Efficient Cu-catalyzed intramolecular: O -arylation for synthesis of benzoxazoles in water

Article abstract of DOI:10.1039/d0ra00570c

An efficient method was developed for synthesis of benzoxazoles by Cu-catalyzed intramolecular O-arylation of o-halobenzanilides in water. This strategy provides several advantages, such as high yields, water as a green solvent and functional groups tolerance.

Full text of DOI:10.1039/d0ra00570c

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Efficient Cu-catalyzed intramolecular O-arylation
for synthesis of benzoxazoles in water†
Cite this: RSC Adv., 2020, 10, 14317
*
*
Yanling Tang,‡ Minxin Li,‡ Hui Gao, Gaoxiong Rao and Zewei Mao
Received 19th January 2020
Accepted 28th March 2020
An efficient method was developed for synthesis of benzoxazoles by Cu-catalyzed intramolecular O-
arylation of o-halobenzanilides in water. This strategy provides several advantages, such as high yields,
water as a green solvent and functional groups tolerance.
DOI: 10.1039/d0ra00570c
rsc.li/rsc-advances
Benzoxazole derivatives not only exist in several important formation of benzoxazoles via a CuI/1,10-phenanthroline-
natural products, but are also present in many important catalyzed cyclization of o-haloanilides in the presence of
classes of organic compounds due to their biological, pharma- Cs2CO3 in DMF.6a Saha et al. have reported cobalt(II)/1,10-
ceutical and catalytic properties, which have attracted more and phenanthroline-catalyzed the intramolecular C–O cross-
more attention from pharmaceutical and synthetic chemists couplings of o-halobenzanilides to give benzoxazoles in
(Fig. 1).1,2 Commonly, the preparation of benzoxazoles has DMSO.6b Dai et al. have prepared 2-substituted benzoxazoles via
attracted considerable attention. Traditional methods to Cu-catalysed intramolecular coupling cyclization reactions
construction of 2-aryl benzoxazoles involve the condensation of using methyl 2-methoxybenzoate (MMB) as the ligand in DMF.7a
2-aminophenol with carboxylic acids or aldehydes under Bonnamour et al. have obtained benzoxazole derivatives by
oxidative conditions, which unfortunately oen suffer from the iron-catalyzed intramolecular O-arylation reaction and 2,2,6,6-
use of harsh reaction conditions involving strong acids or tetramethyl-3,5 heptanedione (TMHD) as the cocatalyst in
highly toxic reagents in combination with high temperatures.3 DMF.7b Tapia et al. described an efficient synthesis of 2-aryl-
In the last decades, some of these drawbacks have been benzoxazoles using (IPr)CuCl via intramolecular coupling
overcome by the development of transition-metal-catalyzed cyclization of 2-haloanilides in DMF.8 Although many
processes for C–O bond formations under comparatively improvements have been achieved for the synthesis of 2-
milder reaction conditions.4 Until now, there are various reac- substituted benzoxazoles from o-halobenzanilides through
tions reported for the construction of benzoxazoles by intra- intramolecular O-arylation by transition-metal-catalyzed
molecular O-arylation of orthohaloanilides under milder processes, many approaches reported so far were harsh condi-
reaction conditions.5 Evindar et al. have improved the tions, such as long reaction time, costly and toxic solvents.3,9
Fig. 1 Examples of biologically and pharmaceutically benzoxazoles.
College of Pharmaceutical Science, Yunnan University of Chinese Medicine, Kunming
650500, P.R. China. E-mail: gaohui_em@126.com; ydmason@163.com; maozw@
ynutcm.edu.cn; Fax: +86 871 65918232; Tel: +86 871 65918232
† Electronic supplementary information (ESI) available: Experimental details and
Scheme
benzoxazoles.
1 Intramolecular O-arylation for the synthesis of
spectra data. See DOI: 10.1039/d0ra00570c
‡ These authors contributed equally to this work.
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Table 2 Cu-catalyzed synthesis of benzoxazoles from 2-iodo/bro-
Therefore, there is still worthwhile to develop an economic,
efficient and eco-friendly catalytic system (Scheme 1).
mophenylbenzanilides using DPPAP as the liganda,b
To the best of our knowledge, no report on the synthesis of
benzoxazoles from o-halobenzanilides in water has been re-
ported so far. In initiatory work, we have found that 1-[2-(N-(3-
diphenylphosphinopropyl))aminoethyl]pyrrolidine
(DPPAP)
could promoted transition metal-catalyzed reactions as NNP-
type pincer ligand, which accelerated Cu-catalyzed intra-
molecular O-arylation of o-halobenzanilides to form benzox-
azoles in water. In present work, we optimum reaction
conditions based on initiatory study, and report a new, efficient
and green Cu-catalyzed synthesis of benzimidazoles in water.
Reaction between N-(2-bromophenyl)benzamide (1a) was
selected as a model substrate and various copper sources were
tested including CuI, CuSO4, Cu(OAc)2 and Cu(OTf)2 to check
and identify optimization of reaction conditions. As shown in
Table 1, the reaction results were distinguishable catalyzed by
various copper sources. In general, CuI could lead to product in
low yield, and CuSO4 was not active to this action and no
product was obtained (Table 1, entries 1–6). To our surprise,
Cu(OTf)2 and Cu(OAc)2 enhanced the reaction yields obviously
(Table 1, entries 7–15). In order to study the effects of different
types of bases on the reaction, 4 bases were employed including
inorganic and organic base such as K3PO4, K2CO3, TMEDA and
Et3N. We could see that compound 2a was formed in the pres-
ence of TMEDA and Et3N in better yields than that of K3PO4 and
K2CO3, and there was nearly no difference.
Yieldc (%)
Entry
1
1
2
present reported
89
92
78 (ref. 7a)
87 (ref. 7a)
2
3
90
92
81
87
88
93
82
85
74
81
79 (ref. 8)
87 (ref. 8)
—
4
5
Furthermore, we examined the effects of temperature and
time on the reaction. With the increasing of temperature from
6
—
Table 1 Optimization of reaction conditions for the synthesis of 2aa,b
7
75 (ref. 8)
82 (ref. 8)
—
8
9
Entry
[Cu]
Base
T (ꢀC)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuSO4
CuSO4
Cu(OTf)2
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
K2CO3
K3PO4
TMEDA
Et3N
TMEDA
Et3N
TMEDA
Et3N
TMEDA
Et3N
100
100
100
100
100
100
100
100
100
100
90
12
12
12
12
12
12
12
12
12
12
12
12
6
22
20
38
36
Trace
Trace
64
62
84
83
70
89
62
81
72
10
—
11
12
80 (ref. 7a)
91 (ref. 7a)
9
10
11
12
13
14
15
Et3N
Et3N
Et3N
Et3N
110
110
110
120
24
12
Et3N
a
All reactions were performed using 1a (1 mmol), [Cu] (5 mol%), DPPAP
b
(10 mol%), base (2 mmol) in water (3 mL). Isolated yield aer
chromatographic purication.
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Table 2 (Contd.)
Table 2 (Contd.)
Yieldc (%)
Yieldc (%)
Entry
13
1
2
present reported
Entry
25
1
2
present reported
76
85
73
78
89
—
—
—
—
—
70
77
—
—
26
27
28
29
14
15
16
79
85
77 (ref. 8)
86 (ref. 8)
17
18
74
83
—
—
30
92
—
a
All reactions were carried out using o-halobenzanilides (1 mmol),
Cu(OAc)2 (0.05 mmol), DPPAP (0.1 mmol), Et3N (2 mmol) in water (3
b
mL) for 12 h at 110 ꢀC. Isolated yield. c ‘—’ presented no report yield
from o-halobenzanilides.
19
20
86
89
—
—
ꢀ
ꢀ
90 C to 110 C, the yield had increased to 89% (Table 1, entry
12). However, further increasing temperature led to decline of
yield(Table 1, entry 15). In addition, reaction time from 6 h to
12 h was favorable to reaction obviously. However, further
increase of reaction time to 24 h had negative effect on the yield
of benzoxazole (Table 1, entry 14). Therefore, it was clear that
the best reaction was performed taking Cu(OAc)2 (5 mol%) and
DPPAP (10 mol%) as the catalyst in water in present of Et3N (2
21
22
23
24
83
90
76
88
92 (ref. 6a)
—
—
—
ꢀ
eq.) for 12 h at 110 C.
With the optimal reaction conditions in hand, a series of o-
halobenzanilides were investigated to study the scope of Cu-
catalyzed intramolecular O-arylation. As shown in Table 2, to
our delight, the O-arylation of various substituted 2-bromo-
benzanilides or 2-iodobenzanilides under standard reaction
condition gave the corresponding title products in good to high
yields, and 2-iodobenzanilides were more active than 2-bro-
mobenzanilides (Table 2). In order to study the inuence of
substituted groups, various substituted o-halobenzanilides were
performed including electron donating groups (CH3, C2H5,
CH3O, F, Cl, Br) and withdrawing group (CF3). From the results,
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Table 3 Cu-catalyzed synthesis of benzoxazoles from N-(2-chloro
phenyl)benzanilides using standard conditiona,b
Scheme 2 Gram-scale synthesis of benzoxazole 2d.
Entry
1
1
2
Yield (%)
22
2
3
4
5
28
13
25
Scheme 3 Possible mechanism of intramolecular O-arylation.
Trace
eager to study O-arylation of 2-chlorobenzanilides. Therefore,
six 2-chlorobenzanilides bearing different substituted groups
were selected as the model reaction under standard conditions.
As shown in Table 3, 2-chlorobenzanilides displayed poor
reactivity under this conditions, and benzoxazoles were ob-
tained in low yields (<30%), respectively.
6
15
a
All reactions were carried out using o-chlorobenzanilides (1 mmol),
In addition, we performed the reaction on a gram-scale by
taking 10 mmol of N-(2-iodophenyl)-4-methoxybenzamide in
Cu(OAc)2 (0.05 mmol), DPPAP (0.1 mmol), Et3N (2 mmol) in water (3
b
mL) for 12 h at 110 ꢀC. Isolated yield.
ꢀ
30 mL water at 110 C for 12 h (Scheme 2). The reaction pro-
ceeded smoothly to form desired product 2d (2.05 g, 91% yield).
Although the mechanism of the present reaction was not yet
clear, based on experimental results mentioned and copper-
catalyzed C–O bond formations in the literature,6a,10 the most
probable mechanism was proposed and depicted for the Cu-
catalytic intramolecular O-arylation of o-halobenzanilides as
shown in Scheme 3. Firstly, o-halobenzanilide converted to enol
I, followed by coordination of the CuL catalyst and Et3N to give
II. Subsequently, intermediate III was formed by oxidative
insertion. Aer that, III underwent reductive elimination to give
benzoxazole as well as CuLX. Finally, CuLX was transformed
into CuL catalyst for reuse in presence of Et3N.
we could nd that this reaction condition was benecial to
prepare 2-substituted benzoxazoles, and substitutions on amide
were tolerated. In general, electron donating groups afforded
the corresponding benzoxazoles in higher yields than that of
CF3. Especially, N-(2-iodophenyl)-4-methoxybenzamide formed
2d in the best yield (93%), and N-(2-bromophenyl)-2,3,4,5-
tetrauorobenzamide formed 2g in the lowest yield (70%).
In addition, the intramolecular O-arylation of various ortho, meta
and para substituted o-halobenzanilides were carried out using the
Cu(OAc)2/DPPAP catalyst system. As shown in Table 2, all desired
products were obtained in good yields, and position of both electron
donating and withdrawing groups did not have obvious inuence
on applicability. It was gratied that N-(2-bromophenyl)-2,3,4,5-
tetrauorobenzamide, N-(2-iodophenyl)-2,3,4,5-tetrauoro benza-
mide, N-(2-bromophenyl)-3,5-dichlorobenzamide and N-(2-
iodophenyl)-3,5-dichlorobenzamide could afford the corresponding
products 2g and 2j in good yields (70%, 77%, 86% and 89%,
respectively) under optimal reaction conditions.
Conclusions
In conclusion, we have developed an efficient method for
synthesis of benzoxazoles by Cu-catalyzed intramolecular O-
arylation of o-halobenzanilides in water. This protocol is
applicable to a wide variety of o-halobenzanilides bearing elec-
tron donating as well as electron withdrawing groups, which
features high yields, water as green solvent and functional
groups tolerable. The simple and green catalytic system
From above results, our improved protocol for synthesis of
benzoxazoles by intramolecular O-arylation of o-hal-
obenzanilides (Br, I) in water is signicantly applicative under
Cu/DPPAP catalyst system. Delighted with this results, we were
provides
a
valuable synthetic approach for industrial
applications.
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4 (a) N. Barbero, M. Carril, R. SanMartin and E. Domınguez,
Conflicts of interest
Tetrahedron, 2007, 63, 10425; (b) S. Ueda and H. Nagasawa,
Angew. Chem., Int. Ed., 2008, 47, 6411; (c) N. Khatun,
S. Guin, S. K. Rout and B. K. Patel, RSC Adv., 2014, 4,
10770; (d) J. Peng, C. Zong, M. Ye, T. Chen, D. Gao,
Y. Wang and C. Chen, Org. Biomol. Chem., 2011, 9, 1225; (e)
A. D. G. Evano, N. Blanchard and M. Toumi, Chem. Rev.,
2008, 108, 3054; (f) A. Ahmed, R. Singha and J. K. Ray,
Tetrahedron Lett., 2015, 56, 2167; (g) X. Zhang, W. Zeng,
Y. Yang, H. Huang and Y. Liang, Org. Lett., 2014, 16, 876;
(h) L. Xiao, H. Gao, J. Kong, G. Liu, X. Peng and S. Wang,
Chin. J. Org. Chem., 2014, 34, 1048.
There are no conicts to declare.
Acknowledgements
This work was nancially supported by the National Natural
Science Foundation of China (81560620), the Yunnan Provincial
Science and Technology Department-Applied Basic Research
Joint Special Funds of Yunnan University of Chinese Medicine
(2017FF117(-023)).
5 (a) S. Sasmal, I. Sen, R. G. Hall and S. Pal, Tetrahedron Lett.,
´
2015, 56, 1374; (b) Y. Yuan, I. Thome, S. H. Kim, D. Chen,
Notes and references
A. Beyer, J. Bonnamour, E. Zuidema, S. Chang and
1 (a) S. M. Johnson, S. Connelly, I. A. Wilson and J. W. Kelly, J.
Med. Chem., 2008, 51, 260; (b) N. Mishra, A. S. Singh,
A. K. Agrahari, S. K. Singh, M. Singh and V. K. Tiwari, ACS
Comb. Sci., 2019, 21, 389; (c) G. Daletos, N. J. de Voogd,
W. E. G. Muller, V. Wray, W. Lin, D. Feger, M. Kubbutat,
A. H. Aly and P. Proksch, J. Nat. Prod., 2014, 77, 218; (d)
S. Aiello, G. Wells, E. L. Stone, H. Kadri, R. Bazzi,
D. R. Bell, M. F. G. Stevens, C. S. Matthews, T. D. Bradshaw
and A. D. Westwell, J. Med. Chem., 2008, 51, 5135.
C. Bolm, Adv. Synth. Catal., 2010, 352, 2892; (c) N. Barbero,
´
M. Carril, R. SanMartin and E. Domınguez, Tetrahedron,
2007, 63, 10425; (d) R. D. Viirre, G. Evindar and R. A. Batey,
J. Org. Chem., 2008, 73, 3452; (e) N. Barbero, M. Carril,
´
R. SanMartin and E. Domınguez, Tetrahedron, 2007, 63,
10425; (f) J. Sedelmeier, F. Lima, A. Litzler, B. Martin and
F. Venturoni, Org. Lett., 2013, 15, 5546; (g) D. Suresh,
A. Dhakshinamoorthy and K. Pitchumani, Tetrahedron
Lett., 2013, 54, 6415.
2 (a) L. Leventhal, M. R. Brandt, T. A. Cummons, M. J. Piesla,
K. E. Rogers and H. A. Harris, Eur. J. Pharmacol., 2006, 553,
146; (b) L. Q. Sun, J. Chen, M. Cruce, J. A. Deskus,
J. R. Epperson, K. Takaki, G. Johnson, L. Iben, C. D. Malhe,
E. Ryan and C. Xu, Bioorg. Med. Chem. Lett., 2004, 14, 3799;
(c) E. Oksuzoglu, O. Temiz-Arpaci, B. Tekiner-Gulbas,
H. Eroglu, G. Sen, S. Alper, I. Yildiz, N. Diril, E. Aki-Sener
and I. Yalcin, Med. Chem. Res., 2007, 16, 1; (d) J. Boyer,
6 (a) G. Evindar and R. A. Batey, J. Org. Chem., 2006, 71, 1802;
(b) P. Saha, M. A. Ali, P. Ghosh and T. Punniyamurty, Org.
Biomol.Chem., 2010, 8, 5692.
7 (a) F. Wu, J. Zhang, Q. Wei, P. Liu, J. Xie, H. Jiang and B. Dai,
Org. Biomol. Chem., 2014, 12, 9696; (b) J. Bonnamour and
C. Bolm, Org. Lett., 2008, 10, 2665.
´
8 J. I. Urzua, R. Contreras, C. O. Salas and R. A. Tapia, RSC Adv.,
2016, 6, 82401.
´
E. Arnoult, M. Medebielle, J. Guillemont and J. Unge, J.
9 (a) K. Bougrin, A. Loupy and M. Souaoui, Tetrahedron, 1998,
54, 8055; (b) G. Alenhoff and F. Glorius, Adv. Synth. Catal.,
2004, 346, 1661; (c) J. Chang, K. Zhao and S. Pan,
Tetrahedron Lett., 2002, 43, 951; (d) M. Carril, R. SanMartin,
Med. Chem., 2011, 54, 7974.
3 (a) K. Bougrin, A. Loupy and M. Souaoui, Tetrahedron Lett.,
1998, 54, 8055; (b) J. Chang, K. Zhao and S. Pan, Tetrahedron
Lett., 2002, 43, 951; (c) K. Bougrin, A. Loupy and M. Souaoui,
Tetrahedron, 1998, 54, 8055; (d) S. M. Inamdar, V. K. More
and S. K. Mandal, Tetrahedron Lett., 2013, 54, 579; (e)
Y. Kawashita, N. Nakamichi, H. Kawabata and M. Hayashi,
Org. Lett., 2003, 5, 3713.
´
I. Tellitu and E. Domınguez, Org. Lett., 2006, 8, 1467.
10 (a) G. D. Allred and L. S. Liebskind, J. Am. Chem. Soc., 1996,
118, 2748; (b) E. R. Strieter, D. G. Blackmond and
S. L. Buchwald, J. Am. Chem. Soc., 2005, 127, 4120.
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