Synthesis of 5-Substituted 7,8-Benzomorphans by Intramolecular Cyclization of N-Protected 4,4-Disubstituted 1,4-Dihydropyridines

Abstract

An efficient and high yielding method for the synthesis of 7,8-benzomorphans with varying substituents at C5 has been developed. It is based on an acid-catalyzed intramolecular cyclization reaction of N-protected 4,4-disubstituted 1,4-dihydropyridines, which are easily accessible by the addition of diorganomagnesium compounds to N-silylpyridinium ions. The cyclization reaction proceeds via N-acyliminium ions generated from the 1,4-dihydropyridine moiety that undergo electrophilic aromatic substitution reaction at the benzyl substituent present at C4 of the 1,4-dihydropyridine ring system.

Key words

alkaloids - benzomorphans - electrophilic aromatic substitution - N-acyliminium ion - intramolecular cyclization

References

• 1 Bosch J. Bonjoch J. Heterocycles  1980,  14:  505 
• 2 Frackenpohl J. Chem. Unserer Zeit  2000,  34:  99 
• 3 Palmer DC. Strauss MJ. Chem. Rev.  1977,  77:  1 
• 4a Carroll FI. Melvin MS. Nuckols MC. Mascarella SW. Navarro HA. Thomas JB. J. Med. Chem.  2006,  49:  1781 
• 4b Kim IJ. Dersch CM. Rothmann RB. Jacobson AE. Rice KC. Bioorg. Med. Chem.  2004,  12:  4543 
• 4c Thomas JB. Zhang L. Navarri HA. Carroll FI. J. Med. Chem.  2006,  49:  5597 
• 5a Latshaw WE. MacDonnell DR. J. Pharm. Sci.  1961,  50:  792 
• 5b Englberger W, Sattlegger M, and Przewosny M. inventors; WO  9,965,485. 
• 6 Yokoyama N. Almaula PI. Block FB. Granat FR. Gottfried N. Hill RT. McMahon EH. Munch WF. Rachlin H. Saelens JK. Siegel MG. Tomaselli HC. Clarke FH. J. Med. Chem.  1979,  22:  537 
• 7a Bosch J. Canals J. Granados R. J. Heterocycl. Chem.  1975,  12:  1117 
• 7b Khartulyari AS. Maier ME. Eur. J. Org. Chem.  2007,  317 
• 7c Magnus P. Fairhurst RA. J. Chem. Soc., Chem. Commun.  1994,  1541 
• 8 Bosch J. Bonjoch J. Diez A. Linares A. Moral M. Rubiralta M. Tetrahedron  1985,  41:  1753 
• 9 Klegraf E. Knauer S. Kunz H. Angew. Chem. Int. Ed.  2006,  45:  2623 
• 10 Kometani T. Shiotani S. J. Med. Chem.  1978,  21:  1105 
• 11a Bräckow J. Wanner KT. Tetrahedron  2006,  62:  2395 
• 11b Bräckow J. Ph.D. Thesis   LMU München; Germany: 2006. 
• 12 Reichardt C. Solvents and Solvent Effects in Organic Chemistry   Vol. 3:  VCH; Weinheim: 2003. 
• 13 Perrin DD. Armarego WLF. In Purification of Laboratory Chemicals   Vol. 3:  Pergamon; New York: 1988. 
• 14 Shiao M.-J. Chia W.-L. Synth. Commun.  1991,  21:  401 
• 15 Wakefield BJ. Organomagnesium Methods in Organic Synthesis   Academic; New York: 1995.  p.65-67  
• 16a Akiba K.-Y. Iseki Y. Wada M. Tetrahedron Lett.  1982,  23:  3935 
• 16b Kalashnikov VV. Tomilova LG. Mendeleev Commun.  2007,  17:  343 
• 17a Sperger CA. Wanner KT. Tetrahedron  2009,  65:  5824 
• 17b Wallace DJ. Gibb AD. Cottrell IF. Kennedy DJ. Brands KMJ. Dolling UH. Synthesis  2001,  1784 

18

Due to the small percentage of the minor rotamer, only the signals of the major rotamer are listed.