Palladium-catalyzed synthesis of benzoxazoles by the cleavage reaction of carbon-carbon triple bonds with o-aminophenol

Article abstract of DOI:10.1039/c3gc42499e

A novel and mild procedure for efficient synthesis of benzoxazoles by the cleavage reaction of carbon-carbon triple bonds with o-aminophenol in the presence of a catalytic amount of palladium chloride has been successfully developed, which provides rapid and efficient access to benzoxazoles. the Partner Organisations 2014.

Full text of DOI:10.1039/c3gc42499e

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Palladium-catalyzed synthesis of benzoxazoles by
the cleavage reaction of carbon–carbon triple
bonds with o-aminophenol†
Cite this: DOI: 10.1039/c3gc42499e
Received 9th December 2013,
Accepted 16th January 2014
Hou-Zhi Xie,‡a,b Qi Gao,‡a,b Ying Liang,*a Heng-Shan Wangb and Ying-Ming Pan*b
DOI: 10.1039/c3gc42499e
www.rsc.org/greenchem
A novel and mild procedure for efficient synthesis of benzoxazoles therapeutically active agents,6 a wide range of natural pro-
by the cleavage reaction of carbon–carbon triple bonds with ducts,7 and functional materials.8
o-aminophenol in the presence of a catalytic amount of palladium
In order to identify the optimal reaction conditions,
chloride has been successfully developed, which provides rapid o-aminophenol 1a and diphenylacetylene 2a were chosen as
and efficient access to benzoxazoles.
model substrates. Firstly, the reaction was carried out in the
presence of 5 mol% PdCl2 in PhCl (1 mL) at reflux for 4 h, and
the desired product 3aa was isolated in 86% yield (Table 1,
entry 2). The reaction using Pd(OAc)2, Cu(OTf)2, In(OTf)3,
AgOTf, ZnCl2, or InCl3 as a catalyst, produced 3aa only in low
yield (Table 1, entries 1 and 5–9). Other catalysts such as
Pd(NO3)2, Pd2(dba)3, FeCl3, and BiCl3 did not promote the
reaction (Table 1, entries 3, 4, 10 and 11). In addition, it was
found that the solvent played a crucial role in this reaction
(Table 1, entries 12–16). When the reaction was carried out in
During the past few decades, the chemistry of the carbon–
carbon triple bond has been a hot research topic since this
functional group has been shown to be one of the main build-
ing blocks of organic and material chemistry.1 Nevertheless,
only a few reports on the Lewis acid catalyzed cleavage of C–C
triple bonds, which is one of the most challenging subjects in
modern synthetic organic chemistry, have been demon-
strated.2 Recently, Yamamoto reported that the hydroamina-
tion of alkynes using o-aminophenol proceeded in good yields
in the presence of Pd(NO3)2 catalyst, but no benzoxazoles are
obtained.3 Then, Yamamoto also reported that the CuC clea-
vage of diynes took place readily in the presence of Ru3(CO)12/
NH4PF6 or Pd(NO3)2, giving the corresponding benzoxazoles
and ketones in good to high yields (Scheme 1a).4 To the best
of our knowledge, the palladium-catalyzed synthesis of benzox-
azoles directly from simple alkynes and o-aminophenols has
not been reported so far.
Table 1 Optimization of reaction conditionsa
Entry
Catalyst
Solvent
Yieldb [%]
In the study of carbon–carbon triple bonds,5 herein we
present our independent finding that a palladium-catalyzed
cleavage reaction of carbon–carbon triple bonds proceeded
smoothly with o-aminophenol to give the corresponding
benzoxazoles (Scheme 1b). Benzoxazoles are frequently found
in a diverse array of compounds, including biologically and
1
2
3
4
5
6
7
8
Pd(OAc)2
PdCl2
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhMe
CH3CN
CH3NO2
DCE
10
86
0
Pd(NO3)2
Pd2(dba)3
Cu(OTf)2
In(OTf)3
AgOTf
ZnCl2
InCl3
FeCl3
BiCl3
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
0
16
29
20
26
31
0
0
43
0
9
10
11
12
13
14
15
16
aSchool of Life and Environmental Sciences, Guilin University of Electronic
Technology, Guilin, 541004, People’s Republic of China. E-mail: yingl@ailiyun.com
bKey Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources
(Ministry of Education of China), School of Chemistry & Chemical Engineering of
Guangxi Normal University, Guilin, 541004, People’s Republic of China.
0
0
0
DMF
E-mail: panym2013@hotmail.com
a Reaction conditions: o-aminophenol 1a (1 mmol), alkyne 2a
(0.5 mmol), and catalyst (5 mol%) in solvent (1 mL), at reflux, 4 h.
b Isolated yield of pure product based on 1a.
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3gc42499e
‡These authors contributed equally to this work.
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Scheme 1 Comparison of Yamamoto’s study and our work.
toluene, the yield of product 3aa dramatically decreased to 11). The alkynes bearing heterocyclic aromatic substituent
43% (Table 1, entry 12). In other solvents, such as CH3CN, such as 2l and 2m also reacted smoothly with o-aminophenol
CH3NO2, DCE, and DMF, most of the starting materials 1a and 1a in the presence of 5 mol% PdCl2 producing the corres-
2a were recovered (Table 1, entries 13–16). Hence, it was con- ponding products in 81% and 82% total yields, respectively
cluded that the best conditions involved 5 mol% PdCl2 in (Table 2, entries 12 and 13). It was particularly noteworthy that
chlorobenzene at reflux.
alkyl alkynes were suitable for this reaction (Table 2, entries 16
With these optimal conditions in hand, we examined the and 17). Furthermore, the reaction of the terminal alkynes 2r–
scope of this reaction. Typical results are shown in Table 2. To 2t with o-aminophenol 1a also gave the desired results, provid-
our delight, not only terminal alkynes, but also internal ing the benzoxazoles in good to excellent yields (Table 2,
alkynes produced the desired products in high to excellent entries 18–20).
yields (Table 2, entries 1–20). Obviously, the desired products
In addition, 2-amino-5-methylphenol 1b and 2-amino-5-
could be obtained in higher yields from electron poor alkynes chlorophenol 1c could be readily introduced into the reaction
than from electron rich alkynes (Table 2, entries 1–10). providing the corresponding desired products in high yields
Additionally, the alkyne bearing polycyclic aromatic substitu- (Table 2, entries 14 and 15).
ent such as 2k was treated with o-aminophenol 1a giving the
On the basis of the experiments mentioned above, a tenta-
desired products 3ak and 3aa in 80% total yield (Table 2, entry tive mechanism was illustrated in Scheme 2. Firstly, the Pd(II)
Scheme 2 The possible reaction mechanism.
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Table 2 Synthesis of benzoxazolesa
Entry
1
o-Aminophenol
1a: R1 = H
1a: R1 = H
1a: R1 = H
1a: R1 = H
1a: R1 = H
1a: R1 = H
1a: R1 = H
1a: R1 = H
1a: R1 = H
1a: R1 = H
1a: R1 = H
1a: R1 = H
1a: R1 = H
1b: R1 = Me
1c: R1 = Cl
1a: R1 = H
1a: R1 = H
1a: R1 = H
1a: R1 = H
1a: R1 = H
Alkyne
Product
3aa
Time/h
4
Yieldb [%]
86
2a: R2 = C6H5;
R3 = C6H5
2
2b: R2 = 4-MeC6H4;
R3 = 4-MeC6H4
2c: R2 = 4-MeOC6H4;
R3 = 4-MeOC6H4
2d: R2 = 4-BrC6H4;
R3 = 4-BrC6H4
2e: R2 = 4-MeC6H4;
R3 = C6H5
3ab
14
16
4
78
3
3ac
73
4
3ad
88
5
3ab + 3aa
3ac + 3aa
3ag + 3aa
3ad + 3aa
3ai + 3aa
3aj + 3aa
3ak + 3aa
3al + 3aa
3am + 3aa
3bn
10
12
16
5
80
6
2f: R2 = 4-MeOC6H4;
R3 = C6H5
76
7
2g: R2 = 4-(Me)2NC6H4;
R3 = C6H5
72
8
2h: R2 = 4-BrC6H4;
R3 = C6H5
87
9
2i: R2 = 4-FC6H4;
R3 = C6H5
4
90
10
11
12
13
14
15
16
17
18
19
20
2j: R2 = 4-CNC6H4;
R3 = C6H5
4
93
2k: R2 = 2-naphthyl;
R3 = C6H5
11
10
11
5
80
2l: R2 = 2-pyridyl;
R3 = C6H5
81
2m: R2 = thienyl;
R3 = C6H5
82
2n: R2 = C6H5;
R3 = C6H5
85
2o: R2 = C6H5;
R3 = C6H5
3co
5
83
2p: R2 = n-propyl;
R3 = C6H5
3ap + 3aa
3ap
18
16
4
71
2q: R2 = n-propyl;
R3 = n-propyl
2r: R2 = H;
69
3aq + 3aa
3aq + 3ab
3aj + 3aq
83
R3 = C6H5
2s: R2 = H;
8
81
R3 = 4-MeC6H4
2t: R2 = 4-CNC6H4;
R3 = H
2
92
a Reaction conditions: 1 (1 mmol), alkyne 2 (0.5 mmol), and PdCl2 (5 mol%) in PhCl (1 mL) at reflux. b Isolated yield of pure product based on 1,
and the ratio of products for the unsymmetrical alkynes was 1 : 1.
coordinated to the alkynes A to form a Pd-π-alkyne complex B, under the mild conditions, affording benzoxazoles in good to
and B reacted with o-aminophenol C to form intermediate D. excellent yields. This operationally simple method gives rapid
Secondly, the intermediate D reacted with another o-amino- access to the benzoxazoles. Air-tolerant characteristics and
phenol C to give intermediate E and liberated the Pd(0), which mild conditions of the method are in accord with the concept
was changed into Pd(II) by the oxidation in the air atmosphere. of modern green chemistry and will be appealing for indus-
Intermediate F could be obtained from E via the intramolecu- tries. Further investigation, including the scope, mechanism
lar cyclization. Finally, the desired products I and intermediate and synthetic applications of this reaction, is in progress in
G were obtained by the intramolecular electron transfer and our laboratory.
oxidation of intermediate F, and the desired products H were
obtained by intramolecular cyclization and oxidation of inter-
mediate G.
Experimental section
1H and 13C NMR spectra were measured on a Bruker Avance
In conclusion, we have demonstrated that the palladium-
catalyzed cleavage of C–C triple bonds in the presence of
o-aminophenol proceeded efficiently using PhCl as a solvent
400 MHz or 500 MHz NMR spectrometer with CDCl3 as a
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solvent and recorded in ppm relative to an internal tetra-
methylsilane standard. General chemicals were purchased
from commercial suppliers and used without further
purification.
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General experimental procedure for the synthesis of
benzoxazoles
The reaction mixture of o-aminophenol 1 (1 mmol), alkynes 2
(0.5 mmol), PdCl2 (5 mol%), and PhCl (1 mL) in a 10 mL flask
was stirred at reflux and monitored periodically by TLC. Upon
reaction completion, chlorobenzene was removed under
reduced pressure using an aspirator, and then the residue was
purified by flash chromatography (hexane–ethyl acetate) on
silica gel to afford benzoxazoles 3.
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Acknowledgements
This research was supported by the National Natural Science
Foundation of China (21362002, 41206077 and 81260472), the
Guangxi
Natural
Science
Foundation
of
China
(2012GXNSFAA053027 and 2011GXNSFD018010), the Guangxi
Scientific Research and Technology Development Program
(1355004-3) and the projects of Key Laboratory for the Chem-
istry and Molecular Engineering of Medicinal Resources
(Guangxi Normal University), Ministry of Education of China
(CMEMR2011-15, CMEMR2012-A and CMEMR2013-C01).
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