I2-Catalyzed three-component protocol for the synthesis of quinazolines

Article abstract of DOI:10.1016/j.tetlet.2012.08.016

An efficient and one-pot three-component strategy for synthesizing highly functionalized quinazoline derivatives is presented. A mixture of 2-aminobenzophenone, aromatic aldehyde and ammonium acetate in the presence of I2-catalyst provides desired product

Full text of DOI:10.1016/j.tetlet.2012.08.016

Tetrahedron Letters 53 (2012) 6167–6172
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
I2-Catalyzed three-component protocol for the synthesis of quinazolines
⇑
Sumit Kumar Panja, Nidhi Dwivedi, Satyen Saha
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and one-pot three-component strategy for synthesizing highly functionalized quinazoline
derivatives is presented. A mixture of 2-aminobenzophenone, aromatic aldehyde and ammonium acetate
in the presence of I2-catalyst provides desired products in excellent yields even at moderate temperature
(40 °C) without the involvement of any chromatographic purification. Oxidizing and Lewis acidic proper-
ties of molecular I2 have been utilized here. Detailed mechanism has been established based on an iso-
lated intermediate and its single crystal X-ray crystallographic structure.
Received 8 June 2012
Revised 31 July 2012
Accepted 3 August 2012
Available online 9 August 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Multicomponent reaction
One-pot synthesis
Green Chemistry
I2-catalyst
2-Amino-benzophenone
Aromatic aldehyde
Ammonium acetate
Solvent-free condition
The development of a new synthetic methodology that provides
an alternative to difficult synthetic protocol to an easier and green-
er strategy for the production of known complex as well as entirely
new organic entity is a key topic of modern synthetic organic
chemistry.1 The creation of carbon-heteroatom (C–X where X@N,
O, S etc.) bond is the central theme in heterocyclic chemistry.2
One relatively modern approach for making organic synthesis
more eco-friendly is the multicomponent strategy.3 The beauty of
the multicomponent synthesis has manifold: several transforma-
tions in a single manipulation, simple reaction design, high selec-
tivity, convergent and atom-efficient nature and substantial
minimization of waste, labour, time and cost.4 Furthermore, sol-
vent-free multicomponent reactions have greater interest in wide
areas of organic chemistry due to the incorporation of eco-friendly
green chemistry principles.5
Quinazoline is an important class of binuclear heterocyclic scaf-
fold which is the building block for several naturally occurring alka-
loids,6 microorganisms7 and in several life saving drugs such as
gefitinib (Iressa)10 and erlotinib (Tarceva).8 Some modified quinaz-
oline derivatives have shown to have remarkable anticancer,9 anti-
tubercular,10 antibacterial11 and antiviral activities.12 A few of them
are also known to act as selective inhibitors of the tyrosine-kinase
activity of the epidermal growth factor receptor (EGFR)13 and as
RNA binding reagents. As the moiety is ubiquitous in modern drugs,
the new methods and techniques for synthesizing are well
sought.14–19 Unfortunately, in most of these synthetic methods
there involves the usage of hazardous, volatile solvents14, toxic
and expensive metal catalysts15 cumbersome chromatographic
,
separation procedures, high heating16c and multistep reaction pro-
cess.17 Zhang et.al.18 have reported quinazoline synthesis with
2-aminobenzophenones and benzylic amines via SP3 C-H activation
where I2 served as catalyst in presence of extra additive oxidant at a
relatively high temperature (90 °C) and relatively longer reaction
time (12 h). A catalyst and solvent-free microwave assisted im-
proved reaction methodology is recently developed by Prajapati
and co-workers for synthesizing dihydroquinazoline derivatives.19
Though the method is novel and exemplary, it lacks selectivity to-
wards quinazoline derivatives. We are intend to develop a superior,
greener and general protocol to fabricate this biologically signifi-
cant substituted quinazolines using molecular iodine as the
catalyst.20 Here, we report the development of one-pot three-
component reaction for functionalized quinazoline derivatives via
reactions with substituted o-aminoarylketone, substituted benzal-
dehyde and ammonium acetate catalyzed by I2. This three-
component reaction leads to an excellent yield in lesser time when
carried out in neat or with ethanol even at moderate temperature. It
was found that I2 is the suitable catalyst counterpart in these reac-
tions due to its Lewis acidity and oxidizing properties.
Initially, we have started following the normal procedure of
multicomponent synthesis; 1 mmol of 2-aminobenzophenone
(1a), 1 mmol of o-pyridinecarboxaldehyde (2a), 2.5 mmol of
ammonium acetate (3) and 0.5 mmol of I2 were taken in one-pot
under solvent free condition and stirred at room temperature
(ꢀ25 °C) for 8 h which yielded the quinazoline 4a product
⇑
Corresponding author. Tel.: +91 9935913366; fax: +91 542 2368127.
E-mail addresses: ssahabhu@yahoo.com, satyen.saha@gmail.com (S. Saha).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.016

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S. K. Panja et al. / Tetrahedron Letters 53 (2012) 6167–6172
O
Ph
varying one or more reaction parameters and the results are pre-
sented in Table 1.
R2
R2
Ph
+
N
I2
1
+
R -CHO
NH4OAc
From Table 1, it is evident that 5 mol % of molecular iodine in
either neat or in ethanol solvent at moderate temperature (40 °C)
provides an impressive yield of more than 95% pure isolated prod-
uct. Similar observations in terms of yield, reaction time and tem-
perature were obtained in ethanol and in solvent-free condition. As
seen from the entry 6 and 7 of Table 1, in the absence of I2, no reac-
tion takes place, either in neat or with ethanol.
The generality of this reaction protocol has been examined by
performing several reactions varying the starting materials and
the results are presented in Table 2.
N
4
R1
NH2
Neat or EtOH,
40°C
3
2
1
R1= o-pyridyl, 2a
R2=H, 1a
R1= o-OHm-OEtC6H4, 2b
R1= p-MeC6H4, 2c
R1= p-ClC6H4, 2d
R2=Cl, 1b
R2=NO2, 1c
R1= o-NO2C6H4, 2e
R1= p-NO2C6H5, 2f
R1= Naphthyl, 2g
Scheme 1. Synthesis of quinazoline derivatives.
The effect of substituent on 2-aminobenzophenone and alde-
hyde derivatives on the yield and reaction time has also been stud-
ied (Table 2, entries 1–12, 18 and 13–17). In the presence of an
electron withdrawing group at 5th position of 2-aminobenzophe-
none, the required reaction time was found to be more than that
of electron donating groups (Table 2, entry 11–15). + I or electron
withdrawing effect at para position of aldehyde group (Table 2, en-
tries 3, 4, 9, 12, 15) was found to be more pronounced than that of
(82%).21 Interestingly, when the reaction was performed at a
slightly elevated temperature (40 °C) within 2.5 h complete
conversion of starting material to desired product (>90% yield)
was observed (Scheme 1).
For optimization of the reaction conditions like temperature,
catalyst loading etc., several sets of reaction were performed
Table 1
Optimization of the reaction conditionsa
Entry
3
I2 (mol %)
Temp (°C)
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
5
5
5
10
15
0
25
40
40
40
40
40
40
Ethanol
Ethanol
Neat
Neat
Neat
8
82
95
96
96
95
2.5
2.5
2.5
2.5
12
c
Ethanol
Neat
—
Trace
0
12
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol) and ammonium acetate (2.5 mmol) were heated and stirred with a catalytic amount of I2 in ethanol or solvent-free
condition.
b
Isolated pure yield.
No reaction.
c
Table 2
Synthesis of substituted quinazoline derivatives
Entry
2-Aminobenzophenone
Aldehyde
Quinazoline
Time (h)
2.5
Yield (%)
95
Ph
N
1
1a
2a
N
N
4a
Ph
N
N
OH
2
3
1a
1a
2b
2c
2.5
0.5
96
96
OEt
4b
Ph
N
N
4c
Ph
N
CH3
4
5
1a
1a
2d
2e
2.5
2.5
95
92
N
4d
Cl
Ph
N
N
NO2
4e

S. K. Panja et al. / Tetrahedron Letters 53 (2012) 6167–6172
6169
Table 2 (continued)
Entry
2-Aminobenzophenone
Aldehyde
Quinazoline
Time (h)
0.5
Yield (%)
Ph
N
6
1a
2f
94
N
4f
NO2
Ph
Cl
Cl
N
7
8
1b
1b
2a
2b
2.5
2.5
95
95
N
N
4g
Ph
N
OH
OEt
N
4h
Ph
Cl
N
9
1b
2c
0.5
97
N
4i
CH3
Ph
Cl
Cl
Cl
N
N
N
0
1b
1b
2d
2e
2.5
2.5
95
93
N
4j
Cl
Ph
NO2
11
N
4k
Ph
12
1b
2f
0.5
95
N
4l
NO2
Ph
O2N
N
N
13
14
1c
1c
2a
2b
3.5
3.5
92
91
N
N
4m
Ph
O2N
O2N
OH
OEt
N
4n
Ph
N
15
1c
2c
1.0
93
N
4o
CH3
Ph
O2N
O2N
N
N
16
17
18
1c
1c
1a
2d
2e
2g
3.5
3.5
2.5
92
90
92
N
4p
Cl
Ph
NO2
N
4q
Ph
N
N
4r

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S. K. Panja et al. / Tetrahedron Letters 53 (2012) 6167–6172
be obtained as expected, the presence of o-hydroxy group in naph-
thaldehyde moiety (Scheme 2) did not allow the reaction to pro-
ceed further to get the desired final product. Instead, the reaction
provides an aldimine intermediate which helped us to formulate
a mechanism for these useful three-component one-pot reaction.
Scheme 2 reveals that the presence of hydroxy group on 2-hydrox-
ynaphthaldehyde prevents the second step of the reaction (i.e.,
cyclization). Analysis of single crystal X-ray structure of 5a
(Fig. 2) provides the clue for this interesting fact. It was found that
the o-hydroxy group attached to naphthyl moiety is H-bonded to
the imine group.
This H-bonding interaction which provides stability to the
intermediate (5a), along with unfavourable orientation of naphthyl
moiety prevents the cyclization process, thereby terminating the
progress of the reaction (step 2 of Scheme 2). This three-compo-
nent reaction (Scheme 2) strongly suggests that the reaction pro-
ceeds through the intermediate 5a. It clearly indicates that the
first step of these multicomponent reactions is the condensation
of aldehyde with the 2-aminobenzophenone substrate, unlikely
the attack of ammonium acetate as presumed in literatures.16a,19
Prajapati and co-wokers19 have identified one of the intermediates,
D (in Scheme 3) as major product, which is formed from C on cycli-
zation. According to their proposed mechanism16,19 C can be
formed in two ways in which the preferred first step was assumed
to be the attack of NH4OAc to the keto group of benzophenone
moiety.
With the synthesis and structural identification of 5a, we have
unambiguously established that the condensation of aldehyde
with amine forming the B intermediate (in Scheme 3) is the first
step. Based on our investigation, we have proposed a mechanism
which is depicted in Scheme 3. The product 5a also indicates that
the formation of aldimine (B) is kinetically more favourable than
that of ketimine (C).
In conclusion, a new synthetic protocol has been described for
the synthesis of quinazoline derivatives. Molecular iodine is used
as the catalyst and oxidant for the three-component synthesis of
a highly substituted quinazoline. This procedure is found to be
much superior in terms of simplicity, high yield and non involve-
ment of chromatographic separation technique compared to previ-
ously reported methods. The mechanistic aspects have been
investigated and a modified mechanism is proposed. The first step
of the reaction is found to be the condensation of aldehyde with
aminobenzophenone moiety forming the aldimine.
Figure 1. Ortep diagram of 2-(2-Nitro-phenyl)-4-phenyl-quinazoline (4e) (50%
ellipsoid probability).
O
Ph
N
CHO
R2
R2
OH
Ph
+
O
OH
I2
+
NH4OAc
NH2
Neat / EtOH
2.5 h, 40
°
C
1
3
2h
5
R2=H, 1a
R2=Cl, 1b
R2 = H, 5a (90%)
R2 = Cl, 5b (91%)
Ph
R2
N
OH
N
Scheme 2. Synthesis of quinazoline intermediate.
Ph
N
Ph
R2
R2
I2
NH4OAc
+
N
O
at ortho-position (Table 2, entries 5, 11, 17). The sensitivity of air
towards product formation was found to be negligible because of
the oxidizing properties of catalyst I2 in contrast to reported proce-
dures16c,19,22 where the presence of aerial oxygen was found to be
must for aromatization.
It is important to note that in none of the reactions, column
purification was necessary. A few simple steps like evaporation
of solvent from the reaction mixture (if ethanol was used), washing
several times with water, followed by ethanol provided the desired
products in pure form. The yields were more than 90% as can be
seen in Table 2.
The confirmations of products were primarily done by the detail
analysis of 1H, 13C NMR, FT-IR and ESI-MS (vide Supplementary
data). In a fortunate case like 4e, where suitable single crystal
could be obtained, the structure was additionally confirmed by
the single crystal X-ray diffraction data (Fig. 1).23 Interestingly, it
was found that while naphthyl derivative (entry 18, Table 2) could
Neat or EtOH, 40°C
R1
R1-CHO
NH2
Aromatization
through
Fast
Ph
oxidation
Ph
R2
R2
O
N
R1-CHO
N
H
R1
NH2
A
B
D
(i)
Cyclization
(ii)
Ph
O
Ph
R2
R2
NH4OAc
NH
R1
N
R1
N
C
(strudture confirmed)
Scheme 3. Proposed mechanism for quinazoline synthesis.

S. K. Panja et al. / Tetrahedron Letters 53 (2012) 6167–6172
6171
Figure 2. Ortep diagram of the intermediate product, 5a (50% ellipsoid probability).
Chemistry-Perspectives and Practice; Oxford University Press: Oxford New York,
2003.
Acknowledgment
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S.S. thanks the Council of Scientific and Industrial Research
(CSIR, Project no. 01(2210)/08/EMR-II), New Delhi, for research
grants. Department of Chemistry, BHU is gratefully acknowledged
for instrumentations (including single crystal X-ray) and infra-
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
08.016.
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21. General procedure for the synthesis of quinazoline derivatives: 2-
aminobenzophenone (1, 1 mmol), an aromatic aldehyde (2, 1 mmol),
23. CCDC No. 876278 for compound 4e and CCDC No. 884436 for compound 5a.