Ring closure reactions of pyrido[2,3-d]pyrimidines to pyrano[2′, 3′:4,5]- and oxazolo[5′,4′:4,5]pyrido[2,3-d]pyrimidines

Article abstract of DOI:10.1002/jhet.5570450517

(Chemical Equation Presented) The cyclocondensation of 5-hydroxy-pyrido[2, 3-d]pyrimidines 1 with malonates gives pyrano[2′,3′:4,5]-pyrido[2,3- d]pyrimidines 2. Nitration of 1 and reduction with zinc in the presence of carboxylic acids/anhydrides gave 2-a

Full text of DOI:10.1002/jhet.5570450517

Sep-Oct 2008
1359
Ring Closure Reactions of Pyrido[2,3-d]pyrimidines to
Pyrano[2',3':4,5]- and Oxazolo[5',4':4,5]pyrido[2,3-d]pyrimidines
Dang Van Tinha and Wolfgang Stadlbauer* b
aUniversity of Medicine and Pharmacy at Hochiminh City
41 Dinh Tien Hoang Str., Dist. 1, Ho Chi Minh City (Viet Nam)
b Institute of Chemistry, Organic Synthesis Group, Karl-Franzens University of Graz,
Heinrichstrasse 28, A-8010 Graz (Austria)
wolfgang.stadlbauer@uni-graz.at
Received January 11, 2008
O
R3
N
Ph
O
O
O
OH
O
OH
O
O
R1
O
R1
O
R1
O
NH2 * HCl
O
R1
O
N
N
N
N
OH
N
N
O
N
N
O
N
N
N
N
O
R1
R2
R1
R2
R1
R2
R1
R2
1
2
6
4, 9
The cyclocondensation of 5-hydroxy-pyrido[2,3-d]pyrimidines 1 with malonates gives pyrano[2',3':4,5]-
pyrido[2,3-d]pyrimidines 2. Nitration of 1 and reduction with zinc in the presence of carboxylic
acids/anhydrides gave 2-alkyloxazolo[5',4':4,5]pyrido[2,3-d]pyrimidines 4, which were ring-opened to 6-
aminopyrido[2,3-d]pyrimidines 5, 6 and 7. Cyclization of 6-aminopyrido[2,3-d]pyrimidines 6 with
benzoylchlorides 8 gave 2-aryloxazolo[5',4':4,5]pyrido[2,3-d]pyrimidines 9. Reaction conditions for the
cyclization have been studied by differential scanning calorimetry (DSC).
J. Heterocyclic Chem., 45, 1359 (2008).
INTRODUCTION
good yields in a ring closure reaction to six-membered
heterocycles
pyrano[2',3':4,5]pyrido[2,3-d]pyrimidines
Pyrido[2,3-d]pyrimidine derivatives form a class of
fused heterocyclic compounds which reveal interesting
pharmacological and biological properties. Thus, they
have been used as effective antitumor agents, as
antibacterial, anticonvulsant or enzyme inhibitors or as a
new class of antileishmanial agents [1]. Oxazolo-,
isoxazolo-, oxadiazolo- and indoloheterocycles in the
quinoline and pyrimidine series were investigated
thoroughly in the last decades and many representatives
were found which show antihypertensive and dopam-
inergic properties [2], antiulcer [3], anticancer [4],
antiallergic and antidepressive [5] or herbicidal activity
[6]. These findings prompted us to study the combination
of these biologically interesting nuclei by synthesis of
pyrido[2,3-d]pyrimidinetriones anellated to the f-side by
pyrano- and oxazolo rings. The ring closure reactions
intended for this project involve cyclocondensation
reactions of ortho-substituted hydroxy-pyrido[2,3-d]py-
rimidinetriones with C1- or C3-fragments leading to
pyrano- and oxazolo-derivatives.
2a-c. The cyclization was carried out in diphenylether
solution and can be observed to proceed in two steps: in
the first step by liberation of one equivalent of ethanol
trans-esterification of the malonate with the hydroxy-
heterocycle 1 takes place. In the next step, at high
temperatures an internal cleavage of ethanol takes place to
form a ketene-ester moiety from the malonate part, which
reacts thermally without catalyst with the heteroaromatic
position 6 of the pyrido[2,3-d]pyrimidine, similar as
observed earlier with other heterocyclic systems [10].
This mechanism is supported by findings, that 1a-c with
alkylmalonates or unsubstituted malonate gave either no
ring closure products or only decomposition products
depending on the substituents and reaction conditions,
which can be explained in terms of the formation of the
ketene intermediate, which is facilitated by the phenyl
substituent of phenylmalonate forming 2a-c, but hindered
by alkyl substituents in alkylmalonates, and giving
multiple condensation reactions with unsubstituted
malonates.
A further ring closure sequence was intended starting
from ortho-aminosubstituted hydroxyheterocycles as
1,4-dinucleophiles, which can be cyclized with electro-
philic C1-fragments to five membered heterocycles. The
pathway to ortho-amino derivatives was planned to lead
via an ortho-nitro group. Nitration of similar pyrido[2,3-
RESULTS AND DISCUSSION
The syntheses started from 6-unsubstituted 5-hydroxy-
pyrido[2,3-d]pyrimidines 1a-c [7]. The thermal cyclo-
condensation of 1a-c as 1,3-dinucleophiles with diethyl
phenylmalonate as an electrophilic C3-fragment gave in

1360
D. V. Tinh and W. Stadlbauer
Vol 45
d]pyrimidines at elevated temperatures was reported
earlier [8a,b]. The nitration of 1a-c with fuming nitric acid
and sodium nitrite as catalyst in acetic acid gave already
at room temperature 6-nitropyrido[2,3-d]pyrimidine-
triones 3. These mild conditions can be explained by
initial nitrosation of 1 with sodium nitrite and subsequent
oxidation to the desired nitro group [8c]. The conversion
of the nitro group of 6-nitropyrido[2,3-d]pyrimidines 3a-c
to a 6-amino group was planned by reduction with zinc
dust in the presence of acetic anhydride. In this way stable
6-acetylamino-5-hydroxy-pyrido[2,3-d]pyrimidine-2,4,7-
triones 5 should be obtained which avoids the isolation of
the sensitive free amino derivatives such as 6 or 7.
The transformation of oxazolo[5',4':4,5]pyrido[2,3-d]-
pyrimidinetriones 4a-c to amino derivatives could be
achieved by kinetically controlled acid catalyzed ring
opening. The reaction with 0.5 M hydrochloric acid in
ethanolic solution gave after 45-60 minutes the
6-acetylamino-5-hydroxy-pyrido[2,3-d]pyrimidinetriones
5 together with small amounts of amino hydrochlorides 6.
Extraction of the mixture with chloroform gave in good
yields acetylamino compounds 5a,b. When the reaction
time was extended to 6-10 hours, the hydrochlorides of
the
6-amino-5-hydroxy-pyrido[2,3-d]pyrimidinetriones
6a-c were isolated, which were rather stable and allowed
us to record all physical and spectroscopical data. To
obtain the free amino bases from hydrochlorides 6, the
salts 6a-c were dissolved in water and extracted with
chloroform. This allowed the isolation of the free amino
bases 7b,c, whereas the isolation of the free amino base
7a failed. Attempts to liberate the free amino bases 7 from
hydrochlorides 6 by addition of sodium hydroxide as a
base failed due to decomposition.
Scheme 1
COOEt
O
Ph CH
Ph
O
O
COOEt
Ph2O
260 oC, 2 h
R1
O
N
OH
73-80%
N
N
O
O
OH
R1
R2
Scheme 2
R1
O
N
2a-c
O
OH
O
OH
H O HCl
/
H
N
2
N
R1
N
R2
O
R1
O
CH3
R1
O
NO2
O
reflux, 45-60 min
C
O
HNO
3 / AcOH
N
N
Me
N
20 °C, 1 h
85-92%
1a-c
61-65%
N
N
O
N
N
O
O
R1
R2
Me Me
Me
R1
R2
R1
R2
1-3
a
b
c
R1
O
N
5a,b
3a-c
Ph
Ph Me
O
OH
R3COOH
reflux, 12 h
85-92%
Zn /
(R3CO)2O
N
R1
N
R2
O
R1
O
NH2 * HCl
O
H O HCl
/
2
N
reflux, 6-10 h
R3
4a-c
R1 R2 R3
4
N
R1
N
R2
O
O
N
94-97%
Me
Me Me
Me Ph Me
Ph Me Me
a
b
c
d
e
f
R1
O
N
6a-c
R1
R2
4-7
Me Et
Ph Et
Me Et
Me
Me
Ph
N
R1
N
R2
O
a
b
c
Me Me
Me Ph
Ph Me
CHCl3
H2O
91-94%
4a-f
O
N
OH
R1
O
NH2
However, acetylamino derivatives 5 could not be
obtained in a pure form from 6-nitropyrido[2,3-d]-
pyrimidines 3, because the acetyl group acts already as a
reactive C1-fragment and a consecutive ring closure to
oxazolo[5',4':4,5]pyrido[2,3-d]pyrimidinetriones 4 occurr-
ed before the reduction to 5 was completed. Therefore we
synthesized 2-alkyloxazolo[5',4':4,5]pyrido[2,3-d]pyrimi-
dines 4a-f both as stable intermediates for the generation
of further amino derivatives and as cyclization examples
of alkyl-substituted oxazoles. This synthesis pathway led
directly from 6-nitro compounds 3 with zinc dust in
mixtures of acetic or propionic acid and their anhydrides
by heating under reflux to oxazoles 4. Attempts to apply
another method for the reduction of the nitro group of 3a-
c to amines using sodium dithionite as reduction agent,
which we have used successfully earlier in the 4-hydroxy-
3-nitro-quinolone series [9], failed.
N
R1
N
R2
O
7b,c
For further ring closure reactions, amine hydrochlorides
6a-c have been found as the most suitable reagents, both
stable enough and reactive towards benzoic acid
derivatives as arylsubstituted C-1 fragments. The ring
closure reaction of amine hydrochlorides 6a-c with the
appropriately substituted benzoyl chlorides 8a-h were
intended to be carried out in polyphosphoric acid. Suitable
reaction conditions were determined by means of
differential scanning calorimetry (DSC), a method used
successfully earlier for the investigation of reaction
conditions [11]. The DSC diagram of a 1:1 mixture of the
amino hydrochloride 6a and benzoyl chloride 8a in

Sep-Oct 2008
Ring Closure Reactions of Pyrido[2,3-d]pyrimidines to
Pyrano[2',3':4,5]- and Oxazolo[5',4':4,5]pyrido[2,3-d]pyrimidines
1361
polyphosphoric acid (Figure 1) shows an onset at 123 °C
and a peak maximum at 153 °C.
In conclusion, the synthesis of several new fused
pyrido[2,3-d]pyrimidines is described, having as anellated
ring either a six-membered pyrano ring, or a five-
membered oxazole ring. The cyclization reaction takes
place by cyclocondensation of bifunctional pyrido[2,3-d]-
pyrimidines with carboxylic acid derivatives applied
either as C1 or C3 fragments. Reaction conditions were
studied in advance by differential scanning calorimetry
(DSC).
EXPERIMENTAL
Melting points were obtained on a Gallenkamp Melting Point
1
Aparatus, Mod. MFB 595 in open capillary tubes. H and 13C
nmr spectra were recorded on a Bruker AMX 360 instrument
(360 or 90 MHz) or on a Bruker Avance DRX 500 instrument
(500 or 125 MHz). Chemical shifts are reported in ppm from
internal tetramethylsilan standard and are given in ꢀ-units. The
solvent was CDCl3 unless otherwise stated. Infrared spectra were
taken on a Mattson Galaxy Series FTIR 7020 instrument with
potassium bromide discs. Elemental analyses were performed on
a Fisons EA 1108 C,H,N-automatic analyzer and are within ±
0.4 of the theoretical percentages. Calorimetric data were
obtained on a Rheometric Scientific DSC-Plus instrument with
the software Orchestrator V6.5.8. between 25 - 700 °C, a heating
rate of 2-10 °C/min, and 1.5-3 mg compound in sealed
aluminium crucibles (11 bar).
Figure 1. Differential scanning diagram of the reaction of salt 6a with
benzoylchloride 8a and polyphosphoric acid.
Similar findings were obtained with a mixture of the
salts 6b,c and benzoyl chloride 8a (onset: 120-125 °C,
peak maximum 155-160 °C). Reaction mixtures of amine
hydrochlorides 6a-c and acetyl chloride, which were
investigated for comparison, showed remarkable lower
onset points of about 60-80° C (peak maximum at 95-115
°C), followed by a second exothermic signal (peak
maximum: 150-160 °C), which explains the quick
cyclization reaction during the reduction of nitro
compounds 3 to oxazoles 4. In a preparative scale, the
reaction of amine hydrochlorides 6a-c and benzoyl
chlorides 8a-h in polyphosphoric acid gave in good yields
at 150 °C as cyclization products the 2-aryloxazolo-
[5',4':4,5]pyrido[2,3-d]pyrimidines 9a-o.
5-Hydroxy-1,3,8-trimethyl-pyrido[2,3-d]pyrimidine-2,4,7-tri-
one (1a), 5-hydroxy-1,3-dimethyl-8-phenyl-pyrido[2,3-d]pyrim-
idine-2,4,7-trione (1b) and 5-hydroxy-8-methyl-1,3-diphenylpy-
rido[2,3-d]pyrimidine-2,4,7-trione (1c) were obtained according
to ref. [7].
4-Hydroxy-6,7,9-trimethyl-3-phenyl-2H-pyrano[2',3':4,5]
pyrido[2,3-d]pyrimidine-2,5,8,10(6H,7H,9H)-tetrone (2a). A
mixture of 5-hydroxypyrido[2,3-d]pyrimidinetrione 1a (2.37 g,
10 mmol) and diethyl phenylmalonate (4.72 g, 20 mmol) in
diphenylether (15 mL) was heated for 2 hours to 250-260 °C
using a short air condenser to remove the liberated ethanol. After
cooling, the reaction mixture was digested with cyclohexane (50
mL), the obtained precipitate was collected by filtration, washed
with cold cyclohexane and dried. Then the precipitate was
boiled with ethanol for 10 minutes, cooled, collected by suction
filtration, washed with ethanol and recrystallized from
dimethylformamide. The yield was 2.8 g (73%), yellow prisms,
mp 310-312 °C (dimethylformamide); ir: 1720 s, 1680 s, 1655 s
Scheme 3
R4
O
OH
8
a
R3
H
R1
O
NH2 * HCl
O
H
H
H
H
H
4-Cl
4-Cl
N
b 4-Me
c
d
e
f
4-OMe
4-Cl
4-NO2
2-Cl
3-Cl
N
R1
N
R2
6a-c
g
1
cm-1; H nmr: ꢀ 3.46 (s, 3 H, NMe), 3.70 (s, 6 H, NMe), 7.25-
h
2-OMe 6-OMe
R3
7.45 (m, 5 H, PhH), 12.40 (s, 1 H, OH). Anal. Calcd. for
C19H15N3O6 (381.35): C, 59.84; H, 3.96; N, 11.02. Found: C,
59.45; H, 3.93; N, 11.05.
PPA
COCl
150 oC, 4 h
9
a
R1 R2 R3
Me Me
b Me
c Me
R4
H
H
H
R4
H
68-78%
Me 4-Me
Me
8a-h
4-Hydroxy-7,9-dimethyl-3,6-diphenyl-2H-pyrano[2',3':4,5]
pyrido[2,3-d]pyrimidine-2,5,8,10(6H,7H,9H)-tetrone (2b).
This compound was obtained from 5-hydroxypyrido[2,3-d]-
pyrimidinetrione 1b (2.99 g, 10 mmol) according to the
procedure described for 2a; the yield was 3.54 g (80%), yellow
prisms, mp 320 °C (dimethylformamide); ir: 1750 s, 1720 s,
1685 s, 1665 s cm-1; 1H nmr (CF3COOD): ꢀ 2.78 (s, 3 H, NMe),
3.30 (s, 3 H, NMe), 7.19-7.22 (m, 7 H, ArH), 7.42-7.44 (m, 3 H,
ArH). Anal. Calcd. for C24H17N3O6 (443.42): C, 65.01; H, 3.86;
N, 9.48. Found: C, 64.67; H, 3.85; N, 9.70.
4-OMe
R4
d
Me Me 4-Cl
H
H
H
H
H
e
Me Me 4-NO2
Ph
f Me
g
h
i
H
R3
Me Ph 4-Me
Me Ph 4-Cl
Me Ph 4-NO2
O
O
R1
N
H
4-Cl
2-Cl
Me Me 3-Cl
H
4-Cl
4-Cl
N
j Ph Me
k
Me Me
O
N
R1
N
R2
O
l
m
Me Me 2-OMe 6-OMe
2-Cl
3-Cl
n Me Ph
4-Cl
4-Cl
o
Me Ph
9a-o

1362
D. V. Tinh and W. Stadlbauer
Vol 45
4-Hydroxy-6-methyl-3,7,9-triphenyl-2H-pyrano[2',3':4,5]-
1H nmr ꢀ 2.70 (s, 3 H, NMe), 2.83 (s, 3 H, NMe), 3.44 (s, 3 H,
NMe), 7.30-7.35 (m, 2 H, PhH), 7.55-7.57 (m, 3 H, PhH). Anal.
Calcd. for C17H14N4O4 (338.33): C, 60.35; H, 4.17; N, 16.56.
Found: C, 60.59; H, 4.03; N, 16.69.
pyrido[2,3-d]pyrimidine-2,5,8,10 (6H,7H,9H)-tetrone (2c).
This compound was obtained from 5-hydroxypyrido[2,3-d]-
pyrimidinetrione 1c (3.61 g, 10 mmol) according to the
procedure described for 2a; the yield was 3.8 g (75%), yellow
prisms, mp 301-303 °C (toluene); ir: 1720 s, 1690 s, 1660 s cm-
2,5-Dimethyl-6,8-diphenyl[1,3]oxazolo[5',4':4,5]pyrido-
[2,3-d]pyrimidine-4,7,9(5H,6H,8H)-trione (4c). This
compound was obtained from 5-hydroxy-6-nitropyrido[2,3-d]-
pyrimidinetrione 3c (4.06 g, 10 mmol) according to the
procedure described for 4a; the yield was 3.40 g (85%) colorless
prisms, mp 352 °C (dimethylformamide); ir: 1730 m, 1690 s,
1620 m cm-1; 1H nmr ꢀ 2.68 (s, 3 H, NMe), 3.05 (s, 3 H, NMe),
7.25-7.50 (m, 10 H, ArH). Anal. Calcd. for C22H16N4O4 (400.40):
C, 66.00; H, 4.03; N, 13.99. Found: C, 65.89; H, 3.93; N, 13.97.
2-Ethyl-5,6,8-trimethyl[1,3]oxazolo[5',4':4,5]pyrido[2,3-d]-
pyrimidine-4,7,9(5H,6H,8H)-trione (4d). This compound was
obtained from 5-hydroxy-6-nitropyrido[2,3-d]pyrimidine-
trione 3a (2.82 g, 10 mmol) according to the procedure
described for 4a; the yield was 2.20 g (76%), colorless prisms,
mp 369 °C (dimethylformamide/ethanol); ir: 1720 m, 1690 s,
1
1; H nmr (CDCl3): ꢀ 3.00 (s, 3 H, NMe), 7.30-7.60 (m, 15 H,
ArH), 12.45 (s, 1 H, OH). Anal. Calcd. for C29H19N3O6 (505.49):
C, 68.91; H, 3.79; N, 8.31. Found: C, 68.72; H, 3.66; N, 8.26.
5-Hydroxy-1,3,8-trimethyl-6-nitropyrido[2,3-d]pyrimid-
ine-2,4,7(1H,3H,8H)-trione (3a). A suspension of 5-hydroxy-
pyrido[2,3-d]pyrimidinetrione 1a (18.00 g, 76 mmol) in glacial
acetic acid (140 mL) was treated with fuming nitric acid (14.0
mL, 213 mmol) and then with sodium nitrite (0.40 g, 5.8 mmol)
to start the slightly exothermic reaction. The starting material
dissolved, followed immediately by precipitation of the product.
The mixture was stirred for 60 minutes at 20 °C and diluted with
ice water (1 L). The product was collected by suction filtration,
washed with water (200 mL) and dried. The yield was 19.00 g
(89%), yellow prisms, mp 223-225 °C (dimethylformamide/
1
1660 s, 1620 m cm-1; H nmr: ꢀ 1.40 (t, 3 H, J = 7 Hz, ethyl-
1
ethanol); ir: 1720 s, 1670 s cm-1; H nmr ꢀ 3.39 (s, 3 H, NMe),
CH3), 2.93 (q, 2 H, J = 7 Hz, ethyl-CH2), 3.41 (s, 3 H, NMe),
3.61 (s, 3 H, NMe), 3.68 (s, 3 H, NMe). Anal. Calcd. for
C13H14N4O4 (290.28): C, 53.79; H, 4.86; N, 19.30. Found: C,
53.81; H, 4.86; N, 19.16.
3.53 (s, 3 H, NMe), 3.55 (s, 3 H, NMe). Anal. Calcd. for
C10H10N4O6 (282.21): C, 42.56; H, 3.57; N, 19.85. Found: C,
42.38; H, 3.60; N, 19.76.
5-Hydroxy-1,3-dimethyl-6-nitro-8-phenylpyrido[2,3-d]pyr-
imidine-2,4,7(1H,3H,8H)-trione (3b). This compound was
obtained from 5-hydroxypyrido[2,3-d]pyrimidinetrione 1b
(22.70 g, 76 mmol) according to the procedure described for 3a;
the yield was 22.00 g (84%), yellow prisms, mp 246-249 °C
(dimethylformamide/ethanol); ir: 1725 s, 1700 s, 1660 s cm-1; 1H
nmr ꢀ2.66 (s, 3 H, NMe), 3.30 (s, 3 H, NMe), 7.57-7.60 (m, 5
H, PhH). Anal. Calcd. for C15H12N4O6 (344.29): C, 52.33; H,
3.51; N, 16.27. Found: C, 52.28; H, 3.50; N, 16.15.
5-Hydroxy-8-methyl-6-nitro-1,3-diphenylpyrido[2,3-d]pyr-
imidine-2,4,7(1H,3H,8H)-trione (3c). This compound was
obtained from 5-hydroxypyrido[2,3-d]pyrimidinetrione 1c
(26.80 g, 76 mmol) according to the procedure described for 3a;
the yield was 28.00 g (91 %), yellow prisms, mp 283-285 °C
(dimethylformamide/ethanol); ir: 1740 s, 1670 s cm-1; 1H nmr ꢀ
2.76 (s, 3 H, NMe), 7.40-7.59 (m, 10 H, ArH). Anal. Calcd. for
C20H14N4O6 (406.36): C, 59.12; H, 3.47; N, 13.79. Found: C,
59.40; H, 3.47; N, 13.88.
2,5,6,8-Tetramethyl[1,3]oxazolo[5',4':4,5]pyrido[2,3-d]pyr-
imidine-4,7,9(5H,6H,8H)-trione (4a). A mixture of 5-hy-
droxy-6-nitropyrido[2,3-d]pyrimidinetrione 3a (2.82 g, 10
mmol) and zinc dust (46 mmol, 3.0 g) in glacial acetic acid (70
mL) and acetic anhydride (48 mL) was heated under reflux for
12 hours. The hot reaction mixture was filtered still hot, then the
filtrate was taken to dryness in vacuo and the residue triturated
with ethanol (50 mL). The solid product was collected by
filtration, washed with ethanol and dried. The yield was 2.30 g
(83%), colorless prisms, mp 282 °C (dimethylformamide); ir:
1720 s, 1690 s, 1665 s cm-1; 1H nmr: ꢀ 2.68 (s, 3 H, NMe), 3.43
(s, 3 H, NMe), 3.63 (s, 3 H, NMe), 3.70 (s, 3 H, NMe). Anal.
Calcd. for C12H12N4O4 (276.25): C, 52.17; H, 4.38; N, 20.28.
Found: C, 52.02; H, 4.35; N, 20.30.
2,6,8-Trimethyl-5-phenyl[1,3]oxazolo[5',4':4,5]pyrido[2,3-d]-
pyrimidine-4,7,9(5H,6H,8H)-trione (4b). This compound was
obtained from 5-hydroxy-6-nitropyrido[2,3-d]pyrimidine-trione
3b (3.44 g, 10 mmol) according to the procedure described for
4a; the yield was 2.90 g (86%), colorless prisms, mp 318 °C
(dimethylformamide); ir: 1730 m, 1700 s, 1665 s, 1620 m cm-1;
2-Ethyl-6,8-dimethyl-5-phenyl[1,3]oxazolo[5',4':4,5]pyrido-
[2,3-d]pyrimidine-4,7,9(5H,6H,8H)-trione (4e). This compound
was obtained from 5-hydroxy-6-nitropyrido[2,3-d]-pyrimidine-
trione 3b (3.44 g, 10 mmol) according to the procedure
described for 4a; the yield was 2.64 g (75%), colorless prisms,
mp 280-282 °C (dimethylformamide); ir: 1720 w, 1690 s, 1655
s, 1620 s cm-1; 1H nmr ꢀ 1.42 (t, 3 H, J = 7 Hz, ethyl-CH3), 2.81
(s, 3 H, NMe), 2.95 (q, 2 H, J = 7 Hz, ethyl-CH2), 3.45 (s, 3 H,
NMe), 7.30-7.34 (m, 2 H, ArH), 7.50-7.52 (m, 3 H, ArH). Anal.
Calcd. for C18H16N4O4 (352.35): C, 61.36; H, 4.58; N, 15.90.
Found: C, 61.16; H, 4.51; N, 15.97.
2-Ethyl-5-methyl-6,8-diphenyl[1,3]oxazolo[5',4':4,5]pyr-
ido[2,3-d]pyrimidine-4,7,9(5H,6H,8H)-trione (4f). This
compound was obtained from 5-hydroxy-6-nitropyrido[2,3-d]-
pyrimidinetrione 3c (4.06 g, 10 mmol) according to the
procedure described for 4a; the yield was 3.10 g (75%),
colorless prisms, mp 307-309 °C (dimethylformamide); ir: 1730
m, 1690 s, 1625 m cm-1; 1H nmr ꢀ 1.40 (t, 3 H, J = 7 Hz, ethyl-
CH3), 2.94 (q, 2 H, J = 7 Hz, ethyl-CH2), 3.07 (s, 3 H, NMe),
7.28-7.48 (m, 10 H, ArH). Anal. Calcd. for C23H18N4O4 (414.42):
C, 66.66; H, 4.38; N, 13.52. Found: C, 66.65; H, 4.27; N, 13.50.
N-(5-Hydroxy-1,3,8-trimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexa-
hydropyrido[2,3-d]pyrimidin-6-yl)acetamide (5a). A mixture
of oxazolo[5',4':4,5]pyrido[2,3-d]pyrimidinetrione 4a (2.76 g, 10
mmol) in 0.2 M hydrochloric acid (100 mL) and ethanol (80
mL) was heated under reflux for about 45 minutes (until a
solution was obtained). The reaction mixture was filtered and
the filtrate taken to dryness under reduced pressure. The residue
was diluted with water (50 mL) and the aqueous solution
extracted with chloroform (3 x 50 mL). From the aqueous layer
6-aminopyrido[2,3-d]pyrimidinetrione hydrochloride 6a could
be isolated (work up described at 6a, method A). The organic
layer was dried over sodium sulfate and the solvent removed in
vacuo. The crystalline residue was dried by the addition and
destillative removal of abs. ethanol (2 x 50 mL). The yield was
1.80 g (61%) colorless prisms, mp 222-223 °C (ethanol); ir:
1
3200 w, 1710 m, 1650 s cm-1; H nmr: ꢀ 2.20 (s, 3 H, acetyl-
CH3), 3.40 (s, 3 H, NMe), 3.56 (s, 6 H, 2 NMe), 6.87 (s, 1 H,

Sep-Oct 2008
Ring Closure Reactions of Pyrido[2,3-d]pyrimidines to
Pyrano[2',3':4,5]- and Oxazolo[5',4':4,5]pyrido[2,3-d]pyrimidines
1363
NH), 12.40 (s, OH). Anal. Calcd. for C12H14N4O5 (294.27): C,
48.98; H, 4.80; N, 19.04. Found: C, 49.36; H, 4.56; N, 18.78.
N-(5-Hydroxy-1,3-dimethyl-2,4,7-trioxo-8-phenyl-1,2,3,4,
7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl)acetamide (5b).
This compound was obtained from oxazolo[5',4':4,5]-pyrido[2,3-
d]pyrimidinetrione 4b (3.38 g, 10 mmol) according to the
method described for 5a; the yield was 2.32 g (65%), colorless
prisms, mp 233-235 °C (ethanol); ir: 3280 m, 2950 w, 1720 m,
ArH), 11.69 (s, 1 H, OH). Anal. Calcd. for C15H14N4O4 (314.30):
C, 57.32; H, 4.49; N, 17.83. Found: C, 56.94; H, 4.31; N, 17.45.
6-Amino-5-hydroxy-8-methyl-1,3-diphenyl-pyrido[2,3-d]-
pyrimidine-2,4,7(1H,3H,8H)-trione (7c). This compound was
obtained from 6-amino-5-hydroxy-pyrido[2,3-d]pyrimidine-
trione hydrochloride 6c (4.13 g, 10 mmol) according to the
method described for 7b; the yield was 3.54 g (94%), yellow
prisms, mp 258-260 °C (ethanol); ir: 3440 m, 3350 m, 1710 s,
1685 s, 1650 s, 1610 m cm-1; 1H nmr: ꢀ 2.98 (s, 3 H, NMe), 3.75
(s, 2 H, NH2), 7.28-7.47 (m, 10 H, ArH), 11.13 (s, 1 H, OH).
Anal. Calcd. for C20H16N4O4 (376.37): C, 63.83; H, 4.28; N,
14.89. Found: C, 63.71; H, 4.24; N, 14.78.
General Procedure for the Preparation of Oxazolo-
[5',4':4,5]pyrido[2,3-d]pyrimidinetriones 9a-o. A mixture of
the corresponding 6-amino-5-hydroxypyrido[2,3-d]pyrimidine-
trione hydrochloride 6a-c (10 mmol) with the appropriate
substituted benzoyl chloride 8a-h (20 mmol) in polyphosphoric
acid (20.00 g) was heated to 150 °C for 4 hours. The warm
reaction mixture was poured into ice/water (400 mL), brought to
pH 6-7 with aqueous concentrated sodium hydroxide. The
formed precipitate was collected by suction filtered, washed
with water and dried. The obtained colorless crystals were
recrystallized from dimethylformamide.
1
1690 s, 1640 s cm-1; H nmr: ꢀ 2.04 (s, 3 H, acetyl-CH3), 2.38
(s, 3 H, NMe), 2.70 (s, 3 H, NMe), 6.48 (s, 1 H, NH), 6.63-6.65
(m, 2 H, PhH), 6.73-6.74 (m, 3 H, PhH), 12.35 (s, OH). Anal.
Calcd. for C17H16N4O5 (356.34): C, 57.30; H, 4.53; N, 15.72.
Found: C, 57.56; H, 4.51; N, 15.44.
6-Amino-5-hydroxy-1,3,8-trimethylpyrido[2,3-d]pyrimid-
ine-2,4,7(1H,3H,8H)-trione hydrochloride (6a). Method A.
From the aqueous layer during the work-up of 5a 6-amino-
pyrido[2,3-d]pyrimidinetrione hydrochloride 6a was isolated: The
aqueous layer was taken to dryness at reduced pressure, and the
residue dried by the addition and destillative removal of abs.
ethanol (2 x 50 mL). The yield was 1.00 g (33%), colorless prisms.
Method B. A mixture of oxazolo[5',4':4,5]pyrido[2,3-d]-
pyrimidinetrione 4a (2.76 g, 10 mmol) in 0.5 M hydrochloric
acid (100 mL) and ethanol (80 mL) was heated under reflux for
8 hours. The reaction mixture was taken to dryness under
reduced pressure. The crystalline residue was dried by the
addition and removal of two portions of abs. ethanol (50 mL).
The yield was 2.70 g (94%), colorless prisms, mp 212 °C
5,6,8-Trimethyl-2-phenyl[1,3]oxazolo[5',4':4,5]pyrido[2,3-d]-
pyrimidine-4,7,9(5H,6H,8H)-trione (9a). The yield was 2.64 g
1
(78%), mp 318 °C; ir: 1720 m, 1695 s, 1670 s, 1620 s cm-1; H
nmr (CF3COOD): ꢀ 3.63 (s, 3 H, NMe), 3.85 (s, 3 H, NMe),
3.94 (s, 3 H, NMe), 7.65-7.83 (m, 3 H, PhH), 8.29-8.33 (m, 2 H,
PhH). Anal. Calcd. for C17H14N4O4 (338.33): C, 60.35; H, 4.17;
N, 16.56. Found: C, 60.33; H, 4.04; N, 16.70.
1
(ethanol); ir: 1720 w, 1650 w cm-1; H nmr (D2O): ꢀ 3.30 (s, 3
H, NMe), 3.55 (s, 3 H, NMe), 3.58 (s, 3 H, NMe). Anal. Calcd.
for C10H13ClN4O4 (288.69): C, 41.61; H, 4.54; N, 19.41. Found:
C, 41.98; H, 4.18; N, 19.76.
5,6,8-Trimethyl-2-(4-methylphenyl)[1,3]oxazolo[5',4':4,5]-
pyrido[2,3-d]pyrimidine-4,7,9(5H,6H,8H)-trione (9b). The
yield was 2.72 g (76%), mp 319 °C; ir: 1720 w, 1690 s, 1665 s,
6-Amino-5-hydroxy-1,3-dimethyl-8-phenyl-pyrido[2,3-d]-
pyrimidine-2,4,7(1H,3H,8H)-trione hydrochloride (6b). This
compound was obtained from oxazolo[5',4':4,5]pyrido[2,3-d]-
pyrimidinetrione 4b (3.38 g, 10 mmol) according to the
procedure described for 6a (method B); the yield was 3.40 g
(95%), colorless prisms, mp 150 °C (ethanol); ir: 1720 w, 1670
1
1620 s cm-1; H nmr (CF3COOD): ꢀ 2.50 (s, 3 H, 4'-Me), 3.58
(s, 3 H, NMe), 3.81 (s, 3 H, NMe), 3.92 (s, 3 H, NMe), 7.48 and
8.20 (2 d, J = 7 Hz, AA'BB' pattern, 4 H, PhH). Anal. Calcd. for
C18H16N4O4 (352.35): C, 61.36; H, 4.58; N, 15.90. Found: C,
61.19; H, 4.48; N, 15.94.
1
m cm-1; H nmr (D2O): ꢀ 2.78 (s, 3 H, NMe), 3.35 (s, 3 H,
NMe), 7.33-7.40 (m, 2 H, ArH), 7.57-7.60 (m, 3 H, ArH). Anal.
Calcd. for C15H15ClN4O4 (350.76): C, 51.36; H, 4.31; N, 15.97.
Found: C, 51.72; H, 3.97; N, 15.58.
2-(4-Methoxyphenyl)-5,6,8-trimethyl[1,3]oxazolo-[5',4':4,
5]pyrido[2,3-d]pyrimidine-4,7,9(5H,6H,8H)-trione (9c). The
yield was 2.39 g (65%), mp 317 °C; ir: 1720 w, 1690 s, 1660 s,
1610 s cm-1; 1H nmr (CF3COOD): ꢀ 3.60 (s, 3 H, NMe), 3.80 (s,
3 H, NMe), 3.95 (s, 3 H, NMe), 4.02 (s, 3 H, 4'-OMe), 7.20 and
8.32 (2 d, J = 7 Hz, AA'BB' pattern, 4 H, PhH). Anal. Calcd. for
C18H16N4O5 (368.35): C, 58.69; H, 4.38; N, 15.21. Found: C,
58.41; H, 4.19; N, 15.00.
2-(4-Chlorophenyl)-5,6,8-trimethyl[1,3]oxazolo[5',4':4,5]-
pyrido[2,3-d]pyrimidine-4,7,9(5H,6H,8H)-trione (9d). The
yield was 2.76 g (74%), mp 336 °C; ir: 1720 m, 1690 s, 1665 s,
1620 s cm-1; 1H nmr (CF3COOD): ꢀ 3.58 (s, 3 H, NMe), 3.80 (s, 3
H, NMe), 3.92 (s, 3 H, NMe), 7.60 and 8.18 (2 d, J = 7 Hz, AA'BB'
pattern, 4 H, PhH). Anal. Calcd. for C17H13ClN4O4 (372.77): C,
54.78; H, 3.52; N, 15.03. Found: C, 54.51; H, 3.25; N, 14.90.
5,6,8-Trimethyl-2-(4-nitrophenyl)[1,3]oxazolo[5',4':4,5]-
pyrido[2,3-d]pyrimidine-4,7,9(5H,6H,8H)-trione (9e). The
yield was 2.72 g (71%), mp 350 °C; ir: 1720 m, 1690 s, 1660 s,
1620 s cm-1; 1H nmr (DMSO-d6): ꢀ 2.69 (s, 3 H, NMe), 3.17 (s, 3
H, NMe), 3.61 (s, 3 H, NMe), 8.33 and 8.42 (2 d, J = 7 Hz,
AA'BB' pattern, 4 H, PhH). Anal. Calcd. for C17H13N5O6 (383.32):
C, 53.27; H, 3.42; N, 18.27. Found: C, 53.52; H, 3.18; N, 18.36.
6,8-Dimethyl-2,5-diphenyl[1,3]oxazolo[5',4':4,5]pyrido-
[2,3-d]pyrimidine-4,7,9(5H,6H,8H)-trione (9f). The yield was
6-Amino-5-hydroxy-8-methyl-1,3-diphenylpyrido[2,3-d]-
pyrimidine-2,4,7(1H,3H,8H)-trione hydrochloride (6c). This
compound was obtained from oxazolo[5',4':4,5]pyrido[2,3-d]-
pyrimidinetrione 4c (4.00 g, 10 mmol) according to the
procedure described for 6a (method B); the yield was 4.00 g
(97%), colorless prisms, mp 170 °C (ethanol); ir: 1730 m, 1660 s
1
cm-1; H nmr (D2O): ꢀ 2.80 (s, 3 H, NMe), 7.25-7.45 (m, 10 H,
ArH). Anal. Calcd. for C20H17ClN4O4 (412.84): C, 58.19; H,
4.15; N, 13.57. Found: C, 57.79; H, 3.87; N, 13.88.
6-Amino-5-hydroxy-1,3-dimethyl-8-phenylpyrido[2,3-d]-
pyrimidine-2,4,7(1H,3H,8H)-trione (7b). A solution of 6-
amino-5-hydroxypyrido[2,3-d]pyrimidinetrione hydrochloride
6b (3.50 g, 10 mmol) and water (30 mL) was extracted with
chloroform (3 x 50 mL), dried over sodium sulfate and the
solution was taken to dryness. In this way the free base 7b was
obtained. The residue was treated with ethanol, and the
precipitate was collected by filtration and dried at room
temperature in vacuo. The yield was 2.86 g (91%), yellow
prisms, mp 250-252 °C (ethanol); ir: 3450 w, 3360 w, 1720 s,
1700 s, 1660 s, 1610 m cm-1; 1H nmr: ꢀ 2.81 (s, 3 H, NMe), 3.45
(s, 3 H, NMe), 7.29-7.32 (m, 2 H, ArH), 7.49-7.56 (m, 3 H,

1364
D. V. Tinh and W. Stadlbauer
Vol 45
1
2.92 g (73%), mp 312 °C; ir: 1730 m, 1700 s, 1665 s, 1620 s
1
1610 s. cm-1; H nmr (CF3COOD): ꢀ 3.00 (s, 3 H, NMe), 3.65
(s, 3 H, NMe), 7.40 (d, J = 7 Hz, 1 H, ArH), 7.45-7.64 (m, 5 H,
ArH), 7.65 (s, 1 H, ArH), 8.05 (d, J = 7 Hz, 1 H, ArH). Anal.
Calcd. for C22H14Cl2N4O4 (469.29): C, 56.31; H, 3.01; N, 11.94.
Found: C, 56.26; H, 2.80; N, 11.89.
cm-1; H nmr (CF3COOH): ꢀ 3.12 (s, 3 H, NMe), 3.71 (s, 3 H,
NMe), 7.51-7.56 (m, 2 H, ArH), 7.71-7.88 (m, 6 H, ArH), 8.38-
8.42 (m, 2 H, ArH). Anal. Calcd. for C22H16N4O4 (400.40): C,
66.00; H, 4.03; N, 13.99. Found: C, 66.28; H, 3.82; N, 13.81.
6,8-Dimethyl-2-(4-methylphenyl)-5-phenyl[1,3]oxazolo-
[5',4':4,5]pyrido[2,3-d]pyrimidine-4,7,9(5H,6H,8H)-trione
(9g). The yield was 3.15 g (76%), mp 304 °C; ir: 1690 s, 1665 s,
1610 s cm-1; 1H nmr (CF3COOD): ꢀ 2.43 (s, 3 H, 4-Me), 2.85 (s,
3 H, NMe), 3.38 (s, 3 H, NMe), 7.30-7.35 (m, 2 H, ArH), 7.35
and 8.12 (2 d, J = 7 Hz, AA'BB' pattern, 4 H, ArH), 7.56-7.58
(m, 3 H, ArH). Anal. Calcd. for C23H18N4O4 (414.42): C, 66.66;
H, 4.38; N, 13.52. Found: C, 66.62; H, 4.22; N, 13.56.
2-(3,4-Dichlorophenyl)-6,8-dimethyl-5-phenyl[1,3]oxazolo-
[5',4':4,5]pyrido[2,3-d]pyrimidine-4,7,9(5H,6H,8H)-trione
(9o). The yield was 2.92 g (72%), mp 334 °C; ir: 1730 w, 1710
s, 1670 s cm-1; 1H nmr (CF3COOD): ꢀ 2.76 (s, 3 H, NMe), 3.35
(s, 3 H, NMe), 7.13-7.15 (m, 2 H, ArH), 7.35-7.42 (m, 4 H,
ArH), 7.76-7.82 (m, 1 H, ArH), 8.03-8.06 (m, 1 H, ArH). Anal.
Calcd. for C22H14Cl2N4O4 (469.29): C, 56.31; H, 3.01; N, 11.94.
Found: C, 56.66; H, 2.88; N, 11.91.
2-(4-Chlorophenyl)-6,8-dimethyl-5-phenyl[1,3]oxazolo-[5',
4':4,5]pyrido[2,3-d]pyrimidine-4,7,9(5H,6H,8H)-trione (9h).
The yield was 3.26 g (75%), mp 323 °C; ir: 1720 w, 1700 s,
1670 s, 1610 s cm-1; 1H nmr (CF3COOD): ꢀ 3.02 (s, 3 H, NMe),
3.63 (s, 3 H, NMe), 7.45 and 8.20 (2 d, J = 7 Hz, AA'BB'
pattern, 4 H, PhH), 7.58-7.65 (m, 5 H, PhH). Anal. Calcd. for
C22H15ClN4O4 (434.84): C, 60.77; H, 3.48; N, 12.88. Found: C,
60.99; H, 3.30; N, 13.00.
Acknowledgement: This work was supported by an ASEA-
Uninet scholarship (D.V.T).
REFERENCES
[1a] Grivsky, E. M.; Lee, S.; Sigel, C. W.; Duch, D. S.; Nichols, C.
A. J. Med. Chem. 1980, 23, 327; [b] Bulicz, J.; Bertarelli, D. C. G.;
Baumert, D.; Fülle, F.; Müller, C. E.; Heber, D. Bioorg. Med. Chem. 2006,
14, 2837; [c] Heber, D.; Heers, C.; Ravens, U. Pharmazie 1993, 48, 537;
[d] Girreser, U.; Heber, D.; Schütt, M. Proceedings of ECSOC-5, The Fifth
International Electronic Conference on Synthetic Organic Chemistry,
2001, poster A0008; Kappe, C. O.; Merino, P.; Marzinzik, A.; Wennemers,
H.; Wirth, T.; Van den Eynde, J.-J.; Lin, S.-K. (Eds). CD-ROM edition,
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2005, 13, 6678; [f] Sladowska, H.; Sabiniarz, A.; Filipek, B.; Kardasz, M.;
Maciag, D. Farmaco 2003, 58, 25.
6,8-Dimethyl-2-(4-nitrophenyl)-5-phenyl[1,3]oxazolo-[5',4':
4,5]pyrido[2,3-d]pyrimidine-4,7,9(5H,6H,8H)-trione (9i). The
yield was 3.12 g (70%), mp 334 °C; ir: 1720 w, 1695 s, 1670 s,
1615 s cm-1; 1H nmr (DMSO): ꢀ 2.66 (s, 3 H, NMe), 3.16 (s, 3 H,
NMe), 7.57 (m, 5 H, PhH), 8.36 and 8.48 (2 d, J = 7 Hz, AA'BB'
pattern, 4 H, PhH). Anal. Calcd. for C22H15N5O6 (445.39): C,
59.33; H, 3.39; N, 15.72. Found: C, 59.66; H, 3.13; N, 15.47.
2-(4-Chlorophenyl)-5-methyl-6,8-diphenyl[1,3]oxazolo-[5',
4':4,5]pyrido[2,3-d]pyrimidine-4,7,9(5H,6H,8H)-trione (9j).
The yield was 3.38 g (68%), mp 322 °C; ir: 1730 m, 1700 s,
1680 s, 1615 m cm-1; 1H nmr (CF3COOD): ꢀ 3.25 (s, 3 H, NMe),
7.35 and 8.18 (2 d, J = 7 Hz, AA'BB' pattern, 4 H, PhH), 7.55-
7.60 (m, 10 H, ArH). Anal. Calcd. for C27H17ClN4O4 (496.91): C,
65.26; H, 3.45; N, 11.27. Found: C, 65.22; H, 3.30; N, 11.41.
2-(2,4-Dichlorophenyl)-5,6,8-trimethyl[1,3]oxazolo-[5',4':
4,5]pyrido[2,3-d]pyrimidine-4,7,9(5H,6H,8H)-trione (9k).
The yield was 2.85 g (70%), mp 348 °C; ir: 1720 m, 1685 s,
1660 s, 1620 s cm-1; 1H nmr (CF3COOD): ꢀ 3.58 (s, 3 H, NMe),
3.75 (s, 3 H, NMe), 3.85 (s, 3 H, NMe), 7.45 (d, J = 7 Hz, 1 H,
ArH), 7.63 (s, 1 H, ArH), 7.98 (d, J = 7 Hz, 1 H, ArH). Anal.
Calcd. for C17H12Cl2N4O4 (407.22): C, 50.14; H, 2.97; N, 13.76.
Found: C, 49.91; H, 2.70; N, 13.67.
[2a] Schaus, J. M.; Titus, R. D. (Eli Lilly & Co.), U. S. Patent
1987, 4,659,832; Chem. Abstr. 1987, 107, 23329; [b] Caprathe, B. W.;
Jaen, J. C., Wise, L. D. (Warner Lambert Co.), European Patent Appl.
1988, 260,642; Chem. Abstr. 1988, 109, 92992v.
[3] Decktor, D. L.; Fitzpatrick, L. R.; Campbell, H. F. (Rorer
Pharmaceutical Corporation), U. S. Patent 1989, 4,831,040; Chem.
Abstr. 1990, 112, 16278p.
[4] Inamoto, Y.; Kawai, S.; Sanada, K.; Endo, T. (Fuji Chemical
Industry Co. Ltd., Japan), Japan Kokai Tokkyo Koho 1991, 03 109388;
Chem. Abstr. 1991, 115, 279995.
[5a] Musser, J. H.; Brown, R. E. (USV Pharmaceutical
Corporation), U. S. Patent 1986, 4,563,463; Chem. Abstr. 1987, 106,
50187u; [b] Renaud, A.; Schoofs, A. R.; Guiraudie, J. M.; Brochet D.
(Delalande S. A.), European Patent Appl. 1989, 322263; Chem. Abstr.
1990, 112, 216909g.
2-(3,4-Dichlorophenyl)-5,6,8-trimethyl[1,3]oxazolo-[5',4':
4,5]pyrido[2,3-d]pyrimidine-4,7,9(5H,6H,8H)-trione (9l). The
yield was 2.93 g (72%), mp 305 °C; ir: 1720 s, 1695 s, 1670 s,
[6a] Brill, G.; Hagen, H.; Westphalen, K. O.; Würzer, B. (BASF
AG), European Patent Appl. 1990, 401582; Chem. Abstr. 1991, 114,
122372r; [b] Brill, G.; Hagen, H.; Westphalen, K. O.; Würzer, B. (BASF
AG), German Offen. 1990, 3,917, 883; Chem. Abstr. 1991, 114, 185503e.
[7] Khattab, A. F. A.; Dang, V. T.; Stadlbauer, W. J. Prakt.
Chem-Chem. Ztg. 1996, 338, 151.
1
1620 s cm-1; H nmr (CF3COOD): ꢀ 3.35 (s, 3 H, NMe, 3.57 (s,
3 H, NMe), 3.66 (s, 3 H, NMe), 7.38 (d, J = 7 Hz, 1 H, ArH),
7.77 (d, J = 7 Hz, 1 H, ArH), 8.02 (s, 1 H, ArH). Anal. Calcd. for
C17H12Cl2N4O4 (407.22): C, 50.14; H, 2.97; N, 13.76. Found: C,
50.10; H, 2.76; N, 13.78.
[8a] Burova, O. A.; Bystryakova, I. D.; Smirnova, N. M.;
Safonova, T. S. Khim. Geterotsikl. Soedin. 1990, 662; [b] Burova, O. A.;
Bystryakova, I. D.; Smirnova, N. M.; Safonova, T. S. Khim. Geterotsikl.
Soedin. 1991, 497; [c] Seidenfaden, W.; Pawellek, D. in Houben-Weyl,
Methoden der Organischen Chemie, 4th ed, Müller, E. (Ed), Vol 10/1,
Georg Thieme Verlag, Stuttgart, 1971, p 849.
2-(2,6-Dimethoxyphenyl)-5,6,8-trimethyl[1,3]oxazolo-[5',
4':4,5]pyrido[2,3-d]pyrimidine-4,7,9(5H,6H,8H)-trione (9m).
The yield was 2.76 g (68%), mp 302 °C; ir: 1715 m, 1690 s, 1665
1
s, 1620 s cm-1; H nmr (CF3COOD): ꢀ 3.32 (s, 3 H, NMe), 3.52
(s, 3 H, NMe), 3.65 (s, 3 H, NMe), 3.75 (s, 3 H, OMe), 3.99 (s, 3
H, OMe), 6.53 (s, 1 H, ArH), 6.65 (d, J = 7 Hz, 1 H, ArH), 8.09
(d, J = 7 Hz, 1 H, ArH). Anal. Calcd. for C19H18N4O6 (398.38): C,
57.29; H, 4.55; N, 14.06. Found: C, 57.62; H, 4.57; N, 14.0.
2-(2,4-Dichlorophenyl)-6,8-dimethyl-5-phenyl[1,3]oxazolo-
[5',4':4,5]pyrido[2,3-d]pyrimidine-4,7,9(5H,6H,8H)-trione
(9n). The yield was 2.88 g (71%), mp 313 °C; ir: 1695 s, 1665 s,
[9] Steinschifter, W.; Fiala, W.; Stadlbauer, W. J. Heterocyclic
Chem. 1994, 31, 1647.
[10] Stadlbauer, W.; Badawey, E.-S.; Hojas, G.; Roschger, P.;
Kappe, T. Molecules 2001, 6, 338.
[11a] Dang, V. T.; Stadlbauer, W. Molecules 1996, 1, 201; [b]
Kappe, T.; Stadlbauer, W. Molecules 1996, 1, 255.