Published on Web 08/29/2003
A Mechanistic Dichotomy in Ruthenium-Catalyzed Propargyl Alcohol
Reactivity: A Novel Hydrative Diyne Cyclization
Barry M. Trost* and Michael T. Rudd
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received May 29, 2003; E-mail: bmtrost@stanford.edu
Table 1. Symmetrical Hydrative Diyne Cyclization
The discovery of new reaction manifolds is often possible through
greater understanding of mechanisms and the factors controlling
various pathways. The development of new mechanistic models to
explain unexpected product formation in one case can lead one to
discovery of novel reactivity in related systems.
In this communication, we demonstrate the delicate balance
among several mechanisms by a simple change of substrate in
ruthenium-catalyzed reactions of diynes. Recently, we have devel-
oped a [CpRu(CH3CN)3]PF6 (1) catalyzed diyne-ol cyclization to
produce cyclic dienones and dienals.1 We proposed a mechanism
for this reaction based upon the known propensity of 1,6- and 1,7-
diynes to form ruthenacyclopentadienes with coordinately unsatur-
ated Ru(II).2 Elimination of a molecule of water was then proposed
to precede attack of water at the incipient carbene carbon center
either through direct attack or metal-coordination and insertion. The
elimination step was proposed to occur first in relation to the related
intermolecular dimerization,3 which only works with propargyl
alcohols, as well as the fact that the reactivity decreases in the order
tertiary > secondary > primary propargylic alcohols. Indeed, while
exploring primary propargyl alcohol diynes for the synthesis of
kainic acid,4 along with the expected product A, we found a side
product B resulting from addition of a water molecule to the carbon
adjacent to the hydroxyl group (eq 1). A possible explanation
a The reactions were carried out at 0.1 M (in substrate) in 10 vol %
water/acetone at 60 °C. b Isolated yields. c Run with 10% 1.
the corresponding substrate cyclizes readily.7 One of the most
mechanistically revealing experiments is the addition of methanol
instead of water. Simple diynes cyclize rapidly in acetone or
dichloromethane with 10 vol % MeOH to yield dienol ethers as
single isomers8 in excellent yields (eq 2, path b).
envisions direct attack of water on the metallacyclopentadiene in
relation to Kirchner‘s stoichiometric work on the addition of
nucleophiles to simple metallacyclopentadienes.5 This led us to
investigate whether the propargylic oxygen was required for
cyclization. We now report, that simple nonterminal diynes cyclize
in the presence of ruthenium catalyst 1 and water to form R,â-
unsaturated ketones in good to excellent yields (eq 2, path a and
Table 1).
While it could be envisioned that the tertiary, secondary, and
primary diyne-ols, as well as the simple diynes, operate by the same
mechanism, and only result in different products because of a facile
elimination pathway, our current work makes evident that these
two reactions operate by distinct mechanisms, with primary
propargyl alcohols bridging the gap between these two pathways.
The first clue of a new mechanistic manifold was the contrasting
reaction rates. The diyne-ol reactions occur rapidly with 1 mol %
1 and ∼1 equiv of water;6 however, for cyclization of simple diynes,
excess water and higher catalyst loadings are required for reaction
to occur at a reasonable rate. Also, diynes containing terminal
alkynes did not lead to the expected products; whereas, terminal
diyne-ols give dienals. Electron-deficient diynes also did not lead
to expected products, while in the case of the diyne-ol reactions,
We anticipate that the isomer that is seen results through
minimization of steric strain in the product. On the other hand,
diyne-ols react very slowly with methanol to yield a mixture of
dienones and the corresponding dimethylacetals. Our current
mechanistic understanding is depicted in Scheme 1. We believe
that Path A is the predominate reaction manifold for tertiary and
secondary diyne-ol substrates, while Path B is followed by simple
diynes, and primary diyne-ols may react by both pathways.
The scope of the hydrative diyne cyclization was then explored
to examine the generality of this novel transformation. Both five-
and six-membered rings with a range of functionality can be formed,
with the five-membered cases giving higher yields with lower
catalyst loadings (Table 1).
Unsymmetrical substrates were examined to explore the pos-
sibility of chemoselective addition. In fact, this reaction seems to
be very sensitive to subtle steric differences. Addition of water takes
9
11516
J. AM. CHEM. SOC. 2003, 125, 11516-11517
10.1021/ja036410f CCC: $25.00 © 2003 American Chemical Society