Efficient Ligandless Palladium-Catalyzed Suzuki Reactions of Potassium Aryltrifluoroborates

Article abstract of DOI:10.1021/ol025845p

R₁BF₃K + R₂X Pd(OAc) ₂ (0.5% mol)→ R₁-R₂ K₂CO ₃ (3 equiv) methanol, reflux R₁ = aryl or heteroaryl R₂ = aryl or heteroaryl X = halide, triflate The ligandless palladium-catalyzed Suzuki cross-coupling reaction of potassium aryl- and heteroaryltrifluoroborates with aryl- or heteroaryl halides or triflates proceeds readily with very good yields. The cross coupling can be effected in methanol or water, in the open air, using Pd(OAc)₂ as a catalyst in the presence of K₂CO₃. A variety of functional groups are tolerated.

Full text of DOI:10.1021/ol025845p

ORGANIC
LETTERS
2002
Vol. 4, No. 11
1867-1870
Efficient Ligandless Palladium-Catalyzed
Suzuki Reactions of Potassium
Aryltrifluoroborates
Gary A. Molander* and Betina Biolatto
Roy and Diana Vagelos Laboratories, Department of Chemistry,
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104-6323
gmolandr@sas.upenn.edu
Received March 8, 2002
ABSTRACT
The ligandless palladium-catalyzed Suzuki cross-coupling reaction of potassium aryl- and heteroaryltrifluoroborates with aryl- or heteroaryl
halides or triflates proceeds readily with very good yields. The cross coupling can be effected in methanol or water, in the open air, using
Pd(OAc)2 as a catalyst in the presence of K2CO . A variety of functional groups are tolerated.
3
The Suzuki cross-coupling reaction, which involves the
coupling of an organoboron compound with an electrophile,
has become an extremely useful method in organic synthesis.1
In general, boronic acids or esters bearing sp2-hybridized
substituents react very well under coupling conditions.
However, the boronic acids are often subject to dimerization
and cyclic trimerization with loss of water to form boronic
acid anhydrides and boroxines, respectively, and the deter-
mination of precise stoichiometry can be extraordinarily
difficult, requiring an excess of these compounds in the
coupling reactions. On the other hand, potassium organo-
trifluoroborate salts offer solutions for these problems. These
salts are easily prepared2 and purified, and thus they are easier
to handle. Geneˆt and co-workers3 and Chen and Xia4 have
demonstrated that aryl- and heteroaryltrifluoroborates couple
well with aryldiazonium and diaryliodonium ions, respec-
tively, under both ligand and ligandless conditions, even in
the presence of halogen functionalities on the substrates.
These reactions were carried out in the absence of base. Fu
and co-workers5 attempted the coupling reaction of an aryl
bromide with potassium o-tolyltrifluoroborate with Pd2(dba)3/
P(t-Bu)3 in the absence of a base, but no coupling was
observed. Previous work in our laboratory demonstrated the
feasibility of the cross-coupling reaction of potassium alkyl-6
and alkenyltrifluoroborates7 with different aryl and alkenyl
halides and triflates, using PdCl2(dppf)‚CH2Cl2 as a catalyst
in the presence of Cs2CO3 or Et3N. Recently, Batey and
Quach8 reported the synthesis and cross-coupling reactions
of tetrabutylammonium organotrifluoroborate salts with a
(3) (a) Darses, S.; Jeffery, T.; Brayer, J.-L.; Demoute, J.-P.; Geneˆt, J.-P.
Bull. Soc. Chim. Fr. 1996, 133, 1095-1102. (b) Darses, J.-P.; Brayer, J.-
L.; Demoute, J.-P.; Geneˆt, J.-P. Tetrahedron Lett. 1997, 38, 4393-4396.
(c) Darses, S.; Michaud, G.; Geneˆt, J.-P. Eur. J. Org. Chem. 1999, 1875-
1883.
(4) Chen, Z.-C.; Xia, M. Synth. Commun. 1999, 29, 2457-2465.
(5) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020-
4028.
(1) For reviews see (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
2457-2483. (b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168. (c)
Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; VCH: Weinheim, Germany, 1998; pp 49-97.
(2) (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.
(6) Molander, G. A.; Ito, T. Org. Lett. 2001, 3, 393-396.
(7) Molander, G. A.; Rodriguez Rivero, M. Org. Lett. 2002, 4, 107-
109.
(8) Batey, R. A.; Quach, T. D. Tetrahedron Lett. 2001, 42, 9099-9103.
10.1021/ol025845p CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/30/2002

variety of alkenyl and aryl halides using Pd(OAc)2/dppb as
a catalyst and Cs2CO3 as a base in DME/water. Ligandless
palladium-catalyzed conditions9 have also been used to
perform cross-coupling reactions of arylboronic acids.
Continuing with our investigation on the application of
potassium organotrifluoroborates in Suzuki cross-coupling
reactions, we have explored conditions for the cross-coupling
reaction of potassium aryl- and heteroaryltrifluoroborates
with various aryl and heteroaryl halides and triflates. We
optimized the conditions for the reaction between potassium
phenyltrifluoroborate (1a) and 1-bromonaphthalene (2a) in
terms of catalyst [PdCl2‚dppf, Pd3(dba)2, or Pd(OAc)2], ligand
[dppf or (t-Bu)3P], base (Et3N, Hunig’s base, t-BuNH2,
K2CO3, Cs2CO3, KF, K3PO4), and different solvent systems
(MeOH, EtOH, n-PrOH, i-PrOH, dioxane, THF, water).
Among the catalyzed conditions in the presence of a ligand,
1% PdCl2(dppf)‚CH2Cl2 and 3 equiv of Hunig’s base in
ethanol proved to be the best, leading to complete conversion
of 2a into 1-phenylnaphthalene (3a) after 7 h of heating at
reflux. This result is in accordance with the conditions found
to be suitable for the cross-coupling of potassium alkenyl-
trifluoroborates.7 In addition to the above-mentioned condi-
tions, the system Pd(OAc)2/K2CO3/methanol proved to be
exceptional for the cross-coupling reaction (Scheme 1).
electron-withdrawing and electron-donating groups, even in
the case of the highly hindered 2-bromomesitylene 2c, where
the coupling led to a 52% yield of the desired product using
5% loading of the catalyst. The reduced yield in the case of
entries 16 and 17 is caused by triflate hydrolysis under the
basic conditions of the coupling reaction. Presumably because
of solubility, the coupling reactions of 4-bromobenzoic acid
2e, 4-bromophenol 2j, and 4′-bromoacetanilide 2m with 1a
were most effective when carried out in water.
We subsequently investigated the coupling reaction be-
tween different potassium aryl- and heteroaryltrifluoroborates
with aryl bromides (Table 2). Electron-deficient and electron-
rich aryl- and heteroaryltrifluoroborates could be efficiently
coupled to 4-bromobenzonitrile 2i. Ortho-substituted tri-
fluoroborates afforded very good yields of biaryls when
coupled with electron-deficient electrophiles, even in hin-
dered situations (entries 4-6).
During the course of this investigation, Batey and Quach
reported their results employing tetrabutylammonium (TBA+)
salts of the aryltrifluoroborates.8 The conditions reported
herein are differentiated from those in that study by the
following significant features. (1) The catalyst loading used
is 10 times lower. (2) No ligands need to be added. (3)
Shorter reaction times are required. (4) Environmentally
sound solvents are used. (5) The process is more economical
and environmentally friendly when potassium trifluoroborate
salts are utilized as the boron reagents.
Scheme 1
Having stated this, our conditions also proved to be
effective in the coupling reactions of TBA+ salts of aryltri-
fluoroborates. When TBA+ phenyltrifluoroborate 1i was
reacted with 4-bromoanisole 2b and 4-bromonitrobenzene
2d, the coupling reaction reached completion for 2d (Table
2, entry 7) after 2 h at reflux, while NMR analysis of the
crude reaction mixture of 2b showed 78% of the product
and 22% of the unreacted electrophile along with some of
the TBA moiety (Table 2, entry 8). Likewise, the reaction
of arylboronic acids under these conditions proceeded readily
(Table 2, entries 9-11) with yields similar to those obtained
for trifluoroborate salts, in accordance with previously
reported results.9
MoreoVer, under these conditions, the reactions could be
performed in the air without a reduction in the yield of
biaryls.8 The ligandless reaction was then optimized in terms
of the reaction time and the amount of catalyst. The catalyst
loading was progressively reduced to 2, 0.5, and finally to
0.2%. An 80% yield of 3a was obtained, and 14% of the
starting material (1-bromonaphthalene, 2a) was recovered
under the latter conditions (Table 1, entry 1).
The optimized conditions were subsequently tested in the
coupling reaction of 1a with different aryl, heteroaryl, and
alkenyl bromides (Scheme 2, Table 1). The reaction pro-
ceeded with very good yields for electrophiles bearing both
Previous reports have indicated that water was required
as a cosolvent for the trifluoroborate coupling reactions6,8
and that one or more hydroxyl groups displace fluorides on
the tetracoordinate boron species involved in the transmeta-
lation step of the catalytic cycle.8,10 We have conducted
experiments heating PhBF3K in methanol at reflux, with the
addition of 0, 1, 2, and 3 equiv of base. After 2 h, all of the
reaction mixtures were filtered, equal amounts of deuterated
acetone were added to each one, and the resulting solutions
Scheme 2
(9) (a) Campi, E. M.; Jackson, W. R.; Marcuccio, S. M.; Naeslund, C.
G. M. Chem. Commun. 1994, 2395. (b) Darses, S.; Jeffery, T.; Geneˆt, J.-
P.; Brayer, J.-L.; Demoute, J.-P. Tetrahedron Lett. 1996, 37, 3857-3860.
(c) Bumagin, N. A.; Bykov, V. V. Tetrahedron 1997, 53, 14437-14450.
(d) Badone, D.; Baroni, M.; Cardamone, R.; Ielmini, A.; Guzzi, U. J. Org.
Chem. 1997, 62, 7170-7173. (e) Goodson, E. F.; Wallow, T. I.; Novak, B.
M. Org. Synth. 1998, 75, 61-68. (f) Zim, D.; Monteiro, A. L.; Dupont, J.
Tetrahedron Lett. 2000, 41, 8199-8202. (g) Ma, D.; Wu, Q. Tetrahedron
Lett. 2001, 42, 5279-5281. (h) Wallow, T. I.; Novak, B. M. J. Org. Chem.
1994, 59, 5034-5037 and refs therein.
(10) Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461-470.
1868
Org. Lett., Vol. 4, No. 11, 2002

Table 1. Cross-Coupling Reactions of Potassium Phenyltrifluoroborate 1a with Organic Halides and Triflates
a Condition A: Pd(OAc)2 (0.5%), K2CO3 (3 equiv), MeOH, reflux. Condition B: Pd(OAc)2 (0.5%), K2CO3 (3 equiv), water, 65 °C. Condition C: addition
of the neat triflate after the catalyst. b Reaction was carried out in the open atmosphere. c Reaction was carried out at room temperature. d Reaction was
carried out on a 4 mmol scale and the product purified by recrystallization. e Determined by NMR analysis.
were then analyzed using 11B and 19F NMR. In these
experiments, the 19F NMR showed the absence of fluorine
bonded to the boron atom after adding 3 equiv of base. The
11B NMR shifts revealed a quadruplet at 4.35 ppm when no
base was added and a singlet at 5.47 ppm when 3 equiv of
base was added. Analysis of phenylboronic acid in the same
solvent mixture showed a singlet at 28.48 ppm (referenced
to external BF3‚OEt2 as 0.0 ppm). We have thus come to
the conclusion that the trifluoroborates do not remain intact
under the reaction conditions and that an intermediate that
does not retain all of the fluorides on the boron species is
involved in the key transmetalation step. Using a different
analysis, Batey and Quach have previously come to the same
conclusion.8 Further mechanistic studies are currently under-
way in order to determine the exact nature of the species
generated.
In summary, ligandless palladium-catalyzed conditions
have been found to be suitable for the coupling of potassium
aryl- and heteroaryltrifluoroborates with aryl and heteroaryl
bromides and triflates. The reaction proved to be tolerant of
a variety of functional groups. It can be carried out in
methanol or water in the air, with as low as 0.2% loading of
catalyst in relatively short reaction times. The high yields,
in addition to the characteristics of the boron byproducts,
allow simple workup techniques to be applied to obtain
products with greater than 95% purity. These features,
Org. Lett., Vol. 4, No. 11, 2002
1869

Table 2. Cross-Coupling Reactions of Aryl- and Heteroaryltrifluoroborates with Organic Halides
a Condition A: Pd(OAc)2 (0.5%), K2CO3 (3 equiv), MeOH, reflux. Condition B: Pd(OAc)2 (0.5%), K2CO3 (3 equiv), water, 65 °C. b Reduced yield due
to low recovery from the reaction mixture. c Reaction was carried out at room temperature. d Reaction was carried out in the open atmosphere. e Determined
by NMR analysis.
combined with the shelf stability of the aryltrifluoroborate
complexes, make this technique environmentally sound,
economical, and very attractive for use in industrial processes
and combinatorial chemistry.
B.B. thanks the Fundacio´n Antorchas (Argentina) and the
Universidad Nacional del Litoral (Santa Fe, Argentina) for
postdoctoral fellowships.
Supporting Information Available: Full experimental
details. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. We thank Johnson & Johnson, Aldrich
Chemical Co., Merck Research Laboratories, Array Bio-
pharma, and Johnson Matthey for their generous support.
OL025845P
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Org. Lett., Vol. 4, No. 11, 2002