Direct β- and γ-C(sp3)?H Alkynylation of Free Carboxylic Acids**

Article abstract of DOI:10.1002/anie.202010784

In this study we report the identification of a novel class of ligands for palladium-catalyzed C(sp³)?H activation that enables the direct alkynylation of free carboxylic acid substrates. In contrast to previous synthetic methods, no introduction/removal of an exogenous directing group is required. A broad scope of acids including both α-quaternary and challenging α-non-quaternary can be used as substrates. Additionally, the alkynylation in the distal γ-position is reported. Finally, this study encompasses preliminary findings on an enantioselective variant of the title transformation as well as synthetic applications of the products obtained.

Full text of DOI:10.1002/anie.202010784

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Accepted Article
Title: Direct β- and γ-C(sp3)–H Alkynylation of Free Carboxylic Acids
Authors: Francesca Ghiringhelli, Alexander Uttry, Kiron Kumar Ghosh,
and Manuel van Gemmeren
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202010784
Link to VoR: https://doi.org/10.1002/anie.202010784

10.1002/anie.202010784
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Direct β- and γ-C(sp3)–H Alkynylation of Free Carboxylic Acids
Francesca Ghiringhelli[a], Alexander Uttry[a], Kiron Kumar Ghosh[a], Manuel van Gemmeren[a]*
Dedicated to Prof. Antonio M. Echavarren on the occasion of his 65th birthday.
[a]
F. Ghiringhelli, A. Uttry, K. K. Ghosh, Dr. M. van Gemmeren
Organisch-Chemisches Institut
Westfalische Wilhelms-Universität Münster
Corrensstraße 40, 48149 Münster (Germany)
E-mail:mvangemmeren@uni-muenster.de
Supporting information for this article is given via a link at the end of the document.
Abstract: In this study we report the identification of a novel class of
ligands for palladium-catalyzed C(sp3)–H activation that enables the
direct alkynylation of free carboxylic acid substrates. In contrast to
previous synthetic methods, no introduction/removal of an exogenous
directing group is required. A broad scope of acids including both α-
quaternary and challenging α-non-quaternary can be used as
substrates. Additionally, the alkynylation in the distal γ-position is
reported. Finally, this study encompasses preliminary findings on an
enantioselective variant of the title transformation as well as synthetic
applications of the products obtained.
research groups such as the groups of Chen, Shi, Colobert, and
Verho developed new catalytic systems and directing groups to
achieve C(sp3)−H alkynylation.[10] Additionally to the development
of palladium-catalyzed alkynylation, cobalt and nickel- catalyzed
reactions using a bidentate auxiliary were reported.[11] Although
these reactions allow the formation of the target compounds, they
are still far from ideal with respect to the atom- and step-economy.
Recently, ourselves and others have demonstrated that the
challenging direct C(sp3)–H activation/functionalization of free
carboxylic acids can be enabled through ligand design and, within
a short period of time, protocols have been developed that enable
valuable transformations, such as direct arylations,[12]
acetoxylations,[13] lactonizations,[14] and olefinations[15] of such
substrates. Based on our experience in the β- and γ-C(sp3)-H
functionalization of free carboxylic acids, we thus expected that
the identification of a suitable ligand would be crucial for the
development of the desired alkynylation process.
The alkyne moiety is widely used in medicinal chemistry, material
science, and synthetic chemistry. It often serves as synthetic
linchpin, due to its tremendous synthetic versatility, which enables
the synthesis of new materials and drugs, through subsequent
transformations.[1] Thus, efficient methods for the introduction of
alkyne moieties into a given organic molecule are required. In this
context, the direct alkynylation of C–H bonds has received
significant attention.[2]
The metal-catalyzed C(sp3)–H alkynylation of carboxylic acids
constitutes a particularly attractive goal, since many carboxylic
acids are cheap, easily available, and abundant starting materials
and the resulting products contain two highly versatile functional
groups.[3] In this regard, the direct use of free, unfunctionalized
carboxylic acids as substrates to achieve
a
C(sp3)–H
activation/alkynylation can be considered the ideal approach
(Scheme 1, Path A). However, the development of such methods
is hampered by several key challenges inherent to the carboxylic
acid moiety as directing group, including, among other reasons,
the low directing ability of the carboxylate unit and the existence
of competing coordination modes between palladium and the
carboxylate moiety.[4] These challenges have traditionally been
addressed through the introduction of specialized exogenous
directing groups (DGs) that enable the key C–H alkynylation, but
add synthetic steps to the overall sequence (Scheme 1, Path B).[5]
The first palladium-catalyzed alkynylation of non-activated
C(sp3)−H bonds in aliphatic carboxylic acid derivatives was
described by Chatani et al. in 2011 using a bidentate auxiliary.[6]
Later, Yu et al. developed a β-methyl C(sp3)−H alkynylation, using
aliphatic amides bearing a perfluorinated arene auxiliary on the
nitrogen.[7] In 2017 the same group reported the first example of
an enantioselective C(sp3)−H alkynylation,[8] as well as the first
C(sp3)−H alkynylation of oligopeptides.9] In parallel, other
Scheme 1. Previous studies on the indirect C−H alkynylation of aliphatic acids
(Path B) and direct C(sp3)−H alkynylation of free carboxylic acids developed in
this study (Path A).
1
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We initiated our studies using pivalic acid 1a as model substrate.
Different ligands, that have been used for the direct C(sp3)–H
activation of free carboxylic acids for other transformations were
tested. The amino acid derivatives L1-L3,[12c,d] thioether ligand
L4,[15a] monoprotected aminoethyl amine ligand L5,[16] anthranilic
acid ligand L6,[15b] and oxazoline ligand L7 all delivered
discouraging results (Scheme 2).[8,17]
Finally, we identified a novel class of diamine-derived ligands
which proved highly efficient in this transformation. Starting from
our initial discovery (L8, 10%), the catalyst efficiency improved
dramatically when an aryl substituent was introduced on the
sulfonamide (L9, 65%). Further optimization on the ligand
structure showed that various substitution on the aromatic ring do
not have
a significant influence on the yield (L10-L13).
Substitution on the ethylenediamine backbone combined with
varied arenes on the sulfonamide likewise delivered no
substantial further improvement in yield for the standard substrate
(L14-L18), such that the comparably simple and easy to access
ligand L9 was chosen for further studies.
Having identified a suitable ligand for the β-alkynylation of free
carboxylic acids, we started to investigate the substrate scope
(Scheme 3). As expected from the optimization studies, the
product 2a derived from the pivalic acid 1a was obtained in 65%
yield. Variation of the aliphatic chain in 2b (70%), 2c (63%), and
2d (65%) is not detrimental for the reaction outcome. A fluorine
substituent was well tolerated (2e, 57%) as well as a TBS-
protected (2f, 55%) and free hydroxy group (2g, 45%). We
furthermore evaluated various aryl-containing carboxylic acids.
Our protocol showed
a broad functional group tolerance
irrespective of the substitution pattern on the arene. Both electron-
donating (2i, 2j) and electron-withdrawing substituents (2k-2r)
were well tolerated under our reaction conditions. Interestingly,
we did not observe competing C(sp2)−H alkynylation under our
reaction conditions and unsubstituted phenyl (2h, 58%) and
naphthyl rings (2s, 59%) provided good yields as well. Importantly,
a series of functional groups that are of relevance in biologically
active substances was well tolerated, such as ethers (2j, 63%),
nitriles (2k, 57%), trifluoromethyl- and trifuoromethylthio-groups
(2l, 58% and 2m, 55%), esters (2n, 57%), sulfonates (2o, 68%),
nitro groups (2p, 75%) and ketones (2q, 67%). Additionally, we
achieved the β-methylene-C(sp3)–H alkynylation of cyclopropane
carboxylic acid (2t, 45%, 98:2 dr).[18]
Scheme 2. Identification of suitable ligands for the β- and γ-C(sp3)–H
alkynylation 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
using 1,3,5-trimethoxybenzene as an internal standard. The mass balance of
the reactions is fully accounted for by the product formed and unreacted starting
material. No di- or tri-substituted product was observed in any case during the
optimization studies.
Scheme 3. Reaction scope. Reactions were conducted on a 0.2 mmol scale. [a] L14 was used instead of L9, LiHFIP (1 equiv), H2O (1.5 equiv), and HFIP (2.0 mL)
were used at 60 °C for 24 h; [b] Pd(OAc)2 (20 mol%), L14 (60 mol%), LiHFIP (2 equiv), Ag2O (2 equiv), 1-bromo-2(triisopropylsilyl)acetylene (3 equiv), and HFIP (4
equiv) were used at 60 °C for 24 h. The structures of the respective starting materials are shown for simplicity with the position that is C–H alkynylated highlighted.
2
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To further broaden the applicability of our method, we proceeded
to study the use of notoriously challenging α-non-quaternary acid
substrates. Notably, due to the absence of an accelerating
Thrope-Ingold-effect and additional possible side reactions, such
substrates are either not included or have proved particularly
challenging in the majority of studies on the direct C–H
activation/functionalization of aliphatic carboxylic acids.[4a,4b]
Interestingly, a re-optimization of the reaction conditions, using
L14 instead of L9 alongside further adaptions, enabled us to
alkynylated α-non-quaternary acid substrates.
Various substrates with varying chain lengths and steric demands
could be alkynylated (2u-2y). It should be noted that, although the
yields of these reactions remained moderate, the fact that the
functionalization can be achieved on the free acid substrate rather
than using an exogenous directing group nevertheless provides a
substantial increase in efficiency.
Building upon the advances in the ligand-enabled C(sp3)–H bond
activation of free carboxylic acids in the proximal β-position,
ourselves and others have recently strived to expand this
reactivity to the more distal γ-position.[12e,12h,15b,15c] Such reactions
face additional challenges with respect to activation entropies and
enthalpies, as well as potential side reactions.
We were thus highly pleased to find that our alkynylation protocol
could be adapted to the γ-C(sp3)–H alkynylation of carboxylic
acids. As for the β-alkylnylation of α-non quaternary acids, the key
to enable this transformation was the use of L14 as ligand, under
partially re-optimised conditions. The alkyl substituted products
2z-2ad were obtained in moderate to good yield.
Scheme 4. Initial findings on the enantioselective β-C(sp3)–H alkynylation of
carboxylic acids 1c and 1t.
Additionally, we were able to synthesize the bioactive valproic
acid (VPA) derivative 5, starting from the easily accessible starting
material 1af (Scheme 5c).[20]
It should be noted that this sequence could be conducted with
synthetically useful yields despite requiring the alkynylation of a
challenging α-non-quaternary substrate.
It should be noted that these yields, despite remaining moderate,
compare well with those that have previously been achieved by
using exogenous directing groups.[6a,7b,10b] Additionally, the yields
in these indirect routes would in practice be reduced further
through losses of material in the steps required for the introduction
and removal of the DG, which adds further value to the direct
protocol described herein.
After completing the investigation on the reaction scope, we
became interested to explore the possibility of achieving
enantioinduction in the reaction of substrates that become chiral
upon alkynylation by using ligands with a chiral, enantiopure
ethylenediamine backbone (Scheme 4).
We observed that the introduction of a benzyl group (L19)
enabled the desymmetrization of 1c, giving 2c in 66% yield and
with 19% ee (Scheme 4a). Similarly, the introduction of an
isopropyl unit induced a moderate enantioselectivity in the
desymmetrization of 1t, giving 2t in 35% yield and with a
promising 39% ee (Scheme 4b).
To further demonstrate the synthetic utility of our protocol, we
proceeded to probe the scalability of our reaction. The product 2a
was obtained with a virtually identical yield of 60% on a 5 mmol
scale (Scheme 5a). Next, we investigated possible derivatizations
[19]
of product 2a.
Compound 3 could be synthesized via a
deprotection/Sonogashira coupling sequence. Interestingly, both
steps could be performed in the presence of the free carboxylic
acid moiety. In parallel, 2a was esterified and subsequently
submitted to a deprotection/coupling sequence to yield compound
4 in a high overall yield of 67% over 3 steps (Scheme 5b).
Scheme 5. Synthetic utility of the β-C(sp3)–H alkynylation of aliphatic carboxylic
acids.
3
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Finally, we focused on obtaining a preliminary mechanistic
understanding of this transformation. We began by determining
the kinetic isotope effect (KIE) both in a competition experiment
and parallel experiments. The clear primary KIE observed in both
experiments indicates that the C–H activation is the rate
determining step (Scheme 6A).[21] Next, we evaluated the
reversibility of the C–H activation step. We conducted two
reversibility experiments (Scheme 6B), one in presence and one
in absence of the TIPS alkynyl bromide reagent. In both cases the
deuteration of the remaining starting material was analyzed.
When no 1-bromo-2(triisopropylsilyl)acetylene was added, a
strong de-deuteration was observed, showing that the C–H
activation step is in principle reversible under the reaction
conditions. In contrast, when the reagent was present, no loss of
deuteration was observed in the remaining starting material.
Based on these observations we conclude that the reaction
occurs through a rate-limiting C–H activation that, although in
principle reversible, is typically not reversed under conditions
suitable for product formation. The subsequent steps of the
catalytic cycle can, based on literature precedent, be assumed to
follow one of two pathways.[2,22] Either a Pd(IV)/Pd(II)-pathway
through an oxidative addition into the C-Br bond followed by a C-C
bond-forming reductive elimination, or through a Pd(II) pathway
consisting of an alkyne insertion followed by Pd-Br elimination. In
both cases the silver salt would act to activate the alkyne and
subsequently bind the bromide ions that could otherwise poison
the catalyst. Finally, the role of the LiHFIP base can be
rationalized in analogy to our recent studies on the acyloxylation
of carboxylic acids: By producing only a solvent molecule as
byproduct, this base avoids possible detrimental effects exerted
by the conjugate acids of many common bases. Additionally, the
presence of an alkali metal ion is likely required to induce a κ1-
coordination mode between the carboxylate and palladium, which
is in turn a prerequisite for the C–H activation to occur.[13a]
In summary, we have developed a protocol for the palladium-
catalyzed β- and γ-C(sp3)–H alkynylation of free carboxylic acids.
The reaction is enabled by a newly discovered ligand class that is
derived from an ethylenediamine backbone. Our protocol gives
access to a broad range of alkynylated products, starting from the
respective acids in one step, without the need to introduce an
exogenous directing group. Importantly, the scope of this reaction
could be extended to α-non-quaternary acid substrates as well as
distal γ-C(sp3)–H bonds. Finally, our study encompasses initial
results on the feasibility of an enantioselective variant of this
transformation and synthetic applications of the products obtained.
We expect that the synthetic method described herein will prove
helpful for example in the synthesis of bioactive molecules or
components for functional materials. Additionally, the novel ligand
class disclosed is expected to prove useful in further studies
towards the development of challenging C–H functionalization
protocols.
Scheme 6. Preliminary mechanistic studies.
Acknowledgements
The authors gratefully acknowledge financial support from the
DFG (Funding through the Emmy Noether Programme, M.v.G.),
the Studienstiftung des deutschen Volkes (fellowship to F.G.) and
the WWU Münster. We thank the members of our NMR and MS
departments for their excellent service. Furthermore we are
indebted to Prof. F. Glorius for his generous support.
Keywords: C–H activation • Alkynylation • Carboxylic acids •
Ligand-enabled catalysis • Palladium
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unsuccessful For further details, see the Supporting Information.
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Entry for the Table of Contents
No detours – The direct C(sp3) –H alkynylation of free carboxylic acids in the β- and γ-position is achieved using a Pd-catalyst with a
newly discovered ligand class. The synthetic method features a broad scope including preliminary findings on an enantioselective
variant and can be conducted on a preparatively useful scale.
Institute and/or researcher Twitter usernames: @vanGemmerenLab @WWU_Muenster
6
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