Reaction of benzyl alcohols, isatoic anhydride, and primary amines mediated by I2/K2CO3 in water: A new and green approach for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones

Article abstract of DOI:10.1016/j.tetlet.2015.11.090

An efficient synthesis of 2,3-dihydroquinazolin-4(1H)-ones proceeding via a three-component reaction between benzyl alcohols, isatoic anhydride, and primary amines in the presence of iodine and potassium carbonate is reported. This protocol allows the straightforward preparation of the titled products using readily available benzyl alcohols instead of unstable aldehydes under mild oxidative conditions.

Full text of DOI:10.1016/j.tetlet.2015.11.090

Accepted Manuscript
Reaction of benzyl alcohols, isatoic anhydride and primary amines mediated by
I2/K2CO3 in water: A new and green approach for the synthesis of 2,3-dihydro-
quinazolin-4(1H)-ones
Seyedeh Bahareh Azimi, Javad Azizian
PII:
S0040-4039(15)30398-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.11.090
TETL 47030
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 June 2015
12 November 2015
28 November 2015
Please cite this article as: Azimi, S.B., Azizian, J., Reaction of benzyl alcohols, isatoic anhydride and primary amines
mediated by I2/K2CO3 in water: A new and green approach for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones,
Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.11.090
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Graphical Abstract
Reaction of benzyl alcohols, isatoic anhydride and
primary amines mediated by I2/K2CO3 in water: a
new and green approach for the synthesis of 2,3-
dihydroquinazolin-4(1H)-ones
Seyedeh Bahareh Azimi, Javad Azizian
O
O
O
R
I2, K2CO3
N
RNH
+
Ar
OH
+
2
water, reflux, 3 h
Ar
N
N
H
O
H

Tetrahedron letters
1
Tetrahedron Letters
journal homepage: www.elsevier.com
Reaction of benzyl alcohols, isatoic anhydride and primary amines mediated by
I2/K2CO3 in water: a new and green approach for the synthesis of 2,3-
dihydroquinazolin-4(1H)-ones
Seyedeh Bahareh Azimi, Javad Azizian*
Department of Chemistry, Science and Research Branch, Islamic Azad University, P. O. Box 19395-1775, Tehran, Iran
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient synthesis of 2,3-dihydroquinazolin-4(1H)-ones proceeding via a three-component
reaction between benzyl alcohols, isatoic anhydride and primary amines in the presence of
iodine and potassium carbonate is reported. This protocol allows the straightforward preparation
of the titled products using readily available benzyl alcohols instead of unstable aldehydes under
mild oxidative conditions.
Available online
2015 Elsevier Ltd. All rights reserved.
Keywords:
Benzyl alcohols
Iodine
Oxidation
2,3-Dihydroquinazolin-4(1H)-ones (DHQZs)
Green chemistry
Green chemistry concerns the design of environmentally
friendly products and chemical processes while minimizing the
usage and generation of hazardous substances. Organic solvents
are a key factor in environmental pollution and many are
carcinogenic and toxic making reactions which do not require the
use of organic solvents desirable. Water is an alternative solvent
for many chemical reactions, possessing desirable properties such
as ready availability, chemical stability, nontoxicity, recyclability
and easy handling.1 Moreover, in many reactions, water has been
shown to significantly enhance the reaction rate in comparison to
organic solvents due to hydrogen bonding, hydrophobic effect,
high heat capacity, high cohesive energy density.2
reaction between isatoic anhydride, amines and aldehydes using
catalysts such as β-cyclodextrin,4 montmorillonite K-10,5
Amberlyst-15,6
molecular
iodine,7
methylimidazolium
tetrafluoroborate ([bmim]BF4),8 silica sulfuric acid,9 1-butyl-3-
cyanuric chloride,10 zinc(II) perfluorooctanoate [Zn(PFO)2],11
KAl(SO4)2•12H2O,12 Al/Al2O3 nanocatalyst,13 Al(H2PO4)3,14
MCM-41-SO3H,15 and gallium(III) triflate.16
O
O
H2NO2S
Cl
NH
N
N
H
N
N
H
aquamox
evodiamine
O
O
2,3-Dihydroquinazolin-4(1H)-ones
(DHQZs)
are
N-
H2NO2S
Cl
H2NO2S
Cl
N
NH
heterocycles that are of notable interest in medicinal chemistry
and have a wide range of biological and pharmaceutical
properties such as antibiotic,3a antiviral,3b antitumor,3c,d
antihistamine,3e anti-inflamatory,3f,g cytotoxic,3c vasodilatory,3h
anticonvulsant,3i antispermatogenic,3d antihypertensive,3j anti-
osteoporosis,3h analgesic,3i and antidefibrillatory activities.3l
Fenquizone, metolazone, evodiamine and aquamox are examples
of clinically significant DHQZ medications (Figure 1).
N
H
N
H
fenquizone
metolazone
Figure 1
However, some of these procedures have noticeable
disadvantages such as long reaction times, harsh reaction
conditions, low yields, and use of toxic and expensive catalysts
or media. In addition, in some of cases the utilized aldehydes are
unstable, oxidizable, volatile or capable of hydrolysis or
polymerization. Therefore, the development a novel and efficient
approach for the preparation of 2,3-dihydroquinazolin-4(1H)-
ones in which the aldehydes are generated in situ is desirable.
Accordingly, several synthetic methods have been developed
for the preparation of DHQZs. The most widely used approaches
for the synthesis of these compounds include the condensation of
anthranilamide with aldehydes or ketones or the three-component
———
* Corresponding author. Tel./fax: +98(21)44580762.
E-mail address: j.azizian13@gmail.com (J. Azizian).

2
Tetrahedron Letters
7
8
9
10
11
12
Dioxane
DCE
1.0 / 1.0
1.0 / 1.0
1.0 / 1.0
1.0 / 1.0
0.5 / 1.0
1.0 / 1.0
10
10
10
10
10
3
46
13
53
48
43
91
Adib and coworkers have reported a novel oxidative reaction
between isatoic anhydride, amines and benzyl halides under
Kornblum oxidation conditions. In this reaction the benzyl
halides were oxidized to required aldehydes, however this
protocol led to the synthesis of 4(3H)-quinazolinones.17
tBuOH
EtOAc
Water
Water
Herein, we describe a convenient and straightforward route for
the synthesis of 2,3-dihydroquinazolin-4(1H)-ones using benzyl
alcohols instead of aldehydes. Thus, treatment of 4-
methoxybenzyl alcohol 1a with iodine and potassium carbonate
led to 4-methoxybenzaldehyde. Subsequently, the 2-amino-N-
phenylbenzamide which was generated from nucleophilic
addition of aniline 3a onto isatoic anhydride 2 was condensed
with the in situ prepared aldehyde to produce 4a.
The reaction was carried out at reflux in several solvents
including acetonitrile, toluene, dimethyl sulfoxide, dioxane, 1,2-
dichloroethane (DCE), tert-butanol, ethyl acetate and water using
various amounts of iodine (Table 1). The maximum yield and
shortest reaction time was obtained in water in the presence of
equimolar iodine and potassium carbonate (entry 12). In addition
to K2CO3, several bases such as Et3N, DBU, pyridine, NaOH and
tBuOK were also examined. Inorganic bases were shown to give
better results, and K2CO3 was chosen due to the high yield of
desired product and relatively lower cost. The reaction did not
proceed cleanly in the absence of base.
O
O
I2, K2CO3
OH
O
N
+
+
PhNH2
MeO
N
H
N
H
O
1a
2
3a
4a
OMe
To demonstrate the generality of this strategy, various primary
amines and benzyl alcohols were examined. All reactions
proceeded to completion within 3 hours. H NMR analysis of the
Scheme 1
Table 1. Optimization for the oxidative synthesis of 4a
1
Entry
Solvent
MeCN
MeCN
MeCN
Toluene
DMSO
DMSO
I2 (eq.) / K2CO3 (eq.)
0.2 / 1.0
0.5 / 1.0
1.0 / 1.0
1.0 / 1.0
0.5 / 1.0
1.0 / 1.0
Time (h)
10
10
10
10
10
10
Yield (%)
Trace
10
25
Trace
26
reaction mixtures clearly indicated formation of the desired
DHQZs 4a‒r in excellent yields (Table 2).
1
2
3
4
5
6
The structures were characterized by melting point
determination and from 1H and 13C NMR spectral data.18
65
Table 2. Direct synthesis of 2,3-dihydroquinazolin-4(1H)-ones 4a–r under oxidative conditionsa
O
O
R
I2, K2CO3
O
N
RNH
+
Ar
OH
+
2
water, reflux, 3 h
Ar
N
H
N
H
O
1
2
3
4
Yield
(%)b
Product Alcohol (1)
Amine (3)
Product Alcohol (1)
Amine (3)
Yield (%)b
9216
9119b
9019b
9219b
9216
4j
Cl
NH2
4a
MeO
MeO
MeO
NH2
OH
OH
OH
OH
4b
4c
4d
4e
4k
4l
9319a
9319c
9219a
9411
Cl
Me
NH2
NH2
Me
Cl
NH2
OH
OH
OH
Cl
Cl
NH2
Br
NH2
NH2
4m
4n
NH2
OH
OH
9211
O2N
Me
NH2
OH
MeO
NH2
4f
9011
939
4o
4p
4q
9319d
9119e
9019e
NH2
OH
OH
OH
Cl
4g
4h
Cl
NH2
NH2
OH
9119a
MeO
MeO
MeO
Me
Me
NH2
NH2
NH2
OH
OH
4i
9319b
4r
9219e
Me
NH2
OH
OH
O2N
a Reaction conditions: 4-methoxy benzyl alcohol (1 mmol), isatoic anhydride (1 mmol), aniline (1 mmol), I2 (1 mmol), K2CO3 (1 mmol), water (5 mL), reflux,
3 h. b Isolated yield.
Formation of 2,3-dihydroquinazolin-4(1H)-ones could be
rationalized via a plausible mechanism (Scheme 2). Treatment of
benzyl alcohol with iodine in the presence of K2CO3 leads to the
formation of intermediate 5 and potassium bicarbonate. This
intermediate undergoes elimination of H and I to form the
corresponding aldehyde 6. Next, the aldehyde is condensed with
substituted anthranilamide 7, generated from nucleophilic
addition of amine 3 onto isatoic anhydride 2, to give the imine
intermediate 8, which undergoes cyclization to afford the isolated
2,3-dihydroquinazolin-4(1H)-ones 4. This mechanism is in
agreement with achieving the best result in water, which can be
explained by better polarizability of molecular iodine in water as
a polar solvent. The relatively better result in DMSO (entry 6:
65%), dioxane (entry 7: 46%), tert-butanol (entry 9: 53%) and
ethyl acetate (entry 10: 48%) in comparison with other nonpolar
solvents, may also be illustrated by the term of polarizability
(Table 1). In addition, the produced KI and H2CO3 are highly
soluble in water; based on Le Châtelier's principle, this favors the

Tetrahedron letters
3
desired aldehyde 6. However, the three-component reaction
between aldehydes, amines and isatoic anhydride have been
reported in various solvents.5–16
I
I
O
H
H
Ar
O
I
KHCO3
H
- KI
Ar
O
Ar
H
- KI, H2CO3
1
K2CO3
5
6
O
N
O
R
R
N
N
H
Ar
N
H
O
O
Ar
8
4
R
N
O
RNH2
H
+
- CO2
N
O
NH2
H
7
2
3
Scheme 2. Plausible reaction mechanism
Lett. 1994, 4, 1141-1146; (l) Bonola, G.; Da Re, P.; Magistretti,
M. J.; Massarani, E.; Setnikar, I. J. Med. Chem. 1968, 11, 1136-
1139.
In conclusion, we have developed a new, efficient and green
approach for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones
of potential synthetic and pharmacological interest using a one-
pot, three-component reaction between benzyl alcohols, isatoic
anhydride and primary amines. Benzyl alcohols were
successfully oxidized in situ using an environmentally friendly
and inexpensive system (I2/K2CO3). Use of stable benzyl alcohols
in place of aldehydes, ease of experimental procedure, relatively
short reaction times and excellent yields are the main advantages
of this reaction. To the best of our knowledge, this is the first
report on the use of benzyl alcohols instead of aldehydes for the
production of DHQZs. We believe that the success in this
oxidative process could open the door to the design of diverse
reactions and the generation of interesting organic compounds in
mild and green oxidative media.
4. Ramesh, K.; Karnakar, K.; Satish, G.; Anil Kumar, B. S. P.;
Nageswar, Y. V. D. Tetrahedron Lett. 2012, 53, 6936-6939.
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6. Surpur, M. P.; Singh, P. R.; Patil, S. B.; Samant, S. D. Synth.
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7. Rostamizadeh, S.; Amani, A. M.; Aryan, R.; Ghaieni, H. R.;
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Acknowledgements
We wish to express our gratitude to the research council of
Islamic Azad University, Tehran Science and Research Branch.
References and notes
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18. General Procedure for the Preparation of Compounds 4: A
mixture of 4-methoxybenzyl alcohol (0.138 g, 1 mmol), I2 (0.254
g, 1 mmol), K2CO3 (0.138 g, 1 mmol), isatoic anhydride (0.163 g,
1 mmol) and aniline (0.093 g, 1 mmol) in water (5 mL) was stirred
for 3 h at reflux. After reaction completion, the mixture was
cooled to room temperature and stirred for 1 h. The resulting
precipitate was filtered, washed with water (3 × 3 mL), and
purified by recrystallization from ethanol to give 4a as a white
solid.
2,3-Dihydro-2-(4-methoxyphenyl)-3-phenylquinazolin-
1
4(1H)-one (4a) Yield: 0.30 g, 91%; m.p = 205–206 ºC. H NMR
(300 MHz, DMSO–d6): δ = 3.67 (3 H, s, OCH3), 6.22 (1 H, br s,
CH), 6.71 (1 H, t, J = 7.7 Hz, CH), 6.76 (1 H, d, J = 7.9 Hz, CH),
6.84 (2 H, d, J = 8.5 Hz, 2 CH), 7.17 (1 H, t, J = 7.1 Hz, 1 CH),
7.23–7.34 (7 H, m, 7 CH), 7.55 (1 H, br s, NH), 7.73 (1 H, d, J =
7.9 Hz, CH). 13C NMR (75 MHz, DMSO–d6): δ = 55.0, 72.3,
113.7, 114.8, 115.3, 117.4, 126.0, 126.3, 127.9, 128.6, 128.7,
132.6, 133.7, 140.8, 146.7, 159.5, 162.3. 3-(4-Methoxybenzyl)-2,3-
dihydro-2-(4-methoxyphenyl)quinazolin-4(1H)-one (4q) Yield:
0.34 g, 90%; m.p = 160–161 ºC. 1H NMR (300 MHz, DMSO–d6):
2
δ = 3.63 (1 H, d, JHH = 15.2 Hz, CH), 3.74 (3 H, s, OCH3), 3.76
(3H, s, OCH3), 5.42 (1 H, d, 2JHH = 15.2 Hz, CH), 6.18 (1 H, br s,
CH), 6.63 (1 H, d, J = 8.0 Hz, CH), 6.87‒6.92 (5 H, m, CH), 7.17
(2 H, d, J = 8.4 Hz, CH), 7.23 (1 H, d, J = 7.9 Hz, CH), 7.26 (2 H,
d, J = 8.3 Hz, CH), 7.61 (1 H, br s, NH), 8.04 (1 H, d, J = 8.0 Hz,
CH). 13C NMR (75 MHz, DMSO–d6): δ = 46.6, 55.4, 55.6, 71.8,
113.8, 114.3, 115.7, 118.7, 127.1, 129.0, 129.1, 129.7, 131.4,
133.6, 144.9, 157.3, 160.2, 162.5.
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