Et₃N-Promoted Tandem Cyclization of Bromomaleimides with Active Methylene Compounds: An Efficient Synthesis of cis-3,4-Dihydropyrrolidine-2,5-diones

Abstract

The Et₃N-promoted tandem cyclization of bromomaleimides with active methylene compounds is presented, providing an efficient method for the synthesis of cis-3,4-dihydropyrrolidine-2,5-diones in moderate to good yields under mild conditions.

Key words

Michael addition - tandem reaction - bromomaleimides - cis-3,4-dihydropyrrolidine-2,5-diones

• References and Notes

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• 13 Compounds cis-c; General ProcedureTo a stirred solution of bromomaleimide a (0.3 mmol) and 1,3-dicarbonyl compound b (0.33 mmol) in THF (5 mL) was added Et₃N (0.5 mL) and the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and the residue purified by silica gel column chromatography (PE–EtOAc, 3:1) to afford the product cis-c. cis-2-Benzyl-6,6-dimethyl-5,6,7,8b-tetrahydro-1H-benzofuro[2,3-c]pyrrole-1,3,8(2H,3aH)-trione (cis-c1)IR (KBr): 2961, 2924, 2869, 1786, 1705, 1629, 1393, 1340, 1212, 1177 cm^–1; ¹H NMR (500 MHz, CDCl₃): δ = 7.33–7.31 (m, 2 H), 7.28–7.25 (m, 3 H), 5.44 (d, J = 8.75 Hz, 1 H), 4.64 (s, 2 H), 4.33 (d, J = 8.75 Hz, 1 H), 2.34 (d, J = 1.25 Hz, 2 H), 2.25 (d, J = 16.25 Hz, 1 H), 2.21 (d, J = 16.25 Hz, 1 H), 1.08 (s, 3 H), 0.99 (s, 3 H); ¹³C NMR (125 MHz, CDCl₃): δ = 192.48, 176.90, 172.54, 171.50, 134.94, 128.81, 128.63, 128.12, 109.39, 81.77, 51.03, 46.06, 42.66, 37.55, 34.02, 28.36, 28.28; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₉H₁₉NO₄Na: 348.1206; found: 348.1213.
• 14 The cis-stereochemistry was based on the same chemical shifts of H-3 and H-4 and of C-3 and C-4, as well as by considering the adjacent dihydropyrrolidine-2,5-dione ring and the fact that the rigid structure of the three-membered ring stopped rotation or distortion, which led to only the cis-configuration.
• 15 Compounds cis-h; General Procedure A mixture of bromomaleimide a (0.3 mmol), active methylene compound g (0.33 mmol), TBAB (5 mol%), Et₃N (0.5 mL) and THF (5 mL) was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and H₂O was added. The aqueous layer was extracted with EtOAc (3 × 20 mL) and the combined organic layers washed with brine and dried over MgSO₄. The solvent was removed in vacuo and the residue purified by column chromatography (PE–EtOAc, 2:1) to give the product cis-h. cis -Ethyl 3-benzyl-6-cyano-2,4-dioxo-3-azabicyclo[3.1.0] hexane-6-carboxylate ( cis -h1) IR (KBr): 3081, 2984, 2248, 1788, 1751, 1710, 1606, 1497, 1393, 1277, 1227, 1165 cm^–1; ¹H NMR (500 MHz, CDCl₃): δ = 7.40–7.38 (m, 2 H), 7.33–7.30 (m, 3 H), 4.60 (s, 2 H), 4.33 (q, J = 6.75 Hz, 2 H), 3.25 (s, 2 H), 1.37 (t, J = 6.40 Hz, 3 H); ¹³C NMR (125 MHz, CDCl₃): δ = 167.99, 162.36, 134.53, 129.12, 128.64, 128.27, 112.07, 64.59, 43.09, 32.66, 30.23, 13.85; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₆H₁₄N₂O₄Na: 321.0846; found: 321.0841.
• 16 The amount of Et₃N could lead to a change in the reaction yield based on the conditions tested (see Table 1, entries 6–8). Therefore, we think Et₃N may have some solvent effect in the reaction besides serving as a base.
• 17 At present, the reason for the formation of cis products is not clear. However, we think that the reason may be due to the effects of the adjacent dihydropyrrolidine-2,5-dione ring and the relative rigidity of the double bonds of the enol anion, or the potential that the three-membered ring stopped its rotation or distortion, which led to subsequent intramolecular nucleophilic attack only occurring on the same side of the ring and thus leading to the cis-isomer.
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