Approach to polysubstituted 4-pyridones from N-Aryl acetoacetamides via a N to C 1,3-acyl migration mediated by sodium persulfate

Article abstract of DOI:10.1021/jo3010217

Mediated by sodium persulfate (Na₂S₂O₈), a series of polysubstituted 4-pyridones were synthesized via self-condensation of N-aryl acetoacetamides, during which a novel N to C 1,3-acyl migration should be involved. The stru

Full text of DOI:10.1021/jo3010217

Note
pubs.acs.org/joc
Approach to Polysubstituted 4‑Pyridones from N‑Aryl
Acetoacetamides via a N to C 1,3-Acyl Migration Mediated by
Sodium Persulfate
Zhiguo Zhang,* Shiliang Fang, Qingfeng Liu, and Guisheng Zhang*
College of Chemistry and Environmental Science, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education,
Henan Normal University, Xinxiang 453007, China
S
* Supporting Information
ABSTRACT: Mediated by sodium persulfate (Na2S2O8), a series of
polysubstituted 4-pyridones were synthesized via self-condensation of N-aryl
acetoacetamides, during which a novel N to C 1,3-acyl migration should be
involved. The structure of 4-pyridone was unequivocally confirmed by X-ray
diffraction analysis. However, the self-condensation of N-benzyl acetoaceta-
mides under the same condition gave polysubstituted 2-pyridones instead of 4-
pyridones.
4-Pyridone derivatives are identified as antibacterial activities,1
antitumor activities,2 antiviral activities,3 antiinflammatory
activities,4 and other bioactivities.5 They are also important
intermediates in the organic synthesis6 and the key structure of
some natural products (Figure 1).4,5b,7 A lot of reports can be
found in the literature concerning the synthesis of N-alkyl- and
N-aryl-2-/4-pyridones.8 For example, the two well-known
methods for preparing 4-pyridones involve the reaction of a
pyrone with a primary amine9 and the hetero Diels−Alder
reaction.10 In this paper, we disclose a direct and simpler
approach to pyridone derivatives via dimerization of industrial
acetoacetamides mediated by sodium persulfate.
evaluation as an alternative approach to 4-pyridones without
using Brønsted acid as catalyst.
To optimize the reaction condition, we used N-(2-
chlorophenyl)-3-oxobutanamide 1a as a model for the
dimerization. The screening of reaction conditions (Table 1)
showed that the 4-pyridone 2a can be obtained in 65% yield
alone with some unidentified complex mixture by treating 1a
(1.0 mmol) with Na2S2O8 (0.5 mmol) in dichloroethane (DCE,
6.0 mL) at reflux for 10 h (entry 3). It would result in a
dramatically lower yield of 2a when the reaction was performed
at lower temperature at 75 °C (entry 4). The experiments also
showed that the equivalent of sulfur was required, while
increasing or decreasing the amount of Na2S2O8 cannot
improve the yield of dimerization (entries 1, 2, 5, 6). It
exhibited uncoordinated yield effects in different halogenous
solvents of 1,1,2,2-tetrachloroethane (1,1,2,2-TeCE) and 1,2-
dibromoethane (1,2-DBE) (entries 7, 8). Other solvents such
as DMF, THF, CH2Cl2, CH3CN, EtOH, DMSO, and toluene
were proved to be fundamentally ineffective, and the material
1a in most of the reactions was recovered (entries 9−15). The
dichloroethane dependent reaction was therefore tested by
other catalysts in dichloroethane. The facts proved that K2S2O8
and (NH4)2S2O8 were less effect for this condensation and only
gave the desired product 2a in yields of 18 and 43%,
respectively, along with 75% 1a was recovered in the case of
K2S2O8 (entries 16, 17 vs 3). Other oxidants like tert-butyl
hydroperoxide (TBHP) and m-chloroperbenzoic acid (m-
CPBA) were also fundamentally ineffective (entries 18, 19).
The optimal condition was finally identified as Na2S2O8 (0.5
equiv) in DCE at reflux (Table 1, entry 3). Consequently, we
Acetoacetamides or their derivatives are really very
convenient and versatile building blocks in the synthesis of
heterocyclic compounds.4,11−17 Combining with our recent
research for the direct synthesis of heterocyclic compounds
from acyclic acetoacetamide derivatives precursors,18 we made
efforts to realize an intramolecular cyclization of 1a to 3
catalyzed by transition metals (Scheme 1), but the results
disappointed. Compound 3 was not observed after many
attempts by using Pd, Fe, and Cu salts. During these attempts,
it was observed that an unexpected product, which was
1
subsequently characterized as a 4-pyridone derivate 2a by H
NMR, 13C NMR, HRMS and the X-ray diffraction (XRD)
analysis, was formed in low yield by treatment of 1a with
sodium persulfate in the presence of FeCl3 (Scheme 1). Further
investigations revealed that FeCl3 was unnecessary for the
reaction and the yield was a little higher in the absence of
FeCl3. To the best of our knowledge, only one direct approach
to polysubstituted 4-pyridones from N-aryl acetoacetamides
was reported,4 which was catalyzed by p-toluenesulfonic acid
via the self-condensation of N-aryl acetoacetamides in moderate
yields. Therefore, the unexpected finding is worthy of further
Received: May 22, 2012
Published: July 31, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Note
Figure 1. Representative 4-pyridones possessing bioactivities.
tested the generality of this dimerization of N-aryl acetoaceta-
mides under the optimal condition (Table 2). Notably, a variety
of substituted N-aryl acetoacetamides 1a−1m could easily be
Scheme 1. Reactions of Acetoacetamide 1a in the Presence
of Transition Metals
a
Table 2. Self-condensation of N-Aryl Acetoacetamides 1
a
Table 1. Survey of Reaction Conditions
b
entry
cat. (equiv)
solvent
DCE
time (h)
yield (%)
c
1
Na2S2O8 (0.1)
Na2S2O8 (0.2)
Na2S2O8 (0.5)
Na2S2O8 (0.5)
Na2S2O8 (1.0)
Na2S2O8 (2.0)
Na2S2O8 (0.5)
Na2S2O8 (0.5)
Na2S2O8 (0.5)
Na2S2O8 (0.5)
Na2S2O8 (0.5)
Na2S2O8 (0.5)
Na2S2O8 (0.5)
Na2S2O8 (0.5)
Na2S2O8 (0.5)
K2S2O8 (0.5)
24
24
10
24
6
46
d
2
DCE
50
3
DCE
65
e
4
DCE
16
5
DCE
62
45
6
DCE
5
f
7
1,1,2,2-TeCE
1,2-DBE
DMF
24
23
30
32
40
13
48
36
48
12
24
12
24
42
f
8
30
g
9
0
10
11
12
13
14
15
16
17
18
19
THF
0
h
CH2Cl2
CH3CN
EtOH
DMSO
Toluene
DCE
0
0
i
0
j
0
k
0
l
18
(NH4)2S2O8 (0.5)
TBHP (1.0)
DCE
43
0
DCE
m
m-CPBA (1.0)
DCE
0
a
Unless otherwise indicated, all reactions were carried out with 1a (1.0
b
c
mmol) and solvent 6.0 mL at reflux. Isolated yield. 48% 1a was
recovered. 30% 1a was recovered. 75 °C was used and 71% 1a was
recovered. 100 °C was used. 120 °C was used and 85% 1a was
recovered. 95% 1a was recovered. 85% 1a was recovered. 120 °C
was used and 70% 1a was recovered. 80% 1a was recovered. 75% 1a
was recovered. 90% 1a was recovered.
d
e
f
g
h
i
j
k
l
m
a
All reactions were carried out with 1 (1.0 mmol), Na2S2O8 (0.5
b
equiv), in Cl(CH2)2Cl (6.0 mL) at reflux. Isolated yield.
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The Journal of Organic Chemistry
Note
converted into the corresponding 4-pyridones 2a−2m in
moderate yields (52−66%) in 7−12 h. Various electron-
withdrawing groups (EWG) (Cl, CO2Et; entries 1−4) and
electron-donating groups (EDG) (Me, OMe, OEt; entries 6−
12) on the aryl ring were tolerated in current transformation,
including without substituents on benzene ring (entry 5) and
with both EWG and EDG substituents on benzene ring (Table
2, entry 13). Furthermore, the positions of the substituents on
the aryl group (para-, meta- and ortho- positions) did not show
any effects on the reaction.
radical pathway for the sole Na2S2O8 to promote the direct self-
condensation of acetoacetamides. As it is well-known that
sodium persulfate is a strong oxidant capable of both electron
transfer and free radical oxidation processes. Under thermally
enhanced conditions (i.e., 30−100 °C) or UV irradiation
conditions, there is considerable evidence19 indicating that
peroxodisulfate S2O82− can be converted into sulfate free radical
·−
SO4 with one unpaired electron, which is a powerful oxidant.
·−
The production of the highly reactive SO4 by the thermal
decomposition (as known “thermal activation”) of the
2−
The scope of the new method was further examined in the
context of N-nonaromatic acetoacetamides (Table 3). It is
persulfate anion in an aqueous phase is: S2O8 + heat →
2SO4·−. To gain insight into the details of the novel Na2S2O8-
catalyzed direct dimerization, radical scavenger, 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO), was employed in the
reaction. Authentically, the reactions were shut off, which could
indicate that this transformation involved radical process.
So far, the mechanism for the present self-condensation of
acetoacetamides catalyzed by Na2S2O8 has not been completely
clear. The plausible mechanism was deduced according to the
above control experiments together with some previous
literature results (Scheme 2). Acetoacetamides 1 initially react
Table 3. Self-condensation of N-Nonaromatic
a
Acetoacetamides 1
Scheme 2. Plausible Mechanism
a
All reactions were carried out with 1 (1.0 mmol), Na2S2O8 (0.5
b
c
equiv), in Cl(CH2)2Cl (6.0 mL) at reflux. Isolated yield. Very
complex mixture.
with Na2S2O8 to generate nitrogen radicals A via a single
electron transfer (SET) process.20 Next, A attacks the enol
form of acetoacetamides 1 to form intermediate B.20b Then, B
affords β-enaminone species C via back electron-transfer (BET)
process and intramolecular dehydration reaction,21 which is the
reason why 0.5 equiv of Na2S2O8 is needed in the dimerization.
Subsequently, a 1,3-acyl migration from N to C of intermediate
C,22 when R2 is aryl, gives imine D and its equilibrium D′,
which undergoes intramolecular nucleophilic cyclization to give
the final product 4-pyridones 2.4,11c,23 On the other hand, for
intermediate C, when R2 is alkyl, a direct ring-closing reaction
takes place to produce 2-pyridone derivatives 4.4 N-Aliphatic-
substituted intermediate C cannot form a stable aryl imine
steady-state D, compared with N-aryl substituents, which
should account for the emergence of terminal 2-pyridone
derivatives 4.
In summary, we have developed a convenient one-pot
process for the synthesis of a variety of biologically potent
polysubstituted 4-pyridones via self-condensation of industrial-
ized N-aryl acetoacetamides in the presence of sole Na2S2O8,
during which, a novel N to C 1,3-acyl migration should be
involved. All products were constructed efficiently in a single
step from the readily available acyclic precursors. As a
representative of a series of 4-pyridones, 2a was characterized
by the XRD analysis for the first time. Also, the simple
noteworthy that N-benzyl substituted acetoacetamides 1n−1p,
under the same conditions, gave eccentric series of 2-pyridones
4n−4p instead of 4-pyridones in moderate yields of 57−60%
(Table 3). Similarly, the EDG (Table 3, entry 3) and EWG
(Table 3, entry 2) on benzyl ring did not show effect on the
reaction. The structures of these compounds 4n−4p were
deduced from a comparison of their NMR spectra with those of
4-pyridones. The chemical shifts of N-H protons of the
carboxanilide groups of 2-pyridones 4 were almost in normal
positions (8.0−10.0 ppm), which were totally different from the
4-pyridones 2 series whose chemical shifts of N-H protons of
the carboxanilide group absorbs unusually far downfield (>12.0
ppm) due to the intramolecular hydrogen bonding interaction
between the N−H moiety and the carbonyl oxygen at 4-
position of the pyridone ring.4 But other N-non aromatic
substituted acetoacetamides, such as N-(tert-butyl)-3-oxobuta-
namide 1q and primary amine 3-oxobutanamide 1r, failed to
convert to either the corresponding 4q and 4r or 2q and 2r for
the subsequent substrate expansion.
Any intermediate, as direct evidence for the mechanism of
the self-condensation, was not isolated in the control
experiments of quenching the reaction in 2.0 h (Table 1,
entry 3) or performing the reaction at a slightly lower
temperature (Table 1, entry 4). We deduced that it may be a
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The Journal of Organic Chemistry
Note
386.0584. IR (KBr, neat): v 3679, 3056, 2340, 1676, 1591, 1457,
1250, 1106, 876 cm−1.
operation with satisfactory yields, metal catalyst-free, a relative
broad range of substrates, and readily availability of catalyst
(Na2S2O8) and substrates make this a valuable addition to
existing methods.
2,6-Dimethyl-4-oxo-N,1-diphenyl-1,4-dihydropyridine-3-carbox-
4
1
amide (2e). Colorless crystal (100 mg, 63%); mp: 209−212 °C; H
NMR (400 MHz, CDCl3) δ 12.74 (s, 1H), 7.70 (d, J = 7.6 Hz, 2H),
7.53 (m, 3H), 7.31 (t, J = 8.0 Hz, 2H), 7.21 (dd, J = 2.0, 5.6 Hz, 2H),
7.19 (t, J = 7.2 Hz, 1H), 6.48 (s, 1H), 2.50 (s, 3H), 1.89 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 177.8, 164.2, 156.2, 148.5, 139.5, 139.0,
130.4, 129.9, 128.7, 127.7, 123.5, 120.6, 118.8, 21.7, 20.7. HRMS (ESI)
m/z calcd for C20H18N2O2: 318.1368, found 318.1363. IR (KBr, neat):
v 3603, 3054, 2842, 1680, 1485, 1277, 1191, 1003, 895 cm−1.
N,1-Bis(4-methoxyphenyl)-2,6-dimethyl-4-oxo-1,4-dihydropyri-
dine-3-carboxamide (2f). Colorless crystal (198 mg, 52%); mp: 211−
214 °C; 1H NMR (400 MHz, CDCl3) δ 12.57 (s, 1H), 7.61 (d, J = 8.8
Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 6.87 (d, J
= 8.8 Hz, 2H), 6.49 (s, 1H), 3.89 (s, 3H), 3.80 (s, 3H), 2.53 (s, 3H),
1.94 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 177.9, 163.9, 160.2,
156.6, 155.8, 148.9, 132.3, 132.2, 128.7, 122.2, 118.8, 118.7, 115. 4,
113.9, 55.6, 55.4, 21.7, 20.7. HRMS (ESI) m/z calcd for C22H22N2O4:
378.1580, found 378.1574. IR (KBr, neat): v 3621, 2931, 1726, 1600,
1439, 1341, 1181, 1030, 836 cm−1.
EXPERIMENTAL SECTION
■
General Information. All reagents were obtained from
commercial sources and used without further purification, unless
otherwise noted. All reactions were monitored by TLC with GF254
silica gel coated plates. Flash column chromatography was carried out
1
by using 200−300 mesh silica gel at increased pressure. H NMR and
13C NMR spectra were recorded on a 400 MHz spectrometer in
solutions of CDCl3 using tetramethylsilane as the internal standard, δ
values are given in ppm and coupling constants (J) in Hz. The high-
resolution mass spectra were measured on a MicroTOF mass
spectrometer. Melting points were measured on a melting point
apparatus equipped with a thermometer and were uncorrected. IR
spectra were recorded on a FT-IR spectrophotometer as KBr pellets.
Typical Experimental Procedure for the Self-condensation of
Acetoacetamides. A mixture of N-(2-chlorophenyl)-3-oxobutanamide
1a (211 mg, 1.0 mmol) and Na2S2O8 (119 mg, 0.5 mmol) in DCE
(6.0 mL) in a round-bottom flask (25 mL) equipped with a spherical
condenser (40 cm length) was well stirred for 10 h at reflux. After
cooling off, the mixture was washed with saturated sodium chloride
solution (6.0 mL × 3). The organic solvent DCE was then removed
under reduced pressure and the residue was purified through a short
flash silica gel column chromatography to give compound 2a (125 mg,
65%) (Eluent: diethyl ether/petroleum ether = 2/1).
N,1-Bis(4-ethoxyphenyl)-2,6-dimethyl-4-oxo-1,4-dihydropyridine-
3-carboxamide (2g). Colorless crystal (106 mg 52%); mp: 223−225
°C; 1H NMR (400 MHz, CDCl3) δ 12.59 (s, 1H,), 7.61 (d, J = 9.2 Hz,
2H), 7.08 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 9.2 Hz, 2H), 6.86 (d, J = 8.8
Hz, 2H), 6.48 (s, 1H), 4.08 (q, J = 6.8 Hz, 2H), 4.01 (q, J = 6.8 Hz,
2H), 2.52 (s, 3H), 1.93 (s, 3H), 1.46 (t, J= 7.2 Hz, 3H), 1.39 (t, J= 7.2
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 177.8, 163.9, 159.6, 156.6,
155.2, 148.9, 132.1, 131.9, 128.6, 122.1, 118.8, 118.6, 115.7, 114.5,
63.9, 63.5, 21.7, 20.7, 14.8, 14.6. HRMS (ESI) m/z calcd for
C24H26N2O4: 406.1893, found 406.1887. IR (KBr, neat): v 3646, 3027,
2879, 1668, 1473, 1243, 1117, 1042, 860 cm−1.
N,1-Bis(2-chlorophenyl)-2,6-dimethyl-4-oxo-1,4-dihydropyridine-
3-carboxamide (2a). Colorless crystal (125 mg, 65%); mp: 184−186
1
°C; H NMR (400 MHz, CDCl3) δ 13.10 (s, 1H), 8.49 (dd, J = 1.2,
2,6-Dimethyl-4-oxo-N,1-di-p-tolyl-1,4-dihydropyridine-3-carbox-
6.8 Hz, 1H), 7.62 (dd, J = 2.0, 6.0 Hz, 1H), 7.55−7.50 (m, 2H), 7.40
(dd, J = 1.2, 6.8 Hz, 1H), 7.35 (dd, J = 2.0, 5.6 Hz, 1H), 7.27−7.23 (m,
1H), 7.03−7.00 (m, 1H), 6.56 (s, 1H), 2.51 (s, 3H), 1.90 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 178.1, 164.3, 156.5, 148.1, 137.1, 136.3,
132.6, 131.6, 131.2, 129.5, 129.2, 128.8, 127.0, 124.2, 124.0, 122.6,
119.2, 118.6, 20.9, 19.7. HRMS (ESI) m/z calcd for C20H16Cl2N2O2:
386.0589, found 386.0584. IR (KBr, neat): v 3658, 3072, 2389, 1674,
1526, 1440, 1193, 1035, 888, 758 cm−1.
1
amide (2h). Colorless crystal (92 mg, 53%); mp: 241−243 °C; H
NMR (400 MHz, CDCl3) δ 12.65 (s, 1H), 7.59 (d, J = 8.0 Hz, 2H),
7.34 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 7.6 Hz,
2H), 6.47 (s, 1H), 2.51 (s, 3H), 2.44 (s, 3H), 2.31 (s, 3H), 1.90 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 177.81, 164.0, 156.3, 148.5,
140.1, 136.9, 136.4, 132.9, 130.8, 129.1, 127.3, 120.5, 118.78, 118.6,
21.6, 21.1, 20.8, 20.6. HRMS (ESI) m/z calcd for C22H22N2O2:
346.1681, found 346.1676. IR (KBr, neat): v 3640, 3017, 2919, 1672,
1529, 1341, 1280, 1190, 1073, 853 cm−1.
N,1-Bis(4-chlorophenyl)-2,6-dimethyl-4-oxo-1,4-dihydropyridine-
3-carboxamide (2b).4 Colorless crystal (125 mg, 65%); mp: 269−271
1
N,1-Bis(2,4-dimethylphenyl)-2,6-dimethyl-4-oxo-1,4-dihydropyri-
dine-3-carboxamide (2i). Colorless crystal (116 mg, 62%); mp: 158−
160 °C; 1H NMR (400 MHz, CDCl3) δ 12.57 (s, 1H), 8.03 (d, J = 8.0
Hz, 1H), 7.17 (d, J = 12.0 Hz, 2H), 7.00 (t, J = 7.2 Hz, 3H), 6.55 (s,
1H), 2.51 (s, 3H), 2.42 (s, 3H), 2.40 (s, 3H), 2.29 (s, 3H), 2.00 (s,
3H), 1.87 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 177.9, 164.1,
156.3, 148.2, 140. 3, 136.0, 134.8, 134.4, 133.1, 132.5, 130.8, 128.8,
128.6, 127.2, 126.6, 122.2, 118.9, 118.8, 21.1, 21.0, 20.7, 19.8 18.4,
16.8. HRMS (ESI) m/z calcd for C24H26N2O2: 374.1994, found
374.1989. IR (KBr, neat): v 3641, 2929, 1673, 1597, 1451, 1341, 1195,
1038, 861 cm−1.
N,1-Bis(2-methoxyphenyl)-2,6-dimethyl-4-oxo-1,4-dihydropyri-
dine-3-carboxamide (2j).4 Colorless crystal (113 mg, 60%); mp:
239−241 °C; 1H NMR (400 MHz, CDCl3) δ 12.74 (s, 1H), 8.51 (d, J
= 7.6 Hz, 1H), 7.49 (m, 1H), 7.13−7.01 (m, 4H), 6.96−6.90 (m, 2H),
6.52 (s, 1H), 3.96 (s, 3H), 3.81 (s, 3H), 2.48 (s, 3H), 1.87 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 178.0, 164.3, 156.5, 154.3, 149.3, 148.7,
131.6, 128.9, 128.8, 128.0, 123.2, 121.6, 120.8, 120.6, 119.3, 118.7,
112.4, 110.2, 55.9, 55.8, 20.9, 19.6. HRMS (ESI) m/z calcd for
C22H22N2O4: 378.1580, found 378.1574. IR (KBr, neat): v 3624, 2963,
1667, 1598, 1460, 1343, 1278, 1120, 1019, 864 cm−1.
°C; H NMR (400 MHz, CDCl3) δ 12.82 (s, 1H), 7.64 (d, J 8.8 Hz,
2H), 7.54 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4
Hz, 2H), 6.46, (s, 1H), 2.49 (s, 3H), 1.89 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 177.8, 164.0, 156.2, 148.3, 137.8, 137.6, 136.3, 130.7,
129.1, 128.7, 128.3, 121.7, 119.0, 118.6, 21.7, 20.7. HRMS (ESI) m/z
calcd for C20H16Cl2N2O2: 386.0589, found 386.0584. IR (KBr, neat): v
3663, 3069, 2390, 1676, 1528, 1443, 1195, 1037, 891, 756 cm−1.
Ethyl 4-(1-(4-(Ethoxycarbonyl)phenyl)-2,6-dimethyl-4-oxo-1,4-di-
hydropyridine-3-carboxamido)benzoate (2c). Colorless crystal (143
mg, 62%); mp: 179−181 °C; 1H NMR (400 MHz, CDCl3) δ 13.13 (s,
1H), 8.28 (d, J= 8.4 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 8.8
Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 6.53 (s, 1H), 4.45 (q, J = 7.2 Hz,
2H), 4.35 (q, J = 7.2 Hz, 2H), 2.52 (s, 3H), 1.92 (s, 3H), 1.45 (t, J =
7.2 Hz, 3H), 1.40 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
178.0, 166.4, 164.9, 164.3, 156.4, 148.1, 143.2, 143.0, 132.4, 131.8,
130.6, 128.0, 125.2, 119.7, 119.2, 118.5, 61.8, 60.7, 21. 8, 20.9, 14.4,
14.3. HRMS (ESI) m/z calcd for C26H26N2O6: 462.1791, found
462.1786. IR (KBr, neat): v 3662, 3058, 2401, 1678, 1518, 1442, 1198,
1040, 879 cm−1.
N,1-Bis(3-chlorophenyl)-2,6-dimethyl-4-oxo-1,4-dihydropyridine-
3-carboxamide (2d). Colorless crystal (127 mg, 66%); mp: 188−190
1
°C; H NMR (400 MHz, CDCl3) δ 12.92 (s, 1H), 7.91 (s, 1H), 7.55
2,6-Dimethyl-4-oxo-N,1-di-o-tolyl-1,4-dihydropyridine-3-carbox-
4
1
amide (2k). Colorless crystal (107 mg, 62%); mp: 163−165 °C; H
NMR (400 MHz, CDCl3) δ 12.7 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H),
7.45−7.39 (m, 3H), 7.20 (t, J = 6.8 Hz, 2H), 7.13 (d, J = 7.6 Hz, 1H),
7.01 (t, J = 7.2 Hz, 1H), 6.57 (s, 1H), 2.52 (s, 3H), 2.46 (s, 3H), 2.05
(s, 3H), 1.87 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 178.0, 164.1,
156.2, 148.0, 138.5, 137.4, 134.8, 131.9, 130.1, 130.1, 128.7, 128.00,
(d, J = 7.6 Hz, 2H), 7.45 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H),
7.2 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 7.04 (d, J = 8.0 Hz,
1H), 6.49 (s, 1H), 2.53 (s, 3H), 1.93 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 177.9, 164.0, 156.3, 148.1, 140.3, 140.1, 136.2, 134.3, 131.4,
130.5, 129.6, 128.1, 126.1, 123.5, 120.5, 119.0, 118.5, 118.4, 21.7, 20.8.
HRMS (ESI) m/z calcd for C20H16Cl2N2O2: 386.0589, found
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dx.doi.org/10.1021/jo3010217 | J. Org. Chem. 2012, 77, 7665−7670

The Journal of Organic Chemistry
Note
127.5, 126.1, 123.7, 122.1, 119.1, 118.8, 21.1, 19.8, 18.5, 16.9. HRMS
(ESI) m/z calcd for C22H22N2O2: 346.1681, found 346.1676. IR (KBr,
neat): v 3646, 3052, 2348, 1675, 1587, 1458, 1378, 1271, 1125, 1046,
872 cm−1.
ACKNOWLEDGMENTS
■
We thank the NSFC (21002051, 21172056) and PCSIRT
(IRT1061) and the Foundation and Frontier Technology
Research Program of Henan Province (112300410313) for
financial support of this research.
2,6-Dimethyl-4-oxo-N,1-di-m-tolyl-1,4-dihydropyridine-3-carbox-
1
amide (2l). Colorless crystal (111 mg, 64%); mp: 158−160 °C; H
NMR (400 MHz, CDCl3) δ 12.74 (s, 1H), 7.58 (s, 1H), 7.50−7.43
(m, 2H), 7.35 (d, J = 7.6 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.00 (d, J =
7.6 Hz, 2H), 6.90 (d, J = 7.6 Hz, 1H), 6.50 (s, 1H), 2.53 (s, 3H), 2.44
(s, 3H), 2.35 (s, 3H), 1.93 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
177.8, 164.1, 156.3, 148.4, 140.8, 139.4, 138.8, 138.4, 130.6, 130.1,
128.1, 128.0, 124.1, 124.3, 121.2, 118.7, 118.6, 117.7, 21.7, 21.5, 21.3,
20.8. HRMS (ESI) m/z calcd for C22H22N2O2: 346.1681, found
346.1676. IR (KBr, neat): v 3639, 2862, 1672, 1592, 1459, 1339, 1202,
1168, 858 cm−1.
N,1-Bis(5-chloro-2-methoxyphenyl)-2,6-dimethyl-4-oxo-1,4-dihy-
dropyridine-3-carboxamide (2m).4 Colorless crystal (129 mg, 58%);
mp: 215−217 °C; 1H NMR (400 MHz, CDCl3) δ 12.91 (s, 1H), 8.60
(d, J = 2.4 Hz, 1H), 7.50 (dd, J = 2.4, 6.4 Hz, 1H), 7.18 (d, J = 2.4 Hz,
1H), 7.05 (d, J = 9.2 Hz, 1H), 6.98 (dd, J = 2.4, 6.4 Hz, 1H), 6.81 (d, J
= 8.8 Hz, 1H), 6.52 (s, 1H), 3.95 (s, 3H), 3.83 (s, 3H), 2.51 (s, 3H),
1.91 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 178.1, 164.2, 156.6,
153.2, 148.4, 147.8, 131.6, 129.8, 128.8, 128.6, 126.3, 125.5, 122.6,
120.5, 118.9, 113.4, 110.8, 56.2, 56.2, 20.9, 19.7. HRMS (ESI) m/z
calcd for C22H20Cl2N2O4: 446.0800, found 446.0795. IR (KBr, neat): v
3507, 2940, 1733, 1497, 1421, 1179, 1131, 1023, 882 cm−1.
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N,1-Dibenzyl-2,4-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxa-
mide (4n).4 Colorless crystal (104 mg, 60%); mp: 96−98 °C; H
1
NMR (400 MHz, CDCl3) δ 8.16 (s, 2H), 7.53 (d, J = 8.0 Hz, 5H),
7.33 (t, J = 8.0 Hz, 5H), 7.16 (t, J = 7.2 Hz, 2H), 5.48 (s, 1H), 5.35 (s,
1H), 2.43 (s, 3H), 2.42 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
167.1, 162.6, 148.2, 143.2, 137.9, 135.5, 128.7, 128.6, 127.98, 127.5,
126.3, 119.3, 116.6, 46.9, 43.8, 19.5, 17.6. HRMS (ESI) m/z calcd for
C22H22N2O2: 346.1681, found 346.1676. IR (KBr, neat): v 3425, 3023,
1677, 1584, 1471, 1387, 1209, 1121, 879 cm−1.
(8) (a) Freeman, S. K.; Ringk, W. F.; Spoerri, P. E. J. Am. Chem. Soc.
N,1-Bis(4-chlorobenzyl)-2,4-dimethyl-6-oxo-1,6-dihydropyridine-
3-carboxamide (4o).4 Colorless crystal (118 mg, 57%); mp: 91−94
°C; 1H NMR (400 MHz, CDCl3) δ 7.36 (br, 1H), 7.30−7.24 (m, 6H),
6.96 (d, J = 8.4 Hz, 2H), 6.19 (s, 1H), 5.05 (s, 2H), 4.51 (d, J = 6.0
Hz, 2H), 2.18 (s, 3H), 2.13 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
166.9, 162.5, 148.4, 143.0, 136.4, 133.8, 133.5, 133.5, 129.5, 129.0,
128.8, 127.8, 119.3, 116.7, 46.4, 43.2, 19.6, 17.7. HRMS (ESI) m/z
calcd for C22H20Cl2N2O2: 414.0902, found 414.0897. IR (KBr, neat): v
3363, 2974, 1657, 1563, 1403, 1376, 1236, 1185, 1074, 849 cm−1.
N,1-Bis(4-methoxybenzyl)-2,4-dimethyl-6-oxo-1,6-dihydropyri-
dine-3-carboxamide (4p).4 Colorless crystal (120 mg, 59%); mp:
151−153 °C; 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.4 Hz, 2H),
7.09 (br, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.83−6.77 (m, 4H), 6.20 (s,
1H), 5.04 (s, 2H), 4.47 (d, J = 5.6 Hz, 2H), 3.76 (s, 3H), 3.75 (s, 3H),
2.21 (s, 3H), 2.12 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 167.0,
162.7, 158.8, 148.0, 143.2, 130.0, 129.4, 128.7, 127.9, 127.6, 119.2,
116.8, 114.1, 113.9, 55.2, 55.2, 46.5, 43.3, 19.5, 17.7. HRMS (ESI) m/z
calcd for C24H26N2O4: 406.1893, found 406.1887. IR (KBr, neat): v
3333, 2973, 1925, 1678, 1584, 1439, 1298, 1106, 873 cm−1.
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■
S
* Supporting Information
1
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zhangzhiguo3030@yahoo.com.cn; zgs@htu.cn
Notes
The authors declare no competing financial interest.
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