First Use of HEH in Oxazine Synthesis: Hydroxy-Substituted 2H-1,4-Benzoxazine Derivatives

Abstract

The synthesis of 2H-1,4-benzoxazine derivatives from 1,2-epoxy-3-(2-nitroaryloxy)propanes in the presence of Hantzsch 1,4-dihydropyridine (HEH) and Pd/C as a catalyst was achieved. The nitro group was reduced before the epoxide functionality, leading to attack of the amino group on the epoxide moiety in a 6-exo-fashion. By introducing a methyl group at the 1-position, the 7-endo ring-closed product could also be formed.

Key words

Hantzsch 1,4-dihydropyridine ester - organic reductant - hydrogen transfer - benzoxazine derivatives - domino reaction

References and Notes

• 1a Sainsbury M. Thiazines and Their Benzoderivatives, In Comprehensive Heterocyclic Chemistry   Vol. 3:  Katritzky AR. Rees CW. Pergamon; Oxford: 1984.  p.995-1038  
• 1b Ellis GP. Synthesis of Fused Heterocycles   John Wiley and Sons; New York: 1987.  p.55-57  
• 2 Niemeyer HM. Phytochemistry  1988,  27:  3349 
• 3a Empfield JR. Russell K. Annu. Rep. Med. Chem.  1995,  30:  81 
• 3b Caliendo G. Grieco P. Perissutti E. Santagada V. Santini A. Alberizio S. Fattorusso C. Pinto A. Sorrentino R. Eur. J. Med. Chem.  1998,  33:  957 
• 3c Sebille S. De Tullio P. Boverie S. Antoine MH. Lebrun P. Pirotte B. Curr. Med. Chem.  2004,  11:  1213 
• 4 Touzeau F. Arrault A. Guillaumet G. Scalbert E. Pfeiffer B. Rettori M. Renard P. Mérour J.-Y. J. Med. Chem.  2003,  46:  1962 
• 5 Matsuoka H. Ohi N. Mihara M. Suzuki H. Miyamoto K. Maruyama N. Tsuji K. Kato N. Akimoto T. Takeda Y. Yano K. Kuroki T. J. Med. Chem.  1997,  40:  105 
• 6 Zhou DH. Harrison BL. Shah U. Andree TH. Hornby GA. Scerni R. Schechter LE. Smith DL. Sullivan KM. Mewshaw RE. Bioorg. Med. Chem. Lett.  2006,  16:  1338 
• 7 Albanese D. Landini D. Lupi V. Penso M. Ind. Eng. Chem. Res.  2003,  42:  680 
• 8 Jiao P.-F. Zhao B.-X. Wang W.-W. He Q.-X. Wan M.-S. Shin D.-S. Miao J.-Y. Bioorg. Med. Chem. Lett.  2006,  16:  2862 
• 9 Zolfigol MA. Safaiee M. Synlett  2004,  827 
• 10a Shen X.-X. Liu Q. Xing R.-G. Zhou B. Catal. Lett.  2008,  126:  361 
• 10b Liu Q. Li J. Shen X.-X. Xing R.-G. Yang J. Liu Z.-G. Zhou B. Tetrahedron Lett.  2009,  50:  1026 
• 11 Niu XQ. Liu ZG. Yu W. Wu LM. Chin. J. Org. Chem.  2009,  29:  229 
• 12a Macchia F. J. Org. Chem.  1991,  56:  5939 
• 12b De A. Ghosh S. Iqbal J. Tetrahedron Lett.  1997,  38:  8379 
• 12c Fagnou K. Lautens M. Org. Lett.  2000,  2:  2319 
• 12d Sekar G. Singh VK. J. Org. Chem.  1999,  64:  287 

13

General procedure for the synthesis of 2,3-dihydro-1,4-benzoxazine derivatives: To a stirred solution of substrate (0.5 mmol) in ethanol (30 mL) was added HEH (0.468 g, 1.85 mmol), and 10% Pd/C (18 mg), and the reaction mixture was refluxed for 12 h under N₂. The mixture was filtered through Celite and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel to give the corresponding product.