Regioswitchable Palladium-Catalyzed Decarboxylative Coupling of 1,3-Dicarbonyl Compounds

Article abstract of DOI:10.1021/acs.orglett.5b01979

A palladium-catalyzed chemo- and regioselective coupling of 1,3-dicarbonyl compounds via an allylic linker has been developed. This reaction, which displays broad substrate scope, forms two C-C bonds and installs two all-carbon quaternary centers. The regioselectivity of the reaction can be predictably controlled by utilizing an enol carbonate of one of the coupling partners.

Full text of DOI:10.1021/acs.orglett.5b01979

Letter
pubs.acs.org/OrgLett
Regioswitchable Palladium-Catalyzed Decarboxylative Coupling of
1,3-Dicarbonyl Compounds
Miles Kenny,† Jeppe Christensen,‡ Simon J. Coles,‡ and Vilius Franckevicius*,†
̌
†Department of Chemistry, Lancaster University, Lancaster LA1 4YB, U.K.
‡National Crystallography Service, School of Chemistry, University of Southampton, Southampton SO17 1BJ, U.K.
S
* Supporting Information
ABSTRACT: A palladium-catalyzed chemo- and regioselective
coupling of 1,3-dicarbonyl compounds via an allylic linker has
been developed. This reaction, which displays broad substrate
scope, forms two C−C bonds and installs two all-carbon
quaternary centers. The regioselectivity of the reaction can be
predictably controlled by utilizing an enol carbonate of one of
the coupling partners.
Scheme 1. Reactivity Modes of Propargylic Compounds with
Nucleophiles
he palladium(0)-catalyzed alkylation reaction of carbon
Tnucleophiles with allylic electrophiles has over the years
matured into a powerful C−C bond-forming tool1 that enables
the stereoselective introduction of congested all-carbon
quaternary centers.2 These processes typically make use of
allylic acetates, carbonates, or halides, which undergo oxidative
addition to give η3-π-allylpalladium(II) intermediates. The
analogous reaction of palladium(0) with propargylic electro-
philes proceeds via η3-π-propargylpalladium(II) intermediates
(Scheme 1A),3 which exhibit three distinct modes of reactivity.4
Nucleophilic addition to one of the terminal carbon atoms
results in either allenylation or propargylation processes.5 In
addition, with stabilized anions as nucleophiles, η3-π-
propargylpalladium(II) intermediates can undergo sequential
double addition,6 first at the central carbon atom and
subsequently at either one of the terminal carbon atoms.7
The synthetic utility of the latter reactivity mode becomes
apparent when two different nucleophiles are coupled, rapidly
generating complexity in a single operation (Scheme 1B). The
challenges associated with this process are control of the
chemoselectivity, whereby the formation of homocoupling
products is avoided, and control of the regioselectivity, whereby
the order of addition of the nucleophiles is controlled. The
associated selectivity issues are typically overcome by designing
the transformation in such a way that one of the nucleophilic
addition steps is intramolecular.8 In contrast, the regioselective
coupling of two different nucleophiles in an intermolecular
sense is much more challenging.9
Inspired by palladium-catalyzed decarboxylative allylic
alkylation processes,10 which enable the regiospecific formation
of enolates under mild and neutral reaction conditions,11 we
recently disclosed the first palladium-catalyzed chemo- and
regioselective coupling of enolates and phenols via an η3-π-
propargylpalladium(II) intermediate (Scheme 1C).12 In this
approach, the regioselectivity is governed by the tight
association of the η3-π-propargylpalladium(II) intermediate
with the enolate. Given the recent drive by the pharmaceutical
industry to find new methodologies that facilitate the synthesis
of sp3-rich molecules,13 we envisaged that a similar strategy
could facilitate the chemo- and regioselective coupling of two
Received: July 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01979
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Organic Letters
Letter
1,3-dicarbonyl compounds, resulting in the formation of two
C−C bonds and two quaternary all-carbon centers in a single
operation (Scheme 1D). In particular, we postulated that both
regioisomers of the product could be predictably accessed by
judiciously subjecting one of the coupling partners to the
reaction as the enol carbonate. Herein we report a
regioswitchable palladium-catalyzed decarboxylative coupling
reaction of 1,3-dicarbonyl compounds via an allylic linker, thus
resulting in the formation of two new C−C bonds and the
installation of two quaternary all-carbon centers.
Table 1. Ligand Screen
At the outset, the intermolecular coupling reaction of two
1,3-diketone nucleophiles 4a and 4g in the presence of
propargylic carbonate 1 in equimolar amounts was investigated
(Scheme 2). Of the four possible products, three were obtained
a
selectivity
b
entry
ligand
regio (5a:7a) chemo (5a:5g) yield of 5a (%)
1
2
3
4
Xantphos
>19:1
>19:1
>19:1
>19:1
5.8:1
5.9:1
6.4:1
6.1:1
56
59
73
85
c
PPh3
Scheme 2. Selectivity Issues in Intermolecular Coupling of
Carbon Nucleophiles
dppf
DPEphos
a
b
Determined by 1H NMR analysis of the crude product mixtures.
Yields of isolated 5a. [Pd(PPh3)4] was used in place of [Pd2(dba)3].
c
ab c
, ,
Scheme 3. 1,3-Dicarbonyl Scope
with moderate regioselectivity, low chemoselectivity, and poor
yield. Specifically, regioisomers 7a and 5a were obtained in a
4.8:1 ratio in 19% and 4% yield, respectively, in addition to
significant quantities of the undesired homocoupling product
5g, which was formed in 13% yield. These results show that the
direct coupling of two similar partners leads to significant
homocoupling, whereas the sense of regioselectivity of
heterocoupling is difficult to predict. In addition, this process
does not allow for efficient access to both regioisomers.
Therefore, we reasoned that the use of one of the coupling
partners as the enol carbonate could bestow predictable
regiocontrol and increased efficiency on the transformation.
Pleasingly, the coupling of propargyl enol carbonate 3 with
1,3-diketone 4a with Xantphos as the ligand for palladium in
1,4-dioxane as the solvent proceeded with complete regiose-
lectivity and moderate chemoselectivity (Table 1, entry 1),
predictably affording 5a as the major product in good yield. A
similar result was obtained with palladium tetrakis-
(triphenylphosphine) as the catalyst (entry 2). Finally, the
best product yields were obtained when the large-bite-angle
ligands dppf and DPEphos were used (entries 3 and 4), with
DPEphos providing product 5a with complete regioselectivity,
good chemoselectivity, and excellent yield. It is worthy of note
that the reaction in other solvents, such as toluene, dichloro-
methane, DMF and acetonitrile, resulted in significant erosion
in both the selectivity and yield of 5a (see the Supporting
Information).
a
Reaction stoichiometry: 0.24 mmol of 3 and 4; concn = 0.16 M.
Regioselectivity (r.r.) and chemoselectivity (chemo) ratios were
b
determined by 1H NMR analysis of the crude product mixtures. n.d. =
not determined due to overlapping signals. Yields of isolated 5 are
shown. Refers to homocoupling of 3. Refers to homocoupling of 4.
c
d
e
Unsurprisingly, the use of 3-methyl-2,4-pentanedione (4g) as
the nucleophile afforded homocoupled 5g. β-Keto esters as
nucleophiles, both acyclic and cyclic, gave products 5h−j in
good yields. Finally, the incorporation of a β-keto lactam and β-
keto sulfone was also successful, providing the respective
coupled products 5k and 5l.
Because the enolate generated in situ following decarbox-
ylation is regioselectively alkenylated and the externally added
partner is allylated, we next investigated the scope of reversing
the regioselectivity by reacting the propargyl enol carbonates of
a range of 1,3-dicarbonyl compounds in the presence of 3-
methyl-2,4-pentanedione (4g) as the external nucleophile
After the optimal ligand for palladium was identified, the
reaction scope was investigated by testing the coupling of linear
propargyl enol carbonate 3 with a range of 1,3-dicarbonyl
compounds 4 (Scheme 3). Specifically, all of the products were
obtained with complete regioselectivity. Cyclohexanone-based
1,3-diketones as external coupling partners provided products
5a and 5b in high yields. Acyclic diketones also took part in
regioselective coupling, giving rise to 5c−f in good yields.
B
DOI: 10.1021/acs.orglett.5b01979
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Letter
(Scheme 4). In this context, both cyclic and acyclic 1,3-
Scheme 5. Deuterium-Labeling Experiments
diketones led to the predictable formation of products 7a−f, in
a b c
, ,
Scheme 4. Carbonate Scope
Scheme 6. Proposed Catalytic Cycle
a
Reaction stoichiometry: 0.24 mmol of 6 and 4g; concn = 0.16 M.
Regioselectivity (r.r.) and chemoselectivity (chemo) ratios were
b
determined by 1H NMR analysis of the crude product mixtures. n.d. =
not determined due to overlapping signals. Yields of isolated 7 are
c
d
e
shown. The reaction was run for 4 h. Refers to homocoupling of 4g.
f
g
Refers to homocoupling of 6. Refers to homocoupling of β-keto ester
4h.
which the original enol carbonate substrate had been
alkenylated. Although the structures of the products were
readily identifiable by long-range HMBC correlations, we
obtained an X-ray crystal structure of 7a to confirm the sense of
regioselectivity of the reaction.14 In the case of a β-keto lactam
and a β-keto ester, both were alkenylated successfully (7g and
7h). However, the use of a carbonate of a fluorinated β-keto
ester gave the corresponding product 7i in low chemoselectivity
and yield. Finally, when the coupling reaction led to the
installation of two stereogenic centers, such as in 7j, the yield of
product was high, but a mixture of diastereoisomers was
obtained.
To rationalize the high regioselectivity of these reactions, an
enolate crossover experiment using equimolar amounts of [D4]-
3 and nondeuterated 3 in the presence of 1,3-diketone 4b as
the external nucleophile was performed (Scheme 5A); the
reaction afforded [D4]-5b and nondeuterated 5b as the only
products, as determined by mass spectrometry. The absence of
enolate crossover strongly suggests a tight association of the η3-
π-propargylpalladium(II) complex with the enolate following
decarboxylation. The intermediacy of an η3-π-allylpalladium(II)
complex, which participates in the second nucleophilic addition,
was supported by the scrambling of the deuterium label in [D]-
5b when carbonate [D]-3 was coupled with 1,3-diketone 4b
(Scheme 5B).
species in the next step determines the high regioselectivity of
the reaction. However, this observation is at variance with the
outer-sphere mechanism proposed for the addition of stabilized
nucleophiles to η3-π-allylpalladium(II) intermediates.15
Although the involvement of a palladacyclobutene intermediate
9 following nucleophilic addition has been previously
suggested,8b,m,16 the lack of experimental evidence for its
existence intimates that nucleophilic addition of the enolate in
8 is followed by immediate protonation by the external
nucleophile 4b in a synchronous manner to give 10.17 In the
final step, the resulting η3-π-allylpalladium(II) complex in 10
undergoes nucleophilic addition by the second enolate coupling
partner, affording product 5b with complete regiocontrol and
regenerating the palladium(0) catalyst.
In summary, a regio- and chemoselective decarboxylative
palladium-catalyzed coupling of two carbon nucleophiles is
disclosed, a transformation that generates two C−C bonds and
two all-carbon quaternary centers in a single operation. The
reaction is predictably regioswitchable, providing access to
either of the two regioisomers of product depending on the
choice of the propargyl enol carbonate substrate. We are now
exploring avenues of accessing these products in an
enantioselective manner.
In light of the deuterium-labeling studies, we propose a
reaction mechanism in which the palladium(0) catalyst
undergoes oxidative addition to carbonate 3 to give
intermediate 8 following decarboxylation (Scheme 6). Because
the palladium metal center is likely to be strongly associated
with the enolate in 8 (see above, Scheme 5), we believe that the
intramolecular inner-sphere mode of addition of the enolate to
the central carbon atom of the η3-π-propargylpalladium(II)
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01979.
C
DOI: 10.1021/acs.orglett.5b01979
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Letter
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Full experimental procedures, characterization data, and
1
HRMS and H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: v.franckevicius@lancaster.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge Lancaster University (M.K. and
V.F.) for financial support. We also thank the EPSRC Mass
Spectrometry Service (Swansea, U.K.) for mass measurements,
the EPSRC UK National Crystallography Service at the
University of Southampton for collection of the crystallographic
data,18 and Dr. Michael Coogan (Lancaster University, U.K.)
for help with crystallization.
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