Ruthenium-catalyzed tandem cross-metathesis/wittig olefination: Generation of conjugated dienoic esters from terminal olefins

Article abstract of DOI:10.1021/ol070445t

In the presence of ruthenium-based olefin metathesis catalysts and triphenylphosphine, α,β-unsaturated aldehydes can be olefinated with diazoacetates. This ruthenium-catalyzed transformation has been employed in tandem with olefin cross-metathesis to convert terminal olefins into 1,3-dienoic esters in a single operation.

Full text of DOI:10.1021/ol070445t

ORGANIC
LETTERS
2007
Vol. 9, No. 9
1749-1752
Ruthenium-Catalyzed Tandem
Cross-Metathesis/Wittig Olefination:
Generation of Conjugated Dienoic
Esters from Terminal Olefins
Ryan P. Murelli and Marc L. Snapper*
Merkert Chemistry Center, Boston College, 2609 Beacon Street,
Chestnut Hill, Massachusetts 02467-3860
marc.snapper@bc.edu
Received February 21, 2007
ABSTRACT
In the presence of ruthenium-based olefin metathesis catalysts and triphenylphosphine,
r
,
â
-unsaturated aldehydes can be olefinated with
diazoacetates. This ruthenium-catalyzed transformation has been employed in tandem with olefin cross-metathesis to convert terminal olefins
into 1,3-dienoic esters in a single operation.
Over the past decade, olefin metathesis has emerged as a
powerful and widely used transformation.1 Among the
structurally defined olefin metathesis catalysts, ruthenium
alkylidenes I-IV (Figure 1) are particularly attractive
in other modes of reactivity.4 Some of the alternative
transformations have been attributed to catalyst impurities
and decomposition pathways, thus extensive studies have
gone into the characterization of these ruthenium species;5
(1) For select reviews on olefin metathesis, see: (a) Grubbs, R. H.;
Trnka, T. M. In Ruthenium in Organic Synthesis; Murahashi, S.-I., Ed.;
Wiley-VCH: Weinheim, 2004; Chapter 6. (b) Katz, T. J. Angew. Chem.,
Int. Ed. 2005, 44, 3010. (c) Schrock, R. R. J. Mol. Catal. A: Chem. 2004,
213, 21. (d) Hoveyda, A. H.; Schrock, R. R. Metathesis Reactions. Comp.
Asym. Cat., Suppl. 2004, 1, 207. (e) Grubbs, R. H. Tetrahedron 2004, 60,
7117.
(2) (a) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, Germany, 2003. (b) Connon, S. J.; Blechert, S. Angew. Chem.,
Int. Ed. 2003, 42, 1900. (c) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res.
2001, 34, 18. (d) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012. (e)
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(3) For examples of olefin metatheses in target-oriented syntheses from
our laboratory, see: (a) Shizuka, M.; Schrader, T. O.; Snapper, M. L. J.
Org. Chem. 2006, 71, 1330. (b) Cheung, A. K.; Murelli, R. P.; Snapper,
M. L. J. Org. Chem. 2004, 69, 5712. (c) Williams, M. J.; Deak, H. L.;
Snapper, M. L. J. Am. Chem. Soc. 2007, 129, 486. (d) Murelli, R. P.;
Cheung, A. K.; Snapper, M. L. J. Org. Chem. 2007, 72, 1545. (e) Cheung,
A. K.; Snapper, M. L. J. Am. Chem. Soc. 2002, 124, 11584. (f) Schrader,
T. O.; Snapper, M. L. J. Am. Chem. Soc. 2002, 124, 10998. (g) Limanto,
J.; Snapper, M. L. J. Am. Chem. Soc. 2000, 122, 8071.
Figure 1. Commercially available ruthenium-based olefin metath-
esis catalysts.
because of their robust activity and functional group toler-
ance.2,3 Despite their recognized importance in effecting
olefin metatheses, these catalysts have also been implicated
10.1021/ol070445t CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/31/2007

however, often the responsible complex is not clear. Nev-
ertheless, these discoveries have opened the door to the
development of several novel ruthenium-catalyzed tandem
processes, in which the metal promotes two or more
mechanistically distinct transformations in the same reaction
vessel.6
acetate (EDA) and Ph3P in the presence of substoichiometric
amounts of RuCl2(PPh3)3 couple to give a phosphonium ylide
capable of aldehyde olefination.12a In the absence of catalyst,
the ethyl diazoacetate reacted with the aldehyde (1) to give
azine 2 (eq 1).13 Since then, several alternative ruthenium
Given the costs associated with reagents, solvents, and
waste for each unique transformation, as well as the time
required for material handling and purification, significant
economic advantages are possible for running multiple
transformations in a single reaction vessel. Accordingly, we
have developed several tandem processes where olefin
metathesis is used in conjunction with olefin isomerizations,7
Kharasch additions,8 cyclopropanations,9 or olefin oxida-
tions.10 Herein, we demonstrate the use of ruthenium catalysts
I-IV in a tandem olefin metathesis/Wittig olefination
sequence.
Over the past decade, metal-catalyzed or “salt-free” Wittig
olefinations have gained interest as an alternative to classic
base-mediated Wittig olefinations.11 To the best of our
knowledge, the first example of a ruthenium-catalyzed
version of this transformation was published in 1998 by
Fujimura and Honma, who demonstrated that ethyl diazo-
catalysts have been developed to carry out this transforma-
tion.14 Although the olefin metathesis catalysts I-IV have
not been used in Wittig olefinations, recent work indi-
cates that a phosphonium ylide is likely generated during
catalyst decomposition.5a In light of these findings, we
anticipated that a metal-catalyzed olefination could be car-
ried out using one of these popular ruthenium metathesis
catalysts.
Preliminary studies on the olefination of benzaldehyde
using ruthenium complexes I-IV were encouraging. Al-
though the reaction did not go to completion using conditions
developed for RuCl2(PPh3)3,12 the desired ethyl cinnamate
3 was observed. In addition, considerable amounts of diethyl
maleate and fumarate were also formed in this reaction. This
was not surprising given a report by Hodgson and Angrish
on the ability of complex II to dimerize EDA.4b To
circumvent this undesired side reaction, slow addition of the
diazoester to the reaction mixture was explored. Gratifyingly,
under these conditions, the desired olefinated product 3 is
obtained with high yield and selectivity (eq 2).
Given the prevalence and synthetic utility of R,â,γ,δ-
unsaturated carbonyl-containing compounds,15 we decided
to explore their preparation through a ruthenium-catalyzed
cross-metathesis (CM) of terminal olefins with acrolein and
methacrolein, followed by a ruthenium-catalyzed Wittig
olefination of the resulting aldehyde with diazoacetates.
Direct CM to generate these electron-deficient dienes is
possible;16 however, the selectivity of the transformation can
be compromised in the absence of steric and/or electronic
bias. For example, Grubbs and co-workers reported access
to such structures from terminal olefins by carrying out a
(4) For example, see: (a) Alcaide, B.; Almendros, P. Chem.-Eur. J.
2003, 9, 1258. (b) Hodgson, D. M.; Angrish, D. Chem. Commun. 2005,
39, 4902. (c) Tallarico, J. A.; Malnick, L. M.; Snapper, M. L. J. Org. Chem.
1999, 64, 344. (d) Schmidt, B. Eur. J. Org. Chem. 2003, 816. (e) Schmidt,
B. Chem. Commun. 2004, 742. (f) Schmidt, B. J. Org. Chem. 2004, 69,
7672. (g) Drouin, S.; Zamanian, F.; Fogg, D. Organometallics 2001, 20,
5495. (h) Schmidt, B.; Pohler, M. Org. Biomol. Chem. 2003, 1, 2512. (i)
Simal, F.; Demonceau, A.; Noels, A. F. Tetrahedron Lett. 1999, 40, 5689.
(j) Bielawski, C. W.; Louie, J.; Grubbs, R. H. J. Am. Chem. Soc. 2000,
122, 12872. (k) Quayle, P.; Fengas, D.; Richards, S. Synlett 2003, 1797. (l)
Schmidt, B.; Pohler, M.; Costisella, B. J. Org. Chem. 2004, 69, 1421. (m)
Lee, B. T.; Schrader, T. O.; Mart´ın-Matute, B.; Kauffman, C. R.; Zhang,
P.; Snapper, M. L. Tetrahedron 2004, 60, 7391.
(5) (a) Hong, S. H.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2004,
126, 7414. (b) Galan, B. R.; Gembicky, M.; Dominiak, P. M.; Keister, J.
B.; Diver, S. T. J. Am. Chem. Soc. 2005, 127, 15702. (c) van Rensburg,
W. J.; Steynberg, P. J.; Meyer, W. H.; Kirk, M. M.; Forman, G. S. J. Am.
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Organometallics 2002, 21, 3335.
(6) For examples of tandem reaction sequences with ruthenium metathesis
catalysts developed outside of our laboratory, see: (a) Schmidt, B.; Pohler,
M. J. Organomet. Chem. 2005, 690, 5552. (b) Whelan, A. N.; Elaridi, J.;
Harte, M.; Smith, S. V.; Jackson, W. R.; Robinson, A. J. Tetrahedron Lett.
2004, 45, 5252. (c) Beligny, S.; Eibauer, S.; Maechling, S.; Blechert, S.
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Biomol. Chem. 2003, 1, 2512. (e) Johnson, L. K.; Mecking, S.; Brookhart,
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S.; Mahon, M. F.; Prior, T. J.; Pregosin, P. S.; Whittlesey, M. K.; Williams,
J. M. J. J. Am. Chem. Soc. 2007, 129, 1987. (i) Otterlo, W. A. L.; Coyanis,
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(12) Fujimura, O.; Honma, T. Tetrahedron Lett. 1998, 39, 625.
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(14) (a) Chen, Y.; Huang, L.; Ranade, M. A.; Zhang, X. P. J. Org. Chem.
2003, 68, 3714. (b) Sun, W.; Yu, B.; Ku¨hn, F. E. Tetrahedron Lett. 2006,
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Organometallics 2007, 26, 302. (d) Lebel, H.; Paquet, V. Organometallics
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Org. Lett., Vol. 9, No. 9, 2007

CM with electron-deficient dienes (eq 3).17 The methodology
tandem, ruthenium-catalyzed metathesis/olefination sequence
are dienoic esters formed in 59-86% yields with >20:1 E,E-
selectivity. Entries 6 and 7 indicate that acrolein can also be
used in this tandem sequence. In this case, ruthenium
alkylidene III was employed given its proven ability to cross-
metathesize acrolein.20 Entries 2 and 6 show that t-butyl
diazoacetate can be substituted for ethyl diazoacetate with
similar efficiency in the Wittig olefination step.21 In entries
1-4, the unsaturated aldehyde is used as the limiting reagent;
however, as demonstrated in entries 5-7, a slightly modified
protocol allows the terminal olefin to be used as the limiting
reagent. In these cases, the excess electron-deficient olefin
needs to be evaporated before the olefination step, reducing
the overall operational simplicity of the tandem sequence.
Entry 7 demonstrates the chemoselectivity of the process.
In this case, the resulting aldehyde generated in the CM is
olefinated selectively in the presence of a ketone to provide
diene 8g.
was limited due to the CM reactivity of both the R,â- and
γ,δ-double bonds of the diene. Fortunately, this drawback
could be overcome with unsaturated amides or unsaturated
esters with internal olefins in the Z-configuration or with
additional substitution. In light of this shortcoming, a
ruthenium-catalyzed tandem cross-metathesis/Wittig olefi-
nation may offer a complementary strategy toward these
polyunsaturated systems. Along these lines, a related
Horner-Wadsworth-Emmons olefination has been shown
to tolerate complex II and can be used in a “one-pot”
operation.18
A successful ruthenium-catalyzed Wittig olefination of a
ketone is also possible if the tandem process is run in toluene
at higher temperatures with the addition of benzoic acid as
an additive (Scheme 1). The conditions are modeled after
Table 1. One-Pot Synthesis of Dienoic Esters.
Scheme 1
those developed by Ku¨hn and co-workers during additive
studies for salt-free ketone olefinations.22 Higher amounts
of the phosphine and diazoacetate are also needed for
complete conversion, and the E/Z selectivity is not as high
as the aldehyde olefinations. Nonetheless, this newly de-
signed tandem process does provide access to these â-sub-
stituted dienoic esters (9).
In summary, we have demonstrated that a variety of
popular ruthenium metathesis catalysts are capable of
(16) (a) Dewi, P.; Randl, S.; Blechert, S. Tetrahedron Lett. 2005, 46,
577. (b) Moura-Letts, G.; Curran, D. P. Org. Lett. 2007, 9, 5. (c) Randl, S.;
Lucas, N.; Connon, S. J.; Blechert, S. AdV. Synth. Catal. 2002, 344, 631.
(d) Cesati, R. R.; de Armas, J.; Hoveyda, A. H. J. Am. Chem. Soc. 2004,
126, 96. (e) Royer, F.; Vilain, C.; Elkaim, L.; Grimaud, L. Org. Lett. 2003,
5, 2007. (f) Ferrie´, L.; Amans, D.; Reymond, S.; Bellosta, V.; Capdevielle,
P.; Cossy, J. J. Organomet. Chem. 2006, 691, 5456. For a recent review of
ene-diene cross metathesis, see: (g) Diver, S. T.; Giessert, A. J. Chem.
ReV. 2004, 104, 1317.
a EDA (ethyl diazoacetate) added over 4 h at 40 °C. Reaction sealed
and heated to 60 °C for an additional 4-8 h. bIsolated yield. ct-Butyl
diazoacetate used in place of EDA.
(17) Funk, T. W.; Efskind, J.; Grubbs, R. H. Org. Lett. 2005, 7, 187.
(18) Trost, B. M.; Gunzner, J. L.; Dirat, O.; Rhee, Y. H. J. Am. Chem.
Soc. 2002, 124, 10396.
(19) Although all ruthenium complexes (I-IV) effected the Wittig
olefination, the catalyst selected for the tandem process was dictated by
reactivity in the CM and relative cost. Chatterjee, A. K.; Morgan, J. P.;
Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 3783.
(20) Cossy, J.; BouzBouz, S.; Hoveyda, A. H. J. Organomet. Chem. 2001,
624, 327.
(21) Chandrasekaran, S.; Kluge, A. F.; Edwards, J. A. J. Org. Chem.
1977, 42, 3972.
(22) Pedro, F. M.; Hirner, S.; Ku¨hn, F. E. Tetrahedron Lett. 2005, 46,
7777.
As summarized in Table 1, vinylidene complex IV is an
effective and selective catalyst for the CM of methacrolein
with terminal olefins (entries 1-5).19 Furthermore, this same
ruthenium complex (IV) can serve as a Wittig olefination
catalyst when the resulting unsaturated aldehydes are treated
in situ with PPh3 and diazoesters. The results from this
Org. Lett., Vol. 9, No. 9, 2007
1751

catalyzing a salt-free Wittig olefination with diazoacetates
and triphenylphosphine. When employed in conjunction with
olefin cross-metathesis, rapid entries into dienoic esters are
achieved.
support. We are also grateful to Materia for the gift of the
metathesis catalyst.
Supporting Information Available: Experimental pro-
cedures and data on new compounds are provided (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. The authors would like to thank the
National Science Foundation (CHE-0612875) for financial
OL070445T
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Org. Lett., Vol. 9, No. 9, 2007