3184
K. Shimizu et al.
LETTER
1. CO2 (1 atm)
MeO
MeO
Ni(cod)2 (20 mol%)
DBU (10 equiv)
MeO
Ph
Ph2Zn (3 equiv)
THF, 40 °C, 24 h
2. CH2N2
+
Ph
Ph
Ph
15
Ph
CO2Me
MeO2C
17 27%
16 67%
Scheme 5 Model study for the synthesis of tamoxifen
Fallis’ procedure, Dess–Martin oxidation of 21 followed
by Wittig reaction and then hydrogenation afforded
tamoxifen, whose spectral data agreed with those reported
in the literature.2p Thus, the synthesis of tamoxifen was
achieved in 36% overall yield over eight steps.
Me2N
1. KOH, EtOH
HO
I
O
I
NMe2
2.
Cl
toluene
reflux, 12 h
18
Synthesis of tamoxifen was achieved using nickel-cata-
lyzed arylative carboxylation. In this synthesis, carbon di-
oxide and an aryl group were introduced into diarylated
alkyne regioselectively. Carbon dioxide is a useful re-
source in synthetic organic chemistry. Further study for
utilization of carbon dioxide is now in progress.
Ph
Me2N
PdCl2(PPh3)2
(1 mol%)
CuI (2 mol%)
Et3N, r.t., 6 h
O
Ph
9
2 steps 80%
1. CO2 (1 atm)
Ni(cod)2 (20 mol%)
DBU (10 equiv)
References
(1) Harpor, M. J. K.; Richardson, D. N.; Walpole, A. L. GB
1013907, 1965; Chem. Abstr. 1965, 62, 10374e.
9
Ph2Zn (3 equiv)
THF, 40 °C, 20 h
2. CH2N2
(2) For recent syntheses of tamoxifen, see: (a) Miller, R. B.; Al-
Hassan, M. I. J. Org. Chem. 1985, 50, 2121. (b) Al-Hassan,
M. I. Synth. Commun. 1987, 17, 1247. (c) Al-Hassan, M. I.
Synthesis 1987, 816. (d) Coe, P. L.; Scriven, C. E. J. Chem.
Soc., Perkin Trans. 1 1986, 475. (e) Potter, G. A.;
NMe2
Ph
NMe2
O
O
McCague, R. J. Org. Chem. 1990, 55, 6184. (f)Stüdemann,
T.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1997, 36, 93.
(g) Stüdemann, T.; Ibrahim-Ouali, M.; Knochel, P.
Tetrahedron 1998, 54, 1299. (h) Brown, S. D.; Armstrong,
R. W. J. Org. Chem. 1997, 62, 7076. (i) Yus, M.; Ramón,
D. J.; Gómez, I. Tetrahedron 2003, 59, 3219. (j) Itami, K.;
Kamei, T.; Yoshida, J. J. Am. Chem. Soc. 2003, 125, 14670.
(k) Shiina, I.; Suzuki, M.; Yokoyama, K. Tetrahedron Lett.
2004, 45, 965. Formal syntheses of tamoxifen: (l) Zhou, C.;
Emrich, D. E.; Larock, R. C. Org. Lett. 2003, 5, 1579.
(m) Shindo, M.; Matsumoto, K.; Shishido, K. Synlett 2005,
176. (n) Shimizu, M.; Nakamaki, C.; Shimono, K.; Scelper,
M.; Hiyama, T. J. Am. Chem. Soc. 2006, 127, 12506.
(o) Tessier, P. E.; Penwell, A. J.; Souza, F. E. S.; Fallis, A.
G. Org. Lett. 2003, 5, 2989. (p) Zhou, C.; Larock, R. C. J.
Org. Chem. 2005, 70, 3765.
+
Ph
Ph
Ph
CO2Me
MeO2C
19 63%
20 22%
DIBAL-H
(3 equiv)
CH2Cl2
–78 °C, 2 h
NMe2
Ph
NMe2
Ph
1. Dess–Martin Ox.
2. Ph3P+CH3 Br–
tBuOK
O
O
(3) Synthesis of tetrasubstituted alkene, see; (a) Shimizu, K.;
Takimoto, M.; Sato, Y.; Mori, M. Org. Lett. 2005, 7, 195.
Other CO2 fixation reaction developed by our group, see:
(b) Takimoto, M.; Mori, M. J. Am. Chem. Soc. 2001, 123,
2895. (c) Takimoto, M.; Shimizu, K.; Mori, M. Org. Lett.
2001, 3, 3345. (d) Takimoto, M.; Mori, M. J. Am. Chem.
Soc. 2002, 124, 10008. (e) Shimizu, K.; Takimoto, M.;
Mori, M. Org. Lett. 2003, 5, 2323. (f) Takimoto, M.;
Kawamura, M.; Mori, M. Org. Lett. 2003, 5, 2599.
(g) Takimoto, M.; Kawamura, M.; Mori, M. Synthesis 2004,
791. (h) Takimoto, M.; Nakamura, Y.; Kimura, K.; Mori, M.
J. Am. Chem. Soc. 2004, 126, 5956. (i) Takimoto, M.;
Kawamura, M.; Mori, M.; Sato, Y. Synlett 2005, 2019.
(j) Takimoto, M.; Mizuno, T.; Sato, Y.; Mori, M.
3. H2, Pd/C
Ph
tamoxifen
71%
Ph
OH
quant.
21
Scheme 6 Synthesis of tamoxifen
Tetrahedron Lett. 2005, 46, 5173.
Synlett 2006, No. 18, 3182–3184 © Thieme Stuttgart · New York