Room temperature, metal-free synthesis of diaryl ethers with use of diaryliodonium salts

Article abstract of DOI:10.1021/ol200265t

A fast, high-yielding synthesis of diaryl ethers with use of mild and metal-free conditions has been developed. The scope includes bulky ortho-substituted diaryl ethers, which are difficult to obtain by metal-catalyzed protocols. Halo-substituents, racemization-prone amino acid derivatives, and heteroaromatics are also tolerated. The methodology is expected to be of high utility in the synthesis of complex molecules and in the pharmaceutical industry.

Full text of DOI:10.1021/ol200265t

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1552–1555
Room Temperature, Metal-Free Synthesis
of Diaryl Ethers with Use of
Diaryliodonium Salts
Nazli Jalalian,† Eloisa E. Ishikawa,‡ Luiz F. Silva Jr.,‡ and Berit Olofsson*,†
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
´
SE-106 91 Stockholm, Sweden, and Departamento de Quımica Fundamental,
Instituto de Quımica, Universidade de Sao Paulo, Caixa Postal 26077,
´
~
~
CEP 05513-970 Sao Paulo SP, Brazil
berit@organ.su.se
Received January 27, 2011
ABSTRACT
A fast, high-yielding synthesis of diaryl ethers with use of mild and metal-free conditions has been developed. The scope includes bulky ortho-
substituted diaryl ethers, which are difficult to obtain by metal-catalyzed protocols. Halo-substituents, racemization-prone amino acid derivatives,
and heteroaromatics are also tolerated. The methodology is expected to be of high utility in the synthesis of complex molecules and in the
pharmaceutical industry.
Diaryl ethers are common structural features in nu-
merous natural products and biologically active
compounds.1 The total synthesis of vancomycin and
other glycopeptide antibiotics, as well as anti-HIV agents
like chloropeptin, which contain this substructure, has
received considerable attention.2 Despite more than a
century of immense focus on finding efficient synthetic
routes to this compound class, substituted diaryl ethers
remain difficult to obtain for applications in life science
and the polymer industry.3
The classical Ullmann synthesis from phenols and aryl
iodides requires stoichiometric amounts of copper and
harsh reaction conditions.4 The catalytic reaction condi-
tions since developed require high catalyst loadings, excess
reagents, elevated temperatures, and long reaction times.1,3,5
Recent progress includes the copper-catalyzed coupling of
phenols and arylboronic acids.6 This ligand-assisted reaction
proceeds at room temperature, but excess amounts of rea-
gents are often needed.3
Pd-catalyzed cross-couplings of phenols and aryl halides
were reported in 1999,7 and give high yields of a range of
diaryl ethers.3 Still, they rely on high reaction temperatures
and expensive, noncommercial ligands. Furthermore,
heteroaromatics and ortho-substituted coupling partners
are often challenging in both Cu- and Pd-catalyzed
† Stockholm University.
‡
~
Universidade de Sao Paulo.
(1) (a) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108,
3054. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400.
(2) (a) Evans, D. A.; Katz, J. L.; Peterson, G. S.; Hintermann, T.
J. Am. Chem. Soc. 2001, 123, 12411. (b) Deng, H.; Jung, J.-K.; Liu, T.;
Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2003,
125, 9032. (c) Nicolaou, K. C.; Boddy, C. N. C.; Natarajan, S.; Yue,
(4) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1904, 37, 853. (b) Lindley,
J. Tetrahedron 1984, 40, 1433.
(5) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954.
(6) (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.
(7) (a) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi,
J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369. (b) Mann, G.;
Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem. Soc. 1999,
121, 3224.
€
T. Y.; Li, H.; Brase, S.; Ramanjulu, J. M. J. Am. Chem. Soc. 1997, 119,
3421. (d) Wang, Z.; Bois-Choussy, M.; Jia, Y.; Zhu, J. Angew. Chem.,
Int. Ed. 2010, 49, 2018. (e) Boger, D. L.; Miyazaki, S.; Kim, S. H.; Wu,
J. H.; Castle, S. L.; Loiseleur, O.; Jin, Q. J. Am. Chem. Soc. 1999, 121,
10004.
(3) (a) Frlan, R.; Kikelj, D. Synthesis 2006, 2271. (b) Sawyer, J. S.
Tetrahedron 2000, 56, 5045. (c) Modern arylation methods; Ackermann, L.,
Ed.; Wiley-WCH: Weinheim, Germany, 2009.
r
10.1021/ol200265t
Published on Web 02/14/2011
2011 American Chemical Society

Table 1. Optimization of the Model Reactiona
Scheme 1. Synthetic Strategies To Form Diaryl Ethers
entry
base
NaH
2 (X)
temp (°C)
time
4 h
yield (%)b
1
2
3
4
5
6
7
2a (OTf)
2a (OTf)
2a (OTf)
2a (OTf)
2b (BF4)
2a (OTf)
2a (OTf)
rt
93
>99
97
NaOH
rt
4 h
t-BuOK
NaOH
rt
4 h
40
40
40
rt
1 h
99
NaOH
1 h
>99
>99
95
t-BuOK
t-BuOK
15 min
2 h
protocols (Scheme 1A).3 Thallium(III)-mediated oxidative
couplings have been employed in natural product
synthesis, although the demand for excess toxic thallium
reagent makes this approach unsuitable for large-scale
reactions.8
a Base (1.1 equiv) and 1a (1.1 equiv) were stirred at 0 °C for 15 min
before addition of salt 2 (1 equiv). b Determined by GC with 1,4-
dimethoxybenzene as internal standard.
Metal-free methods with limited scope include reactions with
benzyne intermediates9 and SNAr additions to electron-poor
aryl halides under mild conditions.10 The synthesis of diaryl
ethers from phenols and diaryliodonium salts was reported
already in the 1950s.11 The reaction employed diaryliodonium
halides and inorganic bases in protic solvents, and required
prolonged reaction times and high temperature to give diaryl
ethers in moderate to good yields.12-14
reactions,17 avoiding the drawbacks of organometallic
chemistry, such as cost, toxicity, and threshold values in
pharmaceutical products.
We and others have developed efficient one-pot routes
to diaryliodonium salts, and these compounds are now
inexpensive and easily available (eq 1).18 We are presently
investigating these selective and nontoxic reagents as elec-
trophilic arylating agents,19 and herein we present our
preliminary results on the arylation of phenols under mild
and racemization-free conditions (Scheme 1B).
The use of diaryliodonium salts has recently gained
considerable attention in organic synthesis.15 Their proper-
ties allow for both metal-catalyzed16 and metal-free
(8) Silva, L. F., Jr; Carneiro, V. M. T. Synthesis 2010, 1059.
(9) Liu, Z.; Larock, R. C. Org. Lett. 2004, 6, 99.
(10) Li, F.; Wang, Q.; Ding, Z.; Tao, F. Org. Lett. 2003, 5, 2169.
(11) Early reports: (a) Beringer, F. M.; Brierley, A.; Drexler, M.;
Gindler, E. M.; Lumpkin, C. C. J. Am. Chem. Soc. 1953, 75, 2708. (b)
Dibbo, A.; Stephenson, L.; Walker, T.; Warburton, W. K. J. Chem.
Soc. 1961, 2645. (c) Crowder, J. R.; Glover, E. E.; Grundon, M. F.;
Kaempfen, H. X. J. Chem. Soc. 1963, 4578. (d) Lubinkowski, J. J.;
Knapczyk, J. W.; Calderon, J. L.; Petit, L. R.; McEwen, W. E. J. Org.
Chem. 1975, 40, 3010.
The previous use of base in refluxing protic solvents is
detrimental to racemization-prone substrates, such as
R-amino acid-substituted phenols that are common in
natural products. We envisioned that a mild arylation
procedure could be developed by using aprotic solvents
and diaryliodonium triflates or tetrafluoroborates, as
salts with those anions are soluble also in less polar
solvents.20
Phenol (1a) and diphenyliodonium triflate (2a) were
chosen as model substrates in the optimization of reaction
conditions yielding diphenyl ether (3a). An initial solvent
screening with NaH as base revealed that DMF, toluene,
THF, and dichloromethane all gave >90% conversion
within 4 h at room temperature, while acetonitrile was less
efficient. Further optimization was performed in THF,
(12) Recent reports: (a) Crimmin, M. J.; Brown, A. G. Tetrahedron
Lett. 1990, 31, 2017 (MeOH or DMF, 95 °C). (b) Huang, X.; Zhu, Q.;
Xu, Y. Synth. Commun. 2001, 31, 2823 (DMF, 100 °C, 10 h). In synthesis
€
of polybrominated ethers:(c) Teclechiel, D.; Sundstrom, M.; Marsh, G.
Chemosphere 2009, 74, 421 (water/dioxane, 80 °C, 3 h). (d) Liu, H.;
Bernhardsen, M.; Fiksdahl, A. Tetrahedron 2006, 62, 3564 (H2O, reflux,
2 h). (e) Marsh, G.; Stenutz, R.; Bergman, A. Eur. J. Org. Chem. 2003,
2566 (H2O/dioxane, 80 °C, 1-8 h). (f) Couladouros, E. A.; Moutsos,
V. I.; Pitsinos, E. N. ARKIVOC 2003, 92 (DMF, 90 °C, 3 h).
(13) Metal-catalyzed reports: (a) Thakur, V. V.; Kim, J. T.; Hamilton,
A. D.; Bailey, C. M.; Domaoal, R. A.; Wang, L.; Anderson, K. S.;
Jorgensen, W. L. Bioorg. Med. Chem. Lett. 2006, 16, 5664. (b) Hickey,
D. M. B.; Leeson, P. D.; Novelli, R.; Shah, V. P.; Burpitt, B. E.; Crawford,
L. P.; Davies, B. J.; Mitchell, M. B.; Pancholi, K. D.; Tuddenham, D.;
Lewis, N. J.; O’Farrell, C. J. Chem. Soc., Perkin Trans. 1 1988, 3103.
(14) Dearomatization of phenols with diaryliodonium salts: Ozanne-
Beaudenon, A.; Quideau, S. Angew. Chem., Int. Ed. 2005, 44, 7065.
(15) (a) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48,
9052. (b) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299. (c)
Wirth, T., Ed. Hypervalent Iodine Chemistry; Topics in Current Chemistry,
224; Springer: Berlin, Germany, 2003. (d) Zhdankin, V. V.. Sci. Synth. 2007,
31a, 161.
(18) (a) Bielawski, M.; Olofsson, B. Chem. Commun. 2007, 2521. (b)
Bielawski, M.; Zhu, M.; Olofsson, B. Adv. Synth. Catal. 2007, 349, 2610.
(c) Bielawski, M.; Aili, D.; Olofsson, B. J. Org. Chem. 2008, 73, 4602. (d)
Zhu, M.; Jalalian, N.; Olofsson, B. Synlett 2008, 592. (e) Merritt, E. A.;
Malmgren, J.; Klinke, F. J.; Olofsson, B. Synlett 2009, 2277. (f)
Bielawski, M.; Olofsson, B. Org. Synth. 2009, 86, 308. (g) Jalalian, N.;
Olofsson, B. Tetrahedron 2010, 66, 5793.
(19) Norrby, P.-O.; Petersen, T. B.; Bielawski, M.; Olofsson, B.
Chem.;Eur. J. 2010, 16, 8251.
(20) The nucleophilicity of the phenoxide was expected to increase in
an aprotic solvent. The previous use of protic solvents is likely due to
insolubility of diaryliodonium halides in aprotic media.
(16) (a) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593. (b)
Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 11234. (c)
Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(17) (a) Dohi, T.; Ito, M.; Yamaoka, N.; Morimoto, K.; Fujioka, H.;
Kita, Y. Angew. Chem., Int. Ed. 2010, 49, 3334. (b) Kita, Y.; Morimoto,
K.; Ito, M.; Ogawa, C.; Goto, A.; Dohi, T. J. Am. Chem. Soc. 2009, 131,
1668.
Org. Lett., Vol. 13, No. 6, 2011
1553

Table 2. Phenylation of Functionalized Phenols 1a
Table 3. Arylation of Functionalized Phenols 1 with Salts 2a
a 1 (1.0-1.1 equiv), t-BuOK (1.1 equiv), and 2 (1.0-1.2 equiv) were
used at 40 °C.
substituents, giving diaryl ethers 3b-e in high yields
(entries 5-9).
Arylation of pentachloro phenol 1f resulted in quanti-
tative yield of product 3f (entry 10). Likewise, iodo-sub-
stituted substrates 1g,h delivered the corresponding diaryl
ethers 3g,h that can easily be used in cross-coupling reac-
tions (entries 11 and 12). These products would be difficult
to obtain with Pd-catalyzed reactions due to chemoselec-
tivity problems, which nicely illustrates the potential of the
developed methodology.
a 1 (1.0-1.1 equiv), t-BuOK (1.1 equiv), and 2 (1.0-1.2 equiv) were
used. b NaOH as base. c 2 equiv of 2a.
Ortho-substituted phenols are problematic substrates in
metal-mediated arylations.1b,3a Gratefully, steric bulk
posed no problem in this reaction, as exemplified by o-
iodo product 3h (entry 12). The sterically hindered 1,10-bi-
2-naphthol (1i) was an excellent substrate, delivering the
diarylatedproduct as a precipitate without need for further
purification (entry 13).
Carbonyl-substituted phenols 1j-l, including paraceta-
mol, were also arylated in good yields (entries 14-18).
Furthermore 3-hydroxypyridine, which is a privileged
scaffold, was smoothly phenylated to give 3m in high yield
(entry 19).
All reactions were run without precautions to avoid air
or moisture. The temperature was selected to 40 °C for
conveniently short reaction times. Itshouldbe stressedthat
room temperature works equally well, as demonstrated in
entries 4, 8, 15, and 17. Likewise, t-BuOK was chosen as
and both NaOH and t-BuOK proved more efficient than
NaH (Table 1, entries 1-3).
At 40 °C, the reaction went to completion within 1 h,
and tetrafluoroborate 2b worked equally well as triflate
2a (entries 4 and 5). The reaction time was finally
investigated, and 3a was obtained in excellent yield
already within 15 min at 40 °C or 2 h at room tempera-
ture (entries 6 and 7).
The reaction scope was subsequently explored by using
substituted phenols 1 and diphenyliodonium triflate 2a or
tetrafluoroborate 2b. Excellent isolated yields of diphenyl
ether 3a were obtained with both salts at 40 °C (Table 2,
entries 1 and 2). Reactions employing NaOH or room
temperature provided equally good results (entries 3
and 4). Phenols with electron-withdrawing substituents
worked equally well as those with electron-donating
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Org. Lett., Vol. 13, No. 6, 2011

base for practical reasons, but NaOH can also be used
(entry 3). Oxidative dearomatization of the phenol was not
observed.14
Scheme 2. Arylation of R-Amino Acid Derivatives 4a and 4b
Various symmetrical diaryliodonium salts 2 were subse-
quently employed. Electron-deficient salt 2c efficiently
arylated 1a to give CF3-substituted product 3b (Table 3,
entry 1, cf. Table 2, entry 5). The electron-rich salt 2d deli-
vered dimethoxy ether 3n without difficulties (entry 2).
Steric hindrance in the diaryliodonium salt posed no
problem, as bis(ortho-substituted) salts 2e,f arylated phe-
nols 1a,c to give 3o,p (entries 3 and 4).
Even highly substituted diaryl ether 3q, with three ortho
substituents, was obtained in quantitative yield (entry 5).
p-Chloro salt 2h was employed to arylate a range of
phenols. Notably, 2,4-di(tert-butyl) phenol 1q delivered
3s in high yield, despite the severe steric hindrance from the
ortho substituent (entry 7). Quinolin-8-ol (1r) was also
arylatedwith2htogiveheteroarylether 3t inexcellent yield
(entry 8).
The mild conditions of this protocol were demonstrated
by arylation of the racemization-prone tyrosine derivative
4a and aryl glycine derivative 4b (Scheme 2). Both R-amino
acid derivatives were arylated in excellent yields without
loss of enantiomeric excess.21
halo-substituted diaryl ethers, which are difficult to obtain
by metal-catalyzed protocols.
The potential of the developed methodology has been
demonstrated by arylation of two R-amino acid derivatives
without racemization. With the recent advancements in
efficient synthetic procedures for diaryliodonium salts, the
reagents are now inexpensive and easily available. The
application to aliphatic alcohols is underway, and will be
reported in due time.
Acknowledgment. This work was financially supported
by the SwedishResearchCouncil, the SwedishFoundation
for International Cooperation in Research and Higher
Education (STINT), and CNPq.
To conclude, we have developed a fast, high-yielding
synthesis of diaryl ethers. The reaction conditions are mild,
metal-free, and avoid the use of halogenated solvents,
additives, or excess reagents. Precautions to avoid air or
moisture are not needed. The scope includes ortho- and
Supporting Information Available. Experimental pro-
1
cedures, analytical data, and H and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Phenol 4b was arylated in dichloromethane, as a byproduct
lowered the yield in THF.
Org. Lett., Vol. 13, No. 6, 2011
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