Rhodium-catalyzed ortho acylation of aromatic carboxylic acids

Article abstract of DOI:10.1002/anie.201301328

New directions: The carboxylic acid functional group directs the ortho acylation of benzoic acids with carboxylic anhydrides in the presence of a rhodium catalyst (see scheme; cod=cyclo-1,5-octadiene). The acylation at the ortho position is complementary to the meta selectivity of Friedel-Crafts reactions. The resulting products can undergo protodecarboxylation to deliver an aryl ketone. Copyright

Full text of DOI:10.1002/anie.201301328

Angewandte
Chemie
DOI: 10.1002/anie.201301328
Synthetic Methods
Rhodium-Catalyzed ortho Acylation of Aromatic Carboxylic Acids**
Patrizia Mamone, Grꢀgory Danoun, and Lukas J. Gooßen*
Transition-metal-catalyzed directed ortho functionalizations
of arenes constitute modern and sustainable tools for the
regiospecific formation of carbon–carbon and carbon–hetero-
atom bonds.[1] In such reactions, coordinating groups direct
metal catalysts into their ortho position, thus enabling site-
We are aware of only two examples of catalytic ortho
acylations in which broadly available carboxylic acid deriv-
atives serve as acylating agents, namely the ruthenium-
catalyzed reaction of phenyl pyridines with acid chlorides
by Kakiuchi et al.[18] and the analogous palladium-catalyzed
reaction with mixed trifluoroacetic anhydrides by Fu et al.[19]
The ortho acylations of benzoic acids with carboxylic acid
derivatives are without literature precedent. Such transfor-
mations would be of considerable interest because they would
open up an expedient synthetic pathway to an important
substrate class.[20] For example, the 2-acylbenzoic acid balanol
is a protein kinase C inhibitor.[20a] Other examples are
synthetic intermediates en route to 2-[2-(imidazolyl)alkyl]-
1(2H)-phthalazinones, which have antiasthma activity,[20b] or
anxiolytic isoindolinone derivatives.[20c]
À
selective C H functionalizations. In most cases, strongly
coordinating nitrogen-, sulfur-, or phosphorus-based directing
groups are employed. Only recently, catalysts have been
discovered that permit the use of more weakly coordinating
carboxylate directing groups,[2] for example, in ortho aryla-
tions,[3] olefinations,[4] carbonylations,[5] allylations,[6] hydrox-
ylations,[7] alkoxylations,[8] amidations,[9] halogenations,[10] and
lactone syntheses.[11] Their key advantage is that the carbox-
ylate group can subsequently be utilized as a leaving group in
further functionalization steps, or tracelessly removed by
protodecarboxylation.[3c,8,12]
A selective ortho acylation of benzoic acids would com-
pare favorably with established acylation methods because
their Friedel–Crafts acylation gives mostly the meta-acylated
products,[21] whereas ring openings of phthalic anhydrides are
either unselective[22] or require costly and sensitive organo-
metallic reagents.[23]
While for example, ortho arylations have already reached
an impressive performance level,[1] ortho acylations are less
developed (Scheme 1).[13] Effective ways of directing acyl
In the course of our work on decarboxylative couplings[24]
targeting aryl ketones,[25] we heated 2-toluic anhydride (1a)
with a rhodium catalyst with the intention of generating the
symmetrical ketone 2aa by extrusion of CO2 (Scheme 2).
À
Scheme 1. Previous work on C H bond acylation. DG=directing
group, Tf=trifluoromethanesulfonyl.
substitutents to the position ortho to a functional group are
oxidative couplings of aldehydes[14] or alcohols,[15] decarbox-
ylative couplings of a-oxoacids,[16] or carbonylative process-
es.[17]
Scheme 2. Discovery of an ortho acylation/decarboxylation reaction.
However, instead of the desired decarboxylative coupling
product 2aa, a mixture of the unsymmetrical ketone 4aa and
6-(2-toluoyl)-2-toluic acid (3aa) was formed.
This seminal experiment pointed to the principal feasi-
bility of an ortho acylation, which in this case proceeded with
a subsequent partial protodecarboxylation. Our mechanistic
rationale is outlined in Scheme 3. The anhydride 1 had
presumably undergone oxidative insertion of the rhodium
[*] P. Mamone, Dr. G. Danoun, Prof. Dr. L. J. Gooßen
FB Chemie—Organische Chemie, TU Kaiserslautern
Erwin-Schrçdinger-Strasse, Geb. 54
67663 Kaiserslautern (Germany)
E-mail: goossen@chemie.uni-kl.de
Homepage: http://www.chemie.uni-kl.de/goossen
[**] We thank Saltigo GmbH and NanoKat for funding, and Umicore for
donating chemicals. We acknowledge T. Knauber and G. Deng for
pioneering experiments, and thank J.-Y. Chung, W. Eichmann, B.
Exner, B. Frensch, K. Messemer, and A. Marxen for technical
assistance.
À
catalyst into its acyl O bond leading to the benzoate B, which
has structural precedent,[26] and has been proposed as
intermediate also in rhodium-catalyzed cross-couplings of
anhydrides.[27] Assisted by the added base, the rhodium would
À
then have inserted intramolecularly into the ortho-C H bond
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301328.
to give C. The formation of ortho-metalated RhIII carbox-
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Table 1: Development of the catalyst system.
Entry
[Rh]
Equivalents
Base
3ab
1b
Yield [%]
Scheme 3. Proposed mechanism of the ortho acylation.
1
2
3
4
5
6
7
8
[{Rh(Cp*)Cl2}2]
[{Rh(OAc)2}2]
[{Rh(coe)Cl}2]
[{Rh(cod)Cl}2]
[{Rh(cod)Cl}2]
[{Rh(cod)Cl}2]
[{Rh(cod)Cl}2]
[{Rh(cod)Cl}2]
[{Rh(cod)Cl}2]
–
1
1
1
1
4
4
4
4
4
4
4
KF
KF
KF
KF
18
23
27
29
68
82
69
71
93
0
ylates is well documented.[28] Reductive elimination would
have furnished the ortho-acylbenzoic acid 3 and regenerated
the rhodium catalyst A. ortho-Acylbenzoates such as 3 are
known to decarboxylate readily above 1608C in the presence
of various metal mediators, thus explaining the formation of
4.[29]
KF
CsF
K3PO4
K2CO3
Cs2CO3
Cs2CO3
–
9
10
11
After the initial serendipitous discovery, we investigated
whether this reaction concept could be transformed into
a general method for the ortho acylation of benzoic acids with
carboxylic anhydrides. We were particularly interested in
selectively coupling two different carboxylic acid residues
with each other, and thus chose the coupling of 2-toluic acid
(5a) with propionic anhydride (1b) as a test reaction
(Table 1). We screened various metal complexes and found
rhodium to be a uniquely active catalyst metal. [{Rh(cod)Cl}2]
provided the desired product 3ab in 29% yield after basic
hydrolysis (entries 1–4). In situ analysis of the reaction
mixture provided an explanation for the incomplete turnover:
The primary reaction product 3ab exists in equilibrium with
its cyclized tautomer 3’ab,[30] which uses up an anhydride
equivalent in an esterification step. As a minor side product,
the aromatic anhydride self-coupling product 6-(2-toluoyl)-2-
toluic acid (3aa; 10–15%) is also observed. Use of 1b in
excess should make up for losses in the parasitic equilibrium
reaction and ensure better conversion of 5a. Indeed, when
using 4 equivalents of 1b, the product 3ab was obtained in
68% yield, and the amount of 3aa was reduced to below 5%
(entry 5). Almost quantitative conversion was obtained when
switching to Cs2CO3 as the base (entry 9), whereas a range of
other inorganic and organic bases were less effective. Control
experiments confirmed that no reaction takes place without
rhodium or without base (entries 10 and 11).
We next investigated the generality of the optimized
protocol using various benzoic acids (5) in combination with
aliphatic anhydrides (1). As can be seen from the examples in
Table 2, both electron-rich and electron-deficient aromatic
and heteroaromatic carboxylic acids (5) were selectively
ortho-acylated with 1b. A variety of functionalities including
alkoxy, trifluoromethyl, bromo, chloro, fluoro, hydroxy,
amino, and keto groups were tolerated. The double acylation
products were observed in trace amounts at most. The meta-
substituted carboxylates were acylated selectively in the less
hindered ortho position and para-substituted compounds
[{Rh(cod)Cl}2]
0
Reaction conditions: 0.50 mmol of 5a, 0.50–2.00 mmol of 1b, 1.5 mol%
of Rh catalyst, 0.50 mmol of base, 0.50 mL of mesitylene, 16 h, 1458C.
Work-up: 12.5 mmol of NaOH, 2 mL of H2O, 1 h, 1008C. Yields were
determined by HPLC analysis using anisole as an internal standard.
cod=cyclo-1,5-octadiene, coe=cyclooctene, Cp*=pentamethylcyclo-
pentadiene.
were monoacylated with high selectivity. In the reaction of
a range of linear and branched aliphatic anhydrides with 5a,
the corresponding ortho-acylbenzoic acids 3ac–3ae were also
formed with high selectivity (Table 2).
In contrast, use of the sterically crowded pivalic anhydride
(1 f) as the acylation agent led to the exclusive formation of
the aromatic anhydride self-coupling product, while the
ortho-pivaloylbenzoic acids were not observed. This result
opened up an additional synthetic opportunity, namely
a selective desymmetrizing self-condensation of benzoic
acids. Upon treating benzoic acids (5) with 1 f in the presence
of the rhodium catalyst, ortho-aroylbenzoic acids (3) are
produced in high yields and selectivities. The products were
isolated as n-propyl esters after in situ alkylation (Scheme 4).
The alternative in situ conversion of a mixture of the
benzoic acid 5 and its acid chloride to the symmetrical
anhydride and then on to the ortho-aroylbenzoic acid 3 was
less effective under identical conditions (33% yield for 3aa).
After ortho acylation, the carboxylate group can option-
ally be removed by in situ protodecarboxylation. However, it
turned out that the rhodium complex mediates this step only
at temperatures above 2008C. Higher yields were obtained
when the ortho acylation was combined with hydrolysis and
subsequent copper-mediated protodecarboxylation[29] in
a sequential one-pot procedure (Scheme 5). The overall aryl
ketone synthesis is a rare example of an aromatic substitution
in which the substitution pattern is changed in a defined way.
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Table 2: Scope of the ortho acylation of carboxylic acids.
Product
Yield [%]
86
Product
Yield [%]
45[b,c]
69
46[b]
74[b,d]
88[b]
60
Scheme 4. Self-acylation of aromatic benzoic acids. NMP=N-methyl-
pyrrolidone.
75
87[a]
92[a]
92[a]
87
20[d]
Scheme 5. One-pot synthesis of meta-substituted ketones.
Phen=1,10-phenanthroline.
82
influence on the reaction outcome, and thus excludes single-
electron transfer processes. When mixed anhydrides were
generated in the absence of free carboxylate groups, that is, by
mixing 2-toluic anhydride (1a) with an excess of 1b, 3ab was
also obtained in high yields. This result indicates that the
anhydride group is capable of directing the acylation to its
ortho position.
70[b]
68[a]
52[b]
73[a]
À
Although an alternative catalytic cycle with the C H
Reaction conditions: 0.5 mmol of 5, 2 mmol of 1, 1.5 mol% of
activation and oxidative addition steps in reverse order
cannot be excluded at that stage, there is some evidence
that the reaction starts with a slow oxidative insertion step
and formation of an acyl rhodium(III) species. When heating
[{Rh(cod)Cl}2] with a stoichiometric amount of 2-toluic
anhydride (1a) to 1458C in the absence of base, no conversion
of the starting material was observed, thus indicating that
oxidative addition is either base-assisted or not the initiating
catalytic step. Upon addition of CsF, the formation of cesium
toluate and toluyl fluoride was observed above 1008C. At
1458C, the product was formed without detection of any
rhodium-containing intermediates. The initial reaction step
must thus be slow. However, in the reaction of a 1:1 mixture of
perdeuterated and undeuterated benzoic acid (5p and [D5]-
5p) with 1b, a kinetic isotope effect of only 1.5 was measured.
[{Rh(cod)Cl}2], 125 mmol of Cs2CO3, 0.5 mL of mesitylene, 16 h, 1458C.
Work-up: 12.5 mmol of NaOH, 2 mL of H2O, 1 h, 1008C. Yields of
isolated products are given. [a] 1 mmol of KF. [b] 1 mmol of CsF, 1558C.
[c] 2 mL of mesitylene. [d] Isolated as the propyl ester following in situ
alkylation with 1-bromopropane.
As demonstrated by the examples 4aa and 4ab, it can be used
to convert 5 into meta-alkyl aryl ketones, which are the
disfavored regioisomers in Friedel–Crafts acylations of the
corresponding alkyl arenes.
A series of mechanistic studies were performed to shed
some light on the reaction mechanism. The addition of
a stoichiometric amount of 2,2,6,6-tetramethylpiperidine-N-
oxyl (TEMPO) as a radical scavenger had only a little
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initial reaction step.
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acylation of benzoic acids with anhydrides into the ortho po-
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Experimental Section
Synthesis of 3ab: Under a nitrogen atmosphere, a vessel was charged
with 2-toluic acid (1.36 g, 10.0 mmol), cesium carbonate (815 mg,
2.50 mmol), and chloro(1,5-cyclooctadiene)rhodium(I) dimer
(74.0 mg, 0.15 mmol). Degassed mesitylene (10 mL) and propionic
anhydride (5.13 mL, 5.21 g, 40.0 mmol) were then injected, and the
mixture was stirred at 1458C for 16 h. After cooling, 6.25m NaOH
solution (40 mL) was added and the solution was heated to 1008C for
1 h. The reaction mixture was then acidified with conc. HCl (pH < 4)
and the aqueous layer was extracted with ethyl acetate (3 ꢀ 100 mL).
The combined organic layers were washed with brine (100 mL), dried
over MgSO4, filtered, and concentrated in vacuo. The crude reaction
mixture was purified by column chromatography (SiO2, ethyl acetate/
n-hexane gradient) to give 3ab (1.37 g, 7.12 mmol, 71%) as a colorless
solid.
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Received: February 14, 2013
Published online: && &&, &&&&
À
Keywords: acylation · anhydrides · C H functionalization ·
.
ketones · rhodium
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Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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.
Angewandte
Communications
Communications
Synthetic Methods
P. Mamone, G. Danoun,
L. J. Gooßen*
&&&& — &&&&
Rhodium-Catalyzed ortho Acylation of
Aromatic Carboxylic Acids
New directions: The carboxylic acid
functional group directs the ortho acyla-
tion of benzoic acids with carboxylic
anhydrides in the presence of a rhodium
catalyst (see scheme; cod=cyclo-1,5-
octadiene). The acylation at the ortho
position is complementary to the meta
selectivity of Friedel–Crafts reactions. The
resulting products can undergo protode-
carboxylation to deliver an aryl ketone.
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!