3-[2(4)-Pyrimidinyl]coumarins and their condensed analogs

Article abstract of DOI:10.1007/s10593-010-0590-2

3-Pyrimidinylcoumarins have been synthesized by interacting 2- and 4-pyrimidinylacetonitriles with substituted salicylic aldehydes, but 9-pyrimidinylpyrano[2,3-f]chromene-4,8-diones were obtained with 8-formyl-7-hydroxychromones. Modification of the corre

Full text of DOI:10.1007/s10593-010-0590-2

Chemistry of Heterocyclic Compounds, Vol. 46, No. 7, 2010
3-[2(4)-PYRIMIDINYL]COUMARINS AND THEIR
CONDENSED ANALOGS
T. V. Shokol1*, I. Yu. Nestorak1, A. V. Turov1, V. M. Gunko2,
Yu. M. Volovenko, and V. P. Khilya1
3-Pyrimidinylcoumarins have been synthesized by interacting 2- and 4-pyrimidinylacetonitriles with
substituted salicylic aldehydes, but 9-pyrimidinylpyrano[2,3-f]chromene-4,8-diones were obtained with
8-formyl-7-hydroxychromones. Modification of the corresponding 7-hydroxycoumarins was carried out
by acylation and aminomethylation.
Keywords: 7-acyloxy-3-pyrimidinylcoumarins, 8-dimethylaminomethyl-7-hydroxy-3-pyrimidinyl-
coumarins, pyrimidinylacetonitriles, 3-(2-pyrimidinyl)coumarins, 3-(4-pyrimidinyl)coumarins, 9-pyrimi-
dinyl-4H,8H-pyrano[2,3-f]chromene-4,8-diones.
The chemistry of hetaryl-substituted coumarins has developed intensively in the last decades [1],
however 3-pyrimidinylcoumarins have been described in only a few studies [2-6]. 3-(2- and 4-Pyrimidinyl)-
coumarins were synthesized previously by building a pyrimidine fragment onto an already existing coumarin
[2-5]. On interacting 5,6-benzocoumarin-3-carboxylic acid chloride with the dimethyl ester of dithio-
malondiimido acid, 3-(4,6-dimethylthiopyrimidin-2-yl)coumarin was obtained [2], but on heterocyclization of
the chalcones with amidines or thiourea, derivatives of 3-(4-pyrimidinyl)coumarin were synthesized [3-5],
possessing antibacterial activity [5]. A different approach was proposed for the synthesis of 3-(5-pyrimi-
dinyl)coumarins, viz. to construct the coumarin system on reaction with pyrimidine derivatives, particularly on
condensation of 2-hydroxyacetophenones with pyrimidine-5-acetic acid [6].
With the aim of expanding the circle of pyrimidinyl-substituted coumarins we took advantage of the
second approach. The subjects of our investigation were 4,6-dimethylpyrimidin-2-ylacetonitrile (1a) and
2,6-dimethylpyrimidin-4-ylacetonitrile (1b), which were introduced into a Knoevenagel reaction with
substituted salicylic aldehydes 2-5 in 2-propanol in the presence of a catalytic amount of piperidine. As a result
of reacting nitrile 1a with aldehyde 3 in pure water 6-chloro-3-(4,6-dimethylpyrimidin-2-yl)-2-iminocoumarin
1
(6a) was isolated, which was confirmed by the presence in its H NMR spectrum, taken in DMSO-d6, of a low
field singlet for the NH proton at 10.79 ppm. The singlet of the proton at position 4 of the 6a molecule was
found in the region of 8.57 ppm.
_______
* To whom correspondence should be addressed, e-mail: shokol_tv@mail.univ.kiev.ua.
1 Taras Shevchenko Kiev National University, Kiev 01033, Ukraine.
2A. A. Chuiko Institute of Surface Chemistry, Kiev 03680, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1027-1038, July, 2010. Original
article submitted October 5, 2009.
0009-3122/10/4607-0829©2010 Springer Science+Business Media, Inc.
829

OH
R
1.
2.
O
O
N
CHO
2–5
R
+
Me
X
H
Y
Me
7a,b, 8b, 9a,b, 10a
O
NH
3
R
Me
N
N
N
CHO
6a
HO
1.
R 1
R 2
Me
Me
O
Me
Me
Y
Y
X
X
O
O
11, 12
Me
N
+
2.
O
CN
H
1a,b
O
O
R1
R2
14a,b, 15a,b
Me
Me
N
N
HN
O
O
R1
R2
O
+
11
H
14a
13a
1,7,9,10,14,15 a X = N, Y = CH; 1, 7-9,14,15 b X = CH, Y = N; 2,7a,b R = H, 3 R = 5-Cl,
6a, 8b R = 6-Cl, 4 R = 4-OH, 5 R = 3-MeO, 9a,b R = 7-OH,
10a R = 8-MeO; 11, 13a, 14a,b R1 = Me, R2 = 4-ClC6H4O, 12, 15a,b R1 = H, R2 = 4-ClC6H4
In the remaining cases the reaction mixture was contaminated by the product of hydrolysis and it was
further hydrolyzed with 3% H2SO4 or MeCOOH to the corresponding coumarins 7-10. In their IR spectra
1
intense bands were present for the stretching vibrations of the lactone carbonyl at 1712-1729 cm-1. In the H
NMR spectra of 3-(4,6-dimethylpyrimidin-2-yl)coumarins 7a, 9a, and 10a, recorded in DMSO-d6, signals were
observed for the pyrimidine fragment, viz. a six-proton singlet for the symmetrical methyl groups fell into the
absorption region of DMSO and the H-5' proton at 7.09-7.20 ppm. The signals of the aromatic protons of the
coumarin portion of the molecule, the most low field of which belonged to the H-4 proton singlet at 8.34-8.42 ppm,
and signals for substituents were also observed.
830

TABLE 1. Characteristics of Compounds 6-10, 12-18
Com-
pound
Empirical
formula
Found, %, N
Calculated, %, N
——————
mp,°C*
Yield, %
6a
C15H12ClN3O
C15H12N2O2
C15H12N2O2
C15H11ClN2O2
C15H12N2O3
C15H12N2O3
C16H14N2O3
C16H9ClO4
14.61
14.71
11.23
11.11
11.10
11.11
10.01
9.77
10.49
10.44
10.57
10.44
9.97
9.92
—*2
198
138
184
220
207
300
181
144
252
288
268
215
292
165
158
178
128
164
80
86
75
70
92
87
75
68
67
78
51
55
42
68
90
65
53
57
7a
7b
8b
9a
9b
10a
12
13a
14a
14b
15a
15b
16a
16b
17b
18a
18b
C25H18ClN3O4
C25H17ClN2O5
C25H17ClN2O5
C24H15ClN2O4
C24H15ClN2O4
C17H14N2O4
C17H14N2O4
C22H16N2O4
C20H23N3O3
C20H23N3O3
9.17
9.14
6.12
6.08
6.15
6.08
6.74
6.50
6.44
6.50
8.91
9.03
9.27
9.03
7.39
7.52
12.12
11.89
11.80
11.89
_______
*Solvents for recrystallization: 2-propanol (compounds 6a, 8b, 13a),
ethanol (compounds 7a,b, 12, 17b), DMF–ethanol (compound 9a), DMF
(compound 9b), methanol (compounds 10a, 16a,b), AcOH (compounds
14a,b, 15a,b), ethyl acetate (compounds 18a,b).
*2Found, Cl, %: 11.91. Calculated, Cl, %: 11.79.
In the spectra of 3-(2,6-dimethylpyrimidin-4-yl)coumarins 7b-9b the signals of the aromatic protons of
the benzene portion of the benzopyrones were observed in the same regions as in products 7a, 9a, and 10a, but
the singlet of the H-4 proton underwent a paramagnetic displacement of 0.6 ppm (8.97-9.04 ppm), the same as
for the singlet of the H-5' pyrimidine proton (7.94-8.04 ppm). Signals of the protons of the unsymmetrical
methyl groups appeared as two three-proton singlets at 2.5 and 2.7 ppm. The most low field singlet of products
9a (10.60 ppm) and 9b (10.69 ppm) belongs to the proton of the OH group at position 7 of the coumarin
nucleus.
If the effect of the structure of the compounds on the values of the chemical shifts in the 1H spectra of the
isomeric compounds 7a,b and 9a,b is considered, then the most characteristic of their differences is the
significant change of chemical shift of the H-4 proton signal of the coumarin nucleus. In products 7a and 9a this
signal absorbs close to 8.4 ppm and in compounds 7b and 9b its chemical shift is found close to 8.9 ppm. So
831

TABLE 2. IR and 1H NMR Spectra of Compounds 6-10, 12-18
IR
Com-
pound
1Н NMR spectrum, , ppm (J,Hz)*
spectrum,
ν
C=O , cm1
1643*2
6a
7a
2.57 (6H, s, 4',6'-CH3); 7.22 (1H, d, J = 8.8, H-8); 7.26 (1H, s, H-5');
7.47 (1H, dd, J7,8 = 8.8, J7,5 = 2.4, H-7); 7.70 (1H, d, J = 2.4, H-5);
8.57 (1H, s, H-4); 10.79 (1H, s, NH)
1727
2.50 (6H, s, 4',6'-CH3); 7.19 (1H, s, H-5'); 7.35 (1H, t, J = 7.6, H-6);
7.40 (1H, d, J = 7.6, H-8); 7.63 (1H, t, J =7.6, H-7); 7.80 (1H, d, J = 7.6, H-5);
8.42 (1H, s, H-4)
7b
8b
9a
1719
1724
1712
2.53 (3H, s, 6'-CH3); 2.68 (3H, s, 2'-CH3); 7.38-7.43 (2H, m, H-6,8); 7.69 (1H, m, H-7);
7.90 (1H, dd, J5,6 = 7.6, J5,7 = 1.2, H-5); 8.04 (1H, s, H-5'); 9.04 (1H, s, H-4)
2.53 (3H, s, 6'-CH3); 2.68 (3H, s, 2'-CH3); 7.46 (1H, d, J = 8.8, H-8);
7.66 (1H, dd, J7,8 = 8.8, J7,5 = 2.4, H-7); 8.01 (2H, s, H-5,5'); 9.01 (1H, s, H-4)
2.48 (6H, s, 4',6'-CH3); 6.72 (1H, d, J = 2.0, H-8);
6.77 (1H, dd, J6,8 = 2.0, J6,5 = 8.4, H-6); 7.09 (1H, s, H-5');
7.55 (1H, d, J = 8.4, H-5); 8.34 (1H, s, H-4); 10.60 (1H, s, 7-OH)
9b
1729
2.41 (3H, s, 6'-CH3); 2.57 (3H, s, 2'-CH3); 6.72 (1H, d, J = 2.0, H-8);
6.81 (1H, dd, J6,8 = 2.0, J6,5 = 8.4, H-6); 7.74 (1H, d, J = 8.4, H-5);
7.94 (1H, s, H-5'); 8.90 (1H, s, H-4); 10.69 (1H, s, 7-OH)
10a
12
1729
1636
2.50 (6H, s, 4',6'-CH3); 3.97 (3H, s, 8-CH3O); 7.18 (1H, s, H-5');
7.26-7.32 (3H, m, H-5,6,7); 8.39 (1H, s, H-4)
7.09 (1H, d, J = 9.2, H-6); 7.43 (2Н, d, J = 8.4, H-2',6');
7.62 (2Н, d, J = 8.4, H-3',5'); 8.26 (1H, d, J = 9.2, H-5); 8.48 (1H, s, H-2);
10.53 (1H, s, CHO); 12.24 (1H, br. s, 7-OH)
13a
14a
14b
15a
1630
2.72 (3H, s, 2-CH3); 3.04 (6H, s, 4",6"-CH3); 6.92 (2Н, d, J = 8.8, H-2',6');
7.33 (2Н, d, J = 8.8, H-3',5'); 7.90 (2H, m, H-5",6); 9.01 (1H, d, J = 9.2, H-5);
10.21 (1H, s, H-10)
1744α,
1651γ
2.74 (3H, s, 2-CH3); 3.03 (6H, s, 4",6"-CH3); 6.94 (2Н, d, J = 8.8, H-2',6');
7.32 (2Н, d, J = 8.8, H-3',5'); 7.79 (1H, d, J = 9.2, H-6); 7.84 (1H, s, H-5");
8.87 (1H, d, J = 9.2, H-5); 10.34 (1H, s, H-10)
1742α,
1651γ
2.75 (3H, s, 2-CH3); 3.02 (3H, s, 6"-CH3); 3.16 (3H, s, 2"-CH3);
6.95 (2Н, d, J = 8.8, H-2',6'); 7.35 (2Н, d, J = 8.8, H-3',5'); 7.73 (1H, d, J = 9.2, H-6);
8.80 (1H, d, J = 9.2, H-5); 9.07 (1H, s, H-5"); 10.20 (1H, s, H-10)
1749α,
1648γ
[3.02 (6H, s, 4",6"-CH3); 7.48 (2Н, d, J = 8.4, H-2',6');
7.53 (2Н, d, J = 8.4, H-3',5'); 7.79 (1H, d, J = 9.2, H-6); 7.83 (1H, s, H-5");
8.50 (1H, s, H-2); 8.93 (1H, d, J = 9.2, H-5); 10.34 (1H, s, H-10)]
2.49 (6H, s, 4",6"-CH3); 6.98 (1H, s, H-5"); 7.39 (2Н, d, J = 8.4, H-2',6');
7.51 (1H, d, J = 9.2, H-6); 7.63 (2Н, d, J = 8.4, H-3',5');
8.35 (1H, d, J = 9.2, H-5); 8.60 (1H, s, H-2); 8.81 (1H, s, H-10)
15b
16a
2.59 (3H, s, 6"-CH3); 2.75 (3H, s, 2"-CH3); 7.46 (2Н, d, J = 8.4, H-2',6');
7.55 (1H, d, J = 9.2, H-6); 7.64 (2Н, d, J = 8.4, H-3',5'); 8.15 (1H, s, H-5");
8.42 (1H, d, J = 9.2, H-5); 8.68 (1H, s, H-2); 9.45 (1H, s, H-10)
1752
2.34 (3H, s, CH3CO); 2.50 (6H, s, 4′,6′-CH3);
7.11 (1H, dd, J6,8 = 2.0, J6,5 = 8.4, H-6); 7.18 (1H, s, H-5);
7.22 (1H, d, J = 2.0, H-8); 7.85 (1H, d, J = 8.4, H-5); 8.45 (1H, s, H-4)
16b
17b
1762,
1734
2.34 (3H, s, CH3CO); 2.53 (3H, s, CH3-6'); 2.68 (3H, s, 2'-CH3);
7.17 (1H, dd, J6,8 = 2.0, J6,5 = 8.4, H-6); 7.27 (1H, d, J = 2.0, H-8);
7.96 (1H, d, J = 8.4, H-5); 8.03 (1H, s, H-5'); 9.07 (1H, s, H-4)
1729
2.53 (3H, s, 6'-CH3); 2.68 (3H, s, 2'-CH3);
7.32 (1H, dd, J6,8 = 1.6, J6,5 = 8.4, H-6); 7.43 (1H, d, J = 1.6, H-8);
7.60 (2H, t, J = 7.6, H-2",6"); 7.74 (1H, t, J = 7.6, H-4");
8.03 (1H, d, J = 8.4, H-5); 8.04 (1H, s, H-5'); 8.18 (2H, d, J = 7.6, H-3",5");
9.09 (1H, s, H-4)
18a
18b
1734
1732
1.17 (6H, t, J = 7.2, 2CH3CH2); 2.50 (6H, s, 4',6'-CH3);
2.74 (4H, q, J = 7.2, 2CH3CH2); 4.09 (2H, s, 8-CH2);
6.64 (1H, d, J = 8.4, H-6); 7.11 (1H, s, H-5'); 7.50 (1H, d, J = 8.4, H-5);
8.35 (1H, s, H-4); (OH exchanged with D2O)
1.19 (6H, t, J = 7.2, 2CH3CH2); 2.50 (3H, s, 6'-CH3); 2.63 (3H, s, 2'-CH3); 2.78 (4H,
q, J = 7.2, 2CH3CH2); 4.12 (2H, s, 8-CH2); 6.66 (1H, d, J = 8.4, H-6); 7.57 (1H,
d, J = 8.4, H-5); 8.01 (1H, s, H-5'); 8.35 (1H, s, H-4); (OH exchanged with D2O)
_______
*1H NMR spectra of compounds 13a, 14a,b, and 15a (given in square
brackets) were recorded in CF3CO2D, the remainder in DMSO-d6.
832

significant a change of chemical shift may only be linked with a different conformation of these substances. The
sole parameter influencing the chemical shift, which may change from one compound to another, is the torsion
angle between the heterocyclic fragments of the molecule. On the basis of the data of NMR spectra given above
the conclusion may be drawn that the H-5' atom of the pyrimidine ring in compounds 7b-9b experiences a
strong nonbonding interaction with the carbonyl oxygen atom, and the H-4 atom of the coumarin nucleus
undergoes a deshielding influence from the unshared pair of electrons of the nitrogen atom of the pyridine ring.
A planar conformation is therefore established in which the similarly charged atoms of nitrogen and oxygen are
removed furthest from one another. On the other hand, in compounds 7a, 9a, and 10a the pyrimidine nucleus is
removed from the plane of the coumarin, as is indicated by the diamagnetic displacement of the H-4 proton
signal by 0.6 ppm.
With the aim of a more detailed investigation of the structure of isomers a and b we studied the NMR
1
spectra of compounds 9a,b. In addition to the proton spectra we also measured heteronuclear H–13C HMQC
and HMBC spectral correlations. Measurement of these spectra enabled reliable assignments of carbon signals
and afforded the possibility of comparing values of chemical shifts of carbon atoms in isomeric compounds. In
such investigations assignment of the signals of protonated carbon atoms may be made on the basis of HMQC
spectra, and assignment of the signals of quaternary carbon atoms on the basis of heteronuclear correlations
through 2-3 chemical bonds in HMBC spectra.
The most important of the correlations found in the HMBC spectra are shown below with pointers, the
found values of the chemical shifts of protons and carbon atoms are shown near the appropriate atoms.
6.72
102.5
10.6
O
HO
O
162.2
156.7
162,9
24.2
N
CH23.48
121.8
114.0
111.7
166.7
158.5
6.77
130.8
145.0
NOE
118.8
N
8.34
7.55
166.7
7.09
NOE
CH3
NOE
2.48
9a
6.72
102.3
NOE
10.90
O
HO
O
7.94
156.6
163,7
160.0
117.9
24.6
CH23.41
114.6
116.0
112.0
168.1
158.5
6.81
132.3
145.2
N
N
167.1
8.90
7.74
26.4
CH3
NOE
2.57
9b
Conclusions on the conformation of molecules 9a,b may be made on the basis of the values of the
chemical shifts of atom C(3). In compound 9a its chemical shift is 121.8 and in product 9b 117.9 ppm. The
chemical shift of this carbon atom is therefore reduced by almost 4 ppm. The diamagnetic displacement of the
signal indicates that in compound 9b conjugation between the heterocyclic fragments of the molecule is
significantly stronger. This is possible by reducing the torsion angle between them on going from product 9a to 9b.
833

Additional information on the relative orientation of the heterocyclic fragments was given by NOESY
spectra. Analysis of the available correlations in the NOESY spectrum of compound 9b shows the absence of a
significant effect between the H-4 atom of the coumarin fragment and H-5' of the pyrimidine nucleus. This
indicates their spatial separation. The conclusion may therefore be drawn as to the existence of this molecule in
the planar (E)-conformation, or in a canted conformation with a small angle between the heterocyclic fragments.
For compound 9a the NOESY method was uninformative in view of the absence of protons in the pyrimidine
nucleus which might have been close to the coumarin proton.
The NMR data therefore indicate that isomers 9a and 9b differ significantly in the torsion angle between
the heterocyclic fragments. If the 9b molecule is practically planar then in 9a the torsion angle between the
heterocyclic fragments has a significant value.
To confirm this conclusion quantum-chemical calculations were carried out of the optimized geometry of
the 9a,b molecules and the NMR spectra were calculated. The orientation of the pyrimidine ring in the planar
structure 9b is given in Fig. 1. Stabilization occurs as a result of intramolecular interactions of two H atoms with
O and N atoms. In spite of the fact that the O···H distance is shorter (Fig. 1) and the charges on both H atoms are
the same (0.132), the mean value of the diagonal elements of the magnetic shielding tensor (σiso) is less for the
hydrogen atom of the coumarin fragment (Hc) σiso = 22.67 ppm (which corresponds to the chemical shift
δH,iso = 9.35 ppm, determined relative to σiso for H atoms in the TMS molecule, calculated by the same method
and on the same basis), than for H of the pyrimidine fragment (Hp) σiso = 23.37 ppm (δH,iso = 8.65 ppm). The
calculated values of δH were slightly overstated in comparison with the experimental δH = 8.90 (Hc) and 7.94
ppm (Hp), which may be caused both by errors of calculation and by the fact that a portion of the molecules are
found in a less stable state (Fig. 2) (the difference in energies of the two structures (Figs. 1 and 2) corresponds to
E1,pl – E1,nonpl = -29.4 kJ/mol, which, as calculations within the framework of DFT by the B3LYP/6-31(d, p)
method showed, is close to the energy of a medium strength H bond), which is characterized by a smaller value
of δH for Hc (7.02 ppm). It should be noted that the value of the anisotropy σii is less for Hc (10.08 ppm) than for
Hp (12.04 ppm) (Fig. 1). It may be concluded that for the planar structure (Fig. 1) the π-electron current shows
up in the value of δH for Hc more strongly than for Hp. This is also indicated by the significant delocalization of
π-orbitals (for example in Fig. 1 the localization of the highest occupied MO is given).
Fig. 1. Most stable, practically planar structure of compound 9b.
A planar structure was unstable for isomer 9a (Fig. 3), optimization of the geometry by the HF/6-31G(d, p)
method gives an angle of about 35o between the planes of the two fragments of this isomer. For Hc the calculated
value of δH = 8.02 ppm, which is somewhat less than the experimental value of δH = 8.34 ppm as a
834

result of errors of calculation or the presence in the system of molecules with a more planar structure. Consequently
additional calculations were carried out with optimization of the geometry within the framework of DFT by the
B3LYP/6-31G(d, p) method, which gave an angle between the planes of about 23o and a value of δH = 8.66 ppm for
atom Hc. The mean value of the two calculations of δH corresponds to the experimental value of δH.
Fig. 2. Less stable structure for isomer 9b (on optimization of the geometry a local minimum
was found on the potential energy surface) with a turn of the pyrimidine fragment by 57.1o
(HF/6-31G(d, p)) or 45.4o (B3LYP/6-31G(d, p)).
Fig. 3. Most stable structure for isomer 9a with a turn of the pyrimidine fragment through an
angle of 35o (HF/6-31G(d, p)) or 23o (B3LYP/6-31G(d, p)).
We also investigated the interaction of pyrimidinylacetonitriles 1a,b with condensed ortho-
hydroxybenzaldehydes, in particular with 8-formyl-7-hydroxychromones 11, 12 obtained by the Daff reaction
from the corresponding 7-hydroxychromones. The condensation was carried out under the same conditions as
for compounds 1 and 2-5. As a result of the reaction of nitrile 1a with aldehyde 11 the intermediate 3-(4-
chlorophenoxy)-9-(4,6-dimethylpyrimidin-2-yl)-8-imino-2-methyl-4H,8H-pyrano[2,3-f]chromen-4-one (13a)
was isolated. Its hydrolysis to the corresponding condensed coumarin 14a was carried out in acetic acid. The
pyrimidine derivatives 4H,8H-pyrano[2,3-f]chromene-4,8-diones 14b and 15a,b were synthesized by the
analogous hydrolysis of partially hydrolyzed condensation products of 1a,b and 11, 12.
835

A strong absorption band was present in the IR spectrum of product 13a for the chromone C=O at
1630 cm-1, and in the spectra of compounds 14a,b and 15a,b there were bands for the stretching vibrations of
1
the C=O of the γ and α pyrone fragments at 1648-1651 and 1742-1749 cm-1 respectively. For the H NMR
spectra of these compounds recorded in CF3CO2D the presence of the most low field singlet of the H-10 proton
at 10.20-10.34 ppm was characteristic. In the spectrum of imino derivative 13a it resonated at 10.21 ppm and in
the corresponding coumarin 14a it was displaced to 10.34 ppm at low field.
The presence of a hydroxyl group at position 7 of coumarins 9a,b made their modification possible. On
acylating products 9a,b with acetic anhydride or benzoyl chloride in pyridine their acetyl (16a,b) and benzoyl
(17b) derivatives were obtained.
The 1H NMR spectra of these derivatives were characterized by the display of signals of the acetyl group
protons at 2.34 ppm (16a,b) or of the aromatic protons of the benzoyl group (17b) and an insignificant
displacement of the protons of the coumarin nucleus towards low field compared with the signals of the initial
products 9a,b. It should be noted that unlike the initial compounds the doublet of the H-8 proton is found at
lower field than the signal of the H-6 proton.
BzCl
or
Ac2O
O
O
N
HO
R
O
O
O
N
Me
X
O
Me
X
Py
Y
Y
9a,b
16a,b, 17b
Me
Me
N(Et)2
O
O
N
HO
CH2(NEt2)2
Me
X
Y
18a,b
Me
16a,b R = Me; 17b R = Ph; 16a, 18a X = N, Y = CH; 1618 b X = CH, Y = N
On aminomethylating 7-hydroxy-3-pyrimidinylcoumarins 9a,b with bis-diethylaminomethane in dioxane
the 8-diethylaminomethyl derivatives 18a,b were synthesized, which was indicated by the absence of a signal
for the H-8 proton at 6.73 ppm observed in the spectra of the initial compounds 9a,b, and the appearance of a
methylene group signal at 4.1 ppm and signals of the ethyl group protons.
Solutions of the synthesized 3-pyrimidinylcoumarins in organic solvents possessed blue fluorescence in
UV light. The most intense fluorescence was observed for the Mannich bases 18a,b.
Previously unknown 3-pyrimidinylcoumarins and their condensed analogs 9-pyrimidinylpyrano-
[2,3-f]chromene-4,8-diones have therefore been synthesized from 2- and 4-pyrimidinylacetonitriles and
substituted salicylic aldehydes. The presence of a hydroxyl group in position 7 of the coumarins made it possible
to modify them by acylation and aminomethylation.
EXPERIMENTAL
1
The IR spectra were taken on a Perkin-Elmer instrument in KBr disks. The H NMR spectra were
recorded in DMSO-d6 and CF3CO2D on a Varian Mercury 400 (400 MHz) spectrometer, internal standard was
836

TMS. Calculations of the optimized geometry were carried out by the HF/6-31G(d, p) or B3LYP/6-31G(d, p)
method, and calculations of the NMR spectra by the GIAO/B3LYP/6-31G(d, p) method using the Gaussian 03
set of programs [7]. A portion of the calculations by the HF/6-31G(d, p) method were carried out using the
GAMESS (version 7.15) set of programs [8, 9]. The purity of the synthesized compounds was checked by TLC
on Silufol UV-254 plates, eluent was chloroform–methanol, 9:1.
6-Chloro-3-(4,6-dimethylpyrimidin-2-yl)-2-iminocoumarin (6a). 5-Chloro-2-hydroxybenzaldehyde
(3) (0.15 g, 1.5 mmol) and piperidine (2 drops) were added to a solution of 4,6-dimethylpyrimidin-2-yl-
acetonitrile (1a) (0.16 g, 1.5 mmol) in 2-propanol (1 ml) with heating. The mixture was maintained at room
temperature for 1 day, the precipitated solid was filtered off, and washed with 2-propanol.
3-Pyrimidinylcoumarins 7-10. Condensation of the appropriate pyrimidinylacetonitrile 1a,b and
substituted 2-hydroxybenzaldehydes 2-5 was carried out analogously to the synthesis of compound 6a. Hydrolysis
of the condensation products to the corresponding coumarins 7a,b, 8b, 9a,b, and 10a was carried out by boiling
(4-6 h) the reaction mixture with 3% aqueous H2SO4 solution (10 ml) (check by TLC), the mixture was cooled,
neutralized with ammonia solution, and the solid filtered off. The partially hydrolyzed condensation product
(0.47 g) of compounds 1a and 5b was dissolved in acetic acid (1 ml), maintained at room temperature for 1 day,
triturated with water (5 ml), the solid was filtered off, and recrystallized from a suitable solvent.
3-(4-Chlorophenyl)-8-formyl-7-hydroxychromone (12). A solution of 3-(4-chlorophenyl)-7-hydroxy-
chromone (1.09 g, 4 mmol) and hexamethylenetetramine (5.6 g, 40 mmol) in acetic acid (20 ml) was heated on a
water bath for 8 h, poured into a boiling mixture (24 ml) of HCl–H2O, 1:2, diluted with water (40 ml), and after
several hours the precipitated solid was filtered off.
3-(4-Chlorophenoxy)-9-(4,6-dimethylpyrimidin-2-yl)-8-imino-2-methyl-4H,8H-pyrano[2,3-f]chro-
men-4-one (13a) was obtained by the condensation of compound 1a (0.33 g, 1 mmol) and 3-(4-chloro-
phenoxy)-8-formyl-7-hydroxy-2-methylchromone (11) (0.15 g, 1 mmol) in 2-propanol (25 ml) by the procedure
for compound 6a.
9-Pyrimidinyl-4H,8H-pyrano[2,3-f]chromene-4,8-diones 14a,b, 15a,b. A solution of compound 13a
(0.46 g, 1 mmol) or the partially hydrolyzed products of compounds 1a,b and 12, 1b and 11 in acetic acid (3 ml)
was boiled for 5 min, cooled, the precipitated solid was filtered off, and washed with ethanol.
7-Acetoxy-3-pyrimidinylcoumarins 16a,b. Acetic anhydride (0.12 g, 1.1 mmol) was added to a
suspension of the appropriate 7-hydroxy-3-pyrimidinylcoumarin 9a,b (0.27 g, 1 mmol) in pyridine (1.5 ml),
heated to solution, and maintained for 2 day at room temperature. The precipitated solid was filtered off, washed
with water, and with methanol.
7-Benzoyloxy-3-(2,6-dimethylpyrimidin-4-yl)coumarin (17b). Benzoyl chloride (0.28 g, 2 mmol) was
added to a solution of 3-(2,6-dimethylpyrimidin-4-yl)-7-hydroxycoumarin (9b) (0.27 g, 1 mmol) in pyridine
(2 ml), maintained for 1 day at room temperature, the precipitated solid was filtered off, and washed with
ethanol.
8-Diethylaminomethyl-7-hydroxy-3-pyrimidinylcoumarins 18a,b. Bis-diethylaminomethane (0.2 g,
1.3 mmol) was added to a suspension of 7-hydroxy-3-pyrimidinylcoumarin (0.27 g, 1 mmol) in dioxane (3 ml)
and boiled for 5-6 h (check by TLC). The solvent was evaporated in vacuum, the oily residue was triturated
under ethyl acetate, and the solid filtered off.
1
The constants and yields of compounds 6-10, 12-18 are given in Table 1, and data of IR and H NMR
spectra in Table 2.
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