Unusual reaction of 5-benzoyl-3-ethoxycarbonyl-6-methylthio-1-r-1,2- dihydropyridin-2-ones with nitrogen-containing 1,4-dinucleophiles

Article abstract of DOI:10.1007/s10593-008-0124-3

The reaction of 5-benzoyl-3-ethoxycarbonyl-6-methylthio-1-R-1,2- dihydropyridin-2-ones with the nitrogen-containing 1,4-dinucleophiles o-phenylenediamine, o-aminothiophenol, and ethylenediamine, proceeds as a recyclization, the products of which are derivatives of 5-(1H-benzimidazol-2-yl) -2H-2-pyranone, 5-(benzothiazol-2-yl)-2H-2-pyranone, and 5-(4,5-dihydro-1H- imidazol-2-yl)-2H-2-pyra-none respectively.

Full text of DOI:10.1007/s10593-008-0124-3

Chemistry of Heterocyclic Compounds, Vol. 44, No. 7, 2008
UNUSUAL REACTION OF 5-BENZOYL-
3-ETHOXYCARBONYL-6-METHYLTHIO-
1-R-1,2-DIHYDROPYRIDIN-2-ONES
WITH NITROGEN-CONTAINING
1,4-DINUCLEOPHILES
V. N. Britsun, A. N. Esipenko, and M. O. Lozinskii
The reaction of 5-benzoyl-3-ethoxycarbonyl-6-methylthio-1-R-1,2-dihydropyridin-2-ones with the
nitrogen-containing 1,4-dinucleophiles o-phenylenediamine, o-aminothiophenol, and ethylenediamine,
proceeds as a recyclization, the products of which are derivatives of 5-(1H-benzimidazol-2-yl)-2H-
2-pyranone, 5-(benzothiazol-2-yl)-2H-2-pyranone, and 5-(4,5-dihydro-1H-imidazol-2-yl)-2H-2-pyra-
none respectively.
Keywords: o-aminothiophenol, 5-(1H-benzimidazol-2-yl)-3-benzoyl-6-(R-amino)-2H-2-pyranones,
5-(benzothiazol-2-yl)-3-benzoyl-6-(R-amino)-2H-2-pyranones, 5-benzoyl-3-ethoxycarbonyl-6-methylthio-
1-R-1,2-dihydropyridin-2-ones, o-phenylenediamine, ethylenediamine, X-ray structural analysis,
recyclization.
Methods are given in [1-5] for the synthesis of 5-aroyl-6-methylthio-3-R-1,2-dihydropyridin-2-ones,
which are polyfunctional compounds and valuable substrates for transformation into condensed bi- or tricyclic
nitrogen-containing heterosystems. However further heterocyclizations of these reactants were not completely
studied, probably because of the absence of satisfactory methods of obtaining them.
Recently we developed a preparative method for the selective synthesis of 5-benzoyl-3-ethoxycarbonyl-
6-methylthio-1-R-1,2-dihydropyridin-2-ones 1a,b from accessible starting materials, and have shown that they
may be used as synthesis blocks for cyclocondensations with nitrogen-containing 1,2- and 1,3-dinucleophiles
[6].
The aim of the present work was the evaluation of the synthetic potential of 5-benzoyl-3-ethoxy-
carbonyl-6-methylthio-1-R-1,2-dihydropyridin-2-ones 1a,b in reactions with the nitrogen-containing 1,4-di-
nucleophiles o-phenylenediamine 2a, o-aminothiophenol 2b, and ethylenediamine 6. It was assumed that the
interaction of dihydropyridin-2-ones 1a,b with reactants 2a,b must occur at the methylthio and benzoyl groups
of substrates 1a,b with the formation of 3-ethoxycarbonyl-5-phenyl-1-R-2,6-dihydro-1H-benzo[b]pyrido[2,3-e]-
[1,4]diazepin-2-ones 3a,b and 3-ethoxycarbonyl-5-phenyl-1-R-1,2-dihydrobenzo[b]pyrido[2,3-e][1,4]thiazepin-
2-ones 3c,d.
__________________________________________________________________________________________
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02660; e-mail:
bvn1967@rambler.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1089-1095, July,
2008. Original article submitted January 8, 2008.
876
0009-3122/08/4407-0876©2008 Springer Science+Business Media, Inc.

However it was established that the reaction of 1,2-dihydropyridin-2-ones 1a,b with reactants 2a,b was
accomplished by a different scheme. The products of this condensation proved to be not the expected diazepines
(or thiazepines) 3a-d, but 5-(1H-benzimidazol-2-yl)-3-benzoyl-6-(R-amino)-2H-2-pyranones 4a,b and 5-
(benzothiazol-2-yl)-3-benzoyl-2-yl)-6-(R-amino)-2H-2-pyranones 4c,d, which are the result of a recyclization
process.
O
Ph
H2N
HX
X
EtO
N
O
N
2a,b
R
3a–d
O
O
Ph
Ph
O
O
EtO
N
2a,b
O
X
N
R
SMe
RNH
O
1a,b
4a–d
NH2
Py
(MeCO)2O
H2N
6
Ph
O
N
X
Ph
N
O
O
N
H
R
N
O
O
O
RNH
O
Me
7a,b
5
1a, 3a,c, 4а,с, 5, 7а R = Me; 1b, 3b,d, 4b,d, 7b R = Et;
2a, 3a,b, 4a,b, 5 X = NH; 2b, 3c,d, 4c,d X = S
Dihydropyridin-2-ones 1a,b also react with 1,2-ethylenediamine 6 in a similar way. 3-Benzoyl-5-(4,5-
dihydro-1H-imidazol-2-yl)-(6-R-amino)-2H-2-pyranones 7a,b were isolated from the reaction mixture (Table 1).
1
The structure of 2H-2-pyranones 4a-d, 7a,b was demonstrated with the aid of H and 13C NMR
spectroscopy and IR spectroscopy (Table 2), and also by conversion of compound 4a into 6-(N-acetyl-
N-methylamino)-5-(1H-benzimidazol-2-yl)-3-benzoyl-2H-2-pyranone (5) by the action of acetic anhydride in
pyridine.
Ph
Ph
Ph
O
O
O
O
O
O
EtO
2a
OEt
2a
Et3N / H2O
EtOH
EtO
4a
1a
O
N
N
O
N
NHPh
O
O
Me
8a
Me
Me
9
We carried out two model reactions to clarify the mechanism of formation of 2H-2-pyranone derivatives
4a-d and 7a,b. It was established that elimination of the methylthio group of 1,2-dihydropyrin-2-one 1a was
also effected by the action of aqueous alcoholic triethylamine solution, when the hydrolysis product was 1,2-di-
hydropyridine 8a. The latter reacts readily with o-phenylenediamine 2a with the formation of 2H-2-pyranone 4a
877

TABLE 1. Characteristics of the Synthesized Compounds
Found, %
Calculated, %
H
——————
Com-
pound
Empirical
formula
mp, °С*
Yield, %
С
N
S
4a
4b
4с
4d
5
C20H15N3O3
C21H17N3O3
C20H14N2O3S
C21H16N2O3S
C22H17N3O4
C16H15N3O3
C17H17N3O3
C32H28N2O9
69.74
69.56
69.89
70.18
66.02
66.29
66.73
67.01
68.06
68.21
64.37
64.64
65.60
65.58
65.94
65.75
4.31
4.38
4.56
4.77
4.15
3.89
4.42
4.28
4.33
4.42
4.98
5.09
5.58
5.50
4.66
4.83
12.13
12.17
11.85
11.69
7.48
7.73
7.29
7.44
11.09
10.85
14.30
14.13
13.61
13.50
4.64
4.79
283-285
272-275
250-252
241-243
245-247
335-337
300-303
100-101
70
63
61
57
75
69
63
52
8.64
8.85
8.40
8.25
7a
7b
8a
_______
* Compounds 4a-d, 5, 7a,b were recrystallized from DMSO, compound 8a
from 2-propanol.
(72% yield). 2H-2-Pyranone 4a was also synthesized by the reaction of 5-benzoyl-3-ethoxycarbonyl-1-methyl-
6-phenylamino-1,2-dihydropyridin-2-one 9 with o-phenylenediamine 2a, but in this way the yield of the desired
product did not exceed 39%.
1
The characteristic signals in the H NMR spectra, confirming the formation of products 4a-d, 5, and
7a,b, are doublets for the CH3NH group (compounds 4a,c, 7a, δ 2.75-2.87 ppm, J = 2.7-4.2 Hz) and singlets for
the (benz)imidazole NH groups (compounds 4a,b, 5, and 7a,b at 13.71-13.78 and 9.37-9.39 ppm respectively).
In the IR spectra of all the 2H-2-pyranones 4a-d, 5, and 7a,b absorption bands were observed for the stretching
vibrations of the NH group (3250-3400 cm-1). The presence of a carbonyl group of the aroyl fragment in
compounds 4a-d, 5, 7a,b, and 8a was identified with the aid of 13C NMR spectroscopy, since in the spectra of
the initial compounds 1a,b [6] and products 4a, 7b, and 8a the signals of the Ph-C=O carbon atom are extremely
characteristic (191.0-192.6 ppm).
On the basis of the experimental data obtained the following scheme may be suggested for the
mechanism of recyclization of dihydropyridin-2-ones 1a,b into 2H-2-pyranones 4a-d, 7a,b. Probably the first
stages of the reaction are hydrolysis and amination of dihydropyridin-2-ones 1a,b into the intermediates 8a,b
and 12a,b respectively.
To all appearances, attack of the 1,4-nucleophile is then effected at the ester group of 1,2-dihydro-
pyridin-2-ones 8a,b and 12a,b, as a result of which 3-heteryl-1,2-dihydropyridin-2-ones 10a,b and 13a,b are
formed. The intermediate 13a,b may be converted into the intermediate product 14a,b on attack by hydroxyl
ion. The pyridine ring of the intermediate 10a,b is opened under the action of nucleophile (intermediate product
11a,b), then intramolecular nucleophilic attack occurs, as a result of which 2H-2-pyranones 4a-d, 7a,b are
obtained. The reason for the recyclization in fact is the presence of two withdrawing substituents (benzoyl and
heteryl [7]) in the pyridine ring of the intermediate compounds 10a,b, which facilitates the ANRORC process
beginning with attack of the nucleophile at position 6 of the pyridine ring. Probably a definite contribution to the
ease of carrying out the reaction is also introduced by the high thermodynamic stability of the resulting 2H-2-
pyranones 4a-d, 7a,b.
The 2H-2-pyranone derivatives 4a-d, 5, and 7a,b are high melting substances of a yellow color, poorly
soluble in polar organic solvents. It should be mentioned that 2H-2-pyranones containing a 1H-benzimidazole
878

879

1
TABLE 2. Data of IR and H NMR Spectroscopy of the Synthesized
Compounds
Com-
pound
IR spectrum,
1Н NMR spectrum, δ, ppm ( J, Hz)
ν, cm-1
4a
3330, 3000, 1675,
1620, 1600, 1560,
1540, 1470, 1450,
1390, 1370
2.85 (3Н, d, J = 3.6, NНCH3); 7.48 (1Н, m, НAr);
7.63-7.69 (6Н, m, НAr); 7.84 (1Н, m, НAr); 8.68 (1Н, s, Н-4);
8.70 (1Н, m, НAr); 9.00 (1Н, br. s, NНCH3); 13.71 (1Н, s, NHHet
)
4b
3330, 3000, 1685,
1610, 1560, 1470,
1440, 1390, 1370,
1340, 1320, 1260,
1230
1.16 (3Н, t, J = 6.3, NНCH2CH3); 3.36 (2Н, m, NНCH2CH3);
7.49 (1Н, m, НAr); 7.62-7.76 (6Н, m, НAr);
7.88 (1Н, m, НAr); 8.69 (1Н, s, Н-4); 8.71 (1Н, m, НAr);
9.11 (1Н, br. s, NНEt); 13.73 (1Н, s, NHHet
)
4c
4d
5
3350, 3000, 1670,
1615, 1560, 1490,
1460, 1420, 1380,
1330
2.87 (3Н, d, J = 2.7, NНCH3); 7.66 (7Н, m, НAr);
8.23 (1Н, m, НHet-7); 8.74 (1Н, s, Н-4); 9.02 (1Н, br. s, NНCH3);
9.20 (1Н, m, HHet-4)
3300, 3000, 1690,
1620, 1570, 1500,
1470, 1385, 1310,
1250
1.18 (3Н, t, J = 6.6, NНCH2CH3); 3.34 (2Н, m, NНCH2CH3);
7.68-7.83 (7Н, m, НAr); 8.26 (1Н, m, НHet-7); 8.78 (1Н, s, Н-4);
9.15 (1Н, br. s, NНEt); 9.24 (1Н, m, HHet-4)
3250, 3000, 2950,
1690, 1670, 1620,
1560, 1540, 1490,
1460, 1390
2.28 (3Н, s, CH3CO); 3.16 (3Н, c, NCH3); 7.51 (1H, m, НAr);
7.55-7.72 (6Н, m, НAr); 7.87 (1Н, m, НAr); 8.18 (1Н, s, Н-4);
8.70 (1Н, m, НHet-4); 13.78 (1Н, s, NHHet
)
7a
7b
8a
3380, 3300, 3050,
2970, 1680, 1640,
1600, 1580, 1500
2.75 (3Н, d, J = 4.2, NНCH3); 3.91 (2H, m, 5'-СН2);
4.14 (2H, t, J = 9.3, 4'-СН2); 7.52 (5Н, m, C6H5);
8.31 (1Н, s, Н-4); 8.90 (1Н, br. s, NНCH3);
9.39 (1Н, br. s, NHHet
)
3400, 3300, 3100,
3000, 1680, 1640,
1610, 1580, 1500,
1450, 1380, 1330
1.08 (3Н, t, J = 7.2, NНCH2CH3); 3.21 (2Н, m, NНCH2CH3);
3.92 (2H, m, 5'-СН2); 4.13 (2H, t, J = 9.0, 4'-СН2);
7.52 (5Н, m, C6H5); 8.32 (1Н, s, Н-4); 9.02 (1Н, br. s, NНEt);
9.37 (1Н, br. s, NHHet
)
3100, 3000, 1730,
1680, 1600, 1530,
1460, 1400, 1380,
1310
1.24 (3Н, t, J = 6.9, ОСН2СН3); 3.29 (3Н, s, NCH3);
4.19 (2Н, q, J = 6.9, ОСН2СН3); 7.56-7.67 (5Н, m, C6H5);
8.18 (1Н, s, Н-4)
(or benzothiazole, 4,5-dihydro-1H-imidazole) substituent in position 5 of the heterocyclic ring have not been
described up to now, which enables us to designate the recyclization investigated by us as new, and as a method
of preparative value for the synthesis of previously unknown compounds. In fact the given reaction is a
retrorecyclization involving conversion of 2H-2-pyranone into 2-oxo-1,2-dihydropyridines occurring under the
action of ammonia and methylamine, respectively, into the methyl ester of coumalic acid [8] and 3,4,6-
triphenyl-2H-2-pyranone [9].
EXPERIMENTAL
The 1H and 13C NMR spectra were recorded on a Varian-300 instrument (300 and 75 MHz respectively)
in DMSO-d6, internal standard was TMS. The IR spectra were recorded on a UR 20 instrument in KBr disks.
5-Benzoyl-3-ethoxycarbonyl-1-methyl-6-phenylamino-1,2-dihydropyridin-2-one 10 was synthesized by the
procedure of [6].
5-(1H-Benzimidazol-2-yl)-3-benzoyl-6-(R-amino)-2H-2-pyranones 4a,b and 5-(Benzothiazol-2-yl)-
3-benzoyl-6-(R-amino)-2H-2-pyranones 4c,d. A solution of 5-benzoyl-3-ethoxycarbonyl-6-methylthio-1-R-
880

1,2-dihydropyridin-2-one 1a,b (1 mmol) and o-phenylenediamine 2a (or o-aminothiophenol 2b) (1 mmol) in
2-propanol (5 ml) was boiled under reflux for 8 h, cooled, and the solid 4a-d filtered off.
Compound 4a. 13C NMR spectrum, δ, ppm: 25.7 (NCH3); 99.4, 105.6, 113.0, 116.4, 123.5, 126.8, 126.9,
128.4, 128.5, 131.2, 131.5, 138.5 (CAr); 144.1 (C-3); 144.9 (C-6); 159.4 (C-2'); 163.8 (C-2); 191.2 (C6H5–C=O).
6-(N-Acetyl-N-methylamino)-5-(1H-benzimidazol-2-yl)-3-benzoyl-2H-2-pyranone (5). A solution of
2H-2-pyranone 4a (0.345 g, 1 mmol) and pyridine (0.158 g, 2 mmol) in acetic anhydride (1.02 g, 10 mmol) was
boiled under reflux for 8 h, cooled, and solid 5 filtered off.
3-Benzoyl-5-(4,5-dihydro-1H-imidazol-2-yl)-6-(R-amino)-2H-2-pyranones 7a,b. A solution of
1,2-dihydropyridin-2-one 1a,b (1 mmol) and ethylenediamine 6 (0.180 g, 3 mmol) in 2-propanol (5 ml) was
boiled under reflux for 2 h, cooled, and solid 7a,b filtered off.
Compound 7b. 13C NMR spectrum, δ, ppm: 14.8 (NCH2CH3); 33.2 (C-5'); 43.1 (NCH2CH3); 43.4
(C-4'); 97.7 (C-4); 106.5 (C-5); 127.8, 128.3, 130.7, 138.8 (CAr); 146.4 (C-3); 156.3 (C-3′); 160.3 (C-6); 162.8
(C-2); 191.3 (C6H5–C=O).
5-Benzoyl-6-(5-benzoyl-3-ethoxycarbonyl-1-methyl-2-oxo-1,2-dihydropyrid-6-yl)oxy-3-ethoxycarbo-
nyl-1-methyl-2-oxo-1,2-dihydropyridine (8a). A solution of 1,2-dihydropyridin-2-one 1a (0.331 g, 1 mmol)
and triethylamine (0.303 g, 3 mmol) in 75% ethanol (3 ml) was boiled under reflux for 10 h. The solvent was
then evaporated, and the oily residue dissolved in water (3 ml). Acetic acid (several drops) was added, the
o
mixture cooled to 5 C, and the solid 8a was filtered off. 13C NMR spectrum, δ, ppm: 14.0 (OCH2CH3); 26.6
(NCH3); 60.3 (OCH2CH3); 104.4 (C-4); 105.5 (C-3); 128.5, 128.8, 132.3, 135.2 (CPh); 144.1 (C-5); 160.3 (C-6);
164.8 (C-2); 166.5 (CO2Et); 191.0 (C6H5–C=O).
Recyclization of 5-Benzoyl-6-(5-benzoyl-3-ethoxycarbonyl-1-methyl-2-oxo-1,2-dihydropyridin-6-yl)-
oxy-3-ethoxycarbonyl-1-methyl-2-oxo-1,2-dihydropyridine (8a) and 5-Benzoyl-3-ethoxycarbonyl-1-methyl-
6-phenylamino-1,2-dihydropyridin-2-one (9) into 3-Benzoyl-5-(1H-benzimidazol-2-yl)-6-(methyl-amino)-
2H-2-pyranone (4a). A solution of 1,2-dihydropyridine 8a (or 9) (1 mmol) and o-phenylenediamine 2a (0.216
g or 0.108 g) in 2-propanol (5 ml) was boiled under reflux for 8 h, cooled, and solid compound 4a filtered off.
1
Yields were 0.497 g (72%) and 0.135 g (39%) respectively. The mp and H NMR spectra of compound 4a
obtained by the reaction of pyridin-2-ones 1a, 8a, and 9 with o-phenylenediamine were identical.
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