Differential reactivities of enyne substrates in ruthenium- and palladium-catalyzed cycloisomerizations

Article abstract of DOI:10.1021/ja103663h

Complementary methods for the transition-metal-catalyzed enyne cycloisomerizations of cyclic olefins have been developed. By using distinct ruthenium and palladium catalysts, decalins and 7,6-bicycles can be obtained with dichotomous stereochemical outcomes. The change in mechanism that accompanies the change in metal affords trans-fused 1,4-dienes with ruthenium and their cis-fused diastereomers under palladium catalysis. In the reactions under ruthenium catalysis, a coordinating group is required and acts to direct the metal to the same side of the carbocycle, resulting in the observed trans diastereoselectivity. Subtle changes in the carbocyclic substrate led to the discovery of a heretofore-unobserved mechanistic pathway, providing bicyclic cycloisomerization products under palladium catalysis and tricyclic products under ruthenium catalysis in N,N-dimethylacetamide (DMA). The differential effect of DMA supports a mechanism in which the coordination requirements of the two paths differ, allowing for the reaction to be shuttled through the metallacycle pathway (generating tricyclic products) when DMA is used as a solvent.

Full text of DOI:10.1021/ja103663h

Published on Web 06/14/2010
Differential Reactivities of Enyne Substrates in Ruthenium-
and Palladium-Catalyzed Cycloisomerizations
Barry M. Trost,* Alicia C. Gutierrez, and Eric M. Ferreira
Department of Chemistry, Stanford UniVersity, Stanford, California 94305
Received May 4, 2010; E-mail: bmtrost@stanford.edu
Abstract: Complementary methods for the transition-metal-catalyzed enyne cycloisomerizations of cyclic
olefins have been developed. By using distinct ruthenium and palladium catalysts, decalins and 7,6-
bicycles can be obtained with dichotomous stereochemical outcomes. The change in mechanism that
accompanies the change in metal affords trans-fused 1,4-dienes with ruthenium and their cis-fused
diastereomers under palladium catalysis. In the reactions under ruthenium catalysis, a coordinating
group is required and acts to direct the metal to the same side of the carbocycle, resulting in the
observed trans diastereoselectivity. Subtle changes in the carbocyclic substrate led to the discovery
of a heretofore-unobserved mechanistic pathway, providing bicyclic cycloisomerization products under
palladium catalysis and tricyclic products under ruthenium catalysis in N,N-dimethylacetamide (DMA).
The differential effect of DMA supports a mechanism in which the coordination requirements of the
two paths differ, allowing for the reaction to be shuttled through the metallacycle pathway (generating
tricyclic products) when DMA is used as a solvent.
Introduction
A primary focus in our laboratory is the invention of
transition-metal-catalyzed reactions for the rapid construction
of molecular complexity from simple starting materials.1 Of
these, atom-economic reactions2 s transformations that use
only catalytic reagents and in which each atom of the starting
materials is contained in the product s exemplify the ideal
of efficient chemical synthesis. Developing methods that meet
these criteria is desirable not only because such processes
generate few byproducts but also because they make more
efficient use of raw materials in an increasingly resource-
conscious world.
A representative example of such a transformation is the
cycloisomerization of enynes.3 Extending our previous work
in this area to enynes containing cyclic olefins would allow
access to fused carbocyclic ring systems (eq 1), chemical
motifs that are abundant in naturally occurring, biologically
active molecules. Recognizing, therefore, that the ability to
rapidly construct fused five-, six-, and seven-membered ring
systems would be an important synthetic tool and that control
over the relative stereochemistry of fused ring junctions is a
long-standing challenge in the synthetic community, we began
a research program to study the reaction of cyclic olefin
substrates (1) with a variety of transition-metal catalysts.
A preliminary account of these studies, detailing palladium-
and ruthenium-catalyzed cycloisomerizations of six- and seven-
membered carbocyclic enynes, was recently disclosed.4 Herein
we present a full account of this work, which has resulted in
the discoveries of (1) diastereoselective enyne cycloisomeriza-
tions to form bicycles that, depending on the metal catalyst,
exclusively form either the cis- or trans-fused ring system (eq
2) and (2) reaction conditions that, depending on the metal
catalyst, selectively yield either bi- or tricyclic products. These
studies provide new insights into the mechanisms of these
reaction manifolds, the implications of which are discussed.
Preparation of Enyne Substrates
The requisite enyne substrates can be readily prepared via a
general synthetic plan that relies on the deconjugative alkylations
of cyclic enoates.5 In the event, commercially available cyclo-
hexene 6 was alkylated with iodides 7, 8, and 9 using LDA/
(1) For a review of atom-economic reactions developed in our laboratory,
see: (a) Trost, B. M. Acc. Chem. Res. 2002, 35, 695–705. For reviews
on non-metathesis, ruthenium-catalyzed carbon-carbon bond-forming
reactions, see: (b) Trost, B. M.; Frederiksen, M. U.; Rudd, M. T.
Angew. Chem., Int. Ed. 2005, 44, 6630–6666. (c) Trost, B. M.; Toste,
F. D.; Pinkerton, A. B. Chem. ReV. 2001, 101, 2067–2096.
(2) Trost, B. M. Science 1991, 254, 1471–1477.
(4) Trost, B. M.; Ferreira, E. M.; Gutierrez, A. C. J. Am. Chem. Soc.
2008, 130, 16176–16177.
(3) For reviews on enyne cycloisomerizations, see: (a) Trost, B. M.;
Krische, M. J. Synlett 1998, 1–16. (b) Trost, B. M. Acc. Chem. Res.
1990, 23, 34–42. (c) Michelet, V.; Toullec, P. Y.; Geneˆt, J.-P. Angew.
Chem., Int. Ed 2008, 47, 4268–4315.
(5) (a) Herrmann, J. L.; Kieczykowski, G. R.; Schlessinger, R. H.
Tetrahedron Lett. 1973, 14, 2433–2436. (b) Kuwajima, I.; Urabe, H.
Org. Synth. 1988, 66, 87–94.
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9206 J. AM. CHEM. SOC. 2010, 132, 9206–9218
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Enyne Substrates in Ru- and Pd-Catalyzed Cycloisomerizations
A R T I C L E S
Scheme 1. Substrate Syntheses
DMPU to provide esters 10, 11, and 12, which vary only in
their tether lengths (eq 3).
Substrates containing both larger and smaller ring sizes
were also synthesized (eqs 4 and 5) following a similar
protocol. Deconjugative alkylations of cyclopentene 18 and
cycloheptene 19 were less effective than the alkylation of
cyclohexene 6 but worked reasonably well using LDA/HMPA
to afford enynes 20 and 21 from iodide 7, and enynes 26
and 27 from iodide 8.6
oxidative cleavage9 and subsequent Fischer esterification (eq
8). Alkylation and functional group manipulation provided
enyne 51.
The silylated esters obtained from the deconjugative
alkylation (10-12 and 26-27) and their desilylated analogues
(13-15, 22, 23, 28, and 29) were used to access an array of
substrates via conventional methods. The synthetic routes to
enynes 34-38 from precursor 11 are illustrated in Scheme
1; the cyclopentene- and cycloheptene-derived congeners
were made analogously.7
Cycloisomerizations
6,6- and 7,6-Bicyclic Structures. We began by studying the
cycloisomerization of enyne 1 using our standard conditions
for ruthenium-catalyzed alkene-alkyne couplings (5 mol %
CpRu(MeCN)3PF6 in acetone at ambient temperature). The
reaction afforded bicycle 2 in 90% yield (Table 1, entry 1).
Remarkably, the transformation was completely diastereose-
lective for the trans-fused ring system.
This result is particularly noteworthy because more classical
ways of making decalins, such as cycloalkylations, generally
lead to cis-fused bicycles.10 The more commonly employed
Enynes containing an amide at the quaternary position were
synthesized via standard conditions (eq 7). Cyclooctene
substrate 50 could not be synthesized using deconjugative
alkylation, likely owing to the conformational restrictions
caused by transannular interactions in a cyclooctyl ring.
Instead, ꢀ,γ-unsaturated ester 49 was synthesized using a
ninhydrin ene reaction reported by Gill et al.,8 followed by
(6) The deprotonation was complicated by competitive conjugate addition
of diisopropylamide into 8, even when using HMPA.
(7) See Supporting Information.
(8) Gill, G. B.; Idris, M. S. H.; Kirollos, K. S. J. Chem. Soc., Perkin
Trans. 1 1992, 2355–2365.
(9) Gill, G. B.; Idris, M. S. H.; Kirollos, K. S. J. Chem. Soc., Perkin
Trans. 1 1992, 2367–2369.
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A R T I C L E S
Trost et al.
Table 1. 6,6- and 7,6-Bicycles via Ru-Catalyzed Cycloisomerizations
b
a Isolated yield. Determined by H NMR. c Using 3 mol % catalyst. d Using 10 mol % catalyst. e Using 20 mol % catalyst. f Temp: 40 °C.
1
protocols for the synthesis of trans-decalins are the Birch
reduction of Wieland-Miescher ketones and intramolecular
enolate alkylation to generate the cis-decalin core, which, in a
second step, is equilibrated to the trans isomer.11 Both of these
methods are limited to decalins containing an epimerizable ring
junctions. Additionally, they are indirect, requiring cyclization
to an intermediate bicycle that is then transformed to the desired
trans isomer.
ynone 55 was heated, complete conversion was obtained at room
temperature when the catalyst loading was increased to 20 mol
% (entry 7).
We were pleased to find that a variety of functionality at the
quaternary carbon, including aldehydes, amides, and carboxylic
acids, proved amenable to the reaction (Table 1, entries 2-5).
Primary alcohol 35 was slightly less reactive under the standard
conditions but was cycloisomerized to bicycle 60 in 86% yield
by increasing the catalyst loading and reaction time (entry 4).
The functionality at the alkyne terminus was then examined.
Substrates in which the alkyne is substituted with either a
trimethylsilyl (TMS) group (11) or a proton (14) failed to
undergo the desired transformation (Figure 1). Enynes 52 and
55, in which the alkyne is substituted with an amide and a
ketone, respectively, underwent the cycloisomerization, albeit
with longer reaction times than alkynoate 1. Gratifyingly, in
the case of ynamide 52, this could be overcome by increasing
the temperature to 40 °C, which provided bicycle 53 in 70%
yield (Table 1, entry 6) as a single diastereomer. While
significant decomposition was observed when the reaction with
Figure 1. Substrates unreactive to ruthenium catalysis.
The cycloheptene-based enynes also underwent the cycloi-
somerization in excellent yield and with complete diastereose-
lectivity (Table 1, entries 8-10). As was observed for the
cyclohexene-containing substrates, the high functional group
tolerance of this reaction allowed for the formation of bicyclic
products containing esters (59, 99% yield), aldehydes (62, 87%
yield), and amides (65, 99% yield).
The limits of this transformation are illustrated in Figure 1.
Silyl ether 37 and carbonate 38 were inert to these reaction
conditions, even with higher catalyst loadings and temperatures.
Nitrile 66, ynal 67, ynoic acid 68, and cyclooctene 51 also did
not react when treated with the ruthenium catalyst, allowing
for the quantitative recovery of the starting enynes.
(10) For a review on approaches to cis-decalins, see: (a) Singh, V.; Iyer,
S. R.; Pal, S. Tetrahedron 2005, 61, 9197–9231. For a review on routes
to trans-decalins, see: (b) Varner, M. A.; Grossman, R. B. Tetrahedron
1999, 55, 13867–13886.
To investigate the potential differences between products
arising from these ruthenium-catalyzed reaction conditions and
our previously reported “ligandless” palladium-catalyzed cy-
(11) For an elegant, direct method employing ꢀ-silyloxy unsaturated nitriles,
see: Fleming, F. F.; Shook, B. C.; Jiang, T.; Steward, O. W. Org.
Lett. 1999, 1, 1547–1550.
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Enyne Substrates in Ru- and Pd-Catalyzed Cycloisomerizations
A R T I C L E S
Scheme 2. Undesired Olefin Isomerization
Figure 2. Stereochemical assignment of trans-2.
cloisomerization,12 ester 1 was examined. Highest conversions
were obtained when HCO2H was used in combination with DCE
as the solvent. Variations to this system (e.g., AcOH in place
of HCO2H or benzene instead of DCE as the solvent) led to
diminished reactivity.
In our initial studies, concomitant formation of olefin isomers
prevented us from obtaining the desired 1,4-diene in acceptable
yields (Scheme 2). Gratifyingly, the addition of 2 vol %
acetonitrile prevented the formation of these byproducts (Scheme
3).13 These optimized conditions (4 mol % Pd2dba3 ·CHCl3, 2
equiv HCO2H, DCE, 2 vol % acetonitrile, 40 °C, Scheme 3)
were applied to all of our subsequent palladium-catalyzed
cycloisomerizations.
vinyl protons (Ha and Hb) for the cis-fused bicycles. Representa-
tive examples are illustrated for cis-69 and cis-74 (Figure 3).
In addition to Hb-Hc enhancements, the strong NOE enhance-
ment between the aldehydic proton Hd and Hc of cis-74 is highly
diagnostic and further confirms our assignments.
Scheme 3. Optimized Pd-Catalyzed Cycloisomerization
Figure 3. Representative stereochemical assignments of cis bicycles.
6,5-Bicyclic System. Decreasing the tether length by one
carbon allowed us to examine the formation of five-membered
rings from cyclohexene- and cycloheptene-containing enynes,
which would produce 6,5- and 7,5-bicycles, respectively.
The formation of 6,5-bicycles via ruthenium-catalyzed cy-
cloisomerization was probed using enyne 16. In the event, 6,5-
bicycle 77 was isolated in 86% yield as a single diastereomer
The cyclic enynes used to illustrate the scope of the
ruthenium-catalyzed reaction (Table 1) were also cycloisomer-
ized under palladium catalysis. The corresponding 6,6- and 7,6-
cis-fused bicycles were obtained in high yields, and, in contrast
to the ruthenium-catalyzed process, in this palladium-catalyzed
reaction they were obtained with complete diastereoselectivity
for the cis isomers (Table 2).
A variety of functional groups are tolerated by the palladium
catalyst, with the exception of acid 57 (entry 3) and ynamide
52 (entry 6). Aldehydes (entries 2 and 9), amides (entries 5 and
10), and ynones (entry 7) underwent the cycloisomerization in
excellent yields and diastereoselectivity. In contrast to the slow
reactivity observed under ruthenium catalysis, under palladium
catalysis alcohol 35 underwent facile cyclization to generate
bicycle cis-73 in less than 3 h (entry 4).
1
(eq 9). Notably, H NMR studies revealed that the product
contained a cis ring fusion (Figure 4). Unfortunately, attempts
to form analogous 7,5-bicycles were not successful.14
The relative stereochemistry of the products was determined
by examination of key coupling constants and nuclear Over-
hauser effect (NOE) enhancements (Figures 2 and 3). In all
cases, the double-bond geometry was secured by observing
NOEs between Ha and Hb. COSY spectra were used to correlate
chemical shift with connectivity. The differences between the
NOEs observed for trans-2 and those observed for cis-69
constitute strong evidence for our stereochemical assignment.
For the trans-fused series, a strong NOE enhancement was
measured between the doubly allylic proton (Hc) and the other
axial protons (illustrated for trans-69 in Figure 2). In contrast,
strong NOE enhancements were observed between Hc and the
Figure 4. Stereochemical NOE analysis of 51.
6,7-System. Attempts to form seven-membered rings via
ruthenium-catalyzed cycloisomerization revealed a limit of this
catalytic system. While small amounts of 6,7-bicycle 79 could
be observed, cycloisomerization did not occur catalytically, even
under forcing conditions (Table 3). After increasing both the
temperature to 60 °C and the catalyst loading to 30 mol %, at
the end of 24 h the reaction had only reached 33% conversion
(entry 4), representing a reaction with minimal catalyst turnover.
(12) (a) Trost, B. M.; Tanoury, G. J.; Lautens, M.; Chan, C.; MacPherson,
D. T. J. Am. Chem. Soc. 1994, 116, 4255–4267. (b) Trost, B. M.;
Romero, D. L.; Rise, F. J. Am. Chem. Soc. 1994, 116, 4268–4278. (c)
Trost, B. M.; Li, Y. J. Am. Chem. Soc. 1996, 118, 6625–6633.
(13) Analogous olefin isomerization is often observed in intramolecular
palladium-catalyzed Heck reactions of cyclic olefins. Silver or thallium
salts, commonly employed as additives to suppress these isomeriza-
tions, were ineffective. See: Link, J. T. Org. React. 2002, 60, 157–
534.
(14) Cycloheptene 25 was found to be unreactive to our optimized
conditions. While 25% conversion to an unidentified product was
observed upon heating to 45 °C, none of the desired 7,5-bicycle was
formed.
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A R T I C L E S
Trost et al.
Table 2. 6,6- and 7,6-Bicycles via Pd-Catalyzed Cycloisomerizations
b
a Isolated yield. NR: no reaction. Determined by H NMR.
1
Table 3. Behavior of the 6,7-System
Table 4. Ru-Catalyzed Cycloisomerizations To Form 5,5-Bicycles
entry
conditions
catalyst loading (mol %)
resultsa
1
2
3
4
2.5 h, 23 °C
3 h, 45 °C
6 h, 45 °C
24 h, 60 °C
5
5
20
30
no reaction
17% conv
25% conv
33% conv
a
1
Determined by H NMR of crude reaction.
5,n-Bicycles. The excellent yields and diastereoselectivities
with which the 6,6- and 7,6-ring systems were obtained led us
to investigate the formation of 5,n-ring systems. Toward this
end, enynes 24 and 80 were subjected to the ruthenium-catalyzed
cycloisomerization reaction conditions. Ester 24 underwent
smooth cyclization to the 5,5-bicyclic product (81), with
complete selectivity for the cis diastereomer (Table 4, entry 1).
Enyne 80, containing a silyl ether at the quaternary carbon, also
underwent cyclization to generate the cis-fused product 82 under
ruthenium catalysis (entry 2). The relative stereochemistry of
the bicyclic products was secured by an analysis of the COSY
spectrum along with the NOE enhancements illustrated in Figure
5.
a
Determined by H NMR. b Isolated yield.
1
Figure 5. Representative stereochemical assignment.
surprise, when 30 was submitted to the ruthenium-catalyzed
reaction conditions, bicycle 83 was formed in equal amounts
along with tricycle 84. Both products were formed as single
diastereomers.
A similar [2+2] cycloaddition with iodoenynes was recently
reported by Fu¨rstner, in which the pentamethylcyclopentene
(Cp*) analogue of our catalyst, Cp*Ru(MeCN)3PF6, was em-
Extending the alkyne tether by one carbon in order to form
the 5,6-bicycle had a profound impact on the reaction. When
substrate 30 was submitted to the optimized palladium-catalyzed
reaction conditions, the expected bicycle 83 was formed in
excellent yield as a single diastereomer (Scheme 4). To our
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Enyne Substrates in Ru- and Pd-Catalyzed Cycloisomerizations
A R T I C L E S
Table 5. Cycloisomerizations under Standard Conditions
Scheme 4. Novel Tricyclic Product Obtained under Ruthenium
Catalysis
ratio
yield
entry
R1
R2
conversion (%) tricycle/bicyclea (tricycle, bicycle, %)b
1
2
3
4
5
6
7
CO2Me
CH2OH
CH2OTBS
CH2OAc
CHO
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
100
100
100
100
100
100
100
∼1:1
∼1:1
∼1:1
∼1:1
∼1:1
∼1:1
∼1:1
89c
43, 53
46, 42
30, 38
49, 50
98c
CH2OTBDPS CHO
CH2OBn CHO
90c
ployed.15 When enyne 30 was submitted to the conditions
reported by Fu¨rstner (catalytic Cp*Ru(MeCN)3PF6 in dimeth-
ylformamide (DMF) at room temperature), no reaction was
observed.
a Determined by 1H NMR of crude reaction. b Isolated yield.
c Isolated as a mixture of tricycle and bicycle.
is also observed between the methylene proton Hc and Hb.
Importantly, the chemical shifts of these diagnostic cyclobutene
protons correlate with the values reported for similar tricyclic
cyclobutenes formed under platinum catalysis.26 Moreover, if
the ester were unsaturated in the other direction of the
cyclobutene, that compound (85) would contain a highly strained
olefin.27
The nickel-catalyzed [2+2] cycloaddition of 1,2-diphenyl-
ethyne and 2,5-norbornadiene (NBD) reported by Schrauzer in
196416 was the first transition-metal-catalyzed alkyne-olefin
[2+2] addition. Since Schrauzer’s initial report, palladium,17
platinum,18 cobalt,19 gold,20 rhodium,21 rhenium,22 ruthenium,23
iridium,24 and molybdenum25 have all been shown to catalyze
the cycloaddition of an alkyne and an olefin. However, despite
the array of metal complexes that have been employed for this
transformation, this reactivity is unprecedented for the
CpRu(MeCN)3PF6 catalyst.
Scheme 5
Under the standard conditions (5 mol % CpRu(MeCN)3PF6,
acetone, 23 °C, 2 h), a 1:1 mixture of bicycle and tricycle was
obtained in high yields for all of the substrates examined (Table
5).
It is believed that cyclobutene 84 as drawn is the product
characterized. Correlations between chemical shift and con-
nectivity were deduced by COSY analysis. Proton NMR studies
show an NOE enhancement between Ha and Hb, as would be
expected for two cis protons (Scheme 5). An NOE enhancement
Given that we could access the bicycle exclusively via
palladium catalysis, we then sought reaction conditions to
provide the tricycle exclusively under ruthenium catalysis
(Scheme 6). We began our optimization studies with enyne
30.
Reasoning that the introduction of another coordinating
solvent with different ligating properties might affect the
selectivity of the reaction, we examined a variety of solvents.
Unfortunately, none of the additives (acetic acid, dioxane, ethyl
acetate, methanol) increased the selectivity for either product
(Table 6). Toluene (Table 6, entry 4) and dimethylsulfoxide
(DMSO) (Table 6, entry 6) completely shut down the reaction,
while the introduction of acetonitrile decreased the reaction
conversion to 44%. The addition of nitromethane proved to be
differential, providing tricycle 84 in a slight excess relative to
bicycle 83 (Table 6, entry 10).
(15) Fu¨rstner, A.; Schlecker, A.; Lehmann, C. W. Chem. Commun. 2007,
4277–4279.
(16) Schrauzer, G. N.; Glockner, P. Chem. Ber. 1964, 97, 2451–2462.
(17) (a) Coulson, D. R. J. Org. Chem. 1972, 37, 1253–1254. (b) Trost,
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B. M.; Yanai, M.; Hoogsteen, K. J. Am. Chem. Soc. 1993, 115, 5294–
5295.
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Goya, T.; Murakami, M. Synlett 2006, 575–578.
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This promising result led us to examine DMF, a solvent
that we have previously shown is compatible for reactions
with CpRu(MeCN)3PF6. In this case, when DMF was
(26) See ref 18b.
(27) The smallest carbocycle that can contain a trans-olefin has been
the subject of continuing interest in organic chemistry. While trans-
cyclooctene is fairly stable (strain energy ∼16 kcal/mol), trans-
cycloheptene is significantly higher in energy (∼27 kcal/mol) and
has only been isolated at low temperatures. For a complete
discussion, see: Anslyn, E. V.; Dougherty, D. A. Modern
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Scheme 6. Desired Catalyst-Controlled Product Selectivity
product selectivity was obtained with 100 vol % DMA at
room temperature (entry 9); however, the reaction stopped
at 74% conversion. Raising the temperature to 40 °C
increased the conversion to 93% while only slightly decreas-
ing the selectivity (entry 10). These conditions (15 mol %
CpRu(MeCN)3PF6, DMA, 40 °C), the best compromise
between conversion and selectivity, were then adopted as the
optimized conditions for tricycle formation.
Using these optimized conditions, a variety of substrates were
examined (Table 8). Free alcohols (Table 8, entry 2) and
aldehydes (Table 8, entry 3) are tolerated, generating the
corresponding cyclobutenes in excellent yields. In contrast to
the cycloisomerization reaction to form 6,6- and 7,6- bicycles,
this system tolerates a wider variety of functional groups, such
as silyl ethers (Table 8, entries 4, 6, and 7) and ynals (Table 8,
entries 4, 5, and 8).
Table 6. Solvent Screen
conversion
(%)a
ratio
tricycle/bicyclea
entry
solvent additive
1
2
3
4
5
6
7
8
9
2.5 vol % AcOH
20 vol % AcOH
20 vol % dioxane
20 vol % toluene
20 vol % EtOAc
20 vol % DMSO
20 vol % MeCN
2.5 vol % MeOH
50 vol % CH2Cl2
20 vol% MeNO2
100
100
100
NR
100
NR
44
100
100
100
1:1
1:1
1:1
Complementary product selectivity can be obtained simply
by changing the catalyst from ruthenium to palladium. To
demonstrate this, the substrates were also subjected to the
palladium-catalyzed cycloisomerization conditions. We were
pleased to find that the reaction produced the desired cis-fused
bicycles in good to excellent yields with complete diastereo-
selectivity (Table 9).
Carbonate 111, silyl ether 112, and alcohol 113 (Figure 6)
were unreactive to ruthenium catalysis as well. In separate
experiments, increasing the temperature of the standard reactions
(in acetone) to 50 °C did not improve the conversion.
Not all of the substrates examined cyclized successfully under
ruthenium catalysis. Curiously, Weinreb amide 43, the cyclo-
pentene analogue of 63 and 44, was not reactive. Under the
standard reaction conditions (acetone, 23 °C), the reaction with
amide 43 failed to go to complete conversion after 3.5 h
(standard reaction time 2 h). Additionally, under these standard
conditions, amide 43 was the only substrate to give an unequal
mixture of bi- and tricyclic products, producing the two in a
1:4 ratio, respectively (Table 10, entry 1). In DMA, conversion
was only 42% after 11 h at 40 °C (entry 2), and after 24 h only
50% (entry 3). Repeated attempts to separate the tricycle from
the starting material were not successful, and the isolation of
tricycle 109 was ultimately abandoned.
1:1
1:1
1:1
1:1
1.2:1
10
a
1
Determined by H NMR of crude reaction. NR: no reaction.
employed as a solvent, the reaction did not proceed at all
after 3 h at 23 °C. The addition of 2 vol % DMF to an acetone
solution of substrate and catalyst (Table 7, entry 1) slowed
the reaction, but cyclobutene formation occurred in more than
2-fold excess relative to bicycle formation. Further increasing
the amount of DMF relative to acetone led to a moderate
increase in selectivity (Table 7, entry 2), but use of greater
than 20 vol % DMF decreased the conversion significantly
(Table 7, entry 3).
Table 7. Nitrogen-Based Solvent Screen
As had been observed previously, enynes containing an
alkyne terminated by a group other than an electron-withdrawing
group were completely unreactive (Figure 7). Ynamide 52 and
ynone 55 (Table 1, entries 6 and 7), used as substrates for
generating the 6,6-bicyclic products, required more forcing
conditions. We reasoned that if the (unknown) factors that
slowed the cycloisomerization of the these enynes were present
in the 5,6-system, a change in product ratio might result,
favoring the cyclobutene product. Instead, reactions with 5,6-
ynone 114 and ynamide 115 were even more sluggish than those
with their 6,6-analogues (Scheme 7).
To determine if these optimized conditions (15 mol %
CpRu(MeCN)3PF6, DMA, 40 °C) were unique to 5,6-
congeners, substrates from the 6,6- and 6,7-systems (esters
52 and 31) were submitted to the reaction under the same
conditions. No reaction was observed after 12 h (eq 10),
indicating that the formation of tricyclic products is indeed
unique to the 5,6-system.
time conversion
(%)d
ratio
tricycle/bicycled
entry
solvent additive
(h)
1
2
3
2 vol % DMF
15
13
13
4
3
3
15
18
18
12
100
80
67
100
100
100
48
63
74
93
2.4:1
3:1
3:1
3.6:1
5:1
3:1
10:1
14.6:1
15.2:1
12.5:1
7:1
20 vol % DMF
50 vol % DMF
5 vol % NMP
10 vol % NMP
20 vol % NMP
50 vol % DMA
80 vol % DMA
100 vol % DMA
4
5a
6a
7
8
9
10b, c 100 vol % DMA
11b
12b
20 vol % NMP, 80 vol % DMA 16
10 vol % NMP, 80 vol % DMA 12
78
40
10.3:1
a Using 20 mol % catalyst. b Using 15 mol % catalyst. c Reaction
conducted at 40 °C. Determined by H NMR of crude reaction
d
1
Hoping that an alternative nitrogen-based solvent might
similarly favor formation of cyclobutene 84, we tested
N-methylpyrrolidone (NMP), nitromethane, and N,N-dim-
ethylacetamide (DMA) as additives (Table 7, entries 4-12).
The use of NMP resulted in faster reaction rates but with
modest product selectivity (entries 5 and 6). The highest
Mechanistic Considerations: Palladium Catalysis. The cis-
selectivity observed in the palladium-catalyzed cycloisomer-
ization can be explained by a mechanism in which the metal
is directed to the same side of the ring as the alkyne (Scheme
8). The active catalyst is generated by oxidative insertion of
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9212 J. AM. CHEM. SOC. VOL. 132, NO. 26, 2010

Enyne Substrates in Ru- and Pd-Catalyzed Cycloisomerizations
A R T I C L E S
Table 8. Cycloisomerizations under Tricycle-Optimized Conditions
b
a Yield of isolated tricycle. Determined by H NMR. c Isolated as an inseparable, 8.3:1 mixture of tricycle and bicycle.
1
Table 9. 5,6-Cis-Fused Bicycles via Pd-Catalyzed Cycloisomerizations
b
a Isolated yield. Determined by H NMR. c Isolated along with 23% of olefin-isomerized 1,5-diene.
1
palladium(0) into HCO2H to generate a palladium(II) species
that then hydrometalates the alkyne to form vinylpalladium
species 117. Intramolecular binding and insertion of the olefin
then provides intermediate 118. Subsequent ꢀ-hydride elimi-
nation produces the 1,4-diene product, which is still bound
to the palladium through η2-coordination of the newly formed
olefin 119. The concomitant formation of olefin isomers
observed in our initial studies is hypothesized as arising from
palladium hydride insertion-elimination pathways at this
Figure 6. Unproductive enynes with electron-deficient alkynes.
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J. AM. CHEM. SOC. VOL. 132, NO. 26, 2010 9213

A R T I C L E S
Trost et al.
enynes28 previously reported s suggest that there are two
operative mechanisms in enyne cycloisomerizations catalyzed
by CpRu(MeCN)3PF6: C-H insertion and metallacycle forma-
tion. The operable, productive mechanism for a given enyne is
dictated by its olefin geometry. The data suggest that, for enynes
containing (E)-olefins, cycloisomerization proceeds via a ruth-
enacycle, while enynes containing (Z)-olefins undergo an allylic
C-H insertion. The two reaction manifolds are illustrated in
Scheme 9. In path A, initial binding is followed by reversible
metallacycle formation (120a f 121a). ꢀ-Hydride elimination
from the pseudoequatorial substituent generates a vinyl ruthe-
nium hydride (122) that undergoes reductive elimination,
yielding the cyclized product 123 and regenerating the catalyst.
Evidence that ꢀ-hydride elimination occurs toward the trans
substituent (CH2R1 in metallacycle 121a, corresponding to the
pseudoequatorial position) was provided by the cycloisomer-
izations of geranyl-derived enyne 128 and neryl-derived enyne
129 (eq 11). ꢀ-Hydride elimination occurred regioselectively
from the (E)-substituent to provide the corresponding cyclo-
pentanones 130 and 131. The product ratios indicate that, while
elimination toward the cis substituent is possible, it is the higher-
energy pathway.
Table 10. Behavior of Weinreb Amide
entry
conditions
time (h)
conversion (%)a
ratio 109/110
1
2
3
acetone, 23 °C
DMA, 40 °C
DMA, 40 °C
3.5
11
24
71
42
50
4:1
8:1
ndb
a Determined by 1H NMR. b Not determined.
Scheme 7. Relatively Slower Reactivity of 115 and 114
a Using 10 mol % CpRu(MeCN)3PF6 in acetone at 40 °C. b Reaction
time was 6 h using 20 mol % CpRu(MeCN)3PF6 in acetone at 23 °C.
Figure 7. Unreactive substrates with electron-rich alkynes.
In the case of (Z)-olefins (120b, Scheme 9), the unfavorable
orbital overlap in metallacycle 121b between the metal and Hb,
the hydrogen required for ꢀ-elimination from the intermediate
ruthenacyclopentene, prevents the reaction from proceeding
forward along this pathway. (Z)-Olefins thus react according to
an alternative mechanism (path B). In this case, initial allylic
C-H activation provides ruthenium-allyl species 124 that
undergoes an intramolecular 1,4-addition to the alkyne, forming
vinylruthenium 125. Reductive elimination affords diene 127
and regenerates the active catalyst 126.
Evidence for this dichotomy was provided by deuterium-
labeling studies, wherein a substrate (132) sterically prohib-
ited from undergoing metallacycle formation underwent
allylic C-H insertion exclusively into the cis-methyl sub-
stituent (eq 12).
step. The introduction of acetonitrile facilitates decomplex-
ation of the product via ligand exchange (119 f 69).
Scheme 8. Proposed Pd-Cycloisomerization Catalytic Cycle
Lastly, careful examination of the dependence of reactivity
on the alkyne substitution pattern of the following enynes
reveals an interesting pattern. The series of enynes containing
(Z)-olefins that were examined in our previous study and the
Mechanistic Considerations: Ruthenium Catalysis. Electronic
Requirements. The sum of our studies on this catalyst
system s both these current studies and the studies of noncyclic
(28) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 9728–
9729. (b) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2002, 124,
5025–5036.
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9214 J. AM. CHEM. SOC. VOL. 132, NO. 26, 2010

Enyne Substrates in Ru- and Pd-Catalyzed Cycloisomerizations
A R T I C L E S
Scheme 9. Possible Mechanistic Manifolds
yields of the corresponding diene products are depicted in
Figure 8. The series of enynes, also containing (Z)-olefins,
examined as part of this current study are illustrated in eq
13. The difference in reactivity between terminal alkyne 134a
and TMS alkyne 134c is intriguing. Specifically, the failure
of cyclohexenyl 14, which, like enyne 134a, is also a 1,6-
enyne containing a terminal alkyne and a cis-olefin, is difficult
to explain. If the metallacycle derived from terminal alkyne
134a is somehow able to achieve the requisite metal-ꢀ-
hydride orbital overlap at higher temperatures, it is odd that
neither silyl-enyne 134c nor cyclic 14 does.
The failure of enynes 111 and 112 (Figure 6) to react is likely
due to the steric demand of the functional groups (a tertiary
carbonate in 111 and a tertiary ether in 112) at the quaternary
center in both enynes. Van der Waals interactions between the
tertiary ether and one of the methylene groups in the side chain
might prevent the pendant alkyne from achieving the orientation
required for orbital overlap that would lead to further reaction.
Trans Diastereoselectivity: 6,6- and 7,6-Bicycles. Although
the aforementioned facets of this chemistry explain reactivity,
they do not explain diastereoselectivity. We had anticipated
generation of the cis-fused decalin system, expecting that a
coordinated alkyne would direct allylic C-H activation. How-
ever, carbon-carbon bond formation occurs syn to the ester,
which implies that the C-H insertion must also occur on the
same face. It appears, therefore, that the carbonyl moiety is
acting to direct the formation of the intermediate allylruthenium
species (Scheme 10). Carbonyl-directed η3-allyl formation (135)
is followed by ligand exchange to form alkynyl-coordinated 136,
in which the metal is bound to the carbocycle in an η1 manner;
subsequent carboruthenation and reductive elimination produce
the observed diastereomer (trans-2).
Further insights into our understanding of this reaction were
provided by other substrates. Silyl ether 37 (see Figure 1),
bearing a non-coordinating moiety at the quaternary carbon, was
completely unreactive to these enyne cycloisomerizations, even
with higher catalyst loadings and at elevated temperatures.
Nitrile 66 was also unreactive, suggesting that C-H insertion
to form the metal allyl species was due not solely to an inductive
effect of the key functional group, but also to a specific Lewis
Figure 8. Reactivity of (Z)-olefin-containing enynes.
One possible explanation for these observations is that the
terminal alkyne in 134a is somehow facilitating an in situ olefin
isomerization, to the corresponding trans-olefin, which then
cycloisomerizes via the metallacycle pathway. If the terminal
alkyne, via vinylidene formation, for instance, aids in this
geometrical isomerization process, it would explain the inability
the silyl alkyne to undergo cyclization. Additionally, it would
explain why the cyclic olefin-containing enynes, whose olefins
are geometrically constrained, do not react.
As noted previously, silyl alkyne 11 and terminal alkyne 14
were completely unreactive (eq 13), while analogous substrate
1, featuring a methyl ester at the alkyne terminus, afforded the
desired 1,4-diene in excellent yield as a single diastereomer (eq
13 and Table 1, entry 1). The reactivities of both of these cyclic
substrates and of linear enynes 134a-c can be rationalized by
a C-H insertion mechanism (path B, Scheme 9), wherein the
nature of the carboruthenation step (124 f 125) is akin to the
conjugate addition of a metal-alkyl species to an unsaturated
carbonyl. The reaction cannot occur, therefore, if the alkyne is
not a 1,4-acceptor (i.e., terminated by an electron-withdrawing
group).29
(29) These requirements do not apply to the palladium-catalyzed reaction.
For example, under palladium catalysis the cycloisomerization of enyne
14 is a facile process (100% conversion, 64% yield, isolated as an
inseparable 8:2 mixture of expected bicycle and olefin-isomerized 1,5-
diene, unoptimized). See ref 3b for additional examples.
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A R T I C L E S
Trost et al.
Scheme 10. Source of Trans Diastereoselectivity
Alternatively, the 1,2-disubstituted intermediate 138 could
form, but the higher level of strain31 involved in forming the
trans-fused 5,6-, 6,5-, and 5,5-ring systems might force the
reaction through a minor intermediate that ultimately leads to
the observed cis-fused bicycle (Scheme 12). By rendering the
carbonyl-directed insertion step (139 f 138) nonproductive, the
reaction is forced to proceed via allylruthenium intermediate
140, in which the carbonyl group is not bound. In this scenario,
strongly coordinating groups might be expected to retard the
reaction rate, as they would cause the equilibrium to lie heavily
toward formation of 138. This is consistent with the behavior
of 5,6-enyne 43, containing a strongly ligating Weinreb amide.
Enyne 43 did not undergo complete conversion (see Table 10),
even under extended reaction times and increased temperatures.
basicity. The lack of reactivity observed for carbonate 38 is
also understood in terms of this proposed mechanism. While
the carbonate group possesses the requisite Lewis basicity, the
position of the carbonyl oxygen in carbonate 38 is two atoms
farther away from the cyclohexyl ring than it is in ester 1. As
a result, the coordination leading to ruthenacycle 136 (Scheme
10) involves a ring of six or seven members, whereas the
corresponding transition state derived from carbonate 38 would
require the formation of an eight- or nine-membered ring, which
should be significantly less facile. Additionally, cyclooctene 51
was found to be inert to these reaction conditions, possibly due
to the conformational rigidity often seen in cyclooctyl systems.30
Scheme 12. Alternative Rationale for Cis Diastereoselectivity of
5,n-Systemsa
Cis Diastereoselectivity: 6,5-, 5,5-, and 5,6-Bicycles. The cis-
bicyclic products formed under ruthenium catalysis can derive
from one of the two mechanisms illustrated in Scheme 9: a
metallacycle pathway (path A), where the intermediate 121
undergoes a ꢀ-hydride elimination of Ha prior to the final
reductive elimination, or a C-H insertion pathway (path B),
via 124 and 125. The cis selectivity observed for the formation
of 6,5-, 5,5-, and 5,6-bicycles could be explained by a catalytic
cycle which proceeds through path A. As discussed, the body
of evidence gathered up to this point suggests that, for
cis-olefinic enynes, the energy barrier associated with the
ꢀ-elimination of the pseudoequatorial Hb is prohibitively high.
Thus, while a mechanism which proceeds via a ruthenacycle
intermediate is possible and cannot be ruled out at this time,
rationales within the C-H insertion manifold have been
primarily considered.
a E ) CO2Me; m ) 1, 2; n ) 0, 1; [Ru] ) RuLn. Ligands removed for
clarity.
Lastly, it is possible that the cis-fused 6,5-, 5,6-, and 5,5-
bicyclic products are formed in the same manner as the
tricyclic products are s via metallacycle formation (path A,
Scheme 13). In this case, the cis-diastereomer would neces-
sarily form. While it does not account for the requirement
that the alkynes be terminated by an electron-withdrawing
group, it would explain why the coordinating group is no
longer required.
Product Selectivity under Ruthenium Catalysis: Bi- versus
Tricycle Formation. Formation of tricycles is thought to occur
via a metallacycle mechanism (path A, Scheme 13). It is likely
that formation of the tricyclic product is seen only in the 5,6-
system and not the 5,5-system because formation of the 5,5,4-
tricycle is too high in energy. Interestingly, calculations32 of
the relative energy differences between the cis-bicyclic products
and the analogous tricycles revealed that the difference is
smallest for the 5,6-system. The difference in energy between
5,6-bicycle 83 and tricycle 84 is calculated to be 11.2 kcal. In
It is possible that increased strain present in the 1,2-
disubstituted five-membered ring (138, Scheme 11), as compared
to the six-membered cyclohexyl intermediate 136, causes the
carboruthenation to occur on the same side of the ring as the
alkyne, yielding the observed cis-fused systems.
Scheme 11. Mechanistic Rationale for Cis Diastereoselectivity of
Cyclopentenyl Enynesa
(31) The higher level of strain would be present in the transition state from
138 to vinyl ruthenium 142, not in the products. Calculations of the
relative equilibrium geometry energies of the products were carried
out using a Hartree-Fock basis set at the 3-21G level. These
calculations showed that, for the 5,6-bicyclic system, trans-83 is
3.96 kcal/mol higher in energy than cis-83; in the hydrindane
system, ∆E(trans-77-cis-77) ) 11.0 kcal/mol, and in the decalin system,
∆E(trans-2-cis-69) ) 8.68 kcal/mol. To validate the accuracy of the
3-21G level, one set of calculations was carried out at the higher
6-31G level; the relative energies differences did not change.
(32) Calculations of the relative equilibrium geometry energies of the
products were carried out using Hartree-Fock basis sets at the 3-21G
level. To validate the accuracy of the 3-21G level, one set of
calculations was carried out at the higher 6-31G level; the relative
energies differences did not change.
a E ) CO2Me; n ) 0, 1; [Ru] ) RuLn. Ligands removed for clarity.
(30) Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981–3996.
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9216 J. AM. CHEM. SOC. VOL. 132, NO. 26, 2010

Enyne Substrates in Ru- and Pd-Catalyzed Cycloisomerizations
A R T I C L E S
Scheme 13. Proposed Mechanistic Pathways for 5,6-Enynesa
Weinreb amide 43, a substrate with a strong ligating group.
While it failed to undergo the reaction in full conversion, enyne
43 was the only substrate that displayed any inherent product
selectivity in acetone: at 71% conversion, the ratio of tricyclic
to bicyclic products was 4:1 (Table 10, entry 1). The reduced
reactivity of 43 would still be explained by unproductive ligation
of the amide moiety to the catalyst. The role of DMA could
take place while it is bound to the metal center or simply present
at a nonbonding distance around the metal. If its contribution
requires the ability to alternate between the two, the presence
of a strong coordinating group bound so close to the reaction
site could hinder the reactivity.
Finally, a unifying mechanism in which the 6,5-, 5,6-, and
5,5-bicyclic products as well as the tricyclic products are all
formed from the same metallacycle intermediate (145, path A
of Scheme 13) cannot be ruled out. If both products derive from
ruthenacyclopentene 145, the subsequent step s ꢀ-hydride
elimination or reductive elimination s is product-determining.
Exclusive formation of the tricyclic product by the 5,6-system
is then understood in terms of the conformational differences
between metallacycle 145 and the metallacycle formed from
the cyclohexene-based substrates (e.g., 121b, Scheme 9). As a
result of the larger H-C-H bond angles in cyclopentane rings
compared to those in cyclohexane rings, the ꢀ-hydrogen (Hb)
and the metal center are placed farther apart in intermediate
145 (Scheme 13) than in metallacycle 121b. As a consequence
of the greater distance between the metal and Hb in 145,
ꢀ-hydride elimination would be kinetically disfavored, in turn
allowing for reductive elimination to become a competitive
process.
a E ) CO2Me.
comparison, the tricycle that would be produced from a
cycloaddition of 16 is 30.1 kcal higher in energy than the
observed bicycle, cis-77. The tricycle that would derive from 1
is 18.4 kcal higher in energy than cis-2, and 9.74 kcal higher in
energy than the observed trans-2.
The precise role that the DMA plays in determining the
product selectivity deserves comment. It is possible that DMA,
a stronger ligand than acetone, occupies the coordination site
otherwise used for ꢀ-hydride elimination, thereby facilitating
the C-C reductive elimination step (145 f 84) of the cycload-
dition (path A, Scheme 13). An alternative hypothesis is that
the open coordination site required for the initial C-H insertion
step of path B is occupied by a molecule of solvent. That is,
the bound molecule of solvent out-competes the agostic C-H
bond as a ligand.
This hypothesis, that DMA is effective because its occupation
of a coordination site on the metal inhibits one of the pathways,
implies that the pathways leading to tricyclic and bicyclic
products have different coordination requirements. The oxidative
metallacycle formation (enyne f 145, path A) requires that two
of ruthenium’s six coordination sites are unoccupied (Scheme
14). The initial coordination and insertion step (enyne f 143)
of path B must then require more than two open sites if it is
inhibited by DMA. Indeed, species 146, in which the enyne
occupies three coordination sites on the metal, is a likely
intermediate. As depicted, substrate-metal interactions occur
through the alkyne, the η2-bound olefin, and the agostic C-H
bond.
Conclusion
In conclusion, we have developed complementary methods
for the transition-metal-catalyzed enyne cycloisomerizations of
cyclic olefins. By using distinct ruthenium and palladium
catalysts, decalins and 7,6-bicycles can be obtained with
dichotomous stereochemical outcomes. The change in mecha-
nism that accompanies the change in metal affords trans-fused
1,4-dienes with ruthenium and their cis-fused diastereomers
under palladium catalysis. In the reactions under ruthenium
catalysis, a coordinating group is required and acts to direct
the metal to the same side of the carbocycle, resulting in the
observed trans diastereoselectivity.
Subtle changes in the carbocyclic substrate led to the
discovery of a heretofore-unobserved mechanistic pathway,
providing bicyclic cycloisomerization products under palladium
catalysis, tricyclic products under ruthenium catalysis in DMA,
and a 1:1 mixture of the two under ruthenium catalysis in
acetone. The different coordination requirements of the two
paths allow for the reaction to be shuttled through the metal-
lacycle pathway (generating tricyclic products) when DMA is
used as a solvent. This method of obtaining these cyclobutene
products complements the existing methods for catalyzing the
formal [2+2] cycloaddition of alkynes. While other methods
have been demonstrated for larger ring sizes with palladium,
and for specific alkyne termini with platinum and gold, this
method is unique in its substrate scope. To the best of our
knowledge, this is the first example of a formal [2+2]
cycloaddition catalyzed by CpRu(MeCN)3PF6.
Scheme 14. Coordination Requirements
This general hypothesis s that the relatively stronger ligating
properties of DMA shunt the reaction through the metallacycle
pathway s is in agreement with the selectivity observed for
Current efforts are directed at gaining a deeper understanding
of some of the fundamental principles dictating the reactivity
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A R T I C L E S
Trost et al.
25.1, 24.3; IR (film) 2938, 2851, 1665, 1100 cm-1; HRMS (ESI+)
of these systems, as well as extending their utility by expanding
the substrate scope.
m/z calcd for [C19H22O2 + Na]+ 305.1520, found 305.1517.
General Procedure for the Palladium-Catalyzed Cycloisomer-
izations. To a solution of the enyne substrate and formic acid (2
equiv) in 49:1 DCE/MeCN (0.025 M) under argon was added
Pd2dba3 ·CHCl3 (4 mol %). The resulting mixture was heated to
40 °C and stirred for the time provided. Upon completion of the
reaction, the solution was cooled to room temperature and
partitioned between EtOAc and saturated NaHCO3. The aqueous
phase was extracted with EtOAc, and the combined organic phases
were washed with brine, dried over Na2SO4, and concentrated in
Vacuo. Purification of the residue by flash chromatography provided
the bicyclic adduct.
Experimental Section
General Procedure for the Ruthenium-Catalyzed Cycloisomer-
izations in Acetone. To a solution of the enyne substrate in acetone
(0.1 M) at 23 °C under argon was added CpRu(MeCN)3PF6 (3-20
mol %, in general 5 mol %, all at once). The resulting mixture was
stirred at room temperature for the time provided, at which point
the solvent was removed via rotary evaporation. The residue was
diluted in the minimum amount of CH2Cl2/Et2O (1:1) and passed
through a small plug of silica gel (Et2O eluent). The filtrate was
concentrated in Vacuo to provide the cyclized adducts, which were
further purified by flash chromatography.
Synthesis of Bicycle 54. According to the general procedure,
20.0 mg of 36 (0.0854 mmol) and 1.9 mg of CpRu(CH3CN)3PF6
(0.00427 mmol) were stirred in 854 µL of acetone for 2 h.
Purification of the residue by flash chromatography (11:1 hexanes/
EtOAc eluent) afforded bicycle 54 (17.5 mg, 88% yield, Rf ) 0.45
in 4:1 hexanes/EtOAc) as a colorless oil: 1H NMR (400 MHz, C6D6)
δ 9.58 (s, 1H), 5.84 (s, 1H), 5.56 (d, J ) 10.4 Hz, 1H), 5.48-5.42
(m, 1H), 4.26 (br d, J ) 12.7 Hz, 1H), 3.37 (s, 3H), 2.46 (br s,
1H), 1.77 (br d, J ) 13.0 Hz, 1H), 1.73-1.54 (comp m, 3H), 1.50
(dt, J ) 5.5, 13.1 Hz, 1H), 1.07-0.98 (m, 1H), 0.78 (dt, J ) 5.5,
13.0 Hz, 1H); 13C NMR (100 MHz, C6D6) δ 206.0, 166.4, 160.6,
130.0, 124.9, 113.3, 51.3, 50.5, 47.9, 35.2, 33.0, 30.4, 24.7, 22.6;
IR (film) 2934, 1717, 1640, 1193, 1161 cm-1; HRMS (ESI+) m/z
calcd for [C14H18O3 + Na]+ 257.1154, found 257.1153.
Synthesis of Bicycle 70. According to the general procedure,
32.0 mg of 36 (0.137 mmol), 10.3 µL of HCO2H (0.274 mmol),
and 5.6 mg of Pd2dba3 ·CHCl3 (0.00548 mmol) were stirred in 5.37
mL of DCE and 110 µL of CH3CN for 5 h. Purification of the
residue by flash chromatography (3:1 PhH/CHCl3 eluent) afforded
bicycle 70 (23.2 mg, 73% yield, Rf ) 0.27 in 9:1 hexanes/EtOAc)
1
as a colorless oil: H NMR (500 MHz, CDCl3) δ 9.44 (s, 1H),
5.83-5.78 (m, 1H), 5.73 (s, 1H), 5.57-5.53 (m, 1H), 3.68 (s, 3H),
3.16 (br s, 1H), 2.86-2.74 (comp m, 2H), 2.14-2.08 (comp m,
2H), 1.76-1.65 (comp m, 2H), 1.63-1.52 (comp m, 4H); 13C NMR
(100 MHz, CDCl3) δ 204.6, 167.1, 162.5, 129.0, 127.0, 116.3, 51.2,
51.1, 44.9, 28.2, 27.5, 25.3, 23.0, 22.2; IR (film) 2934, 1719, 1643,
1435, 1155 cm-1; HRMS (ESI+) m/z calcd for [C14H18O3 + Na]+
257.1154, found 257.1148.
Synthesis of Bicycle 108. According to the general procedure,
20.0 mg of 100 (0.0706 mmol), 5.3 µL of HCO2H (0.141 mmol),
and 2.9 mg of Pd2dba3 ·CHCl3 (0.00282 mmol) were stirred in 2.77
mL of DCE and 56.5 µL of MeCN for 2 h. Purification of the
residue by flash chromatography (7:3 benzene/CHCl3 eluent)
afforded bicycle 108 (16.0 mg, 80% yield, Rf ) 0.25 in 17:3
hexanes/EtOAc) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ
10.0 (d, J ) 8.9 Hz, 1H), 7.36-7.28 (comp m, 5H), 5.88 (d, J )
8.2 Hz, 1H), 5.82 (app dt, J ) 2.6, 8.1 Hz, 1H), 5.49-5.46 (m,
1H), 4.52 (s, 2H), 3.40 (d, J ) 9.0 Hz, 1H), 3.35 (d, J ) 9.0 Hz,
1H), 3.26 (s, 1H), 3.11-3.05 (m, 1H), 2.49 (app dq, J ) 2.6, 16.5
Hz, 1H), 2.35-2.28 (m, 1H), 2.13 (app dq, J ) 2.2, 16.5 Hz, 1H),
1.77-1.65 (comp m, 2H), 1.60-1.49 (comp m, 2H); 13C NMR
(125 MHz, CDCl3) δ 168.0, 132.2, 128.4, 127.6, 127.5, 127.3, 75.4,
73.3, 57.4, 49.9, 43.7, 30.8, 26.0, 22.2; IR (film) 2929, 2851, 1671,
1101 cm-1; HRMS (ESI+) m/z calcd for [C19H22O2 + Na]+
305.1512, found 305.1514.
Prepatory-Scale Example. According to the general procedure,
230 mg of 36 (0.981 mmol) and 21.3 mg of CpRu(CH3CN)3PF6
(0.0491 mmol) were stirred in 9.81 mL of acetone for 2 h.
Purification of the residue by flash chromatography (11:1 hexanes/
EtOAc eluent) afforded bicycle 54 (189 mg, 82% yield).
General Procedure for the Ruthenium-Catalyzed Cycloisomer-
izations in DMA. To a solution of the enyne substrate in DMA
(0.12 M) at 23 °C under argon was added CpRu(MeCN)3PF6 (3-20
mol %, in general 15 mol %). The resulting mixture was stirred in
a preheated oil bath at 40 °C for the time provided (in general 12 h),
at which point the reaction was diluted with diethyl ether and
washed once with water and then once with brine. The aqueous
layers were then combined and extracted once more with ether.
The organic phases were combined, dried over MgSO4, and
concentrated in Vacuo. The residue was further purified by flash
chromatography to afford the cyclobutene adduct.
Synthesis of Tricycle 101. According to the general procedure,
21.0 mg of 100 (0.0741 mmol) and 4.7 mg of CpRu(MeCN)3PF6
(0.0107 mmol) were stirred in 618 µL of DMA for 16 h. Purification
of the residue by flash chromatography (9:1 hexanes/EtOAc eluent)
afforded tricycle 101 (13.8 mg, 66% yield, Rf ) 0.45 in 17:3
hexanes/EtOAc) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ
9.64 (s, 1H), 7.37-7.27 (comp m, 5H), 4.55-4.49 (comp m, 2H),
3.32-3.30 (br m, 1H), 3.20 (d, J ) 9.0 Hz, 1H), 3.19 (d, J ) 9.0
Hz, 1H), 2.84 (dm, J ) 13.1 Hz, 1H), 2.72 (s, 1H), 2.11-2.05 (m,
1H), 2.00-1.96 (m, 1H), 1.78-1.59 (comp m, 6H), 1.45-1.40 (m,
1H); 13C NMR (125 MHz, CDCl3) δ 185.2, 171.6, 138.7, 136.8,
128.4, 127.6, 127.5, 76.2, 73.4, 50.9, 45.7, 44.6, 29.0, 27.5, 27.4,
Acknowledgment. We thank the American Cancer Society for
a postdoctoral fellowship for E.M.F. We also thank the NSF and
NIH (GM13598) for the support of our programs, and Johnson
Matthey for the generous donation of metal salts.
Supporting Information Available: Experimental procedures,
compound characterization data, and spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
JA103663H
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9218 J. AM. CHEM. SOC. VOL. 132, NO. 26, 2010