Synthesis and transformations of 1-[2-(toluene-4-sulfonamido)ethyl]thiourea

Synthesis

1-(Toluene-4-sulfonamidoethyl)-3-benzoylthiourea (1) was synthesized by the reaction of 2-(toluene-4-sulfonylamino)ethylamine with benzoyl isothiocyanate (Scheme 1). Debenzoylation of 1 furnished 1-(toluene-4-sulfonamidoethyl)thiourea (2), heterocyclization of which with ethyl 2-chloro-3-oxobutyrate afforded ethyl 4-methyl-2-[2-(toluene-4-sulfonylamino)ethylamino]thiazole-5-carboxylate (3). Treatment of ester 3 with hydrazine hydrate yielded 4-methyl-2-[2-(toluene-4-sulfonylamino)ethylamino]thiazole-5-carboxylic acid hydrazide (4), which was subsequently transformed into azide 5. The reactions of azide 5 with propylamine and pyrrolidine did not proceed with the expected elimination of nitrogen and formation of 3-ureido derivatives. Instead, the respective product 6 was obtained. The isolation of 6 is fully consistent with ¹H NMR and mass spectra. In particular, the mass spectra of 6a (R = C₃H₇NH) and 6b (R = pyrrolidino) show the respective molecular ion peaks at m/z 396 and m/z 408, as calculated for these structures.

Scheme 1

4-Methyl-2-[2-(toluene-4-sulfonylamino)ethylamino]thiazole-5-carboxylic acid hydrazide (4) was also used as an initial compound for the syntheses of noncondensed bicyclic systems, including thiazole ring in combination with [1,3,4]oxadiazole and [1,3,4]thiadiazole heterocycles (Scheme 2). First, the reaction of hydrazide 4 with carbon disulfide and potassium hydroxide in ethanol furnished the potassium salt of 2-{2-[2-(toluene-4-sulfonylamino)ethylamino]-4-methyl-thiazole-5-carbonyl}hydrazinecarbodithioic acid (7). Then, alkaline and acidic hydrolysis of 7 furnished 2-{[2-(toluene-4-sulfonylamino)ethylamino]-4-methylthiazol-5-yl}-5-thioxo-4,5-dihydro[1,3,4]oxadiazole (8) and 2-{[2-(toluene-4-sulfonylamino)ethylamino]-4-methylthiazol-5-yl}-5-thioxo-4,5-dihydro[1,3,4]thiadiazole (9), respectively.

Scheme 2

The suggested thione forms of 8 and 9 are consistent with their ¹³C NMR spectra that show signals at 176 ppm for the C=S function. The reaction of compounds 8 and 9 with dimethyl sulfate yielded their respective S-methylated derivatives 10 and 11. In ¹³C NMR spectra of these compounds instead of the C=S bond signals, new signals due to C=N bond of 1,3,4-oxadiazole or 1,3,4-thiadiazole system appear.

Biological activity

In preliminary biological tests the growth regulatory properties of synthesized compounds were investigated for their aqueous emulsions (25 mg/L and 50 mg/L) on the germination, growth and survivability of seeds and seedlings of dicotyledonous bean (Phaseolus vulgaris L.). The activities of these compounds were compared with that of heteroauxin. Practically all investigated substances 1–11 have shown strongly pronounced growth stimulant properties and their calculated activities were in the interval of 75–98%.

General

¹H NMR (300 MHz) and ¹³C NMR (75 MHz) spectra were recorded on a Varian Mercury-300 spectrometer, in a mixture of DMSO-d₆ and CCl₄ (1:3) or in pure DMSO-d₆. The reaction progress and purity of products were checked by using TLC on Silufol UV-254 plates with acetone/hexane (2:1) as an eluent. Melting points are uncorrected. 2-(Toluene-4-sulfonylamino)ethylamine was obtained as described previously [2].

General procedure for 6a,b

A suspension of compound 5 (1.14 g, 0.003 mol) and 0.0033 mol of n-propylamine or pyrrolidine in 20 mL of anhydrous benzene in the presence of a catalytic amount of pyridine was heated under reflux for 2 h. Concentration under reduced pressure was followed by crystallization of the residue from aqueous ethanol (50%).

General procedure for 10, 11

A solution of KOH (0.01 mol) in 10 mL of water was treated at 0°С with 0.01 mol of compound 8 (or 9) with continuous stirring, and then portion-wise with 1.1 mL (0.011 mol) of dimethyl sulfate. The mixture was briefly stirred at 20°С and then allowed to stand overnight. The precipitate of 10 (or 11) was filtered, washed with water and dried.