Ionic Liquid Driven Nucleophilic Substitution of Squaric Acid to Squaramides

Abstract

Solubility is a crucial encumbrance for the synthesis of squaramides through nucleophilic substitution of squaric acid. The reactions must be performed in an aqueous medium since squaric acid is insoluble in virtually all organic solvents. The scope of amine nucleophiles was consequently restricted to those amines soluble in water. Owing to remarkable solvating ability of ionic liquid, reactions of squaric acid with a variety of structurally diverse amine nucleophiles were achieved. Interestingly, a catalyst-free reaction in 1-butyl-3-methylimidazolium chloride or [bmim]Cl could produce squaramides up to 99% yield. With the same efficacies, [bmim]Cl could be reused for at least three cycles. The catalyst-free, ionic liquid mediated approach expanded the reactant scope and offered a simple, efficient, and environmentally friendly synthesis of squaramides.

Key words

squaric acid - squaramide - [bmim][Cl] - ionic liquid - solvent effect - catalyst-free

• References and Notes

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• 14 General Procedure for Synthesis of Squaramides in [bmim]Cl A mixture of squaric acid (0.9 mmol) and nitrogen nucleophile (0.9 mmol) in [bmim]Cl (200 mg) was heated to 85 °C. The progress of the reaction was monitored by TLC; after completion of the reaction, the mixture was allowed to cool to room temperature, and 10 mL of water was added to the mixture. The resultant precipitate was filtered to afford the pure compounds. For products that did not precipitate, the aqueous layer was extracted with ethyl acetate (3 × 10 mL), and the combined organic phases were evaporated. The crude product was purified by flash chromatography on a silica gel column with an ethyl acetate–EtOH mixture. Cyclobuta[b]quinoxaline-1,2(3H,8H)-dione (4b) Dark red solid; yield: 97% ([bmim]Cl). ¹H NMR (400 MHz, DMSO-d ₆): δ = 6.67–6.64 (dd, J = 5.67, 3.43 Hz, 2 H), 6.37–6.35 (dd, J = 5.68, 3.43 Hz, 2 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 178.8, 174.9, 132.2, 125.3, 116.9. IR (KBr): ν_max = 3454, 3008, 1791, 1610, 1480, 1358 cm^–1. ESI-MS: m/z = 186 [M]⁺. Decomposition point: 276 °C. 3-(4-Aminophenylamino)-4-hydroxycyclobut-3-ene-1,2-dione (3c) Yellow solid; yield: 99% ([bmim]Cl). ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.95 (s, 1 H), 7.65–7.63 (d, J = 7.13 Hz, 2 H), 7.11–7.09 (d, J = 6.73 Hz, 2 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 191.7, 185.9, 173.0, 145.0, 135.0, 119.8, 119.6. IR (KBr): ν_max = 3415, 3026, 3000, 1793, 1639, 1450, 1336, 832 cm^–1. ESI-MS: m/z = 204 [M]⁺. Decomposition point: 201 °C.
• 15 General Procedure for Synthesis of Squaramides in Aqueous Medium In a 50 mL round-bottomed flask, squaric acid (0.9 mmol), the appropriate water-soluble amine (0.9 mmol), and water (6 mL) were heated at reflux. The progress of the reaction was monitored by TLC. Upon cooling of the reaction mixtures after completion of the reaction, the corresponding squaramides (4a, 4b, 4d, and 3c) precipitated. The resultant precipitate was filtered to afford the pure compounds. For 3h that did not precipitate, the solvent was removed by freeze-drying. The crude product was purified by flash chromatography on a silica gel column with an ethyl acetate–EtOH mixture. 3,4-Bis(4-nitrophenylamino)cyclobut-3-ene-1,2-dione (4d) Red solid; yield: 45% (H₂O). ¹H NMR (500 MHz, DMSO-d ₆): δ = 7.96–7.94 (d, J = 9.05 Hz, 2 H), 6.61–6.59 (d, J = 9.10 Hz, 2 H). ¹³C NMR (400 MHz, DMSO-d ₆): δ = 187.7, 140.6, 127.0, 125.5, 117.7, 113.0. ESI-MS: m/z = 234 [M]⁺. Decomposition point: 205 °C. IR (KBr): ν_max = 3482, 3074, 1791, 1552, 1328, 1304, 842 cm^–1.
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• 17 Recycling of [bmim]Cl in the Synthesis of Squaramide 4b Aqueous residue containing [bmim]Cl was washed six times with 10 mL of ethyl acetate to remove unreacted substrates. The aqueous layer was vacuum dried to yield [bmim]Cl. The recovered ionic liquid was dried in an oven at 75 °C. The prototypical reaction was reproduced by mixing the recycled [bmim]Cl with 1 (0.9 mmol) and 2b (0.9 mmol) in a 50 mL round-bottomed flask. The mixture was stirred at 85 °C for 3 h and then poured into water (10 mL). The resultant precipitate was filtered to afford 4b. Product yield was calculated. The recycling process has been repeated for the aqueous residue obtained. The efficiency of the recycled [bmim]Cl was assessed based on the product yield of each cycle.