Synthesis and DABCO-induced demethylation of 3-cyano-4-methoxy-2-pyridone derivatives

Article abstract of DOI:10.1002/jhet.3783

An efficient method for synthesis and demethylation of 3-cyano-4-methoxy-2-pyridone derivatives has been developed. DABCO-induced demethylation can lead to 3-cyano-4-hydroxy-2-pyridones in DMF at 90°C with high yield. The protocol is applicable for the synthesis of 3-cyano-4-hydroxy-2-pyridone derivatives. The method is simple, efficient, and practical.

Full text of DOI:10.1002/jhet.3783

Received: 5 April 2019
DOI: 10.1002/jhet.3783
Revised: 19 June 2019
Accepted: 7 October 2019
N O T E
Synthesis and DABCO‐induced demethylation of 3‐cyano‐4‐
methoxy‐2‐pyridone derivatives
Jing Li | Hong‐Ru Tan | Yu‐Long An | Zhi‐Yu Shao | Sheng‐Yin Zhao
College of Chemistry, Chemical
Abstract
Engineering and Biotechnology, Donghua
University, No.2999 North Renmin Road,
Shanghai 201620, People's Republic of
China
An efficient method for synthesis and demethylation of 3‐cyano‐4‐methoxy‐2‐
pyridone derivatives has been developed. DABCO‐induced demethylation can
lead to 3‐cyano‐4‐hydroxy‐2‐pyridones in DMF at 90°C with high yield. The
protocol is applicable for the synthesis of 3‐cyano‐4‐hydroxy‐2‐pyridone deriv-
atives. The method is simple, efficient, and practical.
Correspondence
Sheng‐Yin Zhao, College of Chemistry,
Chemical Engineering and Biotechnology,
Donghua University, Shanghai, People's
Republic of China.
Email: syzhao8@dhu.edu.cn
Funding information
Shanghai Municipal Natural Science
Foundation, Grant/Award Number:
10ZR1400700; National Natural Science
Foundation of China, Grant/Award
Number: 21072029
1
| INTRODUCTION
condensation, cyclization, hydrolysis, and decarboxyl-
ation of 5‐chloro‐3‐cyano‐4‐methoxy‐2‐pyridone in HBr
[
7]
4‐Hydroxy‐2‐pyridone derivatives, regarded as an impor-
solution. However, the reported methods for the syn-
thesis of 4‐hydroxy‐2‐pyridones have many disadvantages
such as low yield, high reaction temperature, tedious
steps, and more by‐products. Thus, an efficient synthetic
methodology needs to be developed.
tant class of nitrogen‐containing heterocycles, have been
attractive in both organic and pharmaceutical chemistry
areas. 4‐Hydroxy‐2‐pyridone skeleton is present in diverse
natural products and drug candidates. They exhibited
valuable bioactivities such as antibacterial, antifungal,
antiviral, and cytotoxic activities. Representative exam-
ples are Ilicicolin H, Pyridoxatin, Gimeracil, and so
[1]
Traditionally, demethylation of phenyl methyl ether
and related derivatives was carried out in stronger acid
solution such as HBr or HI solution. Although a variety
[1,2]
on.
5‐Chloro‐2,4‐dihydroxypyridine
(Gimeracil,
of cleavage methods are available such as using BF ‐
3
[11]
[
8]
[9]
[10]
CDHP) is also a component of an oral resectable gastric
cancer drugs S‐1 containing tegafur, Gimeracil, and
potassium oxonate (Figure 1). Their derivatives are also
used as versatile intermediates in organic synthesis.
Generally, 4‐hydroxy‐2‐pyridone derivatives was syn-
thesized by heating ethyl N‐(styrylcarbamoyl)acetates in
diphenyl ether at 230°C to 240°C. Debenzylation of 4‐
benzyloxy‐2‐pyridones by hydrogenation gave 4‐
hydroxy‐2‐pyridones. In addition, 4‐hydroxy‐2‐pyridone
derivatives were also prepared from the raw materials
malononitrile, trimethyl orthoacetate, and N,N‐
dimethylformamide dimethyl acetal by the reactions of
Me2S complex,
SmI2,
AlCl /NaI,
BBr3,
Me SiI,
3
3
[
12]
[13]
[14]
Pd (PPh ) /MeOH,
3 4
or reducing reagents such as L‐selectride
iodocyclohexane/DMF,
[3]
[15]
are employed.
[
4]
They often resulted in undesired reactions and products
and low yields. Several protocols were developed for
[
16]
demethylation in ionic liquids.
The procedures are
[5]
expensive and need a long reaction time.
1,4‐Diazabicyclo[2.2.2]octane (DABCO) is a tertiary
amine base with weak basicity. During the past decade,
DABCO has been served as an organic‐hindered base to
carry out various organic transformations such as
[6]
[17]
Baylis–Hillman reaction and cycloaddition reactions.
J Heterocyclic Chem. 2019;1–11.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

2
LI ET AL.
method for demethylation of 3‐cyano‐4‐methoxy‐2‐
pyridones induced by DABCO.
2
| RESULTS AND DISCUSSION
.1 | Chemistry
2
We have initiated our study with demethylation of 3‐
cyano‐4‐methoxy‐2‐pyridones in the presence of diverse
organic bases such as DABCO, triethylamine, pyridine,
and DBU (Table 1). The effectiveness of DABCO serving
as the demethylation reagent under mild condition was
demonstrated for the reaction of 3‐cyano‐4‐methoxy‐2‐
pyridones with DABCO. In the initial studies, we choose
3‐cyano‐4‐methoxy‐2‐pyridone 1 as our model compound
to carry out this reaction, because this material is com-
mercial available. The product, 3‐cyano‐4‐hydroxy‐2‐
FIGURE 1 Selected examples of 4‐hydroxy‐2‐pyridones [Color
figure can be viewed at wileyonlinelibrary.com]
1b, 1c, 5a, 7c
In our ongoing medicinal chemistry program,
key intermediate is needed for the synthesis of 4‐hydroxy‐
‐pyridones, we herein disclose a simple and efficient
a
2
TABLE 1 Optimization of the demethylation reaction conditions
a
Entry
Reagent
DABCO
Solvent
DMF
T, °C
Reaction Time, h
Yield, %
1
90
90
6
95
80
72
43
0
b
2
DABCO
DABCO
DMF
DMF
6
c
3
90
6
d
4
DABCO
DMF
90
12
24
24
24
24
24
24
24
24
24
24
24
12
24
24
5
6
7
8
9
Triethylamine
Diisopropylethylamine
Pyridine
DMF
90
DMF
90
0
DMF
90
0
K
2
CO
3
DMF
90
0
DBU
DMF
90
58
0
10
11
12
13
14
15
16
17
18
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
HBr
n‐butanol
THF
Reflux
Reflux
Reflux
Reflux
Reflux
100
0
Dioxane
0
CH
3
CN
0
Toluene
DMSO
0
0
CH
ClCH
ClCH
3
COOH/H
2
O
Reflux
Reflux
Reflux
0
BF
3
.Et
2
O
2
2
CH
CH
2
2
Cl
Cl
0
BBr
3
35
Note. All reactions were conducted on a 5‐mmol scale in 10 mL of DMF using 1.0 equiv of reagent at indicated reaction temperature.
a
Yields are based on isolated products.
b
0.6 equiv of DABCO was used.
c
0.5 equiv of DABCO was used.
d
0.3 equiv of DABCO was used.

LI ET AL.
3
pyridone 2, is solid and easy to isolate. The result is
shown in Table 1. DABCO‐induced demethylation of 3‐
cyano‐4‐methoxy‐2‐pyridone was accomplished by
heating the reagent in DMF at 90°C to 100°C for 6 hours
promote this demethylation reaction (Table 1, entries 5‐
8). The starting material was recovered. In contrast,
with use of 1.0 equiv of DBU, 3‐cyano‐4‐hydroxy‐2‐
pyridone was obtained with 58% yield (Table 1, entry
9); 35% starting material was recovered. It should be
noted that the reaction does not carry out by using n‐
butanol, THF, dioxane, acetonitrile, toluene, and DMSO
as solvent (Table 1, entries 10‐15). The starting material
was recovered. It should be noted the reaction did not
provide the desired product at all in HBr solution
because of the hydrolysis of cyano group. BF .Et O is
(
Table 1, entry 1). In the presence of 1.0 equiv of DABCO,
the process provided the 3‐cyano‐4‐hydroxy‐2‐pyridone in
5% yield with 6 hours. Subsequently, the influence of the
9
loading DABCO on the reaction was investigated under
identical reaction condition. Decreasing the amount of
DABCO led to a decline in reaction yield (Table 1, entries
2‐4). The result suggested DABCO can induce this reac-
3
2
tion, not served as a catalyst.
also not an efficient demethylation agent. When using
BBr3 as demethylation agent, only 35% product was
obtained (Table 1, entries 16‐18). The above results sug-
gested that DABCO is a more effective inducer in this
reaction.
Next, our research plan was returned to other classic
organic base, such as triethylamine, diisopropylethylamine,
pyridine, K CO , and DBU. Unfortunately, triethylamine,
2
3
diisopropylethylamine, pyridine, and K CO do not
2
3
SCHEME 1 The synthesis route of
some commercial unavailable 4‐methoxy‐
2‐pyridones

4
LI ET AL.
SCHEME 2 The synthesis route of 4‐
methoxy‐2‐pyridone‐3‐carboxylic acid
derivatives
In order to further reveal the synthetic utility of this
method, a series of 4‐methoxy‐2‐pyridones including
cyano‐5‐(dimethylamino)‐3‐methoxypenta‐2,4‐dienoate
17 was prepared by condensation of N,N‐
dimethylformamide dimethyl acetal with ethyl 2‐cyano‐
3‐methoxybut‐2‐enoate 16, which was obtained by con-
densation of ethyl cyanoacetate 14 with trimethyl
orthoacetate 15. The cyclization of compound 17 in 80%
acetic acid lead to provide ethyl 4‐methoxy‐2‐oxo‐1,2‐
dihydropyridine‐3‐carboxylate 18 with 78% yield. Finally,
the compound 18 was subjected to bromination to pro-
vide compound 19 and hydrolysis to give compound 20.
With those compounds in hand, the demethylation
reaction was performed according to the above proce-
dure. Their spectral data were given in experimental sec-
tion. The reaction yields were satisfactory and ranged
from 84% to 95%. In addition, the demethylation protocol
showed a good chemical selectivity. The methoxy group
attached to phenyl moiety was not removed in this
3
4
‐cyano‐4‐methoxy‐2‐pyridones and related ethyl
‐methoxy‐2‐pyridone‐3‐carboxylates were applied to this
protocol. The synthesized raw materials were shown in
Scheme 1 because they are commercial unavailable.
N‐substituted
3‐cyano‐4‐methoxy‐2‐pyridones
were
obtained by the treatment of 3‐cyano‐4‐methoxy‐2‐
pyridones with alkyl halide in CH CN at reflux with
3
9
0% yield. Their brominated derivatives 5 and 6 were syn-
thesized by bromination of compounds 1 and 3 with NBS
in acetonitrile around 80% yields. 4‐Methoxy‐2‐
pyridonecarboxamide 4 was prepared by hydrolysis of 3‐
cyano‐4‐methoxy‐2‐pyridone 3 in 2N sulfuric acid with
7
2% yield. The synthesis of ethyl 4‐methoxy‐2‐oxo‐1,2‐
dihydropyridine‐3‐carboxylate was given in Scheme 2,
7c
according to our previous published paper. Ethyl 2‐
TABLE 2 Demethylation of 4‐methoxy‐2‐pyridones induced by DABCO
a
Entry
Substrate
Product
Reaction Time, h
Yield, %
1
6
95
2
6
92
3
4
6
6
85
87
5
6
93
(Continues)

LI ET AL.
5
TABLE 2 (Continued)
a
Entry
Substrate
Product
Reaction Time, h
Yield, %
6
7
6
6
92
86
8
9
6
89
6
6
90
84
0
1
1
0
1
No reaction
24
1
1
1
2
3
4
No reaction
No reaction
24
24
24
0
0
5
Note. All reactions were conducted on a 5‐mmol scale in 10 mL of DMF using 1.0 equiv of DABCO at 90°C.
a
Yields are based on isolated products.

6
LI ET AL.
SCHEME 3 Proposed mechanism for
demethylation of 3‐cyano‐4‐methoxy‐1‐
methyl‐2‐pyridone induced by DABCO.
[Color figure can be viewed at
wileyonlinelibrary.com]
reaction condition. (Table 2, entry 7). The reaction also
can be happened when bromo, ester, ketone, and nitro
groups attached to 3‐cyano‐4‐methoxy‐2‐pyridone moiety
pyridones by employing DABCO as an inducer under
mild reaction conditions. 3‐Cyano‐4‐hydroxy‐2‐pyridones
were obtained with high yields. This protocol provides a
practical and environmentally friendly process for an
important chemical transformation.
(
Table 2, entries 3, 4, 8, 9, 10). However, the methodology
is unsuitable to compounds 4, 18 to 19 (Table 2, entries
1‐13). Nothing happened for this running condition.
1
When compounds 4 and 18 were treated with DABCO
in 120°C to 130°C for 48 hours. The reaction does not still
work smoothly. In addition, compound 20 was reacted
with DABCO in DMF in 130°C to 140°C for 24 hours.
4
| EXPERIMENTAL
Melting points were determined with RY‐1 apparatus and
were uncorrected. Infrared (IR) spectra were recorded as
KBr pellets on a Shimadzu model 470 spectrophotometer.
4‐Hydroxy‐2‐pyridone was obtained in 5% yield. We sug-
gested the hydrolysis and decarboxylation reaction of
compound 20 happened in this reaction in high reaction
1
H NMR spectra were obtained using a Bruker AV 400‐
temperature. We supposed
a
stronger electron‐
MHz spectrometer in DMSO‐d6 and CDCl3 with
tetramethylsilane as internal standard. Electron ioniza-
tion (EI) mass spectra were determined on Waters
Micromass GCT system and Shimadzu QP‐2010 GC‐MS
system. ESI mass spectra were recorded on Shimadzu
withdrawing cyano group in 4‐hydroxy‐2‐pyridone ring
may be necessary for the demethylation reaction.
2.2 | Reaction mechanism
2010A LC‐MS instrument. All chemicals are commercial
According to the above experimental results, a plausible
mechanism is proposed in Scheme 3 using compound 3
as an example. We hypothesized that DABCO readily coor-
available and were used without further purification.
Ethyl 4‐methoxy‐2‐oxo‐1,2‐dihydropyridine‐3‐carboxylate
7
c
were synthesized according to our previous report. The
[18]
1
dinates to O atom of 4‐methoxy‐2‐pyridones. Rapid for-
mation of 22 may be due to an enolate and carbonyl group
tautomerization existed in compound 22. A withdraw
group in 3‐position can make this compound stable. The
production was released in the presence of hydrogen
donor. The methyl group was transferred to DABCO to
form compound 23 and generate compound 2a. Com-
pounds 22 and 23 were also detected through liquid
chromatography–mass spectrometry (LC‐MS) analysis
data of mp and H NMR for known products are in
accord with that reported in literature.
4
.1 | General procedure for preparation of
compounds 3, 7, 9a‐9c, 11, and 13
A mixture of 3‐cyano‐4‐methoxy‐2‐pyridone (20 mmol),
CH I (20 mmol) in acetonitrile (20 mL) was stirred and
3
(electrospray ionization [ESI] mass peak for compound
refluxed for 10 hours. After the completion of the reac-
tion, the mixture was cooled to room temperature, and
water (30 mL) was added. After extraction with EtOAc
2
2 at 277 and mass peak for compound 23 at 127; see
Supporting Information). We believe that DABCO func-
tions as an inducer in the demethylation reaction.
(
(
15 mL × 2), the organic phase was washed with water
10 mL × 2) and dried over Na SO . The solvent was
2
4
3
| CONCLUSIONS
removed and the residue was recrystallized from ethanol
to give yellow solid 3. Compounds 7, 9a‐9c, 11, and 13
were synthesized from compound 1 following the proce-
dure given above. Their spectral data are as follows.
In summary, we have presented an efficient protocol for
synthesis and demethylation of 3‐cyano‐4‐methoxy‐2‐

LI ET AL.
7
4
.1.1 | 4‐Methoxy‐1‐methyl‐2‐oxo‐1,2‐
4.1.4 | 5‐Bromo‐4‐methoxy‐1‐methyl‐2‐oxo‐
1,2‐dihydropyridine‐3‐carbonitrile (6)
dihydropyridine‐3‐carbonitrile (3)
White solid, yield: 78%, mp 198°C to 200°C. IR νmax
=
White solid, yield: 81%, mp 242°C to 244°C. IR νmax
=
2
219 (CN), 1653 (C=O), 1604‐1457 (─CH═CH─), 1358
2215 (CN), 1637 (C═O), 1596‐1452 (─CH═CH─), 1406
−
1
1
−1
1
(CH3), 1256 (C─O) cm .
H
NMR (400 MHz,
(CH3), 1093 (C─O) cm .
H NMR (400 MHz,
DMSO‐d ): δ = 3.42 (s, 3H, NCH ), 3.97 (s, 3H, OCH ),
DMSO‐d ): δ = 3.41 (s, 3H, NCH ), 4.31 (s, 3H, OCH ),
6
3
3
6
3
3
13
6
.42 (d, J = 8.0 Hz, 1H, Ar‐H), 8.11 (d, J = 8.0 Hz, 1H,
8.43 (s, 1H, Ar‐H). C NMR (101 MHz, DMSO‐d ): δ =
6
13
Ar‐H). C NMR (101 MHz, DMSO‐d ): δ = 37.15, 58.07,
37.22, 61.33, 88.20, 92.20, 115.28, 145.36, 161.32,
6
[19]
[21]
8
6.18, 94.14, 115.10, 146.54, 161.30, 173.06.
168.45.
4
.1.5 | 1‐N‐Butyl‐4‐methoxy‐2‐oxo‐1,2‐
dihydropyridine‐3‐carbonitrile (7)
4
.1.2 | 4‐Methoxy‐1‐methyl‐2‐oxo‐1,2‐
dihydropyridine‐3‐carbonamide (4)
White solid, yield: 87%, mp 81°C to 83°C. IR νmax = 2273
(
1
CN), 1640 (C═O), 1601‐1536 (─CH═CH─), 1492 (CH ),
2
A mixture of 3‐cyano‐4‐methoxy‐1‐methyl‐2‐pyridone 3
−
1
1
384 (CH ), 1259 (C─O) cm . H NMR (400 MHz,
3
(
20 mmol) in 2N H SO (15 mL) was stirred and heated
2 4
DMSO‐d ): δ = 0.89 (t, J = 8.0 Hz, 3H, CH ), 1.23‐1.29
(
Hz, 2H, CH ), 3.99 (s, 3H, CH ), 6.45 (d, J = 7.7 Hz, 1H,
Ar‐H), 8.13 (d, J = 7.7 Hz, 1H, Ar‐H). C NMR (101
MHz, DMSO‐d ): δ = 13.99, 19.56, 31.11, 48.80, 58.08,
86.46, 94.41, 115.12, 145.90, 160.88, 172.97. MS (ESI): m/
z [M + Na] calcd for C H N O Na: 229.0947; found:
2
6
3
at 80°C to 90°C for 6 hours. After the completion of the
reaction, the mixture was cooled to room temperature.
The solid were filtrated and washed with water to give
white solid, with 72% yield, mp 150°C to 152°C. IR νmax
m, 2H, CH ), 1.57‐1.63 (m, 2H, CH ), 3.89 (t, J = 7.2
2
2
2
3
13
6
=
(
3405 (NH ), 2359 (CN), 1662 (C═O), 1553‐1481-
2
−
1
1
─CH═CH─), 1409 (CH ), 1259 (C─O) cm . H NMR
3
+
11
14 2 2
(
400 MHz, DMSO‐d ): δ = 3.38 (s, 3H, NCH ), 3.79 (s,
6
3
29.0948.
3
H, OCH ), 6.28 (d, J = 8.0 Hz, 1H, Ar‐H), 7.10 (s, 1H,
3
NH ), 7.58 (s, 1H, NH ), 7.77 (s, J = 8.0 Hz, 1H, Ar‐H).
2
2
1
3
C NMR (101 MHz, DMSO‐d ): δ = 36.93, 56.68, 94.75,
11.06, 141.16, 161.04, 165.01, 166.19.
6
4
.1.6 | 1‐(4‐Benzyl)‐4‐methoxy‐2‐oxo‐1,2‐
[20]
1
dihydropyridine‐3‐carbonitrile (9a)
White solid, yield: 86%, mp 200°C to 203°C. IR νmax
=
3
1
1
102‐2921 (═C─H aromatic), 2222 (CN), 1664 (C═O),
4
.1.3 | 5‐Bromo‐4‐methoxy‐2‐oxo‐1,2‐
598‐1493(C═C aromatic, ─CH═CH─), 1424 (CH ),
2
dihydropyridine‐3‐carbonitrile (5)
−1
1
347 (CH ), 1276 (C─O) cm . H NMR (400 MHz,
3
DMSO‐d ): δ = 3.99 (s, 3H, OCH ), 5.11 (s, 2H, CH ),
6
3
2
A mixture of 3‐cyano‐4‐methoxy‐2‐pyridone (20 mmol),
NBS (20 mmol), and trifluoroacetic acid (4 mmol) in ace-
tonitrile (25 mL) was stirred and refluxed for 8 hours.
After the completion of the reaction, the solvent was care-
fully removed in vacuo, and water (30 mL) was added.
After extraction with EtOAc (15 mL × 2), the organic
phase was washed with water (10 mL × 2) and dried over
6
.50 (d, J = 8.0 Hz, 1H, Ar‐H), 7.28‐7.37 (m, 5H, Ar‐H),
13
8.26 (d, J = 8.0 Hz, 1H, Ar‐H). C NMR (101 MHz,
DMSO‐d ): δ = 51.72, 58.20, 86.72, 95.05, 114.97, 128.15,
6
1
28.22, 129.10, 137.05, 145.90, 160.91, 173.25. MS (EI):
+
m/z [M ] calcd for C H N O : 240.0899; found:
14
12 2 4
240.0893.
NaSO . The solvent was removed and the residue was
4
recrystallized from ethanol to give white solids 5. Com-
pounds 6 and 19 were synthesized following the proce-
dure given above. Their spectral data are as follows.
4.1.7 | 1‐(4‐Methoxybenzyl)‐4‐methoxy‐2‐
oxo‐1,2‐dihydropyridine‐3‐carbonitrile (9b)
White solid, yield: 74%, mp 212°C to 214°C. IR νmax
=
White solid, yield: 85%, mp 206°C to 208°C. IR νmax
=
3
(
439 (NH), 2221 (CN), 1642 (C═O), 1597‐1470
2923(═C─H aromatic), 2212 (CN), 1743 (C═O), 1629‐
−
1 1
─CH═CH─), 1346 (CH ), 1229 (C─O) cm . H NMR
1516 (C═C aromatic, ─CH═CH─), 1463 (CH ), 1383
3
2
−
1 1
(400 MHz, DMSO‐d ): δ = 4.32 (s, 3H, OCH ), 8.04 (s,
(CH ) cm . H NMR (400 MHz, DMSO‐d ): δ = 3.73 (s,
6
3
3
6
13
1
H, Ar‐H), 12.42 (s, 1H, NH). C NMR (101 MHz,
3H, OCH ), 3.98 (s, 3H, OCH ), 5.03 (s, 2H, CH ), 6.47
3 3 2
DMSO‐d ): δ = 61.28, 88.83, 92.87, 115.30, 141.55,
(d, J = 8.0 Hz, 1H, A r‐H), 6.90 (d, J = 8.0 Hz, 2H, Ar‐
H), 7.27 (d, J = 8.0 Hz, 2H, Ar‐H), 8.23 (d, J = 8.0 Hz,
6
[21]
1
62.12, 169.18.

8
LI ET AL.
1
3
1
5
1
H, Ar‐H). C NMR (101 MHz, DMSO‐d ): δ = 51.18,
4.1.11 | Ethyl
2‐cyano‐3‐methoxybut‐2‐enoate (16)
6
5.58, 58.16, 86.64, 94.93, 114.48, 115.00, 128.97, 129.96,
45.67, 159.39, 160.89, 173.12. MS (EI): m/z [M ] calcd
+
for C H N O : 270.1004; found: 270.1001.
Ethyl cyanoacetate (0.10 mol, 11 mL) and trimethyl
orthoacetate (0.12 mol, 15 mL) were stirred at 110°C.
After 4 hours, the mixture was heated to 135°C, and
excess reagents were removed. Upon cooling, the mixture
solidified. This mixture was recrystallized from water:
15
14 2 3
4
1
.1.8 | 4‐Methoxy‐1‐(4‐nitrobenzyl)‐2‐oxo‐
,2‐dihydropyridine‐3‐carbonitrile (9c)
methanol (2:1), yielding compound as a colorless powder
1
1
1.2 g, yield 66%, mp 132°C to 135°C. H NMR (400 MHz,
White solid, yield: 81%, mp 150°C to 152°C. IR νmax
=
CDCl ): δ = 1.32 (t, J = 8.0 Hz, 3H, CH ), 2.63 (s, 3H,
3
3
3
1
102‐2921 (═C─H aromatic), 2222 (CN), 1664 (C═O),
598‐1493 (C═C aromatic, ─CH═CH─, NO), 1424
OCH ), 4.00 (s, 3H, OCH ), 4.25 (q, J = 8.0 Hz, 2H,
3
3
13
CH2). C NMR (101 MHz, CDCl ): δ = 14.16, 15.03,
6.66, 61.19, 85.95, 115.03, 163.82, 184.25.
3
−
1
1
(CH2), 1347 (CH3) cm .
H
NMR (400 MHz,
7c, 22
5
DMSO‐d ): δ = 4.02 (s, 3H, OCH ), 5.25 (s, 2H, CH ),
6
3
2
6
.58 (d, J = 8.0 Hz, 1H, Ar‐H), 7.52 (d, J = 8.0 Hz, 2H,
Ar‐H), 8.22 (d, J = 8.0 Hz, 2H, Ar‐H), 8.31 (d, J = 8.0
13
Hz, 1H, Ar‐H). C NMR (101 MHz, DMSO‐d ): δ =
6
4
3
.1.12 | Ethyl 2‐cyano‐5‐(dimethylamino)‐
‐methoxypenta‐2,4‐dienoate (17)
5
1
1.54, 58.33, 86.82, 95.43, 114.83, 124.22, 129.15, 144.62,
46.04, 147.42, 160.89, 173.52. MS (EI): m/z [M ], calcd
+
for C H N O : 285.0750; found: 285.0747.
14
11 3 4
Ethyl 2‐cyano‐3‐methoxybut‐2‐enoate 16 (11.2 g, 66
mmol) and N,N‐dimethylformamide dimethyl acetal
(
14.1 mL, 0.11 mol) were dissolved in methanol (5 mL)
and heated to 130°C for 60 minutes. Excess solvents
and reagents were carefully removed in vacuo. The dark
red residue was purified by column chromatography (n‐
hexane:ethyl acetate = 8:1, v/v) to afford target com-
pound 17 as a red powder 9.01 g, yield 61%, mp 150°C
to 152°C. It was used in the next step without
purification.
4
.1.9 | Ethyl 2‐(3‐cyano‐4‐methoxy‐2‐
oxopyridin‐1(2H)‐yl)acetate (11)
White solid, yield: 83%, mp 154°C to 156°C. IR νmax
=
2
(
210 (CN), 1753 (C═O), 1652 (C═O), 1610‐1494
−
1 1
─CH═CH─), 1473 (CH ), 1374 (CH ) cm . H NMR
2
3
(400 MHz, DMSO‐d ): δ = 1.21 (t, J = 8.0 Hz, 3H, CH ),
6
3
4
2
8
1
1
.0 (s, 3H, CH ), 4.15 (q, J = 8.0 Hz, 2H, CH ), 4.73 (s,
2
3
H, CH ), 6.55 (d, J = 8.0 Hz, 1H, Ar‐H) ,8.09 (d, J =
2
13
.0 Hz, 1H, Ar‐H). C NMR (101 MHz, DMSO‐d ) δ =
6
4
.1.13 | Ethyl
3.97, 49.79, 57.84, 61.23, 85.75, 94.43, 114.21, 145.90,
+
4‐methoxy‐2‐oxo‐1,2‐dihydropyridine‐3‐
carboxylate (18)
60.34, 167.56, 173.20. MS (ESI): m/z [M + H] calcd
for C H N O : 237.0870; found: 237.0865.
12
12 2 4
Ethyl
2‐cyano‐5‐(dimethylamino)‐3‐methoxypenta‐2,4‐
dienoate 17 (5.0 g, 22.3 mmol) was refluxed for 1 hour
in 80% aqueous HOAc (15 mL). The solution was con-
centrated to about one‐third of the original volume. Sat-
4
.1.10 | 4‐Methoxy‐2‐oxo‐1‐(2‐oxo‐2‐
phenylethyl)‐1,2‐dihydropyridine‐3‐
carbonitrile (13)
urated NaHCO solution (50 mL) was added and
3
extracted with chloroform (30 mL × 2). After drying
over Na SO and filtration, the solvents were removed
White solid, yield: 75%, mp 228°C to 230°C. IR νmax
=
2
4
1
695 (C═O), 1645 (C═O), 1603‐1487 (C═C aromatic,
in vacuo. The product was recrystallized from ethyl ace-
−
1
1
─
CH═CH─), 1450 (CH ), 1360 (CH ) cm . H NMR
tate to provide compound 18 2.7 g as colorless crystals
2
3
1
(400 MHz, DMSO‐d ): δ = 4.0 (s, 3H, CH ), 5.57 (s, 2H,
with 62% yield, mp 152°C to 154°C. H NMR (400
6
3
CH ), 6.59 (d, J = 8.0 Hz, 1H, Ar‐H), 7.62 (t, J = 8.0 Hz,
MHz, CDCl ): δ = 1.37 (t, J = 8.0 Hz, 3H, CH ), 3.90
2
3
3
2
H, Ar‐H), 7.77‐7.72 (m, 1H, Ar‐H), 8.10‐8.06 (m, 3H,
(s, 3H, OCH ), 4.40 (q, J = 8.0 Hz, 2H, CH ), 6.14 (d,
3 2
13
Ar‐H). C NMR (101 MHz, DMSO‐d ): δ = 55.18, 58.28,
J = 8.0 Hz, 1H, Ar‐H), 7.51 (d, J = 8.0 Hz, 1H, Ar‐H),
6
13
8
6.34, 94.78, 114.87, 128.48, 129.48, 134.66, 134.73,
13.54 (s, 1H). C NMR (101 MHz, CDCl ): δ = 14.16,
3
+
1
46.72, 160.89, 173.58, 192.92. MS (ESI): m/z [M + H]
56.49, 61.40, 94.80, 108.71, 137.94, 163.65, 164.98,
7b
calcd for C H N O : 269.0921; found: 269.0923.
167.00.
16
12 2 3

LI ET AL.
9
1
3
4
5
.1.14 | Ethyl
‐bromo‐4‐methoxy‐2‐oxo‐1,2‐
Ar‐H), 11.71 (s, 1H, NH), 12.61 (s, 1H, OH). C NMR
(101 MHz, DMSO‐d ): δ = 85.97, 98.35, 115.54, 140.97,
162.69, 173.46. high‐resolution mass spectrometry
6
dihydropyridine‐3‐carboxylate (19)
+
(
HRMS) (EI): m/z [M ] calcd for C H N O : 136.0273;
6 4 2 2
1
White solid, yield: 68%, mp 154°C to 156°C. H NMR (400
found: 136.0276.
MHz, CDCl ): δ = 1.25 (t, J = 8.0 Hz, 3H, CH ), 3.88 (s,
3
3
3
H, OCH ), 4.26 (q, J = 8.0 Hz, 2H, CH ), 7.81 (s, 1H,
3 2
13
4.2.2 | 4‐Hydroxy‐1‐methyl‐2‐oxo‐1,2‐
dihydropyridine‐3‐carbonitrile (2b)
Ar‐H), 12.05 (s, 1H). C NMR (101 MHz, CDCl ): δ =
3
1
4.31, 60.25, 61.89, 93.94, 112.48, 138.31, 161.08, 161.50,
7b
1
65.08.
White solid, yield: 92%, mp 284°C to 286°C.IR νmax
=
3
(
434 (OH), 2211(CN), 1633 (C═O), 1569‐1507
−
1
1
─CH═CH─), 1321 (CH ) cm . H NMR (400 MHz,
3
4
.1.15 | 4‐Methoxy‐2‐oxo‐1,2‐
DMSO‐d ): δ = 3.36 (s, 3H, NCH ), 6.02 (d, J = 8.0 Hz,
1
OH). C NMR (101 MHz, DMSO‐d ): δ = 36.84, 85.55,
9
6
3
dihydropyridine‐3‐carboxylic acid (20)
H, Ar‐H), 7.82 (d, J = 8.0 Hz, 1H, Ar‐H), 12.64 (s, 1H,
13
To
dihydropyridine‐3‐carboxylate 18 (1.5 g, 7.6 mmol) in
0% ethanol, 2N NaOH solution (2 mL) was added and
a
solution of ethyl 4‐methoxy‐2‐oxo‐1,2‐
6
8.26, 115.61, 144.96, 161.96, 172.57. HRMS (EI): m/z
+
[M ] calcd for C H N O : 150.0434; found: 150.0432.
5
4 9 2 2
the reaction mixture was refluxed for 6 hours. Excess eth-
anol were carefully removed in vacuo. The reaction mix-
ture was adjust pH to 4 to 5 with 2N HCl. The precipitate
was collected and recrystallized from ethanol to yield
specified product 15 1.0 g with 78% yield. mp 216°C to
4
.2.3 | 5‐Bromo‐4‐hydroxxy‐2‐oxo‐1,2‐
dihydropyridine‐3‐carbonitrile (2c)
White solid, yield: 85%, mp 248°C to 250°C. IR νmax
=
2
19°C. IR νmax = 3189 (NH), 2198 (CN), 1645 (C═O),
3
(
423 (OH), 2208 (CN), 1611 (C═O), 1569‐1502
−
1
1
562‐1485 (─CH═CH─), 1431 (CH ), 1318 (CH ) cm .
−1 1
2
3
─CH═CH─) cm . H NMR (400 MHz, DMSO‐d ): δ =
6
1
H NMR (400 MHz, DMSO‐d ): δ = 3.95 (s, 3H, OCH ),
6
3
7
.32 (s, 1H, Ar‐H), 8.64 (s, 1H, NH), 10.02 (s, 1H, OH).
6
.55 (d, J = 8.0 Hz, 1H, Ar‐H), 7.84 (s, J = 8.0 Hz, 1H,
13
C NMR (101 MHz, DMSO‐d ): δ = 83.21, 102.85,
6
13
Ar‐H), 12.69 (s, 1H, NH), 15.02 (s, 1H, COOH).
C
121.04, 135.25, 165.31, 174.24. HRMS (EI): calcd for
NMR (101 MHz, DMSO‐d ): δ = 57.83, 97.76, 102.03,
+
6
C H N O Br [M ] 213.9378; found: 213.9380.
6
3 2 2
1
+
40.68, 163.77, 166.42, 172.28. MS (ESI): m/z = 170 [M
H] .
+
[22]
4
1
.2.4 | 5‐Bromo‐4‐hydroxy‐1‐methyl‐2‐oxo‐
,2‐dihydropyridine‐3‐carbonitrile (2d)
4
.2 | Typical procedure for demethylation
of 3‐cyano‐4‐methoxy‐2‐pyridones induced
by DABCO
White solid, yield: 87%, mp 246°C to 248°C. IR νmax
=
3426 (OH), 2218 (CN), 1723 (C═O), 1534‐1467
−
1
1
(
─CH═CH─), 1356 (CH )cm ; H NMR (400 MHz,
3
A mixture of 4‐hydroxy‐2‐pyridones (5 mmol), DABCO (5
mmol) in DMF (10 mL) was stirred at 90°C for 6 hours.
The reaction was monitored by TLC analysis. After the
completion of the reaction, the reaction mixture was
cooled to room temperature, and water (30 mL) was
added. The reaction mixture was adjust pH to 4 to 5 with
DMSO‐d ): δ = 3.36 (s, 3H, NCH ), 8.31 (s, 1H, Ar‐H),
6
3
13
9
.69 (s, 1H, OH); C NMR (101 MHz, DMSO‐d ): δ =
6
3
6.79, 86.86, 92.33, 115.73, 144.99, 161.37, 168.86. HRMS
+
(
EI): m/z [M ] calcd for C H N O Br: 227.9534; found:
6
3 2 2
227.9529.
2
N HCl solution. The precipitate was filtrated and recrys-
4
.2.5 | 1‐N‐Butyl‐4‐hydroxy‐2‐oxo‐1,2‐
tallized from ethanol to yield specified product.
dihydropyridine‐3‐carbonitrile (2e)
4
.2.1 | 4‐Hydroxy‐2‐oxo‐1,2‐
White solid, yield: 93%, mp 185°C to 187°C. IR νmax =
dihydropyridine‐3‐carbonitrile (2a)
3241 (OH), 2244 (CN), 1645 (C═O), 1594‐1485
−
1 1
(
─CH═CH─), 1441 (CH ), 1392 (CH ) cm ; H NMR
2 3
White solid, yield: 95%, mp 154°C to 156°C. IR νmax
=
(400 MHz, DMSO‐d ): δ = 0.89 (t, J = 8.0 Hz, 2H); 1.24
6
3
(
6
427 (OH), 2208 (CN), 1615 (C═O), 1569‐1513
(p, J = 8.0 Hz, 1H), 1.56 (p, J = 8.0 Hz, 1H), 3.82(t, J =
−
1 1
─CH═CH─) cm . H NMR (400 MHz, DMSO‐d ): δ =
7.2 Hz, 1H), 6.05(d, J = 7.6 Hz, 1H), 7.84 (d, J = 7.6 Hz,
6
13
.59 (d, J = 8.0 Hz, 1H, Ar‐H), 7.52 (d, J = 8.0 Hz, 1H,
1H), 12.66 (s, 1H). C NMR (101 MHz, DMSO‐d ): δ =
6

10
LI ET AL.
1
1
4.01, 19.58, 31.18, 48.44, 85.76, 98.41, 115.60, 144.33,
61.52, 172.41. MS (ESI): m/z [M + H] calcd for
4.2.9 | Ethyl 2‐(3‐cyano‐4‐hydroxy‐2‐
oxopyridin‐1(2H)‐yl)acetate (2i)
+
C H N O : 193.0972; found: 193.0975.
11
12 2 2
White solid, yield: 90%, mp 210°C to 212°C. IR νmax
=
1
726 (C═O), 1650(C═O), 1560‐1476 (─CH═CH─), 1392
−
1
1
(
CH2), 1375 (CH3) cm ;
H
NMR (400 MHz,
4
.2.6 | 1‐(4‐Benzyl)‐4‐hydroxy‐2‐oxo‐1,2‐
DMSO‐d
= 8.0 Hz, 2H, CH
6
): δ = 1.21 (t, J = 8.0 Hz, 3H, CH
), 4.66 (s, 2H, CH ), 6.12 (d, J = 8.0
Hz, 1H, Ar‐H), 7.82 (d, J = 8.0 Hz, 1H, Ar‐H), 12.91 (s,
3
), 4.14 (q, J
dihydropyridine‐3‐carbonitrile (2f)
2
2
13
White solid, yield: 92%, mp 227°C to 229°C. IR νmax
=
1H, OH). C NMR (101 MHz, DMSO‐d ): δ = 13.98,
6
3
436 (OH), 3065 (═C─H aromtic), 2212 (CN), 1643
49.54, 61.12, 85.00, 98.43, 114.73, 144.32, 161.02, 167.81,
+
(C═O), 1595‐1520 (─CH═CH─), 1452 (CH ), 1356
172.73. MS (ESI): m/z [M + H] calcd for C H N O :
2
11 110
2
4
−
1 1
(CH ) cm . H NMR (400 MHz, DMSO‐d ): δ = 5.05 (s,
223.0713; found: 223.0712.
3
6
2
5
H, CH ), 6.09 (d, J = 8.0 Hz, 1H, Ar‐H), 7.26‐7.29 (m,
2
H, Ar‐H), 7.95 (d, J = 8.0 Hz, 1H, Ar‐H), 12.78 (s, 1H,
13
4.2.10 | 4‐Hydroxy‐2‐oxo‐1‐(2‐oxo‐2‐
phenylethyl)‐1,2‐dihydropyridine‐3‐
carbonitrile (2j)
OH). C NMR (101 MHz, DMSO‐d ): δ = 51.40, 83.53,
6
9
9.06, 115.62, 128.10, 129.10, 129.14, 137.60, 144.48,
+
1
61.82, 172.97. HRMS (EI): m/z [M ] calcd for
C H N O : 226.0744; found: 226.0742.
13
10 2 2
White solid, yield: 84%, mp 271°C to 273°C.IR νmax
=
1
687 (C═O), 1658 (C═O), 1565‐1472 (─CH═CH─), 1393
−
1
1
(
CH2), 1339 (CH3) cm ;
H
NMR (600 MHz,
DMSO‐d ): δ = 5.49 (s, 2H, CH ), 6.17 (d, J = 8.0 Hz,
6
2
4
.2.7 | 4‐Hydroxy‐1‐(4‐methoxybenzyl)‐2‐
1
1
8
H), 7.61 (t, J = 8.0 Hz, 2H, Ar‐H), 7.73 (t, J = 8.0 Hz,
oxo‐1,2‐dihydropyridine‐3‐carbonitrile (2g)
H, Ar‐H), 7.81 (d, J = 8.0 Hz, 1H, Ar‐H), 8.05 (d, J =
13
.0 Hz, 2H, Ar‐H), 12.89 (s, 1H, OH). C NMR (151
White solid, yield: 86%, mp 238°C to 240°C. IR νmax
437 (OH), 2922‐2843 (═C─H aromtic), 2210 (CN), 1629
C═O), 1587‐1508 (─CH═CH─), 1440 (CH ), 1345
=
MHz, DMSO‐d ): δ = 54.95, 85.57, 98.80, 115.43, 128.48,
6
3
(
1
29.48, 134.63, 134.75, 145.19, 161.56, 173.12, 193.23. MS
2
+
(
ESI): m/z [M+H] calcd for C H N O : 255.0764;
15 10 2 3
−
1
1
(CH ) cm . H NMR (400 MHz, DMSO‐d ): δ = 3.73 (s,
3
6
found: 255.0766.
3
H, OCH ), 4.97 (s, 2H, CH ), 6.07 (d, J = 8.0 Hz, 1H,
3 2
Ar‐H), 6.90 (d, J = 8.0 Hz, 2H, Ar‐H), 7.24 (d, J = 8.0
Hz, 2H, Ar‐H), 7.93(d, J = 8.0 Hz, 1H, Ar‐H), 12.74 (s,
ACKNOWLEDGMENTS
13
1
5
1
H, OH). C NMR (101 MHz, DMSO‐d ): δ = 50.79,
6
We acknowledge financial support from the National
Natural Science Foundation of China (Grants 21072029)
and Shanghai Municipal Natural Science Foundation
5.58, 85.89, 98.91, 114.47, 115.48, 129.24, 129.84,
+
44.14, 159.31, 161.55, 172.57. HRMS (EI): m/z [M ]
calcd for C H N O : 256.0848; found: 256.0852.
14
12 2 3
(
Grants 10ZR1400700).
CONFLICT OF INTEREST
4
1
.2.8 | 4‐Hydroxy‐1‐(4‐nitrobenzyl)‐2‐oxo‐
,2‐dihydropyridine‐3‐carbonitrile (2h)
The authors declare no conflict of interest.
White solid, yield: 89%, mp 252°C to 254°C. IR νmax
=
ORCID
3
429 (OH), 3075‐2858 (═C─H aromtic), 2218 (CN), 1645
−
1
1
Sheng‐Yin Zhao https://orcid.org/0000-0002-5778-8068
(C═O), 1519‐1482 (─CH═CH─), 1388 (CH ) cm . H
2
NMR (400 MHz, DMSO‐d ): δ = 5.20 (s, 2H, CH ), 6.14
6
2
(d, J = 8.0 Hz, 1H, Ar‐H), 7.49 (d, J = 8.0 Hz, 2H, Ar‐
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13 9 3 4
2
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