A novel route to tetracyclic fused tetrazines and thiadiazines

Article abstract of DOI:10.1002/jhet.5570430419

The reaction between 3-amino-2,3-dihydro-7,9-dimethyl-2-thioxo- pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(1H)-one 4 or its 2-methylthio derivative 5 with hydrazonoyl halides 6 in dioxane in the presence of triethylamine under reflux has followed heterocyc

Full text of DOI:10.1002/jhet.5570430419

Jul-Aug 2006
935
A Novel Route to Tetracyclic Fused Tetrazines and Thiadiazines
Ikhlass M. Abbas, Sayed M. Riyadh*, Magda A. Abdallah and Sobhy M. Gomha
Department of Chemistry, Faculty of Science, University of Cairo, Giza, Egypt
Received September 18, 2005
Ar
N
CH3
N
N
Et3N/ Dioxane/ Δ
CH3
N
N
N
N
O
SR
H3C
H3C
R`
9
N
S
S
N
H
R`C(X):NNHAr
O
N
N
CH3
H3C
S
NH2
S
N
NNHAr
NaOEt/ EtOH/ r.t.
4 (5)
R
N
11
O
The reaction between 3-amino-2,3-dihydro-7,9-dimethyl-2-thioxo-pyrido[3',2':4,5]thieno[3,2-d]-
pyrimidin-4(1H)-one 4 or its 2-methylthio derivative 5 with hydrazonoyl halides 6 in dioxane in the
presence of triethylamine under reflux has followed heterocyclization reaction to yield pyrido[3'',2'':4',5']-
thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetrazin-6(4H)-ones 9. On the other hand, reaction of compound 4
with hydrazonoyl halides 6 in sodium ethoxide at room temperature led to formation of hydrazonothioate
compounds 10. The latter on treatment with glacial acetic acid produced tetracyclic compounds, namely 2-
arylhydrazonopyrido[3'',2'':4',5']thieno [3',2':4,5]pyrimido[2,1-b][1,3,4]thiadiazinones 11. An alternative
method was carried out to prove the structure of product 11. The mechanism of the reaction under study
was proposed and the products were screened for their biological activity.
J. Heterocyclic Chem., 43, 935 (2006).
Introduction.
nitrogen heterocycles [10-13] we report herein direct,
efficient and regioselective route for the synthesis of the
new tetraheterocyclic systems namely, pyrido[3'',2'':4',5']-
thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetrazin-6(4H)-
ones (9) and pyrido[3'',2'':4',5']thieno[3',2':4,5]pyrimido-
[2,1-b][1,3,4]thiadiazinones (11). The biological activity
of compounds 9 was also evaluated.
Fused pyrimidines have interesting biological activities
such as inhibitors of phosphodiesterase7 (PDE7) [1] and
potent selective adenosine receptor antagonists (A2B) [2].
In particular, pyridothienopyrimidines an example of
triheterocyclic system have attracted much attention
because of interesting biological activities [3-7].
Moreover, annelated [1,2,4,5]tetrazines were identified to
be one of the most potent inhibitors of the human
Cytomegalovirus protease [8]. On the other hand,
thiadiazine nucleus has been reported for different
biological activities [9] including antituberculostatic,
antiviral and anthelmenthic. Encouraged by the above and
in continuation to our work on the synthesis of bridgehead
Results and Discussion.
The required starting materials namely 3-amino-2,3-dihydro-
7,9-dimethyl-2-thioxo-pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-
4(1H)-one 4 and its 2-methylthio derivative 5 have not been
reported hitherto. They were prepared in good overall yields
according to the reaction sequence depicted in Scheme 1.
Scheme 1
SH
SK
CH3
N
CH3
NH2
N
(CH3)2SO4
CS2/ K2CO3
COOEt
COOEt
S
S
H3C
H3C
N
1
2
SH
CH3
CH3
N
N
H
N
SCH3
i) NH2NH2
ii) H+
S
CH3I/ K2CO3
DMF
COOEt
N
H3C
NH2
S
S
N
H3C
O
3
4
CH3
N
O
SCH3
NH2
N
H3C
N
S
5

936
I. M. Abbas, S. M. Riyadh, M. A. Abdallah and S. M. Gomha
Vol 43
Treatment of ethyl 3-amino-4,6-dimethyl-thieno[2,3-b]-
mechanism to account for the formation of 9 is shown in
Scheme 2.
pyridine-2-carboxylate 1 [14] with carbon disulfide in the
presence of anhydrous potassium carbonate, followed by
methylation of the product 2 with dimethyl sulfate gave
the corresponding methyl dithiocarbonate 3. The latter
reacts with hydrazine hydrate at room temperature
followed by acidification furnished the starting material 4.
Methylation of the latter with methyl iodide in dimethyl-
formamide in the presence of anhydrous potassium
carbonate afforded the corresponding 2-methylthio
derivative 5. The structures of both 4 and 5 were
It is suggested that, reactions of 4 with hydrazonoyl
halides 6 presumably proceed through initial nucleophilic
attack by the amino group of pyrimidine nucleus to give
the transient hydrazine derivatives 7 which subsequently
undergo in situ cyclization with concurrent elimination of
hydrogen sulfide to give the respective annelated tetra-
zines 9 as the end products. The formation of 7 is
analogous to the reactions of hydrazonoyl halides with
hydrazines, which were reported to give the correspon-
ding hydrazidines [15]. The assignment of the proposed
1
evidenced by their spectral data (mass, IR, H NMR) and
microanalysis (see Experimental).
mechanism and the formation of 9 were further
Reaction of 3-amino-2,3-dihydro-7,9-dimethyl-2-thioxo-
pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4(1H)-one 4 with
hydrazonoyl halides 6 in dioxane in the presence of
triethylamine at reflux till hydrogen sulfide gas ceased to
evolve afforded the corresponding tetracyclic compounds
9. The isolated products were assigned the structure of
pyrido[3'',2'':4',5']thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]
tetrazin-6(4H)-ones 9. The structures of the compounds 9
were established on the basis of spectral and
microanalyses data (see Experimental). A plausible
manifested by alternate synthesis. Thus, treatment of 2-
methylthio derivative 5 with each of hydrazonoyl halides
6a,b,g in dioxane in the presence of triethylamine at
reflux led to evolution of methanethiol and the formation
of products that proved to be identical in all respects (mp,
mixed mp and IR) with compounds 9a,b,g (Scheme 2).
Our interest was extended to study the effect of the
basicity of the medium on the reaction of compound 4
with hydrazonoyl halides 6. Thus, treatment of 3-amino-
2,3-dihydro-7,9-dimethyl-2-thioxo-pyrido[3',2':4,5]thieno-
Scheme 2
CH3
N
N
SR
R = H, CH3
R`C(X):NNHAr
+
N
NH2
Et3N/ Dioxane
Reflux
H3C
S
6
O
6a-n, X = Cl
6o-u, X = Br
4 (5)
4, R = H; 5, R = CH3
H
Ar
CH3
CH3
SR
N
N
N
O
SR
N
N
N
NH
H3C
H3C
N
S
N
R`
N
S
H
O
C(R`):NNHAr
8
7
Ar
CH3
N
N
N
-RSH
N
N
H3C
S
N
H
R`
O
9
Ar = ZC6H4
R`/ Z
Compd. No.
R`/ Z
Compd. No.
R`/ Z
Compd. No.
Ph/ H
COCH3/ H
6a, 9a
6b, 9b
6c, 9c
6d, 9d
6e, 9e
6f, 9f
COOEt/ 4-CH3
COOEt/ 4-Cl
COOEt/ 4-NO2
CONHPh/ H
CONHPh/ 4-CH3
CONHPh/ 4-Cl
CONHPh/ 4-NO2
6h, 9h
6i, 9i
6j, 9j
6k, 9k
6l, 9l
6m, 9m
6n, 9n
COPh/ H
6o, 9o
6p, 9p
6q, 9q
6r, 9r
6s, 9s
6t, 9t
COPh/ 4-CH3
COPh/ 4-NO2
COPh/ 3-Cl
COPh/ 4-Cl
2-Thienoyl/ 4-Cl
2-Furoyl/ 4-Cl
COCH3/ 4-CH3
COCH3/ 4-Cl
COCH3/ 4-OCH3
COCH3/ 4-NO2
COOEt/ H
6g, 9g
6u, 9u

Jul-Aug 2006
A Novel Route to Tetracyclic Fused Tetrazines and Thiadiazines
937
[3,2-d]pyrimidin-4(1H)-one 4 with hydrazonoyl halides 6
in ethanol in the presence of sodium ethoxide at room
temperature was found to give products which are
completely different from compounds 9. On the basis of
spectral (IR, 1H NMR, Mass) and elemental analyses data
(see Experimental), the compounds isolated were assigned
structure 10 (Scheme 3).
namely, 2-arylhydrazonopyrido[3'',2'':4',5']thieno[3',2': 4,5]-
pyrimido[2,1-b][1,3,4]thiadiazin-6-ones 11 (Scheme 3).
The structure of the latter products was elucidated on the
basis of their spectral and elemental analyses data. For
example, the IR spectra of 11 revealed the absence of one
of the carbonyl and NH2 absorption bands that were
1
present in the spectra of their precursors 10. Also, the H
Scheme 3
CH3
N
N
O
SH
+
RCOC(X):NNHAr
N
H3C
NH2
S
6
6b,h, X = Cl
6p, X = Br
4
NaOEt/ EtOH
r.t.
CH3
N
O
S
NNHAr
COR
N
H3C
N
S
NH2
10
AcOH/ Δ
R = CH3, C6H5
R = OEt
N
CH3
N
CH3
N
S
NNHC6H4-4-Me
O
N
O
S
NNHAr
R
N
O
N
H3C
S
N
H
H3C
S
N
11h
11b,p
R/ Ar = CH3/ C6H5
11b
C6H5/ 4-CH3C6H4 11p,
PhCOCH2Br
4
+
Ar-N2Cl
Pyridine/ 0-5 0
TEA
Dioxane
C
CH3
N
CH3
N
N
S
N
S
p-TSA
N
COPh
NH2
N
-H2O
H3C
Ph
H3C
S
N
S
O
O
12
13
To account for the formation of products 10 isolated
from the studied reaction, it is assumed that the thiol
tautomer of compound 4 undergoes 1,3-addition to the
nitrilimine (generated in situ by elimination of HX from
the corresponding hydrazonoyl halides 6 in the presence
of a base) to give directly the hydrazonothioate esters 10
(Scheme 3). Next, we directed our interest to investigate
cyclization of hydrazonothioate esters 10 isolated from
the foregoing reactions. Thus, refluxing the latter in
glacial acetic acid yielded the respective cyclized products
NMR spectra of 11 revealed no signal assignable to the
NH2 protons. However, they revealed the presence of
signal assigned to the hydrazono NH proton signal at ꢀ
11.2 ppm (see Experimental). The structure of 11 was
further proved via an alternative method (Scheme 3).
Thus, reaction of compound 4 with phenacyl bromide in
dioxane in the presence of triethyl amine at reflux led to
formation of compound 12. The latter undergoes
dehydrative cyclization on treatment with p-toluene-
sulphonic acid to give compound 13. The structure of

938
I. M. Abbas, S. M. Riyadh, M. A. Abdallah and S. M. Gomha
Vol 43
compound 13 was substantiated by spectral (Mass, IR,
and 1H NMR) and elemental analyses data (See
Experimental). Coupling of compound 13 with p-
toluenediazonium chloride at 0-5 °C in pyridine led to
formation of product which is identical in all respects
(mp, mixed mp and IR) with compound 11p.
Conclusion.
We have encountered a novel series of pyrido-
[3'',2'':4',5']thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetra-
zin-6(4H)-ones and 2-arylhydrazonopyrido[3'',2'':4',5']-
thieno[3',2':4,5]pyrimido[2,1-b][1,3,4]thiadiazinones that
preserve a degree of functionality and potential interest of
biological evaluation.
Antimicrobial Activity.
The compounds 9b-d, 9g, 9i-l and 9o-p were tested for
their antimicrobial activities using four fungi species
namely Aspergillus fumigatus AF, Penicillium italicum
PI, Syncephalastrum racemosum SR and Candida
albicans CA. Also, four bacteria species namely,
Staphylococcus aureus SA, Pesudomonas aeruginosa PA,
Bacillus subtilis BS and Escherichia coli EC were tested.
The organisms were tested against the activity of
solutions of concentration of 5 mg/ml of each compound
and using inhibition zone diameter (IZD) in cm as
criterion for the antimicrobial activity. The fungicide
Terbinafin and the bactericide Chloramphenicol were
used as references to evaluate the potency of the tested
compounds under the same conditions. The results are
depicted in Table 1.
EXPERIMENTAL
Melting points were recorded on Gallenkamp apparatus and
are uncorrected. Infrared spectra (KBr) were determined on a
Pye Unicam SP-3000 infrared spectrophotometer. H NMR was
1
determined on a Varian Gemini 300 spectrometer (300 MHz) in
DMSO-d6 with TMS as internal standard. Mass spectra were
recorded on a GCMS-QP 1000 EX Schimadzu spectrometer.
Elemental analyses were carried out at the Microanalytical
center, University of Cairo, Giza, Egypt. Hydrazonoyl halides 6
[16-24] were prepared by literature methods. They are toxic and
cause skin irritation, so proper safety precautions should be
taken and it is recommended to protect hands with rubber
gloves. The biological evaluation of the products was carried out
at the Regional Center for Mycology and Biotechnology at Al-
Azhar University, Cairo, Egypt.
Synthesis of 3-Amino-2,3-dihydro-7,9-dimethyl-2-thioxo-pyrido-
[3',2':4,5]thieno[3,2-d]pyrimidin-4(1H)-one (4).
Table 1
Antimicrobial Activity of the Productsa 9b-d, 9g, 9i-l and 9o-p
A
mixture of ethyl 3-amino-4,6-dimethyl-thieno[2,3-b]-
pyridine-2-carboxylate (1) [14] (50 g, 20 mmol), carbon
disulfide (20 ml) and anhydrous potassium carbonate (60 g) was
dissolved in 150 ml DMF and stirred for 12 h at room
temperature. The reaction mixture was heated further on a water
bath for 12 h, cooled and poured into ice-water. The reaction
mixture was treated dropwise with dimethyl sulfate (30 ml)
under stirring then allowed to stand at room temperature for 12 h
and extracted with chloroform. The solvent was evaporated
under reduced pressure and the crude product (3) was obtained.
Compound (3) was treated with hydrazine hydrate (80%, 20 ml),
and the reaction mixture was stirred for 3 h at room temperature
then poured into ice-water. The reaction mixture was acidified
with ice-cold hydrochloric acid. The solid formed was collected
by filtration, washed with water, dried and recrystallized from
dioxane to give pure (4); 3.9 g (70%), mp 306 °C; ir: 3359, 3218
Micro-organism/ IZD (cm)*
Compound
No.
AF
PI
SR
CA
SA
PA
BS
EC
9b
9c
9d
9g
9i
9j
9k
9l
9o
9p
CAb
TEc
+
0
0
0
0
+
+
+
+
+
0
0
0
+
0
0
+
+
+
+
+
+
+
0
+
+
+
+
+
+
0
+
0
+
+
+
+
0
0
0
0
0
0
0
0
0
0
0
+
+
0
+
0
0
0
+
0
+
2.8
0
0
0
0
0
0
0
+
0
0
0
+
0
+
+
0
+
0
+
2.6
0
0
0
1.0
1.0
1
(NH2), 3316 (NH), 1652 (CO) cm-1 ; H nmr ꢀ (DMSO-d6) 2.39
3.0
3.6
3.6
3.0
(s, 3H, CH3), 2.55 (s, 3H, CH3), 5.7 (s, 2H, NH2) 7.2 (s, 1H, pyr-
H), 11.2 (s, 1H, NH); ms, m/z (%) 279 (M++1, 16), 278 (M+,
100), 247 (90), 175 (21), 131 (14), 77 (10).
Anal. Calcd. For C11H10N4OS2: C, 47.46; H, 3.62; N, 20.13; S,
23.04. Found: C, 47.21; H, 3.51; N, 19.97; S, 22.87.
a; The concentration of the solution 5.0 mg/ml was tested. b Chloramphenicol;
c, Terbinafin. *IZD beyond control/ (sign): 1.1-1.5 cm/ (+++); 0.6-1.0 cm/ (++);
0.1-0.5 cm/ (+); 0 cm/ (-).
Synthesis of 3-Amino-7,9-dimethyl-2-methylthio-pyrido[3',2':
4,5]thieno[3,2-d]pyrimidin -4(3H)-one (5).
The results revealed that compound 9k-l and 9o-p
exhibited a degree of inhibition against AF, PI and SR
while compounds 9c, 9i and 9k have inhibition effect
against SR and CA. The biological activities of the other
compounds against the tested organisms are weak,
however, the activities of the tested compounds are much
less than that of standard antifungal and antibacterial
agents used.
To a stirred solution of 3-amino-2,3-dihydro-7,9-dimethyl-2-
thioxo-pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4(1H)-one (4)
(2.78 g, 10 mmol) in 50 ml DMF in the presence of anhydrous
K2CO3 (2.07 g, 15 mmol), was added methyl iodide (1.42 g, 10
mmol). The reaction mixture was stirred overnight at room
temperature then poured into ice-water. The solid formed was
filtered, washed with water, dried and recrystallized from

Jul-Aug 2006
A Novel Route to Tetracyclic Fused Tetrazines and Thiadiazines
939
dioxane to give pure (5); 2.1 g (72%), mp 234 °C; ir: 3351, 3211
(NH2), 1642 (CO) cm-1; 1H nmr ꢀ (DMSO-d6) 2.39 (s, 3H, CH3),
2.55 (s, 3H, CH3), 2.87 (s, 3H, SCH3), 5.71 (s, 2H, NH2) 7.2 (s,
1H, pyr-H); ms, m/z (%) 292 (M+, 7), 263 (100), 247 (70), 205
(59), 175 (27), 131 (27), 64 (25).
(%) 440 (M++2, 42), 439 (M++1, 23), 438 (M+, 100), 396 (96),
230 (20), 111 (34).
Anal. Calcd. for C20H15ClN6O2S: C, 54.73; H, 3.44; N, 19.15;
S, 7.31. Found: C, 54.70; H, 3.45; N, 18.96; S, 7.29.
3-Acetyl-9,11-dimethyl-1-(4-methoxyphenyl)pyrido[3'',2'':4',5']-
thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetrazin-6(4H)-one (9e).
Anal. Calcd. for C12H12N4OS2: C, 49.29; H, 4.14; N, 19.16; S,
21.93. Found: C, 49.20; H, 4.15; N, 18.98; S, 21.73.
This compound was obtained in 3.25 g (75%), mp 246 °C; ir:
3278 (NH), 1693, 1647 (2CO) cm-1; ms, m/z (%) 434 (M+, 2),
230 (12), 101 (23), 86 (100).
Anal. Calcd for C21H18N6O3S: C, 58.05; H, 4.18; N, 19.34; S,
7.38. Found: C, 58.11; H, 4.16; N, 19.08; S, 7.37.
Synthesis of 9,11-Dimethyl-1,3-disubstituted-pyrido[3'',2'':4',5']-
thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetrazin-6(4H)-ones
(9a-u).
Method A: To a mixture of equimolar amounts of 4 and the
appropriate hydrazonoyl halides 6 (10 mmol) in 50 ml dioxane
were added triethylamine (1.4 mL, 10 mmol). The reaction
mixture was refluxed till all of the starting materials have
disappeared and hydrogen sulfide gas ceased to evolve (6-10 h,
monitored by TLC). The solvent was evaporated and the residue
was treated with methanol. The solid that formed was filtered
and recrystallized from dioxane to give compounds 9a-u.
Method B: Treatment of 5 with hydrazonoyl halides 6a,b,g
following the same procedure described in method A, led to
formation of products which were found to be identical in all
respects (mp mixed mp and IR) with 9a,b,g.
3-Acetyl-9,11-dimethyl-1-(4-nitrophenyl)pyrido[3'',2'':4',5']-
thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetrazin-6(4H)-one (9f).
This compound was obtained in 3.24 g (72%), mp 238 °C; ir:
3452 (NH), 1683, 1647 (2CO) cm-1; ms, m/z (%) 450 (M+, 50),
369 (40), 230 (39), 115 (56), 58 (100).
Anal. Calcd. for C20H15N7O4S: C, 53.45; H, 3.36; N, 21.82; S,
7.13. Found: C, 53.44; H, 3.34; N, 21.73; S, 7.11.
Ethyl 9,11-dimethyl-6-oxo-1-phenyl-pyrido[3'',2'':4',5']thieno-
[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetrazine-3-carboxylate (9g).
This compound was obtained in 3.39 g (78%), mp 272 °C; ir:
9,11-Dimethyl-1,3-diphenyl-pyrido[3'',2'':4',5']thieno[3',2':4,5]-
pyrimido[2,1-c][1,2,4,5]tetrazin-6(4H)-one (9a).
1
3278 (NH), 1720, 1697 (2CO) cm-1; H nmr (DMSO-d6) ꢀ 1.21
(t, 3H, CH3), 2.37 (s, 3H, CH3), 2.53 (s, 3H, CH3), 4.36 (q, 2H,
CH2), 7.12 (s, 1H, Pyr-H), 7.15-7.68 (m, 5H, Ar-H), 9.21 (s, 1H,
NH); ms, m/z (%) 435 (M++1, 27), 434 (M+, 100), 306 (28), 230
(24), 105 (32), 77 (79).
Anal. Calcd. for C21H18N6O3S: C, 58.05; H, 4.18; N, 19.34; S,
7.38. Found: C, 58.01; H, 4.17; N, 19.20; S, 7.23.
This compound was obtained in 3.37 g (77%), mp 256 °C; ir:
1
3351 (NH), 1670 (CO) cm-1; H nmr (DMSO-d6) ꢀ 2.59 (s, 3H,
CH3), 2.75 (s, 3H, CH3), 7.2-7.8 (m, 11H, Ar-H), 9.21 (s, 1H,
NH); ms, m/z (%) 439 (M++1, 12), 438 (M+, 100), 230 (14), 77
(65).
Anal. Calcd. for C24H18N6OS: C, 65.74; H, 4.14; N, 19.17; S,
7.31. Found: C, 65.72; H, 4.17; N, 19.05; S, 7.29.
Ethyl 9,11-dimethyl-1-(4-methylphenyl)-6-oxo-pyrido[3'',2'':4',5']-
thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetrazine-3-carboxylate
(9h).
3-Acetyl-9,11-dimethyl-1-phenyl-pyrido[3'',2'':4',5']thieno[3',2':
4,5]pyrimido[2,1-c][1,2,4,5]tetrazin-6(4H)-one (9b).
This compound was obtained in 3.6 g (80%), mp 268 °C; ir:
1
This compound was obtained in 2.9 g (72%), mp 284 °C; ir
3271 (NH), 1722, 1687 (2CO) cm-1; H nmr (DMSO-d6) ꢀ 1.23
1
3274 (NH), 1697, 1644 (2CO) cm-1; H nmr (DMSO-d6) ꢀ 2.34
(t, 3H, CH3), 2.37 (s, 3H, CH3), 2.53 (s, 3H, CH3), 2.55 (s, 3H,
Ar-CH3), 4.38 (q, 2H, CH2), 7.12 (s, 1H, Pyr-H), 7.15-7.68 (m,
4H, Ar-H), 9.22 (s, 1H, NH); ms, m/z (%) 449 (M++1, 40), 448
(M+, 97), 320 (29), 230 (28), 131 (12), 91 (100).
Anal. Calcd. for C22H20N6O3S: C, 58.92; H, 4.49; N, 18.74; S,
7.15. Found: C, 58.91; H, 4.50; N, 18.43; S, 7.11.
(s, 3H, CH3), 2.41 (s, 3H, CH3), 3.56 (s, 3H, COCH3), 7.11 (s,
1H, Pyr-H), 7.3-7.8 (m, 5H, Ar-H), 9.00 (s, 1H, NH); ms, m/z
(%) 405 (M++1, 21), 404 (M+, 79) 230 (26), 97 (48), 55 (100).
Anal. Calcd for C20H16N6O2S: C, 59.39; H, 3.99; N, 20.78; S,
7.93. Found: C, 59.38; H, 4.05; N, 20.58; S, 7.91.
3-Acetyl-9,11-dimethyl-1-(4-methylphenyl)pyrido[3'',2'':4',5']-
thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetrazin-6(4H)-one (9c).
Ethyl 1-(4-chlorophenyl)-9,11-dimethyl-6-oxo-pyrido[3'',2'':4',5']-
thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetrazine-3-carboxylate
(9i).
This compound was obtained in 3.13 g (75%), mp 282 °C; ir:
1
3278 (NH), 1705, 1653 (2CO) cm-1; H nmr (DMSO-d6) ꢀ 2.37
This compound was obtained in 3.6 g (77%), mp 264 °C; ir:
1
(s, 3H, CH3), 2.41 (s, 3H, CH3), 2.54 (s, 3H, Ar-CH3), 3.56 (s,
3H, COCH3), 7.16 (s, 1H, Pyr-H), 7.3-7.56 (m, 4H, Ar-H), 9.00
(s, 1H, NH); ms, m/z (%) 419 (M++1, 29), 418 (M+, 100), 376
(76), 230 (18), 91 (27).
Anal. Calcd. for C21H18N6O2S: C, 60.27; H, 4.34; N, 20.08; S,
7.66. Found: C, 60.21; H, 4.35; N, 20.01; S, 7.63.
3290 (NH), 1728, 1674 (2CO) cm-1; H nmr (DMSO-d6) ꢀ 1.32
(t, 3H, CH3), 2.43 (s, 3H, CH3), 2.53 (s, 3H, CH3), 4.39 (q, 2H,
CH2), 7.18 (s, 1H, Pyr-H), 7.55-7.73 (m, 4H, Ar-H), 9.42 (s, 1H,
NH); ms, m/z (%) 470 (M++2, 42), 469 (M++1, 33), 468 (M+,
85), 340 (44), 230 (43), 111 (100), 77 (22).
Anal. Calcd. for C21H17ClN6O3S: C, 53.79; H, 3.65; N, 17.92;
S, 6.84. Found: C, 53.67; H, 3.54; N, 17.71; S, 6.81.
3-Acetyl-1-(4-chlorophenyl)-9,11-dimethyl-pyrido[3'',2'':4',5']-
thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetrazin-6(4H)-one (9d).
Ethyl 9,11-dimethyl-1-(4-nitrophenyl)-6-oxo-pyrido[3'',2'':4',5']-
thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetrazine-3-carboxylate
(9j).
This compound was obtained in 3.2 g (73%), mp 270 °C; ir:
1
3255 (NH), 1697, 1655 (2CO) cm-1; H nmr (DMSO-d6) ꢀ 2.43
(s, 3H, CH3), 2.55 (s, 3H, CH3), 3.56 (s, 3H, COCH3), 7.17 (s,
1H, Pyr-H), 7.55-7.73 (m, 4H, Ar-H), 9.01 (s, 1H, NH); ms, m/z
This compound was obtained in 3.35 g (70%), mp 255 °C; ir:
1
3247 (NH), 1701, 1654 (2CO) cm-1; H nmr (DMSO-d6) ꢀ 1.35

940
I. M. Abbas, S. M. Riyadh, M. A. Abdallah and S. M. Gomha
Vol 43
(t, 3H, CH3), 2.53 (s, 3H, CH3), 2.57 (s, 3H, CH3), 4.42 (q, 2H,
CH2), 7.24 (s, 1H, Pyr-H), 7.93 (d, 2H, Ar-H), 8.38 (d, 2H, Ar-
H), 9.58 (s, 1H, NH); ms, m/z (%) 480 (M++1, 35), 479 (M+,
100), 351 (30), 230 (28), 122 (22).
Anal. Calcd. for C21H17N7O5S: C, 52.60; H, 3.57; N, 20.45; S,
6.69. Found: C, 52.53; H, 3.46; N, 19.26; S, 6.60.
3-Benzoyl-9,11-dimethyl-1-(4-methylphenyl)-pyrido[3'',2'':4',5']-
thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetrazin-6(4H)-one (9p).
This compound was obtained in 3.36 g (70%), mp 266 °C; ir:
1
3240 (NH), 1697, 1651 (2CO) cm-1; H nmr (DMSO-d6) ꢀ 2.36
(s, 3H, CH3), 2.41 (s, 3H, CH3), 2.55 (s, 3H, Ar-CH3), 6.38 (s,
1H, Pyr-H), 7.2-8.16 (m, 9H, Ar-H), 9.53 (s, 1H, NH); ms, m/z
(%) 481 (M++1, 31), 480 (M+, 98), 230 (18), 105 (100), 77 (36).
Anal. Calcd. for C26H20N6O2S: C, 64.98; H, 4.20; N, 17.49; S,
6.67. Found: C, 64.90; H, 4.22; N, 17.11; S, 6.53.
9,11-Dimethyl-1-phenyl-3-(N-phenylcarbamoyl)-pyrido[3'',2'':4',5']-
thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetrazin-6(4H)-one (9k).
This compound was obtained in 3.94 g (82%), mp 264 °C; ir:
1
3367, 3282 (2NH), 1689, 1651 (2CO) cm-1; H nmr (DMSO-d6)
3-Benzoyl-9,11-dimethyl-1-(4-nitrophenyl)-pyrido[3'',2'':4',5']-
thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetrazin-6(4H)-one (9q).
ꢀ 2.41 (s, 3H, CH3), 2.54 (s, 3H, CH3), 7.16 (s, 1H, Pyr-H), 7.27-
7.82 (m, 10H, Ar-H), 9.35 (s, 1H, NH), 10.54 (s, 1H, NH); ms,
m/z (%) 482 (M++1, 36), 481 (M+, 100), 362 (32), 230 (14), 77
(56).
Anal. Calcd. for C25H19N7O2S: C, 62.36; H, 3.98; N, 20.36; S,
6.66. Found: C, 62.34; H, 3.95; N, 20.03; S, 6.64.
This compound was obtained in 3.58 g (70%), mp 226 °C; ir:
1
3255 (NH), 1697, 1655 (2CO) cm-1; H nmr (DMSO-d6) ꢀ 2.39
(s, 3H, CH3), 2.45 (s, 3H, CH3), 6.38 (s, 1H, Pyr-H), 7.21-7.96
(m, 9H, Ar-H), 9.51 (s, 1H, NH); ms, m/z (%) 511 (M+, 8), 230
(22), 105 (100), 77 (76).
Anal. Calcd. for C25H17N7O4S: C, 58.70; H, 3.35; N, 19.17; S,
6.27. Found: C, 58.31; H, 3.30; N, 19.06; S, 6.23.
9,11-Dimethyl-1-(4-methylphenyl)-3-(N-phenylcarbamoyl)-
pyrido[3'',2'':4',5']thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetra-
zin-6(4H)-one (9l).
3-Benzoyl-1-(3-chlorophenyl)-9,11-dimethyl-pyrido[3'',2'':4',5']-
thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetrazin-6(4H)-one (9r).
This compound was obtained in 3.96 g (80%), mp 224 °C; ir:
1
3394, 3282 (2NH), 1689, 1678 (2CO) cm-1; H nmr (DMSO-d6)
This compound was obtained in 3.5 g (70%), mp 278 °C; ir:
1
3229 (NH), 1697, 1655 (2CO) cm-1; H nmr (DMSO-d6) ꢀ 2.39
ꢀ 2.42 (s, 3H, CH3), 2.54 (s, 3H, CH3), 2.62 (s, 3H, Ar-CH3),
7.16 (s, 1H, Pyr-H), 7.21-7.76 (m, 9H, Ar-H), 9.32 (s, 1H, NH),
10.45 (s, 1H, NH); ms, m/z (%) 496 (M++1, 34), 495 (M+, 100),
376 (38), 230 (17), 91 (80).
Anal. Calcd. for C26H21N7O2S: C, 63.02; H, 4.27; N, 19.79; S,
6.47. Found: C, 62.34; H, 4.11; N, 19.54; S, 6.38.
(s, 3H, CH3), 2.45 (s, 3H, CH3), 6.48 (s, 1H, Pyr-H), 7.21-7.96
(m, 9H, Ar-H), 9.61 (s, 1H, NH); ms, m/z (%) 503 (M++2, 11),
501 (M+, 12), 230 (18), 105 (100).
Anal. Calcd. for C25H17ClN6O2S: C, 59.94; H, 3.42; N, 16.78;
S, 6.40. Found: C, 59.84; H, 3.27; N, 16.64; S, 6.21.
1-(4-Chlorophenyl)-9,11-dimethyl-3-(N-phenylcarbamoyl)-
pyrido[3'',2'':4',5']thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetra-
zin-6(4H)-one (9m).
3-Benzoyl-1-(4-chlorophenyl)-9,11-dimethyl-pyrido[3'',2'':4',5']-
thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetrazin-6(4H)-one
(9s).
This compound was obtained in 4.38 g (85%), mp 286 °C; ir:
This compound was obtained in 3.5 g (70%), mp 260 °C; ir:
3433 (NH), 1690, 1647 (2CO) cm-1; ms, m/z (%) 501 (M+, 2),
230 (18), 105 (19), 86 (100).
Anal. Calcd. for C25H17ClN6O2S: C, 59.94; H, 3.42; N, 16.78;
S, 6.40. Found: C, 59.90; H, 3.36; N, 16.55; S, 6.31.
1
3392, 3257 (2NH), 1689, 1652 (2CO) cm-1; H nmr (DMSO-d6)
ꢀ 2.42 (s, 3H, CH3), 2.54 (s, 3H, CH3), 7.16 (s, 1H, Pyr-H), 7.24-
7.78 (m, 9H, Ar-H), 9.42 (s, 1H, NH), 10.21 (s, 1H, NH); ms,
m/z (%) 517 (M++2, 15), 382 (23), 286 (28), 230 (17), 188 (39),
119 (51), 77 (96).
Anal. Calcd. for C25H18ClN7O2S: C, 58.19; H, 3.52; N, 19.00;
S, 6.21. Found: C, 58.12; H, 3.30; N, 18.57; S, 6.15.
1-(4-Chlorophenyl)-9,11-dimethyl-3-(2-thienoyl)-pyrido[3'',2'':
4',5']thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetrazin-6(4H)-
one (9t).
9,11-Dimethyl-1-(4-nitrophenyl)-3-(N-phenylcarbamoyl)-pyri-
do[3'',2'':4',5']thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetrazin-
6(4H)-one (9n).
This compound was obtained in 3.6 g (71%), mp 276 °C; ir:
1
3248 (NH), 1693, 1624 (2CO) cm-1; H nmr (DMSO-d6) ꢀ 2.39
(s, 3H, CH3), 2.45 (s, 3H, CH3), 6.38 (s, 1H, Pyr-H), 7.2-8.1 (m,
7H, Ar-H), 9.51 (s, 1H, NH); ms, m/z (%) 506 (M+, 5), 278 (12),
230 (26), 111 (100), 63 (10).
Anal. Calcd. for C23H15ClN6O2S2: C, 54.49; H, 2.98; N, 16.58;
S, 12.65. Found: C, 54.38; H, 2.91; N, 16.23; S, 12.54.
This compound was obtained in 4.21 g (80%), mp 224 °C; ir:
3306, 3275 (2NH), 1686, 1655 (2CO) cm-1; ms, m/z (%) 527
(M++1, 2), 526 (M+, 6), 351 (2), 230 (17), 101 (25), 86 (100).
Anal. Calcd. for C25H18N8O4S: C, 57.03; H, 3.45; N, 21.28; S,
6.09. Found: C, 57.18; H, 3.12; N, 21.03; S, 6.16.
1-(4-Chlorophenyl)-9,11-dimethyl-3-(2-furoyl)-pyrido[3'',2'':
4',5']thieno[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetrazin-6(4H)-
one (9u).
3-Benzoyl-9,11-dimethyl-1-phenyl-pyrido[3'',2'':4',5']thieno-
[3',2':4,5]pyrimido[2,1-c][1,2,4,5]tetrazin-6(4H)-one (9o).
This compound was obtained in 3.31g (71%), mp 284 °C; ir:
This compound was obtained in 3.43 g (70%), mp 260 °C; ir:
1
3251 (NH), 1701, 1660 (2CO) cm-1; H nmr (DMSO-d6) ꢀ 2.39
1
3252 (NH), 1693, 1643 (2CO) cm-1; H nmr (DMSO-d6) ꢀ 2.39
(s, 3H, CH3), 2.45 (s, 3H, CH3), 6.38 (s, 1H, Pyr-H), 7.2-8.1 (m,
10H, Ar-H), 9.51 (s, 1H, NH); ms, m/z (%) 467 (M++1, 25), 466
(M+, 64), 230 (14), 105 (100), 77 (60).
(s, 3H, CH3), 2.45 (s, 3H, CH3), 6.38 (s, 1H, Pyr-H), 7.2-8.1 (m,
7H, Ar-H), 9.51 (s, 1H, NH); ms, m/z (%) 492 (M++2, 17), 490
(M+, 40), 230 (22), 95 (100).
Anal. Calcd. for C25H18N6O2S: C, 64.36; H, 3.89; N, 18.01; S,
6.87. Found: C, 64.30; H, 3.88; N, 17.76; S, 6.84.
Anal. Calcd. for C23H15ClN6O3S: C, 56.27; H, 3.08; N, 17.12;
S, 6.53. Found: C, 56.10; H, 3.01; N, 16.95; S, 6.40.

Jul-Aug 2006
A Novel Route to Tetracyclic Fused Tetrazines and Thiadiazines
941
Synthesis of Hydrazonothioate esters 10.
9,11-Dimethyl-2-(4-methylphenylhydrazono)-3-phenyl-pyrido-
[3'',2'':4',5']thieno[3',2':4,5]pyrimido[2,1-b][1,3,4]thiadiazin-6-
one (11p).
To a stirred solution of (5 mmol) sodium ethoxide (prepared
by adding 0.115 g sodium to 20 ml absolute ethanol) was added
compound 4 (1.39 g, 5 mmol). The solution was left stirring for
about 10 min. then the appropriate hydrazonoyl halide 6b,h,p
was added. The reaction mixture was left stirring at room
temperature for about 10 hrs. The precipitate formed was
collected by filtration and recrystallized from DMF to give
products 10b,h,p.
This compound was obtained in 1.99 g (80%), mp > 300 °C;
ir: 3263 (NH), 1632 (CO) cm-1; ms, m/z (%) 496 (M+, 60), 366
(52), 267 (64), 175 (56), 111 (92), 84 (100).
Anal. Calcd. for C26H20N6OS2: C, 62.88; H, 4.06; N, 16.92; S,
12.91. Found: C, 62.58; H, 4.00; N, 16.67; S, 12.62.
Synthesis of 9,11-Dimethyl-3-phenyl-pyrido[3'',2'':4',5']thieno-
[3',2':4,5]pyrimido[2,1-b][1,3,4]thiadiazin-6-one (13).
1-[3-Amino-7,9-dimethyl-4-oxo-pyrido[3',2':4,5]thieno[3,2-d]-
pyrimidin-2-yl]thio-1-(N-phenylhydrazono)-2-oxo-propane (10b).
To an equimolecular amounts (0.005 mol) of compound 4 and
phenacyl bromide in dioxane, triethyl amine (0.7 ml, 0.005 mol)
was added. The reaction mixture was refluxed for 15 min.
followed by addition of p-toluenesulphonic acid (0.86 g, 0.005
mol) and the reaction mixture was further refluxed for 2 hrs. The
precipitate that formed was collected by filtration, dried and
recrystallized from acetic acid
This compound was obtained in 1.32 g (70%), mp 252 °C; ir:
1704 (CO) cm-1; 1H nmr (DMSO-d6) ꢀ 2.59 (s, 3H, CH3), 2.84 (s, 3H,
CH3), 4.42 (s, 2H, CH2), 7.28 (s, 1H, Pyr-H), 7.59-8.08 (m, 5H, Ar-
H); ms, m/z (%) 379 (M++1, 29), 378 (M+, 100), 318 (6), 275 (33),
247 (20), 231 (10), 204 (7), 175 (12), 105 (10), 77 (24), 51 (15).
Anal. Calcd. for C19H14N4OS2: C, 60.30; H, 3.73; N, 14.80; S,
16.94. Found: C, 60.10; H, 3.42; N, 14.66; S, 16.36.
This compound was obtained in 1.51 g (70%), mp 260 °C; ir:
3386, 3236 (NH2), 3143 (NH), 1743, 1631 (2CO) cm-1; ms, m/z
(%) 438 (M+, 52), 403 (74), 320 (74), 114 (74), 56 (100).
Anal. Calcd. for C20H18N6O2S2: C, 54.78; H, 4.14; N, 19.16; S,
14.62. Found: C, 54.58; H, 4.01; N, 18.92; S, 14.46.
Ethyl
2-[3-amino-7,9-dimethyl-4-oxo-pyrido[3',2':4,5]thieno-
[3,2-d]pyrimidin-2-yl]thio-2-[(N-(4-methylphenyl)hydrazono)]-
ethanoate (10h).
This compound was obtained in 1.88 g (78%), mp 297 °C; ir:
3381, 3226 (NH2), 3183 (NH), 1743, 1631 (2CO) cm-1; ms, m/z
(%) 482 (M+, 52), 407 (35), 320 (24), 165 (100), 152 (57).
Anal. Calcd. for C22H22N6O3S2: C, 54.75; H, 4.60; N, 17.41; S,
13.29. Found: C, 54.34; H, 4.52; N, 17.13; S, 13.10.
Coupling of 9,11-Dimethyl-3-phenyl-pyrido[3'',2'':4',5']thieno-
[3',2':4,5]pyrimido[2,1-b[1,3,4]thiadiazin-6-one (13).
2-[3-Amino-7,9-dimethyl-4-oxo-pyrido[3',2':4,5]thieno[3,2-d]-
pyrimidin-2-yl]thio-2-[(N-(4-methylphenyl)hydrazono)]-1-
phenylethanone (10p).
To a solution of compound 13 (1.89 g, 0.005 mol) in 20 ml
pyridine was added the diazonium chloride solution, prepared as
usual by diazotizing aniline (5 mmoles) in hydrochloric acid (3
ml, 6 M) with sodium nitrite (0.35 g, 5 mmoles) in 10 ml water
portionwise with stirring and cooling. After complete addition,
the reaction mixture was left for 12 hrs. The precipitate that
formed was collected by filtration, washed with water, dried and
then recrystallized from DMF to give pure 11p.
This compound was obtained in 1.88 g (73%), mp 290 °C; ir:
3394, 3232 (NH2), 3140 (NH), 1741, 1631 (2CO) cm-1; ms, m/z
(%) 514 (M+, 26), 462 (47), 320 (24), 122 (55), 105 (84), 77
(100).
Anal. Calcd. for C26H22N6O2S2: C, 60.68; H, 4.31; N, 16.33; S,
12.46. Found: C, 60.61; H, 4.13; N, 16.20; S, 12.41.
Antimicrobial Assay.
Synthesis of 2-Arylhydrazono-3-substituted-pyrido[3'',2'':4',5']-
thieno[3',2':4,5]pyrimido[2,1-b][1,3,4]thiadiazin-6-ones (11).
The Antimicrobial activity of compounds 9a-u was studied
using four fungal species together with four bacterial species. It
was assayed biologically using a spore suspension of the fungal
species (one ml of sterile water containing approximately 108
conidia) or spreading bacterial suspension over a solidified malt
agar medium. The layer was allowed to set for 30 min. A
solution of each of the tested compounds (5 mg/ml) was placed
onto sterile 5 mm filter paper discs and allowed to dry, then the
discs were placed onto the center of the malt agar plate and
incubated at the optimum incubation temperature 28 °C. A clear
zone around the disc was taken as an indication of the inhibition
of the best organism growth. The size of the clear zone is
proportional to the inhibitory action of the compound under
investigation. The fungicide terbinafin and the bactericide
chloroamphenicol were used as standard under the same
conditions. Measurements were considered after 72 h for fungi
and 24 h for bacteria.
A solution of each of compound 10b,h,p (5 mmol) in 20 ml
glacial acetic acid was heated under reflux for about 1 hr. The
precipitate formed was collected by filtration and recrystallized
from DMF to give the respective 11b,h,p.
2-Phenylhydrazono-3,9,11-trimethyl-pyrido[3'',2'':4',5']thieno-
[3',2':4,5]pyrimido[2,1-b][1,3,4]thiadiazin-6-one (11b).
This compound was obtained in 1.47 g (70%), mp > 300 °C;
ir: 3233 (NH), 1632 (CO) cm-1; ms, m/z (%) 420 (M+, 68), 354
(63), 236 (73), 180 (100), 122 (74), 63 (94).
Anal. Calcd. for C20H16N6OS2: C, 57.12; H, 3.84; N, 19.99; S,
15.25. Found: C, 57.03; H, 3.75; N, 19.88; S, 15.04.
9,11-Dimethyl-3-hydroxy-2-(4-methylphenylhydrazono)-pyrido-
[3'',2'':4',5']thieno[3',2':4,5]pyrimido[2,1-b][1,3,4]thiadiazin-6-
one (11h).
This compound was obtained in 1.7 g (78%), mp > 300 °C; ir:
3387, 3228 (2NH), 1643, 1660 (2CO) cm-1; ms, m/z (%) 436
(M+, 22), 389 (22), 295 (40), 178 (53), 111 (100), 55 (91).
Anal. Calcd. for C20H16N6O2S2: C, 55.03; H, 3.69; N, 19.25; S,
14.69. Found: C, 56.94; H, 3.61; N, 19.20; S, 14.64.
REFERENCES
*
Tel.: +20-25676608; fax: +20-25685799; E-mail address:
riyadh1993@hotmail.com

942
I. M. Abbas, S. M. Riyadh, M. A. Abdallah and S. M. Gomha
Vol 43
[1] J. Kempson, W. J. Pitts, J. Barbosa, J. Guo, O. Omotoso, A.
[10] M. A. Abdallah, Monatsh. Chem., 132, 959 (2001).
Watson, K. Stebbins, G. C. Starling, J. H. Dodd, J. C. Barrish, R. Felix
and K. Fischer, Bioorganic Med. Chem. Lett., 15, 1829 (2005).
[2] E. Elzein, R. Kalla, X. Li, T. Perry, E. Parkhill, V. Palle, V.
Varkhedkar, A. Gimbel, D. Zeng, D. Lustig, K. Leung and J. Zablocki,
Bioorganic Med. Chem. Lett., 16, 302 (2006).
[11] A. S. Shawali, A. A. Elghandour and S. M. El-Sheikh, J.
Prakt. Chem., 342, 96 (2000).
[12] A. S. Shawali and A. El-Sayed, J. Chem. Res., 399 (S) (2004).
[13] A. S. Shawali, M. A. Abdallah and M. M. Zayed, J.
Heterocyclic Chem., 39, 45 (2002).
[3] J. M. Quintela, C. Peinador, L. González, R. Iglesias, A.
Paramá, F. Álvarez, M. L. Sanmartín and R. Riguera, Eur. J. Med.
Chem., 38, 265 (2003).
[4] E. A. Bakhite, A. E. Abdel-Rahman, O. S. Mohamed and E.
A. Thabet, J. Chem. Res., 58 (2003)
[14] Y. W. Ho and I. J. Wang, J. Heterocyclic Chem., 32, 819
(1995).
[15] H. H. Alnima, A. A. Ibrahim and W. F. Hammady, Indian J.
Chem., 34B, 736 (1995).
[16] P. Wolkoff, Can. J. Chem., 53, 1333 (1975).
[17] A. S. Shawali and A. O. Abdelhamid, Bull. Chem. Soc. Jpn,
49, 321 (1976).
[5] E. A. Bakhite, A. E. Abdel-Rahman and E. A. Al-Taifi, J.
Chem. Res., 320 (2003).
[6] J. M. Quintela, C. Peinador, C. Veiga, L. González, L. M.
Botana, A. Alfonso and R. Riguera, Bioorganic Med. Chem. Lett., 6,
1911 (1998).
[7] C. Peinador, M. J. Moreira and J. M. Quintela, Tetrahedron,
50, 6705 (1994).
[8] E. Z. Baum, W. D. Ding, M. M. Siegel, J. Hulmes, G. A.
Bebernitz, L. Sridharan, K. Tabei, G. Krishnamurity, T. Garofiglio, J. T.
Groves, J. D. Bloom, M. DiGrandi, M. Bradley, G. Ellestad, A. P.
Seddon and Y. Gluzman, Biochemistry, 35, 5847 (1996).
[9] M. Ertan, A. Bilgin, A. Palaska, E. Yulug and N. Arzneim,
Forsch./Drug Res., 42, 160 (1992) and the references cited therein.
[18] C. Bullow and E. King, Liebigs Ann., 439, 211 (1924).
[19] G. Favrel, Bull. Soc. Chim. Fr., 31, 150 (1904).
[20] W. Dieckmann and O. Platz, Ber. Dtsch. Chem. Ges., 38,
2989 (1906).
[21] H. M. Hassaneen, A. S. Shawali, and N. M. Abunada, Org.
Prep. Proceed. Int., 24, 171 (1992).
[22] A. M. Farag and M. S. Algharib, Org. Prep. Proceed. Int.,
20, 521 (1988).
[23] A. F. Hegarty, M. P. Cashman and F. L. Scott, J. Chem. Soc.
Perkin Trans. II, 1381 (1972).
[24] T. Curtius, J. Prakt. Chem., 51, 168 (1899).