PAPER
Synthesis of Tamoxifen from trans-Stilbene
2765
(Na2SO4) and the solvent was evaporated to give 1.01 g (78%) of an
E/Z mixture (74:26) of 2b as a white solid.
(4) Coe, P. L.; Scriven, C. E. J. Chem. Soc., Perkin Trans. 1
1986, 475.
(5) Yus, M.; Ramon, D. J.; 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, N. F.; O’Shea, D. F. 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, R. B.; Alhassan, M. I. 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.
1H NMR (300 MHz, CDCl3): d (mixture of diasteroisomers) = 2.25
(E-isomer, s, 6 H), 2.31 (Z-isomer, s, 6 H), 2.62 (E-isomer, t, J = 5.7
Hz, 2 H), 2.65 (Z-isomer, t, J = 5.7 Hz, 2 H), 2.72 (E-isomer, t,
J = 5.7 Hz, 2 H), 3.90 (E-isomer, t, J = 5.7 Hz, 2 H), 4.05 (Z-isomer,
t, J = 5.7 Hz, 2 H), 6.53 (E-isomer, d, J = 8.7 Hz, 2 H), 6.77 (E-iso-
mer, d, J = 8.7 Hz, 2 H), 6.83–7.34 (Z- and E-isomers, m, 10 H).
(E)-2b
Recrystallization of the E/Z mixture of 2b from hexanes afforded
the pure (E)-2b; mp 116–117 °C (Lit.37 mp 116–117 °C).
1H NMR (300 MHz, CDCl3): d = 2.33 (s, 6 H), 2.72 (t, J = 5.7 Hz,
2 H), 3.96 (t, J = 5.7 Hz, 2 H), 6.53 (d, J = 8.9 Hz, 2 H), 6.77 (d,
J = 8.9 Hz, 2 H), 7.08–7.34 (m, 10 H).
13C NMR (75.4 MHz, CDCl3): d = 45.6, 58.1, 65.3, 114.0, 121.4,
127.7, 128.0, 128.3, 128.4, 129.8, 130.5, 131.9, 134.0, 141.5, 143.2,
144.2, 157.5.
HRMS: m/z calcd for C24H25BrNO (M + H+): 422.1119; found:
422.1125.
(14) Tessier, P. E.; Penwell, A. J.; Souza, F. E. S.; Fallis, A. G.
Org. Lett. 2003, 5, 2989.
(15) Zhou, C. X.; Larock, R. C. J. Org. Chem. 2005, 70, 3765.
(16) Brown, S. D.; Armstrong, R. W. J. Org. Chem. 1997, 62,
7076.
(17) Pilli, R. A.; Robello, L. G. J. Braz. Chem. Soc. 2004, 15, 938.
(18) Shindo, M.; Matsumoto, K.; Shishido, K. Synlett 2005, 176.
(19) Potter, G. A.; 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, M. I. Synthesis 1987, 816.
(22) Ishida, N.; Miura, T.; Murakami, M. Chem. Commun. 2007,
4381.
Negishi Coupling of 1-Bromo-2-{4-[2-(dimethylamino)eth-
oxy]phenyl}-1,2 diphenylethene (2b) with Ethylzinc Chloride
An oven-dried resealable Schlenk flask was charged with ZnCl2
(273 mg, 2 mmol), THF (3 mL), and Et2Zn (2 mL of a 1 M solution
in hexane, 2 mmol). The mixture was stirred at r.t. for 1 h before
use. The mixture was transferred to an oven-dried reseable Schlenk
flask containing 2b (630 mg, 1.5 mmol) in THF (5 mL). Finally,
Pd(OAc)2 (6.7 mg, 0.03 mmol) and tol-BINAP (20.3 mg, 0.03
mmol) were added and the mixture was stirred at 30 °C for 2 h. Af-
ter removal of the solvent, the residue was chromatographed on sil-
ica gel (hexanes) to give 412 mg (74%) of an E/Z mixture (74:26)
of tamoxifen. The diastereoisomeric ratio was determined by GC-
MS analysis and configuration of the major diasteroisomer estab-
lished by NMR could be confirmed by GC-analysis of an authentic
sample of (Z)-tamoxifen.17
(23) Shimizu, K.; Takimoto, M.; Mori, M.; Sato, Y. Synlett 2006,
3182.
1H NMR (300 MHz, CDCl3): d = 0.93 (Z-isomer, t, J = 7.3 Hz, 3 H),
0.95 (E-isomer, t, J = 7.3 Hz, 3 H), 2.29 (Z-isomer, s, 6 H), 2.36 (E-
isomer, s, 6 H), 2.42–2.50 (Z- and E-isomers, m, 4 H), 2.65 (Z-iso-
mer, t, J = 5.7 Hz, 2 H), 2.75 (E-isomer, t, J = 5.7 Hz, 2 H), 3.93 (Z-
isomer, t, J = 5.7 Hz, 2 H), 4.09 (E-isomer, t, J = 5.7 Hz, 2 H), 6.56
(Z-isomer, d, J = 9 Hz, 2 H), 6.77 (Z-isomer, d, J = 9 Hz, 2 H), 6.89–
7.37 (Z- and E-isomers, m, 10 H).
(24) Nunes, C. M.; Steffens, D.; Monteiro, A. L. Synlett 2007,
103.
(25) Nunes, C. M.; Monteiro, A. L. J. Braz. Chem. Soc. 2007, 18,
1443.
(26) Buckles, R. E. J. Am. Chem. Soc. 1949, 71, 1157.
(27) Buckles, R. E.; Bader, J. M.; Thurmaier, R. J. 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.
HRMS: m/z calcd for C26H30NO (M + H+): 372.2327; found:
372.2328.
(30) Avraamides, J.; Parker, A. J. Aust. J. Chem. 1983, 36, 1705.
(31) Lando, V. R.; Monteiro, A. L. Org. Lett. 2003, 5, 2891.
(32) Berthiol, F.; Doucet, H.; Santelli, M. Eur. J. Org. Chem.
2003, 1091.
(33) Koelsch, C. F. J. Am. Chem. Soc. 1932, 54, 2487.
(34) Alhassan, M. I. J. Organomet. Chem. 1987, 321, 119.
(35) Bellucci, G.; Chiappe, C.; LoMoro, G. J. Org. Chem. 1997,
62, 3176.
Acknowledgment
We thank CNPq, FAPERGS, PRONEX and INCT-Catalise for par-
tial financial support. We also thank CNPq (C.N.M and S.P.) and
CAPES (J.L.) for scholarships.
References
(36) Alhassan, M. I. Synth. Commun. 1987, 17, 1413.
(37) Foster, A. B.; Jarman, M.; Leung, O. T.; McCague, R.;
Leclercq, G.; Devleeschouwer, N. J. Med. Chem. 1985, 28,
1491.
(1) Flynn, A. B.; Ogilvie, W. W. Chem. Rev. 2007, 107, 4698.
(2) Jordan, V. C. Nat. Rev. Drug Discov. 2003, 2, 205.
(3) Jordan, V. C. J. Med. Chem. 2003, 46, 883.
Synthesis 2009, No. 16, 2761–2765 © Thieme Stuttgart · New York