N - And O -arylation of pyridin-2-ones with diaryliodonium salts: Base-dependent orthogonal selectivity under metal-free conditions

Article abstract of DOI:10.1039/d0sc02516j

Metal-free N- and O-arylation reactions of pyridin-2-ones as ambident nucleophiles have been achieved with diaryliodonium salts on the basis of base-dependent chemoselectivity. In the presence of N,N-diethylaniline in fluorobenzene, pyridin-2-ones were very selectively converted to N-arylated products in high yields. On the other hand, the O-arylation reactions smoothly proceeded with the use of quinoline in chlorobenzene, leading to high yields and selectivities. In these methods, a variety of pyridin-2-ones in addition to pyridin-4-one and a set of diaryliodonium salts were accepted as suitable reaction partners.

Full text of DOI:10.1039/d0sc02516j

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DOI: 10.1039/D0SC02516J
ARTICLE
N- and O-Arylation of Pyridin-2-ones with Diaryliodonium Salts:
Base-Dependent Orthogonal Selectivity under Metal-Free
Conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Masami Kuriyama,* Natsumi Hanazawa, Yusuke Abe, Kotone Katagiri, Shimpei Ono, Kosuke
Yamamoto and Osamu Onomura*
DOI: 10.1039/x0xx00000x
Metal-free N- and O-arylation of pyridin-2-ones as ambident nucleophiles have been achieved with diaryliodonium salts on
the basis of base-dependent chemoselectivity. In the presence of N,N-diethylaniline in fluorobenzene, pyridin-2-ones were
very selectively converted to N-arylated products in high yields. On the other hand, the O-arylation reactions smoothly
proceeded with the use of quinoline in chlorobenzene, leading to high yields and selectivities. In these methods, a variety
of pyridin-2-ones in addition to pyridin-4-one and a set of diaryliodonium salts were accepted as suitable reaction partners.
idin-2-one with aryl iodides (Scheme 1b).12 However, this type
of selectivity-switchable arylation via cross-coupling for N,O-
nucleophiles including aminoalcohols, aminophenols, and tau-
Introduction
Carbon-heteroatom bond forming reactions are one of the fun-
damental transformations in organic synthesis.1 Especially, N-
and O-arylation reactions have been pursued with great vigor
because of their wide utilization in pharmaceutical research and
process development.2,3 Pyridin-2-ones are an ambident nucle-
ophile containing an amide moiety and their arylated products
such as N-aryl pyridin-2-ones and O-aryl 2-hydroxypyridines are
important substructures in bioactive compounds.4,5 Therefore,
N- or O-arylation of pyridin-2-ones has been studied under cata-
lytic and non-catalytic conditions.6-8 In the transition metal-cat-
alyzed methods,6 the O-arylation was realized by using 6-sub-
stituted pyridin-2-ones to suppress the formation of N-arylated
products. As a metal-free process, Mukaiyama achieved the N-
arylation with organobismuth reagents.7a While Gaunt reported
the preparation of 2-phenoxypyridine with the use of diphenyl-
iodonium fluoride,7c Mo developed the metal-free O-arylation
of 6-substituted pyridin-2-ones.7b The utilization of appropriate
catalysts and reagents is a promising approach to control che-
moselectivity for ambident nucleophiles,9,10 and the orthogonal
selectivity in arylation reactions of N,O-nucleophiles has been
realized with transition-metal catalysts to give simple and useful
methods.11 For example, the chemoselectivity in the formation
of arylated aminophenols largely depended on the kind of
catalyst metals,11a while bidentate ligands for a copper catalyst
played key roles in the selective arylation of aminoalcohols
(Scheme 1a).11b Buchwald found that copper catalysts had the
ability to switch the selectivity for the N- and O-arylation of pyr-
tomerizable amides has not been developed under metal-free
conditions in spite of its attractive potential in terms of green
chemistry.13 Among hypervalent halogen compounds,14 diaryl-
iodonium salts have recently received much attention as mild,
less-toxic, and easily accessible arylating agents.15 By leveraging
their beneficial features, transition metal-free carbon-hetero-
atom bond forming reactions have been actively pursued.16,17
Herein, we report metal-free N- and O-arylation of pyridin-2-
(a) Metal-catalyzed selective arylation for N,O-nucleophiles
N,N-ligand
cat. CuI
O,O-ligand
cat. CuI
H
ArO
NH2
n
HO
NH2
n
HO
N
Ar
n
Cs2CO3
Cs2CO3
+
ArI
H
N
ArO
NH2
HO
NH2
HO
Ar
Cu cat.
K3PO4
Pd cat.
NaOt-Bu
+
ArX
(b) Metal-catalyzed selective arylation for pyridin-2-one
N,O-ligand
cat. CuI
N,N-ligand
cat. CuI
N
O
N
H
O
N
O
K2CO3
K2CO3
Ar
Ar
+
up to 4.8:1.0
ArI
up to 1.8:1.0
(c) This work: metal-free selective arylation for pyridin-2-ones
R
R
R
quinoline
ClPh
Et2NPh
FPh
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi,
Nagasaki 852-8521, Japan.
E-mail: mkuriyam@nagasaki-u.ac.jp; onomura@nagasaki-u.ac.jp
Electronic Supplementary Information (ESI) available: Experimental details and
spectroscopic data. CCDC 1999363-1999364 and CCDC 1999366. For ESI and crystal-
lographic data in CIF or other electronic format See DOI: 10.1039/x0xx00000x
N
O
N
H
O
N
O
Ar
Ar
+
up to >20:1
Ar2IOTf
up to >20:1
Scheme 1 Selectivity-switchable arylation for N,O-nucleophiles
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Page 2 of 13
ARTICLE
Journal Name
Table 1 Initial screening of basesa
Table 2 Optimization for N-arylationa
base (2 equiv)
View Article Online
DOI: 10.1039/D0SC02516J
base (2 equiv)
Ph2IOTf
Ph2IOTf
+
+
+
+
solvent (1 mL)
100 °C, 16 h
toluene (2 mL)
100 °C, 16 h
N
H
O
N
O
N
O
N
H
O
N
O
N
O
Ph
Ph
Ph
Ph
1a
2a
3aa
4aa
1a
2a
3aa
4aa
(0.5 mmol)
(1.2 equiv)
(0.5 mmol)
(1.2 equiv)
entry
1
2
3
4
5
6
7
8
base
none
pyridine
DIPEA
DABCO
DBU
Na2CO3
K2CO3
Cs2CO3
NaHCO3
KF
3aa (%)
10
2
80
4
57
46
59
56
70
42
65
43
4aa (%)
11
28
9
3aa : 4aa
48 : 52
7 : 93
entry
1
2
3
4
5
6
7
8
base
solvent
toluene
toluene
toluene
toluene
toluene
dioxane
DMA
DMSO
FPh
ClPh
FPh
FPh
3aa (%)
86
85
88
77
30
83
73
43
90(90)b
85
81
75
4aa (%)
DIPEA
n-Bu3N
Et2NPh
Me2NPh
MeNPh2
Et2NPh
Et2NPh
Et2NPh
Et2NPh
Et2NPh
DIPEA
6
4
6
3
7
4
8
4
90 : 10
67 : 33
70 : 30
72 : 28
66 : 34
67 : 33
78 : 22
55 : 45
65 : 35
67 : 33
2
24
18
31
27
20
35
35
21
9
9
trace(trace)b
10
11
12
10
11
12
6
4
6
K3PO4
KOt-Bu
n-Bu3N
a
a Reaction conditions: 1a (0.5 mmol), Ph2IOTf (1.2 equiv), base (2 equiv), toluene
(2 mL), 100 °C, 16 h.
Reaction conditions: 1a (0.5 mmol), Ph2IOTf (1.2 equiv), base (2 equiv), solvent
(1 mL), 100 °C, 16 h. b 85 °C
ones with diaryliodonium salts based on base-dependent che- selectivity, although 3aa was formed in chlorobenzene with a
moselectivity (Scheme 1c).
slightly reduced yield (entries 9-10). DIPEA and n-Bu3N were
also examined in fluorobenzene only to afford lower yields of
3aa as compared to N,N-diethylaniline (entries 11-12).
Results and discussion
Subsequently, the reaction conditions for the selective O-aryl-
ation were optimized at a higher temperature (Table 3). The
influences of pyridine and related compounds18 were tested in
toluene. The use of pyridine and 2,6-lutidine gave the O-phenyl-
ated product 4aa in moderate yields with good selectivites, and
2,6-lutidine led to a slightly better result (entries 1-2). Pyrazine
caused a significant decrease in yield, while isoquinoline pro-
vided the almost same result as pyridine (entries 3-4). In the
presence of quinoline, 4aa was obtained with a high selectivity
At the first setout, the effects of organic and inorganic bases
were investigated in the phenylation of pyridin-2-one (1a) with
diphenyliodonium triflate (2a) (Table 1). In the absence of
bases, the N-phenylated product 3aa and O-phenylated product
4aa were obtained in low yields with no selectivity (entry 1). The
examination of organic bases proved that the reaction condi-
tions with pyridine gave the O-phenylated product 4aa with a
high selectivity despite a low yield, while the highly selective
formation of the N-phenylated product 3aa was observed with
a high yield in the presence of DIPEA (entries 2-3). The use of
DABCO and DBU afforded the mixtures of 3aa and 4aa with low
selectivities (entries 4-5). In the screening of inorganic bases,
the N-phenylated product 3aa was obtained as a major product
in moderate to good yields with low to moderate selectivities
(entries 6-12). Sodium bicarbonate conduced to a better selec-
tivity than the other inorganic bases only to give 3aa and 4aa in
the ratio of 78:22 (entry 9).
Table 3 Optimization for O-arylationa
base (2 equiv)
Ph2IOTf
+
+
solvent (2 mL)
110 °C, 16 h
N
H
O
N
O
N
O
Ph
Ph
1a
(1 mmol)
2a
3aa
4aa
(1.2 equiv)
The findings of the initial screening encouraged us, and the opti-
mization of conditions for the selective N-arylation were con-
ducted at a higher concentration (Table 2). In the examination
of tertiary amines, the N-phenylated product 3aa was obtained
in high yields and selectivities when using trialkyl amines such
as DIPEA and n-Bu3N (entries 1-2). N,N-Diethylaniline led to a
slightly better yield of 3aa, while a decrease in yield was ob-
served in the presence of N,N-dimethylaniline or N-methyldi-
phenylamine (entries 3-5). Then, a series of solvents were inves-
tigated with N,N-diethylaniline. More polar solvents exhibited a
tendency to give 3aa in lower yields (entries 3 and 6-8). The use
of fluorobenzene resulted in 90% yield of 3aa with an excellent
entry
1
2
3
4
5
6
7
8
base
pyridine
2,6-lutidine
pyrazine
isoquinoline
quinoline
quinoline
quinoline
quinoline
quinoline
quinoline
solvent
toluene
toluene
toluene
toluene
toluene
dioxane
DMA
3aa (%)
4aa (%)
41
51
18
40
47
18
12
4
5
6
2
5
2
1
9
4
2
DMSO
FPh
ClPh
9
10
20
79(96)b
trace(trace)b
a Reaction conditions: 1a (1 mmol), Ph2IOTf (1.2 equiv), base (2 equiv), solvent (2
mL), 110 °C, 16 h. b 130 °C
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
ARTICLE
Table 4 Selective N-arylation of pyridin-2-ones with diaryliodonium salts
Table 5 Selective O-arylation of pyridin-2-ones with diaryliodonium salts
View Article Online
DOI: 10.1039/D0SC02516J
Et2NPh (2 equiv)
quinoline (2 equiv)
Ar2IOTf (2: 1.2 equiv)
Ar2IOTf (2: 1.2 equiv)
R
R
R
R
R
R
FPh (1 mL)
85 °C, 16 h
ClPh (2 mL)
130 °C, 16 h
N
H
O
N
Ar
3
O
N
O
N
H
O
N
O
N
Ar
3
O
Ar
Ar
1
4
1
4
(1 mmol)
(0.5 mmol)
Me
Cl
F3C
n-BuO2C
Me
Cl
F3C
n-BuO2C
N
O
N
O
N
O
N
O
N
O
N
O
N
O
N
O
O
O
O
3ba: 88%a,b
(4ba: 2%)
3ca: 89%b,c
(4ca: trace)
3da: 90%a,b,c
(4da: trace)
4ba: 92%
(3ba: trace)
4ca: 87%
(3ca: trace)
4da: 73%a
(3da: 0%)
4ea: 87%a,b
(3ea: 0%)
3ea: 94%
(4ea: 2%)
Cl
Cl
Me
OMe
F
Me
OMe
F
N
O
N
O
N
O
N
O
N
O
N
O
N
O
O
O
N
4ga: 81%c
(3ga: trace)
4ha: 90%a
(3ha: 4%)
4ia: 82%
(3ia: 2%)
3fa: 71%d
(4fa: 3%)
3ga: 87%a,c,e
(4ga: 4%)
3ha: 88%
(4ha: 3%)
3ia: 89%
(4ia: 2%)
4fa: 90%
(3fa: 0%)
O
MeO
N
O
O
N
O
N
O
Cl
N
O
N
N
N
N
4la: 70%d,e
(3la: 0%)
4ka: 83%f
(3ka: 2%)
3ja: 33%f
(4ja: 0%)
3ka: 65%g
(4ka: 0%)
3ab: 84%
(4ab: 0%)
3ac: 90%a,h
OMe
4ah: 95%
(3ah: trace)
4ai: 99%
(3ai: trace)
t-Bu
CF3
Me
N
(4ac: 0%)
N
O
N
O
N
O
N
O
N
F
O
N
O
N
Me
MeO
CO2Et
4ad: 91%a
(3ad: 0%)
4ae: 96%
(3ae: trace)
4aj: 96%e
(3aj: trace)
4ak: 99%
(3ak: trace)
3ad: 88%a
(4ad: 0%)
3ae: 73%b,c
(4ae: trace)
3af: 85%i
(4af: 3%)
3ag: 75%b,j
(4ag: 8%)
F
Cl
CO2Me
Cl
a 1,2-Cl2Ph, 140 °C. b Ph2IOTf (1.5 equiv). c 8 h. d Ph2IOTf (2.5 equiv). e 0.25 mmol
scale. f 1 h.
a
b
c
d
1 mmol scale. Et2NPh (2.5 equiv). 100 °C. DIPEA (2.5 equiv), Ph2IBF4 (1.2
e
f
g
equiv). DIPEA (3 equiv), 2-fluorotoluene. ClPh, 130 °C. Ph2IOTf (1 equiv).
h (4-MeOPh)2IBF4 (1.2 equiv). i (3-EtO2CPh)2IBF4 (1.2 equiv). j (2-MeOPh)2IBF4 (1.2
equiv).
one, 6-chloropyridin-2-one afforded only the N-phenylated
product in 33% yield (3ia-ja). On the other hand, pyridin-4-one
was found to be a good reaction partner for this transformation
(3ka). In addition, the investigation of diaryliodonium salts was
carried out. A diaryliodonium triflate and tetrafluoroborate
bearing an electron-donating group led to high yields of the N-
arylated products (3ab-ac). Electron-withdrawing substituents
such as fluoro, chloro, and ester groups caused no serious dif-
ficulty (3ad-af). In the presence of steric hindrance close to a
reactive site, the desired product was obtained in 75% yield
with a relatively lower selectivity (3ag). In most cases, quite high
selectivities (> 20:1) were observed except for the selective for-
mation of 3ag.
The examination of pyridin-2-ones and diaryliodonium salts was
conducted in the selective O-arylation (Table 5). Most of the 5-
substituted substrates bearing an electron-donating or -with-
drawing group gave high yields (4ba-ca and 4ea), although a
slight decrease in yield was observed in the presence of a tri-
fluoromethyl group (4da). Even under the electronic and steric
despite a slightly lower yield as compared to 2,6-lutidine (entry
5). Then, the examination of solvents was conducted with quin-
oline. More polar solvents such as dioxane, DMA, and DMSO
conduced to decreased yields of 4aa (entries 6-8). Although
fluorobenzene was not suitable for the O-phenylation of pyri-
din-2-one, chlorobenzene gave 4aa in high yields with excellent
selectivities especially at a higher temperature (entries 9-10).19
The influence of varying pyridin-2-ones and diaryliodonium salts
was studied in the selective N-arylation (Table 4). The transfor-
mation of 5-methylpyridin-2-one (1b) proceeded smoothly to
give the desired product in a high yield (3ba).20 Pyridin-2-ones
with an electron-withdrawing group at the 5-position were con-
verted with no problem, and an ester moiety proved to be toler-
ated under the conditions (3ca-ea). In the examination of 3-sub-
stituted substrates, electron-donating and -withdrawing groups
gave no significant decrease in yield (3fa-ha).21 Whereas a high
yield was observed in the N-phenylation of 4-chloropyridin-2-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Page 4 of 13
ARTICLE
Journal Name
2a (1.2 equiv)
Et2NPh (2.5 equiv)
(a) Substituent influences in N-arylation
Me
Me
Me
View Article Online
+
DOI: 10.1039/D0SC02516J
+
additive (1 equiv)
FPh (2 mL)
85 °C, 16 h
1a (0.5 mmol)
N
H
O
N
O
N
O
Et2NPh (2 equiv)
N
O
N
O
MeO
I
OTf
Ph
Ph
FPh (1 mL)
100 °C, 16 h
1b
(1 mmol)
3ba
88%
85%
86%
86%
4ba
2%
3%
1%
1%
(none)
2l
(1.2 equiv)
(BHT)
(DHA)
(DPE)
3ac
35%
3ai
44%
OMe
N
CF3
N
CF3
2a (1.2 equiv)
quinoline (2 equiv)
Me
Me
Me
+
1a (0.5 mmol)
Et2NPh (2.5 equiv)
+
Me
I
OTf
Me
O
O
additive (1 equiv)
ClPh (2 mL)
130 °C, 16 h
N
H
O
N
O
N
O
Me
FPh (1 mL)
85 °C, 16 h
Ph
Ph
1b
(1 mmol)
3ba
4ba
92%
83%
91%
90%
2m
(1.2 equiv)
3ab
61%
3ak
19%
trace
trace
trace
trace
(none)
Me
(BHT)
(DHA)
(DPE)
(b) Substituent influences in O-arylation
Scheme 4 N- and O-arylation in the presence of radical scavengers
+
1a (0.5 mmol)
quinoline (2 equiv)
MeO
I
OTf
N
O
N
O
ClPh (1 mL)
130 °C, 16 h
the selective N-arylation (Scheme 2a). When a diaryliodonium
triflate with an electron-donating and -withdrawing group was
employed, the N-arylated products 3ac and 3ai were obtained
in 35% and 44% yields, respectively. In the examination of steric
effects in an arylating agent, the diaryliodonium triflate 2m
favorably transferred 4-methylphenyl group to pyridin-2-one,
providing a 3.2:1 ratio of 3ab:3ak. While the anti-ortho effect
was observed, the electronic effect was not pronounced unlike
the reported N-arylation of amides.22 A similar investigation was
conducted in the selective O-arylation (Scheme 2b). The use of
the diaryliodonium triflate 2l caused the selective formation of
the CF3-containing product in a high yield with a 1:27 ratio of
4ac:4ai. A preferential transfer of 2-methylphenyl group from
the aryl source 2m was observed to give 4ab and 4ak in 9% and
84% yields, respectively. These results had a similar tendency to
those in the reported arylation of phenols.23 Besides, the scala-
bility of these transformations was studied in a 10 mmol scale,
and the desired products were obtained with high yields in both
the selective N- and O-phenylation of pyridin-2-one (Scheme 3).
To obtain further information on these methods, 2,6-di-tert-
butyl-4-methylphenol (BHT), 9,10-dihydroanthracene (DHA),
and 1,1-diphenylethylene (DPE) were employed as radical scav-
engers (Scheme 4). The N- and O-phenylation of the substrate
1b smoothly proceeded with high selectivities even in the pres-
ence of these radical trapping reagents, which suggested that
single electron transfer processes might not be included.22,23
Because the reaction mechanism for the carbon-heteroatom
bond formation with diaryliodonium salts has been proposed
on the basis of the T-shaped intermediate A in the literature
(Scheme 5a),16,17 the ligand exchange at the iodine center of 2a
using the sodium salt of the pyridin-2-one 1d was carried out to
afford the iodonium salt 5 (Scheme 5b).24 According to X-ray
analysis, the compound 5 basically possesses the T-shaped
structure with the NI bond length of 2.740 Å and the NIC
bond angle of 168.93°. The carbon-oxygen distance of 1.286 Å
is closer to the C=O bond length.21 The small deviation of the N
IC bond angle from linearity and slightly longer C=O bond
length might result from a partial electron delocalization in the
amidate moiety. The iodonium salt 5 was subjected to the N-
arylation conditions to give the N-phenylated product 3da in a
2l
(1.2 equiv)
4ac
3%
4ai
81%
OMe
CF3
O
CF3
+
1a (1 mmol)
quinoline (2 equiv)
Me
I
OTf
Me
N
O
N
Me
ClPh (2 mL)
130 °C, 16 h
2m
(1.2 equiv)
4ab
9%
4ak
84%
Me
Scheme 2 Substituent influences of diaryliodonium triflates on aryl group transfer
preference in N-arylation and O-arylation
influences of substituents at the 3-position, the O-arylated
products 4fa-ha were also obtained uneventfully. The transfor-
mation of 6-methoxypyridin-2-one as well as 4-chloropyridin-2-
one was carried out with favorable results (4ia and 4la). More-
over, pyridin-4-one proved to be a suitable substrate for the
selective O-arylation (4ka). Subsequently, a set of diaryliodo-
nium triflates were investigated. Aryl moieties with a substitu-
ent such as alkyl, trifluoromethyl, and halogen groups were
efficiently transferred to an oxygen atom of pyridin-2-one (4ah-
ai and 4ad-ae). Neither an ester group nor ortho-methyl group
led to harmful effects, affording 4aj and 4ak in high yields with
almost no side product. In all cases, the O-arylated products
were formed with excellent selectivities (> 20:1).
To explore the influences of substituents on aryl group transfer
preference, unsymmetrical diaryliodonium salts were tested in
Et2NPh (2 equiv)
Ph2IOTf
+
FPh (20 mL)
85 °C, 16 h
N
H
O
N
O
Ph
1a
2a
3aa
(10 mmol)
(1.2 equiv)
91% (1.55 g)
quinoline (2 equiv)
Ph2IOTf
+
ClPh (20 mL)
130 °C, 16 h
N
H
O
N
O
Ph
1a
2a
4aa
(10 mmol)
(1.2 equiv)
97% (1.67 g)
Scheme 3 Examination of the scalability for N- and O-arylation
4 | J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
(a) Proposed mechanism
Conflicts of interest
There are no conflicts to declare.
View Article Online
DOI: 10.1039/D0SC02516J
Nu
H
TfO
I
Ar
Nu
I
Ar
Nu Ar
Ar
Ar
A
ligand exchange
ligand coupling
Acknowledgements
(b) Synthesis of diphenyliodonium 2-oxo-pyridin-1-ide 5
This research was supported by JSPS KAKENHI (18K06582,
19K16317, and 19K05459) and Research Grant for Pharmaceu-
tical Sciences from Takeda Science Foundation. We are grateful
to Prof. T. Dohi of Ritsumeikan University for his helpful advice.
The data collection was conducted with the research equipment
shared in MEXT Project for promoting public utilization of ad-
vanced research infrastructure (Program for supporting intro-
duction of the new sharing system: JPMXS0422500320).
F3C
F3C
Na
O
F
N
N
I
O
N
(10 equiv)
O
Ph2IOTf
CH2Cl2/H2O
0 °C, 12 h
I
2a
5
85% yield
(c) Control experiments with 5
base
Notes and references
F3C
F3C
F3C
+
(2.5 equiv)
1
(a) Arene Chemistry: Reaction Mechanisms and Methods for
Aromatic Compounds, ed. J. Mortier, Wiley, Hoboken, 2016;
(b) J. X. Qiao and P. Y. S. Lam, Synthesis, 2011, 43, 829-856; (c)
I. P. Beletskaya and A. V. Cheprakov, Coord. Chem. Rev., 2004,
248, 2337-2364.
FPh (1 mL)
100 °C, 16 h
N
I
O
N
O
N
O
Ph
Ph
Ph
N-arylation
conditions
4da
14%
14%
3da
74%
74%
Ph
5
(none)
(Et2NPh)
2
3
(a) G. Evano, J. Wanga and A. Nitelet, Org. Chem. Front., 2017,
4, 2480-2499; (b) P. Ruiz-Castillo and S. L. Buchwald, Chem.
Rev., 2016, 116, 12564-12649; (c) B. Schlummer and U. Scholz,
Adv. Synth. Catal., 2004, 346, 1599-1626.
(a) S. Bhunia, G. G. Pawar, S. V. Kumar, Y. Jiang and D. Ma,
Angew. Chem. Int. Ed., 2017, 56, 16136-16179; (b) F. Monnier
and M. Taillefer, Angew. Chem. Int. Ed., 2009, 48, 6954-6971;
(c) S. V. Ley and A. W. Thomas, Angew. Chem. Int. Ed., 2003,
42, 5400-5449.
(0.5 mmol)
base
(2.0 equiv)
F3C
F3C
F3C
+
1,2-Cl2Ph (1 mL)
140 °C, 16 h
N
I
O
N
O
N
O
Ph
Ph
Ph
O-arylation
conditions
3da
58%
59%
4da
35%
33%
Ph
5
(none)
(quinoline)
(0.5 mmol)
4
5
(a) J. L. Engers, K. A. Bollinger, R. L. Weiner, A. L. Rodriguez, M.
F. Long, M. M. Breiner, S. Chang, S. R. Bollinger, M. Bubser, C.
K. Jones, R. D. Morrison, T. M. Bridges, A. L. Blobaum, C. M.
Niswender, P. J. Conn, K. A. Emmitte and C. W. Lindsley, ACS
Med. Chem. Lett., 2017, 8, 925-930; (b) J. Yang, G. Su, Y. Ren
and Y. Chen, Eur. J. Med. Chem., 2015, 101, 41-51; (c) Z. Ma,
Y. Pan, W. Huang, Y. Yang, Z. Wang, Q. Li, Y. Zhao, X. Zhang
and Z. Shen, Bioorg. Med. Chem. Lett., 2014, 24, 220-223.
(a) A. S. Carlson, H. Cui, A. Divakaran, J. A. Johnson, R. M.
Brunner, W. C. K. Pomerantz and J. J. Topczewski, ACS Med.
Chem. Lett., 2019, 10, 1296-1301; (b) T. Ogiyama, M. Yama-
guchi, N. Kurikawa, S. Honzumi, Y. Yamamoto, D. Sugiyama, H.
Takakusa and S. Inoue, Bioorg. Med. Chem., 2017, 25, 2234-
2243; (c) C. M. G. Azevedo, K. R. Watterson, E. T. Wargent, S.
V. F. Hansen, B. D. Hudson, M. A. Kępczyńska, J. Dunlop, B.
Shimpukade, E. Christiansen, G. Milligan, C. J. Stocker and T.
Ulven, J. Med. Chem., 2016, 59, 8868-8878.
N-Arylation (catalytic): (a) S.-H. Jung, D.-B. Sung, C.-H. Park
and W.-S. Kim, J. Org. Chem., 2016, 81, 7717-7724; (b) K. A.
Kumar, P. Kannabonia, C. K. Jaladanki, P. V. Bharatam, P. Das,
ChemistrySelect, 2016, 1, 601-607; (c) C. S. Li and D. D. Dixon,
Tetrahedron Lett., 2004, 45, 4257-4260; O-Arylation (catalyt-
ic): (d) T. Chen, Q. Huang, Y. Luo, Y. Hu and W. Lu, Tetrahedron
Lett., 2013, 54, 1401-1404.
Scheme 5 Synthesis of diaryliodonium salt 5 and control experiments
high yield with a good selectivity, and N,N-diethylaniline show-
ed no significant influence (Scheme 5c). Under the O-arylation
conditions, 3da was obtained from 5 as a major product with a
lower selectivity despite the presence or absence of quinoline.
The interaction between the amidate moiety and iodine center
could play a key role in the selective CN bond formation, but
the decreased selectivity could suggest more than one path-
way.25 Meanwhile, the iodonium salt 5 might not be directly
relevant to the selective O-arylation.
Conclusions
6
In summary, a complementary set of the selective N- and O-
arylation for pyridin-2-ones with diaryliodonium salts has been
developed under metal-free conditions. While N-arylated prod-
ucts were obtained in high yields with high selectivities by using
N,N-diethylaniline in fluorobenzene, the reaction conditions
with quinoline in chlorobenzene led to the highly selective for-
mation of O-arylated products in high yields. These methods
were applicable to various substituted pyridin-2-ones as well as
pyridin-4-one, and a series of diaryliodonium salts proved to be
good reaction partners. Further studies on detailed reaction
mechanism including selectivity and application towards syn-
thesis of bioactive compounds are ongoing in our laboratory.
7
8
N-Arylation (non-catalytic): (a) K. Ikegai and T. Mukaiyama,
Chem. Lett., 2005, 34, 1496-1497; O-Arylation (non-catalytic):
(b) X.-H. Li, A.-H. Ye, C. Liang and D.-L. Mo, Synthesis, 2018, 50,
1699-1710; (c) L. Chan, A. McNally, Q. Y. Toh, A. Mendoza and
M. J. Gaunt, Chem. Sci., 2015, 6, 1277-1281.
The metal-free arylation for quinolin-4-ones depending on
steric effects was reported: M. K. Mehra, M. P. Tantak, V.
Arun, I. Kumar and D. Kumar, Org. Biomol. Chem., 2017, 15,
4956-4961.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Chemical Science
Page 6 of 13
ARTICLE
Journal Name
9
N. A. Afagh and A. K. Yudin, Angew. Chem. Int. Ed., 2010, 49, 25 Olofsson proposed the two possible pathways in the metal-
262-310.
free arylation of amides such as a [1,D2O]-Ir:e1a0r.1r0a3Vn9ieg/weDmA0rSteiCcnl0et2O5an1lni6ndJe
[2,3]-rearrangement in the reference 22.
10 (a) Y. Yamane, K. Miyazaki and T. Nishikata, ACS Catal., 2016,
6, 7418-7425; (b) W.-H. Rao, X.-S. Yin and B.-F. Shi, Org. Lett.,
2015, 17, 3758-3761; (c) T. Xu and H. Alper, J. Am. Chem. Soc.,
2014, 136, 16970-16973; (d) S. Ueda and S. L. Buchwald,
Angew. Chem. Int. Ed., 2012, 51, 10364-10367.
11 (a) D. Maiti and S. L. Buchwald, J. Am. Chem. Soc., 2009, 131,
17423-17429; (b) A. Shafir, P. A. Lichtor and S. L. Buchwald, J.
Am. Chem. Soc., 2007, 129, 3490-3491; (c) G. E. Job and S. L.
Buchwald, Org. Lett., 2002, 4, 3703-3706.
12 R. A. Altman and S. L. Buchwald, Org. Lett., 2007, 9, 643-646.
13 Green and Sustainable Medicinal Chemistry: Methods, Tools
and Strategies for the 21st Century Pharmaceutical Industry,
ed. L. Summerton, H. F. Sneddon, L. C. Jones and J. H. Clark,
Royal Society of Chemistry, Cambridge, 2016.
14 (a) The Chemistry of Hypervalent Halogen Compounds, ed. B.
Olofsson, I. Marek and Z. Rappoport, Weily, Chichester, 2019;
(b) M. Nakajima, K. Miyamoto, K. Hirano and M. Uchiyama, J.
Am. Chem. Soc., 2019, 141, 6499-6503; (c) U. Farooq, A. A.
Shah and T. Wirth, Angew. Chem. Int. Ed., 2009, 48, 1018-
1020.
15 (a) D. R. Stuart, Chem. Eur. J., 2017, 23, 15852-15863; (b) K.
Aradi, B. L. Tóth, G. L. Tolnai and Z. Novák, Synlett, 2016, 27,
1456-1485; (c) E. A. Merritt and B. Olofsson, Angew. Chem.
Int. Ed., 2009, 48, 9052-9070.
16 (a) S. Roshandel, M. J. Lunn, G. Rasul, D. S. M. Ravinson, S. C.
Suri and G. K. S. Prakash, Org. Lett., 2019, 21, 6255-6258; (b)
N. Purkait, G. Kervefors, E. Linde and B. Olofsson, Angew.
Chem. Int. Ed., 2018, 57, 11427-11431; (c) A. H. Sandtorv and
D. R. Stuart, Angew. Chem. Int. Ed., 2016, 55, 15812-15815;
(d) N. Lucchetti, M. Scalone, S. Fantasia and K. Muñiz, Angew.
Chem. Int. Ed., 2016, 55, 13335-13339; (e) M. A. Carroll and R.
A. Wood, Tetrahedron, 2007, 63, 11349-11354.
17 (a) H. Chen, J. Han and L. Wang, Angew. Chem. Int. Ed., 2018,
57, 12313-12317; (b) E. Stridfeldt, E. Lindstedt, M. Reitti, J.
Blid, P.-O. Norrby and B. Olofsson, Chem. Eur. J., 2017, 23,
13249-13258; (c) T. Dohi, D. Koseki, K. Sumida, K. Okada, S.
Mizuno, A. Kato, K. Morimoto and Y. Kita, Adv. Synth. Catal.,
2017, 359, 3503-3508; (d) G. L. Tolnai, U. J. Nilsson and B.
Olofsson, Angew. Chem. Int. Ed., 2016, 55, 11226-11230; (e)
E. Lindstedt, E. Stridfeldt and B. Olofsson, Org. Lett., 2016, 18,
4234-4237; (f) K. Matsuzaki, K. Okuyama, E. Tokunaga, N.
Saito, M. Shiro and N. Shibata, Org. Lett., 2015, 17, 3038-3041;
(g) N. Jalalian, E. E. Ishikawa, L. F. Silva Jr. and B. Olofsson, Org.
Lett., 2011, 13, 1552-1555.
18 Ochiai reported that pyridine acted as a ligand for a diphenyl-
iodonium salt: T. Suefuji, M. Shiro, K. Yamaguchi and M. Ochiai,
Heterocycles, 2006, 67, 391-397.
19 The comparison between the effects of FPh and ClPh is in-
cluded in the electronic supplementary information.
20 The compound 3ba is known as Pirfenidone, a medication
used for idiopathic pulmonary fibrosis: E. S. Kim and G. M.
Keating, Drugs, 2015, 75, 219-230.
21 The X-ray analysis for 3ga and 4ga was carried out (3ga: CCDC
1999363, 4ga: CCDC 1999364). The carbon-oxygen distances:
1.234 Å (3ga) and 1.377 Å (4ga). The data is included in the
electronic supplementary information.
22 F. Tinnis, E. Stridfeldt, H. Lundberg, H. Adolfsson and B.
Olofsson, Org. Lett., 2015, 17, 2688-2691.
23 J. Malmgren, S. Santoro, N. Jalalian, F. Himo and B. Olofsson,
Chem. Eur. J., 2013, 19, 10334-10342.
24 The examples of diaryliodonium salts bearing a nucleophile
were reported in the references 16d, 17c, and the following:
D. I. Bugaenko, M. A. Yurovskaya and A. V. Karchava, Org. Lett.,
2018, 20, 6389-6393.
6 | J. Name., 2012, 00, 1-3
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Page 7 of 13
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DOI: 10.1039/D0SC02516J
Scheme 1
(a) Metal-catalyzed selective arylation for N,O-nucleophiles
N,N-ligand
cat. CuI
O,O-ligand
cat. CuI
H
ArO
NH2
n
HO
NH2
n
HO
N
Ar
n
Cs2CO3
Cs2CO3
+
ArI
H
N
ArO
NH2
HO
NH2
HO
Ar
Cu cat.
K3PO4
Pd cat.
NaOt-Bu
+
ArX
(b) Metal-catalyzed selective arylation for pyridin-2-one
N,O-ligand
cat. CuI
N,N-ligand
cat. CuI
N
O
N
H
O
N
O
K2CO3
K2CO3
Ar
Ar
+
up to 4.8:1.0
ArI
up to 1.8:1.0
(c) This work: metal-free selective arylation for pyridin-2-ones
R
R
R
quinoline
ClPh
Et2NPh
FPh
N
O
N
H
O
N
O
Ar
Ar
+
up to >20:1
Ar2IOTf
up to >20:1
Table 1
base (2 equiv)
Ph2IOTf
+
+
toluene (2 mL)
100 °C, 16 h
N
H
O
N
O
N
O
Ph
Ph
1a
2a
3aa
4aa
(0.5 mmol)
(1.2 equiv)
Table 2
base (2 equiv)
Ph2IOTf
+
+
solvent (1 mL)
100 °C, 16 h
N
H
O
N
O
N
O
Ph
Ph
1a
2a
3aa
4aa
(0.5 mmol)
(1.2 equiv)
Table 3
base (2 equiv)
Ph2IOTf
+
+
solvent (2 mL)
110 °C, 16 h
N
H
O
N
O
N
O
Ph
Ph
1a
(1 mmol)
2a
3aa
4aa
(1.2 equiv)

Chemical Science
Page 8 of 13
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DOI: 10.1039/D0SC02516J
Table 4
Et2NPh (2 equiv)
Ar2IOTf (2: 1.2 equiv)
R
R
R
FPh (1 mL)
85 °C, 16 h
N
H
O
N
Ar
3
O
N
O
Ar
1
4
(0.5 mmol)
Me
Cl
F3C
n-BuO2C
N
O
N
O
N
O
N
O
O
O
O
3ba: 88%a,b
(4ba: 2%)
3ca: 89%b,c
(4ca: trace)
3da: 90%a,b,c
(4da: trace)
3ea: 94%
(4ea: 2%)
Cl
Me
OMe
F
N
O
N
O
N
O
O
O
N
3fa: 71%d
(4fa: 3%)
3ga: 87%a,c,e
(4ga: 4%)
3ha: 88%
(4ha: 3%)
3ia: 89%
(4ia: 2%)
O
Cl
N
O
N
N
N
3ja: 33%f
(4ja: 0%)
3ka: 65%g
(4ka: 0%)
3ab: 84%
(4ab: 0%)
3ac: 90%a,h
OMe
Me
N
(4ac: 0%)
N
F
O
N
O
N
MeO
CO2Et
3ad: 88%a
(4ad: 0%)
3ae: 73%b,c
(4ae: trace)
3ag: 75%b,j
(4ag: 8%)
3af: 85%i
(4af: 3%)
Cl

Page 9 of 13
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DOI: 10.1039/D0SC02516J
Table 5
quinoline (2 equiv)
Ar2IOTf (2: 1.2 equiv)
R
R
R
ClPh (2 mL)
130 °C, 16 h
N
H
O
N
O
N
Ar
3
O
Ar
1
4
(1 mmol)
Me
Cl
F3C
n-BuO2C
N
O
N
O
N
O
N
O
4ba: 92%
(3ba: trace)
4ca: 87%
(3ca: trace)
4da: 73%a
(3da: 0%)
4ea: 87%a,b
(3ea: 0%)
Cl
Me
O
OMe
F
N
N
O
N
O
N
O
4fa: 90%
(3fa: 0%)
4ha: 90%a
(3ha: 4%)
4ia: 82%
(3ia: 2%)
4ga: 81%c
(3ga: trace)
MeO
N
O
O
N
N
O
N
O
4la: 70%d,e
(3la: 0%)
4ka: 83%f
(3ka: 2%)
4ah: 95%
(3ah: trace)
4ai: 99%
(3ai: trace)
t-Bu
CF3
N
O
F
N
O
N
O
N
O
Me
4ad: 91%a
(3ad: 0%)
4ae: 96%
(3ae: trace)
4aj: 96%e
(3aj: trace)
4ak: 99%
(3ak: trace)
Cl
CO2Me

Chemical Science
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DOI: 10.1039/D0SC02516J
Scheme 2
(a) Substituent influences in N-arylation
+
1a (0.5 mmol)
Et2NPh (2 equiv)
N
O
N
O
MeO
I
OTf
FPh (1 mL)
100 °C, 16 h
2l
(1.2 equiv)
3ac
35%
3ai
44%
OMe
N
CF3
N
CF3
+
1a (0.5 mmol)
Et2NPh (2.5 equiv)
Me
I
OTf
Me
O
O
Me
FPh (1 mL)
85 °C, 16 h
2m
(1.2 equiv)
3ab
61%
3ak
19%
Me
(b) Substituent influences in O-arylation
+
1a (0.5 mmol)
quinoline (2 equiv)
MeO
I
OTf
N
O
N
O
ClPh (1 mL)
130 °C, 16 h
2l
(1.2 equiv)
4ac
3%
4ai
81%
OMe
CF3
O
CF3
+
1a (1 mmol)
quinoline (2 equiv)
Me
I
OTf
Me
N
O
N
Me
ClPh (2 mL)
130 °C, 16 h
2m
(1.2 equiv)
4ab
9%
4ak
84%
Me
Scheme 3
Et2NPh (2 equiv)
Ph2IOTf
+
FPh (20 mL)
85 °C, 16 h
N
H
O
N
O
Ph
1a
2a
3aa
91% (1.55 g)
(10 mmol)
(1.2 equiv)
quinoline (2 equiv)
Ph2IOTf
+
ClPh (20 mL)
130 °C, 16 h
N
H
O
N
O
Ph
1a
2a
4aa
(10 mmol)
(1.2 equiv)
97% (1.67 g)

Page 11 of 13
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DOI: 10.1039/D0SC02516J
Scheme 4
2a (1.2 equiv)
Et2NPh (2.5 equiv)
Me
Me
Me
+
additive (1 equiv)
FPh (2 mL)
85 °C, 16 h
N
H
O
N
O
N
O
Ph
Ph
1b
(1 mmol)
3ba
88%
85%
86%
86%
4ba
2%
3%
1%
1%
(none)
(BHT)
(DHA)
(DPE)
2a (1.2 equiv)
quinoline (2 equiv)
Me
Me
Me
+
additive (1 equiv)
ClPh (2 mL)
130 °C, 16 h
N
H
O
N
O
N
O
Ph
Ph
1b
(1 mmol)
3ba
4ba
92%
83%
91%
90%
trace
trace
trace
trace
(none)
(BHT)
(DHA)
(DPE)
Scheme 5
(a) Proposed mechanism
Nu
H
TfO
I
Ar
Nu
I
Ar
Nu Ar
Ar
Ar
ligand exchange
ligand coupling
A
(b) Synthesis of diphenyliodonium 2-oxo-pyridin-1-ide 5
F3C
F3C
Na
O
F
N
N
I
O
N
(10 equiv)
O
Ph2IOTf
CH2Cl2/H2O
0 °C, 12 h
I
2a
5
85% yield
(c) Control experiments with 5
base
F3C
F3C
F3C
+
(2.5 equiv)
FPh (1 mL)
100 °C, 16 h
N
I
O
N
O
N
O
Ph
Ph
Ph
N-arylation
conditions
4da
3da
74%
74%
Ph
5
14%
14%
(none)
(Et2NPh)
(0.5 mmol)
base
(2.0 equiv)
F3C
F3C
F3C
+
1,2-Cl2Ph (1 mL)
140 °C, 16 h
N
I
O
N
O
N
O
Ph
Ph
Ph
O-arylation
conditions
3da
58%
59%
4da
35%
33%
Ph
5
(0.5 mmol)
(none)
(quinoline)

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DOI: 10.1039/D0SC02516J
TOC graphic
Selectivity-switchable arylation under metal-free conditions
R
R
R
quinoline
Et2NPh
N
O
N
H
O
N
O
Ar
Ar
+
up to >20:1
Ar2IOTf
up to >20:1
• high selectivity
• high yields
• broad scope
• gram-scale

Page 13 of 13
Chemical Science
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DOI: 10.1039/D0SC02516J
TOC
Selectivity-switchable arylation under metal-free conditions
R
R
R
quinoline
Et2NPh
N
O
N
H
O
N
O
Ar
Ar
+
up to >20:1
Ar2IOTf
up to >20:1
• high selectivity
• high yields
• broad scope
• gram-scale
The metal-free N- and O-arylation of pyridin-2-ones with diaryliodonium salts were achieved on the
basis of base-dependent chemoselectivity.