Synthesis of substituted aryl enol ethers

Article abstract of DOI:10.1016/j.tetlet.2014.10.018

A facile route toward substituted aryl diarylvinyl ethers 4 is developed from CuI-mediated cross-coupling reaction of substituted phenols 2 with diarylvinyl bromides 3 in the presence of various bidentate-based ligands in DMF. Skeleton 3 is prepared by Yan's bromomethylenation of diarylketones 1 with CHBr₃-TiCl₄-Mg in the co-solvent of DME and CH₂Cl₂. The synthetic route obtains moderate yields from the one-step operation and the key structure of 4k is confirmed by X-ray crystallographic analysis. The CADD docking experiments of 4k have been included.

Full text of DOI:10.1016/j.tetlet.2014.10.018

Tetrahedron Letters 55 (2014) 6482–6485
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of substituted aryl enol ethers
a
a
b
b,
Meng-Yang Chang a, , Hang-Yi Tai , Chung-Yu Tsai , Yi-Jing Chuang , Ying-Ting Lin
⇑
⇑
a Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
b Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 July 2014
Revised 30 September 2014
Accepted 4 October 2014
Available online 21 October 2014
A facile route toward substituted aryl diarylvinyl ethers 4 is developed from CuI-mediated cross-coupling
reaction of substituted phenols 2 with diarylvinyl bromides 3 in the presence of various bidentate-based
ligands in DMF. Skeleton 3 is prepared by Yan’s bromomethylenation of diarylketones 1 with CHBr3–
TiCl4–Mg in the co-solvent of DME and CH2Cl2. The synthetic route obtains moderate yields from the
one-step operation and the key structure of 4k is confirmed by X-ray crystallographic analysis. The CADD
docking experiments of 4k have been included.
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Aryl enol ethers
Cross-coupling reaction
Phenols
Diarylvinyl bromides
CADD
Introduction
as a catalyst (e.g., Cu,6 Pd,7 Ir,8 Cu/Ni9) has been developed for
one-pot construction of vinyl enol ethers. Among these examples,
The novel design and synthesis of conformationally multi-func-
tionalized cyclic vinyl ethers (e.g., 2,3-diarylbenzofurans) have
attracted considerable attention from both the synthetic and
medicinal chemistry communities.1,2 Acyclic aryl enol ethers (aryl
diarylvinyl ethers) have received considerable attention for their
use in organic synthesis.3 Aryl vinyl ethers are important building
blocks in organic synthesis and have been applied as monomers in
material chemistry.4 Compared with the structure of diary-
lbenzofuran and aryl diarylvinyl ethers, the motif of aryl vinyl
ether is a common skeleton (red, green, and blue), as shown in
Scheme 1.
the Cu(I)-mediated vinylation reaction with various ligands is the
major synthetic route. Due to specific pharmaceutical interest con-
cerning the arrangement of substitution patterns of aryl substitu-
ents, we developed an efficient synthetic route to prepare
functionalized aryl diarylvinyl ethers 4 via the CuI-mediated CAO
bond formation of substituted phenols 2 with 1,1-diarylvinyl bro-
mides 3 in the presence of 2,20-bipyridine (a bidentate-based
ligand), as shown in Scheme 2.
Results and discussion
There are two differences. One is the formation of a cyclic ring
(brown), and the other is the C2/C3 position of the aryl group
(black). On the contrary, Tamoxifen (NolvadexÒ) and Afimoxifene
(MifegyneÒ), with specific pharmaceutical activities have exhibited
a triarylethylene skeleton.5 Based on the observation for structural
frameworks of aryl diarylvinyl ethers and Tamoxifen, one C3 aryl
substituent (black-brown) is retained and the other C3 aryl group
(blue) is changed to a C2 position. For linkage of aryloxy-conju-
gated styrene (red-green), the exchange of the ArOAC2 bond and
OArAC2 bond is achieved by a 180° rotation of the aryloxy nucleus.
In addition, the C(sp2)–O vinylation of multi-functionalized
phenols with vinyl halides or triflates by using transition-metals
Yan’s one-step bromomethylenation of diarylketones 1 was
employed to create diarylvinyl bromides 3 by the combination of
CHBr3–TiCl4–Mg in the co-solvent of DME and CH2Cl2.10 Using
the facile synthetic protocol, 3a–g were isolated in acceptable
32–60% yields (Table 1, entries 1–6). Although the presented yields
of 3 were unsatisfactory, it still was an efficient and straightfor-
ward route for synthesizing the skeleton of diarylvinyl bromides.
First, when a CuI-mediated cross-coupling reaction of phenol
(2a) was treated with 3a in toluene at 110 °C for 12 h in the
absence of ligands, phenyl diphenylvinyl ether (4a) was afforded
in only a 30% yield. In an attempt to improve the yield, four biden-
date-based ligands (N,N-dimethylglycine (L1), 1,10-phenantholine
(L2), 2,20-bipyridine (L3), 2-pyridin-2-yl-1H-benzoimidazole (L4))
were examined.6a–e By testing the literature methodologies
(Cs2CO3/1,4-dioxane, K3PO4/1,4-dioxane, Cs2CO3/toluene, K3PO4/tolu-
ene), 4a was isolated in a range of 42–74% yields, as shown in
⇑
Corresponding authors. Tel.: +886 7 3121101x2220.
E-mail addresses: mychang@kmu.edu.tw (M.-Y. Chang), ytlin@kmu.edu.tw
(Y.-T. Lin).
http://dx.doi.org/10.1016/j.tetlet.2014.10.018
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

M.-Y. Chang et al. / Tetrahedron Letters 55 (2014) 6482–6485
6483
R
2
2
O
O
3
3
O
N
Aryl diarylvinyl ether
Diarylbenzofuran
R = H, Tamoxifen
R = OH, Afimoxifene
Scheme 1. Representative structures.
Table 2
O
Ar
1
Br
Reaction condition of 4aa
+
Ar
Br
Br
2
Ph
O
Ph
4a
OH
1
Cu(I), bidentate ligand
Ar
Ar
2
Ph
1
Yan bromomethylenation
Cu(I)-mediated coupling
TiCl , Mg
Br
4
+
DME, CH Cl
2
2
Ph
3a
base, solvent, temp, time
OH
O
2a
CuI, 2,2'-bipyridine
Cs CO , DMF
Ar
H
N
1
Br
O
+
2
2
Ar
2
3
2
HO
NMe
2
N
N
N
N N
2' 2
N
R
R
1
10
N,N-dimethyl
glycine (L1)
1,10-phenanthroline (L2) 2,2'-bipyridine (L3)
2-pyridin-2-yl
benzoimidazole (L4)
2
3
4
Scheme 2. Synthetic route toward skeleton 4.
Entry
Ligand, base, solvent, temp (°C), time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
L1, Cs2CO3, 1,4-dioxane, 80, 24
L2, Cs2CO3, 1,4-dioxane, 80, 24
L3, Cs2CO3, 1,4-dioxane, 80, 24
L4, Cs2CO3, 1,4-dioxane, 80, 24
L1, K3PO4, 1,4-dioxane, 80, 24
L2, K3PO4, 1,4-dioxane, 80, 24
L3, K3PO4, 1,4-dioxane, 80, 24
L4, K3PO4, 1,4-dioxane, 80, 24
L1, Cs2CO3, toluene, 110, 24
L2, Cs2CO3, toluene, 110, 24
L3, Cs2CO3, toluene, 110, 24
L4, Cs2CO3, toluene, 110, 24
L1, K3PO4, toluene, 110, 48
L2, K3PO4, toluene, 110, 48
L3, K3PO4, toluene, 110, 48
L4, K3PO4, toluene, 110, 48
L1, Cs2CO3, DMF, 80, 24
52
55
75
70
42
62
70
66
50
67
78
62
54
66
74
62
66
80
88
71
Table 1
Synthesis of 3a–ga
TiCl , Mg
4
O
Ar
Ar
1
Br
1
Br
+
DME, CH Cl
Ar
Ar
2
2
Br
Br
2
2
1a-g
3a-g
Entry
1, Ar1, Ar2=
3, yield (%)b
3a, 60
1
2
3
4
5
6
7
1a, Ph, Ph
1b, Ph, 4-FPh
1c, Ph, 4-MeOPh
3b, 42 (1:2)c
3c, 57 (1:2)c
3d, 51
1d, 4-MeOPh, 4-MeOPh
1e, 4-MeOPh, 4-FPh
1f, 4-FPh, 4-FPh
3e, 54 (1:1)c
3f, 40
1g, 2-thiophene, Ph
3g, 32 (1:1)c
L2, Cs2CO3, DMF, 80, 24
L3, Cs2CO3, DMF, 80, 24
L4, Cs2CO3, DMF, 80, 24
a
The reaction was run on a 1.0 mmol scale with 1, Mg (243 mg, 10.0 mmol), TiCl4
(1.0 M in CH2Cl2, 1.0 mL, 1.0 mmol), CHBr3 (0.3 mL), in the co-solvent of DME
(1.5 mL) and CH2Cl2 (1.0 mL), ice bath to rt.
a
The reaction was run on
(0.1 mmol), ligands (0.2 mmol), Cs2CO3 (1.2 mmol), solvent (2 mL).
a
1.0 mmol scale with 2a, 3a (1.2 mmol), CuI
b
Isolated yield.
b
c
The ratio of E/Z-isomers was confirmed on the basis of 1H or 13C NMR analysis.
Isolated yield.
As shown in Table 3, 4a–p with electron-donating, electron-
neutral, or electron-withdrawing substituents (Ar1, Ar2 = Ph, 4-
FPh, 4-MeOPh, 2-thiophene) were produced in a range of moderate
yields (70–88%). No obvious yield changes in all the entries were
exhibited besides 4a, 4b, and 4c which provided better (88%,
82%, and 83%) yields, respectively, (by the classical CuI-mediated
cross-coupling of 2a with 3a–b and 3g). The experimental results
showed that the cross-coupling reaction of 2b bearing a 2-bromo
substituent with 3a–c provided 74–78% yields of 4d–f, and no
expected skeleton of dibenzo[1,4]dioxine was observed (by the
self-coupling of 2b). Similar results were described in the forma-
tion of 4g–j from the cross-coupling reaction of 2-allylphenol
(2c) with 3a–b and 3d–e. Furthermore, the double cross-coupling
reactions of 2d or 2e with 3a–c or 3a and 3f performed well. A
selective mono-cross coupling reaction of 2e with 3a was also
achieved to 4n in a 73% yield. For the E/Z-isomers of 4b, 4c, 4e,
Table 2 (entries 1–4, 52–70%; entries 5–8, 42–70%; entries 9–12,
50–70%; entries 13–16, 54–74%). These experimental results
showed that 2,20-bipyridine (L3) provided a better yield. Further-
more, controlling the base (Cs2CO3), temperature (80 °C), solvent
(DMF, 2 mL), and time (24 h) and switching four ligands L1–L4,
we found that 4a provided a better yield (88%). We thought that
entry 19 was an optimal condition to increase the yield of 4a. With
this idea in mind, various substituted phenols were examined. The
starting materials, substituted phenols 2 (phenol (2a), 2-bromo-
phenol (2b), 2-allylphenol (2c), hydroquinone (2d) and 4,40-biphe-
nol (2e)) were easily afforded from commercially available
materials. By the abovementioned protocol, products 4a–p
were isolated in DMF at 80 °C for 24 h via the CuI-mediated
cross-coupling of 2a–e and 3a–g with the combination of Cs2CO3
and 2,20-bipyridine (L3).

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M.-Y. Chang et al. / Tetrahedron Letters 55 (2014) 6482–6485
Table 3
Synthesis of 4a–pa-b
Ar
2
Ar
1
OH
O
CuI, 2,2'-bipyridine (L3)
Cs CO , DMF
Ar
1
Br
+
Ar
2
2
3
R
R
2a, phenol
3a-g, Ar , Ar =,
1 2
2b, 2-bromophenol Ph, 4-FPh, 4-MeOPh, 2-thiophene
2c, 2-allylphenol
4a-p
2d, hydroquinone
2e, 4,4'-biphenol
F
S
O
O
O
O
Br
4a, 88
4b, 82 (1:2)c
4c, 83 (1:1)c
4d, 78
MeO
OMe
F
OMe
O
O
O
O
Br
Br
Figure 2. Our docking experiments show that 4k (golden) can be a stronger binder
to estrogen receptor (ER) than Tamoxifen (green). Of best docked poses, both 4k’s
hydroquinone moiety and Tamoxifen’s trimethylamine have the inhibitory hydro-
gen bonding to the ER Asp351 while 4k has an extended diphenyl group deep into
the ER binding pocket.
4e, 76 (1:2)c
4f, 74 (1:2)c
4g, 70
4h, 76
F
F
OMe
OMe
O
O
O
O
O
O
determined by single-crystal X-ray crystallography.11 The repre-
sentative ORTEP of 4k proved the constitution and relative config-
uration, as shown in Figure 1.
OMe
4i, 73 (1:2)c
4j, 74 (1:1)c
4k, 73
4l, 76 (1:2)c
F
Further CADD (computer assisted drug design) docking experi-
ments indicated that 4k (with the docking score, 66.6) can be a
stronger binder to estrogen receptor (ER) than Tamoxifen (55.8).
As shown in Figure 2, the docked poses revealed that 4k bears a
hydroquinone moiety yielding the inhibitory hydrogen bonding
to the residue Asp351, similar to the role of Tamoxifen’s trimethyl-
amine in the ER binding pocket. We believe that a further diphenyl
group extended into the binding pocket can make 4k a good antag-
onist in respect to the machinery of ER antagonism.12
F
F
O
O
O
O
O
OH
O
O
F
F
F
4m, 70 (1:2)c
4n, 73
4o, 75
4p, 70
a
The reaction was run on a 1.0 mmol scale with 2a–e, 3a–g (1.2 or 2.4 mmol), CuI
Conclusion
(0.1 or 0.2 mmol), L3 (0.2 or 0.4 mmol), Cs2CO3 (1.2 or 2.4 mmol), DMF (2 mL).
b
Isolated yields.
In summary, we have successfully presented an efficient and
straightforward synthetic route for the synthesis of substituted
aryl diarylvinyl ethers 4 via a CuI-mediated cross-coupling reaction
of substituted phenols 2 with diarylvinyl bromides 3 in the pres-
ence of 2,20-bipyridine ligand in DMF. The synthetic route obtained
c
The ratio of E/Z-isomers was confirmed on the basis of 1H or 13C NMR analysis.
4f, 4i, 4j, 4l, and 4m, related ratios were confirmed on the basis of
1H or 13C NMR analysis. The structural framework of 4k was
Figure 1. X-ray structure of 4k.

M.-Y. Chang et al. / Tetrahedron Letters 55 (2014) 6482–6485
6485
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Acknowledgments
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The authors would like to thank the Ministry of Science and
Technology of the Republic of China for its financial support (NSC
102-2113-M-037-005-MY2). Y.-T.L. would also like to thank a
grant from the Kaohsiung Medical University Research Foundation
(KMU-M103027).
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Supplementary data
Supplementary data (Scanned photocopies of 1H and 13C NMR
spectral data as well as details of the docking experiments.) asso-
ciated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.10.018.
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