Synthesis of Multifunctionalized 2,3-Dihydro-4-pyridones and 4-Pyridones via the Reaction of Carbamoylated Enaminones with Aldehydes

Article abstract of DOI:10.1021/acs.joc.8b02075

The novel and effective diastereoselective synthesis of multifunctionalized dihydropyridones, including CF₃-substituted derivatives, has been developed on the basis of the piperidine-promoted domino reaction of carbamoylated enaminones with ald

Full text of DOI:10.1021/acs.joc.8b02075

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Article
Synthesis of multifunctionalized 2,3-dihydro-4-pyridones and 4-
pyridones via the reaction of carbamoylated enaminones with aldehydes
Dmitrii L'vovich Obydennov, Asmaa Ibrahim El-Tantawy, and Vyacheslav Y. Sosnovskikh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02075 • Publication Date (Web): 18 Oct 2018
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Synthesis of multifunctionalized 2,3-dihydro-4-pyridones and 4-pyridones via
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the reaction of carbamoylated enaminones with aldehydes
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Dmitrii L. Obydennov,*a Asmaa I. El-Tantawy,a,b Vyacheslav Y. Sosnovskikha
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a Institute of Natural Sciences and Mathematics, Ural Federal University, 620000 Ekaterinburg,
Russian Federation. E-mail: dobydennov@mail.ru
b Department of Physics and Engineering Mathematics, Faculty of Electronic Engineering, Menoufia
University, 32952 Menouf, Egypt
O
NHR1
O
O
NHR1
O
R1
H
R2CHO
N
O
O
I2
NHR1
, MeCN
, CHCl3
X3C
N
R1
X3C
N
R1
R2
R2
X3C
piperidine
X = H, F; R1 = Ar, Bn; R2 = Ar, Het
- trans-diastereoselectivity
- 21 examples
- yields up to 90%
45-83%
ABSTRACT: The novel and effective diastereoselective synthesis of multifunctionalized
dihydropyridones, including CF3-substituted derivatives, has been developed on the basis of the
piperidine-promoted domino reaction of carbamoylated enaminones with aldehydes. The products
have been prepared in 38–90% yields and can be easily isolated by crystallization. Tautomerism,
epimerization and atropisomerism of dihydropyridones have been studied. The use of the resulting
dihydropyridones in the synthesis of 1,2,6-trisubstituted 4-pyridone-3-сarboxamides has been
demonstrated via oxidative aromatization initiated by iodine.
INTRODUCTION
2,3-Dihydro-4-pyridones are a very important class of valuable intermediates for the preparation
of substituted piperidines,1 including natural compounds and pharmaceuticals, via reduction,
nucleophilic addition of organometallics and cycloaddition. Since piperidine ring is a key unit for
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medicinal chemistry and has been recently reported to be the most frequently used non-aromatic
ring in small molecule drugs,2 the search of new approaches for the preparation of this heterocycle
as well as precursors for it has been highly sought.
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In the literature several strategies for the synthesis of 2,3-dihydro-4-pyridone derivatives have
been described. The most general method includes modification of preconstructed nitrogen
heterocyclic ring system.3 This synthetic methodology extensively developed by Comins has been
applied for the stereoselective construction of many piperidine derived alkaloids by the reaction of
1-acyl salts of 4-methoxypyridines with organometallics.3a,4 There are also transformations of this
type with the use of the modification of piperidine derivatives5 or the transformation of 2,3-
dihydropyran-4-ones with ammonia.6 The other group of modern methods for the construction of
multifunctionalized 2,3-dihydro-4-pyridones is de novo synthesis of these heterocycles based on
intramolecular cyclizations of substituted open chain precursors.7 This type of transformations
includes reactions of imines with electron-rich dienes or 1,3-diketones8a–e and cyclobutanones,8f
cyclization of functionalized amino acid via a nucleophilic attack of the amino group,9 annulation of
α,α-alkenoyl ketene dithioacetals or α,β-unsaturated 1,3-diketones with primary amines,10 [5+1]-
cycloaddition of N-formylmethyl-substituted tertiary enamides to isocyanides.11
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Since dihydropyridones belong to the class of cyclic enaminones, a convenient strategy for the
synthesis of these nonaromatic heterocycles involves the reaction of acyclic enaminones with α,β-
unsaturated acid chlorides,12 the enaminone cyclization via Dieckman condensation13 or generation
of ketenes from diazo ketones14 (Scheme 1). Besides, the approach based on the in situ formation of
possible enaminone intermediates has been reported to be the multicomponent transformation of
3,5-dioxohexanoate with aromatic aldehydes and ammonium acetate leading to N-unsubstituted
trans-dihydropyridones.15 To the best of our knowledge, this reaction is the only example of the
dihydropyridone diastereoselective synthesis via a ring closing process. Although these
transformations are convenient synthetic approaches based on available starting compounds and
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proceed without the use of organometallics, the range of these methods is limited. Thus, there is
continued interest and great importance to explore and develop novel ring closing reactions for the
construction of 2,3-dihydro-4-pyridones as valuable synthetic intermediates for organic synthesis.
Here we report a novel piperidine-mediated diastereoselective synthesis of multiply functionalized
2,3-dihydro-4-pyridones from carbamoylated enaminones and aromatic aldehydes (Scheme 1).
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Scheme 1. Approaches for the de novo synthesis of dihydropyridones on the basis of acyclic
enaminones
Previous work
O
O
O
O
R3
R3
R4
NEt3
+
R4
H
Ref. 12
Cl
R2
O
R2
N
N
CH2R1
CH2R1
O
O
O
Base
t-BuO
t-BuO
OEt
Ref. 13
R1
R1
N
H
R
N
H
R
O
O
O
Ag+
R1
R1
Ref. 14
R2
R2
O
N
R3
N
R3
N2
O
This work
O
R1
H
NHR1
R2CHO
N
O
O
X3C
NHR1
X3C
N
R2
R1
Enaminones and β-ketoamides are known16 to be useful substrates for multiple bond-forming
transformations (MBFTs), including domino and multicomponent reactions, because of exhibiting
several potential reaction sites and the selective control of their reactivity. Carbamoylated
enaminones 1 and 2 incorporate both these moieties (Scheme 2). This structural feature allows to
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consider these substrates as novel multifarious intermediates for organic synthesis. Recently, we
have found that these reactive compounds can be readily obtained from bio-based lactone triacetic
acid or 2-cyano-4-pyrones via the ring-opening transformation with amines.17 It has been shown that
carbamoylated enaminones 1 and 2 react with DMA-DMF to produce 4-pyridone-3-
carboxamides17b,c and undergo cyclization to 4-hydroxy-2-pyridone under acidic conditions (Scheme
2).17a
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Scheme 2. The preparation of carbamoylated enaminones 1, 2 and some of their chemical
properties17
O
O
OH
F3C
CN
Me
O
O
bio-based
triacetic acid
lactone
NH2R1
R1
H
N
O
O
X3C
NHR1
1:
2:
X = H
X = F
H+
DMA-DMF
H
R1
O
O
N
OH
X3C
N
X3C
N
O
R1
R1
Our continuous interest in the exploration of the chemistry of triacetic acid lactone as the
potential platform molecule in the synthesis of heterocyclic products via the formation of the ring-
opening derivatives, has prompted us to study new transformations of carbamoylated enaminones.
Based on the polynucleophilic nature of these polycarbonyl intermediates 1, we envisioned to
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construct partly saturated azaheterocycles by the reaction of enaminones 1 with aromatic aldehydes,
which are known to be 1,1-electrophilic building-blocks for cyclization with nucleophilic
substrates,18 namely the Pictet-Spengler isoquinoline and Hantzsch pyridine syntheses.
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RESULTS AND DISCUSSION
We commenced our study by examining the reaction of N-phenylsubstituted enaminone 1a and p-
bromobenzaldehyde (Table 1). We suggested that the formation of two products, such as endione 3a
and dihydropyridone 4a, can occur. The former is connected with the cyclization of carbamoylated
enaminone following by elimination of aniline (6-exo-trig), the second one is the result of an attack
of the NHPh group on the activated double bond of intermediate A (6-endo-trig).17a
We observed that the reaction led to dihydropyridone 4a, and compound 3a was not detected at
all. It was found that this transformation gave product 4a by simple refluxing in EtOH without any
catalysts for 4 h in 32% yield (entry 1). Carrying out the reaction in pyridine did not lead to desired
dihydropyridone 4a and no product was isolated (entry 2). When piperidinium acetate in EtOH as
the classic Knövenagel reaction catalyst was used, the yield was increased to 49% (entry 3). To our
delight, the reaction in refluxing EtOH in the presence of piperidine (1.2 equiv) gave product 4a in
69% yield (entry 4). Variation of base nature (Et3N, DBU, DABCO, DMAP) did not allow to
improve the outcome of 4a (entries 5–8). Next, solvent screening in the presence of piperidine as the
catalyst of choice (1.2 equiv) indicated that EtOH, dioxane, pyridine, benzene, toluene and DMF
were less effective reaction media (entries 4, 9–13) than MeCN, which provided the best yield
(79%) (entry 14). The change of the piperidine amount did not improve the reaction yield (entries 15
and 16). Performing the transformation in the presence of piperidine (0.6 equiv) still produced 4a in
a high yield (78%), but the reaction time increased to 4 h (entry 16). Finally, the transformation was
shown to be amenable to gram-scale (1 g), as product 4a was isolated in 73% yield.
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Table 1. The optimization of the reaction conditions for the ring-closing transformation of
enaminone 1a with 4-bromobenzaldehydea
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8
Ph
H
N
O
O
Ph
H
N
O
O
Me
NHPh
Me
NHPh
1a
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+
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A
Br
Br
CHO
6-exo-trig
-PhNH2
6-endo-trig
O
N
O
O
NHPh
Me
O
Br
Me
N
Ph
Ph
Br
3a
4a
Entry
Solvent
Base (equiv)
Time, hb
Yield 4a,
c
%
1
2
3
EtOH
pyridine
EtOH
−
−
4
10
6
32
−
49
piperidine (1.2),
AcOH
piperidine (1.2)
4
5
6
7
8
EtOH
EtOH
EtOH
EtOH
EtOH
dioxane
pyridine
benzene
toluene
DMF
MeCN
MeCN
MeCN
2.5
6
6
6
6
5
1.5
3
2
2
69
10
−
Et3N (1.2)
DBU (1.2)
DABCO (1.2)
DMAP (1.2)
piperidine (1.2)
piperidine (1.2)
piperidine (1.2)
piperidine (1.2)
piperidine (1.2)
piperidine (1.2)
piperidine (1.5)
piperidine (0.6)
39
46d
42
40
57
74
10
79
74
78
9
10
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12
13
14
15
16
2
2
4
a Enaminone 1a (0.10 g, 0.34 mmol) and 4-bromobenzaldehyde (68 mg, 0.37 mmol) were used in refluxing solvent.
b The reaction time was determined by TLC.
c Isolated yield.
d The reaction was carried out at 20 °C.
With the optimized conditions in hand, we probed the scope of the reaction with respect to both
enamides 1 and aldehydes. First, the scope of aldehydes was evaluated with regard to enaminone 1a
(Scheme 3, Table 2). Aromatic aldehydes gave dihydropyridones 4a–k in 38–81% yields, which
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could be isolated by simple filtration without the use of chromatography. The yields of the products
depend on both steric and electronic factors of substituents in benzaldehydes. The best yields were
obtained for aldehydes bearing the electron-withdrawing groups (4-halogen and 4-NO2) on the
phenyl ring and products 4a,b,d were obtained under refluxing for 2–3 h in 79–81% yields. The
reaction with less reactive 4-MeO and 4-Me2N-substituted benzaldehydes took a longer time to form
dihydropyridones 4e,f in 65% and 54% yields, respectively. The transformation with 2,4-dichloro-
and 2,4-dimethoxybenzaldehydes bearing substituents at the ortho-position under the optimized
reaction conditions led to 4g,h (66–72%), which contained 10% of 4-hydroxy-N-phenyl-2-pyridone
as the by-product of the competitive enaminone cyclization.17a Recrystallization of dihydropyridone
4g from toluene made it possible to obtain the pyridone in pure form in 38% yield. When 2,4-
dimethoxybenzaldehyde (1.5 equiv) was used for suppressing cyclization of enaminone 1a, pyridone
4h was produced exclusively in 70% yield.
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The reaction was readily expanded to heterocyclic aldehydes to obtain hetaryl substituted
dihydropyridones. Pyridine-2-carbaldehyde and thiophene-2-carbaldehyde gave dihydropyridones
4i,j under the optimized conditions in 22% and 37% yields, respectively, and in the crude products,
an impurity of N-phenyl-4-hydroxy-2-pyridone was also observed. Performing the reaction with 1.5
equiv of the aldehydes increased the reaction efficiency significantly, and products 4i,j were
obtained in high yields (73–76%). For less reactive furfurol, the transformation furnished only traces
of dihydropyridone 4k under the optimized conditions. When pyridine as a solvent was employed,
the desired product 4k was isolated in 68% yield. The proposed mechanism of the dihydropyridone
formation includes the Knövenagel reaction of enamides 1 leading to the intermediate A.
Isomerization of A gives intermediate B, which undergoes the intramolecular Michael reaction to
produce dihydropyridones 4 (Scheme 3).
Interestingly, the reaction of enaminone 1a with salicylic aldehyde bearing the additional
nucleophilic center did not give the desired dihydropyridone and led to N-phenylcoumarin-3-
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carboxamide (6) in 69% yield as the result of C–C cleavage of enaminone 1a (Table 2, Fig. 1). It
should be noted that the reaction of enamide 1a with aliphatic (valeraldehyde) and unsaturated
(cinnamaldehyde) aldehydes did not lead to the desired products because of their low reactivity.
Scheme 3. Reaction of Me-substituted enaminones 1 with aldehydes
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O
N
NHR1
O
R1
H
R2CHO
N
O
O
3
2
Me
NHR1
R2
Me
1a-d
R1
4
R2CHO
R1
H
O
O
N
O
O
NHR1
Me
NHR1
Me
NH R2
R1
R2
A
B
Table 2. Reaction scope study of enaminones 1 with aldehydesa
Enaminone Product
R1
R2
Time, hb
Yield,
%
79
80
77
1a
1a
1a
1a
1a
1a
1a
4a
4b
4c
4d
4e
4f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-BrC6H4
4-ClC6H4
Ph
4-NO2C6H4
4-MeOC6H4
4-Me2NC6H4
2,4-
(MeO)2C6H3
2,4-Cl2C6H3
2-pyridinyl
2-thienyl
2-furyl
4-BrC6H4
4-ClC6H4
Ph
2
3
5
3
7
81
65
4
1.5
54
4g
70c
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
1a
1d
4h
4i
4j
4k
4l
4m
4n
5o
4p
4r
4s
6
Ph
Ph
Ph
Ph
4
3
4
4
4
4
3
13
7
4
38
76c
73c
68d
85
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
2-MeOC6H4
2-MeOC6H4
Ph
70
67
54
55
4-NO2C6H4
4-MeOC6H4
4-BrC6H4
4-ClC6H4
2-HOC6H4
4-BrC6H4
56e,f
64e
69
4
2.5
2
7
Bn
26d
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1d
8
Bn
4-NO2C6H4
2
39g
a Unless otherwise noted, enaminone (0.34 mmol) and aldehyde (0.37 mmol) were refluxed with piperidine (35 mg, 0.41
mmol) in MeCN (2 mL).
b The reaction time was determined by TLC.
c Aldehyde (0.51 mmol) was used.
d Pyridine was used as a solvent instead of MeCN.
e Trans : cis = 94 : 6 (DMSO-d6).
f Pyridone 5r formed in 23% yield at refluxing for 4 h in pyridine.
g The reaction was carried out at 20 °C.
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The structure of enaminones 1 has also an influence on the dihydropyridone formation.
Enaminone 1b (R1 = 4-MeOC6H4) reacted with aromatic amines to produce desired
dihydropyridones 4l–n,p in 55–85% yields (Table 2). However, the transformation of enaminone 1b
with p-NO2-benzaldehyde with did not give dihydropyridone 4o and refluxing in MeCN for 13 h led
to pyridone 5o in 54% yield (Table 2, Fig. 1). The formation of the product can be explained by
auto-oxidative aromatization of intermediately formed compound 4o with the aldehyde or oxygen of
the air. Next, sterically hindered enaminone 1c possessing the MeO group at the ortho-position of
the phenyl moiety was used for the synthesis of dihydropyridones. Introduction of this substituent
did not affect the product formation. In fact, the reaction of 1c with 4-bromo- and 4-
chlorobenzaldehydes under the optimized conditions gave dihydropyridones 4r,s in 56% and 64%
yields, respectively. It should be noted that pyridone 5r (Table 2, Fig. 1) was observed as a by-
product when the transformation of 1c with 4-bromobenzaldehyde was carried out under prolonged
refluxing (14 h) in MeCN or in pyridine (4 h); in the latter case, pyridone 5r was obtained in 23%
yield.
When we carried out the reactions of benzyl substituted enaminone 1d with 4-
bromobenzaldehyde in refluxing pyridine and 4-nitrobenzaldehyde at room temperature in MeCN,
the formation of Knövenagel product 7 (26%) and ketoamide 8 (39%) were observed, respectively
(Table 2, Fig. 1). Thus, for Bn-substituted enamide 1d, the cyclization did not occur under the
optimized conditions, it may be explained by the steric and electronic effects of the Bn group.
Compounds 7 and 8 can be considered as possible intermediates of the described transformation.
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O
O
NHR1
O
NHPh
5
6
7
8
O
O
Me
N
R1
R2
6
(69%)
1
2
5o:
5r:
R = 4-MeOC6H4, R = 4-NO2C6H4 (54%)
R = 2-MeOC6H4, R = 4-BrC6H4 (23%)
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H
H
Ph
Ph
Me
N
O
O
N
O
O
N
H
Ph
Br
Me
N
Ph
H
N
NO2
7
(26%)
8
(39%)
Fig. 1. By-products from the reaction of enaminones 1 with benzaldehydes.
The trans-configuration of dihydropyridones 4 was unambiguously confirmed by X-ray
diffraction analysis of compound 4k as a representative example (Fig. 2). Compounds 4 exist in a
half-chair conformation. The aryl and carbamoyl groups are found to be in the pseudo-axial
positions at the C-2 and C-3 atoms of the dihydropyridone ring, respectively. The aryl group
attached to N-1 is in the pseudo-equatorial orientation. The weak intramolecular NH···O=C
hydrogen bond with a distance of 2.857 Å presents in the molecule as the result of interaction of the
amide moiety and the carbonyl group of the dihydropyridone ring.
1
In the H NMR spectra of dihydropyridones 4a–n,p in DMSO-d6, characteristic doublets of the
H-2 and H-3 protons of the pyridone ring were observed at δ 3.56–4.00 and 5.23–5.67 ppm with J =
3
4.6–6.4 Hz, and the NH group appeared at δ 9.70–9.90 ppm. It should be noted that JH-2,H-3
coupling constant depends on NMR solvents very significantly. For instance, the NMR spectrum of
4a in CDCl3 displayed the appearance of the doublets with J = 0.8 Hz. The small value of the
constant is in accordance with the literature data4a,9d for known N-substituted trans-2,3-
dihydropyridones possessing the carbamoyl or carbomethoxy group at the C-3-position.
3
Interestingly, for N-unsubstituted trans-3-carbomethoxy-2,3-dihydropyridones, JH-2,H-3 coupling
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constant is equal to ca. 13.5 Hz (CDCl3), this fact can be explained by changing the conformation of
the molecules comparing to compounds 4 and the pseudo-equatorial position of the substituents at
the C-2 and C-3 positions.15
8
9
It is noteworthy that the presence of the cis-diastereomer was not observed for compounds 4a–
n,p at all. The high diastereoselectivity of the transformation can be connected with the formation of
the most thermodynamically stable product.
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Fig. 2. Molecular structure of 4k (ORTEP drawing, 50% probability level).
Compounds 4r,s bearing the 2-MeOC6H4 moiety at N-1 can exist as anti- and syn-atropisomers,
which have different orientation of the MeO group relative to the R2 substituent, because rotation
around the C–N bond became impossible under the usual conditions as the result of the steric
hindrance in these molecules (Scheme 4). Besides, the strong spatial interaction of the groups in
molecules 4r,s can lead to high potential energy and conformation movement following by
epimerization at the C-3 position. It was found that the reaction gave a mixture of anti-trans-4 and
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syn-trans-4 in a ratio of 3 : 1 and 4 : 3, when the 1H NMR spectra of products 4r,s were recorded in
CDCl3 and DMSO-d6, respectively. This fact can be explained by the existence of these
atropisomers in equilibrium. It should be noted that isomers cis-4r,s were also detected with a low
content of 6% (DMSO-d6) and 9% (CDCl3).
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1
In the H NMR spectra of cis-4r,s, the characteristic singlet of the NH proton appeared in a
downfield region at ca. δ 11.5 ppm in CDCl3 (for 4r) and at δ 11.35 ppm for anti-cis-4r,s and δ
11.55 ppm for syn-cis-4r,s in DMSO-d6, whereas the NH proton of the trans-isomers manifested at
δ 9.21–9.34 and 9.09 ppm in CDCl3 (for 4r) and DMSO-d6, respectively. The difference in the
chemical shifts of the NH protons can be connected with the strength of the intramolecular hydrogen
bond, which is probably stronger in the case of the cis-isomers possessing more appropriate
geometry for this interaction with shorter NH···O=C distance. It should be noted that for cis-4r, the
doublets of the H-2 and H-3 protons of the pyridone ring in CDCl3 were observed at δ 4.41 and 5.34
ppm with J = 6.6 Hz, which is consistent to the literature data.4a In the case of trans-4r,s, JH-2,H-3
3
coupling constant is equal to 0–1.8 Hz (for trans-4r) in CDCl3 and 8.4–12.2 Hz in DMSO-d6.
Scheme 4. Atropisomerism and epimerization of dihydropyridones 4r,s (selected 1H NMR chemical
shifts, δ, ppm, in DMSO-d6)
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R2
R2
OMe
H
N
H
N
O
O
Me
Me
H
9.09
H
9.09
OMe
O
O
NH
OMe
NH
OMe
9
10
11
12
13
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-
4r,s
-
4r,s
syn trans-
anti trans-
R2
R2
OMe
H
N
H
N
Me
O
O
.
.
11.55
H
11.35
H
.
.
Me
N
N
OMe
H
H
O
O
MeO
MeO
-
4r,s
anti cis-
-
4r,s
syn cis-
2
4r:
R = 4-BrC6H4
2
4s:
R = 4-ClC6H4
Dihydropyridones bearing the CF3 group have attracted attention as intermediates for the
preparation of biologically important CF3-piperidines.17 But a range of such dihydropyridones as
well as approaches to their synthesis is limited by few protocols including radical
trifluoromethylation.19 It should be noted that 6-CF3-2,3-dihydro-4-pyridones are hard-to-reach
compounds and in the literature the only example of them, ethyl 6-(4-chlorophenyl)-4-oxo-2-
(trifluoromethyl)-1,4,5,6-tetrahydropyridine-3-carboxylate, has been described.20 Therefore, we
studied the transformation of CF3-substituted enaminones 2 to develop the approach for the
preparation of 6-CF3-2,3-dihydropyridones. It was also important to investigate the influence of the
strong electron-withdrawing CF3 group on the cyclization process comparing with the Me group.
We observed that CF3-substituted enaminones 2 are more reactive than Me-substituted
enaminones 1 and the transformation of 2a,b with aldehydes led to piperidinium salts 9 at room
temperature (Scheme 5). The formation of salts is connected with higher CH-acidity of CF3-
dihydropyridones 10 in comparison with Me-substituted dihydropyridones 4 as the result of
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carbanion stabilization by the CF3 group. Following acidification of salts 9 with hydrochloric acid (1
: 8) led to desired CF3-dihydropyridones 10a–d in 68–90% yields. At the same time, N-Bn-
substituted enaminone 2c reacted with p-Br-benzaldehyde at room temperature to give only acyclic
derivative 11 in 84% yield (Scheme 5). Unfortunately, all our attempts to undergo selective acid-
catalyzed cyclization of compound 11 into corresponding Bn-substituted dihydropyridone were
unsuccessful. The target dihydropyridone was detected in a complex mixture of products when the
reaction was carried out in the presence of MeSO3H (2 equiv) in acetone.
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Scheme 5. Reaction of CF3-substituted enaminones 2 with aldehydesa
R1
H
H
H
N
R1
H
O
N
N
O
O
piperidine
MeCN, rt
R1 = Ar
O
F3C
NHR1
F3C
N
R1
R2
2a-c
+
R2CHO
9
R1 = Bn,
HCl
R2 = 4-BrC6H4
R1
O
H
H
Bn
O
N
N
O
N
O
H+
F3C
NHBn
F3C
N
R1
R2
Br
11
10a-d
Product
10a
10b
10c
10d
11
Enaminone
R1
Ph
Ph
Ph
R2
4-BrC6H4
4-ClC6H4
Ph
Yield, %
2a
2a
2a
2b
2c
90
81
68
79
84
4-MeOC6H4 4-BrC6H4
Bn 4-BrC6H4
a Enaminone (0.29 mmol) and aldehyde (0.32 mmol) were stirred with piperidine (30 mg, 0.35 mmol) in MeCN (2 mL)
for 24 h.
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It was found that dihydropyridones trans-10a–d exist in equilibrium with the enol form in
DMSO-d6 (15–21%) or the cis-isomer in CDCl3 (13% for 10d) (Scheme 6). Stabilization of the enol
6
7
1
form can be connected with basic properties of DMSO-d6. In the H NMR spectra of
8
9
dihydropyridones trans-10a–d, the characteristic singlet of the amide NH proton appeared at δ
10.03–10.20 ppm in DMSO-d6 and, in the case of 10d, at δ 8.11 ppm in CDCl3. At the same time,
the NH proton of cis-10d was shifted downfield by Δδ ≈ 2.4 ppm and manifested at δ 10.48 ppm as
the result of the formation of the intramolecular hydrogen bond. For enol-10a-d in DMSO-d6, the
OH and NH groups were observed at δ 13.30–13.55 and 9.58–9.89 ppm, respectively (Scheme 6).
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1
Scheme 6. Equilibrium of dihydropyridones 10 (selected H NMR chemical shifts, δ, ppm, in
DMSO-d6 or in CDCl3)
10d
8.11 (for
)
R1
10.03-10.20
H
O
N
O
F3C
N
R2
R1
CDCl3
DMSO-d6
10a-d
trans-
10.48
13.30-13.55
H
H
R1
O
O
O
O
N
9.58-9.89
NHR1
F3C
N
R2
F3C
N
R1
R1
Br
10d
10a-d
cis-
enol-
R1 = 4-MeOC6H4
Next, taking into account the spontaneous oxidation of some dihydropyridones 4 during the
reaction of carbamoylated enaminones with aldehydes, we decided to carry out the oxidative
aromatization of dihydropyridones into new 2,6-disubstituted 4-pyridone-3-carboxamides. The latter
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9
are biologically important compounds for medicinal chemistry, but their methods of construction are
limited by several examples.21 Although the general oxidation of dihydropyridone is based on
treatment with DDQ as an oxidant, we developed a convenient and more applicable approach.
Different oxidants such as K3[Fe(CN)6], DMSO, O2, I2 in various solvents were applied and the best
results were observed with the use of I2 in refluxing CHCl3. When the oxidative aromatization was
carried with iodine (2 equiv) for 4 h, incomplete conversion (~50%) was achieved though TLC did
not display the presence of starting dihydropyridone. Even prolonged refluxing did not improve the
result. We proposed that the partial conversion can be explained by the molecular complex
formation of dihydropyridones with HI. It was found that removal of HI by evaporation or treatment
with water, and the further oxidation with iodine made it possible to transform dihydropyridones to
pyridones completely. As the result, pyridones 5 and 12a were obtained in 45–83% yields by using
this iodine-promoted aromatization (Scheme 7).
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11
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Scheme 7. Iodine-promoted synthesis of pyridones 5 and 12a
O
NHR1
O
O
NHR1
O
I2
CHCl3, 
R
N
R2
R
N
R2
R1
R1
4, 10a
5, 12a
Pyridone
R
R1
Ph
Ph
R2
4-BrC6H4
2-C4H3S
Ph
Yield, %
5a
5j
5n
5r
Me
Me
Me
Me
CF3
78
61
83
45
56
4-MeOC6H4
2-MeOC6H4 4-BrC6H4
Ph 4-BrC6H4
12a
СONCLUSIONS
In summary, we have found the new and efficient approach for the diastereoselective
construction of dihydropyridones via the ring-closing transformation of carbamoylated enaminones
with aldehydes. Enaminones bearing the CF3 group are more reactive than Me substituted ones and
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gave new CF3-dihydropyridones under mild conditions in high yields. The introduction of the CF3
group onto the dihydropyridone moiety leads to increasing their CH-acidity, and these compounds
undergo keto-enol tautomerism or epimerization depending on the solvent medium. The reaction
with N-benzyl substituted enaminones leads to the formation of acyclic ketoamides, which can be
considered as possible intermediates of the transformation. The synthetic potential of the reaction
products has been demonstrated by the convenient preparation of multifunctional pyridones through
iodine-promoted oxidation.
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EXPERIMENTAL SECTION
General information
1H, 19F and 13C NMR spectra were recorded on 500, 471 and 126 MHz instruments, respectively,
1
in DMSO-d6 or CDCl3. Chemical shifts are reported relative to TMS, CHCl3 (δ = 7.26 ppm, H
1
13
NMR), DMSO-d6 (δ = 2.50 ppm, H NMR), and DMSO-d6 (δ = 39.52 ppm, C NMR) as internal
standards. IR spectra were recorded on a FTIR spectrometer with ATR accessory. All solvents used
were dried and distilled by standard procedures. Enaminones 1 and 2 were prepared according to
literature procedures.17
General method for the preparation of dihydropyridones 4
A mixture of carbamoylated enaminone 1 (0.34 mmol) and aldehyde (0.37 mmol, for 4g,i,j – 0.51
mmol) was refluxed with piperidine (35 mg, 0.41 mmol) in dry MeCN (2 mL) for the corresponding
time (Table 2). After the transformation completed (TLC), the reaction mixture was kept at –20 °C,
the product was filtrated and washed with cold toluene.
(2S*,3R*)-2-(4-Bromophenyl)-6-methyl-4-oxo-N,1-diphenyl-1,2,3,4-tetrahydropyridine-3-
carboxamide (4a). Yield 79% (124 mg), white powder, mp 235–237 °C. IR (ATR): 3268, 3168,
3085, 1683, 1602, 1530, 1246, 758 cm−1; 1H NMR (DMSO-d6, ppm) δ 1.85 (s, 3H), 3.65 (d, J = 5.9
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Hz, 1Н), 5.13 (s, 1Н), 5.44 (d, J = 5.9 Hz, 1Н), 7.03 (tt, J = 7.4, 0.9 Hz, 1Н), 7.22–7.38 (m, 9H),
4
5
1
7.49 (d, J = 8.4 Hz, 2Н), 7.54 (d, J = 7.6 Hz, 2Н), 9.91 (s, 1H); H NMR (CDCl3, ppm) δ 3.13 (s,
6
7
8
9
3H), 3.47 (d, J = 0.8 Hz, 1Н), 5.21 (s, 1Н), 5.64 (d, J = 0.8 Hz, 1Н), 7.12 (tt, J = 7.5, 1.1 Hz, 1Н),
7.17–7.25 (m, 1H), 7.25 (d, J = 8.3 Hz, 2Н), 7.30–7.40 (m, 6H), 7.46 (d, J = 8.3 Hz, 2Н), 7.57 (dd, J
10
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13
= 8.7, 0.9 Hz, 2Н), 8.68 (s, 1H); C{1H} NMR (DMSO-d6, ppm) δ 21.9, 59.0, 65.5, 99.9, 119.2,
120.8, 123.4, 127.6, 127.8, 128.7, 129.2, 129.7, 131.3, 137.9, 138.7, 142.9, 161.7, 166.4, 184.3.
Anal. Calcd for C25H21BrN2O2: C, 65.08; H, 4.59; N, 6.07. Found: C, 64.76; H, 4.45; N, 6.02.
(2S*,3R*)-2-(4-Chlorophenyl)-6-methyl-4-oxo-N,1-diphenyl-1,2,3,4-tetrahydropyridine-3-
carboxamide (4b). Yield 113 mg (80%), white powder, mp 219–221 °C. IR (ATR): 3267, 3065,
1682, 1600, 1530, 1487, 1245, 758 cm−1; 1H NMR (DMSO-d6, ppm) δ 1.85 (s, 3H), 3.67 (d, J = 6.0
Hz, 1Н), 5.13 (s, 1Н), 5.45 (d, J = 6.0 Hz, 1Н), 7.03 (tt, J = 7.4, 0.9 Hz, 1Н), 7.22–7.37 (m, 9H),
7.41 (d, J = 8.5 Hz, 2Н), 7.54 (d, J = 8.4 Hz, 2Н), 9.91 (s, 1H); 13C{1H} NMR (DMSO-d6, ppm) δ
21.9, 59.0, 65.5, 99.9, 119.2, 123.4, 127.6, 127.8, 128.3, 128.7, 129.2, 129.5, 132.2, 137.4, 138.7,
142.9, 161.7, 166.4, 184.4. Anal. Calcd for C25H21ClN2O2: C, 72.02; H, 5.08; N, 6.72. Found: C,
72.23; H, 5.06; N, 6.86.
(2S*,3R*)-6-Methyl-4-oxo-N,1,2-triphenyl-1,2,3,4-tetrahydropyridine-3-carboxamide (4c).
Yield 77% (100 mg), white powder, mp 181–182 °C. IR (ATR): 3313, 3056, 1681, 1615, 1600,
1529, 1252, 755 cm−1; H NMR (DMSO-d6, ppm) δ 1.86 (s, 3H), 3.67 (d, J = 5.5 Hz, 1Н), 5.11 (s,
1
1Н), 5.40 (d, J = 5.5 Hz, 1Н), 7.03 (tt, J = 7.4, 0.8 Hz, 1Н), 7.18–7.41 (m, 12H), 7.54 (d, J = 8.4 Hz,
2Н), 9.88 (s, 1H); C{1H} NMR (DMSO-d6, ppm) δ 21.9, 59.2, 66.2, 99.8, 119.2, 123.3, 127.4,
13
127.5, 127.6, 127.7, 128.4, 128.6, 129.1, 138.4, 138.7, 143.1, 161.6, 166.6, 184.4. Anal. Calcd for
C25H22N2O2: C, 78.51; H, 5.80; N, 7.32. Found: C, 78.35; H, 5.77; N, 7.43.
(2S*,3R*)-6-Methyl-2-(4-nitrophenyl)-4-oxo-N,1-diphenyl-1,2,3,4-tetrahydropyridine-3-
carboxamide (4d). Yield 0.117 g (81%), yellowish white powder, mp 223–225 °C. IR (ATR):
3274, 3129, 1688, 1622, 1515, 1322, 754 cm−1; 1H NMR (DMSO-d6, ppm) δ 1.89 (s, 3H), 3.69 (d, J
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= 5.4 Hz, 1Н), 5.16 (s, 1Н), 5.65 (d, J = 5.4 Hz, 1Н), 7.04 (tt, J = 7.4, 0.9 Hz, 1Н), 7.19–7.40 (m,
7H), 7.57 (d, J = 7.6 Hz, 2Н), 7.77 (d, J = 8.8 Hz, 2Н), 8.17 (d, J = 8.8 Hz, 2Н), 9.96 (s, 1H);
13C{1H} NMR (DMSO-d6, ppm) δ 21.9, 58.6, 65.5, 100.2, 119.2, 123.4, 123.5, 127.70, 127.72,
128.7, 128.9, 129.3, 138.6, 142.8, 146.2, 146.9, 161.8, 166.1, 184.0. Anal. Calcd for C25H21N3O4: C,
70.25; H, 4.95; N, 9.83. Found: C, 70.02; H, 4.95; N, 9.81.
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(2S*,3R*)-2-(4-Methoxyphenyl)-6-methyl-4-oxo-N,1-diphenyl-1,2,3,4-tetrahydropyridine-3-
carboxamide (4e). Yield 65% (91 mg), yellowish white powder, mp 208–210 °C. IR (ATR): 3292,
3077, 2928, 1686, 1615, 1599, 1527, 1487, 1248, 1116, 759 cm−1; 1H NMR (DMSO-d6, ppm) δ 1.83
(s, 3H), 3.67 (d, J = 6.2 Hz, 1Н), 3.68 (s, 3H), 5.10 (s, 1Н), 5.33 (d, J = 6.2 Hz, 1Н), 6.82 (d, J = 8.7
Hz, 2Н), 7.03 (tt, J = 7.4, 1.3 Hz, 1Н), 7.21–7.30 (m, 7H), 7.33 (dd, J = 8.5, 7.3 Hz, 2Н), 7.54 (dd, J
13
= 8.4, 1.1 Hz, 2Н), 9.87 (s, 1H); C{1H} NMR (DMSO-d6, ppm) δ 22.0, 54.9, 59.3, 65.7, 99.7,
113.7, 119.1, 123.3, 127.4, 127.8, 128.6, 128.7, 129.1, 130.2, 138.7, 143.0, 158.5, 161.5, 166.6,
184.7. Anal. Calcd for C26H24N2O3: C, 75.71; H, 5.86; N, 6.79. Found: C, 75.77; H, 5.84; N, 6.98.
(2S*,3R*)-2-(4-(Dimethylamino)phenyl)-6-methyl-4-oxo-N,1-diphenyl-1,2,3,4-
tetrahydropyridine-3-carboxamide (4f). Yield 54% (78 mg), beige powder, mp 221–223 °C. IR
1
(ATR): 3267, 3075, 1685, 1599, 1518, 1115, 766 cm−1; H NMR (DMSO-d6, ppm) δ 1.82 (s, 3H),
2.83 (s, 6H), 3.64 (d, J = 5.9 Hz, 1Н), 5.08 (s, 1Н), 5.23 (d, J = 5.9 Hz, 1Н), 6.59 (d, J = 8.8 Hz,
2Н), 7.02 (tt, J = 7.4, 1.1 Hz, 1Н), 7.14 (d, J = 8.7 Hz, 2Н), 7.20–7.30 (m, 5H), 7.33 (d, J = 7.9 Hz,
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2Н), 7.55 (d, J = 7.6 Hz, 2Н), 9.84 (s, 1H); C{1H} NMR (DMSO-d6, ppm) δ 22.0, 39.9, 59.4,
65.9, 99.5, 111.9, 119.1, 123.2, 125.3, 127.3, 127.8, 128.1, 128.6, 129.0, 138.8, 143.2, 149.6, 161.4,
166.8, 184.8. Anal. Calcd for C27H27N3O2: C, 76.21; H, 6.40; N, 9.87. Found: C, 76.03; H, 6.34; N,
9.56.
(2S*,3R*)-2-(2,4-Dimethoxyphenyl)-6-methyl-4-oxo-N,1-diphenyl-1,2,3,4-
tetrahydropyridine-3-carboxamide (4g). Yield 70% (105 mg), white powder, mp 210–211 °C. IR
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(ATR): 3273, 2938, 2837, 1685, 1698 1521, 1489, 1432, 1248, 1027, 684 cm−1; H NMR (DMSO-
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d6, ppm) δ 1.85 (s, 3H), 3.60 (d, J = 4.5 Hz, 1Н), 3.70 (s, 3H), 3.72 (s, 3H), 5.02 (s, 1Н), 5.47 (d, J =
4.5 Hz, 1Н), 6.46–6.52 (m, 2Н), 7.04 (tt, J = 7.4, 0.9 Hz, 1Н), 7.23–7.40 (m, 8Н), 7.59 (dd, J = 8.4,
1.0 Hz, 2Н), 9.81 (s, 1H); 13C{1H} NMR (DMSO-d6, ppm) δ 21.7, 54.9, 55.4, 57.1, 60.6, 98.0, 98.5,
104.4, 116.9, 119.1, 121.3, 123.1, 127.4, 127.5, 128.5, 128.9, 129.1, 138.6, 143.0, 156.8, 160.0,
161.6, 166.7. Anal. Calcd for C27H26N2O4: C, 73.28; H, 5.92; N, 6.33. Found: C, 73.27; H, 6.21; N,
6.48.
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(2S*,3R*)-2-(2,4-Dichlorophenyl)-6-methyl-4-oxo-N,1-diphenyl-1,2,3,4-tetrahydropyridine-
3-carboxamide (4h). After refluxing, the solvent was removed under reduced pressure and the
product was twice recrystallized from cold toluene. Yield 58 mg (38%), white powder, mp 179–180
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°C. IR (ATR): 3271, 3066, 1687, 1616, 1597, 1536, 1313, 746 cm−1; H NMR (DMSO-d6, ppm) δ
1.87 (s, 3H), 3.68 (d, J = 5.0 Hz, 1Н), 5.14 (s, 1Н), 5.67 (d, J = 5.0 Hz, 1Н), 7.05 (tt, J = 7.3, 0.9 Hz,
1Н), 7.27–7.47 (m, 7H), 7.46 (dd, J = 8.4, 2.1 Hz, 1Н), 7.57 (dd, J = 8.4, 0.9 Hz, 2Н), 7.58 (d, J =
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2.1 Hz, 1Н), 7.70 (d, J = 8.5 Hz, 1Н), 9.94 (s, 1H); C{1H} NMR (DMSO-d6, ppm) δ 21.9, 57.1,
62.6, 98.8, 119.3, 123.5, 127.71, 127.74, 128.1, 128.7, 129.38, 129.42, 130.4, 132.8, 133.4, 134.2,
138.5, 142.6, 162.3, 165.9, 183.5. Anal. Calcd for C25H20Cl2N2O2: C, 66.53; H, 4.47; N, 6.21.
Found: C, 66.84; H, 4.48; N, 6.43.
(2S*,3R*)-6-Methyl-4-oxo-N,1-diphenyl-2-(pyridin-2-yl)-1,2,3,4-tetrahydropyridine-3-
carboxamide (4i).Yield 76% (101 mg), brown crystals, mp 181–182 °C.IR (ATR): 3288, 3063,
2929, 1671, 1619, 1533, 1245, 749 cm−1; 1H NMR (DMSO-d6, ppm) δ 1.88 (s, 3H), 4.00 (d, J = 5.2
Hz, 1Н), 5.09 (s, 1Н), 5.42 (d, J = 5.2 Hz, 1Н), 7.03 (t, J = 7.4 Hz, 1Н), 7.20–7.40 (m, 8H), 7.44 (d,
J = 7.8 Hz, 1Н), 7.56 (d, J = 8.0 Hz, 2Н), 7.74 (td, J = 7.6, 1.3 Hz, 1H), 8.55 (d, J = 4.4 Hz, 1H),
9.96 (s, 1H); 13C{1H} NMR (DMSO-d6, ppm) δ 21.8, 57.2, 67.6, 100.1, 119.2, 122.5, 122.9, 123.3,
127.5, 127.6, 128.6, 129.1, 136.9, 138.7, 143.1, 149.4, 157.0, 161.3, 166.5, 184.6. Anal. Calcd for
C24H21N3O2·0.33H2O: C, 74.03; H, 5.61; N, 10.79. Found: C, 74.13; H, 5.85; N, 10.90.
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(2S*,3R*)-6-Methyl-4-oxo-N,1-diphenyl-2-(thiophen-2-yl)-1,2,3,4-tetrahydropyridine-3-
carboxamide (4j). After refluxing, the solvent was removed under reduced pressure and the product
was recrystallized from cold toluene. Yield 73% (98 mg), brown crystals , mp 141–143 °C. IR
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(ATR): 3297, 3274, 2946, 1681, 1619, 1536, 1490, 1247, 692 cm−1; H NMR (DMSO-d6, ppm) δ
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1.79 (s, 3H), 3.69 (d, J = 4.6 Hz, 1Н), 5.14 (s, 1Н), 5.64 (d, J = 4.6 Hz, 1Н), 6.91 (dd, J = 5.1, 3.5
Hz, 1Н), 7.00 (dd, J = 3.5, 1.1 Hz, 1Н), 7.04 (tt, J = 7.4, 0.9 Hz, 1Н), 7.23–7.33 (m, 5H), 7.39 (dd, J
= 7.9, 7.6 Hz, 2Н), 7.42 (dd, J = 5.1, 1.1 Hz, 1Н), 7.56 (dd, J = 8.5, 0.9 Hz, 2Н), 9.95 (s, 1H);
13C{1H} NMR (DMSO-d6, ppm) δ 21.9, 59.0, 62.2, 99.9, 119.2, 123.4, 126.0, 126.4, 127.1, 127.65,
127.74, 128.7, 129.2, 138.7, 141.6, 142.7, 160.5, 166.1, 184.4. Anal. Calcd for
C23H20N2O2S·0.5H2O: C, 69.50; H, 5.33; N, 7.05. Found: C, 69.52; H, 5.13; N, 7.02.
(2S*,3R*)-2-(Furan-2-yl)-6-methyl-4-oxo-N,1-diphenyl-1,2,3,4-tetrahydropyridine-3-
carboxamide (4k). The reaction was carried out in pyridine for 4 h, then the resulted mixture was
acidified with HCl (1 : 2) (0.5 mL) and the product was recrystallized from EtOH. Yield 87 mg
(68%), transparent brown crystals, mp 181–182 °C. IR (ATR): 3260, 3134, 2971, 1679, 1616, 1530,
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1489, 1242, 739 cm−1; H NMR (DMSO-d6, ppm) δ 1.77 (s, 3H), 3.84 (d, J = 6.4 Hz, 1Н), 5.09 (s,
1Н), 5.43 (d, J = 6.4 Hz, 1Н), 6.28–6.35 (m, 2H), 7.04 (tt, J = 7.4, 0.9 Hz, 1Н), 7.25–7.34 (m, 5H),
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7.36–7.42 (m, 2H), 7.55 (dd, J = 8.4, 1.0 Hz, 2Н), 7.57–7.59 (m, 1H), 9.99 (s, 1H); C{1H} NMR
(DMSO-d6, ppm) δ 21.8, 55.7, 60.2, 99.7, 109.0, 110.4, 119.2, 123.4, 127.6, 127.9, 128.7, 129.1,
138.7, 142.6, 143.1, 150.6, 160.7, 166.1, 184.8. Anal. Calcd for C23H20N2O3·0.33H2O: C, 73.01; H,
5.50; N, 7.40. Found: C, 73.06; H, 5.46; N, 7.50.
(2S*,3R*)-2-(4-Bromophenyl)-N,1-bis(4-methoxyphenyl)-6-methyl-4-oxo-1,2,3,4-
tetrahydropyridine-3-carboxamide (4l). Yield 151 mg (85%), white powder, mp 149–151 °C. IR
(ATR): 3276, 3067, 2832, 1688, 1624, 1508, 1247, 803 cm−1; 1H NMR (DMSO-d6, ppm) δ 1.82 (s,
3H), 3.56 (d, J = 5.7 Hz, 1Н), 3.71 (s, 6H), 5.08 (s, 1Н), 5.33 (d, J = 5.7 Hz, 1Н), 6.83–6.91 (m,
4H), 7.14–7.26 (m, 2H), 7.33 (d, J = 8.5 Hz, 2Н), 7.45 (d, J = 8.9 Hz, 2Н), 7.49 (d, J = 8.4 Hz, 2Н),
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9.74 (s, 1H); C{1H} NMR (DMSO-d6, ppm) δ 21.9, 55.1, 55.2, 58.9, 65.7, 99.4, 113.8, 114.3,
120.7, 128.2, 129.0, 129.7, 131.3, 131.9, 135.6, 138.0, 155.2, 158.2, 162.2, 165.9, 184.3. Anal.
Calcd for C27H25BrN2O4: C, 62.20; H, 4.83; N, 5.37. Found: C, 62.53; H, 4.89; N, 5.28.
(2S*,3R*)-2-(4-Chlorophenyl)-N,1-bis(4-methoxyphenyl)-6-methyl-4-oxo-1,2,3,4-
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tetrahydropyridine-3-carboxamide (4m). Yield 70% (114 mg), white powder, mp 188–190 °C. IR
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(ATR): 3263, 3062, 2954, 2843, 1685, 1621, 1505, 1246, 829 cm−1; H NMR (DMSO-d6, ppm) δ
1.82 (s, 3H), 3.57 (d, J = 5.8 Hz, 1Н), 3.70 (s, 3H), 3.71 (s, 3H), 5.08 (s, 1Н), 5.35 (d, J = 5.8 Hz,
1Н), 6.82–6.91 (m, 4H), 7.15–7.25 (m, 2H), 7.35 (d, J = 8.6 Hz, 2Н), 7.40 (d, J = 8.6 Hz, 2Н), 7.45
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(d, J = 9.1 Hz, 2Н), 9.74 (s, 1H); C{1H} NMR (DMSO-d6, ppm) δ 21.9, 55.1, 55.2, 58.9, 65.7,
99.4, 113.8, 114.2, 120.7, 128.3, 129.0, 129.4, 131.9, 132.1, 135.6, 137.6, 155.2, 158.1, 158.2,
162.3, 165.9, 184.3. Anal. Calcd for C27H25ClN2O4: C, 67.99; H, 5.28; N, 5.87. Found: C, 67.95; H,
5.20; N, 6.02.
(2S*,3R*)-N,1-Bis(4-methoxyphenyl)-6-methyl-4-oxo-2-phenyl-1,2,3,4-tetrahydropyridine-
3-carboxamide (4n). Yield 67% (101 mg), yellow powder, mp 177–179 °C. IR (ATR): 3271, 2831,
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1679, 1618, 1509, 1241, 820 cm−1; H NMR (DMSO-d6, ppm) δ 1.83 (s, 3H), 3.57 (d, J = 5.2 Hz,
1Н), 3.70 (s, 3H), 3.71 (s, 3H), 5.06 (s, 1Н), 5.30 (d, J = 5.2 Hz, 1Н), 6.81–6.91 (m, 4H), 7.14–7.25
(m, 3H), 7.29 (t, J = 7.5 Hz, 2Н), 7.37 (d, J = 7.3 Hz, 2Н), 7.46 (d, J = 8.9 Hz, 2Н), 9.72 (s, 1H);
13C{1H} NMR (DMSO-d6, ppm) δ 21.9, 55.1, 55.2, 59.1, 99.2, 113.8, 114.2, 120.7, 127.4, 127.6,
128.4, 129.0, 131.9, 135.9, 138.6, 155.2, 158.1, 162.2, 166.2, 184.4. Anal. Calcd for C27H26N2O4: C,
73.28; H, 5.92; N, 6.33. Found: C, 73.19; H, 5.97; N, 6.51.
(2S*,3R*)-N,1,2-Tris(4-methoxyphenyl)-6-methyl-4-oxo-1,2,3,4-tetrahydropyridine-3-
carboxamide (4p). Afer refluxing, the solvent was removed under reduced pressure and the product
was recrystallized from EtOH. Yield 55% (88 mg), beige crystals, mp 190–192 °C. IR (ATR): 3266,
3128, 2954, 2834, 1673, 1614, 1538, 1506, 1242, 1162, 1030, 827 cm−1; 1H NMR (DMSO-d6, ppm)
δ 1.80 (s, 3H), 3.57 (d, J = 5.8 Hz, 1Н), 3.69 (s, 3H), 3.70 (s, 6H), 5.05 (s, 1Н), 5.23 (d, J = 5.8 Hz,
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1Н), 6.78–6.92 (m, 6H), 7.11–7.21 (m, 2H), 7.26 (d, J = 8.5 Hz, 2Н), 7.45 (d, J = 8.9 Hz, 2Н), 9.70
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(s, 1H); C{1H} NMR (DMSO-d6, ppm) δ 22.0, 54.9, 55.1, 55.2, 59.2, 65.9, 99.1, 113.67, 113.74,
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114.2, 120.7, 128.7, 129.0, 130.4, 132.0, 135.8, 155.2, 158.1, 158.5, 162.1, 166.2, 184.6. Anal.
Calcd for C28H28N2O5: C, 71.17; H, 5.97; N, 5.93. Found: C, 70.92; H, 6.06; N, 5.82.
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2-(4-Bromophenyl)-N,1-bis(2-methoxyphenyl)-6-methyl-4-oxo-1,2,3,4-tetrahydropyridine-3-
carboxamide (4r). Yield 67% (99 mg), yellow powder, mp 179–180 °C. IR (ATR): 3297, 1689,
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1599, 1524, 1457, 1244, 464 cm−1; H NMR (DMSO-d6, ppm) anti-trans-4r : syn-trans-4r = 4 : 3;
anti-trans-4r: δ 1.69 (s, 3H), 3.76 (s, 3H), 3.81 (s, 3H), 4.33 (d, J = 12.2 Hz, 1Н), 5.19 (s, 1Н), 5.42
(d, J = 12.2 Hz, 1Н), 6.71–7.42 (m, 11H), 7.84 (dd, J = 8.0, 1.2 Hz, 1Н), 9.09 (s, 1H); syn-trans-4r:
1H NMR (DMSO-d6, ppm) δ 1.73 (s, 3H), 3.63 (s, 3H), 3.78 (s, 3H), 4.11 (d, J = 8.4 Hz, 1Н), 5.13
(s, 1Н), 5.45 (d, J = 8.4 Hz, 1Н), 6.71–7.43 (m, 10H), 7.46 (dd, J = 7.7, 1.5 Hz, 1Н), 8.00 (dd, J =
8.0, 1.3 Hz, 1Н), 9.09 (s, 1H); 1H NMR (CDCl3, ppm, selected signals) anti-trans-4r : syn-trans-4r
= 3 : 1; anti-trans-4r: δ 5.62 (s, 1H), 5.89 (s, 1H), 7.83 (dd, J = 7.8, 1.5 Hz, 1Н), 8.29 (dd, J = 7.9,
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1.1 Hz, 1Н), 9.31 (s, 1H); syn-trans-4r: H NMR (CDCl3, ppm, selected signals) δ 5.65 (d, J = 1.9
Hz, 1H), 5.84 (s, 1H), 9.24 (s, 1H). Anal. Calcd for C27H25BrN2O4: C, 62.20; H, 4.83; N, 5.37.
Found: C, 62.11; H, 4.89; N, 5.58.
2-(4-Bromophenyl)-N,1-bis(2-methoxyphenyl)-6-methyl-4-oxo-1,2,3,4-tetrahydropyridine-3-
carboxamide (4s). Yield 64% (104 mg), white powder, mp 187–189 °C. IR (ATR): 3330, 3064,
2836, 1691, 1616, 1599, 1529, 1247, 749 cm−1; 1H NMR (DMSO-d6, ppm) anti-trans-4s : syn-trans-
4s = 4 : 3; anti-trans-4s: δ 1.69 (s, 3H), 3.75 (s, 3H), 3.79 (s, 3H), 4.33 (d, J = 12.2 Hz, 1Н), 5.19 (s,
1Н), 5.43 (d, J = 12.2 Hz, 1Н), 6.72–7.36 (m, 11H), 7.83 (dd, J = 8.0, 1.3 Hz, 1Н), 9.08 (s, 1H); syn-
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trans-4s: H NMR (DMSO-d6, ppm) δ 1.73 (s, 3H), 3.63 (s, 3H), 3.77 (s, 3H), 4.11 (d, J = 8.4 Hz,
1Н), 5.13 (s, 1Н), 5.47 (d, J = 8.4 Hz, 1Н), 6.72–7.36 (m, 10H), 7.46 (dd, J = 7.5, 1.5 Hz, 1Н), 7.99
(dd, J = 8.1, 1.3 Hz, 1Н), 9.09 (s, 1H). Anal. Calcd for C27H25ClN2O4: C, 67.99; H, 5.28; N, 5.87.
Found: C, 67.95; H, 5.29; N, 6.07.
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carboxamide (5o). General method for the preparation of dihydropyridones 4. The reaction was
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refluxed for 13 h. Yield 54% (89 mg), beige powder, mp 296–297 °C. IR (ATR): 2838, 1678, 1601,
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1505, 1338, 1240, 862 cm−1; H NMR (DMSO-d6, ppm) δ 1.95 (s, 3H), 3.67 (s, 6H), 6.60 (s, 1Н),
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6.79 (d, J = 8.9 Hz, 2Н), 6.82 (d, J = 8.9 Hz, 2Н), 7.23 (d, J = 8.8 Hz, 2Н), 7.30 (d, J = 8.9 Hz, 2Н),
7.51 (d, J = 8.6 Hz, 2Н), 7.99 (d, J = 8.5 Hz, 2Н), 11.48 (s, 1H); 13C{1H} NMR (DMSO-d6, ppm) δ
22.0, 54.9, 59.3, 65.7, 99.7, 113.7, 119.1, 123.3, 127.4, 127.8, 128.6, 128.7, 129.1, 130.2, 138.7,
143.0, 158.5, 161.5, 166.6, 184.7. Anal. Calcd for C27H23N3O6: C, 66.80; H, 4.78; N, 8.66. Found:
C, 66.94; H, 4.85; N, 8.71.
2-Oxo-N-phenyl-2H-chromene-3-carboxamide (6). General method for the preparation of
dihydropyridones 4. The reaction was refluxed for 2.5 h. Yield 69% (62 mg), beige powder, mp
242–244 °C (lit.22 mp 253–255 °C). 1H NMR (DMSO-d6, ppm) δ 7.16 (tt, J = 7.4, 0.8 Hz, 1Н), 7.40
(t, J = 7.9 Hz, 2Н), 7.48 (td, J = 7.4, 0.8 Hz, 1Н), 7.56 (d, J = 8.4 Hz, 2Н), 7.73 (d, J = 7.7 Hz, 2Н),
7.79 (dd, J = 7.6, 1.6 Hz, 1Н), 8.02 (dd, J = 7.8, 1.4 Hz, 1Н), 8.93 (s, 1Н), 10.67 (s, 1H).
(2Z,4Z)-N-Benzyl-5-(benzylamino)-2-(4-bromobenzylidene)-3-oxohex-4-enamide (7).
General method for the preparation of dihydropyridones 4. The reaction was carried out in pyridine
(2 mL) for 2 h. Then H2O (2 mL) was added and the reaction mixture was acidified with 4M HCl
(0.5 mL). After that, the product was extracted with CHCl3 (3 × 5 mL). The combined extracts were
evaporated under reduced pressure and the formed precipitate was recrystallized from toluene. Yield
26% (44 mg), yellow powder, mp 179–180 °C. IR (ATR): 3229, 3061, 1652, 1626, 1581, 1538,
1311, 1246, 699 cm−1; 1H NMR (DMSO-d6, ppm) δ 1.97 (s, 3H), 4.35 (d, J = 6.1 Hz, 2Н), 4.58 (d, J
= 6.1 Hz, 2Н), 5.13 (s, 1Н), 7.22–7.47 (m, 15H), 7.26 (d, J = 8.5 Hz, 2Н), 8.90 (t, J = 6.1 Hz, 1Н),
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11.57 (t, J = 6.1 Hz, 1Н); C{1H} NMR (DMSO-d6, ppm) δ 19.0, 42.4, 46.3, 93.6, 122.1, 126.8,
127.2, 127.4, 127.9, 128.1, 128.7, 131.0, 131.4, 133.7, 138.1, 138.8, 139.9, 165.8, 167.9, 181.3.
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Anal. Calcd for C27H25BrN2O2·0.33H2O: C, 65.47; H, 5.22; N, 5.66. Found: C, 65.49; H, 5.31; N,
5.67.
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(Z)-N-Benzyl-5-(benzylamino)-2-((4-nitrophenyl)(piperidin-1-yl)methyl)-3-oxohex-4-
enamide (8). General method for the preparation of dihydropyridones 4. The reaction was carried
out at 20 °C for 2 h. Yield 39% (73 mg), yellow powder, mp 192–194 °C. IR (ATR): 3337, 2925,
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2803, 1640, 1602, 1573, 1512, 1342, 694 cm−1; H NMR (DMSO-d6, ppm) δ 1.10–1.22 (m, 2H),
1.28–1.46 (m, 4H), 1.86 (s, 3H), 1.93–2.12 (m, 2H), 2.32–2.47 (m, 2H), 4.19 (d, J = 12.1 Hz, 1Н),
4.21 (dd, J = 15.5, 6.1 Hz, 1Н), 4.35 (dd, J = 15.5, 6.1 Hz, 1Н), 4.39 (dd, J = 15.5, 6.1 Hz, 1Н), 4.46
(dd, J = 15.5, 6.1 Hz, 1Н), 4.48 (d, J = 12.1 Hz, 1Н), 5.14 (s, 1Н), 7.10 (dd, J = 8.1, 1.5 Hz, 2Н),
7.20–7.34 (m, 6H), 7.34–7.41 (m, 4H), 8.16 (d, J = 8.7, 1.5 Hz, 2Н), 8.46 (t, J = 6.1 Hz, 1Н), 10.52
(t, J = 6.1 Hz, 1Н); 13C{1H} NMR (DMSO-d6, ppm) δ 18.7, 24.1, 25.7, 42.4, 45.9, 50.1, 59.5, 67.4,
95.1, 122.4, 126.6, 127.0, 127.2, 128.0, 128.5, 129.8, 138.2, 139.6, 143.3, 146.2, 163.7, 168.3,
188.8. Anal. Calcd for C32H36N4O4·0.5H2O: C, 69.92; H, 6.78; N, 10.19. Found: C, 70.03; H, 6.63;
N, 10.20.
General method for the preparation of CF3-dihydropyridones 10.
A mixture of carbamoylated enaminone 2 (0.29 mmol) and aldehyde (0.32 mmol) was stirred
with piperidine (30 mg, 0.35 mmol) in dry MeCN (2 mL) for 24 h. Then HCl (1 : 8) (2 mL) was
added and the product was extracted with CHCl3 (3 × 5 mL). The combined extracts were
evaporated under reduced pressure and the formed precipitate was recrystallized from toluene–
hexane.
For the preparation of salt 9, after carrying out the transformation, the reaction mixture was
evaporated and the residue was diluted with toluene. The salt formed was filtrated.
(2S*,3R*)-2-(4-Bromophenyl)-4-oxo-N,1-diphenyl-6-(trifluoromethyl)-1,2,3,4-
tetrahydropyridine-3-carboxamide (10a). Yield 90% (135 mg), white powder, mp 198–200 °C.
IR (ATR): 3316, 1687, 1636, 1549, 1490, 1243, 1177, 754 cm−1; 1H NMR (DMSO-d6, ppm) δ 3.91
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(d, J = 6.1 Hz, 1Н), 5.65 (d, J = 6.1 Hz, 1Н), 5.74 (s, 1Н), 7.06 (tt, J = 7.5, 1.0 Hz, 1Н), 7.22–7.36
(m, 7H), 7.37 (d, J = 8.5 Hz, 2Н), 7.50 (d, J = 7.7 Hz, 2Н), 7.56 (d, J = 8.5 Hz, 2Н), 10.19 (s, 1H);
13C{1H} NMR (DMSO-d6, ppm) δ (selected signals) 57.9, 67.2, 101.1 (J = 4.7 Hz), 119.4, 121.0 (q,
J = 274.5 Hz), 128.7, 129.0, 129.6, 141.9, 147.8 (q, J = 31.0 Hz), 165.5, 187.3. Anal. Calcd for
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C22H18O6·0.25H2O: C, 78.53; H, 5.00. Found: C, 78.40; H, 4.95. Salt 9a: H NMR (DMSO-d6,
ppm,) δ 1.48–1.69 (m, 6H), 2.94–3.02 (m, 4H), 3.14–3.59 (m, 2H), 5.81 (s, 1Н), 5.98 (s, 1Н), 6.78
(tt, J = 7.4, 1.0 Hz, 1Н), 7.08–7.33 (m, 7H), 7.35 (dd, J = 8.1, 7.5 Hz, 2Н), 7.43–7.52 (m, 4H), 13.08
(s, 1H).
(2S*,3R*)-2-(4-Сhlorophenyl)-4-oxo-N,1-diphenyl-6-(trifluoromethyl)-1,2,3,4-
tetrahydropyridine-3-carboxamide (10b). Yield 81% (111 mg), white powder, mp 187–188 °C.
IR (ATR): 3317, 1688, 1638, 1573, 1550, 1149, 691 cm−1; 1H NMR (DMSO-d6, ppm) δ 3.93 (d, J =
6.3 Hz, 1Н), 5.58 (d, J = 6.3 Hz, 1Н), 5.74 (s, 1Н), 7.06 (tt, J = 7.4, 1.0 Hz, 1Н), 7.15–7.51 (m,
13H), 10.19 (s, 1H); F NMR (DMSO-d6, ppm) 100.5 (79%), 101.5 (21%, enol); C{1H} NMR
(DMSO-d6, ppm) δ 58.0, 67.2, 101.0 (q, J = 4.0 Hz), 119.3, 120.0 (q, J = 277.2 Hz), 123.7, 128.0,
128.4, 128.7, 128.8, 129.0, 129.3, 132.8, 135.6, 138.3, 141.9, 147.8 (q, J = 31.3 Hz), 165.5, 187.4.
Anal. Calcd for C25H18ClF3N2O2: C, 63.77; H, 3.85; N, 5.95. Found: C, 63.78; H, 3.96; N, 5.86.
(2S*,3R*)-4-Oxo-N,1,2-triphenyl-6-(trifluoromethyl)-1,2,3,4-tetrahydropyridine-3-
carboxamide (10c). Yield 68% (87 mg), beige powder, mp 162–163 °C. IR (ATR): 3353, 1693,
1567, 1522, 1114, 690 cm−1; 1H NMR (DMSO-d6, ppm) δ 3.91 (d, J = 6.1 Hz, 1Н), 5.65 (d, J = 6.1
Hz, 1Н), 5.74 (s, 1Н), 7.06 (tt, J = 7.5, 1.0 Hz, 1Н), 7.10–7.44 (m, 10H), 7.50 (dd, J = 8.6, 1.0 Hz,
2Н), 7.56 (d, J = 8.4 Hz, 2Н), 10.20 (s, 1H); 13C{1H} NMR (DMSO-d6, ppm) δ 58.1, 67.9, 100.9 (q,
J = 4.0 Hz), 119.4, 120.3 (q, J = 277.2 Hz), 123.7, 127.1, 127.8, 128.2, 128.3, 128.69, 128.73, 129.0,
136.6, 138.4, 142.2, 147.8 (q, J = 31.3 Hz), 165.7, 187.5. Anal. Calcd for C25H19F3N2O2·0.25H2O:
C, 68.10; H, 4.46; N, 6.35. Found: C, 68.03; H, 4.37; N, 6.43.
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Salt 9c: H NMR (DMSO-d6, ppm,) δ 1.49–1.68 (m, 6H), 2.94–3.04 (m, 4H), 3.04–3.58 (m, 2H),
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5.81 (s, 1Н), 5.98 (s, 1Н), 6.78 (tt, J = 7.3, 1.0 Hz, 1Н), 7.08–7.31 (m, 8H), 7.35 (dd, J = 8.1, 7.5 Hz,
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2Н), 7.43–7.53 (m, 4H), 13.09 (s, 1H); C{1H} NMR (DMSO-d6, ppm) δ 21.8, 22.5, 43.9, 65.7,
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93.5, 117.9, 120.0, 121.5, 122.3 (q, J = 276.8 Hz), 122.4, 123.8, 126.2, 126.4, 127.4, 128.5, 128.9,
132.7 (q, J = 32.5 Hz), 141.7, 145.2, 147.2, 166.9, 167.8.
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(2S*,3R*)-2-(4-Bromophenyl)-N,1-bis(4-methoxyphenyl)-4-oxo-6-(trifluoromethyl)-1,2,3,4-
tetrahydropyridine-3-carboxamide (10d). Yield 79% (132 mg), beige crystals, mp 205–206 °C.
IR (ATR): 3319, 3003, 2836, 1674, 1637, 1507, 1243, 1031, 823 cm−1; 1H NMR (DMSO-d6, ppm) δ
3.70 (s, 3H), 3.71 (s, 3H), 3.81 (d, J = 6.0 Hz, 1Н), 5.45 (d, J = 6.0 Hz, 1Н), 5.66 (s, 1Н), 6.79–6.91
(m, 4H), 7.00–7.30 (m, 2H), 7.36 (d, J = 8.4 Hz, 2Н), 7.41 (d, J = 9.1 Hz, 2Н), 7.56 (d, J = 8.4 Hz,
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2Н), 10.03 (s, 1H); H NMR (CDCl3, ppm) δ 3.53 (d, J = 0.6 Hz, 1Н), 3.79 (s, 3H), 3.80 (s, 3H),
5.58 (d, J = 0.6 Hz, 1Н), 5.65 (s, 1Н), 6.64–7.07 (m, 6H), 7.20 (d, J = 8.3 Hz, 2Н), 7.44 (d, J = 9.1
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Hz, 2Н), 7.51 (d, J = 8.3 Hz, 2Н), 8.11 (s, 1H); F NMR (DMSO-d6, ppm) 100.2 (85%), 101.1
(75%, enol); 13C{1H} NMR (DMSO-d6, ppm) δ 55.1, 55.3, 57.9, 67.4, 100.1 (q, J = 3.8 Hz), 113.7,
113.9, 114.0, 120.6 (q, J = 276.3 Hz), 120.9, 121.3, 129.5, 131.5, 131.6, 134.4, 136.2, 148.2 (q, J =
31.5 Hz), 155.5, 158.8, 165.0, 187.3. Anal. Calcd for C27H22BrF3N2O4: C, 56.36; H, 3.85; N, 4.87.
Found: C, 56.34; H, 3.89; N, 4.71.
(Z)-N-Benzyl-5-(benzylamino)-2-((4-bromophenyl)(piperidin-1-yl)methyl)-6,6,6-trifluoro-3-
oxohex-4-enamide (11). A mixture of carbamoylated enaminone 2c (150 mg, 0.40 mmol) and p-
bromobenzaldehyde (81 mg, 0.44 mmol) was stirred with piperidine (41 mg, 0.48 mmol) in dry
MeCN (2 mL) for 24 h. After that, the reaction mixture was kept at –20 °C, the product was filtrated
and washed with cold toluene Yield 84% (211 mg), white powder, mp 155–156 °C. IR (ATR):
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3312, 2935, 2762, 1642, 1594, 1296, 1195, 747, 695 cm−1; H NMR (DMSO-d6, ppm) δ 1.12–1.23
(m, 2H), 1.28–1.50 (m, 4H), 1.95–2.16 (m, 2H), 2.31–2.43 (m, 2H), 4.25 (dd, J = 15.5, 5.4 Hz, 1Н),
4.36 (d, J = 12.0 Hz, 1Н), 4.39–4.50 (m, 5H), 5.81 (s, 1Н), 7.04–7.39 (m, 12H), 7.50 (d, J = 8.3 Hz,
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2Н), 8.72 (t, J = 5.9 Hz, 1Н), 9.91 (t, J = 5.4 Hz, 1Н); 13C{1H} NMR (DMSO-d6, ppm) δ (selected
signals) 25.6, 45.3, 90.2, 99.9, 119.8 (q, J = 277.0 Hz), 126.9, 127.0, 127.7, 128.1, 128.7, 131.4,
131.5, 138.5, 166.8, 194.9. Anal. Calcd for C32H33BrF3N3O2: C, 61.15; H, 5.29; N, 6.69. Found: C,
61.18; H, 5.27; N, 6.53.
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General method for the preparation of pyridones 5 and 12a from dihydropyridones.
Dihydropyridone 4 or 10a (0.22 mmol) and iodine (0.11 g, 0.44 mmol) were refluxed in CHCl3
(2 mL) for 4 h. Then the reaction mixture was evaporated under reduced pressure (or treatment with
water saturated solution of Na2S2O3 (4 mL), further extraction with CHCl3 (3 × 5 mL) and
evaporation) and the additional amount of iodine (0.11 g, 0.44 mmol) was added. The resulted
mixture was refluxed in CHCl3 (2 mL) for 4 h. After that, water saturated solution of Na2S2O3 (4
mL) was added and the product was extracted with CHCl3 (3 × 5 mL). The combined extracts were
washed with water (4 mL) and evaporated under reduced pressure. The formed precipitate was
recrystallized from toluene–hexane.
2-(4-Bromophenyl)-6-methyl-4-oxo-N,1-diphenyl-1,4-dihydropyridine-3-carboxamide (5a).
Yield 78% (79 mg), white powder, mp 277–279 °C. IR (ATR): 3287, 3060, 1682, 1624, 1594, 1533,
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1487, 1442, 1101, 755 cm−1; H NMR (DMSO-d6, ppm) δ 2.06 (s, 3H), 6.80 (s, 1Н), 7.01 (tt, J =
7.3, 1.1 Hz, 1Н), 7.20 (d, J = 8.5 Hz, 2Н), 7.23 (dd, J = 8.2, 7.3 Hz, 2Н), 7.28–7.40 (m, 9Н), 10.81
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(s, 1H); C{1H} NMR (DMSO-d6, ppm) δ 24.5, 116.3, 119.2, 122.4, 123.7, 124.8, 128.6, 128.7,
129.4, 129.6, 130.3, 131.3, 131.6, 138.4, 151.3, 152.7, 161.4, 172.2 (1С was not observed). Anal.
Calcd for C25H19BrN2O2: C, 65.37; H, 4.17; N, 6.10. Found: C, 65.58; H, 4.05; N, 6.17.
6-Methyl-4-oxo-N,1-diphenyl-2-(thiophen-2-yl)-1,4-dihydropyridine-3-carboxamide (5j).
Yield 61% (53 mg), grey powder, mp 291–293 °C. IR (ATR): 2813, 1679, 1532, 1487, 1417, 762,
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697 cm−1; H NMR (DMSO-d6, ppm) δ 1.95 (s, 3H), 6.45 (s, 1Н), 6.74 (dd, J = 5.0, 3.6 Hz, 1Н),
6.94– 7.01 (m, 2Н), 7.21 (t, J = 7.9 Hz, 2Н), 7.27 (dd, J = 7.9, 1.6 Hz, 2Н), 7.32–7.45 (m, 6Н),
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129.01, 129.05, 129.09, 129.3, 131.3, 132.0, 138.9, 139.0, 143.1, 149.6, 163.1, 174.5. Anal. Calcd
for C23H18N2O2S·0.5H2O: C, 69.85; H, 4.84; N, 7.08. Found: C, 69.80; H, 4.59; N, 7.05.
N,1-Bis(4-methoxyphenyl)-6-methyl-4-oxo-2-phenyl-1,4-dihydropyridine-3-carboxamide
(5n). Yield 83% (82 mg), white powder, mp 262–264 °C. 1H NMR (DMSO-d6, ppm) δ 1.96 (s, 3H),
3.66 (s, 3H), 3.67 (s, 3H), 6.52 (s, 1Н), 6.76 (d, J = 9.0 Hz, 2Н), 6.81 (d, J = 9.0 Hz, 2Н), 7.07–7.28
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(m, 9Н), 10.36 (s, 1H); C{1H} NMR (DMSO-d6, ppm) δ 21.1, 55.1, 55.2, 113.6, 113.9, 117.6,
120.5, 125.9, 127.0, 128.1, 129.6, 130.3, 131.8, 132.3, 133.3, 149.6, 150.8, 155.0, 158.7, 162.8,
175.1. Anal. Calcd for C27H24N2O4·0.5H2O: C, 72.14; H, 5.61; N, 6.23. Found: C, 71.97; H, 5.32; N,
6.54.
2-(4-Bromophenyl)-N,1-bis(2-methoxyphenyl)-6-methyl-4-oxo-1,4-dihydropyridine-3-
carboxamide (5r). Method A. General method for the preparation of dihydropyridones 4. The
reaction was refluxed for 4 h in pyridine. Yield 23% (36 mg), white powder, mp 298–299 °C.
Method B. General method for the iodine-promoted preparation of pyridones from
dihydropyridones. Yield 45% (45 mg), white powder, mp 298–299 °C. IR (ATR): 2933, 1672, 1631,
1595, 1521, 1249, 752 cm−1; H NMR (DMSO-d6, ppm) δ 1.23 (s, 3H), 3.73 (s, 3H), 3.75 (s, 3H),
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6.63 (s, 1Н), 6.78 (td, J = 7.0, 2.1 Hz, 1Н), 6.86 (td, J = 7.8, 1.0 Hz, 1Н), 6.92–7.02 (m, 4H), 7.13
(dd, J = 8.8, 2.2 Hz, 1Н), 7.22–7.32 (m, 4H), 7.96 (dd, J = 6.9, 1.3 Hz, 1Н), 12.15 (s, 1H); 13C{1H}
NMR (DMSO-d6, ppm) δ 20.2, 55.7, 55.8, 110.8, 112.1, 118.6, 120.1, 120.2, 120.3, 123.4, 127.2,
128.0, 129.0, 129.6, 129.7, 130.2, 131.2, 131.4, 134.3, 148.6, 149.8, 153.6, 154.9, 161.9, 176.8.
Anal. Calcd for C26H24N2O3·H2O: C, 60.34; H, 4.69; N, 5.21. Found: C, 60.70; H, 4.62; N, 5.56.
2-(4-Bromophenyl)-4-oxo-N,1-diphenyl-6-(trifluoromethyl)-1,4-dihydropyridine-3-
carboxamide (12a). Yield 56% (63 mg), white powder, mp 140–142 °C. IR (ATR): 3067, 1634,
1595, 1539, 1248, 1149, 751 cm−1; 1H NMR (DMSO-d6, ppm) δ 7.00 (tt, J = 7.2, 1.1 Hz, 1Н), 7.09
(s, 1Н), 7.19– 7.43 (m, 13Н), 10.31 (s, 1H); F NMR (DMSO-d6, ppm) δ 102.39; C{1H} NMR
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