Lanthanum(III) nitrate hexahydrate or p-toluenesulfonic acid catalyzed one-pot synthesis of 4(3H)-quinazolinones under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2006.04.096

The one-pot synthesis of quinazolinone derivatives from the reaction of anthranilic acid, trialkyl orthoformate and amines in the presence of lanthanum(III) nitrate hexahydrate or p-toluenesulfonic acid has been carried out. The reaction occurred in a few

Full text of DOI:10.1016/j.tetlet.2006.04.096

Tetrahedron Letters 47 (2006) 4381–4383
Lanthanum(III) nitrate hexahydrate or p-toluenesulfonic
acid catalyzed one-pot synthesis of 4(3H)-quinazolinones
,
under solvent-free conditionsI II
Manchala Narasimhulu, Kondempudi Chinni Mahesh, Thummalapally Srikanth Reddy,
Karuturi Rajesh and Yenamandra Venkateswarlu*
Natural Products Laboratory, Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007,
Andhra Pradesh, India
Received 17 March 2006; revised 12 April 2006; accepted 20 April 2006
Available online 12 May 2006
Abstract—The one-pot synthesis of quinazolinone derivatives from the reaction of anthranilic acid, trialkyl orthoformate and
amines in the presence of lanthanum(III) nitrate hexahydrate or p-toluenesulfonic acid has been carried out. The reaction occurred
in a few minutes under solvent-free conditions and in excellent yields.
ꢀ 2006 Elsevier Ltd. All rights reserved.
4(3H)-Quinazolinones are an important class of fused
heterocycles with a wide range of biological activities
such as anti-cancer, anti-inflammatory, anti-convulsant,
anti-hypertensive and anti-malarial activity.1 Several
bio-active natural products including febrifugine and
isofebrifugine contain a quinazolinone moiety and pos-
sess anti-malarial activity.2,3 The most common meth-
ods for the preparation of quinazolinones involve the
amidation of 2-aminobenzonitrile or 2-aminobenzoic
acid or its derivatives followed by oxidative ring closure
under basic conditions.4,5 Other methods involve cyclo-
addition of anthranilic acid derivatives with a diverse
range of substrates including imidates and imino-
halides.6 Recently, 4(3H)-quinazolinones were prepared
been excluded from practical applications due to envi-
ronmental and economic considerations. Hence, there
is still a need to develop efficient methods for the synthe-
sis of 4(3H)-quinazolinones.
We have developed an expeditious one-pot synthesis of
4(3H)-quinazolinones from the reaction of anthranilic
acid, trialkyl orthoformate and amines (alkyl or aryl)
in the presence of lanthanum(III) nitrate hexahydrate
[La(NO3)3Æ6H2O] or p-toluenesulfonic acid (PTSA)
under solvent-free conditions (Scheme 1).
Various 4(3H)-quinazolinones were prepared10 (Table 1)
by reacting anthranilic acid 1 with different substituted
alkyl and aryl amines and trimethyl or triethyl ortho-
formate. The reaction proceeded at room temperature
within few minutes in excellent yields after the addition
of the acid catalyst lanthanum(III) nitrate hexahydrate
or p-toluenesulfonic acid. Only the reaction with 4-nitro-
aniline required reflux and the time required was 15 min.
8
using silica sulfuric acid,7 PCl3 and Zn/HCOONH4
under microwave irradiation.9 However, some of these
methods are associated with drawbacks such as multi-
step procedures, costly reagents, harsh reaction condi-
tions, complex and tedious experimental procedures,
and low yields. Thus, several previous methods have
Keywords: Quinazolinones; Lanthanum(III) nitrate hexahydrate;
p-Toluenesulfonic acid; Three-component reaction; Solvent-free
conditions.
O
O
N
R2
.
La(NO3)3 6H2O
OH
N
HC(OR1)
R2_NH2
+
+
q Reactions using lanthanum(III) nitrate hexahydrate, paper 3; for
3
or PTSA
NH2
Solvent-free
paper 2 refer to Ref. 12.
qq IICT Communication No. 060415.
4
3
1
2
*
Corresponding author. Tel.: +91 40 27193167; fax: +91 40
27160512; e-mail: luchem@iict.res.in
Scheme 1.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.096

4382
M. Narasimhulu et al. / Tetrahedron Letters 47 (2006) 4381–4383
Table 1. Preparation of 4(3H)-quinazolinones using La(NO3)3Æ6H2O
mildness of the catalysts, solvent-free conditions, fast
reaction times (5–15 min), simple experimental proce-
dure and excellent yields (82–98%) are the great advan-
tages of the present protocol.
and PTSA under solvent-free conditionsa
Entry R1 R2
Catalystb Time Isolated
(min) yield (%)
a
b
c
d
e
f
Me C6H5
i
ii
i
ii
i
ii
i
ii
i
ii
i
ii
i
ii
i
ii
i
ii
i
ii
i
ii
i
ii
i
ii
i
ii
i
ii
i
5
5
5
5
5
5
5
5
5
5
5
5
15
15
10
10
5
5
5
5
10
10
5
5
5
5
5
5
5
5
5
5
5
986h
96
Me 2-MeC6H4
Me 4-MeC6H4
Me 2-FC6H4
976h
93
Acknowledgements
986h
96
The authors thank CSIR, New Delhi, India for financial
assistance and Dr. J. S. Yadav, Director, IICT, for his
constant encouragement.
94
92
Me 4-FC6H4
966h
92
Me 2-MeOC6H4
Me 4-NO2C6H4
Me 1-Naphthyl
Me C6H5CH2CH2
Me C6H5CHCH3
Me C6H5CH(CH2)2CH3
Et C6H5
956h
93
References and notes
g
h
i
846h
81
1. (a) Wolfe, J. F.; Rathman, T. L.; Sleevi, M. C.; Campbell,
J. A.; Greenwood, T. D. J. Med. Chem. 1990, 33, 161; (b)
Tereshima, K.; Shimamura, H.; Kawase, A.; Tanaka, Y.;
Tanimura, T.; Kamisaki, T.; Ishizuka, Y.; Sato, M. Chem.
Pharm. Bull. 1995, 43, 2021; (c) Kurogi, Y.; Inoue, Y.;
Tsutsumi, K.; Nakamura, S.; Nagao, K.; Yohsitsugu, H.;
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Med. Chem. Lett. 1998, 8, 483; (e) Gueyrard, D.; Gurnel,
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2. (a) Koepfly, J. B.; Mead, J. F.; Brockman, J. A., Jr. J. Am.
Chem. Soc. 1947, 69, 1837; (b) Ablondi, F.; Gordon, S.;
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(c) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.
Tetrahedron Lett. 1999, 40, 2175.
92
86
94
94
92
91
95
92
j
k
l
976h
96
m
n
o
p
q
r
Et 2-MeC6H4
Et 4-MeC6H4
Et 2-FC6H4
986h
91
966h
96
93
90
3. Jang, C. S.; Fu, F. Y.; Wang, C. Y.; Huang, K. C.; Lu, G.;
Thou, T. C. Science 1946, 103, 59.
4. (a) Bogert, M. T.; Hand, W. F. J. Am. Chem. Soc. 1902,
24, 1031; (b) Bogert, M. T.; Hand, W. F. J. Am. Chem.
Soc. 1903, 25, 935; (c) Taylor, E. C.; Knopf, R. J.; Borror,
A. L. J. Am. Chem. Soc. 1960, 82, 3152.
Et 4-FC6H4
906h
90
ii
i
ii
i
ii
i
ii
i
ii
i
ii
i
Et 2-MeOC6H4
Et 4-NO2C6H4
Et 1-Naphthyl
Et C6H5CH2CH2
Et C6H5CHCH3
Et C6H5CH(CH2)2CH3
966h
93
5
15
15
10
10
5
856h
82
5. Kotsuki, H.; Sakai, H.; Morimoto, H.; Suenaga, H.
Synlett 1999, 1993.
s
92
92
96
93
91
91
96
90
6. (a) Onaka, T. Tetrahedron Lett. 1971, 12, 4387; (b)
Kametani, T.; Loc, C. V.; Higa, T.; Koizumi, M.; Ihara,
M.; Fukumoto, K. J. Am. Chem. Soc. 1997, 99, 2306; (c)
Mori, M.; Kobayashi, H.; Kimura, M.; Ban, Y. Hetero-
cycles 1985, 23, 2803; (d) Sauter, F.; Frohlic, J.; Blast, K.;
Gewald, K. Heterocycles 1985, 40, 851; (e) Majo, V. J.;
Perumal, P. T. Tetrahedron Lett. 1996, 37, 5015; (f)
Prasad, M.; Chen, L.; Repic, O.; Blacklock, T. J. Synth.
Commun. 1998, 28, 2125; (g) Connolly, D. J.; Guiry, P. J.
Synlett 2001, 1707; (h) Wang, L.; Xia, J.; Qin, F.; Qin, C.;
Sun, J. Synthesis 2003, 1241.
t
5
u
v
10
10
15
15
ii
a The structures of the quinazolinone derivatives were determined from
their spectral (1H NMR and MS) and analytical data.
b Catalyst i: La(NO3)3Æ6H2O, ii: PTSA.
7. Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Bahgbanzadeh, M.
Tetrahedron Lett. 2004, 46, 7151.
8. Xue, S.; McKenna, J.; Shieh, W. C.; Repi, O. J. Org.
Chem. 2004, 69, 6474.
This is due to the presence of an electron withdrawing
group (–NO2). Triethyl and trimethyl orthoformates
reacted similarly. Both La(NO3)3Æ6H2O and PTSA
catalyze the reaction under homogeneous conditions.
La(NO3)3Æ6H2O was recently used as a catalyst for the
deprotection of acetonides11 and in selective protection
of primary alcohols.12 PTSA is widely used in organic
synthesis.13
9. Kamal, A.; Reddy, K. S.; Prasad, B. R.; Babu, A. H.;
Ramana, A. V. Tetrahedron Lett. 2004, 45, 6517.
10. General procedure for the preparation of quinazolinones:
To a mixture of anthranilic acid (1 mmol), an ortho ester
(1.2 mmol) and an amine (1.2 mmol) La(NO3)3Æ6H2O
(5 mmol%) or PTSA (5 mmol %) were added. The mixture
was stirred at room temperature for the appropriate time
(Table 1). After completion of the reaction, as monitored
by TLC, water was added followed by extraction into
dichloromethane (3 · 5 mL). The combined organic layer
was washed with aq HCl (5%) (3 · 5 mL) and washed with
saturated NaHCO3 (3 · 5 mL) solution. The organic layer
In conclusion, we have developed a simple and efficient
three-component reaction of anthranilic acid, ortho-
esters and alkyl/aryl amines using La(NO3)3Æ6H2O or
PTSA under the solvent-free conditions for the prepara-
tion of 4(3H)-quinazolinones in a single step. The

M. Narasimhulu et al. / Tetrahedron Letters 47 (2006) 4381–4383
4383
was dried over MgSO4 and the solvent was evaporated to
afford pure 4(3H)-quinazolinones.
EIMS: m/z 250 (M+Æ). Anal. Calcd for C16H14N2O: C,
76.77; H, 5.63; N, 11.19. Found: C, 76.72; H, 5.59; N,
11.28. Compound 4k: 1H NMR (200 MHz, CDCl3): d 8.30
(d, 1H, J = 7.2 Hz), 7.32 (m, 4H), 7.16 (m, 5H), 6.37 (t,
1H, J = 2.5 Hz), 1.72 (m, 2H), 1.32 (m, 2H), 0.91 (t, 3H,
J = 1.05 Hz); EIMS: m/z 278 (M+Æ). Anal. Calcd for
C18H18N2O: C, 77.67; H, 6.51; N, 10.06. Found: C, 77.59;
H, 6.62; N, 10.14.
The spectral (1H NMR and MS) and analytical data of
some representative 4(3H)-quinazolinones are given
below.
Compound 4d: 1H NMR (200 MHz, CDCl3): d 8.22 (d,
1H, J = 7.3 Hz), 7.15 (m, 4H), 7.03 (m, 4H); EIMS: m/z
240 (M+Æ); Anal. Calcd for C14H9N2FO: C, 69.99; H, 3.77;
F, 7.90; N, 11.66. Found: C, 69.82; H, 3.61; N, 11.59.
Compound 4h: 1H NMR (200 MHz, CDCl3): d 8.18 (s,
1H), 7.72 (m, 7H), 7.08 (m, 4H); EIMS: m/z 272 (M+Æ);
Anal. Calcd for C18H12N2O: C, 79.39; H, 4.44; N, 10.28.
Found: C, 79.22; H, 4.54; N, 10.31. Compound 4i: 1H
NMR (200 MHz, CDCl3): d 8.32 (d, 1H, J = 7.7 Hz), 7.62
(m, 4H), 7.20 (m, 5H), 4.22 (t, 2H, J = 2.5 Hz), 3.28 (t, 2H,
J = 2.5 Hz); EIMS: m/z 250 (M+Æ). Anal. Calcd for
C16H14N2O: C, 76.77; H, 5.63; N, 11.19. Found: C,
76.82; H, 5.76; N, 11.24. Compound 4j: 1H NMR
(200 MHz, CDCl3): d 8.28 (d, 1H, J = 7.5 Hz), 7.58 (m,
4H), 7.22 (m, 5H), 6.38 (m, 1H), 1.80 (d, 3H, J = 3.5 Hz);
11. Reddy, S. M.; Reddy, Y. V.; Venkateswarlu, Y. Tetra-
hedron Lett. 2005, 46, 7439.
12. Reddy, T. S.; Ravinder, K.; Suryakiran, N.; Narasimhulu,
M.; Mahesh, K. C.; Venkateswarlu, Y. Tetrahedron Lett.
2006, 47, 2341.
13. (a) Jia, C.-S.; Zhang, Z.; Tu, S.-J.; Wang, G.-W. Org.
Biomol. Chem. 2006, 4, 104; (b) Tantry, S. J.; Kantharaju;
Babu, V. V. S. Tetrahedron Lett. 2002, 43, 9461; (c) Zhao,
F.; Yang, X.; Liu, J. Tetrahedron 2004, 60, 9945; (d)
Goncalo, P.; Roussel, C.; Melot, J. M.; Vebrel, J. J. Chem.
Soc., Perkin Trans. 2 1999, 2111; (e) Paul, S.; Gupta, M.;
Gupta, R.; Loupy, A. Tetrahedron Lett. 2001, 42, 3827.