A novel efficient protocol for preparation of 3-formyl-2-arylbenzo[b]furan derivatives

Article abstract of DOI:10.1016/j.tetlet.2014.04.050

An efficient method for preparation of 3-formyl-2-arylbenzo[b]furan derivatives 4 from 3-chloro-2-(2-methoxyaryl)-1-arylprop-2-en-1-one 2 was developed, and the desired product was obtained in good to excellent yields. By converting 2-(2-methoxyphenyl)-3-oxo-3-phenylpropanal 1 to 2, the regioselectivity problem occurring in the reaction when using 1 as the starting material was successfully avoided. Furthermore, a one-pot procedure for the successive demethylation, cyclization, and hydrolysis was evolved, although the intermediate 3-(dibromomethyl)-2-phenylbenzo[b]furan 3a could be isolated. A plausible mechanism was proposed based on some in situ investigations.

Full text of DOI:10.1016/j.tetlet.2014.04.050

Accepted Manuscript
A novel efficient protocol for preparation of 3-formyl-2-arylbenzo[b]furan de-
rivatives
Benren Liao, Libo Ruan, Min Shi, Nian Li, Liang Chang, Leping Liu, Fan Yang,
Jie Tang
PII:
S0040-4039(14)00662-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.050
TETL 44512
Reference:
Tetrahedron Letters
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17 February 2014
8 April 2014
15 April 2014
Please cite this article as: Liao, B., Ruan, L., Shi, M., Li, N., Chang, L., Liu, L., Yang, F., Tang, J., A novel efficient
protocol for preparation of 3-formyl-2-arylbenzo[b]furan derivatives, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.04.050
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A novel efficient protocol for
preparation of 3-formyl-2-
arylbenzo[b]furan derivatives
Benren Liao, Libo Ruan, Min Shi, Nian Li, Liang Chang, Leping Liu, Fan Yang, Jie Tang

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A novel efficient protocol for preparation of 3-formyl-2-arylbenzo[b]furan derivatives
Benren Liao¶, Libo Ruan¶, Min Shi, Nian Li, Liang Chang, Leping Liu, Fan Yang*, Jie Tang
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, Shanghai 200062, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient method for preparation of 3-formyl-2-arylbenzo[b]furan derivatives 4 from 3-
chloro-2-(2-methoxyaryl)-1-arylprop-2-en-1-one 2 was developed, and the desired product were
obtained in good to excellent yields. By converting 2-(2-methoxyphenyl)-3-oxo-3-
phenylpropanal 1 to 2, the regioselectivity problem occurred in the reaction when using 1 as the
Available online
starting material was successfully avoided. Furthermore, a one-pot procedure for the
successively demethylation, cyclization and hydrolysis was evolved, although the intermediate
3-(dibromomethyl)-2-phenylbenzo[b]furan 3a could be isolated. A plausible mechanism was
proposed based on some in situ investigations.
Keywords:
3-formyl-2-arylbenzo[b]furan
vinyl chloride
demethylation reaction
cyclization reaction
2014 Elsevier Ltd. All rights reserved.
The 3-formyl-2-arylbenzo[b]furan scaffold widely presented
in unnatural products, such as XH-14,1 Puerariafuran,2
Ebenfurans3 which showed interesting biological activities.4 In
addition, 3-formyl-2-arylbenzo[b]furan derivatives are key
precursors in preparation of natural products, such as vibsanol,5
(±)-Rocaglamide,6 and many pharmacologically active
compounds.7 Therefore, 3-formyl-2-arylbenzo[b]furan scaffold
has been served as a versatile building block via a variety of
chemical transformations. 8,7b,9
method.7 Other methods include Pd(0)-catalyzed cross-coupling
of 1-benzofuran-3-carbaldehyde with aryl iodide,10 oxidation of
3-(-alkoxyalkyl)benzofurans with DDQ,5,11 selective oxidation
of the hydroxy group at the 3-position with manganese oxide,12
oxidative cleavage of 3-vinyl benzofuran,6 and oxidation of the
trimethylsilylethyl ether at 3-position, constructed from a PtCl2-
catalyzed cycloisomerization reaction, with (NH4)2Ce(NO3)6/
CH3CN.8 However, most of them suffered from drawbacks such
as expensive metal catalysts, toxic reagents, analogues synthesis
difficulties and low yields as well, significantly limiting their
applications as practical protocols. Therefore, the development of
practical synthetic diversity-oriented methods for 3-formyl-2-
arylbenzofurans are still of great necessary. Based on the
previous work in our group,13 we attempted to conduct
demethylation of 2-(2-methoxyphenyl)-3-oxo-3-phenylpropanal
(1a), readily prepared from the rearrangement of the
corresponding chalcone epoxide by standard literature
procedures,14,15 and then carry out cyclization of the generated
intermediate in the presence of BBr3 to afford 3-formyl-2-
arylbenzo[b]furan. To our satisfaction, the results showed that the
desired cycloisomerization products, 2-phenylbenzo[b]furan-3-
carboxaldehyde (A, 45% yield determined by 1H NMR analysis)
along with its regioisomer 3-benzofuranphenylmethanone (B,
32% yield determined by 1H NMR analysis), were obtained
under the mild conditions (Scheme 1). However, they were very
difficult to separate by silica gel chromatography due to their
similar polarities. Nevertheless, we envisioned that the
regioselectivity problem could be avoided if the starting material
1a was previously transformed to an aldehyde precursor.
Therefore, we prepared 3-chloro-2-(2-methoxyphenyl)-1-
Figure 1. 3-Formyl-2-arylbenzo[b]furan
scaffold presented in natural products.
Due to the importance of this class of molecules, synthetic
access to 3-formyl-2-arylbenzofuran attracts considerable
interests. Over the past decade, several routes for constructing 3-
formyl-2-arylbenzofuran cores have been exhibited in literature,
and the direct formylation of 2-phenylbenzofuran into 3-formyl-
2—-a—rylb—enzofuran derivatives appears to be the most popular
 Corresponding author. Tel.: +86-21-62232764; E-mail: fyang@chem.ecnu.edu.cn; jtang@chem.ecnu.edu.cn
¶These authors contributed equally to this work.

2
Tetrahedron Letters
phenylprop-2-en-1-one (2a) from 1a according to the synthetic
still isolated in as high as 96%. However, partial of the starting
material (2a) remained unchange when 1.0 equivalent of BBr3
was employed in the reaction. Hence, 1.2 equivalents of BBr3
were chosen as the optimal amount for the demethylation
reaction.
method in literature.16 When 2a was treated with 2 equivalents of
BBr3 in DCM, product 3a was obtained in 96% yield. It is well
known that gem-dihalo compounds are widely used as starting
material for preparation of aldehydes.17,18 Actually, treatment of
3a under certain reaction conditions afforded the desired product
4a in excellent yield and the regioselectivity problem was
completely prevented. Herein, we reported this efficient method
for preparation of 3-formyl-2-arylbenzo[b]furans starting from 3-
chloro-2-(2-methoxyaryl)-1-arylprop-2-en-1-one.
With the optimal conditions in hand, the substrate scope was
then examined. As shown in Table 2, 3-formyl-2-arylbenzofuran
derivatives were obtained in good yields for most cases. There
was no significant difference in reactivity between 2-(2-
methoxyphenyl)-3-oxo-3-phenylpropanal (Table 2, entry 1) and
its derivatives containing electron-donating groups (Table 2,
entries 2 and 10) or electron-withdrawing groups (Table 2,
entries 3-9). It was noteworthy that when Ar2 was altered with
heterocyclic groups (Table 2, entry 11), the corresponding
heteroaromatic products 4k was also obtained in excellent yield
(92%). For substrate 2j, a methoxy group substituted at the para
position, product 4j with the p-methoxy group was given when
1.2 equivalents of BBr3 was presented, whereas the demethylated
product 4l was observed in 80% yield when 3 equivalents of
BBr3 was used(Table 2, entry 11).
Scheme 1. Direct demethylation and cyclization of 1a.
The reaction conditions for converting the gem-dibromide 3a
into the corresponding aldehyde were firstly screened (Table 1).
It was sluggish and the product was obtained in low yields while
the reaction was carried out with 20% acetic acid (Table 1, entry
1), 20% sulfuric acid (Table 1, entry 2) or saturated sodium
carbonate solution (Table 1, entry 3) in THF, and the conversion
was incomplete during the giving reaction time. While treatment
of 3a with DMSO18 at 60 °C for 0.5 h, 4a was afforded in 100%
conversion and 96% isolated yield (Table 1, entry 5). Although
Table 2
Conversion of 3-chloro-2-(2-methoxyaryl)-1-arylprop-2-en-1-one
to 3-formyl-2-arylbenzo[b]furansa
19
AgNO3 was a competent reagent for this reaction (Table 1,
entry 4), from the standpoint of overall cost and workup
difficulty, DMSO was chosen as the reagent and solvent as well
in this reaction. By further simplifying the procedure, we tried to
perform the demethylation, cyclization and hydrolysis
successively in one pot without isolating the intermediate 3-
(dibromomethyl)-2-phenylbenzo[b]furan 3a, and the result was
satisfactory, affording the desired product 4a in 92% yield
(Scheme 2). To the best of our knowledge, it should be a new
practical protocol for synthesis of this scaffold.
Entry
1
Substrate
Product
Yield (%)b
92
4a
4b
4c
2a
2b
2c
2
3
90
93
Table 1
Optimization of reaction conditions for converting 3a to 4aa
4
5
6
93
95
89
4d
4e
4f
2d
2e
Time
(h)
Temperature
(°C)
Yield
(%)b
Entry
1
Conditions
5 mL 2N AcOH/ 5
mLTHF
5 mL20 % H2SO4/ 5
mLTHF
5 mL Na2CO3/ 5mLTHF
2 eq. AgNO3/ 5mL
EtOH
4
66
44
2
3
4
5
4
4
66
66
66
60
60
32
90
96
1
2 mL DMSO
0.5
2f
2g
2h
a. All reactions were carried out at 1 mmol scale.
b Isolated yield.
7
8
88
91
4g
4h
Scheme 2. Synthesis of 3-formyl-2-phenylbenzo[b]furan from 2a in
one pot.
9
94
To optimize the demethylation and cyclization reaction
conditions, the amount of BBr3 was investigated. Reducing the
usage of BBr3 from 2 to 1.5 equivalents and further to 1.2
equivalents didn’t affect the yield of the product (3a) which was
4i
2i

3
Acknowledgments
10
11
86
92
This research was supported by Shanghai Science and
Technology Council (No. 12142200800 and 13142200900). We
also thank ―Laboratory of Organic Functional Molecules and The
SINO-FRENCH INSTITUTE OF ECNU‖ for support.
4j
2j
2k
2l
4k
References and notes
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12c
80
4l
a All reactions were run under the same conditions: 1 mmol of start material
was dissolved in 10 mL of CH2Cl2, BBr3 (1 M in CH2Cl2, 1.2 mL, 1.2 mmol)
was added dropwise, the mixture was stirred at 0 °C. After the reaction was
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b Isolated yield.
c 3 equivalents of BBr3 was used, reaction time 5 h.
To clarify the reaction mechanism, the demethylation
reaction was investigated carefully, and the results showed that
the product 3a was formed before the reaction was quenched
with water (detected by NMR analysis, however, no any other
intermediates were detected). Based on the experimental results,
a plausible mechanism for the formation of 3a is illustrated in
Scheme 3. Initially, reaction of vinyl chloride 2a with BBr3
generates intermediate I which converts to intermediate II by
intramolecular condensation. Next, addition of Br- to intermediate
II to form intermediate III and the 2-arylbenzo[b]furan ring is
formed via this addition/elimination sequence. At last,
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In conclusion, we have developed an efficient and practical
method for synthesis of 3-formyl-2-arylbenzofurans via a two-
step one-pot protocol. Various derivatives bearing functional
groups can be obtained in good to excellent yields. Notably, the
products that have halogen substituents on aromatic ring allow
further functionalization to give more sophisticated 3-formyl-2-
arylbenzofuran derivatives. This synthetic method shows a
number of attracting advantages, including high function group
compatibility, low cost, relatively short reaction time, easy
workup and high overall yield. Furthermore, due to the easy
access of a variety of -ketoaldehyde substrates by Meinwald
rearrangement of chalcone epoxides, this work provides a
convenient method to construct 3-formyl-2-arylbenzofuran
derivatives from easy obtainable starting materials. Further
studies of other related applications of this protocol are currently
ongoing in our laboratory.
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