Selenium-containing heterocycles 3*. Synthesis and reactions of selenolo- [2,3-b]pyridine derivatives and related fused tricyclic systems

Article abstract of DOI:10.1007/s10593-011-0766-4

A new series of pyrido[3′,2′:4,5]selenolo[3,2-d]pyrimidine derivatives is reported. The structures of the newly synthesized compounds were elucidated by elemental analyses and spectral data (IR, ¹H and ¹³∈C NMR, MS).

Full text of DOI:10.1007/s10593-011-0766-4

Chemistry of Heterocyclic Compounds, Vol. 47, No. 3, June, 2011 (Russian Original Vol. 47, No. 3, March, 2011)
SELENIUM-CONTAINING HETEROCYCLES
3*. SYNTHESIS AND REACTIONS OF SELENOLO-
[2,3-b]PYRIDINE DERIVATIVES AND RELATED
FUSED TRICYCLIC SYSTEMS
S. H. Abdel-Hafez1*, M. I. Abdel-Monem1, M. G. Mohamed1, and S. A. M. Metwally1
A new series of pyrido[3',2':4,5]selenolo[3,2-d]pyrimidine derivatives is reported. The structures of the
1
13
newly synthesized compounds were elucidated by elemental analyses and spectral data (IR, H and C
NMR, MS).
Keywords: fused pyridines, pyridines, pyridoselenolopyrimidines.
Selenium has long been recognized as a dietary antioxidant and is now known to be an essential
component of the active sites of several enzymes, including glutathione peroxidase [2] and thioredoxin
reductase, which catalyze reactions essential for the protection of cellular components against oxidative and
radical damage [3]. Moreover, previous work in our laboratory describes the synthesis of pyrimidoselenolo-
[2,3-b]quinoline [4] and pyrimidoselenolo[2,3-c]pyridazine derivatives [5] and indicates that certain compounds
possess significant anti-inflammatory and analgesic activities with strong fungicidal effects. Furthermore, in Part
1 [6] and Part 2 [1] we published the synthesis of selenolo[2,3-b]pyridine, pyrido[3',2':4,5]selenolo-
[3,2-d]pyrimidine, 2,4-dimethyl-7,8-dihydropyrrolo[1,2-a]pyrido[3',2':4,5]selenolo[3,2-d]pyrimidin-10(6H)-one,
7,9-dimethylpyrido[3',2':4,5]selenolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine, 7,9-dimethylpyrido[3',2':4,5]sele-
nolo[3,2-d]pyrimidine-2,4(1H,3H)-dithione, 7,9-dimethylpyrido[3',2':4,5]selenolo[2,3-e]tetrazolo[1,5-c]pyrimi-
dine-6(5H)thione, 9,11-dimethylpyrido[3',2':4,5]selenolo[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine, 7,9-dimethyl-
pyrido[3',2':4,5]selenolo[2,3-e]imidazo[1,2-c]pyrimidine, and 10,12-dimethylpyrido[3'',2'':4',5']selenolo-
[3',2':4,5]pyrimido[1,6-a]pyrimidine derivatives. Prompted by these observations and in continuation of our
work we report herein new classes of fused tri- and tetracyclic systems containing the selenolo[2,3-b]pyridine
fragment in the hope that members of these series may find interesting biological applications.
_______
* For Communication, 2 see [1].
*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, Assiut 71516, Egypt.
Chemistry Department, Faculty of Science, Taif University, 888, Alhawiya, Taif,
Kingdom of Saudi Arabia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 450-456, March, 2011. Original
article received October 11, 2010.
0009-3122/11/4703-0371©2011 Springer Science+Business Media, Inc.
371

The starting 4-chloro-2,7,9-trimethylpyrido[3',2':4,5]selenolo[3,2-d]pyrimidine (1) was obtained by
previously described procedures [1, 6] using acetic anhydride instead of formic acid. Compound 1 reacted with
hydrazine hydrate to give 4-hydrazino-2,7,9-trimethylpyrido[3',2':4,5]selenolo[3,2-d]pyrimidine (2), which was
allowed to react with diethyl malonate and afforded ethyl 3-oxo-3-[2-(2,7,9-trimethylpyrido[3',2':4,5]-
selenolo[3,2-d]-pyrimidin-4-yl)hydrazino]propanoate (3) instead of ethyl (5,7,9-trimethylpyrido[3',2':4,5]-
selenolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-3-yl)acetate (4). Compound 2 reacted with cinnamaldehyde in
glacial acetic acid and triethyl orthoformate to give the corresponding cinnamaldehyde hydrazone 5 and 5,7,9-
trimethylpyrido[3',2':4,5]selenolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine (6), respectively (Scheme 1). The
assigned structures of the newly synthesized compounds were consistent with their spectral properties and
elemental analyses.
Scheme 1
Me
N
Me
N
Me
N
Me
N
N
N
Diethyl malonate
.
NH2NH2 H2O
Cl
NHNH2
Se
Se
Me
Me
2
1
Triethyl orthoformate
Cinnamaldehyde/
AcOH
Me
N
Me
Me
N
Me
N
N
N
N
CH2COOEt
N
N
N
N
Se
Se
Me
Me
4
6
Me
N
Me
Me
N
Me
N
N
N
N
NHNHCOCH2COOEt
NHN=CHCH=CHPh
Se
Se
Me
Me
5
3
Chloropyrimidine 1 underwent nucleophilic substitution reactions with thiourea, morpholine, and
ethanolamine. The first reaction led to the formation of 2,7,9-trimethylpyrido[3',2':4,5]selenolo[3,2-d]-
pyrimidine-4(3H)-thione (7), which on treatment with ethyl chloroacetate in the presence of anhydrous
potassium carbonate produced ethyl 2-(2,7,9-trimethylpyrido[3',2':4,5]selenolo[3,2-d]pyrimidin-4-ylsulfanyl)-
acetate (8). Other reactions gave 2,7,9-trimethyl-4-morpholinopyrido[3',2':4,5]selenolo[3,2-d]pyrimidine (9) and
2-[(2,7,9-trimethylpyrido[3',2':4,5]selenolo[3,2-d]pyrimidin-4-yl)amino]ethanol (10), respectively (Scheme 2).
Some other tri- and tetracyclic systems were prepared starting from the previously described [5, 6]
ethoxy-methylideneamino derivative 11 which reacted with thiosemicarbazide, phenylacetohydrazide in acetic
acid, and thiourea to yield 7,9-dimethylpyrido[3',2':4,5]selenolo[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine-2-amine
(12), 2-benzyl-7,9-di-methylpyrido[3',2':4,5]selenolo[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (13), and {[(2-
cyano-4,6-di-methyl-selenolo[2,3-b]pyridin-3-yl)imino]methyl}thiourea (14), respectively, rather than the
expected pyrimidine ring-containing tricyclic system 15 (Scheme 3).
Finally, we used compound 16 as a precursor to prepare new heterocyclic systems containing selenium
via treatment of compound 16 with diethyl malonate and ethyl acetoacetate in the presence of glacial acetic acid,
which afforded ethyl 2-(7,9-dimethyl-4-oxo-3,4-dihydropyrido[3',2':4,5]selenolo[3,2-d]pyrimidin-2-yl)acetate (17)
and 7,9-dimethyl-2-(2-oxopropyl)pyrido[3',2':4,5]selenolo[3,2-d]pyrimidin-4(3H)-one (18) (Scheme 4).
372

Scheme 2
Me
N
Me
NH
Me
N
Me
N
N
N
.
Thiourea/KOH/EtOH
Cl
S
Se
Se
Me
Me
1
7
Ethanolamine
Me
Me
N
ClCH2COOEt
MeCOONa
N
Morpholine
Me
NHCH2CH2OH
Me
Se
Me
N
Me
Me
N
10
N
N
N
SCH2COOEt
Se
N
Se
Me
N
Me
N
O
8
9
Scheme 3
Me
Me
N
N
CHOEt
CN
.
NH2CSNHNH2/AcOH
N
N
NH2
N
Se
12
Se
11
Me
N
Me
N
PhCH2CONHNH2
AcOH
Me
N
N
Thiourea/AcOH
N
N
CH2Ph
N
Se
13
Me
Me
N
Me
N=CHNHCSNH2
CN
N
CONH2
N
NH
Se
15
Se
Me
Me
N
14
EXPERIMENTAL
Melting points were determined using a Kofler melting point apparatus and are uncorrected. IR spectra
were recorded on a Pye-Unicam SP3-100 instrument in KBr pellets. The mass spectra (EI, 70 eV, ion source
temperature 210ºC) were recorded on a Jeol JMS600 instrument. 1H NMR spectra were obtained on a JEOL LA
373

400 spectrometer (400 MHz) in CDCl3 (compound 1) or deuterated trifluoroacetic acid using TMS as internal
standard. Elemental analyses were obtained on an Elementar Vario EL 1150C analyzer. Purity of the compounds
was checked by TLC on Silufol UV-254 plates with 1:1 acetone–benzene as the eluent using UV light for
visualization.
Scheme 4
CH2COOEt
Me
N
Me
N
NH2
N
NH2
O
NH
O
Diethyl malonate
Se
16
Se
17
Me
Me
MeCOCH2COOEt
CH2COMe
Me
N
NH
O
Se
18
Me
N
Compounds 11 and 16 were prepared as previously described [1, 6].
4-Chloro-2,7,9-trimethylpyrido[3',2':4,5]selenolo[3,2-d]pyrimidine (1). A mixture of 2,7,9-trimethyl-
pyrido[3',2':4,5]selenolo[3,2-d]pyrimidin-4(3H)-one (1 g, 3.41 mmol) in excess phosphorus oxychloride (20 ml)
was heated under reflux for 3 h. The cooled reaction mixture was poured onto ice. The precipitated solid was
collected and recrystallized from ethanol to give white crystals, yield 0.75 g (70 %); mp 186-188°C. IR
1
spectrum, , cm-1: 1640 (C=N). H NMR spectrum, δ, ppm: 7.70 (1H, s, CH pyridine); 3.41 (3H, s, CH3); 3.12
(3H, s, CH3); 2.96 (3H, s, CH3). Mass spectrum, m/z (Irel, %): 314 [M+1]+ (40); 313 [M]+ (100). Found, %:
C 46.18; H 3.01; Cl 11.03; N 13.21. C12H10ClN3Se. Calculated, %: C 46.40; H 3.24; Cl 11.41; N 13.53.
4-Hydrazino-2,7,9-trimethylpyrido[3',2':4,5]selenolo[3,2-d]pyrimidine (2). The chloro compound 1
(2.0 g, 6.4 mmol) in ethanol (20 ml) was heated under reflux for 2 h with hydrazine hydrate (99 %, 4 ml,
40 mmol). The product that precipitated while hot was collected and recrystallized from dioxane to give white
crystals, yield 1.70 g (60%); mp >300ºC. IR spectrum, , cm-1: 3400, 3300, 3100 (NHNH2). 1H NMR spectrum,
δ, ppm: 7.55 (1H, s, CH pyridine); 3.41 (3H, s, CH3); 3.12 (3H, s, CH3); 2.96 (3H, s, CH3). Mass spectrum, m/z
(Irel, %): 307 [M]+ (100). Found, %: C 46.88; H 4.25; N 22.51. C12H13N5Se. Calculated, %: C 47.07; H 4.28;
N 22.87.
Ethyl
3-Oxo-3-[2-(2,7,9-trimethylpyrido[3',2':4,5]selenolo[3,2-d]pyrimidin-4-yl)hydrazino]-
propanoate (3). The hydrazino compound 2 (1 g, 3.15 mmol) was heated under reflux with diethyl malonate
(15 ml) for 6 h. The reaction mixture was then cooled and triturated with ethanol (15 ml). The solid that formed
was collected and recrystallized from ethanol to give pale-yellow crystals, yield 1.02 g (75%); mp 224–226ºC.
1
IR spectrum, , cm-1: 1740 (C=O). H NMR spectrum, δ, ppm (J, Hz): 7.90 (1H, s, CH pyridine); 4.30 (2H, q,
J = 7.1, CH2); 3.41 (3H, s, CH3); 3.32 (3H, s, CH3); 2.83 (3H, s, CH3); 1.46 (3H, t, J = 6.9, CH3). Mass
spectrum, m/z (Irel, %): 421 [M]+ (10), 307 [M-C5H7O3]+ (100). Found, %: C 48.33; H 4.59; N 16.28.
C17H19N5O3Se. Calculated, %: C 48.58; H 4.56; N 16.66.
2,7,9-Trimethyl-4-[2-(3-phenylprop-2-en-1-ylidene)hydrazinyl]pyrido[3',2':4,5]selenolo[3,2-d]pyrimi-
dine (5). The hydrazino compound 2 (1 g, 3.15 mmol) was heated under reflux with cinnamaldehyde
374

(2 ml) in 10 ml of acetic anhydride for 3 h. The reaction mixture was then cooled, and the precipitated solid was
collected and recrystallized from ethanol to give yellow crystals, yield 0.34 g (25%); mp 240-242ºC. IR
spectrum, , cm-1: 3200 (NH). 1H NMR spectrum, δ, ppm: 7.95 (1H, s, CH pyridine); 7.15-7.85 (8H, m, H Ar +
3CH); 3.41 (3H, s, CH3); 3.32 (3H, s, CH3); 2.84 (3H, s, CH3). Mass spectrum, m/z (Irel, %): 421 [M + 1]+ (39).
Found, %: C 59.98; H 4.23; N 16.52. C21H19N5Se. Calculated, %: C 60.00; H 4.56; N 16.66.
5,7,9-Trimethylpyrido[3',2':4,5]selenolo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine (6). The hydrazino
compound 2 (1 g, 3.15 mmol) was heated under reflux in triethyl orthoformate (10 ml) for 4 h. The solid product
that formed while hot was collected and recrystallized from dioxane to give white crystals, yield 0.8 g (78%);
mp >300ºC. IR spectrum, , cm-1: 1620 (C=N). 1H NMR spectrum, δ, ppm: 9.77 (1H, s, CH triazole); 7.95 (1H,
s, CH pyridine); 3.41 (3H, s, CH3); 3.32 (3H, s, CH3); 3.13 (3H, s, CH3). Mass spectrum, m/z (Irel, %): 316
[M-1]+ (100). Found, %: C 49.33; H 3.46; N 22.08. C13H11N5Se. Calculated, %: C 49.38; H 3.51; N 22.15.
2,7,9-Trimethylpyrido[3',2':4,5]selenolo[3,2-d]pyrimidine-4(3H)-thione (7). Compound 1 (1.0 g,
3.22 mmol) and thiourea (0.24 g, 3.16 mmol) were heated under reflux in ethanol (20 ml) for 3 h, and then 20 ml
of 10% sodium hydroxide was added to the reaction solution followed by further reflux for 0.5 h. The solution
was then filtered hot, and the cooled filtrate was acidified with acetic acid, giving a yellow precipitate which was
collected and recrystallized from aqueous DMF to give yellow crystals, yield 0.89 g (90%); mp >300ºC. IR
1
spectrum, , cm-1: 3400 (NH). H NMR spectrum, δ, ppm: 7.95 (1H, s, CH pyridine); 3.41 (3H, s, CH3); 3.32
(3H, s, CH3); 2.85 (3H, s, CH3). Found, %: C 46.34; H 3.38; N 13.46; S 10.12. C12H11N3SSe. Calculated, %:
C 46.76; H 3.60; N 13.63; S 10.40.
Ethyl (2,7,9-Trimethylpyrido[3',2':4,5]selenolo[3,2-d]pyrimidin-4-ylsulfanyl)acetate (8). Ethyl
chloroacetate (0.4 g, 3.25 mmol) was added to the thione 7 (1 g, 3.23 mmol) and anhydrous potassium carbonate
(0.5 g, 5.1 mmol) in DMF (20 ml). The mixture was heated under reflux for 2 h and after cooling was poured into
ice-water, giving a white precipitate which was collected and recrystallized from ethanol to give white crystals,
1
yield 0.83 g (65%); mp 160-162ºC. IR spectrum, , cm-1: 1740 (C=O ester). H NMR spectrum, δ, ppm (J, Hz):
7.94 (1H, s, CH pyridine); 3.95 (2H, q, J = 7.0, CH2); 3.71 (2H, s, SCH2); 3.41 (3H, s, CH3); 3.32 (3H, s, CH3);
2.84 (3H, s, CH3); 1.55 (3H, t, J = 7.0, CH3). Mass spectrum, m/z (Irel, %): 397 [M+2]+ (19), 395 [M]+ (9). Found,
%: C 48.40; H 4.21; N 10.57; S 7.98. C16H17N3O2SSe. Calculated, %: C 48.73; H 4.35; N 10.66; S 8.13.
2,7,9-Trimethyl-4-morpholinopyrido[3',2':4,5]selenolo[3,2-d]pyrimidine (9). A mixture of compound
1 (1 g, 3.22 mmol) and morpholine (4 ml) was gently heated under reflux for 2 h, and the reaction mixture was
triturated with ethanol (15 ml) and then left to cool. The precipitated solid was collected and recrystallized from
ethanol to give brown crystals, yield 0.93 g (80 %); mp 243–245ºC. IR spectrum, , cm-1: 1640 (C=N).
1H NMR spectrum, δ, ppm: 7.95 (1H, s, CH pyridine); 4.35–4.53 (8H, m, CH2 morpholine); 3.41 (3H, s, CH3);
3.32 (3H, s, CH3); 2.85 (3H, s, CH3). Mass spectrum, m/z (Irel, %): 362 [M]+ (4). Found, %: C 53.02; H 4.97;
N 15.34. C16H18N4OSe. Calculated, %: C 53.19; H 5.02; N 15.51.
2-[(2,7,9-Trimethylpyrido[3',2':4,5]selenolo[3,2-d]pyrimidin-4-yl)amino]ethanol (10). A mixture of
compound 1 (1 g, 3.22 mmol) in ethanolamine (4 ml) was gently heated under reflux for 2 h, and the reaction
mixture was triturated with ethanol (15 ml) and then left to cool. The precipitated solid was collected and
recrystallized from ethanol to give white crystals, yield 0.81 g (75%); mp >300ºC. IR spectrum, , cm-1: 3400
1
(NH). H NMR spectrum, δ, ppm (J, Hz): 7.95 (1H, s, CH pyridine); 4.31 (2H, t, J = 7.1, CH2); 3.54 (3H, s,
CH3); 3.31 (3H, s, CH3); 2.95 (3H, s, CH3); 2.80 (2H, t, J = 7.1, CH2). Mass spectrum, m/z (Irel, %): 336 [M]+
(78). Found, %: C 50.00; H 4.67; N 16.34. C14H16N4OSe. Calculated, %: C 50.15; H 4.81; N 16.71.
7,9-Dimethylpyrido[3',2':4,5]selenolo[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine-2-amine
(12).
A
mixture of compound 11 (1.5 g, 5 mmol) and thiosemicarbazide (5 mmol) in acetic acid (20 ml) was heated under
reflux for 3 h. The precipitate formed while hot was collected and recrystallized from DMF/water, yield 0.7 g
1
(45%); mp >300ºC. IR spectrum, , cm-1: 3400, 3200 (NH2). H NMR spectrum, δ, ppm: 8.73 (1H, s, CH
pyrimidine); 7.80 (1H, s, CH pyridine); 3.41 (3H, s, CH3); 3.34 (3H, s, CH3). Mass spectrum, m/z (Irel, %): 318
[M]+ (13). Found, %: C 45.22; H 3.17; N 26.34. C12H10N6Se. Calculated, %: C 45.44; H 3.18; N 26.49.
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2-Benzyl-7,9-dimethylpyrido[3',2':4,5]selenolo[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine
(13).
A
mixture of compound 11 (1.5 g, 5 mmol) and 2-phenylacetohydrazide (5 mmol) in acetic acid (20 ml) was
heated under reflux for 3 h. The precipitate formed while hot was collected and recrystallized from DMF/water,
yield 0.93 g (60%); mp >300ºC. IR spectrum, , cm-1: 1640 (C=N). 1H NMR spectrum, δ, ppm: 9.50 (1H, s, CH
pyrimidine); 7.82 (1H, s, CH pyridine); 7.30–7.85 (5H, m, H Ph); 4.64 (2H, s, CH2); 3.41 (3H, s, CH3); 3.20
(3H, s, CH3). Mass spectrum, m/z (Irel, %): 395 [M+1]+ (41), 394 [M]+ (100). Found, %: C 58.05; H 3.59;
N 17.63. C19H15N5Se. Calculated, %: C 58.17; H 3.85; N 17.85.
{[(2-Cyano-4,6-dimethylselenolo[2,3-b]pyridin-3-yl)imino]methyl}thiourea (14). A mixture of
compound 11 (1.5 g, 5 mmol) and thiourea (5 mmol) in acetic acid (10 ml) was heated under reflux for 2 h. The
precipitate formed on cooling was collected and recrystallized from acetic acid to give yellow crystals, yield
1
1.42 g (87%); mp 242-244ºC. IR spectrum, , cm-1: 3410 (NH), 3400, 3300 (NH2), 2200 (CN). H NMR
spectrum, δ, ppm: 7.80 (1H, s, CH pyridine); 7.15 (1H, s, N=CH); 3.41 (3H, s, CH3); 3.22 (3H, s, CH3). Mass
spectrum, m/z (Irel, %): 337 [M]+ (1). Found, %: C 42.55; H 3.09; N 20.53; S 9.22. C12H11N5SSe. Calculated, %:
C 42.86; H 3.30; N 20.83; S 9.54.
Ethyl 2-(7,9-Dimethyl-4-oxo-3,4-dihydropyrido[3',2':4,5]selenolo[3,2-d]pyrimidin-2-yl)acetate (17).
A mixture of compound 16 (1 g, 3.7 mmol) and diethyl malonate (2 ml) in 2 ml of acetic acid was heated under
reflux for 3 h. The reaction mixture was cooled and the product that formed was collected and recrystallized
from ethanol to give white needles, yield 0.67 g (50%); mp 190–193ºC. IR spectrum, , cm-1: 3400 (NH), 1680
1
(C=O). H NMR spectrum, δ, ppm (J, Hz): 7.80 (1H, s, CH pyridine); 4.00 (2H, q, J = 7.1, CH2); 3.65 (2H, s,
CH2); 3.41 (3H, s, CH3); 3.23 (3H, s, CH3); 1.28 (3H, t, J = 7.1, CH3). Mass spectrum, m/z (Irel, %): 364 [M-1]+
(73). Found, %: C 49.05; H 3.99; N 11.23. C15H15N3O3Se. Calculated, %: C 49.46; H 4.15; N 11.54.
7,9-Dimethyl-2-(2-oxopropyl)pyrido[3',2':4,5]selenolo[3,2-d]pyrimidin-4(3H)-one (18). A mixture of
compound 16 (1 g, 3.7 mmol) and ethyl acetoacetate (2 ml) in 2 ml of acetic acid was heated under reflux for
3 h. The reaction mixture was cooled and the product that formed was collected and recrystallized from ethanol
to give white needles, yield 0.81 g (60%); mp 280–282ºC. IR spectrum, , cm-1: 3400 (NH), 1670 (C=O).
1H NMR spectrum, δ, ppm: 7.80 (1H, s, CH pyridine); 3.71 (2H, s, CH2); 3.41 (3H, s, CH3); 3.25 (3H, s, CH3);
1.55 (3H, s, CH3). Mass spectrum, m/z (Irel, %): 335 [M]+ (60). Found, %: C 49.99; H 3.89; N 12.35.
C14H13N3O2Se. Calculated, %: C 50.31; H 3.92; N 12.57.
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