Highly stereoselective Friedel-Crafts alkylations of unactivated benzenes by episulfonium ion cyclizations

Article abstract of DOI:10.1016/S0040-4039(01)02173-6

Intermolecular additions of highly enantiomerically enriched episulfonium ions onto activated benzene rings are known to accomplish chiral Friedel-Crafts alkylations. Unactivated benzenes are either unreactive or can give low stereoselectivities. Intramol

Full text of DOI:10.1016/S0040-4039(01)02173-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 351–353
Highly stereoselective Friedel–Crafts alkylations of unactivated
benzenes by episulfonium ion cyclizations
Bruce P. Branchaud* and Heather S. Blanchette†
Department of Chemistry, University of Oregon, Eugene, OR 97403-1253, USA
Received 8 November 2001; accepted 14 November 2001
Abstract—Intermolecular additions of highly enantiomerically enriched episulfonium ions onto activated benzene rings are known
to accomplish chiral Friedel–Crafts alkylations. Unactivated benzenes are either unreactive or can give low stereoselectivities.
Intramolecular cyclizations should be faster than intermolecular additions; thus, cyclization reactions should be able to avoid
undesired episulfonium ion racemization. The work reported here tests that hypothesis and demonstrates that cyclizations of
enantiomerically enriched episulfonium ions onto unactivated benzene rings are highly stereoselective. © 2002 Elsevier Science
Ltd. All rights reserved.
There have been numerous applications of racemic
episulfonium ions in organic synthesis.1 In the mid
1990s Toshimitsu and co-workers published a series of
papers on some reactions of highly enantiomerically
enriched episulfonium ions. Those reactions included
reactions with nitriles,2,3 sulfonamides,4,5 silyl enol
ethers6 and substituted benzene rings.7
for a successful reaction. Even though mesitylene and
m-xylene did react, the stereoselectivity of their reac-
tions varied with reaction conditions. For example, the
reaction of 1 with m-xylene 4 using BF3·OEt2 in
CH2Cl2 for 20 h at 0°C gave a 74% yield of 5 with 68%
stereospecificity8 (Scheme 1). Lowering the temperature
to −20°C gave a lower 50% yield of 5 with an improved
91% stereospecificity. Lowering the temperature to
−40°C gave a very low 9% yield of 5 with a much
improved 99% stereospecificity. The results indicate
that higher temperatures promote the partial racemiza-
tion of episulfonium ions 2, presumably by reversible
ring opening of the chiral episulfonium ions 2 to gener-
With the exception of Toshimitsu’s work, the reaction
of highly enantiomerically enriched episulfonium ions
with aromatic compounds has not been studied previ-
ously. Such stereoselective Friedel–Crafts alkylations
could be useful in asymmetric organic synthesis, faith-
fully transferring the chirality of alcohol chirality cen-
ters into new chirality centers next to an aromatic ring.
Many important natural products and synthetic com-
pounds have a chirality center next to an aromatic ring.
Well-developed technology for stereoselective Friedel–
Crafts reactions would provide a new strategy for the
synthesis of such stereocenters.
Toshimitsu’s work on stereoselective Friedel–Crafts
alkylations examined intermolecular reactions of some
simple chiral episulfonium ions with substituted ben-
zenes.7 Benzene or t-butylbenzene did not react,
whereas mesitylene, m-xylene, anisole, phenol and N,N-
dimethylaniline did react. Apparently activation by at
least two electron-donating alkyl groups is necessary
* Corresponding author. Tel.: (541) 346-4627; fax: (541) 346-4645;
e-mail: bbranch@oregon.uoregon.edu
† Present Address: Shionogi Bioresearch Corp., 45 Hartwell Avenue,
Lexington, MA 02173, USA.
Scheme 1. Toshimitsu’s stereoselective episulfonium ion inter-
molecular electrophilic aromatic substitution reactions.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02173-6

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B. P. Branchaud, H. S. Blanchette / Tetrahedron Letters 43 (2002) 351–353
ate an achiral carbocation intermediate 3 which can
recyclize to form either enantiomer of 2.
Following a literature procedure,12 5-phenyl-1-pentene
7 was prepared by the condensation of the Grignard
reagent of b-phenylethyl bromide with allyl bromide.
Following a literature procedure,13 7 was epoxidized
with meta-chloroperoxybenzoic acid. The epoxide was
treated with NaSPh in absolute EtOH for 16 h at room
temperature to produce racemic 9 in 97% isolated yield
after purification by radial chromatography.14 Treat-
ment of racemic 9 with BF3·Et2O in CH2Cl2 at 0°C
followed by warming to room temperature with stirring
for 23 h led to racemic 13 in 40% isolated yield after
purification by radial chromatography.15 This reaction
was not optimized, and proceeded in much lower yield
than that of enantiomerically enriched 9 (see below),
but it provided enough pure material to calibrate the
chiral HPLC analyses.
The problems in loss of stereoselectivity and low yields
in the examples described above can be attributed to
the intermolecular nature of the reactions. When unac-
tivated arenes are used, the episulfonium ion will have
more time to remain unreacted, and will thus have
more of an opportunity to racemize. An intramolecular
reaction should not suffer as much from this problem
since the episulfonium ion and the arene will be in close
proximity to react efficiently, thus suppressing racem-
ization. We decided to examine the stereospecificity of
the cyclization of the phenyl episulfonium ion onto
unactivated benzene rings to see if the intramolecularity
of the reaction would make it highly stereoselective.
Enantiomerically enriched hydroxysulfide 8 was pre-
pared by Sharpless asymmetric dihydroxylation of 6
using AD-mix-b, monotosylation of the resulting diol,
then reaction of the tosylate with NaSPh (Scheme 3) to
provide enantiomerically enriched 8 in 57% isolated
overall yield, after radial chromatography of 8, for
three steps from 6.10,16 Sharpless asymmetric dihydroxy-
lation of 6 using AD-mix-b has been reported to pro-
ceed in 84% enantiomeric excess (e.e.).17 We did not
determine the e.e. of the diol produced from Sharpless
asymmetric dihydroxylation of 6. Enantiomerically
enriched 8 was found to have 77% e.e. by chiral HPLC
analysis.18 Treatment of enantiomerically enriched 8
Racemic samples of hydroxysulfides 8 and 9, and
cyclization products 12 and 13 were needed to calibrate
the chiral HPLC analyses used in these studies.
Racemic hydroxysulfides 8 and 9, and cyclization prod-
ucts 12 and 13 were prepared as shown in Scheme 2.
Following a literature procedure,9 commercially avail-
able 4-phenyl-1-butene 6 was epoxidized with meta-
chloroperoxybenzoic acid. The epoxide was treated
with NaSPh (formed by the reaction of PhSSPh with
NaBH4 in absolute EtOH) for 19 h at room tempera-
ture to produce racemic 8 in 94% isolated yield after
purification by radial chromatography.10 Treatment of
racemic 8 with BF3·Et2O in CH2Cl2 at 0°C followed by
warming to room temperature with stirring for 16 h led
to racemic 12 in 63% isolated yield after purification by
radial chromatography.11
Scheme 2. Preparation of racemic standards to calibrate chi-
ral HPLC analyses.
Scheme 3. Preparation of enantiomerically enriched hydoxy-
sulfides and their episulfonium ion cyclizations.

B. P. Branchaud, H. S. Blanchette / Tetrahedron Letters 43 (2002) 351–353
353
(77% e.e.) with BF3·Et2O in CH2Cl2 at 0°C followed by
warming to room temperature with stirring for 16 h led
to enantiomerically enriched 12, in 35% isolated yield
after radial chromatography.11 Enantiomerically
enriched 12 was found to have 75% e.e. by chiral HPLC
analysis.18 Thus, this reaction proceeded with 97%
stereospecificity.8 Although this reaction proceeded in
lower yield than the racemic one, the stereospecificity
for the cyclization reaction is high.
2. Toshimitsu, A.; Hirosawa, C.; Tanimoto, S. Tetrahedron
Lett. 1991, 32, 4317–4320.
3. Toshimitsu, A.; Hirosawa, C.; Tamao, K. Tetrahedron
1994, 50, 8997–9008.
4. Toshimitsu, A.; Abe, H.; Hirosawa, C.; Tanimoto, S. J.
Chem. Soc., Chem. Commun. 1992, 284–285.
5. Toshimitsu, A.; Abe, H.; Hirosawa, C.; Tamao, K. J.
Chem. Soc., Perkin Trans. 1 1994, 3465–3471.
6. Toshimitsu, A.; Hirosawa, C.; Tanimoto, S. Chem. Lett.
1992, 239–242.
Enantiomerically enriched hydroxysulfide 9 was pre-
pared by Sharpless asymmetric dihydroxylation of 7
using AD-mix-b, monotosylation of the resulting diol,
then reaction of the tosylate with NaSPh (Scheme 3) to
provide enantiomerically enriched 9 in 12% isolated
overall yield, after radial chromatography of 9, for
three steps from 7.14 Enantiomerically enriched 9 was
found to have 76% e.e. by chiral HPLC analysis.18
Treatment of enantiomerically enriched 9 (76% e.e.)
with BF3·Et2O in CH2Cl2 at 0°C followed by warming
to room temperature with stirring for 16 h led to
enantiomerically enriched 13 in 98% isolated yield after
radial chromatography.15 Enantiomerically enriched 13
was found to have 76% e.e. by chiral HPLC analysis.18
Thus, this reaction proceeded with ꢀ100% stereospe-
cificity.8 This reaction proceeded in high chemical yield
and high stereospecificity.
7. Toshimitsu, A.; Hirosawa, C.; Tamao, K. Synlett 1996,
465–467.
8. Stereospecificity is defined in Ref. 7 as follows:
stereospecificity=[(% enantiomeric excess of product/%
enantiomeric excess of reactant)×100].
9. Elings, J. A.; Downing, R. S.; Sheldon, R. A. Eur. J. Org.
Chem. 1999, 4, 837–846.
10. Compound 8 is a known compound but has not been
previously used for episulfonium ion cyclizations. See: (a)
Hosomi, A.; Ogata, K.; Hoashi, K.; Kora, S.; Tominaga,
Y. Chem. Pharm. Bull. 1988, 36, 3736–3738; (b) Takeda,
T.; Furukawa, H.; Fujimori, M.; Suzuki, K.; Fujiwara, T.
Bull. Chem. Soc. Jpn. 1984, 57, 1863–1869.
11. Compound 12 is a known compound but has not been
prepared previously using episulfonium ion cyclizations.
See: (a) Reich, H. J.; Peake, S. L. J. Am. Chem. Soc.
1978, 100, 4888–4889; (b) Eisenbraun, E. J.; Bansal, R.
C.; Hertzler, D. V.; Duncan, W. P.; Flanagan, P. W. K.;
Manning, M. C. J. Org. Chem. 1970, 35, 1265–1271.
12. Sih, N.; Pines, H. J. Org. Chem. 1965, 30, 1462–1466.
13. Adamczyk, M.; Johnson, D. D.; Reddy, R. E. Tetra-
hedron 1999, 55, 63–88.
These results demonstrate that cyclizations of phenyl
episulfonium ions onto unactivated (or lightly acti-
vated) benzene rings can be highly stereoselective (97–
100% stereospecificity).8 Since it is easy to prepare
b-hydroxysulfides from epoxides or vicinal diols, the
results also illustrate how episulfonium ion chemistry
can be used to convert the products of contemporary
asymmetric epoxidation and dihydroxylation reactions
into more complex chiral enantiomerically enriched
products.
14. The S enantiomer of 9 is a known compound. See:
Fujisawa, T.; Itoh, T.; Nakai, M.; Sato, T. Tetrahedron
Lett. 1985, 26, 771–774.
15. Compound 13 is a new compound and was characterized
1
by H NMR, 13C NMR and IR.
16. The vicinal diol prepared by Sharpless asymmetric dihy-
droxylation of 6 using AD-mix-b is known (see Ref. 17).
The S enantiomer of the monotosylate derived from the
vicinal diol is a known compound. See: Klunder, J. M.;
Onami, T.; Sharpless, K. B. J. Org. Chem. 1989, 54,
1295–1304.
Acknowledgements
17. Wang, Z.-M.; Zhang, X.-L.; Sharpless, K. B. Tetrahedron
This work was supported by the National Science
Foundation and the Elsa U. Pardee Foundation for
Cancer Research.
Lett. 1993, 34, 2267–2270.
18. All chiral HPLC analyses for 8, 9, 12, and 13 were run
using a Chiracel OD-H column from Daicel Chemical
Industries with 10–20% i-propyl alcohol/hexanes as sol-
vent with UV–vis spectrophotometric detection of peaks.
In each case, the corresponding racemic compounds,
prepared as shown in Scheme 2, were used as calibration
standards.
References
1. Harring, S. R.; Edstrom, E. D.; Livinghouse, T. Adv.
Heterocyclic Nat. Prod. Synth. 1992, 2, 299–376.