Palladium-Catalyzed Decarboxylative γ-Arylation for the Synthesis of Tetrasubstituted Chiral Allenes

Article abstract of DOI:10.1002/anie.201901848

An enantiospecific palladium-catalyzed decarboxylative coupling of acyclic β,γ-alkynoic acids with various aryl iodides to chiral tetrasubstituted allenes is described. The coupling reaction comprises a decarboxylative γ-palladation of α,α-disubstituted carboxylic acids to provide the tetrasubstituted allenes with complete point-to-axial chirality transfer in excellent yields.

Full text of DOI:10.1002/anie.201901848

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Accepted Article
Title: Palladium-catalyzed Decarboxylative γ-Arylation – A Novel
Approach towards Tetrasubstituted Chiral Allenes
Authors: Ina Scheipers, Christian Mück-Lichtenfeld, and Armido Studer
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201901848
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10.1002/anie.201901848
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Palladium-catalyzed Decarboxylative -Arylation – A Novel
Approach towards Tetrasubstituted Chiral Allenes
Ina Scheipers, Christian Mück-Lichtenfeld and Armido Studer*
Abstract: An enantiospecific Pd-catalyzed decarboxylative coupling
reaction of acyclic ,-alkynoic acids with various aryl iodides to chiral
tetrasubstituted allenes is described. The coupling reaction comprises
a decarboxylative -palladation of ,-disubstituted carboxylic acids
to provide the tetrasubstituted allenes with complete point-to-axial
chirality transfer in excellent yields.
the highly stereospecific decarboxylative -arylation of ,-
disubstituted ,-alkynoic acids with aryl iodides under Pd-
catalysis to afford chiral tetrasubstituted allenes (Scheme 1d).
Allenes have become highly important as valuable and versatile
building blocks in organic synthesis. Moreover, they can be found
in natural products, pharmaceutical compounds and in material
science.[1] While the first synthetic allene was published back in
1887 by Burton and von Pechmann,[2] the correct structure was
assigned many years later.[3] Their unique reactivity and intrinsic
chirality (for substituted systems) is based on a cumulative
arrangement of two orthogonal -bonds. These -systems
engage in various chemical transformations, for example
cycloaddition reactions, metal-catalyzed addition reactions and
have also found applications in natural product synthesis.[4] As a
result, great efforts have been devoted to the development of
novel synthetic routes for the preparation of enantiomerically pure
allenes.[5] The most frequently used approaches comprise
stereospecific formal SN2’-substitutions starting with enantiopure
propargylic precursors[6] (Scheme 1a) or sigmatropic
rearrangements[7] also using propargylic compounds. In addition,
other methods for the stereoselective synthesis of di- and tri-
substituted allenes have been developed.[8,9,6b]
However, the synthesis of chiral tetrasubstituted allenes remains
challenging.[5g-h,10] Following selected examples along those lines
are addressed: in 2013, Maruoka published the asymmetric
Scheme 1. Tetrasubstituted allene synthesis.
functionalization
of
ester-substituted
allenes
via
a
Encouraged by our studies on the decarboxylative γ-arylation of
γ-unsaturated carboxylic acids,[15] we decided to choose ,-
alkynoic acids as starting materials to access the targeted allenes
in an unprecedented route. Carboxylic acids 1a-1g were readily
prepared in a two-step procedure via alkynylation of the
corresponding -disubstituted esters and subsequent ester
hydrolysis (see Supporting Information (SI)). For reaction
optimization, carboxylic acid 1a was chosen in combination with
1-ethyl-2-iodo-3-methylbenzene (2b) as the aryl donor. Solvent,
temperature and catalyst were systematically varied (see Table
S1 in the SI) and the best result was obtained using Pd(dba)2 as
the catalyst (10 mol%), Cs2CO3 (1.1 equiv) as the base in
benzene at 110 °C for 2 hours to afford the allene 3ab in 72%
yield (Scheme 2).
deprotonation/alkylation sequence by phase-transfer-catalysis
(Scheme 1b).[11] Sun and coworkers disclosed in 2017 the
synthesis of chiral tetrasubstituted allenes from racemic
propargylic alcohols via asymmetric trapping of intermediate
propargylic cations, that are generated with a chiral Brønsted
acid.[12] Very recently, Aggarwal presented an enantiodivergent
method to access highly substituted allenes by point-to-axial
chirality transfer including examples of chiral tetrasubstituted
allenes using chiral allyl boronic esters as substrates.[13] The
same group also reported an elegant stereospecific deborylative
-arylation of enantioenriched propargylic boronic pinacol esters
with aryl iodides to afford tetrasubstituted allenes using metal-
catalysis (Scheme 1c).[14] Herein, we present our first results on
[*]
I. Scheipers, Dr. C. Mück-Lichtenfeld, Prof. Dr. A. Studer
Westfälische Wilhelms-Universität
Organisch-Chemisches Institut
Corrensstraße 40, 48149 Münster, Germany
E-mail: studer@uni-muenster.de
Supporting information for this article is given via a link at the end of
the document.
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Under optimized conditions, different aryl iodides were tested in
the decarboxylative coupling with acid 1a. Iodoarenes bearing
alkyl substituents at both ortho-positions delivered the
corresponding allenes 3aa-3ac in 68-72% yields. Tri- and
tetrasubstituted aryl iodides, keeping the ortho,ortho’-substitution
pattern, worked well and allenes 3ad and 3ae were isolated in
69% and 58% yield, respectively. Switching to the more sterically
demanding -ethyl--methyl carboxylic acid 1b, the target allenes
3ba-3be were obtained in 75-99% yield. Pleasingly, the -aryl
substituted carboxylic acid 1c engaged in the decarboxylative
coupling reaction with aryl iodides 2a-f to provide 3ca-3cf in good
to very good yields (60-83%).
Yields further increased upon switching to -alkyl--benzyl-
carboxylic acids as substrates, as exemplified by the successful
synthesis of the allenes 3da-3de (78-99%). We also replaced the
phenyl-substituent at the alkyne moiety (R3-substituent) by the
para-methoxy-phenyl group and found the γ-arylation to work in
moderate to excellent yields (3ea-3ec, 49-99%). However,
replacing the R3-aryl substituent by an alkyl group led to a
complete suppression of the γ-coupling. The targeted 3fb was not
identified in the reaction mixture and only starting material was
recovered in high yield, showing the importance of the alkyne-
activating aryl moiety for the decarboxylative coupling reaction.
The ortho,ortho’-substitution pattern on the aryl iodide component
is required to achieve the targeted coupling, since reactions of
iodobenzene or ortho-methyliodobenzene with 1a did not work.
We do currently not understand these failures.
Scheme 3. Pd-catalyzed decarboxylative coupling of -methoxy-substituted
acids provides ,-unsaturated ketones.
Next, we tested the functional group tolerance at the -position of
the carboxylic acid component by introducing an -alkoxy
substituent. Upon running the decarboxylative coupling reaction
on substrate 1g with 2-iodo-1,3-dimethylbenzene or 1-ethyl-2-
iodo-3-methylbenzene, we found that the targeted allenes directly
further reacted under the applied conditions to the corresponding
,-unsaturated ketones 4a and 4b, which were isolated in 72%
and 86% yield as diastereoisomerically pure compounds
(Scheme 3). The relative configuration of the double bond was
assigned based on NOE-experiments (see SI).
Scheme 2. Pd-catalyzed decarboxylative -arylation for the preparation of
tetrasubstituted allenes.
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10.1002/anie.201901848
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Figure 1. Experimental ((P)-enantiomer) and calculated ((M)-enantiomer) CD
spectra of 3de.
Scheme 4. Enantiospecific Pd-catalyzed decarboxylative couplings. [a]
Enantiomeric ratio could not be determined by chiral HPLC and
enantiospecificity was assigned in analogy to the other reactions.
Finally, we investigated the enantiospecificity of the
decarboxylative -arylation. To this end, the carboxylic acid (S)-
1d was prepared in enantioenriched form according to a
procedure developed by Maruoka and coworkers (see SI).[16] To
our delight, for the systems tested, decarboxylative coupling
occurred with > 99% enantiospecificity, showing that our new
approach allows assessing optically active tetrasubstituted
allenes (P)-3da-3de, 72-84%, Scheme 4).
The absolute configuration of 3de was assigned by circular
dichroism (CD) spectroscopy, showing a negative broad band at
230-288 nm along with a sharper positive band at around 220 nm.
DFT calculations (PWPB95-D3//TPSS-D3/def2-TZVP) of the
conformer energies and MD simulations (T = 300 K) with the
semiempirical GFN2-xTB method of (M)-3de provided two
independent ways to generate conformational ensembles.[17] CD
spectra were computed with TD-DFT (LC-BLYP) for the three
dominant conformations and with the approximative sTDA-xTB
method for 100 conformations from the MD trajectory. The
computed CD spectra are given in Figure 1 together with the
experimentally obtained spectrum. Shifting the sTDA-xTB
spectrum by 20 nm corrects for a systematic blue shift error and
inversely matches the shape of the experimentally determined
spectrum, proving the (P)-configuration of the product 3de in our
synthesis. Other compounds were assigned in analogy.
Scheme 5. Proposed mechanism for the stereospecific Pd-catalyzed
decarboxylative -arylation.
The suggested mechanism for the stereospecific Pd-catalyzed
decarboxylative C–C coupling is shown in Scheme 5. Pd(0) first
undergoes an oxidative addition with the aryl iodide to give the
corresponding arylPd(II)-species. Ligand exchange with the in
situ formed cesium carboxylate (S)-A provides the corresponding
arylPd(II)carboxylate which then undergoes concerted
decarboxylative -palladation to generate C via a transition state
of type B, where the Pd-atom coordinates to the triple bond. The
concertness of the -palladation/CO2-extrusion step ensures
perfect point-to-axial chirality transfer. Since the following
reductive elimination step to give (P)-3 along with Pd(0) is also a
stereospecific reaction, the overall sequence proceeds with
complete enantiospecificity.
In summary, we developed a Pd-catalyzed process for the
synthesis of chiral tetrasubstituted allenes from ,-disubstituted
,-alkynoic acids and sterically hindered ortho,ortho’-
disubstituted aryl iodides in up to 99% yield via a decarboxylative
coupling reaction. -Arylation proceeds with excellent
enantiospecificity allowing to prepare highly enantioenriched
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Keywords: allenes • palladium • cross coupling • asymmetric
synthesis • chirality transfer
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COMMUNICATION
Ina
Scheipers,
Christian
Mück-
Lichtenfeld and Armido Studer*
Page No. – Page No.
Palladium-catalyzed Decarboxylative
-Arylation
towards
Allenes
–
A
Novel Approach
Tetrasubstituted Chiral
Point-to-axial chirality transfer is achieved in the decarboxylative -arylation of ,-
disubstituted ,-alkynoic acids with sterically hindered ortho,ortho’-disubstituted aryl
iodides. Reactions proceed by Pd-catalysis with complete enantiospecificity to
provide tetrasubstituted allenes that are valuable compounds in various field.
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