Stereoselective, dual-mode ruthenium-catalyzed ring expansion of alkynylcyclopropanols

Full text of DOI:10.1021/ja807894t

Published on Web 12/03/2008
Stereoselective, Dual-Mode Ruthenium-Catalyzed Ring Expansion of
Alkynylcyclopropanols
Barry M. Trost,* Jia Xie, and Nuno Maulide
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received October 6, 2008; E-mail: bmtrost@stanford.edu
Table 1. Ru-Catalyzed Ring Expansion of Silyl-Substituted
The fascinating chemistry of small-ring compounds stems almost
invariably from the unique reactivity modes allowed by the intrinsic
ring strain.1 In particular, ring-expansion reactions have been abun-
dantly used in organic synthesis to efficiently and expeditiously fashion
functionalized molecules, and the appearance of various transition
metal-catalyzed ring expansion processes has only enriched this
landscape. 2,3
Alkynylcyclopropanols
entry
R
Z/E (5/6) ratioa
time (h)
yieldb
There is a considerable body of work on the transition metal
catalyzed ring expansion of vinyl and allenyl cycloalkanols,4 providing
useful tools for construction of various cyclic ketones. This contrasts
with the scarcity of reports of transition metal promoted skeletal
rearrangements of alkynylcycloalkanols.5
1
2
3
4
5
6
TMS 4a
BDMS 4b
SiMe2Ph 4c
TES 4d
TBS 4e
TIPS 4f
5.7:1
6.0:1
6.0:1
10.0:1
11.4:1
>20:1
2
4
2
2
2
2
98%
94%
96%
97%
98%
87%c
Our recent interest in tapping the potential of alkynes as selective
mediators in metal-catalyzed bond-forming reactions led us to speculate
whether Ru catalysis would provide an interesting addition to the
current arsenal of ring-expansion processes.6 The remote analogy
between the isomerization of a propargyl alcohol 1 to an unsaturated
carbonyl 3 (termed the redox isomerization reaction,7 Scheme 1) and
the skeletal rearrangement of a tertiary, cyclopropyl carbinol 4 further
spurred our interest. We report that Ru catalysis is unique in the
activation of alkynyl cyclopropanols 4 as it mediates a highly selective,
dual ring expansion to either four- or five-membered cyclic ketones.
a Geometry was assigned by analogy to the Z/E isomers 5a/6a: see
Supporting Information (SI) for details. b Total yield of two isomers by
1H NMR with mesitylene as internal standard. c Isolated yield. BDMS )
benzyl(dimethyl)silyl.
Realizing that the electronic properties of silyl moieties might be
playing a prominent role in this outcome, we then examined electron-
withdrawing substituents (results in Table 2).
In contrast to the silyl-substituted substrates, in this case the
conversion was slower, which could be ascribed to the lower electron
density at the alkyne (Vide infra). Nonetheless, good yields of
alkylidene cyclobutanones 8 were obtained and this regardless of the
electron-withdrawing substituent being a ketone (entry 1) or ester
(entries 2-4) group. Note that the nature of the ester group (aliphatic,
benzylic or nitroaromatic) also does not affect the outcome of the
reaction. Importantly, and in analogy with the case of silyl-substituted
alkynylcyclopropanols (cf. Table 1), a single isomer was obtained in
all cases, which was assigned the (Z)-configuration. Note that the
stereochemical outcome for these reactions is the precise opposite of
what was reported using Au catalysis, suggesting that different
mechanistic pathways may be operative in each case.5
Our initial forays were successful. Treatment of the TMS-substituted
alkynylcyclopropanol 4a with catalytic amounts of Ru complex 2
smoothly triggered ring expansion to alkylidene cyclobutanone 5a/6a
in essentially quantitative yield. Interestingly, the least stable (Z)-isomer
5a was formed with nearly 6:1 stereoselectivity (Table 1, entry 1).
Our curiosity piqued, the little precedent found for the expansion of
silyl-substituted alkynyl cyclopropanols5c prompted us to examine
further this class of substrates (results in Table 1).
The trend for the preferential formation of (Z)-silylalkylidene
cyclobutanone products upon exposure to our conditions appears to
be quite general. As the steric bulk of the silyl substituent increases,
so does the Z/E ratio. The corollary of this premise is that the highly
congested TIPS-substituted alkynylcyclopropanol 4f (Table 1, entry
6) leads exclusively (based on NMR) to the (Z)-cyclobutanone 5f, a
most counterintuitive result!
Observing the ability of our catalytic system to efficiently convert
silyl- and acceptor-substituted alkynylcyclopropanols to stereode-
Table 2. Ru-Catalyzed Ring Expansion of Electron-Deficient
Alkynylcyclopropanols
Scheme 1. Redox Isomerization and Proposal for a Ru-Catalyzed
Ring Expansion of Alkynylcyclopropanols
entry
R
Z/E (8/9) ratioa
time (h)
yieldb
1
2
3
4
Cy 7a
OEt 7b
OBn 7c
>20:1
>20:1
>20:1
>20:1
12
8
6
88%
68%
81%
85%
O(p-O2NC6H4) 7d
12
a
1
Olefin geometry assigned based on H NMR chemical shift (see SI for
details). b Yields refer to pure, isolated products.
9
17258 J. AM. CHEM. SOC. 2008, 130, 17258–17259
10.1021/ja807894t CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Mechanistic Proposal for the Dual Ring Expansions
fined alkylidene cyclobutanones, we probed the stereoselectivity
of the analogous process employing electron-“neutral” alkyl sub-
stituents at the alkyne.
When we exposed the hexyl-substituted alkynylcyclopropanol 10a
to our reaction conditions (eq 1), the anticipated cyclobutanone 11a
did not form but rather the unexpected ꢀ-substituted cyclopentenone
12a.
Impressed by this complete shift in reactivity, we set out to examine
the generality of this observation and briefly examined the alkyl-
substituted substrates shown in Table 3.
Ru to selectively mediate either of the two pathways depending on
the electronic properties of the substrate bears testament to the versatile
nature of this metal in catalysis. In particular, the ability to access
functionalized ꢀ-substituted cyclopentenones through a direct two-
carbon homologation is appealing. Moreover, the exclusive obtention
of the (Z)-alkylidene cyclobutanone isomers through the cyclopropanol/
cyclobutanone expansion manifold is unprecedented and serves to
further distinguish Ru from other, alkynophilic transition metals.
Interestingly, substrates comprising benzyl (entry 2), cycloalkyl
(entry 3), or remote alkoxy (entries 4-5) and halide (entry 6)
substituents underwent completely selective ring enlargement to the
corresponding cyclopentenones. In all cases 12 was obtained exclu-
sively, with only trace amounts of the analogous cyclobutanones
1
detectable by H NMR of the crude mixtures. To the best of our
knowledge, only one example of a metal-catalyzed direct cyclopro-
panol-cyclopentenone rearrangement was reported prior to our
findings.5a,b
Acknowledgment. We thank the NSF and NIH (NIH-13598) for
generous support of our programs. N.M. is grateful to the Fundac¸a˜o
para a Cieˆncia e Tecnologia (FCT) for a postdoctoral fellowship. We
thank Johnson-Matthey for a generous gift of Ru salts.
Our mechanistic hypothesis to accommodate these results is shown
in Scheme 2.7 We believe that, in the case of silyl and electron-
withdrawing substituents, the electronic properties of the system are
exacerbated upon coordination to the metal catalyst. Thus, the ability
of Si to stabilize a developing ꢀ-positive charge (Scheme 2, R ) SiR3)
and the propensity of ynones and propiolate derivatives to undergo
Michael addition (Scheme 2, R ) COR) probably favor a rapid,
substrate-controlled 1,2-alkyl shift. Note that the observed (Z)-
selectivity in these cyclopropanol/cyclobutanone rearrangements sug-
gests that internal chelation of the putative vinylmetal intermediate by
the cyclobutanone carbonyl is not operative.
Yet, the electron-“neutral” substrates studied (Table 3) should be
more prone to metal insertion into a C-C bond of the cyclopropane
moiety (Scheme 2, R ) alkyl). Such a process would provide
ruthenacyclohexenone 13, from which reductive elimination accounts
for the observed products. The fact that only trace amounts of the
analogous cyclobutanones are obtained implies that a net 1,2-alkyl shift
is much less favored in these systems.
Supporting Information Available: Experimental procedures and
characterization 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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In summary, we have developed a novel Ru-catalyzed ring
expansion of alkynylcyclopropanols. This atom-economical8 reaction
appears to proceed by two different pathways. The unique ability of
Table 3. Ru-Catalyzed Ring Expansion of Alkyl-Substituted
Alkynylcyclopropanols to Cyclopentenones
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entry
R
product
time (h)
yielda
1
2
3
4
5
6
n-C6H13 10a
Bn 10b
12a
12b
12c
12d
12e
12f
4
6
4
2
2
2
78%
81%
88%
76%
68%
74%
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7666, and references therein. (b) Trost, B. M.; Ball, Z. T.; Laemmerhold,
K. M. J. Am. Chem. Soc. 2005, 127, 10028–10038.
Cy 10c
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9587. (b) Trost, B. M.; Livingston, R. C. J. Am. Chem. Soc. 2008, 130,
11970–11978.
(CH2)3OBn 10d
(CH2)4OBn 10e
(CH2)3Cl 10f
(8) Trost, B. M. Science 1991, 254, 1471–1477.
a Yields refer to pure, isolated products.
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