General method for the preparation of β,β-difluoroacrylates using BrF3

Article abstract of DOI:10.1021/jo0485280

Various esters were reacted with base, carbon disulfide, and methyl iodide, producing 2-carboalkoxy-1,1-bis(methyl sulfide)-1-alkenes (2). The reaction of 2 with BrF₃, followed by oxidation with HOF-CH₃CN gave the bromodifluorosulfon

Full text of DOI:10.1021/jo0485280

General Method for the Preparation of â,â-Difluoroacrylates Using
BrF3
Aviv Hagooly and Shlomo Rozen*
School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences,
Tel-Aviv University, Tel-Aviv 69978, Israel
rozens@post.tau.ac.il
Received August 22, 2004
Various esters were reacted with base, carbon disulfide, and methyl iodide, producing 2-carboalkoxy-
1,1-bis(methyl sulfide)-1-alkenes (2). The reaction of 2 with BrF3, followed by oxidation with HOF‚
CH3CN gave the bromodifluorosulfonyl derivatives 5. Subsequent treatment with Raney nickel
led to R-substituted â,â-difluoroacrylates 6 in overall yields of 50-80%.
SCHEME 1. Docking of BrF3 with Soft Bases
Resulting in Ionic Reactions
Two families of compounds, acrylic esters and fluorine-
containing molecules, command a high interest in organic
chemistry and in material science. Combining these two
subjects is of potential interest for making precursors for
compounds used in coating, polymerization, special opti-
cal properties, and more.1 However, the only known
methods of preparing â,â-difluoroacrylates are the reac-
2
tions of malonic esters with CF2Br2 and reactions of
Grignard reagents with 2-(trifluoromethyl)propenoic acid.3
The incorporation of a CF2 group by fluorodesulfuration
using specialized dithianylium salts or various [BrF]
reagents such as DBH/HF/Py has been recorded in the
literature.4 Bromine trifluoride, which is commercially
available, has been known in the literature for more then
60 years, but for most of this period it was in a stage of
hibernation where organic synthesis was concerned.5 In
the past decade though, we have started exploring its
synthetic potential. It was revealed that it can serve as
deactivated aromatic rings,8 and more.9 Most of these
reactions proceeded through a complexation between the
soft acidic electrophilic bromine of the reagent and soft
basic heteroatoms such as sulfur or nitrogen of the
reactant. Such complexation brings the nucleophilic
fluorides to the vicinity of the electrophilic carbon, leading
to the desired fluorinated products (Scheme 1).
Recently, we prepared R-trifluoromethyl esters by
reacting BrF3 with 2-carboalkoxy-1,1-bis(methyl sulfide)-
1-alkenes (2), easily obtained from carboxylic acids, CS2,
and MeI.10 The reaction resulted immediately in a
mixture of bromodifluorosulfides (3), sulfoxides (4), and
traces of the sulfones (5), which was then oxidized in a
fast and quantitative reaction by HOF‚CH3CN,11 forming
the bromodifluorosulfonyl derivatives 5. We report now
that these intermediates can serve as a good starting
point for preparing the desired alkyl â,â-difluoroacrylates
(6).
6
7
a valuable tool for constructing the CF2 and the CF3
groups attached to specific sites, for bromination of highly
* To whom correspondence should be addressed. Fax: 972-3-
6409293.
(1) (a) Boguslavskaya, L. S.; Panteleeva, I, Y.; Morozova, T. V.;
Kartashov, A. V.; Chuvatkin, N. N. Russ. Chem. Rev. 1990, 59, 906.
(b) Botteghi, C.; Paganelli, S.; Sbrogio, F.; Zarantonello, C. Tetrahedron
Lett. 1999, 40, 8435. (c) Castelvetro, V.; Aglietto, M.; Ciardelli, F. J.
Coating Technol. 2002, 74, 57.
(2) (a) McDonald, A. I.; Lacoste, M. J.; Michael, B. F.; Palfreyman,
G.; Zreika, M. J. Med. Chem. 1985, 28, 186. (b) Bumgardner, L. C.;
Burgess, P. J.; Everett, S. T. J. Fluorine Chem. 1992, 56, 189.
(3) (a) Fuchikami, T.; Shibata, Y.; Suzuki, Y. Tetrahedron Lett. 1986,
27, 3173. (b) Kitazume, T.; Ohnogi, T.; Miyauchi, H.; Yamazaki, T. J.
Org. Chem. 1989, 54, 5630. (c) Watanabe, S.; Sugahara, K.; Fujita, T.;
Sakamoto, M. J. Fluorine Chem. 1993, 62, 201.
(4) (a) Kirsch, p.; Taugerbeck, A. Eur. J. Org. Chem. 2002, 3923.
(b) Kirsch, P.; Lenges, M.; Ruhl, A.; Sevenard, V. D.; Roschenthaler,
V. G. J. Fluorine Chem. 2004, 125, 1025. (c) Furuta, S.; Kuroboshi,
M.; Hiyama, T. Bull. Chem. Soc. Jpn. 1998, 71, 1939.
(5) An important exception was the use of BrF3 for the preparation
of modern anesthetics such as sevoflurane: (a) Rozov, L. A.; Huang,
C. G.; Halpern, D. F.; Vernice, G. G.; Ramig K. Tetrahedron: Asym-
metry 1997, 8, 3023. (b) Halpern, D. F.; Robin, M. L. U.S. Patent
4,996,371, 1991. (c) Ramig, K. Synthesis 2002, 2627.
(6) (a) Rozen, S.; Mishani E.; Bar-Haim, A. J. Org. Chem. 1994, 59,
2918. (b) Sasson, R.; Hagooly A.; Rozen, S. Org. Lett. 2003, 5, 769. (c)
Hagooly, A.; Sasson, R.; Rozen, S. J. Org. Chem. 2003, 68, 8287. (d)
Rozen, S.; Mishani E. Chem. Commun. 1993, 1761.
Results and Discussion
Reacting methyl heptanoate 1a with LDA, carbon
disulfide, and methyl iodide produced 2-carbomethoxy-
(7) (a) Rozen, S.; Rechavi D.; Hagooly, A. J. Fluorine Chem. 2001,
111, 161. (b) Hagooly, A.; Ben-David, I.; Rozen, S. J. Org. Chem. 2002,
67, 8430. (c) Ben- David, I.; Rechavi, D.; Mishani, E.; Rozen, S. J.
Fluorine Chem. 1999, 97, 75. (d) Rozen, S.; Mishani E. J. Chem. Soc.,
Chem. Commun. 1994, 2081.
(8) Rozen, S.; Lerman, O. J. Org. Chem. 1993, 58, 239.
(9) (a) Rozen, S.; Ben-David, I. J. Fluorine Chem. 1996, 76, 145. (b)
Rozen, S.; Ben-David, I. J. Org. Chem. 2001, 66, 496.
(10) Hagooly, A.; Rozen, S. Chem. Commun. 2004, 594.
(11) Rozen, S.; Bareket, Y. Tetrahedron Lett. 1994, 35, 2099.
10.1021/jo0485280 CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/06/2004
8786
J. Org. Chem. 2004, 69, 8786-8788

Preparation of â,â-Difluoroacrylates Using BrF3
SCHEME 2. Preparation of â,â-Difluoroacrylates
reacts much faster and 2-carbomethoxy-3-cyclopentyl-1,1-
bis(methyl sulfide)prop-1-ene (2d) and 2-carbomethoxy-
4-cyclohexyl-1,1-bis(methyl sulfide)but-1-ene (2e), both
of which possess tertiary hydrogens, gave after a short
treatment with BrF3, HOF‚CH3CN, and RaNi the desired
methyl 2-cyclopentylmethylene-â,â-difluoroacrylate (6d)
and methyl 4-cyclohexylethylene-â,â-difluoroacrylate (6e)
in 65% and 80% overall yields, respectively.
Compounds with aromatic rings, which are not ex-
tremely deactivated toward electrophilic reactions, are
not suitable substrates for this process because of their
fast reaction with BrF3.8 However, other functional
groups, such halogens, carbonyls, or hydroxyls, are
tolerated. Thus, 2-carbomethoxy-5-chloro-1,1-bis(methyl
sulfide)pent-1-ene (2f) was converted to methyl 2-(4-
chlorobutyl)-â,â-difluoroacrylate (6f) in 55% yield despite
the fact that in certain cases BrF3 is known to substitute
chlorine with fluorine.5 Free alcohols are easily oxidized
with BrF3,9a but protecting them as either ethyl ether
2g or pivaloyl ester 2h led to ethyl 2-(2-ethoxyethyl)-â,â-
difluoroacrylate (6g) and ethyl 2-(4-pivaloyloxybutyl)-â,â-
difluoroacrylate (6h) in 50% and 55% overall yields. If
an additional carbonyl group is present in the molecule
as in methyl 2-oxo-octanoate (1j), it has to be protected
as a ketal (1i) in order to prevent undesirable reactions
by the strong base, CS2 and MeI. After the formation of
2i the acetal group was removed and the resulting
2-carbomethoxy-1,1-bis(methyl sulfide)oct-7-oxo-1-ene (2j)
was reacted with BrF3 followed by oxidation to produce
5j. Treating the latter with RaNi furnished methyl
2-(hexa-5-one)-â,â-difluoroacrylate (6j) in 55% overall
yield.
In conclusion, reactions with bromine trifluoride should
be considered in many instances when the introduction
of a fluorine atom in organic molecules is the issue. By
using proper conditions it can be instrumental in turning
easily available carboxylic acids into the potentially
important and hard to prepare â,â-difluoroacrylates.
Experimental Section
1H NMR spectra were recorded using a 200 MHz spectrom-
eter with CDCl3 as a solvent and Me4Si as an internal
standard. Only the relevant and characteristic peaks are
reported. The 19F NMR spectra were measured at 188.1 MHz
and are reported upfield from CFCl3, serving as an internal
standard. The proton broad-band decoupled 13C NMR spectra
were recorded at 50.2 MHz. Here too, CDCl3 served as a
solvent and Me4Si as an internal standard. IR spectra were
recorded in CHCl3 solution on a FTIR spectrophotometer.
Silica gel 60H (Merck) and petrol ether/ethyl acetate were used
in the flash chromatography when the purification of the
product was desired.
Preparing and Handling of BrF3. Although commercially
available, we usually prepare our own BrF3 by passing 0.6 mol
of fluorine through 0.2 mol of bromine placed in a copper
reactor and cooled to 0-10 °C. The product can be stored in
Teflon containers indefinitely. BrF3 is a strong oxidizer and
tends to react very exothermically with water and oxygenated
organic solvents such as acetone or THF. Alkanes such as petrol
ether cannot serve as solvents either, because they react quickly
with BrF3. Any work using BrF3 should be conducted in a well-
ventilated area, and caution and common sense should be
exercised.
1,1-bis(methyl sulfide)hept-1-ene (2a) in good yield.
Bringing it in contact with 2.5 molar equiv of bromine
trifluoride for a few seconds gave a mixture of the
corresponding bromodifluoro sulfide 3a, sulfoxide 4a, and
sulfone 5a. The oxidation of this mixture with HOF‚CH3-
CN resulted in a single compound that proved to be the
sulfone 5a. Treating this sulfone with Raney nickel
(RaNi) led to the desired methyl 2-pentyl-â,â-difluoro-
acrylate (6a) in 55% overall yield (Scheme 2). In general,
longer alkyl chains are more sensitive to side reactions
with BrF3. However, when methyl undecanoate 1b and
methyl tetradecanoate 1c served as starting materials,
methyl 2-nonanyl-â,â-difluoroacrylate (6b) and methyl
2-dodecyl-â,â-difluoroacrylate (6c) were ultimately ob-
tained in 75% overall yield each. Such relatively clean
reaction indicates that the complexation of bromine
trifluoride with the sulfur atoms is faster and more
dominant then the indiscriminating radical destruction
of organic molecules by a noncomplexed BrF3 (see warn-
ing at the beginning of Experimental Section).
The fluorine atom in bromine trifluoride, can act, in
certain cases, as an electrophile capable of replacing
tertiary hydrogens12 in a similar manner as F2.13 Again,
however, we found that the bis(methyl sulfide) moiety
(12) Boguslavskaya, L. S.; Kartashov, A. V.; Chuvatkin, N. N. Russ.
J. Org. Chem. 1989, 25, 1835.
(13) (a) Rozen, S.; Gal, C. J. Org. Chem. 1987, 52, 2769. (b) Rozen,
S.; Gal, C. J. Org. Chem. 1987, 52, 4928.
J. Org. Chem, Vol. 69, No. 25, 2004 8787

Hagooly and Rozen
General Procedure for Preparation of 2-Carboalkoxy-
1,1-bis(methyl sulfide)-1-alkenes (2).10 A 10 mmol portion
of an ester (1) was dissolved in 100 mL of dry THF and cooled
to -78 °C, and 12.5 mmol of LDA (1.5 M in cyclohexane) was
added. The reaction was stirred for 2 h with temperature
maintained below -30 °C and cooled again to -78 °C, and
carbon disulfide (about 40 mmol) was added. A brown solution
formed and was stirred for an additional 1 h and again the
reaction was not allowed to warm above -30 °C. It was cooled
once more to -78 °C, and methyl iodide (about 40 mmol) was
added and stirred for an additional 2 h. The reaction mixture
was warmed to room temperature, poured into water, ex-
tracted with ether, and dried over MgSO4, and the organic
solvent was evaporated. The product was isolated by flash
chromatography as a brown oil with yields of 85-90%.
24 Hz, J2 ) 5 Hz), 51.8, 31.8, 29.5, 29.4, 29.3, 29.2, 28.9, 28.4,
24.9, 22.6, 13.9 ppm; HRMS (CI) (m/z) calcd for C16H29F2O2
291.2135 (MH)+, found 291.2138. Anal. Calcd for C16H28F2O2:
C, 66.18; H, 9.72; F, 13.08. Found: C, 66.13; H, 9.69; F, 13.49.
Methyl 2-Cyclopentylmethylene-â,â-difluoroacrylate
(6d). Prepared from 2d as described above in 65% overall
yield: oil; IR 1715 cm-1; 1H NMR 3.78 (3 H, s), 2.26-2.21 ppm
(2 H, m); 19F NMR -70.4 (1 F, dm, J ) 3 Hz), -74.5 ppm (1 F,
dm, J ) 3 Hz); 13C NMR 165.5 (dd, J1 ) 13 Hz, J2 ) 7 Hz),
159.9 (dd, J1 ) 310 Hz, J2 ) 295 Hz), 88.3 (dd, J1 ) 24 Hz, J2
) 5 Hz), 51.9, 39.2, 31.9, 29.8, 24.6 ppm; HRMS (CI) (m/z) calcd
for C10H15F2O2 205.1040 (MH)+, found 205.1036. Anal. Calcd
for C10H14F2O2: C, 58.82; H, 6.91. Found: C, 58.42; H, 6.99.
Methyl 4-Cyclohexylethylene-â,â-difluoroacrylate (6e).
Prepared from 2e as described above in 80% overall yield: oil;
IR 1713 cm-1; 1H NMR 3.78 (3 H, s), 2.28-2.16 ppm (2 H, m);
19F NMR -70.2 (1 F, dm, J ) 3 Hz), -75.2 ppm (1 F, dm, J )
3 Hz); 13C NMR 165.3 (dd, J1 ) 14 Hz, J2 ) 7 Hz), 159.5 (dd,
J1 ) 308 Hz, J2 ) 293 Hz), 89.0 (dd, J1 ) 24 Hz, J2 ) 5 Hz),
51.9, 37.1, 36.1, 32.9, 26.5, 26.1, 21.9 ppm; HRMS (CI) (m/z)
calcd for C12H19F2O2 233.1353 (MH)+, found 233.1360. Anal.
Calcd for C12H18F2O2: C, 62.05; H, 7.81. Found: C, 61.70; H,
7.92.
Methyl 2-(4-Chlorobutyl)-â,â-difluoroacrylate (6f). Pre-
pared from 2f as described above in 55% overall yield: oil; IR
1716 cm-1; 1H NMR 3.80 (3 H, s), 3.54 (2 H, t, J ) 6 Hz), 2.51-
2.36 ppm (2H, m); 19F NMR -68.4 (1 F, dm, J ) 3 Hz), -73.3
ppm (1 F, dm, J ) 3 Hz); 13C NMR 165.0 (dd, J1 ) 13 Hz, J2
) 7 Hz), 160.0 (dd, J1 ) 310 Hz, J2 ) 296 Hz), 87.7 (dd, J1 )
23 Hz, J2 ) 6 Hz), 54.1, 45.8, 33.2, 24.0 ppm; HRMS (CI)
(m/z) calcd for C7H10ClF2O2 199.0337 (MH)+, found 199.0338.
Anal. Calcd for C7H9ClF2O2: C, 42.33; H, 4.57; Cl,17.85.
Found: C, 41.91; H, 4.40; Cl, 18.25.
General Procedure for Preparation of Alkyl 2-Alkyl-
â,â-difluoroacrylates (6). The appropriate 2-carboalkoxy-1,1-
bis(methyl sulfide)-1-alkene (2) derivative (usually 1 mmol)
was dissolved in 10-15 mL of dry CFCl3. About 2.5 mmol of
BrF3 was dissolved in 10 mL of the same solvent, cooled to 0
°C, and added dropwise for about 1 min. The reaction was
quenched with saturated aqueous Na2SO3 and washed until
colorless. The aqueous layer was extracted with CH2Cl2, and
the organic layer was dried over MgSO4. The oily crude that
contained mainly the bromodifluoromethyl sulfide 3 and
sulfoxide 410 was dissolved in 15 mL of CHCl3 and oxidized
with a 3-fold excess of HOF‚CH3CN11 in 0 °C for 20 min. The
reaction was terminated with NaHCO3 solution, extracted with
CH2Cl2, and dried over MgSO4. After evaporation of the
solvent, the reaction mixture contained mainly the corre-
sponding bromodifluoromethylsulfonyl derivative (5), which if
desired could be isolated by flash chromatography.10 The crude
5 (300 mg) was dissolved in 15 mL of THF, and 3 g of RaNi
(Aldrich, 22,167-8) was added. The reaction mixture was
stirred for 30 min at room temperature and filtered through
silica. The product 6 was isolated by flash chromatography in
50-80% overall yields. Compounds 6 possess coupling constant
Ethyl 2-(2-Ethoxyethyl)-â,â-difluoroacrylate (6g). Pre-
pared from 2g as described above in 50% overall yield: oil; IR
1
1718 cm-1; H NMR 4.24 (2 H, q, J ) 7 Hz), 3.53-3.42 (4 H,
m), 2.55-2.45 (2 H, m), 1.30 (3 H, t, J ) 7 Hz), 1.17 ppm (3 H,
t, J ) 7 Hz); 19F NMR -68.5 (1 F, dm, J ) 3 Hz), -73.7 ppm
(1 F, dm, J ) 3 Hz); 13C NMR 164.7 (dd, J1 ) 13 Hz, J2 ) 8
Hz), 160.2 (dd, J1 ) 310 Hz, J2 ) 295 Hz), 85.8 (dd, J1 ) 23
Hz, J2 ) 7 Hz), 68.2, 66.0, 61.0, 25.0, 15.0, 14.0 ppm; MS (CI)
m/z 209 (MH)+. It should be noted that we were unable to run
a microanalysis on this compound due to its volatility.
Ethyl 2-(4-Pivaloyloxybutyl)-â,â-difluoroacrylate (6h).
Prepared from 2h as described above in 55% overall yield: oil;
IR 1714 and 1728 cm-1; 1H NMR 4.23 (2 H, q, J ) 7 Hz), 4.06
(2 H, t, J ) 7 Hz), 2.31-2.11 (2 H, m), 1.29 (3 H, t, J ) 7 Hz),
1.19 ppm (9 H, s); 19F NMR -69.7 (1 F, dm, J ) 3 Hz), -74.7
ppm (1 F, dm, J ) 3 Hz); 13C NMR 178.3, 164.4 (dd, J1 ) 14
Hz, J2 ) 8 Hz), 159.5 (dd, J1 ) 310 Hz, J2 ) 295 Hz), 88.4 (dd,
J1 ) 23 Hz, J2 ) 5 Hz), 63.6, 60.8, 38.5, 27.3, 26.9, 24.7, 23.8,
13.9 ppm; HRMS (CI) (m/z) calcd for C14H23F2O4 293.1564
(MH)+, found 293.1563. Anal. Calcd for C14H22F2O4: C, 57.52;
H, 7.59; F, 13.00. Found: C, 57.48; H, 7.66; F, 13.25.
2JF,F of 0-1 Hz, and the coupling constant represent the 4JF,H
.
This was reported early14 and we observed another small
coupling constant (represented by - m), probably due to the
4
2
other JF,H or the small JF,F constant.
Methyl 2-Pentyl-â,â-difluoroacrylate (6a). Prepared from
2a as described above in 55% overall yield: oil; IR 1718 cm-1
;
1H NMR 3.78 (3 H, s), 2.31-2.05 (2 H, m), 0.90 ppm (3 H, t, J
) 7 Hz); 19F NMR -70.1 (1 F, dm, J ) 3 Hz), -75.0 ppm (1 F,
dm, J ) 3 Hz); 13C NMR 167.3 (dd, J1 ) 13 Hz, J2 ) 6 Hz),
161.7 (dd, J1 ) 310 Hz, J2 ) 295 Hz), 90.6 (dd, J1 ) 23 Hz, J2
) 5 Hz), 53.9, 33.1, 30.1, 26.3, 24.2, 15.8 ppm; MS (CI) (m/z)
193 (MH)+. It should be noted that we were unable to run a
microanalysis on this compound due to its volatility.
Methyl 2-Nonanyl-â,â-difluoroacrylate (6b). Prepared
from 2b as described above in 75% overall yield: oil; IR 1713
1
cm-1; H NMR 3.78 (3 H, s), 2.28-2.10 (2 H, m), 0.89 ppm (3
H, t, J ) 7 Hz); 19F NMR -70.1 (1 F, dm, J ) 3 Hz), -75.0
ppm (1 F, dm, J ) 3 Hz); 13C NMR 165.3 (dd, J1 ) 14 Hz, J2
) 7 Hz), 159.7 (dd, J1 ) 310 Hz, J2 ) 295 Hz), 88.6 (dd, J1 )
24 Hz, J2 ) 5 Hz), 51.8, 31.7, 29.4, 29.2, 29.1, 28.9, 28.4, 24.4,
22.5, 13.9 ppm; HRMS (CI) (m/z) calcd for C13H23F2O2 249.1666
(MH)+, found 249.1665. Anal. Calcd for C13H22F2O2: C, 62.88;
H, 8.93; F, 15.30. Found: C, 61.94; H, 8.88; F, 15.35.
Methyl 2-(Hexa-5-one)- â,â-difluoroacrylate (6j). Pre-
pared from 2j as described above in 55% overall yield: oil; IR
1
1714 and 1720 cm-1; H NMR 3.78 (3 H, s), 2.45 (2 H, t, J )
7 Hz), 2.30-2.19 (2 H, m), 2.14 ppm (3 H, s); 19F NMR -69.4
(1 F, dm, J ) 3 Hz), -74.3 ppm (1 F, dm, J ) 3 Hz); 13C NMR
208.5, 165.2 (dd, J1 ) 14 Hz, J2 ) 8 Hz), 159.8 (dd, J1 ) 310
Hz, J2 ) 295 Hz), 88.2 (dd, J1 ) 25 Hz, J2 ) 5 Hz), 52.0, 43.1,
29.8, 27.9, 24.2, 22.9 ppm; HRMS (CI) (m/z) calcd for C10H15F2O3
221.0989 (MH)+, found 221.0992. Anal. Calcd for C10H14F2O3:
C, 54.54; H, 6.41. Found: C, 54.40; H, 6.42.
Methyl 2-Dodecyl-â,â-difluoroacrylate (6c). Prepared
from 2c as described above in 75% overall yield: oil; IR 1715
1
cm-1; H NMR 3.78 (3 H, s), 2.28-2.15 (2 H, m), 0.90 ppm (3
H, t, J ) 7 Hz); 19F NMR -70.2 (1 F, dm, J ) 3 Hz), -75.0
ppm (1 F, dm, J ) 3 Hz); 13C NMR 165.3 (dd, J1 ) 14 Hz, J2
) 8 Hz), 159.7 (dd, J1 ) 310 Hz, J2 ) 295 Hz), 88.6 (dd, J1 )
Acknowledgment. This work was supported by the
USA-Israel Binational Science Foundation (BSF), Jerus-
alem, Israel.
(14) Bumgardner, L. C.; Burgess, P. J.; Everett, S. T.; Purrington,
T. S. J. Fluorine Chem. 1992, 56, 189.
JO0485280
8788 J. Org. Chem., Vol. 69, No. 25, 2004