position will leave the bromide 14 as S-configured. For the
sulfonate substrates 17, 18, 21 or 22 as activated by titanium
tetrachloride (Table 1, entries 6–9), the bromochlorides 13 and
14 are produced with essentially complete enantiospecificity.**
Thus, the mapping of the stereochemical course of the reaction
provides irrefutable evidence for the intermediacy of enantio-
pure bromonium ion B. Interestingly, when thionyl chloride
was used (Table 1, entries 4 and 5) the bromochlorides 13 and
14 are formed with reduced enantiomeric purity. From the
work of Brown et al.,24 it seems reasonable to suggest a
competing pathway for formation of BrCl by direct
attack of free chloride in solution on the bromonium ion.
Re-addition of BrCl to the resulting olefin occurs without
control of absolute stereochemistry and some leakage of
enantiomeric purity occurs.
3 S. Winstein and H. J. Lucas, J. Am. Chem. Soc., 1939, 61,
2845–2848.
4 (a) G. A. Olah, J. M. Bollinger and J. Brinich, J. Am. Chem. Soc.,
1968, 90, 2587–2594; (b) G. A. Olah and J. M. Bollinger, J. Am.
Chem. Soc., 1968, 90, 6082–6086.
5 J. Strating, J. H. Wieringa and H. Wynberg, J. Chem. Soc., Chem.
Commun., 1969, 907–908.
6 (a) H. Slebocka-Tilk, R. G. Ball and R. S. Brown, J. Am. Chem.
Soc., 1985, 107, 4504–4508; (b) A. J. Bennet, R. S. Brown, R. E.
D. McClung, M. Klobukowski, G. H. M. Aarts, B. D. Santarsiero,
G. Bellucci and R. Bianchini, J. Am. Chem. Soc., 1991, 113,
8532–8535; (c) R. S. Brown, R. W. Nagorski, A. J. Bennet, R. E.
D. McClung, G. H. M. Aarts, M. Klobukowski, R. McDonald and
B. D. Santarsiero, J. Am. Chem. Soc., 1994, 116, 2448–2456.
7 R. S. Brown, Acc. Chem. Res., 1997, 30, 131–137, and references
cited therein.
8 R. E. Buckles and J. E. Maurer, J. Org. Chem., 1953, 18,
1585–1590.
9 R. E. Buckles and J. W. Long, J. Am. Chem. Soc., 1951, 73,
998–1000.
10 (a) For chlorine: N. M. Sergeyev, N. D. Sergeyeva and
W. T. Raynes, J. Magn. Reson, Ser. A, 1995, 115, 174–182;
(b) For bromine: W. T. Raynes, N. M. Sergeyev, P. Sandor and
M. Grayson, Magn. Reson. Chem., 1997, 35, 141–143.
11 For the NGP participation of bromine in 2-cyclohexyl benzene-
sulfonates see: E. Grunwald, J. Am. Chem. Soc., 1951, 73,
5458–5459.
12 H. Sharghi and M. M. Eskandari, Synthesis, 2002, 1519–1522.
13 The racemic compounds are both known: A. Soladie-Cavallo,
´
P. Lupattelli and C. Bonini, J. Org. Chem., 2005, 70, 1605–1611.
14 M.-F. Ruasse, G. Lo Moro, B. Galland, R. Bianchini, C. Chiappe
and G. Bellucci, J. Am. Chem. Soc., 1997, 119, 12492–12502 and
references cited therein.
In conclusion, we have shown that enantiopure bromo-
hydrins can be used to generate enantiopure bromonium ions.
These may be trapped with a nucleophile to provide enantio-
merically pure bromine containing products. Since the bro-
monium ion precursors are generated from readily available
enantiopure epoxides, these results open the door for the use
of enantiopure bromonium ions in asymmetric synthesis. We
regard this as a significant advance in the use of bromonium
ions in synthetic organic chemistry.
We thank the EPSRC and GlaxoSmithKline for a Industrial
CASE award (to J.M.R.), and the EPSRC for further financial
support (EPSRC Grant no. EP/E058272/1).
15 S. E. Schaus, B. D. Brandes, J. F. Larrow, M. Tokunaga,
K. B. Hansen, A. E. Gould, M. E. Furrow and E. N. Jacobsen,
J. Am. Chem. Soc., 2002, 124, 1307–1315.
16 P. S. Savle, M. J. Lamoreaux, J. F. Berry and R. D. Gandour,
Tetrahedron: Asymmetry, 1998, 9, 1843–1846.
Notes and references
z The exact structure of a ‘‘bromonium ion’’ of a styrene depends
strongly on any substituents and on the solvent, and it is understood
that a spectrum of ionic intermediates are possible, of which the cyclic
bromonium ion and the open b-bromocarbocation are the extremes.
See ref. 1a and 1b.
y The enantiomeric purity was assayed by Mosher ester formation and
comparison with the Mosher ester of the racemic halohydrin prepared
in identical fashion from racemic epoxide (see ESIw).
z The enantiomeric purity was assayed by chiral HPLC methods by
reference to a racemic sample (see ESIw).
8 A racemic sample of the major diastereomer 11 proved to be
crystalline and the relative stereochemistry was confirmed by X-ray
crystallography. Both diastereoisomers showed characteristic benzyl
chloride fragments in their MS allowing the minor diastereoisomer to
be assigned as 12 (see ESIw).
17 The racemic compounds are both known: G. Cerichelli, C. Grande,
L. Luchetti and G. Mancini, J. Org. Chem., 1991, 56, 3025–3030.
18 A bromohydrin of unspecified stereochemistry has been converted
into a bromochloride of unspecified stereochemistry using Viehe’s
salt in a synthesis of halomon, where a bromonium ion was
implicated to account for bromine migration: T. Schlama,
R. Baati, V. Gouverneur, Valleix, J. R. Falck and
C. Mioskowski, Angew. Chem., Int. Ed., 1998, 37, 2085–2087.
19 S. D. Lepore, A. K. Bhunia and P. Cohn, J. Org. Chem., 2005, 70,
8117–8121.
20 The treatment of a Lepore sulfonate with titanium tetrachloride
has been reported to give the alkyl chloride with retention of
configuration: S. D. Lepore, A. K. Bhunia, D. Mondal, P. C. Cohn
and C. Lefkowitz, J. Org. Chem., 2006, 71, 3285–3286.
21 The racemic compounds are both known: C. E. Garrett and
G. C. Fu, J. Org. Chem., 1997, 62, 4534–4535.
22 R. Appel, Angew. Chem., Int. Ed. Engl., 1975, 14, 801–811.
23 The racemic compounds are both known: G. Heasley,
J. M. Bundy, V. L. Heasley, S. Arnold, A. Gipe, D. McKee,
R. Orr, S. L. Rodgers and D. F. Shellhamer, J. Org. Chem., 1978,
43, 2793–2799.
24 C. Y. Zheng, H. Slebocka-Tilk, R. W. Nagorski, L. Alvarado and
R. S. Brown, J. Org. Chem., 1993, 58, 2122–2127, and references
cited therein.
** The %ee was calculated on the basis of known specific rotations for
enantiomerically pure S-13 ([a]D ꢂ29) and S-14 ([a]D ꢂ32). Since a
mixture of R-13 and S-14 are obtained, the %ee can be calculated by
[optical rotation of mixture/(0.01 ꢃ ((%13 ꢃ 29) + (%14 ꢃ ꢂ32)))]
(see ESIw).
1 (a) K. Yates and R. S. McDonald, J. Org. Chem., 1973, 38(7),
2465–2478; (b) M.-F. Ruasse, Acc. Chem. Res., 1990, 23, 87–93.
2 I. Roberts and G. E. Kimball, J. Am. Chem. Soc., 1937, 59,
947–948.
ꢁc
This journal is The Royal Society of Chemistry 2009
1084 | Chem. Commun., 2009, 1082–1084