Tetrahedron Letters
FeCl -catalyzed tandem condensation/intramolecular nucleophilic
3
addition/C–C bond cleavage: a concise synthesis of 2-substitued
quinazolinones from 2-aminobenzamides and 1,3-diketones in
aqueous media
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Guanshuo Shen, Haifeng Zhou , Yuebo Sui, Qixing Liu, Kun Zou
Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise approach for the synthesis of 2-substituted quinazolinones using an iron-catalyzed tandem
reaction of 2-aminobenzamides with acyclic or cyclic 1,3-diketones via condensation, intramolecular
nucleophilic addition, C–C bond cleavage in an aqueous solution of poly(ethylene glycol) under
oxidant-free conditions has been developed.
Received 29 October 2015
Revised 7 December 2015
Accepted 23 December 2015
Available online xxxx
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Iron
Quinazolinone
2
1
-Aminobenzamide
,3-Diketone
Green synthesis
Nitrogen heterocycles have aroused considerable interest
because of their presence in many therapeutically and biologically
active compounds. In particular, quinazolinones are building
blocks for approximately 150 naturally occurring alkaloids and
none derivatives through tandem condensation, intramolecular
nucleophilic addition, C–C bond cleavage of 2-aminobenzamides,
and acyclic or cyclic 1,3-diketones in an aqueous solution of poly
(ethylene glycol) under oxidant-free conditions (Scheme 1).
Initially, 2-aminobenzamide (1a) and 2,4-pentanedione (2a)
were used as the model substrates to optimize reaction conditions
including iron catalyst, solvents, and catalyst loading. As shown in
Table 1, eight iron catalysts (10 mol %) were tested in poly(ethy-
lene glycol) (PEG-400) as the solvent at 100 °C for 24 h (entries
1
many marketed drugs. Such compounds have a wide range of use-
2
ful biological and therapeutic activities, such as antimalarial, anti-
hypertensive, antimicrobial, anti-inflammatory, and anticancer
activities.
Because of their remarkable importance, many efforts have
been made to prepare such compounds from a variety of starting
materials, of which 2-aminobenzamides are probably the most
1–8). Iron trichloride hexahydrate (FeCl
3
Á6H
2
O) provided the
desired product 3aA in highest yield (entry 8), which was superior
to the anhydrous counterpart (entry 2). We supposed that water
may enhance the reactivity of this transformation, so the reaction
was attempted in pure water. However, the yield was not
increased due to the poor solubility of the reactants (entry 9). Then,
3
typical. In general, the quinazolinones were constructed by the
4
5
reaction of 2-aminobenzamides with carboxylic acids, carbonyls,
6
5i,7
methylarenes,8 or carbonylative
b-ketoesters, benzyl alcohol,
9
conditions. Notably, most of the reported synthetic routes require
excess amounts of oxidants or bases. Suitable ligands or micro-
wave irradiation conditions are necessary in some cases. Therefore,
eco-friendly and practical methods to access valuable 2-substi-
tuted quinazolinones are highly desirable. To continue our
research interest in iron catalysis and catalytic reactions in green
media, we have reported a simple, eco-friendly, and practical
iron-catalyzed strategy for synthesis of 2-substituted quinazoli-
a mixture of PEG-400/H
desired product was obtained in higher yield (entries 10–12), and
PEG-400/H O (1:9) was the optimal choice (entry 12; 80% yield).
2
O was used as solvent. As expected, the
2
The yield of 3aA could be increased from 80% to 91% when the cat-
alyst loading was doubled (entry 13).
Then, a wide range of 1,3-diketones were employed in the reac-
tions with 2-aminobenzamide (1a) under the optimized conditions
10
1
1
(
Table 2). On comparing with 2A, heptane-3,5-dione (2B) gave a
lower yield of 3aB under identical conditions (3aA: 91%; 3aB:
3%). In contrast, the product 3aC was obtained in moderate yield
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