Microwave-assisted synthesis of diaryl ethers without catalyst

Article abstract of DOI:10.1021/ol0346436

(Matrix presented) Diaryl ethers have been prepared by direct coupling of phenols including those that bear a strong electron-attracting substituent to electron-deficient aryl halides through S_NAr-based addition reactions with assistance of microwave irradiation in high to excellent yields within 5-10 min. No catalysts were required under our conditions.

Full text of DOI:10.1021/ol0346436

ORGANIC
LETTERS
2003
Vol. 5, No. 12
2169-2171
Microwave-Assisted Synthesis of Diaryl
Ethers without Catalyst
Feng Li, Quanrui Wang,* Zongbiao Ding, and Fenggang Tao
Department of Chemistry, Fudan UniVersity, 200433 Shanghai, P. R. China
qrwangb@online.sh.cn
Received April 15, 2003
ABSTRACT
Diaryl ethers have been prepared by direct coupling of phenols including those that bear a strong electron-attracting substituent to electron-
deficient aryl halides through SNAr-based addition reactions with assistance of microwave irradiation in high to excellent yields within 5−10
min. No catalysts were required under our conditions.
Diaryl ether motifs are known to be a presence in a variety
of natural products and biologically interesting compounds1
and consequently provide a strong incentive for synthesis.
Central to this would be the assembly of the ether linkage.
Over the past years, tremendous effort has been devoted to
supplanting the classical Ullmann reaction2 and many valu-
able new methodologies for diaryl ether formation have been
developed.3,4 An important alternative to the Ullmann method
is the nucleophilic SNAr reaction of activated aryl halides,
preferentially in a 1,2- and/or 1,4-substitution pattern, with
phenols under basic conditions.5,6 The other variant, which
is more prevalent, features direct coupling of phenols with
aryl halides under catalytic effects of Cu(I) or Pd(I) species.
Although these advances have largely augmented the syn-
thetic scope, there are still some limitations. For example,
phenols can smoothly be converted to diaryl ethers only if
no strong electron-withdrawing group is present or if
exceedingly strenuous conditions (considerably prolonged
reaction time, elevated reaction temperature) are employed,
thus limiting the substrates employed and substituents in the
products.
Microwave heating has been widely recognized as an
efficient synthetic tool and its benefits have been well-
documented.7,8 Loupy has described a solvent free/microwave
method for the synthesis of aromatic ethers by the SNAr
reaction of 4-nitro-substituted halogenobenzenes or 2-ha-
lonaphthylenes, but only phenol was employed.8a Similar
results have been achieved by Bogdal, who prepared a range
of aromatic ethers by reaction of phenols with primary alkyl
halides under microwave heating, however, in the presence
of TBAB.8b Also Fan has employed the same strategy for
the reaction of 1-chloro-4-nitrobenzene and phenolates,
affording 4-nitrodiphenyl ethers.8c In this Letter, we wish to
(1) (a) Nicolaou, K. C.; Christopher, N. C. B. J. Am. Chem. Soc. 2002,
124, 10451. (b) Evans, D. A.; Dismore, C. J.; Watson, P. S.; Wood, M. R.;
Richardson, T. I.; Trotter, B. W.; Katz, J. L. Angew. Chem., Int. Ed. Engl.
1998, 37, 2704. (c) Nicolauo, K. C.; Takayanagi, M.; Jain, N. F.; Natarajan,
S.; Koumbis, A. E.; Bandi, T.; Ramanjulu, J. M. Angew. Chem., Int. Ed.
Engl. 1998, 37, 2717. (d) Boger, D. L.; Miyazaki, O. L.; Beresis, R. T.;
Castle, S. L.; Wu, J. H.; Jin, Q. J. Am. Chem. Soc. 1998, 120, 8920.
(2) (a) Moroz, A. A.; Shvartsberg, M. S. Russ. Chem. ReV. 1974, 43,
679. (b) Ullmann, F. Chem. Ber. 1904, 37, 853
(3) For a recent review, see: Sawyer, J. S. Tetrahedron 2000, 56, 5045.
(4) (a) Elizabeth, B.; Zhiguo, J. S.; David, T.; Peter, G. D. Org. Lett.
2002, 4, 1623. (b) Simon, J.; Salzbrunn, S.; Surya Prakash, G. K.; Petasis,
N. A.; Olah, G. A. J. Org. Chem. 2001, 66, 633. (c) Gujadhur, R. K.; Bates,
C. G.; Venkataraman, D. Org. Lett. 2001, 3, 4315. (d) Roberto, O.; Raul,
S.; Esther, D. Tetrahedron Lett. 2000, 41, 4357. (e) Shon, R. P.; Subhabrata,
S.; Andrei, V.; Erika, S. Org. Lett. 1999, 1, 1721. (f) Alexey, V. K.; Justin,
F. B.; Peter, R.; Victor, S. J. Org. Chem. 1999, 64, 2986. (g) Attila, A.;
David, W. O.; Ayumu, K.; John, P. W.; Joseph, P. S.; Stephen, L. B. J.
Am. Chem. Soc. 1999, 121, 4369. (h) Grace, M.; Christopher, I.; Arnold,
L. R.; John, F. H. J. Am. Chem. Soc. 1999, 121, 3224. (i) Theil, F. Angew.
Chem., Int. Ed. 1999, 38, 2345.
(7) (a) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199. (b) Lidstrom,
P.; Tierney, J.; Wathey, J. Tetrahedron 2001, 57, 9225. (c) Kaiser, N. F.
K.; Bremberg, U.; Larhed, M.; Moberg, C.; Hallberg, A. Angew. Chem.,
Int. Ed. 2000, 39, 3596. (d) Westman, J. Org. Lett. 2001, 3, 3745. (e) Brain,
C. T.; Brunton, S. A. Synlett. 2001, 382.
(8) For reports on the use of microwave irradiation in the synthesis of
aromatic ethers, see: (a) Chaouchi, M.; Loupy, A.; Marque, S.; Petit, A.
Eur. J. Org. Chem. 2002, 1278. (b) Bogdal, D.; Pielichowski, J.; Boron, A.
Synth. Commun. 1998, 28, 3029. (c) Fan, L.; Zhang, Y.; Wang, Y.; Liu, J.;
Ma, M.; Chen, S. Huaxue Yanjiu Yu Yingyong 2001, 13, 336.
(5) Sawyer, J. S.; Schmittling, E. A.; Palkowitz, J. A.; Smith, W. J., III
J. Org. Chem. 1998, 63, 6338.
(6) For a recent report on the synthesis of dinaphthyl ethers, see: Wipf,
P.; Lynch, S. M. Org. Lett. 2003, 5, 1155.
10.1021/ol0346436 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/14/2003

diverse diaryl ethers within a few minutes (Scheme 1).9 A
range of phenols were employed to couple with the electron-
deficient aryl halides such as mono-halogen substituted
benzonitrile and 1-chloro-4-nitrobenzene in the presence of
2 equiv of potassium carbonate under microwave irradiation
in DMSO medium and the results are shown in Table 1. In
all examples tested, fairly good to excellent yields could be
achieved in less than 10 min. This indicates a dramatic
reduction in reaction time as compared with the conventional
thermal process.10 For example, under the usual heating
conditions, the KF-Al2O3/18-crown-6-catalyzed coupling of
Scheme 1
report the microwave-assisted coupling of phenols, including
those having a strong electron-withdrawing group, with aryl
halides in the presence of potassium carbonate providing
Table 1. Microwave-Enhanced Synthesis of Diaryl Ethers
2170
Org. Lett., Vol. 5, No. 12, 2003

phenols with 2- or 4-flourobenzonitrile has been reported to
require 18-336 h in refluxing acetonitrile and etherification
of 2-hydroxybenzonitrile with 4-fluorobenzonitrile requires
36 h for completion of the reaction in DMSO at 140 °C.5
Our experiments exhibited that a wide variety of phenols,
including highly electron-deficient ones, could be smoothly
coupled with aryl halides. As shown in Table 1, treatment
of 2- or 4-fluorobenzonitrile with diversely substituted
phenols in 10 min under microwave heating led to the
formation of the desired aryoxy-substituted benzonitrile in
85% to 98% yields (entries 1-6).
It should be recalled that phenols bearing an electron-
withdrawing substituent behave poorly or are completely
inert toward diaryl formation. However, under our conditions
even the coupling of 1-chloro-4-nitrobenzene with the
extremely electron-poor 4-nitrophenol proceeded smoothly
leading to satisfactory yields of 4,4′-dinitrodiphenyl ether
(entry 7). To the best of our knowledge, 4-nitrophenol has
only scarcely been used as the coupling partner affording
extremely low yields.5 Again, the reaction with 4-hydroxy-
benzonitrile afforded 4-(4-nitrophenoxy)benzenecarbonitrile
in a high yield of 95% in 5 min (entry 8).
DMSO is the solvent of choice mainly due to its relatively
high boiling point and a high tanδ of the solvent and hence
resulting in rapid microwave heating.11 The effected high
temperature may account for the prominent acceleration in
the present SNAr reaction.12
Instead of 2- or 4-fluorobenzonitrile, the more readily
available 4-bromobenzonitrile can also be employed in the
coupling. Thus, the reaction with guaiacol (entry 9) furnished
the same diaryl ether as entry 2 and the yields are
comparable. Likewise, coupling with 4-chlorophenol led to
the formation of the corresponding diaryl ether in 87% yield
in 10 min (entry 10).
As can be seen from Table 1, not only 2- or 4-fluorine of
aryl halides acted as an ideal leaving group in the coupling
reaction (entries 1-6), 3-fluorine did equally well as
demonstrated by the reaction between guaiacol and 3-fluo-
robenzonitrile giving 3-(2-methoxyphenoxy)benzenecarbo-
nitrile as the sole product in 74% yield (entry 11).
Phenols bearing an electron-donating substituent are
known to be more favored toward the SNAr reaction.
However, our results using guaiacol are slightly controversial.
This might reflect the leveling action of the microwave
heating.
It is worth mentioning that all the diaryl ethers formed
are stable at high temperature and therefore the dielectric
heating has not caused any decomposition problem.
Rather, the reaction under microwave irradiation is very
clean and no byproducts have been detected. Therefore, the
workup procedure involves only a simple filtration of the
precipitation followed by washing with water. In all in-
stances, the products can be obtained in a purity higher than
1
98% as indicated by GC-MS and H NMR analysis.
In conclusion, we have developed a convenient microwave-
assisted version of diaryl ether synthesis. The electron-
deficient phenols have been shown to be well-tolerated in
the coupling process. The simplicity of this short and clean
procedure, no use of any catalyst, and generally satisfactory
yields render this method particularly attractive. The presence
of a diverse range of substituents and functional groups in
the diaryl ethers suggests also an opportunity to acquire many
other derivatives from these initial diaryl ethers.
(9) Typical procedure. The appropriate aryl halide (10 mmol), the phenol
(10-12 mmol), and anhydrous potassium carbonate (20 mmol) were
sequentially added to 50 mL of DMSO (A.R. grade without any previous
workup). The reaction was found not to be sensitive to air and moisture,
hence there was no need for inert atmosphere. With use of a microwave
power of 300 W, the reaction mixture was ramped from room temperature
to the boiling point of DMSO over 30-40 s, and then held at this refluxing
temperature for another 5-10 min until complete consumption of starting
material (GC monitoring). After being cooled to room temperature, the
resulting mixture was mixed with an ample amount of ice water to precipitate
the products and the solution was stirred for 30 min. Normal workup
afforded the pure diaryl ether.
(10) Mann, G.; Hartwig, J. F. Tetrahedron Lett. 1997, 38, 8005.
(11) tanδ ) 0.825. Gabriel, C.; Gabriel, S.; Grant, E. H.; Halstead, B.
S. J.; Mingos, D. M. P. Chem. Soc. ReV. 1998, 27, 213.
(12) (a) Kuhnert, N. Angew. Chem., Int. Ed. 2002, 41, 1863. (b) Sudrik,
S. G.; Chandrakumar, K. R. S.; Pal, S.; Date, S. K.; Chavan, S. P.;
Sonawane, H. R. J. Org. Chem. 2002, 67, 1574.
Acknowledgment. Financial support from the Foundation
for University Key Teacher by the Ministry of Education
and the Key Organic Synthesis Laboratory of Jiangsu
Province is gratefully acknowledged.
Supporting Information Available: Experimental details
concurrent with 1H NMR and GC-MS data of the synthesized
diaryl ethers. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL0346436
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