Synthesis of benzoxazoles via an iron-catalyzed domino C-N/C-O cross-coupling reaction

Article abstract of DOI:10.1039/c7ra13080e

An eco-friendly and efficient method has been developed for the synthesis of 2-arylbenzoxazoles via a domino iron-catalyzed C-N/C-O cross-coupling reaction. Some of the issues typically encountered during the synthesis of 2-arylbenzoxazoles in the presence of palladium and copper catalysts, including poor substrate scope and long reaction times have been addressed using this newly developed iron-catalyzed method.

Full text of DOI:10.1039/c7ra13080e

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Synthesis of benzoxazoles via an iron-catalyzed
domino C–N/C–O cross-coupling reaction†
Cite this: RSC Adv., 2018, 8, 2267
*
Bo Yang, Weiye Hu and Songlin Zhang
An eco-friendly and efficient method has been developed for the synthesis of 2-arylbenzoxazoles via
a domino iron-catalyzed C–N/C–O cross-coupling reaction. Some of the issues typically encountered
during the synthesis of 2-arylbenzoxazoles in the presence of palladium and copper catalysts, including
poor substrate scope and long reaction times have been addressed using this newly developed iron-
catalyzed method.
Received 6th December 2017
Accepted 29th December 2017
DOI: 10.1039/c7ra13080e
rsc.li/rsc-advances
2-Arylbenzoxazoles are an important class of structures in being more abundant, commercially inexpensive, environmen-
natural products, and pharmaceuticals and has shown a wide tally friendly and drug safety.13 Compared with palladium and
range of biological activities, such as antitumor, antiviral, and copper, the use of iron is particularly suitable for reactions
antimicrobial activities.1 In particular, they show a marvellous involving the preparation of therapeutic agents for human
efficacy in the treatment of duchenne muscular dystrophy consumption. With this in mind, it was envisaged that an new
(DMD) which is one of the most common of the muscular method should be developed for the synthesis of benzoxazoles
dystrophies that is caused by a mutation in the gene DMD, via an iron-catalyzed domino C–N/C–O cross-coupling reaction.
located in humans on the X chromosome (Xp21).2 So the
The reaction of benzamide (1a) with 1-bromo-2-iodobenzene
synthesis of 2-arylbenzoxazoles has been intensively studied for was used as model transformation to identify the optimum
use in organic and medicinal chemistry over the past few years. reaction conditions by screening a variety of different iron salts,
Numerous methods have been reported to synthesise this bases, ligands and solvents (Table 1). Several iron salts were
motif, one of the common methods is transition-metal- screened in this reaction, including FeCl3, FeCl2$4H2O, FeSO4-
catalyzed (like Pd,3 Ni,4 Cu,5 Mn6 etc.) cross-coupling from pre- $7H2O, Fe(acac)3, Fe2O3, Fe3O4, Fe3O4(nano), Fe2O3(nano),
existing benzoxazoles with aryl halide or arylboronic acid. And Fe2(SO4)3 and Fe(NO3)3$9H2O, Fe2O3 was found to give the best
another method is the classic one employing
a cyclo- results with the desired product 3a being formed in a yield of
condensation approach between an aminophenol and either 15% while most of the iron salt have no effect on the reaction
a carboxylic acid7 or benzaldehyde8 (Scheme 1, path a). In 2004, (Table 1, entries 1–10). Then, several other bases, including
Frank Glorius' group reported a domino copper-catalyzed C–N LiOtBu, Na2CO3, NaOAc, KOH and K2CO3 were also evaluated
and C–O cross-coupling for the conversion of primary amides under the same conditions using Fe2O3, but all of them failed to
into benzoxazoles9 (Scheme 1, path b) which is a new reaction provided the desired product 3a except K2CO3 with a yield of
type for the synthesis of benzoxazoles. Bunch et al. apply this 37% (Table 1, entries 11–15). When the reaction was stirred for
ꢀ
domino reaction in the synthesis of planar heterocycles in 24 h at 110 C in the presence of 20% mol of Fe2O3, 20% mol
2014.10 In addition the cyclization of o-halobenzenamides to N,N0-dimethylethanediamine (DMEDA) and 1 equiv. of K2CO3 in
benzoxazoles has been reported several times.11,12 Nevertheless, PhMe under nitrogen, (N-(2-bromophenyl)benzamide) was ob-
some limitations in the reported methods need to be overcome, tained as an intermediate which could be converted to the nal
such as the use of palladium complexes and narrow substrate product with a yield of 87% if extend the reaction time from 24 h
range.
to 48 h (Table 1, entries 15, 16). Several ligands were also
In the last few years, there has been a signicant increase in screened in the model reaction, and the results revealed that the
the number of reports pertaining to the development of iron-
catalyzed reactions in organic synthesis, where iron has
shown several signicant advantages over other metals, such as
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123,
P. R. China. E-mail: zhangsl@suda.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c7ra13080e
Scheme 1 Classic method of benzoxazole formation.
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Table 1 Optimization of reaction conditionsa
metals in catalytic, as is well-known, sometime could play an
important role in the reaction,14 high-purity Fe2O3 (99.999%)
and K2CO3 (99.999%) were applied in the reaction (Table 1,
entry 24). The product was formed in a yield of 86% which was
similar with the one of the entry 16.
Table 2 Reagent scope of reactiona
Entry Iron salt
Ligand
Base
Solvent Yb (%)
1
2
3
4
5
6
7
8
FeCl3
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
LiOtBu
Na2CO3
NaOAc
KOH
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
Trace
Trace
0
0
15
0
10
0
0
0
FeCl2$4H2O
FeSO4$7H2O
Fe(acac)3
Fe2O3
Fe3O4
Fe3O4(nano)
Fe2O3(nano)
Fe2(SO4)3
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Fe(NO3)3$9H2O DMEDA
Fe2O3
Fe2O3
Fe2O3
Fe2O3
Fe2O3
Fe2O3
Fe2O3
Fe2O3
Fe2O3
Fe2O3
Fe2O3
Fe2O3
—
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
Phen
0
0
0
0
K2CO3 (24 h) PhMe
K2CO3 (48 h) PhMe
K2CO3
37
87
Trace
0
0
0
PhMe
PhMe
PhMe
DMSO
DMF
PhMe2
PhMe
PhMe
PhMe
L-Proline K2CO3
Dpy
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
0
0
0
Fe2O3
Fe2O3
86c
58d
a
Reaction conditions: benzamides (0.5 mmol), 1-bromo-2-iodobenzene
(1.5 eq.), iron salt (20% mol), base (1 eq.), ligand (20%) were added to
b
a solvent (2 mL) and react at 110 ꢀC for 48 h under N2. Isolated yield
c
based on 1a aer silica gel chromatography. Fe2O3 and K2CO3 were
d
applied in purity of 99.999% from alfa. with Fe2O3 in a dosage of 10
mmol%.
nature of the ligand has a dramatic impact on the yield of the
reaction. For example, the use of DMEDA gave 2-phenylbenzo[d]
oxazole in 85% yield, whereas 1,10-phenanthroline, dipyridyl
and L-proline provided no product (Table 1, entries 16–19). The
reaction was conducted in DMSO, DMF and PhMe2 respectively
and none of them provided a much higher of the desired
product than toluene (Table 1, entries 20–22). Control experi-
ments was taken in the absence of Fe2O3, no product was ob-
tained (Table 1, entry 23). In view of the fact that the trace
a
Reaction conditions: 1a (0.5 mmol), o-dihalo substrate (1.5 eq.), Fe2O3
(20% mol), K2CO3 (1 eq.), DMEDA (20%) were added to PhMe (2 mL) and
react at 110 ꢀC for 48 h under N2.
Scheme 2 The pathway of the reaction.
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Acknowledgements
We gratefully acknowledge A Project Funded by the Priority
Academic Program Development of Jiangsu Higher Education
Institutions, The Project of Scientic and Technologic Infra-
structure of Suzhou (No. SZS201207) and the National Natural
Science Foundation of China (No. 21072143) for nancial
support.
Notes and references
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Scheme 3 Possible catalytic cycle.
At last, the dosage of Fe2O3 was reduce to 10 mmol%, but
only 58% yield was obtained (Table 1, entry 26). Taken together,
the results of these screening experiments revealed that the
optimal conditions for the reaction were Fe2O3 (20 mol%),
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ꢀ
It is noteworthy that the intermediate product 4a was formed
under the optimized conditions via the C–N cross coupling
reaction of benzamide (1a) with 1-bromo-2-iodobenzene (2). So
a possible pathway of the reaction was proposed as shown in
Scheme 2.
With the optimized reaction conditions in hand, we pro-
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Conflicts of interest
There are no conicts to declare.
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