Pd-Catalyzed Etherification of Nitroarenes

Article abstract of DOI:10.1021/acs.organomet.1c00183

The Pd-catalyzed etherification of nitroarenes with arenols has been achieved using a new rationally designed ligand. Mechanistic insights were used to design the ligand so that both the oxidative addition and reductive elimination steps of a plausible catalytic cycle were facilitated. The catalytic system established here provides direct access to a range of unsymmetrical diaryl ethers from nitroarenes.

Full text of DOI:10.1021/acs.organomet.1c00183

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Pd-Catalyzed Etherification of Nitroarenes
Naoki Matsushita, Myuto Kashihara, Michele Formica, and Yoshiaki Nakao*
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ABSTRACT: The Pd-catalyzed etherification of nitroarenes with
arenols has been achieved using a new rationally designed ligand.
Mechanistic insights were used to design the ligand so that both the
oxidative addition and reductive elimination steps of a plausible
catalytic cycle were facilitated. The catalytic system established here
provides direct access to a range of unsymmetrical diaryl ethers from
nitroarenes.
he diaryl ether moiety is an important structural motif
withdrawing group or to nitropyridines. This is presumably
Toften found in natural products and bioactive sub- because these reactions have characteristics akin to those of
stances.1 Classically, diaryl ethers have been synthesized via the
SNAr reactions.
Recently, our group has reported C−C and C−N bond
forming cross-coupling reactions and the reductive denitration
of nitroarenes catalyzed by Pd complexes bearing Buchwald-
type ligands.10a−c,11 These catalytic systems enable the
oxidative addition of C(aryl)−NO2 bonds to the Pd center,
enabling even nitroarenes with electron-donating group to
undergo aromatic substitutions and improving the substrate
tolerance of the reaction. We therefore assumed that the use of
arenol nucleophiles in the same catalytic system would deliver
diaryl ethers via an established catalytic cycle without
compromising the substrate generality. Figure 1 shows a
plausible catalytic cycle whereby a nitroarene undergoes
oxidative addition, ligand exchange (transmetalation), and
reductive elimination to give a diaryl ether.
The denitrative etherification reaction was first attempted
using relatively electron rich 4-nitroanisole (1a) and phenol
(2a) in the presence of various Pd catalysts that had been
effective in our previous studies (Scheme 1b). To our
disappointment, the use of BrettPhos (L1), i.e., one of the
most promising ligands, failed to yield any of the desired
product (3a) (entry 1).6g Furthermore, the imidazo[1,5-
a]pyridinylidene L2/Pd system, which has recently been
established as a more active catalyst for C−NO2 activa-
tions,10d−f also resulted in no reaction (entry 2). In the
proposed catalytic cycle (Figure 1), the oxidative addition of
the C−NO2 bond should proceed with Pd/L1 or Pd/L2, and
Ullmann condensation of aryl halides and arenols, mediated by
a stoichiometric amount of copper, which typically requires
relatively high reaction temperatures.2 Nucleophilic aromatic
substitution (SNAr) reactions offer a transition-metal-free
alternative, although only highly electron-deficient aryl
(pseudo)halides are applicable in this approach.3 Recent
advances in this field have led to improved Ullmann-type
coupling reactions that only require a catalytic amount of
Cu3b,4 or Fe.5 In addition, Pd-catalyzed coupling reactions that
form carbon−oxygen bonds, known as Buchwald−Hartwig
etherifications, have been developed.6 All of these methods rely
on the use of haloarenes, aryl electrophile substrates that can
be difficult to prepare or that result in the emission of
environmentally harmful byproducts. In a complementary
approach, Yamaguchi and Itami have reported a halogen-free
synthesis of diaryl ethers via the decarbonylation of aryl
benzoates.7 However, this method, which requires two formal
synthetic steps starting from a benzoic acid derivative and a
phenol, is limited to the reaction of aryl azinecarboxylate
substrates.
Nitroarenes, on the other hand, are materials that are
industrially easy to access, are obtained by the nitration of
benzenes, and are readily modifiable through various aromatic
substitution reactions or metal-catalyzed functionalizations.8
Thus, the substitution of the nitro group of a nitroarene with
an aryloxy group provides an attractive synthetic route to
produce diaryl ethers. In 2011, Wu and co-workers developed
the first aryloxylation of nitroarenes via the use of arylboronic
acids as pronucleophiles.9a Following this work, several groups
reported transition-metal-catalyzed denitrative C−O coupling
reactions of nitroarenes and phenol derivatives.9b−d Collec-
tively, however, these reactions are only applicable to
nitroarenes that contain at least one additional electron-
Special Issue: Organometallic Solutions to Challenges
in Cross-Coupling
Received: March 26, 2021
Published: June 23, 2021
https://doi.org/10.1021/acs.organomet.1c00183
© 2021 American Chemical Society
Organometallics 2021, 40, 2209−2214
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Scheme 2. Substrate Scope for the Etherification of
Nitroarenes
Figure 1. Plausible mechanism for the Pd-catalyzed etherification of
nitroarenes.
Scheme 1. (a) Ligand Design to Promote the Reductive
Elimination and (b) Optimization Studies for the
Phenoxylation of 1a
a
The reaction was performed using 0.60 mmol of 1e and 0.90 mmol
b
of 2i for 12 h. The reaction was performed with 0.60 mmol of p-
nitrotoluene (1i) and 0.90 mmol of H2O in 3.0 mL of 1,4-dioxane for
12 h.
formation. Buchwald and co-workers have previously reported
a guideline for the modification of their ligands (Scheme 1a);12
the installation of a methyl group at the C6 position of the
upper ring should increase the conformational rigidity, while
bulky substituents at the C3 position and the phosphine atom
should stabilize the P−C bidentate ligation, thus promoting
the reductive elimination. RockPhos (L3), which has a
t
methoxy substituent at the C3 position and Bu groups at
the phosphorus center, successfully delivered the target diaryl
ether in a low, yet promising, 7% yield (entry 3). However, a
bulkier isopropoxy group at the C3 position (L4) did not
enhance the yield (entry 4). Theoretical calculations indicated
that the steric hindrance around the Pd center destabilizes the
Ar−Pd−NO2 species, rendering the oxidative addition
thermodynamically unfavorable.10g Thus, we hypothesized
that it was necessary to ensure that the ligand had sufficient
flexibility to enable cleavage of the C−NO2 bond while still
promoting the reductive elimination. To verify this hypothesis,
we prepared ligands that bear cyclohexyl groups on the P atom
(L5−L9) and assessed their activity in the denitrative
etherification. Pleasingly, a higher yield of 3a was obtained
upon increasing the steric bulk of the substituent at the C3
position (entries 5−9). During further optimization studies, it
was determined that, due to overconsumption of 1a, the
a
1H NMR yields determined using mesitylene as an internal standard.
b
0.15 mmol of 1a and 0.10 of 2a were used.
the phenoxide should be nucleophilic enough to replace the
nitrite ligand following the oxidative addition step. We thus
hypothesized that acceleration of the reductive elimination
would be crucial to achieve the denitrative C−O bond
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a
Scheme 3. Mechanistic Studies: (a) Stoichiometric Reactions and (b) %VBur Values of the Calculated Structures of (L7)AuCl
(6c, 6c*) and (L9)AuCl (6d, 6d*)
a
GC yield of the reaction of 4a (18 μmol), 2b (2.0 equiv), and K3PO4 (3.0 equiv) in 1,4-dioxane (1.0 mL) at 150 °C for 24 h using n-C13H28 as an
internal standard.
conditions. 3-Aryloxypyridine (3g) was obtained from 3-
nitropyridine (1f) in 67% yield. These examples also represent
challenging nitroarene substrates for SNAr-type transforma-
tions. Electron-withdrawing groups on the nitroarene electro-
phile impeded the reaction; 4-trifluoromethylnitrobenzene
(1g) and methyl 3-nitrobenzoate (1h) delivered the
corresponding products (3h and 3i) in moderate yield.13
Next, we examined the scope of the arenols. In addition to p-
cresol (2b) and m-cresol (2c), the sterically hindered o-cresol
(2d) also underwent coupling with 4-nitroanisole (1a) in 81%
yield. Other alkylphenols such as 3,5-dimethylphenol (2e) and
4-tert-butylphenol (2f) were excellent nucleophiles for this
reaction. In line with the reported etherification reaction,14 the
introduction of a fluorine substituent (2h) diminished the
nucleophilicity of the phenol, leading to poor reaction
efficiency. It is notable that nitronaphthalene (1e) could be
coupled with benzyl alcohol (2i), albeit in a lower yield,
representing, to the best of our knowledge, the first example of
the alkoxylation of an electronically unbiased nitroarene.15 We
Table 1. Comparison of AuCl Complexes of Ligands L1, L5,
L7, and L9
a
entry
complex
Au−Cl length (Å)
%VBur
1
2
3
4
5
6
(L1)AuCl (6a)
(L5)AuCl (6b)
(L7)AuCl (6c)
(L9)AuCl (6d)
(L7)AuCl (6c*)
2.291
2.295
2.2851(14)
2.2967(8)
57.5
58.8
58.4 (58.8)
57.9 (59.2)
(61.9)
b
b
(L9)AuCl (6d*)
(62.0)
Calculated using SambVca 2.118b with the following parameters:
a
radius of sphere 3.5 Å; distance from sphere 2.0 Å; mesh step 0.05 Å;
H atoms omitted; Bondi radii scaled by 1.17. Values in parentheses
b
were determined using the calculated structures. The C2−C3−O−R
dihedral angle was fixed to 0°.
stoichiometry of the substrates is critical for efficient product
formation (see below). By adding an excess of 1a relative to 2a
(entries 10 and 11) and using L7 and L9, the yields of 3a were
improved to 68% and 86% (based on 2a), respectively.
t
found that BuOH could be coupled with 1i to afford the
corresponding aryl tert-butyl ether in a very low yield. Other
1°- and 2°-alcohols gave denitrated arenes as major products
possibly through β-hydride elimination from arylpalladium
alkoxide intermediates (vide infra). We also found that the
symmetrical ether 3q could be obtained by adding H2O as the
nucleophile, probably via the in situ formation of phenox-
ide.4d,6g,16
To gain insight into the reaction mechanism, we performed
stoichiometric studies. First, (cod)Pd(CH2SiMe3)2 was used as
a Pd(0) precursor and treated with nitrobenzene (1d) in the
With the optimized conditions in hand, the substrate scope
of the etherification was investigated (Scheme 2). In contrast
to other reported methods,9 it was possible to couple relatively
electron rich nitroanisoles (1a−c) with p-cresol (2b) to
generate the corresponding diaryl ethers (3b−d) in good yield.
While an o-methoxy substituent on the nitroarene did not
affect the reaction, o-nitrotoluene was found to be particularly
unreactive (for unsuccessful substrates, see the Supporting
Information). The electronically neutral nitrobenzene (1d)
and nitronaphthalene (1e) were also reactive under these
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presence of L9 at 60 °C for 48 h to afford the oxidative adduct
(L9)PdII(Ph)(NO2) (4a) in 29% yield (Scheme 3a). A single-
crystal X-ray diffraction analysis revealed that, in the solid state,
4a adopts a structure similar to that of the previously reported
(L1)PdII(Ph)(NO2) (4b).10a The Pd−N bond lengths in 4a
and 4b are identical, indicating that L9 has an electron-
donating ability comparable to that of L1. These results could
support the oxidative addition of nitroarenes to (L9)Pd0
perhaps being a facile process. Next, the nitrite−phenoxide
exchange step was investigated by adding premixed p-cresol
(2b) and K3PO4 to a solution of 4a in 1,4-dioxane-d8. After the
mixture was stirred at ambient temperature for 24 h, a signal in
the 31P NMR spectrum was observed 3 ppm downfield from
that of 4a. Although we failed to fully characterize the product,
we assume that this signal could be attributed to the presence
of (L9)PdII(Ph)(O-p-tol) (5) because diaryl ether 3e was
observed upon heating this complex to 80 °C. An identical 31P
NMR peak was observed during the catalytic reaction of 1d
and 2b, indicating the involvement of this complex in the
catalytic cycle as a resting state. Furthermore, the thermally
inert nature of this complex below 80 °C indicates, as expected,
that the reductive elimination is the rate-determining step.
These experiments revealed that the reductive elimination is
a key step and prompted us to further investigate the steric
properties of the ligand. We synthesized a series of AuCl
complexes (6b−d) with L5, L7, and L9 as the ligands due to
their facile preparation and the prevalence of crystal structures
of AuCl complexes bearing various types of ligands (Table
promoting the C−O bond formation via reductive elimination
while maintaining the activity of the catalyst toward the
oxidative addition of the C−NO2 bond. Experimental and
theoretical analyses indicated that the flexibility and mobility of
the ligand substituents are crucial for these elementary steps to
proceed efficiently. The protocol established here covers both
the aryloxylation and alkoxylation of nitroarenes with an
electron-donating group and the formation of symmetrical
ethers complementing the existing SNAr-like denitrative C−O
couplings.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.1c00183.
■
sı
Detailed experimental procedures including spectro-
scopic and analytical data (PDF)
Cartesian coordinates for the calculated structure (XYZ)
Accession Codes
CCDC 2057920, 2060380, and 2067443−2067444 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
1).17 L5, L7, and L9 contain a Me, Pr, and Cy substituent at
i
AUTHOR INFORMATION
Corresponding Author
■
the C3−O atom, respectively. Single-crystal X-ray diffraction
analyses revealed no substantial differences in the Au−Cl bond
lengths between (L1)AuCl (6a)10d and 6b−d, implying that
the strong electron-donating effects of these ligands facilitate
the oxidative addition. To compare the steric properties, we
then calculated the percent buried volume (%VBur) of each
complex.18a As expected, all of the Au complexes synthesized
had slightly higher %VBur values in comparison to 6a. However,
we uncovered an unexpected pattern where the %VBur value
has an inverse relationship with the size of the O-substituent
[6b (Me) > 6c (iPr) > 6d (Cy)]. The steric bulk around the
metal in the solid-state seemed to have no correlation with the
catalytic activity. We therefore performed density functional
theory (DFT) calculations to study the dynamic behavior of
the ligands: in particular, the rotation of the C−O bond. The
calculated structures of 6c and 6d showed %VBur values almost
identical with those obtained experimentally. We then
optimized the structures with the C2−C3−O−R dihedral
angle fixed at 0° (6c* and 6d*) (Scheme 3b), thus allowing us
to study the metal centers in their most sterically hindered
states. As summarized in Table 1, the ligands in these confined
structures occupy a significantly larger space around the Au
center than in the corresponding unstrained structures. It
should also be noted here that the sterically hindered
(L7)AuCl (6c*) was calculated to be 21.5 kcal/mol higher
in energy than the ground state (6c), while a smaller energy
gap of 15.5 kcal/mol was found for (L9)AuCl (6d and 6d*).
This difference can be correlated with the observation that the
reactivity of Pd/L9 is higher than that of Pd/L7 and with the
fact that the rate-limiting reductive elimination has a lower
barrier for L9 in comparison to L7.
Yoshiaki Nakao − Department of Material Chemistry,
Graduate School of Engineering, Kyoto University, Kyoto
615-8510, Japan; orcid.org/0000-0003-4864-3761;
Email: nakao.yoshiaki.8n@kyoto-u.ac.jp
Authors
Naoki Matsushita − Department of Material Chemistry,
Graduate School of Engineering, Kyoto University, Kyoto
615-8510, Japan
Myuto Kashihara − Department of Material Chemistry,
Graduate School of Engineering, Kyoto University, Kyoto
615-8510, Japan
Michele Formica − Department of Material Chemistry,
Graduate School of Engineering, Kyoto University, Kyoto
615-8510, Japan; Present Address: Chemistry Research
Laboratory, University of Oxford, OX1 3TA Oxford,
United Kingdom.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.1c00183
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
Technology towards the Creation of New Functions”, the
“JSPS KAKENHI Grant Number JP15H05799 in Precisely
Designed Catalysts with Customized Scaffolding’, and
TOSOH corporation. M.K. is grateful for the Research
Fellowship of the Japan Society for the Promotion of Science
(JSPS) for Young Scientists. M.F. thanks the JSPS for an
International Research Fellowship (Postdoctoral Fellowships
In conclusion, we have developed a novel catalytic system
for the etherification of nitroarenes. Using the newly
synthesized L9 as a supporting ligand, we have succeeded in
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Communication
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for Research in Japan (short-term)). We thank Prof. Dr.
Kazuhiko Semba and Dr. Naofumi Hara (Kyoto University)
for X-ray crystallographic analyses.
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