Synthesis of fused uracils: Pyrano[2,3-d]pyrimidines and 1,4-bis(pyrano[2,3-d]pyrimidinyl)benzenes by domino Knoevenagel/Diels-Alder reactions

Article abstract of DOI:10.1007/s00706-012-0781-x

Knoevenagel condensation of barbituric acids with aromatic aldehydes containing one or two formyl groups was carried out. 5-Arylidenebarbituric acids underwent smooth hetero-Diels-Alder (HDA) reactions with enol ethers to afford cis and trans diastereoisomers of pyr-ano[2,3-d]pyrimidine-2,4-diones and 5,5′-(1,4-phenylene)-bis[2H-pyrano[2,3-d]pyrimidine-2,4(3H)-dione] derivatives in excellent yields (75-88%). Syntheses were realized by Knoevenagel condensation and HDA reaction in four different reaction conditions: Knoevenagel condensation in water and Diels-Alder reaction in methylene chloride solution, Knoevenagel condensation in water and Diels-Alder reaction without solvent, three-component one-pot reaction in methylene chloride solution, or three-component one-pot reaction in water. All reactions were carried out without catalyst at room temperature. The reactions of malononitrile with Knoevenagel condensation products of barbituric acids and heteroaromatic aldehydes or terephthalaldehyde were examined and did not provide corresponding pyranopyrimidines.

Full text of DOI:10.1007/s00706-012-0781-x

Monatsh Chem (2012) 143:1175–1185
DOI 10.1007/s00706-012-0781-x
ORIGINAL PAPER
Synthesis of fused uracils: pyrano[2,3-d]pyrimidines
and 1,4-bis(pyrano[2,3-d]pyrimidinyl)benzenes by domino
Knoevenagel/Diels-Alder reactions
Aleksandra Pałasz
Received: 30 January 2012 / Accepted: 24 April 2012 / Published online: 24 May 2012
Ó The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract Knoevenagel condensation of barbituric acids
with aromatic aldehydes containing one or two formyl
groups was carried out. 5-Arylidenebarbituric acids under-
went smooth hetero-Diels-Alder (HDA) reactions with enol
ethers to afford cis and trans diastereoisomers of pyr-
alkaloids, polyether antibiotics, pheromones, and iridoids
[1, 2]. Uracil is one of the five nucleobases and therefore an
important component of nucleic acids. Uracil and its fused
derivatives, such as pyrano[2,3-d]pyrimidines, pyrido[2,3-d]-
pyrimidines, pyrazo[3,4-d]pyrimidines, or pyrimido[4,5-d]-
pyrimidines, are reported to have a wide range of biological
activities such as antiallergic [3], antihypertensive [4], car-
diotonic [5], bronchiodilator [6], antibronchitic [7], or
antitumor [8] activity. The preparation of the compounds
containing a pyran and an uracil ring poses significant syn-
thetic challenges. 3,4-Dihydro-2H-pyrans can be efficiently
synthesized by inverse-electron-demand hetero-Diels-Alder
(HDA) reactions of a,b-unsaturated carbonyl compounds
representing an 1-oxa-1,3-butadiene system with enol ethers
[9–11]. It has been stated that introducing an electron with-
drawing group in the 1-oxa-1,3-diene systems can enhance
their reactivity [12–15]. In our recent work, we showed that
intermolecular and intramolecular HDA reactions are a pow-
erful tool in the synthesis of 2H-pyran and polycyclic 2H-
pyran derivatives [16–24]. Also recently, as a continuation of
the investigations of organic reactions performed in aqueous
medium, a green approach to the synthesis of fused ura-
cils 2-thioxopyrano[2,3-d]pyrimidin-4-ones and pyrano[2,3-d]-
pyrimidin-2,4-diones was made. Three-component one-pot
syntheses of annulated uracils were performed in aqueous
suspensions by domino Knoevenagel/Diels-Alder reactions
without a catalyst and at room temperature [25]. In our last
work we also investigated inverse-electron demand Diels-
Alder cycloadditions of sterically hindered cycloalkylidene
0
ano[2,3-d]pyrimidine-2,4-diones and 5,5 -(1,4-phenylene)-
bis[2H-pyrano[2,3-d]pyrimidine-2,4(3H)-dione] derivatives
in excellent yields (75–88 %). Syntheses were realized by
Knoevenagel condensation and HDA reaction in four dif-
ferent reaction conditions: Knoevenagel condensation in
water and Diels-Alder reaction in methylene chloride
solution, Knoevenagel condensation in water and Diels-
Alder reaction without solvent, three-component one-pot
reaction in methylene chloride solution, or three-compo-
nent one-pot reaction in water. All reactions were carried
out without catalyst at room temperature. The reactions of
malononitrile with Knoevenagel condensation products
of barbituric acids and heteroaromatic aldehydes or
terephthalaldehyde were examined and did not provide
corresponding pyranopyrimidines.
Keywords Cycloadditions ꢀ Drug research ꢀ
Michael addition ꢀ One-pot synthesis
Introduction
Pyran derivatives are common structural subunits in a variety
of important natural products, including carbohydrates,
0
derivatives of benzoyl acetonitrile and N,N -dimethylbarbitu-
ric acid with enol ethers, cyclic enol ethers, and also sterically
hindered cycloalkylidenecycloalkanes [26]. Fused spiroura-
cils and fused dispirouracils can be obtained by this method.
The same a,b-unsaturated carbonyl compounds, obtained
by Knoevenagel condensation of the appropriate CH acids
A. Pałasz (&)
Department of Organic Chemistry,
Jagiellonian University, Krak o´ w, Poland
e-mail: palasz@chemia.uj.edu.pl
123

1
176
A. Pałasz
and aromatic aldehydes, can be used as substrates in pyran
synthesis by conjugate addition-cyclization with malono-
nitrile or cyanoacetate [27–29]. Pyrano[2,3-d]pyrimidine
derivatives can be prepared by conjugate addition-cycli-
zation of malononitrile to 5-arylidenebarbituric acids, or
general procedures include the reaction of arylidenemalo-
nonitriles with barbituric acids under traditional hot
reaction conditions [30, 31] or under microwave irradiation
Knoevenagel condensation in water and HDA reaction
without solvent, C—three-component one-pot reaction in
methylene chloride as solvent, and D—three-component
one-pot reaction in water. All the reactions were carried out
at room temperature in the absence of catalyst.
First, procedures A–D were examined for the Knoeve-
nagel condensation of barbituric acids with aromatic
aldehydes containing only one formyl group and HDA
reactions with enol ether. 5-Arylidenebarbituric acids
3a–3c, as potential heterodienes in Diels-Alder reactions, were
[
32]. Recently, the synthesis of pyrano[2,3-d]pyrimidines
by simply ball-milling a stoichiometric mixture of an
aldehyde, malononitrile, and barbituric acids without any
catalyst or solvent was described [33]. Also microwave-
assisted three-component cyclocondensation of aldehydes,
malononitrile, and barbituric acids proceeds in the absence
or presence of triethylamine to afford pyrano[2,3-d]-
pyrimidines [34]. Direct condensation of aldehydes, mal-
ononitrile, and barbituric acids in aqueous media has been
reported under heating [35] or under ultrasound irradiation
0
synthesized by condensations of N,N -dimethylbarbituric
acid (1a) or barbituric acid (1b) with aromatic aldehydes
2a–2c in water without catalyst and at room temperature
according the procedure described in the literature [37]
(Scheme 1). The condensations occurred smoothly and
were completed in just an hour, giving excellent yields
(95–98 %) of Knoevenagel products 3a–3c. The cycload-
dition reactions of 3a–3c with a tenfold excess of ethyl
vinyl ether 4 were performed with methylene chloride as
the solvent (conditions A) or in the absence of solvent
(conditions B) at room temperature for the time given in
Table 1. New 2H-pyrano[2,3-d]pyrimidine-2,4(3H)-diones
[
36].
Therefore, 5-arylidene derivatives of barbituric acids
seem to be excellent intermediates in pyran synthesis both
by HDA reaction and by conjugate addition-cyclization.
5a–5c were obtained in 77–88 % yields (Scheme 1;
Table 1). Next, three-component one-pot synthesis of
uracils 5a–5c by domino Knoevenagel/Diels-Alder reac-
tions was investigated in methylene chloride (conditions C)
or in aqueous medium (conditions D). The experimental
procedure was simple: equimolar amounts of barbituric
acid 1a or 1b and aromatic aldehyde 2a–2c were mixed
with a tenfold excess of enol ether 4 in methylene chloride
(conditions C) or in aqueous medium (conditions D)
(Scheme 1; Table 1). The progress of the reactions
was monitored by TLC. The ratios of the cis/trans
Results and discussion
The main aim of the studies was the synthesis of new (1,4-
phenylene)bis[2H-pyrano[2,3-d]pyrimidine-2,4(3H)-dione]
derivatives containing two fused uracil moieties joined by a
benzene ring. Syntheses were realized by Knoevenagel
condensation and HDA reaction in four different reaction
conditions: A—Knoevenagel condensation in water and
HDA reaction in methylene chloride as solvent, B—
Scheme 1
R2
O
O
R1
N
R1
O
H2O
N
R2 CHO
+
+
r.t.
stirring
OC2H5
O
N
R1
O
2a-2c
N
R1
O
4
a
3
a-3c
r.t.
1a, 1b
(A) CH2Cl2
(
B) solventless stirring
R2
R2
O
O
R2 CHO
2a-2c
R1
R1
N
O
(
C) CH2Cl2
N
R1
O
(D) H2O
N
+
r.t.
stirring
O
N
R1
O
OC2H5
O
N
R1
O
2 5
OC H
cis-5a-5c
trans-5a-5c
N
O
OC2H5
R1
+
O
CH3
4
a
O
CH3
R1
O
R1
O
1a, 1b
N
N
N
R1
O
OC2H5
N
R1
O
OC2H5
cis-6a, 6b
trans-6a, 6b
1
23

Synthesis of fused uracils
1177
Table 1 Synthesis of the
cycloadducts 5a–5c by
Knoevenagel condensation and
HDA reaction in the reaction
conditions A–D
1
2
a
Reaction Yield/% of 5 Ratio of cis-5/
Entry Method
1
R
2
R
3
5
6
b
time/h
trans-5
1
2
3
4
5
6
7
8
9
1
1
1
A
B
C
D
A
B
C
D
A
B
C
D
1a CH
1a CH
1a CH
1a CH
1a CH
1a CH
1a CH
1a CH
3
3
3
3
3
3
3
3
2a 4-BrC
2a 4-BrC
2a 4-BrC
2a 4-BrC
6
6
6
6
H
H
H
H
4
4
4
4
3a 5a
3a 5a
–
–
–
15
12
15
7
87
86
84
82
81
82
87
86
86
77
82
88
1.8:1
1.6:1
2.5:1
7.2:1
2.3:1
1.8:1
2.5:1
6.9:1
2.0:1
1.5:1
2.2:1
5.6:1
–
–
5a
5a 6a
2b 4-ClC
2b 4-ClC
2b 4-ClC
2b 4-ClC
6
6
6
6
H
H
H
H
4
4
4
4
3b 5b
3b 5b
–
–
–
13
12
13
6
–
–
5b
5b 6a
a
Isolated yields after column
chromatography
1b
1b
1b
1b
H
H
H
H
2c 4-H
2c 4-H
2c 4-H
2c 4-H
3
3
3
3
COC
COC
COC
COC
H
6 4
H
6 4
H
6 4
H
6 4
3c 5c
3c 5c
–
–
–
24
20
22
0
1
2
b
1
Ratio based on H NMR
300 MHz) spectra of crude
products
–
–
5c
(
5c 6b 12
diastereoisomers of the pyrano[2,3-d]pyrimidine-2,4-di-
1
ones 5a–5c were determined on the basis of H NMR
conditions, with acetic acid and sulfuric acid as the reactive
media. The cycloaddition reactions of 3d with a tenfold
excess of enol ethers 4a–4c were performed with methy-
lene chloride as the solvent (conditions A) or in the absence
of solvent (conditions B) at room temperature for the time
given in Table 2. Also three-component one-pot syntheses
of compounds 7a–7c by domino Knoevenagel/Diels-Alder
reactions were investigated in conditions C and D. Equi-
spectra of the crude products, analyzing the signals of
protons 5-H and 7-H. The unexpected 5-methyl-substituted
derivatives of pyrano[2,3-d]pyrimidines 6a–6b were
obtained in aqueous medium (conditions D). This was
1
determined on the basis of the H NMR spectra of the
crude products. Formation of these compounds can be
explained as the result the three-component reaction of
barbituric acid 1a or 1b, the in situ generated acetaldehyde
and ethyl-vinyl ether 4. The addition of water to ether 4
catalyzed by barbituric acid provides a hemiacetal, which
undergoes ethanol elimination to produce the enol tautomer
or finally keto tautomer of acetaldehyde. Only compounds
cis-6a and trans-6a were separated in small amounts by
column chromatography.
0
molar amounts of N,N -dimethylbarbituric acid and 1,4-
benzenedicarbaldehyde were mixed with a tenfold excess
of enol ethers 4a–4c in methylene chloride (conditions C)
or in aqueous medium (conditions D) (Scheme 2; Table 2).
0
5,5 -(1,4-Phenylene)bis[2H-pyrano[2,3-d]pyrimidine-2,4-
(3H)-dione] derivatives 7a–7c were obtained in 75–82 %
yields. The progress of the reactions was monitored by
TLC. The ratios of the cis/trans diastereoisomers of cyc-
1
All diastereoisomers ofcompounds5a–5c werevery easily
separated by column chromatography using t-butyl methyl
ether as an eluent because the difference between R (cis) and
loadducts 7a–7c were determined on the basis of H NMR
spectra of crude products, analyzing the signals of protons
5-H and 7-H. Cycloadducts cis-7a–7c were the major
products. The unexpected pyrano[2,3-d]pyrimidines 6a–6c
(conditions D) and 8a–8c (conditions C, D) were also
obtained in small amounts. It was determined on the
f
Rf (trans) was approximately 0.2. Cycloadducts cis-5a–5c
were the major products in all reactions. Three-component
one-pot syntheses of pyrano[2,3-d]pyrimidines performed in
aqueous medium (conditions D) were faster than those exe-
cuted in dichloromethane or under solvent-free conditions,
and cis/trans selectivity was significantly improved.
1
basis of the H NMR spectra of the crude products. For-
mation of compounds 6a–6c was explained above.
Cycloadducts 8a–8c were obtained as the result of Knoe-
venagel reaction of barbituric acid 1a and only one formyl
group of dicarbaldehyde 2d. Only compounds cis-6a,
trans-6a, cis-8a, and trans-8a were isolated by column
chromatography.
In the second step of the studies, it was decided to test
the synthetic approach to the Knoevenagel condensation of
barbituric acid with an aromatic aldehyde containing two
formyl groups, terephthalaldehyde. HDA reactions with
enol ether were performed in conditions A–D. Condensa-
The three-component one-pot syntheses of pyrano
[2,3-d]pyrimidines 7a–7c performed in aqueous medium
(condition D) were faster than those executed in dichlo-
romethane or under solvent-free conditions, and cis/trans
selectivity was the highest for these reactions.
0
tion of N,N -dimethylbarbituric acid with terephthalalde-
hyde (2d) was carried out in water without catalyst and at
room temperature, giving Knoevenagel product 3d with
9
7 % yield after 1 h (Scheme 2). It is worth noting that
there is only one synthetic method for this compound
described in the literature [38], but it required drastic
Compounds 5a–5c, 6a, 7a–7c, and 8a were character-
1
ized by H, C NMR, IR, and elemental analysis. H and
13
1
123

1
178
A. Pałasz
Scheme 2
CH3
N
O
O
N
CH3
O
O
CHO
O
H3C
O
H3C
O
N
H2O
N
+
+
r.t.
stirring
R2
OR1
4a-4c
N
O
N
O
CH3
CHO
CH3
3
d
1a
2d
(
(
A) CH2Cl2
r.t.
B) solventless stirring
O
CH3
CHO
CHO
CH3
CH3
N
N
1
R2
OR
R O
O
O
2
1
R
O
N
O
N
CH3
CH3
(C) CH2Cl2
6a-6c
O
O
(D) H O
CHO
2
2
d
+
H3C
O
r.t.
N
stirring
+
O
R2
OR1
a-4c
H3C
O
N
O
O
N
R2
OR
CH3
H3C
O
1
N
4
N
O
a-7c
R2
OR
1a
1
CH3
N
O
7
CH3
8
a-8c
Table 2 Synthesis of the
cycloadducts 7a–7c by
Knoevenagel condensation and
HDA reaction in the reaction
conditions A–D
1
2
a
Reaction Yield/% of 7 Ratio of cis-7/
Entry Method
1
2
3
4
R
R
6
7
8
b
time/h
trans-7
1
A
B
C
D
A
B
C
D
A
B
C
D
1a 2d 3d 4a
1a 2d 3d 4a
2
C H
2
C H
2
C H
2
C H
5
5
5
5
H
–
–
–
7a 8a 18
7a 8a 16
7a 8a 15
82
81
80
82
81
78
77
76
78
75
82
80
[100:1
[100:1
[100:1
[100:1
6.3:1
2
H
3
1a 2d
1a 2d
–
–
4a
4a
H
4
H
6a 7a 8a
8
7b 8b 18
7b 8b 17
7b 8b 15
5
1a 2d 3d 4b i-Bu
1a 2d 3d 4b i-Bu
H
–
–
–
6
H
5.9:1
7
1a 2d
1a 2d
–
–
4b i-Bu
4b i-Bu
H
6.5:1
8
H
6b 7b 8b
8
7c 8c 24
7c 8c 20
7c 8c 18
8.1:1
a
9
1a 2d 3d 4c CH
3
CH
3
–
–
–
5.3:1
Isolated yields after column
chromatography
10
11
1a 2d 3d 4c CH3 CH3
5.5:1
b
1
Ratio based on H NMR
300 MHz) spectra of crude
products
1a 2d
1a 2d
–
–
4c CH3 CH3
4c CH CH
5.2:1
(
1
2
3
3
6c 7c 8c 10
7.5:1
1
3
C signal assignments were confirmed by two-dimen-
dihydropyran ring that exists in a half-chair conformation
(Table 3).
sional COSY and HETCOR NMR spectra. The relative cis
and trans configuration of the C-5, C-7 substituents were
1
assigned on the basis of H NMR spectra. They were
1
In the H NMR spectra of the major diastereoisomers
cis-5a–5c, cis-6a, cis-7a–7c, and cis-8a, the signal of
0
deduced from the chemical shift values and coupling
constants of the protons attached to C-5 and C-7 of the
5-H (5-H and 5 -H for cis-7a–7c) appeared as a doublet
of doublets at d = 3.76–4.13 ppm (for cis-6a, ddq
1
23

Synthesis of fused uracils
1179
1
Table 3 Signals of proton 5-H and 7-H in H NMR spectra of
products 5a–5c, 6a, 7a–7c, and 8a
spectra of cis-5a–5c, cis-6a, cis-7a–7c, and cis-8a reveal
0
the signals of proton 7-H (7-H and 7 -H for cis-7a–7c) as a
doublet of doublets at d = 5.07–5.42 ppm with two small
coupling constants J = 3.3–6.0 Hz ( J = 8.4 Hz only for
Compound dd 5-H
d/ppm
dd 7-H
d/ppm
Compound dd 5-H
d/ppm
dd 7-H
d/ppm
3
3
0
J
J
6ax,5
/
J
J
6ax,7
/
J
J
6ax,5
/
J
J
6ax,7
/
cis-7b) and 2.4–3.0 Hz. Thus, 7-H (7-H and 7 -H for cis-
7a–7c) is in the equatorial position, and the alkoxy group
occupies the axial position (Fig. 1).
6eq,5/Hz
6eq,7/Hz
6eq,5/Hz
6eq,7/Hz
cis-5a
cis-5b
cis-5c
cis-6a
4.00
5.38
trans-5a
trans-5b
trans-5c
trans-6a
4.11
5.17
For the minor diastereoisomers trans-5a–5c, trans-6a,
trans-7a–7c, and trans-8a; the protons attached to C-5 (C-5
7
.5/5.1
4.8/2.7
5.38
5.7/5.4
4.12
7.5/2.4
5.17
4.02
0
and C-5 for trans-7a–7c) give rise to a doublet of doublets
7
.5/5.1
4.5/2.7
5.41
5.7/5.1
3.81
7.8/2.7
5.08
3
with coupling constants J = 5.4–11.7 and 3.9–6.6 Hz at
3.76
d = 3.81–4.20 ppm (for trans-6a, ddq d = 2.98 ppm).
7
.2/4.8
4.5/2.4
5.4/4.8
8.1/2.4
0
Thus, 5-H (5-H and 5 -H for trans-7a–7c) is pseudo-axial,
2.88 ddq 5.40
2.98 ddq 5.30
2
and the R moiety occupies the pseudo-equatorial position
6
3
.9/6.9/
.6
3.3/3.0
6.9/6.9/
3.9
8.1/2.7
0
(
Fig. 1). The proton 7-H (7-H and 7 -H for trans-7a–7c) of
trans-5a–5c, trans-6a, trans-7a–7c, and trans-8a resonates
at d = 5.08–5.32 ppm as a doublet of doublets with two
coupling constants ( J = 4.2–8.1 and 2.4–3.0 Hz). This
cis-7a
cis-7b
4.00
5.31
trans-7a
trans-7b
–
–
7
.2/6.3
5.7/2.7
5.07
3
3.99
4.12
5.28
5.7/2.4
5.32
4.2/3.0
–
suggests that for trans-5a–5c, trans-6a, trans-7a–7c, and
trans-8a, the conformation with an axial alkoxy group is
preferred because of stabilization by the anomeric effect
7
4
6
.5/6.0
6.0/2.4
5.11
9.3/4.8
4.19
.03
.9/5.4
8.4/3.0
–
5.4/3.9
3.93
(Fig. 1).
cis-7c
cis-8a
3.97
trans-7c
trans-8a
According to the literature, the Knoevenagel condensa-
7
.2/5.1
11.7/6.6
4.20
tion products obtained by condensation of barbituric acids
and aromatic aldehydes are excellent reagents in pyran
synthesis by conjugate addition-cyclization [27–36]. There
is no information for the same reactions using heteroaro-
matic aldehydes or terephthalaldehyde. Therefore, in the
next step, the Michael addition-cyclization of malononitrile
with a,b-unsaturated carbonyl compounds obtained by
Knoevenagel condensation of barbituric acids and hetero-
aromatic aldehydes or terephthalaldehyde was examined.
The reactions of acids 1a, 1b with heteroaromatic alde-
hydes 2e, 2f in water at room temperature gave the
condensation products 3e and 3f with stoichiometric yields
after 1 h. Heating of 3e or 3f with malononitrile 9 under
reflux in water for 1 h (method E, Scheme 3; Table 4,
entries 1, 7, 13) or under reflux in acetonitrile in the
presence of piperidine for 3 h (method F, Scheme 3;
Table 4, entries 2, 8, 14) did not result in compounds 12.
Therefore, in the next step of the studies, the three-
component one-pot reactions of acids 1a, 1b, aldehydes 2e,
2f, and malononitrile 9 without solvent at 100 °C (method
G, Scheme 3; Table 4, entries 3, 9, 15) or in water (method
H, Scheme 3; Table 4, entries 4, 10, 16) were examined.
There was no trace of the desired products 12 after 1 h of
heating, and compounds 3e–3g were obtained in excellent
4.13
5.42
5.24
7
.5/5.1
4.5/2.7
6.3/6.0
6.9/2.4
R2
H
5
O
O
5
H
H
R2
7
7
H
OC2H5
OC2H5
Major cis- 5a-5c,
Minor trans- 5a-5c,
trans- 6a (R =CH3),
2
2
cis- 6a (R =CH3),
2
2
cis-8a (R =C6H4-CHO)
trans-8a (R =C6H4-CHO)
OR1
7
'
H
R2
H
5
'
5
O
O
2
R
7
OR1
OR1
7'
5
O
2
R2
R
5'
7
O
H
OR1
H
Major cis- 7a-7c
Minor trans- 7a-7c
Fig. 1 Preferred cis/trans configurations and conformations of cyc-
1
loadducts 5a–5c, 6a, 7a–7c, and 8a based on H NMR analysis
85–93 % yields as the only products. Therefore, the next
3
d = 2.88 ppm) with coupling constants ( J = 6.9–7.5 and
attempts to synthesize the compounds 12 were undertaken.
Aldehydes 2e, 2f were first stirred with malononitrile 9 in
water at room temperature, and after 1 h the condensation
products 10a and 10b were isolated with stoichiometric
yields. Further, the mixture of compounds 10a, 10b was
4
.8–6.3 Hz) because of coupling with two protons at C-6
0
(Table 3). Thus, 5-H (5-H and 5 -H for cis-7a–7c) occupies
the pseudo-equatorial position, and the aromatic group
1
adopts the pseudo–axial orientation (Fig. 1). The H NMR
123

1
180
A. Pałasz
Scheme 3
R2
O
O
R1
O
R1
O
N
R2 CHO
e, 2f
H2O
N
+
2
r.t.
stirring
N
R1
O
N
R1
O
3e-3g
1a, 1b
(E) or (F)
-
CH2(CN)2
(G) or (H)
CH2(CN)2
(E) H2O, reflux
(F) CH3CN, piperidine, reflux
R2 CHO
O
R2
R2
O
O
R1
2e, 2f
o
(
G) solventless, 100 C
R1
R1
O
N
CN
CN
+
(H) H2O, reflux
N
N
CH2(CN)2
O
N
R1
O
CN
O
N
R1 12
O
NH2
N
R1
O
9
11
1a, 1b
(
E) H2O, reflux
(F) CH3CN, piperidine, reflux
O
1
R
N
O
N
R
O
1
1a, 1b
H2O
H
R2
CN
CN
R2 CHO
+
CH (CN)
2
2
r.t.
stirring
2e, 2f
9
1
0a, 10b
Table 4 Reactions of barbituric
acids 1a, 1b, heteroaromatic
aldehydes 2e, 2f, and
Entry Reagent
R
Reagent
R
Method Reagent
R
Product
Yield/% of 3
10
3
malononitrile 9 in the reaction
conditions E–H
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1a
1a
1a
1a
2e
2e
1b
1b
1b
1b
2e
2e
1a
1a
1a
1a
2f
CH3
2e
2e
2e
2e
9
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
–
E
F
9
–
–
–
–
–
–
–
–
3e
3e
–
–
CH
CH
CH
3
3
3
9
G
H
E
F
9
3e 89
3e 93
9
2-Thienyl
1a
1a
9
CH
CH
–
3
3
10a 3e 91
10a 3e 85
2-Thienyl
9
–
H
2e
2e
2e
2e
9
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
–
E
F
–
–
–
–
3f
3f
–
H
9
–
–
H
G
H
E
F
9
–
3f 85
3f 89
0
1
2
3
4
5
6
7
8
H
9
–
2-Thienyl
2-Thienyl
1b
1b
9
H
H
–
10a 3f 90
10a 3f 81
9
–
CH
CH
CH
CH
3
3
3
3
2f
2f
2f
2f
9
2-Furyl
2-Furyl
2-Furyl
2-Furyl
–
E
F
–
–
–
–
3g
3g
–
–
9
–
G
H
E
F
9
–
3g 87
3g 90
9
–
2-Furyl
2-Furyl
1a
1a
CH
CH
3
3
10b 3g 88
10b 3g 79
2f
9
–
1
23

Synthesis of fused uracils
1181
heated to reflux with barbituric acids 1a or 1b in water for
1
However, when the three-component one-pot reactions
of acid 1a, aldehyde 2d, and malononitrile 9 were heated at
100 °C (method G, Scheme 4) without solvent for 1 h or in
water under reflux (method H, Scheme 4), compound 3d
was obtained in excellent yield (87–91 %).
h (method E, Scheme 3; Table 4, entries 5, 11, 17) or
heated to reflux in acetonitrile in the presence of piperidine
for 3 h (method F, Scheme 3; Table 4, entries 6, 12, 18). In
these cases also, the only compounds, isolated in good
yields of 79–91 % after the reactions, were condensation
products 3e–3g. This result suggests that in the first step of
the reactions (Table 4, entries 5, 6, 11, 12, 17, 18), the
Michael adducts 11 are furnished (Scheme 3). Intermedi-
ates 11 did not undergo cyclization with formation of
pyrano[2,3-d]pyrimidine derivatives 12, but the elimination
of malononitrile led to undesired 3e–3g.
In conclusion, new fused uracils of possible pharmaco-
phore, the pyrano[2,3-d]pyrimidines and (1,4-phenylene)bis-
[2H-pyrano[2,3-d]pyrimidine-2,4(3H)-diones], were obtained
by domino Knoevenagel/Diels-Alder reactions in different
reaction conditions. All reactions were carried out without
catalyst and at room temperature. Three-component one-pot
syntheses of fused uracils performed in aqueous medium were
faster than those executed in dichloromethane or under
solventless conditions, and cis/trans selectivity was the
highest for these reactions. The reactions of malononitrile with
Knoevenagel condensation products of barbituric acids
and heteroaromatic aldehydes or terephthalaldehyde were
examined, and they do not provide corresponding pyranopyr-
imidines. The presented methods avoid the use of catalysts
and the heating of reaction mixtures for long times at
high temperatures, and the advantages of the presented
At the end of the study, the reaction procedures E–H
presented above were examined for acid 1a, terephthalal-
dehyde 2d, and malononitrile 9. The reaction of 1a with
aldehyde 2d in water at room temperature gave conden-
sation product 3d with almost stoichiometric yield after
1
h. When compound 3d was heated with malononitrile 9
in water for 1 h (method E, Scheme 4) or in acetonitrile in
the presence of piperidine for 3 h (method F, Scheme 4),
the expected compound 13 was not obtained.
Scheme 4
CH3
O
N
O
N
CH3
O
O
CHO
O
N
H C
3
H C
3
N
H2O
N
+
+
CH (CN)2
2
r.t.
stirring
O
N
O
O
O
9
CH3
CHO
CH3
1a
2d
3d
(
E) H O, reflux
2
(
F) CH CN, piperidine, reflux
3
(
G) or (H)
CHO
CHO
CH3
H N
O
N
O
2
N
NC
O
CH3
o
(
(
G) solventless, 100 C
H) H O, reflux
O
O
2
2
d
H C
3
N
+
CH (CN)2
H C
3
CN
2
O
N
O
N
9
CH3
O
N
O
NH2
1a
CH3
1
3
123

1
182
A. Pałasz
3
syntheses are also the excellent yields and short reactions
times.
0.56 g 2b, 0.5 cm 2c, 0.27 g (2.0 mmol) 2d) were mixed
with a tenfold excess (40 mmol) of enol ethers 4a–4c
3
3.8 cm 4a, 5.2 cm 4b, 3.8 cm 4c) in 100 cm dry
3
3
3
(
CH Cl at room temperature for the time given in Tables 1
2
2
Experimental
or 2. The progress of the reactions was monitored by TLC.
The solvent and excess of ethers were evaporated, and the
mixture was separated and purified by the method descri-
bed in procedure A. Products 5a–5c, 7a–7c were obtained
with yields listed in Tables 1 or 2. The diastereoisomers of
product 8a were also separated and recrystallized in small
amounts.
All chemicals were purchased and used without any further
purification. The melting points were determined on a
Boetius hot stage apparatus. The IR spectra were recorded
on a Nicolet IR 200 FT-IR, Thermo Scientific spectro-
photometer. NMR spectra were recorded on Bruker
1
13
Avance II 300 ( H: 300.18 MHz, C: 75.48 MHz) in
CDCl3 or DMSO-d with TMS as an internal standard.
6
Procedure D
Microanalyses were performed with a Euro EA 3000 Ele-
mental Analyzer; their results agreed satisfactorily with the
calculated values. 5-Arylidenebarbituric acids 3a–3g were
obtained according to the general procedure described in
Ref. [37].
A suspension of equimolar amounts (4.0 mmol) of barbi-
turic acid 1a (0.625 g) or 1b (0.51 g) and appropriate
3
aldehyde 2a–2d (0.74 g 2a, 0.56 g 2b, 0.5 cm 2c, 0.27 g
(2.0 mmol) 2d) with a tenfold excess (40 mmol) of enol
3
ether 4a–4c (3.8 cm 4a, 5.2 cm 4b, 3.8 cm 4c) in
3
3
3
0 cm H O was allowed to stay under vigorous stirring at
5
2
Procedures for the synthesis of pyrano[2,3-d]-
room temperature for the time given in Tables 1 or 2. The
progress of the reactions was monitored by TLC. After
that, the reaction mixture was extracted with CH Cl . The
0
pyrimidine-2,4-diones 5a–5c, 6a, 8a, and 5,5 -(1,4-
phenylene)bis[2H-pyrano[2,3-d]pyrimidine-2,4(3H)-
dione] derivatives 7a–7c
2
2
combined organic layers were dried (MgSO ), and the
4
solvent was evaporated under reduced pressure. Diastere-
oisomers were separated and recrystallized by the method
described in procedure A. Products 5a–5c, 7a–7c were
obtained with yields listed in Tables 1 or 2. Both diaste-
reoisomers of product 6a and product 8a were also
separated and recrystallized in small amounts.
Procedure A
A solution of 4.0 mmol 3a–3d (1.29 g 3a, 1.11 g 3b,
3
.99 g 3c, 1.64 g 3d) in dry CH Cl (50 cm for 3a, 3b and
3
00 cm for 3c, 3d) and 40 mmol (10 equivalents) of enol
0
1
2
2
3
3
3
ethers 4a–4c (3.8 cm 4a, 5.2 cm 4b, 3.8 cm 4c) was
kept at room temperature for the time given in Tables 1 or
(
5RS,7SR)-5-(4-Bromophenyl)-7-ethoxy-1,5,6,7-
tetrahydro-1,3-dimethyl-2H-pyrano[2,3-d]pyrimidine-
,4(3H)-dione (cis-5a, C H BrN O )
2
. The progress of the reactions was monitored by TLC.
The solvent and excess of ethers were evaporated, and the
mixture was separated and purified by column chroma-
tography on silica gel using t-butyl methyl ether as an
eluent. Recrystallization from a mixture of t-butyl methyl
ether and petroleum ether gave diastereoisomers 5a–5c,
2
1
7
19
2 4
Colorless crystals; mp: 169–170 °C; R = 0.48 (t-Bu-
f
OMe); IR (powder): ꢀm = 3,012, 2,926, 1,731, 1,664,
-
1
1
; H NMR (300 MHz,
1,504, 1,190, 1,069, 1,017 cm
CDCl ): d = 1.13 (3H, t, J = 7.2 Hz, OCH CH ), 2.14
3
2
3
7
a–7c with yields listed in Tables 1 or 2.
(
1H, ddd, J = 14.4, 5.1, 4.8 Hz, 6-H), 2.34 (1H, ddd,
J = 14.1, 7.5, 2.7 Hz, 6-H), 3.28 (3H, s, N-Me), 3.43 (3H,
s, N-Me), 3.58 (1H, dq, J = 9.3, 6.9 Hz, OCH CH ), 3.86
Procedure B
2
3
A mixture of 4.0 mmol of one of the 5-arylidenebarbituric
acids 3a–3d (1.29 g 3a, 1.11 g 3b, 0.99 g 3c, 1.64 g 3d)
with a tenfold excess (40 mmol) of one of the enol ethers
(1H, dq, J = 9.3, 6.9 Hz, OCH CH ), 4.00 (1H, dd,
2 3
J = 7.5, 5.1 Hz, 5-H), 5.38 (1H, dd, J = 4.8, 2.7 Hz,
-H), 7.07 (2H, d, J = 8.4 Hz, Ar), 7.36 (2H, d,
7
3
3
3
4
a–4c (3.8 cm 4a, 5.2 cm 4b, 3.8 cm 4c) was stirred
1
3
J = 8.7 Hz, Ar) ppm; C NMR (75.5 MHz, CDCl3):
d = 14.9, 28.0, 28.7, 33.5, 35.4, 65.5, 89.0, 101.9, 119.9,
without solvent at room temperature for the time given in
Tables 1 or 2. The progress of the reactions was monitored
by TLC. The excess of ethers was evaporated. Diastereo-
isomers were separated and recrystallized by the method
described in procedure A. Products 5a–5c, 7a–7c were
obtained with yields listed in Tables 1 or 2.
129.1, 131.1, 142.7, 151.2, 155.1, 162.1 ppm.
(5RS,7RS)-5-(4-Bromophenyl)-7-ethoxy-1,5,6,7-
tetrahydro-1,3-dimethyl-2H-pyrano[2,3-d]pyrimidine-
2,4(3H)-dione (trans-5a, C H BrN O )
1
7
19
2 4
Colorless crystals; mp: 198–200 °C; R = 0.65 (t-Bu-
f
Procedure C
OMe); IR (powder): ꢀm = 3,011, 2,964, 1,722, 1,651,
1,503, 1,171, 1,107, 1,017 cm
-
1
1
; H NMR (300 MHz,
Equimolar amounts (4.0 mmol) of barbituric acid 1a
(
0.625 g) or 1b (0.51 g) and aldehydes 2a–2d (0.74 g 2a,
CDCl ): d = 1.26 (3H, t, J = 7.2 Hz, OCH CH ), 2.07
3
2
3
1
23

Synthesis of fused uracils
1183
(
1H, ddd, J = 13.8, 4.8, 2.4 Hz, 6-H), 2.20 (1H, ddd,
J = 13.8, 7.5, 6.3 Hz, 6-H), 3.29 (3H, s, N-Me), 3.43 (3H,
s, N-Me), 3.65 (1H, dq, J = 9.3, 6.9 Hz, OCH CH ), 3.95
s, OCH ), 3.71 (1H, dq, J = 9.6, 7.2 Hz, OCH CH ), 3.76
3
2
3
(1H, dd, J = 7.2, 4.8 Hz, 5-H), 5.41 (1H, dd, J = 4.5,
2.4 Hz, 7-H), 6.75 (2H, d, J = 9.0 Hz, Ar), 7.03 (2H, d,
J = 8.4 Hz, Ar), 10.69 (1H, s, NH), 11.35 (1H, s, NH)
2
3
(
1H, dq, J = 9.3, 6.9 Hz, OCH CH ), 4.11 (1H, dd,
2 3
1
3
J = 5.7, 5.4 Hz, 5-H), 5.17 (1H, dd, J = 7.5, 2.4 Hz,
-H), 7.06 (2H, d, J = 8.4 Hz, Ar), 7.42 (2H, d,
ppm; C NMR (75.5 MHz, DMSO-d ): d = 14.8, 31.4,
6
7
35.4, 54.8, 64.1, 87.8, 100.6, 112.8, 128.2, 136.3, 150.0,
1
3
J = 8.4 Hz, Ar) ppm; C NMR (75.5 MHz, CDCl3):
d = 15.1, 28.0, 28.7, 33.6, 35.9, 66.0, 88.2, 101.2, 120.5,
156.3, 157.1, 163.4 ppm.
(
(
5RS,7RS)-7-Ethoxy-1,5,6,7-tetrahydro-5-
4-methoxyphenyl)-2H-pyrano[2,3-d]pyrimidine-
1
28.8, 131.8, 142.8, 151.3, 155.4, 162.0 ppm.
5RS,7SR)-5-(4-Chlorophenyl)-7-ethoxy-1,5,6,7-
tetrahydro-1,3-dimethyl-2H-pyrano[2,3-d]pyrimidine-
,4(3H)-dione (cis-5b, C H ClN O )
(
2,4(3H)-dione (trans-5c, C H N O )
16 18 2 5
Colorless crystals; mp: 314–315°C; R = 0.65 (t-BuOMe);
f
2
IR (powder): ꢀm = 3,192, 3,120, 3,003, 2,958, 2,884, 2,851,
1,725, 1,632, 1,529, 1,260, 1,186, 1,088, 1,045 cm ; H
1
7
19
2 4
-
1 1
Colorless crystals; mp: 141–142 °C; R = 0.41 (t-Bu-
OMe); IR (powder): ꢀm = 2,992, 2,959, 2,887, 1,725,
f
NMR (300 MHz, DMSO-d ): d = 1.13 (3H, t, J = 7.2 Hz,
6
-
1
1
1
,654, 1,503, 1,280, 1,188, 1,046,1,016 cm ; H NMR
300 MHz, CDCl3): d = 1.13 (3H, t, J = 7.2 Hz,
OCH CH ), 2.14 (1H, ddd, J = 14.4, 5.1, 4.8 Hz, 6-H),
OCH CH ), 1.94 (1H, ddd, J = 13.8, 4.5, 2.4 Hz, 6-H),
2
3
(
2.07 (1H, ddd, J = 13.8, 8.1, 6.0 Hz, 6-H), 3.61 (1H, dq,
J = 9.6, 6.9 Hz, OCH CH ), 3.71 (3H, s, OCH ), 3.81
2
3
2
3
3
2
.33 (1H, ddd, J = 14.1, 7.5, 2.7 Hz, 6-H), 3.28 (3H, s,
N-Me), 3.43 (3H, s, N-Me), 3.58 (1H, dq, J = 9.3, 6.9 Hz,
OCH CH ), 3.86 (1H, dq, J = 9.3, 6.9 Hz, OCH CH ),
(1H, dd, J = 5.4, 4.8 Hz, 5-H), 3.84 (1H, dq, J = 9.6,
6.9 Hz, OCH CH ), 5.08 (1H, dd, J = 8.1, 2.4 Hz, 7-H),
6.83 (2H, d, J = 8.7 Hz, Ar), 7.08 (2H, d, J = 8.7 Hz, Ar)
2
3
2
3
2
3
1
3
4
2
.02 (1H, dd, J = 7.5, 5.1 Hz, 5-H), 5.38 (1H, dd, J = 4.5,
.7 Hz, 7-H), 7.12 (2H, d, J = 8.4 Hz, Ar), 7.21 (2H, d,
10.72 (1H, s, NH), 11.38 (1H, s, NH) ppm; C NMR
(75.5 MHz, DMSO-d ): d = 14.9, 31.8, 36.0, 54.9, 64.8,
6
1
3
J = 8.4 Hz, Ar) ppm; C NMR (75.5 MHz, CDCl3):
d = 14.9, 28.0, 28.7, 33.4, 35.4, 65.5, 89.1, 102.0, 128.2,
87.0, 99.8, 113.6, 128.2, 136.0, 150.1, 156.6, 157.5,
163.4 ppm.
1
28.7, 131.8, 142.2, 151.2, 155.1, 162.1 ppm.
5RS,7RS)-5-(4-Chlorophenyl)-7-ethoxy-1,5,6,7-
tetrahydro-1,3-dimethyl-2H-pyrano[2,3-d]pyrimidine-
,4(3H)-dione (trans-5b, C H ClN O )
(5RS,7RS)-7-Ethoxy-1,5,6,7-tetrahydro-1,3,5-
trimethyl-2H-pyrano[2,3-d]pyrimidine-2,4(3H)-
(
dione (cis-6a, C H N O )
1
2 18 2 4
2
Colorless crystals; mp: 79–80 °C; R = 0.37 (t-BuOMe);
1
7
19
2
4
f
Colorless crystals; mp: 153–155 °C; R = 0.59 (t-Bu-
OMe); IR (powder): ꢀm = 3,004, 2,960, 2,912, 2,887,
IR (powder): ꢀm = 2,968, 2,934, 2,901, 2,879, 1,701, 1,625,
f
-
1
1
1,483, 1,183, 1,144, 1,102, 1,022 cm
;
H NMR
-
1 1
1
,720, 1,651, 1,505, 1,178, 1,118, 1,035 cm ; H NMR
300 MHz, CDCl3): d = 1.27 (3H, t, J = 6.9 Hz,
OCH CH ), 2.07 (1H, ddd, J = 14.1, 5.1, 2.7 Hz, 6-H),
(300 MHz, CDCl3): d = 1.26 (3H, t, J = 7.2 Hz,
OCH CH ), 1.35 (3H, d, J = 6.9 Hz, 5-CH ), 1.90 (1H,
(
2
3
3
ddd, J = 14.1, 3.6, 3.3 Hz, 6-H), 2.05 (1H, ddd, J = 14.1,
6.9, 3.0 Hz, 6-H), 2.88 (1H, ddq, J = 6.9, 6.9, 3.6 Hz,
5-H), 3.34 (3H, s, N-Me), 3.36 (3H, s, N-Me), 3.65 (1H, dq,
J = 9.3, 6.9 Hz, OCH CH ), 3.89 (1H, dq, J = 9.3,
2
3
2
.20 (1H, ddd, J = 13.8, 7.5, 6.3 Hz, 6-H), 3.29 (3H, s,
N-Me), 3.43 (3H, s, N-Me), 3.65 (1H, dq, J = 9.3, 6.9 Hz,
OCH CH ), 3.98 (1H, dq, J = 9.3, 6.9 Hz, OCH CH ),
2
3
2
3
2
3
4
2
.12 (1H, dd, J = 5.7, 5.1 Hz, 5-H), 5.17 (1H, dd, J = 7.8,
.7 Hz, 7-H), 7.11 (2H, d, J = 8.4 Hz, Ar), 7.27 (2H, d,
7.2 Hz, OCH CH ), 5.40 (1H, dd, J = 3.3, 3.0 Hz, 7-H)
2 3
1
3
ppm; C NMR (75.5 MHz, CDCl ): d = 15.1, 20.1, 22.6,
3
1
3
J = 8.4 Hz, Ar) ppm; C NMR (75.5 MHz, CDCl3):
d = 15.1, 28.0, 28.7, 33.5, 36.0, 66.0, 88.3, 101.4, 128.6,
27.9, 28.6, 33.4, 65.6, 92.0, 101.8, 151.2, 153.4,
162.7 ppm.
1
28.8, 132.4, 142.2, 151.3, 155.4, 162.1 ppm.
(5RS,7SR)-7-Ethoxy-1,5,6,7-tetrahydro-1,3,5-
trimethyl-2H-pyrano[2,3-d]pyrimidine-2,4(3H)-dione
(
(
5RS,7SR)-7-Ethoxy-1,5,6,7-tetrahydro-5-
4-methoxyphenyl)-2H-pyrano[2,3-d]pyrimidine-
(trans-6a, C H N O )
1
2 18 2 4
2
,4(3H)-dione (cis-5c, C H N O )
5
Colorless crystals; mp: 88–90 °C; R = 0.43 (t-BuOMe);
1
6
18
2
f
Colorless crystals; mp: 299–300 °C; R = 0.39 (t-Bu-
OMe); IR (powder): ꢀm = 3,200, 3,170, 3,012, 2,938,
IR (powder): ꢀm = 2,972, 2,931, 2,908, 2,883, 1,701, 1,630,
f
-
1
1
1,491, 1,182, 1,140, 1,098, 1,020 cm
;
H NMR
2
,869, 1,732, 1,671, 1,530, 1,270, 1,200, 1,108, 1,068,
-
(300 MHz, CDCl3): d = 1.26 (3H, d, J = 6.9 Hz,
5-CH ), 1.31 (3H, t, J = 7.2 Hz, OCH CH ), 1.85 (1H,
1
1
1
,048 cm ; H NMR (300 MHz, DMSO-d ): d = 1.00
6
3
2
3
(
3H, t, J = 7.2 Hz, OCH CH ), 1.92 (1H, ddd, J = 14.1,
2
ddd, J = 13.8, 3.9, 2.7 Hz, 6-H), 1.94 (1H, ddd, J = 13.8,
8.1, 6.0 Hz, 6-H), 2.98 (1H, ddq, J = 6.9, 6.9, 3.9 Hz,
5-H), 3.33 (3H, s, N-Me), 3.35 (3H, s, N-Me), 3.73 (1H, dq,
3
4
.8, 4.8 Hz, 6-H), 2.23 (1H, ddd, J = 14.1, 7.2, 2.4 Hz,
-H), 3.50 (1H, dq, J = 9.6, 6.9 Hz, OCH CH ), 3.69 (3H,
6
2
3
123

1
184
A. Pałasz
J = 9.6, 7.2 Hz, OCH CH ), 4.01 (1H, dq, J = 9.6,
2
(CH ) ), 4.12 (1H, dd, J = 9.3, 4.8 Hz, 5-H), 4.19 (1H, dd,
3 2
3
0
7
.2 Hz, OCH CH ), 5.30 (1H, dd, J = 8.1, 2.7 Hz, 7-H)
2
J = 5.4, 3.9 Hz, 5 -H), 5.28 (1H, dd, J = 5.7, 2.4 Hz,
0
3
1
3
ppm; C NMR (75.5 MHz, CDCl ): d = 15.1, 20.8, 23.2,
7-H), 5.32 (1H, dd, J = 4.2, 3.0 Hz, 7 -H), 7.00 (2H, br,
3
1
Ar), 7.05 (2H, br, Ar) ppm; C NMR (75.5 MHz, CDCl3):
3
2
7.9, 28.6, 34.6, 66.0, 91.6, 101.2, 151.2, 153.9,
1
62.6 ppm.
d = 19.1, 19.2, 28.0, 28.6, 28.7, 33.6, 33.7, 35.4, 35.5,
7
7.2, 89.2, 90.0, 102.6, 103.0, 126.8, 126.9, 140.8, 141.0,
0 0 0
5RS,7SR,5 RS,7 SR)-5,5 -(1,4-Phenylene)bis[7-
ethoxy-1,5,6,7-tetrahydro-1,3-dimethyl-2H-pyrano[2,3-
(
151.3, 154.9, 162.0 ppm.
d]pyrimidine-2,4(3H)-dione] (cis-7a, C H N O )
2
0 0 0
5RS,7SR,5 RS,7 SR)-5,5 -(1,4-Phenylene)bis[1,5,6,7-
tetrahydro-7-methoxy-1,3,7-trimethyl-2H-pyrano[2,3-
8 34 4 8
(
Colorless crystals; mp:[360 °C; R = 0.14 (t-BuOMe); IR
f
(
powder): ꢀm = 2,973, 2,926, 2,884, 1,703, 1,635, 1,480,
1
d]pyrimidine-2,4(3H)-dione] (cis-7c, C H N O )
2
8 34 4 8
-
1
1
,173, 1,132, 1,035, 1,001 cm ; H NMR (300 MHz,
Colorless crystals; mp:[360 °C; R = 0.27 (t-BuOMe); IR
f
CDCl ): d = 1.15 (3H, t, J = 7.2 Hz, OCH CH ), 2.17
3
2
3
(
powder): ꢀm = 2984, 2958, 2887, 1700, 1627, 1485, 1455,
0
(
2H, ddd, J = 14.7, 6.3, 5.7 Hz, 6-H, 6 -H), 2.32 (2H, ddd,
0
-1
1
1
176, 1072, 1042, 1019 cm
;
H NMR (300 MHz,
0
J = 14.1, 7.2, 2.7 Hz, 6-H, 6 -H), 3.27 (6H, s, N-Me), 3.42
(
CDCl ): d = 1.53 (3H, s, 7-CH ), 1.56 (3H, s, 7 -CH ),
3
3
3
6H, s, N-Me), 3.58 (2H, dq, J = 9.3, 6.9 Hz, OCH CH ),
2
0
3
2.11 (2H, dd, J = 14.1, 7.2 Hz, 6-H, 6 -H), 2.31 (2H, dd,
0
3
.86 (2H, dq, J = 9.3, 7.2 Hz, OCH CH ), 4.00 (2H, dd,
2
3
J = 14.1, 6.0 Hz, 6-H, 6 -H), 3.19 (6H, s, OCH ), 3.29
3
0
J = 7.2, 6.3 Hz, 5-H, 5 -H), 5.31 (2H, dd, J = 5.7, 2.7 Hz,
7
(
6H, s, N-Me), 3.42 (6H, s, N-Me), 3.97 (2H, dd, J = 7.2,
13
.1 Hz, 5-H), 7.03 (4H, br, Ar) ppm; C NMR (75.5 MHz,
0
13
-H, 7 -H), 7.05 (4H, br, Ar) ppm; C NMR (75.5 MHz,
5
CDCl ): d = 14.9, 27.9, 28.7, 34.0, 36.1, 65.5, 90.0, 102.5,
3
CDCl ): d = 22.3, 27.9, 28.6, 34.3, 39.8, 49.6, 88.9, 105.6,
3
1
26.9, 141.1, 151.3, 155.0, 162.1 ppm.
126.7, 126.9, 140.9, 151.4, 155.2, 162.2 ppm.
0
0
0
(
5RS,7SR,5 RS,7 SR)-5,5 -(1,4-Phenylene)bis[1,5,6,7-tetra-
hydro-7-isobutoxy-1,3-dimethyl-2H-pyrano[2,3-d]pyrimi-
0 0 0
5RS,7RS,5 RS,7 RS)-5,5 -(1,4-Phenylene)bis[1,5,6,7-tetra-
hydro-7-methoxy-1,3,7-trimethyl-2H-pyrano[2,3-d]-
(
dine-2,4(3H)-dione] (cis-7b, C H N O )
3
2 42 4 8
pyrimidine-2,4(3H)-dione] (trans-7c, C H N O )
2
8 34 4 8
Colorless crystals; mp:[360 °C; R = 0.24 (t-BuOMe); IR
powder): ꢀm = 2,959, 2,927, 2,864, 2,853, 1,702, 1,636,
f
Colorless crystals; mp:[360 °C; R = 0.39 (t-BuOMe); IR
f
(
(
powder): ꢀm = 2,981, 2,952, 2,885, 1,697, 1,631, 1,486,
-
1
1
1
,458, 1,162, 1,154, 1,047, 1,006 cm
;
H NMR
-1
1
1,449, 1,172, 1,069, 1,047, 1,018 cm
;
H NMR
(
300 MHz, CDCl ): d = 0.90 (12H, d, J = 6.6 Hz, OCH2
CH(CH ) ), 1.67 (2H, m, OCH CH(CH ) ), 2.02 (2H, ddd,
3
3
(
300 MHz, CDCl ): d = 1.53 (3H, s, 7-CH ), 1.55 (3H,
3
3
2
2
3 2
0
0
s, 7 -CH ), 2.12 (2H, dd, J = 14.4, 11.4 Hz, 6-H, 6 -H),
3
0
J = 13.8, 4.8, 2.4 Hz, 6-H, 6 -H), 2.20 (2H, ddd, J = 13.8,
0
0
2.33 (2H, dd, J = 14.4, 6.9 Hz, 6-H, 6 -H), 3.23 (6H, s,
OCH ), 3.31 (6H, s, N-Me), 3.42 (6H, s, N-Me), 3.93 (2H,
8
.4, 6.0 Hz, 6-H, 6 -H), 3.30 (6H, s, N-Me), 3.41 (6H, s,
3
N-Me), 3.54 (1H, dd, J = 9.0, 6.3 Hz, OCH CH
2
0
dd, J = 11.7, 6.6 Hz, 5-H, 5 -H), 7.02 (4H, br, Ar) ppm;
13
(
CH ) ), 3.67 (1H, dd, J = 9.0, 6.6 Hz, OCH CH(CH ) ),
3
2
2
3 2
C NMR (75.5 MHz, CDCl ): d = 22.1, 27.8, 28.5, 34.2,
3
3
5
.99 (1H, dd, J = 7.5, 6.0 Hz, 5-H), 4.03 (1H, dd, J = 6.9,
0
4
1
3.3, 50.0, 91.2, 104.0, 126.5, 127.2, 141.6, 151.4, 154.6,
.4 Hz, 5 -H), 5.07 (1H, dd, J = 6.0, 2.4 Hz, 7-H), 5.11
0
61.8 ppm.
(
1H, dd, J = 8.4, 3.0 Hz, 7 -H), 7.00 (2H, br, Ar), 7.05
1
3
(5RS,7SR)-7-Ethoxy-5-(4-formylphenyl)-1,5,6,7-
tetrahydro-1,3-dimethyl-2H-pyrano[2,3-d]-
pyrimidine-2,4(3H)-dione (cis-8a, C H N O )
(
2H, br, Ar) ppm; C NMR (75.5 MHz, CDCl ): d =
3
1
8
1
9.0, 19.5, 27.8, 28.3, 28.5, 33.5, 33.7, 36.0, 36.1, 77.2,
8.0, 88.3, 101.8, 102.0, 127.3, 127.5, 141.6, 141.7, 151.3,
55.5, 162.3 ppm.
1
8 20 2 5
Colorless crystals; mp: 335–337 °C; R = 0.19 (t-Bu-
f
OMe); IR (powder): ꢀm = 2,975, 2,937, 2,898, 1,703,
1,634, 1,571, 1,486, 1,379, 1,170, 1,092, 1,004 cm ; H
0
0
0
-1 1
(5RS,7RS,5 RS,7 RS)-5,5 -(1,4-Phenylene)bis[1,5,6,7-
tetrahydro-7-isobutoxy-1,3-dimethyl-2H-pyrano[2,3-
NMR (300 MHz, CDCl ): d = 1.26 (3H, t, J = 7.2 Hz,
3
d]pyrimidine-2,4(3H)-dione] (trans-7b, C H N O )
3
OCH CH ), 2.22 (1H, ddd, J = 14.1, 4.8, 4.5 Hz, 6-H),
2
2
42
4
8
3
Colorless crystals; mp:[360 °C; R = 0.37 (t-BuOMe); IR
2.38 (1H, ddd, J = 14.4, 7.5, 2.7 Hz, 6-H), 3.28 (3H, s,
N-Me), 3.45 (3H, s, N-Me), 3.57 (1H, dq, J = 9.3, 6.9 Hz,
OCH CH ), 3.84 (1H, dq, J = 9.3, 7.2 Hz, OCH CH ),
f
(
powder): ꢀm = 2,955, 2,921, 2,868, 2,851, 1,699, 1,634,
-
1
1
1
,455, 1,166, 1,151, 1,053, 1,002 cm
;
H NMR
2
3
2
3
(
300 MHz, CDCl ): d = 0.91 (12H, d, J = 6.9 Hz,
4.13 (1H, dd, J = 7.5, 5.1 Hz, 5-H), 5.42 (1H, dd, J = 4.5,
2.7 Hz, 7-H), 7.36 (2H, d, J = 8.4 Hz, Ar), 7.78 (2H, d,
3
OCH CH(CH ) ), 1.83 (2H, m, OCH CH(CH ) ), 2.13
3 2
2
3 2
2
0
13
J = 8.4 Hz, Ar), 9.95 (1H, s, CHO) ppm; C NMR
(
2H, ddd, J = 13.8, 8.7, 3.9 Hz, 6-H, 6 -H), 2.28 (2H, ddd,
0
J = 13.8, 5.7, 4.8 Hz, 6-H, 6 -H), 3.29 (6H, s, N-Me), 3.40
(
(75.5 MHz, CDCl ): d = 14.8, 28.0, 28.8, 33.9, 35.0, 66.5,
3
6H, s, N-Me), 3.58 (1H, dd, J = 9.0, 6.3 Hz,
OCH CH(CH ) ), 3.65 (1H, dd, J = 9.0, 6.6 Hz, OCH CH
88.4, 101.7, 128.1, 129.7, 134.8, 151.1, 151.2, 155.2,
2
3 2
2
162.7, 192.0 ppm.
1
23

Synthesis of fused uracils
1185
(5RS,7RS)-7-Ethoxy-5-(4-formylphenyl)-1,5,6,7-
tetrahydro-1,3-dimethyl-2H-pyrano[2,3-d]-
8. Anderson GL, Shim JL, Broom AD (1976) J Org Chem 41:1095
9
. Tietze LF, Hartfiel U, Hubsch T, Voss E, Bogdanowicz-Szwed K,
Wichmann J (1991) Liebigs Ann Chem 275
0. Ager DJ, East MB (1993) Tetrahedron 49:5683
pyrimidine-2,4(3H)-dione (trans-8a, C H N O )
1
8 20 2 5
1
Colorless crystals; mp: 168–170 °C; R = 0.29 (t-Bu-
11. Tietze LF (1990) J Heterocycl Chem 27:47
12. John RA, Schmidt V, Wyler H (1987) Helv Chim Acta 70:600
f
OMe); IR (powder): ꢀm = 2,951, 2,898, 2,823, 2,732,
1
1
1
3. Zhuo JC, Wyler H, Schenk K (1995) Helv Chim Acta 78:151
4. Tietze LF, Evers H, Topken E (2001) Angew Chem Int Ed 40:903
5. Haag-Zeino B, Schmidt RR (1990) Liebigs Ann Chem 1197
1
,698, 1,634, 1,574, 1,488, 1,169, 1,118, 1,043,
1 1
-
1
,005 cm ; H NMR (300 MHz, CDCl ): d = 1.26 (3H,
3
t, J = 7.2 Hz, OCH CH ), 2.09 (1H, ddd, J = 13.8, 6.0,
2
16. Bogdanowicz-Szwed K, Pałasz A (1995) Monatsh Chem 126:
1341
3
2.4 Hz, 6-H), 2.27 (1H, ddd, J = 13.8, 7.2, 6.6 Hz, 6-H),
3.28 (3H, s, N-Me), 3.44 (3H, s, N-Me), 3.67 (1H, dq,
1
7. Bogdanowicz-Szwed K, Pałasz A (1997) Monatsh Chem 128:
157
8. Bogdanowicz-Szwed K, Pałasz A (1999) Monatsh Chem 130:795
1
J = 9.3, 6.9 Hz, OCH CH ), 3.95 (1H, dq, J = 9.6,
2
3
1
7
.2 Hz, OCH CH ), 4.20 (1H, dd, J = 6.3, 6.0 Hz, 5-H),
3
19. Bogdanowicz-Szwed K, Pałasz A (2001) Z Naturforsch 56b:416
20. Bogdanowicz-Szwed K, Pałasz A (2001) Monatsh Chem 132:393
2
5.24 (1H, dd, J = 6.9, 2.4 Hz, 7-H), 7.37 (2H, d,
J = 8.1 Hz, Ar), 7.83 (2H, d, J = 8.4 Hz, Ar), 9.97 (1H,
2
2
1. Pałasz A (2005) Org Biomol Chem 3:3207
2. Pałasz A, Jelska K, O z_ o´ g M, Serda P (2007) Monatsh Chem
1
3
s, CHO) ppm; C NMR (75.5 MHz, CDCl ): d = 15.0,
2
3
1
38:481
23. Pałasz A (2008) Monatsh Chem 139:1397
8.0, 28.7, 34.2, 35.9, 66.0, 88.3, 100.9, 127.9, 130.2,
1
35.2, 151.1, 151.2, 155.4, 162.0, 191.7 ppm.
24. Pałasz A, Bogdanowicz-Szwed K (2008) Monatsh Chem 139:647
2
2
2
5. Pałasz A (2010) Synthesis 23:4021
6. Pałasz A, Pałasz T (2011) Tetrahedron 67:1422
7. Ciller JA, Martin N, Seoane C, Soto JL (1985) J Chem Soc Perkin
Trans 1:2581
8. Martin N, Martinez-Grau A, Seoane C, Marco JL, Albert A, Cano
FH (1993) Liebigs Ann Chem 801
9. Bogdanowicz-Szwed K, Budzowski A (1999) Monatsh Chem
Open Access This article is distributed under the terms of the
Creative Commons Attribution License which permits any use, dis-
tribution, and reproduction in any medium, provided the original
author(s) and the source are credited.
2
2
1
30:545
References
3
3
0. Sharanin YA, Klokol GV (1984) Zh Org Khim 20:2448
1. Ibrahim MKA, El-Moghayar MRH, Sharaf MAF (1987) Indian J
Chem Sect B 26B:216
1
. Boger DL, Weinreb SN (1987) Hetero Diels-Alder methodology
in organic synthesis. Academic Press, San Diego
32. Gao Y, Tu S, Li T, Zhang X, Zhu S, Fang F, Shi S (2004) Synth
Commun 34:1295
2
3
. Tietze LF, Kettschau G (1997) Top Curr Chem 189:12
. Kitamura N, Ohnishi A (1984) Eur Pat 163599; Chem Abstr
33. Mashkouri S, Naimi-Jamal MR (2009) Molecules 14:474
34. Devi I, Kumar BSD, Bhuyan PJ (2003) Tetrahedron Lett 44:8307
35. Shaabani A, Samadi S, Rahmati A (2007) Synth Commun 37:491
36. Jin TS, Liu LB, Tu SJ, Zhao Y, Li TS (2005) J Chem Res 3:162
37. Deb ML, Bhuyan PJ (2005) Tetrahedron Lett 46:6453
38. Jursic BS, Stevens ED (2003) Tetrahedron Lett 44:2203
1
04:186439u
4
. Furuja S, Ohtaki T (1994) Chem Abstr 121:205395w. Eur Pat
Appl EP 608565
5
6
7
. Heber D, Heers C, Ravens U (1993) Pharmazie 48:537
. Coates W (1990) Chem Abstr 113:40711r. J Eur Pat 351058
. Sakuma Y, Hasegawa M, Kataoka K, Hoshina K, Yamazaki N,
Kadota T, Yamaguchi H (1989) Chem Abstr 115:71646. PCT Int
Appl WO 9105784
123