Selective aliphatic fluorination by halogen exchange in mild conditions

Article abstract of DOI:10.1016/j.jfluchem.2005.10.006

HF-Base media, in particular (HF)₁₀-pyridine or (HF) ₃-triethylamine, allow aliphatic chlorine-fluorine exchanges on acid-sensitive molecules. Depending on the nature (pyridine or triethylamine), stoichiometry of the base and temperature, selective mono-, di-, or tri-chlorine-fluorine exchanges on trichloromethyl groups alpha to sulfur, oxygen and carbon atoms can be obtained.

Full text of DOI:10.1016/j.jfluchem.2005.10.006

Journal of Fluorine Chemistry 127 (2006) 85–90
www.elsevier.com/locate/fluor
Selective aliphatic fluorination by halogen exchange
in mild conditions
*
Laurent Saint-Jalmes
`
Rhodia Recherche et Technologie, Centre de Recherche de Lyon, 85 Avenue des Freres Perret,
69192 Saint-Fons Cedex, France
Received 21 September 2005; accepted 15 October 2005
Available online 22 November 2005
Abstract
HF-Base media, in particular (HF)10-pyridine or (HF)3-triethylamine, allow aliphatic chlorine–fluorine exchanges on acid-sensitive molecules.
Depending on the nature (pyridine or triethylamine), stoichiometry of the base and temperature, selective mono-, di-, or tri-chlorine–fluorine
exchanges on trichloromethyl groups alpha to sulfur, oxygen and carbon atoms can be obtained.
# 2005 Elsevier B.V. All rights reserved.
Keywords: Selective aliphatic chlorine–fluorine exchange; HF-Base; (HF)10-pyridine; (HF)3-triethylamine
1. Introduction
for example to obtain trifluoromethylsulfonyl chloride or other
derivatives by chlorination [2]. Our approach to synthesize 2 is
shown in Scheme 1 and includes a fluorine–chlorine exchange
on trichloromethylbenzyl sulfide 1.
In accordance with conditions published by Makosza and
Fedorynski [3], trichloromethylbenzyl sulfide 1 is obtained
from benzylthiocyanate and chloroform in basic conditions and
with phase transfer catalysis with 70% yield.
Fluorine–chlorine exchange is the most widely used
technology to synthesize fluorinated molecules. When this
exchange reaction occurs in an aliphatic molecule or at the
benzylic position, anhydrous hydrogen fluoride is the most
versatile industrial reagent. Using this type of reaction,
trifluoromethylbenzene is manufactured from phenylchloro-
form on an industrial scale using liquid HF, and trifluor-
omethoxybenzene from trichloroanisole [1]. The limitation of
this technology comes from the acidity of anhydrous HF. Its
use on fragile or functionalized molecules is limited due to
formation of cationic intermediates and undesired side
reactions. Thus, it is of interest to find mild conditions that
allow fluorine–chlorine exchanges on acid-sensitive mole-
cules.
First trials of fluorination of trichloromethylbenzyl sulfide 1
with anhydrous HF even at low temperature (<0 8C) gave total
decomposition of the starting material and formation of tars.
Analysis of these tars revealed polymers that contain biphenyl-
methylene groups. This shows that the carbon–sulfur bond is
broken and that benzyl carbocation is formed under these acidic
conditions. These first results show that anhydrous HF is a too
acidic medium towards a benzylic position to allow the chlorine–
fluorine exchange reaction on trichloromethylbenzyl sulfide 1.
We thus decided to find fluorination media where chlorine–
fluorine exchange reactions would be favoured with limited
side reactions due to cationic pathways. HF-Base mediums
appeared to be interesting for our goal. HF-Base media are well
known specially (HF)10-pyridine known as Olah’s reagent [4]
and (HF)3-triethylamine [5].
2. Results
2.1. Synthesis of trifluoromethylbenzylsulfide
The starting point of our study was the synthesis of
trifluoromethylbenzyl sulfide 2 which is a useful intermediate,
Use of (HF)10-pyridine and (HF)3-triethylamine on trichloro-
methylbenzyl sulfide 1 give the results shown in Table 1.
Trichloromethylbenzyl sulfide 1 is totally fluorinated at
20 8C in 18 h in (HF)10-pyridine (40 molar equivalents of HF)
* Tel.: +33 1 72 89 65 03; fax: +33 1 72 89 68 55.
E-mail address: laurent.saint-jalmes@eu.rhodia.com.
0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.10.006

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L. Saint-Jalmes / Journal of Fluorine Chemistry 127 (2006) 85–90
and leads to trifluoromethylbenzyl sulfide 2 with 94%
selectivity (19F NMR assay) and 85% isolated yield (entry 1,
Table 1).
Surprisingly (HF)3-triethylamine (50 molar equivalents of
HF) leads to selective fluorination on trichloromethylbenzyl
sulfide 1 through exchange of one or two chlorine atoms
Scheme 1.
Table 1
Entry
1
Substrate
Conditions
Product
Yielda
(HF)10-pyridine HF/substrate = 40, 20 8C, 18 h
94% (85%)b
2
(HF)3-triethylamine HF/substrate = 50, 20 8C, 4 h
90%
3
(HF)3-triethylamine HF/substrate = 55, 50 8C, 10 h
88% (72%)b
a
19F NMR assay.
b
Isolated yield.
Table 2
Entry
1
Substrate
Conditions
Product
Yield (%)a
83
(HF)10-pyridine HF/substrate = 50, 20 8C, 12 h
2
3
(HF)3-triethylamine HF/substrate = 50, 20 8C, 5 h
78
85
(HF)3-triethylamine HF/substrate = 50, 50 8C, 12 h
4
5
(HF)10-pyridine HF/substrate = 50, 20 8C, 16 h
(HF)3-triethylamine HF/substrate = 50, 20 8C, 7 h
79
75
a
19F NMR assay.

L. Saint-Jalmes / Journal of Fluorine Chemistry 127 (2006) 85–90
87
depending on the temperature; at 20 8C in 4 h monofluorodi-
chlorobenzyl sulfide 3 is obtained with 90% selectivity (entry 2,
Table 2), at 50 8C in 10 h difluorochlorobenzyl sulfide 4 is
obtained with 88% selectivity (entry 3, Table 2). These results
are in accordance with the lower acidity of (HF)3-triethylamine
compared to (HF)10-pyridine; the less acidic is the medium of
fluorination the lower is the rate of chlorine–fluorine exchange.
mixture to extract the trifluoromethylsulfides formed. Addition
of a solvent, such as dichloromethane which is not miscible
with (HF)10-pyridine, leads to two easily separable liquid
phases. The dichloromethane phase contains the trifluoro-
methylsulfide. The (HF)10-pyridine phase can be recycled and
used for another batch of fluorination reaction, see Table 3.
After several runs, anhydrous HF can be added to the (HF)10-
pyridine phase to increase the fluorination power of this
medium.
2.2. Selective Cl–F exchange on trichloromethylsulfides
Recycling of (HF)3-triethylamine is more difficult because
most organic solvents are miscible with this medium.
These results confirm that the HF-Base media not only give
good results for complete chlorine–fluorine exchange reaction
on trichloromethylsulfides but lead to selective mono- or di- or
tri-chlorine–fluorine exchange using different HF-Base sys-
tems with varying acidities.
To study the scope and limitation of this selective chlorine–
fluorine exchange reaction several trichloromethylsulfides have
been synthesized. Sulfide 5 is obtained by reaction between
cyclohexene and perchloromethylmercaptan CCl3SCl with
78% yield [6]. Trichloromethyl-methyl sulfide 6 is obtained by
chlorination of dimethylsulfide with sulfuryl chloride with 70%
yield [7].
In the following trials, the stoichiometric ratio between HF
in the HF-Base medium and the substrate is around 50.
On sulfides 5 and 6, (HF)10-pyridine gives complete
chlorine–fluorine exchange at 20 8C with 83% and 79%
selectivity respectively (entries 1 and 4, Table 2). With (HF)3-
triethylamine at 20 8C, sulfides 5 and 6 are fluorinated to
corresponding monochloro-difluoromethylsulfides 8 (78%
selectivity) and 11 (75% selectivity) (entries 2 and 5,
Table 2). Difluorination of sulfide 5 is obtained in (HF)3-
triethylamine at 50 8C in 12 h and difluoro-chloromethylsulfide
9 is formed with 85% selectivity (entry 3, Table 2).
Interestingly, in the case of fluorination of trichloromethyl-
sulfides, we have shown that (HF)10-pyridine medium can be
recycled. In effect, more than 90% of the HCl formed as the co-
product of the fluorination distils during the reaction;
hydrochloride salts of pyridine are not formed in our
conditions. Also, it is not necessary to hydrolyse the reaction
2.3. Selective Cl–F exchange on trichloromethylethers and
phenylchloroform
The results on trichloromethylsulfides prompted us to study
the use of HF-Base media on other substrates, specifically on
trichloromethylethers and phenylchloroform. Table 4 sum-
marises these results.
Trichloromethoxybenzene 12 in (HF)10-pyridine (40
molar equivalents) at room temperature (entry 1, Table 4)
leads to the chloro-difluoromethoxybenzene 13 with 97%
selectivity (GC and NMR assays). Monofluorination of 12 is
observed using (HF)3-triethylamine at 50 8C with 93%
selectivity (entry 2, Table 4). To obtain complete fluorination
of trichloromethoxybenzene 12, it is necessary to warm the
medium to 80–100 8C and to use anhydrous HF [8]. At this
temperature the (HF)10-pyridine medium looses HF and its
acidity and fluorination powers decrease, so trifluoroanisole
Table 3
Run no.
1
Substrate
Conditions
Products
Yielda
(HF)10-pyridine HF/substrate = 50, 20 8C, 18 h
2
3
(HF)10-pyridine HF/substrate = 50, 20 8C, 18 h
(HF)10-pyridine HF/substrate = 50, 20 8C, 18 h
a
19F NMR assay.

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L. Saint-Jalmes / Journal of Fluorine Chemistry 127 (2006) 85–90
Table 4
Entry
1
Substrate
Conditions
Product
Yield (%)a
97
(HF)10-pyridine HF/substrate = 40, 20 8C, 6 h
2
(HF)3-triethylamine HF/substrate = 40, 50 8C, 25 h
93
3
4
5
(HF)10-pyridine HF/substrate = 40, 20 8C, 2 h
(HF)3-triethylamine HF/substrate = 40, 20 8C, 5 h
(HF)10-pyridine HF/substrate = 50, 20 8C, 15 h
91
85
15
6
(HF)10-pyridine HF/substrate = 40, 25 8C, 2 h
92
7
(HF)3-triethylamine HF/substrate = 40, 75 8C, 5 h
86
a
19F NMR assay.
cannot be obtained using (HF)10-pyridine or other HF-Base
media.
Here again we confirm a relationship between the acidity
and fluorination power of HF-Base media and the stabilisation
by heteroatoms, oxygen in our case, of the carbocationic
species which can explain the level (mono, di or tri exchanges)
of fluorination.
On dichloromethylenedioxobenzene 15, chlorine–fluorine
exchange is easier and (HF)10-pyridine (entry 3, Table 4) or
(HF)3-triethylamine (entry 4, Table 4) give complete fluorina-
tion to difluoromethylenedioxobenzene 16. On tetrachloro-
benzodioxane 17, obtained from 1,2-dihydroxybenzene and
tetrachloroethylene carbonate in presence of PCl5 [9], (HF)10-
pyridine leads only to monofluorination of one CCl2 group with
low yield (entry 5, Table 4).
On dichloromethylenedioxobenzene 15, the two oxygen
atoms stabilise the positive intermediate charge on the carbon
that bears the two chlorine atoms and so complete chlorine–
fluorine exchange is obtained even with (HF)3-triethylamine. On
the other hand, in the cases of trichloromethoxybenzene 12 and

L. Saint-Jalmes / Journal of Fluorine Chemistry 127 (2006) 85–90
89
tetrachlorobenzodioxane 17, the stabilisation of cationic
species is not enough efficient (only one oxygen atom) and
fluorination is limited to one or two chlorine–fluorine
exchange reactions.
yield 94%; 19F NMR assay) was obtained. The product was
purified by distillation (yellow oil; 85%).
Boiling point: 77 8C/30 mmHg (54–56 8C/11 mmHg [2]).
1
NMR: 19F NMR (300 MHz): À42.1 (CF3, s). H NMR
Similar results are obtained on phenylchloroform 19; in
(HF)10-pyridine at room temperature difluorochloromethyl-
benzene 20 is obtained with 92% yield (entry 6, Table 4). With
(HF)3-triethylamine at 75 8C the major product is monofluoro-
chloro-methylbenzene 21 (entry 7, Table 4). Trifluoromethyl-
benzene can be synthesized from phenylchloroform with
anhydrous HF at 80 8C, showing that the introduction of the
third fluorine atom needs an acidic medium and high
temperature [1].
(200 MHz): 4.12 (2H, s, benzylic CH2), 7.35 (5H, m, H
aromatic). GCMS: m/z = 192 (45%, Mꢀ+), 123 (65%,
M+ À CF3), 91 (100%, PhCH2).
3.1.2. Benzyl chloro-difluoromethyl sulfide 4 [11]
Benzyltrichloromethylsulfide 1 [2] (20 g, 0.08 mol) was
slowly added at 0 8C to (HF)3-triethylamine (200 g, HF:
4.58 mol; triethylamine: 1.53 mol). The mixture was stirred at
50 8C for 10 h. After work-up, crude benzyl chloro-difluor-
omethyl sulfide 4 was obtained (15.8 g, yield 88%; 19F NMR
assay; benzyl dichloro-fluoromethyl sulfide 3: 5%).
These results have been patented by Rhodia [10].
3. Experimental
The product was purified by distillation (yellow oil; 72%).
Boiling point: 112 8C/30 mmHg (87.5 8C/13 mmHg [11]).
1
NMR spectra were recorded as CDCl3 solutions on a
Bruker AMX-300 spectrometer. Reported coupling constants
and chemicals shifts were based on a first order analysis.
Internal reference was the residual peak of CHCl3 (7.27 ppm)
NMR: 19F NMR (300 MHz): À27.2 (CClF2, s). H NMR
(200 MHz): 4.1 (2H, s, benzylic CH2), 7.4 (5H, m, H aromatic).
GCMS: m/z = 208–210 (28%, Mꢀ+), 173 (75%, M+ À Cl), 91
(100%, PhCH2).
1
for H (200 MHz), central peak of CDCl3 (77 ppm) for 13C
(75 MHz) spectra and internal CCl3F (0 ppm) for 19F
(282 MHz) NMR spectra. GCMS analyses were performed
with JW Scientific Agilent DB-5 chromatography column,
length 30 m, diameter 0.53 mm, film thickness 5 mm, initial
temperature 50 8C, gradient 10 8C/min, final temperature
230 8C on a quadrupolar mass spectrometer. Chemical yields
and selectivity of fluorination were determined by 19F NMR
assays with internal standard (PhOCF3 or PhF or PhCF3).
Purity of isolated products was determined by GC and 19F, 1H
NMR analysis.
3.1.3. 1-Chloro-2-trifluoromethylsulfenyl-cyclohexane 7
[12]
1-Chloro-2-trichloromethylsulfenyl-cyclohexane
5
[4]
(10 g, 0.037 mol) was slowly added at 0 8C to (HF)10-pyridine
(52 g, HF: 1.86 mol; pyridine: 0.19 mol). The mixture was
stirred at 20 8C for 12 h. After work-up, crude 1-chloro-2-
trifluoromethylsulfenyl-cyclohexane 7 was obtained (8.1 g,
yield 83%; 19F NRM assay).
1
NMR: 19F NMR (300 MHz): À43.5 (CF3, s). H NMR
(200 MHz): 1.47, 1.73, 2.16, 2.31 (8H, m, CH2), 3.39 (1H, m,
CH–S), 4.06 (1H, m, CH–Cl), J 1H–1H (CH–S, CH–Cl) = 4Hz.
GCMS: m/z = 218–220 (65%, Mꢀ+), 149–151 (100%,
M+ À CF3), 114 (36%, M+–CF3–Cl).
(HF)10-pyridine was synthesized by slow addition of
anhydrous HF (72 g, 3.6 mol) to pyridine (29 g, 0.36 mol)
cooled to À10 8C. (HF)10-pyridine was used without any
treatment.
(HF)3-triethylamine was purchased from Aldrich.
4. Conclusion
3.1. General procedure
HF-amine reagents are efficient media to accomplish
chlorine–fluorine exchange on fragile molecules without side
reactions involving carbocation intermediates. Depending on
the nature of the amine (pyridine or triethylamine), the
stoichiometry of the HF-Base system and the temperature,
selective mono-, di- or tri-halogen exchanges are obtained with
good yields on trichloromethyl groups alpha to sulfur, oxygen
and carbon atoms. On trichloromethylsulfides (1, 5, 6), (HF)10-
pyridine leads to complete fluorination and (HF)3-triethylamine
leads to mono- or di-chlorine–fluorine exchange depending on
the temperature. On trichloromethoxybenzene 12 and phenyl-
chloroform 19, (HF)10-pyridine leads to difluorination and
(HF)3-triethylamine affords monofluorinated derivatives with
good selectivity.
The substrate was slowly added to (HF)10-pyridine or
(HF)3-triethylamine in polypropylene vessel cooled at 0 8C,
with generally a stoichiometric amount of HF/substrate
between 40 and 50. The reaction mixture was stirred and
warmed to the temperature desired, allowing gaseous HCl to
distil. The level of fluorination of the starting material was
monitored by GC analysis. After cooling to 0 8C, hydrolysis
with ice (100 g) and extraction with dichloromethane
(2 Â 150 ml), the organic layers were combined, washed with
water, dried over sodium sulfate, concentrated in vacuo and
possibly purified by distillation.
3.1.1. Benzyl trifluoromethylsulfide 2 [2]
Benzyltrichloromethylsulfide 1 [2] (30 g, 0.124 mol) was
slowly added to (HF)10-pyridine (140 g, HF: 5 mol; pyridine:
0.5 mol) at 0 8C. The mixture was stirred at 20 8C for 18 h.
After work-up, crude benzyl trifluoromethylsulfide 2 (22.4 g,
Acknowledgements
We thank Robert Janin and Marcel Morel for technical work
and Nicolas Capelle, Laurent Garel and Jacques Chabannes for

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3599.
NMR studies, and Marcello Dimare for help during the
preparation of this manuscript.
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