Promoting or preventing haloaryllithium isomerizations: Differential basicities and solvent effects as the crucial variables

Article abstract of DOI:10.1055/s-2005-861787

Deprotonation-triggered heavy halogen migrations should become a favorite tool in arene synthesis if their occurrence and outcome could be made predictable. Particularly attractive, though extremely rare, are stop-and-go situations where a first intermediate, generated by metalation, can be trapped at -100 °C, whereas at -75 °C halogen migration gives rise to an isomer. As shown now, one can conveniently produce the initial aryllithium species by halogen/metal interconversion in toluene at -100 °C, under conditions that preclude, halogen migration, and unleash the isomerization process by adding tetrahydrofuran at -75 °C.

Full text of DOI:10.1055/s-2005-861787

PAPER
617
Promoting or Preventing Haloaryllithium Isomerizations:
Differential Basicities and Solvent Effects as the Crucial Variables
Haloaryllithium
I
h
somerization
r
s
istophe Heiss, Thierry Rausis, Manfred Schlosser*
Institute of Chemistry and Molecular Sciences, Ecole Polytechnique Fédérale, BCh, 1015 Lausanne, Switzerland
E-mail: manfred.schlosser@epfl.ch
Received 8 October 2004
The stop-and-go situation encountered is both intriguing
and practically useful. The initial metalation product can
be trapped at low temperature whereas at higher tempera-
ture a migration process is unleashed affording an isomer-
Abstract: Deprotonation-triggered heavy halogen migrations
should become a favorite tool in arene synthesis if their occurrence
and outcome could be made predictable. Particularly attractive,
though extremely rare, are stop-and-go situations where a first inter-
mediate, generated by metalation, can be trapped at –100 °C, ic species. However, despite a wealth of pertinent data,5a
whereas at –75 °C halogen migration gives rise to an isomer. As
no consistent picture correlating the ease of molecular re-
shown now, one can conveniently produce the initial aryllithium
organization with structural features and other parameters
species by halogen/metal interconversion in toluene at –100 °C, un-
has yet emerged. In other words, all progress made so far
der conditions that preclude halogen migration, and unleash the
was achieved on a merely empirical basis. The present
isomerization process by adding tetrahydrofuran at –75 °C.
systematic study was undertaken in order to gain insight.
Key words: basicity, halogen/metal permutation, isomerizations,
We decided first to probe how the success of the isomer-
ization depends on the nature of the migrating halogen.
On the basis of the assumed mechanism,3–5a iodine should
outperform bromine whereas chlorine should prove more
or less immovable. This was indeed found to be the case.
2-Chloro-1,3-difluorobenzene could be easily de-
protonated6 with LiTMP at –75 °C to afford, after carbox-
ylation and neutralization, 3-chloro-2,4-difluorobenzoic
acid7 (3; 90%) (Scheme 2).
organometallic intermediates, solvent effects
Basicity gradient-controlled halogen migration has re-
vealed itself as a powerful tool to implement regioflexibil-
ity in the functionalization of arenes and heterocycles.1,2
Using 2-bromobenzotrifluoride as the substrate, an ideal
model case was uncovered.3 The treatment with lithium
2,2,6,6-tetramethylpiperidide (LiTMP) in tetrahydrofuran
for two hours at –100 °C promoted the deprotonation of
the bromine-adjacent position. The organolithium inter-
mediate thus generated could be trapped with carbon di-
oxide to afford the 2-bromo-3-(trifluoromethyl)benzoic
acid (1) in 48% yield3 (Scheme 1). However, the isomeric
2-bromo-6-(trifluoromethyl)benzoic acid (2) was formed
in 71% yield when the solution containing the lithiation
product was left for two hours at –75 °C before being
carboxylated3 (Scheme 1). According to all available evi-
dence, the conversion of the first into the second, less ba-
sic, species is mediated by a halogen/metal permutation
Li
COOH
F
X
F
X
F
LDA or
LTMP
(1) CO2 (2) HCl
X = Cl –75 °C
X = Cl
X = H
3:
4:
X
F
F
F
X
X = Br or I
–125 °C
X
X = Br
5:
F
F
6: X = I
(1) CO2 (2) HCl
Li
COOH
F
F
process involving catalytic amounts of 2,3-dibromoben- Scheme 2 No isomerization of 3-chloro-2,4-difluorophenyllithium;
zotrifluoride as a self-restoring turntable.3–5a
facile halogen migration in the case of the 3-bromo and 3-iodo ana-
logs.
CF3
CF3
CF3
Br
Br
Li
Br
LTMP
(1) CO2
(2) HCl
On the other hand, the lithiated 2-bromo-1,3-difluoroben-
zene and, a fortiori, 1,3-difluoro-2-iodobenzene isomer-
ized even at –125 °C to afford, upon carboxylation
followed by neutralization, 3-bromo-2,6-difluorobenzoic
acid (5; 42%) and 2,6-difluoro-3-iodobenzoic acid (6;
47%; the latter along with 40% of the reduction product
2,6-difluorobenzoic acid), respectively (Scheme 2). The
migration-triggering deprotonation had been accom-
plished with the mixture (‘Faigl mix’8) of LiTMP,
N,N,N¢,N¢¢,N¢¢-pentamethyldiethylenetriamine (PMDTA)
and potassium tert-butoxide in tetrahydrofuran at –125 °C
for 15 min. Even under those conditions, no trace (<0.5%)
of an isomer representing the substituent pattern before
halogen migration, such as the 3-bromo-2,4-difluoroben-
1
–100 °C
COOH
–75 °C
CF3
CF3
CF3
Br
Br
Li
COOH
Br
(1) CO2
(2) HCl
2
Br
Scheme 1 The stop-and-go migration of bromine after deprotona-
tion of 2-bromobenzotrifluoride at the 3-position.
SYNTHESIS 2005, No. 4, pp 0617–0621
Advanced online publication: 18.01.2005
DOI: 10.1055/s-2005-861787; Art ID: T11504SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
5

618
C. Heiss et al.
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zoic acid, was detected by gas chromatography using two proton abstraction was accompanied by a reductive
capillary columns of different polarity.
elimination12 of bromine, setting free 2-fluoro-3-(triethyl-
silyl)phenyllithium as a minor by-product which was
transformed to 2-fluoro-3-(triethylsilyl)benzoic acid (9;
11%) upon carboxylation (Scheme 3).
The catalytic hydrogenation of 3-chloro-2,4-difluoroben-
zoic acid (3) or its treatment with zinc powder in alkaline
medium9,10 provided 2,4-difluorobenzoic acid (4; 91%,
Scheme 2) whereas the analogous reduction of 3-bromo- At this point, we realized that the discovery of the stop-
2,6-difluorobenzoic acid (5) gave 2,6-difluorobenzoic and-go isomerization of 2-bromo-3-(trifluoromethyl)phe-
acid (93%). Thus, depending on whether or not heavy nyllithium to 2-bromo-6-(trifluoromethyl)phenyllithium
halogen migration had occurred, either one of the two iso- was a lucky strike. The temperature dependence of the
mers was obtained as the final product and hence the ulti- heavy halogen migration is exceptional and is linked to
mate goal of the stop-and-go procedure was attained. We the special electronic features of the trifluoromethyl
have nevertheless abandoned the element control of basic- group. This substituent does not only exert a powerful in-
ity-gradient driven heavy halogen migrations as an inele- ductive electron-withdrawing effect on its immediate vi-
gant and not sufficiently versatile option.
cinity but its capacity to stabilize an electron excess
diminishes little with distance.13–15 Thus, guiding a lithi-
um atom from a meta to an ortho position of a CF3 group
provides little driving force, hardly more than 2 kcal/mol.
This increases the activation barrier, which can no longer
be crossed efficiently at –100 °C, but only at –75 °C.
The isomerization of 3-bromo-2,4-difluorophenyllithium
to 3-bromo-2,6-difluoro-phenyllithium formally corre-
sponds to the moving of a fluorine atom from the para to
an ortho position with respect to the lithiated center. If in
accordance with our rule-of-thumb,5b the basicity differ-
ence between two aryllithiums mirrors the basicity differ- However, there should exist a second option to set the
ence found at the level of the corresponding free (‘naked’) stage for more stop-and-go isomerizations. The key step
benzenide ions11 to the extent of 40%, this represents a of the basicity gradient-driven halogen migration is a per-
driving force of roughly 3.4 kcal/mol. This number mutation halogen/metal interconversion. Like any other
shrinks to 2.5 kcal/mol when the fluorine is formally polar organometallic reaction it proceeds sluggishly in hy-
moved from a meta to an ortho position. The gain in ener- drocarbon media and is accelerated to the extent of many
gy is still big enough to fuel the isomerization of 2-bromo- powers of ten when performed in diethyl ether or even
3-fluoro-4-(triethylsilyl)phenyllithium to 6-bromo-2- much more in tetrahydrofuran. 2-Bromo-3-fluorophenyl-
fluoro-3-(triethylsilyl)phenyllithium, the process being lithium, when generated from 2-bromo-1-fluoro-3-iodo-
instantaneous not only at –75 °C, but also at –100 ° C. Af- benzene with butyllithium in toluene at –100 °C was
ter carboxylation, the isolated 6-bromo-2-fluoro-3-(trieth- perfectly stable as evidenced by its clean conversion into
ylsilyl)benzoic acid (7; 64%) was found (again by 2-bromo-3-fluorobenzoic acid (10; 84%) (Scheme 4). In
capillary gas chromatography) to be contaminated not contrast, exclusively the isomeric 2-bromo-6-fluoroben-
even by trace amounts of the isomeric 2-bromo-2-fluoro- zoic acid (11; 58%) was obtained when the same reaction
4-(triethylsilyl)benzoic acid (8) (Scheme 3).
was carried out in tetrahydrofuran. The halogen migration
proved to be slow at –75 °C in neat toluene and was
speeded up considerably upon the addition of a stoichio-
metric amount of N,N,N¢,N¢-tetramethylethylenediamine
(TMEDA), the half-lives of isomerization approximating
four hours and five minutes, respectively (Scheme 4).
Li
COOH
F
(1) CO2
9
8
7
(2) HCl
F
Si(C2H5)3
Si(C2H5)3
Li
COOH
Br
Li
COOH
Br
I
Br
Br
Br
F
Br
F
LTMP
LiC4H9
(1) CO2
(2) HCl
10
–75 °C or
–100 °C
Toluene, –100 °C
F
F
F
F
Si(C2H5)3
Si(C2H5)3
Si(C2H5)3
THF or
TMEDA
–75 °C
Br
Br
Li
F
COOH
F
Br
Li
Br
(1) CO2
(2) HCl
COOH
11
(1) CO2
(2) HCl
F
F
Scheme 4 Generation of 2-bromo-3-fluorophenyllithium by halo-
gen/metal permutation in toluene at –100 °C and its isomerization to
2-bromo-6-fluorophenyllithium upon addition of tetrahydrofuran or a
complexing ligand.
Si(C2H5)3
Si(C2H5)3
Scheme 3 Instantaneous isomerization of 2-bromo-3-fluoro-4-(tri-
methylsilyl)phenyllithium to 6-bromo-2-fluoro-3-(trimethylsi-
lyl)phenyllithium by countercurrent dislocation of bromine and
lithium.
The generation of the first organometallic intermediate by
an iodine/lithium rather than hydrogen/lithium permuta-
tion represents a reliable and generally applicable solu-
tion to our stop-and-go problem. This claim is based on a
systematic study of all parameters affecting the rate and
The organometallic precursor was generated from (3-bro-
mo-2-fluorophenyl)triethylsilane by treatment with
LiTMP at –75 °C or with the ‘Faigl mix’8 at –100 °C. This
Synthesis 2005, No. 4, 617–621 © Thieme Stuttgart · New York

PAPER
Haloaryllithium Isomerizations
619
cooled in a dry ice/MeOH bath. After 45 min at –75 °C, the reaction
mixture was treated with chlorotriethylsilane (17 mL, 15 g, 0.10
mol). Upon distillation, a colorless oil was collected; bp 42–45 °C/
1 mmHg; yield: 19.1 g (91%); nD20 1.4842; d420 0.997.
1H NMR: d = 7.38 (ddd, J = 7.7, 5.4, 1.7 Hz, 1 H), 7.33 (m, 1 H),
7.12 (tt, J = 7.4, 1.0 Hz, 1 H), 6.98 (t, J = 8.6 Hz, 1 H), 1.0 (m, 9 H),
0.8 (m, 6 H).
outcome of permutational halogen/metal interconver-
sions.16Any arene-bound iodine atom can be readily re-
placed by lithium even at –100 °C in toluene using
butyllithium. The bromine/lithium permutation, which is
the key step for any ensuing bromine migration, requires
more polar media (such as tetrahydrofuran at –100 °C or
diethyl ether at –75 °C) to gain impetus.16 Thus, the sol-
vent control of the migration can be exerted rigorously.
On the other hand, there is no risk of aryne formation at
–75 °C as electronegatively substituted 2-bromoaryllithi-
ums are amazingly stable at this temperature.3,4,15
13C NMR: d = 167.6 (d, J = 241 Hz), 136.0 (d, J = 12 Hz), 131.1 (d,
J = 8 Hz), 128.4 (s), 123.1 (d, J = 31 Hz), 7.3 (s), 3.5 (d, J = 1.4 Hz).
Anal. Calcd for C12H19FSi (210.37): C, 68.51; H, 9.10. Found: C,
68.51; H, 9.22.
(3-Bromo-2-fluorophenyl)triethylsilane
Starting from (2-fluorophenyl)triethylsilane (16 mL, 16 g, 75
mmol), the reaction was conducted as described in the preceding
paragraph but chlorotriethylsilane was replaced by Br2 (3.9 mL, 12
g, 75 mmol); colorless oil; bp 79–81 °C/0.8 mmHg; yield: 19.3 g
(89%); nD20 1.4848; d420 1.289.
Laboratory routine and abbreviations have been specified in previ-
ous publications.17,18 1H and (1H decoupled) 13C NMR spectra were
recorded at 400 and 101 MHz, respectively. The solvent was CDCl3
or, if marked with an asterisk, perdeuteroacetone.
1H NMR: d = 7.54 (td, J = 7.5, 1.8 Hz, 1 H), 7.29 (ddd, J = 7.4, 6.2,
2.6 Hz, 1 H), 7.00 (t, J = 7.5 Hz, 1 H), 1.0 (m, 9 H), 0.9 (m, 6 H).
13C NMR: d = 162.6 (d, J = 241 Hz), 134.9 (d, J = 11 Hz), 134.6 (s),
125.3 (d, J = 34 Hz), 125.2 (d, J = 2 Hz), 107.3 (d, J = 25 Hz).
1. 1,3-Difluoro-2-halobenzene Series
2-Chloro-1,3-difluorobenzene
Difluorobenzene (8.7 mL, 11 g, 0.10 mol) was added to a solution
of BuLi (0.10 mol) in hexanes (0.10 L) and THF (140 mL) cooled
in a dry ice/MeOH bath. After 45 min at –75 °C, the reaction mix-
ture was treated with 1,1,2-trichloro-1,2,2-trifluoroethane (12 mL,
19 g, 0.10 mol). After again 45 min at –75 °C, distillation afforded
Anal. Calcd for C12H18BrFSi (289.26): C, 49.83; H, 6.27. Found: C,
49.58; H, 6.06.
a colorless oil; bp 126–131 °C (Lit.19 bp 132 °C); nD20 1.4787; d4
20
2-Bromo-6-fluoro-5-(triethylsilyl)benzoic Acid (7)
1.360; yield: 11.4 g (74%).
2,2,6,6-Tetramethylpiperidine and (3-bromo-2-fluorophenyl)trieth-
ylsilane (7.2 g, 25 mmol) were consecutively added to a solution of
BuLi (25 mmol) in hexanes (15 mL) and THF (35 mL) kept in a dry
ice/MeOH bath. After 2 h at –75 °C, the reaction mixture was
poured onto an excess of freshly crushed dry ice. It was acidified
with aq 2 M HCl and extracted with Et2O (3 × 25 mL). One tenth of
the combined organic layers was treated with an ethereal solution of
diazomethane until the yellow color persisted. According to GC (30
m, DB-WAX, 150 °C; 30 m, DB-1, 150 °C; pentadecane as an in-
ternal calibrated standard), the crude mixture contained the acids 7
and 9 in a 78% and 11% yield respectively. The rest of the organic
phase was evaporated and the residue recrystallized to afford pure
acid 7; colorless needles from hexanes; yield: 5.33 g (64%), mp 74–
76 °C.
3-Chloro-2,4-difluorobenzoic Acid (3)
2,2,6,6-Tetramethylpiperidine (8.5 mL, 7.0 g, 50 mmol) and 1-chlo-
ro-2,6-difluorobenzene (7.4 g, 50 mmol) were added consecutively
to a solution of BuLi (50 mmol) in hexanes (23 mL) and THF (75
mL) cooled in a dry ice/MeOH bath. After 2 h at –75 °C, the reac-
tion mixture was poured onto freshly crushed dry ice before acidifi-
cation with an ethereal solution of HCl (0.10 mol). After
evaporation of the volatiles, the acid 3-chloro-2,4-difluorobenzoic
was extracted with boiling EtOAc (3 × 50 mL). Evaporation and
crystallization (from hexanes) afforded colorless needles; mp 167–
169 °C (Lit.7 mp 169–171 °C); yield: 8.70 g (90%).
1H NMR: d = 7.99 (m, 1 H), 7.07 (m, 1 H).
1H NMR: d = 7.41 (d, J = 7.9 Hz, 1 H), 7.32 (dd, J = 7.6, 2.4 Hz, 1
H), 1.0 (m, 9 H), 0.9 (m, 6 H).
2,4-Difluorobenzoic Acid (4)
3-Chloro-2,4-difluorobenzoic acid (2.9 g, 15 mmol) and elemental
zinc (4.8 g, 75 mmol) were refluxed for 2 h in an aq 10% NaOH so-
lution (15 mL). The reaction mixture was acidified with aq 2 M HCl
(20 mL) and extracted with Et2O (3 × 10 mL). The combined or-
ganic layers were dried and evaporated. Crystallization from hex-
anes afforded colorless needles; mp 187–189 °C (Lit.20,21 mp 186–
189 °C); yield: 2.16 g (91%).
13C NMR: d = 165.7 (d, J = 250 Hz), 157.0 (s), 136.8 (d, J = 4 Hz),
131.5 (s), 128.0 (d, J = 21 Hz), 119.3 (d, J = 5 Hz), 109.8 (d, J = 21
Hz).
Anal. Calcd for C13H18BrFO2Si (333.23): C, 46.85; H, 5.44. Found:
C, 46.83; H, 5.41.
2-Bromo-6-fluoro-5-(triethylsilyl)benzoic Acid Methyl Ester
The acid 7 (2.6 mL, 3.3 g, 10 mmol) was treated with an excess of
diazomethane. Immediate distillation gave a colorless oil; yield:
3.01 g (90%); bp 98–100 °C/0.8 mmHg; nD20 1.5207; d420 1.370.
1H NMR: d = 7.36 (d, J = 7.9 Hz, 1 H), 7.28 (dd, J = 7.7, 4.4 Hz, 1
H), 3.97 (s, 3 H), 1.0 (m, 9 H), 0.9 (m, 6 H).
13C NMR: d = 164.3 (s), 163.2 (d, J = 250 Hz), 137.5 (d, J = 13 Hz),
127.9 (d, J = 3.5 Hz), 123.5 (d, J = 25 Hz), 123.2 (d, J = 32 Hz),
121.0 (d, J = 4.5 Hz), 52.4 (s, 3 H), 6.9 (s), 2.9 (d, J = 1.4 Hz).
3-Bromo-2,6-difluorobenzoic Acid (5)21
Isolated in 92% yield when the commercial 2-bromo-1,3-difluo-
robenzene was subjected to the same protocol as the one applied to
the preparation of acid 3 (see above); mp 140–141 °C.
2,6-Difluoro-3-iodobenzoic Acid (6)22
Obtained analogously as described above for 3-chloro-2,6-difluo-
robenzoic acid from 1,3-difluoro-2-iodobenzene (24 g, 0.10 mol);
yield: 7.0 g (48%); mp 137–139 °C.
2-Fluoro-3-(triethylsilyl)benzoic Acid (9)
2. (3-Bromo-2-fluorophenyl)triethylsilane Series
(2-Fluorophenyl)triethylsilane
Obtained analogously from (2-fluorophenyl)triethylsilane (3.1 mL,
3.1 g, 15 mmol) by consecutive treatment with sec-BuLi (15 mmol)
and CO2, colorless needles from hexanes; yield: 3.05 g (81%); mp
48–50 °C.
1-Fluorobenzene (9.4 mL, 9.6 g, 0.10 mol) was added to a solution
of sec-BuLi (0.10 mol) in cyclohexane (80 mL) and THF (120 mL)
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1H NMR: d = 8.04 (td, J = 7.7, 1.9 Hz, 1 H), 7.62 (ddd, J = 7.1, 4.8,
1.9 Hz, 1 H), 7.24 (t, J = 7.7 Hz, 1 H), 1.0 (m, 9 H), 0.9 (m, 6 H).
1H NMR: d = 7.58 (dm, J = 7.7 Hz, 1 H), 7.35 (td, J = 8.0, 5.1 Hz,
1 H), 7.26 (td, J = 8.0, 1.6 Hz, 1 H), 3.95 (s, 3 H).
13C NMR: d = 170.5 (d, J = 1 Hz), 166.7 (d, J = 255 Hz), 141.9 (d,
J = 14 Hz), 133.9 (s), 125.7 (d, J = 34 Hz), 123.9 (d, J = 1 Hz),
118.9 (d, J = 4 Hz), 7.3 (s), 3.3 (d, J = 1.4 Hz).
13C NMR: d = 165.3 (d, J = 3 Hz), 159.1 (d, J = 247 Hz), 133.8 (s),
128.4 (d, J = 8 Hz), 126.3 (d, J = 4 Hz), 118.8 (d, J = 23 Hz), 108.9
(d, J = 22 Hz), 52.3 (s).
Anal. Calcd for C13H19FO2Si (254.38): C, 61.38; H, 7.53. Found: C,
60.99; H, 7.62.
Anal. Calcd for C8H6BrFO2 (233.00): C, 41.23; H, 2.60. Found: C,
41.04; H, 2.45.
2-Fluoro-3-(triethylsilyl)benzoic Acid Methyl Ester
The acid 9 (2.5 g, 10 mmol) was treated with an excess of diazo-
methane; colorless oil; bp 87–89 °C/1 mmHg; yield: 2.36 g (92%);
nD20 1.4848; d420 1.094.
1H NMR: d = 7.93 (td, J = 7.7, 2.2 Hz, 1 H), 7.55 (ddd, J = 7.4, 4.5,
2.5, 1.9 Hz, 1 H), 7.19 (t, J = 7.4 Hz, 1 H), 3.93 (s, 3 H), 1.0 (m, 9
H), 0.9 (m, 6 H).
13C NMR: d = 165.9 (d, J = 254 Hz), 162.2 (d, J = 4 Hz), 140.5 (d,
J = 14 Hz), 133.1 (s), 125.2 (d, J = 33 Hz), 123.6 (d, J = 3.5 Hz),
52.0 (s), 7.3 (s), 4.1 (d, J = 1.5 Hz).
2-Bromo-6-fluorobenzoic Acid (11)
1-Bromo-2-fluoro-6-iodobenzene (4.5 g, 15 mmol) was added to a
solution of BuLi (15 mmol) in THF (20 mL) and hexanes (10 mL)
kept at –100 °C for 15 min. The reaction mixture was then poured
onto an excess of freshly crushed dry ice and worked up as de-
scribed above for acid 10; colorless needles; yield: 1.70 g (52%),
mp 151–153 °C (Lit.7,24 mp 152–154 °C).
1H NMR: d = 7.43 (dd, J = 8.0, 0.7 Hz, 1 H), 7.31 (td, J = 8.5, 2.8
Hz, 1 H), 7.14 (t, J = 8.5 Hz, 1 H).
The same acid 11 was formed in a 89% yield when BuLi (25 mmol)
in THF (35 mL) and hexanes (15 mL) was consecutively treated
with diisopropylamine (3.5 mL, 2.5 g, 25 mmol) for 1 min and 1-
bromo-3-fluorobenzene (2.7 mL, 4.4 g, 25 mmol) for 2 h at –75 °C
before being poured onto excess dry ice.
Similar results were obtained when LiTMP in the presence of
PMDTA and t-BuOK was used at –100 °C as the metalation re-
agent.
3. 2-Bromo-1-fluoro-3-iodobenzene Series
1-Bromo-2-fluoro-6-iodobenzene
2-Bromo-6-fluorobenzoic Acid Methyl Ester
The acid 11 (3.3 g, 15 mmol) was treated with diazomethane; col-
20
orless oil; yield: 3.08 g (94%); bp 46–48 °C/0.4 mmHg; nD
Diisopropylamine (14 mL, 10 g, 0.10 mol) and 1-fluoro-3-iodoben-
zene (11 mL, 22 g, 0.10 mol) were added consecutively to a solution
of BuLi (0.10 mol) in hexanes (65 mL) and THF (0.14 L) cooled in
a dry ice/MeOH bath. After 2 h at –75 °C, the reaction mixture was
treated with 1,2-dibromo-1,1,2,2-tetrafluoroethane (31 g, 0.12
mol). Immediate distillation afforded a colorless oil which solidi-
fied on standing; bp 61–64 °C/1 mmHg; yield: 25.85 g (86%); mp
31–33 °C.
1.5234; d420 1.789.
1H NMR: d = 7.40 (dm, J = 8.3 Hz, 1 H), 7.27 (m, 1 H), 7.10 (m, 1
H), 3.98 (m, 3 H).
13C NMR: 164.0 (m), 159.3 (dm, J = 256 Hz), 131.8 (d, J = 9 Hz),
128.4 (m), 124.3 (dm, J = 20 Hz), 119.9 (m), 114.7 (dd, J = 21, 6
Hz), 52.9 (m).
Anal. Calcd for C8H6BrFO2 (233.00): C, 41.23; H, 2.60. Found: C,
41.08; H, 2.49.
1H NMR: d = 7.66 (dm, J = 8.0 Hz, 1 H), 7.10 (tm, J = 7.9 Hz, 1 H),
7.02 (td, J = 7.9 Hz, 1H).
13C NMR: d = 158.2 (d, J = 250 Hz), 135.2 (d, J = 4 Hz), 129.6 (d,
J = 10 Hz), 117.2 (d, J = 21 Hz), 115.7 (d, J = 22 Hz), 102.5 (s).
The Time Dimension of the Bromine Migration at –75 °C
1-Bromo-2-fluoro-6-iodobenzene (4.5 g, 15 mmol) was treated with
BuLi (15 mmol) in hexanes (10 mL) and toluene (15 mL) at
–100 °C as described above. Then the flask was immersed in a dry
ice/MeOH bath. Samples were withdrawn at predetermined inter-
vals and the product ratios monitored by GC (using the same condi-
tions as specified above), after converting the acids with
diazomethane into the methyl esters. The amount of 2-fluoro-6-io-
dobenzoic acid (see below) remained constant throughout the entire
period, approximating 5%. In contrast, the amount of acid 10 de-
creased progressively while that of acid 11 increased correspond-
ingly: 86% vs. 0% after 0.5 min, 81% vs. 10% after 15 min, 74% vs.
14% after 45 min, 59% vs. 32% after 180 min and 10% vs. 79% after
1500 min (24 h). The migration was found to be complete already
after 15 min at –75 °C if carried out in the presence of a stoichio-
metric quantity of TMEDA.
Anal. Calcd for C6H3BrFI (300.88): C, 23.95; H, 1.01. Found: C,
24.01; H, 0.88.
2-Bromo-3-fluorobenzoic Acid (10)
1-Bromo-2-fluoro-6-iodobenzene (4.5 g, 15 mmol) was added to a
solution of butylmagnesium chloride (15 mmol) in THF (30 mL) at
–75 °C. After 15 min at –75 °C, the reaction mixture was poured
onto freshly crushed dry ice. After acidification with an ethereal so-
lution of HCl (30 mL, 30 mmol) and evaporation of the volatiles, the
acid was extracted with boiling EtOAc (3 × 15 mL). Recrystalliza-
tion from hexanes (20 mL) gave colorless needles; yield: 2.94 g
(90%); mp 165–167 °C (Lit.23 mp 165–168 °C).
1H NMR: d = 7.83 (dt, J = 7.8, 1.5 Hz, 1 H), 7.40 (td, J = 8.5, 2.8
Hz, 1 H), 7.33 (td, J = 8.0, 1.8 Hz, 1 H).
2-Fluoro-6-iodobenzoic Acid
The same acid 10 was formed in 84% yield when 1-bromo-2-fluoro-
6-iodobenzene (4.5 g, 15 mmol) was treated with BuLi (15 mmol)
in toluene (20 mL) and hexanes (10 mL) at –100 °C for 15 min be-
fore being poured onto dry ice and neutralized. GC analysis (30 m,
DB-1, 150 °C; 30 m, DB-WAX, 150 °C) revealed the presence of
4.7% of 2-fluoro-6-iodobenzoic acid (see below) as a by-product.
When 1-bromo-2-fluoro-6-iodobenzene (4.5 g, 15 mmol) was treat-
ed at –100 °C for 15 min in hexanes (10 mL) and Et2O (20 mL),
rather than THF, 2-fluoro-6-iodobenzoic acid was obtained in a
48% yield along with 43% of acid 11. The products were identified
by GC comparison of their retention times (conditions see above)
with those of authentic samples. To this end, 2-fluoro-6-iodobenzo-
ic acid was made by adding consecutively diisopropylamine (3.5
mL, 2.5 g, 25 mmol) and 1-fluoro-3-iodobenzene (5.5 g, 25 mmol)
to BuLi (25 mmol) in hexanes (15 mL) and THF (35 mL) before
pouring the mixture, after having stored it for 2 h at –75 °C, onto dry
ice; colorless needles (from hexanes); yield: 5.72 g (86%); mp 123–
125 °C (Lit.22 mp 124–125 °C).
2-Bromo-3-fluorobenzoic Acid Methyl Ester
The acid 10 (2.2 g, 10 mmol) was dissolved in an excess of diazo-
methane at 25 °C until the yellow color persisted. Immediate distil-
lation gave a colorless oil; yield: 2.10 g (90%); bp 52–54 °C/0.5
mmHg; nD20 1.5276; d420 1.701.
Synthesis 2005, No. 4, 617–621 © Thieme Stuttgart · New York

PAPER
Haloaryllithium Isomerizations
621
1 H NMR: d = 7.59 (d, J = 7.7 Hz, 1 H), 7.06 (td, J = 8.3 Hz, 1 H),
7.00 (td, J = 8.0, 1.9 Hz, 1 H).
(6) When treated consecutively with butyllithium and carbon
dioxide in tetrahydrofuran at –75 °C, 2-chloro-1,3-
difluorobenzene is converted into the 2,6-difluorobenzoic
acid (70%).
2-Fluoro-6-iodobenzoic Acid Methyl Ester
From the acid (4.0 g, 15 mmol) with diazomethane; colorless oil; bp
(7) Bennetau, B.; Mortier, J.; Moyroud, J.; Guesnet, J.-L. J.
Chem. Soc., Perkin Trans. 1 1995, 1265.
68–70 °C/0.6 mmHg; yield: 3.92 g (93%); nD20 1.5831; d420 2.005.
(8) Faigl, F.; Marzi, E.; Schlosser, M. Chem. Eur. J. 2000, 6,
771.
(9) Tashiro, M.; Fukata, G. J. Org. Chem. 1977, 42, 835.
(10) O’Reilly, N. J.; Derwin, W. S.; Fertel, L. B.; Lin, H. C.
Synlett 1990, 609.
1H NMR: d = 7.64 (m, 1 H), 7.11 (m, 2 H), 3.98 (s, 3 H).
13C NMR: d = 164.0 (s), 158.4 (d, J = 255 Hz), 134.7 (d, J = 3 Hz),
132.2 (d, J = 8 Hz), 128.0 (d, J = 19 Hz), 115.4 (d, J = 15 Hz), 92.1
(d, J = 3 Hz).
(11) Büker, H. H.; Nibbering, N. M. M.; Espinosa, D.; Mongin,
F.; Schlosser, M. Tetrahedron Lett. 1997, 38, 8519.
(12) Mongin, F.; Marzi, E.; Schlosser, M. Eur. J. Org. Chem.
2002, 2771.
Anal. Calcd for C8H6FIO2 (280.00): C, 34.31; H, 2.16; Found: C,
34.30; H, 2.04.
Acknowledgment
(13) Kovačević, B.; Maksić, Z. B.; Primorac, M. Eur. J. Org.
Chem. 2003, 3777.
This work was financially supported by the Schweizerische Natio-
nalfonds zur Förderung der wissenschaftlichen Forschung, Bern
(grants 20-55¢303-98, 20-63¢584-00 and 20-100¢336-02).
(14) Schlosser, M.; Mongin, F.; Porwisiak, J.; Dmowski, W.;
Büker, H. H.; Nibbering, N. M. M. Chem. Eur. J. 1998, 4,
1281.
(15) Castagnetti, E.; Schlosser, M. Chem. Eur. J. 2002, 8, 799.
(16) Leroux, F.; Schlosser, M. recent results (2003) to be
published.
References
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Synthesis 2005, No. 4, 617–621 © Thieme Stuttgart · New York