Facile synthesis, pure DFT calculations, and PM3 semiempirical mo method validation of regiospecificity of novel 1,4-dihydropyrido[2,3-d]pyrimidine derivatives

Article abstract of DOI:10.1080/00397910903534015

Reaction of 6-aminothiouracil (or uracil) with equimolar amounts of different ketones or diketones and the appropriate aromatic aldehydes afforded di-and tricyclic linear pyrido[2,3-d]pyrimidine derivatives 4, 6-12, 14, 16-18, 20, and 21, and pyrimido[4,5

Full text of DOI:10.1080/00397910903534015

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Facile Synthesis, Pure DFT Calculations,
and PM3 Semiempirical MO Method
Validation of Regiospecificity of Novel
1,4-Dihydropyrido[2,3-d]pyrimidine
Derivatives
A. El-Shafei a , A. A. Fadda b , S. Bondock b , A. M. Khalil b & Eman
H. Tawfik b
a Fiber and Polymer Chemistry Program, North Carolina State
University, Raleigh, North Carolina, USA
b Faculty of Science, Department of Chemistry, Mansoura University,
Mansoura, Egypt
Published online: 09 Aug 2010.
To cite this article: A. El-Shafei , A. A. Fadda , S. Bondock , A. M. Khalil & Eman H. Tawfik
(2010) Facile Synthesis, Pure DFT Calculations, and PM3 Semiempirical MO Method Validation of
Regiospecificity of Novel 1,4-Dihydropyrido[2,3-d]pyrimidine Derivatives, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:18, 2788-2805,
DOI: 10.1080/00397910903534015
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Synthetic Communications1, 40: 2788–2805, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903534015
FACILE SYNTHESIS, PURE DFT CALCULATIONS,
AND PM3 SEMIEMPIRICAL MO METHOD VALIDATION
OF REGIOSPECIFICITY OF NOVEL 1,4-
DIHYDROPYRIDO[2,3-d]PYRIMIDINE DERIVATIVES
A. El-Shafei,1 A. A. Fadda,2 S. Bondock,2 A. M. Khalil,2 and
Eman H. Tawfik2
1Fiber and Polymer Chemistry Program, North Carolina State University,
Raleigh, North Carolina, USA
2Faculty of Science, Department of Chemistry, Mansoura University,
Mansoura, Egypt
Reaction of 6-aminothiouracil (or uracil) with equimolar amounts of different ketones or
diketones and the appropriate aromatic aldehydes afforded di- and tricyclic linear pyr-
ido[2,3-d]pyrimidine derivatives 4, 6–12, 14, 16–18, 20, and 21, and pyrimido[4,5-b]quino-
line derivatives 15 and 19 in good yields. The regiospecificity, which led to the formation of
compound 4 not 5, was validated using ab initio at the HF=6–31 Gþ(d,p) level and pure
density functional theory (DFT) calculations using BLYP energy functional and the basis
set DNP via studying the thermodynamics of their possible conformers and regioisomers. In
addition, the total energy of the transition state was calculated for compounds 12 and 13 to
determine whether the reaction products were thermodynamically or kinetically controlled.
Hence, the linear structures and the regiospecificities of the reactions for the structures
reported in this article were established by elemental analysis, spectral data, ab initio
calculations, pure DFT, and PM3 parameters.
Keywords: Ab initio validation; acetylacetone; 6-amino-uracil and thiouracil; molecular modeling; triflor-
oacetylacetone
INTRODUCTION
Pyrimidine is the parent heteroring of a very important group of compounds
that have been extensively studied because of their occurrence in living systems.
Compounds containing pyrimidine rings have been reported as antibacterial,
antifungal, and anti-HIV agents.[1–4]
Substitution of a pyridine ring for a benzene ring often is compatible with
retention of biological activity, and occasionally this moiety is an essential part of
=
=
the pharmacophore. Such substitution of N for CH is an example of the common
medicinal strategy known as bioisosterism. Therefore, pyridine derivatives have a
Received July 10, 2009.
Address correspondence to A. El-Shafei, Fiber and Polymer Chemistry Program, North Carolina
State University, Raleigh, NC 27695, USA. E-mail: Ahmed_El-Shafei@ncsu.edu
2788

REGIOSPECIFICITY OF NOVEL PYRIMIDINE DERIVATIVES
2789
broad spectrum of biological activity, such as antihypertensive, bronchodilator,
anti-inflammatory, and antifungal activities.[5–9]
Moreover, 1,4-dihydropyridines, known as nifedipine, exhibit coronary
vasodilators activity, and therefore they are used for relief of the intense chest pains
of angina pectoris.[10] Compounds having a combination of pyrimidine with 1,4-
dihydropyridine moieties are expected to possess medicinal properties. Encouraged
by these reports and in continuation of our work in this field,[11–16] we report here
the synthesis of some new 1,4-dihydropyridinopyrimidine derivatives.
RESULTS AND DISCUSSION
In this study, 6-aminothiouracil (1), 6-amino-1-methyluracil (2), and 6-amino-
1,3-dimethyluracil (3), are used as starting materials for the synthesis of 1,4-
dihydropyrido[2,3-d]pyrimidines.
1,4-Dihydropyrido[2,3-d]pyrimidines were synthesized by refluxing equimolar
amounts of 6-aminothiouracil (1) in dimethylformamide (DMF) with 1,3-diketones,
(namely acetylacetone, trifloroacetylacetone, dibenzoylmethane, and benzoylacetone)
with appropriate aromatic aldehydes. The cyclocondensation of 1 with acetylacetone
and vaniline in DMF afforded the pyridopyrimidine 4. There are two possibilities for
ring closure: if the N1-position is unsubstituted, as in compound 1, ring closure takes
place at either the N1 or the C-5 atom. Both cyclizations have been reported in the reac-
tion of 5-aminopyrazole with 1,3-dicarbonyl compounds,[17,18] but we observed only
cyclization at C-5 to give 6-acetyl-5-(4-hydroxy-3-methoxyphenyl)-7-methyl-2-thioxo-
2,3,5,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-(1H)one (4) (Scheme 1; Table 1) To gain
deep understanding of the electronic structure, reactivity, and ring cyclization potential
of compound 1 toward vanillin and acetylacetone, quantum mechanical calculations
were performed at the density functional theory (DFT) level using the Becke–
Lee–Yang–Parr (BLYP) energy functional and the basis set DNP (double-numerical
basis functions with polarization functions). Moreover, ab initio calculations at the
Hartree–Fock (HF) level with the basis set 6-31Gþ, and the augmented version of
these sets incorporating extra p and d functions, were performed on the possible
Scheme 1. Cyclocondensation of 1 with acetylacetone and vaniline to afford pyrido[2,3-d]pyrimidine
derivative 4.

2790
A. EL-SHAFEI ET AL.
Table 1. Synthesis of 2-thioxo-2,3,5,8-tetrahydropyrido[2,3-d]pyrimidin-4-(1H)one derivatives (4, 6–9)
Yield
(%)
Entry
Substrate
1,3-Diketone
Aldehyde
Product
R
Y(X)
3-OCH3,
4-OH
1
4a
CF3(CH3)
75
2
3
6
7
2-NO2
2-OH
CF3(CH3)
CF3(CH3)
70
80
4
5
8
9
4-N(CH3)2 CF3(CH3)
67
73
4-NO2
Ph(Ph)
conformers of compounds 4a, b and 5a, b to determine the thermodynamically
favorable regiospecificity and the most stable conformer. First, the equilibrium molecu-
lar geometries of conformers 4a, b and 5a, b were calculated, and key thermodynamic
descriptors were computed. Table 2 shows the calculated total energy for the confor-
mers 4a, b and 5a, b and HOMO-LUMO gap of the constitutional isomers 4a and
5a using ab initio calculations. The data show clearly that the reaction of compound
1 with acetylacetone and vanillin thermodynamically favors conformers 4a, b rather
than conformers 5a, b. Hence, the reaction is regiospecific and furnishes the linear
compound 4, which was confirmed experimentally. Moreover, the data also show that
conformer 4a is more stable than conformer 4b, inferred from the lower total energy
values. However, both ab initio and DFT methods predicted smaller HOMO-LUMO
energy gaps for compounds 4a, 4b, 5a, and 5b to follow the trend 4a< 4b< 5a< 5b,
which could be attributed to the fact that DFT and ab initio methods are not sensi-
tive to the HOMO-LUMO gap of sulfur-containing compounds.[19] Figures 1a and
1b show the equilibrium molecular geometry of conformer 4a with the atomic charge
superimposed on each atom and the HOMO isosurface of the conformer 4a super-
imposed on its equilibrium molecular geometry, respectively.

REGIOSPECIFICITY OF NOVEL PYRIMIDINE DERIVATIVES
2791
Table 2. Calculated total energy [HF=6-31Gþ(d, p)] for conformers 4a, b and 5a, b and HOMO-LUMO
gap for conformers 4a and 5a
Energy (RHF),
Hartree
Energy difference between
conformers (a & b) (kcal=mol)
HOMO-LUMO
energy gap (eV)
Compound
4a
4b
5a
5b
ꢀ1514.050
ꢀ1514.048
ꢀ1514.0334
ꢀ1514.0333
E4a ¼ E4b ꢀ 1.158
E5a ¼ E5b ꢀ 0.0627
9.092
9.113
9.215
9.219
Notes. Hartree ¼ 627.51 kcal=mol; RHF, restricted Hartree–Fock.
Figure 1. (a) Equilibrium molecular geometry of conformer 4a and (b) calculated HOMO superimposed
on the isosurface of the equilibrium molecular geometry of conformer 4a.
Table 3 shows the total energy and binding energy of conformers 4a, b and 5a,
b computed using DFT utilizing BLYP energy functional and the basis set DNP,
which are consistent with the data shown in Table 2 and are in agreement with
the experimental data.
1
The H NMR spectrum of the product, compound 4, showed signals due to
CH3, COCH3, and OCH3 at d 2.73, 2.88, and 3.65 ppm, respectively, in addition
to two sharp singlets at d 5.27 and 8.61 ppm for 5-H and 8-NH, respectively, and
additional NH signals at d 11.75 and 11.97 ppm corresponding to 1,3-NH protons.
Table 3. Calculated total energy and binding energy (BLYP=DNP) for compounds (4a, b) and (5a, b)
using DFT
Energy (RHF),
Hartree
Binding energy,
Hartree
Energy difference between
conformers (a & b) (kcal=mol)
Compound
4a
4b
5a
5b
ꢀ1521.514
ꢀ1521.511
ꢀ1521.505
ꢀ1521.496
ꢀ7.514
ꢀ7.511
ꢀ7.505
ꢀ7.496
Ea ¼ Eb ꢀ 1.883
Ea ¼ Eb ꢀ 5.647

2792
A. EL-SHAFEI ET AL.
On the bases of experimental results coupled with the ab initio and DFT
validations, isomeric structure 5 was discarded. Moreover, the infrared (IR) spectrum
showed stretching frequencies at 3374 cmꢀ1 attributable to the OH function; 3316,
3214, 3168 cmꢀ1 attributable to NH groups; 1700 cmꢀ1 attributable to a,b-unsatu-
rated ketone; 1660 cmꢀ1 attributable to amidic carbonyl; and 1597 cmꢀ1 attributable
=
to C C function. The structure was further confirmed by measuring its mass spec-
trum, which showed molecular ion peak at m=z 358 (Mþ – 1, 45%).
Similarly, 1 reacts with trifloroacetylacetone and o-nitrobenzaldehyde in reflux-
ing DMF to afford 1,4-dihydropyrido[2,3-d]pyrimidine 6. The IR spectrum of 6
showed frequencies at 3350–3187 cmꢀ1 for (NH) groups, 1715–1699 cmꢀ1 for amidic
ꢀ1
and ketonic carbonyls, 1371 cmꢀ1 for C S, and 1530, 1350 cm for NO2 function.
=
Moreover, the mass spectroscopic measurement showed the molecular ion
peak at m=z 410 (Mþ ꢀ 2, 15%). The 1H NMR showed singlet signals at d
2.88 ppm for acetyl protons, 5.87 ppm for C5-H, 8.09 for 8-NH, and 12.02 (b, 2H,
2NH).
On the other hand, 1 reacted with trifloroacetylacetone and salicyaldehyde (or
p-N,N-dimethylaminobenzaldehyde) to give the corresponding 1,4-dihydropyrido-
pyrimidines 7 and 8, respectively. Structures 7 and 8 were established based on both
elemental analysis and spectral data. In general, the IR spectra of 7 and 8 showed
bands at 3377–3190 cmꢀ1 for (NH groups), 1700–1630 cmꢀ1 for carbonyl groups,
1
and 1355 cmꢀ1 for C S function. The H NMR of compound 7 showed singlet
=
signals at d 2.88, 5.87, 8.20, 11.65, and 12.21 ppm due to COCH3, C5-H, 8-NH,
and 1.3-NH protons, respectively. On the other hand, 1H NMR of compound
8 showed signals at d 2.73, 2.88, 4.88, 7.94, 12.14, and 13.16 ppm due to N,N-
(CH3)2, COCH3, C5-H, 8-NH, and 1,3-NH protons, respectively.
In a similar manner, 1 reacted with dibenzoylmethane to give the correspond-
ing 1,4-dihydropyridopyrimidine derivative 9. Compound 9 was proved by elemental
and spectral data. In general, the IR showed signals at 3450–3195 cmꢀ1 for the NH
stretching frequencies, 1720–1700 cmꢀ1 for ketonic and amidic carbonyl groups,
1530, 1350 cmꢀ1 for nitro group, and a band at 1300 cmꢀ1 for C S. Moreover,
=
the mass spectrum of 9 showed the molecular ion beaks at m=z 479 (Mþ ꢀ 3, 14%).
In addition, it was found that refluxing compound 3 in boiling dimethylforma-
mide (DMF) with trifloroacetylacetone and salicyaldehyde yielded a single product,
the elemental analysis of which confirmed the molecular formula (C18H16N3O4F3).
This product was formulated as 6-acetyl-5-[2-hydroxyphenyl]-1,3-dimethyl-7-[tri-
floro-methyl]-5,8-dihydropyrido[2,3-d]pyrimidine-4-[1H]-2,4-dione (10) (Scheme 2;
1
Table 4), and the structure was confirmed by IR, H NMR, and mass spectra. Its
1H NMR spectrum revealed five singlet signals at d 2.91, 3.35, 3.46, 5.06, and
6.94 ppm attributable to the CH3CO, 2(N-CH3), C5-H-pyridine ring, and OH pro-
tons and a multiplet at d 7.07–7.21 ppm for aromatic protons, but the NH proton
was not observed. This could be because the NH exists between one a,b-unsaturated
ketone and one a,b-unsaturated amidic carbonyl. It is very likely that the NH could
undergo tautomerization with one or two a,b-unsaturated carbonyls, in which case
1
the dynamic equilibrium could be so fast that it cannot been seen in an H NMR
experiment at room temperature. The NH proton can be resolved by running a
1
temperature-dependent H NMR experiment at temperatures less than room tem-
perature to freeze out the NH proton conformer. In addition, the mass spectrum

REGIOSPECIFICITY OF NOVEL PYRIMIDINE DERIVATIVES
2793
Scheme 2. Synthesis of pyrido[2,3-d]pyrimidine-4-[1H]-2,4-dione analogs 10–12.
Table 4. Synthesis of 1,3-dimethyl-5,8-dihydropyrido[2,3-d]pyrimidin-4-(1H)-2,4-dione derivatives
(10–12)
Entry
Substrate
Ketone
Aldehyde
Product
Y
Yield (%)
6
10
CF3
78
7
8
11
12
Ph
—
71
69
showed the molecular ion peak at m=z 376 (Mþ ꢀ F, 35%) and the base peak at m=z
172 resulting from the loss of two methyl groups, carbon monoxide, OH, and
fragments.
Moreover, the IR spectrum showed absorption frequencies at 3449 cmꢀ1 for
the OH group, 3337 cmꢀ1 for NH, 1700 cmꢀ1 for the ketonic carbonyl function,
and 1630 cmꢀ1 for the amidic carbonyl.

2794
A. EL-SHAFEI ET AL.
In addition, reaction of 3 with benzoylacetone and o-nitrobenzaldehyde in
refluxing DMF afforded a single product of structure 11. Structure 11 was also
proved on the base of both analytical and spectral data. The IR spectrum showed
absorption frequencies at 3400 cmꢀ1 for NH function, 1707 cmꢀ1 for ketonic car-
bonyl, 1614 cmꢀ1 for amidic carbonyl, 1568, and 1361 cmꢀ1 for symmetric and asym-
1
metric nitro group. Moreover, the H NMR revealed five singlet signals at d 2.77,
3.35, 3.70, 5.12, and 9.08 ppm due to CH3, 2(N-CH3), C-5H-pyridine ring, and
8-NH protons, respectively, besides a multiplet at d 7.55–8.20 ppm for aromatic pro-
tons. The mass spectrum of 11 showed the molecular ion peak as base peak at m=z
386.4 (Mþ – NO2, 100%), whereas the fragment at m=z 342 corresponds to the loss of
acetyl group from the molecular ion.
In continuation of this work, the 1,4-dihydropyido[2,3-d]pyrimidin-4-one 12
has been also synthesized by refluxing equimolar amounts of 1,3-dimethyl-6-
aminouracil (3) in boiling DMF with cyclopentanone and benzaldehyde derivatives.
Of two possible structures, 12 and 13, that can be proposed for such a product, com-
pound 13 was ruled out on the bases of both the elemental and spectral data
(Scheme 2; Table 4).
The cyclocondensation of enamine 3 with cyclopentanone and benzaldehyde
regiospecifically gave the linear isomer pyrido[2,3-d]pyrimidin-4-one 12.
1
The support for the linear structure for 12 was proved by the H NMR spec-
trum, in particular the chemical shift for the H-5 proton and a singlet for the 9-NH
1
proton.[20] The H NMR spectrum of compound 12 contains four singlet signals at
d 3.31, 3.64, 4.51, and 9.49 ppm for 2-(N-CH3), 5-H, and 9-NH, respectively. The
5-H and 9-NH protons are not coupled; this confirms the linear structure 12 and
not the angular structure 13. The signals at d 3.10, 3.44 ppm for 6- and 8-CH2 are
doublets with J ¼ 16.0 ꢁ 0.2 and 17.15 ꢁ 0.2 Hz, whereas those for the 7-CH2 at d
2.12 resonated as a multiplet (see the IR and mass spectra in the Experimental
section). The reaction may proceed via the attack of the active methylene group of
the ketone on the carbonyl group of the aldehyde. Then, subsequent nucleophilic
attack by the amino group of the uracil derivative on the carbonyl carbon of the
a,b-unsaturated ketone intermediate, followed by cyclization and elimination of
water, could furnish the linear structure. The alternative attack of the amino of
the uracil derivative on the methylenic carbon of the a,b-unsaturated ketone fol-
lowed by cyclization could lead to the angular structure. The latter case corresponds
to the Skraup synthesis and Doebner–Miller synthesis of pyridines and quinolines.
Ab initio calculations at the HF level with the basis set 6-31Gþ(d, p) showed that
compounds 12 and 13 are thermodynamically equivalent, which was inferred from
their total energy. This might indicate that both isomers are in thermodynamic
equilibrium. However, the HOMO-LUMO energy gap of compound 12 was greater
than that of compound 13 (Table 5), which confirms that compound 12 is more
thermodynamically stable than compound 13. To understand the reaction kinetics
and gain deep insights on the formation of compounds 12 versus 13, the transition
state for each compound was predicted, refined, and verified using PM3 parameters.
Following the refinement and verification of both transition states, it was found that
the total energy of the transition state of compound 12 is less than that of compound
13 by 4.206 kcal=mol (Table 5). These new and interesting findings confirm that the
formation of compound 12 was thermodynamically (greater HOMO-LUMO gap)

REGIOSPECIFICITY OF NOVEL PYRIMIDINE DERIVATIVES
2795
Table 5. Calculated total energy and HOMO-LUMO gap using HF=6-31Gþ(d, p) and total energy of the
transition state using PM3 parameters for compounds 12 and 13
Energy (RHF),
Hartree
HOMO-LUMO energy
gap (EV)
Energy of the transition
state (kcal=mol)
Compound
12
13
ꢀ1005.867
ꢀ1005.867
9.575
8.846
145.074
149.280
Note. Hartree ¼ 627.5 kcal=mol.
and kinetically controlled. Figures 2 and 3 show the refined equilibrium molecular
geometry of the transition state (Figs. 2a and 3a) and the potential energy surface
of the optimized geometry of the transition state (Figs. 2b and 3b) of compounds
12 and 13, respectively. The optimized geometry for the transition states of com-
pounds 12 and 13 (Figs. 2a and 3a) show the bond distance at which bonds start
to form (Figs. 2b and 3b), and the potential energy surface of the saddle point of
compounds 12 and 13 (Figs. 2b and 3b) are shown with the ball cursor in the red
band. Scheme 2 shows the potential enantiomers for compounds 12 and 13 and that
the enantiomers do have the same energy.
The linear structure is in accordance with the reported results where the 5-H
and 9-NH protons appeared at d 4.00–6.00 and at d 7.50–10.00 ppm, respectively.[21]
In addition, the use of the nuclear Overhauser effect (NOE) technique[22] and
1
1
1
the assignment of the signals in the H and 13C NMR by the H, H COSY (corre-
lation spectroscopy) technique and 1H, 13C shift correlation were reported for similar
systems, which all supported the linear structure.[20,23,24]
Moreover, x-ray crystal studies and two-dimensional 1H and 13C NMR spectra
of a product of a similar cyclocondensation reaction indicated the linear structure
Figure 2. (a) The optimized geometry of the transition state of compound 12 and (b) the potential energy
surface showing the location of the transition state of compound 12, indicated by the black cursor ball.

2796
A. EL-SHAFEI ET AL.
Figure 3. (a) The optimized geometry of the transition state of compound 13 and (b) the potential energy
surface showing the location of the transition state of compound 13, indicated by the black cursor ball.
Scheme 3. Cyclocondensation of 1 with aromatic aldehydes and cyclic ketones to afford pyridopyrimidine
derivatives 14a, 16–18, and pyrimido[4,5-b]quinoline analogs 15a–b.

REGIOSPECIFICITY OF NOVEL PYRIMIDINE DERIVATIVES
2797
rather than angular product was formed.[25] This recent publication provides
additional support for the linear structure.[26]
As we mentioned, there are two possibilities for ring closure of reaction
of 1 with cyclopentanone and benzaldehyde derivatives to give compound
14a (Ar ¼ C6H5) (Scheme 3; Table 6). Structure of 9-phenyl-1-thioxo-1,2,6,7,8,
9-hexahydrocyclopenta[d]pyrimido[1,6-a]pyrimidin-3(5H)-one (14b) was ruled out
based on the spectral data. In addition, ab initio calculations at the HF level with
Table 6. Synthesis of 1,4-dihydropyrido[2,3-d]thiopyrimidine derivatives (14a, 14b, 15a, 15b, 16–18)
Entry
Substrate
Ketone
Aldehyde
Product
Ar
Yield (%)
9
14a
Ph
80
10
14b
C6H4-N,N-(CH3)2
76
11
12
13
14
15
15a
15b
16
C6H4-OCH3-p
C6H4-NO2-m
C6H4-Cl-p
81
79
69
64
73
17
C6H4-Br-p
18
C6H4-Cl-p

2798
A. EL-SHAFEI ET AL.
Table 7. Calculated total energy and HOMO-LUMO gap using HF=6-31Gþ(d, p)
for compounds 14a and 14b
Energy (RHF),
Hartree
HOMO-LUMO energy
gap, (EV)
Compound
14a
14b
ꢀ1250.441
ꢀ1250.423
9.630
9.687
the basis set 6-31Gþ(d, p) showed clearly that the formation of compound 14a is
thermodynamically more favorable than that of compound 14b, which was inferred
from the lower total energy of compound 14a. However, the HOMO-LUMO of
compounds 14b was greater than that of compound 14a, which is a known problem
with sulfur-containing compounds (Table 7).
1
The H NMR spectrum of compound 14a showed signals for the 6- and the
8-CH2 as doublet of doublets with J ¼ 16.0 ꢁ 0.2 and 17.5 ꢁ 0.2 Hz, in addition to
two sharp singlets at d 5.37 and d 7.95 ppm for 5-H and 9-NH, respectively, a multi-
plet at d 7.07–7.24 for aromatic protons, and NH signals at d 11.70 and 11.91 ppm
corresponding to the 1,3-NH protons.
Structure 14b should show three singlet signals at d 6.81, 8.01, and 13.50 ppm
corresponding to C-H and two NH protons, which is not the case. Furthermore, the
mass spectrum of compound 14a has a molecular ion peak at m=z 296 (Mþ ꢀ 1,
18.3%), which confirms that the product should be the structure of compound 14a
not 14b.
Similarly, 4-dihydropyrido[4,5-d]thiopyrimidine 14c was synthesized by the
reaction of 6-aminothiouracil (1) with cyclopentanone and p-(N,N-dimethylamino)
benzaldehyde in boiling DMF. The mass spectrum of compound 14c showed a
molecular ion peak at m=z 321 (Mþ-CH3, 2H2, 77%) corresponding to the loss of
CH3 fragment plus H2 (cf. Experimental section).
On the other hand, 1,4-dihydropyrido[4,5-d]thiopyrimidines 15a, b were
obtained by using dimedone instead of cyclopentanone. Moreover, the reaction
of 1 with cycloheptanone, Meldrum’s acid, and indandione in the presence of
benzaldehyde derivatives afforded the formation of pyrido[4,5-d]thiopyrimidine
derivatives 16–18.
Analogously, 6-amino-1-methyluracil (2) underwent a similar reaction with
dimidone and benzaldehyde derivatives and gave the corresponding pyrido[4,5-d]
pyrimidines 19a, b (Scheme 4; Table 8).
On the other hand, 2 reacted with cycloheptanone in the presence of
p-chlorobenzaldehyde to give the corresponding pyrido[4,5-d]pyrimidine 20, whereas
the reaction of 2 with meldrum’s acid and p-bromobenzaldehyde afforded the
pyrido[4,5-d]pyrimidine 21.
EXPERIMENTAL
Melting points were measured with a Gallenkamp apparatus and are uncor-
rected. The IR spectra were recorded for KBr discs on a Mattson 5000 Fourier trans-
form (FT)–IR spectrophotometer. 1H NMR spectra were measured on a Bruker AC
300 (300-MHz) instrument in CDCl3 or dimethylsulfoxide (DMSO-d6) as solvent,

REGIOSPECIFICITY OF NOVEL PYRIMIDINE DERIVATIVES
2799
Scheme 4. Synthesis of pyrimido[4,5-b]quinoline derivative 19 and pyridopyrimidine derivatives 20–21.
using tetramethylsilane (TMS) as an internal standard, and chemical shifts are
expressed as d ppm. Mass spectra were determined on a Finnigan COS 500 instru-
ment (70 ev). All reactions were followed by thin-layer chromatography (TLC; silica
gel, aluminum sheets 60 F254, Merck). Elemental analyses (C, H, and N) were carried
Table 8. Synthesis of pyrimido[4,5-b]quinoline derivatives (19–21)
Entry
Substrate
Ketone
Aldehyde
Product
Ar
Yield (%)
16
19a
C6H4-OCH3-p
68
17
18
19
19b
C6H4-NO2-m
C6H4-Cl-p
C6H4-Br-p
59
77
82
20
21

2800
A. EL-SHAFEI ET AL.
out at the Microanalytical Center of Cairo University, Giza, Egypt, and the results
were found to be in good agreement (ꢁ0.3%) with the calculated values.
Molecular Modeling
All molecular geometries were fully optimized using either Gaussian 03 W,
DMol3 (Wallingford, CT) implemented in Material Studio 4.2 (Accelrys, CA) or
CAChe 12.12.33 (Fujitsu America Inc., Beaverton, OR). In the case of Gaussian,
ab initio calculations were performed using HF=6-31Gꢂ(d, p),[27] and in the case
of DMol3, BLYP energy functional with the basis set DNP were performed. In
the case of transition-state calculations, harmonic vibration frequencies were calcu-
lated using PM3 parameters implemented in CAChe for all stationary points to
verify that for energy minima all frequencies are real but for the transition state there
is only one imaginary frequency.
General Procedure for the Preparation of Pyrido[2,3-d]pyrimidine
and Pyrimido[4,5-b]quinoline
A mixture of 6-aminothiouracil (1) (1.43 g, 10 mmol) or 6-amino-1-methylura-
cil (2) (1.41 g, 10 mmol) or 6-amino-1,3-dimethyluracil (3) (1.55 g, 10 mmol) with
1,3-diketone (10 mmol) and 10 mmol of the appropriate aldehyde in DMF
(30 cm3) was refluxed for 5 h, cooled, and poured into ice water. The solid that
formed was filtered off and crystallized from mixed solvent, ethanol=DMF (1:2).
Selected Data
6-Acetyl-5-(4-hydroxy-3-methoxyphenyl)-7-methyl-2-thiooxo-2,3,5,8-
tetrahydropyrido[2,3-d]pyrimidin-4-(1H)-one (4). Pale yellow crystal; yield 75%;
mp 225 ꢃC; IR (KBr) nmax cmꢀ1: 3374 (OH), 3316, 3214, and 3168 (NH), 1700 (a,b-
1
=
=
unsaturated ketone), 1660 (C O) and 1597 (C C); H NMR (DMSO-d6) d ppm:
2.73 (s, 3H, CH3), 2.88 (s, 3H, COCH3), 3.65 (s, 3H, OCH3), 5.27 (s, 1H, C5-H),
6.44–6.79 (m, 3H, Ar-H), 7.95 (s, 1H, OH), 8.61 (s, 1H, 8-NH), 11.75 (s, 1H, NH)
and 11.97 (s, 1H, NH); MS: m=z (%), 358 (Mþ – 1, 45%), 221 (73%), 220 (23), 204
(17%), 203 (22%), 202 (83%), 188 (34%), 187 (33%), 174 (22%), 173 (39%), 159
(33%), 158 (22%), 130 (66%), 105 (50%), 91 (45%), 81 (56%), 78 (100%), 77 (10%),
76 (33%), 69 (89%). Anal. calc. for C17H17N3O4S: C, 56.81; H, 4.77; N, 11.69.
Found: C, 56.57; H, 4.52; N, 11.56.
6-Acetyl-5-(2-nitrophenyl)-2-thioxo-7-trifluoromethyl-2,3,5,8-tetrahydro-
1H-pyrido[2,3-d]pyrimidin-4-one (6). Orange crystal; yield 70%; mp 223 ꢃC; IR
(KBr) nmax cmꢀ1: 3350–3187 (NH), 1715–1699 (ketonic and amidic carbonyl), 1371
1
=
(C S) and 1530, 1350 (NO2); H NMR (DMSO-d6) d ppm: 2.88 (s, 3H, COCH3),
5.87 (s, 1H, C5-H), 7.35–7.65 (m, 4H, Ar-H), 8.09 (s, 1H, 8-NH) and 12.02 (b,
2H, 2NH); MS: m=z (%),410 (Mþ – 2, 15%), 409 (37%), 408 (100%), 407 (72%),
406 (43%), 392 (13%), 387 (27%), 365 (25%), 277 (15%), 236 (15%), 205 (20%),
195 (15%), 205 (20%), 196 (15%), 143 (13%), 128 (10%). Anal. calc. for
C16H11F3N4O4S: C, 46.60; H, 2.69; N, 13.59. Found: C, 46.42; H, 2.32; N, 13.14.

REGIOSPECIFICITY OF NOVEL PYRIMIDINE DERIVATIVES
2801
6-Acetyl-5-(2-hydroxyphenyl)-2-thioxo-7-trifluoromethyl-2,3,5,8-tetra-
hydro-1H-pyrido[2,3-d]pyrimidin-4-one (7). Yellow powder; yield 80%; mp
>300 ꢃC; IR (KBr) nmax cmꢀ1: 3377–3190 (NH), 1700–1630 (2C O) and 1355
=
1
=
(C S); H NMR (DMSO-d6) d ppm: 2.88 (s, 3H, COCH3), 5.87 (s, 1H, C5-H),
6.65 (b, 1H, OH), 7.35–7.82 (m, 4H, Ar-H), 8.20 (s, 1H, NH), 11.65 (s, 1H, NH)
and 12.21 (s, 1H, NH). Anal. calc. for C16H12F3N3O3S: C, 50.13; H, 3.16; N,
10.96. Found: C, 49.85; H, 2.87; N, 10.64.
6-Acetyl-5-(4-dimethylaminophenyl)-2-thioxo-7-trifluoromethyl-2,3,5,8-
tetrahydro-1H-pyrido[2,3-d]pyrimidin-4-one (8). Pale brown powder; yield
67%; mp >300 ꢃC; IR (KBr) nmax cmꢀ1: 3377–3190 (NH), 1700–1630 (2C O) and
=
1355 (C S); 1H NMR (DMSO-d6) d ppm: 2.73 [s, 6H, N(CH3)2], 2.88 (s, 3H,
=
COCH3), 4.88 (s, 1H, C5-H), 6.65–7.17 (m, 4H, Ar-H), 7.94 (s, 1H, 8-NH), 12.14
(s, 1H, NH) and 13.16 (s, 1H, NH). Anal. calc. for C18H17F3N4O2S: C, 52.68; H,
4.18; N, 13.65. Found: C, 52.38; H, 3.84; N, 13.36.
6-Benzoyl-5-(4-nitrophenyl)-7-phenyl-2-thioxo-2,3,5,8-tetrahydro-1H-
pyrido[2,3-d]pyrimidin-4-one (9). Yellow powder; yield 73%; mp 83 ꢃC; IR (KBr)
n
max cmꢀ1: 3450–3195 (NH), 1720–1700 (2C O) 1530, 1350 (NO2) and 1300 (C S);
= =
MS: m=z (%): 479 (Mþ ꢀ 3, 14%), 478 (17%), 375 (11%), 374 (15%), 360 (23%), 359
(84%), 357 (25%), 282 (44%), 214 (20%), 172 (14%), 165 (17%), 140 (21%), 136 (26%),
121 (58%), 120 (100%), 79 (25%), 78 (40%), 77 (80%), 76 (11%). Anal. calc. for
C26H18N4O4S: C, 64.72; H, 3.76; N, 11.61. Found: C, 64.93; H, 3.63; N, 11.82.
6-Acetyl-5-(2-hydroxy-phenyl)-1,3-dimethyl-7-trifluoromethyl-5,8-dihydro-
1H-pyrido[2,3-d]pyrimidine-2,4-dione (10). White needles; yield 78%; mp
255 ꢃC; IR (KBr) nmax cmꢀ1: 3449 (OH), 3337 (NH), 1700 (ketonic carbonyl), and
1
1630 (amidic carbonyl); H NMR (DMSO-d6) d ppm: 2.91 (s, 3H, COCH3), 3.35,
3.46 [s, s, 6H, 2N(CH3)], 5.06 (s, 1H, C5-H), 6.94 (s, 1H, OH), 7.07–7.21 (m, 4H,
Ar-H), and unobserved NH proton; MS: m=z (%): 376 (Mþ-F, 35%), 338 (23%),
308 (12%), 250 (48%), 237 (19%), 214 (20%), 173 (15%), 172 (100%), 171 (20%),
168 (15%), 156 (18%), 143 (16%), 127 (5%), 119 (11%), 111 (10%), 108 (28%), 98
(10%), 84 (11%), 76 (12%), 65 (26%). Anal. calc. for C18H16F3N3O4: C, 54.69; H,
4.08; N, 10.63. Found: C, 54.51; H, 3.92; N, 10.45.
6-Acetyl-1,3-dimethyl-5-(2-nitrophenyl)-7-phenyl-5,8-dihydro-1H-pyrido
[2,3-d]pyrimidine-2,4-dione (11). Brown crystals; yield 71%; mp 182 ꢃC; IR (KBr)
n
max cmꢀ1: 3400 (NH), 1707 (ketonic carbonyl), 1614 (amidic carbonyl), and 1568,
1
1361 (symmetric and asymmetric nitro group); H NMR (DMSO-d6) d ppm: 2.77
(s, 3H, COCH3), 3.35, 3.70 [s, s, 6H, 2N(CH3)], 5.12 (s, 1H, C5-H), 7.55–8.20 (m,
4H, Ar-H) and 9.08 (s, 1H, NH); MS m=z (%): 386 (Mþ-NO2, 100%), 343 (31%),
342 (69%), 308 (12%), 242 (14%), 212 (15%), 157 (14%), 143 (8%), 128 (10%), 127
(5%), 115 (8%), 105 (30%), 101 (10%), 90 (7%), 88 (8%), 77 (23%), 76 (10%), 75
(13%), 64 (11%). Anal. calc. for C23H20N4O5: C, 63.88; H, 4.66; N, 12.96. Found:
C, 63.59; H, 4.37; N, 12.61.
1,3-Dimethyl-5-phenyl-5,6,7,8,9-pentahydro-4H-cyclopenta[5,6]pyrido
[2,3-d]pyrimidine-2,4-dione (12). Yellow powder; yield 69%; mp 150 ꢃC; IR
(KBr) nmax cmꢀ1: 3421 (NH), 1700, 1660 (2C O) and 1586 (C C); 1H NMR
=
=

2802
A. EL-SHAFEI ET AL.
(DMSO-d6) d ppm: 2.12, 3.10, 3.44 (m, 6H, 3CH2), 3.31, 3.64 [s, s, 6H, 2N(CH3)],
4.51 (s, 1H, C5-H), 7.52–7.84 (m, 5H, Ar-H), and 9.49 (s, 1H, NH); MS m=z (%):
281 (Mþ – CH2 ¼ CH2 or Mþ – CO, 41.7%), 261 (68%), 259 (88%), 247 (100%), 223
(75%), 218 (48%), 204 (52%), 196 (17%), 194 (77%), 177 (19%), 167 (54%), 166
(27%), 164 (38%), 155 (52%), 146 (85%), 140 (20%), 133 (19%), 132 (43%), 130
(27%), 126 (14%), 119 (25%), 109 (13%), 97 (8%), 84 (12%), 80 (22%), 71 (35%),
69 (45%), 55 (17%), 54 (24%). Anal. calc. for C18H19N3O2: C, 69.88; H, 6.19; N,
13.58. Found: C, 69.57; H, 5.84; N, 13.29.
5-Phenyl-2-thioxo-1,2,3,5,6,7,8,9-octahydro-4H-cyclopenta[5,6]pyrido
[2,3-d]pyrimidin-4-one (14a). Yellow powder; yield 80%; mp 194 ꢃC; IR (KBr)
1
max cmꢀ1: 3407, 3186 (NH), 1619 (C O), 1550 (C C) and 1387 (C S); H NMR
=
=
=
n
(DMSO-d6) d ppm: 2.12, 2.74, 2.89 (m, 6H, 3CH2), 5.37 (s, 1H, C5-H), 7.07–7.24
(m, 5H, Ar-H), 7.95 (s, 1H, 9-NH), 11.70 (s, 1H, NH), 11.91 (s, 1H, NH); MS:
m=z (%): 296 (Mþ ꢀ 1, 18.3%), 295 (100%), 294 (88%), 171 (10%), 144 (9%), 143
(13%), 125 (10%), 105 (11%), 76 (8%), 75 (10%), 68 (10%), 67 (5%), 64 (9%), 51
(15%). Anal. calc. for C16H15N3OS: C, 64.62; H, 5.08; N, 14.13. Found: C, 64.43;
H, 4.91; N, 13.97.
5-(4-Dimethylaminophenyl)-2-thioxo-1,2,3,5,6,7,8,9-octahydro-4H-
cyclopenta[5,6]pyrido[2,3-d]pyrimidin-4-one (14b). Red powder; yield 76%; mp
240 ꢃC; IR (KBr) nmax cmꢀ1: 3402, 3146 (NH), 1659 (C O), 1590 (C C) and 1365
=
=
1
=
(C S); H NMR (DMSO-d6) d ppm: 2.12 (m, 2H, CH2), 2.83 (m, 2H, CH2), 2.95
(m, 2H, CH2), 2.98, 3.04 [s, s, 6H, 2N(CH3)], 5.35 (s, 1H, C5-H), 6.80–7.86 (d.d,
4H, Ar-H), 9.85 (s, 1H, 9-NH) and 12.01–12.80 (br, 2H, 2NH); MS: m=z (%): 321
(Mþ – CH3, 2H2, 77.0%), 305 (38%), 294 (33%), 250 (32%), 220 (14%), 215 (48%),
214 (35%), 190 (54%), 184 (24%), 172 (54%), 167 (15%), 159 (34%), 150 (77%),
149 (100%), 148 (74%), 144 (72%), 133 (26%), 130 (24%), 108 (31%), 105 (52%),
103 (15%), 94 (27%), 92 (23%), 79 (29%), 77 (32%), 65 (21%), 64 (14%), 59 (15%).
Anal. calc. for C18H20N4OS: C, 63.50; H, 5.92; N, 16.46. Found: C, 63.76; H,
6.14; N, 16.73.
5-(4-Methoxyphenyl)-8,8-dimethyl-2-thioxo-2,3,7,8,9,10-hexahydro-
pyrimido[4,5-b]quinolin-4,6-(1H,5H)-dione (15a). White crystal; yield 81%; mp
296 ꢃC; IR (KBr) nmax cmꢀ1: 3402, 3146 (NH), 1700, 1643 (2C O), 1612 (C C)
=
=
1
=
and 1378 (C S); H NMR (DMSO-d6) d ppm: 0.90 (s, 3H, CH3), 1.01 (s, 3H,
CH3), 1.99 (d, 2H, CH2), 2.17 (d, 2H, CH2), 3.66 (s, 3H, OCH3), 4.69 (s, 1H,
C5-H), 6.75–7.10 (d, d, 4H, Ar-H), 7.94 (s, 1H, NH), 8.53 (s, 1H, NH), 12.11 (s,
1H, NH). Anal. calc. for C20H21N3O3S: C, 62.64; H, 5.52; N, 10.96. Found: C,
62.75; H, 5.83; N, 11.24.
5-(2-Nitrophenyl)-8,8-dimethyl-2-thioxo-2,3,7,8,9,10-hexahydro-pyrimido
[4,5-b]quinolin-4,6-(1H,5H)-dione (15b). Buff sheets; yield 79%; mp 182 ꢃC; IR
(KBr) nmax cmꢀ1: 3402, 3146 (NH), 1700, 1643 (2C O), 1612 (C C), 1530, 1350
=
=
1
=
(NO2) and 1378 (C S); H NMR (DMSO-d6) d ppm: 0.90 (s, 3H, CH3), 1.01 (s,
3H, CH3), 1.99 (d, 2H, CH2), 2.17 (d, 2H, CH2), 4.69 (s, 1H, C5-H), 7.07–7.20 (m,
4H, Ar-H), 8.59 (s, 1H, NH), 9.18 (s, 1H, NH), 11.53 (s, 1H, NH). Anal. calc. for
C19H18N4O4S: C, 57.27; H, 4.55; N, 14.06. Found: C, 57.00; H, 4.22; N, 13.77.

REGIOSPECIFICITY OF NOVEL PYRIMIDINE DERIVATIVES
2803
5-(4-Chlorophenyl)-2-thioxo-1,2,3,5,6,7,8,9,10,11-decahydro-4H-cyclopenta
[5,6]pyrido[2,3-d]pyrimidin-4-one (16). Yellow crystal; yield 69%; mp
317–319 ꢃC; IR (KBr) nmax cmꢀ1: 3339, 3151 (NH), 1650 (C O), 1542 (C C) and
=
=
þ
=
1378 (C S); MS: m=z (%): 359 (M , 26%), 315 (15%), 266 (10%), 210 (13%), 143
(65%), 138 (12%), 137 (15%), 127 (10%), 115 (24%), 113 (17%), 101 (32%), 98
(11%), 89 (20%), 87 (30%), 84 (13%), 77 (21%), 76 (17%), 75 (53%), 74 (26%), 70
(15%), 68 (100%). Anal. calc. for C18H18ClN3OS: C, 60.07; H, 5.04; N, 11.68. Found:
C, 59.87; H, 4.71; N, 11.40.
5-(4-Bromophenyl)-2,2-dimethyl-8-thioxo-5,8,9,10-tetrahydro-4H-[1,3]
dioxino[5’,4’:5,6]pyrido[2,3-d]pyrimidin-4,6-(7H)-dione (17). Yellow crystal;
yield 64%; mp 309–311 ꢃC; IR (KBr) nmax cmꢀ1: 3350, 3230 (NH), 1690, 1650
1
=
=
=
(2C O), 1600 (C C) and 1320 (C S); H NMR (DMSO-d6) d ppm: 1.57 (s, 6H,
2CH3), 5.29 (s, 1H, C5-H), 7.02–7.42 (d. d, 4H, Ar-H), 8.20 (s, 1H, 9-NH), 11.80
(s, 1H, NH), 12.02 (s, 1H, NH). Anal. calc. for C17H14BrN3O4S: C, 46.80; H,
3.23; N, 9.63. Found: C, 46.49; H, 2.91; N, 9.33.
5-(4-Chlorophenyl)-2-thioxo-1,2,3,5,6,11-hexahydro-indino[5,6]pyrido
[2,3-d]pyrimidin-4,6-dione (18). Colorless crystal; yield 73%; mp > 300 ꢃC; IR
1
(KBr) nmax cmꢀ1: 3350, 3230 (NH), 1710, 1680 (2C O); H NMR (DMSO-d6) d
=
ppm; 4.05 (s, 1H, C5-H), 7.20–7.45 (d, d, 4H, Ar-H), 7.61–7.89 (m, 4H, Ar-H),
12.50 (s, 1H, NH), 12.50 (s, 1H, NH), 13.51 (s, 1H, NH). Anal. calc. for
C20H12ClN3O2S: C, 60.99; H, 3.07; N, 10.67. Found: C, 60.73; H, 2.75; N, 10.39.
5-(4-Methoxyphenyl)-1,8,8-trimethyl-3,7,8,9,10-pentahydro-pyrimido
[4,5-b]quinolin-2,4,6-(5H)-trione (19a). White sheets; yield 68%; mp 327 ꢃC; IR
(KBr) nmax cmꢀ1: 3275, 3216 (NH), 2960 (CH3), 1720, 1650, 1639 (3C O); 1H
=
NMR (DMSO-d6) d ppm: 0.88 (s, 3H, CH3), 1.02 (s, 3H, CH3), 2.05 (d, 2H, CH2),
2.23 (d, 2H, CH2), 3.66 (s, 3H, N-CH3), 4.05 (s, 3H, O-CH3), 4.77 (s, 1H, C5-H),
6.71–7.11 (d, d, 4H, Ar-H), 8.90 (s, 1H, 10-NH), 10.92 (s, 1H, NH). Anal. calc. for
C21H23N3O4: C, 66.13; H, 6.08; N, 11.02. Found: C, 65.84; H, 5.73; N, 10.72.
5-(3-Nitrophenyl)-1,8,8-trimethyl-3,7,8,9,10-pentahydro-pyrimido[4,5-
b]quinolin-2,4,6-(5H)-trione (19b). Faint brown crystal; yield 59%; mp 296 ꢃC; IR
1
(KBr) nmax cmꢀ1: 3275, 3219 (NH), 2963 (CH3), 1710, 1665, 1634 (3C O); H NMR
=
(DMSO-d6) d ppm: 0.88 (s, 3H, CH3), 1.02 (s, 3H, CH3), 2.05 (d, 2H, CH2), 2.23 (d,
2H, CH2), 3.66 (s, 3H, N-CH3), 4.40 (s, 1H, C5-H), 7.07–7.24 (m, 4H, Ar-H), 9.61 (s,
1H, 10-NH), 11.62 (s, 1H, NH). Anal. calc. for C20H20N4O5: C, 60.60; H, 5.09; N,
14.13. Found: C, 60.42; H, 4.98; N, 13.96.
5-(4-Chlorophenyl)-1-methyl-3,5,6,7,8,9,10,11-octahydro-4H-cyclo-hepta
[5,6]pyrido[2,3-d]pyrimidin-2,4-dione (20). Brown crystal; yield 77%; mp 268 ꢃC;
IR (KBr) nmax cmꢀ1: 3411, 3197 (NH), 2929 (CH3), 1710, 1675 (2C O); MS: m=z (%):
=
355 (Mþ ꢀ 2, 45%), 326 (42%), 308 (31%), 264 (23%), 220 (23%), 218 (23%), 167
(20%), 163 (43%), 152 (23%), 140 (27%), 128 (23%), 117 (20%), 94 (70%), 79 (30%),
75 (93%), 74 (39%), 67 (50%), 63 (53%), 62 (50%), 57 (39%), 55 (54%). Anal. calc.
for C19H20ClN3O2: C, 63.77; H, 5.63; N, 11.74. Found: C, 63.65; H, 5.30; N, 11.46.
5-(4-Bromophenyl)-2,2,9-trimethyl-5,7,10-trihydro-4H-[1,3]dioxino-[5’,4’:
5,6]pyrido[2,3-d]pyrimidin-4,6,8-trione (21). Brown crystal; yield 82%; mp

2804
A. EL-SHAFEI ET AL.
280 ꢃC; IR (KBr) nmax cmꢀ1: 3275, 3220 (NH), 2965 (CH3), 1720, 1650, 1639
1
=
(3C O); H NMR (DMSO-d6) d ppm: 1.62 (s, 6H, 2CH3), 3.86 (s, 3H, N-CH3),
5.29 (s, 1H, C5-H), 7.02–7.40 (d, d, 4H, Ar-H), 9.29 (s, 1H, NH), 11.77 (s, 1H,
10-NH). Anal. calc. for C18H16BrN3O5: C, 49.56; H, 3.71; N, 9.68. Found: C,
49.56; H, 3.63; N, 9.66.
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