Bis(α-bromo ketones): Versatile precursors for novel Bis(s-triazolo[3,4-b][1,3,4]thiadiazines) and Bis(as-triazino[3,4-b][1,3,4] thiadiazines)

Article abstract of DOI:10.1002/jhet.861

A synthesis of bis(α-bromo ketones) 5a-c and 6b,c was accomplished by the reaction of bis(acetophenones) 3a-c and 4b,c with N-bromosuccinimide in the presence of p-toluenesulfonic acid (p-TsOH). Treatment of 5a-c and 6b,c with each of 4-amino-3-mercapto-1

Full text of DOI:10.1002/jhet.861

640
Bis(a-bromo ketones): Versatile Precursors for Novel
Bis(s-triazolo[3,4-b][1,3,4]thiadiazines) and
Bis(as-triazino[3,4-b][1,3,4]thiadiazines)
a
Vol 49
Mohamed R. Shaabana,b and Ahmed H. M. Elwahy
*
aDepartment of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
bDepartment of Chemistry, Faculty of Applied Science, Umm Al-Qura University,
Makkah Almukkarramah, Saudi Arabia
*
E-mail: aelwahy@hotmail.com
Received November 6, 2010
DOI 10.1002/jhet.861
View this article online at wileyonlinelibrary.com.
A synthesis of bis(a-bromo ketones) 5a-c and 6b,c was accomplished by the reaction of bis(acetophe-
nones) 3a-c and 4b,c with N-bromosuccinimide in the presence of p-toluenesulfonic acid (p-TsOH).
Treatment of 5a-c and 6b,c with each of 4-amino-3-mercapto-1,2,4-triazoles 9a,b and 4-amino-6-phenyl-3-
mercapto-1,2,4-triazin-5(4H)-ones 13 in refluxing ethanol afforded the novel bis(s-triazolo[3,4-b]
[1,3,4]thiadiazines) 10a-d and 11a-c as well as bis(as-triazino[3,4-b][1,3,4]thiadiazines) 14a-c and
15, respectively, in good yields. Compounds 11b and 11c underwent NaBH4 reduction in methanol
to give the target 1,ω-bis{4-(6,7-dihydro-3-substituted-5H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazin-6-yl)
phenoxy}butanes 12a and 12b in 42 and 46% yields, respectively.
J. Heterocyclic Chem., 49, 640 (2012).
INTRODUCTION
In general, a-bromo carbonyl compounds can be con-
ventionally obtained by the reaction of carbonyl com-
pounds with various reagents such as bromine [45],
copper (II) bromide [46,47], dioxane dibromide [48] tetra-
butylammonium tribromide [49], and polymer-supported
pyridinium bromide perbromide [50]. In addition, the
N-bromosuccinimide (NBS) has been classically utilized for
the a-bromination of ketones via radical process promoted
by radical initiators such as AIBN and benzoyl peroxide in
CCl4 [51].
Keeping the above facts in mind and in continuation of
our interest in the synthesis of bis(heterocycles) [52–59],
we describe herein a simple and efficient route for the
synthesis of novel bis(a-bromo ketones) and studied their
synthetic utilities as key intermediates for the synthesis
of novel bis(s-triazolo[3,4-b][1,3,4]thiadiazines) as well
as bis(as-triazino[3,4-b][1,3,4]thiadiazines).
Bis-heterocyclic compounds with a suitable alkyl 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,
that 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].
In recent decades, the synthesis and pharmacological
activities of 1,2,4-triazoles and their heterocyclic fused
analogues (e.g., triazolothiadiazoles and triazolothiadiazines)
have attracted much attention because they display a
variety of medical applications such as antibacterial,
antifungal, anticancer, antitumor, anticonvulsant, anti-
inflammatory, antimicrobial activity and analgesic
properties [12–26].
In addition, 1,2,4-triazines and their fused derivatives
have been widely studied in terms of their synthetic
xmethodologies and reactivity since some of these
derivatives were reported to have promising biological
activities [27–35].
a-Bromo ketones are valuable compounds, which are
useful in the synthesis of a variety of heterocycles [36–40]
as well as in other synthetic applications including cross aldol
condensations [41], enaminoketones [42] and Favorskii
rearrangements [43,44]
RESULTS AND DISCUSSION
In search of an expedient pathway to prepare the target
bis(a-bromo ketones) 5a-c and 6b,c our attention focused
on bis(acetophenones) 3a-c and 4a-c as precursors which
could be obtained by the reaction of the potassium salt
2-hydroxyacetophenone 1a and 4-hydroxyacetophenones
1b with the appropriate dibromoalkanes 2a-c in boiling
DMF (Scheme 1).
© 2012 HeteroCorporation

May 2012
Bis(a-bromo ketones): Versatile Precursors for Novel Bis(s-triazolo
[3,4-b][1,3,4]thiadiazines) and Bis(as-triazino[3,4-b][1,3,4]thiadiazines)
641
Scheme 1
N-bridged heterocycles. Thus, reaction of 5a-c and 6b,
c with 9a,b in anhydrous ethanol under reflux afforded
10a-d and 11a-c in 58–95% yields.
Compounds 11b and 11c underwent NaBH4 reduction
in methanol to give the target 1,ω-bis{4-(6,7-dihydro-3-
substituted-5H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazin-6-yl)
phenoxy}butanes 12a,b in 60–65% yields (Scheme 5).
Similarly, a series of 1,2,4-triazino[3,4-b][1,3,4]thiadiazin-
4-ones 14a-c and 15 have been synthesized in 63–72%
yield by the reaction of 4-amino-6-phenyl-3-mercapto-
1,2,4-triazin-5(4H)-ones 14a-c and 15 with the appropriate
bis(a-bromo ketones) 5a-c and 6c in refluxing ethanol
(Scheme 6).
All compounds were characterized by their melting
points, elementary analysis, IR, 1H NMR and mass spectra.
The spectral data agree with the proposed structures. Thus,
the disappearance of NH2 stretching bands in the IR
spectra of triazolothiadiazines 10a-d and 11a-c as well as
triazinothiadiazin-4-ones 14a-c and 15, together with the
disappearance of the characteristic peaks belonging to
1
primary amine in their H NMR spectra are evidences for
the cyclocondensation of the appropriate bis(a-bromo
ketones) with each of 9a,b and 13, respectively. In
addition, the presence of SCH2 protons, resonated at
d 4.24–4.57 ppm as singlet signals integrating four pro-
tons, clearly indicated that ring closure reaction occurred.
All other protons were seen at the expected chemical shifts
and integral values. Compounds 12a and 12b showed in
First attempts to synthesize 5a and 6b by bromination
of 3a and 4b with Br2 in acetic acid led to the formation
of a mixture of the bis(a-bromo ketones) 5a and 6b as
well as the undesirable bis(a,a-dibromoketones) 7a and
8b (Scheme 2). The 1H NMR spectra of the reaction
products indicated the presence of CH2–Br protons, reso-
nated at d 4.39–4.49 ppm as singlet signals integrating four
protons, and CHBr2 protons, resonated at d 6.66–6.96 ppm
as singlet signals integrating two protons. Unfortunately, all
attempts to separate the two products were unsuccessful.
On the other hand, the reaction of 3a-c and 4b,c with
NBS in the presence of p-toluenesulfonic acid (p-TsOH)
in acetonitrile afforded the corresponding bis(a-bromo
ketones) 5a-c and 6b,c as single monobrominated ketones
in most instances in high yield (Scheme 3).
The synthetic utility of compounds 5a-c and 6b,c as
building blocks for novel bis(5,6-dihydro-s-triazolo[3,4-b]
thiadiazines) 10a-d and 11a-c is outlined in Scheme 4.
4-Amino-3-mercapto-1,2,4-triazole derivatives 9a,b were
chosen as ideal heterocyclic reagents. The amino and
mercapto groups of these compounds serve as readily
accessible nucleophilic centers for the preparation of
1
their H-NMR spectra a well resolved doublet signal for
N5-H, two dd singlet for C7-Ha and C7-He and a multiplet
signal for C6-H. The two protons of C7–H2 (for compound
12a and 12b) each appears as dd as a result of the geminal
coupling (2 J = 12.6 Hz) as well as the vicinal coupling
constants with C6-H. The large vicinal coupling
3
3
constants J5,6 = 8.7–9.3 Hz, J6,7 = 8.7 Hz indicate
trans relationship of N5-H, C6-H and C6-H, C7-Ha. On
the other hand, the small vicinal coupling constant
3
J6,7e = 2.7–3.0 Hz indicate the cis relationship of C6-H,
C7-He.
In conclusion we synthesized new series of bis(a-bromo
ketones) via the reaction of bis(acetophenones) with NBS
in the presence of p-TsOH in acetonitrile. The synthetic
utility of these compounds as building blocks for novel
bis(5,6-dihydro-s-s-triazole[3,4-b]thiadiazines) as well as
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

642
M. R. Shaaban and A. H. M. Elwahy
Vol 49
Scheme 3
spectra were recorded in potassium bromide disks on a Pye
Unicam SP 3-300 and Shimadzu FTIR 8101 PC infrared spectro-
photometer. The 1H and 13C NMR spectra were determined on a
Varian Mercury VX 300 NMR spectrometer using TMS as an
internal standard and DMSO-d6 as a solvent. Mass spectra were
measured on a GCMS-QP1000 EX spectrometer at 70 eV. 1,
ω-bis(2-acetylphenoxy)alkanes 3a-c and 1,ω-bis(4-acetylphenoxy)
alkanes 4a,b were prepared according to published procedures
[53,60].
bis(as-triazino[3,4-b][1,3,4] thiadiazines) have been investi-
gated. The novel starting bis(a-bromo ketones) would open
a new access to a variety of heterocyclic systems with possible
pharmaceutical properties. The new synthesized bis (fused het-
erocycles) offer an advantage of their easy synthesis on a large
scale in a simple procedure from inexpensive starting materials
and we believe that they should be useful compounds with po-
tentially high pharmacological and biological activities.
Synthesis of 1,ω-bis(2-acetylphenoxy)alkanes 3a-c and 1,
ω-bis(4-acetylphenoxy)alkanes 4a-c. 2-Hydroxyacetophenone 1a
or 4-hydroxyacetophenone 1b (10 mmol) was dissolved in 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
EXPERIMENTAL
Melting points were determined in open glass capillaries with a
Gallenkamp apparatus and were not corrected. The infrared
Scheme 4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2012
Bis(a-bromo ketones): Versatile Precursors for Novel Bis(s-triazolo
[3,4-b][1,3,4]thiadiazines) and Bis(as-triazino[3,4-b][1,3,4]thiadiazines)
643
Scheme 5
(10 mL) and the appropriate dibromides (5 mmol) was 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 was poured onto crushed ice.
The crude precipitates of bis(acetylphenoxy)alkanes 3a-c and
4a-c were recrystallized from ethanol [53,60].
Hz), 7.22 (d, 2H, J = 9 Hz), 7.58 (t, 2H, J = 9 Hz), 7.69 (d, 2H,
J = 9 Hz); 13C NMR: d 28.10, 28.31, 65.52, 89.5, 113.20,
126.18, 128.98, 129.9, 133.51, 191.69; ms: m/z (%) 472 (M++4, 0.43),
470 (M++2, 0.82), 468 (M+, 0.52), 377 (25), 255 (26), 175 (70), 121
(100). Anal. Calcd. for C19H18Br2O4: C, 48.54; H, 3.86. Found: C,
48.57; H, 3.88.
1,2-bis(2-bromoacetylphenoxy)butane 5c. Yield 92%, mp.
Synthesis of bis(a-bromo ketones) 5a-c and 6b,c.
To a
145ꢁC; IR: (potassium bromide) 1670 (C¼O) cmꢂ1
;
1H
stirred solution of bis(acetophenone) derivatives 3a-c or 4b,c
(l0 mmol) and p-TsOH (5.6 g, 20 mmol) in acetonitrile (50
mL) was slowly added NBS (3.6 g, 20 mmol). After
addition of NBS was complete, the reaction mixture was
refluxed 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 to afford the corresponding bis(a-bromo ketone)
derivatives 5a-c and 6b,c, respectively.
NMR: d 2.00–2.01 (m, 4H), 4.18 (brs, 4H), 4.75 (s, 4H),
7.05 (t, 2H, J = 9 Hz), 7.20 (d, 2H, J = 9 Hz), 7.55 (t, 2H,
J = 9 Hz), 7.68 (d, 2H, J = 9 Hz); ms: m/z (%) 486 (M++4,
0.01), 484 (M++2, 0.05), 482 (M+, 0.02), 325 (0.74), 215
(0.04), 137 (16), 121(59), 55 (100). Anal. Calcd. for
C20H20Br2O4: C, 49.61; H, 4.16. Found: C, 49.60; H, 4.18.
1,2-bis(4-bromoacetylphenoxy)propane 6b.
Yield 85ꢂ%1,
mp. 165ꢁC; IR: (potassium bromide) 1674 (C¼O) cm
;
1H NMR: d 2.22 (brs, 2H), 4.21 (brs, 4H), 4.71(s, 4H), 7.07
(d, 4H, J = 9 Hz), 7.95 (d, 4H, J = 9 Hz); ms: m/z (%) 472
(M++4, 1.04), 470 (M++2, 1.4), 468 (M+, 0.52), 430 (0.7),
375 (12), 297 (30), 241 (9), 149 (35), 121 (100). Anal.
Calcd. for C19H18Br2O4: C, 48.54; H, 3.86. Found: C,
48.55; H, 3.85.
1,2-bis(2-bromoacetylphenoxy)ethane 5a. Yield (68%), mp
1
105ꢁC; IR: (potassium bromide) 1675 (C¼O) cmꢂ1; H NMR:
d 4.55 (s, 4H), 4.74 (s, 4H), 7.07 (t, 2H, J = 9 Hz), 7.27 (d, 2H,
J = 9 Hz), 7.59 (t, 2H, J = 9 Hz), 7.70 (d, 2H, J = 9 Hz);
13C NMR: d 25.14, 29.47, 89.42, 113.49, 121.14, 123.43,
129.9, 136.70, 187.87; ms: m/z (%) 458 (M++4, 1.3), 456
(M++2, 2.6), 454 (M+, 1.35), 361 (44), 241(45), 147 (45),
121 (69), 92 (100). Anal. Calcd. for C18H16Br2O4: C,
1,2-bis(2-bromoacetylphenoxy)butane 6c. Yield 95%, mp.
158ꢁC; IR: (potassium bromide) 1671 (C¼O) cmꢂ1
;
1H
NMR: d 2.01–2.09 (m, 4H), 4.18 (brs, 4H), 4.71 (s, 4H),
7.06 (d, 4H, J = 9 Hz), 7.93 (d, 4H, J = 9 Hz); 13C NMR:
d 25.53, 30.95, 67.57, 114.32, 114.48, 126.63, 129.9, 189.67;
ms: m/z (%) 486 (M++4, 0.16), 484 (M++2, 0.97), 482 (M+, 0.87),
352 (18), 323 (32), 271 (26), 207 (100), 121 (47). Anal. Calcd. for
C20H20Br2O4: C, 49.61; H, 4.16. Found: C, 49.63; H, 4.17.
47.40; H, 3.54. Found: C, 47.38; H, 3.56.
1,2-bis(2-bromoacetylphenoxy)propane 5b. Yield 83%, mp
88–89 ꢁC; IR: (potassium bromide) 1675 (C¼O) cmꢂ1; 1H NMR:
d 2.28–2.39 (m, 2H), 4.3 (t, 4H), 4.78 (s, 4H), 7.06 (t, 2H, J = 9
Scheme 6
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

644
M. R. Shaaban and A. H. M. Elwahy
Vol 49
Synthesis of bis(triazolothiadiazines) 10a-d and 11a-c and bis
(triazinothiadiazines) 14a-c and 15. General procedure.
1,4-bis{4-(3-methyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-
A
6-yl)phenoxy}butane 11c.
Yield 95%, mp. 280ꢁC; IR:
1
mixture of the appropriate bis(a-bromoacetophenone) 5a-c or
6b,c (5 mmol), and the corresponding aminotriazolthiol or
aminotriazinethiol derivative 9a,b or 13 (10 mmol) in
absolute ethanol was heated at refluxing temperature for 2 h.
The reaction mixture was then cooled and the resulting
precipitate was collected by filtration, washed thoroughly
with ethanol and dried. Recrystallization from dioxane/DMF
afforded the corresponding bis(fused heterocycle) derivatives
10a-d, 11a-d, 14a-c, and 15 in 54–95% yield.
1,2-Bis{2-(3-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-6-
yl)phenoxy}ethane 10a. Yield 78%, mp. 250ꢁC; IR: (potassium
bromide) 1608 (C¼N) cmꢂ1; 1H NMR: d 4.18 (s, 4H), 4.53 (s, 4H),
7.06 (t, 2H, J = 9 Hz), 7.28 (d, 2H, J = 9 Hz), 7.48–7.59 (m, 8H),
7.94–7.98 (m, 6H); ms: m/z (%) 642 (M+, 5), 403 (16.4), 309 (6.8),
217 (5.4), 177 (100), 76 (75.5). Anal. Calcd. for C34H26N8O2S2: C,
63.53; H, 4.08; N, 17.43. Found: C, 63.50; H, 4.11; N, 17.48.
1,2-Bis{2-(3-methyl-7 H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-
(potassium bromide) 1609 (C¼N) cmꢂ1; H NMR: d 1.92 (brs,
4H), 2.56 (s, 6H),4.17 (brs, 4H), 4.41(s, 4H), 7.12 (d, 4H, J = 9
Hz), 8.02 (d, 4H, J = 9 Hz); ms: m/z (%) 546 (M+, 20), 276
(19.4), 121 (44.4), 55 (85.2). Anal. Calcd. for C26H26N8O2S2:
C, 57.12; H, 4.79; N, 20.50. Found: C, 57.13; H, 4.81; N,
20.48.
1,2-Bis{2-(3-phenyl-[1,2,4]triazino[3,4-b][1,3,4]thiadiazin-4
(8H)-on-7-yl)phenoxy}ethane 14a.
Yield 63%, mp. 220ꢁC;
IR: (potassium bromide) 1650 (C¼O), 1602 (C¼N) cmꢂ1
;
1H NMR: d 4.17 (s, 4H), 4.57 (s, 4H), 7.10 (t, 2H, J = 9
Hz), 7.30 (d, 2H, J = 9 Hz), 7.46–7.61 (m, 8H), 8.03–8.05
(m, 6H); ms: m/z (%) 698 (M+, 5), 582 (3.5), 304 (66.3),
201 (30.2), 157 (12.8), 103 (100). Anal. Calcd. for
C36H26N8O4S2: C, 61.88; H, 3.75; N, 16.04. Found: C,
61.89; H, 3.74; N, 16.06.
1,3-Bis{2-(3-phenyl-[1,2,4]triazino[3,4-b][1,3,4]thiadiazin-4
(8H)-on-7-yl)phenoxy}-propane 14b.
Yield 68%, mp.
200ꢁC; IR: (potassium bromide) 1642 (C¼O), 1602 (C¼N)
6-yl)phenoxy}ethane 10b.
Yield 58%, mp. 243ꢁC; IR:
cmꢂ1 1H NMR: d 2.22 (brs, 2H), 4.24 (brs, 4H), 4.40 (s,
;
(potassium bromide) 1608 (C¼N) cmꢂ1
;
1H NMR: d 2.49
4H), 7.12–7.16 (m, 4H), 7.55–7.57 (m, 8H), 7.96–8.02 (m,
6H); ms: m/z (%) 712 (M+, 13), 393 (15.8), 276 (16.8), 205
(65.4), 127 (12.1), 103 (100), 76 (75.5). Anal. Calcd. for
C37H28N8O4S2: C, 62.35; H, 3.96; N, 15.72. Found: C,
62.33; H, 3.97; N, 15.75%.
(s, 6H), 4.18 (s, 4H), 4.53 (s, 4H), 7.09 (t, 2H, J = 9 Hz),
7.27 (d, 2H, J = 9 Hz), 7.53 (t, 2H, J = 9 Hz), 7.94 (d, 2H,
J = 9 Hz); ms: m/z (%) 518 (M+, 13), 484 (11.4), 304 (8.8),
213 (7.4), 76 (75.5). Anal. Calcd. for C24H22N8O2S2: C,
55.58; H, 4.28; N, 21.61. Found: C, 55.60; H, 4.26; N, 21.63.
1,3-Bis{2-(3-phenyl-7 H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-
1,4-Bis{2-(3-phenyl-[1,2,4]triazino[3,4-b][1,3,4]thiadiazin-4
Yield 73%, mp. 265ꢁC; IR:
(8H)-on-7-yl)phenoxy}butane 14c.
Yield 70%, mp. 165ꢁC;
6-yl)phenoxy}propane 10c.
IR: (potassium bromide) 1645 (C¼O) cmꢂ1, 1602 (C¼N);
1H NMR: d 1.95 (brs, 4H), 4.20 (brs, 4H), 4.24 (s, 4H),
7.07 (t, 2H, J = 9 Hz), 7.23 (d, 2H, J = 9 Hz), 7.50–7.56
(m, 8H), 8.07–8.10 (m, 6H); ms: m/z (%) 726 (M+, 5), 403
(15.4), 307 (6.8), 220 (5.4), 192 (12.1), 161 (25.8), 121
(19.3), 104 (100), 77 (75.5). Anal. Calcd. for C38H30N8O4S2:
C, 62.79; H, 4.16; N, 15.42. Found: C, 62.78; H, 4.17; N, 15.43%.
1,4-Bis{4-(3-phenyl-[1,2,4]triazino[3,4-b][1,3,4]thiadiazin-4
(potassium bromide) 1600 (C¼N) cmꢂ1
;
1H NMR: d 2.27–
2.31 (m, 2H), 4.24 (t, 4H), 4.32 (s, 4H), 7.01 (t, 2H, J = 9
Hz), 7.20 (d, 2H, J = 9 Hz), 7.48–7.54 (m, 8H), 7.94–7.97
(m, 6H); ms: m/z (%) 656 (M+, 2), 484 (27.0), 369 (1.6),
308 (4.3), 261 (12.1), 177 (100), 104 (63.9). Anal. Calcd.
for C35H28N8O2S2: C, 64.01; H, 4.30; N, 17.06. Found: C,
63.98; H, 4.33; N, 17.07.
1,4-Bis{2-(3-phenyl-7 H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-6-
Yield 83%, mp. 260ꢁC; IR:
(8H)-on-7-yl)phenoxy}butane 15.
Yield 72%, mp. 207ꢁC;
yl)phenoxy}butane 10d.
IR: (potassium bromide) 1642 (C¼O), 1600 (C¼N) cmꢂ1
;
(potassium bromide) 1605 (C¼N) cmꢂ1
;
1H NMR: d 1.92–
1H NMR: d 1.93 (brs, 4H), 4.18 (brs, 4H), 4.35 (s, 4H),
7.13 (d, 4H, J = 9 Hz), 7.47–7.52 (m, 6H), 8.03–8.06 (d, 4H,
J = 9 Hz), 8.08–8.11 (m, 4H); ms: m/z (%) 726 (M+, 9), 393
(15.4), 276 (6.8), 205(35.4), 127(62.1), 103(100), 76(75.5). Anal.
Calcd. for C38H30N8O4S2: C, 62.79; H, 4.16; N, 15.42. Found:
C, 62.81; H, 4.15; N, 15.44%.
1.98 (m, 4H), 4.16–4.23 (m, 4H), 4.22 (s, 4H), 7.03 (t, 2H,
J = 9 Hz), 7.16 (d, 2H, J = 9 Hz), 7.48–7.64 (m, 8H),
7.93–7.95 (m, 6H); ms: m/z (%) 670 (M+, 19), 646 (100),
309 (3.0), 177 (100), 118 (51.0), 76 (52.0). Anal. Calcd. for
C36H30N8O2S2: C, 64.46; H, 4.51; N, 16.70. Found: C,
64.45; H, 4.53; N, 16.72.
1,3-Bis{4-(3-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-
Reduction of bis(triazolothiadiazine) derivatives 11b,c.
General procedure. To a stirred hot (40–50 oC) solution of
each of 11a and 11c (0.7 mmol) in methanol (10 mL) was
added sodium borohydride (0.4 g) over a period of 15 min.
The reaction mixture was heated under reflux for 1 h. The
solvent was then removed in vacuo and the remaining solid
was collected, washed with water and crystallized from
ethanol to give colorless crystals of 12a and 12b
6-yl)phenoxy}propane 11a. Yield 70%, mp. 248ꢁC; IR:
(potassium bromide) 1602 (C¼N) cmꢂ1
;
1H NMR: d 2.22
(brs, 2H), 4.23(brs, 4H), 4.38(s, 4H), 7.11(d, 4H, J = 9 Hz),
7.53–7.55(m, 6H), 7.94–8.01(m, 8H); 13C NMR: d 22.58,
28.36, 64.63, 115.04, 125.51, 126.00, 127.83, 128.68,
129.44, 144.00, 150.10 151.41, 155.46, 161.48; ms: m/z (%)
656 (M+, 5), 630 (15.4), 369 (6.8), 177 (5.4), 104 (12.1).
Anal. Calcd. for C35H28N8O2S2: C, 64.01; H, 4.30; N,
17.06. Found: C, 64.03; H, 4.31; N, 17.05.
1,4-Bis{4-(3-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazine-6-yl)-phenoxy}butane 12a.
Yield 42%,
1,4-Bis{4-(3-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-6-
mp. 174ꢁC; IR: (potassium bromide) 3357 (NH), 1608 (C¼N)
1
3
2
yl)phenoxy}butane 11b. Yield 92%, mp. 240ꢁC; IR: (potassium
cmꢂ1; H NMR: d 1.8 (brs, 4H), 3.42 (dd, 2H, J = 3.0 Hz,
1
bromide) 1608 (C¼N) cmꢂ1; H NMR: d 1.92 (brs, 4H), 4.16
J = 12.6 Hz, He-7), 3.51 (dd, 2H, 3 J = 8.7 Hz, 2 J = 12.6 Hz, Ha-7),
4.0 (brs, 4H), 4.51–4.58(m, 2 H, 6-H), 6.92 (d, 2H, J = 8.7 Hz, NH),
7.14–7.99 (m, 18 H, ArHs) ppm; ms: m/z (%) 674 (M+, 20), 468
(55.6), 357 (100), 276 (18.4), 139 (48.4), 80 (87.2). Anal. Calcd. for
C36H34N8O2S2: C, 64.07; H, 5.08; N, 16.60. Found: C, 64.11; H,
5.05; N, 16.63%.
(brs, 4H), 4.41 (s, 4H), 7.12 (d, 4H, J = 9 Hz), 7.54–7.59 (m, 6H),
7.96–8.03 (m, 8H); ms: m/z (%) 670 (M+, 23), 464 (30.6), 357
(100), 276 (19.4), 139 (44.4), 80 (97.2). Anal. Calcd. for
C36H30N8O2S2: C, 64.46; H, 4.51; N, 16.70. Found: C, 64.44;
H, 4.52; N, 16.71.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2012
Bis(a-bromo ketones): Versatile Precursors for Novel Bis(s-triazolo
[3,4-b][1,3,4]thiadiazines) and Bis(as-triazino[3,4-b][1,3,4]thiadiazines)
645
[26] El-Shehrya, M. F.; Abu-Hashem, A. A.; El-Telbani, E. M. Eur
J Med Chem 2010, 45, 1906.
[27] Phucho, T.; Nongpiur, A.; Tumtin, S.; Nongrum, R.; Myrboh,
B.; Nongkhlaw, R. L. Arkivoc 2008, 15, 79.
[28] Wamhoff, H.; Tzanova, M. Arkivoc 2003, 2, 98.
[29] Mansour, A. K.; Eid, M. M.; Khalil, S. A. M. Nucleos Nucleot
Nucleic Acids 2003, 22, 21.
1,4-Bis{4-(3-methyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazine-6-yl)phenoxy}butane 12b.
Yield 46%,
mp. 202ꢁC; IR: (potassium bromide) 3429 (NH), 1608
(C¼N) cmꢂ1
;
1H NMR: d 1.8 (brs, 4H), 2.26 (s, 6H, CH3),
3
2
3.35 (dd, 2H, J = 2.7 Hz, J = 12.6 Hz, He-7), 3.44 (dd, 2H,
3
2
J = 8.7 Hz, J = 12.6 Hz, Ha-7), 4.04 (brs, 4H), 4.45–4.50
(m, 2H, 6-H), 6.73 (d, 2H, J = 9.3 Hz, NH), 6.94, 7.35 (2 d, 8H,
ArHs) ppm; ms: m/z (%) 550 (M+, 10), 280 (22.4), 121 (49.4), 55
(87.2). Anal. Calcd. for C26H30N8O2S2: C, 56.71; H, 5.49; N,
20.35. Found: C, 56.74; H, 5.51; N, 20.30%.
[30] Sztanke, K.; Fidecka, S.; Kedzierska, E; Karczmarzyk, Z.;
Pihlaja, K.; Matosiuk, D. Eur J Med Chem 2005, 40, 127.
[31] Nyffenegger, C.; Fournet, G.; Joseph, B. Tetrahedron Lett
2007, 48, 5069.
[32] Karpenko, I.; Deev, S.; Kiselev, O.; Charushin, V.; Rusinov,
V.; Ulomsky, E.; Deeva, E.; Yanvarev, D.; Ivanov, A.; Smirnova, O.;
Kochetkov, S.; Chupakhin, O.; Kukhanova, M. Antimicrob Agents
Chemother 2010, 54, 2017.
REFERENCES AND NOTES
[33] Ban, K.; Duffy, S.; Khakham, Y.; Avery, V. M.; Hughes, A.;
Montagnat, O.; Katneni, K.; Ryan, E.; Baell, J. Bioorg Med Chem Lett
2010, 20, 6024.
[34] El-Barbary, A. A.; Sakran, M. A.; El Madani, A. M.; Nielsen,
C. J Heterocycl Chem 2005, 42, 935.
[35] Bazavova, I. M.; Britsun, V. N.; Esipenko A. N.; Lozinskii M.
O. Chem Heterocycl Comp 2003, 39, 809.
[36] Kodomari, M.; Aoyama T.; Suzuki, Y. Tetrahedron Lett 2002,
43, 1717.
[1] Thurston, D. E.; Bose, D. S.; Thompson, A. S.; Howard, P.
W.; Leoni, A.; Croker, S. J.; Jenkins, T. C.; Neidle, S.; Hartley, J. A.;
Hurley, L. H. J Org Chem 1996, 61, 8141.
[2] Shaker, R. M. Phosphorus, Sulfur, Silicon and the Related
Elements 1999, 149, 7.
[3] Kamal, A.; Laxman, N.; Ramesh, G.; Neelima, K.; Anand K. K.
Chem Commun 2001, 437.
[4] Raasch, A.; Scharfenstein, O.; Trankle, C.; Holzgrabe, U.;
Mohr, K. J Med Chem 2002, 45, 3809.
[37] Rudolph, J. Tetrahedron 2002, 56, 3161.
[38] Bell, S. C.; Wei, P. H. J Med Chem 1976, 19, 524.
[39] Kunckell, F. Chem Ber 1901, 34, 637.
[5] Jain, M.; Khanna, P.; Saxena, A.; Bhagat, S.; Olsen, C. E.;
Jain, S. C. Synth Commun 2006, 36, 1863.
[40] Lohrisch, H.-J.; Kopanski, L.; Herrmann, R.; Schmidt, H.;
Steglich, W. Liebigs Ann Chem 1986, 177.
[6] Jain, M.; Sakhuja, R.; Khanna, P.; Bhagat, S.; Jain, S. C.
Arkivoc 2008, 15, 54.
[41] Dubois, J.-E.; Axiotis, G.; Bertounesque, E. Tetrahedron Lett
1985, 26, 4371.
[7] Yang, G. Y.; Oh, K.-A.; Park, N.-J.; Jung, Y.-S. Bioorg Med
Chem 2007, 15, 7704.
[42] Sant, K. V.; South, M. S. Tetrahedron Lett 1987, 28, 6019.
[43] Favorskii, A. E. J Prakt Chem 1913, 88, 658.
[44] Sacks, A. A.; Aston, J. G. J Am Chem Soc 1951, 73, 3902.
[45] Diwu, Z.; Beachdel, C.; Klaubert, D. H. Tetrahedron Lett
1998, 39, 4987.
[46] King, L. C.; Ostrum, G. K. J Org Chem 1964, 29, 3459.
[47] Aoyama, T.; Takido T.; Kodomari, M. Tetrahedron Lett 2004,
45, 1873.
[8] Giacomo, B. D.; Bedini, A.; Spadoni, G.; Tarzia, G.; Fraschini,
F.; Pannaccib, M.; Lucinib, V. Bioorg Med Chem 2007, 15, 4643.
[9] Holla, B. S.; Gonsalves, R.; Shenoy, S. Eur J Med Chem 2000,
35, 267.
[10] Holla, B. S.; Gonsalves, R.; Rao, B. S.; Shenoy, S.;
Gopalakrishna, H. N. Il Farmaco 2001, 56, 899.
[11] Holla, B. S.; Poojary, K. N.; Rao, B. S.; Shivananda, M. K.
Eur J Med Chem 2002, 3, 511.
[12] Turan-Zitouni, G.; Kaplancıklı, Z. A.; Yıldız, M. T.; Chevallet,
P.; Kaya, D. Eur J Med Chem 2005, 40, 607.
[13] Walczak, K.; Gondela, A.; Suwinski, J. Eur J Med Chem 2004,
39, 849.
[14] Mavrova, A. T.; Wesselinova, D.; Tsenov, Y. A.; Denkova, P.
Eur J Med Chem 2009, 44, 63.
[15] Al-Soud, Y. A.; Al-Masoudi, N. A.; Ferwanah, A. R. S. Bioorg
Med Chem 2003, 11, 1701.
[48] Pasaribu, S. J.; Williams, L. R. Aust J Chem 1973, 26, 1327.
[49] Kajigaeshi, S.; Kakinami, T.; Okamoto, T.; Fujisaki, S. Bull
Chem Soc Jpn 1987, 60, 1159.
[50] Habermann, J.; Ley, S. V.; Smits, R. J Chem Soc Perkin Trans
1 1999, 2421.
[51] De Kimpe, N.; Verhé, R. In The Chemistry of a-Haloketones,
a-Haloaldehydes and a-Haloimines; Patai, S.; Rappoport, Z., Eds.; Wiley:
Chichester, 1988; pp 1–119.
[16] Almasirad, A.; Tabatabai, S. A.; Faizi, M.; Kebriaeezadeh, A.;
Mehrabi, N.; Dalvandi, A.; Shafiee, A. Bioorg Med Chem Lett 2004, 14, 6057.
[17] Amir, M.; Shikha, K. Eur J Med Chem 2004, 39, 535.
[18] Karegoudar, P.; Prasad, D. J.; Ashok, M.; Mahalinga, M.;
Poojary, B.; Holla, B. S. Eur J Med Chem 2008, 43, 808.
[19] Amir, M.; Kumar, H.; Javed, S. A. Eur J Med Chem 2008, 43, 2056.
[20] Aytac, S. P.; Tozkoparan, B.; Kaynak, F. B.; Aktay, G.;
Goktas, O.; Unuvar, S. Eur J Med Chem 2009, 44, 4528.
[21] Bhat, K. S.; Poojary, B.; Prasad, D. J.; Naik, P.; Holla, B. S.
Eur J Med Chem 2009, 44, 5066.
[52] (a) Elwahy, A. H. M. J Chem Res (S), 1995, 88; (b) Elwahy,
A. H. M. J Chem Res (M), 1995, 653.
[53] (a) Elwahy, A. H. M. J Chem Res (S), 1999, 602; (b) J Chem
Res (M), 1999, 2582.
[54] (a) Elwahy, A. H. M.; Ahmed, M. H.; Elsadek, M. J Chem Res
(S), 2001, 175; (b) J Chem Res (M), 2001, 525.
[55] Elwahy, A. H. M.; Abbas, A. A. Synth Commun 2000, 30,
2903.
[56] Elwahy, A. H. M.; Abbas, A. A.; Kassab, R. M. Synthesis
2002, 260.
[22] Kaplancikli, Z. A.; Turan-Zitouni, G.; Ozdemir, A.; Revial, G.
Eur J Med Chem 2008, 43, 155.
[57] Elwahy, A. H. M.; Abbas, A. A.; Ahmed, A. M. J Heterocycl
Chem 2005, 42, 93.
[23] Khanum, S. A.; Shashikanth, S.; Umesha, S.; Kavitha, R. Eur J
Med Chem 2005, 40, 1156.
[58] Elwahy, A. H. M.; Masaret, Gh. S. J Heterocycl Chem 2007,
44, 1475.
[24] Demirbas, N.; Demirbas, A.; Karaoglu, S. A.; Celik, E.
Arkivoc 2005, 1, 75.
[59] Muathen, H. A.; Aloweiny, N. A. M.; Elwahy, A. H. M. J
Heterocycl Chem 2009, 46, 656.
[25] Holla, S. B.; Sooryanarayana, B. R.; Sarojini, B. K.; Akberali,
P. M. Eur J Med Chem 2006, 41, 657.
[60] Tani, H.; Murayama, K.; Toda, F. Bull Chem Soc Jpn 1964,
37, 919.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet