DOI: 10.1002/open.201402006
Room Temperature, Metal-Free Arylation of Aliphatic
Alcohols
Raju Ghosh, Erik Lindstedt, Nazli Jalalian, and Berit Olofsson*[a]
Diaryliodonium salts are demonstrated as efficient arylating
agents of aliphatic alcohols under metal-free conditions. The
reaction proceeds at room temperature within 90 min to give
alkyl aryl ethers in good to excellent yields. Aryl groups with
electron-withdrawing substituents are transferred most effi-
ciently, and unsymmetric iodonium salts give chemoselective
arylations. The methodology has been applied to the formal
synthesis of butoxycaine.
philic aromatic substitution is often efficient, but requires
strong electron-withdrawing substituents or forcing condi-
tions.[6] Diaryliodonium salts are stable and low-toxic[7] hyperva-
lent iodine compounds that have recently been utilized as
electrophilic arylation agents with a wide range of nucleo-
philes.[8] Despite this, the arylation of aliphatic alcohols with
these reagents has only briefly been reported with the alcohol
in large excess or as solvent, thus lacking synthetic utility.[9] Vi-
cinal diols have been monoarylated with iodonium salts under
Cu-catalyzed conditions, but regular alcohols could not be ary-
lated.[10]
Efficient transition metal-free transformations are of high im-
portance in organic synthesis, for example in the pharmaceuti-
cal industry where trace amounts of remaining metal in biolog-
ically active compounds must be avoided. Furthermore, many
metal-free reactions utilize inexpensive, readily available re-
agents of low toxicity.[1] The synthesis of alkyl aryl ethers is
a central theme in organic chemistry, as this structural moiety
is present in many drugs and natural products. Several copper-
and palladium-catalyzed arylations of aliphatic alcohols with
aryl halides or aryl boronic acids have been reported.[2] Draw-
backs with metal-catalyzed methods include high tempera-
tures, long reaction times or the need for excess starting mate-
rials and/or reagents (Figure 1A).
We have recently developed several O-arylations with diaryl-
iodonium salts, including an environmentally benign arylation
of allylic and benzylic alcohols in water at 508C for 3 h.[11]
Herein, we report the first general arylation of aliphatic alco-
hols with diaryliodonium salts (Figure 1B).
The arylation of 1-pentanol with diphenyliodonium salts 1a–
c to give alkyl phenyl ether 2a was investigated as model reac-
tion (Table 1). Contrary to our previous O-arylations,[11] sodium
bases were found superior to both lithium and potassium
bases (Entries 1–5).[12] Toluene was a better solvent than di-
chloromethane and tetrahydrofuran (THF), while no reaction
took place in water (Entries 6–9).
Alkyl aryl ethers can also be synthesized by metal-free meth-
ods,[1b] including the Williamson ether synthesis,[3] reactions via
benzyne intermediates[4] or Mitsunobu-type reagents.[5] Nucleo-
Reactions at room temperature for only 30 min provided 2a
in equally good yield, and excess amounts of the reagents
were not beneficial (Entries 10–11). The radical trap 1,1-diphe-
Table 1. Optimization with 1-pentanol.[a]
Entry
Base
Solvent
1a–c X
T [8C]
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
NaOH
NaH
tBuOLi
tBuOK
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
1a OTf
1a OTf
1a OTf
1a OTf
1a OTf
1a OTf
1a OTf
1a OTf
1a OTf
1a OTf
1a OTf
1a OTf
1b BF4
1c OTs
80
80
80
80
80
40
40
40
40
RT
RT
RT
RT
RT
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
0.5
0.5
0.5
0.5
0.5
47
75
45
62
80
80
70
24
0[c]
81
81
74
67
50
tBuONa
tBuONa
tBuONa
tBuONa
NaOH
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
Figure 1. Synthesis of alkyl aryl ethers.
THF
H2O
[a] Dr. R. Ghosh, E. Lindstedt, Dr. N. Jalalian, Prof. B. Olofsson
Department of Organic Chemistry, Stockholm University
10691 Stockholm (Sweden)
9
10
11[d]
12[e]
13
14
toluene
toluene
toluene
toluene
toluene
Supporting information for this article is available on the WWW under
ꢀ 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
reproduction in any medium, provided the original work is properly
cited and is not used for commercial purposes.
[a] Reagents and conditions: 1-Pentanol (0.5 mmol), base, solvent (2.5 mL),
08C, under argon atmosphere; after 15 min at RT, salt 1 was added.
[b] NMR yield with 4-anisaldehyde as internal standard. [c] No reaction.
[d] 2 equiv 1a, 2 equiv base. [e] 1 equiv DPE added.
ꢀ 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemistryOpen 2014, 3, 54 – 57 54