Quinazolines. 4*. Acylation of quinazoline-2,4-diones with aromatic acids chlorides in the presence of ferric chloride hexahydrate

Article abstract of DOI:10.1007/s10593-011-0675-6

The interaction of quinazoline-2,4-diones with aromatic acids chlorides in nitrobenzene has been investigated in the presence of FeCl₃? 6H₂O. Optimum conditions for the acylation reaction have been developed, the used 4-substituted b

Full text of DOI:10.1007/s10593-011-0675-6

Chemistry of Heterocyclic Compounds, Vol. 46, No. 11, February, 2011 (Russian Original Vol. 46, No. 11, November, 2010)
QUINAZOLINES. 4*. ACYLATION OF QUINAZOLINE-
2,4-DIONES WITH AROMATIC ACIDS CHLORIDES
IN THE PRESENCE OF FERRIC CHLORIDE
HEXAHYDRATE
R. Sh. Kuryazov1, Yu. R. Takhirov1, D. A. Dushamov1, N. S. Mukhamedov1*,
K. K. Turgunov1, Kh. M. Shakhidoyatov1, and B. Tashkhodjaev1
The interaction of quinazoline-2,4-diones with aromatic acids chlorides in nitrobenzene has been
investigated in the presence of FeCl3·6H2O. Optimum conditions for the acylation reaction have been
developed, the used 4-substituted benzoyl chlorides have been put in order of relative activity,
depending on the degree of their electrophilicity.
Keywords: 6-aroylquinazoline-2,4-diones, quinazoline-2,4-diones, aromatic acid chlorides, acylation, X-ray
structural analysis.
Quinazoline derivatives have a broad spectrum of biological activity. Among them are found fungicides,
insecticides, bactericides, plant growth regulators [2], and also substances have been discovered possessing
anticholine esterase, anticonvulsive, sedative, tranquilizing, bronchodilating, and other activities [3-8].
Previously we have studied the acylation of benzoxazolin-2-ones [9, 10], benzothiazolin-2-ones [11,
12], and benzimidazolin-2-ones [13,14] with aromatic acid chlorides using small quantities of catalysts. In a
continuation of our investigations on electrophilic substitution in a series of quinazoline derivatives [1] and with
the aim to broaden the boundaries of the rules previously developed [9-14], the acylation of quinazoline-2,4-
diones 1a-c with aromatic acid chlorides 2a-e in the presence of small quantities of ferric chloride hexahydrate
has been studied in the present work. The physicochemical characteristics of the 6-aroyl-quinazoline-2,4-diones
3a-o synthesized in good yield are given in Table 1.
We determined the optimum conditions for acylation. The highest yields for compounds 3 were
achieved at molar reactant ratios of 1:2:FeCl3·6H2O = 1:1.5:0.01.
It was shown that the reaction rate depended on the character of the substituent in reactants 1 and 2. The
yields of products 3 were greater in the case of 1,3-dimethylquinazoline-2,4-dione 1c, than in the case of
quinazoline-2,4-dione 1a.
_______
* Communication 3, see [1].
** To whom correspondence should be addressed, e-mail: nasirxon@rambler.ru, k.rustam80@rambler.ru
1S. Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences, Republic of Uzbekistan,
Tashkent 100170, Uzbekistan.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1702-1708, November, 2010.
Original article submitted May 5, 2010.
1380
0009-3122/11/4611-1380©2011 Springer Science+Business Media, Inc.

O
COCl
O
C
O
.
6H2O
FeCl3
N
R
R2
+
N
R
N
O
R2
2 a–e
N
O
R1
R1
3 a–o
1 a–c
1 a R = R1 = H, b R = H, R1 = Me, c R = R1 = Me; 2 a R2 = H, b R2 = Me, c R2 = OMe,
d R2 = Br, e R2 = NO2; 3ae R = R1 = H, fj R = H, R1 = Me, ko R = R1 = Me, a,f,k R2 = H,
b,g,l R2 = Me, c,h,m R2 = OMe, d,i,n R2 = Br, e,j,o R2 = NO2
This may probably be explained by the positive inductive (+I) and mesomeric (+M) effects of the
methyl groups, increasing the nucleophilicity of the dione molecule and facilitating electrophilic attack from the
side of the acylating agent 2.
The results of experiments carried out under identical conditions with acylating agents 2a-e indicate the
varied activity of the latter decreasing in the series:
4-O2NC6H4COCl > 4-BrC6H4COCl > PhCOCl > 4-MeC6H4COCl > 4-MeOC6H4COCl
TABLE 1. Physicochemical Characteristics of Compounds 3a-o
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C*
Yield, %
N
3а
3b
3c
3d
3e
3f
С15H10N2O3
11.26
10.52
9.81
10.00
9.76
9.45
7.93
8.11
13.26
13.50
9.81
10.00
9.35
9.52
8.69
9.03
8.14
7.79
13.29
12.92
9.83
9.52
9.33
9.09
325-326
338-339
331-333
380-382
298-300
302-304
307-308
300-301
296-298
310-311
191-192
140-141
133-135
218-220
240-241
54
45
41
70
76
62
51
45
74
82
68
55
49
77
86
С16H12N2O3
С16H12N2O4
С15H9BrN2O3
С15H9N3O5
С16H12N2O3
С17H14N2O3
С17H14N2O4
С16H11BrN2O3
С16H11N3O5
С17H14N2O3
С18H16N2O3
С18H16N2O4
С17H13BrN2O3
С17H13N3O5
3g
3h
3i
3j
3k
3l
3m
3n
3o
8.86
8.64
7.81
7.50
12.17
12.38
_______
*Solvents for recrystallization: ethanol (compounds 3a-j,n,o) and benzene
(compounds 3k-m).
1381

The introduction of electrophilic substituents (NO2, Br) into the benzoyl chloride molecule leads to the
increase of acylation products 3 yields but the introduction of an electron-withdrawing group (Me, MeO) to the
reduction in them.
The composition and structure of the synthesized compounds 3a-o were confirmed by the results of
1
elemental analysis and data of IR spectra and mass spectrometry (Table 2), H NMR spectra (Table 3), and in
the case of compound 3k by the data of X-ray analysis also.
Absorption bands for the stretching vibrations of the 6-C=O group (1670-1685 cm-1) and for the CH out-
of-plane deformation vibrations of the 1,2,4-trisubstituted benzene ring (805-825 and 870-885 cm-1) were
characteristic of the IR spectra of compounds 3a-o (Table 2).
In the mass spectra of compounds 3a-o peaks were detected for molecular and fragment ions confirming
completely the proposed structures (Table 2). The mass spectra of compounds 3a-o, independent of the
substituents R, R1, and R2 nature, showed similar fragmentation with cleavage of the Ar–CO bond.
O
C
O
.
+
R2
N
R
N
O
R1
There were characteristic signals in the 1H NMR spectra of compounds 3a-o (Table 3) for protons of the
quinazolinedione fragment, a doublet for H-5 at 8.18-8.21 (mJ = 1.7-1.9), a doublet of doublets for H-7 at 8.03-
8.07 (mJ = 1.7-1.9 and oJ = 8.5-8.6), and also a doublet for H-8 at 7.59-7.66 ppm (oJ = 8.5-8.6 Hz). Multiplets for
the aromatic protons of the acyl residue were found at 7.45-7.55 ppm, signals of the protons of the alkyl
substituents R, R1, and R2 were at fairly high field (2.30-3.81), and the protons of the NH group were at low
field (9.51-11.87 ppm).
We have carried out an X-ray structural investigation of compound 3k to represent the spatial structure
of acylation products 3. The general form of the 3k molecule is shown in Fig. 1. Bond lengths and valence
angles are close to the usual values [15].
TABLE 2. IR and Mass Spectra of Compounds 3a-o
Com-
pound
IR spectrum, , cm–1
2-С=O, 4-С=O, 6-С=О
Mass-spectrum,
[M]+ m/z (Irel, %)
1-NH, 3-NH
3а
3b
3c
3d
1715, 1700, 1670
1710, 1695, 1675
1710, 1695, 1675
1715, 1700, 1680
3200, 3090
3210, 3100
3220, 3110
3230, 3120
266 (27)
280 (37)
296 (41)
344 (52)
(for 79Br)
311 (36)
280 (41)
294 (61)
310 (43)
358 (48)
(for 79Br)
325 (54)
294 (100)
308 (86)
324 (81)
372 (83)
(for 79Br)
339 (77)
3e
3f
1715, 1700, 1685
1715, 1700, 1670
1710, 1695, 1675
1710, 1700, 1675
1715, 1700, 1680
3240, 3130
3070
3g
3h
3i
3080
3090
3100
3j
1715, 1700, 1685
1710, 1700, 1670
1710, 1695, 1675
1710, 1695, 1675
1710, 1700, 1680
3110
—
3k
3l
—
3m
3n
—
—
3o
1710, 1700, 1685
—
1382

Fig. 1. Spatial structure of the compound 3k molecule.
TABLE 3. 1H NMR Spectra of Compounds 3a-o
Com-
pound
Chemical shifts, , ppm (J, Hz)
3а
3b
3c
3d
3e
11.87 (1H, s, H-3); 9.51 (1H, s, H-1); 8.18 (1H, d, J5,7 = 1.7, H-5);
8.05 (1H, dd, J7,5 = 1.7, J7,8 = 8.5, H-7); 7.62 (1H, d, J8,7 = 8.5, H-8);
7.45 (5H, m, C6H5)
11.86 (1H, s, H-3); 9.53 (1H, s, H-1); 8.19 (1H, d, J5,7 = 1.7, H-5);
8.03 (1H, dd, J7,5 = 1.7, J7,8 = 8.6, H-7); 7.63 (1H, d, J8,7 = 8.6, H-8); 7.48 (4H, m, C6H4);
2.30 (3H, s, C6H4–CH3)
11.84 (1H, s, H-3); 9.53 (1H, s, H-1); 8.19 (1H, d, J5,7 = 2.2, H-5);
8.01 (1H, dd, J7,5 = 2.2, J7,8 = 8.6, H-7); 7.59 (1H, d, J8,7 = 8.6, H-8);
7.48 (4H, m, C6H4); 3.81 (3H, s, C6H4–OCH3)
11.81 (1H, s, H-3); 9.55 (1H, s, H-1); 8.21 (1H, d, J5,7 = 1.8, H-5);
8.03 (1H, dd, J7,5 = 1.8, J7,8 = 8.6, H-7); 7.64 (1H, d, J8,7 = 8.6, H-8);
7.50 (4H, m, C6H4)
11.85 (1H, s, H-3); 9.60 (1H, s, H-1); 8.24 (1H, d, J5,7 = 1.7, H-5);
8.05 (1H, dd, J7,5 = 1.7, J7,8 = 8.5, H-7); 7.65 (1H, d, J8,7 = 8.5, H-8);
7.51 (4H, m, C6H4)
3f
11.72 (1H, s, H-3); 8.21 (1H, d, J5,7 = 1.7, H-5); 8.08 (1H, dd, J7,5 = 1.7, J7,8 = 8.5, H-7);
7.62 (1H, d, J8,7 = 8.5, H-8); 7.53 (5H, m, C6H5); 3.45 (3H, s, 1-CH3)
3g
11.71 (1H, s, H-3); 8.20 (1H, d, J5,7 = 1.8, H-5); 8.07 (1H, dd, J7,5 = 1.8, J7,8 = 8.6, H-7);
7.65 (1H, d, J8,7 = 8.6, H-8); 7.50 (4H, m, C6H4); 3.44 (3H, s, 1-CH3);
2.31 (3H, s, C6H4–CH3)
3h
11.69 (1H, s, H-3); 8.19 (1H, d, J5,7 = 1.8, H-5); 8.06 (1H, dd, J7,5 = 1.8, J7,8 = 8.6, H-7);
7.64 (1H, d, J8,7 = 8.6, H-8); 7.55 (4H, m, C6H4); 3.82 (3H, s, C6H4–OCH3);
3.44 (3H, s, 1-CH3)
3i
11.70 (1H, s, H-3); 8.20 (1H, d, J5,7 = 1.7, H-5); 8.05 (1H, dd, J7,5 = 1.7, J7,8 = 8.6, H-7);
7.66 (1H, d, J8,7 = 8.6, H-8); 7.52 (4H, m, C6H4); 3.44 (3H, s, 1-CH3)
3j
3k
11.71 (1H, s, H-3); 8.20 (1H, d, J5,7 = 1.8, H-5); 8.04 (1H, dd, J7,5 = 1.8, J7,8 = 8.5, H-7);
7.63 (1H, d, J8,7 = 8.5, H-8); 7.49 (4H, m, C6H4); 3.44 (3H, s, 1-CH3)
8.21 (1H, d, J5,7 = 1.9, H-5); 8.03 (1H, dd, J7,5 = 1.9, J7,8 = 8.6, H-7);
7.64 (1H, d, J8,7 = 8.6, H-8); 7.47 (5H, m, C6H5); 3.38 (3H, s, 1-CH3); 3.22 (3H, s, 3-CH3)
3l
8.19 (1H, d, J5,7 = 1.8, H-5); 8.04 (1H, dd, J7,5 = 1.8, J7,8= 8.5, H-7);
7.67 (1H, d, J8,7 = 8.5, H-8); 7.45 (4H, m, C6H4); 3.37 (3H, s, 1-CH3);
3.21 (3H, s, 3-CH3); 2.31 (3H, s, C6H4–CH3)
3m
3n
3o
8.20 (1H, d, J5,7 = 1.8, H-5); 8.05 (1H, dd, J7,5 = 1.8, J7,8 = 8.6, H-7);
7.66 (1H, d, J8,7 = 8.6, H-8); 7.46 (4H, m, C6H4); 3.80 (3H, s, C6H4–OCH3);
3.36 (3H, s, 1-CH3); 3.21 (3H, s, 3-CH3)
8.21 (1H, d, J5,7 = 1.7, H-5); 8.05 (1H, dd, J7,5 = 1.7, J7,8 = 8.5, H-7);
7.63 (1H, d, J8,7 = 8.5, H-8); 7.46 (4H, m, C6H4); 3.37 (3H, s, 1-CH3);
3.20 (3H, s, 3-CH3)
8.19 (1H, d, J5,7 = 1.8, H-5); 8.03 (1H, dd, J7,5 = 1.8, J7,8 = 8.6, H-7);
7.62 (1H, d, J8,7 = 8.6, H-8); 7.45 (4H, m, C6H4); 3.36 (3H, s, 1-CH3);
3.20 (3H, s, 3-CH3)
1383

The quinazolinedione nucleus and benzene ring are planar with the precision of ±0.035 and ±0.005 Å
respectively. The 6-C=O group is turned relative to the plane of the benzene ring and the quinazolinedione
nucleus by 31.3(1) and 28.0(1)o respectively, which is characteristic for carbonyl groups linked with aromatic
systems [16]. No anomalously short intermolecular contacts were detected in the crystal.
EXPERIMENTAL
The IR spectra were recorded on a Perkin-Elmer Spectrum GX Fourier spectrometer in KBr disks. The
1H NMR spectra were taken on a UNITY 400+ (400 MHz) spectrometer in DMSO-d6, internal standard was
TMS. Mass spectra were recorded on a Kratos MS-30 instrument with direct insertion of sample into the ion
source (ionization energy 70 eV). A check on the progress of reactions and the homogeneity of the synthesized
compounds was effected by TLC on Sorbfil (Russia) and Whatman® UV-254 (Germany) plates in the solvent
system benzene–ethanol, 5:1, developing with KMnO4 (1 g) in H2SO4 (4 ml) and H2O (96 ml).
6-Benzoylquinazoline-2,4-dione (3a). A mixture of quinazoline-2,4-dione 1a (1.62 g, 10 mmol),
benzoyl chloride 2a (2.1 g, 15 mmol), and FeCl3·6H2O (0.027 g, 0.1 mmol) in nitrobenzene (15 ml) was
maintained at 200-210oC for 4 h. The solvent was steam distilled, the solid filtered off, washed with water,
dried, and recrystallized. Compound 3a (1.43 g, 54%) was obtained.
6-Aroylquinazoline-2,4-diones 3b-o were synthesized analogously.
X-ray Structural Investigation. The crystals of 6-benzoyl-1,3-dimethylquinazoline-2,4-dione (3k)
were obtained from a solution in acetone by slow evaporation of the solvent. The X-ray structural investigation
was carried out on a Stoe Stadi-4 diffractometer (MoKα-radiation, graphite monochromator, ω/2θ scanning) at
room temperature. No absorption corrections were introduced. Crystallographic data were: monoclinic, space
group P21/n, a = 7.665(4), b = 14.388(6), c = 13.032(9) Å, β = 105.73(5)o, V = 1383.4(13) Å3, Mr = 294.30,
Z = 4, dcalc = 1.413 g/cm3, μ =0,099, scanning region 2θ ≤ 50o, crystal size 0.50 x 0.25 x 0.25 mm.
The structure was solved by the direct method with the SHELXS-97 program and refined by the least
squares method in an isotropic–anisotropic approximation with the SHELXL-97 program. The coordinates of
the methyl group hydrogen atoms were found from an electron density difference synthesis. The positions of the
remaining hydrogen atoms were established geometrically and were refined with fixed isotropic displacement
parameters Uiso = nUeq, where n = 1.2 for methylene groups and the aromatic ring, and Ueq is the equivalent
isotropic displacement parameter of the corresponding carbon atoms. Refinement parameters were wR2 = 0.143,
S = 1.19 (for all 2436 reflections), R1 = 0.065 (1145 I ≥ 2σ(I)).
Details of the X-ray analysis in the form of a CIF file have been deposited in the Cambridge structural
data Base (deposit CCDC 765943).
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