Resolution and absolute configuration of bromofluoroacetic acid

Article abstract of DOI:10.1016/S0957-4166(02)00195-7

The resolution of racemic bromofluoroacetic acid (BrFHCCO₂H) 1 was effected by crystallisation of its diastereoisomeric α-methylbenzylamine salts. The crystal structure of the p salt (+)-3a {(+)-BrFHCCO₂H·(R)-(+)-α-methylbenzylamine} was solved by X-ray crystallography and the (S)-(+)/(R)-(-) absolute configuration was established for 1. Diastereoisomeric esters 5a and 5b, obtained by addition of bromofluoroacetic acid to enantiomerically pure epoxychroman 4, were used to determine the enantiomeric excess of 1 by ¹⁹F NMR. Moreover, the diastereoisomerically pure ester 5a, resulting from addition of enantiomerically pure (+)-1 to 4, gave single crystals and its X-ray crystal structure corroborated the (S)-(+)/(R)-(-) absolute configuration of 1.

Full text of DOI:10.1016/S0957-4166(02)00195-7

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TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 975–981
Resolution and absolute configuration of bromofluoroacetic acid
He´le`ne Boussac,a Jeanne Crassous,a,* Jean-Pierre Dutasta,a Laurent Grosvaletb and Alain Thozetb
a
´
Ste´re´ochimie et Interactions Mole´culaires (UMR CNRS n° 5532), Ecole Normale Supe´rieure de Lyon,
F-69364 Lyon cedex 07, France
bLaboratoire de Cristallographie (UMR CNRS n° 5078), Universite´ Claude Bernard-Lyon I, 43 bvd du 11 Novembre 1918,
F-69622 Villeurbanne cedex, France
Received 10 April 2002; accepted 22 April 2002
Abstract—The resolution of racemic bromofluoroacetic acid (BrFHCCO2H) 1 was effected by crystallisation of its diastereoiso-
meric a-methylbenzylamine salts. The crystal structure of the p salt (+)-3a {(+)-BrFHCCO2H·(R)-(+)-a-methylbenzylamine} was
solved by X-ray crystallography and the (S)-(+)/(R)-(−) absolute configuration was established for 1. Diastereoisomeric esters 5a
and 5b, obtained by addition of bromofluoroacetic acid to enantiomerically pure epoxychroman 4, were used to determine the
enantiomeric excess of 1 by 19F NMR. Moreover, the diastereoisomerically pure ester 5a, resulting from addition of enantiomer-
ically pure (+)-1 to 4, gave single crystals and its X-ray crystal structure corroborated the (S)-(+)/(R)-(−) absolute configuration
of 1. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Similarly, he prepared optically active enflurane from
the resolved chlorofluoroacetic acid 7 by forming its
mercury salt and by combining it with bromodi-
fluoromethane, followed by treatment with SF4/HF.6
Bromofluoroacetic acid (FBrHCCO2H) 1 belongs to the
family of chiral fluorinated carboxylic acids, some of
which are commonly used in the NMR determination
of enantiomeric excesses1 (e.e.’s) and in the synthesis of
enantioenriched anaesthetics.2 Indeed, next to the well-
CO2Na
CF3
Cl
SF4 / HF
known
2-methoxy-3,3,3-trifluoro-2-phenylpropionic
Br
Br
Cl
acid (Mosher’s acid MTPA),3 a growing range of fluor-
inated carboxylic acids are being used for NMR deter-
mination of the e.e.’s of alcohols and amines, such as
a-cyano-a-fluorophenylacetic acid (CNFPhCCO2H)4 or
chlorofluoroacetic acid (ClFHCCO2H).5 Their use in
19F NMR offers essentially the following advantages:
the differences in chemical shifts between the
diastereoisomers are in the range of several ppm and
additionally, the fluorine signals are only due to one or
two fluorinated groups and therefore give NMR spectra
which are simple to analyse.1
H
H
(S)-(+)-halothane
(S)-(–)-6
CO2CHF2
CO2H
1) HgO
F
F
2) CHF2Br
Cl
H
Cl
H
SF4 / HF
(R)-(–)-7
CF2OCHF2
F
Cl
H
Chiral fluorinated carboxylic acids are key intermedi-
ates in the synthesis of optically active anaesthetics.2
For example, Pearson has demonstrated that 96% e.e.
samples of (S)-(+) and (R)-(−) halothane could be
prepared by reaction of SF4/HF with the sodium salt of
the resolved bromochloroacetic acid 6 (Scheme 1).6,7
(R)-(–)-enflurane
CO2H
F
CF3
SF4 / HF
Br
Br
F
H
H
(S)-teflurane
(S)-(+)-1
* Corresponding author. Tel: +33 (0)4 72 72 87 33; fax: +33 (0)4 72
72 84 83; e-mail: jeanne.crassous@ens-lyon.fr
Scheme 1. Synthesis of some optically active anaesthetics.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00195-7

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976
H. Boussac et al. / Tetrahedron: Asymmetry 13 (2002) 975–981
Racemic chlorofluoroacetic acid 7 was resolved by crys-
tallisation of its a-methylbenzylamine salts and the
chiral carboxylic acids is to measure the proportions of
their diastereoisomeric covalent esters by NMR.20 For
this purpose, enantiopure (−)-(3S,4S)-6-cyano-2,2-
dimethyl-3,4-epoxychroman 4 was advantageously used
to measure the e.e. of the resolved acid 1, via the
formation of the diastereoisomeric esters 5a and 5b
(Scheme 2). This method was inspired by Belluci et al.
who used enantiopure 1,2-epoxy-1-phenylcyclohexane
to determine the e.e. of chlorofluoroacetic acid 7 by 19F
NMR.21 The advantage of epoxychroman 4 is that it
can be synthesised in enantioenriched form by Jacobsen
asymmetric epoxidation reaction and can be obtained
in enantiomerically pure form by recrystallisation from
toluene.22 Preliminary studies have been performed
with the racemic acid ( )-1 to check that no kinetic
resolution occurred during the opening reaction of the
epoxide. Moreover, the 188.2 MHz 19F NMR spectrum
in C6D6 of the diastereoisomeric mixture gave two 1:1
doublets at −150.03 and −150.13 ppm (CFCl3 as inter-
nal reference). This reaction is very convenient as it can
be conducted on NMR tube scale, and has been applied
to other a-fluorinated carboxylic acids such as chlor-
ofluoroacetic acid.23 The regioselectivity of the opening
reaction of 4 and the trans stereochemistry of the
3,4-bond were first assumed according to published
results.24 The benzylic position is still preferred for the
attack of the nucleophile and the trans stereochemistry
is consistent with the 7.1 Hz coupling constant mea-
sured between C(3)H and C(4)H. These assumptions
were further corroborated by X-ray crystal structure
analysis of the pure diastereoisomer 5a (see Fig. 2
below).
(S)-(+)/(R)-(−) absolute configuration of
7
was
obtained from the X-ray crystal structure analysis of
the less soluble salt. Isoflurane was also synthesised
from 1-chloro-2,2,2-trifluoroethoxidifluoroethanoic acid
by using a highly stereospecific decarboxylation reac-
tion.8 Very recently, racemic fluoroiodoacetic acid was
resolved by crystallisation of its ephedrine salts and
proved to be an important synthon in the asymmetric
synthesis of fluorinated HIV protease inhibitors.9
It is also notable that bromochlorofluoromethane
(CHFClBr),10 one of the simplest chiral molecules, was
synthesised from bromochlorofluoroacetic acid11 by a
decarboxylation reaction which has been shown to pro-
ceed with retention of configuration.12–14 The deuter-
ated analogue CDFClBr12 was also obtained by
conducting the decarboxylation reaction in deuterated
water.15
Most of the fluorinated acids mentioned above were
resolved by crystallisation of their diastereoisomeric
salts formed with chiral amines, which seems to be the
easiest way to resolve such compounds.16,17 However,
the resolution of bromofluoroacetic acid 1 has not been
accomplished so far, although it could probably find
use in the preparation of the two enantiomers of
teflurane by reaction with SF4/HF (see Scheme 1).18
2. Results and discussion
Racemic bromofluoroacetic acid ( )-1 was prepared by
saponification of the commercially available ( )-ethyl-
bromofluoroacetate in 52% yield after distillation
(Scheme 2).19 A general method to determine the e.e. of
The resolution of 1 was investigated by crystallisation
of the diastereoisomeric salts formed with chiral
amines.16,17 Among the seven commercially available
optically active amines tested,25 a-methylbenzylamine 2
gave the best results. Therefore, one recrystallisation of
the diastereoisomeric salt {( )-BrFHCCO2H·(R)-(+)-a-
methylbenzylamine} from chloroform gave the pure
Br O
Br O
1) aq. KOH
F
C
H
C OEt
F
C
H
C OH
2) H2SO4
(52%)
diastereoisomer (+)-3a {(+)-BrFHCCO2H·(R)-(+)-a-
25
436
methylbenzylamine} (p salt)26 in 33% yield ([h] +23.6
(±)-1
(±)-ethylbromo-
fluoroacetate
(c 1, MeOH)) (Scheme 3). Following the same proce-
dure, one recrystallisation of the diastereoisomeric salt
{( )-BrFHCCO2H·(S)-(−)-a-methylbenzylamine}
in
O
Br O
NC
+
4
chloroform gave the diastereoisomer (−)-3a {(−)-
3
F
C
H
C OH
BrFHCCO2H·(S)-(−)-a-methylbenzylamine} (p salt)26
O
25
436
in 33% yield ([h] −22.3 (c 1, MeOH)).
(3S,4S)-(–)-4
C6H6
(95%)
(±)-1
(+)-Bromofluoroacetic acid (+)-1 ([h]2D5 +28.0 (c 1.1,
acetone)) and (−)-bromofluoroacetic acid (−)-1 ([h]D25
−31.1 (c 1, acetone)) were subsequently recovered in
quantitative yield by hydrolysis of the p salts (+)-3a and
(−)-3a, respectively, using strongly acidic Dowex resin
in acetone.27 They were then subjected to reaction with
H
H
15
F
F
Br
Br
15
14
O
O
13
O
O
OH
5
10
9
+
NC
OH
NC
4
4
6
7
3
3
the
(−)-(3S,4S)-6-cyano-2,2-dimethyl-3,4-epoxychro-
12
man 4. From (+)-1, the resulting 19F NMR spectrum
displayed only one doublet at −150.13 ppm correspond-
ing to 5a, suggesting that the (+)-acid was enantiopure
within the NMR measurement error (3–4%). For (−)-1,
an e.e. of 84% ((+)-1/(−)-1 8:92) was obtained by fol-
lowing the same procedure.28
2
O
O
11
8
1
(3S,4R,15R)-5b
(3S,4R,15S)-5a
Scheme 2. Synthesis of ( )-1 and formation of covalent
diastereoisomeric esters 5a and 5b.

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H. Boussac et al. / Tetrahedron: Asymmetry 13 (2002) 975–981
977
the crystal structure, according to the value of 0.012
found for the Flack parameter. Moreover, the S
configuration could be deduced by comparison with the
known R configuration of the a-methylbenzylammo-
nium fragment in (+)-3a. This result is not in accor-
dance with that predicted using Brewster’s rule. This
semi-empirical rule, based on atomic polarisabilities,
has been used for the determination of the absolute
configurations of several classes of chiral compounds.30
It was thus interesting to test the validity of Brewster’s
rule by considering the absolute configuration of the
small a-halogenocarboxylic acids already established.
Brewster observed for a wide range of chiral sub-
stances, that the molecule drawn in Scheme 4 displayed
a positive optical rotation in the Fischer projection
shown, considering the polarisability order A>B>C>D.
In this context, the (S)-(+) assignment for
BrFHCCO2H is not consistent with the polarisability
order Br>Cl>CO2H>H>F used by Brewster. The same
conclusion can be drawn in the case of chlor-
ofluoroacetic acid21 and bromochloroacetic acid.6 In
fact, polarisability orders can be reversed in certain
cases when particular interactions, e.g. hydrogen bonds,
play an important role.31
Ph
Br O
+
C OH
F
C
H
NH2
CH3
H
(±)-1
(R)-(+)-2
MeOH
{(±)-1.(R)-(+)-2}
recrystallization from CHCl3
(33%)
(67%)
{(S)-(+)-1.(R)-(+)-2}
p salt (+)-3a
mother liquors 3b
recrystallization from CHCl3
H+-Dowex resin
(14%)
(60%)
acetone
(100 %)
3c
mother liquors 3d
CO2H
Br
1) H+-Dowex resin, acetone
2) 4, C6D6
F
H
(S)-(+)-1
5a : 5bb
5a : 5bb
Single crystals of pure diastereoisomer 5a were grown
from C6D6 solution in NMR tubes, after several weeks.
The X-ray structure was solved (monoclinic, P21) and
the asymmetric unit corresponds to the ester 5a
together with one molecule of benzene. The solvent was
disordered and localised in two equipopulated posi-
tions, as depicted in Fig. 2. With a Flack parameter of
0.022, the absolute configuration for 5a corresponds to
the (3S,4R,15S) diastereoisomer, confirming the trans
stereochemistry.
4, C6D6
83 : 17
64 : 36
5a : 5bb
100 : 0
Scheme 3. Resolution of ( )-1 into (+)-1 by recrystallisation
in chloroform of its (R)-(+)-a-methylbenzylammonium salts
and determination of the diastereoisomeric purity of the salts
via the formation of esters 5a and 5b. a Specific rotations
[h] (c 1, MeOH). b Proportions of 5a and 5b obtained from
25
436
19F NMR in C6D6.
One can notice on Scheme 3 that the p salt is the major
compound recovered, even in the mother liquors, and
exceeds the expected 50% theoretical percentage.
Indeed, the acids recovered after hydrolysis of the salts,
always led to diastereoisomeric esters enriched in 5a. In
fact, preparation of the (n,p) salt from racemic ( )-1 in
methanol with either (R)- or (S)-a-methylbenzylamine,
always led, after crystallisation, to a mixture of n and p
salts with an n:p ratio different from 1:1 in favour of
the p salt. This was attributed to interconversion
between the S and R acids during the preparation of
the salt in methanol, and to the preferential crystallisa-
tion of the p salt.29
3. Conclusion
Racemic bromofluoroacetic acid 1 was resolved for the
first time by crystallisation of its a-methylbenzylammo-
nium salts. Its absolute configuration ((S)-(+) and (R)-
(−)) could be determined from the X-ray crystal
structure of the less soluble salt (+)-3a. After Dowex
resin hydrolysis of the diastereomeric salts, the e.e. of
the resolved (+) and (−) acids were determined by 19F
NMR of the covalent diastereoisomeric esters 5a and
5b, the structures of which were confirmed by X-ray
crystallography.
Single crystals suitable for X-ray analysis were grown
within one night from a methanol solution of (+)-3a.
The asymmetric unit (Fig. 1) corresponds to an acid–
base pair, where the NH3+ group of the a-methylbenzyl-
ammonium residue shares three hydrogen bonds with
the carboxylate group. The carbonyl C(2)ꢀO(2) bond
4. Experimental
4.1. General
1H, 13C and 19F NMR spectra were recorded on a
1
Bruker DPX 200 spectrometer (at 200.13 MHz for H,
50.4 MHz for 13C and 188.2 MHz for 19F). Melting or
,
(1.227 A) of the carboxylate interacts with the a-
methylbenzylammonium residue through one H bond,
decomposition temperatures were measured on
a
,
whereas the hydroxylate C(2)ꢀO(1) bond (1.268 A)
Perkin–Elmer DSC7 microcalorimeter. Rotations (in
deg cm2 g−1) were measured in a 1 dm thermostatically
controlled quartz cell (25°C) on a Perkin–Elmer 241
micropolarimeter. Elemental analyses were carried out
interacts with the ammonium residue through two H
bonds. The (S)-(+)/(R)-(−) absolute configuration of
the bromofluoroacetic acid could be established from

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978
H. Boussac et al. / Tetrahedron: Asymmetry 13 (2002) 975–981
Figure 1. X-Ray crystal structure of p salt (+)-3a {(S)-(+)-1·(R)-(+)-2}.
by the Service Central d’Analyses, CNRS. Mass spectra
were recorded by the Centre de Spectrome´trie de
Masse, Universite´ de Lyon1, France. Ethyl bromo-
fluoroacetate was purchased from Acros. (+)- and (−)-
a-Methylbenzylamine were purchased from Acros or
Aldrich and were 99 and 98% e.e., respectively. The
Dowex 50x8-100 resin was purchased from Janssen
Chimica.
zene (5 mL) was added dropwise at 0°C under argon to
a solution of bromofluoroacetic acid ( )-1 (95.4 mg,
,
60.8 mmol) in dry benzene (10 mL) containing 4 A
molecular sieves. After stirring under argon at room
temperature for 24 hours, the mixture was filtered,
dried over sodium sulfate and concentrated to give 5a
and 5b as a white paste (218 mg, 95%). 1H NMR
(C6D6) l 0.99 (s, 3H, CH3, 5b), 1.00 (s, 3H, CH3, 5a),
1.09 (s, 3H, CH3, 5b), 1.13 (s, 3H, CH3, 5a), 2.07 (s,
OH), 3.38 (d, 2H, J=7.1 Hz, H3), 5.75 (d, 2H, J=7.1
Hz, H4), 5.94 (d, 1H, J=50.2 Hz, H15, 5b), 6.03 (d, 1H,
J=50.2 Hz, H15, 5a), 6.44 (d, 1H, J=8.6 Hz, H8, 5b),
6.45 (d, 1H, J=8.6 Hz, H8, 5a), 6.84 (m, 2H, H7), 7.23
(d, 1H, J=1.2 Hz, H5, 5b), 7.31 (d, 1H, J=1.1 Hz, H5,
5a). NMR 19F (C6D6, CFCl3 as internal reference) l
−150.13 (d, J=50.4 Hz, 5a), −150.03 (d, J=50.4 Hz,
5b). 13C NMR (C6D6, 50.4 MHz) l 19.80 (CH3, 5a),
4.2. ( )-Bromofluoroacetic acid 1
Ethyl bromofluoroacetate (5 g, 27 mmol) was added
dropwise at 0°C to aqueous KOH (1.25 M, 33 mL, 41
mmol). The solution was stirred at 0°C for 90 min and
acidified at this temperature by addition of aqueous
H2SO4 (4.3 M, 10 mL, 43 mmol). The aqueous phase
was then continuously extracted with diethyl ether for 4
h. The organic layer was concentrated and distilled
under reduced pressure to give ( )-1 as a hygroscopic
white solid (2.2 g, 52%) (Teb 75–80°C/17 torr). 1H
20.33 (CH3, 5b), 25.22 (CH3, 5b), 25.53 (CH3, 5a),
1
72.09, 72.42, 72.64, 73.05, 79.55, 79.78, 80.94 (d, JCF
=
264.5 Hz, CFHBr), 104.77, 118.56, 118.64, 118.81,
119.50, 119.75, 133.34, 133.61, 134.06, 156.63, 165.06
NMR (CDCl3) l 6.64 (1H, d, J=50.6 Hz, CHF), 5–7.5
1
(broad, OH). 13C NMR (CDCl3) l 79.61 (d, JCF
=
F
2
2
263.5 Hz, CFHBr), 170.43 (d, 2JCF=26.4 Hz, CꢁO). 19
(d, JCF=26.5 Hz, CꢁO, 5a), 165.34 (d, JCF=27.1 Hz,
CꢁO, 5b). HR-LSIMS(+): [M+H]+ 358.00952 (calcd for
C14H14BrFNO4 358.0090).
NMR (CDCl3, CFCl3 as internal reference) l from
−150.7 to −152.7 (d, J=50.6 Hz). Due to its highly
hygroscopic character, elemental analysis and melting
point were not determined.
The opening of epoxychroman 4 with resolved samples
of acid 1 (see below) was also conducted on NMR tube
scale. A typical procedure is as follows: To a solution
of epoxychroman 4 (28.1 mg, 0.14 mmol) in benzene-d6
4.3. (3S,4R)-4-[(R,S)-Bromofluoroacetoxy]-3,4-dihydro-
6-cyano-2H-1-benzopyran-3-ol 5a and 5b
,
(0.1 mL) containing 4 A molecular sieves, was added
acid 1 (2.8 mg, 14 mmol) in benzene-d6 (0.4 mL). The
A
solution of (−)-(3S,4S)-6-cyano-2,2-dimethyl-3,4-
epoxychroman 4 (122.45 mg, 60.8 mmol) in dry ben-
NMR spectrum was recorded after 1 day.