Bromofluorination of olefins using BrF3; an efficient route for fluoroalkenes and fluoroamines

Article abstract of DOI:10.1016/j.jfluchem.2006.04.008

A variety of alkenes and α,β-unsaturated carbonyls were reacted with BrF₃ to form vicinal bromofluoro compounds. In most cases, the reactions followed a Markovnikov regioselectivity and anti-addition stereospecifity. They proceeded well even wi

Full text of DOI:10.1016/j.jfluchem.2006.04.008

Journal of Fluorine Chemistry 127 (2006) 962–965
www.elsevier.com/locate/fluor
Bromofluorination of olefins using BrF3; an efficient route
for fluoroalkenes and fluoroamines
*
Revital Sasson, Shlomo Rozen
School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel
Received 26 March 2006; received in revised form 23 April 2006; accepted 24 April 2006
Available online 29 April 2006
Dedicated to Professor Karl Christe on the occasion of his 70th birthday.
Abstract
Avariety of alkenes and a,b-unsaturated carbonyls were reacted with BrF3 to form vicinal bromofluoro compounds. In most cases, the reactions
followed a Markovnikov regioselectivity and anti-addition stereospecifity. They proceeded well even with deactivated olefins in around 70% yield.
The bromofluoro compounds served as starting materials for the synthesis of fluoroalkenes and fluoroamines.
# 2006 Elsevier B.V. All rights reserved.
Keywords: BrF3; Bromofluorination; Fluoroamino acid; Bromofluoroalkane
1. Introduction
double bonds including the very weak ones found in conjugated
enones or esters.
Fluorine compounds are widely used in pharmacology, as
they are known to increase biological activity [1]. One of the
efficient building blocks for monofluorinated molecules are
bromofluoro derivatives [2], made with reagents such as BF3-
CH3OBr [3], BrF [4] or more commonly by [BrF] reagents as
the equivalent combination of NBS-HF [5] and alike [6].
Usually these methods suffer from low yields, prolonged
reaction times, HF eliminations and formation of other by-
products such as alkoxy halides especially when applied to
electron poor olefins like a,b-unsaturated esters. We describe
here a general synthetic method leading to bromofluoro esters
in a fast and improved yields reaction using bromine trifluoride.
The synthetic power of bromine trifluoride has been
investigated in our group over a decade. During this period
several selective reactions leading to fluorinated and non-
fluorinated products have been developed [7]. Synthesizing 1,1-
difluoroolefins [8], converting carbonyls to CF2 group [9],
alcohols to OCF3 moiety [10] and azides to nitriles [11] are just
a few examples. In all these reactions, the electrophilic bromine
of the reagent is subjected to an attack from various
nucleophiles. In this work, these nucleophiles are various
2. Results and discussion
The reaction of unsaturated aliphatic compounds such as 1-
heptene (1a) with BrF3 gave 1-bromo-2-fluoroheptane (2a) [12]
in 50% yield, indicating an ionic Markovnikov regioselective
mechanism.
The process was also found to be a stereospecific (anti-
addition mode) as evident from the reaction with cycloheptene
(1b) and trans-stilbene (1c) which formed threo-1-bromo-2-
fluorocycloheptane (2b) [13] and erythro-1-fluoro-2-bromo-
3
1,2-diphenylethane (2c) (mp 101 8C, JHF = 15 Hz) [14],
respectively, in 50% yields each. Furthermore, bromine
trifluoride is known to brominate aromatic rings [15], but it
reacts faster with double bonds and in the case of trans-stilbene
(1c) no aromatic bromination was observed.
In the past we have shown that sulfur atoms could efficiently
be complexed with the electrophilic bromine atom in BrF3
resulting eventually in their displacement by the fluorine atoms
of the reagent [16]. However, when the sulfur is in its highest
oxidation state such complexation proved impossible and only
the double bond of the 3-sulfolen (1d) reacted with BrF3
forming 2d in 70% yield (Scheme 1).
Some time ago we had tried, unsuccessfully, to produce
bromofluoro esters from the corresponding a,b-unsaturated
* Corresponding author. Fax: +972 3 6409293.
E-mail address: rozens@post.tau.ac.il (S. Rozen).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.04.008

R. Sasson, S. Rozen / Journal of Fluorine Chemistry 127 (2006) 962–965
963
fluoropropionoate (2l) was converted to a-fluoroacrylate 5l
through HBr elimination using triethylamine as a base in 90%
yield.
In conclusion, we are proposing here a new and efficient
procedure for the preparation of vicinal bromofluoro com-
pounds using bromine trifluoride. The advantages of this
method are the short reaction times and the use of a single
commercial reagent. We argue fluorine chemists should not shy
away from BrF3 since under the right conditions it can be a
useful and versatile reagent.
Scheme 1. Reacting olefins with BrF3.
3. Experimental
3.1. General experimental procedure
derivatives using BrF made directly from the elements. The
prolonged reaction times with those deactivated p-centers
often ended in HF elimination. In rare occasions, other
reagents such as NBA and HF, furnished a few bromofluoro
esters in 50–60% but only after 19 h [17]. When bromine
trifluoridewas reacted with ethyl crotonate (1e) ethyl 2-bromo-
3-fluorobutyrate (2e) [18] was obtained in a few minutes in
70% yield (Scheme 2). The cyclic derivative, methyl 1-
cyclohexene-1-carboxylate (1f), was also reacted with BrF3 to
afford the previously unknown compound 2f in 70% yield.
Even more strongly deactivated olefins such as ethyl fumarate
(1g), reacted successfully and ethyl 2-bromo-3-fluorosucci-
nate (2g) was obtained in 50% yield. The importance of this
compound can be found in several papers which revealed that
2g possesses high antifungal activity due to the ease of
dehydrohalogenation [19].
1H NMR, 13C NMR and 19F NMR were obtained at 200,
50.2 and 188.2 MHz respectively, with CDCl3 as a solvent
(unless otherwise stated) and Me4Si and CFCl3 as internal
The reaction can also be extended to other types of enones
such as a,b-unsaturated ketones. This procedure is much faster
than any other method and 2-nonenone (1h), for example, gave
the expected adduct 2h in 50% yield with no HF elimination.
Full regioselectivity was not achieved in the case of terminal
a,b-unsaturated carbonyls. When ethyl acrylate (1i) and 2-
ethylhexyl acrylate (1k) were reacted with BrF3 two
regioisomers were obtained for each acrylate. The expected
bromofluoro esters 2i and 2k were thus produced in 40 and 45%
yield, respectively, accompanied by the minor derivatives 2j
[20] and 2l in 20% yield each (Scheme 2). This somewhat
unexpected distribution can be explained by the similar stability
of the a and b carbocations of the acrylate system.
Fluoroamines, especially b-fluoroamino acids, are very
interesting compounds and used, for example, as drugs in
chemotherapy [21]. The bromofluoro compounds, can be good
precursors for the synthesis of these compounds. Thus, 2a and
2e were reacted with sodium azide forming 1-azido-2-
fluoroheptane (3a) and ethyl 2-azido-3-fluorobutyrate (3e).
Reduction of the azido derivatives gave the target 1-amino-2-
fluoroheptane (4a) and ethyl 2-amino-3-fluorobutyrate (4e)
[22] in 55 and 45% overall yield, respectively (Scheme 3).
Another application of bromofluoro adducts is in their use as
precursors for the synthesis of fluoroalkenes. 3-Bromo-4-
fluorotetrahydrothiophene-1,1-dioxide (2d) was reacted with
potassium carbonate to form 3-fluoro-2,3-dihydrothiophene-
1,1-dioxide (5d) [23] in 97%. Also 2-ethylhexyl 3-bromo-2-
Scheme 2. The reaction of BrF3 with a,b-unsaturated carbonyl derivatives.

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R. Sasson, S. Rozen / Journal of Fluorine Chemistry 127 (2006) 962–965
over MgSO4. Evaporation of the solvent followed by flash
chromatography purification (using petroleum ether/ethyl
acetate as eluent) or recrystallization gave the target bromo-
fluoro derivatives. All known compounds were referenced
throughout this work. Data for the new compounds or for those
not well defined in the literature, is given below.
3-Bromo-4-fluorotetrahydrothiophene 1,1-dioxide (2d)
was prepared from 1d as described above, resulting in 70%
yield of a light brown solid, mp 155–157 8C (from CH2Cl2). 1H
NMR (DMSO-d6): 5.65 (1H, dm, J = 47 Hz), 5.02 (1H, m),
3.6–4.0 ppm (4H, m). 13C NMR (DMSO-d6): 93.8 (d,
J = 187 Hz), 58.1, 55.6 (d, J = 22 Hz), 43.8 ppm (d,
J = 27 Hz). 19F NMR (DMSO-d6): À168.0 ppm (m). MS: m/
z 216.9, 218.9 [MÀH+]. Anal. calcd. for C4H6BrFO2S: C,
22.13; H, 2.79; F, 8.75; S, 14.77. Found: C, 22.25; H, 2.83; F,
8.37; S, 14.75.
Ethyl 2-bromo-3-fluorobutyrate (2e) [18] was prepared
from 1e as described above, resulting in 70% yield of oil. IR:
1743 cmÀ1. 1H NMR: 5.00 (1H, dm, J = 47 Hz), 4.23 (3H, m),
1.55 (3H, dd, J = 24 Hz, J = 6 Hz), 1.29 ppm (3H, t, J = 7 Hz).
13C NMR: 167.4 (d, J = 4.4 Hz), 89.12 (d, J = 173 Hz), 62.3,
46.6 (d, J = 29 Hz), 18.1 (d, J = 22 Hz), 13.9 ppm. 19F NMR:
À175.8 ppm (dqd, J = 47 Hz, J = 24 Hz, J = 7 Hz).
1-Bromo-2-fluorocyclohexanecarboxylic acid methyl
ester (2f) was prepared from 1f as described above, resulting
1
in 70% yield of oil. IR: 1741 cmÀ1. H NMR: 5.12 (1H, dm,
J = 45 Hz), 3.78 (3H, s), 2.0 (4H, m), 1.5 ppm (4H, m). 13C
NMR: 169.9, 90.3 (d, J = 177 Hz), 59.1 (d, J = 25 Hz), 53.0,
30.7, 25.8 (d, J = 21 Hz), 20.7, 18.7 ppm. 19F NMR:
À175.8 ppm (td, J = 45 Hz, J = 12 Hz). Anal. calcd. for
C8H12BrF: C, 40.19; H, 5.06; Br, 33.42. Found: C, 40.43; H,
5.05; Br, 32.93.
Scheme 3. The synthesis of fluoroamines and fluoroalkenes.
standards. IR spectra were recorded in CHCl3 solution on a
FTIR spectrophotometer.
3-Bromo-4-fluorononan-2-one (2h) was prepared from 1h
as described above, resulting in 50% yield of oil. IR:
.
1720 cmÀ1 1H NMR: 5.00 (1H, dtd, J = 47 Hz, J = 8 Hz,
3.2. Preparing and handling BrF3
J = 2.7 Hz), 4.21 (1H, t, J = 8 Hz), 2.37 (3H, s), 1.72 (1H, m),
1.5 (1H, m), 1.43 (1H, m), 1.32 (5H, m), 0.88 ppm (3H, t,
J = 7 Hz). 13C NMR: 200.0, 92.4 (d, J = 175 Hz), 51.9 (d,
J = 28 Hz), 32.1 (d, J = 21 Hz), 31.3, 26.8, 24.1, 22.4,
13.9 ppm. 19F NMR: À178.3 ppm (m). Anal. calcd. for
C9H16BrFO: C, 45.20; H, 6.74; F, 7.94. Found: C, 45.18; H,
6.65; F, 7.88.
Although commercially available, we usually prepare our
own BrF3 by simply passing 0.6 mol of 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 TeflonTM containers indefinitely. 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,
caution and common sense be exercised.
2-Bromo-3-fluoropropionoate (2i) was prepared from 1i as
described above, resulting in 40% yield of an oil. IR:
.
1742 cmÀ1 1H NMR: 4.92–4.37 (3H, m), 4.25 (2H, t,
J = 7 Hz), 1.29 ppm (3H, t, J = 7 Hz). 13C NMR: 167.2, 81.8
(d, J = 177 Hz), 62.5, 40.4 (d, J = 25 Hz), 13.8 ppm. 19F NMR:
À209.7 ppm (td, J = 47 Hz, J = 11 Hz).
3.3. General procedure for reaction of olefins with BrF3
2-Ethylhexyl 2-bromo-3-fluoropropionoate (2k) was
prepared from 1k as described above, resulting in 45% yield
1
The olefin (usually 10 mmol) was dissolved in 20 mL of
CFCl3. About 10 mmol of BrF3 was dissolved in 15 mL of the
same solvent, and the resulting solution was cooled to 0 8C
before added dropwise during 1–2 min to the olefin solution.
After additional 2–3 min the reaction mixture was quenched
with aqueous Na2S2O3 till colorless. The aqueous layer was
extracted twice with CH2Cl2 and the organic layer was dried
of an oil. IR: 1739 cmÀ1. H NMR: 4.92–4.37 (3H, m), 4.13
(2H, m), 1.62 (1H, m), 1.3 (8H, m), 0.9 ppm (6H, t, J = 7 Hz).
13C NMR: 167.2 (d, J = 3.7 Hz), 81.8 (d, J = 177 Hz), 68.6,
40.4 (d, J = 25 Hz), 38.6, 30.1, 28.7, 23.6, 22.8, 13.9, 10.8 ppm.
19F NMR: À209.5 ppm (td, J = 46 Hz, J = 10 Hz). Anal. calcd.
for C9H16BrFO: C, 45.20; H, 6.74; F, 7.94. Found: C, 45.18; H,
6.65; F, 7.88.

R. Sasson, S. Rozen / Journal of Fluorine Chemistry 127 (2006) 962–965
965
2-Ethylhexyl 3-bromo-2-fluoropropionoate (2l) was
obtained as by-product in the preparation of 1k resulting in
dried over MgSO4. Evaporation of the solvent followed by
purification by flash chromatography gave 160 mg (90%).
.
IR: 1656, 1737 cmÀ1 1H NMR: 5.63 (1H, dd, J = 43 Hz,
1
20% yield of an oil. IR: 1760 cmÀ1. H NMR: 5.15 (1H, dt,
J = 48 Hz, J = 4 Hz), 4.14 (2H, d, J = 6 Hz), 3.77 (1H, d,
J = 4 Hz), 3.66 (1H, t, J = 4 Hz), 1.62 (1H, m), 1.3 (8H, m),
0.9 ppm (6H, t, J = 7 Hz). 13C NMR: 167.0 (d, J = 23 Hz), 87.2
(d, J = 191 Hz), 68.6, 38.8, 30.3, 29.9 (d, J = 23 Hz), 28.9, 23.7,
23.0, 14.1, 11.0 ppm. 19F NMR: À189.9 ppm (m).
J = 3.2 Hz), 5.30 (1H, dd, J = 13 Hz, J = 3.2 Hz), 4.10 (2H,
J = 11 Hz), 1.61 (1H, m), 1.3 (8H, m), 0.9 ppm (6H, m). 13C
NMR: 160.45 (d, J = 36 Hz), 153.4 (d, J = 262.1 Hz), 102.3 (d,
J = 15.3 Hz), 68.2, 38.6, 30.2, 28.8, 23.7, 22.8, 13.9, 10.8 ppm.
19F NMR: À117.3 ppm (dd, J = 43 Hz, J = 13.1 Hz).
1-Azido-2-fluoroheptane (3a). To a solution of 0.5 M NaN3
(975 mg, 15.0 mmol) in DMSO was added 2a (2.63 g,
13.3 mmol). After the mixture was stirred at ambient
temperature for 3 h, it was quenched with water. The mixture
was extracted twice with ether; the ether extracts were washed
with water and brine. The organic layer was dried over MgSO4,
filtered and the solvent was evaporated. Purification by flash
chromatography gave 1.625 g (77%) of oil. IR: 2105 cmÀ1. 1H
NMR: 4.63 (1H, dm, J = 48 Hz), 3.36 (2H, dm, J = 20 Hz),
1.26–1.75 (8H, m), 0.90 ppm (3H, t, J = 7 Hz). 13C NMR: 92.7
(d, J = 134 Hz), 54.2 (d, J = 22 Hz), 32.1 (d, J = 20 Hz), 31.4,
24.4 (d, J = 5 Hz), 22.3, 13.8 ppm. 19F NMR: À184.5 ppm (m).
Ethyl 2-azido-3-fluorobutyrate (3e) was prepared from 2e
as described for the preparation of 3a, resulting in 50% yield of
oil. IR: 2117, 1743 cmÀ1. 1H NMR: 5.11 (1H, dm, J = 46 Hz),
4.30 (2H, q, J = 7 Hz), 3.70 (1H, dd, J = 27 Hz, J = 3 Hz), 1.48
(3H, dd, J = 24 Hz, J = 6H), 1.33 ppm (3H, t, J = 7H). 13C
NMR: 167.7 (d, J = 4.4 Hz), 90.0 (d, J = 176 Hz), 65.2 (d,
J = 21 Hz), 17.7 (d, J = 23 Hz), 14.0 ppm. 19F NMR:
À184.3 ppm (dm, J = 46 Hz).
Acknowledgment
This work was supported by the USA-Israel Binational
Science Foundation (BSF), Jerusalem, Israel.
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