One pot synthesis of 4(3H)-quinazolinones

Article abstract of DOI:10.1081/SCC-120038496

Anthranilamides undergo cyclocondensation with aldehydes in presence of iodine in a single-pot reaction to afford 2-substituted 4(3H)-quinazolinones in moderate to excellent yield (40-95%). 2,3-Substituted 4(3H)-quinazolinones are synthesized in moderate to good yield by three-component condensation of isotoic anhydride, amine, and aldehyde in presence of iodine.

Full text of DOI:10.1081/SCC-120038496

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One Pot Synthesis of 4(3H)‐Quinazolinones
Bashir A. Bhat a & Devi P. Sahu a
a Chemical Technology Division, Central Drug Research Institute, Lucknow, 226001, India
Version of record first published: 17 Aug 2006.
To cite this article: Bashir A. Bhat & Devi P. Sahu (2004): One Pot Synthesis of 4(3H)‐Quinazolinones, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:12, 2169-2176
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 12, pp. 2169–2176, 2004
One Pot Synthesis of 4(3H)-Quinazolinones#
*
Bashir A. Bhat and Devi P. Sahu
Chemical Technology Division, Central Drug
Research Institute, Lucknow, India
ABSTRACT
Anthranilamides undergo cyclocondensation with aldehydes in presence of
iodine in a single-pot reaction to afford 2-substituted 4(3H)-quinazolinones
in moderate to excellent yield (40–95%). 2,3-Substituted 4(3H)-quinazoli-
nones are synthesized inmoderate to good yield by three-component conden-
sation of isotoic anhydride, amine, and aldehyde in presence of iodine.
Key Words: 4(3H)-Quinazolinones; Iodine; Three-component reaction;
One pot synthesis.
4(3H)-Quinazolinones 1 are known since more than a century.[1] They
belong to an important class of heterocyclic compounds in medicinal chem-
istry having anticonvulsant,[2] antihypertensive,[3] antidiabetic,[4] and other
#CDRI communication no. 6374.
*
Correspondence: Devi P. Sahu, Chemical Technology Division, Central Drug
Research Institute, Lucknow 226001, India; Fax: 91-522-223405 or 223938; E-mail:
dpsahu@rediffmail.com.
2169
DOI: 10.1081/SCC-120038496
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Bhat and Sahu
biological activities.[5] The important natural and synthetic 4(3H)-
quinazolinones include l-vasicinone 2,[6] chrysogine 3,[7] methaquinalone
4[8] a sedative, febrifugine 5[9] an antimalarial.
While there exists numerous methods for the synthesis of 4(3H)-quinazo-
linones, only a few general methods[10] (for recent review on 2-hetero-substi-
tuted 4(3H)-quinazolinone, see Ref.[10b]) are capable to provide their synthesis
under drastic condition in multi-step protocol. The synthetic approach to
2,3-disubstituted 3(H)-quinazoline-4-one 1 are based on two stage protocol,
i.e., acylation of anthranilamides[11] followed by cyclization. Alternately, 1
can be synthesized in moderate yield from anthranilamide 6 and aldehydes 7 in
two steps by cyclocondensation under drastic condition to afford 1,2-dihydro-
4(3H)-quinazolinones 8 followed by oxidization mediated by potassium
permanganate[10] (for recent review on 2-hetero-substituted 4(3H)-quinazoli-
none, see Ref.[10b]), MnO2[12] to 1 in the subsequent step. Oxidative dehydro-
genation of 8 in same pot during its synthesis can be envisaged to furnish 1.
Synthesis of these compounds under mild conditions in a single-pot
reaction is non-existent. We, herein, report a single pot synthesis of
Scheme 1.

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One Pot Synthesis of 4(3H)-Quinazolinones
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4(3H)-quinazolinones 1 in moderate to high yield under mild conditions based
on oxidative cycloaddition of aldehydes 7 with anthranilamides 6 (Sch. 1).
On stirring a mixture of aldehyde 7 with equimolar amount of anthra-
nilamide 6 in dioxane or DMF at ambient temperature for 20hr did not afford 1.
When half molar amount of I2 was added to a stirred mixture of 6h and 7h, it
warmed up. On stirring the mixture at ambient temperature for 5 hr, 4(3H)-
quinazolinone 1h was isolated 67.5% in yield, while on stirring 60–808C for
5 hr with equimolar I2 and potassium carbonate the yield obtained was 95%.
The product can be conveniently isolated by quenching the reaction mixture
with crushed ice-water and then filtering the solid precipitate thus obtained.
Evidently, iodine catalyses the cyclocondensation aldehyde with anthranilamide
to 1,2-dihydro-4(3H) quinazolinone 8, and it is in situ the oxidation to
4(3H)-quinazolinone 1. We employed DDQ in place of iodine, the conversation
to 4(3H)-quinazolinone 1 is completed within 1/3 hr. The yield of 1b obtained
from the aliphatic aldehydes 7b is moderate whereas aromatic aldehydes furn-
ished corresponding quinazolinones in excellent yield (Table 1).a
To synthesize 2,3-disubstituted 4(3H)quinazolinones, we attempted three-
component reaction[13],b comp‘rising of isotoic anhydride, an amine and alde-
hyde following the developed protocol. Thus, when to the stirred solution of
isotoic anhydride in DMF, the amine, the aldehyde, iodine, and powdered
KOH are sequentially added and stirred the mixture for 5 hr at 60–808C (Sch. 2).
The 2,3-disubstituted quinazolinone were isolated in moderate yield (entry
1k–1n, Table 1).c Examination reaction mixture by TLC and spectroscopic
aTypicalexample: toa solution ofanthranilamide 6 (R3 ¼ H, 5 mmol) dissolved in 20 mL
of anhydrous DMF, 3,4,5-trimethoxybenzaldehyde (5 mmol) is added. To the resulting
mixture while stirring, iodine (6 mmol) and anhydrous potassium carbonate (5 mmol)
are added and then heated at 60–808C for 6 hr. The mixture is poured into crushed ice-
water in (200 mL). The precipitated product is filtered, washed with water, and then
1
recrystallized from alcohol. IR (KBr): 3442, 2935, 1673, 1605, 1457 cm21; H NMR
(200 MHz, CDCl3) (ppm): 3.71 (s, 3H), 3.73 (s, 3H), 3.87 (s, 3H), 7.24–7.34 (m, 3H),
7.59–7.61 (m, 2H), 8.06 (bs, 1H), FAB mass: m/z 213 (Mþ þ 1, 100%), 154, 136.
b2,3-Dihydro 4(3H)-quinazolinones have been synthesized in moderate yield from
isotoic anhydride and aromatic aldimines under drastic conditions.
cTypical example: to a solution of isotoic anhydride (1 mmol) dissolved in 5 mL of anhy-
drous DMF, N-butyl amine (1 mmol) and benzaldehyde (2 mmol) are added. The result-
ing mixture is while stirring; iodine (1.2 mmol) and powdered KOH (1.2 mmol) are
added and then heated at 60–808C for 8 hr. The product mixture is diluted with crushed
ice-water and extracted with ethyl acetate. After usual work-up, liquid product is purified
by silica gel chromatography and recrystallized from alcohol to obtain 1k. IR (KBr):
1662, 1605, 1457 cm21 1H NMR (200 MHz, CDCl3) (ppm): 0.83 (t, 3H), 1.42
;
(m, 4H), 3.86 (m, 3H), 7.43 (s, 5H), 7.44–93 (m, 4H), FAB mass: m/z 279 (Mþ þ 1).

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Bhat and Sahu

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One Pot Synthesis of 4(3H)-Quinazolinones
2173

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Bhat and Sahu
Scheme 2.
means showed that it is a mixture of desired product, anthranilamide and
aldehyde. N-substituted anthranilamide formed by facile condensation of
amine with isotoic anhydride requires drastic condition to undergo cyclocon-
densation with aldehyde compared to N-unsubstituted anthranilamide.
Iodine catalyses the cyclocondensation of aldehyde with anthranilamide
through polarization of its C55O bond. Apparently, the oxidizing rate with
DDQ is higher than that of iodine; hence the formation 1 with it is more facile.
The quinazolinone 1 prepared have been characterized by NMR, IR, and
FAB mass spectra. The other physical properties of known product have
comparable as reported. In conclusion, 4(3H)-quinazolinone are synthesized by
single-pot reaction of either anthranilamide with aldehyde or isotoic anhydride,
amines and aldehyde mediated by iodine or DDQ in moderate to excellent yield.
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Received in India February 9, 2004

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