Stereoselective Suzuki-Miyaura cross-coupling reactions of potassium alkenyltrifluoroborates with alkenyl bromides

Article abstract of DOI:10.1021/jo050286w

The stereoselective synthesis of conjugated dienes using air-stable potassium alkenyltrifluoroborates as coupling partners is described. The palladium-catalyzed cross-coupling reaction of potassium (E)- and (Z)-alkenyltrifluoroborates with either (E)- or

Full text of DOI:10.1021/jo050286w

Stereoselective Suzuki-Miyaura Cross-Coupling Reactions of
Potassium Alkenyltrifluoroborates with Alkenyl Bromides
Gary A. Molander* and Luciana A. Felix
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104-6323
gmolandr@sas.upenn.edu
Received February 14, 2005
The stereoselective synthesis of conjugated dienes using air-stable potassium alkenyltrifluoroborates
as coupling partners is described. The palladium-catalyzed cross-coupling reaction of potassium
(E)- and (Z)-alkenyltrifluoroborates with either (E)- or (Z)-alkenyl bromides proceeds readily with
moderate to excellent yields to give the corresponding (E,E)-, (E,Z)-, (Z,E)-, or (Z,Z)-conjugated
dienes stereospecifically. The cross-coupling can generally be effected using 5 mol % of Pd(OAc)2,
10 mol % of PPh3, and 3 equiv of Cs2CO3 in THF-H2O (10:1). A variety of functional groups are
tolerated in both coupling partners.
Introduction
selectivity.3 However, in certain situations, operational
difficulties make them unfavorable. Organozinc reagents
must be prepared and utilized in situ and do not lend
themselves to storage for long periods of time. This
limitation renders them less than ideal for combinatorial
procedures wherein scores of diverse air-stable organo-
metallic precursors might be desired.
Among the most common storable organometallics,
much attention has been focused on the use of tin (Stille
coupling)4 and boron derivatives (Suzuki-Miyaura coup-
ling).1b,5 Tin and boron reagents are most frequently used
for diene synthesis because they are reasonably easily
synthesized, they are tolerant of a variety of functional
groups, and they afford high fidelity in the conversion of
stereodefined substrates to products. Organoboron re-
agents in particular offer significant advantages. For
example, alkenylboron compounds are more easily ac-
cessed by a variety of routes (e.g., transmetalation of
alkenylmetals and hydroboration of alkynes by catalyzed
and uncatalyzed procedures). Furthermore, the inorganic
byproducts of the reaction with boron derivatives are
nontoxic and can be readily removed by simple workup
Stereo- and regiodefined conjugated dienes and poly-
enes are of great importance in organic chemistry owing
to their presence in biologically active compounds, as well
as for their application in reactions such as the Diels-
Alder reaction. A number of methods for the preparation
of conjugated dienes and polyenes have been developed
utilizing various organometallic reagents. Among these
procedures, the most efficient and widely employed are
those based on the direct cross-coupling reaction of
alkenylmetals with haloalkenes in the presence of a
catalytic amount of a transition-metal complex.1 Al-
though several 1-alkenylmetal reagents undergo coupling
reactions with haloalkenes, many of these have signifi-
cant limitations when compared to an ideal synthetic
procedure.
Alkenylmagnesium derivatives (Kumada coupling) have
been associated with various undesirable characteristics
including low chemoselectivity and low product yields.2
The use of alkenylzincs as organometallic partners in Pd-
catalyzed alkenyl-alkenyl coupling has proven to be
extremely efficient. The organozinc cross-couplings
(Negishi coupling) proceed with high catalytic reactivity,
high yields, high stereoselectivity, and reasonable chemo-
(3) (a) Negishi, E.; Ay, M.; Gulevich, Yu. V.; Noda, Y. Tetrahedron
Lett. 1993, 34, 1437-1440. (b) Zhu, L.; Wehmeyer, R. M.; Rieke, R. D.
J. Org. Chem. 1991, 56, 1445-1453. (c) Duffault, J.-M.; Einhorn, J.;
Alexakis, A. Tetrahedron Lett. 1991, 32, 3701-3704. (d) Lipshutz, B.
H.; Lindsley, C. J. Am. Chem. Soc. 1997, 119, 4555-4556.
(4) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-
524. (b) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997,
50, 1-652.
(1) Reviews: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-
2483. (b) Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998.
(2) Huo, S.; Negishi, E. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E., de Meijere, A., Eds.; Wiley-
Interscience: New York, 2002; pp 335-409.
(5) Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168.
10.1021/jo050286w CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/13/2005
3950
J. Org. Chem. 2005, 70, 3950-3956

Cross-Coupling Reactions of Potassium Alkenyltrifluoroborates
procedures. By contrast, tin presents several operational
complications. The hydrostannation of alkynes is often
capricious, and the regioselectivity of this reaction is
sometimes difficult to predict.6 Many tin compounds are
toxic, and complete removal of tin-containing byproducts
is a well-recognized problem. The presence of even traces
of organotin compounds in organic products must be
avoided, if possible.
Although organoboron reagents have been extensively
used in alkenyl-alkenyl cross-coupling reactions, there
are some notorious problems with the reagents in current
use. 1-Alkenyldialkylboranes, especially (Z)-1-alkenyl-
boron derivatives, give relatively poor yields of the
coupling products and low stereoselectivity.7 In addition,
these compounds possess a relatively high molecular
weight, and thus, a large amount of waste material is
produced that must be separated from the cross-coupled
products. In general, B-alkenyl-9-BBN’s are very reactive
reagents, giving the cross-coupled products in high yields.
Nevertheless, the scope of coupling reactions is limited
by various characteristics exhibited by the organoborane
including air sensitivity, reactivity toward some sensitive
functional groups, and a lack of atom economy. Further-
more, disposal of cyclooctyl byproducts can present dif-
ficulties in coupling reactions of B-organo-9-BBN deriva-
tives.
TlOH.10 Several other research groups have noted similar
requirements within the context of complex molecule
synthesis.11
In an attempt to resolve some of these shortcomings,
we sought to introduce potassium alkenyltrifluoroborates
as key reagents in the alkenyl-alkenyl coupling. It has
previously been revealed that potassium organotrifluoro-
borates provide solutions to the problems inherent in
other organoboron partners.12 These organotrifluoro-
borates are readily prepared by the addition of inexpen-
sive KHF2 to a variety of organoboron intermediates.13
They are monomeric, crystalline solids that are readily
isolated and indefinitely stable in the air.
Previously, our research group has investigated the
Suzuki-Miyaura cross-coupling reaction of alkenyltrif-
luoroborates with aryl halides and triflates. In the first
of these studies, attention was focused on the use of
potassium vinyltrifluoroborate as a uniquely practical
vinylating agent.14 Vinyldialkylboranes are reasonably
difficult to synthesize and are inflammable. Vinylboronic
acid and even vinylboronate esters are unstable to
polymerization.15 By contrast, the analogous vinyltri-
fluoroborate is readily synthesized and completely stable.
It has been prepared in 200 g quantities and stored for
long periods of time. It couples readily with a wide range
of aryl triflates and halides, thus providing distinct
advantages over its vinylmetallic counterparts.
Boronic acids and boronate esters are the most com-
monly utilized derivatives in Suzuki cross-coupling reac-
tions. By using 1-alkenylboronic acids and esters, high
yields and excellent stereoselectivity can be achieved in
the synthesis of dienes. Despite their efficiency and
widespread use in alkenyl-alkenyl coupling, they present
considerable problems. In particular, the boronic acids
are subject to cyclic trimerization with loss of water to
form boroxines. For this reason, the quantitative analysis
of these species and the determination of precise stoi-
chiometry can be difficult. Boronate esters are often
prepared as a means to purify the organoboron species,
but some of these esters are hydrolytically unstable and
difficult to deal with upon completion of the reaction.8
Moreover, the diols utilized to create the boronic esters
(e.g., catechol or pinacol) add considerable expense to the
overall process and, additionally, must be separated from
the desired product after the coupling process. Usually
the use of toxic thallium bases such as TlOH, TlOEt, or
Tl2CO3 are required in the coupling reactions of boronic
acids and esters to increase their reactivity.9 As demon-
strated by Kishi during the course of his palytoxin
synthesis, a significant rate enhancement in cross-
coupling was achieved by using an aqueous solution of
Subsequently, a full study of the scope of cross-coupling
of a variety of alkenyltrifluoroborates with functionalized
aryl halides and triflates and with heteroaryl halides was
undertaken.16 In that study, the coupling of alkenyltri-
fluoroborates was determined to take place efficiently
using PdCl2(dppf)‚CH2Cl2 as a catalyst in i-PrOH/H2O,
using t-BuNH2 or Et3N as a base (eq 1).
The alkenyltrifluoroborate cross-coupling reactions
work well with both electron-rich and electron-poor aryl
halides. Importantly, the reactions were determined to
be stereospecific with regard to the organoboron partner.
(10) Uenishi, J.; Beau, J. M.; Armstrong, R. W.; Kishi, Y. J. Am.
Chem. Soc. 1987, 109, 4756-4758.
(11) (a) Hoshino, Y.; Miyaura, N.; Suzuki, A. Bull. Chem. Soc. Jpn.
1988, 61, 3008-3010. (b) Sato, M.; Miyaura, N.; Suzuki, A. Chem. Lett.
1989, 1405-1408. (c) Torrado, A.; Iglesias, B.; Lopez, S.; de Lera, A.
A. Tetrahedron 1995, 51, 2435-2454. (d) Mergott, D. J.; Frank, S. A.;
Roush, W. R. Org. Lett. 2002, 4, 3157-3160.
(12) (a) Molander, G. A.; Ito, T. Org. Lett. 2001, 3, 393-396. (b)
Molander, G. A.; Biolatto, B. Org. Lett. 2002, 4, 1867-1870. (c)
Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302-4314. (d)
Molander, G. A.; Katona, B. W.; Machrouhi, F. J. Org. Chem. 2002,
67, 8416-8423. (e) Molander, G. A.; Yun, C.; Ribagorda, M.; Biolatto,
B. J. Org. Chem. 2003, 68, 5534-5539. (d) Molander, G. A.; Ribagorda,
M. J. Am. Chem. Soc. 2003, 125, 11148-11149.
(13) (a) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf,
M. R. J. Org. Chem. 1995, 60, 3020-3027. (b) Vedejs, E.; Fields, S. C.;
Hayashi, R.; Hitchcock, S. R.; Powell, D. R.; Schrimpf, M. R. J. Am.
Chem. Soc. 1999, 121, 2460-2470.
(14) Molander, G. A.; Rodriguez-Rivero, M. Org. Lett. 2002, 4, 107-
109.
(6) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524.
(7) Miyaura, N.; Sugimore, H.; Suzuki, A. Tetrahedron Lett. 1981,
22, 127-130.
(8) Lightfoot, A. P.; Maw, G.; Thirsk, C.; Steve, Twiddle, S. J. R.;
Whiting, A. Tetrahedron Lett. 2003, 44, 7645-7648.
(9) (a) Armstrong, R. W.; Beau, J. M.; Cheon, S. H.; Christ, W. J.;
Fujioka, H.; Ham, W.; Hawkins, L. D.; Jin, H.; Kang, S. H.; Kishi, Y.;
Martinelli, M. J.; McWhorter, W. W.; Mizuno, M.; Nakata, M.; Stutz,
A. E.; Talamas, F. X.; Taniguchi, M.; Tino, J. A.; Ueda, K.; Uenishi,
J.; White, J. B.; Yonaga, M. J. Am. Chem. Soc. 1989, 111, 7525-7530.
(b) Kobayashi, S.; Mori, K.; Wakabayashi, T.; Yasuda, S.; Hanada, K.
J. Org. Chem. 2001, 66, 5580-5584. (c) Scheidt, K. A.; Bannister, T.
D.; Tasaka, A.; Wendt, M. D.; Savall, B. M.; Fegley, G. J.; Roush, W.
R. J. Am. Chem. Soc. 2002, 124, 6981-6990. (d) Pazos, Y.; Iglesias,
B.; de Lera, A. R. J. Org. Chem. 2001, 66, 8483-8489.
(15) Matteson, D. S. J. Am. Chem. Soc. 1960, 82, 4228-4233.
(16) Molander, G. A.; Bernardi, C. R. J. Org. Chem. 2002, 67, 8424-
8429.
J. Org. Chem, Vol. 70, No. 10, 2005 3951

Molander and Felix
TABLE 1. Study of the Optimal Conditions for the Cross-Coupling Reaction of Potassium Alkenyltrifluoroborates with
Alkenyl Bromides
entry
catalyst/ligand (9 mol %)
solvent
base (3 equiv)
% yield (ds)a
1
2
Pd(PPh3)4
THF/H2O (10:1)
THF/H2O (10:1)
THF/H2O (10:1)
THF/H2O (10:1)
THF/H2O (10:1)
THF/H2O (10:1)
THF/H2O (10:1)
i-PrOH/H2O (10:1)
MeOH/H2O (10:1)
EtOH/H2O (10:1)
THF/EtOH (1:1)
n-PrOH/H2O (10:1)
DME/H2O (10:1)
THF/H2O (10:1)
THF/H2O (10:1)
THF/H2O (10:1)
i-PrOH/H2O (3:1)
n-PrOH/H2O (3:1)
Cs2CO3
Cs2CO3
K2CO3
K3PO4
81 (>99)
87 (>99)
67 (98)
57 (92)
46 (83)
80 (90)
57 (98)
76 (95)
54 (88)
46 (86)
73 (93.5)
65 (93)
36 (80)
77 (>99)
56 (88)
33 (95)
55 (95)
53 (93)
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
Pd(OAc)2/2PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/dppf
3
4
5
Et3N
6
t-BuNH2
Na2CO3
t-BuNH2
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
t-BuNH2
Et3N
7
8
9
10
11
12
13
14
15
16
17
18
Pd(OAc)2/2PCy3
PdCl2(dppf)‚CH2Cl2
PdCl2(dppf)‚CH2Cl2
a The ds is the predominance of the Z,E diastereomer over the E,E isomer in the crude reaction mixture.
Having established the efficiency and advantages of
alkenyltrifluoroborates in coupling with aryl and het-
eroaryl electrophiles, we sought to extend their utility.
Herein, we report the application of alkenyltrifluoro-
borates toward the stereospecific synthesis of conjugated
dienes, highlighting the advantages in the utilization of
this system for the construction of this synthetically
important functionality.
product in high yield and stereoselectivity. We studied
the reaction of Pd(OAc)2 with different ligands. The use
of a simple ligand such as PPh3 in a 1:2 ratio with respect
to the catalyst (entry 2) proved to be very efficient,
generating the product in even higher yield than that
observed when Pd(PPh3)4 was used as catalyst. Retention
of stereochemistry was also observed, as the reaction
transpired with >99% stereochemical fidelity. When we
used PPh3 in a 1:1 ratio we observed an inferior yield
compared to that achieved when PPh3 was used in a 1:2
ratio. The use of dppf and PCy3 as ligands (entries 15
and 16) afforded the product in low yield and with
isomerization.
To reduce the cost of the reaction, we turned our
attention to the study of bases other than Cs2CO3.
Reactions were carried out in the presence of Pd(OAc)2/
2PPh3 and THF/H2O (10:1), the most efficient catalyst
and solvent, while varying the base. The use of NEt3
(entry 5) afforded a low yield of product with isomeriza-
tion, while t-BuNH2 (entry 6) led to a high yield of the
cross-coupling product, but unfortunately, the product
was obtained with low isomeric purity (90%). Inorganic
bases such as K3PO4 (entry 4) and Na2CO3 (entry 7) led
to similar yields (55-57%) with isomerization, and K2-
CO3 afforded the product in moderate yield (67%) and
high isomeric purity (98%). Subsequently, we attempted
to improve the yield of this reaction by performing
experiments with different solvents such as MeOH,
EtOH, n-PrOH, or DME (entries 9, 10, 12, and 13). In
the end, these solvents were largely ineffective.
Results and Discussion
We initially focused our attention on the determination
of the optimal conditions for the Suzuki-Miyaura cross-
coupling reaction of alkenyltrifluoroborates and alkenyl
halides. Toward this end, we used a variety of catalysts,
ligands, bases, and solvents. The reaction conditions were
explored using stereodefined reagents to study the ster-
eochemistry of the diene formed. Potassium trans-1-dec-
1-enyltrifluoroborate and 6-chloro-cis-1-hex-1-enyl bro-
mide were used as the coupling partners. The reactions
were carried out in a reactor block, using 0.2 mmol of
cis-6-chloro-1-hex-1-enyl bromide and 0.22 mmol of po-
tassium trans-1-dec-1-enyltrifluoroborate in the presence
of 9 mol % of catalyst/ligand, 3 equiv of base, and 2 mL
of solvent heating at reflux overnight under a blanket of
nitrogen (Table 1). The reactions were analyzed by
quantitative gas chromatography using the internal
standard method (undecane used as standard).
Surprisingly, the reactions carried out in the presence
of PdCl2(dppf)‚CH2Cl2 using alcohols as solvents and
amines as bases (entries 16 and 17) led to only moderate
yields and low stereoselectivity, even though these condi-
tions had previously been used successfully for the
coupling of potassium alkenyltrifluoroborates with aryl
halides and triflates.
The best conditions [Pd(OAc)2/2PPh3, Cs2CO3 in THF-
H2O (10:1)] were subsequently employed to study the
catalyst loading (Table 2) and the base loading (Table
3).
Through an empirical search for optimal reaction
conditions, we determined that THF-H2O (10:1), Pd-
(PPh3)4, and Cs2CO3 (entry 1) provided the coupling
The results of these studies indicated that the use of 9
and 5 mol % of Pd(OAc)2/2PPh3 proved to be comparably
effective (Table 2, entries 1 and 2). However, when the
3952 J. Org. Chem., Vol. 70, No. 10, 2005

Cross-Coupling Reactions of Potassium Alkenyltrifluoroborates
SCHEME 1a
TABLE 2. Study of the Catalyst Loading
entry
mol % cat.
time (h)
% yield (GC)
1
2
3
9
5
2
12
12
18
87
85
55
TABLE 3. Study of the Base Loading
a Conditions: 5 mol % of Pd(OAc)2/2PPh3, 3 equiv of Cs2CO3,
THF-H2O (10:1).
both also with high isomeric purities (>99%). These
results demonstrate that this method is stereospecific
with regard to both coupling partners.
entry
base equiv
time (h)
% yield (GC)
To test the scope of this procedure, we examined the
cross-coupling reaction of 1b with a variety of alkenyl
bromides bearing different functionalities and with dif-
ferent substitution patterns (Table 4). In general, all of
the reactions proceeded smoothly with moderate to
excellent yields. Most importantly, the coupling turned
out to be general with respect to a diverse array of
functionality. The reaction showed compatibility with
alcohol, ketone, aldehyde, ester, cyano, and amine groups
despite the aqueous basic conditions.
Tri- and tetrasubstituted alkenyl halide substrates
(entries 1 and 2) reacted with 1b to provide the coupling
products in good yields, showing that the method is not
susceptible to steric hindrance. An alkenyl bromide
bearing a free hydroxyl group (entry 3) led to the desired
product in satisfactory yield (79%). Methods of introduc-
ing an E- or Z-alkenyl group R to aldehydes and ketones
with strict control of regiochemistry are highly desirable.
We have shown that R-bromo R,â-unsaturated carbonyl
derivatives react with alkenyltrifluoroborates under pal-
ladium catalysis to afford the R-alkenyl-substituted
product stereoselectively in excellent yield (entries 4 and
5). Despite the long reaction time (8 h), the reaction with
R-bromoenone (entry 4) turned out to be among the
highest yielding compared with the other substrates. The
sluggishness of this reaction might have been anticipated
on the basis of the low intrinsic reactivity of R-haloenones
in Pd-catalyzed cross-coupling, but the high yield was a
pleasant surprise in view of the general instability of such
electrophiles. In an earlier study, the low reactivity was
also observed when organozinc and organotin compounds
were used.17 Because of that low reactivity, the acetal-
protected R-bromoenones were employed as key inter-
mediates to improve the cross-coupling results.18
1
2
3
3
2
1
12
15
15
87
70
40
loading was dropped to 2 mol % the yield noticeably
decreased, thus revealing the minimum amount of cata-
lyst needed for the reaction carried out on small scale.
A reduction in the amount of base to 2 equiv decreased
the yield, and when only 1 equiv of base was used the
yield was lowered substantially. These results demon-
strated that 3 equiv of base was optimal (Table 3).
After verifying that the reactions needed to be per-
formed under an inert atmosphere, the optimized condi-
tions were subsequently applied to the synthesis of
several conjugated dienes.
The stereochemistry associated with alkenyl-alkenyl
coupling is distinctly more complicated than, for example,
alkenyl-aryl coupling, because four possible stereoiso-
mers, that is, E,E-, E,Z-, Z,E-, and Z,Z-conjugated dienes,
are possible for any given alkenyl-alkenyl coupling, and
all due attention must be paid to this potentially complex
stereochemical aspect. Cognizant of this, we examined
the stereochemistry of this new Suzuki protocol. Thus,
we reacted potassium (E)- and (Z)-4-phenyl-1-but-1-enyl
trifluoroborate with (E)- and (Z)-1-bromo-5-chloropent-
1-ene to conduct a comprehensive study of the stereo-
selectivity of this method for diene synthesis. The use-
fulness of the present method was demonstrated by the
stereospecific synthesis (>99%) of the four geometrical
isomers of 9-chloronona-3,5-dienylbenzene (Scheme 1).
9-Chloronona-(3E,5E)-dienylbenzene and 9-chloronona-
(3Z,5E)-dienylbenzene were synthesized by reacting po-
tassium (E)-4-phenyl-1-but-1-enyl trifluoroborate with
(E)- and (Z)-1-bromo-5-chloropent-1-ene. The products
were generated in yields of 86 and 88%, respectively, both
with high isomeric purities (>99%). Potassium (Z)-4-
phenyl-1-but-1-enyltrifluoroborate was reacted with (E)-
and (Z)-1-bromo-5-chloropent-1-ene to give the (3E,5Z)-
and (3Z,5Z)-isomers in 85 and 86% yields, respectively,
(17) (a) Negishi, E.; Owczarczyk, Z.; Swanson, D. R. Tetrahedron
Lett. 1991, 32, 4453-4456. (b) Lee, J.; Snyder, J. K. J. Org. Chem.
1990, 55, 4995-5008. (c) Malleron, J. L.; Bacque´, E.; Desmazeau, P.;
M’Houmadi, C.; Paris, J. M.; Peyronel, J. F. Synth. Commun. 1995,
25, 2355-2371.
(18) Negishi, E.; Akiyoshi, K. Chem. Lett. 1987, 1007-1010.
J. Org. Chem, Vol. 70, No. 10, 2005 3953

Molander and Felix
TABLE 4. Cross-Coupling of Potassium
(E)-4-Phenyl-1-buten-1-enyltrifluoroborate 1b with
Alkenyl Bromides
TABLE 5. Cross-Coupling of Potassium
(E)-4-Phenyl-1-buten-1-enyltrifluoroborate 1b with
Alkenyl Bromides Containing Different Silyl Ethers
entry
SiR3
TIPS
TBDMS
TES
product
% isolated yield
1
2
3
2n
2o
2p
85
80
80
intact using our optimal conditions (entry 6). The reaction
of methyl dibromo maleic ester with 2 equiv of 1b in the
presence of 10 mol % of Pd(OAc)2/2PPh3 and 6 equiv of
Cs2CO3 led to a mixture of monosubstituted product with
protodehalogenation of the second bromide, along with
the disubstituted product. When PdCl2dppf‚CH2Cl2 was
used as catalyst, the disubstituted product was observed
as the only product (entry 6).
The diene moiety is present in numerous naturally
occurring compounds that exhibit biological activity.
Thus, alkenyl-alkenyl cross-coupling reactions are widely
used in the synthesis of natural products that contain
the conjugated diene moiety. Most of these compounds
incorporate alcohol functionalities within their skeleta
that need to be protected during the course of the
synthesis. Based on this reality, we examined the cross-
coupling reactions of alkenyl halides bearing silyl ether
protected alcohols to verify their compatibility with our
method. An examination of this topic was particulary
important because the trifluoroborates present an obvi-
ous source of fluoride, often used to deprotect silylated
alcohols. In this particular study, we explored the cross-
coupling reactions of alkenyl bromides bearing the most
commonly used silyl ethers: TES, TBDMS, and TIPS
(Table 5).
As observed in previous studies of organotrifluorobo-
rate cross-coupling reactions,11d,20 the silyl ether groups
survived the reaction conditions, even though a fluoride
counterion and base is present during the course of the
reaction. In all cases, the silyl groups were retained and
the products were acquired in excellent yields (80-85%).
As discussed previously, the stability of the silyl ether
groups for these reactions might be ascribed to the use
of a heterogeneous system.
Continuing with our investigation, we applied the
palladium-catalyzed cross-coupling reaction under the
conditions established for the alkenyl bromides to dif-
ferent potassium alkenyltrifluoroborate partners as out-
lined in Table 6.
a PdCl2dppf‚CH2Cl2 was used as the catalyst.
We used more highly substituted alkenyltrifluoro-
borates and also alkenyltrifluoroborates incorporating
functionality to establish the generality of this method.
Alkenyltrifluoroborates were easily synthesized by the
addition of KHF2 to the corresponding boronic acid or
boronate ester. The organotrifluoroborates 1a, 1e, and
One of the difficulties typically encountered during
cross-coupling reactions under basic conditions is the
saponification of esters. This difficulty can be overcome
by the use of heterogeneous bases in the cross-coupling
reactions.19 Thus, we observed that ester groups remain
(19) Kawanaka, Y.; Ono, N.; Yoshida, Y.; Okamoto, S.; Sato, F. J.
Chem. Soc., Perkin Trans. 1 1996, 715-718.
(20) Molander, G. A.; Dehmel, F. J. Am. Chem. Soc. 2004, 126,
10313-10318.
3954 J. Org. Chem., Vol. 70, No. 10, 2005

Cross-Coupling Reactions of Potassium Alkenyltrifluoroborates
TABLE 6. Cross-Coupling of Alkenyl Bromides with Different Potassium Alkenyltrifluoroborates
1h were obtained by hydroboration of the corresponding
alkyne with dibromoborane,21 followed by reaction with
KHF2 in Et2O/H2O. Vinyl trifluoroborate 1d was prepared
by transmetalation of commercially available vinylmag-
nesium bromide with trimethylborate followed by in situ
addition of aqueous KHF2. R- and â-styryl trifluorobo-
rates (1f and 1g) were synthesized from the commercially
available boronic acids by direct treatment with KHF2
in Et2O/H2O. (Z)-4-Phenyl-1-but-1-enyltrifluoroborate (1c)
was prepared by rhodium-catalyzed trans-hydroboration
of the corresponding alkyne with catecholborane to afford
the (Z)-1-alkenylboronate ester.22 Subsequent addition of
(21) Brown, H. C.; Bhat, N. G.; Somayaji, V. Organometallics 1983,
2, 1311-1316.
(22) Ohmura, T.; Yamamoto, Y.; Miyaura, N. J. Am. Chem. Soc.
2000, 122, 4990-4991.
J. Org. Chem, Vol. 70, No. 10, 2005 3955

Molander and Felix
KHF2 to an MeCN/H2O solution of the boronate ester
afforded the alkenyltrifluoroborate. Regioselective hydro-
boration of the corresponding alkynes with pinacolborane
catalyzed by HZrCp2Cl afforded the alkenylboronate
esters that were reacted with KHF2 in MeCN/H2O to
generate the organotrifluoroborates 1j and 1k.23
lation and both catalyzed and noncatalyzed hydrobora-
tion. The ease of isolation, purification, storage, and
handling makes them attractive intermediates for labo-
ratory and industrial use and especially for combinatorial
chemistry. A variety of functionalized alkenyltrifluorobo-
rates can be synthesized and stored for long periods of
time. The ready availability of stereodefined (E)- and (Z)-
alkenyltrifluoroborates and the high stereoselectivity
observed in the cross-coupling reactions make this method
a very efficient route to synthesize virtually all classes
of isomerically pure conjugated dienes. Moreover, a
variety of sensitive functional groups are tolerated in both
partners. Silyl protecting groups for alcohols can be used,
even though a fluoride source is present. Another impor-
tant advantage is that the use of toxic thallium bases is
not required. As a consequence, this procedure can be
used successfully in complex molecule synthesis.19
With the alkenyltrifluoroborates in hand, we began the
study of the cross-coupling reactions. In most cases, the
coupling reactions were carried out using 3-bromo-3-
buten-1-ol, R-bromocinnamaldehyde, or 2-bromo-3-meth-
yl-2-cyclopenten-1-one. These processes all proceeded
with good yields. Once again, the reaction was tolerant
of a variety of functional groups, establishing that both
partners can contain functionality. Vinyltrifluoroborate
reacted with R-bromocinnamaldehyde to give the product
in good yield (entry 1). The influence of an R-substituent
on the organoboron partner was investigated (entries 3
and 4). Potassium R- and â-styryltrifluoroborates were
converted to the product in satisfactory yield. However,
the reaction of an R-substituted organoboron partner was
slower and the yield was lower than that of the â-sub-
stituted organoboron partner. Alkenyltrifluoroborates
with halide and cyano substituents within the organic
moiety were evaluated (entries 6 and 9). The cross-
coupling proceeded with good yields (72 and 80%, respec-
tively).
The reaction of an alkenyltrifluoroborate bearing an
ester group gave the coupled product in good yield (entry
7). This result differs from that obtained when the same
alkenyltrifluoroborate 1i was used for the alkenyl-aryl
coupling under PdCl2(dppf)CH2Cl2, i-PrOH-H2O, and
t-BuNH2 conditions. In that case, the coupled product was
obtained in low yield (33%) because of competitive ester
hydrolysis. The prolonged reaction time and use of basic
conditions in a homogeneous system contributed to the
hydrolysis of the ester. In the present case, the shorter
reaction time and the use of a heterogeneous system
appears to prevent ester hydrolysis. Trimethylsilyleth-
enyl trifluoroborate was used as coupling partner giving
the product in 82% yield (entry 8). The TMS group
survived during the coupling, even though again a
fluoride source was present.
Experimental Section
General Procedure for Suzuki-Miyaura Cross-Cou-
pling Reactions. Preparation of 1-Chloropentadeca-4,6-
diene (2a). To a mixture of potassium (E)-1-dec-1-enyltrifluoro-
borate (2a) (370.4 mg, 1.1 mmol), (Z)-1-bromo-5-chloropent-
1-ene (183.5 mg, 1 mmol), Cs2CO3 (977 mg, 3 mmol), Pd(OAc)2
(11 mg, 0.05 mmol), and PPh3 (26 mg, 0.1 mmol) was added
THF-H2O (10:1, 4 mL). The reaction was heated at 70 °C with
stirring under a nitrogen atmosphere for 2 h, cooled to rt, and
diluted with water (3 mL). The resulting mixture was ex-
tracted with Et2O. The organic layers were combined and
washed with 1 N HCl and brine, dried over MgSO4, and then
filtered. The solvent was removed under vacuum, and the
crude product was purified by silica gel chromatography
(eluting with hexane) to afford a colorless oil (200 mg, 85%):
1H NMR (500 MHz, CDCl3) δ 6.30 (ddt, J ) 15, 10.9, 1.2 Hz,
1H), 6.01 (dd, J ) 10.9, 10.7 Hz, 1H), 5.69 (dt, J ) 15, 6.9 Hz,
1H), 5.24 (dt, J ) 10.7, 7.7 Hz, 1H), 3.54 (t, J ) 6.6 Hz, 2H),
2.32 (q, J ) 7.7 Hz, 2H), 2.10 (q, J ) 7.0 Hz, 2H), 1.86 (dt, J
) 14.2, 6.7 Hz, 2H), 1.39 (dt, J ) 14.2, 7.2 Hz, 2H), 1.30-1.27
(m, 10H), 0.88 (t, J ) 7.0 Hz, 3H); 13C NMR (125.8 MHz,
CDCl3) δ 135.7, 130.2, 127.2, 125.2, 44.4, 32.9, 32.5, 31.9, 29.5,
29.3, 29.3, 29.2, 24.8, 22.7, 14.1; HRMS (CI) m/z calcd. for
C15H27Cl (M+) 242.1800, found 242.1805; IR (neat) 2927, 2856,
1709 cm-1
.
Acknowledgment. We gratefully acknowledge the
National Institutes of Health (GM35249) for funding.
Additionally, we thank Merck Research Laboratories,
Amgen, Johnson & Johnson, and Johnson Matthey for
additional support of this research. We also thank Dr.
Rakesh Kohli for the HRMS data.
Conclusion
In summary, the palladium-catalyzed cross-coupling
reaction of potassium alkenyltrifluoroborates with alk-
enyl bromides has been achieved chemo- and stereo-
selectively with moderate to excellent yields. This pro-
cedure possesses several advantages when compared
with other methods. The alkenyltrifluoroborates can be
prepared easily by different routes, including transmeta-
Supporting Information Available: Full experimental
details and copies of all NMR spectra (1H, 13C, 19F, and 11B).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(23) Pereira, S.; Srebnick, M. Organometallics 1995, 14, 3127-3128.
JO050286W
3956 J. Org. Chem., Vol. 70, No. 10, 2005