Synlett 2011(18): 2740-2744  
DOI: 10.1055/s-0031-1289525
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

1,6-Conjugated Addition of Nitromethane to (E)-2-Styrylchromones: A New Synthesis of Novel 2-Substituted 4-Arylpyrrole Derivatives

Eduarda M. P. Silva, Artur M. S. Silva*, José A. S. Cavaleiro
Department of Chemistry, QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
Fax: +351(234)370714; e-Mail: [email protected];
Further Information

Publication History

Received 19 August 2011
Publication Date:
19 October 2011 (online)

Abstract

The 1,6-conjugate addition of nitromethane to (E)-2-styrylchromones were achieved, in moderate to good yields, by using DBU as organocatalyst. Reduction studies on the 2-(2-aryl-3-nitropropyl)chromone adducts formed surprisingly led to novel 2-substituted 4-arylpyrrole derivatives. These new derivatives are formed from nitro-group reduction, followed by a 1,4-Michael-type addition of the primary amine intermediate to the α,β-unsaturated carbonyl system of the chromone moiety and concomitant heterocyclic ring opening.

    References and Notes

  • 1a Gerwick WH. Lopez A. Van Duyne GD. Clardy J. Ortiz W. Baez A. Tetrahedron Lett.  1986,  27:  1979 
  • 1b Gerwick AWH. J. Nat. Prod.  1989,  52:  252 
  • 1c Yoon JS. Lee MK. Sung SH. Kim YC. J. Nat. Prod.  2006,  69:  290 
  • 2a Gomes A. Freitas M. Fernandes E. Lima JLFC. Mini-Rev. Med. Chem.  2010,  10:  1 
  • 2b Silva AMS. Pinto DCG. Cavaleiro JAS. Levai A. Patonay T. ARKIVOC  2004,  (vii):  106 
  • 3 Pinto DCGA. Silva AMS. Almeida LMPM. Cavaleiro JAS. Levai A. Patonay T. J. Heterocycl. Chem.  1998,  35:  217 
  • 4 Doria G. Romeo C. Forgione A. Sberze P. Tibolla N. Corno ML. Cruzzola G. Cadelli G. Eur. J. Med. Chem.  1979,  347 
  • 5a Momoi K. Sugita Y. Ishihara M. Satoh K. Kikuchi H. Hashimoto K. Yokoe I. Nishikawa H. Fujisawa S. Sakagami H. In Vivo  2005,  19:  157 
  • 5b Marinho J. Pedro M. Pinto DCGA. Silva AMS. Cavaleiro JAS. Sunkel CE. Nascimento MSJ. Biochem. Pharmacol.  2008,  75:  826 
  • 5c Shaw AY. Chang CY. Liau HH. Lu PJ. Chen HL. Yang CN. Li HY. Eur. J. Med. Chem.  2009,  2552 
  • 5d Pinto DCGA. Silva AMS. Cavaleiro JAS. New J. Chem.  2000,  24:  85 
  • 6a Desideri N. Conti C. Mastromarino P. Mastropaolo F. Antivir. Chem. Chemother.  2000,  11:  373 
  • 6b Desideri N. Mastromarino P. Conti C. Antivir. Chem. Chemother.  2003,  14:  195 
  • 6c Conti C. Mastromarino P. Goldoni P. Portalone G. Desideri N. Antivir. Chem. Chemother.  2005,  16:  267 
  • 7a Fernandes E. Carvalho F. Silva AMS. Santos CMM. Pinto DCGA. Cavaleiro JAS. Bastos ML. J. Enzyme Inhib. Med. Chem.  2002,  17:  45 
  • 7b Fernandes E. Carvalho M. Carvalho F. Silva AMS. Santos CMM. Pinto DCGA. Cavaleiro JAS. Bastos ML. Arch. Toxicol.  2003,  77:  500 
  • 7c Filipe P. Silva AMS. Morliere P. Brito CM. Patterson LK. Hug GL. Silva JN. Cavaleiro JAS. Maziere J.-C. Freitas JP. Santus R. Biochem. Pharmacol.  2004,  67:  2207 
  • 7d Gomes A. Fernandes E. Silva AMS. Santos CMM. Pinto DCGA. Cavaleiro JAS. Lima JLFC. Bioorg. Med. Chem.  2007,  15:  6027 
  • 8 Gomes A. Fernandes E. Silva AMS. Pinto DCGA. Santos CMM. Cavaleiro JAS. Lima JLFC. Biochem. Pharmacol.  2009,  78:  171 
  • 9 Karton Y. Jiang J.-L. Ji X.-D. Melman N. Olah ME. Stiles GL. Jacobson KA. J. Med. Chem.  1996,  39:  2293 
  • 10 Perlmutter P. In Conjugate Addition Reactions in Organic Synthesis   Pergamon Press; Oxford: 1992. 
  • 11a Vuagnoux-d’Augustin M. Alexakis A. Chem. Eur. J.  2007,  13:  9647 
  • 11b Alexakis A. Benhaim C. Eur. J. Org. Chem.  2002,  3221 
  • 11c Krause N. Hoffmann-Röder A. Synthesis  2001,  171 
  • 11d Hayashi T. Acc. Chem. Res.  2000,  33:  354 
  • 12 Almasi D. Alonso DA. Najera C. Tetrahedron: Asymmetry  2007,  18:  299 
  • Review:
  • 13a Krause N. Thorand S. Inorg. Chim. Acta  1999,  296:  1 
  • 13b Csákÿ AG. de la Herrán G. Murcia MC. Chem. Soc. Rev.  2010,  39:  4080 
  • 14a Oliva CG. Silva AMS. Paz FAA. Cavaleiro JAS. Synlett  2010,  1123 
  • 14b Oliva CG. Silva AMS. Resende DISP. Paz FAA. Cavaleiro JAS. Eur. J. Org. Chem.  2010,  3449 
  • 17 Patoilo DT. Silva AMS. Cavaleiro JAS. Synlett  2010,  1381 
  • 20 Burros AIRNA. Silva AMS. Tetrahedron Lett.  2003,  44:  5893 
15

Typical Procedure for the Preparation of 2-(2-Aryl-3-nitromethyl)chromones 2a-d
A flask containing the appropriate (E)-2-styrylchromone 1a-d (0.104 mmol), nitromethane (0.33 mL), and DBU
(3 µL, 0.021 mmol) was flushed with nitrogen and stirred vigorously at r.t. After the appropriate time (Table  [²] ), the solvent was evaporated under reduced pressure. The residue was taken in EtOAc and purified by preparative TLC on silica. Elution with hexane-EtOAc (7:3 or 1:1) gave the desired products 2a-d (for yields see Table  [²] ).

16

Physical Data of 2-(3-Nitro-2-phenylpropyl)-4 H -chromen-4-one (2a)
Colourless oil. ¹H NMR (300 MHz, CDCl3): δ = 8.12 (1 H, dd, J = 1.6, 8.1 Hz, H-5), 7.65 (1 H, ddd, J = 1.6, 7.0, 8.5 Hz, H-7), 7.41-7.18 (7 H, m, H-Ph, H-6, and H-8), 6.03 (1 H, s, H-3), 4.72 (2 H, d, J = 7.6 Hz, β-CH2NO2), 4.11-4.01 (1 H, m, H-β), 3.09 (1 H, dd, J = 6.5, 14.5 Hz, H-α), 3.00 (1 H, dd, J = 8.8, 14.5 Hz, H-α). ¹³C NMR (75 MHz, CDCl3): δ = 177.7 (C-4), 164.8 (C-2), 156.2 (C-9), 137.2 (C-1′), 133.7 (C-7), 129.2 (C-3′,5′), 128.3 (C-4′), 127.2 (C-2′,6′), 125.7 (C-5), 125.2 (C-6), 123.5 (C-10), 117.7 (C-8), 111.8 (C-3), 79.4 (β-CH2NO2), 41.9 (C-β), 38.1 (C-α). HRMS (ESI+):
m/z calcd for C18H16NO4 [M + H]+: 310.1074; found: 310.1074.

18

( Z )-(2-Hydroxyphenyl) (4-Phenylpyrrolidin-2-ylidene)methyl Ketone (3a)
Yellow solid; mp 113-115 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 13.80 (1 H, s, OH), 9.95 (1 H, s, NH), 7.65 (1 H, dd, J = 1.4, 8.0 Hz, H-6′′′), 7.37-7.24 (6 H, m, H-Ph and H-4′′′), 6.93 (1 H, dd, J = 1.0, 8.3 Hz, H-3′′′), 6.82-6.79 (1 H, m, H-5′′′), 5.87 (1 H, s, H-2), 4.08 (1 H, ddd, J = 1.0, 7.7, 10.6 Hz, H-5′), 3.71 (1 H, dd, J = 7.7, 10.6 Hz, H-5′), 3.64 (1 H, quin, J = 7.7 Hz, H-4′), 3.19 (1 H, dd, J = 7.7, 16.9 Hz, H-3′), 2.93 (1 H, dd, J = 7.6, 16.9 Hz, H-3′). ¹³C NMR (75 MHz, CDCl3): δ = 191.3 (C-1), 168.6 (C-2′), 162.3 (C-2′′′), 141.8 (C-1′′), 133.5 (C-4′′′), 128.9 (C-3′′,5′′), 127.7 (C-6′′′), 127.2 (C-4′′), 126.8 (C-2′′,6′′), 120.3 (C-1′′′), 118.2 (C-3′′′), 118.1 (C-5′′′), 85.4 (C-2), 55.2 (C-5′), 41.2 (C-3′), 40.7 (C-4′). HRMS (ESI+): m/z calcd for C18H18NO2 [M + H]+: 280.1332; found: 280.1332.

19

Typical Procedure for the Preparation of the 2-Substituted 4-Arylpyrrole Derivatives 3a-d Using Method A Ammonium formate (0.864 mmol) and Pd/C (10%; 7.0 mg) were added to a solution of the appropriate 2-(2-aryl-3-nitropropyl)-4H-chromen-4-one 2a-d (0.082 mmol) in acetone (1 mL), and the reaction mixture was refluxed for 1 h. After cooling to r.t., the reaction mixture was filtered through Celite, and the organic layer was evaporated to dryness. The residue was purified by preparative TLC on silica and eluted with a mixture of hexane-EtOAc (7:3) to give 3a-d (for yields see Table  [³] ).

21

Typical Procedure for the Preparation of the 2-Substituted 4-Arylpyrrole Derivatives 3a-d Using Method B To a solution of the appropriate 2-(2-aryl-3-nitropropyl)-4H-chromen-4-one 2a-d (0.082 mmol) in CHCl3 (10 mL), tin (powder, 0.81 g) and concd HCl (2.7 mL) were added, and the reaction mixture was stirred for 2 h at r.t. After this period, the reaction mixture was neutralized with NaHCO3, filtered through Celite, and the solid residue washed with H2O and CHCl3. The filtrate was extracted with CHCl3 (3 × 15 mL), the organic layer dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative TLC on silica eluting with a mixture of hexane-EtOAc (7:3) to afford 3a-d (for yields see Table  [³] ).