Facile O-Arylation of Phenols and Carboxylic Acids

Article abstract of DOI:10.1021/ol0361406

(Equation presented) A facile, transition-metal-free O-arylation procedure for phenols and aromatic carboxylic acids has been developed that affords good to excellent yields of arylated products under very mild reaction conditions. A methoxy-substituted aryl triflate affords O-arylated products in high yields with excellent regioselectivity. This chemistry tolerates a variety of functional groups.

Full text of DOI:10.1021/ol0361406

ORGANIC
LETTERS
2
004
Vol. 6, No. 1
9-102
Facile O-Arylation of Phenols and
Carboxylic Acids
9
Zhijian Liu and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
Received November 1, 2003
ABSTRACT
A facile, transition-metal-free O-arylation procedure for phenols and aromatic carboxylic acids has been developed that affords good to excellent
yields of arylated products under very mild reaction conditions. A methoxy-substituted aryl triflate affords O-arylated products in high yields
with excellent regioselectivity. This chemistry tolerates a variety of functional groups.
Diaryl ethers and aryl esters are commonly found in a variety
of biologically active and natural compounds. The classical
Pd-catalyzed O-arylation of a variety of phenols by aryl
halides is also a powerful method for the synthesis of diaryl
ethers. Even with these significant improvements in the
synthesis of diaryl ethers, there are still some limitations.
For example, (1) phenols can smoothly be converted to diaryl
ethers only if no strong electron-withdrawing group is
1
copper-mediated Ullmann diaryl ether synthesis usually
requires rather harsh reaction conditions and stoichiometric
2
amounts of copper. Recently, a number of valuable new
methods have been developed for the O-arylation of phenols
3
4
5
6a,b
and carboxylic acids. Evans and Chan have independently
reported the synthesis of diaryl ethers by the copper(II)-
promoted cross-coupling of phenols and arylboronic acids.
present or transition-metal complexes of aryl halides are
8
employed, (2) most reaction conditions are fairly harsh,
usually requiring very high temperatures (>110 °C), (3)
strong polar and often toxic solvents (toluene) are used, and
6
7
Buchwald and Hartwig have demonstrated that the Cu- or
(
4) the yields are often low. Although the microwave-assisted
9
synthesis of diaryl ethers provides some improvements, the
reaction conditions are still fairly harsh and not widely
applicable in organic synthesis.
(1) (a) Evans, D. A.; DeVries, K. M. In Glycopeptide Antibiotics, Drugs
and the Pharmaceutical Sciences; Nagarajan, R., Ed.; Marcel Decker,
Inc.: New York, 1994; Vol. 63, pp 63-104. (b) Deshpande, V. E.;
Gohkhale, N. J. Tetrahedron Lett. 1992, 33, 4213-4216. (c) Fotsch, C.;
Sonnenberg, J. D.; Chen, N.; Hale, C.; Karbon, W.; Norman, M. H. J. Med.
Chem. 2001, 44, 2344-2356. (e) Singh, S. B.; Pettit, G. R. J. Org. Chem.
The direct esterification of phenols by aliphatic or aromatic
carboxylic acids is virtually impossible due to the poor
1
990, 55, 2797-2800. (f) Pettit, G. R.; Singh, S. B.; Niven, M. L. J. Am.
Chem. Soc. 1988, 110, 8539-8540. (g) Jung, M. E.; Rohloff, J. C. J. Org.
Chem. 1985, 50, 4909-4913. (h) Atkinson, D. C.; Godfrey, K. E.; Myers,
P. L.; Philips, N. C.; Stillings, M. R.; Welbourn, A. P. J. Med. Chem. 1983,
(6) (a) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J.
P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369-4378. (b) Marcoux,
J.; Doye, S.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 10539-10540.
(c) Widenhoefer, R. A.; Zhong, H. A.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 6787-6795.
(7) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem.
Soc. 1999, 121, 3224-3225.
(8) (a) Pearson, A. J.; Bruhn, P. R. J. Org. Chem. 1991, 56, 7092-
7097. (b) Pearson, A. J.; Park, J. G.; Zhu, P. Y. J. Org. Chem. 1992, 57,
3583-3589. (c) Segal, J. A. J. Chem. Soc., Chem. Commun. 1985, 1338-
1339. (d) Pearson, A. J.; Bignan, G. Tetrahedron Lett. 1996, 37, 735-738.
(9) (a) Chaouchi, M.; Loupy, A.; Marque, S.; Petit, A. Eur. J. Org. Chem.
2002, 1278-1283. (b) Bogdal, D.; Pielichowski, J.; Boron, A. Synth.
Commun. 1998, 28, 3029-3039. (c) Li, F.; Wang, Q.; Ding, Z.; Tao, F.
Org. Lett. 2003, 5, 2169-2171.
2
6, 1361-1364. (i) Seldon, R. A. Chirotechnology; Marcel Dekker Inc.:
New York, 1998; pp 62-65. (j) Harris, G. D.; Herr, R. J.; Weinreb, S. J.
Org. Chem. 1993, 58, 5452-5462.
(2) (a) Ullmann, F. Chem. Ber. 1904, 37, 853-854. (b) Lindley, J.
Tetrahedron 1984, 40, 1433-1456.
(3) For a recent review, see: (a) Sawyer, J. S. Tetrahedron 2000, 56,
5
2
045-5065. (b) Theil, F. Angew. Chem., Int. Ed. Engl. 1999, 38, 2345-
347.
(4) (a) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998,
3
3
9, 2937-2940. (b) Decicco, C. P.; Song, S.; Evans, D. A. Org. Lett. 2001,
, 1029-1032.
(
5) Chan, D. M. T.; Monaco, K. L.; Wang, R.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933-2936.
1
0.1021/ol0361406 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/16/2003

Scheme 1
Scheme 2
1
0
phenyl trifluoromethanesulfonate (1c)15 is allowed to react
with p-methoxyphenol, we can obtain the corresponding
diaryl ether in a 96% yield (entry 3). It should be noted that
phenols bearing an electron-withdrawing substituent gener-
ally behave poorly or are completely inert toward diaryl ether
nucleophilicity of phenols. The direct coupling of aromatic
carboxylic acids and aryl halides or the carbonylation of aryl
halides using a palladium catalyst to generate the corre-
sponding aryl esters is also difficult.11 In the classical
methods for esterification, a strong acid, such as sulfuric acid,
is needed, which is not suitable for acid-sensitive compounds
and has the disadvantages of the corrosiveness of the strong
acid and accompanying side reactions, such as carbonization,
6
formation when using aryl halides. However, under our
reaction conditions, phenols with an electron-withdrawing
group, such as a nitro or aldehyde group, work quite well to
generate the corresponding diaryl ethers in high yields
(entries 4 and 5). When using the methoxy-substituted
1
2
oxidation, etc. Thus, an efficient and reliable procedure to
synthesize diaryl ethers from phenols and aryl esters from
carboxylic acids under mild reaction conditions, which can
tolerate a wide variety of functional groups, would be quite
attractive.
16
silylaryl triflate 1b, p-nitrophenol affords the corresponding
diaryl ether as a single isomer in a 96% yield (entry 6). Note
that we only obtain the product of nucleophilic attack at the
position meta to the methoxy group of the aryne, which is
Very recently, we have found that silylaryl triflate 1a in
the presence of CsF can react with a variety of amines and
sulfonamides to generate N-arylated amines and sulfonamides
1
3
consistent with our earlier results and the work of others
15,17
with this aryne.
It is noteworthy that 4-iodophenol reacts
1
3
in excellent yields under very mild reaction conditions.
well with silylaryl triflates 1a and 1b to generate the desired
iodo-substituted diaryl ethers in excellent yields (entries 7
and 8). Thus, halides are readily accommodated by our
reaction conditions. We believe that this is the first method
for diaryl ether formation that readily tolerates halides
other than the use of ruthenium-complexed aryl halides.8d
Interestingly, if we use 1,2-benzenediol, we can obtain a 72%
yield of the double O-arylation product (entry 9). The
sterically hindered phenol 2,4,6-trimethylphenol also reacts
smoothly with silylaryl triflate 1a to afford a 68% yield
of the desired product (entry 10). Thus, this chemistry
provides a very convenient method to prepare a variety of
diaryl ethers that tolerates a number of functional groups
and produces very high yields under very mild reaction
conditions.
Thus, it was a natural extension for us to investigate the
O-arylation of phenols and carboxylic acids using this
silylaryl triflate and CsF. Herein, we report a facile, high-
yielding, transition-metal-free method for the O-arylation of
phenols and carboxylic acids by reacting silylaryl triflates
with a variety of phenols and carboxylic acids under very
mild reaction conditions.
We first examined the reaction of phenol with 1.2 equiv
of 2-(trimethylsilyl)phenyl triflate (1a) and 2 equiv of CsF
in acetonitrile at room temperature, which are our standard
reaction conditions for the N-arylation of amines and
sulfonamides. We obtained only a 66% yield of the desired
diphenyl ether in 20 h. After optimizing this reaction system
using phenol and 1.5 equiv of silylaryl triflate 1a, plus 3.0
equiv of CsF in acetonitrile for 1 d at room temperature, we
were able to obtain diphenyl ether in a 92% isolated yield
13
We have also investigated the O-arylation of carboxylic
acids to generate aryl esters (Scheme 2). As shown in Table
(Scheme 1).
1, entries 11-16, benzoic acid and a number of functionally
Using these optimal reaction conditions, this method has
substituted benzoic acids react smoothly with silylaryl
triflates 1a and 1b to generate the corresponding aryl esters
in high yields. Benzoic acids with an electron-donating group,
like a methoxy group (entries 13 and 14), generally afford
better yields than benzoic acids with an electron-withdrawing
group, like a nitro group (entry 12). Once again, the methoxy-
substituted silylaryl triflate 1b affords only one product in
which nucleophilic attack has occurred at the position meta
been applied to the O-arylation of a wide variety of phenols
Table 1, entries 1-10). Phenol itself and phenol with an
electron-donating p-methoxy group react well with silylaryl
(
1
4
triflate 1a to give the corresponding diaryl ethers in high
yields (entries 1 and 2). If 4,5-dimethyl-2-(trimethylsilyl)-
(
10) Beyer, H.; Walter, W. Handbook of Organic Chemistry; Prentice
Hall Europe: London, 1996; p 497.
11) (a) Yamamoto, T. Synth. Commun. 1979, 9, 219-222. (b) Ramesh,
C.; Kubota, Y.; Miwa, M.; Sugi, Y. Synthesis 2002, 2171-2173.
12) (a) Fischer, E. Ber. 1895, 28, 3254-3257. (b) Butts, J. J. Am. Chem.
(
(15) Yoshida, H.; Sugiura, S.; Kunai, A. Org. Lett. 2002, 4, 2767-
2769.
(16) Pena, D.; Perez, D.; Guitian, E.; Castedo, L. J. Am. Chem. Soc.
1999, 121, 5827-5828.
(17) Kessar, S. V. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, England, 1991; Vol. 4, pp 483-
515.
(
Soc. 1931, 53, 3560-3561.
(
13) Liu, Z.; Larock, R. C. Org. Lett. 2003, 5, 4673-4675.
(14) Silylaryl triflate 1a is commercially available or it is can be prepared
according to: Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
211-1214.
1
100
Org. Lett., Vol. 6, No. 1, 2004

Table 1. Facile O-Arylation of Phenols and Carboxylic Acidsa
a
Reaction conditions: 0.25 mmol of phenol or carboxylic acid are allowed to react with the number of equivalents of aryl triflate and CsF shown in the
table and 4.0 mL of MeCN as solvent at room temperature for 1 d. b The reaction time is 2.5 d.
to the methoxy group (entries 14 and 15). Halogen-
substituted benzoic acids also work well, generating the
desired halogen-substituted aryl esters in good yields (entries
15 and 16). Unfortunately, for reasons we do not presently
Org. Lett., Vol. 6, No. 1, 2004
101

understand, we have been unable to get acceptable yields of
aryl esters from simple aliphatic carboxylic acids.
Acknowledgment. We are grateful to the Petroleum
Research Fund, administered by the American Chemical
Society, for their generous financial support.
In summary, we have developed an efficient, mild,
transition-metal-free method for the O-arylation of phenols
and aromatic carboxylic acids. A variety of functional groups
are compatible with the reaction conditions. The regioselec-
tivity of the methoxy-substituted aryl triflate 1b is excellent.
Further studies into the scope of different heteroatom-
containing substrates and additional silylaryl triflates are
currently under way in our laboratories.
Supporting Information Available: Detailed experi-
mental procedures and characterization data for all previously
unknown products. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0361406
102
Org. Lett., Vol. 6, No. 1, 2004