The proposed route for formation of thiazoles 2a,b includes a cyclization stage of amides 1a,b to
dichloroaziridines which undergo recyclization under the reaction conditions to imidoylchloride intermediates
via a 1,2-chlorotropic shift and then undergo heterocyclization upon treatment with thioamides followed by
prototropic reactions as shown in the scheme.
The formation of substituted chloro- and dichloroaziridine derivatives as a result of the reaction of
arenesulfonic acid polychloroethylamides has been reported by us before [4, 5]. The recyclization of
dichloroaziridine systems to imidoylchlorides is also known [6]. However, the reactions of trichloroethylamides
leading to the synthesis of thiazole series heterocycles in a single stage reaction with thioamides has not been
reported in the literature.
We have also brought about an intramolecular cyclization of the N-(2,2-dichloroethyl-2-phenyl-1-thio-
acetamido)-4-chlorobenzenesulfonamide (3) which only leads to the 4-arenesulfonamido-2-methyl-5-phenyl-
thiazole 4. As is shown by comparison of the physicochemical data for thiazoles 2a and 4 these compounds are
isomers which demonstrates the regiodirection of the chemical reactions of the trichloroethylamides 1 to give
the 5-amino-4-arylthiazoles 2a,b.
-ClC H
4
Cl
6
4
H
Me
Ph
Cl
Cl
H
4 -ClC6H4
O
N
Ph
NaOH, H2O,
90–100°C, 4 h
Ph
Cl
N
S
4
-ClC6H4
O
O
N
S
H2N
S
O
S
N
S
HN
Me
O
O
S
Me
4
3
The structure of compounds 2a,b and 4 was confirmed by spectroscopic methods and by elemental
1
analysis. The assignment of signals in the H and 13C NMR spectra was carried out by 2D-NOESY, HSQC,
HMBC and 2D-INADEDQUATE two dimensional homo- and heteronuclear correlation methods.
The optimization of methods for obtaining thiazoles based on trichloroethylamides of type 1 is currently
in progress together with the establishment of the limits and the generality of this novel method to thiazole
derivatives.
13
1H and C NMR spectra were obtained using CDCl3 on a Bruker DPX-400 spectrometer (400 and 100
MHz respectively) at 5-10% concentration and with the addition of HMDS as internal standard. Compounds
1a,b were prepared by method [1] and compound 3 by method [7].
4-Aryl-5-(4-chlorobenzenesulfonamido)-2-methylthiazoles (2a,b) (General Method). 4-Chloro-
benzenesulfonic acid N-(1-aryl-2,2,2-trichloroethyl)amide 1a,b (5 mmol), thioacetamide (1.5 g, 20 mmol), and
Na2CO3 (2.12 g, 20 mmol) was heated at 90-100ºC in DMF (10 ml) for 90 min. The reaction mixture was
cooled, poured into water (50 ml), filtered, and the filtrate was acidified with 10% HCl solution to pH 5-6. The
precipitated thiazole 2a,b was separated, dried, and recrystallized from CHCl3.
5-(4-Chlorobenzenesulfonamido)-2-methyl-4-phenylthiazole (2a) was prepared from amide 1a (2.0 g,
5 mmol). Yield 0.57 g (31%); mp 172ºC. 1H NMR spectrum, δ, ppm: 2.60 (3H, d, 2-CH3); 6.88 (1H, br. s, NH);
13
7.38 and 7.72 (4H, AA'BB', 4-ClC6H4); 7.32, 7.39 (5H, m, C6H5). C NMR spectrum, δ, ppm: 19.17 (CH3);
126.42, 128.16, 128.32, 128.55, 128.73, 128.96, 138.35, 139.09 (C6H4 and C6H5); 129.30 (C-4); 138.07 (C-5);
162.76 (C-2). Found, %: C 52.78; H 3.63; Cl 9.65; N 7.75; S 17.70. C16H13ClN2O2S2. Calculated, %: C 52.67;
H 3.59; Cl 9.72; N 7.68; S 17.57.
5-(4-Chlorobenzenesulfonamido)-2-methyl-4-(4-methylphenyl)thiazole (2b) was prepared from
1
amide 1b (2.07 g, 5 mmol). Yield 0.64 g (34%), mp 185ºC. H NMR spectrum, δ, ppm: 2.38 (3H, s, 2-CH3);
2.63 (3H, s, 4-CH3C6H4); 7.15 and 7.30 (4H, AA'BB', 4-CH3C6H4); 7.31 and 7.65 (4H, AA'BB', 4-ClC6H4); 7.35
(1H, br. s, NH). 13C NMR spectrum, δ, ppm: 19.54 (2-CH3); 21.33 (CH3C6H4); 126.71, 128.55, 128.85, 129.16,
129.69, 138.48, 138.68, 139.30 (2C6H5); 129.17 (C-4); 138.23 (C-5), 162.90 (C-2). Found, %: C 53.77; H 3.96;
Cl 9.49; N 7.47; S 16.98. C17H15ClN2O2S2. Calculated, %: C 53.89; H 3.99; Cl 9.36; N 7.39; S 16.92.
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