An approach to α-keto vinyl carbinols

Article abstract of DOI:10.1021/ol103044x

Adducts from the radical addition of xanthates to ethyl vinyl sulfide readily undergo elimination of the xanthate group upon thermolysis to give vinylic and/or allylic sulfides, depending on the structure. In the case of α-xanthyl ketones, the adducts are converted into α-keto vinyl carbinols by rearrangement of the sulfoxides derived from the vinylic and allylic sulfides.

Full text of DOI:10.1021/ol103044x

ORGANIC
LETTERS
2011
Vol. 13, No. 4
776–779
An Approach to r-Keto Vinyl Carbinols
Marie-Gabrielle Braun and Samir Z. Zard*
ꢀ
Laboratoire de Synthese Organique, CNRS UMR 7652 Ecole Polytechnique, 91128
Palaiseau Cedex, France
zard@poly.polytechnique.fr
Received December 16, 2010
ABSTRACT
Adducts from the radical addition of xanthates to ethyl vinyl sulfide readily undergo elimination of the xanthate group upon thermolysis to give
vinylic and/or allylic sulfides, depending on the structure. In the case of R-xanthyl ketones, the adducts are converted into R-keto vinyl carbinols
by rearrangement of the sulfoxides derived from the vinylic and allylic sulfides.
As part of a synthetic project, we needed to develop a
simple route to R-keto vinyl carbinols of structure 2
starting from monoketones 1 (Scheme 1). R-Keto vinyl
Scheme 1
carbinols motifs are relatively rare, and usually require
reacting R-diketones 3a,b with vinylmetal reagents.1 In the
case of unsymmetrical R-diketones where no steric or elec-
tronic bias exists to direct the addition of the vinylmetal, a
monoprotected substrate 4 has to be used. While this
approach is efficient, it is severely limited by the dearth of
available R-diketones and the problems of regioselectivity
when dealing with unsymmetrical substrates.2
Toward this end, we contemplated the possibility of
obtaining such derivatives through the radical addition
7 into the desired vinyl carbinol 2 (Scheme 1). The addition
of an R-keto-xanthate 6 to commercially available phenyl
of a xanthate to a vinyl sulfide had not hitherto been
vinyl sulfide and elaborating the corresponding adduct
accomplished, but appeared reasonably facile in view of
the mildness of the reaction conditions and the compat-
ibility of the radical process with numerous functional
(1) (a) Runcie, K. A.; Taylor, R. J. K. Org. Lett. 2001, 3, 3237. (b)
Rodriguez, J. R.; Castedo, L.; Mascarenas, J. L. Org. Lett. 2001, 3, 1181.
(c) Brown, M. J.; Harrison, T.; Overman, L. E. J. Am. Chem. Soc. 1991,
113, 5378. (d) Fang, J.-M.; Chen, M.-Y.; Yang, W.-J. Tetrahedron Lett.
1988, 29, 5937. (e) Fugisawa, T.; Watanabe, M.; Sato, T. Chem. Lett.
1984, 2055. (f) Trost, B. M.; Keinan, E. J. Org. Chem. 1980, 45, 2741.
(g) Maignan, C.; Rouessac, M. Bull. Soc. Chim. Fr. 1973, 1454.
(h) Leriverend, P.; Conia, J.-M. Bull. Soc. Chim. Fr. 1970, 1040.
(2) For other routes, see: (a) Nagao, Y.; Tanaka, S.; Ueki, A.;
Kumazawa, M.; Goto, S.; Ooi, S.; Sano, S.; Shiro, M. Org. Lett. 2004,
6, 2133. (b) Stone, G. B.; Liebskind, L. S. J. Org. Chem. 1990, 55, 4614.
(c) Mauze, B.; Doucoure, A.; Miginiac, I. J. Organomet. Chem. 1981,
215, 1.
groups.3 Xanthate 6a was therefore reacted with phenyl
(3) For reviews of the xanthate transfer chemistry, see: (a) Zard, S. Z.
Angew. Chem., Int. Ed. Engl. 1997, 36, 672. (b) Zard, S. Z. In Radicals in
Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim,
Germany, 2001; Vol. 1, p 90. (c) Quiclet-Sire, B.; Zard, S. Z. Chem.;Eur.
J. 2006, 12, 6002. (d) Quiclet-Sire, B.; Zard, S. Z. Top. Curr. Chem. 2006,
264, 201. (e) Zard, S. Z. Aust. J. Chem. 2006, 59, 663. (f) Zard, S. Z. Org.
Biomol. Chem. 2007, 5, 205. (g) Quiclet-Sire, B.; Zard, S. Z.Pure Appl.
Chem. DOI:10.1351/PAC-CON-10-08-07. Published Online: Oct 15, 2010.
r
10.1021/ol103044x
Published on Web 01/18/2011
2011 American Chemical Society

vinyl sulfide in the presence of lauroyl peroxide as the
initiator. Surprisingly, the reaction was abnormally slow
and required near stoichiometric amounts of the peroxide.
The expected adduct 7a could be observed in the crude
NMR of what was clearly a complex mixture. One possible
side reaction accounting for this failure is an undesired
radical neophilic rearrangement of intermediate radical 8,4
resulting in the formation of thiyl radical 10 through the
temporary epi-sulfide 9. Thiyl radical 10 is unable to
propagate the chain and can evolve in a myriad of ways.
It is worth mentioning that we have used phenyl vinyl
sulfone as a radical trap in conjunction with xanthates on
several occasions without encountering such problems.5
To test whether our hardships were indeed caused by a
neophilic rearrangement due to the presence of the phenyl
ring or to an inherent instability of radical adduct 8 under
the reaction conditions, we repeated the addition using
ethyl vinyl sulfide, and conveniently a commercially avail-
able compound. We were pleased to find that the desired
addition proceededtogivethe expected adduct11a ingood
yield (81%) (Scheme 2). One practical advantage of ethyl
vinyl sulfide is its volatility so any unreacted material is
simply removed by evaporation.
Table 1. Radical Addition of Xanthate 6 to Ethyl Vinyl Sulfide
Scheme 2
In a similar fashion, various R-keto-xanthates were made
to add to ethyl vinyl sulfide. The results, collected in Table 1,
testify to the broad generality of the process, its efficiency,
and its tolerance. Yields are generally greater than 80%
and numerous functional groups can be present on the
starting xanthate. The problems initially encountered with
additionstophenyl vinyl sulfidearenotthereforerelatedto
the stability of the adduct, but lie presumably in the
existence of a competing neophilic rearrangement.
a Yields refer to reactions of xanthate 7 with 2 equiv of ethyl vinyl
sulfide in refluxing ethyl acetate at 1 M concentration. b Yield based on
recovered starting material.
furnished adduct 6n, which in turn could be made to add to
ethyl vinyl sulfide to give 11n as a (1:1) mixture of two
diastereoisomers in good yield. Similarly, addition of
xanthate 6e to N-phenyl maleimide followed by reaction
of the resulting adduct 6o with ethyl vinyl sulfide afforded
11o, also as a (1:1) mixture of two diastereoisomers.
With an efficient, flexible, and convergent route to the
desired intermediates in hand, our next task was to convert
these adducts into vinyl sulfides. We found some years ago
that xanthate addition products to N-vinyl pyrrolidone
such as 12 (Scheme 4) underwent smooth elimination to
give the unsaturated product 13 when heated at moderate
temperatures (>100 °C).6 The presence of a geminal
nitrogen substituent on the carbon bearing the xanthate
More complex derivatives could be prepared by cumu-
lating two sequential radical additions, as shown in Scheme 3.
Thus, reaction of xanthate 6c with N-vinyl phthalimide
(4) (a) Studer, A. In Radicals in Organic Synthesis; Renaud, P., Sibi,
M. P., Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 2, pp 62-80.
(b) Studer, A.; Bossart, M. Tetrahedon 2001, 57, 9649.
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2001, 3, 1069. (b) Denieul, M.-P.; Quiclet-Sire, B.; Zard, S. Z. Tetra-
hedron Lett. 1996, 37, 5495. (c) Delduc, P.; Tailhan, C.; Zard, S. Z.
J. Chem. Soc., Chem. Commun. 1988, 308.
Org. Lett., Vol. 13, No. 4, 2011
777

Table 2. Formation of Vinyl and Allyl Sulfides
Scheme 3
group weakens the carbon-sulfur bond through an anomeric
type effect involving the interaction of the lone electron pair
on the nitrogen atom withthe antibonding σ* orbital of the
carbon-sulfur bond. Tertiary7 and benzylic type xanthates
and related dithiocarbonyl derivatives containing a moder-
ately weakcarbon-sulfur bond also undergo elimination but
the temperatures required are generally higher (>150 °C).8
Scheme 4
of the alkene, and the corresponding vinyl sulfides 14a-c
were obtained exclusively as mixtures of geometrical iso-
mers, which could be separated. In contrast, thermolysis of
benzosuberone and indanone derivatives 11i and 11k
afforded only the conjugated allylic sulfides 15d and 15f,
as the E isomers. Finally, in the case of 6-membered-ring
ketone xanthates 11j and 11m, and branched ketone
xanthate 11l, the elimination produced a mixture of the
respective vinylic and allylic sulfides 14e and 15e, 14g and
15g, and 14h and 15h. The latter two mixtures could be
separated into the constituents by chromatography. In all
cases, vinylic sulfides 14e,g,h were again 1:1 mixtures of
geometrical isomers, which were not separated.
Having established an efficient and short route to vinylic
and allylic sulfides, the final operation that remained was
to convert these adducts into the target vinyl carbinols
through their respectivesulfoxides, asdetailedinScheme5.
Selective oxidation of both vinylic and allylic sulfides 14
and 15 into the corresponding sulfoxides 16 and 17 was
accomplished with sodium periodate in a mixture of
methanol and water. Heating the crude mixture of sulf-
oxides with triphenyl phosphine leads to the desired vinyl
We anticipated that thermolysis of adducts 11 should
also be possible, even if anomeric-type weakening exerted
by the sulfide sulfur would be much less powerful than that
with the nitrogen of the pyrrolidone. Ultimately, we found
that heating in diphenyl ether at around 190 °C (bath
temperature) accomplished the desired elimination cleanly
to give the desired unsaturated sulfide, in a few cases as a
mixture of regioisomers 14 and 15 (Scheme 4). The former
is the kinetic product which, depending on the structure
and reaction time, is partially or totally converted into the
more stable conjugated isomer. The results of the thermo-
lyses are compiled in Table 2.
In the case of lactone 11b, unbranched ketone 11d, and
imide 11e, the elimination was not followed by migration
(6) Gagosz, F.; Zard, S. Z. Org. Lett. 2003, 5, 2655.
(7) Bingham, M. J.; Zard, S. Z. Unpublished observations.
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Quevedo, C. E. J. Org. Chem. 2008, 73, 8116. (b) Postma, A.; Davis,
T. P.; Moad, G.; O’Shea, M. S. Macromolecules 2005, 38, 5371. (c) Xu,
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Org. Lett., Vol. 13, No. 4, 2011

Table 3. Formation of Vinyl Carbinols
Scheme 5
carbinol 2 through the well-known Mislow-Braverman-
Evans reaction.9 Separation of the complex mixture of
sulfoxides is neither necessary nor desirable since, under
the reaction conditions, both vinyl and allyl sulfoxides 16
and 17 are in equilibrium via their common enol 18 but
only the latter can undergo the sigmatropic rearrangement
followed by the irreversible reduction of the intermediate
sulfenate by the phosphine.10 The enolate corresponding
to 18 is stabilized by two electron-withdrawing groups, the
ketone and the sulfoxide, and phosphine is sufficiently
basic to mediate its formation.
Examples of the vinyl carbinols obtained by this route
are collected in Table 3. The unoptimized overall yields
from the corresponding sulfides are synthetically useful. It
is worth emphasizing that some of these compounds would
be difficult to access by more conventional approaches.
In summary, we have devised a convergent, flexible
route to R-keto vinyl carbinols. These densely functiona-
lized structures can serve as starting points for numerous
subsequent transformations. More generally, the combi-
nation of the radical addition of a xanthate to ethyl vinyl
sulfide and thermolysis represents a simple access to
variously substituted vinyl sulfides, a class of compounds
with a very rich yet surprisingly underused chemistry.11
Hopefully, the present work will contribute to reviving
interest in this area by providing a practical and versatile
synthetic protocol.
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Acknowledgment. We dedicate this paper with respect
to Professor Koichi Narasaka (Nanyang Technological
University, Singapore). M.-G.B. thanks Ecole Polytechni-
que for a scholarship.
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data, and copies of 1H and 13
C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.
acs.org.
Org. Lett., Vol. 13, No. 4, 2011
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