Catalytic carbometalation/cross-coupling sequence across alkynyl(2-pyridyl)silanes leading to a diversity-oriented synthesis of tamoxifen-type tetrasubstituted olefins

Article abstract of DOI:10.1002/adsc.200404220

A general synthetic scheme for tamoxifen-type tetrasubstituted olefins based on the novel Cu-catalyzed carbomagnesation across alkynyl(2-pyridyl)silane has been developed. A wide array of electronically and structurally diverse tetrasubstituted olefins can be prepared in a regiocontrolled, stereo-controlled, and diversity-oriented manner. Noteworthy features are that (i) the three aryl groups, which are believed to be important (essential) for anti-estrogenic activity, can be varied at will because they all stem from readily available aryl iodides, and (ii) any stereo- and regioisomers can, in principle, be prepared by simply changing the order use of the aryl iodides in the sequence.

Full text of DOI:10.1002/adsc.200404220

FULL PAPERS
Catalytic Carbometalation/Cross-Coupling Sequence across
Alkynyl(2-pyridyl)silanes Leading to a Diversity-Oriented
Synthesis of Tamoxifen-Type Tetrasubstituted Olefins
Toshiyuki Kamei, Kenichiro Itami,* Jun-ichi Yoshida*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University,
Nishikyo-ku, Kyoto 615-8510, Japan
Fax: (þ81)-383-2727, e-mail: yoshida@sbchem.kyoto-u.ac.jp
Received: July 10, 2004; Accepted: October 15, 2004
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A general synthetic scheme for tamoxifen- genic activity, can be varied at will because they all
type tetrasubstituted olefins based on the novel Cu- stem from readily available aryl iodides, and (ii) any
catalyzed carbomagnesation across alkynyl(2-pyrid- stereo- and regioisomers can, in principle, be pre-
yl)silane has been developed. A wide array of elec- pared by simply changing the order use of the aryl io-
tronically and structurally diverse tetrasubstituted dides in the sequence.
olefins can be prepared in a regiocontrolled, stereo-
controlled, and diversity-oriented manner. Notewor- Keywords: carbomagnesation; cross-coupling; direct-
thy features are that (i) the three aryl groups, which ing effect; diversity-oriented synthesis; synthesis de-
are believed to be important (essential) for anti-estro- sign; tamoxifen
Introduction
The regio- and stereoselective synthesis of multisubsti-
tuted olefins is one of themost challenging subjects in or-
ganic synthesis.[1] Since multisubstituted olefins are
widespread found in pharmacologically important mol-
ecules, a general and diversity-oriented approach[2] to-
ward such class of compounds is highly called for.[1f]
Among such multisubstituted olefins, we have been par-
Figure 1. Structure of tamoxifen.
ticularly interested in tamoxifen (Figure 1) and its deriv-
atives.[3] Tamoxifen is the most important anti-breast
cancer drug in clinical use and has the potential to be stereoselective synthesis of tamoxifen (9 steps) using al-
used as a chemopreventive breast cancer agent. It is a se- kyne carbometalation as a key step.[7] Knochel has de-
lective estrogen receptor modulator (SERM) with anti- veloped a similar carbometalation-based synthesis.[8]
estrogenic properties in the breast and estrogenic effects Armstrong has developed an alkyne diboration/cross-
in tissues such as bone and the cardiovascular system. Its coupling sequence for the synthesis of tamoxifen deriv-
SERM profile makes it a valuable alternative to hor- atives.[9] However, new synthetic schemes that allow
mone replacement therapy, especially for women at more flexible structural modifications of the aryl groups,
high risk of endometrial cancer.
which are believed to be important (essential) for anti-
Although these aspects of tamoxifen have stimulated estrogenic activity, are still in high demand.
research for a superior and ideal SERM, rapid and sys-
tematic screenings have been hampered by the lack of
a general and diversity-oriented synthetic scheme for ta- Background: Pyridylsilyl-Directed Organometallic
moxifen-type tetrasubstituted olefins. In addition, insuf- Reactions
ficient stereoselectivity, which is often encountered with
the widely used dehydration reaction[4] and McMurry During the last few years, we have been particularly in-
coupling,[5] has been a bottleneck for rapid evaluation.[6] terested in the utilization of the dimethyl(2-pyridyl)silyl
Alternative to these procedures, Miller has developed a group (2-PyMe2Si group) as a “removable directing
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Catalytic Carbometalation/Cross-Coupling across Alkynyl(2-pyridyl)silanes
FULL PAPERS
Scheme 2. Our synthetic strategy for tamoxifen-type tetra-
substituted olefins using a directed carbometalation across
alkynyl(2-pyridyl)silanes as a key step.
Directed Carbometalation Across Alkynyl(2-
pyridyl)silanes: A Key Step Toward a Diversity-
Oriented Synthesis of Tamoxifen-type Tetrasubstituted
Olefins
Scheme 1. Directed carbomagnesation and carbopalladation
across alkenyl(2-pyridyl)silanes.
As an extension of carbometalation across alkenyl(2-
group” in metal-catalyzed[10] and -mediated[11] processes pyridyl)silanes and as a key step toward the develop-
for enhancing the total efficiency of chemical reac- ment of a diversity-oriented synthesis of tamoxifen-
tions.[12,13] In such a strategy, a range of reactions can type tetrasubstituted olefins, we envisaged that the addi-
1
À
be directed through the agency of the complex-induced tion of arylmetal compounds (Ar M) across alkynyl(2-
proximity effect (CIPE),[14] yet the initial product can pyridyl)silanes would afford alkenylmetal compounds
still be transformed into a variety of products with the suitable for further transformations. We expected this
removal of the directing group. In particular, our find- addition to be regio- and stereoselective as in the cases
ings that a number of previously difficult carbometala- using alkenyl(2-pyridyl)silanes through the agency of
tion reactions could be achieved by utilizing alkenyl(2- the complex-induced proximity effect of the pyridyl
À
pyridyl)silanes are of great interest (Scheme 1). For ex- group on silicon. The sequential arylations at the C M
ample, the addition of Grignard reagents (carbomagne- and C Si bonds of the resultant pyridylsilyl-substituted
À
sation) was found to proceed at room temperature.[11c] alkenylmetal compound utilizing Pd-catalyzed cross-
The facile addition of primary alkyl Grignard reagents coupling reactions with aryl halides (Ar X and
to alkenylsilanes was realized for the first time. We Ar X) would afford the targeted tamoxifen-type tetra-
2
À
3
À
also found that the Mizoroki–Heck reaction, which in- substituted olefins. Since three aryl groups (Ar1, Ar2,
cludes carbopalladation as a key elemental step, of alke- and Ar3), which are believed to be important (essential)
nylsilanes is also facilitated by the pyridyl group on sili- for anti-estrogenic activity,[3] stem from readily available
con.[10a] A “hard-to-achieve” double Mizoroki–Heck re- aryl halides, the synthesis would be sufficiently diversi-
action was also realized by using vinyl(2-pyridyl)sil- ty-oriented. Moreover, any stereo- and regioisomers
ane.[1f] A number of control experiments and X-ray crys- can, in principle, be prepared by simply changing the or-
tal structure analysis supported our supposition that ex- der of application of the aryl halides in the sequence.[17]
tremely facile and regioselective carbometalations are
due to the strong complex-induced proximity effect of
the pyridyl group on silicon, together with the inherent Results and Discussion
silicon a effect. In addition to its utility as a removable
directing group, 2-PyMe2Si group can also be used as a
Aryl Groups Installed into Tamoxifen-Type
“phase tag”[15] and a “removable hydrophilic group”[16]
Tetrasubstituted Olefin Structure in this Study
enabling easy purification (acid/base extraction) and
aqueous reaction, respectively.
By following the synthetic sequence described in
Scheme 2, we succeeded in installing a number of aryl
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Figure 2. Aryl and heteroaryl groups used in this study.
and heteroaryl groups in the targeted tamoxifen-type
tetrasubstituted olefin structure. The following 21
groups were successfully installed in this study (Fig-
ure 2). For simplicity, we assigned them alphabetically
as follows and used them in compound assignment.
Copper-Catalyzed Carbomagnesation across
Alkynyl(2-pyridyl)silanes
Scheme 3. Synthesis of (1-butynyl)dimethyl(2-pyridyl)silane
(1).
As an alkynylsilane platform for the tamoxifen-type tet-
rasubstituted olefin synthesis, we selected (1-butynyl)di-
methyl(2-pyridyl)silane (1) which can be prepared by
the consecutive treatment of 1-butynylmagnesium
chloride and 2-pyridylmagnesium chloride with dichloro- (30 mol %), the regio- and stereoselective addition of
dimethylsilane (Scheme 3). This method can be used for PhMgI (1.0 equiv.) to 1 (1.0 equiv.) took place at 08C
the synthesis of other alkynyl(2-pyridyl)silanes in the in Et2O to afford 2 in 90% yield after aqueous work-
synthesis of tamoxifen-type tetrasubstituted olefins up (Scheme 4). The use of PhMgBr, PhMgCl, or
bearing various alkyl side chains.
Ph2Mg in place of PhMgI resulted in a lower efficiency
With the requisite platform in hand, we examined the of the addition.[20] In addition, we found that the use of
addition of organometallic reagents (carbometalation) 3-pyridyl-, 4-pyridyl-, and phenyl(1-butynyl)silanes in-
to (1-butynyl)dimethyl(2-pyridyl)silane (1). To our sur- stead of 1 resulted in no addition. These results clearly
prise, however, representative organometallic reagents implicate the strong directing effect (complex-induced
including Grignard reagents and organozinc reagents proximity effect) of the 2-pyridyl group on silicon in
did not give the corresponding addition products.[18] the alkynylsilane structure to achieve this Cu-catalyzed
Therefore, we screened various organometallics and carbomagnesation reaction (Scheme 4).[21]
metal catalysts that accomplish a carbometalation
During these investigations, we found that the amount
across 1 and found that the use of PhMgI in combination of CuI employed has a substantial influence on the effi-
with CuI catalyst effects the desired transformation.[19] ciency of carbomagnesation. The results using varied
Thus, in the presence of a catalytic amount of CuI amounts of CuI (0ꢀ100 mol %) in the reaction of 1
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Scheme 4. Cu-catalyzed carbomagnesation across (1-buty-
nyl)dimethyl(2-pyridyl)silane (1).
Figure 3. The effect of catalyst loading of CuI.
(1.0 equiv.) and PhMgI (1.0 equiv.) are shown in Fig-
ure 3. The addition did not occur in the absence of CuI
as already mentioned. The yield of 2 increased with in- sume that the Z isomer of 3aa, which is formed as a mi-
creasing amount of CuI, reaching a maximum yield nor product, is derived from the isomerization of alke-
(90%) when employing 30 mol % based on 1 and nylmagnesium intermediate.[23] Interestingly, NiCl2
PhMgI. However, further increases of employed CuI re- (dppe) was found not to promote this cross-coupling
sulted in lower yields of 2. In particular, the reaction us- presumably reflecting the steric hindrance of the alke-
ing an equimolar amount of CuI resulted in no addition, nylmagnesium compound (run 2). Palladium catalysts
which suggests that the carbometalation does not pro- such as Pd(PPh3)4 and PdCl2(PPh3)2 also promoted the
ceed through organocopper species but rather through cross-coupling, but the yield and stereoselectivity were
organocuprate species. In line with this assumption, somewhat lower than those achieved with the nickel cat-
the adduct 2 was obtained in 83% yield even when using alyst (runs 3 and 4). After further investigation, it was
an equimolar amount of CuI when 2.0 equivs. of PhMgI found that Pd[P(t-Bu)3]2[24] was the most effective cata-
were employed.
lyst for this cross-coupling to afford 3aa in high yield
and stereoselectivity (80% yield, E/Z¼92/8) (run 5).
Although 3aa could be obtained with virtually complete
stereoselectivity (E/Z¼ >99/1) when the cross-cou-
pling step was performed at room temperature with
this catalyst, the low chemical yield (52%) became prob-
Pd-Catalyzed Cross-Coupling Reaction of
Carbomagnesation Products withAryl Halides
With the feasibility of an initial carbometalation proc- lematic (run 6). Thus, we set the conditions described in
ess, we next examined the one-pot diarylation of 1 run 5 as the standard conditions for the catalytic one-pot
through the catalytic carbomagnesation/cross-coupling diarylation of 1.
[22]
À
sequence. Thus, the Tamao–Kumada Corriu-type
The beneficial effect of P(t-Bu)3 ligand may be worthy
cross-coupling reaction of an alkenylmagnesium com- of note. Recently, there have been numerous reports
pound (carbomagnesation product derived from 1 and that the use of the P(t-Bu)3 ligand gives rise to beneficial
PhMgI) with iodobenzene was first examined using var- effects in Pd-catalyzed cross-coupling reactions, in
ious Ni and Pd complexes (Table 1). All reactions were which the electron-richness and steric-bulkiness of P(t-
performed by adding a THF solution of catalyst Bu)3 are believed to accelerate the oxidative addition
(5 mol %) and iodobenzene (1.5 equivs.) to a solution step and the reductive elimination step, respective-
of the alkenylmagnesium compound obtained by the ly.[24,25] However, we assume that the beneficial effect
CuI-catalyzed reaction of 1 and PhMgI, and the resul- of the P(t-Bu)3 ligand observed here is somewhat differ-
tant mixture was stirred at 408C for 16 h unless other- ent from those mentioned above. We suppose that the
wise stated. The use of NiCl2(PPh3)2 resulted in the pro- steric-bulkiness of P(t-Bu)3 ligand should render its dis-
À
À
duction of the diphenylated compound 3aa in good yield sociation from palladium in the Ph Pd I intermediate
(76%), but the stereoselectivity (E/Z¼81/19) was some- so as to make a coordination site required for the subse-
what disappointing (run 1). The two phenyl groups are quent transmetalation (with sterically congested alke-
introduced in a cis fashion, which is in accordance with nylmagnesium compound) more easily. In this context,
syn carbometalation and retention of stereochemistry the use of bulky heterocyclic carbene ligands should
during the subsequent cross-coupling. Currently, we as- shed some light because they are also known as elec-
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À
Table 1. The effect of catalyst in Tamao–Kumada Corriu-
type cross-coupling of an alkenylmagnesium compound
with iodobenzene.
tron-rich and bulky ligands but are known not to disso-
ciate from the metal easily.[26] We found that the use of
the bulky carbene ligand IMes resulted in a substantial
decrease in the coupling efficiency (run 7), which is in
line with our assumption that the ligand dissociation is
a key factor in this cross-coupling. The detrimental ef-
fect of a bidentate ligand (DPPE) also supports this no-
tion.
Catalytic One-Pot Diarylation of 1 with
Arylmagnesium Iodides and Aryl Halides
With efficient catalysts for both carbomagnesation and
cross-coupling in hand, we subsequently examined the
synthesis of 1,2-diaryl-1-butenyl(2-pyridyl)silanes 3
through one-pot diarylation of 1 (Table 2). Thus, by sim-
ply varying Ar MgI and Ar I, we could obtain various
structurally and electronically diverse alkenylsilanes 3.
In all cases examined, the stereoselectivities were high
[a]
The reaction was performed at room temperature.
[b]
IMes·HCl¼N,N’-bis(2,4,6-trimethylphenyl)imidazoyl
chloride.
1
2
À
À
Table 2. Synthesis of 3 by one-pot carbomagnesation/cross-coupling reaction of 1..
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of this mixture with pinacol and triethylamine (one-pot)
afforded alkenylboronate esters 4 in good yield with re-
tention of stereochemistry (Table 3). For compounds
bearing the tamoxifen basic side chain (Me2NCH2CH2
O-) such as 3ab and 3ib, it was necessary to add 3.3
equivs. of BCl3 for borodesilylation and to treat the re-
sultant mixture (after quenching with pinacol) with a
base such as Cs2CO3 to remove a boron residue coordi-
nated to the nitrogen (runs 2 and 6). Interestingly it was
found that the isomeric purities of 4 were greater than
those of the starting alkenylsilanes in all cases examined
except the reaction of 3au(96/4!95/5). This may be due
to the reactivity differences of isomeric alkenylsilanes in
borodesilylation.
Scheme 5. The attempted installation of the third aryl group
via Hiyama-type cross-coupling reaction of 3aa with aryl hal-
ide.
(E/Z¼88/12ꢀ96/4). The cross-coupling occurred effi-
2
À
ciently with Ar I having both electron-donating and
-withdrawing groups. The aryl group containing the ba- Synthesis of Tamoxifen-Type Tetrasubstituted Olefins
sic side chain found in tamoxifen can also be installed 5 by Suzuki–Miyaura Coupling of 4 and Aryl Halide
with ease (runs 3 and 9). Interestingly, the ester group
2
À
in Ar I also tolerated the conditions of this cross-cou- Finally, the Suzuki–Miyaura coupling of alkenylboro-
pling reaction (run 5). Unfortunately, heteroaromatic nate esters 4 with aryl halides was investigated for the
substrates, such as 3-iodopyridine and 3-iodothiophene, synthesis of targeted tamoxifen-type tetrasubstituted
were found to be poor substrates in this reaction (runs 7 olefin 5. At the outset, the examination of catalyst and
and 8).
additive was performed using 4aa and 4-iodotoluene
as model substrates (Table 4, runs 1–4). When these
substrates were subjected to Pd(PPh3)4 and K3PO4 in
THF at 608C, the tetrasubstituted olefin 5aah was ob-
tained in 66% yield together with the protodeboration
product 6 (32%) (run 1). After extensive screening of
Attempted Synthesis of Tetrasubstituted Olefins by
Hiyama-Type Cross-coupling Reactions
Having established the procedure of stereoselective Pd catalysts, the use of Pd[P(t-Bu)3]2, which was demon-
À
one-pot diarylation of 1, the C Si arylation of the resul- strated as a good catalyst for Suzuki–Miyaura coupling
tant 3 has remained as a final transformation toward ta- by Fu,[24a] in combination with K3PO4 or Cs2CO3 resulted
moxifen-type tetrasubstituted olefins. Because we have in efficient coupling to afford 5aah in 92% yield (runs 2
¼
already reported that the 2-pyridylsilyl group on C C and 3). However, the use ofKF, which was reported to be
can be transformed into aryl groups by Hiyama-type sil- an efficient additive in combination with Pd[P-
icon-based cross-coupling reactions[1f,10b,27] with aryl hal- (t-Bu)3]2,[24a] did not give the desired coupling product
ides in the presence of a palladium catalyst and tetrabu- (run 4). Because it was found that the Pd[P(t-Bu)3]2/
tylammonium fluoride, 3aa and 4-iodobenzoic acid eth- Cs2CO3 system gave tamoxifen (5aba) in much lower
yl ester was subjected to our standard conditions [PdCl2 yield (54%) along with considerable amounts of the pro-
(PhCN)2, Bu4NF, THF, 608C]. Unfortunately, however, todeboration product 6ab (run 5), we reinvestigated ad-
the reaction exclusively afforded the protodesilylation ditives suitable for compounds bearing the tamoxifen
product of 3aa with only a trace amount of the desired basic side chain (Me2NCH2CH2O-) such as 4ab. For
coupling product (Scheme 5). Since extensive screening these investigations, we initially used 4ab with a Z/E ra-
of catalyst and activator to transfer these sterically con- tio of 90/10 (runs 5–8). As is usual practice in Suzuki–
densed alkenyl groups from silicon met with no success, Miyaura coupling chemistry, the addition of H2O sub-
we turned our attention to the Si/B exchange reaction stantially improved the coupling efficiency (run 6).
À
À
(borodesilylation) of 3 to achieve the installation of This may be due to the generation an Ar Pd OH inter-
the third aryl group (Ar3) by means of Suzuki–Miyaura mediate that has been suggested to possess high reactiv-
[28]
À
coupling at the resulting C B bond.
ity toward subsequent transmetalation with an alkenyl-
boronate ester.[28] The use of NaOH (with or without
H2O) in place of Cs2CO3 also resulted in improved cou-
pling efficiency giving tamoxifen (5aba) in high yields
and high stereoselectivities (runs 7 and 8). The protode-
boration product 6ab was not observed under these con-
Synthesis of Alkenylboronate Esters 4 by the
Borodesilylation of Alkenylsilanes 3
The stereoselective borodesilylation[29] was found to oc- ditions. When 4ab with Z/E ratio of 94/6 was subjected to
cur by treating alkenyl(2-pyridyl)silanes 3 with BCl3 (2.2 the conditions described in run 8, tamoxifen (5aba) was
equivs.) in CH2Cl2 at À418C, and subsequent treatment obtained in 98% yield with 95% stereoselectivity
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Table 3. Synthesis of alkenylboronate esters 4 by borodesilylation of alkenyl(2-pyridyl)silane 3.
[a]
3.3 equivs. of BCl3 were employed. After the treatment with pinacol, the mixture was treated with Cs2CO3 (10 equivs.) in
toluene (808C, 11 h).
Table 4. Screening of Pd catalyst and additives in Suzuki–Miyaura coupling of 1,2-diarylated alkenylboronate pinacol esters
4aa and 4ab.
[a]
3.0 equivs. of additive were employed.
[b]
6aa was obtained in 33% yield (Z/E¼ >99/1).
[c]
6ab was obtained in 16% yield (Z/E¼ >99/1).
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Table 5. Synthesis of tamoxifen-type tetrasubstituted olefins 5 by Suzuki–Miyaura coupling reaction of alkenylboronate esters
4 with aryl iodides.
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(run 9). Thus, we set the conditions described in run 9 as moxifen-type olefins in this study, our synthetic scheme
the standard conditions for the final Suzuki–Miyaura should be easily expandable to the construction of more
coupling of alkenylboronate esters 4.
general tetrasubstituted olefin structures.
With optimized conditions for the final Suzuki–
Miyaura coupling in hand, the alkenylboronate esters
4 prepared were cross-coupled with various aryl iodides
(Table 5). Although aryl bromides can also be employed
in this cross-coupling, we used aryl iodides in this study
because they usually gave better results in our system.
Thus, in the presence of Pd[P(t-Bu)3]2 (5 mol %),
NaOH (3.0 equivs.), and H2O (3.0 equivs.), the cross-
coupling of alkenylboronate esters 4 (1.0 equiv.) pro-
ceeded with aryl iodides (1.2 equivs.) in THF at 608C
to afford tamoxifen-type tetrasubstituted olefins 5.
The yields are generally very high and a variety of aryl
groups including heteroaryl groups can be installed in
the final tetrasubstituted olefin structure with ease. Un-
fortunately, however, the cross-couplings using aryl io-
dides bearing functional groups sensitive to strong
base were somewhat low-yielding (runs 9, 10, 12, 16,
and 17). It should also be mentioned that this final
cross-coupling step also helped to increase the isomeric
purities of the final olefins 5 (>99% in most cases) pre-
sumably because of the reactivity difference of isomeric
4 in cross-coupling reaction.
Experimental Section
General Remarks
1H and 13C NMR spectra were recorded on Varian GEMINI-
2000 (1H 300 MHz, 13C 75 MHz), Varian MERCURY plus
(1H 400 MHz, 13C 100 MHz), and JEOL A-500 (1H 500 MHz,
13C 125 MHz) spectrometers in CDCl3. EI mass spectra were
recorded on a JMS-SX102A spectrometer. FAB mass spectra
were recorded on a JMS-HX110A spectrometer. Unless other-
wise noted, all materials were obtained from commercial sup-
pliers and used without further purification. Pd[P(t-Bu)3]2 was
purchased from Strem Chemicals, Inc. and used as received.
The characterization data for compounds 3, 4, and 5 are describ-
ed in the Supporting Information.
1-Butynyldimethyl(2-pyridyl)silane (1)
To a solution of dichlorodimethylsilane (25.9 g, 200 mmol) in
dry Et2O (200 mL) was added a solution of 1-butynylmagnesi-
um chloride (100 mmol, 1.18 M) in THF at 08C. After stirring
the mixture at room temperature for12 h, dry hexane (100 mL)
was added. Filtration, removal of solvents, and subsequent dis-
tillation afforded 1-butynyl(chloro)dimethylsilane as a color-
less liquid; yield: 7.53 g (51%); bp 67–688C/55 mmHg.
1H NMR (300 MHz, CDCl3): d¼0.53 (s, 6H), 1.15 (t, J¼
7.2 Hz, 3H), 2.27 (q, J¼7.2 Hz, 2H); 13C NMR (75 MHz,
CDCl3): d¼3.8, 13.2, 13.5, 80.0, 111.6; IR (neat): n¼2979,
2180, 1314, 1256, 1044 cmÀ1; HRMS (EI): m/z calcd. for
C6H11SiCl: 146.0319; found: 146.0316.
Conclusion
In conclusion, we have established a general synthetic
scheme for tamoxifen-type tetrasubstituted olefins
based on a catalytic carbometalation/cross-coupling se-
quence across alkynyl(2-pyridyl)silanes. Copper cataly-
sis as well as the strong directing effect of the 2-pyridyl
group on silicon were revealed in the initial alkyne car-
bomagnesation. By employing a Pd catalyst and aryl io-
dides in the solution of alkenylmagnesium compounds
generated by the Cu-catalyzed carbomagnesation of 1-
butynyldimethyl(2-pyridyl)silane (1), a regio- and ster-
eoselective installation of two aryl groups onto 1 was
To a solution of 2-bromopyridine (15.8 g, 100 mmol) in dry
THF (100 mL) was added a solution of isopropylmagnesium
chloride (100 mmol, 1.88 M) in THF at room temperature,
and the mixture was stirred for 3 h. The resultant solution of
2-pyridylmagnesium chloride was added to a solution of 1-bu-
tynyl(chloro)dimethylsilane (15.1 g, 103 mmol) in THF
(100 mL) at 08C. After stirring the mixture at room tempera-
ture for 15 h, saturated aqueous NaHCO3 (50 mL) was added
to the mixture. The organic phase was separated and the aque-
ous phase was extracted with Et2O (100 mLꢁ3). The com-
bined organic phase was dried over MgSO4. Removal of the
solvent under reduced pressure and subsequent distillation af-
forded 1 as a colorless liquid; yield: 11.6 g (61%); bp 101–
1048C/7.0 mmHg. 1H NMR (300 MHz, CDCl3): d¼0.41 (s,
6H), 1.15 (t, J¼7.5 Hz, 3H), 2.27 (q, J¼7.5 Hz, 2H), 7.17
(ddd, J¼7.5, 4.8, 1.5 Hz, 1H), 7.57 (td, J¼7.5, 1.5 Hz, 1H),
7.72 (dt, J¼7.5, 1.2 Hz, 1H), 8.73 (ddd, J¼4.8, 1.5, 1.2 Hz,
1H); 13C NMR (75 MHz, CDCl3): d¼ À1.5, 13.6 (two car-
bons), 80.8, 111.2, 122.9, 129.4, 134.1, 150.0, 165.4; IR (neat):
n¼2979, 2176, 1576, 1417 cmÀ1; HRMS (FAB): m/z calcd.
À
achieved in one-pot (1!3). Although direct C Si aryla-
tion of the resultant alkenylsilanes 3 was not feasible, we
developed a borodesilylation/cross-coupling sequence
of 3 to achieve the installation of the third aryl group
À
at C Si bonds yielding the targeted tamoxifen-type tet-
rasubstituted olefins 5. With this synthetic scheme in
hand, a wide array of electronically and structurally di-
verse tetrasubstituted olefins can be prepared in a regio-
controlled, stereocontrolled, and diversity-oriented
manner. Noteworthy features of our synthesis are that
(i) the three aryl groups, which are believed to be impor-
tant (essential) for anti-estrogenic activity, can be varied
at will because they all stem from readily available aryl
iodides, and (ii) any stereo- and regioisomers can, in
principle, be prepared by simply changing the order of
application of the aryl iodides in the sequence. Although
we have focused our investigation on the synthesis of ta- for C11H16NSi (MHþ): 190.1052; found: 190.1051.
1832
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Catalytic Carbometalation/Cross-Coupling across Alkynyl(2-pyridyl)silanes
FULL PAPERS
(75 MHz, CDCl3): d¼ À1.6, 13.7, 28.4, 122.7, 123.9, 126.3,
127.4, 128.1, 129.4, 134.0, 142.8, 150.1, 161.1, 167.7; IR (neat):
n¼2967, 1593, 1574, 1418, 1246 cmÀ1; HRMS (EI): m/z calcd.
for C17H21NSi: 267.1443; found: 267.1442.
1-Butynyldimethyl(3-pyridyl)silane
The title compound was prepared according to the procedure
used for the preparation of 1. Yield: 69%; bp 130–1328C/
6.4 mmHg. 1H NMR (300 MHz, CDCl3): d¼0.42 (s, 6H), 1.19
(t, J¼7.5 Hz, 3H), 2.30 (q, J¼7.5 Hz, 2H), 7.28 (ddd, J¼7.5,
4.8, 1.2 Hz, 1H), 7.91 (dt, J¼7.5, 1.8 Hz, 1H), 8.61 (dd, J¼
4.8, 1.8 Hz, 1H), 8.80 (dd, J¼1.8, 1.2 Hz, 1H); 13C NMR
Typical Procedure of Catalytic One-Pot Diarylation of
(75 MHz, CDCl3): d¼ À0.9, 13.5, 13.6, 80.2, 111.8, 123.1, 1 (Table 2)
132.5, 141.3, 150.2, 154.1; IR (neat): n¼2979, 2176, 1574,
To a suspension of 1-butynyldimethyl(2-pyridyl)silane (1;
1559, 1395 cmÀ1; HRMS (EI): m/z calcd. for C11H15NSi:
190.5 mg, 1.01 mmol) and CuI (57.0 mg, 0.30 mmol) in dry
Et2O (2 mL) was added a solution of phenylmagnesium iodide
(Ar1MgI; 1.50 mmol, 1.93 M) in Et2O at 08C. After stirring the
mixture for 6 h, a solution of 4-[2-(N,N-dimethylamino)eth-
oxy]phenyl iodide (Ar2I; 435.8 mg, 1.50 mmol) and Pd[P(t-
Bu)3]2 (25.2 mg, 0.05 mmol) in dry THF (2 mL) was added to
the mixture. The resultant mixture was stirred at 408C for
16 h. After cooling the reaction mixture to room temperature,
H2O (ca. 10 mL) was added. The organic phase was separated
and aqueous phase was extracted with CHCl3 (10 mLꢁ3). The
combined organic phase was washed with H2O (10 mLꢁ2) and
dried over MgSO4. Removal of the solvent under reduced pres-
sure and subsequent silica gel chromatography (CHCl3/
MeOH/Et3N¼100/10/1) afforded 3ab as a pale yellow oil;
yield: 236.1 mg (55%). The stereochemistry was determined
to be 88% E by 1H NMR analysis.
189.0974; found: 189.0974.
1-Butynyldimethyl(4-pyridyl)silane
The title compound was prepared according to the procedure
used for the preparation of 1. Yield: 16%; bp 103–1058C/
2.4 mmHg. 1H NMR (300 MHz, CDCl3): d¼0.39 (s, 6H), 1.18
(t, J¼7.5 Hz, 3H), 2.29 (q, J¼7.5 Hz, 2H), 7.49 (dm, J¼
4.8 Hz, 2H), 8.58 (dm, J¼4.8 Hz, 2H); 13C NMR (75 MHz,
CDCl3): d¼ À1.3, 13.58, 13.61, 79.8, 112.0, 128.3, 147.6,
148.7; IR (neat): n¼3054, 2178, 1578, 1404 cmÀ1. HRMS
(EI): m/z calcd. for C11H15NSi: 189.0974; found: 189.0976.
1-Butynyldimethylphenylsilane
To a solution of chlorodimethylphenylsilane (5.1 g, 30 mmol)
in dry THF (30 mL) was added a solution of 1-butynylmagne-
sium chloride (33 mmol, 2.00 M) in THF at 08C. After stirring
the mixture at room temperature for 17 h and then at 708C (re-
flux) for 7 h, H2O (20 mL) was added. The organic phase was
separated and aqueous phase was extracted with EtOAc
(20 mLꢁ3). The combined organic phase was dried over
MgSO4. Removal of the solvent under reduced pressure and
subsequent distillation afforded the title compound as a color-
less liquid; yield: 3.74 g (66%); bp 97–998C/6.5 mmHg.
1H NMR (300 MHz, CDCl3): d¼0.41 (s, 6H), 1.20 (t, J¼
7.5 Hz, 3H), 2.31 (q, J¼7.5 Hz, 2H), 7.35–7.42 (m, 3H),
7.62–7.68 (m, 2H); 13C NMR (75 MHz, CDCl3): d¼ À0.6,
13.6, 13.8, 81.4, 110.9, 127.8, 129.2, 133.6, 137.6; IR (neat):
n¼2979, 2176, 1429 cmÀ1; HRMS (EI): m/z calcd. for
C12H16Si: 188.1021; found: 188.1020.
Typical Procedure of Borodesilylation of 3
(Table 3, Runs 1, 3, 4, 5, and 7).
To a solution of 3aa (68.8 mg, 0.20 mmol, 92% E) in dry CH2Cl2
(0.5 mL) was added a solution of BCl3 (0.44 mmol, 1.0 M) in
CH2Cl2 at À418C. After stirring the mixture at À418C for
5 h, a solution of pinacol (136.9 mg, 1.16 mmol) and Et3N
(0.5 mL) in dry CH2Cl2 (0.5 mL) was added. After stirring
the mixture at room temperature for 14 h, saturated aqueous
NaHCO3 (ca. 2 mL) was added to the mixture. The organic
phase was separated and the aqueous phase was extracted
with CH2Cl2 (2 mLꢁ3). The combined organic phase was
dried over MgSO4. Removal of the solvent under reduced pres-
sure and subsequent silica gel chromatography (hexane/
EtOAc¼20/1) afforded 4aa as a white solid; yield: 54.8 mg
(82%). The stereochemistry was determined to be 98% Z by
1H NMR analysis.
Typical Procedure of Cu-Catalyzed Carbomagnesation
across 1 (Scheme 4)
Typical Procedure of Borodesilylation of 3 Bearing the
Aminoethoxy Side Chain (Table 3, Runs 2 and 6).
To a suspension of 1-butynyldimethyl(2-pyridyl)silane (1;
66.6 mg, 0.35 mmol) and CuI (17.2 mg, 0.09 mmol) in dry
Et2O (0.6 mL) was added a solution of phenylmagnesium io-
dide (0.30 mmol, 1.20 M) in Et2O at 08C. After stirring the mix-
ture at 08C for 6 h, H2O (1 mL) and 28% aqueous NH3 (1 mL)
were added to the mixture. The organic phase was separated
and aqueous phase was extracted with EtOAc (2 mLꢁ3). Re-
moval of the solvent under reduced pressure afforded the
crude 2. The yield was determined to be 90% by 1H NMR anal-
ysis using 1,2-dichloroethene as an internal standard. 1H NMR
(300 MHz, CDCl3): d¼0.52 (s, 6H), 0.85 (t, J¼7.5 Hz, 3H),
2.60 (q, J¼7.5 Hz, 2H), 5.94 (s, 1H), 7.18–7.23 (m, 1H),
7.25–7.35 (m, 3H), 7.44 (dm, J¼8.1 Hz, 2H), 7.60 (dm, J¼
3.6 Hz, 2H), 8.81 (ddd, J¼4.5, 1.5, 1.2 Hz, 1H); 13C NMR
To a solution of 3ab (1.26 g, 2.93 mmol, 88% E) in dry CH2Cl2
(10 mL) was added a solution of BCl3 (9.90 mmol, 1.0 M) in
CH2Cl2 at À418C. After stirring the mixture at À418C for
5 h, a solution of pinacol (3.65 g, 30.9 mmol) and Et3N
(5 mL) in dry CH2Cl2 (5 mL) was added. After stirring the mix-
ture at room temperature for 3 h, Cs2CO3 (5.90 g, 18.1 mmol)
and dry toluene (6 mL) were added to the mixture. The resul-
tant mixture was stirred at 808C for 13 h. After cooling the mix-
ture to room temperature, saturated aqueous NaHCO3 (ca.
20 mL) was added to the mixture. The organic phase was sep-
arated and the aqueous phase was extracted with CH2Cl2
(20 mLꢁ3). The combined organic phase was dried over
Adv. Synth. Catal. 2004, 346, 1824–1835
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Toshiyuki Kamei et al.
FULL PAPERS
MgSO4. Removal of the solvent under reduced pressure and
subsequent silica gel chromatography (CHCl3/MeOH/Et3N¼
100/10/1) afforded 4ab as a pale yellow oil; yield: 800.7 mg
(65%). The stereochemistry was determined to be 94% Z by
1H NMR analysis.
[6] While the Z-isomer of tamoxifen is antiestrogenic, the E-
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Typical Procedure of Suzuki–Miyaura Coupling of 4
withAryl Iodide (Table 5).
[10] a) K. Itami, K. Mitsudo, T. Kamei, T. Koike, T. Nokami,
J. Yoshida, J. Am. Chem. Soc. 2000, 122, 12013; b) K. Ita-
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To a solution of Pd[P(t-Bu)3]2 (5.2 mg, 0.01 mmol) in dry THF
(0.2 mL) were added iodobenzene (Ar3I; 49.0 mg, 0.24 mmol),
a solution of 4ab (84.3 mg, 0.20 mmol) in dry THF (0.4 mL),
NaOH (24.5 mg, 0.61 mmol), H2O (10.8 mg, 0.60 mmol), and
dry THF (0.1 mL) at room temperature. The mixture was stir-
red at 608C for 24 h. After cooling the reaction mixture to
room temperature, H2O (ca. 1 mL) was added. The organic
phase was separated and the aqueous phase was extracted
with CHCl3 (2 mLꢁ3). The combined organic phase was dried
over MgSO4. Removal of the solvent under reduced pressure
and subsequent silica gel chromatography (CHCl3/MeOH/
Et3N¼100/10/1) afforded 5aba as a white solid; yield:
72.3 mg (98%). The stereochemistry was determined to be
95% Z by 1H NMR analysis.
[11] a) K. Itami, T. Kamei, K. Mitsudo, T. Nokami, J. Yoshi-
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Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Sci-
ence, and Technology, Japan.
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1834
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Catalytic Carbometalation/Cross-Coupling across Alkynyl(2-pyridyl)silanes
FULL PAPERS
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À
[19] The following metal salts and complexes were totally in-
effective as catalysts for the carbomagnesation across
alkynyl(2-pyridyl)silanes: ZnCl2, Mn(acac)3, FeCl3,
CeCl3, AlCl3, TiCl4, Cp2ZrCl2, NiCl2(PPh3)2, PdCl2
(PPh3)2. Copper salts such as CuCl, CuBr, CuCN, and
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across alkynyl(2-pyridyl)silanes, but the efficiency was
much lower than that accomplished with CuI. The addi-
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as arylboronic acids, arylstannanes, and organozinc re-
agents in the presence of Cu or Pd complexes.
[20] The followings are the yields of 2 obtained by the reac-
tions of 1 (1.0 equiv.) and PhMgX (2.0 equivs.) in the
presence of CuI (10 mol%) in Et2O at 08C: PhMgI
(74%), PhMgBr (27%), PhMgCl (0%), Ph2Mg (0%). For
low-yielding reactions, a considerable amount of the
starting material 1 was recovered. At the moment, we
cannot provide a reasonable rationale for the dramatic
difference of counterions on PhMgX.
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1835