Ruthenium(II)-catalyzed C-H alkenylations of phenols with removable directing groups

Article abstract of DOI:10.1002/chem.201301988

Cationic ruthenium(II) complexes enabled oxidative alkenylations of phenols bearing easily cleavable directing groups. The optimized catalytic system allowed twofold C-H bond activations with excellent chemo-, site-, and diastereoselectivities. The double

Full text of DOI:10.1002/chem.201301988

FULL PAPER
DOI: 10.1002/chem.201301988
ꢀ
Ruthenium(II)-Catalyzed C H Alkenylations of Phenols with Removable
Directing Groups
[
a]
Wenbo Ma and Lutz Ackermann*
Abstract: Cationic ruthenium(II) complexes enabled oxidative alkenylations of
phenols bearing easily cleavable directing groups. The optimized catalytic system
allowed twofold CꢀH bond activations with excellent chemo-, site-, and diastereo-
selectivities. The double CꢀH functionalization process proceeded efficiently in an
Keywords: alkenylation · catalysis ·
CꢀH activation · cross-dehydrogen-
ative coupling · reaction mecha-
nisms · ruthenium
aerobic fashion under an atmosphere of ambient air. Detailed mechanistic studies
were performed and provided strong support for an initial reversible CꢀH bond
activation by the formation of six-membered ruthenacycles as the key intermedi-
ates.
Introduction
Results and Discussion
Cross-dehydrogenative alkenylations of arenes by twofold
Optimization studies: Given the broad synthetic utility of
[9]
CꢀH bond activation have emerged as increasingly viable
phenols and derivatives thereof, at the outset of our stud-
ies we probed reaction conditions for the oxidative alkenyla-
tion of arene 1a (Table 1). While carboxylate additives were
found to be mandatory for ruthenium-catalyzed direct aryla-
tools for the atom- and step-economical preparation of styr-
[1]
[2]
ene derivatives. In particular, ruthenium(II) complexes
have very recently been identified as versatile catalysts for
[8]
double CꢀH bond functionalizations with arenes bearing a
tions with aryl halides, they proved to be ineffective for
[3,4]
diverse set of Lewis-basic directing groups.
However, de-
the desired oxidative CꢀH bond functionalization (en-
spite these recent advances, ruthenium-catalyzed oxidative
alkenylations of arenes arguably continue to be limited in
tries 1–4). In contrast, in-situ generated cationic rutheniu-
m(II) complexes enabled the synthesis of desired product
[5–7]
that methods that exploit removable directing groups
are
3aa, with AgSbF giving optimal results (entries 5 and 6).
6
scarce. Given our recent success in the use of a removable
directing group in the direct arylation with aryl halides as
The cationic catalyst thereby even allowed aerobic alkenyla-
[8]
prefunctionalized arylating reagents,
we consequently
became attracted to devising a novel ruthenium-catalyzed
oxidative alkenylation of phenols displaying removable di-
recting groups. As a result of our studies, we report herein
on ruthenium-catalyzed twofold CꢀH functionalization with
Table 1. Optimization of oxidative alkenylation of arene 1a with alkene
2a.
[
a]
arenes and heteroarenes displaying easily cleavable directing
groups. In contrast to the previously reported direct aryla-
tion catalyzed by neutral ruthenium-biscarboxylate com-
[8]
plexes, the new oxidative CꢀH bond functionalization was
only accomplished with cationic ruthenium(II) catalysts.
Entry
Additive
—
KO CMes
2
CsOAc
AgOAc
Cu
A
H
U
G
E
N
N
(OAc)
2
·H
2
O
Yield
[%]
AHCTUNGTR[ENNUNG equiv]
1
2
3
4
5
6
7
8
9
2.0
2.0
2.0
2.0
2.0
2.0
0.3
—
<5
<5
<5
<5
25
KPF
6
AgSbF
AgSbF
AgSbF
AgSbF
6
6
6
6
83
73
[
a] W. Ma, Prof. Dr. L. Ackermann
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt
—
—
[
b]
2.0
Tammannstrasse 2, 37077 Gçttingen (Germany)
Fax : (+49)551-39-6777
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
[
(
a] Reaction conditions: 1a (1.0 mmol), 2a (0.5 mmol), Cu
1.0 mmol), [{RuCl (p-cymene)} (2.5 mol%), t-AmOH (2.0 mL),
AgSbF (10 mol%), yields of isolated products. [b] Without [{RuCl (p-
cymene)} ].
2 2
ACHTUNGTRNENUG( OAc) ·H O
2
A
H
U
G
E
N
N
2
]
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301988.
6
2
ACHTUNGTRENNUNG
2
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tions with cocatalytic amounts of Cu
atmosphere of ambient air as the sacrificial oxidant
entry 7). Furthermore, additional experiments verified that
the transformation did not proceed in the absence of Cu-
(OAc) ·H O or the ruthenium catalyst (entries 8, and 9).
ACHTUNGTNERNU(GN OAc) ·H O under an
2 2
(
ACHTUNGTRENNUNG
2
2
Reaction scope: The versatility of the catalytic system was
subsequently probed in the oxidative alkenylation of differ-
ently substituted 2-aryloxypyridines 1 under an atmosphere
of ambient air (Scheme 1). We were pleased to observe that
Scheme 2. Scope of oxidative twofold CꢀH bond functionalization with
substituted substrates 1.
site selectivities as well (Scheme 2). Notably, various impor-
tant electrophilic functional groups, such as chloro, ester,
ketone, or nitro substituents, were well tolerated by the cat-
alytic system. Moreover, substrate 1q with a substituted pyr-
idyloxy group was converted with a comparable efficacy.
We were, furthermore, delighted to observe that heteroar-
enes proved to be suitable substrates as well, delivering the
synthetically useful indole 3ra and thiophene 3sa
(Scheme 3).
Scheme 1. Ruthenium-catalyzed oxidative direct alkenylation of arenes 1.
the catalyst proved to be broadly applicable and, hence, fur-
nished the desired products 3 in high yields. Notably, an
ortho-CꢀCl bond in substrate 1 f stayed intact, without any
The site-selectivity of the oxidative CꢀH bond functionali-
zation with meta-substituted phenol derivatives was largely
controlled by steric interactions (3ta’–3ua’), whereas the
oxygen of the acetal in arene 1v exerted a notable secon-
dary directing group effect (Scheme 4). It is important to
note that the 2-pyridyloxy directing group was selectively
cleaved to deliver the desired free phenol 4aa (Scheme 5).
indication of its oxidative addition to the ruthenium catalyst.
Furthermore, oxidative alkenylations with a- (1h) and b-
naphthol derivatives (1i) delivered the products 3ha–3hc,
and 3ia and 3ib, respectively, with excellent site selectivities.
Moreover, the catalytic CꢀH bond functionalizations occur-
red with excellent diastereoselectivities, delivering the E dia-
stereomers as the sole products in all cases. However, at-
tempted reactions with cyclohexene were as of yet not
viable.
The optimized ruthenium(II) catalyst was not limited to
substrates bearing ortho substituents, but a variety of phenol
derivatives 1 being devoid of ortho substitution provided the
products of mono-alkenylation 3 with superb chemo- and
Mechanistic studies: Given the high catalytic efficacy of the
optimized catalyst, we became intrigued by probing its
mode of action. To this end, intermolecular competition ex-
periments revealed electron-rich arenes to be preferentially
converted (Scheme 6). This reactivity pattern contrasts pre-
vious observations that we made within direct arylations
with aryl halides catalyzed by neutral ruthenium com-
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CꢀH Alkenylations of Phenols
FULL PAPER
[8]
plexes. In the present study, the inherently higher reactivi-
ty of phenols bearing electron-donating substituents can be
rationalized in terms of an electrophilic-type CꢀH bond
metalation event.
Further support for this mechanistic rationale was ob-
tained from oxidative alkenylations with D O as an additive,
2
which indicated a significant H/D scrambling in the ortho-
positions of the reisolated substrate [D ]-1j and the product
n
[
D ]-3ja (Scheme 7).
n
Scheme 3. Oxidative CꢀH bond functionalization with heterocyclic sub-
strates 1r and 1s.
2 2
Scheme 7. Oxidative alkenylation with D O as an additive (R=CO Et).
Based on these mechanistic studies, we propose the CꢀH
bond activation to occur by a reversible electrophilic-type
metalation event (Scheme 8), which in turn explains the
Scheme 4. Alkenylations with meta-substituted substrates 1t-v.
Scheme 5. Removal of the directing group.
Scheme 8. Proposed catalytic cycle.
unique activity of the cationic ruthenium(II) complexes. The
thus-formed cycloruthenated complex 5 subsequently under-
goes a migratory insertion with the alkene 2 to furnish the
intermediate 6. Finally, b-hydrid-elimination yields the de-
sired product 3, whereas reductive elimination and oxidation
by Cu
ACHTUNGTNERNU(GN OAc) ·H O regenerate the catalytically active ruthe-
2 2
2
Scheme 6. Intermolecular competition experiments (R=CO Et).
nium(II) complex.
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L. Ackermann and W. Ma
Conclusion
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[
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In summary, we have reported on the ruthenium-catalyzed
oxidative alkenylations of arenes displaying removable di-
recting groups. High catalytic efficacy in the twofold CꢀH
bond functionalization process was achieved with a cationic
ruthenium(II) complex, which even occurred in an aerobic
fashion under an atmosphere of ambient air. The optimized
catalyst allowed ruthenium-catalyzed CꢀH bond alkenyla-
tions of phenol derivatives with excellent chemo-, site-, and
diastereoselectivities through the reversible formation of
six-membered ruthenacycles as the key intermediates.
1
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Representative procedure: ruthenium-catalyzed oxidative alkenylation
with substituted pyridines: A suspension of 2-(o-tolyloxy)pyridine (1a)
(
185.4 mg, 1.00 mmol), ethyl acrylate (2a) (52.0 mg, 0.52 mmol), [{RuCl
(p-cymene)} ] (7.6 mg, 2.5 mol%), AgSbF (18.5 mg, 11 mol%) and Cu-
(OAc) ·H O (200 mg, 1.00 mmol) in tAmOH (2.0 mL) was stirred at am-
bient temperature under N for 5 min and then stirred at 1208C for 16 h
under an ambient atmosphere of air. At ambient temperature, the reac-
tion mixture was diluted with saturated aqueous NH Cl/NH (1:1, 10 mL)
and extracted with EtOAc (3ꢃ25 mL). The combined organic layers
were dried over Na SO . After filtration and evaporation of the solvents
2
-
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
6
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
2
2
4
3
3
481.
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86–896.
[
[
2
4
8
in vacuo, the crude product was purified by column chromatography on
silica gel (n-hexane/EtOAc: 15/1!10/1) to yield 3aa (122 mg, 83%) as a
colorless solid.
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[
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Support by the European Research Council under the European Com-
munityꢄs Seventh Framework Program (FP7 2007–2013)/ERC Grant
agreement no. 307535, and the Chinese Scholarship Council (fellowship
to W.M.) is gratefully acknowledged. We further thank Mr. Carsten
Rauch (Georg-August-Universitꢁt) for experimental support.
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Received: May 23, 2013
Published online: && &&, 0000
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CꢀH Alkenylations of Phenols
FULL PAPER
CꢀH Activation
W. Ma, L. Ackermann* ..... &&&& — &&&&
Ruthenium(II)-Catalyzed CꢀH Alke-
nylations of Phenols with Removable
Directing Groups
Cationic ruthenium(II) complexes ena-
bled oxidative alkenylations of phenols
bearing cleavable directing groups with
excellent site- and chemoselectivities.
The twofold CꢀH functionalization
efficiently proceeded in an aerobic
fashion under ambient air.
Chem. Eur. J. 2013, 00, 0 – 0
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!