Sequential and one-pot reactions of phenols with bromoalkynes for the synthesis of (Z)-2-bromovinyl phenyl ethers and benzo[ b ]furans

Article abstract of DOI:10.1021/ol202383z

Benzo[b]furans were prepared in one pot based on the addition/palladium- catalyzed C-H bond functionalization of phenols with bromoalkynes. The addition reactions of phenols to bromoalkynes generated (Z)-2-bromovinyl phenyl ethers in high yields with excellent regio- and stereoselectivity. The obtained (Z)-2-bromovinyl phenyl ethers subsequently proceeded by intramolecular cyclization to afford 2-substituted benzo[b]furans in good yields through palladium-catalyzed direct C-H bond functionalizations. It is important to note that the transformation of phenols with bromoalkynes into benzo[b]furans could be carried out in one pot with a simple and efficient tandem procedure.

Full text of DOI:10.1021/ol202383z

ORGANIC
LETTERS
2011
Vol. 13, No. 22
5968–5971
Sequential and One-Pot Reactions of
Phenols with Bromoalkynes for the
Synthesis of (Z)-2-Bromovinyl Phenyl
Ethers and Benzo[b]furans
Shihua Wang, Pinhua Li, Lin Yu, and Lei Wang*
Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P. R. China
leiwang@chnu.edu.cn
Received September 3, 2011
ABSTRACT
Benzo[b]furans were prepared in one pot based on the addition/palladium-catalyzed CÀH bond functionalization of phenols with bromoalkynes.
The addition reactions of phenols to bromoalkynes generated (Z)-2-bromovinyl phenyl ethers in high yields with excellent regio- and
stereoselectivity. The obtained (Z)-2-bromovinyl phenyl ethers subsequently proceeded by intramolecular cyclization to afford 2-substituted
benzo[b]furans in good yields through palladium-catalyzed direct CÀH bond functionalizations. It is important to note that the transformation of
phenols with bromoalkynes into benzo[b]furans could be carried out in one pot with a simple and efficient tandem procedure.
Benzo[b]furans, which display a wide range of biological
activities, are versatile synthetic blocks and important
structural skeletons of natural products and potential drug
molecules.1 For their potential applications, the develop-
ment of a convenient synthetic pathway is highly desirable.
Among the traditional methods for the synthesis of benzo-
[b]furans, palladium-catalyzed tandem Sonagashira cou-
pling/5-endo-dig cyclization starting from alkynes and
o-halophenols is the most efficient protocol.2 And it offers
increased functional group tolerance and improved yields
of the desired compounds, but the scope of o-halophenols
is limited. However, simple phenols without halogen and
simple alkynes have rarely been used as starting material to
directly prepare them.3 Recently, an iron-catalyzed oxida-
tive Pechmann condensation reaction of simple phenols
with β-ketoesters to benzo[b]furans was developed in the
presence of an oxidant.4
Bromoalkynes, easily prepared from terminal alkynes
with NBS in almost quantitative yields, are one kind of the
mostimportant intermediatesandversatilebuildingblocks
in organic synthesis.5 For example, they are widely used as
one of the coupling partners in transition-metal-catalyzed
carbonÀcarbon and carbonÀheteroatom bond forma-
tions via cross-coupling reactions.6 Meanwhile, transi-
tion-metal-catalyzed C(sp)ÀBr bonds of bromoalkynes
were inserted into unsaturated compounds and C(sp3)ÀX
bonds have been explored recently.7 On the other hand, a
silver-catalyzed nucleophilic addition of an acetic anion to
bromoalkynes and a nucleophilic addition of an iodide
anion to bromoalkynes were developed by Jiang in 2010.8
(1) For recent reviews, see: (a) Patil, N. T.; Yamamoto, Y. Chem.
Rev. 2008, 108, 3395. (b) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106,
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D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893.
(2) For representative examples, see: (a) Anderson, K. W.; Ikawa, T.;
Tundel, R. E.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 10694. (b)
(3) For palladium-catalyzed synthesis of benzo[b]furans from phe-
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Chem. 2011, 76, 4692. (b) For Zn(OTf)2-catalyzed synthesis of benzo-
[b]furans from phenols with proparyl alcohols, see: Kumar, M. P.; Liu,
R.-S. J. Org. Chem. 2006, 71, 4951.
(4) Guo, X.; Yu, R.; Li, H.; Li, Z. J. Am. Chem. Soc. 2009, 131, 17387.
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€
Furstner, A.; Davies, P. W. J. Am. Chem. Soc. 2005, 127, 15024. (c)
Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. Am. Chem. Soc. 2005,
127, 15022. (d) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70,
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^
A.; Neuville, L.; Genet, J.-P. Adv. Synth. Catal. 2004, 346, 1733.
r
10.1021/ol202383z
Published on Web 10/18/2011
2011 American Chemical Society

The reported nucleophilic additions and transition-metal-
catalyzed bond formation reactions encouraged us to
explore the novel reactions on the basis of bromoalkynes.
Herein, we report a base-promoted addition reaction of
phenols to bromoalkynes under metal-free reaction con-
ditions, which generated (Z)-2-bromovinyl phenyl ethers
in high yields with excellent regio- and stereoselectivity.
The obtained (Z)-2-bromovinyl phenyl ethers proceeded
by intramolecular cyclization to afford the corresponding
2-substituted benzo[b]furans in good yields via palladium-
catalyzed direct CÀH bond functionalizations.9 It is im-
portant to note that the transformation of phenols with
bromoalkynes into benzo[b]furans could be carried out in
one pot with a simple and efficient tandem procedure.
In the initial exploration of the addition reaction of
simple phenols to bromoalkynes, 4-nitrophenol (1a) and
phenylethynyl bromide (2a) were chosen as model sub-
strates for our investigation. The effect of base on the
model reaction was examined. To our delight, the model
reaction proceeded smoothly and generated the corre-
sponding addition product 3a in 92 and 94% yields, when
2 equiv of K2CO3 and Cs2CO3 were used as bases in DMF
at 110 °C for 12 h (Supporting Information, Table S1). It
was found that other bases such as LiOtBu, K3PO4,
KOtBu, KOH, Na2CO3, KHCO3, and KF were inferior
and generated the desired product 3a in 18À73% yields.
Only a trace amount of 3a was detected when KOAc was
used as a base. Unfortunately, organic bases such as Et3N
and DBU failed to promote the reaction. With respect to
the base loading, 2 equiv of K2CO3 or Cs2CO3 were found
to be optimal. When the model reaction was carried out in
the presence of Cs2CO3, a significant solvent effect was
observed. Among the solvents tested, DMF was found to
bethebestone. Good yields(71À80%) of3awereobtained
when DMSO, DMA, and NMP were used as solvents
respectively. However, when the reaction was carried out
in CH3CN, a 42% yield of 3a was isolated. Only a trace
amount of 3a was detected when the reaction was carried
Table 1. Addition Reaction of Phenols to Bromoalkynes, and
Intramolecular Cyclization of (Z)-2-Bromovinyl Phenyl Ethersa
3, yield
4, yield
entry
R1
p-NO2
R2
[%]b
[%]b
1
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
3a, 94
3b, 92
3c, 89
3d, 88
3e, 78
3f, 73
3g, 75
3h, 71
3i, 83
3j, 81
3k, 78
3l, 94
4a, 92
4b, 91
4c, 89
4d, 87
4e, 86
4f, 85
4g, 81
4h, 83
4i, 82
4j, 82
4k, 85
4l, 90
2
p-CN
3
p-CHO
p-CO2(n-C4H9)
H
4
5
6
m-CH3
p-CH3
7
8
p-CH3O
o-C6H5
p-NO2
p-NO2
p-NO2
9
10
11
12
p-FC6H4
p-ClC6H4
p-(t-C4H9)C6H4
a Reaction conditions: step 1: phenol (1.1 mmol), bromoalkyne (1.0
mmol), DMF (2.0 mL), Cs2CO3 (2.0 mmol) at 110 °C, 12 h; step 2: (Z)-2-
bromovinyl phenyl ether (3, 1.0 mmol), PdCl2 (0.05 mol), DMF (2.0
mL), K2CO3 (2.0 mmol) at 130 °C, 6 h. b Isolated yields.
out in THF, EtOH, DCE, dioxane, 1,2-dimethoxyethane,
chlorobenzene, toluene, or benzene.
Under the above metal-free reaction conditions, a vari-
ety of substituted phenols reacted smoothly with pheny-
lethynyl bromide (2a) to generate the corresponding
addition products in good yields (Table 1, 3aÀi) with
excellent regio- and stereoselectivity. As can be seen from
Table 1, the reactivity of the phenol with an electron-
withdrawing group, such as NO2, CN, CHO, or CO2(n-
C4H9) at the para-position, is more than that of the phenol
without a substituted group and with an electron-donating
group at the para- or meta-position (Table 1, 3aÀd vs
3eÀh). The ortho-position effect of phenol was not ob-
served in the reaction of 2-phenylphenol with 2a, which
generated 3i in 83% yield. The reactions of 4-nitrophenol
with (4-fluorophenyl)-, (4-chlorophenyl)-, and (4-tert-
butylphenyl)ethynyl bromides proceeded well and gener-
ated the corresponding products 3jÀl in good yields.
With prepared addition products (Z)-2-bromovinyl
phenyl ethers 3aÀl in our hands, we then examined the
second step: transforming 3aÀl into the corresponding
2-substituted benzo[b]furans using palladium-catalyzed
direct CÀH bond functionalization. First, the effect of a
palladium source on the cyclization reaction of model
substrate 3a was examined in the presence of K2CO3 at
130 °C in DMF. The results indicated that the model
reaction could be catalyzed by PdII salts or Pd0 complexes
and PdCl2 displayed the highest reactivity in the model
reaction and generated 5-nitro-2-phenylbenzofuran (4a) in
92% yield (Supporting Information, Table S2). When
another palladium source, such as Pd(OAc)2, Pd(CH3CN)2-
Cl2, Pd(PPh3)2Cl2, or Pd(PPh3)4, was used instead of
PdCl2, 65À89% yields of 4a were obtained. The base also
ꢀ
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Org. Lett., Vol. 13, No. 22, 2011
5969

plays an important role in the cyclization reaction.
K2CO3 was found to be the best one among the bases
investigated. Other bases such as K3PO4, KOtBu,
Cs2CO3, and Na2CO3 were inferior and generated 4a in
16À76% yields. Only a trace amount of 4a was detected
when KOAc or DBU was used as a base. The effect of
solvent on the model reaction was also examined, and a
significant solvent effect was observed. When the model
reaction was carried out in the presence of PdCl2 (5.0mol %)
and K2CO3, DMF was the most suitable reaction
medium. A 51% yield of 4a was isolated when the
reaction was carried out in DMA. However, only a trace
amount of 4a was detected when the reaction was per-
formed in DMSO, NMP, THF, CH3CN, toluene, ben-
zene, or 1,2-dichloroethane.
Scheme 1. Palladium-Catalyzed One-Pot Synthesis of Benzo-
[b]furansa
Under the optimization reaction conditions, the above
prepared addition products (Z)-2-bromovinyl phenyl
ethers 3aÀl proceeded through a palladium-catalyzed in-
tramolecular cyclization smoothly via the direct CÀH
bond functionalization to generate the corresponding
2-substituted benzo[b]furans, 4aÀl. As can be seen from
Table 1, substrates derived from phenylethynyl bromide
and substituted phenols with either electron-donating or-
withdrawing groups attached to the benzene rings were
able to undergo an intramolecular cyclization reaction and
generate the corresponding products 4aÀi in 81À92%
yields. It should be noted that the palladium-catalyzed
intramolecular cyclization reaction of (Z)-2-bromovinyl
phenyl ether could tolerate an ortho-substituted group (4i).
When substrates derived from 4-nitrophenol and substi-
tuted phenylethynyl bromide were also surveyed, 82À90%
yields of 4jÀl were obtained. The results also showed that
the electronic effect of phenylethynyl bromide substituents
on the benzene rings had little impact on the yields of the
products.
With the above addition reaction of simple phenols with
bromoalkynes in the presence of K2CO3 generating (Z)-2-
bromovinyl phenyl ethers in high yields, and the obtained
(Z)-2-bromovinyl phenyl ethers undergoing palladium-
catalyzed intramolecular cyclization to the corresponding
2-substitutedbenzo[b]furans in good yields inour hand, we
next tried the reaction of simple phenols with bromoalk-
ynes in the presence of a base and palladium catalyst in one
pot because the transformation in one pot can simplify the
sequence procedures and enhance the reaction efficiency.
When the model reaction of 1a with 2a was carried out in
the presence of K2CO3 (2.0 equiv) in DMF at 110 °C for
12 h, then PdCl2 (5.0 mol %) was added, and the reaction was
performed at 130 °C for 6 h. To our pleasure, the final
product 4a was isolated in 91% yield (Scheme 1, 4a).
Compared with the above two-step procedure synthesis,
this tandem reaction in one pot could enhance the effi-
ciency of preparing the target products from simple start-
ing materials, avoid the separation of intermediates, save
the use of solvents, and reduce the amount of pollutant
waste emission. To examine the generality of this one-pot
reaction, a variety of simple phenols and bromoalkynes
were used as starting materials for the investigation. As can
be seen from Scheme 1, the reactivity of the phenols with
a Reaction conditions: phenol (1.1 mmol), bromoalkyne (1.0 mmol),
DMF (2.0 mL), K2CO3 (2.0 mmol) at 110 °C for 12 h; then PdCl2 (0.05
mmol) was added, at 130 °C for 6 h. bIsolated yields.
the electron-withdrawing groups at para-positions, such as
NO2, CN, CHO, COPh, and CO2R groups, is more than
that of the phenols with the electron-donating groups at
para- or meta-positions (Scheme 1, 4aÀd and 4pÀs vs
4fÀh). The one-pot reaction also tolerated the ortho-sub-
stituted phenols with phenylethynyl bromide and gener-
ated the corresponding 4i, 4n, 4o, 4t, and 4u in moderate to
good yields under the present reaction conditions. When
both ortho- and meta-positions of phenol were occupied
by a methyl group, a 54% yield of the product 4u was
obtained. It should be noted that the cyclization products
of 3-substituted phenols with phenylethynyl bromide were
6-substituted-2-phenylbenzofurans (4f and 4m). When the
reactions of 4-nitrophenol (1a) with substituted phenyleth-
ynyl bromides, such as (4-fluorophenyl)-, (4-chlorophenyl)-,
(4-methylphenyl)-, and (4-tert-butylphenyl)ethynyl bromides,
were carried out in one pot, the corresponding products
wereobtainedin70À90% yields (Scheme 1, 4jÀl and 4v). It
is important to note that about 40% yields of the desired
products (4w and 4x) were obtained when aliphatic
alkyne bromides were used as one of the substrates.
The reaction was also extended to iodoalkyne with
phenol. The addition of 4-nitrophenol to phenylethynyl
iodide was clean, and an 88% yield of (Z)-2-iodovinyl phenyl
ether was isolated (Supporting Information, Scheme S1).
The one-pot reaction of 4-nitrophenol and phenylethynyl
5970
Org. Lett., Vol. 13, No. 22, 2011

iodide also proceeded efficiently to generate 4a in 80%
yield.
3a reacted with Pd0 from its precursor PdCl2 to form an
intermediate A via oxidative addition. Subsequently, A
underwent an intramolecular electrophilic aromatic palla-
dation of A, through CÀH activation of the aromatic
hydrogen, and subsequent proton abstraction,13 forming
an intermediate B, which followed by a reductive elimina-
tion to afford benzo[b]furan (4a) via the carbonÀcarbon
bond formationand regenerate Pd0 for its catalytic cycle. It
should be noted that the conversion yields of 3aÀi to 4aÀi
in Table 1 are in agreement with the electronic effect of
substituted groups on the benzene rings in the insertion of
Pd(II) to ArÀH.
The prepared (Z)-2-bromovinyl phenyl ether (3a), with
the bromine functional group on the terminal carbonÀ
carbon double bond, as a very useful intermediate in
organic synthesis,7b,10 then reacted with p-tolylboronic
acid, p-(tert-butyl)phenylacetylene, and p-(tert-butyl)-
phenol under Suzuki, Sonogashira, and Ullmann reaction
conditions,11 and the corresponding cross-coupling pro-
ducts were isolated in 82À96% yields (Supporting Infor-
mation, Scheme S2). The obtained products are the key
frameworks for the preparation of a variety of target
compounds with applications ranging from natural pro-
ducts and pharmaceuticals to organic materials.12
In conclusion, we have developed a novel and efficient
protocol for the synthesis of benzo[b]furans from simple
phenols and alkynyl bromides. The reactions could be
carried out in sequential and one-pot reactions of phenols
with bromoalkynes on the basis of addition/palladium-
catalyzed CÀH bond functionalization. The addition
reactions of phenols to bromoalkynes generated (Z)-2-
bromovinyl phenyl ethers in high yields with excellent
regio- and stereoselectivity. The obtained (Z)-2-bromovinyl
phenyl ethers proceeded by intramolecular cyclization to
afford benzo[b]furans in good yields through palladium-
catalyzed direct CÀH bond functionalizations. It is im-
portant to note that the transformation of phenols with
bromoalkynes into benzo[b]furans could be carried out in
one pot with a simple and efficient tandem procedure. The
method provides an efficient, wide scope and attractive
alternative to Sonagashira coupling/5-endo-dig cycliza-
tion, which requires the use of ortho-halogen-substituted
phenols.
Scheme 2. Proposed Reaction Mechanism
Acknowledgment. This work was financially supported
by the National Science Foundation of China.
The reaction occurs probably involving an intermolecu-
lar addition reaction of phenol to bromoalkyne, affording
(Z)-2-bromovinyl phenyl ether, and an intramolecular cycli-
zation of (Z)-2-bromovinyl phenyl ether through CÀH acti-
vation, affording 2-substituted benzo[b]furans (Scheme 2).
First, the intermolecular nucleophilic addition of 4-nitro-
phenol (1a) to phenylethynyl bromide (2a) in the presence
of K2CO3 generated (Z)-2-bromovinyl phenyl ether (3a)
with excellent regio- and stereoselectivity.11b The obtained
Supporting Information Available. Analytical data and
spectra (1H and 13C NMR) for all the products; typical
procedure, Table S1, Table S2, Scheme S1, and Scheme
S2. This material is available free of charge via the
Internet at http://pubs.acs.org.
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