Synthesis and alkylation of piperidinium 4,5-trans-3-cyano-6-hydroxy-4-(2-iodophenyl)-6-methyl-5-(2-methyl phenyl)-carbamoyl-1,4,5,6-tetrahydropyridine-2-thiolate. Molecular and crystal structure of 3-(2-iodophenyl)-2-(4-phenyl-2-thiazolyl)acrylonitrile

Article abstract of DOI:10.1023/A:1012499424379

The reaction of o-iodobenzaldehyde, cyanothioacetamide, and N-acetoacetyl-o-toluidine in the presence of piperidine gave piperidinium 4,5-trans-3-cyano-6-hydroxy-4-(2-iodophenyl) -6-methyl-5-(2-methylphenyl)carbamoyl-1,4,5,6 -tetrahydropyridine-2-thiolate used in the synthesis of substituted 4,5-trans-2-alkylthiotetrahydropyridines and 2-(2-(2-thiazolyl)acrylonitriles. The structure of 3-(2- iodophenyl)-2-(4-phenyl-2-thiazolyl)acrylonitrile was studied using X-ray diffraction structural analysis.

Full text of DOI:10.1023/A:1012499424379

Chemistry of Heterocyclic Compounds, Vol. 37, No. 7, 2001
SYNTHESIS AND ALKYLATION OF
trans
PIPERIDINIUM 4,5-
-3-CYANO-6-HYDROXY-
4-(2-IODOPHENYL)-6-METHYL-5-(2-METHYLPHENYL)-
CARBAMOYL-1,4,5,6-TETRAHYDROPYRIDINE-2-THIOLATE.
MOLECULAR AND CRYSTAL STRUCTURE OF
3-(2-IODOPHENYL)-2-(4-PHENYL-
2-THIAZOLYL)ACRYLONITRILE
S. G. Krivokolysko1, V. D. Dyachenko1, V. N. Nesterov2, and V. P. Litvinov3
The reaction of o-iodobenzaldehyde, cyanothioacetamide, and N-acetoacetyl-o-toluidine in the presence
of piperidine gave piperidinium 4,5-trans-3-cyano-6-hydroxy-4-(2-iodophenyl)-6-methyl-5-(2-
methylphenyl)carbamoyl-1,4,5,6-tetrahydropyridine-2-thiolate used in the synthesis of substituted 4,5-
trans-2-alkylthiotetrahydropyridines and 2-(2-thiazolyl)acrylonitriles. The structure of 3-(2-
iodophenyl)-2-(4-phenyl-2-thiazolyl)acrylonitrile was studied using X-ray diffraction structural
analysis.
Keywords: N-acetoacetyl-o-toluidine, o-iodobenzaldehyde, 3-(2-iodophenyl)-2-(4-phenyl-2-thiazolyl)-
acylonitrile, cyanothioacetamide, condensation, X-ray diffraction structural analysis.
Substituted sulfur-containing tetrahydropyridines have not been extensively studied [1]. In light of the
biological activity of these heterocycles [2], there is interest in developing convenient stereoselective methods
for their preparation.
We are the first to report the preparation of substituted piperidinium tetrahydropyridine-2-thiolate (4) by
the reaction of o-iodobenzaldehyde (1), cyanothioacetamide (2), and N-acetoacetyl-o-toluidine (3) in the
presence of piperidine. Thiolate 4 is stable in the crystalline state but, in contrast to its thienyl analog [3], it
readily converts to dehydration product 5 upon dissolution, which makes analysis of the structure of this salt by
1H NMR spectroscopy impossible. The steric selectivity of this synthetic method may be evaluated relative to
derivative 6 obtained by the reaction of thiolate 4 with halides 7 in ethanol.
1
The H NMR spectra of 6 show signals for all the indicated substituents and NH group (see
Experimental). The signals for 4-H and 5-H appear as doublets at 4.50-4.56 and 2.84-2.90 ppm, respectively
with 3J = 11.8-12.3 Hz. According to the Karplus–Conroy equation [4], at the above 3J values the C(4)H–C(5)H
ϕ
torsion angle is 160-165°, indicating trans-equatorial arrangement of the Ar and ArNHCO groups. The OH
group presumably occupies an axial position, which was noted for isostructural analogs of 4 and 6 [5].
__________________________________________________________________________________________
1
Taras Shevchenko Lugansk State Pedagogical University, 348011 Lugansk, Ukraine.
2 A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 117813 Moscow,
3
Russia. N. D. Zelinsky Institute of Organic Chemistry, 117913 Moscow, Russia. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 7, pp. 929-934, July, 2001. Original article submitted May 18, 1999.
0009-3122/01/3707-0855$25.00©2001 Plenum Publishing Corporation
855

COMe
H
N
CN
H
N
+
+
O
I
S
NH2
CHO
1
Me
2
3
Me
Me
O
DMSO
H2
O
I
I
N
C
N
C
CN
CN
H
H
HO
H2
N
_
_
+
N
H
S
+
N
S
N
Me
Me
H
5
4
Me
O
I
N
C
HalCH2X
7a,b
CN
H
HO
N
SCH2X
Me
6a,b
H
6, 7 a Hal = I, X = H; b Hal = Cl, X = 4-BrC6H4NHCO
The alkylation of salt 4 by bromides 8 in ethanol at 20°C leads to recyclization of the tetrahydropyridine
ring and, through intermediates 9 and 10, to thiazoles 11, which were also obtained independently from 12 and 8
in DMF according to a reported procedure [6]:
BrCH2COAr (8a–d)
EtOH
4
Me
Me
O
O
I
I
N
C
N
C
CN
CN
H
H
HO
Me
HO
Me
N
N
H
S
S
HO
O
Ar
Ar
S
9
10
3
I
I
8a–d,
DMF
NH2
NC
NC
S
N
11a–d
12
Ar
8, 11 a Ar = Ph, b Ar = 4-BuC6H4, c Ar = 4-BrC6H4, d Ar = 4-MeC6H4
856

Fig. 1. General view of 11a molecule.
TABLE 1. Bond Lengths (d) in 11a
Bond
I(18)–C(17)
d, Å
Bond
d, Å
2.096(5)
1.701(5)
1.729(4)
1.289(6)
1.378(5)
1.137(6)
1.479(6)
1.365(7)
1.463(6)
1.388(6)
1.398(7)
1.385(8)
C(8)–C(9)
1.382(8)
1.356(9)
1.392(8)
1.342(6)
1.440(6)
1.459(6)
1.389(7)
1.393(7)
1.392(8)
1.368(11)
1.367(11)
1.386(8)
S(1)–C(5)
S(1)–C(2)
N(3)–C(2)
N(3)–C(4)
N(14)–C(13)
C(2)–C(12)
C(4)–C(5)
C(4)–C(6)
C(6)–C(11)
C(6)–C(7)
C(7)–C(8)
C(9)–C(10)
C(10)–C(11)
C(12)–C(15)
C(12)–C(13)
C(15)–C(16)
C(16)–C(17)
C(16)–C(22)
C(17)–C(19)
C(19)–C(20)
C(20)–C(21)
C(21)–C(22)
An X-ray diffraction structural analysis of 11a was carried out to elucidate the direction of the
recyclization and establish the structure of its products unequivocally. Product 11a is the E-isomer relative to
the C(12)=C(15) bond. A general view of the this molecule is shown in Fig. 1 and the bond lengths and angles are
given in Table 1.
The substituted thiazole ring in 11a is rigorously planar and the deviation of individual atoms is only
±0.002 Å. The dihedral angle between the heterocyclic and phenyl (C(6)···C(11)) substituents is 163°, which
indicates slight twisting about the C(4)–C(6) bond. The C(2)–C(12)=C(15)–C(16) fragment with mean deviation of the
atoms from the mean plane equal to ±0.014 Å lies in the plane of the heterocycle (the corresponding dihedral
angle is only 2.5°), while the o-iodophenyl substituent is twisted relative to this chain by 155.5°. The slight
distortion in molecular planarity probably should be attributed to intramolecular nonbonding contacts:
S(1)···H(15), 2.74(5) Å; C(13)···C(22), 3.045(8) Å; C(13)···H(22), 2,47(5) Å, I(18)···H(15), 2.81(5) Å (the corresponding
sums of the van der Waals radii are 2.91, 3.54, 2.87, and 3.13 Å respectively [7]).
857

TABLE 2. Bond Angles (ω) in
9a
Angle
ω, deg
Angle
ω, deg
С(5)–S(1)–C(2)
С(2)–N(3)–C(4)
N(3)–C(2)–C(12)
N(3)–C(2)–S(1)
C(12)–C(2)–S(1)
C(5)–C(4)–N(3)
C(5)–C(4)–C(6)
N(3)–C(4)–C(6)
C(4)–C(5)–S(1)
C(11)–C(6)–C(7)
C(11)–C(6)–C(4)
C(7)–C(6)–C(4)
C(8)–C(7)–C(6)
C(9)–C(8)–C(7)
C(10)–C(9)–C(8)
C(9)–C(10)–C(11)
88.6(2)
111.2(4)
123.1(4)
115.1(3)
121.8(3)
113.8(4)
126.4(4)
119.8(4)
111.2(3)
118.2(5)
121.7(4)
120.0(4)
120.7(5)
119.6(5)
120.6(6)
120.4(5)
C(6)–C(11)–C(10)
C(15)–C(12)–C(13)
C(15)–C(12)–C(2)
C(13)–C(12)–C(2)
N(14)–C(13)–C(12)
C(12)–C(15)–C(16)
C(17)–C(16)–C(22)
C(17)–C(16)–C(15)
C(22)–C(16)–C(15)
C(16)–C(17)–C(19)
C(16)–C(17)–I(18)
C(19)–C(17)–I(18)
C(20)–C(19)–C(17)
C(21)–C(20)–C(19)
C(20)–C(21)–C(22)
C(21)–C(22)–C(16)
120.5(5)
123.5(4)
123.4(4)
113.0(4)
177.8(5)
130.4(4)
117.1(5)
120.6(4)
122.2(5)
121.7(5)
122.3(4)
116.1(4)
119.1(6)
121.0(6)
119.6(6)
121.5(6)
Conjugation in the heterocycle in this molecule gives rise to significant redistribution of bond lengths,
which are in accord with the values established for thiazoles. The other bond lengths and angles have the
expected values [8].
A short intermolecular contact is found in the crystal: C(5)–H(5)···N(14) (1 + x, y, 1 + z), C(5)···N(14)
,
3.448(7) Å; C(5)–H(5), 0.82(5) Å; H(5)···N(14), 2.64(5) Å; C(5)–H(5)···N(14), 174(3)°.
TABLE 3. Coordinates (×104) and Isotropic Equivalent Temperature
Parameters for Non-hydrogen Atoms and Isotropic Temperature Parameters
for Hydrogen Atoms in 11a
Atom
1
x
2
y
3
z
4
U(eq)
5
I(18)
S(1)
N(3)
N(14)
C(2)
C(4)
C(5)
C(6)
C(7)
-5(1)
1725(1)
285(1)
-496(1)
-353(2)
-22(2)
-651(2)
-272(2)
-1175(2)
-1466(2)
-1957(2)
-2166(2)
-1889(2)
-1393(2)
249(2)
1317(1)
2497(1)
414(4)
-3351(5)
577(5)
1855(5)
3101(6)
1917(6)
389(6)
69(1)
4367(2)
3484(4)
-324(6)
3028(5)
4968(5)
5619(6)
5722(6)
5263(7)
5999(8)
7176(8)
7643(8)
6922(7)
1493(5)
495(6)
46(1)
34(1)
53(1)
33(1)
36(1)
44(1)
37(1)
47(1)
54(1)
59(1)
59(1)
51(1)
31(1)
36(1)
37(1)
39(1)
46(1)
66(2)
C(8)
C(9)
420(8)
1981(8)
3476(8)
3460(7)
-780(5)
-2233(5)
-652(6)
-1881(6)
-1313(7)
-2465(10)
C(10)
C(11)
C(12)
C(13)
C(15)
C(16)
C(17)
C(19)
-84(2)
749(2)
1079(2)
1518(2)
1844(2)
1053(6)
-354(6)
-969(7)
-2287(9)
858

TABLE 3 (continued)
1
2
3
4
5
C(20)
C(21)
C(22)
H(5)
H(7)
H(8)
H(9)
H(10)
H(11)
H(15)
H(19)
H(20)
H(21)
H(22)
-2970(9)
-2377(9)
-1076(8)
6573(88)
4475(74)
5796(79)
7712(72)
8334(86)
7280(76)
1695(63)
-2747(90)
-3868(97)
-2757(91)
-589(71)
1733(3)
1310(3)
985(2)
-4203(10)
-4818(8)
-3663(7)
3947(85)
-586(73)
-551(82)
2024(71)
4505(85)
4458(76)
282(64)
-2043(87)
-4757(92)
-5898(92)
-4086(68)
72(2)
68(2)
52(1)
7(2)
5(2)
6(2)
5(1)
7(2)
5(2)
3(1)
8(2)
8(2)
7(2)
5(1)
-264(25)
-1323(22)
-2121(24)
-2499(24)
-2056(26)
-1204(23)
917(19)
2166(28)
1923(29)
1210(27)
703(23)
EXPERIMENTAL
The IR spectra were taken on an IKS-29 spectrophotometer for vaseline mulls. The mass spectra were
taken on a Kratos MS-30 mass spectrometer with direct sample inlet into the source. The 1H NMR spectra were
registered on a Bruker AM-300 spectrometer for 4 and 6 and Bruker WP-100 SY spectrometer for 11 in
DMSO-d6 with TMS as the internal standard. The reaction course and purity of the products were monitored by
thin-layer chromatography on Silufol UV-254 plates using 3:5 acetone–hexane as the eluent.
trans
Piperidinium 4,5- -3-Cyano-6-hydroxy-4-(2-iodophenyl)-6-methyl-5-(2-methylphenyl)carbamoyl-
1,4,5,6-tetrahydropyridine-2-thiolate (4). A sample of cyanothioacetamide 2 (2 g, 20 mmol) was added with
stirring to a mixture of o-iodobenzaldehyde 1 (4.64 g, 20 mmol) and three drops of piperidine in ethanol (30 ml)
at about 20°C. After 5 min, N-acetoacetyl-o-toluidine 3 (3.83 g, 20 mmol) was added and, then, piperidine
(2.47 ml, 25 mmol) was added. After 30 min, the precipitate formed was filtered off and washed with acetone to
give 11 g (93%) salt 4; mp 171-173°C. IR spectrum, , cm-1: 3150-3330 (NH, OH), 2164 (CN), 1680 (CO). As a
ν
1
result of rapid dehydration of thiolate 4 in DMSO or CDCl3, the H NMR spectrum shows signals for
1,4-dihydropyridine-2-thiolate 5: 1.55-1.68 (6H, m, 3CH2); 1.78 (3H, s, 6-Me); 2.06 (3H, s, 2'-Me); 3.02 (4H, m,
CH2NCH2); 4.81 (1H, s, 4-H); 7.06 m, 7.42 m, and 7.71 d (8H, HAr); 7.65 (1H, s, NH); 8.36 (1H, s, CONH) (the
+
signals for the NH2 group protons are not seen due to deuteroexchange). Electron impact mass spectrum at
70 eV, m/z (Irel, %): 58 (21), 107 (100), 224 (30), 252 (99), 253 (36), 254 (30), 358 (90), 359 (34). The [M+]
peak is lacking. Found, %: C 53.24; H 5.57; N 9.83; S 5.19. C26H31IN4O2S. Calculated, %: C 52.88; H 5.29;
N 9.49; S 5.43.
trans
4,5-
-3-Cyano-6-hydroxy-4-(2-iodophenyl)-6-methyl-2-X-methylthio-5-(2-methylphenyl)-
carbamoyl-1,4,5,6-tetrahydropyridines (6a,b). A mixture of salt 4 (1.77 g, 3 mmol) and corresponding halide
7 (3 mmol) in 30 ml 80% aq. ethanol was stirred at 20°C until the starting reagents were entirely dissolved and
filtered through a paper filter. After 12 h, the fine crystalline precipitate formed in the filtrate was filtered off
and washed with 80% aq. ethanol and hexane.
Yield of 6a 1.71 g (75%); mp 196-198°C. IR spectrum, , cm-1: 3180-3390 (NH, OH), 2174 (CN), 1650
ν
(CO). 1
J (Hz): 1.60 (3H, s, 6-Me); 1.90 (3H, s, 2'-Me); 2.49 (3H, s, SMe); 2.84 (1H,
H NMR spectrum, δ, ppm,
d, 3J = 11.8, 5-H); 4.50 (1H, d, 3J = 11.8, 4-H); 6.10 (1H, s, OH); 7.10 m, 7.38 m, and 7.81 d (8HAr); 7.71 (1H, s,
NH); 9.25 (1H, s, CONH). Electron impact mass spectrum at 70 eV, m/z (Irel, %): 58 (49), 77 (26), 107 (100),
165 (31), 266 (40), 372 (27). The [M+] peak is lacking. Found, %: C 50.41; H 4.76; N 8.46; S 6.29.
C22H22IN3O2S. Calculated, %: C 50.87; H 4.27; I 24.43; N 8.09; S 6.17.
859

Yield of 6b 1.66 g (77%); mp 232-233°C. IR spectrum, , cm-1: 3180-3330 (NH, OH), 2175 (CN), 1650
ν
3
(CO). 1
J (Hz): 1.61 (3H, s, 6-Me); 1.90 (3H, s, 2'-Me); 2.90 (1H, d, J = 12.3, 5-H);
H NMR spectrum, δ, ppm,
3.91 (2H, s, SCH2); 4.48 (1H, d, 3J = 12.3, 4-H); 6.17 (1H, s, OH); 7.09 m, 7.37 d, 7.58 q, 7.81 d (12HAr); 8.29
(1H, s, NH); 9.27 (1H, s, 5-CONH); 10.48 (1H, s, 2-SCH2CONH). Electron impact mass spectrum at 70 eV,
m/z (Irel, %): 58 (78), 65 (54), 77 (75), 91 (91), 107 (76), 133 (90), 171 (85), 173 (61), 197 (99), 199 (89), 220
(58), 239 (55), 266 (82), 326 (49), 393 (44). The [M+] peak is lacking. Found, %: C 48.91; H 3.22; N 8.13;
S 4.75. C29H26BrIN4O3S. Calculated, %: C 48.55; H 3.65; N 7.81; S 4.47.
2-(4-Aryl-2-thiazolyl)-3-(2-iodophenyl)acrylonitriles (11a-d). A. These compounds were obtained
identically to sulfides 6 using corresponding bromides 8a-d.
B. Thiazoles 11a-d were obtained according to a reported procedure [6] using 12 (0.94 g, 3 mmol) and
8a-d (3 mmol).
1H NMR spectrum, δ, ppm:
Yield of thiazole 11a 0.85 g (68%) (A); 0.88 g (71%) (B); mp 112-114°C.
7.42 m, 8.02 m (9H, HAr); 8.30 (1H, s, HHet); 8.36 (1H, s, CH=). Found, %: C 52.45; H 2.82; N 6.97; S 8.01.
C18H11IN2S. Calculated, %: C 52.91; H 2.68; N 6.76; S 7.74.
1H NMR spectrum, δ, ppm:
Yield of thiazole 11b 1.12 g (79%) (A); 1.20 g (85%) (B); mp 77-78°C.
0.89 (3H, t, Me); 1.29 m, 1.52 m, and 2.60 t (6H, 3CH2); 7.28 m, 7.60 t, 7.90 d, and 8.03 d (8HAr); 8.23 (1H, s,
HHet); 8.29 (1H, s, CH=). Found, %: C 56.44; H 4.35; N 5.63; S 7.03. C22H19IN2S. Calculated, %: C 56.18;
H 4.07; N 5.96; S 6.82.
1H NMR spectrum, δ, ppm:
Yield of thiazole 11c 1.32 g (89%) (A); 1.30 g (88%) (B); mp 155-157°C.
7.27 m, 7.62 t, and 8.01 t (8HAr); 8.28 (1H, s, HHet); 8.39 (1H, s, CH=). Found, %: C 43.37; H 2.31; N 5.82;
S 6.81. C18H10BrIN2S. Calculated, %: C 43.84; H 2.04; N 5.68; S 6.50.
Yield of thiazole 11d 0.86 g (67%) (A); 1.05 g (82%) (B); mp 95-97°C. 1
H NMR spectrum, δ, ppm: 2.33
(3H, s, Me); 7.27 m, 7.60 t, 7.94 d, and 8.07 d (8HAr); 8.20 (2H, d, HHet and CH=). Found, %: C 53.45; H 3.17;
N 6.81; S 7.62. C19H13IN2S. Calculated, %: C 53.28; H 3.06; N 6.54; S 7.49.
X-ray Diffraction Structural Analysis of 3-(2-Iodophenyl)-2-(4-phenyl-2-thiazolyl)acrylonitrile
(11a). The unit cell parameters of monoclinic crystals of 11a at 20°C: a = 8.141(3), b = 25.506(8),
c = 8.419(3) Å; V = 1598.5(9) Å3; dcalc = 1.721 g/cm3; Z = 4; space group P21/n. The unit cell parameters and
intensities of 3495 independent reflections were measured on Siemens P3/PC automatic four-circle
diffractometer using λMo α radiation, graphite monochromator, and θ/2θ scanning to θ
K
max = 27°. The structure
was solved by the direct method, which revealed all the nonhydrogen atoms and refined by the full-matrix
method of least squares in anisotropic approximation for the nonhydrogen atoms. All the hydrogen atoms were
found objectively in the Fourier difference map and refined isotropically. The final R1 = 0.052 for
> 2σ(
2980 reflections with I
I) and wR2 = 0.127 for 3436 independent reflections. All the calculations were
carried out using the SHELXTL PLUS and SHELXL-93 (PC version) programs. The coordinates and isotropic
equivalent temperature factors for the nonhydrogen atoms and isotropic temperature factors for the hydrogen
atoms are given in Table 3.
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