Preparation of α,n-dilithiotoluene equivalents. Synthesis of tamoxifen

Article abstract of DOI:10.1016/S0040-4020(03)00428-9

The successive reaction of chlorobenzyl alcohols with n-butyllithium and lithium powder in the presence of a substoichiometric amount of 4,4′-di-tert-butylbiphenyl (DTBB) at -78°C yields the expected (lithiooxymethyl)phenyllithium derivative, which is trapped by reaction with different ketones. The subsequent arene-catalysed lithiation at 25°C permits the one-pot chemoselective lithiation of the primary benzyl alcoholate in the presence of a tertiary one. These new functionalised benzyllithium derivatives react with different electrophilic compounds, such as aldehydes, ketones and chlorotrimethylsilane, to give after hydrolysis the expected functionalised benzyl alcohols. Some of these alcohols are successfully transformed into mono- or di-olefins by acidic treatment. This whole strategy is applied to the preparation of anti-cancer drug tamoxifen.

Full text of DOI:10.1016/S0040-4020(03)00428-9

Tetrahedron 59 (2003) 3219–3225
Preparation of a,n-dilithiotoluene equivalents.
Synthesis of tamoxifen
*
Miguel Yus, Diego J. Ramon and Inmaculada Gomez
´
´
´ ´
Departamento de Quımica Organica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, E-03080 Alicante, Spain
Received 3 January 2003; revised 18 March 2003; accepted 19 March 2003
Abstract—The successive reaction of chlorobenzyl alcohols with n-butyllithium and lithium powder in the presence of a substoichiometric
amount of 4,40-di-tert-butylbiphenyl (DTBB) at 2788C yields the expected (lithiooxymethyl)phenyllithium derivative, which is trapped by
reaction with different ketones. The subsequent arene-catalysed lithiation at 258C permits the one-pot chemoselective lithiation of the
primary benzyl alcoholate in the presence of a tertiary one. These new functionalised benzyllithium derivatives react with different
electrophilic compounds, such as aldehydes, ketones and chlorotrimethylsilane, to give after hydrolysis the expected functionalised benzyl
alcohols. Some of these alcohols are successfully transformed into mono- or di-olefins by acidic treatment. This whole strategy is applied to
the preparation of anti-cancer drug tamoxifen. q 2003 Published by Elsevier Science Ltd.
1. Introduction
di- and tri-deprotonation process of any possible carbon–
hydrogen bonds.6
The huge amount of polyfunctionalised organic compounds
present in Nature1 has prompted chemists to develop new
methodologies to obtain them as easily and selectively as
possible. One very useful methodology consists in the
application of organometallic intermediates2 in their
synthesis, and this is due to the versatility of these
compounds in their reactivity with different reagents.
Within this ample group, polylithiated equivalents3 are a
very interesting subclass due to their higher reactivity
towards electrophilic compounds. In this way, the reaction
of dilithiated species with two (equal or different) electro-
philes allows the direct introduction of two electrophilic
fragments in the molecule in only one synthetic step. This
recently recognised strategy of construction of targets is
divided in two groups:4 (a) the simultaneous two-directional
homologation, when the two electrophiles are the same or
(b) the sequential two-directional homologation, when the
two electrophiles are different. The great difficulty in a two-
directional synthesis resides in the preparation of the
appropriate intermediates having two carbon–lithium
bonds with different reactivity.
An alternative to the direct metalation is the reductive
lithiation of the corresponding dichlorinated materials,7
using an arene as the electron shuttle.8
When at the benzylic position is a phosphorus atom, the
stability of the intermediate is higher and the chemo-
selective polylithiation9 is possible, yielding, for example,
the compound 2, which was characterised by X-ray
analysis.10 However, with this kind of intermediates the
use of two different electrophiles for chemoselective
reacting with the corresponding a,n-dilithiotoluene
derivative is not possible.
In order to overcome this inconvenience and to be able to
use a,2-dilithiotoluene equivalents in sequential two-
directional synthesis, 1-bromo-2-[(trimethylstannyl)-
methyl]benzene (3) was introduced.11 The chemoselective
lithiation of compound 3 using tert-butyllithium gave the
corresponding aryllithium derivative, which was trapped by
reaction with trimethylgermanium chloride. The further
tin–lithium exchange must be conducted by a large excess
of tert-butyllithium to give the expected benzyllithium
derivative. The availability of compound 3, as well as the
Ones of the most simple dilithiated species having different
hybridisation5 are a,n-dilithiotoluenes (1). These inter-
mediates were postulated in the reaction of toluene with a
big excess of n-butyllithium-tetramethylethylendiamine in
hexane, together with other products arising from a mono-,
Keywords: chlorobenzyl alcohol; tamoxifen; a,n-dilithiotoluene.
*
Corresponding author. Tel.: þ34-965-903548; fax: þ34-965-903549;
e-mail: yus@ua.es
0040–4020/03/$ - see front matter q 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4020(03)00428-9

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M. Yus et al. / Tetrahedron 59 (2003) 3219–3225
necessity of a large excess of alkyllithium reagent, limits the
use of this reagent in synthesis.
lead to the benzyllithium derivatives 7. The chemo-
selectivity found may be a consequence of the higher
stability of primary organolithium compounds compared to
the corresponding tertiary ones, and therefore it is based on
thermodynamic considerations. Even for compounds 8b and
8e (derived from acetophenone), the postulate intermediate
7 (R¼Me, R0¼Ph) seems to be preferred compared to the
corresponding tertiary one containing two phenyl groups.
The final reaction of organolithiums 7 with different
electrophiles, followed by hydrolysis, gave the function-
alised benzyl alcohols 8 (see Scheme 1 and Table 1).
In this paper we would like to introduce the commercially
available chlorobenzyl alcohols (4) as ideal starting
materials in the preparation of a,n-dilithiotoluene equiva-
lents (1) and their use in sequential two-directional
homologations. The one-pot sequential chemoselective
lithiation of compounds 4 through a DTBB-catalysed
lithiation process will take place depending on the reaction
conditions, allowing to prepare and use synthetic equiva-
lents of reagent 1.
Global yields are variable, depending on both electrophiles
used, being higher when cyclohexanone was used as the first
electrophilic reagent. The relative position of substituents
had also a great influence, and for example, using the ortho-
chloroalcohol 4a as starting material, the corresponding
benzyl intermediate of type 7 could not be reacted with a
second electrophile (benzaldehyde or cyclohexanone),
giving in both cases the tolyl derivative 8 where X¼H
(see Scheme 1 and Table 1, entry 1). Probably, the ortho-
intermediate 7 is very unstable and takes a proton for the
reaction media, probably from the THF.15
2. Results and discussion
The reaction of chlorobenzyl alcohols 4 with 1 equiv. of
n-BuLi in THF gave the expected lithium alcoholate, which
was then added to a solution of an excess of lithium powder
and a substoichiometric amount of 4,40-di-tert-butyl-
biphenyl (DTBB, 4% molar ratio) at 2788C to give after
1 h the corresponding functionalised organolithium12 5. The
same intermediate could be obtained when compounds 4
were added to a mixture of excess of lithium, DTBB (4%
molar ratio) and n-BuLi. Arylithium derivatives13 5 were
trapped by reaction with different ketones to give the
corresponding alcoholate derivatives 6. Then, the tempera-
ture reaction was allowed to rise from 278 to room
temperature, so the chemoselective lithiation of the primary
alcoholate14 in the presence of the tertiary one took place, to
The treatment of some benzylic alcohols 8 with phosphoric
acid in toluene at room temperature gave the chemio-
selectively dehydration16 to lead to the conjugate olefins 9
(see Table 2) with excellent yields.
In order to perform the full dehydration, the above diols 9
were submitted to the same acid conditions (phosphoric acid
in toluene) but under a higher temperature. At toluene reflux
the dehydration took place in 2 h, giving the expected
diolefins 10 with excellent yields. It is worthy to note that in
the case of the alcohol 9c instead of the expected conjugate
olefin of type 10a,b the only isolated product was the
compound 10c. The reason for this behaviour must include
Scheme 1. Reagents and conditions: (i) n-BuLi (1 equiv.), 2788C, THF and then Li, DTBB (4 mol%) or Li, DTBB (4 mol%), n-BuLi (1 equiv.), THF, 2788C;
(ii) RCOR0¼(CH2)5CO, Et2CO, PhCOMe; (iii) 278 to 258C; (iv) E¼Me3SiCl, ButCHO, PhCHO, Et2CO, (CH2)4CO, THF, 2408C; (v) H2O, 240 to 258C.
Table 1. Preparation of compounds 8
Entry
Starting material
Substitution
E
Substituted benzyl alcohol
R0
No.
No.
R
X
Yield
(%)a
1
2
3
4
5
6
7
8
9
4a
4b
4b
4b
4c
4c
4c
4c
4c
1,2-
1,3-
1,3-
1,3-
1,4-
1,4-
1,4-
1,4-
1,4-
PhCHO
Me3SiCl
PhCHO
Et2CO
Me3SiCl
ButCHO
PhCHO
Et2CO
8a
8b
8c
8d
8e
8f
8g
8h
8i
–(CH2)5–
Me
–(CH2)5–
–(CH2)5–
Me
H
Me3Si
PhCHOH
Et2COH
Me3Si
ButCHOH
PhCHOH
Et2COH
(CH2)4COH
63
21
52
48
35
18
57
51
10
Ph
Ph
Et
Et
–(CH2)5–
–(CH2)5–
–(CH2)5–
(CH2)4CO
a
1
Isolated yield (.95% from GLC and/or 300 MHz H NMR) after column chromatography (silica gel, hexane/ethyl acetate).

M. Yus et al. / Tetrahedron 59 (2003) 3219–3225
3221
Table 2. Preparation of olefins 9
with propanal, to give, after hydrolysis, the expected
1-phenyl-1-propanol.22 This crude alcohol was transformed
to the corresponding chlorinated material 12 with 82%
isolated yield by nucleophilic substitution, using hydro-
chloric acid in hexane.23 The other electrophilic component
for this approach is 4-[2-(dimethylamino)ethoxy]benzo-
phenone (13),21b which was easily prepared by alkylation of
the corresponding 4-hydroxybenzophenone with 2-chloro-
ethyldimethylamine under basic conditions.20c,21b The
DTBB-catalysed lithiation of the chlorinated material 12
in the presence of the aforementioned benzophenone at low
temperature gave, after hydrolysis, a mixture of the
corresponding diastereomeric tertiary alcohol. The final
dehydration using hydrochloric acid under reflux21a of
ethanol gave a ca. 1/1 mixture of Z/E tamoxifen (14) with
51% isolated overall yield (see Scheme 2).
Entry
Diol
Position
Product
No.
8c
8g
8i
No.
9a
9b
9c
R
H
H
R0
Ph
Ph
Yield (%)a
1
2
3
1,3-
1,4-
1,4-
91
97
90
–(CH2)4–
a
Isolated crude yield of pure product 9 (.95% from 300 MHz 1H NMR).
the high torsional deformation of bond angles in over-
crowded alkenes,17 this steric hindrance being vanished in
the case of the endo-cyclic olefin 10c.
3. Conclusions
In conclusion, we have introduce here a simple method for
the preparation of a-n-dilithiotoluene equivalents from
commercial available chlorobenzyl alcohols. This strategy
avoids the use of sophisticated starting materials, giving
similar results. The arene-catalysed reductive lithiation of
aryl and benzyl derivatives has been successfully used in the
preparation of tamoxifen, the overall yield being similar to
the best describes before using a similar strategy.
4. Experimental
4.1. General
This approach of lithiation of aryl- and benzyl derivatives
using a arene-catalysed lithiation followed by dehydration
was thought to be effective in the preparation of anti-
cancer drug tamoxifen. (Z)-2-[4-(1,2-diphenyl-1-butenyl)-
phenoxy]-N,N-dimethylethaneamine (tamoxifen, 14) is a
selective estrogen receptor antagonist, being used for the
treatment for all stages of hormone-reponsive breast
cancer.18 The active metabolite of tamoxifen is the
corresponding (Z)-4-hydroxytamoxifen. In vivo, the Z/E-
mixture equilibrates very rapidly, so the isomeric mixture
can be prescribed.19 As far as the synthetic approaches are
concerned, there are two general pathways to obtain
tamoxifen derivatives: (a) the McMurry approach20 which
has the inconvenience of obtaining a mixture of the desired
hetero-ketone coupling and the undesired homo-ketone
coupling; (b) the use of organometallic nucleophiles
(mainly organomagnesium reagents) to create carbon
skeleton.21 In our case, we followed the second approach,
using phenyllithium and 1-lithio-1-phenylpropane as
reagents. Thus, the naphthalene-catalysed lithiation of
chlorobenzene13a (11) at 2788C gave the expected
phenyllithium reagent, which was trapped by reaction
Full general statements were described elsewhere.24 All
reactions using lithium powder were carried out under an
argon atmosphere. 4-[2-(Dimethylamino)ethoxy]benzo-
phenone (13)21b was prepared according to the reported
procedure,20c,21b starting from the corresponding 4-hydro-
xybenzophenone by deprotonation using K2CO3 in a
solution of H2O/Me2CO and final alkylation of the
phenolate derivative with 2-chloroethyldimethylamine
hydrochloride to give the expected product in 85% overall
yield.
4.2. General procedure for the sequential chemoselective
lithiation of chlorobenzyl alcohol. Isolation of
compounds 8
To a turquoise-coloured suspension of lithium powder
(0.20 g, 28 mmol) and DTBB (0.085 g, 0.32 mmol) in THF
(5 mL) at 2788C was added a solution of n-buthyllithium
(1.6 M, 1.25 mL). After 5 min, a solution of the corresponding
Scheme 2. Reagents and conditions: (i) Li, C10H8 (4 mol%), THF, 2788C; (ii) EtCHO; (iii) H2O, 278 to 258C; (iv) HCl (35%), hexane, 258C; (v) Li, DTBB
(4 mol%), 4-(Me2NCH2CH2O)C6H4COPh (13), THF, 2788C; (vi) HCl (35%), EtOH, 808C.

3222
M. Yus et al. / Tetrahedron 59 (2003) 3219–3225
chlorobenzyl alcohol 4 (2 mmol) in THF (3 mL) was added.
After 45 min, the corresponding ketone (2.2 mmol) was
added, and after 15 min the temperature was allowed to rise
to 258C by removing of cooling bath. The reaction mixture
was kept at this temperature for 4 h. Then, the mixture was
cooled down to 2408C and the second electrophile
(2.2 mmol) was added. After 1 h, the reaction mixture was
successively quenched with H2O (10 mL) and a saturated
solution of NH4Cl (25 mL). The resulting mixture was
extracted with ethyl acetate (3£20 mL). The combined
organic layers were dried over anhydrous MgSO4 and
evaporated (15 Torr) to give a residue, which was purified
by column chromatography, affording the pure title
compounds 8. Yields are included in Table 1. Physical
and spectroscopic data, as well as the literature reference,
follow.
258 (Mþ2H2O, ,1%), 173 (16), 172 (100), 161 (10), 147
(13), 144 (19), 143 (46), 130 (11), 129 (14), 106 (12), 105
(12), 104 (47), 91 (19), 87 (48), 81 (25), 69 (12), 67 (13), 57
(38), 55 (41), 45 (85), 43 (32), 41 (43); HRMS: Mþ2H2O
found 258.1962. C18H26O requires 258.1984.
4.2.5. 1-Phenyl-1-(4-trimethylsilylmethylphenyl)-etha-
nol 8e. tr 15.0; Rf 0.67 (hexane/ethyl acetate: 7/3); n (film)
3466 (OH), 3079, 3056, 1605, 1507 (HCvC), 1155 cm21
(CO); dH 0.0 (9H, s, SiMe3), 1.84 (1H, s, OH), 1.94 (3H, s,
CMe), 2.07 (2H, s, CH2), 6.95–7.00 and 7.25–7.45 (2 and
7H, respectively, 2m, ArH); dC 21.0 (3C), 26.55, 30.9, 76.1,
125.7 (2C), 125.75 (2C), 126.7, 127.75 (2C), 128.05 (2C),
139.25, 143.4, 148.35; m/z 284 (Mþ, 2%), 194 (55), 179
(20), 105 (15), 77 (11), 75 (10), 74 (12), 73 (100), 45 (39),
43 (55); HRMS: Mþ found 284.1614. C18H24SiO requires
284.1596.
4.2.1. 1-(2-Methylphenyl)-1-cyclohexanol 8a.25 tr 11.8; Rf
0.38 (hexane/ethyl acetate: 9/1); n (film) 3451 (OH), 3104,
3057, 3014, 1608 (HCvC), 1171, 1132 cm21 (CO); dH
1.20–2.00 [11H, m, (CH2)5 and OH], 2.61 (3H, s, Me),
7.10–7.25 and 7.40–7.45 (3 and 1H, respectively, 2m,
ArH); dC 22.05 (2C), 22.3, 25.5, 37.25 (2C), 74.15, 125.2,
125.5, 126.8, 132.8, 136.45, 146.1; m/z 190 (Mþ, 15%), 175
(10), 172 (10), 147 (62), 134 (18), 129 (17), 119 (100), 91
(38), 65 (10), 55 (40).
4.2.6. 1-[4-(2-Hydroxy-3,3-dimethylbutyl)phenyl]-3-pen-
tanol 8f. tr 14.4; Rf 0.38 (hexane/ethyl acetate: 7/3); n (film)
3454 (OH), 1614 (CvC), 1159, 1069 cm21 (CO); dH 0.76
(6H, t, J¼7.4 Hz, 2£MeCH2), 1.00 (9H, s, CMe3), 1.50–
1.70 (3H, m, 2£OH and CHO), 1.75–1.85 (4H, m,
2£CH2Me), 2.90 and 3.44 (1 and 1 H, respectively, 2dd,
J¼2, 10.8 Hz, ArCH2), 7.19 and 7.32 (2 and 2H,
respectively, 2d, J¼8.1 Hz, ArH); dC 7.85 (2C), 24.9,
25.85 (3C), 34.8, 34.85, 37.9, 77.3, 80.45, 125.75 (2C),
128.9 (2C), 137.65, 143.85; m/z 235 (Mþ2Et, 100%), 166
(20), 149 (44), 104 (14), 91 (19), 87 (30), 69 (20), 57 (99),
45 (42), 43 (41), 41 (55); HRMS: Mþ2CH3CH2 found
235.1672. C15H23O2 requires 235.1698.
4.2.2. 1-Phenyl-1-(3-trimethylsilylmethylphenyl) ethanol
8b. tr 14.7; Rf 0.64 (hexane/ethyl acetate: 7/3); n (film) 3407
(OH), 3055, 3027, 1599 (HCvC), 1153 cm21 (CO); dH 0.0
(9H, s, SiMe3), 2.00 (3H, s, CMe), 2.12 (2H, s, CH2), 2.20
(1H, broad s, OH), 6.90–6.95, 7.07 and 7.20–7.50 (1, 1 and
7H, respectively, m, s and m, respectively, ArH); dC 22.0
(3C), 27.1, 30.75, 76.2, 121.3, 125.8 (3C), 126.6, 126.8,
127.9, 128.0 (2C), 140.3, 147.75, 148.2; m/z 284 (Mþ,
,1%), 194 (42), 180 (10), 179 (66), 105 (12), 77 (10), 75
(15), 74 (11), 73 (100), 45 (37), 43 (50); HRMS: Mþ found
284.1576. C18H24SiO requires 284.1596.
4.2.7. 1-[4-(2-Hydroxy-2-phenylethyl)phenyl]-1-cyclo-
hexanol 8g. tr 18.4; Rf 0.22 (hexane/ethyl acetate: 7/3); n
(film) 3403 (OH), 3061, 3028, 1604, 1512 (HCvC),
1037 cm21 (CO); dH 1.60–1.85 [11H, m, (CH2)5 and
OH], 2.11 (1H, broad s, OH), 2.90–3.05 (2H, m, ArCH2),
4.85–4.90 (1H, m, ArCHO), 7.15–7.45 (9H, m, ArH); dC
22.1 (2C), 25.45, 38.75 (2C), 45.6, 72.95, 75.2, 124.75 (2C),
125.85 (2C), 127.55, 128.35 (2C), 129.25 (2C), 136.45,
143.85, 147.7; m/z 278 (Mþ2H2O, 2%), 173 (15), 172
(100), 171 (18), 157 (26), 144 (11), 129 (20), 128 (15), 115
(15), 107 (50), 105 (12), 104 (33), 91 (20), 79 (52), 77 (32),
51 (11); HRMS: Mþ2H2O found 278.1674. C20H22O
requires 278.1671.
4.2.3. 1-[3-(2-Hydroxy-2-phenylethyl)phenyl]-1-cyclo-
hexanol 8c. tr 18.0; Rf 0.27 (hexane/ethyl acetate: 7/3); n
(film) 3405 (OH), 3061, 3028, 1604, 1493 (HCvC),
1043 cm21 (CO); dH 1.55–1.75 [10H, m, (CH2)5], 2.12
(2H, broad s, 2£OH), 2.95–3.00 (2H, m, ArCH2), 4.80–
4.85 (1H, m, ArCHO), 7.05–7.10 and 7.20–7.30 (1 and 8H,
respectively, 2m, ArH); dC 22.05 (2C), 25.4, 38.7 (2C),
46.2, 73.05, 75.25, 122.8, 125.9, 127.05, 127.45, 127.8,
128.2, 128.3 (2C), 137.8, 143.8, 149.5; m/z 278 (Mþ2H2O,
3%), 173 (14), 172 (100), 157 (20), 144 (13), 143 (17), 130
(12), 129 (30), 128 (18), 115 (16), 107 (80), 105 (27), 104
(23), 91 (19), 80 (16), 79 (89), 78 (10), 77 (54), 51 (16), 41
(12); HRMS: Mþ2H2O found 278.1656. C20H22O requires
278.1671.
4.2.8. 1-[4-(2-Ethyl-2-hydroxybutyl)phenyl]-1-cyclo-
hexanol 8h. tr 14.5; Rf 0.33 (hexane/ethyl acetate: 7/3); n
(film) 3400 (OH), 3087, 3053, 1613, 1510 (HCvC), 1146,
1128 cm21 (CO); dH 0.91 (6H, t, J¼7.4 Hz, 2£Me), 1.43
(4H, q, J¼7.4 Hz, 2£CH2Me), 1.60–1.80 [12H, m, (CH2)5
and 2£OH], 2.70 (2H, s, ArCH2), 7.17 and 7.41 (2 and 2H,
respectively, 2d, J¼7.9 Hz, ArH); dC 7.9 (2C), 22.1 (2C),
25.45, 30.3 (2C), 38.7 (2C), 44.2, 72.8, 74.5, 124.35 (2C),
130.3 (2C), 135.65, 147.45; m/z 258 (Mþ2H2O, ,1%), 173
(13), 172 (90), 157 (16), 147 (16), 144 (10), 143 (14), 134
(13), 129 (21), 128 (13), 105 (16), 104 (100), 99 (14), 91
(19), 87 (54), 81 (18), 69 (18), 57 (26), 55 (24), 45 (82), 43
(25), 41 (40); HRMS: Mþ found 276.2076. C18H28O2
requires 276.2089.
4.2.4. 1-[3-(2-Ethyl-2-hydroxybutyl)phenyl]-1-cyclo-
hexanol 8d. tr 16.0; Rf 0.27 (hexane/ethyl acetate: 7/3); n
(film) 3411 (OH), 3041, 3025, 1604 (HCvC), 1168,
1131 cm21 (CO); dH 0.93 (6H, t, J¼7.4 Hz, 2£Me), 1.45
(4H, q, J¼7.4 Hz, 2£CH2Me), 1.55–1.85 (12H, m, (CH2)5
and 2£OH), 2.75 (2H, s, ArCH2), 7.10 and 7.25–7.40 (1 and
3H, respectively, d, J¼7.3 Hz and m, respectively, ArH); dC
8.0 (2C), 22.1 (2C), 25.45, 30.3 (2C), 38.75 (2C), 44.95,
73.0, 74.55, 122.6, 126.95, 127.9, 128.8, 137.25, 149.3; m/z
4.2.9. 1-[4-(1-Hydroxycyclopentylmethyl)phenyl]-1-
cyclohexanol 8i. tr 17.5; Rf 0.24 (hexane/ethyl acetate:

M. Yus et al. / Tetrahedron 59 (2003) 3219–3225
3223
7/3); n (film) 3406 (OH), 1644 (CvC), 1086, 1021 cm21
(CO); dH 1.55–1.80 [20H, m, (CH2)5, (CH2)4 and 2£OH],
2.86 (2H, s, ArCH2), 7.21 and 7.43 (2 and 2H, respectively,
2d, J¼8.5 Hz, ArH); dC 23.15 (2C), 24.45 (2C), 26.5, 39.8
(2C), 40.35 (2C), 47.55, 73.95, 83.1, 125.55 (2C), 131.0
(2C), 137.6, 148.55; m/z 274 (Mþ, ,1%), 190 (15), 173
(15), 172 (100), 147 (27), 134 (19), 129 (12), 119 (10), 105
(14), 104 (81), 91 (20), 85 (48), 81 (11), 67 (34), 57 (17), 55
(52), 43 (29), 41 (44); HRMS: Mþ2H2O found 256.1797.
C18H24O requires 256.1827.
172 (100), 171 (12), 157 (45), 144 (18), 129 (37), 128 (20),
115 (19), 104 (53), 91 (22), 85 (57), 80 (13), 79 (12), 67
(46), 57 (16), 55 (20), 43 (21), 41 (52); HRMS: Mþ found
256.1824. C18H24O requires 256.1827.
4.4. General procedure for the dehydration of alcohols 9.
Isolation of compounds 10
To a solution of the corresponding alcohol 9 (0.06 mmol) in
toluene (1 mL) was added H3PO4 (85%, 0.5 mmol) at 258C,
and it was refluxed during 2 h. After cooling down to room
temperature, the reaction was quenched by addition of a
saturated solution of NaHCO3 (5 mL). The resulting
mixture was extracted with ether (2£10 mL) and the
combined organic layers were dried over anhydrous
MgSO4 and evaporated (15 Torr) to give the pure compound
10. Yields are included in the text. Physical and spectro-
scopic data are as follows.
4.3. General procedure for the chemoselective
monodehydration. Isolation of compounds 9
To a solution of the corresponding diol 8 (0.13 mmol) in
toluene was added H3PO4 (85%, 0.29 mmol) at 258C and it
was stirred during 8 h. Then, the reaction was quenched by
addition of a solution of saturated NaHCO3 (10 mL). The
resulting mixture was extracted with ether (2£15 mL) and
the combined organic layers were dried over anhydrous
MgSO4 and evaporated (15 Torr) to give the pure
compounds 9. Yields are included in Table 2. Physical
and spectroscopic data are as follows.
4.4.1. (E)-1-[3-(Cyclohex-1-en-1-yl)phenyl]-2-phenyl-1-
ethene 10a. tr 18.3; Rf 0.30 (hexane); n (film) 3025,
1599 cm21 (HCvC); dH 1.80–1.95 [4H, m, CH2(CH2)2-
CH2], 2.30–2.40 and 2.50–2.60 (2 and 2H, respectively,
2m, CH2CvCHCH2), 6.25–6.35 (1H, m, CH2CHvC),
7.25–7.50 and 7.60–7.65 (9 and 2H, respectively, 2m,
ArCHvCHPh); dC 22.15, 23.05, 25.85, 27.5, 123.3, 124.4,
124.65, 125.1, 126.45 (2C), 127.55, 128.5, 128.65 (2C),
128.95, 129.0, 136.55, 137.1, 137.4, 143.15; m/z 260 (Mþ,
100%), 217 (14), 215 (14), 203 (11), 202 (16), 180 (13), 179
(17), 178 (19), 165 (12), 153 (13), 141 (31), 129 (10), 128
(26), 115 (23), 108 (21), 101 (14), 91 (34), 77 (15), 51 (11),
41 (14); HRMS: Mþ found 260.1550. C20H20 requires
260.1565.
4.3.1. 2-[3-(Cyclohex-1-en-1-yl)phenyl]-1-phenyl-1-etha-
nol 9a. tr 17.8; Rf 0.55 (hexane/ethyl acetate: 7/3); n (film)
3538, 3391 (OH), 3058, 3029, 1601 (HCvC), 1046 cm21
(CO); dH 1.60–1.80 (4H, m, CH2(CH2)2CH2), 2.10 (1H,
broad s, OH), 2.20–2.40 (4H, m, CH2(CH2)2CH2), 2.90–
3.05 (2H, m, ArCH2), 4.85–4.90 (1H, m, ArCHO), 6.05–
6.10 (1H, m, CH2CHvC), 7.05–7.35 (9H, m, ArH); dC
22.1, 23.0, 25.8, 27.35, 46.25, 75.25, 123.3, 124.9, 125.85,
126.15, 127.5, 127.6, 128.3 (2C), 128.35 (2C), 136.4, 137.7,
142.95, 143.8; m/z 278 (Mþ, 3%), 216 (16), 173 (14), 172
(100), 157 (18), 144 (11), 143 (15), 141 (11), 130 (11), 129
(26), 128 (16), 115 (14), 107 (66), 105 (15), 104 (19), 91
(18), 80 (13), 79 (69), 77 (42), 51 (13), 41 (11); HRMS: Mþ
found 278.1664. C20H22O requires 278.1671.
4.4.2. (E)-1-[4-(Cyclohex-1-en-1-yl)phenyl]-2-phenyl-1-
ethene 10b. tr 18.6; Rf 0.40 (hexane); n (film) 3022,
1598 cm21 (HCvC); dH 1.80–1.95 [4H, m, CH2(CH2)2-
CH2], 2.30–2.40 and 2.50–2.60 (2 and 2H, respectively,
2m, CH2CvCHCH2), 6.30–6.35 (1H, m, CH2CHvC),
7.35–7.65 (11H, m, ArCHvCHPh); dC 22.15, 23.0, 25.95,
27.2, 124.9, 125.1 (2C), 126.35 (2C), 126.4 (2C), 127.45,
127.95, 128.45, 128.65 (2C), 135.55, 136.05, 137.45,
141.85; m/z 260 (Mþ, 100%), 232 (12), 217 (12), 215
(11), 202 (14), 179 (11), 178 (16), 153 (13), 141 (25), 130
(11), 128 (25), 115 (19), 114 (10), 107 (12), 101 (11), 91
(25), 77 (15), 51 (10), 41 (13); HRMS: Mþ found 260.1566.
C20H20 requires 260.1565.
4.3.2. 2-[4-(Cyclohex-1-en-1-yl)phenyl]-1-phenyl-1-etha-
nol 9b. tr 18.4; Rf 0.60 (hexane/ethyl acetate: 7/3); n (film)
3534, 3442 (OH), 3029, 1605 (HCvC), 1049 cm21 (CO);
dH 1.50–1.80 [5H, m, CH2(CH2)2CH2 and OH], 2.15–2.20
and 2.30–2.40 [2 and 2H, respectively, 2m, CH2(CH2)2-
CH2], 2.90–3.05 (2H, m, ArCH2), 4.85–4.90 (1H, m,
ArCHO), 6.10–6.15 (1H, m, CH2CHvC), 7.10–7.35 (9H,
m, ArH); dC 22.15, 23.0, 25.85, 27.3, 45.7, 75.25, 124.45,
125.0 (2C), 125.85 (2C), 127.55, 128.35 (2C), 129.3 (2C),
136.1 (2C), 141.0, 143.8; m/z 278 (Mþ, 2%), 173 (15), 172
(100), 171 (17), 157 (25), 144 (10), 129 (18), 128 (13), 115
(13), 107 (47), 105 (11), 104 (30), 91 (18), 79 (47), 77 (26);
HRMS: Mþ found 278.1664. C20H22O requires 278.1671.
4.4.3. 1-(Cyclohex-1-en-1-yl)-4-(cyclopent-1-en-1-
ylmethyl)benzene 10c. tr 15.4; Rf 0.28 (hexane); n (film)
3047, 3024, 1601, 1511 cm21 (HCvC); dH 1.65–1.85 [6H,
m, CH2(CH2)2CH2 and CvCCH2CH2CH2CHvC] 2.20–
2.40 [8H, m, CH2(CH2)2CH2 and CvCCH2CH2CH2-
CHvC], 3.36 (2H, s, ArCH2), 5.30–5.35 (1H, m,
HCvCAr), 6.10–6.15 (1H, m, HCvCCH2Ar), 7.10 and
7.34 (2 and 2H, respectively, 2d, J¼8.2 Hz, ArH); dC 22.2,
23.5, 25.85, 27.35, 29.7, 32.45, 34.8, 37.55, 124.7 (2C),
125.25, 127.75, 128.6 (2C), 130.9, 136.3, 140.2, 143.9; m/z
238 (Mþ, 100%), 171 (10), 170 (11), 157 (61), 155 (13), 142
(18), 141 (23), 130 (11), 129 (62), 128 (27), 115 (28), 91
(45), 81 (25), 80 (20), 79 (35), 77 (17), 67 (22), 65 (11), 53
(19), 41 (47); HRMS: Mþ found 238.1706. C18H22 requires
238.1721.
4.3.3. 1-[4-(Cyclohex-1-en-1-yl)benzyl]-1-cyclopentanol
9c. tr 16.5; Rf 0.52 (hexane/ethyl acetate: 7/3); n (film)
3429 (OH), 3022, 1644 (HCvC), 1013 cm21 (CO); dH
1.55–1.80 [13H, m, (CH2)4, (CH2)2CH2CvC and OH],
2.20–2.25 and 2.30–2.40 (2 and 2H, respectively, 2m,
CH2CvCHCH2), 2.86 (2H, s, ArCH2), 6.10–6.15 (1H, m,
CH2CHvC), 7.18 and 7.33 (2 and 2H, respectively, 2d,
J¼8.3 Hz, ArH); dC 22.15, 23.05, 23.45, 25.85, 27.3, 29.7,
39.35 (2C), 46.65, 82.15, 124.45, 124.75 (2C), 129.95 (2C),
136.15, 136.4, 140.8; m/z 256 (Mþ, 4%), 238 (11), 173 (14),

3224
M. Yus et al. / Tetrahedron 59 (2003) 3219–3225
4.5. Synthesis of tamoxifen 14
65.85, 113.4 (2C), 114.1 (2C), 125.6, 125.95, 126.45 (2C),
127.25 (2C), 127.7, 127.8 (2C), 128.0 (2C), 128.15, 129.45
(2C), 129.65 (2C), 130.5 (2C), 130.75 (2C), 131.8 (2C),
135.55, 136.05, 138.25, 138.4, 141.3, 141.9, 142.4, 143.3,
143.8, 156.7, 157.55; m/z (first isomer) 371 (Mþ, 4%), 72
(24), 58 (100); m/z (second isomer) 371 (Mþ, 3%), 72 (24),
58 (100).
4.5.1. Preparation of 1-phenyl-1-chloropropane 12.26 To
a green suspension of lithium powder (0.1 g, 14 mmol) and
naphthalene (20 mg, 0.16 mmol) in THF (10 mL) at 2788C
was added chlorobenzene (11, 0.2 mL, 2 mmol). After
45 min propionaldehyde (0.18 mL, 2.5 mmol) was added
and the resulting mixture was stirred for 30 min being then
quenched by subsequent addition of H2O (1 mL) and a
solution of saturated NH4Cl (20 mL). The resulting mixture
was extracted with ethyl acetate (3£20 mL), the combined
organic layers were dried over anhydrous MgSO4 and
evaporated (15 Torr) to give 1-phenyl-1-propanol.22 This
alcohol was dissolved in hexane (20 mL) and to the
resulting solution was added HCl (35%, 1 mL) at 258C.
The resulting mixture was stirred over 1 h and the reaction
was quenched by addition of a saturated solution of
NaHCO3 (10 mL). The resulting mixture was extracted
with ether (2£10 mL) and the combined organic layers were
dried over anhydrous MgSO4 and evaporated (15 Torr) to
give the a residue which was distilled bulb to bulb (1308C,
0.1 Torr) to yield the title compound. Overall yield is
included in Scheme 2: tr 7.2; Rf 0.4 (hexane/ethyl acetate:
9/1); n (film) 3063, 3031, 1600, 1491 cm21 (HCvC); dH
0.99 (3H, t, J¼7.3 Hz, Me), 2.00–2.20 (2H, m, CH2), 4.77
(1H, t, J¼7.2 Hz, CHCl), 7.25–7.40 (5H, m, ArH); dC
11.65, 33.2, 65.45, 126.95 (2C), 128.15, 128.55 (2C),
141.75; m/z 156 (Mþþ2, 8%), 154 (Mþ, 23), 127 (20), 125
(62), 119 (69), 117 (11), 115 (11), 91 (100), 89 (14), 51 (11).
Acknowledgements
This work was financially supported by the DGICYT
(Project PB97-0133) and DGI (Project BQU2001-0538)
´
from the Spanish Ministerio de Educacion, Cultura y
Deporte. I. G. thanks the Spanish Ministerio de Ciencia y
´
Tecnologıa for a predoctoral grant.
References
1. Comprehensive Natural Products Chemistry; Barton, D.,
Nakanisky, K., Meth-Cohn, O., Eds.; Pergamon: Exeter,
1999; Vols. 1–9.
2. See, for instance: (a) Comprehensive Organometallic
Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G.,
Eds.;, 1995; Vols. 1–13. (b) Boudier, A.; Bromm, L. O.; Lotz,
M.; Knochel, P. Angew. Chem. Int. Ed. 2000, 39, 4414–4435.
´
(c) Yus, M.; Ramon, D. J. J. Latv. Chem. 2002, 79–92.
4.5.2. Preparation of tamoxifen. To a turquoise-coloured
suspension of lithium powder (0.1 g, 14 mmol) and DTBB
(0.042 g, 0.16 mmol) in THF (3 mL) at 2788C was slowly
added (ca. 1 h) a solution of the chlorinated material 12
(0.23 g, 1.5 mmol) and 4-[2-(dimethylamino)ethoxy]-
benzophenone (13, 0.86 g, 3.2 mmol)21b in THF (2 mL).
After stirring for one additional hour at the same
temperature, the reaction mixture was quenched by
subsequent addition of H2O (1 mL) and a solution of
saturated NH4Cl (20 mL). The resulting mixture was
extracted with ethyl acetate (3£20 mL), the combined
organic layers were dried over anhydrous MgSO4 and
evaporated (15 Torr) to give a residue which contains a ca.
1:1 diastereomeric mixture of expected alcohols. The crude
product was dissolved in ethanol (1 mL) and HCl was added
(35%, 0.2 mL). The resulting mixture was refluxed during
20 min, being then quenched by addition of a saturated
solution of NaOH (3 M, 15 mL). The resulting mixture was
extracted with ether (2£15 mL) and the combined organic
layers were dried over anhydrous MgSO4 and evaporated
(15 Torr) to give a residue, which was purified by column
chromatography (silica gel, hexane/ethyl acetate) to give a
ca. 1:1 mixture of (Z/E)-N,N-dimethyl-2-[4-(1,2-diphenyl-
but-1-en-1-yl)phenoxy]-1-ethylamine [(Z/E)-14]:21b tr 20.2,
20.5; Rf 0.14 (ethyl acetate/methanol: 9/1); n (melted) 3074,
3059, 3028, 1604 (HCvC), 1097, 1030 cm21 (CO); dH
0.85–0.95 (6H, m, 2£MeCH2), 2.28 and 2.35 (6 and 6H,
respectively, 2s, 2£NMe2), 2.65 and 2.75 (2 and 2H,
respectively, 2t, J¼5.8, 5.8 Hz, 2£CH2N), 3.92 and 4.09 (2
and 2H, respectively, 2t, J¼5.8, 5.8 Hz, 2£CH2O), 6.55,
6.75 and 6.85–7.35 (2, 2 and 24H, respectively, 2d and m,
respectively, J¼8.7, 8.7 Hz, respectively, ArH); dC 13.5,
28.95, 29.65, 45.8 (2C), 45.85 (2C), 58.25, 58.35, 65.6,
3. Foubelo, F.; Yus, M. Trends Org. Chem. 1998, 7, 1–26.
4. Poss, C. S.; Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9–17.
´ ´
5. for a recent example, see: Yus, M.; Ramon, D. J.; Gomez, I.
J. Organomet. Chem. 2002, 663, 20–30.
6. West, R.; Jones, P. C. J. Am. Chem. Soc. 1968, 90, 2656–2661.
´
7. (a) Gomez, C.; Huerta, F. F.; Yus, M. Tetrahedron Lett. 1997,
´
38, 687–690. (b) Gomez, C.; Huerta, F. F.; Yus, M.
´
Tetrahedron 1998, 54, 1853–1866. (c) Gomez, C.; Ruiz, S.;
´
Yus, M. Tetrahedron Lett. 1998, 39, 1397–1400. (d) Gomez,
C.; Ruiz, S.; Yus, M. Tetrahedron 1999, 55, 7017–7026.
8. For reviews, see: (a) Yus, M. Chem. Soc. Rev. 1996, 25,
´
155–161. (b) Ramon, D. J.; Yus, M. Eur. J. Org. Chem. 2000,
´
225–237. (c) Yus, M. Synlett 2001, 1197–1205. (d) Ramon,
D. J.; Yus, M. Rev. Cubana Quim. 2002, 14, 76–115.
9. Klein, J.; Medlik, A.; Meyer, A. Y. Tetrahedron 1976, 32,
51–56.
10. Winkler, M.; Lutz, M.; Mu¨ller, G. Angew. Chem., Int. Ed.
Engl. 1994, 33, 2279–2281.
11. de Boer, H. J. R.; Akkerman, O. S.; Bickelhaupt, F.
Organometallics 1990, 9, 2898–2903.
´
12. For reviews, see: (a) Najera, C.; Yus, M. Trends Org. Chem.
1991, 2, 155–181. (b) Gray, M.; Tinkl, M.; Snieckus, V.
Comprehensive Organometallic Chemistry II; Abel, E. W.,
Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, 1995;
´
Vol. 11, pp 1–92. (c) Najera, C.; Yus, M. Recent Res. Dev.
´
Org. Chem. 1997, 1, 67–96. (d) Najera, C.; Yus, M. Curr. Org.
Chem. 2003, in press.
13. For examples on arene-catalysed lithiation of chloroarenes and
the corresponding nitrogenated heterocycles, see: (a) Guijarro,
´
A.; Ramon, D. J.; Yus, M. Tetrahedron 1993, 49, 469–482.
´ ´
(b) Gomez, I.; Alonso, E.; Ramon, D. J.; Yus, M. Tetrahedron
2000, 56, 4043–4052.
14. (a) Alonso, E.; Guijarro, D.; Yus, M. Tetrahedron 1995, 51,

M. Yus et al. / Tetrahedron 59 (2003) 3219–3225
3225
´
11457–11464. (b) Alonso, E.; Ramon, D. J.; Yus, M. J. Org.
Chem. 1997, 63, 417–421.
21. See for example: (a) McCague, R. J. Chem. Soc., Perkin
Trans. 1 1987, 1011–1015. (b) Olier-Reuchet, C.; Aitken,
D. J.; Bucourt, R.; Husson, H.-P. Tetrahedron Lett. 1995, 36,
8221–8224. (c) Lashley, M. R.; Nantz, M. H. Tetrahedron
Lett. 2000, 41, 3295–3298. (d) Busch, F. R.; De Antonis, D. In
Grignard Reagents: New Developments; Richey, H. G., Ed.;
Wiley: Chichester, 2000; pp 165–183 and literature quoted
therein.
15. Bates, R. B.; Koposki, L. M.; Potter, D. E. J. Org. Chem. 1972,
37, 560–562.
´
16. (a) Gil, J. F.; Ramon, D. J.; Yus, M. Tetrahedron 1994, 50,
´ ´
7307–7314. (b) Yus, M.; Ramon, D. J.; Gomez, I.
Tetrahedron 2002, 58, 5163–5172.
17. Bell, T. W.; Catalano, V. J.; Drew, M. G. B.; Phillips, D. J.
Chem. Eur. J. 2002, 8, 5001–5006.
´
22. (a) Ramon, D. J.; Yus, M. Tetrahedron: Asymmetry 1997, 8,
´
2479–2496. (b) Yus, M.; Ramon, D. J.; Prieto, O.
18. Jordan, V. C. J. Steroid Biochem. Mol. Biol. 2000, 74,
269–277.
Tetrahedron: Asymmetry 2002, 13, 1573–1579.
23. Pourahmady, N.; Vickery, E. H.; Eisenbraun, E. J. J. Org.
Chem. 1982, 47, 2590–2593.
´
24. Prieto, O.; Ramon, D. J.; Yus, M. Tetrahedron: Asymmetry
2000, 11, 1629–1644.
19. Robertson, D. W.; Katzenellenbogen, J. A.; Long, D. J.;
Rorke, E. A.; Katzenellenbogen, B. S. J. Steroid Biochem.
1982, 16, 1–13.
`
20. For recent examples, see: (a) Jaouen, G.; Top, S.; Vessieres,
A.; Pigneon, P.; Leclercq, G.; Laios, I. Chem. Commun. 2001,
25. Thurkauf, A.; de Costa, B.; Yamaguchi, S.-i.; Mattson, M. V.;
Jacobson, A. E.; Rice, K. C.; Rogawski, M. A. J. Med. Chem.
1990, 33, 1452–1458.
ˇ ´
26. Orlovic, M.; Kronja, O.; Humski, K.; Borcic, S. J. Org. Chem.
1986, 51, 3253–3256.
`
383–384. (b) Top, S.; Vessieres, A.; Cabestaing, C.; Laios, I.;
Leclercq, G.; Provot, C.; Jaouen, G. J. Organomet. Chem.
2001, 637–639, 500–506. (c) Top, S.; Kaloun, E. B.;
`
¨
Vessieres, A.; Laıos, I.; Leclercq, G.; Jaouen, G.
J. Organomet. Chem. 2002, 643–644, 350–356. (d) Detsi,
A.; Koufaki, M.; Calogeropoulou, T. J. Org. Chem. 2002, 67,
4608–4611.