Ring closure reactions of 5-azidopyrido[2,3-d]pyrimidinetriones to isoxazolo- and oxadiazolopyrido[2,3-d]pyrimidinetriones

Article abstract of DOI:10.1002/jhet.5570450621

(Chemical Equation Presented) Thermal decomposition of 5-azidopyrido[2,3-d] pyrimidines 2 and 7 having reactive ortho-substituents such as a formyl or a nitro group yielded isoxazolo[3′,4′:4,5]pyrido[2,3-d]pyrimidines 3 or oxadiazolo-[3′,4′:4,5]pyrido[2,3-d]pyrimidines 9. The reaction conditions of the azide decomposition were studied by differential scanning calorimetry (DSC). In addition, desoxygenation of N-oxides 9 to oxadiazoles 10 and regioselective reduction of azides 7 to amines 8 were studied.

Full text of DOI:10.1002/jhet.5570450621

Nov-Dec 2008
1695
Ring Closure Reactions of 5-Azidopyrido[2,3-d]pyrimidinetriones
to Isoxazolo- and Oxadiazolopyrido[2,3-d]pyrimidinetriones [1]
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 May 24, 2008
150 °C
O
N
O
O
O
NH2
O
N O
N
O
O
O
N3
N
N
-
+
Me
O
Me
O
NO2
O
Me
O
Me
O
Me
O
X
O
150 °C
PPh3
PPh3
N
N
N
N
N
N
Me
N
R
O
N
Me
N
R
N
Me
N
R
O
N
Me
N
R
O
N
Me
N
R
X = CH=O
X = NO2
10
3
2, 7
8
9
Thermal decomposition of 5-azidopyrido[2,3-d]pyrimidines 2 and 7 having reactive ortho-substituents
such as a formyl or a nitro group yielded isoxazolo[3',4':4,5]pyrido[2,3-d]pyrimidines 3 or oxadiazolo-
[3',4':4,5]pyrido[2,3-d]pyrimidines 9. The reaction conditions of the azide decomposition were studied by
differential scanning calorimetry (DSC). In addition, desoxygenation of N-oxides 9 to oxadiazoles 10 and
regioselective reduction of azides 7 to amines 8 were studied.
J. Heterocyclic Chem., 45, 1695 (2008).
INTRODUCTION
reacted with carboxylic acids to oxazolo[4,5-c]quinolones
by migration of the nitrene nitrogen from the 4- to the
3-position. 6-Azidouracils revealed two reaction pathways
[12]: with benzoic acids, oxazolo[5,4-d]pyrimidinediones
were obtained, whereas with aliphatic carboxylic acids
isoxazolo[3,4-d]pyrimidinediones were formed. When we
tried to transform these reaction sequence to 5-azido-
pyrido[2,3-d]pyrimidines we failed because the required
6-unsubstituted azides were unstable and decomposed to
dark blue, insoluble compounds.
Another approach to isoxazoles via azides of carbo- and
heterocycles was investigated earlier in our group
[9a,9b,9f,13] with substrates having a reactive acyl group
in ortho-position to the azido group. In the pyrido[2,3-d]-
pyrimidine series, we started from 5-chloro-6-formyl-
pyrido[2,3-d]pyrimidines 1a,b, which were prepared from
6-formyl-5-hydroxypyrido[2,3-d]pyrimidines as described
earlier [14]. The reaction of chloro compounds 1 with
sodium azide in dry dimethylformamide at room
temperature gives in good yields and high purity 5-azido-6-
formyl-pyrido[2,3-d]pyrimidines 2a,b. The formyl-azides 2
proved to be very sensitive to thermal cyclization, and
during reaction and work-up elevated temperatures had to
be avoided. To study the thermal properties, we applied
differential scanning calorimetric (DSC) measurements,
which showed that in the solid phase already at about 70 °C
an exothermic reaction started, with a peak maximum at
about 90 °C. DSC experiments revealed in a second
thermolysis run that the first reaction peak had disappeared
and only the second peak - deriving from the formed
Pyrido[2,3-d]pyrimidinedione derivatives form a class
of fused heterocyclic compounds which reveal interesting
pharmacological and biological properties [2]. Isoxazolo-
and oxadiazoloheterocycles in the quinoline and
pyrimidine series were investigated thoroughly in the last
decades and many representatives were found to show
biological activities [3-7]. These findings prompted us to
study the combination of these two biological interesting
nuclei by synthesis of pyrido[2,3-d]pyrimidinetriones
anellated to the f-side by isoxazolo[3',4':4,5]- and
oxadiazolo[3',4':4,5] rings. The ring closure reactions
intended for this project involve a thermal decomposition
of 5-azidopyrido[2,3-d]pyrimidinetriones. Ortho-substi-
tuted azido arenes and heteroarenes are known to give
cyclization reactions induced by thermo- or photolysis [8]
forming predominantly five-membered rings. Some of
these reactions were studied in our group on heterocyclic
systems with aryl, carbonyl and nitro groups as ortho
substituents (recent examples are listed in ref. [9]).
RESULTS AND DISCUSSION
A general approach leading from azidoarenenes to
oxazoles is reported via the thermolysis in the presence of
acetic acid catalyzed by polyphosphoric acid. The
formation of the 5-membered oxazole ring could be
shown to involve a nucleophilic substitution by the
acetoxy-oxygen at the position next to the azido group
[10]. Recently we could show [11] that 4-azidoquinolines

1696
D. Van Tinh and W. Stadlbauer
Vol 45
cyclization product - could be observed. In synthetic
experiments, the ring closure reaction to the isoxazolo-
[3',4':4,5]pyrido[2,3-d]pyrimidines 3a,b could be achieved
by the thermolysis of the azides 2a,b in refluxing
dimethylformamide by loss of nitrogen and cyclization; for
this reaction an electrocyclic mechanism is proposed [15].
To avoid handling with the instable azides 2a,b, a one-step
reaction from chloro compounds 1 to isoxazoles 3 was
developed by heating 1a,b with sodium azide in
dimethylformamide at 80-90 °C.
Scheme 2
O
Cl
O
OH
Et N
/
POCl3
reflux, 4 h
3
Me
O
NO2
O
Me
O
NO2
O
N
N
N
N
R
N
N
R
80-82%
Me
Me
4a,b
5a,b
NaN3 DMF
/
rt, 3 h
80-85%
PPh3
O
N
Ph3P, PhBr
reflux, 8 h
O
N3
Me
O
NO2
O
Me
N
NO2
O
Scheme 1
N
O
N3
N
N
R
O
N
N
R
60-70%
Me
O
CHO
O
NaN3 DMF
/
20 °C, 2 h
Me
Me
N
7a,b
6a,b
N
N
R
80-85%
O
Cl
PhBr
Me
2a,b
DMF
AcOH/H2O
reflux, 60 min
91-93%
Me
O
CHO
O
60-70%
N
reflux, 30 min
94-96%
N
N
R
reflux, 15 min
O
N
O
-
+
N
Me
O
NH2
O
O
N
NaN3
80 oC, 2 h
O
DMF
Me
N
/
1a,b
Me
N
NO2
O
Me
N
O
N
N
R
O
81-85%
R
1-3
a
O
N
N
R
O
N
N
R
O
Me
Me
Ph
Me
Me
b
9a,b
3a,b
8a,b
Ph3P, C6H4Cl2
reflux, 8 h
60-70%
A similar cyclization reaction of azides is known to take
place with ortho-nitro substituents in the same manner as
observed with ortho-acyl groups. Such reactions were
studied earlier in the quinoline and pyridine series [16]
successfully. The synthesis sequence in the pyrido[2,3-
d]pyrimidine series started from 5-hydroxy-6-nitro-
pyrido[2,3-d]pyrimidine-2,4,7-triones 4a,b which were
obtained from 5-hydroxy-pyrido[2,3-d]pyrimidine-2,4,7-
triones [14] by a mild nitration method using sodium nitrite
as catalyst [16a,17]. Conversion to the reactive azides
proceeded via 5-chloro-6-nitro-pyrido[2,3-d]pyrimidine-
2,4,7-triones 5a,b which were obtained by chlorination of 4
with phosphoryl chloride in the presence of triethylamine to
cleave hydrogen bondings of the 5-hydroxy group with
close-by oxo groups. In this way the chloro compounds 5
were obtained in excellent yields. The reaction of 5-chloro-
6-nitropyrido[2,3-d]pyrimidines 5 with sodium azide in
dimethylformamide afforded already at room temperature
in excellent yields by nucleophilic substitution 5-azido-6-
nitropyrido[2,3-d]pyrimidines 7a,b, which showed to be
stable enough for work-up and recrystallization.
O
N
O
N
Me
N
R
Me
4-10
a
b
Ph
O
N
N
R
O
Me
10a,b
Synthetically, the reaction could be achieved by
thermolysis of the azides 7a,b in refluxing bromobenzene.
This thermal decomposition resulted again in a loss of
nitrogen and cyclization by an electrocyclic mechanism
which formed the cyclization products, the furoxans 9a,b.
As further step the reduction to the desoxigenated
oxadiazole ring was planned. The removal of the N-oxide
oxygen of furoxanes is described to take place by
reduction with triphenylphosphane [18]. Application of
the reaction conditions as described in the literature,
however, gave no reaction. So DSC studies of a mixture
of furoxanes 9 with triphenylphosphane were performed
to find out suitable reaction temperatures (see Figure 1).
The DSC diagrams showed after the melting area of
triphenylphosphane strong exothermic reaction peaks with
onset at 186 and 201 °C. From earlier investigations [19]
we know that in solvents the reaction temperature is
lowered for 20-50 °C. According to these findings, the
reaction was performed in boiling 1,2-dichlorobenzene at
179 °C. As a result, a smooth removal of the N-oxide
The thermal behavior of 7 was studied by differential
scanning calorimetry. The observed cyclization
temperatures of 7 with about 120 °C onset are much
higher than that of formyl-azides 2 with onsets at 70 °C.
Again the formation of cyclized products is observed
during the DSC run which produce a second set of
decomposition signals similar to the melting points of the
synthesized products 9.

Nov-Dec 2008
Ring Closure Reactions of 5-Azidopyrido[2,3-d]pyrimidinetriones
1697
(83%), yellow prisms, mp 86 °C (methanol), partial
decomposition, resolidifies and melts again at 274 °C by
formation of 3a; DSC data: cyclization at 70.5 °C onset, 85.8 °C
max., ꢁH = -106 mcal/mg; decomposition at 264.9 °C onset,
274.7 °C max., ꢁH = -102 mcal/mg; second run after thermolyis
and cooling: decomposition at 274.3 °C onset, 281.2 ° max., ꢁH
= -125 mcal/mg; ir: 3060 m, 2120 w (N3), 1700 s, 1675 s, 1600
m cm-1; 1H nmr: ꢀ 3.28 (s, 3 H, NMe), 3.45 (s, 3 H, NMe), 3.46
(s, 3 H, NMe), 10.05 (s, 1 H, CH=O). Anal. Calcd. for
C11H10N6O4 (290.24): C, 45.52; H, 3.47; N, 28.96. Found: C,
46.12; H 3.95; N, 27.35; values are not correct because of the
ease of decomposition of the azide.
oxygen was achieved and [1,2,5]oxadiazolo[3',4':4,5]-
pyrido[2,3-d]pyrimidines 10a,b were obtained.
5-Azido-1,3-dimethyl-2,4,7-trioxo-8-phenyl-1,2,3,4,7,8-
hexahydropyrido[2,3-d]pyrimidine-6-carbaldehyde (2b). This
compound was obtained from 5-chloro-6-formylpyrido[2,3-
d]pyrimidinetrione 1b [14] (3.45 g, 10 mmoles) as described for
2a; the yield was 3.05 g (85%), yellow prisms, mp 88 °C
(methanol), partial decomposition, resolidifies and melts again at
257-260 °C by formation of 3b; DSC data: cyclization at 70.6
°C onset, 87.9 °C, ꢁH = -56 mcal/mg; decomposition: 217.8 °C
onset, 257.1 °C max., ꢁH = -118 mcal/mg; second run after
thermolyis and cooling: decomposition at 236.3 °C onset, 242.3
°C max., ꢁH = -84 mcal/mg; ir: 2140 s (N3), 1710 s, 1670 s cm-
Figure 1. Differential scanning calorimetry diagram of the reaction of
9a to 10a with triphenylphosphane.
In conclusion, a series of new fused pyrido[2,3-d]-
pyrimidine-4,7,9-triones was synthesized having as
anellated ring 5-membered isoxazoles or oxadiazoles. The
cyclization reaction took place via thermal decomposition
of azides with reactive ortho-substituents; the reaction
conditions were studied in advance by differential
scanning calorimetry (DSC).
1
1; H nmr: ꢀ 2.85 (s, 3 H, NMe), 3.42 (s, 3 H, NMe), 7.30-7.35
(m, 2 H, ArH), 7.53-7.57 (m, 3 H, ArH), 10.28 (s, 1 H, CH=O).
Anal. Calcd. for C16H12N6O4 (352.31): C, 54.55; H, 4.43; N,
23.85. Found: C, 55.32; H 4.12; N, 22.53; values are not correct
because of the ease of decomposition of the azide.
5,6,8-Trimethylisoxazolo[3',4':4,5]pyrido[2,3-d]pyrimidine-
4,7,9(5H,6H,8H)-trione (3a). Method A: A suspension of 5-
chloro-6-formylpyrido[2,3-d]pyrimidinetrione 1a [14] (2.83 g,
10 mmoles) and sodium azide (0.98 g, 15 mmoles) in dry
dimethylformamide (30 mL) was stirred at 80-90 °C for 2 hours.
Then the reaction mixture was poured into ice/water (500 mL),
the precipitate collected by filtration, washed with water and
dried. The yield was 2.12 g (81%).
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 tetramethylsilane 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 (DSC) 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 pans (11 bar). All reactions were monitored by thin
layer chromatography, carried out on 0.2 mm silicagel F-254
(Merck) plates using uv light (254 and 366 nm) for detection.
Common reagent-grade chemicals are either commercially
available and were used without further purification or prepared
by standard literature procedures.
Method B: A mixture of 5-azido-6-formylpyrido[2,3-d]-
pyrimidinetrione 2a (2.90 g, 10 mmoles) and dimethyl-
formamide (20 mL) was heated under reflux for 15 minutes. The
reaction mixture was allowed to cool and the formed precipitate
collected by filtration and washed with ethanol (50 mL). The
yield was 2.51 g (96%), colorless prisms, mp 275-277 °C
(dimethylformamide); ir: 3060 s, 1725 m, 1700 s, 1665 s m cm-1;
1H nmr (CF3COOH): ꢀ 3.54 (s, 3 H, NMe), 3.73 (s, 3 H, NMe),
3.75 (s, 3 H, NMe), 9.53 (s, 1 H, 3-H). Anal. Calcd. for
C11H10N4O4 (262.23): C, 50.38; H, 3.84; N, 21.37. Found: C,
50.40; H, 3.85; N, 21.41.
6,8-Dimethyl-5-phenylisoxazolo[3',4':4,5]pyrido[2,3-d]pyr-
imidine-4,7,9(5H,6H,8H)-trione (3b). This compound was
obtained according to the methods described for 3a either from
5-chloro-6-formylpyrido[2,3-d]pyrimidinetrione 1b (3.45 g, 10
mmoles) [14] (method A) or 5-azido-6-formylpyrido[2,3-d]-
pyrimidinetrione 2b (3.52 g, 10 mmoles) (method B); the yield
was 2.69 g (83%) (method A) and 3.08 g (95%) (method B),
colorless prisms, mp 258-260 °C (dimethylformamide); ir: 1710
s, 1670 s, 1610 m cm-1; 1H nmr: ꢀ 2.80 (s, 3 H, NMe), 3.40 (s, 3
H, NMe), 7.35-7.55 (m, 5 H, ArH), 9.25 (s, 1 H, 3-H). Anal.
Calcd. for C16H12N4O4 (324.30): C, 59.26; H, 3.73; N, 17.28.
Found: C, 59.10; H, 3.71; N, 17.06.
5-Azido-1,3,8-trimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-
pyrido[2,3-d]pyrimidine-6-carbaldehyde (2a). A suspension
of 5-chloro-6-formylpyrido[2,3-d]pyrimidinetrione 1a [14] (2.83
g, 10 mmoles) and sodium azide (0.98 g, 15 mmoles) in dry
dimethylformamide (30 mL) was stirred at 20 °C for 2 hours.
Then the reaction mixture was poured into ice/water (500 mL),
the precipitate was collected by filtration, washed with water
and dried at room temperature in vacuo. The yield was 2.40 g
5-Hydroxy-1,3,8-trimethyl-6-nitropyrido[2,3-d]pyrimid-
ine-2,4,7(1H,3H,8H)-trione (4a). A suspension of 5-hydroxy-
1,3,8-trimethylpyrido[2,3-d]pyrimidine-2,4,7-trione [14] (18.00 g,

1698
D. Van Tinh and W. Stadlbauer
Vol 45
76 mmoles) in glacial acetic acid (140 mL) was treated with
fuming nitric acid (14.0 mL, 213 mmoles) and then with sodium
nitrite (0.40 g, 5.8 mmoles) to start the slightly exothermic
reaction. The starting material dissolved, followed immediately by
precipitation of the product. After stirring for 60 minutes, the
mixture was poured into ice/water (1000 mL). The product was
filtered, washed with water and dried. The yield was 19.0 g (89%)
yellow prisms, mp 223-225 °C (dimethylformamide/ethanol); ir:
pyrimidinetrione 7b (3.69 g, 10 mmoles) as described for 6a; the
°
yield was 5.10 g (85%), yellow prisms, mp 289-291
C
(toluene); ir: 1710 s, 1675 s, 1650 s cm-1; 1H nmr: ꢀ 2.55 (s, 3 H,
NMe), 2.65 (s, 3 H, NMe), 7.52-7.70 (m, 20 H, ArH). Anal.
Calcd. for C33H26N5O5P (603.58): C, 65.67, H, 4.34; N, 11.60.
Found: C, 65.56; H, 4.41; N, 11.50.
5-Azido-1,3,8-trimethyl-6-nitropyrido[2,3-d]pyrimidine-
2,4,7(1H,3H,8H)-trione (7a). A suspension of 5-chloropyrido-
[2,3-d]pyrimidinetrione 5a (3.00 g, 10 mmoles) and sodium
azide (0.98 g, 15 mmoles) in dry dimethylformamide (30 mL)
was stirred at room temperature for 3 hours. Then the reaction
mixture was poured into ice water (500 mL), the precipitate
collected by suction filtration, washed with water and dried in
vacuo. The yield was 2.40 g (83%), yellow prisms, mp 140 °C
(methanol), partial decomposition, resolidifies and melts again at
268 °C by formation of 9a; DSC data: cyclization at 120.5 °C
onset; 139.2 °C peak max., ꢁH = -9 mcal/mg; decomposition
261.7 °C onset, 267.9 °C max. , ꢁH = -19 mcal/mg; ir: 2160 s
(N3), 1720 s, 1670 s cm-1; 1H nmr: ꢀ 3.20 (s, 3 H, NMe), 3.52 (s,
3 H, NMe), 3.58 (s, 3 H, NMe). Anal. Calcd. for C10H9N7O5
(307.23): C, 39.10; H, 2.95; N, 31.91. Found: C, 39.50; H, 3.02;
N, 31.18; values are not correct because of the ease of
decomposition of the azide.
5-Azido-1,3-dimethyl-6-nitro-8-phenylpyrido[2,3-d]pyrim-
idine-2,4,7(1H,3H,8H)-trione (7b). This compound was
obtained from 5-chloropyrido[2,3-d]pyrimidinetrione 5b (3.62 g,
10 mmoles) as described for 7a; the yield was 3.14 g (85%),
yellow prisms, mp 128 °C (ethanol) partial decomposition,
resolidifies and melts again at 288 °C by formation of 9b; DSC
data: cyclization at 116.8 °C onset, 127.1 °C max., ꢁH = -8
mcal/mg; decomposition 276.4 °C onset, 287.6 °C max., ꢁH = -
12 mcal/mg; ir: 2160 s (N3), 1740 s, 1660 s cm-1; 1H nmr: ꢀ 2.64
(s, 3 H, NMe), 3.28 (s, 3 H, NMe), 7.65-7.70 (m, 5 H, ArH).
Anal. Calcd. for C15H11N7O5 (369.30): C, 48.79; H, 3.00; N,
26.55. Found: C, 48.71; H, 3.09; N, 25.66; values are not correct
because of the ease of decomposition.
1
1720 s, 1670 s cm-1; H nmr: ꢀ 3.39 (s, 3 H, NMe), 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 (4b). This compound was
obtained from 5-hydroxy-1,3-dimethyl-8-phenylpyrido[2,3-
d]pyrimidine-2,4,7-trione [14] (22.70 g, 76 mmoles) as
described for 4a; the yield was 22.00 g (85%) yellow prisms, mp
246-249 °C (dimethylformamide/ethanol); ir: 1725 s, 1700 s,
1
1660 s cm-1; H nmr: ꢀ 2.66 (s, 3 H, NMe), 3.30 (s, 3 H, NMe),
7.57-7.60 (m, 5 H, ArH). 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-Chloro-1,3,8-trimethyl-6-nitropyrido[2,3-d]pyrimidine-
2,4,7(1H,3H,8H)-trione (5a). Dry triethylamine (5.0 mL) was
added to a solution of 5-hydroxypyrido[2,3-d]pyrimidinetrione
4a (9.87 g, 35 mmoles) in phosphoryl chloride (50 mL). The
mixture was heated under reflux for 3-4 hours, the excess POCl3
was removed by distillation and the residue poured into
ice/water (1000 mL). The solution was brought to pH = 6-7 with
conc. aq. sodium hydroxide solution, collected by suction
filtration and washed with water. The yield was 8.60 g (82%),
yellow prisms, mp 235 °C (dimethylformamide/ethanol); ir:
1730 s, 1675 s cm-1; 1H nmr: ꢀ 3.22 (s, 3 H, NMe), 3.48 (s, 3 H,
NMe), 3.57 (s, 3 H, NMe). Anal. Calcd. for C10H9ClN4O5
(300.66): C, 39.95; H, 3.02; N, 18.63. Found: C, 39.76; H, 3.04;
N, 18.36.
5-Chloro-1,3-dimethyl-6-nitro-8-phenylpyrido[2,3-d]pyr-
imidine-2,4,7(1H,3H,8H)-trione (5b). This compound was
obtained from 5-hydroxypyrido[2,3-d]pyrimidinetrione 4b
(12.00 g, 35 mmoles) as described for 5a; the yield was 10.15 g
(80%) yellow prisms, mp 253 °C (dimethylformamide/ethanol);
ir: 1725 m, 1665 s cm-1; 1H nmr: ꢀ 2.63 (s, 3 H, NMe), 3.34 (s, 3
5-Amino-1,3,8-trimethyl-6-nitro-pyrido[2,3-d]pyrimidine-
2,4,7(1H,3H,8H)-trione (8a). A mixture of 5-triphenylphos-
phoranylideneaminopyrido[2,3-d]pyrimidinetrione 6a (5.41 g,
10 mmoles), 80% aq. acetic acid (50 mL) was heated under
reflux for 1 hour. After cooling, to the reaction mixture water
(50 mL) was added then the precipitate was collected by suction
filtration and washed with water. The yield was 2.52 g (90%),
H, NMe), 7.60-7.62 (m,
5 H, ArH). Anal. Calcd. for
C15H11ClN4O5 (362.73): C, 49.67; H, 3.06; N, 15.45. Found: C,
49.51; H, 3.12; N, 15.43.
°
1,3,8-Trimethyl-6-nitro-5-triphenylphosphoranylideneam-
inopyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione (6a). To
a solution of triphenylphosphane (3.15 g, 12 mmoles) in dry
toluene (30 mL) was added 5-azidopyrido[2,3-d]pyrimidine-
trione 7a (3.10 g, 10 mmoles) to start the slightly exothermic
reaction. The starting material dissolved, followed immediately
by precipitation of the product. After stirring for 30 minutes, the
temperature was gradually raised to 80-100 °C for 30 minutes.
The reaction mixture was then allowed to cool, the mixture kept
at room temperature for some hours, and then the precipitate was
collected by suction filtration and washed with toluene and
cyclohexane. The yield was 4.33 g (80%), yellow prisms, mp
257-259 °C (toluene); ir: 1715 s, 1660 s cm-1; 1H nmr: ꢀ 2.63 (s,
3 H, NMe), 3.35 (s, 3 H, NMe), 3.43 (s, 3 H, NMe), 7.51-7.63
(m, 15 H, ArH). Anal. Calcd. for C28H24N5O5P (541.51): C,
62.11; H, 4.47; N; 12.93. Found: C, 61.93, H, 4.41; N, 12.93.
1,3-Dimethyl-6-nitro-8-phenyl-5-triphenylphosphoranyl-
ideneaminopyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione
(6b). This compound was obtained from 5-azidopyrido[2,3-d]-
yellow prisms, mp 276-278 C (toluene); ir: 3280 m, 3200 m,
1725 m, 1710 m, 1670 m, 1655 s, 1600 s cm-1; 1H nmr
(CF3COOH): ꢀ 3.61 (s, 3 H, NMe), 3.82 (s, 6 H, 2 NMe), 11.37
(s, 2 H, NH2). Anal. Calcd. for C10H11N5O5 (281.23): C, 42.71;
H, 3.94; N, 24.90. Found: C, 42.47; H, 3.93; N, 24.86.
5-Amino-1,3-dimethyl-6-nitro-8-phenylpyrido[2,3-d]pyr-
imidine-2,4,7(1H,3H,8H)-trione (8b). This compound was
obtained from 5-triphenylphosphoranylideneaminopyrido[2,3-
d]pyrimidinetrione 6b (6.03 g, 10 mmoles) as described for 8a.
The yield was 3.20 g (93%), yellow prisms, mp 248 °C
(toluene); ir: 3360 m, 3170 m, 1710 s, 1650 s, 1600 m cm-1; H
1
nmr: ꢀ 2.63 (s, 3 H, NMe), 3.26 (s, 3 H, NMe), 7.53-7.55 (m, 5
H, ArH), 9.18 (s, 1 H, NH2), 10.40 (s, 1 H, NH2). Anal. Calcd.
for C15H13N5O5 (343.30): C, 52.48; H, 3.82; N; 20.40. Found: C,
52.34; H, 3.86; N, 20.36.
5,6,8-Trimethyl-4,7,9-trioxo-4,5,6,7,8,9-hexahydro[1,2,5]-
oxadiazolo[3',4':4,5]pyrido[2,3-d]pyrimidine-3-oxide (9a). A
solution of 5-azido-6-nitropyrido[2,3-d]pyrimidinetrione 7a
(3.07 g, 10 mmoles) in bromobenzene (50 mL) was heated under

Nov-Dec 2008
Ring Closure Reactions of 5-Azidopyrido[2,3-d]pyrimidinetriones
1699
Jaen, J. C. ,Wise, L. D. (Warner Lambert Co.), European Patent Appl.
1988, 260,642; Chem. Abstr. 1988, 109, 92992v.
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Pharmaceutical Corporation), U. S. Patent 1989, 4,831,040; Chem.
Abstr. 1990, 112, 16278p.
[5] 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.
[6a] Musser, J. H.; Brown, R. E. (USV Pharmaceutical
Corporation), U. S. Patent 1986, 4,563,463; Chem. Abstr. 1987, 106,
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(Delalande S. A.) European Patent Appl. 1989, 322263; Chem. Abstr.
1990, 112, 216909g.
[7] Brill, G.; Hagen, H.; Westphalen, K. O.; Würzer, B. (BASF
AG), European Patent Appl. 1990, 401582; Chem. Abstr. 1991, 114,
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185503e.
[8] Smith, P. A. S. in Azides and Nitrenes, E. F. Scriven, Ed,
Academic Press, New York, 1984, pp 95-204; Scriven, E. F. V.;
Turnbull, K. Chem. Rev., 1988, 88, 297.
reflux until evolution of nitrogen had stopped (about 30
minutes). Then the solvent was removed in vacuo and the
remaining solid digested with cyclohexane (40 mL). The product
was filtered and washed with cyclohexane. The yield was 2.60 g
(93%), yellow prisms, mp 266-268 °C (toluene); ir: 1710 s, 1665
s, 1615 m cm-1; 1H nmr (CDCl3): ꢀ = 3.29 (s, 3 H, NMe), 3.48 (s,
6 H, 2 NMe). Anal. Calcd. for C10H9N5O5 (279.21): C, 43.02; H,
3.25; N, 25.08. Found: C, 42.78; H, 3.27; N, 25.07.
6,8-Dimethyl-5-phenyl-4,7,9-trioxo-4,5,6,7,8,9-hexahydro-
[1,2,5]oxadiazolo[3',4':4,5]pyrido[2,3-d]pyrimidine-3-oxide
(9b). This compound was obtained from 5-azido-6-nitropyrido-
[2,3-d]pyrimidinetrione 7b (3.69 g, 10 mmoles) as described for
9a; the yield was 3.10 g (91%), yellow prisms, mp 292 °C
(toluene); ir: 1730 s, 1670 s, 1620 m cm-1; 1H nmr (CF3COOD): ꢀ
3.06 (s, 3 H, NMe), 3.63 (s, 3 H, NMe), 7.46-7.50 (m, 2 H, ArH),
7.66-7.69 (m, 3 H, ArH). Anal. Calcd. for C15H11N5O5 (341.29): C,
52.79; H, 3.25; N, 20.52. Found: C, 52.57; H, 3.20; N, 20.47.
5,6,8-Trimethyl[1,2,5]oxadiazolo[3',4':4,5]pyrido[2,3-d]pyr-
imidine-4,7,9(5H,6H,8H)-trione (10a).
A mixture of
[9a] Stadlbauer, W.; Prattes, S.; Fiala, W. J. Heterocycl. Chem.
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Chem. 2000, 37, 1559; [d] Stadlbauer, W.; Hojas, G. J. Chem. Soc.,
Perkin Trans. 1, 2000, 3085; [e] Stadlbauer, W.; Fiala W.; Fischer, M.;
Hojas, G. J. Heterocyclic Chem., 2000, 37, 1253; [f] Stadlbauer, W.;
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1966, 1980; [b] Garner, R.; Suschitzky, H. J. Chem. Soc. (C), 1967, 74;
[c] Mullock, E. B.; Suschitzky, H. J. Chem. Soc. 1968, 1937; [e]
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Chem. 1994, 31, 1647.
[1,2,5]oxadiazolo[3',4':4,5]pyrido[2,3-d]pyrimidine-3-oxide (9a)
(2.79 g, 10 mmoles) and triphenylphosphane (3.15 g, 12 mmoles)
in 1,2-dichlorobenzene (50 mL) was heated under reflux for 8
hours, cooled to room temperature, the formed precipitate was
collected by suction filtration and washed with cyclohexane. The
yield was 1.60 g (61%), yellow prisms, mp 270 °C (dimethyl-
formamide/ethanol); ir: 1730 m, 1710 s, 1665 s, 1610 s cm-1; H
nmr (CDCl3): ꢀ 3.30 (s, 3 H, NMe), 3.51 (s, 3 H, NMe), 3.53 (s, 3
H, NMe). Anal. Calcd. for C10H9N5O4 (263.21): C, 45.63; H, 3.45;
N, 26.61. Found: C, 45.34; H, 3.47; N, 26.52.
6,8-Dimethyl-5-phenyl[1,2,5]oxadiazolo[3',4':4,5]pyrido-
[2,3-d]pyrimidine-4,7,9(5H,6H,8H)-trione (10b). This
compound was obtained from [1,2,5]oxadiazolo[3',4':4,5]-
pyrido[2,3-d]pyrimidine-3-oxide 9b (3.41 g, 10 mmoles) as
described for 10a; the yield was 2.28 g (70%), yellow prisms,
mp 290 °C (dimethylformamide/ethanol); ir: 1745 s, 1665 s
cm-1; 1H nmr (CDCl3): ꢀ 2.68 (s, 3 H, NMe), 3.30 (s, 3 H, NMe),
7.58-7.60 (m, 5 H, ArH). Anal. Calcd. for C15H11N5O4 (325.29):
C, 53.59; H, 3.41; N, 21.53. Found: C, 53.22; H, 3.51; N, 21.42.
1
[12] Dang, V. T.; Stadlbauer, W. J. Heterocycl. Chem. 1996, 33,
1025.
Acknowledgement. This work was supported by an ASEA-
Uninet scholarship (D.V.T).
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