Regio- and stereoselective route to tetrasubstituted olefins by the palladium-catalyzed three-component coupling of aryl iodides, internal alkynes, and arylboronic acids

Article abstract of DOI:10.1021/jo048265+

The Pd-catalyzed three-component coupling of readily available aryl iodides, internal alkynes, and arylboronic acids provides a convenient, one-step, regio- and stereoselective route to tetrasubstituted olefins in good to excellent yields, although electron-poor aryl iodides and dialkylalkynes normally afford only low yields under our standard reaction conditions. The proper combination of substrates and reaction conditions is important for high yields. The presence of water generally substantially increases the yields of the desired tetrasubstituted olefins. The reaction involves cis-addition of the aryl group from the aryl iodide to the less hindered or more electron-rich end of the alkyne, while the aryl group from the arylboronic acid adds to the other end. A modified, room-temperature procedure has also been successfully developed, which works very well for some substrates. Tamoxifen and its derivatives are synthesized in a concise, regio- and stereoselective manner by applying our synthetic protocol.

Full text of DOI:10.1021/jo048265+

VOLUME 70, NUMBER 10
MAY 13, 2005
© Copyright 2005 by the American Chemical Society
Regio- and Stereoselective Route to Tetrasubstituted Olefins by
the Palladium-Catalyzed Three-Component Coupling of Aryl
Iodides, Internal Alkynes, and Arylboronic Acids
Chengxiang Zhou and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastate.edu
Received October 3, 2004
The Pd-catalyzed three-component coupling of readily available aryl iodides, internal alkynes, and
arylboronic acids provides a convenient, one-step, regio- and stereoselective route to tetrasubstituted
olefins in good to excellent yields, although electron-poor aryl iodides and dialkylalkynes normally
afford only low yields under our standard reaction conditions. The proper combination of substrates
and reaction conditions is important for high yields. The presence of water generally substantially
increases the yields of the desired tetrasubstituted olefins. The reaction involves cis-addition of
the aryl group from the aryl iodide to the less hindered or more electron-rich end of the alkyne,
while the aryl group from the arylboronic acid adds to the other end. A modified, room-temperature
procedure has also been successfully developed, which works very well for some substrates.
Tamoxifen and its derivatives are synthesized in a concise, regio- and stereoselective manner by
applying our synthetic protocol.
Introduction
(including McMurry,3 Wittig,4 and Horner-Wadsworth-
Emmons5 reactions), olefin metathesis,6 and various
other methods (including cycloaddition,7 dehydration,8
ynolate anions,9 vinylic radical chemistry,10 etc.). Reac-
The expeditious, regio- and stereoselective synthesis
of tetrasubstituted olefins has provided a challenge for
synthetic organic chemists for years.1 Tetrasubstituted
olefins can be obtained by carbonyl olefination reactions2-5
(5) For the Horner-Wadsworth-Emmons reaction, see: (a) Sano,
S.; Takehisa, T.; Ogawa, S.; Yokoyama, K.; Nagao, Y. Chem. Pharm.
Bull. 2002, 50, 1300. (b) Gallagher, G., Jr.; Webb, R. L. Synthesis 1974,
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H. J. Org. Chem. 1997, 62, 7310.
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10.1021/jo048265+ CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/13/2005
J. Org. Chem. 2005, 70, 3765-3777
3765

Zhou and Larock
tions involving trisubstituted vinylic metal substrates
(metal ) B,11 Si,12 S,13 Zr,14 Sn,15 Te,16 etc.) or intermedi-
ates (metal ) Li,17 Mg,18 Ni,19 Cu,20 Zn,21 Pd,22 etc.) have
also been widely used in the synthesis of tetrasubstituted
olefins. However, these approaches are still fairly limited
in scope due to one or more of the following problems:
limited generality; poor regio- and/or stereoselectivity;
limited availability of starting materials; tedious multi-
step syntheses. Thus, developing an efficient, regio- and
stereoselective route to tetrasubstituted olefins is highly
desirable and a considerable challenge for the organic
chemist.
and ability to tolerate a wide range of important organic
functional groups.23 The carbopalladation of alkynes has
provided a versatile approach to various olefins and
heterocycles.24 The intermolecular Rh-,25 Ni-,26 and Pd-
catalyzed27 addition of arylboronic acids to alkynes has
been reported to produce di- and trisubstituted alkenes.
Some specific tetrasubstituted olefins have also been
prepared in a highly efficient manner by the intra-
molecular addition of arylpalladium intermediates to
internal alkynes followed by cross-coupling with boron,
tin, and zinc organometallics.28 Multicomponent reactions
have attracted much attention from chemists, because
they are highly atom-economical.29 For example, pal-
ladium-catalyzed tandem reactions involving organic
halides, unsaturated compounds (allene and norbornene),
and organometallics (organoboron and -tin reagents) have
been reported to furnish relatively complex products in
a one-pot reaction.30 The palladium-catalyzed sequential
haloallylation/Suzuki cross-coupling of alkynes has been
reported as a convenient synthetic route to highly func-
tionalized 1,4-dienes.31
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Herein, we provide a full account of the scope and
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3766 J. Org. Chem., Vol. 70, No. 10, 2005

Route to Tetrasubstituted Olefins
TABLE 1. Optimization Studies (Eq 2)a
entry
ratiob
Pd catalyst
base
DMF/H2O
% yieldc,d
Ar-Ph (mmol)
1
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
2:1:2
2:1:2
2:1:2
2:1:3
3:1:3
1:1:1
5% PdCl2(PhCN)2
1 K2CO3
1 K2CO3
1 K2CO3
1 K2CO3
1 K2CO3
1 K2CO3
1 K2CO3
1 K2CO3
1 K2CO3
1 K2CO3
1 K2CO3
1 K2CO3
1 KHCO3
2 KHCO3
2 KHCO3
2 KHCO3
2 KHCO3
3 KHCO3
3 KHCO3
1 KHCO3
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
90:10
80:20
80:20
80:20
80:20
80:20
80:20
80:20
80:20
80:20
39 (35)
36
0.03
0.03
0.03
0.02
0.03
0.04
0.04
0.03
0.02
0.02
0.06
0.05
0.04
0.05
0.26
0.26
0.25
0.25
0.49
0.08
2
5% PdCl2
3
5% Pd(OAc)2
35
4
5% Pd(dba)2
38
5e
5% Pd(PPh3)4
15
6e
5% PdCl2(PPh3)2
31
7e
5% Pd(OAc)2/10% PPh3
5% Pd(OAc)2/10% PPh3
5% Pd(OAc)2/10% [2,4,6-(MeO)3C6H4] 3P
5% Pd(OAc)2/10% TMEDA
5% PdCl2(PhCN)2
5% PdCl2(PhCN)2
5% PdCl2(PhCN)2
5% PdCl2(PhCN)2
5% PdCl2(PhCN)2
2% PdCl2(PhCN)2
1% PdCl2(PhCN)2
1% PdCl2(PhCN)2
1% PdCl2(PhCN)2
1% PdCl2(PhCN)2
29
8e,f
9e
20
20
10e
11
12
13
14
15
16
17
18
19
20
15
50
63
57
66
72
78 (75)
85
88 (86)
88
55
a All reactions were run on a 0.25 mmol scale (limiting reagent) employing the Pd catalyst in 10 mL of DMF/H2O at 100 °C for 3 h
unless otherwise indicated. b Ratio of aryl iodide/alkyne/arylboronic acid. c GC yields of 1a plus 1b based on the limiting reagent; yields
of products obtained by column chromatography are reported in parentheses. d Regioisomers 1a and 1b are inseparable by GC; they are
actually obtained in approximately a 1:6.5 ratio, based on 1H NMR spectroscopic analysis of the products after column chromatography.
e The reaction was run for 24 h. f LiCl (1 equiv) was added.
temperature reaction conditions have also been success-
fully developed.
desired product. We were pleased to find that the yield
could be significantly improved to 50% by simply running
the reaction in 90:10 DMF/H2O (entry 11). The yield could
be further increased to 63% in 80:20 DMF/H2O (entry
12). The presence of water obviously greatly accelerates
the desired reaction, perhaps because water is needed
to dissolve the inorganic base that combines with the
arylboronic acid to form the “ate complex”, which is
crucial in Suzuki-type coupling reactions.35 The yield was
slightly increased when 2 equiv of KHCO3 was used as
the base, instead of 1 equiv of K2CO3 (compare entries
12 and 14).36 Since biaryl side-product was evident in all
reactions, the alkyne was chosen as the limiting reagent
in order to increase the yield. When 2 equiv of aryl iodide,
1 equiv of alkyne, and 2 equiv of arylboronic acid were
employed, the yield increased to 72% (entry 15). Simply
reducing the loading of the palladium catalyst further
increased the yield (entries 15-17). An 85% yield of the
desired tetrasubstituted olefin was obtained by employing
only 1% of the palladium catalyst (entry 17). The yield
could be further increased to 88% by using 3 equiv of
arylboronic acid and KHCO3 as the base (entry 18). The
same yield was obtained when 3 equiv of aryl iodide was
employed (entry 19). A moderate 55% yield of the desired
product could be obtained employing a 1:1:1 ratio of the
aryl iodide, alkyne, and arylboronic acid (entry 20). The
“optimal” procedures from entries 18 and 19 have thus
been employed for the synthesis of a wide variety of
tetrasubstituted olefins.37
Results and Discussion
(a) Optimization of the Reaction Conditions. For
optimization of the reaction conditions used in our
tetrasubstituted olefin synthesis, we investigated a simple,
representative model system consisting of 4-iodotoluene,
1-phenyl-1-propyne, and phenylboronic acid (eq 2). In
early experiments, we found that a 35% isolated yield of
a 1:6.5 mixture of regioisomeric 1a and 1b (as determined
by 1H NMR spectroscopy after column chromatography)
could be obtained by the reaction of 1 equiv of 4-iodo-
toluene, 2 equiv of 1-phenyl-1-propyne, and 2 equiv of
phenylboronic acid in the presence of 5 mol % PdCl2-
(PhCN)2 and 1 equiv of K2CO3 in DMF (Table 1, entry
1). Changing the Pd catalyst to either PdCl2, Pd(OAc)2,
or Pd(dba)2 had little effect on the yield (entries 2-4).
Employing phosphine or amine ligands slows the reaction
and has a detrimental effect on the yields (entries 5-10).
Employing LiCl as an additive also lowers the yield of
the reaction (entry 8).34 A small amount of 4-methylbi-
phenyl side-product was also formed along with the
(35) For reviews of the Suzuki reaction, see: (a) Miyaura, N.; Suzuki,
A. Chem. Rev. 1995, 95, 2457. (b) Suzuki, A. J. Organomet. Chem. 1999,
576, 147.
(36) The yield is lower if 2 equiv of KF is used as the base; none of
the desired product is observed if 2 equiv of KOAc is used as the base.
(37) Entries 18 and 19 were chosen as optimal conditions to extend
this chemistry, for the convenience of product purification. However,
the 2:1:3 (in entry 18) and the 3:1:3 (in entry 19) stoichiometries are
not necessarily the best stoichiometries for an atom-economical reac-
tion. One can certainly run the reaction using other stoichiometries
for better use of all reagents.
(34) For a review discussing the halide effect in Pd catalysis, see:
Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26.
J. Org. Chem, Vol. 70, No. 10, 2005 3767

Zhou and Larock
(b) Scope and Limitations. (1) Scope of the Reac-
tion Using Various Internal Alkynes. Under our
optimal conditions, a wide variety of internal alkynes
have been successfully employed in this tetrasubstituted
olefin synthesis (eq 3, Table 2). When iodobenzene and
of the desired product is obtained when 2-iodotoluene is
used, presumably due to the steric hindrance of the ortho
methyl group, which inhibits the addition of the o-tolyl
group to the alkyne (entry 5). It is noteworthy that the
unprotected 4-iodophenol also works well in this chem-
istry and provides the corresponding phenol in a good
yield (entry 6). Electron-poor aryl iodides work poorly in
this chemistry. For example, the relatively electron-poor
4-chloroiodobenzene provides only a 65% yield of the
desired tetrasubstituted olefin (entry 7). The more electron-
poor 4-iodoacetophenone provides a very poor 10% yield
of the corresponding olefinic ketone (entry 8). 4-Iodo-
nitrobenzene provides none of the desired product (entry
9). Almost quantitative conversion of this aryl iodide and
phenylboronic acid to 4-nitrobiphenyl is observed instead.
Presumably in this case the Suzuki-type reaction is much
faster than carbopalladation of the alkyne; thus, the
formation of the biaryl side-product is more favorable.
(3) Scope of the Reaction Using Various Aryl-
boronic Acids. We next investigated the scope of the
reaction using various arylboronic acids plus iodobenzene
and diphenylacetylene (eq 5, Table 4). Both electron-
phenylboronic acid are employed, the reaction works very
well with 1-phenyl-1-propyne and 1-phenyl-1-hexyne and
provides the desired tetrasubstituted olefins in excellent
yields (entries 1 and 2). Relatively electron-poor and more
sterically hindered diphenylacetylene also provides the
desired tetraphenylethene in an excellent yield, although
the reaction is slower and a longer reaction time (24 h)
is needed (entry 3). The reaction tolerates ketone, ester,
and alcohol functional groups and provides the desired
tetrasubstituted olefins in good to excellent yields (entries
4-7). Although an acetal has been successfully employed
in this chemistry, the product hydrolyzed on silica gel
during column chromatography, providing the corre-
sponding aldehyde in a good yield (entry 8). Electron-
poor diethyl acetylenedicarboxylate and (4-nitrophenyl)-
phenylacetylene have also been efficiently coupled with
iodobenzene and phenylboronic acid (entries 9 and 13).
Relatively electron-rich 4-octyne, however, provides the
desired tetrasubstituted olefin in only a 32% yield, and
the product from di-insertion of the alkyne is also isolated
in a 48% yield (entry 10). None of the desired product is
obtained when relatively electron-rich and sterically
hindered 4,4-dimethyl-2-butyne is employed (entry 11).
This may in part be due to the fact that the 4,4-dimethyl-
2-butyne is relatively volatile (bp 80 °C) under our
standard reaction conditions (100 °C). The terminal
alkyne phenylacetylene is not a good substrate for this
chemistry, since a substantial amount of tetraphenyl-
ethene is also obtained along with the desired tri-
phenylethene product (entry 12). Presumably diphenyl-
acetylene is first being formed by a Sonogashira-type38
reaction of iodobenzene and phenylacetylene and then
reacts with iodobenzene and phenylboronic acid in the
usual fashion to generate the tetraphenylethene side-
product.
neutral and electron-rich arylboronic acids work very well
in this chemistry (entries 1-4, Table 4). We were pleased
to find that the scope of the reaction using various
arylboronic acids is pretty general compared to that of
the aryl iodides. o-Tolylboronic acid affords a good yield
of the desired olefin (entry 5, Table 4), as opposed to the
relatively poor yield obtained when using o-iodotoluene
(entry 5, Table 3). Furthermore, electron-poor arylboronic
acids, such as 4-chlorophenylboronic acid and 4-acetyl-
phenylboronic acid, also afford the desired tetrasubsti-
tuted olefins in good yields (entries 6 and 7, Table 4).
The same products could be obtained only in low yields
when employing the corresponding aryl iodides and
phenylboronic acid (entries 7 and 8, Table 3). On the
other hand, the more electron-poor 4-nitrophenylboronic
acid provides only a trace amount of the desired product
(compare entry 8 in Table 4 with entry 9 in Table 3). It
is noteworthy that product 22 could be obtained by
employing iodobenzene, (4-nitrophenyl)phenylacetylene,
and phenylboronic acid as substrates (entry 13, Table 2).
Other organoboron reagents, such as sodium tetra-
phenylborate and potassium phenyltrifluoroborate, also
work well and provide the desired tetrasubstituted olefins
in good yields (entries 9 and 10). It is noteworthy that
the base is still necessary in the potassium phenyltri-
fluoroborate reaction, since only a trace amount of the
product is obtained without the KHCO3 base (entry 11).39
(c) Regioselectivity and Stereoselectivity. This
approach to tetrasubstituted olefins is often both regio-
and stereoselective. The three-component reaction in-
volves clean cis-addition to the alkyne in all cases studied
so far. Two regioisomers have usually been obtained
when unsymmetrical alkynes are employed as starting
materials. The structures of the major isomers have been
(2) Scope of the Reaction Using Various Aryl
Iodides. Employing diphenylacetylene and phenyl-
boronic acid as substrates, we then investigated the scope
of the reaction using various aryl iodides (eq 4, Table 3).
Iodobenzene affords the desired tetraphenylethene in an
excellent 92% yield. Electron-rich aryl iodides, such as
4-iodoanisole, 4-iodotoluene, and 3-iodotoluene, efficiently
cross-couple with diphenylacetylene and phenylboronic
acid to provide the corresponding tetrasubstituted olefins
in good yields (entries 2-4). However, only a 48% yield
(38) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467. (b) Takahashi, K.; Kuroyama, Y.; Sonogashira, K.;
Hagihara, N. Synthesis 1980, 627. (c) For a general review, see:
Sonogashira, K. In Metal Catalyzed Cross-Coupling Reactions; Dieder-
ich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998.
(39) For similar observations about the importance of the base when
using ArBF3K in the Suzuki reaction, see: Littke A. F.; Dai, C.; Fu,
G. C. J. Am. Chem. Soc. 2000, 122, 4020.
3768 J. Org. Chem., Vol. 70, No. 10, 2005

Route to Tetrasubstituted Olefins
TABLE 2. Scope of the Internal Alkynes (Eq 3)a
a All reactions were run using 0.50 mmol of aryl iodide, 0.25 mmol of alkyne, 0.75 mmol of arylboronic acid, 0.75 mmol of KHCO3, and
0.0025 mmol of PdCl2(PhCN)2 in 10 mL of 4:1 DMF/H2O at 100 °C for 12 h unless otherwise indicated. b The yields are based on products
1
isolated by column chromatography; the ratio of regioisomers is given in parentheses as determined by H NMR spectroscopic analysis.
c Aryl iodide (3 equiv) was used in this entry and the reactions were run for 24 h.
J. Org. Chem, Vol. 70, No. 10, 2005 3769

Zhou and Larock
TABLE 3. Scope of the Aryl Halides (Eq 4)a
TABLE 4. Scope of the Reaction Using Various
Arylboronic Acids (Eq 5)a
a All reactions were run using 0.75 mmol of aryl iodide, 0.25
mmol of alkyne, 0.75 mmol of arylboronic acid, 0.75 mmol of
KHCO3, and 0.0025 mmol of PdCl2(PhCN)2 in 10 mL of 4:1 DMF/
H2O at 100 °C for 24 h. b The yields are based on products isolated
by column chromatography. c The yield is based on 1H NMR
spectroscopic analysis of the crude product, which contains the
desired olefin product and the 4-phenylphenol side-product.
determined by examining their NOESY H-H interac-
tions.32 The regiochemistry is primarily controlled by
steric effects, which is consistent with our previous work40
on palladium-catalyzed additions to alkynes and analo-
gous work of Cacchi.41 Thus, the aryl group from the aryl
iodide generally favors the less hindered end of the
a All reactions were run using 0.75 mmol of aryl iodide, 0.25
mmol of alkyne, 0.75 mmol of arylboronic acid, 0.75 mmol of
KHCO3, and 0.0025 mmol of PdCl2(PhCN)2 in 10 mL of 4:1 DMF/
H2O at 100 °C for 24 h. b The yields are based on products isolated
by column chromatography. c No KHCO3 was added.
(40) (a) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998,
63, 7652. (b) Larock, R. C. Pure Appl. Chem. 1999, 71, 1453. (c) Larock,
R. C. J. Organomet. Chem. 1999, 576, 111. (d) Roesch, K. R.; Zhang,
H.; Larock, R. C. J. Org. Chem. 2001, 66, 8042.
(41) (a) Cacchi, S. J. Organomet. Chem. 1999, 576, 42. (b) Arcadi,
A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Pace, P. Eur. J. Org. Chem.
1999, 3305, 5. (c) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Pace,
P. Eur. J. Org. Chem. 2000, 4099.
alkyne, while the aryl group from the arylboronic acid
adds to the other end of the alkyne (entry 1, Table 5; eq
6). Electronic effects also play an important role in the
regiochemistry. The aryl group from the arylboronic acid
prefers to add to the more electron-poor end of the alkyne,
assuming steric effects are comparable. Only a 2:1
3770 J. Org. Chem., Vol. 70, No. 10, 2005

Route to Tetrasubstituted Olefins
TABLE 5. Regioselectivity Studies (Eq 6)a
a All reactions were run using 0.50 mmol of aryl iodide, 0.25 mmol of alkyne, 0.75 mmol of arylboronic acid, 0.75 mmol of KHCO3, and
0.0025 mmol of PdCl2(PhCN)2 in 10 mL of 4:1 DMF/H2O at 100 °C for 12 h unless otherwise indicated. b The yields are based on products
isolated by column chromatography; the ratio of regioisomers is given in parentheses as determined by 1H NMR spectroscopic analysis
of the products obtained by column chromatography.
J. Org. Chem, Vol. 70, No. 10, 2005 3771

Zhou and Larock
was improved to 18:1 when we carried out the reaction
at room temperature (entry 1, Table 6; eq 8). This is
opposed to the 6:1 mixture of regioisomers obtained at
100 °C (entry 1, Table 5). With the proper choice of base,
we were pleased to find that the reaction could be
efficiently carried out at room temperature. For example,
with K2CO3 as the base, the three-component reaction
of iodobenzene, 1-phenylpropyne, and p-tolylboronic acid
at room temperature after 24 h provided the desired
products in an excellent 82% overall yield with excellent
18:1 regioselectivity (entry 2). The choice of the base is
essential to the efficiency of the chemistry. It is important
to note that the Suzuki-coupling between iodobenzene
and p-tolylboronic acid can be accomplished using K2CO3
as the base at room temperature in 95% yield (eq 9).
regioselectivity is observed when a ketone or ester-
containing internal alkyne is employed, probably due to
the opposite steric and electronic effects of the ketone or
ester groups versus the phenyl group (entries 2 and 3).42
It is interesting to note that better regioselectivity is
observed if an electron-withdrawing group is introduced
into the aromatic ring of the 1-phenylpropyne (compare
entries 4 and 5 with entry 1). Excellent 15:1 regioselec-
tivity is observed when 1-(4-nitrophenyl)propyne is used
as the alkyne (entry 5). Introduction of an electron-poor
pyrimidine group has a similar effect (compare entries 6
and 1). Poor regioselectivity along with a lower yield is
observed when an electron-donating group is introduced
into the aromatic ring of the 1-phenylpropyne (entries 7
and 8). It is noteworthy that the regiochemistry can be
readily reversed by interconverting functionality on the
aryl iodide and the arylboronic acid [compare entry 1 in
Table 5 with entry 19 in Table 1 (see footnote d), and
entry 5 in Table 5 with the results reported in eq 7]. For
However, the same reaction only leads to a low yield of
biaryl product when KHCO3 is used as the base. It is
noteworthy that the minor isomer in Table 6, entry 1,
could be obtained as the major product again with
excellent 18:1 regioselectivity by simply using 4-iodo-
toluene, 1-phenyl-1-propyne, and phenylboronic acid as
the starting materials (entry 3, Table 6). The regioselec-
tivity is poor, however, when ethyl phenylpropynoate is
used as the alkyne. Although an excellent 87% yield is
obtained using the room-temperature conditions, the two
regioisomers are obtained in a 3:2 ratio (entry 4, Table
6) as compared to the 78% yield and 2:1 regioselectivity
observed earlier (entry 5, Table 2). Employing 4-octyne
as the starting material is known to lead to a low yield
of tetrasubstituted alkene when the process is run at 100
°C (entry 10, Table 2). A similar low yield is obtained
under our room-temperature reaction conditions, since
a substantial amount of double insertion product is also
obtained (entries 5 and 6, Table 6). The milder reaction
conditions make it possible to employ 4,4-dimethyl-2-
butyne as the alkyne, and the reaction now affords the
desired product regioselectively in a 42% yield (entry 7,
Table 6), while none of this product is observed when the
same alkyne is employed at 100 °C (entry 11, Table 2).
The room-temperature reaction turns out to be sluggish
and only a 20% yield of the desired product is obtained
after 24 h when diphenylacetylene is used as the start-
ing material (entry 8, Table 6). Presumably diphenyl-
acetylene is too sterically hindered, and thus carbo-
palladation of this alkyne is not efficiently achieved
at room temperature. The room-temperature process
works well for 1-(4-nitrophenyl)-1-butyne, affording the
desired products in good yields with almost complete
control of the regiochemistry (entries 9 and 10, Table 6).
It is noteworthy that the products obtained in these
reactions are possible precursors to tamoxifen deriva-
example, the minor regioisomer 25b in the process
reported in Table 5, entry 5, can be easily prepared, again
with excellent 15:1 regioselectivity, simply by reversing
the position of the substituents in the aryl iodide and the
arylboronic acid (eq 7). The electronic effect of an
electron-withdrawing nitro group has also been studied
using (4-nitrophenyl)phenylacetylene as a substrate;
moderate 2:1 regioselectivity is observed (entry 9).
(d) Modified Room-Temperature Reaction. Al-
though our process normally involves clean cis-addition
to the internal alkyne, the regioselectivity is sometimes
only fair under our optimal reaction conditions (Table 5).
We envisioned that better regioselectivity might possibly
be accomplished under milder reaction conditions. Al-
though only a small amount of the desired olefin product
was obtained, the regioselectivity of the reaction of
iodobenzene, 1-phenylpropyne, and p-tolylboronic acid
(42) Presumably the phenyl group is more sterically hindered than
the ketone or ester groups, and the ketone and ester groups are more
electron-poor than the phenyl group.
3772 J. Org. Chem., Vol. 70, No. 10, 2005

Route to Tetrasubstituted Olefins
TABLE 6. Synthesis of Tetrasubstituted Olefins at Room Temperature (Eq 8)a
a All reactions were run using 0.75 mmol of aryl iodide, 0.25 mmol of alkyne, 0.75 mmol of arylboronic acid, 0.75 mmol of K2CO3, and
0.005 mmol of PdCl2(PhCN)2 in 10 mL of 4:1 DMF/H2O at room temperature for 24 h unless otherwise indicated. b The yields are based
on products isolated by column chromatography; the ratio of regioisomers is given in parentheses as determined by 1H NMR spectroscopic
analysis. c 0.75 mmol of KHCO3 was employed instead of K2CO3. d The reaction was run under N2. A slightly lower yield was obtained if
the reaction was run under air.
tives,43 since demethylation of the methyl ether, followed
by alkylation, is a known process to synthesize tamoxifen
derivatives.11a,22k,44,45
(e) Reaction Mechanism. We propose the mecha-
nism illustrated in Scheme 1 for this process, which
consists of the following key steps: (1) reduction of Pd(II)
J. Org. Chem, Vol. 70, No. 10, 2005 3773

Zhou and Larock
SCHEME 1
SCHEME 3
o-tolyl group is more sterically hindered and thus the
carbopalladation is less favorable. We also believe that
the aromatic ring adjacent to the Pd moiety of the
vinylpalladium intermediate may coordinate with the Pd
by η1 or η2 coordination46a and thus stabilize the vinyl-
palladium intermediate in the catalytic cycle (Scheme 2).
Similar adjacent coordination has been reported in the
literature.46 This stabilization may also inhibit further
insertion of another molecule of alkyne. No such stabi-
lization of the Pd intermediate exists after insertion of a
second alkyne. The facile 1,4-palladium migration from
similar vinylic (and aryl) palladium species47 to the
neighboring arene provides further support for such an
interaction. Electron-deficient aryl iodides generally lead
to low yields in this chemistry (entries 7-9, Table 3),
possibly because the electron-deficient aromatic ring is
less likely to coordinate with the vinylic Pd intermediate.
The addition of phosphine ligands may also interfere with
coordination of the neighboring arene in these vinylic
palladium intermediates and thus be responsible for the
lower yields of tetrasubstituted olefin (see Table 1, entries
5-10). On the other hand, the carbopalladation process
is apparently still facile when using iodobenzene and
either electron-rich or electron-deficient arylboronic acids.
Another feature of this chemistry is the fact that the
Pd favors the more electron-deficient end of the alkyne
during carbopalladation. For example, excellent regio-
selectivity (15:1) is observed when 1-(4-nitrophenyl)-
propyne is employed, as opposed to only 6:1 regioselec-
tivity when using 1-phenylpropyne (compare entries 1
and 5 in Table 5). Thus, the reaction is further favored
via vinylpalladium intermediate A over B by the presence
of the nitro group (Scheme 3). Presumably, delocalization
of the vinylic anion by the nitro group in A leads to a
SCHEME 2. Carbopalladation of Internal Alkynes
to Pd(0), the actual catalyst, presumably by the aryl-
boronic acid;48 (2) oxidative addition of the aryl iodide to
Pd(0); (3) cis-carbopalladation of the internal alkyne by
the resulting arylpalladium species to generate a vinylic
palladium intermediate; (4) subsequent Suzuki-type
transmetalation with the “ate complex” ArB(OH)3-; (5)
reductive elimination producing the tetrasubstituted
olefin with simultaneous regeneration of the Pd(0) cata-
lyst. Alternatively, transmetalation can occur directly
between the initial arylpalladium intermediate and the
arylboronic acid ate complex producing the biaryl side-
product.
Carbopalladation of the internal alkyne by the aryl-
palladium intermediate (Ar-Pd-I in Scheme 1) is believed
to be the key step in the catalytic cycle. This presumably
proceeds through a four-member ring transition state in
which the aromatic ring and Pd in Ar-Pd-I are positioned
on the same side of the internal alkyne (Scheme 2).40,41a
Thus, carbopalladation generates a vinylic palladium
species by a cis-addition. It is reasonable to assume that
the relatively large aromatic group of the Ar-Pd-I inter-
mediate should approach the internal alkyne from the
less hindered end of the internal alkyne due to steric
hindrance. While p-iodotoluene affords a high yield of
tetrasubstituted olefin in this chemistry, o-iodotoluene
only affords a fair yield of the desired product (entries 3
and 5 in Table 3, respectively), probably because the
(46) (a) Catellani, M.; Mealli, C.; Motti, E.; Paoli, P.; Perez-Carreno,
E.; Pregosin, P. S. J. Am. Chem. Soc. 2002, 124, 4336. (b) Campora,
J.; Gutierrez-Puebla, E.; Lopez, J. A.; Monge, A.; Palma, P.; Del Rio,
D.; Carmona, E. Angew. Chem., Int. Ed. 2001, 40, 3641. (c) Campora,
J.; Lopez, J. A.; Palma, P.; Valerga, P.; Spillner, E.; Carmona, E. Angew.
Chem., Int. Ed. 1999, 38, 147. (d) Falvello, L. R.; Fornies, J.; Navarro,
R.; Sicilia, V.; Tomas, M. J. Chem. Soc., Dalton Trans. 1994, 3143. (e)
Fornies, J.; Menjon, B.; Gomez, N.; Tomas, M. Organometallics 1992,
11, 1187. (f) Li, C. S.; Cheng, C. H.; Wang, S. L. J. Chem. Soc., Chem.
Commun. 1991, 710. (g) Wehman, E.; van Koten, G.; Jastrzbeski, T.
B. H.; Ossor, H.; Pfeffer, M. J. Chem. Soc., Dalton Trans. 1988, 2975.
(47) (a) Campo, M. A.; Huang, Q.; Yao, T.; Tian, Q.; Larock, R. C. J.
Am. Chem. Soc. 2003, 125, 11506. (b) Campo, M. A.; Larock, R. C. J.
Am. Chem. Soc. 2002, 124, 4326. (c) Karig, G.; Moon, M.-T.; Thasana,
N.; Gallagher, T. Org. Lett. 2002, 4, 3115. (d) Larock, R. C.; Tian, Q.
J. Org. Chem. 2001, 66, 7372. (e) Tian, Q.; Larock, R. C. Org. Lett.
2000, 2, 3329.
(43) For representative reviews on tamoxifen and derivatives, see:
(a) Jordan, V. C. Nat. Rev. Drug Discovery 2003, 2, 205. (b) Jordan, V.
C. J. Med. Chem. 2003, 46, 883. (c) Jordan, V. C. J. Med. Chem. 2003,
46, 1081. (d) Salih, A. K.; Fentiman, I. S. Cancer Treat. Rev. 2001, 27,
261. (e) Harper, M. J. K.; Walpole, A. L. Nature 1966, 212, 87.
(44) For some representative tamoxifen syntheses, see: (a) Potter,
G. A.; McCague, R. J. Org. Chem. 1990, 55, 6184. (b) Brown, S. D.;
Armstrong, R. W. J. Org. Chem. 1997, 62, 7076. (c) Yus, M.; Ramon,
D. J.; Gomez, I. Tetrahedron 2003, 59, 3219.
(45) For some representative syntheses of tamoxifen derivatives,
see: (a) Yu, D. D.; Forman, B. M. J. Org. Chem. 2003, 68, 9489. (b)
Valliant, J. F.; Schaffer, P.; Stephenson, K. A.; Britten, J. F. J. Org.
Chem. 2002, 67, 383. (c) Foster, A. B.; Jarman, M.; Leung, O. T.;
McCague, R.; Leclercq, G.; Devleeschouwer, N. J. Med. Chem. 1985,
28, 1491. (d) Watts, C. K. W.; Murphy, L. C.; Sutherland, R. L. J. Biol.
Chem. 1984, 259, 4223.
3774 J. Org. Chem., Vol. 70, No. 10, 2005

Route to Tetrasubstituted Olefins
CHART 1
more stable anionic-like transition state and thus im-
proves the regioselectivity of carbopalladation. It is also
possible that the more stable vinylic anion in A is a
weaker donor for Pd and leads to a more reactive vinylic
palladium intermediate and therefore improves the re-
gioselectivity of the reaction.
The proposed reaction mechanism also indicates that
the arylpalladium intermediate Ar-Pd-I can undergo
either the desired carbopalladation of the internal alkyne
or an undesired Suzuki-type transmetalation directly
with the boronic acid “ate complex”. That competition
limits the efficiency of our tetrasubstituted olefin syn-
thesis. An efficient reaction requires that the rate of
carbopalladation of the alkyne by Ar-Pd-I be faster than
SCHEME 4
-
that of transmetalation of ArB(OH)3 by Ar-Pd-I. When
transmetalation is much faster than carbopalladation,
the reaction favors formation of the biaryl side-product
as seen when 4-iodonitrobenzene is employed (entry 9
in Table 3). The desired reaction is also less favorable
when carbopalladation is much faster than transmeta-
lation. In this case, multiple insertion of the alkyne is
likely to occur, despite the fact that stabilization of the
vinylic palladium intermediate by the adjacent aromatic
ring should favor formation of the desired “mono-alkyne-
insertion” product, as stated earlier. Such an imbalance
may be responsible for the substantial amount of the di-
insertion product formed when less hindered, electron-
rich 4-octyne is employed (entry 10 in Table 2).
This aryl iodide-alkyne-organoboron reaction system
is quite complicated, since each of the three components
is highly reactive toward Pd catalysis. Depending on the
reaction conditions employed, the following side-reactions
would appear to be possible in our reaction system: the
direct Suzuki reaction of aryl iodide and arylboronic
acid;35 homocoupling of the arylboronic acid;48 insertion
of the alkyne, followed by possible reduction;41,49 insertion
of the alkyne, followed by migration and ring closure;47d,e
double-insertion of the alkyne, followed by ring closure
to a naphthalene;50 and multiple insertion of the alkyne.51
Fortunately, most of the above side-reactions, except for
the Suzuki reaction, are apparently suppressed under our
optimal reaction conditions. Due to the many competing
reactions possible in this multicomponent reaction sys-
tem, the choice of reaction conditions, stoichiometry, and
sometimes the proper combination of substrates are
essential for the success of this chemistry.
steroidal antiestrogens, and the antiestrogenic activity
is highly dependent on the olefin geometry.43 In particu-
lar, tamoxifen has been widely used for the treatment of
breast cancer at all stages and is believed to be respon-
sible for the survival of hundreds of thousands of breast
cancer patients (Chart 1).43 The regio- and stereoselective
synthesis of tamoxifen and its derivatives has been of
major interest to organic and pharmaceutical chemists
for years, and yet it remains today a considerable
challenge for the synthetic chemist. Recently, some
elegant syntheses of tamoxifen and its derivatives have
been reported.3c,11a,12a,18c,21a,22k,44,45 However, either they
are not regio- and stereoselective or they involve multi-
step procedures employing starting materials that are
not readily available. Thus, a simple, regio- and stereo-
selective synthetic approach to tamoxifen and its deriva-
tives is highly desirable and should pave the way for
rapid development of these highly potent nonsteroidal
antiestrogens.
By employing our new approach to tetrasubstituted
olefins, we anticipated that it should be possible to
prepare tamoxifen and analogues in a very concise
manner. Our route to tamoxifen involves a three-
component reaction of readily available iodobenzene,
1-phenyl-1-butyne, and 4-[2-(dimethylamino)ethoxy]-
phenylboronic acid (Scheme 4).
(f) Synthesis of Tamoxifen and Derivatives. The
triaryl alkene moiety is a key structure in many non-
The dimethylamino-containing boronic acid has been
successfully synthesized in two steps from readily avail-
able starting materials. The requisite aryl bromide
precursor has been obtained by reaction of p-bromophenol
and 2-(dimethylamino)ethyl chloride (eq 10). The aryl-
boronic acid has subsequently been prepared in good yield
through reaction of the corresponding Grignard reagent
with B(OMe)3 (eq 11).52
In an attempt to control the regioselectivity, a three-
component approach to tamoxifen has been attempted
employing our modified room-temperature reaction con-
ditions. However, the reaction was sluggish under those
(48) (a) Miyaura, N.; Suzuki, A. Main Group Met. Chem. 1987, 10,
295. (b) Song, Z. Z.; Wong, H. N. C. J. Org. Chem. 1994, 59, 33. (c)
Moreno-Manas, M.; Perez, M.; Pleixats, R. J. Org. Chem. 1996, 61,
2346. (d) Wong, M. S.; Zhang, X. L. Tetrahedron Lett. 2001, 42, 4087.
(e) Koza, D. J.; Carita, E. Synthesis 2002, 2183. (f) Falck, J. R.;
Mohapatra, S.; Bondlela, M.; Venkataraman, S. K. Tetrahedron Lett.
2002, 43, 8149. (g) Lei, A.; Zhang, X. Tetrahedron Lett. 2002, 43, 2525.
(h) Yoshida, H.; Yamaryo, Y.; Ohshita, J.; Kunai, A. Tetrahedron Lett.
2003, 44, 1541.
(49) We hypothesize that the reducing reagent might be formate,
which could possibly be produced by the hydrolysis of DMF in the
presence of base.
(50) (a) Kawasaki, S.; Satoh, T.; Miura, M.; Nomura, M. J. Org.
Chem. 2003, 68, 6836. (b) Kotora, M.; Matsumura, H.; Gao, G.;
Takahashi, T. Org. Lett. 2001, 3, 3467. (c) Larock, R. C.; Doty, M. J.;
Han, X. J. Org. Chem. 1999, 64, 8770. (d) Sakakibara, T.; Tanaka, Y.;
Yamasaki, T. I. Chem. Lett. 1986, 797.
(51) Wu, G.; Rheingold, A. L.; Geib, S. J.; Heck, R. F. Organo-
metallics 1987, 6, 1941.
(52) (a) Washburn, R. M.; Levens, E.; Albright, C. F.; Billig, F. A.
Organic Syntheses; Wiley: New York, 1963; Collect. Vol. IV, p 68. (b)
Brown, H. C.; Cole, T. E. Organometallics 1983, 2, 1316.
J. Org. Chem, Vol. 70, No. 10, 2005 3775

Zhou and Larock
reaction conditions, and most of the starting materials
remained unreacted after 24 h (eq 12). Fortunately, the
the desired product when using 1-(4-nitrophenyl)-1-
butyne as the starting alkyne. No biaryl side-product is
formed, and the starting materials remain essentially
untouched. None of the biaryl or the tetrasubstituted
olefin is observed even after heating the reaction at 100
°C for 24 h. It is interesting to note that the analogous
reaction of the closely related electron-rich 4-methoxy-
phenylboronic acid works well for 1-(4-nitrophenyl)-1-
butyne even at room temperature (entry 9, Table 6). The
direct Suzuki reaction of iodobenzene and 4-[2-(dimethyl-
amino)ethoxy]phenylboronic acid affords a high yield of
biaryl at room temperature (eq 14).
reaction could be speeded up by simply changing the
amount of water. After a 48 h reaction in 2:1 DMF/H2O,
a 60% yield of the desired tamoxifen was isolated by
column chromatography. It is noteworthy that the reac-
tion seems to be highly regioselective (possibly >20:1),
since the crude tamoxifen obtained is around 95% pure
according to 1H NMR spectral analysis.53 By raising the
reaction temperature to 45 °C, a slightly higher 68% yield
of tamoxifen has been obtained in 24 h. We also observed
the formation of about 2 equiv of N,N-dimethyl-2-(4-
biphenyloxy)ethylamine as a side-product, which could
be separated from tamoxifen by column chromatography.
The tamoxifen derivatives 36 and 3745d could also be
prepared using this chemistry. Thus, methyl- and meth-
oxy-substituted tamoxifen have been obtained in good
yields with good regiochemistry by simply employing
4-iodotoluene or 4-iodoanisole as the starting materials
(eq 13).
It would appear that the combination of the aryl iodide,
alkyne, and boronic acid might be forming a stable Pd
complex, which prevents further reaction. We hypoth-
esize such a Pd complex in which the N and O in the
(dimethylamino)ethoxy group coordinate with the vinylic
Pd intermediate, forming a stable chelation complex.
With the strong delocalization of the vinylic anion by the
nitro group, coordination of the vinylic anion to the Pd
should be weakened, allowing stronger coordination of
the N and O in the (dimethylamino)ethoxy group due to
the trans effect. On the other hand, without delocalization
by the nitro group, coordination of the vinylic anion to
the Pd should be strong, leading to weaker coordination
of the N and O in the (dimethylamino)ethoxy group. We
hypothesize an equilibrium between this chelation com-
plex and the free reactive vinylpalladium intermediate,
which is free to undergo transmetalation with the boronic
acid “ate complex”, producing the desired product. So far,
all attempts to prepare such a nitro-substituted tamox-
ifen by employing 1-(4-nitrophenyl)-1-butyne have failed.
It is noteworthy that one can possibly obtain such
tamoxifen derivatives through the triarylalkene pre-
cursor generated earlier (entries 9 and 10, Table 6),
since demethylation of the methyl ether, followed by
alkylation to generate tamoxifen derivatives, is well-
established.11a,22k,44,45
This approach to tamoxifen derivatives is not very
general, however, since we have found that the reaction
of iodobenzene and boronic acid 34 fails to give any of
(53) The purity of the product is based on 1H NMR spectroscopic
analysis of the crude product obtained from column chromatography.
We cannot rule out the possibility that some of the minor regioisomer
has been separated out during column chromatography, since the
biaryl side-product and the desired tetrasubstituted olefin have very
similar polarities in this case.
3776 J. Org. Chem., Vol. 70, No. 10, 2005

Route to Tetrasubstituted Olefins
times with ethyl ether. The combined organic layers were dried
over anhydrous MgSO4, and the solvent was evaporated under
reduced pressure. The product was isolated by chromatography
on a silica gel column.
Conclusions
A new palladium-catalyzed route to tetrasubstituted
olefins has been successfully developed. The synthesis
involves a one-pot, three-component cross-coupling of
readily available aryl iodides, internal alkynes, and
arylboronic acids. The synthetic protocol is conceptually
simple and quite practical. The reaction is quite efficient
and is normally insensitive to air. In fact, the presence
of water greatly facilitates formation of the desired
tetrasubstituted olefins. Furthermore, the reaction can
be carried out at room temperature. The mild reaction
conditions accommodate a number of functional groups,
such as a ketone, an ester, an alcohol, and a phenol. Thus,
we envision that this chemistry should find wide applica-
tion for the synthesis of tetrasubstituted olefins.
A wide variety of tetrasubstituted olefins have been
prepared in good to excellent yields. The reaction involves
cis-addition to the internal alkyne. The aryl group from
the aryl iodide favors the less hindered or more electron-
rich end of the alkyne, while the aryl group from the
arylboronic acid adds to the other end. The proper
combination of substrates, as well as reaction conditions,
is important for the efficiency of the reaction. Although
the reaction generates a fair amount of the biaryl side-
product, it can usually be easily separated by column
chromatography.
(b) General Procedure for the Synthesis of Tetrasub-
stituted Olefins at Room Temperature (Table 6). DMF
(8 mL), H2O (2 mL), K2CO3 (0.75 mmol), ArI (0.75 mmol),
arylboronic acid (0.75 mmol), and the internal alkyne (0.25
mmol) were placed in a 6-dram vial. The contents were stirred
at room temperature for 10 min. PdCl2(PhCN)2 catalyst (0.005
mmol in 0.1 mL of DMF) was injected. The vial was stirred at
room temperature (20-30 °C) for 24 h. The reaction mixture
was then quenched with 30 mL of saturated NaCl solution,
and the aqueous layer was extracted three times with ethyl
ether. The combined organic layers were dried over anhydrous
MgSO4, and the solvent was evaporated under reduced pres-
sure. The product was isolated by chromatography on a silica
gel column.
(c) General Procedure for the Synthesis of Tamoxifen
and Derivatives (Eqs 12 and 13). DMF (8 mL), H2O (4 mL),
K2CO3 (0.75 mmol), ArI (0.75 mmol), arylboronic acid 34 (0.75
mmol), and 1-phenyl-1-butyne (0.25 mmol) were placed in a
6-dram vial. The contents were stirred at room temperature
for 10 min. PdCl2(PhCN)2 catalyst (0.0025 mmol in 0.1 mL of
DMF) was injected. The vial was stirred at 45 °C for 24 h.
The reaction mixture was then quenched with 30 mL of
saturated NaCl solution, and the aqueous layer was extracted
with ethyl ether three times. The combined organic layer was
dried over anhydrous MgSO4, and the solvent was evaporated
under reduced pressure. The product was isolated by chroma-
tography on a silica gel column.
Employing this new approach to tetrasubstituted ole-
fins, we have successfully synthesized tamoxifen and
several derivatives in a very concise, regio- and stereo-
selective manner. We believe this synthetic protocol
should allow the straightforward syntheses of various
tamoxifen derivatives.
Acknowledgment. Partial financial support from
the Petroleum Research Fund administered by the
American Chemical Society is gratefully acknowl-
edged. We also acknowledge Johnson Matthey, Inc.,
and Kawaken Fine Chemicals Co. Ltd. for providing
the palladium compounds and Frontier Scientific Co.
for providing the arylboronic acids. We acknowledge
the technical and creative assistance of Mr. Tanay
Kesharwani, Ms. Guoxin Lu, and Mr. John Maves in
the creation of the cover art.
Experimental Section
(a) General Procedure for the Synthesis of Tetrasub-
stituted Olefins at 100 °C (Tables 2-5). DMF (8 mL), H2O
(2 mL), KHCO3 (0.50 or 0.75 mmol), ArI (0.50 or 0.75 mmol),
arylboronic acid (0.75 mmol), and the internal alkyne (0.25
mmol) were placed in a 6-dram vial. The contents were stirred
and heated in a 100 °C oil bath for 10 min. PdCl2(PhCN)2
catalyst (0.0025 mmol, dissolved in 0.1 mL of DMF) was
injected. The vial was then heated in an oil bath at 100 °C
until palladium black appeared (usually 1-24 h). The reaction
mixture was cooled and quenched with 30 mL of saturated
NaCl solution, and the aqueous layer was extracted three
Supporting Information Available: Experimental de-
tails and product characterization data and 1H and 13C NMR
spectra for compounds 3, 7-12, 19, 21-23, 29-33, 35-37,
38a, and 38b. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO048265+
J. Org. Chem, Vol. 70, No. 10, 2005 3777