Novel Synthesis of trans-4,6-Diaryl-5-nitropiperidin-2-ones via Four-Component Reaction from Substituted Nitrostyrenes, Aromatic Aldehydes, Dimethyl Malonate, and Formamide

Abstract

An effective and practical method has been developed for the diversity-oriented synthesis of trans-4,6-diaryl-5-nitro­piperidin-2-ones via four-component reaction from substituted nitro­styrenes, aromatic aldehydes, dimethyl malonate, and formamide for the generation of a wide range of structurally interesting and pharmacologically significant compounds. It is worth mentioning that in the course of this reaction, the formation of products was highly stereoselective.

Key words

multicomponent reaction - combinatorial chemistry - piperidines - Michael addition - piperidin-2-ones

• References

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• 5 General Procedure for the Preparation of trans-4,6-Diaryl-5-nitropiperidin-2-ones: The appropriate 2-aryl-1-nitroethene (1f–k; 2 mmol), dimethyl malonate (264 mg, 2 mmol) and NaOH (320 mg, 8 mmol) were dissolved in MeOH (15 mL) at 0 °C, and the resultant mixture was stirred at 0 °C (ice-water bath) for 45 min, then the mixture was stirred sequentially from 0 °C to r.t. To the resultant solution appropriate aromatic aldehyde (2a–h; 2 mmol) and form-amide (135 mg, 3 mmol) were added at r.t. The reaction mixture was stirred under reflux for 40 h, and the completion of reaction was confirmed by TLC (EtOAc–MeOH, 10:1). Subsequently, the precipitated product was filtered off and the solid was washed with MeOH and Et₂O several times to give the product 3a–w. The filtrate was purified by flash chromatography (silica gel, EtOAc–CH₂Cl₂, 10:1) to give an additional amount of product 3a–w. The combined crude product was purified finally by crystallization from hot EtOH–EtOAc or EtOAc–CH₂Cl₂ to yield pure 3a–w. The air-dried product thus obtained showed a single spot on TLC and was pure enough for all analytical purposes. 6-(4-Chlorophenyl)-4-(4-methoxyphenyl)-5-nitropiperidin-2-one (3a): white solid; mp 275–277 °C (MeOH–CH₂Cl₂). ¹H NMR (600 MHz, DMSO-d ₆): δ = 8.21 (s, 1 H), 7.47 (d, J = 8.4 Hz, 2 H), 7.43 (d, J = 9.0 Hz, 2 H), 7.31 (d, J = 8.4 Hz, 2 H), 6.87 (d, J = 9.0 Hz, 2 H), 5.45 (dd, J = 11.4, 10.2 Hz, 1 H), 4.93 (d, J = 10.2 Hz, 1 H), 3.80 (dt, J = 12.0, 5.4 Hz, 1 H), 3.71 (s, 3 H), 2.80 (dd, J = 17.4, 12.6 Hz, 1 H), 2.54 (dd, J = 17.4, 5.4 Hz, 1 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ = 168.61, 158.70, 136.56, 133.48, 130.15, 129.57, 128.65, 128.62, 114.01, 91.85, 59.31, 54.98, 42.67, 37.65. IR (KBr): 3171, 3051, 2910, 1651, 1560, 1514, 1327, 1251, 1013, 821 cm^–1. MS (EI): m/z = 359.11 (100%) [M – 1]⁺. Anal. Calcd for C₁₈H₁₇ClN₂O₄: C, 59.92; H, 4.75; N, 9.83. Found: C, 59.90; H, 4.88; N, 9.86. 4,6-Bis(4-bromophenyl)-5-nitropiperidin-2-one (3b): white solid; mp 285–286 °C (MeOH–CH₂Cl₂). ¹H NMR (600 MHz, DMSO-d ₆): δ = 8.26 (s, 1 H), 7.61 (d, J = 8.4 Hz, 2 H), 7.54 (d, J = 8.4 Hz, 2 H), 7.37 (d, J = 7.8 Hz, 4 H), 5.55 (t, J = 10.8 Hz, 1 H), 4.93 (d, J = 10.2 Hz, 1 H), 3.91 (dt, J = 12.0, 6.0 Hz, 1 H), 2.81 (dd, J = 17.4, 12.6 Hz, 1 H), 2.58 (dd, J = 17.4, 5.4 Hz, 1 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ = 168.22, 137.78, 136.81, 131.62, 131.57, 129.90, 129.84, 122.19, 121.04, 91.18, 59.31, 42.79, 37.23. IR (KBr): 3172, 3047, 2911, 1646, 1559, 1488, 1326, 1108, 1009, 812 cm^–1. MS (EI): m/z = 452.92 (100%) [M + 1]⁺. Anal. Calcd for C₁₇H₁₄Br₂N₂O₃: C, 44.96; H, 3.11; N, 6.17. Found: C, 44.87; H, 3.18; N, 6.26.
• 6 See Supporting Information.
• 7 Crystallographic data for 3a have been deposited with the Cambridge Crystallographic Data Centre with the deposition number CCDC 842352. These data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone]; e-mail: [e-mail]].