A highly efficient TBAF-promoted intramolecular cyclization of gem-dibromoolefins for the synthesis of 2-bromobenzofurans(thiophenes)

Article abstract of DOI:10.1039/c1cc13967c

A highly efficient tetra-(n-butyl)ammonium fluoride (TBAF)-promoted intramolecular cyclization of gem-dibromoolefins has been developed for the synthesis of 2-bromobenzofused heterocycles. The reaction provides a convenient approach to 2-bromobenzofurans(

Full text of DOI:10.1039/c1cc13967c

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COMMUNICATION
A highly efficient TBAF-promoted intramolecular cyclization of
gem-dibromoolefins for the synthesis of 2-bromobenzofurans(thiophenes)w
Wei Chen,a Yicheng Zhang,a Lei Zhang,a Min Wang*a and Lei Wang*ab
Received 3rd July 2011, Accepted 4th August 2011
DOI: 10.1039/c1cc13967c
A highly efficient tetra-(n-butyl)ammonium fluoride (TBAF)-
promoted intramolecular cyclization of gem-dibromoolefins has
been developed for the synthesis of 2-bromobenzofused hetero-
intramolecular cross-coupling reactions of 2-(gem-dibromovinyl)-
phenols(thiophenols) for the preparation of 2-bromobenzofurans-
(thiophenes), and Pd(OAc)2/P(t-Bu)3-catalyzed intramolecular
cross-coupling reactions of 2-(gem-dibromovinyl)anilines for the
synthesis of 2-bromoindoles.5b,9 It expanded the scope of the
versatility of gem-dihaloolefins and provided a new and practical
straightforward route to 2-halogenated benzofused heterocycles,
which are significant synthetic intermediates that can be used for
carbon–carbon and carbon–heteroatom bond formation via
transition-metal-catalyzed cross-coupling reactions.
cycles. The reaction provides
a convenient approach to
2-bromobenzofurans(thiophenes) from the corresponding readily
available gem-dibromovinyl substrates without a metal.
Halogenated organic compounds have been widely used as
important building blocks in organic synthesis, materials
science, and the chemical industry in view of their activity
and ease of derivatization.1 In particular, halogenated hetero-
cycles are of important value mainly due to their cross-
coupling reactions of carbon–halide bonds with various
nucleophiles for the formation of heteroaromatic derivatives
of interest in biology, pharmacology, optics, and electronics
fields.2 The synthesis of halogenated heterocycles is accom-
plished normally by the direct electrophilic halogenation of
heterocycles in the presence of a Lewis acid catalyst. However,
apart from the method involving hazardous, toxic, and corrosive
electrophilic halogen sources and catalysts which further limit
their applications in large-scale transformations for environ-
mental reasons, the conventional electrophilic halogenation
reactions typically provide 3-halogenated substrates for benzo-
fused five-membered heterocycles, such as benzofurans,
benzothiophenes, and indoles. Therefore, development of an
environmentally benign method with high selectivity for the
preparation of 2-halogenated benzofused heterocycles from
the readily available starting materials is highly desirable.
The versatility of gem-dihaloolefins, owing to higher reactivity
and easy accessibility from inexpensive aldehydes, has been
exploited,3 notably, as a key unit for the synthesis of various
heterocycles such as indoles,4 benzothiophenes,5 benzofurans,4i,5b,6
isocoumarins,7 and other heterocycles8 through transition-
metal-catalyzed tandem Ullman-type or Suzuki–Miyaura coupling/
amination, Suzuki, Sonogashira, Heck, or C–H activation. Most
recently, Lautens and co-workers elegantly utilized CuI-catalyzed
Herein, we wish to report a tetra-(n-butyl)ammonium
fluoride (TBAF)-promoted intramolecular cyclization of
gem-dibromoolefins for the synthesis of 2-bromobenzofused
heterocycles. The reactions generated 2-bromobenzofurans
and 2-bromobenzothiophenes from the corresponding readily
available gem-dibromovinyl substrates in high efficiency and
excellent selectivity under metal-free reaction conditions, which
can overcome the drawbacks of their expensive, poisonous,
and air-sensitive properties.10 In addition, this mild, operationally
simple methodology can also be readily extended to synthesis
of 2-chlorobenzofuran (Scheme 1).
In our attempt to prepare 2-(bromoethynyl)phenol from
2-(gem-dibromovinyl)phenol according to the elimination
reaction utilizing TBAFÁ3H2O reported in the literature,11
2-bromobenzofuran was obtained but no 2-(bromoethynyl)-
phenol was detected during our investigation. When a reaction
of 2-(gem-dibromovinyl)phenol was carried out in the presence
of TBAFÁ3H2O (1.0 equiv.) in THF at 45 1C for 4 h, to our
delight, 2-bromobenzofuran was obtained in 98% isolated
yield. This result aroused our great interest, because it not
only developed an alternative halogenation route to 2-bromo-
benzofurans, but also could be expanded to the synthesis of
2-bromobenzothiophenes. The biggest advantages of the reaction
are avoiding corrosive and irritant halogen sources used in the
reaction, as well as resolving the regio-selectivity of the general
electrophilic halogenation reactions, which in some cases
a Department of Chemistry, Huaibei Normal University, Huaibei,
Anhui 235000, P R China. E-mail: leiwang@chnu.edu.cn;
Fax: +86-561-309-0518; Tel: +86-561-380-2069
b State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P R China
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc13967c
Scheme 1
c
10476 Chem. Commun., 2011, 47, 10476–10478
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generate a mixture of mono- and multi-halogenated products
that are difficult to separate.
anion source. However, neither KF nor CsF as a fluoride anion
source promoted the model reaction very well and over 85% of
the starting material 1a was recovered (Table 1, entries 13 and 14).
With the combination of TBAC–CsF, TBAB–CsF, TBAI–CsF,
TBAÁOH–CsF, and TBAÁOAc–CsF in 1 : 1 molar ratios, 33–89%
yields of desired product 2a were obtained (Table 1, entries
15–19). It appears that both a soluble cation and an F anion
are important. With respect to the TBAF loading, 1 equiv. of
TBAF was found to be optimal. When less than 1 equiv. of
TBAF was used, the reaction did not proceed to completion. No
significant improvement of product yield was observed with more
than 1 equiv. of TBAF, which could enhance the reaction
(Table 1, entries 20–22). By changing different TBAF–CsF molar
ratios, such as TBAF–CsF (0.3 : 1 equiv.), TBAF–CsF (0.5 : 1
equiv.) and TBAF–CsF (1 : 1 equiv.), 50, 65 and 99% yields of 2a
were isolated, respectively (Table 1, entries 23–25). Thus, a
stoichiometric amount of TBAF is necessary in the reaction.
The choice of solvent was also important and different solvents
were examined for the intramolecular cyclization of 2-(gem-
dibromovinyl)phenol (1a). The results indicated that the cycliza-
tion of 1a in a polar aprotic solvent was generally better than that
in a non-polar aprotic solvent. However, the intramolecular
cyclization reaction did not occur in polar protic solvents such
as H2O, C2H5OH and n-C4H9OH. Because of the good solubility
of TBAF in THF, THF was chosen as the reaction medium for
the cyclization reaction (see ESIw for details). During the course
of our further optimization of the reaction conditions, the
reaction was completed in 4 h at 45 1C.
To establish the feasibility of our approach to 2-bromo-
benzofurans and 2-bromobenzothiophenes, a model conversion of
2-(gem-dibromovinyl)phenol (1a) into the corresponding
2-bromobenzofuran (2a) promoted by a variety of organic
and inorganic bases or additives under metal-free reaction
conditions was explored. As listed in Table 1, a base is
essential for the model reaction and TBAF is the best one
among the examined bases. Either the commercially available
solid TBAFÁ3H2O or TBAF solution in THF (commercially
available as a 1.0 M solution in THF, also containing approxi-
mately 5% water) was an effective promoter in the model
reaction. It also indicated that the presence of water in TBAF
had little effect on the reaction (Table 1, entries 1 and 2). When
other organic or inorganic bases, such as K3PO4, K2CO3,
tBuOLi, Et3N, or pyridine, were used instead of TBAF in the
xmodel reaction, no desired product 2a was isolated (Table 1,
entries 3–7). However, the analogues of TBAF, tetra-(n-butyl)-
ammonium chloride (TBAC), tetra-(n-butyl)ammonium bromide
(TBAB), tetra-(n-butyl)ammonium iodide (TBAI), tetra-(n-butyl)-
ammonium hydroxide (TBAH), and tetra-(n-butyl)ammonium
acetate (TBAÁOAc) were ineffective promoters in the reaction
(Table 1, entries 8–12). It is reasonable to speculate that a fluoride
anion is an efficacious basic activator for the intramolecular
cyclization of 1a because TBAF is a good candidate for a fluoride
Table 1 The effect of a base or an additive on the intramolecular
cyclization of 2-(gem-dibromovinyl)phenol (1a)a
Having established our approach for the preparation of 2a, we
decided to investigate the reaction scope under the optimized
reaction conditions, which involved 1.0 equiv. of TBAF in THF
at 45 1C for 4 h. A variety of 2-(gem-dibromovinyl)phenols
bearing substituents on the benzene rings were examined and the
results are summarized in Table 2. As shown in Table 2, a variety
of functional groups, including electron-donating and electron-
withdrawing ones, were tolerated under the present mild reaction
conditions, and provided the desired cyclization products in
nearly quantitative yields. Halogen substituents, either Cl or
Br, as well as either mono-halogen or di-halogens on the benzene
rings underwent the clean conversions and afforded very high
yields of the corresponding di- or multi-halogenated benzofurans
2b–g (Table 2), which are the potentially versatile building blocks
in organic synthesis and can provide the opportunities for further
transformation through transition metal-catalyzed cross-coupling
reactions with various nucleophiles. 2-(gem-Dibromovinyl)-
phenol with a strong electron-withdrawing functionality, such
as NO2, on the phenol gave a superior product (2h) yield to
that of 2i and 2j, with a strong electron-donating group, such as
OCH3 on the phenols (Table 2). Meanwhile, a little ortho-position
effect has been observed in the reaction (2i vs. 2j). Under the
recommended reaction conditions, 1-(gem-dibromovinyl)-2-
naphthalenol also underwent the intramolecular cyclization
well to generate the corresponding product 2k in 92% yield. It
is important to note that even the sterically hindered substituted
2-(gem-dibromovinyl)phenol (1l) also gave the corresponding
product 2l in 91% isolated yield. Notably, 2-(gem-dichlorovinyl)-
phenol (1m) also could proceed the intramolecular
cyclization to generate the corresponding 2-chlorobenzofuran
(2m) in good yield under the present reaction conditions.
Yieldb
(%)
Entry Base or additive
1
tetra-Butylammonium fluoride (TBAF)Á3H2O (1 equiv.) 98
99
2
3
4
5
6
7
TBAFÁTHF (1 equiv.)
K3PO4 (1 equiv.)
K2CO3 (1 equiv.)
N.R.
N.R.
N.R.
N.R.
N.R.
Trace
Trace
Trace
Trace
Trace
8
12
89
82
65
46
33
tBuOLi (1 equiv.)
Et3N (1 equiv.)
Pyridine (1 equiv.)
8
9
tetra-Butylammonium chloride (TBAC) (1 equiv.)
tetra-Butylammonium bromide (TBAB) (1 equiv.)
tetra-Butylammonium iodide (TBAI) (1 equiv.)
tetra-Butylammonium hydroxide (TBAH) (1 equiv.)
tetra-Butylammonium acetate (TBAÁOAc) (1 equiv.)
KF (1 equiv.)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
CsF (1 equiv.)
TBACÀCsF (1 : 1 equiv.)
TBABÀCsF (1 : 1 equiv.)
TBAIÀCsF (1 : 1 equiv.)
TBAÁOHÀCsF (1 : 1 equiv.)
TBAÁOAcÀCsF (1 : 1 equiv.)
TBAF (0.75 equiv.)
78
58
TBAF (0.5 equiv.)
TBAF (2.0 equiv.)
TBAFÀCsF (0.3 : 1 equiv.)
TBAFÀCsF (0.5 : 1 equiv.)
TBAFÀCsF (1 : 1 equiv.)
99c
50
65
99
a
Reaction conditions: 2-(gem-dibromovinyl)phenol (1a, 1.0 mmol), a
base or an additive (amount indicated in parentheses), THF (2.0 mL)
b
c
at 45 1C for 4 h. Isolated yield. At room temperature for 4 h.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10476–10478 10477

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Table
2
Synthesis of 2-bromo(chloro)benzofurans(thiophenes)
Suzuki and Sonogashira reaction conditions,4d,6 respectively (see
ESIw for details).
through TBAF-promoted intramolecular cyclization of 1a
In conclusion, we have developed a highly efficient TBAF-
promoted intramolecular cyclization of gem-dibromoolefins for
the synthesis of 2-bromobenzofused heterocycles. The reactions
generated 2-bromobenzofurans and 2-bromobenzothiophenes
from the corresponding readily available gem-dibromovinyl
substrates in nearly quantitative yields. In addition, this mild,
operationally simple methodology can also be readily extended
to synthesis of 2-chlorobenzofuran. The present method has
advantages of availability of reagents, broad substrate scope,
operational simplicity, mild reaction conditions, high regio-
selectivity, excellent yields of the products, and metal-free
reaction conditions. The detailed mechanistic study and
further investigation on metal-free reactions is currently
underway.
This work was financially supported by the National
Science Foundation of China (No. 20972057).
Notes and references
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a
Reaction conditions: 1 (1.0 mmol), TBAF (1.0 mmol), THF (2.0 mL)
at 45 1C for 4 h.bIsolated yields.
To demonstrate the general applicability of the reaction system
for synthesis of 2-halogenated benzofurans, we would like to
extend this methodology to synthesize 2-bromobenzothiophenes
and 2-bromoindoles. As anticipated, the intramolecular
cyclizations of 2-(gem-dibromovinyl)thiophenol (1n) and substituted
2-(gem-dibromovinyl)thiophenols, such as 1o, 1p and 1q,
proceeded very well to give the corresponding products, with
2-bromobenzothiophene (2n), 2o, 2p and 2q, in 90–93% yields
under the present reaction conditions (Table 2). It was obvious
that the electronic and steric effect of substituted groups on
benzene rings had little impact on the yields of the products. It
also provides an alternative route to 2-bromobenzothiophenes
using commercially available materials in a simple metal-free
protocol. However, the present reaction conditions were not
suitable for the synthesis of 2-bromoindoles from the
corresponding 2-(gem-dibromovinyl)aniline, 2-(gem-dibromo-
vinyl)-N-acetylaniline, 2-(gem-dibromovinyl)-N-trifluoroacety-
laniline and 2-(gem-dibromovinyl)-N-Boc-aniline.
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The prepared 2-bromobenzofuran (2a) was then reacted
with phenylboronic acid and phenylacetylene to generate the
corresponding cross-coupling products in high yields under the
c
10478 Chem. Commun., 2011, 47, 10476–10478
This journal is The Royal Society of Chemistry 2011