ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Metal-Free Synthesis of Aryl Ethers in
Water
Erik Lindstedt, Raju Ghosh, and Berit Olofsson*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
SE-106 91 Stockholm, Sweden
Received October 14, 2013
ABSTRACT
The first arylation of allylic and benzylic alcohols with diaryliodonium salts is reported. The reaction yields alkyl aryl ethers under mild and metal-
free conditions. Phenols are arylated to diaryl ethers in good to excellent yields. The reaction employs diaryliodonium salts and sodium hydroxide
in water at low temperature, and excess amounts of the coupling partners are avoided.
Aryl ethers are important structural motifs in many
natural products and drugs, and heteroatom arylation
and alkylation rank as the most common transformations
in the synthesis of drug candidates.1 Consequently, there
are many synthetic routes to this compound class, ranging
from the classical Ullmann coupling to recent copper- and
palladium-catalyzed coupling reactions employing alco-
hols and aryl halides or arylboronic acids.2 Metal-
catalyzed reactions are often high-yielding, but generally
suffer from the need for expensive catalysts, ligands, high
temperatures, and long reaction times.3
electron-deficient aryl fluorides,5 and reactions with
Mitsunobu type reagents,6 aryl mesylates,7 or benzyne
intermediates.8 These reactions are either performed at
high temperature, require toxic reagents, or have a limited
substrate scope.9 A metal-free O-alkylation of naphthols
under acidic conditions was recently reported, which
addressed some of the environmental issues usually asso-
ciated with ether formation.10
We have recently reported an efficient and metal-free
synthesis of diaryl ethers by arylation of phenols with
diaryliodonium salts at room temperature.11 The aryla-
tion of aliphatic alcohols with these reagents was briefly
reported some decades ago,12 but a synthetically useful method
isstill lacking. A recentcopper-catalyzedmonoarylation of
Metal-free syntheses of aryl ethers from alcohols include
the Williamson ether synthesis,4 SNAr reactions with
(1) (a) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451–
3479. (b) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org.
Biomol. Chem. 2006, 4, 2337–2347.
(2) Recent reports: (a) Anderson, K. W.; Ikawa, T.; Tundel, R. E.;
Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 10694–10695. (b) Wu, X.;
Fors, B. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 9943–9947.
(c) Maligres, P. E.; Li, J.; Krska, S. W.; Schreier, J. D.; Raheem, I. T.
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Sergeev, A. G.; Anbarasan, P.; Spannenberg, A.; Neumann, H.; Beller,
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(9) Recent review: Mehta, V. P.; Punji, B. RSC Advances 2013, 3,
11957–11986.
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Ed. 2003, 42, 5400–5449. (b) Qiao, J. X.; Lam, P. Y. S. Synthesis 2011,
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Green Chem. 2011, 13, 2482–2488.
(11) (a) Jalalian, N.; Petersen, T. B.; Olofsson, B. Chem.;Eur. J.
2012, 18, 14140–14149. (b) Jalalian, N.; Ishikawa, E. E.; Silva, L. F., Jr.;
Olofsson, B. Org. Lett. 2011, 13, 1552–1555.
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Lumpkin, C. C. J. Am. Chem. Soc. 1953, 75, 2708–2712 (5 equiv
NaOMe, Ph2IBr in refluxing MeOH). Mechanistic studies: (b)
Lubinkowski, J. J.; Gimenez Arrieche, C.; McEwen, W. E. J. Org. Chem.
1980, 45, 2076–2079. (c) Lubinkowski, J. J.; Knapczyk, J. W.; Calderon,
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10.1021/ol402960f
XXXX American Chemical Society