LETTER
Synthesis of 2-Substituted-5-Bromobenzoic Acids
1951
(8) Halogen–metal exchange of 1,2-dibromobenzene
derivatives using alkyllithium: (a) Piette, J. L.; Renson, L.
Bull. Soc. Chim. Belg. 1970, 79, 353. (b) Hardcastle, I. R.;
Hunter, R. F.; Quayle, P. Tetrahedron Lett. 1994, 35, 3805.
(c) Schlosser, M.; Heiss, C. Eur. J. Org. Chem. 2003, 447.
(d) Halogen–metal exchange of 1,2,3-trichlorobenzene
using alkyllithium: Haiduc, I.; Gilman, H. J. Organomet.
Chem. 1968, 13, P4.
(21) An acceleration of exchange reaction using excess of
Grignard reagents: Hoffmann, R. W.; Holzer, B.; Knopff,
O.; Harms, K. Angew. Chem. Int. Ed. 2000, 39, 3072.
(22) The ratio of 94:6 corresponds to the protonated products of
A and B. The regioselectivity was confirmed by
commercially available samples of 2- and 3-bromo-
benzonitrile.
(23) Chou, T.; Chen, S.; Chen, Y. Tetrahedron 2003, 59, 9939.
(24) (a) 1,2-dibromo-3-methoxybenzene (1g) was prepared
following a modified procedure of: Shnur, R. C.; Morvilee,
M. J. Med. Chem. 1986, 29, 770. (b) Preparation of 1,2-
Dibromo-3-methoxybenzene (1g).
(9) Halogen–metal exchange of 1,2-dibromo-benzene
derivatives using isopropylmagnesium chloride:
(a) Krasovskiy, A.; Knochel, P. Angew. Chem. Int. Ed. 2004,
43, 3333. (b) Cottet, F.; Castagnetti, E.; Schlosser, M.
Synthesis 2005, 798. (c) Van der Winkel, Y.; Akkerman, O.
S.; Bickelhaupt, F. Main Group Met. Chem. 1988, 11, 91.
(10) For the preparation of 3-substituted 1,2-dibromo arene
derivatives, see: Menzel, K.; Fisher, E. L.; DiMichele, L.;
Frantz, D. E.; Nelson, T. D.; Kress, M. H. J. Org. Chem.
2006, 71, 2188.
(11) (a) Dabrowski, M.; Kubicka, J.; Lulinski, S.; Serwatowski,
J. Tetrahedron 2005, 61, 4175. (b) Hoffmann, R. W.
Dehydrobenzene and Cycloalkynes; Academic Press: New
York, 1967. (c) Wickham, P. P.; Hazen, K. H.; Guo, H.;
Jones, G.; Reuter, K. H.; Scott, W. J. J. Org. Chem. 1991, 56,
2045. (d) Wenwei, L.; Sapountzis, I.; Knochel, P. Angew.
Chem. Int. Ed. 2005, 44, 4258.
In a round-bottom flask, 1.12 mL (4.09 mmol) of a 25%
w/w solution of MeONa in MeOH was added to a solution
of 2,3-dibromo-1-fluorobenzene (500 mg, 1.97 mmol) in
MeOH (6 mL) and DMSO (10.5 mL) under nitrogen. The
solution was heated to reflux for 2 h and then allowed to cool
to 25 °C before being transferred into H2O (20 mL). The
stream was extracted three times with a total volume of 60
mL tert-butyl methyl ether. The combined organic layers
were washed with H2O (2 × 15 mL), dried over Na2SO4,
filtered and concentrated in vacuum. The remaining residue
was purified by flash column chromatography (3% EtOAc in
hexane) affording 430 mg (60%) of a colorless liquid. 1H
NMR (300 MHz, CDCl3): d = 7.25 (dd, J = 8.1, 1.4 Hz, 1 H),
7.14 (t, J = 8.1 Hz, 1 H), 6.83 (dd, J = 8.2, 1.3 Hz, 1 H), 3.90
(s, 3 H). 13C NMR (75 MHz, CDCl3): d = 157.5, 128.8,
126.3, 125.6, 114.9, 110.3, 56.6.
(12) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew.
Chem. Int. Ed. 2000, 39, 4414.
(13) Authentic samples of 3-bromo-1-chlorobenzene (2a) and 2-
bromo-1-chlorobenzene (3a) are commercially available
from Aldrich. Both 2a and 3a can be followed by HPLC and
are baseline-separated signals with different retention times.
Therefore the regioisomeric distribution of 2a and 3a could
be analyzed by integration of the corresponding signal areas.
(14) Major by-products of the halogen–metal exchange reaction
were debrominated chlorobenzene derivatives and
polyhalogenated biphenyls. The debrominated chloro arene
may be indicative of a benzyne side reaction.
(15) The decomposition was accompanied by copious amounts of
chlorobenzene and biphenyl derivatives, which can be
generated by a dehydrobenzene pathway.
(16) Significant amounts of debrominated arenes and biphenyl
derivatives had been identified by GC-MS. The impurity
profiles of theses reaction conditions and using n-BuLi were
similar.
(25) Preparation of 1,2-Dibromo-3-methylbenzene (1h).
In a Schlenk flask, a BuLi solution in hexane (1.44 M, 14.7
mL, 21.2 mmol) was diluted with THF (22 mL) under
nitrogen. The solution was cooled to –50 °C before 2,2,6,6-
tetramethylpiperidine (3.0 g, 21.2 mmol) of was added
dropwise. After 15 min the reaction mixture was cooled to
–100 °C and then charged with 1,2-dibromobenzene (2.5 g,
10.6 mmol). The reaction mixture was aged for 2 h at –100
°C before 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxa-
borolane (4.90 g, 26.3 mmol) was added. After 30 min at
–100 °C the reaction mixture was allowed to warm to 15 °C
before brine (20 mL) was added to the reaction mixture. The
organic layer was separated and the aqueous phase was
extracted two times with a total amount of 20 mL of tert-
butyl methyl ether. The combined organic layers were dried
over Na2SO4, filtered and concentrated in vacuum. The
remaining solid (3.0 g) was diluted in 5% tert-butyl methyl
ether in hexane and purified by flash column chromatog-
raphy affording 1.3 g (34%) of a white solid. 1H NMR (300
MHz, CDCl3): d = 1.42 (s, 12 H), 7.14 (t, J = 7.62 Hz, 1 H),
7.48 (dd, J = 7. 30, 1.52 Hz, 1 H), 7.66 (dd, J = 7.97, 1.60
Hz, 1 H). 13C NMR (75 MHz, CDCl3): d = 24.8, 84.6, 126.0,
127.8, 129.3, 134.4, 135.5 (C–B not seen).
(17) Reetz, M. T.; Harmat, N.; Mahrwald, R. Angew. Chem., Int.
Ed. Engl. 1992, 31, 342.
(18) It is well known that in THF the Grignard reagents tend to
form solvent-separated aggregates. In less-coordinating
solvents, like methyl-tert-butyl ether or toluene, the
Grignard reagents favor the formation of halogen-bridged
dimers. For reference, see: Parris, G. E.; Ashby, E. C. J. Am.
Chem. Soc. 1971, 93, 106.
(19) Van der Waals radius: fluoride (135 pm), chloride (175 pm),
bromide (185 pm): Iikubo, T.; Itoh, T.; Hirai, K.; Takahashi,
Y.; Kawano, M.; Ohashi, Y.; Tomioka, H. Eur. J. Org.
Chem. 2004, 3004.
(20) Similar conclusions were drawn for the regioselective
deprotonation reaction of haloarenes using LDA or LiTMP:
(a) Gorecka, J.; Heiss, C.; Scopelliti, R.; Schlosser, M. Org.
Lett. 2004, 6, 4591. (b) Pozharskii, A. F.; Ryabtsova, O. V.;
Ozeryanskii, V. A.; Degtyarev, A. V.; Kazheva, O. N.;
Alexandrov, G. G.; Dyachenko, O. A. J. Org. Chem. 2003,
68, 10109. (c) Marull, M.; Schlosser, M. Eur. J. Org. Chem.
2003, 1576. (d) Mongin, F.; Marzi, E.; Schlosser, M. Eur. J.
Org. Chem. 2001, 2771.
In a Schlenk flask, 2-(2,3-dibromophenyl)-4,4,5,5-tetra-
methyl[1,3,2]dioxaborolane (3.0 g, 8.3 mmol) was dissolved
in toluene (80 mL), EtOH (8 mL) and 2 M aq K2CO3 solution
(8 mL) under nitrogen. The biphasic reaction mixture was
charged with MeI (1.42 g, 10.0 mmol) followed by tetrakis
(triphenylphosphine)palladium (350 mg, 0.30 mmol). The
reaction mixture was heated to 80 °C for 18 h and then
cooled down to 0 °C in an ice bath The reaction mixture was
charged carefully with a 1 M aq HCl solution (20 mL). The
organic layer was separated and the aqueous phase was
extracted two times with a total amount of 30 mL of tert-
butyl methyl ether. The organic phase was dried over
MgSO4, filtered and concentrated in vacuum. The liquid
residue was purified by flash column chromatography (1%
tert-butyl methyl ether in hexane) affording 1.7 g (82%) of a
colorless liquid. 1H NMR (300 MHz, CDCl3): d = 2.47 (s,
Synlett 2006, No. 12, 1948–1952 © Thieme Stuttgart · New York