Propargyl alcohols as β-oxocarbenoid precursors for the ruthenium-catalyzed cyclopropanation of unactivated olefins by redox isomerization

Article abstract of DOI:10.1021/ja200971v

An atom-economical method for the direct synthesis of [3.1.0]- and [4.1.0]-bicyclic frameworks via Ru-catalyzed redox bicycloisomerization of enynols is reported. The presented results highlight the unique reactivity profile of propargyl alcohols, which f

Full text of DOI:10.1021/ja200971v

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Propargyl Alcohols as β-Oxocarbenoid Precursors for the
Ruthenium-Catalyzed Cyclopropanation of Unactivated Olefins by
Redox Isomerization
Barry M. Trost,* Alexander Breder, B. Michael O’Keefe, Meera Rao, and Adam W. Franz
Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States
S Supporting Information
b
Scheme 1. Synthetic Concept
ABSTRACT: An atom-economical method for the direct
synthesis of [3.1.0]- and [4.1.0]-bicyclic frameworks via Ru-
catalyzed redox bicycloisomerization of enynols is reported.
The presented results highlight the unique reactivity profile
of propargyl alcohols, which function as β-oxocarbene
precursors, in the presence of a ruthenium(II) complex.
Furthermore, a rare case of a formal vinylic CꢀH insertion
reaction is described.
Scheme 2. Access to β-Oxo Ruthenium Carbenoids via
Redox Isomerization of Propargyl Alcohols
ransition-metal carbenes play a fundamental role as reactive
T
intermediates in modern synthetic chemistry.1 Common
transformations include CꢀH insertion reactions and hetero-
atomꢀhydrogen bond functionalization as well as olefin
cyclopropanations.1 In view of their synthetic utility, significant
efforts have been devoted to the development of novel proce-
dures for the generation and use of transition-metal carbenes.
Among other applications, metal carbenes have proven to be
particularly useful in the construction of complex molecular
frameworks.2 A prevalent method for accessing these reactive
intermediates is the metal-catalyzed fragmentation of diazo
compounds.3 In particular, R-diazo carbonyl compounds have
found multifarious application in carbene chemistry.2 In stark
contrast to the well-studied R-oxo metal carbenes, the corre-
sponding β-homologues with acidic R-protons have, to the best
of our knowledge, not been the subject of investigations regard-
ing catalytic transformations.4 This substantial lack of preparative
applications is in part due to the fact that methods for the
synthesis of the corresponding β-diazo carbonyl precursors are
absent (Scheme 1).5 As a viable solution, we herein report the
ruthenium-catalyzed redox bicycloisomerization of enynol deri-
vatives, which presumably proceeds via a β-oxo ruthenium
carbenoid intermediate.
versatile avenue to a large variety of carbo- and heterocyclic
frameworks possessingan intricate architecture. The cyclopropane
entity can easily be subjected to further manipulation (e.g.,
hydrogenolysis), allowing for facile construction of quaternary
stereogenic centers in five- and six-membered-ring systems.10 (3)
Under optimized conditions, the ruthenium carbenoid displays
high selectivity for cyclopropanation over CꢀH insertion, which is
in diametrical contrast to some cases of rhodium-based carbenes.2b
In order to test our hypothesis, enynol 3a was initially reacted
with 3 mol % IndRu(PPh3)2Cl (1; Ind = indenyl anion) in the
presence of indium triflate (3 mol %) and CSA (5 mol %) in
tetrahydrofuran (THF) (0.05 M) at 66 °C (Table 1).11 Over the
course of 6 h under these conditions, an inseparable mixture of
three compounds in a 1:1:1 ratio was isolated (30% yield;
1
entry 1).12 By means of H NMR analysis, the products were
In the course of our research program on the redox isomer-
ization of propargyl alcohols to R,β-unsaturated carbonyl
compounds,6 we became interested in the question of whether
transiently formed ruthenium carbenoid species IIb could react
with a pendant olefin to provide an annulated cyclopropane ring
system (Scheme 2).7 Such a process bears significant advantages
over traditional methods: (1) The formation of bicyclic ketones
and aldehydes of type 4 proceeds in an isohypsic (overall redox-
neutral) manner, which efficiently circumvents the need for
separate redox manipulation steps (e.g., diazotization). (2) This
protocol provides a nondissipative,8 atom-economical,9 and
identified to be the desired bicyclic ketone 5a along with enone
6a and unexpected cyclohexane 7a. Use of sterically less demand-
ing CpRu(PPh3)2Cl (2) as the precatalyst and extension of the
reaction time to 18 h resulted in an increase in the overall yield to
78% (entry 2). More importantly, under these conditions,
cycloadduct 5a was the major product. A screening for solvents
revealed that the use of acetone (0.25 M) further increased the
Received: January 31, 2011
Published: March 14, 2011
r
2011 American Chemical Society
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Table 1. Optimization of the Redox Bicycloisomerization
Reactiona
isomer selectivity in favor of compound 5a (74% yield; entry 4).
Under these conditions, the formation of the corresponding
enone 6a was completely suppressed. Increasing the concentra-
tion to 1 M (entry 5) did not significantly affect either the overall
yield or the product selectivity. However, when the reaction was
carried out in toluene, diminished product selectivity was ob-
served (5a:6a = 2.8:1; entry 3). It is important to note that other
transition-metal complexes containing platinum, palladium, and
chromium have been reported to catalyze enyne cycloisomeriza-
tion reactions, but in contrast to our observations, formation of
[4.1.0]-bicyclic structures has been reported to be generally
either impossible or low-yielding.13
With an efficient set of conditions in hand, we next analyzed
the scope of this process. For this purpose, a variety of functio-
nalized enynols was prepared and tested in the redox bicyclo-
isomerization (Table 2). In general, both the [3.1.0]- and [4.1.0]-
bicyclic ring systems were obtained in reasonable to very good
yields ranging from 52 to 88%. Furthermore, functional groups
such as ethers, esters, sulfonamides, and olefins were all tolerated
under the operating reaction conditions. Of particular impor-
tance is the observation that additional alkenes distal to the
propargyl alcohol entity (entry 5) are well-tolerated in this
transformation. This finding underscores the pronounced degree
of chemoselectivity inherent in this method. As indicated in
Table 1, the isomer selectivity was strongly dependent on the
nature of the precatalyst and the solvent. This impact was
yield [%]b
entry
complex
solvent/conc.
5a
6a
7a
1
1
2
2
2
2
THF/0.05 M
THF/0.05 M
toluene/0.25 M
acetone/0.25 M
acetone/1 M
10
53
41
74
72
10
2
10
23
0
2
3c
17
0
4
9
5
0
8
a Conditions: enynol (0.19 mmol) was heated to 56 °C (acetone) or 66 °C
(THF, toluene). b Yields of the various isomers were determined by H
1
NMR analysis. c 42% of 3a was recovered.
Table 2. Scope of the Redox Bicycloisomerization Reactiona
a Conditions: enynol (0.19ꢀ0.25 mmol), CpRu(PPh3)2Cl (5 mol %), CSA (3 mol %), and In(OTf)3 (5 mol %) were heated to reflux in freshly distilled
acetone (0.25 M) for 2ꢀ21 h. b Isomer 7 was also formed during this experiment (for more details, see the Supporting Information). c Yields refer to the
depicted isomer 5. d For this experiment, the conditions described in entry 1 of Table 1 were applied.
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Scheme 3. Proposed Catalytic Cycle
’ AUTHOR INFORMATION
Corresponding Author
bmtrost@stanford.edu
’ ACKNOWLEDGMENT
This work was supported in part by fellowships for A.B.,
B.M.O., and A.W.F. from the German Academic Exchange
Service (DAAD), the American Cancer Society, and the
Deutsche Akademie der Naturforscher Leopoldina, respectively.
We thank the U.S. National Science Foundation for their
generous support of our program. We thank Umicore for a
generous gift of ruthenium salts used to prepare the catalysts.
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particularly evident in the case of substrate 3d. While the use of
precatalyst 1 in THF (Table 1, entry 1) afforded isomers 5d and
7d in 26 and 52% isolated yield, respectively (not shown), the
formation of isomer 7d was completely suppressed when pre-
catalyst 2 in acetone was employed (Table 2, entry 4).
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On the basis of mechanistic investigations previously reported
by our group,6a we propose the following catalytic cycle
(Scheme 3). Upon bidentate coordination of propargyl alcohol
3to the catalyst (structure I) followedby1,2-hydridemigration, the
resulting ruthenium carbenoid species IIb presumably undergoes a
[2 þ 2] cycloaddition to give metallacyclobutane intermediate III.
The latter can in turn either proceed through a sequence consisting
of reductive elimination and protiodemetalation to give compound
5 or undergo β-hydride elimination followed by reductive elimina-
tion to afford isomer 7.
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β-oxo carbenoid species for the efficient cyclopropanation of
unactivated olefins. Both [3.1.0]- and [4.1.0]-bicyclic ring sys-
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excellent chemoselectivity. The use of simple propargyl alcohols
as starting materials for the generation of reactive carbenoid
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details and spec-
b
troscopic data (IR, NMR). This material is available free of
charge via the Internet at http://pubs.acs.org.
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