A two-step synthesis of α-keto vinyl carbinols from ketones

Article abstract of DOI:10.1021/ol4029594

Conjugate addition of lithium enolates onto terminal alkynyl- and allenyl-sulfoxides furnishes the corresponding allylic sulfoxides. The latter readily undergo a Mislow-Braverman-Evans rearrangement to yield the targeted α-keto vinyl carbinols. This two-s

Full text of DOI:10.1021/ol4029594

ORGANIC
LETTERS
2013
Vol. 15, No. 23
6066–6069
A Two-Step Synthesis of r‑Keto Vinyl
Carbinols from Ketones
Laurent Debien and Samir Z. Zard*
ꢀ
Laboratoire de Synthese Organique, CNRS UMR 7652 Ecole Polytechnique,
91128 Palaiseau Cedex, France
Zard@poly.polytechnique.fr
Received October 14, 2013
ABSTRACT
Conjugate addition of lithium enolates onto terminal alkynyl- and allenyl-sulfoxides furnishes the corresponding allylic sulfoxides. The latter readily
undergo a MislowÀBravermanÀEvans rearrangement to yield the targeted R-keto vinyl carbinols. This two-step procedure does not require
purification of the intermediates and constitutes the shortest approach to R-keto vinyl carbinols.
R-Keto vinyl carbinols are polyfunctional compounds
bearing three of the most essential functionalities in
organic synthesis: a ketone, an alkene, and an alcohol.
Not surprisingly they are important synthetic intermedi-
ates that can be further elaborated into 1,4-diketones,1
heterocycles,2 or R,β-unsaturated ketones.3 They have
also been exploited in total syntheses4 and are present in
some biologically active compounds.5 Their chemistry
has nevertheless remained underexplored due to the lack
of general methods for their preparation. Indeed, the main
routes to R-keto vinyl carbinols exploit the addition
of vinylmetal reagents to symmetric or monoprotected
1,2-diones,6 the addition of acyl anions to enones,7 or the
rearrangement of R-epoxy enones.4d,8 These established
routes generally require over three steps and are often
limited by the use of elaborate building blocks, some of
which are quite tedious to prepare.9
We recently reported that allylic sulfoxides obtained
in three steps from xanthates and ethyl vinyl sulfide are
readily converted into R-keto vinyl carbinols under MislowÀ
BravermanÀEvans (MBE) conditions.10,11 Herein, we
(6) For recent examples, see: (a) Cossy, J.; BouzBouz, S.; Laghgar,
M.; Tabyaoui, B. Tetrahedron Lett. 2002, 43, 823. (b) Runcie, K. A.;
Taylor, R. J. K. Org. Lett. 2001, 3, 3237. (c) Rodriguez, J. R.; Castedo,
L.; Mascarenas, J. L. Org. Lett. 2001, 3, 1181.
(1) (a) Ruedi, G.; Oberli, M. A.; Nagel, M.; Hanse, H.-J. Org. Lett.
2004, 6, 3179. (b) Hancock, K. G.; Wylie, P. L.; Lau, J. T. J. Am. Chem.
Soc. 1977, 99, 1149.
(2) (a) Brown, M. J.; Harrison, T.; Herrinton, P. M.; Hopkins, M. H.;
Hutchinson, K. D.; Overman, L. E.; Mishra, P. J. Am. Chem. Soc. 1991,
113, 5365. (b) Trost, B. M.; Keinan, E. J. Org. Chem. 1980, 45, 2741.
(3) (a) Stone, G. B.; Liebeskind, L. S. J. Org. Chem. 1990, 55, 4614.
(b) Taub, D.; Hoffsommer, R. D.; Wendler, N. L. J. Org. Chem. 1964,
29, 3486.
(4) (a) Suzuki, H.; Aoyagi, S. Org. Lett. 2012, 14, 6374. (b) Buchanan,
G. S.; Cole, K. P.; Tang, Y.; Hsung, R. P. J. Org. Chem. 2011, 76, 7027.
(c) Chanu, A.; Castellote, I.; Commeureuc, A.; Safir, I.; Arseniyadis, S.
Tetrahedron: Asymmetry 2006, 17, 2565. (d) Syhora, K. Tetrahedron
Lett. 1960, 17, 34.
(7) (a) Hanzawa, Y.; Tabuchi, N.; Narita, K.; Kakuuchi, A.; Yabe,
M.; Taguchi, T. Tetrahedron 2002, 58, 7559. (b) Fronza, G.; Fuganti, C.;
Pedrocchi-Fantoni, G.; Servi, S. J. Org. Chem. 1987, 52, 1141. (c)
Souppe, J.; Mamy, J.-L.; Kagan, H. B. Tetrahedron Lett. 1984, 25,
2869. (d) Corey, E. J.; Erickson, B. W. J. Org. Chem. 1971, 36, 3553.
(8) (a) Maignan, C.; Rouessac, F. Bull. Soc. Chim. Fran. 1976, 3À4,
550. (b) Mehrhof, W.; Irmscher, K.; Erb, R.; Pohl, L. Chem. Ber. 1969,
102, 643.
(9) For other methods, see: (a) Trost, B. M.; Xie, J. J. Am. Chem. Soc.
2008, 130, 6231. (b) Nagao, Y.; Tanaka, S.; Ueki, A.; Kumazawa, M.;
Goto, S.; Ooi, S.; Sano, S.; Shiro, M. Org. Lett. 2004, 6, 2133. (c) Mauze,
B.; Doucoure, A.; Miginiac, L. J. Organomet. Chem. 1981, 215, 1. (d)
Stone, G. B.; Liebeskind, L. S. J. Org. Chem. 1990, 55, 4614.
(10) Braun, M.-G.; Zard, S. Z. Org. Lett. 2011, 13, 776.
(5) (a) Liu, L.; Song, Y.-X.; Li, S.-W.; Cheng, B.; Chen, B.; Lin,
Y.-C.; Wang, J.; Li, L.; Gu, Y.-C. Planta Medica 2012, 78, 172.
(b) Klaiklay, S.; Rukachasirikul, V.; Sukpondma, Y.; Phongpaichit,
S.; Buatong, J.; Bussaban, B. Arch. Pharm. Res. 2012, 35, 1127.
(c) Sugawara, F.; Strobel, G.; Fisher, L. E.; Van Duyne, G. D.; Clardy,
J. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 8291.
(11) For other examples exploiting the MBE rearrangement for the
synthesis of R-keto vinyl carbinols, see: (a) Tuba, Z.; Bardin, C. W.;
ꢁ
€
Francsics-Czinege, E.; Molnar, C.; Csorgei, J.; Falkay, G.; Koide, S. S.;
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Kumar, N.; Sundaram, K.; Dukat-Abrοk, V.; Nalogh, G. Steroids 2000,
65, 266. (b) Boivin, J.; Chauvet, C.; Zard, S. Z. Tetrahedron Lett. 1992,
33, 4913. (c) Lidert, Z.; Williams, S. F. Tetrahedron Lett. 1988, 29, 1347.
r
10.1021/ol4029594
Published on Web 11/11/2013
2013 American Chemical Society

report that R-keto vinyl carbinols 5 may similarly be
obtained from allylic arylsulfoxides 4, which are obtained
ina single stepfromterminalalkynyl-sulfoxide2 orallenyl-
sulfoxide 3 and simple ketones 1 (Scheme 1). This method
relies on the use of sulfoxides 2 and 3 that are readily
made on gram scale from commercially available starting
materials.12
Table 1. Optimization of the Reaction Conditionsa
entry
base
LDA
conv 1ab
conv 2b
yield 4ac
E/Zd
Scheme 1. Strategy for the Rapid Assembly of R-Keto Vinyl
Carbinols
1
2
3
4
5
6f
50%
55%
<5%
90%
38%
77%
80%
50%
50%b
À
85:15
83:17b
À
LiTMP
NaHe
100%
100%
>90%
100%
g90%
LiHMDS
KHMDS
LiHMDS
80%
35%b
75%
85:15
g90:10b
90:10
a Reactions were carried out on a 0.5 mmol scale. b Estimated by
analysis of the crude 1H NMR. c Isolated yields. d Ratio based on 1H
NMR analysis of purified allylic sulfoxide. e 1.1 equiv of NaH were used.
f The reaction was run using 1.3 equiv of ketone 1a and LiHMDS and
1 equiv of sulfoxide 2.
of androstanone derivatives 1b and 1c. Cyclohexanone
derived ketones 1d, 1e, and 1f also gave satisfactory results,
and adducts were isolated in somewhat decreased yields
compared with cyclopentenones 4b and 4c. Symmetrical
ketones 1gÀj were finally evaluated, and in this situation,
the reaction yield strongly depended on the structure of
the starting material. Overall, the desired allylic sulfoxides
4 were obtained in fair to good yield and as mixtures
of geometric isomers in favor of the E isomer. Further-
more, in all cases, the reaction proceeded to full conversion
in sulfoxide 2, which allowed for straightforward product
isolation.
Although higher yields were generally obtained using
excess sulfoxide 2 (examples 4a and 4b), running the
reaction with excess enolate turned out to be beneficial in
the case of functionalized cyclohexanone 1d. Moreover, a
larger enolate excess was required in the case of symmetric
ketones 1gÀj with two enolizable sites in order to minimize
side reactions.
As illustrated by examples 4b, 4c, and 4d, the process is
tolerant of various functional groups including acid sensi-
tive silyl or enol ether moieties. Interestingly, examples 4c
and 4d highlight the possibility to selectively transform
substrates bearing various carbonyls by preliminary mono-
protection of one of these functional groups (Table 2).
The MislowÀBravermanÀEvans rearrangement of
allylic sulfoxides 4 was subsequently examined. Surpris-
ingly, our previously reported conditions10 for the rearran-
gement of ethyl-allylsulfoxides (PPh3, 2 equiv in refluxing
toluene) proved ineffective in the case of phenyl-allylsulf-
oxides 4a, and under these conditions, a rapid degradation
of the substrate was observed. We then examined THF as a
more basic and lower boiling solvent, with the eventual
prospect of developing a one-pot procedure. THF proved
to be effective in some cases (carbinols 4a and 4b), but
unfortunately the reaction was not general in this solvent.
For instance, sulfoxide 4d remained intact upon prolonged
exposure to triphenylphosphine in refluxing THF. After a
Ourinvestigation began by examining the reactionofthe
enolate derived from R-tetralone 1a with excess alkynyl-
sulfoxide 2 in THF. We thus evaluated different bases
for this transformation (Table 1). In our first attempt, the
use of LDA gave a moderate but promising 50% isolated
yield (entry 1). The compound corresponding to the direct
addition of diisopropylamine onto acceptor sulfoxide 2
was identified as a byproduct and isolated in 25% yield.
Such a reaction is known13 and hinges on the relative
nucleophilicity of the starting amine. We thus considered
the use of a more hindered base such as LiTMP (entry 2).
A very similar result was nevertheless obtained in this
case, and the formation of the desired allylic sulfoxide 4a
was again accompanied by the enamine derived from
the addition of tetramethylpiperidine to sulfoxide 2. The
choice of a traceless base such as NaH proved disappoint-
ing, as a quick degradation of the substrate was observed
upon addition of the Michael acceptor 2 (entry 3).
To our relief, treatment of R-tetralone 1a with LiHMDS
followed by addition of sulfoxide 2 furnished the desired
allylic sulfoxide 4a in 80% isolated yield (entry 4). Substitut-
ing LiHMDS for KHMDS was found to be detrimental
resulting in a diminished 35% yield (entry 5). Finally,
running the reaction with excess ketone and LiHMDS or
excess sulfoxide gave comparable yields (entry 6 vs 4).
With these two sets of conditions in hand, we proceeded
to probe the substrate scope of the methodology. Various
unsymmetrical functionalized ketones were found to be
competent substrates in this transformation (1b, 1c, 1d,
and 1f, Table 2). The best results were obtained in the case
(12) See Supporting Information for more details.
(13) Yan, S.; Lam, K. T.; Wong, W. Y.; Chan, W. H.; Lee, A. W. M.
Lett. Org. Chem. 2005, 2, 33.
Org. Lett., Vol. 15, No. 23, 2013
6067

with triphenylphosphine in refluxing isopropanol afforded
sulfoxide 5a in a good 80% isolated yield (Scheme 2). This
sequence was repeated for the preparation of previously
synthesized R-keto vinyl carbinols 5b and 5d as well as
some others (Scheme 2). In particular, the rearrangement
of sulfoxides 4a and 4b proved both much faster and much
more efficient in isopropanol than in THF, furnishing the
corresponding carbinols 5a and 5b in overall better yields
(Table 2 vs Scheme 2). This sequence proceeds under mild
reaction conditions and gives access to the desired R-keto
vinyl carbinol motif in useful yields.
Table 2. Scope of the Conjugate Addition onto Sulfoxide 2
Scheme 2. Direct Synthesis of R-Keto Vinyl Carbinols
The results obtained with alkynyl-sulfoxide 2 encouraged
us to evaluate the use of alkynyl-sulfoxide 7 and allenyl-
sulfoxide 3 for the preparation of R-keto vinyl carbinols
bearing a synthetically useful isopropenyl moiety. The reac-
tion of R-tetralone 1a with sulfoxide 7 furnished an equimo-
lar mixture of enone 4n and β,γ-unsaturated ketone 6n in a
combined 48% isolated yield (Table 3). The presence of 10%
of allene 3 in the crude mixture indicated that the lack
of efficiency of the reaction is likely due to the deprotonation
of the propargylic position in 7.
To our delight, substituting sulfoxide 7 for allene 3 pro-
vided a 78% isolated yield of Michael adduct, albeit as
a 1:1 mixture of regioisomers 4n and 6n. Noteworthy, in
this case, the mechanism of the reaction is different and
compound 6n is derived from protonation of the allylic
anion generated after conjugate addition.14
Sulfoxide 4n and 6n were then separately subjected to
the MislowÀBravermanÀEvans rearrangement. Enone 4n
smoothly rearranged in THF to give carbinol 5n in good
yield while β,γ-unsaturated ketone 6n proved to be surpris-
ingly rather unreactive in either THF or isopropanol
(Scheme 3).
In contradistinction, submitting androsterone deriva-
tive 1b and 1c to the reaction gave the corresponding
R,β-unsaturated ketones 4o and 4p as the sole products.
a Reaction conditions: ketone 1 (1 equiv), LiHMDS (1 equiv), sulf-
oxide 2 (1.3 equiv). b Reaction conditions: ketone 1 (1.3 equiv), LiHMDS
(1.3 equiv), sulfoxide2 (1 equiv). c Reaction conditions: ketone1 (2 equiv),
LiHMDS (2 equiv), sulfoxide 2 (1 equiv). d 4f was obtained as a mixture of
allylic and vinylic sulfoxides. e 4j was obtained as a 85:15 mixture of allylic
and vinylic sulfoxides.
screen, we found that isopropanol was the best solvent for
this transformation, as it allowed quick conversion of the
starting sulfoxides and obtention of high yields (Table 2,
carbinols 5c, 5d, and 5gÀj). Unfortunately, carbinols 5e and
5f could not be obtained using this approach. Indeed, the
starting sulfoxides 4e and 4f proved rather unreactive or
unstable in isopropanol or other higher boiling alcohols
such as n-butanol.
With these results in hand, we attempted preparing the
desired R-keto vinyl carbinols in a one pot manner. All our
efforts to develop such a sequence with our model sub-
strate 1a failed and a quick degradation of allylic sulfoxide
4a was generally observed upon heating in the presence of
excess triphenylphosphine. We were, however, able to
demonstrate that a simple workup of the conjugate addi-
tion reaction followed by treatment of the crude mixture
(14) Protonation of allylic anions generally give mixtures of regio-
siomers; however, in our case, enone 4n probably arises from the
isomerization of the vinylic sulfoxide upon aqueous workup.
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Org. Lett., Vol. 15, No. 23, 2013

Table 3. Evaluation of Sulfoxides 7 and 3a
Scheme 4. Preparation of R-Keto Vinyl Carbinols from Steroids
a Reactions were carried out on a 0.5 mmol scale. b Estimated
by analysis of the crude 1H NMR. c Isolated yields. d Ratio based on
1H NMR analysis of purified allylic sulfoxide.
Scheme 5. Case of Symmetric Ketones
Scheme 3. Rearrangement of Sulfoxides 4n and 6n
conjugate addition of enolates to alkynyl- and allenyl-
sulfoxide acceptors with the well-known MislowÀBraver-
manÀEvans rearrangement. Extension of the process
to stabilized anions other than enolates are currently
under study and will be reported in due course. It is finally
interesting to note that an asymmetric version of this
transformation is in principle possible, since the chiral
sulfoxide reagents 2 and 3 can be easily obtained,15 and
the stereospecific rearrangement of chiral allylic sulfoxides
has been documented.16
These, in turn, provided the desired R-keto vinyl carbinols
5o and 5p in good yields and good diastereoselectivities
upon treatment with triphenylphosphine in refluxing iso-
propanol (Scheme 4).
We next studied symmetrical ketones possessing two
enolizable centers. Reacting 8-pentadecanone 1g with
sulfoxide 3 gave rise to the desired adduct in good yield
(Scheme 5). This product was however obtained as a
65:35 mixture of inseparable β,γ-unsaturated ketone 6q
and enone 4q. Unexpectedly, subjecting this mixture to
the MislowÀBravermanÀEvans rearrangement furnished
allylic alcohol 8 as a major product (Scheme 5). The forma-
tion of such a product is synthetically interesting but narrows
somewhat the scope of our method.
Acknowledgment. We thank the ANR for financial
support. This manuscript is dedicated with respect
and admiration to Professor Johann Mulzer (University
of Vienna).
Supporting Information Available. Experimental pro-
cedures and characterization spectral data. This material
is available free of charge via the Internet at http://
pubs.acs.org.
In summary, we have developed a new, operationally
simple method for the rapid construction of R-keto vinyl
carbinols from simple starting materials by combining the
(16) See, for example: (a) Evans, D. A.; Sims, C. L.; Andrews, G. C.
J. Am. Chem. Soc. 1977, 99, 5453. (b) Kano, S.; Tanaka, K.; Hibino, S.;
Shibuya, S. J. Org. Chem. 1979, 44, 1582. For a review, see:
(c) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1979, 18, 563.
(15) The preparation of chiral sulfoxide 2 is known; see: (a) Paley,
R. S.; de Dios, A.; Estroff, L. A.; Lafontaine, J. A.; Montero, C.;
McCulley, D. J.; Rubio, M. B.; Paz Ventura, M.; Weers, H. L. J. Org.
Chem. 1997, 62, 6326. The preparation of chiral sulfoxide 3 could be
achieved by enantioselective oxidation; see: (b) Brunel, J. M.; Diter, P.;
Deutsch, M.; Kagan, H. B. J. Org. Chem. 1995, 60, 8086.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 23, 2013
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