Substituent Effects of 2-Pyridones on Selective O-Arylation with Diaryliodonium Salts: Synthesis of 2-Aryloxypyridines under Transition-Metal-Free Conditions

Article abstract of DOI:10.1055/s-0036-1591884

An efficient transition-metal-free strategy to synthesize 2-aryloxypyridine derivatives has been developed by a selective O-arylation of 2-pyridones with diaryliodonium salts. The reaction was compatible with a series of functional groups for 2-pyridones and diaryliodonium salts such as halides, nitro, cyano, and ester groups. The substituents at the C6-position of 2-pyridones favored O-arylation products because of steric hindrance. The reaction was easily performed on a gram-scale and 6-chloro-2-pyridone was a good precursor to access various unsubstituted 2-aryloxypyridines by dehalogenation. A P2Y ₁ lead compound analogue could be prepared in good yield over two steps.

Full text of DOI:10.1055/s-0036-1591884

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–L
paper
A
en
X.-H. Li et al.
Paper
Synthesis
Substituent Effects of 2-Pyridones on Selective O-Arylation with
Diaryliodonium Salts: Synthesis of 2-Aryloxypyridines under
Transition-Metal-Free Conditions
Xiao-Hua Li‡
Ai-Hui Ye‡
O
O
N
R
Ar1
Cs2CO3
Ar1
I
OTf
F
Cui Liang
NH
R
+
O
O
CF3
DCE, 120 °C
Ar2
Dong-Liang Mo*
0
0
0
0
0-
0
0
2
4-
0
0
5
2-
2
4
9
60–99% yields
N
N
N
H
H
F
State Key Laboratory for Chemistry and Molecular Engineering
of Medicinal Resources, Ministry of Science and Technology of
China; School of Chemistry and Pharmaceutical Sciences,
Guangxi Normal University, 15 Yu Cai Road, Guilin 541004,
P. R. of China
@ Exclusively transition-metal-free O-arylation
@ Steric effect controlled regioselectivity
@ Broad substrate scope
Me
Me
51% yield over two steps
@ Good functional group tolerance
moeastlight@mailbox.gxnu.edu.cn
‡ X.-H. Li and A.-H. Ye contributed equally to this work
Received: 03.12.2017
Accepted after revision: 08.12.2017
Published online: 24.01.2018
H
Me
N
N
Me
HO
Me
Me
Me
DOI: 10.1055/s-0036-1591884; Art ID: ss-2017-h0647-op
HN
O
O
F
N
Abstract An efficient transition-metal-free strategy to synthesize
2-aryloxypyridine derivatives has been developed by a selective O-aryla-
tion of 2-pyridones with diaryliodonium salts. The reaction was com-
patible with a series of functional groups for 2-pyridones and dia-
ryliodonium salts such as halides, nitro, cyano, and ester groups. The
substituents at the C6-position of 2-pyridones favored O-arylation
products because of steric hindrance. The reaction was easily per-
formed on a gram-scale and 6-chloro-2-pyridone was a good precursor
to access various unsubstituted 2-aryloxypyridines by dehalogenation.
A P2Y1 lead compound analogue could be prepared in good yield over
two steps.
N
Cl
N
Me
N
N
F
H
H
(CRF) antagonist
PDE10A Inhibitor
CF3
H2N
O
O
NH
O
N
O
N
F
NH
OH
N
F
F
LOXL2 CCM IC50 = 74 nM
P2Y1 antagonist
Key words aryloxypyridine, diaryliodonium salt, O-arylation, 2-pyridone,
substituent effects
Figure 1 Biologically active molecules containing a 2-aryloxypyridine
scaffold
2-Aryloxypyridine is an important class of pyridine de-
rivatives, and is an ubiquitous scaffold existing in many bio-
logically active molecules and pharmaceutical drugs, such
as corticotropin-releasing factor (CRF) antagonist, PDE 10A
inhibitors, lysyl oxidase-like 2 (LOXL2) inhibitors, or P2Y1
antagonist (Figure 1).1
Due to their intriguing biological activity, many studies
were focused on the preparation or modification of 2-aryl-
oxypyridines up to now.2,3 2-Pyridones serving as ambident
nucleophiles (N- or O-atoms as nucleophilic sites) have at-
tracted many chemists’ interest to control the reaction se-
lectivity. In most cases, transition-metal-catalyzed aryla-
tion of 2-pyridones dominantly afforded N-arylation prod-
ucts while only few examples of O-arylation products were
reported.4,5 However, selective O-arylation of 2-pyridones is
a direct strategy to synthesize 2-aryloxypyridines. In 2012,
Luo and co-workers developed a copper-mediated selective
O-arylation of 2-pyridones with arylboronic acids to pro-
vide 2-aryloxypyridines in moderate to good yields
(Scheme 1, A).5a DABCO as a ligand played an important role
in the selective O-arylation of 2-pyridones under copper-
mediated conditions. This method controlled the O-aryla-
tion by using C6-position of 2-pyridones, but the reaction
scope was limited and not tolerated with ortho-substituted
arylboronic acids owing to the sensitive steric effects on the
coupling reaction. In recent years, diaryliodonium salts
serving as useful arylation reagents have been applied ex-
tensively in organic synthesis because of their easy prepa-
ration, high selectivity and reactivity, as well as nontoxici-
ty.6 Arylation of heteroatom nucleophiles was successfully
utilized to construct C–N and C–O bonds in the past de-
cade.7 In 2016, Kim and co-workers reported an efficient
copper-catalyzed coupling of 2-pyridones with diaryliodo-
nium salts under mild conditions, but N-arylation products
were obtained as major products for most of the substitut-
ed 2-pyridones (Scheme 1, B).8 When there were methyl or
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

B
X.-H. Li et al.
Paper
Synthesis
phenyl substituents at C6-position of 2-pyridones, however,
a mixture of N-arylation and O-arylation products were ob-
tained. From the work of Luo and Kim, it was shown that
substituent effects on both 2-pyridones and arylation re-
agents were sensitive to the arylation reaction under cop-
per catalysis, which might affect the oxidative addition or
reductive elimination steps for copper species. During the
studies on selective N- or O-arylation of N–O bond by di-
aryliodonium salts in our group,9,10 to avoid the formation
of copper species and figure out the limitation and scope of
preparation of 2-aryloxypyridines, we surmised that a
strong base might directly promote the arylation of 2-pyri-
dones by diaryliodonium salts according to the pKa (about
17)11 of 2-pyridone. Substituents at C6-position of 2-pyri-
dones would favor access to O-arylation products due to
the ‘T-shape’ of iodonium salts. Herein, we report a substit-
uent effect-controlled O-arylation of 2-pyridones with di-
aryliodonium salts to prepare diverse 2-aryloxypyridines
under transition-metal-free conditions (Scheme 1, C).
Screening of bases revealed that bases such as KOH, K2CO3,
or Cs2CO3 gave good yields of arylation products except that
NaH and Et3N did not promote the reaction (entries 5–9).
The best total yield of 3aa and 4aa was obtained in 99% by
using Cs2CO3 (entry 8). Next, we examined the solvent ef-
fects for arylation of 2-pyridone (1a) (entry 8 vs entries 10–
16). Products 3aa and 4aa were formed in high total yields
in toluene, THF, DMF, and DMSO while lower yields were
obtained in 1,4-dioxane, MeCN, and H2O. The additives such
as LiCl or AlCl3 decreased the yield of 3aa and 4aa and did
not affect the ratio of N-arylation or O-arylation products
obviously (entries 17, 18). When diphenyliodonium triflate
(2a) was replaced with Ph2IBF4, product 3aa was obtained
in 60% yield accompanied by 4aa in 15% yield (entry 19). In
all cases, the ratio of 3aa and 4aa ranged from 1:1 to 3:1.
Although a mixture of N-arylation and O-arylation prod-
ucts was obtained, the two products can be easily purified
Table 1 Optimization of the Reaction Conditionsa
A) Copper-catalyzed O-arylation of 2-pyridones with arylboronic acids
O
O
N
O
N
Ph
Cu(OTf)2 (20 mol%)
conditions
+
Ph2IOTf
NH
Ph
+
DABCO (20 mol%)
6
(HO)2B
+
R
N
O
R1
R
N
O
Et3N, K2HPO4
DMSO, 50 °C
H
1a
2a
3aa
4aa
R1
Entry
Solvent
Base
t-BuOK
Temp (°C) 3aa (%)b 4aa (%)b
R1 = para, meta-substituents, 23–81% yields
1 = ortho-substituents, failed
R
1
2
DCE
25
60
33
39
47
53
55
39
<5
63
<5
58
62
19
35
47
57
6
14
13
15
31
28
31
<5
36
<5
28
29
13
<5
33
17
10
26
29
15
B) Copper-catalyzed N-arylation of 2-pyridones with diaryliodonium salts
DCE
t-BuOK
t-BuOK
t-BuOK
KOH
CuCl (5 mol%)
3
DCE
100
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
6
Ar
I
OTf
+
+
R
N
O
Et3N, toluene, rt
R
N
O
R
N
O
Ar
H
4
DCE
Ar
Ar
5
DCE
R = H, N-arylation products, 23–99% yields
R = Me, ratio of O- and N-products: 1.5:1
R = Ph, ratio of O- and N-products: 3:1
6
DCE
K2CO3
NaH
7
DCE
C) Transition-metal-free O-arylation of 2-pyridones with diaryliodonium salts
8
DCE
Cs2CO3
Et3N
9
DCE
vs
R
N
O
I
T-shape
R
O
N
I
Ar
Ar
10
11
12
13
14
15
16
17c
18d
19e
toluene
THF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Ar
Ar
MeCN
Cs2CO3
DCE, 120 °C
Ar1
I
OTf
6
+
R
N
O
Ar1
Ar2
R
N
H
O
1,4-dioxane
DMF
only O-arylation; 60–99% yields; broad scope of Ar1
DMSO
H2O
Scheme 1 Arylation of 2-pyridones
DCE
39
40
60
Initially, we evaluated the arylation of 2-pyridone (1a)
with diphenyliodonium triflate (2a) under transition-met-
al-free conditions. As shown in Table 1, when t-BuOK was
used as a base in dichloroethane (DCE), N-arylation product
3aa was obtained as a major product while O-arylation
product 4aa was formed as a minor product either at room
temperature or higher; however, high yields of 3aa and 4aa
were attained at increasing temperature (Table 1, entries 1–4).
DCE
DCE
a Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol, 1.5 equiv), base
(0.75 mmol, 1.5 equiv), solvent (5 mL), 2–18 h.
b Isolated yield.
c In the presence of LiCl.
d In the presence of AlCl3.
e Triflate 2a was replaced by Ph2IBF4.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

C
X.-H. Li et al.
Paper
Synthesis
by flash column chromatography. Finally, the optimal con-
ditions for the arylation process were Cs2CO3 as base in DCE
at 120 °C (entry 8).
O
O
N
3
O
Cs2CO3
Ph
Ph
I
OTf
+
NH
Ph
+
4
N
DCE, 120 °C
Ph
5
6
R
R
With the optimized conditions in hand, the substituent
effects of 2-pyridones were evaluated. As shown in Scheme
2, substituted groups could be present at the 3-, 4-, 5-, or 6-
position of 2-pyridones, and N-arylation product 3 and
O-arylation product 4 were obtained in good to excellent
total yields. For 5-methyl-2-pyridone (1g), N-arylation
product 3ga was achieved in 53% yield accompanied by
O-arylation product 4ga in 30% yield. Product 3ga is known as
Pirfenidone, a widely used antifibrotic agent for idiopathic
pulmonary fibrosis.12 The ratio of products 3 and 4 depend-
ed on the substituents of the 2-pyridone substrate. When
there was a strongly electron-withdrawing group at C5-po-
sition, the ratio of products 3 and 4 was 1.1:1 (Scheme 2,
3ha and 4ha). Product 3ha is a precursor for the synthesis
of polymyxin lipopeptide.13 2-Pyridones 1i and 1j facilitat-
ed the formation of O-arylation products 4ia and 4ja as ma-
jor products, while N-arylation products 3ia and 3ja were
obtained as minor products. With a substituent at the C6-
position, no N-arylation products were observed, whereas
O-arylation products were obtained in excellent yields
(Scheme 2, 4ka, 4la, and 4ma). The reaction was compati-
ble with diverse functional groups for 2-pyridones, such as
halides, nitro, cyano, and ester groups. The results revealed
that the substituent effects at the 6-position of 2-pyridones
controlled the selectivity of O-arylation.
R
1
2a
3
4
Me
O
Me
O
O
O
Ph
Ph
N
Ph +
N
Ph +
N
N
3aa (63%)
4aa (36%)
3ba (74%)
4ba (16%)
O
NO2
O2N
O
N
Me
Ph
O
O
Ph
Ph
Ph
Ph
Me
N
+
Ph
+
N
N
3ca (48%)
4ca (24%)
3da (53%)
4da (30%)
CN
NC
O
N
O
MeO
Ph
O
I
O
Ph
MeO
I
N
Ph
+
+
N
N
3ea (52%)
4ea (43%)
3fa (67%)
4fa (21%)
O
O
O
O
N
Ph
+
N
Ph
N
Ph
+
N
MeO2C
Me
MeO2C
Me
3ga (42%)
4ga (33%)
3ha (40%)
4ha (34%)
O
O
N
O
O
Ph
Ph
N
Ph
+
Ph
+
N
N
3ja (18%)
4ja (81%)
3ia (26%)
4ia (57%)
Encouraged by the highly selective O-arylation of 2-pyr-
idones with substituents at the C6-position, a series of di-
aryliodonium salts were used to react with 2-pyridone 1l to
investigate the scope of O-arylation process. As shown in
Table 2, various diaryliodonium salts containing electron-
donating or electron-withdrawing groups with para, meta,
and ortho-substituents delivered the corresponding O-ary-
lation products in excellent yields. When iodonium salt 2b
with a methoxy group was used, the desired product 4lb
was obtained in 60% by extending the reaction time to 30
hours (Table 2, entry 2). In particular, iodonium salt 2n
with 2,4,6-trimethyl groups also resulted in product 4ln in
99% yield, which could not be prepared by Luo’s and Kim’s
methods (entry 14).5a,8 It suggests that the steric effects of
diaryliodonium salts have little influence on the metal-free
selective O-arylation process, which is a good supplement
for copper-catalyzed coupling reaction to prepare these
ortho-substituted O-arylation products. When unsymmet-
rical diaryliodonium salts 2o and 2q were used, the elec-
tron-deficient aryl moieties were preferentially transferred
to the desired products 4lm and 4lq in excellent yields (en-
tries 15 and 17). Unsymmetrical diaryliodonium salts 2p
afforded product 4ln in 92% yield, which suggested that the
steric hindrance of aryl moiety was transferred to the de-
O
O
O
O
Ph
Ph
N
Ph
+
N
Ph
+
N
N
Cl
Me
Cl
4la (93%)
Me
3ka (0%)
4ka (85%)
3la (0%)
CN
NC
O
Me
O
Ph
Me
N
Ph
+
N
Me
Me
4ma (86%)
3ma (0%)
Scheme 2 Reaction scope of 2-pyridones. Reagents and conditions: 1
(0.5 mmol), 2a (0.75 mmol, 1.5 equiv), Cs2CO3 (0.75 mmol, 1.5 equiv),
DCE (5 mL), 120 °C, 2–18 h. Isolated yields are shown.
sired products. These results show high chemoselectivity
for unsymmetric diaryliodonium salts with both electronic
effects and steric effects of substituents (entries 15–17). In
all cases, the yield of the N-arylation product 3 was less
than 5%. Furthermore, the reaction tolerated various func-
tional groups such as chloro, bromo, fluoro, nitro, and ester
groups. Particularly, the chloro-substituted group at C6-po-
sition of 2-pyridones will allow these products for more po-
tential applications by SN2 substitution or coupling reaction
via transition-metal catalysis.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

D
X.-H. Li et al.
Paper
Synthesis
Table 2 Scope of O-Arylation for 6-Chloro-2-pyridone (1l)a
Table 3 Substituent Effects of Diaryliodonium Salts for 2-Pyridone
(1a)a
R1
O
R1
O
O
R1
Cs2CO3
O
N
I
OTf
R2
NH
Cl
O
+
N
DCE
I
OTf
R2
+
DCE,120 °C
NH
R1
+
N
120 °C
Cl
R1
1l
2
4
1a
2
3
4
Entry
2
R1
R2
4
Yield (%)b
Entry
2
R1
R2
4-Me
3 (%)b
4 (%)b
1
2
2a
2b
2c
2d
2e
2f
H
H
4la
4lb
4lc
4ld
4le
4lf
93
60c
95
92
95
94
86
96
98
92
97
87
97
99
89
92
97
1
2
3
4
5
6
7
2c
4-Me
4-F
3ac, 60
3af, 71
3al, 59
3an, 33
3ao, 77
3an, 54
3aq, 74
4ac, 23
4af, 10
4al, 19
4an, 20
4ao, 20
4an,18
4aq, <5
4-MeO
4-Me
4-Br
4-MeO
4-Me
4-Br
2f
4-F
3
2l
2-Me
2-Me
4
2n
2o
2p
2q
2,4,6-Me3
2-Br
2,4,6-Me3
5
4-Cl
4-Cl
4-MeO
6
4-F
4-F
2,4,6-Me3
4-CO2Me
H
H
7
2g
2h
2i
4-CF3
3-Me
3-Br
4-CF3
3-Me
3-Br
4lg
4lh
4li
8
a Reaction conditions: 1a (0.5 mmol), 2 (0.75 mmol, 1.5 equiv), Cs2CO3
(0.75 mmol, 1.5 equiv), DCE (5 mL), 120 °C, 2–24 h.
b Isolated yield.
9
10
11
12
13
14
15
16
17
2j
3-NO2
3-NO2
3,5-Me2
2-Me
2-Br
4lj
2k
2l
3,5-Me2
2-Me
4lk
4ll
When 2-pyridone 1l was reacted with 2a in the pres-
ence of radical scavenger TEMPO (2.0 equiv) under the opti-
mal conditions, product 4la was still obtained in 94% yield
(Scheme 3, 1). This result suggests that the arylation pro-
cess might not involve a radical intermediate. When a 1:1
ratio of diaryliodonium salt 2b with electron-donating
group and 2g with electron-withdrawing group reacted
with 2-pyridone 1l under the optimized conditions for 6
hours, the O-arylation product 4lg was obtained in 81%
yield while the O-arylation product 4lb was formed in less
than 5% yield (Scheme 3, 2). This result demonstrated that
the O-arylation process showed more reactivity for di-
aryliodonium salt with electron-withdrawing group.
2m
2n
2o
2p
2q
2-Br
4lm
4ln
4lm
4ln
4lq
2,4,6-Me3
2-Br
2,4,6-Me3
4-MeO
H
2,4,6-Me3
4-CO2Me
H
a Reaction conditions: 1l (0.5 mmol), 2 (0.75 mmol, 1.5 equiv), Cs2CO3
(0.75 mmol, 1.5 equiv), DCE (5 mL), 120 °C, 1–18 h.
b Isolated yield.
c Reaction time: 30 h.
To better understand the substituent effect of di-
aryliodonium salts, some electron-donating or electron-
withdrawing groups, as well as ortho-substituted dia-
ryliodonium salts were reacted with 2-pyridone (1a) (Table
3). Both iodonium salts bearing electron-donating or electron-
withdrawing groups gave a mixture of N-arylation product
3 and O-arylation product 4, but affording N-arylation
product 3 as the major product. Iodonium salts with ortho-
substituted groups, such as 2l and 2n, also underwent
N-arylation to afford N-arylation products as major products
(Table 3, entries 3, 4). However, for unsymmetrical iodoni-
um salt 2q, the reaction showed high chemoselectivity and
regioselectivity affording the N-arylation product 3aq in
74% accompanied by less than 5% yield of O-arylation prod-
uct 4aq (entry 7). These results revealed that substituent of
diaryliodonium salt moieties might favor N-arylation of
2-pyridone (1a). In particular, the electron-wtihdrawing
group at diaryliodonium salt provided N-arylation product
as a single product while steric effect of substituents did
not improve the selectivity (entries 5–7).
1) Radical trapping experiment
TEMPO (2.0 equiv)
Cs2CO3
+
Ph2IOTf
DCE, 120 °C
94%
Cl
N
H
O
Cl
N
OPh
1l
2a
4la
2) Reactivity of diaryliodonium salt
MeO OTf
I
OMe
Cl
N
O
4lb, <5%
OMe
+
2b
Cs2CO3
DCE, 120 °C
Cl
N
H
O
+
CF3
F3C
I
OTf
1l
Cl
N
O
2g
4lg, 81%
CF3
Scheme 3 Control experiments
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

E
X.-H. Li et al.
Paper
Synthesis
On the basis of experimental results, a possible mecha-
nism of selective O-arylation of 6-substituted 2-pyridones
is proposed (Scheme 4). Intermediate A is formed first by
deprotonation under base conditions. Diaryliodonium salt
is then attacked by intermediate A to give intermediate B.
When a substituent group is present at the 6-position, dia-
ryliodonium salt is unfavorable to be attacked to form in-
termediate B, which is also unfavorable to undergo reduc-
tive elimination (RE) to provide N-arylation product 3 due
to the steric hindrance of 6-substituents and the ‘T-shape’
of iodonium salt. Consequently, intermediate A gets con-
verted into intermediate C by isomerization.14 Then, inter-
mediate C attacks diaryliodonium salt to give the interme-
diate D, which favorably undergoes reductive elimination or
1,2-aryl migration to give the O-arylation product 4.6c,15
1) Gram-scale preparation of 4la
m-CPBA, TfOH, C6H6, 77% yield
O
Cs2CO3
NH
Ph2IOTf
+
+
PhI
DCE, 120 °C
Cl
N
O
1.94 g
Cl
2a
Ph
1l
10 mmol, 1.28 g
4la
1.96 g, 96% yield
2) Dehalogenation of 6-chloro-2-aryloxypyridines
H2, Pd/C (5%)
Ph
N
O Ph
K2CO3, DMF, rt
Cl
N
O
4la
4aa, 75%
O
H2, Pd/C (5%)
K2CO3, DMF, rt
N
N
O
Cl
O
N
R
O
N
R
O
N
R
4ln
4an, 72%
O
R.E
not favored
Cs2CO3
DCE
Scheme 5 Applications of O-arylation reaction
Ar1
I
Ar2
NH
R
Ar1
B
A
3
1
Next, we attempted to modify a lead compound for P2Y1
(see Figure 1), which has demonstrated to possess good bio-
activity.18 As shown in Scheme 6, the O-arylation product 5
was obtained in 80% yield by reacting 2-pyridone 1m and
diaryliodonium salt 2r under optimal conditions. Reduction
of compound 5 with LiAlH4 in Et2O for 2 hours and followed
by addition of 2,4-difluoro-1-isocyanatobenzene gave the
desired product 6 in 62% yield. This new approach to access
P2Y1 lead compound analogue is meaningful for future
potential applications in pharmaceuticals.
Ar2
I
OTf
Ar2I
Ar1
2
Ar1
O
Ar2
O
Ar1
O
N
R
I
N
R
N
R
favored
R. E
4
C
D
Scheme 4 Possible mechanism for steric effects on O-arylation
OTf
Finally, inspired by the feasibility of the transition-
metal-free O-arylation of 2-pyridones with diaryliodonium
salts, a gram-scale procedure was performed. When 1.28
grams of 2-pyridone 1l was reacted with 2a under the opti-
mal conditions, 1.96 grams of product 4la was obtained in
96% yield accompanied by 1.94 grams of PhI (Scheme 5, 1).
To make a green process, the producing PhI could be con-
verted to iodonium salts 2a in 77% yield following Olofs-
son’s procedure.16 Comparing Scheme 2, Table 2, and Table
3, we can see that O-arylation products can not be synthe-
sized with high regioselectivity and yields when there was
no substituent at C6-position of 2-pyridones. To figure out
high-yielding unsubstituted 2-aryloxypyridines, dehaloge-
nation of 6-chloro-2-aryloxypyridine products was per-
formed (Scheme 5, 2). Treatment of compounds 4la and 4ln
with 5% of Pd/C with H2 at room temperature for 3 hours,17
afforded 4aa and 4an in 75% and 72% yield, respectively,
which were difficult to obtain by copper-catalysis, especial-
ly for ortho-substituted aryl groups. These results showed
that 6-chloro-2-pyridone (1l) was a good precursor to ac-
cess various unsubstituted 2-aryloxypyridines by highly
selective O-arylation and sequential dehalogenation pro-
cess.
Me
F3C
I
CF3
CN
O
Me
CN
O
2r
Me
N
Cs2CO3, 120 °C, 12 h
83%
Me
N
H
F3C
1m
5
F
F
Me
N
O
1) LiAlH4, Et2O
F
N
H
N
H
Me
O
NCO
2)
F
CF3
DCE, rt, 30 min
6, 62%
Scheme 6 Preparation of P2Y1 lead compound analogue 6
In summary, we have described a new synthetic method
to prepare 2-aryloxypyridine derivatives by O-arylation of
2-pyridones and diaryliodonium salts under transition-
metal-free conditions. It was found that 2-pyridones con-
taining substituents at the 6-position definitely controlled
the reaction selectivity to provide O-arylation products.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

F
X.-H. Li et al.
Paper
Synthesis
The O-arylation reaction was compatible with diaryliodoni-
um salts containing various electron-donating or electron-
withdrawing groups, as well as ortho-substituted groups.
Furthermore, it is easy to be performed at gram-scale and a
P2Y1 lead compound analogue could be synthesized in two
steps using the transition-metal-free O-arylation strategy.
HRMS (ESI): m/z (M + H)+ calcd for C11H9N2O3: 217.0613; found:
217.0634.
4-Methyl-1-phenylpyridin-2(1H)-one (3da)21
Yield: 0.049 g (53%); orange solid; mp 104–105 °C.
1H NMR (400 MHz, CDCl3): δ = 7.49 (t, J = 7.5 Hz, 2 H), 7.41–7.35 (m,
3 H), 7.23 (d, J = 6.5 Hz, 1 H), 6.46 (s, 1 H), 6.09 (d, J = 6.0 Hz, 1 H), 2.23
(s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.3, 151.5, 140.8, 136.7, 129.2,
128.2, 126.5, 120.0, 108.5, 21.2.
All reactions were performed under an air atmosphere. Commercially
available reagents were used without further purification. The NMR
spectra were recorded in CDCl3 or DMSO-d6 using 400 or 500 MHz in-
strument with TMS as the internal standard. NMR data are represent-
ed as follows: chemical shift (pap), multiplicity (standard abbrevia-
tions), coupling constants (Hz), and integration. IR spectra were re-
corded on FT-IR spectrophotometer, and only major peaks are
reported in cm–1. HRMS were measured in ESI mode and the mass an-
alyzer of the HRMS was TOF. Flash column chromatography was per-
formed on silica gel (300–400 mesh). 2-Pyridones 1a–m were pur-
chased directly from Sigma-Aldrich. Diaryliodonium salts 2a–r10a,b
were prepared according to literature methods and their spectral data
matched literature values.
4-Iodo-1-phenylpyridin-2(1H)-one (3ea)
Yield: 0.077 g (52%); yellow oil.
IR (film): 3057, 2924, 1662, 1577, 1454, 1276, 1134, 632 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 2.0 Hz, 2 H), 7.51–7.41 (m,
4 H), 7.36 (d, J = 7.2 Hz, 2 H), 6.50 (d, J = 9.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 160.8, 147.2, 142.7, 140.0, 129.5,
128.9 126.4, 123.6, 64.4.
HRMS (ESI) m/z (M + H)+ calcd for C11H9INO: 297.9729; found:
297.9719.
2-Pyridones 3 and 4; General Procedure
4-Methoxy-2-oxo-1-phenyl-1,2-dihydropyridine-3-carbonitrile
(3fa)
A 25 mL Teflon-sealed flask was charged with the corresponding 2-
pyridone 1 (0.5 mmol), diaryliodonium salt 2 (0.75 mmol, 1.5 equiv),
and Cs2CO3 (0.75 mmol, 1.5 equiv) under an air atmosphere. DCE (5
mL) was added to the flask. Then, the reaction vessel was sealed with
a Teflon cap. The reaction mixture was stirred at 120 °C until the
2-pyridone 1 was consumed completely (monitored by TLC). At this
time, the solvent was removed in vacuo and the residue was purified
by flash column chromatography (the crude residue was dry loaded
on silica gel, 1:20 to 1:1, EtOAc/PE) to provide the desired products 3
and 4 (Scheme 2, Tables 2, 3).
Yield: 0.076 g (67%); white solid; mp 236–237 °C.
IR (film): 3098, 2216, 1657, 1524, 1340, 1239, 1106, 774 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 8.13 (d, J = 8.4 Hz, 1 H), 7.55–7.41
(m, 3 H), 7.42 (d, J = 8.4 Hz, 1 H), 4.06 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 173.7, 160.7, 145.9, 139.8, 129.6,
129.3, 127.3, 114.9, 95.2, 86.9, 58.4.
HRMS (ESI) m/z (M + H)+ calcd for C13H11N2O2: 227.0821; found:
227.0813.
1-Phenylpyridin-2(1H)-one (3aa)19
5-Methyl-1-phenylpyridin-2(1H)-one (3ga)8
Yield: 0.054 g (63%); orange solid; mp 94–95 °C.
1H NMR (500 MHz, CDCl3): δ = 7.50–7.47 (m, 2 H), 7.43–7.36 (m, 4 H),
7.34 (d, J = 8.5 Hz, 1 H), 6.66 (d, J = 10.5 Hz, 1 H), 6.25 (t, J = 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 162.3, 140.9, 139.8, 137.9, 129.2,
128.4, 126.4, 121.8, 105.8.
Yield: 0.040 g (42%); yellow solid; mp 106–107 °C.
1H NMR (500 MHz, CDCl3): δ = 7.50 (t, J = 7.0 Hz, 2 H), 7.42–7.36 (m,
3 H), 7.28–7.25 (m, 1 H), 7.11 (s, 1 H), 6.62 (d, J = 9.0 Hz, 1 H), 2.10 (s, 3
H).
13C NMR (125 MHz, CDCl3): δ = 161.7, 142.6, 141.1, 135.3, 129.3,
128.3, 126.6, 121.5, 114.8, 17.0.
3-Methyl-1-phenylpyridin-2(1H)-one (3ba)20
Yield: 0.068 g (74%); yellow solid; mp 113–114 °C.
Methyl 6-Oxo-1-phenyl-1,6-dihydropyridine-3-carboxylate (3ha)13
1H NMR (500 MHz, CDCl3): δ = 7.49 (t, J = 7.5 Hz, 2 H), 7.41–7.37 (m,
3 H), 7.27 (d, J = 5.0 Hz, 1 H), 7.23 (d, J = 7.0 Hz, 1 H), 6.17 (t, J = 7.5 Hz,
1 H), 2.19 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 162.8, 141.3, 136.9, 135.3, 130.8,
129.1, 128.2, 126.6, 105.5, 17.3.
Yield: 0.047 g (40%); yellow solid; mp 70–71 °C.
1H NMR (400 MHz, CDCl3): δ = 7.52–7.49 (m, 2 H), 7.46–7.37 (m, 4 H),
6.74 (d, J = 6.5 Hz, 1 H), 3.94 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.9, 162.0, 140.8, 140.4, 138.1,
129.4, 128.8, 126.3, 123.8, 104.3, 52.9.
3-Nitro-1-phenylpyridin-2(1H)-one (3ca)
5-Phenylphenanthridin-6(5H)-one (3ia)22
Yield: 0.052 g (48%); orange solid; mp 140–141 °C.
IR (film): 3033, 2954, 1660, 1573, 1459, 1288, 1104, 734 cm–1
1H NMR (500 MHz, CDCl3): δ = 8.38 (dd, J = 7.5, 1.5 Hz, 1 H), 7.73 (dd,
J = 6.5, 1.5 Hz, 1 H), 7.53–7.49 (m, 3 H), 7.38 (d, J = 7.5 Hz, 2 H), 6.40 (t,
J = 7.5 Hz, 1 H).
Yield: 0.035 g (26%); orange solid; mp 106–107 °C.
.
1H NMR (400 MHz, CDCl3): δ = 8.57 (d, J = 7.8 Hz, 1 H), 8.35–8.30 (m,
2 H), 7.83 (t, J = 7.2 Hz, 1 H), 7.64 (t, J = 8.0 Hz, 3 H), 7.56 (t, J = 7.2 Hz,
1 H), 7.35–7.25 (m, 4 H), 6.71–6.69 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 161.7, 139.1, 138.2, 133.9, 132.8,
130.1, 129.1, 129.0, 128.7, 128.1, 125.8, 122.9, 122.6, 121.7, 119.0,
117.0.
13C NMR (125 MHz, CDCl3): δ = 154.3, 144.2, 139.6, 139.4, 138.8,
129.6, 129.5, 126.3, 103.2.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

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X.-H. Li et al.
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Synthesis
1-Phenylquinolin-2(1H)-one (3ja)23
Methyl 4-[2-Oxopyridin-1(2H)-yl]benzoate (3aq)25
Yield: 0.020 g (18%); yellow solid; mp 124–125 °C.
Yield: 0.084 g (74%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 9.6 Hz, 1 H), 7.62–7.58 (m,
3 H), 7.54–7.50 (m, 1 H), 7.34–7.25 (m, 3 H), 7.21 (d, J = 7.2 Hz, 1 H),
6.80 (d, J = 9.6 Hz, 1 H), 6.66 (d, J = 8.8 Hz, 1 H).
1H NMR (400 MHz, CDCl3): δ = 8.17 (d, J = 6.4 Hz, 2 H), 7.50 (d, J = 6.8
Hz, 2 H), 7.42 (t, J = 6.0 Hz, 1 H), 7.34 (d, J = 5.2 Hz, 1 H), 6.67 (d, J = 7.2
Hz, 1 H), 6.28 (q, J = 5.6 Hz, 1 H), 3.95 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.3, 141.1, 139.8, 137.6, 130.2,
13C NMR (100 MHz, CDCl3): δ = 166.1, 162.0, 144.6, 140.0, 137.2,
130.1, 128.9, 128.8, 128.2, 122.3, 122.2, 120.3, 115.9.
130.7, 130.1, 126.6, 122.1, 106.2, 52.3.
1-(4-Methylphenyl)pyridin-2(1H)-one (3ac)20
2-Phenoxypyridine (4aa)2a
Yield: 0.055 g (60%); yellow oil.
Yield: 0.033 g (36%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.36 (m, 1 H), 7.32–7.24 (m, 5 H),
6.66 (d, J = 9.6 Hz, 1 H), 6.23 (t, J = 6.8 Hz, 1 H), 2.40 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.5, 139.7, 138.4, 138.3, 138.0,
1H NMR (400 MHz, CDCl3): δ = 8.20 (d, J = 4.0 Hz, 1 H), 7.69–7.64 (m,
1 H), 7.41 (d, J = 8.0 Hz, 2 H), 7.21–7.12 (m, 3 H), 6.99–6.94 (m, 1 H),
6.90 (d, J = 8.2 Hz, 1 H).
129.8, 126.1, 121.7, 105.7, 21.1.
13C NMR (100 MHz, CDCl3): δ = 163.7, 154.2, 147.7, 139.4, 129.6,
124.6, 121.1, 118.4, 111.5.
1-(4-Fluorophenyl)pyridin-2(1H)-one (3af)24
3-Methyl-2-phenoxypyridine (4ba)2a
Yield: 0.067 g (71%); yellow solid; mp 131–132 °C.
Yield: 0.015 g (16%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.42–7.35 (m, 3 H), 7.32 (d, J = 4.0 Hz,
1 H), 7.20 (t, J = 6.8 Hz, 2 H), 6.67 (d, J = 7.2 Hz, 1 H), 6.26 (d, J = 5.2 Hz,
1 H).
13C NMR (100 MHz, CDCl3): δ = 163.4 (d, J = 247.1 Hz), 162.4, 140.0,
137.8, 136.8 (d, J = 3.1 Hz), 128.4 (d, J = 8.8 Hz), 121.9, 116.4 (d, J =
22.6 Hz), 106.2.
1H NMR (500 MHz, CDCl3): δ = 7.99 (d, J = 4.0 Hz, 1 H), 7.52 (d, J = 7.0
Hz, 1 H), 7.39 (t, J = 7.5 Hz, 2 H), 7.18–7.15 (m, 1 H), 7.11 (d, J = 8.0 Hz,
2 H), 6.91–6.89 (m, 1 H), 2.34 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 161.8, 154.5, 144.7, 139.7, 129.4,
124.1, 122.0, 120.9, 118.6, 15.9.
1-o-Tolylpyridin-2(1H)-one (3al)4c
3-Nitro-2-phenoxypyridine (4ca)26
Yield: 0.055 g (59%); yellow solid; mp 67–68 °C.
Yield: 0.026 g (24%); yellow solid; mp 85–86 °C.
1H NMR (400 MHz, CDCl3): δ = 7.45–7.41 (m, 1 H), 7.34–7.31 (m, 3 H),
7.21 (t, J = 4.4 Hz, 2 H), 6.70 (d, J = 9.6 Hz, 1 H), 6.26 (d, J = 6.4 Hz, 1 H),
2.16 (s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 8.37 (t, J = 8.4 Hz, 2 H), 7.47 (t, J = 8.0
Hz, 2 H), 7.30 (t, J = 7.2 Hz, 1 H), 7.20–7.14 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 155.9, 152.6, 151.7, 135.4, 134.6,
13C NMR (100 MHz, CDCl3): δ = 162.0, 140.0, 139.9, 137.8, 134.8,
129.7, 125.8, 121.7, 118.2.
130.9, 128.9, 126.9, 126.8, 121.6, 105.7, 17.4.
4-Methyl-2-phenoxypyridine (4da)27
1-Mesitylpyridin-2(1H)-one (3an)
Yield: 0.028 g (30%); orange oil.
Yield: 0.034 g (33%); yellow solid; mp 125–126 °C.
IR (film): 3055, 2923, 1667, 1580, 1501, 1274, 1008, 694 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.45–7.41 (m, 1 H), 7.08 (q, J = 5.6 Hz,
1 H), 6.98 (s, 2 H), 6.72 (d, J = 9.2 Hz, 1 H), 6.28 (t, J = 6.8 Hz, 1 H), 2.31
(s, 3 H), 2.05 (s, 3 H).
1H NMR (500 MHz, CDCl3): δ = 8.06 (d, J = 5.0 Hz, 1 H), 7.39 (t, J = 7.5
Hz, 2 H), 7.19 (t, J = 7.0 Hz, 1 H), 7.12 (d, J = 8.0 Hz, 2 H), 6.81 (d, J = 5.0
Hz, 1 H), 6.70 (s, 1 H), 2.32 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 164.0, 154.3, 150.9, 147.3, 129.6,
124.4, 121.0, 119.8, 111.7, 20.9.
.
13C NMR (100 MHz, CDCl3): δ = 162.0, 140.0, 138.6, 137.8, 138.7,
134.3, 129.2, 122.1, 106.2. 20.9, 17.5.
4-Iodo-2-phenoxypyridine (4ea)
HRMS (ESI): m/z (M + H)+ calcd for C14H16NO: 214.1232; found:
Yield: 0.065 g (43%); yellow oil.
IR (film): 3033, 2934, 1580, 1496, 1256, 1123, 734 cm–1
.
214.1242.
1H NMR (400 MHz, CDCl3): δ = 8.36 (d, J = 2.0 Hz, 1 H), 7.92 (dd, J = 8.4
Hz, 2.0 H, 1 H), 7.42 (t, J = 8.0 Hz, 2 H), 7.23 (t, J = 7.6 Hz, 1 H), 7.13 (d,
J = 8.0 Hz, 2 H), 6.76 (d, J = 8.2 Hz, 1 H).
1-(2-Bromophenyl)pyridin-2(1H)-one (3ao)
Yield: 0.096 g (77%); yellow solid; mp 170–171 °C.
IR (film): 3045, 2938, 1665, 1578, 1496, 1236, 1022, 734 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 163.2, 153.7, 153.6, 147.3, 129.7,
125.0, 121.1, 113.7, 84.1.
HRMS (ESI): m/z (M + H)+ calcd for C11H9INO: 297.9729; found:
297.9730.
1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 8.0 Hz, 1 H), 7.47–7.42 (m,
2 H), 7.37–7.31 (m, 2 H), 7.16 (d, J = 5.6 Hz, 1 H), 6.69 (d, J = 9.2 Hz, 1
H), 6.28 (t, J = 6.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 161.8, 140.3, 140.1, 137.7, 133.7,
130.5, 129.2, 128.6, 122.1, 121.6, 105.8.
4-Methoxy-2-phenoxynicotinonitrile (4fa)28
HRMS (ESI): m/z (M + H)+ calcd for C11H9BrNO: 249.9868; found:
Yield: 0.024 g (21%); white solid; mp 236–237 °C.
1H NMR (500 MHz, CDCl3): δ = 8.16 (d, J = 6.0 Hz, 1 H), 7.44–7.10 (m,
2 H), 7.27–7.24 (m, 1 H), 7.18 (d, J = 8.0 Hz, 2 H), 6.65 (d, J = 6.0 Hz,
1 H), 4.02 (s, 3 H).
249.9870.
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Synthesis
13C NMR (125 MHz, CDCl3): δ = 170.0, 165.6, 152.7, 152.1, 129.6,
125.6, 121.6, 112.4, 102.2, 86.6, 56.8.
1H NMR (400 MHz, CDCl3): δ = 7.41–7.38 (m, 2 H), 7.26–7.22 (m, 2 H),
7.18 (d, J = 8.0 Hz, 1 H), 6.80 (s, 1 H), 2.52 (s, 3 H), 2.35 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 163.5, 161.1, 154.8, 153.0, 129.3,
125.9, 121.4, 119.1, 114.6, 95.1, 24.5, 20.1.
5-Methyl-2-phenoxypyridine (4ga)29
HRMS (ESI): m/z (M + H)+ calcd for C14H13N2O: 225.1028; found:
Yield: 0.031 g (33%); orange oil.
1H NMR (500 MHz, CDCl3): δ = 8.01 (s, 1 H), 7.48 (d, J = 6.5 Hz, 1 H),
7.38 (t, J = 8.0 Hz, 2 H), 7.17 (t, J = 8.0 Hz, 1 H), 7.11 (d, J = 7.0 Hz, 2 H),
6.80 (d, J = 8.5 Hz, 1 H), 2.27 (s, 3 H).
225.1020.
2-Chloro-6-(4-methoxyphenoxy)pyridine (4lb)
13C NMR (125 MHz, CDCl3): δ = 161.8, 154.6, 147.4, 140.1, 129.5,
Yield: 0.071 g (60%); colorless oil.
127.7, 124.2, 120.7, 111.0, 17.4.
IR (film): 3055, 2956, 1590, 1430, 1256, 1167, 774 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.60 (t, J = 8.0 Hz, 1 H), 7.07 (d, J = 9.2
Hz, 2 H), 7.00 (d, J = 7.6 Hz, 1 H), 6.93 (d, J = 9.2 Hz, 2 H), 6.70 (d, J = 8.0
Hz, 1 H), 3.81 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 163.6, 156.8, 149.0, 147.0, 141.3,
122.1, 118.0, 114.7, 108.6, 55.6.
Methyl 6-Phenoxynicotinate (4ha)30
Yield: 0.040 g (34%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 8.32 (d, J = 4.0 Hz, 1 H), 7.53 (d, J = 4.0
Hz, 1 H), 7.43–7.40 (m, 2 H), 7.26–7.21 (m, 1 H), 7.15 (d, J = 6.8 Hz, 2
H), 3.95 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 165.2, 164.5, 153.8, 148.5, 141.0,
129.8, 125.0, 121.2, 117.6, 111.4, 52.7.
HRMS (ESI): m/z (M + H)+ calcd for C12H11ClNO2: 236.0478; found:
236.0483.
2-Chloro-6-(p-tolyloxy)pyridine (4lc)
6-Phenoxyphenanthridine (4ia)31
Yield: 0.105 g (95%); colorless oil.
IR (film): 3032, 2923, 1960, 1582, 1428, 1287, 1159, 789 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.58 (t, J = 8.0 Hz, 1 H), 7.19 (t, J = 8.0
Hz, 2 H), 7.02–6.98 (m, 3 H), 6.70 (d, J = 7.6 Hz, 1 H), 2.35 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 163.4, 151.3, 149.0, 141.3, 134.6,
130.2, 120.7, 118.1, 108.1, 20.8.
HRMS (ESI): m/z (M + H)+ calcd for C12H11ClNO: 220.0529; found:
220.0521.
Yield: 0.078 g (57%); orange solid; mp 141–142 °C.
.
1H NMR (400 MHz, CDCl3): δ = 8.57 (d, J = 8.0 Hz, 1 H), 8.36–8.29 (m, 2
H), 7.84 (t, J = 7.2 Hz, 1 H), 7.64 (t, J = 8.0 Hz, 3 H), 7.56 (t, J = 7.2 Hz, 1
H), 7.35–7.26 (m, 4 H), 6.71–6.69 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 161.7, 139.2, 138.3, 134.0, 132.8,
130.2, 129.1, 129.0, 128.8, 128.2, 125.9, 123.0, 122.6, 121.8, 119.0,
117.0.
2-Phenoxyquinoline (4ja)32
2-(4-Bromophenoxy)-6-chloropyridine (4ld)
Yield: 0.089 g (81%); orange solid; mp 57–58 °C.
Yield: 0.131 g (92%); colorless oil.
IR (film): 3088, 2545, 2198, 1884, 1568, 1427, 1159, 792 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.64 (t, J = 8.0 Hz, 1 H), 7.50 (d, J = 8.0
Hz, 2 H), 7.04 (d, J = 8.8 Hz, 3 H), 6.80 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 162.5, 152.6, 149.0, 141.5, 132.7,
1H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 8.8 Hz, 1 H), 7.81 (d, J = 8.0
Hz, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.63–7.59 (m, 1 H), 7.44–7.41 (m, 3
H), 7.26–7.21 (m, 3 H), 7.08 (d, J = 8.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 161.5, 153.8, 146.3, 139.7, 129.7,
129.4, 127.8, 127.2, 125.6, 124.7, 124.6, 121.3, 116.2.
.
122.8, 118.8, 117.8, 109.5.
HRMS (ESI): m/z (M + H)+ calcd for C11H8BrClNO: 283.9478; found:
2-Methyl-6-phenoxypyridine (4ka)2a
Yield: 0.079 g (85%); yellow oil.
283.9467.
1H NMR (500 MHz, CDCl3): δ = 7.54 (t, J = 7.5 Hz, 1 H), 7.38 (t, J = 8.0
Hz, 2 H), 7.18 (t, J = 7.5 Hz, 1 H), 7.13 (d, J = 7.5 Hz, 2 H), 6.87 (d, J = 7.5
Hz, 1 H), 6.57 (d, J = 8.5 Hz, 1 H), 2.46 (s, 3 H).
2-Chloro-6-(4-chlorophenoxy)pyridine (4le)
Yield: 0.113 g (95%); colorless oil.
13C NMR (125 MHz, CDCl3): δ = 163.2, 157.6, 154.7, 139.5, 129.6,
IR (film): 3070, 1890, 1571, 1496, 1120, 798 cm–1
.
124.3, 120.7, 118.0, 107.6, 24.1.
1H NMR (400 MHz, CDCl3): δ = 7.62–7.58 (m, 1 H), 7.34 (d, J = 8.4 Hz, 2
H), 7.08 (d, J = 8.4 Hz, 2 H), 7.03 (d, J = 7.6 Hz, 1 H), 6.78 (d, J = 8.0 Hz,
1 H).
2-Chloro-6-phenoxypyridine (4la)27
Yield: 0.097 g (93%); colorless oil.
13C NMR (100 MHz, CDCl3): δ = 162.4, 151.9, 148.8, 141.5, 130.0,
129.5, 122.3, 118.6, 109.3.
HRMS (ESI): m/z (M + H)+ calcd for C11H8Cl2NO: 239.9983; found:
239.9990.
1H NMR (400 MHz, CDCl3): δ = 7.62 (t, J = 8.0 Hz, 1 H), 7.41 (t, J = 8.0
Hz, 2 H), 7.23 (t, J = 7.6 Hz, 1 H), 7.14 (t, J = 8.0 Hz, 2 H), 7.03 (d, J = 7.6
Hz, 1 H), 6.74 (t, J = 8.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 163.1, 153.7, 149.1, 141.4, 129.8,
125.0, 121.0, 118.4, 109.1.
2-Chloro-6-(4-fluorophenoxy)pyridine (4lf)
Yield: 0.105 g (94%); white solid; mp 72–73 °C.
IR (film): 3077, 2345, 1585, 1427, 1288, 1155, 913, 768 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.64 (t, J = 8.0 Hz, 1 H), 7.13–7.02 (m, 5
H), 6.77 (d, J = 8.0 Hz, 1 H).
4,6-Dimethyl-2-phenoxynicotinonitrile (4ma)
.
Yield: 0.096 g (86%); white solid; mp 96–97 °C.
IR (film): 3054, 2954, 2251, 1589, 1495, 1283, 1120, 783 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

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X.-H. Li et al.
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Synthesis
13C NMR (100 MHz, CDCl3): δ = 163.0, 161.0 (d, J = 241.0 Hz), 149.3 (d,
J = 2.2 Hz), 149.0, 141.4, 122.6 (d, J = 8.0 Hz), 118.5, 116.4 (d, J = 2.4
Hz), 109.1.
HRMS (ESI): m/z (M + H)+ calcd for C13H13ClNO: 234.0686; found:
234.0678.
HRMS (ESI): m/z (M + H)+ calcd for C11H8FClNO: 224.0278; found:
224.0271.
2-Chloro-6-(o-tolyloxy)pyridine (4ll)
Yield: 0.096 g (87%); colorless oil.
IR (film): 3062, 2926, 1957, 1571, 1285, 1179, 1041, 787 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.60 (t, J = 8.0 Hz, 1 H), 7.28–7.21 (m,
2 H), 7.17 (t, J = 6.0 Hz, 1 H), 7.06 (d, J = 8.0 Hz, 1 H), 7.00 (d, J = 8.0 Hz,
1 H), 6.63 (d, J = 8.0 Hz, 1 H), 2.19 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.2, 151.8, 149.3, 141.3, 131.5,
130.5, 127.2, 125.5, 121.5, 118.0, 108.0, 16.3.
HRMS (ESI): m/z (M + H)+ calcd for C12H11ClNO: 220.0529; found:
220.0520.
2-Chloro-6-[4-(trifluoromethyl)phenoxy]pyridine (4lg)
.
Yield: 0.118 g (86%); yellow oil.
IR (film): 3060, 2926, 1918, 1583, 1431, 1107, 1065, 783 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.70–7.65 (m, 3 H), 7.26 (d, J = 7.6 Hz,
2 H), 7.11 (d, J = 7.6 Hz, 1 H), 6.88 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 162.0, 156.3, 149.0, 141.7, 127.0 (q, J =
3.6 Hz), 125.4 (q, J = 269.8 Hz), 121.0, 120.9, 119.3, 110.1.
.
HRMS (ESI): m/z (M + H)+ calcd for C12H8ClF3NO: 274.0247; found:
274.0236.
2-(2-Bromophenoxy)-6-chloropyridine (4lm)
2-Chloro-6-(m-tolyloxy)pyridine (4lh)
Yield: 0.138 g (97%); yellow oil.
Yield: 0.106 g (96%); colorless oil.
IR (film): 3055, 2919, 1943, 1580, 1427, 1281, 1138, 1213, 788 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.61 (t, J = 8.0 Hz, 1 H), 7.27 (t, J = 6.4
Hz, 1 H), 7.03 (d, J = 7.6 Hz, 2 H), 6.94 (d, J = 8.2 Hz, 2 H), 6.72 (d, J = 8.0
Hz, 1 H), 2.36 (s, 3 H).
IR (film): 3088, 1589, 1426, 1281, 1157, 1045, 921, 785 cm–1
.
.
1H NMR (400 MHz, CDCl3): δ = 7.66–7.62 (m, 2 H), 7.37 (t, J = 7.2 Hz,
1 H), 7.21 (d, J = 7.6 Hz, 1 H), 7.15 (t, J = 8.0 Hz, 1 H), 7.05 (d, J = 7.6 Hz,
1 H), 6.81 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 162.3, 150.5, 149.0, 141.5, 133.7,
128.6, 126.7, 123.6, 118.6, 116.3, 109.0.
13C NMR (100 MHz, CDCl3): δ = 163.3, 153.7, 149.2, 141.3, 140.0,
129.4, 125.9, 121.5, 118.3, 117.9, 109.0, 21.4.
HRMS (ESI): m/z (M + H)+ calcd for C12H11ClNO: 220.0529; found:
HRMS (ESI): m/z (M + H)+ calcd for C11H8ClBrNO: 283.9478; found:
283.9480.
220.0520.
2-Chloro-6-(mesityloxy)pyridine (4ln)
2-(3-Bromophenoxy)-6-chloropyridine (4li)
Yield: 0.124 g (99%); yellow oil.
Yield: 0.140 g (98%); yellow oil.
IR (film): 3086, 2146, 1932, 1577, 1427, 1280, 1160, 786 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.66 (t, J = 8.0 Hz, 1 H), 7.35 (t, J = 8.0 Hz,
2 H), 7.28 (t, J = 8.4 Hz, 1 H), 7.10–7.05 (m, 2 H), 6.81 (d, J = 8.0 Hz, 1 H).
IR (film): 2919, 1985, 1582, 1427, 1281, 1197, 1034, 771 cm–1
.
.
1H NMR (400 MHz, CDCl3): δ = 7.55 (t, J = 8.0 Hz, 1 H), 6.97 (d, J = 8.0
Hz, 1 H), 6.89 (s, 2 H), 6.51 (d, J = 8.0 Hz, 1 H), 2.29 (s, 3 H), 2.08 (s,
6 H).
13C NMR (100 MHz, CDCl3): δ = 162.3, 154.3, 149.0, 141.6, 130.7,
13C NMR (100 MHz, CDCl3): δ = 162.9, 149.4, 147.6, 141.3, 134.9,
128.1, 124.3, 122.6, 119.7, 119.0, 109.6.
130.4, 129.5, 117.5, 106.6, 20.7, 16.3.
HRMS (ESI): m/z (M + H)+ calcd for C11H8BrClNO: 283.9478; found:
HRMS (ESI): m/z (M + H)+ calcd for C14H15ClNO: 248.0842; found:
283.9469.
248.0832.
2-Chloro-6-(3-nitrophenoxy)pyridine (4lj)
Methyl 4-(6-Chloropyridin-2-yloxy)benzoate (4lq)
Yield: 0.115 g (92%); white solid; mp 50–51 °C.
Yield: 0.129 g (97%); yellow oil.
IR (film): 3084, 2422, 1962, 1518, 1322, 1160, 1076, 793 cm–1
.
IR (film): 3080, 2944, 1927, 1720, 1579, 1424, 1276, 768 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.09 (d, J = 8.0 Hz, 1 H), 8.02 (s, 1 H),
7.74 (t, J = 8.0 Hz, 1 H), 7.59–7.50 (m, 2 H), 7.13 (d, J = 7.6 Hz, 1 H),
6.94 (d, J = 8.0 Hz, 1 H).
1H NMR (500 MHz, CDCl3): δ = 8.09 (d, J = 8.5 Hz, 2 H), 7.69 (t, J = 8.0
Hz, 1 H), 7.20 (d, J = 8.5 Hz, 2 H), 7.10 (d, J = 8.0 Hz, 1 H), 6.86 (d, J = 8.5
Hz, 1 H), 3.92 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 161.7, 154.0, 149.0, 148.9, 141.9,
13C NMR (125 MHz, CDCl3): δ = 166.4, 162.0, 157.6, 149.1, 141.7,
130.1, 127.4, 119.7, 119.5, 116.4, 110.1.
131.5, 126.6, 120.3, 119.3, 110.1, 52.1.
HRMS (ESI): m/z (M + H)+ calcd for C11H8ClN2O3: 251.0223; found:
HRMS (ESI): m/z (M + H)+ calcd for C13H11ClNO3: 264.0428; found:
251.0224.
264.0417.
2-Chloro-6-(3,5-dimethylphenoxy)pyridine (4lk)
2-(4-Methylphenoxy)pyridine (4ac)2a
Yield: 0.114 g (97%); colorless oil.
Yield: 0.021 g (23%); yellow oil.
IR (film): 3021, 2737, 1979, 1574, 1295, 1260, 1023, 796 cm–1
1H NMR (500 MHz, CDCl3): δ = 7.59 (t, J = 7.5 Hz, 1 H), 7.01 (d, J = 7.5 Hz,
1 H), 6.84 (s, 1 H), 6.73 (s, 2 H), 6.69 (d, J = 8.0 Hz, 1 H), 2.31 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 163.4, 153.6, 149.1, 141.2, 139.6,
126.8, 118.4, 118.2, 108.9, 21.2.
.
1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 4.0 Hz, 1 H), 7.66 (t, J = 6.8
Hz, 1 H), 7.19 (d, J = 8.0 Hz, 2 H), 7.03 (d, J = 8.0 Hz, 2 H), 6.96 (t, J = 6.4
Hz, 1 H), 6.88 (d, J = 8.4 Hz, 1 H), 2.34 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.0, 151.7, 147.6, 139.2, 134.1,
130.1, 130.0, 121.0, 118.1, 111.2, 20.8.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

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Synthesis
2-(4-Fluorophenoxy)pyridine (4af)2a
13C NMR (100 MHz, CDCl3): δ = 126.8, 161.1, 155.1, 152.9, 132.3 (q, J =
32.1 Hz), 129.9, 124.9, 122.2 (q, J = 269.1 Hz), 121.9 (q, J = 3.6 Hz),
119.7, 118.8 (q, J = 3.6 Hz), 114.3, 95.3, 24.4, 20.2.
HRMS (ESI): m/z (M + H)+ calcd for C15H12F3N2O: 293.0902; found:
293.0891.
Yield: 0.010 g (10%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 2.8 Hz, 1 H), 7.71–7.66 (m,
1 H), 7.12–7.07 (m, 4 H), 7.00–6.98 (m, 1 H), 6.92 (d, J = 6.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 163.6, 160.7 (d, J = 241.4 Hz), 149.8 (d,
J = 2.9 Hz), 147.5, 139.4, 122.7 (d, J = 8.8 Hz), 118.4, 116.3 (d, J = 23.3
Hz), 111.3.
N-(2,4-Difluorophenyl)-N′-({4,6-dimethyl-2-[3-(trifluoromethyl)-
phenoxy]pyridin-3-yl}metyl)urea (6)
A 100 mL round-bottom flask was charged with the nitrile 5 (292 mg,
1.0 mmol) under N2 atmosphere. Et2O (10 mL) was then added to the
flask. LiAlH4 (152 mg, 4 mmol, 4.0 equiv) was added in portions. The
reaction mixture was stirred at 25 °C until the nitrile 5 was consumed
completely (monitored by TLC). At this time, the reaction was
quenched by H2O (10 mL) and extracted with Et2O (3 × 10 mL). The
combined organic extracts were dried (Na2SO4), filtered, and the sol-
vent was removed under reduced pressure. The crude residue was
dissolved in CH2Cl2 (5 mL) in a 25 mL round-bottom flask, and 2,4-
difluoro-1-isocyanatobenzene (310 mg, 2.0 mmol, 2.0 equiv) was
added. The reaction mixture was stirred at r.t. After completion of the
reaction as monitored by TLC analysis, the solvent was removed un-
der reduced pressure and the crude product was purified by flash col-
umn chromatography (the crude residue was dry loaded on silica gel,
1:10 EtOAc/PE) to provide 6; yield: 279 mg (62%); white solid;
mp 174–175 °C.
2-(o-Tolyloxy)pyridine (4al)33
Yield: 0.018 g (19%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 3.6 Hz, 1 H), 7.68–7.63 (m,
1 H), 7.28–7.21 (m, 2 H), 7.16 (t, J = 7.2 Hz, 1 H), 7.06 (d, J = 7.6 Hz, 1
H), 6.96 (t, J = 6.4 Hz, 1 H), 6.86 (d, J = 8.4 Hz, 1 H), 2.18 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 163.7, 152.2, 147.8, 139.3, 131.4,
130.7, 127.1, 125.2, 121.8, 117.9, 110.6, 16.3.
2-(Mesityloxy)pyridine (4an)34
Yield: 0.022 g (20%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 8.15 (d, J = 3.6 Hz, 1 H), 7.65 (m, 1 H),
6.92 (t, J = 6.0 Hz, 3 H), 6.82 (d, J = 8.0 Hz, 1 H), 2.29 (s, 3 H), 2.08 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 163.4, 147.9, 139.2, 134.6, 130.6,
129.4, 117.5, 109.7, 20.8, 16.4.
IR (film): 3313, 2926, 1638, 1566, 1449, 1323, 1114, 694 cm–1
.
2-(2-Bromophenoxy)pyridine (4ao)3d
1H NMR (400 MHz, CDCl3): δ = 7.92–7.86 (m, 1 H), 7.24 (s, 1 H), 7.19
(t, J = 8.0 Hz, 1 H), 7.10 (d, J = 7.8 Hz, 1 H), 6.96 (s, 1 H), 6.80 (d, J = 7.8
Hz, 1 H), 6.72–6.66 (m, 3 H), 5.98 (t, J = 5.6 Hz, 1 H), 4.44 (d, J = 5.6 Hz,
2 H), 2.57 (s, 3 H), 2.40 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 160.7, 158.6 (d, J = 10.9 Hz), 156.2,
155.3, 154.8, 153.3 (d, J = 11.7 Hz), 151.4, 150.9 (d, J = 11.7 Hz), 132.0
(q, J = 32.1 Hz), 129.8, 124.8 (q, J = 271.3 Hz), 123.7 (dd, J = 10.2, 3.7
Hz), 122.7, 121.8 (d, J = 8.7 Hz), 121.4, 120.7, 120.1 (q, J = 3.7 Hz),
115.7 (q, J = 3.6 Hz), 110.9 (dd, J = 21.8, 3.6 Hz), 103.4 (dd, J = 26.1,
24.1 Hz), 34.9, 23.2, 19.3.
Yield: 0.026 g (20%); yellow solid; mp 68–69 °C.
1H NMR (400 MHz, CDCl3): δ = 8.16 (d, J = 3.6 Hz, 1 H), 7.72–7.68 (m,
1 H), 7.65 (d, J = 7.6 Hz, 1 H), 7.37 (d, J = 7.2 Hz, 1 H), 7.21 (d, J = 7.6 Hz,
1 H), 7.13 (t, J = 7.6 Hz, 1 H), 7.01–6.96 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 163.1, 154.8, 147.7, 139.6, 130.6,
127.7, 124.5, 122.6, 119.9, 119.0, 110.8.
Dehalogenation of 4la and 4ln
A mixture of 4la or 4ln (0.5 mmol), anhyd K2CO3 (80 mg), and 5% Pd/C
(20 mg) in DMF (5 mL) was hydrogenated under atmospheric pres-
sure at r.t. over a 3 h period. After the reaction was completed, CH2Cl2
(10 mL) and H2O (10 mL) were added to the mixture. The organic lay-
er was separated, washed with 5% aq Na2CO3 (10 mL) and brine (10
mL), dried (anhyd Na2SO4) and filtered. The solvent was removed in
vacuo and the residue was purified by flash column chromatography
(the crude residue was dry loaded on silica gel, 1:10, EtOAc/PE) to
provide the desired product 4aa or 4an.
HRMS (ESI): m/z (M + H)+ calcd for C22H19F5N3O2: 452.1397; found:
452.1391.
Funding Information
Financial support from the ‘Overseas 100 Talents Program’ of Guangxi
Higher Education, National Natural Science Foundation of China
(21562005, 21602037), State Key Laboratory for Chemistry and Mo-
lecular Engineering of Medicinal Resources, Ministry of Science and
Technology of China (CMEMR2015-A05), and Natural Science Foun-
dation of Guangxi (2015GXNSFCA139001, 2016GXNSFFA380005) are
4,6-Dimethyl-2-[3-(trifluoromethyl)phenoxy]nicotinonitrile (5)
A 100 mL Teflon-sealed flask was charged with the 2-pyridone 1m
(296 mg, 2.0 mmol), diaryliodonium salts 2r (1.695 g, 3.0 mmol, 1.5
equiv), and Cs2CO3 (975 mg, 3.0 mmol, 1.5 equiv) under air atmo-
sphere. DCE (20 mL) was then added to the flask. The reaction mix-
ture was stirred at 120 °C until the 2-pyridone 1m was consumed
completely (monitored by TLC). At this time, the solvent was removed
in vacuo and the residue was purified by flash column chromatogra-
phy (the crude residue was dry loaded on silica gel, 1:10 EtOAc/PE) to
provide the desired product 5; yield: 485 mg (83%); white solid; mp
102–103 °C.
greatly appreciated.
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Supporting information for this article is available online at
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References
IR (film): 3073, 2922, 2229, 1600, 1449, 1327, 1179, 799 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.54–7.48 (m, 3 H), 7.39 (d, J = 7.2 Hz,
1 H), 6.86 (s, 1 H), 2.54 (s, 3 H), 2.37 (s, 3 H).
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K
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Synthesis
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