Bifunctional Urea/Hg(OAc)2-Mediated Synthesis of 4-Aryl-6-oxycarbonyl-2-pyrones and 2-Pyridones from Dithiomalonate and β,γ-Unsaturated α-Keto Esters

Article abstract of DOI:10.1021/acs.joc.1c00323

Disubstituted 2-pyrones and 2-pyridones were obtained by bifunctional urea-catalyzed Michael addition/lactonization or lactamization followed by a Hg(OAc)2- or Hg(OAc)2/DBU-mediated hydrolysis/decarboxylation/dehydrogenation process. This one-pot two-stage protocol enabled the rapid synthesis of 4,6-disubstituted 2-pyrones and 2-pyridones from dithiomalonate and β,γ-unsaturated α-keto esters in practical yields under mild reaction conditions. Additionally, the obtained 2-pyridones were facilely transformed to 2,4,6-trisubstituted pyridines in excellent yields.

Full text of DOI:10.1021/acs.joc.1c00323

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Note
Bifunctional Urea/Hg(OAc)2‑Mediated Synthesis of 4‑Aryl-6-
oxycarbonyl-2-pyrones and 2‑Pyridones from Dithiomalonate and
β,γ-Unsaturated α‑Keto Esters
Daeil Bae, Juyeol Lee, Hui Jin,* and Do Hyun Ryu*
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ABSTRACT: Disubstituted 2-pyrones and 2-pyridones were obtained by bifunctional urea-catalyzed Michael addition/
lactonization or lactamization followed by a Hg(OAc)2- or Hg(OAc)2/DBU-mediated hydrolysis/decarboxylation/dehydrogenation
process. This one-pot two-stage protocol enabled the rapid synthesis of 4,6-disubstituted 2-pyrones and 2-pyridones from
dithiomalonate and β,γ-unsaturated α-keto esters in practical yields under mild reaction conditions. Additionally, the obtained 2-
pyridones were facilely transformed to 2,4,6-trisubstituted pyridines in excellent yields.
of transition-metal enolates from β-keto acids9 and the Pd(II)-
mediated dehydrogenation of carbonyl compounds to form the
corresponding α,β-unsaturated carbonyl products,10 we
became interested in whether this methodology could be
further developed by incorporating a suitable transition-metal
ion to access functionalized 2-pyrones and 2-pyridones. In a
continuation of our research, we here present an efficient one-
pot two-stage protocol for the rapid synthesis of 4-aryl-6-
oxycarbonyl disubstituted 2-pyrones and 2-pyridones from
readily available dithiomalonate and β,γ-unsaturated α-keto
esters via a Hg(OAc)2-mediated hydrolysis/decarboxylation/
dehydrogenation process (Scheme 1d). Furthermore, the
obtained 2-pyridones can be easily transformed to synthetically
valuable 2,4,6-trisubstituted pyridines11 via isomerization and
functionalization.
2-Pyrone1 and 2-pyridone2 are two classes of important
heterocycles that form the core of many biologically active and
natural products and are used as versatile synthons. Due to the
broad synthetic and medicinal applications of these molecules,
much effort has been directed toward the preparation of
diverse and functionalized 2-pyrones and 2-pyridones.3,4 For
example, Smith developed a one-pot isothiourea-mediated
Michael addition/lactonization/thiol elimination cascade se-
quence for the formation of trifluoromethyl-substituted 2-
pyrones (Scheme 1a)3b, and Chi reported NHC-catalyzed
reactions of alkyne esters with enamides to synthesize
functionalized 2-pyridone and pyridines (Scheme 1b).4l
However, most of these methods suffer from a variety of
drawbacks, such as limited substrates and harsh reaction
conditions, and there are few synthetic routes to the useful 6-
oxycarbonyl-substituted 2-pyrones and 2-pyridones.3a,4k
In biological systems, S-to-N and S-to-O acyl transfer
reactions of thioesters are among the most important methods
for the formation of amide and ester bonds, respectively.5,6
Inspired by nature, we recently developed the organocatalytic7
asymmetric Michael addition/lactonization reactions of β,γ-
unsaturated α-keto esters with dithiomalonates to produce 3-
(phenylthio)carbonyl-substituted 3,4-dihydropyranones
(Scheme 1c).8 Enlightened by the decarboxylative generation
The synthetic strategy was first investigated with the reaction
of S,S′-diphenyl dithiomalonate 1 with the β,γ-unsaturated α-
Received: February 9, 2021
Published: April 5, 2021
https://doi.org/10.1021/acs.joc.1c00323
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 6001−6014
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Scheme 1. Synthesis of 4,6-Disubstituted 2-Pyrones and 2-Pyridones
keto ester 2a (Table 1). In the presence of the 10 mol %
bifunctional urea catalyst EU,12 the reaction worked smoothly
and completely yielded the 3,4-dihydropyrone 3a at room
temperature (rt) in 0.5 h. Then, the following transition-metal-
ion-mediated hydrolysis/decarboxylation/dehydrogenation
cascade was examined. Pd(OAc)2 was first tested in this
reaction. After removing the solvent in the first stage, crude 3a
was directly treated with 0.5 equiv of Pd(OAc)2 in EtCN at
reflux for 1 h. The desired 2-pyrone 5a was obtained in only a
5% yield, and 3,4-dihydropyranone 4a was obtained in a 41%
yield (Table 1, entry 1). Then, the thiophilic metal ion13
Hg(OAc)2 (0.5 equiv) was tested, which resulted in a similar
conversion into 2-pyrone 5a; however, 4a was obtained in a
90% yield (Table 1, entry 2). The use of 2.5 equiv of
Hg(OAc)2 effectively promoted the formation of an α,β-
carbon−carbon double bond, giving the desired 2-pyrone 5a in
a 68% yield, and metallic Hg could be observed with the naked
eye (Table 1, entry 3). Changing the solvent to MeCN or THF
had a negative effect upon the yield of 5a (Table 1, entries 4
and 5, respectively). Product 5a was obtained at a higher yield
of 75% after the catalyst loading of EU was increased to 20 mol
% (Table 1, entry 6), which implies that EU acted as a positive
factor in the second step. Finally, adding 1 equiv of N-
ethylmorpholine (NME) and extending the reaction time to 3
h in EtCN at reflux was determined to be the optimal reaction
conditions, giving 5a at an overall yield of 82% (Table 1,
entries 7 and 8). The results showed that an effective one-pot
two-stage protocol to functionalized 2-pyrones had been
established. Additionally, Hg(OCOCF3)2 and Hg(OTf)2
were examined in place of Hg(OAc)2 under the optimized
conditions (Table 1, entries 9 and 10, respectively), and
Hg(OCOCF3)2 provided 5a with a slightly better yield of 86%
(Table 1, entry 10). However, the use of 1.2 equiv of
Hg(OCOCF3)2 did not promote this reaction well (Table 1,
entry 11).
With the optimized reaction conditions in hand, the
substrate scope of the reactions between dithiomalonate 1
and various aryl β,γ-unsaturated α-keto esters 2 was then
examined (Table 2). Electron-donating substrates (Table 2,
entries 7 and 8) afforded relatively higher yields compared with
those of electron-withdrawing substrates (Table 2, entries 2, 3,
9, and 10). For example, the electron-withdrawing nitro group
decreased the yield to 30% (Table 2, entry 9). Substrates 2
with substitutions at the para- and meta-positions were all well-
tolerated, affording the corresponding products in moderate to
good yields. However, the ortho-substituted substrate gave a
lower yield of 36% (Table 2, entry 6). Heterocycles and
naphthyl-substituted substrates were also examined and
provided desired products 5 in moderate yields (Table 2,
62−70%, entries 11−13). It is noteworthy that the reaction
proceeded smoothly when the R2 group of 2 was changed to
the p-methoxybenzyl (PMB) group, quantitatively affording
product 5n (Table 2, entry 14); however, the reason for this is
not yet clear.
The generality of this process was next investigated in the
synthesis of functionalized 2-pyridones (Table 3). A range of
aryl β,γ-unsaturated α-keto esters 2 bearing a variety of
substituents and naphthyl groups were reacted with p-
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a
Table 1. Optimization of the Reaction Conditions for the Synthesis of 4,6-Disubstituted 2-Pyrones
b
b
entry
M(X)2 (equiv)
solvent
4a, yield (%)
5a, yield (%)
1
2
3
4
5
6
7
8
Pd(OAc)2 (0.5)
Hg(OAc)2 (0.5)
Hg(OAc)2 (2.5)
Hg(OAc)2 (2.5)
Hg(OAc)2 (2.5)
Hg(OAc)2 (2.5)
Hg(OAc)2 (2.5)
Hg(OAc)2 (2.5)
Hg(OCOCF3)2 (2.5)
Hg(OTf)2 (2.5)
Hg(OCOCF3)2 (1.2)
EtCN
EtCN
EtCN
MeCN
THF
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
41
90
5
6
15
5
5
68
60
40
75
c
11
cd
,
e
trace
trace
79
cdf
, ,
e
82
cdf
, ,
e
e
9
10
11
5
86
cdf
, ,
e
e
4
15
cdf
, ,
e
e
44
8
a
Unless otherwise noted, the first step of all the reactions was carried out with 1 (0.1 mmol), 2 (0.25 mmol), and EU (10 mol %) in 1 mL of
b
c
d
1
MTBE at rt. Determined by H NMR analysis of the crude reaction mixture using DMF as an internal standard. Used 20 mol % of EU. The
second step of the reaction was refluxed for 3 h. Isolated yield. In the second step, 1 equiv of NME was added.
e
f
a
Table 2. Substrate Scope of the Synthesis of 4,6-Disubstituted 2-Pyrones
entry
R1
phenyl
R2
5
yield (%)
b
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
PMB
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
82 (82)
4-FC6H4
66
76
82
77
36
79
92
30
68
70
63
63
99
4-ClC6H4
4-BrC6H4
3-BrC6H4
2-Br C6H4
4-MeC6H4
4-MeOC6H4
4-NO2C6H4
4-CF3C6H4
2-thiophenyl
2-furyl
c
9
10
11
12
13
14
2-naphthyl
phenyl
a
The reaction was carried out with 1 (0.1 mmol), 2 (0.25 mmol), and EU (20 mol %) in 1 mL of MTBE at rt. Then, MTBE was removed in vacuo,
followed by the addition of EtCN (1 mL), Hg(OAc)2 (2.5 equiv), H2O (5 equiv), and N-ethylmorpholine (1 equiv), and the mixture was refluxed
b
c
for 3 h. The reactions was carried out with 2.5 mmol 1. CH2Cl2 was used as a solvent in the first stage of the reaction.
toluenesulfonamide (TsNH2) to generate the corresponding
ketimines in situ, which were then treated with dithiomalonate
1 to promote Michael addition/lactamization and provided
3,4-dihydropyridinones 6′ (Table 3). However, these reactions
stopped at the Michael addition steps, and the following
lactamization did not occur under the presented conditions.
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Table 3. Synthesis of 4,6-Disubstituted 2-Pyridones
a
b
c
entry
R
6, yield (%)
7, yield (%)
8, yield (%)
d
e
1
2
3
4
5
6
7
8
9
phenyl
4-FC6H4
6a, 55 (52)
6b, 55 (51)
7a, 95
7b, 96 (90)
7c, 94
7d, 95
7e, 90
7f, 92
7g, 80
7h, 83
7i, 85
8a, 96 (89)
d
e
8b, 95
8c, 95
8d, 92
8e, 89
8f, 92
8g, 79
8h, 86
8i, 94
8j, 83
4-ClC6H4
4-BrC6H4
2-BrC6H4
3-BrC6H4
4-CF3C6H4
4-MeC6H4
4-MeOC6H4
2-naphthyl
6c, 56
6d, 53
6e, 50
6f, 51
6g, 52
6h, 46
6i, 51
6j, 71
10
7j, 74
a
b
c
The reactions were carried out with 1.0 mmol 2, and Michael adducts 6 were isolated. The reactions were carried out with 0.1 mmol 6. The
d
e
reactions were carried out with 0.1 mmol 6. The reactions were carried out with 2.5 mmol 2. The reactions were carried out with 1.0 mmol 6.
Then, the Michael adducts 6 were treated with Hg(OAc)2
under the previously optimized conditions. The Michael
adducts 6 were well-tolerated, giving excellent conversions to
4,6-disubstituted 2-pyridones 7 (85−96%) through a lactam-
ization/hydrolysis/decarboxylation/dehydrogenation sequence
(Table 3, method A). Alternatively, the treatment of Michael
adducts 6 with 1 equiv of Hg(OAc)2 and excess 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) led to 2-pyridones 8,
containing a free (NH)-lactam, in good yields (79−96%)
(Table 3, method B).
To gain insight into the reaction mechanism, two control
experiments were performed (Scheme 2). Isolated 3,4-
dihydropyranone 4a was exposed to the standard reaction
conditions (Scheme 2a). After refluxing for 3 h, the 2-pyrone
5a was obtained in a 75% yield. This result indicated that
product 5a could be generated from 4a by Hg-ion-mediated
dehydrogenation and allowed us to assume that 2-pyridones 7
were formed in a similar way under the same reaction
conditions (Table 3, method A). We then focused our
attention on the DBU-mediated lactamization/hydrolysis/
decarboxylation/elimination cascades of Michael adducts 6
(Table 3, method B). Conceptually, DBU alone can promote
this reaction sequence to produce detosylated 2-pyridones 8.
To ascertain if Hg(OAc)2 was necessary in this cascade
process, the Michael adduct 6a was treated with DBU in the
absence of Hg(OAc)2 (Scheme 2b). Despite elevating the
reaction temperature by 60 °C, 8a was obtained in only a 60%
yield with a full consumption of 6a. This showed that
Hg(OAc)2 plays an important role in facilitating the
lactamization and chemoselective hydrolysis and decarbox-
ylation of the Michael adducts 6.
Based on reports in the literature and our observations, a
possible mechanism is proposed (Scheme 3). First, 3,4-
dihydropyranones and 3,4-dihydropyridones 9 are formed
through a bifunctional urea-catalyzed [4 + 2] annulation of
dithiomalonate with either β,γ-unsaturated α-keto esters or β,γ-
unsaturated α-ketimino esters generated in situ. Under the
conditions of method A, two plausible routes for the
generation of Hg enolates 11 can be envisioned (Scheme 3).
According to previous reports,9 decarboxylation can give C-
bound Hg enolates 10, which are in equilibrium with O-bound
Hg enolates 11. Alternatively, based on our control experiment
(Scheme 2a), Hg enolates 11 can also be generated from
intermediates 12. Then, Hg enolates 11 will undergo
elimination to yield the product (5 or 7) and generate metallic
Hg. When the stronger DBU base is used instead of NME with
a smaller amount of Hg(OAc)2 at a lower temperature (40 °C)
Scheme 2. Control Experiments for the Mechanism
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Scheme 3. Proposed Mechanism
Table 4. Transformations of Pyridones 8 to Functionalized Pyridines 14 and 15
a
b
entry
R
14, yield (%)
15, yield (%)
1
2
3
4
5
6
phenyl
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
2-naphthyl
14a, 98
14b, 98
14c, 98
14d, 97
14e, 97
14f, 97
15a, 97
15b, 84
15c, 86
15d, 85
15e, 93
15f, 92
a
Reaction conditions are as follows: TsCl (0.2 mmol) and K2CO3 (0.3 mmol) were added to pyridones 8 (0.1 mmol) in DMF (1 mL) and stirred
b
for 24 h at rt. Reaction conditions are as follows: pyridones 8 (0.1 mmol) were added to POCl3 (1 mL) and stirred for 16 h at 50 °C.
(method B), dihydropyridinone intermediates 12 transform
into detosylated 2-pyridones 8 via a Ts group elimination/
double-bond migration pathway.4k
Given the wide interest in the preparation of functionalized
pyridines,14 the pyridones 8 were further transformed into
synthetically useful pyridines with the functional handles 2-
sulfonate and 2-chloro groups, thus allowing subsequent
derivatization into a variety of products (Table 4).11 As
shown in Table 4, the yields of the desired products 14 and 15
were excellent in all cases(84−98%).
In conclusion, taking advantage of the affinity of thioester
groups for Hg(OAc)2, we have developed an organocatalyst/
Hg(OAc)2-mediated two-stage protocol for the synthesis of
4,6-disubstituted 2-pyrones and 2-pyridinones. This process
works by the intermolecular Michael addition/lactonization or
lactamization of dithiomalonate 1 and β,γ-unsaturated α-keto
esters 2, followed by the Hg(OAc)2-mediated hydrolysis/
decarboxylation/dehydrogenation sequence to form the 2-
pyrones 5 and 2-pyridinones (7, 8). Additionally, the
pyridones 8 could then be transformed into valuable 2,4,6-
trisubstituted pyridines bearing readily modifiable 2-sulfonate
and 2-chloro functional handles.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise states, all the reactions
were carried out under air, and reagents were obtained from
commercial suppliers and directly used without further purification.
Flash column chromatography was performed using silica gel (200−
300 meshes). 1H, 13C{1H}, and 19F NMR spectra were recorded on a
Bruker NMR spectometer. Chemical shifts are reported in parts per
million (ppm) using TMS or the residual solvent peak as a reference
(CDCl3, δ 7.26 ppm for 1H and δ 77.0 ppm for 13C; DMSO-d6: δ 2.50
1
ppm for H and δ 39.5 ppm for 13C). The coupling constants J are
given in Hertz. Melting points were determined using the optimelt
model. Infrared spectra were recorded on a Jasco FT/IR-4100 (KBr
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Note
thin film) instrument. HRMS spectra were recorded on compact
instrument (Bruker, ESI-QTOF). MS spectra were recorded using a
Xevo G2-XS Q-TOF instrument (Waters, ESI-QTOF).
Methyl 4-(3-Bromophenyl)-2-oxo-2H-pyran-6-carboxylate (5e).
Following the general procedure with2f (67.3 mg, 0.25 mmol), 5e was
obtained as a yellow solid (23.8 mg, 77% yield): Rf (ethyl acetate/
1
hexane 1:4) = 0.25; mp 158−161 °C; H NMR (500 MHz, CDCl3)
General Procedure for the Synthesis of 2-Pyrones (5). To a
10 mL round-bottom flask were added dithiomalonate 1 (29.0 mg, 0.1
mmol), β,γ-unsaturated α-ketoesters 2 (0.25 mmol), catalyst EU (6.9
mg, 0.02 mmol), and methyl tert-butyl ether (1 mL) at rt. The
resulting mixture was stirred at rt until the reaction was complete
(monitored using TLC) and then concentrated in vacuo. To the
residue were added Hg(OAc)2 (80.0 mg, 0.25 mmol), propionitrile (1
mL), H2O (9.0 μL, 0.5 mmol), and NEM (12.7 μL, 0.1 mmol), and
the reaction mixture was refluxed using an oil bath for 3 h. After
cooling to room temperature, the reaction mixture was diluted with
dichloromethane (5 mL), washed with a saturated solution of NH4Cl
(5 mL), and concentrated in vacuo. The residue was purified by
column chromatography (ethyl acetate/hexane 1:6) to provide the
desired products 5.
7.76 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.43−
7.36 (m, 2H), 6.70 (d, J = 1.5 Hz, 1H), 3.98 (s, 3H) ppm; 13C{1H}
NMR (125 MHz, CDCl3) δ 160.1, 159.9, 152.1, 149.1, 136.5, 134.2,
131.0, 129.8, 125.3, 123.6, 115.7, 109.8, 53.3 ppm; IR (KBr thin film)
3630, 3429, 3084, 2961, 2921, 2851, 1717, 1640, 1566, 1546, 1478,
1442, 1377, 1330, 1287, 1261, 1192, 1113, 1078, 1042, 997, 916, 881,
861, 793, 767 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for
C13H9BrO4Na 330.9582, found 330.9583.
Methyl 4-(2-Bromophenyl)-2-oxo-2H-pyran-6-carboxylate (5f).
Following the general procedure with 2e (67.3 mg, 0.1 mmol), 5f was
obtained as an ivory solid (11.1 mg, 36% yield): Rf (ethyl acetate/
hexane 1:4) = 0.26; mp 137−142 °C; 1H NMR (500 MHz, CDCl3) δ
7.70 (dd, J = 8.0, 1.0 Hz, 1H), 7.43 (td, J = 7.5, 1.2 Hz, 1H), 7.36−
7.32 (m, 1H), 7.31 (dd, J = 7.6, 1.7 Hz, 1H), 7.28 (d, J = 1.6 Hz, 1H),
6.55 (d, J = 1.5 Hz, 1H), 3.95 (s, 3H) ppm; 13C{1H} NMR (125
MHz, CDCl3) δ 160.0, 159.9, 154.7, 147.9, 136.8, 133.8, 131.4, 129.8,
128.1, 121.0, 119.4, 112.7, 53.2 ppm; IR (KBr thin film) 3567, 3432,
3096, 2960, 2923, 2851, 2363, 2344, 1734, 1685, 1639, 1590, 1547,
1466, 1432, 1389, 1335, 1276, 1238, 1127, 1107, 1064, 1025, 992,
956, 877, 862, 839, 761, 724 cm−1; HRMS (ESI-QTOF) m/z [M +
Na]+ Calcd for C13H9BrO4Na 330.9582, found 330.9579.
Methyl 2-Oxo-4-p-tolyl-2H-pyran-6-carboxylate (5g). Following
the general procedure with 2h (51.1 mg, 0.25 mmol), 5g was obtained
as a yellow solid (17.7 mg, 79% yield): Rf (ethyl acetate/hexane 1:4)
= 0.27; mp 136−141 °C; 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J =
8.2 Hz, 2H), 7.47 (d, J = 1.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.70
(d, J = 1.6 Hz, 1H), 3.97 (s, 3H), 2.43 (s, 3H) ppm; 13C{1H} NMR
(125 MHz, CDCl3) δ 160.8, 160.2, 153.3, 148.7, 142.0, 131.4, 130.2,
126.6, 114.1, 110.2, 53.2, 21.4 ppm; IR (KBr thin film) 3433, 3096,
3036, 2956, 2923, 2852, 2361, 1930, 1715, 1646, 1609, 1550, 1513,
1440, 1421, 1387, 1334, 1289, 1258, 1216, 1190, 1107, 1038, 998,
958, 885, 860, 816, 768, 735, 710 cm−1; HRMS (ESI-QTOF) m/z [M
+ Na]+ Calcd for C14H12O4Na 267.0633, found 267.0631.
Methyl 2-Oxo-4-phenyl-2H-pyran-6-carboxylate (5a). Following
the general procedure with 2a (47.6 mg, 0.25 mmol), 5a was obtained
as a white solid (18.9 mg, 82% yield). For a large scale synthesis
following the general procedure with dithiomalonate 1 (721.0 mg, 2.5
mmol), 5a was obtained as a white solid (470.0 mg, 82% yield): Rf
1
(ethyl acetate/hexane 1:4) = 0.26; mp 146−150 °C; H NMR (500
MHz, CDCl3) δ 7.65−7.61 (m, 2H), 7.54−7.50 (m, 3H), 7.46 (d, J =
1.6 Hz, 1H), 6.71 (d, J = 1.6 Hz, 1H), 3.97 (s, 3H) ppm; 13C{1H}
NMR (125 MHz, CDCl3) δ 160.5, 160.0, 153.5, 148.8, 134.3, 131.3,
129.4, 126.7, 114.9, 110.2, 53.2 ppm; IR (KBr thin film) 3423, 3099,
3068, 3050, 3002, 2955, 1704, 1642, 1547, 1499, 1450, 1438, 1399,
1338, 1289, 1264, 1194, 1160, 1117, 1081, 1044, 1002, 888, 856, 763
cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for C13H10O4Na
253.0477, found 253.0474.
Methyl 4-(4-Fluorophenyl)-2-oxo-2H-pyran-6-carboxylate (5b).
Following the general procedure with 2b (52.0 mg, 0.25 mmol), 5b
was obtained as a white solid (16.4 mg, 66% yield): Rf (ethyl acetate/
hexane 1:4) = 0.25; mp 172−179 °C; 1H NMR (500 MHz, CDCl3) δ
7.66−7.62 (m, 2H), 7.43 (d, J = 1.7 Hz, 1H), 7.24−7.19 (m, 2H),
6.68 (d, J = 1.6 Hz, 1H), 3.97 (s, 3H) ppm; 13C{1H} NMR (125
MHz, CDCl3) δ 164.6 (C−F, 1JC−F = 250.0 Hz), 160.4, 160.0, 152.4,
149.0, 130.6, 128.9 (C−F, 3JC−F = 12.5 Hz), 116.7 (C−F, 2JC−F = 25.0
Hz), 114.7, 109.9, 53.3 ppm; 19F NMR (658 MHz, CDCl3) δ −108.1
(s, 1F) ppm; IR (KBr thin film) 3434, 3098, 3073, 3019, 2959, 2363,
1718, 1644, 1604, 1549, 1514, 1439, 1422, 1389, 1336, 1294, 1264,
1237, 1167, 1119, 1107, 1038, 999, 898, 881, 833, 809, 769, 728
cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for C13H9FO4Na
271.0383, found 271.0379.
Methyl 4-(4-Chlorophenyl)-2-oxo-2H-pyran-6-carboxylate (5c).
Following the general procedure with 2c (56.2 mg, 0.25 mmol), 5c
was obtained as a yellow solid (20.0 mg, 76% yield): Rf (ethyl acetate/
hexane 1:4) = 0.25; mp 152−156 °C; 1H NMR (500 MHz, CDCl3) δ
7.58 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 1.5 Hz,
1H), 6.70 (d, J = 1.5 Hz, 1H), 3.97 (s, 3H) ppm; 13C{1H} NMR (125
MHz, CDCl3) δ 160.3, 160.0, 152.3, 149.1, 137.7, 132.8, 129.8, 128.0,
115.1, 109.8, 53.3 ppm; IR (KBr thin film) 3447, 3091, 3066, 2962,
2927, 2855, 1732, 1645, 1594, 1546, 1496, 1441, 1416, 1339, 1288,
1255, 1192, 1107, 1092, 1038, 1013, 993, 956, 895, 874, 834, 816,
766, 719 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for
C13H9ClO4Na 287.0087, found 287.0085.
Methyl 4-(4-Bromophenyl)-2-oxo-2H-pyran-6-carboxylate (5d).
Following the general procedure with 2d (67.3 mg, 0.25 mmol), 5d
was obtained as a yellow solid (25.3 mg, 82% yield): Rf (ethyl acetate/
hexane 1:4) = 0.25; mp 153−158 °C; 1H NMR (500 MHz, CDCl3) δ
7.70−7.63 (m, 2H), 7.52−7.48 (m, 2H), 7.41 (d, J = 1.7 Hz, 1H),
6.70 (d, J = 1.7 Hz, 1H), 3.97 (s, 3H) ppm; 13C{1H} NMR (125
MHz, CDCl3) δ 160.3, 160.0, 152.4, 149.1, 133.3, 132.7, 128.2, 126.1,
115.1, 109.7, 53.3 ppm; IR (KBr thin film) 3447, 3090, 3064, 2964,
2922, 2853, 1733, 1645, 1588, 1545, 1492, 1440, 1413, 1338, 1285,
1254, 1190, 1106, 1076, 1038, 1009, 993, 956, 894, 872, 834, 816,
766, 725, 717 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for
C13H9BrO4Na 330.9582, found 330.9580.
Methyl 4-(4-Methoxyphenyl)-2-oxo-2H-pyran-6-carboxylate
(5h). Following the general procedure with 2i (55.1 mg, 0.25
mmol), 5h was obtained as a yellow solid (24.0 mg, 92% yield): Rf
1
(ethyl acetate/hexane 1:4) = 0.24; mp 161−167 °C; H NMR (500
MHz, CDCl3) δ 7.61 (d, J = 8.9 Hz, 2H), 7.46 (d, J = 1.7 Hz, 1H),
7.02 (d, J = 8.9 Hz, 2H), 6.65 (d, J = 1.7 Hz, 1H), 3.97 (s, 3H), 3.88
(s, 3H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 162.3, 160.9,
160.2, 152.7, 148.6, 128.4, 126.4, 114.9, 112.9, 110.0, 55.5, 53.2 ppm;
IR (KBr thin film) 3422, 3074, 3007, 2957, 2923, 2843, 2366, 1739,
1640, 1606, 1578, 1551, 1515, 1464, 1432, 1394, 1339, 1304, 1272,
1189, 1129, 1107, 1063, 1038, 994, 952, 875, 844, 825, 795, 767, 734,
714 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for
C14H12O5Na 283.0582, found 283.0580.
Methyl 4-(4-Nitrophenyl)-2-oxo-2H-pyran-6-carboxylate (5i).
Following the general procedure with 2k (58.8 mg, 0.25 mmol), 5i
was obtained as a yellow solid (8.3 mg, 30% yield): Rf (ethyl acetate/
hexane 1:4) = 0.23; mp 210−215 °C; 1H NMR (500 MHz, CDCl3) δ
8.42−8.36 (m, 2H), 7.83−7.78 (m, 2H), 7.42 (d, J = 1.7 Hz, 1H),
6.77 (d, J = 1.7 Hz, 1H), 3.99 (s, 3H) ppm; 13C{1H} NMR (125
MHz, CDCl3) δ 159.7, 159.6, 151.4, 149.6, 149.3, 140.5, 127.9, 124.6,
117.1, 109.4, 53.4 ppm; IR (KBr thin film) 3461, 3300, 3109, 3095,
2963, 2924, 2852, 2363, 1769, 1743, 1639, 1601, 1518, 1438, 1419,
1386, 1352, 1337, 1320, 1294, 1271, 1255, 1187, 1117, 1038, 1009,
999, 893, 880, 857, 840, 828, 770, 754, 700 cm−1; HRMS (ESI-
QTOF) m/z [M + Na]+ Calcd for C13H9NO6Na 298.0328, found
298.0325.
Methyl 2-Oxo-4-(4-(trifluoromethyl)phenyl)-2H-pyran-6-carbox-
ylate (5j). Following the general procedure with 2g (64.5 mg, 0.25
mmol), 5j was obtained as a yellow solid (20.3 mg, 68% yield): Rf
1
(ethyl acetate/hexane 1:4) = 0.25; mp 157−162 °C; H NMR (700
MHz, CDCl3) δ 7.78 (d, J = 7.7 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H),
7.43 (d, J = 1.4 Hz, 1H), 6.74 (d, J = 1.4 Hz, 1H), 3.98 (s, 3H) ppm;
13C{1H} NMR (175 MHz, CDCl3) δ 160.0, 159.9, 152.2, 149.3,
6006
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Note
2
4
138.0, 133.0 (C−3F, JC−F = 33.2 Hz), 127.2, 126.5 (C−3F, JC−F
=
F
butyl ether (2 mL). To the solution were subsequently added
dithiomalonate 1 (288.0 mg, 1.0 mmol), and catalyst EU (34.0 mg, 10
mol %) at 0 °C, and the reaction mixture was stirred for 1 h at 0 °C.
The reaction was quenched with 10% NH4Cl, and the mixture was
extracted with DCM, dried with Na2SO4, and concentrated in vacuo.
The residue was purified by column chromatography (ethyl acetate/
hexane 1:3) to provide the desired products 6.
3.5 Hz), 123.6 (C−3F, 1JC−F = 271.0 Hz), 116.4, 109.8, 53.4 ppm; 19
NMR (658 MHz, CDCl3) δ −63.0 (s, 3F) ppm; IR (KBr thin film)
3630, 3114, 3085, 2953, 2853, 2366, 1936, 1704, 1618, 1547, 1522,
1442, 1426, 1338, 1302, 1272, 1257, 1159, 1115, 1074, 1041, 1016,
997, 962, 887, 845, 771, 744, 721 cm−1; HRMS (ESI-QTOF) m/z [M
+ Na]+ Calcd for C14H9F3O4Na 321.0351, found 321.0348.
Methyl 2-Oxo-4-(thiophen-2-yl)-2H-pyran-6-carboxylate (5k).
Following the general procedure with 2l (49.1 mg, 0.25 mmol), 5k
was obtained as a yellow solid (16.5 mg, 70% yield): Rf (ethyl acetate/
hexane 1:4) = 0.25; mp 153−158 °C; 1H NMR (500 MHz, CDCl3) δ
7.59 (t, J = 3.8 Hz, 2H), 7.42 (d, J = 1.6 Hz, 1H), 7.20 (dd, J = 4.9,
3.9 Hz, 1H), 6.65 (d, J = 1.6 Hz, 1H), 3.97 (s, 3H) ppm; 13C{1H}
NMR (125 MHz, CDCl3) δ 160.4, 160.1, 148.8, 146.3, 137.7, 130.8,
129.0, 128.9, 111.5, 109.1, 53.3 ppm; IR (KBr thin film) 3423, 3110,
3092, 2964, 2924, 2851, 2366, 1717, 1638, 1556, 1440, 1427, 1395,
1336, 1279, 1260, 1211, 1184, 1169, 1111, 1058, 1018, 989, 943, 880,
865, 840, 815, 769, 727, 707 cm−1; HRMS (ESI-QTOF) m/z [M +
Na]+ Calcd for C11H8O4SNa 259.0041, found 259.0040.
Methyl 4-(Furan-2-yl)-2-oxo-2H-pyran-6-carboxylate (5l). Fol-
lowing the general procedure with 2m (45.0 mg, 0.25 mmol), 5l was
obtained as a yellow solid (13.9 mg, 63% yield): Rf (ethyl acetate/
hexane 1:4) = 0.25; mp 165−168 °C; 1H NMR (500 MHz, CDCl3) δ
7.65 (d, J = 1.6 Hz, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.02 (d, J = 3.5 Hz,
1H), 6.71 (d, J = 1.5 Hz, 1H), 6.61 (dd, J = 3.6, 1.8 Hz, 1H), 3.97 (s,
3H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 160.6, 160.1, 149.0,
148.4, 146.5, 141.4, 114.1, 113.0, 109.5, 107.4, 53.2 ppm; IR (KBr
thin film) 3425, 3129, 3087, 2923, 2852, 2364, 1716, 1650, 1588,
1536, 1472, 1456, 1426, 1375, 1338, 1281, 1238, 1178, 1157, 1112,
1078, 1052, 1030, 989, 970, 916, 883, 860, 848, 814, 770, 726 cm−1;
HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for C11H8O5Na
243.0269, found 243.0266.
Methyl (Z)-2-((4-Methylphenyl)sulfonamido)-6-oxo-4-phenyl-6-
(phenylthio)-5-((phenylthio)-carbonyl)hex-2-enoate (6a). Follow-
ing the general procedure with keto ester 2a (190 mg, 1.0 mmol),
6a was obtained as a white solid (347 mg, 55% yield). For a large scale
synthesis following the general procedure with keto ester 2a (476.0
mg, 2.5 mmol), 6a was obtained as a white solid (821.0 mg, 52%
yield): Rf (ethyl acetate/hexane 1:3) = 0.31; mp 61−65 °C; 1H NMR
(400 MHz, CDCl3) δ 7.46−7.44 (m, 2H), 7.43−7.39 (m, 3H), 7.37−
7.29 (m, 8H), 7.27−7.25 (m, 2H), 7.09 (dd, J = 7.6 Hz, 1.3 Hz, 2H),
6.95 (d, J = 8.1 Hz, 2H), 6.78 (d, J = 10.6 Hz, 1H), 6.60 (s, 1H), 5.35
(t, J = 10.8 Hz, 1H), 4.47 (d, J = 10.9 Hz, 1H), 3.54 (s, 3H), 2.27 (s,
3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 189.7, 189.6, 163.2,
143.8, 138.8, 135.6, 134.5, 134.4, 134.2, 129.9, 129.8, 129.5, 129.4,
129.3, 128.8, 128.6, 127.6, 127.4, 126.7, 126.6, 125.2, 72.9, 52.6, 44.9,
21.5 ppm; IR (KBr thin film) 3268, 3061, 3030, 2952, 1713, 1598,
1584, 1493, 1478, 1440, 1365, 1317, 1264, 1237, 1186, 1167, 1137,
1090, 1023, 977, 916, 877, 815, 769, 747, 700 cm−1; HRMS (ESI-
QTOF) m/z [M + Na]+ Calcd for C33H29NO6S3Na 654.1055, found
654.1052.
Methyl (Z)-4-(4-Fluorophenyl)-2-((4-methylphenyl)-
sulfonamido)-6-oxo-6-(phenylthio)-5-((phenylthio)carbonyl)hex-2-
enoate (6b). Following the general procedure with keto ester 2b (208
mg, 1.0 mmol), 6b was obtained as a white solid (357 mg, 55% yield).
For a large scale synthesis following the general procedure with keto
ester 2b (520.0 mg, 2.5 mmol), 6b was obtained as a white solid
(820.0 mg, 51% yield): Rf (ethyl acetate/hexane 1:3) = 0.31; mp 50−
Methyl 4-(Naphthalen-2-yl)-2-oxo-2H-pyran-6-carboxylate
(5m). Following the general procedure with 2j (60.1 mg, 0.25
mmol), 5m was obtained as a yellow solid (17.7 mg, 63% yield): Rf
1
55 °C; H NMR (400 MHz, CDCl3) δ 7.46−7.45 (m, 4H), 7.44−
7.37 (m, 6H), 7.28−7.24 (m, 2H), 7.17−7.14 (m, 2H), 7.09−7.01
(m, 4H), 6.75 (d, J = 10.6 Hz, 1H), 6.56 (s, 1H), 5.36 (t, J = 10.7 Hz,
1H), 4.43 (d, J = 10.9 Hz, 1H), 3.58 (s, 3H), 2.33 (s, 3H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ 189.6, 189.5, 163.0, 162.0 (C−
F, 1JC−F = 245 Hz), 144.0, 135.6, 134.7 (C−F, 4JC−F = 3.0 Hz), 134.3
1
(ethyl acetate/hexane 1:4) = 0.23; mp 186−190 °C; H NMR (500
MHz, CDCl3) δ 8.14 (d, J = 1.2 Hz, 1H), 7.95 (dd, J = 13.7, 5.7 Hz,
2H), 7.91−7.88 (m, 1H), 7.69 (dd, J = 8.6, 1.9 Hz, 1H), 7.63−7.56
(m, 3H), 6.84 (d, J = 1.7 Hz, 1H), 3.99 (s, 3H) ppm; 13C{1H} NMR
(125 MHz, CDCl3) δ 160.6, 160.2, 153.3, 148.9, 134.4, 133.1, 131.5,
129.5, 128.9, 128.1, 127.8, 127.3, 127.3, 123.1, 115.1, 110.2, 53.3
ppm; IR (KBr thin film) 3423, 3098, 3045, 3022, 3000, 2958, 2924,
2853, 2362, 2344, 1710, 1641, 1627, 1599, 1547, 1507, 1476, 1458,
1441, 1399, 1385, 1352, 1319, 1269, 1231, 1189, 1167, 1112, 1040,
1021, 997, 975, 958, 916, 888, 853, 818, 765, 754, 729, 714 cm−1;
HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for C17H12O4Na
303.0633, found 303.0631.
2
3
(C−F, JC−F = 30.0 Hz), 133.9, 130.2 (C−F, JC−F = 8.0 Hz), 129.9,
129.5, 129.4, 129.3, 127.4, 126.5, 126.4, 126.3, 125.3, 115.8, 115.6,
72.9, 52.7, 44.0, 21.5 ppm; 19F NMR (658 MHz, CDCl3) δ −114.2 (s,
1F) ppm; IR (KBr thin film) 3272, 3062, 2953, 2923, 1714, 1626,
1600, 1509, 1478, 1440, 1365, 1321, 1264, 1226, 1166, 1138, 1090,
1042, 1023, 965, 916, 877, 834, 814, 802, 747, 705 cm−1; HRMS
(ESI-QTOF) m/z [M + Na]+ Calcd for C33H28FNO6S3Na 672.0961,
found 672.0958.
4-Methoxybenzyl 2-Oxo-4-phenyl-2H-pyran-6-carboxylate (5n).
Following the general procedure with 2n (74.1 mg, 0.25 mmol), 5n
was obtained as a yellow solid (33.3 mg, 99% yield): Rf (ethyl acetate/
hexane 1:4) = 0.23; mp 163−166 °C; 1H NMR (500 MHz, CDCl3) δ
7.64−7.58 (m, 2H), 7.51 (d, J = 7.1 Hz, 3H), 7.44 (s, 1H), 7.39 (d, J
= 8.5 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 6.70 (s, 1H), 5.33 (s, 2H),
3.82 (s, 3H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 160.7, 160.1,
159.6, 153.6, 149.1, 134.5, 131.3, 130.7, 129.4, 126.8, 126.7, 115.0,
114.1, 110.3, 68.0, 55.3 ppm; IR (KBr thin film) 3420, 3087, 3008,
2952, 2929, 2833, 2362, 1716, 1637, 1615, 1586, 1544, 1518, 1451,
1392, 1338, 1297, 1259, 1172, 1120, 1036, 997, 958, 928, 913, 882,
866, 830, 809, 762 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd
for C20H16O5Na 359.0895, found 359.0893.
General Procedure for the Synthesis of the Michael Adduct
(6). To a solution of β,γ-unsaturated α-ketoesters 2 (1.0 mmol) and p-
toluenesulfonamide (171.0 mg, 1.0 mmol) in dichloromethane (5
mL) was added a 1 M solution of TiCl4 in dichloromethane (1 mL,
1.0 mmol) at room temperature. After stirring for 30 min, TEA (0.279
mL, 2.0 mmol) was added to the reaction mixture. After stirring for
additional 1 h at rt, the reaction mixture was concentrated in vacuo.
To the mixture was added a mixture of ethyl acetate and hexane (1:1,
15 mL). The insoluble solid was filtered off, and the filtrate was
evaporated in vacuo. The residue was redissolved with methyl tert-
Methyl (Z)-4-(4-Chlorophenyl)-2-((4-methylphenyl)-
sulfonamido)-6-oxo-6-(phenylthio)-5-((phenylthio)carbonyl)hex-2-
enoate (6c). Following the general procedure with keto ester 2c (225
mg, 1.0 mmol), 6c was obtained as a white solid (373 mg, 56% yield):
1
Rf (ethyl acetate/hexane 1:3) = 0.31; mp 42−45 °C; H NMR (400
MHz, CDCl3) δ 7.46−7.44 (m, 4H), 7.42−7.38 (m, 5H), 7.35−7.33
(m, 3H), 7.22−7.19 (m, 2H), 7.17−7.15 (m, 2H), 7.02 (d, J = 8.1 Hz,
2H), 6.72 (d, J = 10.5 Hz, 1H), 6.57 (s, 1H), 5.35 (t, J = 10.7 Hz,
1H), 4.42 (d, J = 11.0 Hz, 1H), 3.59 (s, 3H), 2.33 (s, 3H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ 189.5, 189.4, 163.0, 144.0,
137.5, 135.5, 134.5, 134.2, 133.4, 133.2, 130.0, 129.9, 129.7, 129.5,
129.4, 129.3, 128.9, 127.4, 126.5, 126.3, 125.5, 72.6, 52.7, 44.0, 21.5
ppm; IR (KBr thin film) 3270, 3062, 2952, 2923, 1713, 1625, 1597,
1491, 1478, 1440, 1409, 1364, 1323, 1263, 1236, 1167, 1139, 1090,
1051, 1015, 963, 916, 878, 815, 748, 729, 705 cm−1; HRMS (ESI-
QTOF) m/z [M + Na]+ Calcd for C33H28ClNO6S3Na 688.0665,
found 688.0663.
Methyl (Z)-4-(4-Bromophenyl)-2-((4-methylphenyl)-
sulfonamido)-6-oxo-6-(phenylthio)-5-((phenylthio)carbonyl)hex-2-
enoate (6d). Following the general procedure with keto ester 2d (269
mg, 1.0 mmol), 6d was obtained as a white solid (377 mg, 53% yield):
1
Rf (ethyl acetate/hexane 1:3) = 0.30; mp 50−55 °C; H NMR (400
MHz, CDCl3) δ 7.48−7.43 (m, 6H), 7.4−7.34 (m, 6H), 7.15−7.11
6007
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Note
(m, 4H), 6.99 (d, J = 8.0 Hz, 2H), 6.69 (d, J = 10.5 Hz, 1H), 6.56 (s,
1H), 5.31 (t, J = 10.8 Hz, 1H), 4.41 (d, J = 10.9 Hz, 1H), 3.57 (s,
3H), 2.31 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 189.5,
189.4, 162.9, 144.0, 138.0, 135.5, 134.5, 134.2, 133.1, 131.9, 130.2,
130.0, 129.7, 129.5, 129.4, 129.3, 127.4, 126.5, 126.3, 125.5, 121.5,
72.5, 52.7, 44.1, 21.5 ppm; IR (KBr thin film) 3265, 3061, 2952, 2924,
1714, 1625, 1597, 1479, 1440, 1405, 1365, 1307, 1264, 1237, 1167,
1137, 1090, 1071, 1051, 1024, 1010, 963, 917, 879, 816, 747, 706
129.8, 129.7, 129.6, 129.5, 129.4, 129.3, 129.2, 128.4, 127.4, 126.7,
126.6, 124.9, 72.9, 52.6, 44.5, 21.5, 21.2 ppm; IR (KBr thin film)
3272, 3060, 3026, 2952, 2923, 1717, 1625, 1597, 1582, 1512, 1477,
1440, 1367, 1317, 1239, 1167, 1138, 1090, 1042, 1022, 963, 917, 875,
815, 748, 706 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for
C34H31NO6S3Na 668.1211, found 668.1210.
Methyl (Z)-4-(4-Methoxyphenyl)-2-((4-methylphenyl)-
sulfonamido)-6-oxo-6-(phenylthio)-5-((phenylthio)carbonyl)hex-2-
enoate (6i). Following the general procedure with keto ester 2i (220
mg, 1.0 mmol), 6i was obtained as a yellow solid (338 mg, 51%
yield): Rf (ethyl acetate/hexane 1:3) = 0.29; mp 43−47 °C; 1H NMR
(400 MHz, CDCl3) δ 7.45−7.31 (m, 10H), 7.18−7.12 (m, 4H), 6.97
(d, J = 8.0 Hz, 2H), 6.88−6.85 (m, 2H), 6.74 (d, J = 10.7 Hz, 1H),
6.49 (s, 1H), 5.30 (t, J = 10.8 Hz, 1H), 4.41 (d, J = 10.9 Hz, 1H), 3.82
(s, 3H), 3.55 (s, 3H), 2.29 (s, 3H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ 189.8, 189.7, 163.3, 158.9, 143.8, 135.6, 134.8, 134.5, 134.2,
130.8, 129.8, 129.8, 129.6, 129.4, 129.3, 129.2, 127.4, 126.7, 126.6,
124.8, 114.2, 73.1, 55.3, 52.6, 44.1, 21.5 ppm; IR (KBr thin film)
3269, 3060, 3000, 2953, 2838, 1715, 1608, 1583, 1511, 1478, 1440,
1364, 1305, 1252, 1167, 1137, 1090, 1033, 977, 918, 877, 829, 814,
791, 748, 706 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for
C34H31NO7S3Na 684.1160, found 684.1158.
cm−1
; HRMS (ESI-QTOF) m/z [M +
Na]+ Calcd for
C33H28BrNO6S3Na 732.0160, found 732.0157.
Methyl (Z)-4-(2-Bromophenyl)-2-((4-methylphenyl)-
sulfonamido)-6-oxo-6-(phenylthio)-5-((phenylthio)carbonyl)hex-2-
enoate (6e). Following the general procedure with keto ester 2e (269
mg, 1.0 mmol), 6e was obtained as a white solid (355 mg, 50% yield):
1
Rf (ethyl acetate/hexane 1:3) = 0.30; mp 59-63 °C; H NMR (400
MHz, CDCl3) δ 7.58 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H),
7.44−7.39 (m, 3H), 7.38−7.32 (m, 5H), 7.21−7.13 (m, 5H), 7.03−
6.99 (m, 3H), 6.70 (s, 1H), 5.58 (t, J = 9.2 Hz, 1H), 4.70 (m, 1H),
3.59 (s, 3H), 2.30 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ
189.9, 189.5, 163.4, 143.8, 138.6, 135.6, 134.4, 134.3, 134.1, 133.6,
129.9, 129.8, 129.7, 129.5, 129.3, 129.2, 129.1, 129.0, 128.9, 127.7,
127.6, 126.8, 126.5, 125.9, 69.1, 52.9, 21.5 ppm; IR (KBr thin film)
3270, 3061, 2952, 2924, 1714, 1598, 1494, 1471, 1440, 1367, 1317,
1277, 1236, 1186, 1166, 1090, 1023, 981, 870, 814, 747, 706 cm−1;
HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for C33H28BrNO6S3Na
732.0160, found 732.0157.
Methyl (Z)-2-((4-Methylphenyl)sulfonamido)-4-(naphthalen-2-
yl)-6-oxo-6-(phenylthio)-5-((phenylthio)carbonyl)hex-2-enoate
(6j). Following the general procedure with keto ester 2j (240 mg, 1.0
mmol), 6j was obtained as an ivory solid (484 mg, 71% yield): Rf
1
(ethyl acetate/hexane 1:3) = 0.25; mp 51−54 °C; H NMR (400
Methyl (Z)-4-(3-Bromophenyl)-2-((4-methylphenyl)-
sulfonamido)-6-oxo-6-(phenylthio)-5-((phenylthio)carbonyl)hex-2-
enoate (6f). Following the general procedure with keto ester 2f (269
mg, 1.0 mmol), 6f was obtained as a white solid (362 mg, 51% yield):
MHz, CDCl3) δ 7.89−7.83 (m, 3H), 7.70 (s, 1H), 7.55−7.53 (m,
2H), 7.51−7.40 (m, 6H), 7.36−7.32 (m, 2H), 7.28−7.25 (m, 4H),
6.99 (m, 2H), 6.89 (d, J = 10.6 Hz, 1H), 6.79 (d, J = 8.1 Hz, 2H),
5.55 (t, J = 10.8 Hz, 1H), 4.60 (d, J = 10.9 Hz, 1H), 3.62 (s, 3H), 2.21
(s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 189.7, 189.7,
163.2, 143.8, 136.4, 135.4, 134.5, 134.2, 133.8, 133.5, 132.7, 129.9,
129.8, 129.4, 129.3, 129.2, 128.6, 127.9, 127.7, 127.6, 127.4, 126.6,
126.5, 126.4, 126.2, 126.1, 125.3, 72.7, 52.7, 44.9, 21.4 ppm; IR (KBr
thin film) 3180, 3055, 2973, 2953, 2745, 1704, 1677, 1646, 1598,
1577, 1507, 1478, 1440, 1386, 1362, 1327, 1267, 1240, 1201, 1174,
1146, 1107, 1091, 1044, 1024, 981, 960, 921, 893, 880, 862, 815, 778,
750, 703 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for
C37H31NO6S3Na 704.1211, found 704.1209.
1
Rf (ethyl acetate/hexane 1:3) = 0.30; mp 65−73 °C; H NMR (400
MHz, CDCl3) δ 7.46−7.38 (m, 8H), 7.36−7.34 (m, 4H), 7.25−7.21
(m, 2H), 7.16−7.14 (m, 2H), 7.02 (d, J = 8.2 Hz, 2H), 6.68 (d, J =
10.5 Hz, 1H), 6.59 (s, 1H), 5.29 (t, J = 10.7 Hz, 1H), 4.39 (d, J = 10.9
Hz, 1H), 3.58 (s, 3H), 2.31 (s, 3H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ 189.6, 189.3, 163.0, 144.0, 141.3, 135.5, 134.5, 134.3, 132.4,
131.7, 130.7, 130.3, 130.0, 129.9, 129.5, 129.4, 129.3, 127.4, 127.0,
126.5, 126.3, 125.7, 122.7, 72.5, 52.8, 44.4, 21.5 ppm; IR (KBr thin
film) 3267, 3060, 2952, 1710, 1595, 1569, 1476, 1440, 1365, 1305,
1260, 1236, 1186, 1167, 1138, 1090, 1071, 1043, 1023, 977, 888, 814,
787, 748, 705 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for
C33H28BrNO6S3Na 732.0160, found 732.0158.
General Procedure for the Synthesis of 2-Pyridones (7). To
a 10 mL round-bottom flask were added Michael adduct 6 (0.1
mmol), Hg(OAc)2 (80.0 mg, 0.25 mmol), NEM (12.7 μL, 0.1 mmol),
H2O (9.0 μL, 0.5 mmol), and propionitrile (1 mL) at rt. The resulting
mixture was refluxed for 3 h using a heating mantle. After cooling to
room temperature, the reaction mixture was diluted with dichloro-
methane, washed with a 1 M aqueous solution of HCl (5 mL), and
concentrated in vacuo. The residue was purified by column
chromatography (ethyl acetate/hexane 1:4) to provide the desired
products 7.
Methyl (Z)-2-((4-Methylphenyl)sulfonamido)-6-oxo-6-(phenyl-
thio)-5-((phenylthio)carbonyl)-4-(4-(trifluoromethyl)phenyl)hex-2-
enoate (6g). Following the general procedure with keto ester 2g (258
mg, 1.0 mmol), 6g was obtained as a yellow solid (364 mg, 52%
yield): Rf (ethyl acetate/hexane 1:3) = 0.31; mp 59−65 °C; 1H NMR
(400 MHz, CDCl3) δ 7.62−7.59 (m, 3H), 7.47−7.42 (m, 5H), 7.40−
7.34 (m, 6H), 7.10−7.07 (m, 2H), 6.97 (d, J = 8.0 Hz, 2H), 6.73 (d, J
= 10.4 Hz, 1H), 6.57 (s, 1H), 5.40 (t, J = 10.7 Hz, 1H), 4.45 (d, J =
10.8 Hz, 1H), 3.58 (s, 3H), 2.29 (s, 3H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ 189.4, 189.3, 162.8, 144.1, 143.1, 135.5, 134.6, 134.5,
Methyl 6-Oxo-4-phenyl-1-tosyl-1,6-dihydropyridine-2-carboxy-
late (7a). Following the general procedure with the Michael addition
product 6a (63.0 mg, 0.1 mmol), 7a was obtained as a white solid
(36.4 mg, 95% yield). Analytical data are consistent with the reported
2
134.1, 132.4, 130.0, 129.8 (C−3F, JC−F = 32.0 Hz), 129.5, 129.4,
1
129.3, 129.1, 129.0, 127.4 (C−3F, JC−F = 252.0 Hz), 127.3, 126.4,
data:11a Rf (ethyl acetate/hexane 1:4) = 0.32; mp 150−153 °C; H
1
125.9, 125.6 (C−3F, 4JC−F = 4.0 Hz), 72.5, 52.8, 44.3, 21.5 ppm; 19F
NMR (658 MHz, CDCl3) δ −62.6 (s, 3F) ppm; IR (KBr thin film)
3265, 3062, 2954, 2927, 1715, 1618, 1597, 1583, 1493, 1478, 1440,
1365, 1325, 1240, 1167, 1124, 1067, 1018, 978, 917, 837, 814, 781,
747, 705 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for
C34H28F3NO6S3Na 722.0929, found 722.0926.
NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.2 Hz, 2H), 7.54−7.53 (m,
2H), 7.47−7.45 (m, 3H), 7.37−7.35 (m, 2H), 6.78 (d, J = 1.6 Hz,
1H), 6.66 (d, J = 1.6 Hz, 1H), 4.00 (s, 3H), 2.45 (s, 3H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ 163.4, 161.0, 151.0, 146.2,
137.3, 135.3, 134.3, 130.6, 130.2, 129.4, 129.3, 126.7, 121.1, 110.7,
53.5, 21.8 ppm; IR (KBr thin film) 3454, 3070, 3023, 2955, 2923,
2851, 1965, 1920, 1737, 1682, 1619, 1595, 1548, 1503, 1448, 1399,
1374, 1339, 1322, 1292, 1268, 1247, 1224, 1176, 1084, 1059, 1027,
1000, 985, 934, 878, 865, 847, 811, 762, 748, 737, 701 cm−1; MS
(ESI-QTOF) m/z [M + H]+ 384.10.
Methyl (Z)-2-((4-Methylphenyl)sulfonamido)-6-oxo-6-(phenyl-
thio)-5-((phenylthio)carbonyl)-4-(p-tolyl)hex-2-enoate (6h). Fol-
lowing the general procedure with keto ester 2h (204 mg, 1.0
mmol), 6h was obtained as a white solid (297 mg, 46% yield): Rf
1
(ethyl acetate/hexane 1:3) = 0.32; mp 56−60 °C; H NMR (400
MHz, CDCl3) δ 7.47−7.40 (m, 6H), 7.37−7.31 (m, 6H), 7.14−7.11
(m, 4H), 6.96 (d, J = 8.2 Hz, 2H), 6.76 (d, J = 10.7 Hz, 1H), 6.52 (s,
1H), 5.32 (t, J = 10.8 Hz, 1H), 4.44 (d, J = 10.9 Hz, 1H), 3.56 (s,
3H), 2.36 (s, 3H), 2.29 (s, 3H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ 189.7, 163.3, 143.8, 137.3, 135.7, 135.6, 134.6, 134.5, 134.2,
Methyl 4-(4-Fluorophenyl)-6-oxo-1-tosyl-1,6-dihydropyridine-2-
carboxylate (7b). Following the general procedure with the Michael
addition product 6b (65.0 mg, 0.1 mmol), 7b was obtained as a white
solid (38.5 mg, 96% yield). For a large scale synthesis following the
general procedure with the Michael addition product 6b (650.0 mg,
6008
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Note
1.0 mmol), 7b was obtained as a white solid (360.0 mg, 90% yield): Rf
1187, 1179, 1159, 1121, 1108, 1084, 1059, 1030, 1015, 995, 981, 941,
911, 897, 862, 844, 811, 801, 784, 774, 754, 727, 702 cm−1; HRMS
(ESI-QTOF) m/z [M + Na]+ Calcd for C20H16BrNO5SNa 483.9830,
found 483.9830.
1
(ethyl acetate/hexane 1:4) = 0.32; mp 175−179 °C; H NMR (500
MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 2H), 7.55−7.52 (m, 2H), 7.37
(d, J = 8.1 Hz, 2H), 7.18−7.13 (m, 1H), 6.73 (d, J = 1.9 Hz, 1H),
6.61 (d, J = 1.9 Hz, 1H), 4.01 (s, 3H), 2.45 (s, 3H) ppm; 13C{1H}
Methyl 6-Oxo-1-tosyl-4-(4-(trifluoromethyl)phenyl)-1,6-dihydro-
pyridine-2-carboxylate (7g). Following the general procedure with
the Michael addition product 6g (70.0 mg, 0.1 mmol), 7g was
obtained as a yellow solid (36.0 mg, 80% yield): Rf (ethyl acetate/
hexane 1:4) = 0.31; mp 118−122 °C; 1H NMR (700 MHz, CDCl3) δ
8.14 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz,
2H), 7.38 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 2.1 Hz, 1H), 6.68 (d, J =
2.1 Hz, 1H), 4.02 (s, 3H), 2.46 (s, 3H) ppm; 13C{1H} NMR (175
MHz, CDCl3) δ 163.2, 160.7, 149.7, 146.4, 138.9, 137.8, 134.0, 132.4
1
NMR (125 MHz, CDCl3) δ 164.2 (C−F, JC−F = 251.2 Hz), 163.4,
160.9, 149.9, 146.3, 137.4, 134.2, 131.4 (C−F, 4JC−F = 3.7 Hz), 130.2,
3
2
129.4, 128.8 (C−F, JC−F = 8.7 Hz), 120.8, 116.5(C−F, JC−F = 22.5
Hz), 110.4, 53.6, 21.8 ppm; 19F NMR (658 MHz, CDCl3) δ −108.1
(s, 1F) ppm; IR (KBr thin film) 3432, 3098, 3073, 3019, 2958, 2923,
1719, 1643, 1604, 1548, 1514, 1439, 1422, 1389, 1336, 1294, 1264,
1238, 1180, 1106, 1038, 998, 963, 897, 881, 848, 833, 808, 769, 727
cm−1
; HRMS (ESI-QTOF) m/z [M +
Na]+ Calcd for
2
4
(C−3F, JC−F = 33.2 Hz), 130.3, 129.5, 127.2, 126.3 (C−3F, JC−F
=
C20H16FNO5SNa 424.0631, found 424.0630.
1
3.5 Hz), 123.6 (C−3F, JC−F = 271.2 Hz), 122.3, 110.0, 53.7, 21.9
ppm; 19F NMR (658 MHz, CDCl3) δ −63.0 (s, 3F) ppm; IR (KBr
thin film) 3074, 2955, 2925, 2854, 2593, 1924, 1741, 1682, 1616,
1597, 1546, 1493, 1436, 1420, 1373, 1325, 1294, 1267, 1175, 1127,
1085, 1071, 1057, 1027, 1017, 925, 913, 839, 814, 787, 760, 747, 728,
701 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for
C21H16F3NO5SNa 474.0599, found 474.0595.
Methyl 4-(4-Chlorophenyl)-6-oxo-1-tosyl-1,6-dihydropyridine-2-
carboxylate (7c). Following the general procedure with the Michael
addition product 6c (67.0 mg, 0.1 mmol), 7c was obtained as a yellow
solid (39.3 mg, 94% yield): Rf (ethyl acetate/hexane 1:4) = 0.32; mp
1
166−170 °C; H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz,
2H), 7.49−7.46 (m, 2H), 7.45−7.42 (m, 2H), 7.36 (d, J = 8.2 Hz,
2H), 6.72 (d, J = 1.9 Hz, 1H), 6.63 (d, J = 1.9 Hz, 1H), 4.01 (s, 3H),
2.45 (s, 3H). ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 163.3, 160.9,
149.8, 146.3, 137.6, 137.0, 134.2, 133.7, 130.2, 129.6, 129.4, 128.0,
121.1, 110.1, 53.6, 21.8 ppm; IR (KBr thin film) 3172, 3075, 2966,
2922, 2862, 2376, 1741, 1648, 1597, 1435, 1402, 1366, 1281, 1259,
1137, 1095, 1014, 979, 924, 824, 773, 711 cm−1; HRMS (ESI-QTOF)
m/z [M + Na]+ Calcd for C20H16ClNO5SNa 440.0335, found
440.0332.
Methyl 6-Oxo-4-(p-tolyl)-1-tosyl-1,6-dihydropyridine-2-carboxy-
late (7h). Following the general procedure with the Michael addition
product 6h (65.0 mg, 0.1 mmol), 7h was obtained as a white solid
(33.0 mg, 83% yield): Rf (ethyl acetate/hexane 1:4) = 0.32; mp 143−
148 °C; 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 2H), 7.44
(d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H),
6.78 (d, J = 1.9 Hz, 1H), 6.63 (d, J = 1.8 Hz, 1H), 4.00 (s, 3H), 2.45
(s, 3H), 2.40 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ
163.5, 161.1, 150.8, 146.1, 141.2, 137.1, 134.4, 132.3, 130.1, 130.0,
129.4, 126.6, 120.3, 110.7, 53.5, 21.8, 21.4 ppm; IR (KBr thin film)
3032, 2955, 2924, 2853, 2592, 2359, 1919, 1740, 1681, 1612, 1597,
1573, 1542, 1514, 1492, 1435, 1371, 1337, 1308, 1288, 1254, 1214,
1191, 1175, 1121, 1084, 1058, 1026, 983, 925, 913, 868, 816, 759,
744, 701 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for
C21H19NO5SNa 420.0882, found 420.0880.
Methyl 4-(4-Bromophenyl)-6-oxo-1-tosyl-1,6-dihydropyridine-2-
carboxylate (7d). Following the general procedure with the Michael
addition product 6d (71.0 mg, 0.1 mmol), 7d was obtained as a
yellow solid (44.0 mg, 95% yield): Rf (ethyl acetate/hexane 1:4) =
1
0.31; mp 135−138 °C; H NMR (500 MHz, CDCl3) δ 8.12 (d, J =
8.4 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 7.37
(d, J = 8.1 Hz, 2H), 6.71 (d, J = 1.9 Hz, 1H), 6.63 (d, J = 1.9 Hz, 1H),
4.01 (s, 3H), 2.45 (s, 3H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ
163.3, 160.9, 149.9, 146.3, 137.6, 134.2, 134.2, 132.5, 130.2, 129.4,
128.2, 125.3, 121.1, 110.1, 53.6, 21.8 ppm; IR (KBr thin film) 3177,
3064, 2956, 2927, 2866, 1728, 1647, 1549, 1523, 1496, 1442, 1418,
1396, 1367, 1337, 1261, 1173, 1149, 1078, 1009, 994, 940, 862, 822,
769, 711 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for
C20H16BrNO5SNa 483.9830, found 483.9830.
Methyl 4-(4-Methoxyphenyl)-6-oxo-1-tosyl-1,6-dihydropyridine-
2-carboxylate (7i). Following the general procedure with the Michael
addition product 6i (66.0 mg, 0.1 mmol), 7i was obtained as a yellow
solid (35.1 mg, 85% yield): Rf (ethyl acetate/hexane 1:4) = 0.30; mp
1
144−147 °C; H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz,
2H), 7.51 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 6.96 (d, J =
8.8 Hz, 2H), 6.78 (d, J = 1.9 Hz, 1H), 6.60 (d, J = 1.9 Hz, 1H), 4.00
(s, 3H), 3.85 (s, 3H), 2.44 (s, 3H). ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ 163.5, 161.8, 161.2, 150.3, 146.1, 137.1, 134.5, 130.1, 129.4,
128.3, 127.2, 119.3, 114.7, 110.6, 55.5, 53.5, 21.8 ppm; IR (KBr thin
film) 3268, 3095, 2967, 2919, 2849, 2740, 2376, 1742, 1637, 1509,
1440, 1243, 1184, 1028, 835, 770, 710 cm−1; HRMS (ESI-QTOF) m/
z [M + Na]+ Calcd for C21H19NO6SNa 436.0831, found 436.0828.
Methyl 4-(Naphthalen-2-yl)-6-oxo-1-tosyl-1,6-dihydropyridine-
2-carboxylate (7j). Following the general procedure with the Michael
addition product 6j (68.0 mg, 0.1 mmol), 7j was obtained as a yellow
solid (32.0 mg, 74% yield): Rf (ethyl acetate/hexane 1:4) = 0.29; mp
Methyl 4-(2-Bromophenyl)-6-oxo-1-tosyl-1,6-dihydropyridine-2-
carboxylate (7e). Following the general procedure with the Michael
addition product 6e (71.0 mg, 0.1 mmol), 7e was obtained as a white
solid (41.6 mg, 90% yield): Rf (ethyl acetate/hexane 1:4) = 0.31; mp
1
102−106 °C; H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.4 Hz,
2H), 7.65 (d, J = 7.8 Hz, 1H), 7.39−7.37 (m, 3H), 7.30−7.28 (m,
1H), 7.25−7.22 (m, 1H), 6.59 (d, J = 1.6 Hz, 1H), 6.49 (d, J = 1.6
Hz, 1H), 3.99 (s, 3H), 2.46 (s, 3H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ 163.2, 160.7, 151.9, 146.3, 137.4, 136.3, 133.6, 130.9, 130.2,
129.9, 129.6, 129.4, 127.9, 125.0, 121.1, 112.8, 53.5, 21.8 ppm; IR
(KBr thin film) 3648, 3460, 3359, 3296, 3071, 2953, 2925, 2855,
2734, 2678, 2592, 2544, 2412, 1925,1746, 1683, 1617, 1595, 1563,
1541, 1493, 1469, 1435, 1374, 1336, 1269, 1175, 1122, 1084, 1027,
982, 912, 854, 814, 754, 730, 701 cm−1; HRMS (ESI-QTOF) m/z [M
+ Na]+ Calcd for C20H16BrNO5SNa 483.9830, found 483.9829.
Methyl 4-(3-Bromophenyl)-6-oxo-1-tosyl-1,6-dihydropyridine-2-
carboxylate (7f). Following the general procedure with the Michael
addition product 6f (71.0 mg, 0.1 mmol), 7f was obtained as an ivory
solid (42.5 mg, 92% yield): Rf (ethyl acetate/hexane 1:4) = 0.32; mp
1
150−153 °C; H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.4 Hz,
2H), 8.04 (s, 1H), 7.91−7.85 (m, 3H), 7.61−7.54 (m, 3H), 7.37 (d, J
= 8.2 Hz, 2H), 6.94 (d, J = 1.8 Hz, 1H), 6.77 (d, J = 1.5 Hz, 1H), 4.04
(s, 3H), 2.45 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ
163.5, 161.0, 150.8, 146.2, 137.3, 134.4, 134.1, 133.1, 132.3, 130.2,
129.8, 129.4, 129.3, 129.0, 128.7, 127.8, 127.7, 127.1, 127.0, 123.4,
121.2, 110.7, 53.6, 21.8 ppm; IR (KBr thin film) 3477, 3096, 3057,
2957, 2919, 2490, 1747, 1621, 1529, 1479, 1443,1366, 1331, 1276,
1232, 1200, 1154, 1118, 1030, 1005, 928, 894, 864, 817, 773, 739,
710 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for
C24H19NO5SNa 456.0882, found 456.0879.
1
146−152 °C; H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz,
2H), 7.66 (d, J = 1.6 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.45 (d, J =
7.8 Hz, 1H), 7.38−7.31 (m, 3H), 6.70 (d, J = 1.8 Hz, 1H), 6.62 (d, J
= 1.8 Hz, 1H), 4.01 (s, 3H), 2.45 (s, 3H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ 163.3, 160.7, 149.6, 146.3, 137.6, 137.4, 134.1, 133.5,
130.8, 130.2, 129.8, 129.4, 125.3, 123.4, 121.7, 110.1, 53.6, 21.8 ppm;
IR (KBr thin film) 3444, 3271, 3090, 3058, 3009, 2959, 2919, 2860,
2592, 1955, 1922, 1887, 1732, 1670, 1617, 1594, 1562, 1542, 1487,
1445, 1420, 1400, 1373, 1339, 1317, 1306, 1274, 1253, 1227, 1200,
General Procedure for the Synthesis of 2-Pyridones (8). To
a solution of the Michael adduct 6 (0.1 mmol) in THF and H2O (1
mL, THF/H2O 20:1) was added Hg(OAc)2 (32.0 mg, 0.1 mmol).
The resulting mixture was stirred for 20 min at rt; then, DBU (105.0
μL, 0.7 mmol) was added, and the mixture was stirred for additional 6
h at 40 °C using a heating mantle. The reaction was quenched with a
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J. Org. Chem. 2021, 86, 6001−6014

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Note
1 M aqueous solution of HCl, extracted with ethyl acetate, dried with
Na2SO4, and concentrated in vacuo. The residue was purified by
column chromatography (dichlorometane/MeOH 20:1) to provide
the desired products 8.
NMR (100 MHz, CDCl3) δ 162.7, 161.4, 152.9, 138.7, 133.5, 132.8,
130.5, 130.1, 127.8, 126.2, 121.3, 112.0, 53.4 ppm; IR (KBr thin film)
3455, 3399, 3269, 3011, 2887, 2851, 2783, 2670, 1963, 1928, 1839,
1739, 1660, 1651, 1614, 1539, 1267, 1233, 1192, 1159, 1133, 1076,
1018, 982, 934, 906, 878, 863, 817, 754, 726, 717 cm−1; HRMS (ESI-
QTOF) m/z [M + Na]+ Calcd for C13H10BrNO3Na 329.9742, found
329.9739.
Methyl 6-Oxo-4-phenyl-1,6-dihydropyridine-2-carboxylate (8a).
Following the general procedure with the Michael addition product
6a (63.0 mg, 0.1 mmol), 8a was obtained as a white solid (22.0 mg,
96% yield). Analytical data are consistent with reported data.11d For a
large scale synthesis following the general procedure with the Michael
addition product 6a (632.0 mg, 1.0 mmol), 8a was obtained as a
white solid (204.0 mg, 89% yield): Rf (dichloromethane/MeOH
20:1) = 0.51; mp 192−197 °C; 1H NMR (400 MHz, CDCl3) δ 10.04
(br, 1H), 7.61−7.59 (m, 2H), 7.50−7.46 (m, 3H), 7.28−7.26 (m,
1H), 7.00 (d, J = 1.7 Hz, 1H), 3.99 (s, 3H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ 162.6, 161.4, 152.3, 136.7, 133.4, 130.0, 129.2, 126.8,
122.7, 109.5, 53.5 ppm; IR (KBr thin film) 3437, 3386, 3265, 1981,
1958, 1905, 1871, 1735, 1647, 1613, 1501, 1468, 1437, 1405, 1329,
1291, 1198, 1162, 1139, 1099, 1077, 1054, 1015, 1001, 971, 937, 903,
875, 860, 848, 778, 760, 737, 720 cm−1; MS (ESI-QTOF) m/z [M +
H]+ 230.09.
Methyl 4-(3-Bromophenyl)-6-oxo-1,6-dihydropyridine-2-carbox-
ylate (8f). Following the general procedure with the Michael addition
product 6f (71.0 mg, 0.1 mmol), 8f was obtained as a brown solid
(28.3 mg, 92% yield): Rf (dichloromethane/MeOH 20:1) = 0.50; mp
1
180−186 °C; H NMR (400 MHz, CDCl3) δ 10.05 (br, 1H), 7.74−
7.73 (m, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.36
(t, J = 7.8 Hz, 1H), 7.21 (d, J = 1.6 Hz, 1H), 6.96 (d, J = 1.6 Hz, 1H),
4.01 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 162.4, 161.3,
150.8, 138.8, 133.7, 132.9, 130.7, 129.9, 125.5, 123.3, 123.2, 109.0,
53.5 ppm; IR (KBr thin film) 3450, 3275, 3062, 3018, 2928, 1928,
1810, 1735, 1655, 1619, 1564, 1484, 1439, 1428, 1388, 1335, 1312,
1281, 1253, 1188, 1133, 1086, 1075, 1060, 1022, 994, 977, 942, 901,
877, 859, 780, 765, 737 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+
Calcd for C13H10BrNO3Na 329.9742, found 329.9740.
Methyl 4-(4-Fluorophenyl)-6-oxo-1,6-dihydropyridine-2-carbox-
ylate (8b). Following the general procedure with the Michael addition
product 6b (65.0 mg, 0.1 mmol), 8b was obtained as a brown solid
(23.5 mg, 95% yield): Rf (dichloromethane/MeOH 20:1) = 0.51; mp
197−202 °C; 1H NMR (400 MHz, CDCl3) δ 10.17 (br, 1H), 7.60−
7.57 (m, 2H), 7.26 (s, 1H), 7.23−7.15 (m, 2H), 6.95 (d, J = 1.5 Hz,
1H), 3.99 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ163.9
Methyl 6-Oxo-4-(4-(trifluoromethyl)phenyl)-1,6-dihydropyridine-
2-carboxylate (8g). Following the general procedure with the
Michael addition product 6g (70.0 mg, 0.1 mmol), 8g was obtained
as a brown solid (23.5 mg, 79% yield): Rf (dichloromethane/MeOH
20:1) = 0.50; mp 180−185 °C; 1H NMR (700 MHz, CDCl3) δ 10.02
(br, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.24 (d, J
= 1.7 Hz, 1H), 7.01 (d, J = 1.7 Hz, 1H), 4.01 (s, 3H) ppm; 13C{1H}
NMR (175 MHz, CDCl3) δ 162.4, 161.2, 150.9, 140.2, 133.9, 131.9
(C−3F, 2JC−F = 31.5 Hz), 127.3, 126.2 (C−3F, 4JC−F = 3.5 Hz), 123.8
1
(C−F, JC−F = 251.0 Hz), 162.6, 161.4, 151.2, 133.6, 132.8 (C−F,
3
4JC−F = 3.0 Hz), 128.8 (C−F, JC−F = 8.0 Hz), 122.5, 116.4 (C−F,
2JC−F = 21.0 Hz), 109.2, 53.5 ppm; 19F NMR (658 MHz, CDCl3) δ
1
(C−3F, JC−F = 271.2 Hz), 123.7, 109.0, 53.6 ppm; 19F NMR (658
−110.7 (s, 1F) ppm; IR (KBr thin film) 3438, 3390, 3268, 3131,
3099, 3033, 2922, 2785, 2669, 2522, 1942, 1920, 1898, 1869, 1726,
1652, 1613, 1542, 1515, 1442, 1429, 1396, 1338, 1289, 1249, 1221,
1192, 1160, 1131, 1104, 1055, 1018, 969, 934, 892, 877, 869, 857,
836, 806, 772, 744, 726 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+
Calcd for C13H10FNO3Na 270.0542, found 270.0544.
MHz, CDCl3) δ −62.8 (s, 3F) ppm; IR (KBr thin film) 3448, 3275,
3139, 3030, 2952, 2906, 2791, 1925, 1795, 1733, 1655, 1618, 1473,
1439, 1396, 1325, 1304, 1280, 1169, 1110, 1072, 1015, 979, 957, 938,
921, 879, 836, 781, 768, 745 cm−1; HRMS (ESI-QTOF) m/z [M +
Na]+ Calcd for C14H10F3NO3Na 320.0511, found 320.0507.
Methyl 6-Oxo-4-(p-tolyl)-1,6-dihydropyridine-2-carboxylate
(8h). Following the general procedure with the Michael addition
product 6h (65.0 mg, 0.1 mmol), 8h was obtained as a white solid
(21.0 mg, 86% yield): Rf (dichloromethane/MeOH 20:1) = 0.52; mp
179−183 °C; 1H NMR (400 MHz, CDCl3) δ 9.51 (br, 1H), 7.50 (d, J
= 8.2 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 1.7 Hz, 1H), 6.97
(d, J = 1.6 Hz, 1H), 3.99 (s, 3H), 2.41 (s, 3H) ppm; 13C{1H} NMR
(100 MHz, CDCl3) δ 162.4, 161.4, 152.2, 140.4, 133.7, 133.1, 129.9,
126.7, 122.2, 109.4, 53.4, 21.3 ppm; IR (KBr thin film) 3452, 3262,
3048, 2946, 2851, 2783, 1993, 1914, 1872, 1735, 1652, 1614, 1515,
1437, 1393, 1331, 1287, 1266, 1245, 1213, 1191, 1159, 1128, 1058,
1023, 976, 937, 916, 870, 860, 818, 793, 767, 740, 717 cm−1; HRMS
(ESI-QTOF) m/z [M + Na]+ Calcd for C14H13NO3Na 266.0793,
found 266.0792.
Methyl 4-(4-Chlorophenyl)-6-oxo-1,6-dihydropyridine-2-carbox-
ylate (8c). Following the general procedure with the Michael addition
product 6c (67.0 mg, 0.1 mmol), 8c was obtained as an ivory solid
(25.0 mg, 95% yield): Rf (dichloromethane/MeOH 20:1) = 0.51; mp
1
188−195 °C; H NMR (400 MHz, CDCl3) δ 9.76 (br, 1H), 7.55−
7.45 (m, 4H), 7.22 (d, J = 1.7 Hz, 1H), 6.95 (d, J = 1.7 Hz, 1H), 4.00
(s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 162.2, 161.3,
151.1, 136.4, 135.1, 133.5, 129.5, 128.1, 122.8, 109.0, 53.5 ppm; IR
(KBr thin film) 3456, 3394, 3261, 3050, 2923, 2856, 2789, 2090,
1911, 1736, 1660, 1497, 1437, 1423, 1388, 1329, 1284, 1240, 1191,
1129, 1111, 1091, 1059, 1014, 974, 936, 916, 849, 831, 818, 765, 732,
715 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for
C13H10ClNO3Na 286.0247, found 286.0246.
Methyl 4-(4-Bromophenyl)-6-oxo-1,6-dihydropyridine-2-carbox-
ylate (8d). Following the general procedure with the Michael addition
product 6d (71.0 mg, 0.1 mmol), 8d was obtained as an ivory solid
(28.3 mg, 92% yield): Rf (dichloromethane/MeOH 20:1) = 0.51; mp
196−203 °C; 1H NMR (400 MHz, CDCl3) δ 10.45 (br, 1H), 7.61 (d,
J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 1.5 Hz, 1H),
6.97 (d, J = 1.5 Hz, 1H), 3.99 (s, 3H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ 162.8, 161.3, 151.1, 135.6, 133.9, 132.4, 128.4, 124.6,
122.7, 109.0, 53.5 ppm; IR (KBr thin film) 3455, 3384, 3257, 3098,
3049, 2930, 2088, 1993, 1910, 1825, 1737, 1652, 1614, 1529, 1496,
1437, 1421, 1384, 1328, 1284, 1241, 1192, 1130, 1075, 1059, 1021,
1009, 973, 935, 914, 861, 829, 766, 732, 715 cm−1; HRMS (ESI-
QTOF) m/z [M + Na]+ Calcd for C13H10BrNO3Na 329.9742, found
329.9740.
Methyl 4-(4-Methoxyphenyl)-6-oxo-1,6-dihydropyridine-2-car-
boxylate (8i). Following the general procedure with the Michael
addition product 6i (66.0 mg, 0.1 mmol), 8i was obtained as an ivory
solid (24.4 mg, 94% yield): Rf (dichloromethane/MeOH 20:1) =
1
0.49; mp 206−212 °C; H NMR (400 MHz, CDCl3) δ 10.25 (br,
1H), 7.57 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 2.8 Hz, 1H), 7.01−6.96
(m, 3H), 4.00 (s, 3H), 3.87 (s, 3H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ 163.0, 161.5, 161.2, 151.6, 133.4, 128.8, 128.2, 121.2, 114.6,
109.3, 55.5, 53.4 ppm; IR (KBr thin film) 3452, 3389, 3266, 3135,
3095, 2036, 1926, 1897, 1836, 1739, 1644, 1608, 1519, 1442, 1396,
1343, 1241, 1180, 1145, 1118, 1058, 1019, 976, 907, 873, 832, 814,
796, 773, 733, 721 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd
for C14H13NO4Na 282.0742, found 282.0740.
Methyl 4-(Naphthalen-2-yl)-6-oxo-1,6-dihydropyridine-2-car-
boxylate (8j). Following the general procedure with the Michael
addition product 6j (68.0 mg, 0.1 mmol), 8j was obtained as a brown
solid (23.2 mg, 83% yield): Rf (dichloromethane/MeOH 20/:1) =
0.49; mp 187−193 °C; 1H NMR (400 MHz, CDCl3) δ 9.87 (br, 1H),
8.09 (s, 1H), 7.97−7.88 (m, 3H), 7.71−7.68 (m, 1H), 7.58−7.55 (m,
2H), 7.41 (d, J = 1.6 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H), 4.03 (s, 3H)
Methyl 4-(2-Bromophenyl)-6-oxo-1,6-dihydropyridine-2-carbox-
ylate (8e). Following the general procedure with the Michael addition
product 6e (71.0 mg, 0.1 mmol), 8e was obtained as a yellow solid
(27.4 mg, 89% yield): Rf (dichloromethane/MeOH 20:1) = 0.50; mp
121−124 °C; 1H NMR (400 MHz, CDCl3) δ 10.64 (br, 1H), 7.68 (d,
J = 7.8 Hz, 1H), 7.41−7.38 (m, 1H), 7.30−7.27 (m, 2H), 7.10 (d, J =
1.1 Hz, 1H), 6.81 (d, J = 1.0 Hz, 1H), 3.97 (s, 3H) ppm; 13C{1H}
6010
https://doi.org/10.1021/acs.joc.1c00323
J. Org. Chem. 2021, 86, 6001−6014

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 162.5, 161.5, 152.2, 133.9,
133.8, 133.4, 133.2, 129.2, 128.6, 127.8, 127.4, 127.0, 126.7, 123.9,
123.0, 109.5, 53.5 ppm; IR (KBr thin film) 3409, 3290, 3133, 3052,
2959, 2925, 2853, 2802, 1735, 1648, 1616, 1531, 1506, 1440, 1403,
1348, 1327, 1280, 1219, 1195, 1128, 1084, 1052, 1020, 975, 955, 933,
890, 857, 822, 807, 794, 772, 765, 750, 733, 712 cm−1; HRMS (ESI-
QTOF) m/z [M + Na]+ Calcd for C17H13NO3Na 302.0793, found
302.0791.
General Procedure for the Synthesis of Pyridines (14). To a
solution of pyridinone 8 (0.1 mmol) in DMF (1 mL) were added
TsCl (38.5 mg, 0.2 mmol) and K2CO3 (41.5 mg, 0.3 mmol). The
resulting mixture was stirred at rt for 24 h, them ethyl acetate and a
10% NH4Cl aqueous solution were added. The organic layer was
separated, dried with Na2SO4, and concentrated in vacuo. The residue
was purified by column chromatography (ethyl acetate/hexane 1:4) to
provide the desired products 14.
3455, 3114, 3084, 3056, 2951, 2924, 2851, 2184, 2115, 2082, 2018,
1921, 1902, 1820, 1802, 1739, 1604, 1577, 1549, 1523, 1493, 1453,
1414, 1382, 1342, 1307, 1293, 1255, 1199, 1177, 1152, 1122, 1109,
1089, 1073, 1038, 1012, 970, 950, 932, 911, 884, 861, 843, 833, 823,
805, 786, 761, 721, 702 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+
Calcd for C20H16BrNO5SNa 483.9830, found 483.9828.
Methyl 4-(4-Methoxyphenyl)-6-(tosyloxy)picolinate (14e). Fol-
lowing the general procedure with pyridinone 8e (26.0 mg, 0.1
mmol), 14e was obtained as a white solid (40.0 mg, 97% yield): Rf
1
(ethyl acetate/hexane 1:4) = 0.29; mp 133−136 °C; H NMR (400
MHz, CDCl3) δ 8.22 (d, J = 1.4 Hz, 1H), 8.07 (d, J = 8.3 Hz, 2H),
7.63−7.61 (m, 2H), 7.46 (d, J = 1.4 Hz, 1H), 7.37 (d, J = 8.1 Hz,
2H), 7.03−7.01 (m, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 2.47 (s, 3H)
ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 164.8, 161.4, 157.6, 153.6,
146.7, 145.5, 133.6, 129.5, 129.4, 128.5, 128.2, 121.2, 115.3, 114.8,
55.5, 52.9, 21.8 ppm; IR (KBr thin film) 3438, 3191, 3037, 3006,
2979, 2942, 2845, 2594, 2550, 2512, 2110, 2053, 1950, 1885, 1732,
1601, 1542, 1520, 1495, 1437, 1427, 1402, 1372, 1337, 1295, 1262,
1197, 1170, 1144, 1121, 1092, 1073, 1030, 1018, 997, 941, 912, 892,
856, 827, 809, 785, 774, 745, 730, 705 cm−1; HRMS (ESI-QTOF) m/
z [M + Na]+ Calcd for C21H19NO6SNa 436.0831, found 436.0830.
Methyl 4-(Naphthalen-2-yl)-6-(tosyloxy)picolinate (14f). Follow-
ing the general procedure with pyridinone 8f (28.0 mg, 0.1 mmol),
14f was obtained as a white solid (42.0 mg, 97% yield): Rf (ethyl
Methyl 4-Phenyl-6-(tosyloxy)picolinate (14a). Following the
general procedure with pyridinone 8a (23.0 mg, 0.1 mmol), 14a
was obtained as a white solid (37.6 mg, 98% yield). Analytical data are
consistent with reported data:11c Rf (ethyl acetate/hexane 1:4) = 0.31;
mp 133−139 °C; 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 8.09−
8.06 (m, 2H), 7.66−7.63 (m, 2H), 7.54−7.38 (m, 4H), 7.37 (d, J =
8.0 Hz, 2H), 3.98 (s, 3H), 2.46 (s, 3H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ 164.6, 157.6, 154.1, 146.8, 145.5, 136.1, 133.5, 130.2,
129.6, 129.5, 129.4, 127.2, 121.9, 116.2, 52.9, 21.8 ppm; IR (KBr thin
film) 3426, 3095, 3079, 3058, 2999, 2922, 2852, 2593, 2524, 1965,
1947, 1884, 1829, 1796, 1725, 1680, 1608, 1553, 1504, 1454, 1439,
1408, 1376, 1357, 1336, 1313, 1293, 1253, 1196, 1176, 1147, 1090,
1072, 1040, 1032, 1018, 999, 943, 917, 900, 878, 862, 827, 802, 789,
761, 718, 703 cm−1; MS (ESI-QTOF) m/z [M + H]+ 384.10.
Methyl 4-(4-Fluorophenyl)-6-(tosyloxy)picolinate (14b). Follow-
ing the general procedure with pyridinone 8b (25.0 mg, 0.1 mmol),
14b was obtained as a white solid (39.3 mg, 98% yield): Rf (ethyl
1
acetate/hexane 1:4) = 0.28; mp 164−168 °C; H NMR (400 MHz,
CDCl3) δ 8.40 (d, J = 1.3 Hz, 1H), 8.16 (s, 1H), 8.10 (d, J = 8.3 Hz,
2H), 7.99−7.89 (m, 3H), 7.75 (dd, J = 8.5 Hz, 1.8 Hz, 1H), 7.64 (d, J
= 1.3 Hz, 1H), 7.60−7.56 (m, 2H), 7.39 (d, J = 8.2 Hz, 2H), 4.00 (s,
3H), 2.48 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 164.7,
157.7, 154.1, 146.9, 145.5, 133.9, 133.6, 133.3, 133.2, 129.6, 129.5,
129.4, 128.7, 127.8, 127.5, 127.1, 127.0, 124.0, 122.0, 116.4, 53.0, 21.8
ppm; IR (KBr thin film) 3422, 3087, 3048, 3001, 2950, 2931, 2536,
1961, 1908, 1793, 1719, 1608, 1599, 1579, 1555, 1506, 1494, 1449,
1410, 1370, 1352, 1335, 1306, 1263, 1235, 1196, 1173, 1141, 1119,
1091, 1068, 1048, 1008, 997, 966, 939, 916, 891, 875, 862, 824, 808,
781, 765, 755, 732, 721, 700 cm−1; HRMS (ESI-QTOF) m/z [M +
Na]+ Calcd for C24H19NO5SNa 456.0882, found 456.0880.
1
acetate/hexane 1:4) = 0.31; mp 127−131 °C; H NMR (400 MHz,
CDCl3) δ 8.21 (d, J = 1.3 Hz, 1H), 8.07 (d, J = 8.3 Hz, 2H), 7.66−
7.63 (m, 2H), 7.47 (d, J = 1.3 Hz, 1H), 7.37 (d, J = 8.1 Hz, 2H),
7.23−7.19 (m, 2H), 3.98 (s, 3H), 2.47 (s, 3H) ppm; 13C{1H} NMR
1
(100 MHz, CDCl3) δ 165.3 (C−F, JC−F = 250.0 Hz), 164.5, 157.6,
General Procedure for the Synthesis of Pyridines (15). To a
10 mL round-bottom flask were added pyridinone 8 (0.1 mmol) and
POCl3 (1 mL, neat). The resulting mixture was stirred for 16 h at 50−
60 °C using a heating mantle. The reaction was diluted with ethyl
acetate, quenched with a 10% Na2CO3 aqueous solution, and
extracted with ethyl acetate. After removing the solvent of the
combined organic layers in vacuo, the residue was purified by column
chromatography (ethyl acetate/hexane 1:4) to provide the desired
products 15.
Methyl 6-Chloro-4-phenylpicolinate (15a). Following the general
procedure with pyridinone 8a (23.0 mg, 0.1 mmol), 15a was obtained
as a white solid (24.0 mg, 97% yield): Rf (ethyl acetate/hexane 1:4) =
0.39; mp 72−78 °C; 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 1.4
Hz, 1H), 7.73 (d, J = 1.4 Hz, 1H), 7.69−7.65 (m, 2H), 7.55−7.50 (m,
3H), 4.03 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 164.7,
152.6, 152.3, 148.5, 135.9, 130.2, 129.4, 127.1, 125.3, 122.0, 53.2
ppm; IR (KBr thin film) 3416, 3187, 3080, 3008, 2953, 2922, 2851,
2484, 2312, 2130, 1968, 1948, 1888, 1715, 1675, 1646, 1595, 1539,
1499, 1451, 1425, 1400, 1318, 1265, 1190, 1160, 1129, 1068, 1031,
1001, 988, 971, 922, 889, 871, 821, 788, 760, 749, 715 cm−1; HRMS
(ESI-QTOF) m/z [M + Na]+ Calcd for C13H10ClNO2Na 270.0298,
found 270.0295.
153.0, 146.9, 145.6, 133.5, 132.2 (C−F, 4JC−F = 4.0 Hz), 129.5 (C−F,
2
3JC−F = 9.0 Hz), 129.1, 129.0, 121.6, 116.6 (C−F, JC−F = 22.0 Hz),
116.0, 53.0, 21.8 ppm; 19F NMR (658 MHz, CDCl3) δ −110.3 (s, 1F)
ppm; IR (KBr thin film) 3426, 3122, 3095, 3078, 3059, 3006, 2957,
2920, 2855, 2591, 2121, 1984, 1938, 1894, 1822, 1800, 1724, 1609,
1554, 1517, 1495, 1454, 1439, 1423, 1396, 1375, 1356, 1311, 1256,
1178, 1147, 1102, 1090, 1074, 1040, 997, 943, 901, 882, 864, 835,
823, 801, 787, 763, 744, 720, 702 cm−1; HRMS (ESI-QTOF) m/z [M
+ Na]+ Calcd for C20H16FNO5SNa 424.0631, found 424.0629.
Methyl 4-(4-Chlorophenyl)-6-(tosyloxy)picolinate (14c). Follow-
ing the general procedure with pyridinone 8c (26.0 mg, 0.1 mmol),
14c was obtained as a white solid (41.0 mg, 98% yield): Rf (ethyl
1
acetate/hexane 1:4) = 0.31; mp 158−162 °C; H NMR (400 MHz,
CDCl3) δ 8.21 (d, J = 1.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 2H), 7.61−
7.57 (m, 2H), 7.51−7.47 (m, 3H), 7.38 (d, J = 8.0 Hz, 2H), 3.98 (s,
3H), 2.47 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 164.5,
157.6, 152.8, 147.0, 145.6, 136.7, 134.5, 133.5, 129.7, 129.6, 129.5,
128.4, 121.6, 116.0, 53.0, 21.8 ppm; IR (KBr thin film) 3431, 3097,
3075, 3007, 2957, 2924, 1925, 1911, 1803, 1727, 1654, 1608, 1578,
1550, 1499, 1453, 1440, 1418, 1394, 1368, 1337, 1308, 1262, 1197,
1173, 1150, 1123, 1109, 1090, 1072, 1038, 1014, 994, 940, 903, 882,
862, 827, 817, 800, 787, 765, 720, 702 cm−1; HRMS (ESI-QTOF) m/
z [M + Na]+ Calcd for C20H16ClNO5SNa 440.0335, found 440.0333.
Methyl 4-(4-Bromophenyl)-6-(tosyloxy)picolinate (14d). Follow-
ing the general procedure with pyridinone 8d (31.0 mg, 0.1 mmol),
14d was obtained as a white solid (44.8 mg, 97% yield): Rf (ethyl
Methyl 6-Chloro-4-(4-fluorophenyl)picolinate (15b). Following
the general procedure with pyridinone 8b (25.0 mg, 0.1 mmol), 15b
was obtained as a white solid (22.3 mg, 84% yield): Rf (ethyl acetate/
hexane 1:4) = 0.39; mp 107−110 °C; 1H NMR (400 MHz, CDCl3) δ
8.25 (d, J = 1.5 Hz, 1H), 7.68−7.64 (m, 3H), 7.24−7.19 (m, 2H),
4.03 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ164.7, 164.1
1
acetate/hexane 1:4) = 0.30; mp 171−174 °C; H NMR (400 MHz,
1
4
(C−F, JC−F = 250.0 Hz), 152.3, 151.5, 148.6, 132.1 (C−F, JC−F
=
CDCl3) δ 8.21 (d, J = 1.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 2H), 7.67−
7.64 (m, 2H), 7.54−7.48 (m, 2H), 7.47 (s, 1H), 7.38 (d, J = 8.0 Hz,
2H), 3.98 (s, 3H), 2.47 (s, 3H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ 164.5, 157.7, 152.9, 147.1, 145.6, 135.0, 133.5, 132.7, 129.6,
129.5, 128.7, 124.9, 121.5, 116.0, 53.0, 21.8 ppm; IR (KBr thin film)
3
3.0 Hz), 129.1 (C−F, JC−F = 8.0 Hz), 125.1, 121.8, 116.7 (C−F,
2JC−F = 22.0 Hz), 53.3 ppm; 19F NMR (658 MHz, CDCl3) δ −110.3
(s, 1F) ppm; IR (KBr thin film) 3421, 3184, 3166, 3081, 3016, 2963,
2924, 2853, 2485, 2451, 1930, 1899, 1749, 1720, 1597, 1537, 1512,
6011
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J. Org. Chem. 2021, 86, 6001−6014

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pubs.acs.org/joc
Note
1444, 1418, 1392, 1319, 1265, 1231, 1193, 1164, 1127, 1105, 1069,
1010, 988, 973, 942, 887, 870, 833, 805, 785, 746, 722, 708 cm−1;
HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for C13H9ClFNO2Na
288.0204, found 288.0202.
AUTHOR INFORMATION
Corresponding Authors
■
Do Hyun Ryu − Department of Chemistry, Sungkyunkwan
University, Suwon 16419, Korea; orcid.org/0000-0001-
7615-4661; Email: dhryu@skku.edu
Hui Jin − Liaoning Province Key Laboratory of Green
Functional Molecular Design and Development, Institute of
Functional Molecules, Shenyang University of Chemical
Technology, Shenyang 110142, China; orcid.org/0000-
0002-7154-5628; Email: hjin@syuct.edu.cn
Methyl 6-Chloro-4-(4-chlorophenyl)picolinate (15c). Following
the general procedure with pyridinone 8c (26.0 mg, 0.1 mmol), 15c
was obtained as a white solid (24.3 mg, 86% yield): Rf (ethyl acetate/
hexane 1:4) = 0.38; mp 114−118 °C; 1H NMR (400 MHz, CDCl3) δ
8.25 (d, J = 1.4 Hz, 1H), 7.69 (d, J = 1.4 Hz, 1H), 7.61 (d, J = 8.6 Hz,
2H), 7.50 (d, J = 8.2 Hz, 2H), 4.03 (s, 3H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ 164.6, 152.4, 151.3, 148.7, 136.7, 134.3, 129.7, 128.4,
125.1, 121.7, 53.3 ppm; IR (KBr thin film) 3414, 3187, 3077, 3047,
3004, 2954, 2925, 2851, 2489, 2314, 2242, 2125, 1942, 1901, 1784,
1718, 1647, 1596, 1536, 1497, 1442, 1414, 1390, 1317, 1259, 1192,
1171, 1132, 1095, 1067, 1013, 989, 977, 915, 901, 892, 872, 824, 785,
756, 732 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for
C13H9Cl2NO2Na 303.9908, found 303.9905.
Authors
Daeil Bae − Department of Chemistry, Sungkyunkwan
University, Suwon 16419, Korea
Juyeol Lee − Department of Chemistry, Sungkyunkwan
University, Suwon 16419, Korea
Methyl 4-(4-Bromophenyl)-6-chloropicolinate (15d). Following
the general procedure with pyridinone 8d (31.0 mg, 0.1 mmol), 15d
was obtained as a white solid (27.8 mg, 85% yield): Rf (ethyl acetate/
hexane 1:4) = 0.38; mp 111−116 °C; 1H NMR (400 MHz, CDCl3) δ
8.25 (J = 1.4 Hz, 1H), 7.69−7.64 (m, 3H), 7.55−7.53 (m, 2H), 4.03
(s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 164.6, 152.4,
151.4, 148.7, 134.8, 132.7, 128.6, 125.0, 124.9, 121.7, 53.3 ppm; IR
(KBr thin film) 3415, 3182, 3076, 3044, 3002, 2952, 2924, 2850,
2722, 2583, 2489, 2241, 2129, 1939, 1903, 1716, 1595, 1575, 1536,
1494, 1468, 1448, 1426, 1412, 1386, 1317, 1258, 1192, 1170, 1132,
1096, 1077, 1068, 1009, 988, 975, 916, 899, 892, 872, 819, 785, 754,
730 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd for
C13H9BrClNO2Na 347.9403, found 347.9401.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00323
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by National Research Foundation of
Korea (NRF) grants funded by the Korean government
(MSIT) (nos. NRF-2019R1 A4A200144 0 and
2019R1A2C2087018) and by the 111 Project (D18012).
Methyl 6-Chloro-4-(4-methoxyphenyl)picolinate (15e). Follow-
ing the general procedure with pyridinone 8e (26.0 mg, 0.1 mmol),
15e was obtained as a white solid (25.8 mg, 93% yield): Rf (ethyl
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1
acetate/hexane 1:4) = 0.37; mp 95−99 °C; H NMR (400 MHz,
CDCl3) δ 8.25 (d, J = 1.5 Hz, 1H), 7.67 (d, J = 1.5 Hz, 1H), 7.65−
7.62 (m, 2H), 7.02 (d, J = 8.8 Hz, 2H), 4.02 (s, 3H), 3.87 (s, 3H)
ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 164.9, 161.5, 152.2, 152.0,
148.4, 128.4, 128.0, 124.4, 121.4, 114.9, 55.5, 53.2 ppm; IR (KBr thin
film) 3418, 3131, 3081, 3052, 3000, 2954, 2927, 2837, 2366, 2321,
2066, 2026, 1889, 1720, 1611, 1594, 1536, 1519, 1449, 1427, 1399,
1322, 1294, 1267, 1187, 1169, 1130, 1068, 1041, 1021, 989, 975, 963,
915, 888, 873, 822, 785, 775, 742, 710 cm−1; HRMS (ESI-QTOF) m/
z [M + Na]+ Calcd for C14H12ClNO3Na 300.0403, found 300.0401.
Methyl 6-Chloro-4-(naphthalen-2-yl)picolinate (15f). Following
the general procedure with pyridinone 8f (28.0 mg, 0.1 mmol), 15f
was obtained as a white solid (27.4 mg, 92% yield): Rf (ethyl acetate/
hexane 1:4) = 0.35; mp 126−131 °C; 1H NMR (400 MHz, CDCl3) δ
8.43 (d, J = 1.5 Hz, 1H), 8.17 (d, J = 1.4 Hz, 1H), 7.99 (d, J = 8.6 Hz,
1H), 7.96−7.93 (m, 1H), 7.91−7.89 (m, 1H), 7.85 (d, J = 1.5 Hz,
1H), 7.76 (dd, J = 8.5 Hz, 1.8 Hz, 1H), 7.60−7.56 (m, 2H), 4.05 (s,
3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 164.8, 152.5, 152.3,
148.6, 133.9, 133.3, 133.1, 129.4, 128.7, 127.8, 127.6, 127.2, 127.1,
125.4, 124.0, 122.2, 53.3 ppm; IR (KBr thin film) 3419, 3076, 3058,
3007, 2956, 2925, 2854, 2644, 2492, 2363, 1960, 1930, 1717, 1631,
1592, 1538, 1507, 1447, 1404, 1386, 1372, 1343, 1314, 1302, 1264,
1232, 1192, 1161, 1122, 1062, 1022, 978, 948, 898, 886, 854, 819,
785, 772, 742, 734 cm−1; HRMS (ESI-QTOF) m/z [M + Na]+ Calcd
for C17H12ClNO2Na 320.0454, found 320.0453.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00323.
Optimization details for the synthesis of 6 and 8; control
experiment details; and copies of 1H, 13C, and 19F NMR
spectra for all products (PDF)
6012
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pubs.acs.org/joc
Note
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