Angewandte
Chemie
DOI: 10.1002/anie.201500600
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C H Activation
Hot Paper
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Ruthenium(II)-Catalyzed C H Activation/Alkyne Annulation by
Weak Coordination with O2 as the Sole Oxidant**
Svenja Warratz, Christoph Kornhaaß, Ana Cajaraville, Benedikt Niepçtter, Dietmar Stalke, and
Lutz Ackermann*
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Abstract: Aerobic oxidative C H functionalizations of weakly
coordinating benzoic acids have been accomplished with
versatile ruthenium(II) biscarboxylates under ambient
oxygen or air. Mechanistic studies identified the key factors
controlling the elementary step of the oxidation of the
ruthenium(0) complex.
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F
unctionalizations of unreactive C H bonds by annulations
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of substrates bearing C C multiple bonds are powerful tools
for the step-economical synthesis of bioactive heterocycles.[1]
Recent years have witnessed the emergence of particularly
versatile ruthenium(II) catalysts for oxidative alkyne annula-
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Figure 1. C H activation of weakly coordinating benzoic acids 1 with
O2.
tions[2] by site-selective C H functionalizations.
Despite
[3,4]
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these advances, all the ruthenium(II)-catalyzed alkyne annu-
lations thus far required the use of additional oxidants, such as
copper(II) or silver(I) salts, thereby leading to the formation
of undesired stoichiometric metal-containing by-products. In
contrast, molecular oxygen is significantly more attractive as
a sacrificial oxidant, since it is inexpensive and leads to the
formation of water as the only by-product.[5] Selected aerobic
alkyne annulations have in the past few years been accom-
plished by palladium or rhodium catalysts by exploiting
strongly coordinating nitrogen-containing directing groups, as
elegantly developed by the research groups of Jiao[6] and
Huang.[7–9] In contrast, ruthenium(II)-catalyzed oxidative
the cheapest sacrificial oxidant in the absence of any
cooxidant (Figure 1). Herein, we present a user-friendly
ruthenium(II) biscarboxylate catalyst that allowed for first
aerobic alkyne annulations by weak oxygen-coordina-
tion,[11,12] along with mechanistic insights that highlight the
key factors governing the crucial oxidation by molecular
oxygen.
We commenced our studies by probing the oxidative
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C H/O H functionalization of 2-methylbenzoic acid (1a)
with diphenylacetylene (2a) under an atmosphere of ambient
oxygen (see Table 1 and Tables S1–S3 in the Supporting
Information).
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C H alkynylations with ambient oxygen have unfortunately
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proven elusive. Within our program on sustainable C H
Methanol was identified as being the optimal solvent
(entries 1–7). The desired synthesis of isocoumarin 3aa also
occurred under an atmosphere of ambient air, albeit with
a somewhat reduced efficacy (entry 8). Interestingly, different
ruthenium(II) precursors could be employed for efficient
aerobic alkyne annulations (entries 9–11). It is noteworthy
that the well-defined ruthenium(II) biscarboxylate com-
plex[13,14] 4 delivered a comparable yield of the isocoumarin
product 3aa (entry 12).
activation,[10] we developed unprecedented ruthenium-cata-
lyzed oxidative alkyne annulations with molecular oxygen as
[*] M. Sc. S. Warratz,[+] Dr. C. Kornhaaß,[+] M. Sc. A. Cajaraville,
Prof. Dr. L. Ackermann
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt Gçttingen
Tammannstrasse 2, 37077 Gçttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
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We tested the versatility of the aerobic oxidative C H/
O H functionalization under the optimized reaction condi-
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B. Niepçtter, Prof. Dr. D. Stalke
Institut fꢀr Anorganische Chemie
Georg-August-Universitꢁt Gçttingen
Tammannstrasse 4, 37077 Gçttingen (Germany)
tions (Scheme 1). The in situ formed ruthenium(II) biscarb-
oxylate complex proved to be broadly applicable and ortho-,
para-, and meta-substituted benzoic acids 1 were efficiently
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converted into the corresponding isocoumarins 3. The C H
[+] These authors contributed equally to this work.
functionalizations proceeded with excellent positional selec-
tivity induced by the proximal carboxylic acid functionality.
The robust ruthenium(II) catalyst was tolerant of valuable
electrophilic functional groups, such as amino, bromo, and
iodo substituents. We were also pleased to observe that
heteroaromatic substrates, such as indoles, furans, and
thiophenes, proved suitable for the alkyne annulation process
[**] Generous support by the European Research Council under the
European Community’s Seventh Framework Program (FP7 2007–
2013)/ERC Grant agreement no. 307535, and the CaSuS PhD
program is gratefully acknowledged. We thank Dr. Frauendorf
(University Gçttingen) for support of the mass spectrometry
studies.
Supporting information for this article is available on the WWW
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(3na–3pa). Interestingly, the C H ruthenation occurred site-
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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