Bi(TFA)3-[nbp]FeCl4: a new, efficient and reusable promoter system for the synthesis of 4(3H)-quinazolinone derivatives

Article abstract of DOI:10.1016/j.tetlet.2006.03.079

4(3H)-Quinazolinones have been synthesized in high to excellent yields through the one-pot condensation of anthranilic acid, trimethyl orthoformate and primary amines in the presence of 5 mol % of Bi(TFA)₃ immobilized on [nbp]FeCl₄ a

Full text of DOI:10.1016/j.tetlet.2006.03.079

Tetrahedron Letters 47 (2006) 3561–3564
Bi(TFA)3–[nbp]FeCl4: a new, efficient and reusable promoter
system for the synthesis of 4(3H)-quinazolinone derivatives
Ahmad R. Khosropour,a,* Iraj Mohammadpoor-Baltorka and Hamid Ghorbankhanib
aDepartment of Chemistry, Faculty of Science, Isfahan University, Isfahan 81746-73441, Iran
bDepartment of Chemistry, Faculty of Science, Razi University, Kermanshah 67149, Iran
Received 15 November 2005; revised 27 February 2006; accepted 10 March 2006
Available online 5 April 2006
Abstract—4(3H)-Quinazolinones have been synthesized in high to excellent yields through the one-pot condensation of anthranilic
acid, trimethyl orthoformate and primary amines in the presence of 5 mol % of Bi(TFA)3 immobilized on [nbp]FeCl4 as a room
temperature ionic liquid.
ꢀ 2006 Published by Elsevier Ltd.
1. Introduction
flexible but needs toxic reagents and harsh reaction
conditions are required.
4(3H)-Quinazolinones have emerged as an important
class of nitrogenated heterocycles that have attracted
significant synthetic interest because of their pharmaco-
logical and therapeutic properties such as antibacterial,
antifungal, antimalarial, antihypertensive, anticonvul-
sant, anti-Parkinsonism, antihistaminic and local anaes-
thetic, analgesic, anti-inflammatory antiviral and
anticancer activities.1 A small number of quinazolinones
have been reported as potent chemotherapeutic agents
in the treatment of tuberculosis. For example, 3-aryl-
6,8-dichloro-2H-1,3-benzoxazine-2,4(3H)-diones and 3-
arylquinazoline-2,4(1H,3H)-diones as antimycobacterial
agents2 and quinazolinone derivatives as antitubercular
agents.3 The antihyperlipidemic activities of these com-
pounds were also investigated.4 There are several meth-
ods for the synthesis of 4(3H)-quinazolinones.5
However, most of these procedures have significant
drawbacks such as long reaction times, low yields, harsh
reaction conditions, difficult work-up and use of environ-
mentally toxic reagents or media. Recently, Das et al.,
have demonstrated a green process for the synthesis of
4(3H)-quinazolinones, which is limited in that only phe-
nyl R groups are tolerated.6 More recently, Liu et al. re-
ported another procedure for the synthesis of these
compounds through a two-step reaction in the presence
of P(PhO)3/anhydrous pyridine under microwave irradi-
ation at 250 ꢁC.7 The second strategy seems to be more
The demand for increasingly clean and efficient chemical
synthesis is important from both economic and environ-
mental points of view.8 One commonly used method is
the immobilization of Lewis acids on ionic liquids. Sev-
eral catalysts have been immobilized on ionic liquids
and successfully recycled as a result of the involatile nat-
ure of these media.9 These ionic catalytic systems gave
much higher reaction rates and selectivities than those
performed in classical organic solvents.10 In recent
years, we have reported that bismuth(III) trifluoroace-
tate is a mild and non-toxic catalyst that is stable in
water and is reusable.11 Also, we have examined some
important transformations in the presence of Lewis
acids immobilized on ionic liquids.12 In continuation
of our work to develop new synthetic methodologies,
we report a facile and efficient method for the synthesis
of 4(3H)-quinazolinone derivatives by the condensation
reaction of anthranilic acid, trimethyl orthoformate and
primary amines in the presence of a catalytic amount
of Bi(TFA)3 in n-butylpyridinium tetrachloroferrate
([nbp]FeCl4)13 as a room temperature ionic liquid
(Scheme 1).
O
R
CO2H
NH2
HC(OCH3)3
N
+
RNH2
Bi(TFA)3-[nbp]FeCl4
N
*
Corresponding author. Tel./fax: +98 311 6689732; e-mail:
arkhosropour@razi.ac.ir
Scheme 1.
0040-4039/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.03.079

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A. R. Khosropour et al. / Tetrahedron Letters 47 (2006) 3561–3564
The experimental procedure is simple. The reactions
were carried out at 60 ꢁC for 5–20 min by reacting a
1:1.2:1.2 mole ratio mixture of anthranilic acid, tri-
methyl orthoformate and primary amine in the presence
of 5 mol % of Bi(TFA)3 in [nbp]FeCl4 to give the desired
products in high to excellent yields. As shown in Table
1, both aniline derivatives and primary aliphatic amines
react without any significant difference to give the corre-
sponding 4(3H)-quinazolinones. The reaction is fairly
general, clean, rapid and efficient. Significant amounts
of undesirable side products were not formed. Unlike
previously reported methods, the present method does
Table 1. Synthesis of 4(3H)-quinazolinones in the presence of Bi(TFA)3 immoblized on [nbp]FeCl4 as a room temperature ionic liquid
Entry
Amine
Quinazolinone
Time (min)
Yield (%)a
O
N
NH2
1
10
94
N
O
N
N
Br
NH2
2
15
90
Br
O
N
NH2
Br
3
4
15
15
83
92
Br
N
O
Cl
NH2
NH2
N
Cl
N
O
N
F
5
6
7
15
20
15
90
79
93
F
N
O
O2N
NH2
NO2
N
N
CH3
H3C
NH2
CH3
NH2
O
N
CH3
N
O
N
OCH3
OCH3
8
9
10
5
95
91
H3CO
OCH3
N
O
CH2NH2
N
N
O
10
11
N
5
98
97
NH2
N
O
N
N
10
NH2
a Yields refer to isolated pure products characterized by NMR and MS spectra.

A. R. Khosropour et al. / Tetrahedron Letters 47 (2006) 3561–3564
3563
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not require toxic or anhydrous organic solvents. All the
products were characterized by NMR, IR and mass
spectroscopy and also by comparison with authentic
samples.
Interestingly, we observed that the combination of
Bi(TFA)3–[nbp]FeCl4 was essential for this transforma-
tion. Attempts to carry out the reaction in the absence of
each of these did not yield the products and only the
starting materials were isolated. On the other hand, tri-
methyl and triethyl orthoformate reacted similarly these
reaction conditions. Another advantage of this method
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Bi(TFA)3–[nbp]FeCl4 was weakly soluble in Et2O, it
could be separated by washing with Et2O and dried at
80 ꢁC under reduced pressure and reused in three runs
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To a mixture of anthranilic acid (1 mmol), trimethyl
orthoformate (1.2 mmol) and 4-bromoaniline (1.2
mmol) in [nbp]FeCl4 (1 mmol), Bi(TFA)3 (0.05 mmol)
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Mp 185 ꢁC; 1H NMR (200 MHz, CDCl3) d 8.43 (d, 1H,
J = 8.6 Hz), 8.12 (s, 1H), 7.95–7.21 (m, 7H), 13C NMR
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Acknowledgements
We are thankful to Isfahan University and Razi Univer-
sity Research Council for partial support of this work.
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