I. Shiina et al. / Tetrahedron Letters 45 (2004) 965–967
967
room temperature and then saturated aqueous sodium
hydrogencarbonate was added. The mixture was
extracted with diethyl ether, and the organic layer was
washed with brine, dried over sodium sulfate. After fil-
tration of the mixture and evaporation of the solvent,
the crude product was purified by thin layer chroma-
tography to afford 4-(4-methoxyphenyl)-3,4-diphenyl-
but-1-ene (42.4 mg, 57%) as a colorless oil.
NMe2
OMe
O
a
X
X
5i X = 3-Br
5ii X = 4-Br
5iii X = 4-I
E-6i X = 3-Br
E-6ii X = 4-Br
E-6iii X = 4-I
References and notes
1. (a) Harper, M. J. K.; Walpole, A. L. Nature 1966, 212, 87;
(b) Bedford, G. R.; Richardson, D. N. Nature 1966, 212,
733–734; for a review of the pharmacology, see: (c) Heel,
R. C.; Brogdon, R. N.; Speight, T. M.; Avery, G. S. Drugs
1978, 16, 1–24.
2. (a) Harper, M. J. K.; Richardson, D. N.; Walpole, A. L.
GB1013907, 1965, Imperial Chemical Industries, Ltd (b)
Robertson, D. W.; Katzenellenbogen, J. A. J. Org. Chem.
1982, 47, 2387–2393; (c) McCague, R. J. Chem. Soc.,
Perkin Trans. 1 1987, 1011–1015.
Scheme 3. Reagents and conditions: (a) (1) tBuOK, DMSO, rt, 15 min
(i; 68%, ii; 89%, iii; 85%); (2) BBr3, CH2Cl2, )78 °C, 2 h (i; 94%, ii; 92%,
iii; 95%); (3) NaH, ClCH2CH2NMe2ÆHCl, DMF, 50 °C, 8–13 h (6i;
82% (46% of E-6i, 36% of Z-6i), 6ii; 88% (45% of E-6ii, 43% of Z-6ii),
6iii; 95% (44% of E-6iii, 51% of Z-6iii)), (4) Z-6, TfOH, CH2Cl2, 0 °C,
3 h (6i; 88% (44% of E-6i, 44% of Z-6i), 6ii; 89% (46% of E-6ii, 43% of
Z-6ii), 6iii; 87% (42% of E-6iii, 45% of Z-6iii)).
Using this transformation and the second separation of
the geometrical isomers, Z-1 was obtained in 28% total
yield from the starting substrate (benzaldehyde).
3. (a) Coe, P. L.; Scriven, C. E. J. Chem. Soc., Perkin Trans.
1 1986, 475–477; See also a similar method for the
synthesis of tamoxifen derivatives (b) Gauthier, S.; Mail-
hot, J.; Labrie, F. J. Org. Chem. 1996, 61, 3890–3893; (c)
Finally, the substituted tamoxifens were also prepared in
good yields by a similar protocol as shown in Scheme 3.
Successive double bond migrations took place again to
afford the desired tetra-substituted olefins in good yields.
The usual treatments of these isomers with BBr3 and
NaH/ClCH2CH2NMe2 gave the 3- or 4-halogenated
tamoxifen relatives (E-6i–iii)15 in 23%, 34%, and 32%
total yields, respectively, from the corresponding aro-
matic aldehydes. It is noted that these halogenated
derivatives might not be efficiently prepared by the
transition metal coupling methodology since aryl halide
parts competitively react to form by-products under the
reaction conditions.5
ꢀ
Gauthier, S.; Sanceau, J.-Y.; Mailhot, J.; Caron, B.;
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2121–2123; (b) Al-Hassan, M. I. Synth. Commun. 1987, 17,
1247–1251; (c) Al-Hassan, M. I. Synthesis 1987, 816–817.
5. Potter, G. A.; McCague, R. J. Org. Chem. 1990, 55, 6184–
6187.
€
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1997, 36, 93–95; (b) Studemann, T.; Ibrahim-Ouali, M.;
€
Knochel, P. Tetrahedron 1998, 54, 1299–1316.
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Org. Lett. 2003, 5, 2989–2992.
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10. Shiina, I.; Suzuki, M.; Yokoyama, K. Tetrahedron Lett.
2002, 43, 6395–6398.
11. (a) Shiina, I.; Miyoshi, S.; Miyashita, M.; Mukaiyama, T.
Chem. Lett. 1994, 515–518; (b) Shiina, I.; Mukaiyama, T.
Chem. Lett. 1994, 677–680.
12. Bank, S.; Rowe, C. A., Jr.; Schriesheim, A.; Naslund, L.
A. J. Org. Chem. 1968, 33, 221–223.
Thus, we developed a new pathway for the synthesis of
tamoxifen and its derivatives via the successive allylation
of aromatic aldehydes and Friedel–Crafts alkylation,
followed by migration of the double bond. This method
seems to be a practical and useful way for the
preparation of other tamoxifen analogues since various
substances are easily applicable for the first three-com-
ponent coupling.
13. For the large scale purification, recrystallization of the
corresponding hydrochloric or hydrobromic acid salt is
recommended. See: (a) White, D. A. EP127128, 1984,
Bristol-Myers Co; (b) Shinozaki, F.; Nagasawa, H.;
Maruhashi, K. WO9511879, 1995, Taiho Pharmaceutical
Co., Ltd.
14. Some other methods for the Z–E isomerization have been
reported. See: Refs. 4b, 4c and 13. See also Winkler, V. W.;
Nyman, M. A.; Egan, R. S. Steroids 1971, 17, 197–207.
15. McCague, R. EP260066, 1988, National Research Devel-
opment Corporation.
A typical experimental procedure is described for the
three-component coupling reaction among benzalde-
hyde, cinnamyltrimethylsilane, and anisole: to a sus-
pension of hafnium tetrachloride (75.6 mg, 0.236 mmol)
and trimethylsilyl trifluoromethanesulfonate (26.2 mg,
0.118 mmol) in anisole (1.2 mL) at 0 °C was added a
solution of cinnamyltrimethylsilane (57.9 mg, 0.283
mmol) and benzaldehyde (25.0 mg, 0.236 mmol) in ani-
sole (1.2 mL). The reaction mixture was stirred for 2 h at