Synthesis of heterocycles on the basis of products of arylation of unsaturated compounds 22.*3-Aryl-2-chloropropanal in the synthesis of N-Aryl-5-(R-benzyl)-1,3-thiazole-2-amines

Article abstract of DOI:10.1007/s10593-010-0537-7

3-Aryl-2-chloropropanal was obtained by the reaction of arenediazonium chlorides with acrolein in the presence of copper(II) chloride. N-Aryl(2-pyridyl)-5-(R-benzyl)-1,3-thiazole-2-amines were formed in high yield by the reaction of these aldehydes with a

Full text of DOI:10.1007/s10593-010-0537-7

Chemistry of Heterocyclic Compounds, Vol. 46, No. 4, 2010
SYNTHESIS OF HETEROCYCLES ON THE BASIS OF
PRODUCTS OF ARYLATION OF UNSATURATED COMPOUNDS
22.* 3-ARYL-2-CHLOROPROPANAL IN THE SYNTHESIS OF
N-ARYL-5-(R-BENZYL)-1,3-THIAZOLE-2-AMINES
V. S. Matiychuk, N. D.Obushak1**, N. I. Pidlypnyi1,
Yu. V. Ostapiuk1, and R. M. Voloshchuk1
3-Aryl-2-chloropropanal was obtained by the reaction of arenediazonium chlorides with acrolein in the
presence of copper(II) chloride. N-Aryl(2-pyridyl)-5-(R-benzyl)-1,3-thiazole-2-amines were formed in
high yield by the reaction of these aldehydes with aryl- and 2-pyridylthioureas. The same compounds
were obtained by the reaction of 5-(R-benzyl)-1,3-thiazole-2-amines with aniline.
Keywords: 2-aminothiazoles, arylthioureas, derivatives of thiazole, α-chloro aldehydes, arylation, the
Meerwein reaction.
Derivatives of 2-aminothiazole cover a wide spectrum of biological activity [2-8] and are also used in
various fields of technology [9, 10]. One of the most suitable methods for the synthesis of 2-aminothiazole is the
interaction of α-halocarbonyl compounds with thioamides and thioureas [11-13]. 5-Substituted 2-aminothiazoles
have been obtained by this method, using α-halo aldehydes, the range of which is limited. The development of a
preparative method for the synthesis of 3-aryl-2-chloropropanal [14,15] provided the possibility to easily obtain
2-amino-5-(R-benzyl)thiazoles.
In this paper a method is proposed for the synthesis of N-aryl-5-(R-benzyl)-1,3-thiazole-2-amines 5a-o
by the interaction of chloro aldehydes 3a-f with arylthioureas 4a-e and N-(2-pyridyl)thioureas 4f,g. The
aldehyde starting materials 3a-e were obtained by chloroarylation of acrolein 1 with the aryldiazonium salts
2a-e. We note that compounds 3 can also be obtained from 3-arylpropanols which, in their turn, were
synthesized from the corresponding cinnamic acids [16]. However this method is preparatively less suitable and
the overall yields of the aldehydes 3 are not large.
It was established that cyclization of the chloro aldehydes 3a-e with arylthioureas 4 occurs on boiling in
ethanol, and the presence of bases is not required (method A).
2-Chloro-3-(1-naphthyl)propanal 3f, prepared by the interaction of naphthyldiazonium tetrachloro-
cuprate (2f) with acrolein 1 [8, 14], was used in the synthesis of compounds 5n,o.
_______
* For Communication 21, see [1].
** To whom correspondence should be addressed, e-mail: obushak@in.lviv.ua.
1Ivan Franko Lviv National University, Lviv 79005, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.4, 624-629, April 2010. Original article
submitted May 28, 2009.
0009-3122/10/4604-0495©2010 Springer Science+Business Media, Inc.
495

The interaction of the chloro aldehydes 3 with aryl thioureas 4 occurred selectively in all cases: The
thiazole ring was formed with the more nucleophilic nitrogen atom. Isomeric 3-aryl-5-(R-benzyl)-
2-iminothiazoles were not observed in the reaction mixture. Compounds 5a-o are readily soluble in polar
solvents, insoluble in mineral acids, and form salts with difficulty.
+
N2
Cl
O
CuCl2
O
+
Cl
3a–e
Me2CO–H2O
R1
R1
1
2a–e
H
N
NH2
R1
R2
S
N
R2
4a–e
N
S
H
5a–j
2, 3 a R1 = 4-Cl, b R1 = 2,3-Cl2, c R1 = 3,4-Cl2, d R1 = 2-Me, e R1 = 3-NO2; 4 a R2 = H,
b R2 = 4-Cl, c R2 = 4-Me, d R2 = 3-Me, e R2 = 4-MeO; 5a–c R2 = H, a R1 = 4-Cl, b R1 = 2,3-Cl2,
c R1 = 3,4-Cl2; d–g R2 = 4-Cl, d R1 = 4-Cl, e R1 = 2,3-Cl2, f R1 = 3,4-Cl2, g R1 = 2-Me;
h R1 = 2,3-Cl2, R2 = 4-Me; i R1 = 3-NO2, R2 = 3-Me; j R1 = 2-Me, R2 = 4-OMe
H
R3
N
N
NH2
R1
N
R3
3b,d
+
S
N
N
S
H
5k–m
4f,g
4 f R3 = H, g R3 = Me; 5 k, l R3 = H, k R1 = 2-Me, l R1 = 2,3-Cl2; m R1 = 2-Me, R3 = Me
R
N
Cl
O
N
O
H
4a, b
–
2
+
S
1
(C10H7N2 )2CuCl4
3f
5 n R = H , o R = Cl
5n, o
2f
1
The structures of compounds 5 were confirmed by H NMR spectroscopic data and by directed
synthesis, starting from 5-(R-benzyl)-1,3-thiazole-2-amine hydrochlorides 6a,b and aniline (method B):
R1
H
NH2
Cl
N+
+
5a, b
NH2
S
6a, b
6 a R1 = 4-Cl, b R1 = 2,3-Cl2
496

Table 1. Characteristics of Compounds 5a-o
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
50
C
H
N
5a
С16H13ClN2S
63.61
63.89
4.24
4.36
9.04
9.31
130-132
5b
5c
5d
5e
5f
С16H12Cl2N2S
С16H12Cl2N2S
С16H12Cl2N2S
С16H11Cl3N2S
С16H11Cl3N2S
C17H15ClN2S
C17H14Cl2N2S
C17H15N3O2S
C18H18N2OS
C16H15N3S
57.05
57.32
57.03
57.32
57.07
57.32
51.67
51.98
51.62
51.98
64.72
64.85
58.24
58.46
62.65
62.75
69.42
69.65
68.03
68.30
53.40
53.58
68.97
69.12
75.55
75.92
68.06
68.46
3.44
3.61
3.42
3.61
3.43
3.61
2.79
3.00
2.79
3.00
4.63
4.80
3.92
4.04
4.57
4.65
5.42
5.84
5.21
5.37
3.13
3.30
5.68
5.80
5.02
5.10
4.17
4.31
8.20
8.36
8.20
8.36
8.21
8.36
7.42
7.58
7.31
7.58
8.78
8.90
8.28
8.02
12.83
12.91
8.80
9.02
14.77
14.93
12.36
12.50
14.04
14.22
9.02
8.85
7.81
7.98
194-195
117-118
145-148
185-187
192-193
158
61
49
52
71
64
61
54
52
49
69
73
67
42
45
5g
5h
5i
155-156
184-185
122
5j
5k
5l
172
C15H11Cl2N3S
C17H17N3S
227
5m
5n
5o
195
С20H16N2S
155
С20H15ClN2S
153
It should be noted that amino-imino tautomerism is possible for compounds 5 in solution [17, 20]:
H
N
Ar2
Ar1
N
Ar2
Ar1
N
S
N
H
S
Evidently tautomeric conversion occurs rapidly in solution as a result of which broadening of the NH
signal is observed in the 1H NMR spectrum. To judge by the chemical shift and the form of the signal (a singlet),
equilibrium is shifted to the side of the amino form.
EXPERIMENTAL
1H NMR Spectra of compounds 5a,e,g,i-o were recorded on a Varian Mercury (400 MHz) instrument,
compounds 5b-d,f, h on a Bruker WP-200 (200 MHz) in DMSO-d6 (5a,e,i,n,o), deuteroacetone (5b-d,f,h), or
CDCl3 (5g, j-m) with TMS as internal standard. Compounds 6a,b were obtained by a known method [15].
N-Aryl(2-pyridyl)-5-(R-benzyl)-1,3-thiazole-2-amines 5a-o. A. A solution of the corresponding
arylthiourea 4 (10 mmol) and the aldehyde 3 (10 mmol) in ethanol (10 ml) was boiled for 3 h. The residue was
decanted, suspended in boiling water and made alkaline with ammonia. It was filtered off and recrystallized
from DMF.
497

Table 2. 1H NMR Spectra of Compounds 5a-o
Com-
pound
Chenical shifts, , ppm (J, Hz)
5a
4.02 (2H, s, CH2); 6.91 (1H, t, J = 7.2, H-4 C6H5); 7.03 (1H, s, thiazole);
7.24-7.30 (4H, m, Ar); 7.37 (2H, d, J = 8.1, H-3,5 C6H4);
7.56 (2H, d, J = 7.8, H-2,6 C6H5); 9.99 (1H, s, NH)
5b
5c
4.10 (2H, s, CH2); 7.10 (1H, s, thiazole); 7.20-7.72 (8H, m, Ar); 9.50 (1H, s, NH)
4.09 (2H, s, CH2); 6.95 (1H, t, J = 7.2, H-4 C6H5); 7.10 (1H, s, thiazole);
7.20-7.70 (7H, m, Ar); 9.40 (1H, s, NH)
5d
4.03 (2H, s, CH2); 7.06 (1H, s, thiazole); 7.28 (2H, d, J = 8.8, H-3,5 C6H4NH);
7.32 (2H, d, J = 8.4, H-2,6 C6H4); 7.37 (2H, d, J = 8.4, H-3,5 C6H4);
7.62 (2H, d, J = 8.8, H-2,6 C6H4NH); 10.16 (1H, s, NH)
5e
5f
4.23 (2H, s, CH2); 7.09 (1H, s, thiazole); 7.25-7.73 (7H, m, Ar); 9.45 (1H, s, NH)
4.10 (2H, s, CH2); 7.10 (1H, s, thiazole); 7.25-7.58 (5H, m, Ar);
7.72 (2H, d, J = 8.7, H-2,6 C6H4); 9.22 (1H, s, NH)
5g
2.30 (3H, s, CH3); 4.01 (2H, s, CH2); 6.97 (1H, s, thiazole);
7.11-7.22 (4H, m, C6H4); 7.31 (2H, d, J = 8.8, H-3,5 C6H4NH);
7.61 (2H, d, J = 8.8, H-2,6 C6H4NH); 10.11 (1H, s, NH)
5h
5i
2.23 (3H, s, CH3); 4.09 (2H, s, CH2); 6.70-7.58 (8H, m, thiazole + Ar);
9.40 (1H, br. s, NH)
2.27 (3H, s, CH3); 4.26 (2H, s, CH2); 7.11 (1H, s, thiazole);
6.90- 7.17 (4H, m, C6H4NH); 7.65 (1Н, t, J = 7.6, H-5 C6H4);
7.83 (1Н, d, J = 7.6, H-6 C6H4); 8.13 (1Н, dd, 4J = 2.1, 3J = 8.0, H-4 C6H4);
8.23 (1Н, br. s, H-2 C6H4); 9.81 (1H, s, NH)
5j
2.29 (3H, s, CH3); 3.71 (3H, s, ОCH3); 3.98 (2H, s, CH2);
6.86-6.89 (3H, m, thiazole + Ar); 7.13-7.20 (4H, m, Ar);
7.47 (2H, d, J = 8.8, Ar); 9.72 (1H, s, NH)
5k
2.30 (3H, s, CH3); 4.05 (2H, s, CH2); 6.84-6.89 (1H, m, H-5 Py);
7.00-7.04 (1H, m, H-3 Py); 7.06 (1H, s, thiazole);
7.12-7.24 (4H, m, C6H4); 7.63-7.67 (1H, m, H-4 Py);
8.20-8.23 (1H, m, H-6 Py); 11.03 (1H, s, NH)
5l
4.23 (2H, s, CH2); 6.85-6.90 (1H, m, H-5 Py); 7.02-7.06 (1H, m, H-3 Py);
7.12 (1H, s, thiazole); 7.30-7.71 (4H, m, C6H3 + H-4 Py);
8.23-8.26 (1H, m, H-6 Py); 11.11 (1H, s, NH)
5m
2.32 (3H, s, CH3); 2.39 (3H, s, CH3); 4.04 (2H, s, CH2);
6.73 (1H, d, J = 7.6, H-5 Py); 6.83 (1H, d, J = 7.8, H-3 Py);
7.00 (1H, s, thiazole); 7.11-7.21 (4H, m, C6H4);
7.54 (1H, t, J = 7.8, H-4 Py); 10.96 (1H, s, NH)
5n
5o
4.41 (2H, s, CH2); 6.79 (1H, t, J = 7.8, H-4 C6H5); 6.85 (1H, s, thiazole);
7.14 (2H, t, J = 7.8, H-3,5 C6H5); 7.36-7.50 (6H, m, Ar);
7.70-7.74 (1H, m, C10H7); 7.82 (1H, d, J = 7.4, C10H7);
8.07 (1H, d, J = 7.4, C10H7); 9.68 (1H, s, NH)
4.41 (2H, s, CH2); 6.85 (1H, s, thiazole); 7.12 (2H, d, J = 8.2, H-3,5 C6H4);
7.35-7.50 (4H, m, C10H7); 7.53 (2H, d, J = 8.2, H-2,6 C6H4);
7.71-7.75 (1H, m, C10H7); 7.83 (1H, d, J = 7.3, C10H7);
8.05 (1H, d, J = 7.3, C10H7); 9.83 (1H, s, NH)
B. Equimolar mixtures of the hydrochlorides 6a,b and aniline were heated at 180-200°C. After cooling,
the oily residue was treated successively with hot water and alcohol and recrystallized from DMF. The yields of
compounds 5a and 5b were 24 and 20% respectively.
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