An unusual ruthenium-catalyzed cycloisomerization of alkynes and propargyl alcohols

Article abstract of DOI:10.1021/ja012672a

CpRu(NCCH₃)₃⁺PF₆- catalyzes the cycloisomerization of diyne-ols to α,β,γ,δ-unsaturated aldehydes and ketones in good-to-excellent yields. 1-Hydroxy-2,7-diynes and 1-hydroxy-2,8-diynes can be utilized to form hig

Full text of DOI:10.1021/ja012672a

Published on Web 03/27/2002
An Unusual Ruthenium-Catalyzed Cycloisomerization of Alkynes and
Propargyl Alcohols
Barry M. Trost* and Michael T. Rudd
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received December 4, 2001
Scheme 1. A Mechanistic Rationale for the Intramolecular
Coupling of Alkynes and Propargyl Alcohols
Utilization of easily accessible starting materials to create highly
functionalized ring structures through addition reactions allows the
creation of molecular complexity1 while preserving atom economy.2
The intramolecular aldol condensation3 is a classic method to
construct 1-acyl-cyclopentenes and 1-acyl-cyclohexenes. However,
some of the disadvantages of this reaction are the difficult or lengthy
syntheses of the ketoaldehyde starting materials and the potential
complications inherent when more than a single enolate can be
formed.4 Also, ketones and aldehydes can be difficult to carry
through many steps in a synthesis without protection. In contrast,
alkynes are known to be synthetically robust, and the synthesis of
substituted alkynes and propargyl alcohols is very straightforward.
Also, ruthenium catalysts have been shown to be remarkably
tolerant of many functional groups.5 Therefore, we suggest that a
potential alternative to the intramolecular aldol condensation is the
ruthenium-catalyzed cycloisomerization of diyne-ols to diene-ones
or diene-als (eq 1).
Recently, we have shown that, in the presence of CpRu-
(NCCH3)3+PF6- (1),6 tertiary propargyl alcohols dimerize in a tail-
to-tail fashion to form 6-hydroxy-1,3-dien-5-ones (eq 2).7
A
mechanistic rationale8,9 was proposed that includes metallacycle
formation, an elimination of the hydroxy group, and attack of water
at the resulting carbene carbon. On the basis of this mechanism,
one molecule of propargyl alcohol and one molecule of alkyne
should be all that is required. To minimize chemoselectivity issues,
an intramolecular version of this latter proposal was envisioned as
depicted in Scheme 1. A major issue to be resolved was the general
lack of reactivity of disubstituted alkynes in reactions analogous
to that of eq 2.10
alcohol. Entries 4 and 5 demonstrate this aspect as well as illustrate
a range of substitution on the tether. In the case of the benzo
derivative 7, a higher catalyst loading was needed for the reaction
to proceed at a comparable rate.
In the intermolecular dimerization, tertiary propargylic alcohols
were required for reasonable rates.7 This limitation is not shared
by the intramolecular reaction as shown in entries 6 and 7. While
the reactions are slower, good yields of the desired products were
obtained even at room temperature. The geometry of the γ,δ double
bond was exclusively E, presumably the result of thermodynamic
control.12
Although many transition-metal-catalyzed cyclizations appear
restricted to formation of five-membered rings,13 such a limitation
is not present here. The reactions are slower, however, in the bis-
propargylic alcohol example 9 (entry 8); higher catalyst loading
and higher concentration allowed complete reaction within 1 h at
room temperature to form R′-hydroxydienone 10. A somewhat faster
reaction occurred with diyne 11 to form dienone 12 (entry 9) which
may reflect the geminal substitution in the tether.14 Alternatively,
the reaction can be performed at elevated temperature to achieve
similar rates (entry 10). As for five-membered rings, a secondary
alcohol reacts equally well (entry 11).
The prospect of the reaction was explored with bis-propargyl
alcohol 3 in analogy to our intermolecular dimerization. In contrast
to our experience in the intermolecular reaction, treatment with the
ruthenium complex 1 in moist acetone at room temperature gave
the R′-hydroxydienone 411 within 1 h (Table 1, entry 1). Remark-
ably, removing one of the propargyl alcohol functional groups, as
in dyne 5, led to complete reaction within 5 min (entry 2) to form
the dienal 6. In both cases, the reactions proceeded with only 1
mol % catalyst to give nearly quantitative yields. Water is required
for the reaction, and typically 1 equiv is added. The geminal
substitution in the tether is not required as shown in entry 3. Both
alkynes can be disubstituted even though only one is a propargyl
An alternative substitution of this bis-propargylic alcohol system
as in 13 and 15 (eqs 3 and 4) also led to cyclization. In these cases,
the “internal” hydroxyl group was best converted to its acetate.
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10.1021/ja012672a CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Representative Examples of the Cycloisomerization of
Alkynes and Propargyl Alcohols
Acknowledgment. We thank the National Science Foundation
and the National Institute of Health, General Medical Sciences, for
their generous support of our programs. Mass spectra were provided
by the Mass Spectrometry Regional Center of the University of
California-San Francisco, supported by the NIH Division of
Research Resources.
Supporting Information Available: Experimental procedures for
the preparation of new compounds as well as characterization data are
included (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
References
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1 All reactions at 0.1 M in acetone for 1 hr at rt unless otherwise noted;
E ) COOMe. 2 Reaction performed at 1.0 M. 3 Reaction performed at
60 °C.
The free hydroxyl compounds cyclize to give the same products,
but in slightly diminished yield. The cyclization was accompanied
by elimination of the elements of acetic acid to give cyclopenta-
dienes 14 and 16. A mechanistic rationale, depicted in eq 5,
envisions facilitation of ionization of the tertiary acetate in the initial
ruthenacyclopentadiene followed by the normal sequence as
depicted in Scheme 1.
This observation suggests that the alternative propargyl alcohol
17 might also participate in a cyclization as depicted in eq 6. Indeed,
both the bis-propargylic alcohol 18 and monopropargylic alcohol
20 cyclize under more stringent conditions to form enals 19 and
21. In these cases, the addition of an acid promoter, presumably to
facilitate ionization of the tertiary alcohol, was required.
A new ruthenium-catalyzed cycloisomerization provides ready
access to five- and six-membered ring dienals and dienones that
would not be easily accessed. The substrates are easily accessible
because of the flexibility of alkyne chemistry. For example,
propargylation of dimethyl malonate or p-toluenesulfonamide
followed by addition of the monolithium salt of the symmetrical
diyne provided the substrates of entries 2, 3, 6, and 7. The diyne 7
is accessed as shown in eq 9 which translates into dienone 8 being
prepared in four steps from inexpensive commercially available
starting materials.
(4) Carey, F. A.; Sundberg, R. J. AdVanced Organic Chemistry, 3rd ed.;
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alcohols to alkylidene cyclobutenes: Le Paih, J.; Derien, S.; Bruneau,
C.; Demerseman, B.; Toupet, L.; Dixneuf, P. H. Angew. Chem., Int. Ed.
2001, 40, 2912.
(8) Mechanism related to those proposed in enyne cyclizations: Trost, B. M.
Chem. Ber. 1996, 129, 1313.; Trost, B. M.; Toste, F. D.; Pinkerton, A. B.
Chem. ReV. 2001, 101, 2067.
(9) For ionization of propargyl alcohols during enyne couplings: Trost, B.
M.; Krause, L.; Portnoy, M. J. Am. Chem. Soc. 1997, 119, 11319.
(10) Disubstituted propargyl alcohols react in a similar manner; however, at
present the yields are very low due to poor conversion.
(11) Cyclization products and elemental composition have been characterized
by spectroscopic means and by combustion analysis or high-resolution
mass spectrometry, respectively.
(12) Compare ref 7.
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2379
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