A green approach to the synthesis of fused uracils: Pyrano[2,3-d] pyrimidines. On-water one-pot synthesis by domino Knoevenagel/Diels-Alder reactions

Article abstract of DOI:10.1055/s-0030-1258292

On-water Knoevenagel condensations of 2-thiobarbituric acid and N,N-dimethylbarbituric acid with aromatic and heteroaromatic aldehydes were carried out without a catalyst and at room temperature. Condensations in aqueous suspensions occurred rapidly, giving excellent yields. Solvent-free hetero-Diels-Alder reactions of 5-arylidene derivatives of barbituric acids with ethyl vinyl ether were investigated at room temperature and pyrano[2,3-d]pyrimidines of potential pharmacological activity were obtained in excellent yields. Three-component one-pot syntheses of annulated uracils were performed in aqueous suspensions. Reactions of barbituric acids, aldehydes, and ethyl vinyl ether were carried out at ambient temperature, whereas the one-pot synthesis with barbituric acids, aldehydes, and styrene or N-vinyl-2- oxazolidinone required the heating of aqueous suspensions at 60°C. On-water cycloadditions were characterized by high diastereoselectivity in contrast to reactions carried out in homogeneous organic media (dichloromethane, toluene). They allowed the cis adducts to be obtained preferentially or exclusively. The presented green methods avoid the use of catalysts, the heating of reaction mixtures for long times at high temperatures, and the use of organic solvents, and make the synthesis of a variety of pyrano[2,3-d]pyrimidines chemically efficient. The results reveal water as the medium of choice for the examined cycloadditions. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258292

PAPER
4021
A Green Approach to the Synthesis of Fused Uracils: Pyrano[2,3-d]pyrimidines.
‘On-Water’ One-Pot Synthesis by Domino Knoevenagel/Diels–Alder Reactions
G
reen Approach to
l
S
ynth
e
esis of Pyra
k
no[2,3-
d
]pyr
s
imidine
s
andra Pałasz*
Department of Organic Chemistry, Jagiellonian University, ul. Ingardena 3, 30-060 Kraków, Poland
Fax +48(12)6340515; E-mail: palasz@chemia.uj.edu.pl
Received 29 May 2010; revised 6 September 2010
family of valuable drugs that depress nerve activity.2
5-Arylidene derivatives of barbituric acids are bioactive
compounds3 and are also important intermediates in the
preparation of other pharmaceuticals, for example
Abstract: ‘On-water’ Knoevenagel condensations of 2-thiobarbi-
turic acid and N,N-dimethylbarbituric acid with aromatic and het-
eroaromatic aldehydes were carried out without a catalyst and at
room temperature. Condensations in aqueous suspensions occurred
rapidly, giving excellent yields. Solvent-free hetero-Diels–Alder re- annulated uracils. Uracil and its fused derivatives, such
actions of 5-arylidene derivatives of barbituric acids with ethyl vi-
nyl ether were investigated at room temperature and pyrano[2,3-
as pyrano[2,3-d]pyrimidines, pyrido[2,3-d]pyrimidines,
pyrazo[3,4-d]pyrimidines, or pyrimido[4,5-d]pyrim-
d]pyrimidines of potential pharmacological activity were obtained
idines, are reported to have a wide range of biological ac-
in excellent yields. Three-component one-pot syntheses of annulat-
tivities such as antiallergic,4 antihypertensive,5
ed uracils were performed in aqueous suspensions. Reactions of
cardiotonic,6 bronchiodilator,7 antibronchitic,8 or
barbituric acids, aldehydes, and ethyl vinyl ether were carried out at
ambient temperature, whereas the one-pot synthesis with barbituric
antitumor9 activity.
acids, aldehydes, and styrene or N-vinyl-2-oxazolidinone required
the heating of aqueous suspensions at 60 °C. ‘On-water’ cycloaddi-
taining a uracil ring poses significant synthetic challenges.
tions were characterized by high diastereoselectivity in contrast to
reactions carried out in homogeneous organic media (dichlo-
romethane, toluene). They allowed the cis adducts to be obtained
The preparation of the above-mentioned compounds con-
The synthesis of annulated uracils is well described in the
literature,10 but the synthetic methods usually require
preferentially or exclusively. The presented green methods avoid drastic conditions, long reaction times, and complex syn-
the use of catalysts, the heating of reaction mixtures for long times
thetic pathways and the yields are poor. There have been
at high temperatures, and the use of organic solvents, and make the
novel approaches to the synthesis of annulated uracils of
synthesis of a variety of pyrano[2,3-d]pyrimidines chemically effi-
biological importance recently. These new synthetic
cient. The results reveal water as the medium of choice for the ex-
methods rely on a multicomponent reaction in the solid
amined cycloadditions.
state,11 a stereoselective intramolecular hetero-Diels–
Key words: Diels–Alder reactions, drugs, green chemistry, pyra-
Alder reaction (HDA),12 an intermolecular [4+2]-cyclo-
no[2,3-d]pyrimidines, solvent effects
addition reaction,13 or a photo-induced oxidative cycliza-
tion.14 The HDA is an excellent method for the synthesis
of fused uracils, because this reaction is a simple and effi-
Water is the solvent of choice for nature to carry out syn-
cient tool for the construction of six-membered heterocy-
theses of complex organic molecules. Water is a clean, in-
clic systems. As active heterodienes in Diels–Alder
expensive, environmentally friendly reaction medium.
reactions, 5-arylidene derivatives of barbituric acid are
Therefore the choice of water as solvent for organic reac-
used. The Knoevenagel condensation of various aromatic
tions in the laboratory is obvious. However, water as a sol-
and heteroaromatic aldehydes with active methylene
vent was ruled out from organic reactions during the
compounds such as barbituric acids, Meldrum’s acid,
preceding decades. The situation changed in 1980 by the
dimedone, malononitrile, or ethyl cyanoacetate has been
pioneering work of Breslow and Rideout, who demon-
widely used in the synthesis of arylidene derivatives. The
strated that Diels–Alder reactions of water-soluble re-
reactions with aromatic aldehydes are usually catalyzed
agents would be greatly accelerated in aqueous solution.1a
by bases15 such as amines, ammonia, or sodium ethoxide.
In 2005, Sharpless and co-workers demonstrated that the
Acids such as acetic acid, hydrochloric acid, or sulfuric
Diels–Alder reaction of the water-insoluble reactants
acid can also be used as catalysts.16
showed substantial rate acceleration in aqueous suspen-
sion over homogeneous solution.1b Hydrophobic interac-
tions of reagents with water are invoked for the observed
effects.
As a continuation of the investigations of organic reac-
tions performed in aqueous medium, a green method for
the synthesis of the fused uracils 2-thioxopyrano[2,3-
d]pyrimidin-4-ones and pyrano[2,3-d]pyrimidin-2,4-di-
ones by uncatalyzed Knoevenagel condensation ‘on wa-
ter’ at room temperature and a solvent-free hetero-Diels–
Alder cycloaddition at room temperature is reported.
Barbituric acids and their derivatives are reported to have
a wide range of pharmacological activities. For example,
5,5-disubstituted derivatives, known as barbiturates, are a
5-Arylidene-2-thiobarbituric acids 3a–g and 5-arylidene-
N,N-dimethylbarbituric acids 3h–m, as potential hetero-
dienes in Diels–Alder reactions, were synthesized by
SYNTHESIS 2010, No. 23, pp 4021–4032
Advanced online publication: 12.10.2010
DOI: 10.1055/s-0030-1258292; Art ID: T12110SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0

4022
A. Pałasz
PAPER
modification of the procedure described in literature ether 4 at room temperature, but dichloromethane was
(Scheme 1, Table 1).17 Condensations of 2-thiobarbituric used as solvent.18 While reaction mixtures 3a–m with 4
acid 1a or N,N-dimethylbarbituric acid 1b with appropri- without solvent were stirred, solid compounds 3a–m did
ate aromatic or heteroaromatic aldehydes 2a–i were car- not dissolve in a tenfold excess of 4, but a change in the
ried out in water without catalyst at room temperature. It color of the precipitate from the yellow of dienes 3a–m to
is worth noting that Bhuyan et al.17 described this method the colorless cycloadducts 5a–m was observed.
for barbituric acid and N,N-dimethylbarbituric acid, solu-
ble in water at room temperature. In the present work this
Next, the ‘on-water’ Knoevenagel condensation proce-
dures, used for aldehydes 2a–i, were applied to cyclic
ketones such as cyclopentanone, cyclohexanone, cyclo-
method was for the first time used for water-insoluble 2-
thiobarbituric acid. It is reported in the literature3 that 5-
heptanone, and cyclooctanone. There are no reports in the
arylidene derivatives of 2-thiobarbituric acid were ob-
literature describing such green procedures for ketones,
tained by an uncatalyzed Knoevenagel condensation in
because they have too low reactivity in the condensations
aqueous medium, but the solution was heated at 80 °C for
with CH acids. Only cyclopentanone gave cyclopentyl-
several hours. In the present study it was found that the
idene derivatives 3n,o in excellent 93 and 95% yield, re-
spectively, without further purification (Scheme 1,
heating of the reaction mixture is not necessary and that it
is also not necessary to dissolve the 2-thiobarbituric acid
Tables 1 and 2, entries 14 and 15). The Diels–Alder reac-
in water by heating before the addition of the aldehyde.
tions of the Knoevenagel products 3n,o with a tenfold ex-
cess of 4 needed heating in ethyl acetate at 77 °C for four
hours, and the spirouracils 5n,o were synthesized in good
yields (88 and 91%, respectively; Table 2, entries 14 and
The examined reactions are examples of ‘on-water’ reac-
tions, in which insoluble reactants are stirred in aqueous
suspension. All the reactions occurred rapidly and were
completed in just an hour, giving excellent yields of 88–
15).
98% of Knoevenagel products 3a–m (Tables 1 and 2).
The progress of all the reactions was monitored by TLC.
The ratios of the cis and trans diastereoisomers of the pyr-
The cycloaddition reactions of 5-arylidenebarbituric acids
3a–m with a tenfold excess of ethyl vinyl ether (4) were
performed in the absence of solvent at room temperature
for one to five hours, and the uracils 5a–m were obtained
in excellent 88–96% yields (Scheme 1, Tables 1 and 2).
Previously, I described reactions of 5-arylidene deriva-
tives of N,N-dimethylbarbituric acids 3h–m with enol
5a–g prepared from 2-thiobarbituric acid are new com-
ano[2,3-d]pyrimidines 5a–m were determined on the ba-
1
sis of the H NMR spectra of the crude products, by
analysis of the signal of proton H-7. All diastereoisomers
of compounds 5a–m were separated by column chroma-
tography by using ethyl acetate as eluent. Cycloadducts
O
R3
O
O
R1
X
R1
X
H2O
N
N
R3CHO
+
r.t.
stirring
N
O
N
R2
R2
1a,b
2a–i
3a–m
R3
O
O
R3
O
O
R3
O
R1
R1
X
R1
X
N
N
N
+
+
r.t.
stirring
X
N
OEt
N
OEt
N
O
OEt
R2
R2
R2
3a–m
4
trans-5a–m
cis-5a–m
O
O
R1
N
R1
X
H2O
N
+
r.t.
stirring
N
R2
O
X
N
O
R2
O
2j
3n–o
1a,b
O
O
R1
X
R1
X
N
N
+
N
R2
O
OEt
N
R2
O
OEt
3n,o
4
5n,o
Scheme 1
Synthesis 2010, No. 23, 4021–4032 © Thieme Stuttgart · New York

PAPER
Green Approach to Synthesis of Pyrano[2,3-d]pyrimidines
4023
Table 1 Synthesis of Pyrano[2,3-d]pyrimidines 5a–o by Solvent-
Free HDA Reactions of 5-Arylidene-2-thiobarbituric Acids 3a–g, 5-
Arylidene-N,N-dimethylbarbituric Acids 3h–m, or Barbituric Acids
3n,o with Enol Ether 4
Table 2 Synthesis of Pyrano[2,3-d]pyrimidines 5a–o by Solvent-
Free HDA Reactions of 3a–o with 4
Entry
3
Yield
(%) of 3
5
Reaction Yield
Ratio
time (h) (%)a of 5 cis/transa
Entry 1
R1
H
R2
H
X
S
2
R3
3
5
1
2
3a
3b
3c
3d
3e
3f
93
90
91
89
88
91
95
91
98
95
92
91
93
93
95
5a
5b
5c
5d
5e
5f
1
1
2
3
3
5
5
1
1
2
5
5
5
4b
4b
88
96
92
89
92
90
89
94
95
95
91
92
90
88
91
2.1:1
2.3:1
1:1
1
1a
2a
2b
2c
2d
2e
2f
C6H5
3a
3b
3c
3d
3e
3f
3g
3h
3i
5a
5b
5c
5d
5e
5f
5g
5h
5i
2
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1a
1b
H
H
S
4-MeOC6H4
4-NCC6H4
4-ClC6H4
4-BrC6H4
2-thienyl
2-furyl
3
3
H
H
S
4
3.4:1
2.8:1
1:1.5
1:1
4
H
H
S
5
5
H
H
S
6
6
H
H
S
7
3g
3h
3i
5g
5h
5i
7
H
H
S
2g
2a
2b
2h
2f
8
1.8:1
2.5:1
1.2:1
2.6:1
1.9:1
1.8:1
–
8
Me
Me
Me
Me
Me
Me
H
Me
Me
Me
Me
Me
Me
H
O
O
O
O
O
O
S
C6H5
9
9
4-MeOC6H4
4-O2NC6H4
2-thienyl
2-furyl
10
11
12
13
14
15
3j
5j
10
11
12
13
14
15
3j
3k
3l
5j
5k
5l
3k
3l
5k
5l
2g
2i
3m
3n
3o
5m
5n
5o
4-pyridyl
3m 5m
a
2j
–
3n
3o
5n
5o
–
a
Me
Me
O
2j
–
a Ratio based on 1H NMR (300 MHz) spectra of crude products.
b Reaction mixture was heated in EtOAc at 77 °C.
a See Scheme 1 for the structures of 3n,o and 5n,o.
rial position and the alkoxy group occupies the axial po-
sition (Figure 1).
pounds, not yet described in the literature. The relative cis
and trans configurations of the C-5 and C-7 substituents
were assigned on the basis of 1H NMR spectra. They were
deduced from the chemical shift values and coupling con-
stants of the protons attached to C-5 and C-7 of the dihy-
dropyran ring that exists in a half-chair conformation
(Figure 1).19
For the minor diastereoisomers trans-5a–g, the protons at-
tached to C-5 give rise to a doublet of doublets with cou-
3
pling constants J = 5.1–7.2 and 4.2–6.6 Hz at d = 3.71–
4.16 (Table 3). Thus, H-5 is pseudo-axial and the aryl
moiety occupies the pseudo-equatorial position
(Figure 1). The proton H-7 of trans-5a–g resonates at
d = 5.16–5.29 as a doublet of doublets with two coupling
constants 3J = 5.7–7.5 and 2.1–5.4 Hz. This suggests that
for trans-5a–g the conformation with an axial alkoxy
group is preferred due to stabilization by the anomeric ef-
fect. Cycloadducts cis-5a–g were the major products. The
preferred formation of the cis diastereoisomers (see
Table 2) results from the endo transition state interaction,
which is energetically more favorable than the exo transi-
tion state. Thus, cis products arise from a kinetically con-
trolled process.20 The stereochemical structure of cis/
trans cycloadducts 5h–m was described in previous
work.18 The orientation of the ethoxy substituent at C-7¢
was assigned on the basis of 1H NMR spectra. It was de-
duced from the chemical shift values and the coupling
constants of the proton attached to C-7¢ of the dihydropy-
ran ring that exists in a half-chair conformation.19 In the
1H NMR spectra of spiropyrans 5n,o, the signal of H-7¢
appears as a doublet of doublets at d = 5.08–5.29 with
R3
5
H
O
O
5
O
H
5
H
H
7
7
R3
7
H
OEt
OEt
OEt
major cis-5a–g
minor trans-5a–g
5n,o
Figure 1 Preferred cis/trans configurations and conformations of
cycloadducts 5a–g and 5n,o, determined on the basis of 1H NMR ana-
lysis
In the 1H NMR spectra of the major diastereoisomers cis-
5a–g, the signal of H-5 appeared as a doublet of doublets
at d = 3.79–4.14, with coupling constants 3J = 6.9–7.2 and
3.6–5.1 Hz due to coupling with two protons at C-6
(Figure 1, Table 3). Thus, H-5 occupies the pseudo-equa-
torial position, and the aromatic group adopts the pseudo-
1
axial orientation (Figure 1).The H NMR spectra of cis-
5a–g reveal the signals of proton H-7 as a doublet of dou-
blets at d = 5.46–5.52 with two small coupling constants
(3J = 3.3–4.8 and 2.4–3.0 Hz). Thus, H-7 is in the equato-
3
coupling constants J = 2.1 and 6.9–8.1 Hz due to cou-
pling with two protons at C-6¢. Thus, H-7¢ is in the equa-
Synthesis 2010, No. 23, 4021–4032 © Thieme Stuttgart · New York

4024
A. Pałasz
PAPER
Table 3 Signals of H-5 and H-7 in the 1H NMR Spectra of 2-Thioxopyrano[2,3-d]pyrimidin-4-ones 5a–g
cis-5
d (dd, H-5) (ppm)
J6ax,5/J6eq,5 (Hz)
d (dd, H-7) (ppm)
J6ax,7/J6eq,7 (Hz)
trans-5
d (dd, H-5) (ppm)
J6ax,5/J6eq,5 (Hz)
d (dd, H-7) (ppm)
J6ax,7/J6eq,7 (Hz)
cis-5a
cis-5b
cis-5c
cis-5d
cis-5e
cis-5f
cis-5g
3.86
7.2/5.1
5.47
4.5/2.7
trans-5a
trans-5b
trans-5c
trans-5d
trans-5e
trans-5f
trans-5g
3.87
6.3/5.4
5.19
7.5/2.4
3.79
7.2/4.8
5.46
4.8/2.4
3.83
6.6/4.8
5.16
7.5/2.4
3.94
7.2/3.9
5.50
3.3/3.0
3.92
6.6/6.6
5.29
6.3/2.4
3.85
6.9/4.2
5.48
3.6/2.7
3.71
7.2/5.7
5.23
6.6/2.4
3.84
7.2/4.5
5.48
3.9/2.7
3.84
6.6/6.6
5.23
6.9/2.1
4.14
6.9/3.6
5.52
3.3/3.0
4.16
5.1/4.2
5.25
5.7/5.4
3.94
6.9/3.9
5.51
3.0/2.7
3.85
6.6/6.3
5.23
7.5/2.4
torial position and the alkoxy group occupies the axial unexpectedly, products 6a,b were obtained in 88–96%
position (Figure 1).
yields (Scheme 2, Tables 4 and 5). While the reaction
mixtures of 1a,b, 2a–h, and 4 were stirring as aqueous
suspensions, a change of the precipitate color from yellow
to colorless was observed; this is characteristic for cy-
cloadducts 5a–k.
It is well-known that a Knoevenagel condensation fol-
lowed by a hetero-Diels–Alder reaction, realized as a one-
pot synthesis, can be used in dihydropyran preparation.21
Therefore, in the next step of these studies, three-
component one-pot synthesis of uracils 5a–k by domino The progress of the reactions was monitored by TLC. The
Knoevenagel/Diels–Alder reactions was investigated in molar ratios of the cis-5/trans-5/6 derivatives of pyra-
aqueous medium. The Knoevenagel product was formed no[2,3-d]pyrimidines were determined on the basis of the
in situ in aqueous suspensions and the next hetero-Diels– 1H NMR spectra of the crude products and also on the ba-
Alder reaction proceeded smoothly in biphasic condi- sis of the mass of the products obtained after column chro-
tions. The experimental procedure was simple: equimolar matography. The major products in the ‘on-water’ one-pot
amounts of barbituric acids 1a,b and aromatic or heteroaro- synthesis were compounds cis-5a–k. Formation of the un-
matic aldehydes 2a–h were mixed with a tenfold excess expected 5-methyl-substituted derivatives of pyrano[2,3-
of enol ether 4 in water at room temperature for one to d]pyrimidines 6a,b can be explained as shown in
three hours, and the pyrano[2,3-d]pyrimidines 5a–k and, Scheme 2. In the first step, the addition of water to alkene
O
O
R3CHO
R1
R1
X
cis-5a–k
N
2a–h
H2O
N
+
+
r.t.
X
N
R2
O
OEt
trans-5a–k
stirring
N
R2
O
OEt
1a,b
4
6a X = S
6b X = O
H2O, H+
H+
EtOH
OEt
OH
OH
MeCHO
OEt
B
C
4
A
O
O
O
R1
X
R1
R1
X
N
N
N
MeCHO
+
+
N
R2
O
OEt
X
N
R2
O
N
R2
O
OEt
C
1a,b
3p X = S
3q X = O
4
6a,b
Scheme 2
Synthesis 2010, No. 23, 4021–4032 © Thieme Stuttgart · New York

PAPER
Green Approach to Synthesis of Pyrano[2,3-d]pyrimidines
4025
of the crude products that only one of the two diastereo-
isomers cis/trans 6a,b was created. Compounds 6a,b were
observed as one spot on TLC plates when ethyl acetate or
ethyl acetate–petroleum ether (5:1) were used as eluent. It
is impossible to assign the relative cis or trans configura-
tion of the C-5 and C-7 substituents in cycloadducts 6a,b
unambiguously on the basis of the 1H NMR spectra.
Table 4 Synthesis of Pyrano[2,3-d]pyrimidines 5a–k and 6a,b by
‘On-Water’ Three-Component One-Pot Reactions amongst 1a,b,
2a–h, and 4
Entry 1
R1
H
R2
H
X
S
2
R3
5
6
1
2
1a
2a
2b
2c
2d
2e
2f
C6H5
5a 6a
1a
1a
1a
1a
1a
1b
1b
1b
1b
H
H
S
4-MeOC6H4 5b 6a
Three-component one-pot syntheses of pyrano[2,3-d]py-
rimidines performed in aqueous suspension were faster
than those executed in dichloromethane18 or under sol-
ventless conditions. The ‘on-water’ one-pot synthesis
(OPS) gave the highest yields and the endo/exo selectivity
was significantly improved (Table 6).
3
H
H
S
4-NCC6H4
4-ClC6H4
4-BrC6H4
2-thienyl
C6H5
5c
6a
4
H
H
S
5d 6a
5
H
H
S
5e
5f
6a
6a
6
H
H
S
7
Me
Me
Me
Me
Me
Me
Me
Me
O
O
O
O
2a
2b
2h
2f
5h 6b
Table 6 Comparison of Reaction Times, Yields, and Ratios of cis-
5/trans-5 for the Synthesis of Pyrano[2,3-d]pyrimidines 5b, 5f, 5i,
and 5k under Different Reaction Conditions
8
4-MeOC6H4 5i
4-O2NC6H4 5j
6b
6b
9
5
Medium
Reaction
time (h)
Yield
(%)
Ratio cis-5/
trans-5
10
2-thienyl
5k 6b
5b
5b
5b
5b
5f
no solvent
1
1
3
4
5
3
8
8
1
1
2
3
5
3
5
7
96
96
94
92
90
90
84
87
95
95
94
95
91
91
84
87
2.3:1
OPSa ‘on-water’
8.5:1:1.8c
2.2:1
Table 5 Synthesis of Pyrano[2,3-d]pyrimidines 5a–k and 6a,b by
‘On-Water’ Three-Component One-Pot Reactions
b
CH2Cl2
Entry
5
6
Time Yield Ratio (6 + cis-5)/ Ratio 6/cis-5/
b
(h)
(%)a trans-5b
trans-5d
2.5:6.4:1
1.8:8.5:1
1.6:6.0:1
1.7:6.5:1
2.0:5.2:1
0.5:6.3:1
1.3:4.1:1
1.5:6.6:1
1.4:5.3:1
0.6:5.3:1
OPS in CH2Cl2
2.4:1
1
2
5a
5b
5c
5d
5e
5f
6a
6a
6a
6a
6a
6a
6b
6b
6b
6b
1
88
96
92
89
92
90
94
95
95
91
9.2:1c
no solvent
1.0:1.5
6.3:1:0.5c
1.0:1.1
1.0:1.0
2.5:1
5f
OPS ‘on-water’
1
10.0:1
7.8:1
b
5f
CH2Cl2
3
2
b
5f
OPS in CH2Cl2
4
2
8.1:1
5i
no solvent
5
2
7.2:1
5i
OPS ‘on-water’
6.6:1:1.5d
2.6:1
6
3
7:1
b
5i
CH2Cl2
7
5h
5i
1
1.5:4.3:1
1.8:6.6:1
1.5:5.5:1
0.5:5.6:1
b
5i
OPS in CH2Cl2
2.6:1
8
1
5k
5k
5k
5k
no solvent
2.6:1
9
5j
2
OPS ‘on-water’
5.3:1:0.6d
1.25:1
2.6:1
10
5k
3
a Isolated yields after column chromatography.
b
CH2Cl2
b Ratio based on analysis of signal of proton H-7 of 6, cis-5, and trans-
5 in 1H NMR (300 MHz) spectra of crude products.
c Overlap of d = 5.43 (dd) and 5.47 (dd) of H-7 for 6a with d = 5.46–
5.52 of H-7 for cis-5a–f.
b
OPS in CH2Cl2
a OPS = one-pot synthesis.
b Diels–Alder reactions of 3g–m with 4 at r.t. in CH2Cl2 and OPS of
uracils 5g,m in CH2Cl2 are described in a previous paper.18 Syntheses
of 5b and 5f in CH2Cl2 were carried out according to the procedure
reported in ref. 18.
d Molar ratio based on mass of products obtained after column chro-
matography.
c Ratio cis-5/trans-5/6a.
4 catalyzed by barbituric acid provides hemiacetal A,
which undergoes ethanol elimination to produce enol tau-
tomer B or keto tautomer of acetaldehyde C. Next, the in
situ generated aldehyde C undergoes Knoevenagel con-
densation with barbituric acids 1a,b to furnish intermedi-
ate condensation product 3p,q. In the final step, Diels–
Alder reaction of intermediate 3p,q with ethyl vinyl ether
4 resulted in the unexpected products 6a,b. Compounds
6a,b are new and have not been described in the literature
yet. It was determined on the basis of the 1H NMR spectra
d Ratio cis-5/trans-5/6b.
Next, ‘on-water’ one-pot syntheses of uracils 8a–h by re-
action of barbituric acids 1a or 1b, aldehydes 2a or 2h,
and styrene 7a or N-vinyl-2-oxazolidinone 7b were exam-
ined (Scheme 3, Table 7). Equimolar amounts of com-
pounds 1, 2, and 7 were mixed in water at 60 °C for one to
three hours, and the pyrano[2,3-d]pyrimidines 8a–h were
obtained in 89–95% yields (Table 8). The only products
Synthesis 2010, No. 23, 4021–4032 © Thieme Stuttgart · New York

4026
A. Pałasz
PAPER
of the reactions were cis-8a–h diastereoisomers. Cycload- and C-7 of the dihydropyran ring in the 1H NMR spectra
ducts 8a–d prepared from 2-thiobarbituric acid are new (Figure 2, Table 9). In previous papers,22,23 it was shown
compounds and have not yet been described in the litera- that reactions 5-arylidene-N,N-dimethylbarbituric acids
ture. The relative cis configuration of the C-5 and C-7 with styrenes or N-vinyl-2-oxazolidinone required reflux-
substituents in compounds 8a–h was assigned on the basis ing in toluene for 24–36 hours for styrenes22 and 3–5
of analysis of the signals of the protons attached to C-5 hours for N-vinyl-2-oxazolidinone.23 The reactions per-
formed ‘on water’ in heterogeneous phase were faster
Table 7 Synthesis of Pyrano[2,3-d]pyrimidines 8a–h by ‘On-
Water’ Three-Component One-Pot Reactions amongst 1a,b, 2a,h,
The ‘on-water’ reactions were characterized by very high
and 7a,b
(1–3 h) than those executed in refluxing toluene solution.
endo/exo diastereoselectivity in contrast to reactions in
boiling toluene for which a cis/trans diastereoselectivity
of 1:1 was observed.
Entry
1
2
R3
7
R4
7a 4-MeOC6H4
8
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1b
2a
2h
2a
2h
2a
2h
2a
2h
C6H5
8a
8b
O
R3
O
4-O2NC6H4 7a 4-MeOC6H4
C6H5
4-O2NC6H4 7b 2-oxooxazolidin-3-yl 8d
O
R3CHO
R1
X
R1
X
2a,h
N
7b 2-oxooxazolidin-3-yl 8c
N
H2O
+
60 °C
R4
N
O
N
stirring
R4
R2
R2
C6H5
4-O2NC6H4 7a 4-MeOC6H4
C6H5
4-O2NC6H4 7b 2-oxooxazolidin-3-yl 8h
7a 4-MeOC6H4
8e
8a–h
1a,b
7a,b
8f
Scheme 3
7b 2-oxooxazolidin-3-yl 8g
R3
O
R4
H
Table 8 Synthesis of Pyrano[2,3-d]pyrimidines 8a–h by ‘On-
Water’ Three-Component One-Pot Reactions amongst 1a,b, 2a,h, and
7a,b
H
Figure 2 Preferred cis configuration of 8a–h
Entry
1
2
7
8
Reaction Yield Ratio cis-8/
time (h) (%)a trans-8b
In conclusion, very simple and highly efficient green
methods for the synthesis of fused uracils, namely pyra-
no[2,3-d]pyrimidines of potential pharmacological activi-
ty, were described. The Knoevenagel condensations of
aromatic and heteroaromatic aldehydes 2a–g with 2-
thiobarbituric acid 1a were carried out in aqueous suspen-
sions as ‘on-water’ reactions without catalyst and at room
temperature. Condensations occurred rapidly and were
completed in only an hour giving good yields (88–95%)
of Knoevenagel products 3a–g. Solvent-free hetero-
Diels–Alder reactions of 5-arylidene derivatives of barbi-
turic acids 1a,b with ethyl vinyl ether 4 were carried out
at room temperature. Cycloadducts 5a–m were obtained
in excellent yields (88–96%). The same ‘on-water’ proce-
dures for Knoevenagel condensation at room temperature,
without catalyst, were used for cyclopentanone. Cyclo-
pentylidene derivatives 3n,o were obtained in excellent
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1b
2a
2h
2a
2h
2a
2h
2a
2h
7a
7a
7b
7b
7a
7a
7b
7b
8a
8b
8c
8d
8e
8f
3
2
2
1
2
1
2
1
89
94
91
92
91
93
90
95
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
8g
8h
a Isolated yields after column chromatography.
b Ratio based on analysis of signal of proton H-7 of cis-8 and trans-8
in 1H NMR (300 MHz) spectra of crude products.
Table 9 Signals of Protons H-5 and H-7 in the 1H NMR Spectra of 2-Thioxopyrano[2,3-d]pyrimidin-4-ones cis-8a–h
cis-8
d (dd, H-5) (ppm)
J6ax,5/J6eq,5 (Hz)
d (dd, H-7) (ppm)
J6ax,7/J6eq,7 (Hz)
cis-8
d (dd, H-5) (ppm)
J6ax,5/J6eq,5 (Hz)
d (dd, H-7) (ppm)
J6ax,7/J6eq,7 (Hz)
cis-8a
cis-8b
cis-8c
cis-8d
3.96
11.3/6.6
5.49
11.3/1.8
cis-8e
cis-8f
cis-8g
cis-8h
4.18
11.3/6.7
5. 21
11.5/2.0
4.10
11.1/6.5
5.51
11.3/2.0
4.22
11.2/6.8
5.23
11.8/1.8
4.05
11.0/6.3
5.91
11.1/1.8
4.29
11.2/6.5
5.93
11.0/6.7
4.09
5.96
4.31
5. 95
11.3/6.5
11.0 / 2.1
11.3/6.6
11.3/6.5
Synthesis 2010, No. 23, 4021–4032 © Thieme Stuttgart · New York

PAPER
Green Approach to Synthesis of Pyrano[2,3-d]pyrimidines
4027
13C NMR (75.5 MHz, DMSO-d6): d = 111.7 (methylene-C), 128.6,
136.6, 143.1, 146.3 (C-2¢, C-3¢, C-4¢, C-5¢), 146.6 (C-5), 160.7
(C=O), 161.7 (C=O), 178.2 (C=S).
yields (93–95%). Diels–Alder reactions of compounds
3n,o with vinyl ether 4 needed heating in ethyl acetate and
the spirouracils 5n,o were synthesized in good yields (88–
91%). Three-component one-pot syntheses of annulated
uracils by domino Knoevenagel/Diels–Alder reactions of
barbituric acids 1a,b, aldehydes 2a–h, and ethyl vinyl
ether 4 were performed in aqueous suspension at ambient
temperature, whereas one-pot synthesis from 1a,b, 2a,h,
and styrene 7a or N-vinyl-2-oxazolidinone 7b required
heating of aqueous suspensions at 60 °C. They furnished
the Diels–Alder products 5a–k in 88–96% and 8a–h in
89–95% yields after one to three hours. Formation of cy-
cloadducts 5a–k was accompanied by the unexpected for-
mation of 5-methyl-substituted derivatives of pyrano[2,3-
d]pyrimidines 6a,b. The endo-cis adducts 5 were prefer-
entially or exclusively produced. The results suggest that
the presented green methods may displace all other meth-
ods that use various organic solvents and catalysts and
that are performed at high temperature. No organic sol-
vents are used in this sequence, although extraction, heat-
ing, and column chromatography were carried out with
ethyl acetate. The obtained results reveal water as the me-
dium of choice for the examined Knoevenagel condensa-
tions and cycloaddition reactions.
Anal. Calcd for C9H6N2O2S2: C, 45.37; H, 2.54; N, 11.76; S, 26.91.
Found: C, 45.41; H, 2.62; N, 11.79; S, 27.18.
5-(2-Furylmethylene)-2-thioxo-1,3-dihydropyrimidine-4,6-di-
one (3g)
Yellow crystals; mp >360 °C; yield: 1.48 g (95%).
IR (KBr): 3125 (NH), 3080 (CH), 1672 (C=O), 1569 (C=S), 1521
(C=C) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 6.96 (ddd, J = 0.6, 1.8, 3.6 Hz,
1 H, furyl-H), 8.05 (s, 1 H, methylene-H), 8.32 (dd, J = 0.6, 1.8 Hz,
1 H, furyl-H), 8.54 (dd, J = 0.6, 3.9 Hz, 1 H, furyl-H), 12.37 (s, 1 H,
NH), 12.44 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 112.80, 115.53 (methylene-
H), 127.45, 137.37, 150.39, 151.96 (C-2¢, C-3¢, C-4¢, C-5¢), 146.6
(C-5), 159.82 (C=O), 161.48 (C=O), 178.18 (C=S).
Anal. Calcd for C9H6N2O3S: C, 48.65; H, 2.72; N, 12.61; S, 14.43.
Found: C, 48.91; H, 2.69; N, 12.78; S, 14.52.
5-Cyclopentylidene-2-thioxo-1,3-dihydropyrimidine-4,6-dione
(3n)
Colorless crystals; mp 290 °C; yield: 1.37 g (93%).
IR (KBr): 3159 (N–H), 2947, 2882 (CH), 1705 (C=O), 1668 (C=S),
1572 (C=C) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.70 (dtt, J = 3.9, 7.2, 10.5 Hz,
4 H, H-3¢), 3.08 (dtt, J = 4.5, 7.2, 9.9 Hz, 4 H, H-2¢), 12.13 (s, 2 H,
NH).
13C NMR (75.5 MHz, DMSO-d6): d = 25.1 (C-3¢), 38.8 (C-2¢),
114.5 (C-1¢), 160.9 (C-5), 177.9 (C=O), 193.0 (C=S).
All chemicals were purchased from Alfa-Aesar, Aldrich and Fluka
and used without any further purification. Melting points were de-
termined on a Boetius hot stage apparatus. IR spectra of samples in
KBr pellets were recorded on a Bruker IFS 48. NMR spectra were
recorded on a Bruker Avance II 300 (1H: 300.18 MHz, 13C: 75.48
MHz); samples were prepared in DMSO or CDCl3 with TMS as an
internal standard. Microanalyses were performed on a Euro EA
3000 Elemental Analyzer.
Anal. Calcd for C9H10N2O2S: C, 51.41; H, 4.79; N, 13.32; S, 15.25.
Found: C, 51.52; H, 4.75; N, 13.31; S, 15.55.
5-Cyclopentylidene-1,3-dimethylpyrimidine-2,4,6-trione (3o)
Colorless crystals; mp 113 °C; yield: 1.48 g (95%).
IR (KBr): 2972, 2883 (CH), 1727, 1665 (C=O), 1572 (C=C) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.81 (dtt, J = 3.3, 7.5, 15.0 Hz,
4 H, H-3¢), 3.24 (dtt, J = 3.0, 7.5, 15.0 Hz, 4 H, H-2¢), 3.34 (s, 6 H,
N-CH3).
13C NMR (75.5 MHz, DMSO-d6): d = 25.78 (C-3¢), 28.28 (N-CH3),
39.62 (C-2¢), 100.88 (C-1¢), 114.10 (C-5), 151.34 (C=O), 161.84
(C=O), 194.57 (C=O).
2-Thioxo-1,3-dihydropyrimidine-4,6-diones 3a–g; General Pro-
cedure for the Knoevenagel Condensation between 2-Thiobar-
bituric Acid 1a and Aldehydes 2a–g or Ketone 2j
The appropriate aldehyde 2a–g or cyclopentanone (2j; 7 mmol) was
added all at once to a stirred suspension of 2-thiobarbituric acid (1a;
1.00 g, 7 mmol) in distilled H2O (50 mL) at r.t. The mixture was al-
lowed to stir at r.t. for 1 h. The progress of the reaction was moni-
tored by TLC (CHCl3–MeOH, 1:1) until full consumption of the
aldehyde. The thus formed precipitate of Knoevenagel products
3a–g or 3n,o was collected by filtration, washed with H2O, and
dried under vacuum. The compounds needed no further purifica-
tion, but in some cases they were recrystallized from EtOAc; 3a–g
and 3n,o were obtained in 88–95% yields. Compounds 3a–e have
been described previously: 3a,24a 3b,24b 3c,24c 3d,24d and 3e.24e Spec-
troscopic data of compounds 3f, 3g, 3n, and 3o have not been re-
ported before. Compounds 3h–m were prepared by a published
procedure.17
Anal. Calcd for C11H14N2O3: C, 59.45; H, 6.35; N, 12.60. Found: C,
59.46; H, 6.15; N, 12.67.
Pyrano[2,3-d]pyrimidines 5a–m; General Procedure for the
Solvent-Free Hetero-Diels–Alder Cycloaddition
A mixture of one of Knoevenagel condensation products 3a–m (4
mmol) with a tenfold excess of ethyl vinyl ether (4; 2.9 g, 3.8 mL,
40 mmol) was stirred without solvent at r.t. for 1–5 h. During stir-
ring, solid compounds 3a–m did not dissolve in the excess 4, but a
change in the color of the precipitate was observed, from yellow for
dienes 3a–m to colorless for cycloadducts 5a–m. The progress of
the reaction was monitored by TLC (EtOAc). The excess of ether
was evaporated and the mixture was separated and purified by col-
umn chromatography (silica gel, EtOAc). Recrystallization
(EtOAc–PE, 3:1) gave uracils 5a–m in 88–96% yield (see Table 2).
5-(2-Thienylmethylene)-2-thioxo-1,3-dihydropyrimidine-4,6-
dione (3f)
Yellow crystals; mp 315 °C; yield: 1.52 g (91%).
IR (KBr): 3125 (NH), 3080 (CH), 1672 (C=O), 1569 (C=S), 1521
(C=C) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.38 (dd, J = 3.9, 5.1 Hz, 1 H,
thienyl-H), 8.23 (ddd, J = 0.3, 1.2, 3.9 Hz, 1 H, thienyl-H), 8.35
(ddd, J = 1.2, 1.2, 5.1 Hz, 1 H, thienyl-H), 8.59 (s, 1 H, methylene-
H), 12.36 (s, 1 H, NH), 12.38 (s, 1 H, NH).
Spirouracils 5n,o
A mixture of the appropriate compound 3n or 3o (4 mmol) with a
tenfold excess of 4 (2.9 g, 3.8 mL, 40 mmol) was heated in EtOAc
Synthesis 2010, No. 23, 4021–4032 © Thieme Stuttgart · New York

4028
A. Pałasz
PAPER
(20 mL) at 77 °C in a pressure flask for 4 h. The progress of the re-
action was monitored by TLC (EtOAc). The solvent and the excess
ether was evaporated and the mixture was separated and purified by
column chromatography (silica gel, EtOAc). Recrystallization
(EtOAc–PE, 3:1) gave spirouracils 5n,o in yields 88–91% (see
Table 2).
IR (KBr): 3435, 3110 (NH), 2973, 2904, 2836 (CH), 1694 (C=O),
1648 (C=C), 1572 (C=C), 1256 (C=S), 1141, 1045 (C–O) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.02 (t, J = 7.05 Hz, 3 H,
OCH2CH3), 1.93 (ddd, J = 4.8, 4.8, 14.1 Hz, 1 H, 6-H), 2.26 (ddd,
J = 2.4, 7.2, 14.1 Hz, 1 H, 6-H), 3.69 (s, 3 H, OCH3), 3.52 (dq,
J = 7.2, 9.9 Hz, 1 H, OCH2CH3), 3.79 (dq, J = 7.2, 9.9 Hz, 1 H,
OCH2CH3), 3.79 (dd, J = 4.8, 7.2 Hz, 1 H, H-5), 5.46 (dd, J = 2.4,
4.8 Hz, 1 H, H-7), 6.75 (d, J = 8.7 Hz, 2 H, ArH), 7.05 (d, J = 8.7
Hz, 2 H, ArH), 12.08 (s, 1 H, NH), 12.83 (s, 1 H, NH).
Pyrano[2,3-d]pyrimidines 5a–k; General Procedure for the
One-Pot Synthesis in Aqueous Suspension
A suspension of equimolar amounts (4 mmol) of one of barbituric
acids 1a or 1b and the appropriate aromatic aldehyde 2a–i with a
tenfold excess of enol ether 4 (2.9 g, 3.8 mL, 40 mmol) in H2O (50
mL) was allowed to stay under vigorous stirring at r.t. for 1–3 h. The
progress of the reaction was monitored by TLC (EtOAc). After that,
the reaction mixture was extracted with EtOAc (3 × 20 mL). The
combined organic layers were dried (MgSO4) and the solvent was
evaporated under reduced pressure. The mixture was separated and
purified by column chromatography and the diastereoisomers were
recrystallized by the procedure described above. During column
chromatography, compounds were obtained in order of elution:
6a,b, trans-5a–k, cis-5a–k. The total yields and ratios of 6a,b,
trans-5a–k, and cis-5a–k are given in Table 5.
13C NMR (75.5 MHz, DMSO-d6): d = 14.7 (OCH2CH3), 31.6 (C-6),
35.2 (C-5), 54.8 (OCH3), 64.3 (OCH2CH3), 93.3 (C-4a), 100.9 (C-
7), 112.9, 128.2, 135.5, 155.7 (ArC), 157.2 (C-8a), 160.9 (C=O),
173.7 (C=S).
Anal. Calcd for C16H18N2O4S: C, 57.47; H, 5.43; N, 8.38; S, 9.59.
Found: C, 57.18; H, 5.42; N, 8.41; S, 9.67.
(5RS,7RS)-7-Ethoxy-5-(4-methoxyphenyl)-2-thioxo-1,5,6,7-tet-
rahydro-2H-pyrano[2,3-d]pyrimidin-4(3H)-one (trans-5b)
Colorless crystals; mp 130 °C; yield: 0.373 g (29%); Rf = 0.65
(EtOAc).
IR (KBr): 3466, 3134 (NH), 2974, 2902, 2839 (CH), 1693 (C=O),
1613 (C=C), 1562 (C=C), 1250 (C=S), 1176, 1040 (C–O) cm–1.
(5RS,7SR)-7-Ethoxy-5-phenyl-2-thioxo-1,5,6,7-tetrahydro-2H-
pyrano[2,3-d]pyrimidin-4(3H)-one (cis-5a)
Colorless crystals; mp 175 °C; yield: 0.638 g (60%); Rf = 0.56
(EtOAc).
1H NMR (300 MHz, DMSO-d6): d = 1.14 (t, J = 7.05 Hz, 3 H,
OCH2CH3), 1.95 (ddd, J = 2.4, 4.8, 14.1 Hz, 1 H, 6-H), 2.10 (ddd,
J = 6.6, 7.5, 13.5 Hz, 1 H, 6-H), 3.71 (s, 3 H, OCH3), 3.64 (dq,
J = 6.9, 9.6 Hz, 1 H, OCH2CH3), 3.85 (dq, J = 6.9, 9.6 Hz, 1 H,
OCH2CH3), 3.83 (dd, J = 4.8, 6.6 Hz, 1 H, H-5), 5.16 (dd, J = 2.4,
7.5 Hz, 1 H, H-7), 6.82 (d, J = 8.7 Hz, 2 H, ArH), 7.08 (d, J = 8.7
Hz, 2 H, ArH), 12.10 (s, 1 H, NH), 12.86 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.9 (OCH2CH3), 31.8 (C-
6), 35.8 (C-5), 54.9 (OCH3), 64.9 (OCH2CH3), 92.5 (C-4a), 100.0
(C-7), 113.6, 128.2, 135.3, 155.9 (ArC), 157.6 (C-8a), 161.0 (C=O),
173.8 (C=S).
IR (KBr) 3453, 3111 (NH), 3028, 2975, 2905 (CH), 1694 (C=O),
1647 (C=C), 1570 (C=C), 1247 (C=S), 1140, 1069 (C–O) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 0.99 (t, J = 7.2 Hz, 3 H,
OCH2CH3), 1.99 (ddd, J = 4.5, 5.1, 14.1 Hz, 1 H, 6-H), 2.29 (ddd,
J = 2.7, 7.5, 14.1 Hz, 1 H, 6-H), 3.51 (dq, J = 6.9, 9.6 Hz, 1 H,
OCH2CH3), 3.72 (dq, J = 6.9, 9.6 Hz, 1 H, OCH2CH3), 3.86 (dd,
J = 5.1, 7.2 Hz, 1 H, H-5), 5.47 (dd, J = 2.7, 4.5 Hz, 1 H, H-7), 7.10–
7.22 (m, 5 H, PhH), 12.12 (s, 1 H, NH), 12.86 (s, 1 H, NH).
Anal. Calcd for C16H18N2O4S: C, 57.47; H, 5.43; N, 8.38; S, 9.59.
Found: C, 57.48; H, 5.41; N, 8.32; S, 9.67.
13C NMR (75.5 MHz, DMSO-d6): d = 14.7 (OCH2CH3), 32.2 (C-6),
35.0 (C-5), 64.2 (OCH2CH3), 92.9 (C-4a), 100.8 (C-7), 125.5,
127.3, 127.5, 143.5 (PhC), 155.9 (C-8a), 161.0 (C=O), 173.7 (C=S).
(5RS,7SR)-5-(4-Cyanophenyl)-7-ethoxy-2-thioxo-1,5,6,7-tet-
rahydro-2H-pyrano[2,3-d]pyrimidin-4(3H)-one (cis-5c)
Colorless crystals; mp 175 °C; yield: 0.606 g (46%); Rf = 0.47
(EtOAc).
Anal. Calcd for C15H16N2O3S: C, 59.19; H, 5.30; N, 9.20; S, 10.53.
Found: C, 59.23; H, 5.40; N, 9.14; S, 10.40.
(5RS,7RS)-7-Ethoxy-5-phenyl-2-thioxo-1,5,6,7-tetrahydro-2H-
pyrano[2,3-d]pyrimidin-4(3H)-one (trans-5a)
Colorless crystals; mp 140 °C; yield: 0.304 g (28%); Rf = 0.68
(EtOAc).
IR (KBr): 3413, 3097, 3052 (NH), 2973, 2907, 2869 (CH), 2226
(CN), 1681 (C=O), 1643 (C=C), 1577 (C=C), 1248 (C=S), 1140,
1069 (C–O) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 0.95 (t, J = 6.9 Hz, 3 H,
OCH2CH3), 2.05 (ddd, J = 3.9, 3.9, 14.4 Hz, 1 H, 6-H), 2.32 (ddd,
J = 2.7, 7.5, 14.1 Hz, 1 H, 6-H), 3.49 (dq, J = 6.9, 9.6 Hz, 1 H,
OCH2CH3), 3.69 (dq, J = 6.9, 9.6 Hz, 1 H, OCH2CH3), 3.94 (dd,
J = 3.9, 7.2 Hz, 1 H, H-5), 5.50 (t, J = 3.0 Hz, 1 H, H-7), 7.37 (d,
J = 8.1 Hz, 2 H, ArH), 7.65 (d, J = 8.4 Hz, 2 H, ArH), 12.20 (s, 1 H,
NH), 12.94 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.58 (OCH2CH3), 31.19 (C-
5), 33.90 (C-6), 64.19 (OCH2CH3), 91.80 (C-4a), 100.39 (C-7),
108.20 (CN), 119.02, 128.62, 131.39, 149.72 (ArC), 156.05 (C-8a),
161.12 (C=O), 173.93 (C=S).
IR (KBr): 3452, 3062 (NH), 2977, 2905 (CH), 1692 (C=O), 1648
(C=C), 1571 (C=C), 1248 (C=S), 1145, 1062 (C–O) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.14 (t, J = 6.9 Hz, 3 H,
OCH2CH3), 1.97 (ddd, J 2.4, 5.4, 13.8 Hz, 1 H, 6-H), 2.15 (ddd,
J = 6.3, 7.5, 14.1 Hz, 1 H, 6-H), 3.64 (dq, J = 6.9, 9.6 Hz, 1 H,
OCH2CH3), 3.84 (dq, J = 6.9, 9.6 Hz, 1 H, OCH2CH3), 3.87 (dd,
J = 5.4, 6.3 Hz, 1 H, H-5), 5.19 (dd, J = 2.4, 7.5 Hz, 1 H, H-7), 7.16–
7.30 (m, 5 H, PhH), 12.12 (s, 1 H, NH), 12.88 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.9 (OCH2CH3), 32.6 (C-6),
35.7 (C-5), 64.9 (OCH2CH3), 92.3 (C-4a), 99.9 (C-7), 126.1, 127.2,
128.2, 143.5 (PhC), 156.0 (C-8a), 161.0 (C=O), 173.9 (C=S).
Anal. Calcd for C16H15N3O3S: C, 58.35; H, 4.59; N, 12.76; S, 9.73.
Found: C, 58.42; H, 4.51; N, 12.91; S, 9.63.
Anal. Calcd for C15H16N2O3S: C, 59.19; H, 5.30; N, 9.20; S, 10.53.
Found: C, 59.34; H, 5.33; N, 9.22; S, 10.71.
(5RS,7RS)-5-(4-Cyanophenyl)-7-ethoxy-2-thioxo-1,5,6,7-tet-
rahydro-2H-pyrano[2,3-d]pyrimidin-4(3H)-one (trans-5c)
Colorless crystals; mp 175 °C; yield: 0.606 g (46%); Rf = 0.59
(EtOAc).
(5RS,7SR)-7-Ethoxy-5-(4-methoxyphenyl)-2-thioxo-1,5,6,7-tet-
rahydro-2H-pyrano[2,3-d]pyrimidin-4(3H)-one (cis-5b)
Colorless crystals; mp 314 °C; yield: 0.858 g (67%); Rf = 0.45
(EtOAc).
Synthesis 2010, No. 23, 4021–4032 © Thieme Stuttgart · New York

PAPER
Green Approach to Synthesis of Pyrano[2,3-d]pyrimidines
4029
IR (KBr): 3415, 3100, 3049 (NH), 2971, 2902, 2859 (CH), 2219
(CN), 1683 (C=O), 1648 (C=C), 1572 (C=C), 1250 (C=S), 1139,
1062 (C–O) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.15 (t, J = 6.9 Hz, 3 H,
OCH2CH3), 1.94 (ddd, J = 2.4, 6.9, 14.1 Hz, 1 H, 6-H), 2.19 (ddd,
J = 6.3, 6.6, 14.1 Hz, 1 H, 6-H), 3.67 (dq, J = 7.2, 9.9 Hz, 1 H,
OCH2CH3), 3.84 (dq, J = 7.2, 9.9 Hz, 1 H, OCH2CH3), 3.92 (t,
J = 6.6, 6.6 Hz, 1 H, H-5), 5.29 (dd, J = 2.4, 6.3 Hz, 1 H, H-7), 7.44
(d, J = 8.1 Hz, 2 H, ArH), 7.72 (d, J = 8.4 Hz, 2 H, ArH), 12.15 (s,
1 H, NH), 12.93 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.88 (OCH2CH3), 32.59 (C-
5), 35.22 (C-6), 64.84 (OCH2CH3), 91.88 (C-4a), 99.50 (C-7),
108.91 (CN), 118.83, 128.44, 132.06, 149.54 (ArC), 156.15 (C-8a),
160.88 (C=O), 173.98 (C=S).
1H NMR (300 MHz, DMSO-d6): d = 0.99 (t, J = 6.9 Hz, 3 H,
OCH2CH3), 1.98 (ddd, J = 3.9, 4.2, 14.4 Hz, 1 H, 6-H), 2.28 (ddd,
J = 2.7, 7.5, 14.4 Hz, 1 H, 6-H), 3.50 (dq, J = 6.9, 9.6 Hz, 1 H,
OCH2CH3), 3.71 (dq, J = 7.2, 9.6 Hz, 1 H, OCH2CH3), 3.84 (dd,
J = 4.5, 7.2 Hz, 1 H, H-5), 5.48 (dd, J = 2.7, 3.9 Hz, 1 H, H-7), 7.12
(d, J = 8.4 Hz, 2 H, ArH), 7.36 (d, J = 8.7 Hz, 2 H, ArH), 12.15 (s,
1 H, NH), 12.89 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.65 (OCH2CH3), 31.39 (C-
5), 34.37 (C-6), 64.21 (OCH2CH3), 92.40 (C-4a), 100.56 (C-7),
118.33, 127.32, 129.28, 129.71, 130.24, 143.10 (ArC), 155.93 (C-
8a), 161.04 (C=O), 173.81 (C=S).
Anal. Calcd for C15H15BrN2O3S: C, 47.01; H, 3.94; N, 7.31; S, 8.37.
Found: C, 47.12; H, 4.01; N, 7.32; S, 8.41.
(5RS,7RS)-5-(4-Bromophenyl)-7-ethoxy-2-thioxo-1,5,6,7-tet-
rahydro-2H-pyrano[2,3-d]pyrimidin-4(3H)-one (trans-5e)
Colorless crystals; mp 314 °C; yield: 0.371 g (24%); Rf = 0.64
(EtOAc).
Anal. Calcd for C16H15N3O3S: C, 58.35; H, 4.59; N, 12.76; S, 9.73.
Found: C, 58.29; H, 4.48; N, 12.68; S, 9.57.
(5RS,7SR)-5-(4-Chlorophenyl)-7-ethoxy-2-thioxo-1,5,6,7-tet-
rahydro-2H-pyrano[2,3-d]pyrimidin-4(3H)-one (cis-5d)
Colorless crystals; mp 175 °C; yield: 0.932 g (69%); Rf = 0.49
(EtOAc).
IR (KBr): 3392, 3135 (NH), 2977, 2902 (CH), 1680 (C=O), 1647
(C=C), 1570 (C=C), 1244 (C=S), 1217, 1126 (C–O) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.15 (t, J = 7.2 Hz, 3 H,
OCH2CH3), 1.93 (ddd, J = 2.1, 6.0, 14.1 Hz, 1 H, 6-H), 2.15 (ddd,
J = 6.3, 6.9, 14.1 Hz, 1 H, 6-H), 3.66 (dq, J = 7.2, 9.6 Hz, 1 H,
OCH2CH3), 3.84 (dq, J = 6.9, 9.9 Hz, 1 H, OCH2CH3), 3.84 (dd,
J = 6.6, 6.6 Hz, 1 H, H-5), 5.23 (dd, J = 2.1, 6.9 Hz, 1 H, H-7), 7.17
(d, J = 8.4 Hz, 2 H, ArH), 7.43 (d, J = 8.4 Hz, 2 H, ArH), 12.13 (s,
1 H, NH), 12.90 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.88 (OCH2CH3), 32.02 (C-
5), 35.44 (C-6), 64.86 (OCH2CH3), 92.08 (C-4a), 99.69 (C-7),
119.09, 128.03, 129.15, 129.56, 130.95, 142.96 (ArC), 156.05 (C-
8a), 160.92 (C=O), 173.92 (C=S).
IR (KBr): 3415, 3135, 3063 (NH), 2978, 2913 (CH), 1682 (C=O),
1631 (C=C), 1561 (C=C), 1253 (C=S), 1217, 1134 (C–O) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 0.99 (t, J = 7.2 Hz, 3 H,
OCH2CH3), 2.0 (ddd, J = 4.2, 4.2, 14.1 Hz, 1 H, 6-H), 2.28 (ddd,
J = 2.7, 7.5, 14.1 Hz, 1 H, 6-H), 3.50 (dq, J = 7.2, 9.6 Hz, 1 H,
OCH2CH3), 3.69 (dq, J = 7.2, 9.6 Hz, 1 H, OCH2CH3), 3.85 (dd,
J = 4.2, 6.9 Hz, 1 H, H-5), 5.48 (dd, J = 2.7, 3.6 Hz, 1 H, H-7), 7.16
(d, J = 8.4 Hz, 2 H, ArH), 7.23 (d, J = 8.4 Hz, 2 H, ArH), 12.15 (s,
1 H, NH), 12.89 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.64 (OCH2CH3), 31.39 (C-
5), 34.41 (C-6), 64.21 (OCH2CH3), 92.45 (C-4a), 100.58 (C-7),
127.32, 129.27, 129.89, 142.63 (ArC), 155.89 (C-8a), 161.04
(C=O), 173.81 (C=S).
Anal. Calcd for C15H15BrN2O3S: C, 47.01; H, 3.94; N, 7.31; S, 8.37.
Found: C, 47.18; H, 3.98; N, 7.16; S, 8.66.
(5RS,7SR)-7-Ethoxy-5-(2-thienyl)-2-thioxo-1,5,6,7-tetrahydro-
2H-pyrano[2,3-d]pyrimidin-4(3H)-one (cis-5f)
Colorless crystals; mp 135 °C; yield: 0.447 g (36%); Rf = 0.49
(EtOAc).
Anal. Calcd for C15H15ClN2O3S: C, 53.18; H, 4.46; N, 8.27; S, 9.46.
Found: C, 53.27; H, 4.59; N, 8.16; S, 9.74.
(5RS,7RS)-5-(4-Chlorophenyl)-7-ethoxy-2-thioxo-1,5,6,7-tet-
rahydro-2H-pyrano[2,3-d]pyrimidin-4(3H)-one (trans-5d)
Colorless crystals; mp 135 °C; yield: 0.274 g (20%); Rf = 0.61
(EtOAc).
IR (KBr): 3416, 3106 (NH), 2976, 2894 (CH), 1694 (C=O), 1645
(C=C), 1569 (C=C), 1249 (C=S), 1216, 1140 (C–O) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.01 (t, J = 6.9 Hz, 3 H,
OCH2CH3), 2.14 (ddd, J = 3.3, 3.6, 14.4 Hz, 1 H, 6-H), 2.32 (ddd,
J = 3.0, 6.9, 14.4 Hz, 1 H, 6-H), 3.53 (dq, J = 6.9, 9.6 Hz, 1 H,
OCH2CH3), 3.71 (dq, J = 7.2, 9.9 Hz, 1 H, OCH2CH3), 4.14 (dd,
J = 3.6, 6.9 Hz, 1 H, H-5), 5.52 (dd, J = 3.0, 3.3 Hz, 1 H, H-7), 6.83–
6.89 (m, 2 H, thienyl-H), 7.20 (dd, J = 2.1, 4.5 Hz, 1 H, thienyl-H),
12.18 (s, 1 H, NH), 12.88 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.64 (OCH2CH3), 27.10 (C-
5), 34.60 (C-6), 64.26 (OCH2CH3), 93.36 (C-4a), 100.24 (C-7),
122.70, 124.06, 125.96, 147.76 (thienyl-C), 155.22 (C-8a), 160.96
(C=O), 173.78 (C=S).
IR (KBr): 3412, 3062 (NH), 2977, 2910 (CH), 1684 (C=O), 1632
(C=C), 1563 (C=C), 1252 (C=S), 1218, 1135 (C–O) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.05 (t, J = 7.2 Hz, 3 H,
OCH2CH3), 1.93 (ddd, J = 2.4, 5.7, 14.1 Hz, 1 H, 6-H), 2.15 (ddd,
J = 6.3, 7.2, 14.1 Hz, 1 H, 6-H), 3.52 (dq, J = 7.2, 9.6 Hz, 1 H,
OCH2CH3), 3.70 (dq, J = 7.2, 9.6 Hz, 1 H, OCH2CH3), 3.71 (dd,
J = 5.7, 7.2 Hz, 1 H, H-5), 5.23 (dd, J = 2.4, 6.6 Hz, 1 H, H-7), 7.29
(d, J = 8.4 Hz, 2 H, ArH), 7.31 (d, J = 8.4 Hz, 2 H, ArH), 12.13 (s,
1 H, NH), 12.89 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.87 (OCH2CH3), 31.96 (C-
5), 35.48 (C-6), 64.85 (OCH2CH3), 92.14 (C-4a), 99.70 (C-7),
128.03, 129.15, 130.62, 142.51 (ArC), 156.04 (C-8a), 160.92
(C=O), 173.93 (C=S).
Anal. Calcd for C13H14N2O3S2: C, 50.31; H, 4.55; N, 9.03; S, 20.66.
Found: C, 50.38; H, 4.72; N, 8.71; S, 20.45.
(5RS,7RS)-7-Ethoxy-5-(2-thienyl)-2-thioxo-1,5,6,7-tetrahydro-
2H-pyrano[2,3-d]pyrimidin-4(3H)-one (trans-5f)
Colorless crystals; mp 140 °C; yield: 0.67 g (54%); Rf = 0.60
(EtOAc).
Anal. Calcd for C15H15ClN2O3S: C, 53.18; H, 4.46; N, 8.27; S, 9.46.
Found: C, 53.29; H, 4.38; N, 8.32; S, 9.57.
(5RS,7SR)-5-(4-Bromophenyl)-7-ethoxy-2-thioxo-1,5,6,7-tet-
rahydro-2H-pyrano[2,3-d]pyrimidin-4(3H)-one (cis-5e)
Colorless crystals; mp 314 °C; yield: 1.039 g (68%); Rf = 0.45
(EtOAc).
IR (KBr): 3413, 3068 (NH), 2975, 2897 (CH), 1694 (C=O), 1629
(C=C), 1559 (C=C), 1247 (C=S), 1218, 1137 (C–O) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.16 (t, J = 6.9 Hz, 3 H,
OCH2CH3), 2.14 (ddd, J = 5.1, 5.4, 10.5 Hz, 2 H, 6-H), 3.67 (dq,
J = 6.9, 9.6 Hz, 1 H, OCH2CH3), 3.88 (dq, J = 7.2, 9.9 Hz, 1 H,
IR (KBr): 3408, 3062 (NH), 2977, 2905 (CH), 1690 (C=O), 1631
(C=C), 1562 (C=C), 1242 (C=S), 1217, 1133 (C–O) cm–1.
Synthesis 2010, No. 23, 4021–4032 © Thieme Stuttgart · New York

4030
A. Pałasz
PAPER
OCH2CH3), 4.16 (dd, J = 4.2, 5.1 Hz, 1 H, H-5), 5.25 (dd, J = 5.4,
5.7 Hz, 1 H, H-7), 6.90 (ddd, J = 0.9, 1.5, 3.0 Hz, 1 H, thienyl-H),
6.93 (dd, J = 3.0, 8.4 Hz, 1 H, thienyl-H), 7.33 (dd, J = 1.5, 5.1 Hz,
1 H, thienyl-H), 12.20 (s, 1 H, NH), 12.91 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.87 (OCH2CH3), 28.29 (C-
5), 35.46 (C-6), 65.09 (OCH2CH3), 92.71 (C-4a), 100.37 (C-7),
123.89, 124.51, 126.93, 147.24 (thienyl-C), 155.63 (C-8a), 160.95
(C=O), 173.99 (C=S).
2.05 (ddd, J = 4.2, 7.8, 12.0 Hz, 1 H, cyclopentane-H), 2.22 (ddd,
J = 2.7, 8.1, 12.3 Hz, 1 H, cyclopentane-H), 3.67 (dq, J = 6.9, 9.6
Hz, 1 H, OCH2CH3), 3.84 (dq, J = 6.9, 9.6 Hz, 1 H, OCH2CH3),
5.29 (dd, J = 2.1, 6.9 Hz, 1 H, H-7¢), 12.01 (s, 1 H, NH), 12.66 (s, 1
H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.89 (OCH2CH3), 24.28,
24.61, 37.54 (cyclopentane-H), 35.52 (C-6¢), 64.69 (OCH2CH3),
96.98 (C-4¢a), 100.71 (C-7¢), 154.72 (C-8¢a), 160.80 (C=O), 172.98
(C=S).
Anal. Calcd for C13H14N2O3S2: C, 50.31; H, 4.55; N, 9.03; S, 20.66.
Found: C, 50.47; H, 4.76; N, 8.71; S, 20.49.
Anal. Calcd for C13H18N2O3S: C, 55.30; H, 6.43; N, 9.92; S, 11.35.
Found: C, 55.25; H, 6.52; N, 9.79; S, 11.45.
(5RS,7SR)-7-Ethoxy-5-(2-furyl)-2-thioxo-1,5,6,7-tetrahydro-
2H-pyrano[2,3-d]pyrimidin-4(3H)-one (cis-5g)
Colorless crystals; mp 295 °C; yield: 0.524 g (44.5%); Rf = 0.47
(EtOAc).
(7¢RS)-7¢-Ethoxy-1¢,3¢-dimethylspiro[cyclopentane-1,5¢-
{1¢,5¢,6¢,7¢-tetrahydro-2H-pyrano[2,3-d]pyrimidin-2¢,4¢(3¢H)-di-
one}] (5o)
Colorless oil; yield: 1.071 g (91%); Rf = 0.59 (EtOAc).
IR (KBr): 3414, 3112 (NH), 2972, 2896 (CH), 1691 (C=O), 1648
(C=C), 1559 (C=C), 1248 (C=S), 1212, 1138 (C–O) cm–1.
IR (KBr): 2955, 2873 (CH), 1704, 1645 (C=O), 1613 (C=C), 1178
(C–O) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 0.97 (t, J = 6.9 Hz, 3 H,
OCH2CH3), 2.13 (ddd, J = 3.0, 6.9, 14.1 Hz, 1 H, 6-H), 2.24 (ddd,
J = 3.3, 3.6, 14.1 Hz, 1 H, 6-H), 3.52 (dq, J = 6.9, 9.6 Hz, 1 H,
OCH2CH3), 3.69 (dq, J = 6.9, 9.6 Hz, 1 H, OCH2CH3), 3.94 (dd,
J = 3.9, 6.9 Hz, 1 H, H-5), 5.51 (dd, J = 2.7, 3.0 Hz, 1 H, H-7), 5.89
(ddd, J = 0.9, 0.9, 3.3 Hz, 1 H, furyl-H), 6.25 (dd, J = 1.8, 3.3 Hz, 1
H, furyl-H), 7.40 (dd, J = 0.9, 2.0 Hz, 1 H, furyl-H), 12.18 (s, 1 H,
NH), 12.85 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.61 (OCH2CH3), 25.35 (C-
5), 30.57 (C-6), 64.08 (OCH2CH3), 91.14 (C-4a), 100.02 (C-7),
104.68, 110.14, 140.18, 155.38 (furyl-C), 155.46 (C-8a), 161.04
(C=O), 173.85 (C=S).
1H NMR (300 MHz, DMSO-d6): d = 1.24 (t, J = 7.2 Hz, 3 H,
OCH2CH3), 1.38–1.87 (m, 6 H, cyclopentane-H), 1.72 (dd, J = 8.1,
13.8 Hz, 1 H, H-6¢), 1.93 (dd, J = 2.1, 13.8 Hz, 1 H, H-6¢), 2.16
(ddd, J = 3.9, 8.7, 12.6 Hz, 1 H, cyclopentane-H), 2.37 (ddd,
J = 3.0, 6.9, 12.6 Hz, 1 H, cyclopentane-H), 3.25 (s, 3 H, N-CH3),
3.30 (s, 3 H, N-CH3), 3.65 (dq, J = 7.2, 9.6 Hz, 1 H, OCH2CH3),
3.93 (dq, J = 7.2, 9.6 Hz, 1 H, OCH2CH3), 5.08 (dd, J = 2.1, 8.1 Hz,
1 H, H-7¢).
13C NMR (75.5 MHz, DMSO-d6): d = 14.95 (OCH2CH3), 25.12,
25.50, 36.93, 38.82, 40.33 (cyclopentane-C), 27.58 (N-CH3), 28.56
(N-CH3), 41.70 (C-6¢), 65.63 (OCH2CH3), 93.66 (C-4¢a), 101.82
(C-7¢), 150.85 (C-8¢a), 153.73 (C=O), 161.69 (C=O).
Anal. Calcd for C13H14N2O4S: C, 53.05; H, 4.79; N, 9.52; S, 10.89.
Found: C, 53.35; H, 4.82; N, 9.63; S, 10.93.
Anal. Calcd for C15H22N2O4: C, 61.21; H, 7.53; N, 9.52. Found: C,
61.29; H, 7.62; N, 9.47.
(5RS,7RS)-7-Ethoxy-5-(2-furyl)-2-thioxo-1,5,6,7-tetrahydro-
2H-pyrano[2,3-d]pyrimidin-4(3H)-one (trans-5g)
Colorless crystals; mp 305 °C; yield: 0.524 g (44.5%); Rf = 0.65
(EtOAc).
7-Ethoxy-5-methyl-2-thioxo-1,5,6,7-tetrahydro-2H-pyrano[2,3-
d]pyrimidin-4(3H)-one (6a)
Colorless crystals; mp 200 °C; Rf = 0.75 (EtOAc).
IR (KBr): 3409, 3059 (NH), 2981, 2892 (CH), 1691 (C=O), 1635
(C=C), 1558 (C=C), 1249 (C=S), 1216, 1131 (C–O) cm–1.
IR (KBr): 3479, 3150 (NH), 3059, 2978, 2901 (CH), 1680 (C=O),
1621 (C=C), 1248 (C=S), 1156, 1135, 1033 (C–O) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.05 (t, J = 6.9 Hz, 3 H,
OCH2CH3), 2.07 (ddd, J = 2.4, 6.6, 14.1 Hz, 1 H, 6-H), 2.12 (ddd,
J = 6.3, 7.2, 14.1 Hz, 1 H, 6-H), 3.68 (dq, J = 6.9, 9.6 Hz, 1 H,
OCH2CH3), 3.86 (dq, J = 6.9, 9.6 Hz, 1 H, OCH2CH3), 3.85 (dd,
J = 6.3, 6.6 Hz, 1 H, H-5), 5.23 (dd, J = 2.4, 7.5 Hz, 1 H, H-7), 6.11
(ddd, J = 0.9, 0.9, 3.3 Hz, 1 H, furyl-H), 6.33 (dd, J = 1.8, 3.3 Hz, 1
H, furyl-H), 7.51 (dd, J = 0.9, 1.8 Hz, 1 H, furyl-H), 12.16 (s, 1 H,
NH), 12.85 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.86 (OCH2CH3), 27.07 (C-
5), 30.80 (C-6), 65.08 (OCH2CH3), 90.45 (C-4a), 100.58 (C-7),
106.22, 110.35, 141.59, 155.18 (furyl-C), 155.18 (C-8a), 160.92
(C=O), 174.01 (C=S).
1H NMR (300 MHz, DMSO-d6): d = 1.15 (dd, J = 4.5, 6.9 Hz, 3 H,
5-CH3), 1.20 (t, J = 6.9 Hz, 3 H, OCH2CH3), 1.69–1.79 (m, 0.8 H,
6-H), 1.85 (dd, J = 7.2, 14.4 Hz, 0.8 H, 6-H), 2.02 (ddd, J = 3.0, 7.2,
14.4 Hz, 0.4 H, 6-H), 2.59–2.71 (m, 1 H, H-5), 3.70 (dq, J = 6.9,
10.8 Hz, 1 H, OCH2CH3), 3.86 (dq, J = 7.2, 9.9 Hz, 1 H,
OCH2CH3), 5.43 (dd, J = 2.4, 7.2 Hz, 0.6 H, H-7), 5.47 (dd, J = 3.0,
3.3 Hz, 0.4 H, H-7), 12.07 (s, 1 H, NH), 12.69 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.91 (OCH2CH3), 19.39 (5-
CH3), 21.27, 21.70 (C-6), 32.51, 33.95 (C-5), 64.58, 64.74
(OCH2CH3), 95.18, 95.38 (C-4a), 99.93, 100.66 (C-7), 154.18,
154.72 (C-8a), 161.46, 161.52 (C=O), 173.31, 173.42 (C=S).
Anal. Calcd for C10H14N2O3S: C, 49.57; H, 5.82; N, 11.56; S, 13.23.
Found: C, 49.78; H, 5.79; N, 11.23; S, 13.48.
Anal. Calcd for C13H14N2O4S: C, 53.05; H, 4.79; N, 9.52; S, 10.89.
Found: C, 53.16; H, 4.70; N, 9.58; S, 10.81.
7-Ethoxy-1,3,5-trimethyl-1,5,6,7-tetrahydro-2H-pyrano[2,3-
d]pyrimidin-2,4(3H)-dione (6b)
Colorless oil; Rf = 0.72 (EtOAc).
(7¢RS)-7¢-Ethoxy-2¢-thioxospiro[cyclopentane-1,5¢-{1¢,5¢,6¢,7¢-
tetrahydro-2H-pyrano[2,3-d]pyrimidin-4¢(3¢H)-one}] (5n)
Colorless crystals; mp 217 °C; yield: 0.993 g (88%); Rf = 0.64
(EtOAc).
IR (KBr): 3046, 2985, 2899 (CH), 1705, 1652 (C=O), 1549 (C=C),
1152, 1129, 1058 (C–O) cm–1.
IR (KBr): 3414, 3204 (NH), 2971, 2932, 2873 (CH), 1643 (C=O),
1550 (C=C), 1336 (C=S), 1152, 1055 (C–O) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.1 (t, J = 7.2 Hz, 3 H,
OCH2CH3), 1.32–1.39 (m, 1 H, cyclopentane-H), 1.42–1.49 (m, 1
H, cyclopentane-H), 1.58–1.64 (m, 4 H, cyclopentane-H), 1.70 (dd,
J = 6.9, 13.5 Hz, 1 H, H-6¢), 1.89 (dd, J = 2.1, 14.1 Hz, 1 H, H-6¢),
1H NMR (300 MHz, DMSO-d6): d = 1.17 (t, J = 7.2 Hz, 3 H,
OCH2CH3), 1.28 (dd, J = 4.5, 7.2 Hz, 3 H, 5-CH3), 1.86–1.94 (m,
0.8 H, 6-H), 2.04 (dd, J = 6.9, 14.1 Hz, 0.8 H, 6-H), 2.35 (ddd,
J = 3.2, 7.0, 14.1 Hz, 0.4 H, 6-H), 2.61–2.72 (m, 1-H, H-5), 3.29 (s,
3 H, N-CH3), 3.42 (s, 3 H, N-CH3), 3.65 (dq, J = 7.2, 10.0 Hz, 1 H,
Synthesis 2010, No. 23, 4021–4032 © Thieme Stuttgart · New York

PAPER
Green Approach to Synthesis of Pyrano[2,3-d]pyrimidines
4031
OCH2CH3), 3.87 (dq, J = 7.2, 9.9 Hz, 1 H, OCH2CH3), 5.30 (dd,
J = 3.0, 7.8 Hz, 0.6 H, H-7), 5.40 (dd, J = 3.0, 3.3 Hz, 0.4 H, H-7).
IR (KBr) 3449, 3135 (NH), 3031, 2985, 2901 (CH), 1765 (C=O),
1686 (C=O), 1645 (C=C), 1561 (C=C), 1241 (C=S), 1135, 1069
(C–O) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.07 (ddd, J = 11.0, 11.4, 14.2
Hz, 1 H, 6-H), 2.41 (ddd, J = 2.0, 6.5, 14.1 Hz, 1 H, 6-H), 3.55 (dt,
J = 5.0, 8.5 Hz, 1 H, H-4¢), 3.63 (q, J = 8.5 Hz, 1 H, H-4¢), 4.05 (dd,
J = 6.3, 11.0 Hz, 1 H, H-5), 4.28 (q, J = 8.5 Hz, 1 H, H-5¢), 4.40 (dt,
J = 5.0, 8.5 Hz, 1 H, H-5¢), 5.91 (dd, J = 1.8, 11.1 Hz, 1 H, H-7),
7.33–7.75 (m, 5 H, PhH), 12.09 (s, 1 H, NH), 12.87 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.89 (OCH2CH3), 20.12 (5-
CH3), 22.60, 23.18 (C-6), 27.86 (N-CH3), 28.67 (N-CH3), 33.30,
33.67 (C-5), 65.90, 65.99 (OCH2CH3), 91.57, 91.95 (C-4a), 101.23,
101.84 (C-7), 151.23, 151.38 (C-8a), 153.94, 162.16, 162.62,
162.75 (C=O).
Anal. Calcd for C12H1N2O4: C, 56.68; H, 7.13; N, 11.02. Found: C,
56.92; H, 7.24; N, 11.13.
13C NMR (75.5 MHz, DMSO-d6): d = 33.4 (C-6), 34.7 (C-5), 87.5
(C-7), 87.2 (C-4a), 125.7, 127.5, 128.6, 143.9 (PhC), 155.9 (C-8a),
161.5 (C=O), 161.9 (C-2¢), 174.7 (C=S).
Pyrano[2,3-d]pyrimidines 8a–h; General Procedure for the
One-Pot Synthesis in Aqueous Suspension
A suspension of equimolar amounts (4 mmol) of one of barbituric
acids 1a or 1b, the appropriate aromatic aldehyde 2a or 2h, and sty-
rene 7a or N-vinyl-2-oxazolidinone 7b in H2O (50 mL) was stirred
at 60 °C for 1–3 h. The progress of the reaction was monitored by
TLC (EtOAc). After that, the reaction mixture was extracted with
EtOAc (3 × 20 mL). The combined organic layers were dried
(MgSO4) and the solvent was evaporated under reduced pressure.
The crude products were purified by column chromatography (sili-
ca gel, EtOAc). Recrystallization (EtOAc–PE, 4:1) gave uracils cis-
8a–h in 89–95% yields (see Table 8).
Anal. Calcd for C16H15N3O4S: C, 55.64; H, 4.38; N, 12.17; S, 9.28.
Found: C, 55.77; H, 4.35; N, 12.28; S, 9.43.
(5RS,7SR)-5-(4-Nitrophenyl)-7-(2-oxooxazolidin-3-yl)-2-
thioxo-1,5,6,7-tetrahydro-2H-pyrano[2,3-d]pyrimidin-4(3H)-
one (cis-8d)
Colorless crystals; mp 263 °C; yield: 1.437 g (92%); Rf = 0.53
(EtOAc).
IR (KBr) 3447, 3139 (NH), 3038, 2981, 2912 (CH), 1768 (C=O),
1686 (C=O), 1649 (C=C), 1557 (C=C), 1245 (C=S), 1139, 1072
(C–O) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.10 (ddd, J = 11.1, 11.3, 14.1
Hz, 1 H, 6-H), 2.39 (ddd, J = 1.8, 6.3, 14.2 Hz, 1 H, 6-H), 3.57 (dt,
J = 5.0, 8.5 Hz, 1 H, H-4¢), 3.63 (q, J = 8.5 Hz, 1 H, H-4¢), 4.09 (dd,
J = 6.5, 11.3 Hz, 1 H, H-5), 4.30 (q, J = 8.5 Hz, 1 H, H-5¢), 4.45 (dt,
J = 5.0, 8.5 Hz, 1 H, H-5¢), 5.96 (dd, J = 2.1, 11.0 Hz, 1 H, H-7),
7.40 (d, J = 9.0 Hz, 2 H, ArH), 8.20 (d, J = 9.0 Hz, 2 H, ArH), 12.10
(s, 1 H, NH), 12.85 (s, 1 H, NH).
(5RS,7SR)-7-(4-Methoxyphenyl)-5-phenyl-2-thioxo-1,5,6,7-tet-
rahydro-2H-pyrano[2,3-d]pyrimidin-4(3H)-one (cis-8a)
Colorless crystals; mp 196 °C; yield: 1.304 g (89%); Rf = 0.51
(EtOAc).
IR (KBr) 3451, 3130 (NH), 3032, 2981, 2904 (CH), 1687 (C=O),
1647 (C=C), 1565 (C=C), 1249 (C=S), 1138, 1073 (C–O) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.03 (ddd, J = 11.3, 11.3, 14.4
Hz, 1 H, 6-H), 2.45 (ddd, J = 1.8, 6.3, 14.1 Hz, 1 H, 6-H), 3.83 (s, 3
H, OCH3), 3.96 (dd, J = 6.6, 11.3 Hz, 1 H, H-5), 5.49 (dd, J = 1.8,
11.3 Hz, 1 H, H-7), 7.10–7.92 (m, 9 H, PhH), 12.10 (s, 1 H, NH),
12.92 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 32.8 (C-6), 35.0 (C-5), 88.2
(C-7), 87.3 (C-4a), 124.0, 127.9, 129.6, 149.7 (ArC), 155.6 (C-8a),
162.1 (C=O), 162.5 (C-2¢), 174.5 (C=S).
13C NMR (75.5 MHz, DMSO-d6): d = 32.0 (C-6), 34.8 (C-5), 81.8
(C-7), 93.2 (C-4a), 125.5, 126.4, 127.3, 127.5, 128.4, 129.1 143.5,
144.6 (PhC), 156.8 (C-8a), 161.7 (C=O), 174.1 (C=S).
Anal. Calcd for C16H14N4O6S: C, 49.23; H, 3.61; N, 14.35; S, 8.21.
Found: C, 49.45; H, 3.67; N, 14.27; S, 8.46.
Anal. Calcd for C20H18N2O3S: C, 65.56; H, 4.95; N, 7.64; S, 8.75.
Found: C, 65.82; H, 4.81; N, 7.82; S, 8.69.
Acknowledgment
The author thanks the students Anna Górak and Ewelina Chwałek
of Environmental Protection in the Department of Chemistry of the
Jagiellonian University in Kraków for the syntheses of some com-
pounds.
(5RS,7SR)-7-(4-Methoxyphenyl)-5-(4-nitrophenyl)-2-thioxo-
1,5,6,7-tetrahydro-2H-pyrano[2,3-d]pyrimidin-4(3H)-one (cis-
8b)
Colorless crystals; mp 212 °C; yield: 1.547 g (94%); Rf = 0.49
(EtOAc).
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IR (KBr) 3448, 3127 (NH), 3029, 2983, 2901 (CH), 1678 (C=O),
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(EtOAc).
Synthesis 2010, No. 23, 4021–4032 © Thieme Stuttgart · New York

4032
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Synthesis 2010, No. 23, 4021–4032 © Thieme Stuttgart · New York