Csp3-H bond activation triggered by formation of metallacycles: Rhodium(I)-catalyzed cyclopropanation/cyclization of allenynes

Article abstract of DOI:10.1002/anie.201203772

Giving direction: An Ca spa 3-H bond activation directed by a rhodacycle intermediate has been found to occur in a Rh^I-catalyzed reaction between an allene moiety having a tert-butyl substituent, and tethered alkynes. Cyclic compounds containing a cyclopropane ring were obtained in good to high yields (up to 92%). Copyright

Full text of DOI:10.1002/anie.201203772

Angewandte
Chemie
DOI: 10.1002/anie.201203772
Homogeneous Catalysis
À
Csp3 H Bond Activation Triggered by Formation of Metallacycles:
Rhodium(I)-Catalyzed Cyclopropanation/Cyclization of Allenynes**
Yoshihiro Oonishi,* Yoshitaka Kitano, and Yoshihiro Sato*
solvent employed (Scheme 2).[6] That is, the reaction of an
allenyne with [Cp*RuCl(cod)] in toluene proceeded via
ruthenacycle intermediate I, which then underwent cyclo-
dimerization to give a pentacyclic compound.[6a] On the other
hand, the reaction of the same substrate with the same
catalyst in MeOH proceeded via ruthenacycle II, and
a bicyclic compound was exclusively produced through
a [2+2] cycloaddition.[6b]
À
Transition-metal-catalyzed selective C H activation has
become one of the most powerful and straightforward
strategies for the construction of complex molecules in
synthetic organic chemistry.[1,2] Aliphatic Csp3 H bonds have
no p electrons that can readily interact with transition metal
complexes, and site-selective activation of Csp3 H bonds
À
À
therefore remains as one of the most challenging topics for
synthetic chemists.[1k] Most of the Csp3 H activations that have
À
been reported so far need the assistance of directing groups
(DG), most of which contain a nitrogen or oxygen atom at the
appropriate position in the substrate [Scheme 1, Eq. (1)] for
site-selective activation. However, such directing groups
À
Scheme 1. C H activation process.
might be incorporated in the products, and they often
cannot be easily removed or be converted into other valuable
Scheme 2. [Cp*RuCl(cod)]-catalyzed cyclizations of allenynes. cod=cy-
clooctadiene.
functional groups.[3] Thus, new strategies for Csp3 H activa-
À
tions that do not incorporate directing groups in the product
are needed.[1k] Herein we report a Csp3 H bond activation that
During the course of screening catalysts for these
reactions, we encountered another type of cyclization of
allenynes (Scheme 3).[7,8] Thus, treatment of substrate 1a[6a]
with 10 mol% of [Rh(IMes)(cod)]ClO4, which was generated
in situ from [Rh(IMes)(cod)Cl] and AgClO4, in dichloro-
ethane at 658C for 2 h gave [2+2] cyclization product 2a in
À
is triggered by the formation of a metallacycle intermediate
[Scheme 1, Eq. (2)].[4,5]
We recently reported two types of novel ruthenium-
catalyzed cyclizations of allenynes; the reaction pathway of
the cyclization dramatically changed depending on the
[*] Dr. Y. Oonishi, Y. Kitano, Prof. Dr. Y. Sato
Faculty of Pharmaceutical Sciences, Hokkaido University
Nishi 6, Kita 12, Kita-ku, Sapporo 060-0812 (Japan)
E-mail: biyo@pharm.hokudai.ac.jp
Homepage: http://gouka.pharm.hokudai.ac.jp/FSC/jpn/page/
top_page.htm
[**] This work was financially supported by Grants-in-Aid for Young
Scientist (B) (No. 20790002) and for Scientific Research (B) (No.
23390001) from the Japan Society for the Promotion of Science
(JSPS) and also by a Grant-in-Aid for Scientific Research on
Innovative Areas “Molecular Activation Directed toward Straight-
forward Synthesis (No. 23105501)” from the Ministry of Education,
Culture, Sports, Science and Technology (Japan). Y.O. acknowledges
the Akiyama Foundation for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203772.
Scheme 3. RhI-catalyzed cyclization of allenyne.
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Table 2: Cyclization of a range of substrates.[a,b]
8% yield[6b,9,10] along with the unexpected cyclic product 3a,
which contains a cyclopropane ring, in 15% yield.[11] We
hypotesized that the cyclic compound 3a could be produced
À
through a process that involves a Csp3 H activation of the tert-
butyl moiety in the substrate. We therefore decided to further
investigate this cyclization.[12]
To improve the yield of 3a, the reaction of 1a in the
presence of various cationic RhI complexes was examined
(Table 1). In contrast to the use of [Rh(IMes)(cod)]ClO4
Table 1: Cyclopropanation/cyclization using various RhI complexes.
Entry
RhI Complex
t [h]
Yields [%][a]
2a
3a
1[b]
2[b]
3[b]
4[c]
[Rh(IMes)(cod)]ClO4
[Rh(IiPr)(cod)]ClO4
[Rh(ICy)(cod)]ClO4
[Rh(tBu3P)(cod)]ClO4
2
1
1
1
8
–
–
–
15
90(88)
89(80)
60
[a] Yields were determined by 1H NMR spectroscopy using 1,1,2,2-
tetrachloroethane as an internal standard. Yields of the isolated products
are given in parentheses. [b] [Rh(NHC)(cod)Cl] (10 mol%) + AgClO4
(10 mol%). [c] [Rh(cod)2]ClO4 (10 mol%) + tBu3P (10 mol%).
(Table 1, entry 1), when [Rh(IiPr)(cod)]ClO4 or [Rh(ICy)-
(cod)]ClO4, which both have a bulky alkyl group on the
nitrogen atom of the N-heterocyclic carbene (NHC), were
used, the cyclopropane-containing cyclized product 3a was
formed selectively, in 90% and 89% yield, respectively
(Table 1, entries 2 and 3). The use of a bulky electron-rich
phosphine, tBu3P, also gave the desired product 3a in 60%
yield (Table 1, entry 4). On the other hand, the use of other
Rh/NHC complexes (e.g., [Rh(IPr)(cod)]ClO4 and
[Rh(IMe)(cod)]ClO4) as well as rhodium phosphine com-
plexes (e.g., [Rh(PPh3)3]ClO4, [Rh(dppe)(cod)]ClO4, and
[Rh(dppb)(cod)]ClO4) did not afford the cyclic compound
3a.[13]
[a] All reactions were carried out using 10 mol% of [Rh(IiPr)(cod)]ClO4 in
ClCH2CH2Cl. E=CO2Me. [b] Yields of the isolated products. [c] The
cycloisomerization product 4i was obtained (66% yield) via rhodacycle
intermediate III followed by b-hydride elimination (see below).
To investigate the generality of this cyclization, various
substrates were examined (Table 2). The reaction of 1b,[6a]
which has a cyclic acetal moiety, in the presence of 10 mol%
of [Rh(IiPr)(cod)]ClO4 catalyst smoothly proceeded even at
room temperature to give the cyclopropane-containing
cyclized product 3b in 92% yield (Table 2, entry 1). In the
reactions of 1c[6a] and 1d, which contain a heteroatom in the
chain, the corresponding heterocycles 3c and 3d were
produced in modest yields (Table 2, entries 2 and 3). The
presence of an oxygen-containing functionality such as
a silyloxy group (1e) or an aldehyde moiety (1 f) in the
alkyne side chain is tolerated in this cyclization, thus giving 3e
and 3 f in 75% and 91% yields, respectively (Table 2, entries 4
and 5). The reaction of 1g, which contains an electron-
withdrawing substituent on the alkyne moiety, also afforded
the desired product 3g in 51% yield (Table 2, entry 6). This
cyclization was also applied to the construction of a five-
membered ring, and the desired compound 3h was obtained
from 1h in 63% yield (Table 2, entry 7). On the other hand,
the cyclization of 1i, which has an isopropyl moiety instead of
a tert-butyl moiety at the terminus of the allene, afforded no
cyclopropane-containing product 3i but produced cycloiso-
merization product 4i in 66% yield (Table 2, entry 8).[8a–c]
A plausible mechanism for this cyclopropanation/cycliza-
tion is shown in Scheme 4. Initially, oxidative cycloaddition of
2
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Scheme 6. Kinetic isotope competition experiment.
Scheme 4. Plausible reaction mechanism.
effect.[15] Thus, we performed a kinetic isotope competition
experiment using an equimolar mixture of allenyne 1a and
[D9]-1a (Scheme 6).[16] Several reactions of a 1:1 mixture of 1a
and [D9]-1a with 10 mol% of [Rh(IiPr)(cod)]ClO4 at room
temperature were carried out and quenched at various stages
(20–120 min). The reactions quenched at an early stage
(20 min) gave a mixture of 3a and [D9]-3a in a range of 9–
14% yields in a ratio of 3a/[D9]-3a = 77.8:22.2 ꢀ 80.7:19.3,
from which the KIE of this reaction is calculated to be
approximately 3.9. These results strongly support our hypoth-
esis that the cyclopropanation/cyclization proceeds according
to the mechanism shown in Scheme 4, as well as our
=
the alkyne and the external C C bond of the allene moiety of
substrate 1 to a cationic RhI complex would occur to produce
rhodacycle intermediate A. By virtue of the formation of
À
rhodacycle A, one Csp3 H bond on the tert-butyl moiety would
be close to the cationic RhIII center, thus resulting in Csp3
À
H
bond activation (A’). Subsequently, s-bond metathesis
À
À
between the activated Csp3 H bond and the Rh Csp3 bond of
the rhodacycle would occur via a transition state such as B to
produce rhodium hydride intermediate C.[14] Finally, reduc-
tive elimination from C would lead to the cyclopropane-
containing product 3 with regeneration of a cationic RhI
complex.
To gain an insight into the reaction mechanism, we
investigated the reaction of [D9]-1a, which contains a com-
pletely deuterium-labeled tert-butyl moiety (Scheme 5).
À
hypothesis that the cleavage of the Csp3 H bond is the rate-
determining step.
In summary, we have succeeded in demonstrating a pro-
À
tocol for an Csp3 H bond activation directed by the formation
of metallacycle intermediates in the cyclization of allenynes,
thus giving cyclic compounds containing a cyclopropane
structure in good to high yields. Deuterium-labeling experi-
À
ments supported the occurence of a Csp3 H bond activation
À
followed by cleavage of the C H bond, which is most likely
the rate-determining step in this cyclization. These results
À
should provide new insights into the chemistry of Csp3
activations, and further studies along this line are now in
progress.
H
Scheme 5. Cyclization of [D9]-1a.
Received: May 16, 2012
Published online: && &&, &&&&
Unexpectedly, the reaction of [D9]-1a under the same
reaction conditions as those shown in Table 1, entry 2 gave
a complex mixture of products instead of the desired cyclo-
propane-containing product [D9]-3a. On the other hand,
when the reaction of [D9]-1a was carried out at room
temperature, the reaction was sluggish but produced the
corresponding cyclopropane-containing cyclized product
[D9]-3a in a low yield (29%); in this reaction a deuterium
atom was transferred to the expected position on the alkene
moiety in > 95%.
À
Keywords: allenyne · C H activation · cyclization ·
cyclopropane · rhodium
.
À
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À
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À
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À
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À
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À
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À
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À
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4
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
À
Homogeneous Catalysis
Giving direction: An Csp3 H bond activa-
tion directed by a rhodacycle intermediate
has been found to occur in a RhI-cata-
lyzed reaction between an allene moiety
having a tert-butyl substituent, and teth-
ered alkynes. Cyclic compounds contain-
ing a cyclopropane ring were obtained in
good to high yields (up to 92%).
Y. Oonishi,* Y. Kitano,
Y. Sato*
&&&& — &&&&
À
Csp3 H Bond Activation Triggered by
Formation of Metallacycles: Rhodium(I)-
Catalyzed Cyclopropanation/Cyclization
of Allenynes
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!