Synthesis of All-Carbon Quaternary Centers by Palladium-Catalyzed Olefin Dicarbofunctionalization

Article abstract of DOI:10.1002/anie.201911012

The redox-neutral dicarbofunctionalization of tri- and tetrasubstituted olefins to form a variety of (hetero)cyclic compounds under photoinduced palladium catalysis is described. This cascade reaction process was used to couple styrenes or acryl amides with a broad range of highly decorated olefins tethered to aryl or alkyl bromides (>50 examples). This procedure enables one or two contiguous all-carbon quaternary centers to be formed in a single step. The products could be readily diversified and applied in the synthesis of a bioactive oxindole analogue.

Full text of DOI:10.1002/anie.201911012

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Accepted Article
Title: Synthesis of All-Carbon Quaternary Centers by Palladium-
Catalyzed Olefin Dicarbofunctionalization
Authors: Maximilian Koy, Peter Bellotti, Felix Katzenburg, Constantin
Daniliuc, and Frank Glorius
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201911012
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Synthesis of All-Carbon Quaternary Centers by Palladium-
Catalyzed Olefin Dicarbofunctionalization
Maximilian Koy+, Peter Bellotti+, Felix Katzenburg, Constantin G. Daniliuc and Frank Glorius*[a]
Dedicated to Prof. Roland Winter on the occasion of his 65th birthday
Abstract: The redox-neutral dicarbofunctionalization of tri- and
tetrasubstituted olefins to form a variety of (hetero)cyclic
compounds using photoinduced palladium catalysis is described.
This cascade reaction process was used to couple a broad range
of highly decorated olefins tethered to aryl or alkyl bromides with
styrenes or acryl amides (> 50 examples). Through this protocol,
one or two contiguous all-carbon quaternary centers can be
formed in a single step. The products were readily diversified and
applied in the synthesis of a bioactive oxindole analogue.
methods available for the transition-metal catalyzed
dicarbofunctionalization of trisubstituted olefins and, to the best of
our knowledge, none for tetrasubstituted olefins.[9] Here, we
envisioned that a photoexcited palladium catalyst could be used
to generate a radical intermediate via single electron transfer,
which could then rapidly undergo an intramolecular Baldwin-type
cyclization to afford a tertiary radical species. This tertiary radical
could then be trapped by an olefin coupling partner to form a
secondary radical, which would recombine with the palladium(I)
catalyst species and undergo β-hydride elimination to regenerate
the palladium(0) catalyst and close the catalytic cycle in a redox
neutral fashion (see Scheme 1b).
Dicarbofunctionalization reactions provide a powerful method to
access complex molecular frameworks in a single operational
step.[1] Long standing challenges, such as unwanted β-hydride
elimination of intermediate metal species have been addressed
through ligand design, tailored substrates or the use of early
transition metals, which are less prone to β-hydride elimination.[2]
Numerous elegant intramolecular versions to access valuable
cyclic motifs have been developed, but reports using highly
decorated olefins are still limited.[3] This limitation may be due to
the formation of C(sp3)-metal species A, which is challenging to
form with higher substituted olefins due to steric repulsion or fast
β-hydride elimination.[1a] Additionally, existing methods are
typically either suitable for only aryl or alkyl electrophiles, while
general methods for both classes are rare (see Scheme 1a).[4]
Palladium catalyzed cross-coupling manifolds to construct
carbon-carbon or carbon-heteroatom bonds have reached
remarkable levels of versatility.[5] Classically, these reactions
occur mostly through two-electron processes. Conversely,
reactions occurring through radical intermediates involving
palladium(I) hybrid species are less well explored.[6] Recently,
several elegant protocols using palladium catalysts as single
electron donors have been reported. Single electron transfer from
a palladium species can either be triggered thermally[7] or through
photoexcitation[8] and used to generate radicals from various alkyl
or aryl halides and activated carboxylic acids.
As the formation of highly-substituted moieties is generally
hampered by classical two-electron cross-coupling processes, we
questioned whether open-shell palladium chemistry could be
used to enable dicarbofunctionalization reactions with tri- and
tetrasubstituted olefins. It should be noted that there are very few
[a]
M. Koy+, P. Bellotti+, F. Katzenburg, Dr. C. G. Daniliuc, Prof. Dr. F.
Glorius
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstraße 40, 48149 Münster (Germany)
E-mail: glorius@uni-muenster.de
[+]
Both authors contributed equally to this work.
Scheme 1. a) Dicarbofunctionalization methodology. b) Reaction design. c)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Optimization parameters and sensitivity assessment. adetermined by GC-FID
analysis. bdetermined by 1H NMR analysis. TEMPO
tetramethylpiperidine-1-oxyl.
=
2,2,6,6-
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Potential pitfalls of this reaction design include: i) unproductive
protodehalogenation, or ii) premature recombination of the initial
cyclization radical with palladium. However if successful, this
reaction cascade would provide a powerful method to access
various unstrained cyclic scaffolds decorated with one or even two
quaternary centers adjacent to each other within a single
operational step from easily accessible olefins. Such structurally
dense motifs are still highly challenging targets in synthetic
organic chemistry, especially in related transition metal catalyzed
reactions.[10]
with blue LEDs. Interestingly, in the absence of xantphos, or with
other bidentate ligands, the product was formed in diminished
yield. No product was obtained without Pd(PPh3)4, base or light.
Dihydrobenzofurane 3 was obtained in 10% yield from the
corresponding iodide, while the corresponding chloride was not
reactive at all. Notably, classical photocatalysts based on
ruthenium or iridium completely failed to afford the corresponding
product, highlighting the unique reactivity of palladium under
visible light irradiation. Finally, the addition of TEMPO completely
inhibited product formation. Nevertheless, a TEMPO adduct of a
cyclized intermediate was detected, which suggests a radical
mechanism was in operation (for further preliminary mechanistic
experiments, see the Supporting Information). The reaction was
assessed to be sensitive towards the presence of oxygen and low
light intensity, while other parameters, such as wet solvent and
reaction scale, had no significant effect on the outcome of the
reaction (see radar diagram in Scheme 1c).[11]
We started our investigations by reacting prenylated 2-
bromophenol 1 and styrene 2 with various palladium catalysts
under visible light irradiation. After optimization, we were
delighted to obtain the desired cross-coupled product 3 in 80%
isolated yield and complete (E)-selectivity using commercially
available Pd(PPh3)4, xantphos as an ancillary ligand and
potassium carbonate as a base in 1,4-dioxane under irradiation
Scheme 2. Scope of aryl bromides. Yields of isolated product are given. For experimental details, see the Supporting Information. aYield was determined by 1H
NMR spectroscopy using an internal standard. bContains an inseparable impurity of approx. 8%. c4-Acetoxystyrene was used as olefin. Ph = Phenyl, Ar = 4-
Acetoxyphenyl, 1-Ada = 1-Adamantyl, Boc = tert-butyloxycarbonyl, Cbz = benzyloxycarbonyl, Ac = acetyl.
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To examine the generality of our developed reaction conditions,
we initiated scope and limitation studies, from which we were
pleased to observe that these conditions were widely applicable
(>50 examples). Furthermore, the E/Z selectivity was >99:1 for all
entries. We first examined different olefin substitution patterns
with a special emphasis on cyclic motifs. Four and six membered
rings containing different heteroatoms were readily converted the
products (4 – 8) in generally good yields. Oxetane 8, was
particularly pleasing to obtain as oxetanes are frequently used in
medicinal chemistry as prominent bioisosteres of carbonyl and
gem-dimethyl groups.[12] The highly sterically demanding
adamantyl motif (9) could also be installed following our
developed methodology. Acyclic substitution patterns at the newly
formed quaternary carbon center was also well tolerated (10).
protecting groups, were accessible through this method. The
structure of Cbz-protected indoline 36 was validated by single-
crystal X-ray diffraction (see Scheme 2c).[14]
We next examined alkyl electrophiles, which are typically
challenging substrates in the field of palladium catalysis due to
their sluggish oxidative addition and fast β-hydride elimination.
Here, we were pleased to find that complex tetrahydrofuran 40,
carbocyclic compound 41, pyrrolidines (42, 44 – 47) and
piperidine 43 were all accessible in generally good yields from the
respective alkyl bromides. These products were formed with
moderate (44, 45) to good (46) diastereoselectivities, as expected
with open-shell intermediates. Finally, highly congested
pyrrolidine 47 was prepared through the challenging
dicarbofunctionalization of a tetrasubstituted olefin, albeit in
diminished yield (18%, see Scheme 3).
Scheme 3. Scope of alkyl bromides. Yields of isolated product are given. For
Next, the accepting olefins were evaluated under our reaction
conditions. Styryl compounds bearing various electron-donating
as well as -withdrawing substituents and heteroatoms were well
tolerated (48 – 59). Interestingly, α-methyl styrene reacted to
selectively afford the terminal olefin product 59, while the
thermodynamically more favourable internal olefin was not
detected. Pleasingly, acryl amides were also suitable reaction
partners in the synthetic manifold to access the product in fair
yield (60) (see Scheme 4).
experimental details, see the Supporting Information. Ar = 4-Acetoxyphenyl.
We next turned our attention to tetrasubstituted olefins, which are
generally challenging substrates in metal catalyzed reactions,[10d,
f]
and were not previously amenable to dicarbofunctionalization
reactions. Thus, we were delighted to obtain products 11 and 12
in synthetically useful yield. Notably, both compounds contain two
contiguous quaternary centers – each of them within a cyclic
scaffold – which are highly challenging targets in natural product
synthesis.[13] Di- and monosubstituted olefins – generally used for
related dicarbofunctionalization reactions – are also suitable
substrates (13 – 16). The structure of product 16 was additionally
verified through single crystal X-ray diffraction, confirming the
anti-stereochemistry at the cyclohexyl fragment.[14] It should be
noted that the fused tricyclic scaffold of 15 and 16 can also be
found in various natural products e.g. Cannabielsoin or Linderol
A (see Scheme 2a).[15] Substitution patterns on the aryl ring of the
bromide (17 – 33) were similarly tolerated. Substrates bearing
either electron-donating or electron-withdrawing groups at
different positions of the aryl ring were all converted into the
corresponding products in moderate to excellent yields (37 –
95%). Medicinally relevant pyridine and benzimidazole
derivatives (33, 34) were also readily prepared. Furthermore,
indolines (35 – 37) and oxindoles (38, 39) containing different
Scheme 4. Scope of accepting olefins. Yields of isolated product are given. For
experimental details, see the Supporting Information.
The scalability of the reaction was shown through a large-scale
reaction (5 mmol), in which product 3 was prepared in a slightly
diminished yield of 73%. Finally, the products were further
derivatized to illustrate potential synthetic applications (see
Scheme 5a): Hydrogenation (61), ozonolysis (62), Suzuki-
Miyaura coupling (63) and epoxidation (64) reactions all
proceeded in high yields. Importantly, cleavage of the double
bond through ozonolysis offers a synthetic handle for further
transformations directly at the newly formed quaternary carbon
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center. Furthermore, an analogue of a dimethylaminophenyl
oxindole 67 – which are reported to have neurological activity –
was easily synthesized with this protocol in four linear steps from
inexpensive 2-bromoaniline. Notably, in previous studies of these
neurologically active compounds, quaternary centers α-to the
oxindole core were not accessible through the reported multistep
synthesis (see Scheme 5b).[16]
bromides were both suitable to the developed reaction conditions.
Various (hetero)cyclic compounds with different cyclic and acyclic
quaternary carbon centers adjacent to the newly formed ring were
prepared. The products were further modified through selected
transformations. Finally, an analogue of a class of neurologically
active oxindoles was prepared with this dicarbofunctionalization
protocol as the key step. We believe that this approach enables
the synthesis of more highly complex and congested cyclic
frameworks in a fast and facile fashion.
In conclusion, we have developed a general method for the
dicarbofunctionalization of tri- and tetrasubstituted olefins via
open-shell intermediates using palladium as a non-classical
photocatalyst. Impressively, aryl bromides as well as alkyl
Scheme 5. a.) Diversification of products. b.) Synthesis of an analogue of a bioactive oxindole containing a quaternary carbon center.
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Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft
(SFB 858, Leibniz Award) is gratefully acknowledged. We thank
Cornelia Weitkamp, Dr. Michael J. James, Frederik Sandford, J.
Luca Schwarz, Marco Wollenburg and Tobias Wagener for
excellent experimental support and/or helpful discussions.
Keywords: dicarbofunctionalization • palladium catalysis •
quaternary centers • radicals • heterocycles
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Entry for the Table of Contents (Please choose one layout)
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M. Koy, P. Bellotti, F. Katzenburg, C. G.
Daniliuc, F. Glorius*
High C
-100%
-75%
Page No. – Page No.
Big Scale
High I
Low C
-50%
-25%
0%
+25%
+50%
H2O
Synthesis of All-Carbon Quaternary
Centers by Palladium-Catalyzed
Olefin Dicarbofunctionalization
Low I
Low O2
High T
High O2
The dicarbofunctionalization of tri- and tetrasubstituted olefins to form (hetero)cyclic compounds using photoinduced palladium catalysis
is described. A broad range of highly decorated olefins tethered to aryl or alkyl bromides were coupled with styrenes or acryl amides
(> 50 examples). Through this protocol, one or two contiguous all-carbon quaternary centers can be formed in a single step. The
products were readily diversified and applied in the synthesis of a bioactive oxindole analogue.
This article is protected by copyright. All rights reserved.