Microwave-assisted one-pot synthesis of 2,3-disubstituted 3H-quinazolin-4-ones

Article abstract of DOI:10.1016/j.tetlet.2005.01.008

A practical synthesis of 2,3-disubstituted 3H-quinazolin-4-ones 1 with broad chemistry scope is described. The key step is the microwave promoted one-pot, two-step reaction sequence combining anthranilic acids, carboxylic acids, and amines providing efficient access to this important class of heterocycles.

Full text of DOI:10.1016/j.tetlet.2005.01.008

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1241–1244
Microwave-assisted one-pot synthesis of 2,3-disubstituted
3H-quinazolin-4-ones
Ji-Feng Liu,a,* Jaekyoo Lee,a Audra M. Dalton,a Grace Bi,a Libing Yu,a
Carmen M. Baldino,a Eric McEloryb and Matt Brownb
aDivision of Chemical Technologies, ArQule, Inc., 19 Presidential Way, Woburn MA 01801, USA
bPfizer Global Research and Development, Pfizer Inc., Eastern Point Road, Groton CT 06340, USA
Received 19 November 2004; revised 23 December 2004; accepted 5 January 2005
Abstract—A practical synthesis of 2,3-disubstituted 3H-quinazolin-4-ones 1 with broad chemistry scope is described. The key step is
the microwave promoted one-pot, two-step reaction sequence combining anthranilic acids, carboxylic acids, and amines providing
efficient access to this important class of heterocycles.
Ó 2005 Elsevier Ltd. All rights reserved.
2,3-Disubstituted 3H-quinazolin-4-ones 1 are a privi-
leged structure present in many biologically active com-
pounds such as sedative-hypnotic 2 (methaqualone),1
antitussive 3 (chloroqualone),2 and anticonvulsant 4
(piriqualone)3 (Fig. 1). Although there are many reports
describing the synthesis of this class of compounds,
most of these approaches are limited in that only phenyl
groups at R2 are tolerated.4 There are only a fewspecific
reports on the preparation of the simple aliphatic, Bn,
and other heterocyclic functional group substituted
2,3-disubstituted 3H-quinazolin-4-ones.5
A
general
method for the synthesis of the 2,3-disubstituted 3H-
quinazolin-4-ones would be required in order to more
comprehensively explore this chemical space through
the variation of the R2 substituent to include a diverse
sampling of aliphatic, benzylic, aromatic, and hetero-
aromatic groups.
In an effort to develop a more widely applicable method-
ology, we chose to evaluate one of the more commonly
employed synthetic strategies via benzoxazinone 9 as an
intermediate.4a–c This synthesis begins with the conden-
sation of an anthranilic acid 5, with either an acylchlo-
ride 6 or a carboxylic acid 7 followed by dehydration
to form the intermediate benzoxazinones 9. Subsequent
addition of an aniline 10 (R2 = Ar) initially provides the
transient amidine salt species 11,4b which rapidly cyc-
lizes to yield the desired 2,3-disubstituted 3H-quinazo-
lin-4-ones 1 (R2 = Ar) (Scheme 1). In addition, Sillion
demonstrated that diamide 12 (R2 = Ar) could not
cyclize under the conventional heating conditions to give
the 2,3-disubstituted 3H-quinazolin-4-ones 1 (R2 = Ar),
which indicated that diamide 12 (R2 = Ar) was not the
precursor of 1 (R2 = Ar).4c However, while adapting this
method to the parallel synthesis of a diverse set of ana-
logs, we found that when aliphatic and benzylic amines
were used under the standard conventional heating con-
ditions, instead of forming the intermediate 11, the reac-
tion surprisingly generated diamides 12 (Scheme 2).
Consequently, we examined the possibility that micro-
wave irradiation could facilitate this cyclization step
O
O
R2
R1
N
N
R
N
N
2,3-disubstituted 3H-quinazolin-4-one 1
Methaqualone 2
O
Cl
O
N
N
N
Cl
N
N
Chloroqualone 3
Piriqualone 4
Figure 1. Biologically relevant 2,3-disubstituted 3H-quinazolin-4-one
analogs.
Keywords: Microwave; Quinazolinone.
*
Corresponding author. Tel.: +1 7819940446; fax: +1 7819940678;
e-mail: jliu@arqule.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.008

1242
J.-F. Liu et al. / Tetrahedron Letters 46 (2005) 1241–1244
O
method, which afforded benzoxazinone 9. Cyclohexyl-
O
1. R1COCl
O
N
OH
amine (1.0 equiv) and P(PhO)3 (1.2 equiv) were then
added and the mixture was heated at 120 °C under con-
ventional heating conditions providing <50% conver-
sion of cyclized product 1b,7 along with the diamide
126 and multiple side products. However, when micro-
wave irradiation was applied at >200 °C to the same
reaction mixture, the desired product 1b was formed
as the major component along with diamide 12 as a minor
by-product. Further optimization of amounts of
reagents used, the reaction time, solvent, and
temperature resulted in 1b in 90% conversion with
60% isolated yield (entry 2, Table 1).8 This initial result
clearly indicated that microwave irradiation played a
critical role in driving this reaction to completion and
providing access to a uniquely substituted heterocyclic
scaffold not available from conventional heating. Subse-
quently, it was also discovered that microwave condi-
tions promoted the initial condensation of the
anthranilic acid with a carboxylic acid, further expand-
ing the scope of this chemistry.
OH
NH2
6
O
O
N
H
8
R1
R1
or R1CO2H
5a
9
7
2. ArNH2
10
O
Ar
-
O
N
N
CO2
H
Ar
Ar
+
N
NH
N
x
N
H
H
R1
O
R1
R1
11
1
12
Scheme 1. Synthesis of 2,3-disubstituted 3H-quinazolin-4-ones 1 by
reaction of benzoxazinones 9 with anilines 10.4a–c
from the diamides 12 to form the desired products. The
details of this effort, including an optimized one-pot,
two-step microwave-assisted synthesis providing an effi-
cient route to 2,3-disubstituted 3H-quinazolin-4-ones 1,
are described.
With these exciting results in hand, we applied our opti-
mized microwave reaction conditions to a variety of
anthranilic acids and both acyl chlorides (R1COCl)
and carboxylic acids (R1CO2H)9 in the presence of the
coupling reagent (P(PhO)3) to generate the intermediate
benzoxazinones 9, followed by the addition of amines to
Experimentation on a simple model system was initiated
to understand the impact of microwave irradiation on
this known procedure (Scheme 2).4a–c A reaction mix-
ture consisting of anthranilic acid (1.0 equiv), benzoyl
chloride (1.0 equiv) in pyridine was prepared and then
stirred at room temperature according to the literature
yield the 2,3-disubstituted 3H-quinazolin-4-ones
(Table 1). The results confirmed that aromatic acyl
1
O
1. R1COCl
O
O
N
O
2. R2NH2
10
R2
N
H
R2
R1
6
µwave
OH
NH2
O
N
R
R
R
R
NH
or R1CO2H
R1
N
O
R1
5
9
1
7
12
Scheme 2. Optimized one-pot microwave promoted synthesis of 2,3-disubstituted 3H-quinazolin-4-ones 1. Optimized conditions: (1) For R1COCl
(1.5 equiv), P(PhO)3 (1.2 equiv), pyridine (2.0 mL), 25 °C, 60 min; or for R1CO2H (1.0 equiv), P(PhO)3 (1.2 equiv), pyridine (1.0 mL), lwave, 150 °C,
10 min; (2) R2NH2 (1.5 equiv) when R1COCl used, R2NH2 (1.0 equiv) when R1CO2H used, lwave, 250 °C, 3–10 min.
Table 1. Chemistry scope of the microwave promoted synthesis of 2,3-disubstituted 3H-quinazolin-4-ones 1
Entry
1
R
H
R1
R2
Reaction time (min)
3
Yielda of 1b (%)
Phc
Ph
100 (88)
(1a)
(1b)
2
H
Phc
6
90 (60)
3
4
H
H
Phc
Phc
Bn
3
3
95 (80)
(1c)
(1d)
O
O
100 (85)
5
6
H
H
Phc
5
3
95 (66)
(1e)
(1f)
Bnd
100 (62)
Ph
N
d
7
8
H
H
6
6
94 (46)
(1g)
(1h)
O
c
100 (53)
O

J.-F. Liu et al. / Tetrahedron Letters 46 (2005) 1241–1244
1243
Table 1 (continued)
Entry
9
R
R1
R2
Bn
Reaction time (min)
6
Yielda of 1b (%)
d
Ph
H
95 (50)
(1i)
10
11
H
Etd
3
6
100 (64)
100 (59)
(1j)
5-Me
Med
(1k)
d
12
13
4-Cl
Bn
Bn
6
6
100 (66)
100 (64)
(1l)
4-OMe–Bnd
Phc
(1m)
N
4,5-(OMe)2
14
15
Notee
H
6
3
95 (68)
95 (65)
(1n)
(1o)
H
Ph
Med
N
S
O2
a The yields are determined by HPLC (ELSD) from LC–MS results of the reaction mixture. In parentheses, isolated yields by preparative TLC or
flash column chromatography.
b Characterized by 1H NMR, 13C NMR, and HRMS.
c R1COCl used: 25 °C/60 min.
d R1CO2H used: lwave/150 °C/10 min.
e 2-Aminonicotinic acid used.
chlorides (entries 1–5, 8, and 14), and aliphatic carbox-
ylic acids (entries 6, 7, and 9–13) all worked smoothly
providing overall yields ranging from 46% to 88% with
all conversion >90%. Aliphatic amines (entries 2–14)
performed as well as aromatic amines (entry 1), expand-
ing the scope of this chemistry from that previously
reported.4 The reaction was also extended to include
anthranilic acids containing both electron-donating
(entries 11 and 13), and electron-withdrawing (entry
12) substituents, as well as aza-anthranilic acids (entry
14). Moreover, sulfonyl hydrazide (entry 15) also
worked as good as amines and reported methods.10 In
addition to the broad range of tolerated reagents, all
of the reactions were conducted in a one-pot, two-step
fashion without the need for intermediate work-ups,
which provided an efficient and convenient solution-
phase parallel synthesis protocol.
Supplementary data
The supplementary data is available online with the
paper in ScienceDirect. 1HNMR, 13CNMR, and HRMS
for compounds 1a–o are available as supplementary
data. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2005.01.008.
References and notes
1. (a) Wolfe, J. F.; Rathman, T. L.; Sleevi, M. C.; Campbell,
J. A.; Greenwood, T. D. J. Med. Chem. 1990, 33, 161; (b)
Kacker, I. K.; Zaheer, S. H. J. Indian Chem. Soc. 1951, 28,
344–346.
2. Buzas, A.; Hoffmann, C. Bull. Soc. Chim. Fr. 1959, 1889.
3. (a) Welch, W. M.; Ewing, F. E.; Huang, J.; Menniti, F. S.;
Pagnozzi, M. J.; Kelly, K.; Seymour, P. A.; Guanowsky,
V.; Guhan, S.; Guinn, M. R.; Critchett, D.; Lazzaro, J.;
Ganong, A. H.; DeVries, K. M.; Staigers, T. L.; Chenard,
B. L. Bioorg. Med. Chem. Lett. 2001, 177; (b) Ref. 1a.
4. (a) Jackson, T. G.; Morris, S. R.; Turner, R. H. J. Chem.
Soc. (C) 1968, 13, 1592–1593; (b) Errede, L. A. J. Org.
Chem. 1976, 41, 1763–1765; (c) Rabilloud, G.; Sillion, B.
J. Heterocyclic Chem. 1980, 17, 1065–1068; (d) Okabe, M.;
Sun, R.-C. Tetrahedron 1995, 51, 1861–1866; (e) Chenard,
B. L.; Welch, W. M.; Blake, J. F.; Butler, T. W.; Reinhold,
A.; Ewing, F. E.; Menniti, F. S.; Pagnozzi, M. J. J. Med.
Chem. 2001, 44, 1710–1717; (f) Xue, S.; McKenna, J.;
In summary, we have developed an efficient microwave-
assisted, one-pot, two-step synthesis of 2,3-disubstituted
3H-quinazolin-4-ones from anthranilic acids, carboxylic
acids or acyl chlorides, and amines. These results dem-
onstrate the value of microwave-assisted chemistry not
only to provide increased yields and shortened reaction
times, but also to expand the accessible chemical space
by generating otherwise unavailable reaction products.
This method has nowbeen adapted to the synthesis of
diverse screening libraries of related quinazolin-4-ones
and also to the total synthesis of a number of natural
products that contain this heterocyclic scaffold, which
will be published in due course.
ˇ
Shieh, W.-C.; Repic, O. J. Org. Chem. 2004, 69, 6474–
6477.
5. (a) Witt, A.; Bergman, J. Tetrahedron 2000, 56, 7245–7253;
(b) Kumari, T. A.; Reddy, M. S.; Rao, P. J. P. Synth.
Commun. 2002, 32, 235–240; (c) OÕMahony, D. J. R.;
Krchnak, V. Tetrahedron Lett. 2002, 43, 939–942; (d)
Dabiri, M.; Salehi, P.; Khajavi, M. S.; Mohammadi, A. A.
Heterocycles 2004, 63, 1417–1421, and references cited in.
6. This diamide was isolated and characterized by NMR and
compared with the authentic sample prepared with known
Acknowledgements
The authors thank Dr. Daniel Yohannes for helpful
discussion. The authors also thank Ms. Jun Zhao and
Ms. Martina DeSomma for technical assistance.

1244
J.-F. Liu et al. / Tetrahedron Letters 46 (2005) 1241–1244
procedure. Hart, D. J.; Magomedov, N. Tetrahedron Lett.
1999, 40, 5429–5432.
(200 lmol), phenylacetic acid (200 lmol), and triphenyl
phosphite (63 lL, 220 lmol) in 1 mL of anhydrous pyri-
dine were charged. The vial was irradiated under micro-
wave conditions in the sealed reaction vessel at 150 °C for
10 min. Upon consumption of anthranilic acid, an amine
(200 lmol) was added and the resulting mixture was
heated in microwave at 250 °C for 3–6 min. The reaction
mixture was concentrated in vacuo, and the residue was
purified by silica gel flash chromatography (ethyl acetate/
hexanes) to give the desired product. 1j: 3-Benzyl-2-ethyl-
3H-quinazolin-4-one; 34 mg (64%); 1H NMR (CDCl3,
300 MHz) d 1.32 (t, J = 7.2 Hz, 3H), 2.77 (q, J = 7.2 Hz,
2H), 5.42 (s, 2H), 7.17 (dd, J = 8.1, 1.5 Hz, 2H), 7.25–7.35
(m, 3H), 7.43–7.49 (m, 1H), 7.66–7.77 (m, 2H), 8.31 (dd,
J = 7.8, 1.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 11.51,
28.57, 46.47, 120.61, 126.60, 126.68, 127.29, 127.31,
127.82, 129.15, 134.53, 136.42, 147.66, 158.18, 162.82;
HRMS calcd for (C17H16N2O + H) 265.1335, found
265.1350.
7. Errede and others reported that conversion of 12a
(R1 = R2 = Ph, R = H) to 1a requied fusion temperature
of about 250 °C, although yield was not given. Errede, L.
A.; Oien, H. T.; Yarian, D. R. J. Org. Chem. 1977, 42, 12–
18, and related references therein.
8. General reaction procedure to synthesis 2,3-disubstituted
3H-quinazolin-4-ones 1 from acyl chlorides in Table 1: In a
conical-bottomed Smith Process vial, anthranilic acid 5a
(200 lmol), benzoyl chloride (300 lmol), and triphenyl
phosphite (63 lL, 220 lmol) in 2 mL of anhydrous pyri-
dine were charged. The resulting mixture was stirred at
room temperature for 1 h. Upon consumption of anthra-
nilic acid, an amine (300 lmol) was added and the vial was
irradiated under microwave conditions in the sealed
reaction vessel for 3–6 min at 250 °C. After cooling, the
reaction mixture was concentrated in vacuo and the residue
was purified by preparative TLC (ethyl acetate/hexanes) to
give the desired product. 1d: 3-(2-Methoxy-ethyl)-2-phen-
yl-3H-quinazolin-4-one; 47.5 mg (85%); 1H NMR (CDCl3,
300 MHz) d 3.16 (s, 3H), 3.60 (t, J = 5.1 Hz, 2H), 4.28 (t,
J = 5.1 Hz, 2H), 7.53–7.60 (m, 6H), 8.35 (br d, J = 8.10 Hz,
1H); 13C NMR (CDCl3, 75 MHz) d 46.04, 58.97, 69.10,
120.35, 125.35, 127.34, 128.19, 128.75, 128.98, 131.06,
132.68, 135.54, 144.25, 158.42, 161.47; HRMS calcd for
(C17H16N2O2 + Na+) 303.1111, found 303.1097.
10. When this manuscript was in preparation, a method of
synthesis of 3-sulfonamide-substituted quinazolinones was
reported Zhou, Y.; Murphy, D. E.; Sun, Z.; Gregor, V. E.
Tetrahedron Lett. 2004, 45, 8049–8051, in which neat
benzoxazinones and sulfonyl hydrazides reacted under
melting temperature (130 °C) generated target products.
However, when we applied reported method to aliphatic
amines (Table 1, entry 3 combination), we only obtained
<10% cyclized prodcut 1c along with >85% diamide 12. In
contrast, sulfonyl hydrazides worked very well under our
reaction conditions.
9. General reaction procedure to 2,3-disubstituted 3H-qui-
nazolin-4-ones 1 from carboxylic acids in Table 1: In a
conical-bottomed Smith Process vial, anthranilic acid 5a