Multicomponent synthesis of nicotinic acid derivatives

The synthesis of previously unknown nitriles, esters, and an amide of 6-alkoxy-2-alkylsulfanyl-4-methyl(4,4-dimethyl)nicotinic acid has been developed. The structure of a number of the obtained derivatives was proved by X-ray structural analysis.

Among 2-oxo(thio)nicotinonitrile derivatives, dyes,¹ stimulants of the growth of sunflower seedlings,² antidotes to the herbicide 2,4-B,³ compounds with bactericidal and fungicidal activity,⁴ as well as compounds that inhibit acetylcholinesterase and butyrylcholinesterase in the treatment of Alzheimer’s disease⁵ have been found. The principal methods for the synthesis of 2-oxo(thio)nicotinonitriles involve the condensation of 1,3-dicarbonyl compounds⁶ or their enamines⁷ with nitrogen-containing CH acids.

Considering the high practical importance of this class of heterocyclic compounds and in continuation of our research on multicomponent condensations,⁸ we studied a new reaction of ethyl β-(morpholin-4-yl)crotonate (1) with cyanothioacetamides 2а,b, morpholine, and alkylating agents 3a–h.

The condensation in EtOH at 20°С gives rise to 6-alkoxy-2-alkylsulfanyl-4-methylnicotinonitriles 4а–f (Scheme 1). We believe that the first step of the reaction is the conjugated addition of ethyl β-(morpholin-4-yl)crotonate (1) to the activated double bond of substrate 2a,b. In the course of the reaction, a morpholine molecule is eliminated with the formation of the intermediate adduct 5, which, as a result of intramolecular heterocyclization, forms pyridinethiolate morpholine salt 6.⁹

Scheme 1

Salt 6 is subsequently regioselectively alkylated with alkyl halides 3a–d to form thioesters 7, the treatment of which with KOH in DMF generates anions 8, presented in the form of resonance forms 8 and 9. This fact is confirmed by the formation of compound 10 when using 1,2-dibromoethane (3d) as an alkylating agent. As a result of repeated alkylation during this condensation with the use of compounds 3e–h, the expected 4-methylnicotinic acid derivatives 4a–f are formed. Their structure is consistent with the data of spectral studies.

We previously reported that alkylation of morpholinium 3-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-thiolate with a twofold excess of benzyl chloride¹⁰ or phenacyl bromide¹¹ in DMF occurs at the S and N atoms.

In order to unambiguously establish the direction of alkylation of substituted pyridines containing the O, S, N nucleophilic centers, the structure of compounds 4a,b was proved by X-ray structural analysis (Fig. 1). It is important to note that the 2-alkylsulfanyl and 6-alkoxy substituents in compounds 4a,b are in a tick-shaped mutual conformation, which is apparently determined by steric preferences in the solid phase. In addition, the ester fragment in compound 4b has the most energetically favorable linear structure.

Figure 1.

Molecular structure of compounds 4a,b with atoms represented as thermal vibration ellipsoids of 50% probability.

In the solid state of compound 4a, the molecules form dimers due to S···S nonvalent interactions with a distance of 3.4705(9) Å (Fig. 2). Dimers are packed in stacks along the crystallographic axis a and are located at the distances of the van der Waals radii.

Figure 2.

Dimer of compound 4a in the solid state. The dotted line depicts the intermolecular interaction S···S.

Compound 4b in the solid state forms zigzag chains along the crystallographic axis b via intermolecular hydrogen bonds С–H···O (Table 1, Fig. 3).

Table 1. Hydrogen bonds and their characteristics (bond lengths and angles) in compounds 4b, 13, and 17

Figure 3.

Zigzag chains of compound 4b in the solid state. The dotted lines depict intermolecular hydrogen bonds.

The introduction of cyanomethylbutene derivative 11, cyanothioacetamide (2а), ethyl monochloroacetate (12), and NaOEt at 20°С in EtOH into multicomponent condensation leads to the formation of ethyl 2-[(3,5-dicyano-4,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridin-2-yl)-sulfanyl]acetate 13. The conversion probably begins with the Michael addition of the formed CH acid anion 2а to the activated double bond of cyanomethylbutene 11 with the formation of the corresponding salt 14. Then, salt 1 is alkylated at the S atom to form sulfide 13. The use of CH acids 2а,с and 1,2-dibromoethane (3d), and benzyl chloride (3с) or 2-bromoacetophenone (15) as alkylating agents in this condensation leads to the formation of condensation products 16 and 17. We assume that the thioether of tetrahydropyridine 18 is formed as an intermediate in the course of the reaction (Scheme 2).

Scheme 2

Note that the second alkylation happens at the C-6 atom of the thiazolopyridine ring, not at the O atom of the carbonyl fragment of the molecule. Obviously, this is due to the absence of the possibility of enolization and aromatization of the pyridine ring.

Spectral data confirm the structure of the synthesized compounds 4a–f, 10, 13, 16, 17. A characteristic feature of the ¹H NMR spectra of compounds 13 and 16 is the splitting of the proton signals of the methylene fragments SCH₂ and PhCH₂ into two doublets, which indicates the absence of free rotation of these groups and, as a consequence, nonequivalence of the indicated protons.

The X-ray structural analysis data for single crystals 13 and 17 conclusively confirm the structures of the compounds obtained in the course of multicomponent condensation (Fig. 4).

Figure 4.

Molecular structure of compounds 13 and 17 with atoms represented as thermal vibration ellipsoids of 50% probability.

It should be noted that molecule 13 assumes a spatial arrangement in which the thioacetate fragment is located practically above the tetrahydropyridine ring. The tetrahydropyridine ring has a distorted half-chair conformation with the carbon atom C(4) exiting from the plane drawn through the rest of the ring atoms (the standard deviation of 0.082 Å).

In the bicyclic structure 17, the thiazole ring has the envelope conformation with the carbon atom C(2) exiting from the plane drawn through the rest of the ring atoms (the standard deviation of 0.044 Å), and the six-membered tetrahydropyridine ring has the half-chair conformation with the carbon atom C(6) exiting from the plane drawn through the remaining atoms of the ring (the standard deviation of 0.032 Å). It should be noted that the bulky 2-oxo-2-phenylethyl substituent occupies a sterically less preferred axial position.

In the solid state, the molecules of compound 13 form centrosymmetric dimers due to the intermolecular hydrogen bonds N–H···O and С–H···O (Table 1, Fig. 5a), which form hydrogen-bonded ribbons along the crystallographic axis b located at the distance of the van der Waals radii (Fig. 5b).

Figure 5.

a) Centrosymmetric hydrogen-bonded dimers of compound 13 in the solid state. The dotted lines depicts intermolecular hydrogen bonds N–H···O and С–H···O. b) Hydrogen-bonded ribbons of compound 13 in the solid state. The dotted lines depict intermolecular hydrogen bonds N–H···O and С–H···O.

Molecules 17 in the solid state form centrosymmetric dimers due to intermolecular hydrogen bonds С–H···O (Table 1, Fig. 6). The dimers are packed in stacks along the crystallographic axis a and are located at the distance of the van der Waals radii.

Figure 6.

Centrosymmetric hydrogen-bonded dimers of compound 17 in the solid state. The dotted lines depict intermolecular hydrogen bonds С–H···O.

To conclude, new derivatives of 6-alkoxy-2-alkylsulfanyl-4-methyl(4,4-dimethyl)nicotinonitriles, as well as esters and an amide of nicotinic acid were synthesized as a result of multicomponent condensation of ethyl β-(morpholin-4-yl)crotonate or ethyl isopropylidenecyanoacetate, CH acids with the thioamide group, alkylating derivatives, and morpholine or sodium ethylate.

Experimental

IR spectra were registered on a IKS-40 spectrometer in thin film (suspension in petroleum jelly). ¹H and ¹³C NMR spectra were acquired on a Varian VXR-400 spectrometer (400 MHz) in DMSO-d₆, using residual solvent signals as internal standard (2.50 ppm for ¹H nuclei, 39.5 for ¹³С nuclei). High-resolution mass spectra were recorded on an Orbitrap Elite mass spectrometer, DMSO solvent, atmospheric pressure electrospray ionization, voltage 3.5 kV, capillary temperature 275°С. Mass spectra were recorded in the positive and negative ion modes in an orbital trap with a resolution of 480,000. Mass spectra of compounds 4c–f were registered on an Agilent 1100 mass spectrometer with an Agilent LS/MSDLS selective detector (the sample was injected in an AcOH matrix, EI ionization, 70 eV).

Elemental analysis was performed on a PerkinElmer CHNanalyzer. Melting points were determined on a Kofler bench. Monitoring of the reaction progress and assessment of the purity of synthesized compounds were done by TLC on Silufol UV-254, eluent Me₂CO–hexane, 5:3, visualization by iodine vapor and UV light.

Synthesis of 6-alkoxy-2-alkylsulfanyl-4-methylnicotinonitriles 4a–f (General method). Morpholine (3 drops) was added to a mixture of ethyl β-(morpholin-4-yl)crotonate (1) (2.0 g, 10 mmol), cyanothioacetamide 2a (1.0 g, 10 mmol), and anhydrous EtOH (30 ml) at 20°С; and the resulting mixture was stirred for 4 h. Then, alkylating agent 3а–d (10 mmol) was added, and the mixture was stirred for 14 h. DMF (30 ml), 10% aqueous KOH (5.6 ml, 10 mmol), and alkyl halide 3e–h (10 mmol) were then successively added. The reaction mixture was stirred for 30 h and diluted with an equal volume of H₂O. The formed precipitate was filtered off, washed with H₂O (20 ml), EtOH, and hexane.

6-Benzyloxy-2-ethylsulfanyl-4-methylnicotinonitrile (4а). Yield 2.2 g (77%), colorless crystals, mp 78–80°С (AсOH). IR spectrum, ν, cm^–1: 2218 (C≡N). ¹H NMR spectrum, δ, ppm (J, Hz): 1.21 (3H, t, J = 7.3, CH₃СH₂); 2.33 (3H, s, CH₃); 3.14 (2H, q, J = 7.3, CH₃СH₂); 5.43 (2H, s, СH₂O); 6.66 (1H, s, H-5 Py); 7.21–7.48 (5H, m, H Ph). ¹³C NMR spectrum, δ, ppm: 15.1; 20.1; 24.6; 68.3; 100.1; 107.4; 115.8; 128.0 (2С); 128.4; 128.9 (2С); 137.0; 155.0; 162.4; 164.2. Found, m/z: 285.1056 [M+H]⁺. C₁₆H₁₇N₂OS. Calculated, m/z: 285.0983. Found, %: С 67.46; H 5.55; N 9.73. C₁₆H₁₆N₂OS. Calculated, %: С 67.58; H 5.67; N 9.85.

Propyl 2-[(6-allyloxy-3-cyanopyridin-2-yl-4-methyl)-sulfanyl]acetate (4b). Yield 2.1 g (68%), colorless plates, mp 68–70°С (AсOH). IR spectrum, ν, cm^–1: 2215 (C≡N), 1707 (С=O). ¹H NMR spectrum, δ, ppm (J, Hz): 0.78 (3H, t, J = 7.5, СH₃СH₂СH₂); 1.42–1.61 (2H, m, СH₃СH₂СH₂); 2.34 (3H, s, CH₃); 3.98 (2H, t, J = 6.6, СH₃СH₂СH₂); 4.10 (2H, s, SCH₂); 4.79 (2H, d, J = 11.7, OСH₂СH); 5.24 (1H, d, J_cis = 11.7, СH₂=); 5.33 (1H, d, J_trans = 17.2, СH₂=); 5.89–6.14 (1H, m, =СH); 6.64 (1H, s, H-5 Py). ¹³C NMR spectrum, δ, ppm: 10.5; 20.0; 21.8; 32.6; 67.1; 67.5; 99.5; 107.7; 115.6; 118.7; 133.3; 155.1; 161.2; 164.1; 169.0. Found, m/z: 307.1111 [M+H]⁺. C₁₅H₁₉N₂O₃S. Calculated, m/z: 307.1038. Found, %: С 58.74; H 5.84; N 9.03. C₁₅H₁₈N₂O₃S. Calculated, %: С 58.80; H 5.92; N 9.14.

6-Allyloxy-2-benzylsulfanyl-4-methylnicotinonitrile (4с). Yield 2.3 g (79%), colorless crystals, mp 66–68°С (AсOH). IR spectrum, ν, cm^–1: 2220 (C≡N). ¹H NMR spectrum, δ, ppm (J, Hz): 2.33 (3H, s, CH₃); 4.50 (2H, s, SCH₂); 4.87 (2H, d, J = 5.0, OСH₂); 5.22 (1H, d, J_cis = 10.5, СH₂=); 5.34 (1H, d, J_trans = 17.5, СH₂=); 5.81–6.15 (1H, m, =СH); 6.60 (1H, s, H-5 Py); 7.23 (1H, t, J = 7.5, H Ph); 7.30 (2H, t, J = 7.5, H Ph); 7.39 (2H, t, J = 7.5, H Ph). ¹³C NMR spectrum, δ, ppm: 21.3; 33.9; 66.8; 99.3; 106.4; 115.1; 117.6; 126.8; 127.3 (2С); 127.9 (2С); 132.5; 137.1; 154.0; 158.2; 163.3. Mass spectrum, m/z (I_rel, %): 297 [M+H]⁺ (100). Found, %: С 68.75; H 5.39; N 9.33. C₁₇H₁₆N₂OS. Calculated, %: С 68.85; H 5.49; N 9.45.

2-Benzylsulfanyl-6-[2-(4-chlorophenyl)-2-oxoethyl]-4-methylnicotinonitrile (4d). Yield 3.3 g (81%), colorless needles, mp 101–103°С (AсOH). IR spectrum, ν, cm^–1: 2217 (C≡N), 1702 (С=O). ¹H NMR spectrum, δ, ppm (J, Hz): 2.40 (3H, s, CH₃); 4.14 (2H, s, SCH₂); 5.83 (2H, s, OСH₂); 6.82 (1H, s, H-5 Py); 7.11–7.23 (5H, m, H Ph); 7.57 (2H, d, J = 8.4, H Ar); 7.97 (2H, d, J = 8.4, H Ar). ¹³C NMR spectrum, δ, ppm: 20.2; 33.9; 69.0; 100.3; 107.8; 115.5; 127.5; 128.7 (2С); 128.8 (2С); 129.5 (2С); 130.2 (2С); 133.1; 137.0; 139.3; 155.5; 161.5; 163.7; 193.2. Mass spectrum, m/z (I_rel, %): 409 [M+H]⁺ (100). Found, %: С 64.24; H 4.08; N 6.79. C₂₂H₁₇ClN₂O₂S. Calculated, %: С 64.62; H 4.19; N 6.85.

2-Benzylsulfanyl-6-methoxy-4-methylnicotinonitrile (4е). Yield 2.0 g (75%), colorless crystals, mp 114–116°С (AсOH). IR spectrum, ν, cm^–1: 2219 (С≡N). ¹H NMR spectrum, δ, ppm (J, Hz): 2.34 (3H, s, CH₃); 3.94 (3H, s, CH₃O); 4.54 (2H, s, СH₂); 6.61 (1H, s, H-5 Py); 7.25 (1H, t, J = 7.5, H Ph); 7.31 (2H, t, J = 7.5, H Ph); 7.41 (2H, d, J = 7.0, H Ph). ¹³C NMR spectrum, δ, ppm: 20.1; 34.0; 54.8; 99.7; 107.5; 115.8; 127.8; 129.0 (2С); 129.2 (2С); 137.9; 154.9; 161.9; 164.9. Mass spectrum, m/z (I_rel, %): 271 [M+H]⁺ (100). Found, %: С 66.55; H 5.14; N 10.27. C₁₅H₁₄N₂OS. Calculated, %: С 66.64; H 5.22; N 10.36.

2-Ethylsulfanyl-4-methyl-6-(prop-2-yn-1-yloxy)nicotinonitrile (4f). Yield 1.8 g (76%), colorless powder, mp 75–77°С (EtOH). IR spectrum, ν, cm^–1: 3300 (≡С–H), 2256 (С≡С), 2218 (С≡N). ¹H NMR spectrum, δ, ppm (J, Hz): 1.31 (3H, t, J = 7.3, СH₃СH₂); 2.34 (3H, s, CH₃); 3.21 (2H, q, J = 7.3, СH₃СH₂); 3.52 (1H, s, HС≡С); 5.02 (2H, s, СH₂); 6.62 (1H, s, H-5 Py). ¹³C NMR spectrum, δ, ppm: 15.3; 20.1; 24.8; 54.5; 78.2; 79.3; 100.5; 107.2; 115.6; 155.2; 162.4; 163.2. Mass spectrum, m/z (I_rel., %): 233 [M+H]⁺ (100). Found, %: С 61.96; H 5.14; N 11.92. C₁₂H₁₂N₂OS. Calculated, %:С 62.04; H 5.21; N 12.06.

7-Methyl-5-oxo- N -phenyl-3,5-dihydro-2 H -thiazolo-[3,2- a ]pyridine-8-carboxamide (10). Morpholine (3 drops) was added to a mixture of ethyl β-(morpholin-4-yl)-crotonate (1) (2.0 g, 10 mmol), cyanothioacetamide 2b (1.94 g, 10 mmol), 1,2-dibromoethane (3d) 0.9 ml, 10 mmol), and anhydrous EtOH (30 ml) at 20°С; and the resulting mixture was stirred for 30 h. Then, DMF (30 ml) and 10% aqueous KOH (5.6 ml, 10 mmol) were added to the reaction mixture. After 24 h, the reaction mixture was diluted with an equal volume of H₂O. The formed precipitate was filtered off, washed with H₂O (20 ml), EtOH, and hexane. Yield 2.3 g (79%), yellow needles, mp 268–270 °С (AсOH), sublimate into rhombic crystals. IR spectrum, ν, cm^–1: 1664 (СO). ¹H NMR spectrum, δ, ppm (J, Hz): 2.19 (3H, s, CH₃); 3.43 (2H, t, J = 6.4, SCH₂); 4.31 (2H, t, J = 6.4, NCH₂); 6.02 (1H, c, H-5 Py); 7.11 (1H, t, J = 7.6, H Ph); 7.30 (2H, t, J = 7.6, H Ph); 7.60 (2H, d, J = 7.6, H Ph); 10.18 (1H, br. s, NH). ¹³C NMR spectrum, δ, ppm: 20.0; 28.6; 51.1; 112.6; 114.4; 120.0 (2С); 124.2; 129.2 (2С); 139.2; 149.4; 150.4; 160.4; 164.6. Found, m/z: 287.0851 [M+H]⁺. Calculated, m/z: 287.0849. Found, %: С 62.86; H 4.88; N 9.69. C₁₅H₁₄N₂O₂S. Calculated, %: С 62.92; H 4.93; N 9.78.

Ethyl 2-[(3,5-dicyano-4,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridin-2-yl)sulfanyl]acetate (13). Na (0.23 g, 10 mmol) in anhydrous EtOH (10 ml) was added with stirring to a solution of cyanomethylbutene 11 (1.53 g, 10 mmol) and cyanothioacetamide 2a (1.0 g (10 mmol) in anhydrous EtOH (15 ml). The resulting mixture was stirred for 15 min and kept for 24 h. Then, ethyl chloroacetate (12) (1.1 ml, 10 mmol) was added to the mixture, stirring was continued for 4 h, and the mixture was diluted with an equal volume of H₂O. The formed precipitate was filtered off, washed with H₂O (20 ml), EtOH, and hexane. Yield 2.2 g (74%), colorless plates, mp 133–135°С (AсOH). IR spectrum, ν, cm^–1: 3300 (NH), 2202 (C≡N), 1708 (C=O), 1666 (CONH). ¹H NMR spectrum, δ, ppm (J, Hz): 1.11 (3H, s, CH₃); 1.17 (3H, t, J = 7.1, СH₃СH₂); 1.30 (3H, s, CH₃); 3.90 (1H, d, ²J = 15.7, SCH₂); 3.95 (1H, d, ²J = 15.7, SCH₂); 4.09 (2H, q, J = 7.1, OСH₂); 4.53 (1H, s, H-5 Py); 11.22 (1H, br. s, NH). ¹³C NMR spectrum, δ, ppm: 14.4; 22.3; 29.7; 32.8; 36.6; 46.5; 61.9; 100.0; 115.1; 116.2; 145.2; 162.9; 168.3. Found, m/z: 292.0761 [M–1]–. C₁₃H₁₄N₃O₃S. Calculated, m/z: 292.0834. Found, %: С 53.16; H 5.06; N 14.22. C₁₃H₁₅N₃O₃S. Calculated, %: С 53.23; H 5.15; N 14.32.

Synthesis of tetrahydro-2 H -thiazolo[3,2- а ]pyridines 16 and 17 (General method). Na (0.23 g, 10 mmol) in anhydrous EtOH (10 ml) was added with stirring to a solution of cyanomethylbutene 11 (1.53 g, 10 mmol), and cyanothioacetamide 2a (1.00 g, 10 mmol) or ethyl 3-amino-3-thioxopropanoate (2c) (1.5 g, 10 mmol) in anhydrous EtOH (15 ml). The resulting mixture was stirred for 15 min and kept for 24 h. Then, 1,2-dibromoethane (3d) (0.9 ml, 10 mmol) was added to the mixture, stirring was continued for 4 h. 10% Aqueous KOH (5.6 ml, 10 mmol) was then added, the mixture was stirred for 15 min and kept for 24 h. The reaction mixture was diluted with an equal volume of H₂O. The formed precipitate was filtered off and dissolved in DMSO (20 ml). 10% Aqueous KOH (5.6 ml, 10 mmol) and benzyl chloride (3c) (1.15 ml, 10 mmol) or 2-bromoacetophenone (15) (1.99 g, 10 mmol) were then successively added. Stirring was continued for 2 h, and the mixture was kept for 24 h. It was then diluted with an equal volume of H₂O. The formed precipitate was filtered off, washed with H₂O (20 ml), EtOH, and hexane.

Ethyl 6-benzyl-6-cyano-7,7-dimethyl-5-oxo-3,5,6,7-tetrahydro-2 H -thiazolo[3,2- а ]pyridine-8-carboxylate (16). Yield 2.5 g (71%), colorless powder, mp 150–152°С (EtOH). IR spectrum, ν, cm^–1: 2244 (C≡N), 1707 (C=O), 1666 (C=O). ¹H NMR spectrum, δ, ppm (J, Hz): 1.22 (3H, s, CH₃); 1.25 (3H, t, J = 7.1, СH₃СH₂); 1.54 (3H, s, CH₃); 2.94 (1H, d, ²J = 13.8, CH₂Ph); 3.15 (1H, d, ²J = 13.8, CH₂Ph); 3.17–3.28 (2H, m, SCH₂); 3.73–3.86 (1H, m, NСH₂); 3.98–4.13 (1H, m, NСH₂); 4.16 (2H, q, J = 7.1, OСH₂); 7.06 (2H, d, J = 6.9, H Ph); 7.19–7.32 (3H, m, H Ph). ¹³C NMR spectrum, δ, ppm: 17.4; 22.6; 25.1; 27.9; 36.9; 42.1; 49.0; 60.5; 60.8; 105.1; 117.9; 128.0; 128.8 (2C); 130.2 (2C); 134.8; 151.4; 162.1; 166.2. Found, m/z: 371.1432 [M+H]⁺. Calculated, m/z: 371.1424. Found, %: С 64.76; H 5.86; N 7.49. C₂₀H₂₂N₂O₃S. Calculated, %: С 64.85; H 5.99; N 7.56.

7,7-Dimethyl-5-oxo-6-(2-oxo-2-phenylethyl)-3,5,6,7-tetrahydro-2 H -thiazolo[3,2- a ]pyridine-6,8-dicarbonitrile (17). Yield 2.5 g (70%), colorless prisms, mp 166–168°С (AсOH). IR spectrum, ν, cm^–1: 2248 (C≡N), 1707, 1668 (C=O). ¹H NMR spectrum, δ, ppm (J, Hz): 1.25 (3H, s, CH₃); 1.34 (3H, s, CH₃); 3.25–3.48 (2H, m, СH₂S); 3.59 (2H, s, СH₂); 3.82–3.94 (1H, m, СH₂N); 4.11–4.23 (1H, m, СH₂N); 7.52 (2H, t, J = 7.0, H Ph); 7.67 (1H, t, J = 7.0, H Ph); 7.98 (2H, d, J = 7.0, H Ph). ¹³C NMR spectrum, δ, ppm: 22.3; 24.0; 29.1; 32.5; 42.0; 50.8; 51.7; 86.5; 117.0; 117.3; 128.8 (2С); 129.1 (2С); 134.1; 136.6; 154.2; 161.3; 195.5. Found, m/z: 352.1115 [M+H]⁺. C₁₉H₁₇N₃O₂S. Calculated, m/z: 352.1114.

X-ray structural analysis of compounds 4a,b, 13, and 17 was performed on the BELOK synchrotron station of the National Research Center “Kurchatov Institute” using a Rayonix SX165 CCD two-dimensional detector (100.0(2) K, λ 0.96990 Å, φ-scanning with a 1.0° step). Experimental data were processed using the iMOSFLM program included in the CCP4 software package.¹² The correction for X-ray absorption for the obtained data was done using the Scala software.¹³ All calculations were performed using the SHELXTL software package.¹⁴

Compound 4a. Colorless plates (C₁₆H₁₆N₂OS, M 284.37), triclinic, space group $P\overline{1}$; a 7.1700(11), b 8.3464(12), c 12.2736(19) Å; α 88.844(10), β 84.381(11), γ 84.474(12)°; V 727.53(19) ų; Z 2; d_calc 1.298 g/cm³; F(000) 300; μ 0.506 mm^–1. A total of 9830 reflections were collected (2876 independent reflections, R_int 0.079, 2θ 76.80°). The structure was solved by direct methods and refined by the least squares technique against F² in the full-matrix anisotropic approximation for non-hydrogen atoms. The positions of hydrogen atoms were calculated geometrically and included in the refinement with fixed positional parameters (the rider model) and isotropic displacement parameters (U_iso(H) = 1.5U_eq(C) for CH₃ group and U_iso(H) = 1.2U_eq(C) for the remaining groups). The final probability factors R₁ 0.062 for 2409 independent reflections with I ≥ 2σ(I) and wR₂ 0.125 for all independent reflections, S 1.068. Maximum and minimum values of the peaks of residual electron density were 0.35 and –0.47 e/ų, respectively. The full set of X-ray structural data for compound 4a was deposited at the Cambridge Crystallographic Data Center (deposit CCDC 2013812)

Compound 4b. Colorless plates (C₁₅H₁₈N₂O₃S, M 306.37), monoclinic, space group P2₁/c; a 12.1141(14), b 7.3360(9), c 17.9322(19) Å; β 91.166(14)°; V 1593.3(3) ų; Z 4; d_calc 1.277 g/cm³; F(000) 648; μ 0.494 mm^–1. A total of 20726 reflections were collected (2977 independent reflections, R_int 0.054, 2θ 76.90°). The structure was solved by direct methods and refined by the least squares technique against F² in the full-matrix anisotropic approximation for non-hydrogen atoms. The positions of hydrogen atoms were calculated geometrically and included in the refinement with fixed positional parameters (the rider model) and isotropic displacement parameters (U_iso(H) = 1.5U_eq(C) for CH₃ group and U_iso(H) = 1.2U_eq(C) for the remaining groups). The final probability factors R₁ 0.045 for 2511 independent reflections with I ≥ 2σ(I) and wR₂ 0.119 for all independent reflections, S 1.098. Maximum and minimum values of the peaks of residual electron density were 0.33 and –0.44 e/ų, respectively. The full set of X-ray structural data for compound 4b was deposited at the Cambridge Crystallographic Data Center (deposit CCDC 2013813).

Compound 13. Colorless plates (C₁₃H₁₅N₃O₃S, M 293.34), triclinic, space group $P\overline{1}$; a 6.9299(11), b 10.1301(15), c 10.6602(16) Å; α 71.220(11), β 84.130(12), γ 86.331(12)°; V 704.41(19) ų; Z 2; d_calc 1.383 g/cm³; F(000) 308; μ 0.557 mm^–1. A total of 5935 reflections were collected (2346 independent reflections, R_int 0.065, 2θ 76.84°). The structure was solved by direct methods and refined by the least squares technique against F² in the full-matrix anisotropic approximation for non-hydrogen atoms. The hydrogen atom of the amino group is localized objectively in difference Fourier syntheses and included in the refinement with fixed positional parameters (the rider model) and isotropic displacement parameters (U_iso(H) = 1.2U_eq(N)). The rest of the hydrogen atoms, the positions of which were calculated geometrically, and included in the refinement with fixed positional parameters (the rider model) and isotropic displacement parameters (U_iso(H) = 1.5U_eq(C) for CH₃ group and U_iso(H) = 1.2U_eq(C) for the remaining groups). The final probability factors R₁ 0.053 for 1873 independent reflections with I ≥ 2σ(I) and wR₂ 0.157 for all independent reflections, S 1.099. Maximum and minimum values of the peaks of residual electron density were 0.44 and −0.54 e/ų, respectively. The full set of X-ray structural data for compound 13 was deposited at the Cambridge Crystallographic Data Center (deposit CCDC 2013814).

Compound 17. Colorless prisms (C₁₉H₁₇N₃O₂S, M 351.42), triclinic, space group $P\overline{1}$; a 8.2999(12), b 10.3501(15), c 10.9502(16) Å; α 107.470(11), β 95.711(11), γ 98.639(12)°; V 876.6(2) ų; Z 2; d_calc 1.331 g/cm³; F(000) 368; μ 0.463 mm^–1. A total of 12885 reflections were collected (3011 independent reflections, R_int 0.048, 2θ 76.80°). The structure was solved by direct methods and refined by the least squares technique against F² in the full-matrix anisotropic approximation for non-hydrogen atoms. The positions of hydrogen atoms were calculated geometrically and included in the refinement with fixed positional parameters (the rider model) and isotropic displacement parameters (U_iso(H) = 1.5U_eq(C) for CH₃ and U_iso(H) = 1.2U_eq(C) for the remaining groups). The final probability factors R₁ 0.041 for 2672 independent reflections with I ≥ 2σ(I) and wR₂ 0.111 for all independent reflections, S 1.018. Maximum and minimum values of the peaks of residual electron density were 0.30 and −0.33 e/ų, respectively. The full set of X-ray structural data for compound 17 was deposited at the Cambridge Crystallographic Data Center (deposit CCDC 2013815).