Synthesis and Properties of New N-(Hydroxyalkyl)thioacrylamides ^†

Abstract

Cyanothioacetamide readily reacts with aromatic aldehydes in an aqueous–alcoholic medium in the presence of triethylamine as a catalyst, resulting in arylmethylene cyanothioacetamides (3-aryl-2-cyanothioacrylamides). The latter react with formaldehyde (HCHO), yielding N-(hydroxymethyl) derivatives. This work proposes a method for the preparation of new derivatives of N-(hydroxyalkyl)thioacrylamides. The details of the synthesis and spectral data are discussed. Biological effects are also considered as 2,4-D herbicide antidotes (safeners).

1. Introduction

N-(Hydroxymethyl)thioamides are readily available compounds that are widely used in the synthesis of nitrogen- and sulfur-containing heterocycles, such as 1,3-thiazines, 1,2,4-dithiiazoles, 1,3,5-oxathiazines, 1,3,5-thiadiazines, and thiazolidines. In addition to their application in fine organic synthesis, N-(hydroxymethyl)thioamides are also used for other purposes. For example, some representatives of this series act as bidentate ligands for creating selective sorbents for heavy metal ions such as Cu(II), Cd(II), and Hg(II) [1,2]. These compounds are intermediates in the synthesis of a number of biologically active substances [3,4]. At the same time, the literature presents a limited number of methods for obtaining such compounds, and the variability of structures is not sufficiently high. Thus, N-(hydroxyalkyl)thioamides belong to a promising group of compounds, and the development of methods for their synthesis can be considered an important problem.

2. Results and Discussion

The starting compound 3 was obtained from cyanothioacetamide 1 and aromatic aldehydes 2 in an aqueous–alcoholic medium using a basic catalyst (Scheme 1) [5]. Compound 3 was then reacted with HCHO at 60 °C (Scheme 1) [5]. To confirm the structure of compounds 3 and 4, spectral methods (IR, ¹H and ¹³C NMR spectroscopy) were used (Scheme 1, Figure 1).

It is known that salicylaldehyde 5, when reacting with cyanothioacetamide 1, undergoes intramolecular cyclization, forming product 6. The resulting substance interacts with HCHO to form compound 7 (Scheme 2).

To determine the biological activity of compounds 4 and 7, the Pass Online service was used. Compound 4 is more likely to exhibit properties of an inhibitor of tyrosine kinases (87.4%) and S-methyltransferase of homocysteine (78.2%); it may also exhibit antitumor properties (78.8%) and, to a lesser extent, anti-psoriatic properties (57.3%). The predicted undesirable effects include adrenal cortex hypoplasia (67.9%) and anemia (53.8%). Compound 7 is more likely to exhibit properties as a spasmolytic, diuretic (62.6%), membrane integrity agonist (53.9%), and antifungal agent (44.5%); it is also a potential anti-tuberculosis agent (42.8%). Negative effects may include causing acne (73.2%), various allergic reactions (55.7%), and carcinogenicity (for mice—63.8%).

Compounds 4a and 4c were tested for herbicide safening activity (for reviews, see [6,7]) against the herbicide 2,4-D on sunflower seedlings of the Master variety. The results showed that both compounds have significant activity: for compound 4a, the antidote effect was 66%, and for 4c, it was 30%. The obtained data are promising regarding further research.

3. Experimental Section

Synthesis of starting compounds 3a–e and 6. In a 50 mL beaker, 0.01 mol of the starting aldehyde and 0.01 mol of cyanothioacetamide 1 [8] were placed in 15 mL of ethanol. Catalytic amounts of Et₃N (2 drops) were added. A yellow or orange precipitate formed within a few minutes; the solid was filtered off and washed with alcohol. The compounds were further reacted without additional purification.

Synthesis of N-(hydroxymethyl)thioacrylamides 4 (a–e) and 2-iminocoumarine 7. In a 25 mL beaker, 0.0021 mol of the starting compound (3a–e, 6) was placed. Then 3 mL (excess) of 37% aq. HCHO was added, and the temperature in the system was maintained at 50–55 °C, with stirring for 40 min, during which the solution acquired a more intense orange color. Upon cooling, a precipitate formed, which was filtered off and washed with cold distilled water.

(E)-N-(Hydroxymethyl)-3-(4-chlorophenyl)-2-cyanoprop-2-ene thioamide (4a). Yellow powder, 0.34 g (64%). R_f = 0.43 (ethyl acetate). IR spectrum, ν, cm⁻¹: 3444 br, 3322 br (O-H, N-H), 2204 br (C≡N). ¹H NMR spectrum (400 MHz, DMSO-d₆), δ, ppm: 5.06 m (2H, CH₂), 6.33 t (1H, OH), 7.65 d (2H, H Ar), 7.91 s (1H, CH=), 7.93 d (2H, H Ar), 10.93 br.s (1H, NH). ¹³C NMR spectrum (101 MHz, DMSO-d₆) δ, ppm: 70.0 (-CH₂OH). 113.91 (=C(CN)-), 116.70 (C≡N), 129.93 (C Ar), 132.18 (C Ar), 132.20 (C Ar), 137.14 (C¹ Ar), 145.38 (CH=), 189.60 (C=S),

(E)-N-(Hydroxymethyl)-3-(4-bromophenyl)-2-cyanoprop-2-ene thioamide (4b). Yellow powder weighing 0.34 g (68%). IR spectrum, ν, cm⁻¹: 3415 br, 3317 br (O-H, N-H), 2204 br (C≡N). ¹³C NMR spectrum (101 MHz, DMSO-d₆) δ, ppm: 70.0 (-CH₂OH), 113.85 (=C(CN)-), 116.62 (C≡N), 132.81 (C Ar), 132.21 (C Ar), 131.65 (C, Ar), 132.37 (C Ar), 145.39 (CH=), 189.49 (C=S).

(E)-N-(Hydroxymethyl)-3-(3,4-dimethoxyphenyl)-2-cyanoprop-2-ene thioamide (4c). Light orange powder weighing 0.34 g (62%). R_f = 0.473 (ethyl acetate). IR spectrum, ν, cm⁻¹: 3415 br, 3241 br (O-H, N-H), 2221 br (C≡N). ¹H NMR spectrum (400 MHz, DMSO-d₆), δ, ppm: 7.16 d (1H, H Ar), 6.34 t (1H, OH), 5.06 d (2H, CH₂), 7.57 d (1H, H Ar), 7.68 c (1H, CH=), 8.07 s (1H, H Ar), 9.99 br.s (1H, NH), 3.86 s (3H, CH₃), 3.82 s (3H, CH₃). ¹³C NMR spectrum (101 MHz, DMSO-d₆) δ, ppm: 149.25 (C Ar), 148.12 (C Ar), 126.21 (C Ar), 124.80 (C Ar), 117.59 (C Ar), 117.53 (C Ar), 153.10 (CH=), 109.53 (=C(CN)-), 112.79 (C≡N), 193.12 (C=S), 109.51 (CH₂OH), 56.36 (OCH₃), 56.00 (OCH₃).

(E)-N-(Hydroxymethyl)-3-(4-hydroxy-3-methoxy-5-nitrophenyl)-2-cyanoprop-2-ene thioamide (4d). Ochre powder weighing 0.32 g (64%). IR spectrum, ν, cm⁻¹: 3415 br, 3317 br (O-H, N-H), 2204 br (C≡N). ¹H NMR spectrum (400 MHz, DMSO-d₆), δ, ppm: 3.93 s (3H, CH₂O), 3.97 s (2H, CH₃), 7.64 c (1H, H Ar), 7.96 br.d (1H, H Ar), 8.11 s (1H, CH=), 9.88 br.t (1H, OH). ¹³C NMR spectrum (101 MHz, DMSO-d₆) δ, ppm: 192.56 (C=S), 193.93 (2C, Ar), 150.51 (CH=), 150.14 (C Ar), 148.25 (C Ar), 146.45 (C Ar), 145.86 (C Ar), 137.64 (C Ar), 122.30 (=C(CN)-), 127.24 (C≡N), 57.28 (CH₂OH), 57.16 (CH₃).

2-(Hydroxymethylamino)-2H-chromen-3-carbothioamide (7). Ochre powder weighing 0.35 g (51%). R_f = 0.451 (ethyl acetate). IR spectrum, ν, cm⁻¹: 3400 br (O-H), 3317 br, 3203 br (NH). ¹H NMR spectrum (400 MHz, DMSO-d₆), δ, ppm: 5.740 t (1H, OH), 8.85 s (1H, H Ar), 7.79 d (1H, H Ar), 7.57 t (1H, H Ar), 7.24 d (1H, H Ar), 7.27 d (1H, H Ar), 5.01 d (2H, CH₂), 10.04 br.s (2H, NH₂). ¹³C NMR spectrum (101 MHz, DMSO-d₆) δ, ppm: 192.75 (C=S), 153.50 (C=N), 146.74 (C, Ar), 144.16 (C, Ar), 133.72 (C, Ar), 130.80 (C, Ar), 124.96 (C, Ar), 123.22 (C, Ar), 118.73 (C, Ar), 115.54 (C, Ar), 71.52 (CH₂OH).