Constructing the CF3 group; Unique trifluorodecarboxylation induced by BrF3

Article abstract of DOI:10.1016/j.tet.2004.11.063

A variety of 2-alkyl-1,3-dithiane-2-carboxylic acids was prepared from the appropriate alkyl halides, 1,3-dithiane and CO₂. These acids were reacted with BrF₃ to form the trifluoromethylalkyl derivatives via a combination of ionic and radical trifluorodecarboxylation in about 50-60% yield.

Full text of DOI:10.1016/j.tet.2004.11.063

Tetrahedron 61 (2005) 1083–1086
Constructing the CF3 group; unique trifluorodecarboxylation
induced by BrF3
*
Revital Sasson and Shlomo Rozen
School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel
Received 4 September 2004; revised 2 November 2004; accepted 25 November 2004
Available online 15 December 2004
Abstract—A variety of 2-alkyl-1,3-dithiane-2-carboxylic acids was prepared from the appropriate alkyl halides, 1,3-dithiane and CO2.
These acids were reacted with BrF3 to form the trifluoromethylalkyl derivatives via a combination of ionic and radical
trifluorodecarboxylation in about 50–60% yield.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
The trifluoromethyl group has a great impact on a wide
range of man-made chemicals such as dyes, polymers,
agrochemicals, pharmaceuticals. Incorporating this group
into a molecule can often modify the biological activity and
physiological properties. These modifications are associated
with increased stability and lipophilicity, while the steric
distortion, compared to the parent compound, is relatively
small. Quite a few methods for trifluoromethylation
have been developed using trifluoromethyl trimethylsilane
(Ruppert’s reagent-CF3SiMe3),1 fluoroform or trifluoro-
methyl halides,2 (trifluoromethyl) dibenzothiophenium
triflate salt,3 and more.4
Scheme 1. General mechanism for selective reactions with BrF3.
known reactions in organic chemistry dealing with halo-
decarboxylation of carboxylic acids. Chlorine, bromine or
iodine are brought in contact with the acids’ salt (usually
silver) forming the corresponding alkyl halides.10 Fluorine,
however, was conspicuously missing from this list of
halogens. Fluorodecarboxylation reactions are very rare and
the few described required xenon difluoride. These reactions
proceeded through the RCOOXeF intermediate character-
ized by the very weak bonds around the Xe atom.11 We now
report a new method for transforming alkyl halides to the
trifluoromethyl moiety via a crucial Hunsdiecker-like
trifluorodecarboxylation, using BrF3.
In recent years, we and others have devised several methods
for incorporating fluorine atom(s) into organic molecules by
employing bromine trifluoride. The synthesis of a-trifluoro-
methyl carboxylic acids,5 transformation of carbonyls to the
CF2 group,6 forming alkyltrifluoromethyl ethers,7 synthe-
sizing modern anaesthetics8 and converting RX to RCHF2
derivatives,9 are only a few examples. These works have
already established the conditions for selective reactions of
BrF3 with organic substrates. Such substrates should possess
soft bases such as nitrogen or sulfur atoms, in order to
complex the soft acidic bromine in BrF3 and place the naked
nucleophilic fluorides close to the electrophilic carbon
positioned a to the heteroatom (Scheme 1).
2. Results and discussion
Following a known procedure,12 the lithium salt of dithiane
(1) was reacted with decyl bromide (2a) followed by
reaction with carbon dioxide to produce 2-decyl-1,3-
dithiane-2-carboxylic acid (3a). Reacting 3a with BrF3
resulted in a fast trifluorodecarboxylation producing 1,1,1-
trifluoroundecane (4a)13 in 60% yield (Scheme 2). The
reaction with the disubstituted 1,10-dibromodecane (2b)
The Hunsdiecker reaction is one of the oldest and most well
Keywords: Bromine trifluoride; Trifluoromethyl; Trifluorodecarboxylation;
Dithiane.
* Corresponding author. Tel.: C972 364 08378; fax: C972 364 09293;
e-mail: rozens@post.tau.ac.il
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.063

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R. Sasson, S. Rozen / Tetrahedron 61 (2005) 1083–1086
carbons. Thus, 2-bromooctane (2e) was eventually con-
verted to 1,1,1-trifluoro-2-methyloctane (4e) although in
a somewhat lower yield of 35%.
Bromine trifluoride is known to substitute chlorine atoms
for fluorine ones as demonstrated in the syntheses of modern
anaesthetics such as sevoflurane.18 Here again, the reaction
with the dithiane moiety is much faster, and hence chlorine
atoms can be tolerated in this reaction. 1,10-Dichlorodecane
(2f) was easily converted to 2-(10-chlorodecyl)-1,3-
dithiane-2-carboxylic acid (3f) and when reacted with
BrF3, the previously unknown 11-chloro-1,1,1-trifluoro-
undecane (4f) was obtained in 55% yield. Despite the fact
that alcohols are easily oxidized by BrF3 to acyl fluorides,19
the presence of an hydroxyl group in a molecule is not a
reason for excluding it from the list of materials which can
participate in this reaction. Protecting the hydroxyl group of
1-chloro-8-hydroxyoctane (2g) as a tetrahydropyranyl
(THP) (2h) enabled the clean formation of 3h under the
strong basic conditions characteristic to BuLi. The protect-
ing THP was then replaced by acetyl to form 2-(8-
acetoxyoctyl)-1,3-dithiane-2-carboxylic acid (3i) suitable
for the fast reaction with BrF3 forming eventually 9,9,9-
trifluorononyl acetate (4i) in 50% yield.
We believe that the first step of the reaction is ionic in
nature. First, the sulfur atoms serve as a coordinating site for
the BrF3 and when the complexation is completed these
atoms are substituted by the nucleophilic fluorides which by
now are in suitable close proximity.9,21 As a result of this
substitution, however, BrF3 can no longer complex itself
around any particular site of the reactant. Consequently,
radical reactions, which are always option for this reagent,
become dominant and a process with a chain radical
decarboxylation (Scheme 3) takes place. Indeed, when the
Scheme 2. Formation of trifluoromethyl derivatives. (*) Yield of the
trifluorodecarboxylation step; (#) these compounds could not be fully
analyzed by conventional MS (no molecular ion could be detected).
However, we have successfully used the Amirav’s supersonic GC–MS
developed in our department. The main feature of this method is to provide
electron ionization while the sample is vibrationally cooled in a supersonic
molecular beam. This considerably enhances the relative abundance of
molecular ions.20
also proceeded as expected and 1,1,1,12,12,12-hexafluoro-
dodecane (4b)14 was obtained in 40% yield.
While the fluorine atoms in BrF3 can act in some cases as
electrophiles,15 substituting tertiary hydrogens in a similar
way to F2,16 the reaction with the dithiane moiety seems to
be much faster. Thus, 2-(3-cyclohexylpropyl)-1,3-dithiane-
2-carboxylic acid (3c) and 2-(2-norbonylethyl)-1,3-
dithiane-2-carboxylic acid (3d), made correspondingly
from 1-chloro-3-cyclohexylpropane (2c) and 1-bromo-2-
(2-norbornyl)ethane (2d), were reacted with BrF3 forming
the by now expected 4-cyclohexyl-1,1,1-trifluorobutane
(4c)17 and 2-(3,3,3-trifluoropropyl)norbornane (4d)13 in 50
and 55% yields, respectively.
In many cases the chemistry of a functional group attached
to a primary carbon differs from the chemistry of the same
group bonded to a secondary site. The present chemistry,
however, is applicable for both primary and secondary
Scheme 3. Radical chain trifluorodecarboxylation.

R. Sasson, S. Rozen / Tetrahedron 61 (2005) 1083–1086
1085
reaction of 3c with bromine trifluoride was carried under
either oxygen-rich atmosphere or in the presence of
dinitrobenzene, the radical chain process was interrupted
and the yields of 4c dropped to 15 and 0%, respectively.
Additional support for this mechanism was found in
reactions with a,a-difluoro acids. Thus, for example,
a,a-difluorododecanoic acid (5) was reacted with BrF3
resulting in a fast fluorodecarboxylation forming 1,1,1-
trifluoroundecane (4a) in 60% yield. For comparison, no
such reaction takes place with the corresponding dodeca-
noic acid itself. The fluorodecarboxylation can be explained
by pointing out that the difluoromethylene radical is more
stable than the methylene counterpart and better sustains a
chain reaction with BrF3 to form the CF3 group. This
hypothesis was also confirmed by reacting BrF3 with
4-nitrophenylacetic acid (6). Since the benzylic radical is
relatively stable, fluorodecarboxylation occurs producing
2-bromo-4-nitrobenzylfluoride (7) in 50% yield. The ring
bromination is unavoidable as BrF3 is a very powerful
brominating agent.22
1,3-dithiane was added 10.5 mmol of n-butyllithium (1.6 M
in n-hexane) under nitrogen. The mixture was stirred for
1.5 h and poured on to freshly chopped dry ice. After
stirring for another hour at room temperature, 10% NaOH
was added. The organic layer was extracted twice with the
NaOH solution and the combined alkaline layers were
acidified with concentrated HCl. The aqueous layer was
extracted three times with ether and the organic layer was
dried over MgSO4. After evaporation of the solvent, the
crude product was purified by flash chromatography (using
petroleum ether/ethyl acetate as eluent) or recrystallization.
1
The main characteristic features are as follows: H NMR:
3.3 (2H, td, J1Z13 Hz, J2Z2.5 Hz), 2.7 ppm (2H, dt, J1Z
13 Hz, J2Z3.5 Hz); 13C NMR: 177.0, 52.9 ppm; IR:
1697 cmK1
.
3.3. General procedure for reaction of 2-alkyl-1,3-
dithiane-2-carboxylic acid derivatives with BrF3
The 2-alkyl-1,3-dithiane-2-carboxylic acid (usually
2 mmol) was dissolved in 10–15 mL of CFCl3. About
6 mmol of BrF3 was dissolved in 10 mL the same solvent,
and the resulting solution was cooled to 0 8C and added
dropwise during 1–2 min to the dithiane derivative solution.
The reaction mixture was quenched with aqueous Na2S2O3
till colorless. The aqueous layer was extracted twice with
CH2Cl2 and the organic layer was dried over MgSO4.
Evaporation of the solvent followed by purification by flash
chromatography (using petroleum ether as eluent) gave the
target trifluoromethyl derivatives.
In conclusion, this paper widens the scope of reactions with
bromine trifluoride, especially when the construction of
the important trifluoromethyl group is concerned. We hope
that this work will be an additional step in demonstrating
that BrF3, like F2 some years ago, can and should be used, as
a powerful fluorinating agent in organic chemistry.
3. Experimental
1H and 13C NMR were obtained at 200 and 50.2 MHz,
respectively, with CDCl3 as solvent and Me4Si as an
internal standard. The 19F NMR spectra were measured at
188.1 MHz and are reported upfield from CFCl3, serving as
an internal standard. IR spectra were recorded in CHCl3
solution on a FTIR spectrophotometer. HRMS spectra were
measured under CI conditions. In extreme cases where the
CI method could not detect the molecular ion, we have
successfully used the Amirav’s supersonic GC–MS devel-
oped in our department. The main feature of this method is to
provide electron ionization while the sample is vibrationally
cooled in a supersonic molecular beam. This considerably
enhances the relative abundance of molecular ions.20
3.3.1. 1,1,1-Trifluoroundecane.13 (4a) Compound was
prepared from 3a as described above, resulting in 60%
1
yield of an oil. H NMR: 2.06–2.00 (2H, m), 1.59–1.51
(2H, m), 1.27 (14H, br s), 0.89 ppm (3H, t, JZ6.8 Hz). 13C
NMR: 127.2 (q, JZ276 Hz), 33.6 (q, JZ28 Hz), 31.8, 29.4,
29.3, 29.2, 29.1, 28.6, 22.6, 21.8, 14.0 ppm. 19F NMR:
K67.0 ppm (t, JZ11 Hz). MS (supersonic molecular
beam): m/z 210 (M)C.
3.3.2. 1,1,1,12,12,12-Hexafluorododecane.14 (4b) Com-
pound was prepared from 3b as described above, resulting
in 40% yield of an oil. 1H NMR: 2.2–2.0 (4H, m), 1.62–1.51
(4H, m), 1.4–1.3 ppm (12H, br s). 13C NMR: 127.3 (q,
JZ276 Hz), 33.7 (q, JZ28 Hz), 29.2, 29.1, 28.7, 21.8 ppm.
19F NMR: K66.9 ppm (t, JZ11 Hz).
3.1. Preparing and handling BrF3
Although commercially available, we usually prepare our
own BrF3 by simply passing 0.6 mol of pure fluorine
through 0.2 mol of bromine placed in a copper reactor and
cooled to 0–10 8C. Under these conditions, the higher
oxidation state, BrF5, will not form in any appreciable
amount. The product can be stored in Teflon containers
indefinitely. Caution: BrF3 is a strong oxidizer and tends to
react exothermically with water and oxygenated organic
solvents such as acetone or THF. Any work using BrF3
should be conducted in a well-ventilated area, and caution
and common sense should be exercised.
3.3.3. 4-Cyclohexyl-1,1,1-trifluorobutane.17 (4c) Com-
pound was prepared from 3c as described above, resulting
in 55% yield of an oil. 1H NMR: 2.06–2.00 (2H, m), 1.71–
1.68 (6H, m), 1.55 (2H, m), 1.27–1.25 ppm (7H, m). 13C
NMR: 127.3 (q, JZ276 Hz), 37.8, 36.4, 34.0 (q, JZ28 Hz),
31.1, 26.6, 26.3 ppm. 19F NMR: K66.9 ppm (t, JZ11 Hz).
3.3.4. 2-(3,3,3-Trifluoropropyl)norbornane.13 (4d) Com-
pound was prepared from 3d as described above, resulting
in 55% yield of an oil. 1H NMR: 2.22 (1H, br s), 2.06–2.00
(2H, m), 1.96 (1H, br s), 1.53–1.26 (7H, m) 1.15–1.00 ppm
(4H, m). 13C NMR: 127.3 (q, JZ276 Hz), 41.7, 40.8, 37.8,
36.4, 35.1, 32.2 (q, JZ28 Hz), 29.9, 29.6, 28.5 ppm. 19F
NMR: K66.8 ppm (t, JZ11 Hz).
3.2. General procedure for preparing 2-alkyl-1,3-
dithiane-2-carboxylic acid derivatives.12
To a cold (K45 8C) THF solution of 10 mmol of 2-alkyl-
3.3.5. 1,1,1-Trifluoro-2-methyloctane (4e). Compound

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R. Sasson, S. Rozen / Tetrahedron 61 (2005) 1083–1086
was prepared from 3e as described above, resulting in 35%
yield of an oil. 1H NMR: 2.0–2.2 (1H, m), 1.8–1.6 (2H, m),
1.3 ppm (8H, br s), 1.05 (3H, d, JZ7 Hz), 0.89 ppm (3H, t,
JZ7 Hz). 13C NMR: 128.3 (q, JZ279 Hz), 37.6 (q, JZ
26 Hz), 31.6, 29.4, 28.7, 26.5, 22.3, 13.8 ppm. 19F NMR:
K73.8 ppm (d, JZ9 Hz). MS: m/z 182 (M)C, 162 (MK
HF)C, 142 (MK2 HF)C, 113 (MKCF3)C.
Acknowledgements
This work was supported by the USA-Israel Binational
Science Foundation (BSF), Jerusalem, Israel.
References and notes
3.3.6. 11-Chloro-1,1,1-trifluoroundecane (4f). Compound
was prepared from 3f as described above, resulting in 55%
yield of an oil. 1H NMR: 3.53 (2H, t, JZ6.7 Hz), 2.06–2.00
(2H, m), 1.77 (4H, quin, JZ6.7 Hz), 1.30 ppm (12H, br s).
13C NMR: 127.3 (q, JZ276 Hz), 45.1, 33.7 (q, JZ28 Hz),
32.6, 29.3, 29.2, 29.1, 28.8, 28.7, 26.7, 22.7 ppm. 19F NMR:
K66.9 ppm (t, JZ11 Hz). MS (supersonic molecular
beam): m/z 244 (M)C. Anal. Calcd for C11H20ClF3: C,
53.99; H, 8.24; Cl, 14.49. Found: C, 54.59; H, 8.45; Cl,
14.30.
1. Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem.
Soc. 1989, 111, 393–395.
2. (a) Ait-Mohand, S.; Takechi, N.; Medebielle, M.; Dolbier,
W. R., Jr. Org. Lett. 2001, 26, 4271–4273. (b) Shono, T.; Kise,
N.; Oka, H. Tetrahedron Lett. 1991, 32, 6567–6570.
3. (a) Umemoto, T.; Ishihara, S.; Adachi, K. J. Fluorine Chem.
1995, 74, 77–82. (b) Ma, J. A.; Cahard, D. J. Org. Chem. 2003,
68, 8726–8729.
4. Langlois, B. L.; Billard, T. Synthesis 2003, 185–194.
5. Hagooly, A.; Rozen, S. Chem. Commun. 2004, 5, 594–595.
6. Rozen, S.; Mishani, E.; Bar-Haim, A. J. Org. Chem. 1994, 59,
2918.
3.3.7. 9,9,9-Trifluorononyl acetate (4i). Compound was
prepared from 3i as described above, resulting in 50% yield
7. Ben-David, I.; Rechavi, D.; Mishani, E.; Rozen, S. J. Fluorine
Chem. 1999, 97, 75–78.
1
of an oil. H NMR: 4.04 (2 H, t, JZ6.7 Hz), 2.03 (3 H, s),
8. (a) Rozov, L. A.; Huang, C.; Halpern, D. F.; Vernice, G. G. US
Patent 1994, 5,283,372.(b) Halpern, D. F.; Robin, M. L.; US
Patent 1991, 4,996,371.
2.07–2.00 (2 H, m), 1.60–1.46 (4H, m), 1.32 ppm (8H, br s).
13C NMR: 171.1, 127.2 (q, JZ276 Hz), 64.4, 33.6
(q, JZ28 Hz), 28.9, 28.8, 28.5, 28.4, 25.7, 21.7,
20.8 ppm. 19F NMR: K67.0 ppm (t, JZ11 Hz). IR:
1720 cmK1. HRMS (CI) (m/z): (MH)C calcd for
C11H19F3O2, 241.1425; found, 241.1454. Anal. Calcd for
C11H19F3O2: C, 54.99; H, 7.97. Found: C, 54.98; H, 8.08.
9. Sasson, R.; Hagooly, A.; Rozen, S. Org. Lett. 2003, 5,
769–771.
10. This reaction was first reported by the chemist-composer
Borodin, A. Liebigs Ann. Chem. 1861, 119–121.
11. (a) Patrick, B. T.; Johri, K. K.; White, H. D. J. Org. Chem.
1983, 48, 4158–4159. (b) Della, E. W.; Head, N. J. J. Org.
Chem. 1992, 57, 2850–2855. (c) Patrick, B. T.; Khazaeli, S.;
Nadji, S.; Herling-Smith, K.; Reif, D. J. Org. Chem. 1993, 58,
705–708.
3.3.8. 2-Bromo-4-nitrobenzylfluoride (7). About 18 mmol
of BrF3 was dissolved in 25 mL of CFCl3, and the resulting
solution was cooled to 0 8C and added dropwise during
1–2 min to a solution of 4-nitrophenylacetic acid (6)
(10 mmol) in 40 mL of CFCl3. The reaction mixture was
quenched with aqueous Na2S2O3 till colorless. The aqueous
layer was extracted twice with CH2Cl2 and the organic layer
was dried over MgSO4. Evaporation of the solvent followed
by purification by flash chromatography (using petroleum
ether/ethyl acetate as eluent) gave 7 in 50% yield. 1H NMR:
8.42 (1 H, d, JZ2 Hz), 8.24 (1 H, dd, JZ8.5, 2 Hz), 7.67
(1 H, d, JZ8.5 Hz) 5.53 (2H, d, JZ47 Hz). 13C NMR:
148.0, 143.1 (d, JZ18 Hz), 127.6 (d, JZ11 Hz), 127.5,
122.5, 120.3 (d, JZ6 Hz) 82.7 (d, JZ174 Hz) ppm. 19F
NMR: K222.4 ppm (t, JZ46 Hz). HRMS (CI) (m/z):
(MH)C calcd for C7H5BrFNO2, 233.9559; found,
233.9566. Anal. Calcd for C7H5BrFNO2: C, 35.93; H,
2.15; F, 8.12; Br, 34.14; N, 5.99. Found: C, 35.55; H, 2.05;
F, 7.67; Br, 34.21; N, 5.68.
12. Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231–237.
13. Hagooly, A.; Ben-David, I.; Rozen, S. J. Org. Chem. 2002, 67,
8430–8434.
14. Muller, N.; Birkhahn, R. H. J. Phys. Chem. 1967, 71, 957–962.
15. Boguslavskaya, L. S.; Kartashov, A. V.; Chuvatkin, N. N. Zh.
Org. Khim. (Eng. Transln) 1989, 25, 2029–2030.
16. Rozen, S.; Gal, C. J. Org. Chem. 1987, 52, 2769–2779.
17. Hasek, W. R.; Smith, W. C.; Engelhardt, V. A. J. Am. Chem.
Soc. 1960, 82, 543–551.
18. Huang, C.; Vernice, G. G. US Patent 1989, 4,874,902.
19. Rozen, S.; Ben-David, I. J. Fluorine Chem. 1996, 76, 145–148.
20. (a) Dagan, S.; Amirav, A. J. Am. Soc. Mass Spectrom. 1996, 7,
550–558. (b) Fialkov, A. B.; Amirav, A. Rapid Commun. Mass
Spectrom. 2003, 17, 1326–1338.
21. Hagooly, A.; Sasson, R.; Rozen, S. J. Org. Chem. 2003, 68,
8287–8289.
22. Rozen, S.; Lerman, O. J. Org. Chem. 1993, 58, 239–240.