Iodine-mediated arylation of benzoxazoles with aldehydes

Article abstract of DOI:10.1039/c3gc41027g

A simple and efficient methodology for the arylation of benzoxazoles with aldehydes using iodine as the mediator has been developed. The reaction proceeded smoothly with a range of substrates to give the corresponding arylated products in moderate to good yields.

Full text of DOI:10.1039/c3gc41027g

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Iodine-mediated arylation of benzoxazoles with
aldehydes†
Cite this: DOI: 10.1039/c3gc41027g
Received 31st May 2013,
Accepted 27th June 2013
Yew Chin Teo, Siti Nurhanna Riduan and Yugen Zhang*
DOI: 10.1039/c3gc41027g
www.rsc.org/greenchem
A simple and efficient methodology for the arylation of benzox- acids,9 arylamides,10 simple arenes11 and, more recently, alde-
azoles with aldehydes using iodine as the mediator has been hydes.12 These convenient direct arylation methods have
developed. The reaction proceeded smoothly with a range of sub- received increasing attention as they avoid the use of stoichio-
strates to give the corresponding arylated products in moderate metric amounts of expensive organometallic reagents and
to good yields.
eliminate the need for pre-installation of activating agents,
thereby generating less waste.13 While these direct coupling
strategies between benzoxazoles and an arylating agent are
often efficient, there are some limitations such as the utility of
relatively expensive transition metal catalysts or ligands and
the risk of metal impurities in the synthesized drug intermedi-
ates or bioactive molecules. Therefore, the development of an
alternative metal-free approach for the arylation of benzox-
azoles remains highly desirable. Although several metal-free
approaches have been demonstrated for the synthesis of 2-aryl-
benzothiazoles or 2-acylbenzothiazoles from benzothiazoles
and aryl aldehydes or aromatic ketones, none of these method-
ologies are suitable for arylation of benzoxazole.14,15 Aromatic
aldehydes are ideal arylation reagents as they are readily avail-
able and cheap. We envision that a reaction between benzox-
azoles and aldehydes could occur by using a suitable oxidant.
Molecular iodine has often been used as a catalyst/reagent in
effecting certain organic transformations owing to its oxidative
properties and low cost.16 Herein, we report a simple and
efficient method for the direct arylation of benzoxazoles with
aromatic aldehydes mediated by molecular I2 (Scheme 2B).
We began our investigation by using benzoxazole (1a) and
4-bromobenzaldehyde (2a) as the model substrates. When the
model reaction was carried out in DMSO at 85 °C in the pres-
ence of I2 (2 equiv.), we were pleased to find that the desired
Aryl-substituted benzoxazoles are important structural motifs
in many biologically active molecules, pharmaceuticals and
natural products (Scheme 1).1 The development of efficient
protocols to construct such biaryl moieties is therefore of great
importance to drug discovery. There are several strategies
employed for the synthesis of 2-aryl substituted benzoxazoles.
Conventional synthetic methods include the condensation of
2-aminophenols with aromatic carboxylic acids or aldehydes,2
oxidative cyclization of phenolic Schiff bases promoted by oxi-
dants3 and metal-catalyzed intramolecular cross-coupling of
2-halo anilides or benzanilides.4 While good yields can be
obtained with a wide substrate scope, these protocols often
suffer from various drawbacks such as the synthesis of start-
ing materials as precursors and the use of harsh reaction
conditions.
Alternatively, direct arylation of benzoxazoles represents a
straightforward and versatile method for 2-arylbenzoxazoles
synthesis. It has been reported that the transition metals could
catalyze the direct C–H activation and subsequent C–C coup-
ling of benzoxazole (Scheme 2A) with aromatic carboxylic
acids,5 aryl halides,6 arylsilanes,7 aryl triflates,8 aryl boronic
Scheme 1 Medicinal applications of 2-aryl substituted benzoxazoles.
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos,
Singapore 138669, Singapore. E-mail: ygzhang@ibn.a-star.edu.sg;
Fax: (+65) 6478-9020
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3gc41027g
Scheme 2 Strategies for arylation of benzoxazole.
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Table 1 Optimization of the reaction conditionsa
product (3aa) was detected, albeit in low yield (Table 1, entry 1).
We proceeded to screen several organic solvents and found
that a higher yield was obtained when the reaction was con-
ducted in dioxane or PhCl (Table 1, entries 2–8). Further
optimization by screening the reaction temperature (Table 1,
entries 9–14) using dioxane, PhCl and a mixed solvent of
dioxane–PhCl (1 : 1) showed that a temperature of 130 °C using
PhCl as the solvent was optimal for the arylation reaction
(Table 1, entry 12). Lower yield was obtained when the reaction
was conducted under an argon or O2 atmosphere (Table 1,
entries 15 and 16). The addition of H2O (2 equiv.) to the reac-
tion proved to be undesirable as it resulted in a reduction in
yield to 43% (Table 1, entry 17). As prolonged heating was
required for 4-bromobenzaldehyde (2a) to go into complete
conversion, the effects of additives were studied next in an
attempt to improve the reaction efficiency (Table 1, entries
18–20). However, the addition of DMSO (5% v/v) to the reac-
tion resulted in poor yield and the formation of a black pre-
cipitate during the reaction (Table 1, entry 19). We were
delighted to find that the reaction yield could be improved to
73% and the reaction time reduced to 30 h in the presence of
DMF (5% v/v) (Table 1, entry 20). The reaction certainly bene-
fited from the addition of the DMF aliquot; however, the exact
role of DMF in the reaction system still remains unclear. The
maximum yield was achieved with two equivalents of benzoxa-
zole. In the absence of I2, no desired product was observed
(Table 1, entry 21).
Entry
Additives
T (°C)
Solvent
Yieldb (%)
1
2
—
—
85
85
DMSO
1,2-Dichloroethane
10
12
11
15
11
<10
22
21
56
56
55
60
51
57
46
48
43
52
3
4
—
—
85
85
MeCN
Toluene
5
6
—
—
85
85
Toluene–DMSO (1 : 1)
DMF
7
8
—
—
85
85
Dioxane
PhCl
9
—
—
—
—
—
—
—
—
120
120
130
130
140
130
130
130
130
130
130
130
130
Dioxane
PhCl
Dioxane
PhCl
10
11
12
13
14
15c
16d
17
18
19
20e
21f
PhCl
PhCl–dioxane (1 : 1)
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
H2O (2 equiv.)
Dioxane (5%)
DMSO (5%)
DMF (5% v/v)
—
27
73 (71)
0
a Conditions: 1a (1.0 mmol), 2a (0.5 mmol), I2 (1.0 mmol), solvent
(1.0 mL), 40 h. b 1H NMR yield based on 2a, isolated yield in
parentheses. c Reaction conducted under argon. d Reaction conducted
under an O2 atmosphere. e Reaction time: 30 h. f No I2 added.
With the established optimized conditions, the substrate
scope of the iodine-mediated arylation reaction was investi-
gated (Table 2). The reaction with benzaldehyde afforded the
Table 2 Arylation of benzoxazoles with aldehydesa
a Conditions: 1 (1.0 mmol), 2 (0.5 mmol), I2 (1.0 mmol), PhCl (1 mL), DMF (50 μL), 130 °C, isolated yield.
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desired arylated product (3ab) in good yield. A range of aro-
matic aldehydes bearing electron-donating substituents
(methyl, ethyl, methoxy) as well as electron-withdrawing sub-
stituents (halide) also underwent the desired reaction to
provide the arylated products (3ac–3ai) in moderate to good
yields. However, the presence of a strongly electron-withdraw-
ing 4-cyano substituent on the benzaldehyde led to significant
reduction in product yield (3aj). Benzaldehydes with ortho-sub-
stituents also resulted in lower product yields (3ak–al). While
most aromatic aldehydes underwent the desired arylation reac-
tion readily, a lower yield of 20% was obtained from the reac-
tion between 1-heptanal and benzoxazole (3am). Several
heteroaromatic aldehydes were also tested in this reaction
system, and no promising results were obtained. For example,
no desired product formation was observed with furfural and
low yields (20%) of the desired product were observed for
2-pyridinecarboxaldehyde. Next, the scope of the reaction was
expanded to include benzoxazoles bearing substituents on the
phenyl ring. Benzoxazoles with electron-donating methyl
groups and electron-neutral phenyl groups gave the corres-
ponding arylated products (3bc–cc) in good yields. Various
functional groups including chloro, methoxy and nitro on the
benzoxazoles were also well tolerated under the optimized
reaction conditions and the desired products were obtained in
moderate to good yields (3dc–gc).
Scheme 4 Control experiments.
that 2-aminophenol could also be a starting material for the
synthesis of 2-substituted benzoxazoles, including its reaction
with aldehydes.2 Therefore, in this reaction, 2-aminophenol is
also a possible intermediate other than 1aa. In fact, the reac-
tion between 2-aminophenol and 4-methylbenzaldehyde also
afforded the desired product 3ac, but the yield (47%) was sig-
nificantly lower as compared to the reaction using benzox-
azole. However, 2-aminophenol was not observed as an
intermediate or a by-product in the reaction mixture. It was
also found that 2-aminophenol itself is not stable (decom-
posed) under the current reaction conditions. In addition, the
reaction between 2-aminophenol and benzoxazole was also
observed to form 1aa analogue.
Next, we proceeded to explore the substrate scope with
various azoles. Unfortunately, there was no desired product
formation with benzimidazoles and oxazoles. Interestingly, the
reaction between 4-methylbenzaldehye and benzothiazole gave
both the arylated (4a) and acylated (4b) products (Scheme 3) in
a ratio of 1 : 2.5. This result showed that iodine could also
promote the arylation of benzothiazole with aldehyde and the
formation of 4b may go through an oxidative coupling reaction
between benzothiazole and aldehyde.
To better understand the reaction mechanism, several
control reactions were conducted. A 13C-labeled benzaldehyde
was reacted with benzoxazole under the optimized reaction
conditions and a 13C-labeled product was detected as the
major product by using GC-MS (Scheme 4). This result clearly
showed that the reaction goes through the benzoxazole ring
opening pathway.12,14,15,17 Another control experiment was set
up whereby benzoxazole was reacted with I2 at 130 °C
(Scheme 4). A pale yellow solid 1aa was isolated and its struc-
With these observations, a plausible reaction pathway is
proposed as shown in Scheme 5. We postulate that I2 could
promote the oxidative ring-opening of benzoxazole14,15 and
thereafter, two possible reaction pathways can occur. The ring-
opening intermediate can generate 2-aminophenol in situ and
subsequent condensation reaction with benzaldehyde followed
by oxidative ring-closure would give the final product via
path A. Alternatively, the ring opening intermediate may be
1
ture was confirmed by using H NMR and mass spectroscopy
(see ESI†). In fact, 1aa is always observed as a by-product in the
reaction system (Scheme 4). The formation of 1aa thus corro-
borated our earlier proposal of a ring-opening mechanism.
The desired product was also detected when benzaldehyde
was reacted with 1aa, suggesting that 1aa could be an inter-
mediate in the reaction system. However, it was well known
Scheme 5 Proposed reaction mechanism for the iodine-mediated arylation of
Scheme 3 Reaction of 4-methylbenzaldehyde with benzothiazole.
benzoxazole.
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stabilized as 1aa which would react with aldehyde to give the
arylated product via path B. As 2-aminophenol was not
detected during the course of the reaction, we believe that
path B is the more probable reaction route.
In summary, we have demonstrated the first metal-free
direct arylation of benzoxazoles with aromatic aldehydes
mediated by molecular I2. Mechanistic studies with the iso-
lation of key intermediates revealed that a ring-opening mech-
anism is operative. This method constitutes a simple and
inexpensive route to obtain 2-aryl substituted benzoxazoles
which are of great importance in medicinal chemistry.
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Acknowledgements
This work was supported by the Institute of Bioengineering
and Nanotechnology (Biomedical Research Council, Agency for
Science, Technology and Research, Singapore).
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