Synthesis of indolylquinazolinone: A novel bisazaheterocycle

Article abstract of DOI:10.1055/s-2000-6429

A facile synthesis of 2-(2-aryl-1H-7-indolyl)-3,4-dihydroquinazolin-4-ones is reported.

Full text of DOI:10.1055/s-2000-6429

SHORT PAPER
1217
Synthesis of Indolylquinazolinone: A Novel Bisazaheterocycle
D. Sahadeva Reddy, P. Pratap Reddy, P. S. N. Reddy*
Department of Chemistry, Osmania University, Hyderabad-500 007, India
Fax +91(40)7669909; E-mail: psnreddy@123india.com
Received 10 December 1999; revised 1 March 2000
Abstract: A facile synthesis of 2-(2-aryl-1H-7-indolyl)-3,4-dihyd-
roquinazolin-4-ones is reported.
Key words: hydroxamic acids, indoles, ketones, amides, condensa-
tion, heterocycles
Our interest in developing quinazolinone based heterocy-
cles prompted us to react 2-(2-aminophenyl)-3-hydrox-
yquinazolin-4(3H)-one (3) with aralkyl ketones. The aim
was to isolate quinazolino[3,2-d][3,1,4]benzoxadiazepin-
9-ones (4) by bridging with carbon the N-hydroxyl and
amino groups in 3. But surprisingly the reaction
yielded 2-(2-aryl-1H-7-indolyl)-3,4-dihydroquinazolin-
4-ones (6), providing a facile synthetic route for the less
known indolyl quinazolinones which are anti-inflamma-
tory, psychotrophic agents,1,2 CCK receptors3 and CNS
active as well as depressant agents.4
Scheme 1
The cyclic hydroxamic acid 3 was prepared in one-step
from 2-aminobenzhydroxamic acid (1) and isatoic anhy-
The mechanism of formation of 6 is both interesting and
intriguing (Scheme 2). We presume that the reaction pro-
ceeds via a transient quinazolino[3,2-d][3,l,4]benzoxadi-
azepin-9-one 4 and 2-(2-oxirinylaminophenyl)quinozo-
lin-4(3H)-one 5. Intramolecular oxygenation of C=N in
cyclic hydroxamic acids was reported earlier from our
laboratories.10
dride (2). Refluxing an equimolar mixture of 3 and 4-me-
thylacetophenone in nitrobenzene for 6 hours, followed
by usual workup yielded a crystalline solid (M+ at m/z
351) (Scheme 1). It is devoid of N-OH group (negative
FeCl3 color test).5 The UV spectrum showed two absorp-
tion maxima at lmax = 327.7 nm and 266.7 nm, respec-
tively and appeared as a combination spectrum of
2-phenylindole (328 nm) and quinazolin-4(3H)-one (265
nm) rings.6,7 The presence of indole moiety was further
evident from the signals at d = 6.6 (s, l H, 3-H) and 7.95
(NH, D2O exchangeable). On adding D2O, the 3-H signal
shifted to downfield (d = 6.8), a characteristic feature of
indoles.8 The appearence of a doubly charged ion peak (at
m/z 176) is also reminiscent of indoles.9
The quinazolinone moiety revealed itself by the ap-
pearence of CO peak (n = 1702 cm-1) in the IR spectrum
and the peri-proton signal as doublet at d = 8.2 in the 1H
NMR spectrum. The 13C NMR spectrum revealed a total
of 19 different carbons including quinazolinone carbonyl
(d = 156.9), azomethine carbon (d = 153.3) and C3 of in-
dole (d = 108.6).
The reaction was extended to six other aralkyl ketones
(Scheme 1), and in each case the corresponding 2-(2-aryl-
lH-7-indoyl)-3,4-dihydroquinazolin-4-one was isolated
and characterized. As expected, there is no peak around
d = 6.6 in the 1H NMR spectra for the products obtained
with propiophenone and dibenzyl ketone, to confirm that
C3 of indole carried substituents in 6f and 6g (see experi-
mental scetion).
Scheme 2
Synthesis 2000, No. 9, 1217–1218 ISSN 0039-7881 © Thieme Stuttgart · New York

1218
D. S. Reddy et al.
SHORT PAPER
2-(2-Aminophenyl)-3-hydroxyquinazolin-4(3H)-one (3)
To a solution of 2-aminobenzhydroxamic acid (1; 1.52 g, 10 mmol)
and isatoic anhydride (2; 1.63 g, 10 mmol) in EtOH (20 mL) was
added a pinch of p-toluenesulfonic acid. The mixture was refluxed
for 4 h. On cooling, the title compound separated out as colorless
crystalline solid. It was filtered, and recrystallized from MeOH;
yield: 2.28 g (90%); mp 258 °C.
MS: m/z = 371 (M+).
6d
Yield: 74%; mp 317 °C.
UV (MeOH): lmax = 327.4, 266.1 nm.
IR (KBr): n = 3062br (N-H), 1699 cm-1 (C=O).
MS: m/z = 382 (M+).
UV (MeOH): lmax (log e) = 304 (3.91), 270 (3.84), 231 nm (3.41).
IR (KBr): n = 3371, 3316, 3033 (br), 1667, 1609, 1589, 1574, 1415,
6e
1317 cm-1.
Yield: 71%; mp 296 °C.
1H NMR (DMSO-d6/TMS): d = 6.6-7.9 (m, 7 H, Ar-H), 8.2 (d, 1 H,
J = 10 Hz, peri Ar-H).
MS: m/z = 253 (M+ 100), 237, 236, 223, 120, 119, 118, 92, 91, 90,
UV (MeOH): lmax = 329.1, 267.4 nm.
IR (KBr): n = 3066br (N-H), 1710 cm-1 (C=O).
MS: m/z = 353 (M+).
77, 63.
2-(2-Aryl-1H-7-indolyl)-3,4-dihydroquinazolin-4-ones 6a-g;
General Procedure
6f
Yield: 69%; mp 316 °C.
A mixture of 3 (0.8 g, 3 mmol) and the appropriate aralkyl ketone
(3 mmol) was dissolved in nitrobenzene (10 mL, bp 210-211 °C)
and refluxed for 6 h. On cooling the reaction mixture, the corre-
sponding 2-(2-aryl-lH-7-indolyl)-3,4-dihydro-4-quinazolinone 6
separated out from the clear solution as a colorless crystalline solid.
It was filtered, dried and passed over a column of neutral alumina
(~150 mesh) using EtOAc as eluent (7 × 30 mL). The analytical
(satisfactory microanlyses obtained: C ±0.39, H ±0.20, N ±0.11)
and spectral data of compounds 6a-g prepared are listed below.
Compounds 6d and 6e were not sufficiently soluble in the usual
NMR solvents and hence their 1H NMR spectra were not recorded.
UV (MeOH): lmax = 328.4, 266.9 nm.
IR (KBr): n = 3066br (N-H), 1708 cm-1 (C=O).
1H NMR (DMSO-d6/TMS): d = 2.00 (s, 3 H, CH3), 7.20-7.65 (m, 12
H, Ar-H), 8.25 (d, J = 10 Hz, peri Ar-H), 11.2 (s, 1 H, amide NH).
Indole NH signal was found to be merged with Ar-H.
MS: m/z = 351 (M+).
6g
Yield: 79%; mp 312 °C.
UV (MeOH): lmax = 328.1, 265.4 nm.
IR (KBr): n = 3066br (N-H), 1709 cm-1 (C=O).
1H NMR (DMSO-d6/TMS): d = 3.95 (s, 2 H, CH2), 7.00-7.78 (m,
16 H, Ar-H), 7.9 (s, 1 H, indole NH), 8.2 (d, 1 H, J = 10 Hz, peri
Ar-H), 11.5 (s, 1 H, amide NH).
6a
Yield: 68%; mp 298 °C.
UV (MeOH): lmax = 327.4, 266.7 nm.
IR (KBr): n = 3126br (N-H), 1700 cm-1 (C=O).
1H NMR (DMSO-d6/TMS): d = 6.65 (s, 1 H, 3-Hindole), 6.95-7.90
(m, 11 H, Ar-H), 8.1 (s, 1 H, indole NH), 8.25 (d, 1 H, J = 8 Hz, peri
ArH), 11.2 (s, 1 H, amide NH).
MS: m/z = 427 (M+).
References
MS: m/z = 337 (M+).
(1) Yu, M. J.; Thrasher, K. J.; McCowan, J. R.; Mason, N. R.;
Mendelsohn, L. G. J. Med. Chem. 1991, 34, 1505.
(2) Rajesh, A.; Agarwal, C.; Singh, C.; Vinay, S. M. J. Chem.
Soc., Perkin Trans 1 1984, 89.
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5075313; Chem. Abstr. 1992, 116, 128964.
(4) Rajesh, A.; Choudhary, C.; Srivastav, V. K.; Mistra, V. S.
Acta. Pharm. 1982, 32, 37.
(5) Schapira, C. B.; Lamdan, S. J. Heterocycl. Chem. 1972, 9,
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(7) Hearn, J. M.; Morton, R. A.; Simpson, E. C E. J. Chem. Soc.
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6b
Yield: 81%; mp >320 °C.
UV (MeOH): lmax = 327.7, 266.7 nm.
IR (KBr): n = 3119br (N-H), 1702 cm-1 (C=O).
1H NMR (DMSO-d6/TMS): d = 2.39 (s, 3 H, CH3), 6.6 (s, 1 H,
3-Hindole), 6.95-8.10 (m, 10 H, Ar-H), 7.95 (s, 1 H, indole NH), 8.25
(d, 1 H, J = 10 Hz, peri Ar-H), 11.2 (s, 1 H, amide NH).
13C NMR (DMSO-d6/TMS): d = 156.9, 153.3, 149.2, 140.5, 139.8,
135.2, 130.9, 130.6, 129.7, 129.5, 128.9, 127.2, 127.0, 123.6, 122.1,
121.1, 118.2, 109.4, 108.6, 20.9.
MS: m/z = 351 (M+).
(8) Remers, W. A.; Brown, R. K. The Chemistry of Heterocyclic
Compounds, Indoles (Part I); Wiley-Interscience: New York,
1972; pp 33-40.
6c
(9) Beynon, J. H. Mass Spectrometry and its Applications to
Organic Chemistry; Elsevier: New York, 1960; p 397.
(10) Sahadeva Reddy, D.; Pratap Reddy, P.; Reddy, P. S. N.
Synth. Commun. (in press).
Yield: 78%; mp 318 °C.
UV (MeOH): lmax = 325.9, 264.6 nm.
IR (KBr): n = 3128br (N-H), 1702 cm-1 (C=O).
1H NMR (DMSO-d6/TMS): d = 6.6 (s, 1 H, 3-Hindole), 6.95-7.9 (m,
10 H, Ar-H), 8.1 (s, 1 H, indole NH), 8.25 (d, 1 H, J = 10 Hz, peri
Ar-H), 11.2 (s, 1 H, amide NH).
Article Identifier:
1437-210X,E;2000,0,09,1217,1218,ftx,en;Z09099SS.pdf
Synthesis 2000, No. 9, 1217–1218 ISSN 0039-7881 © Thieme Stuttgart · New York