Synthesis of 2,3-Dihydro-4-pyridones and 4-Pyridones by the Cyclization Reaction of Ester-Tethered Enaminones

Article abstract of DOI:10.1021/acs.joc.0c01537

2,3-Dihydro-4-pyridone skeleton is an important building block in organic synthesis because it features several reaction sites with nucleophilic or electrophilic properties. Herein, we disclose a method for its formation by intramolecular cyclization of ester-tethered enaminones, which can easily be synthesized from readily available materials, such as amines, activated alkynes, and activated alkenes. 2,3-Dihydro-4-pyridones have been isolated in 41-90% yields. We also demonstrate the transformation of these heterocycles into another important class of compounds, 4-pyridones, by utilizing 2,3,5,6-tetrachloro-p-benzoquinone (chloranil) as an oxidizing agent. The latter products were isolated in 65-94% yields.

Full text of DOI:10.1021/acs.joc.0c01537

pubs.acs.org/joc
Article
Synthesis of 2,3-Dihydro-4-pyridones and 4‑Pyridones by the
Cyclization Reaction of Ester-Tethered Enaminones
́
́
Milovan Stojanovic,* Slobodan Bugarski, and Marija Baranac-Stojanovic*
Cite This: https://dx.doi.org/10.1021/acs.joc.0c01537
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: 2,3-Dihydro-4-pyridone skeleton is an important
building block in organic synthesis because it features several
reaction sites with nucleophilic or electrophilic properties. Herein,
we disclose a method for its formation by intramolecular
cyclization of ester-tethered enaminones, which can easily be
synthesized from readily available materials, such as amines,
activated alkynes, and activated alkenes. 2,3-Dihydro-4-pyridones
have been isolated in 41−90% yields. We also demonstrate the
transformation of these heterocycles into another important class
of compounds, 4-pyridones, by utilizing 2,3,5,6-tetrachloro-p-
benzoquinone (chloranil) as an oxidizing agent. The latter
products were isolated in 65−94% yields.
induced Dieckmann condensation leading to N-unsubstituted
2,3-dihydro-4-pyridone derivatives,16b cyclization of in situ
formed ester group-containing enaminone with aldehydes,16c
the recently reported cyclization of amide group-containing
enaminones with aldehydes,16d and cyclization of ketenes
generated from diazoketones.16e,f
INTRODUCTION
■
Cyclic enaminones, 2,3-dihydro-4-pyridinones, are versatile
and important synthetic intermediates owing to their stability,
nucleophilicity, and electrophilicity arising from the push−
pull-type electron delocalization. They can undergo a variety of
chemical transformations, such as 1,2- and 1,4-addition,
cycloaddition, N- or O-functionalization, direct formation of
the C−C bond, and reduction, and are widely used for the
synthesis of various nitrogen-containing compounds and
alkaloids.1,2 They also have the potential to be used as
bioactive compounds.3 2,3-Dihydro-4-pyridones are exper-
imentally accessible via two main routes: chemical modifica-
tion of a preformed nitrogen heterocycle and de novo
construction of the heterocycle usually by the intramolecular
cyclization of an acyclic intermediate. The first approach
involves the addition of organometallic reagents to N-acyl salts
of 4-methoxypyridine, developed by Comins,2de.g.,4 dehydro-
genation of the corresponding saturated heterocycle,5 con-
jugate addition of the Grignard reagent on N-carbamoyl-4-
pyridones,6 and reaction of 2,3-dihydropyran-4-ones with
ammonia and primary amines.7 The second approach includes
reactions of imines with dienes;8 cyclizations of primary
amines with α,ß-unsaturated-1,3-diketones,9 dienones,10 and
α-alkenoyl ketene dithioacetals;11 cyclizations of nitrogen-
containing ynones;3,12 reactions of amino esters with β-keto
esters;13 [5 + 1] cycloaddition of N-formylmethyl-substituted
tertiary enamides to isocyanides;14 [4 + 2] cycloaddition of 3-
phenylcyclobutanones with nitriles;15 and cyclizations involv-
ing enaminones.16
There is, obviously, a great and continuing interest in the
development of novel methods for the synthesis of 2,3-
dihydro-4-pyridones, either by modifying an azacycle or by
exploring new ring-closing reactions. As part of our project is
directed toward the synthesis of enaminones and their
utilization as synthetic intermediates, we wish to report the
synthesis of 2,3-dihydro-4-pyridones via an intramolecular
cyclization involving the C−C bond formation (Figure 1). The
open-chain enaminone, used as a precursor for the heterocycle,
resembles that of ref 16b (prepared from β-amino esters and β-
keto esters) but cannot be simply cyclized under basic
conditions17 because it lacks the acidic N−H group of the
enaminone moiety enabling carbanion formation. Instead, the
reaction has to be based on the nucleophilicity of the olefinic
carbon atom and the cyclization leads to a N-substituted
dihydropyridone ring.
Received: June 29, 2020
Examples of the latter synthetic methods are depicted in
Figure 1. They are based on the reaction of preformed
enaminones with α,β-unsaturated acid chlorides,16a base-
https://dx.doi.org/10.1021/acs.joc.0c01537
© XXXX American Chemical Society
J. Org. Chem. XXXX, XXX, XXX−XXX
A

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
the nitrogen atom, it can give rise to two regioisomers 1 and 4
upon reaction with another mole of ethyl propiolate. Thus, an
important task was to achieve the chemoselectivity of this
reaction. When the reaction was performed in EtOH at rt, only
enaminone 3 was formed (Table 1, entry 1). Increasing the
temperature to the bp of EtOH resulted in the isolation of
conjugated diene 4 as the sole product, in good yield (75%,
entry 2). We then examined reactions at elevated temperatures
in other solvents, such as more polar water, nonpolar toluene,
and polar but aprotic acetonitrile. In all cases, only carbon
atom was alkenylated, but less efficiently than in EtOH (entries
3−5). Next, we included a base in the reaction mixture to
improve the nucleophilicity of the nitrogen atom but that of
the α-carbon atom was improved, too. A base can be used in
an equimolar or a submolar quantity since it can be
regenerated during the reaction. The combinations EtONa/
EtOH and K2CO3/dimethylformamide (DMF) at rt resulted
in complex mixtures (entries 6 and 7). To our delight, a
complete reversion of chemoselectivity took place when 0.5
mol of Cs2CO3 was used in DMF at rt and N,N-dialkenyl
product 1 was isolated in 51% yield, with no trace of 4 (entry
8). An increase in temperature decreased the reaction time to
only 5 min and increased the yield of 1 to 69% (entry 9). The
use of less polar solvents at elevated temperatures, tetrahy-
drofuran (THF) and toluene, decreased both chemoselectivity
and the overall reaction yield (entries 10 and 11), and the use
of more polar dimethyl sulfoxide (DMSO) gave almost the
same result (entry 12). We also tried to substitute DMF with
similarly polar but more volatile acetonitrile, and this
combination gave the highest isolated yield of 1 within only
5 min (85%, entry 13). With a lower quantity of Cs2CO3 (0.3
equiv), the yield decreased to 65% (entry 14), while an
increase in its quantity (0.75 equiv) gave a slightly lower yield
(entry 15). A test reaction without the solvent resulted in
enaminone 3 as the only product (entry 16).
It should be noted that compounds of structure 4 were used
as substrates for cyclization reactions that yielded biaryl-2-
carbaldehydes,18 1,2-dihydropyridines,19 2-pyridinones,20 and
pyrroles,21 and we recently reported metal-free and solvent-
free conditions for their synthesis from aliphatic amines and
weakly nucleophilic aromatic amines.22 However, structure 1 is
less common. A few examples involve N-trimethylsilyloxy
derivatives (R = Me3SiO) obtained by silylation of β-
substituted aliphatic nitro compounds,23 N-heteroaryl deriva-
tives formed by the reaction of annelated 2-aminothiophene
with methyl propiolate in refluxing toluene,24 bis-
(chlorodifluoromethyl)keto derivatives (ClF2CO instead of
CO2Et in 1) formed by the self condenzation of the
corresponding enamino ketone under basic conditions,25 and
mixed keto−ester derivatives obtained by the reaction of
enamino ketone with ethyl propiolate in the presence of a
base.26,27 This unsymmetrical dialkenyl amine could rearrange
to polysubstituted conjugated dienes26 or afford spirooxindoles
Figure 1. Synthetic approaches to 2,3-dihydro-4-pyridones using
enaminones as their precursors.
RESULTS AND DISCUSSION
■
We envisioned to obtain the open-chain precursor 2 from
simple and commercially available reagents, an amine and an
activated alkyne (ethyl propiolate), in two steps (Figure 2). In
the first step, the amine would react with 2 equiv of ethyl
propiolate to give N,N-dialkenyl product 1, which would give 2
after the selective reduction of only one CC double bond.
In fact, when an amine reacts with 2 mol of ethyl propiolate,
the first product to be formed is enaminone 3 (Table 1). Since
it possesses two nucleophilic centers, the α-carbon atom and
Figure 2. Our synthetic approach to acyclic intermediate 2.
B
https://dx.doi.org/10.1021/acs.joc.0c01537
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a b
,
Table 1. Optimization of Reaction Conditions for the Synthesis of N,N-Dialkenyl Compound 1
c
entry
solvent
base (equiv)
reaction temperature (°C)
reaction time
products and yields (%)
d
1
2
3
4
5
6
7
8
EtOH
EtOH
H2O
PhMe
MeCN
EtOH
DMF
DMF
DMF
THF
PhMe
DMSO
MeCN
MeCN
MeCN
25
78
100
100
82
25
25
25
100
66
100
100
82
82
82
10 h
4 h
8 h
12 h
8 h
10 h
10 h
1 h
5 min
20 min
20 min
5 min
5 min
5 min
5 min
3
4 (75)
4 (41)
4 (58)
4 (70)
complex mixture
complex mixture
1 (51)
EtONa (1.0)
K2CO3 (1.0)
Cs2CO3 (0.5)
Cs2CO3 (0.5)
Cs2CO3 (0.5)
Cs2CO3 (0.5)
Cs2CO3 (0.5)
Cs2CO3 (0.5)
Cs2CO3 (0.3)
Cs2CO3 (0.75)
Cs2CO3 (0.5)
9
1 (69)
10
11
12
13
14
15
16
1 (12) 4 (6)
1 (12) 4 (12)
1 (71)
1 (85)
1 (65)
1 (75)
d
25
1 h
3
a
b
c
d
R = Bn. A slight excess of ethyl propiolate (2.5 equiv) was used in each reaction. Isolated yields. Identified by thin-layer chromatography
(TLC).
Table 2. Synthesis of Compounds 2 by the Sequence Shown in the Scheme
a
entry
R
product
1a
1b
1c
1d
1e
1f
1g
no product
no product
no product
no product
yield
product
yield
1
2
3
4
5
6
7
8
Bn
85
59
55
32
55
58
52
2a
2b
2c
2d
2e
2f
80
77
98
80
92
65
56
BnCH2
allyl
Me
n-Pr
n-hexyl
i-Bu
i-Pr
Cy
t-Bu
Ph
2g
9
10
11
a
Isolated yields (%).
upon treatment with isatin.27 Obviously, the synthetic
potential of structure 1 has yet to be disclosed.
reaction intermediate, underwent exclusive alkenylation at the
nitrogen atom, giving rise to N,N-dialkenyl product 1. Our
density functional theory (DFT) calculations of Fukui indices,
showing the most nucleophilic and electrophilic sites in a
molecule, revealed that in both neutral and anionic 3 the
nitrogen atom is almost twice more nucleophilic as the α-
carbon atom. In addition, calculations suggested that structure
4 (R = Bn) is thermodynamically more stable than structure 1
(R = Bn) by 3.13 kcal/mol at the B3LYP 6-31G(d) level of
Thus, we used the optimized reaction conditions shown in
Table 1, entry 13, to synthesize a series of compounds 1, which
were isolated in 32−85% yield (Table 2). We also demonstrate
that these compounds can be selectively reduced to
compounds 2 by Mg/HgCl2 in methanol,28 in 56−98% yields
(Table 2). Mechanistic details of both steps are depicted in
Figure 3. Deprotonated enaminone 3, formed as the first
C
https://dx.doi.org/10.1021/acs.joc.0c01537
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Figure 3. Mechanistic details of the synthesis of compounds 2 from an amine and ethyl propiolate.
theory. These results pointed to kinetic and thermodynamic
control as the origin of chemoselectivity reversal when going
from neutral to basic conditions. Thus, under neutral
conditions reversibility of reaction allowed thermodynamic
control, while in basic conditions irreversible formation of 1
was kinetically controlled.29 The selectivity of the following
reduction step can be explained by the enhanced push−pull
electronic delocalization in product 2, compared to 1 in which
nitrogen lone pair delocalizes into two CC double bonds, but
into only one in 2. This change in electronic distribution
prevented the reduction of another double bond. It should be
mentioned that the ester moiety bonded to the saturated
carbon atom underwent a transesterification reaction, while
another one was protected from the nucleophilic attack due to
the increased electron density arising from the push−pull
electron delocalization.
However, the first step of this reaction sequence showed
sensitivity to the steric and electronic effects of the starting
amine. Thus, no product 1 was obtained when R was a
sterically more demanding group (i-Pr, Cy, and t-Bu) and
when R was an aromatic group that decreases the
nucleophilicity of the nitrogen atom by −I and −R effects,
(Table 2, entries 8−11). Therefore, double alkenylation was
feasible for amines containing short-chain (entries 4 and 5)
and long-chain primary alkyl groups (entry 6), which could
also have a branch at the β-carbon (Table 2, entry 7), double
bond (entry 3), and aromatic ring (entries 1 and 2).
Thus, we explored another route to the open-chain
precursor 2, in which we replaced the CC triple bond with
the more electrophilic CC double bond in the second step of
the Michael addition reactions, also with no need for the
reduction step (Table 3). Accordingly, enaminones 5, formed
in the first step, were allowed to react with ethyl acrylate under
basic and solvent-free conditions. In this way, products 2,
containing a secondary alkyl group as an R substituent, were
easily obtained (entries 2−4). The reaction also worked for R
= primary alkyl group and allowed one-pot synthesis of 2a′
(entry 1). We next examined the tolerance of the reaction to
the presence of functional groups, such as halogen, amide,
amine, and hydroxy (entries 5−8). In all cases, compounds 2
were isolated. For ethylenediamine as the starting amine,
reaction conditions were adopted to yield the bis-alkenylated/
alkylated product, while in the case of OH functionality,
product 2 was isolated as 2-ethoxycarbonylethyl ether,
resulting from the OH group addition to ethyl acrylate.
Replacement of the ethyl ester of propiolic acid with the larger
and more hydrophobic cyclohexyl ester, or the use of ketone
(3-butyn-2-one) as the activated alkyne, yielded the corre-
sponding products 2 (entries 9 and 10). Finally, the synthesis
Table 3. Synthesis of Compounds 2 by the Sequence Shown
in the Scheme
a
entry
R
R1
R2
product
yield
1
2
3
4
5
6
7
8
Bn
Cy
i-Pr
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OCy
Me
H
H
H
H
H
H
H
H
H
H
2a′
92
62
53
83
73
67
2h
2i
2j
2k
2l
2m
2n
2o
2p
Me(Ph)CH
ClCH2CH2
AcNHCH2CH2
H2NCH2CH2
HOCH2CH2
Bn
Bn
Bn
Bn
b
47
48
c
9
63
68
46
10
11
12
OEt
OEt
CO2Et
Me
2q
no product
a
b
Isolated yields (%). 2.4 equiv of alkyne and 3.0 equiv of alkene were
c
used to allow bis-alkenylation and bis-alkylation. Isolated as 2-
ethoxycarbonylethyl ether.
of 2 could also be run with diethyl acetylenedicarboxylate (R2
= CO2Et, entry 11) but failed for R2 = Me (entry 12). The
yields of compounds 2 ranged from 46 to 92%.
While intermediates 5 are easily obtainable from aliphatic
amines, this is not the case with aromatic amines, which is due
to their inherent weak nucleophilicity, making them as poor
Michael donors.30 Even though the addition of an aromatic
amine onto an activated alkyne is made possible under solvent-
free conditions in a planetary ball mill, with ZrO2 milling balls
and SiO2 added,31 our experiments showed that the solvent-
free, silica gel-mediated reaction is accompanied by the
formation of diene 4 (Table 1), which can become the
ultimate product with both aliphatic and aromatic amines.22
Furthermore, since the nucleophilicity of the nitrogen atom
decreases further in enaminones due to the extended electron
delocalization involving the aromatic ring and the double
D
https://dx.doi.org/10.1021/acs.joc.0c01537
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Table 4. Synthesis of Compounds 2 from Aromatic Amines
a
entry
R
product
yield
product
yield
1
2
3
C6H5
p-MeOC6H4
p-ClC6H4
6a
6b
6c
60
80
69
2r
2s
2t
70
85
46
a
Isolated yields (%).
Figure 4. Mechanistic details of the formation of 2,3-dihydro-4-pyridones 9 by the cyclization of compound 2.
bond, we did not expect that 5 would show any tendency to
react with ethyl acrylate even under basic conditions.
delocalization. The resulting salt 7 was allowed to react with
acetic anhydride, and the obtained mixed anhydride 8 readily
cyclized to the final product 9. All substrates provided products
in good to high yields (41−90%, Table 5), except 2m and 2n.
Therefore, we envisioned another strategy to obtain
precursor 2 from aromatic amines to reverse the above-
described reaction sequence. In this way, the nucleophilicity of
the nitrogen atom would be improved by alkylation. The thus-
obtained secondary amine would be treated with activated
alkyne (ethyl propiolate). To accelerate the reactions, both
steps were performed on the surface of silica gel, with no
solvent added (Table 4; for details, see the Experimental
Section). Such conditions were primarily chosen on the basis
of our previous results, showing that silica gel activates amine
and activated alkyne toward the Michael addition reaction,22
although there are also reports on the use of silica gel as a
promoter of Michael additions of amines to electron-poor
alkenes.30c,32 Since silica gel is nontoxic, inexpensive, and
present in almost every organic chemistry laboratory, it gains
popularity as a promoter of various kinds of reactions.33 The
applied reaction sequence afforded compounds 2 (Table 4)
from activated aromatic amine (p-methoxyaniline), unsub-
stituted one (aniline), and deactivated aromatic amine (p-
chloroaniline). It should be noted that when this reaction
sequence was applied to aliphatic amines, a mixture of mono-
and dialkylated amines was formed in the first step.
Having synthesized the open-chain precursors 2, containing
primary, secondary, and functionalized aliphatic R moieties
and (substituted)aromatic R moieties, we came to the last step
of the synthesis of 2,3-dihydro-4-pyridone derivatives. Even
though the olefinic α-carbon atom of the enaminone fragment
is electron-rich, we assumed that the ester functionality is not
electrophilic enough to be attacked by it. Therefore, we first
tried to perform the cyclization step under Baylis−Hillman
reaction conditions,34 by which the α-carbon atom would be
transformed into a carbanion after the addition of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) to the electrophilic β-
carbon atom. However, no cyclized product was obtained in
CHCl3 as the solvent at rt or reflux temperature. In the next
attempt, the ester group was activated by the formation of a
mixed anhydride, as shown in Figure 4. First, selective base
hydrolysis of one ester moiety, bonded to the saturated carbon
atom, was performed, while another one remained intact owing
to its attenuated electrophilicity due to the push−pull electron
Table 5. Synthesis of 2,3-Dihydro-4-pyridones 9
a
entry
R
R1
R2
R3
product yield
1
2
3
4
5
6
7
8
Bn
BnCH2
allyl
Me
n-Pr
n-Hexyl
i-Bu
Cy
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OCy
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Et
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9o
9p
9q
9r
9s
9t
91
89
87
83
80
86
82
84
90
55
59
41
75
74
64
45
63
48
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
9
i-Pr
10
11
12
13
14
15
16
17
18
Me(Ph)CH
ClCH2CH2
AcNHCH2CH2
Bn
Bn
Bn
C6H5
p-MeOC6H4
p-ClC6H4
OEt
OEt
OEt
OEt
CO2Et
H
H
H
a
Isolated yields (%).
When substrate 2m was employed only a complex mixture was
obtained. In the case of 2n, hydrolysis liberated two
carboxylate groups, which both were activated toward the
nucleophilic attack. Although the formation of the six-
membered ring product was much more favored than any
intramolecular reaction of another anhydride functionality, no
signals of the 2,3-dihydro-4-pyridone skeleton were observed
in the NMR spectra of the crude reaction mixture.
E
https://dx.doi.org/10.1021/acs.joc.0c01537
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
To demonstrate the applicability of the presented method to
the gram-scale synthesis of 2,3-dihydropyridines, compound
2a′ was prepared from 1.00 g of benzylamine in 86% yield and
cyclized to 9a in 84% yield (see the Experimental Section).
We also wished to explore the synthetic utility of the
synthesized compounds 9 by oxidizing them into 4-pyridones,
which are another class of useful intermediates in organic
synthesis35 and important subunits in biologically active
compounds.36 Methods for their synthesis include reactions
of pyrons with primary amines,37 self-condensation of N-aryl
acetoamides,38 NIS-promoted cyclizations of diynones,39
cyclizations of 1,5-bis(dimethylamino)penta-1,4-dien-3-ones
with amines,40 [4 + 2] cycloaddition of 3-aminocyclobute-
nones with electron-deficient alkynes,41 iridium-catalyzed
alkenylation of 4-hydroxypyridones,42 and oxidation of
dihydropyridone with iodine.16d
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out under
standard conditions. The quoted reaction temperatures refer to the
temperature of an oil bath. All materials were purchased from
commercial suppliers and used without further purification. All
solvents were distilled before use. Silica gel 60 (0.063−0.200 mm,
Merck) was used for solvent-free reactions and column chromatog-
raphy. Thin-layer chromatography was performed on precoated silica
gel 60 F254 (Merck) and on silica gel 60 Å, 12-26 ICN Biomedicals.
TLC spots were visualized by UV light and iodine vapor for the
former and by iodine vapor for the latter. Melting points were
determined on a Stuart SMP10 apparatus. IR spectra were recorded
on a Thermo Scientific Nicolet 6700 FT-IR spectrometer using the
ATR technique. NMR spectra were recorded in CDCl3, or in DMSO-
d6, on a Bruker Avance III spectrometer, operating at 500.3 MHz for
1H and 125.8 MHz for 13C, or on a Bruker Ascend 400 spectrometer,
1
operating at 400.1 MHz for H and 100.6 MHz for 13C. Chemical
We first explored the often used 2,3-dichloro-5,6-dicyano-p-
benzoquinone (DDQ) as the oxidizing agent, but it did not
provide the desired product from compound 9a. Then, we
tested another agent 2,3,5,6-tetrachloro-p-benzoquinone,
known as chloranil. When applied in toluene at 100 °C, it
oxidized the selected heterocycles 9a, 9j, 9l, and 9r to 4-
pyridones 10a−10d in good to high yields (Table 6). The
shifts are given as δ values in ppm and are referenced to the residual
proton resonance of CHCl3 at 7.26 ppm, or of DMSO-d5 at 2.50 ppm,
and to the solvent carbon resonance of CDCl3 at 77.0 ppm, or of
DMSO-d6 at 39.5 ppm. Coupling constants J are given in hertz. High-
resolution mass spectrometry (HRMS) spectra were recorded only for
new compounds on an LTQ Orbitrap XL mass spectrometer
(Thermo Fisher Scientific), with heated electrospray ionization
(HESI) as an ion source.
Synthesis of Cyclohexyl Propiolate. This is the only starting
material that was not commercially available and was synthesized
according to the following procedure. To a solution of propiolic acid
(176.4 mg, 2.52 mmol) and cyclohexanol (323 mg, 3.22 mmol) in
toluene (5 mL) was added conc. H2SO4 (150 μL), and the mixture
was heated at 100 °C for 30 min. The dark-colored solution was
cooled to rt, and CH2Cl2 (20 mL) was added. It was then washed
with 5% aqueous NaHCO3 and water and dried over anhydrous
Na2SO4. After filtration, the solvent was evaporated under reduced
pressure and the residue was purified by column chromatography on
silica gel using PE (bp 40−60 °C)/EtOAc (100:0 to 95:5) to give
287.0 mg (75%) of the ester as a colourless liquid. IR: ν 3263, 2118,
1711, 1235 cm−1; 1H NMR (500.3 MHz, CDCl3):43 δ 4.84−4.89 (m,
1H), 2.85 (s, 1H), 1.87−1.91 (m, 2H), 1.73−1.78 (m, 2H), 1.22−
1.56 (m, 6H); 13C{1H} NMR (125.8 MHz, CDCl3): δ 152.2, 75.3,
75.2, 73.9, 31.3, 25.1, 23.6.
General Procedure for the Synthesis of Dialkenyl Amines 1.
To a solution of amine (1.0 mmol) and ethyl propiolate (2.5 mmol)
in acetonitrile (1.2 mL) was added Cs2CO3 (0.5 mmol), and the
mixture was heated at 70 °C for 5−10 min. After cooling to rt, the
reaction mixture was filtered, the solvent was evaporated under
reduced pressure, and the crude product was purified by column
chromatography on silica gel using a gradient of PE (bp 40−60 °C)/
EtOAc as the eluent.
(2E,2′E)-Diethyl 3,3′-(Benzylazanediyl)diacrylate (1a). Reaction
time: 10 min; eluent: PE (bp 40−60 °C)/EtOAc (100:0 to 80:20, v/
v); White crystals, mp 90−91 °C; 258.0 mg, 85% yield; IR (ATR):
1712, 1685, 1604, 1276, 1142 cm−1; 1H NMR (500.3 MHz, CDCl3):
δ 7.69 (d, 2H, J = 13.5 Hz), 7.33 (t, 2H, J = 7.5 Hz), 7.27 (t, 1H, J =
7.5 Hz), 7.13 (d, 2H, J = 7.0 Hz), 5.15 (d, 2H, J = 13.5 Hz), 4.15 (q,
4H, J = 7.0 Hz), 4.64 (s, 2H), 1.25 (t, 6H, J = 7.0 Hz); 13C{1H} NMR
(125.8 MHz, CDCl3): δ 167.4, 147.4, 133.5, 129.0, 127.8, 126.0, 96.8,
60.0, 50.3, 14.3; HRMS (HESI) m/z: [M + H]+ calcd for C17H22NO4
304.1549; Found 304.1543.
Table 6. Oxidation of 2,3-Dihydro-4-pyridones 9 to 4-
Pyridones 10
a
entry
R
product
yield
1
2
3
4
Bn
10a
10b
10c
10d
80
70
94
65
Me(Ph)CH
AcNHCH2CH2
C6H5
a
Isolated yields (%).
selected set of dihydropyridones showed that compounds 10,
having primary, secondary, functionalized alkyl and aryl
substituents at the nitrogen atom, can be obtained by this
procedure.
CONCLUSIONS
■
In summary, we have introduced a method for the synthesis of
N,C-di- or trisubstituted 2,3-dihydro-4-pyridones involving
intramolecular cyclization of an ester-tethered enaminone,
which can easily be prepared in two steps from amines,
activated alkynes, and activated alkenes. The method tolerates
weakly nucleophilic functional groups, such as amide, halogen,
CC double bond, and aryl group, and is applicable for amines
having primary or secondary alkyl substituents and also for
weakly nucleophilic aromatic amines. The synthesis starts from
readily available materials and is operationally simple. Further
oxidation of the synthesized dihydro-4-pyridones to another
class of synthetically and biologically important compounds, 4-
pyridones, was achieved using chloranil as an oxidizing agent.
(2E,2′E)-Diethyl 3,3′-(Phenethylazanediyl)diacrylate (1b). Reac-
tion time: 5 min; eluent: PE (bp 40−60 °C)/EtOAc (100:0 to 80:20,
v/v); pale yellow crystals, mp 86−87 °C; 188.7 mg, 59% yield; IR
1
(ATR): 1706, 1650, 1600, 1230, 1132 cm−1; H NMR (500.3 MHz,
CDCl3): δ 1.30 (t, 6H, J = 7.0 Hz), 2.86−2.89 (m, 2H), 3.59−3.62
(m, 2H), 4.20 (q, 4H, J = 7.0 Hz), 7.51 (d, 2H, J = 13.5 Hz), 7.33 (t,
2H, J = 7.0 Hz), 7.26−7.27 (m, 1H), 7. 21 (d, 2H, J = 7.0 Hz), 5.19
(d, 2H, J = 13.5 Hz); 13C{1H} NMR (125.8 MHz, CDCl3): δ 167.5,
146.9, 137.2, 128.8, 128.6, 127.0, 95.9, 60.3, 48.0, 31.4, 14.4; HRMS
F
https://dx.doi.org/10.1021/acs.joc.0c01537
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(HESI) m/z: [M + Na]+ calcd for C18H23NO4Na 340.1525; Found
340.1525.
2H, J = 7.5 Hz), 4.67 (d, 1H, J = 13.0 Hz), 4.36 (s, 2H), 4.12 (q, 2H,
J = 7.0 Hz), 3.64 (s, 3H), 3.42, (broad s, 2H), 2.53 (t, 2H, J = 7.0
Hz), 1.25 (t, 3H, J = 7.0 Hz); 13C{1H} NMR (125.8 MHz, CDCl3): δ
171.6, 169.4, 151.6, 136.3, 128.8, 127.8, 127.2, 85.8, 59.0, 51.8, 50.6,
14.5; HRMS (HESI) m/z: [M + H]+ calcd for C16H22NO4 292.1549;
Found 292.1544.
(2E,2′E)-Diethyl 3,3′-(Allylazanediyl)diacrylate (1c). Reaction
time: 10 min; eluent: PE (bp 40−60 °C)/EtOAc (100:0 to 80:20,
v/v); white crystals, mp 83−84 °C; 140.2 mg, 55% yield; IR (ATR):
1705, 1651, 1600, 1269, 1139 cm−1; 1H NMR (500.3 MHz, CDCl3):
δ 7.56 (d, 2H, J = 13.5 Hz), 5.66−5.73 (m, 1H), 5.24−5.26 (m, 1H),
5.15−5.16 (m, 1H) and 5.14 (d, 2H, J = 13.5 Hz) (these two signals
are overlapped in the spectrum), 4.17 (q, 4H, J = 7.0 Hz), 4.03 (m,
2H), 1.27 (t, 6H, J = 7.0 Hz); 13C{1H} NMR (125.8 MHz, CDCl3): δ
167.5, 147.0, 128.3, 118.0, 96.4, 60.0, 48.9, 14.3; HRMS (HESI) m/z:
[M + H]+ calcd for C13H20NO4 254.1392; Found 254.1389.
(2E,2′E)-Diethyl 3,3′-(Methylazanediyl)diacrylate (1d). Methyl
amine (2 mmol) in THF (1.08 M) and ethyl propiolate (2.4
mmol) were allowed to react at rt for 24 h, and the solvent was
evaporated under reduced pressure. The obtained enamino ester was
dissolved in MeCN (1.8 mL), CsCO3 (0.8 mmol) and ethyl
propiolate (1.2 mmol) were added, and the mixture was refluxed
for 10 min.
Eluent: PE (bp 40−60 °C)/EtOAc (100:0 to 80:20, v/v); pale
yellow crystals, mp 94−95 °C; 145.3 mg, 32% yield; IR (ATR): 1705,
1653, 1601, 1240, 1173, 1090 cm−1; 1H NMR (500.3 MHz, CDCl3):
δ 7.54 (d, 2H, J = 13.5 Hz), 5.13 (d, 2H, J = 13.5 Hz), 4.16 (q, 4H, J
= 7.0 Hz), 2.98 (s, 3H), 1.26 (t, 6H, J = 7.0 Hz); 13C{1H} NMR
(125.8 MHz, CDCl3): δ 167.5, 147.9, 96.0, 60.0, 33.0, 14.4; HRMS
(HESI) m/z: [M + H]+ calcd for C11H18NO4 228.1236; Found
228.1233.
(E)-Ethyl 3-((3-Methoxy-3-oxopropyl)(phenethyl)amino)acrylate
(2b). Pale yellow oil, 118.3 mg, 77% yield; IR (ATR): 1737, 1688,
1
1610, 1253, 1138 cm−1; H NMR (400.1 MHz, CDCl3): δ 7.41 (d,
1H, J = 13.2 Hz), 7.32 (t, 2H, J = 7.2 Hz), 7.24 (t, 1H, J = 7.2 Hz),
7.18 (d, 2H, J = 7.2 Hz), 4.65 (d, 1H, J = 13.2 Hz), 4.15 (q, 2H, J =
6.8 Hz), 3.69 (s, 3H), 3.35−3.41 (m, 4H), 2.85 (t, 2H, J = 7.2 Hz),
2.53 (t, 2H, J = 6.8 Hz), 1.28 (t, 3H, J = 6.8 Hz); 13C{1H} NMR
(100.6 MHz, CDCl3): δ 171.6, 169.4, 150.7, 138.2, 128.7, 126.6, 85.6,
59.0, 51.8, 14.6; HRMS (HESI) m/z: [M + H]+ calcd for C17H24NO4
306.1705; Found 306.1699.
(E)-Ethyl 3-(Allyl(3-methoxy-3-oxopropyl)amino)acrylate (2c).
Pale yellow oil, 118.1 mg, 98% yield; IR (ATR): 1737, 1687, 1610,
1268, 1146 cm−1; 1H NMR (500.3 MHz, CDCl3): δ 7.36 (d, 1H, J =
13.5 Hz), 5.64−5.72 (m, 1H), 5.09−5.15 (m, 2H), 4.54 (d, 1H, J =
13.5 Hz), 4.05 (q, 2H, J = 7.0 Hz), 3.70 (d, 2H, J = 5.5 Hz), 3.62 (s,
3H), 3.39 (t, 2H, J = 7.0 Hz), 2.52 (t, 2H, J = 7.0 Hz), 1.18 (t, 3H, J =
7.0 Hz); 13C{1H} NMR (125.8 MHz, CDCl3): δ 171.4, 169.2, 150.9,
132.2, 117.9, 85.5, 58.8, 51.7, 31.8, 14.4; HRMS (HESI) m/z: [M +
H]+ calcd for C12H20NO4 242.1392; Found 242.1392.
(E)-Ethyl 3-((3-methoxy-3-oxopropyl)(methyl)amino)acrylate
(2d). Pale yellow oil, 86.5 mg, 80% yield; IR (ATR): 1734, 1667,
1608, 1226, 1157, 1028 cm−1; 1H NMR (500.3 MHz, CDCl3): δ 7.39
(d, 1H, J = 13.0 Hz), 4.50 (d, 1H, J = 13.0 Hz), 4.08 (q, 2H, J = 7.0
Hz), 3.65 (s, 3H), 3.44 (t, 2H, J = 7.0 Hz), 2.79 (broad s, 3H), 2.52
(t, 2H, J = 7.0 Hz), 1.21 (t, 3H, J = 7.0 Hz); 13C{1H} NMR (125.8
MHz, CDCl3): δ 171.4, 169.3, 151.8, 85.3, 58.8, 51.8, 14.5; HRMS
(HESI) m/z: [M + H]+ calcd for C10H18NO4 216.1236; Found
216.1236.
(2E,2′E)-Diethyl 3,3′-(Propylazanediyl)diacrylate (1e). Reaction
time: 10 min; eluent: PE (bp 40−60 °C)/EtOAc (100:0 to 80:20, v/
v); pale yellow crystals, mp 94−95 °C; 140.9 mg, 55% yield; IR
1
(ATR): 1711, 1688, 1604, 1262, 1175, 1113 cm−1; H NMR (500.3
MHz, CDCl3): δ 7.50 (d, 2H, J = 13.5 Hz), 5.13 (d, 2H, J = 13.5 Hz),
4.17 (q, 4H, J = 7.0 Hz), 3.34 (t, 2H, J = 7.5 Hz), 1.63 (sext, 2H, J =
7.5 Hz), 1.27 (t, 6H, J = 7.0 Hz), 0.94 (t, 3H, J = 7.5 Hz); 13C{1H}
NMR (125.8 MHz, CDCl3): δ 167.6, 147.3, 95.7, 60.0, 48.1, 18.6,
14.4, 11.2; HRMS (HESI) m/z: [M + H]+ calcd for C13H22NO4
256.1549; Found: 256.1548.
(E)-Ethyl 3-((3-Methoxy-3-oxopropyl)(propyl)amino)acrylate
(2e). Pale yellow oil, 111.6 mg, 92% yield; IR (ATR): 1738, 1687,
1
1610, 1259, 1144 cm−1; H NMR (500.3 MHz, CDCl3): δ 7.37 (d,
1H, J = 13.0 Hz), 4.53 (d, 1H, J = 13.0 Hz), 4.09 (q, 2H, J = 7.0 Hz),
3.66 (s, 3H), 3.41 (t, 2H, J = 7.0 Hz), 3.07 (broad signal, 2H), 2.55 (t,
2H, J = 7.0 Hz), 1.54 (sext, 2H, J = 7.5 Hz), 1.22 (t, 3H, J = 7.0 Hz),
0.86 (t, 3H, J = 7.5 Hz); 13C{1H} NMR (125.8 MHz, CDCl3): δ
171.6, 169.5, 151.1, 84.7, 58.8, 51.8, 14.5, 11.0; HRMS (HESI) m/z:
[M + H]+ calcd for C12H22NO4 244.1549 Found 244.1549.
(2E,2′E)-Diethyl 3,3′-(Hexylazanediyl)diacrylate (1f). Reaction
time: 5 min; eluent: PE (bp 40−60 °C)/EtOAc (100:0 to 80:20,
v/v); yellow oil; 173.7 mg, 58% yield; IR (ATR): 1706, 1653, 1598,
1157, 1111 cm−1; 1H NMR (400.1 MHz, CDCl3): δ 7.50 (d, 2H, J =
13.6 Hz), 5.14 (d, 2H, J = 13.6 Hz), 4.19 (q, 4H, J = 7.2 Hz), 3.37 (t,
2H, J = 8.0 Hz), 1.57−1.62 (m, 2H), 1.25−1.34 (m, 6H) and 1.29 (t,
6H, J = 7.2 Hz) (these two signals are overlapped in the spectrum),
0.89 (t, 3H, J = 6.8 Hz); 13C{1H} NMR (100.6 MHz, CDCl3): δ
167.6, 147.3, 95.6, 60.0, 46.7, 31.4, 26.6, 25.2, 22.5, 14.4, 13.9; HRMS
(HESI) m/z: [M + Na]+ calcd for C16H27NO4Na 320.1838; Found
320.1826.
(E)-Ethyl 3-(Hexyl(3-methoxy-3-oxopropyl)amino)acrylate (2f).
Pale yellow oil, 93.1 mg, 65% yield; IR (ATR): 1738, 1689, 1610,
1248, 1142 cm−1; 1H NMR (400.1 MHz, CDCl3): δ 7.39 (d, 1H, J =
13.2 Hz), 4.56 (d, 1H, J = 13.2 Hz), 4.12 (q, 2H, J = 7.2 Hz), 3.69 (s,
3H), 3.43 (t, 2H, J = 7.2 Hz), 3.12 (t, 2H, J = 7.2 Hz), 2.57 (t, 2H, J =
7.2 Hz), 1.51−1.55 (m, 2H), 1.25 (t, 3H, J = 7.2 Hz) and 1.23−1.28
(m, 6H) (these two signals are overlapped in the spectrum), 0.88 (t,
3H, J = 6.8 Hz); 13C{1H} NMR (100.6 MHz, CDCl3): δ 171.6, 169.6,
151.1, 84.9, 58.9, 51.8, 31.5, 26.4, 22.5, 14.6, 13.9; HRMS (HESI) m/
z: [M + H]+ calcd for C15H28NO4 286.2018; Found 286.2015.
(E)-Ethyl 3-(Isobutyl(3-methoxy-3-oxopropyl)amino)acrylate
(2g). Pale yellow oil, 72.1 mg, 56% yield; IR (ATR): 1739, 1689,
(2E,2′E)-Diethyl 3,3′-(Isobutylazanediyl)diacrylate (1g). Reaction
time: 10 min; eluent: PE (bp 40−60 °C)/EtOAc (100:0 to 80:20, v/
v); pale yellow crystals, mp 66−67 °C; 139.5 mg, 52% yield; IR
1
(ATR): 1707, 1650, 1598, 1274, 1170, 1110 cm−1; H NMR (500.3
MHz, CDCl3): δ 7.53 (d, 2H, J = 13.5 Hz), 5.15 (d, 2H, J = 14.0 Hz),
4.17 (q, 4H, J = 7.0 Hz), 3.22 (d, 2H, J = 7.5 Hz), 2.12 (m, 1H), 1.27
(t, 6H, J = 7.0 Hz), 0.92 (d, 6H, J = 7.0 Hz); 13C{1H} NMR (125.8
MHz, CDCl3): δ 167.6, 147.7, 96.2, 60.0, 54.3, 25.9, 20.2, 14.4;
HRMS (HESI) m/z: [M + H]+ calcd for C14H24NO4 270.1705;
Found 270.1709.
General Procedure for the Reduction of Dialkenyl Amines 1
to Compounds 2. To a solution of 1 (0.5 mmol) in dry MeOH (5
mL) were added Mg (5.0 mmol) and HgCl2 (0.05 mmol), and the
mixture was stirred at rt for 1 h. DCM (20 mL) was then added, and
the organic layer was washed with saturated aqueous NH4Cl (5 mL ×
3) and dried over anhydrous Na2SO4. After filtration, the solvent was
evaporated under reduced pressure. The obtained products 2 were
pure enough (NMR) to be used as such for the next step.
1
1610, 1143, 1119 cm−1; H NMR (500.3 MHz, CDCl3): δ 7.36 (d,
1H, J = 13.0 Hz), 4.54 (d, 1H, J = 13.0 Hz), 4.10 (q, 2H, J = 7.0 Hz),
3.66 (s, 3H), 3.41 (t, 2H, J = 7.0 Hz), 2.92 (d, 2H, J = 7.5 Hz), 2.56
(t, 2H, J = 7.0 Hz), 1.91 (broad s, 1H), 1.23 (t, 3H, J = 7.0 Hz), 0.86
(t, 6H, J = 7.0 Hz); 13C{1H} NMR (125.8 MHz, CDCl3): δ 171.7,
169.5, 151.4, 84.6, 58.9, 51.8, 27.6, 19.8, 14.6; HRMS (HESI) m/z:
[M + H]+ calcd for C13H24NO4 258.1705; Found 258.1706.
General Procedure for the Synthesis of Compounds 2 from
Aliphatic Amines, Activated Alkynes, and Ethyl Acrylate. To a
solution of amine (1.0 mmol) in DCM (2 mL) was added an
activated alkyne (1.2 mmol). The mixture was stirred at rt for 15 min,
and the solvent was evaporated under reduced pressure. Ethyl acrylate
(1.5 mmol) and Cs2CO3 (0.5 mmol) were then added, and the
mixture was stirred at rt until the completion of the reaction, checked
by TLC (10 min to 10 h). The obtained mixture was purified by
(E)-Ethyl 3-(Benzyl(3-methoxy-3-oxopropyl)amino)acrylate (2a).
Pale yellow oil; 116.0 mg, 80% yield; IR (ATR): 1737, 1688, 1612,
1256, 1144 cm−1; 1H NMR (500.3 MHz, CDCl3): δ 7.58 (d, 1H, J =
13.0 Hz), 7.33 (t, 2H, J = 7.5 Hz), 7.28 (t, 1H, J = 7.5 Hz), 7.18 (d,
G
https://dx.doi.org/10.1021/acs.joc.0c01537
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
column chromatography on silica gel using a gradient of PE (bp 40−
60 °C)/EtOAc as the eluent.
13C{1H} NMR (125.8 MHz, CDCl3): δ 171.3, 170.7, 169.4, 151.2,
85.7, 61.0, 59.1, 23.1, 14.5, 14.1; HRMS (HESI) m/z: [M + Na]+
calcd for C14H24N2O5Na 323.1583; Found 323.1572.
(E)-Ethyl 3-(Benzyl(3-methoxy-3-oxopropyl)amino)acrylate
(2a′). Reaction time: 15 min; eluent: PE/EtOAc (100:0 to 80:20,
v/v); pale yellow oil; 281.9 mg, 92% yield; IR (ATR): 1732, 1688,
(2E,2′E)-Diethyl 3,3′-(4,13-Dioxo-3,14-dioxa-7,10-diazahexade-
cane-7,10-diyl)diacrylate (2m). Reaction time: 0.5 h; eluent: PE/
EtOAc (100:0 to 30:70, v/v); pale yellow oil; 215.0 mg, 47% yield; IR
1
1612, 1255, 1144 cm−1; H NMR (500.3 MHz, CDCl3): δ 7.59 (d,
1
(ATR): 1732, 1687, 1610, 1260, 1143 cm−1; H NMR (500.3 MHz,
1H, J = 13.0 Hz), 7.33 (t, 2H, J = 7.0 Hz), 7.28 (t, 1H, J = 7.0 Hz),
7.18 (d, 2H, J = 7.0 Hz), 4.67 (d, 1H, J = 13.0 Hz), 4.36 (s, 2H), 4.13
(q, 2H, J = 7.0 Hz), 4.10 (q, 2H, J = 7.0 Hz), 3.64 (s, 3H), 3.42,
(broad s, 2H), 2.52 (t, 2H, J = 7.0 Hz), 1.25 (t, 3H, J = 7.0 Hz), 1.24
(t, 3H, J = 7.0 Hz); 13C{1H} NMR (125.8 MHz, CDCl3): δ 171.2,
169.5, 151.6, 136.3, 128.8, 127.8, 127.2, 85.8, 60.8, 59.0, 14.5, 14.1;
HRMS (HESI) m/z: [M + H]+ calcd for C17H24NO4 306.1705;
Found 306.1706.
CDCl3): δ 7.31 (d, 2H, J = 13.5 Hz), 4.59 (d, 2H, J = 13.5 Hz), 4.09−
4.15 (m, 8H), 3.41 (t, 4H, J = 6.5 Hz), 3.31 (s, 4H, integral value 3.01
in the spectrum), 2.54 (t, 4H, J = 6.5 Hz), 1.245 (t, 6H, J = 7.0 Hz)
and 1.240 (t, 6H, J = 7.0 Hz) (these two signals are overlapped in the
spectrum); 13C{1H} NMR (125.8 MHz, CDCl3): δ 171.1, 169.0,
150.4, 86.7, 61.0, 59.1, 14.5, 14.1; HRMS (HESI) m/z: [M + H]+
calcd for C22H37N2O8 457.2550; Found 457.2562.
(E)-Ethyl 3-(Cyclohexyl(3-ethoxy-3-oxopropyl)amino)acrylate
(2h). Reaction time: 2.5 h; eluent: PE/EtOAc (100:0 to 80:20, v/
v); pale yellow oil, 183.9 mg, 62% yield; IR (ATR): 1734, 1689, 1606,
1188, 1135 cm−1; 1H NMR (500.3 MHz, CDCl3): δ 7.47 (d, 1H, J =
13.5 Hz), 4.56 (d, 1H, J = 13.5 Hz), 4.08−4.14 (m, 4H), 3.39 (t, 2H,
J = 7.5 Hz), 3.02 (t, 1H, J = 11.0 Hz), 2.54 (t, 2H, J = 7.5 Hz), 1.79 (t,
4H, J = 12.0 Hz), 1.63 (d, 1H, J = 13.5 Hz), 1.35−1.42 (m, 2H),
1.22−1.26 (m, 8H), 1.07−1.12 (m, 1H); 13C{1H} NMR (125.8 MHz,
CDCl3): δ 171.3, 169.7, 149.1, 84.3, 60.7, 58.8, 43.3, 32.2, 31.4, 25.7,
25.2, 14.6, 14.1; HRMS (HESI) m/z: [M + H]+ calcd for C16H28NO4
298.2018; Found 298.2020.
(E)-Ethyl 3-((3-Ethoxy-3-oxopropyl)(isopropyl)amino)acrylate
(2i). Reaction time: 5 h; eluent: PE/EtOAc (100:0 to 80:20, v/v);
pale yellow oil, 135.8 mg, 53% yield; IR (ATR): 1734, 1689, 1608,
1190, 1138 cm−1; 1H NMR (500.3 MHz, CDCl3): δ 7.48 (d, 1H, J =
13.0 Hz), 4.58 (d, 1H, J = 13.0 Hz), 4.13 (q, 2H, J = 7.0 Hz), 4.11 (q,
2H, J = 7.0 Hz), 3.52 (sept, 1H, J = 6.5 Hz), 3.38 (t, 2H, J = 7.5 Hz),
2.56 (t, 2H, J = 7.5 Hz), 1.25 (t, 3H, J = 7.0 Hz), 1.24 (t, 3H, J = 7.0
Hz), 1.19 (d, 6H, J = 6.5 Hz); 13C{1H} NMR (125.8 MHz, CDCl3):
δ 171.3, 169.7, 148.8, 84.6, 60.8, 58.9, 42.7, 32.2, 21.5, 14.6, 14.1;
HRMS (HESI) m/z: [M + H]+ calcd for C13H24NO4 258.1705;
Found 258.1705.
(E)-Ethyl 3-((2-(3-Ethoxy-3-oxopropoxy)ethyl)(3-ethoxy-3-
oxopropyl)amino)acrylate (2n). Reaction time: 15 min; eluent:
PE/EtOAc (100:0 to 40:60, v/v); pale yellow oil; 174.0 mg, 48%
yield; IR (ATR): 1734, 1688, 1611, 1188, 1147, 1120 cm−1; 1H NMR
(400.1 MHz, CDCl3): δ 7.39 (d, 1H, J = 13.0 Hz), 4.55 (d, 1H, J =
13.0 Hz), 4.09−4.16 (m, 6H), 3.68 (t, 2H, J = 6.5 Hz), 3.54 (t, 2H, J
= 5.2 Hz), 3.48 (t, 2H, J = 6.5 Hz), 3.32 (t, 2H, J = 5.2 Hz), 2.52−
2.59 (m, 4H), 1.23−1.27 (m, 9H); 13C{1H} NMR (100.6 MHz,
CDCl3): δ 171.4, 171.3, 169.4, 151.2, 85.3, 66.6, 60.7, 60.6, 59.0,
35.01, 34.98, 14.6, 14.2, 14.1; HRMS (HESI) m/z: [M + H]+ calcd
for C17H30NO7 360.2022; Found 360.2028.
Cyclohexyl (E)-3-(Benzyl(3-ethoxy-3-oxopropyl)amino)acrylate
(2o). Reaction time: 15 min; eluent: PE/EtOAc (100:0 to 80:20, v/
v); pale yellow oil; 227.3 mg, 63% yield; IR (ATR): 1733, 1685, 1611,
1
1186, 1144, 1120 cm−1; H NMR (500.3 MHz, CDCl3): δ 7.57 (d,
1H, J = 13.0 Hz), 7.33 (t, 2H, J = 7.5 Hz), 7.28 (t, 1H, J = 7.5 Hz),
7.18 (d, 2H, J = 7.0 Hz), 4.74−4.78 (m, 1H), 4.67 (d, 1H, J = 13.0
Hz), 4.37 (s, 2H), 4.11 (q, 2H, J = 7.0 Hz), 3.42 (broad s, 2H), 2.52
(t, 2H, J = 7.0 Hz), 1.87 (m, 2H), 1.71−1.73 (m, 3H), 1.53−1.55 (m,
1H), 1.32−1.42 (m, 4H), 1.24 (t, 3H, J = 7.0 Hz); 13C{1H} NMR
(125.8 MHz, CDCl3): δ 171.2, 169.0, 151.5, 136.5, 128.8, 127.8,
127.3, 86.3, 71.0, 60.8, 32.1, 25.5, 24.0, 14.1; HRMS (HESI) m/z: [M
+ H]+ calcd for C21H30NO4 360.2175; Found 360.2180.
(E)-Ethyl 3-((3-Ethoxy-3-oxopropyl)(1-phenylethyl)amino)-
acrylate (2j). Reaction time: 10 h; eluent: PE/EtOAc (100:0 to
80:20, v/v); pale yellow oil; 265.0 mg, 83% yield; IR (ATR): 1732,
1686, 1606, 1191, 1148 cm−1; 1H NMR (500.3 MHz, CDCl3): δ 7.69
(d, 1H, J = 13.0 Hz), 7.32 (t, 2H, J = 7.0 Hz), 7.26 (t, 1H, J = 7.0 Hz),
7.20 (d, 2H, J = 7.5 Hz), 4.66 (d, 1H, J = 13.0 Hz), 4.58 (q, 1H, J =
7.0 Hz), 4.13 (q, 2H, J = 7.0 Hz), 4.07 (q, 2H, J = 7.0 Hz), 3.30 (t,
2H, J = 7.0 Hz), 2.42 (t, 2H, J = 7.0 Hz), 1.57 (d, 3H, J = 7.0 Hz),
1.25 (t, 3H, J = 7.0 Hz), 1.21 (t, 3H, J = 7.0 Hz); 13C{1H} NMR
(125.8 MHz, CDCl3): δ 171.3, 169.6, 148.8, 140.9, 128.7, 127.8,
126.6, 85.2, 60.7, 59.0, 43.4, 31.4, 19.4, 14.6, 14.1; HRMS (HESI) m/
z: [M + H]+ calcd for C18H26NO4 320.1862; Found 320.1861.
(E)-Ethyl 3-((2-Chloroethyl)(3-ethoxy-3-oxopropyl)amino)-
acrylate (2k). Reaction time: 1 h; eluent: PE/EtOAc (100:0 to
70:30, v/v); pale yellow oil; 203.3 mg, 73% yield; IR (ATR): 1732,
1689, 1612, 1192, 1141 cm−1; 1H NMR (500.3 MHz, CDCl3): δ 7.38
(d, 1H, J = 13.0 Hz), 4.62 (d, 1H, J = 13.0 Hz), 4.14 (q, 2H, J = 7.0
Hz), 4.12 (q, 2H, J = 7.0 Hz), 3.59 (t, 2H, J = 7.0 Hz), 3.50 (t, 4H, J =
6.5 Hz), 2.59 (t, 2H, J = 7.0 Hz), 1.26 (t, 3H, J = 7.0 Hz), 1.25 (t, 3H,
J = 7.0 Hz); 13C{1H} NMR (125.8 MHz, CDCl3): δ 171.2, 169.1,
150.6, 86.7, 61.0, 59.2, 14.5, 14.1; HRMS (HESI) m/z: [M + Na]+
calcd for C12H20ClNO4Na 300.0979; Found 300.0979.
Ethyl (E)-3-(Benzyl(3-oxobut-1-en-1-yl)amino)propanoate (2p).
Reaction time: 10 min; eluent: PE/EtOAc (100:0 to 80:20, v/v); pale
yellow oil; 186.9 mg, 68% yield; IR (ATR): 1731, 1657, 1606, 1564,
1261, 1187 cm−1; 1H NMR (500.3 MHz, CDCl3): δ 7.60 (d, 1H, J =
13.0 Hz), 7.27−7.33 (m, 3H), 7.16 (d, 2H, J = 7.5 Hz), 5.17 (d, 1H, J
= 13.0 Hz), 4.38 (s, 2H), 4.09 (q, 2H, J = 7.0 Hz), 3.43 (broad s, 2H),
2.51 (t, 2H, J = 6.5 Hz), 2.08 (s, 3H), 1.22 (t, 3H, J = 7.0 Hz);
13C{1H} NMR (125.8 MHz, CDCl3): δ 195.6, 171.0, 151.5, 135.9,
128.8, 127.9, 127.2, 97.7, 60.8, 51.4, 43.3, 30.6, 28.0, 14.0; HRMS
(HESI) m/z: [M + H]+ calcd for C16H22NO3 276.1600; Found
276.1596.
Diethyl 2-(Benzyl(3-ethoxy-3-oxopropyl)amino)maleate (2q).
Reaction time: 1 h; eluent: PE/EtOAc (100:0 to 90:10, v/v); pale
yellow oil; 173.8 mg, 46% yield; IR (ATR): 1734, 1567, 1266, 1209,
1
1028 cm−1; H NMR (500.3 MHz, CDCl3): δ 7.26−7.29 (m, 2H),
7.18−7.22 (m, 3H), 4.62 (s, 1H), 4.31 (q, 2H, J = 7.0 Hz) and 4.29
(s, 2H) (these two signals are overlapped in the spectrum), 4.02 (q,
4H, J = 7.0 Hz), 3.36 (t, 2H, J = 7.0 Hz), 2.50 (t, 2H, J = 7.0 Hz),
1.25 (t, 3H, J = 7.0 Hz), 1.16 (t, 3H, J = 7.0 Hz) and 1.15 (t, 3H, J =
7.0 Hz) (these signals are overlapped in the spectrum); 13C{1H}
NMR (125.8 MHz, CDCl3): δ 171.0, 167.4, 165.4, 154.0, 135.6,
128.8, 127.8, 127.3, 85.6, 62.2, 60.8, 59.3, 54.5, 45.4, 31.6, 14.4, 14.1,
13.8; HRMS (HESI) m/z: [M + H]+ calcd for C20H28NO6 378.1917;
Found 378.1913.
(E)-Ethyl 3-((2-Acetamidoethyl)(3-ethoxy-3-oxopropyl)amino)-
acrylate (2l). Ethylenediamine was monoacylated according to the
published procedure.44
In this case, the reaction mixture was refluxed in MeCN for 20 min.
Eluent: PE/EtOAc (100:0 to 0:100, v/v); pale yellow oil; 200.5 mg,
67% yield; IR (ATR): 3310, 1731, 1662, 1609, 1149 cm−1; 1H NMR
(500.3 MHz, CDCl3): δ 7.35 (d, 1H, J = 13.5 Hz), 6.23 (s, 1H), 4.60
(d, 1H, J = 13.5 Hz), 4.12 (q, 2H, J = 7.0 Hz) and 4.08 (q, 2H, J = 7.0
Hz) (these two signals are overlapped in the spectrum), 3.44 (t, 2H, J
= 7.0 Hz), 3.38 (q, 2H, J = 6.0 Hz), 3.28 (t, 2H, J = 6.0 Hz), 2.56 (t,
2H, J = 7.0 Hz), 1.95 (s, 3H), 1.24 (t, 3H, J = 7.0 Hz) and 1.22 (t,
3H, J = 7.0 Hz) (these two signals are overlapped in the spectrum);
General Procedure for the Synthesis of Compounds 2 from
Aromatic Amines, Ethyl Acrylate, and Ethyl Propiolate. Silica
gel (five times the amount of reactants) was added to the mixture of
amine (1.0 mmol) and ethyl acrylate (1.5 mmol). The resultant solid
was stirred at the temperature of 70 °C of an oil bath until the
completion of the reaction, checked by TLC (2−3 h). After cooling to
rt, compound 6a was isolated by washing the silica gel with EtOAc
and evaporating the solvent under reduced pressure. In the case of 6b
and 6c, the complete solid was transferred to a chromatography
H
https://dx.doi.org/10.1021/acs.joc.0c01537
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
column containing silica gel, which was eluted using a gradient of PE
(bp 40−60 °C)/EtOAc. The obtained compounds 6 were
characterized by NMR spectroscopy.
General Procedure for the Synthesis of 2,3-Dihydro-4-
pyridones 9. To a solution of enaminone 2 (0.28 mmol) in EtOH/
H2O 2:1 (v/v) (6 mL) was added KOH (0.34 mmol). The mixture
was stirred at rt for 1 h, and then, the solvent was evaporated under
reduced pressure. Acetonitrile (3 mL) and Ac2O (1.4 mmol) were
added, and the mixture was stirred at rt for 1 h and then allowed to
reflux for 1 h. After cooling to rt, saturated aqueous NaHCO3 was
added (5 mL) and the mixture was stirred at rt for 0.5 h. It was then
extracted with DCM (5 mL × 3) and dried over anhydrous Na2SO4.
After filtration, the solvent was evaporated under reduced pressure to
give pure products (9a−9i), or the residue was purified by column
chromatography on silica gel using a gradient of PE (bp 40−60 °C)/
EtOAc as the eluent and, in several cases, additionally, EtOAc/MeOH
as the eluent or only a gradient of EtOAc/MeOH as the eluent.
Ethyl 1-Benzyl-4-oxo-1,4,5,6-tetrahydropyridine-3-carboxylate
(9a). Pale yellow oil, 65.2 mg, 91% yield; IR (ATR): 1718, 1658,
1599, 1300, 1241, 1147 cm−1; 1H NMR (400.1 MHz, CDCl3): δ 8.24
(d, 1H, J = 1.6), 7.31−7.36 (m, 3H), 7.19−7.21 (m, 2H), 4.48 (s,
2H), 4.18 (dq, 2H, J = 7.2, 2.0 Hz), 3.38 (dt, 2H, J = 7.2, 1.6 Hz),
2.42 (dt, 2H, J = 7.2, 1.6 Hz), 1.24 (dt, 3H, J = 7.2, 2.0 Hz); 13C{1H}
NMR (100.6 MHz, CDCl3): δ 186.3, 165.2, 159.4, 134.1, 129.2,
128.8, 127.7, 100.7, 60.9, 59.8, 46.0, 35.9, 30.8, 14.4; HRMS (HESI)
m/z: [M + H]+ calcd for C15H18NO3 260.1287; Found 260.1284.
Ethyl 4-Oxo-1-phenethyl-1,4,5,6-tetrahydropyridine-3-carboxy-
late (9b). Pale yellow oil, 68.1 mg, 89% yield; IR (ATR): 1717,
1660, 1601, 1244, 1156 cm−1; 1H NMR (400.1 MHz, CDCl3): δ 7.88
(s, 1H), 7.26 (t, 2H, J = 7.6 Hz), 7.19−7.21 (m, 1H), 7.10 (d, 2H, J =
7.6 Hz), 4.12 (q, 2H, J = 7.2 Hz), 3.57 (t, 2H, J = 6.8 Hz), 3.41 (t,
2H, J = 7.6 Hz), 2.89 (t, 2H, J = 6.8 Hz), 2.38 (t, 2H, J = 7.6 Hz),
1.20 (t, 3H, J = 7.2 Hz); 13C{1H} NMR (100.6 MHz, CDCl3): δ
186.4, 165.1, 159.2, 136.7, 129.0, 128.6, 127.2, 100.3, 59.6, 58.5, 47.0,
35.8, 35.2, 14.4; HRMS (HESI) m/z: [M + H]+ calcd for C16H20NO3
274.1443; Found 274.1438.
Ethyl 3-(Phenylamino)propanoate (6a). Reaction time: 3 h;
eluent: PE/EtOAc (100:0 to 80:20, v/v); yellow oil, 116.7 mg, 60%
45
1
yield; H NMR (500.3 MHz, CDCl3): δ 7.20 (t, 2H, J = 7.5 Hz),
6.74 (t, 1H, J = 7.5 Hz), 6.64 (d, 2H, J = 8.0 Hz), 4.17 (q, 2H, J = 7.0
Hz), 3.46 (t, 2H, J = 6.5 Hz), 2.62 (t, 2H, J = 6.5 Hz), 1.28 (t, 3H, J =
7.0 Hz); 13C{1H} NMR (125.8 MHz, CDCl3): δ 172.4, 147.5, 129.2,
117.7, 113.0, 60.6, 39.4, 33.9, 14.1.
Ethyl 3-((4-Methoxyphenyl)amino)propanoate (6b). Reaction
time: 2 h; eluent: PE/EtOAc (100:0 to 80:20, v/v); Yellow oil,
46
1
179.1 mg, 80% yield; H NMR (500.3 MHz, CDCl3): δ 6.79 (m,
2H), 6.63 (m, 2H), 4.15 (q, 2H, J = 7.0 Hz), 3.75 (s, 3H), 3.40 (t,
2H, J = 6.5 Hz), 2.60 (t, 2H, J = 6.5 Hz), 1.26 (t, 3H, J = 7.0 Hz);
13C{1H} NMR (125.8 MHz, CDCl3): δ 172.4, 152.6, 141.4, 115.0,
114.9, 60.6, 55.8, 40.8, 33.9, 14.2.
Ethyl 3-((4-Chlorophenyl)amino)propanoate (6c). Reaction time:
2 h; eluent: PE/EtOAc (100:0 to 90:10, v/v); yellow oil, isolated in a
1
mixture with dialkylated product (5:1); yield is based on H NMR
46
1
data; 156.6 mg, 69% yield; H NMR (400.1 MHz, CDCl3): δ 7.12
(d, 2H, J = 8.0 Hz), 6.54 (d, 2H, J = 8.0 Hz), 4.15 (q, 2H, J = 7.2 Hz),
3.41 (t, 2H, J = 6.4 Hz), 2.59 (t, 2H, J = 6.4 Hz), 1.26 (t, 3H, J = 7.2
Hz); 13C{1H} NMR (100.6 MHz, CDCl3): δ 172.2, 146.2, 129.1,
122.2, 114.1, 60.7, 39.5, 33.7, 14.2.
Conversion of 6 to 2. Silica gel (five times the amount of
reactants) was added to the mixture of secondary amine 6 (0.6 mmol)
and ethyl propiolate (0.9 mmol). The resultant solid was stirred at the
temperature of 70 °C of an oil bath until the completion of the
reaction, checked by TLC (0.5−3 h). After cooling to rt, compound
2s was isolated by washing the silica gel with EtOAc and evaporating
the solvent under reduced pressure. In the case of 2r and 2t, the
complete solid was transferred to a chromatography column
containing silica gel, which was eluted using a gradient of PE (bp
40−60 °C)/EtOAc to give pure products.
Ethyl 1-Allyl-4-oxo-1,4,5,6-tetrahydropyridine-3-carboxylate
(9c). Pale yellow oil, 51.1 mg, 87% yield; IR (ATR): 1716, 1646,
1
1601, 1242, 1174 cm−1; H NMR (400.1 MHz, CDCl3): δ 8.15 (s,
(E)-Ethyl 3-((3-Ethoxy-3-oxopropyl)(phenyl)amino)acrylate (2r).
Reaction time: 1 h; eluent: PE/EtOAc (100:0 to 80:20, v/v); pale
yellow oil; 122.7 mg, 70% yield; IR (ATR): 1733, 1693, 1618, 1588,
1252, 1148 cm−1; 1H NMR (500.3 MHz, CDCl3): δ 7.78 (d, 1H, J =
13.5 Hz), 7.36 (t, 2H, J = 8.0 Hz), 7.13−7.18 (m, 3H), 4.94 (d, 1H, J
= 13.5 Hz), 4.16 (q, 2H, J = 7.0 Hz), 4.10 (q, 2H, J = 7.0 Hz), 3.96 (t,
2H, J = 7.5 Hz), 2.65 (t, 2H, J = 7.5 Hz), 1.27 (t, 3H, J = 7.0 Hz),
1.22 (t, 3H, J = 7.0 Hz); 13C{1H} NMR (125.8 MHz, CDCl3): δ
171.0, 169.1, 147.9, 144.8, 129.6, 125.1, 121.6, 90.4, 60.9, 59.3, 46.3,
31.5, 14.5, 14.1; HRMS (HESI) m/z: [M + H]+ calcd for C16H22NO4
292.1549; Found 292.1551.
(E)-Ethyl 3-((3-Ethoxy-3-oxopropyl)(4-methoxyphenyl)amino)-
acrylate (2s). Reaction time: 0.5 h; eluent: PE/EtOAc (100:0 to
80:20, v/v); pale yellow oil; 164.6 mg, 85% yield; IR (ATR): 1733,
1690, 1616, 1512, 1248, 1146 cm−1; 1H NMR (500.3 MHz, CDCl3):
δ 7.36 (d, 1H, J = 13.0 Hz), 7.06 (m, 2H), 6.88 (m, 2H), 4.78 (d, 1H,
J = 13.0 Hz), 4.13 (q, 2H, J = 7.0 Hz) and 4.08 (q, 2H, J = 7.0 Hz)
(these two signals are overlapped in the spectrum), 3.87 (t, 2H, J =
7.5 Hz), 3.79 (s, 3H), 2.59 (t, 2H, J = 7.5 Hz), 1.25 (t, 3H, J = 7.0
Hz) and 1.22 (t, 3H, J = 7.0 Hz) (these two signals are overlapped in
the spectrum); 13C{1H} NMR (125.8 MHz, CDCl3): δ 171.0, 169.3,
157.5, 149.5, 124.8, 114.8, 88.9, 60.8, 59.2, 55.5, 32.0, 14.5, 14.1;
HRMS (HESI) m/z: [M + H]+ calcd for C17H24NO5 322.1654;
Found 322.1658.
(E)-Ethyl 3-((4-chlorophenyl)(3-ethoxy-3-oxopropyl)amino)-
acrylate (2t). Reaction time: 3 h; eluent: PE/EtOAc (100:0 to
80:20, v/v); pale yellow oil; 89.6 mg, 46% yield; IR (ATR): 1733,
1695, 1616, 1587, 1251, 1148 cm−1; 1H NMR (500.3 MHz, CDCl3):
δ 7.71 (d, 1H, J = 13.0 Hz), 7.29 (m, 2H), 7.07 (m, 2H), 4.95 (d, 1H,
J = 13.0 Hz), 4.16 (q, 2H, J = 7.0 Hz), 4.10 (q, 2H, J = 7.0 Hz), 3.93
(t, 2H, J = 7.5 Hz), 2.63 (t, 2H, J = 7.5 Hz), 1.26 (t, 3H, J = 7.0 Hz),
1.23 (t, 3H, J = 7.0 Hz); 13C{1H} NMR (125.8 MHz, CDCl3): δ
171.0, 169.9, 147.4, 143.3, 129.7, 122.8, 91.3, 61.0, 59.5, 46.3, 31.5,
14.5, 14.1; HRMS (HESI) m/z: [M + H]+ calcd for C16H21ClNO4
326.1159; Found 326.1161.
1H), 5.79−5.89 (m, 1H), 5.32−5.39 (m, 2H), 4.23 (q, 2H, J = 7.2
Hz), 3.98 (d, 2H, J = 6.0 Hz), 3.53 (t, 2H, J = 7.6 Hz), 2.54 (t, 2H, J =
7.6 Hz), 1.30 (t, 3H, J = 7.2 Hz); 13C{1H} NMR (125.8 MHz,
CDCl3): δ 186.5, 165.3, 159.3, 131.0, 120.6, 100.6, 59.8, 59.4, 46.2,
35.9, 14.5; HRMS (HESI) m/z: [M + H]+ calcd for C11H16NO3
210.1130; Found 210.1130.
Ethyl 1-Methyl-4-oxo-1,4,5,6-tetrahydropyridine-3-carboxylate
(9d). Pale yellow oil, 42.8 mg, 83% yield; IR (ATR): 1717, 1612,
1
1331, 1247, 1175 cm−1; H NMR (500.3 MHz, CDCl3): δ 8.08 (s,
1H), 4.20 (q, 2H, J = 7.0 Hz), 3.54 (t, 2H, J = 7.5 Hz), 3.23 (s, 3H),
2.54 (t, 2H, J = 7.5 Hz), 1.28 (t, 3H, J = 7.0 Hz); 13C{1H} NMR
(125.8 MHz, CDCl3): δ 186.2, 165.1, 160.0, 100.1, 59.7, 48.4, 44.1,
35.6, 14.4; HRMS (HESI) m/z: [M + H]+ calcd for C9H14NO3
184.0974; Found 184.0972.
Ethyl 4-Oxo-1-propyl-1,4,5,6-tetrahydropyridine-3-carboxylate
(9e). Pale yellow oil, 47.5 mg, 80% yield; IR (ATR): 1717, 1646,
1603, 1333, 1244, 1160 cm−1; 1H NMR (400.1 MHz, CDCl3): δ 8.08
(s, 1H), 4.22 (q, 2H, J = 7.2 Hz), 3.53 (t, 2H, J = 7.6 Hz), 3.36 (t, 2H,
J = 7.2 Hz), 2.53 (t, 2H, J = 7.6 Hz), 1.70 (sext, 2H, J = 7.2 Hz), 1.30
(t, 3H, J = 7.2 Hz), 0.96 (t, 3H, J = 7.2 Hz); 13C{1H} NMR (125.8
MHz, CDCl3): δ 186.4, 165.1, 159.2, 99.8, 59.5, 58.8, 46.1, 35.7, 21.4,
14.4, 10.7; HRMS (HESI) m/z: [M + H]+ calcd for C11H18NO3
212.1287; Found 212.1287.
Ethyl 1-Hexyl-4-oxo-1,4,5,6-tetrahydropyridine-3-carboxylate
(9f). Pale yellow oil, 61.6 mg, 86% yield; IR (ATR): 1720, 1662,
1603, 1334, 1244, 1156 cm−1; 1H NMR (400.1 MHz, CDCl3): δ 8.12
(s, 1H), 4.17 (q, 2H, J = 7.2 Hz), 3.53 (t, 2H, J = 7.6 Hz), 3.38 (t, 2H,
J = 7.2 Hz), 2.53 (t, 2H, J = 7.2 Hz), 1.66 (m, 2H), 1.28−1.31 (m,
9H), 0.89 (m, 3H); 13C{1H} NMR (100.6 MHz, CDCl3): δ 186.5,
165.4, 159.4, 100.0, 59.8, 57.3, 46.3, 35.8, 31.2, 28.2, 26.0, 22.4, 14.5,
13.8; HRMS (HESI) m/z: [M + H]+ calcd for C14H24NO3 254.1756;
Found 254.1755.
Ethyl 1-Isobutyl-4-oxo-1,4,5,6-tetrahydropyridine-3-carboxylate
(9g). Pale yellow oil, 51.6 mg, 82% yield; IR (ATR): 1712, 1645,
1603, 1332, 1246, 1159 cm−1; 1H NMR (500.3 MHz, CDCl3): δ 8.06
I
https://dx.doi.org/10.1021/acs.joc.0c01537
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(s, 1H), 4.19 (q, 2H, J = 7.0 Hz), 3.51 (t, 2H, J = 7.5 Hz), 3.16 (d,
2H, J = 7.5 Hz), 2.50 (t, 2H, J = 7.5 Hz), 1.93−2.04 (m, 1H), 1.27 (t,
3H, J = 7.0 Hz), 0.93 (t, 6H, J = 6.5 Hz); 13C{1H} NMR (125.8 MHz,
CDCl3): δ 186.4, 165.2, 159.6, 99.8, 64.8, 59.6, 46.7, 35.8, 27.2, 19.5,
14.4; HRMS (HESI) m/z: [M + H]+ calcd for C12H20NO3 226.1443;
Found 226.1446.
Ethyl 1-Cyclohexyl-4-oxo-1,4,5,6-tetrahydropyridine-3-carboxy-
late (9h). Yellow oil, 59.3 mg, 84% yield; IR (ATR): 1719, 1660,
1596, 1298, 1243, 1149 cm−1; 1H NMR (500.3 MHz, CDCl3): δ 8.19
(s, 1H), 4.21 (q, 2H, J = 7.0 Hz), 3.52 (t, 2H, J = 7.5 Hz), 3.24 (tt,
1H, J = 11.5, 3.0 Hz), 2.47 (t, 2H, J = 7.5 Hz), 1.90 (t, 4H, J = 14.5
Hz), 1.69 (d, 1H, J = 13.0 Hz), 1.43−1.51 (m, 2H), 1.30−1.36 (m,
2H), 1.28 (t, 3H, J = 7.0 Hz), 1.08−1.17 (m, 1H); 13C{1H} NMR
(125.8 MHz, CDCl3): δ 186.6, 165.5, 157.3, 100.0, 65.8, 59.6, 44.0,
36.1, 31.4, 25.2, 25.0, 14.5; HRMS (HESI) m/z: [M + H]+ calcd for
C14H22NO3 252.1600; Found 252.1603.
MHz, CDCl3): δ 195.1, 187.8, 159.1, 133.8, 129.2, 128.9, 127.7,
109.9, 61.1, 46.1, 35.6, 30.4; HRMS (HESI) m/z: [M + H]+ calcd for
C14H16NO2 230.1181; Found 230.1181.
Diethyl 1-Benzyl-4-oxo-1,4,5,6-tetrahydropyridine-2,3-dicarbox-
ylate (9q). Eluent: PE/EtOAc (100:0 to 30:70, v/v); yellow oil, 59.5
1
mg, 64% yield; IR (ATR): 1739, 1671, 1551, 1257, 1172 cm−1; H
NMR (500.3 MHz, CDCl3): δ 7.33−7.42 (m, 5H), 4.48 (s, 2H), 4.39
(q, 2H, J = 7.0 Hz), 4.25 (q, 2H, J = 7.0 Hz), 3.50 (t, 2H, J = 7.5 Hz),
2.45 (t, 2H, J = 7.5 Hz), 1.33 (t, 3H, J = 7.0 Hz), 1.32 (t, 3H, J = 7.0
Hz); 13C{1H} NMR (125.8 MHz, CDCl3): δ 186.9, 165.3, 163.6,
160.3, 134.0, 129.2, 128.8, 127.9, 100.6, 62.9, 60.5, 57.2, 47.0, 35.5,
14.4, 13.8; HRMS (HESI) m/z: [M + H]+ calcd for C18H22NO5
332.1498; Found 332.1502.
Ethyl 4-Oxo-1-phenyl-1,4,5,6-tetrahydropyridine-3-carboxylate
(9r). Eluent: PE/EtOAc (100:0 to 0:100, v/v); yellow oil, 30.7 mg,
45% yield; IR (ATR): 1724, 1677, 1576, 1255, 1148 cm−1; 1H NMR
(400.1 MHz, CDCl3): δ 8.49 (s, 1H), 7.45 (t, 2H, J = 8.0 Hz), 7.29 (t,
1H, J = 7.2 Hz,), 7.23 (d, 2H, J = 8.4 Hz,), 4.28 (q, 2H, J = 7.2 Hz),
4.08 (t, 2H, J = 7.6 Hz), 2.73 (t, 2H, J = 7.6 Hz), 1.32 (t, 3H, J = 7.2
Hz); 13C{1H} NMR (125.8 MHz, CDCl3): δ 186.9, 165.0, 156.2,
144.3, 129.9, 129.6, 126.5, 119.7, 103.8, 60.2, 48.1, 36.3, 14.4; HRMS
(HESI) m/z: [M + H]+ calcd for C14H16NO3 246.1130; Found
246.1127.
Ethyl 1-Isopropyl-4-oxo-1,4,5,6-tetrahydropyridine-3-carboxy-
late (9i). Yellow oil, 53.3 mg, 90% yield; IR (ATR): 1718, 1654,
1
1598, 1247, 1149 cm−1; H NMR (500.3 MHz, CDCl3): δ 8.19 (s,
1H), 4.20 (q, 2H, J = 7.0 Hz), 3.72 (sept, 1H, J = 7.0 Hz), 3.48 (t, 2H,
J = 7.5 Hz), 2.47 (t, 2H, J = 7.5 Hz), 1.30 (d, 6H, J = 7.0 Hz), 1.27 (t,
3H, J = 7.0 Hz); 13C{1H} NMR (125.8 MHz, CDCl3): δ 186.61,
165.4, 157.2, 100.0, 59.6, 57.8, 42.8, 36.0, 20.8, 14.4; HRMS (HESI)
m/z: [M + H]+ calcd for C11H18NO3 212.1287; Found 212.1286.
Ethyl 4-Oxo-1-(1-phenylethyl)-1,4,5,6-tetrahydropyridine-3-car-
boxylate (9j). Eluent: PE/EtOAc (100:0 to 0:100, v/v), then
EtOAc/MeOH (90:10, v/v); yellow oil, 42.3 mg, 55% yield; IR
Ethyl 1-(4-Methoxyphenyl)-4-oxo-1,4,5,6-tetrahydropyridine-3-
carboxylate (9s). Eluent: PE/EtOAc (100:0 to 0:100, v/v), then
EtOAc/MeOH (80:20, v/v); yellow oil, 48.8 mg, 63% yield; IR
1
(ATR): 1722, 1673, 1583, 1512, 1252, 1149 cm−1; H NMR (500.3
1
(ATR): 1718, 1660, 1597, 1245, 1141 cm−1; H NMR (500.3 MHz,
MHz, CDCl3): δ 8.37 (s, 1H), 7.15 (m, 2H), 6.93 (m, 2H), 4.24 (q,
2H, J = 7.0 Hz), 4.02 (t, 2H, J = 7.5 Hz), 3.82 (s, 2H), 2.69 (t, 2H, J =
7.5 Hz), 1.30 (t, 3H, J = 7.0 Hz); 13C{1H} NMR (125.8 MHz,
CDCl3): δ 186.8, 165.0, 158.2, 156.6, 137.7, 121.6, 114.9, 102.8, 60.0,
55.6, 48.7, 36.2, 14.4; HRMS (HESI) m/z: [M + H]+ calcd for
C15H18NO4 276.1236; Found 276.1235.
CDCl3): δ 8.39 (s, 1H), 7.35 (t, 2H, J = 7.0 Hz), 7.30 (t, 1H, J = 7.0
Hz), 7.22 (d, 2H, J = 7.0 Hz), 4.66 (q, 1H, J = 7.0 Hz), 4.21 (q, 2H, J
= 7.0 Hz), 3.32−3.38 (m, 1H), 3.23−3.29 (m, 1H), 2.32−2.43 (m,
2H), 1.66 (d, 3H, J = 7.0 Hz), 1.27 (t, 3H, J = 7.0 Hz); 13C{1H}
NMR (125.8 MHz, CDCl3): δ 186.6, 165.6, 157.1, 138.6, 129.2,
128.6, 126.3, 100.5, 64.4, 59.8, 44.4, 35.9, 19.0, 14.5; HRMS (HESI)
m/z: [M + H]+ calcd for C16H20NO3 274.1443; Found 274.1446.
Ethyl 1-(2-Chloroethyl)-4-oxo-1,4,5,6-tetrahydropyridine-3-car-
boxylate (9k). Eluent: PE/EtOAc (100:0 to 0:100, v/v), then
EtOAc/MeOH (80:20, v/v); white solid, mp 114−115 °C, 38.2 mg,
59% yield; IR (ATR): 1716, 1658, 1600, 1245, 1170 cm−1; 1H NMR
(500.3 MHz, CDCl3): δ 8.12 (s, 1H), 4.20 (q, 2H, J = 7.0 Hz), 3.72
(s, 4H), 3.62 (t, 2H, J = 7.5 Hz), 2.55 (t, 2H, J = 7.5 Hz), 1.28 (t, 3H,
J = 7.0 Hz); 13C{1H} NMR (125.8 MHz, CDCl3): δ 186.5, 164.9,
159.8, 101.1, 59.8, 57.9, 46.6, 41.3, 35.8, 14.4; HRMS (HESI) m/z:
[M + Na]+ calcd for C10H14ClNO3Na 254.0560; Found 254.0555.
Ethyl 1-(2-Acetamidoethyl)-4-oxo-1,4,5,6-tetrahydropyridine-3-
carboxylate (9l). Eluent: EtOAc/MeOH (100:0 to 50:50, v/v);
yellow oil, 29.3 mg, 41% yield; IR (ATR): 3311, 1711, 1658, 1604,
Ethyl 1-(4-Chlorophenyl)-4-oxo-1,4,5,6-tetrahydropyridine-3-
carboxylate (9t). Eluent: PE/EtOAc (100:0 to 0:100, v/v); yellow
oil, 37.6 mg, 48% yield; IR (ATR): 1725, 1675, 1576, 1495, 1255,
1
1153 cm−1; H NMR (400.1 MHz, CDCl3): δ 8.42 (s, 1H), 7.41 (d,
2H, J = 8.8 Hz), 7.16 (d, 2H, J = 8.8 Hz), 4.27 (q, 2H, J = 7.2 Hz),
4.05 (t, 2H, J = 7.6 Hz), 2.72 (t, 2H, J = 7.6 Hz), 1.32 (t, 3H, J = 7.2
Hz); 13C{1H} NMR (100.6 MHz, CDCl3): δ 186.6, 164.8, 155.6,
142.9, 132.0, 129.9, 120.9, 104.3, 60.3, 48.2, 36.2, 14.4; HRMS
(HESI) m/z: [M + Na]+ calcd for C14H14ClNO3Na 302.0560; Found
302.0546.
Gram-Scale Synthesis of Ethyl 1-Benzyl-4-oxo-1,4,5,6-tetrahy-
dropyridine-3-carboxylate (9a). A solution of of benzylamine (1.000
g, 9.33 mmol) in DCM (5 mL) was cooled to 0 °C, and the solution
of ethyl propiolate (1.020 g, 10.40 mmol) in DCM (2 mL) was added
dropwise over of period of 10 min. The reaction mixture was warmed
to rt, stirred for 15 min, and the solvent was evaporated under
reduced pressure. Ethyl acrylate (1.378 g, 13.76 mmol) and Cs2CO3
(1.500 g, 4.60 mmol) were added, and the mixture was stirred at rt for
30 min to give 2a′ (2.462 g, 86%; 8.06 mmol). It was dissolved in
EtOH/H2O 2:1 (v/v) (9 mL), and KOH (0.539 g, 9.61 mmol) was
added. The mixture was stirred at rt for 1 h, and the solvent was
evaporated under reduced pressure. Acetonitrile (10 mL) and Ac2O
(4.114 g, 40.30 mmol) were added, and the mixture was stirred at rt
for 1 h and then allowed to reflux for 1 h. After cooling to rt, the
reaction mixture was filtered and the solid was washed with DCM (20
mL). Saturated aqueous NaHCO3 (20 mL) was added to the filtrate,
and the mixture was stirred at rt for 0.5 h. It was then extracted with
DCM (10 mL × 3) and dried over anhydrous Na2SO4. After filtration,
the solvent was evaporated under reduced pressure to give 9a (2.04 g,
98%), which was purified by column chromatography (eluent:
gradient of EtOAc/MeOH 100:0 to 80:20 v/v) to give pure product
(1.75 g, 84%).
1
1245, 1158 cm−1; H NMR (500.3 MHz, CDCl3): δ 7.99 (s, 1H),
7.91 (s, 1H), 4.11 (q, 2H, J = 7.0 Hz), 3.59 (t, 2H, J = 7.5 Hz), 3.55
(s, 4H), 2.43 (t, 2H, J = 7.5 Hz), 2.08 (s, 3H), 1.24 (t, 3H, J = 7.0
Hz); 13C{1H} NMR (125.8 MHz, CDCl3): δ 187.3, 171.8, 164.1,
159.8, 99.2, 59.3, 56.8, 46.6, 37.8, 35.7, 22.8, 14.5; HRMS (HESI) m/
z: [M + H]+ calcd for C12H19N2O4 255.1345; Found 255.1344.
Cyclohexyl 1-Benzyl-4-oxo-1,4,5,6-tetrahydropyridine-3-carbox-
ylate (9o). Eluent: PE/EtOAc (100:0 to 0:100, v/v), then EtOAc/
MeOH (80:20, v/v); yellow oil, 65.8 mg, 75% yield; IR (ATR): 1715,
1660, 1601, 1242, 1167 cm−1; 1H NMR (500.3 MHz, CDCl3): δ 8.20
(s, 1H), 7.29−7.36 (m, 3H), 7.20 (d, 2H, J = 6.5 Hz), 4.80−4.84 (m,
1H), 4.47 (s, 2H), 3.38 (t, 2H, J = 7.5 Hz), 2.42 (t, 2H, J = 7.5 Hz),
1.79−1.81 (m, 2H), 1.65−1.68 (m, 2H), 1.41−1.47 (m, 3H), 1.28−
1.34 (m, 2H), 1.18−1.25 (m, 1H); 13C{1H} NMR (125.8 MHz,
CDCl3): δ 186.4, 164.4, 159.1, 134.1, 129.2, 128.8, 127.7, 101.1, 71.6,
60.9, 46.0, 35.9, 31.7, 25.5, 23.7; HRMS (HESI) m/z: [M + H]+ calcd
for C19H24NO3 314.1756; Found 314.1762.
5-Acetyl-1-benzyl-2,3-dihydropyridin-4(1H)-one (9p). Eluent:
PE/EtOAc (100:0 to 0:100, v/v); then EtOAc/MeOH (80:20, v/
v); yellow oil, 47.4 mg, 74% yield; IR (ATR): 1729, 1637, 1578, 1326,
General Procedure for the Oxidation of 2,3-Dihydro-4-
pyridones 9 to 4-Pyridones 10. A solution of 2,3-dihydro-4-
pyridone 9 (0.1 mmol) and 2,3,5,6-tetrachloro-p-benzoquinone
(chloranil, 0.12 mmol) in toluene (3 mL) was heated at 100 °C for
0.5−1 h. After that time, the solvent was evaporated under reduced
1
1147 cm−1; H NMR (500.3 MHz, CDCl3): δ 8.44 (s, 1H), 7.36−
7.41 (m, 3H), 7.27 (d, 2H, J = 7.0 Hz), 4.59 (s, 2H), 3.47 (t, 2H, J =
7.5 Hz), 2.51 (s, 3H), 2.49 (t, 2H, J = 7.5 Hz); 13C{1H} NMR (125.8
J
https://dx.doi.org/10.1021/acs.joc.0c01537
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
pressure and the residue was purified by column chromatography on
silica gel using a gradient of PE (bp 40−60 °C)/EtOAc (100:0 to
0:100, v/v) as the eluent followed by EtOAc/EtOH or pure EtOH as
the eluent.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01537
Notes
Ethyl 1-Benzyl-4-oxo-1,4-dihydropyridine-3-carboxylate (10a).
Reaction time: 0.5 h; eluent: PE/EtOAc (100:0 to 0:100, v/v),
then EtOAc/EtOH (50:50, v/v); yellow oil, 20.6 mg, 80% yield; IR
The authors declare no competing financial interest.
1
(ATR): 1726, 1645, 1579, 1299, 1204, 1178 cm−1; H NMR (400.1
ACKNOWLEDGMENTS
■
MHz, CDCl3): δ 8.21 (d, 1H, J = 2.8 Hz), 7.39−7.44 (m, 3H), 7.24
(dd, 1H, J = 8.0, 2.8 Hz), 7.20 (dd, 2H, J = 7.6, 2.4 Hz), 6.49 (d, 1H, J
= 7.6 Hz), 4.98 (s, 2H), 4.34 (q, 2H, J = 7.2 Hz), 1.35 (t, 3H, J = 7.2
Hz); 13C{1H} NMR (100.6 MHz, CDCl3): δ 175.3, 165.0, 145.8,
138.8, 134.0, 129.5, 129.2, 127.5, 123.1, 119.1, 61.1, 60.6, 14.3;
HRMS (HESI) m/z: [M + H]+ calcd for C15H16NO3 258.1130;
Found 258.1128.
This work was financially supported by the Ministry of
Education, Science and Technological Development of the
Republic of Serbia (Contract number 451-03-68/2020-14/
200168).
REFERENCES
■
Ethyl 4-Oxo-1-(1-phenylethyl)-1,4-dihydropyridine-3-carboxy-
late (10b). Reaction time: 0.5 h; eluent: PE/EtOAc (100:0 to
0:100, v/v), then EtOAc/EtOH (80:20, v/v); yellow oil, 19.1 mg,
(1) For reviews, see: (a) Chattopadhyay, A. K.; Hanessian, S. Cyclic
enaminones. Part I: stereocontrolled synthesis using diastereoselective
and catalytic asymmetric methods. Chem. Commun. 2015, 51, 16437−
16449. (b) Chattopadhyay, A. K.; Hanessian, S. Cyclic enaminones.
Part II: Applications as versatile intermediates in alkaloid synthesis.
Chem. Commun. 2015, 51, 16450−16467. (c) Seki, H.; Georg, G. I.
2,3-Dihydropyridin-4(1H)-ones and 3-Aminocyclohex-2-enones: Syn-
thesis, Functionalization, and Applications to Alkaloid Synthesis.
Synlett 2014, 25, 2536−2557.
1
70% yield; IR (ATR): 1729, 1645, 1581, 1296, 1207, 1170 cm−1; H
NMR (500.3 MHz, CDCl3): δ 8.29 (s, 1H), 7.7.38−7.43 (m, 3H),
7.22−7.26 (m, 3H), 6.51 (d, 1H, J = 7.5 Hz), 5.17−5.21 (q, 1H, J =
7.0 Hz), 4.35 (q, 2H, J = 7.0 Hz), 1.87 (d, 3H, J = 7.0 Hz), 1.36 (t,
3H J = 7.0 Hz); 13C{1H} NMR (125.8 MHz, CDCl3): δ 175.2, 165.0,
145.9, 139.1, 133.9, 129.5, 129.2, 127.5, 122.9, 119.0, 61.1, 60.7, 14.3;
HRMS (HESI) m/z: [M + H]+ calcd for C16H18NO3 272.1287;
Found 272.1285.
(2) For selected examples, see: (a) Kiren, S.; Brooks, A. M.; Graves,
J. J. Pyrroles from TosMIC and Substituted-N-acyl-2,3-dihydro-4-
pyridones: A Short Access to a 4-Azaisoindole Unit. Tetrahedron Lett.
2019, 60, 1490−1492. (b) Inoshita, T.; Goshi, K.; Morinaga, Y.;
Umeda, Y.; Ishikawa, H. Enantioselective Construction of Octahy-
droquinolines via Trienamine-Mediated Diels−Alder Reactions. Org.
Lett. 2019, 21, 2903−2907. (c) Yang, Y.; Hardman, C. Synthetic
Versatility of 2-Substituted-6-methyl 2,3-Dihydropyridinones in the
Synthesis of Polyfunctional Piperidine-Based Compounds and
Related β Amino Acid Derivatives. Org. Biomol. Chem. 2017, 15,
8576−8593. (d) Enamorado, M. F.; Connelly, C. M.; Deiters, A.;
Comins, D. L. A concise synthesis of the Lycopodium alkaloid
cermizine D. Tetrahedron Lett. 2015, 56, 3683−3685. (e) Tsukanov,
S. V.; Comins, D. L. Total Synthesis of Alkaloid 205B. J. Org. Chem.
2014, 79, 9074−9085. (f) Brimioulle, R.; Bach, T. Enantioselective
Lewis Acid Catalysis of Intramolecular Enone [2+2] Photo-
cycloaddition Reactions. Science 2013, 342, 840−843. (g) Kuethe, J.
T.; Comins, D. L. Asymmetric Total Synthesis of (+)-Cannabisati-
vine. J. Org. Chem. 2004, 69, 5219−5231.
(3) Eiden, C. G.; Aldrich, C. C. Synthesis of a 3-Amino-2,3-
dihydropyrid-4-one and Related Heterocyclic Analogues as Mecha-
nism-Based Inhibitors of BioA, a Pyridoxal Phosphate-Dependent
Enzyme. J. Org. Chem. 2017, 82, 7806−7819.
(4) (a) Comins, D. L.; Zeller, E. N-Acyldihydropyridones as
Synthetic Intermediates. A Short Synthesis of ( )-Indolizidine 209B.
Tetrahedron Lett. 1991, 32, 5889−5892. (b) Comins, D. L.; Morgan,
L. A. N-Acyldihydropyridones as Synthetic Intermediates. Synthesis of
(+)-Septicine and (+)-Tylophorine. Tetrahedron Lett. 1991, 32,
5919−5922. (c) McCall, W. S.; Grillo, T. A.; Comins, D. L. N-
Acyldihydropyridones as Synthetic Intermediates. A Stereoselective
Synthesis of Acyclic Amino Alcohols Containing Multiple Chiral
Centers. J. Org. Chem. 2008, 73, 9744−9751.
(5) (a) Flick, A. C.; Padwa, A.; High, A. Yielding Oxidation Method
for the Preparation of Substituted 2,3-Dihydro-4-pyridones from 4-
Piperidones. Arkivoc 2009, 4−14. (b) Diao, T.; Stahl, S. S. Synthesis
of Cyclic Enones via Direct Palladium-Catalyzed Aerobic Dehydro-
genation of Ketones. J. Am. Chem. Soc. 2011, 133, 14566−14569.
(c) Yoshii, D.; Jin, X.; Yatabe, T.; Hasegawa, J.-y.; Yamaguchi, K.;
Mizuno, N. Gold Nanoparticles on OMS-2 for Heterogeneously
Catalyzed Aerobic Oxidative α,β-Dehydrogenation of β-Heteroatom-
Substituted Ketones. Chem. Commun. 2016, 52, 14314−14317.
(d) Sevenich, A.; Mark, P. S.; Behrendt, T.; Groß, J.; Opatz, T.
Synthesis of 2,3-Dihydro-4-pyridones, 4-Quinolones, and 2,3-
Dihydro-4-azocinones by Visible-Light Photocatalytic AerobicDehy-
drogenation. Eur. J. Org. Chem. 2019, 1505−1514.
Ethyl 1-(2-Acetamidoethyl)-4-oxo-1,4-dihydropyridine-3-carbox-
ylate (10c). Reaction time: 0.5 h; eluent: PE/EtOAc (100:0 to 0:100,
v/v), then EtOH; yellow oil, 23.8 mg, 94% yield; IR (ATR): 3289,
1
1728, 1649, 1565, 1293, 1196 cm−1; H NMR (500.3 MHz, DMSO-
d6): δ 8.24 (s, 1H), 8.18 (t, 1H, J = 5.5 Hz), 7.68 (d, 1H, J = 8.0 Hz),
6.23 (d, 1H, J = 8.0 Hz), 4.18 (q, 2H, J = 7.0 Hz), 3.99 (t, 2H, J = 5.5
Hz), one CH2 signal is covered by water from DMSO-d6, 1.76 (s,
3H), 1.24 (t, 3H, J = 7.0 Hz); 13C{1H} NMR (125.8 MHz, DMSO-
d6): δ 174.2, 169.7, 164.5, 146.2, 141.0, 120.8, 117.6, 59.9, 55.2, 22.4,
14.2; HRMS (HESI) m/z: [M + H]+ calcd for C12H17N2O4 253.1188;
Found 253.1180.
Ethyl 4-Oxo-1-phenyl-1,4-dihydropyridine-3-carboxylate (10d).
Reaction time: 1 h; eluent: PE/EtOAc (100:0 to 0:100, v/v), then
EtOAc/EtOH (80:20, v/v); yellow oil, 15.7 mg, 65% yield; IR
1
(ATR): 1732, 1647, 1592, 1310, 1246 cm−1; H NMR (400.1 MHz,
CDCl3): δ 8.41 (s, 1H), 7.54−7.57 (m, 3H), 7.49 (t, 1H, J = 7.2 Hz),
7.39 (d, 2H, J = 7.2 Hz), 6.62 (d, 1H, J = 7.2 Hz), 4.38 (q, 2H, J = 7.2
Hz), 1.37 (t, 3H, J = 7.2 Hz); 13C{1H} NMR (125.8 MHz, CDCl3): δ
175.4, 164.9, 144.8, 142.7, 138.6, 130.4, 129.1, 123.0, 122.7, 119.4,
61.3, 14.3; HRMS (HESI) m/z: [M + H]+ calcd for C14H14NO3
244.0974; Found 244.0971.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01537.
■
sı
Copies of 1H NMR and 13C NMR spectra of the
synthesized compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
́
Milovan Stojanovic − University of Belgrade, Institute of
Chemistry, Technology and MetallurgyCenter for Chemistry,
11000 Belgrade, Serbia; Email: milovans@chem.bg.ac.rs
́
Marija Baranac-Stojanovic − University of BelgradeFaculty
of Chemistry, 11000 Belgrade, Serbia; orcid.org/0000-
0002-6203-2361; Email: mbaranac@chem.bg.ac.rs
Author
Slobodan Bugarski − University of BelgradeFaculty of
Chemistry, 11000 Belgrade, Serbia
K
https://dx.doi.org/10.1021/acs.joc.0c01537
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(6) Guo, F.; Dhakal, R. C.; Dieter, R. K. Conjugate Addition
Reactions of N-Carbamoyl-4-pyridones and 2,3-Dihydropyridones
with Grignard Reagents in the Absence of Cu(I) Salts. J. Org. Chem.
2013, 78, 8451−8464.
Convenient Synthesis of Functionalized 2,3-Dihydro-4-pyridones.
Tetrahedron Lett. 2005, 46, 5511−5514. (d) Obydennov, D. L.; El-
Tantawy, A. I.; Sosnovskikh, V. Y. Synthesis of Multifunctionalized
2,3-Dihydro-4-pyridones and 4-Pyridones via the Reaction of
Carbamoylated Enaminones with Aldehydes. J. Org. Chem. 2018,
83, 13776−13786. (e) Seki, H.; Georg, G. I. Synthesis of Amino Acid
Derived Enaminones via Wolff Rearrangement Using Vinylogous
Amides as Carbon Nucleophiles. J. Am. Chem. Soc. 2010, 132, 15512−
15513. (f) Seki, H.; Georg, G. I. Three-Component Synthesis of
Cyclic Enaminones via Ketene Cyclization. Org. Lett. 2011, 13, 2147−
2149.
(7) Eskenazi, C.; Lhommet, G.; Richaud, M.-G.; Maitte, P. Nouvelle
̀
voie d′acces aux 1H-dihydro-2,3 pyridones-4. J. Heterocycl. Chem.
1976, 13, 253−256.
(8) (a) Chen, W.-Y.; Li, X.-S. Three-Component Synthesis of
Dihydro-4-pyridones Catalyzed by Silica Sulfuric Acid. Lett. Org.
́
Chem. 2007, 4, 129−133. (b) Pegot, B.; Vo-Thanh, G. Ionic Liquid
Promoted Aza-Diels−Alder Reaction of Danishefsky’s Diene with
Imines. Synlett 2005, 1409−1412. (c) Yuan, Y.; Li, X.; Ding, K. Acid-
Free Aza Diels-Alder Reaction of Danishefsky’s Diene with Imines.
Org. Lett. 2002, 4, 3309−3311. (d) Yang, Y. Building Polyfunctional
Piperidines: a Stereoselective Strategy of a Three-Component
Mannich Reaction Inspired by Biosynthesis and Applications in the
Synthesis of Natural Alkaloids (+)-241D; (−)-241D; Isosolenopsin A
and (−)-Epimyrtine. RSC Adv. 2015, 5, 18894−18908. (e) Dziedzic,
M.; Malecka, M.; Furman, B. Rhodium-Catalyzed Intramolecular
Conjugate Addition of Vinylstannanes to 2,3-Dihydro-4-pyridones.
An Efficient Route to Stereoselective Construction of Indolizidines.
Org. Lett. 2005, 7, 1725−1727. (f) Jørgensen, K. A. Catalytic
Asymmetric Hetero-Diels Alder Reactions of CarbonylCompounds
and Imines. Angew. Chem., Int. Ed. 2000, 39, 3558−3588.
(17) The syntheses reported in ref 13a, involving β-amino esters and
β-keto esters, should proceed via the same kind of NH intermediate,
which was cyclized in situ by treatment with a base.
(18) Challa, C.; Vellekkatt, J.; Ravindran, J.; Lankalapalli, R. S. A
Metal-Free One-Pot Cascade Synthesis of Highly Functionalized
Biaryl-2-carbaldehydes. Org. Biomol. Chem. 2014, 12, 8588−8592.
(19) Challa, C.; John, M.; Lankalapalli, R. S. Cascade synthesis of
1,2-dihydropyridine from dienaminodioate andan imine: a three-
component approach. Tetrahedron Lett. 2013, 54, 3810−3812.
(20) (a) Adams, J.; Hardin, A.; Vounatsos, F. Microwave-Assisted
Synthesis of New Polysubstituted Dienaminoesters and Their
Cyclization to 3-Bromo-2(1H)-Pyridinones. J. Org. Chem. 2006, 71,
9895−9898. (b) Agami, C.; Dechoux, L.; Hebbe, S.; Moulinas, J. An
Efficient Synthesis of Polysubstituted 3-Halo-2(1H)-Pyridinones.
Synthesis 2002, 79−82. (c) Anghelide, N.; Draghici, C.; Raileanu,
D. New Dienamino Esters and Their Cyclization to α-Pyridones of
Nicotonic Acid. Tetrahedron 1974, 30, 623−632.
(9) (a) MacDonald, F. K.; Burnell, D. J. 2,3-Dihydro-4H-pyran-4-
ones and 2,3-Dihydro-4-pyridinones by Cyclizations of α,β-Unsatu-
rated 1,3-Diketones. J. Org. Chem. 2009, 74, 6973−6979. (b) Elias, R.
S.; Saeed, B. A.; Saour, K. Y.; Al-Masoudi, N. A. Microwave-assisted
synthesis of dihydropyridones from curcumin. Tetrahedron Lett. 2008,
49, 3049−3051.
(10) Harmata, M.; Lee, D. R. A synthesis of 2,3-dihydro-4-
pyridones. Arkivoc 2007, 91−103.
(11) Dong, D.; Bi, X.; Liu, Q.; Cong, F. [5C + 1N] Annulation: a
Novel Synthetic Strategy for Functionalized 2,3-dihydro-4-pyridones.
Chem. Commun. 2005, 3580−3582.
(21) (a) Agami, C.; Dechoux, L.; Hamon, L.; Hebbe, S. Synthesis of
Polysubstituted Pyrroles: Further Advances in the Reactivity of δ-
Dienamino Esters. Synthesis 2003, 859−862. (b) Agami, C.; Dechoux,
L.; Hebbe, S. Efficient and Flexible Access to Polysubstituted Pyrroles.
Synlett 2001, 1440−1442.
́
́
́
(22) Aleksic, J.; Stojanovic, M.; Baranac-Stojanovic, M. Silica Gel as
a Promoter of Sequential Aza-Michael/Michael Reactions of Amines
and Propiolic Esters: Solvent- and Metal-Free Synthesis of
Polyfunctionalized Conjugated Dienes. Chem. Asian J. 2018, 13,
1811−1835.
(12) (a) Niphakis, M. J.; Turunen, B. J.; Georg, G. I. Synthesis of 6-
and 7-Membered Cyclic Enaminones: Scope and Mechanism. J. Org.
Chem. 2010, 75, 6793−6805. (b) Ranade, A. R.; Georg, G. I.
Enantioselective Synthesis of 3,4-Dihydro-1,2-oxazepin-5(2H)-ones
and 2,3-Dihydropyridin-4(1H)-ones from β-Substituted β-Hydrox-
yaminoaldehydes. J. Org. Chem. 2014, 79, 984−992. (c) Trinh, T. T.
H.; Nguyen, K. H.; Amaral, P. d. A.; Gouault, N. Total Synthesis of
(−)-Epimyrtine by a Gold-Catalyzed Hydroamination Approach.
Beilstein J. Org. Chem. 2013, 9, 2042−2047. (d) Gouault, N.; Le Roch,
M.; Cheignon, A.; Uriac, P.; David, M. Enantiospecific Synthesis of
Pyridinones as Versatile Intermediates toward Asymmetric Piper-
idines. Org. Lett. 2011, 13, 4371−4373.
(13) (a) Ma, D.; Sun, H. A Simple and Stereospecfic Route to 2,6-
Disubstituted 4-Hydroxypiperidines. Synthesis of Dendrobate Alka-
loid (+)-241D and Formal Synthesis of (-)-Indolizidine 167B. Org.
Lett. 2000, 2, 2503−2505. (b) Shashidhar Kumar, A.; Haritha, B.;
Venkateswara Rao, B. A Versatile and Efficient Synthesis of (2S)-2-
(Hydroxymethyl)-N-Boc-2,3-dihydro-4-pyridone. Tetrahedron Lett.
2003, 44, 4261−4263.
(14) Lei, C.-H.; Wang, D.-X.; Zhao, L.; Zhu, J.; Wang, M.-X.
Synthesis of Multifunctionalized 1,2,3,4-Tetrahydropyridines, 2,3-
Dihydropyridin-4(1H)-ones, and Pyridines from Tandem Reactions
Initiatedby [5+1] Cycloaddition of N-Formylmethyl-Substituted
Enamides to Isocyanides: Mechanistic Insight and Synthetic
Application. Chem. - Eur. J. 2013, 19, 16981−16987.
(15) Igarashi, E.; Sakamoto, K.; Yoshimura, T.; Matsuo, J.-i. Formal
[4 + 2] Cycloaddition of 3-Phenylcyclobutanones with Nitriles.
Tetrahedron Lett. 2019, 60, 13−15.
(23) Ioffe, S. L.; Lyapkalo, I. M.; Tishkov, A. A.; Danilenko, V. M.;
Strelenko, Y. A.; Tartakovsky, V. A. β,β′-Functionalized N,N-Divinyl-
N-trimethylsilyloxyamines via Silylation of β-Substituted Aliphatic
Nitro Compounds. The Investigation of the Mechanism of the
Process Using Selective Trapping Reagents. Tetrahedron 1997, 53,
13085−13098.
̈
(24) Fondjo, E. S.; Dopp, D.; Henkel, G. Reactions of Some
Anellated 2-Aminothiophenes with Electron Poor Acetylenes.
Tetrahedron 2006, 62, 7121−7131.
́
(25) Fenain, F.; Medebielle, M.; Rocher, M.; Onomura, O.; Okada,
E.; Shibata, D. Indium-Mediated Reduction of β-Aminovinyl Chloro-
difluoromethylated Ketones in the Presence of Heteroaryl Aldehydes.
A Mild Entry to Novel Difluoromethylene Enaminone Derivatives. J.
Fluorine Chem. 2007, 128, 1286−1299.
(26) Zhao, Y.; Zhang, F.; Yao, W.; Wang, C.; Liu, Y.; Li, Y. Base-
Promoted Approach to Highly Functionalized Conjugated Dienes
through Enamine Migration. Eur. J. Org. Chem. 2015, 7984−7991.
(27) Zhou, P.; Hu, B.; Yang, J.; Li, L.; Rao, K.; Zhu, D.; Yu, F. Two
Complementary Cyclization Reactions for the Chemoselective
Synthesis of Spirooxindoles. Eur. J. Org. Chem. 2017, 7256−7265.
(28) Lee, G. H.; Lee, H. K.; Choi, E. B.; Pak, C. S. Intramolecular
Hydrodimerization of Activated Dienes Mediated by Magnesium in
Methanol. Bull. Korean Chem. Soc. 1995, 16, 1141−1143.
́
́
̌
́
(29) Stojanovic, M.; Aleksic, J.; Dzambaski, Z.; Baranac-Stojanovic,
M. In Chemoselective Alkylation of β-Enamino Esters with Ethyl
Propiolate: Experimental and Theoretical Study, The 13th International
Conference on Fundamental and Applied Aspects of Physical
Chemistry; Belgrade, Serbia, September 26−30, 2016; Vol. 1, pp
26−30.
(16) (a) Murphy, J. P.; Hadden, M.; Stevenson, P. J. Aza-Annulation
of Enaminones with Crotonyl Chloride - Formal reversal of
regioselectivity. Tetrahedron 1997, 53, 11827−11834. (b) Leflemme,
N.; Dallemagne, P.; Rault, S.; Versatile, A. and Efficient Synthesis of
2-Alkyl and 2-Aryl-6-alkyl-2,3-dihydro-1H-pyridin-4-ones. Synthesis
2002, 1740−1746. (c) Svetlik, J.; Kettmann, V.; Zaleska, B. A New
(30) (a) Shaikh, N. S.; Deshpande, V. H.; Bedekar, A. V. Clay
Catalyzed Chemoselective Michael Type Addition of Aliphatic
L
https://dx.doi.org/10.1021/acs.joc.0c01537
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Amines to α,β-Ethylenic Compounds. Tetrahedron 2001, 57, 9045−
9048. (b) Varala, R.; Alam, M. M.; Adapa, S. R. Chemoselective
Michael Type Addition of Aliphatic Amines to α,β-Ethylenic
Compounds Using Bismuth Triflate Catalyst. Synlett 2003, 720−
722. (c) Basu, B.; Das, P.; Hossain, I. Synthesis of β-Amino Esters via
Aza-Michael Addition of Amines to Alkenes Promoted on Silica: A
Useful and Recycable Surface. Synlett 2004, 2630−2632.
(31) Thorwirth, R.; Stolle, A. Solvent-Free Synthesis of Enamines
from Alkyl Esters of Propiolic or But-2- yne Dicarboxylic Acid in a
Ball Mill. Synlett 2011, 2200−2202.
4-Pyridone, and 3-Pyrrolone Derivatives. J. Org. Chem. 2013, 78,
12018−12028.
(40) Zupancic, S.; Svete, J.; Stanovnik, B. Synthesis and Trans-
formations of Alkyl 1,5-Bis(dimethylamino)-3-oxopenta-1,4-diene-
2,4-dicarboxylates. A Simple Synthesis of Dialkyl 1-Substituted 4-
Oxo-1,4-dihydropyridine-3,5-dicarboxy-lates. Heterocycles 2000, 53,
2033−2042.
(41) Yu, Y.; Zhang, Y.; Xiao, L.-Y.; Peng, Q.-Q.; Zhao, Y.-L.
Thermally induced formal [4+2] cycloaddition of 3-aminocyclobute-
nones with electron-deficient alkynes: facile and efficient synthesis of
4-pyridones. Chem. Commun. 2018, 54, 8229−8232.
(32) You, L.; Feng, S.; An, R.; Wang, X.; Bai, D. Silica gel accelerated
aza-Michael addition of amines to α,β-unsaturated amides. Tetrahe-
dron Lett. 2008, 49, 5147−5149.
(42) Bai, X.-d.; Wang, J.; He, Y. Iridium-Catalyzed Propenylation
Reactions for the Synthesis of 4-Pyridone Derivatives. Adv. Synth.
Catal. 2019, 361, 496−501.
́
(33) (a) Szaloki, G.; Sanguinet, L. Silica-Mediated Synthesis of
(43) Shiotsuki, M.; Kai, H.; Endo, T. Radical Polymerization of 2,5-
Norbornadienes Containing Ester Groups byAIBN and Oxygen Gas.
J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 2528−2536.
Indolinooxazolidine-Based Molecular Switches. J. Org. Chem. 2015,
80, 3949−3956. (b) Susanti, D.; Ng, L. L. R.; Chan, P. W. H. Silica
Gel-Mediated Hydroamination/Semipinacol Rearrangementof 2-
Alkylaminophenylprop-1-yn-3-ols: Synthesis of 2-Oxindolesfrom
Alkynes and 1-(2-Aminophenyl) Ketones. Adv. Synth. Catal. 2014,
356, 353−358. (c) Chaturvedi, A. K.; Negi, A. S.; Khare, P. A Simple
and Straightforward Synthesis of Substituted 2-Arylbenzimidazoles
over Silica Gel. RSC Adv. 2013, 3, 4500−4504.
́
́
(44) Jasinski, M.; Mloston, G.; Mucha, P.; et al. Synthesis of New
Bis-imidazole Derivatives. Helv. Chim. Acta 2007, 90, 1765−1780.
(45) Sawant, D. P.; Justus, J.; Balasubramanian, V. V.; Ariga, K.;
Srinivasu, P.; Velmathi, S.; Halligudi, S. B.; Vinu, A. Heteropoly Acid
Encapsulated SBA-15/TiO2 Nanocomposites and Their Unusual
Performance in Acid-Catalysed Organic Transformations. Chem. Eur.
J. 2008, 14, 3200−3212.
(34) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Recent Advances in
the Baylis−Hillman Reaction and Applications. Chem. Rev. 2003, 103,
811−891.
(46) Kour, M.; Paul, S. A Green and Convenient Approach for the
One-Pot Solvent-Free Synthesis of Coumarins and β-Amino Carbonyl
Compounds Using Lewis Acid Grafted Sulfonated Carbon@Titania
Composite. Monatsh. Chem. 2017, 148, 327−337.
(35) (a) Gao, X.; Singh, R. P.; Corey, E. J. Enantioselective Synthesis
of a Chiral C3-Symmetric Bridgehead Amine. Org. Lett. 2010, 12,
1812−1814. (b) Burckhardt, T.; Harms, K.; Koert, U. Total Synthesis
of Lodopyridone. Org. Lett. 2012, 14, 4674−4677. (c) Koperniku, A.;
Zamiri, M.; Grierson, D. S. The Reaction of N-Trimethylsilyl-
Substituted Heteroarylamines with Esters and Thioesters: An Efficient
Protocol To Access Diheteroarylamides. Synthesis 2019, 51, 1779−
1790.
(36) (a) Tan, L.; Tao, Y.; Wang, T.; Zou, F.; Zhang, S.; Kou, Q.;
Niu, A.; Chen, Q.; Chu, W.; Chen, X.; Wang, H.; Yang, Y. Discovery
of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-
Spectrum Antibiotics for Multidrug-Resistant GramNegative Infec-
tions. J. Med. Chem. 2017, 60, 2669−2684. (b) Miyagawa, M.;
Akiyama, T.; Mikamiyama-Iwata, M.; Hattori, K.; Kurihara, N.;
Taoda, Y.; Takahashi-Kageyama, C.; Kurose, N.; Mikamiyama, H.;
Suzuki, N.; Takaya, K.; Tomita, K.; Matsuo, K.; Morimoto, K.;
Yoshida, R.; Shishido, T.; Yoshinaga, T.; Sato, A.; Kawai, M.
Discovery of novel 5-hydroxy-4-pyridone-3-carboxy acids as poten-
tinhibitors of influenza Cap-dependent endonuclease. Bioorg. Med.
Chem. Lett. 2016, 26, 4739−4742. (c) Kitagawa, H.; Ozawa, T.;
Takahata, S.; Iida, M.; Saito, J.; Yamada, M. Phenylimidazole
Derivatives of 4-Pyridone as Dual Inhibitors of Bacterial Enoyl-Acyl
Carrier Protein Reductases FabI and FabK. J. Med. Chem. 2007, 50,
4710−4720. (d) Mitscher, L. A. Bacterial Topoisomerase Inhibitors:
Quinolone and Pyridone Antibacterial Agents. Chem. Rev. 2005, 105,
559−592.
̈
(37) (a) Obydennov, D. L.; Roschenthaler, G.-V.; Sosnovskikh, V. Y.
An improved synthesis and some reactions of diethyl4-oxo-4H-pyran-
2,5-dicarboxylate. Tetrahedron Lett. 2013, 54, 6545−6548.
̃ ̃
(b) Rumbo, A.; Mourino, A.; Castedo, L.; Mascarenas, J. L. 3-
Hydroxy-4-pyrones as Precursors of 4-Methoxy-3-oxidopyridinium
Ylides. An Expeditious Entry to Highly Substituted 8-
Azabicyclo[3.2.1]octanes. J. Org. Chem. 1996, 61, 6114−6120.
(c) Elkaschef, M. A.-F.; Nosseir, M. H. The 4-Pyrones. Part I.
Reactions of Some 4-Pyrones and 4-Thiopyrones Involving the Ring
Oxygen. J. Am. Chem. Soc. 1960, 82, 4344−4347.
(38) Zhang, Z.; Fang, S.; Liu, Q.; Zhang, G. Approach to
Polysubstituted 4-Pyridones from N-Aryl Acetoacetamides via a N
to C 1,3-Acyl Migration Mediated by Sodium Persulfate. J. Org. Chem.
2012, 77, 7665−7670.
(39) Qiu, Y.-F.; Yang, F.; Qiu, Z.-H.; Zhong, M.-J.; Wang, L.-J.; Ye,
Y.-Y.; Song, B.; Liang, Y.-M. Brønsted Acid Catalyzed and NIS-
Promoted Cyclization of Diynones: Selective Synthesis of 4-Pyrone,
M
https://dx.doi.org/10.1021/acs.joc.0c01537
J. Org. Chem. XXXX, XXX, XXX−XXX