Expeditious one-pot and solvent-free synthesis of dihydroquinazolin-4(1H)- ones in the presence of microwaves

Article abstract of DOI:10.1080/00397910701354699

Dihydroquinazolin-4(1H)-ones were synthesized for the first time by a novel three-component condensation of isatoic anhydride, a primary amine, and an aldehyde catalyzed by Amberlyst-15 in the presence of microwaves under neat conditions. The catalyst is reusable, thus making the process more environmentally friendly. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701354699

This article was downloaded by: [University of California, San Diego]
On: 18 February 2013, At: 03:27
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Expeditious One‐Pot and Solvent‐Free
Synthesis of Dihydroquinazolin‐4(1H)‐ones in
the Presence of Microwaves
Mandar P. Surpur a , Pankajkumar R. Singh a , Sachin B. Patil a & Shriniwas D.
Samant a
a Organic Chemistry Research Laboratory, Department of Chemistry,
Institute of Chemical Technology, Mumbai, India
Version of record first published: 22 Jun 2007.
To cite this article: Mandar P. Surpur , Pankajkumar R. Singh , Sachin B. Patil & Shriniwas D. Samant
(2007): Expeditious One‐Pot and Solvent‐Free Synthesis of Dihydroquinazolin‐4(1H)‐ones in the Presence
of Microwaves, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 37:12, 1965-1970
To link to this article: http://dx.doi.org/10.1080/00397910701354699
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the
contents will be complete or accurate or up to date. The accuracy of any instructions, formulae,
and drug doses should be independently verified with primary sources. The publisher shall not
be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or
howsoever caused arising directly or indirectly in connection with or arising out of the use of this
material.

Synthetic Communicationsw, 37: 1965–1970, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701354699
Expeditious One-Pot and Solvent-Free
Synthesis of Dihydroquinazolin-4(1H)-ones
in the Presence of Microwaves
Mandar P. Surpur, Pankajkumar R. Singh, Sachin B. Patil,
and Shriniwas D. Samant
Organic Chemistry Research Laboratory, Department of Chemistry,
Institute of Chemical Technology, Mumbai, India
Abstract: Dihydroquinazolin-4(1H)-ones were synthesized for the first time by a novel
three-component condensation of isatoic anhydride, a primary amine, and an aldehyde
catalyzed by Amberlyst-15 in the presence of microwaves under neat conditions. The
catalyst is reusable, thus making the process more environmentally friendly.
Keywords: dihydroquinazolin-4(1H)-ones, Amberlyst-15, microwaves, multicompo-
nent reactions
INTRODUCTION
Dihydroquinazolin-4(1H)-ones (1) are an important class of heterocycles that
exhibit biological and pharmaceutical activities. These compounds are known
to be antitumur agents, diuretics, plant-growth regulators, herbicidal agents,
anticonvulsants, and anticancer agents.[1] These compounds can be easily
oxidized to their quinazolin-4(3H)-one analogues,[2] which are important bio-
logically active heterocyclic compounds[3] and are found in some natural
products.[4] A three-component, one-pot reaction of isatoic anhydride,
primary amine, and aldehyde could be envisaged to give 1. Recently, these
compounds have been synthesized by this route, using silica-sulfuric acid,[5]
Received October 27, 2006
Address correspondence to Shriniwas D. Samant, Organic Chemistry Research
Laboratory, Department of Chemistry, Institute of Chemical Technology, N. M.
Parekh Road, Matunga, Mumbai 400 019, India. E-mail: samantsd@udct.org
1965

1966
M. P. Surpur et al.
Scheme 1.
p-TSA,[6] and Montomorillonite K10.[7] However, these methodologies have
long reaction times and use hazardous chemicals. Therefore, discovery of
new, inexpensive, and environmentally benign catalysts for the preparation
of dihydroquinazolinones is of prime importance. In continuation of our
ongoing research toward the synthesis of heterocyclic compounds by
greener and environmentally benign approaches, we report the synthesis of
dihydroquinazolin-4(1H)-one derivatives by the condensation of isatoic
anhydride, primary amines, and aldehydes in the presence of Amberlyst-15
under microwave irradiation.
Cationic exchange resins, particularly the macroporous ones, are versatile
catalysts that offer several advantages over the homogeneous catalysts with
respect to corrosion, product recovery, and selectivity.[8] Amberlyst-15 is a
cationic exchange resin with a Hammett acidity function of 22.2.[9] It has a
cross-linking density (i.e., percentage of divinylbenzene) 20, surface area of
45 m2/g, and pore volume of 0.35 ml/g.[8] When the condensation of isatoic
anhydride, aniline, and benzaldehyde was carried out in the presence of
Amberlyst-15 at 1308C, the reaction took a long time for completion (i.e.,
3–4 hr).
Microwave irradiation of organic reactions has rapidly gained popularity
a
variety of synthetic transformations.[10,11]
because it accelerates
Table 1. Effect of various solid Brønsted acid catalysts on
the condensation of isatoic anhydride, benzaldehyde, and
aniline under microwave irradiation
Catalyst
Time (min)
Yield (%)a
Amberlyst-15
Indion 130
3
12
16
5
81
68
65
77
Indion FF-IP
Sulphamic acid
Notes. Isatoic anhydride (1 mmol, 0.163 g); aniline
(1.2 mmol, 0.091 ml); benzaldehyde (1 mmol, 0.101 ml);
catalyst (50% by wt of isatoic anhydride). Microwave
power: 360 W. Solvent free.
aIsolated and unoptimized yield.

Dihydroquinazolin-4(1H)-ones
Table 2. Recyclability study of Amberlyst-15
1967
Run
Time (min)
Yield (%)a
1
2
3
4
3
3
4
4
81
81
80
78
Notes. Isatoic anhydride (1 mmol, 0.163 g); aniline
(1.2 mmol, 0.091 ml); benzaldehyde (1 mmol, 0.101 ml);
Amberlyst-15 (80 mg, 50% by wt of isatoic anhydride).
Microwave power: 360 W, Solvent free.
aIsolated and unoptimized yield.
Table 3. Microwave-assisted one-pot synthesis of dihydroquinazolin-4-(1H)-one
derivatives catalyzed by Amberlyst-15
Product
R1
R2
Time (min)
Yield (%)a
4a
4b
4c
4d
4e
4f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
3
6
6
5
3
5
6
3
3
6
4
7
7
6
6
5
5
7
81
83
84
64
72
85
68
78
86
77
87
75
70
73
71
74
75
69
3-NO2Ph
4-ClPh
4-NO2Ph
2-CH3Ph
4-BrPh
4-FPh
4g
4h
4i
Ph
4-ClPh
3-NO2Ph
4-BrPh
H
4j
H
4k
4l
H
4-CH3OPh
3,4-(CH3O)2Ph
4-NO2Ph
Ph
H
4m
4n
4o
4p
4q
4r
H
Pr
Me
Me
Me
Me
4-ClPh
4-BrPh
4-CH3OPh
Notes. Isatoic is anhydride (1 mmol); amine (1.2 mmol); aldehyde (1 mmol);
Amberlyst-15 (80 mg, 50% by wt of isatoic anhydride). Microwave power: 360 W.
Solvent free.
aIsolated and unoptimized yield.

1968
M. P. Surpur et al.
The application of microwaves with the use of certain catalysts or
reagents provides unique chemical processes with special attributes such as
enhanced reaction rates, higher yields, greater selectivity, and ease of manipu-
lation. Thus, the reaction was also attempted under microwave irradiation
(Scheme 1).
RESULTS AND DISCUSSION
Isatoic anhydride (1) was treated with aniline (2) and benzaldehyde (3) in the
presence of different solid Brønsted acid catalysts under microwave
irradiation (Table 1). Amberlyst-15 was found to be the best catalyst, as it
gave 81% yield of the product in a short time of (3 min).
To check the reusability of the catalyst, the reaction of isatoic anhydride,
aniline, and benzaldehyde was carried out three to four times using
Amberlyst-15, and the effect on yield and time required for the reaction was
seen (Table 2).
The catalyst was active even after four consecutive runs. Encouraged by
these results, we decided to further explore the scope of the reaction by
carrying out the condensation of a variety of substituted primary amines
and aldehydes with isatoic anhydride. The condensation went smoothly,
giving the desired products in less time and in good yields (Table 3). No
side products were formed.
CONCLUSION
In conclusion, a simple, short, and environmentally friendly method for the
synthesis of a novel class of dihydroquinazolin-4(1H)-ones is described.
The workup procedure is simple, and chromatography is not required.
Starting materials are inexpensive and commercially available. By the
reaction of a range of amines and aldehydes with isatoic anhydride, novel
libraries of dihydroquinazolinones could be developed, which would make
this process suitable for parallel synthesis in drug discovery.
EXPERIMENTAL
All the products are known and were characterized by comparison of their
spectroscopic and physical data with authentic samples synthesized by the
reported procedure.[6] The microwave irradiation was carried out using a
domestic microwave oven (LG: Little Chef) at power of 360 W.

Dihydroquinazolin-4(1H)-ones
1969
Typical Experimental Procedure
Isatoic anhydride (1 mmol), aniline (1.2 mmol), benzaldehyde (1 mmol), and
Amberlyst-15 (80 mg) were put in a 25-ml, round-bottom flask. The reaction
mixture was stirred at room temperature with the help of a magnetic stirrer.
The flask was kept in the domestic microwave oven, and the contents were
irradiated with microwaves at 360 W, with irradiation pulses of 1 min each
followed by a cooling period of 30 s at room temperature after every pulse.
After the completion of the reaction (as indicated on TLC), the reaction
mixture was cooled to room temperature, and hot ethanol (10 ml) was
added. The reaction mixture was filtered using a G-3 filter to separate the
catalyst. The filtrate was concentrated under vacuum to obtain the solid
product. The product was crystallized from absolute alcohol. To study the
recyclability of the catalyst, the catalyst was isolated after each run, washed
with hot ethanol, and dried at 1008C for 6 h.
REFERENCES
1. (a) Hamel, E.; Lin, C. M.; Plowman, J.; Wang, H.; Lee, K.; Paull, K. D. Biochem.
Pharmacol. 1996, 51, 53; (b) Biressi, M. G.; Cantarelli, G.; Carissimi, M.;
Catteneo, A.; Ravenna. Ed. Sci. 1969, 24, 199; (c) Bhalla, P. R.;
Walworth, B. L. Chem. Abstr. 1983, 98, 1669; (d) Bhalla, P. R. Walworth, B. L.
Chem. Abstr. 1984, 100, 174857; (e) Hour, M.; Huang, L.; Kuo, S.; Xia, Y.;
Bastow, K.; Nakanishi, Y.; Hamel, E.; Lee, K. 6-Alkylamino- and 2,3-dihydro-
30-methoxy-2-phenyl-4-quinazolinones and related compounds: Their synthesis,
cytotoxicity and inhibition of tubilin polymerization. J. Med. Chem. 2000, 43,
4479–4487.
2. (a) Rao, V. B.; Hanumanthu, P.; Ratnam, C. V. Indian J. Chem. 1979, 18B, 493;
(b) Lopez, S. E.; Rosales, M. E.; Urdaneta, N.; Godoy, M. V.; Charris, J. E.
J. Chem. Res., Synop. 2000, 258; (c) Abdel-Jalil, R. J.; Volter, W.; Saeed, M. A
novel method for the synthesis of 4(3H)quinazolinone. Tetrahedron Lett. 2004,
45, 3475–3478.
3. (a) Wolf, J. F.; Rathman, T. L.; Sleevi, M. C.; Campbell, J. A.; Greenwood, T. D.
Synthesis and anticonvulsant activity of some new 2-substituted 3-aryl-4(3H)-qui-
nazolinones. J. Med. Chem. 1990, 33, 161–166; (b) Padia, J. K.; Field, M.;
Hinton, J.; Meecham, K.; Pablo, J.; Pinnock, R.; Roth, B. D.; Singh, L.; Suman-
Chauhan, N.; Trivedi, B. K.; Webdale, L. Novel non-peptide CCK-B antagonists:
Design and development of quinazolinone derivatives as potent, selective, and
orally active CCK-B antagonists. J. Med. Chem. 1998, 41, 1042–1049;
(c) Kung, P.-P.; Casper, M. D.; Cook, K. L.; Wilson-Lingard, L.; Risen, L. M.;
Vickers, T. A.; Ranken, R.; Blyn, L. B.; Wyatt, R.; Cook, P. D.; Ecker, D. J.
Structure–Activity relationship of novel 2-substituted quinazoline antibacterial
agents. J. Med. Chem. 1999, 42, 4705–4713; (d) Tsou, H.-R.; Mamuya, N.;
Johnson, B. D.; Reich, M. F.; Gruber, B. C.; Y.-F.; Wissner, A. 6-Substituted-4-
(3-bromophenylamino) quinazolines as putative irreversible inhibitors of the
epidermal growth factor receptor(EFGR) and human epidermal growth factor
receptor (HER-2) tyrosine kinases with enhanced anti-tumour activity. J. Med.

1970
M. P. Surpur et al.
Chem. 2000, 44, 2719–2734; (e) Matsuno, K.; Ichimura, M.; Nakajima, T.;
Tahara, K.; Fujiwara, S.; Kase, H.; Vishiki, J.; Giese, N. A.; Pandey, A.;
Scarborough, R. M.; Lokker, N. A.; Yu, J.-C.; Irie, J.; Tsukda, E.; Ide, S.-I.;
Oda, S.; Nomoto, Y. Potent and selective inhibitors of platelet-derived growth
factor receptor phosphorylation 1: Synthesis, structure-activity relationship, and
biological effects of a new class of quinazoline derivatives. J. Med. Chem. 2002,
45, 3057–3066.
4. Maskey, R. P.; Shaaban, M.; Grun-Wollnu, I.; Laatsch, H. Quinazolin-4-one
derivatives from Streptomyces isolates. J. Nat. Prod. 2004, 67, 1131–1134.
5. Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Baghbanzdeh, M. A novel method for the
one-pot three-component synthesis of 2,3-dihydroquinazolin-4(1H)-ones. Synlett
2005, 1155–1157.
6. Baghbanzdeh, M.; Salehi, P.; Dabiri, M.; Kozehgary, G. Water-accelerated
synthesis of novel bis-2,3-dihydroquinazolin-4(1H)-one derivatives. Synthesis
2006, 344–348.
7. Salehi, P.; Dabiri, M.; Baghbanzadeh, M.; Bahramnejad, M. One-pot, three-
component synthesis of 2,3-dihydro-4(1H)-quinazolinones by Montmorillonite
K-10 as an efficient and reusable catalyst. Synth. Commun. 2006, 2287–2292.
8. Sharma, M. M. Some novel aspects of cationic ion exchange resins as catalysts:
Review. React. Funct. Polym. 1995, 26, 3–23.
9. Chakrabarti, A.; Sharma, M. M. Cationic ion exchange resins as catalyst. React.
Polym. 1993, 20, 1–45.
10. Caddick, S. Microwave assisted organic reactions. Tetrahedron 1995, 51 (38),
10403–10432.
11. For recent reviews on microwave-assisted organic reactions, see (a) Varma, R. S.
Solvent-free synthesis of heterocyclic compounds using microwaves.
J. Heterocycl. Chem. 1999, 36, 1565–1571; (b) Varma, R. S. Solvent-free
organic synthesis. Green Chem. 1999, 1 (1), 43–55; (c) Bose, A. K.;
Banik, B. K.; Lavlinskaia, N.; Jayaraman, M.; Manhas, M. S. More chemistry in
a microwave. Chemtech 1997, 27 (9), 18–24; (d) Majetich, G.; Hicks, R.
Radiat. applications of microwave accelerated organic synthesis. Phys. Chem.
1995, 45 (4), 567–569; (e) Abramovich, R. A. Applications of microwave
energy in organic chemistry: A review. Org. Prep. Proced. Int. 1991, 23 (6),
683–711.