A general and efficient protocol for the synthesis of biaryl ethers from aryl silyl ethers using Cs2CO3

Article abstract of DOI:10.1055/s-2004-829567

A general and efficient one-step procedure has been developed for the synthesis of biaryl ethers via direct coupling of electron-deficient arylhalides or aryl triflates to aryl t-butyldimethylsilyl (TBS) ethers using Cs ₂CO₃. The protocol was also applied to electron-rich arylhalides by addition of a catalytic amount of copper(I) iodide. The reaction is rapid and provides good to excellent yields.

Full text of DOI:10.1055/s-2004-829567

LETTER
1829
A General and Efficient Protocol for the Synthesis of Biaryl Ethers from Aryl
Silyl Ethers Using Cs2CO3
Protocol
f
or th
u
e
S
ynthesis
o
n
f
Biaryl
E
th
-
ers Liang Cui, Zhi-Yong Jiang, Yan-Guang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
Fax +86(571)87951512; E-mail: orgwyg@zju.edu.cn
Received 9 May 2004
substances, ranging from nitrofluorobenzene to bro-
mophenyl methylsulfone, worked well under these condi-
tions (Scheme 1).
Abstract: A general and efficient one-step procedure has been de-
veloped for the synthesis of biaryl ethers via direct coupling of elec-
tron-deficient arylhalides or aryl triflates to aryl t-butyldimethyl-
silyl (TBS) ethers using Cs2CO3. The protocol was also applied to
electron-rich arylhalides by addition of a catalytic amount of cop-
per(I) iodide. The reaction is rapid and provides good to excellent
yields.
X
O
solvent
Ar
+
ArOTBS
Cs2CO3
Key words: biary ethers, aryl TBS ether, Cs2CO3, copper(I) iodide
R
R
(X=F,Cl,Br,OTf)
1
2
3
Biaryl ethers are known to be important organic com-
pounds for their biological activity and significant pres-
ence in life science industries.1 A number of them have
consequently provided a strong incentive for synthetic
methods, including the classical Ullman reaction, metal-
catalyzed substitution reactions, SNAr-based additions,
intramolecular oxidative couplings and MW-assisted
methods.2 Although the above synthetic strategies are par-
ticularly important, a method is required for the direct
conversion of phenoxy silane to biaryl ethers without re-
course to hydrolytic conditions. Such a method would be
of direct benefit to the synthesis of many natural products
as their hydroxyl silyl protected derivatives.
Scheme 1
Initially, we optimized the reaction conditions involving
solvent, temperature, equivalence of cesium carbonate
and reaction time. The phenoxy TBS ether and p-nitro-
fluorobenzene were employed as model and the solvents
CH2Cl2, DMF and MeCN were tested. As shown in
Table 1, the best conversion was observed when the
reaction was performed in DMF at 100 °C for one hour.
Furthermore, one equivalent of Cs2CO3 gave the highest
yield.
We examined a variety of phenoxy TBS ethers and aryl-
halides and triflates using the optimized conditions.5 As
shown in Table 2, the electron-deficient arylhalides gave
the corresponding biaryl ethers in moderate to excellent
yields (Table 2, entries 1–22).
As we know, t-butyldimethylsilyl (TBS) ether is widely
used for the protection of phenol ever since Corey and
Venkateswarlu introduced it in 1972. It is well known for
its easy installation and general stability to basic and mild-
ly acidic conditions. The synthesis of biaryl ethers and
aryl alkyl ethers through coupling of aryl- or alkylhalides Table 1 Optimization of Reaction Conditions for Biaryl Ethers
with phenolic TBS ethers using cesium fluoride,3a tetrabu-
from Phenoxy TBS Ether and p-Fluoronitrobenzene
tylammonium fluoride,3b or lithium hydroxide3c as bases
Entry
Equiv of Solvent
Cs2CO3
Temp
(°C)
Time
(h)
Yield
(%)a
has been reported. However, only active substances such
as benzyl halides, allyl halides or nitrophenylfluoride
were employed in these conversions. Therefore, the de-
velopment of a more general etherification of aryl TBS
ethers with arylhalides or aryl triflates is required.
1
2
3
4
5
6
7
8
0.5
0.5
0.5
1.0
1.0
1.0
1.5
1.0
CH2Cl2
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
Reflux
Reflux
70
8
No reaction
8
No reaction
8
47
82
70
92
92
91
Recently, we have successfully developed a novel selec-
tive deprotection of TBS-protected phenols using cesium
carbonate.4 With the intention of further expanding the
scope of this methodology, we explored the synthesis of
biaryl ethers via direct coupling of electron-deficient aryl
halides or triflates to substituted phenoxy t-butyldimeth-
ylsilane using cesium carbonate. To our delight, many
70
8
100
0.5
1.0
2
100
100
130
1.0
a Isolated yield (average of two runs).
SYNLETT 2004, No. 10, pp 1829–1831
Advanced online publication: 15.07.2004
0
9
.0
8
.2
0
0
4
DOI: 10.1055/s-2004-829567; Art ID: U12904ST
© Georg Thieme Verlag Stuttgart · New York

1830
S.-L. Cui et al.
LETTER
Table 2 Synthesis of Biaryl Ethers
1 equiv Cs2CO3
0.2 equiv CuI
R
R
Entry
X
R
Ar
Product
+
ArOTBS
(Yield, %)a
Ar
DMF, 100 °C, 8 h
O
Br
1
2
F
p-NO2
Phenyl
3a (92)
3b (92)
3c (90)
3a (90)
3b (91)
3c (89)
3a (85)
3b (86)
3c (83)
3d (86)
3e (86)
3f (83)
3g (88)
3h (89)
3i (86)
3j (85)
3k (85)
3l (86)
3m (82)
3a (90)
3b (90)
3c (89)
No reaction
Trace
1
2
3
F
p-NO2
p-Methylphenyl
Quinolin-8-yl
Phenyl
Scheme 2
Table 3 Synthesis of Biaryl Ethers Catalyzed by Copper(I) Iodide
3
F
p-NO2
4
Cl
Cl
Cl
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Cl
OTf
OTf
OTf
Cl
I
p-NO2
Entry
R
Ar
Product
5
p-NO2
p-Methylphenyl
Quinolin-8-yl
Phenyl
(Yield, %)a
6
p-NO2
1
2
3
4
5
6
H
Phenyl
3n (72)
3o (73)
3p (74)
3q (69)
3r (71)
3s (81)
7
p-NO2
p-Methoxyl
o-Methoxyl
p-Methoxyl
o-Methoxyl
p-Methyl
p-Methylphenyl
p-Methylphenyl
Phenyl
8
p-NO2
p-Methylphenyl
Quinolin-8-yl
Phenyl
9
p-NO2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
p-COCH3
p-COCH3
p-COCH3
p-CHO
p-CHO
p-CHO
p-SO2CH3
p-SO2CH3
p-SO2CH3
p-COPh
p-NO2
Phenyl
p-Methylphenyl
Quinolin-8-yl
Phenyl
p-Methylphenyl
a Isolated yield (average of two runs).
The chemoselectivity of the conversion between phenolic
and alcoholic TBS ethers was established to consummate
the protocol, employing 4-nitro-fluorobenzene and bis-
TBS protected 4-(2-hydroxyethyl) phenol to illustrate it.
The coupling product of phenolic TBS ether was selec-
tively achieved in 90% yield (Scheme 3).
p-Methylphenyl
Quinolin-8-yl
Phenyl
p-Methylphenyl
Quinolin-8-yl
Phenyl
OTBS
NO2
F
O
1 equiv Cs2CO3
DMF, 100 °C, 2 h
p-Methylphenyl
p-Methylphenyl
Quinolin-8-yl
p-Methylphenyl
p-Methylphenyl
+
p-NO2
(CH2)2OTBS
NO2
(CH2)2OTBS
p-NO2
Scheme 3
H
p-NO2
In summary, we have exploited a general and efficient
procedure for the synthesis of biaryl ethers via a direct
coupling of aryl TBS ethers to electron-deficient arylha-
lides or aryl triflates using Cs2CO3 in good yields, and ex-
panded it to electron-rich halides by adding copper(I)
iodide as catalyst. This method produced the coupling
product of phenolic TBS ether selectively in the presence
of alcoholic TBS group. The methodology can be extend-
ed to synthesis of complex molecules.
a Isolated yield (average of two runs).
The most active substances were p-nitrofluorobenzene
(Table 2, entries 1–3) and p-nitrophenoxytriflate (Table 2,
entries 20–22). However, chlorobenzene did not react
(Table 2, entry 23) and p-nitroiodobenzene gave traces of
the coupling product (Table 2, entry 24).
We also investigated the possibility of biaryl ether synthe-
sis from the electron-rich halides by this direct coupling,
and found that copper(I) iodide as additive catalyst (20%
mol with respect to aryl halides) could promote the reac-
tion (Scheme 2).6 As shown in Table 3, both bromoben-
zene (Table 3, entry 1) and its electron-rich derivatives
(Table 3, entries 2–6) gave the expected products in good
yields.
References
(1) (a) Theil, F. Angew. Chem. Int. Ed. 1999, 38, 2345.
(b) Nicolaou, K. C.; Christopher, N. C. B. J. Am. Chem. Soc.
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P. S.; Wood, M. R.; Richardson, T. I.; Trotter, B. W.; Katz,
J. L. Angew. Chem. Int. Ed. 1998, 37, 2704.
Synlett 2004, No. 10, 1829–1831 © Thieme Stuttgart · New York

LETTER
Protocol for the Synthesis of Biaryl Ethers
1831
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(5) General Procedure: A mixture of Cs2CO3 (1 mmol), aryl
TBS ether 2 (1 mmol) and arylhalide or aryl triflate 1 (1
mmol) in DMF (4.0 mL) was stirred at 100 °C under
nitrogen until the reaction was finished as indicated by TLC
(about 1–2 h). Then the mixture was partitioned between the
aqueous and the organic phase (EtOAc). The organic layer
was washed with brine, dried over anhyd Na2SO4 and
evaporated under reduced pressure. The crude product was
purified by flash column chromatography over silica gel
using EtOAc–hexane (1:20 or 1:3, v/v) as eluent to afford the
biaryl ether 3. All data for compound 3l are as follows: white
crystals; mp 165 °C. IR (KBr): 2915, 1596, 1499, 1313,
1290, 1256, 1142, 961 cm–1. 1H NMR (500 MHz, CDCl3):
d = 8.92 (m, 1 H), 8.25 (dd, J = 1.40, 8.35 Hz, 1 H), 7.87 (d,
J = 8.83 Hz, 2 H), 7.75 (d, J = 8.17 Hz, 1 H), 7.56 (t,
J = 7.83 Hz, 1 H), 7.50 (m, 1 H), 7.39 (d, J = 7.58 Hz, 1 H),
7.11 (d, J = 8.83 Hz, 2 H), 3.05 (s, 3 H) ppm. MS (EI):
m/z = 299 [M+].
(6) General Procedure: A mixture of Cs2CO3 (1 mmol), CuI
(0.2 mmol), aryl TBS ether 2 (1 mmol) and arylbromide 1 (1
mmol) in DMF (2.0 mL) was stirred at 100 °C under
nitrogen until the reaction was finished as indicated by TLC
(about 8 h). Then the mixture was allowed to cool to r.t. and
purified by flash column chromatography over silica gel
eluted with hexane to afford biaryl ether 3. All data for 3p
are as follows: colorless oil. IR (neat): 3022, 2955, 1608,
1590, 1509, 1219, 1110, 1021 cm–1. 1H NMR (500 MHz,
CDCl3): d = 7.14–7.08 (m, 3 H), 7.00 (dd, J = 7.95 Hz, 1 H),
6.94–6.82 (m, 4 H), 3.90 (s, 3 H), 2.30 (s, 3 H) ppm. MS (EI):
m/z = 214 [M+].
Synlett 2004, No. 10, 1829–1831 © Thieme Stuttgart · New York