Copper-catalysed intramolecular O-arylation: A simple and efficient method for benzoxazole synthesis

Article abstract of DOI:10.1039/c4ob02068e

A wide range of 2-substituted benzoxazoles can be efficiently synthesized from N-(2-iodo-/bromo-phenyl)benzamides, and even the less reactive N-(2-chlorophenyl)benzamides, via Cu-catalysed intramolecular coupling cyclization reactions using methyl 2-methoxybenzoate as the ligand under mild reaction conditions. In addition, the benzoxazoles can be easily prepared from the primary amides coupling with o-dihalobenzenes in a single step. This journal is

Full text of DOI:10.1039/c4ob02068e

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DOI: 10.1039/C4OB02068E
ARTICLE
Copper-catalysed intramolecular O-arylation: a
simple and efficient method for benzoxazoles
synthesis
Cite this: DOI: 10.1039/x0xx00000x
Fengtian Wu, Jie Zhang, Qianbing Wei, Ping Liu, Jianwei Xie*, Haojie Jiang and
Bin Dai
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
A wide range of 2-substituted benzoxazoles could be efficiently synthesized from the
N-(2-
iodo-/bromo-phenyl)benzamides, even less reactive -(2-chlorophenyl)benzamides via Cu-
N
www.rsc.org/
catalysed intramolecular coupling cyclization using methyl 2-methoxybenzoate as the ligand
under mild reaction conditions. In addition, the benzoxazoles are well prepared from the
primary amides coupling with the
o
-dihalobenzene in a single step.
Introduction
OMe
Cl
N
O
F
Benzoxazole motifs not only exist in several important natural
products1 but also are important subunits of many compounds
due to their efficient biological and pharmaceutical activities
(Fig. 1),2 some of which with the recent application include
antitumor agents,2a-2d HIV reverse transcriptase inhibitors,2e,f
cathepsin S inhibitors,2g 5-HT3 receptor partial agonists,2h DNA
topoisomerase inhibitors,2i peroxisome proliferator-activated
receptor γ (PPARγ) antagonists,2j estrogen receptor-β agonists2k
and epifluorescence excitation ratio imaging agents.2l
Consequently, their preparation has attracted considerable
attention. Classical methods for the construction of benzoxazole
ring system involve the condensation of ortho-aminophenol
with either carboxylic acid or aldehydes,3 which unfortunately
often suffered from harsh reaction conditions such as strong
acids in combination with high temperature. Recently, some of
these drawbacks have been overcome by the development of
N
CH3
OMe
O
antitumor activity
DNA topoisomerase II inhibitor
COOMe
O
N
N
HO
S
N
O
N
O
N
F
F
HIV reverse transcriptase inhibitor
natural product (UK-1)
Fig. 1 Examples of biologically and pharmaceutically active compounds.
Previously, we have reported a typical Ullmann-type C-N
coupling reaction in water using CuSO4 as the catalyst and 2-
hydroxybenzohydrazides as the ligands.8 In order to explore the
scope of the catalytic system to other types of coupling
reactions, we have carried out a set of experiments to test all the
ligands activities for copper-based intramolecular
of -(2-bromophenyl)benzamides. In surprise, methyl 2-
methoxybenzoate, an intermediate for 2-hydroxybenzohydra-
zides synthesis, showed the highest activity (ESI†). To further
check the catalytic activity, we undertook studies to evaluate
transition-metal-catalysed intramolecular
O-arylation of ortho-
haloanilides under comparatively milder reaction conditions.
For example, several copper-based catalytic systems have been
O-arylation
used for intramolecular
O-arylation of N-(2-halophenyl)-
N
benzamides, which provided a straight forward route for the
synthesis of functionalized benzoxazoles frameworks.4 At the
same time, iron5 and cobalt6 were employed as the catalyst for
the cyclization of
N-(2-bromo- or iodo-phenyl)benzamides to
copper-based cyclization of
N-(2-halophenyl)-benzamides
using methyl 2-methoxybenzoate as the ligand. Herein, we wish
to report our results.
provide 2-arylbenzoxazoles. Transition-metal-catalyst free
direct base-mediated intramolecular C-O couplings have also
been demonstrated, but with relatively high reaction
temperature.7 Although significant improvements have been
Results and discussion
achieved for the synthesis of benzoxazoles from
N-(2-
halophenyl)benzamides through intramolecular C-O bond
formation, there is still a need to develop a generally efficient
catalytic system for this class of reaction.
In preliminary studies, the optimized reaction conditions were
carried out with
N-(2-bromophenyl)benzamide as a model
substrate using different copper sources, bases and solvents at
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J. Name., 2013, 00, 1‐3 | 1

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ARTICLE
varied temperature, and the results were summarised in Table 1. iodoanilides gave preferable results to their bromo analogues.
Several copper catalysts containing CuI, CuBr, CuCl, Cu2O, For 2-iodoanilides, we found that both of the electron-releasing
View Article Online
CuO and CuSO4 were tested by using methyl 2- and electron-withdrawing group of the aromatic motifs linked
DOI: 10.1039/C4OB02068E
methoxybenzoate as the ligand, KOH as the base in DMF at to the carbonyl moiety could smoothly be converted to the
90
6). Carrying out the reaction in the absent of copper catalyst Interestingly, ortho-substituted substrate seemed not to hamper
resulted in no product, whereas only 15% yield of the product the reaction and afforded 75% yield (entry 4). -(2-
obtained without ligand (entries 7 and 8). Screening the bases iodophenyl)cinnamamide and aliphatic -(2-iodophenyl)-
C for 12 h, and CuI was found to be the best one (entries 1- desired products in good to excellent yields (entries 1-7).
N
N
of K2CO3, K3PO4 and Cs2CO3, potassium phosphate was turned dodecanamide were successfully cyclised in 82% and 65%
out to be the best choice in terms of isolated yield (entries 9-11). yields, respectively (entries 8 and 9). Conversely, the intra-
Also the use of DMF is superior to other solvents, such as molecular
DMSO, 1,4-dioxane and toluene (entries 12-14). Lowering carried out by using CuI/methyl 2-methoxybenzoate catalyst
reaction temperature from 90 C to 80 C led to a dramatically system, and substitutions on the aromatic moiety of both the
decrease of the yield, whereas raising the reaction temperature aryl halide as well as the amide were tolerated. In addition, we
from 90 C to 110 C only led to a slight increase of the yield carried out the reaction in a large scale by taking 10 mmol of
(entries 15 and 16). In addition, decreasing the catalyst loading (2-iodophenyl)benzamide in 15 mL DMF at 90 C for 12 h. The
O-arylation of bromo derivatives was also efficiently




N-

from 10 mol% to 5 mol%, only 55% yield was obtained (entry reaction proceeded without any difficulty to obtain 80% yield
17). In summary, the optimal conditions for the intramolecular (1.56g) of the desired product (Fig. 2).
coupling cyclization of
of the combination of CuI (10 mol%), ligand (20 mol%), K3PO4
(2 equiv) in DMF (1 mL) at 90 C for 12 h.
N-(2-bromophenyl)benzamide consist

Table 1 Screening reaction conditions for the synthesis of 2-phenyl-
benzoxazolea
Fig. 2 Large‐scale reaction of N‐(2‐iodophenyl)benzamide.
We are pleased to find that various less reactive ortho
-
chloroanilides could be reacted well under the optimal
conditions to give the respective benzoxazoles in good to
excellent yields only by increasing the reaction temperature to
Entry
1
2
3
4
5
6
7
8
[Cu]
CuI
Base
KOH
KOH
KOH
KOH
KOH
KOH
KOH
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
Dioxane
Toluene
DMF
DMF
DMF
Yieldb (%)
T (C)
90
90
90
90
90
90
90
90
90
90
90
90
90
90
110
80
90
40
29
28
19
0
135
C. Furthermore, the substrates with electron-releasing
CuBr
CuCl
Cu2O
CuO
CuSO4
-
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
group, electron-neutral and electron-withdrawing were all well
tolerated (Table 3).
As reported, benzoxazoles could be prepared in a single step
36
0
from primary amides and
catalyst.9 Therefore, we reasonably explored
intermolecular C-N intramolecular C-O cross-coupling
o
-dihalobenzenes using copper
KOH
15c
41
78
10
66
12
0
a
domino
9
K2CO3
K3PO4
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
/
10
11
12
13
14
15
16
17
protocol to afford benzoxazoles (Table 4). Utilizing the reaction
conditions described for cyclization of ortho-chloroanilides,
1,2-diiodobenzene (entries 1-3), 1-bromo-2-iodobenzene
(entries 4-6) and 1,2-dibromobenzene (entry 7) could react with
benzamides to yield promising results, which will increase the
popularity of the synthetic methodology. But it was still a
challenge for ortho-chlorohalobenzene (entry 8).
79
46
55d
a Reaction conditions: N-(2-bromophenyl)benzamide (0.5 mmol), [Cu] (10
mol%), L (20 mol%), base (1.0 mmol), solvent (1.0 mL), 90 C, 12 h. b
Isolated yield. c Ligand-free. d CuI (5 mol%), L (10 mol%).
Conclusion
With the optimal conditions in hand, the scope of this
transformation was initially extended toward the synthesis of
In summary, we have established an efficient CuI/methyl 2-
methoxybenzoate catalytic systems for intramolecular
O-
various 2-substituted benzoxazoles from
benzamide and -(2-bromophenyl)benzamide, and the results
were showed in Table 2. Most of the substrates worked well
to afford the corresponding products in good to excellent yields
N-(2-iodophenyl)-
arylation for the synthesis of benzoxazoles from -(2-iodo or
N
N
bromo-phenyl)benzamides with high yields, broad functional
group tolerance and ambient reaction conditions. Less reactive
chloro precursors were also worked well under the similar
reaction conditions. In addition, the benzoxazoles can be gained
1
under the standard reaction conditions. In general, ortho
-
2 | J. Name., 2012, 00, 1‐3
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Journal Name
Organic & Biomolecular Chemistry
ARTICLE
Table 2 CuI-catalysed synthesis of benzoxazoles from N-(2-iodo/bromo-
phenyl)benzamides using methyl-2-methoxybenzoate as the liganda
12
View Articl7e2Online
2c
DOI: 10.1039/C4OB02068E
13
14
53
70
2d
2e
Entry
1
Yieldb
(%)
1
2
87
2a
2b
15
16
17
18
80
65
71
2f
2g
2j
H
N
2
3
98
90
O
I
2c
4
5
75
99
2d
2e
65
75
2k
2l
19
20
21
22
6
7
8
91
78
82
2f
2m 70
2g
2h
75
70
2n
2o
23
24
63
82
2p
2q
9
65
2i
10
11
78
75
2a
2b
a Reaction conditions: N-(2-iodo/bromo-phenyl)benzamides (0.5 mmol), CuI
(10 mol%), L (20 mol%), K3PO4 (1.0 mmol), DMF (1.0 mL), 90 C, 12 h. b
Isolated yield.
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Table 3 CuI-catalysed synthesis of benzoxazoles from N-(2-chlorophenyl)
Table 4 One-step synthesis of benzoxazoles from orth-dihalobenzene and
benzamides using methyl-2-methoxybenzoate as the liganda
primary amides using methyl-2-methoxybenzoate as the liganda
View Article Online
DOI: 10.1039/C4OB02068E
Entry
1
Yieldb
(%)
4
5
2
Entry
1
Yieldb (%)
80
3
2
H
N
30
28
2a
2b
2a
O
Cl
2
3
2
3
78
73
2b
2c
57
2f
4
5
45
25
2a
2b
4
85
2f
5
6
70
85
2r
6
50
2f
2n
7
8
25
0
2a
2a
7
8
80
86
2o
2s
a Reaction conditions: orth-dihalobenzene (0.5 mmol), amide (0.75 mmol),
CuI (10 mol%), L (20 mol%), K3PO4 (1.5 mmol), DMF (1.0 mL), 135 C, 12
h. b Isolated yield.
a Reaction conditions: N-(2-chlorophenyl)benzamides (0.5 mmol), CuI (10
mol%), L (20 mol%), K3PO4 (1.0 mmol), DMF (1.0 mL), 90 C, 12 h. b
Isolated yield.
plates. All 2-substituted benzoxazoles were characterized by 1H
NMR, 13C NMR and MS, which were compared with the
previously reported data. NMR spectra were recorded at room
temperature on a Bruker Avance III HD 400 instrument at 400
through domino intermolecular C-N bond formation followed
by intramolecular C-O bond formation from coupling of
primary amides with ortho-dihalobenzene. The convenient
operation, stable and simple catalytic system, in combination
with the efficient process for large scale preparation, made the
operation much more practical.
MHz for H NMR and 100 MHz for 13C NMR. Mass spectra
1
were recorded on GC-MS (Agilent 7890A/5975C) instrument
under EI model.
General procedure for benzoxazoles synthesis via intra-
molecular
To a 10 mL of tube was added CuI (0.05 mmol), L (0.1 mmol),
-(2-halophenyl)benzamide (0.5 mmol), K3PO4 (1.0 mmol) and
O-arylation
Experimental
N
General information
anhydrous DMF (1 mL). The tube was then sealed with a
rubber septum without inert atmosphere and heated at 90 °C
(for 2-iodoanilides and 2-bromoanilides) or 135 °C (for 2-
chloroanilides) in a preheated oil bath for 12 h. The reaction
mixture was cooled to room temperature, diluted with 10 mL
water and extracted with ethyl acetate (3×20 mL). The
combined organic phase was washed with water and brine,
All reagents were purchased from commercial suppliers and
used without further purification. Column chromatography was
performed with silica gel (200-300 mesh) purchased from
Qingdao
Haiyang
Chemical
Co.
Ltd.
Thin-layer
chromatography was carried out with Merck silica gel GF254
4 | J. Name., 2012, 00, 1‐3
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ARTICLE
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General procedure for benzoxazoles synthesis via domino
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benzamides (0.75 mmol), 1,2-dihalobenzene (0.5 mmol),
K3PO4 (1.0 mmol) and anhydrous DMF (1 mL). The tube was
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Notes and references
a
School of Chemistry and Chemical Engineering/Key Laboratory for
Green Processing of Chemical Engineering of Xinjiang Bingtuan, Shihezi
University, Shihezi 832003, China. E-mail: cesxjw@gmail.com;
Fax: +86-0993-2057270; Tel: +86-0993-2057213
†
Electronic Supplementary Information (ESI) available: Experimental
procedures and spectroscopic data for all products. See DOI: 10.1039/
b000000x/
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