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Synlett 2012; 23(15): 2255-2260
DOI: 10.1055/s-0032-1317044
letter
© Georg Thieme Verlag Stuttgart · New York

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

Zhengquan Zhou
School of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Street, Yangzhou 225002, P. R. of China, Fax: +86(514)87975244   Email: wangcd@yzu.edu.cn
,
Hui Liu
School of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Street, Yangzhou 225002, P. R. of China, Fax: +86(514)87975244   Email: wangcd@yzu.edu.cn
,
Qian Sun
School of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Street, Yangzhou 225002, P. R. of China, Fax: +86(514)87975244   Email: wangcd@yzu.edu.cn
,
Yun Li
School of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Street, Yangzhou 225002, P. R. of China, Fax: +86(514)87975244   Email: wangcd@yzu.edu.cn
,
Jing Yang
School of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Street, Yangzhou 225002, P. R. of China, Fax: +86(514)87975244   Email: wangcd@yzu.edu.cn
,
Juanjuan Liu
School of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Street, Yangzhou 225002, P. R. of China, Fax: +86(514)87975244   Email: wangcd@yzu.edu.cn
,
Peiyun Yan
School of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Street, Yangzhou 225002, P. R. of China, Fax: +86(514)87975244   Email: wangcd@yzu.edu.cn
,
Cunde Wang*
School of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Street, Yangzhou 225002, P. R. of China, Fax: +86(514)87975244   Email: wangcd@yzu.edu.cn
› Author Affiliations
Further Information

Publication History

Received: 17 June 2012

Accepted after revision: 16 July 2012

Publication Date:
08 August 2012 (online)

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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

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
  • Supporting Information
 

  • References

  • 4 Liu H, Zhou Z, Sun Q, Li Y, Li Y, Liu J, Yan P, Wang D, Wang C. ACS Comb. Sci. 2012; 14: 366
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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: +44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk].