Chemical modification and Physicochemical properties of new derivatives 5-(thiophen-3-ilmethyl)-4-R₁-1,2,4-triazole-3-thiol

 

O.A. Bihdan*, V.V. Parchenko

Zaporizhzhya State Medical University, Ukraine.

 

ABSTRACT:

Current trends in the search for new biologically active compounds among synthetic molecules have arguably proved a priority in studies of the heterocyclic 1,2,4-triazole system. For many years, 1,2,4-triazole derivatives remain the object of close attention of scientists of various scientific fields. The unique properties of 1,2,4-triazole derivatives include high reactivity, which allows different modification of this system, practical absence of toxicity of these derivatives and the presence of a wide range of biological, pharmacological properties, which in the complex provides the prerequisites for the creation of new biologically active compounds, and in the future, active pharmaceutical ingredients (AFI). The aim of our work is to investigate some transformations in a number of derivatives of 5-(thiophen-3-ylmethyl) -4-R₁-1,2,4-triazole-3-thiol, to study the physicochemical properties of the new synthesized compounds. A well-known fact remains the successful attempt of many scientists involved in the study of the heterocyclic 1,2,4-triazole system to synthesize potential biologically active compounds. The process of creating new molecules is very painstaking and requires considerable effort. The chemical approaches for the synthesis of the starting compounds required for further transformations are well known and described. Therefore, we used the corresponding N-R₁-2 as intermediates for the synthesis of new 5-(thiophen-3-ylmethyl) -4-R₁-1,2,4-triazole-3-thiols appropriate ones were used N-R₁-2-(2-(thiophen-3-yl) acetyl) hydrazinocarbothioamide.

 

 

 

INTRODUCTION:

Current trends in the search for new biologically active compounds among synthetic molecules have arguably proved a priority in studies of the heterocyclic 1,2,4-triazole system^1,2. For many years, 1,2,4-triazole derivatives remain the object of close attention of scientists of various scientific fields^3,4. The unique properties of 1,2,4-triazole derivatives include high reactivity, which allows different modification of this system, practical absence of toxicity of these derivatives and the presence of a wide range of biological, pharmacological properties, which in the complex provides the prerequisites for the creation of new biologically active compounds, and in the future, active pharmaceutical ingredients (AFI)^4,5.

 

Earlier, we reported that the introduction of 1,2,4-triazole derivatives of fluorophenyl substituents into the molecules promotes the appearance of biological activity². Further chemical modification of the fluorophenyl derivatives of 1,2,4-triazole contributes to the expansion of the range of promising molecules⁴. It is also a well-known fact that some furan derivatives of 1,2,4-triazole are a promising class of compounds that exhibit different types of biological activity^5-8. It is worth mentioning separately the scientific successes of the combination of the thiophene fragment and the 1,2,4-triazole nucleus^9,10. The authors investigated other thiophene derivatives as potential anti-corrosion agents, the effectiveness of which was due to the blocking of active sites on a steel surface¹¹. As biologically active compounds, a series of new 3-alkylthio-5-pyridyl-1,2,4-triazoles has been studied¹². Among them, compounds with anti-inflammatory action were found. A team of scientists discovered antimicrobial activity in new 3-substituted-4H-1,2,4-triazole derivatives¹³. Thus, in our opinion, further chemical modification of 1,2,4-triazole derivatives by the additional introduction of a typical thiophene pharmacophore is a scientifically grounded and relevant task and can assist in the implementation phase of new low-toxic compounds. It should also be noted the presence of anti-corrosion properties in 4-amino-3-phenyl-1,2,4-triazole-5-thiols. In the present investigation 4-amino-3-phenyl-5-mercapto-1, 2, 4-triazole has been synthesized and studied as inhibitor for the corrosion of copper in 3.5 % NaCl solution. The inhibition efficiency of the compound have been evaluated by weight loss and electrochemical methods (Impedance spectroscopy and polarization curves)¹⁴. The authors investigated another group of promising derivatives of 1,2,4-triazole¹⁵. In addition, in a review article, the authors reasonably prove the presence of a wide range of biological properties in derivatives of 1,2,4-triazole¹⁶. Thiosemicarbazides containing a 1,2,4-triazole fragment as biologically and pharmacologically active compounds deserve special attention¹⁷. Promising according to the authors is a group of compounds for which investigated synthesis and biological evaluation^{18, 19}.

 

The aim of our work is to investigate some transformations in a number of derivatives of 5-(thiophen-3-ylmethyl)-4-R₁-1,2,4-triazole-3-thiol, to study the physicochemical properties of the new synthesized compounds.

 

MATERIALS AND METHODS:

A well-known fact remains the successful attempt of many scientists involved in the study of the heterocyclic 1,2,4-triazole system to synthesize potential biologically active compounds^1,3. The process of creating new molecules is very painstaking and requires considerable effort². The chemical approaches for the synthesis of the starting compounds required for further transformations are well known and described⁶. Therefore, we as intermediates for the synthesis of new ones 5- (thiophen-3-ylmethyl)-4-R₁-1,2,4-triazol-3-thiols (compounds 3, 4 of Fig. 1), the corresponding N-R₁-2-(2-(thiophen-3-yl)acetyl) hydrazinocarbothioamides (compounds 1, 2 of Fig. 1).

 

Further transformations were performed by adding equivalent amounts of chloroethanol in an alkaline methanol medium to 5- (thiophene-3-ylmethyl) -4-methyl-1,2,4-triazole-3-thiol (compound 3) and to 5- (thiophene-3 -ylmethyl) -4-ethyl-1,2,4-triazole-3-thiol (compound 4). In each case, the mixture is refluxed for 3 hours, filtered, and the solvent is evaporated. Compounds were obtained with high yields (5, 6 Fig. 1).

 

The next stage of the study was to investigate the interaction of the corresponding 5-(thiophen-3-ylmethyl)-4-R₁-1,2,4-triazole-3-thiols (compounds 3, 4) with 2-bromo-1-arylethanones: 2-bromo-1-(2-bromophenyl)ethanone, 2-bromo-1-(3-fluorophenyl) ethanone and 2-bromo-1-(4-fluorophenyl) ethanone. The reaction was carried out under similar conditions described in⁶. In each case, equivalent amounts of the corresponding 2-bromo-1 were added to the corresponding 5-(thiophen-3-ylmethyl) -4-R₁-1,2,4-triazole-3-thiols (compounds 3, 4) in an alkaline methanol medium. -arylethanones. The mixture is boiled for 4 hours, filtered, the solvent is evaporated. After high-yield crystallization, compounds were obtained (7-11, Fig. 1).

 

Continuing to expand the range of potential biologically active compounds, we have reacted 5- (thiophen-3-ylmethyl) -4-R₁-1,2,4-triazole-3-thiols (compounds 3, 4) with 2-phenylacetyl chloride and 3- fluorobenzoyl chloride (Fig. 1). The reactions were carried out in an alkaline medium in the presence of methanol. In each case, equivalent amounts of the compounds were mixed. The mixture is boiled for 4 hours, filtered, the solvent is evaporated, the compounds are obtained (12-15, Fig. 1).

 

Scientific publications have shown that the presence of alcohol hydroxyl in the molecule reduces its toxicity and leads to the emergence of new types of pharmacological action [5, 6]. Therefore, in the next stage of work, we considered it advisable to synthesize a number of new alcohols (Fig. 2). To the corresponding 2-((4-R₁-5- (thiophen-3-ylmethyl)-1,2,4-triazol-3-yl) thio)-1-arylethanone in each case was added 20 ml of methanol, heated to 35 degrees to complete dissolution and gradually with stirring add a double excess of sodium borohydride. The solution was stirred for 24 hours, the solvent was evaporated, 50 ml of water was added to the precipitate, filtered. The precipitate crystallizes. Thus, a number of new thio derivatives are obtained (compounds 16-24, Fig. 2).

 

Carrying out a comparative analysis of information from scientific sources, our attention was drawn to the possibility of modification of the thio-derivative molecule 1,2,4-triazole due to the additional introduction of functional substitutes^{2, 6}. Therefore, we considered it necessary to

 

Using the compounds that were synthesized earlier (compounds 5, 6, 16-24) as starting materials, we performed the transformation (Fig. 3). To the corresponding compounds (5, 6, 16-24) in each case add excess acetic anhydride and heat in a water bath for 6 hours until complete dissolution of the precipitates, cool, in each case add water, leave for 24 hours. The precipitates thus formed are filtered off, crystallized, and compounds obtained (25-35, Fig. 3).investigate the acylation of some thio-derivatives of 5-(thiophen-3-ylmethyl)-4-R₁-1,2,4-triazole-3-thiols (Fig. 3).

The structure of the synthesized compounds in all cases is confirmed by modern physicochemical methods of analysis, and their individuality - chromatographically.

 

RESULTS AND DISCUSSION:

It is known that 1,2,4-triazole derivatives are the subject of attention of scientists in various fields due to the many unique properties of this heterocycle^{1, 4}. By constantly replenishing, the "libraries" of the original compounds create favorable conditions for the search for new biologically active molecules, which in the future may be active pharmaceutical ingredients of drugs, substances of plant growth regulators, etc.^{7, 8}. The physicochemical properties of the synthesized compounds 3-35 are shown in Table 1.

 

4-R₁-5-(thiophen-3-ylmethyl)-1,2,4-triazole-3-thiol (compounds 3, 4), 2-((4-R₁-5-(thiophen-3-ylmethyl)-1,2,4-triazol-3-yl)thio)ethanol (compounds 5, 6), 1-R₂-2-((4-R₁-5-(thiophen-3-ylmethyl)-1,2,4- triazol-3-yl)thio)ethanones (compounds 7-11), 4-R₁-5-(thiophen-3-ylmethyl)-1,2,4-triazol-3-yl)-2-phenylethanethioate (compounds 12, 13), 4-R₁-5-(thiophen-3-ylmethyl)-1,2,4-triazol-3-yl)-3-fluorobenzothioate (Compounds 14, 15), 1-R₂-2-((4- R₁-5-(thiophen-3-ylmethyl)-1,2,4-triazol-3-yl)thio)ethanol (Compounds 16-20), 1-((4-R₁-5-(thiophen-3-ylmethyl))-1,2,4-triazol-3-yl)thio)-2-phenylethanol (compounds 21, 22), (3-fluorophenyl)((4-R₁-5-(thiophen-3-ylmethyl)-1,2,4-triazol-3-yl)thio)methanols (compounds 23, 24), 2-((4-R₁-5-(thiophen)-3-ylmethyl)-1,2,4-triazol-3-yl)thio)ethyl acetate (compounds 25, 26), 1-R₂-2-((R₁-5-(thiophen-3-ylmethyl)-1,2,4-triazol-3-yl)thio) ethyl acetate (compounds 27-31), 1-((4-R₁-5-(thiophen-3-ylmethyl)-1,2,4-triazol-3-yl)thio)-2-phenylethyl acetate (compounds 32, 33), (3-fluorophenyl) ((4-R₁-5-(thiophen-3-ylmethyl)-1,2,4-triazol-3-yl)thio)methyl acetate (compounds 34, 35) individual crystalline compounds of white (compounds 3, 4, 22, 26, 27, 32, 33), yellow (compounds 5, 6, 7, 11-13, 19, 23, 25, 28-31, 34), red (compounds 8, 10, 18, 24, 35), brown (compounds 9, 16, 21) and orange (compounds 14, 15, 17, 20), insoluble in water. For analysis, recrystallized from 1,4-dioxane (compounds 3, 4), methanol (compounds 5-24), acetic acid (compounds 25-35).

 

Melting points were determined in open capillary tubes in a “Stanford Research Systems Melting Point Apparatus 100” (SRS, USA). The elemental analysis (C, H, N, S) were performed using the “Elementar vario EL cube” analyzer (Elementar Analysensysteme, Germany). The ¹H NMR spectra were recorded invDMSO-d 6 at 400 MHz on a Varian MR-400 spectrometer and analysed with ADVASP™ Analyzer programv (Umatek International Inc.); chemical shifts are reported in ppm (δ scale) down field with residual protonsvof the solvent (DMSO-d 6, δ = 2.49 ppm) as internal standard. The EI mass spectra were obtained on Varian 1200L with electron energy 70 eV.

 

1, 3, 5, 12, 14 R₁=CH₃; 2, 4, 6, 13, 15 R₁=C₂H₅; 7 R₁=CH₃, R₂=2-Br; 8 R₁=CH₃, R₂=3-F; 9 R₁=CH₃, R₂=4-F; 10 R₁=C₂H₅, R₂=2-Br; 11 R₁=C₂H₅, R₂=4-F

Fig. 1 Synthesis scheme for thio-derivatives of 5-(thiophen-3-ylmethyl)-4-R₁-1,2,4-triazol-3-thiols

 

 

16 R₁=CH₃, R₂=2-Br; 17 R₁=CH₃, R₂=3-F; 18 R₁=CH₃, R₂=4-F; 19 C₂H₅, R₂=2-Br; 20 C₂H₅, R₂=4-F; 21, 23 R₁=CH₃; 22, 24 R₁=C₂H₅

Fig. 2 Recovery scheme for 2-((4-R₁-5-(thiophen-3-ylmethyl)-1,2,4-triazol-3-yl)thio)-1-arylethanones

 

25, 32, 34 R₁=CH₃; 26, 33, 35 R₁=C₂H₅; 27 R₁=CH₃, R₂=2-Br; 28 R₁=CH₃, R₂=3-F; 29 R₁=CH₃, R₂=4-F; 30 C₂H₅, R₂=2-Br; 31 C₂H₅, R₂=4-F

Fig. 3 Scheme of acylation of some thio-derivatives of 5-(thiophen-3-ylmethyl)-4-R₁-1,2,4-triazol-3-thiols

 

Table 1: Physico-chemical constants of some S-derivatives of 5-(thiophen-3-ylmethyl)-4-R₁-1,2,4-triazole-3-thiol

Compound	R1	R2	Т ml., оС	Gross formula	Received, %
1	2	3	4	5	6
3	CH3	-	180-182	C8H9N3S2	77
4	C2H5	-	191-193	C9H11N3S2	82
5	CH3	-	162-164	C10H13N3OS2	78
6	C2H5	-	145-147	C11H15N3OS2	76
7	CH3	2-Br	127-129	C16H14BrN3OS2	77
8	CH3	3-F	124-126	C16H14FN3OS2	69
9	CH3	4-F	113-115	C16H14FN3OS2	75
10	C2H5	2-Br	117-119	C17H16BrN3OS2	72
11	C2H5	4-F	107-109	C17H16FN3OS2	70
12	CH3	-	111-115	C16H15N3OS2	67
13	C2H5	-	123-125	C17H17N3OS2	71
14	CH3	-	121-123	C15H12FN3OS2	69
15	C2H5	-	116-118	C16H14FN3OS2	73
16	CH3	2-Br	125-127	C16H16BrN3OS2	69
17	CH3	3-F	133-135	C16H16FN3OS2	71
18	CH3	4-F	121-123	C16H16FN3OS2	74
19	C2H5	2-Br	137-139	C17H18BrN3OS2	73
20	C2H5	4-F	132-134	C17H18FN3OS2	69
21	CH3	-	104-106	C16H17N3OS2	87
22	C2H5	-	113-115	C17H19N3OS2	73
23	CH3	-	109-110	C15H14FN3OS2	70
24	C2H5	-	115-117	C16H16FN3OS2	73
25	CH3	-	141-143	C12H15N3O2S2	64
26	C2H5	-	152-154	C13H17N3O2S2	61
27	CH3	2-Br	134-136	C18H18BrN3O2S2	64
28	CH3	3-F	133-135	C18H18FN3O2S2	68
29	CH3	4-F	128-130	C18H18FN3O2S2	67
30	C2H5	2-Br	140-142	C19H20BrN3O2S2	67
31	C2H5	4-F	143-145	C19H20FN3O2S2	63
32	CH3	-	125-127	C18H19N3O2S2	71
33	C2H5	-	129-131	C19H21N3O2S2	65
34	CH3	-	126-128	C17H16FN3O2S2	68
35	C2H5	-	135-137	C18H18FN3O2S2	65

Continued tab. 1

Compound	Found, %				Calculated, %
	C	H	N	S	C	H	N	S
1	7	8	9	10	11	12	13	14
3	45,37	4,29	19,93	30,28	45,47	4,29	19,89	30,35
4	48,05	4,91	18,68	28,40	47,97	4,92	18,65	28,46
5	47,12	5,12	16,49	25,04	47,03	5,13	16,46	25,11
6	49,14	5,60	15,63	23,75	49,04	5,61	15,60	23,81
7	47,14	3,47	10,26	15,68	47,06	3,46	10,29	15,71
8	55,40	4,05	12,07	18,49	55,31	4,06	12,09	18,46
9	55,20	4,05	12,11	18,49	55,31	4,06	12,09	18,46
10	48,24	3,83	9,93	15,20	48,34	3,82	9,95	15,18
11	56,60	4,45	11,60	17,77	56,49	4,46	11,63	17,74
12	58,05	4,49	12,75	19,37	58,53	4,52	12,73	19,42
13	59,56	4,98	12,20	18,70	59,45	4,99	12,29	18,67
14	55,20	4,07	5,48	18,42	55,31	4,06	5,47	18,46
15	54,13	3,64	12,57	19,20	54,04	3,63	12,60	19,29
16	46,74	3,92	10,26	15,65	46,83	3,93	10,24	15,63
17	54,90	4,63	12,04	18,32	54,99	4,62	12,02	18,35
18	55,02	4,63	12,00	18,38	54,99	4,62	12,02	18,35
19	48,01	4,27	9,92	15,14	48,11	4,23	9,90	15,11
20	56,06	4,98	11,58	17,60	56,18	4,99	11,56	17,64
21	58,00	5,18	12,65	19,31	57,98	5,17	12,68	19,35
22	59,00	5,55	12,13	18,52	59,10	5,54	12,16	18,56
23	53,61	4,29	12,51	19,15	53,71	4,21	12,53	19,12
24	54,87	4,63	12,05	18,31	54,99	4,62	12,02	18,35
25	48,56	5,07	14,15	21,52	48,46	5,08	14,13	21,56
26	50,05	5,49	13,51	20,55	50,14	5,50	13,49	20,59
27	47,70	40,20	17,69	14,16	47,79	4,01	17,66	14,18
28	55,30	4,64	10,71	16,35	55,22	4,63	10,79	16,38
29	55,31	4,62	10,75	16,95	55,22	4,63	10,79	16,38
30	48,01	4,33	8,99	13,77	48,10	4,32	9,01	13,75
31	56,39	4,98	10,33	15,77	56,28	4,97	10,36	15,81
32	57,75	5,14	11,23	17,20	57,88	5,13	11,25	17,17
33	58,77	5,47	10,81	16,58	58,89	5,46	10,84	16,55
34	54,01	4,28	11,10	17,02	54,09	4,27	11,13	16,99
35	55,29	4,62	10,79	16,34	55,22	4,63	10,73	16,38

 

Thorough analysis of the ¹H NMR spectra of the synthesized compounds (3-35, Table 1) shows the reaction and formation of a number of new S-derivatives of 5-(thiophen-3-ylmethyl)-4-R₁-1,2,4-triazole- Of 3-thiol (Table 2). ¹H NMR spectra of thio-derivatives of 5-(thiophene-3-ylmethyl)-4-R₁-1,2,4-triazole-3-thiol derivatives (7-15, Fig. 1), typical thiophene cycle signals observed in the region typical of aromatic compounds in the form of multiplets or doublets at 6,94-7.10 ppm and 7,25-7,85 ppm, also in this area there are signals of the phenyl radical.

 

The singlet signal of methylene spacers is detected in a weak field. Methyl at the N¹ atom of 1,2,4-triazole heterocycle is recorded as singlet and ethyl as triplet and quintet or complex multiplets. ₁H NMR spectrum of 1-(4-fluorophenyl)-2-((4-methyl-5-(thiophen-3-ylmethyl)-1,2,4-triazol-3-yl)thio)ethanone (9) is shown in Figure 4.

 

Figure 4: ¹H NMR spectrum of 1-(4-fluorophenyl)-2-((4-methyl-5-(thiophen-3-ylmethyl)-1,2,4-triazol-3-yl)thio)ethanone (9 ).

 

Fig. 6 ¹H NMR spectrum of (3-fluorophenyl) ((4-ethyl-5-(thiophen-3-ylmethyl)-1,2,4-triazol-3-yl)thio)methyl acetate (35).

 

The ¹H NMR spectra of the acylation products of some thio-derivatives of 5-(thiophen-3-ylmethyl)-4-R₁-1,2,4-triazol-3-thiols are characterized by a single acyl methyl signal in the area of 2.60-3.39 ppm. By increasing the acceptor effect of the acyl radical, almost all the signals of the compounds are slightly shifted to a weaker field. The signal -S-CH-O- is registered as an extended singlet at 7.28-7.32 ppm. Typical signals of the thiophene and phenyl cycle observed in the region typical of aromatic compounds in the form of multiplets or doublets at 6.82-7.10 ppm and 7.29-7.75 ppm The ¹H NMR spectrum of (3-fluorophenyl) ((4-ethyl-5-(thiophen-3-ylmethyl)-1,2,4-triazol-3-yl)thio)methyl acetate (35) is shown in Figure 6.

 

Table 2: ¹H (500 MHz, DMSO-d6) NMR data of S-derivatives of 5-(thiophen-3-ylmethyl)-4-R₁-1,2,4-triazole-3-thiol

№	R1	δn, m.h.; J, Hz; DMSO -d6
		Methylene linker R1		Phenyl	Thiophene cycle, 3H	Other signals
		-S-CH2-C(O)-	2Н,thienyl-CH2-triazole
3.	3.32 (s, 3 H)		4.08 (s, 2 H)		6.97 (d, J=4.94 Hz, 1 H) 7.32 (br. s., 1 H) 7.46 - 7.54 (m, 1 H)
4.	0.95 (td, J = 7.1, 2.1 Hz, 3H) 3.94 – 3.79 (m, 2H)				6.97 (d, J = 4.9 Hz, 1H) 7.35 (d, J = 3.0 Hz, 1H) 7.50 (dt, J = 4.8, 2.4 Hz, 1H)
5.	3.93 (с, 3 H)		3.14 (d, J = 2.3 Hz, 2H)		7.07 (dd, J = 8.9, 2.4 Hz, 2H) 7.48 (dd, J = 8.8, 2.3 Hz, 1H)	3.14 (d, J = 2.2 Hz, 2H), 4.03 (d, J = 2.2 Hz, 2H), 8.88 (s, 1H)
6.	1.26 (t, J = 8.0 Hz, 3H) 4.14 – 3.99 (m, 2H)		4.14 – 3.99 (m, 2H)		7.22 (dd, J = 6.3, 2.7 Hz, 1H), 6.97 – 6.86 (m, 2H)	3.44 (t, J = 7.1 Hz, 2H), 3.71 (q, J = 6.9 Hz, 2H), 4.66 (t, J = 6.6 Hz, 1H)
7.	3.43 (d, J = 6.5 Hz, 3H)	4.71 (t, J = 3.2 Hz, 2H), ,	4.15 (s, 2H)	7.92 – 7.78 (m, 1H), 7.77 – 7.64 (m, 1H), 7.35 (ddd, J = 19.9, 10.0, 6.3 Hz, 2H)	7.25 (d, J = 3.4 Hz, 1H), 6.94 (dd, J = 5.1, 1.3 Hz, 1H), 7.49 (td, J = 5.7, 5.0, 3.0 Hz, 1H),
8.	3.58 (s, 3H).		4.13 (s, 2H),	7.76 (ddt, J = 8.2, 4.3, 1.5 Hz, 2H), 7.54 (td, J = 7.4, 4.9 Hz, 1H), 7.41 (tt, J = 7.8, 1.5 Hz, 1H),	7.24 (dd, J = 6.5, 2.4 Hz, 1H), 6.97 – 6.87 (m, 2H),
9.	3.42 (s, 3 H)	4.71 (br. s., 2 H)	4.14 (s, 2 H)	7.29 - 7.42 (m, 2 H) 7.47 - 7.52 (m, 1 H) 7.65 - 7.73 (m, 1 H)	6.94 (d, J=4.39 Hz, 1 H) 7.25 (br. s., 1 H) 7.84 (t, J=7.41 Hz, 1 H)
10.	1.05 – 0.89 (m, 3H) ),	4.76 (s, 2H)	4.13 (s, 2H),	7.84 (td, J = 7.6, 2.0 Hz, 1H), 7.68 (tt, J = 7.3, 3.2 Hz, 1H), 7.47 (h, J = 4.5, 3.2 Hz, 1H), 7.41 – 7.30 (m, 1H),	7.41 – 7.30 (m, 1H), 7.28 (d, J = 2.9 Hz, 1H), 6.99 – 6.85 (m, 1H),
11.	1.29 (t, J = 8.0 Hz, 3H). 4.08 (dd, J = 16.1, 8.1 Hz3.86 (q, J = 7.2 Hz, 2H, 2H),	4.92 – 4.74 (m, 2H),	4.08 (dd, J = 16.1, 8.1 Hz, 2H),	8.19 – 8.08 (m, 2H), 7.34 – 7.18 (m, 2H),	7.34 – 7.18 (m, 1H), 6.98 – 6.86 (m, 2H)
12.	2.28 (s, 3 H)	3.33 (br. s., 2 H)	4.09 (s, 2 H)	7.20 - 7.36 (m, 5 H)	6.99 (d, J=4.39 Hz, 1 H) 7.20 - 7.36 (m, 1 H) 7.52 (dd, J=4.94, 2.74 Hz, 1 H)
13.	0.95 (t, J=6.86 Hz, 3 H) 3.88 (q, J=6.77 Hz, 2 H)	3.54 (s, 2 H)	4.10 (s, 2 H)	7.19 - 7.39 (m, 5 H)	6.97 (d, J=4.39 Hz, 1 H) 7.19 - 7.39 (m, 1 H) 7.47 - 7.53 (m, 1 H)
14.	3.35 (с, 3H).	4.78 (br. s., 2 H),	4.12 (s, 2 H)	7.83 (q, J = 7.9, 7.4 Hz, 1H), , 7.64 – 7.41 (m, 3H),	6.93 (ddt, J = 19.5, 14.8, 6.3 Hz, 1H), 7.28 – 7.19 (m, 1H), 7.75 (dd, J = 24.2, 15.5 Hz, 1H)
15.	0.95 (t, J=6.86 Hz, 3 H) 3.88 (d, J=6.59 Hz, 2 H)	—	4.11 (br. s., 2 H)	7.35 (br. s., 1 H) 7.50 (d, J=2.74 Hz, 1 H) 7.62 (d, J=4.94 Hz, 1 H) 7.80 - 7.89 (m, 1 H)	6.97 (d, J=4.39 Hz, 1 H) 7.24 - 7.33 (m, 2 H)
16.	3.62 (s, 3H)	3.67 – 3.50 (m, 2H)	4.17 (s, 2 H)	7.56 (dd, J = 7.2, 1.7 Hz, 1H) 7.31 – 7.20 (m, 1H) 6.98 – 6.87 (m, 2H)	7.40 – 7.26 (m, 2H) 7.31 – 7.20 (m, 1H)	4.66 (d, J = 7.0 Hz, 1H), 5.19 (qd, J = 6.8, 1.0 Hz, 1H)
17.	1.77 (s, 3 H)	4.13 (s, 2 H)	4.13 (s, 2 H)	6.90 - 6.98 (m, 1 H), 7.45 - 7.63 (m, 2 H), 7.84 (d, J=7.68 Hz, 1 H)	7.45 - 7.63 (m, 2 H) 7.77 (d, J=9.88 Hz, 1 H)	4.82 - 4.89 (m, 1 H) 7.28 (br. s., 1 H)
18.	3.13 - 3.18 (с, 3 H)	4.10 (br. s., 2 H)	4.10 (br. s., 2 H)	7.07 - 7.12 (m, 2 H) 7.47 - 7.53 (m, 2 H)	6.94 (d, J=4.94 Hz, 1 H) 7.17 (d, J=7.14 Hz, 1 H) 7.20 - 7.32 (m, 1 H)	5.08 (d, J=5.49 Hz, 1 H) 5.93 (br. s., 1 H)
19.	1.29 (t, J = 8.0 Hz, 3H) 4.18 (d, J = 12.5 Hz, 2H),	3.59 (qd, J = 12.4, 7.0 Hz, 2H),	4.14 (s, 2H),	7.41 – 7.22 (m, 4H)	6.93 (t, J = 7.4 Hz, 1H) 7.55 (td, J = 7.5, 1.7 Hz, 2H)	4.66 (d, J = 7.0 Hz, 1H) 5.19 (qd, J = 6.8, 1.0 Hz, 1H),
20.	1.30 (t, J = 8.0 Hz, 3H) 4.18 (d, J = 12.5 Hz, 2H)	3.53 (dd, J = 12.4, 6.9 Hz, 2H),	4.14 (с, 2H)	7.16 – 7.06 (m, 2H), 7.41 (ddt, J = 6.7, 4.1, 1.4 Hz, 2H),	6.97 – 6.87 (m, 2H) 7.24 (dd, J = 6.5, 2.4 Hz, 1H),	4.64 (d, J = 7.0 Hz, 1H)5.05 (qt, J = 7.0, 1.0 Hz, 1H)
21.	3.54 (s, 3H),	3.11 (ddt, J = 6.8, 2.1, 1.0 Hz, 2H).	4.13 (с, 2H)	7.33 – 7.14 (m, 5H),	7.33 – 7.14 (m, 1H), 6.97 – 6.87 (m, 2H),	6.03 (d, J = 7.2 Hz, 1H),
22.	0.84 - 0.98 (m, 3 H) 3.75 - 3.90 (m, 2 H)	3.23 (s, 2 H)	4.02 (s, 2 H)	6.94 (d, J=4.39 Hz, 2 H) 7.15 - 7.22 (m, 1 H) 7.43 - 7.52 (m, 2 H)	7.09 (d, J=6.59 Hz, 1 H) 7.15 - 7.22 (m, 1 H) 7.43 - 7.52 (m, 1 H)	7.29 (br. s., 1 H)
23.	1.77 (s, 3 H)	4.13 (s, 2 H)	4.13 (s, 2 H)	6.90 - 6.98 (m, 1 H), 7.45 - 7.63 (m, 2 H), 7.84 (d, J=7.68 Hz, 1 H)	7.45 - 7.63 (m, 2 H) 7.77 (d, J=9.88 Hz, 1 H)	4.82 - 4.89 (m, 1 H) 7.28 (br. s., 1 H)
24.	0.86 (t, J=6.86 Hz, 3 H) 3.72 (q, J=6.59 Hz, 2 H)		3.90 (s, 2 H)	6.89 (d, J=4.94 Hz, 1 H)7.38 - 7.48 (m, 1 H) 7.56 (d, J=9.88 Hz, 1 H) 7.68 (d, J=7.14 Hz, 1 H)	7.10 (t, J=7.96 Hz, 2 H) 7.30 (q, J=7.14 Hz, 1 H)	7.19 (br. s., 1 H)
25.	3.55 (s, 3H)		4.13 (s, 2H)		7.22 (dd, J = 5.5, 3.5 Hz, 1H), 6.97 – 6.87 (m, 2H),	2.03 (s, 3H). , , 3.45 (t, J = 7.1 Hz, 2H), 4.34 (t, J = 7.1 Hz, 2H),
26.	0.93 (dt, J = 23.4, 7.2 Hz, 3H) 3.85 (q, J = 7.2 Hz, 2H)		4.15 (s, 2H),		7.48 (dd, J = 4.9, 3.0 Hz, 1H), 7.30 (d, J = 2.9 Hz, 1H), 6.94 (d, J = 5.0 Hz, 1H),	1.94 (s, 3H), 3.36 (d, J = 5.9 Hz, 1H),4.24 (t, J = 6.1 Hz, 2H), ,
27.	1.67 (s, 3 H)	3.82 (q, J=6.77 Hz, 2 H)	4.03 (s, 2 H)	6.84 - 7.03 (m, 2 H) 7.27 - 7.37 (m, 1 H) 7.43 - 7.57 (m, 1 H)	6.84 - 7.03 (m, 2 H) 7.27 - 7.37 (m, 1 H)	4.02 (s, 3 H) 6.84 - 7.03 (m, 1 H)
28.	3.24 (s, 3 H)	3.36 (d, J=6.04 Hz, 2 H)	4.41 (br. s., 2 H)	7.22 - 7.39 (m, 3 H) 7.49 (dd, J=14.27, 6.59 Hz, 1 H)	7.22 - 7.39 (m, 1 H) 7.49 (dd, J=14.27, 6.59 Hz, 2 H)	2.84 - 2.90 (m, 3 H) 3.97 - 4.08 (m, 1 H)
29.	3.13 - 3.25 (m, 3 H)	3.89 (s, 2 H)	3.89 (s, 2 H)	7.12 - 7.28 (m, 2 H) 7.41 - 7.49 (m, 2 H)	6.89 (d, J=4.39 Hz, 2 H) 7.41 - 7.49 (m, 1 H)	3.13 - 3.25 (m, 3 H) 6.94 - 7.08 (m, 1 H)
30.	1.32       (d, J=6.04 Hz, 3 H) 3.37 - 3.47 (m, 2 H)	4.05 - 4.17 (m, 2 H)	4.05 - 4.17 (m, 2 H)	6.95 (d, J=4.94 Hz, 1 H) 7.18 (td, J=7.60, 2.30 Hz, 1 H) 7.22 - 7.34 (m, 1 H) 7.47 - 7.55 (m, 1 H)	7.11 (t, J=9.33 Hz, 2 H) 7.18 (td, J=7.60, 2.30 Hz, 1 H) 7.22 - 7.34 (m, 1 H) 7.47 - 7.55 (m, 1 H)	3.17 (br. s., 3 H) 5.09 (br. s., 1 H)
31.	0.95         (t, J=7.14 Hz, 3 H) 3.83 - 3.91 (m, 2 H)	4.10 (s, 2 H)	4.10 (s, 2 H)	7.31 - 7.47 (m, 2 H) 7.58 - 7.66 (m, 2 H)	7.31 - 7.47 (m, 1 H) 7.47 - 7.55 (m, 1 H) 7.76 (d, J=7.68 Hz, 1 H)	2.62 (br. s., 3 H) 6.97 (d, J=4.94 Hz, 1 H)
32.	3.85 - 3.98 (m, 3 H)	4.20 (s, 2 H)	4.20 (s, 2 H)	7.33 - 7.49 (m, 5 H)	7.06 (d, J=4.39 Hz, 2 H) 7.49 - 7.57 (m, 1 H)	2.60 (s, 3 H) 7.49 - 7.57 (m, 1 H)
33.	1.31 (t, J = 8.0 Hz, 3H) 4.17 – 3.98 (m, 2H)	3.18 (ddt, J = 7.0, 1.9, 1.0 Hz, 2H)	4.17 – 3.98 (m, 2H)	7.34 – 7.14 (m, 5H)	7.34 – 7.14 (m, 1H) 7.01 – 6.88 (m, 2H)	2.06 (s, 3H) 6.60 (t, J = 7.0 Hz, 1H)
34.	3.32 (s, 3 H)	7.32 (br. s., 1 H)	4.08 (s, 2 H)	6.97 (d, J=4.39 Hz, 2 H) 7.50 (dd, J=4.39, 2.74 Hz, 2 H)	6.97 (d, J=4.39 Hz, 1 H) 7.50 (dd, J=4.39, 2.74 Hz, 2 H)	3.32 (s, 3 H)
35.	0.88 (t, J=6.86 Hz, 3 H) 3.73 (q, J=6.60 Hz, 2 H)	7.41 - 7.49 (m, 1 H)	3.91 (s, 2 H)	6.97 - 7.09 (m, 1 H) 7.18 - 7.29 (m, 2 H) 7.54 - 7.62 (m, 1 H)	6.91 (d, J=4.39 Hz, 1 H) 6.97 - 7.09 (m, 1 H) 7.18 - 7.29 (m, 1 H)	3.38 (br. s., 3 H)

 

CONCLUSION:

1.     For the first time, a number of new derivatives of 5-(thiophen-3-ylmethyl)-4-R₁-1,2,4-triazol-3-thiol have been synthesized, and in some cases further transformations of the compounds have been investigated.

2.     The structure of the obtained substances is confirmed by modern physicochemical methods of analysis. The ¹H NMR spectrum of the synthesized compounds was carefully studied and described.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

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Received on 08.04.2020           Modified on 18.10.2020

Accepted on 03.02.2021         © RJPT All right reserved