The Suzuki-Miyaura Coupling of Nitroarenes

Article abstract of DOI:10.1021/jacs.7b03159

Synthesis of biaryls via the Suzuki-Miyaura coupling (SMC) reaction using nitroarenes as an electrophilic coupling partners is described. Mechanistic studies have revealed that the catalytic cycle of this reaction is initiated by the cleavage of the aryl-nitro (Ar-NO₂) bond by palladium, which represents an unprecedented elemental reaction.

Full text of DOI:10.1021/jacs.7b03159

Communication
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The Suzuki−Miyaura Coupling of Nitroarenes
M. Ramu Yadav,†,∥ Masahiro Nagaoka,†,∥ Myuto Kashihara,† Rong-Lin Zhong,‡ Takanori Miyazaki,§
Shigeyoshi Sakaki,*,‡ and Yoshiaki Nakao*,†
†Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto 615-8510, Japan
‡Fukui Institute for Fundamental Chemistry, Kyoto University, Sakyo-ku, Kyoto 606-8103, Japan
§Tosoh Corporation, 4560 Kaisei-cho, Shunan-shi, Yamaguchi 746-0006, Japan
S
* Supporting Information
76% isolated yield when using Pd(acac)2 (5.0 mol %), BrettPhos
(20mol%),21 18-crown-6(10mol%),22 andK3PO4·nH2O(ca.11
wt % H2O, n = ca. 1.5, 1.8 mmol) in 1,4-dioxane at 130 °C for 24 h
(Table S1). The absence of 18-crown-6 from the reaction
medium resulted in a slightly decreased yield of 3 (Table S1). The
choiceofaligandiscritical inorder toobtain thecouplingproduct
in high yield; Buchwald’s ligands23 SPhos, RuPhos, and CPhos
were found to be ineffective, whereas XPhos provided 3 in
moderate yield. In contrast, PCy3, PtBu3, and IPr, which are
effective for SMC of aryl halides and arene sulfonates, did not
provide any 3. When Pd(OAc)2, Pd2(dba)3, PEPPSI-IPr,24 or
BrettPhos Pd G325 were employed instead of Pd(acac)2, 3 was
obtained in moderate yield, whereas Pd(PPh3)4 was not effective.
Subsequently, we examined the impact of bases onto the progress
of the reaction. While CsF afforded the targeted biaryl, Cs2CO3
and K2CO3 did not. The water contamination in K3PO4 seemed
important, as its presence (1−2 equiv) with dried K3PO4 (ca. 1 wt
% H2O) recaptured the reactivity, while the rationale for the effect
was unclear. Using toluene or THF as a solvent resulted in a
diminished yield of 3.
ABSTRACT: Synthesis of biaryls via the Suzuki−Miyaura
coupling (SMC) reaction using nitroarenes as an electro-
philic coupling partners is described. Mechanistic studies
have revealed that the catalytic cycle of this reaction is
initiated by the cleavage of the aryl−nitro (Ar−NO2) bond
by palladium, which represents an unprecedented
elemental reaction.
he Pd-catalyzed Suzuki−Miyaura coupling (SMC) reaction
T
is a highly useful and versatile method for the construction
of carbon−carbon bonds.1 The reaction is particularly important
to afford unsymmetric biaryl compounds, which are frequently
encountered as core structural motifs in pharmaceuticals,
agrochemicals, and organic materials. Conventionally, these
cross-coupling reactions employ halogen-containing aromatic
compounds such as aryl halides2 as electrophilic coupling
partners, while aromatic boron compounds serve as nucleophilic
coupling partners. Recently, substantial efforts have also been
devoted to the development of alternatives to aryl halides as the
aromatic electrophiles.3−14 However, their preparation are often
laborious when parent arenes are used as starting materials.
Nitroarenes, on the other hand, are highly versatile and
common aromatic building blocks in organic synthesis.15 They
can be directly obtained from the nitration of the parent arenes,
which is generally highly selective toward monofunctionalization,
while the halogenation of arenes sometimes affords a mixture of
mono- and dihalogenated arenes.16 In the chemical industry, it is
indeed the nitration that often serves as the starting point for the
derivatization of benzene, toluene, and xylene.17 Nitroarenes,
particularly those bearing other electron-withdrawing groups,
undergo nucleophilic substitution reactions, in which the NO2
group serves as a leaving group. These reactions have recently
been shown to be catalyzed by transition metals such as copper18
and rhodium,19 and afford diaryl ethers and thioethers.20
Nevertheless, nitroarenes have not yet been reported to undergo
SMC reactions with the NO2 group serving as a leaving group.
Based on the aforementioned availability, the SMC of nitroarenes
should offer a straightforward and highly versatile way to access a
widerangeoffunctionalizedbiaryls. Herein,wereportthefirstPd-
catalyzed SMC of nitroarenes via the cleavage of Ar−NO2 bonds.
Various reaction parameters, including metal catalysts, ligands,
and bases, were screened extensively in order to optimize the
reaction conditions for the coupling of 4-nitroanisole (1a) with
phenylboronic acid (2a). We obtained 4-methoxybiphenyl (3) in
The thus optimized reaction conditions were then applied to
the coupling of a variety of nitroarenes (1) and arylboronic acids
(2) (Table 1). Nitroarenes with electron-donating or -with-
drawing groups were tolerated well and engaged in reactions with
2a or p-anisylboronic acid (2b). Notably, selective functionaliza-
tion of the Ar−NO2 bond could be achieved, while leaving other
C−N bonds intact. Although free carbonyl functionalities such as
formyl and acetyl groups at the para-position of the nitrobenzene
were incompatible with the optimal reaction conditions (see
Figure S1 for unsuccessful substrates), their acetal-protected
analogues engaged in the reaction to furnish carbonyl-substituted
biaryls in good yields after deprotection. In contrast to
conventional SNAr reactions, the reaction of 4-fluoronitro-
benzene proceeded, albeit in modest yield, exclusively via Ar−
NO2 activation. Other halogen functionalities, on the other hand,
reacted faster than the NO2 group. Dinitroarenes coupled with 2a
to selectively afford monophenylation products. Subsequent
reactions of 16, 20, and 22 with 2b furnished unsymmetric
teraryls 13, 19, and 23, respectively. Sterically hindered ortho-
substituted biaryls were also obtained in good yields. NO2-
substituted polyaromatic hydrocarbons could also be coupled
successfully with 1a. Finally, the optimal reaction conditions
could also be applied to nitroheteroarenes such as 3-nitro-
Received: March 29, 2017
© XXXX American Chemical Society
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DOI: 10.1021/jacs.7b03159
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Journal of the American Chemical Society
Communication
Table 1. Substrate Scope for the SMC of Nitroarenes
a
b
c
Isolated yield after hydrolysis of the corresponding acetals. Reaction with arylboronic acid (1.2 mmol). Reaction with CsF (1.8 mmol) in toluene
d
e
(3.0 mL). Reaction with CsF (3.0 mmol) in toluene (3.0 mL). Reaction with RuPhos (20 mol %) instead of BrettPhos and CsF (1.8 mmol).
f
g
h
i
Reaction with CsF (1.8 mmol). Reaction with 22 (0.58 mmol). Reaction without 18-crown-6. Reaction with Pd(acac)2 (10 mol %).
pyridine, which is the initial product for the industrial
derivatization of pyridine. The scope of arylboronic acids was
also examined, and the results revealed that a range of substituted
phenylboronic acids can participate in the SMC with different
nitroarenes, irrespective of the electronic and/or steric environ-
ment of the reaction site, to give the corresponding biaryls. Biaryl
35 can be a useful precursor to prepare an intermediate of AMG
837, which is a pharmaceutically important GPR40 receptor
agonist.26 Naphthyl- and thienylboronic acids were also
susceptible to this biaryl synthesis.
Scheme 1. Stoichiometric Reactions of BrettPhos−Pd(0) with
Nitrobenzene and 1-Nitronaphthalene
To gain insight into the underlying reaction mechanism, the
reactions of 1a and 2a were examined in the presence of radical
scavengers such as TEMPO or Galvinoxyl, which afforded 3 in
modest yields, suggesting that radical pathways are unlikely. We
also found that nitrosobenzene and aniline, which can be formed
in situ from the reduction of nitrobenzene, did not furnish any
biaryls. An aqueous solution obtained from the workup of a
reaction under the optimized cross-coupling reactions was
analyzed by ion chromatography to reveal the formation of
nitrite ions in a yield estimated to be comparable with that of 3.
We then examined a stoichiometric reaction of (cod)Pd-
(CH2SiMe3)2,aPd(0)precursor, withnitroarenesinthepresence
of BrettPhos. The reaction with nitrobenzene at 60 °C afforded
BrettPhosPd(Ph)(NO2) (41) via the oxidative addition of the
Ph−NO2 bond (Scheme 1). (BrettPhos)Pd(η2-nitrobenzene)
(vide infra), (BrettPhos)Pd(cod), and free BrettPhos were also
observed in this reaction. This result represents the first
observation of an oxidative addition of an Ar−NO2 bond onto a
Pd(0) center. Similar reactions have been proposed for allylic27
and benzylic28 C−NO2 bonds, and the formation of nitro
complexes upon radical-based cleavage of an aryl− and alkyl−
NO2 bondhasalsobeenreported.29 Theunprecedentedoxidative
addition product 41 was characterized by multinuclear NMR
spectroscopy, IR spectroscopy, and elemental analysis. The
molecular structure of41 wasdetermined byasingle-crystal X-ray
diffraction study and found to be similar to that derived from the
oxidative addition of aryl halides21 with the Pd center coordinated
not only by the phosphorus atom but also by the triisopropyl-
phenyl ring of BrettPhos (Figure S4). The oxidative addition
could be reversible, as 41 reacted with bromoarenes to give
arylpalladium bromides. The reductive elimination of nitroarenes
B
DOI: 10.1021/jacs.7b03159
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Figure 1. DFT-calculated geometries and Gibbs energy changes of the proposed catalytic cycle.
has been proposed.30 During the formation of 41, the 31P NMR
spectrum revealed a signal at δ 39.6 ppm, which should be
attributed to a reaction intermediate of the oxidative addition. In
the 1H NMR spectrum of the intermediate,31 the signals derived
from the meta- and para-positions of the nitrobenzene moiety
were observed at δ 5.61 and 4.90, respectively. These signals
observed significantly upfield in comparison with those observed
with free nitrobenzene (δ 7.60 for meta and 7.74 for para) should
be ascribed to the π-coordination of nitrobenzene to the electron-
rich Pd(0) center with strong back-donation of an electron from
Pd to the benzene ring. It is noteworthy that the arene−Pd(0)
species was also observed under catalytic conditions. Although
the observed intermediate could not be isolated because of its
instability,32 it was tentatively assigned to be an η2-arene complex,
whose arene ligand coordinates to Pd through the π-bonds.
Conversely, the reaction of (cod)Pd(CH2SiMe3)2, BrettPhos,
and 1-nitronaphthalene instead of nitrobenzene furnished
isolable η2-arene complex 42 (Scheme 1). A single-crystal X-ray
diffraction study on 42 showed that the π-bond between the C3
and C4 positions of the naphthalene ring coordinated to the Pd
center (Figure S4). In the 31P NMR spectrum of 42, a signal
emerged at δ 40.9 ppm, which is identical to that observed during
the catalytic coupling reaction of 1-nitronaphthalene with 2a.
These results strongly indicate that the η2-arene complex is a
resting state in the catalytic cycle. Finally, 41 reacted with 2b at 25
°C inthepresence ofK3PO4·nH2O orCsFtoafford 3, possibly via
transmetalation and a subsequent reductive elimination (eq 1).
which the oxidative addition of the Ar−NO2 bond should occur
(Scheme 2). Transmetalation between the resulting Pd(II)
Scheme 2. Plausible Catalytic Cycle
intermediate and the arylboronic acid, followed by reductive
elimination, should then generate the biaryl. The rate-
determining step could be the oxidative addition of the Ar−
NO2 bondoftheη2-arenecomplex. Competitionbetween1awith
4-trifluoromethylnitrobenzene giving a biaryl from the latter in a
higher yield could also support this assumption (see Supporting
Information (SI)). DFT calculations also supported the catalytic
cycle of Scheme 2, as shown in Figure 1, where CsF was employed
asaLewisbaseinsteadofK3PO4 becauseCsFwasalsoeffectivefor
this cross-coupling reaction. First, 1a should form a stable π-
complex with Pd(BrettPhos), and then cleavage of the Ar−NO2
bond should occur via oxidative addition to Pd(BrettPhos) with
the Gibbs activation energy (ΔG°‡) of 29.6 kcal·mol−1 to afford
Pd(II)(C6H4OMe-p)(NO2)(BrettPhos) 46. Because NMR
measurements indicated that boronic acid interacts with CsF to
form boronate species Cs[Ph−B(OH)2F] 47, the formation of
which was estimated to be highly exerganoic, and that 46 did not
react with CsF, it is likely that the next step is transmetalation
between this Pd(II) complex and a boronate anion. 47 reacts with
46 to afford an intermediate Pd(II)(C6H4OMe-p){FB-
(OH)2Ph}Cs(NO2) 48 in which the nitro group dissociates
The formation of the biaryl was observed even in the absence of a
base, albeit the reaction rate was slower and thus heating at 60 °C
was necessary. This result supports that 41 is an intermediate of
the present SMC of nitroarenes to form biaryls.
The catalytic cycle of the present reaction should thus be
initiated by the formation of a nitroarene−Pd complex, from
C
DOI: 10.1021/jacs.7b03159
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
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simultaneously with the PhB(OH)2 moiety. This reaction occurs
with the ΔG°‡ of 25.2 kcal mol−1 to afford Pd(II)(Ph)-
(C6H4OMe-p)(BrettPhos) 50 and Cs(NO2){FB(OH)2} 49.
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(Figure S7). The reductive elimination of the biaryl product
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to access a variety of substituted benzenes (Scheme S1).
The nitroarene-based SMC protocol developed herein delivers
a range of biaryls from readily available arene feedstocks and
should have the potential to substantially impact conventional
chemical processes for the generation of functional biaryls.
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ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/jacs.7b03159.
■
S
Crystallographic data for 41 (CIF)
Crystallographic data for 42 (CIF)
Detailed experimental procedures including spectroscopic
and analytical data (PDF)
(23) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.
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(25) Bruno, N. C.; Buchwald, S. L. The Strem Chemiker XXVII; Strem
Chemicals, Inc.: MA, 2014. Residual carbazole could affect the reaction
(Table S1).
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AUTHOR INFORMATION
Corresponding Authors
*sakaki.shigeyoshi.47e@st.kyoto-u.ac.jp
*nakao.yoshiaki.8n@kyoto-u.ac.jp
ORCID
■
Shigeyoshi Sakaki: 0000-0002-1783-3282
Yoshiaki Nakao: 0000-0003-4864-3761
(29) Trzcinska-Bancroft, B.; Khan, M. N. I.; Fackler, J. P. Organo-
metallics 1988, 7, 993.
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(b) Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 12898.
(31)FortheNMRanalyses, theintermediate wasalternativelyprepared
by the reaction of BrettPhos Pd G3 with nitrobenzene and nBuLi.
(32) The intermediate decomposed under reduced pressure due
possibly to the decoordination of the nitrobenzene ligand from Pd.
(33) (a) Butters, M.; Harvey, J. N.; Jover, J.; Lennox, A. J. J.; Lloyd-
Jones, G. C.; Murray, P. M. Angew. Chem., Int. Ed. 2010, 49, 5156.
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Author Contributions
∥M.R.Y. and M.N. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the “JST CREST program Grant
Number JPMJCR14L3 in Establishment of Molecular Technol-
ogy towards the Creation of New Functions” and by the “JSPS
KAKENHI Grant Number JP15H05799 in Precisely Designed
Catalysts with Customized Scaffolding”. We thank Dr. H. Eguchi
of Tosoh Corporation for helpful discussions.
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(35) Caron, L.; Campeau, L.-C.; Fagnou, K. Org. Lett. 2008, 10, 4533.
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DOI: 10.1021/jacs.7b03159
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX