2c H Synthesis Essay

1. Introduction

Thiosemicarbazones are a class of small molecules that have been evaluated over the last 50 years as antiviral [1] and as antitumoral agents [2,3,4], in addition to their antiparasitic and bacterial action against Trypanasoma cruzi [5,6,7] and Toxoplasma gondii and several bacterial strains [8]. Thiosemicarbazones have been used as intermediates for a great variety of heterocyclic products, such as thiazolidinones, thiohydantoins, thioxopyrimidinediones. It is reported that thiazolidinones exhibit antibacterial [9], antifungal [10], anticonvulsant [11], antitubercular [12], anti-inflammatory [13], antihistaminic [14,15], cardiovascular [16] and anti-HIV [17] activities. As part of our research program on new bioactive compounds [18,19,20,21,22], we report herein an efficient synthesis of some new highly functionalized thiazolidinones derived from 4-phenyl-3-thiosemicarbazones.

2. Results and Discussion

The starting materials, 4-phenyl-3-thiosemicarbazones 4ah, were synthesized in two steps. The first step was the preparation of 4-phenyl thiosemicarbazide (2) in 86% yield from phenyl isothiocyanate (1) and hydrazine hydrate in ethanol at room temperature [23] (Scheme 1).

Scheme 1. Preparation of 4-phenyl-3-thiosemicarbazide (2).

Scheme 1. Preparation of 4-phenyl-3-thiosemicarbazide (2).

The reaction of 4-phenyl-3-thiosemicarbazide (2) with various aromatic aldehydes 3ah in the presence of few drops of acetic acid at 85 °C for 1–3 h, led to the corresponding 4-phenyl-3-thiosemicarbazone derivatives 4ah in good yields (70%–93%), as shown in Scheme 2 and Table 1.

Scheme 2. Preparation of 4-phenyl-3-thiosemicarbazones 4ah.

Scheme 2. Preparation of 4-phenyl-3-thiosemicarbazones 4ah.

The most characteristic signals in the 1H-NMR spectrum of this family of thiosemicarbazones were those corresponding to the CH=N and N-H protons. 1H-NMR studies showed the CH=N protons in the 7.86–8.62 ppm range, whereas thiourea N-H protons are found in the 9.13–11.78 ppm interval for N-H adjacent to the monosubstituted phenyl ring and for the N-H adjacent to the CH=N moiety, respectively. All of the synthesized compounds were in the E-configuration, which was confirmed using 1H-NMR spectroscopy, as the signal of the NH group was in the 9–12 ppm range, in comparison to the Z-isomer, which possesses a characteristic NH signal in the 14–15 ppm range [24].

Table 1. Reaction of 2 with various aromatic aldehydes 3ah.

The reaction of various 4-phenyl thiosemicarbazones 4ah with ethyl 2-bromoacetate (5) as cyclizing reagent in boiling absolute ethanol containing three equivalents of anhydrous sodium acetate during 1–3 h, afforded to the thiazolidin-4-ones 6ah in good yields (68%–91%) as shown in Scheme 3 and Table 2.

Scheme 3. Preparation of thiazolidinones 6ah.

Scheme 3. Preparation of thiazolidinones 6ah.

Table 2. Reactions of 4ah with ethyl 2-bromoacetate (5).

The structures of all new compounds 6ah were established by analysis of their IR, 1H-NMR and 13C-NMR data. The IR spectra of the thiazolidin-4-ones 6ah showed absorption bands at about 1,734–1,716 cm−1 characteristic of (amide group) C=O stretching vibrations. Further support was obtained from the 1H-NMR spectra, where it did not display signs of the 4-phenyl-3-thiosemicarbazone (NH) protons. On the other hand, the 1H-NMR spectra exhibited resonances assigned to the SCH2 group of the thiazolidine ring appearing as a singlet at 3.97–4.10 ppm due to the methylene protons. The CH=N protons in these structures were observed in the 7.67–8.57 ppm region. The formation of thiazolidinones 6ah ocurred in two steps: the first step of this reaction is thought to be S-alkylation of thiosemicarbazide in its thiol form due to the sodium acetate used. Second step involved loss of ethanol to give the thiazolidin-4-one. The electronic and steric properties of the substituent at the 4-position of the thiosemicarbazones seems to be a determining factor for the formation of the thiazolidinone ring. Previous reports on these types of compounds reveal a small substituent such as phenyl or alkyl leads to a 4-thiazolidinone ring by loss of ethanol [25].

The next cyclization reaction of 4-phenyl-3-thiosemicarbazones derivatives 4ah was conducted using diethyl acetylenedicarboxylate in methanol for 1 h [26], as shown in Scheme 4 and Table 3. In this reaction both of the sulfur group and the amino group are capable of reacting with diethyl acetylenedicarboxylate. It was found that the 4-phenyl thiosemicarbazone derivatives 4ah reacted with diethyl acetylenedicarboxylate exclusively with the sulfur atom. In this reaction the intermediate 7 undergoes an intramolecular cyclization which leads to the compounds 8ah.

Scheme 4. Preparation of 8ah with 4-phenyl-3-thiosemicarbazones 4ah and diethyl acetylenedicarboxylate.

Scheme 4. Preparation of 8ah with 4-phenyl-3-thiosemicarbazones 4ah and diethyl acetylenedicarboxylate.

Table 3. Reactions of 4ah with diethyl acetylenedicarboxylate.

CompoundProductProduct numberYield (%)
4a8a73
4b8b70

Method B: Synthesis of 2a,d:

A mixture of 1a,b (2 mmol), phenylthiourea (2 mmol) and 5 drops of dry ethanol was placed in a 50 mL beaker, covered with a watch glass, and was then irradiated with microwave (800 W) for 20 seconds. The cold reaction mixture was treated with crushed ice; the solid product was filtered, dried and recrystallized.

3-Ethoxycarbonyl-2-(3-phenylthioureido)-4,5,6,7-tetrahydrobenzo[b]thiophene (2a): Fine pale yellow needles, m.p. 191-193°C (from ethanol); Yield 64%; IR (cm-1): 3416, 3179 (2NH), 1656 (C=O), 1195 (C=S); 1H-NMR (DMSO-d6): 1.30 (3H, t, J = 7.1, CH2CH3), 1.70-1.86 (4H, m, 2CH2 at C-5, C-6), 2.67-2.80 (4H, m, 2CH2 at C-4, C-7), 4.52 (2H, q, J = 7.1, CH2CH3), 7.29-7.33 (2H, m, H-2`, H-6`), 7.52-7.56 (3H, m, H-3`, H-4`, H-5`), 10.21 (1H, br. s, NH), 12.25 (1H, br. s, NH); 13C-NMR: 14.31, 60.75 (Et carbons), 22.09, 23.51, 24.43, 26.42 (aliphatic ring sp3 carbons), 113.02, 121.32, 126.94, 127.11, 130.91, 133.15, 149.85, 135.23 (sp2 carbons), 166.73 (C=O), 176.25 (C=S).

3-Ethoxycarbonyl-2-[3-(4-chlorophenyl)thioureido]-4,5,6,7-tetrahydrobenzo[b]thiophene (2b): Color-less needles, m.p. 221-223°C (from ethanol); Yield 70%; IR (cm-1): 3442, 3196 (2NH), 1663 (C=O), 1198 (C=S); 1H-NMR (DMSO-d6): 1.27 (3H, t, J = 7.3, CH2CH3), 1.68-1.69 (4H, m, 2CH2 at C-5, C-6), 2.51-2.55 (2H, m, CH2 at C-4), 2.67-2.68 (2H, m, CH2 at C-7), 4.18 (2H, q, J = 7.3, CH2CH3), 7.23 (2H, d, J = 8.8, H-2`, H-6`), 7.41 (2H, d, J = 8.8, H-3`, H-5`), 10.53 (1H, br. s, NH), 12.02 (1H, br. s, NH); 13C-NMR: 14.37, 60.49 (Et carbons), 22.97, 23.04, 24.34, 26.43 (aliphatic ring sp3 carbons), 112.23, 126.24, 128.93, 130.58, 137.24 150.42, 161.32, 125.71, (sp2 carbons), 166.66 (C=O), 176.18 (C=S).

2-(3-Butylthioureido)-3-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (2c): Fine pale yellow needles, m.p. 123-125°C (from ethanol); Yield 59%; IR (cm-1): 3429, 3230 (2NH), 1655 (C=O), 1175 (C=S); 1H-NMR (CDCl3): 0.93 (3H, t, J = 8.0, CH2CH2CH3), 1.35 (3H, t, J = 7.1, OCH2CH3), 1.40 (2H, sext., J = 8.0, CH2CH2CH3), 1.63 (2H, quint., J = 8.0, CH2CH2CH2), 1.72-1.78 (4H, m, 2CH2 at C-5, C-6), 2.56-2.61 (2H, m, CH2 at C-4), 2.71-2.76 (2H, m, CH2 at C-7), 3.45 (2H, br peak, NHCH2CH2), 4.30 (2H, q, J = 7.1, OCH2CH3), 6.44 (1H, br. s, NH), 12.10 (1H, br. s, NH); 13C-NMR: 14.42, 60.71 (Et carbons), 13.81, 20.11, 30.73, 44.15 (butyl group), 22.92, 23.15, 24.42, 26.51 (aliphatic ring sp3 carbons) 112.01, 126.32, 130.67, 151.43 (thiophene carbons), 167.25 (C=O), 177.03 (C=S).

3-Ethoxycarbonyl-6-methyl-2-(3-phenylthioureido)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (2d): Fine yellow needles, m.p. 186-188°C (from ethanol/chloroform); Yield 60%; IR (cm-1): 3467, 3175 (2NH), 1658 (C=O), 1195 (C=S); 1H-NMR (CDCl3): 1.24 (3H, t, J = 7.2, CH2CH3), 2.46 (3H, s, CH3N), 2.66 (2H, t, J = 5.9, CH2 at C-4), 2.85 (2H, t, J = 5.8, CH2 at C-5), 3.49 (2H, s, CH2 at C-7), 4.12 (2H, q, J = 7.2, CH2CH3), 7.31-7.36 (3H, m, H-2`,H-4` ,H-6`), 7.47 (2H, t, J =7.4, H-3`,H-5`), 8.01 (1H, br. s, NH), 12.12 (1H, br. s, NH); 13C-NMR: 14.25, 60.56 (Et carbons), 45.63 (CH3N), 52.50, 26.88, 53.24 (aliphatic ring sp3 carbons), 112.54, 124.07, 125.80, 127.95, 129.04, 130.13, 135.81 150.52, (sp2 carbons), 166.14 (C=O), 176.29 (C=S); MS: m/z (%) 375 [M+] (96) (C18H21N3O2S2), 332 [M-CH3-C2H5] (18), 282 [M-C6H5-CH3-H] (13), 239 [M-C6H5NHCS] (100), 166 [M-C6H5NHCS-C2H5OH-C2H4+H] (36).

3-Ethoxycarbonyl-2-[3-(4-chlorophenyl)-6-methylthioureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (2e): Fine yellow cubes, m.p. 206-208°C (from ethanol/ chloroform); Yield 60%; IR (cm-1): 3415, 3180 (2NH), 1659 (C=O), 1195 (C=S); 1H-NMR (CDCl3): 1.27 (3H, t, J = 7.2, CH2CH3), 2.46 (3H, s, CH3N), 2.67 (2H, t, J = 5.7, CH2 at C-4), 2.86 (2H, t, J = 5.7, CH2 at C-5), 3.50 (2H, s, CH2 at C-7), 4.18 (2H, q, J = 7.2, CH2CH3), 7.26 (2H, d, J = 8.8, H-2`, H-6`), 7.41(2H, d, J = 8.8, H-3`, H-5`), 7.89 (1H, br. s, NH), 12.21 (1H, br. s, NH); 13C-NMR: 14.25, 60.78 (Et carbons), 45.63 (CH3N), 26.88, 52.46, 53.21 (aliphatic ring sp3 carbons), 112.46, 123.91, 126.92, 129.04, 130.18, 133.17, 134.53, 150.27 (sp2 carbons), 166.43 (C=O), 176.17 (C=S); MS: m/z (%) 409 [M+] (59) (C18H2035ClN3O2S2), 411 [M+2] (22) (C18H2037ClN3O2S2), 366 [M-CH3-C2H4] (12), 282 [M-ClC6H4-CH3–H] (37), 239 [M-ClC6H4NHCS] (91), 169 [M-ClC6H4NHCS-C2H5OH-C2H4+3H] (58).

2-(3-Butylthioureido)-3-ethoxycarbonyl-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (2f): Fine red needles, m.p. 224-226°C (from ethanol/chloroform);Yield 60%; IR (cm-1): 3434, 3162 (2NH), 1650 (C=O), 1169 (C=S); 1H-NMR (DMSO-d6): 0.89 (3H, t, J = 8.0, CH2CH2CH3), 1.09 (3H, t, J = 7.3, OCH2CH3), 1.31 (2H, sext., J = 7.3, CH2CH2CH3), 1.62 (2H, quint., J = 7.3, CH2CH2CH2), 2.41 (3H, s, CH3N), 2.68 (2H, t, J = 5.9, CH2 at C-4), 2.91-2.95 (2H, m, CH2 at C-5), 3.47 (2H, s, CH2 at C-7), 3.52 (2H, t, J = 7.3, NHCH2CH2), 4.31 (2H, q, J = 7.1, OCH2CH3), 8.85 (1H, br. s, NH), 9.29 (1H, br. s, NH); 13C-NMR: 18.59, 57.36 (Et carbons), 13.93, 20.29, 28.69, 45.98 (Bu carbons), 45.28 (CH3N), 25.47, 51.59, 52.97 (aliphatic ring sp3 carbons), 116.02, 125.17, 129.89, 149.62 (thiophene carbons), 157.19 (C=O), 174.25 (C=S); MS: m/z (%) 355 [M+] (12) (C16H25N3O2S2), 309 [M-C2H5OH] (100), 252 [M-C4H9-C2H5OH] (13), 210 [M-C4H9NHCS-2CH3+H] (35).

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