Dichloromethane as methylene donor for the one-pot synthesis of bisaryloxy methanes via Williamson etherification and Suzuki coupling

Article abstract of DOI:10.1016/j.tetlet.2016.10.023

The multicomponent reactions of o-, m, or p-iodophenols, arylboronic acids, and dichloromethane (DCM) have been designed for the synthesis of various bisaryloxy methanes via one-pot procedure consists of Williamson etherification and Suzuki coupling.

Full text of DOI:10.1016/j.tetlet.2016.10.023

Accepted Manuscript
Dichloromethane as methylene donor for the one-pot synthesis of bisaryloxy
methanes via Williamson etherification and Suzuki coupling
Xuwen Chen, Changfeng Hu, Jie-Ping Wan, Yunyun Liu
PII:
S0040-4039(16)31326-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.023
TETL 48193
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 June 2016
26 September 2016
8 October 2016
Please cite this article as: Chen, X., Hu, C., Wan, J-P., Liu, Y., Dichloromethane as methylene donor for the one-
pot synthesis of bisaryloxy methanes via Williamson etherification and Suzuki coupling, Tetrahedron Letters
(2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.10.023
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Graphical Abstract
Dichloromethane as methylene donor for the
one-pot synthesis of bisaryloxy methanes via
Williamson etherification and Suzuki
coupling
Leave this area blank for abstract info.
Xuwen Chen, Changfeng Hu, Jie-Ping Wan, Yunyun Liu*

1
Tetrahedron Letters
Dichloromethane as methylene donor for the one-pot synthesis of bisaryloxy
methanes via Williamson etherification and Suzuki coupling
Xuwen Chen,a Changfeng Hu,b Jie-Ping Wana and Yunyun Liua,*
a College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, P.R. China. Email: chemliuyunyun@jxnu.edu.cn
bCollege of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, P.R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The multicomponent reactions of o-, m, or p-iodophenols, arylbronic acids and dichloromethane
(DCM) have been designed for the synthesis of various bisaryloxy methanes via one-pot
procedure consists of Williamson etherification and Suzuki coupling.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Keyword_1 One-pot reaction
Keyword_2 Williamson etherification
Keyword_3 Suzuki coupling
Keyword_4 Palladium catalysis
Keyword_5 Bisaryloxy methanes
potentially an important solution in terms of extending the
diversity of bisaryloxy methane products.
The formation of acetals (bisalkoxy or bisaryloxy methanes) is
an important and fundamental protocol in organic synthesis.1
Beside the classical utilization as protection step in many linear
organic synthesis,2 the structure of the acetals are well
documented organic synthons and targets in numerous synthetic
reactions.3 Conventionally, the formation of acetals can be
readily executed via the acetalization of aldehydes.4 While the
acetalization of aldehydes benefits from the availability of
diverse substrates and tolerance to a broad array of different
catalytic conditions, however, this typical protocol is mainly
restricted for the synthesis of dialkyl acetals via the reactions of
alcohols and aldehydes. Corresponding synthesis of bisaryloxy
acetals via the reactions employing phenols as O-nucleophiles is
usually not practical via analogous approach because of the lower
nucleophilicity of the phenol hydroxyl than equivalent alcohols.
In the available literature, the synthesis of bisaryloxy methanes
are generally accomplished by employing the Williamson-type
etherification between phenols and dihalomethane under the
promotion of a base.5 The main defect of the synthesis in known
reports is that the diversity of the product substructure is
rigorously limited to the variation of phenol substrates. In
addition, because of the reaction model involving the direct
etherification of two identical phenol molecules, the synthesis of
unsymmetrical bisaryloxy methane products is therefore not
practical. Considering the potential application of the bisaryloxy
methanes in biological studies,6 devising alternative synthetic
methods which allow the generally of significantly product
diversity is an issue of urgency. In this context, the strategy of
one-pot reaction by combining the Williamson etherification of
phenols and DCM and other chemical transformations is
Suzuki coupling reaction is a reliable synthetic tool in the
construction of new C-C double bonds, this transformation has
been ubiquitously employed in the designation of organic
syntheses.7 In light of the efficiency of the Suzuki coupling
reaction and our recent research interest in organic synthesis
involving dichloromethane as low cost methylene donor and
Suzuki coupling reaction,8 we envision that designing one-pot
reactions combining the Williamson etherification and Suzuki
coupling may provide a practical new route for the synthesis of
bisaryloxy methanes, by which the product diversity of the
bisaryloxy methanes can be significantly expanded on the basis
of all previous synthesis employing only phenols and
dihalomethanes as substrates.
At the beginning of exploration, the reaction of o-iodophenol
1a, phenyl boronic acid 2a and DCM 3 was conducted in the
presence of PdCl2 and Cs2CO3. The formation of product 4a via
the assembly of the three components was observed by heating at
o
90 C in DMF (entry 1, Table 1). Being inspired by the result,
systematical optimization experiments were then carried out.
While the initial efforts in increasing or reducing the loading of
DCM did not give improved yield (entries 2-3, Table 1), the
attempt at employing a variety of different palladium species led
to no observation of better catalyst, either (entries 4-9, Table 1).
In subsequent investigation, the impact of catalyst loading
(entries 10-11, Table 1), base additive (entries 12-15) and the
reaction medium (entries 16-18, Table 1) again turned out to be
incapable of providing higher yield of the target product. Finally,
the entries performed under different temperature indicated that
o
the heating at 100 C gave evidently higher yield of 4a (entries

2
Tetrahedron Letters
Entry
R1
H
R2
4-CH3
4-CH3
H
Product
4a
Yieldb (%)
74
19-21). Additionally, an entry using o-bromophenol as
alternative starting material of 1a provided 4a with 41% yield
(entry 22, Table 1). No target product was acquired when o-
chlorophenol was used for similar reaction.
Table 1 Optimization on reaction conditiona
1
2c
3
H
4a
75
4-CH3
H
4b
4c
47
4
3-CH3
H
60
5
H
4d
4d
4e
73
6c
H
H
71
7
4-CH3
4-t-Bu
H
4-CH3
4-CH3
4-OCH3
4-OCH3
4-OCH3
3-CHO
4-F
71
Entry
1
Catalyst
PdCl2
Base
Solvent
DMF
T (oC) Yield (%)b
8
4f
50
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
90
90
60
54
50
35
41
53
52
15
54
43
52
22
nr
9
4g
61
2c
PdCl2
DMF
10
11
12
13
14
15
16
17
18
4-CH3
4-t-Bu
H
4h
4i
68
3d
PdCl2
DMF
90
54
4
Pd(OAc)2
Pd(TFA)2
Pd2(dba)3
Pd(PhCN)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)4
PdCl2
DMF
90
4j
39
5
DMF
90
H
4k
4l
62
6
DMF
90
4-CH3
4-t-Bu
4-Cl
H
4-F
58
7
DMF
90
4-F
4m
4n
4o
66
8
DMF
90
4-OCH3
4-Cl
47
9
DMF
90
61
10e
11f
12
13
14
15
16
17
18
19
20
21
22g
DMF
90
H
1-naphthyl
4p
58
aReaction conditions: 1 (0.6 mmol), 2 (0.84 mmol), 3 (0.9
PdCl2
DMF
90
mmol), PdCl2 (0.03 mmol), Cs2bCO3 (1.8 mmol), DMF (2 ml),
PdCl2
DMF
90
o
reflux (heating at 100 C), 12 h. Yield of isolated product based
PdCl2
Na2CO3
K3PO4
DMF
90
on 1. cCH2Br2 was employed in place of DCM.
PdCl2
DMF
90
trace
nr
On the basis of the work in synthesizing the symmetrical
bisaryloxy methanes, we subsequently made efforts to tune the
selectivity of the reaction for the potential synthesis of
unsymmetrical product via reactions involving only mono-Suzuki
coupling. Concise further explore in reaction condition proved
that employing DMSO as the reaction medium allowed the
synthesis of unsymmetrical products 5 with sound selectivity
(Scheme 1).10 The successful synthesis of 5 further demonstrated
the significantly extended diversity of bisaryloxy products via
this one-pot reaction tactic. The successful generation of 5 with
reasonable yields might be attributed to the reduced loading of
aryl boronic acids 2 in these reactions.
PdCl2
NaHCO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
90
PdCl2
1,4-dioxane
p-xylene
EtOH
DMF
90
nr
PdCl2
90
11
trace
45
74
53
41
PdCl2
reflux
80
PdCl2
PdCl2
DMF
100
110
100
PdCl2
DMF
PdCl2
DMF
aReaction conditions: 1a (0.6 mmol), 2a (0.84 mmol, 1.4
equiv.) and 3 (0.9 mmol, 3 equiv.), catalyst (0.03mol), base (1.8
mmol), in 2 mL solvent, 12h. nr = no reaction. Yield of isolated
b
c
d
product based on 1. 0.6 mmol CH2Cl2 was used. 1.2 mmol
CH2Cl2 was used. e0.015mmol PdCl2 was used. 0.045mmol
f
PdCl2 was used. go-Bromophenol was used as alternative
substrate of 1a.
The application of this three-component reaction was then
examined by conducting the reactions of various o-iodophenols 1
and aryl boronic acids 2 with DCM under the optimized
condition. As presented in Table 2, this synthetic protocol
displayed good tolerance to both the component of o-iodophenol
and aryl boronic acid. In addition, corresponding entries
employing CH2Br2 as the alternative substrate of DCM gave
generally similar results (entries 2 and 6, Table 2).9 Reactions
employing o-methoxyphenyl boronic and and m-nitrophenyl
boronic acids both failed to provide target product, suggesting
that that the steric hindrance and electron withdrawing effect
were both negative for this multicomponent reactions.
Scheme 1 Selective synthesis of unsymmetrical bisaryloxyl
methanes
As further efforts in expanding the application scope, the
reactions employing m- and p-iodophenols
6 were also
investigated (Scheme 2). The results in forming corresponding
products 7 proved the general applicability of such synthetic
protocol towards the synthesis of different bisaryloxy methanes.
Table 2 Scope of the synthesis of bisaryloxy methanesa
Scheme 2 Reactions of m- and p-iodophenols
In conclusion, we have successfully designed a practical
synthetic approach toward the synthesis of bisaryloxy methanes

3
2961. (d) Timofeeeva, M. N.; Panchenko, V. N.; Jun, J. W.;
by combining the DCM-based Williamson etherification with
phenols and the Suzuki-coupling reactions. Both the synthesis of
symmetrical and unsymmetrical bisaryloxy methanes are found
accessible via the one-pot reactions between these 3 substrates
under slightly different reaction conditions. The new structural
feature of these bisaryloxy methanes as well as the simple one-
pot operation would be helpful for related further investigation to
the application of these products.
Hasan, Z.; Matrosova, M. M.; Jhung, S. H. Appl. Catal. A.
General 2014, 471, 91. (e) Böse, D.; Lübcke, M.; Pietruszka, J.
Synthesis 2013, 45, 729.
(a) Liu, W.; Szewczyk, J.; Waykole, L.; Repič, O.; Blacklock, T. J.
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Miron, S.; Lowy, A. J. Am. Chem. Soc. 1951, 73, 1872.
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General procedure for the synthesis of bisaryloxy methanes 4
and 7. To a 25 mL round-bottom flask equipped with stirring bar
and condenser was charged with o-, m- or p-iodophenol 1 or 6 (0.6
mmol), arylboronic acid 2 (0.84 mmol), DCM 3 (0.9 mmol), PdCl2
(0.03 mmol), Cs2CO3 (1.8 mmol) and DMF (2 mL). The resulting
mixture was stirred at reflux (heating at 100 oC) under air
atmosphere for 12 h. Upon completion, the reaction mixture was
allowed to cool down to rt, and H2O (10 mL) was added to the
vessel. The resulting suspension was extracted with ethyl acetate
(3 × 10 mL). The organic phases were combined and dried over
Na2SO4. After filtration, the solvent in the solution was removed
under reduced pressure. The acquired residue was subjected to
silica gel column chromatography to provide pure product by
using mixed petroleum ether/ethyl acetate 200:1 (v/v) as the
eluent.
5.
6.
7.
Acknowledgments
This work is financially supported by National Natural
Science Foundation of China (21562024).
8.
9.
Supplementary Material
Supplementary data (general details, synthetic procedure,
1
characterization data as well as H and 13C NMR spectra for
products 4, 5 and 7) associated with this article can be found, in
the online version, at http://
References and notes
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10. General procedure for the synthesis of bisaryloxy methanes 5.
To a 25 mL round-bottom flask equipped with stirring bar and
condenser was charged with o-iodophenol
1 (0.6 mmol),
arylboronic acid 2 (0.36 mmol), dichloromethane 3 (0.9 mmol),
PdCl2 (0.03 mmol), Cs2CO3 (1.8 mmol) and DMSO (2 mL). The
resulting mixture was stirred at reflux (heating at 100 oC) under air
atmosphere for 12 h. Upon completion, the reaction mixture was
allowed to cool down to rt, and H2O (10 mL) was added to the
vessel. The resulting suspension was extracted with ethyl acetate
(3 × 10 mL). The organic phases were combined and dried over
Na2SO4. After filtration, the solvent was removed from the
solution under reduced pressure. The acquired residue was
subjected to silica gel column chromatography to provide pure
product by using mixed petroleum ether/ethyl acetate 400:1 (v/v)
as the eluent.
3.
4.
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4
Tetrahedron
Highlights
1. Facile one-pot reactions consist of DCM-based Williamson etherification and Suzuki coupling.
2. Novel bisaryloxy methane products.
3. Selective synthesis of products with both symmetrical and unsymmetrical structures.