Green Microwave-assisted Multicomponent Route to the Formation of 5,8-Dihydropyrido[2,3-d]pyrimidine Skeleton in Aqueous Media

Article abstract of DOI:10.1002/jhet.2586

Three-component synthesis of 5-substituted 6-acetyl-2-amino-7-methyl-5,8-dihydropyrido[2,3-d]pyrimidines was brought to facile energy-efficient and environmental-friendly conditions using multicomponent reaction, microwave field as an activation method and hot water as a solvent. A series of the target compounds was synthesized using the developed procedure.

Full text of DOI:10.1002/jhet.2586

Month 2015
Green Microwave-assisted Multicomponent Route to the Formation of
,8-Dihydropyrido[2,3-d]pyrimidine Skeleton in Aqueous Media
5
a
a,b
c
a
a,b
Vyacheslav E. Saraev, Ievgen M. Zviagin, Rafael G. Melik-Oganjanyan, Yulia V. Sen’ko, Sergey M. Desenko,
a,b
and Valentin A. Chebanov *
a
State Scientific Institution “Institute for Single Crystals”, National Academy of Sciences of Ukraine, Nauky Avenue, 60,
Kharkiv 61001, Ukraine
V.N. Karazin Kharkiv National University, Svobody sq., 4, Kharkiv 61022, Ukraine
b
c
A.L. Mnjoyan Institute of Fine Organic Chemistry, National Academy of Sciences of Republic of Armenia, Azatutyan
Avenue, 26, Yerevan 0014, Armenia
*
E-mail: chebanov@isc.kharkov.com
Additional Supporting Information may be found in the online version of this article.
Received September 19, 2015
DOI 10.1002/jhet.2586
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
Three-component synthesis of 5-substituted 6-acetyl-2-amino-7-methyl-5,8-dihydropyrido[2,3-d]pyrimi-
dines was brought to facile energy-efficient and environmental-friendly conditions using multicomponent re-
action, microwave field as an activation method and hot water as a solvent. A series of the target compounds
was synthesized using the developed procedure.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
diversity and combinatorial capacity [6], and so on; there-
fore, they have become widely used in the latest few decades
in the field of organic synthesis [7] and in many cases have
already proven their advantage over sequential reactions.
On the other hand, along with the common-used thermal
heating non-classical methods of activation, such as micro-
wave irradiation or ultrasonication, become popular that
may also be used in the synthesis of various nitrogen-
containing heterocycles [8–11].
In general, synthesis of nitrogen-containing heterocycles
has gained much interest because the first methods had
been discovered. One of the reasons of such level of inter-
est is highly possible biological activity of this type of
compounds. Pyrido[2,3-d]pyrimidines, being one of the
classes of bioactive heterocycles, are in the field of atten-
tion as well. These fused heterocycles are known to show
positive biological activity against various types of disease
agents, that is bacteria [12,13] and fungi [13,14]. Deriva-
tives of pyrido[2,3-d]pyrimidines can be used for inhibi-
tion of HIF prolyl hydroxylase [15] and as for treating
cancer [16,17], leishmaniasis [18], can be effective antago-
nists of calcium channel [19] and CCR4 [20], tyrosine
kinase inhibitors [21]. Due to all these indisputably impor-
tant qualities, there are many synthetic methods to obtain
these heterocyclic compounds using different reagents
[15,20,22–28].
The search and efficient synthesis of bioactive organic
compounds is now one of the major priorities in modern
medicinal-orientated chemistry because it may help with
the treatment of diseases like tuberculosis, diabetes, cancer,
AIDS, and other disastrous illnesses. However, one of the
most serious problems of the synthesis of pharmaceuticals
is its controversy with the principles of green chemistry,
which makes pharmacological industry a top waster [1].
The problem of reducing of waste amount is widely
discussed in many branches of modern science. Green
chemistry, being one of these branches, is known not for
methods of utilization of wastes but, first of all, for its
benefits in preventing of waste generation and energy
economy. The principles of green chemistry [2] lead us
to several important ways of industry development, such
as using of minimum amount of solvents and auxiliary
substances (except for biosolvents, easily utilized by living
organisms – water, ethanol, acetic acid, and so on), discov-
ering new ways of syntheses (optimization of amounts of
process steps, using alternative methods of reaction activa-
tion), and involving of renewable reagents (biomass
recycling, development of bioengineering).
Multicomponent reactions have many benefits, such as
step [3] and atom economy [4,5], low E-factor [6], high
©
2015 HeteroCorporation

V. E. Saraev, I. M. Zviagin, R. G. Melik-Oganjanyan, Y. V. Sen'ko,
S. M. Desenko, and V. A. Chebanov
Vol 000
One of the most popular methods of synthesis of pyrido
2,3-d]pyrimidine is base on three-component reaction in-
satisfy these principles, we proceeded to carry out the reac-
tion studied in such solvents as alcohols and water with the
use of catalysts.
Rare-earth metals(III) salts proved their efficiency in
multicomponent reactions in non-aqueous media [30], while
cetyltrimethylammonium bromide (CTAB) – vitamin B1
[
volving non-cyclic carbonyl-containing CH-acids, deriva-
tives of 6-aminouracile and different aldehydes [27,28].
Nevertheless, there is no procedure for obtaining com-
pounds of this class in high yields under green conditions
because the known methods involve hazardous or poison-
ous solvents, require high temperatures or long time ranges
or both. Moreover, some of the procedures published
earlier turned up to be irreproducible. At the same time,
similar products are obtained in “green” conditions using
cyclic CH-acids like derivatives of cyclohexan-1,3-dione
in high yields [26,29].
The main goal of our work was to elaborate efficient
green conditions for the three-component reaction of 2,6-
diaminopyrimido-2,4(1H,3H)-dione, acetylacetone, and
substituted aromatic aldehydes to obtain 5-substituted-6-
acetyl-2-amino-5,8-dihydro-7-methylpyrido[2,3-d]-4(3H)-
ones (Scheme 1).
(VB ) couple was used in water [31]. Nevertheless, applica-
1
tion of Sc(OTf) (10mol%) in 1-butanol (BuOH) showed
3
poor results using both conventional and microwave irradia-
tion heating (Entries 13 and 14). Finally, the moderate yield
of 4a was observed after 8-hours heating in boiling water (En-
try 15) with additives of CTAB and VB (10mol% of both).
1
Then, it was found (Entries 16–22) that the maximum
yield of the target heterocycle was observed after 4hours
heating (68%, Entry 16). The ratio of reagents sometimes
neglected the principle of atom economy for multicomponent
reactions and, therefore, experiments to minimize consump-
tion of substances were carried out as well. The most prefer-
able combination of yield and reagents expense took place
when the ratio of reagents 1:2a:3 equaled to 1:1:2 (mol.).
The excess of reagents in different entries can be explained
by the evaporation of the liquid initial substances used.
In order to check whether catalysts are surely essential for
the efficient proceeding the process, a series of experiments
was carried out that showed, surprisingly, that, indeed, in
contrast to earlier described data for similar reactions
RESULTS AND DISCUSSIONS
Initially, the three-component treatment between 2,6-
diaminouracil 1, 4-methoxybenzaldehyde 2a, and acetyl-
acetone 3 was selected as model one to find and optimize
the most suitable reaction conditions (Table 1). Firstly, to
reduce the reaction time, we followed Van’t Hoff’s rule
and chose high-boiling solvents, such as dimethyl sulfox-
ide (DMSO), N-methyl-2-pyrrolidone, polyethylene glycol
[31,32], the presence of B decreases product yield (Entry
1
23), while CTAB does not affect it at all (Entry 24).
Further, in chase of reducing process time, microwave
irradiation as a source of energy was used instead of the
conventional heating. Temperature, time, and ratio of the
reagents were the optimized parameters (Entries 25–33).
As it was noted, the excess of reagents was added because
their evaporation; therefore, the microwave-assisted synthe-
ses firstly were carried out with equimolar ratio of reagents
(Entries 25–30). But after doubling the acetylacetone 3 quan-
tity, higher yields were observed.
(
PEG-300), dimethylformamide, and so on.
Entries 1 and 2 show that an excess of volatile reagents
is needed because their vaporization during the process.
Increasing the temperature with application of microwave
irradiation ended with no positive result at any process
time even after consequent heating (Entries 3–11). Only
prolonged heating of initial mixture of the reagents in
dimethylformamide resulted in 43% yield of 4a (Entry
Finally, the experiments showed that the best conditions
of the multicomponent reaction studied were heating of the
starting materials 1, 2a, and 3 in 1:1:2 ratios in microwave
field in water without any catalyst for 10min at 180°C.
1
2). The probable reasons of such results are degradation
of DMSO at high temperatures, interactions of solvent’s
molecules with reagents, and non-compatible physical
parameters of the media with the reaction flow. However,
most of the solvents used in Entries 1–12 do not obtain
along with the principles of green chemistry, because they
are hazardous, carcinogenic and can hardly be utilized. To
1
However, the H NMR spectra in all cases contains signals
of impurities (up to ~5 mol%) caused by the presence of
initial benzaldehyde and 2,6-diaminouracil that were re-
moved by the use of saturated NaHSO solution as a puri-
3
fying agent (Entry 34).
Having optimized reaction conditions on the asset side, a
series of experiments was carried out to estimate the scope
and limitations of this multicomponent reaction with differ-
ent aryl and hetaryl aldehydes (Table 2).
Scheme 1. The reaction studied.
It can be seen that higher yields are observed in the cases
of aldehydes containing electron-withdrawing substituents
(
–M and –I effects, compounds 4c,d,l, and so on). On the
other hand, surprisingly, the presence of o-substituents in
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Green Microwave-assisted Multicomponent Route to the Formation of
5,8-Dihydropyrido[2,3-d]pyrimidine Skeleton in Aqueous Media
Table 1
Optimization of the reaction conditions.
Entry
Ratio 1:2а:3
Conditions
Solvent
Catalyst
Yield
1
2
3
4
5
6
7
8
1:1:1
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:15
1:2:3
1:2:2
1:2:2
1:2:3
1:2:3
1:2:3
1:2:3
1:2:3
1:2:3
1:2:3
1:2:2
1:1:3
1:1:2
1:1:2
1:1:2
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:2
1:1:2
1:1:2
1:1:2
8 h 110°C
8 h 110°C
1 h MW 150°C
2 h MW 150°C
(2 h MW + 8 h heating) 140°C
8 h 140°C
DMSO
DMSO
DMSO
DMSO
DMSO
NMP
None
None
None
None
None
None
None
None
None
None
None
Trace
80%
None
Trace
Trace
None
None
Trace
None
Trace
43%
None
None
41%
68%
39%
33%
21%
Trace
48%
55%
68%
69%
67%
53%
56%
63%
38%
56%
57%
62%
71%
66%
10 h 140°C
10 h 140°C
8 h 200°C
8 h 140°C
10 h 140°C
1 h MW 200°C
8 h 120°C
8 h 100°C
4 h 100°C
2 h 100°C
1 h 100°C
0.5 h 100°C
4 h 100°C
4 h 100°C
4 h 100°C
4 h 100°C
4 h 100°C
1 h MW 150°C
30 min MW 180°C
15 min MW 180°C
10 min MW 180°C
5 min MW 180°C
5 min MW 200°C
2 h MW 150°C
1 h MW 180°C
10 min MW 180°C
10 min MW 180°C
MeNO
2
Acetylacetone
PEG-300
DMF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
DMF
BuOH
BuOH
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
Sc(OTf)
Sc(OTf)
3
3
CTAB, VB
CTAB, VB
CTAB, VB
CTAB, VB
CTAB, VB
CTAB, VB
CTAB, VB
CTAB, VB
CTAB
1
1
1
1
1
1
1
1
None
None
None
None
None
None
None
CTAB, VB
CTAB, VB
None
1
1
a
Water
None
a
3
purification by NaHSO solution.
initial benzaldehydes 2a-s increases yield as well (comparing
yields of 4f and 4 l, also 4a, 4 m, and 4o). The reaction of
gives us the right to presume that the reaction carried out
by our method using other equipment could lead to even
higher results that the authors of the article [25] report
(Table 3).
2
,6-diamonouracil 1 (2 eq.), acetylacetone 3 (2 eq.) and
teraphtalaldehyde 2p (1 eq.) resulted in a mixture of
mono-(4p’) and bis-(6-acetyl-2-amino-7-methyl-5,8-dihydro-
pyrido[2,3-d]pyrimidin-4(3H)-one-5-yl) (4p) products with
molar ratio 1:1.
CONCLUSION
We also managed to repeat the experiment of Tu et al.
[
25] but, unfortunately, under the same conditions as stated
In summary, we have developed a microwave-assisted
method for one-pot synthesis of pyrido[2,3-d]pyrimidine
derivatives using multicomponent reaction between 2,6-
in their study, we did not observe the results of claimed ef-
fectiveness. The most probable reason is instrumental: it
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

V. E. Saraev, I. M. Zviagin, R. G. Melik-Oganjanyan, Y. V. Sen'ko,
S. M. Desenko, and V. A. Chebanov
Vol 000
Table 2
Microwave irradiation synthesis of 5-substituted-6-acetyl-2-amino-5,8-dihydro-7-methylpyrido[2,3-d]pyrimidin-4(3H)-ones 4.
4
b, 59%
4c, 76%
4d, 76%
4a, 66%
4
g, 63%
4
4
h, 66%
l, 71%
4
4
e, 61%
i, 60%
4f, 61%
4
j, 61%
4k, 62%
4
m, 76%
4
4
o, 83%
a
4
p , 42%
4
4
n, 51%
q, 68%
a
r, 63%
4p′ , 42%
a
compounds 4p and 4p′ were obtained in a single experiment.
diaminouracil, acetylacetone, and various aromatic and
heteroaromatic aldehydes. The procedure elaborated is re-
producible with application of wide range of the starting
materials and allows moderate-to-good yields of final het-
erocyclic compounds with a profit in atom economy, small
waste amount, short reaction time and minimum use of wa-
ter as a green solvent. Microwaves assisting also gives an
advantage in energy consumption towards common
heating [33,34]. All these aspects can be the reasons for
further development of this method due to its friendliness
to the environment. A huge variety of similar compounds
can be also synthesized by this very method using other
derivatives of uracil and different CH-acids, for instance,
barbituric acid, cyclic 1,3-diketones, malonic dinitrile and
so on, and possibly other heterocycles.
EXPERIMENTAL
General information. 2,6-Diaminouracil was synthesized
from guanidinium chloride and ethyl cyanoacetate using
procedure shown later. Guanidinium chloride, ethyl
cyanoacetate, aromatic aldehydes and acetylacetone,
solvents, catalysts, and inorganic compounds were
obtained from commercial suppliers and were used without
Table 3
Comparison of the developed and existing methods.
Stated
yield (%)
[25]
Reproduced
yield (%)
Our method
yield (%)
1
further purification. H NMR spectra were recorded at
Entry
Aldehyde
13
2
00MHz on a Varian Mercury VX-200 instrument,
C
1
2
3
2a
2i
2d
92
95
90
55
45
58
66
60
76
NMR – at 126MHz on a Bruker Avance spectrometer.
Mass spectra were recorded on Varian 1200L Mass
Spectrometer (direct input, EI, 70eV). LC-MS analysis
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Green Microwave-assisted Multicomponent Route to the Formation of
,8-Dihydropyrido[2,3-d]pyrimidine Skeleton in Aqueous Media
5
1
3
data were obtained with the use of Agilent 1100 instrument
ES-API). Microwave experiments were performed using
the EmrysTM Creator EXP from Biotage AB (Uppsala,
Sweden) possessing a single-mode microwave cavity
NH), 10.32 (s, 1H, 3-NH). C NMR (126MHz, DMSO) δ
(ppm): 19.27, 20.57, 29.79, 36.68, 91.90, 110.28, 127.12,
128.54, 134.72, 141.97, 144.47, 146.68, 153.27, 153.93,
(
+
161.41, 196.59. MS for C H N O , m/z: 310 (M ). Anal.
1
7 18 4 2
(2.45GHz). Elemental analysis was realized on EuroVector
Calcd for C H N O : C, 65.79; H, 5.85; N, 18.05.
17 18 4 2
EA-3000 (samples for elemental analysis were additionally
dried in vacuo).
Found: C, 65.52; H, 5.78; N, 17.91.
6-Acetyl-2-amino-5-(4′-carboxyphenyl)-7-methyl-5,8-dihy-
Typical procedure for synthesis of 2,6-diaminouracil
dropyrido[2,3-d]pyrimidin-4(3H)-one (4c). Yield 76% as red
solid; mp: over 300°C. H NMR (200MHz, DMSO) δ
1
(
1).
Guanidinium chloride (4.5 g, 47 mM) and ethyl
cyanoacetate (5mL, 5.3g, 47mM) were added to a solution
of sodium methylate in methanol obtained by adding of
solid sodium (2.4g, 104mM) to 50mL of methanol. The
mixture was refluxed for 4 h, and then 50 mL of warm
water were added to solve the precipitate. Methanol was
removed in vacuo and after cooling to room temperature
(ppm): 2.02 (s, 3H, CH ), 2.32 (s, 3H, CH CO), 4.95 (s,
3
3
1H, CH), 6.37 (s, 2H, NH ), 7.31 (d, J=8.3Hz, 2H, ArH),
2
7.78 (d, J=8.2Hz, 2H, ArH), 9.14 (s, 1H, 8-NH), 10.53
13
(br.s, 1H, COOH and 1H, 3-NH),. C NMR (126MHz,
DMSO) δ (ppm): 19.47, 30.16, 37.30, 91.11, 110.17,
127.43 (2C), 128.59, 129.30 (2C), 147.43, 152.23,
153.66, 154.24, 161.52, 167.41, 196.26. MS for C H
6
mL of glacial acetic acid were added. The gold-yellow
1
7 16
+
substance precipitated was filtered off and dried in the air.
The method stated is modified comparing to the method of
VanAllan et al. [35].
N O , m/z: 340 (M ). Anal. Calcd for C H N O : C,
4 4 17 16 4 4
60.00; H, 4.74; N, 16.46. Found: C, 60.25; H, 4.79; N,
16.62.
General procedure for the synthesis of 6-acetyl-2-amino-5-
aryl-5,8-dihydro-7-methylpyrido[2,3-d]pyrimidin-4(3H)-ones
6-Acetyl-2-amino-5-(2′,4′-dichlorophenyl)-7-methyl-5,8-dihy-
dropyrido[2,3-d]pyrimidin-4(3H)-one (4d).
orange solid; mp: over 300°C. H NMR (200MHz, DMSO)
Yield 76% as
1
(
4). In a microwave reaction vial (maximum reaction
volume 5mL) 2,6-diaminouracil 1 (0.200g, 1.59mM),
acetylacetone (0.34 mL, 0.318 g, 3.18 mM) and
δ (ppm): 2.05 (s, 3H, CH ), 2.21 (s, 3H, CH CO), 5.20 (s,
3
3
3
1H, CH), 6.33 (s, 2H, NH ), 7.26 (s, 2H, ArH), 7.33 (s, 1-
2
13
corresponding aldehyde 2 (1.59mM) were mixed in 3mL
H, ArH), 9.10 (s, 1H, 8-NH), 10.32 (s, 1H, 3-NH). C N-
MR (126MHz, DMSO) δ (ppm): 19.38, 30.29, 35.90,
90.74, 110.79, 127.23, 128.36, 130.91, 132.49, 132.95, 14-
of H O. The vial was capped, and the reaction mixture was
2
irradiated at 180°C for 10min (with fixed hold time
option). Then, 1mL of saturated NaHSO solution was
4.23, 146.26, 153.78, 154.30, 161.25, 196.71. MS for C
3
16-
+
added to the vial (without isolation of the product), and the
mixture was irradiated by microwaves at 95°C for
additional 5min. The precipitate formed was filtered off,
washed with 10mL of hot water, and dried in the air.
H Cl N O , m/z: 364, 366, 365 (M ). Anal. Calcd for
14
2 4 2
C H Cl N O : C, 52.62; H, 3.86; N, 15.34. Found: C, 5-
16
14
2 4 2
2.21; H, 3.78; N, 14.99.
6-Acetyl-2-amino-5-(4′-(N,N-dimethylamino)phenyl)-7-methyl-
2
,6-Diaminouracil (1). Yield 5.28g (83%); mp: 262°C.
H NMR (200 MHz, DMSO) δ (ppm): 4.43 (s, 1H, CH),
.93 (s, 2H, 6-NH ), 6.18 (s, 2H, 2-NH ), 9.77 (s, 1H, 3-NH).
5,8-dihydropyrido[2,3-d]pyrimidin-4(3H)-one (4e).
61% as pale orange solid; mp: over 300°C. H NMR
(200 MHz, DMSO) δ (ppm): 1.99 (s, 3H, CH ), 2.28
Yield
1
1
5
2
2
3
6-Acetyl-2-amino-5-(4′-methoxyphenyl)-7-methyl-5,8-dihydro-
(s, 3H, CH CO), 2.78 (s, 6H, N-CH ), 4.74 (s, 1H,
3
3
pyrido[2,3-d]pyrimidin-4(3H)-one (4a). Yield 66% as pale
yellow solid; mp: over 300°C. H NMR (200MHz,
CH), 6.22 (s, 2H, NH ), 6.56 (d, J = 8.7 Hz, 2H, Ar-
2
1
H), 7.02 (d, J=8.6Hz, 2H, ArH), 8.97 (s, 1H, 8-NH), 10.3-
13
DMSO) δ (ppm): 1.99 (s, 3H, CH ), 2.29 (s, 3H, CH CO),
5 (s, 1H, 3-NH). C NMR (126MHz, DMSO) δ (ppm):
19.29, 29.68, 36.16, 40.40 (2C), 110.48, 112.40 (2C), 127-
.82 (2C), 131.59, 135.76, 146.23, 148.91, 153.07, 153.86,
3
3
3
.65 (s, 3H, OCH ), 4.81 (s, 1H, CH), 6.23 (s, 2H, NH ),
3
2
6
.75 (d, J=8.4Hz, 2H, ArH), 7.11 (d, J=8.4Hz, 2H,
13
+
ArH), 9.02 (s, 1H, 8-NH), 10.33 (s, 1H, 3-NH). C NMR
161.54. MS for C H N O , m/z: 339 (M ). Anal. Calcd f-
1
8 21 5 2
(126MHz, DMSO) δ (ppm): 19.35, 29.82, 36.32, 54.96,
or C H N O : C, 63.70; H, 6.24; N, 20.64. Found: C, 6-
18 21 5 2
9
1
2.17, 110.51, 113.44 (2C), 128.26 (2C), 139.74, 146.64,
53.30, 154.00, 157.50, 161.60, 196.78. MS for C H
4.01; H, 6.27; N, 20.82.
6-Acetyl-2-amino-5-(4′-fluorophenyl)-7-methyl-5,8-dihydro-
pyrido[2,3-d]pyrimidin-4(3H)-one (4f). Yield 61% as pale
yellow solid; mp: over 300°C. H NMR (200MHz,
DMSO) δ (ppm): 2.02 (s, 3H, CH ), 2.31 (s, 3H, CH CO),
17 18
+
N O , m/z: 326 (M ). LC-MS analysis data: max peak
4
3
1
9
6
3.46% at 0.885min. Anal. Calcd for C H N O : C,
1
7 18 4 3
2.57; H, 5.56; N, 17.17. Found: C, 62.88; H, 5.64; N, 17.12.
3
3
6
-Acetyl-2-amino-7-methyl-5-(p-tolyl)-5,8-dihydro-pyrido[2,3-
4.91 (s, 1H, CH), 6.26 (s, 2H, NH ), 6.99 (t, J=8.9Hz,
2
d]pyrimidin-4(3H)-one (4b). Yield 59% as pale yellow solid;
mp: over 300°C. H NMR (200MHz, DMSO) δ (ppm): 1.99
2H, ArH), 7.23 (t, J=8.8Hz, 2H, ArH), 9.02 (s, 1H, 8-
NH), 10.39 (br.s, 1H, 3-NH). C NMR (126MHz,
1
13
(
4
2
s, 3H, CH ), 2.18 (s, 3H, CH CO), 2.29 (s, 3H, Ar-CH ),
DMSO) δ (ppm): 19.40, 30.03, 36.43, 91.70, 110.38,
114.57, 114.73, 128.94, 129.00, 143.62, 147.11, 153.42,
154.11, 159.62, 161.48, 196.40. MS for C H FN O ,
3
3
3
.83 (s, 1H, CH), 6.23 (s, 2H, NH ), 6.96 (d, J=7.9Hz,
2
H, ArH), 7.11 (d, J=7.8Hz, 2H, ArH), 9.02 (s, 1H, 8-
1
6
15
4 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

V. E. Saraev, I. M. Zviagin, R. G. Melik-Oganjanyan, Y. V. Sen'ko,
S. M. Desenko, and V. A. Chebanov
Vol 000
+
13
m/z: 314 (M ). Anal. Calcd for C H FN O : C, 61.14;
10.37 (s, 1H, 3-NH). C NMR (126 MHz, DMSO) δ
(ppm): 19.34, 29.88, 36.78, 91.93, 100.65, 107.80,
107.84, 110.27, 119.94, 141.60, 145.34, 146.86, 146.96,
153.31, 154.01, 161.53, 196.64. MS for C H N O ,
1
6
15
4 2
H, 4.81; N, 17.83. Found: C, 61.33; H, 4.75; N, 17.65.
-Acetyl-2-amino-5-(3′-bromophenyl)-7-methyl-5,8-dihydro-
pyrido[2,3-d]pyrimidin-4(3H)-one (4g). Yield 63% as pale
6
17 16 4 4
1
+
yellow solid; mp: over 300°C. H NMR (200 MHz,
m/z: 340 (M ). Anal. Calcd for C H N O : C, 60.00;
17 16 4 4
DMSO) δ (ppm): 2.05 (s, 3H, CH ), 2.32 (s, 3H,
H, 4.74; N, 16.46. Found: C, 59.59; H, 4.64; N, 16.76.
6-Acetyl-2-amino-5-(2′-fluorophenyl)-7-methyl-5,8-dihydro-
pyrido[2,3-d]pyrimidin-4(3H)-one (4l). Yield 71% as pale
3
CH CO), 4.90 (s, 1H, CH), 6.30 (s, 2H, NH ), 7.27 (m,
3
2
13
4
H, ArH), 9.10 (s, 1H, 8-NH) 10.36 (s, 1H, 3-NH).
C
1
NMR (126 MHz, DMSO) δ (ppm): 19.46, 30.25, 36.95,
yellow solid; mp: over 300°C. H NMR (200 MHz,
9
1
1.16, 110.12, 121.40, 126.28, 128.76, 129.92, 130.38,
DMSO) δ (ppm): 2.05 (s, 3H, CH ), 2.23 (s, 3H,
3
47.52, 150.14, 153.59, 154.22, 161.43, 196.12. MS for
CH CO), 5.10 (s, 1H, CH), 6.30 (s, 2H, NH ), 7.06 (m,
3
2
+
13
C H BrN O , m/z: 374, 376 (M ). Anal. Calcd for
4H, ArH), 9.07 (s, 1H, 8-NH), 10.35 (s, 1H, 3-NH).
C
16
15
4 2
C H BrN O : C, 51.22; H, 4.03; N, 14.93. Found: C,
NMR (126 MHz, DMSO) δ (ppm): 19.36, 29.69, 32.04,
90.67, 110.32, 114.99, 115.17, 124.21, 127.75, 130.79,
134.55, 146.32, 153.77, 154.24, 161.30, 196.61. MS for
16
15
4 2
51.01; H, 4.07; N, 15.02.
6
-Acetyl-2-amino-5-(4′-bromophenyl)-7-methyl-5,8-dihydro-
+
pyrido[2,3-d]pyrimidin-4(3H)-one (4h). Yield 66% as pale
C H FN O , m/z: 314 (M ). Anal. Calcd for
16
15
4 2
1
yellow solid; mp: over 300°C. H NMR (200MHz,
C H FN O : C, 61.14; H, 4.81; N, 17.83. Found: C,
16 15 4 2
DMSO) δ (ppm): 2.02 (s, 3H, CH ), 2.30 (s, 3H, CH CO),
61.01; H, 4.74; N, 18.02.
3
3
4
.88 (s, 1H, CH), 6.30 (s, 2H, NH ), 7.16 (d, J=8.3Hz,
6-Acetyl-2-amino-7-methyl-5-(2′-methoxyphenyl)-5,8-dihydro-
2
2
H, ArH), 7.38 (d, J=8.3Hz, 2H, ArH), 9.11 (s, 1H, 8-
pyrido[2,3-d]pyrimidin-4(3H)-one (4m). Yield 76% as pale
yellow solid; mp: over 300°C. H NMR (200MHz, DMSO)
1
3
1
NH), 10.41 (s, 1H, 3-NH). C NMR (126MHz, DMSO) δ
(ppm): 19.44, 30.11, 36.73, 91.30, 110.16, 118.89, 129.54
δ (ppm): 2.08 (s, 3H, CH ), 2.10 (s, 3H, CH CO), 3.71 (s,
3
3
(
1
2C), 130.90 (2C), 146.76, 147.30, 153.52, 154.17, 161.50,
3H, OCH ), 5.15 (s, 1H, CH), 6.22 (m, 2H, NH ), 6.95 (m,
3
2
+
13
96.27. MS for C H BrN O , m/z: 374, 376 (M ). Anal.
4H, ArH), 8.90 (s, 1H, 8-NH), 10.21 (s, 1H, 3-NH).
C
16
15
4 2
Calcd for C H BrN O : C, 51.22; H, 4.03; N, 14.93.
Found: C, 51.50; H, 4.09; N, 15.08.
NMR (126 MHz, DMSO) δ (ppm): 18.74, 29.17, 32.23,
55.59, 90.71, 111.31, 111.60, 120.49, 127.15, 129.47,
135.92, 143.76, 154.01, 154.38, 155.92, 161.31, 198.13.
16
15
4 2
6
-Acetyl-2-amino-5-(4′-chlorophenyl)-7-methyl-5,8-dihydro-
+
pyrido[2,3-d]pyrimidin-4(3H)-one (4i). Yield 60% as pale
MS for C H N O , m/z: 326 (M ). Anal. Calcd for
17 18 4 3
1
yellow solid; mp: over 300°C. H NMR (200MHz,
C H N O : C, 62.57; H, 5.56; N, 17.17. Found: C,
17 18 4 3
DMSO) δ (ppm): 2.02 (s, 3H, CH ), 2.31 (s, 3H, CH CO),
62.42; H, 5.66; N, 17.02.
3
3
4
.90 (s, 1H, CH), 6.25 (s, 2H, NH ), 7.23 (s, 4H, ArH),
6-Acetyl-2-amino-7-methyl-5-(4′-(2-hydroxyethyl)-3′-metho-
2
1
3
9
.07 (s, 1H, 8-NH), 10.34 (s, 1H, 3-NH). C NMR
xyphenyl)-5,8-dihydropyrido[2,3-d]pyrimidin-4(3H)-one (4n).
1
(126MHz, DMSO) δ (ppm): 19.44, 30.09, 36.65, 91.38,
Yield 51% as pale yellow solid; mp: over 300°C. H NMR
1
1
10.20, 127.98 (2C), 129.11 (2C), 130.39, 146.35, 147.30,
(200MHz, DMSO) δ (ppm): 2.02 (s, 3H, CH ), 2.31 (s,
3
53.51, 154.17, 161.48, 196.28. MS for C H ClN O , m/
3H, CH CO), 3.66 (s, 3H, OCH ), 3.86 (t, J=5.1Hz, 2H,
1
6
15
4
2
3
3
+
z: 330, 332 (M ). Anal. Calcd for C H ClN O : C,
CH ), 4.79 (t, J=5.5Hz, 2H, ArOCH ), 4.84 (s, 1H, CH),
2 2
16
15
4
2
5
8.10; H, 4.57; N, 16.94. Found: C, 58.16; H, 4.70; N, 17.00.
6.32 (s, 2H, NH ), 6.62 (dd, J=8.4Hz, J=1.9Hz, 1H,
2
6
-Acetyl-2-amino-7-methyl-5-phenyl-5,8-dihydro-pyrido[2,3-
ArH), 6.78 (d, J=8.4Hz, 1H, ArH), 6.93 (d, J=1.9Hz,
13
d]pyrimidin-4(3H)-one (4j). Yield 61% as pale yellow solid;
mp: over 300°C. H NMR (200MHz, DMSO) δ (ppm): 2.01
s, 3H, CH ), 2.31 (s, 3H, CH CO), 4.89 (s, 1H, CH), 6.27
s, 2H, NH ), 7.21 (m, 5H, ArH), 9.06 (s, 1H, 8-NH), 10.36
1H, ArH), 9.04 (s, 1H, 8-NH), 10.48 (s, 1H, 3-NH).
C
1
NMR (126 MHz, DMSO) δ (ppm): 19.31, 29.83, 36.56,
55.42, 59.69, 70.28, 92.07, 110.13, 111.86, 113.19,
118.99, 140.36, 146.48, 146.77, 148.54, 153.31, 153.96,
(
(
(
3 3
2
13
+
br.s., 1H, 3-NH). C NMR (126MHz, DMSO) δ (ppm):
161.66, 196.79. MS for C H N O , m/z: 386 (M ). Anal.
1
9 22 4 5
1
1
1
9.36, 29.96, 37.14, 91.80, 110.34, 125.87, 127.29 (2C),
Calcd for C H N O : C, 59.06; H, 5.74; N, 14.50. Found:
19 22 4 5
C, 59.00; H, 5.70; N, 14.44.
28.05 (2C), 146.96, 147.46, 153.44, 154.06, 161.47,
+
96.53. MS for C H N O , m/z: 296 (M ). Anal. Calcd
6-Acetyl-2-amino-5-(2′,5′-dimethoxyphenyl)-7-methyl-5,8-
1
6 16 4 2
for C H N O : C, 64.85; H, 5.44; N, 18.91. Found: C,
dihydropyrido[2,3-d]pyrimidin-4(3H)-one (4o). Yield 66% as
pale yellow solid; mp: over 300°C. H NMR (200MHz,
1
6 16 4 2
1
6
4.40; H, 5.40; N, 19.08.
6
-Acetyl-2-amino-7-methyl-5-(benzo[d][1,3]dioxol-5-yl)-5,8-
DMSO) δ (ppm): 2.09 (s, 3H, CH ), 2.10 (s, 3H, CH CO),
3
3
dihydropyrido[2,3-d]pyrimidin-4(3H)-one (4k). Yield 62%
as pale yellow solid; mp: over 300°C. H NMR
3.59 (s, 3H, 5′-OCH ), 3.67 (s, 3H, 2′-OCH ), 5.11 (s, 1H,
3 3
1
CH), 6.25 (s, 2H, NH ), 6.54 (d, J=4.8Hz, 1H, ArH), 6.66
2
(
3
200 MHz, DMSO) δ (ppm): 2.02 (s, 3H, CH ), 2.30 (s,
(dd, J=8.7Hz, J=4.8Hz, 1H, ArH), 6.80 (d, J=8.6Hz,
3
13
H, CH CO), 4.83 (s, 1H, CH), 5.90 (s, 2H, CH ), 6.28
1H, ArH), 8.93 (s, 1H, 8-NH), 10.30 (br.s, 1H, 3-NH).
C
3
2
(
s, 2H, NH ), 6.71 (m, 3H, ArH), 9.05 (s, 1H, 8-NH),
2
NMR (126 MHz, DMSO) δ (ppm): 18.73, 29.20, 32.35,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Green Microwave-assisted Multicomponent Route to the Formation of
,8-Dihydropyrido[2,3-d]pyrimidine Skeleton in Aqueous Media
5
5
1
5.13, 56.39, 90.67, 110.68, 111.31, 112.81, 116.14, 137.35,
43.80, 150.25, 153.26, 154.04, 154.36, 161.28, 198.10. MS
Acknowledgments. We thank Dr. V. Polovinko (Enamine Ltd,
13
Kyiv, Ukraine) for the recording C NMR spectra.
+
for C H N O , m/z: 356 (M ). Anal. Calcd for
18 20 4 4
C H N O : C, 60.66; H, 5.66; N, 15.72. Found: C,
18 20 4 4
61.02; H, 5.73; N, 15.92.
REFERENCES AND NOTES
5
,5′-(1,4-Phenylene)bis(6-acetyl-2-amino-7-methyl-5,8-dihydro-
[
[
1] Sheldon, R. A. Green Chem 2007, 9, 1273.
2] Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
pyrido[2,3-d]pyrimidin-4(3H)-one) (4p). Yield 42% as bro-
wnish yellow solid; mp: over 300°C. H NMR (200MHz,
1
Practice; Oxford University Press: Oxford, UK, 1998.
DMSO) δ (ppm): 1.99 (s, 6H, CH ), 2.27 (s, 6H, CH CO),
[3] Wender, P. A.; Baryza, J. L.; Brenner, S. E.; DeChristopher, B. A.;
Loy, B. A.; Schrier, A. J Proc Natl Acad Sci U S A 2011, 108, 6721.
3
3
4
.80 (s, 2H, CH), 6.25 (s, 4H, NH ), 7.02 (s, 4H, ArH), 9.-
2
[
[
4] Dömling, A.; Wang, W.; Wang, K. Chem Rev 2012, 112, 3083.
5] Trost, B. Science 1991, 254, 1471.
13
0
2 (s, 2H, 3-NH), 10.38 (m, 2H, 8-NH). C NMR spectrum
is not obtained because of extremely low solubility. MS for
[6] Cioc, R. C.; Ruijter, E.; Orru, R. V. A. Green Chem 2014, 16, 2958.
7] Müller, T. J. J. In Mcr 2009; Mironov, Ed.; Springer New
York: New York, NY, 2011, vol. 699.
+
[
C H N O , m/z: 514 (M ).
26 26 8 4
4
-(6-acetyl-2-amino-7-methyl-4-oxo-3,4,5,8-tetrahydropyrido
[
[
8] Kappe, C. O. Angew Chem Int Ed Engl 2004, 43, 6250.
9] Chebanov, V. A.; Gura, K. A.; Desenko, S. M. In Synthesis of
[
2,3-d]pyrimidin-5-yl)benzaldehyde (4p′).
Yield 42% as
1
brownish yellow solid; mp: over 300°C. H NMR
Heterocycles via Multicomponent Reactions I; Orru and Ruijter, Ed.;
Springer Berlin Heidelberg: Berlin, 2010, pp 41–84.
(
200MHz, DMSO) δ (ppm): 2.04 (s, 3H, CH ), 2.33 (s,
3
[
10] Chebanov, V. A.; Desenko, S. M. Chem Heterocycl Compd
2012, 48, 566.
[11] Chebanov, V. A.; Desenko, S. M. Divers Oriented Syn th 2014 43.
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[13] Chaudhari, P. K. Int J Life Sci Pharma Res 2011, 1, 1.
14] Kumar, N.; Tiwari, S.; Yadav, A. K. Indian J Chem 2007, 46, 702.
3
H, CH CO), 4.99 (s, 1H, CH), 6.34 (s, 2H, NH ), 7.43 (d,
3 2
J=8.1Hz, 1H, ArH), 7.75 (d, J=8.4Hz, 1H, ArH), 9.18 (s,
[
1
H, 3-NH), 9.88 (s, 1H, CHO), 10.27 (br.s., 1H, 8-NH).
13
C NMR spectrum is not obtained because of extremely
[
+
low solubility. MS for C H N O , m/z: 324 (M ).
1
7
16
4
3
[15] Ibrahim, D. A.; Ismail, N. S. M. Eur J Med Chem 2011, 46, 5825.
[16] Elgohary, A. M. F. Sci J Chem 2013, 1, 1.
6
-Acetyl-2-amino-5-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-7-
[
17] Antonio, J.; Plano, D.; Moreno, E.; Sanmartín, C. ARKIVOC
014, ii, 187.
18] Agarwal, A.; Ramesh, R.; Ashutosh, A.; Goyal, N.; Chauhan,
P. M. S.; Gupta, S. Bioorg Med Chem 2005, 13, 6678.
19] Pastor, A.; Alajarin, R.; Vaquero, J. J.; Alvarez-Builla, J.; de
methyl-5,8-dihydropyrido[2,3-d]pyrimidin-4(3H)-one (4q).
2
1
Yield 68% as pale yellow solid; mp: over 300°C. H
[
NMR (200 MHz, DMSO) δ (ppm): 1.23 (t, J = 7.2 Hz,
[
3
H, CH CH ), 2.03 (s, 3H, CH ), 2.12 (s, 3H, CH ),
3 2 3 3
Casa-Juana, M. F.; Sunkel, C.; Priego, J. G.; Fonseca, I.; Sanz-Aparicio, J.
Tetrahedron 1994, 50, 8085.
[20] Gong, H.; Qi, H.; Sun, W.; Zhang, Y.; Jiang, D.; Xiao, J.;
Yang, X.; Wang, Y.; Li, S. Molecules 2012, 17, 9961.
[21] Thompson, A. M.; Bridges, A. J.; Fry, D. W.; Kraker, A. J.;
Denny, W. A. J Med Chem 1995, 38, 3780.
2
.23 (s, 3H, CH CO), 3.87 (q, J = 7.2 Hz, 2H,
3
CH CH ), 4.69 (s, 1H, CH), 6.22 (s, 2H, NH ), 7.17
3
2
2
(
s, 1H, HetCH), 8.98 (s, 1H, 8-NH), 10.29 (br.s, 1H,
1
3
3
1
1
1
-NH). C NMR (126 MHz, DMSO) δ (ppm): 12.07,
5.46, 19.21, 27.47, 29.47, 45.54, 91.88, 110.72,
25.04, 128.17, 144.18, 145.36, 153.16, 153.80,
[
22] Abdolmohammadi, S.; Balalaie, S. Int J Org Chem 2012, 2, 7.
[23] Mont, N.; Teixidó, J.; Kappe, C. O.; Borrell, J. I. Mol Divers
2003, 7, 153.
24] Tu, S.; Zhang, J.; Jia, R.; Jiang, B.; Zhang, Y.; Jiang, H. Org
+
61.46, 196.83. MS for C H N O , m/z: 328 (M ).
1
6
20
6
2
[
Anal. Calcd for C H N O : C, 58.52; H, 6.14; N,
1
6
20
6
2
Biomol Chem 2007, 5, 1450.
2
5.59. Found: C, 58.90; H, 6.25; N, 25.85.
[25] Tu, S.; Zhang, J.; Xiang, Z.; Fang, F.; Li, T. ARKIVOC 2005,
xiv, 76.
6
-Acetyl-5-(1-allyl-3-methyl-1H-pyrazol-4-yl)-2-amino-7-
[
26] Saraev, V. E.; Chebanov, V. A.; Desenko, S. M.; Afanasiadi,
L. M. UA Pat. 85082 2008.
27] Nia, R. H.; Mamaghani, M.; Tabatabaeian, K.; Shirini, F.;
Rassa, M. Acta Chim Slov 2013, 60, 889.
28] Yao, C.; Lu, T.; Yu, C.; Wang, X.; Li, T. J Heterocycl Chem
014, 6, 7.
[29] Lu, G.; Cai, C. J Heterocycl Chem 2014, 51, 1595.
[30] Muravyova, E. A.; Tkachenko, V. V.; Desenko, S. M.; Sen’ko,
Y. V.; Müller, T. J. J.; Vashchenko, E. V.; Chebanov, V. A. ARKIVOC
013, iii, 338.
methyl-5,8-dihydropyrido[2,3-d]pyrimidin-4(3H)-one (4r).
1
Yield 63% as pale yellow solid; mp: over 300°C. H NMR
200MHz, DMSO) δ (ppm): 2.02 (s, 2H, CH ), 2.12 (s,
[
(
3
[
3
H, CH CO), 2.22 (s, 3H, 3′-CH ), 4.69 (s, 1H, 5-CH),
3 3
2
4
.52 (m, 2H, N-CH ), 5.07 (m, 2H, terminal CH ), 5.86
2
2
(m, 1H, allyl-CH), 6.21 (s, 2H, NH ), 7.15 (s, 1H, HetCH),
2
1
3
8
.99 (s, 1H, 8-NH), 10.26 (br.s., 1H, 3-NH). C NMR
2
(126MHz, DMSO) δ (ppm): 12.02, 19.21, 27.50, 29.45,
[31] Lei, M.; Ma, L.; Hu, L. Synth Commun 2011, 41, 3424.
5
1
3.36, 91.82, 110.69, 117.50, 125.53, 128.72, 134.50,
44.59, 145.40, 153.14, 153.82, 161.43, 196.78. MS for
[32] Lei, M.; Ma, L.; Hu, L. Synth Commun 2011, 41, 1969.
[33] Loupy, A. Microwaves in Organic Synthesis; Wiley-VCH:
+
Weinheim, 2006.
C H N O , m/z: 340 (M ). Anal. Calcd for C H N O :
C, 59.99; H, 5.92; N, 24.69. Found: C, 59.93; H, 5.98;
N, 24.60.
17
20
6
2
17 20 6 2
[34] Kappe, C. O.; Stadler, A. Microwaves in Organic and Medicinal
Chemistry; Wiley-VCH: Weinheim, 2005.
[35] VanAllan, J. A. Org Synth 1952, 32, 45.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet