trans-Stilbene as a Starting Material for the Synthesis of Tamoxifen Based on Palladium-Catalyzed Cross-Coupling Reactions

Abstract

(Z)-Tamoxifen was synthesized from a simple olefin (trans-stilbene) in 5 steps and 40% overall yield (Z/E = 74:26). The phenyl substituted group (4-Me₂NCH₂CH₂OC₆H₄) was attached by a bromination-dehydrobromination-Suzuki reaction sequence. Subsequently, the ethyl group was attached to the triarylated olefin by a bromination-Negishi reaction sequence. Both the Suzuki and Negishi cross-coupling processes are stereospecific, and the stereoselectivity depends only on the bromination-dehydrobromination reactions. (Z)-Tamoxifen was also obtained from trans-stilbene in only 3 steps by using Heck reaction-bromination-Negishi reaction sequence in 57% overall yield (Z/E = 65:35).

Key words

tamoxifen - cross-coupling - stilbene - substituted olefins - palladium

References

• 1 Flynn AB. Ogilvie WW. Chem. Rev.  2007,  107:  4698 
• 2 Jordan VC. Nat. Rev. Drug Discov.  2003,  2:  205 
• 3 Jordan VC. J. Med. Chem.  2003,  46:  883 
• 4 Coe PL. Scriven CE. J. Chem. Soc., Perkin Trans. 1  1986,  475 
• 5 Yus M. Ramon DJ. Gomez I. Tetrahedron  2003,  59:  3219 
• 6 Shiina I. Suzuki M. Yokoyama K. Tetrahedron Lett.  2004,  45:  965 
• 7 Shiina I. Sano Y. Nakata K. Suzuki M. Yokoyama T. Sasaki A. Orikasa T. Miyamoto T. Ikekita M. Nagahara Y. Hasome Y. Bioorg. Med. Chem.  2007,  15:  7599 
• 8 McKinley NF. O’Shea DF. J. Org. Chem.  2006,  71:  9552 
• 9 Nishihara Y. Miyasaka M. Okamoto M. Takahashi H. Inoue E. Tanemura K. Takagi K. J. Am. Chem. Soc.  2007,  129:  12634 
• 10 Miller RB. Alhassan MI. J. Org. Chem.  1985,  50:  2121 
• 11 Studemann T. Knochel P. Angew. Chem., Int. Ed. Engl.  1997,  36:  93 
• 12 Studemann T. Ibrahim-Ouali M. Knochel P. Tetrahedron  1998,  54:  1299 
• 13 Itami K. Kamei T. Yoshida J. J. Am. Chem. Soc.  2003,  125:  14670 
• 14 Tessier PE. Penwell AJ. Souza FES. Fallis AG. Org. Lett.  2003,  5:  2989 
• 15 Zhou CX. Larock RC. J. Org. Chem.  2005,  70:  3765 
• 16 Brown SD. Armstrong RW. J. Org. Chem.  1997,  62:  7076 
• 17 Pilli RA. Robello LG. J. Braz. Chem. Soc.  2004,  15:  938 
• 18 Shindo M. Matsumoto K. Shishido K. Synlett  2005,  176 
• 19 Potter GA. McCague R. J. Org. Chem.  1990,  55:  6184 
• 20 Shimizu M. Nakamaki C. Shimono K. Schelper M. Kurahashi T. Hiyama T. J. Am. Chem. Soc.  2005,  127:  12506 
• 21 Al-Alhassan MI. Synthesis  1987,  816 
• 22 Ishida N. Miura T. Murakami M. Chem. Commun.  2007,  4381 
• 23 Shimizu K. Takimoto M. Mori M. Sato Y. Synlett  2006,  3182 
• 24 Nunes CM. Steffens D. Monteiro AL. Synlett  2007,  103 
• 25 Nunes CM. Monteiro AL. J. Braz. Chem. Soc.  2007,  18:  1443 
• 26 Buckles RE. J. Am. Chem. Soc.  1949,  71:  1157 
• 27 Buckles RE. Bader JM. Thurmaier RJ. J. Org. Chem.  1962,  27:  4523 
• 28 Chiappe C. Capraro D. Conte V. Pieraccini D. Org. Lett.  2001,  3:  1061 
• 29 Tanaka K. Shiraishi R. Toda F. J. Chem. Soc., Perkin Trans. 1  1999,  3069 
• 30 Avraamides J. Parker AJ. Aust. J. Chem.  1983,  36:  1705 
• 31 Lando VR. Monteiro AL. Org. Lett.  2003,  5:  2891 
• 32 Berthiol F. Doucet H. Santelli M. Eur. J. Org. Chem.  2003,  1091 
• 33 Koelsch CF. J. Am. Chem. Soc.  1932,  54:  2487 
• 34 Alhassan MI. J. Organomet. Chem.  1987,  321:  119 
• 35 Bellucci G. Chiappe C. LoMoro G. J. Org. Chem.  1997,  62:  3176 
• 36 Alhassan MI. Synth. Commun.  1987,  17:  1413 
• 37 Foster AB. Jarman M. Leung OT. McCague R. Leclercq G. Devleeschouwer N. J. Med. Chem.  1985,  28:  1491