Effective synthesis of tamoxifen using nickel-catalyzed arylative carboxylation

Article abstract of DOI:10.1055/s-2006-951517

Tamoxifen was synthesized using a nickel-catalyzed arylative carboxylation developed by our group. The key compound, tetrasubstituted alkene, was synthesized from disubstituted alkyne using a catalytic amount of Ni(0) and DBU in the presence of Ph₂Zn under an atmosphere of carbon dioxide. The reaction proceeded smoothly in a regio- and stereoselective manner, and the resultant tetrasubstituted alkene was converted into tamoxifen. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951517

3182
LETTER
Effective Synthesis of Tamoxifen Using Nickel-Catalyzed Arylative
Carboxylation
S
hort-Step Synthe
a
sis of Tamo
z
xifen uya Shimizu,a Masanori Takimoto,b Miwako Mori,*c Yoshihiro Sato*a
a
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
b
Organometallic Chemistry Laboratory, RIKEN (The Institute of Physical and Chemical Research), 2-1 Hirosawa, Wako,
Saitama 351-0198, Japan
c
Health Sciences University of Hokkaido, Ishikari-Tobetsu 061-0293, Japan
Fax +81(11)7064982; E-mail: mori@pharm.hokudai.ac.jp
Received 2 May 2006
Dedicated to Professor Richard F. Heck for his contributions to organopalladium chemistry
R2
R1
R2
R1
Ni
Abstract: Tamoxifen was synthesized using a nickel-catalyzed
CO2 (1 atm)
R1
R2
arylative carboxylation developed by our group. The key com-
pound, tetrasubstituted alkene, was synthesized from disubstituted
alkyne using a catalytic amount of Ni(0) and DBU in the presence
of Ph2Zn under an atmosphere of carbon dioxide. The reaction pro-
ceeded smoothly in a regio- and stereoselective manner, and the re-
sultant tetrasubstituted alkene was converted into tamoxifen.
+
Ni
R3
cat. Ni(cod)2
DBU
R3ZnX
O
O
O
O
1
R3
XZn
Zn
X
2
3
transmetalation
Key words: tetrasubstituted alkenes, nickel catalyst, zinc reagent,
tamoxifen, carbon dioxide
R1
R3Ni
R1
R2
R2
+
NiR3
Tamoxifen1 is an antiestrogenic anticancer drug that is ef-
fective for the treatment of metastatic breast cancer. The
structure of tamoxifen, which has tetrasubstituted alkene,
prompted us to synthesize2 this compound in a regio- and
stereoselective manner because we have developed a nov-
el method for synthesizing tetrasubstituted alkene from
disubstituted alkyne, CO2, a zinc reagent and DBU (1,8-
diazabicyclo[5.4.0]undec-7-ene) using a catalytic amount
of Ni(0).3a
CO2ZnX
XZnO2C
4
5
reductive elimination
and H3O+
R1
R3
R2
R1
R2
+
HO2C
R3
CO2H
6
7
The reaction proceeded through the formation of oxanick-
elacycle 2 and/or 3 by oxidative cyclization of alkyne 1,
CO2 and Ni(0) followed by transmetalation of 2 and/or 3
with a zinc reagent and then reductive elimination from
alkylnickel complex 4 and/or 5 to give tetrasubstituted
alkene 6 and/or 7 (Scheme 1).
Scheme 1 Synthesis of tetrasubstituted alkenes using nickel-cataly-
zed alkylative carboxylation
1. CO2
Ni(cod)2, DBU
Me2Zn
R1
TMS
To realize the regioselective synthesis of tetrasubstituted
alkene, the effect of the substituent on an alkyne is very
important. That is, alkyne 1a having a trimethylsilyl group
gave tetrasubstituted alkene 6a predominantly via oxa-
nickelacycle 2a, but the alkynes 1b and 1c having a t-Bu
group and an aryl group gave tetrasubstituted alkenes 7b
and 7c predominantly in high yields via oxanickelacycles
3b and 3c, respectively (Scheme 2). Presumably, an oxa-
nickelacycle made thermodynamically more stable by
conjugation of the carboxyl group with the substituent R1
or R2 on the oxanickelacycle would give a major tetra-
substituted alkene.
R1
TMS
2. H3O+
Me
CO2H
1a
6a
1. CO2
Ni(cod)2, DBU
Me2Zn
R1
HO2C
R2
R1
R2
2. H3O+
Me
1b,c
7b,c
R1 = alkyl, R2 = tBu
1b
1c R1 = alkyl, R2 = Ar
R1
Ni
TMS
O
R1
R2
Ni
O
O
O
2a
3b,c
SYNLETT 2006, No. 18, pp 3182–3184
0
3
.1
1
.2
0
0
6
Advanced online publication: 25.10.2006
DOI: 10.1055/s-2006-951517; Art ID: S10206ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Electronic effects on the regioselectivity of nickel-cata-
lyzed carboxylation

LETTER
Short-Step Synthesis of Tamoxifen
3183
Our retrosynthetic analysis of tamoxifen is shown in in 19% yield (entry 4). The latter compound 13e should be
Scheme 3. Tamoxifen would be synthesized from tetra- formed by transmetalation of oxanickelacycle with Bu2Zn
substituted alkene 8, which would be obtained from dis- followed by b-hydrogen elimination from butyl nickel
ubstituted alkyne 9, CO2 and Ph2Zn in the presence of a complex 14d and reductive elimination of hydride nickel
catalytic amount of nickel complex.
complex (Scheme 4).
Ph
Ph
Ar
NMe2
NMe2
Ar
Ni
O
Bu2Zn
Ni
O
13e
O
O
BuZnO2C
(R = H)
14d
H
Ar = p-MeOC6H4
CO2H
Scheme 4
8
tamoxifen
In the synthesis of tamoxifen, oxanickelacycle 10a should
be formed predominantly because oxanickelacycle 10a is
more stable than 11a due to the conjugation of the p-
alkoxyphenyl group with the carboxyl group in 10a and
compound 8 would be obtained as a major product from
10a. To confirm this, synthesis of tetrasubstituted alkene
was examined using a model compound 15. When a THF
solution of alkyne 15 and Ph2Zn in the presence of 20
mol% of Ni(cod)2 and 10 equivalents of DBU was stirred
under an atmosphere of carbon dioxide at 40 °C for 17
hours, desired tetrasubstituted alkene 16 was obtained in
67% yield along with 17 in 27% yield (Scheme 5). As ex-
pected, oxanickelacycle 10a (R = Me) was preferentially
formed as an intermediate.
Me2N
CO2
cat. Ni(0)
O
Ph
Ph2Zn
9
RO
RO
Ni
Ni
O
O
O
O
11a
10a
R = CH2CH2NMe2
The synthesis of starting disubstituted alkyne 9 was car-
ried out. Alkylation of p-iodophenol gave 18,2o which was
condensed with phenylacetylene in the presence of a pal-
ladium catalyst to afford desired alkyne 9. When a reac-
tion of 9, CO2, and Ph2Zn was carried out in a manner
similar to that for the synthesis of 16, desired tetrasubsti-
tuted alkene 19 was obtained in 63% yield along with 20
in 22% yield. Reduction of the ester group of 19 with
DIBAL-H gave alcohol 21, which was already converted
into tamoxifen by Fallis (Scheme 6).2o According to the
Scheme 3 Retrosynthetic analysis of tamoxifen using nickel-cataly-
zed phenylative carboxylation
To examine whether other zinc reagents can be used for
this reaction, various zinc reagents were examined and the
results are shown in Table 1. The use of Ph2Zn and Bn2Zn
gave the corresponding tetrasubstituted alkenes 13b and
13c in high yields, respectively (entries 2 and 3). In the
case of Bu2Zn, tetrasubstituted alkene 13d was obtained
in 79% yield along with trisubstituted alkene 13e (R = H)
Table 1 Nickel-Catalyzed Carboxylation in the Presence of Various Zinc Reagents
OMe
1. CO2 (1 atm)
Ni(cod)2 (20 mol%)
DBU (10 equiv)
Ph
Ph
OMe
R2Zn (3 equiv)
THF
R
MeO2C
12
2. CH2N2
13
Entry
R2Zn
Temp
Time (h)
R
Product
13a
Yield (%)
quant.a
97
1
2
3
4
Me2Zn
Ph2Zn
Bn2Zn
Bu2Zn
r.t.
18
15
12
18
Me
Ph
40 °C
40 °C
r.t.
13b
Bn
Bu
13c
90
13d
79b
a Previously reported.
b Trisubstituted alkene 13e (R = H) formed by b-hydrogen elimination was obtained in 19% yield.
Synlett 2006, No. 18, 3182–3184 © Thieme Stuttgart · New York

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.
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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.
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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