A general route for the synthesis of β,β-difluorocarboxylic acids

Article abstract of DOI:10.1016/j.tet.2008.03.018

A new method for the preparation of β,β-difluoro- (and other gem-difluoro) acids has been developed. It is based on the fact that 3-oxocarboxylic esters are easy to make and convert to the corresponding dithiane derivatives. These dithianes reacted with B

Full text of DOI:10.1016/j.tet.2008.03.018

Tetrahedron 64 (2008) 5362–5364
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A general route for the synthesis of b,b-difluorocarboxylic acids
*
Or Cohen, Shlomo Rozen
School of Chemistry, Tel-Aviv University, Ramat Aviv, Tel-Aviv 69978, Israel
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method for the preparation of b,b-difluoro- (and other gem-difluoro) acids has been developed. It
is based on the fact that 3-oxocarboxylic esters are easy to make and convert to the corresponding
dithiane derivatives. These dithianes reacted with BrF3, a commercial, but rarely used reagent in organic
chemistry, under very mild conditions to form the corresponding difluoroesters, which in turn could be
quantitatively hydrolyzed to the free gem-difluoroacids.
Received 11 December 2007
Received in revised form 17 February 2008
Accepted 6 March 2008
Available online 18 March 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
alkanes15 starting from the corresponding alkyl halides, and
more.16 Most transformations were made possible due to the fact
As with so many fluoro derivatives, various fluorocarboxylic
acids are a subject of enormous biological interest.1 Many schemes
that the bromine in BrF3 is a soft acid, which complexes most effec-
tively with soft bases such as sulfur and nitrogen atoms. The com-
plexation positions the ‘naked’ nucleophilic fluorides near the
potential reaction center and eventually substitute the nitrogen
or sulfur heteroatom (Scheme 1). This complexation also reduces
the chances of possible radical brominations and fluorinations.17
have been developed by us and others for the synthesis of a-fluoro-
2
,
a,a-difluoro-,3 u-fluoro-4 or a-trifluoromethylcarboxylic acids.5
The family of b,b-difluorocarboxylic acids, however, is almost
unknown.6 Some specific acids of this type were tailor made and
found to be, among other things, inhibitors of the biosynthesis of
certain sex pheromones.7 We report here a new general method
for the preparation of b,b-difluorocarboxylic acids using BrF3 and
b-dithiane esters readily synthesized from b-ketoesters and
dithiols. While some of these esters are commercially available,
most of them can be readily synthesized from the corresponding
acyl halides and esters via a Claisen type condensation.
F
F
Soft acid
F
Br
Soft base
F
F
Br
F
S
R
R'
S
R'
R
C
Z
C
Z
or N
X
X
or N
Bromine trifluoride is a commercial reagent, but it can also be
prepared directly from the elements. Until recently, organic chem-
ists shied away from it, mainly because of its violent nature when
handled improperly (using it with oxygenated or hydrocarbon sol-
vents such as THF or hexanedsee Section 3). In the past only a few
examples of its use were reported,8 but over the last decade, we
have shown that bromine trifluoride can serve as a selective re-
agent for many reactions using halogenated solvents, such as chlo-
roform or CFCl3 and ordinary glass apparatuses. It can
electrophilically brominate most aromatic rings, including very
deactivated ones even in the absence of any Friedel–Crafts catalyst.9
Regarding fluorination, it can transform carbonyls to the CF2
group,10 nitriles to the corresponding CF3 moiety,11 and alcohols
or acids to acyl fluorides.12 Bromine trifluoride can also help in syn-
thesizing trifluoromethyl ethers,13 trifluoro-14 and difluoromethyl
R
X
F
C
Z
R
O R'
BrF3
C
Z
No Reaction
X
Hardbase
Scheme 1. The complexation of BrF3 with soft heteroatoms.
2. Results and discussion
When the 1,3-dithiane of ethyl 3-oxooctadecanoate (1) was
reacted for 1–2 min at 0 ꢀC with a threefold excess of BrF3, the
expected ethyl 3,3-difluorohexadecanoate (2) was formed in 75%
yield. Similarly, the 1,3-dithiane of diethyl 3-oxoglutarate (3) was
converted to diethyl b,b-difluoroglutarate 418 in 60% yield (Table 1).
Since BrF3 is known to be able to substitute chlorine atoms with
fluorine (e.g., the conversion of (S)-isoflurane to the (R)-desflur-
ane)19 it was of interest to see if such processes take place during
* Corresponding author. Fax: þ972 3 6409293.
E-mail address: rozens@post.tau.ac.il (S. Rozen).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.018

O. Cohen, S. Rozen / Tetrahedron 64 (2008) 5362–5364
5363
Table 1
O
F
O
O
O
HCl
F
F
F
Preparation of b,b-difluoroesters
EtO
OEt
HO
OH
17
Scheme 3. Hydrolysis of difluoroesters.
4
O
O
S
R
S
F
R
F
BrF3
R''
R''
O
O
R'
R'
low temperatures, make this reaction suitable to many types of
compounds.
(Yield, %)
1 R¼C15H31; R0¼H; R00¼Et
2 (75)
4 (60)
6 (65)
8 (75)
10 (80)
3 R¼CH2COOEt; R0¼H; R00¼Et
5 R¼Cl(CH2)4; R0¼H; R00¼Et
7 R¼Me; R0¼Et; R00¼Et
3. Experimental section
3.1. General
9 R¼R0¼(CH2)4; R00¼Et
CH
11 R¼
; R0¼H; R00¼Et
12 (70)
14 (55)
1H NMR spectra were recorded using a 200 MHz spectrometer
with CDCl3 as a solvent and Me4Si as an internal standard. The
19F NMR spectra were measured at 188.1 MHz using CFCl3 as an in-
ternal standard. The proton broadband decoupled 13C NMR spectra
were recorded at 100.5 MHz. Here too, CDCl3 served as a solvent
and Me4Si as an internal standard. IR spectra were recorded neat
or in CH2Cl2 solution on a FTIR spectrophotometer. MS spectra
were measured under ESI–QqTOF or CI conditions.
13 R¼Me; R0¼R00¼(CH2)2
the reactions with dithiane derivatives when chlorine atoms are
present. Evidently, the complexation of the reagent with the sulfur
atoms is by far the dominant reaction as demonstrated by 1,3-
dithiane of ethyl 7-chloro-3-oxoheptanoate (5), which resulted in
ethyl 7-chloro-3,3-difluoroheptanoate (6) in 65% yield.
The fluorine atoms in bromine trifluoride can in certain cases act
as electrophiles8b and substitute tertiary hydrogens similar to F2.20
Such outcomes, however, seem to require long reaction times and
do not compete with the rapid complexation of the soft bromine
with the soft sulfur atoms. Indeed when we reacted the dithiane
derivatives of ethyl 2-ethyl-3-oxobutyrate (7), ethyl 2-oxocyclohex-
anecarboxylate (9), and ethyl 3-cyclohexyl-3-oxopropionate (11) all
possessing tertiary hydrogens, the only products formed in good
yields were ethyl 2-ethyl-3,3-difluorobutyrate (8),6a ethyl 2,2-
difluorocyclohexanecarboxylate (10),6b and ethyl 3-cyclohexyl-
3,3-difluoropropionate (12) in reactions completed in less then
a minute. The speed of the reaction and the mild conditions
employed were responsible for the fact that even lactones such as
the dithiane of a-(1-oxoethyl)-g-butyrolactone (13) was found to
be a suitable substrate for the formation the corresponding a-
(1,1-difluoroethyl)-g-butyrolactone 14 although the yield (55%)
was somewhat lower than usual. It should be mentioned that occa-
sionally small fractions of the products, in addition to the difluoro
moiety, contained also a bromine atom. This, however, could easily
and quantitatively be removed by tributyltin hydride, thus increas-
ing the overall yield of the desired product.
3.2. Preparing and handling of BrF3
Although commercially available, we usually prepare our own
BrF3 simply by passing 0.6 mol fluorine through 0.2 mol of bromine
placed in a copper reactor and held at temperatures between 0 and
þ10 ꢀC. Under these conditions, the higher oxidation state of
bromine, BrF5, will not be formed in any appreciable amount. The
reagent can be stored in TeflonÒ 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,
like petrol ether, cannot serve as solvents either since they also react
quickly with BrF3. Solvents such as CHCl3, CH2Cl2, CFCl3 or, if solubility
is not an issue, any perfluoroalkane or perfluoroether can be used. Any
work using BrF3 should be conducted in a well ventilated area and
caution and common sense should be exercised.
3.3. General procedure for preparing difluoroesters
A dithiane (1–10 mmol) was dissolved in 10–20 mL of CFCl3 and
cooled to 0 ꢀC. About 3 mol equiv of BrF3 was dissolved in the same
solvent, cooled to 0 ꢀC, and added dropwise to the reaction mixture
for 1–2 min. After the addition was completed, the reaction mixture
was washed with Na2S2O3 solution till colorless. The aqueous layer
was extracted with CH2Cl2 and the organic layer dried over MgSO4.
Evaporation of the solvent followed by flash chromatography (us-
ing 5% ethyl acetate in petroleum ether as eluent) gave the desired
difluoro ester derivative. In the case of the reaction of 11 and 13
a minor fraction, which contained bromine was also found. This
atom was substituted with hydrogen with the help of tributyltin
hydride, increasing the overall yield of the products 12 and 14 to
70 and 55%, respectively (see below).
The above method seems to be suitable for transforming any
ketoester to its difluoro derivative. This could be demonstrated by
reacting the dithiane of ethyl 2-(2-oxocyclohexyl)ethanoate (15)
with BrF3 forming ethyl 2-(2,2-difluorocyclohexyl)ethanoate (16)
(g,g-difluoroesters) in 55% yield (Scheme 2).
S
S
BrF3
F
F
OEt
OEt
O
O
(yield)
(55%)
15
16
Scheme 2. Preparation of g,g-difluoroesters.
3.3.1. Ethyl 3,3-difluorooctadecanoate (2)
Compound 2 was prepared from 1 (417 mg, 1 mmol) as de-
The difluoroesters could be hydrolyzed almost quantitatively to
the free acids by refluxing them with concentrated HCl for 4 h.
Thus, for example, diethyl 3,3-difluoroglutarate (4) was converted
to the known 3,3-difluoroglutaric acid (17)18 in higher than 95%
yield (Scheme 3).
In conclusion, the above method has the advantage of being
a general one for the synthesis of many types of gem-difluoroacids.
The mild conditions, as expressed in the short reaction times and
scribed above in 75% yield. d 4.19 (2H, q, J¼7 Hz), 2.89 (2H, t,
H
J¼14 Hz), 2.06–1.54 (2H, m), 1.53–1.43 (2H, m), 1.25 (27H, br s),
0.88 (3H, t, J¼7 Hz); d 167.1, 122.3 (t, J¼242 Hz), 61.1, 41.7 (t,
C
J¼28.5 Hz), 36.1 (t, J¼24 Hz), 31.9, 29.7, 29.6, 29.3 (t, J¼11 Hz),
22.7, 22.2, 14.1; d ꢁ94.3 (quin, J¼14 Hz); IR 1740 cmꢁ1; HRMS
F
(ESI–QqTOF) (m/z) calcd for C20H38F2O2¼371.2732 (MþNa)þ, found
371.2759. Anal. Calcd for C20H38F2O2: C, 68.93; H, 10.95; F, 10.90.
Found: C, 68.88; H, 10.95; F, 10.54.

5364
O. Cohen, S. Rozen / Tetrahedron 64 (2008) 5362–5364
3.3.2. Diethyl b,b-difluoroglutarate (4)18
chromatography using 5% ethyl acetate in petroleum ether, 14
was obtained in 55% yield. dH 4.41 (1H, dt, J¼8.8, 5.0 Hz), 4.28
(1H, q, J¼8.2 Hz), 3.09–2.96 (1H, m), 2.60–2.41 (2H, m), 1.87 (3H,
dd, J¼19.8, 18.7 Hz); dC 173.6 (d, J¼11 Hz), 122.6 (t, J¼241 Hz),
Compound 4 was prepared from 3 (400 mg, 1.44 mmol) as
described above in 60% yield. d 4.19 (4H, q, J¼7 Hz), 3.25 (4H,
H
t, J¼15 Hz), 1.28 (6H, t, J¼7 Hz); dC 167.3 (t, J¼9 Hz), 119.8
(t, J¼242 Hz), 61.4, 40.8 (t, J¼27.5 Hz), 14.2; d ꢁ89.5 (quin,
67.4, 47.6 (t, J¼30 Hz), 23.8, 22.7 (t, J¼26.0 Hz); d ꢁ86.3 (1F, dqd,
F
F
J¼14.7 Hz); IR 1745 cmꢁ1; HRMS (ESI–QqTOF) (m/z) calcd for
J¼248, 19.6, 4.1 Hz), ꢁ97.6 (1F, dqd, J¼248, 24.5, 18.4 Hz); IR
1790 cmꢁ1; HRMS (CI, MeOH) (m/z) calcd for C6H8F2O2¼151.0571
(MþH)þ, found 151.0572. Anal. Calcd for C6H8F2O2: C, 48.00; H,
5.37. Found: C, 47.68; H, 5.12.
C9H14F2O4¼247.0752 (MþNa)þ, found 247.0668.
3.3.3. Ethyl 7-chloro-3,3-difluoroheptanoate (6)
Compound 6 was prepared from 5 (297 mg, 1 mmol) as de-
scribed above in 65% yield. d 4.19 (2H, q, J¼7 Hz), 3.56 (2H, t,
3.3.8. Ethyl 2-(2,2-difluorocyclohexyl)ethanoate (16)
H
J¼6.3 Hz), 2.91 (2H, t, J¼14.5 Hz), 2.19–1.58 (6H, m), 1.29 (3H, t,
Compound 16 was prepared from 15 (823 mg, 3 mmol) as
J¼7 Hz); d 167.7 (t, J¼8 Hz), 122.8 (t, J¼242 Hz), 62.0, 45.2, 42.7
described above in 55% yield. d 4.15 (2H, q, J¼7 Hz), 2.77 (1H,
C
H
(t, J¼28.5 Hz), 35.9 (t, J¼24.5 Hz), 32.7, 20.4 (t, J¼4.5 Hz), 14.2; dF
ꢁ94.5 (quin, J¼15.5 Hz); IR 1743 cmꢁ1; HRMS (ESI–QqTOF) (m/z)
calcd for C9H15ClF2O2¼251.0635 (MþNa)þ, found 251.0620. Anal.
Calcd for C9H15ClF2O2: C, 47.27; H, 6.61; F, 16.62. Found: C, 47.60;
H, 6.51; F, 16.40.
dd, J¼16, 4 Hz), 2.22–2.08 (2H, m), 1.86–1.83 (1H, m), 1.78–1.61
(5H, m), 1.33–1.29 (2H, m), 1.26 (3H, J¼7 Hz); d 173.2, 124.4
C
(t, J¼244 Hz), 61.3, 41.3 (t, J¼21 Hz), 34.8 (dd, J¼25, 22 Hz), 14.9;
d
ꢁ95.1 (1F, dm, J¼236 Hz), ꢁ112.5 (1F, dm, J¼237 Hz); IR
F
1742 cmꢁ1
;
HRMS (ESI–QqTOF) (m/z) calcd for C10H16F2O2¼
229.0994 (MþNa)þ, found 229.1010. Anal. Calcd for C10H16F2O2: C,
3.3.4. Ethyl 2-ethyl-3,3-difluorobutyrate (8)6a
58.24; H, 7.82; F, 18.42. Found: C, 58.49; H, 7.63; F, 18.48.
Compound 8 was prepared from 7 (497 mg, 2 mmol) as de-
scribed above in 75% yield. d 4.21 (2H, q, J¼7 Hz), 2.90–2.71 (1H,
H
Acknowledgements
m), 1.83–1.57 (5H, m), 1.29 (3H, t, J¼7 Hz), 0.95 (3H, t, J¼7 Hz); d
C
171.3, 123.6 (t, J¼243 Hz), 61.8, 56.0 (t, J¼26 Hz), 21.8 (t, J¼27 Hz),
This work was supported by the USA–Israel Binational Science
Foundation (BSF), Jerusalem, Israel.
21.2 (dd, J¼5.4, 2.7 Hz), 14.9, 12.6; d ꢁ89.3 (1F, dqd, J¼262, 20,
F
10 Hz), ꢁ91.4 (1F, dqd, J¼262, 20, 14 Hz); IR 1739 cmꢁ1; HRMS
(ESI–QqTOF) (m/z) calcd for C8H14F2O2¼203.0842 (MþNa)þ, found
203.0854.
References and notes
3.3.5. Ethyl 2,2-difluorocyclohexanecarboxylate (10)6b
1. See for example: (a) Gelb, H. M.; Lin, Y.; Pickard, A. M.; Song, Y.; Vederas, C. J.
J. Am. Chem. Soc. 1990, 112, 4932; (b) Shiozaki, M.; Deguchi, N.; Macindoe, M.
W.; Arai, M.; Miyazaki, H.; Mochizuki, T.; Tatsuta, T.; Ogawa, J.; Maeda, H.;
Kurakata, S.-I. Carbohydr. Res. 1996, 283, 27; (c) Thaisrivongs, S.; Schostarez,
J. H.; Pals, T. D.; Turner, R. S. J. Med. Chem. 1987, 30, 1837.
2. Rozen, S.; Hagooly, A.; Harduf, R. J. Org. Chem. 2001, 66, 7464.
3. (a) Hagooly, A.; Sasson, R.; Rozen, S. J. Org. Chem. 2003, 68, 8287; (b) Yang, Z. Y.;
Burton, D. J. J. Org. Chem. 1992, 57, 5144.
Compound 10 was prepared from 9 (521 mg, 2 mmol) as de-
scribed above in 80% yield. d 4.19 (2H, q, J¼7 Hz), 2.95–2.73 (1H,
H
m), 2.33–1.61 (8H, m), 1.28 (3H, t, J¼7 Hz); dC 170.2 (d, J¼6 Hz),
122.1 (t, J¼246 Hz), 61.3, 49.2 (t, J¼23 Hz), 33.6 (t, J¼23 Hz), 26.9,
22.7, 14.5; dF ꢁ94.5 (1F, dd, J¼240, 17 Hz), ꢁ105.0 (1F, d,
J¼239 Hz); IR 1737 cmꢁ1; HRMS (ESI–QqTOF) (m/z) calcd for
C9H14F2O2¼215.0854 (MþNa)þ, found 218.0850.
4. Shahak, I.; Rozen, S.; Bergmann, E. D. Isr. J. Chem. 1970, 8, 763.
5. (a) Hagooly, A.; Rozen, S. Chem. Commun. 2004, 594; (b) Hagooly, A.; Rozen, S.
J. Org. Chem. 2004, 69, 7241.
6. (a) The preparation of a few b,b-difluorocarboxylic acids was mentioned by
Yagupolskii who used high pressured reactions employing SF4 and anhydrous
HF: Bloshchitsa, F. A.; Burmakov, A. I.; Kunshenko, B. V.; Alekseeva, L. A.; Yagu-
polskii, L. M. Zh. Org. Khim. 1982, 18, 782; (b) Some of these acids have also been
prepared electrochemically: Hara, S.; Chen, S.-Q.; Horisho, T.; Fukuhara, T.;
Yoneda, N. Tetrahedron Lett. 1996, 37, 8511; (c) Similar derivatives have also
been formed as a result of sigmatropic rearrangements: Broadhurst, J. M.;
Brown, J. S.; Percy, M. J.; Prime, E. M. J. Chem. Soc., Perkin Trans. 1 2000, 3217;
(d) Hagooly, A.; Rozen, S. J. Org. Chem. 2004, 69, 8786.
7. Bosch, M. P.; Perez, R.; Lahuerta, G.; Hernanz, D.; Camps, F.; Guerrero, A. Bioorg.
Med. Chem. 1996, 4, 467.
8. (a) Michalak, R. S.; Wilson, S. R.; Martin, J. C. J. Am. Chem. Soc. 1984, 106, 7529;
(b) Boguslavskaya, L. S.; Kartashov, A. V.; Chuvatkin, N. N. J. Org. Chem. USSR
(Engl. Transl.) 1989, 25, 1835; (c) Kartashov, A. V.; Chuvatkin, N. N.; Boguslav-
skaya, L. S. J. Org. Chem. USSR (Engl. Transl.) 1988, 24, 2276.
3.3.6. Ethyl 3-cyclohexyl-3,3-difluoropropionate (12)
Compound 12 was prepared from 11 (577 mg, 2 mmol) as
described above. The mixture of the desired and the brominated
products (370 mg) was dissolved in 20 mL anhydrous THF into
which 100 mg of 1,10-azobis(cyclohexane-carbonitrile) (ABCN
0.4 mmol) and 2.4 mL of tributyltin hydride (8.9 mmol) were added.
The solution was refluxed for 2 h. After evaporation of the solvent,
the product was purified by flash chromatography (using 5% ethyl
acetate in petroleum ether) and 12 was obtained in 70% yield. dH
4.20 (2H, q, J¼7.1 Hz), 2.89 (2H, t, J¼15.8 Hz), 2.06–1.90 (1H, m),
1.90–1.65 (4H, m), 1.32–1.10 (9H, m); dC 167.9, 123.9 (t, J¼245 Hz),
61.8, 44.2 (t, J¼23 Hz), 40.8 (t, J¼28.3 Hz), 26.6, 26.3, 26.2, 14.8; d
F
9. Rozen, S.; Lerman, O. J. Org. Chem. 1993, 58, 239.
ꢁ102.4 (q, J¼15 Hz); IR 1745 cmꢁ1; HRMS (ESI–QqTOF) (m/z) calcd
10. Rozen, S.; Mishani, E.; Bar-Haim, A. J. Org. Chem. 1994, 59, 2918.
11. Rozen, S.; Rechavi, D.; Hagooly, A. J. Fluorine Chem. 2001, 111, 161.
12. (a) Rozen, S.; Ben-David, I. J. Fluorine Chem. 1996, 76, 145; (b) Cohen, O.; Sasson,
R.; Rozen, S. J. Fluorine Chem. 2006, 127, 433.
for C11H18F2O2¼243.1158 (MþNa)þ, found 243.1167. Anal. Calcd for
C
11H18F2O2: C, 59.98; H, 8.24. Found: C, 60.05; H, 8.35.
13. Ben-David, I.; Rechavi, D.; Mishani, E.; Rozen, S. J. Fluorine Chem. 1999, 97, 75.
14. Hagooly, A.; Ben-David, I.; Rozen, S. J. Org. Chem. 2002, 67, 8430.
15. Sasson, R.; Hagooly, A.; Rozen, S. Org. Lett. 2003, 5, 769.
16. Rozen, S. Acc. Chem. Res. 2005, 38, 803.
17. Sasson, R.; Rozen, S. Tetrahedron 2005, 60, 1083.
18. Kulchitskii, M. M.; Ilchenko, A. Y.; Yagupolskii, L. M. Zh. Org. Khim. (Engl. Transl.)
1973, 9, 827.
19. Rozov, L. A.; Huang, C. G.; Halpern, D. F.; Vernice, G. G.; Ramig, K. Tetrahedron:
Asymmetry 1997, 8, 3023.
20. Rozen, S.; Gal, C. J. Org. Chem. 1987, 52, 4928.
3.3.7. a-(1,1-Difluoroethyl)-g-butyrolactone (14)
Compound 14 was prepared from 13 (2.18 g, 10 mmol) as de-
scribed above. Eventually 2.5 g of a mixture of the desired product
along with its minor brominated companion was dissolved in
100 mL anhydrous THF. ABCN (530 mg, 2.17 mmol) and 5.67 mL
(21.7 mmol) of tributyltin hydride were added and the solution
was refluxed for 1 h. After evaporation of the solvent, and flash