Synthesis of 5-mono- and 5,7-diamino-pyrido[2,3-d]-pyrimidinediones with potential biological activity by regioselective amination

Article abstract of DOI:10.1002/jhet.5570450329

(Chemical Equation Presented) 5-Alkyl/arylamino- and 5,7-dialkyl/arylamino- pyrido[2,3-d]pyrimidine-2,4-diones (4,5, 7-9) were prepared from the corresponding 5,7-dichloro-pyrido[2,3-d]pyrimidine-2,4-diones 2 with aliphatic and aromatic amines 3 and 6 in a regioselective reaction. The 7-monoazides 10, obtained by azidation of 5-amino-7-chloro derivatives 4, were converted to iminophosphoranes by reaction with triphenylphosphane via Staudinger reaction. Hydrolysis with aqueous acetic acid produced in one step 7-unsubstituted-amino- pyrido[2,3-d]pyrimidine-2,4-diones 12. In a similar amination reaction, 5-chloropyrido[2,3-d]pyrimidine-2,4,7-triones 13 were aminated and formylated to 5-alkyl/arylamino-6-formyl derivatives 14-16 in a combined one-step-reaction with bulky arylamines or alkylamines in the presence of dimethylformamide.

Full text of DOI:10.1002/jhet.5570450329

May-Jun 2008
821
Synthesis of 5-Mono- and 5,7-Diamino-pyrido[2,3-d]-
pyrimidinediones with Potential Biological Activity by
Regioselective Amination [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 October 2, 2007
R'NHR"
(3, 6)
R"
O
R'
R"
R'
N
O
N
N
O
Cl
N
R
O
R
O
R
O
N
N
N
R'NHR"
R'NHR"
R'
N
R
N
Cl
N
R
N
N
R
Cl
(6)
(3, 6)
R"
2
4
5,7-9
NaN3
R"
R'
R"
N
R'
R"
O
R'
O
N
O
N
N
1. PPh3
2. H+
R
O
R
CHO
O
R
O
N
N
N
N
R
N
NH2
O
N
R
N
N
R
N3
R'''
12
10
14-16
5-Alkyl-/arylamino- and 5,7-dialkyl/arylamino-pyrido[2,3-d]pyrimidine-2,4-diones (4,5, 7-9) were
prepared from the corresponding 5,7-dichloro-pyrido[2,3-d]pyrimidine-2,4-diones 2 with aliphatic and
aromatic amines 3 and 6 in a regioselective reaction. The 7-monoazides 10, obtained by azidation of
5-amino-7-chloro derivatives 4, were converted to iminophosphoranes by reaction with triphenyl-
phosphane via Staudinger reaction. Hydrolysis with aqueous acetic acid produced in one step
7-unsubstituted-amino-pyrido[2,3-d]pyrimidine-2,4-diones 12. In
a similar amination reaction,
5-chloropyrido[2,3-d]pyrimidine-2,4,7-triones 13 were aminated and formylated to 5-alkyl/arylamino-
6-formyl derivatives 14-16 in a combined one-step-reaction with bulky arylamines or alkylamines in
the presence of dimethylformamide.
J. Heterocyclic Chem., 45, 821 (2008).
Scheme 1
INTRODUCTION
O
NHR
N
O
Pyrido[2,3-d]pyrimidinediones form a class of fused
heterocyclic compounds which reveal interesting
pharmacological and biological properties generated from
the two biological interesting structural elements, the
uracil and the pyridine part, present in a number of
biological active products. Thus, they have been used as
effective antitumor agents, as antibacterial, anticonvulsant
or enzyme inhibitor agents [2]. Amino-substituted pyrido-
[2,3-d]pyrimidinediones with structures A and B have
been recently investigated [3]. They were found to bind to
adenosine A1 and A2A receptor in micromolar concen-
tration and the structure-activity relationship for
pyrido[2,3-d]pyrimidinediones as ligands of adenosine
receptors has been studied.
Me
O
R'
Me
O
R'
N
N
N
N
N
NHR
Me
Me
A
B
(R' : H, CN, CO2C2H5)
These findings prompted us to study the synthesis of 5-
amino- and 5,7-diamino-pyrido[2,3-d]pyrimidinediones
having similar structural elements as the above mentioned
structures A and B. The synthetic routes described in ref.
[3] involve either a 2-step reaction via a Vilsmeier
formylation and ring closure with acetonitrile derivatives,
or cyclization of dimethyluracil with ethoxymethylene-

822
D. V. Tinh and W. Stadlbauer
Vol 45
malonate, followed by a chlorination step. We started
according to our earlier studies on pyrido[2,3-d]pyrim-
idinediones from substituted uracils and malonate [4b] to
obtain in one step 5-hydroxy-pyrido[2,3-d]pyrimidine-
2,4,7-triones 1, which should give in a chlorination step
the starting material for amination. The dichloro-pyridine
part of the pyrido[2,3-d]pyrimidinedione structure 2
should have similar properties as observed in well
investigated amination reactions of dichloroquinolines
[5]; in this reaction with several amines, 2,4-diamino-
quinolines, 2-amino-4-chloroquinolines or 4-amino-2-
chloroquinolines were obtained. Kinetic studies indicate
that the chloro atom in position 4 of 2,4-dichloro-
quinolines is about two times more reactive towards
nucleophiles [6] and predominantly an addition-
elimination mechanism is observed [7].
The reaction of 5,7-dichloro-pyrido[2,3-d]pyrimid-
inediones 2a,b with benzylamine (3b) or 3-picolylamine
(3c) in refluxing 2-propanol as the solvent gave similar
results as obtained with aniline: again 5-mono-amination
products such as 5-benzylamino-7-chloro- and 7-chloro-5-
(3-picolylamino)-pyrido[2,3-d]pyrimidinedione 4c-f were
1
obtained. H nmr data showed a shift to lower δ-values:
the NH signals appeared in 4c-f between δ 9.55 and 9.70
ppm.
Scheme 1
R1 R2
1,2,4,5
O
OH
a
b
c
Me
Ph
Ph
Ph
CH2Ph
R1
O
N
Me
Ph CH2Ph
Me
Ph CH2(pyridyl-3)
d
e
f
N
R1
N
O
CH2(pyridyl-3)
Me
In this contribution the transformation of such
amination reactions to the pyrido[2,3-d]pyrimidinedione
1a,b
R2
O
HN
POCl3
110 oC, 2 h
heterocyclic sytstem is described. Furthermore,
a
2-propanol
reflux, 5-8 h
R1
80-87%
Cl
N
synthetic sequence via a 2-step reaction of azides to
amines is developed, similar as described earlier in the
quinoline series [8].
73-80%
O
N
R1
N
Cl
O
R2 NH2
R1
N
4a-f
(3a-c)
R2
RESULTS AND DISCUSSION
O
N
R1
N
Cl
O
HN
without solvent
reflux 8 h
R1
2a,b
5,7-Dichloro-pyrido[2,3-d]pyrimidine-2,4-diones 2a,b,
which were used as starting materials for regioselective
amination reactions, were obtained from 5-hydroxy-8-
methyl-pyrido[2,3-d]pyrimidine-2,4,7-triones 1a,b [4b].
During the chlorination reaction, not only the oxygen
atom in position 5 was substituted by a chloro atom, but
also the methyl group in position 8 was cleaved already at
rather mild reaction conditions to form the tautomeric 7-
hydroxy intermediate. This hydroxy group was then in
turn converted to the 7-chloro group. The methyl groups
of 1a at position 1 and 3 remained unchanged. Such a
demethylation cleavage is also known from the 4-
hydroxypyridone series [9].
N
R2
3
a
R2
81-82%
Ph
O
N
R1
N
N
H
HN
X
b
c
CH2Ph
81-82%
(6a,b)
CH2(pyridyl-3)
5c-e
2-propanol
reflux, 5 h
X
O
N
R1
7
X
R1
O
a
Me CH2
6
N
X
CH2
Ph
Me
Ph
b
c
d
a
CH2
O
X
O
O
N
R1
N
N
b
7a-d
When the reaction of dichloro compounds 2a,b with
amines 3b,c was carried out using the amine as the
solvent, a substitution of the both chloro atoms in 2 was
observed and 5,7-dibenzylamino- or 5,7-di-(3-picolyl-
amino)-pyrido[2,3-d]pyrimidinediones 5c-e were obtained
When dichloro compounds 2a,b were heated with
aniline (3a) under reflux in 2-propanol as the solvent, in
excellent yields as the only products the mono-amination
derivatives, 7-chloro-5-phenylamino-pyrido[2,3-d]pyrim-
1
1
idinediones 4a,b were isolated. Comparison of H nmr
in excellent yields. The H nmr data of 5 indicated the
data of dichloro compound 2 and anilino compound 4
indicates the appearence of an amine signal in 4 at δ
10.85-10.90 ppm caused by the formation of the -NH-
group. To exclude a 7-anilino structure, spectra of 4a,b
were compared with those of 5-phenylaminopyrido-
[2,3-d]pyrimidinetriones, obtained from its 5-tosyloxy
derivative with aniline [4b]. Both 1H NMR spectra
showed the proton signal of the aniline-NH at δ 10.10-
10.90 ppm, which is a proof for substitution at the
position 5 and not at 7. Also 13C nmr data confirm the
structure of 4.
appearence of an additional signal of the NH at C-7 at δ
4.50-5.20 ppm (besides the signal of the NH at C-5 at δ
9.10-9.40 ppm). These different values of the NH signals
could be explained by a shift of the NH in position 5 by
hydrogen bonding with the 4-oxo group, whereas the NH
in position 7 without any neighbour groups did not show a
shift. So it was possible due to the different reactivity of
the chloro atoms in position 5 and 7 to get in a simple way
mono- or diaminated products 4 and 5.
The reaction of 5,7-dichloro compounds 2a,b with
secondary alkyl amines such as piperidine (6a) or

May-Jun 2008
Synthesis of 5-Mono- and 5,7-Diamino-pyrido[2,3-d]pyrimidinediones
by Regioselective Amination
823
morpholine (6b) gave - in contrast to primary alkylamines
3b,c - already in 2-propanol under reflux conditions a
substitution of both chloro atoms leading to 5,7-
dipiperidino- and 5,7-dimorpholino-pyrido[2,3-d]pyrimi-
dinediones 7a-d. It was not possible when using lower
phenylamino- or a benzylamino group. At these reaction
conditions no displacement of the primary introduced
amine at position 5 was observed.
Whereas N-substituted amines 4, 5, 7-9 are amenable in
good yields by direct amination, the introduction of an
unsubstituted amino group showed some difficulties.
Direct amination with ammonia produced a mixture of
decomposition products, and debenzylation of 4c,d
destroyed the 7-chloro group. So another pathway via the
introduction of the azido group followed by a Staudinger
and an Aza-Wittig reaction, which was applied in our lab
several times (e.g. ref. [8,4a]), was started. When
dichloro-pyrido[2,3-d]pyrimidinediones 2a,b were heated
with sodium azide in dry dimethylformamide at room
temperature for 2 hours, in good yields azides of
pyrido[2,3-d]pyrimidinediones were isolated; however,
these compounds were rather unstable. The characteristic
azido infrared signals could be detected, but further
purification or exact structural assignment failed.
Attempts to convert the azides to iminophosphoranes as
more stable intermediates by reaction with triphenyl-
phosphane via a Staudinger reaction produced a mixture
of compounds, which could not be purified sufficiently
for structure elucidation and further reactions.
reaction temperatures to obtain
derivative.
a
mono-aminated
The reaction of 5,7-dichloro compounds 2a,b with
aniline (3a) both in refluxing 2-propanol or at higher
reaction temperatures using refluxing aniline as the
solvent, gave only a substitution of the chloro atom at the
position 5. When dimethylformamide as a high boiling
solvent was applied to raise the reactivity and to force a
di-substitution, a substitution of the both chloro atoms
was observed. Surprisingly, the second chloro atom at
position 7 was not replaced by aniline, but structure
elucidation revealed the presence of a dimethylamino
group. The formation of 7-dimethylamino-5-phenyl-
amino-pyrido[2,3-d]pyrimidinediones 8a,b can only be
explained by decomposition of dimethylformamide used
as the solvent and substitution of the 7-chloro substituent
by the resulting dimethylamine. 1H nmr data of 8 indicate
the appearence of the already known phenylamine NH
signal in at δ 10.50-10.60 ppm formed by the substitution
of the 5-chloro atom, and an additional dimethylamine
signal at δ 2.75-3.07. The reaction of the 5,7-dichloro
compound 2a with benzylamine (3b) in dimethyl-
formamide gave in good yields 5-benzylamino-7-
dimethylamino-pyrido[2,3-d]pyrimidine-2,4-dione (8c),
similar as observed with aniline.
In contrast to the unstable azides described above,
7-azido-pyrido[2,3-d]pyrimidinediones were prepared
easily from the corresponding 5-amino-substituted-7-
Scheme 4
R2
R2
The meanwhile obtained results show a significant
difference in the reactivity of the chloro atoms at position
5 and 7 which allowed us to obtain in one-pot reactions
either mono- or diaminated pyrido[2,3-d]pyrimidine-
diones 4, 5, 7 and 8.
HN
2-propanol
O
HN
N
O
HN
N
(6a)
Me
O
Me
O
N
N
reflux, 3 h
N
Cl
N
N
75-76%
Me
Me
4a-f
R2
Ph
9
a
b
NaN3
DMF
110-120 o
3 h
Scheme 3
CH2Ph
80-89%
R2
R2
C
O
Cl
N
O
HN
R2 NH2
DMF
(3a,c)
R1
O
R1
O
N
N
R1
reflux, 8 h
70-73%
O
HN
10-12
a
R2
Me
Me
R1
N
Me Ph
N
Cl
N
R1
N
N
Ph
Ph
b
c
R1
8a-c
Me
2a,b
CH2Ph
2,8 R1 R2
O
N
N
N3
Ph CH2Ph
d
e
f
R1
Me
Ph Ph
Me CH2Ph
Ph
a
b
c
CH2(pyridyl-3)
CH2(pyridyl-3)
Me
Ph
10a-f
Ph3P
toluene
82-88%
R2
100 o
30 min
C
To get other mixed diamines, a sequential amination
reaction was applied, in the first step with less reactive
amines or by mild reaction conditions, which gave only 5-
amino products 4. In the second step, with more reactive
amines such as piperidine (6a) the reaction at C-7 took
place, and with 2-propanol as the solvent we obtained in
good yields the mixed amines, 7-piperidino-pyrido[2,3-d]-
pyrimidinediones 9a,b, having at position 5 either a
R2
O
HN
O
HN
N
AcOH
R1
O
reflux, 3 h
R1
N
N
80-82%
PPh3
O
N
R1
N
NH2
N
R1
N
11a-d
12a-d

824
D. V. Tinh and W. Stadlbauer
Vol 45
chloro-compounds 4. Reaction of 7-chloro-5-amino-
substituted compounds 4a-f with sodium azide in dimethyl-
formamide gave 7-azido-5-amino-substituted compounds
10a-f in good yields and already in a pure form.
subsequent cyclization of the 5-arylamino substituent with
the 6-formyl group to give benzo[b]-pyrido[4,5-h]1,6-
naphthyridinetrione derivatives.
To stop the reaction at the amination step, 13b was
reacted with 2,6-dimethylaniline, which is unable to
cyclize in ortho-position. This amination reaction gave in
excellent yields 6-formyl-1,3-dimethyl-5-(2,6-dimethyl-
phenylamino)-8-phenyl-pyrido[2,3-d]pyrimidine-2,4,7-
Heterocyclic azides having a ring-nitrogen in ortho-
position are known to exist either in the openchain azido-
form or in the cyclized tautomeric tetrazolo form [10]. In
contrast to the findings in the quinoline series [8], the 7-
monoazides 10 showed strong azide signals in the infrared
spectra which reveals that the equilibrium is shifted in 7-
azido-pyrido[2,3-d]pyrimidinediones 10 to the azide form.
To perform a chemical structural assignment and for the
synthetic aim, the 7-monoazido-pyrido[2,3-d]pyrimi-
dinediones 10a-d were converted to iminophosphoranes
1
trione (14). H nmr data of 14 showed the NH signal at δ
11.88 ppm. A differential scanning calorimetry (DSC)
plot of 14 revealed that no cyclization of the 2,6-
dimethylanilino substituent with the formyl group took
place; the diagram contained only the melting point of the
amine 14. Amination of chloro compounds 13a-c in
position 5 with benzylamine and 3-picolylamine (3b,c) as
aliphatic primary amines could be carried out under mild
conditions to afford in good yields 5-alkylamino
derivatives 15a-c. No further reaction with the formyl
group was observed. With morpholine and piperidine
(6a,b) 5-alkylamino derivatives 16a-d were formed in
excellent yields.
In conclusion, we have developed a regioselective
amination on 5,7-dichloro-pyrido[2,3-d]pyrimidinediones
2. Due to the different reactivity of the chloro atoms in
position 5 and 7, a regioselective mono-amination at
position 5 and a subsequent amination reaction with
different, however more reactive amines at position 7 was
achieved. Unsubstituted amino groups could be
introduced at position 7 via azidation followed by
Staudinger and Aza-Wittig reaction. As additional
substituent the formyl group was introduced at position 5
by a Vilsmeier type reaction.
11a-d by reaction with triphenylphosphane via
a
Staudinger reaction. Hydrolysis with aqueous acetic acid
produced in one step 7-amino-pyrido[2,3-d]pyrimidine-
1
diones 12a-d. The H nmr spectra of 7-amino compounds
12a-d showed the NH2 protons at δ 4.50-6.70 ppm; the 5-
NH signals were observed as expected between 9.10-
11.40 ppm, depending on the nature of the amino
substituent.
The investigated amino-pyridopyrimidinediones of type
A and B [3] (Scheme 1) bear in many cases an electron
withdrawing group in position 6, such as an ester or cyano
substituent, which was observed to change Adenosine A2A
receptor affinity. So we intended to introduce a formyl
group as a versatile substituent at position 6 in a reaction
similar to the Vilsmeier formylation using dimethyl-
formamide as formylation agent. From our earlier studies
[4b] we knew that amination of 5-chloro-6-formyl-
pyrido[2,3-d]pyrimidinetriones 13 resulted in
a
EXPERIMENTAL
Scheme 5
Melting points were obtained on a Gallenkamp Melting Point
1
Me
Aparatus, Mod. MFB 595 in open capillary tubes. H and 13C
NH2
Me
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 δ-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. Mass spectra were obtained
from a HP 1100 LC/MSD mass spectral instrument (positive or
negative APCI ion source, 50–200 V, nitrogen). 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).
(3d)
R3
R2
Me
13,15
a
Me
O
HN
N
DMF
Me
CH2Ph
80 oC, 2 h
Me
O
CHO
b
c
Ph CH2Ph
N
Ph
CH2(pyridyl-3)
82%
R3 = Ph
N
O
Me
Ph
14
R2
R2 NH2
(3b,c)
O
N
Cl
O
HN
DMF
Me
CHO
Me
O
CHO
O
N
80 oC, 1 h
N
60-82%
O
N
O
N
N
Me R3
Me R3
15a-c
13a,b
X
HN
(6a,b)
X
O
N
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.
R3
X
16
DMF
Me
O
CHO
N
a
b
c
Me CH2
Ph CH2
80 oC, 1 h
N
N
O
81-86%
Me
Ph
O
O
Me R3
d
16a-d

May-Jun 2008
Synthesis of 5-Mono- and 5,7-Diamino-pyrido[2,3-d]pyrimidinediones
by Regioselective Amination
825
5,7-Dichloro-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,
3H)-dione (2a). A mixture of 5-hydroxypyrido[2,3-d]pyrimidine
1a [4b] (2.37 g, 10 mmol) in phosphoryl chloride (20 mL) was
heated under reflux for 2-3 hours. Then the excess solvent was
removed by distillation, the residue poured into ice/water (200
mL) and brought to pH = 6-7 with 2 N aq. sodium hydroxide.
The obtained precipitate was filtered by suction, washed with
water and dried. The yield was 1.80 g (80%), colorless prisms,
mp 247-250 °C (dimethylformamide); ir: 3085 w, 1715 s, 1670 s
cm-1; 1H nmr: δ 3.46 and 3.70 (2 s, 2x3 H, 2 NMe), 7.25 (s, 1 H,
6-H). Anal. Calcd. for C9H7Cl2N3O2 (260.08): C, 41.56; H, 2.71;
N, 16.16. Found: C, 41.41; H, 2.55; N, 16.08.
5,7-dichloropyrido[2,3-d]pyrimidine 2b (3.84 g, 10 mmol) and
benzylamine (3b) (3.20 g, 30 mmol) in 2-propanol (20 mL) as
described for 4c; the yield was 3.41 g (75%), colorless prisms,
mp 190 °C (ethanol); ir: 3260 w, 1720 s, 1660 s cm-1; 1H nmr: δ
4.42 (d, J = 5 Hz, 2 H, CH2), 6.38 (s, 1 H, 6-H), 7.28-7.55 (m, 15
H, ArH), 9.50 (t, J = 4.5 Hz, 1 H, NH). Anal. Calcd. for
C26H19ClN4O2 (454.92): C, 68.65; H, 4.21; N, 12.32. Found: C,
68.48; H, 4.13; N, 12.35.
7-Chloro-1,3-dimethyl-5-[(pyridin-3-ylmethyl)amino]-
pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (4e). A mixture of
5,7-dichloropyrido[2,3-d]pyrimidine 2a (2.60 g, 10 mmol) and
3-picolylamine (3c) (3.24 g, 30 mmol) in 2-propanol (20 mL) was
heated under reflux for 5 hours with intensive stirring. After
cooling, the formed precipitate was collected by suction, washed
with 2-propanol and dried. The yield was 2.40 g (73%), colorless
prisms, mp 178-180 °C (ethanol); ir: 3280 w, 1720 s, 1650 s cm-1;
1H nmr: δ 3.40 and 3.63 (2 s, 2x3 H, 2 NMe), 4.48 (d, J = 5 Hz, 2
H, CH2), 6.29 (s, 1 H, 6-H), 7.29 (t, J = 7 Hz, 1 H, 5'-H of
pyridyl), 7.63 (d, J = 8 Hz, 1 H, 6'-H of pyridyl), 8.58 (d, J = 8 Hz,
1 H, 4'-H of pyridyl), 8.60 (s, 1 H, 2'-H of pyridyl), 9.70 (t, J = 4.5
Hz, 1 H, NH). Anal. Calcd. for C15H14ClN5O2 (331.76): C, 54.31;
H, 4.25; N, 21.11. Found: C, 54.46; H, 4.13; N, 21.21.
7-Chloro-1,3-diphenyl-5-[(pyridin-3-ylmethyl)amino]-
pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (4f). This compound
was obtained from 5,7-dichloropyrido[2,3-d]pyrimidine 2b (3.84
g, 10 mmol) and 3-picolylamine (3c) (3.24 g, 30 mmol) in 2-
propanol (20 mL) as described for 4e; the yield was 3.60 g
(79%), colorless prisms, mp 220-222 °C (ethanol); ir: 3270 w,
1710 s, 1640 s cm-1; 1H nmr: δ 4.44 (d, J = 5 Hz, 2 H, CH2), 6.35
(s, 1 H, 6-H), 7.26-7.52 (m, 11 H, ArH and 5'-H of pyridyl), 7.63
(d, J = 8 Hz, 1 H, 6'-H of pyridyl), 8.57 (d, J = 8 Hz, 1 H, 4'-H of
pyridyl), 8.62 (s, 1 H, 2'-H of pyridyl), 9.55 (t, J = 4.5 Hz, 1 H,
NH). Anal. Calcd. for C25H18ClN5O2 (455.91): C, 65.86; H, 3.98;
N, 15.36. Found: C, 65.82; H, 3.87; N, 15.18.
5,7-Dichloro-1,3-diphenylpyrido[2,3-d]pyrimidine-2,4(1H,
3H)-dione (2b). This compound was obtained from 5-hydroxy-
pyrido[2,3-d]pyrimidine 1b [3b] (3.13 g, 10 mmol) as described
for 2a; the yield was 3.16 g (82%), colorless prisms, mp 286-
288 °C (dimethylformamide/ethanol); ir: 3080 w, 1715 s, 1670 s
1
cm-1; H nmr: δ 7.25 (s, 1 H, 6-H), 7.28-7.35 (m, 4 H, ArH),
7.45-7.55 (m, 6 H, ArH). Anal. Calcd. for C19H11Cl2N3O2
(384.22): C, 59.40; H, 2.89; N, 10.94. Found: C, 59.07; H, 2.84;
N, 10.89.
7-Chloro-1,3-dimethyl-5-phenylaminopyrido[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione (4a).
A mixture of 5,7-dichloro-
pyrido[2,3-d]pyrimidine 2a (2.60 g, 10 mmol) and aniline (3a)
(4.70 g, 50 mmol) in 2-propanol (20 mL) was heated under
reflux for 8 hours with intensive stirring. After cooling, the
solvent was evaporated under reduced pressure, and the residue
was digested with water (20 mL). The formed precipitate was
collected by suction, washed with water and dried. The yield
was 2.53 g (80%), colorless prisms, mp 197-199 °C (dimethyl-
1
formamide/ethanol); ir: 3220 w, 1710 s, 1650 s cm-1; H nmr: δ
3.45 and 3.65 (2 s, 2x3 H, 2 NMe), 6.60 (s, 1 H, 6-H), 7.25-7.30
(m, 3 H, ArH), 7.42-7.48 (m, 2 H, ArH), 10.90 (s, 1 H, NH).
Anal. Calcd. for C15H13ClN4O2 (316.75): C, 56.88; H, 4.14; N,
17.69. Found: C, 57.13; H, 4.02; N, 17.53.
5,7-Dibenzylamino-1,3-dimethylpyrido[2,3-d]pyrimidine-
2,4(1H,3H)-dione (5c). A mixture of 5,7-dichloropyrido[2,3-d]-
pyrimidine 2a (2.60 g, 10 mmol) and benzylamine (3b) (20 mL,
190 mmol) was heated under reflux for 8 hours. The solvent was
evaporated under reduced pressure, and the residue was digested
with water (20 mL), then brought to pH = 6 with hydrochloric
acid and extracted with chloroform (3x50 mL). The combined
organic solvent was dried over anhydrous calcium chloride and
taken to dryness i.vac. The residue was digested with ethanol
and the formed precipitate was collected by suction, washed
with ethanol and dried. The yield was 3.30 g (81%), colorless
prisms, mp 165 °C (ethanol); ir: 3300 w, 3280 w, 1680 s, 1640 s
7-Chloro-1,3-diphenyl-5-phenylaminopyrido[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione (4b). This compound was obtained
from 5,7-dichloropyrido[2,3-d]pyrimidine 2b (3.84 g, 10 mmol)
and aniline (3a) (4.70 g, 50 mmol) in 2-propanol (20 mL) as
described for 4a; the yield was 3.43 g (78%), colorless prisms,
1
mp 228-231 °C (ethanol); ir: 3220 w, 1715 s, 1660 s cm-1; H
nmr: δ 6.68 (s, 1 H, 6-H), 7.20-7.55 (m, 15 H, ArH), 10.85 (s, 1
H, NH). Anal. Calcd. for C25H17ClN4O2 (440.89): C, 68.11; H,
3.89; N, 12.71. Found: C, 67.89; H, 3.82; N, 12.79.
5-Benzylamino-7-chloro-1,3-dimethylpyrido[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione (4c).
A mixture of 5,7-dichloro-
1
cm-1; H nmr: δ 3.38 and 3.55 (2 s, 2x3 H, 2 NMe), 4.33 and
pyrido[2,3-d]pyrimidine 2a (2.60 g, 10 mmol) and benzylamine
(3b) (3.20 g, 30 mmol) in 2-propanol (20 mL) was heated under
reflux for 5 hours with intensive stirring. After cooling, the
formed precipitate was collected by suction, washed with 2-
propanol and dried. The yield was 2.60 g (78%), colorless
prisms, mp 165 °C (dimethylformamide/ethanol); ir: 3280 w,
4.43 (2 d, J = 5 Hz, 2x2 H, 2 CH2), 5.13 (t, J = 4.5 Hz, 1 H, 7-
NH), 5.23 (s, 1 H, 6-H), 7.28-7.30 (m, 10 H, ArH), 9.32 (t, J =
4.5 Hz, 1 H, 5-NH). Anal. Calcd. for C23H23N5O2 (401.47): C,
68.81; H, 5.77; N, 17.44. Found: C, 68.52; H, 5.81; N, 17.44.
5,7-Dibenzylamino-1,3-diphenylpyrido[2,3-d]pyrimidine-
2,4(1H,3H)-dione (5d). This compound was obtained from 5,7-
dichloropyrido[2,3-d]pyrimidine 2b (3.84 g, 10 mmol) and
benzylamine (3b) (20 mL, 190 mmol) as described for 5c; the
yield was 4.36 g (82%), colorless prisms, mp 233-235 °C
(dimethylformamide/ethanol); ir: 3430 w, 3330 w, 1710 s, 1645,
1
1710 s, 1655 s cm-1; H nmr: δ 3.43 and 3.65 (2 s, 2x3 H, 2
NMe), 4.46 (d, J = 5 Hz, 2 H, CH2), 6.35 (s, 1 H, 6-H), 7.32-7.38
(m, 5 H, ArH), 9.65 (t, J = 4.5 Hz, 1 H, NH); 13C nmr: δ 27.9
and 30.1 (2 Me), 46.9 (CH2), 76.7, 77.0 and 77.4 (PhC), 99.9 (C-
6).127.1, 127.9 and 129.5 (C-4a, C-5 and C-8a), 136.3 (C-7),
156.9 and 163.9 (C-2 and C-4). Anal. Calcd. for C16H15ClN4O2
(330.78): C, 58.10; H, 4.57; N, 16.94. Found: C, 58.20; H, 4.43;
N, 16.94.
1
1610 s cm-1; H nmr: δ 4.13 and 4.30 (2 d, J = 5 Hz, 2x2 H, 2
CH2), 4.49 (t, J = 4.5 Hz, 1 H, 7-NH), 5.21 (s, 1 H, 6-H), 7.05-
7.50 (m, 20 H, ArH), 9.18 (t, J = 4.5 Hz, 1 H, 5-NH). Anal.
Calcd. for C33H27N5O2 (525.62): C, 75.41; H, 5.18; N, 13.32.
Found: C, 74.73; H, 5.14; N, 13.24.
5-Benzylamino-7-chloro-1,3-diphenylpyrido[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione (4d). This compound was obtained from

826
D. V. Tinh and W. Stadlbauer
Vol 45
Anal. Calcd. for C27H27N5O4 (485.55): C, 66.79; H, 5.61; N,
14.42. Found: C, 66.37; H, 5.51; N, 14.35.
7-Dimethylamino-1,3-dimethyl-5-phenylaminopyrido[2,3-
1,3-Dimethyl-5,7-bis[(pyridin-3-ylmethyl)amino]pyrido-
[2,3-d]pyrimidine-2,4(1H,3H)-dione (5e). A mixture of 5,7-
dichloropyrido[2,3-d]pyrimidine 2a (2.60 g, 10 mmol) and
3-picolylamine (3c) (20 mL, 190 mmol) was heated under reflux
for 8 hours. The solvent was evaporated under reduced pressure,
and the residue was digested with water (50 mL), the formed
precipitate was collected by suction, washed with ethanol and
dried. The yield was 3.30 g (82%), colorless prisms, mp 194-196
d]pyrimidine-2,4(1H,3H)-dione (8a).
A mixture of 5,7-
dichloro-pyrido[2,3-d]pyrimidine 2a (2.60 g, 10 mmol) and
aniline (3a) (4.70 g, 50 mmol) in dimethylformamide (20 mL)
was heated under reflux for 8 hours with intensive stirring. After
cooling, the solution was evaporated under reduced pressure,
and the residue digested with water (50 mL). The formed
precipitate was collected by suction, washed with water and
dried. The yield was 2.28 g (70%), colorless prisms, mp 182-184
°C (dimethylformamide); ir: 1690 s, 1645 s cm-1; 1H nmr: δ 3.07
(s, 6 H, NMe2), 3.42 and 3.62 (2 s, 2x3 H, NMe), 5.85 (s, 1 H, 6-
H), 7.18-7.40 (m, 5 H, ArH), 10.62 (s, 1 H, NH) MS: m/z (%)
326 (8), 325 (41), 317 (37), 316 (100). Anal. Calcd. for
C17H19N5O2 (325.37): C, 62.76; H, 5.89; N, 21.52. Found: C,
62.72; H, 5.79; N, 21.54.
1
°C (ethanol); ir: 3290 w, 1670 s, 1645 s cm-1; H nmr (DMSO-
d6): δ 3.19 and 3.38 (2 s, 2x3 H, 2 NMe), 4.44 and 4.47 (2 d, J =
6 Hz, 4 H, 2 CH2), 5.41 (s, 1 H, 7-NH), 7.30 (m, J = 7 Hz, 2 H,
2x 5'-H of pyridyl), 7.67 (t, J = 8 Hz, 3 H, 6-H and 2x 6'-H of
pyridyl), 8.41 (dd, J = 2 and 8 Hz, 2 H, 2x 4'-H of pyridyl), 8.50
and 8.54 (2 s, 2x1 H, 2x 2'-H of pyridyl), 9.14 (s, 1 H, 5-NH).
Anal. Calcd. for C21H21N7O2 (403.45): C, 62.52; H, 5.25; N,
24.30. Found: C, 62.61; H, 5.31; N, 24.55.
1,3-Dimethyl-5,7-dipiperidin-1-ylpyrido[2,3-d]pyrimidine-
2,4(1H,3H)-dione (7a). A mixture of 5,7-dichloropyrido[2,3-d]-
pyrimidine 2a (2.60 g, 10 mmol) and piperidine (6a) (4.25 g, 50
mmol) in 2-propanol (20 mL) was heated under reflux for 5
hours with intensive stirring. After cooling, the formed
precipitate was collected by suction, washed with 2-propanol
and dried. The yield was 3.02 g (84%) colorless prisms, mp 180
7-Dimethylamino-1,3-diphenyl-5-phenylaminopyrido[2,3-d]-
pyrimidine-2,4(1H,3H)-dione (8b). This compound was
obtained from 5,7-dichloropyrido[2,3-d]pyrimidine 2b (3.84 g,
10 mmol) and aniline (1a) (4.70 g, 50 mmol) in dimethyl-
formamide (20 mL) as described for 8a; the yield was 3.28 g
(73%), colorless prisms, mp 260-262 °C (dimethylform-
-1
1
1
amide/ethanol); ir: 1710 s, 1645 s, 1610 s cm-1; H nmr: δ 2.75
°
C (ethanol); ir: 2930 w, 1695 s, 1650 s cm ; H nmr: δ 1.60 and
1.77 (2 m, 2x6 H, 2x 3,4,5-piperidinyl-CH2), 3.04 and 3.60 (2 m,
2x4 H, 2x 2,6-piperidinyl-CH2), 3.39 and 3.58 (2 s, 2x3 H, 2
NMe), 5.78 (s, 1 H, 6-H). Anal. Calcd. for C19H27N5O2 (357.46):
C, 63.84; H, 7.61; N, 19.59. Found: C, 63.78; H, 7.74; N, 19.64.
1,3-Diphenyl-5,7-dipiperidin-1-ylpyrido[2,3-d]pyrimidine-
2,4(1H,3H)-dione (7b). This compound was obtained from 5,7-
dichloropyrido[2,3-d]pyrimidine 2b (3.84 g, 10 mmol) and
piperidine (6a) (4.25 g, 50 mmol) in 2-propanol (20 mL) as
described for 7a; the yield was 4.01 g (85%), colorless prisms,
mp 259-261 °C (dimethylformamide/ethanol); ir: 2930 w, 2845
w, 1720 s, 1660 s cm-1; 1H nmr: δ 1.45, 1.58 and 1.78 (3 m, 3x4
H, 2x 3,4,5-piperidinyl-CH2), 3.10 and 3.25 (2 m, 2x4 H, 2x 2,6-
piperidinyl-CH2), 5.88 (s, 1 H, 6-H), 7.29-7.45 (m, 10 H, ArH).
Anal. Calcd. for C29H31N5O2 (481.60): C, 72.33; H, 6.49; N,
14.54. Found: C, 72.11; H, 6.52; N, 14.56.
(s, 6 H, NMe2), 5.88 (s, 1 H, 6-H), 7.13-7.50 (m, 15 H, ArH),
10.50 (s, 1 H, NH). Anal. Calcd. for C27H23N5O2 (449.52): C,
72.14; H, 5.16; N, 15.58. Found: C, 71.73; H, 5.01; N, 15.46.
5-Benzylamino-7-dimethylamino-1,3-dimethylpyrido[2,3-
d]pyrimidine-2,4(1H,3H)-dione (8c).
A mixture of 5,7-
dichloropyrido[2,3-d]pyrimidine 2a (2.60 g, 10 mmol) and
benzylamine (3b) (3.20 g, 30 mmol) in dimethylformamide (20
mL) was heated under reflux for 8 hours with intensive stirring.
After cooling, the solution was evaporated under reduced
pressure, and the residue was digested with water (50 mL). The
formed precipitate was collected by suction, washed with water
and dried. The yield was 2.44 g (72%) colorless prisms, mp 185-
187 °C (ethanol); ir: 3280 w, 1695 s, 1650 s cm-1; 1H nmr: δ 3.04
(s, 6 H, NMe2), 3.40 and 3.58 (2 s, 2x3 H, 2 NMe), 4.42 (d, J = 5
Hz, 2 H, CH2), 5.21 (s, 1 H, 6-H), 7.30-7.35 (m, 5 H, ArH), 9.25
(t, J = 4.5 Hz, 1 H, NH). Anal. Calcd. for C18H21N5O2 (339.40):
C, 63.70; H, 6.24; N, 20.63. Found: C, 63.37; H, 6.25; N, 20.69.
1,3-Dimethyl-5-phenylamino-7-piperidin-1-ylpyrido[2,3-d]-
pyrimidine-2,4(1H,3H)-dione (9a). A mixture of 7-chloro-
pyrido[2,3-d]pyrimidine 4a (3.31 g, 10 mmol) and piperidine
(6a) (1.70 g, 20 mmol) in 2-propanol (20 mL) was heated under
reflux for 3 hours. The solvent was removed under reduced
pressure, and the residue was digested with ethanol (20 mL), the
formed precipitate was collected by suction, washed with
ethanol and dried. The yield was 2.74 g (75%), colorless prisms,
mp 145 °C (ethanol); ir: 2935 w, 2835 w, 1690 s, 1650, 1610 s
1,3-Dimethyl-5,7-dimorpholin-4-ylpyrido[2,3-d]pyrimidine-
2,4(1H,3H)-dione (7c). A mixture of 5,7-dichloropyrido-
[2,3-d]pyrimidine 2a (2.60 g, 10 mmol) and morpholine (6b)
(4.35 g, 50 mmol) in 2-propanol (20 mL) was heated under
reflux for 5 hours with intensive stirring. After cooling, the
formed precipitate was collected by suction, washed with 2-
propanol and dried. The yield was 3.21 g (88%), colorless
prisms, mp 233-235 °C (ethanol); ir: 2960 w, 1680 s, 1645 s
1
cm-1; H nmr: δ 3.12 (t, J = 4.5 Hz, 4 H, 2x 3,5-morpholinyl-
CH2), 3.40 and 3.59 (2 s, 2x3 H, 2 NMe), 3.62 (t, J = 4.5 Hz, 4
H, 3,5-morpholinyl-CH2), 3.78 and 3.91 (2 t, J = 4.5 Hz, 2x4
H, 2x 2,6-morpholinyl-CH2), 5.76 (s, 1 H, 6-H). Anal. Calcd.
for C17H23N5O4 (361.40): C, 56,50; H, 6.41; N, 19.38. Found:
C, 56.35; H, 6.40; N, 19.27.
1
cm-1; H nmr: δ 1.58 (m, 6 H, 3,4,5-piperidinyl-CH ), 3.42 (s, 3
2
H, NMe), 3.52 (m, 4 H, 2,6-piperidinyl-CH2), 3.60 (s, 3 H,
NMe), 5.98 (s, 1 H, 6-H), 7.15-7.45 (m, 5 H, ArH), 10.63 (s, 1
H, NH). Anal. Calcd. for C20H23N5O2 (365.44): C, 65.74; H,
6.34; N, 19.16. Found: C, 65.33; H, 6.17; N, 18.99.
5,7-Dimorpholin-4-yl-1,3-diphenylpyrido[2,3-d]pyrimidine-
2,4(1H,3H)-dione (7d). This compound was obtained from 5,7-
dichloropyrido[2,3-d]pyrimidine 2b (3.84 g, 10 mmol) and
morpholine (6b) (4.35 g, 50 mmol) in 2-propanol (20 mL) as
described for 7c; the yield was 4.02 g (83%), colorless prisms,
mp 291-294 °C (ethanol); ir: 2960 w, 2850 w, 1715 s, 1665 s
5-Benzylamino-1,3-dimethyl-7-piperidin-1-ylpyrido[2,3-d]-
pyrimidine-2,4(1H,3H)-dione (9b). This compound was
obtained from 7-chloropyrido[2,3-d]pyrimidine 4c (3.30 g, 10
mmol) and piperidine (6a) (1.70 g, 20 mmol) in 2-propanol (20
mL) as described for 9a; the yield was 2.96 g (78%), colorless
prisms, mp 173 °C (ethanol); ir: 2940 w, 2860 w, 1690 s, 1660,
1
cm-1; H nmr: δ 3.18 and 3.30 (2 t, J = 4.5 Hz, 2x4 H, 2x 3,5-
morpholinyl-CH2), 3.60 and 3.88 (2 t, J = 4.5 Hz, 2x4 H, 2x 2,6-
morpholinyl-CH2), 5.75 (s, 1 H, 6-H), 7.26-7.49 (m, 10 H, ArH).
1
1610 s cm-1; H nmr: δ 1.55 (m, 6 H, 2x 3,4,5-piperidinyl-CH2),

May-Jun 2008
Synthesis of 5-Mono- and 5,7-Diamino-pyrido[2,3-d]pyrimidinediones
by Regioselective Amination
827
3.40 (s, 3 H, NMe), 3.50 (m, 4 H, 2,6-piperidinyl-CH2), 3.56 (s,
3 H, NMe), 4.38 (d, J = 4.5 Hz, 2 H, CH2), 5.38 (s, 1 H, 6-H),
7.25-7.35 (m, 5 H, ArH), 9.24 (t, J = 4.5 Hz, 1 H, NH). Anal.
Calcd. for C21H25N5O2 (379.47): C, 66.47; H, 6.64; N, 18.46.
Found: C, 66.75; H, 6.69; N, 18.60.
General Procedure for the Preparation of 5-Amino-
substituted 7-Azido-pyrido[2,3-d]pyrimidine-2,4(1H, 3H)-
diones 10. A suspension of the appropriate 7-chloro-pyrido-
[2,3-d]pyrimidine 4 (10 mmol) and sodium azide (2.00 g, 30
mmol) in dry dimethylformamide (30 mL) was stirred at 110-
120 °C for 3 hours. Then the reaction mixture was poured into
ice/water (300 mL), the precipitate filtered, washed with water
and dried to obtain colorless prisms. Further data: see Table 1
and 3.63 (2 s, 2x3 H, 2 NMe), 4.45 (d, J = 5 Hz, 2 H, CH2), 5.73
(s, 1 H, 6-H), 7.30 (t, J = 7 Hz, 1 H, 5'-H of pyridyl), 7.63 (d, J =
8 Hz, 1 H, 6'-H of pyridyl), 8.55 (d, J = 8 Hz, 1 H, 4'-H of
pyridyl), 8.60 (s, 1 H, 2'-H of pyridyl), 9.65 (t, J = 4.5 Hz, 1 H,
NH). Anal. Calcd. for C15H14N8O2 (338.33): C, 53.25; H, 4.17;
N, 33.12. Found: C, 53.37; H, 3.98; N, 33.18.
7-Azido-1,3-diphenyl-5-[(pyridin-3-ylmethyl)amino]-
pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (10f). From 4f
1
(4.56 g, 10 mmol); ir: 3330 m, 2140 s, 1705 s, 1640 s cm-1; H
nmr: δ 4.34 (d, J = 5 Hz, 2 H, CH2), 5.75 (s, 1 H, 6-H), 7.25-7.50
(m, 11 H, ArH & 5'-H of pyridyl), 7.60 (d, J = 8 Hz, 1 H, 6'-H of
pyridyl), 8.52 (d, J = 8 Hz, 1 H, 4'-H of pyridyl), 8.55 (s, 1 H, 2'-
H of pyridyl), 9.50 (t, J = 4.5 Hz, 1 H, NH). Anal. Calcd. for
C25H18N8O2 (462.47): C, 64.93; H, 3.92; N, 24.23. Found: C,
65.06; H, 3.78; N, 23.90.
Table 1
General Procedure for the Preparation of 5-Aminosubsti-
tuted 7-[(Triphenylphosphoranylidene)amino]pyrido[2,3-d]-
pyrimidine-2,4(1H,3H)-diones 11. To a solution of triphenyl-
phosphane (3.15 g, 12 mmol) in dry toluene (30 mL) was added
the appropriate 7-azidopyrido[2,3-d]pyrimidine 10 (10 mmol) at
room temperature; a slightly exothermic reaction started, and 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 cooled to room temperature and
allowed to stand overnight, then filtered by suction and washed
with cyclohexane to obtain colorless prisms. Further data see
Table 1.
1,3-Dimethyl-5-phenylamino-7-[(triphenylphosphoranyli-
dene)amino]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (11a).
From 10a (3.23 g, 10 mmol); ir: 1700 s, 1640 s cm-1; 1H nmr: δ
2.78 and 3.36 (2 s, 2x3 H, 2 NMe), 6.40 (s, 1 H, 6-H), 7.10-7.75
(m, 20 H, ArH), 10.51 (s, 1 H, NH). Anal. Calcd. for
C33H28N5O2P (557.60): C, 71.09; H, 5.06; N, 12.56. Found: C,
71.11; H, 5.01; N, 12.64.
1,3-Diphenyl-5-phenylamino-7-[(triphenylphosphoranyli-
dene)amino]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (11b).
From 10b (4.47 g, 10 mmol); ir: 1700 s, 1655 s cm-1; 1H nmr: δ
6.52 (s, 1 H, 6-H), 6.80-7.52 (m, 30 H, ArH), 10.50 (s, 1 H,
NH). Anal. Calcd. for C43H32N5O2P (681.74): C, 75.76; H, 4.73;
N, 10.27. Found: C, 75.56; H, 4.54; N, 10.18.
5-Benzylamino-1,3-dimethyl-7-[(triphenylphosphoranyli-
dene)amino]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (11c).
From 10c (3.37 g, 10 mmol); ir: 3330 w, 1680 s, 1645 s cm-1; 1H
nmr: δ 2.73 and 3.32 (2 s, 2x3 H, 2 NMe), 4.43 (d, J = 5 Hz, 2
H, CH2), 5.90 (s, 1 H, 6-H), 7.28-7.75 (m, 20 H, ArH), 9.03 (t, J
= 4.5 Hz, 1 H, NH). Anal. Calcd. for C34H30N5O2P (571.62): C,
71.44; H, 5.29; N, 12.25. Found: C, 71.61; H, 5.27; N, 12.09.
5-Benzylamino-1,3-diphenyl-7-[(triphenylphosphoranyli-
dene)amino]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (11d).
From 10d (4.61 g, 10 mmol); ir: 1730 s, 1642 m cm-1; 1H nmr: δ
4.42 (d, J = 5 Hz, 2 H, CH2), 6.07 (s, 1 H, 6-H), 6.80-7.50 (m, 30
H, ArH), 8.95 (t, J = 4.5 Hz, 1 H, NH). Anal. Calcd. for
C44H34N5O2P (695.77): C, 75.96; H, 4.93; N, 10.07. Found: C,
75.44; H, 4.99; N, 10.20.
Chemical Yields and Mp for Compounds 10-12.
Yield
Mp (°C)
180-182
192-194
173-175
185
Recryst. Solvent
ethanol
10a
10b
10c
10d
10e
10f
2.58 g (80%)
4.00 g (89%)
2.70 g (81%)
3.82 g (83%)
2.65 g (82%)
3.74 g (81%)
4.74 g (85%)
6.02 g (88%)
4.85 g (85%)
5.70 g (82%)
2.38 g (80%)
3.45 g (82%)
2.55 g (82%)
3.52 g (81%)
ethanol
ethanol
ethanol
186
ethanol
189-191
234-236
303-305
238-230
299-301
238-240
270
ethanol
11a
11b
11c
11d
12a
12b
12c
12c
ethanol
ethanol
ethanol
dimethylformamide
ethanol
ethanol
213-215
300-302
ethanol
DMF/ethanol
7-Azido-1,3-dimethyl-5-phenylaminopyrido[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione (10a). From 4a (3.16 g, 10 mmol); ir:
3220 w, 2140 s, 2110 s, 1710 s, 1650 s, 1610 m cm-1; 1H nmr: δ
3.45 and 3.65 (2 s, 2x3 H, 2 NMe), 6.12 (s, 1 H, 6-H), 7.21-7.30
(m, 3 H, ArH), 7.39-7.45 (m, 2 H, ArH), 10.90 (s, 1 H, NH).
Anal. Calcd. for C15H13N7O2 (323.32): C, 55.72; H, 4.05; N,
30.33. Found: C, 55.81; H, 3.94; N, 30.60.
7-Azido-1,3-diphenyl-5-phenylaminopyrido[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione (10b). From 4b (4.50 g, 10 mmol); ir:
1
3260 w, 2130 s, 1715 s, 1650 s, 1610 cm-1; H nmr: δ 6.15 (s, 1
H, 6-H), 7.18-7.55 (m, 15 H, ArH), 10.82 (s, 1 H, NH). Anal.
Calcd. for C25H17N7O2 (447.46): C, 67.11; H, 3.83; N, 21.91.
Found: C, 67.07; H, 3.78; N, 21.53.
7-Azido-5-benzylamino-1,3-dimethylpyrido[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione (10c). From 4c (3.30 g, 10 mmol); ir:
3280 w, 2140 s, 2120 s, 1690 s, 1655 s cm-1; 1H nmr: δ 3.41 and
3.63 (2 s, 2x3 H, 2 NMe), 4.42 (d, J = 5 Hz, 2 H, CH2), 5.75 (s, 1
H, 6-H), 7.28-7.35 (m, 5 H, ArH), 9.62 (t, J = 4.5 Hz, 1 H, NH).
Anal. Calcd. for C16H15N7O2 (337.34): C, 56.97; H, 4.48; N,
29.06. Found: C, 56.86; H, 4.43; N, 28.49.
7-Azido-5-benzylamino-1,3-diphenylpyrido[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione (10d). From 4d (4.55 g, 10 mmol); ir: 3280
w, 2130 s, 1715 s, 1655 s, 1600 m cm-1; 1H nmr: δ 4.35 (d, J = 5 Hz,
2 H, CH2), 5.78 (s, 1 H, 6-H), 7.25-7.55 (m, 15 H, ArH), 9.44 (t, J =
4.5 Hz, 1 H, NH). Anal. Calcd. for C26H19N7O2 (461.49): C, 67.67;
H, 4.15; N, 21.25. Found: C, 67.70; H, 4.01; N, 20.97.
General Procedure for the Preparation 5-Aminosubsti-
tuted 7-Amino-pyrido[2,3-d]pyrimidine-2,4(1H, 3H)-diones
12. A mixture of the appropriate phosphazene 11 (10 mmol),
glacial acetic acid (40 mL) and water (10 mL) was refluxed for 3
hours. After cooling, to the reaction mixture was added water
(50 mL), then the precipitate was filtered by suction and washed
with water. Further data: see Table 1.
7-Azido-1,3-dimethyl-5-[(pyridin-3-ylmethyl)amino]pyrido-
[2,3-d]pyrimidine-2,4(1H,3H)-dione (10e). From 4e (3.31 g, 10
1
mmol); ir: 3280 w, 2160 s, 1700 s, 1650 s cm-1; H nmr: δ 3.42

828
D. V. Tinh and W. Stadlbauer
Vol 45
7-Amino-1,3-dimethyl-5-phenylaminopyrido[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione (12a). From 11a (5.57 g, 10 mmol); ir:
5-Benzylamino-1,3,8-trimethyl-2,4,7-trioxo-1,2,3,4,7,8-
hexahydropyrido[2,3-d]pyrimidine-6-carbaldehyde (15a).
From 13a (2.83 g, 10 mmol) and benzylamine (3b) (1.28 g, 12
1
3440 m, 3340 m, 3230 w, 1690 s, 1635 s cm-1; H nmr (DMSO-
1
mmol); ir: 3080 w, 1715 s, 1665 s, 1640 s cm-1; H nmr: δ 3.35,
d6): δ 3.25 and 3.47 (2 s, 2x3 H, 2 NMe), 5.90 (s, 1 H, 6-H), 6.66
(s, 2 H, 7-NH2), 7.18-7.33 (m, 3 H, ArH), 7.40-7.50 (m, 2 H,
ArH), 10.64 (s, 1 H, 5-NH). Anal. Calcd. for C15H15N5O2
(297.32): C, 60.60; H, 5.09; N, 23.55. Found: C, 60.43; H, 5.12;
N, 23.78.
3.50 and 3.55 (3 s, 3x3 H, 3 NMe), 4.22 (d, J = 5 Hz, 2 H,
benzyl-CH2), 7.25-7.32 (m, 5 H, ArH), 10.10 (s, 1 H, CH=O),
10.58 (t, J = 4.5 Hz, 1 H, NH). Anal. Calcd. for C18H18N4O4
(354.37): C, 61.01; H, 5.12; N, 15.81. Found: C, 60.80; H, 4.95;
N, 15.79.
7-Amino-1,3-diphenyl-5-phenylaminopyrido[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione (12b). From 11b (6.82 g, 10 mmol); ir:
5-Benzylamino-1,3dimethyl-2,4,7-trioxo-8-phenyl-1,2,3,4,
7,8-hexahydropyrido[2,3-d]pyrimidine-6-carbaldehyde (15b).
From 13b (3.45 g, 10 mmol) and benzylamine (3b) (1.28 g, 12
1
3470 m, 3340 m, 1710 s, 1615 s cm-1; H nmr (DMSO-d6): δ
4.48 (s, 2 H, 7-NH2), 5.80 (s, 1 H, 6-H), 7.20-7.50 (m, 15 H,
ArH), 10.60 (s, 1 H, 5-NH). Anal. Calcd. for C25H19N5O2
(421.46): C, 71.25; H, 4.54; N, 16.62. Found: C, 70.97; H, 4.42;
N, 16.40.
7-Amino-5-benzylamino-1,3-dimethylpyrido[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione (12c). From 11c (5.71 g, 10 mmol); ir:
3480 w, 3430 w, 3340 m, 3230 w, 1670 s, 1645 s, 1620 s cm-1;
1H nmr (DMSO-d6): δ 3.21 and 3.43 (2 s, 2x3 H, NMe), 4.39 (d,
J = 5 Hz, 2 H, CH2), 5.40 (s, 1 H, 6-H), 6.53 (s, 2 H, 7-NH2),
7.32-7.38 (m, 5 H, ArH), 9.15 (t, J = 4.5 Hz, 1 H, 5-NH). Anal.
Calcd. for C16H17N5O2 (311.35): C, 61.72; H, 5.50; N, 22.49.
Found: C, 61.02; H, 5.39; N, 22.28.
1
mmol); ir: 3150 w, 3080 w, 1710 s, 1670 s, 1655 m cm-1; H
nmr: δ 2.85 and 3.35 (2 s, 2x3 H, 2 NMe), 4.44 (d, J = 5 Hz, 2
H, benzyl-CH2), 7.30-7.50 (m, 10 H, ArH), 10.10 (s, 1 H,
CH=O), 10.80 (t, J = 4.5 Hz, 1 H, NH). Anal. Calcd. for
C23H20N4O4 (416.44): C, 66.34; H, 4.84; N, 13.45. Found: C,
66.13; H, 4.73; N, 13.43.
1,3-Dimethyl-2,4,7-trioxo-8-phenyl-5-[(pyridin-3-ylmethyl)-
amino]-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-6-car-
baldehyde (15c). From 13b (3.45 g, 10 mmol) and 3-picolyl-
amine (3c) (1.29 g, 12 mmol); ir: 1720 s, 1670 s, 1650 s cm-1; 1H
nmr: δ 2.87 and 3.40 (2 s, 2x3 H, 2 NMe), 4.50 (d, J = 5 Hz, 2
H, CH2), 7.25-7.35 (m, 3 H, ArH and 5'-H of pyridyl), 7.48-7.52
(m, 3 H, ArH), 7.70 (d, J = 8 Hz, 2 H, 4'-H and 6'-H of pyridyl),
8.62 (s, 1 H, 2'-H of pyridyl), 10.10 (s, CH=O). Anal. Calcd. for
C22H19N5O4 (417.43): C, 63.30; H, 4.59; N, 16.78. Found: C,
62.94; H, 4.58; N, 16.45.
7-Amino-5-benzylamino-1,3-diphenyl-pyrido[2,3-d]pyrim-
idine-2,4(1H,3H)-dione (12d). From 11d (6.96 g, 10 mmol); ir:
1
3500 w, 3390 m, 3300 w, 1700 s, 1640, 1600 s cm-1; H nmr
(DMSO-d6): δ 4.40 (d, J = 5 Hz, 2 H, CH2), 5.44 (s, 1 H, 6-H),
6.32 (s, 2 H, 7-NH2), 7.32-7.52 (m, 15 H, ArH), 9.05 (t, J = 4.5
Hz, 1 H, 5-NH). Anal. Calcd. for C26H21N5O2 (435.49): C, 71.71;
H, 4.86; N, 16.08. Found: C, 71.41; H, 4.82; N, 16.07.
General Procedure for the Preparation of 5-Aminosubsti-
tuted 2,4,7-Trioxo-8-phenyl-1,2,3,4,7,8-hexahydropyrido[2,3-
1,3,8-Trimethyl-2,4,7-trioxo-5-piperidin-1-yl-1,2,3,4,7,8-
hexahydropyrido[2,3-d]pyrimidine-6-carbaldehyde (16a).
From 13a (2.83 g, 10 mmol) and piperidine (6a) (1.02 g, 12
mmol); ir: 3400 w, 2940 w, 2850 w, 1710 s, 1670 s, 1640 s cm-1;
1H nmr: δ 1.67 (m, 6 H 3,4,5-piperidinyl-CH2), 3.30 (m, 4 H,
2,6-piperidinyl-CH2), 3.32, 3.48 and 3.50 (3 s, 3x3 H, 3 NMe),
9.83 (s, 1 H, CH=O). Anal. Calcd. for C16H20N4O4 (332.36): C,
57.82; H, 6.07; N, 16.86. Found: C, 57.43; H, 5.99; N, 16.67.
1,3-Dimethyl-2,4,7-trioxo-8-phenyl-5-piperidin-1-yl-1,2,3,
4,7,8-hexahydropyrido[2,3-d]pyrimidine-6-carbaldehyde
(16b). From 13b (3.45 g, 10 mmol) and piperidine (6a) (1.02 g,
12 mmol); ir: 3060 w, 2930 w, 2850 w, 1720 s, 1680 s, 1655 s
d]pyrimidine-6-carbaldehydes 14-16.
A mixture of the
appropriate 5-chloropyrido[2,3-d]pyrimidine-trione 13 [4b] (10
mmol) and amine 3 (12 mmol) in dimethyl-formamide (15 mL)
was stirred fro 1-2 hours at 70-80 °C. The solvent was removed
in vacuo, and the residual product triturated with water (100
mL). The resulting precipitate was filtered and washed with
water to give yellow prisms. Further data: see Table 2.
Table 2
1
cm-1; H nmr: δ 1.75 (m, 6 H, 3,4,5-piperidinyl-CH2), 2.85 and
Chemical Yields and Mp for Compounds 14-16.
3.39 (2 s, 2x 3 H, 2 NMe), 3.51 (m, 4 H, 2,6-piperidinyl-CH2),
7.25-7.50 (m, 5 H, ArH), 9.80 (s, 1 H, CH=O). Anal. Calcd. for
C21H22N4O4 (394.43): C, 63.95; H, 5.62; N, 14.20. Found: C,
63.73; H, 5.57; N, 14.27.
Yield
Mp (°C)
232-234
205-207
214-216
233-235
167-169
265-267
194-196
273-275
Recryst. Solvent
ethanol
14
3.53 g (82%)
2.83 g (80%)
3.41 g (82%)
2.50 g (60%)
2.87 g (86%)
3.39 g (86%)
2.70 g (81%)
3.37 g (85%)
15a
15b
15c
16a
16b
16c
16d
ethanol
1,3,8-Trimethyl-5-morpholin-4-yl-2,4,7-trioxo-1,2,3,4,7,8-
hexahydropyrido[2,3-d]pyrimidine-6-carbaldehyde
DMF/ ethanol
ethanol
(16c).
From 13a (2.83 g, 10 mmol) and morpholine (6b) (1.03 g, 12
mmol); ir: 2970 w, 1710 s, 1675 s, 1650 s, 1635 s cm-1; 1H nmr:
δ 3.33 (t, J = 4.5 Hz, 4 H, 3,5-morpholinyl-CH2), 3.51, 3.52 and
3.53 (3 s, 3x3 H, 3 NMe), 3.92 (t, J = 4.5 Hz, 4 H, 2,6-
morpholinyl-CH2), 9.92 (s, 1 H, CH=O). Anal. Calcd. for
C15H18N4O5 (334.33): C, 53.89; H, 5.43; N, 16.76. Found: C,
53.72; H, 5.57; N, 16.75.
1,3-Dimethyl-5-morpholin-4-yl-2,4,7-trioxo-8-phenyl-1,2,3,
4,7,8-hexahydropyrido[2,3-d]pyrimidine-6-carbaldehyde (16d).
From 13b (3.45 g, 10 mmol) and morpholine (6b) (1.03 g, 12
mmol); ir: 3060 w, 2980 w, 2850 w, 1720 s, 1675 s, 1650 s cm-1;
1H nmr (DMSO-d6) δ 2.62 and 3.20 (2 s, 2x3 H, NMe), 3.47 (t, J
= 4.5 Hz, 4 H, 3,5-morpholinyl-CH2), 3.82 (t, J = 4.5 Hz, 4 H,
2,6-morpholinyl-CH2), 7.52 (m, 5 H, ArH), 9.61 (s, 1 H, CH=O).
ethanol
dimethylformamide
ethanol
dimethylformamide
5-(2,6-Dimethylphenylamino)-1,3-dimethyl-2,4,7-trioxo-8-
phenyl-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-6-car-
baldehyde (14). From 13b (3.45 g, 10 mmol) and 2,6-
dimethylaniline (13d) (1.45 g, 12 mmol); ir: 1720 s, 1670 s,
1610 s cm-1; H nmr: δ 2.16 (s, 6 H, 2 Me), 2.90 and 3.47 (2 s,
1
2x3 H, 2 NMe), 7.09 (s, 3 H, ArH), 7.30-7.50 (m, 5 H, ArH),
9.63 (s, 1 H, CH=O), 11.88 (s, 1 H, NH). Anal. Calcd. for
C24H22N4O4 (430.47): C, 66.97; H, 5.15; N, 13.02. Found: C,
66.82; H, 5.12; N, 13.04.

May-Jun 2008
Synthesis of 5-Mono- and 5,7-Diamino-pyrido[2,3-d]pyrimidinediones
by Regioselective Amination
829
140, 93938; [b] Ukrainets, I. V.; Taran, S. G.; Gorokhova, O. V.;
Marusenko, N. A.; Kovalenko, S. N.; Turov, A. V.; Filimonova, N. I.;
Ivkov, S. M. Khim. Get. Soedin. 1995; 195; [c] Patel, H. V.; Vyas, K. A.;
Fernandes, P. S. Ind. J. Chem. 1990, 29b, 836; [d] Di Braccio, M.; Roma,
G.; Balbi, A.; Sottofattori, E.; Carazzone, M. Farmaco, Ed. Sci. 1989, 44,
865; [e] Van der Plas, H. C.; Wozniak, M. J. Heterocycl. Chem. 1986, 23
573; [f] Fournier, C.; Decombe, J. C. R. Acad. Sci.Paris, Ser. C 1967, 265,
1169; [g] Curd, F. H. S.; Raison, C. G.; Rose, F. L. J. Chem. Soc. 1947,
899; [h] Dziewonski, K.; Dymek, W. Bull. Int. Acad. Pol. Sci. A, 1936,
413; [i] Ephraim, J. Ber. Dtsch. Chem. Ges. 1893, 26, 2230.
[6a] Albert, A., Chemie der Heterocyclen, Verlag Chemie,
Weinheim, 1962; [b] Lettau, H. Chemie der Heterocylen, S. Hirzel-
Verlag, Leipzig, 1981; [c] Belli, M. L.; Illuminati, G.; Marino, G.
Tetrahedron 1963, 19, 345; [d] Belli, M. L.; Fatutta, S.; Forchiassin, M.;
Illuminati, G.; Linda, P.; Marino, G.; Zinato, E. Ric. Sci., Rend. Sez. A.
1963, 3, 530.
[7] Newkome, G. R.; Paudler, W. W. Contemporary
Heterocyclic Chemistry, J. Wiley and Sons, Inc., New York, 1982.
[8] Steinschifter, W.; Stadlbauer, W. J. Prakt. Chem. - Chem.
Ztg. 1994, 336, 311.
[9a] Knops, H. J.; Born, L. Tetrahedron Lett., 1983, 24, 2973; [b]
Kappe, T.; Ajili, S.; Stadlbauer, W. J. Heterocycl. Chem. 1988, 25, 463.
[10] Sasaki, T.; Kanematsu, K.; Murata, M. Tetrahedron 1972,
28, 2383.
Anal. Calcd. for C20H20N4O5 (396.41): C, 60.60; H, 5.09; N,
14.13. Found: C, 60.21; H, 5.06; N, 14.24.
Acknowledgement. This work was supported by an ASEA-
Uninet scholarship (D.V.T).
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