Synthesis and intramolecular cyclization of N-acyl- and N-allyl-N'-(2-oxo-1,2-dihydro-pyridin-3-yl)thiourea

Article abstract of DOI:10.1007/s10593-014-1519-y

The reaction of 3-amino-4,6-dimethylpyridin-2(1H)-one and 3-amino-4-phenylpyridin-2-one with acyl isothiocyanates (benzoyl-, 4-bromobenzoyl-, and methacryloyl isothiocyanates) and with allyl isothiocyanate has been studied. The N-carbamothioyl methacrylam

Full text of DOI:10.1007/s10593-014-1519-y

Chemistry of Heterocyclic Compounds, Vol. 50, No. 5, August, 2014 (Russian Original Vol. 50, No. 5, May, 2014)
SYNTHESIS AND INTRAMOLECULAR CYCLIZATION
OF N-ACYL- AND N-ALLYL-N'-(2-OXO-1,2-DIHYDRO-
PYRIDIN-3-YL)THIOUREA
1
1
1,2
1
I. V. Kulakov *, O. S. Nikitina , A. S. Fisyuk , D. S. Goncharov ,
3
3
Z. T. Shul'gau , and A. E. Gulyaev
The reaction of 3-amino-4,6-dimethylpyridin-2(1H)-one and 3-amino-4-phenylpyridin-2-one with acyl
isothiocyanates (benzoyl-, 4-bromobenzoyl-, and methacryloyl isothiocyanates) and with allyl
isothiocyanate has been studied. The N-carbamothioyl methacrylamides and N-allylthioureas obtained
undergo intramolecular heterocyclization reactions to give the corresponding 1,3-thiazin-4-one and
1
,3-thiazoline derivatives. It was found that the starting 3-amino-4,6-dimethylpyridin-2(1H)-one shows
antiradical activity but the synthesized thioureas do not.
Keywords: 3-aminopyridin-2(1H)-ones, isothiocyanates, 1,3-thiazines, 1,3-thiazolines, thioureas,
intramolecular cyclization.
3
-Aminopyridin-2-ones are of interest due to their biological activity. These include anticoagulants,
thrombin inhibitors [1], and antiviral agents [2] including those active against HIV-1 [3]. In clinical practice the
medication amrinone shows cardiotonic and vasodilator activities [4]. Mexidol (2-ethyl-3-oxo-6-methyl-
pyridine succinate) shows antioxidant and membrane protective properties and can be mentioned amongst
3
-aminopyridone analogs. A feature of the structure of these compounds is the presence of an inherent amino
acid structure fragment which allows their use as peptide mimetics [5].
It is known that thioureide derivatives have valuable pharmacological properties and find use as
antiepileptic [6], antidiabetic [7], anticancer [8], antitubercular [9], and as other therapeutically active agents
[
10]. They are also starting synthons in the preparation of many sulfur-containing heterocycles. Hence the
introduction into the 3-aminopyridones of sulfur-containing (including heterocyclic) fragments may lead to an
increase in basic, or the appearance of novel, biological properties.
We have previously developed [11, 12] a convenient method for the preparation of 3-aminopyridin-
(1H)-ones based on an intramolecular cyclization of -enamino ketone chloroacetamides.
2
_
*
______
To whom correspondence should be addressed, e-mail: kulakov@chemomsu.ru.
1
F. M. Dostoevskii State University, 55a Mir Ave., Omsk 644077, Russia.
Omsk State Technical University, 11 Mir Ave., Omsk 644050, Russia, e-mail: fisyuk@chemomsu.ru.
Nazarbayev University, Center for Life Sciences, 53 Kabanbai Batyr Ave., Astana 010000, Kazakhstan, e-mail:
2
3
zarina.shulgau@nu.edu.kz.
_
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 729-736, May, 2014. Original
article submitted January 12, 2014.
70
0009-3122/14/5005-0670©2014 Springer Science+Business Media New York
6

Up to the time of our investigation preparation of a thiourea from 3-aminopyridin-2(1H)-one has only
been reported in a single example [13]. With the aim of obtaining the previously unknown thioureide and
thiourea derivatives of pyridones 2-5 we studied the reaction of compounds 1a,b with acyl isothiocyanates
using the method reported before [14, 15].
Synthesis of the starting acyl isothiocyanates was carried out in situ by heating the corresponding acid
chlorides (benzoyl, p-bromobenzoyl, and methacryloyl chlorides) with potassium thiocyanate in acetone.
Further reaction of the acyl isothiocyanates with 3-aminopyridin-2(1H)-ones 1a,b gave the thiourea derivatives
2
-5 a,b. Compounds 2-5 a,b are finely crystalline, white or light-yellow powders which are moderately soluble
in polar organic solvents.
R
R
H
N
H
N
NH2
1
Me CO, , 3 h
2
R
1
+
R NCS
S
Me
N
H
O
Me
N
H
O
(for Me CO
2–4 a,b)
2
1a,b
2–5 a,b
, 2 h
1
R Cl + KSCN
1
1
1
1
a R = Me, b R = Ph; 2 R = PhCO, 3 R = 4-BrC
6
H
4
CO, 4 R = H
2
C=C(Ме)СO, 5 R = allyl
1
The structure of compounds 2-5 a,b was confirmed by IR and H NMR spectroscopic data and
elemental analysis. Hence, the spectrum of compound 3a shows two singlets for the methyl group protons at
2
7
1
.05 and 2.15 ppm. The pyridine ring H-5 proton gives a singlet at 5.92 ppm. Two doublets are seen at 7.73 and
.91 ppm for the four aromatic protons. The NH group protons are seen at low field at 11.57, 11.63, and
1.67 ppm.
It has been reported [16] that methacryloyl thioureas can undergo an intramolecular cyclization in the
presence of base. We had shown that heating compounds 4a,b in 2-propanol in the presence of morpholine for 3
h gives this intramolecular cyclization and forms the 5,6-dihydro-1,3-thiazin-4-ones 6a,b in 60-70% yields. In
contrast to compound 4a, the methacryloyl thiourea 4b cyclizes without the addition of catalytic amounts of the
base upon heating in acetone. Similar behavior of methacryloyl thiourea has been noted before [17]. Closing of
the 1,3-thiazine ring evidently occurs as a result of an intramolecular nucleophilic attack of the sulfur atom at
the activated double bond of the methacryloyl ureide fragment of compounds 4a,b.
R
H
N
Me
R
Me
H
N
H
N
N
8
0°C
CH2
CH2
S
O
SH
O
Me
N
H
O
4
Me
N
H
O
a,b
R
H
2
-PrOH
N
S
morpholine
, 3 h
N
Me
N
H
O
Me
6
a,b
O
a R = Me, b R = Ph
1
Formation of the 5,6-dihydro-1,3-thiazin-4-ones 6a,b was confirmed by the absence in their H NMR
spectra of signals for the terminal protons of the double bond in the starting compounds (seen, for example, in
compound 4a as double doublets at 5.69 and 5.99 ppm) and also of the singlet for the thioureide CONH proton
6
71

1
at 11.49 ppm. In addition the H NMR spectra of compounds 6a,b show splitting of the methyl signals to
doublets at 1.13 and 1.19 ppm as a result of their interaction with the methine proton of the 1,3-thiazine ring.
The presence of signals for the methine and methylene protons of the 1,3-thiazine ring as multiplets and double
doublets also supports the formation of compound 6a.
It is known [18] that the allyl thioureas cyclize under the action of acids or halogens to 1,3-thiazolines.
In continuing previously started work on the synthesis and reactivity of unsaturated thioureas [15, 19] we have
carried out an intramolecular cyclization of compounds 5a,b by heating them in hydrochloric acid for 5 h in a
sealed glass ampoule on a boiling water bath. The reaction products obtained in good yields proved to be the
1
,3-thiazolines 7a,b.
R
H
N
S
conc. HCl
00°C, 5 h
Me
5a,b
1
N
Me
N
H
O
7a,b
a R = Me, b R = Ph
1
A study of the reaction products by H NMR spectroscopy showed that the methyl protons of the
thiazoline ring formed upon cyclization occurred as a doublet at 1.28 ppm with spin-spin coupling of 6.7 Hz
(
compound 7a). The methylene protons of the thiazoline ring appeared as two double doublets with spin-spin
couplings 10.6 and 6.1 Hz at 3.18 and 3.63 ppm.
In order to reveal the potential biological activity of the synthesized compounds we carried out a study
of compounds 1a, 3a, 4a, and 6a for their antiradical behavior towards the 2,2'-azinobis(3-ethylbenzo-
+
+
thiazoline-6-sulfonic acid cation radical (ABTS ). In this work we compared the rate of "quenching" the ABTS
by the studied compounds and a standard. The latter was the semisynthetic, water-soluble vitamin E analog
(
±)-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (commercial name Trolox). The use of Trolox
allows a calculation of the efficiency of the antioxidant through the TEAC (Trolox Equivalent Antioxidant
+
Capacity). This TEAC value indicates the amount of Trolox (in mmol per liter, mM) that "quenches" the ABTS
with the same efficiency as 1 mM of the analyzed compound.
As a result of the study carried out, it was found that compound 1a shows an antiradical activity towards
+
the ABTS radical which is comparable with Trolox; the TEAC value for the compound being 1.11±0.04.
Compounds 3a, 4a and 6a did not show antiradical activity under these test conditions.
Hence, from 4,6-disubstituted 3-aminopyridin-2(1H)-ones, we have prepared previously unknown
thioureide derivatives and studied the conversion of these compounds to pyridin-2(1H)-ones containing a
nitrogen atom at position 3 bonded to thiazine and thiazoline rings. It was found that 3-amino-4,6-di-
methylpyridin-2(1H)-one has high antiradical activity.
EXPERIMENTAL
1
13
IR spectra were recorded on an Infralum FT-801 spectrometer for KBr pellets. H and C NMR spectra
were recorded on a Bruker DRX400 instrument (400 and 100 MHz, respectively) using CDCl (compound 5b)
3
or DMSO-d (remaining compounds) with TMS as internal standard. Elemental analysis was performed on a
6
Carlo Erba 1106 CHN instrument. Melting points were determined using a Kofler hot bench. Monitoring of the
reaction course and the purity of the products was carried out by TLC on Sorbfil UV-254 plates and visualized
using iodine vapor or UV light.
The starting 3-aminopyridin-2(1H)-ones 1a,b were prepared by the reported method [12].
6
72

N-[(4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)carbamothioyl]benzamide (2a). A mixture of
KSCN (311 mg, 3.2 mmol), PhCOCl (0.4 ml, 3.2 mmol), and acetone (30 ml) was refluxed for 2 h. The
precipitated KCl was filtered off, and the filtrate was added dropwise to a solution of 3-amino-4,6-dimethyl-
pyridin-2(1H)-one (1a) (414 mg, 3.0 mmol) in acetone (10 ml). The product was stirred under reflux for a
further 3 h, and the reaction mixture and precipitate were cooled. The precipitate was filtered, washed with
acetone, and recrystallized from a 2:1 mixture of 2-PrOH and DMF. Yield 682 mg (76%), light-yellow, finely
-
1
crystalline powder, mp 230-232C. IR spectrum, ν, cm : 3132, 2998, 2914 (NH), 1676, 1632 (С=O), 1532
1
(
(
С=S). H NMR spectrum, δ, ppm (J, Hz): 2.07 (3Н, s, 4-СН ); 2.16 (3Н, s, 6-СН ); 5.92 (1Н, s, H-5); 7.53
3
3
2Н, t, J = 7.6, Н-3,5 Ph); 7.65 (1Н, t, J = 7.6, Н-4 Ph); 7.98 (2Н, d, J = 7.8, Н-2,6 Ph); 11.42 (1Н, s,
NHСSNHCO); 11.62 (1Н, br. s, NHСО); 11.64 (1Н, s, 1-NH). C NMR spectrum, δ, ppm: 18.2 (4,6-СН3);
06.6 (C-5); 123.4 (C-4); 128.4 (C 2,6 Ph); 128.6 (C-3,5 Ph); 132.1 (C-1 Ph); 133.1 (C-4 Ph); 143.1 (C-3);
47.6 (C-6); 159.5 (C-2); 168.3 (COPh); 180.9 (C=S). Found, %: C 60.19; H 5.44; N 14.36. C H N O S.
Calculated, %: C 59.78; H 5.02; N 13.94.
1
3
1
1
1
5
15
3
2
N-[(6-Methyl-2-oxo-4-phenyl-1,2-dihydropyridin-3-yl)carbamothioyl]benzamide (2b) was obtained
similarly to compound 2a from KSCN (117 mg, 1.2 mmol), PhCOCl (0.14 ml, 1.2 mmol), and 3-amino-
6
-methyl-4-phenylpyridin-2(1H)-one (1b) (200 mg, 1.0 mmol). Yield 244 mg (67%), light-yellow, finely
-1
1
crystalline powder, mp 218-220C. IR spectrum, ν, cm : 3140 (NH), 1643 (С=O), 1533 (С=S). H NMR spectrum,
δ, ppm (J, Hz): 2.24 (3Н, s, 6-СН ); 6.05 (1Н, s, Н-5); 7.34-7.41 (3Н, m, Н-2,4,6 Ph); 7.47-7.51 (4Н, m, Н-3,5
3
Ph, H-3,5 COPh); 7.62 (1Н, t, J = 7.4, Н-4 COPh); 7.91 (2Н, d, J = 7.2, Н-2,6 COPh); 11.41 (1Н, s,
1
3
NHСSNHCO); 11.63 (1Н, br. s, NHСО); 11.92 (1Н, s, 1-NH). C NMR spectrum, δ, ppm: 18.9 (6-СН ); 106.0
3
(
C-5); 122.8 (C-1 Ph); 128.1 (C-2,6 Ph); 128.7 (С-3,5 Ph); 128.9 (C-4 Ph, C-2,6 COPh); 129.0 (С-3,5 COPh);
32.4 (С-1 COPh); 133.6 (C-4 COPh); 137.6 (С-4); 144.5 (C-3); 149.4 (C-6); 160.0 (C-2); 168.4 (COPh); 182.0
C=S). Found, %: C 66.47; H 5.03; N 11.89. C H N O S. Calculated, %: C 66.10; H 4.71; N 11.56.
1
(
20
17
3
2
4
-Bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)carbamothioyl]benzamide (3a) was
obtained similarly to compound 2a from KSCN (0.60 mg, 6.2 mmol), 4-bromobenzoyl chloride (1.36 g,
.2 mmol), and 3-amino-4,6-dimethylpyridin-2(1H)-one (1a) (0.80 g, 5.8 mmol). Yield 1.87 g (85%), white,
6
-
1
finely crystalline powder, mp 225-227C. IR spectrum, ν, cm : 3139, 2994, 2924 (NH), 1677, 1632 (С=O),
1
1
7
528 (С=S). H NMR spectrum, δ, ppm (J, Hz): 2.05 (3Н, s, 4-СН ); 2.15 (3Н, s, 6-СН ); 5.92 (1Н, s, Н-5);
3
3
.73 (2Н, d, J = 6.8, H-3,5 Ar); 7.91 (2Н, d, J = 6.8, H-2,6 Ar); 11.57 (1Н, s, NHСSNHCO); 11.63 (1Н, s,
1
3
NHCO); 11.67 (1Н, s, 1-NH). C NMR spectrum, δ, ppm: 18.2 (4,6-СН ); 106.6 (C-5); 123.4 (C-4); 127.1 (C-4
3
Ar); 130.8 (C-2,6 Ar); 131.4 (С-1 Ar); 131.5 (C-3,5 Ar); 143.1 (C-3); 147.6 (C-6); 159.4 (C-2); 167.4 (COAr);
180.8 (C=S). Found, %: C 47.75; H 4.14; N 11.37. C H BrN O S. Calculated, %: C 47.38; H 3.71; N 11.05.
15
14
3
2
4
-Bromo[N-[(6-methyl-2-oxo-4-phenyl-1,2-dihydropyridin-3-yl)carbamothioyl]benzamide
was prepared similarly to compound 2a from KSCN (107 mg, 1.1 mmol), 4-bromobenzoyl chloride (242 mg,
.1 mmol), and 3-amino-6-methyl-4-phenylpyridin-2(1H)-one (1b) (200 mg, 1.0 mmol). Yield 288 mg (65%),
(3b)
1
-1
white, finely crystalline powder, mp 214-215C. IR spectrum, ν, cm : 3213, 3010, 2927 (NH), 1651, 1632 (С=O),
1
1
540 (С=S). H NMR spectrum, δ, ppm (J, Hz): 2.23 (3Н, s, 6-СН ); 6.04 (1Н, s, Н-5); 7.34-740 (3Н, m, Н-3,4,5
3
Ph); 7.48 (2Н, d, J = 8.2, Н-2,6 Ph); 7.70 (2Н, d, J = 8.6, Н-3,5 Ar); 7.85 (2Н, d, J = 8.6, Н-2,6 Ar); 11.52 (1Н, s,
13
NHСSNHCO); 11.55 (1Н, s, NHСО); 11.92 (1Н, s, 1-NH). C NMR spectrum, δ, ppm: 18.9 (6-СН ); 106.0 (C-5);
3
1
22.8 (C-1 Ph); 127.6 (С-4 Ar); 128.1 (C-2,6 Ph); 128.7 (С-3,5 Ph); 128.9 (С-4 Ph); 131.1 (С-3,5 Ar); 131.6 (С-1
Ar); 131.9 (С-2,6 Ar); 137.6 (С-4); 144.7 (C-3); 149.4 (C-6); 160.0 (C-2); 167.5 (COAr); 181.8 (C=S). Found, %:
C 54.68; H 3.96; N 9.87. C H BrN O S. Calculated, %: C 54.31; H 3.65; N 9.50.
20
16
3
2
N-[(4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)carbamothioyl]methacrylamide (4a) was prepared
similarly to compound 2a from KSCN (505 mg, 5.2 mmol), methacrylic acid chloride (0.5 ml, 5.2 mmol), and
3
-amino-4,6-dimethylpyridin-2(1H)-one (1a) (690 mg, 5.0 mmol). Yield 968 mg (73%), white, finely
-
1
crystalline powder, mp 229-230C. IR spectrum, ν, cm : 3143, 2998 (NH), 1686, 1634 (С=O, С=С), 1526
1
(C=S). H NMR spectrum, δ, ppm (J, Hz): 1.94 (3Н, s, СОС(СН )=СН ); 2.02 (3Н, s, 4-СН ); 2.14 (3Н, s, 6-СН );
3
2
3
3
6
73

5
.69 (1Н, d, J = 1.4) and 5.99 (1Н, br. d, J = 0.6, =СН
2
); 5.91 (1Н, s, Н-5); 10.95 (1Н, s, NHСSNHCO); 11.49 (1Н,
13
s, NHСО); 11.62 (1Н, s, 1-NH). C NMR spectrum, δ, ppm: 18.5 (=C–CH ); 18.6 (4-CH ); 18.7 (6-CH ); 107.0
3
3
3
(
C-5); 123.8 (=CH ); 124.9 (С-4); 138.1 (C=CH ); 143.5 (C-3); 148.0 (C-6); 159.9 (C-2); 169.8 (CSNHCO); 181.2
2
2
(
C=S). Found, %: C 54.71; H 6.14; N 15.37. C H N O S. Calculated, %: C 54.32; H 5.70; N 15.84.
12
15
3
2
N-[(6-Methyl-2-oxo-4-phenyl-1,2-dihydropyridin-3-yl)carbamothioyl]methacrylamide (4b) was prepared
similarly to compound 2a (without additional refluxing of the obtained isothiocyanate with compound 1b) from
KSCN (107 mg, 1.1 mmol), methacrylic acid chloride (0.12 g, 1.1 mmol), and 3-amino-6-methyl-4-phenylpyridin-
2(1H)-one (1b) (200 mg, 1.0 mmol). Yield 154 mg (47%), white, fine crystalline powder, mp 175-177C.
-1
1
IR spectrum, ν, cm : 1640 (С=O, С=С), 1523 (C=S), 3134, 3020 (NH). H NMR spectrum, δ, ppm (J, Hz): 1.87 (3Н, s,
СОС(СН )=СН ); 2.22 (3Н, s, 6-СН ); 5.66 (1Н, d, J = 1.5) and 6.03 (1Н, d, J = 0.8, =СН ); 5.93 (1Н, s, Н-5);
3
2
3
2
13
7
.34-7.46 (5Н, m, H Ph); 10.96 (1Н, s, NHСSNHCO); 11.47 (1Н, s, NHСО); 11.95 (1Н, s, 1-NH). C NMR spectrum,
δ, ppm: 18.5 (=C–CH ); 18.9 (6-СН ); 106.0 (C-5); 122.7 (=CH ); 125.0 (С-1 Ph); 128.1 (C-2,6 Ph); 128.7 (C-3,5 Ph);
3
3
2
1
28.9 (С-4 Ph); 137.6 (C-4); 137.9 (C=CH ); 144.5 (C-3); 149.3 (C-6); 160.0 (C-2); 169.5 (CSNHCO); 181.9 (C=S).
2
Found, %: C 62.51; H 5.01; N 12.49. C H N O S. Calculated, %: C 62.37; H 5.23; N 12.83.
17
17
3
2
1
-Allyl-3-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)thiourea (5a). Allyl isothiocyanate (1.5 ml,
1
1
5 mmol) was added dropwise to a suspension of 3-amino-4,6-dimethylpyridin-2(1H)-one (1a) (1.50 g,
1 mmol) in acetone (30 ml). The reaction mixture was refluxed with stirring for 3 h. The precipitate formed
was cooled, filtered off, washed with cold acetone, and recrystallized from 2-PrOH. Yield 2.21 g (85%), white,
-
1
finely crystalline powder, mp 190-192C. IR spectrum, ν, cm : 3280, 3107 (NH), 1638 (С=O), 1537 (С=S).
1
H NMR spectrum, δ, ppm (J, Hz): 1.98 (3Н, s, 4-СН
3
); 2.12 (3Н, s, 6-СН
3
); 4.06 (2H, br. s, СН ); 5.03 (1Н, dd,
2
J = 10.3, J = 1.5) and 5.16 (1H, dd, J = 17.3, J = 1.7, =СН ); 5.82 (1H, ddt, J = 17.2, J = 10.4, J = 5.2,
2
–
1
1
СН=СН ); 5.89 (1Н, s, Н-5); 7.58 (1H, br. s, NHСН ); 8.45 (1H, br. s, NHСSNHCH ); 11.60 (1H, br. s,
2
2
2
1
3
-NH). C NMR spectrum, δ, ppm: 18.0 (4-CH ); 18.1 (6-СH ); 46.4 (NHСН ); 106.8 (C-5); 115.2 (=CH );
3
3
2
2
35.1 (CH СH=CH ); 142.3 (C-4); 148.2 (C-3); 148.4 (C-6); 160.4 (C-2); 181.9 (C=S). Found, %: C 55.98;
2
2
H 5.97; N 18.17. C H N OS. Calculated, %: C 55.67; H 6.37; N 17.71.
1
1
15
3
1
-Allyl-3-(6-methyl-2-oxo-4-phenyl-1,2-dihydropyridin-3-yl)thiourea (5b) was prepared similarly to
compound 5a from 3-amino-6-methyl-4-phenylpyridin-2(1H)-one (1b) (800 mg, 4.0 mmol) and allyl
isothiocyanate (0.4 ml, 4.2 mmol). Yield 849 mg (71%), white, finely crystalline powder, mp 185-186C.
1
H NMR spectrum, δ, ppm (J, Hz): 2.30 (3Н, s, 6-СН
3
); 4.13 (2H, br. s, СН ); 5.03 (1Н, d, J = 9.6) and 5.13 (1H, d,
2
J = 17.0, =СН ); 5.76 (1H, ddt, J = 11.1, J = 5.4, J = 5.1, –СН=СН ); 6.19 (1Н, s, Н-5); 7.38-7.44 (5Н, m, H Ph);
2
2
1
3
7
.45 (1H, br. s, NHСН ); 7.71 (1H, br. s, NHСSNHCH ); 13.09 (1H, br. s, 1-NH). C NMR spectrum, δ, ppm:
2
2
1
8.8 (6-СH ); 48.1 (NHСН ); 109.2 (C-5); 116.5 (=CH ); 122.7 (C-1 Ph); 128.4 (C-2,6 Ph); 128.9 (C-3,5 Ph);
3
2
2
1
29.4 (С-4 Ph); 133.7 (CH СH=CH ); 135.9 (C-4); 143.4 (C-3); 149.6 (C-6); 162.3 (C-2); 183.5 (C=S). Found,
2
2
%
: C 64.58; H 5.39; N 14.43. C H N OS. Calculated, %: C 64.19; H 5.72; N 14.03.
1
6
17
3
2
-[4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)amino]-5-methyl-5,6-dihydro-4H-1,3-thiazin-4-one
(
6a). A suspension of N-methacrylamide (4a) (260 mg, 1.0 mmol) was refluxed in 2-PrOH (20 ml) for 3 h in the
presence of morpholine (0.5 ml) until the starting material had dissolved completely. The precipitate formed on
cooling was filtered off, washed with cold 2-PrOH, and dried in air. Yield 179 mg (67%), light-yellow, finely
-
1
1
crystalline powder, mp 249-250C. IR spectrum, ν, cm : 1699, 1634 (С=O), 1604 (C=N). H NMR spectrum, δ,
ppm (J, Hz): 1.19 (3Н, d, J = 6.9, СHСН ); 1.87 (3Н, s, 4'-СН ); 2.09 (3Н, s, 6'-СН ); 2.69-2.82 (1Н, m,
3
3
3
СНMе); 2.89 (1Н, dd, J = 12.9, J = 9.8) and 3.03 (1Н, dd, J = 12.9, J = 3.7, SCН ); 5.81 (1Н, s, Н-5'); 11.08
2
1
3
(
(
2Н, br. s, 2NH). C NMR spectrum, δ, ppm: 15.4 (СHСН ); 17.5 (4'-СН ); 18.5 (6'-СН ); 29.4 (SCH ); 37.4
3
3
3
2
CHMе); 107.1 (C-5'); 132.9 (C-4'); 137.4 (С-3'); 138.8 (C-6'); 153.1 (C-2'); 157.7 (S–C=N); 173.4 (C-4).
Found, %: C 54.77; H 5.37; N 15.40. C H N O S. Calculated, %: C 54.32; H 5.70; N 15.84
1
2
15
3
2
5
-Methyl-2-[(6-methyl-2-oxo-4-phenyl-1,2-dihydropyridin-3-yl)amino]-5,6-dihydro-4H-1,3-thiazin-
4
4
-one (6b) was prepared similarly to compound 6a from compound 4b (or at the stage of preparing compound
b with refluxing in acetone). Yield 60%, light-yellow, finely crystalline powder, mp 255-257C (2-PrOH).
-
1
1
IR spectrum, ν, cm : 2850 (NH), 1693, 1628 (С=O). H NMR spectrum, δ, ppm (J, Hz): 1.13 (3Н, d, J = 7.0,
6
74

СHСН
3
); 2.18 (3Н, s, 6'-СН
3
); 2.69 (1Н, br. s, СНMе); 2.89 (1Н, dd, J = 12.9, J = 9.6) and 3.05 (1Н, dd,
13
J = 12.9, J = 3.7, SCН ); 5.99 (1Н, s, Н-5'); 11.35 (2Н, br. s, 2NH). C NMR spectrum, δ, ppm: 15.3 (СHСН );
2
3
1
8.7 (6'-CH ); 29.6 (SCH ); 37.4 (CHMе); 105.9 (C-5'); 128.3 (C-4 Ph); 128.4 (C-3,5 Ph); 128.6 (C-2,6 Ph); 131.9
3
2
(
C-3'); 138.3 (C-1 Ph); 139.1 (C-4'); 139.3 (C-6'); 153.7 (C-2'); 158.0 (S–C=N); 173.2 (C-4). Found, %: C 62.70;
H 5.64; N 12.52. C H N O S. Calculated, %: C 62.37; H 5.23; N 12.83.
17
17
3
2
4
,6-Dimethyl-3-[(5-methyl-4,5-dihydro-1,3-thiazol-2-yl)amino]pyridin-2(1H)-one (7a). A solution
of compound 5a (640 mg, 3.0 mmol) in conc. HCl (10 ml) was heated in a sealed glass ampoule on a water bath
for 5 h. The ampoule was opened after cooling, and the reaction mixture was basified using 40% NaOH solution
to neutrality and extracted with ethyl acetate (3×30 ml). The organic extract was dried over Na SO , solvent was
2
4
distilled off, and the residue was triturated with hexane. Yield 396 mg (56%), light-yellow, finely crystalline
-
1
1
powder, mp 222-223C. IR spectrum, ν, cm : 3449, 3325 (NH), 1638 (С=O), 1597 (С=N). H NMR spectrum,
δ, ppm (J, Hz): 1.28 (3Н, d, J = 6.7, СHСН ); 1.89 (3Н, s, 4-СН ); 2.05 (3Н, s, 6-СН ); 3.18 (1Н, dd, J = 10.6,
3
3
3
J = 6.1) and 3.63 (1Н, dd, J = 10.6, J = 6.5, NСН ); 3.73-3.81 (1Н, m, СНMе); 5.76 (1Н, s, Н-5); 9.41 (1Н, br. s,
2
1
3
3
1
-NH)*. C NMR spectrum, δ, ppm: 17.3 (4-CH ); 17.7 (6-СH ); 20.3 (СHСН ); 42.4 (СНMe); 71.8 (=NCH );
3
3
3
2
06.6 (C-5); 133.8 (C-4); 137.5 (C-3); 138.6 (C-6); 158.9 (C-2); 160.7 (S–C=N). Found, %: C 56.13; H 6.02;
N 18.09. C H N OS. Calculated, %: C 55.67; H 6.37; N 17.71
1
1
15
3
6
-Methyl-3-[3-[(5-methyl-4,5-dihydro-1,3-thiazol-2-yl)amino]-4-phenylpyridin-2(1H)-one (7b) was
prepared similarly to the thiazoline 7a from the thiourea 5b (600 mg, 2.0 mol). After opening the ampoule and
basification of the hydrochloric acid solution, the precipitated white crystalline material was filtered off and
-
1
dried. Yield 533 mg (89%), light-yellow, finely crystalline powder, mp 251-253C. IR spectrum, ν, cm : 3143
1
(
(
NH), 1650, 1630 (С=O), 1603 (С=N). H NMR spectrum, δ, ppm (J, Hz): 1.23 (3Н, d, J = 6.7, СHСН ); 2.14
3
3Н, s, 6-СН ); 3.08 (1Н, dd, J = 10.3, J = 5.6) and 3.54 (1Н, dd, J = 10.3, J = 6.4, =NСН ); 3.71 (1Н, td, J = 12.7,
3
2
13
J = 6.7, CНMе); 5.90 (1Н, s, H-5); 7.25-7.41 (5Н, m, H Ph); 7.95 (1Н, br. s, 3-NH)*. C NMR spectrum, δ, ppm:
1
(
7.9 (6-CH ); 20.1 (СHСН ); 41.8 (СНMe); 71.7 (=NCH ); 105.3 (C-5); 127.0 (С-4 Ph); 127.4 (C-3,5 Ph); 128.2
3
3
2
C-2,6 Ph); 137.2 (C-3); 138.6 (C-4, C-1 Ph); 138.7 (C-6); 159.1 (C-2); 161.7 (S–C=N). Found, %: C 64.57;
H 5.38; N 14.36. C H N OS. Calculated, %: C 64.19; H 5.72; N 14.03.
1
6
17
3
Biological Study. The antiradical activity of compound 1a, 3a, 4a, and 6a samples was studied towards
+
the 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid cation radical (ABTS ) using a Sigma Antioxidant
Assay Kit as shown in the product instructions. The principle of the method includes the formation of a
ferrylmyoglobin radical from methmyoglobin and hydrogen peroxide, which oxidizes the ABTS to the
+
corresponding cation radical ABTS . Introduction into the solution of various antiradical agents leads to their
+
+
interaction with the ABTS and a rapid consumption ("quenching") of the latter. The consumption of the ABTS
is accompanied by characteristic spectroscopic changes which allow the reaction rate to be recorded [20].
This work was carried out with the financial support of the Russian Foundation for Basic Research
project 11-03-00338a).
(
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