Synthesis and reactions of some new selenolo[2,3-c]pyridazines

Article abstract of DOI:10.1007/s10593-011-0765-5

New series of selenolo[2,3-c]pyridazine and pyrimido[4′,5′:4,5] selenolo[2,3-c]pyridazine derivatives were prepared from 4-cyano-5,6- diphenylpyridazine-3(2H)-selenone. Elemental analysis, IR, ¹H NMR, and mass spectra confirmed the structures o

Full text of DOI:10.1007/s10593-011-0765-5

Chemistry of Heterocyclic Compounds, Vol. 47, No. 3, June, 2011 (Russian Original Vol. 47, No. 3, March, 2011)
SYNTHESIS AND REACTIONS OF SOME
NEW SELENOLO[2,3-c]PYRIDAZINES
S. H. Abdel-Hafez1, M. I. Abdel-Monem1, M. G. Mohamed1,
F. M. Abdelrazek2*, S. A. M. Metwally1
New series of selenolo[2,3-c]pyridazine and pyrimido[4',5':4,5]selenolo[2,3-c]pyridazine derivatives
1
were prepared from 4-cyano-5,6-diphenylpyridazine-3(2H)-selenone. Elemental analysis, IR, H NMR,
and mass spectra confirmed the structures of the newly synthesized compounds.
Keywords: pyridazines, selenolopyridazines, pyrimidoselenolopyridazines.
Selenium has attracted great interest as an essential element, and certain diseases have been eradicated
by dietary supplementation of this element. Selenium is essential for cell metabolism as a component of
glutathione peroxidase and other enzyme systems. Current interest lies in the prevention of certain cancers by
supplementation with selenium [1–4]. One proposed mechanism for this activity is the cytotoxic effect of
selenium on tumor cells [5, 6]. Organoselenium compounds continue to attract the attention of many
investigators owing to a series of unique properties. There are data showing that organoselenium compounds are
capable of sensitizing processes in the living organism, and there are four known naturally occurring proteins
containing the selenium atom. Therefore, despite the high toxicity of selenium compounds [7–9], many of them
have been prepared as and anticancer agents [10–15] and for other medicinal effects like antiviral [16–18],
antimicrobial [19–22], and fungicidal [23–25] activities. Heterocyclic annelated pyridazines also attract
considerable attention, which arises mainly from the large variety of interesting pharmacological, herbicidal,
insecticidal, and fungicidal activities [26–30]. In the last two decades we have been involved in a program aimed
at developing new synthesis of heterocyclic systems of anticipated biological and/or pharmacological effects
[31–37]. In continuation of this program, some selenium-containing heterocyclic compounds were required for
evaluation as biodegradable agrochemicals. The starting compound 4-cyano- 5,6-diphenylpyridazine-3(2H)-
selenone 1, which was prepared as previously described [38] seemed suitable to fulfill this objective.
_______
*To whom correspondence should be addressed, e-mail: sabdel68@yahoo.co.uk, e-mail: shams@aun.edu.eg.
1Chemistry Department, Faculty of Science, Assiut University, Assuit 71516, Egypt.
2Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt; e-mail:
prof.fmrazek@gmail.com.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 441-449, March, 2011. Original
article received September 17, 2010.
0009-3122/11/4703-0363©2011 Springer Science+Business Media, Inc.
363

The reaction of compound 1 with chloroacetonitrile 2a, chloroacetamide 2b, or ethyl chloroacetate 2c in
refluxing ethanol in the presence of a few drops of sodium ethoxide led to the corresponding selenolo-
[2,3-c]pyridazine derivatives 3a–c [38]. The reaction apparently involves a ThorpeZiegler cyclization [39].
Ph
Ph
Cl
X
CN
Se
NH2
X
Ph
Ph
2a–c
N
N
N
H
Se
N
1
3a–c
2, 3 a X = CN, b X = CONH2, c X = COOEt
The reaction of 5-amino-3,4-diphenylselenolo[2,3-c]pyridazine-6-carbonitrile (3a) with formamide
under reflux gave 3,4-diphenylpyrimido[4',5':4,5]selenolo[2,3-c]pyridazine-8-amine (4).
Compound 3a reacts with acetic anhydride to give 6-methyl-3,4-diphenylpyrimido[4',5':4,5]selenolo-
[2,3-c]pyridazin-8(7H)-one (5). Compound 3a also reacts with triethyl orthoformate in refluxing acetic acid in
the presence of acetic anhydride to give ethyl N-(6-cyano-3,4-diphenylselenolo[2,3-c]pyridazin-5-yl)methan-
imidate (6). This methanimidate 6 reacts with hydrazine hydrate in dioxane at room temperature to give
8-imino-3,4-diphenylpyrimido[4',5':4,5]selenolo[2,3-c]pyridazine-7(8H)-amine (7). Compound 3a reacts also
with malononitrile in the presence of acetic acid under reflux to produce 2-(8-amino-3,4-diphenyl-
pyrimido[4',5':4,5]selenolo[2,3-c]pyridazin-6-yl)acetonitrile (8).
Ph
Ph
N
Ph
HCONH2
CH2(CN)2
N
Ph
CN
3a
N
N
N
N
N
Se
N
Se
NH2
NH2
HC(OEt)3
AcOH
4
8
Ac2O
Ph
N
Ph
N
Ph
Me
NH
N
O
N
Ph
Ph
OEt
N
Ph
N2H
4·· H2O
N
N
N
N
NH2
Se
Se
CN
N
Se
NH
5
6
7
The reaction of 5-amino-3,4-diphenylselenolo[2,3-c]pyridazine-6-carboxamide (3b) with 4-chloro-
butyryl chloride was carried out under neat conditions and did not give the expected chloropropyl derivative 9,
but instead resulted in a pyrrole ring-containing structure 10. This result can be explained by formation of the
intermediate 9 followed by cyclization with loss of HCl to give compound 10. Compound 3b reacts with
chloroacetyl chloride under heating on a refluxing water bath to give 6-chloromethyl-3,4-diphenyl-
pyrimido[4',5':4,5]selenolo[2,3-c]pyridazin-8(7H)-one (11). Compound 3b reacts also with formic acid under
reflux to give 3,4-diphenylpyrimido-[4',5':4,5]selenolo[2,3-c]pyridazin-8(7H)-one (12). Compound 12 reacts
with phosphorus pentasulfide in pyridine under reflux to produce 3,4-diphenylpyrimido[4',5':4,5]selenolo-
[2,3-c]pyridazine-8(7H)-thione (13).
364

Ph
N
Ph
N
NH2
CH2Cl
N
O
Ph
Ph
Ph
Ph
ClCH2COCl
NH
NH
NH
N
N
N
N
CONH2
Se
Se
3b
11
HCOOH
Cl(CH2)3COCl
Ph
Ph
N
(CH2)3Cl
N
O
N
O
Ph
NH
N
N
Se
Se
9
12
P2S5
– HCl
Ph
Ph
N
N
O
N
S
Ph
N
N
N
Se
Se
10
13
Compound 3b reacts with the aromatic aldehydes (4-hydroxybenzaldehyde, 4-(dimethylamino)-
benzaldehyde and 4-nitrobenzaldehyde) 14a–c in the presence of acetic acid to afford 6-aryl-3,4-diphenyl-
6,7-dihydropyrimido[4',5':4,5]selenolo[2,3-c]pyridazin-8(5H)-ones 15a–c, respectively. The reaction of the
Ph
ArCHO
NH2
Ph
14a–c
HC(OEt)3
Ph
N
CONH2
N
Se
Ph
N
H
N
3b
Ar
NH
Ph
OEt
N
Ph
N
N
N
Se
CONH2
Se
PhNCS
Benzil
O
15a–c
18
Ph
N
O
Ph
N
H
N
S
Ph
N
N
Ph
Ph
Ph
N
O
N
Ph
Se
16
CONH2
Se
17
14,15 a Ar = 4-HOC6H4, b Ar = 4-Me2NC6H4, c Ar = 4-O2NC6H4
365

carboxamide derivative 3b with phenyl isothiocyanate in pyridine under reflux afforded 3,4,7-triphenyl-6-thioxo-
6,7-dihydropyrimido[4',5':4,5]selenolo[2,3-c]pyridazin-8(5H)-one (16). When compound 3b reacted with benzil
in refluxing dioxane in the presence of a few drops of triethylamine, 5-(2-oxo-1,2-diphenylethylideneamino)-
3,4-diphenylselenolo[2,3-c]pyridazine-6-carboxamide (17) was obtained. Compound 3b reacts also with triethyl
orthoformate in the presence of a few drops of acetic acid to give ethyl N-(6-carbamoyl-3,4-
diphenylselenolo[2,3-c]pyridazine-5-yl)methanimidate (18).
The reaction of ethyl 5-amino-3,4-diphenylselenolo[2,3-c]pyridazine-6-carboxylate (3c) with alcoholic
sodium hydroxide under reflux afforded 5-amino-3,4-diphenylselenolo[2,3-c]pyridazine-6-carboxylic acid (19),
which reacted with acetic anhydride under reflux to give 6-methyl-3,4-diphenyl-8H-pyridazino[4',3':4,5]-
selenolo[3,2-d][1,3]oxazin-8-one (20).
Compound 20 reacts with aniline under reflux to give 6-methyl-3,4,7-triphenylpyrimido-
[4',5':4,5]selenolo[2,3-c]pyridazin-8(7H)-one (21).
Ph
Ph
NH2
NH2
Ph
Ph
NaOH
N
N
COOH
N
Se
COOEt
N
Se
3c
19
Ac2O
Ph
N
Ph
N
Me
Me
N
O
N
O
Ph
Ph
PhNH2
N
O
N
N
Ph
Se
Se
21
20
EXPERIMENTAL
Melting points were determined using a Kofler melting point apparatus. IR spectra were recorded on a
Pye-Unicam SP3-100 instrument in KBr pellets. The mass spectra (EI, 70 eV, ion source temperature 210ºC)
13
were recorded on a Jeol JMS600 instrument. 1H and C NMR spectra were obtained on a JEOL LA 400 NMR
spectrometer (400 and 100 MHz, respectively), solvents CDCl3 (compounds 6, 7, and 16), TFA (compounds 11,
12, and 15ac), and DMSO-d6 (compounds 8, 10, 13, 1721), using TMS as the internal standard. Elemental
analyses were obtained on an Elementar Vario EL 1150C analyzer (Heraeus, Germany).
Compounds 3a–c were prepared according to the previously reported method [38].
3,4-Diphenylpyrimido[4',5':4,5]selenolo[2,3-c]pyridazine-8-amine (4). A mixture of compound 3a
(0.5 g, 1.329 mmol) and 10 ml of formamide was heated for 5 h under reflux. The mixture was cooled, and the
precipitate was filtered off, washed with water, and recrystallized from aqueous dioxane, yield 37%; mp
178-180°C. IR spectrum, , cm1: 3420, 3310 (NH2), 1620 (C=N). Found, %: C 59.60; H 3.32; N 17.56.
C20H13N5Se. Calculated, %: C 59.71; H 3.26; N 17.41.
6-Methyl-3,4-diphenylpyrimido[4',5':4,5]selenolo[2,3-c]pyridazin-8(7H)-one (5). Compound 3a (2 g,
5.319 mmol) was heated under reflux in acetic anhydride (10 ml) for 3 h. The product that formed on cooling
was collected and recrystallized from aqueous dioxane to give yellow crystals, yield 53%; mp >300°C. IR
1
spectrum, , cm1: 1680 (C=O). H NMR spectrum, δ, ppm: 7.20–7.55 (10H, m, H Ar); 2.81 (3H, s, CH3).
13C NMR spectrum, δ, ppm: 165.10 (C=O), 158.89 (C=N pyridazine), 157.54, 153.13, 147.56, 137.36, 136.95,
366

135.28, 133.24, 130.59, 130.38, 130.29, 130.13, 128.14, 128.02, 127.68, 127.29 (Ar), 40.39 (CH3). Found, %:
C 60.55; H 3.60; N 12.98. C21H14N4OSe. Calculated, %: C 60.44; H 3.38; N 13.43.
Ethyl N-(6-Cyano-3,4-diphenylselenolo[2,3-c]pyridazin-5-yl)methanimidate (6). Nitrile 3a (0.5 g,
1.329 mmol) and triethyl orthoformate (7 ml) were refluxed in acetic acid (20 ml) in the presence of a few drops
of acetic anhydride for 5 h. The precipitate that formed on cooling was collected and recrystallized from ethanol
1
to afford white crystals, yield 37%; mp 180–182°C. IR spectrum,, cm-1: 2200 (CN), 1620 (C=N). H NMR
spectrum, δ, ppm (J, Hz): 7.20-7.55 (10H, m, H Ar); 3.44 (2H, q, J = 7.1, CH2); 1.20 (3H, t, J = 7.1, CH3).
Found, %: C 61.05; H 3.57; N 12.75. C22H16N4OSe. Calculated, %: C 61.26; H 3.74; N 12.99.
8-Imino-3,4-diphenylpyrimido[4',5':4,5]selenolo[2,3-c]pyridazine-7(8H)-amine (7). The imino ether 6
(1 g, 2.314 mmol) was suspended in dioxane (10 ml), and hydrazine hydrate (2 ml) was added. The reaction
mixture was stirred at room temperature for 3 h, and the solid product was collected by filtration and
recrystallized from dioxane. White crystals, yield 33%; mp 140–143°C. IR spectrum, , cm1: 3410 (NH), 3320,
3300 (NH2). Found, %: C 57.48; H 3.42; N 20.25. C20H14N6Se. Calculated, %: C 57.56; H 3.38; N 20.14.
2-(8-Amino-3,4-diphenylpyrimido[4',5':4,5]selenolo[2,3-c]pyridazin-6-yl)acetonitrile (8). The nitrile 3a
(0.5 g, 1.329 mmol) was heated under reflux for 3 h in glacial acetic acid (10 ml) with malononitrile (0.087 g,
1.33 mmol). The product that separated on cooling was collected and recrystallized from dioxane, yield 40%;
mp >300°C. IR spectrum, , cm-1: 3480, 3310 (NH2). 1H NMR spectrum, δ, ppm: 7.20-7.57 (10H, m, H Ar); 4.32
(2H, s, CH2). Found, %: C 59.65; H 3.15; N 19.10. C22H14N6Se. Calculated, %: C 59.87; H 3.20; N 19.04.
3,4-Diphenyl-7,8-dihydropyrrolo[1'',2'':1',2']pyrimido[4',5':4,5]selenolo[2,3-c]pyridazin-10(6H)-
one (10). The amide 3b (2 g, 5.07 mmol) was heated in 4-chlorobutyryl chloride (10 ml) on a water bath for 3 h.
The solid product that formed on cooling was collected and recrystallized from ethanol–dioxane to give pale-
1
yellow crystals, yield 86%; mp 295–298°C. IR spectrum, ,, cm-1: 3168 (CH aromatic), 1704 (C=O). H NMR
spectrum, δ, ppm (J, Hz): 7.20–7.55 (10H, m, H Ar); 2.55 (2H, m, CH2); 2.30 (2H, t, J = 7.1, CH2); 2.01 (2H, t,
J = 7.1, CH2). Found, %: C 62.40; H 3.54; N 12.80. C23H16N4OSe. Calculated, %: C 62.31; H 3.64; N 12.64.
6-Chloromethyl-3,4-diphenylpyrimido[4',5':4,5]selenolo[2,3-c]pyridazin-8(7H)-one (11). Compound 3b
(1 g, 2.54 mmol) in chloroacetyl chloride (15 ml) was heated under reflux on a water bath for 3 h. The reaction
mixture was cooled and poured on ice–water. The product that formed on cooling was collected and
recrystallized from ethanol to give white needles, yield 75%; mp 293–295°C. IR spectrum, , cm1: 3200 (NH),
1
13
1725 (C=O). H NMR spectrum, δ, ppm: 7.20–7.56 (10H, m, H Ar); 3.42 (2H, s, CH2). C NMR spectrum, δ,
ppm: 165.65 (C=O), 162.68 (C=N pyridazine), 162.47, 156.69, 147.54, 136.87, 135.37, 132.63, 131.97, 130.33,
130.23, 130.04, 128.16, 128.03, 127.88, 127.74, 127.61, 127.50, 127.14 (Ar), 41.61 (CH2). Found, %: C 55.57;
H 2.94; N 12.18. C21H13ClN4OSe. Calculated, %: C 55.83; H 2.90; N 12.40.
3,4-Diphenylpyrimido[4',5':4,5]selenolo[2,3-c]pyridazin-8(7H)-one (12). Compound 3b (2.68 g, 6.8
mmol) was heated under reflux in formic acid (10 ml) for 3 h. The product that formed on cooling was collected
and recrystallized from dioxane–DMF to give white crystals, yield 64%; mp >300°C. IR spectrum, , cm1:
1
3360 (NH), 1663 (C=O). H NMR spectrum, δ, ppm: 8.28 (1H, s, CH pyrimidine); 7.20–7.55 (10H, m, H Ar);
13C NMR spectrum, δ, ppm: 165.09 (C=O), 158.73 (C=N pyridazine), 157.54, 156.29, 153.12, 147.41, 137.37,
136.93, 133.22, 130.55, 130.41, 130.28, 130.12, 128.14, 128.01, 127.67, 127.29, 122.38 (Ar), 66.37 (CH
pyrimidine). Found, %: C 58.99; H 3.45; N 13.47. C20H12N4OSe. Calculated, %: C 59.56; H 3.00; N 13.89.
3,4-Diphenylpyrimido[4',5':4,5]selenolo[2,3-c]pyridazine-8(7H)-thione (13). Compound 12 (1 g,
2.475 mmol) and phosphorus pentasulfide (0.3 g, 2.459 mmol) in pyridine (20 ml) were heated on water bath
for 6 h. The solid product was collected and recrystallized from dioxane to form yellow crystals, yield 80%; mp
1
>300°C. IR spectrum, , cm1: 3360 (NH). H NMR spectrum, δ, ppm: 8.01 (1H, s, CH pyrimidine); 7.30–7.59
13
(10H, m, H Ar). C NMR spectrum, δ, ppm: 165.10 (C=S), 163.87 (C=N pyridazine), 159.62, 158.76, 157.56,
153.13, 147.43, 137.38, 136.94, 133.23, 130.56, 130.41, 130.29, 130.13, 128.15, 128.02, 127.68, 127.30 (Ar),
58.09 (CH pyrimidine). Found, %: C 57.55; H 3.43; N 13.44. C20H12N4SeS. Calculated, %: C 57.28; H 2.88;
N 13.36.
367

6-Aryl-3,4-diphenyl-6,7-dihydropyrimido[4',5':4,5]selenolo[2,3-c]pyridazin-8(5H)-ones
15a–c
(General Method). The amide 3b (2 g, 5.07 mmol) was heated under reflux for 6 h in glacial acetic acid (10 ml)
with the appropriate aromatic aldehyde 14a–c (10 mmol). The products that formed on cooling were collected
and recrystallized from DMF.
6-(4-Hydroxyphenyl)-3,4-diphenyl-6,7-dihydropyrimido[4',5':4,5]selenolo[2,3-c]pyridazin-8(5H)-one
(15a). Yellow crystals, yield 60%; mp >300ºC. IR spectrum, , cm1: 3400 (OH), 3200, 3180 (2NH), 1620 (C=O).
1H NMR spectrum, δ, ppm: 7.20-7.55 (14H, m, H Ar); 6.09 (1H, s, CH pyrimidine). Found, %: C 62.72; H 3.59;
N 11.38. C26H18N4O2Se. Calculated, %: C 62.78; H 3.65; N 11.26.
6-(4-Dimethylaminophenyl)-3,4-diphenyl-6,7-dihydropyrimido[4',5':4,5]selenolo[2,3-c]pyridazin-
8(5H)-one (15b). Green crystals, yield 60%; mp >300ºC. IR spectrum, , cm1: 3400 (NH). 1H NMR spectrum,
δ, ppm: 8.88 (1H, s, CH pyrimidine); 7.20-7.55 (14H, m, H Ar); 2.35 (6H, s, CH3). Found, %: C 63.85; H 4.50;
N 13.40. C28H23N5OSe. Calculated, %: C 64.12; H 4.42; N 13.35.
6-(4-Nitrophenyl)-3,4-diphenyl-6,7-dihydropyrimido[4',5':4,5]selenolo[2,3-c]pyridazin-8(5H)-one
1
(15c). Yellow crystals, yield 50%; mp 300ºC. IR spectrum, , cm1: 3398 (NH), 1690 (C=O). H NMR
spectrum, δ, ppm: 7.20-7.55 (14H, m, H Ar); 6.39 (1H, s, CH pyrimidine). Found, %: C 59.25; H 3.32; N 13.40.
C26H17N5O3Se. Calculated, %: C 59.32; H 3.26; N 13.30.
3,4,7-Triphenyl-6-thioxo-6,7-dihydropyrimido[4',5':4,5]selenolo[2,3-c]pyridazin-8(5H)-one
(16).
Amide 3b (2 g, 5.07 mmol) in pyridine (15 ml) was heated with phenyl isothiocyanate (1.9 ml, 10 mmol) under
reflux for 4 h. The solid product that separated while hot was recrystallized from ethanol. White crystals, yield
25%; mp 148–150ºC. IR spectrum, , cm1: 3200 (NH), 1690 (C=O). 1H NMR spectrum, δ, ppm: 10.15 (1H, s,
NH); 7.20–7.55 (15H, m, H Ar). Found, %: C 60.85; H 3.30; N 11.20; S 6.32. C26H16N4OSeS. Calculated, %:
C 61.06; H 3.15; N 10.95; S 6.27.
5-(2-Oxo-1,2-diphenylethylideneamino)-3,4-diphenylselenolo[2,3-c]pyridazine-6-carboxamide (17).
Amide 3b (2 g, 5.07 mmol) was heated under reflux for 6 h in dioxane (10 ml) with benzil (1g, 4.76 mmol) in
the presence of a few drops of triethylamine. The product that formed on cooling was collected and
recrystallized from aqueous DMF to give orange crystals, yield 85%; mp >300ºC. IR spectrum, , cm1: 3420,
1
3300 (NH2), 1680 (C=O). H NMR spectrum, δ, ppm: 7.25-8.10 (20H, m, H Ar); 5.95 (2H, s, NH2). Found, %:
C 67.65; H 3.84; N 9.78. C33H22N4O2Se. Calculated, %: C 67.69; H 3.79; N 9.57.
Ethyl N-(6-Carbamoyl-3,4-diphenylselenolo[3,4-c]pyridazin-5-yl)methanimidate (18). Amide 3b (2 g,
5.07 mmol) and triethyl orthoformate (7 ml) were refluxed in acetic anhydride (20 ml) for 1 h. The precipitate
that formed in the hot solution was collected by filtration and recrystallized from dioxane to give yellow
1
crystals, yield 80%; mp >300ºC. IR spectrum, , cm1: 3300, 3200 (NH2), 1640 (C=O). H NMR spectrum, δ,
ppm (J, Hz): 9.28 (1H, s, CH); 7.20-7.56 (10H, m, H Ar); 4.30 (2H, q, J = 7.1, CH2); 1.55 (3H, t, J = 7.1, CH3).
13C NMR spectrum, δ, ppm: 165.10, 163.76 (2C=O), 162.94 (C=N pyridazine), 159.98, 147.43, 141.59, 137.09,
136.94, 135.86, 133.65, 130.29, 130.14, 130.03, 128.15, 128.02, 127.82, 127.68, 127.58, 127.30 (Ar), 66.39,
62.05 (CH, CH2), 13.61 (CH3). Found, %: C 58.43; H 4.14; N 12.90. C22H18N4O2Se. Calculated, %: C 58.80;
H 4.04; N 12.47.
5-Amino-3,4-diphenylselenolo[2,3-c]pyridazine-6-carboxylic Acid (19). A suspension of ester 3c
(1 g, 2.37 mmol) in 10% ethanolic sodium hydroxide (40 ml) was heated under reflux for 4 h and then allowed
to cool. The reaction mixture was diluted with 50 ml of water, filtered, and then acidified with dilute acetic acid.
The precipitate was filtered off and recrystallized from dioxane to give red crystals, yield 60%; mp 240–242ºC.
1
IR spectrum, , cm1: 3420, 3300 (NH2), 1640 (C=O). H NMR spectrum, δ, ppm: 10.55 (1H, s, COOH);
7.25-7.78 (12H, m, H Ar + NH2). Found, %: C 57.39; H 3.18; N 10.35. C19H13N3O2Se. Calculated, %: C 57.88;
H 3.32; N 10.66.
368

6-Methyl-3,4-diphenyl-8H-pyridazino[4',3':4,5]selenolo[3,2-d][1,3]oxazin-8-one (20). Compound 19
(1 g, 2.02 mmol) in acetic anhydride (15 ml) was heated under reflux for 4 h and allowed to cool to room
temperature. The crystalline product was collected, dried in air, and applied in the next reaction without
1
recrystallization, yield 30%; mp 260–263ºC. IR spectrum, , cm1: 1740 (C=O). H NMR spectrum, δ, ppm:
7.20–7.55 (10H, m, H Ar); 2.15 (3H, s, CH3). Found, %: C 60.34; H 3.38; N 9.98. C21H13N3O2Se. Calculated, %:
C 60.30; H 3.13; N 10.05.
6-Methyl-3,4,7-triphenylpyrimido[4',5':4,5]selenolo[2,3-c]pyridazin-8(7H)-one (21). A mixture of
compound 20 (1 g, 2.39 mmol) and aniline (0.4 ml) in glacial acetic acid (10 ml) was heated under reflux for
3 h. The reaction mixture was cooled and diluted with water. The solid precipitate was collected and
recrystallized from an ethanol–chloroform mixture to give white needles, yield 30%; mp 233–235ºC. IR
1
spectrum, , cm1: 1660 (C=O). H NMR spectrum, δ, ppm: 7.20-7.55 (15H, m, H Ar); 2.15 (3H, s, CH3).
Found, %: C 65.35; H 3.64; N 11.05. C27H18N4OSe. Calculated, %: C 65.72; H 3.68; N 11.35.
F. M. Abdelrazek thanks the Alexander von Humboldt Foundation (Germany) for granting him a
research fellowship July-August, 2009 during which the elemental analyses and spectral measurements of a
considerable part of this work were carried out. The kind hospitality of Prof, Peter Metz, Institute of Organic
Chemistry, TU-Dresden is also highly appreciated.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
M. Hill, Eur. J. Clin. Nutr., 56, Suppl. 1, S36 (2002).
M. A. Moyad, Urology, 59, 9 (2002).
J. E. Spallholz, Bull. Selenium-Tellurium, No. 05, 1 (2001).
J. E. Spallholz, Bull. Selenium-Tellurium, No. 10, 1 (2001).
G. Mugesh, W.-W. Du Mont, and H. Sies, Chem. Rev., 101, 2125 (2001).
M. S. Alaejos, F. J. Diaz Romero, and C. Diaz Romero, Nutrition, 16, 376 (2000).
V. P. Litvinov and V. D. Dyachenko, Usp. Khim., 66, 1025 (1997).
Zh. I. Abramova and Z. Kh. Chernyi, in: N. V. Lazarev and I. D. Gadaskina (editors), Hazardous
substances in industry, Vol. 3, Khimiya, Leningrad, 1977, p. 75.
K. E. Panter, W. J. Hartley, L. F. James, H. F. Mayland, B. L. Stegelmeier, and P. O. Kechele, Toxicol.
Sci., 32, 217 (1996).
9.
10.
11.
R. Bohm, Pharmazie, 42, 793 (1987).
M. Koketsu, K. Tanaka, Y. Takenaka, C. D. Kwong, and H. Ishihara, Eur. J. Pharm. Sci., 15, 307
(2002).
12.
13.
14.
15.
16.
T. Wirth, Tetrahedron, 55, 1 (1999).
N. Petragnani, H. A. Stefani, and C. J. Valduga, Tetrahedron, 57, 1411 (2001).
S. Uemura, Chem. Ind., 40, 106 (1987).
A. Dari, L. E. Christiaens, and M. J. Renson, Acta Chem. Scand., 47, 208 (1993).
V. Yu. Mortikov, V. P. Litvinov, A. M. Shestopalov, Yu. A. Sharanin, E. E. Apenova, G. A. Galegov,
I. I. Abdullaev, and F. I. Abdullaev, Khim.-farm. Zh., 25, № 5, 41 (1991).
Yu. A. Sharanin, A. M. Shestopalov, G.. I. Khoroshilov, and V. D. Dyachenko, in: Abstracts of Reports
at the All-Union Meeting "Natural Sciences for the National Economy", Perm, 1988, p. 126.
A. M. Shestopalov, Yu. A. Sharanin, A. S. Demerkov, and L. A. Rodinovskaya, in: Abstracts of Reports
at the All-Union Meeting "Natural Sciences for the National Economy", Perm, 1988, p. 126.
Yu. N. Klimochkin, I. L. Moiseev, O. V. Abramov, G. V. Vladyko, L. V. Korobchenko, and
E. I. Boreiko, Khim.-farm. Zh., 25, № 7, 49 (1991).
17.
18.
19.
369

20.
J. Młochowski, K. Klos, L. Syper, A. Dubowska-Inglot, and J. Zielińska-Jenczylik, Pol. Pat. 159 930;
Ref. Zh. Khim., 17O67P (1994).
21.
22.
23.
24.
25.
S. El-Bahaic, M. G. Assy, and M. M. Hassanier, Pharmazie, 45, 791 (1990).
J. R. Hwu, L. L. Lai, G. H. Hakimelahi, and H. Davari, Helv. Chim. Acta, 77, 1037 (1994).
B. E.-S. Bayomy, J. Serb. Chem. Soc., 55, 205 (1990).
H. Ishihara, M. Koketsu, Y. Fukuta, and F. Nada, J. Am. Chem. Soc., 123, 8408 (2001).
K. D. Berlin, M. D. Thompson, B. J. Scherlag, and G. S. Smith, US Pat. 4 778 892; Ref. Zh. Khim.,
14O108P (1989).
26.
27.
A. M. Shestopalov, Yu. A. Sharanin, L. A. Rodinovskaya, V. Yu. Mortikov, V. P. Litvinov, and
V. K. Promonenkov, in: Abstracts of Reports at the All-Union Conference "The Chemistry and
Technology of Pyridine-Containing Pesticides", Chernogolovka, 1988, p. 122.
L. Yu. Kuleshova, A. P. Burtnev, L. R. Kubasova, and G. V. Bergovykh, in: Topical Problems of the
Pharmacy of the Non-Black Earth Zone. Collected Proceedings of the Ryazan Medical Institute, Ryazan,
1987, Vol. 92, p. 149.
28.
29.
30.
N. A. Platonova, Z. F. Gromova, and L. G. Breeva, in: Topical Problems of the Pharmacy of the Non-
Black Earth Zone. Collected Proceedings of the Ryazan Medical Institute, Ryazan, 1987, Vol. 92, p. 53.
G. Heinisch and H. Kopelent-Frank, in: Progress in Medicinal Chemistry, G. P. Ellis, G. B. West
(editors), 1990, Vol. 27, p. 141.
G. Heinisch and H. Kopelent-Frank, in: G. P. Ellis, G. B. West (editors), Progress in Medicinal
Chemistry, 1990, Vol. 27, p. 1.
31.
32.
33.
F. M. Abdelrazek, P. Metz, and E. K. Farrag, Arch. Pharm., 337, 482 (2004).
F. M. Abdelrazek, P. Metz, N. H. Metwally, and S. F. El-Mahrouky, Arch. Pharm., 339, 456 (2006).
F. M. Abdelrazek, P. Metz, O. Kataeva, A. Jaeger, and S. F. El-Mahrouky, Arch. Pharm., 340, 543
(2007).
34.
35.
Sh. H. Abdel-Hafez and M. A. Hussein, Arch. Pharm., 341, 240 (2008).
F. M. Abdelrazek, N. H. Metwally, N. A. Kassab, and N. A. Sobhy, J. Heterocycl. Chem., 46, 1380
(2009).
36.
37.
S. H. Abdel-Hafez, Russ. J. Bioorg. Chem., 36, 370 (2010).
F. M. Abdelrazek, N. H. Metwally, N. A. Kassab, N. A.Sobhy, P. Metz, and A. Jaeger, J. Heterocycl.
Chem., 47, 384 (2010).
38.
39.
Sh. H. Abdel-Hafez, Eur. J. Med. Chem., 43, 1971 (2008)
J. P. Schaefer and J. Bloomfield, Org. Reactions, 15, 1 (1967).
370