Enantioselective preparation of 4-substituted cyclohexenes by radical fragmentation of sulfoxides

Article abstract of DOI:10.1021/ol990859p

(equation presented) Radical fragmentation of o-bromophenyl sulfoxides is reported. Starting from enantiomerically pure material, 4-substituted cyclohexene derivatives have been prepared with enantiomeric excesses between 70% and 86%. The key step of the process is a diastereoselective abstraction of a hydrogen atom by the initial aryl radical. The highest enantiomeric exesses have been obtained in the presence of aluminum Lewis acids.

Full text of DOI:10.1021/ol990859p

ORGANIC
LETTERS
1999
Vol. 1, No. 6
873-875
Enantioselective Preparation of
4-Substituted Cyclohexenes by Radical
Fragmentation of Sulfoxides†
Christoph Imboden, Fe´lix Villar, and Philippe Renaud*
UniVersite´ de Fribourg, Institut de Chimie Organique, Pe´rolles,
CH-1700 Fribourg, Switzerland
philippe.renaud@unifr.ch
Received July 23, 1999
ABSTRACT
Radical fragmentation of o-bromophenyl sulfoxides is reported. Starting from enantiomerically pure material, 4-substituted cyclohexene derivatives
have been prepared with enantiomeric excesses between 70% and 86%. The key step of the process is a diastereoselective abstraction of a
hydrogen atom by the initial aryl radical. The highest enantiomeric exesses have been obtained in the presence of aluminum Lewis acids.
Recently, radical reactions have been applied to the prepara-
tion of enantiomerically enriched material.1 All of the
reported reactions were based on diastereoselective (chiral
auxiliary control) or enantioselective (catalyst or reagent
control) formation of carbon-carbon and carbon-hydrogen
bonds.2 No process involving bond breaking has been
reported. In this Letter, we report the first example of this
type: a radical fragmentation reaction of sulfoxides leading
to highly enantiomerically enriched material has been
designed. The key step of the process is a diastereoselective
hydrogen atom abstraction.
to develop an enantioselective elimination procedure of H-X
from 4-alkylcyclohexyl halides via a radical process. The
strategy is depicted in Scheme 1 and is based on the
conversion of the halide A into a sulfoxide followed by
generation of an o-aryl radical B which undergoes 1,5-
hydrogen atom translocation. The 2-sulfinylated radical C
fragments extremely rapidly to the desired alkene D.5 The
fragmentation of a 2-phenylsulfinylated radical of type C is
a fast and well documented process whose rate is ap-
proximately 10 times faster than the radical elimination of a
bromine atom and only two times slower than the elimination
of an iodine atom.6-8 The stereoselectivity control of the
The thermal syn elimination of sulfoxides is a well-known
reaction occurring at temperatures higher than 200 °C when
nonstabilized alkenes are formed.3 This reaction has been
applied in a pioneer work of Goldberg for the preparation
of 4-substituted cyclohexene.4 We were very interested in
finding a mild alternative to this process. Our intention was
Scheme 1
† Part of the Ph.D. Dissertation of Christoph Imboden, Universite´ de
Fribourg, Switzerland (Diss. Nr. 1241).
(1) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions; VCH: Weinheim, 1996.
(2) Chatgilialoglu, C.; Renaud, P. In General Aspects of Free Radical
Chemistry; Alfassi, Z. B., Ed.; Wiley: Chichester, U.K., 1999; pp 501-
538.
(3) Cram, D. J.; Kingsbury, C. A. J. Am. Chem. Soc. 1960, 82, 1810-
1819.
(4) Goldberg, S. I.; Sahli, M. S. Tetrahedron Lett. 1965, 4441-4444.
Goldberg, S. I.; Sahli, M. S. J. Org. Chem. 1967, 32, 2059-2062.
10.1021/ol990859p CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/24/1999

whole process should take place in the hydrogen atom
abstraction step.9
diastereomers was also possible by flash chromatography.
The optical purity (>99% ee) of the four sulfoxides trans-
1a, cis-1a, trans-1b, and cis-1b was determined by HPLC
on a chiral column (Daicel, Chiralcel OB-H).
To test the feasibility of the translocation-elimination
cascade, the o-bromosulfoxide 1a was prepared in racemic
form from 2-bromothiophenol by alkylation with the corre-
sponding bromide followed by oxidation with m-CPBA
(Scheme 2). The cis/trans mixture of isomers of 1a was
treated with tin hydride AIBN in refluxing benzene to give
4-phenylcyclohexene 2a in excellent yield.
Scheme 2
The cis and trans isomers of 1a and 1b were submitted
separately to classical radical tin hydride reduction conditions
according to eq 2 (slow addition of Bu3SnH over 12 h, AIBN,
300 W sun lamp, 10 °C); results are shown in Table 1, entries
1-4.
The enantiomerically pure sulfoxides 1a and 1b were
prepared from the diastereomerically pure menthyl (S)-2-
bromophenylsulfinate 3 (eq 1).10 The cis and trans isomers
were separated by flash chromatograhy. To isolate satisfac-
tory quantities of the minor cis isomer, epimerization of the
R-center was achieved by deprotonation of trans-1a with
LDA followed by protonation with 2,6-di-tert-butyl-4-
methylphenol. This procedure afforded 1a as a cis/trans 2:1
mixture of diastereomers. After flash chromatography, di-
astereomerically pure cis-1a (52%) and trans-1a (25%) were
isolated. A nonoptimized isomerization procedure was used
with trans-1b using water instead of 2,6-di-tert-butyl-4-
methylphenol for the protonation step. It afforded 1b as a
cis/trans 1:1 mixture in 80% yield. Separation of the
The expected 4-substituted cyclohexenes 2a and 2b were
isolated in 65-75% yields. Starting from the trans isomer,
the cyclohexenes 2a and 2b were nearly racemic. However,
cis-1a and cis-1b gave 2a and 2b with ee’s of 70% and 80%,
respectively. The absolute configuration the major isomer
of 2b was deduced from the comparison of the optical
rotatory power with the one reported in the literature for (R)-
2b.11 The absolute configuration of 2a was assigned by
analogy to the case to 2b. A model for the transition state
of the reaction with cis-1b supported by ab initio calculations
(UHF 6-31G*) is reported in Figure 1. The cyclohexane ring
lies in a chair conformation, and the sulfinyl group occupies
an axial position. The distance between the Car(‚) and the
abstracted hydrogen atom was set at 1.4 Å. The preferred
transition state E (∆∆Hf ) 0 kcal/mol) minimizes the steric
interactions between the oxygen atom of the sulfoxide and
the cyclohexyl group. The minor transition state F (∆∆Hf
) +2.0 kcal/mol) is destabilized by interaction of the oxygen
atom with the cyclohexyl ring.
(5) For a related hydrogen abstraction/fragmentation process involving
sulfones, see: Brown, C. D. S.; Dishington, A. P.; Shiskin, O.; Simpkins,
N. S. Synlett 1995, 943-914. Vandort, P. C.; Fuchs, P. L. J. Org. Chem.
1997, 62, 7142-7147.
(6) For mechanistical and kinetic studies, see: Wagner, P. J.; Sedon, J.
H.; Lindstrom, M.-J. J. Am. Chem. Soc. 1978, 100, 2579-2580. Synthetic
applications: Shevlin, P. B.; Boothe, T. J.; Greene, J. L.; Willcott, M. R.;
Inners, R. R.; Cornelis, A. J. Am. Chem. Soc. 1978, 100, 3874-3879. Russel,
G. A.; Tashtoush, H.; Ngoviwatchai, M. J. Am. Chem. Soc. 1984, 106,
4622-4623.
(7) For an early synthetic application of the radical fragmention of
â-sulfinylated radicals, see: Miyamato, N.; Furuoka, D.; Utimoto, K.;
Nozaki, H. Bull. Chem. Soc. Jpn. 1974, 47, 503-504. For a recent
application to the preparation of allenes, see: Delouvrie´, B.; Lacoˆte, E.;
Fensterbank, L.; Malacria, M. Tetrahedron Lett. 1999, 40, 3565-3568.
(8) For an application in asymmetric synthesis, see: (a) Malacria, M.;
Lacoˆte, E.; Delouvrie´, B.; Fensterbank, L. Angew. Chem., Int. Ed. Engl.
1998, 37, 2116-2118. For a related example based on sulfimide, see: (b)
Clark, A. J.; Rooke, S.; Sparey, T. J.; Taylor, P. C. Tetrahedron Lett. 1996,
37, 909-912.
Table 1. Radical Mediated Fragmentation of Sulfoxides 1a and
1b According to eq 2
sulfoxide
Lewis acid
product
yield [%]
ee [%]
1
2
3
4
5
6
7
trans-1a
cis-1a
trans-1b
cis-1b
cis-1a
cis-1a
none
none
none
none
MADa
MADPPb
MADPc
2a
2a
2b
2b
2a
2a
2a
75
65
70
70
60
65
57
0
70 (R)
0
80 (R)
76 (R)
84 (R)
86 (R)
(9) The diastereoselectivity of hydrogen transfer has not been investigated
in a systematic fashion. For an isolated example of diastereoselective
hydrogen transfer, see: Bogen, S.; Malacria, M. J. Am. Chem. Soc. 1996,
118, 3992-3993.
(10) Imboden, C.; Renaud, P. Tetrahedron: Asymmetry 1999, 10, 1051-
1060.
cis-1a
a MAD ) methylaluminum di(2,6-di-tert-butyl-4-methylphenoxide).
b MADPP ) methylaluminum di(2,6-diphenylphenoxide). c MADP ) meth-
ylaluminum diphenoxide.
(11) Sodozai, S. K.; Lepoivre, J. A.; Dommisse, R. A.; Alderweireldt,
F. C. Bull. Soc. Chim. Belg. 1980, 89, 637-642.
874
Org. Lett., Vol. 1, No. 6, 1999

(Table 1, entries 5-7). In the presence of methylaluminum
di(2,6-di-tert-butyl-4-methylphenoxide) () MAD),13 the
selectivity went slightly up (entry 5, 76% ee) relative to the
reaction in the absence of Lewis acid (entry 2, 70% ee).
Better results were obtained with less bulky Lewis acid such
as methylaluminum di(2,6-diphenylphenoxide) and methyl-
aluminum diphenoxide (entries 6 and 7, 84% and 86% ee)
indicating that presumably only partial complexation was
taking place with the sterically highly hindered MAD.
For comparison purposes, the thermal elimination of the
sulfoxide cis-1a and trans-1a was examined (eq 3). The cis
isomer fragmented at 200 °C and gave (S)-2a in 64% yield
and moderate enantioselectivity (54% ee). The trans isomer
gave (R)-2a in 57% yield and 44% ee.
Figure 1. Calculated transitions states (ab initio UHF 6-31g*) E
and F leading to (R)-2b (major) and (R)-2b (minor), respectively.
In conclusion, we have presented here a new way for the
elimination of sulfoxides under extremely mild conditions.
This reaction is expected to find applications for regio-,
diastereo-, and enantioselective preparation of alkenes. For
instance, we have shown that by using enantiomerically pure
4-substituted cyclohexyl sulfoxides, it is possible to prepare
enantiomerically enriched 4-substituted cyclohexenes. Further
applications to other classes of chiral alkenes such as
tropidine alkaloids are currently being investigated in our
laboratory.
According to the models E and F, complexation of the
oxygen atom of the sulfinyl group by a Lewis acid should
destabilize F relative to G due to an increase of steric
interactions between the complexed oxygen atom and the
cyclohexyl ring.12 This hypothesis was confirmed by our
experiments with methylaluminum di(aryloxide) derivatives
(12) For a recent review on the use of Lewis acids in radical reaction,
see: Renaud, P.; Gerster, M. Angew. Chem., Int. Ed. Engl. 1998, 37, 2562-
2579. For the use of Lewis acids in radical reactions involving sulfoxides,
see ref 8a and Waldner, A.; De Mesmaeker, A.; Hoffmann, P.; Mindt, T.;
Winkler, T. Synlett 1991, 101-104. Renaud, P.; Ribezzo, M. J. Am. Chem.
Soc. 1991, 113, 7803. Curran, D. P.; Kuo, L. H. J. Org. Chem. 1994, 59,
3259-3261. Renaud, P.; Bourquard, T.; Gerster, M.; Moufid, N. Angew
Chem., Int. Ed. Engl. 1994, 33, 1601-1603. Renaud, P.; Moufid, N.; Kuo,
L. H.; Curran, D. P. J. Org. Chem. 1994, 59, 3547-3552. Renaud, P.;
Bourquard, T.; Gerster, M.; Moufid, N. Angew. Chem., Int. Ed. Engl. 1994,
33, 1601-1603. Renaud, P.; Bourquard, T.; Carrupt, P.-A.; Gerster, M.
HelV. Chim. Acta 1998, 81, 1048-1063. Toru, T.; Watanabe, Y.; Tsusaka,
M.; Ueno, Y. J. Am. Chem. Soc. 1993, 115, 10464-10465. Toru, T.;
Watanabe, Y.; Mase, N.; Tsusaka, M.; Hayakawa, T.; Ueno, Y. Pure Appl.
Chem. 1996, 68, 711-714. Mase, N.; Watanabe, Y.; Ueno, Y.; Toru, T. J.
Org. Chem. 1997, 62, 7794-7800.
Acknowledgment. This work was funded by the Fonds
National Suisse de la Recherche Scientifique and by the
Office Fe´de´ral pour l’Education et la Science (project COST-
D2). We thank Professor Max Malacria for helpful discus-
sions.
Supporting Information Available: Experimental details
for all procedures including full characterization of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) Maruoka, K.; Itoh, T.; Yamamoto, H. J. Am. Chem. Soc. 1985, 107,
4573-4576. Saito, S.; Yamamoto, H. Chem. Commun. 1997, 1585-1592.
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