Synthesis of conjugated enediynes via palladium catalyzed cross-coupling reactions of potassium alkynyltrifluoroborates

Article abstract of DOI:10.1016/j.tetlet.2004.12.021

An efficient synthesis of cross-conjugated enediynes has been developed utilizing the palladium catalyzed cross-coupling reactions of 1,1-dibromo-1-alkenes with potassium alkynyltrifluoroborates under mild conditions.

Full text of DOI:10.1016/j.tetlet.2004.12.021

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 763–765
Synthesis of conjugated enediynes via palladium catalyzed
cross-coupling reactions of potassium alkynyltrifluoroborates
George W. Kabalka,* Gang Dong and Bollu Venkataiah
Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, TN 37996-1600, USA
Accepted 6 December 2004
Available online 21 December 2004
Abstract—An efficient synthesis of cross-conjugated enediynes has been developed utilizing the palladium catalyzed cross-coupling
reactions of 1,1-dibromo-1-alkenes with potassium alkynyltrifluoroborates under mild conditions.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Cross-conjugated enediynes have recently received con-
siderable attention due to their extensive applications
in non-linear optics (NLO),1 macrocyclic ligands,2 opti-
cal switches,3 and the synthesis of polycyclic aromatic
hydrocarbons (PAHs).4 Preparative methods for enedi-
ynes are limited. The Sonogashira reaction can be uti-
lized5 as well as the palladium catalyzed coupling reac-
tion of ketene butyltelluroacetals with alkynes.6 The
Sonogashira reaction normally produces a mixture of
bromoenyne, enediyne, and recovered starting di-
bromoalkene.5e,7 In some cases the yields are low.5c,d
The butyltelluroacetal method involves the use of vinylic
telluride compounds that are toxic and often difficult to
prepare. Thus, the development of a simple and efficient
approach to cross-conjugated enediynes is of great
interest.
reactions can be problematic. Recently the use of potas-
sium alkynyltrifluoroborates in carbon–carbon bond
forming reactions has attracted significant attention
due to their stability and accessibility.13 In connection
with our ongoing studies of cross-coupling reactions
using potassium organotrifluoroborates,14 we developed
an efficient synthesis of cross-conjugated mono-enedi-
ynes using the cross-coupling of potassium alkynyltrifluo-
roborates with 1,1-dibromo-1-alkenes. Herein, we wish
to disclose the results of this study.
Various palladium catalysts, solvents, and reaction con-
ditions were examined using (2,2-dibromovinyl)-benz-
ene, 1, and potassium (p-tolylethynyl)trifluoroborate,
2, as model substrates (Table 1). 1 (1 equiv) was treated
with 2 (2 equiv) in the presence of 5 mol % of
Pd(dppf)Cl2/Cs2CO3 (3 equiv) at 50 ꢁC in methanol (Ta-
ble 1, entry 1). Under these conditions, the reaction was
sluggish. Fifty-two percent of the starting material, 1,
was recovered after 12 h. The corresponding enediyne
3 was obtained in 10% yield, and 1,3-diyne 4 was
isolated as the major product in 36% yield. The homo-
coupling product of 1,1-dibromo-1-alkene and mono-
substituted bromoenyne were not detected although
they are commonly reported as byproducts in Sonogash-
ira reactions.5,6 Using DMF and toluene as solvents, the
isolated yields of enediyne 3 were 21% and 18%, respec-
tively (Table 1, entries 2 and 3). When THF was used as
solvent, the yield of 3 increased to 43% and only 26% of
starting material 1 was recovered (Table 2, entry 4). The
addition of a small amount of water increased the yield
of 3 to 52% as well as decreased the reaction time to 4 h
(Table 1, entry 5).15 As the reaction proceeds, the mix-
ture becomes black. Gas chromatographic analysis of
the black reaction mixture (presumably due to metallic
During the past 20 years, Suzuki-Miyaura cross-cou-
pling reactions have provided preparative methods for
effectively creating carbon–carbon bonds. The coupling
reactions of aryl-, alkyl-, and alkenylboron compounds
(including boronate esters, boranes, and boronic acids)
have been investigated extensively.8 However, the cou-
pling of alkynylboron compounds has been limited to
B-alkynyl-9-BBN borate complexes,9 alkynyltrialkoxy-
borate complexes,10 and lithium 1-alkynyl(triisoprop-
oxy)borates.11 Because alkynylboronic esters are
stronger Lewis acids than aryl- and alkenylboronate
esters and are easily hydrolyzed,12 their use in organic
Keywords: Enediynes; Trifluoroborate; Cross-coupling; Palladium
catalyzed.
*
Corresponding author. Tel.: +865 974 3260; fax: +865 974 2997;
e-mail: kabalka@utk.edu
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.021

764
G. W. Kabalka et al. / Tetrahedron Letters 46 (2005) 763–765
Table 1. Optimization of reaction conditions using reaction of 1 with 2a
Entry
Conditionsb
Yield %c
3
4
1 (recovered)
1
2
3
4
5
6
7
8
9d
Pd(dppf)Cl2, MeOH, 12 h
Pd(dppf)Cl2, DMF, 16 h
10
21
18
43
52
76
23
21
30
36
20
12
19
16
8
52
56
64
26
14
0
Pd(dppf)Cl2, Toluene, 12 h
Pd(dppf)Cl2, THF, 6 h
Pd(dppf)Cl2, THF/H2O (20:1), 4 h
Pd(dppf)Cl2 10 mol %, THF/H2O (20:1), 2 h
Pd(OAc)2 10 mol %, THF/H2O (20:1), 16 h
Pd(PPh3)4 10 mol %, THF/H2O (20:1), 12 h
Pd(dppf)Cl2, THF/H2O (20:1), 16 h
26
22
18
45
54
50
a The ratio of 1 to 2 was 1:2.
b Reaction carried out at 50 ꢁC in the presence of 5 mol % of catalyst and 3 equiv of Cs2CO3.
c Isolated yield.
d 3 equiv of (i-Pr)2NEt were used in place of Cs2CO3.
Table 2. Cross-coupling of 1,1-dibromo-1-alkenes with potassium alkynyltrifluoroboratesa
Entry
R
R0
Yield (%)b
1
Phenyl
Phenyl
n-Butyl
85
82
74
73
76
81
73
76
66
82
64
75
2
3-Chloropropyl
Isopropenyl
Phenyl
3
Phenyl
Phenyl
Phenyl
4
5
p-Tolyl
Phenyl
6
p-Chlorophenyl
p-Chlorophenyl
p-Tolyl
7
3-Chloropropyl
3-Chloropropyl
3-Chloropropyl
3-Chloropropyl
3-Chloropropyl
Phenyl
8
9
o-Tolyl
10
11
12
1-Naphthyl
p-Nitrophenyl
Octyl
a Reactions carried out using 10 mol % of Pd(dppf)Cl2 with 3 equiv of Cs2CO3 in THF/H2O (20:1) at 50 ꢁC for 2 h.
b Isolated yield.
palladium) indicated formation of the desired product.
Increasing the amount of catalyst to 10 mol % generated
3 in 76% yield (Table 1, entry 6). Other palladium cata-
lysts, such as Pd(OAc)2 and Pd(PPh3)4, were less effec-
tive (Table 1, entries 7 and 8). Cs2CO3 gave higher
yields of enediyne than diisopropylethylamine (Table
1, entry 9). Optimum conditions for the reaction were
found to be 10 mol % of Pd(dppf)Cl2 and 3 equiv of
Cs2CO3 in THF/H2O (20:1) at 50 ꢁC for 2 h.
tonation of 1-alkynes, followed sequentially by trans-
metallation with boronic esters and treatment in situ
with KHF2. 1,1-Dibromo-1-alkenes were prepared by
literature methods.16 Under the optimized conditions,
reactions of various potassium alkynyltrifluoroborates
with different 1,1-dibromo-1-alkenes were evaluated17
and the results are summarized in Table 2. The reaction
resulted in good isolated yields. No significant differ-
ences in reactivity with respect to the electronic and
steric effects of the substituents were observed. 1-(2,2-
Dibromovinyl)-4-nitrobenzene also gave a good yield,
54%.
To enhance the utility of the reaction, we prepared a
variety of potassium alkynyltrifluoroborates via depro-

G. W. Kabalka et al. / Tetrahedron Letters 46 (2005) 763–765
765
K.; Ohmiya, H. J. Org. Chem. 2002, 653, 141; (f) Zhao, Y.;
Tykwinski, R. R. J. Am. Chem. Soc. 1999, 121, 458.
6. Zeni, G.; Perin, G.; Cella, R.; Jacob, R. G.; Braga, A. L.;
Silveira, C. C.; Stefani, H. A. Synlett 2002, 6, 975.
7. Shen, W.; Thomas, S. A. Org. Lett. 2000, 2, 2857.
8. For reviews see: (a) Suzuki, A. J. Org. Chem. 2002, 653,
83; (b) Suzuki, A. J. Org. Chem. 1999, 576, 147; (c)
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
9. (a) Soderquist, J. A.; Matos, K.; Rane, A.; Ramos, J.
In summary, we have developed a convenient method
for preparing cross-conjugated geminal enediynes from
readily accessible 1,1-dibromo-1-alkenes and stable
potassium alkynyltrifluoroborates. The reaction condi-
tions are very straightforward and enediynes are ob-
tained in high yield.
Acknowledgements
Tetrahedron Lett. 1995, 36, 2401; (b) Furstner, A.; Seidel,
G. Tetrahedron 1995, 51, 11165.
¨
We thank the U.S. Department of Energy, The National
Institutes of Health, and the Robert H. Cole Founda-
tion for support of this research.
10. Castanet, A. S.; Colobert, F.; Schlama, T. Org. Lett. 2000,
2, 3559.
11. (a) Oh, C. H.; Jung, S. H. Tetrahedron Lett. 2000, 41,
8513; (b) Brown, H. C.; Bhat, N. G.; Srebnik, M.
Tetrahedron Lett. 1998, 29, 2631.
12. (a) Soulie, J.; Cadiot, P. Bull. Soc. Chim. Fr. 1966, 3846;
(b) Molander, G. A.; Brown, H. C. Synthesis 1979, 104; (c)
Blanchard, C.; Framery, E.; Vaultier, M. Synthesis 1996,
45.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2004.12.021.
ˆ
13. (a) Darses, S.; Michaud, G.; Genet, J. P. Eur. J. Org.
Chem. 1999, 1875; (b) Molander, G. A.; Katona, B. W.;
Machrouhi, F. J. Org. Chem. 2002, 67, 8416.
14. (a) Kabalka, G. W.; Venkataiah, B.; Dong, G. Org. Lett.
2003, 5, 3803; (b) Kabalka, G. W.; Dong, G.; Venkataiah,
B. Tetrahedron Lett. 2004, 45, 5139; (c) Kabalka, G. W.;
Venkataiah, B.; Dong Tetrahedron Lett. 2004, 45, 729; (d)
Kabalka, G. W.; Venkataiah, B.; Dong, G. J. Org. Chem.
2004, 69, 5807–5809; (e) Kabalka, G. W.; Mereddy, A. R.
Tetrahedron Lett. 2004, 45, 343; (f) Kabalka, G. W.;
Mereddy, A. R. Tetrahedron Lett. 2004, 45, 1417.
References and notes
1. (a) Moonen, N. N. P.; Boudon, C.; Gisselbrecht, J.-P.;
Seiler, P.; Gross, M.; Diederich, F. Angew. Chem., Int. Ed.
2002, 41, 3044; (b) Nielsen, M. B.; Schreiber, M.; Beak, Y.
G.; Seiler, P.; Lecomte, S.; Boudon, C.; Tykwinski, R. R.;
Gisselbrecht, J.-P.; Gramlich, V.; Skinner, P. J.; Bosshard,
C.; Gunter, P.; Gross, M.; Diederich, F. Chem. Eur. J.
15. It has been reported water accelerates coupling reactions
involving cesium carbonate Johnson, C. R.; Braun, M. P.
J. Am. Chem. Soc. 1993, 115, 11014.
16. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
17. Typical experimental procedure: (2,2-dibromovinyl)ben-
zene, 1, (0.2 mmol) was placed in an oven-dried round-
¨
2001, 7, 3263.
2. (a) Campbell, K.; McDonald, R.; Ferguson, M. J.;
Tykwinski, R. R. Organometallics 2003, 22, 1353; (b)
Campbell, K.; McDonald, R.; Tykwinski, R. R. J. Org.
Chem. 2002, 67, 1133.
3. Gobbi, L.; Seiler, P.; Diederich, F.; Gramlich, V.; Boudon,
C.; GisselBrecht, J.-P.; Gross, M. Helv. Chem. Acta 2001,
84, 743.
4. Donovan, P. M.; Scott, L. T. J. Am. Chem. Soc. 2004, 126,
3108.
5. (a) Rankin, T.; Tykwinski, R. R. Org. Lett. 2003, 5, 213;
(b) Hwang, G. T.; Son, H. S.; Ku, J. K.; Kim, B. H. J. Am.
Chem. Soc. 2003, 125, 11241; (c) Kaafarani, B. R.;
Neckers, D. C. Tetrahedron Lett. 2001, 42, 4099; (d)
Kaafarani, B. R.; Pinkerton, A. A.; Neckers, D. C.
Tetrahedron Lett. 2001, 42, 8137; (e) Uenishi, J.; Matsui,
bottomed flask under a nitrogen atmosphere. THF
(2.0 mL) and H2O (0.1 mL) were added and the resultant
solution stirred. Potassium (p-tolylethynyl)trifluoroborate,
2, (0.4 mmol), Cs2CO3 (196 mg, 0.6 mmol), and
Pd(dppf)Cl2 (10 mol %) were then added. The mixture
was stirred at 50 ꢁC for 2 h. The mixture was extracted
with ethyl ether (4 · 5 mL). The organic layer was
separated, dried over anhydrous MgSO4, and filtered.
The solvent was removed under reduced pressure and the
product purified by silica gel chromatography (ethyl
acetate–hexane).