5-Aminouracil as a building block in heterocyclic synthesis, Part II. One-pot synthesis of pyrido[3,2-d:6,5-d] dipyrimidines under microwave irradiation without catalyst

Article abstract of DOI:10.1515/znb-2009-1013

An efficient and direct procedure for the synthesis of pyrido[3,2-d:6,5-d'] dipyrimidine derivatives under microwave-assisted conditions is been described. The structures of the products were characterized by elemental analyses, and their IR, ¹

Full text of DOI:10.1515/znb-2009-1013

5-Aminouracil as a Building Block in Heterocyclic Synthesis, Part II.
One-pot Synthesis of Pyrido[3,2-d:6,5-dꢀ]dipyrimidines under Microwave
Irradiation without Catalyst
Raafat M. Shaker, Mohamed A. Ameen, Afaf M. Abdel Hameed,
and Mohamed Abd Elrady
Chemistry Department, Faculty of Science, Minia University, 61519 El-Minia, Egypt
Reprint requests to Prof. Dr. Raafat M. Shaker. Fax: +20862363011. E-mail: rmshaker@yahoo.com
Z. Naturforsch. 2009, 64b, 1193 – 1198; received June 30, 2009
An efficient and direct procedure for the synthesis of pyrido[3,2-d:6,5-dꢀ]dipyrimidine derivatives
under microwave-assisted conditions is been described. The structures of the products were charac-
terized by elemental analyses, and their IR, 1H NMR, 13C NMR, and MS spectra.
Key words: 5-Aminouracil, Barbituric Acid, Thiobarbituric Acid, Microwave Irradiation,
Pyrido[3,2-d:6,5-dꢀ]dipyrimidine
Introduction
Considering the above reports in conjunction with
our recent work on the synthesis of polyheterocyclic
systems [19 – 30], we wish to report a novel, effi-
cient, one-pot and three-component method for the
preparation of pyrido[3,2-d:6,5-dꢀ]dipyrimidines un-
der microwave-assisted conditions.
The derivatives of fused pyrimidines are valued not
only for their rich and varied chemistry, but also for
many important biological properties [1 – 3]. Among
them, the pyridodipyrimidines (PDP) have been shown
to exhibit antibacterial and antiviral properties [4, 5]
as well as NAD-type redox catalytic activity [6 – 10].
A few methods are reported in the literature for
the preparation of pyrido[2,3-d:6,5-dꢀ]dipyrimidine-
2,4,6,8-tetrones [4 – 18], but to the best of our knowl-
edge, there are no reports in the literature for the
formation of pyrido[3,2-d:6,5-dꢀ]dipyrimidine-2,4,6,8-
tetrones.
Recently, we described a new, simple and efficient
synthesis of 6,7,8,10-tetrahydropyrimido[5,4-b]quin-
oline-2,4,9-(1H,3H,5H)-triones (4) [19], by the reac-
tion of 5-aminouracil (1), benzaldehyde derivatives 2
and dimedone (3) under microwave irradiation without
catalyst, which could have interesting effects on bio-
logical targets (Scheme 1).
Results and Discussion
The synthesis of 10-aryl-pyrido[3,2-d:6,5-dꢀ]dipyr-
imidin-2,4,7,9-tetrones 6a – e through a one-pot reac-
tion of 5-aminouracil (1), benzaldehydes 2 and bar-
bituric acid (5) was accomplished under microwave
irradiation (method A), as shown in Scheme 2. The
molecular structures of the pyridodipyrimidines 6a –
e were supported on the basis of elemental and spec-
tral analyses, which were found to be in good agree-
ment with the assigned structures. For example, com-
pound 6e exhibits an IR spectrum with strong ab-
sorption bands at 3402 and 3189 cm−1, belonging to
stretching vibrations of the NH groups, and a carbonyl
absorption band at 1706 cm−1. Its 1H NMR spec-
trum revealed four characteristic, relatively sharp sin-
glets at 11.79, 11.67, 11.21 and 8.96 ppm due to NH
groups, in addition to the methoxy and phenyl pro-
tons at 3.83 and 7.00 – 7.16 ppm, respectively. The 13
C
NMR spectrum also agreed with the proposed struc-
ture 6e. Moreover, the mass spectrum of 6e exhib-
ited a molecular ion peak at m/z = 353 (100%), and
other significant peaks were as expected. Structural
Scheme 1. Synthesis of 6,7,8,10-tetrahydropyrimido[5,4-b]-
quinolinetriones 4.
c
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R. M. Shaker et al. · 5-Aminouracil as a Building Block in Heterocyclic Synthesis
a, R = H; b, R = 4-Cl; c, R = 4-F; d R = 2,4-Cl2; e, R =
4 -OCH3.
Scheme 3. Synthesis of pyrido[3,2-d:6,5-dꢀ]dipyrimidines
12.
(C-Ar, C-6ꢀ), 145.38 (C-Ar, C-4ꢀ), 149.92 (C-Ar, C-2ꢀ),
150.15 (C-Ar, C1ꢀ), 150.37 (C-5a), 159.00 (C-2 and
C-7), and 162.82 (C-4 and C-9). The structure proof
of 9 was further supported by an alternative synthe-
sis. Thus, the two-component condensation of 1 and
arylidenebarbiturates 7a, b in equimolar proportions in
DMF under reflux also afforded 9a, b (Scheme 2). Re-
fluxing 9 in DMF for 2 – 6 h gave the pyrido[3,2-d:6,5-
dꢀ]dipyrimidines 6 in excellent yields (Scheme 2). Ac-
a, R = H; b, R = 4-Cl; c, R = 4-F; d R = 2,4-Cl2; e, R =
4 -OCH3
cording to this results, the reaction can mechanistically
be considered to proceed via the initial formation of
arylidenebarbiturates 7, which suffer a Michael addi-
tion of the aminouracil 1 to the C=C bond of 7. The
Michael adducts 8 undergo intramolecular cyclization
through elimination of a molecule of water to afford
the final products 9 which by air oxidation afford 6
(Scheme 2). The disappearance of 10-H and 5-NH in
the 1H NMR spectra indicated that only these protons
were removed from 9.
Scheme 2. Synthesis of pyrido[3,2-d:6,5-dꢀ]dipyrimidines 6
and 9.
proof was obtained through a two-component conden-
sation of 1 with 5-arylidenebarbiturates 7a, b [31, 32]
in equimolar proportions under the previous conditions
(method B).
For the investigation of the reaction mechanism, it is
notable that, when 5-aminouracil, benzaldehydes and
barbituric acid were refluxed in DMF for 2 – 5 h, the
As an extension of our synthetic methodology, 5-
intermediate 9 was formed, which was isolated and aminouracil (1), benzaldehydes 2 and thiobarbituric
characterized by spectroscopic methods. The struc- acid (10) were also exposed to MW irradiation. The re-
ture of compound 9d was confirmed by its elemen- actions proceeded similarly to give 12a – e (Scheme 3).
tal and spectral analyses, which showed the molecular The molecular formula of compounds 12a – e is sup-
1
ion peak at m/z = 394.41 (6.5 %). Its H NMR spec- ported by elemental analyses and mass spectra that
trum showed characteristic singlets at δ = 8.40, 9.88 gave the expected molecular ion peaks at m/z = 407.44
and 11.52 for three NH groups, a broad singlet at δ = (90 %), and other significant peaks were as expected.
10.64 for two NH groups, a singlet at δ = 4.74 due The IR, 1H NMR as well as the 13C NMR spec-
to 10-H, in addition to the multiplet signals for the tra agreed with the proposed structures 12a – e. For
phenyl protons at δ = 7.23– 7.58 ppm. Moreover, the example, the IR spectrum of 12d showed absorp-
13C NMR spectrum of 9d showed signals at δC = 36.26 tion bands at 3360, 3220 (NH) and 1730, 1652 cm−1
(C-10), 83.86 (C-9a), 110.95 (C-4a), 128.52 (C-10a), (CO groups). Its 1H NMR spectrum characteristi-
131.10 (C-Ar, C-5ꢀ), 136.49 (C-Ar, C-3ꢀ), 144.42 cally revealed four relatively sharp singlets at δ =
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R. M. Shaker et al. · 5-Aminouracil as a Building Block in Heterocyclic Synthesis
Experimental Section
1195
General procedures
Melting points were measured with a Gallenkamp appa-
ratus and are uncorrected. The reactions and purity were
monitored by thin layer chromatography (TLC) on alu-
minum plates coated with silica gel with fluorescent indica-
tor (Merck, 60 F254) using CHCl3/CH3OH (5:2) as eluent.
Microwave irradiation was carried out using a commercial
microwave oven (KOR-131G, 1350 W). The infrared spec-
tra were recorded in potassium bromide disks on a Jasco
FT/IR-450 Plus infrared spectrophotometer. The NMR spec-
tra were obtained on a JHA-LAA 400 WB-FT spectrom-
eter (400 MHz for 1H NMR, 100 MHz for 13C NMR),
with deuterated chloroform (CDCl3) or dimethylsulfoxide
([D6]DMSO) as solvent. Chemical shifts are quoted in δ and
are referenced to TMS or the solvent signal. The mass spec-
tra were recorded on a Trace GC 2000 / Finnigan Mat SSQ
7000 and a Shimadzu GCMS-QP-1000EX mass spectrome-
ter at 70 eV. Elemental analyses were carried out at the Mi-
croanalytical Center of Cairo University.
Synthesis of 10-aryl-pyrido[3,2-d:6,5-dꢀ]dipyrimidin-
2,4,7,9-tetrones 6a – e
Method A: These compounds were prepared by reaction
of 1 with the appropriate benzaldehyde derivatives 2 and bar-
bituric acid (5), which were placed in an open Pyrex-glass
vessel and irradiated in a microwave oven with a power of
1000 Watt for 7 – 11 min using DMF (1 mL) as energy trans-
fer medium. The resulting product was left to cool to r. t., col-
lected by filtration, dried and crystallized from DMF/EtOH.
Method B: A mixture of 1 mmol of 1 and 1 mmol of 7a,
b was placed in an open Pyrex-glass vessel and irradiated
in a microwave oven with 1000 Watt power for 6 – 10 min
using DMF (1 mL) as energy transfer medium. The resulting
mixture was left to cool to r. t., and the solid product was then
collected by filtration and crystallized from DMF/EtOH.
Scheme 4. Synthesis of pyrido[3,2-d:6,5-dꢀ]dipyrimidines
6b, d or 12b, d from Schiff base 13a, b.
8.20, 10.90, 11.58 and at 12.11 ppm assigned to the
four NH groups, in addition to the signals for the
phenyl protons. Structural proof of 12 was obtained
through another route of synthesis by refluxing 5-
arylidene-thiobarbiturates 11a, b [33] with 1 in DMF
(Scheme 3).
However, other reaction pathways cannot be ruled
out. One of these includes the initial formation of
Schiff base 13 [19]. Hence, the structures of 6 and
12 were confirmed further by the reaction of Schiff
base 13 with 5 or 10 under the previous conditions
(Scheme 4). No alternative products like 15 were de-
tected. The formation of 6 or 12 may have taken place
through addition of the barbituric acid to the C=N
function of the Schiff base 13 to form the adduct
14. Subsequent elimination of the 5-aminouracil moi-
ety, rather than cyclization to the dipyrimidines 15,
afforded the adduct 7 and/or 11, which by reaction
with 1 gave 6b, d and 12b, d, respectively. These
products were identical in all aspects with the corre-
sponding compounds obtained by three-component re-
actions. According to the TLC data, under these condi-
tions compound 13 decomposes to the initial amine 1
and aldehyde 2.
10-Phenyl-1,3,6,8-tetrahydropyrido[3,2-d:6,5-dꢀ ]dipyrimid-
ine-2,4,7,9-tetrone (6a)
Yellow crystals, (yield: method A: 88 %; method B:
80 %), m. p. 339 – 341 ◦C. – IR (film): ν = 3338, 3275,
3177, 1708, 1617 cm−1. – 1H NMR (400 MHz, [D6]DMSO,
TMS): δ = 7.12 – 7.25 (m, 5H, ArH), 9.60 (s, 1H, NH), 10.3
(s, 1H, NH), 10.71 (s, 1H, NH), 11.52 (s, 1H, NH). – MS (EI,
70 eV): m/z (%) = 323.3 (75) [M]+, 246.12 (90) [M–C6H5]+
77.09 (7). – Anal. for C15H9N5O4: calcd. C 55.73, H 2.81,
N 21.66; found C 55.62, H 2.71, N 21.54.
10-(4-Chlorophenyl)-1,3,6,8-tetrahydropyrido[3,2-d:6,5-
dꢀ]dipyrimidine-2,4,7,9-tetrone (6b)
Pale-brown crystals (yield: method A: 85 %; method B:
88 %), m. p. 350 – 354 ◦C. – IR (film): ν = 3360, 3190,
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R. M. Shaker et al. · 5-Aminouracil as a Building Block in Heterocyclic Synthesis
3073, 1712, 1612 cm−1. – 1H NMR (400 MHz, [D6]DMSO, was concentrated, and the product obtained was recrystal-
TMS): δ = 7.15 – 7.44 (m, 4H, ArH), 9.63 (s, 1H, 1NH), lized from DMF.
10.21 (s, 1H, 1NH), 11.11 (brs, 2H, 2NH). – MS (EI,
70 eV): m/z (%) = 359.31 (21), 357.13 (79) [M]+. – Anal.
for C15H8ClN5O4: calcd. C 50.37, H 2.25, N 19.58; found
C 50.28, H 2.17, N 19.67.
Method B: A Solution of equimolar amounts of 1 and 7a,
b in DMF (3 mL) was refluxed for 2 – 6 h (TLC control).
Products 9a, b were isolated as described above.
10-Phenyl-1,3,5,6,8,10-hexahydropyrido[3,2-d:6,5-dꢀ ]di-
10-(4-Fluorophenyl)-1,3,6,8-tetrahydro-pyrido[3,2-d:6,5-
pyrimidine-2,4,7,9-tetrone (9a)
dꢀ]dipyrimidine-2,4,7,9-tetrone (6c)
Pale-yellow crys◦tals (yield: method A: 80 %; method B:
76 %), m. p. > 360 C. – IR (film): ν = 3345, 3273, 3186,
1704, 1617 cm−1. – 1H NMR (400 MHz, [D6]DMSO,
TMS): δ = 4.73 (s, 1H, 10-H), 7.23 – 7.35 (m, 5H, ArH), 8.33
(s, 1H, NH), 9.85 (s, 1H, NH), 10.59 (s, 1H, NH), 10.88 (s,
1H, NH), 11.47 (s, 1H, NH). – MS (EI, 70 eV): m/z (%) =
325.3 (60) [M]+, 323.1 (20.0) [M–2]+, 248.4 (95.0) [M–
C6H5]+. – Anal. for C15H11N5O4: calcd. C 55.39, H 3.41,
N 21.53; found C 55.27, H 3.34 N 21.45.
Pale-brown crystals (yield: method A: 91 %; method B:
85 %), m. p. 340 – 341 ◦C. – IR (film): ν = 3343, 3378, 3179,
3014, 1703, 1663 cm−1. – 1H NMR (400 MHz, [D6]DMSO,
TMS): δ = 7.19 – 7.35 (m, 5H, ArH), 8.64 (s, 1H, 2NH),
10.59 (s, 1H, 1NH), 11.43 (brs, 2H, 2NH). – MS (EI, 70 eV):
m/z (%) = 341.21 (90) [M]+. – Anal. for C15H8FN5O4:
calcd. C 52.48, H 2.94, N 20.40; found C 52.41, H 2.87,
N 20.31.
10-(2,4-Dichlorophenyl)-1,3,6,8-tetrahydropyrido[3,2-
10-(4-Chlorophenyl)-1,3,5,6,8,10-hexahydropyrido[3,2-d:
d:6,5-dꢀ]dipyrimidine-2,4,7,9-tetrone (6d)
6,5-dꢀ]dipyrimidine-2,4,7,9-tetrone (9b)
Brown ◦crystals (yield: method A: 96 %; method B: 91 %),
m. p. 285 C (decomp.). – IR (film): ν = 3387, 3317, 3130,
3010, 1725, 1670, 1629 cm−1. – 1H NMR (400 MHz,
[D6]DMSO, TMS): δ = 7.20 – 7.25 (m, 1H, ArH), 7.49 – 4.73 (s, 1H, 10-H), 7.19 – 7.23 (m, 2H, ArH), 7.33 (s, 1H,
7.55 (m, 2H, ArH), 9.66 (s, 1H, NH), 10.98 (brs, 2H,
Yellow cr◦ystals (yield: method A: 76 %; method B: 71 %),
m. p. > 360 C. – IR (film): ν = 3354, 3175, 3062, 1712,
1614 cm−1. – 1H NMR (400 MHz, [D6]DMSO, TMS): δ =
NH), 7.46 – 7.50 (m, 2H, ArH), 9.85 (s, 1H, 1NH), 10.66
NH), 11.31 (brs, 1H, NH). – MS (EI, 70 eV): m/z (%) =
(s, 1H, 1NH), 11.47 (brs, 2H, 2NH). – MS (EI, 70 eV): m/z
393.13 (25), 391.01 (80) [M]+, 246.0263 (92) [M–2,4- (%) = 359.32 (60) [M]+. – Anal. for C15H10ClN5O4: calcd.
Cl2C6H3]+. – Anal. for C15H7Cl2N5O5: calcd. C 45.94,
H 1.80, N 17.86; found C 45.83, H 1.89, N 17.75.
C 50.08, H 2.80, N 19.47; found C 50.21, H 2.72, N 19.41.
10-(4-Fluorophenyl)-1,3,5,6,8,10-hexahydropyrido[3,2-d:
6,5-dꢀ]dipyrimidine-2,4,7,9-tetrone (9c)
10-(4-Methoxyphenyl)-1,3,6,8-tetrahydropyrido[3,2-d:6,5-
dꢀ]dipyrimidine-2,4,7,9-tetrone (6e)
Yellow crystals (yield: 85 %), m. p. > 360 ◦C. – IR (film):
Pale-brown crystals (yield: method A: 74 %, method B: ν = 3347, 3398, 3156, 2992, 1708, 1660 cm−1. – 1H NMR
67 %), m. p. 340 – 342 ◦C. – IR (film): ν = 3402, 3189, (400 MHz, [D6]DMSO, TMS): δ = 4.73 (s, 1H, 10-H)
3053, 1706, 1610 cm−1. – 1H NMR (400 MHz, [D6]DMSO, 7.07 – 7.13 (m, 2H, ArH), 7.20 (s, 1H, NH), 7.25 – 7.35 (m,
TMS): δ = 3.83 (s, 3H, OCH3), 7.00 – 7.04 (d, 2H, J = 2H, ArH), 10.59 (brs, 2H, 2NH), 11.56 (brs, 2H, 2NH). –
8.70 Hz, ArH), 7.13 – 7.16 (d, 2H, ArH), 8.96 (brs, 1H, MS (EI, 70 eV): m/z (%) = 343.18 (83) [M]+. – Anal.
NH), 11.21 (s, 1H, NH), 11.67 (s, 1H, NH), 11.79 (s, 1H, for C15H10FN5O4: calcd. C 52.48, H 2.94, N 20.40; found
NH). – 13CNMR (100 MHz, [D6]DMSO): δ = 56.70 (C- C 52.41, H 2.87, N 20.31.
OCH3), 110.02 (C-Ar, C-3ꢀ), 114.39 (C-9a), 129.17 (C-Ar,
C-2ꢀ), 131.30 (C-Ar, C1ꢀ), 133.37 (C-10a), 137.99 (C-4a),
143.40 (C-10), 150.43 (C-Ar, C-4ꢀ), 150.88 (C-5a), 158.22
(C-2), 159.99 (C-7), 163.25 (C-4), 163.45 (C-9). – MS (EI,
70 eV): m/z (%) = 352 (35.7), 353 (100) [M]+, 354 (21), 322
(32) [M–OCH3]+. – Anal. for C16H11N5O5: calcd. C 54.39,
H 3.14, N 19.82; found C 54.28, H 3.06, N 19.89.
10-(2,4-Dichlorophenyl)-1,3,5,6,8,10-hexahydropyrido[3,2-
d:6,5-dꢀ]dipyrimidine-2,4,7,9-tetrone (9d)
Yellow crystals (yield: 90 %), m. p. 352 – 354 ◦C (de-
comp.). – IR (film): ν = 3382, 3306, 3156, 3021, 1711, 1676,
1629 cm−1. – 1H NMR (400 MHz, [D6]DMSO, TMS): δ =
4.74 (s, 1H, 10-H), 7.23 – 7.27 (m, 1H, ArH), 7.53 – 7.58
(m, 2H, ArH), 8.40 (s, 1H, NH), 9.88 (s, 1H, NH), 10.64
(brs, 2H, NH), 11.52 (s, 1H, NH). – 13C NMR: (100 MHz,
[D6]DMSO): δ = 36.26 (C-10), 83.86 (C-9a), 110.95 (C-4a),
Synthesis of 10-aryl-1,3,5,6,7,10-hexahydropyrido[3,2-d:
6,5-dꢀ]dipyrimidines 9a – e
Method A: A Solution of 5-aminouracil (1), the appropri- 128.52 (C-10a), 131.10 (C-Ar, C-5ꢀ), 136.49 (C-Ar, C-3ꢀ),
ate benzaldehyde derivative 2 and barbituric acid (5) in DMF 144.42 (C-Ar, C-6ꢀ), 145.38 (C-Ar, C-4ꢀ), 149.92 (C-Ar,
(2 mL) was refluxed for 2 – 5 h (TLC control). The solvent C-2ꢀ), 150.15 (C-Ar, C1ꢀ), 150.37 (C-5a), 159.00 (C-2 and
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R. M. Shaker et al. · 5-Aminouracil as a Building Block in Heterocyclic Synthesis
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C-7), 162.82 (C-4 and C-9). – MS (EI, 70 eV): m/z (%) = 132.37 (C-Ar, C-3ꢀ), 133.43 (C-4a), 135.33 (C-Ar, C1ꢀ),
394.41 (6.5) [M]+, 393.40 (30), 322.20 (93). – Anal. for 136.26 (C-10), 139.57 (C-5a), 150.23 (C-2), 158.84 (C-4),
C15H9Cl2N5O4: calcd. C 45.71, H 2.30, N 17.77; found 162.83 (C-9), 167 (C-7). – MS (EI, 70 eV): m/z (%) =
C 45.79, H 2.39, N 17.61.
339.04 (60) [M]+, 265.07 (100) [M–CH2N2S]+. – Anal. for
C15H9N5O3S: calcd. C 53.09, H 2.67, N 20.64, S 9.45; found
C 53.14, H 2.62, N 20.59, S 9.41.
10-(4-Methoxyphenyl)-1,3,5,6,8,10-hexahydropyrido[3,2-
d:6,5-dꢀ]dipyrimidine-2,4,7,9-tetrone (9e)
10-(4-Chlorophenyl)-1,3,6,8-tetrahydro-7-thioxopyrido[3,2-
Yellow crystals (yield: 73 %), m. p. > 360 ◦C. – IR (film):
ν = 3210, 3079, 1712, 1614 cm−1. – 1H NMR (400 MHz,
[D6]DMSO, TMS): δ = 3.80 (s, 3H, O-CH3), 4.67 (s, 1H,
10-H) 7.00 – 7.03 (d, 2H, ArH), 10-H), 6.8 – 6.9 (m, 2H,
ArH), 7.13 – 7.20 (m, 2H, ArH), 7.95 (s, 1H, 5-NH), 8.96
(brs, 1H, NH), 9.07 (s, 1H, 6-NH), 10.96 (s, 1H, 1-NH),
11.65 (s, 1H, NH). – 13C NMR (100 MHz, [D6]DMSO):
δ = 37.13 (C-10), 55.51 (C-OCH3), 83.3 (C-9a), 114.14
(C-4a), 127.93 (C-Ar, C-3ꢀ), 128.67 (C-10a), 129.17 (C-Ar,
C-2ꢀ), 136.00 (C-Ar, C1ꢀ), 150.00 (C-Ar, C-4ꢀ), 150.45
(C-5a), 159.10 (C-2 and C-7), 162.82 (C-4 and C-9). –
d:6,5-dꢀ]dipyrimidine-2,4,9-trione ( 12b)
Brown crystals (yield: method A: 94 %), m. p. > 360 ◦C. –
IR (film): ν = 3325, 3140, 2965, 2927, 2883, 1722, 1662,
1617 cm−1. – 1H NMR (400 MHz, [D6]DMSO, TMS): δ =
7.31 – 7.37 (m, 4H, ArH), 8.39 (s, 1H, 6-NH), 10.91 (s,
1H, 1-NH), 11.53 (s, 1H, 8-NH), 12.06 (s, 1H, 3-NH). –
MS (EI, 70 eV): m/z (%) = 373.2 (55) [M]+. – Anal. for
C15H8ClN5O3S: calcd. C 48.20, H 2.16, N 18.74, S 8.58;
found C 48.25, H 2.22, N 18.69, S 8.52.
MS (EI, 70 eV): m/z (%) = 355.02 (100) [M]+. – Anal. 10-(4-Fluorophenyl)-1,3,6,8-tetrahydro-7-thioxopyrido[3,2-
d:6,5-dꢀ]dipyrimidine-2,4,9-trione (12c)
for C16H13N5O5: calcd. C 54.09, H 3.69, N 19.71; found
C 54.17, H 3.57 N 19.61.
Brown crystals (yield: method A: 98 %), m. p. > 340 –
338 ◦C. – IR (film): ν = 3390, 3335, 3114, 3046, 2929,
Alternative synthesis of 6
1726, 1669, 1614 cm−1. – 1H NMR (400 MHz, [D6]DMSO,
A solution of 1 mmol of 9a – c in DMF (3 mL) was re-
TMS): δ = 7.08 – 7.14 (m, 2H, ArH), 7.32 – 7.36 (m, 2H,
fluxed for 3 – 5 h. The solvent was concentrated, and the
ArH), 8.38 (s, 1H, 6-NH), 10.91 (s, 1H, 1-NH), 11.47 (s,
1H, 8-NH), 12.04 (s, 1H, 3-NH). – 13C NMR (100 MHz,
[D6]DMSO): δ = 110.26 (C-9a), 115.65 (C-Ar, C-3ꢀ), 130.24
(C-10a), 130.33 (C-Ar, C-2ꢀ), 132.08 (C-Ar, C1ꢀ), 134.29
(C-4a), 136.26 (C-10), 144.64 (C-5a), 159.97 (C-Ar, C-4ꢀ),
150.39 (C-2), 160.30 (C-4), 162.83 (C-9), 173.81 (C-7). –
MS (EI, 70 eV): m/z (%) = 357.19 (65.0) [M]+, 359.44 (40.0)
[M+2]+. – Anal. for C15H8FN5O3S: calcd. C 50.42, H 2.26,
N 19.60, S 8.97; found C 50.49, H 2.31, N 19.53, S 8.92.
product obtained was recrystallized from DMF/EtOH (yield
of 6a: 82 %; 6b: 85 %; 6c: 89 %).
Synthesis of 10-aryl-1,3,6,8-tetrahydro-7-thioxopyrido[3,2-
d:6,5-dꢀ]dipyrimidine-2,4,9-triones 12a – e
Method A: Using the procedure described for the synthe-
sis of compound 6 (method A), compounds 12a – e were pre-
pared by reaction of equmolar amounts of 1 with the appro-
priate benzaldehyde derivatives 2 and thiobarbituric acid (10)
with microwave heating at 800 Watt for 4 – 7 min. The prod-
ucts were recrystallized from DMF/MeOH.
10-(2,4-Dichlorophenyl)-1,3,6,8-tetrahydro-7-thioxopyr-
ido[3,2-d:6,5-dꢀ]dipyrimidine-2,4,9-trione (12d)
Method B: A mixture of 1 (1 mmol), 11a, b (1 mmol)
and DMF (1 mL) was placed in open Pyrex-glass vessels and
irradiated in a microwave oven with 800 Watt power for 4 –
6 min. The resulting mixture was left to cool to r. t., and the
solid product was then collected by filtration and crystallized
from DMF/MeOH (yield of 12a: 83 %; 12b: 90 %).
Dark-brown crystals (yield: method A: 95 %), m. p. 350 –
353 ◦C. – IR (film): ν = 3360, 3220, 2980, 2892, 1730, 1652,
1612 cm−1. – 1H NMR (400 MHz, [D6]DMSO, TMS): δ =
7.17 – 7.19 (dd, 1H, ArH), 7.49 – 7.50 (s, 1H, ArH), 7.68 –
7.70 (dd, 1H, ArH), 8.2 (s, 1H, 6-NH), 10.90 (s, 1H, 1-NH),
11.58 (s, 1H, 8-NH), 12.11 (s, 1H, 3-NH). – H, H COSY
spectrum indicated the correlation between a double doublet
at δH = 7.2 (J = 1.8, 8.2 Hz, 5ꢀ-H) with a doublet at δH = 7.7
(J = 8.2 Hz, 6ꢀ-H) and a long-range correlation with δH = 7.5
10-Phenyl-1,3,6,8-tetrahydro-7-thioxo-pyrido[3,2-d:6,5-
dꢀ]dipyrimidine-2,4,9-trione (12a)
Pale-brown crystals (yield: method A: 83 %), m. p. 338 – (J = 1.8 Hz, 3ꢀ-H). – 13C NMR (100 MHz, [D6]DMSO):
340 ◦C. – IR (film): ν = 3154, 3030, 2922, 2830, 1713, δ = 113.6 (C-9a), 127.12 and 134.10 (Ar-C and C-10a,
1639 cm−1. – 1H NMR (400 MHz, [D6]DMSO, TMS): δ = C-4a), 137.43 (C-10), 146.97 (C-5a), 149.28 (C-2), 158.1
7.22 – 7.36 (m, 5H, ArH), 9.10 (s, 1H, 6-NH), 10.98 (s, (C-4), 159.91 (C-9), 174.70 (C-7). – MS (EI, 70 eV): m/z
1H, 1-NH), 11.51 (s, 1H, 8-NH), 12.03 (s, 1H, 3-NH). – (%) = 407.44 (90) [M]+, 262.08 (73) [M–2,4-Cl2C6H3]+. –
13C NMR (100 MHz, [D6]DMSO): δ = 112.43 (C-9a), Anal. for C15H7Cl2N5O3S: calcd. C 44.13, H 1.73, N 17.16,
128.86 (C-Ar, C-4ꢀ), 129.45 (C-Ar, C-2ꢀ), 131.33 (C-10a), S 7.85; found C 44.09, H 1.81, N 17.23, S 7.79.
Unauthenticated
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1198
R. M. Shaker et al. · 5-Aminouracil as a Building Block in Heterocyclic Synthesis
10-(4-Methoxyphenyl)-1,3,6,8-tetrahydro-7-thioxopyrido-
C 52.03, H 3.00, N 18.96, S 8.68; found C 52.11, H 2.94,
N 18.91, S 8.61.
[3,2-d:6,5-dꢀ]dipyrimidine-2,4,9-trione (12e)
Brown crystals (yield: method A: 74 %), m. p. > 360 ◦C. –
IR (film): ν = 3323, 3289, 3144, 2962, 2813, 1718, 1667,
1618 cm−1. – 1H NMR (400 MHz, [D6]DMSO, TMS): δ =
3.70 (s, 3H, OCH3), 6.83 – 6.92 (m, 2H, ArH), 7.13 – 7.20
(m, 2H, ArH), 9.07 (s, 1H, 6-NH), 10.88 (s, 1H, 1-NH), 11.49
(s, 1H, 8-NH), 12.01 (s, 1H, 3-NH). – MS (EI, 70 eV): m/z
(%) = 369.0 (53) [M]+, 371.2 (60) [M]+, 264.1 (100) [M–
CH3OC6H4]+, 263.0 (25). – Anal. for C16H11N5O4S: calcd.
Alternative synthesis of 6 and 12
A mixture of 5 and/or 10 (1 mmol) and Schiff base
13a, b (1 mmol) in 1 mL of DMF was irradiated in a
microwave oven with 1000 Watt power for 4 – 10 min.
Products 6b, d and/or 12b, d were isolated as de-
scribed above; yield of 6b: 85 %; 6d: 96 %; 12b: 92 %;
12d: 95 %.
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Unauthenticated
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