A simple approach to fused pyrido[2,3-d] pyrimidines incorporating khellinone and trimethoxyphenyl moieties as new scaffolds for antibacterial and antifungal agents

Article abstract of DOI:10.1515/hc-2013-0199

2-Amino-3-cyanopyridine is a simple precursor for the synthesis of analogues of Egyptian natural products visnagin and khellin. Fused pyrido[2,3-d]pyrimidines were prepared under mild reaction conditions. The detailed syntheses and spectroscopic data of the synthesised compounds are reported. Some isolated compounds show antibacterial and antifungal activity.

Full text of DOI:10.1515/hc-2013-0199

ꢁꢁꢁꢂ
ꢀHeterocycl. Commun. 2014; 20(2): 93–102
DOI 10.1515/hc-2013-0199ꢀ
Khadiga M. Abu-Zied, Tahia K. Mohamed, Omar K. Al-Duiaj and Magdi E.A. Zaki*
A simple approach to fused pyrido[2,3-d]
pyrimidines incorporating khellinone and
trimethoxyphenyl moieties as new scaffolds
for antibacterial and antifungal agents
Me
Abstract: 2-Amino-3-cyanopyridine is
a
simple
O
O
Me
O
O
N
N
O
precursor for the synthesis of analogues of Egyptian
natural products visnagin and khellin. Fused pyrido[2,3-
d]pyrimidines were prepared under mild reaction
conditions. The detailed syntheses and spectroscopic
data of the synthesised compounds are reported. Some
isolated compounds show antibacterial and antifungal
activity.
N
N
HC
O
C
NH
Cl
F
NH
O
Me
N
Gefitinib
Erlotinib
Pyrido[2,3-d]pyrimidines, as analogues of quinazo-
Keywords: 2-amino-3-cyanopyridine; antibacterial activity;
antifungal activity; khellinone; N-pyrazolyl derivatives;
pyrido[2,3-d]pyrimidine; trimethoxyphenyl.
line, have been intensively investigated. This scaffold
is associated with a wide range of biological activi-
ties including dihydrofolate reductase (DHFR) inhi-
bition, antitumor activity [9–11], adenosine kinase
inhibition [12] and tyrosine kinase inhibition [13, 14],
among other properties [15–18]. Part of our ongoing
interest is to explore new scaffolds based on analogues
of Egyptian natural products such as khellinone and its
analogues.
*Corresponding author: Magdi E.A. Zaki, National Research
Centre, Photochemistry Department, Cairo, Egypt; and Chemistry
Department, College of Science, IMSIU (Al-Imam Mohammad Ibn
Saud Islamic University), Riyadh 11623, Kingdom of Saudi Arabia,
e-mail: mezaki@imamu.edu.sa
Khadiga M. Abu-Zied: National Research Centre, Photochemistry
Department, Cairo, Egypt
Tahia K. Mohamed: National Research Centre, Chemistry of Natural
Compounds Department, Cairo, Egypt
Omar K. Al-Duiaj: Chemistry Department, College of Science, IMSIU
(Al-Imam Mohammad Ibn Saud Islamic University), Riyadh 11623,
Kingdom of Saudi Arabia
Results and discussion
Chemistry
The interesting biological activity of khellinone deriva-
tives [19] prompted us to continue our investigation of
pyrido[2,3-d]pyrimidine incorporating 4,7-dimethoxy-
Introduction
Bicyclic nitrogen-containing heterocyclic compounds 1-benzofuran-5-ol moiety or trimethoxyphenyl moiety. A
such as purines [1–3], quinazolines [4–6], pteridines and facile synthesis of 2-amino-3-cyanopyridine derivatives in
pyrido-pyrimidines [7, 8] are well-known pharmacophores a one-pot reaction was achieved using aromatic aldehyde,
in drug discovery. Gefitinib and erlotinib are examples methyl ketone, malononitrile and ammonium acetate [20]
of market drugs with a bicyclic core structure, which are or by preparing α,β-unsaturated ketone followed by reac-
quinazoline derivatives acting as tyrosine kinase inhibi- tion with malononitrile in the presence of ammonium
tors and both are used for treatment of non-small cell lung acetate [21, 22]. 2-Amino-3-cyanopyridine is considered
cancer.
a simple and convenient precursor for the synthesis of
pyrido[2,3-d]pyrimidine incorporating some new khell-
inone derivatives and its analogues.
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94ꢀ
ꢀK.M. Abu-Zied et al.: Fused pyrido[2,3-d]pyrimidines incorporating khellinone and trimethoxyphenyl moieties
R 2
Thus, refluxing substrate 1a [21, 22] or 1b with anhy-
NC
CN
drous ammonium acetate and malononitrile in ethanol for
8 h led to the formation of the product 2a or 2b, respectively,
in good yield (Scheme 1). Treatment of 2a with formic acid
yielded pyrido[2,3-d]pyrimidine-4(3H)-one 3 in a moder-
ate yield (Scheme 2). Treatment of 3 with phosphorus oxy-
chloride in dioxane led to the formation of a pyrido[2,3-d]
pyrimidine derivative 4 in poor yield. We believe that
the formation of a hydrochloride salt of the pyrido[2,3-d]
pyrimidine substrate may be responsible for the low yield.
The dichloro-pyrido[2,3-d]pyrimidine 4 was allowed to
react with hydrazine hydrate to give derivative 5 in low
yield. Compound 5 was transformed into triazolo[4,3-c]
O
H
C N
R1
R 2
AcONH4, EtOH
OMe
R1
N
N H2
1a-b
2a-b
a: R 1
=
; R2 = 4-OMe-C6H4
O
OH
MeO
b: R1 = 3,4,5-(OMe)3C6H2; R2 = 2,4,6-(OMe)3C6H2
Scheme 1ꢀ
OMe
O
N
OMe
OMe
NH
POCl3
HCOOH, HCl
2a
O
N
O H
3
OMe
OMe
NH-NH2
N
C l
N
OCH3
OMe
OCH3
NH
NH2-NH2
EtOH
O
O
N
N
N
C l
C l
4
5
OMe
OMe
N
N
for 6a: HCOOH, HCl
for 6b: Ac2O
R
OMe
N
for 6c: CS2, dioxane
O
N
N
C l
6a c
-
OMe
a : R = H
b
: R = Me
c : R = SH
Scheme 2ꢀ
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K.M. Abu-Zied et al.: Fused pyrido[2,3-d]pyrimidines incorporating khellinone and trimethoxyphenyl moietiesꢀ
ꢀ95
pyrimidines 6a–c (Scheme 2), which may possess pharma- pyrido[2,3-d][1,3]thiazolo[3,2-a]pyrimidine
derivatives
cological properties similar to theophylline [23–26].
The poor yield was a problem in the synthesis of a
8–11.
The introduction of a good leaving group was pursued
variety of fused pyridopyrimidine derivatives. Herein, we in another approach. Thus, compounds 7a,b were treated
explored a method that can offer a better yield of pyri- with iodomethane leading to formation of the respective
dopyrimidine products. As can be seen from Scheme 3, methylthio derivatives 12a,b in good yield. The nucleo-
compounds 2a,b were allowed to react with carbon disul- philic substitution of the methylthio group took place by
phide in the presence of hydrogen sodium carbonate treatment of compounds 12a,b with hydrazine hydrate
yielding the respective dithiones 7a and 7b in good yield. leading to the formation of hydrazino derivatives 13a,b
Compound 7b was allowed to react with chloroacetic (Scheme 4). Compound 13a was allowed to react with two
acid and benzaldehyde in the presence of sodium acetate ortho esters and carbon disulphide to furnish the respec-
under reflux in a mixture of acetic acid and acetic anhy- tive thiones 14a, 14b and 15. Yet, another approach to the
dride to afford the product 8 in a moderate yield.
construction of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimi-
The alkylation of compound 7b with the appropriate dine derivatives utilises the reaction of compound 13b
functionalised halo compounds, followed by intramolec- with appropriate carboxylic acid in the presence of phos-
ular cyclisation, led to the formation of the corresponding phorus oxychloride. Compounds 16a,b were synthesised
R2
S
O
ClCH2COOH, PhCHO
AcONa, AcOH, Ac2O
H
N
N
for 7b
R1
N
N
S
Ph
8
R2
S
NH2
ClCH2CN
EtONa
R1
N
N
S
7b
for
9
Cl
R2
N
S
R2
S
OEt
NH2
NC
CS2, KHCO3
OEt
O
O
N
NH
2a, b
EtONa
7b
R1
N
H
S
R1
N
N
S
for
7a, b
10
R2
S
Br
NH2
CN
OMe
NC
CN
N
2a, 7a, 12a: R1
=
O
R1
N
EtONa
S
OH
for 7b
MeO
R2 = 4-OMe-C6H4
11
R2
N
S
MeI
2b, 7b, 8, 9, 10,11, 12b: R1 = 3,4,5-(OMe)3C6H2
NH
R2 = 2,4,6-(OMe)3C6H2
R1
N
SMe
12a, b
Scheme 3ꢀ
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96ꢀ
ꢀK.M. Abu-Zied et al.: Fused pyrido[2,3-d]pyrimidines incorporating khellinone and trimethoxyphenyl moieties
HC(OEt)3
R2
S
N
R3
N
or
MeC(OEt)3
N
R1
N
for 13a
N
H
14a, b
a: R3 = H; b: R3 = Me
R2
N
S
N
S
CS2
N
N
NH
for 13a
R1
N
H
15
R2
N
S
N
R2
S
N
R3COOH
R3
POCl3
NH2-NH2
NH
NH-NH2
N
12a, b
R1
R1
N
N
H
for 13b
13a, b
16a, b
a: R3 = Ph; b: R3 = 4-OMe-C6H4
NC
H
CN
Ph
R2
N
S
N
NH
N
R1
N
for 13b
Ph
H2N
OMe
OH
17
CN
O
13a, 14a, b, 15: R1 =
NC
H
O
R2
N
S
N
OEt
MeO
Ph
NH
N
O
R1
N
R2 = 4-OMe-C6H4
for 13b
Ph
H2N
OEt
16a, b, 17, 18, 19: R1 = 3,4,5-(OMe)3C6H2
18
R2 = 2,4,6-(OMe)3C6H2
R2
S
N
Ph
O
OH
Ph
Ph
N
Ph
N
R1
N
N
H
POCl3
for 13b
19
Scheme 4ꢀ
in this way. A different methodology for the preparation Biological activity
of unfused biheterocyclic products 17 and 18 involves
conjugate addition of the hydrazine derivative 13b with Some of the synthesised compounds were evaluated for
appropriate α,β-unsaturated nitriles in the presence of their antimicrobial activity. The results were compared with
piperidine as a catalyst. Compound 13b was also allowed the activity of well-known antimicrobial and antifungal
to react with benzoin in the presence of phosphorus oxy- standards. The results of the preliminary screening tests are
chloride (Scheme 4). This reaction led to the formation of given in Table 1. As can be seen, some khellinone deriva-
the fused tricyclic thione 19.
tives show higher antimicrobial activity than the standard.
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K.M. Abu-Zied et al.: Fused pyrido[2,3-d]pyrimidines incorporating khellinone and trimethoxyphenyl moietiesꢀ
ꢀ97
Table 1ꢀAntimicrobial activity of selected compounds.
Tested compounds and
standards (μg/mL)
ꢁ
Inhibition zone diameter (mm/mg sample)
Escherichiaꢁ
coli (G-)
Staphylococcusꢁ
aureus (G+)
Bacillus
ꢁ
Candida
albicans (yeast)
ꢁ
Aspergillus
niger (fungi)
subtilis (G+)
1
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
++
++
+++
+++
+++
+
++
++
++
++
++
+++
++
++
+++
–
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
++
++
++
++
+++
+
++
++
++
++
++
++
+
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
+++
++
+++
++
++
+
++
++
++
++
++
++
+
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
–
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
–
2a
–
–
3
++
++
++
++
++
++
++
+++
++
++
+
–
4
+++
++
–
5
6a
6b
++
+++
++
++
++
++
++
+++
–
6c
7a
12a
13a
14a
14b
14c
+++
+++
–
++
+++
–
+
-
+++
Levofloxacina
Nystatinb
+++
+++, Highly active (21–25 mm); ++, fairly active (16–20 mm); +, slightly active (15–10 mm); –, not active.
aLevofloxacin is an anti-Gram positive and anti-Gram negative antibiotic.
bNystatin is an antifungal antibiotic.
using an automatic micropipette. The Petri dishes were lef at 5°C for
1 h to allow diffusion of the antibiotic through the agar medium prior
to the growth of the test organism, and then they were incubated at
30°C for 24 h. The antimicrobial data are compiled in Table 1.
Experimental
General
2-Amino-6-(5-hydroxy-4,7-dimethoxy-1-benzofuran-6-yl)-4-
(4-methoxyphenyl)nicotinonitrile (2a)ꢀCompound 1 (1 mmol),
malononitrile (1.1 mmol) and anhydrous ammonium acetate (2
mmol) were heated under reflux in absolute ethanol (15 mL) for 8 h.
The reaction mixture was cooled to room temperature and the precip-
itate was collected upon filtration, washed several times with water,
dried and crystallised from ethanol to give compound 2a as yellow
crystals in 53% yield; mp 201–203°C; IR (cm-1, ν): 3440 (br, OH), 3256,
Melting points are uncorrected. Microanalyses were carried out at the
Microanalytical Unit, National Research Centre and Faculty of Sci-
ence, Cairo University. The IR spectra were recorded in KBr pellets
1
on an FT-IR NEXCES spectrophotometer (Shimadzu, Japan). H NMR
(500 MHz) and 13C NMR (125 MHz) spectra were measured with a Jeol
ECA 500 (Japan) in DMSO-d6 or CDCl3. Mass spectra (EI) were run at
70 eV with a Finnigan SSQ 7000 spectrometer (Thermo Instrument
System Incorporation, USA). All reactions were followed up by TLC
analysis.
1
3253 (NH2), 2224 (CN); H NMR (CDCl3): δ 3.85 (s, 3H, OCH3), 3.88 (s,
3H, OCH3), 4.1 (s, 3H, OCH3), 7.11 (d, J ꢀ= ꢀ 7.25 Hz, 1H, CH), 7.45 (d, J ꢀ= ꢀ
8.4 Hz, 2H, ArH), 7.69 (d, J ꢀ= ꢀ 8.4 Hz, 2H, ArH), 7.73 (s, 1H, ArH), 7.78 (d,
J ꢀ= ꢀ 7.3 Hz 1H, CH) and 8.2 (br, s, 2H, NH2, D2O exchangeable); 13C NMR
(CDCl3): δ 46.6, 46.8, 52.7, 99.1, 111.3, 128.1, 134, 138, 143, 145, 146.2,
147.1, 147.4, 147.7, 147.8, 148.6, 148.9, 149.2, 149.6, 149.8,151.3; MS: m/z
414 (M+, 100%). Anal. Calcd for C23H19N3O5: C, 66.18; H, 4.59; N, 10.07.
Found: C, 66.35; H, 4.78; N, 10.19.
Biological evaluation
The antimicrobial activity was determined by the cup plate technique
method with some modifications. Levofloxacin and nystatin were
used as reference antibiotics. The medium was nutrient agar for bac-
teria, potato dextrose for fungi, and the tested microorganisms were
Gram-positive bacteria Staphylococcus aureus, Bacillus subtilis, Gram-
negative bacteria Escherichia coli, yeast (single cell fungus) Can-
dida albicans and multicellular fungus Aspergillus niger. Data were
obtained according to the following procedure. A volume of 40 mL of
the medium (at 55–60°C) was inoculated with 200 μL of the prepared
2-Amino-4-(2,4,6-trimethoxyphenyl)-6-(3,4,5-trimethoxyphe-
nyl)nicotinonitrile (2b) A mixture of 1 (1 mmol), malononitrile (1.2
mmol) and anhydrous ammonium acetate (80 mmol) in absolute eth-
anol was heated on a water bath for 8 h. Afer cooling, the obtained
product was filtered and washed several times with water, dried and
then crystallised from ethanol affording 2b in 78% yield; mp 256°C;
test microorganism suspensions and poured into 15 cm diameter IR (cm-1, ν): 3266, 3242 (NH2), 2231 (CN); 1H NMR (DMSO-d6): δ 3.62 (s,
plates, mixed well and allowed to solidify. Afer solidification, holes 6H, 2 OCH3), 3.71 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.86 (s, 6H, 2 OCH3),
(0.9 cm diameter) were made in the agar plates with the aid of a ster- 6.81 (s, 2H, ArH), 7.01 (s, 2H, ArH), 7.75 (s, 1H, CH), 8.07–8.10 (br, 2H,
ile cork-borer. In the holes, 50 μL of the dissolved sample was placed NH2, exchangeable with D2O); 13C NMR (DMSO-d6): δ 55.1, 55.9, 57.1,
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98ꢀ ꢀK.M. Abu-Zied et al.: Fused pyrido[2,3-d]pyrimidines incorporating khellinone and trimethoxyphenyl moieties
59.7, 92.4, 97.6, 103.6, 114.2, 118.1, 119.9, 124.1, 147.4, 151.9, 152.4, 158.4, 8-(5-Chloro-4,7-dimethoxy-1-benzofuran-6-yl)-10-(4-methoxy-
158.9, 159.3, 164.7. Anal. Calcd for C24H25N3O6: C, 63.85; H, 5.58; N, 9.31. phenyl)pyrido[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (6a)ꢀThis
Found: C, 63.69; H, 5.78.; N, 9.19.
compound was isolated in 61% yield; mp 161–162°C; 1H NMR (CDCl3):
δ 3.78 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 4.10 (s, 3H, OCH3), 7.20 (d, J ꢀ= ꢀ
7-(5-Hydroxy-4,7-dimethoxybenzofuran-6-yl)-5-(4-methoxyphe- 6.7 Hz, 1H, CH), 7.55 (d, J ꢀ= ꢀ 8.7 Hz, 2H, ArH), 7.66 (s, 1H, CH), 7.77 (d,
nyl)pyrido[2,3-d]pyrimidine-4(3H)-one (3)ꢀA mixture of com-
pound 2 (1 mmol) and formic acid (5 mL) was heated and stirred for 8
h. The precipitate, isolated afer neutralisation with sodium hydrox-
ide solution, was crystallised from ethanol to furnish compound 3 as
shiny yellow crystals in 55% yield; mp 188°C; IR (cm-1, ν): 3443 (br,
J ꢀ= ꢀ 8.7 Hz, 2H, ArH), 7.88 (d, J ꢀ= ꢀ 6.7 Hz, 1H, CH), 8.56 (s, 1H, CH, ArH),
8.68 (s, 1H, CH, ArH). Anal. Calcd for C25H18ClN5O4: C, 61.54; H, 3.72; N,
14.35. Found: C, 61.38; H, 3.57; N, 14.21.
8-(5-Chloro-4,7-dimethoxy-1-benzofuran-6-yl)-10-(4-
methoxyphenyl)-3-methylpyrido[3,2-e][1,2,4]triazolo[4,3-c]
pyrimidine (6b)ꢀThis compound was isolated in 58% yield; mp
1
OH), 3358, (NH), 1668 (Cꢀ= ꢀO); H NMR (CDCl3): δ 3.83 (s, 3H, OCH3),
3.85 (s, 3H, OCH3), 4.1(s, 3H, OCH3), 7.15 (d, J ꢀ= ꢀ 7.3 Hz, 1H, CH), 7.45
(d, J ꢀ= ꢀ 8.4 Hz, 2H, ArH), 7.69 (d, J ꢀ= ꢀ 8.4 Hz, 2H, ArH), 7.74 (s, 1H, ArH),
7.78 (d, J ꢀ= ꢀ 7.3 Hz, 1H, CH), 8.31 (s, 1H, ArH), 8.49 (br, s, 1H, NH, D2O
exchangeable); MS: m/z 417 (M+, 100%). Anal. Calcd for C24H19N3O6: C,
64.72; H, 4.30; N, 9.43. Found: C, 64.59; H, 4.08; N, 9.23.
1
183–184°C; yellow crystals; H NMR (CDCl3): δ 2.21 (s, 3H, CH3), 3.74
(s, 3H, OCH3), 3.90 (s, 3H, OCH3), 4.08 (s, 3H, OCH3), 7.20 (d, J ꢀ= ꢀ 6.7
Hz, 1H, CH), 7.55 (d, J ꢀ= ꢀ 8.7 Hz, 2H, ArH), 7.78 (d, J ꢀ= ꢀ 8.7 Hz, 2H, ArH),
7.84 (s, 1H, CH, ArH), 7.88 (d, J ꢀ= ꢀ 6.7 Hz, 1H, CH), 8.66 (s, 1H, CH, ArH).
Anal. Calcd for C26H20ClN5O4: C, 62.22; H, 4.02; N, 13.95. Found: C,
61.95; H, 3.77; N, 14.21.
4-Chloro-7-(6-chloro-4,7-dimethoxy-1-benzofuran-6-yl)-5-(4-
methoxyphenyl)pyrido[2,3-d]pyrimidine (4)ꢀA mixture of
compound 3 (5 mmol) and phosphorus oxychloride (10 mL) in dry
dioxane (15 mL) was heated under reflux for 1 h, then the mixture was
cooled to room temperature and poured into crushed ice. The result-
ant precipitate was filtered, washed with ice water and dried to afford
compound 4 in 56% yield; mp 175°C; IR (cm-1, ν): 3349 (NH); 1H NMR
(CDCl3): δ 3.85 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.0 (s, 3H, OCH3), 7.22
(d, J ꢀ= ꢀ 6.7 Hz, 1H, CH), 7.45 (d, J ꢀ= ꢀ 8.7 Hz, 2H, ArH), 7.73 (d, J ꢀ= ꢀ 8.7 Hz,
2H, ArH), 7.77 (d, J ꢀ= ꢀ 6.7 Hz, 1H, CH), 7.69 (s, 1H, CH), 8.28 (s, 1H, CH);
13C NMR (CDCl3): δ 43.6, 46.8, 52.8 (3 OCH3), 99.1, 111.3, 128.1, 134.0,
138.0, 143.0, 145.0, 146.2, 147.4, 147.7, 147.8, 148.3, 148.6, 148.7, 148.9,
149.2, 149.6, 149.8, 151.3. Anal. Calcd for C24H17Cl2N3O4: C, 59.77; H, 3.55;
N, 8.71. Found: C, 56.59; H, 3.87; N, 8.58.
8-(5-Chloro-4,7-dimethoxy-1-benzofuran-6-yl)-10-(4-methoxy-
phenyl)pyrido[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-3-thiol (6c)
This compound was isolated in 67% yield; mp 211–212°C; IR (cm-1,
1
ν): 3440 (br, NH); H NMR (DMSO-d6): δ 1.77 (s, 1H, SH), 3.78 (s, 3H,
OCH3), 3.88 (s, 3H, OCH3), 4.07 (s, 3H, OCH3), 7.20 (d, J ꢀ= ꢀ 6.7 Hz, 1H,
CH), 7.57 (d, J ꢀ= ꢀ 8.7 Hz, 2 H, ArH), 7.77 (d, J ꢀ= ꢀ 8.7 Hz, 2 H, ArH), 7.81 (s,
1H, CH, ArH), 7.88 (d, J ꢀ= ꢀ 6.7 Hz, 1H, CH), 8.56 (s, 1H, CH, ArH). Anal.
Calcd for C26H18ClN5O4S: C, 57.75; H, 3.49; N, 13.47. Found: C, 57.57; H,
3.77; N, 13.19.
7-(5-Hydroxy-4,7-dimethoxybenzofuran-6-yl)-5-(4-methoxyphe-
nyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dithione (7a)ꢀA mixture
of compound 2a (10 mmol) and sodium bicarbonate solution [0.084 g
of sodium bicarbonate dissolved in 15 mL water/ethanol mixture (2:3)]
was heated under reflux for 2 h and then cooled to room temperature.
Carbon disulphide (0.08 mL) was then added and the heating was
continued on a water bath for an additional 2 h. The formed precipi-
tate was isolated afer neutralisation with diluted hydrochloric acid,
washed with water, dried and crystallised from an ethanol/dioxane
mixture (3:1) affording 7a in 71% yield; mp 304–305°C; IR (cm-1, ν):
7-(5-Chloro-4,7-dimethoxy-1-benzofuran-6-yl)-4-hydrazino-5-(4-
methoxyphenyl)pyrido[2,3-d]pyrimidine (5)ꢀA solution of com-
pound 4 (5 mmol) and hydrazine hydrate (0.15 mL) in ethanol (15 mL)
was stirred under reflux for 10 h (under TLC control) whereby a green-
ish yellow precipitate was formed. The precipitate was filtered, washed
with water, dried and crystallised from ethanol to furnish 5 in a yield of
48%; mp 204–206°C; IR (cm-1, ν): 3344 (NH), 3277, 3270 (NH2); 1H NMR
(DMSO-d6): δ 3.74 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.1 (s, 3H, OCH3), 6.65
(br, s, 2 H, NH2, D2O exchangeable), 7.40 (d, J ꢀ= ꢀ 6.7 Hz, 1H, CH), 7.55 (d,
J ꢀ= ꢀ 8.6 Hz, 2H, ArH), 7.77 (d, J ꢀ= ꢀ 8.6 Hz, 2H, ArH), 7.81 (s, 1H, CH), 7.88 (d,
J ꢀ= ꢀ 6.7 Hz 1H, CH), 8.56 (s, 1H, Ar-H), 9.12 (br, s, H, NH, D2O exchange-
able); 13C NMR (DMSO-d6): δ 43.6, 46.8, 52.8 (3 OCH3), 99.1, 111.3, 128.1,
134.0, 138.0, 143.0, 145.0, 146.2, 147.1, 147.4, 147.7, 147.8, 148.3, 148.6, 148.7,
148.9, 149.2, 149.6, 149.8 and 151.3. Anal. Calcd for C24H20ClN5O4: C, 60.30;
H, 4.22; N, 14.65. Found: C, 59.98; H, 4.57; N, 14.43.
1
3430 (OH), 3345 (NH), 1555 (SH); H NMR (CDCl3): δ 1.60 (s, 1H, SH),
3.74 (s, H, OCH3), 3.86 (s, H, OCH3), 4.04 (s, 3H, OCH3), 7.25 (d, J ꢀ= ꢀ 7. 2
Hz, 1H, CH), 7.65 (d, J ꢀ= ꢀ 8.4 Hz, 2 H, ArH), 7.74 (d, J ꢀ= ꢀ 8.4 Hz, 2 H, ArH),
7.77 (s, 1H, CH, ArH), 7.79 (d, J ꢀ= ꢀ 7.2 Hz, 1H, CH), 8.60 (br, s, 1H, NH,
D2O exchangeable) and 10.60 (br, s, 1H, NH, D2O exchangeable); 13C
NMR (CDCl3): δ 46.6, 48.8, 52.8 (3 OCH3), 100.3, 113.4, 128.6, 133.8,
138.6, 145.7, 145.8, 146.8, 147.6, 147.9, 148.3, 148.6, 148.8, 149, 150, 150.6,
151, 151.6, 153.1, 166.8, 168.9; MS: m/z 493 (M+, 100%). Anal. Calcd for
C24H19N3O5S2: C, 58.40; H, 3.88; N, 8.51. Found: C, 58.57; H, 4.12; N, 8.72.
General procedure for pyrido[3,2-e][1,2,4]
triazolo[4,3-c]pyrimidine derivatives 6a–c
A mixture of compound 5 (1 mmol), formic acid (1 mL) and concen-
trated hydrochloric acid (1 mL) in the case of 6a or acetic anhydride
(5 mL) in the case of 6b or carbon disulphide (1 mL) in the case of 6c,
5-(2,4,6-Trimethoxyphenyl)-7-(3,4,5-trimethoxyphenyl)
pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dithione (7b)ꢀCompound 2b
(1 mmol) was subjected to the procedure described above. Product 7b
was obtained as yellowish brown powder; yield 78%; mp 295–296°C;
1
IR (cm-1, ν): 3349 (NH) and 1561 (SH); H NMR (DMSO-d6): δ 3.64 (s,
6H, 2 OCH3), 3.73 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 3.92 (s, 6H, 2 OCH3),
was heated gently on a water bath for 6–8 h (under TLC control). The 6.92 (s, 2H, ArH), 7.04 (s, 2H, ArH), 7.76 (s, 1H, CH), 8.84–8.79 ppm
reaction mixture was cooled to room temperature, poured into cold (br, 1H, NH, D2O exchangeable), 9.60 (br, s, 1H, NH, D2O exchange-
water (100 mL), and the resultant precipitate was collected by filtra- able); 13C NMR (DMSO-d6): δ 169.2, 164.7, 154.2, 152.3, 151.1, 147.7, 138.7,
tion, washed several times with water, dried and crystallised from 128.1, 127.6, 126.2, 112.1, 103.5, 92.1, 59.3, 55.9, 55.8, 54.8. Anal. Calcd for
ethanol.
C25H25N3O6S2: C, 56.91; H, 4.78; N, 7.96. Found: C, 56.79; H, 4.87; N, 7.68.
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K.M. Abu-Zied et al.: Fused pyrido[2,3-d]pyrimidines incorporating khellinone and trimethoxyphenyl moietiesꢀ
ꢀ99
2-Benzylidene-5-thioxo-6-(2,4,6-trimethoxyphenyl)-8-(3,4,5- carbonate solution [0.084 g of sodium bicarbonate dissolved in 15 mL
trimethoxyphenyl)-5H-pyrido[2,3-d][1,3]thiazolo[3,2-a]pyrimi- water/ethanol mixture (2:3)] and compound 4 (1 mmol) was stirred
din-3(2H)-one (8)ꢀA mixture of compound 7b (1 mmol), chloroacetic for 4 h at room temperature, then heated under reflux for 3 min, and
acid (1.2 mmol), benzaldehyde (1.2 mmol) and anhydrous sodium cooled to room temperature. Iodomethane (1.4 mmol) was added to
acetate (4 mmol) in a mixture of acetic acid and acetic anhydride (1:1) sodium salt 4 and heating was continued for an additional 2 h. The
was heated under reflux for 8 h. The formed solid was collected and reaction mixture was cooled to room temperature and poured onto
washed with acetic acid and ethanol several times yielding 8 in 76% cold water (25 mL). The resultant precipitate was filtered, washed
yield; mp 310–311°C; 1H NMR (DMSO-d6): δ 3.61 (s, 6H, 2 OCH3), 3.75 (s, well with water, dried and crystallised from an ethanol/dioxane mix-
3H, OCH3), 3.84 (s, 3H, OCH3), 3.95 (s, 6H, 2 OCH3), 6.96 (s, 2H, ArH), ture (3:2) to furnish 12a as pale yellow powder in 55% yield; mp 251–
7.03 (s, 2H, ArH), 7.28–7.36 (m, 5H, ArH), 8.32 (s, CH), 8.71 (s, CH); 13
C
252°C; IR (cm-1, ν): 3430 (br, OH), 3345 (NH); 1H NMR (CDCl3): δ 2.63 (s,
NMR (DMSO-d6): δ 54.7, 55.2, 55.8, 59.3, 94.1, 96.3, 107.3, 113.7, 121.1, 3H, SCH3), 3.78 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.1 (s, 3H, OCH3), 7.25
124.2, 127.9, 128.3, 129.8, 131.7, 138.4, 139.9, 143.4, 145.6, 148.2, 152.4, (d, J ꢀ= ꢀ 7.2 Hz, 1H, CH), 7.65 (d, J ꢀ= ꢀ 8.7 Hz, 2H, ArH), 7.74 (d, J ꢀ= ꢀ 8.7 Hz,
154.8, 159.7, 162.6, 163.9, 172.4. Anal. Calcd for C33H26N3O7S2: C, 61.86; 2H, ArH), 7.77 (s, 1H, CH, ArH), 7.79 (d, J ꢀ= ꢀ 7.2 Hz, 1H, CH), 9.70 (br, s,
H, 4.09; N, 6.56. Found: C, 61.48; H, 4.37; N, 6.78.
1H, NH, D2O exchangeable); MS: m/z 521 (M+, 100%). Anal. Calcd for
C25H21N3O5S2: C. 59.16; H, 4.17; N, 8.28. Found: C, 59.39; H, 4.41; N, 8.35.
3-Amino-6-(2,4,6-trimethoxyphenyl)-8-(3,4,5-trimetho-
xyphenyl)-5H-pyrido[2,3-d][1,3]thiazolo[3,2-a]pyrimidine- 2-(Methylthio)-5-(2,4,6-trimethoxyphenyl)-7-(3,4,5-trimethoxy-
5-thione (9)ꢀA mixture of compound 7b (1 mmol) and sodium phenyl)pyrido[2,3-d]pyrimidine-4(3H)-thione (12b)ꢀA mixture
methoxide (1.5 mmol) in methanol was stirred at room temperature of compound 7b (1 mmol) and sodium methoxide (1.5 mmol) in
for 1 h. Chloroacetonitrile (1.2 mmol) was added to the reaction mix- methanol was stirred at room temperature for 1 h. Iodomethane (1.2
ture, followed by gentle heating for 3 h. The formed solid was filtered mmol) was added to the reaction mixture, followed by gentle heating
and washed several times with water, affording 9 in 67% yield; mp on a water bath for 2 h. The reaction mixture was cooled and poured
1
283–284°C; H NMR (DMSO-d6): δ 3.63 (s, 6H, 2 OCH3), 3.72 (s, 3H, onto cold water. The resultant precipitate was filtered and washed
OCH3), 3.86 (s, 3H, OCH3), 3.97 (s, 6H, 2 OCH3), 5.8 (s, 1H), 6.43–6.76 several times with water yielding 12b in 83% yield, mp 212–213°C; 1H
(br, 2H, NH2, exchangeable with D2O), 6.96 (s, 2H, ArH), 7.02 (s, 2H, NMR (DMSO-d6): δ 2.72 (s, 3H, CH3), 3.61 (s, 6H, 2 OCH3), 3.75 (s, 3H,
ArH), 8.25 (s, 1H, CH); 13C NMR (DMSO-d6): δ 54.8, 55.1, 55.9, 59.4, 93.4, OCH3), 3.88 (s, 3H, OCH3), 3.96 (s, 6H, 2 OCH3), 6.96 (s, 2H, ArH), 7.01
95.6, 108.2, 115.1, 117.2, 122.6, 124.1, 138.1, 147.1, 149.4, 151.3, 153.9, 157.6, (s, 2H, ArH), 8.26 (s, CH), 9.57 (s, 1H, NH, exchangeable with D2O).
159.1, 159.9, 162.2, 170.3. Anal. Calcd for C27H26N4O6S2: C, 57.23; H, 4.62; Anal. Calcd for C26H27N3O6S2: C, 57.65; H, 5.02; N, 7.76. Found: C, 57.45;
N, 9.89. Found: C, 57.06; H, 4.79; N, 9.57.
H, 5.23; N, 7.54.
Ethyl 3-amino-5-thioxo-6-(2,4,6-trimethoxyphenyl)-8-(3,4,5-tri- 2-Hydrazinyl-7-(5-hydroxy-4,7-dimethoxybenzofuran-6-yl)-5-(4-
methoxyphenyl)-5H-pyrido[2,3-d][1,3]thiazolo[3,2-a]pyrimi- methoxyphenyl)pyrido[2,3-d]pyrimidine-4(3H)-thione (13a)ꢀA
dine-2-carboxylate (10)ꢀA mixture of compound 7b (1 mmol) and mixture of compound 6 (1 mmol) and hydrazine hydrate (99%,
sodium methoxide (1.5 mmol) in methanol was stirred at room tem- 1.5 mL) in ethanol (10 mL) was heated on a water bath for 8 h (moni-
perature for 1 h, then treated with ethyl chloro(cyano)acetate (1.2 tored by TLC) whereby a yellow precipitate was formed. The pre-
mmol), and the mixture was heated for 5 h. The resultant solid was cipitate was filtered, washed well with water, dried and crystallised
filtered and washed several times with water, affording 10 in 63% from an ethanol/dioxane mixture (3:1) to afford 13a in 80% yield; mp
yield; mp 292–293°C; 1H NMR (DMSO-d6): δ 1.34 (t, 3H, J ꢀ= ꢀ 7.1 Hz, CH2- 291–292°C; IR (cm-1, ν): 3445 (br, OH), 3325 (NH), 3240, 3244(NH2); 1H
CH3), 3.61 (s, 6H, 2 OCH3), 3.75 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.96 NMR (DMSO-d6): δ 3.79 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 4.05 (s, 3H,
(s, 6H, 2 OCH3), 4.21 (q, 2H, J ꢀ= ꢀ 7.1 Hz, CH2-CH3), 6.43–6.76 (br, 2H, NH2, OCH3), 7.25 (d, J ꢀ= ꢀ 7.2 Hz, 1H, CH), 7.65 (d, J ꢀ= ꢀ 8.4 Hz, 2H, ArH), 7.74 (d,
exchangeable with D2O), 6.98 (s, 2H, ArH), 7.06 (s, 2H, ArH), 8.29 (s, J ꢀ= ꢀ 8.4 Hz, 2H, ArH), 7.77 (s, 1H, CH, ArH), 7.79 (d, J ꢀ= ꢀ 7.2 Hz, 1H, CH),
CH). Anal. Calcd for C30H30N4O8S2: C, 56.41; H, 4.73; N, 8.72. Found: C, 8.15 (br, s, 2H, NH2, D2O exchangeable), 9.42 (s, 1H, NH, exchangeable
56.24; H, 4.93; N, 8.59.
with D2O), 10.70 (br, s, 1H, NH, D2O exchangeable); MS: m/z 491 (M+,
100%). Anal. Calcd for C24H21N5O5S: C, 58.65; H, 4.31; N, 14.25. Found:
3-Amino-5-thioxo-6-(2,4,6-trimethoxyphenyl)-8-(3,4,5- C. 58.45; H, 4.13; N, 14.41.
trimethoxyphenyl)-5H-pyrido [2,3-d][1,3]thiazolo[3,2-a]pyrimi-
dine-2-carbonitrile (11)ꢀA mixture of compound 7b (1 mmol) and 2-Hydrazino-5-(2,4,6-trimethoxyphenyl)-7-(3,4,5-trimethoxy-
sodium methoxide (1.5 mmol) in methanol was stirred at room tem- phenyl)pyrido[2,3-d]pyrimidine-4(3H)-thione (13b)ꢀA mixture
perature for 1 h, then treated with bromomalononitrile (1.2 mmol), of compound 12b (1 mmol) and hydrazine hydrate (99%, 1.5 mmol) in
and the mixture was heated for 5 h. The resultant solid was filtered ethanol (10 mL) was stirred on a water bath for 8 h. A yellow precipi-
and washed several times with water, affording 11 in 69% yield; mp tate was formed afer all the starting material was consumed (moni-
1
284–285°C; H NMR (DMSO-d6): δ 3.61 (s, 6H, 2 OCH3), 3.75 (s, 3H, toring by TLC). The precipitate was filtered, washed well with water,
OCH3), 3.88 (s, 3H, OCH3), 3.96 (s, 6H, 2 OCH3), 5.98–6.11 (br, 2H, NH2, dried and crystallised from an ethanol/dioxane mixture affording 13b
exchangeable with D2O), 6.93 (s, 2H, ArH), 7.08 (s, 2H, ArH), 8.36 (s, in 86% yield; mp 303–305°C; IR (cm-1, ν): 3325 (NH), 3240, 3244 (NH2);
CH). Anal. Calcd for C28H25N5O6S2: C, 56.84; H, 4.26; N, 11.84. Found: 1H NMR (DMSO-d6) δ ppm: 3.63 (s, 6H, 2 OCH3), 3.79 (s, 3H, OCH3), 3.91
C, 56.69; H, 4.53; N, 11.72.
(s, 3H, OCH3), 4.02 (s, 6H, 2 OCH3), 6.98 (s, 2H, ArH), 7.04 (s, 2H, ArH),
8.26 (s, CH, ArH), 8.39 (br, 2H, NH2, D2O exchangeable), 9.47 (s, 1H,
7-(5-Hydrox y- 4, 7- dimethox ybenzofur an- 6-yl)-5-(4- NH, exchangeable with D2O), 10.32 (br, 1H, NH, D2O exchangeable).
methoxyphenyl)-2-(methylthio)-2,3-dihydropyrido[2,3-d]pyrim- Anal. Calcd for C25H27N5O6S: C, 57.13; H, 5.18; N, 13.33. Found: C, 57.03;
idine-4(1H)-thione (12a)ꢀA mixture of ethanolic sodium hydrogen H, 5.42.; N, 13.08.
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100ꢀ ꢀK.M. Abu-Zied et al.: Fused pyrido[2,3-d]pyrimidines incorporating khellinone and trimethoxyphenyl moieties
173.1, 162.6, 157.2, 156.8, 153.7, 151.1, 149.6, 148.9, 145.7, 141.2, 135.1,
130.3, 129.6, 128.9, 122.3, 119.6, 118.2, 112.9, 94.6, 89.9, 59.6, 55.3, 54.8,
53.9. Anal. Calcd for C32H29N5O6S: C, 62.84; H, 4.78; N, 11.45. Found: C,
62.66; H, 4.55.; N, 11.28.
General procedure for pyrido[2,3-d]
[1,2,4]-triazolo[4,3-a]pyrimidine-5(1H)-
thiones 14a,b
A mixture of compound 12a (1 mmol) and trimethyl orthoformate
(5 mL for 14a) or triethyl orthoacetate (5 mL for 14b) was heated
gently on a water bath for 6–8 h (under TLC control). The formed
precipitate was collected upon filtration, dried and crystallised from
ethanol.
3-(4-Methoxyphenyl)-6-(2,4,6-trimethoxyphenyl)-8-(3,4,5-tri-
methoxyphenyl)pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-
5(1H)-thione (16b)ꢀA mixture of compound 13b (1 mmol) and anisic
acid (1.2 mol) in phosphorus oxychloride (5 mL) was stirred under
reflux for 2 h. The reaction mixture was cooled and poured onto ice
with stirring. The produced precipitate was filtered, washed well with
water, dried and crystallised from dioxane, affording 16b in 86%
8-(5-Hydroxy-4,7-dimethoxybenzofuran-6-yl)-6-(4-methoxy-
phenyl)pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-5(1H)-
thione (14a)ꢀThis compound was isolated as pale yellow crystals;
1
yield; mp 327–328°C; IR (cm-1, ν): 3329 (NH); H NMR (DMSO-d6): δ
3.63 (s, 6H, 2 OCH3), 3.77 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 3.92 (s,
3H, OCH3), 3.97 (s, 6H, 2 OCH3), 6.98 (s, 2H, ArH), 7.05 (s, 2H, ArH),
7.34–7.37 (d, 2H, J ꢀ= ꢀ 9.0 Hz, ArH), 7.61–7.64 (d, 2H, J ꢀ= ꢀ 9.0 Hz, ArH), 8.26
(s, CH), 11.22 (s, 1H, NH, exchangeable with D2O); 13C NMR (DMSO-d6):
δ 172.8, 161.9, 159.7, 158.1, 156.4, 153.8, 151.6, 149.7, 148.8, 145.8, 138.9,
131.9, 127.6, 123.4, 119.7, 118.7, 118.1, 116.3, 113.4, 94.7, 90.3, 59.8, 55.8,
55.1, 54.9, 54.2. Anal. Calcd for C33H31N5O7S: C. 61.77; H, 4.87; N, 10.91.
Found: C, 61.51; H, 4.65; N, 10.84.
1
yield 53%; mp 188–190°C; IR (cm-1, ν): 3400 (br, OH), 3333 (NH); H
NMR (DMSO-d6): δ 3.79 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.98 (s, 3H,
OCH3), 7.40 (d, J ꢀ= ꢀ 6.7 Hz, 1H, CH), 7.55 (d, J ꢀ= ꢀ 8.7 Hz, 2H, ArH), 7.77 (d,
J ꢀ= ꢀ 8.7 Hz, 2H, ArH), 7.81 (s, 1H, CH, ArH), 7.88 (d, J ꢀ= ꢀ 6.7 Hz, 1H, CH),
8.23 (s, 1H), 9.12 (br, s, H, NH, D2O exchangeable); 13C NMR (DMSO-
d6): δ 43.6, 46.8, 52.7 (3 CH3), 99.1, 111.3, 128.1, 134, 138, 143, 145, 146.2,
147.1, 147.4, 147.7, 147.8, 148.3, 148.6, 148.7, 148.9, 149.2, 149.6, 149.8,
151.3; MS: m/z 501 (100%).
5-Amino-3-phenyl-1-[4-thioxo-5-(2,4,6-trimethoxyphenyl)-7-
(3,4,5-trimethoxyphenyl)-3,4-dihydropyrido[2,3-d]pyrimidin-
2-yl]-1H-pyrazole-4-carbonitrile (17)ꢀA mixture of compound
13b (1 mmol) and benzylidenemalononitrile (1.1 mmol) in ethanol
was heated under reflux for 10 h, then concentrated under reduced
pressure and the resultant solid was filtered and washed with etha-
nol and ether, affording 17 in 77% yield; mp 276–277°C; IR (cm-1, ν):
3425–3100 (NH2), 2210 (CN); 1H NMR (DMSO-d6): δ 3.62 (s, 6H, 2 OCH3),
3.75 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.96 (s, 6H, 2 OCH3), 6.2 (br, 2H,
NH2), 6.96 (s, 2H, ArH), 7.04 (s, 2H, ArH), 7.32–7.49 (m, 5H, ArH), 8.26
(s, CH), 9.82 (s, 1H, NH, exchangeable with D2O); 13C NMR (DMSO-d6):
δ 171.3, 159.9, 157.8, 157.1, 155.4, 151.9, 149.6, 148.9, 144.9, 138.6, 131.9,
129.7, 127.2, 126.9, 123.6, 119.7, 118.9, 117.7, 113.8, 92.8, 89.6, 73.2, 59.8,
55.7, 54.8, 53.9. Anal. Calcd for C35H31N7O6S: C, 62.03; H, 4.61; N, 14.47.
Found: C, 61.89; H, 4.75; N, 14.19.
8-(5-Hydroxy-4,7-dimethoxybenzofuran-6-yl)-6-(4-methoxy-
phenyl)-3-methylpyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-
5(1H)-thione (14b)ꢀThis compound was isolated as shiny yellow
crystals in 61% yield; mp 206–208°C; IR (cm-1, ν): 3408 (br, OH), 3335
(NH); 1H NMR (DMSO-d6): δ 2.34 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 3.87
(s, 3H, OCH3), 4.01 (s, 3H, OCH3), 7.40 (d, J ꢀ= ꢀ 6.7 Hz, 1H, CH), 7.57 (d,
J ꢀ= ꢀ 8.7 Hz, 2H, ArH), 7.77 (d, J ꢀ= ꢀ 8.7 Hz, 2H, ArH), 7.80 (d, J ꢀ= ꢀ 6.7 Hz, 1H,
CH), 7.86 (s, 1H, CH, ArH) and 10.11 (br, s, 1H, NH, D2O exchangeable);
MS: m/z 515 (100%), 516 (31%).
8-(5-Hydroxy-4,7-dimethoxybenzofuran-6-yl)-3-mercapto-
6-(4-methoxyphenyl)pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrim-
idine-5(1H)-thione (15)ꢀTo a warm ethanolic sodium hydroxide
solution [prepared by dissolving sodium hydroxide (1 mmol) in etha-
nol (10 mL)], compound 12a (1 mmol) and carbon disulphide (3 mL)
were added. The mixture was heated on a water bath at 80°C under
reflux for 8 h, and then cooled, poured into cold water (25 mL) and
neutralised with dilute acetic acid. The formed precipitate was fil-
tered, dried and crystallised from ethanol/dioxane (15 mL, 2:1) to
yield 15 as yellow powder in 52% yield; mp 223–225°C; IR (cm-1, ν):
3408 (br, -OH), 3335 (NH); 1H NMR (DMSO-d6): δ 1.82 (s, 1H, SH), 3.78
(s, 3H, OCH3), 3.90 (s, 3H, OCH3), 4.01 (s, 3H, OCH3), 7.40 (d, J ꢀ= ꢀ 6.7 Hz,
1H, CH), 7.55 (d, J ꢀ= ꢀ 8.4 Hz, 2H, ArH), 7.77 (d, J ꢀ= ꢀ 8.4 Hz, 2H, ArH), 7.80
(d, J ꢀ= ꢀ 6.7 Hz, 1H, CH), 7.86 (s, 1H, CH, ArH), 10.11 (br, s, 1H, NH, D2O
exchangeable); MS: m/z 533.08 (100%), 534.09 (27%).
Ethyl 5-amino-3-phenyl-1-[4-thioxo-5-(2,4,6-trimethoxyphenyl)-
7-(3,4,5-trimethoxyphenyl)-3,4-dihydropyrido[2,3-d]pyrimidin-
2-yl]-1H-pyrazole-4-carboxylate (18)ꢀA mixture of compound 13b
(1 mmol) and ethyl-2-cyano-3-phenylacrylate (1.1 mmol) in ethanol
was heated under reflux for 10 h, then concentrated under reduced
pressure, and the resultant solid was filtered and washed with etha-
nol and ether, affording 18 in 69% yield; mp 256–257°C; IR (cm-1, ν):
3425–3100 (NH2); 1H NMR (DMSO-d6): δ 1.31 (t, 3H, J ꢀ= ꢀ 7.2 Hz, CH2-CH3),
3.62 (s, 6H, 2 OCH3), 3.75 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.96 (s, 6H, 2
OCH3), 4.21 (q, 2H, J ꢀ= ꢀ 7.2 Hz, CH2-CH3), 5.96 (br, 2H, NH2), 6.96 (s, 2H,
ArH), 7.01 (s, 2H, ArH), 7.32–7.49 (m, 5H, ArH), 8.26 (s, CH), 9.82 (s, 1H,
NH, exchangeable with D2O). Anal. Calcd for C37H36N6O6S: C, 61.31; H,
5.01; N, 11.61. Found: C, 61.11; H, 4.85.; N, 11.49.
3-Phenyl-6-(2,4,6-trimethoxyphenyl)-8-(3,4,5-trimethoxyphe-
nyl)pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-5(1H)-thione
(16a)ꢀA mixture of compound 13b (1 mmol) and benzoic acid (1.2
mmol) in phosphorus oxychloride (5 mL) was stirred under reflux for
2 h. The reaction mixture was cooled and poured onto ice with stir-
ring. The produced precipitate was filtered, washed well with water,
3,4-Diphenyl-7-(2,4,6-trimethoxyphenyl)-9-(3,4,5-trimethoxy-
phenyl)-1,4-dihydro-6H-pyrido[2′,3′:4,5]pyrimido[2,1-c][1,2,4]
triazine-6-thione (19)ꢀA mixture of compound 13b (1 mmol),
dried and crystallised from dioxane, affording 16a in 81% yield; mp benzoin (1.1 mmol) and phosphorus oxychloride (5 mL) was heated
316–317°C; IR (cm-1, ν): 3325 (NH); H NMR (DMSO-d6): δ 3.62 (s, 6H, under reflux for 1 h, cooled and then poured onto ice. The precipi-
1
2 OCH3), 3.75 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.96 (s, 6H, 2 OCH3), tated product was collected and washed several times with water and
6.96 (s, 2H, ArH), 7.01 (s, 2H, ArH), 7.34–7.53 (m, 5H, ArH), 8.26 (s, CH), dried yielding 19 in 68% yield; mp 385–386°C; IR (cm-1, ν): 3227 (NH);
11.12 (s, 1H, NH, exchangeable with D2O); 13C NMR (DMSO-d6) δ ppm: 1H NMR (DMSO-d6): δ 3.62 (s, 6H, 2 OCH3), 3.75 (s, 3H, OCH3), 3.89 (s,
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K.M. Abu-Zied et al.: Fused pyrido[2,3-d]pyrimidines incorporating khellinone and trimethoxyphenyl moietiesꢀ
ꢀ101
3H, OCH3), 3.96 (s, 6H, 2 OCH3), 5.98 (s, 1H), 6.96 (s, 2H, ArH), 7.01
(s, 2H, ArH), 7.32–7.59 (m, 10 H, ArH), 8.36 (s, CH), 12.18 (s, 1H, NH,
exchangeable with D2O); 13C NMR (DMSO-d6): δ 54.8, 55.9, 56.6, 57.1,
58.9, 89.4, 92.6, 112.9, 114.9, 119.4, 123.3, 126.9, 127.1, 127.9, 128.8, 129.5,
130.1, 136.9, 138.2, 142.8, 144.9, 147.9, 149.7, 151.3, 154.2, 156.1, 157.4,
159.2, 168.1. Anal. Calcd for C39H35N5O6S: C, 66.75; H, 5.03; N, 9.98.
Found: C, 66.53; H, 4.85; N, 9.79.
Acknowledgments: We thank the Department of Microbi-
ology, National Research Centre, Cairo, Egypt for perform-
ing antibacterial and antifungal testing.
Received October 7, 2013; accepted December 16, 2013
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