New highly stereoselective synthesis of (Z)-4-hydroxytamoxifen and (Z)-4-hydroxytoremifene via McMurry reaction

Full text of DOI:10.1021/jo952279l

3
890
J . Org. Chem. 1996, 61, 3890-3893
Sch em e 1a
New High ly Ster eoselective Syn th esis of
Z)-4-Hyd r oxyta m oxifen a n d
(
(
Z)-4-Hyd r oxytor em ifen e via McMu r r y
Rea ction
Sylvain Gauthier,* J os e´ e Mailhot, and Fernand Labrie*
Medicinal Chemistry Division, Laboratory of Molecular
Endocrinology, CHUL Research Centre, Qu e´ bec City,
Qu e´ bec G1V 4G2, Canada
Received December 28, 1995
(Z)-Tamoxifen (1) is the first antiestrogen to be widely
used for the treatment of breast cancer, and this drug is
presently being evaluated for preventive therapy for
breast cancer in normal women.1 (Z)-Toremifene (2) has
recently been introduced for the treatment of advanced
breast cancer.2 (Z)-4-Hydroxytamoxifen (3), a metabolite
3
of (Z)-tamoxifen (1), is the active antiestrogenic com-
pound.4 We presume that (Z)-4-hydroxytoremifene (4),
lanes.9 The synthesis of (Z)-4-hydroxytoremifene (4) has
not yet been reported in the literature. The challenge
in the preparation of compounds 3 and 4 is to obtain good
stereoselectivity, avoid isomerization,10 introduce an ad-
ditional chloro functionality in compound 4,11 and have
a convergent and scalable approach. According to the
preceding criteria and the success of a described stereo-
selective synthesis of (Z)-tamoxifen (1),12 the McMurry
reaction became a possible strategy for a new stereose-
lective synthesis of (Z)-4-hydroxytamoxifen (3) and (Z)-
5
a metabolite of (Z)-toremifene (2), has a role similar to
that of (Z)-4-hydroxytamoxifen (3).6 Our interest in these
hydroxylated triphenylethylene derivatives is to reach a
better understanding of their contribution in the observed
(Z)-tamoxifen (1) and (Z)-toremifene (2) biological activi-
ties, and the development of resistance to treatment.
4
-hydroxytoremifene (4).
The first attempt for the synthesis of (Z)-4-hydroxyta-
moxifen (3) and (Z)-4-hydroxytoremifene (4) is outlined
in Scheme 1. This strategy consists of a McMurry
reaction between benzophenone derivative 8 containing
a 2-(dimethylamino)ethoxy chain and propiophenone
derivatives 9 or 10. 4,4′-Dihydroxybenzophenone (7) was
monoalkylated with 2-(dimethylamino)ethyl chloride hy-
drochloride in the presence of cesium carbonate in DMF
1
3a
at 80 °C to yield benzophenone 8 in 40%.
Then, several
McMurry conditions12 between equimolar quantities of
benzophenone 8 and propiophenone (9) were tried in
The known routes of synthesis of (Z)-4-hydroxytamox-
ifen (3) are long and involve the separation of E and Z
isomers7 except the last reported synthesis, which is
stereoselective and uses carbometalation of alkynylsi-
order to reach the best stereoselectivity (TiCl
Li (14 equiv)/DME, 13% yield, 1:3 3:5 ratio; TiCl
equiv)-Zn (6 equiv)/DME, 33% yield, 1:1.7 3:5 ratio; TiCl
3
(4 equiv)-
(3
8
4
4
(
3 equiv)-Zn (6 equiv)/THF, 41% yield, 1:2.3 3:5 ratio;
14
yield and ratio were obtained from crude material). The
(
1) J ordan, V. C. Breast Cancer Res. Treat. 1994, 31, 41.
(2) Valavaara, R.; Pyrrhonen, S.; Heikkinen, M.; Rissanen, P.;
cross-coupling products 3 and 5 were favored, and the
Blanco, G.; Tholix, E.; Nordman, E.; Taskinen, P.; Holsti, L.; Hajba,
A. Eur. J . Cancer Clin. Oncol. 1988, 24, 785.
TiCl (4 equiv)-Zn (8 equiv)-propiophenone (9) (3 equiv)/
4
THF system under darkness conditions gave the best
result (87% yield, 1:5.7 3:5 ratio after chromatography
with 19:1 dichloromethane-methanol). Unfortunately,
the McMurry reaction gave the expected (Z)-4-hydrox-
(
3) (a) J ordan, V. C. Breast Cancer Res. Treat. 1982, 2, 123. (b)
Daniel, C. P.; Gaskell, S. J .; Bishop, H.; Nicholson, R. I. J . Endocrinol.
979, 83, 401.
4) (a) J ordan, V. C.; Collins, M. M.; Rowsby, L.; Prestwich, G. J .
1
(
Endocrinol. 1977, 75, 305. (b) Binart, N.; Catelli, M. G.; Geynet, C.;
Puri, V.; Hahnel, R.; Mester, J .; Baulieu, E. E. Biochem. Biophys. Res.
Commun. 1979, 91, 812.
ytamoxifen (3) as the minor product. The isomeric
10a
mixture was separated by preparative TLC.
However,
(5) Sipil a¨ , H.; Kangas, L.; Vuorilehto, L.; Kalapudas, A.; Eloranta,
M.; S o¨ derwall, M.; Toivala, R.; Anttila, M. J . Steroid Biochem. 1990,
3
6, 211.
(9) Miller, R. B.; Al-Hassan, M. I. J . Org. Chem. 1985, 50, 2121.
(10) (a) Robertson, D. W.; Katzenellenbogen, J . A. J . Org. Chem.
1982, 47, 2387. (b) Katzenellenbogen, B. S.; Norman, M. J .; Eckert, R.
L.; Peltz, S. W.; Mangel, W. F. Cancer Res. 1984, 44, 112. (c)
Katzenellenbogen, J . A.; Carlson, K. E.; Katzenellenbogen, B. S. J .
Steroid Biochem. 1985, 22, 589.
(11) We believe that carbometalation of alkynylsilanes cannot be a
successful method for the preparation of compound 4.
(12) Coe, P. L.; Scriven, C. E. J . Chem. Soc., Perkin Trans. 1 1986,
475.
(6) Simberg, N. H.; Murai, J . T.; Siiteri, P. K. J . Steroid Biochem.
1
990, 36, 197.
(7) (a) Grafe, I.; Schickaneder, H.; J ungblut, P. W.; Ahrens, K. H.
EP 287690 A1 881026, Heumann Pharma G.m.b.H. und Co. (b)
McCague, R. J . Chem. Res., Synop. 1986, 2, 58. (c) McCague, R. J .
Chem. Res., Miniprint 1986, 771. (d) Forster, A. B.; J arman, M.; Leung,
O. T.; McCague, R.; Leclercq, G.; Devleeschouwer, N. J . Med. Chem.
1
985, 28, 1491. (e) Toivola, R. J .; Karjalainen, A. J .; Kurbela, K. O.
A.; Soderwall, M. L.; Kangas, L. V. M.; Blanco, G. L.; Sundquist, H. K.
EP 95875 A2 831207, Farmos Group Ltd. (f) Richardson, D. N. DE
(13) (a) We recovered 45% of starting material and 8% of corre-
sponding dialkylated compound 16. (b) We recovered 30% of starting
material and 25% of corresponding dipivaloate compound 17.
2
807599 780831, Imperial Chemical Industries Ltd.
8) Al-Hassan, M. I. Synth. Commun. 1989, 19, 1619.
(
S0022-3263(95)02279-1 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 11, 1996 3891
Sch em e 2a
has a very encouraging 14:1 E/Z ratio14 and was purified
by trituration from methanol to give a >100:1 E/Z ratio
in 82% yield. An improved E stereoselectivity of com-
pound 12 over compound 5 (14:1 vs 5.7:1 E/Z ratio) was
1
2
obtained. According to the present and previous work,
the phenol functionality is always on the opposite side
of the ethyl chain in the McMurry product, thus providing
an important element of the involved mechanism. Varia-
tion in the stereoselectivity depends upon the nature of
substituents on benzophenone. Thus, phenol derivative
1
2 was alkylated with 2-(dimethylamino)ethyl chloride
(2.0 equiv) in the presence of potassium carbonate (1.27
equiv) in acetone-water to give the amine 14 in 46%
yield with a 99:1 E/Z ratio. The small decrease in the
crude E/Z ratio (32:1) could be explained by transesteri-
fication.16 Finally, the amine 14 was deprotected with
methyllithium at -78 °C in THF to yield the desired (Z)-
4
-hydroxytamoxifen (3) with a crude 99:1 Z/E ratio, which
was then triturated from ethanol to a >100:1 Z/E ratio
in 66% yield. The present synthesis was expanded with
success in an analogous manner to obtain the first
described synthesis of (Z)-4-hydroxytoremifene (4) using
3
-chloropropiophenone (10) (crude compound 13, 22:1 E/Z
ratio; purified compound 4, >100:1 Z/E ratio, four steps,
1
0% overall yield).
when separation was performed by column chromatog-
raphy, (Z)-4-hydroxytamoxifen (3) could not be obtained
as a pure isomeric material (3:1 3:5 ratio after three
chromatography with 99:1 benzene-piperidine) but chro-
matographed (E)-4-hydroxytamoxifen (5) became pure
after recrystallization. We finally found that (E)-4-
hydroxytamoxifen (5) could be directly purified by tritu-
ration and recrystallization from ethanol to achieve a 66:1
The present study demonstrates the high efficiency of
the McMurry strategy for the synthesis of the Z and E
isomers of both 4-hydroxytamoxifen and 4-hydroxy-
toremifene. Investigation of mechanisms responsible for
this observed stereoselectivity could lead to an expansion
of this class of compounds.
Exp er im en ta l Section
5
:3 ratio in 26% yield.
Gen er a l P r oced u r es. All reagents were purchased from
Aldrich Chemical Co. All reactions were carried out in flame-
dried glassware under a positive atmosphere of dry Ar. THF
was freshly distilled from sodium/benzophenone prior to use. All
The above-described reaction was expanded to the first
synthesis of (E)-4-hydroxytoremifene (6) (20% yield for
the last step) with the same E:Z ratio of the crude and
purified product as observed for compound 5, using
extracts were dried over MgSO , and solvents were removed by
4
3
-chloropropiophenone (10). Thus, the McMurry reaction
rotary evaporation under reduced pressure. Column chroma-
tography was carried out using silica gel (230-400 mesh) (EM
Science). Compounds 3-6 were synthetized under reduced light
and kept in the dark at -20 °C. Melting points are uncorrected.
between monoalkylated benzophenone 8 and propiophe-
nones 9 or 10 gave E isomer as the major product. This
observation is contrary to the reported synthesis of (Z)-
tamoxifen (1) where the Z isomer is the major product.12
Current knowledge of the mechanisms of the mixed
1
13
H NMR spectra were recorded at 300 MHz and C NMR
spectra were recorded at 75 MHz. Mass spectra were provided
by Le Centre R e´ gional de Spectrom e´ trie de Masse, Universit e´
de Montr e´ al, Montr e´ al, Canada. Elemental analyses and Karl
Fisher (KF) were performed by Robertson Microlit Laboratories,
Inc., Madison, NJ .
carbonyl-coupling reaction does not provide an explana-
tion for the observed stereoselectivity.15
The second attempt for the synthesis of compounds 3
and 4 utilized monoprotected 4,4′-dihydroxybenzophe-
none in the McMurry reaction in order to reverse the
olefin stereochemistry (Scheme 2). Thus, 4,4′-dihydroxy-
4
-[2-(N,N-Dim eth yla m in o)eth oxy]-4′-h yd r oxyben zop h e-
n on e (8) a n d 4,4′-Bis[2-(N,N-d im et h yla m in o)et h oxy]-
ben zop h en on e (16). A solution of 4,4′-dihydroxybenzophenone
(7) (10 g, 47 mmol) in DMF (100 mL) was treated with Cs CO
2
3
benzophenone (7) was monoprotected to give the monopiv-
which was treated under the McMurry
reaction conditions described above. Crude compound 12
(46 g, 141 mmol) and heated in an oil bath at 80 °C. The
resulting suspension was treated with 2-(dimethylamino)ethyl
chloride hydrochloride (7.5 g, 51 mmol) in three portions over a
aloate 111
3b
2
h period and stirred for 16 h. The reaction mixture was cooled
to rt, quenched with saturated ammonium chloride (300 mL),
and extracted with ethyl acetate (4 × 150 mL). The combined
organic phase was washed with brine (4 × 150 mL), dried, and
concentrated. Flash chromatography (methanol-ethyl acetate
(
14) The stereochemistry of the olefin 18 (compounds 3, 4, 5, 6, 12,
and 13) was determined using NOE NMR experiments. The irradiation
of allylic methylene protons (H ) of these compounds showed a NOE
with aryl protons (H ). Moreover, Z isomers 3 and 4 have upfield NMR
a
b
1
2 2
:9) and trituration (hexanes-CH Cl 9:1) afforded compound
signals of the 2-dimethylaminoethoxy chain protons compared to the
corresponding E isomers 5 and 6 (see ref. 7c, 7d and 10a).
(
16) When the benzoate as a protecting group was used in the
synthesis, we obtained low yield (20-30%) and decreased E/Z ratio
19:1 in the best cases) of desired amine. This phenomena could be
(
explained via the transesterification. In order to decrease the amount
of diester olefin and other byproducts, the less reactive pivaloate as a
protecting group was used.
(
17) 2-(Dimethylamino)ethyl chloride was obtained by treating
2
-(dimethylamino)ethyl chloride hydrochloride with saturated sodium
carbonate for 30 min. Then, the amine was extracted with ether, and
the solution was dried and distilled under atmospheric pressure (bp
95-100 °C, 80% yield).
(15) McMurry, J . E. Chem. Rev. 1989, 89, 1513.

3
892 J . Org. Chem., Vol. 61, No. 11, 1996
Notes
: C,
8
2
5
7
8
1
(5.35 g, 40%) as a white solid: mp 150-153 °C; IR (KBr) 3200-
134.82, 154.47, 176.58, 194.40. Anal. Calcd for C23
72.23; H, 6.85. Found: C, 72.22; H, 6.74.
H
26
O
5
-
1 1
200, 1642 cm ; H NMR (CD OD) δ 2.36 (s, 6H), 2.81 (t, J )
3
.5 Hz, 2H), 4.18 (t, J ) 5.5 Hz, 2H), 6.85 (d, J ) 8.7 Hz, 2H),
.00 (d, J ) 8.7 Hz, 2H), 7.65 (d, J ) 8.7 Hz, 2H), 7.72 (d, J )
(E)-1-(4-Hydr oxyph en yl)-1-[4-(tr im eth ylacetoxy)ph en yl]-
2-p h en ylbu t-1-en e (12). The same procedure for compound 5
was used, starting from benzophenone 11 (2.0 g, 7.0 mmol) and
propiophenone (9). Trituration of the crude solid from methanol
(13 mL) gave compound 12 (2.29 g, 82%) with a >100:1 E/Z ratio
as a white solid: mp 165-167 °C; IR (KBr) 3600-3100, 1754
1
3
.7 Hz, 2H); C NMR δ 45.82, 58.95, 66.89, 115.21, 116.20,
30.30, 132.17, 133.25, 133.70, 163.59, 196.80. Anal. Calcd for
C
17
H
19NO
3
: C, 71.56; H, 6.71; N, 4.91. Found: C, 71.28; H, 6.70;
N, 4.76. Compound 16 was isolated by flash chromatography
methanol-ethyl acetate 2:3) to give 1.31 g (8%) of a white solid.
A sample was recrystallized from methanol: mp 89-91 °C; IR
-
1 1
(
3
cm ; H NMR (CD OD) δ 0.91 (t, J ) 7.4 Hz, 3H), 1.36 (s, 9H),
2.46 (q, J ) 7.4 Hz, 2H), 6.40 (d, J ) 8.7 Hz, 2H), 6.66 (d, J )
-
1
1
13
(
(
(
KBr) 3100-2300, 1639, 1602 cm ; H NMR (CD
3
OD) δ 2.36
8.7 Hz, 2H), 7.02-7.25 (m, 9H); C NMR δ 13.85, 27.49, 29.82,
s, 12H), 2.81 (t, J ) 5.4 Hz, 4H), 4.21 (t, J ) 5.4 Hz, 4H), 7.07
40.12, 115.24, 122.21, 127.13, 128.90, 130.85, 131.50, 133.00,
135.49, 142.68, 142.85, 143.79, 151.20, 156.58, 178.80. Anal.
1
3
d, J ) 8.8 Hz, 4H), 7.76 (d, J ) 8.8 Hz, 4H); C NMR δ 45.86,
8.96, 66.98, 115.26, 131.87, 133.36, 163.80, 196.60. Anal. Calcd
for C21 ‚0.05H O: C, 70.58; H, 7.93; N, 7.84. Found: C,
0.62; H, 7.89; N, 7.79 (KF ) 0.25%).
E)-4-Hyd r oxyta m oxifen (5). To a suspension of zinc (1.8
g, 28 mmol) in 30 mL of dry THF, under Ar, was added dropwise
TiCl (1.6 mL, 14 mmol). The mixture was refluxed for 2 h. A
solution of ketone 8 (1.0 g, 3.5 mmol) and propriophenone (9)
1.4 mL, 10.5 mmol) in 50 mL of dry THF was added at once,
and the reflux was continued for 5 h. The reaction mixture was
cooled to rt, quenched with 10% K CO (100 mL), and extracted
with ethyl acetate (3 × 100 mL). The combined organic phase
was washed with 10% K CO
5
28 3
Calcd for C26H O : C, 80.38; H, 7.26. Found: C, 80.35; H, 7.15.
H
28
N
2
O
3
2
(E)-1-[4-[2-(N,N-Dim eth ylam in o)eth oxy]ph en yl]-1-[4-(tr i-
m eth yla cetoxy)p h en yl]-2-p h en ylbu t-1-en e (14). A solution
of phenol 12 (0.60g, 1.5 mmol), freshly distilled 2-(dimethylami-
7
(
no)ethyl chloride17 (0.32 g, 3.0 mmol) and K
CO (0.27g, 1.9
2 3
4
mmol) in 19:1 acetone-water (20 mL) was refluxed for 5 h in
the dark. The reaction mixture was cooled to rt, dried, and
(
2 2
evaporated. Flash chromatography (CH Cl -methanol 19:1)
and recrystallization from isopropyl alcohol gave compound 14
(0.32 g, 46%) with a 99:1 E/Z ratio as a white solid: mp 114-
2
3
-
1 1
3 3
116 °C; IR (CHCl ) 1744, 1606 cm ; H NMR (CDCl ) δ 0.92 (t,
2
3
(2 × 50 mL) and brine (50 mL),
J ) 7.4 Hz, 3H), 1.37 (s, 9H), 2.29 (s, 6H), 2.46 (q, J ) 7.4 Hz,
2H), 2.64 (t, J ) 5.8 Hz, 2H), 3.93 (t, J ) 5.8 Hz, 2H), 6.56 (d, J
dried, and concentrated. Trituration of the crude solid from
ethanol (20 mL) yielded 0.78 g (57%) of 1:32 3/5 isomeric mixture
ratio. Recrystallization of the mixture from ethanol decreased
to 1.5% the Z isomer 3 and gave compound 5 (0.35 g, 26%): mp
1
OD) δ 0.90 (t, J ) 7.5 Hz, 3H), 2.26 (s, 6H), 2.45 (q, J ) 7.5 Hz,
2
)
1
3
) 8.7 Hz, 2H), 6.77 (d, J ) 8.7 Hz, 2H), 7.04-7.26 (m, 9H);
C
NMR δ 13.54, 27.16, 29.00, 39.09, 45.92, 58.32, 65.77, 113.43,
121.07, 126.05, 127.87, 129.66, 130.41, 131.88, 135.31, 137.43,
141.17, 141.68, 142.32, 149.71, 156.87, 177.08. Anal. Calcd for
55-157 °C; IR (KBr) 3500-2200, 1606 cm-1; H NMR (CD
1
-
3
C
31
H
37NO
3
2
‚0.06H O: C, 78.76; H, 7.91; N, 2.96. Found: C,
H), 2.79 (t, J ) 5.4 Hz, 2H), 4.12 (t, J ) 5.4 Hz, 2H), 6.39 (d, J
78.76; H, 8.14; N, 2.89 (KF ) 0.24%).
8.4 Hz, 2H), 6.63 (d, J ) 8.4 Hz, 2H), 6.92 (d, J ) 8.7 Hz, 2H),
(Z)-4-Hyd r oxyta m oxifen (3). MeLi (4.2 mL of a solution
1.4 M in ether, 5.8 mmol) was added to a solution of amine 14
(0.92g, 1.9 mmol) in dry THF (40 mL) at -78 °C. The reaction
mixture was stirred for 2 h, quenched with saturated ammonium
chloride (2 mL), allowed to warm to rt, and extracted with ethyl
acetate (4 × 50 mL). The combined organic phase was dried
and concentrated. Trituration from ethanol (25 mL) gave
compound 3 (0.49 g, 66%) with a >100:1 Z/E ratio as a white
solid: mp 140-143 °C; IR (KBr) 3602, 3491, 3250-2100, 1606
1
3
7
1
1
.08-7.15 (m, 7H); C NMR δ 13.91, 29.85, 45.84, 59.18, 66.64,
15.14, 126.95, 128.85, 130.90, 131.62, 133.03, 136.00, 137.95,
39.74, 141.86, 144.12, 156.40, 158.94; FAB-MS (thio), m/e 388
+
(100, [M + H] ), 217 (17). Anal. Calcd for C26
H
29NO
2
: C, 80.59;
H, 7.54; N, 3.61. Found: C, 80.40; H, 7.40; N, 3.62.
E)-4-Hyd r oxytor em ifen e (6). The same procedure for
compound 5 was used, starting from benzophenone 8 (1.16 g,
.1 mmol) and 3-chloropropiophenone (10). Trituration of the
crude solid (CCl
(
4
-
1 1
4
-ethanol 9:1) yielded 1.08 g (63%) of 1:16 4/6
3
cm ; H NMR (CD OD) δ 0.90 (t, J ) 7.4 Hz, 3H), 2.28 (s, 6H),
isomeric mixture ratio. Recrystallization of the mixture from
ethanol decreased to 1.5% the Z isomer 4 and gave compound 6
2.47 (q, J ) 7.4 Hz, 2H), 2.68 (t, J ) 5.5 Hz, 2H), 3.94 (t, J ) 5.5
Hz, 2H), 6.55 (d, J ) 8.7 Hz, 2H), 6.74 (d, J ) 8.7 Hz, 2H), 6.75
(d, J ) 8.6 Hz, 2H), 7.00-7.15 (m, 7H); 13C NMR δ 12.41, 28.40,
44.29, 57.60, 64.91, 112.87, 114.37, 125.46, 127.36, 129.41,
130.10, 131.54, 134.84, 136.09, 138.28, 140.56, 142.65, 155.80,
(
1
2
0.342 g, 20% yield): mp 167-169 °C; IR (CHCl
3
) 3500-2200,
OD) δ 2.37 (s, 6H), 2.81 (t, J ) 5.5 Hz,
H), 2.91 (t, J ) 7.6 Hz, 2H), 3.40 (t, J ) 7.6 Hz, 2H), 4.14 (t, J
5.5 Hz, 2H), 6.41 (d, J ) 8.7 Hz, 2H), 6.65 (d, J ) 8.6 Hz, 2H),
.96 (d, J ) 8.7 Hz, 2H), 7.00-7.21 (m, 7H); 13C NMR (DMSO-
-
1 1
608 cm ; H NMR (CD
3
+
)
156.60; FAB-MS (thio), m/e 388 (100, [M + H] ), 217 (28). Anal.
6
d
1
1
3
7
8
Calcd for C26
H
29NO
2
2
‚0.34H O: C, 79.33; H, 7.60; N, 3.56.
6
) δ 38.01, 42.95, 45.53, 57.74, 65.72, 114.13, 114.33, 126.31,
Found: C, 79.73; H, 7.60; N, 3.44 (KF ) 0.69%).
28.00, 129.30, 130.21, 131.18, 133.13, 134.08, 134.93, 140.94,
(E)-1-(4-Hydr oxyph en yl)-1-[4-(tr im eth ylacetoxy)ph en yl]-
2-p h en yl-4-ch lor obu t-1-en e (13). The same procedure for
compound 12 was used, starting from benzophenone 11 (2.5 g,
8.3 mmol) and 3-chloropropiophenone (10) to afford compound
13 (1.7 g, 47%). Flash chromatography (hexanes-ethyl acetate
9:1) on the mother liquors gave 1.1 g of supplementary material
for an overall yield of 77% with a >100:1 Z/E ratio: mp 161-
+
41.06, 155.45, 157.34; FAB-MS (thio), m/e 422 (100, [M + H] ),
+
88 (26, [M + 2H - Cl] ). Anal. Calcd for C26
H
28ClNO
2
: C,
4.01; H, 6.69; Cl, 8.40, N, 3.32. Found: C, 73.80; H, 6.70; Cl,
.54; N, 3.29.
4
-Hyd r oxy-4′-(tr im eth yla cetoxy)ben zop h en on e (11) a n d
4
,4′-Bis(tr im eth yla cetoxy)ben zop h en on e (17). Sodium hy-
-
1 1
dride in 60% dispersion in mineral oil (5.1 g, 77 mmol) was added
to a solution of 4,4′-dihydroxybenzophenone (7) (15.0 g, 70 mmol)
in dry THF (160 mL). The solution was strirred at rt for 30
min, cooled to 0 °C, treated with trimethylacetyl chloride (9.5
mL, 77 mmol) and stirred for 2 h after removing the ice-water
bath. The reaction mixture was quenched with distilled water
3 3
163 °C; IR (CHCl ) 2977, 1743, 1605 cm ; H NMR (CDCl ) δ
1.37 (s, 9H), 2.93 (t, J ) 7.2 Hz, 2H), 3.40 (t, J ) 7.2 Hz, 2H),
5.19 (s, 1H), 6.45 (d, J ) 8.4 Hz, 2H), 6.71 (d, J ) 8.4 Hz, 2H),
7.05-7.31 (m, 9H); 13C NMR δ 27.14, 38.36, 39.12, 42.75, 114.43,
121.32, 126.64, 128.22, 129.52, 130.48, 131.91, 134.73, 135.62,
140.18, 140.84, 150.00, 153.93, 177.20. Anal. Calcd for
(
100 mL) and extracted with ethyl acetate (4 × 200 mL). The
combined organic phase was dried and concentrated. Flash
chromatography (CH Cl -ethyl acetate 19:1) and trituration
hexanes-CH Cl 9:1) afforded compound 11 (8.7 g, 42%) as a
white solid: mp 171-173 °C; IR (CHCl ;
26 3
C H27ClO : C, 73.84; H, 6.43; Cl, 8.38. Found: C, 73.98; H,
6.27; Cl, 8.09.
2
2
(E)-1-[4-[2-(N,N-Dim eth ylam in o)eth oxy]ph en yl]-1-[4-(tr i-
m eth yla cetoxy)p h en yl]-2-p h en yl-4-ch lor obu t-1-en e (15).
The same procedure for compound 14 was used, starting from
phenol 13 (1.5 g, 3.7 mmol). Flash chromatography (ethyl
acetate-methanol 19:1) and recrystallization from ethanol gave
compound 15 (0.81 g, 43%) with a 99:1 E/Z ratio as a white
(
2
2
-1
3
) 3585, 3360, 1748 cm
) δ 1.38 (s, 9H), 6.90 (d, J ) 8.7 Hz, 2H), 7.17
1
H NMR (CDCl
3
(
7
1
d, J ) 8.7 Hz, 2H), 7.52 (br s, 1H), 7.72 (d, J ) 8.7 Hz, 2H),
.79 (d, J ) 8.7 Hz, 2H); 13C NMR δ 27.08, 39.23, 115.38, 121.45,
29.45, 131.44, 132.98, 135.51, 154.11, 160.86, 177.21, 195.46.
-
1
solid: mp 125-127 °C; IR (CHCl
3
) 3690, 3597, 1743, 1607 cm
;
1
Anal. Calcd for C18
H, 6.24. Compound 17 was isolated by flash chromatography
H
18
O
4
: C, 72.46; H, 6.08. Found: C, 72.44;
H NMR (CDCl ) δ 1.37 (s, 9H), 2.28 (s, 6H), 2.64 (t, J ) 5.8 Hz,
3
2H), 2.94 (t, J ) 7.3 Hz, 2H), 3.41 (t, J ) 7.3 Hz, 2H), 3.92 (t, J
) 5.8 Hz, 2H), 6.56 (d, J ) 8.6 Hz, 2H), 6.76 (d, J ) 8.6 Hz, 2H),
7.06-7.32 (m, 9H); 13C NMR δ 27.14, 38.40, 39.12, 42.76, 45.92,
58.29, 65.81, 113.54, 121.31, 126.61, 128.21, 129.52, 130.47,
131.70, 134.67, 135.52, 140.21, 140.84, 140.95, 150.01, 157.16,
(CH
2
Cl
2
) and trituration (hexanes-CH
2
Cl
2
9:1) to give 6.7 g
) 1749, 1203
) δ 1.20 (s, 18H), 7.18 (d, J ) 8.7 Hz, 4H),
.84 (d, J ) 8.7 Hz, 4H); 13C NMR δ 27.08, 39.23, 121.52, 131.52,
(
25%) of a white solid: mp 163-164 °C; IR (CHCl
3
-
1 1
cm ; H NMR (CDCl
3
7

Notes
J . Org. Chem., Vol. 61, No. 11, 1996 3893
1
7
77.01. Anal. Calcd for C31
.01; N, 2.77. Found: C, 73.29; H, 7.24; Cl, 6.72; N, 2.52.
Z)-4-Hyd r oxytor em ifen e (4). The same procedure for
H
36ClNO
3
: C, 73.57; H, 7.17; Cl,
66.42, 114.46, 116.05, 127.46, 129.14, 130.81, 131.66, 132.86,
135.50, 136.28, 137.05, 142.90, 143.14, 157.62, 158.36; FAB-MS
+
+
(
(thio), m/e 422 (100, [M + H] ), 388 (18, [M + 2H - Cl] ). Anal.
compound 3 was used, starting from amine 15 (0.20 g, 0.39
mmol). Trituration from isopropyl alcohol (5 mL) gave com-
pound 4 (0.13 g, 75%) with a >100:1 Z/E ratio as a white solid:
Calcd for C26 28ClNO : C, 74.01; H, 6.69; Cl, 8.40; N, 3.32.
H
2
Found: C, 73.99; H, 6.45; Cl, 8.37; N, 3.17.
-1 1
mp 160-164 °C; IR (KBr) 3630, 3200-2200, 1609 cm ; H NMR
CD OD) δ 2.30 (s, 6H), 2.70 (t, J ) 5.4 Hz, 2H), 2.94 (t, J ) 7.4
Hz, 2H), 3.40 (t, J ) 7.4 Hz, 2H), 3.96 (t, J ) 5.4 Hz, 2H), 6.58
d, J ) 8.7 Hz, 2H), 6.78 (d, J ) 8.7 Hz, 2H), 6.79 (d, J ) 8.7 Hz,
H), 7.10-7.19 (m, 7H); 13C NMR δ 39.76, 43.59, 45.78, 59.08,
Ack n ow led gm en t. This work was supported by
Endorecherche. We thank Dr. Patricia Dionne for the
NMR experiments (NOE).
(
3
(
2
J O952279L