Ruthenium(II)-Catalyzed C?C Arylations and Alkylations: Decarbamoylative C?C Functionalizations

Article abstract of DOI:10.1002/anie.201701231

Ruthenium(II)biscarboxylate catalysis enabled selective C?C functionalizations by means of decarbamoylative C?C arylations. The versatility of the ruthenium(II) catalysis was reflected by widely applicable C?C arylations and C?C alkylations of aryl amides

Full text of DOI:10.1002/anie.201701231

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201701231
German Edition: DOI: 10.1002/ange.201701231
À
C C Activation
À
Ruthenium(II)-Catalyzed C C Arylations and Alkylations:
Decarbamoylative C C Functionalizations
À
Marc Moselage+, Jie Li+, Frederik Kramm, and Lutz Ackermann*
Abstract: Ruthenium(II)biscarboxylate catalysis enabled
À
selective C C functionalizations by means of decarbamoyla-
À
tive C C arylations. The versatility of the ruthenium(II)
À
catalysis was reflected by widely applicable C C arylations
and C C alkylations of aryl amides, as well as acids with
modifiable pyrazoles, through facile organometallic C C
À
À
activation.
À
T
he recent progress in C H activation chemistry has
arguably revolutionized the way in which molecular synthesis
À
Figure 1. C C functionalizations by ruthenium(II) catalysis.
is conducted.[1] In sharp contrast, selective functionalizations
of otherwise inert C C s-bonds continue to be scarce,[2] with
À
[a]
À
Table 1: Ruthenium(II)-catalyzed decarbamoylative C C arylation.
notable recent progress achieved by ruthenium(II) catalysis.[3]
À
In spite of undisputable advances, ruthenium-catalyzed C C
activations are thus far largely restricted to decarboxylation[4]
À
manifolds being devoid of ipso-C C functionalization. Within
our ongoing program on ruthenium(II)-catalyzed[5] step-
economical diversifications,[6] we have identified reaction
conditions for the first ruthenium-catalyzed[7] decarbamoyla-
Entry [Ru]
Additive
Base
Yield [%]
À
tive C C functionalization, on which we report herein.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
[{RuCl2(p-cymene)}2]
MesCO2H KOAc
PPh3
PCy3
AcOH
PhCO2H
1-AdCO2H K2CO3
MesCO2H Na2CO3
MesCO2H Cs2CO3
MesCO2H K2CO3
5
–
–
Notable features of our findings are not limited to 1) versatile
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[Ru(O2CMes)2(p-cymene)] (4)
[{RuCl2(p-cymene)}2]
[Ru3(CO)12]
K2CO3
K2CO3
K2CO3
K2CO3
À
ruthenium(II)-catalyzed decarbamoylative C C arylations,
À
À
2) expedient C C arylations and C C alkylations on modifi-
5
able[8] pyrazoles, as well as 3) detailed mechanistic insights
51
64
38
66
78
71
75[b]
–
À
into organometallic C C cleavage reactions (Figure 1).
Our studies were initiated by probing various reaction
À
conditions for the envisioned C C functionalization of the
indazolyl (Ind) amide 1a with the aryl chloride 2a (Table 1;
–
K2CO3
MesCO2H K2CO3
K2CO3
MesCO2H K2CO3
K2CO3
MesCO2H K2CO3
MesCO2H
see Table S1 in the Supporting Information). We were pleased
À
to observe that [{RuCl2(p-cymene)}2] enabled the desired C
—
C arylation, however with low efficacy when using KOAc as
the base (entry 1). A careful interrogation of additives and
bases revealed MesCO2H and K2CO3 to be optimal
(entries 2–9). Likewise, the well-defined complex [Ru-
(O2CMes)2(p-cymene)] (4)[9] proved to be active as a user-
friendly single-component catalyst (entry 10). It is also note-
RuCl3·(H2O)n
[{RuCl2(p-cymene)}2]
–
–
11
–
–
[{RuCl2(p-cymene)}2]
–
–
[a] Reaction conditions: 1a (0.20 mmol), 2a (0.40 mmol), [Ru]
(5.0 mol%), additive (10 mol%), o-xylene (0.5 mL), 1208C, 16 h.
[b] Under microwave irradiation at 200 W for 30 min. Ad=adamantyl,
Ind=N-indazolyl.
À
worthy that the C C arylation could be performed by means
À
of microwave irradiation, thus furnishing the C C arylation
product within only 30 minutes (entry 11). Reactions con-
ducted with other typical ruthenium sources, such as [Ru3-
(CO)12][3f] or RuCl3·(H2O)n, failed to give any conversion of
the substrate 1a (entries 12 and 13). Further, control experi-
ments verified the essential role of the base, the additive, and
the ruthenium catalyst (entries 14–16).
[*] M. Moselage,[+] Dr. J. Li,[+] F. Kramm, 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
Homepage: http://ackermann.chemie.uni-goettingen.de
With the optimized ruthenium(II) catalyst in hand, we
À
tested its versatility in the C C arylation of 1a with
[+] These authors contributed equally to this work.
a representative set of aryl halides (2; Scheme 1). Thus, we
were delighted to observe that aryl bromides, as well as more
challenging aryl chlorides, proved to be viable substrates in
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201701231.
À
the C C functionalization process. The remarkable chemo-
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Scheme 2. Decarbamoylative C C arylation of the arenes 1. [a] 1
(0.20 mmol), 2a (0.50 mmol), [{RuCl2(p-cymene)}2] (2.5 mol%), PhMe
(1.0 mL), 1208C, 18 h.
À
Scheme 1. Decarbamoylative C C arylation with the aryl halides 2.
[a] [{RuCl2(p-cymene)}2] (5.0 mol%).
selectivity of the ruthenium(II) catalyst was reflected by fully
tolerating valuable functional groups, including nitriles,
amines, halides, activated alkenes, esters, and enolazible
ketones, in either the ortho-, meta-, or para-position. The
widely applicable ruthenium(II) biscarboxylate catalyst
proved effective for the conversion of both electron-deficient
as well as electron-rich, thus deactivated, aryl halides. Hence,
the direct introduction of either heteroarenes (3aq) or the
À
fluorescent pyrene motif (3ar) was enabled. The twofold C C
activation also proved viable to furnish the product 3as.
Thereafter, we explored the scope of amenable pyrazoyl-
À
substituted arenes 1 in the C C arylation regime (Scheme 2).
Here, the site selectivity of an intramolecular competition
experiment with the meta-substituted arene 1b was guided by
repulsive steric interactions. In addition, various pyrazolyl-
substituted arenes delivered the desired products 3 with
excellent mono-selectivity. The outstanding robustness of the
À
Scheme 3. Decarboxylative C C arylation with the aromatic acids 5.
trast to recently reported protocols,[3a–d] the arylation did not
À
ruthenium C C activation catalyst was reflected by fully
tolerating, among others, cyano or free NH2 amino functional
groups.
occur at the ortho-position, but instead with ipso-selectivity. It
À
is noteworthy that the decarboxylative C C functionalization
was viable in the absence of either copper(II) or silver(I) salts,
which are typically required for either palladium- or rhodium-
catalyzed decarboxylative transformations.[10] Generally, the
The widely applicable ruthenium(II) catalysis regime was
not restricted to C C cleavages with amides 1. Indeed,
decarboxylative C C arylations proved to be viable under
otherwise identical reaction conditions (Scheme 3). In con-
À
À
À
versatile ruthenium(II) biscarboxylate catalyst allowed C C
arylation with aryl bromides and demanding chlorides.
2
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The power of the ruthenium(II)-catalyzed C C function-
cosolvent [D4]MeOH delivered the partially deuterated arene
[Dn]8a, thus providing strong support for the organometallic
alization approach was further illustrated by enabling effi-
[11]
À
À
cient C C alkylations when using the alkenes 6, thereby
selectively delivering the monoalkylated products
(Scheme 4).
nature of the C C cleavage step (Scheme 5b). Fourth,
7
variation of the N-substitution pattern was probed. Thus,
the NH2 amide 1l failed to give any arylation product,
whereas an intramolecular competition with the tertiary
À
amide 1m solely led to C H arylation (Scheme 5c). These
À
observations highlight the importance of a deprotonatable N
À
H bond to initiate the decarbamoylative C C cleavage. Fifth,
the use of the isocyanate[13] 10 provided evidence for a facile
À
reversible C C metalation.
On the basis of our mechanistic findings we propose
a plausible catalytic cycle to commence with a rapid organ-
À
ometallic C C cleavage induced by the formation of the
ruthenium(II) complex 11 (Scheme 6). Thereafter, the acti-
À
Scheme 4. Ruthenium-catalyzed C C alkylation.
Given the unique features of the ruthenium(II)-catalyzed
À
C C functionalization, we became intrigued in unravelling its
mode of action. To this end, we first performed competition
experiments using an electron-deficient aryl halide 2, which is
inherently more reactive (Scheme 5a). Second, reactions
performed in the presence of BHTand TEMPO led to partial
and complete inhibition, respectively, of the catalytic activ-
ity.[12] Third, C C arylations with the isotopically labelled
À
À
Scheme 6. Proposed catalytic cycle for the ruthenium-catalyzed C C
arylation.
À
vation of the C Hal bond occurs by the action of the
intermediate 12, arguably through an SET-type (SET=
single-electron transfer) process. Finally, reductive elimina-
À
tion delivers the C C arylation product 3, while regenerating
the catalytically active ruthenium(II) catalyst 4.
Finally, the synthetic utility of the ruthenium(II)-cata-
À
lyzed C C activation strategy was illustrated by the successful
late-stage diversification by ozonolysis[14] to provide access to
the arylated anilides 14 (Scheme 7).
In summary, we have reported on the unprecedented
À
ruthenium-catalyzed decarbamoylative s-C C arylation.
Hence, a versatile ruthenium(II) catalyst enabled efficient
À
decarbamoylative C C arylations with modifiable pyrazoles
À
as well as ipso-C C arylations and alkylations of benzoic
acids. Mechanistic studies provided strong support for an
À
Scheme 5. Summary of key mechanistic findings.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
organometallic mode of action through facile C C cleavage.
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Manuscript received: February 3, 2017
Final Article published: && &&, &&&&
4
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Communications
À
C C Activation
M. Moselage, J. Li, F. Kramm,
L. Ackermann*
&&&& — &&&&
À
Ruthenium(II)-Catalyzed C C Arylations
À
À
À
and Alkylations: Decarbamoylative C C
Amid the methods: Amide s-C C aryla-
lative ipso C C alkylations by facile or-
À
Functionalizations
tions were accomplished by versatile
ruthenium(II) carboxylate decarbamoyla-
tive catalysis, which enabled decarboxy-
ganometallic C C cleavage. The method
is versatile, robust, and mild, and mech-
anistic insights are discussed.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
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