Highly c3-selective direct alkylation and arylation of 2-pyridones under visible-light-promoted photoredox catalysis

Article abstract of DOI:10.3987/COM-16-13459

An Ir photoredox catalyst-mediated highly site-selective direct alkylation and arylation of 2-pyridones has been developed. Under visible-light-promoted conditions, ethyl 2-bromo-2,2-difluoroacetate couples with various 2-pyridones exclusively at the C3 position. A similar photoredox catalysis is also effective for the direct C3- Arylation with diaryliodonium triflates. Thus, these reactions occurs under very mild conditions (blue LEDs irradiation and ambient temperature) to form the corresponding C3- Alkylated and arylated 2-pyridones of potential interest in medicinal and pharmaceutical chemistry.

Full text of DOI:10.3987/COM-16-13459

HETEROCYCLES, Vol. 92, No. 7, 2016, pp. -. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 12th March, 2016, Accepted, 25th April, 2016, Published online, 10th May, 2016
DOI: 10.3987/COM-16-13459
HIGHLY C3-SELECTIVE DIRECT ALKYLATION AND ARYLATION
OF
2-PYRIDONES
UNDER
VISIBLE-LIGHT-PROMOTED
PHOTOREDOX CATALYSIS
Atifah Najib, Sho Tabuchi, Koji Hirano,* and Masahiro Miura*
Department of Applied Chemistry, Graduate School of Engineering, Osaka
University,
Suita,
Osaka
565-0871,
Japan.
E-mail:
k_hirano@chem.eng.osaka-u.ac.jp; miura@chem.eng.osaka-u.ac.jp
Abstract – An Ir photoredox catalyst-mediated highly site-selective direct
alkylation and arylation of 2-pyridones has been developed. Under
visible-light-promoted conditions, ethyl 2-bromo-2,2-difluoroacetate couples with
various 2-pyridones exclusively at the C3 position. A similar photoredox
catalysis is also effective for the direct C3-arylation with diaryliodonium triflates.
Thus, these reactions occurs under very mild conditions (blue LEDs irradiation
and ambient temperature) to form the corresponding C3-alkylated and arylated
2
-pyridones of potential interest in medicinal and pharmaceutical chemistry.
INTRODUCTION
Since 2-pyridones are prevalent structural motifs in many pharmaceutical targets and biologically active
natural and unnatural products, as exemplified by ciclopirox, milrinone, camptothecin, perampanel,
1
fredericamycin, and PD180970, the C–C forming process on the 2-pyridone ring ranks as one of
long-standing important topics in synthetic organic chemistry. While most traditional strategies rely on
2
preactivated halogenated 2-pyridones as starting materials, recent advances in the C–H functionalization
allow unfunctionalized 2-pyridones to be directly adopted in several types of C–C formations. The
biggest challenge in the C–H functionalization of the 2-pyridone is the control of the site-selectivity. In
3
1
984, Itahara and Ouseto reported the Pd-mediated direct alkenylation of the 2-pyridone with acrylates.
The reaction was stoichiometric in palladium, but the high C5-selectivity was observed. Li then
developed the catalytic variant of this process by using a Cu(OAc) terminal oxidant and also succeeded
2
4
in the related C5-arylation with polyfluoroarenes under Pd/Ag catalysis (Scheme 1a). Additionally,
Nakao and Hiyama achieved the Ni/Al-catalyzed direct alkenylation and alkylation with alkynes and
5
alkenes, respectively, at the otherwise difficult C6 position. Our group also developed the Cu-mediated

6
or Cu/O -catalyzed C6-selective heteroarylation with the aid of a pyridine directing group. Since then,
2
some groups successfully applied the pyridine-directed methodology to the Rh-catalyzed C6-selective
7
alkylation and alkynylation (Scheme 1b). On the other hand, the C3-selective C–H functionalization
8
has been less studied, despite relatively high electron density at the C3 position. In this context, we
recently revisited the unique nature of classical carbon-centered radical species and developed the
9
10
Ni-catalyzed and Mn-mediated radicalic direct C3 alkylation and arylation. Subsequently, Maiti
1
1
reported a related arylation reaction in the presence of a Fe catalyst (Scheme 1c).
However, heating
o
conditions (70–130 C) and/or excess metallic salts are often necessary for a satisfactory conversion.
Thus, despite certain advances mentioned above, there still remains a large demand for further
development of the site-selective C–H functionalization of 2-pyridones, particularly at the relatively
inaccessible C3 position. Herein, we report an Ir-catalyzed, radical-mediated direct C3-alkylation and
1
2
arylation of 2-pyridones with ethyl 2-bromo-2,2-difluoroacetate and diaryliodonium triflates,
respectively. The reactions proceed smoothly at ambient temperature under visible-light-promoted
1
3
conditions (Scheme 2).
RESULTS AND DISCUSSION
1
4
Prompted by recent rapid progress of the radical-mediated, visible-light-promoted photoredox catalysis,
we commenced optimization studies with N-methyl-2-pyridone (1a, 1.25 mmol) and ethyl
1
5
2
-bromo-2,2-difluoroacetate (2a, 0.25 mmol) as model substrates under blue LEDs irradiation (Table 1).
Initial catalyst screening identified Ir(ppy) to be a good candidate in MeCN, and the corresponding
3
C3-alkylated 2-pyridone 3aa was isolated in 74% yield: other representative photoredox catalysts,
Ir(ppy) (dtbpy)PF , Ru(bpy) Cl •6H O, and Eosin Y (Na), showed no catalytic activity (entries 1–4).
2
6
3
2
2
Among solvents we tested, MeCN was found to be optimal (entries 5–8). The addition of external
inorganic bases gave negligible or negative impact on the reaction efficiency (entries 9–12). A decrease
of amount of the pyridone 1a to 0.75 mmol provided a slightly lower but still synthetically useful yield of
3
aa (entry 13). The control experiments in the absence of light or catalyst resulted in no conversion
entry 14 and 15). Additionally, an investigation of on/off-switching of the light source revealed that the
reaction progressed steady under blue LEDs irradiation and stopped in the dark (see the Experimental
(
1
6
section). These outcomes suggest the operation of photoredox catalysis (vide infra).
Also note that
the difluorinated α-bromo ester 2a did not work at all under previously reported Ni-catalyzed conditions
9
(data not shown).

a) C5-Selective C–H functionalization
R'
R'
H
H
N
R
O
(cat.) Pd(II)
+
or
ArF
Cu(II) or Ag(I) oxidant
ArF
N
R
O
H
or
N
R
O
b) C6-Selective C–H functionalization
cat. Ni(0)/Al
+
R'
R'
H
N
R
O
R'
N
R
O
R'
N
N
Z
Y
cat. Cu(II)/O2
+
H
H
N
O
N
O
Y
Py
Z
Py
Py = 2-pyridyl
R
N2
R
N
O
R
cat. Rh(III)
+
H
N
O
or
R
Py
Py
or
TIPS
I(III)
N
O
Py = 2-pyridyl
TIPS
Py
c) C3-Selective C–H functionalization
R'
O
H
R'
OR''
cat. Ni(0)
OR''
+
Br
O
N
R
O
N
O
R
R'
H
Mn(III) or cat. Fe(II)
R'
+
N
R
O
(HO) B
N
R
O
2
Scheme 1. Site-selective C–H functionalization approaches to substituted 2-pyridones
F F
OEt
F F
OEt
H
Br
O
cat. Ir(III)
N
R
O
R'
+
O
blue LEDs
ambient temp
or
R'
N
R
O
or Ar
I
N
R
O
OTf
radical process
F F
OEt
or
via
•
R'
•
O
Scheme 2. Visible-light-promoted Ir photoredox catalysis for C3-selective direct alkylation and arylation
of 2-pyridones at ambient temperature (this work)

Table 1. Optimization studies for C3-selective alkylation of N-methyl-2-pyridone (1a) with ethyl
a
2
-bromo-2,2-difluoroacetate (2a) under visible-light-promoted photoredox catalysis
F F
catalyst (2 mol%)
F F
OEt
base (2.0 equiv)
+
OEt
Br
solvent, N , 6 h
O
2
N
O
N
O
O
blue LEDs
ambient temp
Me
Me
1a (5.0 equiv)
2a
3aa
b
entry
catalyst
Ir(ppy)3
base
none
none
none
none
none
none
none
none
solvent
MeCN
MeCN
MeCN
MeCN
DMSO
yield of 3aa (%)
1
2
3
4
5
6
7
8
9
(74)
0
Ir(ppy) (dtbpy)PF6
2
Ru(bpy) Cl •6H O
0
3
2
2
Eosin Y (Na)
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
none
0
24
36
20
44
65
73
73
60
(58)
0
1,4-dioxane
DMF
ClCH CH Cl
2
2
K PO
MeCN
3
4
1
1
1
1
1
1
0
1
2
3
4
5
Na CO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
2
3
NaOAc
KOAc
none
c
d
none
none
0
a
Conditions: 1a (1.3 mmol), 2a (0.25 mmol), catalyst (0.0050 mmol), solvent (3.0 mL), ambient temp,
b
1
blue LEDs irradiation, 6 h, N .
in parentheses.
Yields are estimated by H NMR or GC analysis. Isolated yields are
2
c
d
With 0.75 mmol (3.0 equiv) of 1a.
In the dark.
t-Bu
N
Ir
N
N
N
N
N
N
CO Na
2
Ir+
PF6–
Ru2+
Br
Br
2Cl–
N
N
N
N
N
N
NaO
O
O
t-Bu
6H O
2
Br
Br
Ir(ppy)3
Ir(ppy) (dtbpy)PF
Ru(bpy) Cl •6H O
3 2 2
Eosin Y (Na)
2
6

Under the conditions of entry 1 in Table 1, we subsequently performed the direct alkylation of various
substituted 2-pyridones 1 with 2a (Scheme 3). Regardless of the substitution pattern of the methyl
group, the reaction occurred exclusively at the C3 position, and the corresponding C3-difluoroalkylated
products 3ba–3da were formed in substantial yields. The Ir photoredox catalysis was tolerated with
electron-donating methoxy and benzyloxy groups (3ea and 3fa) while the electron-withdrawing
trifluoromethyl and halogen substituents dropped the yield (3ga–3ia). The observed trend is consistent
with the plausible radical mechanism including SOMO/HOMO interaction between the electrophilic
9
,10
difluoromethyl radicals and electron-rich pyridones.
We also tested the NH 2-pyridone but the yield
was lower (3ja). In most cases, the starting alkyl bromide 2a fully consumed despite the moderate yield
of 3. We could not identify any byproducts, but homocoupling and/or reduction of 2a might
1
7
competitively occur. Although we also tested other fluorinated alkyl halides, only sulfone derivative 4
1
8
moderately reacted with 1a under slightly modified conditions using Na S O as an additive (Scheme 4).
2
2
3
F F
F F
OEt
Ir(ppy) (2 mol%)
3
R
+
OEt
R
Br
MeCN, N , 6 h
2
O
N
O
N
O
O
blue LEDs
ambient temp
Me
Me
1
(5.0 equiv)
2a
3
Me
F F
F F
OEt
F F
OEt
Me
OEt
O
O
O
O
N
O
N
Me
N
O
Me
Me
Me
3ba 43%
3ca 46%
3da 68%
MeO
BnO
F F
F F
F F
OEt
OEt
F C
OEt
3
O
O
O
O
O
N
N
O
N
Me
Me
Me
3
ea 41%
3fa 57%
3ga (21%)
F F
F F
F F
Cl
OEt
Br
OEt
OEt
O
O
O
N
O
N
O
N
H
O
Me
Me
3ha (23%)
3ia (28%)
3ja (17%)
Scheme 3. C3-Selective direct alkylation of various 2-pyridones 1 with ethyl 2-bromo-2,2-difluoroacetate
1
(
2a) under visible-light-promoted Ir(ppy) catalysis. Isolated yields are shown. H NMR yields are in
3
parentheses.

F F
Ir(ppy) (2 mol%)
3
F F
Na S O (2.0 equiv)
2
2
3
+
S
I
S
MeCN, N , 6 h
2
O O
N
O
N
O
O O
blue LEDs
ambient temp
Me
Me
1a (5.0 equiv)
4
5 24%
5% w/o Na S O )
(
2
2
3
Scheme 4. C3-Selective direct alkylation of N-methyl 2-pyridone (1a) with
(difluoroiodomethyl)sulfonyl]benzene (4) under Na S O -modified conditions
[
2
2
3
Table 2. Optimization studies for C3-selective phenylation of N-methyl-2-pyridone (1a) with
a
diphenyliodonium triflate (6a) under visible-light-promoted photoredox catalysis
Ir(ppy) (2 mol%)
3
base (2.0 equiv)
+
MeCN, N , 6 h
I
2
N
O
N
O
blue LEDs
ambient temp
Me
OTf
Me
1a (5.0 equiv)
6a
7aa
b
entry
base
yield of 7aa (%)
1
2
3
4
5
6
7
8
none
28
7
i-Pr NEt
2
LiOAc
NaOAc
KOAc
CsOAc
29
30
(40)
30
(39)
2
K PO4
3
KO-t-Bu
KOAc
KOAc
KOAc
c
9
(55)
0
d
1
1
0
1
e
0
a
Conditions: 1a (1.3 mmol), 6a (0.25 mmol), Ir(ppy) (0.0050 mmol), MeCN (3.0 mL), ambient temp,
3
b
1
blue LEDs irradiation, 6 h, N .
in parentheses.
Yields are estimated by H NMR or GC analysis. Isolated yields are
2
c
d
e
In MeCN (1.0 mL).
In the dark.
Without Ir(ppy)3.
We then turned our attention to the related direct C3-phenylation of N-methyl-2-pyridone (1a) with
1
9
diphenyliodonium triflate (6a) (Table 2).
The conditions same as those in Scheme 3 afforded the
desired C3-phenylation product 7aa albeit with 28% yield (entry 1). Given the liberation of strongly
acidic TfOH, we investigated basic additives to quench with it (entries 2–8). Gratifyingly, some
potassium inorganic bases improved the yield, with KOAc to be optimal (entry 5). Although additional

solvent and catalyst screening gave no further improvement as far as we examined, we finally obtained
5% isolated yield of 7aa by reducing the amount of MeCN solvent into 1.0 mL (entry 9). Also in the
direct alkylation, both visible light and Ir(ppy) were essential for the promotion of the reaction (entries
5
3
1
0 and 11).
We next investigated the scope and limitation of the direct arylation reaction. Representative products
are shown in Scheme 5. The C3 selectivity was uniformly high, and C4-, C5-, and C6-methylated
substrates furnished the corresponding C3-phenylated pyridones 7ba–7da as the single isomers. In
contrast to the difluoroalkylation in Scheme 3, electron-withdrawing trifluoromethyl and chloro
substituents were found to be better than electron-donating methoxy group (7ea–7ga vs 7ha). This
outcome could arise from an effective SOMO/LUMO interaction between nucleophilic phenyl radical and
9
,10
electron-deficient 2-pyridones.
N-butenyl, N-phenyl, and even free N-H substituents (7ja–7la). The introduction of 4-methylphenyl,
-tert-butylphenyl, and 4-bromophenyl groups was also possible, and the corresponding C3-arylated
The direct phenylation was compatible with 2-pyridones bearing
4
products 7ab–7ad were formed in moderate yields. In most cases, the yield was moderate probably
because the Ir catalyst gradually decomposed during the course of the reaction. Actually, we recovered
the starting diaryliodonium triflates 6 in some cases. Additionally, the O-analogue of 2-pyridone,
coumarin (8), also coupled with 6a under identical conditions (Scheme 6).
1
4
On the basis of the literature information and our findings, the plausible catalytic cycle of the reaction of
1
a with 2a or 6a is illustrated in Scheme 7. Initial visible light irradiation excites the starting Ir(III)
catalyst to the active Ir(III)* species. Subsequent reversible single electron transfer (SET) from Ir(III)*
to 2a or 6a delivers the Ir(IV) of the higher oxidation state and anion radical species, which smoothly
undergoes the fragmentation to the corresponding alkyl or aryl radical 10. The 2-pyridone 2a then reacts
with 10 at the C3 position to afford the allylic radical intermediate 11. The second SET process between
1
1 and Ir(IV) closes the Ir catalytic cycle and generates the cationic species 12, which is finally
deprotonated to furnish the observed C3-alkylated 3aa or -arylated 7aa. The regioselectivity can be
determined in the radical addition step and controlled by the inherent nature of radical intermediates: the
higher stability associated with the resonance effect of the allylic radical 11 and relatively large
9
,10
contributions of HOMO and LUMO at the C3 position of the 2-pyridone 2a may be major controlling
1
6
factors. However, the exact mechanism still remains to be elucidated.
In the above arylation reaction, one aryl group of symmetrical diaryliodonium salts 6 was lost as the aryl
iodide. This is problematic and less atom-economical particularly when more complex and highly

functionalized aryl moiety is installed. Thus, we attempted the arylation with unsymmetrical
Mes-I(III)-Ar reagent 13 (Mes = mesityl) instead of 6 (Scheme 8a). Although the yield was lower than
that with the symmetrical 6, the Mes group did not transfer at all, and the desired aryl group was
selectively incorporated to the pyridone molecules. Trifluoromethyl- and ester-containing aromatic
rings were also accessible (7ae and 7af). Additionally notable is that the phenyldiazonium salt 14,
which is readily available from the corresponding aniline, is a potential alternative to the diaryliodonium
salt (Scheme 8b).
R3
R3
R3
Ir(ppy) (2 mol%)
KOAc (2.0 equiv)
3
R1
R1
+
N
R2
O
MeCN, N2, 6 h
I
N
O
blue LEDs
ambient temp
R2
OTf
6
1
(5.0 equiv)
Me
7
CF3
Me
N
O
N
O
Me
N
O
N
O
Me
Me
Me
Me
7ba 35%
7ca 23%
7da 51%
7ea 54%
Cl
MeO
N
O
Cl
N
O
N
O
N
H
O
Me
Me
Me
7ja 20%
7fa 43%
7ga 42%
7ha (7%)
Me
t-Bu
Br
N
O
N
Ph
7la 40%
O
N
O
N
O
N
O
Me
Me
Me
7
ka 27%
7ab 30%
7ac 39%
7ad 38%
Scheme 5. C3-Selective direct arylation of 2-pyridones 1 with diaryliodonium triflates 6 under
1
visible-light-promoted Ir(ppy) catalysis. Isolated yields are shown. H NMR yields are in
3
parentheses.
Ir(ppy) (2 mol%)
3
KOAc (2.0 equiv)
+
MeCN, N , 6 h
I
2
O
O
O
O
blue LEDs
ambient temp
OTf
6a
8
(5.0 equiv)
9 53%
Scheme 6. C3-Selective direct phenylation of coumarin (8) with diphenyliodonium triflate (6a) under
visible-light-promoted Ir(ppy) catalysis
3

–
–
Br or Ph-I + OTf
1a
R• or Ph•
F F
10
OEt
R =
R/Ph
O
2a]•– or [6a]•–
[
•
O
N
Ir(IV)
11
Me
2a or 6a
R/Ph
R/Ph
(
KOAc)
+
Ir(III)*
Ir(III)
–
H+
N
O
N
O
Me
Me
12
3aa or 7aa
visible light
Scheme 7. Plausible mechanism for C3-selective direct alkylation and arylation of 2-pyridone 1a with 2a
or 6a under visible-light-promoted Ir(ppy) catalysis
3
a) C3-Selective arylation with unsymmetrical Mes-I(III)-Ar triflates 13
R
Ir(ppy) (2 mol%)
KOAc (2.0 equiv)
R
3
+
N
O
MeCN, N , 6 h
I
2
N
O
Me
blue LEDs
ambient temp
OTf
13
Me
1
a (5.0 equiv)
7
t-Bu
Br
CF3
CO Me
2
N
O
N
O
N
O
N
O
Me
Me
Me
Me
7ac 25%
7ad 23%
7ae 33%
7af 26%
b) C3-Selective arylation with phenyldiazonium salt 14
Ir(ppy) (2 mol%)
3
KOAc (2.0 equiv)
+
MeCN, N , 6 h
2
N
O
BF4– +N2
N
O
blue LEDs
ambient temp
Me
Me
1a (5.0 equiv)
14
7aa 29%
Scheme 8. C3-Selective direct arylation of N-methyl-2-pyridone (1a) with unsymmetrical Mes-I(III)-Ar
triflates 13 or phenyldiazonium salt 14 under visible-light-promoted Ir(ppy) catalysis. Isolated yields
3
are shown.
CONCLUSION
We have developed a highly C3-selective difluoroalkylation and arylation of 2-pyridones under
visible-light-promoted Ir(ppy) photoredox catalysis. The reactions proceed smoothly at ambient
3
temperature and provide a direct access to the C3-functionalized 2-pyridones of great potential in
medicinal and pharmaceutical chemistry, although the reaction efficiency is still moderate. The present

catalysis can complement the known C–H functionalization protocols in view of the site-selectivity.
Ongoing work seeks to develop new strategies for the site-selective and diverse C–H functionalization of
2
-pyridones.
EXPERIMENTAL
1
13
19
General. H, C, and F NMR spectra were recorded at 400, 100, and 376 MHz, respectively, for CDCl
3
solutions. HRMS data were obtained by APCI. GC analysis was carried out using a silicon OV-17
column (i. d. 2.6 mm x 1.5 m) or a CBP-1 capillary column (i. d. 0.5 mm x 25 m). TLC analyses were
performed on commercial glass plates bearing 0.25-mm layer of Merck Silica gel 60F . Silica gel
2
54
(Wakogel 200 mesh) was used for column chromatography. Blue light irradiation was conducted by a
blue LED tape light. Gel permeation chromatography (GPC) was performed with a CHCl eluent (3.5
3
mL/min, UV detector). Unless otherwise noted, materials obtained from commercial suppliers were
used without further purification. MeCN was dried on a Glass Contour Solvent dispending system
(Nikko Hansen & Co., Ltd.) prior to use.
Ir(ppy) was synthesized from IrCl •3H O and
3 3 2
2
0
2
-phenylpyridine under the reported conditions.
Symmetrical and unsymmetrical diaryliodonium
2
1
triflates were prepared according to the literature.
Visible-light-promoted Ir(ppy) -catalyzed C3-alkylation of 2-pyridones. The reaction of 1a with 2a
3
is representative (Table 1, entry 1). Ir(ppy) (3.3 mg, 0.0050 mmol) was placed in a Schlenk tube.
3
Nitrogen gas displacement was done by using the standard Schlenk technique, and N-methyl-2-pyridone
(1a, 136.4 mg, 1.25 mmol) and ethyl bromodifluoroacetate (2a, 50.7 mg, 0.25 mmol) were added using
syringe followed by addition of MeCN (3 mL). The mixture was stirred for 6 h under blue light LED
irradiation (12 DC/3 W). Water (20 mL) was added, and extraction was done with EtOAc (15 mL x 3).
The combined organic phase was dried over sodium sulfate and then concentrated in vacuo. Purification
via column chromatography (Wakosil C-200, hexane/EtOAc = 20/1 to EtOAc/CH Cl /Et N = 1/1/0.05)
2
2
3
provided pure ethyl 2,2-difluoro-2-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)acetate (3aa, 42.7 mg, 0.19
mmol, 74% yield).
Visible-light-promoted Ir(ppy) -catalyzed C3-arylation of 2-pyridones. The reaction of 1a with 6a
3
is representative (Table 2, entry 9). In a glovebox filled with nitrogen, Ir(ppy) (3.3 mg, 0.0050 mmol),
3
Ph IOTf (6a, 136.4 mg, 0.25 mmol), and potassium acetate (49.1 mg, 0.50 mmol) were placed in a
2
Schlenk tube. The tube was sealed with a septum and then taken out of the glovebox. A solution of
N-methyl-2-pyridone (1a, 136.4 mg, 1.25 mmol) in MeCN (1 mL) was added using a syringe. The
mixture was stirred for 6 h under blue light LED irradiation (12 DC/3 W). Water (20 mL) was added,
and extraction was done with EtOAc (15 mL x 3). The combined organic phase was dried over sodium

sulfate and then concentrated in vacuo. Purification via column chromatography (Wakosil C-200,
hexane/EtOAc = 20/1 to EtOAc/CH Cl /Et N = 1/1/0.05) followed by GPC provided pure
2
2
3
1
-methyl-3-phenylpyridin-2(1H)-one (7aa, 25.4 mg, 0.14 mmol, 55% yield).
Experiment of ON/OFF Switching of Light Source. In the glove box filled with nitrogen, Ir(ppy)3
1.3 mg, 0.0020 mmol), N-methyl-2-pyridone (1a, 54.6 mg, 0.50 mmol), ethyl bromodifluoroacetate (2a,
0.3 mg, 0.10 mmol), dibenzyl ether (internal standard, 12.3 mg), and MeCN-d (0.75 mL) were placed in
(
2
3
a NMR tube. The tube was sealed with a septum and taken out of the glovebox. After sonication for a
few seconds, the on-off switching of light source was performed, and the reaction progress was monitored
1
by H NMR. The obtained result is shown in Scheme 9.
7
6
5
4
3
2
1
0
0
0
0
0
0
0
lightꢀon
lightꢀoff
0
0
20
40
60
80
100
120
140
160
180
timeꢀ(min)
Scheme 9. Reaction progress in on/off switching of the light source
Characterization Data for Products
Ethyl 2,2-difluoro-2-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)acetate (3aa): 42.7 mg, 74%, yellow
-
1
1
oil; IR (neat, cm ) 767, 1041, 1112, 1276, 1560, 1662, 1772; H NMR (400 MHz, CDCl ) δ 1.36 (t, J =
3
7
.2 Hz, 3H), 3.56 (s, 3H), 4.38 (q, J = 7.2 Hz, 2H), 6.29 (t, J = 6.9 Hz, 1H), 7.44 (d, J = 6.9 Hz, 1H), 7.78
1
3
(
dt, J = 6.9, 1.0 Hz, 1H); C NMR (100 MHz, CDCl ) δ 13.89, 37.43, 62.98, 104.88, 111.54 (t, J = 247.7
3
Hz), 124.36 (t, J = 24.5 Hz), 137.60 (t, J = 7.0 Hz), 140.82, 159.96 (t, J = 5.0 Hz), 163.33 (t, J = 32.7
1
9
+
Hz); F NMR (376 MHz, CDCl ) δ -105.86; HRMS (APCI) m/z (M+H) calcd for C H F NO :
3
10 12
2
3
2
32.0780, found: 232.0779.
Ethyl 2-(1,4-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-2,2-difluoroacetate (3ba): 26.3 mg, 43%, white
o
-1
1
solid, mp 83.8-85.9 C; IR (neat, cm ) 785, 1114, 1354, 1604, 1654, 1772; H NMR (400 MHz, CDCl ) δ
3
1
.36 (t, J = 7.2 Hz, 3H), 2.44 (t, J = 4.0 Hz, 3H), 3.48 (s, 3H), 4.38 (q, J = 7.2 Hz, 2H), 6.07 (d, J = 7.0
1
3
Hz, 1H), 7.27 (d, J = 7.0 Hz, 1H); C NMR (100 MHz, CDCl ) δ 13.92, 20.19 (t, J = 5.4 Hz), 37.35,
3

6
1
2.64, 110.48, 113.86 (t, J = 247.3 Hz), 121.05 (t, J = 24.2 Hz), 138.77, 152.87, 160.57 (t, J = 6.43 Hz),
1
9
+
63.83 (t, J = 32.2 Hz); F NMR (376 MHz, CDCl ) δ -99.34; HRMS (APCI) m/z (M+H) calcd for
3
C H F NO : 246.0936, found 246.0939.
1
1
14
2
3
Ethyl 2-(1,5-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-2,2-difluoroacetate (3ca): 28.2 mg, 46%,
-
1
1
yellow oil; IR (neat, cm ) 744, 796, 1132, 1568, 1606, 1668, 1772; H NMR (400 MHz, CDCl ) δ 1.35 (t,
3
1
3
J = 7.2 Hz, 3H), 2.15 (s, 3H), 3.52 (s, 3H), 4.38 (q, J = 7.2 Hz, 2H), 7.22 (s, 1H), 7.65 (s, 1H); C NMR
(
100 MHz, CDCl ) δ 13.89, 17.09, 37.23, 62.96, 111.61 (t, J = 247 Hz), 114.08, 123.72 (t, J = 24.0 Hz),
3
1
9
1
38.51, 139.90 (t, J = 6.6 Hz), 159.21 (t, J = 4.4 Hz), 163.41 (t, J = 32.0 Hz); F NMR (376 MHz,
+
CDCl ) δ -105.75; HRMS (APCI) m/z (M+H) calcd for C H F NO : 246.0936, found 246.0931.
3
11 14
2
3
Ethyl 2-(1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-2,2-difluoroacetate (3da): 41.7 mg, 68%, white
o
-1
1
solid, mp 107.2-108.2 C; IR (neat, cm ) 1112, 1296, 1575, 1653, 1774; H NMR (400 MHz, CDCl ) δ
3
1
.35 (t, J = 7.2 Hz, 3H), 2.41 (s, 3H), 3.53 (s, 3H), 4.37 (q, J = 7.2 Hz, 2H), 6.17 (d, J = 7.3 Hz, 1H), 7.66
1
3
(
d, J = 7.3 Hz, 1H); C NMR (100 MHz, CDCl ) δ 13.91, 21.16, 31.09, 62.86, 105.58, 111.89 (t, J =
3
2
3
2
46.9 Hz), 120.84 (t, J = 24.5 Hz), 136.59 (t, J = 6.6 Hz), 149.75, 160.68 (t, J = 5.3 Hz), 163.60 (t, J =
1
9
+
3.6 Hz); F NMR (376 MHz, CDCl ) δ -105.70; HRMS (APCI) m/z (M+H) calcd for C H F NO :
3
11 14
2
3
46.0936, found: 246.0936.
Ethyl 2,2-difluoro-2-(4-methoxy-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)acetate (3ea): 26.8 mg,
o
-1
1
4
1%, yellow solid, mp 104.7-106.5 C; IR (neat, cm ) 788, 1028, 1263, 1363, 1544, 1654, 1772; H
NMR (400 MHz, CDCl ) δ 1.36 (t, J = 7.2 Hz, 3H), 3.47 (s, 3H), 3.92 (s, 3H), 4.38 (q, J = 7.2 Hz, 2H),
3
1
3
6
6
.09 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H); C NMR (100 MHz, CDCl ) δ 13.95, 37.18, 56.56,
3
2.60, 70.57, 94.46, 105.64 (t, J = 24.2 Hz), 113.17 (t, J = 246.2 Hz), 141.48, 161.09, 164.15 (t, J = 32.1
1
9
+
Hz), 168.00; F NMR (376 MHz, CDCl ) δ -100.17; HRMS (APCI) m/z (M+H) calcd for C H F NO :
3
11 14
2
4
2
62.0885, found: 262.0881.
Ethyl 2-(4-(benzyloxy)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2,2-difluoroacetate (3fa): 48.0 mg,
o
-1
1
5
7%, white solid, mp 84.5-86.1 C; IR (neat, cm ) 1080, 1109, 1152, 1363, 1541, 1653, 1772; H NMR
(
400 MHz, CDCl ) δ 1.34 (t, J = 7.2 Hz, 3H), 3.45 (s, 3H), 4.34 (q, J = 7.2 Hz, 2H), 5.22 (s, 2H), 6.09 (d,
3
1
3
J = 7.8 Hz, 1H), 7.32-7.40 (m, 6H); C NMR (100 MHz, CDCl ) δ 13.93, 37.11, 62.57, 70.88, 95.55,
3
1
06.07 (t, J = 23.6 Hz), 113.20 (t, J = 246.8 Hz), 126.78, 128.33, 128.74, 135.16, 141.52, 161.10 (t, J =
1
9
4
.7 Hz), 164.17 (t, J = 31.7 Hz), 167.12; F NMR (376 MHz, CDCl ) δ -99.90; HRMS (APCI) m/z
3
+
(
M+H) calcd for C H F NO : 338.1198, found: 338.1198.
1
7
18
2
4
3
1
6
1
-(Difluoro(phenylsulfonyl)methyl)-1-methylpyridin-2(1H)-one (5): 18.3 mg, 24%, white solid, mp
o
-1
1
74.2-176.2 C; IR (neat, cm ) 590, 1074, 1165, 1550, 1653; H NMR (400 MHz, CDCl ) δ 3.58 (s, 3H),
3
.28 (t, J = 6.8 Hz, 1H), 7.56 (dd, J = 6.8, 2.0 Hz, 1H), 7.62 (t, J = 8.1 Hz, 2H), 7.76 (tt, J = 7.5, 2.0 Hz,
1
3
H), 7.80 (dd, J = 7.5, 4.1 Hz, 1H), 8.07 (d, J = 7.8 Hz, 2H); C NMR (100 MHz, CDCl ) δ 38.12,
3

1
7
04.35, 116.80 (t, J = 20.5 Hz), 121.52 (t, J = 287.6 Hz), 129.18, 130.92, 133.42, 135.15, 143.00 (t, J =
1
9
+
.3 Hz), 143.24, 158.71; F NMR (376 MHz, CDCl ) δ -99.64; HRMS (APCI) m/z (M+H) calcd for
3
C H F NO S: 300.0500, found: 300.0500.
1
3
12
2
3
o
1
-Methyl-3-phenylpyridin-2(1H)-one (7aa): 20.8 mg, 55%, white solid, mp 106.4-108.4 C; IR (neat,
-
1
1
cm ) 702, 773, 1583, 1647; H NMR (400 MHz, CDCl ) δ 3.62 (s, 3H), 6.25 (t, J = 7.0 Hz, 1H), 7.32 (tt,
3
J = 7.2, 2.1 Hz, 2H), 7.40 (t, J = 7.2 Hz, 2H), 7.49 (dd, J = 7.0, 2.1 Hz, 1H), 7.69 (dd, J = 7.0, 1.2 Hz,
1
3
2
1
1
H); C NMR (100 MHz, CDCl ) δ 38.24, 105.82, 127.66, 128.10, 128.62, 131.64, 136.83, 137.41,
3
+
37.59, 161.95; HRMS (APCI) m/z (M+H) calcd for C H NO: 186.0913, found: 186.0914.
1
2
12
o
-Methyl-3-(p-tolyl)pyridin-2(1H)-one (7ab): 15.0 mg, 30%, white solid, mp 135.2-137.1 C; IR (neat,
-
1
1
cm ) 825, 1282, 1560, 1585, 1645; H NMR (400 MHz, CDCl ) δ 2.37 (s, 3H), 3.61 (s, 3H), 6.23 (t, J =
3
6
.7 Hz, 1H), 7.20 (d, J = 8.2 Hz, 2H), 7.27 (dd, J = 2.0, 6.7 Hz, 1H), 7.46 (dd, J = 2.0, 7.0 Hz, 1H), 7.59
1
3
(
d, J = 8.2 Hz, 2H); C NMR (400 MHz, CDCl ) δ 21.23, 38.20, 105.79, 128.45, 128.80, 131.63,
3
+
1
33.93,137.06, 137.10, 137.45, 162.02; HRMS (APCI) m/z (M+H) calcd for C H NO: 200.1070,
1
3
14
found: 200.1070.
3
9
3
-(4-(tert-Butyl)phenyl)-1-methylpyridin-2(1H)-one (7ac): 23.5 mg, 39%, yellowish-brown solid, mp
o
-1
1
4.5-96.2 C; IR (neat, cm ) 570, 1595, 1647, 2960; H NMR (400 MHz, CDCl ) δ 1.34 (s, 9H), 3.61 (s,
3
H), 6.24 (t, J = 6.8 Hz, 1H), 7.29 (dd, J = 6.8, 2.0 Hz, 1H), 7.42 (d, J = 8.7 Hz, 2H), 7.48 (dd, J = 6.8, 2.0
1
3
Hz, 1H), 7.64 (d, J = 8.7 Hz, 2H); C NMR (100 MHz, CDCl ) δ 31.33, 34.58, 38.21, 105.83, 125.08,
3
+
1
2
3
28.26, 131.56, 133.88, 137.08, 137.16, 150.60, 162.06; HRMS (APCI) m/z (M+H) calcd for C H NO:
1
6
20
42.1539, found: 242.1541.
o
-(4-Bromophenyl)-1-methylpyridin-2(1H)-one (7ad): 25.1 mg, 38%, white solid, mp 157.0-158.5 C;
-
1
1
IR (neat, cm ) 1008, 1550, 1583, 1647; H NMR (400 MHz, CDCl ) δ 3.62 (s, 3H), 6.25 (t, J = 6.9 Hz,
3
1
8
1
1
9
H), 7.33 (dd, J = 6.9, 2.0 Hz, 1H), 7.48 (dd, J = 6.9, 2.0 Hz, 1H), 7.52 (d, J = 8.7 Hz, 2H), 7.59 (d, J =
1
3
.7 Hz, 2H); C NMR (400 MHz, CDCl ) δ 38.27, 105.83, 121.77, 130.21, 130.36, 131.22, 135.70,
3
+
37.55, 137.80, 161.67; HRMS (APCI) m/z (M+H) calcd for C H BrNO: 264.0019, found: 264.0027.
1
2
11
-Methyl-3-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (7ae): 20.7 mg, 33%, brown solid, mp
o
-1
1
8.9-101.0 C; IR (neat, cm ) 773, 840, 1112, 1161, 1327, 1554, 1595, 1647; H NMR (400 MHz,
CDCl ) δ 3.63 (s, 3H), 6.29 (t, J = 6.9 Hz, 1H), 7.37 (dd, J = 6.9, 2.0 Hz, 1H), 7.53 (dd, J = 6.9, 2.0 Hz,
3
1
3
1
1
1
2
H), 7.65 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.2 Hz, 2H); C NMR (100 MHz, CDCl ) δ 38.29, 105.81,
3
24.26 (q, J = 270.4 Hz), 125.03 (q, J = 3.9 Hz), 128.86, 129.55 (q, J = 32.2 Hz), 130.14, 138.26, 138.35,
1
9
+
40.40, 161.63; F NMR (376 MHz, CDCl ) δ -62.56; HRMS (APCI) m/z (M+H) calcd for C H F NO:
3
13 11 3
54.0787, found: 254.0789.
Methyl 4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)benzoate (7af): 15.8 mg, 26%, white solid, mp
o
-1
1
1
32.5-134.6 C; IR (neat, cm ) 759, 1109, 1290, 1558, 1595, 1653, 1720; H NMR (400 MHz, CDCl ) δ
3

3
1
1
.63 (s, 3H), 3.93 (s, 3H), 6.28 (t, J = 6.9 Hz, 1H), 7.36 (dd, J = 6.9, 2.1 Hz, 1H), 7.48 (dd, J = 6.9, 2.1 Hz,
1
3
H), 7.51 (d, J = 8.3 Hz, 2H), 5.59 (d, J = 8.3 Hz, 2H); C NMR (400 MHz, CDCl ) δ 38.31, 52.08,
3
05.84, 128.49, 129.09, 129.40, 130.40, 138.25, 138.30, 141.45, 161.63, 167.02; HRMS (APCI) m/z
+
(
M+H) calcd for C H NO : 244.0968, found: 244.0968.
1
4
14
3
o
1
,4-Dimethyl-3-phenylpyridin-2(1H)-one (7ba): 17.4 mg, 35%, white solid, mp 65.0-67.0 C; IR (neat,
-
1
1
cm ) 771, 1263, 1598, 1647; H NMR (400 MHz, CDCl ) δ 2.04 (s, 3H), 3.54 (s, 3H), 6.11 (d, J = 7.0 Hz,
3
1
2
1
1
H), 7.18 (d, J = 7.0 Hz, 1H), 7.25 (d, J = 7.1 Hz, 2H), 7.31 (tt, J = 1.4, 7.1 Hz, 1H), 7.40 (t, J = 7.1 Hz,
1
3
H); C NMR (100 MHz, CDCl ) δ 20.44, 37.76, 108.92, 127.20, 128.16, 129.95,131.02, 135.69, 136.15,
3
+
47.03, 162.32; HRMS (APCI) m/z (M+H) calcd for C H NO: 200.1070, found: 200.1073.
1
3
14
o
,5-Dimethyl-3-phenylpyridin-2(1H)-one (7ca): 12.5 mg, 23%, white solid, mp 114.0-115.2 C; IR
-
1
1
(
neat, cm ) 694, 1282, 1419, 1577, 1595, 1653; H NMR (400 MHz, CDCl ) δ 2.13 (s, 3H), 3.58 (s, 3H),
3
1
3
7
1
.09 (d, J = 2.3 Hz, 1H), 7.29-7.41 (m, 4H), 7.69 (d, J = 6.0 Hz, 2H); C NMR (100 MHz, CDCl ) δ
3
7.21, 38.04, 114.61, 127.60, 128.06, 128.64, 131.01, 135.04, 136.89, 140.28, 161.15; HRMS (APCI) m/z
+
(
M+H) calcd for C H NO: 200.1070, found: 200.1070.
1
3
14
o
1
,6-Dimethyl-3-phenylpyridin-2(1H)-one (7da): 23.9 mg, 51%, white solid, mp 104.4-106.2 C; IR
-
1
1
(
neat, cm ) 785, 1120, 1259, 1431, 1566, 1587, 1639; H NMR (400 MHz, CDCl ) δ 2.40 (s, 3H), 3.60 (s,
3
1
3
3
H), 6.38 (d, J = 7.2 Hz, 1H), 7.28 (tt, J = 5.3, 1.3 Hz, 1H), 7.36-7.40 (m, 3H), 7.66-7.69 (m, 2H); C
NMR (100 MHz, CDCl ) δ 21.15, 31.70, 106.43, 127.28, 128.05, 128.08, 128.55, 136.89, 137.40, 145.49,
3
+
1
62.58; HRMS (APCI) m/z (M+H) calcd for C H NO: 200.1070, found: 200.1070.
1
3
14
1
-Methyl-3-phenyl-4-(trifluoromethyl)pyridin-2(1H)-one (7ea): 33.9 mg, 54%, brown oil; IR (neat,
-
1
1
cm ) 702, 769, 945, 1136, 1184, 1325, 1606, 1659; H NMR (400 MHz, CDCl ) δ 3.61 (s, 3H), 6.45 (d,
3
1
3
J = 7.2 Hz, 1H), 7.23-7.26 (m, J = 7.1 Hz, 2H), 7.26-7.40 (m, 4H); C NMR (100 MHz, CDCl ) δ 38.46,
3
1
01.49 (q, J = 4.9 Hz), 122.34 (q, J = 274.3 Hz), 127.93, 128.25, 129.35, 132.80, 133.36, 137.55 (q, J =
1
9
+
3
0.9 Hz), 137.85, 162.25; F NMR (376 MHz, CDCl ) δ -59.5749; HRMS (APCI) m/z (M+H) calcd for
3
C H F NO: 254.0787, found: 254.0785.
1
3
11 3
-
1
4
7
7
1
-Chloro-1-methyl-3-phenylpyridin-2(1H)-one (7fa): 23.6 mg, 43%, brown oil; IR (neat, cm ) 696,
1
58, 1047, 1076, 1259, 1546, 1643; H NMR (400 MHz, CDCl ) δ 3.56 (s, 3H), 6.34 (d, J = 7.3 Hz, 1H),
3
1
3
.23 (d, J = 7.3 Hz,1H), 7.35-7.38 (m, 3H), 7.41-7.45 (m, 2H); C NMR (100 MHz, CDCl ) δ 37.94,
3
08.21, 128.06, 129.12, 130.00, 130.51, 134.07, 136.44, 143.66, 161.62; HRMS (APCI) m/z (M+H)+
calcd for C H ClNO: 220.0524, found: 220.0522.
1
2
11
o
6
-Chloro-1-methyl-3-phenylpyridin-2(1H)-one (7ga): 23.1 mg, 42%, white solid, mp 99.1-100.8 C; IR
-
1
1
(
neat, cm ) 700, 781, 1047, 1446, 1533, 1596, 1641; H NMR (400 MHz, CDCl ) δ 3.76 (s, 3H), 6.41 (d,
3
1
3
J = 7.6 Hz, 1H), 7.33 (tt, J = 7.3, 1.3 Hz, 1H), 7.37-7.42 (m, 3H), 7.64 (d, J = 6.2 Hz, 2H); C NMR (100
MHz, CDCl ) δ 33.80, 106.58, 127.86, 128.21, 128.51, 129.31, 136.39, 136.67, 136.76, 162.10; HRMS
3

+
(
APCI) m/z (M+H) calcd for C H ClNO: 220.0524, found: 220.0524.
12 11
o
-1
3
1
7
-Phenylpyridin-2(1H)-one (7ja): 8.6 mg, 20%, white solid, mp 199-201 C; IR (neat, cm ) 1458, 1508,
1
541, 1558, 1535, 1653, 1683; H NMR (400 MHz, CDCl
3
) δ 6.30 (t, J = 6.7 Hz, 1H), 7.26-7.32 (m, 2H),
1
3
.36 (td, J = 7.2, 1.3 Hz, 2H), 7.52 (dd, J = 7.0, 2.0 Hz, 1H), 7.64 (d, J = 7.0 Hz, 2H), 12.66 (bs, 1H); C
NMR (100 MHz, CDCl
3
) δ 106.00, 127.81, 127.28, 127.49, 130.74, 132.68, 135.48, 138.63, 162.74;
+
HRMS (APCI) m/z (M+H) calcd for C11
H
10NO: 172.0757, found: 172.0761.
-
1
1
-(But-3-en-1-yl)-3-phenylpyridin-2(1H)-one (7ka): 15.2 mg, 27%, brown oil; IR (neat, cm ) 698, 754,
1
9
18, 1217, 1379, 1460, 1550, 1597, 1645; H NMR (400 MHz, CDCl ) δ 2.57 (q, J = 7.2 Hz, 2H), 4.06 (t,
3
J = 7.2 Hz, 2H), 5.06-6.14 (m, 2H), 5.83 (ddt, J = 15.5, 10.2, 7.0 Hz, 1H), 6.24 (t, J = 7.0 Hz, 1H),
7
7
1
2
1
1
7
.2-47.27 (m, 1H), 7.32 (tt, J = 7.3, 1.3 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.48 (dd, J = 6.9, 2.0 Hz, 1H),
1
3
.69 (d, J = 7.0 Hz, 2H); C NMR (100 MHz, CDCl ) δ 33.26, 50.25, 105.67, 117.89, 127.64, 128.08,
3
+
28.66, 131.83, 134.19, 136.90, 136.92, 137.49, 161.36; HRMS (APCI) m/z (M+H) calcd for C H NO:
1
5
16
26.1226, found: 226.1230.
-
1
,3-Diphenylpyridin-2(1H)-one (7la): 24.4 mg, 40%, brown oil; IR (neat, cm ) 698, 752, 1265, 1544,
1
604, 1654; H NMR (400 MHz, CDCl ) δ 6.35 (t, J = 6.9 Hz, 1H), 7.32 (tt, J = 7.3, 1.4 Hz, 1H),
3
1
3
.38-7.45 (m, 6H), 7.46-7.53 (m, 2H), 7.58 (dd, J = 6.9, 2.1 Hz, 1H), 7.74 (dd, J = 7.0, 1.2 Hz, 2H); C
NMR (100 MHz, CDCl ) δ 106.00, 126.72, 127.83, 128.08, 128.43, 128.72, 129.25, 132.56, 136.62,
3
+
1
2
3
7
7
1
37.10, 137.86, 141.32, 161.43; HRMS (APCI) m/z (M+H) calcd for C H NO: 248.1070, found:
1
7
14
48.1073.
o
-1
-Phenyl-2H-chromen-2-one (9): 29.4 mg, 53%, white solid, mp 133.0-134.8 C; IR (neat, cm ) 694,
1
58, 1118, 1454, 1716; H NMR (400 MHz, CDCl ) δ 7.31 (dt, J = 7.5, 1.2 Hz, 1H), 7.37-7.49 (m, 4H),
3
1
3
.54 (t, J = 8.2 Hz, 2H), 7.72 (t, J = 6.7 Hz, 2H), 7.83 (s, 1H); C NMR (100 MHz, CDCl ) δ 116.50,
3
19.70, 124.50, 127.91, 128.42, 128.49, 128.55, 128.88, 131.41, 134.73, 139.87, 153.56, 160.60; HRMS
+
(
APCI) m/z (M+H) calcd for C H O : 223.0754, found: 223.0754.
1
5
11
2
ACKNOWLEDGEMENTS
This work was supported by JSPS KAKENHI Grant Nos. 15K13696 (Grant-in-Aid for Exploratory
Research) and 15H05485 (Grant-in-Aid for Young Scientists (A)) to K.H. and 24225002 (Grant-in-Aid
for Scientific Research (S)) to M.M.
REFERENCES (AND NOTES)
1
.
(a) M. Torres, S. Gil, and M. Parra, Curr. Org. Chem., 2005, 9, 1757; (b) I. M. Lagoja, Chem.
Biodiversity, 2005, 2, 1; (c) S. Hibi, K. Ueno, S. Nagato, K. Kawano, K. Ito, Y. Norimine, O.
Takenaka, T. Hanada, and M. Yonaga, J. Med. Chem., 2012, 55, 10584; (d) A. A. Cumaraswamy, A.

Todic, D. Resetca, M. D. Minden, and P. T. Gunning, Med. Chem. Commun., 2012, 3, 22; (e) P. Wu
and Y. Hu, Med. Chem. Commun., 2012, 3, 1337.
2
.
Selected reviews and accounts: (a) D. Alberico, M. E. Scott, and M. Lautens, Chem. Rev., 2007, 107,
174; (b) T. Satoh and M. Miura, Chem. Lett., 2007, 36, 200; (c) F. Kakiuchi and T. Kochi, Synthesis,
2008, 3013; (d) X. Chen, K. M. Engle, D.-H. Wang, and J.-Q. Yu, Angew. Chem. Int. Ed., 2009, 48,
5094; (e) L. Ackermann, R. Vicente, and A. R. Kapdi, Angew. Chem. Int. Ed., 2009, 48, 9792; (f) T.
W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147; (g) A. E. Wendlandt, A. M. Suess, and S.
S. Stahl, Angew. Chem. Int. Ed., 2011, 50, 11062; (h) J. Yamaguchi, A. D. Yamaguchi, and K. Itami,
Angew. Chem. Int. Ed., 2012, 51, 8960; (i) M. Miura, T. Satoh, and K. Hirano, Bull. Chem. Soc. Jpn.,
2
014, 87, 751; (j) X.-X. Guo, D.-W. Gu, Z. Wu, and W. Zhang, Chem. Rev., 2015, 115, 1622; (k) K.
Hirano and M. Miura, Chem. Lett., 2015, 44, 868; (l) C. Liu, J. Yuan, M. Gao, S. Tang, W. Li, R.
Shi, and A. Lei, Chem. Rev., 2015, 115, 12138.
3.
4.
5.
T. Itahara and F. Ouseto, Synthesis, 1984, 488.
Y. Chen, F. Wang, A. Jia, and X. Li, Chem. Sci., 2012, 3, 3231.
(a) Y. Nakao, H. Idei, K. S. Kanyiva, and T. Hiyama, J. Am. Chem. Soc., 2009, 131, 15996; (b) R.
Tamura, Y. Yamada, Y. Nakao, and T. Hiyama, Angew. Chem. Int. Ed., 2012, 51, 5679; Also see:
(c) P. A. Donets and N. Cramer, Angew. Chem. Int. Ed., 2015, 54, 633.
6
7
.
.
R. Odani, K. Hirano, T. Satoh, and M. Miura, Angew. Chem. Int. Ed., 2014, 53, 10784.
(a) Y. Li, F. Xie, and X. Li, J. Org. Chem., 2016, 81, 715; (b) D. Das, A. Biswas, U. Karmaker, S.
Chand, and R. Samanta, J. Org. Chem., 2016, 81, 842; (c) T. Li, Z. Wang, K. Xu, W. Liu, X. Zhang,
W. Mao, Y. Guo, X. Ge, and F. Pan, Org. Lett., 2016, 18, 1064.
8
.
While limited in scope, Zografos reported a Pd-catalyzed C3-arylation of 4-hydroxy-2-pyridones
with arylboronic acids; E. A. Anagnostaki, A. D. Fotiadou, V. Demertzidou, and A. L. Zografos,
Chem. Commun., 2014, 50, 6879.
9
1
1
1
1
.
A. Nakatani, K. Hirano, T. Satoh, and M. Miura, Chem. Eur. J., 2013, 19, 7691.
0. A. Nakatani, K. Hirano, T. Satoh, and M. Miura, J. Org. Chem., 2014, 79, 1377.
1. A. Modak, S. Rana, and D. Maiti, J. Org. Chem., 2015, 80, 296.
2. We reported a preliminary single example using related photoredox catalysis, see: ref. 10.
3. In the course of this study, Yadav reported the radical-mediated, C3-selective direct arylation of
2
-pyridones with arylhydrazines by using K CO and O as promoters; P. Chauhan, M. Ravi, S.
2 3 2
Singh, P. Prajapati, and P. P. Yadav, RSC Adv., 2016, 6, 109.
1
4. Recent selected reviews: (a) J. M. R. Narayanam and C. R. J. Stephenson, Chem. Soc. Rev., 2011, 40,
1
02; (b) S. Fukuzumi and K. Ohkubo, Chem. Sci., 2013, 4, 561; (c) C. K. Prier, D. A. Rankic, and D.
W. C. MacMillan, Chem. Rev., 2013, 113, 5322; (d) D. M. Schultz and T. M. Yoon, Science, 2014,

3
43, 985; (e) M. H. Hopkinson, B. Sahoo, J.-L. Li, and F. Glorius, Chem. Eur. J., 2014, 20, 3874.
1
5. For the related alkylation of alkenes and electron-rich benzenes with 2a under visible-light-promoted
Ru or Ir catalysis, see: (a) C.-J. Wallentin, J. D. Nguyen, P. Finkbeiner, and C. R. J. Stephenson, J.
Am. Chem. Soc., 2012, 134, 8875; (b) J. Jung, E. Kim, Y. You, and E. J. Cho, Adv. Synth. Catal.,
2
014, 356, 2741.
1
6. The radical chain propagation mechanism cannot be completely excluded; see ref. 14 and 15a.
7. Unsuccessful substrates included diethyl (bromodifluoromethyl)phosphonate, nonafluoroiodobutane,
and ethyl bromofluoroacetate.
1
–
1
1
2
2
8. Although the exact reason is not clear yet, Na S O can reduce catalyst poison, molecular I into I .
2
2
3
2
9. M. Tobisu, T. Furukawa, and N. Chatani, Chem. Lett., 2013, 42, 1203.
0. H. Konno and Y. Sasaki, Chem. Lett., 2003, 32, 252.
1. Y. Gu, D. Chang, X. Leng, Y. Gu, and Q. Shen, Organometallics, 2015, 34, 3065.