New approach to the synthesis of substituted 5-arylcarbamoyl-3-cyano-6- methylpyridine-2(1H)-thiones. Molecular and crystal structure of 2-allylthio-3-cyano-5-(2-methoxyphenylcarbamoyl)-6-methyl-4-(5-methyl-2-furyl) -1,4-dihydropyridine

Article abstract of DOI:10.1007/s10593-006-0045-y

Morpholinium 5-arylcarbamoyl-3-cyano-6-methyl-4-(5-methyl-2-furyl)-1,4- dihydropyridine-2-thiolates have been obtained by the interaction of enamines of acetoacetanilides with 5-methyl-2-furfurylidenecyanothioacetamide. Alkylation of the salts gives thioe

Full text of DOI:10.1007/s10593-006-0045-y

Chemistry of Heterocyclic Compounds, Vol. 42, No. 1, 2006
NEW APPROACH TO THE SYNTHESIS OF SUBSTITUTED
5-ARYLCARBAMOYL-3-CYANO-6-METHYLPYRIDINE-
2(1H)-THIONES. MOLECULAR AND CRYSTAL STRUCTURE
OF 2-ALLYLTHIO-3-CYANO-5-(2-METHOXYPHENYLCARBAMOYL)-
6-METHYL-4-(5-METHYL-2-FURYL)-1,4-DIHYDROPYRIDINE
V. D. Dyachenko1 and A. N. Chernega2
Morpholinium 5-arylcarbamoyl-3-cyano-6-methyl-4-(5-methyl-2-furyl)-1,4-dihydropyridine-2-thiolates
have been obtained by the interaction of enamines of acetoacetanilides with 5-methyl-2-
furfurylidenecyanothioacetamide. Alkylation of the salts gives thioethers and oxidation gives the
corresponding substituted pyridine-2(1H)-thiones. The structure of 2-allylthio-3-cyano-5-(2-
methoxyphenylcarbamoyl)-6-methyl-4-(5-methyl-2-furyl)-1,4-dihydropyridine was studied by X-ray
crystallographic analysis.
Keywords:
morpholinium
5-arylcarbamoyl-3-cyano-6-methyl-4-(5-methyl-2-furyl)-1,4-dihydro-
pyridine-2-thiolates, enamines of acetoacetanilides, (5-methyl-2-furfurylidene)cyanothioacetamide,
pyridine-2(1H)-thiones, thioethers, alkylation, X-ray structural analysis.
Previously we developed methods of synthesizing 4-aryl(heteryl)-substituted 5-arylcarbamoyl-3-cyano-
6-methylpyridine-2(1H)-thiones by the interaction of aryl(heteryl)methylenecyanothioacetamides with acetocetic
acid anilides [1, 2] or by a three-component condensation of aromatic aldehydes, cyanothioacetamide, and
acetoacetanilides [3].
In the present investigation we have found a new approach to functionally substituted 2-mercapto-1,4-
dihydropyridines, which are potential antiradical [4], cardiovascular [5], and hepatoprotective [6] agents. It
comprises a regioselective reaction of enamines of acetoacetanilides 1 with 5-methyl-2-furfurylidenecyano-
thioacetamide 2, leading to the corresponding Michael adduct 3. The latter is heterocyclized in situ by a type of
intramolecular transamination [7] with the formation of morpholinium 5-arylcarbamoyl-3-cyano-6-methyl-4-(5-
methyl-2-furyl)-1,4-dihydropyridine-2-thiolates 4, brief boiling of which in glacial acetic acid in the air leads to
protonation and dehydration to the corresponding substituted pyridine-2(1H)-thiones 5.
The structures of compounds 4 and 5 were confirmed by data of physicochemical and spectral
investigations (Tables 1, 2, Experimental), and also by alkylation of them with alkyl halides 6. The formation of
thioethers 7 and 8 in the course of this reaction is a reliable demonstration of the structure of salts 4 and thiones 5
[8].
__________________________________________________________________________________________
1
Lugansk T. Shevchenko State Pedagogical University, Lugansk 91011, Ukraine; e-mail:
dvd_lug@online.lg.ua. 2 Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 51-58, January, 2006. Original article
submitted July 15, 2003.
0009-3122/06/4201-0045©2006 Springer Science+Business Media, Inc.
45

Me
Me
R
O
R
O
O
O
N
CN
S
+
N
H
CN
S
H
..
H2N
Me
N
O
Me
N
H2N
1a–c
2
O
3
Me
Me
R
O
O
R
O
O
CN
∆, AcOH
CN
S
N
N
H
+
–2[H]
H
–
Me
N
H
S
H2N
O
Me
N
H
4a–c
5a–c
X
Hal
6f–l / KOH
6a–f
Me
Me
R
R
O
O
O
O
CN
S
CN
S
N
N
H
H
Me
N
H
X
Me
N
X
8a–g
7a–g
1a, 4a, 5a, 7e,f R = H; 1c, 4c, 5c, 7a-d, 8a,f R = OMe; 1b, 4b, 5b, 7g, 8g R = Me;
6a, 7a X = CH=CH2; 6b, 7b X = Et; 6c, 8a X = PhCO; 6d, 8c X = (CH2)3Br;
6e, 8d X = (CH2)2Br; 6f, 8e X= CH2Br; 6g, 8g X = 3-coumarinylcarbonyl; 6h, 7c,f X= H;
6i, 7d X = Me; 6j, 7e, 8f X= Ph; 6k, 7g X = CO2Et; 6l, 8b X = CO2Bn;
6 a-g Hal = Br; h,i Hal = I; j,l Hal = Cl
To establish unequivocally the regioselectivity of the reaction of acetoacetic acid enamines with
5-methyl-2-furfurylidenecyanothioacetamide and to clarify the direction of alkylation of its products, the
structure of compound 7a was investigated by X-ray crystallographic analysis. The general shape of the 7a
molecule is given in Fig. 1. The central six-membered ring N(1)C(1-5) is significantly nonplanar (the deviation of
atoms from the mean square plane reached 0.23 Å) and has a half-chair conformation (modified Cremer–Pople
parameters [9] S = 0.48, θ = 69.5°, Ψ = 1.5°). The N(1) and N(3) atoms have a plane-trigonal configuration of
bonds (the sum of the valence angles was 358.9 and 358.1°). The efficient conjugation between the unshared
electron pair of the N(1) atom and the π-systems of the C(1)=C(2) and C(4)=C(5) double bonds leads to a significant
shortening of the N(1)–C(1) and N(1)–C(5) bonds to 1.365(4) and 1.387(3) Å respectively (standard value for a pure
single N(sp2)–C(sp2) bond is 1.45 Å [10]. Similarly for n(N(3))–π(C(16)=O(2)) the interaction causes a shortening
of the N(3)–C(16) bond to 1.354(3) Å. The S(1)–C(1) bond length is 1.749(3) and S(1)–C(13) is 1.816(4) Å and the
C(1)S(1)C(13) bond angle is 104.4(1)°, practically coinciding with the corresponding values found in the Ph–S–Me
molecule (S–C(sp2) 1.749(4), S–C(sp3) 1.803(4) Å, CSC 105.6(7)°) [11]. In the crystal, the 7a molecules, due to
intermolecular hydrogen bonds N(1)–H(1)···O(2)) [N(1)–H(1) is 0.91(3), N(1)···O(2) 2.911(3), H(1)···O(2) 2.02(3) Å,
N(1)–H(1)···O(2) 2°] of moderate stability [12], are combined into endless spiral chains (Fig. 2).
46

TABLE 1. Characteristics of the Synthesized Compounds 4a-c, 5a-c, 7a-g,
and 8a-g
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
C
H
N
4a
4b
4c
5a
5b
5c
7a
7b
7c
7d
7e
7f
C23H26N4O3S
C24H28N4O3S
C24H28N4O4S
C19H15N3O2S
C20H17N3O2S
C20H17N3O3S
C23H23N3O3S
C23H25N3O3S
C21H21N3O3S
C22H23N3O3S
C26H23N3O2S
C20H19N3O2S
C24H25N3O4S
C28H23N3O4S
C29H25N3O5S
C24H24BrN3O3S
C23H22BrN3O3S
C22H20BrN3O3S
C27H23N3O3S
C31H23N3O5S
62.80
62.99
63.50
63.69
61.40
61.52
65.20
65.31
65.92
66.10
63.14
63.31
65.50
65.54
65.10
65.23
63.81
63.78
64.30
64.54
70.58
70.72
65.69
65.73
63.95
63.84
67.40
67.59
65.89
66.02
55.81
56.03
5.79
5.98
6.31
6.24
5.87
6.02
4.41
4.33
4.80
4.71
4.63
4.52
5.33
5.50
6.12
5.95
5.39
5.35
5.71
5.66
5.18
5.25
5.33
5.24
5.44
5.58
4.37
4.66
4.60
4.78
4.64
4.70
12.81
12.76
12.25
12.38
12.14
11.96
11.85
12.03
11.43
11.56
10.88
11.07
10.12
9.97
9.74
9.92
10.50
10.62
10.02
10.26
9.64
9.52
11.38
11.50
9.19
9.31
8.52
8.44
8.12
7.96
8.25
8.17
139-141
291-293
140-143
298-300*
288-290
262-264
118-120
136-138
142-143
147-148
164-166
156-158
161-163
160-161
116-117
222-224
206-208
273-275
174-175
247-248
83
88
72
70
65
68
85
72
67
79
78
80
71
85
67
79
62
64
75
72
7g
8a
8b
8c
8d
8e
8f
55.32
55.21
54.42
54.33
68.87
69.06
67.49
67.75
4.30
4.43
3.89
4.14
5.11
4.94
4.12
4.22
8.25
8.40
8.50
8.64
9.04
8.95
7.73
7.65
8g
_______
* Sublimation occurs at 200°C.
EXPERIMENTAL
The IR spectra of the synthesized compounds were recorded on a IKS 29 instrument in nujol. The
1H NMR spectra were recorded on Gemini 200 (200 MHz) (for compounds 7a-d, 8a-f), Bruker AC 200
(200 MHz) (for compounds 7f,g, 8g), and Bruker WP 100 SY (100 MHz) (for compounds 4a-c, 5a-c, 7e)
instruments in DMSO-d6, internal standard was Me4Si. The mass spectra were taken on a Kratos MS 890 (70 eV)
spectrophotometer. Melting points were determined on a Kofler block. A check on the progress of reactions and
the purity of the compounds obtained was effected by TLC (Silufol UV 254, acetone–hexane, 3:5, visualization
with iodine vapor).
47

48

49

Fig. 1. General shape of the 7a molecule. Main bond lengths (l, Å) and valence angles (ω, deg):
S(1)−C(1) 1.749(3), S(1)−C(13) 1.816(4), N(1)−C(1) 1.365(4), N(1)−C(5) 1.387(3), N(2)−C(7) 1.137(4),
N(3)−C(16) 1.354(3), N(3)−C(17) 1.411(4), C(1)−C(2) 1.347(4), C(2)−C(3) 1.520(3), C(3)−C(4) 1.525(3),
C(4)−C(5) 1.353(4), C(4)−C(16) 1.489(3); C(1)S(1)C(13) 104.4(1), C(1)N(1)C(5) 120.5(2), C(16)N(3)C(17) 126.3(3),
N(1)C(1)C(2) 120.0(2), C(1)C(2)C(3) 120.4(2), C(2)C(3)C(4) 107.26(19), C(3)C(4)C(5) 120.2(2), N(1)C(5)C(4) 119.5(2).
Fig. 2. Crystal packing of compound 7a (dotted lines indicate intermolecular hydrogen bonds). For simplicity the
C4H2O–CH3 substituent at the C(3) atom is not shown.
50

X-Ray Structural Investigation of a Monocrystal of Compound 7a of linear dimensions
0.37 × 0.43 × 0.47 mm was carried out at room temperature on an automatic Enraf-Nonius CAD-4 four-circle
diffractometer (MoKα radiation, ratio of scanning rates 2θ/ω = 1.2, θmax = 27°, segment of sphere 0 ≤ h ≤ 17, 0 ≤
k ≤ 10, -27 ≤ l ≤ 27. In all 5935 reflections were collected, of which 5322 were symmetrically independent (Rint =
0.012). The crystals of 7a were monoclinic, a = 13.535(4), b = 8.367(2), c = 21.847(8) Å; β = 99.08(2)°; V =
2443(1); M = 421.51; Z = 4; dcalc = 1.15 g/cm3; µ = 1.50 cm-1; F(000) = 888.62; space group P21/n. The structure
was solved by the direct method and refined by least squares in a full-matrix anisotropic approach using the
CRYSTALS [13] set of programs. In the refinement 2565 reflections with I > 4(I) (279 refined parameters,
number of reflections per parameter 9.2). All the hydrogen atoms (apart from the H atoms at C(14) and C(15)) were
made apparent from an electron density difference synthesis. The H(1) and H(3) atoms were refined isotropically,
the remaining hydrogen atoms were included in the refinement with fixed positions and thermal parameters. An
estimate of absorption in the crystal was carried out with the aid of the azimuthal scanning method [14]. The
Chebyshev weighting factor method [15] was used in the refinement with the three parameters: 2.21, 2.19, and
1.59. The final values of the divergence factors R = 0.069 and RW = 0.068, GOF = 1.125. The residual electron
density from the Fourier difference series was 1.15 and -0.36 e/Å3. The coordinates of the nonhydrogen atoms
may be obtained from the authors.
Morpholinium
thiolates 4a-c.
5-Arylcarbamoyl-3-cyano-6-methyl-4-(5-methyl-2-furyl)-1,4-dihydropyridine-2-
mixture of acetoacetanilide enamine (10 mmol) and (5-methyl-2-
A
1
furfurylidene)cyanothioacetamide 2 (1.92 g, 10 mmol) in ethanol (15 ml) was stirred for 20 min and left. After
1 day the solid which had formed was filtered off, washed with ethanol, and with hexane. Salts 4a-c were
obtained (Tables 1, 2).
5-Aroylcarbamoyl-3-cyano-6-methyl-4-(5-methyl-2-furyl)pyridine-2(1H)-thiones
5a-c
were
obtained on recrystallizing the appropriate salt 4a-c from glacial acetic acid (Tables 1, 2). Mass spectrum of
compound 5c, m/z (Irel, %): 379 (48) [M]+, 271 (10), 257 (100), 229 (11), 123 (44), 92 (10), 77 (9), 65 (11),
43 (14).
5-Arylcarbamoyl-3-cyano-6-methyl-4-(5-methyl-2-furyl)-2-X-methylthio-1,4-dihydropyridines 7a-g.
A mixture of the appropriate salt 4 (10 mmol) and alkyl halide 6 (10 mmol) in DMF (8 ml) was stirred for 4 h,
diluted with water (10 ml), and left for 1 day. The resulting solid was filtered off, washed with water, then with
ethanol and with hexane. Compounds 7a-g were obtained, which were recrystallized from ethanol (Tables 1, 2).
Mass spectra of compounds 7a-d, m/z (Irel, %). 7a: 421 (10) [M]+, 380 (42), 299 (38), 271 (35), 257
(100), 135 (14), 123 (58), 108 (19), 77 (13), 41 (27). 7b: 423 (22) [M]+, 380 (46), 338 (82), 299 (38), 273 (66),
259 (84), 123 (100), 108 (30), 77 (14), 65 (19), 43 (58). 7c: 395 (22) [M]+, 393 (13) [M-2]+, 380 (16), 338 (28),
273 (44), 271 (100), 245 (22), 123 (43), 77 (11), 65 (17). 7d: 409 (27) [M]+, 380 (35), 366 (20), 338 (65), 287
(39), 259 (100), 257 (48), 123 (86), 108 (24), 92 (21), 77 (12), 65 (18), 43 (17).
5-Arylcarbamoyl-3-cyano-6-methyl-4-(5-methyl-2-furyl)-2-Z-methylpyridines 8a-g. An aqueous
10% solution (5.6 ml, 10 mmol) of KOH and alkyl halide 6 (10 mmol) were added with stirring to a suspension
of the appropriate pyridinethione 5 (10 mmol) in DMF (8 ml), after which the mixture was stirred for 4 h. The
reaction mixture was then diluted with water (10 ml), and left for a day. The resulting solid was filtered off,
washed with water, with ethanol, and with hexane. Compound 8 was obtained and was recrystallized from
glacial acetic acid (Tables 1, 2).
Mass spectra of compounds 8a-f, m/z (Irel, %). 8a: 497 (9) [M]+, 392 (11), 376 (13), 375 (57), 105 (100),
77 (37). 8b: 527 (18) [M]+, 405 (88), 269 (13), 241 (14), 155 (12), 91 (100), 65 (12). 8c: [M]+ absent, 434 (100)
[M-Br]+, 348 (12), 311 (69), 284 (72), 257 (41), 225 (18), 123 (38), 108 (14), 87 (16), 55 (17), 43 (39). 8d: [M]+
absent, 420 (80) [M-Br]+, 297 (100), 277 (76), 257 (40), 241 (10), 127 (69), 108 (20), 92 (19), 77 (11), 43 (35).
8e: [M]+ absent, 406 (95) [M-Br]+, 313 (27), 283 (64), 257 (32), 123 (100), 77 (14), 40 (38). 8f: 469 (42) [M]+,
468 (27) [M-1]+, 347 (74), 91 (100), 65 (20).
51

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