecular cyclocondensation to give 4, 5, 6. The successful isolation of the corresponding bis(aminotriazole) intermediates provides strong evidence for the proposed mechanism. The novel bis(thiazoles) 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, linked to alkyl or aryl spacers can also be synthesized by reaction of the appropriate bis(bromoacetyl) compounds 12a, 12b, 12c and 14, 15, 16, 17, 18, 19 with the corresponding thioamide derivatives 20, 21, 22.

Full text of DOI:10.1002/jhet.2223

Month 2014 Bis(α-bromo ketones): Versatile Precursors for Novel Bis(s-triazolo[3,4-b]
[1,3,4]thiadiazines) and Bis(thiazoles)
a
a
Ahmed R. S. Ginidi,a Mohamed R. Shaaban,a,b Ahmad M. Farag, and Ahmed H. M. Elwahy
*
aFaculty of Science, Department of Chemistry, Cairo University, Giza, Egypt
bFaculty of Applied Science, Department of Chemistry, Umm Al-Qura University, Makkah Almukkarramah, Saudi Arabia
*
E-mail: aelwahy@hotmail.com
Received February 23, 2014
DOI 10.1002/jhet.2223
Published online 00 Month in Wiley Online Library (wileyonlinelibrary.com).
A synthesis of novel bis(s-triazolo[3,4-b][1,3,4]thiadiazines) 4–6 in which the triazolothiadiazine is linked
to the benzene core through the thiadiazine ring via phenoxymethyl spacers was reported. First attempt to
synthesize 4–6 by the reaction of the appropriate bis(acetophenones) with 4-amino-3-mercapto-1,2,
4-triazole derivatives using an acidified acetic acid method were unsuccessful. On the other hand, reaction
of the corresponding bis(α-bromoketones) with 4-amino-3-mercapto-1,2,4-triazole derivatives afforded
4–6 in good yields. The reaction pathway is assumed to involve S-alkylation to give bis(aminotriazole)
intermediates, followed by intramolecular cyclocondensation to give 4–6. The successful isolation of the
corresponding bis(aminotriazole) intermediates provides strong evidence for the proposed mechanism. The
novel bis(thiazoles) 23–36, linked to alkyl or aryl spacers can also be synthesized by reaction of the appropriate
bis(bromoacetyl) compounds 12a–c and 14–19 with the corresponding thioamide derivatives 20–22.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
moieties are attached to a benzene core or alkyl spacer
through the triazole ring via thioether group. We have also
reported the synthesis of bis(triazolothiadiazines) 3 in
which the triazolothiadiazine moieties are linked to alkyl
spacer through the thiadiazine ring via phenoxy group
(Chart 1) [38–40]. Preliminary evaluation of the biological
activities of 1–3 indicates that bis(triazolothiadiazines) of
type 3 are more effective.
As a continuation of this work, we describe herein
simple and efficient routes for the synthesis of novel bis
(s-triazolo[3,4-b][1,3,4]thiadiazines) 4–6 in which the
triazolothiadiazine are linked to the benzene core through
the thiadiazine ring via phenoxymethyl group (Chart 2).
Bis-heterocyclic compounds with a suitable spacer
constitute an important class of compounds and their
various types of activities, especially, as antitumor [1]
and as antimicrobial [2], have been studied. These
activities, which result in their pharmacological utility,
have been reported to be enhanced when different
functionalities or substitutions are present on the two
heterocyclic moieties in the bis-compound [3–11].
Moreover, the synthesis and pharmacological activities
of 1,2,4-triazoles and their heterocyclic fused analogs
(e.g., triazolothiadiazoles and triazolothiadiazines)
have attracted much attention in recent decades because
they display a variety of medical applications such
as antibacterial, antifungal, anticancer, antitumor,
anticonvulsant, anti-inflammatory, antimicrobial activity,
and analgesic properties [12–26]. Furthermore, thiazole
derivatives have also attracted increasing attention due
to their numerous pharmacological applications and
biological activities, such as anti-inflammatory, analgesic,
antimicrobial, anti-HIV, antihypertensive, and herbicidal
activity [27–37].
RESULTS AND DISCUSSION
Recently, El-Sherief et al. reported the synthesis of
s-triazolo[3,4-b][1,3,4]thiadiazines 9a–g by the reaction of
4-amino-3-mercapto-5-phenyl-s-triazole 7a with aromatic
ketones 8a–g containing active α-hydrogens as a methyl
group using an acidified acetic acid method [41]. The
advantages of this method are short reaction time, one-pot
reaction, and direct use of ketones without the formation
phenacyl bromides (Scheme 1).
Recently, we reported the synthesis of bis(triazolo-
thiadiazines) 1 and 2 in which the triazolothiadiazine
© 2014 HeteroCorporation

A. R. S. Ginidi, M. R. Shaaban, A. M. Farag, and A. H. M. Elwahy
Vol 000
Chart 1
Chart 2
Scheme 1
Scheme 2
In connection with this findings, we studied the synthe-
sis of bis(acetophenones) 11a–c by the reaction of the
potassium salt of 4-hydroxyacetophenone 8 g with the
appropriate bis(bromomethyl)benzenes 10a–c in boiling
dimethylformamide (DMF). The synthetic utility of 11a–c
as building blocks for novel bis(s-triazolo[3,4-b][1,3,4]
thiadiazines) 4–6 were investigated. Unfortunately, repeated
attempts to synthesize 4–6 by the reaction of 11a–c
as suitable precursors for 4–6. First attempt to synthesize
12a–c by bromination of 11a–c with bromine in acetic
acid led to the formation of an unseparable mixture of the
bis(α-bromoketone) 12 as well as the corresponding
undesirable bis(α,α-dibromoketone). On the other hand,
the reaction of 11a–c with N-bromosuccinimide (NBS) in
the presence of p-toluenesulfonic acid (p-TsOH) in aceto-
nitrile afforded the corresponding bis(α-bromoketones)
12a–c as single monobrominated ketones in most instances
in high yield (Scheme 3).
with 4-amino-3-mercapto-1,2,4-triazole derivatives
7
using an acidified acetic acid method were unsuccessful,
and the starting materials were recovered completely
unchanged (Scheme 2).
The unsuccessful synthesis of 4–6 from 11a–c prompted
us to study the synthesis of the bis(α-bromoketones) 12a–c
Thus, reaction of 12a–c with 4-amino-3-mercapto-1,2,4-
triazole derivatives 7a–c in ethanol-DMF mixture in the
presence of few drops of piperidine as a catalyst under
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Bis(α-bromo ketones): Versatile Precursors for Novel Bis(s-triazolo[3,4-b][1,3,4]
thiadiazines) and Bis(thiazoles)
Scheme 3
Chart 3
reflux afforded the novel bis(5,6-dihydro-s-triazolo[3,4-b]
thiadiazines) 4–6 in 50–70% yields (Scheme 4).
All of the isolated compounds were characterized by ele-
mental analyses, as well as their spectral data, which agree
with the proposed structures. Thus, the disappearance of NH2
stretching bands in the IR spectra of the triazolothiadiazines
Scheme 4
Scheme 5
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. R. S. Ginidi, M. R. Shaaban, A. M. Farag, and A. H. M. Elwahy
Vol 000
Scheme 6
4–6 together with the absence of the characteristic
signals belonging to primary amine in their 1H-NMR
spectra are evidences for the cyclocondensation of the ap-
propriate bis(α-bromoketones) 12a–c with aminotriazoles
7a–c, respectively. In addition, the presence of SCH2
protons, resonated at (δ) 4.32–4.40 ppm as singlet signals
integrating four protons, clearly indicating that ring closure
reaction occurred. All other protons were seen at the
expected chemical shifts and integral values (See
Experimental section).
In a typical experiment, an equimolar amount of bis
(bromo) derivatives 12a, 17 and 19, and thiourea 20 was
reacted in refluxing ethanol to afford the corresponding
bis(aminothiazoles) 23–25 (Scheme 6). The reaction was
completed within 3–5 h, and the product was obtained in
good yields.
In a similar manner, bis(bromo) derivatives 12a–c and
14–19 were reacted smoothly with N-methylthiourea 21
and thioacetamide 22 successfully to give the correspond-
ing bis(thiazole) derivatives 26–36 (Scheme 3).
The reaction pathway is assumed to involve S-alkylation
to give bis(aminotriazole) intermediates 13, followed
by intramolecular cyclocondensation to give 4–6. The cor-
responding bis(aminotriazoles) 13a,b could be
isolated thereby providing strong evidence for the
proposed mechanism. The latter compounds underwent
cyclocondensation in refluxing acetic acid or DMF
containing few drops of piperidine to give 5b and 6b,
respectively (Scheme 5).
Encouraged by the results obtained with the aforemen-
tioned experiments, we have extended our study to include
the synthesis of novel bis(thiazoles) 24–37 by reaction of
the appropriate bis(bromoacetyl) compounds 12a–c as well
as 14–19 [40] with the corresponding thioamide
derivatives. Compounds 14–19 were recently prepared in
our laboratory from the corresponding bis-acetophenones
with NBS in acetonitrile (Chart 3).
CONCLUSIONS
We developed a simple method for the synthesis of bis
(triazolothiadiazinyl)arenes. The triazolothiadiazine moi-
ety in the novel compounds are linked to benzene core
via phenoxy group. Attempts to synthesize these com-
pounds directly from the corresponding bis ketones
according to recently published results were unsuccessful.
Confirmation of the suggested mechanism for the synthesis
of these compounds by isolation of the intermediates bis
(triazoles) was reported. We have also synthesized a series
of novel bis(thiazoles), linked to alkyl or aryl spacers. Full
characterization of these compounds is reported. The new
synthesized compounds are interesting both in their own
right as unusual molecules and for their promising pharma-
cological and biological activities. They offer an advantage
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Bis(α-bromo ketones): Versatile Precursors for Novel Bis(s-triazolo[3,4-b][1,3,4]
thiadiazines) and Bis(thiazoles)
Anal. calcd for C24H20Br2O4 (529.97): C, 54.16; H, 3.79; Br,
30.03. Found: C, 54.28; H, 3.61; Br, 30.11.
of their easy synthesis in a simple one step or two steps
procedure from inexpensive starting materials.
1,4-Bis(4-bromoacetylphenoxymethyl)benzene (12c).
(95%
Yield), mp 140–142 °C (ethylacetate); IR (cmÀ1): 1681 (C═O); 1H-
NMR (DMSO): δ 4.83 (s, 4H), 5.24 (s, 4H), 7.10–8.07 (m, 12H,
ArH’s). Anal. calcd for C24H20Br2O4 (529.97): C, 54.16; H, 3.79;
EXPERIMENTAL
General. Melting points were determined in open glass
capillaries with a Gallenkamp apparatus and were not corrected.
The infrared spectra were recorded in potassium bromide disks
on a Pye Unicam SP 3–300 and Shimadzu FTIR 8101 PC
Br, 30.03. Found: C, 53.89; H, 3.62; Br, 29.74.
Synthesis of bis(triazolo[3,4-b]thiadiazine) derivatives 4a,b,
5a,b, and 6a–c
General procedure.
Method A: to a solution of 12a–c
1
infrared spectrophotometer. The H-NMR and 13C-NMR spectra
(10 mmol) in EtOH/DMF [50 mL (30:20)] containing few drops
of piperidine, aminotriazolethiol 7a–c (20 mmol) was added.
The reaction mixture was heated under reflux for 5 h. The
solvent was then removed in vacuo, and the remaining solid
was diluted with ice-cold water (100 mL). The precipitate
obtained was collected and crystallized from the proper solvent
to give compounds 4a,b, 5a,b, and 6a–c.
Method B: A solution of 13a,b (10 mmol) in EtOH/DMF
[50 mL (30:20)] containing few drops of piperidine, or AcOH
(20 mL), was heated under reflux for 2 h. The solvent was then
removed in vacuo, and the remaining solid was diluted with ice-
cold water (100 mL). The precipitate obtained was collected and
crystallized from the proper solvent to give compounds 5b and
6b, respectively.
were determined on
a Varian Mercury VX 300 NMR
spectrometer using tetramethylsilane TMS as an internal
standard and DMSO-d6 as a solvent. Mass spectra were
measured on a GCMS-QP1000 EX spectrometer at 70eV. 1,ω-
bis(2-acetylphenoxy)alkanes 3a–c were prepared using
modified procedure to a published method [42–45].
1,ω-Bis(4-acetylphenoxy)benzenes 11a–c
a
General procedure. 4-Hydroxyacetophenone 9g (10 mmol)
was dissolved in a hot ethanolic KOH solution (prepared by
dissolving 0.56 g (10 mmol) of KOH in 10 mL of absolute
ethanol), and the solvent was then removed in vacuo. The
remaining material was dissolved in DMF (10 mL), and the
appropriate dibromides (5 mmol) were added. The reaction
mixture was refluxed for 10 min during which KBr was
separated. The solvent was then removed in vacuo, and the
remaining materials were poured onto crushed ice. The crude
precipitate of bis(acetylphenoxy)benzenes 11a–c were
recrystallized from ethanol.
6-(4-(2-((4-(3-Phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-
6-yl)phenoxy)methyl)-benzyloxy)-phenyl)-3-phenyl-7H-[1,2,4]
triazolo[3,4-b][1,3,4]thiadiazine (4a).
(55% Yield), mp
248–250 °C; IR (cmÀ1): 1601 (C═N); MS: m/z 718 (M+, 4.6%),
307 (100%), 103 (49.8%), 79 (48.6%); 1H-NMR (DMSO): δ 4.38
(s, 4H), 5.36 (s, 4H), 7.20–7.23 (d, 4H, J = 9 Hz), 7.38–7.43
(m, 4H), 7.53–7.56 (m, 6H), 7.95–7.99 (m, 4H), 7.99–8.02
(m, 4H). Anal. calcd for C40H30N8O2S2 (718.85): C, 66.83; H,
4.21; N, 15.59; S, 8.92. Found: C, 66.71; H, 3.89; N, 15.73; S, 8.66.
6-(4-(2-((4-(3-((4-Chlorophenoxy)methyl)-7H-[1,2,4]triazolo
[3,4-b][1,3,4]-thiadiazin-6-yl)phenoxy)methyl)benzyloxy)phenyl)-
3-((4-chlorophenoxy)methyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazine (4b). (63% Yield), mp 132–134 °C; IR (cmÀ1): 1602
(C═N); MS: m/z 848 (M++2, 7.5%), 846 (M+, 15.2%),
354 (17.2%), 97 (53.5%), 69 (60.3%), 57 (100%), 55 (87.3%);
1H-NMR (DMSO): δ 4.38 (s, 4H), 5.30 (s, 4H), 5.35 (s, 4H),
6.95–6.98 (m, 4H), 7.07–7.09 (m, 4H), 7.17 (d, 4H, J = 8.7 Hz),
7.35–7.43 (m, 2H), 7.46–7.52 (m, 2H), 7.93 (d, 4H, J = 8.4 Hz).
Anal. calcd for C42H32Cl2N8O4S2 (847.79): C, 59.50; H, 3.80;
Cl, 8.36; N, 13.22; S, 7.56. Found: C, 59.37; H, 3.59; Cl, 8.12;
N, 13.16; S, 7.44.
1,2-Bis(4-acetylphenoxymethyl)benzene
(11a).
(93%
Yield), mp 136 °C (ethanol); IR (cmÀ1): 1666 (C═O); MS: m/z
374 (M+, 57.9%), 357 (14.36%), 239 (100%); 1H-NMR
(DMSO): δ 2.50 (s, 6H), 5.33 (s, 4H), 7.11 (d, 4H, J = 6.9 Hz),
7.37–7.40 (m, 2H), 7.53–7.54 (m, 2H), 7.90 (d, 4H, J = 7 Hz).
Anal. calcd for C24H22O4 (374.43): C, 76.99; H, 5.92. Found:
C, 77.14; H, 5.93.
1,3-Bis(4-acetylphenoxymethyl)benzene (11b). (90% Yield),
mp 140 °C (ethanol) (ref. [42] 139–140 °C).
1,4-Bis(p-acetylphenoxymethyl)benzene (11c). (92% Yield),
mp 200–202 °C (ethanol) (ref. [43] 181–182 °C).
Synthesis of bis(α-bromoacetophenones) (12a–c)
General procedure. To a stirred solution of bis(acetophenone)
derivatives 11a–c (10 mmol) and p-TsOH (5.6 g, 20 mmol) in
acetonitrile (50 mL) was slowly added NBS (3.6 g, 20 mmol).
The reaction mixture was heated under reflux with stirring for
1–2 h then left to cool to room temperature. The solvent was
evaporated in vacuo, and the residue was dissolved in
chloroform (50 mL), washed with water (2 × 20 mL), and dried
over MgSO4. After evaporation of the solvent, the resulting
solid was recrystallized from benzene or ethyl acetate to afford
the corresponding bis(α-bromoketone) derivatives 12a–c,
respectively.
6-(4-(3-((4-(3-Phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-
6-yl)phenoxymethyl)-benzyloxy)-phenyl)-3-phenyl-7H-[1,2,4]
triazolo[3,4-b][1,3,4]-thiadiazine (5a).
(50% Yield), mp
245–247 °C (acetic acid); IR (cmÀ1): 1599 (C═N); MS: m/z 718
(M+, 0.1%), 308 (53.7%), 276 (100%), 119 (88%), 103 (96%);
1H-NMR (DMSO): δ 4.40 (s, 4H), 5.24 (s, 4H), 7.20 (d, 4H,
J = 8.7Hz), 7.43–7.47 (m, 4H), 7.53–7.58 (m, 6H), 7.96–8.03
(m, 8H). Anal. calcd for C40H30N8O2S2 (718.85): C, 66.83;
H, 4.21; N, 15.59; S, 8.92. Found: C, 66.49; H, 3.88; N, 15.23;
1,2-Bis(4-bromoacetylphenoxymethyl)benzene (12a).
(96%
1
Yield), mp 132 °C (ethylacetate); IR (cmÀ1): 1662 (C═O); H-
NMR (DMSO): δ 4.81 (s, 4H), 5.36 (s, 4H), 7.15 (d, 4H,
J = 8.7 Hz), 7.41 (m, 2H, ArH’s), 7.54 (m, 2H, ArH’s), 7.97
(d, 4H, J = 8.7 Hz). Anal. calcd for C24H20Br2O4 (529.97): C,
54.16; H, 3.79; Br, 30.03. Found: C, 54.42; H, 3.81; Br, 29.93.
S, 8.67.
6-(4-(3-((4-(3-((4-Chlorophenoxy)methyl)-7H-[1,2,4]triazolo
[3,4-b][1,3,4]thiadiazin-6-yl)phenoxy)-methyl)benzyloxy)phenyl)-
3-((4-chlorophenoxy)methyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazine (5b). (70% Yield), mp 128–130 °C; IR (cmÀ1):
1597 (C═N); MS: m/z 848 (M++2, 8.3%), 846 (M+, 8.2%),
240 (100%), 136 (60.7%), 78 (69.7%); 1H-NMR (DMSO): δ
4.40 (s, 4H), 5.23 (s, 4H), 5.38 (s, 4H), 7.10–7.94 (m, 20H,
1,3-Bis(4-bromoacetylphenoxymethyl)benzene (12b).
(90%
Yield), mp 108–110 °C (ethylacetate); IR (cmÀ1): 1668 (C═O); 1H-
NMR (DMSO): δ 4.82 (s, 4H), 5.25 (s, 4H), 7.15 (d, 4H, J=9.15Hz),
7.44–7.45 (m, 3H, ArH’s), 7.57 (s, 1H), 7.98 (d, 4H, J=6.9Hz).
Journal of Heterocyclic Chemistry
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A. R. S. Ginidi, M. R. Shaaban, A. M. Farag, and A. H. M. Elwahy
Vol 000
ArH’s). Anal. calcd for C42H32Cl2N8O4S2 (847.79): C, 59.50;
Synthesis of bis(thiazole) derivatives (23–36)
H, 3.80; Cl, 8.36; N, 13.22; S, 7.56. Found: C, 59.22; H,
3.68; Cl, 7.94; N, 12.91; S, 7.52.
6-(4-(4-((4-(3-Phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-
6-yl)phenoxy)methyl)-benzyloxy)-phenyl)-3-phenyl-7H-[1,2,4]
General procedure.
A mixture of the appropriate bis
(bromoacetophenone) compounds 12a–c and 14–19 (0.01 mol),
thiourea, N-mehtylthiourea, or thioacetamide (0.02 mol) in
ethanol or ethanol/dioxane was heated under reflux for 3–5 h.
The solid obtained upon cooling was filtered, collected, and
recrystallized from acetic acid to give the corresponding bis
triazolo[3,4-b][1,3,4]thiadiazine (6a).
(55% Yield), mp
252–254 °C (acetic acid); IR (cmÀ1): 1600 (C═N); MS: m/z
718 (M+, 3.5%), 213 (7.3%), 98 (86.3%), 80 (100%),
55 (51.1%); 1H-NMR (DMSO): δ 4.32 (s, 4H), 5.20 (s, 4H),
7.14–7.99 (m, 22H, ArH’s); 13C-NMR: δ 22.50, 69.21, 115.51,
125.71, 126.07, 127.85, 128.65, 129.20, 130.07, 136.28,
142.48, 151.43, 155.37, 161.26, 171.89. Anal. calcd for
C40H30N8O2S2 (718.85): C, 66.83; H, 4.21; N, 15.59; S, 8.92.
Found: C, 66.51; H, 3.87; N, 15.24; S, 8.69.
(thiazole) products 23–36.
5-(4-(2-(4-(2-Aminothiazol-5-yl)phenoxy)ethoxy)phenyl)thiazol-
2-amine (23). (60% Yield), mp 301 °C; IR (cmÀ1): 3231–3181
(NH2);MS: m/z 410 (M+, 100%) 218 (47%), 191 (72%); 1H-
NMR (DMSO): δ 3.57 (br, 4H), 4.36–4.39 (m, 4H), 7.03–7.77
(m, 8H, ArH’s), 7.74 (s, 2H). Anal. calcd forC20H18N4O2S2
(410.09): C, 58.52; H, 4.42; N, 13.65. Found: C, 57.98; H,
4.16; N, 13.41.
6-(4-(4-((4-(3-((4-Chlorophenoxy)methyl)-7H-[1,2,4]triazolo
[3,4-b][1,3,4]-thiadiazin-6-yl)phenoxy)methyl)benzyloxy)phenyl)-
3-((4-chlorophenoxy)methyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazine (6b). (57%, Method A, % Method B), 198–200 °C;
IR (cmÀ1): 1598 (C═N); MS: m/z 848 (M++ 2, 1.2%), 847
(M+, 0.8%), 339 (2.2%), 245 (100%), 84 (57.5%); 1H-
NMR (DMSO): δ 4.40 (s, 4H), 5.22 (s, 4H), 5.38 (s,
4H), 7.12–7.95 (m, 20H, ArH’s). Anal. calcd for
C42H32Cl2N8O4S2 (847.79): C, 59.50; H, 3.80; Cl, 8.36;
N, 13.22; S, 7.56. Found: C, 50.19; H, 3.64; Cl, 8.41;
N, 12.88; S, 7.44.
5-(4-(4-(4-(2-Aminothiazol-5-yl)phenoxy)butoxy)phenyl)thiazol-
2-amine (24). (65% Yield), mp 285 °C; IR (cmÀ1): 3299–3184
(NH2);MS: m/z 438 (M+, 11%), 246 (42%), 57 (100%);1H-
NMR (DMSO): δ 1.88–1.92 (m, 4H), 4.09–4.12 (m, 4H), 4.10
(s, 4H), 7.03–7.67 (m, 8H, ArH’s), 7.05 (s, 2H); 13C-NMR
(DMSO): δ25.27,67.53, 100.51, 114.87, 120.54, 127.28,
159.37, 168.16, 170.09. Anal. calcd for C22H22N4O2S2
(438.12): C, 60.25; H, 5.06; N, 12.78. Found: C, 59.79; H,
4.82; N, 12.41.
5-(4-(2-((4-(2-Aminothiazol-5-yl)phenoxy)methyl)benzyloxy)
6-(4-(4-((4-(3-((p-Tolyloxy)methyl)-7H-[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazin-6-yl)phenoxy)-methyl)benzyloxy)phenyl)-3-
((p-tolyloxy)methyl)-7H-[1,2,4]-triazolo[3,4-b][1,3,4]thiadiazine
phenyl)thiazol-2-amine (25).
(55% Yield), mp 250–252 °C
(acetic acid); IR (cmÀ1): 3223 (br, NH2); MS: m/z 486.1 (M+,
10.2%), 295 (25.6%), 192 (100%), 150 (46.3%), 64 (54.5%);
1H-NMR (DMSO): δ 3.76 (br, 4H), 5.30 (s, 4H), 7.06 (s, 2H),
7.09–7.73 (m, 12H, ArH’s). Anal. calcd forC26H22N4O2S2
(486.12): C, 64.17; H, 4.56; N, 11.51. Found: C, 63.81; H,
4.23; N, 11.58.
(6c).
(65% Yield), mp 90–92 °C (acetic acid); IR (cmÀ1):
1600 (C═N); MS: m/z 806 (M+, 3.4%), 402 (7.5%), 107
(100%), 79 (21.7%); 1H-NMR (DMSO): δ 2.23 (s, 6H), 4.39
(s, 4H), 5.23 (s, 4H), 5.31 (s, 4H), 6.96–7.95 (m, 20H,
ArH’s). Anal. calcd for C44H38N8O4S2 (806.95): C, 65.49;
H, 4.75; N, 13.89; S, 7.95. Found: C, 65.11; H, 4.43; N,
13.91; S, 7.84.
5-(2-(2-(2-(2-(Methylamino)thiazol-5-yl)phenoxy)ethoxy)phenyl)-
N-methylthiazol-2-amine (26).
(63% Yield), mp 282–284 °C;IR
(cmÀ1): 3174 (NH);: m/z 438 (M+, 36%), 260 (72%), 149
(100%);1H-NMR (DMSO): δ 2.91 (s, 6H), 3.72 (br, 2H), 4.46 (s,
4H), 7.05–7.70 (m, 8H, ArH’s), 7.09 (s, 2H); Anal. calcd for
C22H22N4O2S2 (438.12): C, 60.25; H, 5.06; N, 12.78. Found: C,
59.91; H, 5.18; N, 12.66.
Synthesis of bis(aminotriazoles) (13a,b). To a solution of
12b,c (10 mmol) in EtOH/DMF [50 mL (30:20)] containing few
drops of piperidine, aminotriazole 7c (20 mmol) was added. The
reaction mixture was heated under reflux for 2 h. The solvent
was then removed in vacuo, and the remaining solid was diluted
with ice-cold water (100 mL). The precipitate obtained was
collected and crystallized from the proper solvent to give
5-(2-(3-(2-(2-(Methylamino)thiazol-5-yl)phenoxy)propoxy)
phenyl)-N-methylthiazol-2-amine (27).
(58% Yield), mp
178–180 °C;IR (cmÀ1): 3349 (NH);: m/z 452 (M+, 100%), 246
(74%);1H-NMR (DMSO): δ 2.18–2.22 (m, 2H), 2.96–3.05 (m,
6H), 3.79 (br, 2H),4.17–4.21 (m, 4H),7.00–7.08–7.69 (m, 10H,
ArH’s); Anal. calcd for C23H24N4O2S2 (452.13): C, 61.04; H,
5.34; N, 12.38. Found: C, 60.71; H, 5.18; N, 12.27.
compounds 13a,b.
1,1′-(4,4′-(1,3-Phenylenebis(methylene))bis(oxy)bis(4,1-phenylene))
bis(2-(4-amino-5-phenyl-4H-1,2,4-triazol-3-ylthio)ethanone)
(13a). (75% Yield), mp 202–204 °C; IR (cmÀ1): 1670 (C═O),
3170–3313 (NH2); MS: m/z 883 (M+, 45.4%), 882 (8.7%),
555 (51.3%), 320 (48.2%), 128 (100%); 1H-NMR (DMSO):
δ 4.84 (s, 4H), 5.17 (s, 4H), 5.25 (s, 4H), 6.08 (s, 4H),
5-(4-(4-(4-(2-(Methylamino)thiazol-5-yl)phenoxy)butoxy)
phenyl)-N-methylthiazol-2-amine (28).
(70% Yield), mp
258 °C;IR (cmÀ1): 3224 (NH);: m/z 466 (M+, 100%), 177
(59%), 149 (64%);1H-NMR (DMSO): δ 1.88–1.90 (m, 4H),
3.00 (s, 6H), 3.56 (br, 2H), 4.03–4.10 (m, 4H), 6.98–7.77
(m, 8H, ArH’s), 7.02 (s, 2H); Anal. calcd for C24H26N4O2S2
(466.15): C, 61.78; H, 5.62; N, 12.01. Found: C, 61.41; H,
7.09–8.02
(m,
20H,
ArH’s).
Anal.
calcd
for
C42H36Cl2N8O6S2 (883.82): C, 57.08; H, 4.11; Cl, 8.02; N,
12.68; S, 7.26. Found: C, 55.79; H, 3.84; Cl, 7.71; N,
12.45; S, 7.19.
1,1′-(4,4′-(1,4-Phenylenebis(methylene))bis(oxy)bis(4,1-phenylene))
bis(2-(4-amino-5-phenyl-4H-1,2,4-triazol-3-ylthio)ethanone)
5.55; N, 11.89.
5-(2-(2-(2-(2-Methylthiazol-5-yl)phenoxy)ethoxy)phenyl)-2-
(13b). (70% Yield), mp 182–184 °C; 1671 (C═O), 3171–3316
methylthiazole (29).
(72% Yield), mp 263–265 °C; MS:
(NH2); MS: m/z 883 (M+, 4.8%), 882 (11.3%), 211 (58.4%), 64
m/z 408 (M+, 4.4%), 407 (6.6%), 217 (15%), 190 (17.6%),
79 (100%), 63 (46.9%); 1H-NMR (DMSO): δ 2.70 (s, 6H),
4.58 (s, 4H), 7.02-7.33 (m, 6H, ArH’s), 7.82 (s, 2H), 7.14
(d, 2H, J = 7.8 Hz). Anal. calcd for C22H20N2O2S2 (408.1):
C, 64.68; H, 4.93; N, 6.86. Found: C, 64.96; H, 4.72;
N, 6.98.
1
(100%), 54 (98.4%); H-NMR (DMSO): δ 4.84 (s, 4H), 5.17 (s,
4H), 5.24 (s, 4H), 6.07 (br, 4H), 7.09–8.02 (m, 20H, ArH’s).
Anal. calcd for C42H36Cl2N8O6S2 (883.82): C, 57.08; H, 4.11; Cl,
8.02; N, 12.68; S, 7.26. Found: C, 56.63; H, 3.78; Cl, 7.81; N,
12.47; S, 6.92.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Bis(α-bromo ketones): Versatile Precursors for Novel Bis(s-triazolo[3,4-b][1,3,4]
thiadiazines) and Bis(thiazoles)
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5-(2-(4-(2-(2-Methylthiazol-5-yl)phenoxy)butoxy)phenyl)-2-
methylthiazole (30).
(66% Yield), mp 234 °C; 1H-NMR
(DMSO): δ 2.02 (br, 4H), 2.48 (s, 6H), 4.19 (s, 4H), 6.99–7.32
(m, 6H, ArH’s), 7.88 (s, 2H), 8.07–8.09 (m, 2H, ArH’s). Anal.
calcd for C24H24N2O2S2 (436.13): C, 66.02; H, 5.54; N, 6.42.
Found: C, 65.71; H, 5.23; N, 6.11.
5-(4-(2-(4-(2-Methylthiazol-5-yl)phenoxy)ethoxy)phenyl)-2-
methylthiazole (31). (80% Yield), mp 216 °C; MS: m/z 408
(M+, 33.6%), 353 (56.9%), 80 (100%), 64 (72.5%); 1H-NMR
(DMSO): δ 2.69 (s, 6H), 4.36 (s, 4H), 7.04 (d, 4H, J = 6.9 Hz),
7.75 (s, 2H), 7.86 (d, 4H, J = 6.9 Hz). Anal. calcd for
C22H20N2O2S2 (408.1): C, 64.68; H, 4.93; N, 6.86. Found: C,
64.47; H, 4.66; N, 6.95.
5-(4-(3-(4-(2-methylthiazol-5-yl)phenoxy)propoxy)phenyl)-2-
methylthiazole (32).
(58% Yield), mp 176 °C; MS: m/z 422
1
(M+, 28.6%), 421 (100%), 232 (55.5%), 121 (28.5%); H-NMR
(DMSO): δ 2.18–2.20 (m, 2H), 2.69 (s, 6H), 4.17-4.21 (m, 4H),
7.00 (d, 4H, J = 7.8 Hz), 7.66 (s, 2H), 7.84 (d, 4H, J = 8.1 Hz).
Anal. calcd for C23H22N2O2S2(422.11): C, 65.37; H, 5.25; N,
6.63. Found: C, 64.96; H, 5.48; N, 6.59.
5-(4-(4-(4-(2-Methylthiazol-5-yl)phenoxy)butoxy)phenyl)-2-
methylthiazole (33).
(83% Yield), mp 173 °C; 1H-NMR
[14] Mavrova, A. T.; Wesselinova, D.; Tsenov, Y. A.; Denkova, P.
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Mehrabi, N.; Dalvandi, A.; Shafiee, A. Bioorg Med Chem Lett 2004, 14,
6057–6059.
(DMSO): δ 1.88–1.91 (m, 4H), 2.68 (s, 6H), 4.06–4.07
(m, 4H), 6.98 (d, 4H, J = 7.8 Hz), 7.72 (s, 2H), 7.84
(d, 4H, J = 8.1 Hz); Anal. calcd for C24H24N2O2S2(436.13):
C, 66.02; H, 5.54; N, 6.42. Found: C, 65.73; H, 5.12;
N, 6.55.
5-(4-(2-((4-(2-Methylthiazol-5-yl)phenoxy)methyl)benzyloxy)
phenyl)-2-methylthiazole (34). (88% Yield), mp 190–192 °C;
[17] Amir, M.; Shikha, K. Eur J Med Chem 2004, 39, 535–545.
[18] Karegoudar, P.; Prasad, D. J.; Ashok, M.; Mahalinga, M.;
Poojary, B.; Holla, B. S. Eur J Med Chem 2008, 43, 808–815.
[19] Amir, M.; Kumar, H.; Javed, S. A. Eur J Med Chem 2008, 43,
2056–2066.
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Goktas, O.; Unuvar, S. Eur J Med Chem 2009, 44, 4528–4538.
[21] Bhat, K. S.; Poojary, B.; Prasad, D. J.; Naik, P.; Holla, B. S.
Eur J Med Chem 2009, 44, 5066–5070.
[22] Kaplancikli, Z. A.; Turan-Zitouni, G.; Ozdemir, A.; Revial, G.
Eur J Med Chem 2008, 43, 155–159.
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Med Chem 2005, 40, 1156–1162.
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Arkivoc 2005, 1, 75–91.
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P. M. Eur J Med Chem 2006, 41, 657–663.
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J Med Chem 2010, 45, 1906–1911.
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R.; Gupta, J. K. Med Chem Res 2012, 21, 2123–2132.
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M. Bioorg Med Chem 2011, 19, 3135–3140.
IR (cmÀ1):1604 (C═N); MS: m/z 484 (M+, 28.9%), 294
1
(100%), 293 (50.5%), 104 (63.4%); H-NMR (DMSO): δ 2.70
(s, 6H), 5.285 (s, 4H), 7.09 (d, 4H, J = 8.4 Hz), 7.36–7.56 (m,
4H, ArH’s), 7.74 (s, 2H), 7.85 (d, 4H, J = 8.4 Hz). Anal. calcd
for C28H24N2O2S2 (484.13): C, 69.39; H, 4.99; N, 5.78. Found:
C, 68.85; H, 4.73; N, 5.56.
5-(4-(3-((4-(2-Methylthiazol-5-yl)phenoxy)methyl)benzyloxy)
phenyl)-2-methylthiazole (35).
(65% Yield), mp 153–155 °C
(acetic acid); IR (cmÀ1): 1606 (C═N); MS: m/z 484 (M+,
1.9%), 395 (49.7%), 372 (49.7%), 278 (50.7%), 128 (100%);
1H-NMR (DMSO): δ 2.66 (s, 6H), 5.13 (s, 4H), 7.04 (d, 4H,
J = 9.3 Hz), 7.40–7.53 (m, 4H, ArH’s), 7.64 (s, 2H), 7.82 (d,
4H, J = 9 Hz); 13C-NMR: δ 18.79, 69.17, 111.88, 114.80,
115.15, 127.13, 127.45, 129.29, 137.24, 153.40, 158.11,
165.40. Anal. calcd for C28H24N2O2S2 (484.13): C, 69.39; H,
4.99; N, 5.78. Found: C, 69.66; H, 5.25; N, 5.42.
5-(4-(4-((4-(2-Methylthiazol-5-yl)phenoxy)methyl)benzyloxy)
phenyl)-2-methylthiazole (36). (68% Yield), mp 230 °C (acetic
acid); IR (cmÀ1): 1605 (C═N); MS: m/z 484 (M+, 15.5%), 294
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1
(48.2%), 190 (74.6%), 104 (100%); H-NMR (DMSO): δ 2.66
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Güllüce, M. Eur J Med Chem 2006, 41, 353–359.
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Abdalla, M. M. Monatsh Chem 2008, 139, 1083–1090.
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(s, 6H), 5.12 (s, 4H), 7.03 (d, 4H, J = 6.9 Hz), 7.45–7.47
(m, 4H, ArH’s), 7.66 (s, 2H), 7.82 (d, 4H, J = 6.9 Hz). Anal.
calcd forC28H24N2O2S2 (484.13): C, 69.39; H, 4.99; N, 5.78.
Found: C, 68.97; H, 5.22; N, 5.46.
REFERENCES AND NOTES
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