Efficient synthesis of uracil-derived hexa- and tetrahydropyrido[2,3-d] pyrimidines

Article abstract of DOI:10.1002/ejoc.201300683

A reaction of 6-amino-1,3-dimethyluracil with 3-(hetero)aroylacrylic acids and their methyl esters leads to hexahydropyrido[2,3-d]pyrimidine-5-carboxylic acids or the corresponding methyl esters in high to excellent yields. One-pot oxidation of the acid d

Full text of DOI:10.1002/ejoc.201300683

FULL PAPER
DOI: 10.1002/ejoc.201300683
Efficient Synthesis of Uracil-Derived Hexa- and Tetrahydropyrido[2,3-
d]pyrimidines
Nikita Tolstoluzhsky,[a,b,c] Pavlo Nikolaienko,[c] Nikolay Gorobets,[b]
Erik V. Van der Eycken,[a] and Nadezhda Kolos*[c]
Keywords: 6-Aminouracil / Cyclization / Michael addition / Oxidation / Nitrogen heterocycles
A reaction of 6-amino-1,3-dimethyluracil with 3-(hetero)-
aroylacrylic acids and their methyl esters leads to hexa-
ines, while oxidation with bromine resulted in the formation
of tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acids. The
hydropyrido[2,3-d]pyrimidine-5-carboxylic acids or the cor- aromatization of methyl hexahydropyrido[2,3-d]pyrimidine-
responding methyl esters in high to excellent yields. One-pot
oxidation of the acid derivatives with CAN is accompanied
by decarboxylation to give tetrahydropyrido[2,3-d]pyrimid-
5-carboxylates was achieved by K2CO3-mediated air oxi-
dation under ambient conditions.
Introduction
In recent decades, heteroannulated pyrimidines have re-
ceived considerable attention. This interest is a result of
their various pharmacological activities. For example, ura-
cil-derived pyrido[2,3-d]pyrimidines have a range of bio-
logical properties, such as phosphodiesterase 2 (PDE 2) in-
hibition,[1a] or antihypertensive,[1b,1c] cardiotonic,[2] analge-
sic,[3a] antiviral,[3b] anti-inflammatory,[4] antimicrobial,[5,6]
or anticancer activities[7,8] (Figure 1). Therefore, the synthe-
sis of diverse structures belonging to this class of com-
pounds is important.
Several synthetic approaches for the construction of the
pyrido[2,3-d]pyrimidine scaffold have been reported in
which 6-aminouracils react with different types of 1,3-di-
electrophiles, such as α,β-unsaturated carbonyl com-
pounds,[9–12] electron-rich enamines,[13] Meldrum’s acid de-
rivatives,[14] compounds with a reactive methylene group, or
Mannich adducts.[15] They have also been synthesized by
multicomponent reactions.[16–20]
3-(Hetero)aroylacrylic acids or esters are reactive 1,3-di-
electrophiles that are commonly used as versatile building
blocks for diversity-oriented synthesis.[21–27] They are com-
mercially available, or can be easily obtained by a recently
Figure 1. Various biologically active pyrido[2,3-d]pyrimidines.
reported procedure.[28] However, to the best of our knowl-
edge, they have never been used for the synthesis of uracil-
derived pyrido[2,3-d]pyrimidine-5-carboxylic acids or their
esters.[29]
In this paper, we report the synthesis of tetra- and hexa-
hydro-7-arylpyrido[2,3-d]pyrimidines bearing a 5-carboxylic
acid or ester moiety, by condensation of 3-aroylacrylic acids
with 1,3-dimethyl-6-aminouracil. This approach is straight-
forward, metal-free, and atom-efficient.
[a] Laboratory for Organic & Microwave-Assisted Chemistry
(LOMAC), Katholieke Universiteit Leuven,
Celestijnenlaan 200F, 3001 Leuven, Belgium
[b] Department of Chemistry of Heterocyclic Compounds, SSI
“Institute for Single Crystals” of the National Academy of
Sciences of Ukraine,
Results and Discussion
Lenin Ave 60, Kharkiv 61001, Ukraine
Initially, p-methoxybenzoylacrylic acid (1a) was treated
with an equimolar amount of 1,3-dimethyl-6-aminouracil
(2) in DMF at room temp. for 12 h (Table 1, Entry 1) and,
to our delight, a new compound was formed. NMR spec-
troscopic analysis of the crude mixture showed remaining
[c] Department of Organic Chemistry, V. N. Karazin Kharkiv
National University,
Svobody Sq. 4, Kharkiv 61077, Ukraine
E-mail: nadezhda.n.kolos@gmail.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300683.
5364
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Uracil-Derived Hexa- and Tetrahydropyrido[2,3-d]pyrimidines
starting materials and also a new hexahydropyrido[2,3-d]- Table 2. Synthesis of 1,3-dimethyl-2,4-dioxo-7-aryl-1,2,3,4,5,6-
hexahydropyrido[2,3-d]pyrimidine-5-carboxylic acids 3a–o and
pyrimidine derivative 3a, formed in 35% yield.
methyl esters 7a–n.[a]
Table 1. Optimization of the reaction conditions.[a]
Yield [%][b]
Entry
Solvent
T/t
Yield [%][b]
Entry
Ar
Product
1
2
3
4
5
DMF
DMF
EtOH
r.t./12 h
60 °C/5 h
60 °C/5 h
60 °C/5 h
60 °C/5 h
60 °C/5 h
r.t./12 h
r.t./12 h
r.t./30 min
reflux/45 min
35
42
50
54
44
1
2
3
4
5
6
7
8
4-methoxyphenyl-
3a
7a
3b
7b
3c
7c
3d
7d
3e
7e
3f
95
90
94
80
98
89
98
86
95
95
90
92
94
90
93
84
95
90
89
95
90
85
97
96
95
89
87
87
85
phenyl-
MeOH
CH3CN
1,4-dioxane
DMF
DMF
DMF
AcOH
4-fluorophenyl-
6
40
7[c]
8[d]
9[e]
10
Ͻ5
Ͻ5
71
4-bromophenyl-
5-bromothienyl-
2-bromophenyl-
3,4,5-trimethoxyphenyl-
4-MeS-phenyl-
9
99 (95)[f]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
[a] Reaction conditions: 1a (0.5 mmol), 2 (0.5 mmol), solvent
(0.5 mL). [b] Yields based on NMR spectroscopy using mesitylene
as internal standard. [c] Et3N (1 equiv.) was used. [d] K2CO3
(1 equiv.) was used. [e] HCl (1 m aq.; 20 mol-%) was used. [f] Iso-
lated yield.
7f
3g
7g
3h
7h
3i
2,4-difluorophenyl-
perfluorophenyl-
3-methoxyphenyl-
4-MeSO2-phenyl-
2,4-dichlorophenyl-
3,4-difluorophenyl-
3-CF3-phenyl-
Inspired by this result, different reaction conditions were
screened. Altering the reaction temperature in the same sol-
vent gave no appreciable improvements in the outcome of
the reaction (Table 1, Entry 2). Heating in polar protic sol-
vents, such as alcohols, or in polar aprotic solvents, such as
acetonitrile or 1,4-dioxane, resulted in the formation of the
target compound, but only in moderate yields (Table 1, En-
tries 3–6). Additionally, NMR spectroscopic analysis indi-
cated the formation of the dehydrogenated product, pre-
sumably because of air present under the reaction condi-
tions. The use of bases such as Et3N and K2CO3 (Table 1,
Entries 7 and 8) was totally unsuccessful, due to salt forma-
tion with the aroylacrylic acids. On the other hand, when
we used aqueous HCl as a catalyst in DMF, after 3 h at
room temperature, we obtained hexahydropyrido[2,3-d]pyr-
imidine derivative 3a in 71% yield (Table 1, Entry 9). How-
7i
3j
7j
3k
7k
3l
7l
3m
7m
3n
7n
3o
[a] Reaction conditions: 1 (1 equiv., 1 mmol), 2 (1 equiv., 1 mmol),
AcOH (1 mL). [b] Isolated yields.
To expand the scope of our method, we also used the
ever, many by-products were formed under these condi- methyl esters of the 3-aroylacrylic acids, synthesized by es-
tions, which made purification of the target molecule prob- terification of acids 1a–o. The corresponding hexahydropyr-
lematic. These results suggested that acetic acid could be ido[2,3-d]pyrimidines (i.e., 7a–n) were smoothly obtained in
used as a solvent. This idea was also supported by studies high yields under the optimized conditions (Table 2). The
of the Bohlmann–Rahtz reaction,[11d] which were extended comparable yields of the methoxycarbonyl products (i.e.,
by Bagley and co-authors[12b,12c] for the formation of re- 7a–n) show that there is no significant difference between
lated pyrido[2,3-d]pyrimidines. Surprisingly, under these the reactivity of the acids and the esters.
conditions, the desired hexahydropyrido[2,3-d]pyrimidine
The proposed mechanism is shown in Scheme 1. Based
derivative 3a was formed in 95% isolated yield (Table 1, En- on literature data, we propose that the α-position is the
try 10). The product was isolated as a single compound re- most electrophilic center of the 3-aroylacrylic acids, and
quiring no further purification by simple dilution of the re- that C-5 is the most nucleophilic position in 6-aminouracil.
action mixture with ice-cold water and filtration of the re- Most probably, an initial Michael-type addition leads to ad-
sulting solid.
duct X1, and then nucleophilic attack of the 6-amino group
Subsequently, these optimized conditions were used for onto the carbonyl group results in the formation of interme-
a series of reactions of 3-(het)aroylacrylic acids 1b–o with diate X2. Finally, two possible pathways of dehydration
1,3-dimethyl-6-aminouracil, and target compounds 3b–o could give the product either in imine form A or enamine
were formed in high to excellent yields (Table 2).
form B.
Eur. J. Org. Chem. 2013, 5364–5369
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N. Kolos et al.
FULL PAPER
Scheme 2. Oxidation products of hexahydropyrido[2,3-d]pyrimid-
ines 3.
For complete decarboxylation, cerium ammonium nitrate
(CAN) was successfully used in water/acetone (1:9) under
ambient conditions to give decarboxylated product 5a ex-
clusively in 74% yield. The use of iodine pentoxide in water
also led to oxidative decarboxylation, but gave a much
lower yield.
Having found optimized reaction conditions, we devel-
oped a one-pot synthesis of two arrays of compounds 4a–e
and 5a–e, which were obtained in good to excellent isolated
yields (Table 3).
Table 3. Synthesis of 7-aryl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetra-
hydropyrido[2,3-d]pyrimidine-5-carboxylic acids 4a–e and 1,3-di-
methyl-7-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones 5a–e.[a]
Scheme 1. Plausible mechanism for the formation and imine/en-
amine tautomerism of hexahydropyrido[2,3-d]pyrimidines 3 and 7.
For the structural elucidation of previously unknown
hexahydropyrido[2,3-d]pyrimidines 3a–o and 7a–n, a full as-
1
signment of their H and 13C NMR spectra was performed
by using DEPT, HSQC, and HMBC in CDCl3. Hexahydro-
pyrido[2,3-d]pyrimidines 3a–o and 7a–n exist mainly as
their imine forms (i.e., A) in CDCl3, whereas in [D6]DMSO,
their enamine form (i.e., B) predominates (Scheme 1). This
was clear from the correlation of the key carbon signal of
C-7 with the neighboring aliphatic -CH2- and -CH- pro-
tons, as well as with protons of the aromatic ring.
The imino form could easily be identified by a 13C NMR
DEPT experiment, due to the presence of a 6-CH2 carbon
signal (at δ = 26.0 ppm for compound 3a). For the enamine
form, a pair of doublets due to protons 5-H and 6-H (δ =
4.2 and 5.2 ppm, respectively, J = 5.0 Hz for compound 3b)
Entry
Ar
Product
Yield [%][b]
1
2
3
4
5
6
7
8
9
4-methoxyphenyl
4a
5a
4b
5b
4c
5c
4d
5d
4e
5e
75
74
67
75
76
96
75
94
73
86
phenyl
4-fluorophenyl
4-bromophenyl
5-bromothienyl
1
was observed in the H NMR spectrum. It was found that
the the tautomeric ratio is determined by the substituent.
For example, phenyl derivative 3b is present in form B in
both solvents, whereas compound 3h exists in [D6]DMSO
as a tautomeric mixture of A and B forms in a ratio of 1:4
10
(see Supporting Information for 2D NMR spectra). A sim- [a] Reaction conditions: (i) 1 (1 equiv., 1 mmol),
2 (1 equiv.,
1 mmol), AcOH (1 mL), reflux, 45 min; (ii) Br2 (1.2 mmol)/CH2Cl2,
reflux, 3 h; KOH (4 mmol), iPrOH, reflux, 30 min, then HCl (aq.).
(iii) CAN (2.5 mmol), acetone/water (9:1; 15 mL), room temp., 3 h.
[b] Isolated yields.
ilar observation was made for ester derivatives 7b and 7h.
For the purposes of further functionalization, we investi-
gated the ease of oxidation of hexahydropyrido[2,3-d]pyr-
imidine 3a into its tetrahydro analog 4a (Scheme 2).
An initial attempted oxidation with air by using N-
In an attempt to stabilize the enamine form we per-
hydroxyphthalimide (NHPI) and Co(OAc)2 in refluxing formed alkylation at the N-8 position of the (methoxycarb-
MeCN[30] led only to the recovery of starting material 3a. onyl)hexahydropyrido[2,3-d]pyrimidine derivative 7a with
When N-bromosuccinimide (NBS) or bromine was used in benzyl bromide. We used K2CO3 (2.0 equiv.) as a base, and
refluxing AcOH or CHCl3, a mixture of the desired com- conducted the reaction in acetone at room temperature for
pound (i.e., 4a) and decarboxylated derivative 5a was ob- 24 h. To our great surprise, we obtained no alkylation prod-
tained. Conversely, when bromine was used in refluxing uct, but only aromatic tetrahydropyrido[2,3-d]pyrimidine
dichloromethane, and the reaction was worked up with derivative 8a, which was formed in excellent yield. To be
KOH and HCl (aq.), pure acid 4a was isolated in 75% yield. certain, we repeated this reaction without benzyl bromide
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Uracil-Derived Hexa- and Tetrahydropyrido[2,3-d]pyrimidines
and with other esters 7b–e, and we obtained only oxidized dation of these acid products in a one-pot fashion gives the
products 8a–e in high yields (Table 4, Entries 1–5).
aromatized compounds or the products of oxidative de-
carboxylation, depending on the oxidative system used. Re-
markably, efficient air oxidation of the corresponding esters
was demonstrated to occur in the presence of K2CO3 in
acetone at room temperature.
Table 4. Synthesis of methyl 7-aryl-1,3-dimethyl-2,4-dioxo-1,2,3,4-
tetrahydropyrido[2,3-d]pyrimidine-5-carboxylates 8a–e.[a]
Experimental Section
General Methods: 3-(het)aroylacrylic acids 1a–o were prepared by
a slightly modified previously published procedure.[28] Methyl esters
6a–o were prepared by an unmodified previously published pro-
cedure.[32] All other chemicals were obtained from commercial
sources and used without further purification. All solvents were
used as received. Mass spectra were recorded with a Varian 1200
L GC–MS instrument by using the direct exposure probe (DEP)
method with EI at 70 eV. High-resolution mass spectrometry was
performed with a KRATOS MS50TC instrument. NMR spectra
were recorded with Varian Mercury VX 200, Bruker AMX 300,
Bruker AMX 400, or Bruker AMX 600 spectrometers by using [D6]-
DMSO or CDCl3 as solvent and TMS as an internal standard. All
2D NMR experiments were performed by using a Bruker AMX
400 spectrometer. Microwave-assisted reactions were carried out in
a Milestone MicroSYNTH Labstation apparatus in 35 mL vials.
Melting points were determined with a Kofler apparatus.
Entry
Ar
Product
Yield [%][b]
1
2
3
4
5
4-methoxyphenyl
phenyl
4-fluorophenyl
4-bromophenyl
5-bromothienyl
8a
8b
8c
8d
8e
94
92
96
94
90
[a] Reaction conditions: (i) 7 (1 equiv., 1 mmol), K2CO3 (2 equiv.,
2 mmol), acetone (5 mL). [b] Isolated yields.
We believe that this process occurs by a sequence of α-
deprotonation, formation of intermediate X3, which is sta-
bilized by conjugation, a 1,5-hydrogen shift promoted by
aromatization, and finally air oxidation of the resulting
hemiacetal X4 to give the product (Scheme 3). This proto-
col appears to be superior to other typically used condi-
tions, and deserves further investigation.
General Procedure for the Microwave-Assisted Synthesis of 3-(Het)-
aroylacrylic Acids 1a–o: Glyoxylic acid monohydrate (37 mmol),
acetic anhydride (39 mmol), and ytterbium triflate (0.57 g,
0.925 mmol) were mixed, and 20 mL of this mixture was put into
a microwave reaction vial and stirred at room temperature for
10 min. Then, an acetophenone (37 mmol) and glacial acetic acid
(6 mL) were added. The reaction vial was sealed, and the mixture
was subjected to microwave irradiation under the conditions speci-
fied in Table 1 (initial power 150 W). The internal pressure was not
higher than 5–6 bar during the experiment. After cooling, the sol-
vent was evaporated. The residue was washed with ice-cold water
(50 mL) by decantation or on a filter. The crude product was dis-
solved in K2CO3 (25% aq.) and washed with CH2Cl2 (5ϫ 60 mL).
Then, the aqueous phase was cooled in an ice-bath and acidified
with HCl (concentrated aq.). The solid product was filtered off,
washed with water, and dried in air at 50 °C for 24 h. The acids
were checked by 1H NMR spectroscopy, and then used for further
reaction without any additional purification; however, in some
cases (1g, 1h, 1k), recrystallization from EtOH/H2O was carried
out.
Scheme 3. Plausible mechanism for the K2CO3-mediated aerial oxi-
dation of hexahydropyrido[2,3-d]pyrimidines 7.
Finally, to demonstrate the utility of our method, we pre-
pared compound 5b, which has been described as a herbi-
cide agent for the selective control of unwanted plant
growth.[31] Pyrido[2,3-d]pyrimidine derivative 5b can be
easily accessed from readily available starting materials in a
one-pot approach with an overall yield of 75%.
General Procedure for the Preparation of 3-(Het)aroylacrylic Acid
Methyl Esters 6a–n: 3-(Het)aroylacrylic acid 1a–n (10 mmol) and
dimethyl sulfate (12 mmol) were dissolved in DMF (5 mL), and
then K2CO3 (10 mmol) was added to the stirred mixture. The re-
sulting mixture was stirred at room temp. (it is important to prevent
overheating to temperatures above 25 °C) for 8 h. Then the mixture
was poured into ice-cold water, and the solid precipitate was filtered
off and dried in air at 50 °C for 24 h to obtain a crude product
(95–97%).
Conclusions
General Procedure for the Preparation of 7-Aryl-1,3-dimethyl-2,4-
dioxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyrimidine-5-carboxylic Acids
3a–o: A mixture of 6-amino-1,3-dimethyluracil (1.0 mmol) and a
3-aroylacrylic acid (1.0 mmol) in acetic acid (1 mL) was stirred at
reflux for 45 min. The solvent was removed under reduced pressure,
and the solid residue was suspended in cold water (50 mL), filtered,
We have developed a new approach for the synthesis of
pyrido[2,3-d]pyrimidine-5-carboxylic acids and their corre-
sponding methyl esters. The reaction of 3-(hetero)aroylac-
rylic acids or their methyl esters with 6-amino-1,3-dimeth-
yluracil leads to the formation of hexahydropyrido[2,3-d]-
pyrimidines in high to excellent yields. The further oxi- washed with cold water, and dried in air at 50 °C for 24 h to give
Eur. J. Org. Chem. 2013, 5364–5369
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dihydropyridine derivatives 3a–o. No additional purification was
required.
General Procedure for the Preparation of Methyl 1,3-Dimethyl-2,4-
dioxo-7-aryl-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyrimidine-5-carb-
oxylates 7a–n: The same procedure as for compounds 3a–o was
used. Crude products 7a–n were recrystallized from iPrOH/hexane
mixtures.
[4]
General Procedure for the One-Pot Preparation of 7-Aryl-1,3-di-
methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carb-
oxylic Acids 4a–e: A mixture of 6-amino-1,3-dimethyluracil
(1.0 mmol) and a 3-aroylacrylic acid (1.0 mmol) in acetic acid
(1 mL) was stirred at reflux for 45 min. The solvent was removed
under reduced pressure, and then CH2Cl2 (10 mL) and Br2
(1.2 mmol) were added sequentially. The resulting mixture was
stirred at reflux for 3 h. The CH2Cl2 was removed under reduced
pressure. 1-Propanol (4 mL) and KOH (3.00 mmol) were added se-
quentially to the residue, and the resulting mixture was heated at
reflux for 30 min. The reaction mixture was allowed to cool, then
the solid precipitate was filtered off and washed with 1-propanol
(10 mL). The salt was dried on the filter, then it was mixed with
brine (10 mL), and the mixture was acidified with HCl (10% aq.)
until neutral pH was reached. A precipitate formed, which was fil-
tered off, washed with cold water (2ϫ 5 mL), and dried in air at
50 °C for 24 h. No additional purification was required.
[5]
[6]
[7]
[8]
General Procedure for the One-Pot Preparation of 1,3-Dimethyl-7-
phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones 5a–e: A mixture
of 6-amino-1,3-dimethyluracil (2) (1.0 mmol) and a 3-aroylacrylic
acid (1.0 mmol) in acetic acid (1 mL) was stirred at reflux for
45 min. Then the acetic acid was removed under reduced pressure.
The residue was stirred with CAN (2.5 mmol) in water/acetone
(1:9; 15 mL) at room temp. for 3 h. The solvent was removed under
reduced pressure, and the residue was washed with water (50 mL)
and methanol, and dried in air at 50 °C for 24 h to give pyridine
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Supporting Information (see footnote on the first page of this arti-
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Received: May 10, 2013
Published Online: July 4, 2013
Eur. J. Org. Chem. 2013, 5364–5369
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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