Highly Stereoselective Synthesis of 2-Aminobenzylidene Derivatives by a Convergent 3-Component Approach

Abstract

An one-pot stereoselective synthesis of 2-aminobenzylidene derivatives from readily available 5-nitro/cyano-activated 2-halobenzaldehydes (2-chloro-5-nitrobenzaldehyde, 2-bromo-5-nitrobenzaldehyde, 2-fluoro-5-nitrobenzaldehyde, 5-cyano-2-fluorobenzaldehyde), the active methylidene compounds (cyanoacetamide and ethyl cyanoacetate), and secondary cycloamines via a novel parallel convergent Knoevenagel–nucleophilic aromatic substitution and nucleophilic aromatic substitution–Knoevenagel condensation cascade approach under mild conditions has been developed with high stereoselectivity and in 52–88% yields.

Key words

convergent cascade - Knoevenagel–S_NAr reaction - one-pot reaction - 2-halobenzaldehyde

• References and Notes


For selected recent reviews of MCR, see:
• 1a Brauch S, van Berkel SS, Westermann B. Chem. Soc. Rev. 2013; 42: 4948
• 1b Dömling A, Wang W, Wang K. Chem. Rev. 2012; 112: 3083
• 1c de Graaff C, Ruijter E, Orru RV. A. Chem. Soc. Rev. 2012; 41: 3969
• 1d Ruijter E, Scheffelaar R, Orru RV. A. Angew. Chem. Int. Ed. 2011; 50: 6234
• 1e Estevez V, Villacampa M, Menendez JC. Chem. Soc. Rev. 2010; 39: 4402
• 1f Ganem B. Acc. Chem. Res. 2009; 42: 463
• 1g Hulme C. Multicomponent Reactions . Zhu J, Bienyamé H. Wiley-VCH; Weinheim: 2005: 311-341

For selective recent examples of MCR, see:
• 2a Deng XX, Du FS, Li ZC. ACS Macro Lett. 2014; 3: 667
• 2b Liu FL, Chen JR, Zou YQ, Wei Q, Xiao WJ. Org. Lett. 2014; 16: 3768
• 2c Powner MW, Zheng SL, Szostak JW. J. Am. Chem. Soc. 2012; 134: 13889
• 2d Chen MZ, Micalizio GC. J. Am. Chem. Soc. 2012; 134: 1352
• 2e Jiang B, Yi MS, Shi F, Tu SJ, Pindi S, McDowell P, Li G. Chem. Commun. 2012; 48: 808
• 2f Kumar A, Gupta MK, Kumar M. Green Chem. 2012; 14: 290
• 2g Burchak ON, Mugherli L, Ostuni M, Lacapere JJ, Balakirev MY. J. Am. Chem. Soc. 2011; 133: 10058
• 2h Maeda S, Komagawa S, Uchiyama M, Morokuma K. Angew. Chem. Int. Ed. 2011; 50: 644
• 2i Znabet A, Ruijter E, de Kanter FJ. J, Koehler V, Helliwell M, Turner NJ, Orru RV. A. Angew. Chem. Int. Ed. 2010; 49: 5289
• 2j Presset M, Coquerel Y, Rodriguez J. Org. Lett. 2009; 11: 5706
• 2k Airiau E, Girard N, Mann A, Salvadori J, Taddei M. Org. Lett. 2009; 11: 5314
• 3 Powers JC, Asgian JL, Ekici ÖD, James KE. Chem. Rev. 2002; 102: 4639
• 4a Cao J, Feng JX, Wu YX, Tuo YY. P. Chin. Chem. Lett. 2010; 21: 935
• 4b Medimagh R, Marque S, Prim D, Chatti S, Zarrouk H. J. Org. Chem. 2008; 73: 2191
• 4c Sutharsan J, Lichlyter D, Wright NE, Dakanali M, Haidekker MA, Theodorakis EA. Tetrahedron 2010; 66: 2582
• 5a Xu H, Yu X.-H, Sun L.-Y, Liu J, Fan W, Shen Y.-J, Wang W. Tetrahedron Lett. 2008; 49: 4687
• 5b Zu L.-S, Xie H.-X, Li H, Wang J, Yu X.-H, Wang W. Chem. Eur. J. 2008; 14: 6333
• 5c Wang J, Zhang M.-M, Zhang S.-L, Xu Z.-A, Li H, Yu X.-H, Wang W. Synlett 2011; 473
• 5d Zou Z.-Q, Deng Z.-J, Yu X.-H, Zhang M.-M, Zhao S.-H, Luo T, Yin X, Xu H, Wang W. Sci. China Chem. 2012; 55: 43
• 5e Xie H.-X, Zhang S.-L, Li HX.-S, Zhao S.-H, Xu Z.-A, Song X.-X, Yu X.-H, Wang W. Chem. Eur. J. 2012; 18: 2230
• 5f Zhang X.-S, Song X.-X, Li H, Zhang S.-L, Chen X.-B, Yu X.-H, Wang W. Angew. Chem. Int. Ed. 2012; 51: 7282
• 6 Nitsche C, Steuer C, Klein CD. Bioorg. Med. Chem. 2011; 19: 7318
• 7 Mečiarová M, Toma S, Podlesná J, Kiripolský M, Císařová I. Monatsh. Chem. 2003; 134: 37
• 8 Prim D, Kirsch G. Tetrahedron 1999; 55: 6511
• 9 Typical Experimental Procedure Cyclic secondary amine (2.5 equiv) was treated with 2-halobenzaldehyde (1 mmol) and active methylidene compound (1 mmol) in EtOH (2 mL) or DMF (2 mL). The mixture was stirred and heated to reflux. After the reaction was completed, the mixture was cooled down to r.t. and poured into H₂O (10 mL). Crude products were filtered off and purified by recrystallization in EtOH or by column chromatography on silica gel; 52–88% yield. (E)-α-Cyano-3-[5-nitro-2-(piperidin-1-yl)phenyl]-acrylamide (4a) Yield 81%; yellow solid; 0.24 g. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.66 (1 H, d, J = 2.4 Hz), 8.36 (1 H, m, J = 2.4, 2.8 Hz), 8.08 (1 H, s), 7.96 (1 H, s), 7.84 (1 H, s), 7.24 (1 H, d, J = 9.2 Hz), 3.13 (4 H, s), 1.68 (4 H,s), 1.61 (2 H, s). ¹³C NMR (101 MHz, DMSO-d ₆) δ = 162.58, 158.82, 147.99, 140.06, 127.74, 125.50, 123.44, 119.09, 116.37, 106.10, 53.54, 25.98, 23.82. (E)-α-Cyano-3-[5-nitro-2-(pyrrolidin-1-yl)phenyl]-acrylamide (4b) Yield 72%; yellow solid; 0.24g. ¹H NMR (400 MHz, DMSO-d ₆) δ = 8.68 (1 H, d, J = 2.4 Hz), 8.31 (1 H, m, J = 2.4, 2.8 Hz), 8.13 (1 H, s), 7.99 (1 H, s), 7.85 (1 H, s), 7.31 (1 H, d, J = 8.8Hz), 3.78 (4 H, s), 3.16 (4 H, s). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 162.45, 157.87, 147.47, 140.88, 127.82, 125.53, 123.97, 119.29, 116.28, 109.10, 66.39, 52.66. (E)-α-Cyano-3-[5-nitro-2-(morpholin-1-yl)phenyl]-acrylamide(4c) Yield 88%; yellow solid; 0.25g. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.68 (1 H, d, J = 2.4 Hz), 8.31 (1 H, m, J = 2.4, 2.8 Hz), 8.13 (1 H, s), 7.99 (1 H, s), 7.86 (1 H, s), 7.32 (1 H, d, J = 9.2 Hz), 3.79 (4 H, m), 3.17 (4 H, m). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 162.44, 157.87, 147.47, 140.87, 127.80, 125.51, 123.98, 119.26, 116.28, 109.05, 66.39, 52.66. (E)-α-Cyano-3-[5-nitro-2-(4-methylpiperazin-1-yl)phenyl]acrylamide(4d) Yield 76%; yellow solid; 0.25g. ¹HNMR (400 MHz, DMSO-d ₆): δ = 8.66 (1 H, d, J = 2.4 Hz), 8.26 (1 H, m, J = 2.2, 9.0 Hz), 8.08 (1 H, s), 7.97 (1 H, s), 7.84 (1 H, s), 7.27 (1 H, d, J = 9.2 Hz), 3.16 (4 H, s), 2.51 (4 H, s), 2.25 (3 H, s). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 162.47, 158.04, 147.70, 140.56, 127.77, 125.48, 123.72, 119.28, 116.32, 108.64, 54.74, 52.28, 45.99.
• 10a Lee J, Gauthier D, Rivero R. J. Org. Chem. 1999; 64: 3060
• 10b Gazit A, Yaish P, Gilon C, Levitzki A. J. Med. Chem. 1989; 32: 2344
• 10c Xu H, Yu X.-H, Sun L.-Y, Liu J, Fan W, Shen Y.-J, Wang W. Tetrahedron Lett. 2008; 49: 4687
• 10d Sutharsan J, Lichlyter D, Wright N, Dakanali M, Haidekker MA, Theodorakis EA. Tetrahedron 2010; 66: 2582
• 10e Balalaie S, Bararjanian M, Hekmat S, Salehi P. Synth. Commun. 2006; 36: 3703