A novel route for the preparation of chromenoquinazolines

Full text of DOI:10.1007/s10593-012-1134-8

Chemistry of Heterocyclic Compounds, Vol. 48, No. 8, November, 2012 (Russian Original Vol. 48, No. 8, August, 2012)
A NOVEL ROUTE FOR THE PREPARATION
OF CHROMENOQUINAZOLINES
O. A. Mazhukina1*, A. G. Platonova1, O. V. Fedotova1, and P. V. Reshetov2
Keywords: 2H-chromen-2-one, chromenoquinazoline, microwave irradiation, Biginelli reaction.
It is known that multicomponent reactions involving three or more reagents reacting successively to
form a novel product containing the basic structural components of all of the starting molecules are a promising
approach for the preparation of heterocyclic compounds. One such method is the Biginelli reaction [1-5].
In this study, 3-(1,3-dioxobutan-1-yl)-2H-chromen-2-one (1), aromatic aldehydes 2a,b, and urea (3)
have been used in the Biginelli reaction for the first time. The reaction has been carried out, again for the first
time, in both the classical one-pot variation via refluxing in ethanol in the presence of hydrochloric acid, and
also solvent-free by 700 Watt microwave irradiation and zinc chloride catalyst.
It was found that the nature of the substituent in the aromatic component did not affect the direction of
transformation and the yield of the novel, linearly structured condensed systems, namely, 11a-hydroxy-
4-phenyl- (4) and 11a-hydroxy-4-(4-methoxyphenyl)-4,4a,11a,12-tetrahydro-2H-chromeno[3,2-g]quinazoline-
2,5(3H)-diones (5). The yield (43-85%) depends on the reaction conditions, reaching the maximum values for
the microwave action on the reagent mixture.
Formation of compounds 4, 5 points to a Schiff type condensation of the aldehydes 2a,b and urea (3) in
the first stage. Without separation, the intermediate is protonated and plays the role of electrophile in attacking
the 3-(1,3-dioxobutan-1-yl)-2H-chromen-2-one (1) at the methylene group, to give the adduct A. An
intramolecular nucleophilic attack of the carbonyl group by the amino group and carbocyclization of the adduct
B gives the stable condensed systems 4, 5.
1H NMR spectroscopic data suggests that chromenoquinazolines exist in the tautomeric forms 4,4' and
5,5'. The two methine protons on the tertiary carbon atoms appear as multiplets in the regions 2.17-2.72 and
3.58-3.81 ppm respectively, and this is likely associated with the presence of three chiral centers and the
possibility of the products occurring in multiple stereoisomeric forms.
1
13
IR spectra were recorded on an FSM 1201 FTIR spectrometer using KBr pellets. The H and C NMR
spectra were recorded on a Varian 400 spectrometer (400 and 100 MHz, respectively) using DMSO-d6 with TMS as
internal standard. Elemental analysis was carried out on a Perkin Elmer 2400 Series II CHNS/O analyzer.
_______
*To whom correspondence should be addressed, e-mail: mazhukinaoa@gmail.com.
1Chemistry Institute, N. G. Chernyshevsky Saratov State University, 83 Astrakhanskaya St., Saratov 410012,
Russia.
2
V. I. Razumovsky State Medical University, 112 Bolshaya Kazachya St., Saratov 410012, Russia; e-mail:
grigoryevaoa@mail.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1368-1370, August, 2012.
Original article submitted March 5, 2012.
1278
0009-3122/12/4808-1278©2012 Springer Science+Business Media New York

Melting points were determined by the capillary method. Monitoring of the course of the reaction and the purity
of the compounds obtained was carried out by TLC on Silufol UV-254 plates using acetone–ethyl acetate–
hexane (1:2:3) as eluent and visualized with iodine vapor.
O
NH2
NH
NH2
+
H2N
NH2
CHO
H+
3
O
N
O
H
R
R
R
R
2a,b
O
O
Me
O
O
1
O
H
NH
O
O
Me
O
O
NH2
A
R
R
O
O
O
NH
NH
O
N
H
O
O
N
H
O
OH
Me
B
4', 5'
R
O
NH
O
N
O
OH
4, 5
2a, 4 R = H; 2b, 5 R = OMe
11a-Hydroxy-4-phenyl-4,4a,11a,12-tetrahydro-2H-chromeno[3,2-g]quinazoline-2,5(3H)-dione (4).
A. A mixture of 3-(1,3-dioxobutan-1-yl)-2H-chromen-2-one (1) (0.50 g, 2.2 mmol), benzaldehyde (2a) (0.24 g,
0.23 ml, 2.2 mmol), urea (3) (0.13 g, 2.2 mmol) and conc. HCl (0.1 ml) was refluxed in EtOH (20 ml) for 120 h.
The reaction mixture was cooled, solvent was removed, and the residue was treated with hexane. The
precipitated crystals were separated, washed with hexane and dried. Yield 0.28 g (43%); mp 94-95ºC.
B. 3-(1,3-Dioxobutan-1-yl)-2H-chromen-2-one (1) (2.00 g, 8.7 mmol), urea (3) (0.78 g, 13 mmol), and
benzaldehyde (2a) (0.94 g, 7.9 mmol) were placed in a porcelain crucible, EtOH (5 drops) and ZnCl2 (0.01 g,
0.07 mmol) were added. The reaction mixture was subjected to 700 W microwave irradiation for 20 min. The
yellow crystals formed were washed with water. Yield 2.66 g (85%); mp 94-95ºC. A sample mixed with that
prepared by method A did not give a melting point depression. IR spectrum, , cm-1: 1692 (C(5)=O), 1709
1
(C(2)=O), 3240-3230 (NH), 3480-3380 (OH). H NMR spectrum, , ppm (J, Hz): 2.17-2.66 (1Н, m, 4a-СН);
3.51 (2Н, br. s, 12-СН2); 3.66-3.81 (1Н, m, 4-СН); 6.77-7.64 (10Н, m, Н-6,7,8,9,10, H Ph); 8.66 (1Н, d,
1279

13
J = 7.8, NH); 11.37 (1Н, br. s, ОН). C NMR spectrum, , ppm: 40.2 (С-12); 48.5 (C-4); 54.0 (C-4a); 92.1
(C-11а); 114.3; 117.8; 120.8; 121.2; 122.5; 122.9; 135.8; 138.4; 141.1; 143.6 (C Ar); 134.0 (C-6); 140.3 (C-5a);
154.7 (C-10a); 163.2 (C-2); 164.5 (C-12a); 196.1 (C-5). Found, %: С 69.59; Н 4.06; N 8.07. C21H16N2O4.
Calculated, %: С 69.99; Н 4.48; N 7.77.
11a-Hydroxy-4-(4-methoxyphenyl)-4,4a,11a,12-tetrahydro-2H-chromeno[3,2-g]quinazoline-2,5(3H)-
dione (5). A. Compound 5 was prepared similarly to compound 4 by using 3-(1,3-dioxobutan-1-yl)-
2H-chromen-2-one (1) (0.5 g, 2.2 mmol), urea (3) (0.13 g, 2.2 mmol), and 4-methoxybenzaldehyde (2b) (0.34 g,
0.30 ml, 2.2 mmol) and refluxing for 70 h. Yield 0.37 g (59%); mp 81-82ºC.
B. Compound 5 was prepared similarly to compound 4, by using 3-(1,3-dioxobutan-1-yl)-2H-chromen-
2-one (1) (0.5 g, 2.2 mmol), urea (3) (0.13 g, 2.2 mmol), 4-methoxybenzaldehyde (2b) (0.34 g, 2.2 mmol), and
ZnCl2 (0.01 g, 0.07 mmol). Yield 0.48 g (76%); mp 80-81ºC. A sample mixed with that prepared by method A
did not give a melting point depression. IR spectrum, , cm-1: 1693 (C(5)=O), 1712 (C(2)=O), 3238-3225 (NH),
3460-3350 (OH). 1H NMR spectrum, , ppm (J, Hz): 2.17 (3Н, s, OCH3); 2.20-2.72 (1Н, m, 4а-СН); 3.02 (2Н,
br. s, 12-СН2); 3.58-3.73 (1Н, m, 4-СН); 6.65-7.75 (9Н, m, Н-6,7,8,9,10, H Ar); 7.83 (1Н, d, J = 7.8, NH); 9.89
13
(1Н, br. s, ОН). C NMR spectrum, , ppm: 28.9 (CH3); 41.0 (С-12); 49.6 (C-4); 52.2 (C-4a); 90.1 (C-11а);
114.1; 114.3; 115.1; 115.5; 120.3; 121.1; 128.0; 128.1; 128.6; 134.8 (C Ar); 135.9 (C-6); 145.8 (C-5a); 156.7
(C-10a); 160.5 (C-2); 163.6 (C-12a); 192.7 (C-5). Found, %: С 67.39; Н 4.67; N 6.79. С22H18N2O5. Calculated,
%: С 67.69; Н 4.65; N 7.18.
REFERENCES
1.
2.
3.
4.
5.
S. V. Vdovina and V. A. Mamedov, Russ. Chem. Rev., 77, 1017 (2008).
J. Lu and Y. Bai, Synthesis, 466 (2002).
K. S. Niralwad, B. B. Shingate, and M. S. Shingare, Tetrahedron Lett., 51, 3616 (2010).
D. S. Bose, L. Fatima, and H. B. Mereyala, J. Org. Chem., 68, 587 (2003).
M. Kidwai and P. Sapra, Synth. Сommun., 32, 1639 (2002).
1280