One-pot synthesis of trisubstituted conjugated dienes via sequential Suzuki - Miyaura cross-coupling with alkenyl- and alkyltrifluoroborates

Article abstract of DOI:10.1021/jo052636k

The sequential, stereoselective disubstitution of 1,1-dibromoalkenes using a variety of alkenyltrifluoroborates followed by alkyltrifluoroborates in the presence of Pd(PPh₃)₄ is described. This synthetic method proceeds smoothly in o

Full text of DOI:10.1021/jo052636k

One-Pot Synthesis of Trisubstituted Conjugated Dienes via
Sequential Suzuki-Miyaura Cross-Coupling with Alkenyl- and
Alkyltrifluoroborates
,
†
†,‡
Gary A. Molander* and Yasuo Yokoyama
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104-6323, and Department of Chemistry, Faculty of Science and
Technology, Sophia UniVersity, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan
gmolandr@sas.upenn.edu; yasuo-y@sophia.ac.jp
ReceiVed December 22, 2005
The sequential, stereoselective disubstitution of 1,1-dibromoalkenes using a variety of alkenyltrifluo-
roborates followed by alkyltrifluoroborates in the presence of Pd(PPh ) is described. This synthetic method
3 4
proceeds smoothly in one pot under mild reaction conditions to provide the corresponding trisubstituted,
conjugated dienes in excellent yield. Moreover, the method is operationally very simple because the
organotrifluoroborates are stable in air, and the byproducts are innocuous inorganic salts.
Introduction
(e.g., Wittig and related approaches, as well as hydrometalation
and carbometalation procedures) have been elegantly pointed
out by Negishi et al.
The regio- and stereoselective synthesis of trisubstituted
alkenes remains one of the more troublesome problems in
organic synthesis. Although this structural unit appears in a
variety of natural products and advanced materials, general,
stereoselective approaches to compounds of this class remain
elusive.
Depending on the array of functionality and types of organic
groups desired to be proximal to the alkene, a number of diverse
approaches to trisubstituted alkenes can be chosen. The scope
2
One very attractive approach to stereodefined trisubstituted
alkenes is the stepwise double substitution of readily available
3
1
,1-dihaloalkenes by organometallic reagents in the presence
of a transition-metal catalyst. Prominent among such approaches
are Tamao, Stille, Negishi, and Suzuki-Miyaura couplings.
Among the earliest examples of this reactivity pattern, in 1987,
Minato and Tamao revealed that organomagnesiums and orga-
nozincs could be partnered with 1,1-dichloroalkenes to afford
several trisubstituted alkenes via two-pot diarylation and di-
1
and limitations of many of the most popular and useful protocols
4
alkylation sequences. In 1999, Shen and Wang applied the Stille
5
6
†
coupling to the disubstitution of 1,1-dibromo-1-alkenes. In this
case, trisubstituted alkenes could be synthesized through ste-
reoselective arylation/alkenylation, arylation/alkylation, and
University of Pennsylvania.
Sophia University.
‡
(1) (a) Itami, K.; Mineno, M.; Muraoka, N.; Yoshida, J. J. Am. Chem.
Soc. 2004, 126, 11778-11779. (b) Itami, K.; Tonogaki, K.; Ohashi Y.;
Yoshida, J. Org. Lett. 2004, 6, 4093-4096. (c) Tonogaki, K.; Soga, K.;
Itami, K.; Yoshida, J. Synlett 2005, 1802-1904. (d) Chen, Y. K.; Walsh,
P. J. J. Am. Chem. Soc. 2004, 126, 3702-3703. (e) Li, H.; Walsh, P. J. J.
Am. Chem. Soc. 2005, 127, 8355-8361. (f) Xu, C.; Negishi, E. Tetrahedron
Lett. 1999, 40, 431-434. (g) Roush, W. R.; Koyama, K. Curtin, M. L.;
Moriarty, K. J. J. Am. Chem. Soc. 1996, 118, 7502-7512. (h) Satoh, M.;
Miyaura, N.; Suzuki, A. Chem. Lett. 1986, 1329-1332. (i) Brown, H. C.;
Bhat, N. G. J. Org. Chem. 1988, 53, 6009-6013. (j) Martin, S. F.; Daniel,
D.; Cherney, R. J.; Liras, S. J. Org. Chem. 1992, 57, 2523-2525. (k)
Denmark, S. E.; Amburgey, J. J. Am. Chem. Soc. 1993, 115, 10386-10387.
(2) Zeng, X.; Qian, M.; Hu, Q.; Negishi, E. Angew. Chem., Int. Ed. 2004,
43, 2259-2263.
(3) (a) Ramirez, F.; Desai, N. B.; McKelvie, N. J. Am. Chem. Soc. 1962,
84, 1745-1747. (b) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972,
3769-3772. (c) Fisher, R. P.; On, H. P.; Snow, J. T.; Zweifel, G. Synthesis
1982, 127-129.
(4) Minato, A.; Suzuki, K. J. Am. Chem. Soc. 1987, 109, 1257-1258.
(5) Some reviews: (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew.
Chem., Int. Ed. 2005, 44, 4442-4489. (b) Li, C.-J. Chem. ReV. 2005, 105,
3095-3165. (c) Echavarren, A. M. Angew. Chem., Int. Ed. 2005, 44, 3962-
3965.
(
l) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751-1753. (m)
Trost, B. M.; Shen, H. C.; Pinkerton, A. B. Chem. Eur. J. 2002, 8, 2341-
349.
2
(6) Shen, W.; Wang, L.J. Org. Chem. 1999, 64, 8873-8879.
1
0.1021/jo052636k CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/15/2006
J. Org. Chem. 2006, 71, 2493-2498
2493

Molander and Yokoyama
alkenylation/arylation sequences in moderate to good yields in
two-pot processes. Additionally, access to several trisubstituted
alkenes via one-pot alkylation and arylation protocols was
reported.
Most recently, Negishi and co-workers reported that pal-
ladium complexes, such as Cl2Pd(DPEphos) or Pd(PPh3)4,
successfully catalyzed various disubstitutions of 1,1-dihaloal-
kenes. Stereoselective arylation/alkylation and alkynylation/
alkylation sequences were accomplished with organozincs in
the presence of the foregoing catalysts, and the desired com-
In fact, Kabalka has recently described the synthesis of
trisubsituted, conjugated enediynes via palladium-catalyzed
cross-coupling of 2 equiv of alkynyltrifluoroborates with 1,1-
12
dibromoalkenes (eq 2). Thus, it seemed likely that other
organotrifluoroborates could be coupled sequentially to 1,1-
dibromides, providing access to trisubstituted alkenes. As a
starting point for these studies, the serial coupling of alkenyl-
trifluoroborates followed by alkyltrifluoroborates was explored
7
pounds were obtained in good to excellent yield. This group
also reported that stereoinverted alkylations may occur in the
2
second step when utilizing certain dihalogenated compounds.
(eq 3).
Soderquist and co-workers investigated the double-intermo-
lecular Suzuki-Miyaura cross-coupling reaction (methylation/
methylation) of 1,1-dibromo-1-alkenes8 and also applied a
9
related protocol to the formation of various cyclic compounds.
In the latter scenario, R,ω-diborylalkanes synthesized from the
corresponding diene and 9-BBN reacted with 1,1-dibromoal-
kenes to give the desired compounds.
Most of these synthetic methods were very effective for the
synthesis of the desired trisubstituted alkenes, but some
substrates were transformed to the desired compound in low
yield in a two-pot procedure wherein the intermediate alkenyl
halide was isolated. Furthermore, the organozinc and some of
the organoboron compounds used in such transformations are
impossible to store in the air and are sometimes difficult to
synthesize. The organostannanes used in Stille coupling reactions
generally suffer from toxicity and environmental concerns, as
well as purity issues of the final product associated with tin-
containing byproducts. Thus, the development of more effective,
convenient, and environmentally sound reagents for a sequential
coupling process was strongly desired.
Herein, the successful results of these studies are reported,
wherein a stereoselective, one-pot process has been developed
utilizing Pd(PPh3)4 as a catalyst. The protocol developed is
operationally simple and easy to carry out, and moreover, the
target compounds are obtained stereoselectively in excellent
yield under mild reaction conditions.
Results and Discussion
The application of air-stable, storable potassium organotri-
fluoroborates in one-pot cross-coupling reactions with 1,1-
dibromoalkenes was recognized as one potential solution to
some of the drawbacks associated with other procedures. The
advantages of this protocol would be derived in part from the
unique nature of the coupling reagents. Organotrifluoroborates
are inherently more stable to air and moisture than the
To begin, 1,1-dibromo-2-cyclohexylethene (1), potassium (E)-
-hex-5-enoic acid trifluoroborate, methyl ester (2), and potas-
1
sium 2-phenylethyl trifluoroborate (3) were chosen as model
substrates. Conditions for the one-pot synthesis of the trisub-
stituted diene derivative using Suzuki-Miyaura cross-coupling
were sought, and the process was optimized. Pertinent results
from these studies are summarized in Table 1.
The geminal dibromide 1 reacted with 1.1 equiv of 2 in the
3 4 2 3
presence of 7 mol % of Pd(PPh ) and 3 equiv of Cs CO at 80
C for 1.25 h. Subsequently, alkyl trifluoroborate 3 (1.1 equiv)
and an aqueous solution of Cs2CO3 (3.0 equiv) were added to
afford the target compound 4 with complete stereoselectivity
in 85% yield (entry 1). No other catalysts were explored
extensively, and on the scale the reactions performed, 7 mol %
catalyst loading proved optimum. This protocol was high-
yielding, but an undesired byproduct was formed that originated
corresponding organozincs, organomagnesiums, and organobo-
ron reagents.10 Various organotrifluoroborates can be synthe-
10
sized easily and at low cost, and many organotrifluoroborates
are now commercially available. Finally, the waste materials
of these reactions are nontoxic inorganic salts, which can be
easily removed from the reaction system.
°
In previous investigations, the scope of cross-coupling
reactions of various organotrifluoroborates with functionalized
11
alkenyl halides has been studied. In these explorations,
palladium complexes promoted the smooth Suzuki-Miyaura
cross-coupling reaction of organotrifluoroborates, and the cor-
responding compounds were obtained stereoselectively in good
to excellent yields (eq 1).
(11) (a) Molander, G. A.; Petrillo, D. E.; Landzberg, N. R.; Rohanna, J.
C.; Biolatto, B. Synlett 2005, 1763-1766. (b) Molander, G. A.; Felix, L.
A. J. Org. Chem. 2005, 70, 3950-3956. (c) Molander, G. A.; Dehmel, F.
J. Am. Chem. Soc. 2004, 126, 10313-10318. (d) Molander, G. A.;
Ribagorda, M. J. Am. Chem. Soc. 2003, 125, 11148-11149. (e) Molander,
G. A.; Yun, C.-S.; Ribagorda, M.; Biolatto, B. J. Org. Chem. 2003, 68,
5534-5539. (f) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68,
4302-4314. (g) Molander, G. A.; Bernardi, C. R. J. Org. Chem. 2002, 67,
8424-8429. (h) Molander, G. A.; Katona, B. W.; Machrouhi, F. J. Org.
Chem. 2002, 67, 8416-8423. (i) Molander, G. A.; Biolatto, B. Org. Lett.
2002, 4, 1867-1870. (j) Molander, G. A.; Rivero, M. R. Org. Lett. 2002,
4, 107-109. (k) Molander, G. A.; Ito, T. Org. Lett. 2001, 3, 393-396.
(12) Kabalka, G. W.; Dong, G.; Venkataiah, B. Tetrahedron Lett. 2005,
46, 763-765.
(
7) (a) Shi, J.-C.; Zeng, X.; Negishi, E. Org. Lett. 2003, 5, 1825-1828.
b) Shi, J.-C.; Negishi, E. J. Organomet. Chem. 2003, 687, 518-524. (c)
Review: Negishi E.; Hu Q.; Huang Z.; Qian M.; Wang G. Aldrichim. Acta
(
2
005, 38, 72-38.
8) Soderquist, J. A.; Bantiago, B. Tetrahedron Lett. 1990, 31, 5541-
542.
9) Soderquist, J. A.; Le o´ n, G.; Colberg, J. C.; Martinez, I. Tetrahedron
Lett. 1995, 36, 3119-3122.
10) Molander, G. A.; Figueroa, R. Aldrichim. Acta 2005, 38, 49-56.
(
5
(
(
2494 J. Org. Chem., Vol. 71, No. 6, 2006

One-Pot Synthesis of Trisubstituted Conjugated Dienes
TABLE 1. One-Pot Synthesis of a Trisubstituted Diene Derivative
FIGURE 1. Determination of stereochemistry by NOE.
TABLE 2. One-Pot Reaction of Various Potassium
Alkyltrifluoroborates
first coupling
second coupling
%
isolated
entry 2 (equiv) T (°C) time (h) T (°C) time (h)
yield of 4
1
2
3
4
5
1.1
1.1
1.1
1.0
1.05
80
60
60
60
60
1.25
2.0
2.0
8.0
2.0
80
60
80
1.0
3.0
2.5
85a
b
84
89
c
80
2.5
second
coupling
time (h)
a
b
isolated
1
0% of bis(alkenyl) coupled product was formed. Second coupling
c
entry
RBF K
product
yield (%)
reaction was not complete. First coupling reaction was not complete.
3
1
2
3
4
5
PivO(CH2)4BF3K (5)
BzO(CH2)4BF3K (7)
NC(CH2)4BF3K (9)
2.0
2.0
3.0
3.0
1.5
6
8
10
12
14
89
90
89
89
90
from coupling of 1 with two equivalents of 2 [i.e., a bis(alkenyl)-
coupled product] in about 10% yield. Further experimentation
determined that the first step of the two-step process could be
carried out at lower temperature, but the second reaction required
a higher temperature to proceed to completion. For example,
when the entire process was carried out at 60 °C, the sequentially
coupled compound was not obtained at all, although formation
of the initial monoalkenyl-coupled compound was complete
CH3CO(CH2)4BF3K (11)
PhS(CH ) BF K (13)
2
3
3
TABLE 3. Reaction of Less Reactive Potassium
Alkyltrifluoroborates
(entry 2). To rectify this problem, the first coupling reaction
was carried out at 60 °C, while the second coupling reaction
was conducted at 80 °C. Under these conditions, the target
compound was obtained in good yield (entry 3). An attempt
was made to reduce the excess of alkenyl trifluoroborate utilized
in the initial reaction. However, when only one equivalent of
alkenyl trifluoroborate 2 was used as a substrate, the first step
required a relatively long time to go to completion (entry 4).
Finally, it was found possible to reduce the formation of the
bis(alkenyl) coupled byproduct and to obtain a high yield of
the target compound by using just a slight excess (1.05 equiv)
of 2, and in this case, the desired diene was obtained in 89%
yield (entry 5). Under these conditions, the yield of the bis-
isolated
yield (%)
entry
RBF3K
MeBF3K (15)
EtBF3K (17)
H2CdCH(CH2)3BF3K (19)
time (h)
product
1
2
3
2.5
2.5
1.0
16
18
20
84
82
83
of our studies confirmed that diversely functionalized alkyl
trifluoroborates were effective substrates for the reaction
employing the reaction conditions developed in the model
reaction, and this prompted us to explore the scope and
limitations in greater detail.
Interestingly, in contrast to the functionalized alkyl trifluo-
roborates described above, organotrifluoroborates such as potas-
sium methyl trifluoroborate (15), potassium ethyl trifluoroborate
(17), and potassium 4-pentenyl trifluoroborate (19), proved to
be more reluctant coupling partners (Table 3). These substrates
could not be transformed to the desired products at all when
the reactions were carried out under the same reaction conditions
utilized for substrates in Table 2. Consequently, we refined the
reaction conditions for the second coupling step for these
organotrifluoroborates. A series of investigations guided us to
a solution to this problem. Thus, at a higher reaction temperature
(90 °C), with the addition of PdCl2(dppf)‚CH2Cl2 complex (used
previously in related coupling processes), and by using solid
Cs2CO3 (as opposed to an aqueous solution), effective meth-
ylation, ethylation, and pentenylation of the monobromodiene
initially formed in situ could be achieved. The results of these
modified conditions are displayed in Table 3. When 15 was
used as a substrate for the second coupling reaction, the desired
product was obtained in good yield (entry 1). Furthermore, ethyl
(alkenyl)-coupled byproduct was reduced to levels e5%. Efforts
were made to improve the process further by examining different
palladium catalysts and bases. However, Pd(PPh3)4 was deter-
mined to be the best catalyst for this reaction system in terms
of yield and cost, and Cs2CO3 remained the most effective
11b
among the diverse bases examined.
With a suitable protocol in hand, the scope of this synthetic
method was examined by first using various alkyltrifluoroborates
(
[
Table 2). When alkyltrifluoroborates bearing ester substituents
trimethylacetyloxy (PivO) and benzoyloxy (BzO) groups] were
used as substrates in the second coupling reaction, the target
compounds were accessed in excellent yields (entries 1 and 2).
Ester hydrolysis products were not detected, even though
aqueous basic conditions were employed.11b A cyano-substituted
alkyltrifluoroborate could also be transformed to the desired
product very effectively (entry 3). The 5,7-dienyl carboxylate
incorporating a ketone unit could be synthesized easily employ-
ing 11 (entry 4). When thioether 13 was used as a substrate,
the second reaction proceeded smoothly to give the target
compound in good yield (entry 5). In all cases, only one
stereoisomer of the target compound was obtained, and the sense
of this diastereoselection was determined by NOE studies (see
Figure 1 below). The experiments completed in the first phase
1
1g
J. Org. Chem, Vol. 71, No. 6, 2006 2495

Molander and Yokoyama
TABLE 4. Formation of Functionalized Dienes
a
Isolated yield. b Compound 30 (1.1 equiv) was used.
trifluoroborate and 4-pentenyl trifluoroborate were also effective
substrates in this synthetic reaction. Compounds 17 and 19 could
be transformed to the corresponding diene derivatives in good
yields (entries 2 and 3). Of particular note, this transformation
exhibits significant advantages over many other disubstitution
reactions of 1,1-dihaloalkenes in the sense that methylation in
the second step was highly successful, affording the desired
compound in good yield. High-yielding methylations of this type
have proven to be challenging in previously reported proto-
reaction conditions, and this intermediate could be transformed
in situ to the desired compound in the presence of 5 or 11 in
excellent yields (entries 1 and 2). Potassium (E)-5-chloro-1-
pent-1-enyl trifluoroborate 24 was also used as a substrate. The
target compounds were obtained in excellent yields with
retention of the chloride (entries 3 and 4). Some alkenyl
trifluoroborates incorporating simple hydrocarbon chains reacted
with dibromide 1 under the optimized reaction conditions. When
27 was treated with dibromide 1, the desired monobromide was
very effectively generated in situ, and this compound reacted
with organotrifluoroborates 5 or 11 to give the corresponding
dienes in excellent yields (entries 5 and 6). When 30 was used
as a substrate under the standard conditions, the first coupling
reaction took a longer period of time, and many unidentified
byproducts were obtained. Given our experience with other
recalcitrant coupling partners, we performed this reaction using
compound 30 at a higher temperature (80 °C). As shown in
entries 7-9 of Table 4, when the first step of these reactions
was carried out at 80 °C for 5.0 h followed by a second reaction
with alkyl trifluoroborates 5, 11, or 3, the desired compounds
were isolated in excellent yields. Overall, the synthetic method
developed showed high compatibility with all manner of
organotrifluoroborate coupling partners.
2
,7a,b,13
cols,
and a general one-pot, two-stage conversion of the
6
,7b,13
type described herein appears to be extremely rare.
In
previous attempts at such transformations, a mismatch occurs
between the two different organometallic partners and the
catalyst complexes (specifically the ligand array) required to
7
b
support their successive in situ coupling to the halide.
The results depicted in Table 2 compared to those in Table
appear to demonstrate that the reactivity of the alkyl
3
trifluoroborate is somehow associated with functionality incor-
porated within the substrate itself. Whether the small, aliphatic
trifluoroborate salts are simply less soluble than more elaborate
reagents or whether these polar groups in conjunction with the
trifluoroborate somehow change the nature of the palladium
catalyst is unknown. However, it is clear that polar functional
groups enhance the reactivity of the organotrifluoroborates,
indicating that reaction conditions may have to be customized
to some extent depending on the nature of the organic moiety
in the reagent.
In addition to being able to use a variety of alkyl trifluo-
roborates in the second step of the sequential one-pot process,
diverse alkenyl trifluoroborates could be used as starting
materials for the first step of the synthesis. The results of these
investigations are summarized in Table 4. Thus, an alkenyl
trifluoroborate possessing a cyano substituent (21) reacted with
dibromide 1 to give the corresponding monobromide under mild
Owing to the reports of Negishi concerning a stereoinversion
process that can occur during related trisubstituted alkene
1
3
syntheses, there was some concern about the sense of
diastereoselection in these processes. These concerns were
allayed upon finding an 11.8% NOE enhancement between two
vinylic protons in 22 to establish the E,E stereochemistry by a
technique that has been utilized previously for stereochemical
2
,13
confirmation in related systems (Figure 1).
In the final phase of our studies, the diversity allowed in the
last of the three components was explored. Thus, several
different 1,1-dibromoalkenes were examined for their effective-
ness in the reaction. For example, 1,1-dibromonon-1-ene 34 was
used as a substrate, and the target compound was obtained in
(
13) Zeng, X.; Hu, Q.; Qian, M.; Negishi, E. J. Am. Chem. Soc. 2003,
1
25, 13636-13637.
2496 J. Org. Chem., Vol. 71, No. 6, 2006

One-Pot Synthesis of Trisubstituted Conjugated Dienes
good yield (eq 4). 1,1-Dibromo-4-phenyl-but-1-ene 36 also
reacted with 2 and then 5 to give the corresponding compound
in good yield (eq 5). When these acyclic dibromides possessing
a methylene group at the allylic position were employed as
starting materials, a mixture of stereoisomeric products was
formed, with the E,E-isomer still predominating (E,E/E,Z )
Conclusion
In summary, we have developed an effective and convenient
one-pot synthesis of stereodefined, trisubstituted, conjugated
dienes using alkenyl- and alkyltrifluoroborates through the
sequential disubstitution of 1,1-dibromoalkenes. This synthetic
method proceeded smoothly to provide the desired products in
excellent yields. At this point in time, the protocol developed
appears general for all three components of the reaction. Thus,
a variety of functionalized alkenyl trifluoroborates have been
employed, although diverse stereochemistries and substitution
patterns remain to be examined. Perhaps most importantly,
conditions are reported for primary alkyl trifluoroborates ranging
from simple methyl and ethyl derivatives to more highly
functionalized alkyl trifluoroborates. Finally, a diverse group
of 1,1-dibromoalkenes takes part in the reaction, including
conjugated 1,1-dibromoalkenes. Stereoselectivities are generally
quite high, although dependent upon the steric properties of the
geminal dihalide. In most cases, a single catalyst precursor can
be employed to carry out the transformation. Curiously, Pd-
>92/<8). Thus, the sterically demanding cyclohexyl group of
dihalide 1 utilized in Tables 1-4 more effectively controlled
the stereoselectivities of the initial coupling reaction than
unbranched aliphatic groups. (S)-(+)-1,1-Dibromo-4,8-dimethyl-
1
,7-nonadiene 38 derived from (S)-(-)-citronellal sequentially
reacted with organotrifluoroborates 2 and then 5 to form the
corresponding chiral product in good yield (eq 6). Finally, the
R,â,γ,δ-unsaturated dibromide 40, which was prepared from
(S)-(-)-perillaldehyde, was also transformed to the desired
product with complete stereochemical control (eq 7). In this
way, the method was extended to conjugated 1,1-dibromides,
indicating that more highly conjugated systems are also very
effective substrates for this reaction.
(PPh3)4 has proven to be the most effective precatalyst, although
this particular system is not normally used for alkyl cross-
coupling because of its inability to suppress competitive
â-hydride elimination. Finally, utilizing this protocol the use
of superstoichiometric thallium bases are avoided that often
plague the construction of trisubstituted dienes using other boron
1
4
reagents. Sequential protocols for the one-pot synthesis of
complementary classes of trisubstituted alkenes involving
diverse trifluoroborates in both reaction order combinations are
currently in progress.
Experimental Section
General Procedure for the Cross-Coupling Reaction of 1,1-
Dibromoalkenes with Potassium Alkenyltrifluoroborates and
Alkyltrifluoroborates. Synthesis of (E,E)-8-Cyclohexyl-7-(4-
trimethylacetoxybutyl)octa-5,7-dienoic Acid, Methyl Ester (6).
1
,1′-Dibromo-2-cyclohexylethene (268 mg, 1.0 mmol) was added
slowly to a toluene-H O solution (3.0 mL + 1.0 mL) of Cs CO
977 mg, 3 mmol), potassium (E)-1-hex-5-enoic acid trifluoroborate,
methyl ester (245 mg, 1.05 mmol), and Pd(PPh (80 mg, 0.07
mmol) at 60 °C under N . After the mixture was stirred for 2.0 h,
potassium 1-trimethylacetyloxybutyl trifluoroborate (291 mg, 1.1
mmol) and an aqueous solution of Cs CO (3.0 M, 1 mL) were
added to the reaction mixture. After the mixture was stirred for 2
h at 80 °C, a mixture of silica gel and Na SO (1/1, 13 g) was
added to the mother liquor, and this mixture was passed through a
short column of silica gel (7.0 g, hexane) and eluted with Et
120 mL). Concentration of this eluate followed by column
chromatographic purification (SiO , hexane/Et O ) 20/1) afforded
(348 mg, 89%) as a colorless oil: 1H NMR (500 MHz, CDCl
2
2
3
(
3 4
)
2
2
3
2
4
2
O
(
2
2
6
3
)
δ 5.91 (d, J ) 15.9 Hz, 1H), 5.49 (dt, J ) 15.9, 6.6 Hz, 1H), 5.19
(
(
d, J ) 9.8 Hz, 1H), 4.08 (t, J ) 6.3 Hz, 2H), 3.66 (s, 3H), 2.31
t, J ) 8.0 Hz, 2H), 2.23-2.20 (m, 3H), 2.11 (q, J ) 7.6 Hz, 2H),
1
(
.74-1.58 (m, 10H), 1.47-1.43 (m, 2H), 1.29-1.26 (m, 2H), 1.19
s, 9H), 1.18-1.05 (m, 2H); 13C NMR (125.8 MHz, CDCl
3
) δ
1
3
2
78.6, 174.0, 137.5, 135.5, 134.7, 125.8, 64.2, 51.4, 38.7, 37.2,
3.5, 33.3 (2C), 32.3, 28.9, 27.2 (3C), 26.7, 26.0, 25.9 (2C), 25.8,
+
4.8; HRMS (ESI) m/z calcd for C24
H
40NaO
4
(M + Na) 415.2824,
(14) (a) 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,
6
981-6990. (b) Kobayashi, S.; Mori, K.; Wakabayashi, T.; Yasuda, S.;
Hanada, K. J. Org. Chem. 2001, 66, 5580-5584. (c) Shimizu, T. Satoh,
T.; Murakoshi, K.; Sodeoka, M. Org. Lett. 2005, 7, 5573-5576.
J. Org. Chem, Vol. 71, No. 6, 2006 2497

Molander and Yokoyama
found 415.2823; IR (neat) 2926, 2851, 1732, 1448, 1284, 1155,
performing some preliminary studies in this area and Dr. Rakesh
Kohli for the HRMS data.
-
1
9
66, 771 cm
.
Acknowledgment. We acknowledge the National Institutes
Supporting Information Available: Full experimental details
and copies of all NMR spectra ( H, C, F, and B). This material
is available free of charge via the Internet at http://pubs.acs.org.
of Health (GM35249), Amgen, and Merck Research Labora-
tories for their generous support of this work. Additionally, we
thank Johnson-Matthey for supplying the catalysts used in this
research. Finally, we acknowledge Ms. Luciana Felix for
1
13
19
11
JO052636K
2498 J. Org. Chem., Vol. 71, No. 6, 2006