Synthesis of diheterocyclic compounds based on triazolyl methoxy phenylquinazolines via a one-pot four-component-click reaction

Article abstract of DOI:10.1021/cc100043z

A facile and highly efficient method for one-pot four-component synthesis of triazolyl methoxy phenylquinazolines is described. A mixture of aromatic propargylated aldehydes, different azides, 2-aminobenzophenone derivatives, and ammonium acetate were condensed in the presence of catalytic amounts of acidic ionic liquid, 1-methylimidazolium trifluoroacetate, ([Hmim]TFA), and Cu(OAc)₂/sodium ascorbate to afford the corresponding products in excellent yields. This methodology is highly efficient for structurally diverse azides.

Full text of DOI:10.1021/cc100043z

638
J. Comb. Chem. 2010, 12, 638–642
Synthesis of Diheterocyclic Compounds Based on Triazolyl
Methoxy Phenylquinazolines via a One-Pot Four-Component-Click
Reaction
Minoo Dabiri,*,† Peyman Salehi,‡ Mahboobeh Bahramnejad,† and Fatemeh Sherafat†
Department of Chemistry, Faculty of Science and Department of Phytochemistry,
Medicinal Plants and Drugs Research Institute, Shahid Beheshti UniVersity, G. C., EVin,
Tehran 1983963113, Iran
ReceiVed March 16, 2010
A facile and highly efficient method for one-pot four-component synthesis of triazolyl methoxy
phenylquinazolines is described. A mixture of aromatic propargylated aldehydes, different azides,
2-aminobenzophenone derivatives, and ammonium acetate were condensed in the presence of catalytic
amounts of acidic ionic liquid, 1-methylimidazolium trifluoroacetate, ([Hmim]TFA), and Cu(OAc)2/
sodium ascorbate to afford the corresponding products in excellent yields. This methodology is highly
efficient for structurally diverse azides.
(MCRs),15,16 we also became interested in combining click
Introduction
chemistry with MCR strategies. Here, we report an
Click chemistry is a rather new approach to the synthesis
of chemical scaffolds that was introduced by Sharpless
in 2001 and describes chemistry tailored to generate
substances quickly and reliably by joining small units
together. This is inspired by the fact that nature also
generates substances by joining small modular units.1
Click chemistry has been defined as reactions that are
modular, wide in scope, high yielding, free from offensive
byproduct, stereospecific, and simple to perform that
require benign or no solvent.2 Such chemistry has found
wide applications not only in synthetic organic chemistry3
but also in dendrimer and polymer chemistry,4 material
sciences,5 bioconjugation chemistry,6 and pharmaceutical
sciences.7
From the list of click reactions, we were especially
interested in the Cu (I)-catalyzed variant of the Huisgen
1,3-dipolar cycloaddition of azides and alkynes for the
synthesis of 1,4-disubstituted 1,2,3-triazoles, which are
important targets for drug discovery.8 1,2,3-Triazoles
possess diverse biological properties including antibacte-
rial, antiallergic, anti-HIV, herbicidal, fungicidal, and
anticonvulsant activity.9 Additionally, they are used as
optical brighteners, light stabilizers, fluorescent whiteners,
and corrosion retarding agents.10
efficient approach for the one-pot synthesis of libraries
including both quinazoline and triazole rings in their
structures. Quinazolines are an important class of bio-
logically active N-heterocycles. They have been introduced
with diverse activities, such as fungicide, antican-
cer, antiinflammatory, antimicrobial, and antihyperten-
sive.17,18
Results and Discussion
As a part of our ongoing project devoted toward the
development of a practical synthesis of biologically
interesting heterocyclic molecules,19-21 herein, we have
explored the possibility of one-pot synthesis of triazolyl
methoxy phenylquinazolines from suitable precursors.
Therefore, we designed a one-pot four-component reaction
of aromatic propargylated aldehydes 1a-d, azides22 2a-f,
2-aminobenzophenones 3a, b, and ammonium acetate 4
for the synthesis of compounds 5a-v (Scheme 1).
Encouraged by gaining satisfactory results in this stage,
the synthesis of 5a was selected for optimization of the
reaction conditions. As listed in Table 1, the optimal
reaction conditions for the reaction of propargylated
aldehyde 1a, benzyl azide 2a, 2-amino-5-chlorobenzophe-
none 3a, and ammonium acetate 4 were screened. After
preliminary screening of copper salts as catalyst (entries
1-4), Cu(OAc)2 was be found the most effective (entry
4). In addition, the use of H2O as solvent resulted in higher
yield than CH2Cl2 and CH3CN (Table 1, entries 4, 6, 8).
The use of p-TsOH as a Bro¨nsted acid did not led to an
improved yield (Table 1, entries 9 and 10), while an
excellent yield was obtained when 1-methylimidazolium
Several multicomponent reactions with a subsequent
click step have already been reported.11-14 In the context
of our studies in the area of multicomponent reactions
* To whom correspondence should be addressed. Fax: 0098-21-
22431663. E-mail: m-dabiri@sbu.ac.ir.
† Department of Chemistry, Faculty of Science.
‡ Department of Phytochemistry, Medicinal Plants and Drugs Research
Institute.
10.1021/cc100043z  2010 American Chemical Society
Published on Web 07/19/2010

Synthesis of Diheterocyclic Compounds
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 639
Scheme 1. Synthesis of Triazolyl Methoxphenyl Quinazolines 5a-v
Table 1. Optimization of the Reaction Conditionsa
were tolerated on aromatic azides that could be successfully
converted to the desired product in high yields. (Table 2,
entries 3-6, 8-18 and 21). Benzyl azide also reacted
satisfactorily in all reactions (Tables 2, entries 1, 2, 7, 19,
and 20). Moreover, the effect of the character of substituent
in the benzene ring of aromatic propargylated aldehydes were
examined. Results revealed that both an electron-releasing
group, such as methyl, and an electron-withdrowing group,
such as bromo, substitution led to the corresponding adducts
(Table 2, entries 19-22).
Conclusions
temp
(°C)
yield
of 5a (%)
In summary, we have developed the combination of the
four-component reaction with the intermolecular azide-
alkyne cyclization provides access to unique fused triazole
ring systems in high yields and simple procedure. This
protocol may have interesting implications on the con-
struction of structurally diverse heterocyclic molecules and
will find applications in combinatorial chemistry, diversity-
oriented synthesis and drug discovery.
entry
catalyst
solvent
H2O
H2O
H2O
1
CuCl
CuI
reflux
reflux
reflux
trace
35
40
2
3b
CuSO4/sodium
ascorbate
Cu(OAc)2/sodium
ascorbate
4b
H2O
reflux
55
5
CuI
CH3CN
CH3CN
reflux
reflux
20
43
6b
Cu(OAc)2/sodium
ascorbate
7
CuI
CH2Cl2
CH2Cl2
reflux
reflux
23
47
Experimental Section
8b
Cu(OAc)2/sodium
ascorbate
CuI/p-TsOH
Cu(OAc)2/sodium
ascorbate/ p-TsOH
CuI/IL
General. Melting points were measured on an Electro-
thermal 9100 apparatus and were not corrected. IR spectra
were recorded on a FT-IR 10MB BOMEM spectrometer.
1H and 13C NMR spectra were recorded on a Bruker
DRX-300 AVANCE spectrometer (300.13 and 75.47
MHz, respectively). Mass spectra were determined on a
FINNIGAN-MAT8430 mass spectrometer operating at an
ionization-potential of 70 eV. Elemental analyses were
performed on an Elementar Analysensysteme GmbH
VarioEL CHNS mode. All reagents were purchased from
Merck or Fluka and used without purification.
9c
H2O
H2O
reflux
reflux
45
53
10d
11e
12f
solvent-free
solvent-free
80
80
62
87
Cu(OAc)2/sodium
ascorbate/IL
a Reaction conditions: propargylated aldehyde 1a (1 mmol), benzyl
azide 2a (1 mmol), 2-amino-5-chlorobenzophenone 3a (1 mmol),
ammonium acetate 4 (1 mmol), catalyst (10 mol %), solvent (10
mL), 2 h, reflux. b Sodium ascorbate (20 mol %). c p-TsOH (10 mol %).
d Sodium ascorbate (20 mol %), p-TsOH (10 mol %). e IL
([Hmim]TFA), (10 mol %), under solvent-free condition at 80 °C.
f Sodium ascorbate (20 mol %) and [Hmim]TFA, (10 mol %), under
solvent-free condition at 80 °C.
Typical Procedure for the Synthesis of 2-(4-((1-Benzyl-
1H-1,2,3-triazol-4-yl)methoxy)phenyl)-6-chloro-4-phe-
nylquinazoline (5a). Propargylated aldehyde 1a (0.16 g,
1.0 mmol), benzyl azide (0.13 g, 1.0 mmol), 5-chloro-2-
aminobenzophenone 3a (0.23 g, 1.0 mmol), and am-
monium acetate 4 (0.07 g, 1.0 mmol) in the presence of
Cu(OAc)2 (0.02 g, 10 mol %), sodium ascorbate (0.04 g,
20 mol %), and [Hmim]TFA (0.02 g, 10 mol %) were
mixed thoroughly. The mixture was stirred for 2 h at 80
°C. Water was added, and the solid was filtered. Finally,
the pure product 5a was obtained after recrystallization
from ethanol as yellow solid (0.44 g, 87%). mp: 160-162
trifluoroacetate, ([Hmim]TFA), as an IL was used (Table
1, entry 12).
To probe the scope and generality of this new four-
component reaction, different aromatic propargylated
aldehydes 1, various azides 2, and two types of 2-ami-
nobenzophenones 3 were selected to undergo one-pot
reaction in the presence of catalytic amounts of Cu(OAc)2
(10 mol %), sodium ascorbate (20 mol %) as a reducing
agent for Cu(Π) and [Hmim]TFA as an IL at 80 °C under
solvent-free condition (Scheme 1). The results of this study
are summarized in Table 2 and the structure of target
compounds 5a-v is represented in Figure 1.
1
°C. IR (KBr) (Vmax, cm-1): 1601, 1533, 1510, 1245. H
NMR (300.13 MHz, CDCl3) δ: 5.28 (2H, s, CH2), 5.54
(2H, s, CH2), 7.09-8.61 (18H-Ar, m). 13C NMR (75.47
MHz, CDCl3) δ: 54.30, 62.13, 114.72, 121.88, 122.83,
To investigate the scope of this method, a variety of
functional groups such as nitro, chloro, methyl, and methoxy

640 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Dabiri et al.
Table 2. One-Pot Four-Component Synthesis of Triazolyl Methoxphenyl Quinazolines 5a-v
a Isolated yield based on the 2-aminobenzophenones 3.
122.91, 125.79, 128.15, 128.73, 128.84, 129.17, 130.02,
130.21, 130.42, 130.58, 130.93, 132.18, 134.12, 134.48,
137.12, 150.44, 160.08, 160.54, 167.48. MS, m/z (%): 503
(M+, 20), 332 (40), 144 (58), 91 (100). Anal. Calcd for
C30H22ClN5O: C, 71.49; H, 4.40; N, 13.90. Found: C,
71.38; H, 4.51; N, 14.03.

Synthesis of Diheterocyclic Compounds
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 641
Figure 1. Structure of products 5a-v.
Acknowledgment. Financial support from the Research
Council of Shahid Beheshti University and Catalyst Center
of Excellence (CCE) is gratefully acknowledged.
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CC100043Z