An efficient strategy for the synthesis of aryl ethers

Article abstract of DOI:10.1055/s-2007-983777

An efficient strategy for the construction of aryl ethers using aryl fluorides and silyl ethers is described. This protocol uses a sub-stoichiometric amount of silicon-based reagent and proceeds under milder conditions than previously reported reactions of this type. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983777

SHORT PAPER
2237
An Efficient Strategy for the Synthesis of Aryl Ethers
S
T
ynthesis of
A
r
o
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada
Fax +1(604)8223187; E-mail: jenlove@chem.ubc.ca
Received 12 March 2007
Dedicated to Professor Paul A. Wender on the occasion of his 60 birthday
th
would be to use readily available tetraaryloxysilanes,
which would substantially reduce the amount of silicon
by-product. In addition, the ability to generate aryl alkyl
ethers using tetraalkoxysilanes would increase the gener-
ality of the methodology.
Abstract: An efficient strategy for the construction of aryl ethers
using aryl fluorides and silyl ethers is described. This protocol uses
a sub-stoichiometric amount of silicon-based reagent and proceeds
under milder conditions than previously reported reactions of this
type.
Key words: nucleophilic aromatic, substitutions, aryl ether, aryl We report herein that tetraphenoxysilane and tetraalkoxy-
fluoride, silicon reagents, synthetic method
silanes react readily with aryl fluorides in the presence of
TBAF and that a sub-stoichiometric amount of silane, rel-
ative to the aryl fluoride, can indeed effect the transforma-
The aryl ether moiety is found in a wide range of bioactive tion without compromising reaction outcome. Moreover,
1
,2
3
molecules and materials. Not surprisingly, efforts to- the reaction scope is broader and the reaction conditions
ward developing efficient and convenient protocols for are milder than those reported for related fluoride-promot-
the synthesis of aryl ethers has received considerable at- ed reactions.1
3,14
4
tention. The Ullmann coupling has been used extensively
Our study began with 2,4-dinitrofluorobenzene (1a),
which was reacted with 0.3 equivalent of tetraphenoxysi-
lane in acetone at 50 °C for 24 hours to generate phenyl
for aryl ether synthesis, yet suffers from the requirement
5
for high reaction temperatures and excess Cu salt. Efforts
to circumvent these limitations have been reported,6 with
,7
ether 2a in 73% isolated yield (Table 1, entry 1). The con-
the first example of a catalytic Ullmann coupling appear-
14b
14c
ditions reported by Wang as well as Burgess and Zhu
indicated the use of base (Et N and K CO , respectively),
7
ing in 1997. Despite this considerable advance, high re-
3
2
3
action temperatures were still required. In comparison,
Cu-mediated cross couplings of aryl boronic acids can be
run at room temperature, but require stoichiometric cop-
whereas we found that this was not necessary for high
conversion. We also found that the reaction proceeded ef-
ficiently at a considerably lower reaction temperature than
8
per. Pd-catalyzed cross-coupling of aryl bromides with
14b
reported by Wang (50 °C compared with 100 °C).
phenoxides and alkoxides was introduced in 1999 inde-
9
Based on this initial success, we investigated aryl fluo-
rides containing only one additional activating group.
Both 4-nitrofluorobenzene (1b) and 2-cyanofluoroben-
zene (1c) reacted smoothly to generate the corresponding
diaryl ethers in 92% and 80% yields, respectively (entries
pendently by Hartwig and Buchwald. These methods still
required high temperatures, as well as pre-formation of
the alkoxide or aryl oxide. Shortly thereafter, room-tem-
perature coupling was achieved, but a limited substrate
1
0
scope was described.
2
and 3).
More recently, S Ar reactions have been developed as a
N
To test the selectivity of the process, we explored the use
of 5-chloro-2,4,6-trifluoropyrimidine (1d). With tetraphe-
noxysilane, 1d reacted efficiently to generate the triphe-
noxy pyrimidine 2d in 82% yield (entry 4). Importantly,
only substitution of fluorine was observed, consistent with
strategy for diaryl ether formation. For example, activated
aryl fluorides have been coupled with aryl alcohols using
excess KF·Al O and catalytic 18-crown-6, in refluxing
2
3
1
1
acetonitrile. Addition of phenols to benzynes generated
from silylaryl triflates has also been reported.1
2
an S Ar mechanism. The generality of the methodology
N
An alternate strategy involves the coupling of silyl-pro-
tected aryl alcohols with aryl fluorides. A variety of re-
agents have been used to promote deprotection of the silyl
was demonstrated by the use of tetraalkoxysilanes. For
example, pyrimidine 1d reacted with tetramethoxysilane
(
entry 5) and tetraethoxysilane (entry 6) in 81% and 75%
1
3
14
15
group, including CsF, TBAF, phosphazenes or
yield, respectively. Likewise, the use of tetraallyloxysi-
lane allows the generation of aryl allyl ethers (entry 7).
1
6
proazaphosphatranes. These protocols all use trialkylsi-
lyl-protected aryl alcohols. As such, these reactions pro-
duce one equivalent of silicon by-product relative to the
amount of aryl ether formed. A more efficient protocol
In summary, we have established a convenient protocol
for the synthesis of aryl ethers from aryl fluorides and si-
lyl-protected alcohols. Notably, less than one equivalent
of silyl reagent is consumed in the reaction. Both tetraphe-
noxy- and tetraalkoxysilanes can be used. These reactions
proceed efficiently at 50 °C and do not require added base.
SYNTHESIS 2007, No. 15, pp 2237–2239
x
x.
x
x
.
2
0
0
7
Advanced online publication: 12.07.2007
DOI: 10.1055/s-2007-983777; Art ID: C01907SS
Georg Thieme Verlag Stuttgart · New York
©

2
238
T. Wang, J. A. Love
SHORT PAPER
Table 1 Preparation of Aryl Ethers
Si(OR)4, TBAF
Ar
F
Ar OR
acetone, 50 °C, 16–24 h
Entry
1
Aryl fluoride
Silane
Time (h)
24
Product
Yield (%)a
F
OPh
Si(OPh)4
1a
1b
1c
2a
2b
2c
73b
92
(
0.3 equiv)
O2N
O2N
NO2
F
O2N
O2N
NO2
OPh
Si(OPh)4
0.3 equiv)
2
3
24
21
(
F
OPh
Si(OPh)4
0.3 equiv)
80
(
CN
CN
N
F
N
F
F
PhO
Cl
OPh
OMe
OEt
Si(OPh)4
(1.2 equiv)
4
5
6
1d
1d
1d
16
24
24
2d
2e
2f
82
81
75
N
N
Cl
OPh
N
MeO
Cl
Si(OMe)4
(
1.2 equiv)
N
OMe
EtO
Cl
N
Si(OEt)4
1.2 equiv)
N
(
OEt
O
N
N
O
O
Si(OCH CH=CH )
2
2 4
7
1d
24
2g
79
(
1.2 equiv)
Cl
a
Isolated yields.
b
1
Yield determined by H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.
Aryl Ether Formation; 5-Chloro-2,4,6-triphenoxypyrimidine
(2d); Typical Procedure
All reactions were performed using oven-dried glassware sealed
with rubber septa under a positive pressure of dry N from a Schlenk
In an N -filled Vacuum Atmospheres glovebox, acetone (1.0 mL)
2
2
line. Similarly sensitive liquids and solutions were transferred via
syringe. Reactions were run using Teflon-coated magnetic stir bars.
Elevated temperatures were maintained in thermoregulated oil
baths. Organic solutions were concentrated using a Büchi rotary
evaporator using a water aspirator. TLC plates were visualized by
ultraviolet light. Chromatographic purification of products was ac-
complished by flash chromatography using silica gel (70–230
mesh). All reagents were obtained from commercial sources and
used as received. TBAF (1.0 M in THF) solution was purchased
was transferred into a 5 mL test tube equipped with a magnetic stir
bar and a screw cap with a septum. 5-Chloro-2,4,6-trifluoropyrimi-
dine (1e; 120 mL, 1.0 mmol) and Si(OPh) (405 mL, 1.0 mmol) and
4
TBAF (2.2 mL of a 1.0 M solution in THF, 2.2 mmol) were injected
by syringe into the test tube. The test tube was put into the preheated
oil bath at 50 °C. Analysis by TLC indicated that the reaction was
completed in 16 h. The mixture was transferred into a 20 mL vial
and the solution was concentrated by rotary evaporation. The resi-
due was purified by column chromatography (SiO , 9:1 hexane–
2
from Aldrich. Si(OPh) was prepared following the literature proce-
EtOAc) to give 332 mg (85%) of 2d as a white solid.
4
dure.17 NMR spectra were recorded on Bruker Avance 300 spec-
1
H NMR (acetone-d , 300 MHz): d = 7.41–7.03 (m, ArH).
1
13
19
6
trometers. H, C and F NMR spectra are reported in parts per
million and were referenced to residual solvent. All spectra were
obtained at 25 °C. Mass spectra were recorded on a Kratos MS-50
13C NMR (acetone-d
, 300 MHz): d =168.0, 161.7, 158.6, 153.8,
6
129.6, 129.2, 125.8, 125.1, 121.7, 121.3, 96.0.
1
8
19
mass spectrometer. Spectroscopic data for aryl ethers 2a, 2b,
HRMS (EI): m/z calcd for C H ClN O + Na: 413.0669; found:
2
2
15
2
3
2
0
21
21
2
c, 2e, and 2f were identical to reported values.
4
13.0655.
Synthesis 2007, No. 15, 2237–2239 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of Aryl Ethers
2239
2
g
(4) For a review, see: Sawyer, J. A. Tetrahedron 2000, 56, 5045.
(5) Ullmann, F. Ber. Dtsch. Chem. Ges. 1904, 37, 853.
(6) Intramolecular reactions: (a) Boger, D. L.; Yohannes, D. J.
Org. Chem. 1991, 56, 1763. (b) Boger, D. L.; Sakya, S. M.;
Yohannes, D. J. Org. Chem. 1991, 56, 4204. Use of ortho
activating group: (c) Nicolaou, K. C.; Boddy, C. N. C.;
Natarajan, S.; Yue, T.-Y.; Li, H.; Bräse, S.; Ramanjulu, J. M.
J. Am. Chem. Soc. 1997, 119, 3421.
Yield: 79%.
1
H NMR (acetone-d , 300 MHz): d = 6.07 (m, 3 H), 5.50–5.35 (m,
6
3
H), 5.30–5.20 (m, 3 H), 4.95–4.93 (m, 4 H), 4.86–4.83 (m, 2 H).
1
3
C NMR (acetone-d , 300 MHz): d = 167.7, 162.6, 134.6, 134.2,
18.9, 97.1, 69.7, 69.4.
6
1
MS (ESI): m/z = 483.0.
(
7) (a) Marcoux, J. F.; Doye, S.; Buchwald, S. L. J. Am. Chem.
Soc. 1997, 119, 10539. (b) Kalinin, A. V.; Bower, J. F.;
Riebel, P.; Snieckus, V. J. Org. Chem. 1999, 64, 2986.
HRMS (EI): m/z calcd for C H N O Cl + H: 283.0849; found:
2
1
3
15
2
3
83.0855.
(
c) Ouali, A.; Spindler, J.-F.; Cristau, H.-J.; Taillefer, M.
Adv. Synth. Catal. 2006, 348, 499.
Acknowledgment
(
8) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters, M.
P. Tetrahedron Lett. 1998, 39, 2933. (b) Evans, D. A.; Katz,
J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937.
(9) (a) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F.
J. Am. Chem. Soc. 1999, 121, 3224. (b) Aranyos, A.; Old,
D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald,
S. L. J. Am. Chem. Soc. 1999, 121, 4369.
We thank the following for support of this research: University of
British Columbia, NSERC (Discovery Grant, Research Tools and
Instrumentation Grants), the Canada Foundation for Innovation
(
New Opportunities Grant), and the British Columbia Knowledge
Development Fund.
(
10) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. F. J. Am.
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Synthesis 2007, No. 15, 2237–2239 © Thieme Stuttgart · New York