Preparation of aliphatic ketones through a ruthenium-catalyzed tandem cross-metathesis/allylic alcohol isomerization

Article abstract of DOI:10.1021/ol060918g

Grubbs' 2nd generation and Hoveyda-Grubbs' ruthenium alkylidenes are shown to be effective catalysts for cross-metatheses of allylic alcohols with cyclic and acyclic olefins, as well as isomerization of the resulting allylic alcohols to alkyl ketones. The net result of this new tandem methodology is a single-flask process that provides highly functionalized, ketone-containing products from simple allylic alcohol precursors.

Full text of DOI:10.1021/ol060918g

ORGANIC
LETTERS
2006
Vol. 8, No. 12
2603-2606
Preparation of Aliphatic Ketones
through a Ruthenium-Catalyzed Tandem
Cross-Metathesis/Allylic Alcohol
Isomerization
David Finnegan, Benjamin A. Seigal, and Marc L. Snapper*
Department of Chemistry, Merkert Chemistry Center, Boston College,
2609 Beacon Street, Chestnut Hill, Massachusetts 02467
marc.snapper@bc.edu
Received April 14, 2006
ABSTRACT
Grubbs’ 2nd generation and Hoveyda−Grubbs’ ruthenium alkylidenes are shown to be effective catalysts for cross-metatheses of allylic alcohols
with cyclic and acyclic olefins, as well as isomerization of the resulting allylic alcohols to alkyl ketones. The net result of this new tandem
methodology is a single-flask process that provides highly functionalized, ketone-containing products from simple allylic alcohol precursors.
Accomplishing several transformations in a single reaction
vessel in a controlled and predictable manner can lead to
more economical approaches to valuable products. Costs can
be reduced if the structural changes that usually require
several steps to achieve, in which each step involves time,
solvent, reagents, and energy, are realized under a set of
compatible reaction conditions in one formal process.
Development of new tandem, sequential, cascade, or domino
processes provides powerful strategies that help address this
objective.1
olefin cross-metathesis and then modified in situ to effect
an olefin isomerization in the same reaction vessel. The net
(1) For recent reviews, see: (a) Tejedor, D.; Gonzalez-Cruz, D.; Santos-
Exposito, A.; Marrero-Tellado, J. J.; de Armas, P.; Garcia-Tellado, F. Chem.
Eur. J. 2005, 11, 3502. (b) Tius, M. A. Eur. J. Org. Chem. 2005, 2193. (c)
Padwa, A. J. Organomet. Chem. 2005, 690, 5533. (d) Ohno, H. Chem.
Pharm. Bull. 2005, 53, 1211. (e) Chiou, W.-H.; Lee, S.-Y.; Ojima, I. Can.
J. Chem. 2005, 83, 681. (f) Nagy, A.; Novak, Z.; Kotschy, A. J. Organomet.
Chem. 2005, 690, 4453. (g) de Meijere, A.; von Zezschwitz, P.; Braese, S.
Acc. Chem. Res. 2005, 38, 413. (h) Tietze, L. F.; Rackelmann, N. Pure
Appl. Chem. 2004, 76, 1967. (i) Padwa, A. Pure Appl. Chem. 2004, 76,
1933.
(2) (a) Bazan, G. C.; Baker, R. T.; Obrey, S. J.; Wasilke, J. C. Chem.
ReV. 2005, 105, 1001. (b) Han, K. D.; Chung, Y. K. Synlett 2005, 12, 1889.
(c) Maier, M. E.; Varseev, G. N. Org. Lett. 2005, 7, 3881. (d) Pal, M.;
Dakarapu, R.; Parasuraman, K.; Subramanian, V.; Yeleswarapu, K. R. J.
Org. Chem. 2005, 70, 7179. (e) Fogg, D. E.; Dos Santos, E. N. Coord.
Chem. ReV. 2004, 248, 2365. For examples that include olefin metatheses,
see: (f) Schmidt, B. Pure Appl. Chem. 2006, 78, 469. (g) Aitken, S. G.;
Abell, A. Aust. J. Chem. 2005, 58, 3.
Tandem or concurrent catalysis is a subset of tandem
reactions that uses only one catalyst or precatalyst for
multiple sequential, but mechanistically distinct transforma-
tions.2 In this report, we describe a tandem catalytic process
in which a single ruthenium complex is used to carry out an
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result is a unique, single-pot method for converting allylic
alcohols into highly functionalized, carbonyl-containing
compounds.3
yield aldehyde-containing products. We found that after the
ROCM was complete, the ruthenium complex could then
be transformed into an effective isomerization catalyst
through heating. Our previous work suggested that hydrogen
was necessary to effect the isomerization;8 however, in the
presence of allylic alcohols, alternative catalyst “decomposi-
tion” pathways are known.6a This mechanistic possibility was
supported by the observation of a CO absorption (1941 cm-1)
in the ruthenium complex recovered after silica gel chro-
matography,9 a ligand functionality consistent with Werner’s
allylic-alcohol mediated decomposition of Grubbs’ catalyst.
The ruthenium catalysts 1-3, shown in Figure 1, have
A persistent problem in these tandem reactions, however,
is the variable yields of the desired dialdehyde 6 and the
isolation of significant amounts of over-reduced byproducts
(7). In the case of reactions with diol 5, the isolation of
γ-hydroxybutyrolactone 8 suggested the hydride source. The
excess butene-1,4-diol was isomerizing to γ-hydroxybutanal
and then undergoing a hydride transfer to form lactone 8
(Scheme 1).10 This hydride may in fact be the source of the
over-reduction problem, as well as the ruthenium hydride
deemed responsible for the olefin isomerization reaction.
Because the isomerization and reduction occurred with
similar efficiencies, stopping the isomerization reaction early
did not allow for the isolation of appreciable amounts of the
desired aldehyde-containing products. Adjusting temperature
and screening additives also failed to provide high yields of
the nonreduced products. Given this shortcoming, we decided
to work around the over-reduction problem by shifting our
focus to the synthesis of ketones.
Figure 1. Ruthenium metathesis catalysts.
been employed extensively for olefin metatheses due to their
functional-group tolerance and relative ease of handling.4 Our
experience with the synthesis of cyclic enol ethers5 through
a tandem metathesis/isomerization process suggested that
saturated carbonyls could be derived from allylic alcohols
through a similar isomerization. This idea was supported
substantially by several reports demonstrating the isomer-
ization of allylic alcohols to saturated carbonyl compounds6
with Grubbs’ first generation catalyst 3.7 Given these
observations, we expected cross-metathesis of an allylic
alcohol followed by an olefin isomerization would offer a
unique and rapid entry into saturated, carbonyl-containing
compounds.
Our initial studies employed allyl alcohol or (Z)-but-2-
ene-1,4-diol (5) in ring-opening cross-metatheses (ROCM)
with strained, cyclic olefins (Scheme 1). In this case, the
Reducing the likelihood of hydride transfer by using a
secondary allylic alcohol, such as but-3-en-2-ol or (Z)-hex-
3-ene-2,5-diol (9), in the cross-metatheses proved to be a
robust method for generating methyl ketone-containing
substrates. To avoid oligomerization of the strained olefins
(i.e., ROMP) during cross-metathesis with diol 9, slower
addition of the cyclic olefin to the reaction was necessary.
Moreover, the isomerization led to the desired diketones in
Scheme 1. Ruthenium-Catalyzed Tandem Ring-Opening
Cross-Metathesis/Isomerization with (Z)-Butene-1,4-diol 5
(5) (a) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J.
Am. Chem. Soc. 2002, 124, 13390. For related examples from other
laboratories, see: (b) Fustero, S.; Sa´nchez-Rosello´, M.; Jime´nez, D.; Sanz-
Cervera, J. F.; del Pozo, C.; Acen˜a, J. L. J. Org. Chem. 2006, 71, 2706. (c)
Schmidt, B. Eur. J. Org. Chem. 2004, 1865. (d) Schmidt, B. J. Org. Chem.
2004, 69, 7672. (e) Schmidt, B. Eur. J. Org. Chem. 2003, 816. (f) Schmidt,
B. Chem. Commun. 2004, 742. (g) Schmidt, B. Eur. J. Org. Chem. 2004,
1865. (h) Bressy, C.; Menant, C.; Piva, O. Synlett 2005, 577.
(6) For example, see: (a) Werner, H.; Grunwald, C.; Stuer, W.; Wolf,
J. Organometallics 2003, 22, 1558. (b) Edlin, C. D.; Faulkner, J.; Fengas,
D.; Knight, C. K.; Parker, J.; Preece, I.; Quayle, P.; Richards, S. N. Synlett
2005, 572.
(7) For studies on the decomposition of alkylidene 3, see: (a) Hoye, T.
R.; Zhao, H. Org. Lett. 1999, 1, 169. (b) Hoye, T. R.; Zhao, H. Org. Lett.
1999, 1, 1123. (c) Gurjar, M. K.; Yakambram, P. Tetrahedron Lett. 2001,
42, 3633. For decomposition studies of alkylidene 1, see: (d) Grubbs, R.
H.; Hong, S. H.; Day, M. W. J. Am. Chem. Soc. 2004, 126, 7414. (e) Grubbs,
R. H.; Louie, J. Organometallics 2002, 21, 2153.
(8) For examples of ruthenium hydride formation through hydrogenation
of ruthenium alkylidenes, see: (a) Caulton, K. G.; Olivan, M. Inorg. Chem.
1999, 38, 566. (b) Fogg, D. E.; Yap, G. P. A.; Drouin, S. D. Inorg. Chem.
2000, 39, 5412.
(9) For formation of monometallic ruthenium carbonyls see the reference
above, as well as: Moers, F. G.; Ten Hoedt, R. W. M.; Langhout, J. P. J.
Organomet. Chem. 1974, 65, 93.
(10) For a review of similar transformations, see: Huskens, J.; Van
Bekkum, H.; Peters, J. A.; De Graauw, C. F. Synthesis 1994, 10, 1007.
isomerization of the primary allylic alcohol was expected to
(3) (a) Gree, R.; Cre´visy, C.; Uma, R. Chem. ReV. 2003, 103, 27. (b)
van der Drift, R. C.; Bouwman, E.; Drent, E. J. Organomet. Chem. 2002,
650, 1.
(4) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953. (b) Garber, S. B.; Kingbury, J. S.; Gray, B. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2000, 122, 8168. (c) Schwab, P.; France, M. B.; Ziller, J.
W.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2039. For reviews
on olefin metatheses, see: (d) Furstner, A. Angew. Chem., Int. Ed. Engl.
2000, 39, 3012. (e) Grubbs, R. H.; Trnka, T. M. Acc. Chem. Res. 2001, 34,
18. For a comparison of Mo- and Ru-catalyzed olefin-metatheses, see; (f)
Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592.
2604
Org. Lett., Vol. 8, No. 12, 2006

higher yields with shorter reaction times when run at higher
temperatures (i.e., 200 °C).
The data summarized in Table 1 show the optimized
Scheme 2. Optimizations of a Tandem, Ruthenium-Catalyzed
Cross-Metathesis/Isomerization with (Z)-Hex-3-ene-1,4-diol 9
Table 1. Tandem Ring-Opening
Cross-Metathesis/Isomerization
time was found to be a key substrate-dependent variable in
these reactions. The transformation shown in entry 1 indicates
that aliphatic acetates (i.e., 17) are compatible in this tandem
process. Phthalimide 19 (entry 2) requires a slightly higher
catalyst loading to drive the olefin isomerization step to
completion. With lower catalyst loadings, a variety of other
olefin isomers was obtained. Entry 3 shows that trialkylsilyl
ether 21 is a suitable substrate in this tandem process.11 The
additional metathesis time required for this example is
presumably due to the slightly more hindered nature of the
terminal olefin. The influence of an aromatic group in close
proximity to the olefin is examined in entry 4. In this case,
a minor byproduct where the olefin migrated into conjugation
with the aromatic ring was isolated in addition to the desired
Table 2. Tandem Cross-Metathesis/Isomerization
results for tandem ROCM/isomerizations with use of ruthe-
nium complexes 1 and 2. Entries 1 and 2 demonstrate that
7-oxobicyclo[2.2.1]heptenes (4 and 11) are suitable substrates
for the tandem ROCM/isomerization. Likewise, entry 3
indicates that the corresponding cyclopentadienyl cycloadduct
13 is also a competent cyclic olefin for this tandem process,
albeit with a slightly reduced efficiency. In general, the
Hoveyda-Grubbs’ alkylidene 2 proved more effective in
these reactions, allowing for reduced catalyst loading with
only minimal reduction in overall yields.
While the use of strained cyclic olefins is an important
feature for driving the ROCM step to completion, we felt
that the inclusion of terminal olefins as cross-metathesis
(CM) partners would significantly expand the utility of this
tandem methodology. Unfortunately, our initial CM/isomer-
izations were hindered by low conversion in the metathesis
step. The observation that the cross-metatheses of allyl
benzene with diol 9 with use of ruthenium complex 2 resulted
in 90% yield (86% conversion) was useful (Scheme 2).
Further optimization of each cross-metathesis allowed for
reasonable yields in this tandem CM/isomerization process
with relatively low catalyst loading (0.5 to 2 mol %).
The cross-metathesis/isomerizations of various aliphatic
terminal olefins are illustrated in Table 2. The metathesis
(11) Takei, I.; Nishibayashi, Y.; Ishii, Y.; Mizobe, Y.; Uemura, S.; Hidai,
M. J. Organomet. Chem. 2003, 679, 32.
Org. Lett., Vol. 8, No. 12, 2006
2605

methyl ketone 16. Entries 5 and 6 illustrate two examples
in which the terminal olefins possess benzyl ethers. In either
case, ruthenium hydride-mediated hydrogenolysis of the
benzyl ethers does not appear to be an issue in these
transformations.12 The example shown in entry 7 demon-
strates the chemoselectivity of the tandem process. The
preexisting ketone functionality found in substrate 27 does
not interfere with the reaction. This observation is useful if
the resulting diketone 28 were to be employed in subsequent
intramolecular aldol transformations.
isomerization protocol that generates methyl ketones13 from
terminal and strained cyclic olefins in a single reaction flask.
This advancement extends the utility of the popular ruthe-
nium alkylidenes 1 and 2 by allowing for the direct access
of carbonyl functionality through an olefin metathesis-based
process.
Acknowledgment. We thank the National Science Foun-
dation and Boston College for financial support. We are
grateful to Schering-Plough for X-ray facility support and
Materia for the gift of metathesis catalyst.
In summary, we have developed a new, ruthenium-
catalyzed, tandem olefin cross-metathesis/allylic alcohol
Supporting Information Available: Experimental pro-
cedures and data on new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(12) Bond, G. C.; Hooper, A. D. Appl. Catal., A 2000, 191, 69.
(13) We anticipate that more functionalized allylic alcohols, if viable
substrates in the cross metathesis step, will provide similar access to
functionalized ketones through this tandem process.
OL060918G
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Org. Lett., Vol. 8, No. 12, 2006