Decarbonylative C-H coupling of azoles and aryl esters: Unprecedented nickel catalysis and application to the synthesis of muscoride A

Article abstract of DOI:10.1021/ja306062c

A nickel-catalyzed decarbonylative C-H biaryl coupling of azoles and aryl esters is described. The newly developed catalytic system does not require the use of expensive metal catalysts or silver- or copper-based stoichiometric oxidants. We have successfully applied this new C-H arylation reaction to a convergent formal synthesis of muscoride A.

Full text of DOI:10.1021/ja306062c

Communication
pubs.acs.org/JACS
Decarbonylative C−H Coupling of Azoles and Aryl Esters:
Unprecedented Nickel Catalysis and Application to the Synthesis of
Muscoride A
Kazuma Amaike, Kei Muto, Junichiro Yamaguchi,* and Kenichiro Itami*
Department of Chemistry, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan
S
* Supporting Information
palladium−copper bimetallic catalysis (Scheme 1).2 Since this
ABSTRACT: A nickel-catalyzed decarbonylative C−H
biaryl coupling of azoles and aryl esters is described. The
newly developed catalytic system does not require the use
of expensive metal catalysts or silver- or copper-based
stoichiometric oxidants. We have successfully applied this
new C−H arylation reaction to a convergent formal
synthesis of muscoride A.
epoch-making discovery, a number of variant coupling reactions
have been reported. For example, palladium-catalyzed oxidative
decarboxylative coupling using metalloarenes was reported,3
and decarbonylative arylation of aroyl compounds with
metalloarenes was achieved by using a rhodium catalyst4 or a
stoichiometric nickel complex (Scheme 1).5
In recent years, with the advent of C−H functionalization
chemistry,6,7 efforts have been directed toward the develop-
ment of decarboxylative or decarbonylative arylation of aroyl
compounds with simple aromatic compounds. In 2008,
Crabtree and co-workers reported a palladium-catalyzed
decarboxylative C−H arylation of aromatic carboxylic acids
with heteroarenes or with polyfluorobenzenes (Scheme 1).8a In
the same year, Yu and co-workers developed a rhodium-
catalyzed decarbonylative C−H coupling of 2-pyridylbenzenes
and acyl chlorides (Scheme 1).9a Following these contributions,
various decarboxylative8 and decarbonylative9 C−H arylation
reactions of aroyl compounds have been reported. We herein
describe a new nickel-based catalytic system with a number of
advantages, which we believe to be a useful addition to the
existing repertoire of decarboxylative/decarbonylative C−H
arylation tools (Scheme 1). This catalytic system does not
require the use of expensive metal catalysts or silver- or copper-
based stoichiometric oxidants.
royl compounds, such as aromatic carboxylic acids, acid
Achlorides, anhydrides, and esters, have received significant
attention as useful aryl sources in metal-catalyzed decarbox-
ylative or decarbonylative biaryl coupling reactions.1 In
comparison with typical cross-coupling partners such as
metalloarenes or haloarenes, aroyl compounds are usually
inexpensive, stable, and readily available. We herein report a
novel nickel-catalyzed decarbonylative C−H arylation of azoles
with aryl esters and its application to natural product synthesis
(Scheme 1).
In 2006, Gooßen and co-workers reported the breakthrough
finding that decarboxylative biaryl coupling of aromatic
carboxylic acids and haloarenes can be promoted by
Scheme 1. Decarboxylative/Decarbonylative Biaryl Coupling
We have already reported that azoles can be coupled with
phenol derivatives in a C−H/C−O coupling fashion under the
catalytic influence of Ni(cod)2/dcype [cod =1,5-cycloocta-
diene; dcype =1,2-bis(dicyclohexylphosphino)ethane].7i,10 For
example, benzoxazole (1A) can be coupled with naphthalen-2-
yl pivalate (2a; R = t-Bu) using this nickel catalyst and Cs2CO3
in 1,4-dioxane at 120 °C to give the corresponding C−H/C−O
coupling product 3Aa in 96% yield (Scheme 2). Quite
surprisingly, however, when a similar naphthalen-2-yl thio-
phene-2-carboxylate (2b′; R = 2-thienyl) was used as the
substrate, the thienyl-transferred product 3Ab was produced in
20% yield without the formation of 3Aa. When the coupling
partner 2b′ was changed to phenyl thiophene-2-carboxylate
(2b), the reaction also gave 3Ab in 20% yield. After an
extensive screening of catalysts, bases, temperature, and
reaction time, optimal conditions for this decarbonylative C−
H coupling were identified: Ni(cod)2/dcype (1:2 ratio), K3PO4
Received: June 21, 2012
Published: August 7, 2012
© 2012 American Chemical Society
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products) are privileged structures in pharmaceutically relevant
molecules and natural products10d and (ii) heteroaromatic
esters (the starting materials) can be prepared readily by
common heteroarene synthesis methods (e.g., Hantzsch
Scheme 2. Discovery of Nickel-Catalyzed Decarbonylative
C−H Coupling
́
dihydropyridine synthesis, Feist−Benary furan synthesis, and
Knorr pyrrole synthesis). Thus, in the present decarbonylative
coupling strategy, ester groups that often result from
heteroaromatic syntheses can be directly used as “leaving
groups” for further transformations.
A plausible mechanism for this decarbonylative C−H
arylation reaction is shown in Scheme 4. The reaction might
Scheme 4. A Plausible Mechanism for the Decarbonylative
C−H Biaryl Coupling Using a Ni−dcype Catalytic System
(2.0 equiv), 1,4-dioxane, 150 °C, 24 h.11 Under these
conditions, the yield of 3Ab increased to 96% (Scheme 3).
With optimized conditions in hand, various azoles and aryl
esters were tested (Scheme 3). The coupling of 1A with phenyl
Scheme 3. Substrate Scope
undergo a Ni0/NiII redox catalysis involving (i) oxidative
addition of the phenyl ester C−O bond to Ni0; (ii) CO
migration onto the nickel center to produce an Ar−
NiII(CO)n+1−OPh species (n = 0, 1);13 (iii) C−H nickelation
of azole (Het−H) with Ar−NiII(CO)n+1−OPh to generate Ar−
NiII(CO)n+1−Het;14 and (iv) reductive elimination to release
the coupling product (Het−Ar) and generate a Ni0(CO)n+1
species. Although the seemingly inactive complex Ni(dcype)-
(CO)2 (4) would be produced after two turnovers, the active
Ni0 catalyst could be regenerated by thermal extrusion of CO
from 4.15
To shed further light on the reaction mechanism, we
prepared the assumed intermediate 4 as a possible precatalyst.
After some experimentation, we found that complexation of
dcype with dicarbonylbis(triphenylphosphine)nickel (5) in
tetrahydrofuran (THF) at 40 °C afforded 4 in 96% yield
(Scheme 5). The preparation of 4 performed well on a gram
scale (1.5 g), and the structure of 4 was determined by single-
crystal X-ray diffraction analysis. Complex 4 turned out to be
air-stable in the solid state, showing no sign of decomposition
after 1 month. Most importantly, complex 4 was found to be a
competent catalyst, as 3Ab was obtained in 96% yield from the
reaction of 1A and 2b in the presence of catalytic amounts of 4
(10 mol %). In an effort to establish more user-friendly
conditions, we also found that the use of stable and less
expensive NiCl2 in combination with zinc powder also
promotes the decarbonylative C−H coupling (Scheme 5).
While the proposed mechanism shown in Scheme 4 seemed
reasonable, details regarding the elementary steps of the
thiophene-3-carboxylate (2c) also afforded the corresponding
coupling product 3Ac in 96% yield. Furancarboxylic acid
phenyl esters, such as phenyl furan-2-carboxylate (2d) and
phenyl furan-3-carboxylate (2e), reacted with 1A to produce
heterobiaryls 3Ad and 3Ae, respectively, in excellent yields.
Electron-deficient azine esters, such as phenyl pyridine-3-
carboxylate (2f), phenyl pyridine 4-carboxylate (2g), phenyl
quinoline-4-carboxylate derivative 2j, and phenyl 2-phenyl-
thiazole-4-carboxylate (2k), were coupled with 1A to give the
corresponding products 3Af, 3Ag, 3Aj, and 3Ak in good to
excellent yields, whereas phenyl pyridine-2-carboxylate (2h)
and phenyl pyrazine-2-carboxylate (2i) gave products in
moderate yields. In addition, oxazole (1B) and thiazole (1C)
derivatives were found to react smoothly with heteroaromatic
phenyl esters to furnish the corresponding coupling products
3Bf and 3Cf.
In this study, we extensively investigated the coupling of
heteroaromatic esters12 because (i) heteroarylated azoles (the
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Scheme 5. Preparation of Ni(dcype)(CO)2 and
Development of Alternative Protocols for Decarbonylative
C−H Coupling
Scheme 6. Formal Synthesis of Muscoride A (6) Using
Nickel-Catalyzed Decarbonylative C−H Coupling
assumed mechanism remained unclear. For example, there was
a possibility that the C2 carbon atom of the azole portion of the
coupling product could originate from the aryl ester carbonyl
carbon by a ring-opening/closing process of the azole rather
than the azole starting material as assumed. Thus, we carried
out a 13C labeling experiment to verify the origin of the C2
carbon in the product (eq 1). When 13C-labeled benzoxazole
This reaction operates on an inexpensive catalyst system and
performs without stoichiometric oxidants. In addition to
preliminary mechanistic experiments, we successfully applied
this newly developed reaction to a convergent formal synthesis
of muscoride A (6). In combination with common hetero-
aromatic synthesis, where ester groups are typically coinstalled
onto a heterocycle, the present decarbonylative coupling
method should find many uses in the construction of complex
heterocyclic frameworks. Further mechanistic investigations of
decarbonylative C−H coupling and the development of a
second-generation catalyst with broader scope are now the
focus of our ongoing efforts.
(1A-13C, 99% purity) and ester 2f were subjected to our
standard conditions, the corresponding coupling product
(3Af-13C, 99% purity) was obtained in 72% yield. This result
is in agreement with the proposed azole C−H arylation
pathway. However, some of the mechanistic details still remain
unclear, including the effects of the dcype ligand and K3PO4 in
the catalytic cycle. Further detailed studies to elucidate the
reaction mechanism are currently underway.
ASSOCIATED CONTENT
■
S
* Supporting Information
Finally, we applied the nickel-catalyzed decarbonylative C−H
arylation to the synthesis of muscoride A (6), a natural product
with antibacterial activity (Scheme 6). 6 was isolated by
Sakakibara in 1995,16a and its total synthesis has been
accomplished by Wipf,16b Pattenden,16c and Ciufolini.16d
Although all of these groups adopted linear approaches, we
imagined that our decarbonylative C−H coupling would allow
an efficient synthesis of 6 in a convergent manner. Thus, two
azole esters 7 (1.5 equiv) and (−)-8 (1.0 equiv), which were
readily prepared in one step and five steps respectively, were
successfully coupled under our standard conditions to afford
the corresponding coupling product (−)-9 in 39% yield.
Subsequently, (−)-9 was treated with LiOH, after which
condensation with prenyl alcohol afforded (−)-10 in 72% yield
over the two steps.16b,17 Since the conversion of (−)-10 to
(−)-6 was described previously by Wipf,16b the work reported
here represents a formal synthesis of 6. If the synthesis were
planned and executed with typical cross-coupling substrates
(aryl halides and organometallic reagents) instead, it would
have become much less efficient, with many added steps.
In summary, we have established the first nickel-catalyzed
decarbonylative C−H biaryl coupling of azoles with aryl esters.
Detailed experimental procedures and spectral data for all
compounds, including scanned images of H and 13C NMR
1
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
junichiro@chem.nagoya-u.ac.jp; itami.kenichiro@a.mbox.
nagoya-u.ac.jp
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Yasutomo Segawa for assistance with X-ray
crystal structure analysis. This work was supported by the
Funding Program for Next Generation World-Leading
Researchers from JSPS (220GR049 to K.I.), a Grant-in-Aid
for Scientific Research on Innovative Areas “Molecular
Activation Directed toward Straightforward Synthesis”
(23105517 to J.Y.) from MEXT, and a SUNBOR Grant from
the Suntory Institute for Bioorganic Research (to J.Y.).
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12070. (f) Hachiya, H.; Hirano, K.; Satoh, T.; Miura, M.
ChemCatChem 2010, 2, 1403. (g) Hachiya, H.; Hirano, K.; Satoh,
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(11) See the Supporting Information for details and further screening
of reaction conditions.
(12) General aromatic esters also coupled with azoles under nickel
catalysis. For example, 1A was coupled with phenyl 2-naphthoate (2l)
under our standard conditions to afford the corresponding coupling
product 3Aa in 82% yield.
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