Improved synthesis of substituted pyrido[2,3-d]pyrimidinediones

Article abstract of DOI:10.1016/j.tetlet.2011.05.021

An improved methodology for the synthesis of substituted pyrido[2,3-d]pyrimidinediones from 6-aminouracils and the corresponding enaminone has been developed which provides high yields via an operationally simple process. The method has been extended to e

Full text of DOI:10.1016/j.tetlet.2011.05.021

Tetrahedron Letters 52 (2011) 3657–3661
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Tetrahedron Letters
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Improved synthesis of substituted pyrido[2,3-d]pyrimidinediones
⇑
Gwydion H. Churchill , Steven A. Raw, Lyn Powell
Pharmaceutical Development, AstraZeneca, Charter Way, Macclesfield SK10 2NA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
An improved methodology for the synthesis of substituted pyrido[2,3-d]pyrimidinediones from 6-amino-
Received 15 March 2011
Revised 18 April 2011
Accepted 6 May 2011
Available online 13 May 2011
uracils and the corresponding enaminone has been developed which provides high yields via an opera-
tionally simple process. The method has been extended to encompass
enaminones, a substrate class that does not perform well under the standard conditions.
Ó 2011 Elsevier Ltd. All rights reserved.
a range of electron-rich
Keywords:
Heteroannulation
Enaminone
6-Aminouracil
Pyrimidinedione
O
1. Introduction
O
NH
The pyrido[2,3-d]pyrimidinedione1 and related pyrido[2,3-
d]pyrimidine2 motifs are common pharmacophores and, as such,
are found in a wide range of pharmaceutically active compounds.
Due to this biological importance, construction of the pyrido[2,3-
d]pyrimidinedione skeleton has attracted much interest.3,4 One of
the more common methods used is the heteroannulation reaction
of an enaminone (1) with 6-aminouracil (2) or a derivative thereof
(e.g., see Scheme 1).3
NMe2
+
N
H
O
H
N2
MeO
2
1
O
O
O
-H2O
NH
NH
MeO
N
H
O
N
H
O
As part of an ongoing research programme,4 we desired expedi-
ent access to 7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine-2,4
(1H,3H)-dione (4) and chose to exploit this heteroannulation
reaction (Scheme 1)3 as it uses more stable and easily accessible
precursors than, for instance, the Bohlmann–Rahtz annulation of
alkynones.5 The reaction is usually carried out under acidic condi-
tions (e.g., neat AcOH,3a–c H2O/AcOH3d or MeCN/AcOH3e). Reported
yields are good to excellent, in the region of 73–99% for most
enaminones. However, yields for electron-rich aromatic enaminon-
es are significantly lower (47–52%).3d Why this should be the case
was not commented upon in the available literature.
N
N
2 H
3
MeO
4 MW=269
Scheme 1. Heteroannulation reaction of enaminone 1 with 6-aminouracil (2).
O
O
O
Ar
AcOH
Ar
Ar
Me2N
When we reacted 16 and 2 in acetic acid at reflux, 7-(4-methoxy-
phenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (4) was formed
in just 37% yield and was accompanied by two principal by-prod-
ucts, A and B. Analysis by LC–MS showed these to be: A molecular
weight (MW) = 297, or 4 + 28, and B MW = 429, or 4 + 160.
Further investigation of the reaction conditions quickly showed
that neutral (DMSO, H2O, DMF) and basic (KOH, Et3N) media failed
1
Me2N
Dimer
Ar
O
Ar
O
O
Ar
O
Ar
O
Ar
NMe2
Ar
O
5
Trimer
Scheme 2. AcOH-catalysed polymerisation of enaminone 1.
⇑
Corresponding author. Tel.: +44 1625 232426; fax: +44 1625 515853.
E-mail address: gwydion.churchill@astrazeneca.com (G.H. Churchill).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.021

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G. H. Churchill et al. / Tetrahedron Letters 52 (2011) 3657–3661
Table 1
Enaminone substrate scope
Entry
Enaminonea
Product
Yieldb,c (%)
96 (37)
O
O
NMe2
NH
1
MeO
O
N
N
H
4
1
MeO
O
O
NMe2
NH
O
2
3
4
95 (62)
O
6
N
H
O
N
O
7
O
NMe2
NH
79
8
O
N
N
H
9
O
O
NMe2
10
NH
82
N
H
O
N
11
O
O
NMe2
NH
5
6
7
78 (27)
84 (44)
Me2N
12
O
N
N
H
13
Me2N
O
O
NMe2
NH
O
N
N
H
14
15
O
O
NMe2
NH
88 (36)
Br
O
N
N
H
16
Br
17
O
O
NMe2
NH
8
81
O2N
N
N
H
O
18
O2N
19
a
Enaminone (1.0 equiv) in DMSO (1 M) added to 6-aminouracil (2) (2 equiv) in AcOH/H2O (1.5:1, 0.8 M in 6-aminouracil) at 90 °C.
Reaction yield of the isolated solid.
Conversion by HPLC recorded in parentheses for the reaction of enaminone (1.0 equiv) and 6-aminouracil (1.0 equiv) in neat AcOH (0.4 M in 6-aminouracil) at 100 °C.
b
c
to give any product, except in neutral water where the ratio of
product to by-products was good, but the isolated yield was low
(48%). A wide range of acidic conditions was investigated (AcOH,
HCl, AcOH/DMSO, AcOH/H2O) giving poor product/by-product ra-
tios except with DMSO/AcOH but, once again, the isolated yield
of 4 was low (51%). Lewis acids were similarly unreactive, while
the additional presence of a Brønsted acid merely gave poor prod-
uct/by-product ratios. Most importantly, all the conditions
screened resulted in incomplete conversion of starting materials
even after extended reaction times (P24 h), except for neat AcOH.
This may go some way to explaining the low isolated yields.
AcOH-catalysed polymerisation/cyclisation of amphiphilic
enaminones, including 1, to give substituted benzenes (e.g., 5)
has been reported (Scheme 2).7 Unfortunately, neither the dimer,
trimer nor benzene 5 has the correct mass for A or B.
However, closer examination of the LC–MS data from the initial
screen showed that 5 was not formed under any set of conditions.
We thought this unusual, as it is reported to form rapidly in hot
AcOH.6 Given that it is reasonable to expect the dimerisation path-
way to be operating under acid-mediated conditions, we postu-
lated that the dimer (presumably more reactive than 1, having
two carbonyls conjugated to the same
a,b-system) is being inter-
cepted by 6-aminouracil (2) in a relatively fast reaction, before
any trimerisation takes place (Scheme 3). A final cyclisation is then
simple as a potential 6-exo-trig reaction is available regardless of
the orientation of the C@C double bond. Simple condensation

G. H. Churchill et al. / Tetrahedron Letters 52 (2011) 3657–3661
3659
O
Slow
Slow
O
+
1
2
3
Desired pathway
4
R
X
R
X
N
1 in DMSO
N
N
N
R
O
O
H
N
R
N2
AcOH/H2O
90 ºC
Ar
NH
MeO
O
23 R = Me, X = O
25 R = H, X = S
24 R = Me, X = O 94%
26 R = H, X = S 78%
Ar
O
N
N
H
O
Ar
O
Fast
[Dimer]
6-exo-trig
Fast
2
O
Ar
B, MW=429
Scheme 5. Alternative 6-aminouracil coupling partners.
NH
O
N
H
O
H2N
NH
Ar
cyclisation the desired product 21 was isolated in a moderate
53% yield as a 1.3:1 mixture with species 22. That 21 is formed
at all is pleasing given the 2,6 bis-ortho substitution, which might
be expected to force the carbonyl functionality of the enaminone
orthogonal to the plane of the trimethoxyphenyl moiety, thus pre-
venting formation of the pyridine ring. This result is even more
surprising when compared with the corresponding ‘all-in’ reaction.
In this instance, compound 22 was almost exclusively formed and
isolated from the reaction in 17% yield.8
Fast
N
O
N
H
H
O
O
O
Ar
NH
Ar
N
O
N
A, MW=297
H
Ar = 4-(MeO)C6H4-
Scheme 3. Competing reaction pathways in the heteroannulation process.
A final measure of the utility of this process was to vary the
nature of the uracil component (Scheme 5). 1,3-Dimethyl-6-
aminouracil (23) coupled uneventfully with para-methoxy
phenylenaminone 1 to give the corresponding doubly methylated
pyrimidinedione 24 in excellent yield (94%), hinting that further
substitution of the uracil portion could be well tolerated in this
process. The reactivity of the thiouracil 25 was also of interest as
the thiocarbonyl functionality has been shown to be amenable to
subsequent direct substitution, thereby allowing differential sub-
stitution at the 2- and 4- positions of the product. Thiopyrimidin-
edione 26 was thus obtained in 78% yield under our improved
conditions.
In summary, we have identified an alternative reaction pathway
operating in the acid-catalysed heteroannulation of electron-rich
enaminones and 6-aminouracil (2), which accounts for the low
yields of the reaction, both observed and reported.3d We have
developed and applied an improved methodology for the reaction
in which a simple change in the mode of addition delivers dramatic
improvements in reaction performance and yield. The scope of the
new methodology has been exemplified with a range of electron-
rich substrates and different uracil partners.
would lead to B, MW = 429. Michael addition, followed by aroma-
tization via elimination of an enolate gives A, MW = 297.
These competitive processes explain the production of A and/or
B in the acid-mediated heteroannulations of 1. The proposed struc-
tures for A and B were subsequently confirmed by 1H NMR spec-
troscopic and mass spectrometric analysis of an isolated mixture.
Understanding the mechanism of by-product formation then
gave us the opportunity to overcome this issue. We reasoned that
slow addition of enaminone 1 to a mixture of excess 6-aminouracil
(2) in hot AcOH/water should bias the system in favour of the de-
sired reaction (entry 1, Table 1). We were gratified to discover that
this approach gave immediate success. The levels of by-products
were reduced to 60.5 area% by HPLC and, after a simple work-
up, the desired 7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine-
2,4(1H,3H)-dione (4) was isolated in an excellent 96% yield.
In order to explore the utility of this practical heteroannulation
procedure we prepared a range of electron-rich enaminone sub-
strates and subjected them to the optimised conditions (Table 1).
In all instances, the desired pyrido-pyrimidinedione was isolated
in high yield and with excellent purity. Notably the hindered tri-
subsituted enaminone 10 (entry 4) gave the tetracyclic product
11, and the very electron-rich dimethylaniline 12 (entry 5) gave
the desired pyrimidinedione 13 in high yield. The benefit of this
new protocol is clearly demonstrated by comparison with the yield
for the ‘all-in’ reactions (where both starting materials are present
from the start of the reaction) in neat acetic acid (entries 1, 2, 5, 6,
and 7). This method also tolerates electron-poor precursors, con-
firming its broad applicability, as exemplified by the cyclisation
of the nitrophenyl enaminone 18 to give pyrimidinedione 19 in
good yield (entry 8).
2. Representative procedure
To a slurry of 6-aminouracil (2) (2.55 g, 19.5 mmol) in AcOH
(15 mL) and H2O (10 mL) at 90 °C was added a solution of enami-
none 15 (2.00 g, 9.7 mmol) in DMSO (10 mL) dropwise via a syringe
pump over 4 h. The mixture was then stirred at 90 °C for a further
12 h to ensure complete cyclisation of intermediate 3. The mixture
was cooled to ambient temperature and the solids recovered by vac-
uum filtration. The filter cake was washed with EtOH (10 mL) and
the solid dried in vacuo to a constant mass, giving 7-(4-methoxy-
phenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (4) (2.53 g, 96%
The highly sterically hindered trimethoxyphenyl substrate 20
was subsequently prepared. This allowed us to test the limits of
the methodology (Scheme 4). When this substrate underwent
O
OMe
O
O
20 in DMSO added dropwise to
OMe
O
6-aminouracil (2) in AcOH/H2O, 90 O C
OMe
NH
NH
+
NMe2
or
N
N
O
OMe
N
N
H
MeO
O
H
1 eq of 6-aminouracil (2), 1 eq of 20
H
MeO
OMe
AcOH, 90 OC
MeO
OMe
20
21
22
dropwise 21:22 1.3:1 (53% isolated yield of 21)
'all-in' 21:22 1:15 (17% isolated yield of 22)
Scheme 4. 2,4,6-Trimethoxyphenylenaminone cyclisation.

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G. H. Churchill et al. / Tetrahedron Letters 52 (2011) 3657–3661
yield) as a colourless crystalline solid: 1H NMR (300 MHz, DMSO-d6)
d ppm: 3.85 (3H, s), 7.10 (2H, d, J 9.0 Hz), 7.76 (1H, d, J 8.5 Hz), 8.14
(2H, d, J 9.0 Hz), 8.25 (1H, d, J 8.5 Hz), 11.20–11.80 (2H, br s). MS: m/z
(EI) 270 (M+1). Spectroscopic data were in agreement with
literature values.3d Occasionally, the isolated product was contami-
nated with a small amount of 6-aminouracil (2). If necessary this
was removed by suspending the recovered solid in 3 M K2CO3 solu-
tion. Compound 4 was then isolated as its K-salt by vacuum filtra-
tion. This was suspended in 1 M citric acid solution to convert K-4
into its neutral form. Analytically pure 4 was then recovered quan-
titatively by vacuum filtration and washing with H2O.
121.9 (d), 135.7 (d), 150.4 (s), 152.1 (s), 158.1 (s  2), 161.5 (s),
162.3 (s). MS: m/z (EI) 330 (M+1); HR-MS (ESI) calcd for
C16H16N3O5: 330.1084, found: 330.1086 (0.4 ppm).
5-Methyl-6-[(2,4,6-trimethoxyphenyl)carbonyl]-1H,2H,3H,4H,5H,
8H-pyrido[2,3-d]pyrimidine-2,4-dione (22): 1H NMR (400 MHz,
DMSO-d6) d: 1.01 (3H, d, J 6.4 Hz), 3.68 (6H, s), 3.78 (1H, q, J
6.4 Hz), 3.80 (3H, s), 6.27 (2H, s), 6.76 (1H, s), 8.21 (1H, br s),
10.70 (2H, br s); 13C NMR (100 MHz, DMSO-d6) d: 20.1 (q), 22.0
(d), 53.8 (q), 54.0 (q  2), 87.8 (q), 89.2 (d  2), 109.0 (s), 118.8
(s), 137.5 (d), 142.6 (s), 156.4 (s), 159.8 (s  2), 161.8 (s), 189.5
(s). MS: m/z (EI) 374 (M+1); HR-MS (ESI) calcd for C18H20N3O6:
374.1347, found: 374.1349 (0.7 ppm).
Spectroscopic data for A: 1H NMR (300 MHz, DMSO-d6) d: 3.85
(3H, s), 7.05–7.15 (2H, m), 7.87 (2H, d, J 8.7 Hz), 8.39 (1H, d, J
2.4 Hz), 8.90 (1H, d, J 2.4 Hz). MS: m/z (EI) 298 (M+1); HR-MS
(ESI) calcd for C15H12N3O4: 298.0828, found: 298.0832 (1.4 ppm).
Spectroscopic data for B: 1H NMR (300 MHz, DMSO-d6) d ppm:
3.86 (3H, s), 3.88 (3H, s), 7.05–7.15 (4H, m), 7.53 (2H, d, J 8.7 Hz),
7.68 (1H, d, J 15.5 Hz), 8.08 (1H, d, J 15.5 Hz), 8.22 (2H, d, J
8.9 Hz), 8.96 (1H, s). MS: m/z (EI) 430 (M+1); HR-MS (ESI) calcd
for C24H20N3O5: 430.1403, found: 430.1414 (2.6 ppm).
7-(4-Methoxyphenyl)-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4-
dione (24 ): 1H NMR (400 MHz, DMSO-d6) d: 3.31 (3H, s), 3.66
(3H, s), 3.86 (3H, s), 7.07 (2H, d, J 8.9 Hz), 7.77 (1H, d, J 7.9 Hz),
8.15 (2H, d, J 8.9 Hz), 8.32 (1H, d, J 7.9 Hz); 13C NMR (100 MHz,
DMSO-d6) d: 25.8 (q), 26.8 (q), 53.4 (q), 106.0 (s), 112.1 (d), 112.4
(d  2), 126.9 (s), 127.5 (d  2), 135.6 (d), 148.3 (s), 149.0 (s),
157.6 (s), 158.5 (s), 159.5 (s). MS: m/z (EI) 298 (M+1); HR-MS
(ESI) calcd for C16H16N3O3: 298.1186, found: 298.1193 (2.2 ppm).
7-(4-Methoxyphenyl)2-sulfanylidenepyrido[2,3-d]pyrimidine-4-
(1H,3H)-one (26): 1H NMR (400 MHz, DMSO-d6) d: 3.86 (3H, s),
7.10 (2H, d, J 9.0 Hz), 7.86 (1H, d, J 8.4 Hz), 8.17 (2H, d, J 9.0 Hz),
8.28 (1H, d, J 8.4 Hz), 12.55 (1H, br s), 13.07 (1H, br s); 13C NMR
(100 MHz, DMSO-d6) d: 55.3 (q), 109.8 (s), 114.3 (d  2), 115.9
(d), 123.0 (s), 129.0 (d  2), 136.9 (d), 151.4 (s), 159.6 (s), 160.6
(s), 161.5 (s), 176.0 (s). MS: m/z (EI) 286 (M+1); HR-MS (ESI) calcd
for C14H12N3O2S: 286.0645, found: 286.0643 (0.7 ppm).
7-(2-Furyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (7): 1H NMR
(400 MHz, DMSO-d6) d: 6.74 (1H, dd, J 3.6 and 1.8 Hz), 7.29 (1H, dd,
J 3.6 and 0.8 Hz), 7.59 (1H, d, J 8.2 Hz), 7.97 (1H, dd, J 1.8 and
0.8 Hz), 8.29 (1H, d, J 8.2 Hz), 11.43 (1H, br s), 11.70 (1H, br s);
13C NMR (100 MHz, DMSO-d6) d: 108.1 (s), 112.4 (d), 112.9 (d),
113.4 (d), 137.4 (d), 146.0 (d), 150.5 (s), 151.8 (s), 152.1 (s),
152.5 (s), 162.0 (s). MS: m/z (EI) 230 (M+1); HR-MS (ESI) calcd
for C11H8N3O3: 230.0560, found: 230.0558 (1.0 ppm).
7-(2,4-Dimethylphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione
(9): 1H NMR (400 MHz, DMSO-d6) d: 2.33 (3H, s), 2.36 (3H, s),
7.13 (2H, m), 7.35 (1H, d, J 8.1 Hz), 7.36 (1H, d, J 7.5 Hz), 8.29
(1H, d, J 7.9 Hz), 11.44 (1H, br s), 11.66 (1H, br s); 13C NMR
(100 MHz, DMSO-d6) d: 20.2 (q), 20.7 (q), 107.8 (s), 126.5 (d),
129.5 (d), 131.6 (d), 135.6 (s), 135.8 (s), 136.6 (d), 138.5 (s),
150.5 (s), 151.8 (s), 162.2 (s), 164.0 (s). MS: m/z (EI) 268 (M+1);
HR-MS (ESI) calcd for C15H14N3O2: 268.1081, found: 268.1077
(1.3 ppm).
Acknowledgements
The authors would like to thank Anthony Bristow and Janet
Hammond for accurate mass spectrometric analysis. We are grate-
ful to the referee for mechanistic proposals.
References and notes
1,2,3,4,6,7-Hexahydro-1,3,12-triazatetraphene-2,4-dione (11): 1H
NMR (400 MHz, DMSO-d6) d: 2.94 (4H, m), 7.33 (1H, m), 7.41
(2H, m), 8.13 (1H, s), 8.20 (1H, m), 11.38 (1H, br s), 11.59 (1H, br
s); 13C NMR (100 MHz, DMSO-d6) d: 26.2 (t), 27.1 (t), 108.4 (s),
125.5 (d), 126.9 (d), 127.0 (s), 128.2 (d), 130.6 (d), 132.7 (s),
135.4 (d), 139.5 (s), 150.5 (s), 151.5 (s), 155.9 (s), 162.2 (s). MS:
m/z (EI) 266 (M+1); HR-MS (ESI) calcd for C15H12N3O2: 266.0924,
found: 266.0926 (0.7 ppm).
7-(4-Dimethylaminophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-
dione (13): 1H NMR (400 MHz, DMSO-d6) d: 3.01 (6H, s), 6.80
(2H, d, J 9.0 Hz), 7.66 (1H, d, J 8.3 Hz), 8.04 (2H, d, J 9.0 Hz), 8.16
(1H, d, J 8.3 Hz), 11.30 (1H, br s), 11.51 (1H, br s); 13C NMR
(100 MHz, DMSO-d6) d: 39.7 (q  2), 106.7 (s), 111.7 (d  2),
113.1 (d), 124.0 (s), 128.4 (d  2), 136.5 (d), 151.2 (s), 151.8 (s),
153.1 (s), 160.8 (s), 162.6 (s). MS: m/z (EI) 283 (M+1); HR-MS
(ESI) calcd for C15H15N4O2: 283.1190, found: 283.1191 (0.7 ppm).
7-(4-Phenylphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione
(15): 1H NMR (400 MHz, DMSO-d6) d: 7.40-7.54 (3H, m), 7.77–
7.90 (5H, m), 8.25–8.34 (3H, m), 11.44 (1H, br s), 11.72 (1H, br
s); 13C NMR (100 MHz, DMSO-d6) d: 108.2 (s), 114.8 (d), 126.4
(d), 126.7 (d), 127.5 (d), 127.6 (d), 128.6 (d), 135.6 (s), 137.0 (d),
138.8 (s), 141.6 (s), 150.2 (s), 152.0 (s), 159.6 (s), 161.8 (s). MS:
m/z (EI) 316 (M+1); HR-MS (ESI) calcd for C19H14N3O2: 316.1081,
found: 316.1087 (2.1 ppm).
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935–942.
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M. N.; Powell, L.; Raw, S. A. Int. patent WO 2009153597, 2009, Chem. Abstr. 2009,
152, 75063.
5. Bohlmann–Rahtz heteroannulation of alkynones: Hughes, D. D.; Bagley, M. C.
Synlett 2002, 1332–1334. and references therein.
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3775–3780.
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Chem. 2002, 39, 1035–1038.
8. The structure of 22 was confirmed by 2D NMR and we postulate that its
formation is due to residual acetaldehyde present in acetic acid. The formation
of 22 may be explained by reaction of 6-aminouracil (2) with acetaldehyde to
7-(2,4,6-Trimethoxyphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-
dione (21): 1H NMR (400 MHz, DMSO-d6) d: 3.66 (6H, s), 3.83
(3H, s), 6.32 (2H, s), 7.07 (1H, d, J 7.9 Hz), 8.20 (1H, d, J 7.9 Hz),
11.37 (1H, br s), 11.60 (1H, br s); 13C NMR (100 MHz, DMSO-d6)
d: 55.4 (q), 55.7 (q  2), 90.9 (d  2), 92.8 (s), 107.9 (s), 110.4 (d),

G. H. Churchill et al. / Tetrahedron Letters 52 (2011) 3657–3661
give species 27. Elimination of water under the acidic conditions could give
3661
reactive intermediate 28, which upon b-alkylation of the enamine followed by
heteroannulation and elimination of dimethylamine would give 22. We
attribute the increased ratio of 22:21 in the neat acetic acid process to an
increased rate of reaction of 2 with acetaldehyde and/or greater stability/
concentration of intermediate 28 under these conditions. Furthermore, when
three equivalents of acetaldehyde were doped into the acetic acid ‘all-in’
reaction, compound 22 was obtained in 65% yield.
O
NMe2
O
Ar
O
OH
O
O
H+
NH
NH
NH
Ar
22
N
H
O
N2H
27
O
H2N
+
N
H
Me2N
H+
N
H
O
N2H
28