A rhodium-catalyzed C-H activation/cycloisomerization tandem

Article abstract of DOI:10.1021/ja0746316

A reaction cascade comprising a rhodium-catalyzed C-H activation, a subsequent hydrometalation of an alkylidene cyclopropane in vicinity, regioselective C-C bond activation of the flanking cyclopropane ring, followed by reductive elimination of the result

Full text of DOI:10.1021/ja0746316

Published on Web 11/10/2007
A Rhodium-Catalyzed C-H Activation/Cycloisomerization Tandem
Christophe A¨ıssa and Alois Fu¨rstner*
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim/Ruhr, Germany
Received June 25, 2007; E-mail: fuerstner@mpi-muelheim.mpg.de
Scheme 1. Envisaged C-H Activation/Cycloaddition Crossover
Transition-metal-catalyzed C-H activation has recently gained
considerable momentum and is now widely recognized for its
potential to form a host of C-C and C-heteroatom bonds in an
inherently benign fashion.1 We now present a further expansion of
the scope of this methodology by merging catalytic C-H activation
with higher order cycloaddition into an efficient manifold for the
formation of seven-membered rings.
Scheme 2 a
Our first approach employed substrates of type A bearing an
anchor group G to direct a suitable catalyst M toward a proximal
olefinic Csp2-H bond (Scheme 1).2 Following initial C-H activa-
tion, the resulting vinylmetal hydride species B might undergo
hydrometalation of an alkylidenecyclopropane in vicinity to give
metallacycle C poised for cleavage of the C-C bond of the adjacent
cyclopropane3 to give the ring enlarged complex D. Reductive
elimination then delivers a functionalized cycloalkene and regener-
ates the catalytically competent species.4
a Conditions: (a) (PPh3)3RhCl (5 mol %), AgSbF6 (7.5 mol %), THF,
Relying on the proven efficiency of pyridines as directing groups
in catalytic C-H activation,2b,5 substrate 1 was chosen as a suitable
model.6,7 As shown in Scheme 2, exposure of 1 to (PPh3)3RhCl (5
mol %) and AgSbF6 (7.5 mol %) in THF or 1,2-dichloroethane
(DCE) at 120 °C furnished cycloheptene 2 in 77% yield. It should
be noted that the addition of AgSbF6 was necessary to achieve clean
conversions. The phosphine-free complexes [Rh(CO)2Cl]2 and [Rh-
(coe)2Cl]2 (coe ) cyclooctene) were also suitable, yet somewhat
less efficient. As can be seen from Table 1, substrates with aromatic
as well as aliphatic backbones reacted well with (PPh3)3RhCl/
AgSbF6, independent of whether they are conformationally biased
for ring closure or not; pre-existing chiral centers next to the reacting
sites remained uncompromised. The geometry of the newly formed
trisubstituted exocyclic double bond is evident from pertinent NOE
data and from the X-ray crystal structure of compound 2 (Scheme
2).
120 °C (sealed tube); structure of product 2 in the solid state.
Table 1. Preparation of Cycloheptene Derivatives by a
Pyridine-Directed, Rhodium-Catalyzed C-H
Activation/Cycloisomerizationa
The formation of an E-configured exocyclic olefin is consistent
with a mechanistic scenario comprising a C-H activation/hydro-
metalation/cycloaddition sequence directed by the basic nitrogen
atom of the pyridine ring. This interpretation is also strongly
supported by the labeling experiment depicted in Scheme 3, which
features the expected and, within the limits of detection, quantitative
transfer of the deuterium atom from the site of initial C-H(D)
activation to the newly formed double bond.
Next, we aimed at replacing the 2-vinylpyridine trigger by other
moieties amenable to catalytic C-H activation.7 To this end,
alkylidenecyclopropanes with a pendant aldehyde group were
subjected to rhodium-catalyzed cycloisomerization.6,8-10 After some
experimentation, it was found that these substrates convert into
cycloheptenones on exposure to catalytic amounts of [Rh(coe)2Cl]2
and (p-MeOC6H4)3P in DCE at 80-120 °C. Thereby it was
necessary to perform the reaction under ethylene atmosphere to
ensure high yields.11 Under these conditions, the outcome was
largely insensitive to changes in the electronic nature of the substrate
(Table 2, entries 1-3). Like in the pyridine series, compounds with
a Isolated yields. All reactions were preformed with (PPh3)3RhCl (5 mol
%) and AgSbF6 (7.5 mol %) in THF at 120 °C (sealed tube).
aliphatic and aromatic backbones worked equally well and chiral
centers remained unaffected.
The regio- and stereoselectivity of this novel transformation was
further examined with the enantiopure substrates 19 and 20 bearing
a methyl substituent on the reacting cyclopropyl ring (Scheme 4).6
Insertion of the catalyst into the C-H bond of the aldehyde group
of 19 followed by syn-addition of the resulting Rh-H species to
the adjacent alkene provides metallacycle E as the primary product.
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10.1021/ja0746316 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Deuterium Labeling Experiment
a combination of NMR-based conformational analysis and chirop-
tical methods (cf. Supporting Information), indicates that C-C bond
cleavage as well as reductive elimination took place with retention
of configuration. This finding is in excellent agreement with
conclusions previously reached for related metal-catalyzed higher
order cycloadditions.12
In summary, we have outlined a productive crossover between
catalytic C-H activation and cycloisomerization chemistry. Further
studies on this and related catalysis tandems are subject to ongoing
studies in our laboratories.
Acknowledgment. Financial support by the MPG and the Fonds
der Chemischen Industrie is gratefully acknowledged. We thank
our X-ray and NMR departments for excellent support.
Table 2. Cycloheptenones by Rhodium-Catalyzed C-H
Activation/ Cycloisomerization of Aldehyde Derivativesa,b
Supporting Information Available: Experimental part, NMR
spectra of new compounds, and CD spectra of compound 21. This
material is available free of charge via the Internet at http://pubs.acs.org.
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