Convenient Synthesis of 2-Thioimidazolone/Menadione Conjugates via a Two-Step Sequence Starting with Direct Amination of Menadione

Abstract

A convenient route to conjugates of 2-thiohydantoins and menadione with linkers of various chemical nature through a two-stage reaction sequence (direct amination of the menadione with a functional amine followed by modification of a functional group) is presented. Optimal conditions for the direct amination of menadione using alkyl amines with substituents such as azide, alkyne, hydroxyl, amine, halogen, and carboxyl have been developed. Further modification of selected functionalities using CuAAC or esterification reactions with 2-thio­hydantoines has been performed.

Key words

quinone - direct amination - 2-thio-imidazol-4-ones - click chemistry

• References and Notes

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• 32 Direct Amination of Menadione; General Procedure: To a stirred solution of menadione (100 mg, 0.6 mmol) in EtOH (10 mL), primary amine (1.2 mmol) was added in one portion. After 12 hours of stirring in the dark, the reaction mixture became dark red. The alcohol was evaporated under reduced pressure, and the residue was dissolved in a mixture of DCM/MeOH (30:1) and purified by silica gel column chromatography, eluting with the same solvent system. All products were isolated in the form of bright-red oils that crystallized with difficulty. Crystallization occurred when oils were left standing, giving red powders.
• 33 2-Methyl-3-(prop-2-yn-1-ylamino)naphthalene-1,4-dione (1): From menadione and propargylamine (66 mg, 1.2 mmol), 1 was obtained as a bright-orange powder. Yield after purification by column chromatography: 105 mg (80%); mp 156 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.92 (d, J = 6.85 Hz, 2 H, Ar), 7.77 (t, J = 7.34 Hz, 1 H, Ar-CO), 7.69 (t, J = 7.34 Hz, 1 H, Ar-CO), 6.93 (t, J = 6.85 Hz, 1 H, NH), 4.28 (d, J = 6.85 Hz, 2 H, CH₂), 3.25 (s, 1 H, C≡CH), 2.15 (s, 3 H, CH₃). ¹³C NMR (100.67 MHz, DMSO-d ₆): δ = 182.2 (CO), 181.9 (CO), 146.0 (C-NH), 134.5 (Ar), 132.4 (Ar), 130.3 (Ar), 125.7 (Ar), 113.3 (C-CH₃), 82.0 (-C≡), 74.6 (≡CH), 33.9 (CH₂), 10.19 (CH₃). HRMS: m/z [M + H]⁺ calcd 226.0863; found. 226.0865. UV/Vis: λ (ε, Lmol^–1cm^–1): 457 (1587) nm.2-((2-Hydroxyethyl)amino)-3-methylnaphthalene-1,4-dione (2): From menadione and ethanolamine (73 mg, 1.2 mmol), 2 was obtained as a deep-violet powder. Yield after purification by column chromatography: 98 mg (73%); mp 98 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.90 (ddd, J = 7.58, 4.4, 1.17 Hz, 2 H, Ar), 7.76 (td, J = 7.58, 1.27 Hz, 1 H, Ar-CO), 7.66 (t, J = 7.58 Hz, 1 H, Ar-CO), 6.49 (t, J = 5.67, 1 H, NH), 4.90 (t, J = 5.09 Hz, 1 H, OH), 3.58 (m, 4 H, 2 × CH₂), 2.09 (s, 3 H, CH₃). ¹³C NMR (100.67 MHz, DMSO-d ₆): δ = 182.5 (CO), 182.3 (CO), 147.3 (C-NH), 134.8 (Ar), 133.2 (Ar), 132.5 (Ar), 130.6 (Ar), 126.0 (Ar), 125.8 (Ar), 111.2 (C-CH₃), 60.9 (CH₂-NH), 47.2 (CH₂-OH), 11.2 (CH₃). HRMS: [M + H]⁺ calcd 232.0968; found: 232.0969. UV/Vis: λ (ε, Lmol^–1 cm^–1): 472 (2240) nm.2-((2-Azidoethyl)amino)-3-methylnaphthalene-1,4-dione (3): From menadione and 2-azidoethylamine (103 mg, 1.2 mmol), 3 was obtained as a bright-red powder. Yield after purification by column chromatography: 122 mg (82%); mp 100 °C (dec.). ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.92 (d, J = 7.70 Hz, 2 H, Ar), 7.78 (td, J = 7.47, 1.38 Hz, 1 H, Ar-CO), 7.69 (t, J = 7.47 Hz, 1 H, Ar-CO), 6.68 (t, J = 6.69, 1 H, NH), 3.75 (q, J = 6.17 Hz, 2 H, NH-CH₂), 3.53 (t, J = 5.78 Hz, 2 H, CH₂-N₃), 2.06 (s, 3 H, CH₃). ¹³C NMR (100.67 MHz, CDCl₃): δ = 183.6 (CO), 182.1 (CO), 145.7 (C-NH), 135.6 (Ar), 134.3 (Ar), 133.6 (Ar), 132.0 (Ar), 126.5 (Ar), 126.3 (Ar), 114.0 (C-CH₃), 51.5 (CH₂-NH), 44.2 (CH₂-N_3­), 11.2 (CH₃). HRMS: m/z [M + H]⁺ calcd 257.1033; found: 257.1036. UV/Vis: λ (ε, Lmol^–1cm^–1): 467 (2797) nm
• 34 Click Reactions in CH₂Cl₂/H₂O; General Procedure: To a solution of alkyne (0.33 mmol) in CH₂Cl₂ (7.5 mL), CuSO₄·5H₂O (8 mg, 0.033 mmol) dissolved in distilled water (200 μL), followed by sodium ascorbate (14 mg, 0.066 mmol) in distilled water (200 μL) were added under an argon atmosphere. The mixture was stirred for 30 minutes and the azide (0.33 mmol) in CH₂Cl₂ (2.5 mL) was added to the dark-brown solution. The reaction mixture was then stirred overnight under argon. The reaction mixture was evaporated under reduced pressure and the solid residue was purified by silica gel column chromatography, eluting with CH₂Cl₂/MeOH (40:1).
• 35 (Z)-2-Methyl-3-(((1-(2-(5-oxo-4-(pyridin-2-ylmethylene)-2-thioxoimidazolidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-amino)naphthalene-1,4-dione (11): To 2-methyl-3-(prop-2-yn-1-ylamino)naphthalene-1,4-dione (1; 150 mg, 0.67 mmol) in CH₂Cl₂ (7.5 mL), CuSO₄·5H₂O (17 mg) dissolved in distilled water (200 μL), followed by sodium ascorbate (28 mg) in distilled water (200 μL) were added under an argon atmosphere. The mixture was stirred for 30 minutes and 5-(Z)-3-(2-azidoethyl)-2-(methylthio)-5-(pyridine-2-ylmethylene)-1H-imidazol-4H-one (193 mg, 0.67 mmol) in CH₂Cl₂ (2.5 mL) was added to the dark-brown solution and the reaction mixture was stirred overnight under argon. The pink precipitate was filtered off, dried in air and purified by silica gel column chromatography, eluting with CH₂Cl₂/MeOH (40:1). Yield after purification by column chromatography: 299 mg (87%); mp 212 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.71 (d, J = 8.1 Hz, 1 H, Нα-Ру), 8.63 (d, J = 3.91 Hz, 1 H, Нγ-Ру), 8.05 (s, 1 H, H-triazole), 7.88 (m, 2 H, Ar), 7.75 (td, J = 7.52, 1.1 Hz, 1 H, Ar), 7.66 (m, 1 H, Ar), 7.34 (m, 1 H, Нβ-Ру), 7.04 (t, J = 6.72 Hz, 1 H, Нβ′-Ру), 6.69 (s, 1 H, -CH=), 4.78 (d, J = 6.6 Hz, 2 H, NH-CH₂-), 4.60 (t, J = 6.6 Hz, 2 H, -CH₂-CH₂-), 3.95 (t, J = 5.3 Hz, 2 H, -CH₂-CH₂-), 2.58 (s, 3 H, SCH₃), 2.07 (s, 3 H, CH₃). ¹³C NMR (100.67 MHz, CDCl₃): δ = 168.7 (CO), 167.7 (CO), 149.9 (CON), 146.2 (C-SCH₃), 146.0 (Cα′-Py), 139.9 (Cα-Py), 136.6 (C-NH), 134.4 (Cγ-Py), 132.6 (CH=C<), 132.2 (CH-Ar), 130.3 (CH-Ar), 126.5 (C-Ar), 125.7 (C-Ar), 125.5 (-CH=), 123.6 (C-triazole), 123.4 (C-triazole), 121.8 (Cβ-Py), 112.1 (C-CH3), 50.3 (N-CH2-CH2-), 47.5 (NH-CH2-), 41.4 (N-CH2-CH2-), 12.9 (SCH3), 10.4 (CH3). HRMS: m/z [M + H]+ calcd 514.1656; found: 514.1664.
• 36 (Z)-2-((3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)ethyl 2-(5-Oxo-4-(pyridin-2-ylmethylene)-2-thioxoimidazolidin-1-yl)acetate (13): To a stirred solution of (Z)-2-(5-oxo-4-(pyridin-2-ylmethylene)-2-thioxoimidazolidin-1-yl)acetic acid (50 mg, 0.2 mmol) in anhydrous CH₂Cl₂ (20 mL) were added DMAP (12 mg, 0.1 mmol) and EDC·HCl (44 mg, 0.23 mmol). After stirring for 20 minutes, a solution of 2 (60 mg, 0.26 mmol) in CH₂Cl₂ (3 mL) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the solid residue was purified by silica gel column chromatography, eluting with CH2Cl2/MeOH (40:1). Yield after purification by column chromatography: 60 mg (67%); mp 196 °C. 1H NMR (400 MHz, CDCl3): δ = 8.65 (d, J = 3.96 Hz, 1 H, Hα′-Py), 8.03 (dd, J = 7.70, 0.95 Hz, 1 H, CH-Ar), 7.92 (dd, J = 7.63, 1.03 Hz, 1 H, CH-Ar), 7.73 (td, J = 7.70, 1.76 Hz, 1 H, CH′-Ar), 7.63 (td, J = 7.56, 1.32 Hz, 1 H, CH-Ar′′), 7.53 (m, 1 H, Hβ-Py), 7.38 (d, J = 7.92 Hz, 1 H, Hβ′-Py), 7.24 (m, 1 H, Hγ-Py), 6.56 (s, 1 H, -CH=), 5.72 (br. s, 1 H, NH), 4.69 (s, 2 H, CH2COO), 4.37 (t, J = 5.21 Hz, 2 H, NH-CH2-), 3.83 (q, J = 5.67 Hz, 1 H, -CH2CH2-), 2.18 (s, 3 H, CH3). 13C NMR (100.67 MHz, CDCl3): δ = 183.5 (CO), 182.1 (CO), 176.9 (CS), 173.5 (COO), 166.6 (CON), 163.3 (αC-Py), 153.4 (α′C-Py), 149.7 (>C=CH), 145.9 (CH-NH), 137.1 (γC-Py), 134.1 (βC-Py), 131.9 (CH-Ar), 130.4 (C-Ar), 130.0 (C-Ar), 126.5 (CH-Ar), 126.1 (CH-Ar), 125.9 (CH-Ar), 123.1 (β′C-Py), 114.0 (-CH=), 108.9 (CH-CH₃), 64.7 (CH₂-CH₂-COO), 44.0 (COO-CH₂-NH), 41.7 (CH₂-CH₂-COO), 11.1 (CH₃). HRMS: m/z [M + H]⁺ calcd 477.1227; found: 477.1223.