Ruthenium-catalyzed hydrative cyclization of 1,5-enynes

Article abstract of DOI:10.1021/ja053462r

A ruthenium-catalyzed hydrative cyclization of enynes has been developed. The reaction converts a range of 1,5-enynes bearing terminal alkyne and Michael acceptor moieties into cyclopentanone derivatives. From extensive catalyst screening experiments, a t

Full text of DOI:10.1021/ja053462r

Published on Web 08/12/2005
Ruthenium-Catalyzed Hydrative Cyclization of 1,5-Enynes
Yiyun Chen, Douglas M. Ho, and Chulbom Lee*
Department of Chemistry, Princeton UniVersity, Princeton, New Jersey, 08544-1009
Received May 27, 2005; E-mail: cblee@princeton.edu
Scheme 1 Addition-Cyclization of 1 via Ru Vinylidene Catalysis
Transition-metal-catalyzed alkyne addition is a process of wide
utility for the formation of carbon-carbon and carbon-heteroatom
bonds with high regio- and stereocontrol.1 While numerous strate-
gies have been developed to effect carbofunctionalization via a 1,2-
addition process (eq 1), such a reaction enabling a multicomponent
coupling has remained elusive in the 1,1-mode due to the
susceptibility of the putative vinylmetal intermediate to a protic
quench (eq 2).2,3 Given the facility with which metal vinylidenes
are available from alkynes and the versatility of a metal-carbon
σ-bond, such tandem 1,1-addition reactions would be of significant
utility in organic synthesis. Herein, we describe a ruthenium-
catalyzed hydrative cyclization of 1,5-enynes that occurs through
a 1,1-difunctionalization of terminal alkynes.
Table 1. Ruthenium-Catalyzed Hydrative Cyclization of Enyne 1
yieldb
entry
[Ru]
ligand
5
6
7+8+9
1a
2a
3a
4
5
6
7
8
9
10
CpRuCl(PPh3)2
CpRuCl(PPh3)2
(Ind)Ru(PPh3)2Cl
[(COD)RuCl2]n
Ru(PPh3)3Cl2
[(p-cymene)RuCl2]2
[(p-cymene)RuCl2]2
[(p-cymene)RuCl2]2
[(p-cymene)RuCl2]2
[(p-cymene)RuCl2]2
dppm
P,N-Lc
-
dppm
dppm
dppm
PPh3
dppe
dppp
BINAP
0%
0%
0%
29%
28%
64%
2%
47%
6%
0%
0%
0%
5%
0%
0%
6%
4%
9%
4%
0%
0%
0%
24%
42%
4%
21%
5%
0%
Our initial studies focused on testing the feasibility of an internal
Michael acceptor to intercept the vinylmetal species emanating from
an attack of a nucleophile to the vinylidene complex (Scheme 1).
The addition of benzoic acid to 1 under ruthenium catalysis,4
however, did not provide 3, but resulted in the formation of 2 in
70% yield. The exclusive Z-selectivity of 2 suggests that the reaction
involves B as the intermediate rather than C, which is required for
cyclization.5 Noting the reports on ruthenium-catalyzed anti-
Markovnikov hydration,6 we reasoned that this problem of geo-
metric isomerism might be circumvented by targeting D arising
from tautomerization of either water adduct B or C. Subsequently,
the acylmetal species would then undergo a C-C bond-forming
cyclization with the pendant alkene to form 5, overriding a reductive
elimination pathway to 4.7
0%
13%
a The reactions of entries 1-3 were carried out following ref 6. All other
reactions were performed with 0.2 mmol of 1, 10 mmol of H2O, 10 mol %
of [Ru], and 10 mol % of ligand (or 20 mol % of monophosphine) in 1.0
mL of 1,4-dioxane at 120 °C for 12 h. b Determined by 1H NMR. c P,N-L
) 2-Diphenylphosphino-6-methylpyridine.
Scheme 2 Synthesis and X-ray Single-Crystal Structure of 11a
On the basis of the mechanistic proposition, hydrative cyclization
of 1 was examined using various ruthenium catalysts (Table 1).
Following literature protocols,6 1 was subjected to conditions known
to promote anti-Markovnikov hydration (entries 1-3). These
catalyst systems, however, induced neither cyclization nor hydration,
returning mainly starting material (ca. 80%). In contrast, employing
non-half-sandwich ruthenium complexes and dppm produced the
desired cyclopentanone 5 along with the Markovnikov hydration
adduct 6 and reduced products 7-9 (entries 4 and 5).8 Further
screening revealed the combination of [(p-cymene)RuCl2]2 and
dppm (entry 6) to be a superior catalyst which improved the yield
of 5 to 64% while minimizing formation of the byproducts. The
use of dppm as the ligand proved to be critical as reactions with
other mono- and diphosphine ligands gave poor results (entries
7-10).
a H atoms and the two phenyl rings on P atoms are omitted for clarity.
exchange, afforded the trinuclear ruthenium 11 of 3-fold symmetry.9
Both 10 and 11 were air and moisture stable and found to be more
effective than the in situ generated catalyst for the cyclization of
1, furnishing 5 in 76 and 80% isolated yield, respectively (2 mol
% catalyst loading). However, it is unclear whether these trinuclear
complexes themselves are the active catalyst or mere progenitors
of mononuclear complexes.
The hydrative cyclization process was further examined with an
assortment of substrates using trinuclear complex 11 as the catalyst
(Table 2). A range of 1,5-enynes with R,â-unsaturated ketones,
To gain insight into the active catalyst, all of the reagents
employed in entry 6 of Table 1 were reacted in the absence of 1
(Scheme 2). This reaction led to decomplexation of p-cymene from
the ruthenium center and formation of 10, which upon anion
9
12184
J. AM. CHEM. SOC. 2005, 127, 12184-12185
10.1021/ja053462r CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Ruthenium-Catalyzed Hydrative Cyclization of
formation suggest the latter pathway to be the more likely
mechanism.13
1,5-Enynesa
In summary, we have developed a new ruthenium-catalyzed
method for the tandem formations of C-O and C-C bonds via
1,1-difunctionalization of alkynes. This reaction achieves an um-
polung cyclization in which a terminal alkyne is hydrated and
undergoes an intramolecular Michael addition. While mirroring the
Stetter reaction,14 the new process proceeds through an acyl
ruthenium species catalytically generated from hydration of a
vinylidene complex. Efforts are currently directed at further
expanding the scope of the transformation.
Acknowledgment. We thank Princeton University for support
of this research, and Dr. Istva´n Pelczer at the Princeton University
NMR facility for helpful discussion.
Supporting Information Available: Experimental details and
spectral data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
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a All reactions were performed with 0.2 mmol of substrate, 10 mmol of
H2O, and 2 mol % of 11 in 1.0 mL of 1,4-dioxane at 120 °C for 12 h.
b Isolated yields. c A single diastereomer was obtained as the product. d E:
Z ) 5:1. e E:Z ) 1:1. f E:Z ) 1:2.
Scheme 3 Proposed Catalytic Cycle for Hydrative Cyclization
(8) Acyl ruthenium D can undergo decarbonylation followed by a â-hydrogen
or reductive elimination to give 8 or 9 with concomitant generation of a
ruthenium hydride that can reduce 1 to 7. For related examples, see: (a)
Bianchini, C.; Casares, J. A.; Peruzzini, M.; Romerosa, A.; Zanobini, F.
J. Am. Chem. Soc. 1996, 118, 4585. (b) Datta, S.; Chang, C. L.; Yeh, K.
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Inorg. Chem. 2004, 810. (d) ref 6c.
(9) See Supporting Information for details of the X-ray single-crystal analysis.
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(13) A mechanism, whereby a Ru alkylidene rather than an acyl Ru is formed
and undergoes a cycloaddition with the alkene followed by â-hydride and
reductive eliminations to give the product, cannot be excluded. For an
example of a Ru R-hydroxyalkylidene, see: (a) Esteruelas, M. A.; Go´mez,
A. V.; Lahoz, F. J.; Lo´pez, A. M.; On˜ate, E.; Oro, L. A. Organometallics
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Lee, C. J. Am. Chem. Soc. 2005, 127, 10180.
aldehydes, nitriles, and esters participated well in the reaction to
give the cyclopentanone derivatives as the product. In most cases,
the combined yield of the uncyclized products analogous to
compounds 6-9 was less than 5%. Notably, 34 was converted to
35 (entry 12) presumably through a â-elimination after cyclization,
despite the presence of the internal hydroxyl group which could
form a dihydrofuran.10
The mechanism of the hydrative cyclization is proposed in
Scheme 3, in which the catalytic cycle involves the formation of a
ruthenium vinylidene, an anti-Markovnikov addition of water, and
cyclization of an acylmetal species onto the alkene. Although the
cyclization may occur through a hydroacylation11 or Michael
addition (paths A and B),12 the requirement of an electron-
withdrawing substituent on the alkene and the lack of aldehyde
(14) (a) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407. (b) Johnson, J.
S. Angew. Chem., Int. Ed. 2004, 43, 1326.
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