Synthesis, characterization, and biological activity of some aza-uracil derivatives

Article abstract of DOI:10.1002/jhet.235

Thiation of 1 by LR gave the corresponding 3,5-dithioxo derivative 2 and the trimer 3. Methylation of 1 afforded the S-methyl derivative 4. Compound 1 was fused with 6-bromo-2-phenyl-benzo[1,3-d]oxazin-4-one (5) and gave 6. Condensation of 1 with some acid derivatives 7a-d and/or 8a-c yielded thiadiazolo-triazine derivatives 9a-d and 10a-c. Compounds 9a,c and 10c were hydrolyzed to furnish 11a-c. Acetylation of 14 afforded mono- and diacetyl-derivatives 15 and 16. Benzoylation of 14 afforded mono- and dibezoyl-derivatives 17 and 18. 14 with some aromatic aldehydes yielded 19a-c. Reacting 14 with phenyl (iso- and/or isothio-) cyanate gave the urea derivatives 20a,b. Thiation of 14 with P₄S₁₀ furnished 21. The newly synthesized compounds were tested as antimicrobial agents.

Full text of DOI:10.1002/jhet.235

May 2011
Synthesis, Characterization, and Biological Activity of Some
Aza-Uracil Derivatives
639
Ahmed Ahmed El-Barbary, Yehia Ahmed Hafiz,
and Mohamed Shaker Abdel-Wahed*
Department of Chemistry, Faculty of Science, Tanta University, Tanta, Egypt
*E-mail: MSA_paper@yahoo.com
Received January 9, 2009
DOI 10.1002/jhet.235
Published online 23 March 2011 in Wiley Online Library (wileyonlinelibrary.com).
Thiation of 1 by LR gave the corresponding 3,5-dithioxo derivative 2 and the trimer 3. Methylation
of 1 afforded the S-methyl derivative 4. Compound 1 was fused with 6-bromo-2-phenyl-benzo[1,3-
d]oxazin-4-one (5) and gave 6. Condensation of 1 with some acid derivatives 7a-d and/or 8a-c yielded
thiadiazolo-triazine derivatives 9a-d and 10a-c. Compounds 9a,c and 10c were hydrolyzed to furnish
11a-c. Acetylation of 14 afforded mono- and diacetyl-derivatives 15 and 16. Benzoylation of 14
afforded mono- and dibezoyl-derivatives 17 and 18. 14 with some aromatic aldehydes yielded 19a–c.
Reacting 14 with phenyl (iso- and/or isothio-) cyanate gave the urea derivatives 20a,b. Thiation of 14
with P4S10 furnished 21. The newly synthesized compounds were tested as antimicrobial agents.
J. Heterocyclic Chem., 48, 639 (2011).
INTRODUCTION
this direction and synthesize some new 1,2,4-triazine
derivatives to explore their biological activity as
antibacterial and antifungal agents.
Compounds containing the 1,2,4-triazine moiety are
found in natural sources and many of them showed im-
portant biological activities. Azaribine-antiviral drug is
structurally based on the 1,2,4-triazine heterocyclic sys-
tem [1]. Condensed 1,2,4-triazines found application as
pharmaceuticals, herbicides, pesticides, and dyes [2–6].
1,2,4-Triazines were reported to posses anti-HIV, anti-
cancer [7–10], antihypertensive, anesthetic, antidepres-
sant, tranquilizer, sedative, muscle relaxant [10,11], her-
bicidal, selective weed control in wheat, antibacterial,
antiviral, antifungal, anti-inflammatory, anticonvulsant
activities as well as carragreen-inducededema inhibitor.
[10,11]. Moreover, some substituted 1,2,4-triazino[5,6-
b]indole derivatives act as antiviral and anticancer
agents [12]. All these facts encouraged us to continue in
DISCUSSION
When
4-amino-6-methyl-3-thioxo-3,4-dihydro-2H-
[1,2,4]triazin-5-one (1) [13] reacted with P4S10 in anhy-
drous dioxane [14] or 2,4-bi-(4-methoxyphenyl)-1,3,2,4-
dithiadiphosphetane-2,4-disulfide (Lawesson’s reagent,
LR) in anhydrous xylene, it gave the corresponding 3,5-
dithioxo derivative 2. In case of using LR, by-product 3
could be detected and isolated [15]. The synthesis of
4-amino-6-methyl-3-methylsulfanyl-4H-[1,2,4]triazin-5-
one (4) was described earlier by J. Lee and W. W.
Paudler [16] and others [17,18] (Fig. 1).
C
V
2011 HeteroCorporation

640
A. A. El-Barbary, Y. A. Hafiz, and M. S. Abdel-Wahed
Vol 48
Figure 3. Acidic hydrolysis of 9a,c and 10c.
erties similar to those of well-known sulphonamide
drugs [21]. The thiadiazole nucleus which incorporates a
NACAS linkage exhibits a large number of biological
activities [22].
Condensation of 1 with N-benzene sulfonylglycine
derivatives 7a–d and/or N-phthalimidoglycine deriva-
tives 8a–c [23] yielded the new thiadiazolotriazines 9a–
d and 10a–c, respectively (Fig. 2).
Figure 1. The reaction of 1 with Lawesson’s reagent.
El-Barbary et al. [19] have reported that aminotria-
zines can be condensed with bezoxazones to afford the
corresponding quinazolinyl derivatives. Accordingly,
fusion of 1 with 5 in oil bath at 165ꢀC furnished 6-
bromo-3-(6-methyl-5-oxo-3-thioxo-2,5-dihydro-3H-[1,2,4]
triazin-4-yl)- 2-phenyl-3H-quinazolin-4-one (6) (Fig. 1).
The structure of 6 was deduced from spectroscopic
and elemental analyses. Its mass spectrum showed the
molecular ion peak Mþ at m/z 442 and the base peak at
m/z ¼ 441, the ions at 300 (11.46, C14H8BrN2Oþ), 220
(3.32, C14H8N2Oþ) and 142 (2.92, C4H4N3OSþ) were
observed. Its 13C NMR spectrum supported the struc-
ture, which showed the signals at d 156.03 (C¼¼O), in
the range 121.36–139.57 (Carom) ppm.
The IR spectra of compounds 9a–d and 10a–c
showed no absorption bands related to NH2 and NH
groups, thus confirming the bi-cyclic ring formation.
The C¼¼O stretching frequency was appeared at the
range t 1695–1720 cmꢁ1
.
The mass spectrum of compound 9c showed the mo-
lecular ion peak Mþ at 351.39, which corresponds to the
expected molecular formula, its 1H NMR spectrum
showed absence of a singlet at d 6.00 ppm assigned to
NH2 group and showed a singlet (1H) at d 8.12 ppm
assigned to NH proton and its 13C NMR spectrum sup-
ported the structure which showed the signals at d 31.15
(CH3CH), 40.94 (CHCH3), at the range 126.44–139.95
(Carom) ppm.
In view of the possible pharmacological activity of
new purine analogues, a series of 1,3,4-thiadiazolo[2,3-
c]-1,2,4-triazines were reported in the literature [20]. A
number of 1,3,4-thiadiazoles showed antibacterial prop-
Compounds 9a,c were hydrolyzed by heating with dil.
HCl and furnished 7-aminomethyl-3-methyl[1,3,4]thia-
diazolo[2,3-c][1,2,4]triazin-4-one and 7-(1-aminoethyl)-3-
methyl[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-4-one (11a,b),
respectively as well as benzene sulfonic acid (Fig. 3). The
IR spectra of compounds 11a,b showed bands at 3248 and
3358 cmꢁ1 related to NH2 groups.
Figure 2. Condensation of 1 with N-benzene sulfonylglycine deriva-
tives and/or N-phthalimidoglycine derivatives.
Figure 4. Synthesis of compound 14.
Journal of Heterocyclic Chemistry
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May 2011
Synthesis, Characterization, and Biological Activity of Some Aza-Uracil Derivatives
641
Similarly, Compound 10c was hydrolyzed by diluted
HCl and the corresponding amino derivative 7-(amino-
phenylmethyl)-3-methyl[1,3,4]thiadiazolo[2,3-c][1,2,4]tria-
zin-4-one (11c) was formed. The isolation of phthalic
acid gave an additional proof for the formation of 11c
(Fig. 3).
Compound 12 could be synthesized by refluxing 4
with either P4S10 in anhydrous dioxane [14] or LR in
anhydrous xylene without formation of any other prod-
ucts (Fig. 4). Badawy et al. [24] have synthesized
compound 14 by reacting 4 with 2-aminobenzoic acid.
(Fig. 4).
Figure 6. Thiation of compound 14.
1
The H NMR spectra of 19a–c showed a singlet (1H,
CHAr ) in the range 8.7–9.3 ppm.
The amino group in compound 14 is a versatile moi-
ety and could be used for producing new heterocyclic
derivatives. Thus, refluxing 14 with acetic anhydride in
glacial acetic acid gave the mono- and di-acetyl
products N-(3-methyl-2,10-dioxo-2H,10H-1,4,4a,9-tetraa-
zaanthracen-1-yl)acetamide (15) and N-acetyl-N-(3-
methyl-2,10-dioxo-2H,10H-1,4,4a,9-tetraazaanthracen-1-yl)
acetamide (16) (Fig. 5).
Similarly, the mono- and di-benzoyl products N-(3-
methyl-2,10-dioxo-2H,10H-1,4,4a,9-tetraazaanthracen-1-
yl)benzamide (17) and N-benzoyl-N-(3-methyl-2,10-
dioxo-2H,10H-1,4,4a,9-tetraazaanthracen-1-yl)benzamide
(18) were obtained when compound 14 was refluxed
with benzoyl chloride in anhydrous pyridine (Fig. 5).
The Schiff bases 1-(benzylideneamino)-3-methyl-1H-
1,4,4a,9-tetraazaanthracene-2,10-dione (19a), 1-[(2-chloro-
benzylidene)amino]-3-methyl-1H-1,4,4a,9-tetraaza-anthra-
cene-2,10-dione (19b) and/or 3-methyl-1-[(thiophen-2-
ylmethylene)amino]-1H-1,4,4a,9-tetraazaanthracene-2,10-
dione (19c) could be synthesized by condensation of
compound 14 with some aromatic aldehydes, namely:
benzaldehyde, 2-chloro-benzaldehyde and thiophene-2-
carboxaldehyde in DMF (Fig. 5).
Refluxing 14 with phenyl (iso- and/or isothio-)cyanate
in DMF gave 1-(3-methyl-2,10-dioxo-2H,10H-1,4,4a,9-
tetraazaanthracen-1-yl)-3-phenylurea (20a) and 1-(3-
methyl-2,10-dioxo-2H,10H-1,4,4a,9-tetraazaanthracen-1-
yl)-3-phenylthiourea (20b) (Fig. 6).
The H NMR spectrum of compound 20b showed a
doublet at d 8.19 ppm assigned to two NH protons
which appeared in the IR spectrum at 3188 and 3436
1
cmꢁ1
.
On the other hand, thiation of compound 14 with
phosphorus pentasulfide in anhydrous boiling dioxane
furnished 1-amino-3-methyl-1H-1,4,4a,9-tetraazaanthra-
cene-2,10-dithione (21) as the sole product (tlc) (Fig. 6).
The IR spectrum of 21 showed two sharp bands at t
1695 and 1773 cmꢁ1 related to the presence of two
C¼¼S groups and no absorption bands for C¼¼O groups.
Surprisingly, in our hands, trying to thiate compound
14 by its treatment with LR in anhydrous boiling xylene,
we have obtained starting material unreacted (Fig. 6).
BIOLOGICAL ACTIVITY REPORT
The newly synthesized compounds were screened for
their in vitro antibacterial activities using the cut plug
method [25] against the gram positive bacteria (Bacillus
subtilius and Staphylococcus aureus) and the gram nega-
tive bacteria (Escherichia coli, Salmonella typhae and
Klebsilla sp.) and antifungal activity against yeast (Can-
dida albicans) using Chloramophenicol and Streptomy-
cin as standard drugs. The results are summarized and
illustrated in Table 1.
The results revealed that most of the tested com-
pounds showed antibacterial and antifungal (anticandi-
dal) activity with varying magnitudes. The zone of inhi-
bition above 7 mm in diameters was taken as a positive
result.
Compounds 9a, 11a, 20a showed the highest activity
against all the tested bacteria and yeast. However, other
compounds showed low and/or no antibacterial or anti-
fungal activity. These differences varied according to
Figure 5. The amino group in compound 14, a versatile moiety, can
be used for producing new heterocyclic derivatives.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

642
A. A. El-Barbary, Y. A. Hafiz, and M. S. Abdel-Wahed
Vol 48
Table 1
Diameters of inhibition zones (mm) of newly synthesized 1,2,4-triazines against different test bacteria on nutrient agar and yeast after 24 hr by the
cut-plug method on nutrient agar at 35–37ꢀC.
Test organisms
Escherichia
coli
Bacillus
subtilus
Staphylococcus
aurus
Salmonella
typhae
Candida
albicans
Cpd.
Klebsilla sp.
Chloramophenicol
(30 lgm)
Streptomycin
(10 lgm)
(1)
(4)
(6)
(9a)
(9b)
(9c)
(9d)
(10a)
(10b)
(10c)
(11a)
(11b)
(11c)
(14)
(15)
(16)
(17)
(18)
(19a)
(19b)
(19c)
(20a)
(20b)
(21)
20
14
20
23
38
12
__
__
23
__
__
11
__
10
12
17
__
__
__
15
12
__
20
10
13
8
17
__
__
15
15
__
__
18
__
__
20
__
__
7
__
__
20
15
__
__
__
__
__
__
20
10
13
9
7
__
20
20
12
__
__
18
__
25
20
__
10
20
__
10
__
__
__
22
10
15
15
9
40
9
__
10
8
9
__
__
20
15
11
__
12
__
11
20
12
__
16
__
__
12
__
__
10
7
__
__
13
__
9
11
__
15
__
__
__
__
__
15
__
__
12
__
7
__
10
10
__
10
__
27
12
15
__
__
__
__
__
__
__
__
15
__
__
__
22
10
__
__
__
9
17
20
__
25
__
8
d6): d 2.27 (s, 3H, CH3), 3.40 (s, 1H, SH), 7.52-8.50 (m, 8H,
Harom); 13C NMR (DMSO-d6): d16.92 (CH3-6’), 145.44 (C-3’),
147.48 (C-6’), 151.04 (C-2), 156.03 (C-4), 172.98 (C-5’),
121.36, 128.64, 130.08 and 139.57 (Carom); ms: m/z 442 (34),
441 (100), 300 (11), 220 (3), 153 (10), 142 (3), 127 (1), 77
(23). Anal. Calcd. For C18H12BrN5O2S: C, 48.88; H, 2.73; N,
15.83. Found: C, 48.93; H, 2.72; N, 16.25.
the differences in the structure of the cell wall of the
tested organism and the structure of compound.
EXPERIMENTAL
All melting points are uncorrected and performed by the
open capillary melting point apparatus. Microanalyses were
performed by Microanalysis Unit, Faculty of Science, Tanta
University, Egypt. IR spectra were recorded with a Perkin-
Elmer spectrometer. The NMR spectra were recorded on a
Bruker 300 MHz and Bruker 200 MHz spectrometer using
TMS as an internal standard, DMSO and CHCl3 as solvents.
Mass spectra (ms) were recorded using electron ionization
(E.I.) on a Varian Mat 311A spectrometer.
Condensation of compound 1 with mono carboxylic acid
derivatives 7a–d and 8a–c: Formation of compounds 9a–d
and 10a–c. General procedure. Compound 1 (1.58 g, 0.010
mole) and mono carboxylic acids (if any, 0.010 mole) in
POCl3 (15 mL) were heated at 85ꢀC for 6–8 h (tlc). The sol-
vent was concentrated to its 1/3 volume under reduced pres-
sure (5 mL) and cooled water (20 mL) was added drop wise at
(0ꢀC) to the above reaction mixture and the solid product
formed was filtered off and recrystallized from DMF/water.
N-(3-methyl-4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]tria-
zin-7-ylmethyl)benzene sulfonamide (9a). Yield 2.01 g
(62%); mp 119–121ꢀC; IR (potassium bromide): 1617 (CN),
Compounds 1 [13], 2 & 12 [14], 4 [16–18], and 14 [24],
were prepared according to known methods.
Formation of 6-bromo-3-(6-methyl-5-oxo-3-thioxo-2,5-
dihydro-3H-[1,2,4]triazin-4-yl)-2-phenyl-3H-quinazolin-4-
one (6). A mixture of compound 1 (1.58 g, 0.010 mole) and 5
(3.02 g, 0.010 mole) was fused at 165ꢀC in an oil bath for 3 h
(tlc). The reaction mixture was cooled and titrated with ethanol
(10 mL), filtered off and chromatographed on a column of
silica gel with chloroform:ethanol (9:1, v/v) to yield 1.33 g
(30%), mp 276–278ꢀC; IR (potassium bromide): 1693 (CN),
1709 (CO), 2922 (CH), 3056 (Ph), 3353 and 3554 (NH) cmꢁ1
;
1H NMR (DMSO-d6): d 2.41 (s, 3H, CH3-3), 4.50 (s, 2H, CH2),
7.50-8.00 (m, 5H, Harom), 9.00 (s, 1H, NH); 13C NMR (DMSO-
d6): d 17.44 (CH3-3), 42.42 (CH2), 148.67 (C-3), 154.16 (C-9),
159.72 (C-6), 163.95 (C-4), 126.96, 129.71, 133.33, and 139.95
(Carom). Anal. Calcd. For C12H11N5O3S2: C, 42.72; H, 3.29; N,
20.76. Found: C, 40.22; H, 3.31; N, 20.22.
2919 (CH), 3088 (Ph), 3241 (NH) cmꢁ1 1H NMR (DMSO-
;
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Synthesis, Characterization, and Biological Activity of Some Aza-Uracil Derivatives
643
4-Methyl-N-(3-methyl-4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]
triazin-7-ylmethyl) benzenesulfonamide (9b). Yield 1.47 g
(42%); mp 209–211ꢀC; IR (potassium bromide): 1632 (CN), 1705
(CO), 2932 (CH), 3126 (Ph), 3398 (NH) cmꢁ1; 1H NMR (DMSO-
d6): d 2.41 (s, 3H, CH3-3), 3.42 (s, 3H, CH3-4), 4.53 (s, 2H, CH2),
7.50-8.03 (m, 4H, Harom), 9.00 (s, 1H, NH); 13C NMR (DMSO-
d6): d 17.44 (CH3-3), 21.25 (CH3-4’), 42.41 (CH2), 148.65 (C-3),
154.13 (C-9), 159.73 (C-6), 163.93 (C-4), 127.07, 130.06, 137.08
and 143.73 (Carom). Anal. Calcd. For C13H13N5O3S2: C, 44.43; H,
3.73; N, 19.93. Found: C, 43.52; H, 3.61; N, 19.70.
Hydrolysis of compounds 9a,c and 10c: Formation of
compounds 11a–c. Thirty milliliter of 30% HCl was added to
compounds 9a,c and /or 10c (0.010 mole) then heated at 80ꢀC
5 h (tlc). The reaction mixture was allowed to cool to room
temperature, diluted with water (30 mL) and neutralized with
ammonia solution. The solid obtained was filtered off, dried
and recrystallized from DMF/water to give compounds 11a–c.
7-Aminomethyl-3-methyl[1,3,4]thiadiazolo[2,3-c][1,2,4]tri-
azin-4-one (11a). Yield 1.64 g (83%); mp 179-181 ꢀC; IR
(potassium bromide): 1614 (CN), 2922 (CH), 3248 (NH2)
cmꢁ1 1H NMR (DMSO-d6): d 2.25 (s, 3H, CH3-3), 3.67 (s,
;
N-[1-(3-methyl-4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]tri-
g
2H, CH2), 5.64 (s, 2H, NH2). Anal. Calcd. For C6H7N5OS: C,
36.54; H, 3.58; N, 35.51. Found: C, 36.44; H, 3.37; N 35.29.
7-(1-Aminoethyl)-3-methyl[1,3,4]thiadiazolo[2,3-c][1,2,4]tri-
azin-4-one (11b). Yield 1.94 g (92%); mp 212–213ꢀC; IR (po-
tassium bromide): 1629 (CN), 2923 (CH), 3290 and 3358
;
(NH2) cmꢁ1 1H NMR (DMSO-d6): d 2.15 (s, 3H, CH3-3),
3.69 (s, 3H, CHCH3), 4.35 (s, 1H, CHNH2), 5.55 (s, 2H,
NH2). Anal. Calcd. For C7H9N5OS: C, 39.80; H, 4.29; N,
33.15. Found: C, 39.73; H, 4.18; N, 33.07.
azin-7-yl)ethyl]benzene sulfonamide (9c). Yield 2.9
(75%); mp 171–173ꢀC; IR (potassium bromide): 1553 (CN),
1
1695 (CO), 2932 (CH), 3070 (Ph), 3218 (NH) cmꢁ1; H NMR
(DMSO-d6): d 2.40 (s, 3H, CH3-3), 3.22, 3.41 (m, 4H,
CH3CHA), 7.51-7.90 (m, 5H, Harom), 8.12 (s, 1H, NH); 13C
NMR (DMSO-d6): d 17.11 (CH3-3), 31.15 (CH3CH), 40.94
(CHCH3), 148.52 (C-6), 153.49 (C-3), 159.89 (C-9), 161.73
(C-4), 126.44, 129.24, 132.52 and 139.95 (Carom); ms: m/z 351
(0.31), 169 (7), 168 (100), 156 (2), 95 (23). Anal. Calcd. For
C13H13N5O3S2: C, 44.43; H, 3.73; N, 19.93. Found: C, 43.86;
H, 3.57; N, 19.85.
7-(Aminophenylmethyl)-3-methyl[1,3,4]thiadiazolo[2,3-c][1,2,
4]triazin-4-one (11c). Yield 2.21 g (81%); mp 240–242ꢀC; IR
(potassium bromide): 1605 (CN), 1694 (C¼¼O), 3247 (NH)
4-Methyl-N-[1-(3-methyl-4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,
2,4]triazin-7-yl)ethyl] benzenesulfonamide (9d). Yield 3.02 g
(83%); mp 221–223ꢀC; IR (potassium bromide): 1598
(CN),1699 (CO), 2914 (CH), 3139 (Ph), 3385 and 3558 (NH)
cmꢁ1; 1H NMR (DMSO-d6): d 2.41 (s, 3H, CH3-3), 3.22 (m, 4H,
CH3CHA), 3.40 (s, 3H, CH3-4), 7.31-7.70 (m, 4H, Harom), 7.99
(s, 1H, NH); 13C NMR (DMSO-d6): d 17.10 (CH3-3), 20.92
(CH3-4’), 31.12 (CH3CH), 40.93 (CHCH3), 148.28 (C-3),
153.44 (C-9), 159.89 (C-6), 161.78 (C-4), 126.50, 129.60,
137.13, and 142.83 (Carom). Anal. Calcd. For C14H15N5O3S2: C,
46.02; H, 4.14; N, 19.16. Found: C, 45.50; H, 4.01; N, 18.77.
2-(3-Methyl-4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-
ylmethyl)isoindole-1,3-dione (10a). Yield 2.64 g (81%); mp
320–322ꢀC; IR (potassium bromide): 1609 (CN), 1720 (CO),
cmꢁ1 1H NMR (DMSO-d6): d 2.64 (s, 3H, CH3-3), 3.41 (s,
;
3H, CH3-4), 4.27 (s, 1H, CHNH2), 5.56 (s, 2H, NH2), 7.02-
7.61 (m, 5H, Harom). Anal. Calcd. For C12H11N5OS: C, 52.74;
H, 4.06; N, 25.62. Found: C, 52.63; H, 3.89; N, 25.57.
Acetylation of compound 14: Formation of compounds 15
and 16. Compound 14 (2.43 g, 0.010 mole) was refluxed with a
mixture of acetic acid (15 mL) and acetic anhydride (5 mL) for
1 h (tlc). The solvent was evaporated till dryness under reduced
pressure. The residue was chromatographed on a column of silica
gel petroleum ether:ethylacetate (3:1, v/v) to give 15 and 16.
N-(3-methyl-2,10-dioxo-2H,10H-1,4,4a,9-tetraazaanthracen-1-
yl)acetamide (15). Yield 1.2 g (85%); mp 255–257ꢀC; IR (po-
tassium bromide): 1599 and 1725 (2CO), 2928 (CH), 3014
1
2925 (CH), 3099 (Ph) cmꢁ1; H NMR (DMSO-d6): d 2.21 (s,
1
(Ph), 3234 (NH) cmꢁ1; H NMR (deuteriochloroform): d 3.60
3H, CH3-3), 4.50 (s, 2H, CH2), 7.91–8.21 (m, 4H, Harom); 13C
NMR (DMSO-d6): d 16.74 (CH3-3), 147.50 (C-3), 151.17 (C-
9), 164.69 (C-6), 167.17 (C-4), 174.65 (CONCO), 123.39,
131.59 and 134.79 (Carom). Anal. Calcd. For C14H9N5O3S: C,
51.37; H, 2.77; N, 21.40. Found: C, 50.91; H, 2.87; N, 20.87.
2-[1-(3-Methyl-4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]tria-
zin-7-yl)ethyl]isoindole-1,3-dione (10b). Yield 3.06 g (90%);
mp 248–250ꢀC; IR (potassium bromide): 1705 (CO), 1614 (CN),
2929 (CH), 3054 (Ph) cmꢁ1; 1H NMR (DMSO-d6): d 3.40 (s, 7H,
CH3-3, CHCH3), 7.92 (m, 4H, Harom); 13C NMR (DMSO-d6): d
17.40 (CH3-3), 29.58 (CH3CH), 36.20 (CHCH3), 153.87 (C-9),
161.85 (C-4), 167.97 (CONCO), 123.50, 131.83 and 134.84
(Carom); ms: m/z 341 (56), 195 (4), 167 (6), 160 (100), 159 (2),
147 (13), 77 (20). Anal. Calcd. For C15H11N5O3S: C, 52.78; H,
3.25; N, 20.52. Found: C, 52.53; H, 3.27; N, 20.44.
(s, 3H, CH3CO), 3.81 (s, 3H, CH3-3), 7.42-7.91 (m, 4H,
Harom), 8.43 (s, 1H, NHCO). Anal. Calcd. For C13H11N5O3: C,
54.74; H, 3.89; N, 24.55. Found: C, 54.30; H, 3.97; N, 24.61.
N-acetyl-N-(3-methyl-2,10-dioxo-2H,10H-1,4,4a,9-tetraazaan-
thracen-1-yl)acetamide (16). Yield 1.37 g (84%); mp 264–
266ꢀC; IR (potassium bromide): 1603 and 1728 (2CO), 2936
(CH) cmꢁ1 1H NMR (deuteriochloroform): d 3.50 (s, 3H,
;
CH3-3), 3.31 (s, 6H, 2CH3CO), 7.50-7.92 (m, 4H, Harom).
Anal. Calcd. For C15H13N5O4: C, 55.05; H, 4.00; N, 21.40.
Found: C, 54.86; H, 4.08; N, 21.33.
Benzoylation of compound 14: Formation of compounds
17 and 18. A mixture of compound 14 (2.43 g, 0.010 mole)
and benzoyl chloride (5 mL) in anhydrous pyridine was
refluxed for 3 h (tlc). The reaction mixture was worked up as
above to give 17 and 18.
2-[(3-Methyl-4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-
7-yl)phenylmethyl] isoindole-1,3-dione (10c). Yield 3.06 g
(76%); mp 117–119ꢀC; IR (potassium bromide): 1605 (CN),
;
1713 (CO), 2928 (CH), 3028 (Ph) cmꢁ1 1H NMR (DMSO-
N-(3-methyl-2,10-dioxo-2H,10H-1,4,4a,9-tetraazaanthracen-1-
yl)benzamide (17). Yield 1.35 g (78%); mp 270–272ꢀC; IR
(potassium bromide): 1603 (CN), 1668 and 1722 (2CO), 3055
1
(Ph), 3450 (NH) cmꢁ1; H NMR (deuteriochloroform): d 2.61
d6): d 2.52 (s, 4H, CH3-3, CHPh), 7.31 (m, 5H, CH Ph). 7.90-
8.13 (m, 4H, Harom); 13C NMR (DMSO-d6): d 17.45 (CH3-3),
36.05 (CHPh), 148.72 (C-3), 154.28 (C-9), 161.95 (C-4),
167.13 (CONCO), 123.99, 127.51, 128.84, 130.79, and 135.84
(Carom). Anal. Calcd. For C20H13N5O3S: C, 59.55; H, 3.25; N,
17.36. Found: C, 59.11; H, 3.08; N, 16.92.
(s, 3H, CH3-3), 7.40-8.00 (m, 9H, Harom), 8.41 (s, 1H,
NHCO). Anal. Calcd. For C18H13N5O3: C, 62.25; H, 3.77; N,
20.16. Found: C, 61.99; H, 3.58; N, 20.11.
N-benzoyl-N-(3-methyl-2,10-dioxo-2H,10H-1,4,4a,9-tetraazaan-
thracen-1-yl) benzamide (18). Yield 1.78 g (79%); mp 262–
264ꢀC; IR (potassium bromide): 1603 and 1702(2CO),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

644
A. A. El-Barbary, Y. A. Hafiz, and M. S. Abdel-Wahed
Vol 48
2923(CH), 3056 (Ph) cmꢁ1
;
1H NMR (deuteriochloroform): d
DMF to yield 1.98 g (72%); mp 276–278ꢀC; IR (potassium
2.60 (s, 3H, CH3-3), 7.32-7.91 (m, 14H, Harom). Anal. Calcd.
For C25H17N5O4: C, 66.51; H, 3.80; N, 15.51. Found: C,
66.36; H, 3.62; N, 15.46.
bromide): 1611 and 1695 (2CS), 2944 (CH), 3183 (Ph), 3397
(NH2) cmꢁ1 1H NMR (DMSO-d6): d 2.70 (s, 3H, CH3),
;
7.31(s, 2H, NH2), 7.51-8.42 (m, 4H, Harom). Anal. Calcd. For
C11H9N5S2: C, 47.98; H, 3.29; N, 25.43. Found: C, 47.55; H,
3.27; N, 25.39.
Condensation of compound 14 with aldehydes: Forma-
tion of compounds 19a–c. To compound 14 (2.43 g, 0.010
mole) in boiling DMF (10 mL) benzaldehyde, 2-chlorobenzal-
dehyde and/or thiophen-2-carboxaldehyde (0.010 mole) was
added. The reaction mixture was refluxed for 3 h (tlc). The
reaction mixture was cooled and poured onto ice. The solid
obtained was filtered off, dried and recrystallized from DMF/
water to afford compounds 19a–c.
Acknowledgment. Thanks are due to Dr. Abdel-Rehem El-Shan-
shory Professor of Microbiology, Botany Department, Faculty of
Science, Tanta University, Tanta, Egypt, for antimicrobial testing.
1-(Benzylideneamino)-3-methyl-1H-1,4,4a,9-tetraazaanthra-
cene-2,10-dione (19a). Yield 2.1 g (66%); mp 233–235ꢀC; IR
(potassium bromide): 1722 and 1847 (2CO), 1688 (CN), 2923
REFERENCES AND NOTES
[1] Negwer, M.; Organisch-Chemische Arzneimittel und ihre
Synonyma; Akademie—Verlag: Berlin, 1987.
1
(CH) cmꢁ1; H NMR (DMSO-d6): d 2.62 (s, 3H, CH3), 7.41-
8.43 (m, 9H, Harom), 8.71 (s, 1H, CHAr). Anal. Calcd. For
C18H13N5O2: C, 65.25; H, 3.95; N, 21.14. Found: C, 65.56; H,
3.74; N, 21.22.
1-[(2-Chlorobenzylidene)amino]-3-methyl-1H-1,4,4a,9-tet-
raazaanthracene-2,10-dione (19b). Yield 2.19 g (60%); mp
264–266ꢀC; IR (potassium bromide): 1593 and 1706 (2CO),
2923(CH), 3073 (Ph) cmꢁ1 1H NMR (DMSO-d6): d 2.60 (s,
;
3H, CH3-3), 7.42-8.41 (m, 8H, Harom), 9.33 (s, 1H, CHAr).
Anal. Calcd. For C18H12ClN5O2: C, 59.11; H, 3.31; N, 19.15.
Found: C, 58.67; H, 3.27; N, 19.09.
[2] (a) Abdel-Rahman, R. M. Pharmazie 2001, 56, 275. (b)
Abdel-Rahman, R. M. Pharmaco 1991, 46, 37.
[3] El-Gendy, Z.; Morsy, J. M.; Allimony, H. A.; Ali, W. R.;
Abdel-Rahman, R. M. Pharmazie 2001, 56, 376.
[4] Holla, B. S.; Rao, B. S.; Gonsalves, R.; Sarojini B. K.;
Shridhara, K. Pharmaco 2002, 57, 693.
[5] Habib, N. S.; Soliman, R.; Ismail, K.; Hassan, A. M.; Sarg,
M. T. Boll Chim Fram 2003, 142, 396.
[6] El Ashry, E. S. H.; Rashed, M.; Taha, E.; Ramadan, E. Adv
Heterocycl Chem 1994, 59, 39.
[7] El-Gendy, Z.; Morsy, J. M.; Allimony, H. A.; Ali, W. R.;
Abdel-Rahman, R. M. Pharmazie 2001, 56, 376.
[8] El-Gendy, Z.; Morsy, J.; Allimony, H.; Abdel-Rehman, R.
Phosphorous Sulphur Silicon Relat Elem 2003, 178, 2055.
[9] Abdel-Rahman, R. M.; Morsy, J. M.; El-Edfawy, S.;
Amine, H. A. Pharmazie 1999, 54, 667.
3-Methyl-1-[(thiophen-2-ylmethylene)amino]-1H-1,4,4a,9-
tetraazaanthracene-2,10-dione (19c). Yield 2.19 g (65%);
mp 262–264ꢀC; IR (potassium bromide): 1593, 1706 (2CO),
1
2923 (CH), 3073 (Ph) cmꢁ1; H NMR (DMSO-d6): d 2.62 (s,
3H, CH3-3), 7.32-7.41 (m, 4H, Harom), 8.83 (s, 1H, CHAr).
Anal. Calcd. For C16H11N5O2S: C, 56.97; H, 3.29; N, 20.76.
Found: C, 56.62; H, 3.37; N, 20.37.
[10] Abdel-Halim, A. M.; El-Gendy, Z.; Abdel-Rahman, R. M.
Pharmazie 1995, 50, 726.
Reaction of compound 14 with phenyl (iso- and/or iso-
thio-)cyanate: Formation of compounds 20a,b. A mixture of
phenyl (iso- and/or isothio-)cyanate (0.010 mole) and com-
pound 14 (2.43 g, 0.010 mole) was refluxed in DMF (30 mL)
for 3–5 h (tlc). The reaction mixture was cooled and poured
onto ice. The solid obtained was filtered off, dried and recrys-
tallized from DMF/water to afford compounds 20a,b.
[11] El Ashry, E. S. H.; Rashed, N.; Mousaad, A.; Ramadan, E.
Adv Heterocycl Chem 1994, 61, 207.
[12] Eshba, N. H.; Salama, H. M.; Labouta, I. M.; Mohsen, A.;
Omar, M. Pharmazie 1987, 42, 664.
[13] PridhamT. G.; Shotwell, O. L.; Stodola, F. H.; Lindeufelser,
L. A.; Benedict, R. G.; Jackson, R. W. Phytopathology 1956, 46, 575.
[14] Hozien, Z. A. J Chem Res 2000, 3, 401.
[15] Wen, T.; Bau, R.; McKenna, C. E. J Chem Soc Chem
Commun 1991,1223.
1-(3-Methyl-2,10-dioxo-2H,10H-1,4,4a,9-tetraazaanthracen-
1-yl)-3-phenylurea (20a). Yield 2.57 g (71%); mp 250–252ꢀC;
IR (potassium bromide): 1646 and 1793 (2CO), 3057 (Ph),
[16] Lee, J.; Paudler, W. W. J Heterocycl Chem 1972, 9, 995.
[17] Hauptmann, S.; Blattman G.; Schindler, W. J Prakt Chem
1976, 318, 835.
3284 and 3319 (NH) cmꢁ1 1H NMR (deuteriochloroform): d
;
3.25 (s, 3H, CH3-3), 7.21-7.41 (m, 9H, Harom), 8.13 (s, 2H,
2NH). Anal. Calcd. For C18H14N6O3: C, 59.67; H, 3.89; N,
23.19. Found: C, 59.47; H, 3.69; N, 23.07.
[18] Ulmoskil, E. N.; Rusinov, V. L.; Chupakhim, D. N.;
Kusinov, G. L.; Chernychev, A. I.; Aleksandrov, G. G. Khim Geterot-
sikl Seodin 1987, 11, 1543.
1-(3-Methyl-2,10-dioxo-2H,10H-1,4,4a,9-tetraazaanthracen-
1-yl)-3-phenylthiourea (20b). Yield 3.13 g (83%); mp 350–
352ꢀC; IR (potassium bromide): 1665 and 1728 (2CO), 1620
[19] El-Barbary, A. A.; Sakran, M. A.; El-Madani, A. M.;
Nielsen, C. J Heterocycl Chem 2005, 42, 1.
[20] Golgolab, H.; Lalezari, I.; Gohari, L. H.; J Heterocycl
Chem 1973, 10, 387.
1
(CS), 3070 (Ph), 3188 and 3436 (NH) cmꢁ1; H NMR (deuter-
iochloroform): d 3.08 (s, 3H, CH3-3), 8.19 (d, 2H, 2NH), 6.89-
7.06 (m, 9H, Harom). Anal. Calcd. For C18H14N6O2S: C, 57.13;
H, 3.73; N, 22.21. Found: C, 57.03; H, 3.54; N, 21.78.
Thiation of compound 14 with P4S10. Formation of 1-
amino-3-methyl-1H-1,4,4a,9-tetraazaanthracene-2,10-dithione
(21). A mixture of compound 14 (2.43 g, 0.010 mole) and
P4S10 (2.22 g, 0.005 mole) was refluxed in anhydrous dioxane
(20 mL) for 1 h (tlc). The precipitate thus formed was filtered
off, washed with cold water, dried, and recrystallized from
[21] Sandstrom, J.; Katritzky, A. R.; Boulton, A. J. Advances in
Heterocyclic Chemistry. Academic Press: New York, 1968.
[22] Omar, A.; Omaima, M. E.; Aboulwafa, M. J Heterocycl
Chem 1986, 23, 1339.
[23] Okuda, J.; Inagaki, K.; Miwa, I.; Yashira, T. Chem Pharm
Bull 1982, 30, 3244.
[24] Badawy, M. A.; Abdel-Hay, S. A.; Eid, M. M.; Ibrahim,
Y. A. Chem Ber 1984, 117, 1083.
[25] Biltz, H. Chem Ber 1905, 38, 1417.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet