Cycloacylation of 3-oxo-3-R1-N-R2-propanethioamides by 3-aryl-2-propenoyl chlorides

Article abstract of DOI:10.1007/s10593-006-0124-0

The products of cyclocondensation of 3-oxo-3-R¹-N-R ²-propanethioamides with 3-aryl-2-propenoyl chlorides in acetone in the presence of potassium carbonate are 5-acyl-1-aryl(alkyl)-4-aryl-6- thioxopiperidin-2-ones, 5-acyl-2-aryl-6-aryl(alkyl)amino-2,3-dihydro-4H- thiopyran-4-ones, and 2-acetonylidene-3,6-diaryl-5,6-dihydro-4H-1,3-thiazin-4- ones, the structure of which is proven by both spectral methods and chemical conversions. 2006 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-006-0124-0

Chemistry of Heterocyclic Compounds, Vol. 42, No. 4, 2006
CYCLOACYLATION OF 3-OXO-
3-R1-N-R2-PROPANETHIOAMIDES BY
3-ARYL-2-PROPENOYL CHLORIDES
V. N. Britsun, A. N. Borisevich, A. N. Esipenko, and M. O. Lozinskii
The products of cyclocondensation of 3-oxo-3-R1-N-R2-propanethioamides with 3-aryl-2-propenoyl
chlorides in acetone in the presence of potassium carbonate are 5-acyl-1-aryl(alkyl)-4-aryl-6-
thioxopiperidin-2-ones,
5-acyl-2-aryl-6-aryl(alkyl)amino-2,3-dihydro-4H-thiopyran-4-ones,
and
2-acetonylidene-3,6-diaryl-5,6-dihydro-4H-1,3-thiazin-4-ones, the structure of which is proven by both
spectral methods and chemical conversions.
Keywords: 3-aryl-2-propenoyl chlorides, aryl bromomethyl ketones, 5,6-dihydro-4H-1,3-thiazin-4-
ones, 2,3-dihydro-4H-thiopyran-4-ones, 3-oxopropanethioamides, cycloacylation.
Earlier we developed a general method for obtaining condensed heterocycles containing a 1,3-triazine
ring, based on the reaction of nitrogen-containing thiones with 3-aryl-2-propenoyl chlorides in pyridine [1-4]. In
this work, we have studied the reaction of 3-oxo-3-R1-N-R2-propanethioamides 1a-c with 3-aryl-2-propenoyl
chlorides 2a-c. Since 3-oxo-3-R1-N-R2-propanethioamides 1a-c have several reaction centers [5, 6], the products
of this reaction can be 3,4-dihydro-2H-pyran-2-ones, 4H-pyran-4-ones, 4H-1,3-thiazin-4-ones, 6H-1,3-thiazin-6-
ones, 4H-thiopyran-4-ones, 2H-thiopyran-2-ones, 4H-piperidin-4-ones, and 6-thioxopiperidin-2-ones, which
complicates isolation and identification of the compounds formed.
The optimal conditions for carrying out the reaction involve stirring a solution of 3-oxo-3-R1-N-R2-
propanethioamides 1a-c and 3-aryl-2-propenoyl chlorides 2a-c in acetone in the presence of K2CO3 at 20-50°C
1
for 2.5 h. The products of each reaction, according to TLC and H NMR spectroscopy, are a mixture of two
compounds which have the same elemental composition and were separated by treatment of the reaction mixture
1
13
with a 5% aqueous NaOH solution. Detailed analysis of the H NMR, C NMR, and IR spectra of the reaction
products, and also comparison of this information with the spectral data for 4H-thiopyran-4-ones and 4H-
piperidin-4-ones given in [7], showed that as a result of the reaction, 4-aryl-1-aryl(alkyl)-5-acyl-6-
thioxopiperidin-2-ones 3a-d, 2-aryl-6-aryl(alkyl)amino-5-acyl-2,3-dihydro-4H-thiopyran-4-ones 4a-d, and
2-acetonylidene-6-(4-nitrophenyl)-3-phenyl-5,6-dihydro-4H-1,3-thiazin-4-one (5) were formed.
The type of heterocycles, their ratio and yield depend on the nature of the substituents R1, R2, and Ar1 in
the starting 3-oxo-3-R1-N-R2-propanethioamides 1a-c and 3-aryl-2-propenoyl chlorides 2a-c. Acylation of
3-oxo-N-phenylbutanethioamide 1a by 3-phenyl-2-propenoyl chloride (2a) and 3-(4-chlorophenyl)-2-propenoyl
chloride (2b) leads to formation of 6-thioxopiperidin-2-ones 3a,b and 4H-thiopyran-4-ones 4a,b in 1:1 ratio, the
products of condensation of thioamide 1a with 3-(4-nitrophenyl)-2-propenoyl chloride 2c are 6-thioxopiperidin-
2-one 3c and 4H-1,3-thiazin-4-one 5, also in an equimolar ratio.
__________________________________________________________________________________________
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094; e-mail:
iochkiev@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 623-628, April,
2006. Original article submitted January 21, 2005.
546
0009-3122/06/4204-0546©2006 Springer Science+Business Media, Inc.

S
O
K2CO3 / Me2CO
R2
Ar1
R1
COCl
O
+
+
N
H
2a–c
1a–c
R2
O
H
R1
R2
N
S
O
N
S
R2
R1
R1
Ar1
N
S
O
+
O
Ar1
O
Ar1
5
Ar2COCH2Br
4a–d
3a–d
7a
1.
KOH
1. NaOH
HCl
R2
O
2. Ar2COCH2Br
2.
N
S
7a,b
R1
10
HBr
+
+
Ar2COCH2Br
Ar2
7a
S
O
O
Ar1
R2
O
1
R
S
11
N
H
R2
O
R1
H
R1
2
R
COOH
N
Ar1
N
6
Ar1
O
S
O
+
HBr
+
Ar2COMe
8a,b
10
Ar1
9
1a, 3а-c, 4a,b, 5, 8a,b, 9, 11 R1 = Me; 1b,c, 3d, 4c,d, 6 R1 = Ph; 1a,c, 3a-c, 4a,b,d, 5, 8a,b, 9-11 R2 = Ph;
1b, 3d, 4c, 6 R2 = Me; 2a, 3a,d, 4a,c,d, 6, 8a, 9 Ar1 = Ph; 2b – 4b Ar1 = p-ClC6H4; 2c, 3c, 5, 8b, 11 Ar1 = p-O2NC6H4;
7b, 8a Ar2 = p-FC6H4; 7a, 8b, 10 Ar2 = Ph
In reaction of compound 2a with 3-oxo-3-phenyl-N-methylpropanethioamide (1b), we obtain
6-thioxopiperidin-2-one 3d and 4H-thiopyran-4-one 4c in 1.8:1 ratio, and when 2a reacts with 3-oxo-3-N-
diphenylpropanethioamide (1c), only 4H-thiopyran-4-one 4d is formed. We should note that the amide bond of
6-thioxopiperidin-2-ones 3a-d (for the example of compound 3d) in an aqueous NaOH solution is readily
hydrolyzed at elevated temperature. In this case, the sodium salt of the corresponding carboxylic acid is formed,
from which by treatment with HCl we isolated 4-benzoyl-5-methylamino-5-thioxo-3-phenylpentanoic acid (6) in
pure form (Tables 1 and 2).
1
In the H NMR spectra, characteristic features are signals from protons of the OH(SH) groups of
6-thioxopiperidin-2-ones 3a-d (δ 15.79-16.14 ppm), the protons of the NH groups of 4H-thiopyran-4-ones 4a-d
(δ 12.1-14.26 ppm), the proton of the O=C–CH= group of 1,3-thiazin-4-one 5 (δ 5.38 ppm). Characteristic
features of the IR spectra are absorption bands for the carbonyl group O=C–N of 6-thioxopiperidin-2-ones 3a-d
(ν 1720 cm-1), bands for the O=C–C group of 4H-thiopyran-4-ones 4a-d (ν 1640-1650 cm-1), bands for the
O=C–CH= (ν 1600 cm-1) and O=C–N (ν 1730 cm-1) groups of 1,3-thiazin-4-one 5. The downfield shift of the
signals for the protons of the NH groups of 4H-thiopyran-4-ones 4a-d (δ 12.15-14.26 ppm) is explained by the
existence of an intramolecular hydrogen bond NH···O=C [7]. Since 6-thioxopiperidin-2-ones 3a-d are
β-thioxocarbonyl compounds, as we know [8] they can exist in ketone, enol, and enethiol forms, where the latter
two forms apparently are stabilized by an intramolecular hydrogen bond. In solution, there is probably a
dynamic equilibrium between these tautomeric forms, and the singlet signals far downfield (δ 15.79-16.14 ppm)
are averaged signals for the protons of the chelated OH groups of the enol forms and SH groups of the enethiol
forms of 3a-d.
547

TABLE 1. Characteristics of Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
H
N
3a
3b
3c
3d
4a
C19H17NO2S
70.35
70.56
63.52
63.77
61.73
61.95
70.70
70.56
5.28
5.30
4.27
4.51
4.49
4.38
5.09
5.30
4.49
4.33
4.20
3.91
7.39
7.60
4.49
4.33
153-154
158-160
182-184
147-149
44
39
43
50
40
C19H16ClNO2S
C19H16N2O4S
C19H17NO2S
C19H17NO2S
70.68
70.56
5.11
5.30
4.52
4.33
140-142
(145-146 [7])
4b
4c
4d
5
C19H16ClNO2S
C19H17NO2S
C24H19NO2S
C19H16N2O4S
C19H19NO3S
C27H20FNO2S
C27H20N2O4S
C19H15NO2S
C8H8O
63.59
63.77
70.74
70.56
75.03
74.78
62.13
61.95
66.99
66.84
73.62
73.45
68.93
69.22
70.82
71.01
4.30
4.51
5.42
5.30
4.98
4.97
4.62
4.38
5.70
5.61
4.61
4.57
4.21
4.30
4.58
4.70
4.09
3.91
4.46
4.33
3.74
3.63
7.84
7.60
4.35
4.10
3.03
3.17
6.13
5.98
4.21
4.36
157-159
136-138
180-183
185-187
240-243
229-231
237-239
225-227
41
28
72
46
72
80
76
51
42
6
8a
8b
9
10
80.24
79.97
6.93
6.71
__
15-17
(20-20.5 [11])
11
C19H14N2O4S
62.55
62.29
3.72
3.85
7.86
7.65
245-247
45
With the aim of confirming the structure of heterocycles 3a-d, 4a-d, and 5, we chemically studied their
reaction with aryl bromomethyl ketones. The products of reaction of 6-thioxopiperidin-2-ones 3a,c with aryl
bromomethyl ketones 7a,b are 2-aroyl-4,7-diaryl-3-methyl-4,5-dihydro-6H-thieno[2,3-b]pyridin-6-ones 8a,b,
where these compounds were obtained in preparative yields (76-80%). We also planned to carry out
recyclization of the thiopyran and thiazine ring to form a thiazole ring by treatment with bromomethyl phenyl
ketone, as we were able to do in [9]. However, we found that when 4H-thiopyran-4-one 4a and compound 5
were melted at 150°C with phenacyl bromide 7a, recyclization did not occur but rather we saw dehydrogenation
of compounds 4a and 5 with formation of more stable aromatic heterocycles: respectively 3-acetyl-6-phenyl-2-
phenylamino-4H-thiopyran-4-one (9) and 2-acetonylidene-6-(4-nitrophenyl)-3-phenyl-2H-1,3-thiazin-4-one
(11).
Since there are different substituents near the CH=(C-2) double bond of 1,3-thiazin-4-ones 5 and 11,
these compounds can exist in E- and Z-forms. Earlier we carried out an X-ray diffraction study of
2-acetonylidene-3,4-diphenyl-2,3-dihydrothiazole, which is similar in structure to compounds 5 and 11, and we
established that this compound is the Z-isomer due to steric conditions [10]. Therefore with high percentage
probability, we can say that 1,3-thiazin-4-ones 5 and 11 are also Z-isomers.
The results obtained for cycloacylation of 3-oxo-3-R1-N-R2-propanethioamides 1a-c are probably
explained by the fact that thioamides 1a-c in the presence of K2CO3 can be acylated by 3-aryl-2-propenoyl
chlorides 2a-c both at the NH group and at the site of highest nucleophilicity: the active methylene group. In the
first case, probably an intermediate amide is formed, which may be converted (depending on the nature of the
548

TABLE 2. IR and 1H NMR Spectra of Synthesized Compounds
Com-
pound
IR spectrum, ν, cm-1
1Н NMR spectrum, δ, ppm (J, Hz)
3a*
3400, 3000, 1720 (C=O),
1560, 1500, 1460, 1420,
1330
2.17 (3Н, s, СН3C=O); 2.96 (1Н, m, H-3);
3.34 (1Н, m, H-3); 4.42 (1Н, m, H-4); 6.83 (1Н, br. s, НAr);
7.15-7.41 (9Н, m, НAr); 16.09 (1Н, s, ОН)
3b
3c
3400, 3000, 1720 (C=O),
1600, 1570, 1500, 1420
2.16 (3Н, s, СН3C=O); 2.90 (1Н, m, H-3); 3.30 (1Н,
m, H-3); 4.43 (1Н, m, H-4); 6.86 (1Н, br. s, НAr);
7.15 (1Н, br. s, НAr); 7.30 (2Н, d, J = 9.0, НAr);
7.40-7.45 (5Н, m, НAr); 16.10 (1Н, s, ОН)
3400, 3000, 1720 (C=O),
1610, 1580, 1530, 1470,
1420
2.17 (3Н, s, СН3C=O); 3.00 (1Н, m, H-3); 3.45 (1Н, m,
H-3); 4.63 (1Н, m, H-4); 6.93 (1Н, br. s, НAr);
7.16 (1Н, br. s, НAr); 7.39 (3Н, m, НAr); 7.57 (2Н, d,
J = 7.3, НAr); 8.27 (2Н, d, J = 7.3, НAr); 16.14 (1Н, s, ОН)
3d
3400, 3000, 1720 (C=O),
1610, 1570, 1500, 1460
2.98 (2Н, m, H-3); 3.59 (3Н, s, СH3N); 4.07 (1Н, m, H-4);
7.05-7.57 (10Н, m, НAr); 15.79 (1Н, s, ОН)
4a*2
—
2.50 (3Н, s, СН3C=O); 2.86 (1Н, m, H-3); 3.27 (1Н, m,
H-3); 4.84 (1Н, m, H-2); 7.30-7.52 (10Н, m, НAr);
14.13 (1Н, s, NН)
4b
4c
3000, 1650, 1590, 1530,
1500, 1470, 1420, 1390
2.51 (3Н, s, СН3C=O); 2.82 (1Н, m, H-3); 3.21 (1Н, m,
H-3); 4.86 (1Н, m, H-2); 7.05-7.58 (9Н, m, НAr);
14.26 (1Н, s, NН)
3100, 1645, 1560, 1440,
1380
2.79 (1Н, m, H-3); 3.09 (3Н, d, J = 3.4, СН3NН);
3.25 (1Н, m, H-3); 4.48 (1Н, m, H-2);
7.25-7.61 (10Н, m, НAr); 13.90 (1Н, br. s, NН)
4d
5
3050, 1650, 1610, 1540,
1470
2.82 (1Н, m, Н-3); 3.04 (1Н, m, Н-3); 5.12 (1Н, m, Н-2);
7.03-7.60 (15Н, m, НAr); 12.15 (1Н, br. s, NH)
3100, 1730, 1660, 1610,
1530, 1470, 1360
1.94 (3Н, s, СН3С=О); 3.35 (1Н, m, Н-5);
3.58 (1Н, m, Н-5); 4.65 (1Н, m, Н-6); 5.38 (1Н, s, СН=);
7.43-7.62 (7Н, m, НAr); 8.20 (2Н, d, J = 8.4, НAr)
6
3000, 1720, 1680, 1610,
1560, 1470, 1430
3.03 (3Н, d, J = 4.0, СН3NН); 3.60 (2Н, m, Н-2);
4.01 (1Н, m, Н-3); 5.31 (1Н, d, J = 11.2, Н-4);
7.06-7.51 (8Н, m, НAr); 7.80 (2Н, m, НAr);
10.62 (1Н, q, J = 4.0, СН3NН); 12.01 (1Н, br. s, СООН)
8a
8b
3000, 1700, 1630, 1610,
1570, 1410
2.16 (3Н, s, 3-СН3); 2.84 (1Н, m, H-5); 3.49 (1Н, m, H-5);
4.47 (1Н, m, Н-4); 7.24-7.68 (14Н, m, НAr)
3000, 1710, 1630, 1610,
1540, 1500
2.15 (3Н, s, 3-СН3); 2.87 (1Н, m, H-5); 3.54 (1Н, m, H-5);
4.70 (1Н, m, Н-4); 7.31-7.63 (12Н, m, НAr);
8.24 (2Н, d, J = 8.6, НAr)
9
3100, 1680, 1630, 1580,
1430, 1200
2.52 (3Н, s, СН3С=О); 7.32-7.54 (10Н, m, НAr);
7.71 (1Н, s, Н-5); 12.56 (1Н, s, NH)
11
3000, 1720, 1670, 1600,
1550, 1500
2.10 (3Н, s, СН3С=О); 5.70 (1Н, s, СН=); 7.40 (2Н, m,
НAr); 7.61 (3Н, m, НAr); 7.81 (1Н, s, Н-5); 7.93 (2Н, d,
J = 8.4, НAr); 8.41 (2Н, d, J = 8.4, НAr)
_______
13C NMR spectrum of compound 3a (75 MHz, CDCl3), δ, ppm: 22.1
*
(CH3), 38.1 (C-4), 39.6 (C-3), 109.8 (C-6), 126.6, 127.7, 128.5, 128.8,
129.1, 129.8, 138.5, 139.8 (CAr), 167.8 (C-2), 180.5 (C-5), 194.3 (C=O).
1
*2 The H and 13C NMR spectra of compound 4a in CDCl3 and also the IR
spectrum match those described in [7].
substituent on the phenyl ring and the electron density on the C-3 atom of the 3-aryl-2-propenoyl substituent)
either to 6-thioxopiperidin-2-ones 3a-d or to 4H-1,3-thiazin-4-one 5. In the second case, probably the
C-acylation product is obtained, intramolecular cyclization of which leads to 4H-thiopyran-4-ones 4a-d.
549

EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian-300 (300 MHz) in DMSO-d6, internal standard TMS.
The IR spectra were taken on a UR-20 in KBr disks.
5-Acyl-4-aryl-1-aryl(alkyl)-6-thioxopiperidin-2-ones 3a-d, 5-Acyl-2-aryl-6-aryl(alkyl)amino-2,3-
dihydro-4H-thiopyran-4-ones 4a-d, and 2-Acetonylidene-6-(4-nitrophenyl)-3-phenyl-5,6-dihydro-4H-1,3-
thiazin-4-one (5). A solution of 3-aryl-2-propenoyl chloride 2a-c (10 mmol) in acetone (3 ml) was added with
vigorous stirring at 20°C to a solution of 3-oxo-3-R1-N-R2-propanethioamide 1a-c (10 mmol) in anhydrous
acetone (5 ml) containing suspended dry K2CO3 (15 mmol). The mixture was stirred for 2 h at 20°C and then for
0.5 h at 50°C, and then cooled down. The suspension of potassium hydrogen carbonate and potassium chloride
was filtered out from the reaction mixture. The filtrate was evaporated down and the crystalline residue was
ground with a 5% aqueous NaOH solution (10 ml) at 20°C. The 4H-thiopyran-4-one 4a-d (1,3-thiazin-4-one 5)
insoluble in alkaline solution was filtered out, dried in air, and recrystallized from ethanol. The alkaline filtrate,
containing the sodium salt of 6-thioxopiperidin-2-one, was acidified with a 20% aqueous HCl solution; the
precipitated reaction product 3a-d was filtered out, dried, and recrystallized from ethanol.
4-Benzoyl-5-methylamino-3-phenyl-5-thioxopentanoic Acid (6). A solution of 5-benzoyl-1-methyl-4-
phenyl-6-thioxopiperidin-2-one (3d) (5 mmol) and NaOH (15 mmol) in water (5 ml) was held for 10 min at
60°C, cooled down, and acidified with 10% aqueous HCl. The precipitated product 6 was filtered out, dried, and
recrystallized from acetic acid.
2-Aroyl-4,7-diaryl-3-methyl-4,5-dihydro-6H-thieno[2,3-b]pyridin-6-ones 8a,b. Aryl bromomethyl
ketone 7a,b (5 mmol) was added at 20°C to a solution of 5-acyl-1,4-diaryl-6-thioxopiperidin-2-one 3a,c
(5 mmol) and KOH (5 mmol) in ethanol (3 ml). The reaction mixture was diluted with cold water (10 ml), and
the precipitated reaction product 8a,b was filtered out, dried, and recrystallized from acetic acid.
3-Acetyl-6-phenyl-2-phenylamino-4H-thiopyran-4-one (9) and 2-acetonylidene-6-(4-nitrophenyl)-3-
phenyl-2H-1,3-thiazin-4-one (11). A mixture of 4H-thiopyran-4-one (4a) (5 mmol) (4H-1,3-thiazin-4-one 5)
and bromomethyl phenyl ketone (7a) (5 mmol) was held for 5 min at a temperature of 150°C, cooled down, and
ground with ethanol (3 ml), then boiled for 5 min, and cooled. Then 4H-thiopyran-4-one (9) (2H-1,3-thiazin-4-
one 11) was filtered out, dried, and recrystallized from acetic acid. The ethanol solution was evaporated down,
and the oil obtained was extracted with hot hexane (3 × 5 mL). The hexane was evaporated off and the
acetophenone 10 was distilled under a water-jet vacuum.
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550