Practical and general method for direct synthesis of alkyl fluorides from alcohols under mild conditions

Article abstract of DOI:10.1007/s00706-005-0296-9

A variety of alcohols were treated with Ph ₃P and KF in CCl ₄-DMF at room temperature to afford the corresponding fluorides in very good yields. Springer-Verlag 2005.

Full text of DOI:10.1007/s00706-005-0296-9

Monatshefte f€ur Chemie 136, 1579–1582 (2005)
DOI 10.1007/s00706-005-0296-9
Practical and General Method
for Direct Synthesis of Alkyl Fluorides
from Alcohols under Mild Conditions
ꢀ
Babasaheb P. Bandgar , Vinod T. Kamble, and Ankush V. Biradar
Organic Chemistry Research Laboratory, School of Chemical Sciences,
Swami Ramananad Teerth Marathwada University, Nanded-431 606, Maharashtra, India
Received November 11, 2004; accepted (revised) January 26, 2005
Published online August 22, 2005 # Springer-Verlag 2005
Summary. A variety of alcohols were treated with Ph3P and KF in CCl4-DMF at room temperature to
afford the corresponding fluorides in very good yields.
Keywords. Alcohols; Alkyl fluorides; Triphenyl phosphine; Potassium fluoride; Chemoselective.
Introduction
Increasing interest in fluorine containing medicines and pesticides stimulate the
development of new methodologies for the preparation of specifically fluorinated
compounds [1]. One of the most important and straightforward strategies for the
introduction of fluorine into a target molecule is the conversion of a hydroxyl into a
fluorine group. The common method for the transformation of alcohols into alkyl
fluorides is substituting the hydroxyl group first with chlorine or bromine and then
with fluorine using alkali fluorides. This method is not applicable when the alcohol
contains substituents which should not be halogenated, for instance, double or
triple bonds. Other limitations associated with this method are high temperatures
and=or long reaction times generally necessary due to the low solubility and
nucleophilicity of the fluoride ion. Furthermore, significant amounts of alkenes
and alcohols are concomitantly formed because the fluoride ion also behaves as
a strong base and hydrolyzing agent. In another method the hydroxyl group is first
tosylated and then treated with potassium fluoride [2]. The third method is to
decompose fluoroformates derived from alcohols by warming it in the presence
of pyridine [3]. The fourth one is by pyrolysis of 2-alkylpseudouromium fluorides
derived from alcohols and fluoroborates [4]. However, all these methods starting
from alcohols require two steps or more.
ꢀ
Corresponding author. E-mail: vtkd@rediffmail.com

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B. P. Bandgar et al.
Alkyl fluorides are also prepared in one step from alcohols by heating with
difluorotriphenyl phosphorane [5a] or diphenyltrifluoro phosphorane [5b] at
140–150ꢁC. However, drastic conditions, long reaction times, poor to low yields,
and requirement of specially prepared reagents by heating at 150ꢁC for longer peri-
ods make this process less attractive. Expensive reagents such as diethylaminosulfur
trifluoride (DAST) [6] and bis(2-methoxyethyl)aminosulfur trifluoride [7] are also
reported. However, these reagents are hazardous, thermally unstable, and therefore
utilization of these reagents for large scale applications is limited. Primary and
secondary alcohols can be transformed to the corresponding fluorides in one step
using 2-chloro-1,1,2-trifluorotriethylamine [8]. Considering the complexity of this
reagent and its unsatisfactory yields with tertiary alcohols, a more practical, mild,
one-step, and general reagent for this kind of transformation should increase the
synthetic potential of the reaction. Recently, Ph3P and NaN3 in CCl4-DMF (1:4)
have been used as a mild reagent for the direct conversion of alcohols into
azides=amines [9].
Results and Discussions
We report in this communication our results for the direct conversion of alcohols
into fluorides using triphenyl phosphine and KF in CCl4-DMF (1:4) under mild
conditions (Scheme 1).
When alcohols were treated with Ph3P and KF in CCl4-DMF (1:4) at room
temperature, the corresponding fluorides were obtained in very good yields. The
results are summarized in Table 1. The method appears to be general, as a variety
of alcohols such as primary, secondary, tertiary, benzylic, allylic and propargylic
alcohols underwent smooth fluorination. It is important to note that any C¼C and
CꢂC bonds present elsewhere in the molecule remained unaltered under these
reaction conditions (Table 1, entries 14, 15, 16). Thus, the reaction is highly
chemoselective and the functional groups in the substrate such as phenol (entry
1), chloro (entry 2), MeO (entry 4), methylenedioxy (entry 5), ketone (entry 8),
and tosyl (entry 18) were tolerated under the reaction conditions. Benzyl alcohol
is selectively converted into corresponding fluoride in the presence of phenol
(entry 1) and primary alcohol. Diols (entries 7, 11) are also smoothly transformed
into the corresponding difluorides with two equivalents of Ph3P and KF. Methods
reported so far gave unsatisfactory yields of fluorides in the case of secondary and
tertiary alcohols. In this context, the present procedure is noteworthy because even
secondary and tertiary alcohols furnished very good yields of the corresponding
fluorides.
In conclusion, we have found a convenient, mild, and general procedure for the
direct conversion of alcohols into the corresponding fluorides in very good yields.
Scheme 1

Synthesis of Alkyl Fluorides from Alcohols
1581
Table 1. Preparation of alkyl fluorides
Time
h
Yielda;b
Entry
Alcohol
Fluoride
%
1
2
4-HO–C6H4–CH2OH
4-Cl–C6H4–CH2OH
3-O2N–C6H4–CH2OH
4-MeO–C6H4–CH2OH
3,4-CH2(O)2C6H3–CH2OH
Furfuryl alcohol
4-HO–C6H4–CH2F
4-Cl–C6H4–CH2F
3-O2N–C6H4–CH2F
4-MeO–C6H4–CH2F
3,4-CH2(O)2C6H3–CH2F
Furfuryl fluoride
0.5
0.75
1.5
1.5
2.5
2.0
3.5
4.0
3.0
2.5
3.0
3.5
4.0
2.0
2.0
4.5
1.0
1.0
92
93
90
88
91
90
90
84
86
86
91
89
87
85
87
89
80
86
3
4
5
6
7
4-HOH2C–C6H4–CH2OH
Ph–CO–CHOH–Ph
CH3(CH2)6OH
4-FH2C–C6H4–CH2F
Ph–CO–CHF–Ph
CH3(CH2)6F
8
9
10
11
12
13
14
15
16
17
18
Tetrahydrofurfuryl alcohol
HO(CH2)6OH
Tetrahydrofurfuryl fluoride
F(CH2)6F
Cyclohexanol
Cyclohexyl fluoride
Menthyl fluoride
Menthol
Cinnamyl alcohol
Cinnamyl fluoride
Citronellyl fluoride
Ph–CH2–CH(F)–CHꢂCH
Ph–CH(F)–(CH2)2F
4-TsO–C6H4–CH2F
Citronellol
Ph–CH2–CH(OH)–CHꢂCH
Ph–CH(OH)–(CH2)2OH
4-TsO–C6H4–CH2OH
a
Yield of isolated pure product; b products are characterized by IR, 1H NMR, elemental analysis, and
comparison with authentic samples
Tolerance of other functional groups present elsewhere in the molecule is superior
compared to the reported ones.
Experimental
All chemicals were of analytical grade and used as obtained. IR spectra were recorded on a Bomem
MB 104 FT-IR spectrometer and 1H NMR spectra were recorded on an AC 300F NMR spectrometer
(300 MHz).
General Procedure
KF (10 mmol) was added to a mixture of 5 mmol alcohol, and 12.5 mmol triphenyl phosphine dis-
solved in 5 cm3 CCl4-DMF (1:4). The mixture was stirred at room temperature. After completion of the
reaction (TLC), the mixture was extracted with 2 ꢃ 5 cm3 of n-pentane. The combined organic layers
were dried (Na2SO4) and the solvent was removed under reduced pressure to isolate the crude product,
which was further purified by column chromatography on silica gel (ethyl acetate:n-hexane ¼ 1:9).
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B. P. Bandgar et al.: Synthesis of Alkyl Fluorides from Alcohols
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