Synthesis and properties of 7-acetyl-8-aryl-9-cyano-3-hydroxy-6-methyl-3,4- dihydro-2H,8H-pyrido[2,1-6][1,3]thiazines

Article abstract of DOI:10.1007/s10593-005-0302-5

7-Acetyl-8-aryl-2-(1-chloro-2-hydroxy-3-propyl)thio-9-cyano-6-methyl-1, 4-dihydropyndines were obtained by treatment of 1,4-dihydropyridine-2(3H)- thiones with epichlorohydrin in the presence of sodium bicarbonate. When treated with NaOMe, these compounds are readily intramolecularly alkylated with formation of 7-acetyl-8-aryl-3-hydroxy-9-cyano-6-methyl-3,4-dihydro-2H,8H- pyrido[2,1-b]-[1,3]thiazines. We have studied amination of 2-(1-chloro-2- hydroxy-3-propyl)thio-1,4-dihydropyridines and acylation of 3-hydroxy-3,4- dihydro-2H,8H-pyrido[2,1-b][1,3]thiazines. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-005-0302-5

Chemistry of Heterocyclic Compounds, Vol. 41, No. 9, 2005
SYNTHESIS AND PROPERTIES OF 7-ACETYL-
8-ARYL-9-CYANO-3-HYDROXY-6-METHYL-
3,4-DIHYDRO-2H,8H-PYRIDO[2,1-b][1,3]THIAZINES
A. Krauze, L. Sile, R. Danne, and G. Duburs
7-Acetyl-8-aryl-2-(1-chloro-2-hydroxy-3-propyl)thio-9-cyano-6-methyl-1,4-dihydropyridines
were
obtained by treatment of 1,4-dihydropyridine-2(3H)-thiones with epichlorohydrin in the presence of
sodium bicarbonate. When treated with NaOMe, these compounds are readily intramolecularly
alkylated with formation of 7-acetyl-8-aryl-3-hydroxy-9-cyano-6-methyl-3,4-dihydro-2H,8H-pyrido[2,1-
b]-[1,3]thiazines. We have studied amination of 2-(1-chloro-2-hydroxy-3-propyl)thio-1,4-
dihydropyridines and acylation of 3-hydroxy-3,4-dihydro-2H,8H-pyrido[2,1-b][1,3]thiazines.
Keywords: 2-alkylthio-1,4-dihydropyridines, 1,4-dihydropyridine-2(3H)-thiones, 3,4-dihydro-2H,8H-
pyrido[2,1-b][1,3]thiazines, epichlorohydrin, amination, acylation.
Based on our early studies of the reaction of 1,4-dihydropyridine-2(3H)-thiolates with electrophilic
reagents [1-3], we used the reactions of 5-acetyl-4-aryl-3-cyano-6-methyl-1,4-dihydropyridine-2(3H)-thiones
with electrophilic epichlorohydrin for synthesis of 2-(1,2-dihydroxy-3-propyl)thio-1,4-dihydropyridines,
mimetics of glyceride derivatives of 1,4-dihydropyridines, and their cyclic analogs: acylated and hydrogenated
pyrido[2,1-b][1,3]thiazines.
Although 3,4-dihydro-2H,8H-pyrido[2,1-b][1,3]thiazines have been poorly studied, their synthesis is of
interest since the combination in one molecule of a 1,4-dihydropyridine ring (calcium antagonists, antioxidants,
hepatoprotectors) and a 1,3-thiazine ring (antibiotics of the cephalosporin group) can lead to potential
biologically active compounds. Antihypertensive and anti-inflammatory activities have been found in the
corresponding hydrogenated pyrido[2,1-b][1,3]oxazines [4].
1,4-Dihydropiperidine-2(3H)-thiones 1 were obtained by two routes: thione 1a [5] and thione 1b by
condensation of acetylacetone, an aromatic aldehyde, and 2-cyanothioacetamide; and thione 1c [6] by reaction of
2-(3-nitrophenyl)methyleneacetylacetone with 2-cyanothioacetamide in the presence of an equimolar amount of
piperidine followed by acidification.
5-Acetyl-4-aryl-2-(1-chloro-2-hydroxy-3-propyl)thio-3-cyano-6-methyl-1,4-dihydropyridines
2
were
obtained in moderate yields by treatment of compound 1 with epichlorohydrin in the presence of sodium
bicarbonate. When using stronger bases (KOH or NaOMe) instead of sodium bicarbonate, the 7-acetyl-8-aryl-9-
cyano-3-hydroxy-6-methyl-3,4-dihydro-2H,8H-pyrido[2,1-b][1,3]thiazines 3 crystallize out from a complex
reaction medium in 50%-59% yields. Compounds 3 were also obtained in 62-69% yields by intramolecular
alkylation of compounds 2 by treatment with NaOMe at room temperature.
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: krauze@osi.lv; gduburs@osi.lv.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1394-1399, September, 2005. Original
article submitted May 10, 2004.
0009-3122/05/4109-1189©2005 Springer Science+Business Media, Inc.
1189

O
Ar
O
Ar
CN
S
CN
S
Me
Me
O
NaHCO 3
+
Cl
Me
N
H
Me
N
H
Cl
OH
1a–c
2a–c
NaOMe
(KOH)
KOH
O
Ar
O
Ar
CN
S
CN
Me
Me
ClCOMe
Me
N
Me
N
S
OH
3a–c
OCOMe
4a–c
1-4 a Ar = Ph, b Ar = 2-ClC6 H4 , c Ar = 3-O2NC6 H4
We should note that intermolecular alkylation of 2-alkylthio-1,4-dihydropyridines at the N-1 atom
occurs with significantly greater difficulty, often with transformation of the functional groups and oxidation of
the ring.
Cl
O
O
Cl
N
CN
.
HCl
H
Me
CN
Me
Me
N
S
N
H
S
Me
N
Cl
OH
H
5
OH
2b
When 2-(1-chloro-2-hydroxy-3-propyl)thio-1,4-dihydropyridine 2b is treated with excess piperidine, we
see formation of 2-(2-hydroxy-1-piperidyl-3-propyl)thio-1,4-dihydropyridine 5. We should note that the
presence of a 2-[1-(4-arylpiperazyl)-2-hydroxy-3-propyl]oxy group in the molecule is favorable for the
formation of α1-adrenoreceptor ligands [7, 8]. Antihypertensive properties are often exhibited by
α1-adrenoreceptor blockers. Thus combining in a single molecule 1,4-dihydropyridine groups (calcium
antagonists with antihypertensive properties) [9, 10]) with potential α1-adrenoreceptor ligands may lead to new
biologically active compounds.
Upon acetylation of 3-hydroxy-3,4-dihydro-2H,8H-pyrido[2,1-b][1,3]thiazines 3, we obtain 3-acetoxy-
3,4-dihydro-2H,8H-pyrido[2,1-b][1,3]thiazines 4.
The most characteristic features of the IR spectra for compounds 1-5 are absorption bands for stretching
vibrations of the cyano group, which in the case of compounds 2-5 are observed at 2188-2204 cm-1 and in the
case of thione 1b, at 2258 cm-1. The frequencies νC=O in the case of compounds 1, 2, and 5 decrease due to
β-aminovinylcarbonyl conjugation. For compounds with a free amino group (compounds 3 and 4), the νC=O take
on values (1664-1682 cm-1) typical of an acetyl group bonded to an sp2-hybridized carbon.
1190

1
In the H NMR spectra, the most characteristic features are signals from H-4 (compounds 2 and 5) and
H-8 protons (compounds 3, 4) at 4.66-5.38 ppm, confirming the hydrogenated structure. In the 1H NMR spectra
of thione 1b, we observe cis and trans isomerism [11]. Compound 1b is insoluble in CDCl3, while in DMSO-d6
we can determine only the trans isomer (δ 4.37 ppm and 4.81 ppm, J = 3.4 Hz). The signals from the cis isomer
are strongly broadened. This means that in the case of this isomer, we observe a thione–enthiol tautomeric
equilibrium [12, 13].
EXPERIMENTAL
The IR spectra of the starting compounds were recorded on a Perkin-Elmer 580B spectrometer in nujol.
The H NMR spectra were recorded on a WH 90/DC spectrometer (90 MHz), internal standard HMDS
1
(δ 0.05 ppm). The course of the reaction and the purity of the compounds were monitored using TLC on Silufol
UV-254 plates, eluent 5:5:1 dichloromethane–hexane–ethanol. The compounds were recrystallized from ethanol.
The characteristics and 1H NMR and IR spectral data for the synthesized compounds are shown in Tables 1 and
2.
5-Acetyl-4-(2-chlorophenyl)-3-cyano-6-methyl-1,4-dihydropyridine-2(3H)-thione (1b). A mixture of
2-chlorobenzaldehyde (2.80 g, 20 mmol), acetylacetone (2.00 g, 20 mmol) in ethanol (20 ml) and piperidine (0.5
ml, 5 mmol) was stirred for 5 min at room temperature. Then 2-cyanothioacetamide (2.00 g, 20 mmol) and
piperidine (2.5 ml, 25 mmol) were added and the reaction mixture was stirred for 30 min at room temperature.
Then an alcoholic solution of HCl (3 mol/l) (12 ml) was added gradually dropwise and after 20 min, the
precipitate was filtered out and washed with ethanol (10 ml) (cooled down to 0°C) and water (10 ml). We
obtained 4.36 g (72%) of the yellow compound 1b; mp 159-161°C.
TABLE 1. Characteristics of Synthesized Compounds 1-5
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
Yield, %
(method)
mp, °С
C
H
N
S
1b
C15H13Сl N2OS
59.15
59.11
4.28
4.30
9.20
9.19
10.50
10.52
159-161
72
2а
2b
2c
3a
C18H19Сl N2O2S
C18H18Cl2N2O2S
C18H18СlN3O4S
C18H18N2O2S
59.87
59.58
54.09
54.41
53.09
53.01
65.95
66.23
5.42
5.28
4.48
4.57
4.39
4.45
5.52
5.56
7.68
7.72
6.97
7.05
10.16
10.30
8.41
8.58
9.07
8.84
8.05
8.07
7.86
7.59
9.70
9.82
202-203
137-139
139-141
245-247
68
59
45
60 (A),
50 (B),
69 (C)
3b
3c
4a
4b
4c
5
C18H17ClN2O2S
C18H17N3O4S
59.70
59.91
57.94
58.21
64.90
65.20
59.62
59.62
57.75
58.10
57.20
57.26
4.65
4.75
4.48
4.61
5.48
5.47
4.51
4.75
4.39
4.63
6.00
6.06
7.73
7.76
11.23
11.31
7.58
7.60
6.73
6.95
10.00
10.16
8.55
8.71
8.90
8.89
8.61
8.63
8.83
8.70
7.90
7.96
7.71
7.76
6.53
6.53
226-228
195-197
182-184
176-178
199-201
115-117
82 (A)
62 (C)
64
C20H20N2O3S
C20H19ClN2O3S
C20H19N3O5S
82
78
C23H28СlN3O2S·HCl
71
1191

TABLE 2. Spectral Characteristics of Compounds 1-5
Com-
pound
IR spectrum, ν, cm-1
1Н NMR spectrum, δ, ppm (J, Hz )*
1b
1640, 1655 (C=O); cis-isomer: 2.06 (2.1H, s, COCH3); 2.37 (2.1H, s, 6-CH3);
2258 (C≡N); 3250
(NH)
4.90-5.10 (0.7Н, m, Н-3 and Н-4); 7.0-7.7 (2.8Н, m, C6H4);
12.12 (0.7H, br. s, NH) trans-isomer: 2.14 (0.9Н, s, СОCH3);
2.45 (0.9Н, s, 6-CH3); 4.37 and 4.81 (0.3Н, d and d, J = 3.4,
Н-3 and Н-4); 7.0-7.7 (1.2Н, m, C6H4); 12.40 (0.3H, s, NH)
2a
2b
2c
1654 (C=O); 2194
2.06 (3H, s, COCH3); 2.33 (3H, s, 6-CH3); 3.06-3.17 (2Н, m,
(C≡N); 3128, 3240, SCH2); 3.54-3.70 (2Н, m, CH2Cl); 3.70-3.88 (1H, m, СН-ОН);
3274 sh. (NH, ОН) 4.66 (1Н, s, H-4); 6.00 (1Н, br. s, ОH); 7.1-7.4 (5Н, m, C6H5);
9.52 (1Н, s, NH)
1655 (C=O); 2196
2.04 (3H, s, COCH3); 2.34 (3H, s, 6-CH3); 2.88-3.20 (2Н, m,
(C≡N); 3130, 3215, SCH2); 3.50-3.66 (2Н, m, CH2Cl); 3.88-4.27 (2H, m, СН-ОН);
3490 (NH, ОН)
5.28 (1Н, s, H-4); 7.10-7.50 (4Н, m, C6H4);
8.68 and 8.74 (1Н, s and s, NH)
1617, 1628 sh.
(C=O); 2202
2.16 (3H, s, COCH3); 2.40 (3H, s, 6-CH3); 3.04-3.24 (2Н, m,
SCH2); 3.50-3.70 (2Н, m, CH2Cl); 4.10-4.37 (2H, m, СН-ОН );
(C≡N); 3152, 3252 4.82 (1Н, s, H-4); 7.40-8.20 (4Н, m, C6H4);
(NH, ОН)
8.82 and 8.93 (1Н, s and s, NH)
3a
3b
3c
4a
1682 (C=O); 2204
(C≡N); 3412 (NH,
ОН)
1.90 (3H, s, COCH3); 2.36 (3H, s, 6-CH3); 3.37-3.57 (4Н, m
and m, SCH2 and CH2N); 3.56-3.78 (1H, m, СН-ОН );
4.80 (1Н, s, H-8); 5.32 (1Н, m, ОH); 7.15-7.40 (5Н, m, C6H5)
1670 (C=O); 2200
1.90 (3H, s, COCH3); 2.34 (3H, s, 6-CH3); 3.36-3.62 (4Н, m
(C≡N); 3418 (ОН) and m, SCH2 and CH2N); 3.56-3.82 (1H, m, СН-ОН);
5.27 (1Н, s, H-8); 5.32 (1Н, m, ОH); 7.20-7.55 (4Н, m, C6H4)
1672 (C=O); 2195
(C≡N); 3444,
3544 (ОН)
2.01 (3H, s, COCH3); 2.42 (3H, s, 6-CH3); 3.36-3.66 (4Н, m
and m, SCH2 and CH2N); 4.60-4.88 (1H, m, СН-ОН );
5.08 (1Н, s, H-8); 5.37 (1Н, m, ОH); 7.80-8.20 (4Н, m, C6H4)
1665, 1736 (C=O); 1.92 (3H, s, 7-COCH3); 2.10 (3H, s, OCOCH3);
2198 (C≡N) 2.40 (3H, s, 6-CH3); 3.09-3.53 (2Н, m, SCH2); 3.96-4.42 (2H, m,
CH2N); 4.52-4.82 (1H, m, H-3); 4.68 (1Н, s, H-8);
7.10-7.40 (5Н, m, C6H5)
4b
4c
5
1664, 1736 (C=O); 1.94 (3H, s, 7-COCH3); 2.10 (3H, s, OCOCH3);
2194 (C≡N) 2.38 (3H, s, 6-CH3); 3.08-3.56 (2Н, m, SCH2); 3.97-4.46 (2H, m,
CH2N); 4.54-4.83 (1H, m, H-3); 5.38 (1Н, s, H-8);
7.10-7.50 (4Н, m, C6H4)
1677, 1746 (C=O); 1.98 (3H, s, 7-COCH3); 2.12 (3H, s, OCOCH3);
2188 (C≡N)
2.44 (3H, s, 6-CH3); 3.15-3.59 (2Н, m, SCH2);
3.97-4.43 (2H, m, CH2N); 4.52-4.82 (1H,
m, H-3); 4.85 (1Н, s, H-8); 7.40-8.20 (4Н, m, C6H4)
1665 (C=O);
1.35-1.75 [6H, s, (CH2)3]; 2.02 (3H, s, CO CH3CH3);
2200 (C≡N); 3120, 2.25-2.45 [4H, m, +N(CH2)2]; 2.36 (3H, s, 6-CH3);
3496 (NH, OH)
2.50-2.67 (2H, m, CH2N); 2.70-2.92 (2Н, m, SCH2);
3.70-4.10 (2H, m, CН-ОН);
5.28 (1Н, s, H-4); 7.4-7.5 (4Н, m, C6H4); 9.30 (1H, s, NH)
_______
1
* The H NMR spectra for compounds 2a-c, 4b,c, and 5 were taken in
CDCl3; the rest were taken in DMSO-d6.
5-Acetyl-2-(1-chloro-2-hydroxy-3-propyl)-3-cyano-6-methyl-4-phenyl-1,4-dihydropyridine (2a). A
mixture of 1,4-dihydropyridine-2(3H)-thione 1a (0.54 g, 2 mmol) [4], sodium bicarbonate (0.19 g, 2.2 mmol),
and epichlorohydrin (0.20 ml, 2.4 mmol) in ethanol (10 ml) was stirred for 24 h at room temperature. The
sodium bicarbonate was filtered out, the filtrate was concentrated down and treated with petroleum ether. The
precipitate was filtered out and washed with ethanol (cooled down to 0°C) (2 ml) and water (10 ml). We
obtained 0.49 g (68%) of the colorless compound 2a with mp 202-203°C.
Compounds 2b and 2c (light yellow) were obtained similarly from thiones 1b and 1c in 59 and 45%
yields.
1192

7-Acetyl-9-cyano-3-hydroxy-6-methyl-8-phenyl-3,4-dihydro-2H,8H-pyrido[2,1-b][1,3]thiazine (3a).
A. A mixture of compound 1a (0.54 g, 2 mmol), a sodium methoxide solution (1 mol/l) (2 ml), and
epichlorohydrin (0.20 ml, 2.4 mmol) in methanol (10 ml) was stirred for 3 h at room temperature. The precipitate
was filtered out and washed with ethanol (5 ml) and water (10 ml). The filtrate was concentrated down and an
additional amount of precipitate was filtered out, which was also washed with ethanol and water. We obtained
0.39 g (60%) of the yellow compound 3a; mp 245-247°C.
Compound 3b (light yellow) was obtained similarly from thione 1b in 82% yield.
B. A mixture of compound 1a (0.54 g, 2 mmol), a potassium hydroxide solution (2 mol/l) in water
(1 ml), and epichlorohydrin (0.20 ml, 2.4 mmol) in ethanol (4 ml) was stirred for 6 h at room temperature. The
precipitate was filtered out and washed with 5 ml ethanol and water (10 ml). We obtained 0.33 g (50%) of the
yellow compound 3a; mp 245-247°C.
C. A mixture of compound 2a (0.72 g, 2 mmol) and a sodium methoxide solution (1 mol/l) (2 ml) in
methanol (10 ml) was stirred for 3 h at room temperature. The precipitate was filtered out and washed with
ethanol (5 ml) and water (10 ml). We obtained 0.45 g (69%) of the yellow compound 3a; mp 245-247°C.
Compound 3c (yellow) was obtained similarly from 1,4-dihydropyridine 2c in 62% yield.
3-Acetoxy-7-acetyl-9-cyano-6-methyl-8-phenyl-2H,8H-pyrido[2,1-b][1,3]thiazine (4a). A mixture of
compound 3a (0.65 g, 2 mmol), acetyl chloride (5 ml), and potassium hydroxide (0.12 g, 2 mmol) was boiled for
3 h in a water bath. The potassium chloride was filtered out; the filtrate was concentrated down and treated with
ethanol. The product was filtered out and washed with ethanol (5 ml) and water (10 ml). We obtained 0.51 g
(69%) of the colorless compound 4a; mp 182-184°C.
Compounds 4b,c (yellow) were obtained similarly in 82 and 78% yields.
5-Acetyl-3-cyano-2-(2-hydroxy-1-piperidyl-3-propyl)-6-methyl-4-phenyl-1,4-dihydropyridine
hydrochloride (5). A mixture of 2-(2-hydroxy-1-chloro-3-propyl)thio-1,4-dihydropyridine (2b) (0.20 g,
0.5 mmol) and piperidine (0.2 ml, 2 mmol) in ethanol (3 ml) was boiled for 15 min in a water bath and stirred for
24 h at room temperature. The precipitate was filtered out and washed with ethanol (2 ml) and water (5 ml). We
obtained 0.17 g (71%) of the yellow compound 5; mp 115-117°C.
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1193