A simple and efficient synthesis of new 6-arylimino-6H-indolo[2,1-b]quinazolin-12-ones under microwave irradiation

Article abstract of DOI:10.3987/COM-03-9937

A ring opening and selective reaction of isatoic anhydride with isatin-3-imine in the presence of catalytic amount of KF-Al₂O ₃, a reusable catalyst, to yield a novel series of 6-arylimino-6H-indolo[2,1-b]quinazolin-12-one under microwave irradiation, is described.

Full text of DOI:10.3987/COM-03-9937

HETEROCYCLES, Vol. 63, No. 4, 2004, pp. 791 - 795
Received, 20th October, 2003, Accepted, 22nd January, 2004, Published online, 30th January, 2004
A SIMPLE AND EFFICIENT SYNTHESIS OF NEW 6-ARYLIMINO-
6H-INDOLO[2,1-b]QUINAZOLIN-12-ONES UNDER MICROWAVE
IRRADIATION
Javad Azizian,* Ali A. Mohammadi, F. Ardakani, Ali R. Karimi, and
Mohammad R. Mohammadizadeh
Department of Chemistry, Faculty of Science, Shahid Beheshti University,
P. O. Box 19395-4716, Tehran, Iran
E-mail: j-azizian@cc.sbu.ac.ir
Abstract- A ring opening and selective reaction of isatoic anhydride with isatin-3-
imine in the presence of catalytic amount of KF-Al2O3, a reusable catalyst, to yield a
novel series of 6-arylimino-6H-indolo[2,1-b ]quinazolin- 12-one under microwave
irradiation, is described.
Polyheterocyclic systems with quinazoline ring skeleton, for example, the pyrroloquinazolinoquinoline
alkaloids, luotonin A (1)1 and indolopyridoquinazolinone, rutaecarpin (2),2 are isolated from plants. They are
well known for their antitumor activity and intrinsic hypertensive, diuretic and uterotonic properties,
respectively (Figure 1).
O
O
N
N
N
N
N
N
H
1
2
Figure 1
There exist numerous methods for the synthesis of quinazolinones and their derivatives.3 Furthermore, the
synthesis of these useful compounds has been reported by fusing the quinazolinone derivatives prepared from
anthranilic acid,4 by the cyclocondensation of 3-oxo-1H-pyrrolo[3,4-b]quinolin with isatoic anhydride,5 and by
the condensation of 2-amino-N-(1-H-benzimidazol-2-yl)benzamide with orthoester,6 under microwave
irradiation.
Very recently, we have reported the preparation of quinazolinediones derivatives by the three-component
condensation reaction of isatoic anhydride, primary amine and urea or thiourea,7a and by oxidation of isatin-3-
imines.7b Along this line, we planned the synthesis of new tetracyclic 6-arylimino-6H-indolo[2,1- b]quinazolin-

12-one (5), from isatoic anhydride8 as a useful starting material and isatin-3-imine under microwave
irradiation.9
We have found that the condensation of isatin-3-phenylimine (3a) with the isatoic anhydride (4) results in rapid
formation of the 6-phenylimino-6H-indolo[2,1-b]quinazolin-12-one (5a) when the reaction was conducted in
open vessels in a microwave oven (Scheme 1). In order to increase the energy input in a shorter time and
provide a uniform heating, a small amount of N,N-dimethyleacetamide (DMAC), an excellent energy – transfer
solvent with a high dielectric constant, was added to the reaction mixture. In addition, we have also found that
the reaction was promoted with KF-Al2O3 and K2CO3, but KF-Al2O3 is highly efficient (Table 1).
R2
N
R 2
O
R 1
N
R 1
O
MW/ DMAC
O
+
O
NH2
N
KF- Al2O3
-CO2
N
H
N
H
O
O
-H2O
4
3(a-f)
R2
N
R 1
R
1
N
HN
N
O
R 2
N
O
O
N
H
5(a-f)
(6)
Scheme 1
Promoted by this success, we extended this reaction of isatoic anhydride with a range of other isatin-3-
arylimines (3b-f) under similar conditions, furnishing the respective 6-arylimino-6H-indolo[2,1-b]quinazolin-
12-one (5 b-f) in good to excellent yields.
Table1. Preparation of 6-arylimino-6H-indolo[2,1-b]quinazolin-12-ones (5) in the presence of KF-
Al2O3
3
5
R1
R2
Timea Yielda Timeb Yieldb
mp
(min)
(%)c
(min)
(%)c
(˚C)
3a
3b
3c
3d
3e
3f
5a
5b
5c
5d
5e
5f
H
Br
H
C6H5
4
4
4
4
4
4
71
5
5
5
5
5
5
42
234(decomp)
255(decomp)
233(decomp)
270(decomp)
200(decomp)
238(decomp)
C6H5
76
24
4-Cl-C6H4
4-Cl-C6H4
4-Me-C6H4
4-Me-C6H4
79
45
Br
H
83
50
73
42
Br
70
42
a: Cat. KF-Al2O3.. b: Cat. K2CO3. c: Yields of pure isolated product based on isatin-3-imine
In summary, we have describe a facile and efficient procedure for the preparation of new tetracyclic6-arylimino-

6H-indolo[2,1-b]quinazolin-12-ones using the inexpensive and non-toxic and easily available KF-Al O3
2
catalyst. The method offers several advantages including high yield of products, short reaction times, cleaner
reaction, easy experimental work-up procedure. Surprisingly, this reaction is regioselective10 in the preparation
of 6-arylimino-6H-indolo[2,1-b]quinazolin-12-ones, since no detectable amount of compound (6) was observed
and the imine group remained intact under the described reaction conditions, which makes it a useful process
for the synthesis of 6-arylimino-6H-indolo[2,1-b]quinazolin- 12-ones.
EXPERIMENTAL
Melting points were measured on the Electrothermal 9100 apparatus and are uncorrected. IR spectra were
1
13
measured on a Shimadzu IR-470 Spectrophotometer. H NMR and C NMR spectra were determined on a
bruker 500 DRX AVNCE instrument at 500 and 125 MHz, respectively. Elemental analyses were performed
using a Heracus CHN-O-Rapid analyzer. Microwave irradiation were carried out in a National oven, model
5250, at 2450 MHz.
General procedures: Isatin-3-arylimine (1 mmol) and isatoic anhydride (1 mmol, 163.13 mg) were mixed in
N,N-dimethylacetamide (3 mL) in a tall beaker which was covered with a stemless funnel and subjected to
microwave irradiation at 450 watts for 4 min (Table 1). After complete conversion, as indicated by TLC, the
KF-Al2O3 was separated and the reaction mixture was allowed to cool to rt. Then water was added to the
mixture and the separated solid was filtered off and recrystallized from ethanol to give a pure product.
Spectral data for product:
6-Phenylimino-6H-indolo[2,1-b]quinazolin-12-one (5a): orange crystalline solid, yield 71%, mp 234 ˚C
1
(decomp), IR (KBr), (νmax /cm-1): 1690 (C=O), 1648, 1581 (2C=N) , H NMR (CDCl 3) δH : 6.84 – 8.73 (13H,
13
m, arom). C NMR (CDCl 3) δC: 118.23, 118.42, 119.59, 123.20, 125.77, 126.73, 127.65, 129.26, 130.03,
130.17,130.48, 134.80, 135.32, 143.87, 147.47, 148.85 (arom ), 150.91, 154.98 (2 C=N), 159.34 (C=O), MS
(m/z, %): 323 (M +, 75), 322 (90), 295(10), 246 (15), 205 (10), 77 (70), 51 (49). Anal. Calcd for C21H13N3O: C,
78.04; H, 4.02; N, 12.99. Found: C, 77.96; H, 3.96; N, 12.91.
8-Bromo-6-phenylimino-6H-indolo[2,1-b]quinazolin-12-one (5b): yellow brown crystalline solid, yield 76%,
mp 255 ˚C (decomp), IR(KBr), (νmax /cm-1): 1680 (C=O), 1653, 1580 (2 C=N), 1H NMR (CDCl 3) δH: 6.93-8.62
(12 H, m, arom). 13 C NMR (CDCl3) δC : 118.13, 119.61, 119.87, 121.04, 123.03, 125.34, 127.62, 129.50,
130.02, 130.15, 130.26, 135.51, 137.32, 142.56, 147.38, 148.29 (arom), 150.35, 154.98 (2 C=N), 159.13 (C=O),
MS (m/z, %): 402 (M + , 90), 404 (75), 406 (25), 374 (10), 325 (20), 77 (80), 51 (70). Anal. Calcd for C21 H12
N3OBr: C, 62.72; H, 2.98; N, 10.44. Found: C, 62.64; H, 2.90; N, 10.32.
6-(4-Chlorophenylimino)-6H-indolo[2,1-b]quinazolin-12-one (5c): dark orange crystalline solid, yield 79%,
mp 233 ˚C (decomp), IR (KBr), (νmax /cm-1): 1680 (C=O), 1641, 1573 (2 C=N), 1H NMR (CDCl 3) δH : 6.95-

13
8.74 (12H, m, arom). C NMR (CDCl3) δC: 118.31, 119.35, 119.92, 123.16, 126.59, 126.76, 127.66, 129.38,
130.14, 130.22, 131.16, 135.11, 135.36, 143.93, 147.32, 148.65, (arom), 149.18, 155.93 (2 C=N), 159.15
(C=O), MS (m/z, %): 358 (M +, 50), 356 (90), 328 (10), 322 (25), 232 (10), 114 (15), 75 (90), 50 (50). Anal.
Calcd for C21 H12 N3OCl: C, 70.52; H, 3.35; N, 11.74. Found: C, 70.46; H, 3.26; N, 11.65.
8-Bromo-6-(4-chlorophenylimino)-6H-indolo[2,1-b]quinazolin-12-one (5d): orange crystalline solid, yield
1
83%, mp 270 ˚C (decomp), IR (KBr), (νmax /cm-1): 1685 (C=O), 1660, 1576 (2 C=N), H NMR (CDCl 3) δH :
13
7.05-8.64 (11 H, m, arom). C NMR (CDCl3) δC: 119.75, 119.92, 120.84, 121.88, 123.01, 127.73, 129.23,
129.64, 130.28, 130.33, 131.83, 135.58, 137.69, 142.69, 147.28, 148.13 (arom), 148.44, 153.80 (2 C=N),
159.02 (C=O), MS (m/z, %): 436 (M +, 50), 438 (30), 440 (10), 408 (10), 359 (15), 318 (10), 75 (50), 50 (3 0).
Anal. Calcd for C21 H11 N3OBrCl: C, 57.77; H, 2.52; N, 16.65. Found: C, 57.70; H, 2.44; N, 16.56.
6-(4-Methylphenylimino)-6H-indolo[2,1-b]quinazolin-12-one(5e): orange-brown crystalline solid, yield 73%,
mp 200 ˚C (decomp), IR (KBr), (νmax cm-1): 1685 (C=O), 1643, 1570 (2 C=N), 1H NMR (CDCl 3) δH: 1.64 (3H,
13
s, CH3 ), 6.99-8.73 (12 H, m, arom). C NMR (CDCl3) δC : 21.56 (CH3), 118.19, 118.44, 119.69, 123.15,
126.59, 126.66, 127.62, 129.16, 130.13, 130.36, 130.55, 134.63, 135.62, 143.78, 147.51, 148.26 (arom), 148.94,
154.73 (2 C=N), 159.36 (C=O), MS (m/z, %): 336 (M +, 60), 309 (10), 260 (15), 91 (60), 65 (100), 44 (90).
Anal. Calcd for C22 H15 N3O: C, 78.35; H, 4.45; N, 12.45. Found: C, 78.26; H, 4.36; N, 12.37.
8-Bromo-6-(4-methylphenylimino)-6H-indolo[2,1-b]quinazolin-12-one (5f): Brown crystalline solid, yield
70%, mp 238 ˚C (decomp), IR (KBr), (νmax/ cm-1): 1686 (C=O), 1639, 1600 (2 C=N), 1H NMR (DMSO-d6) δH:
1.38 (3H, s, CH 3 ), 6.55-7.53 (11 H, m, arom). 13C NMR (DMSO-d6) δC: 21.46 (CH3), 118.25, 119.50, 119.86,
121.22, 123.03, 126.61, 127.64, 129.87, 130.02, 130.15, 130.26, 135.61, 137.34, 142.36, 147.38, 149.39 (arom),
150.25, 155.69 (2C=N), 158.13 (C=O), MS (m/z, %): 416 (M +, 50), 388 (10), 325 (20), 91 (90), 65 (80). Anal.
Calcd for C22 H14 N3OBr: C, 63.50; H, 3.36; N, 10.09. Found: C, 63.42; H, 3.26; N, 9.98.
ACKNOWLEDGMENTS
We gratefully acknowledge the financial support from the Research Council of Shahid Beheshti University and
Professor A. Khodai for helpful suggestions.
REFERENCES
1. (a) Z. Z. Ma, Y. Hano, T. Nomura, and J. Chen, Heterocycles, 1997, 46, 541. (b) M. Toyota, C. Komori,
and M. Ihara, Heterocycles, 2002, 56, 101.
2. (a) L-M. Yang, C-F. Chen, and K-H. Lee, Bioorg. Med. Chem. Lett., 1995, 5, 465. (b) T. Kametani, T. Higa,
C. V. Loc, M. Ihara, M. Koizumi, and K. Fukumoto, J. Am. Chem. Soc., 1976, 98, 6186. (c) T. Kametani,
C. V. Loc, T. Higa, M. Koizumi, M. Ihara, and K. Fukumoto, J. Am. Chem. Soc., 1977, 99, 2306.
3. (a) L. A. Errede, J. Org. Chem., 1976, 41, 1763. (b) H. Taheuchi, S. Hagiwara, and S. Eguchi,

Tetrahedron, 1989, 45, 6375. (c) A. A. Bekhit and M. A. Khalil, Pharmazie, 1998, 53, 539. (d) S.
Makino, N. Suzuki, E. Nakaishi, and T. Tsuji, Synlett, 2000, 11, 1670. (e) A. P. Kesarwani, G. K.
Srivastava, S. K. Rastogi, and B. Kundu, Tetrahedron Lett., 2002, 43, 5579. (f) H. Ishigami, H.
Kawaguchi, and A. Sugai, Jpn. Kokai Tokkyo Koho Jp., 2000, 219, 689 [Chem. Abstr., 2000, 133,
157643z]. (g) H. Ishigami and H. Kawaguchi, Jpn. Kokai Tokkyo Koho JP., 08, 328, 277 [Chem.
Abstr., 1997, 126, 164236c]. (h) H. Ishigami and H. Kawaguchi, Jpn. Kokai Tokkyo Koho JP., 09, 87,
283[Chem. Abstr., 1997, 127, 25978d].
4. F-R. Alexander A. Berecibar, R. Wrigglesworth, and T. Besson, Tetrahedron, 2003, 59, 1413.
5. J. S. Yadav and B. V. S. Reddy, Tetrahedron Lett., 2002, 43, 1905.
6. H. Hazarkhani and B. Karimi, Tetrahedron, 2003, 59, 4757.
7. (a) J. Azizian, Ali A. Mohammadi, and Ali R. Karimi, Synth. Commun., 2003, 33, 415. (b) J. Azizian,
M. Mehrdad, K. Jadidi, and Y. Sarraf, Tetrahedron Lett., 2000, 41, 5265.
8. For review on isatoic anhydride see: G. M. Coppola, Synthesis, 1980, 505.
9. For reviews on microwave assisted organic reaction see: (a) p. Lidstrom, J. Tierney, B Wathey, and J.
Westman, Teterahedron, 2001, 57, 9225. (b) J. Azizian, A. Varasteh Morady, S. Soozaangarzadeh,
and A. Asadi, Tetrahedron Lett., 2002, 43, 9721. (c) J. Azizian, A. Asadi, and K. Jadidi, Synth.
Commun., 2001, 31, 1. (d) J. Azizian, S. Soozangarzadeh, and K. Jadidi, Synth. Commun., 2001, 31,
1069.
10. For reviews of reaction of isatoic anhydride with imine and amide functional groups see: (a) R. P.
Stariger, C. L. Moyer, and G. R. Pitcher, J. Chem. Eng. Data, 1963, 8, 454. (b) W. Stieger, T. Kappe,
and E. Ziegler, Monatsh. Chem., 1969, 100, 146.