POCl3-Mediated Reaction: A New Entry to Polysubstituted 2-Pyridones via Self-condensation of β-Keto Amides

Article abstract of DOI:10.1002/jhet.3613

Synthesis of polysubstituted 2-pyridones and their analogues from β-keto amides via self-condensation cyclization is described. Notable advantages include mild reaction conditions, reduced synthetic steps, high yields, and a readily available starting mat

Full text of DOI:10.1002/jhet.3613

Month 2019
POCl3-Mediated Reaction: A New Entry to Polysubstituted 2-Pyridones
via Self-condensation of β-Keto Amides
Yufeng Sun, Jun Wang, Chang Cao, Zhigang Yuan, Yuan Tian, Yu Shi, and Wenbin Liu
b
a
c
c
b
b
a
Baochang Gao,a,b
*
*
aInstitute of Composite Materials, Key Laboratory of Superlight Material and Surface Technology of Ministry of
Education, College of Materials Science and Chemical Engineering, Harbin Engineering University, Harbin 150001, P.R.
China
bDaqing Branch of Heilongjiang Academy of Sciences, Daqing 163319, P.R. China
cChemistry and Chemical Engineering, Northeast Petroleum University, Daqing 163319, P.R. China
*E-mail: chemgbc@163.com; wjlwb@163.com
Received September 25, 2018
DOI 10.1002/jhet.3613
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
Synthesis of polysubstituted 2-pyridones and their analogues from β-keto amides via self-condensation
cyclization is described. Notable advantages include mild reaction conditions, reduced synthetic steps, high
yields, and a readily available starting materials. Further mechanistic studies suggest that the transformation
proceeds through self-condensation, intramolecular nucleophilic cyclization, and elimination.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
valuable heterocycles. The development of an efficient
synthetic method that furnishes 2-pyridone derivatives is
still highly desirable.
2-Pyridone derivatives are identified as one of the
most important classes of heterocyclic compounds,
which constitute the core of bioactive molecules and
pharmaceutical agents in natural products (Fig. 1) [1–4].
Such well-known molecules have diverse biological
properties (e.g., antimalarial [5], antihepatitis B [6],
vasorelaxant [7], antifungal [8], antiepilepsy [9],
antifibrosis [10], anti-HIV [11], MEK-1 inhibitor [12],
antitumor [13], antiulcer [14], antioxidant, and
antituberculos properties [15]). Moreover, 2-pyridone-
based bioactive molecules are also used as important
versatile building blocks for the synthesis of
heterocycles in the field of synthetic organic chemistry
like pyridines [16], piperidines [17], b-lactams [18],
indolizidines, and quinolizidines [19]. 2-Pyridones are
prevalent in many areas, and thus, many approaches for
their construction have been developed. The notable
approaches for the synthesis of 2-pyridones are the
following: (i) the modification of the heterocyclic ring
by pyridinium salt chemistry and N-alkylation [20,21],
(ii) the construction of the heterocyclic skeleton via
Guareschi–Thorpe reaction [22], (iii) Dieckmann-type
condensations [23], (iv) hetero Diels–Alder reaction
[24], (v) halogenated 2-pyridones under Vilsmeier–
Haack reaction [25], and (vi) metal-mediated
cycloaddition [26]. All these strategies represent
important progress for the development of 2-pyridones;
however, the construction of simple and efficient
synthetic strategies is desirable for the synthesis of the
β-Keto amide or their derivatives are important
precursors of bioactive and functional materials,
especially in the construction of heterocyclic systems
because of its specific six reactive sites in the same
molecule [27–34]. Considering the environmental
concerns, yield, and safety, thus, the development of a
new method for the direct synthesis of 2-pyrones is
highly critical. Our group reported a facile and efficient
one-pot synthesis of pyridine derivatives from the same
starting materials [35]. According to continuing studies
on the fields of cleavage or construction of C─C and
C─N bonds because of its importance and usefulness
[36,37], similar methods for their construction have been
reported, Dong and coworkers reported a new series of 2-
pyridones via the Vilsmeier conditions (Fig. 2A) [38a].
Zhang and coworkers reported one direct synthesis of 4-
pyridones through migration of N to C 1,3-acyl and use
Na2S2O8 as the mediate to induce this transformation
(Fig. 2B) [38b].
Given that the approach of Dong and Zhang involved
the cyclization reaction of the same substrate reactants
to the corresponding functionalized heterocycles [38],
we supposed that the direct synthesis 2-pyridones via
dimerization of β-keto amides mediated by POCl3
would furnish 2-pyridones with diverse structures
(Fig. 2C). When CH2Cl2 was used as a solvent, the same
substrates, β-keto amides, afforded different 2-pyridones
in good yields. The result suggested that POCl3/CH2Cl2
© 2019 Wiley Periodicals, Inc.

B. Gao, Y. Sun, J. Wang, C. Cao, Z. Yuan, Y. Tian, Y. Shi, and W. Liu
Vol 000
continuation to our efforts to develop valuable
heterocycles, we provided an improved convenient
synthesis method for the construction of important
2-pyridones mediated by POCl3. Herein, we wish to
disclose our findings and present a proposed mechanism
for the self-condensation.
RESULTS AND DISCUSSION
In our initial study, 3-oxo-N-phenyl-butyramide 1a was
selected as a model substrate to examine its reaction
behavior. First, the reaction of 1a with POCl3 (1.0 equiv.)
was initially attempted in CH2Cl2 at room temperature
(RT) based on the literature report. Unfortunately, the
result disappointed, no major product was observed as
indicated by TLC (Table 1, entry 1). Upon treatment of
1a with 1.0 equiv. of POCl3 in the presence of CH2Cl2 at
reflux for 6 h, the expected product 2a was furnished,
although the yield of 2a was very low (25%, Table 1,
entry 2). Surprisingly, it was observed that the reaction
converts 1a into product 2a using POCl3 to mediate this
transformation. The structure of compound 2a was
confirmed by analyses of the spectroscopic data (1D
NMR, 2D NMR). Furthermore, the structure of 2a was
confirmed by nuclear Overhauser effect spectra
experiments. The nuclear Overhauser effect correlation
signals between H-7, H-11 and H-9, H-11 highly
indicated a 2-pyridones unit (Figure S2). Therefore,
compound 2a was finally established as 2,4-dimethyl-6-
Figure 1. Representative 2-pyridones core structure.
reagent showed different reaction behavior from the
Vilsmeier reagent, POCl3/N,N-Dimethylformamide [38].
Base on experiments, we envisioned the construction of
2-pyridones via dimerization of β-keto amides. In
oxo-1-phenyl-1,6-dihy-dropyridine-3-carbo-xylic
phenylamide.
acid
To investigate the optimization of the reaction
conditions, β-keto amide 1a was investigated by
treatment with a different molar ratio of 1a to POCl3,
Figure 2. Representative reactions of β-keto amides. (A) Vilsmeier–
Haack reaction. (B) N to C 1,3-acyl migration reaction. (C) Proposed
method.
Table 1
Screening of the reaction conditionsa.
Entry
Mediated (equiv.)
Solvent
Temp. (°C)
Yield (%)b
1
2
3
4
5
6
7
8
POCl3(1.0)
POCl3(1.0)
POCl3(3.0)
POCl3(3.0)
POCl3(3.0)
POCl3(3.0)
PBr3(3.0)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
CH3CN
CH2Cl2
CH2Cl2
RT
Reflux
RT
Reflux
Reflux
Reflux
RT
Mixture
25
42
90
53
45
47
59
PBr3(3.0)
Reflux
aReaction conditions: 1a (1.0 mmol), solvent (5.0 mL).
bIsolated yield.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Self-condensation of β-Keto Amides
reaction temperatures, and solvent (Table 1, entries 2–6).
When 3.0 equiv. of POCl3 in the presence of CH2Cl2 at
RT for 6 h (Table 1, entry 3), 42% product 2a was
obtained. To our delight, increasing the reaction
temperature from RT to reflux, the desired 2-pyridone
product 2a was formed in 90% yield (Table 1, entry 4).
Keeping POCl3 as the efficient medium, we then tested
the solvent effect. However, the reaction provided less
satisfactory results in terms of dimerization when
conducted in MeCN and DCE, affording product 2a in
low yields of 53 and 45%, respectively (Table 1, entries
5 and 6). Encouraged by this result, another reagent was
tested. The reaction was performed in the presence of
PBr3 at RT and under reflux for 6 h, product 2a was
furnished in 47% and 51% yield, respectively (Table 1,
entries 7 and 8). The result proved that PBr3 was less
Table 2
The scope of the substratesa.
Entry
1
R
2
Time (h:min)
Yield (%)b
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
6.0
6.0
7.0
6:30
6.0
6.0
7:30
6:30
6.0
90
95
85
88
91
85
87
85
n.d.
4-ClC6H4
4-MeOC6H4
2-ClC6H4
2,4-Me2C6H3
4-MeC6H4
2-MeOC6H4
2-MeC6H4
CH3
aReaction conditions: 1 (1.0 mmol), POCl3 (3.0 equiv.), CH2Cl2 (5.0 mL), reflux.
bIsolated yield.
Scheme 1. Screening of the cross-condensation products.
Scheme 2. Plausible mechanism.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

B. Gao, Y. Sun, J. Wang, C. Cao, Z. Yuan, Y. Tian, Y. Shi, and W. Liu
effective for this condensation. The optimization of the EXPERIMENTAL
Vol 000
reaction conditions was finally identified as POCl3 (3.0
equiv.) at reflux for 6 h (Table 1, entry 4).
The 1H and 13C NMR spectra were recorded at 300 MHz
(or 500 MHz), with trimethylsilyl as an internal standard
on Bruker spectrometer in solutions of DMSO. Melting
points were recorded on a melting point apparatus and
were uncorrected. Elemental analyses were performed on
a Vario EL analyzer.
Having established the optimized reaction conditions
for product 2a, we next probed the scope of self-
condensation of the substrate 1 (Table 2). Under the same
conditions, a diverse range of β-keto amides 1 with
different substitution groups were examined, and the
results are listed in Table 2. Notably, it was observed that
the method was compatible with various electron-
donating and electron-withdrawing groups 1b–1h could
easily be converted into the corresponding product 2b–2h
in high yields (85–95%) (Table 2, entries 2–8).
Furthermore, all the reactions of 1b–1h with POCl3/
CH2Cl2 proceeded smoothly. The scope of the substrate
was further investigated in the context of N-nonaromatic
group (Table 2, entry 9). It is observed that N-
methylacetoacetamide 1i, under the same conditions, did
not convert into the corresponding product 2i, no reaction
occurred even till 6 h as indicated by thin-layer
chromatography (Table 2, entry 9). According to the
result, the method was next extended for the synthesis of
cross-condensation products. What is the result? Thus,
we attempted the reactions in accordance with the new
method; unfortunately, the reactions were unsuccessful,
no major product was observed (Scheme 1). Increasing
or decreasing the amount of POCl3 or PBr3 did not
lead the reaction to furnish the expected product in
good yields,
General procedure for the self-condensation of β-keto
amides 2a–h. A mixture of β-keto amides 1 (1.0 mmol)
and POCl3 (3.0 mmol) in CH2Cl2 (5 mL) was well stirred
at reflux for 6 h. After cooling to RT, the mixture was
washed with sat.aq NaCl (10 mL × 3) and dried over
anhydrous MgSO4. The organic solvent was then
removed in vacuo and the residue was purified through
flash silica gel chromatography to give product 2a–h
(Eluent: PE/EtOAc = 5:1, v/v).
2,4-Dimethyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-
carboxylic acid phenylamide (2a). Yield: 150 mg (90%);
white solid; mp 251–253°C. 1H NMR (300 MHz,
CDCl3): δ = 2.06 (s, 3 H), 2.30 (s, 3 H), 6.33 (s, 1 H),
7.08–7.15 (m, 3 H), 7.26–7.33 (m, 2 H), 7.41–7.51 (m, 3
H), 7.56 (d, J = 7.5 Hz, 2H), 8.74 (s, 1 H); 13C NMR
(75 MHz, DMSO-d6): δ = 18.9, 19.2, 116.6, 118.2,
119.4, 123.9, 128.2, 128.6, 128.8, 129.6, 138.4, 138.8,
143.2, 148.2, 161.5, 165.1; MS: m/z = 319.0, calcd for
[M + 1]: 318.1. Anal. Calcd for C20H18N2O2: C, 75.45;
H, 5.70; N, 8.80; found: C, 75.43; H, 5.71; N, 8.81.
1-(4-Chloro-phenyl)-2,4-dimethyl-6-oxo-1,6-dihydro-
pyridine-3-carboxylic acid (4-chloro-phenyl)-amide (2b).
According to the obtained results and previous literature
report [38,39], a plausible mechanism for the self-
condensation reaction is presented in Scheme 2. The
transformation commences from the phosphorylation
1
Yield: 185 mg (95%); white solid; mp 143–145°C; H
NMR (300 MHz, DMSO-d6): δ = 1.92 (s, 3 H), 2.18 (s,
3 H), 6.36 (s, 1 H), 7.30 (d, J = 7.9 Hz, 2 H), 7.42 (d,
J = 8.8 Hz, 2 H), 7.64 (d, J = 8.8 Hz, 2 H), 7.74 (d,
J = 8.8 Hz, 2 H), 10.68 (s, 1 H); 13C NMR (75 MHz,
DMSO-d6): δ = 19.5, 19.7, 117.0, 118.5, 121.5, 127.9,
129.2, 130.1, 130.7, 133.7, 137.6, 138.2, 143.7, 148.8,
161.9, 165.6; MS: m/z = 387.2, calcd for [M + 1]: 386.1.
Anal. Calcd for C20H16Cl2N2O2: C, 62.03; H, 4.16; N,
between β-oxo amide
1 with POCl3 to generate
phosphorate intermediate 3 and 4 [39b]; following by the
attack of the lone-pair electrons of the amide nitrogen to
the carbonyl carbon, intermediate 5 was formed along
with the elimination of dichlorophosphate [40].
Alternatively, when R is aliphatic, the self-condensation
is not observed. Subsequently, the intramolecular
dehydration process to give the final product 2.
7.23; found: C, 62.05; H, 4.14; N, 7.24.
1-(4-Methoxy-phenyl)-2,4-dimethyl-6-oxo-1,6-dihydro-
pyridine-3-carboxylic acid(4-methoxy-phenyl)-amide (2c).
Yield: 165 mg (85%); white solid; mp 215–217°C; H
1
NMR (300 MHz, DMSO-d6): δ = 1.91 (s, 3 H), 2.17 (s,
3 H), 3.73 (s, 3 H), 3.82 (s, 3 H), 6.31 (s, 1 H), 6.90–
6.94 (m, 2 H), 7.06–7.15 (m, 4 H), 7.56–7.61 (m, 2 H),
10.31 (s, 1 H); 13C NMR (75 MHz, DMSO-d6): δ = 19.5,
19.6, 55.7, 55.9, 114.4, 115.2, 116.9, 118.7, 121.4,
129.7, 131.4, 132.4, 144.1, 148.6, 156.1, 159.5, 162.2,
165.2. Anal. Calcd for C22H22N2O4: C, 69.83; H, 5.86;
CONCLUSION
A
simple and efficient one-pot synthesis of
polysubstituted 2-pyridones from β-keto amides via self-
condensation cyclization has been developed, which
involves sequential self-condensation, halogenation, and
intramolecular nucleophilic cyclization reactions. This
N, 7.40; found: C, 69.81; H, 5.87; N, 7.41.
method allows
a direct access to the 2-pyridone
1-(2-Chloro-phenyl)-2,4-dimethyl-6-oxo-1,6-dihydro-
pyridine-3-carboxylic acid(2-chloro-phenyl)-amide (2d).
Yield: 180 mg (88%); white solid; mp 175–177°C; H
framework. Notable advantages include mild reaction
conditions, reduced synthetic steps, high yields, and a
readily available starting materials.
1
NMR (300 MHz, DMSO-d6): δ = 1.89 (s, 3 H), 2.38 (s,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Self-condensation of β-Keto Amides
3 H), 6.63 (s, 3 H), 7.13 (t, J = 7.3 Hz, 1 H), 7.34 (t,
J = 7.3 Hz, 1 H), 7.52 (d, J = 7.6 Hz, 1 H), 7.63–7.71
(m, 2 H), 7.73–7.81 (m, 1 H), 7.84 (d, J = 6.7 Hz, 1 H),
8.38 (d, J = 8.0 Hz, 1 H), 13.08 (s, 1 H). 13CNMR
(75 MHz, DMSO-d6): δ = 19.6, 20.8, 118.4, 118.7,
123.2, 123.8, 125.1, 127.9, 129.7, 129.8, 130.9, 131.2,
131.6, 132.6, 136.3, 136.8, 149.4, 156.1, 164.5. Anal.
Calcd for C20H16Cl2N2O2: C, 62.03; H, 4.16; N, 7.23;
13CNMR (75 MHz, DMSO-d6): δ = 17.5, 18.6, 18.9,
19.8, 117.1, 118.8, 126.2, 126.4, 126.6, 127.8, 128.5,
129.3, 131.0, 131.5, 133.0, 135.6, 136.2, 138.2, 143.2,
148.8, 161.5, 165.8. Anal. Calcd for C22H22N2O2: C,
76.28; H, 6.40; N, 8.09; found: C, 76.24; H, 6.43; N, 8.11.
Acknowledgments. We thank the financial support from
National Natural Science Foundation of China (grant number
0973022) and the International Science & Technology Coopera-
tion Program of China (grant number 2015DFR50260).
found: C, 62.05; H, 4.14; N, 7.24.
1-(2,4-Dimethyl-phenyl)-2,4-dimethyl-6-oxo-1,6-dihydro-
pyridine-3-carboxylic acid(2,4-dimethyl-phenyl)-amide (2e).
Yield: 170 mg (91%); white solid; mp 262–264°C; H
1
NMR (300 MHz, DMSO-d6): δ = 1.87 (s, 3 H), 1.95 (s,
3 H), 2.18 (s, 3 H), 2.22 (d, J = 4.4 Hz, 6 H), 2.31 (s, 3
H), 6.28 (s, 1 H), 6.96 (t, J = 8.3 Hz, 2 H), 7.02 (s, 1 H),
7.13 (d, J = 7.3 Hz, 1 H), 7.21 (d, J = 11.5 Hz, 2 H),
9.81 (s, 1 H); 13C NMR (75 MHz, DMSO-d6): δ = 17.4,
18.6, 18.9, 19.8, 21.0, 21.1, 117.1, 118.8, 126.2, 127.0,
128.2, 131.4, 132.0, 133.6, 135.1, 135.5, 135.6, 138.6,
143.3, 148.7, 161.5, 165.9. Anal. Calcd for C24H26N2O2:
C, 76.98; H, 7.00; N, 7.48; found: C, 76.96; H, 7.01; N,
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7.29.
2,4-Dimethyl-6-oxo-1-p-tolyl-1,6-dihydro-pyridine-3-
carboxylic acid p-tolylamide (2f). Yield: 155 mg (85%);
white solid; mp 194–196°C; 1H NMR (300 MHz,
DMSO-d6): δ = 1.89 (s, 3 H), 2.16 (s, 3 H), 2.26 (s, 3
H), 2.38 (s, 3 H), 6.30 (s, 1 H), 7.11 (dd, J = 15.9,
8.0 Hz, 4 H), 7.34 (d, J = 8.0 Hz, 2 H), 7.55 (d,
J = 8.2 Hz, 2 H), 10.36 (s, 1 H); 13C NMR (75 MHz,
DMSO-d6): δ = 19.4, 19.6, 21.0, 21.2, 117.0, 118.7,
120.0, 128.4, 129.6, 130.6, 133.3, 136.3, 136.8, 138.5,
143.8, 148.6, 162.1, 165.4; MS: m/z = 347.3, calcd for
[M + 1]: 346.2. Anal. Calcd for C22H22N2O2: C, 76.28;
H, 6.40; N, 8.09; found: C, 76.25; H, 6.42; N, 8.11.
1-(2-Methoxy-phenyl)-2,4-dimethyl-6-oxo-1,6-dihy-dro-
pyridine-3-carboxylic acid (2-methoxy-phenyl)-amide (2g).
1
Yield: 168 mg (87%); white solid; mp 110–112°C; H
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NMR (300 MHz, DMSO-d6): δ = 1.89 (s, 3 H), 2.19 (s,
3 H), 3.76 (s, 3 H), 3.78 (s, 3 H), 6.25 (s, 1 H), 6.89–
6.98 (m, 1 H), 7.07 (t, J = 8.0 Hz, 1 H), 7.11 (d,
J = 2.3 Hz, 1 H), 7.14 (dd, J = 7.2, 1.8 Hz, 1 H), 7.16–
7.20 (m, 1 H), 7.22 (d, J = 8.2 Hz, 1 H), 7.46 (ddd,
J = 8.8, 7.0, 2.2 Hz, 1 H), 7.70 (dd, J = 7.8, 1.4 Hz, 1
H), 9.71 (s, 1 H); 13C NMR (75 MHz, DMSO-d6):
δ = 18.6, 19.7, 56.1, 56.2, 112.1, 113.0, 116.8, 11 8.5,
120.6, 121.5, 125.0, 126.5, 126.8, 127.3, 129.8, 130.7,
144.1, 148.8, 152.3, 154.8, 161.7, 166.0. Anal. Calcd for
C22H22N2O4: C, 69.83; H, 5.86; N, 7.40; found: C,
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69.81; H, 5.86; N, 7.42.
2,4-Dimethyl-6-oxo-1-o-tolyl-1,6-dihydro-pyridine-3-
carboxylic acid o-tolylamide (2h). Yield: 150 mg (85%);
white solid; mp 124–126°C; 1H NMR (300 MHz,
DMSO-d6): δ = 1.92 (s, 3 H), 2.04 (s, 3 H), 2.26 (s, 6
H), 6.35 (s, 1 H), 7.09–7.19 (m, 2 H), 7.20–7.28 (m, 2
H), 7.40–7.42 (d, J = 6.3 Hz, 4 H), 9.94 (s, 1 H).
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet