Carboxylate-assisted ruthenium(II)-catalyzed hydroarylations of unactivated alkenes through C-H cleavage

Article abstract of DOI:10.1002/anie.201208446

Catalytic: Ruthenium(II)biscarboxylate complexes enabled highly effective hydroarylations of unactivated alkenes through C-H bond activation. This method has a broad substrate scope and allowed for versatile functionalizations of highly fluorinated alkenes.

Full text of DOI:10.1002/anie.201208446

Angewandte
Chemie
DOI: 10.1002/anie.201208446
C–H Activation
Carboxylate-Assisted Ruthenium(II)-Catalyzed Hydroarylations of
Unactivated Alkenes through C–H Cleavage**
Marvin Schinkel, Ilan Marek, and Lutz Ackermann*
Table 1: Optimization of ruthenium-catalyzed hydroarylation.[a]
À
Metal-catalyzed functionalizations of unactivated C H bonds
have in recent years emerged as increasingly viable methods
[1]
À
for the step-economical formation of C C bonds. Partic-
À
ularly, direct additions of arenes onto C C multiple bonds are
highly attractive because of their perfect atom-economy.[2,3]
Based on pioneering studies by Murai, Kakiuchi, and
Chatani,[4,5] ruthenium complexes were identified as arguably
Entry
Additive
–
Solvent
T [8C]
Yield [%]
the most versatile catalysts for hydroarylations through
cleavages of unactivated C H bonds. Thus far, the highest
1
2
3
4
5
6
7
8
PhMe
PhMe
PhMe
PhMe
120
100
100
100
100
120
120
120
120
120
120
80
–
–
[c]
[6]
À
NaPF6
[c]
KPF6
–
catalytic activities were achieved with low-valent ruthenium
catalysts, such as [RuH2(CO)(PPh3)3], [RuH2(PPh3)4],
[Ru(CO)2(PPh3)3], [Ru3(CO)12], or [RuH2(H2)2(PCy3)2],
which are unfortunately often rather unstable or relatively
expensive. A significant practical progress was, however,
recently achieved by Darses, Genet et al. through the elegant
in situ formation of [RuH2(PPh3)4] from [{RuCl2(p-
cymene)}2], sodium formate, and PPh3.[7] Whereas this
catalytic system displayed a remarkably high catalytic activity,
it proved as of yet restricted to activated alkenes, namely vinyl
silanes and styrenes. In recent years, carboxylate assistance
was found to be the key to success for versatile ruthenium-
AgOTf
AgOAc
KOAc
KOPiv
13[b]
PhMe
27[b]
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
PhMe
H2O
PhMe
PhMe
PhMe
48[b]
56[b]
KO2CAd
KO2CMes
KO2CMes
KO2CMes
KO2CMes
KO2CMes[c,d]
KOAc[c,d]
80,[b] 71
85,[b] 72
95,[b] 79
>99,[b] 74
90,[b] 75
95,[b] 82
66,[b] 54
6[b]
9
10
11
12
13
14
15
100
100
120
[c]
PPh3
PhMe
HCO2Na
À
catalyzed direct C H bond arylations and alkylations as well
[a] Reaction conditions: 1a (1.0 mmol), 2a (3.0 mmol), [{RuCl2(p-
cymene)}2] (2.5 mol%), additive (30 mol%), solvent (3.0 mL), yields of
isolated products. Ad=adamantyl; Mes=2,4,6-trimethylphenyl; Piv=
pivaloyl; Tf=trifluoromethanesulfonyl. [b] Conversion determined by GC
using ntridecane as internal standard. [c] Additive (15 mol%). [d] 2a
(2.0 mmol), [{RuCl2(p-cymene)}2] (1.25 mol%).
[8,9]
À
as oxidative C H bond transformations.
Despite these
notable advances, metal carboxylates[10] were as of yet not
exploited as cocatalytic additives for ruthenium-catalyzed
hydroarylations. Within our research program on atom-
economical hydroarylations,[11] we unraveled highly efficient
and broadly applicable ruthenium(II)biscarboxylate catalysts
À
for additions of C H bonds onto unactivated alkenes, on
which we report herein.
À
We commenced our studies by exploring the effect of
representative cocatalytic additives for the ruthenium-cata-
lyzed hydroarylation of the challenging unactivated alkene 2a
(Table 1). Not surprisingly, simple [{RuCl2(p-cymene)}2] did
not affect the desired C H bond functionalization in the
absence of an additive (entry 1). Likewise, the use of cationic
complexes derived in situ from among others KPF6 or AgOTf
led only to unsatisfactorily low yields (entries 2–5). On the
contrary, more promising results were achieved when utilizing
metal carboxylates as additives, with sterically demanding
KO2CMes providing optimal yields of the desired mono-n-
alkylated product 3aa (entries 6–9). Among a set of repre-
sentative solvents, most efficient catalysis was accomplished
in toluene (entries 9–13). However, the excellent chemo-
selectivity also allowed the use of water as environmentally
benign, nontoxic, and inexpensive reaction medium
(entry 11), and enabled efficient catalysis at lower reaction
temperatures, thereby again illustrating the beneficial fea-
tures of the KO2CMes-derived catalyst (entries 12–14). Nota-
bly, the carboxylate-derived ruthenium(II) complex was
found to be superior in the hydroarylation of unactivated
alkene 2a when compared to reported[7] ruthenium catalysts
(entry 15).
[*] Dipl.-Chem. M. Schinkel, Prof. Dr. L. Ackermann
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt
Tammannstrasse 2, 37077 Gçttingen (Germany)
E-mail: lutz.ackermann@chemie.uni-goettingen.de
Homepage: http://www.org.chemie.uni-goettingen.de/ackermann/
Prof. Dr. I. Marek
Schulich Faculty of Chemistry
Technion-Israel Institute of Technology
Haifa 32000 (Israel)
[**] Support by the Niedersachsen-Technion Research Cooperation
Program and the European Research Council under the European
Community’s Seventh Framework Program (FP7 2007–2013)/ERC
Grant agreement no. 307535 is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208446.
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Scheme 1. Scope of hydroarylations of alkenes 2.
With an optimized catalytic system in hand, we next
explored its versatility by employing a variety of unactivated
alkenes 2 (Scheme 1). Differently substituted unactivated
alkenes furnished the corresponding products 3 in high yields.
The catalytic system proved to be tolerant of valuable
functional groups, such as ether, ketone, hydroxy, or ester
substituents. Intriguingly, competition experiments with halo-
alkenes 2o and 2p highlighted the excellent chemoselectivity
of the carboxylate-assisted hydroarylations, in that products
Scheme 2. Carboxylate-assisted hydroarylations with arenes 1.
À
stemming from direct C H bond alkylations with alkyl halide
moieties[12] were not observed. This selectivity pattern is likely
due to the absence of stoichiometric amounts of a carbonate
base.
Carboxylate-assisted ruthenium(II)-catalyzed hydroary-
lation further set the stage for the high-yielding conversion of
ortho-, meta-, and para-substituted arenes, thereby selectively
delivering the monosubstituted products 3ba–3ka
(Scheme 2). Notably, the optimized catalyst was not restricted
À
to pyridine derivatives. Indeed, the C H bond functionaliza-
tion also occurred site-selectively on pyrazolyl and imida-
zolyl-substituted arenes (3li–3ni), even when being N-unpro-
tected (3ni).
In consideration of the crucial importance of heteroarenes
as the key structural motifs in various bioactive molecules, we
were delighted to observe that hydroarylations with indole
and thiophene derivatives 4a–4d proceeded in a site-selective
manner as well (Scheme 3). The use of 2-pyrimidyl directing
groups on the indole nitrogen atom[13] (4b, and 4c) could
furthermore be utilized for a strategy employing removable
directing groups.
Scheme 3. Carboxylate-assisted hydroarylations with heteroarenes 4.
interactions were largely influencing the site selectivity
(Scheme 4). However, heteroatom substituents in substrates
1q and 1r led to the predominant functionalization at the
sterically more congested C2 positions.
Given the high catalytic activity and remarkably broad
scope of the carboxylate-assisted ruthenium-catalyzed hydro-
arylation, we became attracted by probing its mode of action.
To this end, intramolecular competition experiments with
meta-substituted arenes 1o and 1p revealed that steric
Intermolecular competition experiments with substituted
starting materials highlighted that the nucleophilicity of the
arenes did not influence their relative reactivities (Scheme 5
and the Supporting Information), thus rendering an electro-
philic reaction mechanism unlikely to be operative. Contra-
2
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Scheme 4. Hydroarylations with meta-substituted arenes 1o–r.
Scheme 7. Hydroarylations with isotopically labeled compounds.
Based on these experimental findings, our competition
experiments, and previous mechanistic insight,[6] we propose
the reductive elimination to be the rate-determining step
(Scheme 8).
Scheme 8. Proposed reaction mechanism. Alk=alkyl.
Scheme 5. Intermolecular competition experiments.
In recent years, the preparation of fluorinated compounds
has attracted significant interest, since fluorine uniquely
affects the properties of organic molecules and thus enhances
solubility, bioavailability, and metabolic stability compared to
nonfluorinated analogues.[15,16] Therefore, we were pleased to
observe an outstanding catalytic efficacy in challenging
hydroarylations with highly fluorinated alkene 7 through
rily, the inductive effect of the heteroatom substituent was
found to be of key importance.
As to the working mode of the catalyst, it is further
noteworthy that well-defined biscarboxylate complex 6[12a,14]
led to isolation of product 3aa in a yield comparable to the
one obtained with the in situ generated catalytic system
(Scheme 6).
À
carboxylate-assisted C H bond functionalization (Scheme 9).
Ruthenium-catalyzed hydroarylations with D2O or iso-
In summary, we have reported on carboxylate-assisted
ruthenium-catalyzed hydroarylations of unactivated alkenes
employing various (hetero)arenes with ample scope. Thus,
ruthenium(II)biscarboxylate complexes enabled versatile
À
topically labeled substrate [D5]-1a indicated the C H bond
metalation to be reversible in nature (Scheme 7).
À
atom- and step-economical additions of C H bonds onto
unactivated alkenes, and allowed for the synthesis of highly
fluorinated alkylated arenes.
Received: October 19, 2012
Revised: February 1, 2013
Scheme 6. Ruthenium(II)biscarboxylate catalyst 6.
Published online: && &&, &&&&
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Scheme 9. Hydroarylations of fluorinated alkene 7.
Keywords: alkenes · arenes · C–H functionalization ·
.
homogeneous catalysis · ruthenium
À
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4
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Angewandte
Chemie
Communications
C–H Activation
M. Schinkel, I. Marek,
L. Ackermann*
&&&& — &&&&
Carboxylate-Assisted Ruthenium(II)-
Catalyzed Hydroarylations of Unactivated
Alkenes through C–H Cleavage
Catalytic: Ruthenium(II)biscarboxylate
complexes enabled highly effective
hydroarylations of unactivated alkenes
method has a broad substrate scope and
allowed for versatile functionalizations of
highly fluorinated alkenes.
À
through C H bond activation. This
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5
These are not the final page numbers!