Synthesis of 3-amino-6-methyl-4-phenylpyridin-2(1H)-one and its derivatives

Article abstract of DOI:10.1007/s10593-017-2038-4

[Figure not available: see fulltext.] A reaction of 2-cyanoacetamide with benzylideneacetone in DMSO containing potassium tert-butoxide was used to synthesize 3-cyano-6-methyl-4-phenylpyridin-2(1H)-one, which was converted by acidic hydrolysis to 6-methyl-2-oxo-4-phenyl-1,2-dihydropyridine-3-carboxamide. A Hofmann reaction of this compound in the presence of sodium hypobromite led to 3-amino-5-bromo-6-methyl-4-phenylpyridin-2(1H)-one, while its treatment with calcium hypochlorite produced 5-methyl-7-phenyloxazolo[5,4-b]pyridin-2(1H)-one. The latter compound was converted by heating with alkali to 3-amino-6-methyl-4-phenylpyridin-2(1H)-one, which gave azomethine in a reaction with benzaldehyde, while N-acylated derivatives were obtained in reactions with acyl halides. The heating of N₁,N₂-bis(6-methyl-2-oxo-4-phenyl-1,2-dihydropyridin-3-yl)oxalylamide in the presence of POCl₃ allowed to obtain 5,5'-dimethyl-7,7'-diphenyl-2,2'-bis-(oxazolo[5,4-b]pyridine).

Full text of DOI:10.1007/s10593-017-2038-4

DOI 10.1007/s10593-017-2038-4
Chemistry of Heterocyclic Compounds 2017, 53(2), 186–191
Synthesis of 3-amino-6-methyl-4-phenylpyridin-2(1Н)-one
and its derivatives
Anton L. Shatsauskas1, Anton A. Abramov2, Elina R. Saibulina2,
Irina V. Palamarchuk2, Ivan V. Kulakov2, Alexander S. Fisyuk1,2*
1
Omsk State Technical University,
11 Mir Ave., Omsk 644050, Russia; e-mail: fisyuk@chemomsu.ru
2
Omsk State University named after F. M. Dostoevsky,
55a Mir Ave., Omsk 644077, Russia; e-mail: fisyuk@chemomsu.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2017, 53(2), 186–191
Submitted November 20, 2016
Accepted December 20, 2016
A reaction of 2-cyanoacetamide with benzylideneacetone in DMSO containing potassium tert-butoxide was used to synthesize 3-cyano-
6-methyl-4-phenylpyridin-2(1Н)-one, which was converted by acidic hydrolysis to 6-methyl-2-oxo-4-phenyl-1,2-dihydropyridine-3-
carboxamide. A Hofmann reaction of this compound in the presence of sodium hypobromite led to 3-amino-5-bromo-6-methyl-
4-phenylpyridin-2(1H)-one, while its treatment with calcium hypochlorite produced 5-methyl-7-phenyloxazolo[5,4-b]pyridin-2(1H)-one.
The latter compound was converted by heating with alkali to 3-amino-6-methyl-4-phenylpyridin-2(1Н)-one, which gave azomethine in a
reaction with benzaldehyde, while N-acylated derivatives were obtained in reactions with acyl halides. The heating of N1,N2-bis(6-methyl-
2-oxo-4-phenyl-1,2-dihydropyridin-3-yl)oxalylamide in the presence of POCl3 allowed to obtain 5,5'-dimethyl-7,7'-diphenyl-2,2'-bis-
(oxazolo[5,4-b]pyridine).
Keywords: 3-aminopyridin-2(1Н)-one, oxazolo[5,4-b]pyridin-2(1H)-one, Hofmann reaction, intramolecular cyclization.
Aminopyridin-2(1Н)-ones are commonly employed as
molecular scaffolds for the synthesis of biologically active
compounds,1–3 including drugs that have been approved for
clinical use, such as amrinone.4 The presence of an amino
acid motif incorporated in the structure of 3-aminopyridin-
2(1Н)-ones presents opportunities for their use as building
blocks in the synthesis of peptidomimetics.5–7
We have previously developed a method for the
preparation of pyridin-2(1Н)-ones and -thiones functiona-
lized at position 3, based on an intramolecular cyclization
of N-(3-oxoalkyl)- and N-(3-oxoalkenyl)amides and
thioamides.8–13 This approach was used for the preparation
of insufficiently studied 4-aryl-substituted 3-aminopyridin-
2(1Н)-ones.14–16 Some of these compounds are lumino-
phores, show antiradical activity,15 and may present interest
as specific intracellular probes for detecting the generation
of reactive oxygen species. Previously reported method14
for the preparation of 4-aryl-substituted 3-aminopyridin-
2-(1Н)-ones had some drawbacks due to scaling of starting
N-(3-oxoalkenyl)chloroacetamide synthesis, which re-
quired a large volume of solvent. For this reason, we
studied the possibility of an alternative approach to the
synthesis of 4-aryl-substituted 3-aminopyridin-2(1Н)-ones,
based on Hofmann reaction of the appropriate amides.
It is known that 3-cyano-3,4-dihydropyridin-2(1Н)-ones,
which are accessible by condensation of α,β-unsaturated
ketones and cyanoacetamide in alkaline medium, are
capable of oxidation by air oxygen to 3-cyanopyridin-2(1Н)-
ones.17 This method was used for the synthesis of 6-methyl-
2-oxo-4-phenyl-1,2-dihydropyridine-3-carbonitrile
(2)
0009-3122/17/53(02)-0186©2017 Springer Science+Business Media New York
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Chemistry of Heterocyclic Compounds 2017, 53(2), 189–194
which was obtained as a result of oxidation of the dianion 1,
A reaction of compound 7 with methyl bromoacetate in
dimethylformamide in the presence of potassium carbonate
was used to prepare methyl (5-methyl-2-oxo-7-phenyl[1,3]-
oxazolo[5,4-b]pyridin-1(2H)-yl)acetate (8) in 67% yield
formed as the intermediate in condensation of benzylidene-
acetone with 2-cyanoacetamide in the presence of potassium
tert-butoxide in DMSO, in 80% yield (Scheme 1). The
attempts to change potassium tert-butoxide with sodium
hydroxide or ethoxide led to decreasing the yield of
compound 2 to 35 and 51%, respectively. Acidic
hydrolysis of nitrile 2 in concentrated sulfuric acid
produced 6-methyl-2-oxo-4-phenyl-1,2-dihydropyridine-
3-carboxamide 3 in 86% yield.
(Scheme 3). Oxazolo[5,4-b]pyridin-2(1H)-one
7 was
converted to 3-aminopyridin-2(1Н)-one 4 (87% yield) by
heating with an alcoholic sodium hydroxide solution.
Scheme 3
Scheme 1
It is known that N-acylated 3-amino-4-arylquinolines
can participate in Bischler–Napieralski reaction with the
formation of dibenzo[c,f][1,7]naphthyridines.23,24 We
studied the applicability of this reaction for amide 9, which
was obtained by heating of compound 4 with ethyl oxalate
according to a literature procedure.14 The Bischler–Napieralski
reaction in our case was expected to produce 2,2'-dimethyl-
6,6'-bis(dibenzo[c][1,7]naphthyridine)-4,4'(3H,3'H)-dione
(11). However, the heating of compound 9 with phosphorus
oxychloride led to 5,5'-dimethyl-7,7'-diphenyl-2,2'-bis-
(oxazolo[5,4-b]pyridine) (10) in 88% yield (Scheme 4).
The reaction of amide 3 with 1 equiv of sodium
hypobromite that was obtained in situ from elemental
bromine and sodium hydroxide resulted in a product
mixture consisting of 3-amino-6-methyl-4-phenylpyridin-
2(1H)-one (4) and its brominated derivative 5 (Scheme 2).
When the amount of sodium hypobromite was increased to
3 equiv, the main product of the reaction, which was
isolated in 68% yield, was identified as 3-amino-5-bromo-
6-methyl-4-phenylpyridin-2(1H)-one (5).
Scheme 2
Scheme 4
Performing the Hofmann reaction with calcium
hypochlorite containing 2 equiv of active chlorine relative
to the amount of amide 3 produced 5-methyl-7-phenyl-
oxazolo[5,4-b]pyridin-2(1H)-one (7) (92% yield) as a result
of intramolecular cyclization of the isocyanаte intermediate 6
(Scheme 3). Analogous transformations of 4-alkyl-
substituted 2-oxo-1,2-dihydropyridine-3-carboxamides in
the presence of sodium hypochlorite have been previously
reported in the literature.18,19 It is important to note that
oxazolo[5,4-b]pyridin-2(1H)-ones are also of interest.
Modulators of calcium channel activity have been recently
found among compounds of this series.20 They are used for
the treatment of type 2 diabetes21 and also exhibited
analgetic activity.22
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Chemistry of Heterocyclic Compounds 2017, 53(2), 189–194
Scheme 5
The formation of isoquinoline system may be also
one, previously unknown N-acylated derivatives and
5,5'-dimethyl-7,7'-diphenyl-2,2'-bis(oxazolo[5,4-b]pyridine)
were obtained.
achieved by amidoalkylation,25 which in several cases
occurred under milder conditions26–30 than the Bischler–
Napieralski reaction. We used the reaction of compound 4
with benzaldehyde in isopropanol to obtain the azomethine
12 in 82% yield. Further treatment of this azomethine with
acetyl chloride gave N-(6-methyl-2-oxo-4-phenyl-1,2-di-
hydropyridin-3-yl)acetamide (15) (Scheme 5). Apparently,
the acyliminium salt 13 that was formed by acylation of
azomethine 12 also cyclized to the oxazole derivative 14,
which hydrolyzed during the work-up of reaction mixture,
producing the acetamide 15.
Experimental
IR spectra were recorded on an FT-801 FT-IR spectro-
meter in KBr pellets. 1H and 13C NMR spectra were acquired
on a Bruker DRX-400 instrument (400 and 100 MHz,
respectively), with TMS as internal standard. 13С NMR
spectra were acquired in J-modulation mode. Elemental
analysis was performed on a Carlo Erba 1106 CHN-
analyzer. Melting points were determined on a Kofler
bench. The reaction progress and purity of the obtained
compounds were controlled by TLC on Sorbfil UV-254
plates, with visualization under UV light. The products
were purified by silica gel column chromatography.
The acylation of 3-aminopyridin-2(1Н)-one 4 with 2 equiv
of chloroacetyl chloride led to the respective chloro-
acetamide.14 Analogously, the use of 3-bromopropanoyl
chloride in dichloromethane in the presence of pyridine
gave amide 16 (Scheme 6). When the amount of
chloroacetyl chloride was increased to 3 equiv, imide 17
was unexpectedly obtained as the main reaction product in
75% yield.
6-Methyl-2-oxo-4-phenyl-1,2-dihydropyridine-3-carbo-
nitrile (2). Method I. Potassium tert-butoxide (61.5 g,
0.548 mol) was added to a cooled solution of benzyl-
ideneacetone (20.0 g, 0.137 mol) and 2-cyanoacetamide
(12.6 g, 0.150 mol) in DMSO (200 ml). Cooling was
stopped after 30 min and the reaction mixture was stirred at
room temperature for 4 h with barbotation of dry air
through it. Then the reaction mixture was poured into water
(1 l) and neutralized by 2 N HCl solution. The precipitate
formed was filtered off, washed with water, and
recrystallized from EtOH. Yield 23.0 g (80%), white crystals,
mp 274–275°С (mp 274–275°С31). IR spectrum, ν, cm–1:
Scheme 6
1
1669, 2234, 3069, 3156. H NMR spectrum (DMSO-d6),
δ, ppm: 1.81 (3H, s, CH3); 6.31 (1H, s, H-5); 7.51–7.59
(5H, m, H Ph); 12.60 (1H, br. s, NH). 13C NMR spectrum,
δ, ppm (DMSO-d6): 18.7 (CH3); 97.7 (C-3); 107.0 (C-5);
117.1 (CN); 128.4, 129.2 (C-2,3,5,6 Ph); 134.4 (C-4 Ph);
136.5 (C-1 Ph); 141.1 (C-4); 152.6 (C-6); 163.2 (C-2).
Method II. Solid sodium hydroxide (1.6 g, 0.04 mol)
was added to a cooled solution of benzylideneacetone (1.46 g,
0.010 mol) and 2-cyanoacetamide (0.92 g, 0.011 mol) in
DMSO (10 ml). Cooling was stopped after 30 min, and the
reaction mixture was stirred at room temperature for 18 h
while barbotating with air, then transferred to a beaker
containing water (50 ml) and neutralized with 2 N HCl
solution. The precipitate that formed was filtered off,
washed with water, and recrystallized from EtOH. Yield
0.73 g (35%).
The structures of all synthesized compounds were
1
established by IR spectroscopy, Н and 13С spectroscopy,
as well as elemental analysis data.
Thus, we have found a new approach to the synthesis of
5-methyl-7-phenyloxazolo[5,4-b]pyridin-2(1H)-one, 3-amino-
6-methyl-4-phenylpyridin-2(1Н)-one and its brominated
derivative by relying on Hofmann reaction of 6-methyl-
2-oxo-4-phenyl-1,2-dihydropyridine-3-carboxamide, which
was obtained in two stages from readily available starting
materials – benzylideneacetone and 2-cyanoacetamide. The
proposed method allow to obtain 3-amino-6-methyl-
4-phenylpyridin-2(1Н)-one on preparative scale in four
steps with the overall yield of 55%, exceeding the yield of
a previously reported method on the basis of 1-phenyl-
butane-1,3-dione and chloroacetamide (42% yield).
Starting from 3-amino-6-methyl-4-phenylpyridin-2(1Н)-
Method III. Sodium ethoxide solution was prepared by
from metallic sodium (0.24 mg, 10 mmol) and anhydrous
ethanol (10 ml). 2-Cyanoacetamide (0.92 g, 11 mmol) was
added to the sodium ethoxide solution and the mixture was
vigorously stirred for 15 min, then treated by dropwise
188

Chemistry of Heterocyclic Compounds 2017, 53(2), 189–194
addition of a solution of benzylideneacetone (1.46 g, 10
3-Amino-6-methyl-4-phenylpyridin-2(1H)-one (4). Solid
sodium hydroxide (160 mg, 4 mmol) was added to a sus-
pension of oxazolone 7 (226 mg, 1 mmol) in ethanol (2 ml),
and the mixture was refluxed for 1 h, then poured into water
(10 ml) and neutralized. The precipitate that formed was
filtered off. Yield 174 mg (87%), white crystals, mp 194–
195°С (ethanol) (mp 194–195°С14).
mmol) in anhydrous ethanol (5 ml). The reaction mixture
was refluxed for 8 h, cooled, and poured into water (100
ml), then neutralized with 2 N solution of HCl. The
precipitate that formed was filtered off, washed with water,
and crystallized from ethanol. Yield 1.07 g (51%).
6-Methyl-2-oxo-4-phenyl-1,2-dihydropyridin-3-carb-
oxamide (3). Nitrile 2 (21.0 g, 0.10 mol) was dissolved in
concentrated H2SO4 (30 ml) and heated to 90–95°С for 3 h.
After cooling, the reaction mixture was poured onto ice
(100 g) and neutralized with aqueous ammonia. The solid
that formed was filtered off, washed with water, and
recrystallized from EtOH. Yield 19.6 g (86%), mp 255–
257°С (mp 253–255°С31). IR spectrum, ν, cm–1: 1658,
Methyl (5-methyl-2-oxo-7-phenyl[1,3]oxazolo[5,4-b]-
pyridin-1(2H)-yl)acetate (8). Dry potassium carbonate
(5.52 g, 0.4 mol) and methyl bromoacetate (0.95 ml,
0.1 mol) were added to a solution of oxazolone 7 (2.25 g,
0.1 mol) in anhydrous DMF (10 ml). The reaction mixture
was heated for 3 h at 60°С, then poured into water, neutra-
lized, extracted with chloroform, and purified by column
chromatography using chloroform as eluent. Yield 2.00 g
(67%), white crystals, mp 92–93°С. IR spectrum, ν, cm–1:
1635, 1742, 1796. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz):
2.56 (3H, s, CH3); 3.52 (3H, s, OCH3); 4.24 (2H, s,
NCH2CO); 6.89 (1H, s, H-6); 7.29 (2H, dd, 3J = 7.4, 4J = 1.5,
H-2,6 Ph); 7.44–7.50 (3H, m, H-3,4,5 Ph). 13C NMR
spectrum (CDCl3), δ, ppm: 23.5 (CH3); 44.1 (OCH3); 52.4
(NCH2CO); 119.1 (C-7a); 121.2 (C-6); 128.5, 128.6
(C-2,3,5,6 Ph); 129.2 (C-4 Ph); 133.2 (C-1 Ph); 134.0
(C-7); 150.3 (C-5); 151.4 (C-3a); 153.2 (C-2); 167.0
(CH2CO2CH3). Found, %: С 64.31; Н 4.85; N 9.28.
C16H14N2O4. Calculated, %: С 64.42; Н 4.73; N 9.39.
1
1677, 3313, 3436. H NMR spectrum (DMSO-d6), δ, ppm:
2.20 (3H, s, CH3); 6.01 (1H, s, H-5); 7.15 (1H, s, CONH2);
7.36–7.41 (5H, m, H Ph); 7.70 (1H, s, CONH2); 11.94 (1H,
br. s, NH). 13C NMR spectrum, δ, ppm (DMSO-d6): 18.4
(CH3); 106.5 (C-5); 122.9 (C-3); 127.5, 128.1 (C-2,3,5,6
Ph); 128.2 (C-4 Ph); 139.0 (C-1 Ph); 145.4 (C-4); 150.8
(C-6); 161.3 (C-2); 167.3 (3-CONH2).
3-Amino-5-bromo-6-methyl-4-phenylpyridin-2(1H)-
one (5). Ice (5 g) and elemental bromine (0.16 ml, 3 mmol)
were added to a solution of NaOH (240 mg, 6 mmol) in
water (2 ml). The mixture was stirred until it became
homogeneous, then amide 3 (228 mg, 1 mmol) was added.
The resulting mixture was heated to 100°С for 4 h, then
cooled on ice bath and acidified with 6 N solution of HCl
to pH ~3, stirred at room temperature for additional 30 min,
then neutralized with a saturated NaHCO3 solution (pH ~7–8).
The precipitate was filtered off, washed with water, and
recrystallized from EtOH. Yield 190 mg (68%), decomp.
temp. 191–192°С. IR spectrum, ν, cm–1: 1617, 1646, 3349,
3456. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 2.23
5,5'-Dimethyl-7,7'-diphenyl-2,2'-bis(oxazolo[5,4-b]pyri-
dine) (10). A mixture of oxalylamide 914 (0.227 g,
0.5 mmol) and phosphorus oxychloride (1.0 ml) was heated
for 9 h at 100°С. The solvent was removed by evaporation,
the residue was treated with ice water. The precipitate that
formed was filtered off and recrystallized from a 2-PrOH–
DMF mixture. Yield 0.185 g (88%), white powder, mp 263–
265°С (2-PrOH). IR spectrum, ν, cm–1: 1608, 1675. 1H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 2.71 (6Н, s,
3
(3H, s, CH3); 4.36 (2H, s, NH2); 7.18 (2H, d, J = 7.0,
3
3
H-2,6 Ph); 7.38 (1H, t, J = 7.4, H-4 Ph); 7.47 (2H, t,
5,5'-СН3); 7.59 (2Н, d, J = 7.3, H-4,4' Ph); 7.66 (4Н, t,
3J = 7.4, H-3,5 Ph); 11.87 (1H, br. s, NH). 13C NMR
spectrum (DMSO-d6), δ, ppm: 18.9 (CH3); 100.7 (C-5);
124.7 (C-3); 127.7 (C-4 Ph); 128.7, 129.1 (C-2,3,5,6 Ph);
133.5 (C-1 Ph, C-4); 136.8 (C-6); 156.9 (C-2). Found, %:
С 51.49; Н 3.81; N 10.16. C12H11BrN2O. Calculated, %:
С 51.63; Н 3.97; N 10.04.
3J = 7.3, H-3,3',5,5' Ph); 7.86 (2Н, s, H-6,6'); 8.26 (2Н, d,
3J = 7.3, Н-2,2',6,6' Ph). 13C NMR spectrum (DMSO-d6),
δ, ppm: 24.2 (5,5'-СН3); 119.4 (С-6,6'); 127.6 (C-7a,7a');
128.9, 129.0 (C-2,2',3,3',5,5',6,6' Ph); 130.1 (С-4,4' Ph); 133.6
(C-1,1' Ph); 141.0 (C-7,7'); 150.2 (C-5,5'); 157.6 (С-3a,3a');
159.4 (С-2,2'). Found, %: С 74.44; Н 4.50; N 13.52.
C26H18N4O2. Calculated, %: С 74.63; Н 4.34; N 13.39.
3-(Benzylideneamino)-6-methyl-4-phenylpyridin-
2(1H)-one (12). A mixture of compound 4 (200 mg,
1 mmol), benzaldehyde (160 mg, 1.5 mmol), and a
catalytic amount of formic acid in isopropanol (5 ml) was
refluxed for 5 h. After cooling, the crystals that precipitated
were filtered off and washed with cold isopropanol, then
with hexane. Yield 236 mg (82%), yellow crystals, mp 208–
209°С (isopropanol). IR spectrum, ν, cm–1: 1525, 1636,
5-Methyl-7-phenyl[1,3]oxazolo[5,4-b]pyridin-2(1H)-one
(7). Calcium hypochlorite (2.53 g, 56% content of active
chlorine, 0.2 mol Cl2) was added to a suspension of amide
3 (2.28 g, 0.1 mol) in 2 N NaOH solution (40 ml). The
mixture was vigorously stirred at room temperature for 1 h
and then neutralized. The precipitate was filtered off,
washed with water, then recrystallized from CHCl3. Yield
2.08 g (92%), white crystals, decomp. temp. 225–228°С. IR
spectrum, ν, cm–1 :1642, 1798, 3122 (br.). 1H NMR spectrum
(acetone-d6), δ, ppm: 2.43 (3H, s, CH3); 7.12 (1H, s, H-6);
7.43–7.48 (3H, m, H-2,4,6 Ph); 7.60–7.62 (2H, m, H-3,5
Ph); 10.61 (1H, br. s, NH). 13C NMR spectrum (acetone-d6),
δ, ppm: 22.7 (CH3); 118.2 (C-6); 119.04 (C-7a); 127.9,
129.1 (C-2,3,4,5,6 Ph); 131.4 (C-1 Ph); 134.7 (C-7); 149.9
(C-5); 152.7 (C-3a); 153.2 (C-2). Found, %: С 68.89; Н 4.53;
N 12.52. C13H10N2O2. Calculated, %: С 69.02; Н 4.46;
N 12.38.
1
3352, 3450. H NMR spectrum (CDCl3), δ, ppm (J, Hz):
2.41 (3H, s, CH3); 6.25 (1H, s, H-5); 7.35–7.40 (5H, m,
H 4-Ph); 7.48–7.53 (3H, m, H-3,4,5 Ph); 7.75 (2H, dd,
4
3J = 7.1, J = 2.4, H-2,6 Ph); 9.35 (1H, s, N=CH); 13.18
(1H, br. s, NH). 13C NMR spectrum (CDCl3), δ, ppm: 18.7
(CH3); 108.7 (C-5); 121.6 (C-3); 127.5, 128.0 (C-4 Ph);
128.4 (C-2,3,5,6 Ph); 128.6, 130.0 (C-2,3,5,6 Ph); 130.6
(C-4 Ph); 131.0 (C-1 Ph); 131.7 (C-1 Ph); 140.8 (C-4);
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Chemistry of Heterocyclic Compounds 2017, 53(2), 189–194
146.3 (C-6); 161.2 (C-2); 162.6 (N=CH). Found, %:
IR spectrum, ν, cm–1: 1633, 1648, 1732, 3305. 1H NMR spect-
rum (DMSO-d6), δ, ppm (J, Hz): 2.42 (3H, s, CH3); 4.34
(2H, d, 2JAB = 8.0) and 4.36 (2H, d, 2JAB = 8.0, 2CH2); 6.23
(1H, s, H-5); 7.24–7.28 (2H, m, H-2,6 Ph); 7.42–7.46 (3H,
m, H-3,4,5 Ph); 13.50 (1H, br. s, NН). 13C NMR spectrum
(DMSO-d6), δ, ppm: 19.3 (CH3); 45.2 (N(COCH2Cl)2);
108.7 (C-5); 120.4 (C-3); 127.1, 129.4 (C-2,3,5,6 Ph);
130.0 (C-4); 135.2 (C-1 Ph); 147.8 (C-4); 154.3 (C-6); 161.9
(C-2); 169.0 (N(COCH2Cl)2). Found, %: С 54.29; Н 4.12;
N 8.06. C16H14Cl2N2O3. Calculated, %: С 54.41; Н 4.00;
N 7.93.
C 79.52; H 5.87; N 9.91. C19H16N2O. Calculated, %:
C 79.14; H 5.79; N 9.72.
N-(6-Methyl-2-oxo-4-phenyl-1,2-dihydropyridin-3-yl)-
acetamide (15). A solution of azomethine 12 (200 mg,
0.69 mmol) in anhydrous dichloromethane (5 ml) was
cooled and treated with aluminum chloride (93 mg,
0.69 mmol). After maintaining for 45 min, the reaction
mixture was cooled and treated by dropwise addition of
acetyl chloride (0.059 ml, 0.83 mmol) solution in
dichloromethane (1 ml). The reaction mixture was stirred at
room temperature for 1 day, then quenched with water
(10 ml) and extracted with ethyl acetate. The product was
purified by column chromatography, while using 1:1
benzene–isopropanol mixture as eluent. Yield 95 mg (41%),
pale-yellow crystals, mp 159°С. IR spectrum, ν, cm–1: 1631,
1696, 3479 (br). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.75
(3H, s, 6-CH3); 2.20 (3H, s, COCH3); 5.96 (1H, s, H-5); 7.33–
7.38 (5H, m, H Ph); 8.64 (1H, br. s, NHCOCH3); 11.63 (1H,
br. s, 1-NH). 13C NMR spectrum (DMSO-d6), δ, ppm: 18.3
(CH3); 22.5 (COCH3); 106.3 (C-5); 121.5 (C-3); 127.6,
128.1 (C-2,3,5,6 Ph); 129.0 (C-4 Ph); 137.7 (C-1 Ph); 143.1
(C-4); 149.2 (C-6); 160.8 (C-2); 169.0 (NHCOCH3). Found,
%: С 69.29; Н 5.94; N 11.38. C14H14N2O2. Calculated, %:
С 69.41; Н 5.82; N 11.56.
3-Bromo-N-(6-methyl-2-oxo-4-phenyl-1,2-dihydro-
pyridin-3-yl)propanamide (16). Pyridine (0.081 ml,
1 mmol) was added to a solution of compound 4 (100 mg,
0.5 mmol) in dichloromethane (3 ml), the mixture was
cooled to 5°С and treated by dropwise addition of
3-bromopropanoyl chloride (0.1 ml, 1 mmol). The reaction
mixture was stirred at room temperature for 15 h. The
solvent was removed by evaporation, the residue was
treated with ice water. The precipitate that formed was
filtered off, washed with distilled water, and recrystallized
from a 1:1 mixture of 2-propanol–hexane. Yield 111 mg
(67%), white crystals, mp 186–188°С. IR spectrum, ν, cm–1:
1632, 1651, 1675, 3224, 3283. 1H NMR spectrum (DMSO-d6),
δ, ppm: 2.20 (3H, s, CH3); 2.57–2.60 (1H, m) and 2.71–
2.74 (1H, m, CОCH2CH2Br); 3.49–3.51 (1H, m) and 3.64–
3.67 (1H, m, CОCH2CH2Br); 6.00 (1H, s, H-5); 7.31–7.41
(5H, m, Н Ph); 8.98 (1H, s, NHCOCH2); 11.78 (1H, s,
1-NH). 13C NMR spectrum (DMSO-d6), δ, ppm: 18.2
(CH3); 28.4 (CОCH2CH2Br); 40.3 (CОCH2CH2Br); 105.4
(C-5); 121.0 (C-3); 127.6 (C-4 Ph); 127.9, 128.0 (C-2,3,5,6
Ph); 137.4 (C-1 Ph); 142.8 (C-4); 148.6 (C-6); 160.6 (C-2);
168.5 (NHCOCH2). Found, %: С 53.89; Н 4.39; N 8.20.
C15H15BrN2O2. Calculated, %: С 53.75; Н 4.51; N 8.36.
2-Chloro-N-(2-chloroacetyl)-N-(6-methyl-2-oxo-4-phenyl-
1,2-dihydropyridin-3-yl)acetamide (17). Pyridine (0.243 ml,
3 mmol) was added to a solution of compound 4 (200 mg,
1 mmol) in dichloromethane (6 ml), the resulting mixture
was cooled to 5°С and treated by dropwise addition of
chloroacetyl chloride (1 ml, 3 mmol). The reaction mixture
was stirred at room temperature for 15 h. The solvent was
removed by evaporation, the residue was treated with ice
water. The precipitate was filtered off, washed with
distilled water, and recrystallized from 50% ethanol. Yield
208 mg (75%), white crystals, mp 192–194°С.
The work was performed with financial support from the
Russian Foundation for Basic Research (project 15-53-
45084 IND_a).
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