Synthesis of 6-(2-hydroxyaryl)-2-pyridones by the reaction of chromones with cyanoacetic, acetoacetic, and malonic acid amides

Article abstract of DOI:10.1007/s11172-013-0181-3

A reaction of chromones with cyanoacetic, acetoacetic, and malonic acid amides in the presence of sodium ethoxide furnished a number of new 3-substituted 6-(2-hydroxyaryl)-2-pyridones in good yields, including those containing a polyfluoroalkyl group at position 4.

Full text of DOI:10.1007/s11172-013-0181-3

Russian Chemical Bulletin, International Edition, Vol. 62, No. 5, pp. 1299—1303, May, 2013
1299
Synthesis of 6ꢀ(2ꢀhydroxyaryl)ꢀ2ꢀpyridones by the reaction of chromones
with cyanoacetic, acetoacetic, and malonic acid amides
A. V. Safrygin, V. A. Anufriev, and V. Ya. Sosnovskikh
B. N. Eltsin Ural Federal University,
51 prosp. Lenina, 620000 Ekaterinburg, Russian Federation.
Fax: +7 (343) 261 5978. Eꢀmail: Vyacheslav.Sosnovskikh@usu.ru
A reaction of chromones with cyanoacetic, acetoacetic, and malonic acid amides in the
presence of sodium ethoxide furnished a number of new 3ꢀsubstituted 6ꢀ(2ꢀhydroxyaryl)ꢀ2ꢀ
pyridones in good yields, including those containing a polyfluoroalkyl group at position 4.
Key words: chromones, active methylene amides, 2ꢀpyridones, RFꢀcontaining compounds.
4ꢀArylꢀ3ꢀcyanoꢀ6ꢀ(2ꢀhydroxyphenyl)ꢀ2ꢀpyridones 1
are known as compound possessing a wide range of bioꢀ
logical activity, which exhibit antiinflammatory, antibacꢀ
terial, and analgesic properties.1 Besides, they are Pimꢀ1
kinase inhibitors,2 can be used in the studies of biochemiꢀ
cal role of a unique apoptosis inhibitor survivine,3 and
can successfully compete as calcium channel blockers
with such medicine of the benzothiazepine series as dilthꢀ
iazem 2 (see Ref. 4).
fluoroꢀ4ꢀmethoxypentꢀ3ꢀenꢀ2ꢀone,9 and 4,4ꢀbis(methylꢀ
thio)ꢀ1,1,1ꢀtrifluorobutꢀ3ꢀenꢀ2ꢀone.11 In the present
work, we studied a reaction of 2ꢀpolyfluoroalkylchromꢀ
ones, unsubstituted chromone, and 2ꢀmethylchromones
with active methylene amides, thus obtaining a number of
new biologically active analogs of 2ꢀpyridones 1, includꢀ
ing those containing polyfluoroalkyl group at position 4
(see preliminary communication12).
At the same time, the introduction of a trifluoromethyl
group in the bioactive molecules is an important aspect in
the pharmaceutical studies, which stimulates research diꢀ
rected on the search and development of new methods for
the preparation of CF3ꢀcontaining heterocycles. In this
connection, the replacement of the 4ꢀaryl substituent in
2ꢀpyridones 1 with the CF3 group is of undoubted interest
as an approach to the synthesis of new 2ꢀpyridone derivaꢀ
tives with potential biological activity.
Results and Discussion
The reactions of 2ꢀpolyfluoroalkylchromones 3 with
1,3ꢀdinucleophiles are fairly well studied.13 The studies
showed that imines and enamines resulted in the formaꢀ
tion of RFꢀcontaining pyridines14,15 and benzenes,16
whereas amidines gave pyrimidines.14 However, there are
no literature data on the reaction of 2ꢀRFꢀchromones 3
with amides having an active methylene group. As to
2ꢀmethylchromones, they depending on the conditions
react with active methylene amides at both the carbonyl
group, giving rise to the corresponding methylidene derivꢀ
atives (1,2ꢀaddition),17 and at atom C(2), which leads to
4ꢀmethylꢀ2ꢀpyridones (1,4ꢀaddition).18,19
We found that 2ꢀRFꢀchromones 3 react with cyanoacꢀ
etamide, Nꢀmethylcyanoacetamide, as well as with aceꢀ
toacetic and malonic acid amides in the presence of sodiꢀ
um ethoxide upon reflux in ethanol for 4—6 h, giving
6ꢀ(2ꢀhydroxyaryl)ꢀ4ꢀpolyfluoroalkylꢀ2ꢀpyridones 4a—l in
65—95% yields (the yield of pyridone 4m from acetoacetꢀ
anilide was 38%). Pyridone 4a was also obtained from
malononitrile and 2ꢀtrifluoromethylchromone in 65%
yield. NꢀEthylꢀ and Nꢀphenylcyanoacetamides did not
give this reaction, whereas the use of piperidinium acetate
as the catalyst, showing good results in the reaction of
cyanoacetamide with trifluorobenzoylacetone,6 did not
increase the yield. The products obtained are colored (from
Earlier, 3,6ꢀdisubstituted 4ꢀtrifluoromethylꢀ2ꢀpyriꢀ
dones were obtained by cyclocondensation of 1ꢀtrifluoꢀ
romethylꢀ1,3ꢀdiketones with cyanoacetamide1,5—7 and
Nꢀmethylcyanoacetamide,8 whereas monoꢀ and disubstiꢀ
tuted 6ꢀtrifluoromethylꢀ2ꢀpyridones by the reaction of
cyanoacetic, acetoacetic, and malonic acid amides with
4ꢀalkoxyꢀ1,1,1ꢀtrifluorobutꢀ3ꢀenꢀ2ꢀones,9,10 1,1,1ꢀtriꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1299—1303, May, 2013.
1066ꢀ5285/13/6205ꢀ1299 © 2013 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 62, No. 5, May, 2013
Safrygin et al.
Scheme 2
pale yellow to light brown) highꢀmelting powders, whose
structure was confirmed by elemental analysis, IR and
1H, 19F, and 13C NMR spectroscopy. The reaction folꢀ
lows the mechanism of nucleophilic 1,4ꢀaddition to
chromones 3 with subsequent pyrone ring opening and
heterocyclization upon the attack by the amino group at
the carbonyl carbon atom (Scheme 1).
Scheme 1
The latter tautomer is more preferable, since due to the
formation of the intramolecular hydrogen bond (IMHB)
between the phenol hydroxyl and the pyridine nitrogen
atom both aromatic rings are placed in one plane, that
results in the deshielding the proton H(6´) ( ~ 7.6). In
contrast to Nꢀunsubstituted 2ꢀpyridones 4a—d, the phenol
ring in compounds 4e—m (R´ = Me, Ph) deviates from
the plane of the molecule because of steric hindrance,
which results in the upfield shift of the signal for proton
H(6´) ( 7.0—7.3). The pyridone proton H(5) in this
compounds is observed as a sharp singlet in the region
 6.4—6.7, whereas the singlet of the CF3 group in the
19F NMR spectra is found around  –64 for 3ꢀcyanoꢀ
substituted and  –61 for 3ꢀacetyl and 3ꢀethoxycarbonyl
derivatives, that corresponds to 4ꢀCF3ꢀ2ꢀpyridones7,20 (in
6ꢀCF3ꢀ2ꢀpyridones, this group is in the region  –6711,20).
Taking into account that 3ꢀcyanoꢀ6ꢀ(2ꢀhydroxypheꢀ
nyl)ꢀ2ꢀpyridones 1 exhibit various types of biological acꢀ
tivity and are of great interest for medicinal chemistry,1—4
we extended the reaction with active methylene amides to
the unsubstituted chromone, as well as obtained a number
of new 4ꢀmethylꢀ2ꢀpyridones with 2ꢀhydroxyaryl substitꢀ
uent at position 6 from 2ꢀmethylꢀ and 2ꢀmethylꢀ6ꢀnitroꢀ
chromones 5. It was found that the reaction of these comꢀ
pounds with cyanoacetamide, Nꢀmethylcyanoacetamide,
and malonic acid diamide in the presence of sodium ethꢀ
oxide in ethanol afforded pyridones 6a—f in 32—71%
yields, whose structure is in good agreement with the eleꢀ
mental analysis data and the 1H NMR spectra (Scheme 3).
4
a
b
c
d
e
f
g
h
i
RF
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF2H
CF2H
(CF2)2H
C2F5
CF3
R
H
H
R´
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Ph
X
CN
COMe
COMe
CO2Et
CN
CN
CN
CN
CN
Yield (%)
68
65
74
85
74
85
88
88
95
80
78
75
38
5´ꢀMe
H
H
5´ꢀMe
4´,6´ꢀ2Me
5´ꢀNO2
5´ꢀMe
4´ꢀMeO
4´ꢀMeO
4´ꢀMeO
H
j
k
l
CN
CN
CN
COMe
m
Scheme 3
As in the case of trifluoromethylated 1,3ꢀdiketones,1,5—8
we observed the formation of only single 4ꢀRFꢀregioisoꢀ
mer. The choice between 4ꢀCF3ꢀ and 6ꢀCF3ꢀ2ꢀpyridones
was made in favor of the former based on the 13C NMR
spectrum of compound 4e, which exhibited the quartets
for carbon atoms C(3), C(5), and C(4) at  97.0 (3JC,F
=
=
= 2.2 Hz), 103.8 (3JC,F = 4.4 Hz), and 143.9 (2JC,F
= 33.0 Hz), respectively; all the signals were assigned based
on the analysis of 1H—13C HSQC and HMBC 2D experiꢀ
ments. The 1H NMR spectra of pyridones 4a—d (R´ = H)
in DMSOꢀd6 are characterized by the presence of very
broad singlets for protons H(5) and H(6´), that indicates
a slow in the NMR spectroscopy time scale prototropic
tautomerism between the 2ꢀpyridone (4) and 2ꢀhydroxyꢀ
pyridine (4´) forms (Scheme 2).
6
a
b
c
d
e
f
R
H
H
R´
H
H
R
H
Me
H
H
Me
H
X
CN
CN
CONH2
CN
CN
Yield (%)
60
47
32
71
69
H
H
Me
Me
Me
NO2
NO2
H
CONH2
37

Synthesis of 6ꢀ(2ꢀhydroxyaryl)ꢀ2ꢀpyridones
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 5, May, 2013
1301
(br.s, 1 H, OH); 12.2—12.7 (br.s, 1 H, NH/OH). 19F NMR
(DMSOꢀd6), : –60.7 (s, CF3).
Note that flavone did not react with cyanoacetamide under
similar conditions. The regiochemistry of the products obꢀ
tained from 2ꢀmethylchromones was confirmed earlier.19
In conclusion, the behavior of 2ꢀpolyfluoroalkylꢀ
chromones and unsubstituted chromone in the reaction
with active methylene amides is similar to that of 2ꢀmethylꢀ
chromones studied earlier: the reaction gives a number of
new 6ꢀ(2ꢀhydroxyaryl)ꢀ2ꢀpyridones with high regioselecꢀ
tivity and good yields.
Ethyl 6ꢀ(2ꢀhydroxyphenyl)ꢀ2ꢀoxoꢀ4ꢀtrifluoromethylꢀ1,2ꢀdiꢀ
hydropyridineꢀ3ꢀcarboxylate (4d). The yield was 85%, pale yelꢀ
low crystals, m.p. 202—204 C. Found (%): C, 54.82; H, 3.87;
N, 4.30. C15H12F3NO4. Calculated (%): C, 55.05; H, 3.70; N, 4.28.
IR, /cm–1: 3155, 2988, 1740, 1625, 1584, 1556. 1H NMR
(DMSOꢀd6), : 1.33 (t, 3 H, Me, J = 7.1 Hz); 4.31 (q, 2 H, CH2,
J = 7.1 Hz); 6.88 (td, 1 H, H(5´), J = 7.4 Hz, J = 0.8 Hz); 6.94
(d, 1 H, H(3´), J = 8.1 Hz); 6.9–7.2 (br.s, 1 H, H(5)); 7.28 (ddd,
1 H, H(4´), J = 8.1 Hz, J = 7.4 Hz, J = 1.5 Hz); 7.62 (br.s, 1 H,
H(6´)); 10.4—11.7 (br.s, 1 H, OH); 12.2—12.6 (br.s, 1 H,
NH/OH). 19F NMR (DMSOꢀd6), : –62.2 (s, CF3).
Experimental
6ꢀ(2ꢀHydroxyphenyl)ꢀ1ꢀmethylꢀ2ꢀoxoꢀ4ꢀtrifluoromethylꢀ
1,2ꢀdihydropyridineꢀ3ꢀcarbonitrile (4e). The yield was 74%, light
brown crystals, m.p. 221—222 C. Found (%): C, 57.02; H, 3.43;
N, 9.50. C14H9F3N2O2. Calculated (%): C, 57.15; H, 3.08; N, 9.52.
IR, /cm–1: 3151, 2232, 1634, 1601, 1571, 1557. 1H NMR
(DMSOꢀd6—CCl4), (2 : 3), : 3.40 (s, 3 H, Me); 6.47 (s, 1 H,
H(5)); 6.94 (td, 1 H, H(5´), J = 7.5 Hz, J = 1.0 Hz); 6.99 (d, 1 H,
H(3´), J = 8.3 Hz); 7.23 (dd, 1 H, H(6´), J = 7.5 Hz, J = 1.6 Hz);
7.36 (ddd, 1 H, H(4´), J = 8.3 Hz, J = 7.5 Hz, J = 1.6 Hz); 10.34
(s, 1 H, OH). 1H NMR (DMSOꢀd6), : 3.38 (s, 3 H, Me); 6.67
(s, 1 H, H(5)); 6.99 (t, 1 H, H(5´), J = 7.5 Hz); 7.02 (d, 1 H,
H(3´), J = 8.3 Hz); 7.32 (dd, 1 H, H(6´), J = 7.5 Hz, J = 1.6 Hz);
7.43 (ddd, 1 H, H(4´), J = 8.3 Hz, J = 7.5 Hz, J = 1.6 Hz); 10.48
(s, 1 H, OH). 19F NMR (DMSOꢀd6), : –64.6 (s, CF3). 13C NMR
(DMSOꢀd6), : 34.8 (Me), 97.0 (q, C(3), 3JC,F = 2.2 Hz), 103.8
IR spectra were obtained on a Bruker Alpha FTIR specꢀ
trometer using a frustrated total internal reflection (FTIR) apꢀ
1
pliance (ZnSeꢀcrystal). H, 19F and 13C NMR spectra were reꢀ
corded on Bruker DRXꢀ400 and Bruker Avance II spectrometers
(400, 376 and 100 MHz, respectively) in DMSOꢀd6, using Me4Si
and CFCl3 as internal standards. Elemental analysis was perꢀ
formed on a PE 2400 automatic analyzer. Chromones 3 were
obtained according to the known procedure.21
Synthesis of pyridones 4 and 6 (general procedure). Chromone 3
or 5 (3.0 mmol) and the corresponding amide (3.6 mmol) were
added to a solution of sodium ethoxide prepared from sodium
(83 mg, 3.6 mmol) in anhydrous ethanol (10 mL). The mixture
obtained was refluxed for 4—6 h, then the orange reaction mixꢀ
ture formed was cooled to ~20 C, acidified with 3 M aqueous
hydrochloric acid (25 mL), diluted with water to 75 mL, and
allowed to stand for 16 h at room temperature or in a refrigerator.
A precipitate formed was filtered off, washed with reflux aqueꢀ
ous ethanol or recrystallized from aqueous ethanol (from acetoꢀ
nitrile for 4d).
6ꢀ(2ꢀHydroxyphenyl)ꢀ2ꢀoxoꢀ4ꢀtrifluoromethylꢀ1,2ꢀdihydroꢀ
pyridineꢀ3ꢀcarbonitrile (4a). The yield was 68%, yellow crystals,
m.p. 317—318 C. Found (%): C, 55.70; H, 2.33; N, 9.97.
C13H7F3N2O2. Calculated (%): C, 55.72; H, 2.52; N, 10.00.
IR, /cm–1: 3403, 3145, 2227, 1659, 1645, 1605, 1576, 1551.
1H NMR (DMSOꢀd6), : 6.92 (t, 1 H, H(5´), J = 7.5 Hz); 6.98
(d, 1 H, H(3´), J = 8.3 Hz); 6.9—7.3 (br.s, 1 H, H(5)); 7.34 (ddd,
1 H, H(4´), J = 8.3 Hz, J = 7.5 Hz, J = 1.5 Hz); 7.63 (br.s, 1 H,
H(6´)); 10.4—11.2 (br.s, 1 H, OH); 12.8—13.4 (br.s, 1 H,
NH/OH). 19F NMR (DMSOꢀd6), : –63.9 (s, CF3).
3
(q, C(5), JC,F = 4.4 Hz), 113.4 (CN), 116.0 (C(3´)), 119.7
1
(C(5´)), 120.7 (C(1´)), 121.1 (q, CF3, JC,F = 275.8 Hz), 129.8
2
(C(6´)), 132.5 (C(4´)), 143.9 (q, C(4), JC,F = 33.0 Hz), 154.3
(C(2´)), 156.7 (C(6)), 160.1 (C(2)).
6ꢀ(2ꢀHydroxyꢀ5ꢀmethylphenyl)ꢀ1ꢀmethylꢀ2ꢀoxoꢀ4ꢀtrifluoroꢀ
methylꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbonitrile (4f). The yield was
85%, greenish crystals, m.p. 267—268 C. Found (%): C, 58.28;
H, 3.60; N, 9.11. C15H11F3N2O2. Calculated (%): C, 58.45; H, 3.60;
N, 9.09. IR, /cm–1: 3221, 2233, 1635, 1613, 1598, 1572, 1556, 1508.
1H NMR (DMSOꢀd6), : 2.26 (s, 3 H, Me); 3.36 (s, 3 H, MeN);
6.66 (s, 1 H, H(5)); 6.91 (d, 1 H, H(3´), J = 8.4 Hz); 7.13 (d, 1 H,
H(6´), J = 1.8 Hz); 7.23 (dd, 1 H, H(4´), J = 8.4 Hz, J = 1.8 Hz);
10.21 (s, 1 H, OH). 19F NMR (DMSOꢀd6), : –64.0 (s, CF3).
6ꢀ(2ꢀHydroxyꢀ4,6ꢀdimethylphenyl)ꢀ1ꢀmethylꢀ2ꢀoxoꢀ4ꢀtriꢀ
fluoromethylꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbonitrile (4g). The yield
was 88%, colorless crystals, m.p. 244—245 C. Found (%): C, 59.21;
H, 4.07; N, 8.59. C16H13F3N2O2. Calculated (%): C, 59.63;
H, 4.07; N, 8.69. IR, /cm–1: 3357, 2239, 1649, 1618, 1581,
1553. 1H NMR (DMSOꢀd6), : 2.06 (s, 3 H, Me(4´)); 2.26
(s, 3 H, Me(6´)); 3.28 (s, 3 H, MeN); 6.65 (s, 1 H, H(5)); 6.67
(s, 1 H, H(3´)); 6.68 (s, 1 H, H(5´)); 10.03 (s, 1 H, OH). 19F NMR
(DMSOꢀd6), : –63.9 (s, CF3).
6ꢀ(2ꢀHydroxyꢀ5ꢀnitrophenyl)ꢀ1ꢀmethylꢀ2ꢀoxoꢀ4ꢀtrifluoroꢀ
methylꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbonitrile (4h). The yield was
88%, beige crystals, m.p. 261—262 C. Found (%): C, 49.50;
H, 2.45. C14H8F3N3O4. Calculated (%): C, 49.57; H, 2.38. IR,
/cm–1: 3091, 2233, 1641, 1617, 1573, 1558, 1527, 1492, 1338.
1H NMR (DMSOꢀd6), : 3.36 (s, 3 H, MeN); 6.87 (s, 1 H,
H(5)); 7.18 (d, 1 H, H(3´), J = 9.0 Hz); 8.31 (d, 1 H, H(6´),
J = 2.8 Hz); 8.34 (dd, 1 H, H(4´), J = 9.0 Hz, 2.8 Hz); 12.0—12.2
(br.s, 1 H, OH).
3ꢀAcetylꢀ6ꢀ(2ꢀhydroxyphenyl)ꢀ4ꢀtrifluoromethylpyridinꢀ2(1H)ꢀ
one (4b). The yield was 65%, pale yellow crystals, m.p. 256—257 C.
Found (%): C, 56.61; H, 3.39; N, 4.76. C14H10F3NO3. Calculatꢀ
ed (%): C, 56.57; H, 3.39; N, 4.71. IR, /cm–1: 3178, 1709,
1
1625, 1599, 1551. H NMR (DMSOꢀd6), : 2.48 (s, 3 H, Me);
6.5—7.2 (br.s, 1 H, H(5)); 6.87 (td, 1 H, H(5´), J = 7.5 Hz,
J = 0.9 Hz); 6.94 (d, 1 H, H(3´), J = 8.1 Hz); 7.27 (ddd, 1 H, H(4´),
J = 8.1 Hz, J = 7.5 Hz, J = 1.5 Hz); 7.58 (br.s, 1 H, H(6´));
10.0—11.0 (br.s, 1 H, OH); 12.1—12.7 (br.s, 1 H, NH/OH).
19F NMR (DMSOꢀd6), : –60.8 (s, CF3).
3ꢀAcetylꢀ6ꢀ(2ꢀhydroxyꢀ5ꢀmethylphenyl)ꢀ4ꢀtrifluoromethylpyrꢀ
idinꢀ2(1H)ꢀone (4c). The yield was 74%, yellow crystals,
m.p. 266—267 C. Found (%): C, 57.82; H, 3.68; N, 4.45.
C15H12F3NO3. Calculated (%): C, 57.88; H, 3.89; N, 4.50.
IR, /cm–1: 3152, 1708, 1631, 1591, 1536, 1509. 1H NMR
(DMSOꢀd6), : 2.26 (s, 3 H, Me); 2.49 (s, 3 H, MeCO); 6.6—7.0
(br.s, 1 H, H(5)); 6.88 (d, 1 H, H(3´), J = 8.3 Hz); 7.15 (dd, 1 H,
H(4´), J = 8.3 Hz, J = 2.0 Hz); 7.44 (br.s, 1 H, H(6´)); 10.0—10.8
4ꢀDifluoromethylꢀ6ꢀ(2ꢀhydroxyꢀ5ꢀmethylphenyl)ꢀ1ꢀmethylꢀ
2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbonitrile (4i). The yield was 95%,

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Russ.Chem.Bull., Int.Ed., Vol. 62, No. 5, May, 2013
Safrygin et al.
orange crystals, m.p. 267—268 C. Found (%): C, 61.94; H, 3.97;
N, 9.70. C15H12F2N2O2. Calculated (%): C, 62.07; H, 4.17; N, 9.65.
IR, /cm–1: 3190, 2226, 1633, 1612, 1597, 1573, 1552, 1509.
1H NMR (DMSOꢀd6), : 2.25 (s, 3 H, Me); 3.33 (s, 3 H, MeN);
6.48 (s, 1 H, H(5)); 6.90 (d, 1 H, H(3´), J = 8.3 Hz); 7.10 (d, 1 H,
H(6´), J = 1.7 Hz); 7.14 (t, 1 H, CF2H, J = 53.6 Hz); 7.22 (dd, 1 H,
H(4´), J = 8.3 Hz, J = 1.7 Hz); 10.16 (s, 1 H, OH). 19F NMR
(DMSOꢀd6), : –118.2 (dd, 1 F, CFFH, J = 310.0 Hz, J = 53.6 Hz);
–117.2 (dd, 1 F, CFFH, J = 310.0 Hz, J = 53.6 Hz).
4ꢀDifluoromethylꢀ6ꢀ(2ꢀhydroxyꢀ4ꢀmethoxyphenyl)ꢀ1ꢀmethylꢀ
2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbonitrile (4j). The yield was 80%,
red crystals, m.p. 217—218 C. Found (%): C, 58.67; H, 3.81;
N, 9.19. C15H12F2N2O3. Calculated (%): C, 58.83; H, 3.95;
N, 9.15. IR, /cm–1: 3279, 2223, 1644, 1613, 1577, 1555, 1518.
1H NMR (DMSOꢀd6), : 3.34 (s, 3 H, MeN); 3.78 (s, 3 H, MeO);
6.46 (s, 1 H, H(5)); 6.54 (d, 1 H, H(3´), J = 2.4 Hz); 6.58 (dd, 1 H,
H(5´), J = 8.5 Hz, J = 2.4 Hz); 7.14 (t, 1 H, CF2H, J = 53.7 Hz);
7.23 (d, 1 H, H(6´), J = 8.5 Hz); 10.48 (s, 1 H, OH). 19F NMR
(DMSOꢀd6), : –118.2 (dd, 1 F, CFFH, J = 310.0 Hz, J = 53.7 Hz);
–117.2 (dd, 1 F, CFFH, J = 310.0 Hz, J = 53.7 Hz).
6ꢀ(2ꢀHydroxyphenyl)ꢀ1ꢀmethylꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ
3ꢀcarbonitrile (6b). The yield was 47%, light brown crystals,
m.p. 280—281 C. Found (%): C, 67.70; H, 4.65; N, 11.89.
C13H10N2O2•0.25H2O. Calculated (%): C, 67.67; H, 4.59;
1
N, 12.14. IR, /cm–1: 2226, 1626, 1601, 1553, 1500. H NMR
(DMSOꢀd6), : 3.28 (s, 3 H, Me); 6.30 (d, 1 H, H(5), J = 7.5 Hz);
6.96 (td, 1 H, H(5´), J = 7.6 Hz, J = 1.0 Hz); 7.00 (dd, 1 H,
H(3´), J = 8.2 Hz, J = 0.9 Hz); 7.24 (dd, 1 H, H(6´), J = 7.6 Hz,
J = 1.7 Hz); 7.38 (ddd, 1 H, H(4´), J = 8.2 Hz, J = 7.6 Hz,
J = 1.7 Hz); 8.13 (d, 1 H, H(4), J = 7.5 Hz); 10.30 (s, 1 H, OH).
6ꢀ(2ꢀHydroxyphenyl)ꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarboxꢀ
amide (6c). The yield was 32%, light yellow crystals, m.p.
306—307 C. Found (%): C, 62.50; H, 4.50. C12H10N2O3. Calꢀ
culated (%): C, 62.60; H, 4.38. IR, /cm–1: 3367, 3143, 1668,
1575, 1556. 1H NMR (DMSOꢀd6), : 6.68 (br.s, 1 H, H(5)); 6.93
(td, 1 H, H(5´), J = 7.6 Hz, J = 1.0 Hz); 6.99 (d, 1 H, H(3´),
J = 8.2 Hz); 7.33 (ddd, 1 H, H(4´), J = 8.2 Hz, J = 7.6 Hz,
J = 1.7 Hz); 7.47 (br.d, 1 H, NH); 7.52 (br.s, 1 H, H(6´)); 8.34
(d, 1 H, H(4), J = 7.6 Hz); 9.09 (br.s, 1 H, NH); 10.4—10.6
(br.s, 1 H, OH); 12.1—12.3 (br.s, 1 H, NH/OH).
6ꢀ(2ꢀHydroxyꢀ4ꢀmethoxyphenyl)ꢀ1ꢀmethylꢀ2ꢀoxoꢀ4ꢀ(1,1,2,2ꢀ
tetrafluoroethyl)ꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbonitrile (4k). The
yield was 78%, orange crystals, m.p. 249—250 C. Found (%):
C, 53.62; H, 3.27; N, 7.83. C16H12F4N2O3. Calculated (%):
C, 53.94; H, 3.39; N, 7.86. IR, /cm–1: 3248, 2232, 1642, 1613,
1578, 1548, 1518. 1H NMR (DMSOꢀd6), : 3.37 (s, 3 H, MeN);
3.78 (s, 3 H, MeO); 6.42 (s, 1 H, H(5)); 6.55 (d, 1 H, H(3´),
J = 2.3 Hz); 6.60 (dd, 1 H, H(5´), J = 8.5 Hz, J = 2.3 Hz); 6.90
(tt, 1 H, (CF2)2H, J = 51.7 Hz, J = 4.0 Hz); 7.24 (d, 1 H, H(6´),
J = 8.5 Hz); 10.53 (s, 1 H, OH). 19F NMR (DMSOꢀd6), : –136.3
(dt, 2 F, CF2H, J = 51.7 Hz, J = 5.5 Hz); –116.0 (q, 2 F, CF2,
J = 5.5 Hz).
6ꢀ(2ꢀHydroxyꢀ5ꢀnitrophenyl)ꢀ4ꢀmethylꢀ2ꢀoxoꢀ1,2ꢀdihydroꢀ
pyridineꢀ3ꢀcarbonitrile (6d). The yield was 71%, light brown crysꢀ
tals, m.p. >330 C. Found (%): N, 15.25. C13H9N3O4. Calculatꢀ
ed (%): N, 15.49. IR, /cm–1: 2230, 1651, 1605, 1528. 1H NMR
(DMSOꢀd6), : 2.47 (s, 3 H, Me); 6.87 (br.s, 1 H, H(5)); 7.10
(d, 1 H, H(3´), J = 9.1 Hz); 8.16 (dd, 1 H, H(4´), J = 9.1 Hz,
J = 2.7 Hz); 8.42 (br.s, 1 H, H(6´)); 11.0—13.2 (br.s, 2 H, NH, OH).
6ꢀ(2ꢀHydroxyꢀ5ꢀnitrophenyl)ꢀ1,4ꢀdimethylꢀ2ꢀoxoꢀ1,2ꢀdiꢀ
hydropyridineꢀ3ꢀcarbonitrile (6e). The yield was 69%, light brown
crystals, m.p. >330 C. Found (%): C, 58.91; H, 4.08; N, 14.71.
C14H11N3O4. Calculated (%): C, 58.95; H, 3.89; N, 14.73. IR,
1
/cm–1: 2229, 1614, 1563, 1549, 1489. H NMR (DMSOꢀd6),
6ꢀ(2ꢀHydroxyꢀ4ꢀmethoxyphenyl)ꢀ1ꢀmethylꢀ2ꢀoxoꢀ4ꢀperfluoroꢀ
ethylꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbonitrile (4l). The yield was 75%,
orange crystals, m.p. 208—209 C. Found (%): C, 51.25; H, 2.86;
N, 7.48. C16H11F5N2O3. Calculated (%): C, 51.35; H, 2.96;
N, 7.48. IR, /cm–1: 3292, 2235, 1639, 1615, 1581, 1551, 1517.
1H NMR (DMSOꢀd6), : 3.38 (s, 3 H, MeN); 3.78 (s, 3 H, MeO);
6.53 (s, 1 H, H(5)); 6.55 (s, 1 H, H(3´)); 6.60 (d, 1 H, H(5´),
J = 8.5 Hz); 7.24 (d, 1 H, H(6´), J = 8.5 Hz); 10.54 (s, 1 H,
OH). 19F NMR (DMSOꢀd6), : –115.3 (s, 2 F, CF2); –83.4
(s, 3 F, CF3).
3ꢀAcetylꢀ6ꢀ(2ꢀhydroxyphenyl)ꢀ4ꢀtrifluoromethylꢀ1ꢀphenylpyrꢀ
idinꢀ2(1H)ꢀone (4m). The yield was 38%, colorless crystals, m.p.
216—217 C. Found (%): C, 64.46; H, 3.57; N, 3.85. C20H14F3NO3.
Calculated (%): C, 64.34; H, 3.78; N, 3.75. IR, /cm–1: 3140,
1713, 1644, 1601, 1572, 1556, 1502, 1490. 1H NMR (DMSOꢀd6),
: 2.48 (s, 3 H, Me); 6.35 (s, 1 H, H(5)); 6.60—6.65 (m, 2 H,
H(5´), H(3´)); 6.98—7.04 (m, 2 H, H(4´), H(6´)); 7.12—7.27
(m, 5 H, Ph); 9.71 (s, 1 H, OH). 19F NMR (DMSOꢀd6), : –61.7
(s, CF3).
6ꢀ(2ꢀHydroxyphenyl)ꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarboꢀ
nitrile (6a). The yield was 60%, light yellow crystals, m.p.
307—308 C. Found (%): C, 67.59; H, 3.83; N, 12.86. C12H8N2O2.
Calculated (%): C, 67.92; H, 3.80; N, 13.20. IR, /cm–1: 2225,
1644, 1574, 1558. 1H NMR (DMSOꢀd6), : 6.63 (br.s, 1 H,
H(5)); 6.93 (td, 1 H, H(5´), J = 7.4 Hz, J = 0.8 Hz); 6.99 (dd, 1 H,
H(3´), J = 8.2 Hz, J = 0.8 Hz); 7.35 (ddd, 1 H, H(4´), J = 8.2 Hz,
J = 7.4 Hz, J = 1.7 Hz); 7.49 (br.s, 1 H, H(6´)); 8.15 (d, 1 H,
H(4), J = 7.6 Hz); 10.3—10.8 (br.s, 1 H, OH); 12.2—12.6 (br.s,
1 H, NH/OH).
: 2.40 (s, 3 H, Me); 3.23 (s, 3 H, MeN); 6.42 (s, 1 H, H(5));
7.17 (d, 1 H, H(3´), J = 9.0 Hz); 8.21 (d, 1 H, H(6´),
J = 2.7 Hz); 8.31 (dd, 1 H, H(4´), J = 9.0 Hz, J = 2.7 Hz); 11.98
(s, 1 H, OH).
6ꢀ(2ꢀHydroxyphenyl)ꢀ4ꢀmethylꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ
3ꢀcarboxamide (6f). The yield was 37%, beige crystals, m.p.
251—252 C. Found (%): C, 63.86; H, 4.74; N, 11.41. C13H12N2O3.
Calculated (%): C, 63.93; H, 4.95; N, 11.47. IR, /cm–1: 1684,
1
1619, 1575, 1517. H NMR (DMSOꢀd6), : 2.40 (s, 3 H, Me);
6.42 (br.s, 1 H, H(5)); 6.90 (td, 1 H, H(5´), J = 7.6 Hz,
J = 1.0 Hz); 6.95 (d, 1 H, H(3´), J = 8.3 Hz); 7.29 (ddd, 1 H,
H(4´), J = 8.3 Hz, J = 7.0 Hz, J = 1.6 Hz); 7.2—7.6 (br.s, 2 H,
H(6´), NH); 8.55 (br.s, 1 H, NH); 10.40 (br.s, 1 H, OH); 11.72
(br.s, 1 H, NH/OH).
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Received November 29, 2012;
in revised form February 20, 2013