3.3. Chemistry
All of the employed reagents were purchased from common commercial suppliers (Sigma-Aldrich, Milan, Italy and Alfa Aesar, Karlsruhe, Germany). A Buchi B-545 instrument (BUCHI Labortechnik AG, Flawil, Switzerland) was used to determine melting points. Combustion analysis (C, H, N), performed with a Carlo Erba Model 1106-Elemental Analyzer (Milan, Italy), revealed ≥95% purity of the obtained compounds. Merck Silica Gel 60 F254 plates (Milan, Italy) were employed for thin-layer chromatography (TLC; Merck KGaA, Darmstadt, Germany). 1H NMR and 13C NMR spectra were recorded in deuterated dimethylsulfoxide (DMSO-d6) or chloroform (CDCl3) with a Varian Gemini 500 spectrometer (Palo Alto, CA, USA), Bruker Avance III 400 (Rheinstetten, Germany), or Jeol ECZR600 (Milan, Italy), with chemical shifts (δ) expressed in ppm and coupling constants (J) in hertz (Hz).
3.3.1. General Procedures for the Synthesis of Key Intermediate 1-[(3-Chloro-4-fluorophenyl)methyl]piperazine (6)
A mixture of tert-butyl piperazine-1-carboxylate (300 mg, 1.61 mmol), 3-chloro-4-fluorobenzylbromide (5, 217.6 µL, 1.61 mmol), and K2CO3 (445 mg, 3.22 mmol) in EtOH (10 mL) was refluxed for 18 h. Then, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL, ×3) to furnish different organic phases, which were collected and dried over Na2SO4; then, the mixture was concentrated in vacuo to yield the intermediate tert-butyl 4-[(3-chloro-4-fluorophenyl)methyl]piperazine-1-carboxylate. Subsequently, a solution of tert-butyl 4-[(3-chloro-4-fluorophenyl)methyl]piperazine-1-carboxylate (519 mg, 1.57 mmol) in DCM (8 mL) was treated with TFA (15.7 mmol); the resulting mixture was stirred at room temperature for 5 h. After the reaction was completed, it was cooled on ice and diluted with DCM (2 mL) and a solution of K2CO3 (2M, 2 mL). The mixture was extracted with DCM (10 mL, ×2); the combined organic layers were dried over Na2SO4 and the solvent was removed in vacuo. Finally, the desired intermediate 1-[(3-chloro-4-fluorophenyl)methyl]piperazine (6) was obtained by crystallization with diethyl ether.
tert-Butyl 4-[(3-chloro-4-fluorophenyl)methyl]piperazine-1-carboxylate (intermediate)
Yield: 98%. Oily residue. 1H-NMR (500 MHz, CDCl3): (δ) 1.44 (s, 9H, 3CH3), 2.35 (bs, 4H, 2CH2), 3.40 (m, 4H, 2CH2), 3.42 (s, 2H, CH2), 7.06 (t, J = 8.7 Hz, 1H, ArH, H-5′), 7.16 (m, 1H, ArH, H-6′), 7.36 (d, J = 7.1 Hz, 1H, ArH, H-2′). Anal. Calculated for C16H22ClFN2O2: C 58.44, H 6.74, N 8.52. Found: C 58.39, H 6.71, N 8.56.
1-[(3-Chloro-4-fluorophenyl)methyl]piperazine (6)
Yield: 62%. White powder. M.p. 147–150 °C. 1H-NMR (500 MHz, DMSO-d6): (δ) 2.54 (m, 4H, 2CH2), 3.08 (t, J = 5.1 Hz, 4H, 2CH2), 3.33 (s, 1H, NH), 3.53 (s, 2H, CH2), 7.33 (m, 1H, ArH, H-5′), 7.39 (t, J = 8.8 Hz, 1H, ArH, H-6′), 7.53 (dd, J = 7.4, 2.1 Hz, 1H, ArH, H-2′). Anal. Calculated for C11H14ClFN2: C 57.77, H 6.17, N 12.25. Found: C 57.81, H 6.13, N 12.19.
3.3.2. General Procedures for the Synthesis of Amides 1d–f
Route (a) To a solution of 1-[(3-chloro-4-fluorophenyl)methyl]piperazine (
6) (0.66 mmol) in DCM (4 mL), the suitable benzoyl chloride (0.66 mmol) and
N,N-diisopropylethylamine (DIPEA, 0.99 mmol) were added. The reaction mixture was stirred at room temperature for 5 h; after the completion of the reaction, the work-up to obtain target compounds
1d and
1e was performed as previously reported for analogues
1a and
1b [
15,
18].
Route (b) A mixture of benzothiophene-2-carboxylic acid (1.05 mmol) and
N,N,N′,N′-tetramethyl-O-(1
H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) (1.05 mmol) in DMF (4 mL) was stirred at room temperature for 1 h. Then, 1-[(3-chloro-4-fluorophenyl)methyl]piperazine (1.05 mmol) and TEA (2.1 mmol) were added and it was stirred for 17 h. The target compound
1f was obtained as previously reported for analog compound
1c [
17].
(4-(3-Chloro-4-fluorobenzyl)piperazin-1-yl)(2,4-dichlorophenyl)methanone (1d)
Yield: 58%. White powder. M.p. 121–124 °C. 1H-NMR (500 MHz, DMSO-d6): (δ) 2.33 (t, J = 3.36 Hz, 2H, CH2), 2.43 (m, 2H, CH2), 3.13 (m, 2H, CH2), 3.49 (s, 2H, CH2), 3.63 (m, 2H, CH2), 7.31 (m, 1H, ArH, H-5′), 7.35 (d, J = 9.2 Hz, 1H, ArH, H-6′), 7.39 (m, 1H, ArH, H-2′), 7.49 (d, J = 2.02 Hz, 1H, ArH, H-5”), 7.51 (d, J = 2.02 Hz, 1H, ArH, H-6”), 7.72 (d, J = 1.9 Hz, 2H, ArH, H-3”). 13C-NMR (126 MHz, DMSO-d6): (δ) 41.1 (C-5), 46.2 (C-3), 51.8 (C-2), 52.5 (C-6), 60.1 (CH2), 116.6 (d, JC-F = 20.77 Hz, C-5′), 119.1 (d, JC-F = 17.66 Hz, C-3′), 127.9 (C-5”), 129.1 (C-6′), 129.3 (C-6”), 129.4 (C-3″), 130.3 (C-2′), 130.6 (C-2″), 134.2 (C-4″), 134.7 (C-1″), 135.9 (d, JC-F = 3.86 Hz, C-1′), 156.3 (d, JC-F = 245.5 Hz, C-4′), 164.6 (C=O). Anal. Calculated for C18H16Cl3FN2O: C 53.82, H 4.01, N 6.97. Found: C 53.88, H 3.99, N 7.03.
(4-(3-Chloro-4-fluorobenzyl)piperazin-1-yl)(5-fluoro-2-(trifluoromethyl)phenyl)methanone (1e)
Yield: 40%. White powder. M.p. 133–135 °C. 1H-NMR (500 MHz, CDCl3): (δ) 2.42 (bs, 2H, CH2), 2.59 (bs, 2H, CH2), 3.24 (bs, 2H, CH2), 3.55 (s, 2H, CH2), 3.84 (m, 2H, CH2), 7.03 (d, J = 8.1 Hz, 1H, ArH, H-5′), 7.09 (m, 1H, ArH, H-6′), 7.20 (m, 2H, ArH, H-3″ and H-6″), 7.39 (m, 1H, ArH, H-2′), 7.70 (m, 1H, ArH, H-4″). 13C-NMR (126 MHz, CDCl3): (δ) 41.6 (C-5), 46.9 (C-3), 52.3 (C-2), 52.4 (C-6), 61.4 (CH2), 114.9 (d, JC-F = 23.67 Hz, C-5′), 116.5 (d, JC-F = 21.86 Hz, C-6″), 116.6 (d, JC-F = 21.05 Hz, C-4″), 116.9 (C-2″), 121.1 (q, JC-F = 17.8 Hz, CF3, C-3′), 124.4 (d, JC-F = 272.45 Hz, CF3), 128.9 (d, JC-F = 7.2 Hz, C-6′), 129.6 (q, JC-F = 4.5 Hz, C-3″), 131.2 (C-2′), 134.1 (C-1′), 137.4 (C-1″), 157.6 (d, JC-F = 248.6 Hz, C-4′), 164.4 (d, JC-F = 255.5 Hz, C-5″), 165.9 (C=O). Anal. Calculated for C19H16ClF5N2O: C 54.49, H 3.85, N 6.69. Found: C 54.56, H 3.90, N 6.62.
Benzo[b]thiophen-2-yl(4-(3-chloro-4-fluorobenzyl)piperazin-1-yl)methanone (1f)
Yield: 51%. White powder. M.p. 111–113 °C. 1H-NMR (500 MHz, CDCl3): (δ) 2.49 (bs, 4H, 2CH2), 3.49 (s, 2H, CH2), 3.79 (bs, 4H, 2CH2), 7.09 (m, 1H, ArH, H-5′), 7.18 (m, 1H, ArH, H-6′), 7.39 (m, 3H, ArH, H-2″, H-5″ and H-6″), 7.46 (bs, 1H, ArH, H-2′), 7.80 (m, 1H, ArH, H-4″), 7.85 (m, 1H, ArH, H-5″). 13C-NMR (126 MHz, CDCl3): (δ) 29.8 (C-3 and C-5), 53.1 (C-2 and C-6), 61.7 (CH2), 116.5 (d, JC-F = 20.95 Hz, C-5′), 121.0 (C-3′), 122.5 (C-3″), 124.7 (C-7″), 124.9 (C-3″a), 125.3 (C-5″) 125.9 (C-6″), 128.6 (d, JC-F = 7.05 Hz C-6′), 131.0 (C-2′), 134.9 (d, JC-F = 3.74 Hz C-1′), 136.7 (C-3″), 138.7 (C-7″a) 140.3 (C-2″), 157.5 (d, JC-F = 247.4 Hz, C-4′), 163.9 (C=O). Anal. Calculated for C20H18ClFN2OS: C 61.77, H 4.67, N 7.20. Found: C 61.80, H 6.64, N 7.22.
3.3.3. General Procedures for the Synthesis of Amides 2b–d
To a solution of 4-(1-piperazinyl)phenol (7, 300 mg, 1.68 mmol) in DMF (4 mL), the suitable acyl chloride (1.68 mmol) was slowly added at 0 °C. Then, the reaction mixture was stirred at room temperature for 3 h. After the completion of the reaction, as indicated by TLC, a saturated solution of NaHCO3 (5 mL) was added to quench the reaction. The reaction mixture was extracted with EtOAc (×2); the organic layers were collected and dried over Na2SO4 and the solvent was removed under vacuum to afford intermediates 2-chloro-1-[4-(4-hydroxyphenyl)piperazin-1-yl]ethanone (8a, R1 = H) or 2-chloro-1-(4-(4-hydroxyphenyl)piperazin-1-yl)propan-1-one (8b, R1 = Me) as powder through treatment with EtOH and Et2O. To a solution of 2-chloro-1-[4-(4-hydroxyphenyl)piperazin-1-yl]ethanone (8a, 210 mg, 0.82 mmol) or 2-chloro-1-(4-(4-hydroxyphenyl)piperazin-1-yl)propan-1-one (8b, 220 mg, 0.82 mmol) in DMF (4 mL), 1-[(3-chloro-4-fluorophenyl)methyl]piperazine (6) (0.82 mmol) or 1-[(4-fluorophenyl)methyl]piperazine (9, 0.82 mmol) was added. This was followed by the addition of K2CO3 (56.7 mg, 0.41 mmol); then, the reaction mixture was refluxed for 18 h and quenched with a saturated solution of NaHCO3 (5 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL) and the obtained organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under a reduced pressure. Finally, the desired compounds 2b–d were crystallized with Et2O and EtOH.
2-Chloro-1-[4-(4-hydroxyphenyl)piperazin-1-yl]ethanone (8a)
Yield: 49%. White powder. M.p.: 162–163 °C.
1H-NMR (500 MHz, DMSO-
d6): (δ) 2.92 (m, 2H, CH
2), 2.98 (m, 2H, CH
2), 3.58 (m, 4H, 2CH
2), 4.41 (s, 2H, CH
2), 6.66 (d,
J = 8.9 Hz, 2H, ArH, H-2′ and H-6′), 6.81 (d,
J = 8.9 Hz, 2H, ArH, H-3′ and H-5′), 8.89 (bs, 1H, OH). Anal. Calculated for C
12H
15ClN
2O
2: C 56.59, H 5.94, N 11.00. Found: C 56.65, H 5.83, N 11.07. The structural characterization of the pure intermediate 2-chloro-1-[4-(4-hydroxyphenyl)piperazin-1-yl]ethanone (
8a) was in good agreement with previous data reported in the literature [
20].
2-Chloro-1-(4-(4-hydroxyphenyl)piperazin-1-yl)propan-1-one (8b)
Yield: 64%. White powder. M.p.: 148–150 °C. 1H-NMR (500 MHz, DMSO-d6): (δ) 1.52 (d, J = 6.4 Hz, 3H, CH3), 2.96 (m, 4H, 2CH2), 3.63 (m, 4H, 2CH2), 5.09 (q, J = 6.4 Hz, 1H, CH), 6.66 (d, J = 8.9 Hz, 2H, ArH, H-2′ and H-6′), 6.81 (d, J = 8.9 Hz, 2H, ArH, H-3′ and H-5′), 8.88 (bs, 1H, OH). Anal. Calculated for C13H17ClN2O2: C 58.10, H 6.38, N 10.42. Found: C 58.16, H 6.40, N 10.39.
2-(4-(4-Fluorobenzyl)piperazin-1-yl)-1-(4-(4-hydroxyphenyl)piperazin-1-yl)ethanone (2b)
Yield: 85%. White powder. M.p. 185–187 °C. 1H-NMR (500 MHz, DMSO-d6): (δ) 2.38 (m, 6H, 3CH2), 2.87 (bs, 2H, CH2), 2.95 (bs, 2H, CH2), 3.15 (s, 2H, CH2), 3.22 (s, 2H, CH2), 3.42 (s, 2H, CH2), 3.55 (bs, 2H, CH2), 3.65 (bs, 2H, CH2), 6.66 (d, J = 8.84 Hz, 2H, ArH, H-2′ and H-6′), 6.80 (d, J = 8.84 Hz, 2H, ArH, H-3′ and H-3′), 7.12 (m, 2H, ArH, H-3″ and H-5″), 7.30 (m, 2H, ArH, H-2″ and H-6″), 8.86 (s, 1H, OH). 13C-NMR (126 MHz, DMSO-d6): (δ) 41.2 (C-2a and C-6a), 45.3 (C-3a and C-5a), 50.3 (C-3b and C-5b), 50.9 (C-2b and C-6b), 52.5 (CH2-C=0), 61.1 (CH2), 114.8 (d, JC-F = 20.84 Hz, C-3″ and C-5″), 115.4 (C-2′ and C-6′), 118.3 (C-3′ and C-5′), 130.6 (d, JC-F = 7.82 Hz, C-2″ and C-6″), 134.3 (C-1″), 144.0 (C-1′), 151.3 (C-4′), 161.2 (d, JC-F = 241.71 Hz, C-4″), 167.3 (C=O). Anal. Calculated for C23H29FN4O2: C 66.97, H 7.09, N 13.58. Found: C 67.00, H 7.12, N 13.54.
2-(4-(3-Chloro-4-fluorobenzyl)piperazin-1-yl)-1-(4-(4-hydroxyphenyl)piperazin-1-yl)ethanone (2c)
Yield: 53%. White powder. M.p. 165–168 °C. 1H-NMR (500 MHz, DMSO-d6): (δ) 2.40 (m, 4H, 2CH2), 2.88 (m, 2H, CH2), 2.96 (m, 2H, CH2), 3.22 (m, 2H, CH2), 3.46 (s, 2H, CH2), 3.56 (m, 2H, CH2), 3.64 (s, 2H, CH2), 6.66 (d, J = 8.94 Hz, 2H, ArH, H-2′ and H-6′), 6.80 (d, J = 8.94 Hz, 2H, ArH, H-3′ and H-3′), 7.30 (m, 1H, ArH, H-5″), 7.35 (t, J = 6.6 Hz, 1H, ArH, H-6″), 7.48 (d, J = 8.9 Hz, 1H, ArH, H-2″), 8.88 (s, 1H, OH). 13C-NMR (126 MHz, DMSO-d6): (δ) 41.3 (C-2a and C-6a), 45.2 (C-3a and C-5a), 50.3 (C-3b and C-5b), 50.9 (C-2b and C-6b), 52.4 (CH2-C=0), 60.2 (CH2), 115.5 (C-2′ and C-6′), 116.6 (C-5″), 118.4 (C-3′ and C-5′), 118.5 (C-3″), 119.1 (C-6″), 129.3 (C-2″), 130.6 (C-1″), 143.9 (C-1′), 151.3 (C-4′), 156.2 (d, JC-F = 245.23 Hz, C-4″), 172.0 (C=O). Anal. Calculated for C23H28ClFN4O2: C 61.81, H 6.31, N 12.54. Found: C 61.84, H 6.35, N 12.50.
2-(4-(3-Chloro-4-fluorobenzyl)piperazin-1-yl)-1-(4-(4-hydroxyphenyl)piperazin-1-yl)propan-1-one (2d)
Yield: 39%. Beige powder. M.p. 172–174 °C. 1H-NMR (500 MHz, DMSO-d6): (δ) 1.03 (d, J = 6.64 Hz, 3H, CH3), 2.34 (bs, 4H, 2CH2), 2.45 (bs, 4H, 2CH2), 2.71 (m, 2H, CH2), 2.89 (m, 2H, CH2), 3.02 (m, 2H, CH2), 3.41 (s, 2H, CH2), 3.65 (d, J = 6.68 Hz, 1H, CH), 3.80 (m, 2H, CH2), 6.66 (d, J = 8.83 Hz, 2H, ArH, H-2′ and H-6′), 6.80 (d, J = 8.83 Hz, 2H, ArH, H-3′ and H-5′), 7.28 (m, 1H, ArH, H-5″), 7.33 (1H, ArH, H-6″), 7.46 (1H, ArH, H-2″), 8.90 (s, 1H, OH). 13C-NMR (126 MHz, DMSO-d6): (δ) 9.6 (CH3), 41.5 (C-2a and C-6a), 45.3 (C-3a and C-5a), 50.4 (C-3b), 51.1 (C-5b), 52.9 (C-2b and C-6b), 58.9 (CH), 60.5 (CH2), 115.5 (C-2′ and C-6′), 116.6 (C-5″), 118.4 (C-3′ and C-5′), 119.1 (C-3″), 129.3 (C-6″), 130.5 (C-2″), 136.4 (C-1″), 144.1 (C-1′), 151.4 (C-4′), 156.2 (d, JC-F = 244.7 Hz, C-4″), 169.8 (C=O). Anal. Calculated for C24H30ClFN4O2: C 62.53, H 6.56, N 12.15. Found: C 62.57, H 6.53, N 12.10.
3.3.4. General Procedure for the Synthesis of the 4H-1,2,4-Triazol-4-amines (3b–d)
To a mixture of suitable 4-amino-4
H-1,2,4-triazole-3-thiol (
10a or
10b, 1.03 mmol) and NaOH (41 mg, 1.03 mmol) in MeOH (8 mL), the suitable fluorobenzylbromide derivative
11a or
11b (1.03 mmol) was added dropwise. The pure compounds
3b–d were obtained following the procedure already reported for parent compound
3a [
14].
3-(3-Chloro-4-fluorobenzylthio)-5-(pyridin-4-yl)-4H-1,2,4-triazol-4-amine (3b)
Yield: 100%. Yellow powder. M.p. 164–165 °C. 1H NMR (500 MHz, DMSO-d6): (δ) 4.46 (s, 2H, CH2), 6.28 (s, 2H, NH2), 7.36 (t, J = 9.1 Hz, 1H, ArH, H-5″), 7.48 (m, 1H, ArH, H-6″), 7.70 (d, J = 7.1 Hz, 1H, ArH, H-2″), 8.00 (d, J = 3.2 Hz, 2H, pyridine, H-2′ and H-6′), 8.72 (d, J = 3.2 Hz, 2H, pyridine, H-3′ and H-5′). 13C NMR (126 MHz, DMSO-d6): (δ) 33.4 (CH2), 116.8 (C-3″), 119.1 (C-5″), 121.3 (C-2′ and C-6′), 129.8 (C-2″), 131.1 (C-1″), 133.9 (C-6″), 135.9 (C-1′), 150.1 (C-3′ and C-5′), 152.1 (C-3), 154.3 (C-5), 156.4 (C-4″, d, JC-F = 246 Hz). Anal. Calculated for C14H11ClFN5S: C 50.08, H 3.30, N 20.86. Found: C 51.10, H 3.76, N 20.31.
3-((2-Chloro-4-fluorobenzyl)thio)-5-(pyridin-4-yl)-4H-1,2,4-triazol-4-amine (3c)
Yield 100%. Whitish powder. M.p. 171–172 °C. 1H NMR (500 MHz, DMSO-d6): (δ) 4.52 (s, 2H, CH2), 6.27 (s, 2H, NH2), 7.20 (m, 1H, ArH, H-5″), 7.49 (m, 1H, ArH, H-3″), 7.66 (m, 1H, ArH, H-6″), 8.00 (dd, J = 4.5, 1.6 Hz, 2H, pyridine, H-2′ and H-6′), 8.73 (dd, J = 4.5, 1.6 Hz, 2H, pyridine, H-3′ and H-5′). 13C-NMR (126 MHz, DMSO-d6): (δ) 32.3 (CH2), 114.4 (C-5″), 116.8 (C-3″), 121.4 (C-2′ and C-6′), 131.3 (C-1″), 132.9 (C-6″), 133.9 (C-1′), 134.1 (C-2″), 150.1 (C-3′ and C-5′), 152.2 (C-3), 153.9 (C-5), 161.4 (C-4″, d, JC-F = 246.4 Hz). C14H11ClFN5S Anal. Calculated for C14H11ClFN5S: C 50.08, H 3.30, N 20.86. Found: C 50.38, H 3.60, N 21.16.
3-(3-Chloro-4-fluorobenzylthio)-5-phenyl-4H-1,2,4-triazol-4-amine (3d)
Yield: 100%. White powder. M.p. 164–166 °C. 1H NMR (500 MHz, DMSO-d6): (δ) 4.43 (s, 2H, CH2), 6.17 (bs, 2H, NH2), 7.36 (t, J = 9.0 Hz, 1H, ArH, H-5″), 7.47 (m, 1H, ArH, H-6″), 7.50 (d, J = 5.14 Hz, 1H, ArH, H-3″ and 5″), 7.69 (d, J = 7.15 Hz, 1H, ArH, H-2′), 7.97 (m, 2H, ArH, H-2′ and H-6′).13C NMR (126 MHz, DMSO-d6): (δ) 33.5 (CH2); 116.8 (C-5″); 119.1 (C-3″); 126.2 (C-2′ and C-6′); 127.9 (C-1′); 128.5 (C-3′ and C-5′); 130.5 (C-6″); 130.9 (C-4′); 131.2 (C-1″); 135.9 (C-2″); 153.1 (C-3); 154.1 (C-5); 156.4 (C-4″, d, JC-F = 246 Hz). Anal. Calculated for C15H12ClFN4S: C 53.81, H 3.61, N 16.73. Found: C 53.87, H 3.68, N 16.75.
3.3.5. General Procedures for the Synthesis of Dithioacetals 4b and 4f
To a stirred solution of thiophenol (1.2 mmol) in dry isopropanol, NaOH (2.4 mmol) was added. After stirring the reaction at 80 °C under argon for 1 h, it was cooled to rt and diiodomethane was added (1.2 mmol). The mixture was then stirred for a further hour at 80 °C under argon. Afterwards, it was cooled to rt, the solvent was removed under reduced pressure, and the mixture was quenched with water (5 mL). The extraction of the water phase was carried out with EtAOc (3 × 5 mL), while the organic phase was washed with water (2 × 5 mL) and brine (2 × 5 mL) and dried over Na2SO4. The solvent was concentrated in vacuo and the crude compounds were purified through column chromatography on silica gel (96:4 v/v, petroleum ether/dichloromethane).
Phenylsulfanylmethylsulfanylbenzene (4b)
Yield: 93%. White solid. M.p. 34–35 °C. 1H NMR (400 MHz, CDCl3): (δ) 4.35 (s, 2H, SCH2), 7.25 (m, 2H, ArH, H-4′), 7.32 (m, 4H, ArH, H-3′ and H-5′), 7.43 (m, 4H, ArH, H-2′ and H-6′). 13C NMR (100 MHz, CDCl3): (δ) 40.6 (SCH2), 127.1 (C-4), 129.0 (C-3 and C-5), 130.7 (C-2 and C-6), 135.0 (C-1). Anal. Calculated for C13H12S2: C 67.20, H 5.21. Found: C 67.24, H 5.19.
2-Chloro-4-[(3-chloro-4-fluorophenyl)sulfanylmethylsulfanyl]-1-fluorobenzene (4f)
Yield: 93%. Colorless oil. 1H NMR (600 MHz, CDCl3): (δ) 4.24 (s, 2H, SCH2), 7.09 (m, 2H, ArH), 7.29 (m, 2H, ArH), 7.46 (m, 2H, ArH). 13C NMR (150 MHz, CDCl3): (δ) 42.5 (SCH2), 117.1 (d, J = 21.6 Hz), 121.6 (d, J = 18.6 Hz), 130.6 (d, J = 3.5 Hz), 131.8 (d, J = 7.2 Hz), 133.9, 157.8 (d, JC-F = 249.5 Hz). Anal. Calculated for C13H8Cl2F2S2: C 46.30, H 2.39. Found: C 46.27, H 2.20.
3.3.6. Synthesis of 1-[(Chloromethyl)sulfanyl]-4-fluorobenzene (14c)
To a mixture of toluene (5 mL) and HCl (37%, 5 mL), paraformaldehyde was added (152 mg, 5.1 mmol). The resulting mixture was stirred at 50 °C for 10 min and then a solution of 4-fluorobenzene-1-thiol (13) (500 mg, 3.9 mmol) in toluene (5 mL) was added dropwise at the same temperature. The reaction was stirred at 50 °C for 1 h and then at room temperature for 3 h and then flushed with Ar, and the layers were separated. The water phase was extracted with DCM (3 × 10 mL) and the organic phase was concentrated in vacuo to obtain the desired compound, which was used without further purification.
Yield: 90%. Yellow oil. 1H NMR (600 MHz, CDCl3): (δ) 4.89 (s, 2H, SCH2Cl), 7.08 (m, 2H, Ar H), 7.54 (m, 2H, ArH). 13C NMR (150 MHz, CDCl3): (δ) 52.0 (SCH2Cl), 128.1 (d, J = 2.8 Hz), 116.4 (d, J = 21.9 Hz), 134.3 (d, J = 8.4 Hz), 163.0 (d, JC-F = 249.6 Hz). Anal. Calculated for C7H6ClFS: C 47.60, H 3.42. Found: C 47.66, H 3.47.
3.3.7. General Procedure for the Preparation of the Dithioacetals 4c–e and 4g–h
To a stirred solution of the suitable chloro(methylsulfanyl) derivative (1.0 mmol) (14a–c) and K2CO3 (2.0 mmol) in DMF (5 mL), the proper thiophenol (1.5 mmol) was added. The reaction was stirred at room temperature overnight and then quenched with water and extracted with Et2O (3 × 5 mL). The organic phase was washed with brine and concentrated in vacuo. The desired products 4c–e and 4g–h were obtained after purification through column chromatography on silica gel (96:4 v/v, petroleum ether/dichloromethane).
1-Fluoro-4-{[(phenylsulfanyl)methyl]sulfanyl}benzene (4c)
Yield: 91%. Yellow oil. 1H NMR (400 MHz, CDCl3): (δ) 4.29 (s, 2H, SCH2), 7.01 (m, 2H, ArH, H-2′ and H-6′), 7.26 (m, 1H, ArH, H-4″), 7.32 (m, 2H, ArH, H-3′ and H-5″), 7.41 (m, 2H, ArH, H-2″ and H-6″), 7.44 (m, 2H, ArH, H-3′ and H-5″). 13C NMR (100 MHz, CDCl3): (δ) 41.9 (d, J = 1.2 Hz, SCH2), 116.1 (d, J = 21.9 Hz, C’2 and C-6′), 127.1 (C″-4), 129.0 (C’’-3 and C’’-5), 129.6 (d, J = 3.3 Hz, C’-4), 130.7 (C-2″ and C-6″), 134.1 (d, J = 8.2 Hz, C-3′), 134.2 (d, J = 8.2 Hz, C-5′), 134.8 (C-1″), 162.5 (d, JC-F = 247.9 Hz). Anal. Calculated for C13H11FS2: C 62.37, H 4.43. Found: C 62.53, H 4.48.
2-Chloro-1-fluoro-4-{[(phenylsulfanyl)methyl]sulfanyl}benzene (4d)
Yield: 87%. Colorless oil. 1H NMR (600 MHz, CDCl3): (δ) 4.29 (s, 2H, SCH2), 7.28 (m, 1H, ArH), 7.32 (m, 2H, ArH), 7.41 (m, 2H, ArH), 7.47 (m, 1H, ArH). 13C NMR (150 MHz, CDCl3): (δ) 41.7 (SCH2), 117.0 (d, J = 21.7 Hz), 121.4 (d, J = 17.6 Hz), 127.4, 129.1, 131.0, 131.1 (d, J = 4.1 Hz), 131.7 (d, J = 7.1 Hz), 133.7, 134.3, 157.7 (d, JC-F = 248.4 Hz). C13H10ClFS2 Anal. Calculated for C13H10ClFS2: C 54.83, H 3.54. Found: C 54.90, H 3.55.
2-Chloro-1-fluoro-4-(([(4-fluorophenyl)sulfanyl]methyl)sulfanyl)benzene (4e)
Yield: 94%. Colorless oil. 1H NMR (600 MHz, CDCl3): (δ) 4.23 (s, 2H, SCH2), 7.02 (m, 2H, Ph H), 7.08 (m, 1H, ArH), 7.28 (m, 1H, ArH), 7.43 (m, 3H, ArH). 13C NMR (150 MHz, CDCl3): (δ) 42.8 (SCH2), 116.2 (d, J = 21.2 Hz), 117.0 (d, J = 23.3 Hz), 121.4 (d, J = 19.6 Hz), 129.1 (d, J = 2.7 Hz), 131.0 (d, J = 4.3 Hz), 131.5 (d, J = 7.0 Hz), 133.6, 134.2 (d, J = 8.5 Hz), 157.6 (d, JC-F = 251.9 Hz), 162.6 (d, JC-F = 245.9 Hz). Anal. Calculated for C13H9ClF2S2: C 51.57, H 3.00. Found: 51.33, H 2.95.
1-Fluoro-4-{[(methylsulfanyl)methyl]sulfanyl}benzene (4g)
Yield: 88%. Colorless oil. 1H NMR (600 MHz, CDCl3): (δ) 2.22 (s, 3H, SCH3), 3.93 (s, 2H, SCH2), 7.02 (m, 2H, ArH), 7.44 (m, 2H, ArH). 13C NMR (150 MHz, CDCl3): (δ) 15.0 (SCH3), 41.8 (SCH2), 116.0 (d, J = 21.9 Hz), 129.8 (d, J = 2.8 Hz), 133.9 (d, J = 8.0 Hz), 162.4 (d, JC-F = 245.7 Hz). Anal. Calculated for C8H9FS2: C 51.04, H 4.82. Found: C 51.34, H 4.75.
1-Fluoro-3-{[(methylsulfanyl)methyl]sulfanyl}benzene (4h)
Yield: 94%. Brown oil. 1H NMR (400 MHz, CDCl3): (δ) 2.24 (s, 3H, SCH3), 4.01 (s, 2H, SCH2S), 6.92 (m, 1H, ArH, H-6), 7.13 (m, 1H, ArH, H-2), 7.17 (m, 1H, ArH, H-4), 7.27 (m, 1H, ArH, H-5). 13C NMR (100 MHz, CDCl3): (δ) 15.2 (SCH3), 39.8 (SCH2S), 113.7 (d, J = 21.2 Hz, C-6), 116.7 (d, J = 23.0 Hz, C-2), 125.4 (d, J = 3.0 Hz, C-4), 130.1 (d, J = 8.5 Hz, C-5), 137.6 (d, J = 7.8 Hz, C-3), 162.7 (d, JC-F = 248.4 Hz). Anal. Calculated for C8H9FS2: C 51.04, H 4.82. Found: C 51.11, H 4.78.