Palladium-catalyzed oxidative homocoupling of potassium alkenyltrifluoroborates: synthesis of symmetrical 1,3-dienes

Article abstract of DOI:10.1016/j.tetlet.2009.04.127

Herein, we describe a convenient method for the synthesis of symmetrical 1,3-dienes employing an oxidative palladium-catalyzed homocoupling of potassium alkenyltrifluoroborates providing products in good yields relative to existing methodologies. This is the first report of a cross-dimerization of potassium alkenyltrifluoroborates.

Full text of DOI:10.1016/j.tetlet.2009.04.127

Tetrahedron Letters 50 (2009) 4324–4327
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed oxidative homocoupling of potassium
alkenyltrifluoroborates: synthesis of symmetrical 1,3-dienes
c,
Minéia Weber a, Fateh V. Singh b, Adriano S. Vieira b, Hélio A. Stefani a,b, , Marcio W. Paixão
*
*
a Universidade Federal de São Paulo, Departamento de Biofisica, São Paulo—SP, Brazil
b Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo—SP, Brazil
c Instituto de Química, Universidade de São Paulo—SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, we describe a convenient method for the synthesis of symmetrical 1,3-dienes employing an oxi-
dative palladium-catalyzed homocoupling of potassium alkenyltrifluoroborates providing products in
good yields relative to existing methodologies. This is the first report of a cross-dimerization of potassium
alkenyltrifluoroborates.
Received 16 March 2009
Revised 27 April 2009
Accepted 30 April 2009
Available online 5 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Homocoupling reaction
1,3-Dienes
Organotrifluoroborates
Alkenyltrifluoroborates
Transition metal-catalyzed cross-coupling reactions have
emerged as powerful and general methods for the synthesis of or-
ganic compounds.1 C–C bond-formation processes, which are typ-
ically mediated by nickel, palladium, iron, or copper catalysis, are
now ubiquitous in both academia and industry.2
The stereo and regio-defined synthesis of conjugated dienes has
been a long-standing challenge in organic synthesis. Success in this
area is still warranted as this structural motif is prevalent in bio-
logically active compounds, as well as in conducting polymers
and liquid crystalline materials.3
A number of methods for the preparation of conjugated dienes
and polyenes have been previously developed employing a number
of varied organometallic reagents. However, apart from the forma-
tion of the major cross-coupling product, a minor byproduct result-
ing from the palladium-catalyzed homocoupling reaction is often
observed.4 Recently, the palladium-catalyzed homocoupling of an
alkenyl-metal was developed as the primary pathway when per-
formed in the presence of a chemical oxidant, either oxygen or air.5
Among the organometallic reagents employed in cross-cou-
pling reactions, organoboron species (in particular in the Suzu-
ki–Miyaura reaction) offer advantages over other partners such
as Grignard reagents, organozinc reagents, and organostannanes.6
They are readily prepared and in many cases they are commer-
cially available. Additionally, the coupling reaction conditions
are often mild and the resulting inorganic byproducts are envi-
ronmentally benign and are easily removed by simple workup
procedures.
The most commonly used organoboron species include boronic
acids and boronate esters. Unfortunately, these functionalities bear
certain drawbacks, including high price, and sensitivity to air and
moisture. As such, organoboronic acid and ester derivatives have
been replaced by potassium organotrifluoroborate salts, which
are crystalline solids, stable under air and moisture, and readily
prepared from inexpensive materials. They are also considerably
more nucleophilic than their predecessors.7
As a part of our research efforts with potassium organotrifluorob-
orates as a key reagent in cross- or homocoupling reactions,8 we re-
cently reported the use of potassium alkynyltrifluoroborates for the
simple and efficient synthesis of symmetrical 1,3-diynes.9 To this
end, we propose herein a simple analogous experimental procedure
employing potassium alkenyltrifluoroborates.10 These reagents are
easy to handle, less toxic than alkenylstannanes, and active enough
to promote direct oxidative homocoupling (Scheme 1, Eq. A vs B).
Our study resulted in the synthesis of conjugated 1,3-diene deriva-
tives under mild and neutral conditions.
We initially focused our attention on optimization of reaction
conditions for the Suzuki–Miyaura homocoupling reaction of
potassium alkenyltrifluoroborates. We used a variety of catalysts,
co-oxidants, and solvents. Model reaction conditions were ex-
plored using stereodefined reagents to study the stereochemistry
of the formed 1,3-diene.
* Corresponding authors. Tel.: +55 11 3091 3654; fax: +55 11 3 815 4418 (H.A.S.).
E-mail address: hstefani@usp.br (H.A. Stefani).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.127

M. Weber et al. / Tetrahedron Letters 50 (2009) 4324–4327
4325
''Pd''
R
''Pd''
R
KF3B
SnEt3
R
R
Equation B
Equation A
Scheme 1.
Ni
Fe
Cu
Pd
BF3K
DMSO, 60 oC, 6h
E,E
Catalyst
(10 mol%):
CuCl2, yield: 50%
NiCl2.6H2O, yield: traces
FeCl3, yield: traces
Pd(OAc)2, yield: 70%
Scheme 2.
A series of catalysts (e.g., Ni, Fe, Cu, and Pd) were first examined
for the homocoupling of trans-styryltrifluoroborate using DMSO as
solvent at 70 °C for 7 h (Scheme 2).
generality of the present method. Various, potassium alkenyltrifluo-
roborates10 were than examined for homocoupling with the
Pd(OAc)2/Ag2O system,11 and the results are summarized in Table 2.
Deactivated aromatic alkenyltrifluoroborates bearing electron-
donating substituents such as methoxy or methyl, reacted
smoothly under these conditions to afford the desired products
in moderate yield (Table 2, entries 2 and 3). Interestingly, activated
alkenylborates also undergo the self-coupling reaction with the
same range of yield (entries 3 vs 4). In all cases (entries 1–4), the
(E,E)-dienes were obtained as pure isomers as determined by 1H
NMR.
We next examined the application of this palladium system to
the coupling reaction of aliphatic alkenyltrifluoroborates (entries
5 and 6). When the alkenyltrifluoroborate derived from but-3-
ynylbenzene was employed, the corresponding 1,3-dienes were
obtained in suitable yield (56%). The substrate derived from 1-hep-
tyne provided the homocoupling product in 42% yield (entry 6). Fi-
Unfortunately, the methodology that had previously been de-
scribed for achieving the homocoupling of potassium alkynyltriflu-
oroborates9 was not useful for alkenylboron species. Suboptimal
results were also obtained with 10 mol % NiCl2Á6H2O or FeCl3.
However, Pd(OAc)2 proved to be efficient, providing the E,E-1,3-
dienes in 70% yield. Other Pd precursors including Pd(Acac)2,
PdCl2(PhCN), and Pd(PPh3)4 afforded significantly moderate results
(Table 1, entries 1–3). The yield could be further improved by
employing 15 mol % of Pd(OAc)2 in the presence of Ag2O as a co-
oxidant (78%, entry 4).
Upon identification of an efficient catalyst, we studied the influ-
ence of solvent. The desired 1,3-diene was generated in moderate
yield in polar aprotic and protic solvents such as DMF, CH3CN,
and MeOH (entries 5-7 vs 10). THF provided a significantly lower
yield (entry 9). As a result of the solvent screening, subsequent
studies were performed in DMSO. We also examined the participa-
tion of other co-oxidants. For example, when (diacetoxyiodo)ben-
zene was employed, the desired homocoupling product was
obtained in 63% yield (entry 11).
nally, the presence of
a-substitution in the organoboron partner
(entry 7) was also studied. Interestingly, potassium isopropenyltri-
fluorate proved to be an ineffective reagent for the homocoupling
reaction.
Next, we turned our attention to competition experiments to
determine if the reactivity trends of the alkenyltrifluoroborates
were dependent upon the reaction conditions. For this reaction
type, we employed capillary gas chromatographic analysis of
the reaction mixture as the analytical tool for accurate determina-
tion of product ratios. Competition experiments were conducted
with different aromatic alkenyltrifluoroborates12 in the presence
of 15 mol % of Pd(OAc)2 and Ag2O using DMSO as solvent
(Table 3).
The mild reaction conditions, the high reaction rate, and the rea-
sonable yields obtained encouraged us to examine the scope and
Table 1
Effect of reaction parameters
Pd catalyst
(10 mol%):
Solvent, 70 oC, N2, 7h
BF3K
After complete consumption of starting materials (observed by
TLC), the product ratios were determined quantitatively by GC–MS
analysis. The self-coupling product ratios obtained with a mixture
of p-tolyl alkenyltrifluoroborate and p-bromophenyl alkenyltriflu-
oroborate were 24% and 16%, respectively; however, the cross-cou-
pling product was obtained in 60% (Table 3, entry 1). By contrast,
p-anisole alkenyltrifluoroborate was significantly less reactive than
the p-bromophenyl alkenyltrifluoroborate. The desired homocou-
pling products were obtained in a 2:1 ratio in preference of the
activated alkenylborate. Again, the cross-coupling product was ob-
tained as the major product (entry 2).
Entry
Pd source
Solvent
Yield (%)a
1
2
3
Pd(Acac)2
PdCl2(PhCN)
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
DMSO
DMSO
DMSO
DMSO
DME
54
47
43
78
66
72
71
49
18
51
63
4b
5b
6b
7b
8b
9b
10b
11c
DMF
CH3CN
1,4-Dioxane
THF
MeOH
DMSO
In conclusion, we have demonstrated a convenient method for
the synthesis of symmetrical 1,3-dienes. Products are formed in
good yields with pertinent modifications over existing methodolo-
gies. Additionally, this method represents the first report of a
cross-dimerization of potassium alkenyltrifluoroborates. Further
extensions of this methodology will be reported in due course.
a
Yields describe the isolation of pure products characterized by spectroscopic
data.
b
The reactions were conducted using 15 mol % of catalyst in the presence of
3 equiv of Ag2O.
c
The reaction was carried out using 15 mol % catalyst and 1 equiv
(diacetoxyiodo)benzene.

4326
M. Weber et al. / Tetrahedron Letters 50 (2009) 4324–4327
Table 2
Synthesis of symmetric 1,3-dienes from potassium alkenyltrifluoroborates using the Pd(OAc)2/Ag2O system
Pd(OAc)2, Ag2O
R
R
BF3K
R
DMSO, 70°C, N2, 7h
Entry
1
Substrate
Product
Yield (%)a
78
BF3K
MeO
MeO
2
3
42
65
BF3K
OMe
BF3K
Br
Br
4
62
BF3K
Br
5
6
56b
42b
n.r.
BF3K
BF3K
7
BF3K
a
Yields describe the isolation of pure products characterized by spectroscopic data.
Mixture of isomers (entry 5, 30:70; entry 6, 88:8:4).
b
Table 3
Competition experiments: effect of the aromatic substituents
R1
R2
R1
R1
R2
Pd(OAc)2, Ag2O
DMSO, 60 oC, N2, 7h
BF3K
KF3B
R2
R1
R2
Entry
R1
R2
Product ratiosa (%)
R1
R2
R1
R1
R2
R2
1
2
3
4
MeC6H4
MeOC6H4
Ph
BrC6H4
BrC6H4
MeC6H4
BrC6H4
24
19
28
38
16
36
14
32
60
45
58
30
Ph
a
Product ratios were determined by GC–MS.
Weinheim, Germany, 2004; For
Coupling Reactions in Total Synthesis see: (b) Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442.
a Review in Palladium-Catalyzed Cross-
Acknowledgments
The authors gratefully acknowledge CNPq (300613/2007-5),
CAPES (fellowship to M.W.), and FAPESP (Grant 07/59404-2) for
financial support.
3. Negishi, E.; Huang, Z.; Wang, G.; Mohan, S.; Wang, C.; Hattori, H. Acc. Chem. Res.
2008, 41, 1474.
4. Kotora, M.; Takahashi, T. Handbook of Organopalladium Chemistry for Organic
Synthesis 2002; Vol. 1, p 973.
5. Nishibayashi, Y.; Cho, C. S.; Ohe, K.; Uemura, S. J. Organomet. Chem. 1996, 526,
335.
References and notes
6. (a) Matteson, D. S. Stereodirected Synthesis with Organoboranes; Springer: Berlin,
1995; (b) Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents; Academic: London,
1988; (c) Ling, R.; Yoshida, M.; Mariano, P. S. J. Org. Chem. 1996, 61, 4439.
7. For reviews of organotrifluoroborate salts, see: (a) Darses, S.; Genêt, J. P. Eur. J.
Org. Chem. 2003, 4313; (b) Molander, G. A.; Figueroa, R. Aldrichim. Acta 2005,
38, 49; (c) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275; (d) Stefani, H.
1. (a) Doucet, H.; Hierso, J.-C. Angew. Chem., Int. Ed. 2007, 46, 834; (b) Johnson, J.
B.; Rovis, T. Angew. Chem., Int. Ed. 2008, 47, 840–871.
2. (a)For an indispensable book on cross-coupling, see: Metal-Catalyzed Cross
Coupling Reactions; de Meijere, A., Diederich, F., Eds., 2nd ed.; Wiley-VCH:

M. Weber et al. / Tetrahedron Letters 50 (2009) 4324–4327
4327
A.; Cella, R.; Vieira, A. S. Tetrahedron 2007, 63, 3623; (e) Darses, S.; Genêt, J. P.
Chem. Rev. 2008, 108, 288.
21.16. 11B NMR (DMSO-d6, 96 MHz): d 3.61; 19F NMR (DMSO-d6, 282 MHz): d
À137.7.
8. (a) Cella, R.; Venturoso, R. C.; Stefani, H. A. Tetrahedron Lett. 2008, 49, 16; (b)
Bellomo, A.; Gonzalez, D.; Stefani, H. A. J. Organomet. Chem. 2008, 693, 1136; (c)
Vieira, A. S.; Guadagnin, R. C.; Fiorante, P. F.; Ferreira, F. P.; Stefani, H. A.
Tetrahedron 2008, 64, 3306; (d) Vieira, A. S.; Fiorante, P. F.; Zukerman-
Schpector, J.; Alves, D.; Botesselle, G. V.; Stefani, H. A. Tetrahedron 2008, 64,
7234; (e) Guadagnin, R. C.; Suganuma, C.; Vieira, A. S.; Cella, R.; Stefani, H. A.
Tetrahedron Lett. 2008, 49, 4713; (f) Singh, F. V.; Weber, M.; Guadagnin, R. C.;
Stefani, H. A. Synlett 2008, 1889; (g) Botteselle, G. V.; Hough, T. L. S.; Venturoso,
R. C.; Cella, R.; Vieira, A. S.; Stefani, H. A. Aust. J. Chem. 2008, 61, 870; (h) Vieira,
A. S.; Fiorante, P. F.; Hough, T. L. S.; Ferreira, F. P.; Lüdtke, D. S.; Stefani, H. A. Org.
Lett. 2008, 10, 5215; (i) Singh, F. V.; Stefani, H. A. Synlett 2008, 3221.
9. Paixão, M. W.; Weber, M.; Stefani, H. A.; Braga, A. L.; Azeredo, J. B.; Deobald, A.
M. Tetrahedron Lett. 2008, 49, 2366.
10. General procedure for potassium alkenyltrifluoroborate synthesis: In a dried two-
necked 50-mL flask with a nitrogen atmosphere was added dropwise 4-methyl
phenylacetylene (20 mmol, 2.65 mL) at 0 °C. Catecholborane (20 mmol,
2.15 mL) was then added dropwise at the same temperature. The ice bath
was removed, and the resulting mixture was heated and stirred for 4 h at 75 °C,
after which it was allowed to cool to room temperature. Next, a saturated
aqueous solution of potassium hydrogen difluoride (80 mmol, 6.24 g) was
added to the vigorously stirred solution. After 5 h, a white precipitate was
formed, the solvent was removed under reduced pressure, and the resulting
white solid was washed with acetone (100 mL) and with hot acetone. The
resulting organic solution was filtered, and the solvent was removed to afford a
fluffy white solid. This solid was then dissolved in hot acetone and precipitated
with cold diethyl ether (40 mL), after which the solution was cooled to À20 °C
to complete the precipitation of the solid. The product was collected as a white
crystalline solid (62%). 1H NMR: (DMSO-d6, 300 MHz): d 7.18 (d, J = 7.6 Hz, 2H);
7.03 (d, J = 7.6 Hz, 2H); 6.42 (d, J = 18.2 Hz, 1H); 6.09 (d, J = 18.2 Hz, 1H); 2.23
(s, 3H). 13C NMR (DMSO-d6, 75 MHz): d 138.05, 135.21, 133.37, 129.30, 125.75,
11. General procedure for all homocoupling reactions (Table 2, entry 2): A 50-mL
flask under
a nitrogen atmosphere was charged with potassium methyl
styryltrifluoroborate (0.5 mmol, 0.112 g), Pd(OAc)2 (15 mol %, 16.50 mg), Ag2O
(3 equiv, 34.76 mg), and DMSO (3 mL). The reaction mixture was heated at
70 °C for 7 h and the reaction was followed by TLC. After completion, the
reaction mixture was allowed to reach rt and then NH4Cl (30 mL) was added,
and the organic phase was extracted with ethyl acetate (3 Â 30 mL). The
organic layers were combined, dried (MgSO4), and the solvent was removed
under vacuum to provide a viscous yellow oil. The oil was purified by column
chromatography using a mixture of hexane/ethyl acetate (96:4) as the eluent
to afford the solid products (see Table 2). Yield 65%. White solid. 1H NMR:
(CDCl3, 300 MHz): d 7.38 (d, J = 7.95 Hz, 4H); 7.18 (d, J = 7.86 Hz, 4H); 6.95 (dd,
J = 12.0, 2.65 Hz, 2H); 6.66 (dd, J = 12.0, 2.91, 2H); 2.39 (s, 6H). 13C NMR (CDCl3,
75 MHz): d 137.36, 134.72, 132.26, 129.38, 128.51, 126.25, 21.26. MS 234 (82);
219 (100); 204 (49); 115 (24); 105 (47); 77 (21).
12. General procedure for all cross-coupling reactions: A two-necked 50-mL flask
under a nitrogen atmosphere was charged with potassium 4-methyl styryl-
trifluoroborate (0.5 mmol, 0.112 g), potassium 4-bromo styryltrifluoroborate
(0.5 mmol; 14.4 mg), Pd(OAc)2 (15 mol %, 16.50 mg), Ag2O (3 equiv, 34.76 mg),
and DMSO (3 mL). The reaction mixture was heated at 70 °C for 7 h, and the
reaction was followed by TLC. After completion, the reaction mixture was
allowedtoreachrtand thenNH4Cl(30 mL)wasadded, andtheorganicphase was
extracted with ethyl acetate (3 Â 30 mL). The organic layers were combined,
dried (MgSO4), and the solvent was removed under vacuum to provide a viscous
yellow oil. The oil was purified by column chromatography using a mixture of
hexane/ethylacetate (96:4)as the eluentto afford the solid products(see Table 3,
entry 4: 38%—MS = 206 (100), 191 (40), 128 (36), 91 (71), 77 (17); 32%—MS = 284
(56), 205 (100), 190 (25), 128 (27), 101 (37), 89 (33); 30%—MS = 204 (100), 101
(27), 89 (17), 76 (14).