Catalytic mesylation of alcohols: A highly productive process for trifluoroethyl mesylate

Article abstract of DOI:10.1021/op050105s

"Intermediate" Lewis acids are efficient catalysts for mesylation of trifluoroethanol (TFE) by mesyl chloride at 80 °C. In the absence of solvent, trifluoroethyl mesylate (TFEMes) is obtained in a chemical yield of 98% with total conversion of TFE. The only coproduct of the reaction, hydrochloric acid, simply distills from the reaction mixture. Distillation of TFEMes allows for recycle of the catalyst without any treatment.

Full text of DOI:10.1021/op050105s

Organic Process Research & Development 2006, 10, 194−197
Full Papers
Catalytic Mesylation of Alcohols: A Highly Productive Process for
Trifluoroethyl Mesylate
Johann Vastra* and Laurent Saint-Jalmes
Rhodia Recherches et D e´ Veloppement, Centre de Recherches et de Technologies de Lyon, 85 rue des Fr e` res Perret,
BP62, 69192 Saint-Fons Cedex, France
Abstract:
Intermediate” Lewis acids are efficient catalysts for mesylation
Scheme 1. Classical synthesis of TFEMes
“
of trifluoroethanol (TFE) by mesyl chloride at 80 °C. In the
absence of solvent, trifluoroethyl mesylate (TFEMes) is obtained
in a chemical yield of 98% with total conversion of TFE. The
only coproduct of the reaction, hydrochloric acid, simply distills
from the reaction mixture. Distillation of TFEMes allows for
recycle of the catalyst without any treatment.
Thus, the aqueous phases have to be neutralised to a basic
pH to release the amine, which must be distilled and, if
possible, recycled. In the case of triethylamine these last steps
are very time- and energy consuming. Use of an amine such
as diisopropylethylamine permits an easier recycling due to
its lower solubility in water than that of triethylamine.
Other important criteria for an efficient process are the
volume efficiency and throughput. Analysis of the reaction
step shows that in theory only 30% of the total weight of
the medium is really necessary to synthesise TFEMes: TFE
Introduction
3 2
Trifluoroethoxy group CF CH is widely present in active
molecules in the pharmaceutical, agrochemical, and perfor-
mances markets. There are different ways to introduce the
3 2
CF CH moiety into a molecule: nucleophilic substitution
of a leaving group (halogen, nitro) by trifluoroethanol or
nucleophilic substitution of an activated trifluoroethanol
(14% of the weight) and mesyl chloride (16% of the weight).
1
derivatives such as mesylate, tosylate, triflate. Trifluoroethyl
The base (Et N) and the solvent occupy 70% of weight and
3
mesylate (TFEMes) is a good compromise between reactivity
volume of the vessel.
These statements prompted us to try to find a more
efficient process, with the following goals:
3 2
and price to introduce the CF CH group for large-scale
2
production. Our goal to develop an industrial process for
TFEMes prompted us to find a new and very efficient means
of mesylation and, more generally, esterification of electron-
poor alcohols.
(i) Increase the volume efficiency and throughput
(ii) Reduce the number of unit operations
(iii) Keep a good yield of TFEMes.
Our first approach was to remove solvent and to change
the nature of the base.
4
Results and Discussion
Classical Synthesis of Trifluoroethyl Mesylate. Mesy-
lation of alcohols such as trifluoroethanol (TFE) is a very
classical reaction: use of an organic base, generally an amine
In the absence of solvent, with triethylamine as the base,
mesylation of TFE occurred, but quickly the reaction mixture
became pasty and difficult to stir.
3
like triethylamine, pyridine, or diisopropylethylamine, in
stoichiometric amount, leads to good performances of
esterification with mesyl chloride as shown in Scheme 1.
From the process point of view this approach includes
several process units as shown in the flow sheet (Figure 1).
This process produces aqueous wastes containing the
corresponding chlorhydrate salts of the amine, in our case
triethylamine. These wastes must be treated because of their
toxicity for microorganisms used for purification of water.
Replacing triethylamine with an inorganic base presents
the advantage of limiting the aqueous waste treatment issues.
Attempts were made to use sodium hydroxide in inert
solvents such as chlorobenzene or potassium carbonate in
acetonitrile. The performances of these systems are presented
in Table 1.
With sodium hydroxide in chlorobenzene the yield of
TFEMes was too low to reach an economical process. Partial
hydrolysis of mesyl chloride by NaOH explains limitation
on the yield. Surprisingly, the use of a usual phase transfer
*
Corresponding author. E-mail: Johann.Vastra@eu.rhodia.com.
5
catalysis contributed to a decrease in the yield of TFEMes.
(1) Langlois, B.; Desbois, M. L’actualit e´ Chimique 1987, 151.
(2) Camps, F.; Coll, J.; Messeguer, A.; Pericas, M. A. Synthesis 1980, 727.
(3) (a) Crossland, R. K.; Servis K. L. J. Org. Chem. 1970, 35, 3195. (b) Prescher,
D.; Rhumann, T. J. Fluorine Chem. 1996, 79(2), 145. (c) King, J. F.; Gill,
M. S. J. Org. Chem. 1998, 63, 808.
(4) DSC analysis of an equimolar mixture of TFE and mesyl chloride without
base showed a very small exotherm above 150 °C, but no traces of TFEMes
were detected in the cell content.
1
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10.1021/op050105s CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/10/2006

Figure 1. Flow sheet of TFEMes synthesis using Et
3
N.
Table 1. Comparison of inorganic bases with Et
3
N
encouraging, this result was not good enough for the purposes
of a future industrial process.
(CMS/TFE: 1/1)
temp
yieldb
To improve mesyl chloride electrophilicity, we decided,
on the basis of the previous results, to explore the possibility
of its catalytic activation using Lewis acids (Scheme 3). Such
mesyl chloride activation is known in the literature for
base
solvent
(°C) TFEMes (%)
NaOH (1.1 mol equiv)
NaOH (1.1 mol equiv)
chlorobenzene
chorobenzene
50
50
74
61
a
6
and TBAC (5% mol)
Friedel-Crafts-type reactions. Nevertheless, in the current
K
2
CO
3
(1.1 mol equiv)
CH
3
CN
65
82
case we had to deal with a better Lewis base (TFE) than
aromatic rings, which can compete with mesyl chloride for
the Lewis acid coordination.
a
Tetrabutylammonium chloride. b GC with internal standard.
7
A screening of several Lewis acids was scheduled, and
2 3
A better yield of TFEMes was obtained with K CO in
acetonitrile, but performances were still inferior to those of
the classical route.
the results were compared, following the HSAB classifica-
8
tion, to extract a correlation if any. The experiments have
been run in a batch manner using 5 mol % of catalyst at
Taking the following results into account and looking at
economic impacts on the process, which is highly dependent
on the volume efficiency, we tried to proceed without solvent
using weak bases in catalytic amount. The idea was to
regenerate the base by thermal decomposition of its chlor-
hydrate salt (Scheme 2).
8
0-85 °C. Reactions were monitored by GC using an
internal standard.
Generally, complete recovery of starting material was
observed with hard Lewis acids such as AlCl
ZrCl
of conversion of TFE has been observed but without any
formation of TFEMes (TiCl , SiCl ), indicating that TFE has
probably replaced the chlorine ion as ligand.
3
, FeCl
3
, MgCl
2
,
+
4
, BF
3
.Et
2
O, ZrCl
4
, H , etc... In some cases up to 25%
The results obtained were somewhat disappointing. None
of the amine bases tested at 80-100 °C during 10 h
4
4
(triethylamine, diisopropylethylamine, pyridine, DMAP, imi-
Formation of TFEMes occurred with some borderline
dazole, TMEDA) allowed to get satisfactory yields of
TFEMes (<2% GC, with internal standard). Better conver-
sion of TFE was observed at higher temperature but with a
poor selectivity, indicating that side reactions occurred. Same
observations were made with the use of phosphites such as
trimethyl phosphite. Running the reaction with 5 mol % of
triphenylphospine in a batch manner or slowly adding either
TFE or CMS at 100 °C gave up to 68% of conversion of
TFE in 10 h with 39% yield of TFEMes. Even though
Lewis acids such as BiCl
3
(12%), ZnCl
2 2
(44%), or SnCl
(32%), but with various selectivities (conversion of TFE: 37,
6
6, and 38% respectively, Table 2). The same metal cations
7
tested with other ligands gave lower yields of TFEMes.
(6) Olah, G. A.; Lin, H. C. Synthesis 1974, 342.
(7) Around 50 Lewis acids have been tested, essentially metal ion with chlorine
ligands. When formation of TFEMes was observed with metal-chloride salt,
-
-
-
other counterions have been tested (Br , OTf , TFSI , oxide,...). Better
results were always obtained with chlorine derivatives.
8) (a) Pearson, R. G. J. Am. Chem. Soc. 1963, 85, 3533. (b) Tse-Lok Ho Chem.
ReV. 1975, 75, 1.
(
(5) Tappe, H. Synthesis 1979, 822-823; Szeja, W. Synthesis 1980, 577.
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Scheme 2. Catalytic base principle
Scheme 3. Acid catalysis principle
Table 2. Test of some soft and borderline Lewis acids
5
Scheme 4. Esters formed using SbCl catalytic process
yield
temp time conversion TFEMes
Lewis acid mol equiv
(°C)
(h)
TFE (%)
(%)
BiCl
ZnCl
TeCl
SnCl
SbCl
3
0.05
0.05
0.05
0.05
0.05
80-85
80-85
80-85
80-85
9
8
6
4
37
66
62
38
98
12
44
42
32
91
a
a
a
a
2
4
To determine limits and expectations of this chemistry,
several esters were synthesized using the same catalytic
2
5
80-85 3.5
9
process. Some examples of the products synthesised using
a
Batch conditions (CMS/TFE: 1.1).
SbCl
In comparison with the classical chemistry and process
solvent, amine) the SbCl -catalysed process presents several
advantages:
i) maximum productivity because no solvent or base is
used
5
as catalyst are represented in Scheme 4.
(
5
Finally, the best results were obtained with borderline
TeCl and SbCl Lewis acids (Table 2), the last one giving
singular excellent yield and selectivity. Taking into account
that both mesyl chloride and TFE are present in the reaction
mixture (batch reaction), these results suggest that SbCl
intrinsically possesses adequate Lewis acidity to activate
CMS without reacting with TFE hydroxyl function.
4
5
(
(ii) reduction of process unit: only reaction and distillation
5
instead of five process units in the classical process
(iii) very efficient reduction of amounts of wastes: with
Lewis acid the amount of waste is estimated to be 15 kg per
ton of TFEMes instead of 3 tons per ton of TFEMes in the
triethylamine process.
5
Catalytic amounts of SbCl led to direct mesylation of
trifluoroethanol in high yields without any other reagent and
any solvent. Optimisation of the reaction conditions allowed
synthesis of TFEMes on 3-kg scale (98% yield) without any
scale-up issues and the use of a reduced amount of catalyst
Conclusion
9-11
(
0.05 mol %).
Direct distillation from the reaction mixture
5
Some soft and borderline Lewis acids, especially SbCl ,
permits isolation of pure TFEMes, and the residue containing
are efficient catalysts for mesylation of trifluoroethanol by
mesyl chloride. In the absence of solvent, trifluoroethyl
mesylate is obtained with a chemical yield of 98%. The
amount of catalyst required is very low (0.05 mol %), and it
can be recycled for several batches since the residue is
keeping out of moisture. Hydrochloric acid, which is the only
side product, distills from the reaction mixture, giving a
global athermic reaction. No scale-up issue has been identi-
fied. In comparison with the classical process using a
12
catalyst can be reused for a new reaction. This additionally
contributes to reduction of the global amount of catalyst
needed. The reaction is globally athermic due to HCl
evolution all along the reaction.13
(
9) Vastra, J.; Saint-Jalmes, L. (Rhodia Chimie). WO 02/28826, 2002.
10) From an environmental and an economical point of view it was important
to reduce as much as possible the amount of SbCl to be handled.
(
5
Furthermore, the catalyst could be easily recycled since it stays in the
distillation residue.
stoichiometric base, such as triethylamine, the SbCl
5
catalytic
(
11) Alkaline hydrolysis of the residue gives antimony oxide (Sb
2 5
O ) which can
be used as halogen-free flame retardant in clothing.
(12) The residue has been successfully reused three times in the laboratory without
loss of yield.
(13) Heat of reaction was determined by Mettler RC1 experimentation (∆H
-0.2 kcal/mol of mesyl chloride).
r
)
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process leads to an optimum productivity, to a reduction of
process units, and a drastic reduction in the amount of wastes
generated. This type of chemistry has been extended to
esterification of some electron-poor alcohols.9
chromatograph using the same temperature gradient as
described for GC analysis.
Safety. SbCl is an irrating and corrrosive reagent.
5
Although it is less toxic than its Sb(III) analogue, it must be
handled with care, and any trace of moisture must be avoided.
Experimental Section
SbCl
ling the exotherm.
2,2,2-Trifluoroethyl Methanesulfonate (Trifluroethyl
Mesylate, TFEMes). SbCl (0.49 g; 1.5 mmol) is slowly
added to mesyl chloride (62.3 g, 544 mmol) at room
temperature. An exotherm is noted. The medium is warmed
to 80 °C, and trifluoroethanol (50.5 g, 504.7 mmol) is added
over 5 h. HCl evolution is observed all along the addition.
The reaction mixture is then maintained at 80 °C for 1.5 h
to remove remaining HCl. Analysis by GC of aliquot showed
total conversion of trifluoroethanol and formation of TFEMes
with 98% yield. Trifluoroethanol mesylate is purified by
distillation on seven plates column, bp: 99 °C/ 35 mmHg.
5
can be destroyed with basic aqueous medium control-
1
1
General Procedure. Trifluoroethyl mesylate is com-
mercially available from Fluka (2,2,2-trifluoroethyl meth-
anesulfonate, RN CAS 25236-64-0). All reagents were
obtained at industrial scale and used without further purifica-
5
1
tion. H NMR spectra were determined on a 200 MHz
spectrometer. Each compound prepared herein was charac-
terized by GC, GC-MS, and H NMR spectroscopy.
Gas Chromatography. Gas chromatography was carried
out using a Varian CP-3800 gas chromatograph equipped
with a catharometer detector and a column DB-210 (30 m
1
×
0.53 mm × 1 µm). All samples were examined under the
following temperature gradient: temp 1, 40 °C (5 min); temp
, 140 °C (5 min); rate 5 °C/min. Conversions and yields
2
were determined by calibration curves using standard solu-
tions of each component; internal standard is n-decane. GC-
MS data were acquired using a HP 5890 series II gas
Received for review June 23, 2005.
OP050105S
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