Ruthenium(II)-catalyzed C-H arylation of azoarenes by carboxylate assistance

Article abstract of DOI:10.1021/acscatal.5b00939

Ruthenium(II)carboxylate complexes enabled the unprecedented direct C-H arylation of azoarenes with aryl halides through chelation assistance. The mild reaction conditions of the optimized C-H functionalization process resulted in a remarkable functional

Full text of DOI:10.1021/acscatal.5b00939

Letter
pubs.acs.org/acscatalysis
Ruthenium(II)-Catalyzed C−H Arylation of Azoarenes by Carboxylate
Assistance
Jonathan Hubrich,† Thomas Himmler,‡ Lars Rodefeld,‡ and Lutz Ackermann*,†
†Institut fur Organische und Biomolekulare Chemie, Georg-August-Universitat, Tammannstraße 2, 37077 Gottingen, Germany
̈
̈
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‡Bayer CropScience AG, BCS AG-R&D, Alfred-Nobel-Straße 50, 40789 Monheim, Germany
S
* Supporting Information
ABSTRACT: Ruthenium(II)carboxylate complexes enabled the unprecedented direct C−H arylation of azoarenes with aryl
halides through chelation assistance. The mild reaction conditions of the optimized C−H functionalization process resulted in a
remarkable functional group tolerance. The proximity-induced C−H arylation proceeded with high positional selectivity and
could be performed in a one-pot protocol along with a azoarene reduction, providing expedient access to ortho-arylated anilines.
KEYWORDS: anilines, arylation, azoarenes, C−H activation, ruthenium
material sciences10,11 and as molecular switches,13 we became
attracted by establishing reaction conditions for C−H arylations
of substituted azoarenes with user-friendly organic electro-
philes, on which we report herein. Notably, the optimized
catalytic system showed a high efficacy through carboxylate
assistance14−16 with broad functional group tolerance and set
the stage for a one-pot synthesis of ortho-arylated anilines.
We initiated our studies by evaluating reaction conditions for
the C−H arylation of azoarene 1a with aryl bromide 2a (Table
1 and Tables S-1−S-3 in the Supporting Information).
Preliminary experiments indentified ruthenium(II) complex
[RuCl2(p-cymene)]2 as the most powerful catalyst. Among a
variety of bases (Na2CO3, K3PO4, KOAc, NaOAc, or CsOPiv),
K2CO3 furnished optimal results. A set of representative
additives was probed and revealed MesCO2H as being superior,
thereby delivering the arylated product 3aa with high chemo
and positional selectivity (Table 1, entries 1−6). It is
noteworthy that KOAc and the phosphoric acid diester
(PhO)2P(O)OH17 also furnished the arylated product 3aa.
The C−H arylation did not occur in the absence of the
ruthenium catalyst (entry 7), and the loading of the preligand
MesCO2H could be reduced without a significant loss of
catalytic activity (entries 8 and 9). As to the solvent, 1,4-
dioxane was found to be most suitable, and the use of THF,
DCE, t-AmOH, toluene, or o-xylene led to somewhat lower
yields under otherwise identical reaction conditions (entries
10−14). In contrast, solvents, such as DMSO, AcOH, or
MeOH, failed to provide the desired product 3aa.18
ransition metal-catalyzed cross-coupling reactions1,2 are
Tindispensable tools for the synthesis of unsymmetrically
substituted biaryls, valuable building blocks in, among others,
natural products, liquid crystals, drugs, or crop protection
agents.2 Because these methods strongly rely on the synthesis
and use of prefunctionalized starting materials, direct C−H
arylations3 have received significant recent attention as
environmentally benign and economically superior alterna-
tives.4 Hence, the step-economy of biaryl synthesis has been
significantly improved with the aid of versatile transition metal
complexes for C−H functionalizations.3,5 Particularly,
ruthenium(II) complexes have been identified as powerful
catalysts for chelation-assisted6,7 C−H arylations using organic
halides as electrophilic arylating reagents,8 with carboxylate
assistance as an enabling technology.9 Despite these recent
advances, ruthenium-catalyzed direct arylations of aniline
derivatives, including azoarenes,10,11 with organic (pseudo)-
halides12 have unfortunately thus far proven elusive, whereas
rhodium- or palladium-catalyzed functionalizations of azoarenes
were largely achieved in an oxidative fashion.11 Given the
practical importance of ortho-arylated anilines as key structural
motifs in fungicides (Figure 1) as well as of azoarenes in
Received: May 5, 2015
Revised: May 29, 2015
Figure 1. Representative ortho-arylated anilides with fungicidal
activity.
© XXXX American Chemical Society
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Table 1. Optimization of Ruthenium-Catalyzed C−H
Scheme 1. Scope of C−H Arylation
a
Arylation of Azoarene 1a
entry
additive
PPh3
solvent
yield (%)
1
2
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
44
74
75
79
76
(PhO)2P(O)OH
KPF6
3
4
KOAc
5
t-BuCO2H
MesCO2H
MesCO2H
MesCO2H
MesCO2H
MesCO2H
MesCO2H
MesCO2H
MesCO2H
MesCO2H
6
87
b
7
c
8
83
d
9
54
10
11
12
13
14
42
43
75
83
84
DCE
t-AmOH
PhMe
o-xylene
a
Reaction conditions: 1a (1.0 mmol), 2a (0.5 mmol), base (2.0 equiv),
[RuCl2(p-cymene)]2 (5.0 mol %), additive (30 mol %), solvent (2.0
b
mL), 120 °C, 18 h, isolated yields. In the absence of [RuCl2(p-
c
d
cymene)]2. MesCO2H (15 mol %). [RuCl2(p-cymene)]2 (2.5 mol
%).
With the optimized reaction conditions in hand, we explored
the substrate scope of the ruthenium(II)-catalyzed C−H
arylation employing substituted azoarenes 1 and bromoarenes
2 (Scheme 1). The most user-friendly ruthenium(II) catalyst
was found to be widely applicable and allowed for the direct
C−H functionalization of the parent azobenzene 1b as well as
of azoarenes 1c and 1d bearing ortho or para substituents,
respectively. Here, only minor amounts of the 2,2′-diarylated
products 3′ were formed, even when using an excess of the aryl
bromide 2a (3ca′: 10% isolated yield).18 Intramolecular
competition experiments with meta-substituted substrates 1a,
and 1e−1g generally occurred with excellent positional
selectivities at the less hindered C(6)−H bonds. The optimized
ruthenium(II) catalyst displayed a useful chemoselectivity in
that valuable electrophilic functional groups, such as chloride,
enolizable ketone, ester, amine, nitro, or aldehyde substituents,
were fully tolerated. The electronic nature of the aryl bromide
did not significantly affect the catalysts’ performance, and both
electron-deficient as well as more challenging electron-rich
electrophiles were efficiently converted.
Scheme 2. Ruthenium(II)-Catalyzed C−H Functionalization
with Heteroaryl Bromides 2
The ruthenium(II) catalyst was not limited to aryl bromides
2 as the electrophilic arylating reagents. Indeed, heteroaromatic
electrophiles 2k−2m proved to be viable substrates, as well,
thereby delivering the thiophene and indole derivatives 3ak−
3am (Scheme 2).
Furthermore, direct arylations of the unsymmetrically
substituted azoarene 1h occurred with excellent regiocontrol,
thereby delivering azoarene 3ha as the sole product (Scheme
3).
The well-defined ruthenium(II) biscarboxylate complex
as well, which at the same time allowed for a significant
reduction of the catalyst loading (Scheme 4; Table 1, entry 9).
419,20 was found to be a competent C−H arylation catalyst,
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Scheme 3. C−H Arylation of Unsymmetrical Azoarene 1h
Scheme 6. H/D-Exchange Experiments in the Presence of
D2O
Scheme 4. Well-Defined Ruthenium(II) Biscarboxylate
Catalyst 4 for C−H Arylation
We were pleased to find that the ruthenium(II)-catalyzed C−
H arylation strategy could be conducted in a one-pot protocol,
along with an in situ reduction of the arylated azoarenes 3.
Thus, we identified a practical method that furnishes ortho-
arylated anilines 5 in a highly economical manner (Scheme 5).
Scheme 5. One-pot Synthesis of ortho-Arylated Anilines 5
In consideration of the unique selectivity of the ruthenium-
(II)-catalyzed C−H functionalizations of azoarenes, we
performed experimental studies to probe the working mode
of the ruthenium(II) biscarboxylate-mediated C−H activation.
To this end, the use of the deuterated cosolvent D2O clearly
revealed a significant H/D scrambling, solely occurring in the
ortho position. This observation highlights the reversible19,21
nature of the C−H ruthenation step (Scheme 6).
Because the C−H metalation was identified as being
reversible, we subsequently determined the initial rates for
reactions with differently para-substituted aryl bromides 2
(Figure 2). A Hammett plot was constructed from the
correlation between the initial rates and the σp values. The
plot resulted in a linear fit with a negative slope of −0.21,
indicating that electron-donating groups facilitate the C−H
arylation. In contrast to our previous findings,19 this
observation renders a rate-limiting C−Br oxidative addition
Figure 2. Hammett plot correlation using aryl bromides 2.
less likely. Instead, our results can be rationalized in terms of a
rate-determining reductive elimination.
On the basis of our observations and our previous
mechanistic findings on ruthenium-catalyzed direct arylations,18
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1
we propose the catalytic cycle to initiate by a reversible,
isohypsic cyclometalation with a ruthenium(II) complex,
delivering the five-membered ruthena(II)cycle 6 (Scheme 7).
Experimental procedures, characterization data, and H
and 13C NMR spectra for new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: Lutz.Ackermann@chemie.uni-goettingen.de.
■
Scheme 7. Proposed Catalytic Cycle
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Support by the Georg-August-University Gottingen is gratefully
acknowledged.
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REPRESENTATIVE PROCEDURE:
RUTHENIUM(II)-CATALYZED C−H ARYLATION OF
AZOARENES 1
■
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(E)-1,2-di-m-tolyldiazene (1a) (210 mg, 1.0 mmol), [RuCl2(p-
cymene)]2 (15.3 mg, 5.0 mol %), MesCO2H (24.6 mg, 30 mol
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ASSOCIATED CONTENT
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S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.5b00939.
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