Convergent domino Knoevenagel hetero-Diels-Alder and domino oxidation hetero-Diels-Alder reactions encountered in an unexpected formation of novel 5-aryl-1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-diones and 5-aryl-2,3-dihydro-2- thioxo-1H-pyrano[2,3-d]pyrimid

Article abstract of DOI:10.1002/hlca.201000325

Convergent domino Knoevenagel hetero-Diels-Alder and domino oxidation hetero-Diels-Alder reactions, in which both diene and dienophile are formed under the same reaction conditions in situ, are described for the first time, and their application is demons

Full text of DOI:10.1002/hlca.201000325

Helvetica Chimica Acta – Vol. 94 (2011)
859
Convergent Domino Knoevenagel Hetero-DielsꢀAlder and Domino
Oxidation Hetero-DielsꢀAlder Reactions Encountered in an Unexpected
Formation of Novel 5-Aryl-1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-diones
and 5-Aryl-2,3-dihydro-2-thioxo-1H-pyrano[2,3-d]pyrimidin-4(5H)-ones
by Nace Zidar and Danijel Kikelj*
ˇ
ˇ
Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia
(phone: þ 38614769561; fax: þ 38614258031; e-mail: danijel.kikelj@ffa.uni-lj.si)
Convergent domino Knoevenagel hetero-DielsꢀAlder and domino oxidation hetero-DielsꢀAlder
reactions, in which both diene and dienophile are formed under the same reaction conditions in situ, are
described for the first time, and their application is demonstrated by a one-pot synthesis of novel 5-aryl-
1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-diones and 5-aryl-2,3-dihydro-2-thioxo-1H-pyrano[2,3-d]pyri-
midin-4(5H)-ones.
Introduction. – Domino reactions involving hetero-DielsꢀAlder cycloaddition
reaction constitute a powerful strategy for the synthesis of complex organic molecules
[1]. Among them, the domino Knoevenagel hetero-DielsꢀAlder reaction [1b][2], in
which a diene, generated from a 1,3-dicarbonyl compound and an aldehyde, reacts with
a dienophile, e.g., an enol ether [3a], alkene [2d][2e], alkyne [3b][3c], or enamine
[3d], has been frequently applied for the synthesis of natural products and highly
diversified molecules. Whereas, in such reactions, different substrates, e.g., barbituric
acids and Meldrumꢀs acid, have been used for generating dienes, dienophiles have not
been produced in situ but added as reagents. A domino process in which both the diene
and the dienophile would be generated in situ under the same reaction conditions, and
would subsequently react to give a hetero-DielsꢀAlder product, is a challenging
concept, which, to the best of our knowledge, has not been encountered in domino
sequences involving a hetero-DielsꢀAlder reaction.
5-Unsubstituted barbituric acids I undergo the Knoevenagel condensation with
aldehydes to afford 5-ylidene derivatives II [4], which have been reported to react as
dienes in a hetero-DielsꢀAlder reaction to give 6/7-substituted 5-aryl-1H-pyrano[2,3-
d]pyrimidine-2,4(3H,5H)-diones or their 2-thioxo analogues III (X ¼ S) [3]
(Scheme 1). As fused uracils, these compounds have received considerable attention
due to their biological effects, including antiviral [5], antibacterial [6], antifungal [7],
and prostate-protective activities [8]. 6,7-Unsubstituted derivatives of III have not
been obtained by cycloaddition so far. The development of new synthetic strategies for
the synthesis of novel 5-aryl-1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-diones and their
2-thioxo analogs is, therefore, of significant relevance. 5-Arylidenebarbituric acid
derivatives II obtained by Knoevenagel condensation can also be easily reduced at the
exocyclic C¼C bond [9], so they can be considered as models of redox coenzymes such
ꢁ 2011 Verlag Helvetica Chimica Acta AG, Zꢂrich

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Helvetica Chimica Acta – Vol. 94 (2011)
as FAD and NAD, and used as oxidants for mild oxidation of alcohols [10] and thiols
[11].
Scheme 1. Synthesis of 5-Aryl-1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-diones and Their 2-Thioxo
Analogs via Consecutive Knoevenagel Condensation and Hetero-DielsꢀAlder Cycloaddition
Results and Discussion. – In the course of our research on novel antibacterial
compounds [12][13], we discovered an unexpected synthesis of novel 6,7-unsubstituted
5-aryl-1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-diones and their 2-thioxo analogues
3a – 3l in a catalyst-free, one-pot reaction, which was performed simply by heating
barbituric or 2-thiobarbituric acid with a benzaldehyde derivative, 1a – 1g, in EtOH/
H2O1). Application of microwave irradiation substantially reduced the reaction times
(from 3 d to ca. 1 – 2 h) but did not significantly influence the reaction yields (Table).
This is, to the best of our knowledge, the first domino Knoevenagel hetero-DielsꢀAlder
reaction in which both diene and dienophile are formed in situ. The conversion in fact
comprises two interconnected domino reaction sequences: i) a domino Knoevenagel
hetero-DielsꢀAlder reaction, and ii) a domino oxidation hetero-DielsꢀAlder reaction,
both converging in products 3a – 3l (Scheme 2). The sequences can thus be described as
convergent domino Knoevenagel hetero-DielsꢀAlder and domino oxidation hetero-
DielsꢀAlder reactions.
A
proposed mechanism for the reaction of barbituric (¼ pyrimidine-
2,4,6(1H,3H,5H)-trione) or 2-thiobarbituric acid (¼2,3-dihydro-2-thioxopyrimidine-
4,6(1H,5H)-dione) (2a and 2b, resp.) and substituted benzaldehydes 1a – 1g in EtOH/
H2O leading to 5-aryl-1H-pyrano[2,3-d]-pyrimidinones and 5-aryl-2,3-dihydro-2-thio-
xo-1H-pyrano-[2,3-d]pyrimidin-4(5H)-ones 3a – 3l is depicted in Scheme 3. First,
Knoevenagel condensation of an aromatic aldehyde 1a – 1g with 2a or 2b affords a 5-
benzylidenebarbituric acid A, which, due to its readily reducible exocyclic C¼C bond, is
responsible for oxidation of EtOH to acetaldehyde (MeCHO) [10]. It is noteworthy
that MeCHO enters the following reaction step in its enol form, B (R1 ¼ H). As a
dienophile, it reacts with A in a hetero-DielsꢀAlder reaction to give, after elimination
of H2O from intermediate C, the fused products 3a – 3l. Alternatively, formation of
ethyl vinyl ether, B (R1 ¼ Et) from MeCHO and EtOH, and elimination of EtOH from
1
)
So far, only 6- and 7-substituted derivatives of III have been obtained by cycloaddition. Only two
6,7-unsubstituted derivatives of III (R1 ¼ Me, R2 ¼ R3 ¼ H, Ar¼ Ph or 4-MeOꢀC6H4) are known.
They were obtained as side-products by elimination of a substituent at C(7) (see [3d]).

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861
Table. Synthesis of 5-Aryl-1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-diones and Their 2-Thioxo Analogs
3a – 3la)
Entry
1
R
2
X
Product
Yield [%]b)
Method A
Method B
1
2
3
4
5
6
7
8
9
1a
1b
1b
1c
1c
1d
1d
1e
1e
1f
1f
1g
H
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
S
O
S
O
S
O
S
O
S
O
S
3a
3b
3c
3d
3e
3f
3g
3h
3i
24
56
34
58
58
58
26
58
46
44
20
28
23
3-NO2
3-NO2
4-NO2
4-NO2
3-CN
3-CN
4-CN
4-CN
35c)
33
46
40
57c)
44
46
60
42c)
27
10
11
12
4-COOH
4-COOH
4-COOMe
3j
3k
3l
O
30
a) Reaction conditions: 1 (1 mmol), 2 (1 mmol), and EtOH/H2O 1 : 1, reflux, 3 d (Method A) or
microwave irradiation: 1208, 30 W, 40 min (Method B). b) Yield of isolated pure product; yields were
calculated considering that 100% yield corresponds to the conversion of 1 mmol of 1a – 1g to 0.5 mmol of
3a – 3l, which is in agreement with the reaction mechanism depicted in Scheme 3. c) Reaction time: 2 h.
Scheme 2. Formation of 5-Aryl-1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-diones and Their 2-Thioxo
Analogs by Convergent Domino Knoevenagel Hetero-DielsꢀAlder and Domino Oxidation Hetero-
DielsꢀAlder Reactions
intermediate C could be anticipated. A formal domino Knoevenagel hetero-Dielsꢀ
Alder reaction has been proposed previously for the reaction of ethyl vinyl ether with
various benzaldehydes and 1,3-dimethylbarbituric acid [3a]. An alternative mecha-

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Scheme 3. Mechanistic Proposal for the Synthesis of 5-Aryl-1H-pyrano[2,3-d]pyrimidinones and 5-Aryl-
2,3-dihydro-2-thioxo-1H-pyrano[2,3-d]-pyrimidin-4(5H)-ones 3a – 3l
nistic explanation for the formation of 3a – 3l could be a Michael addition of the enol
form of MeCHO at the 5-benzylidenebarbituric acid A, followed by the cyclization to C
and subsequent elimination of H2O (Scheme 4). Yields compiled in the Table were
calculated considering that 100% yield corresponds to the conversion of 1 mmol of
1a – 1g to 0.5 mmol of 3a – 3l, which is in agreement with the described reaction
mechanism. According to Yoneda et al. [10], the oxidizing ability of 5-benzylidene-
barbituric acids depends on the electron density in the C¼C bond and, hence, on the
number and strength of electron-withdrawing substituents on the aromatic ring. This
explains why the reaction proceeds well with nitro-, carboxy- and cyanobenzaldehydes,
but not with 4-hydroxybenzaldehyde. Although oxidation of several alcohols with 5-
arylidene-barbituric acids has been described [10], in our hands the reaction with other
alcohols (PrOH, i-PrOH) was not successful, indicating that steric factors in the
dienophile might play a role. To verify the proposed reaction mechanism, we heated 5-
(4-nitrobenzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione (A, R ¼ 4-NO2, X ¼ O) in
EtOH/H2O and obtained the product 3d in 30% yield, indicating that the Knoevenagel
condensation indeed occurs first. To confirm that the oxidation of EtOH to MeCHO
and the reduction of the exocyclic C¼C bond of 5-arylidene-barbituric acids take place
in the next step, we examined the reaction of 4-nitrobenzaldehyde and barbituric acid

Helvetica Chimica Acta – Vol. 94 (2011)
863
Scheme 4. Alternative Mechanism for the Synthesis of 3a – 3l
(2a) in EtOH/H2O. After filtering off the product 3d from the mixture, the reduced
derivative, 5-(4-nitrobenzyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4), was isolated from
the mother liquid by column chromatography. The reaction gave identical results under
Ar atmosphere, thus excluding a possible oxidation of EtOH2) by atmospheric O2.
Finally, we sought to establish whether MeCHO reacts with 5-(4-nitrobenzylidene)-
pyrimidine-2,4,6(1H,3H,5H)-trione (A; R ¼ 4-NO2, X ¼ O) in a hetero-DielsꢀAlder
reaction. To this end, 4-nitrobenzaldehyde and barbituric acid (2a) were reacted in pure
H2O at 1008 to give first 5-(4-nitrobenzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione (A;
R ¼ 4-NO2, X ¼ O). After subsequent addition of MeCHO, crystals formed in the
reaction mixture were filtered off and confirmed to be identical to product 3d. The
formation of 3d from 1c, 2a, and MeCHO in the absence of EtOH thus excludes the
intermediacy of ethyl vinyl ether (B; R1 ¼ Et). All these experiments support a three-
component convergent domino reaction mechanism for the formation of 5-aryl-1H-
pyrano[2,3-d]pyrimidinones and 5-aryl-2,3-dihydro-2-thioxo-1H-pyrano[2,3-d]pyri-
midin-4(5H)-ones 3a – 3l, comprising a hetero DielsꢀAlder reaction of 5-arylidene-
barbituric acid A with the enol of MeCHO, both formed in situ, as proposed in
Scheme 3.
Conclusions. – In conclusion, we have described the first convergent domino
Knoevenagel hetero-DielsꢀAlder and domino oxidation hetero-DielsꢀAlder reactions,
in which both diene and dienophile are formed in situ under the same reaction
conditions, and demonstrated their application in a surprising one-pot synthesis of
novel 6,7-unsubstituted 5-aryl-1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-diones and 5-
aryl-2,3-dihydro-2-thioxo-1H-pyrano[2,3-d]pyrimidin-4(5H)-ones 3a – 3l. Although, in
this particular case, the overall yields of products 3a – 3l were low, possibly due to
interference of competing reactions3), we assume that the reported strategy of
2
)
)
EtOH with less than 0.001% MeCHO content was used.
3
Acetaldehyde, which is formed in situ, can compete with benzaldehyde 1a – 1g for barbituric acids
2a and 2b as a substrate for the Knoevenagel reaction. Additionally, the Knoevenagel product A can
undergo Michael addition with a second molecule of barbituric acid.

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Helvetica Chimica Acta – Vol. 94 (2011)
generating both the diene and the dienophile in situ in two converging domino
processes could open new opportunities for sequential transformations which include
hetero-DielsꢀAlder reaction.
Experimental Part
General. All reagents were used as received from commercial sources without further purification
unless otherwise indicated. Anal. TLC: Merck silica gel (60 F254) plates (0.25 mm), components
visualized with UV light. Column chromatography (CC): silica gel 60 (particle size 240 – 400 mesh;
Merck). Microwave-assisted reactions were conducted in a sealed glass vessel (capacity 10 ml) on a CEM
Discover microwave synthesizer (CEM Corporation, USA) with a built-in pressure measurement sensor
and operator-selectable power output from 0 to 300 W. The temp. was monitored using an IR temp.
sensor mounted under the reaction vessel. All experiments were performed using a high-speed stirring
option. M.p.: Reichert hot stage microscope; uncorrected. IR Spectra: PerkinꢀElmer 1600 FT-IR
1
spectrometer. H- and 13C-NMR spectra: at 300 and 75 MHz, resp., on a Bruker AVANCE DPX300
spectrometer in (D6)DMSO or D2O with TMS as the internal standard at 258. Spectra were assigned
using gradient COSY, HSQC and DEPTexperiments. MS: VG Analytical Autospec Q mass spectrometer.
Microanalyses: Perkin-Elmer C,H,N analyzer 240 C. All reported yields are yields of purified products.
General Procedure for the Preparation of 5-Phenyl-1H-pyrano[2,3-d]pyrimidine-4(3H,5H)-ones and
Their 2-Thioxo Analogs 3a – 3l. Method A (Conventional Heating (i)). A suspension of benzaldehyde
1a – 1g (1.00 mmol) and barbituric or 2-thiobarbituric acid (2a or 2b, resp.; 1.00 mmol) in EtOH/H2O 1:1
(20 ml) was refluxed for 3 d, then the mixture was cooled to r.t., and the product was filtered off and
washed with EtOH.
Method B (Microwave-Assisted Synthesis (ii)). A suspension of benzaldehyde 1a – 1g (1.00 mmol),
and 2a or 2b (1.00 mmol) in EtOH/H2O 1:1 (3 ml) was heated in a sealed 10-ml glass vessel in a
microwave reactor for 1 – 2 h (Table) at 1208 (power, 30 W; ramp time, 3 min). The mixture was cooled to
r.t., and the product was filtered off and washed with EtOH.
1,2,3,5-Tetrahydro-5-phenyl-2-thioxo-4H-pyrano[2,3-d]pyrimidin-4-one (3a). Yield: 31 mg (24%i),
30 mg (23%ii). Orange crystals. M.p. 276 – 2798. IR (KBr): 3441, 3078, 2895, 1651, 1597, 1574, 1556, 1526,
1450, 1430, 1379, 1324, 1308, 1223, 1175, 1152, 998, 848, 787, 758, 687. 1H-NMR (300 MHz, (D6)DMSO):
7.49 – 7.51 (m, HꢀC(3’), HꢀC(4’), HꢀC(5’)); 7.68 – 7.71 (m, HꢀC(2’), HꢀC(6’)); 7.79 (d, 3J ¼ 15.3,
HꢀC(5)); 8.06 (d, 3J ¼ 12.0, HꢀC(7)); 8.45 (dd, 3J(5,6) ¼ 15.3, 3J(6,7) ¼ 12.0, HꢀC(6)); 12.31 (br. s, NH);
12.34 (br. s, NH). 13C-NMR (75 MHz, (D6)DMSO): 116.8; 125.5; 129.7; 130.2; 132.4; 136.2; 154.6; 155.5;
161.7 (arom. C, C¼O); 162.2 (arom. C, C¼O); 179.4 (C¼S). ESI-MS: 257 ([M ꢀ H]ꢀ). HR-MS: 257.0381
([M ꢀ H]ꢀ, C13H9N2O2Sꢀ; calc. 257.0385). Anal. calc. for C13H10N2O2S (258.30): C 60.45, H 3.90, N 10.85;
found: C 60.42, H 3.78, N 10.94.
1,5-Dihydro-5-(3-nitrophenyl)-2H-pyrano[2,3-d]pyrimidine-2,4(3H)-dione (3b). Yield: 80 mg
(56%i), 50 mg (35%ii). Yellow crystals. M.p. 286 – 2888. IR (KBr): 3527, 3185, 3056, 2836, 1743, 1668,
1600, 1562, 1520, 1438, 1413, 1377, 1359, 1322, 1304, 1216, 1172, 1107, 1008, 998, 810, 794, 754, 736.
1H-NMR (300 MHz, (D6)DMSO): 7.73 – 7.82 (m, HꢀC(5), HꢀC(5’)); 7.97 (d, 3J ¼ 11.7, HꢀC(7)); 8.09 (d,
3J ¼ 7.8, HꢀC(6’)); 8.25 – 8.28 (m, HꢀC(4’)); 8.40 (s, HꢀC(2’)); 8.49 (dd, 3J(5,6) ¼ 15.6, 3J(6,7) ¼ 11.7,
HꢀC(6)); 11.27 (br. s, NH); 11.31 (br. s, NH). 13C-NMR (75 MHz, (D6)DMSO): 118.3; 123.6; 125.8;
127.3; 131.7; 134.8; 137.8; 149.2; 149.8; 151.2; 153.1; 163.7 (C¼O); 163.8 (C¼O). ESI-MS: 286 ([M ꢀ
H]ꢀ). HR-MS: 286.0476 ([M ꢀ H]ꢀ, C13H8N3O5ꢀ ; calc. 286.0464). Anal. calc. for C13H9N3O5 (287.23):
C 54.36. H 3.16, N 14.63; found: C 54.15, H 3.11, N 14.64.
1,2,3,5-Tetrahydro-5-(3-nitrophenyl)-2-thioxo-4H-pyrano[2,3-d]pyrimidin-4-one (3c). Yield: 52 mg
(34%i), 50 mg (33%ii). Yellow crystals. M.p. > 3508. IR (KBr): 3487, 3091, 2893, 2595, 1706, 1674, 1599,
1532, 1452, 1435, 1373, 1351, 1320, 1292, 1224, 1211, 1172, 1152, 1100, 1002, 880, 812, 785, 736, 666.
3
3
3
1H-NMR (300 MHz, (D6)DMSO): 7.78 (t, J ¼ 7.8, HꢀC(5’)); 7.88 (d, J ¼ 15.6, HꢀC(5)); 8.02 (d, J ¼
3
4
11.7, HꢀC(7)); 8.14 (d, J ¼ 7.8, HꢀC(6’)); 8.28 – 8.31 (m, HꢀC(4’)); 8.44 (t, J ¼ 1.8, HꢀC(2’)); 8.52 (dd,
3J(5,6) ¼ 15.6, 3J(6,7) ¼ 11.7, HꢀC(6)); 12.38 (br. s, NH); 12.41 (br. s, NH). 13C-NMR (75 MHz,
(D6)DMSO): 118.4; 123.8; 126.0; 127.5; 131.7; 135.0; 137.7; 149.2; 150.7; 154.0; 161.5 (arom. C, C¼O);

Helvetica Chimica Acta – Vol. 94 (2011)
865
162.0 (arom. C, C¼O); 179.5 (C¼S). ESI-MS: 302 ([M ꢀ H]ꢀ). HR-MS: 302.0244 ([M ꢀ H]ꢀ,
C13H8N3O4Sꢀ; calc. 302.0236). Anal. calc. for C13H9N3O4S (303.29): C 51.48, H 2.99, N, 13.85; found:
C 51.33, H 2.96, N 13.75.
1,5-Dihydro-5-(4-nitrophenyl)-2H-pyrano[2,3-d]pyrimidine-2,4(3H)-dione (3d). Yield: 83 mg
(58%i), 66 mg (46%ii). Yellow crystals. M.p. > 3508. IR (KBr): 3526, 3176, 3030, 2878, 1756, 1715,
1668, 1590, 1568, 1520, 1447, 1417, 1374, 1336, 1318, 1224, 1172, 1001, 844, 794, 754, 748. 1H-NMR
3
3
3
(300 MHz, (D6)DMSO): 7.79 (d, J ¼ 15.6, HꢀC(5)); 7.90 (d, J ¼ 8.7, HꢀC(2’), HꢀC(6’)); 8.00 (d, J ¼
11.7, HꢀC(7)); 8.30 (d, 3J ¼ 8.7, HꢀC(3’), HꢀC(5’)); 8.53 (dd, 3J(5,6) ¼ 15.6, 3J(6,7) ¼ 11.7, HꢀC(6));
11.29 (br. s, NH); 11.33 (br. s, NH). 13C-NMR (75 MHz, (D6)DMSO): 118.8; 125.2 (C(3’), C(5’)); 128.7
(C(6)); 130.2 (C(2’), C(6’)); 142.3; 148.9; 149.4 (C(5)); 151.1; 152.7 (C(7)); 163.6 (C¼O); 163.7 (C¼O).
EI-MS: 287 (Mþ, 100), 270 (42), 257 (8), 240 (13). HR-MS: 287.0550 (Mþ, C13H9N3Oþ5 ; calc. 287.0542).
Anal. calc. for C13H9N3O5 (287.23): C 54.36, H 3.16, N 14.63; found: C 54.30, H 3.06, N 14.78.
1,2,3,5-Tetrahydro-5-(4-nitrophenyl)-2-thioxo-4H-pyrano[2,3-d]pyrimidin-4-one (3e). Yield: 88 mg
(58%i), 61 mg (40%ii). Orange crystals. M.p. > 3508. IR (KBr): 3488, 3075, 2887, 2592, 2441, 1711, 1665,
1593, 1564, 1520, 1446, 1416, 1379, 1340, 1315, 1296, 1214, 1172, 995, 841, 786, 746. 1H-NMR (300 MHz,
(D6)DMSO): 7.85 (d, 3J ¼ 15.3, HꢀC(5)), 7.92 (d, 3J ¼ 9.0, HꢀC(2’), HꢀC(6’)); 8.03 (d, 3J ¼ 11.7, HꢀC(7));
3
3
8.31 (d, J ¼ 9.0, HꢀC(3’), HꢀC(5’)); 8.54 (dd, J(5,6) ¼ 15.3, 3J(6,7) ¼ 11.7, HꢀC(6)); 12.38 (br. s, NH);
12.41 (br. s, NH). 13C-NMR (75 MHz, (D6)DMSO): 118.8; 125.2; 128.9; 130.4; 142.2; 149.0; 150.3; 153.6;
161.5 (arom. C, C¼O); 162.0 (arom. C, C¼O); 179.5 (C¼S). ESI-MS: 302 ([M ꢀ H]ꢀ). HR-MS: 302.0243
([M ꢀ H]ꢀ, C13H8N3O4Sꢀ; calc. 302.0236). Anal. calc. for C13H9N3O4S (303.29): C 51.48, H 2.99, N 13.85;
found: C 51.37, H 2.81, N 13.83.
3-(1,3,4,5-Tetrahydro-2,4-dioxo-2H-pyrano[2,3-d]pyrimidin-5-yl)benzonitrile (3f). Yield: 77 mg
(58%i), 76 mg (57%ii). Yellow crystals. M.p. 308 – 3108. IR (KBr). 3526, 3384, 3252, 2845, 2492, 2232
(CN), 1731, 1690, 1603, 1558, 1427, 1397, 1366, 1314, 1292, 1211, 1176, 1040, 1005, 956, 837, 793, 758, 676.
3
1H-NMR (300 MHz, (D6)DMSO): 7.65 – 7.70 (m, HꢀC(5), HꢀC(5’)); 7.89 (d, J ¼ 7.5, HꢀC(4)); 7.94 –
7.98 (m, HꢀC(6), HꢀC(7’)); 8.08 (s, HꢀC(2)); 8.45 (dd, 3J(5,6) ¼ 15.6, 3J(6,7) ¼ 11.7, HꢀC(6’)); 11.26
(br. s, NH); 11.30 (br. s, NH). 13C-NMR (75 MHz, (D6)DMSO): 113.3; 118.1; 119.1; 127.0; 131.3; 132.9;
133.3; 134.7; 137.3; 150.1; 151.2; 153.3; 163.6 (C¼O); 163.8 (C¼O). ESI-MS: 266 ([M ꢀ H]ꢀ). HR-MS:
266.0570 ([M ꢀ H]ꢀ, C14H8N3O3ꢀ ; calc. 266.0566). Anal. calc. for C14H9N3O3 (267.24): C 62.92, H 3.39, N
15.72; found: C 62.62, H 3.26, N 15.62.
3-(1,3,4,5-Tetrahydro-4-oxo-2-thioxo-2H-pyrano[2,3-d]pyrimidin-5-yl)benzonitrile (3g). Yield:
37 mg (26%i), 62 mg (44%ii). Orange crystals. M.p. 285 – 2898. IR (KBr): 3560, 3254, 3125, 3084, 3017,
2891, 2571, 2234 (CN), 1708, 1674, 1595, 1553, 1525, 1434, 1380, 1314, 1296, 1242, 1216, 1184, 1144, 997,
1
3
3
844, 817, 786, 734, 674. H-NMR (300 MHz, (D6)DMSO): 7.69 (t, J ¼ 7.8, HꢀC(5)); 7.76 (d, J ¼ 15.6,
HꢀC(5’)); 7.93 (d, 3J ¼ 7.8, HꢀC(4)); 7.99 – 8.03 (m, HꢀC(6), HꢀC(7’)); 8.13 (s, HꢀC(2)); 8.47 (dd,
3J(5,6) ¼ 15.6, 3J(6,7) ¼ 11.7, HꢀC(6’)); 12.36 (br. s, NH); 12.39 (br. s, NH). 13C-NMR (75 MHz,
(D6)DMSO): 113.3; 118.2; 119.1; 127.3; 131.3; 133.1; 133.4; 135.0; 137.3; 151.1; 154.2; 161.5 (arom. C,
C¼O); 162.0 (arom. C, C¼O); 179.5 (C¼S). ESI-MS: 282 ([M ꢀ H]ꢀ). HR-MS: 282.0336 ([M ꢀ H]ꢀ,
C14H8N3O2Sꢀ; calc. 282.0337). Anal. calc. for C14H9N3O2S (283.31): C 59.35, H 3.20, N 14.83; found: C
58.95, H 3.12, N 14.66.
4-(1,3,4,5-Tetrahydro-2,4-dioxo-2H-pyrano[2,3-d]pyrimidin-5-yl)benzonitrile (3h). Yield: 77 mg
(58%i), 61 mg (46%ii). Yellow crystals. M.p. 316 – 3188. IR (KBr): 3613, 3350, 3055, 2827, 2228 (CN),
1
1732, 1693, 1556, 1417, 1372, 1322, 1300, 1209, 1168, 1004, 871, 846, 824, 792, 756. H-NMR (300 MHz,
(D6)DMSO): 7.74 (d, 3J ¼ 15.6, HꢀC(5’)); 7.83 (d, 3J ¼ 8.4, HꢀC(2), HꢀC(6)); 7.93 (d, 3J ¼ 8.4, HꢀC(3),
HꢀC(5)); 7.99 (d, 3J ¼ 11.7, HꢀC(7’)); 8.50 (dd, 3J(5,6) ¼ 15.6, 3J(6,7) ¼ 11.7, HꢀC(6’)); 11.27 (br. s, NH);
11.31 (br. s, NH). 13C-NMR (75 MHz, (D6)DMSO): 113.3; 118.4; 119.4; 128.0; 129.8; 133.8; 140.4; 150.1;
151.1; 153.0; 163.6 (C¼O); 163.7 (C¼O). ESI-MS: 266 ([M ꢀ H]ꢀ). HR-MS: 266.0570 ([M ꢀ H]ꢀ,
C14H8N3Oꢀ3 ; calc. 266.0566). Anal. calc. for C14H9N3O3 (267.24): C 62.92, H 3.39, N 15.72; found: C 62.67,
H 3.30, N 15.68.
4-(1,3,4,5-Tetrahydro-4-oxo-2-thioxo-2H-pyrano[2,3-d]pyrimidin-5-yl)benzonitrile (3i). Yield:
65 mg (46%i), 85 mg (60%ii). Orange crystals. M.p. 310 – 3138. IR (KBr): 3364, 3271, 3087, 3017, 2887,
2584, 2224 (CN), 1682, 1599, 1531, 1447, 1413, 1369, 1318, 1279, 1227, 1201, 1166, 1145, 1003, 826, 801, 657.
3
3
1H-NMR (300 MHz, (D6)DMSO): (d, J ¼ 15.6, HꢀC(5’)); 7.84 (d, J ¼ 8.4, HꢀC(2), HꢀC(6)); 7.93 (d,

866
Helvetica Chimica Acta – Vol. 94 (2011)
3J ¼ 8.4, HꢀC(3), HꢀC(5)); 8.02 (d, 3J ¼ 11.7, HꢀC(7’)); 8.50 (dd, 3J(5,6) ¼ 15.6, 3J(6,7) ¼ 11.7, HꢀC(6’));
12.37 (br. s, NH); 12.40 (br. s, NH). 13C-NMR (75 MHz, (D6)DMSO): 113.5; 118.6; 119.4; 128.3; 129.9;
133.9; 140.4; 151.1; 153.8; 161.5 (arom. C, C¼O); 162.0 (arom. C, C¼O); 179.5 (C¼S). ESI-MS: 282
([M ꢀ H]ꢀ). HR-MS: 282.0349 ([M ꢀ H]ꢀ, C14H8N3O2Sꢀ; calc. 282.0337). Anal. calc. for C14H9N3O2S
(283.31): C 59.35, H 3.20, N 14.83; found: C 59.26, H 3.11, N 14.78.
4-(1,3,4,5-Tetrahydro-2,4-dioxo-2H-pyrano[2,3-d]pyrimidin-5-yl)benzoic Acid (3j). Yield: 63 mg
(44%i), 60 mg (42%ii). Yellow crystals. M.p. > 3508. IR (KBr): 3550, 3284, 3054, 2847, 2652, 2519, 1731,
1694, 1607, 1598, 1568, 1549, 1506, 1440, 1415, 1383, 1319, 1295, 1238, 1214, 1175, 1113, 1052, 1013, 961,
848, 827, 790, 767. 1H-NMR (300 MHz, (D6)DMSO): 7.73 – 7.78 (m, HꢀC(3), HꢀC(5), HꢀC(5’)); 8.00 –
8.04 (m, HꢀC(2), HꢀC(6), HꢀC(7’)); 8.50 (dd, 3J(5,6) ¼ 15.6, 3J(6,7) ¼ 11.7, HꢀC(6’)); 11.25 (br. s, NH);
11.29 (br. s, NH); 13.14 (br. s, COOH). 13C-NMR (75 MHz, (D6)DMSO): 117.8; 127.1; 129.4; 130.9;
133.2; 140.1; 151.2; 151.4; 153.6; 163.7 (C¼O); 163.9 (C¼O); 167.6 (C¼O). ESI-MS: 285 ([M ꢀ H]ꢀ).
HR-MS: 285.0501 ([M ꢀ H]ꢀ, C14H9N2O5ꢀ ; calc. 285.0511). Anal. calc. for C14H10N2O5 (286.24): C 58.74,
H 3.52, N 9.79; found: C 58.46, H 3.43, N 9.66.
4-(1,3,4,5-Tetrahydro-4-oxo-2-thioxo-2H-pyrano[2,3-d]pyrimidin-5-yl)benzoic Acid (3k). Yield:
30 mg (20%i), 41 mg (27%ii). Orange crystals. M.p. > 3508. IR (KBr): 3360, 3148, 3092, 2888, 2668,
1
2541, 1693, 1660, 1607, 1555, 1532, 1417, 1380, 1300, 1224, 1172, 1147, 1104, 998, 847, 787, 766. H-NMR
(300 MHz, (D6)DMSO): 7.77 – 7.84 (m, HꢀC(3), HꢀC(5), HꢀC(5’)); 8.01 – 8.07 (m, HꢀC(2), HꢀC(6),
HꢀC(7’)); 8.51 (dd, 3J(5,6) ¼ 15.6, 3J(6,7) ¼ 12.0, HꢀC(6’)); 12.35 (br. s, NH); 12.38 (br. s, NH); 13.15 (br.
s, COOH). 13C-NMR (75 MHz, (D6)DMSO): 118.0; 127.4; 129.6; 131.0; 133.4; 140.0; 152.4; 154.5; 161.6
(arom. C, C¼O); 162.1 (arom. C, C¼O); 167.6 (C¼O); 179.5 (C¼S). ESI-MS: 301 ([M ꢀ H]ꢀ). HR-MS:
301.0290 ([M ꢀ H]ꢀ, C14H9N2O4Sꢀ; calc. 301.0283). Anal. calc. for C14H10N2O4S (302.31): C 55.62, H 3.33,
N 9.27; found: C 55.27, H 3.35, N 8.95.
Methyl 4-(1,3,4,5-Tetrahydro-2,4-dioxo-2H-pyrano[2,3-d]pyrimidin-5-yl)benzoate (3l). Yield: 42 mg
(28%i), 45 mg (30%ii). Yellow crystals. M.p. 296 – 3008. IR (KBr): 3468, 3218, 3079, 2957, 2809, 1739,
1694, 1716, 1678, 1606, 1427, 1379, 1309, 1279, 1264, 1213, 1179, 1106, 1000, 958, 827, 766, 696. 1H-NMR
(300 MHz, (D6)DMSO): 3.88 (s, Me); 7.73 – 7.81 (m, HꢀC(3), HꢀC(5), HꢀC(5’)); 8.00 – 8.06 (m,
3
3
HꢀC(2), HꢀC(6), HꢀC(7’)); 8.51 (dd, J(5,6) ¼ 15.6, J(6,7) ¼ 12.0, HꢀC(6’)); 11.26 (br. s, NH); 11.30
(br. s, NH); 13.14 (br. s, COOH). 13C-NMR: compound could not be dissolved in sufficient concentration
in any known solvent. ESI-MS: 299 ([M ꢀ H]ꢀ). HR-MS: 299.0670 ([M ꢀ H]ꢀ, C15H11N2Oꢀ5 ; calc.
299.0668). Anal. calc. for C15H12N2O5 (300.27): C 60.00, H 4.03, N 9.33; found: C 59.79, H 3.88, N 9.34.
5-(4-Nitrobenzyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4). Yield: 42 mg (32%). Orange crystals. M.p.
> 3008 ([14]: 265 – 2668). IR (KBr): 3427, 3157, 3013, 2928, 2853, 1674, 1654, 1616, 1508, 1490, 1387, 1368,
1350, 1175, 1111, 860, 834, 807, 774, 700. 1H-NMR (300 MHz, (D6)DMSO): 3.49 (s, CH2); 7.45 (d, 3J ¼ 8.7,
HꢀC(2), HꢀC(6)); 8.05 (d, 3J ¼ 8.7, HꢀC(3), HꢀC(5)); 9.08 (br. s, NH); signal for CH not seen.
13C-NMR (75 MHz, D2O þ 10 ml 40% NaOD): 28.4 (CH2); 89.0 (CH); 123.2 (arom. C); 128.2 (arom. C);
145.2 (arom. C); 151.7 (arom. C); 159.5 (C¼O); 171.3 (C¼O). ESI-MS: 262 ([M ꢀ H]ꢀ). HR-MS:
262.0461 ([M ꢀ H]ꢀ, C11H8N3Oꢀ5 ; calc. 262.0464).
Preparation of 3d from 5-(4-Nitrobenzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione. 5-(4-Nitroben-
zylidene)pyrimidine-2,4,6(1H,3H,5H)-trione (100 mg, 383 mmol) was heated to reflux for 3 d in EtOH/
H2O 1:1 (20 ml), then the mixture was cooled to r.t., and the product filtered off and washed with EtOH
to afford 22 mg (20%) of yellow crystals. The product was identical to the one obtained according to the
General Procedure for the preparation of 3a – 3l.
Preparation of 3d from MeCHO. 4-Nitrobenzaldehyde (250 mg, 1.65 mmol) and barbituric acid (2a;
212 mg, 1.65 mmol) were dissolved in H2O (40 ml) at 1008, the soln. was cooled to r.t., and acetaldehyde
(280 ml, 4.96 mmol) was added. The mixture was heated at 1008 for 1 h, and the product was filtered off,
and washed with H2O and EtOH to give 309 mg (65%) of yellow crystals. The product was identical to
the one obtained according to the General Procedure for the preparation of 3a – 3l.
This work was supported by the EU FP6 Project EUR-INTAFAR (LSHM-CT-2004-512138) and by
the Slovenian Research Agency (Grant P1-0208).

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Received August 27, 2010