Facile and efficient synthesis of fluoroalkyl aryl ethers

Article abstract of DOI:10.1016/S0040-4039(02)01719-7

A convenient and practical method for the preparation of fluoroalkyl aryl ethers via substitution of iodoalkyl fluorides is described. This method involves KF complexation of the phenol, which increases the nucleophilicity of oxygen for the formation of the ether linkage.

Full text of DOI:10.1016/S0040-4039(02)01719-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7353–7355
Facile and efficient synthesis of fluoroalkyl aryl ethers
Ahmed Kamal,* T. B. Pratap, K. Venkata Ramana, A. V. Ramana and A. Hari Babu
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 20 June 2002; revised 7 August 2002; accepted 16 August 2002
Abstract—A convenient and practical method for the preparation of fluoroalkyl aryl ethers via substitution of iodoalkyl fluorides
is described. This method involves KF complexation of the phenol, which increases the nucleophilicity of oxygen for the formation
of the ether linkage. © 2002 Elsevier Science Ltd. All rights reserved.
It is well known that the substitution of hydrogen with
fluorine in organic compounds can sometimes dramati-
cally change physical, chemical and biological proper-
ties.1 Therefore, the synthesis of organofluorine
compounds has become an important area of chemistry
both in academia and in industry. A large number of
methods have been developed for the introduction of
fluorine into different organic compounds.2 Recently,
enantioselective fluorination3 to obtain chiral fluorinated
molecules has attracted considerable interest due to the
unique properties of the CꢀF bond, and the importance
of the fluorine moiety in molecules of pharmaceutical and
biological interest is undisputed.4 Amongst fluorinated
organic materials, fluoroalkyl aromatics and, more pre-
cisely, fluoroalkyl aryl ethers have been found useful as
insecticides,5 fungicides,6 herbicides,7 dyes,8 and as inter-
mediates for antiulcer agents,9 and some examples are
shown below.
not offer practical convenience and simplicity. For exam-
ple, aromatic fluoroalkoxylation has been carried out by
aromatic nucleophilic substitution with fluorinated
alkoxide anions in solvents such as HMPA at tempera-
tures of 90–150°C. This route is useful for tri-
fluoroethoxylation, whereas tetrafluoroethoxylations
have not been attempted by this approach. In connection
with a programme directed towards the preparation of
fluorinated alkylaryl ethers, our earlier attempts to
displace the iodo functionality of alkyl halides by
employing different bases such as K2CO3 and NaOH,
and also involving techniques like sonification and phase
transfer conditions did not yield the desired results.
In this communication, we wish to report an easy and
efficient procedure for the preparation of fluoro alkyl aryl
ethers by the direct iodine displacement of alkyl halides
employing KF (Scheme 1). The etherification of 4-substi-
tuted phenols with iodofluoro alkanes proceeds smoothly
to afford the corresponding fluoro substituted alkyl aryl
ethers as illustrated in Table 1. It is observed that the
yields are excellent for entries a–h and good to moderate
in case of i–n. These etherification reactions are generally
completed within 3–7 hours and no significant amounts
of any side-products have been observed suggesting that
the nucleophilicity of fluoride is effectively suppressed by
complexation with phenolic -OH.
The majority of reported synthetic procedures10 for
fluoroalkyl aryl ethers involve the reaction of an elec-
trophilic iodo/bromoalkylfluoride or fluoroalkene or
fluoroalkyl sulfonate with a nucleophilic phenol. A single
vessel process for the preparation of trifluoromethyl aryl
ethers employing HF has also been reported.11 However,
most of the methods employed for the preparation of
fluoroalkyl aromatic components generally involve the
use of strongly basic conditions, and, moreover, they do
* Corresponding author. Tel.: +91-40-7193157; fax: 91-40-7160512; e-mail: ahmedkamal@iict.ap.nic.in
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01719-7

7354
A. Kamal et al. / Tetrahedron Letters 43 (2002) 7353–7355
Scheme 1.
Table 1. Potassium fluoride-mediated preparation of fluoroalkyl aryl ethers
Entry
Phenol (1)
Iodoalkyl halide (2)
Product (3)
Reaction time (h)
Yield (%)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
4-NCC6H4OH
4-NCC6H4OH
ICH2CF3
4-NCC6H4OCH2CF3
4
5
4
4
6
4
3
5
5
4
6
6
6
7
85
75
90
90
80
85
80
75
50
50
35
50
40
30
ICF2CF2Cl
ICF2CF2H
ICH2CF3
ICF2CF2Cl
ICF2CF2H
ICH2CF3
ICF2CF2Cl
ICF2CF2H
ICH2CF3
ICF2CF2Cl
ICF2CF2H
ICH2CF3
4-NCC6H4OCF2CF2Cl
4-O2NC6H4OCF2CF2H
4-O2NC6H4OCH2CF3
4-O2NC6H4OCF2CF2Cl
4-F3CC6H4OCF2CF2H
4-F3CC6H4OCH2CF3
4-F3CC6H4OCF2CF2Cl
4-H3CC6H4OCF2CF2H
4-H3CC6H4OCH2CF3
4-H3CC6H4OCF2CF2Cl
4-C2H5O2CC6H4OCF2CF2
4-C2H5O2CC6H4OCH2CF3
4-H5C2O2CC6H4OCF2CF2Cl
4-O2NC6H4OH
4-O2NC6H4OH
4-O2NC6H4OH
4-F3CC6H4OH
4-F3CC6H4OH
4-F3CC6H4OH
4-H3CC6H4OH
4-H3CC6H4OH
4-H3CC6H4OH
4-C2H5O2CC6H4OH
4-C2H5O2CC6H4OH
4-C2H5O2CC6H4OH
ICF2CF2Cl
In the literature, a report12 regarding the synthesis of
biaryl ethers claimed that KF forms a complex with
4-cyanophenol thereby localizing the charge on oxygen.
This complex was analyzed by thermogravimetric analy-
sis and infrared spectroscopy. Based on this finding, it
is considered that in the present method a similar
mechanism may be operating for the formation of
fluoroalkyl aryl ethers.
procedure. Further, this method is devoid of the use of
corrosive starting materials like tetrafluoroethylene and
strong bases.
Acknowledgements
Two of the authors (T.B.P. and K.V.R.) are thankful to
IICT, Hyderabad and CSIR, New Delhi, respectively
for the award of Research Fellowships.
In a typical experiment, the 4-substituted phenol (1
mmol) and KF (1 mmol) were dissolved in methanol
(10 ml) and the methanol was gradually distilled off.
The solid obtained was washed with dry ether (3×10
ml) and dried under vacuum to obtain a nonhygro-
scopic white solid (unlike KF, which is hygroscopic).
This complex was dissolved in DMSO (15 ml) and to
this was added to a solution of the iodofluoroalkane (3
mmol) in DMSO (3 ml). The mixture was heated at
120°C in a sealed reactor and the reaction was moni-
tored by TLC. The reaction mixture was diluted with
ice-cold water and subsequently extracted with ethyl
acetate (3×20 ml). The combined ethyl acetate layers
were dried over anhydrous Na2SO4 and evaporated
under reduced pressure to obtain an oily residue. This
was purified by column chromatography (silica gel,
hexane/EtOAc, 9:1) to obtain the pure fluoroalkyl aryl
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