Download PDF
Synthesis 2010(8): 1371-1380  
DOI: 10.1055/s-0029-1219277
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Lateral Lithiation of N′-(2-Methylbenzyl)-N,N-dimethylurea and N-(2-Methylbenzyl)pivalamide: Synthesis of Tetrahydroisoquinolines

Keith Smith*, Gamal A. El-Hiti, Amany S. Hegazy
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, UK
Fax: +44(2920)870600; e-Mail: smithk13@cardiff.ac.uk; e-Mail: el-hitiga@cardiff.ac.uk;
Further Information

Publication History

Received 18 December 2009
Publication Date:
25 January 2010 (online)

    Permissions and Reprints All articles of this category

Abstract

Lithiation of N′-(2-methylbenzyl)-N,N-dimethylurea and N-(2-methylbenzyl)pivalamide with two mole equivalents of tert-butyllithium at -78 ˚C takes place on the nitrogen and on the methyl group at position 2. The lithium reagents thus obtained react with a variety of electrophiles to give the corresponding side-chain-substituted derivatives in high yields. Dehydration of the products obtained from reactions with carbonyl compounds in some cases gives the corresponding tetrahydroisoquinolines in excellent yields, while in other cases dehydration takes place within the substituted side chain to produce the corresponding alkenes in excellent yields.

Key words

lateral lithiation - isoquinolines - N′-(2-methylbenzyl)-N,N-dimethylurea - N-(2-methylbenzyl)pivalamide - dehydration

    References

  • 1 Clayden J. Organolithiums: Selectivity for Synthesis   Pergamon; Oxford: 2002. 
    Google Scholar
  • 2 Wilkinson JA. Raiber E.-A. Ducki S. Tetrahedron  2008,  64:  6329 
    CrossrefGoogle Scholar
  • 3 Führer W. Gschwend HW. J. Org. Chem.  1979,  44:  1133 
    CrossrefGoogle Scholar
  • 4 Burgos PO. Fernández I. Iglesis MJ. García-Granda S. Ortiz FL. Org. Lett.  2008,  4:  537 
    Google Scholar
  • 5 Uchida K. Fukuda T. Iwao M. Tetrahedron  2007,  63:  7178 ; and references cited therein
    CrossrefGoogle Scholar
  • 6 Clayden J. Dufour J. Grainger DM. Helliwell M. J. Am. Chem. Soc.  2007,  129:  7488 
    CrossrefGoogle Scholar
  • 7 Smith K. El-Hiti GA. Abdo MA. Abdel-Megeed MF. J. Chem. Soc., Perkin Trans. 1  1995,  1029 
    CrossrefGoogle Scholar
  • 8 Smith K. El-Hiti GA. Abdel-Megeed MF. Abdo MA. J. Org. Chem.  1996,  61:  656 
    CrossrefGoogle Scholar
  • 9 Gitto R. Caruso R. Pagano B. De Luca L. Citraro R. Russo E. De Sarro G. Chimirri A. J. Med. Chem.  2006,  49:  5618 
    CrossrefGoogle Scholar
  • 10 Kuo C.-Y. Wu M.-J. Eur. J. Med. Chem.  2009,  44:  1271 
    CrossrefGoogle Scholar
  • 11 Luszczki JJ. Antkiewicz-Michaluk L. Czuczwar SJ. Eur. J. Pharmacol.  2009,  602:  298 
    CrossrefGoogle Scholar
  • 12 Grunewald GL. Seim MR. Bhat SR. Wilson ME. Criscione KR. Bioorg. Med. Chem.  2008,  16:  542 
    CrossrefGoogle Scholar
  • 13 Cheng P. Huang N. Jiang Z.-Y. Zhang Q. Zheng Y.-T. Chen J.-J. Zhang X.-M. Ma Y.-B. Bioorg. Med. Chem.  2008,  18:  2475 
    CrossrefGoogle Scholar
  • 14 Nikulin VI. Rakov IM. De Los Angeles JE. Mehta RC. Boyd LY. Fellerb DR. Miller DD. Bioorg. Med. Chem.  2006,  14:  1684 
    CrossrefGoogle Scholar
  • 15 Scott JD. Williams RM. Chem. Rev.  2002,  102:  1669 
    CrossrefPubMedGoogle Scholar
  • 16 Schneider CS. Weber KH. Daniel H. Bechtel WD. Boeke-Kuhn K. J. Med. Chem.  1984,  27:  1150 
    CrossrefGoogle Scholar
  • 17a Kuhakarn C. Panyachariwat Somsak Ruchirawat S. Tetrahedron Lett.  2007,  48:  8182 
    Google Scholar
  • 17b Saito A. Takayama M. Yamazaki A. Numaguchi J. Hanzawa Y. Tetrahedron  2007,  63:  4039 
    Google Scholar
  • 17c Zhong HM. Villani FJ. Marzouq R. Org. Process Res. Dev.  2007,  11:  463 
    Google Scholar
  • 17d Chrzanowska M. Rozwadowska MD. Chem. Rev.  2004,  104:  3341 
    Google Scholar
  • 17e Silveira CC. Bernardi CR. Braga AL. Kaufm TS. Tetrahedron Lett.  2003,  44:  6137 
    Google Scholar
  • 18 Ruchirawat S. Tontoolarug S. Sahakitpichan P. Heterocycles  2001,  55:  635 
    CrossrefGoogle Scholar
  • 19 Couture A. Deniau E. Lebrun S. Grandclaudon P. J. Chem. Soc., Perkin Trans. 1  1999,  789 
    Google Scholar
  • 20a Philippe N. Denivet F. Vasse J.-L. Sopkova-de Olivera Santos J. Levacher V. Dupas G. Tetrahedron  2003,  59:  8049 
    Google Scholar
  • 20b Toda J. Sonobe A. Ichikava T. Saitoh T. Horiguchi Y. Sano T. ARKIVOC  2000,  (ii):  165 
    Google Scholar
  • 21a Umetsu K. Asao N. Tetrahedron Lett.  2008,  49:  2722 
    Google Scholar
  • 21b Deng X. Liang JT. Liu J. McAllister H. Schubert C. Mani NS. Org. Process Res. Dev.  2007,  11:  1043 
    Google Scholar
  • 21c Raju BC. Neelakantan P. Bhalerao UT. Tetrahedron Lett.  2004,  45:  7487 
    Google Scholar
  • 21d Schlosser M. Simig G. Tetrahedron Lett.  1991,  32:  1965 
    Google Scholar
  • 22 Clark RD. Jahangir A. Langston JA. Can. J. Chem.  1994,  72:  23 
    CrossrefGoogle Scholar
  • See for example:
  • 23a Smith K. El-Hiti GA. Abdel-Megeed MF. Abdo MA. J. Org. Chem.  1996,  61:  647 
    Google Scholar
  • 23b Smith K. El-Hiti GA. Pritchard GJ. Hamilton A. J. Chem. Soc., Perkin Trans. 1  1999,  2299 
    Google Scholar
  • 23c Smith K. El-Hiti GA. Shukla AP. J. Chem. Soc., Perkin Trans. 1  1999,  2305 
    Google Scholar
  • 23d Smith K. El-Hiti GA. Hawes AC. Synthesis  2003,  2047 
    Google Scholar
  • 23e Smith K. El-Hiti GA. Mahgoub SA. Synthesis  2003,  2345 
    Google Scholar
  • 23f El-Hiti GA. Synthesis  2003,  2799 
    Google Scholar
  • 23g Smith K. El-Hiti GA. Abdel-Megeed MF. Synthesis  2004,  2121 
    Google Scholar
  • 23h El-Hiti GA. Synthesis  2004,  363 
    Google Scholar
  • 23i Smith K. El-Hiti GA. Hegazy AS. J. Sulfur Chem.  2005,  26:  121 
    Google Scholar
  • 23j Smith K. El-Hiti GA. Hegazy AS. Synthesis  2005,  2951 
    Google Scholar
  • 23k Smith K. Barratt ML. J. Org. Chem.  2007,  72:  1031 
    Google Scholar
  • 23l Smith K. El-Hiti GA. Hegazy AS. Synlett  2009,  2242 
    Google Scholar
  • 25 Sheldrick GM. Acta Crystallogr., Sect. A.  1990,  46:  467 
    CrossrefGoogle Scholar
  • 26 Sheldrick GM. SHELXS-97, Program for Crystal Structure Refinement   University of Göttingen; Germany: 1997. 
    Google Scholar
  • 27 Watson SC. Eastham JF. J. Organomet. Chem.  1967,  9:  165 
    CrossrefGoogle Scholar
  • 28a Vogel’s Textbook of Practical Organic Chemistry   5th ed.:  Longman; Harlow: 1989. 
    Google Scholar
  • 28b Perrin DD. Armarego WLF. Purification of Laboratory Chemicals   Pergamon; Oxford: 1988.  3rd ed.
    Google Scholar
  • 29 Hegazy AS. Ph.D. Thesis   Cardiff University; UK: 2009. 
    Google Scholar
24

Full crystallographic data of compounds 15, 24, 26, and 28 have been deposited with the CCDC under reference numbers 737412, 737417, 737416, and 737414, respectively, and can be obtained free of charge via
http://www.ccdc.ac.uk/data_request/cif.