Palladium-Catalyzed Decarboxylative Heck-Type Coupling of Activated Aliphatic Carboxylic Acids Enabled by Visible Light

Article abstract of DOI:10.1002/chem.201800813

The palladium-catalyzed coupling reaction of N-hydroxyphthalimide esters and styrenes to deliver exclusively (E)-substituted olefins under irradiation with visible light is reported. This method tolerates N-hydroxyphthalimide esters derived from primary, secondary, tertiary as well as benzylic carboxylic acids. Notably, Pd(PPh₃)₄ is employed as an inexpensive palladium source and no addition of base or classical photocatalyst is required. Mechanistic studies suggest a light-mediated single-electron reduction of the activated acid by a photoexcited palladium(0) species to access alkyl radicals through decarboxylation.

Full text of DOI:10.1002/chem.201800813

A Journal of
Accepted Article
Title: Palladium-Catalyzed Decarboxylative Heck-Type Coupling of
Activated Aliphatic Carboxylic Acids Enabled by Visible Light
Authors: Maximilian Koy, Frederik Sandfort, Adrian Tlahuext-Aca,
Linda Quach, Constantin Daniliuc, and Frank Glorius
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.201800813
Link to VoR: http://dx.doi.org/10.1002/chem.201800813
Supported by

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COMMUNICATION
Palladium-Catalyzed Decarboxylative Heck-Type Coupling of
Activated Aliphatic Carboxylic Acids Enabled by Visible Light
[
+]
[+]
Maximilian Koy , Frederik Sandfort , Adrian Tlahuext-Aca, Linda Quach, Constantin G. Daniliuc and
Frank Glorius*
Abstract: The palladium-catalyzed coupling reaction of N-
hydroxyphthalimide esters and styrenes to deliver exclusively (E)-
substituted olefins under irradiation with visible light is reported. This
method tolerates N-hydroxyphthalimide esters derived from primary,
secondary, tertiary as well as benzylic carboxylic acids. Notably,
due to fast -hydride elimination of related palladium(II) alkyl
species.
3 4
Pd(PPh ) is employed as an inexpensive palladium source and no
addition of base or classical photocatalyst is required. Mechanistic
studies suggest a light-mediated single electron reduction of the
activated acid by a photoexcited palladium(0) species to access alkyl
radicals via decarboxylation.
The palladium-catalyzed reaction between olefins and aryl or
alkenyl halides to deliver substituted olefins with high (E)-
selectivity – generally known as the Mizoroki-Heck reaction – is
one of the most fundamental reactions in cross-coupling
[
1]
0
II
chemistry. Detailed investigations have revealed a Pd /Pd
mechanistic cycle, initiated by oxidative addition of the respective
aryl or alkenyl halide (Figure 1a).[2] The extension of Heck
methodology to the analogous coupling of alkyl halides is not
trivial due to challenging oxidative addition of palladium(0) and
fast -hydride elimination of the intermediate palladium(II) alkyl
Figure 1. a. – c. Overview of classical and decarboxylative Heck(-type)
methodology (X = halide). d. Expansion to alkyl carboxylic acids.
species.[3] Pioneering work by the groups of Alexanian and J.
Zhou suggests a single electron transfer (SET) from palladium(0)
to the respective alkyl halide, thereby generating a palladium(I)
species and an alkyl radical, which then adds to the olefin.[4] After
recombination, β-hydride elimination and reductive elimination is
proposed to occur in analogy to standard Heck coupling chemistry.
Recently, the groups of Gevorgyan and Y. Fu reported on mild
Heck-type couplings with an impressively expanded scope of
alkyl halides under visible light irradiation (Figure 1b).[5]
Thus, we sought to develop a process that would enable the
combination of the broad structural diversity of alkyl carboxylic
acids with Heck coupling methodology to deliver highly valuable
(
E)-substituted olefins. We envisioned a radical process initiated
by SET between a palladium species and an alkyl carboxylic acid
or its derivative.[8] Motivated by various reports about reduction of
easily accessible N-hydroxyphthalimide esters 2 – also known as
redox active esters – by organometallic nickel,[9] iron,[9f,h,10]
Carboxylic acids are a cheap, stable, non-toxic and often naturally
abundant feedstock for organic synthesis. Therefore, they present
an attractive replacement for organic halides. In 2002, Myers
reported on the decarboxylative Heck-type coupling of aryl
carboxylic acids with olefins (Figure 1c).[6] Mechanistic
investigations support a palladium(II)-mediated decarboxylation
iridium[11] and copper[12] species to access alkyl radicals; and of
an emerging number of reports about SET processes from
[13]
palladium(0) species to organic halides, we wondered whether
a photochemically or thermally induced SET could also occur
between a palladium(0) species and N-hydroxyphthalimide esters
(Figure 1d).[14]
2
to access palladium(II) aryl species.[7] This Pd /Pd mechanistic
II
0
2
2
paradigm has only been applied to sp -sp couplings, presumably
[*]
M. Koy[+], F. Sandfort[+], A. Tlahuext-Aca, L. Quach, Dr. C. G.
Daniliuc, Prof. Dr. F. Glorius
Figure 2. General reaction conditions. Phth
= Phthalimide, Boc = tert-
Organisch-Chemisches Institut
1
butyloxycarbonyl. Yields determined by H NMR, isolated yield in parentheses.
Westfälische Wilhelms-Universität Münster
Corrensstraße 40, 48149 Münster (Germany)
E-mail: glorius@uni-muenster.de
We started our investigations with the reaction of styrene (1a) and
N-hydroxyphthalimide ester 2a. Pleasingly, the (E)-substituted
olefin 3aa was exclusively obtained in 86% isolated yield (87%
[+
]
Both authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
1H NMR yield) by reaction with Pd(PPh
3 4
) (5 mol%) in THF (0.1 M)
under irradiation with blue LEDs (455 nm, 5 W, Figure 2). No
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product formation was observed in the dark or in the absence of
the palladium catalyst (see the Supporting Information for further
However, this screen indicated that sulfur and bromide containing
substrates are not suitable for this transformation (Figure 3a and
see the Supporting Information). The substrate scope of the
transformation was evaluated using 15 different styrene coupling
details). Notably, under these conditions Pd(PPh
employed as a commercially available and inexpensive palladium
3 4
) could be
source without requiring additional use of base or ligand. However, partners. Electron-donating as well as electron-withdrawing
inspired by the work of Gevorgyan and Y. Fu, who reported on a
beneficial effect of xantphos in light mediated palladium(0)
chemistry, we also investigated the effect of a bidentate ligand
and product 3aa was observed in slightly improved yield with
groups were tolerated on the arene ring and (E)-substituted
olefins (3aa – 3ja) were isolated in high yields. Notably,
heteroaromatic 2-vinylpyridine was tolerated and product 3ka was
isolated in high yield. Expansion of the aromatic ring gave product
3la in good yield, while two ortho-substituents of the styrenyl
coupling partner led to diminished yield of product 3ma. Reaction
with an -substituted styrene was also successful, as exemplified
by product 3na (Figure 3b).
6
mol% of xantphos (91% NMR yield).[5] For simplicity of the
system and to avoid the use of an expensive ligand, we decided
to use xantphos only in exceptional cases.
An additive-based robustness screen[15] revealed high functional
group tolerance for synthetically important functional groups like
free alcohols, terminal alkynes, carbonyl compounds and nitriles.
Figure 3. Additive–based robustness screen (a.) and scope of the decarboxylative Heck-type coupling (b.-e.). Standard conditions: 2 (0.3 mmol, 1 eq.), 1
0.45 mmol, 1.5 eq.), Pd(PPh
(5 mol%), THF (3.0 mL), RT, 24 h, 455 nm LEDs (5 W). a 0.1 mmol scale. b With xantphos (6 mol%). c 48 h reaction time.
Irradiation with Kessil lights (32 W).
(
3 4
)
d
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A wide variety of N-hydroxyphthalimide esters derived from
primary, secondary and tertiary carboxylic acids were also
compatible coupling partners. While product 3fb, derived from a
primary carboxylic acid, was isolated in synthetically useful yield
under the standard conditions, the addition of xantphos was
essential to obtain olefin 3fc containing a terminal alkyne in 59%
isolated yield. Product 3fd with an ester group was isolated in
mechanism being operative. In these studies, the formation of
adduct 4k between TEMPO and the alkyl radical stemming from
decarboxylation of N-hydroxyphthalimide 2k was observed, while
the corresponding product 3fk was not detected (Figure 4a).
Additionally, rapid ring-opening of the cyclopropyl moiety of redox
active ester 2t was found upon decarboxylation to give product
3ft’ in 44% NMR yield (Figure 4b and see the Supporting
Information). UV/vis spectroscopic analysis of each individual
43% yield, where no beneficial effect of added xantphos was
observed. Esters of naturally abundant molecules such as
dehydrocholic acid and fatty acids could be derivatized in high and
satisfying yield, respectively (3fe, 3af and 3ag). A benzylic
substrate could also be used to prepare product 3fh in a
synthetically useful yield of 58% by irradiation with higher intensity
blue Kessil lights (32 W). Additionally, activated phenoxyacetic
acid gave access to -unsaturated ether 3fi in good yield. Both,
cyclic and acyclic, secondary carboxylic acid esters were
successfully coupled (3fj – 3fn). However, acyclic compound 3fn
required the addition of xantphos to obtain a good yield. Notably,
esters derived from naturally occurring amino acids proline and
phenyl alanine gave the corresponding products (3al and 3am) in
high yield. Tertiary acids could also be used to give access to
synthetically valuable quaternary carbon centers. Olefinated
products (3fo – 3as) were isolated in good yields. To show the
utility of this methodology, esters from natural products
gemfibrozil and oleanolic acid, containing a free alcohol, were
successfully coupled in good yield (3fr and 3as).
3 4
reaction component indicated that Pd(PPh ) is the only light
absorbing species at 455 nm. Furthermore, the UV/vis spectrum
of the reaction mixture with all components and the spectrum only
of Pd(PPh ) were nearly identical, which indicates that no
3 4
chemical modification of the palladium catalyst occurs prior to
photoexcitation (see the Supporting Information for details). To
3 4
verify this hypothesis, Pd(PPh ) and N-hydroxyphthalimide ester
2u were stirred in THF-d
8
at room temperature (72 h) and at 35 °C
(12 h). No reaction was observed in either case by H and 31P
NMR spectroscopy. Upon irradiation with 455 nm light for 12 h,
complete conversion of 2u to cyclohexene 6u from direct β-
hydride elimination and to cyclohexane 7u from hydrogen-atom
1
1
abstraction was detected by H NMR spectroscopy (Figure 4c).
Finally, the quantum yield of the reaction was determined to be
0.21.
Based on these studies and on literature precedence,[
5]
a
mechanistic proposal is depicted in Figure 5. The catalytic cycle
is initiated by photoexcitation of the palladium(0) catalyst,
followed by single electron transfer to N-hydroxyphthalimide ester
For all olefins, we exclusively obtained the (E)-isomer and no (Z)-
isomer was detectable by NMR. The (E)-substitution pattern was
additionally verified by crystal structures of compounds 3ca and
2a, which forms the corresponding alkyl radical upon release of
CO . Addition of the radical to the corresponding styrene gives the
2
more stabilized radical species 9a. Recombination followed by β-
hydride elimination gives the product and palladium(II) hydride
species 10. Formal reductive elimination of phthalimide
regenerates the catalyst.
3
fk.[16] For analogous reactions with organic alkyl halides,
especially with primary halides, the formation of a small amount
of the (Z)-isomer was observed.[5a-c]
Figure 5. Proposed mechanistic cycle.
In conclusion, we have developed the Heck-type coupling of
activated aliphatic acids with styrenes. Primary, secondary,
tertiary and benzylic carboxylic acids are tolerated and the
reaction proceeds in the absence of base under irradiation with
commercially available and cheap blue LED lights to give access
to valuable (E)-substituted olefins in perfect selectivity. The
applicability of the methodology was demonstrated through the
functionalization of various naturally occurring carboxylic acids.
Figure 4. Selected mechanistic studies.
To shed light on the mechanism of this light-mediated,
decarboxylative Heck-type coupling, TEMPO trapping and radical
clock experiments were conducted to verify a radical-type
Mechanistic studies revealed
a radical mechanism being
operative and that a single electron transfer between the
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photoexcited palladium catalyst and the N-hydroxyphthalimide
ester occurs as the initial step.
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Acknowledgements
Generous
financial
support
by
the
Deutsche
Forschungsgemeinschaft (Leibniz Award) and the Graduate
School of Chemistry NRW (A. T.-A.) is gratefully acknowledged.
We are thankful to Dr. Michael J. James and Andreas Lerchen for
helpful discussions.
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Keywords: Palladium • Heck-Type Coupling • Carboxylic Acids •
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[
[
14] We estimated the oxidation potential of photoexcited Pd(PPh
3
)
4
to be
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+
E(M /M*)
=
-1.72
V
vs. SCE.
A
single electron reduction of N-
hydroxyphthalimide esters (E1/2
=
-1.4 V) should therefore be
thermodynamically feasible. See the Supporting Information for details.
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Entry for the Table of Contents (Please choose one layout)
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[
+]
[+]
Maximilian Koy , Frederik Sandfort ,
Adrian Tlahuext-Aca, Linda Quach, Dr.
Constantin G. Daniliuc and Prof. Dr.
Frank Glorius*
Page No. – Page No.
Palladium-Catalyzed Decarboxylative
Heck-Type Coupling of Activated
Aliphatic Carboxylic Acids Enabled
by Visible Light
Text for Table of Contents
We report a palladium-catalyzed coupling reaction of N-hydroxyphthalimide esters and styrenes to deliver (E)-substituted olefins in
perfect selectivity under irradiation with visible light. This method tolerates N-hydroxyphthalimide esters derived from primary,
secondary, tertiary and benzylic carboxylic acids, also including complex naturally occuring carboxylic acids. Pd(PPh ) is employed as
3 4
an inexpensive palladium source and no addition of base or classical photocatalyst is required. Mechanistic studies suggest a light-
mediated single electron reduction of the activated acid by a photoexcited palladium(0) species.
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