Acid fluorides and 1,1-difluoroethyl methyl ethers as new organic sources of fluoride for antimony pentachloride-catalyzed halogen-exchange reactions

Article abstract of DOI:10.1016/S0022-1139(98)00347-9

1,1-Difluoroethyl methyl ethers such as the commercial veterinary anesthetic methoxyflurane (2,2-dichoro-1,1-difluoroethyl methyl ether, 6) decompose in the presence of a catalytic amount of antimony pentachloride. The rate of decomposition is dependent upon the number and position of halogen atoms in the ether: a high degree of halogenation at the methyl group or at the 2-position of the ethyl group makes the ether less prone to decomposition. The decomposition products are acid fluorides and halogenated methanes. The fate of the antimony pentachloride is conversion to a fluorochloroantimony species which can be used in situ to selectively fluorinate a polychlorinated substrate. Thus, 1,2,2,2-tetrachloro-1-fluoroethyl methyl ether (1) is converted cleanly to the anesthetic compound 2,2,2-trichloro-1,1-difluoroethyl methyl ether (2) using 6 as the fluoride source, exploiting the difference in stability of 2 and 6 to the pentavalent antimony species. It is also demonstrated that the acid fluorides obtained from decomposition of the 1,1-difluoroethyl methyl ethers are fluoride sources for halex reactions.

Full text of DOI:10.1016/S0022-1139(98)00347-9

Journal of Fluorine Chemistry 94 (1999) 1±5
Acid ¯uorides and 1,1-di¯uoroethyl methyl ethers as new
organic sources of ¯uoride for antimony pentachloride-catalyzed
halogen-exchange reactions
Keith Ramig*, Linas V. Kudzma, Ralph A. Lessor, Leonid A. Rozov
Baxter Pharmaceutical Products Division Inc., 100 Mountain Ave., Murray Hill, NJ 07974, USA
Received 17 March 1998; accepted 6 May 1998
This paper is dedicated to Professor Theodore Cohen on the occasion of his 70th birthday.
Abstract
1,1-Di¯uoroethyl methyl ethers such as the commercial veterinary anesthetic methoxy¯urane (2,2-dichoro-1,1-di¯uoroethyl methyl
ether, 6) decompose in the presence of a catalytic amount of antimony pentachloride. The rate of decomposition is dependent upon the
number and position of halogen atoms in the ether: a high degree of halogenation at the methyl group or at the 2-position of the ethyl group
makes the ether less prone to decomposition. The decomposition products are acid ¯uorides and halogenated methanes. The fate of the
antimony pentachloride is conversion to a ¯uorochloroantimony species which can be used in situ to selectively ¯uorinate a polychlorinated
substrate. Thus, 1,2,2,2-tetrachloro-1-¯uoroethyl methyl ether (1) is converted cleanly to the anesthetic compound 2,2,2-trichloro-1,1-
di¯uoroethyl methyl ether (2) using 6 as the ¯uoride source, exploiting the difference in stability of 2 and 6 to the pentavalent antimony
species. It is also demonstrated that the acid ¯uorides obtained from decomposition of the 1,1-di¯uoroethyl methyl ethers are ¯uoride
sources for halex reactions. # 1999 Elsevier Science S.A. All rights reserved.
Keywords: Antimony pentachloride; Catalyzed halogen-exchange; Acid ¯uorides; 1,1-di¯uoroethyl methyl ether
1. Introduction
wish to report observations on the stability of 1,1-diha-
loalkyl ethers which culminated in a high-yielding synthesis
of 2.
Recently we disclosed the use of ¯uoromethyl ethers as
sources of ¯uoride for halogen-exchange (halex) reactions
[1]. For example, the commercial anesthetic sevo¯urane
acted as a ¯uoride source for the completely selective
conversion of carbon tetrachloride to trichloro¯uoro-
methane (Scheme 1). However, when the sevo¯urane/anti-
mony pentachloride system was used as the ¯uoride source
for the conversion of 1,2,2,2-tetrachloro-1-¯uoroethyl
methyl ether (1) [2] to the anesthetic compound 2,2,2-
trichloro-1,1-di¯uoroethyl methyl ether (2) [2,3], a dis-
appointingly low yield of the desired product was seen. Use
of the sevo¯urane/antimony pentachloride system was
prompted by our failure to achieve an acceptable yield of
2 from 1 with the usual Swarts-type antimony tri¯uoride/
antimony pentachloride reagent. This is not surprising,
considering the known tendency of 1,1-dihaloalkyl methyl
ethers to decompose to acid halides and methyl halides in the
presence of Lewis acids [4±8]. In this communication we
2. Discussion
Treatment of 1 with 5 mol% antimony pentachloride at
room temperature resulted in an immediate exotherm with
evolution of methyl chloride. After 5 min, NMR analysis of
the crude mixture in CDCl3 showed complete conversion of
the starting material to a 1.3:1 mixture of 2 and trichlor-
oacetyl ¯uoride (4), plus an undetermined amount of tri-
chloroacetyl chloride (5) (Scheme 2). Further heating at 55-
608C for 1 h resulted in complete conversion to a mixture of
4 and 5. No products of halogen-exchange at the a-position
of 4 and 5 were seen. A possible explanation is that
disproportionation of the CFCl group [1,9] initially
occurred, giving 2 and the unobserved 3, which immediately
decomposed to 5 and methyl chloride. However, the inter-
mediacy of 3 is not required to explain the results, as it is also
possible that the initial step is conversion of a certain
percentage of 1 to 5 and methyl chloride through the loss
*Corresponding author. Address: Department of Natural Science,
Baruch College, Cuny, 17 Lexington Ave, New York, NY 10010, USA.
0022-1139/99/$ ± see front matter # 1999 Elsevier Science S.A. All rights reserved.
P I I : S 0 0 2 2 - 1 1 3 9 ( 9 8 ) 0 0 3 4 7 - 9

2
K. Ramig et al. / Journal of Fluorine Chemistry 94 (1999) 1±5
Scheme 1. Use of sevoflurane in a halex reaction.
Scheme 3. Synthesis of 2,2,2-trichloro-1,1-difluoroethyl methyl ether (2).
methyl chloride. It is apparent that transfer of ¯uoride from
6 is faster than complete decomposition of 1, and that 2 is
much more stable to antimony pentachloride than its closely
related analogue 6.
This prompted us to perform a qualitative stability study
of closely related 1,1-di¯uoroethyl methyl ethers (Table 1).
The decomposition products in all cases were the corre-
sponding acid ¯uorides and halogenated methanes. We
found that a high degree of halogenation at either the 2-
position of the ethyl group or at the methyl group markedly
enhances the stability of the ethers. The greater stability of
2 vs. 6, which differ by only one halogen atom at the
2-position of the ethyl group, is a trend mirrored by the
pairs 2 and 9 [11], 13 [11] and 12 [11], and 16 [11] and 15
[11]. Comparison of 11 [12] vs. 10 [12] shows an exception
to the trend, although a more re®ned study may be required
to indicate a difference between the two. The data in Table 1
also show that halogen substitution on the methyl group
results in a large stability enhancement. This trend can be
seen by comparing 14 (the commercial anesthetic en¯urane)
and 10, 15 and 12, and 17 [11] and 15. Both these trends may
indicate that the initial step, which would be rate-determin-
Scheme 2. Possible decomposition pathways of 1,2,2,2-tetrachloro-1-
fluoroethyl methyl ether.
of ¯uoride by 1 to the antimony pentachloride, thereby
forming a ¯uorochloroantimony species. The antimony
species then can ¯uorinate the unconverted 1 to give 2.
Compound 2 slowly decomposed to 4 and methyl halide, a
pathway which is known in analogous systems [4±8]. It was
apparent at this point that the above mentioned failure of 1 to
undergo smooth ¯uorination was due to facile decomposi-
tion of the starting material.
The solution to the problem of a high-yielding synthesis
of 2 was achieved by accident. Following the method of
Terrell [2], the commercial veterinary anesthetic methoxy-
¯urane (6) [2] was dehydro¯uorinated to give a mixture of
enol ether 7 and unconverted starting material (Scheme 3).
Chlorination of 7 in this mixture gave 1. At this point, the
reaction mixture contained 1 and 6 in a molar ratio of
approximately 1:1. Treatment of the mixture with sevo¯ur-
ane and a catalytic amount of antimony pentachloride at
room temperature resulted in an exotherm with rapid con-
sumption of 6 and evolution of methyl chloride. After
50 min, aqueous work-up furnished 2 in 74% yield. Based
on our earlier work (see Scheme 1, [1]), it was expected that
sevo¯urane was the source of ¯uoride, but we later found
that sevo¯urane could be omitted from the reaction mixture
with no effect. NMR analysis of the crude mixture before
work-up showed that dichloroacetyl ¯uoride (8) [10] was
present. A plausible explanation of these results ®rst
requires rapid decomposition of 6 by antimony pentachlor-
ide to give 8, methyl chloride, and a ¯uorochloroantimony
species. Next, transfer of ¯uoride from the antimony to
either 1 or its putative disproportionation product 3 must
occur before complete decomposition to 5 and additional
Table 1
Stability of 1,1-difluoroethyl methyl ethers to 5 mol% antimony
pentachloride
Fluoroether
Timea
Temperature
(8C)
CHCl2CF2OCH3, 6 (methox-20 min
yflurane)
r.t. 40b
CCl3CF2OCH3, 2
1 h
55±60
CHClFCF2OCH3, 9
CHClFCF2OCH2F, 10
CFCl2CF2OCH2F, 11
CHClFCF2OCH2Cl, 12
CFCl2CF2OCH2Cl, 13
CHClFCF2OCHF2, 14
(enflurane)
30 min
r.t.
20 min
20 min
r.t. to 20c
r.t. to 20c
r.t. 2c
20 min
Stable at r.t. for ꢀ20 h
Stable at reflux for ꢀ1 h
CHClFCF2OCHCl2, 15
CFCl2CF2OCHCl2, 16
CHClFCF2OCCl3, 17
Conversion to enfluraned
Stable at 608C for ꢀ2 h
Stable at 608C for ꢀ2 h
aTime required for complete disappearance of fluoroether.
bThe reaction was exothermic.
cThe temperature fell after addition of SbCl5 due to evaporation of the
halogenated methane decomposition product.
dAfter 20 h at r.t., the reaction consisted of a 2.3:1.8:1.8:1.5:1.0 mixture of
chloroform, enflurane, CHFClOCF2CHFCl [12], 15, and chlorofluoro-
acetyl fluoride, plus some unidentified components.

K. Ramig et al. / Journal of Fluorine Chemistry 94 (1999) 1±5
3
ing, in the decomposition of the ¯uoroethers is breakage of
the ethyl group's C-1 to ¯uorine bond, as electon-with-
drawing atoms at both C-2 and at the methyl group would
tend to destabilize the resulting cation. The other possible
®rst step in the decomposition reaction is complexation of
the antimony pentachloride with the ether's oxygen atom.
Electron-withdrawing atoms would tend to lower the
electron density at oxygen, making this complexation less
likely.
Scheme 4. Synthesis of acid fluorides from 1,1-difluoroethyl methyl
ethers.
We have also explored the possibility of using 6 and 2 as
¯uoride sources for other halex reactions. The by-products
of halex reactions between a chlorinated substrate and the
1,1-di¯uoroethers are the highly volatile methyl chloride
(and/or methyl ¯uoride) and acid ¯uorides, which react
readily with water during work-up to form a water-soluble
acid. Thus, 6 and 2 have an advantage over sevo¯urane as a
¯uoride source [1] (see Scheme 1), because the by-product
of sevo¯urane, chloromethyl 2,2,2-tri¯uoro-1-(tri¯uoro-
methyl)ethyl ether, stays in the organic layer and must be
separated from the product by distillation. As the test
substrate, trichloromethyl 2,2,2-tri¯uoro-1-(tri¯uoromethy-
l)ethyl ether (18) [13] was chosen because the trichloro-
methyl group can readily be over-¯uorinated in halex
reactions under Swarts-type conditions [1,13±18]. Treat-
ment of a 1:1 mixture of 18 and 6 with a catalytic amount of
antimony pentachloride at room temperature did indeed
result in immediate conversion to the expected product
19 [13], but a small amount of the product of di¯uorination,
20 [13], also was formed (Table 2). After stirring overnight
at room temperature, 20 was the predominant product.
Monitoring of the reaction by NMR also showed that the
by-product acid ¯uoride 8 was converted to the correspond-
ing acid chloride after the overnight period. This indicated
that the acid ¯uoride 8 was acting as a secondary ¯uoride
source, although at a much slower rate. The same trend was
seen with 2 as the ¯uoride source. Due to some loss of
¯uoride as methyl ¯uoride in the initial decomposition
reaction, further conversion to 20 was not possible if just
one equivalent of 6 was used, despite prolonged heating.
However, if 1.5 equivalents of 6 was present at the beginning
of the reaction, then the conversion of 18 to 20 was >96%
after 3.5 h at 408C.
Scheme 5. Fluorination using acid fluorides as sources of fluoride.
We then turned our attention to the evaluation of two acid
¯uorides, 8 and 21 [7], as sources of ¯uoride in halex
reactions. The acid ¯uorides were synthesized by antimony
pentachloride-catalyzed decomposition of 6 and 9 [4±8]
(Scheme 4; see also Table 1). After a short heating period,
the acid ¯uorides were distilled from the reaction ¯ask in
ꢀ70% yield. Acid ¯uoride 8 was also synthesized by
treatment of dichloroacetyl chloride with sevo¯urane and
antimony pentachloride [1] (see Scheme 1), but separation
of the by-product was troublesome.
Treatment of the test substrate 18 with one equivalent of 8
and a catalytic amount of antimony pentachloride for 1.5 h
at room temperature, followed by addition of water and
separation of the phases, gave exclusively 19 in 91% yield
(Scheme 5). Acid ¯uoride 21 was less prone to donate
¯uoride and also less selective in the halex reaction: after
1 h at 608C, 90% of 18 was consumed, while both 19 and 20
had formed in a 13:1 ratio.
3. Conclusion
To summarize, two types of molecules were found to be
sources of ¯uoride in antimony pentachloride-catalyzed
halex reactions: halogenated acid ¯uorides, and 1,1-di¯uor-
oethyl methyl ethers. In the former case, ¯uoride transfer to
a polychlorinated substrate proceeded under mild condi-
tions and was highly selective for mono¯uorination, while
Table 2
Fluorination using 1,1-difluoroethyl methyl ethers as sources of fluoride
Ether
Temperature (8C)
Time
Molar ratio
Conversion of 18 (%)
19
20
6
r.t.
r.t.
40
40
r.t.
50
50
10 min
15 h
10
1
1
>90
100
100
100
67
6
2.6
7.8
30
6a
6a
2
1.5 h
3.5 h
1 h
1
1
100
13
1
0
2
30 min
15 h
1
100
100
2
4.7
a1.5 equivalents used.

4
K. Ramig et al. / Journal of Fluorine Chemistry 94 (1999) 1±5
in the latter case, lower selectivity resulted because the
¯uoride source decomposed after ¯uoride donation to give
an acid ¯uoride, which caused an appreciable amount of
¯uorination itself. In both cases, the by-products from the
¯uoride source were either highly volatile or water-reactive,
which simpli®ed puri®cation after aqueous work-up. The
new ¯uorination system was applied to an improved synth-
esis of the anesthetic compound 2,2,2-trichloro-1,1-di¯uoro-
ethyl methyl ether (2).
8 were easily removed by distillation through a short
Vigreux column to give pure 2, bp 568C/80 mmHg (lit.
1
bp 468C/46 mmHg [2]). 2: H NMR ꢀ 3.77 ppm (s); 19F
NMR ꢀ 89.5 ppm (s); 13C NMR ꢀ 52.7 (t, Jˆ6.2 Hz), 94.0
(t, Jˆ44 Hz) 120 (t, Jˆ271 Hz) ppm.
4.4. Dichloroacetyl fluoride (8)
SbCl5 (2.20 g, 7.36 mmol) was added dropwise to meth-
oxy¯urane (6) (56.7 g, 344 mmol) at r.t. under N2. After
heating at 408C for 1 h, additional SbCl5 (2.57 g,
8.59 mmol) was added and the mixture was heated for an
additional 45 min to complete the reaction. The mixture was
distilled under N2 using a short Vigreux column, giving
31.4 g (70% yield) of dichloroacetyl ¯uoride (8) as a clear
liquid, bp 688C (lit. bp 708C [10]). 8: 1H NMR ꢀ 6.09 ppm
(d, Jˆ2.6 Hz); 19F NMR ꢀ ‡21.1 ppm (s).
4. Experimental
4.1. General
Antimony pentachloride was obtained from Aldrich and
was of 99.99‡% purity. All reactions were run under an
atmosphere of N2. Boiling points are uncorrected. 1H NMR
spectra (TMS reference) were recorded at 300 MHz, 19F
NMR spectra (CFCl3 reference, proton decoupled) at
282 MHz, and 13C NMR spectra (TMS reference, proton
decoupled) at 75 MHz.
4.5. Chlorofluoroacetyl fluoride (21)
SbCl5 (5.00 g, 16.9 mmol) was added dropwise to 2-
chloro-1,1,2-tri¯uoroethyl methyl ether (9) (50.0 g,
337 mmol) at r.t. under N2 using a condenser kept at
58C. After heating at 25±308C for 30 min, distillation
gave 28.1 g (73% yield) of chloro¯uoroacetyl ¯uoride (21)
4.2. 1,2,2,2-Tetrachloro-1-fluoroethyl methyl ether (1)
1
Methoxy¯urane (6) (500 g, 3.03 mol) was heated at re¯ux
under N2 over KOH pellets (175 g (85%), 2.66 mol) over-
night. Distillation to dryness under N2 gave a mixture of
water and crude product. The crude product was dried over
KOH, giving 424 g of a mixture of methoxy¯urane (6) and
2,2-dichloro-1-¯uorovinyl methyl ether (7) which was car-
ried into the chlorination without further puri®cation. 7: lit.
bp 1018C [2], 1H NMR ꢀ 3.81 ppm (s), 19F NMR ꢀ
90.7 ppm (s).
A 413 g portion of the mixture was cooled to 408C and
chlorine was bubbled through until uptake ceased. At this
point, the solution was a 50:50 mixture of 1 and methoxy-
¯urane. Fractional distillation in vacuo gave 171 g of
1,2,2,2-tetrachloro-1-¯uoroethyl methyl ether (1), bp 58±
618C/25 mmHg (lit. bp 578C/18 mmHg [2]). Overall
yieldˆ42%, based on consumed methoxy¯urane. 1: 1H
NMR ꢀ 3.84 ppm (s); 19F NMR ꢀ 69.5 ppm (br s).
as a clear liquid, bp 32±338C (lit. bp 34±448C [7]). 21: H
NMR ꢀ 6.45 ppm (d, Jˆ49 Hz); 19F NMR ꢀ ‡20.0 (d,
Jˆ22 Hz, 1 F), 148 (d, Jˆ22 Hz, 1 H) ppm.
4.6. Fluorination of trichloromethyl 2,2,2-trifluoro-1-
(trifluoromethyl)ethyl ether (18) with dichloroacetyl
fluoride (8)
SbCl5 (1.01 g, 3.38 mmol) was added dropwise to a
stirred solution of trichloromethyl 2,2,2-tri¯uoro-1-(tri-
¯uoromethyl)ethyl ether (18) (23.5 g, 82.5 mmol) and
dichloroacetyl ¯uoride (8) (10.8 g, 82.5 mmol) at r.t. under
N2. After 1.5 h, the mixture was cooled to 38C and ice-cold
H2O (20 ml) was added in portions with rapid stirring. After
the exotherm had subsided, the organic layer was washed
with dilute Na2CO3 solution (10 ml) and dried over CaCl2.
Isolated was 21.0 g liquid which by NMR contained 95%
dichloro¯uoromethyl 2,2,2-tri¯uoro-1-(tri¯uoromethyl)-
ethyl ether (19) (yieldˆ91% based on 8); the remainder
was 18.
4.3. 2,2,2-Trichloro-1,1-difluoroethyl methyl ether (2)
SbCl5 (3.36 g, 11.2 mmol) was added dropwise to a
stirred solution of 1,2,2,2-tetrachloro-1-¯uoroethyl methyl
ether (1) (80.9 g, 375 mmol) and methoxy¯urane (6)
(61.9 g, 375 mmol) at r.t. under N2. Vigorous gas evolution
and an exotherm to 408C resulted. After 50 min, the mixture
was cooled to 08C and ice-cold H2O (70 ml) was added
dropwise. Vigorous gas evolution [CAUTION: probably
HF] and an exotherm to 458C resulted. After thorough
mixing, the lower organic phase was dried over CaCl2,
giving 65.1 g clear liquid which by NMR contained
55.3 g (74%) of 2. The contaminants methyl chloride and
4.7. Fluorination of trichloromethyl 2,2,2-trifluoro-1-
(trifluoromethyl)ethyl ether (18) with
chlorfluoroacetyl fluoride (21)
SbCl5 (1.57 g, 5.25 mmol) was added dropwise to a
stirred solution of trichloromethyl 2,2,2-tri¯uoro-1-(tri-
¯uoromethyl)ethyl ether (18) (15.0 g, 52.5 mmol) and
chloro¯uoroacetyl ¯uoride (21) (6.00 g, 52.5 mmol) at r.t.
under N2. The mixture was heated at 608C for 1 h. Aqueous
work-up as before gave 10.6 crude product. NMR analysis

K. Ramig et al. / Journal of Fluorine Chemistry 94 (1999) 1±5
5
[5] D.G. Anderson, D.C. England, A.S. Milian Jr., US Patent 4 357 282
(1982) (DuPont).
showed 18, 19, and 20 in a 1.5:13:1 molar ratio. Yield of
19ˆ64% based on 21.
[6] D.C. England, J. Org. Chem. 49 (1984) 4007±4008.
[7] M. Hudlicky, J. Fluorine Chem. 29 (1985) 349±354.
[8] T. Nguyen, J. Fluorine Chem. 38 (1988) 95±105.
[9] M. Prober, J. Am. Chem. Soc. 76 (1954) 4189±4191.
[10] P. Tarrant, H.C. Brown, J. Am. Chem. Soc. 73 (1951) 1781±1783.
[11] R.C. Terrell, L. Speers, A.J. Szur, J. Treadwell, T.R. Ucciardi, J.
Med. Chem. 14 (1971) 517±519.
Acknowledgements
Many thanks to Dr. Yuri Cheburkov for helpful discus-
sions and to Dr. Ashok Krishnaswami for assistance with the
NMR spectroscopy.
[12] R.C. Terrell, L. Speers, A.J. Szur, T. Ucciardi, J.F. Vitcha, J. Med.
Chem. 15 (1972) 604±606.
References
[13] L. Speers, A.J. Szur, R.C. Terrell, J. Treadwell, T.R. Ucciardi, J.
Med. Chem. 14 (1971) 593±595.
[14] T. Ishihara, M. Kuroboshi, Chem. Lett. (1987) 1145±1148.
[15] M. Hudlicky, Chemistry of Organic Fluorine Compounds, 2nd ed.,
Ellis Horwood, Chichester, 1992, pp. 100±106.
[1] L.A. Rozov, R.A. Lessor, L.V. Kudzma, K. Ramig, J. Fluorine Chem.
88 (1998) 51±54.
[2] R.C. Terrell, L. Speers, A.J. Szur, T. Ucciardi, J.F. Vitcha, J. Med.
Chem. 15 (1972) 606±608.
[16] A.N. Nesmeyanov, V.N. Kost, L.I. Zakharkin, R. Kh. Freidlina, Izv.
Akad. Nauk S.S.R., Otdel. Khim. Nauk (1960) 447±451.
[17] L.A. Rozov, P.W. Rafalko, S.M. Evans, L. Brockunier, K. Ramig,
J. Org. Chem. 60 (1995) 1319±1325.
[3] F.G. Rudo, S.L. Pollack, H.F. Cascorbi, M. Helrich, M.I. Gold,
Anesth. Analg. (Cleveland) 49 (1970) 251±256.
[4] I.L. Knunyants, Yu.A. Cheburkov, M.D. Bargamova, Izv. Akad.
Nauk. SSSR, Ser. Khim. (Eng.) (1963) 1265-1268 and references
therein.
[18] K. Ramig, A. Krishnaswami, L.A. Rozov, Tetrahedron 52 (1996)
319±330.