A Practical Method for the Synthesis of Mesoionic 1,3-Diaryltetrazolium Derivatives Bearing a para-Substituted Phenyl Group at the 1- or 3-Position from Anilines

Abstract

A simple, economical, and safe method for the synthesis of mesoionic 1,3-diaryltetrazolium derivatives bearing a para-substituted phenyl group at the 1- or 3-position via thiosemicarbazides was established. Such compounds were directly obtained from the corresponding para-substituted anilines instead of aryl isothiocyanates and arylhydrazines. The newly synthesized mesoionic compounds were successfully converted into the corresponding nitrosotetrazolium salts, which were utilized as catalysts for oxidation of an aliphatic alcohol and analyzed by cyclic voltammetry to determine the correlation between the catalytic efficiencies and redox potentials. The proposed method can be widely applied and is valuable for investigating the substituent effects in mesoionic and related compounds.

Key words

mesoions - isothiocyanate - hydrazine - aniline - oxidation

• References and Notes

• 1 Current address: Graduate School of Life Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan.
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• 11 Synthesis of 1-Phenyl-4-(p-fluorophenyl)thiosemicarbazide (1b): To p-fluoroaniline (11.1 g, 100 mmol) in toluene (50 mL) were added CS₂ (12.2 mL, 200 mmol) and Et₃N (27.6 mL, 200 mmol), and the mixture was vigorously stirred at room temperature for 6 h. The formed precipitate was filtered and washed with Et₂O to give yellow crystals (27.9 g), which were dissolved in CH₂Cl₂ (10 mL) followed by addition of Et₃N (13.8 mL, 100 mmol). To this solution, ethyl chloroformate (9.53 mL, 100 mmol) in CH₂Cl₂ (10 mL) was added slowly dropwise at 3–5 °C and the reaction mixture was stirred for 15 min while maintaining the temperature. After further stirring for 1 h at room temperature, the mixture was washed with water, dried with anhydrous Na₂SO₄ and evaporated in vacuo to give a pale-yellow liquid. Following addition of Et₂O (200 mL), the formed precipitate was removed by filtration and phenylhydrazine (9.82 mL, 100 mmol) was added to the filtrate. The mixture was stirred vigorously for 1 h, and the formed crystals were filtered and washed with hexane to give colorless crystals of 1b (19.8 g, 75.7 mmol, 76%). To the filtrate, hexane was added and then ultrasonicated. The resulting precipitate was filtered and washed with Et₂O to give 1b (2.68 g, 10.3 mmol, 10%). Melting point: 182.5–184.9 °C. Anal. Calcd for C₁₃H₁₂FN₃S: C, 59.75; H, 4.63; N, 16.08; S, 12.27. Found: C, 59.51; H, 4.61; N, 16.07; S, 12.38 (from acetone/Et₂O+hexane). ¹H NMR (400 MHz, acetone-d ₆): δ = 6.89 (t, J = 8.8 Hz, 3 H, p and m of 1-Ph), 7.07 (t, J = 8.8 Hz, 2 H, o of 1-Ph), 7.26 (t, J = 7.8 Hz, 2 H, m of 4-Ph), 7.41 (s, 1 H, NH), 7.69–7.72 (m, 2 H, o of 4-Ph), 8.74 (s, 1 H, NH), 9.71 (s, 1 H, NH). ¹³C NMR (100 MHz, acetone-d ₆): δ = 114.3 (o of 1-Ph), 115.4 (J = 22.5 Hz, m of 4-Ph), 121. 7 (p of 1-Ph), 127.4 (J = 8.2 Hz, o of 4-Ph), 130.0 (m of 1-Ph), 136.5 (i of 4-Ph), 148.8 (i of 1-Ph), 160.8 (J = 240.8 Hz, p of 4-Ph), 183.4 (C=S). ¹⁹F NMR (280 MHz, CDCl₃): δ = –116.0. IR (KBr): 430, 486, 499, 604, 620, 693, 735, 759, 820, 838, 1064, 1092, 1110, 1153, 1216, 1242, 1288, 1491, 1513, 1558, 1601, 2970, 3146, 3277, 3319 cm^–1. HRMS (ESI⁻-TOF): m/z [M − H]⁻ calcd for C₁₃H₁₁FN₃S: 260.0658; found: 260.0660. Analogously to the preceding reactions, p-anisidine (12.3 g, 100 mmol) was converted into 1d (20.7 g, 76.1 mmol, 76%). Melting point: 174.0–174.9 °C. Anal. Calcd for C₁₄H₁₅N₃OS: C, 61.51; H, 5.53; N, 15.37; S, 11.73. Found: C, 61.31; H, 5.44; N, 15.34; S, 11.70 (from acetone/Et₂O). ¹H NMR (400 MHz, acetone-d ₆): δ = 3.77 (s, 3 H, OMe), 6.84–6.91 (m, 5 H, o and m of 4-Ph and p of 1-Ph), 7.26 (t, J = 8.0 Hz, 2 H, m of 1-Ph), 7.38 (s, 1 H, NH), 7.53 (d, J = 8.8 Hz, 2 H, o of 1-Ph), 8.63 (s, 1 H, NH), 9.53 (s, 1 H, NH). ¹³C NMR (100 MHz, acetone-d ₆): δ = 114.1, 114.2, 121.6 (p of 1-Ph), 127.0, 129.9, 133.0 (i of 4-Ph), 148.8 (i of 1-Ph), 158.1 (p of 4-Ph), 183.3 (C=S). IR (KBr): 497, 519, 543, 578, 615, 694, 740, 768, 806, 828, 1028, 1102, 1173, 1202, 1248, 1271, 1298, 1350, 1415, 1441, 1466, 1495, 1517, 1538, 1603, 2836, 2905, 2932, 2956, 3014, 3060, 3177, 3282, 3315 cm^–1. HRMS (ESI⁺-TOF): m/z [M + Na]⁺ calcd for C₁₄H₁₅N₃OSNa: 274.1014; found: 274.1020.
• 12a https://www.sigmaaldrich.com/US/en/product/aldrich/ f3800 (accessed March 18, 2024)
• 12b https://www.sigmaaldrich.com/US/en/product/aldrich/ 128406 (accessed March 18, 2024)
• 12c https://www.sigmaaldrich.com/US/en/product/aldrich/ f14203 (accessed March 18, 2024)
• 13 Synthesis of 1-(p-Fluorophenyl)-4-phenylthiosemicarbazide (1c): NaNO₂ (2.28 g, 110 mmol) in H₂O (22.5 mL) was added in a dropwise manner to p-fluoroaniline (3.33 g, 30.0 mmol) in HCl (3.77 M, 111 mL) at 3–5 °C, and the mixture was stirred for 45 min while maintaining the temperature. The mixture was treated with SnCl₂ (11.4 g, 60.0 mmol) in concentrated HCl (13.2 mL) at 3–5 °C and stirred for 30 min at room temperature. The formed precipitate was filtered, washed with THF followed by Et₂O, suspended in H₂O (100 mL), and basified with NaOH (3.22 g, 80.5 mmol) in H₂O (80 mL). The resulting mixture was extracted with CH₂Cl₂ (3 × 100 mL), and the combined organic phases were dried with anhydrous Na₂SO₄ and evaporated in vacuo to give a yellow-brown liquid. Following the addition of Et₂O (50 mL), phenyl isothiocyanate (3.54 mL, 30.0 mmol) was added to the solution, and the mixture was stirred vigorously for 2 h. The formed crystals were filtered and washed with Et₂O to give 1c (5.01 g, 19.2 mmol, 64%). Melting point: 201.0–202.0 °C. Anal. Calcd for C₁₃H₁₂FN₃S: C, 59.75; H, 4.63; N, 16.08; S, 12.27. Found: C, 59.83; H, 4.64; N, 16.08; S, 12.28 (from acetone/Et₂O). ¹H NMR (400 MHz, acetone-d ₆): δ = 6.91 (dd, J = 4.6, 8.0 Hz, 2 H, o of 1-Ph), 7.05 (t, J = 8.8 Hz, 2 H, m of 1-Ph), 7.14 (t, J = 7.4 Hz, 1 H, p of 4-Ph), 7.31 (t, J = 8.0 Hz, 2 H, m of 4-Ph), 7.43 (s, 1 H, NH), 7.73 (d, J = 8.0 Hz, 2 H, o of 4-Ph), 8.76 (s, 1 H, NH), 9.70 (s, 1 H, NH). ¹³C NMR (100 MHz, acetone-d ₆): δ = 114.8 (d, J = 7.7 Hz, o of 1-Ph), 115.5 (d, J = 22.6 Hz, m of 1-Ph), 124.1 (o of 4-Ph), 124.8 (p of 4-Ph), 128.0 (m of 4-Ph), 139.2 (i of 4-Ph), 144.3 (i of 1-Ph), 157.7 (d, J = 235.0 Hz, p of 1-Ph), 182.0 (C=S). ¹⁹F NMR (280 MHz, acetone-d ₆): δ = 123.1. IR (KBr): 494, 512, 555, 594, 634, 693, 717, 750, 776, 822, 869, 930, 1083, 1109, 1153, 1212, 1278, 1448, 1502, 1551, 1598, 2945, 3042, 3087, 3152, 3301 cm⁻¹. HRMS (ESI⁻-TOF): m/z [M − H]⁻ calcd for C₁₃H₁₁FN₃S: 260.0658; found: 260.0658. Analogously to the preceding reactions, p-trifluoromethylaniline (162 mg, 1.00 mmol) was converted into 1e (180 mg, 0.578 mmol, 58%). Melting point: 204.4–205.2 °C Anal. Calcd for C₁₄H₁₂F₃N₃S: C, 54.01; H, 3.89; N, 13.50; S, 10.30. Found: C, 53.95; H, 3.90; N, 13.47; S, 10.28 (from acetone/Et₂O). ¹H NMR (300 MHz, CDCl₃): δ = 6.16 (s, 1 H, NH), 7.01 (d, 2 H, J = 8.4 Hz), 7.26–7.27 (m, 1 H, p of 4-Ph), 7.39 (t, J = 7.8 Hz, 2 H, m of 4-Ph), 7.44 (s, 1 H, NH), 7.56–7.60 (m, 4 H), 8.77 (s, 1 H, NH). ¹³C NMR (125 MHz, acetone-d ₆): δ = 113.0, 121.6 (J = 32.1 Hz, p of 3-Ph), 124.5, 124.95 (J = 269 Hz, CF₃), 125.03, 126.4 (J = 3.8 Hz, m of 3-Ph), 128.1, 139.2 (i of 4-Ph), 151.3 (i of 1-Ph), 182.2 (C=S). ¹⁹F NMR (280 MHz, acetone-d ₆): δ = 59.4. IR (KBr): 494, 611, 695, 724, 781, 832, 1067, 1118, 1160, 1211, 1248, 1282, 1333, 1504, 1543, 1598, 1619, 2945, 3163, 3299 cm⁻¹. HRMS (ESI⁻-TOF): m/z [M − H]⁻ calcd for C₁₄H₁₁F₃N₃S: 310.0626; found: 310.0623.
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