R. Rajagopal et al. / Tetrahedron Letters 44 (2003) 1815–1817
1817
aprotic solvents commonly used in NBS bromination.
This results in greater polarization of the NꢀBr bond in
the IL to generate the bromo cation leading to the
observed enhanced reactivity. The inherent Brønsted
and Lewis acidities of ring protons H2, H4 and H5 in
the imidazolium cation in [bbim]BF4 may have con-
tributed to the observed enhanced polarization of NBS
in the IL. Previous studies involving multi-nuclear
NMR spectroscopy and conductivity measurements for
imidazolium ions correlating their acidity characteris-
tics substantiate the above observations.17–19 Further
evidence came when we conducted the bromination of
anisole with NBS in the IL, N-n-octylpyridinium tetra-
fluoroborate which does not exhibit such acidity char-
acteristics. Indeed this reaction was quite sluggish
taking 5 h at 30°C as compared to 5 min in [bbim]BF4
for complete conversion.
H. J.; van Erden, J.; Harkema, S.; Reinboudt, D. N. J. Org.
Chem. 1988, 53, 374–382; (c) Gnaim, J. M.; Keehn, P. M.;
Green, B. S. Tetrahedron Lett. 1992, 33, 2883–2886.
12. Carreno, M. C.; Garcia Ruano, J. L.; Sans, G.; Toledo, M.
A.; Urbano, A. J. Org. Chem. 1995, 60, 5328–5331.
13. (a) Welton, T. Chem. Rev. 1999, 99, 2071–2083; (b)
Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. Engl.
2000, 39, 3772–3789; (c) Earle, M. J.; Seddon, K. R. Pure
Appl. Chem. 2000, 72, 1391–1398; (d) Charles, G. M. Appl.
Catal. A: Gen. 2001, 222, 101–117; (e) Sheldon, R. Chem.
Commun. 2001, 2399–2407.
14. (a) Deshmukh, R. R.; Rajagopal, R.; Srinivasan, K. V.
Chem. Commun. 2001, 1544–1545; (b) Rajagopal, R.;
Jarikote, D. V.; Srinivasan, K. V. Chem. Commun. 2002,
616–617.
15. Bromination of aromatics: To a stirred solution of the
aromatic substrate (0.018 mol) in [bbim]BF4 (4 g) [the IL
prepared as per the method reported by us14] at 28°C, NBS
(0.018 mol) was added in one portion when the temperature
rose to ꢀ35°C. A clear solution resulted immediately. The
reaction was monitored by TLC and complete conversions
were achieved after 5 min for most of the substrates. At
this stage, the reaction mixture turned turbid due to the
precipitation of succinimide. The mixture was extracted
with ether (3×10 ml) when all the products were extracted
into it leaving behind a slurry of succinimide in IL. The
ether layer was separated, washed with water, brine, dried
over sodium sulphate and solvent evaporated to furnish the
products which were further purified by chromatography
through a column of silica gel (60–120 mesh) or by
distillation under reduced pressure.
In conclusion, we have developed an efficient new
method for the regioselective monobromination of aro-
matic substrates using NBS in a room temperature
ionic liquid [bbim]BF4 in very short reaction times. The
considerably enhanced reactivity even in the absence of
an acid catalyst has been explained on the basis of
increased polarization of NBS in the IL based on the
evidence of 13C NMR chemical shifts. The high reac-
tion rates with excellent regioselectivities makes this
methodology a valuable tool for combinatorial chem-
istry to generate dynamic combinatorial libraries of
bromo compounds of importance. It has also been
demonstrated that the process is amenable to scale up.
The remaining mixture of IL with succinimide was diluted
with ethyl acetate and filtered to recover succinimide. The
filtrate consisting of the IL in ethyl acetate was subjected
to distillation under reduced pressure to remove ethyl
acetate. The recovered IL was pure enough for at least two
recycles.
Acknowledgements
R.R. thanks CSIR, New Delhi for a research associate-
ship. The authors acknowledge financial assistance
from Department of Science and Technology, New
Delhi, vide Project No. SP/S5/OC-23/02.
16. Scaled up batch operation with controlled addition of NBS:
To a stirred solution of anisole (25 g, 0.23 mol) in
[bbim]BF4 (50 g) at 28°C, NBS (41.25 g, 0.23 mol) was
introduced in small portions slowly over 30 min in such a
way as to maintain the temperature of the reaction at
30 2°C. After the complete addition, the mixture was
stirred further for 15 min at 30°C. The completion of the
reaction was monitored by GC. The reaction mixture was
subjected to distillation under reduced pressure when
4-bromoanisole distilled out at 90°C/8 mmHg in 98% yield.
The distillation residue was diluted with ethyl acetate (100
ml) and the thin slurry was filtered to remove succinimide.
The filtrate was subjected to distillation under reduced
pressure to remove ethyl acetate and to recover the IL
completely. The recovered IL could be recycled four times
for the bromination of anisole successfully.
17. Avent, A. G.; Chaloner, P. A.; Day, M. P.; Seddon, K. R.;
Welton, T. J. Chem. Soc., Dalton Trans. 1994, 3405–3413.
18. Howarth, J.; Hanlon, K.; Fayne, D.; McCormac, P.
Tetrahedron Lett. 1997, 38, 3097–3100.
19. (a) Arduengo, A. J.; Harlow, R. L.; Kline, M. J. Am. Chem.
Soc. 1991, 113, 361–363; (b) Arduengo, A. J.; Dias, H. V.
R.; Harlow, R. L.; Kline, R. L. J. Am. Chem. Soc. 1992,
114, 5530–5534.
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