Rhodium-Catalyzed ortho-Arylation of (Hetero)aromatic Acids

Article abstract of DOI:10.1002/adsc.201900596

Rhodium acetate effectively promotes the carboxylate-directed ortho-arylation of (hetero)aromatic carboxylates with aryl bromides. The main advantage of this phosphine-free, redox-neutral method arises from its efficiency in assembling biologically meaningful electron-rich arylpyridines, which are problematic substrates in known C?H arylations using Pd, Ru, and Ir catalysts. (Figure presented.).

Full text of DOI:10.1002/adsc.201900596

Title: Rhodium-catalyzed ortho-Arylation of (Hetero)aromatic Acids
Authors: Philip Weber, Christian K. Rank, Enis Yalcinkaya, Marco
Dyga, Tim van Lingen, Rochus Schmid, Frederic W.
Patureau, and Lukas J. Goossen
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900596
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10.1002/adsc.201900596
Advanced Synthesis & Catalysis
COMMUNICATION
Rhodium-catalyzed ortho-Arylation of (Hetero)aromatic Acids
Philip Weber,[a] Christian K. Rank,[b,c] Enis Yalcinkaya,[a] Marco Dyga,[a] Tim van Lingen,[a] Rochus
Schmid,*[d] Frederic W. Patureau,*[b,c] and Lukas J. Gooßen*[a]
Abstract: Rhodium acetate effectively promotes the carboxylate-
directed ortho-arylation of (hetero)aromatic carboxylates with aryl
bromides. The main advantage of this phosphine-free, redox-neutral
method arises from its efficiency in assembling biologically meaningful
electron-rich arylpyridines, which are problematic substrates in known
C–H arylations using Pd, Ru, and Ir catalysts.
nitrogen atom.[17]
The use of carboxylates as directing groups is particularly
advantageous for heterocyclic substrates, because they are often
present as leftovers from the construction of the heterocycle
skeleton.[18] Following the arylation step, they can either be
removed tracelessly, or reused as leaving groups in
decarboxylative couplings.[19,20] Carboxylate-directed C–H
arylations are effectively promoted by Pd[21–29], Ir,[30] or Ru[31–34]
systems. Rh systems, and Cp*Rh in particular, are at the heart of
modern C–H functionalization chemistry.[35–40] Su and You have
used Rh in carboxylate-directed oxidative (decarboxylative)
arylation processes, e.g. thiophenes.[41–43]
Keywords: rhodium • aryl bromides • benzoic acids • biaryls •
heteroarenes • C-H arylation
Arylated pyridines represent
a
key motif in various
pharmaceutically active substances,[1–3] and expedient synthetic
Bergman and Ellman et al.
entries to this substructure are constantly sought.
ArBr
[RhCl(CO)2]2
Dioxane, 175 °C
C2-selectivity
ortho-Arylations of Benzoic Acids
Ar-X
[Pd, Ir, Ru]
[Rh], Ar-H
(Het)Ar
(Het)Ar
(Het)Ar
X= BR2, OTf,
Cenerimod (S1P1 agonist, lupus)
Netupitant (antiemetic)
Cl, Br, I, N2+
our work
Figure 1. Pharmaceuticals containing heteroaromatic biaryl motifs.[4,5]
ArBr
Rh2(OAc)4, K2CO3
(Het)Ar
(Het)Ar
up to 95% yield
Known methods for the arylation of (hetero)arenes include
cross-couplings of organometallic reagents with aryl
(pseudo)halides, Ullmann reactions, or decarboxylative
couplings.[6–11] In the case of pyridines, most preformed
organometallic reagents are unstable, C–H arylations are
particular advantageous for the construction of heteroaryl
skeletons.[12] The arylation can be directed into specific positions
by various donor groups, and even by the heteroatom of
heteroarenes. In this context, Bergman and Ellmann
demonstrated that pyridines can be arylated selectively at the C-
2 position of the pyridine ring.[13–16] This directing effect of the
heterocyclic nitrogen can be overridden by other ring substituents,
for example by carboxylates. Larrosa showed that in the presence
of a sophisticated Pd catalyst, nicotinic acid derivatives are
arylated in the position ortho to the carboxylate rather than the
Scheme 1. C–H Arylations directed by neighboring atoms and o-carboxylates.
In the context of
a planned synthesis of 2-alkoxy-4-
arylpyridines, we identified 2-alkoxynicotinic acids as the optimal
starting materials. Based on the work by Larrosa, one would
expect it to undergo selective arylation at the 4-position.
Thereafter, the carboxylate group could subsequently be
removed by protodecarboxylation or converted to halides,
alkoxides, amines, etc. However, the known Pd and Ru systems
gave unsatisfactory yields for our model reaction, the coupling of
2-alkoxynicotinic acid with 4-bromotoluene (Table 1, entries 1, 2),
and all our attempts to develop effective protocols based on the
above catalysts failed.
[a]
Evonik Chair of Organic Chemistry, Ruhr-Universität Bochum,
ZEMOS, Universitätsstr. 150, 44801 Bochum, Germany.
E-mail: lukas.goossen@rub.de
In search for alternative catalysts, we identified dirhodium
tetraacetate as a promising candidate. Aryl phosphines have
been reported to react with this dinuclear RhII complex, liberating
acetic acid and forming a carbometalated dinuclear aryl–Rh
species in which the phosphine coordinates to one of the Rh
nuclei, and the C-2 carbon binds to the other Rh.[44,45] Considering
the proverbial affinity of RhII to carboxylates, we reasoned that a
similar base-assisted cyclometallation deprotonation (CMD)
[b]
[c]
FB Chemie – Organische Chemie, TU Kaiserslautern, Erwin-
Schrödinger-Str. Geb. 52, 67663 Kaiserslautern, Germany.
Present address: Institute of Organic Chemistry, RWTH Aachen,
Landoltweg 1, 52074 Aachen, Germany.
E-mail: frederic.patureau@rwth-aachen.de
[d]
Chair of Inorganic Chemistry 2 – Computational Materials Chemistry
Group, Ruhr-Universität Bochum, Universitätsstr. 150, 44801
Bochum, Germany.
E-mail: rochus.schmid@rub.de
Supporting information for this article is available on the WWW
under
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10.1002/adsc.201900596
Advanced Synthesis & Catalysis
COMMUNICATION
mechanism might be possible with a carboxylate rather than a
phosphine as ortho-directing group. This would open up the
catalytic cycle sketched out in Scheme 2. It starts with a directed
CMD reaction furnishing cyclometallated RhII carboxylate II, which
has a structure analogous to that observed in the reaction with
aryl phoshines. It reacts with an aryl bromide to give the diaryl
RhIII complex III, along with stable RhIII carboxylate VI. The
intermediacy of III seems in line with literature reports on Rh-
catalyzed arylations.[41,43] The desired biaryl product is then
formed by reductive elimination and released by salt metathesis
with fresh carboxylate substrate. The coordinatively unsaturated
RhI species V could be stabilized by conproportionation with VI
regenerating RhII carboxylate I.
arylations, competing diarylation was observed when two ortho-
positions were accessible, e.g. for 1p. While most acids were
converted with a low Rh-loading of 0.5 mol%, a few examples like
2-fluorobenzoic acid 1c or 2-cyanobenzoic acid 1e need larger
amounts of Rh.
Table 1. Screening of the reaction conditions.[a]
cat, base
solvent, 140 °C, Ar, 18 h
1k
2a
3ka
Entry
mol% cat
equiv
Base
Solvent
Yield
3[b] [%]
1
2
5.0 cataCXium A-Pd-G3
2.2 Cs2CO3
1.1 K2CO3
DMF
NMP
14
E = - 9.2 kcal/mol
4.0 [(p-cym)RuCl2]2 + 8
PEt3·HBF4
0
E = 7.3 kcal/mol
3
4.0 Rh2(OAc)4
1.0 K2CO3
"
77
79
23
5
I
4
"
"
DMF
V
5
"
"
DMSO
6
"
"
mes
7
"
–
DMF
1
3
E = 3.7 kcal/mol
8
"
0.5 K2CO3
1.5 K2CO3
2.0 K2CO3
1.5 K2CO3
"
"
"
"
"
"
24
87
33
7
VI
II
9
"
Ph-Br
E = - 44.1 kcal/mol
10
11[b]
12[c]
"
IV
E = 14.7 kcal/mol
"
R = Me / Ar
KBr
0.25 Rh2(OAc)4
91
III
Scheme 2. Mechanistic blueprint for a RhII catalysed arylation.
[a] Reactions conditions: 1k (0.5 mmol), 2a (0.75 mmol), cat, base, solvent (2
mL), 140 °C, 18 h. 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 internal standard. [b] 130 °C. [c] 6 h. DMF: dimethylformamide,
NMP: N-methylpyrrolidone, mes: mesitylene, DMSO: dimethylsulfoxide.
When probing Rh2(OAc)2 in our model reaction, it gave good
results in combination with the simple base K2CO3 (Table 1, Entry
3). The C-H arylation was directed exclusively ortho to the
carboxylate group rather than the pyridine nitrogen.
Systematic studies revealed that aprotic polar solvents are
beneficial with best results obtained in DMF. The catalyst loading
can be reduced to 0,5 mol% Rh (Table 1, Entry 12), and only a
slight excess of the base is required. A temperature of 140°C is
optimal, below that, the yields drop markedly (Table 1, Entry 11).
Further studies revealed that many rhodium(III) salts showed
similar activity in this transformation (Supporting Information),
which can be rationalized with their swift conversion to RhII
carboxyates when heated in the presence of carboxylates.[46]
In order to probe the general applicability of our new protocol,
we investigated its scope with regard to both coupling partners
(Tables 2, 3, and S10). As can be seen in Table 2, benzoic acids
bearing electron-donating or -withdrawing substituents were
smoothly coupled with 4-bromotoluene (2a), among them even
unprotected anthranilic acid (1h). Various heterocyclic acids gave
good results, including our targeted nicotinates bearing ortho-
amino or ortho-methoxy groups. Similarly to other directed ortho-
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10.1002/adsc.201900596
Advanced Synthesis & Catalysis
COMMUNICATION
Table 2. Substrate scope with regard to the carboxylate component.[a]
0.25 mol% Rh2OAc4, 1.5 eq K2CO3
DMF, 140°C, Ar, 18 h
(het)Ar-CO2H
Br-Ar
(Het)Ar
0.25 mol% Rh2(OAc)4
1.5 eq K2CO3
(Het)Ar-CO2H
(Het)Ar
1
2
3
DMF, 140 °C, Ar, 18 h
1
2a
3
3aa, R = Me 91%
3ba, R = OMe 89%
3ca, R = F 84%
[b]
3kh, R = OMe 85%
3ki, R = tBu 89%
3kj 86%
3kk 89%
3ko 74%
3kb, R = H 85%
[c]
3ia 87%
3ja 96%
3ka 86%
3la 84%
3kc, R = OMe 89%
[b]
[b]
3kd, R = F 71%
3da, R = CF3 86%
[b]
3ke, R = CO2Et 63%
[c]
3ea, R = CN 50%
3kf, R = Ph 87%
3kg, R = SMe 51%
3fa, R = Ac 55%
[b]
[b]
3ga, R = NHAc 63%
[d]
3ha, R = NH2 63%
3ma 51%
3na 80%
3oa 63%
3kl 81%
3km 82%
3kn 69%
3ax 75%
[e]
[c]
3pa 65%
3qa 87%
3ra 90%
3sa 90%
3ta 27%
[c]
3ad, R = F 95%
[c]
3ap, R = Cl 86%
[c]
3aq, R = CF3 89%
[c]
3ar, R = Ac 87%
[a] Reactions conditions: 1 (0.5 mmol), 2a (0.75 mmol), 0.25 mol% Rh2(OAc)4,
K2CO3 (1.5 equiv), DMF (2 mL), 140 °C, 18 h. Yields of the corresponding
methyl esters after esterification with K2CO3 (2 equiv) and MeI (5 equiv) in NMP.
[b] 1 mol% Rh2(OAc)4. [c] 4 mol% Rh2(OAc)4. [d] Isolated as the corresponding
dimethyl amine. [e] 2a (1.25 mmol).
[c]
3as, R = CN 20%
[d]
3at, R = OH 89%
[c]
[c]
[c]
3av 92%
3az 14%
3aw 82%
3ay 30%
[c]
3au, R = NO2 58%
[a] Reactions conditions: 1 (0.5 mmol), 2 (0.75 mmol), 4 mol% Rh2(OAc)4,
K2CO3 (1.5 equiv), DMF (2 mL), 140 °C, 18 h. Yields of the corresponding
methyl esters after esterification with K2CO3 (2 equiv) and MeI (5 equiv) in NMP.
[b] 1 mol% Rh2(OAc)4. [c] 4 mol% Rh2(OAc)4. [d] 1 mol% Rh2(OAc)4, Isolated as
the free carboxylic acid.
The coupling is broadly applicable with regard to the aryl
bromide (Table 3). Various functional groups including esters,
ketones were tolerated, and even 4-bromophenol 2t was coupled
in excellent yield. Arylated phenols are structural components of
several drug precursors.[47]
Removal of the carboxylate group by protodecarboxylation
was possible in situ by heating the reaction mixture in the
presence of CuII/tetramethylphenanthroline and quinoline (see
the supporting information).[48]
Table 3. Substrate scope with regard to aryl bromides.
To probe the validity of our mechanistic blueprint, a series of
control experiments, kinetic investigations and DFT calculations
were performed (see the supporting information). Heating o-toluic
acid in deuterated methanol in the presence of rhodium acetate
led to selective ortho-deuteration.[49] In contrast, rhodium acetate
did not promote halogen exchange between aryl iodide and
potassium bromide.[50] The findings support our hypothesis that
the reaction is initiated by a reversible ortho-metallation step. A
competition experiment of deuterated and non-deuterated ortho-
toluic acid with 4-bromotoluene showed only a moderate kinetic
isotope effect, suggesting that this step is not alone rate-
determining (Scheme 3, top). ESI-MS analysis of reaction
mixtures of ortho-toluic acid under catalytic conditions, both in the
presence and absence of 4-bromotoluene, display several
dinuclear Rh fragments carrying the 2-methylbenzoate fragments,
suggesting that the reaction is indeed initiated by carboxylate
coordination. We additionally synthesized dirhodium tetra-ortho-
toluate (5) and found it to effectively catalyse the reaction and
quantitatively form the product if coupled with 4-bromotoluene
and without Rh2(OAc)4 (Table S9).
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10.1002/adsc.201900596
Advanced Synthesis & Catalysis
COMMUNICATION
1.5 eq Br-pTol 2a
pharmaceutical research. Dinuclear Rh2(OAc)2 was found to be
particularly suited for ortho-C-H bond activation of benzoic acids
opening up further opportunities for directed functionalizations.
2 mol% Rh2(OAc)4
1.5 eq K2CO3
DMF, 140 °C, 4 h
1a-D7
1a
kH / kD = 1.8
Acknowledgements
Funded by the Deutsche Forschungsgemeinschaft (DFG,
2 mol% Rh2(OAc)4
German Research Foundation) under Germany’s Excellence
1.5 eq K2CO3
Strategy
– EXC-2033 – Projektnummer 390677874 and
DMF, 140 °C, 4 h
Transregional Collaborative Research Center SFB/TRR 88
“3MET”. We thank Umicore for the donation of chemicals, Annika
Steiner and Matthias P. Klein for ESI measurements, Laura
Schneider for HRMS measurements and Florian Papp for
technical assistance.
1a
2b
2c
X = H 23% : OMe 17%
Scheme 3. Selected mechanistic experiments (see SI for conditions).
Conflict of interest
In a competition experiment, ortho-toluic acid was allowed to
react with a mixture of bromobenzene and electron-rich 4-
methoxyaryl bromide, furnishing similar quantities of both
arylation products. This indicates that oxidative addition is not
rate-determining, either (Scheme 3, bottom), so that the overall
rate seems to be mostly limited by the C-C bond-forming step.
The authors declare no conflict of interest.
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10.1002/adsc.201900596
Advanced Synthesis & Catalysis
COMMUNICATION
COMMUNICATION
Philip Weber, Christian K. Rank, Enis
Yalcinkaya, Marco Dyga, Tim van
Lingen, Rochus Schmid, Frederic W.
Patureau, and Lukas J. Gooßen
Rh2(OAc)4, K2CO3
DMF, 140 °C
Br-Ar
(Het)Ar
(Het)Ar
Page No. – Page No.
Rhodium-catalyzed ortho-Arylation of
(Hetero)aromatic Acids
Rhodium acetate effectively promotes the carboxylate-directed ortho-arylation of
aromatic carboxylates with aryl bromides. It is particularly effective in the synthesis
of biologically meaningful electron-rich aryl pyridines. 56 examples demonstrate the
efficiency and broad application of this straightforward arylation protocol.
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