Synthesis of new furo[2,3-d]pyrimidines and pyrimido[4′,5′:4,5] furo[2,3-d]pyrimidines

Article abstract of DOI:10.1002/jccs.200400198

Sodium salt of 4-hydroxy-6-methyl-2-phenylpyrimidine-5-carbonitrile (3) was subjected to alkylation with different α-halo compounds, where the corresponding O-alkylated products 4_a-g were obtained. Ring closure of the O-alkylated product 4_a-c performed using sodium ethoxide in refluxing ethanol afforded furo[2,3-d]pyrimidines 5_a-c. The latter compounds on reaction with a variety of reagents gave other new furopyrimidines as well as a number of furodipyrimidines.

Full text of DOI:10.1002/jccs.200400198

Journal of the Chinese Chemical Society, 2004, 51, 1357-1366
1357
Synthesis of New Furo[2,3-d]pyrimidines and
Pyrimido[4¢,5¢:4,5]furo[2,3-d]pyrimidines
Maisa I. Abdel Moneam*, Ahmed A. Geies, Galal M. El-Naggar and Soliman M. Mousa
Chemistry Department, Faculty of Science, Assiut University, Assiut, 71516, Egypt
Sodium salt of 4-hydroxy-6-methyl-2-phenylpyrimidine-5-carbonitrile (3) was subjected to alkylation
with different a-halo compounds, where the corresponding O-alkylated products 4a-g were obtained. Ring clo-
sure of the O-alkylated product 4a-c performed using sodium ethoxide in refluxing ethanol afforded furo[2,3-
d]pyrimidines 5a-c. The latter compounds on reaction with a variety of reagents gave other new furopyrimi-
dines as well as a number of furodipyrimidines.
Keywords: Furopyrimidines; Pyrimidofuropyrimidines; Synthesis; Biological activity.
INTRODUCTION
Pyrimidine derivatives play important roles as analge-
good yield. Some of the O-alkylated derivatives 4a-c were
chosen and subjected to additional reactions to build up new
furo[2,3-d]pyrimidines, e.g. compounds 4a-c underwent ring
closure by refluxing in ethanol containing sod. ethoxide to
give furo[2,3-d]pyrimidine derivatives 5a-c. Furthermore, the
compounds 5a,b may also be synthesized in one step by direct
interaction of 3 with respective halo compounds in acetone
containing anhydrous pot. carbonate (Scheme I). It is impor-
tant to note that the reason for using compound 4c as interme-
diate to obtain the o-amino ester instead of cyclisation of
compound 4d directly is that attempts to cyclize compound 4d
failed. So we use compound 4c in which cyclisation was
found more easily due to the high activation of the methine
proton with two ester groups followed by loss of an ester
group to give the desired compound. Compound 5b was re-
acted with chloroacetyl chloride in dioxane to yield N-(6-
benzoyl-4-methyl-2-phenylfuro[2,3-d]pyrimidine-5-yl)-2-
chloroacetamide (6), which underwent nucleophilic dis-
placement when treated with piperidine to give piperidine-1-
yl-acetamide derivative 7.
sic,1 antihypertensive,2 antipyretic,3 antiviral,4 and anti-
inflammatory drugs.5 Also they are used in agriculture as pes-
ticides6 and plant growth regulators.7 In addition, the furo-
[2,3-d]pyrimidine ring system is of biological interest; thus
furo[2,3-d]pyrimidine derivatives were reported as inhibitors
of dihydrofolate reductase, thymidyates synthase, antitumor
agents antibacterial and antiprotozoan agents.7-10
Because the chemistry of furopyrimidines has been lit-
tle explored and in view of the above observation, we report
herein the synthesis of new furopyrimidines and pyrimido-
furopyrimidines hoping to get compounds with enhanced bi-
ological activity and medicinal applications.
RESULTS AND DISCUSSION
The target compound 3 was synthesized through hydro-
lysis of S-ethylthio derivative 2 in alcoholic sodium hydrox-
ide to give the corresponding sodium salt. The reason for us-
ing sodium salt rather than the hydroxyl derivative is to force
the reaction towards the formation of O-alkylated products
instead of the expected N-alkylated products.11
Saponification of O-amino ester 5c with an ethanolic
sodium hydroxide solution resulted in formation of sodium
salt 8, which in turn was treated with orthophosphoric acid at
room temperature and underwent smooth decarboxylation
followed by hydrolysis of the imino group to give 4-methyl-
2-phenylfuro[2,3-d]pyridin-5(6H)-one (9).12 Condensation
of 9 with aromatic aldehydes in ethanol in the presence of a
catalytic amount of piperidine furnished the arylidene deriva-
tives 10a,b (Scheme II). Refluxing of compound 8 with an ex-
cess amount of acetic anhydride didn’t give the expected ox-
Compound 3 was subjected to react with different halo
compounds, namely chloroacetone, phenacyl bromide, di-
ethyl bromolmalonate, ethyl chloroacetate, methyl 2-bromo-
propionate, ethyl bromoacetoacetate and chloroacetonitrile
in refluxing acetone yielded O-alkylated products 4a-g in
* Corresponding author. E-mail: maisaabdelmoneam@hotmail.com

1358 J. Chin. Chem. Soc., Vol. 51, No. 6, 2004
Abdel Moneam et al.
Scheme I
CH3
CH3
CH3
N
CN
CN
N
CN
CH3CH2I / EtOH
AcONa
N
NaOH / EtOH
N
Ph
N
SH
Ph
N
SCH2CH3
Ph
ONa
1
3
2
acetone
RX
RX
K2CO3 acetone
CH3
CH3
CH3
NHCOCH2Cl
NH2
N
CN
OR
5b
N
EtONa
4a-c
N
ClCH2COCl
dioxan
Ph
COPh
Ph
R
N
O
N
O
Ph
N
6
5a-c
4a-g
piperidine
EtOH
5
a
R
R
4
a
-COCH3
-CH2COCH3
CH3
N
NHCOCH2
COPh
N
b
c
-COPh
b
c
d
e
f
-CH2COPh
N
Ph
O
7
-COOEt
-CH(COOEt)2
-CH2COOEt
CH3-CH-COOCH3
CH3-CO-CH-COOEt
-CH2CN
g
azine derivative 11 and instead 5-(N,N-diacetylamino)-4-
methyl-2-phenylfuro[2,3-d]pyrimidine (12) was produced.
Hydrazonolysis of 12 failed to give the corresponding amino
derivative; instead N-acetylamino derivative 13 was ob-
tained.
Some new pyrido[2¢,3¢:4,5]furo[2,3-d]pyrimidines 21,
22 (Scheme IV) may be obtained by the reaction of 5a,b with
an equimolar amount of ethyl cyanoacetate in the presence of
an excess amount of ammonium acetate.13
Ethyl 5-amino-4-methyl-2-phenylfuro[2,3-d]pyrimi-
dine-6-carboxylate (5c) proved also to be a versatile synthon
for some new pyrimido[4¢,5¢:4,5]furo[2,3-d]pyrimidines.
Thus, the reaction of 5c with an equimolar quantity of phenyl-
isothiocyanate in pyridine gave 4-methyl-8-oxo-5,6,7,8-tet-
rahydro-2,7-diphenyl[4¢,5¢:4,5]pyrimidofuro[2,3-d]pyrimi-
din-6-thione (23). Heating 5c in formamide lead to the forma-
tion of pyrimido[4¢,5¢:4,5]furo[2,3-d]pyrimidine derivative
24 in moderate yield.
Refluxing 5c with hydrazine hydrate in ethanol af-
forded carbohydrazide derivative 14 (Scheme III). Treatment
of compound 14 with nitrous acid yielded the corresponding
carboazide 15, which upon boiling in dry xylene underwent
Curtius rearrangement to give 4-methyl-2-phenylimidazo-
[4¢,5¢:4,5]furo[2,3-d]pyrimidin-6(5H,7H)-one (16).
Furthermore, heating of carbohydrazide 14 with formic
acid and/or acetic anhydride led to the formation of 7-N-for-
mylamino-4-methyl-2-phenyl pyrimido[4¢,5¢:4,5]furo[2,3-
d]pyrimidine (17) and 7-N-diacetylamino-4,6-dimethyl-2-
phenylpyrimido[4¢,5¢:4,5]furo[2,3-d]pyrimidin-8(7H)-one
(18), respectively. Condensation of the carbohydrazide 14
with different aromatic aldehydes in ethanol in the presence
of a catalytic amount of piperidine furnished arylidene deriv-
atives 19a-c in high yield. New 3,5-dimethylpyrazolyl com-
pound 20 was prepared by the condensation of 14 with acetyl
acetone in refluxing ethanol.
Chlorination of 24 an with excess amount of phos-
phoryl chloride gave 8-chloro-4-methyl-2-phenylpyrimido-
[4¢,5¢:4,5]furo[2,3-d]pyrimidine (25). Treatment of the latter
compound with hydrazine hydrate 99% in ethanol gave the
corresponding hydrazino compound 26.
Biological Activity
Thirteen compounds were selected and screened in vi-
tro for their antimicrobial activity against two strains of bac-

Synthesis of New Furopyrimidines
J. Chin. Chem. Soc., Vol. 51, No. 6, 2004 1359
Scheme II
CH3
CH3
N
CH3
N
NH2
N
NH2
CH3
Ac2O
X
NaOH/ EtOH
Ph
COOEt
N
N
O
Ph
N
O
COONa
Ph
O
N
O
O
11
8
5c
H3PO3
Ac2O
CH3
N
CH3
N
NH2
CH3
COCH3
COCH3
NH
N
N
N
O
N
Ph
O
N
Ph
Ph
N
O
O
12
H2NNH2/EtOH
CH3
Ph
CH3
N
O
NHCOCH3
9
N
Ph
N
O
ArCHO EtOH/piperidine
13
CH3
O
N
Ph
CH
R
N
O
10
R
a
b
-OCH3
-Cl
teria (Escherichia coli and Bacillus cereus) and six fungal
species (Aspergillus terreus, Penicillium chrysogenum,
Fusarium solani, Paecilomyces variotii, Alternaria alternata
and Scopulariopsis brumptii) using the filter paper disc
method.14 The biological activity, as expressed by the growth
of the inhibition zones of the tested microorganism are sum-
marized in Table 1. From Table 1, it is obvious that, as bacte-
ricides there is no activity for the tested compounds against
Bacillus cereus except for compound 13, while Escherichia
coli showed a moderate sensitivity against most of the newly
synthesized compounds. As for fungicides, high activity was
shown against Aspergillus terreus, Paecilomyces variotii,
Alternaria alternata and Scopulariopsis brumptii while
Penicillium chrysogenum and Fusarium solani showed no
sensitivity against the tested compounds.
EXPERIMENTAL
Melting points were recorded on a Gallen-Kamp appa-
ratus and are uncorrected. (IR) spectra were recorded on a
Shimadzu-470 IR-Spectrophotometer (KBr; nmax in cm-1), 1H
NMR Spectra on a Varian EM-390, 90 MHz spectrometer
with TMS as internal standard or on a Jeol LA 400 MHz FT.
NMR spectrometer (d in ppm), and MS on a Jeol JMS-600
mass spectrometer. Elemental analyses were recorded on a
Perkin Elmer 240C elemental analyzer.
4-Methyl-6-mercapto-2-phenylpyrimidine-5-carbonitrile
(1)
This compound was prepared according to a literature
procedure.15

1360 J. Chin. Chem. Soc., Vol. 51, No. 6, 2004
Abdel Moneam et al.
Scheme III
5c
H2NNH2/EtOH
CH3
CH3
CH3
N
NH2
NaNO2/AcOH
N
N
NH2
HCOOH
N
N
N
Ph
CONHNH2
N
O
Ph
NH.CHO
N
O
Ph
CON3
14
O
O
15
17
Ac2O
dry xylene
CH3
N
ArCHO EtOH/piperidine
CH3
N
N
O
CH3
H
N
N
N
N
Ac2CH2
N(COCH3)2
Ph
O
Ph
O
N
H
O
16
18
CH3
N
CH3
N
NH2
CO
NH2
N
N
N
N
Ph
O
Ph
CONHN=CH
R
O
20
H3C
CH3
19a-c
19
R
a
b
c
-H
-NO2
-Cl
6-Ethylthio-4-methyl-2-phenylpyrimidine-5-carbonitrile
(2)
General procedure for the synthesis of 4a-g
A mixture of 3 (2.33 gm; 0.01 mol) and respective halo
compounds (0.01 mol) in acetone (20 mL) was refluxed for 4
hours then allowed to cool and poured on cold water with stir-
ring. The solid product was collected and recrystallized from
ethanol as white crystals.
A mixture of 1 (2.27 gm, 0.01 mol), ethyl bromide
(0.015 mol) and anhydrous potassium carbonate (0.015 mol)
in ethanol (30 mL) was refluxed for 3 hours. The solid prod-
uct separated from the hot mixture was filtered off, washed
with water and recrystallized from ethanol as pale yellow
crystals in 85% yield, mp 118-120 °C. Anal. Calcd. for
C14H13N3S (255.34): C, 65.58; H, 5.13; N, 16.46; S, 12.56.
Found: C, 65.60; H, 5.10; N, 16.50; S, 12.52. IR: n 2200
(CºN) cm-1. 1H NMR in (DMSO-d6): d 1.3-1.5 (t, 3H, CH3);
2.7 (s, 3H, CH3), 3.3-3.6 (q, 2H, CH2), 7.6-7.7(m, 3H, Ar-H),
8.4-8.6 (m, 2H, Ar-H).
5-Cyano-4-methyl-2-phenylpyrimidin-6-yloxy)acetone (4a)
Produced in 76% yield; mp 179-181 °C. Anal. Calcd.
for C15H13N3O2 (267.28): C, 67.40; H, 4.90; N, 15.72. Found:
C, 67.35; H, 4.80; N, 15.63. IR: n 2200 (CºN), 1720 (C=O)
cm-1. 1H NMR (CDCl3): d 2.3 (s, 3H, CH3), 2.7 (s, 3H, CH3),
5.0 (s, 2H, CH2), 7.2-7.4 (m, 3H, Ar-H), 8.2-8.4 (m, 2H,
Ar-H).
Sodium-5-cyano-4-methyl-2-phenyl-6-pyrimidinate (3)
A mixture of 2 (2.55 gm; 0.01 mol) and sodium hydrox-
ide (0.02 mol) in ethanol (20 mL) and water (3 mL) was
refluxed for 4 hours then allowed to cool. The solid product
was filtered off as white crystals in 60% yield. Compound 3
was subjected to the next step without further purification.
6-Benzoylmethoxy-4-methyl-2-phenylpyrimidine-5-car-
bonitrile (4b)
Produced in 73% yield; mp 163-165 °C. Anal. Calcd.
for C20H15N3O2 (329.35): C, 72.94; H, 4.59; N, 12.76. Found:
C, 72.90 H, 4.60; N, 12.73. IR: n 2200 (CºN), 1690 (C=O),

Synthesis of New Furopyrimidines
J. Chin. Chem. Soc., Vol. 51, No. 6, 2004 1361
Scheme IV
CH3
N
H
N
O
NCCH2COOEt
N
5a,b
CH3COONH4
Ph
CN
O
R
21 ; R=Ph
22 ; R=CH3
CH3
NH2
N
Ph
COOEt
HCONH2
N
O
5C
PhNCS
pyridine
CH3
N
CH3
N
H
N
N
O
S
N
N
NH
Ph
Ph
Ph
N
O
O
O
( 24 )
( 23)
POCl3
N
CH3
N
CH3
N
N
N
NH2NH2.H2O
EtOH
N
N
Ph
Ph
O
N
O
NHNH2
Cl
( 26)
( 25)
Table 1. The antimicrobial activity of selected compounds
Bacteria
Fungi
Inhibition zone (mm)
F. P.
terreus chrysogenum solani variotti alternata brumptii
Inhibition zone (mm)
E.
B.
A.
P.
A.
S.
No
coli
cereus
4a
4b
5b
5c
-
-
15
-
12
15
-
14
14
-
-
-
-
-
-
-
13
-
-
-
13
-
15
-
14
-
-
12
14
12
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
12
-
-
-
-
-
14
-
13
-
14
14
-
-
12
-
12
12
-
-
-
-
14
-
-
-
-
9
15
14
12
14
15
13
-
10a
13
17
18
19b
20
25
26
-
-
-
-
-
14
-
-
-
-
12
-
-
13
12
12

1362 J. Chin. Chem. Soc., Vol. 51, No. 6, 2004
Abdel Moneam et al.
1580 (C=N) cm-1. 1H NMR (DMSO-d6): d 2.7 (s, 3H, CH3),
Ar-H), 8.4-8.5 (m, 2H, Ar-H).
6.0 (s, 2H, CH2), 7.2-8.8 (m, 10H, Ar-H).
General procedure for the synthesis of 5a-c
Diethyl 2-(5-cyano-4-methyl-2-phenylpyrimidin-6-yloxy)-
malonate (4c)
A mixture of compound 4a-c (0.05 mol) in absolute etha-
nol (50 mL) containing sodium (0.5 gm) was refluxed for 1
hour. The solid product was collected, washed with water and
recrystallized from suitable solvent.
Produced in 74% yield; mp 98-100 °C. Anal. Calcd. for
C19H19N3O5 (369.13): C, 61.78; H, 5.18; N, 11.38. Found; C,
61.80; H, 5.16; N, 11.41. IR: n 2900 (CH, aliphatic), 2200
1
(CºN), 1760, 1750 (C=O) cm-1. H NMR (CDCl3): d 1.08-
5-Amino-6-acetyl-4-methyl-2-phenylfuro[2,3-d]pyrimidine
(5a)
1.12 (m, J = 7 Hz, 6H, 2CH3), 2.55 (s, 3H, -CH3), 4.11-4.13
(m, J = 7 Hz, 4H, 2CH2), 5.7 (s, 1H, CH), 7.26-7.32 (m, 3H,
Ar-H), 8.14-8.16 (m, 2H, Ar-H).
Produced in 90% yield, yellow crystals from ethanol;
mp 208-210 °C. Anal. Calcd. for C15H13N3O2 (267.28); C,
67.40; H, 4,90; N, 15.72. Found: C, 67.35; H, 4.92; N, 15.64.
IR: n 3400, 3300 (NH2); 1630 (C=O); 1H NMR (DMSO-d6): d
2.5 (s, 3H, CH3), 2.9 (s, 3H, CH3), 6.9 (s, 2H, NH2), 7.4-7.6
(m, 3H, Ar-H), 8.3-8.5 (m, 2H, Ar-H).
Ethyl (5-cyano-4-methyl-2-phenylpyrimidin-6-yloxy)ace-
tate (4d)
Produced in 73% yield; mp 118-119 °C. Anal. Calcd.
for C16H15N3O3 (297.31); C, 64.64; H, 5.09; N, 14.13. Found:
C, 64.62; H, 5.14; N, 14.01. IR: n 2960 (CH, aliphatic), 2200
(CºN), 1740 (C=O) cm-1. 1H NMR (CDCl3): d 1.15-1.30 (t,
3H, CH3), 2.7 (s, 3H, -CH3), 4.05-4.30 (q, 2H, CH2), 5.0 (s,
2H, CH2), 7.2-7.5 (m, 3H, Ar-H), 8.2, 8.4 (m, 2H, Ar-H).
5-Amino-6-benzoyl-4-methyl-2-phenylfuro[2,3-d]pyrimi-
dine (5b)
Produced in 76% yield, yellow crystals from ethanol
mp 218-220 °C. Anal. Calcd. for C20H15N3O2 (329.35): C,
72.94; H, 4.59; N, 12.76. Found: C, 72.92; H, 4.60; N, 12.80.
IR: n = 3350, 3450 (NH2), 1610 (C=O), 1560 (C=N) cm-1. 1H
NMR (CDCl3): d 2.9 (s, 3H, CH3), 6.3 (s, 2H, NH2), 7.4-8.7
(m, 10H, Ar-H).
Methyl 2-(5-cyano-4-methyl-2-phenyl-pyridin-6-yloxy)-
propanoate (4e)
Produced in 75% yield; mp 138-140 °C. Anal. Calcd for
C16H15N3O3 (297.31); C, 64.64; H, 5.09; N, 14.13. Found: C,
64.61; H, 5.31; N, 14.11. IR: n 2950 (CH, aliphatic), 2200
(CºN), 1750 (C=O) cm-1. 1H NMR (DMSO-d6): d 1.8-1.9 (d,
3H, CH3), 2.8 (s, 3H, CH3), 4.2 (s, 3H, OCH3), 5.4-5.7 (q, 1H,
CH), 7.4-7.6 (m, 3H, Ar-H), 8.3-8.5 (m, 2H, Ar-H).
5-Amino-4-methyl-2-phenylfuro[2,3-d]pyrimidine-6-car-
boxylate (5c)
Produced in 83% yield, yellow crystals from ethanol,
mp 178-180 °C. Anal. Calcd. for C16H15N3O3 (297.11): C,
64.64; H, 5.09; N, 14.13. Found: C, 64.64; H, 5.13; N, 14.16.
IR: n 3480, 3380 (NH2); 1680 (C=O); 1600 (C=N) cm-1. 1H
NMR (CDCl3): d 1.4-1.5 (t, 3H, CH3), 2.8 (s, 3H, CH3),
4.3-4.6 (q, 2H, CH2), 5.2 (s, 2H, NH2), 7.2-7.4 (m, 3H, Ar-H),
8.4-8.6 (m, 2H, Ar-H).
Ethyl 3-oxo-2-(5-cyano-4-methyl-2-phenylpyrimidin-6-
yloxy)butanoate (4f)
Produced in 78% yield, mp 119-121 °C. Anal Calcd. for
C18H17N3O4 (339.35): C, 63.71; H, 5.05; N, 12.38, Found: C,
63.65; H, 5.0; N, 12.32. IR: n 2960 (CH, aliphatic), 2200
(CºN), 1750, 1730 (2C=O) cm-1. 1H NMR (CDCl3): d 1.2-1.4
(t, 3H, CH3), 2.7 (s, 3H, CH3), 3.7 (s, 3H, OCH3), 4.0-4.3 (q,
2H, CH2), 5.2 (s, H, CH), 7.3-7.5 (m, 3H, Ar-H), 8.2-8.4, (m,
2H, Ar-H).
N-(6-Benzoyl-4-methyl-2-phenylfuro[2,3-d]pyrimidin-5-
yl)-2-chloroacetamide (6)
A mixture of 5b (1.65 g; 0.005 mol), chloroacetyl chlo-
ride (0.005 mol) in dioxane (20 mL) was refluxed for 2 hours;
after cooling the reaction mixture was poured into cold water.
The solid product was collected and recrystallized from etha-
nol as pale yellow crystals, yield 81%, mp 248-250 °C. Anal.
Calcd. for C22H16ClN3O3 (405.8): C, 65.11; H, 3.97; Cl, 8.74;
N, 10.35. Found: C, 65.15; H, 3.86; Cl, 8.80; N, 10.46. IR: n
3250 (NH), 1680, 1630 (2C=O), 1570 (C=N) cm-1. 1H NMR
(DMSO-d6): d 2.8 (s, 3H, CH3), 4.3 (s, 2H, CH2), 7.5-8.5 (m,
6-Cyanomethoxy-4-methyl-2-phenylpyrimidine-5-carbo-
nitrile (4g)
Produced in 76% yield; mp 173-175 °C. Anal. Calcd.
for C14H10N4O (250.26); C, 67.19; H, 4.03; N, 22.39. Found:
C, 67.23; H, 4.14; N, 22.34. IR: n 2200 (CºN) cm-1. 1H NMR
(CDCl3): d 2.8 (s, 3H, CH3), 5.2 (s, 2H, CH2), 7.4-7.6 (m, 3H,

Synthesis of New Furopyrimidines
10H, Ar-H), 10.6 (s, H, NH).
J. Chin. Chem. Soc., Vol. 51, No. 6, 2004 1363
(s, 3H, OCH3), 7.3 (s, 1H, CH), 6.9-7.1 (m, 2H, Ar-H), 7.45-
7.65 (m, 3H, Ar-H), 7.94, 7.96 (d, 2H, Ar-H), 8.58-8.60 (d,
2H, Ar-H).
N-(6-Benzoyl-4-methyl-2-phenylfuro[2,3-d]pyrimidin-5-
yl)-2-piperidin-1-yl)acetamide (7)
A mixture of 6 (2 gm; 0.05 mol), piperidine (0.005 mol)
in ethanol (20 mL) was refluxed for 4 hours then allowed to
cool. The solid product was collected and recrystallized from
a mixture of benzene: pet. ether (2:1) as pale yellow crystals.
Yield 75%, mp 228-230 °C. Anal. Calcd. for C27H26N4O3
(454.52): C, 71.35; H, 5.77; N, 12.33. Found: C, 71.28; H,
5.78; N, 12.35. IR: n 3200 (NH), 1700, 1682 (2C=O), 1580
(C=N) cm-1; Ms: m/z 454 (M+).
6-(p-Chlorobenzylidene)-4-methyl-2-phenylfuro[2,3-d]-
pyrimidin-5-one (10b)
Produced in 76% yield; mp 174-176 °C; yellow crystals
from ethanol Anal. Calcd. for C20H13N2O2Cl (348.78): C,
68.87; H, 3.76; N, 8.03; Cl, 10.16. Found: C, 68.84; H, 3.77;
N, 8.00; Cl, 10.12. IR: n 1700 (C=O) cm-1. 1H NMR (CDCl3):
d 2.8 (s, 3H, CH3), 6.7-8.7 (m, 10H, Ar-H and CH).
5-N,N-Diacetylamino-4-methyl-2-phenylfuro[2,3-d]pyrimi-
dine (12)
Sodium 5-amino-4-methyl-2-phenylfuro[2,3-d]pyrimidine-
6-carboxylate (8)
A sample of 8 (1.45 g, 0.005 mol) was refluxed in (30
mL) acetic anhydride for 4 hours, then allowed to cool and
poured into a ice/water mixture. The solid product was fil-
tered off and recrystallized from ethanol as pale yellow crys-
tals in 74% yield, mp 138-140 °C. Anal. Calcd. for C17H15N3O3
(309.32): C, 66.01; H, 4.89; N, 13.58. Found: C, 66.03; H,
A mixture of 5c (1.5 gm; 0.005 mol), sodium hydroxide
(0.2 gm; 0.005 mol) in ethanol (20 mL) was refluxed for 5
hours then allowed to cool. The solid product was filtered off,
washed with ethanol and air dried to give a yellowish white
solid in 80% yield. Compound 8 was subjected to the next
step without further purification.
1
4.90; N, 13.56. IR: n 1720, 1700 (2C=O) cm-1. H NMR
(CDCl3): d 2.5 (s, 6H, 2COCH3), 2.8 (s, 3H, CH3), 7.7 (s, 1H,
4-Methyl-2-phenylfuro[2,3-d]pyrimidin-5(6H)-one (9)
A sample of compound 8 (2 g) was stirred for 2 hours in
orthophosphoric acid (10 mL), then neutralized by ammo-
nium hydroxide. The solid product was filtered off and re-
crystallized from ethanol as white crystals in 72% yield, mp
148-150 °C. Anal. Calcd. for C13H10N2O2 (226.23): C, 69.02;
H, 4.46; N, 12.38. Found: C, 69.00; H, 4.43; N, 12.35. IR: n
CH), 7.4-7.6 (m, 3H, Ar-H), 8.4-8.6 (m, 2H, Ar-H).
N-(4-Methyl-2-phenylfuro[2,3-d]pyrimidin-5-yl)acetamide
(13)
A mixture of 12 (1.55 gm; 0.05 mol), hydrazine hydrate
(3 mL) in ethanol (30 mL) was refluxed for 4 hours then al-
lowed to cool. The solid product which formed after cooling
was filtered off and recrystallized from ethanol as yellowish
white crystals in 70% yield, mp 208-210 °C. Anal. Calcd. for
C15H13N3O2 (267.28): C, 67.40; H, 4.90; N, 15.72. Found: C,
1
1710 (C=O); 1580 (C=N) cm-1. H NMR (CDCl3): d 2.8 (s,
3H, CH3), 4.8 (s, 2H, CH2), 7.4-7.6 (m, 3H, Ar-H), 8.4-8.6
(m, 2H, Ar-H). 13C NMR 15.6, 77.8, 118.8, 126.9, 127.0,
128.7, 129.0, 129.2, 135.4, 166.3, 172.2, 172.6, 192.4; Ms:
m/z 226 (M+).
1
67.38; H, 4.87; N, 15.74. H NMR (CDCl3): d 2.3 (s, 3H,
COCH3), 2.9 (s, 2H, CH3), 7.4-7.6 (m, 3H, Ar-H), 8.1 (s, 1H,
CH), 8.3-8.5 (m, 2H, Ar-H); Ms: m/z 267 (M+).
General procedure for the synthesis of 10a,b
A mixture of 9 (2.269; 0.01 mol) and the respective aro-
matic aldehyde (0.01 mol) in ethanol (50 mL) containing a
catalytic amount of piperidine was refluxed for 2 hours. The
solid product which formed after cooling was filtered off and
recrystallized from a suitable solvent.
5-Amino-4-methyl-2-phenylfuro[2,3-d]pyrimidine-6-car-
bohydrazide (14)
A mixture of 5c (2.97; 0.01 mol) and hydrazine hydrate
(3 mL) in ethanol (20 mL) were refluxed for 3 hours. The
solid product which formed during reflux was filtered off and
recrystallized from dioxane as pale yellow crystals in 73%
yield, mp 263-265 °C. Anal. Calcd. for C14H13N5O2 (283.29):
C, 59.36; H, 4.63; N, 24.72. Found: C, 59.2; H, 4.62; N,
24.75. IR: n 4500, 3350, 3250 (NH, NH2), 1620 (C=O) cm-1.
1H NMR (DMSO-d6): d 2.9 (s, 3H, CH3), 4.5 (s, 2H, NH2), 6.0
(s, 2H, NH2), 7.4-7.6 (m, 3H, Ar-H), 8.3-8.5 (m, 2H, Ar-H),
9.0 (s, 1H, NH).
6-(p-Methoxybenzyledine)-4-methyl-2-phenylfuro[2,3-d]-
pyrimidin-5-one (10a)
Produced in 78% yield, mp 230-232 °C, yellow crystals
from ethanol. Anal. Calcd. for C21H16N2O3 (344.36): C, 73.24;
H, 4.68; N, 8.13. Found: C, 73.18; H, 4.71; N, 8.07. IR: n
1690 (C=O) cm-1. 1H NMR (CDCl3): d 2.8 (s, 3H, CH3), 3.8

1364 J. Chin. Chem. Soc., Vol. 51, No. 6, 2004
Abdel Moneam et al.
5-Amino-4-methyl-2-phenylfuro[2,3-d]pyrimidine-6-car-
boazide (15)
General procedure for the synthesis of (19a-c
)
A mixture of furopyrimidine carbohydrazide 14 (2.83
gm; 0.01 mole) and an appropriate aromatic aldehyde (0.01
mol) in ethanol : acetic acid mixture (30 mL) was refluxed for
4 hours then allowed to cool at room temperature. The solid
product was collected and recrystallized from a suitable sol-
vent.
To a cooled solution of compound 14 (1.4 gm; 0.005
mol) in glacial acetic acid (20 mL), sodium nitrite solution
(0.69 gm in 5 mL H2O) was added dropwise with stirring. The
stirring was continued for an additional 2 hours, then the re-
action mixture was allowed to stand 5 hours. The solid prod-
uct was filtered off, washed several times with water and air
dried to give pale yellow crystals without purification in 84%
yield, mp 179-180 °C. Anal. Calcd. for C14H10N6O2 (294.27):
C, 57.14; H, 3.43; N, 28.56. Found: C, 57.24; H, 3.84; N,
28.39. IR: n 3450, 3350 (NH2), 3130 (N3), 1650 (C=O) cm-1.
Benzylidene 5-amino-4-methyl-2-phenylfuro[2,3-d]pyrim-
idine-6-carbohydrazone (19a)
Produced in 86% yield, mp 256-258 °C, yellow crystals
from acetic acid. Anal. Calcd. for C21H17N5O2 (371.39): C,
67.91; H, 4.61; N, 18.86. Found: C, 67.83; H, 4.51; N, 18.93.
1
4-Methyl-2-phenylimidazo[4¢,5¢:4,5]furo[2,3-d]pyrimidin-
6-(5H,7H)-one (16)
IR: n 3450, 3350 (NH, NH2), 1640 (C=O) cm-1. H NMR
(DMSO-d6): d 2.9 (s, 3H, CH3), 6.2 (s, 2H, NH2), 7.3-7.8,
A sample of compound 15 (0.5 gm) in dry xylene (10
mL) was heated under reflux for 3 hours then allowed to cool
to room temperature. The solid product which separated from
the hot mixture was filtered off and recrystallized from di-
oxane as brownish red crystals in 73% yield, mp > 300 °C.
Anal. Calcd. for C14H10N4O2 (266.25): C, 63.15; H, 3.79; N,
21.04. Found: C, 63.26; H, 3.71; N, 21.00. IR: n 3200 (NH),
1710 (C=O) cm-1, Ms: m/z 266 (M+).
8.3-8.5 (2m, 10H, Ar-H), 8.6 (s, 1H, CH), 12.2 (s, 1H, NH).
5-Amino-6-(p-nitrobenzylidene)-4-methyl-2-phenylfuro-
[2,3-d]pyrimidine-6-carbohydrazone (19b)
Produced in 81% yield, mp 308-310 °C, reddish yellow
crystals from acetic acid. Anal. Calcd. for C21H16N6O4
(416.39): C, 60.57; H, 3.87; N, 20.18. Found: C, 60.65; H,
4.00; N, 20.03. IR: n 3450, 3300 (NH, NH2), 1640 (C=O)
cm-1. 1H NMR (T.F.A): d 3.3 (s, 3H, CH3), 7.6-8.5 (m, 10H,
Ar-H and -N=CH).
7-N-Formylamino-4-methyl-2-phenylpyrimido[4¢,5¢:4,5]-
furo[2,3-d]pyrimidin-8-(7H)-one (17)
A sample of compound 14 (0.5 g) in formic acid (10
mL) was refluxed for 5 hours then allowed to cool to the room
temperature. The solid product was collected and recrystal-
lized from dioxane as pale yellow crystals in 80% yield, mp
290-292 °C. Anal. Calcd. for C16H11N5O3 (321.29): C, 59.81;
H, 3.45; N, 21.80. Found: C, 59.72; H, 3.50; N, 21.74. IR: n
3170 (NH); 1720, 1680 (2C=O) cm-1. 1H NMR (DMSO-d6): d
2.9 (s, 3H, CH3) 7.4-7.6 (m, 3H, Ar-H), 8.4-8.5 (m, 2H, Ar-H
and 1H, pyrimidine), 8.5 (s, 1H, CHO), 9.4 (s, 1H, NH).
5-Amino-6-(p-chorobenzylidene)-4-methyl-2-phenylfuro-
[2,3-d]pyrimidine-6-carbohydrazone (19c)
Produced in 78% yield, mp 268-270 °C, yellow crystals
from acetic acid. Anal. Calcd. for C21H16ClN5O2 (405.84): C,
62.15; H, 3.97; Cl, 8.74; N, 17.26. Found: C, 62.23; H, 4.01;
Cl, 8.62; N, 17.08. IR: n 3450, 3300 (NH, NH2), 1670 (C=O)
cm-1. 1H NMR (CDCl3): 2.8 (s, 3H, CH3), 6.9 (s, 2H, NH2),
7.3, 7.32 (d, 2H, Ar-H), 7.65, 7.67 (d, 2H, Ar-H), 7.4-7.6 (m,
3H, Ar-H), 8.4-8.6 (m, 2H, Ar-H), 8.0 (s, 1H, CH), 9.6 (s, 1H,
NH).
7-N,N-Diacetylamino-4,6-dimethyl-2-phenylpyrimido-
[4¢,5¢:4,5]furo[2,3-d]pyrimidin-8-(7H)-one (18)
5-Amino-4-methyl-2-phenyl-6-[3¢,5¢-dimethylpyrazol-1-
ylcarbonyl]furo[2,3-d]pyrimidine (20)
A sample of compound 14 (0.5 gm) in acetic anhydride
(10 mL) was refluxed for 2 hours then allowed to cool and
poured into cold water. The solid product was collected and
recrystallized from dioxane as pale yellow crystals in 82%
yield, mp 220-221 °C. Anal. Calcd. for C20H17N5O4 (391.38):
C, 61.38; H, 4.38; N, 17.89. Found: C, 61.29; H, 4.48; N,
17.90. IR: n 1730, 1620 (C=O), 1560 (C=N) cm-1. 1H NMR
(CDCl3): d 2.46 (s, 6H, 2COCH3), 2.52 (s, 3H, CH3), 3.0 (s,
3H, CH3), 7.8-8.6 (2m, 5H, Ar-H).
A mixture of carbohydrazide 14 (2.83 gm; 0.01 mol)
and acetyl acetone (0.021 mol) in ethanol (40 mL) was
refluxed for 2 hours then allowed to cool at room tempera-
ture. The solid product was collected and recrystallized from
ethanol as yellow needles in 69% yield, mp 200-202 °C.
Anal. Calcd. for C19H17N5O2 (347.37): C, 65.69; H, 4.93; N,
20.16. Found: C, 65.61; H, 4.83; N, 20.26. IR: n 3450, 3350
1
(NH2); 1630 (C=O) cm-1. H NMR (DMSO-d6): d 2.3, 2.5

Synthesis of New Furopyrimidines
J. Chin. Chem. Soc., Vol. 51, No. 6, 2004 1365
(2S, 6H, 2CH3), 2.9 (s, 3H, CH3), 6.2 (s, 1H, CH), 7.3 (s, 2H,
NH2), 7.4-7.6 (m, 3H, Ar-H), 8.4-8.6 (m, 2H, Ar-H).
8-Chloro-4-methyl-2-phenylpyrimido[4¢,5¢:4,5]furo[2,3-d]-
pyrimidine (25)
A sample of compound 24 (1 g) in phosphoryl chloride
(15 mL) was heated under reflux for 3 hours, then allowed to
cool and poured on ice-water mixture with stirring. The solid
product was collected and recrystallized from ethanol as yel-
lowish red crystals in 68% yield, mp 210-212 °C. Anal.
Calcd. for C15H9N4Ocl (296.71): C, 60.72; H, 3.06; N, 18.88;
Cl, 11.95. Found: C, 60.64; H, 2.97; N, 19.01; Cl, 11.78. IR: n
General procedure for the synthesis of 21, 22
A mixture of 5a or 5b (0.01 mol), ethyl cyanoacetate
(1.13 gm; 0.01 mol) and ammonium acetate (3 gm) was
refluxed for 3 hours. The solid product was collected and
recrystallized from dioxane as yellow crystals.
1
7-Cyano-4-methyl-2,8-diphenylpyrido[2¢,3¢:4,5]furo[2,3-d]-
pyrimidin-6-(5H)-one (21)
1580 (C=N) cm-1. H NMR (CDCl3): d 3.0 (s, 3H, CH3),
7.2-7.4 (m, 3H, Ar-H), 8.51-8.63 (m, 2H, Ar-H), 8.9 (s, 1H,
CH). Ms: m/z 296 (M+).
Produced in 61% yield, mp > 350 °C. Anal. Calcd. for
C23H14N4O2 (378.38): C, 73.01; H, 3.73; N, 14.81. Found: C,
72.86; H, 3.70; N, 14.80. IR: n 3150 (NH); 2200 (C=N); 1620
(C=O); 1580 (C=N) cm-1. 1H NMR (DMSO-d6): 2.9 (s, 3H,
CH3), 7.6-7.8, 8.4-8.5 (2m, 11H, NH and Ar-H).
8-Hydrazino-4-methyl-2-phenylpyrimido[4¢,5¢:4,5]furo-
[2,3-d]pyrimidine (26)
A sample of 25 (1 gm), hydrazine hydrate (2 mL) in eth-
anol (15 mL) was refluxed for 4 hours then allowed to cool.
The solid product was collected and recrystallized from etha-
nol as yellowish red crystals, in 71% yield, mp 218-220 °C.
Anal. Calcd. for C15H12N6O (292.30): C, 61.64; H, 4.14; N,
28.75. Found: C, 61.57; H, 4.21; N, 28.85. IR: n 3450, 3300,
3200 (NH, NH2); 1590 (C=N) cm-1. 1H NMR (DMSO-d6): d
3.0 (s, 3H, CH3), 3.5 (s, 2H, NH2), 7.56-7.57 (m, 3H, Ar-H),
8.47-8.50 (m, 2H, Ar-H), 8.57 (s, 1H, CH). 13C NMR
(DMSO-d6) 17.9, 121.3, 127.4, 127.7, 128.5, 129.4, 129.6,
135.8, 155.5, 156.4, 165.6, 165.9, 165.3, 166.4, 168.6.
7-Cyano-4,8-dimethyl-2-phenylpyrido[4¢,5¢:4,5]furo[2,3-d]-
pyrimidin-6(5H)-one (22)
Produced in 60% yield, mp > 350 °C. Anal. Calcd. for
C18H12N4O2 (316.70): C, 68.35; H, 3.82; N, 17.71. Found: C,
68.31; H, 3.85; N, 17.74. IR: n 3150 (NH); 2200 (C=N); 1630
(C=O); 1580 (C=N); Ms: m/z 316 (M+).
4-Methyl-8-oxo-5,6,7,8-tetrahydro-2,7-diphenylpyrimido-
[4¢,5¢:4,5]furo[2,3-d]pyrimidin-6-thione (23)
A mixture of 5c (1.5 gm; 0.005 mol), phenyl isothiocya-
nate (0.67 gm; 0.005 mol) in pyridine (30 mL) was refluxed
for 10 hours then allowed to cool at room temperature. The
solid product was filtered off and recrystallized from DMF as
yellow crystal in 56% yield, mp > 350 °C. Anal. Calcd. for
C21H14N4O2S (386.43): C, 65.27; H, 3.65; N, 14.50; S, 8.30.
Found: C, 65.24; H, 3.57; N, 14.45; S, 8.33. IR: n 3300 (NH);
1700 (C=O), 1590 (C=N) cm-1. 1H NMR (T.F.A): d 3.6 (s, 3H,
CH3), 7.4-8.5 (m, 10H, Ar-H).
Received February 9, 2004.
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