Microwave enhanced cross-coupling reactions involving alkenyl- and alkynyltrifluoroborates

Article abstract of DOI:10.1016/j.tetlet.2007.08.002

Cross-coupling reactions of potassium alkenyltrifluoroborates and alkynyltrifluoroborates with aryl triflates in the presence of a palladium catalyst occur rapidly utilizing microwave irradiation. The coupled products are generated in good to excellent yi

Full text of DOI:10.1016/j.tetlet.2007.08.002

Tetrahedron Letters 48 (2007) 7091–7093
Microwave enhanced cross-coupling reactions involving
alkenyl- and alkynyltrifluoroborates
George W. Kabalka,* Abhijit Naravane and Li Li Zhao
Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, TN 37996-1600, USA
Received 6 July 2007; revised 27 July 2007; accepted 1 August 2007
Available online 6 August 2007
Abstract—Cross-coupling reactions of potassium alkenyltrifluoroborates and alkynyltrifluoroborates with aryl triflates in the pres-
ence of a palladium catalyst occur rapidly utilizing microwave irradiation. The coupled products are generated in good to excellent
yields.
Ó 2007 Elsevier Ltd. All rights reserved.
Palladium-catalyzed cross-coupling reactions are of
great utility in organic chemistry.1 Suzuki–Miyaura
reactions are particularly useful since a wide variety of
boron compounds are readily prepared or are commer-
cially available. In addition, boron is relatively non-
toxic, readily available, and has a low environmental
load. The most common organoboron derivatives used
in Suzuki reactions are boronic acids and boronic esters.
There are several potential problems with these deriva-
tives. For example, vinylboronic acids can be lost via
polymerization side reactions. Furthermore, vinylboron-
ic esters are not always selective in cross-coupling reac-
tions, often yielding mixtures of Suzuki–Miyaura and
Heck coupled products.2 Recent studies have shown
that potassium alkenyltrifluoroborates and alkynyltri-
fluoroborates offer solutions to problems that sometimes
occur in organoboron coupling reactions.3 The trifluo-
roborates are readily prepared by the addition of inex-
pensive KHF2 to a variety of boronic acid derivatives.
These materials are crystalline, air stable solids that
are easy to manipulate yet remain quite reactive.
reactions using microwave irradiation.5 We discovered
that palladium-catalyzed coupling reactions of alkenyl-
trifluoroborates and alkynyltrifluoroborates with aryl
triflates furnish the desired products within 15 min un-
der aqueous conditions and in good yields (Scheme 1).
Similar reactions require several hours under thermal
conditions.3g In this Letter we outline the scope of the
microwave assisted cross-coupling reactions of alkenyl-
trifluoroborates and alkynyltrifluoroborates with aryl
triflates (Scheme 1).
Various palladium catalysts, solvents, and reaction con-
ditions were examined using potassium (phenylethyn-
yl)trifluroborate, 1, and 4-cyanophenyl triflate, 2, as
model substrates (Scheme 1 and Table 1). A catalyst
loading of 5 mol % PdCl2(dppf)CH2Cl2, along with
3.0 equiv of Hunig’s base (i-Pr2NEt), in 2-propanol/
water (2:1) at 100 °C was found to provide the coupled
products in good to excellent yields (Table 1, entry 5).
Reactions using Pd2dba3ÆCHCl3/dppf, Pd2dba3/(o-toyl)3,
Pd(OAc)2/dppf, and Pd(OAc)2 resulted in lower yields
than those using PdCl2(dppf)CH2Cl2. In the absence
of a palladium catalyst, no coupling product was
observed. Reactions did not occur in pure water (Table
1, entry 4) whereas a mixture of THF–H2O (2:1) gave
moderate yield (67%). Hunig’s base was found to be
the most effective. Decreasing the reaction time to
10 min gave lower yields (Table 1, entry 6).
In recent years, microwave technology has gained
importance in organic chemistry.4 Microwave induced
reactions are energy efficient and generally lead to
enhanced product yields. As part of an ongoing project
focused on microwave assisted Suzuki coupling reac-
tions, we initiated a study of the behavior of alkenyltri-
fluoroborates and alkynyltrifluoroborates in Suzuki
After optimization of the reaction conditions, we inves-
tigated the coupling of various alkynyltrifluoroborates
with a number of triflates (Table 2). Triflates containing
electron withdrawing groups successfully coupled with
*
Corresponding author. Tel.: +1 865 974 3260; fax: +1 865 974
2997; e-mail: kabalka@utk.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.002

7092
G. W. Kabalka et al. / Tetrahedron Letters 48 (2007) 7091–7093
OTf
5 mol % PdCl (dppf)CH Cl
2
2
2
BF K
3
+
CN
CN
i-PrOH-H O(2:1), i-Pr NEt
2
2
º
1
2
MW, 100 C, 15 min.
Scheme 1.
Table 1. Optimization of reaction conditionsa
Entry
Base
Conditions
Catalysts
Solvent
Yieldsb (%)
1
2
3
4
5
6
7
CsCO3
CsCO3
MW—15 min
MW—15 min
MW—15 min
MW—15 min
MW—15 min
MW—10 min
MW—15 min
Pd(OAc)2
Pd2dba3ÆCHCl3
THF–water
i-PrOH–water
THF–water
Water
i-PrOH–water
i-PrOH–water
i-PrOH–water
45
50
67
0
91
80
60
Hunig’s base
Hunig’s base
Hunig’s base
Hunig’s base
K2CO3
PdCl2(dppf)CH2Cl2
PdCl2(dppf)CH2Cl2
PdCl2(dppf)CH2Cl2
PdCl2(dppf)CH2Cl2
Pd2dba3ÆCHCl3
a All reactions were carried out at 100 °C.
b All yields are of pure products isolated by silica gel chromatography.
Table 2. Coupling reactions of alkynyltrifluoroboratesa
Entry
R1BF3K
R2-TOf
R1–R2
Yieldb (%)
91
OTf
1
BF3K
CN
CN
OTf
2
96
NO2
BF3K
NO2
Cl
OTf
OTf
Cl
3
4
5
6
94
90
79
65
CN
CN
BF3K
BF3K
CN
CN
OTf
BF3K
OTf
O
BF3K
O
a All reactions were run in i-PrOH–H2O (2:1) at 100 °C for 15 min.
b All yields are of pure products isolated by silica gel chromatography.
alkynyltrifluoroborates in good yields (Table 2, entries
1–4). Triflates containing electron donating groups gave
moderately lower yields (Table 2, entries 5 and 6). Alke-
nyltrifluoroborates also readily participated in the reac-
tion (Table 3), highest yields were obtained when
electron withdrawing groups were present in the triflates
(Table 3, entries 1–3). Electron withdrawing groups in
the alkenyltrifluoroborates also enhanced the yields
(Table 3, entry 4). All alkenyltrifluoroborates provided
cross-coupled products in good yields (Table 3, entry
1–6).
Reactions are rapid and simple to perform. In a typical
experiment, the organotrifluoroborate (0.55 mmol) and
palladium catalyst (5 mol %) are placed in an argon
flushed Pyrex tube. The aryl triflate (0.50 mmol) is then
added along with di-isopropyl ethyl amine (1.5 mmol)
and 5 ml of isopropanol/water (2:1). The Pyrex tube is

G. W. Kabalka et al. / Tetrahedron Letters 48 (2007) 7091–7093
Table 3. Coupling reactions of alkenyltrifluoroboratesa
7093
Entry
R1BF3K
R2-OTf
R1–R2
Yieldsb (%)
NO2
OTf
OTf
BF3K
BF3K
1
82
92
90
90
75
61
C5H11
NO2
C5H11
NO
2
2
3
4
5
6
NO2
CN
OTf
BF K
3
CN
BF3K
OTf
OTf
CF3
CF
Cl
3
BF3K
Cl
OCH3
OTf
BF3K
C5H11
CH O
3
C5H11
a All reactions were run in i-PrOH–H2O (2:1) at 100 °C for 15 min.
b All yields are of pure products isolated by silica gel chromatography.
A.; Ribagorda, M. J. Am. Chem. Soc. 2003, 125, 11148; (d)
Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 1381; (e)
Darses, S.; Michauld, G.; Genet, J.-P. Eur. J. Org. Chem.
1999, 1875; (f) Molander, G. A.; Bernardi, C. R. J. Org.
Chem. 2002, 67, 8424; (g) Molander, G. A.; Katona, B. W.;
Machrouhi, F. J. Org. Chem. 2002, 67, 8416; (h) Pucheault,
M.; Darses, S.; Genet, J.-P. Eur. J. Org. Chem. 2002, 3552;
(i) Molander, G. A.; Rivero, M. R. Org. Lett. 2002, 4, 107;
(j) Batey, R. A.; Thadani, A. N.; Smil, D. V.; Lough, A.
Synthesis 2000, 990.
then capped with a rubber septum, placed in a CEM
microwave unit, and allowed to react at 100 °C for
15 min. The product is isolated by adding water
(15 ml) and ether (15 ml), the ether layer separated, the
solvent removed under reduced pressure, and the prod-
uct isolated by column chromatography.
Acknowledgments
4. For microwave assisted coupling reactions, see: (a) Arvela,
R. K.; Leadbeater, N. E.; Collins, M. J., Jr. Tetrahedron
2005, 61, 9349; (b) Varma, R. S. Microwave Technology—
Chemical Applications: Kirk-Othmer Encyclopedia of Chem-
ical Technology, 5th ed.; John Wiley and Sons: New York,
2004; (c) Arvela, R. K.; Leadbeater, N. E. Org. Lett. 2005,
7, 2101; (d) Miao, G.; Ye, P.; Yu, L.; Baldino, C. M. J. Org.
Chem. 2005, 70, 2332; (e) Singh, R.; Viciu, M. S.;
Kramareva, N.; Navarro, O.; Noland, S. P. Org. Lett.
2005, 7, 1829; (f) Liu, Y.; Khemtong, C.; Hu, J. Chem.
Commun. 2004, 398; (g) Wang, Y.; Sauer, D. R. Org. Lett.
2004, 6, 2793; (h) Solodenko, W.; Schoen, U.; Messinger, J.;
Glinschert, A.; Kirschning, A. Synlett 2004, 1699; (i)
Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250; (j)
Gong, Y.; He, W. Org. Lett. 2002, 4, 3803; (k) Villemin, D.;
Gomez-Escalonilla, M. J.; Saint-Clair, J. F. Tetrahedron
Lett. 2001, 42, 635.
We wish to thank the US Department of Energy and the
Robert H. Cole Foundation for support of this research.
References and notes
1. (a) Barder, T. E.; Walker, S. D.; Martinelli, J. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685; (b)
Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
4176; (c) Suzuki, A. J. Organomet. Chem. 1999, 576, 147;
(d) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; (e)
Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim,
Germany, 1998, Chapter 2; (f) Miyaura, N.; Yamada, K.;
Suzuki, A. Tetrahedron Lett. 1979, 36, 3437.
5. (a) Kabalka, G. W.; Al-Masum, M. Tetrahedron Lett. 2005,
46, 6329; (b) Kabalka, G. W.; Al-Masum, M. Org. Lett.
2006, 8, 11; (c) Kabalka, G. W.; Zhou, L. Lett. Org. Chem.
2006, 3, 320; (d) Kabalka, G. W.; Wang, L.; Pagni, R. M.;
Hair, C. M.; Venkataiah, B. Synthesis 2003, 217; (e)
Kabalka, G. W.; Pagni, R. M.; Wang, W.; Venkataiah,
B.; Hair, C. M. Green Chem. 2000, 2, 120.
2. (a) Lightfoot, A. P.; Maw, G.; Thirsk, C.; Twiddle, S.;
Whiting, A. Tetrahedron Lett. 2003, 44, 7645; (b) Hunt, A.
R.; Stewart, S. K.; Whiting, A. Tetrahedron Lett. 1993, 34,
3599.
3. (a) Tremblay-Morin, J.-P.; Raeppel, S.; Gaudette, F.
Tetrahedron Lett. 2004, 45, 3471; (b) Molander, G. A.;
Felix, L. A. J. Org. Chem. 2005, 70, 3950; (c) Molander, G.