Metal-free synthesis of aryl ethers in water

Article abstract of DOI:10.1021/ol402960f

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.

Full text of DOI:10.1021/ol402960f

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
berit@organ.su.se
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.
Angew. Chem., Int. Ed. 2012, 51, 9071–9074. (d) Gowrisankar, S.;
Sergeev, A. G.; Anbarasan, P.; Spannenberg, A.; Neumann, H.; Beller,
M. J. Am. Chem. Soc. 2010, 132, 11592–11598.
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(7) Sach, N. W.; Richter, D. T.; Cripps, S.; Tran-Dube, M.; Zhu, H.;
Huang, B.; Cui, J.; Sutton, S. C. Org. Lett. 2012, 14, 3886–3889.
(8) (a) Cano, R.; Ramon, D. J.; Yus, M. J. Org. Chem. 2011, 76, 654–
660. (b) Yuan, Y.; Thome, I.; Kim, S. H.; Chen, D.; Beyer, A.;
Bonnamour, J.; Zuidema, E.; Chang, S.; Bolm, C. Adv. Synth. Catal.
2010, 352, 2892–2898.
ꢀ
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(9) Recent review: Mehta, V. P.; Punji, B. RSC Advances 2013, 3,
11957–11986.
(3) Recent reviews: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int.
Ed. 2003, 42, 5400–5449. (b) Qiao, J. X.; Lam, P. Y. S. Synthesis 2011,
829–856. (c) Frlan, R.; Kikelj, D. Synthesis 2006, 2271–2285.
(4) Fuhrmann, E.; Talbiersky, J. R. Org. Process Res. Dev. 2005, 9,
206–211.
(10) Cazorla, C.; Pfordt, E.; Duclos, M.-C.; Metay, E.; Lemaire, M.
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.
(5) (a) Woiwode, T. F.; Rose, C.; Wandless, T. J. J. Org. Chem. 1998,
63, 9594–9596. (b) Bunce, R. A.; Easton, K. M. Org. Prep. Proced. Int.
2004, 36, 76–81.
(6) (a) Manivel, P.; Rai, N. P.; Jayashankara, V. P.; Arunachalam,
P. N. Tetrahedron Lett. 2007, 48, 2701–2705. (b) Shintou, T.; Mukaiyama,
T. J. Am. Chem. Soc. 2004, 126, 7359–7367.
(12) (a) Beringer, F. M.; Brierley, A.; Drexler, M.; Gindler, E. M.;
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,
J. L.; Petit, L. R.; McEwen, W. E. J. Org. Chem. 1975, 40, 3010–3015.
r
10.1021/ol402960f
XXXX American Chemical Society

vicinal diols with diaryliodonium salts was inefficient for
regular alcohols.13
Table 1. Optimization with Cinnamyl Alcohol
The lack of a general, metal-free arylation methodology
for aliphatic alcohols under mild and environmentally
benign conditions prompted us to develop an arylation
reaction with diaryliodonium salts, which are stable hy-
pervalent iodine reagents of low toxicity.14,15 Herein our
preliminary results are disclosed.
T
t
yield
(%)a
An initial screening revealed that conjugated and regular
alcohols displayed rather different reactivity toward di-
aryliodonium salts. Conjugated alcohols are easily oxidized
to the corresponding aldehydes/ketones or carboxylic
acids, thus complicating the use of hypervalent iodine
reagents, which are powerful oxidants.
entry
base
(equiv)
solvent
(°C)
(h)
1
t-BuOK
NaH
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2.0
5.0
2.0
2.0
1.5
2.0
2.0
2.0
toluene
toluene
THF
CH2Cl2
H2O
40
40
40
40
40
60
80
100
rt
4
6
6
2
3
3
3
3
3
3
3
3
1
1
1
1
3
38
46
29
29
32
56
55
49
3
2
3
NaH
4
NaH
5
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
KOH
A thorough optimization was performed with cinnamyl
alcohol and diphenyliodonium triflate (1a), giving ether 2a
in moderate yields using various bases and solvents (Table 1,
entries 1À5). Water in combination with the mild base
NaOH is ideal for environmental purposes, and these
conditions were thus optimized further. Pleasingly, 2a
was obtained in 56% yield at 60 °C (entry 6). Further
temperature increases were not fruitful, and ambient tem-
perature was inefficient (entries 7À9).
6
H2O
7
H2O
8
H2O
9
H2O
10
11
12
13
14
15
16
17b
H2O
60
60
50
60
60
60
60
60
64
65
62
63
60
61
61
64
H2O
H2O
H2O
H2O
H2O
LiOH
NaOH
H2O
The yield of 2a increased to 64% with 2 equiv of base
(entries 10À11), and the reaction could be performed at
50 °C for 3 h instead (entry 12). A 1 h reaction time was
sufficient, and potassium or lithium hydroxide gavesimilar
results (entries 13À16).
H2O
a NMR yield with 4-anisaldehyde as the internal standard. b 5% DPE
added.
performed at room temperature to avoid competitive
arylation of the base (vide infra).
The addition of the radical trap 1,1-diphenylethylene
(DPE) did not influence the reaction outcome (entry 17),
indicating that neither products nor byproducts are formed
via a radical pathway.16 Diphenyliodonium tetrafluorobo-
rate (1b) was as efficient as the triflate salt, whereas the
corresponding tosylate salt 1c gave product 2a in 55% yield.
Symmetric and unsymmetric diaryliodonium salts are easily
available,17 and the arylation scope was subsequently
investigated with salts 1 (Scheme 1).18 Cinnamyl alcohol
was chemoselectively arylated with nitrophenyl(phenyl)-
iodonium triflate (1d) to give 2b. This reaction was best
4-Trifluoromethylphenyl salt 1e was highly reactive and
delivered product 2c in high yield. The synthesis of bromo-
substituted ether 2d further illustrates the functional group
tolerance of the methodology. Alkyl-substituted salts re-
acted slower than unsubstituted or electron-withdrawing
salts, and 2e was formed in moderate yield. The arylation
of allyl alcohol required a longer reaction time to give ether
Scheme 1. Arylation of Allylic Alcohols
(13) Kuriyama, M.; Hamaguchi, N.; Onomura, O. Chem.;Eur. J.
2012, 18, 1591–1594.
(14) (a) Yusubov, M. S.; Maskaev, A. V.; Zhdankin, V. V. ARKI-
VOC 2011, 370–409. (b) Merritt, E. A.; Olofsson, B. Angew. Chem., Int.
Ed. 2009, 48, 9052–9070. (c) Quideau, S.; Wirth, T. Tetrahedron 2010, 66,
5737–5738.
(15) The biological activities of several diaryliodonium salts have
been studied in detail, and the results are summarized in: Stang, P. J.;
Zhdankin, V. V. Chem. Rev. 1996, 96, 1123–1178. Diaryliodonium salts
have even been found suitable to use in oral mouthwash; see: Goldstein,
E. J. C.; Citron, D. M.; Warren, Y.; Merriam, C. V.; Tyrrell, K.;
Fernandez, H.; Radhakrishnan, U.; Stang, P. J.; Conrads, G. Antimi-
crob. Agents Chemother. 2004, 48, 2766–2770.
(16) Radicals were involved in byproduct formation in the mecha-
nistic studies by McEwen; see refs 12b, 12c.
(17) (a) Bielawski, M.; Aili, D.; Olofsson, B. J. Org. Chem. 2008, 73,
4602–4607. (b) Bielawski, M.; Zhu, M.; Olofsson, B. Adv. Synth. Catal.
2007, 349, 2610–2618. (c) Zhu, M.; Jalalian, N.; Olofsson, B. Synlett
2008, 592–596. (d) Hossain, M. D.; Kitamura, T. Bull. Chem. Soc. Jpn.
2007, 80, 2213–2219. (e) Hossain, M. D.; Ikegami, Y.; Kitamura, T.
J. Org. Chem. 2006, 71, 9903–9905.
(18) Triflate salts were used, as those are generally easier and more
inexpensive to synthesize compared to the tetrafluoroborates (see ref 17).
Triflate salts are also efficiently obtained from other salts by anion
exchange with NaOTf. See the Supporting Information for structures
and synthetic details of salts 1.
a Unsymmetric salt 1d used. b At rt. c BF4 salt 1e used. d 22 h.
Org. Lett., Vol. XX, No. XX, XXXX
B

2f, and geraniol proved to be a better substrate (2g). Even a
sterically hindered, secondary alcohol could be arylated to
yield 2h.
We have recently reported a high-yielding synthesis
of diaryl ethers with diaryliodonium salts in THF or
toluene.11 Despite the efficiency of this transformation,
the arylation conditions presented herein are preferable for
environmental reasons. Phenols have previously been
arylated in water under more forcing conditions,21 and
we were therefore keen to see the scope under our mild
reaction conditions.
Pleasingly, the arylation of phenols in water was efficient
(Scheme 4). Good to excellent yields were obtained with
various iodonium salts, tolerating both nitro- and halide
substituents (4bÀ4e). The reaction proved insensitive to
steric hindrance on both coupling partners (4fÀ4h). Phe-
nols with electron-donating or -withdrawing substituents
were also arylated (4h, 4i).
The arylation of benzylic alcohols was subsequently
examined (Scheme 2). Benzyl alcohol was arylated in
moderate to good yields with a variety of salts, to give
products with electron-withdrawing, halide, and alkyl
substituents (3aÀ3e).
Again, complete chemoselectivity was observed in aryla-
tions with 4-nitrophenyl salt 1d. The reactivity difference
of salts 1d and 1a is illustrated by the higher yield of nitro
product 3b compared to phenyl product 3a.
Electron-donating groups on the alcohol were tolerated
(3fÀ3g), and even sterically hindered secondary and ter-
tiary alcohols were arylated (3hÀ3i). Arylations with
ortho-substituted iodonium salts were poor-yielding.
Scheme 4. Arylation of Phenols
Scheme 2. Arylation of Benzylic Alcohols
a Unsymmetric salt 1d used. b BF4 salt 1e used. c At 60 °C.
a 60 °C for 1 h. b Unsymmetric salt 1d used. c 6 h. d 17.5 h.
The moderate arylation yields of allylic and benzylic
alcohols are explained by competitive oxidation to the
corresponding aldehydes/ketones and carboxylic acids,
which could not be prevented with these oxidation-prone
substrates.19
As mentioned above, reactions with nitro-substituted
salt 1dwere best performed at room temperature due tothe
increased reactivity of this salt. The main byproduct
was found to be the symmetric di(4-nitrophenyl) ether 4a,
which was formed by sequential arylation of the base and
the resulting phenol. In the absence of alcohol, this back-
ground reaction provided diaryl ether 4a in 52% yield
(Scheme 3).20 Arylation of the base was not seen with the
other salts.
Even diarylation of binaphthol, with substantial steric
hindrance, was successful, and the product fell out as a
solid during the reaction in almost quantitative yield (4j).
We have previously investigated the chemoselectivity of
phenol arylations with unsymmetric salts and found them
to follow the ortho-effect with sterically hindered salts.11,22
Under the current arylation conditions, the ortho-effect
was dominant in reactions with phenol (Scheme 5a, 4k:4b),
whereas 2,4-dimethylphenol gave a 1:1 mixture of 4l:4f in
reactions with phenyl(triisopropylphenyl)iodonium tri-
flate (1f) (Scheme 5b). This illustrates the delicate balance
(19) 16% acid, 9% aldehyde, and 3% remaining alcohol were
identified in the synthesis of 2a. Acetophenone was formed in 20% yield
in the synthesis of 3h. Excess alcohol or salt did not improve the yield,
nor did an inert atmosphere.
(20) This kind of transformation was reported as a side reaction in:
Li, J.; Liu, L. RSC Advances 2012, 2, 10485–10487. For a Pd-catalyzed
version of this reaction with ArX, see ref 2a.
Scheme 3. Synthesis of Diaryl Ether 4a by Arylation of NaOH
(21) (a) Crowder, J. R.; Glover, E. E.; Grundon, M. F.; Kaempfen,
€
H. X. J. Chem. Soc. 1963, 4578–4585. (b) Teclechiel, D.; Sundstrom, M.;
Marsh, G. Chemosphere 2009, 74, 421–427. (c) Marsh, G.; Stenutz, R.;
˚
Bergman, A. Eur. J. Org. Chem. 2003, 2566–2576.
(22) Malmgren, J.; Santoro, S.; Jalalian, N.; Himo, F.; Olofsson, B.
Chem.;Eur. J. 2013, 19, 10334–10342.
Org. Lett., Vol. XX, No. XX, XXXX
C

between steric and electronic effects, as product 4g
(Scheme 4) was formed in good yield from symmetric
mesityl salt 1g despite the steric hindrance.
of this substrate class is underway and will be reported in
due time.
In conclusion, the first arylation of activated aliphatic
alcohols with diaryliodonium salts hasbeen presented. The
reaction is simple to perform, takes place in water under
mild and metal-freeconditions, and does notrequire excess
amounts of the coupling partners.
Scheme 5. Chemoselectivity with Ortho-Substituents
The yields are moderate to good, and the aryl scope is
broader than in SNAr or benzyne reactions. Aryl groups
with electron-deficient, halide, or alkyl substituents are
efficiently transferred, while more electron-donating sub-
stituents are unsuitable.
Phenols are arylated in good to excellent yields with the
same range of diaryliodonium salts, and sterically hindered
substrates are well tolerated. Complete chemoselectivity
was observed in reactions with unsymmetric salts having
different electronic properties, whereas salts with ortho-
substituents were less selective.
The iodoarene that is formed in reactions with di-
aryliodonium salts could be recovered in 87À95% yield
in arylations of both alcohols and phenols and reused
for the synthesis of the diaryliodonium salt.23 This
facile recovery improves the atom economy and de-
creases the environmental impact further in large-scale
reactions.
Acknowledgment. This work was financially supported
by the Swedish Research Council and Wenner-Gren
Foundations.
Supporting Information Available. Experimental details,
analytical data, and NMR copies of novel compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Regular aliphatic alcohols were poor substrates in this
arylation, likely due to their higher pKa values, which
makes deprotonation with NaOH difficult. The arylation
(23) The iodoarene is recovered during product purification by silica
gel chromatography; see the Supporting Information for details.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX