Expeditious ‘On-Water’ Cycloaddition between N-Substituted Maleimides and Furans

Abstract

Cycloaddition reactions between N-alkyl and N-aryl-substituted maleimides and furan derivatives have been carried out using the ‘on-water’ methodology. Transformations are faster and products can easily be isolated by simple workup protocols, often in quantitative yields.

Key words

cycloaddition - heterocycles - green chemistry

• References and Notes

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• 24 General Procedure for Cycloadditions between N-Phenyl- or N-Ethylmaleimides 5a,b and Furans 6a–c A) In a 10 mL round-bottom flask the maleimide (ca. 0.5 g) was dissolved in the minimum quantity of furan 6a–c (0.5–1.7 mL); H₂O (3 mL) was added, and the resulting mixture was subjected to vigorous magnetic vigorous at 25 °C. After the time specified in Table 1, ¹H NMR spectroscopic analysis and TLC (EtOAc–hexane, 1:1) revealed the absence of starting materials and appearance of the respective cycloadducts. The products either immediately precipitated, from the reaction medium or after overnight storage in the refrigerator, and were filtered and washed on the filter with cold H₂O. In the case of reaction between 5b and 6b, the reaction mixture was diluted with brine (5 mL), extracted with CH₂Cl₂ (3 × 5 mL), the combined extracts dried over MgSO₄, filtered, and evaporated to afford an oil that crystallized after 24 h into the freezer. Then, the solid was collected by filtration and washed on the filter with cold H₂O. Yields were quantitative and, in all cases, analytically pure samples of each one of the adducts could be isolated by preparative TLC. The exo adduct 7b was the only product obtained after refluxing an aqueous suspension of a mixture of 7a and 7b for 45 min. B) Following the same procedure above, reactions were complete after stirring at 65 °C for times specified in Table 1. Then, the adducts, which precipitated in the reaction mixture, were filtered and collected as indicated above.
• 25 General Procedure for Cycloadditions between N-tert-Butylmaleimide 5c and Furans 6a–c In a 10 mL round-bottom flask, N-tert-butylmaleimide (5c, 0.2 mL, 1.38 mmol) was mixed with an equimolar quantity of the furans 6a–c (0.10–0.15 mL), H₂O was added (3 mL), and the resulting suspension was subjected to magnetic vigorous stirring at 25 °C. After times specified in Table 1, ¹H NMR and TLC (EtOAc–hexane, 1:2) analyses showed no further progress of the reaction with the mixture still containing unreacted starting materials. Except for the reaction between 5c and 6a, the products precipitated and were collected by filtration and washed on the filter with cold H₂O. In this case, workup of the reaction mixture was the same as indicated in ref. 24. Adducts 13a and 13b were separated by preparative TLC.
• 26 1-[(E)-2,2-Dimethylhydrazono]-7-oxabicyclo[2.2.1]hept-5-ene-2,3-exo-dicarboxy-N-phenylimide (16a) and 4-[(E)-2,2-Dimethylhydrazono]-2-phenylisoindoline-1,3-dione (17a) Following the two methods A and B as described above, cycloaddition of N-phenylmaleimide (5a) and furfural N,N-dimethylhydrazone (9) led quantitatively to adduct 16a as a yellow solid that was filtered and washed on the filter with cold H₂O. By refluxing a suspension of 16a (0.85 g) in H₂O (25 mL) for 50 min, this compound was converted quantitatively into phenylisoindoline 17a, isolated by filtration as an yellow-orange solid and recrystallized from EtOH.
• 27 4-[(E)-2,2-Dimethylhydrazono]-2-ethylisoindoline-1,3-dione (19b) Following methods A and B as described above, treatment of N-ethylmaleimide (5b, 0.4 g, 3.20 mmol) and furfural N,N-dimethyl hydrazone (9, 0.5 mL, 3.77 mmol) led quantitatively to ethylisoindoline 19b as a solid that was filtered and washed on the filter with cold H₂O.
• 28 1-[(E)-2,2-Dimethylhydrazono]-7-oxabicyclo[2.2.1]hept-5-ene-2,3-exo-dicarboxy-N-tert-butylimide (20c) and 4-[(E)-2,2-Dimethylhydrazono]-2-tert-butylisoindoline-1,3-dione (21c) Following the general procedure above described for the reactions of furans with N-tert-butyl maleimide (5c), treatment of the latter compound (0.2 mL, 1.38 mmol) with furfural N,N-dimethylhydrazone (9, 0.185 mL, 1.39 mmol) led to an equilibrium mixture (see Table 1) from which 37% yield of the title compounds were isolated by filtration and washing on the filter with cold H₂O.
• 29 For ¹H NMR and ¹³C NMR spectra of all compounds see the Supporting Information.