Microwave-assisted Cu(I)-catalyzed, three-component synthesis of 2-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1H-benzo[d]imidazoles

Article abstract of DOI:10.3762/bjoc.10.145

A microwave-assisted synthesis of 2-(4-((1-phenyl-1H-1,2,3-triazol-4-yl) methoxy)phenyl)-1H-benzo[d]imidazoles from a phenylazide, propargyloxybenzaldehyde and a 1,2-diaminobenzene is proposed.

Full text of DOI:10.3762/bjoc.10.145

Microwave-assisted Cu(I)-catalyzed, three-
component synthesis of 2-(4-((1-phenyl-1H-1,2,3-
triazol-4-yl)methoxy)phenyl)-1H-benzo[d]imidazoles
Yogesh Kumar1, Vijay Bahadur1, Anil K. Singh1, Virinder S. Parmar1,
Erik V. Van der Eycken2 and Brajendra K. Singh*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 1413–1420.
1Bioorganic Laboratory, Department of Chemistry, University of Delhi,
Delhi 110 007, India and 2Laboratory for Organic &
Microwave-Assisted Chemistry (LOMAC), Department of Chemistry,
University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001
Leuven, Belgium
doi:10.3762/bjoc.10.145
Received: 16 February 2014
Accepted: 22 May 2014
Published: 24 June 2014
Email:
This article is part of the Thematic Series "Multicomponent reactions II".
Guest Editor: T. J. J. Müller
Brajendra K. Singh* - singhbk@chemistry.du.ac.in
* Corresponding author
© 2014 Kumar et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
benzimidazole; Cu(I) catalysis; microwave-assisted synthesis;
multicomponent; three component synthesis
Abstract
A microwave-assisted synthesis of 2-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1H-benzo[d]imidazoles from a phenyl-
azide, propargyloxybenzaldehyde and a 1,2-diaminobenzene is proposed.
Introduction
Due to their structural range and biological importance are composed of several heterocyclic rings in which the benz-
nitrogen-containing heterocycles have been striking targets for imidazole and the 1,2,3-triazole constitute an important pos-
many years. They are found in a variety of natural products and ition. Benzimidazole derivatives have been shown to posses
are characterized by an appreciable chemical and biological anticancer [1,2], antihypertensive [3], antibacterial [4] and
importance. The synthesis of nitrogen-containing heterocyclic enzyme inhibition activity [5,6]. They have also been used to
compounds and their derivatives plays an important role in synthesize dyes [7], chemosensitizers [8] and fluorophores [9].
organic chemistry as they frequently exhibit therapeutic and Triazole derivatives have shown antifungal [10], anticancer [11]
pharmacological properties. They have emerged as an integral antituberculosis [12] and antimicrobial [13] activities. Recently,
backbone of several existing drugs. Various medicinal agents hybrid molecules, connecting two or more distinct drug entities
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in one molecule, have drawn the attention of medicinal chemists tively (Scheme 1, path A and B). However, we reasoned that the
[14-18]. This logical approach is a promising path for those desired adduct could also be formed in a one-pot fashion
drug molecules which can effectively and selectively target (Scheme 1, path C) as a multicomponent reaction (MCR). The
multifunctional diseases. It has also been found that hybrid utility and importance of MCRs have been recognized by
molecules are sometimes much more effective than the sum of chemists [20-23]. Several MCRs are now well-established reac-
their individual components.
tions, such as Ugi [24], Passerini [25], Van Leusen [26],
Strecker [27], Hantzsch [28], and Biginelli [29-31].
The therapeutic application of 2-(3-fluoro-phenyl)-1-[1-(substi-
tuted-phenyl)-1H-[1,2,3]-triazol-4-yl-methyl)-1H- However, when path A and path B were explored, the desired
benzo[d]imidazoles has been demonstrated by treating tuber- product was afforded in different yields (Scheme 1). The treat-
culosis[19]. However, there has been little progress in the ment of acetylene 2a with phenylazide (1a) in the presence of
development of such hybrid molecules to date. An extensive copper sulfate and D-glucose as a reductant [32,33] in THF/
literature survey revealed the existence of a multistep synthesis H2O (2:1) as a solvent under stirring at rt as well as under
with low yields and long reaction times. This encouraged us to microwave irradiation resulted in the obtainment of the desired
develop a new methodology for this synthesis.
product in excellent yields of 91% and 95% in 12 h and 15 min,
respectively. However, when the manufactured 4-((1-phenyl-
1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde was treated with
Results and Discussion
Three different approaches for the construction of the proposed 1,2-diaminobenzene, the desired product was obtained in an
2-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1H- inferior yield of 59% and 42% under conventional heating and
benzo[d]imidazole are illustrated in Scheme 1. In a two-step microwave irradiation in 50 and 20 min, respectively (path A).
process the triazole and imidazole ring are synthesized consecu- On the other hand, when 4-(prop-2-yn-1-yloxy)benzaldehyde
Scheme 1: Synthesis of 2-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1H-benzo[d]imidazoles.
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(2a) was first treated with 1,2-diaminobenzene in the presence N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO) or
of copper sulfate and D-glucose in a THF/H2O (2:1) mixture 1,4-dioxane, no product formation was observed (Table 1,
under conventional heating as well as microwave irradiation, entries 1–4). However, upon microwave irridiation the reaction
the desired product was obtained in a better yield (70%) under went to completion in a non-polar solvent, such as tetrahydro-
conventional heating compared to microwave irradiation (54% furan (THF) or toulene, and the desired product was isolated in
yield). The compound was subsequently coupled with phenyl- 20% and 25% yields (Table 1, entry 5 and entry 6) in THF and
azide (1a), which afforded the desired product in 67% and 78% toluene, respectively. Moreover, when the reaction was carried
yield upon stirring at rt and microwave irradiation, respectively out in an aqueous solvent system, decent improvements of the
(path B). However, in the MCR approach (Scheme 1, path C) yields were observed (Table 1, entries 7–11). The best result
the desired product was obtained in a good yield. The reaction was obtained with THF/H2O 2:1 (Table 1, entry 8). It is
proceeded smoothly in the presence of CuSO4.5H2O and believed that the higher solubility of CuSO4 in this aqueous
D-glucose under microwave irradiation for 15 min and gave the solvent system is responsible for the enhanced product forma-
desired compound in 80% yield. Surprisingly, under conven- tion. On the contrary, the formation of aggregates of the copper
tional heating with this MCR approach no product formation acetylide intermediate in polar solvents results in a failure of the
was observed, even after an extended period of time (24 h) with reaction [34].
heating under reflux .
Various 1,2-diaminobenzenes 3a,b and phenylazides 1a–j were
In order to optimize the reaction conditions for this protocol, we explored in order to estabilish the applicability of this protocol
screened several organic solvents. We explored the reaction and the results are summarized in Table 2. Different azides 1a–j
between phenylazide (1a), 4-(prop-2-yn-1-yloxy)benzaldehyde with electron-donating groups (Table 2, entries 2–8, 12–17,
(2a) and 1,2-diaminobenzene (3a). It was found that when the 20–23), electron-withdrawing groups (Table 2, entries 9, 10, 18
reactions were carried out in polar solvents, such as acetonitrile, and 19), two different 4-(prop-2-yn-1-yloxy)benzaldehydes
Table 1: Optimization of the solvent system.a
Entry
Solvent
Time (min)/temperature (oC)
Yield (%)b
1
2
Acetonitrile
DMF
30/80
15/100
15/100
15/110
20/70
0
0
3
DMSO
0
4
1,4-Dioxane
THF
0
5
20
25
56
80
30
25
40
6
Toluene
20/100
20/100
15/70
7
Toluene/H2O 2:1
THF/H2O 2:1
DMF/H2O 2:1
DMSO/H2O 2:1
1,4-Dioxane/H2O 2:1
8
9
15/100
15/100
15/100
10
11
aPhenylazide (1a, 1.0 mmol), 4-(prop-2-yn-1-yloxy)benzaldehyde (2a, 1.2 mmol), 1,2-diaminobenzene (3a, 2 mmol), CuSO4·5H2O (0.2 equiv),
D-glucose (0.4 equiv) in different solvents were irradiated for the indicated time and temperature at 100 W maximum power; bisolated yields.
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Table 2: Scope and limitations of the protocol employing different 4-(prop-2-yn-1-yloxy)benzaldehydes (2), phenylazides (1) and 1,2-diaminoben-
zenes (3)a.
Entry
1
R1
H
R2
H
X
H
Product
Yield (%)b
80
4a
2
4-OCH3
H
H
92
4b
4c
4d
3
4
3-OCH3
2-OCH3
H
H
H
H
83
75
5
4-CH3
H
H
79
4e
4f
6
7
3-CH3
2-CH3
H
H
H
H
68c
60
4g
8
4-Br
H
H
75
4h
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Table 2: Scope and limitations of the protocol employing different 4-(prop-2-yn-1-yloxy)benzaldehydes (2), phenylazides (1) and 1,2-diaminoben-
zenes (3)a. (continued)
9
3-Cl
2-F
H
H
H
H
H
H
73
60c
90
4i
4j
10
11
Cl
4k
12
4-OCH3
H
Cl
91
4l
4m
4n
13
14
3-OCH3
2-OCH3
H
H
Cl
Cl
73
76c
15
16
17
18
4-CH3
3- CH3
4-Br
H
H
H
H
Cl
Cl
Cl
Cl
82
69
78
77
4o
4p
4q
4r
3-Cl
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Table 2: Scope and limitations of the protocol employing different 4-(prop-2-yn-1-yloxy)benzaldehydes (2), phenylazides (1) and 1,2-diaminoben-
zenes (3)a. (continued)
19
20
2-F
H
Cl
H
67c
69
4s
4-CH3
OCH3
4t
21
22
23
4-OCH3
OCH3
OCH3
OCH3
H
Cl
Cl
83c
4u
4v
4w
4-CH3
68
4-OCH3
85
aPhenylazide 1 (1.0 mmol), propargyloxybenzaldehyde 2 (1.2 mmol), 1,2-diaminobenzene 3 (2 mmol), CuSO4·5H2O (0.2 equiv), D-glucose
(0.4 equiv) were irradiated at 70 °C and 100 W maximum power; bisolated yields after work-up, no further purification was required; cIsolated yields
after column chromatography.
2a,b, and two different 1,2-diaminobenzenes 3a,b were used. In mediate reacts with 1,2-diaminobenzene (3a) under the forma-
general, good to excellent yields were obtained for the desired tion of the corresponding Schiff’ base, which further cyclizes to
cyclized products.
dihyrobenzimidazole. Finally, D-glucose [37] oxidizes the dihy-
robenzimidazole to the benzimidazole. Moreover, if the
reaction proceeds via route B the benzimidazole formation
Plausible mechanism
The desired product could be obtained by the two mechanistic from 4-(prop-2-yn-1-yloxy)benzaldehyde 2a and 1,2-
pathways A and B as described in Scheme 2. The CuAAC could diaminobenzene 3a takes place first, followed by the
take place prior to or after benzimidazole formation and we do formation of triazole by CuAAC reaction to give the desired
not have a clear mechanistic proof. However, we believe that if product 4a.
the reaction proceed via route A in situ generation of Cu(I)
[32,33] from Cu(II) takes place first upon reduction with Conclusion
D-glucose. Then, this Cu(I) reacts with 4-(prop-2-yn-1- We developed a novel microwave-assisted, Cu(I)-catalyzed,
yloxy)benzaldehyde 2a to form the copper acetylide [35,36] 5, three-component reaction for the synthesis of 2-(4-((1-phenyl-
which reacts with azidobenzene 1a affording intermediate 6 by 1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1H-benzo[d]imidazoles
a [3 + 2] cycloaddition reaction. The intermediate 6 yields in good to excellent yields. This protocol is applicable to
4-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde various phenylazides, propargyloxybenzaldehydes and 1,2-
intermediate 7 after protonolysis of the C–Cu bond. This inter- diaminobenzenes.
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Scheme 2: Plausible mechanism for the synthesis of 2-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1H-benzo[d]imidazole.
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