One-pot Synthesis of Substituted Quinazolin-4(3H)-ones under Microwave Irradiation

Article abstract of DOI:10.1039/a802853b

Synthesis of the title compounds by cyclocondensation of anthranilic acid, formic acid (or orthoesters) and an amine in one pot under microwave irradiation takes place in a few minutes.

Full text of DOI:10.1039/a802853b

View Article Online / Journal Homepage / Table of Contents for this issue
702 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 702±703$
One-pot Synthesis of Substituted Quinazolin-4(3H)-
ones under Microwave Irradiation$
Kurosh Rad-Moghadam* and Mohammad S. Khajavi
Chemistry Department, Shahid Beheshti University, Evin 19839, Tehran, Iran
Synthesis of the title compounds by cyclocondensation of anthranilic acid, formic acid (or orthoesters) and an amine in
one pot under microwave irradiation takes place in a few minutes.
Preparations of quinazolin-4(3H)-ones are in demand
because of their potential biological and pharmaceutical
activities.1 Synthesis of these compounds by one-pot
reaction of anthranilic acid with an amine and formic acid,
as two separate synthons for N-3 and C-2 in the quinazolin-
4(3H)-one ring system, has not been reported. We wish to
report here a facile synthesis of substituted quinazolin-
4(3H)-ones in fairly high yields by three-component cyclo-
condensation under microwave irradiation.
and during the short reaction time. Attempts to use
CH3CO2H instead of HCO2H were not successful. The
success of the reaction with HCO2H can be ascribed to
the intermediate formation of N-formyl derivatives that
form more readily than other N-acyl derivatives.
Using orthoesters with a catalytic amount of toluene-p-
sulfonic acid instead of formic acid in the above reaction
leads to the formation of 2,3-disubstituted quinazolin-
4(3H)-ones 6 in fairly high yields (Table 1). The reaction
occurs in a much reduced time with respect to conventional
re¯uxing method.5 Recently, it was reported that 2-
substituted-3,1-benzoxazin-4-ones are obtained from micro-
wave promoted reaction of orthoesters with anthranilic acid
in a few minutes and high yields.6 Thus, by considering that
3,1-benzoxazin-4-ones are very prone to react with amines,7
the intermediacy of these compounds in this one-pot syn-
thesis is probable. However, the intermediacy of amidines 5
in these reactions cannot be ruled out (Scheme 2).5,8,11
All the products 4a±f and 6a±c are known and were
characterized by mp, IR, 1H and 13C NMR spectral
analyses.14
In conclusion we have introduced a simple method for
preparing (2),3-(di)substituted quinazolin-4(3H)-ones in a
few minutes and high yields by microwave irradiation of
simple starting materials in one pot.
Experimental
Melting points are uncorrected. Infrared spectra were obtained
in KBr wafers on a Shimadzu IR-470 spectrometer. NMR spectra
were recorded on a JEOL-EX-90 spectrometer at 90 and 22.63 MHz
for 1H and 13C, respectively. J values are given in Hz. Microwave
irradiation was carried out in a National oven, Model 5250 at
2450 MHz. All the experiments were performed in an ecient hood,
in order to avoid contact with vapors.
Scheme 1
General Procedure for Preparation of Compounds 4a±f.ÐA
mixture of anthranilic acid (1.37 g, 10 mmol), formic acid (0.69 g,
15 mmol) and the amine (13 mmol for liquids or 10 mmol for solids)
contained in a tall beaker was placed in the microwave oven and
the beaker was covered with a stemless funnel and irradiated for
time t1 at power p1 (Table 1). After about 5 min, as it cooled to
room temperature, the reaction mixture was irradiated again for t2
at p2. Then the reaction mixture was dissolved in hot ethanol±water
from which products crystallized. Use of 1 M NaOH±ethanol (2:5)
A
mixture of the reactants was irradiated under
conditions described in Table 1 in the absence of solvent or
any dehydrating agents.2 In order to control the reaction,
the irradiation was carried out in two stages (t1 and t2) with
a cooling time between them. In both cases, however, to
ensure optimum yields of products, an excess of formic acid
had to be employed. The reaction can proceed via two
pathways, namely A and B (Scheme 1). Path A involves
N-formylation of anthranilic acid, condensation of the
resultant 2-formamidobenzoic acid 1 with the amine and
then intramolecular amidation of the intermediate amidine
3. On the other hand, the amine instead of anthranilic acid
may be formylated and so the reaction would go through
the known Niementowski reaction (path B). When the
reactions of 2-formamidobenzoic acid 1 with aniline3 and
the condensation of formanilide 2 with anthranilic acid4
were conducted under microwave irradiation, the desired
3-phenylquinazolin-4(3H)-one 4a was obtained in a few
minutes. Thus, the N-formylation step occurs very quickly,
*To receive any correspondence.
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
Scheme 2

View Article Online
J. CHEM. RESEARCH (S), 1998 703
Table 1 Melting points and irradiation conditions
Irradiation conditions
Product
R1
R2
t1/min
p1/W
t2/min
p2/W
Yield (%)a
Mp/8C
Lit. mp/8C
4a
4b
4c
4d
4e
4f
6a
6b
6c
Ph
Ð
Ð
Ð
Ð
Ð
Ð
Ph
Ph
Me
3
3
3
3
3
3
5
5
5
210
210
210
210
210
210
385
385
385
4
6
3
3
3
3
1
2
1
385
385
385
385
385
385
490
490
490
76
68
73
72
84
87
79
81
89
139±140
119±120
182±183
146±147
130±131
134.5±135.5
159±160
138±139
147±149
138±139b
117±118b
180±181c
148±149d
126±128e
135f
PhCH2
4-ClC6H4
4-MeC6H4
4-EtC6H4
3,4-Me2C6H3
Ph
158±159g
137±139g
147±148h
PhCH2
Ph
aYield of pure isolated product based on anthranilic acid. bRef. 12. cRef. 8. dRef. 13. eRef. 9. Ref. 3. gRef. 10. hRef. 11.
f
as crystallization solvent accelerates the crystallization with a slight
decrease in yield. Products before analysis were recrystallized from
95% ethanol.
Received, 16th April 1998; Accepted, 8th July 1998
Paper E/8/02853B
1
Selected Data for 4f.ÐColorless needles, ꢀmax (KBr)/cm 1699
.
(C O), 1598, 1463 (pyrimidine ring); ꢁH (CDCl3) 8.36 (1 H, dd, J 7.7
and 0.7, 5-H), 8.11 (1 H, s, 2-H), 7.05±7.85 (6 H, m, 6-, 7-, 8-H
and Ar), 2.3 (6 H, s, 2 Me); ꢁC [(CD3)2SO] 160.07 (C-4), 147.74
(C-2), 147.25 (C-8a), 137.39 (C-1'), 137.15 (C-7), 135.23, 134.62
(C-3' and -4'), 121.92 (C-4a), 124.56, 126.44, 127.33, 127.41, 128.11,
130.10 (6 CH), 19.34 and 19.06 (2 Me).
Alternative Procedures for Preparation of 4a.ÐA mixture of
2-formamidobenzoic acid7 1 (1.65 g, 10 mmol) and aniline (1.21 g,
13 mmol) contained in a tall beaker was covered with a stemless
funnel and irradiated for 6 min at 385 W. After cooling, the
resultant red±brown residue was crystallized from hot ethanol±
water, yielding 1.57 g (71%) of 4a (path A). In order to verify
the viability of path B under the above condition, a mixture of
formanilide 2a (1.21 g, 10 mmol), anthranilic acid (1.37 g, 10 mmol)
and a few drops of N,N-dimethylacetamide, as fusion accelerator,
were irradiated as above. The resultant residue after crystallization
from hot ethanol±water gave 1.81 g (83%) of 4a.
References
1 (a) D. Gravier, J. P. Dupin, F. Casadebaig, G. Hou, M. Boisseau
and H. Bernard, Pharmazie, 1992, 47(2), 91; (b) B. R. Baker,
R. E. Schaub, J. P. Joseph, F. J. McEvoy and J. H. Williams,
J. Org. Chem., 1953, 18, 133; (c) J. F. Wolfe, T. L. Rathman,
M. C. Sleevi, J. A. Campbell and T. D. Greenwood, J. Med.
Chem., 1990, 33, 161.
2 R. Hurmer and J. Vernin, Br. Pat., 1967, 1, 093, 977 (Chem.
Abstr., 1968, 68, 39648w).
3 S. S. Parmar, K. Kishor, P. K. Seth and R. C. Arora, J. Med.
Chem., 1969, 12, 138.
4 J. F. Meyer and E. C. Wagner, J. Org. Chem., 1943, 8, 239.
5 R. W. Leiby, J. Org. Chem., 1985, 50, 2926.
6 M. S. Khajavi, N. Montazari and S. S. Sadat-Hosseini, J. Chem.
Res. (S), 1997, 286.
General Procedure for Preparation of Compounds 6a±c.ÐA
mixture of anthranilic acid (1.37 g, 10 mmol), triethyl orthoacetate
or triethyl orthobenzoate (20 mmol) and the amine (13 mmol) with
a catalytic amount of toluene-p-sulfonic acid (PTSA) contained in a
tall beaker was placed in the microwave oven and covered with a
stemless funnel. The beaker was irradiated for 5 min at 385 W and
then for 1±2 min at 490 W. The resultant residues were crystallized
from ethanol±water or ethanol±1 M NaOH (5:2 v/v). The separated
crystals were further recrystallized from 95% ethanol.
7 D. T. Zentmyer and E. C. Wagner, J. Org. Chem., 1949, 14,
967.
8 C. Runti, C. Nisi and L. Sindellari, Ann. Chim., 1961, 51, 719.
9 K. Nagahara, K. Takagi and T. Ueda, Chem. Pharm. Bull.,
1976, 24 (6), 1310.
10 P. A. Petyunin, Yu. V. Kozhevnikov and I. S. Berdinskii, Uch.
Zap., Perm. Gos. Univ., 1966, 141, 309 (Chem. Abstr., 1968, 69,
77226k).
11 L. A. Errede, J. J. McBrady and H. T. Oien, J. Org. Chem.,
1977, 42, 656.
1
Selected Data for 6a.ÐColorless needles, ꢀmax (KBr)/cm 1679
.
(C O), 1599, 1583, 1463 (pyrimidine ring); ꢁH (CDCl3) 8.36 (1 H,
12 P. A. Petyunin and Yu. V. Kozhevnikov, Zh. Obshch. Khim.,
1960, 30, 2352 (Chem. Abstr., 1961, 55, 9402c).
13 J. Stefan, Ger., O€en, 1969, 1, 908, 097 (Chem. Abstr., 1969, 71,
124484w).
14 M. Chakrabarty, A. Batabyal, M. S. Morales-Rios and P. Joseph-
Nathan, Monatsh. Chem., 1995, 126, 789.
ddd, J 7.8, 1.5 and 0.5, 5-H), 7.70±7.90 (2 H, m, 7-, 8-H), 7.05±7.65
(11 H, m, 6-H and 2 Ph); ꢁC [(CD3)2SO] 161.50 (C-4), 155.27 (C-2),
147.33 (C-8a), 135.68, 134.87 (C-1' and -10), 137.88, 129.57, 128.97,
128.85, 128.68, 128.27, 127.58, 127.50, 127.30 (9 CH), 126.56 (C-5),
120.78 (C-4a).