Palladium-Catalyzed Mizoroki-Heck Reaction of Nitroarenes and Styrene Derivatives

Article abstract of DOI:10.1021/acs.orglett.0c00983

We have developed a Mizoroki-Heck reaction of nitroarenes with alkenes under palladium catalysis. The use of a Pd/BrettPhos catalyst promoted the alkenylation, whereas other catalysts led to a decrease in the product yield. In addition to nitroarenes, nitroheteroarenes were also applicable to the present reaction. The combination of a nucleophilic aromatic substitution (S_NAr) with the denitrative alkenylation produced a multifunctionalized arene in a one-pot operation.

Full text of DOI:10.1021/acs.orglett.0c00983

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Letter
Palladium-Catalyzed Mizoroki−Heck Reaction of Nitroarenes and
Styrene Derivatives
Toshimasa Okita,† Kitty K. Asahara,† Kei Muto, and Junichiro Yamaguchi*
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ABSTRACT: We have developed a Mizoroki−Heck reaction of
nitroarenes with alkenes under palladium catalysis. The use of a
Pd/BrettPhos catalyst promoted the alkenylation, whereas other
catalysts led to a decrease in the product yield. In addition to
nitroarenes, nitroheteroarenes were also applicable to the present
reaction. The combination of a nucleophilic aromatic substitution
(SNAr) with the denitrative alkenylation produced a multi-
functionalized arene in a one-pot operation.
he Mizoroki−Heck reaction is a powerful catalytic method
Tfor carbon−carbon (C−C) bond formation in synthetic
organic chemistry (Figure 1A).1 Typically, aryl halides (C−
halogen bond) are coupled with alkenes in the presence of a
palladium catalyst.2 Over the past decade, various aryl
electrophiles that operate under palladium catalysis instead of
aryl halides have been developed. Currently, C−O bond-
containing groups such as triflates, tosylates, and nonaflates are
the most popular alternative aryl electrophiles.3,4 Other aryl
electrophiles such as diazonium salts (C−N bond),5 sulfonyl
chlorides, thiazolium salts (C−S bond),6 acyl chlorides, acid
anhydrides, esters, amides (C−C bond),7 and telluronium salts8
have been used for the Mizoroki−Heck reaction.
Meanwhile, Nakao and co-workers successfully developed
palladium-catalyzed denitrative cross-coupling reactions be-
tween nitroarenes and nucleophiles, giving rise to arylation,
amination (aliphatic amines), and hydrogenation (Figure 1B).9
Other groups followed these pioneering results, thereby
developing methods for alkylation, amination (aromatic
amines), and alkynylation.10 In collaboration with the Nakao
group, our group also reported a denitrative intramolecular C−
H coupling.11 The use of a Pd/BrettPhos catalyst is effective for
these transformations. Recently, the groups of Nakao and Wu
independently reported that an NHC ligand, {5-(2,4,6-
triisopropylphenyl)imidazolylidene[1,5a]pyridines}, is more
effective than the Pd/BrettPhos catalytic system for denitrative
transformations.10a,b,12 However, there are no instances of
denitrative alkenylation reported thus far. Herein, the first
Received: March 17, 2020
Figure 1. (A) Aryl electrophiles for the Mizoroki−Heck reaction. (B)
Denitrative coupling. (C) Denitrative Mizoroki−Heck reaction.
https://dx.doi.org/10.1021/acs.orglett.0c00983
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a
Table 1. Screening of Reaction Conditions
Scheme 1. Substrate Scope for Nitroarenes
a
Conditions: 1A−1N (1.5 equiv), 2a (0.20 mmol), Pd(acac)2 (5 mol
%), BrettPhos (20 mol %), Rb2CO3 (3.0 equiv), PhCF3 (1.0 mL), 150
°C, 24 h. 1.0 mmol scale.
b
a
Conditions: 1A (1.5 equiv), 2a (0.20 mmol), Pd(acac)2 (5 mol %),
ligand (20 mol %), base (3.0 equiv), solvent (1.0 mL), 150 °C, 24 h.
b
c
ligands were investigated. NHC L1 was not effective for this
alkenylation (Table 1, entry 10). Electron-rich phosphines such
as PCy3 and dcype completely shut down this reaction (Table 1,
entries 11 and 12).
When phenanthroline-type ligands were used (such as L2 and
L3), the desired product 3Aa was obtained, albeit in lower yields
(Table 1, entries 13 and 14). Other Buchwald ligands such as
XPhos, SPhos, and RuPhos worked, but the yields of 3Aa were
lower (Table 1, entries 15−17). t-BuBrettPhos (L4) was
effective, but the yield was inferior to BrettPhos (Table 1,
entry 18 vs entry 10). It should be noted that this reaction
worked in the presence of H2O (10 equiv), but did not work
without bases.14
With optimal conditions in hand, the substrate scope
regarding the nitroarene component was examined (Scheme
1). Electron-rich nitroarenes such as tert-butyl- or methoxy-
substituted nitrobenzenes worked well to give the corresponding
alkenes 3Ba and 3Ca in good yields, even at 1 mmol scale. To
test electron-deficient nitroarenes, 4-trifluoronitrobenzene was
subjected to the reaction conditions, giving 3Da in moderate
yield. meta-Methyl and ortho-methyl nitrobenzene afforded the
corresponding products 3Ea and 3Fa, while an ortho-phenyl
group decreased the yield significantly (3Ga). Methyl ester,
GC yields. Ligand (40 mol %) was used.
Mizoroki−Heck-type alkenylation of nitroarenes under palla-
dium catalysis is described (Figure 1C).
To commence the screening of reaction conditions for the
denitrative Mizoroki−Heck reaction, we selected 4-nitrotoluene
(1A) and styrene (2a) as model substrates (Table 1). First, using
5 mol % Pd(acac)2/BrettPhos as the catalyst (which has been
effective for all denitrative couplings thus far), bases (3.0 equiv)
and solvents were examined. All reactions were conducted at
150 °C for 24 h. CsF in 1,4-dioxane, which was one of the best
combinations for denitrative Suzuki−Miyaura coupling,9a
successfully afforded the desired coupling product 3Aa in 8%
yield (Table 1, entry 1). When the solvent was changed to higher
boiling point solvents such as toluene, m-xylene, anisole, and
benzotrifluoride (PhCF3), the yields of 3Aa increased to 20−
53% (Table 1, entries 2−5). Using PhCF3 as the solvent, we next
examined the bases. K3PO4, which was the best base for the
intramolecular denitrative C−H arylation,11 did not work well
(Table 1, entry 6). Interestingly, when carbonate bases were
screened, the use of Rb2CO3 dramatically increased the yield of
3Aa (80% yield, Table 1, entries 7−9).13 Next, a variety of
B
https://dx.doi.org/10.1021/acs.orglett.0c00983
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tbutyl, and methoxy on the C4-position of the phenyl group gave
the corresponding coupling products 3Ab−3Ad in good yields.
Changing the para-methoxy group to the meta- and ortho-
positions on the phenyl group did not affect the yield (3Ae and
3Af). Functional groups such as amine (3Ag), silyl (3Ah), fluoro
(3Ai), and amide (3Aj) are tolerated under these reaction
conditions. Not only substituted styrene derivatives but also
vinylnaphthalenes (3Ak and 3AI) and vinylisoquinoline (3Am)
can be applied to this reaction to afford the corresponding
coupling products in moderate to good yields. Cyclooctene
worked as the alkenylating agent to give the coupling product
3An as a mixture of isomers in 52% yield. However, the current
limitation of this denitrative alkenylation is that disubstituted
linear alkenes (3Ao) and α,β-unsaturated ester (3Ap) do not
work well under the present reaction conditions.
Scheme 2. Substrate Scope for Alkenes
Fluoronitroarenes can be readily substituted by a nucleophilic
aromatic substitution (SNAr). Using this feature, a nucleophile
was added to the denitrative alkenylation (Scheme 3). To this
end, treating a mixture of 4-fluoronitrobenzene (4), 3,5-
dimethylphenol (5), and styrene (2a) with the Pd/BrettPhos
catalyst smoothly allowed for the three-component reaction to
proceed, giving the coupling product 6 in 41% yield. Various
disubstituted benzenes would be readily synthesized by
changing the nucleophile.
In summary, we successfully developed a Mizoroki−Heck
reaction of nitroarenes with styrene derivatives. Pd/BrettPhos
was the most effective catalyst for this reaction, leading to
stilbene derivatives with various functional groups. Expanding
the range of applicable alkenes and developing more efficient
catalysts are current objectives in our laboratory.15
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00983.
Experimental procedures and spectroscopic data for
compounds including 1H, 13C NMR spectra (PDF)
a
Conditions: 1A (1.5 equiv), 2b−2p (0.20 mmol), Pd(acac)2 (5 mol
%), BrettPhos (20 mol %), Rb2CO3 (3.0 equiv), PhCF3 (1.0 mL), 150
°C, 24 h. 0.80 mmol scale.
b
AUTHOR INFORMATION
Corresponding Author
■
Scheme 3. Three-Component Coupling by SNAr/Denitrative
Alkenylation
Junichiro Yamaguchi − Department of Applied Chemistry,
Waseda University, Shinjuku, Tokyo 169-8555, Japan;
orcid.org/0000-0002-3896-5882; Email: junyamaguchi@
waseda.jp
Authors
Toshimasa Okita − Department of Applied Chemistry, Waseda
University, Shinjuku, Tokyo 169-8555, Japan
Kitty K. Asahara − Department of Applied Chemistry, Waseda
University, Shinjuku, Tokyo 169-8555, Japan
Kei Muto − Department of Applied Chemistry, Waseda University,
Shinjuku, Tokyo 169-8555, Japan; orcid.org/0000-0001-
8301-4384
acetal, and amine were tolerated under these reaction conditions
to furnish the desired products 3Ha−3Ja in moderate yields.
Nitronaphthalene also gave the product 3Ka in moderate yield.
Not only nitroarenes, but also nitroheteroarenes, can be used in
this reaction. Indeed, nitroquinoline and nitroindole can be
coupled with 2a to furnish the products 3La and 3Ma.
Nimesulide, which is a well-known NSAID, can also be coupled
with 2a to give alkene 3Na in 31% yield.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00983
Author Contributions
†T.O. and K.K.A. contributed equally.
Notes
Next, the alkene partner was investigated (Scheme 2). Styrene
derivatives with an electron-donating substituent such as methyl,
The authors declare no competing financial interest.
C
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Chem. Commun. 2016, 52, 11893−11896. (d) Uno, D.; Minami, H.;
Otsuka, S.; Nogi, K.; Yorimitsu, H. Palladium-Catalyzed Mizoroki−
Heck-Type Alkenylation of Monoaryldialkylsulfoniums. Chem. - Asian
J. 2018, 13, 2397−2400.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant Number
JP19H02726 (to J.Y.), JP18H04661 (Hybrid Catalysis), and
JP19K15573 (to K.M.). We thank Kaoru Matsushita and
Tomoya Hisada (Waseda University) for initial experiments.
We also thank Prof. Yoshiaki Nakao (Kyoto University) for
providing NHC ligands. The Materials Characterization Central
Laboratory in Waseda University is acknowledged for the
support of HRMS measurements.
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D
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