Regioselectivity of bromofluorination of functionalized 1-alkenes

Article abstract of DOI:10.1016/S0022-1139(99)00230-4

The regiochemistry of bromofluorinations of 1-alkenes with the combination of N-bromosuccinimide and amine/HF reagents mainly depends on the character of functional groups in the neighborhood of the double bond and only weakly from the fluorinating agent. While mono-substituted terminal alkenes mainly yield Markovnikov-oriented products, electron withdrawing groups in allylic or homoallylic position to the double bond destabilize carbenium centers in 2-position. Consequently, the part of anti-Markovnikov-oriented bromofluorides increases. Besides, with dropping reactivity of alkenes, the formation of dibromides becomes a competitive side reaction of bromofluorination. The extent of this process depends on the nature of the amine/HF reagent. This reaction is most important in case of the more nucleophilic trimethylamine bishydrofluoride, while this process is neglectible with pyridinium poly(hydrogen fluoride) (Olah's reagent).

Full text of DOI:10.1016/S0022-1139(99)00230-4

Journal of Fluorine Chemistry 102 (2000) 125±133
Regioselectivity of bromo¯uorination of functionalized 1-alkenes
Martin LuÈbke, Rolf Skupin, GuÈnter Haufe*
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat, Corrensstraûe 40, D-48149 Munster, Germany
Received 22 June 1999; received in revised form 30 June 1999; accepted 27 August 1999
Dedicated to Professor Paul Tarrant on the occasion of his 85th birthday
È
È
È
Abstract
The regiochemistry of bromo¯uorinations of 1-alkenes with the combination of N-bromosuccinimide and amine/HF reagents mainly
depends on the character of functional groups in the neighborhood of the double bond and only weakly from the ¯uorinating agent. While
mono-substituted terminal alkenes mainly yield Markovnikov-oriented products, electron withdrawing groups in allylic or homoallylic
position to the double bond destabilize carbenium centers in 2-position. Consequently, the part of anti-Markovnikov-oriented
bromo¯uorides increases. Besides, with dropping reactivity of alkenes, the formation of dibromides becomes a competitive side reaction of
bromo¯uorination. The extent of this process depends on the nature of the amine/HF reagent. This reaction is most important in case of the
more nucleophilic trimethylamine bishydro¯uoride, while this process is neglectible with pyridinium poly(hydrogen ¯uoride) (Olah's
reagent). # 2000 Elsevier Science S.A. All rights reserved.
Keywords: 1-Alkenes; Bromo¯uorination; Regioselectivity; Amine/HF reagents; Electrophilic addition; Mechanism
1. Introduction
The mechanism of bromo¯uorination involves the elec-
trophilic, acid catalyzed attack of a positive bromine species
to give a p-complex followed by generation of a cationic s-
complex in the rate determining step. Finally, the backside
attack of a nucleophilic ¯uoride species yields the bromo-
¯uorides (Scheme 1). Mechanistic alternatives have also
been discussed [27].
The regiochemistry of bromo¯uorinations of ole®ns
depends on the structure of the s-complex. The ¯uoride
equivalent attacks non-symmetrically bridged species
mainly at the position of better charge stabilization and
Halo¯uorination of unsaturated compounds is an impor-
tant method to place ¯uorine into organic molecules. Several
of the commonly used protocols have been reviewed
recently [1±5]. One of the most versatile procedures for
bromo¯uorination has proved the combination of N-bromo-
succinimide (NBS) as the source of the bromonium ion and
triethylamine trishydro¯uoride (Et3NÁ3HF) as the ¯uoride
equivalent [6,7]. Among others also N-bromoacetamide
[8,9] or 1,3-dibromo-5,5-dimethylhydantoin [10] have been
applied as donors of the electrophile. Alternative ¯uoride
sources such as liquid hydrogen ¯uoride [11,12] or ammo-
nium- [13±16], pyridinium- [17,18], polymeric pyridinium
poly(hydrogen ¯uorides) [19±21] or potassium ¯uoride in
poly(hydrogen ¯uorides) [22], tetrabutyl-phosphonium
dihydrogen tri¯uoride [23] and several others [15,24] have
also been used. The poly(hydrogen ¯uorides) are relatively
acidic and do attack glassware. So, they have to be applied in
Te¯onTM or polypropylene ¯asks. Moreover, susceptible
alkenes can oligomerize or isomerize prior to bromo¯uor-
ination [25]. Recently, a comparison of several methods of
generation of intermediary interhalogen ¯uorides in halo-
¯uorinations has been published [26].
* Corresponding author. Fax: ‡49-251-83-39772.
E-mail address: haufe@uni-muenster.de (G. Haufe).
Scheme 1. Mechanism of bromofluorination.
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 2 3 0 - 4

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M. Lubke et al. / Journal of Fluorine Chemistry 102 (2000) 125±133
126
the Markovnikov-orientation is found in the main product.
With aliphatic terminal ole®ns the ratio of regioisomers
varies between 94:6 and 86:14 [7], while reactions of 2,2-
dialkyl- or aryl-substituted 1-alkenes show almost exclusive
Markovnikov-orientation. Moreover, enolesters on bromo-
¯uorination with NBS/Et3NÁ3HF showed exclusive Mar-
kovnikov-orientation, too [28].
Scheme 4. Bromofluorination of allylphenyl ether.
2. Results and discussion
Bromo¯uorination of ‡I- or ‡M-substituted terminal
unsaturated compounds as mentioned above are well known
in literature. However, reactions of ole®ns bearing I-
substituents in allylic or homoallylic position are rarely
investigated. The in¯uence on the regioselectivity of bro-
mo¯uorination of a hydroxyl group or an acetate or trichloro
acetate function in b-position to the double bond was found
relatively small. From allylic alcohol with NBS/Et3NÁ3HF a
90:10 mixture of 3-bromo-2-¯uoropropanol and its regioi-
somer was formed (52% yield) [29] (Scheme 2), while from
propene under the same conditions a 94:6 mixture of
regioisomers was obtained [7].
For the corresponding reactions of allylic alcohol or its
acetate with NBS (or NBA) and HF or pyridine/HF in ether
formation of the primary bromide was reported as the sole
product, however, in very low yields [29,30] while treatment
of allylic trichloroacetate with NBA/HF in ether/pyridine
gave the corresponding Markovnikov product in 69% yield
[31] (Scheme 3).
Interestingly, the reaction of 2-methylbut-3-en-2-ol with
NBS/Et3NÁ3HF gave no Markovnikov product at all, but
yielded an 1:1 mixture of 3-bromo-4-¯uoro-2-methylbutan-
2-ol (anti-Markovnikov-orientation) and 4-bromo-3-¯uoro-
2-methylbutan-3-ol, a rearranged product [29].
The portion of the anti-Markovnikov product increases in
case when an electron withdrawing substituent like a phenyl
group is placed at the oxygen function. The bromo¯uorina-
tion of allylphenyl ether, which is only weakly-dependent
on the ¯uorinating agent, gave 63:37 or 67:33 mixtures of
the regioisomers in the presence of Et3NÁ3HF or Olah's
reagent, respectively, (Scheme 4). Besides, p-bromination
Scheme 5. Bromofluorination of vinyl oxirane.
of the aromatic ring was obtained to some extent (11% or
13%, respectively) [32].
Bromo¯uorination of vinyl oxirane with NBS/Et3NÁ3HF
gave a 73:27 mixture of the regioisomers (55% yield) in
favor of the Markovnikov adduct (Scheme 5). Both regioi-
somers were formed as approximate 1:1 mixtures of ery-
thro- and threo-isomers [33].
In contrast the product bearing the bromine next to the
hydroxyl function was mainly formed when the positive
charge can be stabilized by a methyl group in g-position to
an oxygen. By way of example in the reaction of trans-but-
3-enol with NBS/Et3NÁ3HF mainly 2-bromo-3-¯uorobutan-
1-ol was found [28] (Scheme 6). Similar results have also
been reported for reactions of other allylic alcohols [29,34].
Allylic chloride on the other hand on reaction with NBS/
HF in THF gave a 80:20 mixture of the trihalopropanes in
35% yield in favor of the Markovnikov product [35,36]
(Scheme 7).
This means that there is not a big difference in the
in¯uence of the hydroxy function, an epoxy function, a
phenoxy group or a chlorine-substituent in allylic position
of a terminal alkene in cases when no other stabilizing
substituents are acting.
In contrast allylic bromide under similar conditions led to
a 41:59 mixture of regioisomers in favor of the anti-Mar-
kovnikov product [37] (Scheme 8).
Scheme 6. Bromofluorination of trans-but-3-enol.
Scheme 2. Bromofluorination of allylic alcohol.
Scheme 3. Bromofluorination of allylic trichloroacetate.
Scheme 7. Bromofluorination of allylic chloride.

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M. Lubke et al. / Journal of Fluorine Chemistry 102 (2000) 125±133
127
The extent of the formation of dibromides under the
conditions of bromo¯uorination seems to depend on the
reactivity of the ole®n as on the nature of the ¯uorinating
reagent. Consequently, for the following experiments with
several terminal alkenes bearing electron withdrawing func-
tional groups in allylic or homoallylic position (in all cases
the electronegative element is tied at carbon 4 in relation to
the terminal unsaturated carbon atom), two different amine/
HF reagents have been used in combination with NBS as the
electrophilic reagent. Trimethylamine bishydro¯uoride
(Me3NÁ2HF) which is known to be a source of a relatively
nucleophilic ¯uoride equivalent [38] or Olah's reagent
(PyÁ9HF), a more acidic but less nucleophilic ¯uorinating
reagent, have been applied.
Scheme 8. Mechanism of bromofluorination of allylic bromide.
Bromo¯uorination of but-3-en-1-ol (homoallylic alcohol)
with NBS/Me3NÁ2HF gave a 83:17 mixture of 4-bromo-3-
¯uoro- and 3-bromo-4-¯uorobutanols contaminated with
5% of 3,4-dibromobutanol. The corresponding reaction with
Olah's reagent yielded the bromo¯uorides in the same ratio,
however, no traces of the dibromide have been detected by
GC. Similarly, the reaction of 1-chloropent-4-en-2-ol under
the mentioned conditions gave the regioisomeric bromo-
¯uorides in 79:21 or 85:15 ratio, respectively, as mixtures of
diastereomers. In the ®rst case also 6% of the diastereomeric
dibromides was formed (Scheme 10). Compared to the
corresponding reactions of allylic alcohol (90:10) and 1-
butene (94:6), the regioselectivity of bromo¯uorination
unexpectedly dropped only slightly.
In case of 4-bromobut-1-ene (homoallylic bromide) a 3:1
mixture of regioisomers was formed independently from the
¯uorinating agent. The crude product of the reaction with
Me3NÁ2HF contained 4% of the tribromide (Scheme 11).
In contrast, allylic bromide gave mainly the anti-Mar-
kovnikov product [37]. In comparison to the reaction of 1-
butene the regioselectivity of bromo¯uorination of homo-
allylic bromide dropped as expected.
One possible explanation for this ratio of regioisomers is
the formation of a symmetrically bridged cationic inter-
mediate I including two bromine atoms. Sterically hindered
attack of the nucleophilic ¯uoride equivalent at the second-
ary carbon atom by two bromine substituents and better
accessibility of the primary position in the mesomeric
cationic structure II may determine the preferred formation
of the anti-Markovnikov product.
In order to examine the in¯uence of other electron with-
drawing substituents on the regioselectivity of bromo¯uor-
inations of terminal ole®ns we investigated N-allylic imides
and several other allylic and homoallylic systems. More-
over, in several cases under the conditions of bromo¯uor-
ination the formation of 1,2-dibromides was obtained (wide
infra). Factors in¯uencing this process have also been
evaluated.
The reaction of N-allylphthalic imide with NBS/
Et3NÁ3HF gave 28:72 mixture of the Markovnikov product
and its regioisomer. N-Allylsuccinic and N-allylmaleic imi-
des behave analogously. Obviously the strong electron
withdrawing effect of the imide moiety disfavors a potential
secondary cationic center. Thus, the intermediate cation is
mainly attacked in terminal position. In addition approxi-
mately 2% of vicinal dibromides have been isolated
(Scheme 9).
Reactions of vinylacetic acid under the conditions of
bromo¯uorination gave mainly 3-bromobutyrolactone.
Besides, some traces of ¯uorinated compounds were formed
which have not been identi®ed. On the other hand, the
Scheme 9. Bromofluorination of N-allylphthalic imide.

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M. Lubke et al. / Journal of Fluorine Chemistry 102 (2000) 125±133
128
Scheme 10. Bromofluorination of but-3-ene-1-ol and 1-chloropent-4-ene-2-ol.
Scheme 11. Bromofluorination of 4-bromobut-1-ene.
Scheme 12. Bromofluorination of vinylacetic acid benzyl ester.
benzylic ester of this acid gave 3:1 mixtures of the bromo-
¯uorides, independently from the ¯uorinating agent. Apply-
ing the more basic Me3NÁ2HF the yield was quite low and
14% of the dibromide was found, while no traces of this
compound have been detected in the product mixture of the
reaction with Olah's reagent (Scheme 12).
Bromo¯uorination with BrF (generated in situ from the
elements) of the methyl ester of vinylacetic acid gave a
63:37 mixture of the Markovnikov and the anti-Markovni-
kov products in high yield [39] (Scheme 13). Formation of a
dibromide has not been reported.
Finally, the reaction of allylic cyanide with NBS and
Me3NÁ2HF gave less than 2% of a 46:54 mixture of bromo-
¯uorides, while 3,4-dibromobutyronitril was the main pro-
duct (>98%, GC). In contrast with Olah's reagent this
compound was not detected, but a 45:55 mixture of 4-
bromo-3-¯uoro- and 3-bromo-4-¯uorobutyronitrile was iso-
lated (Scheme 14).
Scheme 13. Bromofluorination of vinylacetic acid methyl ester.
Scheme 14. Bromofluorination of allylic cyanide.

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M. Lubke et al. / Journal of Fluorine Chemistry 102 (2000) 125±133
129
(d ˆ 0.0 ppm, 19F NMR). Multiplicities of signals in 13C
NMR spectra were determined by DEPT operation, 19F
NMR chemical shifts of signals were obtained from
decoupled spectra. Abbreviations mean m ˆ multiplet,
s ˆ singlet,
d ˆ doublet,
t ˆ triplet,
q ˆ quartet,
dm ˆ doublet of multiplet, dd ˆ doublet of doublet,
dt ˆ doublet of triplet, etc. GC investigations were done
with a Hewlett±Packard GC 6890 (quartz capillary column
1
HP 5 (0.11 mm) dimensions 25 m, 0.2 mm). Mass spectra
(70 eV) were recorded by GC/MS technique using a com-
Scheme 15. Mechanism of the formation of bromine by reaction of NBS
and HF2 [40].
bination of a Varian GC 3400 (quartz capillary column DB 5
1
(0.33 mm) dimensions: 25 m, 0.2 mm) and Saturn II (Ion
Trap) or a Varian GC 3400 (quartz capillary column HP 1
1
The formation of dibromides as minor side products has
already been observed in some cases during our ®rst studies
of bromo¯uorination of alkenes with NBS/Et3NÁ3HF [40].
Also in reactions with HF pyridine with excess NBS [10]
(0.52 mm) dimensions: 50 m, 0.2 mm) and Finnigan MAT
8230; main peaks and speci®c fragmentations are listed.
Column chromatography was done with silica gel (Merck
60, 70±230 mesh) and combinations of solvents, which are
speci®ed for the corresponding experiments. Elemental
analyses were carried out by the Mikroanalytisches Labor-
È
atorium, Organisch-Chemisches Institut, Universitat Mun-
ster with a Perkin±Elmer 240 Elemental Analyzer.
Olah's reagent (PyÁ9HF) was obtained from Aldrich and
has a 65±70% share of HF. Triethylamine trishydro¯uoride
‡
and in reactions of several ole®ns with NBS=Bu4N H2F3
dibromides have been formed [16]. Since the part of dibro-
mides in our reactions [6,40] never extended 5% (GC) we
believed, that a small amount of elemental bromine which is
usually present in NBS was responsible. However, in 1989
Guerrero and coworkers [41] showed that in reactions of
ole®ns with NBS and tetrabutylammonium hydrogen
È
(Et3NÁ3HF)
and
trimethylamine
bishydro¯uoride
‡
di¯uoride (Bu4N HF2 ) bromine can be formed according
to the chain-mechanism shown in Scheme 15.
(Me3NÁ2HF) were kindly disposed by Hoechst [45]. The
latter reagent contains 2.2 mol HF per mole trimethylamine.
Cyclohexane and ethyl acetate for column chromatography
were puri®ed by distillation, pentane and ether were used
without puri®cation. CH2Cl2 was dried by distillation over
In an initial step the reaction of NBS with HF2 (Scheme
15) gives the interhalogen, HF and a succinimidyl anion.
Succeeding reactions of this anion with NBS produce
bromide which gives elemental bromine by reaction with
a third molecule of NBS.
Assuming a hydrogendi¯uoride anion as ¯uorinating
species of Me3NÁ2HF this mechanism could operate in
the considered reactions as well. Consequently, in case
of less reactive ole®ns the reduction of NBS to form
elemental bromine is faster than bromo¯uorination. Since
two molecules of NBS are consumed for this process the
relatively low chemical yield of the reaction could be
explained. Calculated on consumed NBS the yield of the
dibromide is almost quantitative in the reaction with allylic
cyanide.
Ê
P2O5 and stored over molecular sieves (4 A). The ratio of
¯uorinated regio and stereoisomers was determined by
integration of 19F NMR signals or by GC of the crude
product mixture.
3.1. Bromofluorinations
3.1.1. General procedure for bromofluorination with NBS
and Me3NÁ2HF
Method A. To a solution of the ole®n (10 mmol) and
Me3NÁ2HF (4.7 ml, 46 mmol) in CH2Cl2 (50 ml) NBS
(1.96 g, 11 mmol) is added in portions at 08C. The mixture
is stirred at 08C for 30 min and at room temperature for 4±
6 h, poured into ice-water (100 ml) and neutralized with
concentrated ammonia. The organic phase is separated and
the aqueous phase is extracted with ether (3 Â 20 ml). The
combined organic extracts are washed with 0.1 N HCl, 5%
aq. solution of NaHCO3 and dried (MgSO4). After removing
the solvent the products are isolated by column chromato-
graphy to give mixtures of the regioisomeric bromo¯uorides
and occasionally the dibromide as light yellow liquids.
Formation of dibromides has also been observed in
bromo¯uorinations with NBS/Et3NÁ3HF of other less
reactive alkenes such as 1,2-di¯uoro-1,2-di(p-tolyl)ethene
and 1,2,3,4-tetra¯uoro-1,4-di(p-tolyl)butadiene [5] or 2-
methylene-1,3-propanediol and its mono or bisalkyl ethers
[42].
3. Experimental
1H NMR (300.13 MHz), 13C NMR (75.48 MHz) and 19
F
3.1.2. General procedure for bromofluorination with NBS
and PyÁ9HF
NMR (282.37 MHz) were recorded on a Bruker WM 300.
Chemical shifts are reported as d values in units of ppm
related to the internal standards TMS (d ˆ 0.0 ppm, 1H
NMR), CDCl3 (d ˆ 77.0 ppm, 13C NMR) and CFCl3
Method B. To a solution of the ole®n (10 mmol) and
PyÁ9HF (2.6 ml, 11 mmol) in CH2Cl2 (50 ml) NBS (1.96 g,
11 mmol) is added in portions at 08C. The mixture is stirred

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M. Lubke et al. / Journal of Fluorine Chemistry 102 (2000) 125±133
130
2
3
at 08C for 30 min and at room temperature for 2 h. The
work-up is done as mentioned above. After puri®cation by
column chromatography mixtures of the regioisomers are
obtained as light yellow liquids.
212.4 (dt, JHF ˆ 45.8 Hz, JHF ˆ 15.3 Hz)) and N-(3-
bromo-2-fluoropropyl)-succinic imide (19F NMR d:
184.4 (m)) was obtained.
3.1.3.5. N-(2-bromo-3-fluoropropyl)-maleic imide and N-
(3-bromo-2-fluoropropyl)-maleic imide. According to the
above mentioned procedure a 70:30 mixture (19F NMR) of
N-(2-bromo-3-fluoropropyl)-maleic imide (19F NMR d:
213.4 (dt, JHF ˆ 45.8 Hz, JHF ˆ 15.3 Hz)) and N-(3-
bromo-2-fluoropropyl)-maleic imide (19F NMR d:
184.0 (m)) was obtained.
3.1.3. Bromofluorination of N-allylic imides with
NBS/Et3NÁ3HF
To a solution of the N-allylic imide (15 mmol) and
Et3NÁ3HF (5 ml, 30 mmol) in CH2Cl2 (20 ml) NBS
(3.94 g, 16.5 mmol) is added in portions under stirring at
room temperature. After 18 h the reaction mixture is worked
up as mentioned above.
2
3
According to this procedure from N-allylphthalic imide a
28:72 mixture of N-(2-bromo-3-¯uoropropyl)-phthalic
imide and its regioisomer was obtained (19F NMR). Addi-
tionally a small amount of N-(2,3-dibromopropyl)-phthalic
imide was isolated by chromatography (CH2Cl2).
3.1.4. Bromofluorination of 4-buten-1-ol
Method A. 960 mg (52%) of a 83:17 mixture (GC) of 4-
bromo-3-¯uorobutan-1-ol, 3-bromo-4-¯uorobutan-1-ol and
3,4-dibromobutan-1-ol (5%) was isolated by chromatogra-
phy (pentane/ether 2:1).
Method B. 790 mg (39%) of a 84:16 mixture (GC) of 4-
bromo-3-¯uorobutan-1-ol and 3-bromo-4-¯uorobutan-1-ol
was isolated by chromatography (pentane/ether 2:1).
3.1.3.1. N-(2,3-dibromopropyl)-phthalic imide. Yield:
0.1 g (2%), m.p. 1088C (CH2Cl2), [46]: m.p. 112±1148C
2
(ethanol). 1H NMR d: 3.73 (dd, 1H, JHH ˆ 10.7 Hz,
3JHH ˆ 8.6 Hz, 3-Ha), 3.86 (dd, 1H, JHH ˆ 10.7 Hz,
3.1.4.1. 4-Bromo-3-fluorobutan-1-ol. 1H NMR d: 1.85±
2.04 (m, 2H, 2-H2), 3.45±3.64 (m, 2H, 4-H2), 3.78±3.83
2
3JHH ˆ 4.8 Hz, 3-Hb), 4.15 (dd, 2JHH ˆ 14.3 Hz,
2
2
3JHH ˆ 8.6 Hz, 1-Ha), 4.25 (dd, 1H, JHH ˆ 14.3 Hz,
(m, 2H, 1-H2), 4.90 (dddt, 1H, JHF ˆ 47.9 Hz,
3
3JHH ˆ 5.3 Hz, 1-Hb), 4.62±4.68 (m, 1H, 2-H), 7.72±7.80
(m, 2H, Harom), 7.85±7.93 (m, 2H, Harom). 13C NMR d: 33.7
(t, C-3), 43.2 (t, C-1), 47.5 (d, C-2), 123.6 (d, Carom), 131.8
(s, Carom), 134.2 (d, Carom), 168 (s, C=O). MS m/z (%): 349/
3JHH ˆ 6.2 Hz, JHH ˆ 4.5 Hz, 3-H). 13C NMR d: 33.7
2
2
(td, JCF ˆ 22.9 Hz, C-2), 36.1 (td, JCF ˆ 20.3 Hz, C-4),
3
1
58.4 (td, JCF ˆ 5.1 Hz, C-1), 89.7 (dd, JCF ˆ 173.0 Hz).
‡
19F NMR d: 180.6 (m). MS m/z (%): 172/170 (<0.01, M ),
‡
‡
‡
‡
‡
347/345 (0.01, M ), 268/266 (11, M
‡
Br), 267/265 (82,
Br HBr), 160
153/151 (0.2, M ‡ 1 HF), 122/120 (36,
M
‡
M
(100,C9H6NO2 ).
HBr),
186
(23,
M
HF CH2O), 71 (74, 153/151 HBr), 41 (100, C3H5 ).
‡
3.1.4.2. 3-Bromo-4-fluorobutan-1-ol. 1H NMR d: 1.83±
2.02 (m, 2H, 2-H2), 3.42±3.61 (m, 2H, 1-H2), 4.27±4.40
3.1.3.2. N-(2-bromo-3-fluoropropyl)-phthalic imide. 1H
NMR d: 4.07±4.26 (m, 2H, 1-H2), 4.45±4.82 (m, 3H, 2-H
and 3-H2), 7.70±7.75 (m, 2H, Harom), 7.82±7.90 (m, 2H,
Harom). 13C NMR d: 41.2 (t, C-1), 45.3 (dd,
1
(m, 1H, 3-H), 4.46±4.74 (dm, 2H, JHF ˆ 47.0 Hz, 4-H2).
2
13C NMR d: 36.8 (t, C-2), 47.8 (dd, JCF ˆ 20.3 Hz, C-3),
59.7 (t, C-1), 85.5 (td, 1JHF ˆ 178.0 Hz, C-4). 19F NMR d:
211.3 (dt, 2JHF ˆ 45.8 Hz, 3JHF ˆ 15.3 Hz). MS m/z (%):
1
1JCF ˆ 20.35 Hz, C-2), 83.8 (td, JCF ˆ 178.0 Hz, C-3),
‡
‡
123.6 (d, Carom), 131.8 (s, Carom), 134.3 (d, Carom), 167.7
2
172/170 (0.5, M ), 152/150 (1.1, M HF), 122/120 (22,
HF CH2O), 71 (60, 152/150 Br), 41 (100,
‡
(s, C=O). 19F NMR d: 213.69 (dt, JHF ˆ 45.7 Hz,
M
C3H5 ).
‡
‡
3JHF ˆ 17.2 Hz). MS m/z (%): 288/286 (0.24, M ‡ 1),
‡
‡
287/285 (0.03, M ), 286/284 (0.27, M 1), 206 (5,
Br), 186 (17, 206 HF), 185 (92), 162 (26) 160
‡
M
(100, C9H6NO2 ), 133 (11), 130 (9), 105 (10, 133 CO),
104 (22, 132 CO), 77 (17, C6H5 ), 76 (26, C6H4 ).
3.1.5. Bromofluorination of 1-chloro-4-penten-2-ol
‡
Method A. 1.21 g (55%) of a 79:21 mixture (GC) of 5-
bromo-1-chloro-4-¯uoropentan-2-ol, 4-bromo-1-chloro-5-
¯uoropentan-2-ol and 4,5-dibromo-1-chloropentan-2-ol
(6%) was isolated by chromatography (pentane/ether 9:1).
Method B. 0.96 g (44%) of a 85:15 mixture (GC) of 5-
‡
‡
3.1.3.3. N-(3-bromo-2-fluoropropyl)-phthalic imide. 19F
‡
NMR d: 184.0 (m). MS m/z (%): 287/285 (0.01, M ),
‡
207 (2), 206 (12, M
162 (2), 161 (10) 160 (100, C9H6NO2 ), 133 (4), 130 (3), 105
Br), 186 (4, 206 HF), 185 (24),
‡
bromo-1-chloro-4-¯uoropentan-2-ol
and
4-bromo-1-
chloro-5-¯uoropentan-2-ol was isolated chromatographi-
cally (pentane/ether 9:1).
‡
(4, 133 CO), 104 (10, 132 CO), 77 (10, C6H5 ), 76 (11,
‡
C6H4 ).
3.1.5.1. 4,5-Dibromo-1-chloropentan-2-ol. MS m/z (%):
‡
3.1.3.4. N-(2-bromo-3-fluoropropyl)-succinic imide and N-
(3-bromo-2-fluoropropyl)-succinic imide. According to the
above mentioned procedure a 71:29 mixture (19F NMR) of
N-(2-bromo-3-fluoropropyl)-succinic imide (19F NMR d:
233/231/229 (18,
‡
M
CH2Cl CH2O), 151/149 (14,
CH2Cl), 203/201/199 (3,
‡
M
M
CH2Cl
HBr), 123/121 (12, 151/149 CO), 121/119 (10, 151/
149 CH2O), 79 (47), 41 (100).

È
M. Lubke et al. / Journal of Fluorine Chemistry 102 (2000) 125±133
131
3.1.5.2. 5-Bromo-1-chloro-4-fluoropentan-2-ol. 19F NMR
d: 177.9 and 180.4 (m, two diastereomers). MS m/z
(GC) of benzyl 4-bromo-3-¯uorobutanoate and benzyl 3-
bromo-4-¯uorobutanoate were isolated by chromatography
(cyclohexane/ethyl acetate 15:1).
‡
‡
(%): 222/220/218 (0.07, M ), 171/169 (75, M
CH2Cl),
151/149 (64, 171/169 HF), 123/121 (23, 151/149 CO),
121/119 (24, 151/149 CH2O), 105/103 (6), 89 (4, 171/
169 HBr), 79 (48, 150 HBr), 41 (100).
Method B. 1.40 g (51%) of a 74:26 mixture (GC) of
benzyl 4-bromo-3-¯uorobutanoate and benzyl 3-bromo-4-
¯uorobutanoate was isolated by chromatography (cyclohex-
ane/ethyl acetate 15:1).
3.1.5.3. 4-Bromo-1-chloro-5-fluoropentan-2-ol. 19F NMR
d:
211.6 and
3
211.9 (ddd, 2JHF ˆ 46.7 Hz,
3.1.7.1. Benzyl 4-bromo-3-fluorobutanoate. 1H NMR d:
2.81±2.90 (m, 2H, 2-H2), 3.50±3.61 (m, 2H, 4-H2), 4.99±
5.20 (m, 1H, 3-H), 5.16 (s, 2H, 5-H2), 7.25±7.47 (m, 5H, 7-H
bis 11-H). 13C NMR d: 33.1 (td, 2JCF ˆ 25.7 Hz, C-2), 38.2
3JHF ˆ 17.2 Hz, JHF ˆ 15.2 Hz, two diastereomers). MS
‡
‡
m/z (%): 222/220/218 (<0.01, M ), 184/182 (4, M
171/169 (100, M
HCl),
CH2Cl), 164/162 (8, 184/182 HF),
‡
2
151/149 (78, 171/169 HF); 123/121 (30, 151/149 CO),
121/119 (35, 151/149 CH2O), 105/103 (11), 89 (5, 171/
169 HBr), 79 (47), 69 (10, 150 HBr), 41 (70).
(td, JCF ˆ 24.9, C-4), 66.8 (t, C-5), 87.8 (dd,
1JCF ˆ 178.1 Hz, C-3), 128.2 (d, 1C, C-9), 128.4 (d, 2C,
C-8, C-10), 128.6 (d, 2C, C-7, C-11), 135.4 (s, C-6), 169.0
2
(s, C-1). 19F NMR d:
177.4 (dtt, JHF ˆ 45.8 Hz,
3
3.1.6. Bromofluorination of 4-bromo-1-butene
3JHF ˆ 21.0 Hz, JHF ˆ 17.2 Hz). MS m/z (%): 276/274
‡
‡
Method A. 930 mg (40%) of a 75:25 mixture (GC) of 1,4-
dibromo-2-¯uorobutane, 2,4-dibromo-1-¯uorobutane and
1,2,4-tribromobutane (4%) was isolated chromatographi-
cally (pentane/ether 1:1).
Method B. 820 mg (35%) of a 78:22 mixture (GC) of 1,4-
dibromo-2-¯uorobutane and 2,4-dibromo-1-¯uorobutane
was isolated chromatographically (pentane/ether 1:1). Spec-
troscopic data were taken from the mixture of regioisomers.
(20, M ), 174 (5,
M
C6H5CH2O), 141/139 (2, M
HF Br), 170/168 (4,
‡
‡
M
108 (100, C6H5CH2OH ), 91 (41, C6H5CH2 ), 59 (4,
C6H5CH2CO2),
‡
‡
‡
CH2CFCH2 ). C11H12BrFO2 (275.1): ca. C, 48.02; H,
4.40; found C, 48.64; H, 4.64%.
3.1.7.2. Benzyl 3-bromo-4-fluorobutanoate. 1H NMR d:
2
3
2.84 (dd, 1H, JHH ˆ 16.6 Hz, JHH ˆ 8.3 Hz, 2-H, ABX-
system), 3.06 (dd, 1H, 2JHH ˆ 16.6 Hz, 3JHH ˆ 5.0 Hz, 2-H,
ABX-system), 4.32±4.50 (m, 1H, 3-H), 4.50±4.67 (m, 2H,
4-H2), 5.10 (s, 2H, 5-H2), 7.17±7.35 (m, 5H, 7-H bis 11-H).
3.1.6.1. 1,4-Dibromo-2-fluorobutane. 1H NMR d: 2.20±
2.46 (m, 2H, 3-H2), 3.48±3.57 (m, 4H, 1-H2 and 4-H2),
4.89 (ddddd, 1H, 2JHF ˆ 47.7 Hz, 3JHH ˆ 5.0 Hz,
2
13C NMR d: 39.7 (t, C-2), 43.1 (dd, JCF ˆ 21.9 Hz, C-3),
3
3
3JHH ˆ 4.8 Hz, JHH ˆ 3.3 Hz, JHH ˆ 3.1 Hz, 2-H). 13C
67.0 (t, C-5), 84.3 (td, 1JCF ˆ 178.1 Hz, C-4); 128.3 (d, C-
3
NMR d: 27.6 (td, JCF ˆ 4.5 Hz, C-4), 32.8 (td,
9), 128.4 (d, 2C, C-8, C-10), 128.6 (d, 2C, C-7, C-11), 135.4
(s, C-6), 169.4 (s, C-1). 19F NMR d:
2JCF ˆ 25.1 Hz, C-3), 36.5 (td, JCF ˆ 20.4 Hz, C-1),
211.5 (dt,
2
89.4 (dd, JCF ˆ 175.5 Hz, C-2). 19F NMR d: 182.4
2JHF ˆ 47.7 Hz, JHF ˆ 13.3 Hz). MS m/z (%): 276/274
1
3
‡
‡
‡
M
C6H5CH2O), 141/139 (5, M
(m). MS m/z (%): 236/234/232 (4, M ), 155/153 (28,
(24, M ), 194 (5,
HBr), 170/168 (4,
‡
‡
‡
‡
M Br), 154/152 (42, M
214/212 HBr), 109/107 (22, BrCH2CH2 ), 95/93 (12,
BrCH2 ), 73 (100, 155/153 HBr), 53 (39, 73 HF), 47
(30).
HBr), 135/133 (4, 216/
‡
M
C6H5CH2CO2),
‡
‡
108 (100, C6H5CH2OH ), 91 (48, C6H5CH2 ), 87 (9,
‡
‡
‡
FCH2CHCHCO ), 59 (5, FCH2CHCH ).
3.1.8. Bromofluorination of allylic cyanide
3.1.6.2. 2,4-Dibromo-1-fluorobutane. 1H NMR d: 2.09±
2.20 (m, 2H, 3-H2), 3.45±3.58 (m, 2H, 4-H2), 4.27±4.40
Method A. 960 mg (42%) of 3,4-dibromobutyronitrile
isolated by chromatography (pentane/ether 1:1). Minor
amounts of a 46:54 mixture of 4-bromo-3-¯uorobutyronitril
and 3-bromo-4-¯uorobutyronitril were not isolated.
Method B. 480 mg (29%) of a 45:55 mixture of 4-bromo-
3-¯uorobutyronitrile and 3-bromo-4-¯uorobutyronitrile
(GC) was isolated chromatographically (pentane/ether
1:1). Elemental analysis and NMR spectra were recorded
from the mixture of regioisomers.
2
3
(m, 1H, 2-H), 4.55 (ddd, JHF ˆ 47.0 Hz, JHH ˆ 9.8 Hz,
3JHF ˆ 6.4 Hz, 1-H), 4.65 (ddd, 2JHF ˆ 47.0 Hz,
3
3JHH ˆ 9.8 Hz, JHF ˆ 4.8 Hz, 1-H). 13C NMR d: 30.1 (t,
C-4), 37.1 (t, C-3), ca. 48 (dd, C-2), 84.9 (td,
1JCF ˆ 178.0 Hz, C-1). 19F NMR d:
211.7 (dt,
3
2JHF ˆ 46.7 Hz, JHF ˆ 16.2 Hz). MS m/z (%): 236/234/
‡
‡
232 (16, M ), 216/214/212 (14, M
Br), 154/152 (42, M
HF), 155/153 (28,
HBr), 135/133 (11, 216/214/
‡
‡
M
‡
‡
1
212 HBr), 109/107 (17, BrCH2CH2 ), 95/93 (5, BrCH2 ),
73 (100, 155/153 HBr), 53 (27, 73 HF), 47 (16).
3.1.8.1. 3,4-Dibromobutyronitrile [48]. H NMR d: 3.22
(d, 2H, 3JHH ˆ 5.2 Hz, 2-H2), 3.72 (dd, 1H,
3
2JHH ˆ 10.7 Hz, JHH ˆ 10.5 Hz, 4-H, ABX system),
2
3
3.1.7. Bromofluorination of benzyl 3-butenoate
3.91 (dd, 1H, JHH ˆ 10.7 Hz, JHH ˆ 4.1 Hz, 4-H, ABX
system), 4.26±4.34 (m, 1H, 3-H). 13C NMR d: 26.1 (t, C-2),
33.6 (t, C-4), 41.8 (d, C-3), 115.4 (s, C-1). MS m/z (%): 229/
Method A. 470 mg (14%) of benzyl 3,4-dibromobutano-
ate (spectroscopic data correspond to those reported in
literature [47]) and 610 mg (22%) of a 3.6:1 mixture
‡
‡
227 (0.3, MH ), 189/187 (1.8, MH
CH2CN), 148/146

È
M. Lubke et al. / Journal of Fluorine Chemistry 102 (2000) 125±133
132
‡
(96, MH
(6, 148/146 CH3CN), 95/93 (18, BrCH2 ), 66 (100, 148/
HBr), 121/119 (4, 148/146 HCN), 107/105
‡
The nature of the amine/HF reagent does not strongly
in¯uence the regioselectivity of bromo¯uorination, but
in¯uences the extent of side reactions, namely the formation
of dibromides. While in reactions with the more acidic
Olah's reagent dibromides were not found, these products
were formed in all reactions with the less acidic, but more
nucleophilic [38] Me3NÁ2HF. The portion of these products
increases with decreasing reactivity of the double bond and
becomes almost the exclusive reaction with allylic cyanide.
Thus, application of the combination NBS/Et3NÁ3HF or
NBS/Me3NÁ2HF is recommended for bromo¯uorinations of
reactive alkenes, while NBS/Olah's reagent can also be
applied for less reactive alkenes which, however, should
not be susceptible against cationic oligomerization or iso-
merization [25,40,44].
‡
146 HBr), 39 (40, C3H3 ).
3.1.8.2. 4-Bromo-3-fluorobutyronitrile. 1H NMR d: 2.93
3
3
(dd, 2H, JHF ˆ 19.6 Hz, JHH ˆ 5.5 Hz, 2-H2), 3.57±3.64
2
(m, 2H, 4-H2), 4.94 (dtt, 1H, JHF ˆ 46.0 Hz,
3JHH ˆ 5.5 Hz, JHH ˆ 5.2 Hz, 3-H). 13C NMR d: 22.4
3
2
2
(td, JCF ˆ 25.4 Hz, C-2), 30.6 (td, JCF ˆ 25.4 Hz, C-4),
86.2 (dd, 1JCF ˆ 183.1 Hz, C-3), 114.8 (s, C-1). 19F NMR d:
174.8
(dtt,
2JHF ˆ 45.8 Hz,
3JHF ˆ 19.1 Hz,
‡
3JHF ˆ 17.2 Hz). MS m/z (%): 168/166 (2, MH ), 167/
‡
‡
165 (20, M ), 147/145 (3, M HF), 127/125 (30,
CH2CN), 107/105 (15, 127/125 HF), 95/93 (10,
‡
M
BrCH2 ), 86 (14, MH
‡
‡
‡
HBr, M Br), 72 (100,
BrCH2), 45 (24, 72 HCN), 41 (71). C4H5BrFN
‡
M
(166.0): ca. C, 28.94; H, 3.04; N, 8.44; found C, 29.15%; H,
3.06%; N, 8.14% (obtained for the mixture of the isomers).
Acknowledgements
1
3.1.8.3. 3-Bromo-4-fluorobutyronitrile. H NMR d: 3.06±
Financial support by the Fonds der Chemischen Industrie
is gratefully acknowledged. We are grateful to the Hoechst
AG, Frankfurt/Main and the Bayer AG, Leverkusen for the
kind donation of chemicals.
3.11 (m, 2H, 2-H2); 4.18±4.31 (m, 1H, 3-H); 4.44±4.80 (m,
2H, 4-H2). 13C NMR d: 23.8 (td, 3JCF ˆ 5.1 Hz, C-2); 40.4
(dd, 2JCF ˆ 22.9 Hz, C-3); 83.0 (td, 1JCF ˆ 180.6 Hz, C-4);
115.7 (s, C-1). 19F NMR d: 210.4 (dt, JHF ˆ 45.8 Hz,
2
‡
3JHF ˆ 13.3 Hz). MS m/z (%): 168/166 (2, M ‡ 1); 167/
‡
‡
References
165 (24, M ); 134/132 (4, M FCH2); 127/125 (8,
CH2CN), 107/105 (8, 127/125 HF), 86 (100,
‡
M
MH
‡
‡
‡
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Â
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