Manganese-mediated C3-selective direct alkylation and arylation of 2-pyridones with diethyl malonates and arylboronic acids

Article abstract of DOI:10.1021/jo4027885

A manganese-mediated dehydrogenative direct alkylation of 2-pyridones with diethyl malonates has been developed. A similar reaction system is applicable to the direct arylation with arylboronic acids. These manganese-based reactions occur regioselectively at the C3 position of the 2-pyridones. The observed high C3 regioselectivity can complement precedented C-H functionalization protocols of the 2-pyridones in view of the site selectivity.

Full text of DOI:10.1021/jo4027885

Article
pubs.acs.org/joc
Manganese-Mediated C3-Selective Direct Alkylation and Arylation of
2‑Pyridones with Diethyl Malonates and Arylboronic Acids
Akihiro Nakatani, Koji Hirano,* Tetsuya Satoh, and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: A manganese-mediated dehydrogenative direct
alkylation of 2-pyridones with diethyl malonates has been
developed. A similar reaction system is applicable to the direct
arylation with arylboronic acids. These manganese-based
reactions occur regioselectively at the C3 position of the 2-
pyridones. The observed high C3 regioselectivity can comple-
ment precedented C−H functionalization protocols of the 2-pyridones in view of the site selectivity.
INTRODUCTION
■
2-Pyridones frequently occur in pharmaceutical targets and
biologically active natural and unnatural products. Such well-
known compounds include ciclopirox, milrinone, camptothecin,
fredericamycin, and perampanel (Figure 1).1 The most
Figure 2. Reactivity profiles of the 2-pyridone ring under metal-
mediated C−H functionalization.
mediate generated in situ. The observed unique regioselectivity
prompted us to further explore the radical-mediated direct C3
functionalization of 2-pyridones. Here, we report manganese-
mediated direct alkylation and arylation with diethyl malonates
and arylboronic acids (Scheme 1b,c). The C−C bond
formations occur exclusively at the C3 position. Thus, the
manganese-based system can complement the above prece-
dents from the viewpoint of site selectivity and directly give C3-
decorated 2-pyridones of potential interest in medicinal
Figure 1. 2-Pyridone rings in biologically active compounds.
chemistry.
RESULTS AND DISCUSSION
Mn(III)-Mediated Direct Alkylation with Diethyl
■
powerful and reliable approach to these densely functionalized
pyridone cores is considered to be the metal-catalyzed cross-
coupling reactions with halogenated pyridone derivatives. On
the other hand, recent progress in the metal-mediated C−H
functionalization2 can provide a more straightforward route to
the target compounds (Figure 2). So far, palladium-mediated
and -catalyzed direct alkenylation and arylation at the C5
position have been reported.3 On the other hand, the nickel/
aluminum bimetallic catalyst system enables direct C6
alkenylation and alkylation.4 However, despite the relatively
high electron density, the selective C−H functionalization at
the C3 position remains somewhat of a challenge.5 In this
context, we have recently found the nickel-catalyzed C3-
selective alkylation with α-bromocarbonyl compounds (Scheme
1a).6 Under this nickel catalysis, the otherwise difficult C3-
selective direct functionalization was possible through a
SOMO/HOMO interaction including an alkyl radical inter-
Malonates. On the basis of our previous mechanistic insight
into the nickel-catalyzed, radical-mediated C3-selective alkyla-
tion,6 we initially focused on a combination of Mn(III) salts
and malonic acid esters because it is a well-known system for
the generation of the corresponding alkyl radical intermediates,
which then undergo smooth addition to electron-rich indoles
and pyrroles.7 Pleasingly, treatment of excess of N-methyl-2-
pyridone (1a; 2.5 mmol) with diethyl 2-methylmalonate (2a;
0.50 mmol) in the presence of 1.2 mmol (2.4 equiv) of
Mn(OAc)3·2H2O and 2.5 mmol (5.0 equiv) of NaOAc in hot
AcOH (70 °C) afforded the alkylated product 3aa in 52% GC
yield (Table 1, entry 1). Expectedly, the exclusive C3 selectivity
Received: December 16, 2013
Published: January 23, 2014
© 2014 American Chemical Society
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Scheme 1. Metal-Mediated C3-Selective C−H Functionalization of 2-Pyridones via Radical Species
efficiency (entry 5), in subsequent studies we employed PhCF3
as the best solvent, because it could be evaporated more easily
under reduced pressure. Additionally notable is that NaOAc
was not necessary in this reaction (entry 2 vs 3). The higher
concentration could reduce the amount of 1a to 1.5 mmol (3.0
equiv) (entry 10). In addition, to cut down the amount of
Mn(OAc)3·2H2O, we next tested some co-oxidants. While
organic peroxides, MnO2, and potassium-based persulfates were
ineffective (entries 11−15), Na2S2O8 showed good perform-
ance. Although the catalytic variant in Mn(III) remained
unsuccessful, 0.60 mmol (1.2 equiv) of Mn(OAc)3·2H2O
combined with 0.60 mmol (1.2 equiv) of Na2S2O8 resulted in a
comparable yield (entry 16). Additionally, 3.0 equiv of 1a was
still essential for the satisfactory yield, but about half of the
unreactive 1a could be recovered by simple extraction with
chloroform (see the Experimental Section).8 On the other
hand, excess 2a (3.0 equiv with respect to 1a) diminished the
yield of 3aa (entry 17).
With the conditions of entry 16 in Table 1, we examined the
substrate scope of the 2-pyridone (Scheme 2). Irrespective of
the substitution pattern and electronic and steric nature of the
substituent, the alkylation reaction occurred exclusively at the
C3 position. The 4-, 5-, and 6-methyl-2-pyridones were equally
tolerated, and the corresponding alkylated products 3ba−3da
were obtained in moderate to good yields, while the
introduction of a methyl group at the C3 position completely
shut down the reaction (data not shown). Electron-with-
drawing trifluoromethyl-, chloro-, and bromo-substituted as
well as electron-donating methoxy-substituted substrates also
underwent the alkylation to form 3ea−3ha, albeit with
somewhat lower yields. The resultant chloride and bromide
moieties can be useful synthetic handles for further
manipulations under the conventional palladium catalysis.
The more readily detachable benzyl protection on the nitrogen
was compatible (3ia). Additionally, the C3-selective alkylation
of 2-quinolinone also proceeded under the standard conditions
to furnish 3ja in an acceptable yield. In some cases of lower
product yields, the homocoupling byproducts of 2a7c were
detected by GC and GCMS analysis.
Table 1. Optimization Studies for Manganese-Mediated
Direct Alkylation of N-Methyl-2-pyridone (1a) with Diethyl
2-Methylmalonate (2a)
1a:2a:Mn(III) additive (amt solvent (amt temp
yield
a
entry
(mmol)
(mmol))
(mL))
(°C)
(%)
1
2
3
4
2.5:0.50:1.2
2.5:0.50:1.2
2.5:0.50:1.2
2.5:0.50:1.2
NaOAc (2.5)
NaOAc (2.5)
none
AcOH (3.0)
PhCF3 (3.0)
PhCF3 (3.0)
70
90
52
46
68
55
90
none
toluene
(3.0)
100
5
6
2.5:0.50:1.2
2.5:0.50:1.2
none
none
PhCl (3.0)
120
100
66
40
1,4-dioxane
(3.0)
7
8
9
2.5:0.50:1.2
2.5:0.50:1.2
2.5:0.50:1.2
none
none
none
DCE (3.0)
DMF (3.0)
70
140
90
24
29
20
t-AmOH
(3.0)
10
11
1.5:0.50:1.2
none
PhCF3 (1.0)
PhCF3 (1.0)
90
90
70
42
1.5:0.50:0.60 (t-BuO)2
(0.60)
12
1.5:0.50:0.60 t-BuOOH
PhCF3 (1.0)
90
14
(0.60)
13
14
1.5:0.50:0.60 MnO2 (0.60)
1.5:0.50:0.60 oxone (0.60)
PhCF3 (1.0)
PhCF3 (1.0)
90
90
90
90
35
35
b
15
1.5:0.50:0.60 K2S2O8 (0.60) PhCF3 (1.0)
53
b
16
1.5:0.50:0.60 Na2S2O8
(0.60)
PhCF3 (1.0)
70 (75)
b
17
0.50:1.5:0.60 Na2S2O8
(0.60)
PhCF3 (1.0)
90
28
a
b
GC yield. Yield after purification is given in parentheses. 24 h.
was observed. With this intriguing result in hand, we optimized
the reaction conditions. Investigation of some solvents
identified aromatic systems to be promising (entries 3−9),
with PhCF3 giving a 68% GC yield of 3aa (entry 3). The
benzylic C−H bonds of toluene could be abstracted under
current conditions to form the benzylated pyridone as a
byproduct (entry 4). Although PhCl showed similar good
An array of malonic acid coupling partners were also
evaluated (Scheme 3). The 2-benzylmalonate reacted with 1a
very smoothly to form 3ab in 83% yield. Notably, the nitrile
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a
Scheme 2. Manganese-Mediated C3-Selective Direct Alkylation of Various 2-Pyridones 1 with Diethyl 2-Methylmalonate (2a)
a
The formed C−C bonds are illustrated with a bold line.
Scheme 3. Manganese-Mediated C3-Selective Direct
Mn(III)-Mediated Direct Arylation with Arylboronic
Acids. On the basis of the success in Mn(III)-Mediated Direct
Alkylation with Diethyl Malonates, we next envisioned the C3-
selective direct arylation by using aryl radical species. After the
extensive screening of metals, oxidants, and aryl sources, the
Mn(III)/ArB(OH)2 system9 was identified to be optimal.
Namely, N-methyl-2-pyridone (1a; 1.5 mmol) coupled with
phenylboronic acid (4a; 0.30 mmol) in the presence of 0.90
mmol (3.0 equiv) of Mn(OAc)3·2H2O in hot PhCF3 to
produce the C3-phenylated 2-pyridone 5aa in 58% yield
(Scheme 4a). An increase of the amount of 1a to 3.0 mmol (10
equiv) improved the yield to 69%. As shown in the direct
alkylation, unreactive 1a could be easily recovered after the
coupling reaction, although excess 1a was inevitable (see the
Experimental Section). The choice of boryl groups was also
critical: the corresponding boronic acid pinacol and neo-
pentylglycol esters, MIDA boronate, and sodium borate were
Alkylation of N-Methyl-2-pyridone (1a) with Various 1,3-
a
Dicarbonyl Compounds 2
a
Scheme 4. Studies for C3-Selective Direct Arylation of N-
Methyl-2-pyridone (1a)
The formed C−C bonds are illustrated with a bold line. EWG =
electron-withdrawing group.
and alkyl bromide functionalities remained intact during the
reaction course (3ac and 3ad). On the other hand, a secondary
alkyl group at the C2 position of the malonate largely decreased
the reaction efficiency (3ae). The current major limitation of
this protocol is the inaccessibility to other 1,3-dicarbonyl
compounds: the keto ester, cyano ester, and diketone gave only
a <5% yield of the alkylated products. In addition, the simple
diethyl malonate was also ineffective. In these cases, similar
radical species could be generated but readily decompose under
present oxidative conditions, probably through disproportiona-
tion, overoxidation, or homocoupling, prior to addition to the
pyridone (vide infra). Actually, the Mn(III)-mediated inter-
molecular aromatic substitution reactions with 1,3-dicarbonyl
compounds other than malonates are not trivial in the
literature.7c,d In addition, α-unsubstituted diethyl malonate
cannot form the corresponding radical species, due to its
instability associated with the lack of substituents at the α
position.7b Thus, suitable stability and reactivity of the radical
intermediate can be necessary for this transformation.
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less effective, while the boroxine and potassium trifluoroborate
showed comparable reactivities (under conditions with 5.0
equiv of 1a). We also tested some representative catalytic
systems for the generation of the phenyl radical species from
4a, including FeCl3/(t-BuO)2,10 CuCl2/(t-BuO)2,11 Ni(acac)2/
(t-BuO)2,12 and AgNO3/K2S2O8,13 but the desired 5aa was not
detected at all, and biphenyl was instead formed in 4−46%
yields (by GC and GCMS analysis) (see the Supporting
Information for details). In contrast, the Mn(III)-based
conditions did not form any detectable amounts of the
biphenyl byproduct. Only with an excess of 4a (5.0 equiv to
1a) did the formation of 5aa not occur at all, and the biphenyl
was detected dominantly in 32% yield (data not shown). On
the other hand, while the results were preliminary, we observed
the formation of 5aa under the Ru(II)- or Ir(III)-based
photoredox catalysis with Ph2IOTf as the phenyl source
(Scheme 4b).14
pyridones and 2-quinolinone also coupled with 4a to furnish
the corresponding 3-phenylpyridones directly (5ia, 5la, and
5ja). In most cases of Scheme 5, the yields were somewhat
moderate, but this methodology enables the direct introduction
of aryl groups at the C3-position of unactivated 2-pyridones,
which is otherwise difficult by reported C−H activation
protocols3 as well as traditional procedures. Although all
byproducts were not completely identified, the major
component was found to be the simple protonated product:
e.g., naphthalene in the case of 5an.
Mechanistic Discussion. Our original working scenario is
shown in Scheme 6. Initial alkyl or aryl radical (R•) generation
Scheme 6. Plausible Mechanism
The Mn(III)-mediated C3-selective arylation was applicable
to various electron-poor arylboronic acids that bear trifluor-
omethyl, ester, ketone, aldehyde, nitrile, chloride, bromide, and
iodide functionalities (Scheme 5, 5ab−5ai). The moderately
Scheme 5. Mn(III)-Mediated C3-Selective Direct Arylation
and Alkylation of 2-Pyridones with Organoboronic Acids
is mediated by Mn(III) through the in situ generation of
Mn(III) enolates/oxidation sequence7 or single electron
transfer (SET) oxidation of organoboronic acid (radical
generation step, Scheme 6a)).9 Subsequent regioselective
addition of R• to the C3 position of the N-methyl-2-pyridone
(1a) ring forms the allylic radical intermediate, in which the
resonance stabilization occurs. Additional SET to Mn(III) (or
Na2S2O8 in case of the alkylation with malonates) is followed
by deprotonation to produce the C3-functionalized 2-pyridone
(C−C bond forming step, Scheme 6b)). This mechanistic
proposal is analogous to the well-established but recently
revisited homolytic radical aromatic substitution (HAS).18
The radical inhibitor 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) gave a large negative impact on the reaction
efficiency with either diethyl 2-methylmalonate (2a) or
phenylboronic acid (4a), which supports the postulated radical
mechanism (Scheme 7). Additional information was available
from the experiments in Scheme 8: the xanthate 6, which
generated the corresponding alkyl radical 7 under the
conventional peroxide-promoted conditions,18 coupled with
1a selectively at the C3 position (Scheme 8a); phenylazo-
electron-donating methyl substituent was also tolerated (5aj).
On the other hand, the reaction with electron-rich 4-
methoxyboronic acid was sluggish (5ak), whereas the 3-
methoxyboronic acid afforded a 39% yield of the product (5al).
Unfortunately, the reaction was sensitive to the steric hindrance
around the boron moiety (5am). Additionally notable is the
accessibility to primary and secondary alkylboronic acids (5ao
and 5ap).15,16
Scheme 7. Reactions in the Presence of TEMPO
We then tested some substituted 2-pyridones for the direct
arylation with phenylboronic acid (4a). All substitution patterns
at the C4, C5, and C6 positions were well tolerated, and the
C−C bond was formed exclusively at the C3 position (5da,
5ea, 5ka, 5ga, and 5ha). The N-benzyl- and N-(3-butenyl)-2-
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Scheme 8. Attempts at the Direct Alkylation and Arylation of
1a under the Conventional Radical Conditions
CONCLUSION
■
We have developed Mn(III)-mediated direct C3 alkylation and
arylation of 2-pyridones with diethyl malonates and arylboronic
acids, respectively.20 The Mn-based system can provide direct
access to C3-alkylated and -arylated 2-pyridone cores, which are
conventionally prepared in multiple steps.1 The observed
unique C3 selectivity can complement precedented C−H
activation systems of 2-pyridones3,4 in view of the site
selectivity, although excesses of 2-pyridones and Mn(III) salts
are essential at present. Further studies on the direct
functionalization of the 2-pyridone at other positions are
ongoing in our laboratory and will be reported in due course.
EXPERIMENTAL SECTION
(triphenyl)methane (PAT)19 also gave the C3-phenylated 2-
pyridone exclusively through the phenyl radical 8 under
pyrolysis, with concomitant formation of 11% of biphenyl
(Scheme 8b). These reaction outcomes suggest that an Mn-
nonassociated, free radical mechanism is operative at least in
the addition step, and the observed high C3 selectivity is
attributed to the radical nature of the intermediates. A
preliminary DFT calculation revealed the relatively large atomic
contributions of both the HOMO and LUMO at the C3
position of 1a (Figure 3). Thus, the regioselectivity might be
■
Instrumentation and Chemicals. 1H, 13C, and 19F NMR spectra
were recorded at 400, 100, and 376 MHz, respectively, for CDCl3
solutions. HRMS data were obtained by EI or APCI using a double-
focusing mass spectrometer or TOF, respectively. GC analysis was
carried out using a silicon OV-17 column (i.d. 2.6 mm × 1.5 m) or a
CBP-1 capillary column (i.d. 0.5 mm × 25 m). TLC analyses were
performed on commercial glass plates bearing a 0.25 mm layer of
Merck silica gel 60F254. Silica gel was used for column chromatog-
raphy. Gel permeation chromatography (GPC) was performed with a
CHCl3 eluent (3.5 mL/min, UV detector). Unless otherwise noted,
materials obtained from commercial suppliers were used without
further purification. Trifluoromethylbenzene was freshly distilled from
CaH2 prior to use. 2-Pyridone derivatives 1 were prepared from the
parent 2-hydroxypyridones (tautomers of NH 2-pyridones) and the
appropriate alkylating reagents.4a,21 PAT was synthesized according to
the literature.22 Unless otherwise noted, all reactions were carried out
under N2 conditions.
Typical Procedure for Mn(III)-Mediated Direct Alkylation of
2-Pyridones with Diethyl Malonates. The synthesis of 3aa is
representative (Table 1, entry 16): Mn(OAc)3·2H2O (161 mg, 0.60
mmol) and Na2S2O8 (143 mg, 0.60 mmol) were placed in a 10 mL
Schlenk tube, which was filled with nitrogen by using the standard
Schlenk technique. A solution of N-methyl-2-pyridone (1a; 164 mg,
1.5 mmol) and diethyl 2-methylmalonate (2a; 87.1 mg, 0.50 mmol) in
PhCF3 (1.0 mL) was added to the tube, and the suspension was stirred
for 24 h at 90 °C. The resulting mixture was quenched with water and
then extracted four times with ethyl acetate. The combined organic
layer was dried over sodium sulfate. Concentration in vacuo and
subsequent purification by column chromatography on silica gel with
dichloromethane/ethyl acetate/triethylamine (1/1/0.05 v/v/v) as an
eluent gave diethyl 2-methyl-2-(1-methyl-2-oxo-1,2-dihydropyridin-3-
yl)malonate (3aa; 85 mg, 0.37 mmol) in 75% yield. When the residual
water layer was extracted four times again with chloroform, N-methyl-
2-pyridone (1a) left intact was recovered (76 mg, 0.70 mmol).
Diethyl 2-methyl-2-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-
malonate (3aa): purified by column chromatography on silica gel
with dichloromethane/ethyl acetate/triethylamine (1/1/0.05 v/v/v) as
an eluent; 85 mg (75%), oil; 1H NMR (400 MHz, CDCl3) δ 1.26 (t, J
= 7.2 Hz, 6H), 1.81 (s, 3H), 3.53 (s, 3H), 4.23 (dq, J = 7.2, 10.6 Hz,
2H), 4.27 (dq, J = 7.2, 10.6 Hz, 2H), 6.19 (dd, J = 6.9, 6.9 Hz, 1H),
7.26 (dd, J = 1.9, 6.9 Hz, 1H), 7.29 (dd, J = 1.9, 6.9 Hz, 1H); 13C
NMR (400 MHz, CDCl3) δ 14.1, 20.9, 37.9, 57.5, 61.8, 105.1, 131.9,
135.6, 137.4, 161.4, 170.8; HRMS (EI) m/z (M+) calcd for
C14H19NO5 281.1263, found 281.1259.
Figure 3. Atomic contributions of HOMO (left) and LUMO (right)
in N-methyl-2-pyridone (1a) calculated by DFT at the RB3LYP/6-
31G(d) level of theory.
controlled by a SOMO/HOMO or a SOMO/LUMO
interaction between the radical intermediates and the C3
carbon atom on the pyridone as well as a resonance
stabilization of the resultant radical adduct. In the case of the
malonylation through the electrophilic malonyl radical species,
the HOMO is believed to work predominantly, while the
LUMO might play a more important role in the butylation and
cyclohexylation, including the carbon radicals of nucleophilic
characters. Although the exact reason for the arylation activity
unique in the Mn(III) system is not clear at present, the
relatively slow release of the highly reactive aryl radical species
is believed to be beneficial for suppressing the undesired
homocoupling leading to the biphenyl byproduct.
However, reactivity trends of 2-pyridones were not always in
accord with our proposal; for example, the electron-donating
methyl and methoxy groups at the C4 and C6 positions
diminished the efficiency of the alkylation reaction (Scheme 2,
3aa vs 3ba, 3da, and 3ha). Moreover, the possibility of
reversibility in the addition process7c also needs to be taken
into consideration. Thus, neither an Mn-associated radical
process nor other organometallic pathways are excluded at this
stage. Further efforts are essential for clarification of the
detailed mechanism.
Diethyl 2-(1,4-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-2-methyl-
malonate (3ba): purified by column chromatography on silica gel
with dichloromethane/ethyl acetate/triethylamine (1/1/0.05 v/v/v) as
an eluent; 78 mg (53%), oil; 1H NMR (400 MHz, CDCl3) δ 1.26 (t, J
= 7.2 Hz, 6H), 1.71 (s, 3H), 2.05 (s, 3H), 3.45 (s, 3H), 4.19 (dq, J =
7.2, 10.9 Hz, 2H), 4.29 (dq, J = 7.2, 10.9 Hz, 2H), 5.95 (d, J = 6.9 Hz,
1H), 7.09 (d, J = 6.9 Hz, 1H); 13C NMR (400 MHz, CDCl3) δ 14.1,
20.4, 20.9, 37.9, 57.4, 61.9, 110.2, 130.3, 135.3, 147.2, 161.4, 170.8;
HRMS (EI) m/z (M+) calcd for C15H21NO5 295.1420, found
295.1417.
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Diethyl 2-(1,5-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-2-methyl-
malonate (3ca): purified by column chromatography on silica gel with
dichloromethane/ethyl acetate/triethylamine (1/1/0.05 v/v/v) as an
eluent; 106 mg (71%), oil; 1H NMR (400 MHz, CDCl3) δ 1.27 (t, J =
7.2 Hz, 6H), 1.80 (s, 3H), 2.07 (s, 3H), 3.49 (s, 3H), 4.23 (dq, J = 7.2,
11.0 Hz, 2H), 4.27 (dq, J = 7.2, 11.0 Hz, 2H), 7.04 (d, J = 2.4 Hz, 1H),
7.15 (d, J = 2.4 Hz, 1H); 13C NMR (400 MHz, CDCl3) δ 14.1, 17.4,
21.0, 37.7, 57.5, 61.7, 113.9, 131.3, 135.0, 138.2, 160.5, 170.8; HRMS
(EI) m/z (M+) calcd for C15H21NO5 295.1420, found 295.1419.
Diethyl 2-(1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-2-methyl-
malonate (3da): purified by column chromatography on silica gel
with dichloromethane/ethyl acetate/triethylamine (1/1/0.05 v/v/v) as
an eluent; 86 mg (58%), oil; 1H NMR (400 MHz, CDCl3) δ 1.26 (t, J
= 7.1 Hz, 6H), 1.79 (s, 3H), 2.34 (s, 3H), 3.51 (s, 3H), 4.22 (dq, J =
7.1, 10.1 Hz, 2H), 4.26 (dq, J = 7.1, 10.1 Hz, 2H), 6.02 (d, J = 7.3 Hz,
1H), 7.18 (d, J = 7.3 Hz, 1H); 13C NMR (400 MHz, CDCl3) δ 14.1,
20.9, 21.0, 31.6, 57.5, 61.7, 105.6, 128.4, 134.8, 145.5, 162.0, 171.0;
HRMS (EI) m/z (M+) calcd for C15H21NO5 295.1420, found
295.1421.
Diethyl 2-methyl-2-(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-
malonate (3ja): purified by column chromatography on silica gel
with dichloromethane/ethyl acetate/triethylamine (10:1:0.5, v/v/v) as
an eluent; 75 mg (45%), oil; 1H NMR (400 MHz, CDCl3) δ 1.28 (t, J
= 7.1 Hz, 6H), 1.88 (s, 3H), 3.72 (s, 3H), 4.26 (dq, J = 7.1, 10.5 Hz,
2H), 4.30 (dq, J = 7.2, 10.5 Hz, 2H), 7.24 (ddd, J = 1.0, 7.5, 7.5 Hz,
1H), 7.34 (dd, J = 1.0, 8.9 Hz, 1H), 7.55 (dd, J = 1.4, 7.5 Hz, 1H), 7.57
(ddd, J = 1.4, 7.5, 8.9 Hz, 1H), 7.68 (s, 1H); 13C NMR (400 MHz,
CDCl3) δ 14.1, 21.5, 30.0, 57.6, 61.9, 114.0, 120.1, 122.3, 129.3, 130.6,
132.4, 135.2, 139.6, 160.9, 170.8; HRMS (EI) m/z (M+) calcd for
C18H21NO5 331.1420, found 331.1419.
Diethyl 2-benzyl-2-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-
malonate (3ab): purified by column chromatography on silica gel
with dichloromethane/ethyl acetate/triethylamine (2/1/0.05 v/v/v) as
an eluent; 147 mg (83%), oil; 1H NMR (400 MHz, CDCl3) δ 1.26 (t, J
= 7.2 Hz, 6H), 3.55 (s, 3H), 3.66 (s, 2H), 4.23 (dq, J = 7.2, 10.9 Hz,
2H), 4.26 (dq, J = 7.2, 10.9 Hz, 2H), 5.99 (dd, J = 6.9, 6.9 Hz, 1H),
6.86 (dd, J = 2.1, 6.8 Hz, 2H), 7.10−7.14 (m, 3H), 7.22 (dd, J = 2.0,
6.9 Hz, 1H), 7.30 (dd, J = 2.0, 6.9 Hz, 1H); 13C NMR (400 MHz,
CDCl3) δ 14.1, 38.0, 39.2, 61.7, 61.8, 105.1, 126.6, 127.7, 128.7, 130.8,
137.0, 137.1, 139.7, 161.4, 169.5; HRMS (EI) m/z (M+) calcd for
C20H23NO5 357.1576, found 357.1578.
Diethyl 2-methyl-2-[1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihy-
dropyridin-3-yl]malonate (3ea): purified by column chromatography
on silica gel with dichloromethane/ethyl acetate/triethylamine (1/1/
1
0.05 v/v/v) as an eluent; 99 mg (57%), oil; H NMR (400 MHz,
Diethyl 2-(2-cyanoethyl)-2-(1-methyl-2-oxo-1,2-dihydropyridin-
3-yl)malonate (3ac): purified by column chromatography on silica
gel with dichloromethane/ethyl acetate/triethylamine (1/1/0.05 v/v/
CDCl3) δ 1.27 (t, J = 7.2 Hz, 6H), 1.81 (s, 3H), 3.58 (s, 3H), 4.24 (dq,
J = 7.2, 10.9 Hz, 2H), 4.27 (dq, J = 7.2, 10.9 Hz, 2H), 7.83 (d, J = 2.6
Hz, 1H), 7.68 (d, J = 2.6 Hz, 1H); 13C NMR (400 MHz, CDCl3) δ
14.1, 20.9, 38.5, 57.2, 62.0, 108.9 (q, J = 31.6), 123.5 (q, J = 262.4),
131.4 (q, J = 2.2), 132.7, 136.9 (q, J = 5.1), 161.0, 170.2; 19F NMR
(376 MHz, CDCl3) δ −62.17; HRMS (EI) m/z (M+) calcd for
C15H18F3NO5 349.1137, found 349.1136.
Diethyl 2-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-
methylmalonate (3fa): purified by column chromatography on silica
gel with dichloromethane/ethyl acetate/triethylamine (2/1/0.05 v/v/
v) as an eluent; 70 mg (45%), mp 82−83 °C (from dichloromethane/
ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 1.27 (t, J = 7.1 Hz, 6H),
1.79 (s, 3H), 3.52 (s, 3H), 4.23 (dq, J = 7.1, 10.7 Hz, 2H), 4.27 (dq, J
= 7.1, 10.7 Hz, 2H), 7.33 (s, 2H); 13C NMR (400 MHz, CDCl3) δ
14.1, 21.0, 38.1, 57.3, 62.0, 111.5, 132.8, 134.9, 136.9, 159.9, 170.3;
HRMS (EI) m/z (M+) calcd for C14H18ClNO5 315.0874, found
315.0876.
1
v) as an eluent; 136 mg (85%), oil; H NMR (400 MHz, CDCl3) δ
1.27 (t, J = 7.2 Hz, 6H), 2.46 (t, J = 7.5, 2H), 2.73 (t, J = 7.5, 2H), 3.54
(s, 3H), 4.24 (dq, J = 7.2, 10.7 Hz, 2H), 4.29 (dq, J = 7.2, 10.7 Hz,
2H), 6.20 (dd, J = 6.9, 6.9 Hz, 1H), 7.34 (dd, J = 1.8, 6.9 Hz, 1H), 7.43
(dd, J = 1.8, 6.9 Hz, 1H); 13C NMR (400 MHz, CDCl3) δ 13.8, 14.1,
28.9, 38.1, 60.1, 62.2, 105.2, 119.5, 128.0, 137.8, 138.3, 161.3, 169.2;
HRMS (EI) m/z (M+) calcd for C16H20N2O5 320.1372, found
320.1373.
Diethyl 2-(5-bromopentyl)-2-(1-methyl-2-oxo-1,2-dihydropyri-
din-3-yl)malonate (3ad): purified by column chromatography on
silica gel with dichloromethane/ethyl acetate/triethylamine (1/1/0.05
v/v/v) as an eluent; 114 mg (55%), oil; 1H NMR (400 MHz, CDCl3)
δ 1.24 (t, J = 7.1 Hz, 2H), 1.25 (t, J = 7.2 Hz, 6H), 1.41 (tt, J = 7.1, 7.1
Hz, 2H), 1.82 (tt, J = 7.1, 7.1 Hz, 2H), 2.27−2.31 (m, 2H), 3.35 (t, J =
6.9 Hz, 2H), 3.52 (s, 3H), 4.21 (dq, J = 7.2, 10.7 Hz, 2H), 4.25 (dq, J
= 7.2, 10.7 Hz, 2H), 6.17 (dd, J = 7.0, 7.0 Hz, 1H), 7.26 (dd, J = 2.1,
7.0 Hz, 1H), 7.61 (dd, J = 2.1, 7.0 Hz, 1H); 13C NMR (400 MHz,
CDCl3) δ 14.1, 24.5, 28.4, 32.6, 33.3, 33.9, 37.9, 60.7, 61.6, 105.1,
130.1, 137.2, 137.4, 161.4, 170.1; HRMS (EI) m/z (M+) calcd for
C18H26BrNO5 415.0994, found 415.099.
Diethyl 2-cyclopentyl-2-(1-methyl-2-oxo-1,2-dihydropyridin-3-
yl)malonate (3ae): purified by column chromatography on silica gel
with dichloromethane/ethyl acetate/triethylamine (1/1/0.05 v/v/v) as
an eluent; 34 mg (20%), oil; 1H NMR (400 MHz, CDCl3) δ 1.25 (t, J
= 7.2 Hz, 6H), 1.31−1.42 (m, 2H), 1.45−1.56 (m, 4H), 1.73−1.80 (m,
2H), 3.19 (tt, J = 8.1, 9.1 Hz, 1H), 3.51 (s, 3H), 4.19 (dq, J = 7.2, 10.9
Hz, 2H), 4.24 (dq, J = 7.2, 10.9 Hz, 2H), 6.15 (dd, J = 6.9, 6.9 Hz,
1H), 7.24 (dd, J = 1.8, 6.9 Hz, 1H), 7.70 (dd, J = 1.8, 6.9 Hz, 1H); 13C
NMR (400 MHz, CDCl3) δ 14.1, 25.3, 29.2, 37.9, 43.1, 61.2, 63.1,
105.0, 130.5, 136.9, 137.1, 161.7, 170.2; HRMS (EI) m/z (M+) calcd
for C18H25NO5 335.1733, found 335.1734.
Typical Procedure for Mn(III)-Mediated Direct Arylation of
2-Pyridones with Arylboronic Acids. The synthesis of 5aa is
representative (Scheme 4a): Mn(OAc)3·2H2O (241 mg, 0.90 mmol)
and PhB(OH)2 (4a; 36.6 mg, 0.30 mmol) were placed in a 10 mL
Schlenk tube, which was filled with nitrogen by using the standard
Schlenk technique. A solution of N-methyl-2-pyridone (1a; 164 mg,
1.5 mmol) in PhCF3 (1.0 mL) was added to the tube, and the
suspension was stirred for 4 h at 90 °C. The resulting mixture was
quenched with water and then extracted four times with ethyl acetate.
The combined organic layer was dried over sodium sulfate.
Concentration in vacuo and subsequent purification by column
chromatography on silica gel with dichloromethane/ethyl acetate/
triethylamine (1/1/0.05 v/v/v) as an eluent gave 1-methyl-3-
phenylpyridin-2(1H)-one (5aa; 32 mg, 0.17 mmol) in 58% yield.
Diethyl 2-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-
methylmalonate (3ga): purified by column chromatography on silica
gel with dichloromethane/ethyl acetate/triethylamine (2/1/0.05 v/v/
v) as an eluent; 70 mg (39%), mp 93−94 °C (from dichloromethane/
ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 1.27 (t, J = 7.1 Hz, 6H),
1.79 (s, 3H), 3.51 (s, 3H), 4.23 (dq, J = 7.1, 10.7 Hz, 2H), 4.27 (dq, J
= 7.1, 10.7 Hz, 2H), 7.39 (d, J = 2.7 Hz, 1H), 7.41 (d, J = 2.7 Hz, 1H);
13C NMR (400 MHz, CDCl3) δ 14.1, 21.0, 38.0, 57.3, 62.0, 97.1,
133.2, 137.3, 138.9, 160.0, 170.3; HRMS (EI) m/z (M+) calcd for
C14H18BrNO5 359.0368, found 359.0365.
Diethyl 2-(4-methoxy-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-
methylmalonate (3ha): purified by column chromatography on silica
gel with dichloromethane/ethyl acetate/triethylamine (1/1/0.05 v/v/
v) as an eluent; 63 mg (40%), oil; 1H NMR (400 MHz, CDCl3) δ 1.26
(t, J = 7.2 Hz, 6H), 1.67 (s, 3H), 3.47 (s, 3H), 3.78 (s, 3H), 4.19 (dq, J
= 7.2, 10.8 Hz, 2H), 4.27 (dq, J = 7.2, 10.8 Hz, 2H), 6.03 (d, J = 7.4
Hz, 1H), 7.26 (d, J = 7.4 Hz, 1H); 13C NMR (400 MHz, CDCl3) δ
14.2, 19.7, 37.5, 54.8, 56.1, 61.6, 94.9, 114.9, 137.9, 161.7, 163.3, 170.7;
HRMS (APCI) m/z ([M + H]+) calcd for C15H22NO6 312.1442,
found 312.1441.
Diethyl 2-(1-benzyl-2-oxo-1,2-dihydropyridin-3-yl)-2-methylmal-
onate (3ia): purified by column chromatography on silica gel with
dichloromethane/ethyl acetate/triethylamine (20:1:0.5, v/v/v) as an
1
eluent; 81 mg (44%), oil; H NMR (400 MHz, CDCl3) δ 1.23 (t, J =
7.2 Hz, 6H), 1.82 (s, 3H), 4.21 (dq, J = 7.2, 10.8 Hz, 2H), 4.24 (dq, J
= 7.2, 10.8 Hz, 2H), 5.14 (s, 2H), 6.13 (dd, J = 6.9, 6.9 Hz, 1H), 7.23−
7.34 (m, 7H); 13C NMR (400 MHz, CDCl3) δ 14.1, 21.0, 52.3, 57.6,
61.8, 105.4, 128.1, 128.2, 128.9, 132.5, 135.3, 136.4, 136.6, 161.0,
170.9; HRMS (EI) m/z (M+) calcd for C20H23NO5 357.1576, found
357.1578.
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When the residual water layer was extracted four times again with
chloroform, N-methyl-2-pyridone (1a) left intact was recovered (62
mg, 0.57 mmol).
(s, 4H); 13C NMR (400 MHz, CDCl3) δ 38.4, 106.0, 128.3, 128.5,
130.0, 130.1, 130.3, 132.4, 136.5, 137.8, 138.4 (two peaks are
overlapped), 141.1, 161.7, 196.5; HRMS (EI) m/z (M+) calcd for
C19H15NO2 289.1103, found 289.1106.
1-Methyl-3-phenylpyridin-2(1H)-one (5aa): purified by column
chromatography on silica gel with dichloromethane/ethyl acetate/
triethylamine (1/1/0.05 v/v/v) as an eluent; 32 mg (58%), mp 136−
4-(1-Methyl-2-oxo-1,2-dihydropyridin-3-yl)benzaldehyde (5ah):
purified by column chromatography on silica gel with dichloro-
methane/ethyl acetate/triethylamine (1/1/0.05 v/v/v) as an eluent;
29 mg (44%), mp 111−112 °C (from dichloromethane/ethyl acetate);
1H NMR (400 MHz, CDCl3) δ 3.63 (s, 3H), 6.30 (dd, J = 6.9, 6.9 Hz,
1H), 7.40 (dd, J = 1.8, 6.9 Hz, 1H), 7.58 (dd, J = 1.8, 6.9 Hz, 1H), 7.90
(s, 4H), 10.03 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 38.4, 106.0,
129.2, 129.7, 130.1, 135.4, 138.7, 138.8, 143.2, 161.6, 192.1; HRMS
(EI) m/z (M+) calcd for C13H11NO2: 213.0790, found 213.0788.
4-(1-Methyl-2-oxo-1,2-dihydropyridin-3-yl)benzonitrile (5ai): pu-
rified by column chromatography on silica gel with dichloromethane/
ethyl acetate/triethylamine (2/1/0.05 v/v/v) as an eluent; 33 mg
1
137 °C (from dichloromethane/ethyl acetate); H NMR (400 MHz,
CDCl3) δ 3.61 (s, 3H), 6.25 (dd, J = 6.8, 6.8 Hz, 1H), 7.30 (dd, J =
2.0, 6.8 Hz, 1H), 7.32 (tt, J = 1.4, 7.4 Hz, 1H), 7.39 (ddd, J = 1.5, 7.4,
7.4 Hz, 2H), 7.48 (dd, J = 2.0, 6.8 Hz, 1H), 7.69 (dd, J = 1.4, 7.4 Hz,
2H); 13C NMR (400 MHz, CDCl3) δ 38.4, 105.9, 127.8, 128.2, 128.8,
131.8, 137.0, 137.5, 137.7, 162.1; HRMS (EI) m/z (M+) calcd for
C12H11NO 185.0841, found 185.0839.
1-Methyl-3-[4-(trifluoromethyl)phenyl]pyridin-2(1H)-one (5ab):
purified by column chromatography on silica gel with dichloro-
methane/ethyl acetate/triethylamine (2/1/0.05 v/v/v) as an eluent;
36 mg (47%), mp 111−112 °C (from dichloromethane/ethyl acetate);
1H NMR (400 MHz, CDCl3) δ 3.63 (s, 3H), 6.28 (dd, J = 6.9, 6.9 Hz,
1H), 7.36 (dd, J = 2.0, 6.9 Hz, 1H), 7.53 (dd, J = 2.0, 6.9 Hz, 1H), 7.64
(d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.2 Hz, 2H); 13C NMR (400 MHz,
CDCl3) δ 38.4, 105.9, 124.4 (q, J = 272.1 Hz), 125.2 (q, J = 3.9 Hz),
129.0, 129.7 (q, J = 31.6 Hz), 130.2, 138.4, 138.5, 140.5, 161.8; 19F
NMR (376 MHz, CDCl3) δ −62.56; HRMS (EI) m/z (M+) calcd for
C13H10F3NO 253.0714, found 253.0716.
3-(4-Chlorophenyl)-1-methylpyridin-2(1H)-one (5ac): purified by
column chromatography on silica gel with dichloromethane/ethyl
acetate/triethylamine (2/1/0.05 v/v/v) as an eluent; 36 mg (54%),
mp 142−144 °C (from dichloromethane/ethyl acetate); 1H NMR
(400 MHz, CDCl3) δ 3.61 (s, 3H), 6.25 (dd, J = 6.8, 6.8 Hz, 1H), 7.32
(dd, J = 2.0, 6.8 Hz, 1H), 7.36 (d, J = 8.6 Hz, 2H), 7.47 (dd, J = 2.0,
6.8 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H); 13C NMR (400 MHz, CDCl3) δ
38.4, 106.0, 128.4, 130.0, 130.5, 133.7, 135.4, 137.7, 137.9, 161.9;
HRMS (EI) m/z (M+) calcd for C12H10ClNO 219.0451, found
219.0449.
3-(4-Bromophenyl)-1-methylpyridin-2(1H)-one (5ad): purified by
column chromatography on silica gel with dichloromethane/ethyl
acetate/triethylamine (2/1/0.05 v/v/v) as an eluent; 42 mg (48%),
mp 146−147 °C (from dichloromethane/ethyl acetate); 1H NMR
(400 MHz, CDCl3) δ 3.60 (s, 3H), 6.24 (dd, J = 6.8, 6.8 Hz, 1H), 7.32
(dd, J = 2.1, 6.8 Hz, 1H), 7.47 (dd, J = 2.1, 6.8 Hz, 1H), 7.50 (d, J =
8.3 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H); 13C NMR (400 MHz, CDCl3) δ
38.4, 106.0, 121.9, 130.3, 130.4, 131.3, 135.8, 137.7, 137.9, 161.8;
HRMS (EI) m/z (M+) calcd for C12H10BrNO 262.9946, found
262.9943.
1
(52%), mp 130−133 °C (from dichloromethane/ethyl acetate); H
NMR (400 MHz, CDCl3) δ 3.63 (s, 3H), 6.31 (dd, J = 6.8, 6.8 Hz,
1H), 7.40 (dd, J = 2.0, 6.8 Hz, 1H), 7.55 (dd, J = 2.0, 6.8 Hz, 1H), 7.68
(d, J = 8.3 Hz, 2H), 7.84 (d, J = 8.3 Hz, 2H); 13C NMR (400 MHz,
CDCl3) δ 38.5, 106.0, 111.1, 119.2, 129.3, 129.5, 132.0, 138.7, 139.0,
141.60, 161.50; HRMS (EI) m/z (M+) calcd for C13H10N2O 210.0793,
found 210.0796.
1-Methyl-3-(4-methylphenyl)pyridin-2(1H)-one (5aj): purified by
column chromatography on silica gel with dichloromethane/ethyl
acetate/triethylamine (1/1/0.05 v/v/v) as an eluent; 70 mg (45%),
mp 135−137 °C (from dichloromethane/ethyl acetate); 1H NMR
(400 MHz, CDCl3) δ 2.37 (s, 3H), 3.60 (s, 3H), 6.22 (dd, J = 6.9, 6.9
Hz, 1H), 7.20 (d, J = 7.9 Hz, 2H), 7.28 (dd, J = 2.0, 6.9 Hz, 1H), 7.46
(dd, J = 2.0, 6.9 Hz, 1H), 7.59 (d, J = 7.9 Hz, 2H); 13C NMR (400
MHz, CDCl3) δ 21.4, 38.3, 105.9, 128.6, 128.9, 131.7, 134.1, 137.2,
137.2, 137.6, 161.1; HRMS (EI) m/z (M+) calcd for C13H13NO
199.0997, found 199.0994.
3-(4-Methoxyphenyl)-1-methylpyridin-2(1H)-one (5ak): purified
by column chromatography on silica gel with dichloromethane/ethyl
acetate/triethylamine (1/1/0.05 v/v/v) as an eluent; 18 mg (28%),
1
oil; H NMR (400 MHz, CDCl3) δ 3.61 (s, 3H), 3.83 (s, 3H), 6.23
(dd, J = 6.9, 6.9 Hz, 1H), 6.93 (dd, J = 2.1, 7.9, 2H), 7.27 (dd, J = 2.1,
6.9 Hz, 1H), 7.45 (dd, J = 2.1, 6.9 Hz, 1H), 7.67 (dd, J = 2.1, 7.9 Hz,
2H); 13C NMR (400 MHz, CDCl3) δ 38.3, 55.5, 106.0, 113.7, 129.4,
129.9, 131.3, 136.7, 136.9, 159.4, 162.2; HRMS (APCI) m/z ([M +
H]+) calcd for C13H14NO2 216.1019, found 216.1017.
3-(3-Methoxyphenyl)-1-methylpyridin-2(1H)-one (5al): purified
by column chromatography on silica gel with dichloromethane/ethyl
acetate/triethylamine (1/1/0.05 v/v/v) as an eluent; 26 mg (39%),
3-(4-Iodophenyl)-1-methylpyridin-2(1H)-one (5ae): purified by
column chromatography on silica gel with dichloromethane/ethyl
acetate/triethylamine (1/1/0.05 v/v/v) as an eluent; 36 mg (38%),
mp 135−137 °C (from dichloromethane/ethyl acetate); 1H NMR
(400 MHz, CDCl3) δ 3.61 (s, 3H), 6.25 (dd, J = 6.9, 6.9 Hz, 1H), 7.32
(dd, J = 2.0, 6.9 Hz, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.47 (dd, J = 2.0,
6.9 Hz, 1H), 7.72 (d, J = 8.7 Hz, 2H); 13C NMR (400 MHz, CDCl3) δ
38.4, 93.6, 106.0, 130.5, 136.5 (two peaks are overlapped), 137.3,
137.7, 138.0, 161.8; HRMS (EI) m/z (M+) calcd for C12H10INO
310.9807, found 310.9805.
1
oil; H NMR (400 MHz, CDCl3) δ 3.61 (s, 3H), 3.84 (s, 3H), 6.23
(dd, J = 6.9, 6.9 Hz, 1H), 6.88 (ddd, J = 1.0, 2.6, 8.1 Hz, 1H), 7.22−
7.33 (m, 4H), 7.49 (dd, J = 2.0, 6.9 Hz, 1H); 13C NMR (400 MHz,
CDCl3) δ 38.3, 55.4, 105.9, 113.9, 114.1, 121.2, 129.2, 131.5, 137.6,
137.8, 138.3, 159.5, 162.0; HRMS (EI) m/z (M+) calcd for
C13H13NO2 215.0946, found 215.0947.
3-(2-Chlorophenyl)-1-methylpyridin-2(1H)-one (5am): purified by
column chromatography on silica gel with dichloromethane/ethyl
acetate/triethylamine (1/1/0.05 v/v/v) as an eluent; 10 mg (15%),
Methyl 4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)benzoate
(5af): purified by column chromatography on silica gel with
dichloromethane/ethyl acetate/triethylamine (2/1/0.05 v/v/v) as an
eluent; 34 mg (46%), mp 135−137 °C (from dichloromethane/ethyl
1
mp 82−83 °C (from dichloromethane/ethyl acetate); H NMR (400
MHz, CDCl3) δ 3.62 (s, 3H), 6.24 (dd, J = 6.8, 6.8 Hz, 1H), 7.27 (dd,
J = 1.8, 6.8 Hz, 1H), 7.34−7.37 (m, 1H), 7.28 (d, J = 9.5 Hz, 1H), 7.38
(dd, J = 1.8, 6.8 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.42−7.46 (m, 1H);
13C NMR (400 MHz, CDCl3) δ 38.2, 105.3, 126.7, 129.2, 129.8, 130.7,
131.7, 133.7, 136.0, 138.4, 139.8, 161.5; HRMS (EI) m/z (M+) calcd
for C12H10ClNO 219.0451, found 219.0452.
1
acetate); H NMR (400 MHz, CDCl3) δ 3.63 (s, 3H), 3.92 (s, 3H),
6.28 (dd, J = 6.8, 6.8 Hz, 1H), 7.36 (dd, J = 1.9, 6.8 Hz, 1H), 7.55 (dd,
J = 1.9, 6.8 Hz, 1H), 7.79 (d, J = 8.7 Hz, 2H), 8.05 (d, J = 8.7 Hz, 2H);
13C NMR (400 MHz, CDCl3) δ 38.4, 52.2, 106.0, 128.6, 129.21, 129.5,
130.5, 138.41, 138.43, 141.6, 161.8, 167.1; HRMS (EI) m/z (M+)
calcd for C14H13NO3 243.0895, found 243.0893.
3-(4-Benzoylphenyl)-1-methylpyridin-2(1H)-one (5ag): purified by
column chromatography on silica gel with dichloromethane/ethyl
acetate/triethylamine (5:1:0.10, v/v/v) as an eluent; 50 mg (58%), oil;
1H NMR (400 MHz, CDCl3) δ 3.64 (s, 3H), 6.30 (dd, J = 6.7, 6.7 Hz,
1H), 7.38 (d, J = 6.7 Hz, 1H), 7.49 (dd, J = 7.5, 7.5 Hz, 2H), 7.58 (d, J
= 6.7 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.83 (d, J = 7.5 Hz, 2H), 7.84
1-Methyl-3-(naphthalen-2-yl)pyridin-2(1H)-one (5an): purified by
column chromatography on silica gel with dichloromethane/ethyl
acetate/triethylamine (2/1/0.05 v/v/v) as an eluent; 29 mg (41%),
mp 159−160 °C (from dichloromethane/ethyl acetate); 1H NMR
(400 MHz, CDCl3) δ 3.64 (s, 3H), 6.29 (dd, J = 6.8, 6.8 Hz, 1H), 7.33
(dd, J = 1.6, 6.8 Hz, 1H), 7.45−7.48 (m, 2H), 7.61 (dd, J = 1.6, 6.8 Hz,
1H), 7.79−7.88 (m, 4H), 7.23 (s, 1H); 13C NMR (400 MHz, CDCl3)
δ 38.4, 106.1, 126.1, 126.1, 126.7, 127.61, 127.64, 127.8, 128.5, 131.6,
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133.0, 133.5, 134.5, 137.6, 138.1, 162.2; HRMS (EI) m/z (M+) calcd
for C16H13NO 235.0997, found 235.0994.
3-Butyl-1-methylpyridin-2(1H)-one (5ao): purified by column
1-Methyl-3-phenylquinolin-2(1H)-one (5ja): purified by column
chromatography on silica gel with dichloromethane/ethyl acetate/
triethylamine (5:1:0.1, v/v/v) as an eluent; 22 mg (31%), mp 138−
1
chromatography on silica gel with dichloromethane/ethyl acetate/
139 °C (from dichloromethane/ethyl acetate); H NMR (400 MHz,
1
triethylamine (2/1/0.05 v/v/v) as an eluent; 25 mg (50%), oil; H
CDCl3) δ 3.80 (s, 3H), 7.25 (ddd, J = 2.0, 7.7, 7.7 Hz, 1H), 7.37 (tt, J
= 1.3, 7.3 Hz, 1H), 7.38 (dd, J = 2.0, 7.7 Hz, 1H), 7.43 (ddd, J = 1.4,
7.3, 7.3 Hz, 2H), 7.56 (ddd, J = 1.8, 7.7, 7.7 Hz, 1H), 7.60 (dd, J = 1.8,
7.7 Hz, 1H), 7.71 (dd, J = 1.3, 7.3 Hz, 2H), 7.79 (s, 1H); 13C NMR
(400 MHz, CDCl3) δ 30.1, 114.1, 120.9, 122.3, 128.2, 128.3, 129.0,
129.1, 130.4, 132.6, 136.9 (two peaks are overlapped), 139.7, 161.7;
HRMS (EI) m/z (M+) calcd for C16H13NO 235.0997, found
235.0996.
1-Methyl-3-phenyl-4-(trifluoromethyl)pyridin-2(1H)-one (5ka):
purified by column chromatography on silica gel with dichloro-
methane/ethyl acetate/triethylamine (5:1:0.1, v/v/v) as an eluent; 22
mg (31%), oil; 1H NMR (400 MHz, CDCl3) δ 3.59 (s, 3H), 6.43 (d, J
= 7.3 Hz, 1H), 7.25 (dd, J = 1.7, 8.6 Hz, 2H), 7.37−7.43 (m, 4H); 13C
NMR (400 MHz, CDCl3) δ 38.6, 101.6 (q, J = 3.8 Hz), 122.5 (q, J =
275.8 Hz), 128.0, 128.3, 129.5, 132.8, 133.5, 137.7 (q, J = 30.7 Hz),
138.1, 162.3; 19F NMR (376 MHz, CDCl3) δ −59.55; HRMS (EI) m/
z (M+) calcd for C13H10F3NO 253.0714, found 253.0714.
NMR (400 MHz, CDCl3) δ 0.93 (t, J = 7.3, 3H), 1.38 (tq, J = 7.3, 7.3
Hz, 2H), 1.57 (tt, J = 7.3, 7.4 Hz, 2H), 2.53 (t, J = 7.4 Hz, 2H), 3.54
(s, 3H), 6.09 (dd, J = 6.8, 6.8 Hz, 1H), 7.15 (d, J = 6.8 Hz, 2H); 13C
NMR (400 MHz, CDCl3) δ 14.1, 22.7, 30.57, 30.60, 37.8, 105.6, 134.8,
135.6, 135.9, 163.3; HRMS (EI) m/z (M+) calcd for C10H15NO
165.1154, found 165.1154.
3-Cyclohexyl-1-methylpyridin-2(1H)-one (5ap): purified by col-
umn chromatography on silica gel with dichloromethane/ethyl
acetate/triethylamine (1/1/0.05 v/v/v) as an eluent; 70 mg (45%),
1
oil; H NMR (400 MHz, CDCl3) δ 1.16−1.28 (m, 3H), 1.39−1.50
(m, 2H), 1.73−1.83 (m, 3H), 1.86−1.91 (m, 2H), 2.89 (tt, J = 3.1,
11.9, 1H), 3.54 (s, 3H), 6.12 (dd, J = 6.8, 6.8 Hz, 1H), 7.14 (d, J = 6.8
Hz, 2H); 13C NMR (400 MHz, CDCl3) δ 26.5, 26.9, 32.6, 37.7, 37.9,
105.7, 133.5, 135.2, 138.9, 162.9; HRMS (EI) m/z (M+) calcd for
C12H17NO 191.1310, found 191.1309.
1,6-Dimethyl-3-phenylpyridin-2(1H)-one (5da): purified by col-
umn chromatography on silica gel with dichloromethane/ethyl
acetate/triethylamine (2/1/0.05 v/v/v) as an eluent; 27 mg (46%),
mp 103−105 °C (from dichloromethane/ethyl acetate); 1H NMR
(400 MHz, CDCl3) δ 2.39 (s, 3H), 3.60 (s, 3H), 6.13 (d, J = 7.0 Hz,
1H), 7.29 (tt, J = 1.6, 7.4 Hz, 1H), 7.38 (d, J = 7.0 Hz, 1H), 7.38 (dd, J
= 7.4, 7.4 Hz, 2H), 7.67 (dd, J = 1.6, 7.4 Hz, 2H); 13C NMR (400
MHz, CDCl3) δ 21.3, 31.8, 106.5, 127.4, 128.2 (two peaks are
overlapped), 128.7, 137.0, 137.5, 145.6, 162.7; HRMS (EI) m/z (M+)
calcd for C13H13NO 199.0997, found 199.0994.
1-(But-3-en-1-yl)-3-phenylpyridin-2(1H)-one (5la): purified by
column chromatography on silica gel with hexane/triethylamine
(2:1, v/v) as an eluent; 22 mg (33%), mp 82−83 °C (from hexane/
1
ethyl acetate); H NMR (400 MHz, CDCl3) δ 2.57 (dt, J = 7.1, 7.1
Hz, 2H), 4.06 (t, J = 7.1 Hz, 2H), 5.07 (dd, J = 1.6, 10.1 Hz, 1H), 5.12
(dd, J = 1.6, 17.1 Hz, 1H), 5.82 (ddt, J = 10.1, 17.1, 7.1 Hz, 1H), 6.24
(dd, J = 6.9, 6.9 Hz, 1H), 7.25 (dd, J = 2.1, 6.9 Hz, 1H), 7.31 (tt, J =
1.3, 7.4 Hz, 1H), 7.39 (ddd, J = 1.5, 7.4, 7.4 Hz, 2H), 7.48 (dd, J = 2.1,
6.9 Hz, 1H), 7.69 (dd, J = 1.3, 7.4 Hz, 2H); 13C NMR (400 MHz,
CDCl3) δ 33.4, 50.4, 105.8, 118.0, 127.8, 128.2, 128.8, 132.0, 134.3,
137.0, 137.0, 137.6, 161.5; HRMS (EI) m/z (M+) calcd for C15H15NO
225.1154, found 225.1155.
1-Methyl-3-phenyl-5-(trifluoromethyl)pyridin-2(1H)-one (5ea):
purified by column chromatography on silica gel with dichloro-
methane/ethyl acetate/triethylamine (10:1:0.5, v/v/v) as an eluent; 30
mg (40%), mp 138−139 °C (from dichloromethane/ethyl acetate);
1H NMR (400 MHz, CDCl3) δ 3.64 (s, 3H), 7.38 (tt, J = 1.5, 7.0 Hz,
1H), 7.42 (ddd, J = 1.7, 7.0, 7.0 Hz, 2H), 7.59 (d, J = 2.7 Hz, 1H) 7.67
(dd, J = 1.5, 7.0 Hz, 2H), 7.71 (d, J = 2.7 Hz, 1H); 13C NMR (400
MHz, CDCl3) δ 38.9, 109.6 (q, J = 34.7 Hz), 123.6 (q, J = 269.8 Hz),
128.4, 128.6, 128.7, 132.3, 132.9 (q, J = 2.2 Hz), 135.6, 136.6 (q, J =
5.1 Hz), 161.6; 19F NMR (376 MHz, CDCl3) δ −62.23; HRMS (EI)
m/z (M+) calcd for C13H10F3NO 253.0714, found 253.0714.
5-Bromo-1-methyl-3-phenylpyridin-2(1H)-one (5ga): purified by
column chromatography on silica gel with dichloromethane/ethyl
acetate/triethylamine (40:1:0.5, v/v/v) as an eluent; 30 mg (37%), mp
ASSOCIATED CONTENT
■
S
* Supporting Information
Figures detailing attempts to apply some catalyst systems for
C3-selective direct phenylation of 1a with 4a and H, 13C, and
1
19F NMR spectra for products. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: k_hirano@chem.eng.osaka-u.ac.jp (K.H.); miura@
chem.eng.osaka-u.ac.jp (M.M.).
■
1
135−138 °C (from dichloromethane/ethyl acetate); H NMR (400
MHz, CDCl3) δ 3.59 (s, 3H), 7.35 (tt, J = 1.5, 7.2 Hz, 1H), 7.40 (ddd,
J = 1.5, 7.2, 7.2 Hz, 2H), 7.44 (d, J = 2.7 Hz, 1H), 7.53 (d, J = 2.7 Hz,
1H), 7.66 (dd, J = 1.5, 7.2 Hz, 2H); 13C NMR (400 MHz, CDCl3) δ
38.4, 97.8, 128.37, 128.44, 128.7, 133.0, 135.7, 137.2, 140.4, 160.7;
HRMS (EI) m/z (M+) calcd for C12H10BrNO 262.9946, found
262.9943.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by Grants-in-Aid for Scientific
Research from the MEXT and JSPS, Japan.
■
4-Methoxy-1-methyl-3-phenylpyridin-2(1H)-one (5ha): purified
by column chromatography on silica gel with dichloromethane/ethyl
acetate/triethylamine (1/1/0.05 v/v/v) as an eluent; 15 mg (23%),
mp 139−140 °C (from dichloromethane/ethyl acetate); 1H NMR
(400 MHz, CDCl3) δ 3.55 (s, 3H), 3.78 (s, 3H), 6.15 (d, J = 7.7 Hz,
1H), 7.27 (tt, J = 1.8, 7.2 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.38 (ddd,
J = 1.7, 7.2, 7.2 Hz, 2H), 7.43 (dd, J = 1.8, 7.2 Hz, 2H); 13C NMR
(400 MHz, CDCl3) δ 37.7, 56.2, 94.9, 114.8, 127.1, 127.8, 130.8,
133.2, 137.8, 163.0, 163.5; HRMS (APCI) m/z ([M + H]+) calcd for
C13H14NO2 216.1019, found 216.1023.
1-Benzyl-3-phenylpyridin-2(1H)-one (5ia): purified by column
chromatography on silica gel with dichloromethane/ethyl acetate/
triethylamine (5:1:0.1, v/v/v) as an eluent; 39 mg (49%), oil; 1H
NMR (400 MHz, CDCl3) δ 5.20 (s, 2H), 6.23 (dd, J = 6.9, 6.9 Hz,
1H), 7.27−7.41 (m, 9H), 7.46 (dd, J = 2.1, 6.9 Hz, 1H), 7.69 (dd, J =
1.3, 7.0 Hz, 2H); 13C NMR (400 MHz, CDCl3) δ 52.8, 106.3, 127.8,
128.1, 128.2, 128.4, 128.8, 129.0, 132.2, 136.5, 136.6, 137.0, 137.6,
161.6; HRMS (EI) m/z (M+) calcd for C18H15NO 261.1154, found
261.1155.
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