Decarbonylative Diaryl Ether Synthesis by Pd and Ni Catalysis

Article abstract of DOI:10.1021/jacs.7b00049

Because diaryl ethers are present as an important motif in pharmaceuticals and natural products, extensive studies for the development of novel methods have been conducted. A conventional method for the construction of the diaryl ether moiety is the intermolecular cross-coupling reaction of aryl halides and phenols with a copper or palladium catalyst. We developed a catalytic decarbonylative etherification of aromatic esters using a palladium or nickel catalyst with our enabling diphosphine ligand to give the corresponding diaryl ethers. The present reaction can be conducted on gram scale in excellent yield. This reaction not only functions in an intramolecular setting but also allows for a cross-etherification using other phenols.

Full text of DOI:10.1021/jacs.7b00049

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Communication
Decarbonylative Diaryl Ether Synthesis by Pd and Ni Catalysis
Ryosuke Takise, Ryota Isshiki, Kei Muto, Kenichiro Itami, and Junichiro Yamaguchi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b00049 • Publication Date (Web): 19 Feb 2017
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Decarbonylative Diaryl Ether Synthesis by Pd and Ni Catalysis
Ryosuke Takise,1 Ryota Isshiki,2 Kei Muto,2 Kenichiro Itami,*1,3 and Junichiro Yamaguchi*2
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1 Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science, Nagoya University, Chikusa,
Nagoya 464-8602, Japan.
2 Department of Applied Chemistry, Waseda University, 3-4-1 Ohkubo, Shinjuku, Tokyo 169-8555, Japan.
3 JST-ERATO, Itami Molecular Nanocarbon Project, Nagoya University, Chikusa, Nagoya 464-8602, Japan.
Supporting Information Placeholder
Scheme 1. (A) Diaryl ethers in pharmaceutically relevant
compounds. (B) Conventional diaryl ether synthesis by transi-
tion-metal catalysis. (C) Decarbonylative coupling reaction
and diaryl ether synthesis by Ni or Pd catalysis.
ABSTRACT: Since diaryl ethers are present as an important
motif in pharmaceuticals and natural products, extensive stud-
ies for the development of novel methods have been conduct-
ed. A conventional method for the construction of the diaryl
ether moiety is the intermolecular cross-coupling reaction of
aryl halides and phenols with a copper or palladium catalyst.
We developed a catalytic decarbonylative etherification of
aromatic esters using a palladium or nickel catalyst with our
enabling diphosphine ligand to give the corresponding diaryl
ethers. The present reaction can be conducted on gram scale in
excellent yield. This reaction not only functions in an intramo-
lecular setting, but also allows for a cross-etherification using
other phenols.
The diaryl ether scaffold has often been seen in pharmaceuti-
cals and natural products, and particularly, arenoxyazine
frameworks are observed in pharmaceutically relevant com-
pounds such as Sorafenib, XK469, Tafenoquine, and AMG900
(Scheme 1A).1,2 Therefore, the development of methods for
diaryl ether synthesis is in high demand. Classically, the cop-
per-mediated Ullmann ether synthesis is known to be one of
the most reliable methods for the synthesis of diaryl ethers.3
However, over the past few decades, palladium- and copper-
catalyzed cross-coupling of aryl halides with phenols has been
developed extensively and is now considered to be a “conven-
tional” route (Scheme 1B).4,5 Additionally, copper-mediated or
catalyzed Chan–Lam–Evans-type Ar–B/Ar–OH couplings are
well-established methods for diaryl ether synthesis.6
In related work, our group and others have recently de-
veloped a range of decarbonylative coupling reactions using
nickel or palladium catalysts (Scheme 1C).7,8 These reactions
proceed through ester C–O bond activation by a metal catalyst
(intermediate A), after which nucleophiles attack the metal
center and decarbonylation produces intermediate B. Finally,
reductive elimination from B can form coupling products.
However, in an alternative pathway from intermediate A, if
decarbonylation occurred without an external nucleophile,
diaryl ethers could be obtained by reductive elimination
through intermediate C. Capitalizing on this blueprint, we
herein report a de novo synthesis of diaryl ethers by decar-
bonylation from aromatic esters.
Firstly, we attempted to react many aromatic esters under
our catalytic nickel protocol7 without additional nucleophiles.
After extensive screening, we found that phenyl picolinate
(1Aa) was converted to 2-phenoxypyridine (2Aa) under
Ni(cod)2
(5
mol%),
dcype
[1,2-
bis(dicyclohexyl)phosphino]ethane, 10 mol%], and K3PO4
(1.5 equiv) in toluene at 150 ºC for 18 h in 37% isolated yield
(Table 1, entry 1).9 When we changed the ligand to other di-
phosphine ligands such as dppf (entry 2) and BINAP (entry 3),
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the reaction completely shut down, and only starting material
was obtained in 62% yield (entry 17), but after optimizing the
reaction conditions further, dcppt [3,4-
1
2
3
4
5
6
7
8
was recovered. Monophosphines PPh3 (entry 4), PCy3 (entry
5), and P(n-Bu)3 (entry 6) as well as bipy (entry 7) also led to
no reaction. Although NHC ligands, e.g., IPr and ICy were
reported to be effective for the C–heteroatom bond activa-
tion,8h,9 they did not work at all in this reaction (entries 8 and
9). Finally, dcypt [3,4-bis(dicyclohexylphosphino)thiophene],
which was developed by our group,10 was found to dramatical-
ly increase the yield, affording 2Aa in 90% yield (entry 10).
bis(dicyclopentylphosphino)thiophene] as the ligand and
K3PO4 as the base led to 2Aa in 82% yield (entry 18).11
Under the established conditions, the substrate scope for
this nickel- or palladium-catalyzed decarbonylative diaryl
ether synthesis was examined (Table 2). The phenyl group on
the picolinate was changed to 4-methoxyphenyl, 4-
fluorophenyl, 4-cyanophenyl, 4-trifluoromethylphenyl and 4-
trifluoromethyloxyphenyl to give 2-arenoxypyridines (2Ab–
2Af) in good to moderate yields. Disubstituted aryl groups on
the picolinate such as 3,5-dimethylphenyl and 3,5-
dimethoxyphenyl worked well to afford arenoxypyridines 2Ag
(69% by Ni) and 2Af (80% by Ni). Even if the aryl group has
a substituent on the ortho position, decarbonylative etherifica-
tion proceeded to furnish the corresponding products 2Ai–
2Ak. Reactive functional groups on the aryl moiety such as
amines, ketones, methyl esters, and amides were tolerated to
give diaryl ethers 2Am–2Ao in good yields. For these sub-
strates, dcypt instead of dcppt, and different bases (CsF or KF)
for palladium catalysis gave better yields. Additionally, elec-
tron-deficient aryl groups such as 2,6-difluorophenyl, as well
as a naphthalenyl group still reacted to form 2Ap (54% by Ni)
and 2Aq (64% by Pd), respectively. Substituents on the pyri-
dine portion of the starting material such as 3-methyl, 6-
methyl, 6-methoxy, and 5-trifluoromethyl gave the corre-
sponding diaryl ethers 2Ba, 2Ca, 2Da, 2Ea in good to excel-
lent yields. Next, we screened other phenyl azinecarboxylates.
Although phenyl pyrazinecarboxylate gave 2Fa in moderate
yield, quinoline, quinoxaline and their derivatives afforded the
corresponding 2-phenoxyazines 2Ga, 2Ha, 2la, and 2Ja in
nearly quantitative yields. Unfortunately, this reaction only
proceeds generally on aryl 2-azinecarboxylates, but specific
aryl 4-azinecarboxylates did react under palladium catalysis to
give 2Ka and 2Kb in good yields. Furthermore, azinecarbox-
ylates derived from natural products such as estrone and
tocopherol can be etherified under the standard conditions to
form diaryl ethers 2Ar (62% by Ni) and 2ls (93% by Pd),
respectively. While palladium catalysis generally gave slightly
lower yields compared to nickel catalysis, both modes of ca-
talysis gave the desired product, otherwise the starting materi-
al was recovered. Although it remains unclear why 2-
azinecarboxylates discretely work well in this reaction, a plau-
sible reason can be elaborated as follows: i) typically, reduc-
tive elimination from Ar–M–OAr’ intermediate C is the rate-
determining step for the formation of Ar–OAr’; and ii) it is
known that the reductive elimination is faster using 2-azine–
M–OR than for 3-azine and 4-azine,12 possibly accelerated by
the electron-withdrawing nature of a 2-azinyl group bestowing
a greater positive charge and destabilizing the metal center.
Table 1. Screening of the reaction conditions.a
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Entry Metal Ligand
Base
Solvent
toluene
toluene
toluene
toluene
toluene
2Aa/%b
Ni
Ni
Ni
Ni
Ni
Ni
1
2
3
4
5
dcype
dppf
K3PO4
K3PO4
37
0
BINAP K3PO4
0
PPh3
PCy3
K3PO4
K3PO4
0
0
P(n-
6
K3PO4
toluene
0
Bu)3
7
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Pd
Pd
bipy
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
CsF
toluene
toluene
toluene
toluene
dioxane
THF
0
8
IPr
0
9
ICy
0
10
11
12
13
14
15
16
17
18
dcypt
dcypt
dcypt
dcypt
dcypt
dcypt
dcypt
dcypt
dcppt
90
79
67
20
90
82
74
62
82c
DMF
toluene
Na2CO3 toluene
–
toluene
toluene
toluene
CsF
K3PO4
aUnless otherwise noted, the reactions conditions were as fol-
lows: 1Aa (0.40 mmol), Ni(cod)2 (5 mol%) or Pd(OAc)2 (10
mol%), ligand (bidentate: 10 mol%, monodentate: 20 mol%),
b
base (1.5 equiv), solvent (1.6 mL), 150 °C for 18 h. Isolated
yield. c140 °C for 12 h.
Next, we conducted experiments to showcase the utility
of this reaction in a variety of settings (Scheme 2). This decar-
bonylative etherification can be applied on gram-scale
(Scheme 2A). For example, 1Ga (6.5 mmol) was subjected to
this reaction under Ni catalysis using anisole as solvent to
afford the desired product 2Ga in 91% yield (1.31 g of prod-
uct).
Regarding the solvent, it can be changed to 1,4-dioxane, THF,
and DMF, albeit in decreased yields (entries 11–13). When the
base was changed CsF (entry 14) and Na2CO3 (entry 15), the
yield was the same or slightly decreased, and even without
base, the desired product 2Aa can be obtained in 74% yield
(entry 16). When the metal catalyst was changed from nickel
to palladium [Pd(OAc2)] (same conditions as entry 13), 2Aa
Table 2. Decarbonylative diaryl ether synthesis.a
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aUnless otherwise noted, reactions conditions were as follows: [Ni]: 1 (0.40 mmol) , Ni(cod)2 (5 mol%), dcypt (10 mol%), K3PO4
(1.5 equiv), toluene (1.6 mL), 150°C, 18 h. [Pd]: 1 (0.40 mmol), Pd(OAc)2 (5 mol%), dcppt (10 mol%), K3PO4 (1.5 equiv), toluene
(1.6 mL), 150°C, 18 h. bdcypt (5 mol%) was used instead of dcppt. CsF (2.0 equiv) was used instead of K3PO4 (1.5 equiv). cdcypt (5
mol%) was used instead of dcppt. KF (2.0 equiv) was used instead of K3PO4 (1.5 equiv). MS 3Å was used as an additive. d170°C.
material is available free of charge via the Internet at
Additionally, when an azinecarboxylate with bulky aryl sub-
http://pubs.acs.org. The Supporting Information is available free
of charge on the ACS Publications website.
stituents such as 1Gt was used, cross-etherification was made
possible with 4-methoxyphenol to furnish 2Gb in 75% yield
(Scheme 2B). Finally, site-selective decarbonylative etherifica-
tion was achieved (Scheme 2C): a diphenyl azinedicarboxylate
was treated under nickel catalysis to afford aryl ether 2La in
83% yield with exclusive C2-selectivity. Subsequently, 2La
was reacted with 4-methoxyphenyl boronic acid using a
Ni(OAc)2/P(n-Bu)3 catalyst and Na2CO3 in toluene to give
AUTHOR INFORMATION
Corresponding Author
* itami@chem.nagoya-u.ac.jp, junyamaguchi@waseda.jp
ACKNOWLEDGMENT
coupling
product
2Ma
in
66%
yield
by
a
de(phenoxy)carbonylative Suzuki–Miyaura cross-coupling.7b
This work was supported by JSPS KAKENHI Grant Number
JP16H01011, and JP16H04148 (to J. Y.), the ERATO program
from JST (to K. I.), the Early Bird Program of Waseda Univer-
sity (to K. M.), and a JSPS research fellowship for young sci-
entists (to R. T.). We thank Dr. Yoshihiro Ishihara (Vertex
Pharmaceuticals) for fruitful discussion and critical comments.
ITbM is supported by the World Premier International Re-
search Center (WPI) Initiative, Japan.
In conclusion, we have developed the first decarbonyla-
tive ether synthesis by nickel or palladium catalysis. Use of
our in-house ligands, dcypt and dcppt, were critical for this
reaction, in which a variety of aryl azinecarboxylates lead to
the corresponding 2-arenoxyazines by decarbonylation. Fur-
ther optimization of reaction conditions to achieve a broader
scope is ongoing in our laboratory.
Scheme 2. (A) Gram-scale decarbonylative diaryl ether syn-
thesis. (B) Cross-decarbonylative etherification. (C) Site-
selective decarbonylative etherification and decarbonylative
Suzuki–Miyaura coupling.
ASSOCIATED CONTENT
Supporting Information
Detailed experimental procedures, and spectral data for all com-
1
pounds, including scanned images of H, 13C NMR spectra. This
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(11) See Supporting Information for further experimental details.
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