Synthesis of esters by selective methanolysis of the trifluoromethyl group

Article abstract of DOI:10.1016/S0040-4039(02)01836-1

The trifluoromethyl group of certain compounds containing one or two trifluoromethyl groups can be converted to the carbomethoxy group by treatment with sodium methoxide followed by aqueous acidic work-up. α-Trifluoromethyl esters can be obtained by selective methanolysis of the 1,1,1,3,3,3-hexafluoroisopropyl group in some cases. The structural requirements for the transformation are delineated, and a mechanistic study confirms the proposed mechanism, a dehydrofluorination-addition-elimination process.

Full text of DOI:10.1016/S0040-4039(02)01836-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7731–7734
Synthesis of esters by selective methanolysis of the
trifluoromethyl group
Keith Ramig,* Miriam Englander, Florida Kallashi, Lilia Livchits and Jessica Zhou
Department of Natural Sciences, Baruch College, City University of New York, 17 Lexington Ave., New York, NY 10010, USA
Received 9 August 2002; revised 27 August 2002; accepted 29 August 2002
Abstract—The trifluoromethyl group of certain compounds containing one or two trifluoromethyl groups can be converted to the
carbomethoxy group by treatment with sodium methoxide followed by aqueous acidic work-up. a-Trifluoromethyl esters can be
obtained by selective methanolysis of the 1,1,1,3,3,3-hexafluoroisopropyl group in some cases. The structural requirements for the
transformation are delineated, and a mechanistic study confirms the proposed mechanism, a dehydrofluorination–addition–elim-
ination process. © 2002 Elsevier Science Ltd. All rights reserved.
We disclose here a method for the conversion of the
trifluoromethyl group into a carbomethoxy group. The
trifluoromethyl group is normally very resistant to
attack by both electrophilic and nucleophilic reagents,
but when the molecule bearing this group contains a
properly positioned hydrogen atom—one which can be
lost in an initial dehydrofluorination reaction—and cer-
tain other structural features, all the fluorine atoms
may be lost. Alcoholysis under basic conditions of
compounds containing a trifluoromethyl group has
been shown to yield carboxylic esters,1–7 sometimes
through the intermediacy of orthoesters2–4 or ketene
acetals.1 There have also been reports of application of
these reaction conditions to compounds containing
multiple trifluoromethyl groups.3,8–11 In two of these
cases, the observed chemoselectivity is not surprising
because only one of the groups is proximate to an
active hydrogen atom.3,8 However, there have been four
examples of chemoselective hydrolysis or alcoholysis of
molecules containing multiple equivalent trifluoro-
methyl groups.9–12
conditions for the alcoholysis of a-trifluoromethyl-b,b-
difluorostyrenes13 can be applied to the methanolysis of
several different types of substrates containing one or
two trifluoromethyl groups, and in the case of sub-
strates with two, the process occurs chemoselectively.
Treatment of fluoroether 1 with sodium methoxide in
methanol—conditions similar to those which had been
successfully applied by others9–11 to related substrates—
gave a complex mixture of products rather than pre-
dominantly the desired ester 2 (Scheme 1). In an
attempt to produce the carboxylic acid derivative of
ester 2, recourse was made to hydrolysis of fluoroether
1 with aqueous solutions of various metal hydroxides in
a number of different co-solvents, but the yields of the
acid were in all cases very low. These reactions were
complicated by hydrolysis of both the difluoromethoxy
group and the other trifluoromethyl group. However,
when treated with 3 equiv. of sodium methoxide in
acetonitrile13 as solvent, ester 2 was isolated in 55%
yield after brief treatment with aqueous acid during
work-up. The ester was purified by either fractional
distillation or radial chromatography. Application of
the methanolysis conditions to other substrates gave
synthetically useful yields of esters (Table 1). The reac-
tion works for a fairly wide variety of structural types,
as long as the aforementioned active hydrogen atom is
All of the examples cited above involve the transforma-
tion of molecules of a limited structural type—or even
just one particular molecule—under a number of differ-
ent conditions. It would be desirable to have one set of
conditions that would be applicable to a broader class
of molecules containing trifluoromethyl groups, and
also have that method be chemoselective when applied
to molecules containing multiple trifluoromethyl
groups. We report here that a modification of the
* Corresponding author. Tel.: +1-212-802-3099; fax: +1-212-802-3082;
e-mail: keith ramig@baruch.cuny.edu
Scheme 1. Methanolysis of fluoroether 1.
–
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01836-1

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K. Ramig et al. / Tetrahedron Letters 43 (2002) 7731–7734
Table 1. Methanolysis reactions
a Determined by 1H and 19F NMR analysis, except for entry 3, which was determined by quantitative GC analysis.
b Speers, L.; Szur, A. J.; Terrell, R. C.; Treadwell, J.; Ucciardi, T. R. J. Med. Chem. 1971, 14, 593–595.
c After washing with water to remove acetonitrile, and distillation.
d Treatment with acid after reflux period was 1.5 h at rt.
e Yield of orthoester 13 when acidic work-up is omitted.
f The crude product was treated with excess methanol/cat. sulfuric acid for 2 h at reflux.
present, and the functional groups around the tri-
fluoromethyl group are sufficiently electron-withdraw-
ing. In the cases of the substrates which contain two
trifluoromethyl groups, entries 1–3, small amounts of
diesters which are the result of methanolysis of both
trifluoromethyl groups were detected in the crude reac-
tion mixtures. The discrepancies in the crude and iso-
lated yields for these cases and also the case of entry 4
are due to either simple handling losses or due to
thermal instability of the esters during distillation. For
the case of entry 3, separation of the volatile ester 6
from the acetonitrile solvent was problematic and
resulted in a low isolated yield of product.
little of the corresponding ester when subjected to the
reaction conditions. This and other bits of evidence
point to a dehydrofluorination–addition–elimination
sequence as the most probable mechanism by which the
transformation occurs. In the case of the commercial
anesthetic isoflurane (7), if the aqueous acidic work-up
is left out and the crude reaction mixture is simply
filtered to remove the by-product salts, followed by
removal of the solvent under reduced pressure, then
three products are seen, difluoroether 16, mono-
fluoroether 17 and enol ether 18 (Scheme 2). The use of
4 equiv. of sodium methoxide is required for the best
yields of monofluoroether 17 (50% crude yield) and
enol ether 18 (27% crude yield), both of which are
converted to ester 2 after brief exposure to aqueous
acid; difluoroether 16 is resistant to hydrolysis and
remains as a troublesome contaminant in ester 2 if only
3 equiv. of sodium methoxide are used.
The substrates in Table 1 were chosen based on the
presence of electron-withdrawing groups positioned
around the trifluoromethyl group. When the substrate
lacks these structural features, the reaction fails. For
example, 1,1,1,3,3,3-hexafluoroisopropyl methyl ether,
which lacks the two fluorine atoms of its analog ether 1,
gives a complex mixture of products containing very
The observation of these intermediates led to a labeling
study to elucidate the mechanism. When the methanoly-

K. Ramig et al. / Tetrahedron Letters 43 (2002) 7731–7734
7733
Scheme 2. Labeling study and proposed mechanism for production of 16, 17, and 18.
sis reaction producing compounds 16, 17, and 18 was
run in acetonitrile-d3 as solvent, and the aqueous acidic
work-up was omitted, the products had incorporated
was added portionwise with rapid mechanical stirring to
a solution of methanol (29 mL, 0.72 mol) in 500 mL
anhydrous acetonitrile under N2 in an ice bath. The
mixture was stirred at rt for 100 min, at which point
very little gas production was apparent. The resulting
white slurry was cooled to −45°C, and fluoroether 1
(52.3 g, 0.240 mol) was added dropwise over a period of
40 min, keeping the reaction temperature <−35°C. The
mixture was stirred for 30 min at −45°C, and then was
removed from the cold bath for 65 min. The resulting
off-white slurry was suction filtered, washing with 100
mL acetonitrile. The filtrate was treated with 1 L of 1 M
HCl solution with rapid mechanical stirring for 20 min,
giving a biphasic mixture. The bottom phase (57.0 g of
clear colorless liquid), which contained both product
and acetonitrile, was removed and dried over CaCl2; the
upper aqueous phase was extracted with 2×200 mL of
ether, and the combined ether extracts were dried over
MgSO4. The ether was removed under reduced pressure
at rt with a minimum pressure of 150 mmHg, giving a
mixture of product and acetonitrile which was shaken
with 300 mL water. The resulting bottom phase was
dried over MgSO4 giving 10.8 g clear colorless liquid
which contained product and acetonitrile. The two
product-containing liquids were combined and fraction-
ally distilled under vacuum using a silvered, vacuum-
jacketed 1×24 cm column packed with ceramic saddles,
and a reflux-splitter head. The acetonitrile was first
removed at 150 mmHg, and then the pressure was
reduced gradually to 50 mmHg. Ester 2 (28 g, 55%
yield) was collected at 59°C as a clear colorless liquid.
deuterium
to
give
difluoroether
16-d
and
monofluoroether 17-d as determined by 1H NMR analy-
sis: In 16-d, the triplet at 5.87 ppm, assigned to the
proton on the carbon atom bearing the chlorine atom in
16, had disappeared, while for 17-d, the doublet at 5.87
ppm, assigned to the corresponding proton in 17, had
also disappeared. The notion of this addition–elimina-
tion process is further bolstered by the isolation of
orthoester 13 if the acidic treatment is omitted from the
reaction which produces aromatic ester 12 (Table 1).
Orthoester 13 is most likely formed by initial dehy-
drofluorination of phenol 11 followed by successive
addition–elimination steps, eventually giving enol ether
19 (Scheme 3). At this point, all 3 equiv. of sodium
methoxide are used up, and an equivalent of methanol
has been produced by the initial dehydrofluorination.
Enol ether 19 is especially activated for addition of
methanol across the unsaturated system because the
aromaticity of the ring is reestablished. A similar pro-
cess is probably at work in the case of acid 14.
To conclude, we have found a method for the methanol-
ysis of the trifluoromethyl group which shows signs of
being generally applicable to compounds which contain
both an appropriately positioned active hydrogen atom
and an electron-withdrawing group. When the substrate
contains two trifluoromethyl groups, chemoselectivity
was seen. The method is primarily useful for the synthe-
sis of a-trifluoromethyl carboxylic esters.
Physical and spectral data for new compounds:
Representative experimental procedure. Ester 2:
All NMR spectra were recorded in CDCl3 solvent,
reporting in units of ppm relative to tetramethylsilane
for the 1H and 13C spectra, and relative to fluoro-
trichloromethane for the 19F spectra. The 19F spectra
are proton-coupled and the 13C spectra are proton-
decoupled.
Sodium hydride (30.2 g, 60% in mineral oil, 0.75 mol)
1
Compound 2: bp=59°C/50 mmHg; H: 3.90 (s, 3H),
Scheme 3. Proposed formation of orthoester 13.
5.00 (q, J=6.5 Hz, 1H), 6.45 (t, J=71 Hz); 19F (H-cou-

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K. Ramig et al. / Tetrahedron Letters 43 (2002) 7731–7734
pled): −74.6 (dt, J=6.5, 20 Hz, 3F), −85.7 (dq, J=71,
2.0 Hz, 2F); 13C (H-decoupled): 54.0 (s), 70.0 (qt,
J=35, 55 Hz), 116 (t, J=267 Hz), 122 (q, J=280 Hz).
164 (q, J=1.8 Hz). Compound 4: bp=76°C/40 mmHg;
1H: 3.96 (s, 3H), 5.11 (q, J=6.3 Hz, 1H); 19F (H-cou-
pled): −12.4 (q, J=2.1 Hz, 1F), −74.0 (dd, J=6.3, 2.1
Hz, 3F); 13C (H-decoupled): 54.1 (s), 74.3 (qd, J=35,
2.5 Hz), 121 (q, J=282 Hz), 125 (d, J=314 Hz). 165
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1
(br s). Compound 8: bp=63°C/20 mmHg; H: 3.90 (s,
3H), 6.12 (s, 1H), 6.49 (dd, J=73, 70 Hz, 1H); 19F
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Acknowledgements
Lakshmi Krishnamurthy and Yelena Makeyev are
thanked for experimental assistance.