Ligand-Enabled γ-C(sp3)?H Olefination of Free Carboxylic Acids

Article abstract of DOI:10.1002/anie.202002362

We report the ligand-enabled C?H activation/olefination of free carboxylic acids in the γ-position. Through an intramolecular Michael addition, δ-lactones are obtained as products. Two distinct ligand classes are identified that enable the challenging palladium-catalyzed activation of free carboxylic acids in the γ-position. The developed protocol features a wide range of acid substrates and olefin reaction partners and is shown to be applicable on a preparatively useful scale. Insights into the underlying reaction mechanism obtained through kinetic studies are reported.

Full text of DOI:10.1002/anie.202002362

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Accepted Article
Title: Ligand-Enabled γ-C(sp3)–H Olefination of Free Carboxylic Acids
Authors: Kiron Kumar Ghosh, Alexander Uttry, Arup Mondal,
Francesca Ghiringhelli, Philipp Wedi, and Manuel van
Gemmeren
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Ligand-Enabled γ-C(sp3)–H Olefination of Free Carboxylic Acids
Kiron Kumar Ghosh,+ Alexander Uttry,+ Arup Mondal, Francesca Ghiringhelli, Philipp Wedi, Manuel van
Gemmeren*
Dedicated to the memory of Prof. Rolf Huisgen
Abstract: We report the ligand enabled C–H activation/olefination of
free carboxylic acids in the γ-position. Through an intramolecular
Michael-addition, δ-lactones are obtained as products. Two distinct
ligand classes are identified that enable the challenging palladium-
catalyzed activation of free carboxylic acids in the γ-position. The
developed protocol features a wide range of acid substrates and olefin
reaction partners and is shown to be applicable on a preparatively
useful scale. Insights into the underlying reaction mechanism
obtained through kinetic studies are reported.
cyclization (Scheme 1C).[6l] While constituting a synthetically
highly attractive approach towards the valuable δ-lactone motif,[7]
the analogous γ-olefination/cyclization has remained elusive to
date. It should be noted that research towards the direct γ-C(sp3)–
H activation of free carboxylic acids is still at its infancy and to the
best of our knowledge only two synthetic methods relying on this
type of process have been reported to date by the groups of Maiti
and Shi, in both cases enabling the γ-arylation of free carboxylic
acids through Pd(II)/Pd(IV)-catalytic cycles, albeit with
complementary acid scopes.[8] We thus became interested in
developing a method for the synthesis of δ-lactones through the
direct γ-C(sp3)–H olefination of free carboxylic acids. Herein we
report the realization of this goal enabled through the identification
of two suitable ligand-classes: N-acetyl anthranilic acid-
derivatives and N-acetyl amino acids.
The synthesis of complex carboxylic acid derivatives from simple
and readily available carboxylic acids is highly attractive, due to
the prevalence of the carboxylic acid moiety in compounds such
as pharmaceuticals, odors, flavors, etc.[1] However, despite some
recent progress, the direct C–H activation and functionalization of
free carboxylic acids remains highly challenging, due to the weak
directing ability of the carboxylate group and competing
coordination modes amongst other reasons, and thus requires the
identification of suitable ligands and a careful fine-tuning of the
associated reaction conditions.[2] These challenges can be
circumvented through the introduction of more strongly directing
exogenous directing groups, a strategy that has enabled a variety
of highly useful transformations.[3] One highly attractive synthetic
target in the field has been the C–H olefination of carboxylic acid
derivatives. Yu and coworkers have developed conditions for the
β-olefination of aliphatic amides bearing a perfluorinated arene
substituent on the nitrogen, which delivered γ-lactams through a
C–H-olefination followed by an intramolecular Michael addition
(Scheme 1A).[4] Later, the same group developed ligands that
allowed them to expand this reactivity to the C–H olefination of
the substantially more challenging γ-position giving access to δ-
lactams (Scheme 1B).[5] In parallel to the development of methods
relying on exogenous directing groups, substantial efforts by
ourselves and others have recently been directed towards the use
of free carboxylic acids in C–H activation processes and the
identification of suitable ligands enabled several highly useful
transformations.[6] Amongst these, Yu and coworkers have
reported a direct synthesis of γ-lactones through the β-(Csp3)–H
olefination of free carboxylic acids, followed by an intramolecular
Scheme 1. Key advances in the C(sp3)–H olefination of carboxylic acid
derivatives.
Based on our experience in the development of challenging β-
C(sp3)–H functionalization processes for free carboxylic acids, we
expected that the identification of suitable ligands would be key in
order to establish the desired protocol. We thus initiated our
studies using 3,3-dimethylbutyric acid (1a) and ethyl acrylate (2a)
as model substrates. After an initial identification of L10 as
particularly promising ligand, we optimized the reaction conditions
using this ligand (for details see the Supporting Information). After
identifying the otherwise best reaction conditions, we re-
evaluated representatives of common ligand classes in the
C(sp3)–H activation (Scheme 1). We found that the anthranilic
acid derivative L10 continues to deliver superior results compared
to pyridone L1,[9] pyridine L2,[6g, 10] and the bidentate ligands L3-
L7.[6g, 6j-l, 11] Structural variants of the anthranilic acid motif L8 and
L9 gave no further improvements. Finally, a re-investigation of
amino acid-derived ligands L11-L14[6h, 6i, 8] showed that N-Ac-β-
alanine L14 gave equally good results as L10. Notably this ligand
performed substantially worse than L10 in an initial comparison
under non-optimized conditions. Having identified two suitable
ligands for the γ-olefination of free carboxylic acids, we chose to
[*]
Kiron Kumar Ghosh, Alexander Uttry, Francesca Ghiringhelli,
Dr. M. van Gemmeren
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstraße 40, 48149 Münster (Germany)
E-mail: mvangemmeren@uni-muenster.de
Arup Mondal, Philipp Wedi, Dr. M. van Gemmeren
Max Planck Institute for Chemical Energy Conversion
Stiftstraße 34-36, 45470 Mülheim an der Ruhr (Germany)
K.K.G. and A.U. contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
[+]
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investigate the scope of this transformation using L14, simply
As expected based on our optimization studies, the model product
3a could be obtained in good yield (64%). This example was also
used to probe the scalability of our protocol. Importantly, a virtually
identical yield of 62% was obtained on a 5 mmol scale. For
structurally more complex acid substrates we found that an
increased reaction time and acrylate loading were required to
obtain optimal yields and used these conditions for the remainder
of the acid scope. The alkyl substituted products 3b-e were
obtained in good yields and with moderate diastereoselectivities
in favor of the cis-configured isomer. The spirocyclic products 3f
and 3g, as well as 3h, bearing two non-methyl substituents were
all obtained in synthetically useful yields. Finally, products 3i-m,
containing aromatic substituents were again obtained in good
yields and moderate to good diastereoselectivities. Several
limitations were also encountered during the evaluation of the acid
scope.[12] When we examined the reactivity of substrates without
a quaternary center in the β-position, no conversion of the starting
material was observed, presumably due to the absence of an
accelerating Thorpe-Ingold effect. Furthermore, it should be noted
that in case of competition between β- and γ-methyl groups, the
β-position is expected to react preferentially.[6h,l]
based on the broader availability of this ligand.
We proceeded to study the scope of this transformation with
respect to the olefinic reaction partner (Scheme 4).
Scheme 2. Identification of suitable ligands for the γ-C(sp3)–H olefination of free
carboxylic acids. Reactions were conducted on a 0.2 mmol scale. Yields were
determined by 1H-NMR analysis of the crude reaction mixture with 1,3,5-
trimethoxy benzene as internal standard.
It should be noted however, that the discovery of anthranilic acid
ligand L10, which has not previously been used in C–H activation
to the best of our knowledge may prove helpful in future related
studies. We began by studying the substrate scope with respect
to the acid substrate (Scheme 3).
Scheme 4. Olefin scope of the ligand-enabled γ-C(sp3)–H olefination of free
carboxylic acids. Reactions were conducted on a 0.2 mmol scale. a. Diethyl
vinylphosphate (7 equiv) was used with 72 h reaction time.
Various acrylates were found to react smoothly, giving products
4a-d in good yields. Olefins bearing other electron withdrawing
groups, such as methyl vinyl ketone (4e), acrylonitrile (4f), phenyl
vinyl sulfone (4g), ethenesulfonyl fluoride (4h), diethyl
vinylphosponate (4i) could all be used as reaction partners.
Finally, olefins containing structurally more complex subunits
were also successfully employed in the reaction, giving product
4j-l in good yields.
Scheme 3. Acid scope of the ligand-enabled γ-C(sp3)–H olefination of free
carboxylic acids. Reactions were conducted on a 0.2 mmol scale. a. 2a (2.5
equiv) and Ag2CO3 (1.75 equiv) were used with 40 h reaction time. b. 2a (7
equiv) and Ag2CO3 (2.5 equiv) were used with 72 h reaction time. c. The yield
in parentheses was obtained on a 5 mmol scale.
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Having studied the scope of this transformation, we became
interested in obtaining basic insights into the underlying reaction
mechanism. We began by evaluating whether the C–H activation
contributes to the overall rate of the transformation (Scheme 5A).
The clear primary kinetic isotope effect observed both in a
competition experiment and in parallel experiments indicates that
the C–H activation is indeed rate-determining.[13]
When we attempted to determine the order with respect to the
acid component, we found that both an increase and a decrease
in acid concentration were detrimental to the reaction outcome. In
light of the known importance of speciation in such
transformations discussed above, this result can easily be
rationalized: The rate of product formation is influenced by the
amount of substrate-palladium pre-reactive complex formed,
which in turn depends more on the acid-base balance of the
reaction mixture than on the actual substrate concentration. Since
we optimized the acid and base amounts during our optimization
studies, deviations in both directions are detrimental. Finally, we
found a small, but non-zero (0.2) order in the olefin reaction
partner. This result was unexpected, due to the previous
identification of the C–H activation as rate-determining step,
which implies a zero order in the olefin that enters the catalytic
cycle after this step. We hypothesized that this result can be
explained by a reversibility of the C–H activation step, together
with a lower, but comparable barrier for a subsequent step
involving the olefin. In such a scenario, the C–H activation step
would determine the overall rate of product formation, but a small
fraction of the palladacycle formed could statistically revert to the
starting material, when the subsequent reaction with the olefin
does not occur fast enough. In order to probe this hypothesis, we
conducted two reversibility experiments (Scheme 5C), one during
the product forming reaction with 1a-d9 as substrate and one in
the absence of the olefin reaction partner. In both cases the
deuteration of the remaining starting material was analyzed.
When no olefin is available, a strong de-deuteration was
observed, showing that the C–H activation is in principle
reversible under the reaction conditions. However, the result in
the presence of olefin clearly demonstrates that when product
formation is possible, it mostly outcompetes the retro-C–H
activation, while a small but measurable backwards reaction
occurs. These results are in good agreement with the observed
0.2 order in olefin. Overall, we propose the mechanism shown in
Scheme 6A, which takes into account the observations discussed
above.
1,6
R² = 0.996
slope = 1.044 ± 0.037
1,2
0,8
0,4
0,0
-0,4
-0,8
-1,2
-1,6
1,4
1,6
1,8
2,0
2,2
2,4
2,6
ln(initial catalyst conentration)
1,5
1,0
R² = 0.59
slope = 0.19 ± 0.09
0,5
0,0
-0,5
-1,0
-1,5
-2,0
-2,5
-3,0
-3,5
-4,0
4,6 4,8 5,0 5,2 5,4 5,6 5,8 6,0 6,2
ln(initial olefin conentration)
Accordingly, the reaction would proceed through a (mostly) rate-
determining C–H activation by a mononuclear Pd(II)-catalyst.
Next, a sequence of ligand exchange, carbopalladation, β-H-
elimination and decoordination would result in the formation of the
product in its non-cyclized form (4-open), which could
subsequently cyclize to product 4 though an intramolecular
Michael addition. Concominantly, the product decoordination
would deliver a Pd(II)-hydride species that could undergo a
reductive elimination giving a Pd(0)-species, which would then be
re-oxidized by the silver salt employed as terminal oxidant. A final
mechanistic feature of our protocol concerns a side product
observed in small quantities throughout these studies (5, Scheme
6B). We could isolate and characterize this side product in two
cases, 5e and 5m. Since the formation of these compounds
requires a second oxidation event, we hypothesize that they are
formed through a carboxylate directed C–H activation/oxidation
starting from the open form of the primary product.
Scheme 5. Preliminary mechanistic studies. Experiments in Scheme 5A and B
were conducted on a 0.2 mmol scale. The reversibility experiments were
conducted on a 0.1 mmol scale.
To obtain further knowledge about this step, we proceeded to
determine the kinetic orders in both reaction partners and the
catalyst (Scheme 5B). We began by determining the initial rates
of the reaction varying one of the starting concentrations. The
results were analyzed by determining the slope of the double
natural logarithmic plot of the initial rate vs. the varied starting
concentration.[14] The analysis revealed an order of 1 in catalyst.
Importantly, monomer-dimer-equilibria are known to exist for
palladium catalysts with amino acid-derived ligands and both
monomers and dimers have been shown to be the active catalyst
depending on the transformation and reaction conditions.[15] The
order of 1 indicates that only monomers or dimers can be present
in non-negligible amounts under the reaction conditions, such that
a change in concentration is not correlated with a shift in
equilibrium.[16] Based on the closest literature reports,[15b-f] we
propose the reaction to occur though monomeric catalyst species.
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Scheme 6. Proposed catalytic cycle and mechanism for side product formation.
In summary, we have developed a protocol for the palladium-
catalyzed γ-C(sp3)–H olefination of free carboxylic acids. Through
an in situ Michael addition δ-lactones are obtained without the
need to install/remove exogenous directing groups. Our protocol
features a broad scope of both reaction partners. Mechanistic
experiments support a Pd(II)/Pd(0)-catalytic cycle, which renders
this study the first report on a direct γ-C(sp3)–H activation/
functionalization of free carboxylic acids through this redox
manifold. We expect that these results will serve as a proof of
principle and inspire research towards further transformations of
this kind.
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We gratefully acknowledge financial support from the Max Planck
Society (Otto Hahn Award to M.v.G.), FCI (Liebig Fellowship to
M.v.G.), the DFG (SFB 858), and WWU Münster. We thank the
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Keywords: γ-C(sp3)–H activation • Carboxylic Acids • δ-
Lactones • Ligand-Enabled Catalysis • Palladium
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Entry for the Table of Contents
COMMUNICATION
Kiron Kumar Ghosh, Alexander
Uttry, Arup Mondal, Francesca
Ghiringhelli, Philipp Wedi,
Manuel van Gemmeren*
Page No. – Page No.
A direct γ-C–H olefination of carboxylic acids has been developed. Through a
subsequent intramolecular cyclization δ-lactones are obtained. Two suitable ligand
classes are identified to enable this palladium catalyzed transformation that
features a broad scope of both reaction partners. The reaction is achieved without
introducing an exogenous directing group and can be performed on a synthetically
useful scale. Kinetic studies provide first mechanistic insights.
Ligand-Enabled γ-C(sp3)–H
Olefination of Free Carboxylic Acids
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