ortho-C?H Arylation of Benzoic Acids with Aryl Bromides and Chlorides Catalyzed by Ruthenium

Article abstract of DOI:10.1002/anie.201607270

A system consisting of catalytic amounts of [(p-cym)RuCl₂]₂/PEt₃?HBF₄, K₂CO₃as the base, and NMP as the solvent efficiently mediates the ortho-C?H arylation of benzoic acids with aryl bromides at 100 °C. Replacing the phosphine ligand with the amino acid dl-pipecolinic acid enables the analogous transformation with aryl chlorides. The key advantage of this broadly applicable transformation is the use of an inexpensive ruthenium catalyst in combination with simple carboxylates as directing groups, which can either be tracelessly removed or used as anchor points for decarboxylative ipso substitutions.

Full text of DOI:10.1002/anie.201607270

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201607270
German Edition: DOI: 10.1002/ange.201607270
À
C H Activation
À
ortho-C H Arylation of Benzoic Acids with Aryl Bromides and
Chlorides Catalyzed by Ruthenium
Agostino Biafora, Thilo Krause, Dagmar Hackenberger, Florian Belitz, and Lukas J. Gooßen*
Abstract:
A
system consisting of catalytic amounts of
the resulting metallacycle towards aryl electrophiles. ortho
Arylations of benzoic acids were first reported by the groups
of Daugulis,[8] Larrosa,[9] Su,[10] and Yu,[11] who employed
expensive palladium catalysts.[12] With aryl iodides, these
transformations proceeded smoothly even at room temper-
ature.[10] The conversion of aryl bromides is possible only
under rather harsh conditions, and the coupling of aryl
chlorides has thus far required such high temperatures that
selective monoarylation could not be achieved.[8] With
arenediazonium salts as electrophiles, ortho arylation pro-
ceeds under mild conditions, but requires expensive iridium
catalysts.[13] Oxidative arylations have been reported with
expensive aryl boronic acids and a limited set of heteroarenes
as arylating agents.[14]
[(p-cym)RuCl2]2/PEt3·HBF4, K2CO3 as the base, and NMP
as the solvent efficiently mediates the ortho-C H arylation of
À
benzoic acids with aryl bromides at 1008C. Replacing the
phosphine ligand with the amino acid dl-pipecolinic acid
enables the analogous transformation with aryl chlorides. The
key advantage of this broadly applicable transformation is the
use of an inexpensive ruthenium catalyst in combination with
simple carboxylates as directing groups, which can either be
tracelessly removed or used as anchor points for decarbox-
ylative ipso substitutions.
B
iaryls are ubiquitous in pharmaceuticals, agrochemicals,
and functional materials, and efficient methods to access
these substructures are constantly sought after.[1] Tradition-
ally, these structures are accessed by cross-coupling of
preformed organometallic reagents with aryl halides[2] or by
oxidative or reductive couplings of prefunctionalized sub-
strates.[3]
Despite the remarkable progress achieved in this highly
À
topical area, a broadly applicable carboxylate-directed C H
arylation that is based on readily available aryl bromides or
chlorides and the use of a reasonably priced catalyst[15] has not
yet been described. Ackermann and co-workers as well as our
group have recently demonstrated that simple and affordable
ruthenium catalysts efficiently promote regioselective hydro-
arylations of carboxylates.[16] We reasoned that the addition of
electron-rich ligands might activate the intermediary ruthena-
The discovery of directing groups that efficiently control
the regioselectivity of C H arylations has recently revolu-
À
tionized this field, enabling the regiospecific introduction of
aryl groups in unfunctionalized positions.[4] However, this
great conceptual advantage is often offset by the structural
complexity of the required directing groups.[5] Their intro-
duction and subsequent removal adds several steps to the
overall synthetic process. Only recently, abundant functional
groups with low coordinating ability, such as carboxylates,
À
À
cycle towards oxidative insertion into Ar Br or Ar Cl bonds
by increasing its electron density, as outlined in Scheme 1.
This hypothesis was supported by results of Dixneuf,[17]
Larrosa,[18] Ackermann,[19] and others,[20] who demonstrated
that ruthenium catalysts can activate aryl chlorides or
bromides, and the observations by Daugulis,[8] Dixneuf,[21]
have successfully been used as directing groups for ortho-
[6]
À
C H arylations. The key benefit of carboxylate groups is
that they can be tracelessly removed by protodecarboxylation
or utilized as leaving groups in a rapidly growing number of
À
decarboxylative coupling reactions, with formation of C C,
[7]
À
À
À
À
C O, C N, C S, C P, and C–halogen bonds, for example.
The development of transformations based on carboxyl-
ate directing groups is highly challenging. The low s-donating
ability of the carboxylate limits their ability to direct metal
À
centers to one specific C H bond and reduces the activity of
[*] A. Biafora, F. Belitz
FB Chemie-Organische Chemie, TU Kaiserslautern
Erwin-Schrçdinger-Strasse Geb. 54, 67663 Kaiserslautern (Germany)
T. Krause, D. Hackenberger, Prof. Dr. L. J. Gooßen
Fakultꢀt Chemie und Biochemie
Ruhr Universitꢀt Bochum
Universitꢀtsstrasse 150, 44801 Bochum (Germany)
E-mail: lukas.goossen@rub.de
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.201607270.
À
Scheme 1. Carboxylate-directed C H arylation of arenes with aryl
electrophiles assisted by electron-rich ligands.
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and Ackermann[22,19b] that such processes are facilitated by
electron-rich phosphine and amino acid ligands.
To confirm our hypothesis, we chose the reaction of
2-methylbenzoic acid (1a) and bromobenzene (2a) as
a model system and investigated various catalysts and
conditions (Table 1). Encouragingly, traces of the desired
product 3a were detected when [(p-cym)RuCl2]2 was used as
When chlorobenzene was used as the electrophile, only
modest yields were observed under these conditions
(entry 13), even upon increasing the temperature to 1208C
(entry 14). Once again, the ligand turned out to be the
decisive factor in the reaction development. Phosphine
ligands were almost ineffective whereas amino acids strongly
promoted the desired transformation (entry 15). After
increasing the amount of aryl chloride, the monoarylated
product 3a was obtained in 80% yield. Although pipecolinic
acid is a more efficient ligand than PEt3·HBF4, the latter gave
high yields when the reaction time was extended to 48 h,
indicating that the reaction proceeds through a similar
mechanism for aryl chlorides and bromides. Control experi-
ments revealed that the optimal system for aryl chlorides is
less effective for aryl bromides (33% yield, see the Support-
ing Information).
With effective methods in hand for the conversion of both
aryl bromides and chlorides, we investigated the scope of the
transformation. The model substrate 2-methylbenzoic acid
(1a) was successfully coupled with various aryl bromides
using method A (Table 2). Electron-rich and electron-poor
substrates reacted similarly, and common functional groups,
such as CF3, CN, ester, halo, keto, alkyl, and methoxy moieties
as well as unprotected phenolic and benzylic hydroxy groups,
Table 1: Optimization of the ortho arylation reaction.[a]
Entry Catalyst
PhX Base
Ligand
Yield[b] [%]
1
2
3
[(p-cym)RuCl2]2 PhBr GuanCO3
[(p-cym)RuCl2]2 PhBr K2CO3
[(p-cym)RuCl2]2 PhBr K2CO3
–
–
PPh3
trace
13
35
4
5
6
[(C6H6)RuCl2]2
[(C6Me6)RuCl2]2 PhBr K2CO3
[(p-cym)RuI2]2 PhBr K2CO3
PhBr K2CO3
PPh3
PPh3
PPh3
34
0
35
7
8
9
10
11
12[c]
[(p-cym)RuCl2]2 PhBr K2CO3
[(p-cym)RuCl2]2 PhBr K2CO3
[(p-cym)RuCl2]2 PhBr K2CO3
[(p-cym)RuCl2]2 PhBr K2CO3
[(p-cym)RuCl2]2 PhBr K2CO3
[(p-cym)RuCl2]2 PhBr K2CO3
PPhCy2
PCy3
59
76
80
73
90
93 (93)
PiPr3
PMe3·HBF4
PEt3·HBF4
PEt3·HBF4
Table 2: Substrate scope of the direct arylation with various aryl
bromides and chlorides.[a]
13[c]
14[d]
15[d]
16[d]
[(p-cym)RuCl2]2 PhCl K2CO3
[(p-cym)RuCl2]2 PhCl K2CO3
[(p-cym)RuCl2]2 PhCl K2CO3
[(p-cym)RuCl2]2 PhCl K2CO3
PEt3·HBF4
PEt3·HBF4
l-proline
dl-pipecolinic
acid
12
12/75[e]
47
80 (75)
[a] Reaction conditions: 1a (1 equiv), 2a (4 equiv), [Ru] (4 mol%), ligand
(8 mol%), base (1.1 equiv), NMP (3 mL), 1008C, 18 h, N2 atmosphere.
[b] Yields of the corresponding methyl esters determined by GC analysis
after esterification with K2CO3 (2 equiv) and MeI (5 equiv) in NMP using
n-tetradecane as the internal standard; yields of isolated products are
given in parentheses. [c] PhX (1 equiv). [d] 1208C. [e] After 48 h.
Cy =cyclohexyl, GuanCO3 =guanidine carbonate, NMP=N-methylpyr-
rolidone, p-cym=para-cymene.
the catalyst in combination with guanidine carbonate at
1208C (entry 1), conditions that had been highly effective for
our hydroarylation reaction.[16b] A major increase in yield was
achieved upon switching to potassium carbonate as the base
(entry 2). As anticipated, the yields improved substantially
upon addition of a phosphine ligand (entry 3). Systematic
variation of the ruthenium precursor confirmed that [(p-
cym)RuCl2]2 is the optimal precatalyst (entries 4–6). The
nature of the ligand had a decisive influence on the reaction
outcome. Among the ligands tested, electron-rich alkyl
phosphines turned out to be superior. The best yields were
achieved with triethylphosphine (entry 11), which can be
conveniently administered in the form of its HBF4 salt. After
optimization of the reaction conditions (4 mol% [(p-cym)-
RuCl2]2, 8 mol% PEt3·HBF4, and 1.1 equiv K2CO3 in 3 mL
NMP at 1008C), high yields were obtained even when using
only one equivalent of the aryl bromide (entry 12). NMP is
uniquely effective as the solvent (see the Supporting Infor-
mation).
[a] Reaction conditions: Method A: 1a (0.5 mmol), ArBr (0.5 mmol),
[(p-cym)RuCl2]2 (4 mol%), PEt3·HBF4 (8 mol%), K2CO3 (1.1 equiv), NMP
(3 mL), 1008C, 18 h, N2 atmosphere. Method B: 1a (0.5 mmol), ArCl
(0.75 mmol), [(p-cym)RuCl2]2 (4 mol%), dl-pipecolinic acid (8 mol%),
K2CO3 (1.1 equiv), NMP (3 mL), 1208C, 18 h. Yields of the correspond-
ing methyl esters after esterification with K2CO3 (2 equiv) and MeI
(5 equiv) in NMP. [b] Isolated as the methyl ether. [c] ArBr (1.5 equiv).
[d] Isolated as the free acid.
2
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À
were tolerated in the para or meta position. ortho Substituents
led to only moderate yields. It is noteworthy that under these
conditions, aryl halides bearing functional groups that would
be expected to be more efficient directing groups smoothly
reacted with the ortho position of the carboxylates. This opens
up welcome opportunities for polyfunctionalization. Products
3aa and 3ab demonstrate that comparable yields were
achieved starting from aryl chlorides using method B
(4 mol% [(p-cym)RuCl2]2, 8 mol% dl-pipecolinic acid,
1.1 equiv K2CO3 in 3 mL NMP at 1208C).
The scope with regard to the aromatic carboxylate was
investigated with bromobenzene (2a) and chlorobenzene
(2a’; Table 3). Benzoic acids bearing electron-donating or
electron-withdrawing substituents, including methoxy, halo,
and acyl groups, were smoothly coupled. Heterocyclic car-
boxylates were also successfully converted into the desired
products. Unwanted double arylation could not be suppressed
with unsubstituted or para-substituted benzoic acids. How-
ever, a substituent in the 3-position was sufficient to direct the
arylation to the 6-position exclusively. This regioselectivity
towards the less hindered ortho position was also observed
with fused (hetero)aromatic quinoline 6-carboxylic acid (1l)
and 2-naphthylcarboxylic acid (1i). A particularly remarkable
example is the coupling of 2-acetamidobenzoic acid with 2a.
The new bond is selectively formed in the ortho position of
the benzoic acid rather than in the ortho position of the amide
despite the C H directing ability of the latter, which by far
À
exceeds that of carboxylic acids in related C H functional-
izations. Four additional examples demonstrate that meth-
od B permits the coupling of aryl chlorides in comparable
yields.
We next probed whether the biaryl synthesis could also be
combined with concomitant protodecarboxylation.[23] The
examples in Scheme 2 demonstrate that this process does
not even require an additional reaction step. By simply adding
a copper catalyst to the reaction medium and increasing the
temperature to 1908C, the corresponding biaryl products 4
were formed in good yields. The ortho arylation can also be
combined with decarboxylative cross-couplings,[24] as demon-
strated by the synthesis of terphenyl 5ca in 55% non-
optimized yield.
Scheme 2. ortho Arylations followed by decarboxylative reactions.
To shed light on the mechanism proposed in Scheme 1, we
synthesized ortho-ruthenated toluate 6a. The stoichiometric
reaction of 6a and PEt3·HBF4 with bromobenzene (2a)
yielded 3aa in 57% yield (Scheme 3), which supports the
intermediacy of an ortho-metalated species in the catalytic
cycle. In the presence of only pyridine as the ligand, no
product formation was observed, which confirmed the
necessity for a suitable ligand (see the Supporting Informa-
tion). In-depth mechanistic studies are underway to fully
clarify the reaction pathway.
Table 3: Substrate scope of the direct arylation with various benzoic
acids.[a]
Scheme 3. Stoichiometric reaction of the ortho-ruthenated toluate 6a.
In conclusion, we have shown that cost-effective ruthe-
nium complexes are at least as effective and broadly
applicable as state-of-the-art palladium systems for catalyzing
the synthetically useful ortho arylation of benzoic acids. In
combination with subsequent decarboxylative ipso substitu-
tions, they promise to open up new perspectives for sustain-
able, regioselective arene (di)functionalization.
Experimental Section
An oven-dried 20 mL vessel was charged with [Ru(p-cym)Cl2]2
(12.2 mg, 0.02 mmol, 4 mol%), triethylphosphonium tetrafluorobo-
rate (8.3 mg, 0.04 mmol, 8 mol%, method A) or dl-pipecolinic acid
(5.2 mg, 0.04 mmol, 8 mol%, method B), K2CO3 (76 mg, 0.55 mmol,
1.1 equiv), and benzoic acid 1 (0.50 mmol). After the vessel had been
subjected to three alternating vacuum and nitrogen purge cycles,
NMP (3 mL) and the aryl halide 2 (0.50 mmol, method A; 0.75 mmol,
method B) were added via syringe. The resulting mixture was stirred
at 1008C for 18 h. After the reaction was complete, the mixture was
[a] Reaction conditions: Method A: 1 (0.5 mmol), 2a (0.75 mmol),
[(p-cym)RuCl2]2 (4 mol%), PEt3·HBF4 (8 mol%), K2CO3 (1.1 equiv), NMP
(3 mL), 1008C, 18 h. Method B: 1 (0.5 mmol), 2a’ (0.75 mmol),
[(p-cym)RuCl2]2 (4 mol%), dl-pipecolinic acid (8 mol%), K2CO3
(1.1 equiv), NMP (3 mL), 1208C, 18 h. Yields of the corresponding
methyl esters after esterification with K2CO3 (2 equiv) and MeI (5 equiv)
in NMP. [b] ArBr (1 equiv). [c] Yield determined by GC analysis.
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allowed to cool to room temperature. NMP (2 mL), K2CO3 (207 mg,
3 equiv), and MeI (156 mL, 5 equiv) were added, and the mixture was
stirred at 608C for 2 h. The mixture was allowed to cool to room
temperature, ethyl acetate (20 mL) was added, and the resulting
mixture was washed with water, aqueous LiCl solution (20%), and
brine (20 mL each). The organic layer was dried over MgSO4, filtered,
and the volatiles were removed under reduced pressure. The residue
was purified by column chromatography (SiO2, ethyl acetate/hexane
gradient), yielding the corresponding biaryl.
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We thank Umicore for donating chemicals, the DFG (SFB/
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À
Keywords: aryl halides · benzoic acids · biaryls · C H arylation ·
ruthenium
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Received: July 27, 2016
Revised: September 2, 2016
Published online: && &&, &&&&
À
e) C H Activation (Eds.: J.-Q. Yu, L. Ackermann, Z. Shi),
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C H Activation
A. Biafora, T. Krause, D. Hackenberger,
F. Belitz, L. J. Gooßen*
&&&& — &&&&
Bromides and chlorides: A system con-
sisting of [(p-cym)RuCl2]2/PEt3·HBF4 as
the catalyst, K2CO3 as the base, and NMP
as the solvent efficiently mediates the
aryl bromides at 1008C. Replacing the
À
ortho-C H Arylation of Benzoic Acids
with Aryl Bromides and Chlorides
Catalyzed by Ruthenium
phosphine ligand with the amino acid dl-
pipecolinic acid enables the analogous
transformation with aryl chlorides.
À
ortho-C H arylation of benzoic acids with
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!