Pd-Catalyzed Denitrative Intramolecular C-H Arylation

Article abstract of DOI:10.1021/acs.orglett.9b01593

A Pd-catalyzed intramolecular C-H arylation of nitroarenes has been developed. Nitroarenes bearing tethered aryl groups at the ortho-position can be readily prepared in one step from 2-halonitroarenes by a nucleophilic aromatic substitution (S_NAr). Under Pd/BrettPhos catalysis, activations of the C-NO₂ bond as well as the C-H bond on arenes generated the corresponding biaryl linkage in moderate to excellent yields.

Full text of DOI:10.1021/acs.orglett.9b01593

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd-Catalyzed Denitrative Intramolecular C−H Arylation
Kitty K. Asahara,†,§ Toshimasa Okita,†,§ Ami N. Saito,† Kei Muto,† Yoshiaki Nakao,‡
and Junichiro Yamaguchi*,†
†Department of Applied Chemistry, Waseda University, 3-4-1 Ohkubo, Shinjuku, Tokyo 169-8555, Japan
‡Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan
S
* Supporting Information
ABSTRACT: A Pd-catalyzed intramolecular C−H arylation of
nitroarenes has been developed. Nitroarenes bearing tethered aryl
groups at the ortho-position can be readily prepared in one step
from 2-halonitroarenes by a nucleophilic aromatic substitution
(SNAr). Under Pd/BrettPhos catalysis, activations of the C−NO2
bond as well as the C−H bond on arenes generated the corresponding biaryl linkage in moderate to excellent yields.
itroarenes are produced in the petrochemical industry
N
from simple arenes and are a source of haloarenes and
functionalized aromatic compounds.1 For example, haloarenes,
which are well-known aryl electrophiles for metal-catalyzed
cross-coupling reactions, have frequently been synthesized in
four steps: (1) nitration of arenes, (2) reduction of nitroarenes,
(3) diazotization of anilines, and (4) halogenation of
diazonium aromatics. Including the cross-coupling reaction,
this involves a multistep reaction of five steps. Therefore, the
direct coupling of a more “synthetically upstream” nitroarene
instead of a haloarene would lead to a facile access to
functionalized aromatics. Furthermore, this could reduce the
number of steps as well as the manufacturing cost of the
aromatic products. However, the coupling of nitroarenes with
nucleophiles has rarely been reported.2 Recently, our group
successfully developed palladium-catalyzed coupling reactions
of nitroarenes with external nucleophiles, which include
Suzuki−Miyaura coupling,3a amination,3b and reductive hydro-
genation (Figure 1A).3c A Pd/BrettPhos catalytic system has
also been known to activate a C−NO2 bond, with the formed
complex reacting with nucleophiles.3d
Meanwhile, C−H arylation using (hetero)arenes as aryl
nucleophiles instead of metalloarenes is also quite effective in
reducing the number of steps.4 Recently, C−H arylation of
(hetero)arenes with various aryl electrophiles (i.e., aryl
pseudohalides, arenols, aryl carboxylic acids, aromatic esters,
and aromatic amides) has been reported.4,5 However, the C−
H nucleophile component has been limited, and the use of
simple arenes continues to be a challenging issue. To
circumvent this problem, an internal nucleophile can be
used, changing the reaction mode from intermolecular to
intramolecular. Similarly, intramolecular C−H arylations of
various “tethered” aryl electrophiles and arenes have been
developed,6 but the use of a nitro group as a formal leaving
group has not been previously reported. We hypothesized that
the nitro group and the C−H bond of an aromatic compound
can be simultaneously activated using Pd/BrettPhos or a new
catalytic system, leading to a significant reduction in the
number of steps in the synthesis of biaryl linkages such as
Figure 1. (A) Catalytic denitrative functionalization. (B) Catalytic
denitrative intramolecular C−H arylation.
dibenzofurans, carbazoles, and fluorenones (Figure 1B).
Herein, we report the first intramolecular coupling reaction
between a nitroarene and an aromatic C−H bond.
Our study began by optimizing the reaction between 1-nitro-
2-phenoxybenzene (1A) as the model substrate, particularly
focusing on the ligand structure (Table 1).7 The reaction was
conducted using 1A with 5 mol % Pd(acac)2 and a variety of
ligands (15−30 mol %), along with K3PO4 (3.0 equiv) as an
additive in toluene at 150 °C. First, we screened several
electron-rich alkyl phosphine ligands, but the reaction did not
Received: May 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01593
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Screening of Ligands and Other Reaction
Parameters
Scheme 1. Substrate Scope of Denitrative Intramolecular
C−H Arylation
a
a
b
b
entry
ligand (X mol %)
recovery of 1A (%)
yield of 2A (%)
1
2
3
4
5
6
7
8
P(n-Bu)3 (30)
PCy3·HBF4 (30)
dcype (15)
81
95
77
86
64
81
53
50
25
0
0
0
0
0
0
22
15
24
50
54
0
dppp (15)
Xantphos (15)
2,9-dmphen (15)
phen L1 (15)
phen L2 (15)
BrettPhos (15)
tBuBrettPhos (15)
JohnPhos (15)
XPhos (15)
9
10
11
12
13
14
15
76
72
88
6
0
3
JackiePhos (15)
c
BrettPhos (12)
71
89 (70)
d
e
BrettPhos (12)
0
a
Conditions: 1A (0.20 mmol), Pd(acac)2 (5 mol %), ligand (15−30
mol %), K3PO4 (3.0 equiv), toluene (1.0 mL), 150 °C, 24 h.
b
1H NMR yield determined by using CH2Br2 as an internal standard.
c
d
e
Toluene (2.5 mL) was used. 160 °C. Isolated yield.
work at all (Table 1, entries 1 and 2). Diphosphines were also
completely ineffective, for example, with dcype, dppp, and
Xantphos (Table 1, entries 3−5). Delightfully, when 2,9-
dimethylphenanthroline(2,9-dimephen) was used, the desired
coupling product 2A was produced in 22% yield (Table 1,
entry 6). However, after extensive screening of phenanthroline
derivatives, a result that exceeds that of 2,9-dimephen was not
obtained (Table 1, entries 7 and 8).7 In the end, BrettPhos or
tBuBrettPhos were the most effective ligands to give 2A in 50%
and 54% yields, respectively (Table 1, entries 9 and 10),
whereas other Buchwald ligands gave almost no reaction
(Table 1, entries 11−13). Finally, slightly decreasing the
amount of the ligand and changing the reaction concentration
from 0.2 to 0.08 M increased the yield of 2A (71%); elevating
the temperature from 150 to 160 °C afforded 2A in 89% yield.
With the optimal conditions (Table 1, entry 15) in hand, we
then investigated the substrate scope (Scheme 1). The starting
materials can be readily prepared in one step from o-
halonitroarenes and arenols. At first, we modified the arenol
unit (Ar2) to check the generality. Diarylethers bearing a
substituent on the para position of the arenol unit, such as
methoxy and phenyl, afforded the corresponding biaryls 2B
(95% yield) and 2C (57% yield). The reaction proceeded
a
Conditions: 1 (0.20 mmol), Pd(acac)2 (5 mol %), BrettPhos (12
mol %), toluene (1.0 mL), K3PO4 (3.0 equiv), 160 °C, 24 h; (a) 150
°C.
smoothly even if one ortho position of the arenol was blocked,
such as with a t-Bu and a methoxy group, giving the products
2D and 2E in moderate yields. meta-Substituted arenols (e.g.,
with a methoxy group) afforded 2F and 2F′ (2F/2F′ = 87/13)
in a good yield (66%) Diarylethers derived from 1- or 2-
naphthols gave the corresponding products 2G and 2H, along
with a regioisomer 2H′ (2H/2H′ = 69/31) in moderate yields.
Next, we investigated applicable nitroarene units (Ar1).
Methoxy (1B), methoxycarbonyl (1I), dimethylaminocarbonyl
(1J), trifluoromethyl (1K), and methylsulfonyl (1L) groups
were tolerated under the standard conditions to furnish the
corresponding products 2B−2L in moderate to good yields.8
Additionally, although the esters on the aromatic rings were
changed to different positions, the products (2M−2O) were
formed in excellent yields.
Subsequently, the “tether” which connects the aromatic rings
was changed (Scheme 2). For example, when 1P (changed
B
DOI: 10.1021/acs.orglett.9b01593
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Carbonyl Tether (Instead of an Oxygen Atom)
Detailed experimental procedures, spectral data for all
1
compounds, and H, and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: junyamaguchi@waseda.jp
ORCID
from an oxygen atom to a carbonyl group) was used, the
desired fluorenone 2P was obtained in 44% yield. On the other
hand, when the arenol oxygen atom was changed to a nitrogen
atom (NH), carbazole was obtained, albeit in a low yield.7
Although there remains room for further improvement, these
results indicate that this reaction is not restricted to diarylether
formation and that various denitrative intramolecular C−H
arylations proceed under the catalytic conditions.
Kei Muto: 0000-0001-8301-4384
Yoshiaki Nakao: 0000-0003-4864-3761
Junichiro Yamaguchi: 0000-0002-3896-5882
Author Contributions
§These authors contributed equally.
Notes
The authors declare no competing financial interest.
Finally, the denitrative C−H arylation reaction was
combined with a state-of-the-art cross-coupling reaction
(Scheme 3). 4-Fluoro-3-nitrobenzoic acid (3) was converted
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI grant no.
JP19H02726, JP18H04272 (to J.Y.), JP15H05799 (to Y. N.),
and JP19K15573 (to K.M.). We thank Myuto Kashihara
(Kyoto University) for fruitful discussion and critical com-
ments. The Materials Characterization Central Laboratory in
Waseda University is acknowledged for HRMS measurement.
Scheme 3. Denitrative C−H Arylation/Decarbonylative
a
Alkynylation
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(dicyclohexylphosphino)thiophene.
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DOI: 10.1021/acs.orglett.9b01593
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