Scope of the suzuki-Miyaura cross-coupling reactions of potassium heteroaryltrifluoroborates

Article abstract of DOI:10.1021/jo802590b

A wide variety of bench-stable potassium heteroaryltrifluoroborates were prepared, and general reaction conditions were developed for their cross-coupling to aryl and heteroaryl halides. The cross-coupled products were obtained in good to excellent yields. This method represents an efficient and facile installation of heterocyclic building blocks onto preexisting organic substructures.

Full text of DOI:10.1021/jo802590b

Scope of the Suzuki-Miyaura Cross-Coupling Reactions of
Potassium Heteroaryltrifluoroborates
Gary A. Molander,* Belgin Canturk, and Lauren E. Kennedy
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104-6323
gmolandr@sas.upenn.edu
ReceiVed NoVember 21, 2008
A wide variety of bench-stable potassium heteroaryltrifluoroborates were prepared, and general reaction
conditions were developed for their cross-coupling to aryl and heteroaryl halides. The cross-coupled
products were obtained in good to excellent yields. This method represents an efficient and facile installation
of heterocyclic building blocks onto preexisting organic substructures.
Introduction
progress has recently been made by numerous groups in the
development of highly active catalyst systems that promote the
cross-coupling of a broad range of heteroarylboronic acids with
aryl and heteroaryl halides using a single set of reaction
conditions.4-8 For example, Buchwald and co-workers reported
that palladium precatalysts {[Pd2(dba)3] and Pd(OAc)2}, steri-
cally bulky, electron-rich phosphine ligands (SPhos and
XPhos),9 and K3PO4 in n-butanol at 100 °C constituted an
efficient system to cross-couple a wide range of heteroarylbo-
ronic acids with aryl and heteroaryl halides.4 Additionally, Fu
and co-workers utilized [Pd2(dba)3], PCy3, and K3PO4 in
dioxane/H2O at 100 °C to facilitate the cross-coupling of a broad
range of nitrogen-containing heterocycles with aryl and het-
eroaryl halides.5 Both of these recent improvements in heteroaryl
cross-couplings focused on the development of efficient catalyst
Heterobiaryls are ubiquitous in natural products, pharmaco-
logically active compounds, polymers, and other useful materi-
als. Transition-metal-catalyzed cross-coupling reactions are often
utilized for the construction of these compounds because they
can directly assemble valuable motifs in a highly convergent
fashion. Among the various cross-coupling reactions, the
Suzuki-Miyaura reaction is the most extensively used method
to prepare these compounds owing to the relatively low toxicity
of the boron byproducts, the tolerance of a wide range of
functional groups, and the ready availability of organoboron
compounds.1,2
Although the cross-coupling of arylboronic acids with aryl
and heteroaryl halides has been studied extensively, until
recently, the cross-coupling of heteroarylboronic acid counter-
parts had received less attention, and only isolated examples
had been reported. The relative lack of concerted effort in this
area might be attributed in part to the difficult preparation and
isolation of heteroarylboronic acids.3 Fortunately, remarkable
(5) Kudo, N.; Perseghini, M.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45,
1282–1284.
(6) (a) Kondolff, I.; Doucet, H.; Santelli, M. Synlett 2005, 2057–2061. (b)
Kondolff, I.; Doucet, H.; Santelli, M. J. Mol. Catal. A: Chem. 2007, 269, 110–
118.
(7) (a) Fleckenstein, C. A.; Plenio, H. J. Org. Chem. 2008, 73, 3236–3244.
(b) Fleckenstein, C. A.; Plenio, H. Eur. J. Org. Chem. 2008, 4267–4279.
(8) (a) Smith, A. E.; Clapman, K. M.; Batsanov, A. S.; Bryce, M. R.; Tarbit,
B. Eur. J. Org. Chem. 2008, 1458–1463. (b) Guram, A. S.; King, A. O.; Allen,
J. G.; Wang, X.; Schenkel, L. B.; Chan, J.; Bunel, E. E.; Faul, M. M.; Larsen,
R. D.; Martinelli, M. J.; Reider, P. J. Org. Lett. 2006, 8, 1787–1789. (c) Guram,
A. S.; Wang, X.; Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M. J.
Org. Lett. 2007, 72, 5104–5112.
(1) For reviews on palladium-catalyzed Suzuki-Miyaura reactions, see: (a)
Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483. (b) Suzuki, A. J.
Organomet. Chem. 1999, 576, 147–168. (c) Little, A. F.; Fu, G. C. Angew. Chem.,
Int. Ed. 2002, 41, 4177–4211.
(2) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry; Pergamon
Press: Amsterdam, 2000.
(3) Tyrell, E.; Brookes, P. Synthesis 2004, 469–483.
(4) (a) Billingsley, K.; Anderson, K. W.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2006, 45, 3484–3488. (b) Billingsley, K.; Buchwald, S. L. J. Am. Chem.
Soc. 2007, 129, 3358–3366. (c) Billingsley, K.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2008, 47, 4695–4698.
(9) SPhos, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl; XPhos, 2-di-
cyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.
10.1021/jo802590b CCC: $40.75
Published on Web 12/23/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 973–980 973

Molander et al.
systems and employed what is to date the most readily available
nucleophilic organoboron reagents (i.e., boronic acids).
Because of their commercial availability, boronic acids are
most often utilized in the Suzuki-Miyaura cross-coupling
reactions. However, boronic acids are far from ideal, and they
exhibit several limitations that make them unattractive nucleo-
philic coupling partners. Boronic acids are not monomeric
materials, but rather exist in equilibrium with dimers and cyclic
trimers (boroxines).10 Consequently, many boronic acids are
waxy solids that are difficult to purify. Most importantly, many
boronic acids, and especially electron-deficient heteroarylboronic
acids, have a short shelf life owing to their tendency to undergo
facile protodeboronation. This instability often requires their
storage at low temperatures. The tendency to protodeboronate
quite often manifests itself during cross-coupling reactions
carried out in polar protic solvents.7a The protodeboronation
influences the stoichiometry of the reaction, requiring practi-
tioners to use excess boronic acids to ensure that an adequate
amount of this nucleophilic partner is available in cross-coupling
reactions. In fact, with a few exceptions,11 Virtually eVery study
focusing on heteroarylboronic acid coupling employs excess
organoboron reagent (as high as 250%) to achieVe satisfactory
yields.
preparation of a wide variety of these bench-stable heteroaryl-
trifluoroborates and disclose their efficient cross-couplings to a
broad range of aryl and heteroaryl halides using a single set of
reaction conditions that include near stoichiometric amounts of
the nucleophilic coupling partner.
Results and Discussion
In a previous communication, our group disclosed the
preparation of a limited number of heteroaryltrifluoroborates
and demonstrated their cross-coupling with aryl and heteroaryl
halides.13 Slightly modifying the previous procedure, a large
number of potassium heteroaryltrifluoroborates were prepared,
including furanyl-, thiophenyl-, pyrrolyl-, pyrazinyl-, isoxazolyl-,
pyridinyl-, pyrimidinyl-, indolyl-, benzothiophenyl-, benzofura-
nyl-, and benzopyridinyl derivatives from commercially avail-
able heteroarylboronic acids (Table 1). The reactions were
monitored by 11B NMR spectroscopy, and in all cases, the
transformations were complete in less than 10 min.
The conversion of heteroarylboronic acids to the correspond-
ing heteroaryltrifluoroborates gave the products in yields ranging
from 31 to 95% (Table 1). Immediate conversions of com-
mercially received heteroarylboronic acids provided the het-
eroaryltrifluoroborates in good to excellent yields (Table 1,
entries 1, 4, 5, 7, 10-15, 17, 18, 21, and 22). As a testament to
their instability, the heteroarylboronic acids that were stored at
-28 °C for several weeks and then converted to trifluoroborates
gave the products in moderate to low yields (Table 1, entries 2,
3, 6, 8, 9, 16, 19, and 23). Analysis of these commercial samples
by 11B NMR spectroscopy revealed that the heteroarylboronic
acids had partially protodeboronated (boric acid was observed
at δ ∼18 ppm). To confirm that the loss of a considerable
amount of material was from protodeboronation, we investigated
two of the low-yielding trifluoroborates [isoquinolin-4-yltri-
fluoroborate (1) and 4-methylthiophen-2-yltrifluoroborate (2f)]
more deeply. In the first investigation, 1 was prepared from the
corresponding 4-bromoisoquinoline in a sequential process of
lithium-halogen exchange, boration using triisopropyl borate and
quenching with KHF2 (eq 1).14 The one-pot, unoptimized
reaction provided the isoquinolin-4-yltrifluoroborate (1) in 62%
overall yield compared to a 34% yield from the one step
procedure using commercially available heteroarylboronic acid
(Table 1, entry 23).
Easily prepared, monomeric organoboron reagents that would
be more resistant to protodeboronation would eliminate many
of the problems encountered with the cross-coupling of het-
eroarylboronic acids. Heteroarylboronate esters could partially
circumvent the problems associated with heteroarylboronic
acids, but they themselves suffer from limitations that make
them less appealing alternatives, including a lack of atom
economy and problematic purification steps.
In recent years, there has been increased interest in the use
of potassium organotrifluoroborates as coupling partners for the
Suzuki-Miyaura reaction.12 Unlike their tricoordinate orga-
noboron counterparts, these tetracoordinate species are less prone
to undergo protodeboronation. Consequently, near-stoichiometric
amounts of the nucleophilic partner are employed for cross-
coupling reactions. The trifluoroborates are easily prepared from
a wide variety of organoboron reagents by the addition of
inexpensive potassium hydrogen fluoride (KHF2).12 The result-
ing organotrifluoroborates are air and moisture stable and can
be stored indefinitely at room temperature without any precau-
tion. Additionally, the vast majority of these salts are easily
purified via recrystallization, precipitation, or Soxhlet extraction.
We envisioned that the union of highly active catalyst systems
with potassium heteroaryltrifluoroborates as nucleophilic cou-
pling partners would be an ideal platform for the cross-coupling
of aryl and heteroaryl systems. Toward this end, we sought
unified, general reaction conditions that could be broadly applied
to virtually all heterocyclic nucleophiles and a wide range of
electrophilic coupling partners. For this study, we specifically
employed heteroaryltrifluoroborates for which the corresponding
boronic acids were highly problematic. Herein, we describe the
In the second study, recrystallization of the commercially
obtained 4-methylthiophen-2-ylboronic acid from CHCl3 and
subsequent conversion to the corresponding trifluoroborate
afforded the product 2f in 95% yield compared to a 69% yield
achieved from the boronic acid used as received (Table 1, entry
6). Of special note, several heteroaryltrifluoroborates (2a, 2i,
2j, 2l) that were stored at ambient temperature for three months
displayed tremendous stability, as they showed no sign of
protodeboronation over this period of time as determined by
11B NMR spectroscopy.
(10) (a) Boronic Acids; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2005. (b)
Onak, T. Organoborane Chemistry; Academic Press: New York, 1975.
(11) (a) Baxendale, I. R.; Griffiths-Jones, C. M.; Ley, S. V.; Tranmer, G. K.
Chem.sEur. J. 2006, 12, 407–4416. (b) Parry, P. P.; Bryce, M. R.; Tarbit, B.
Synthesis 2003, 7, 1035–1038. (c) Parry, P. P.; Bryce, M. R.; Tarbit, B. Org.
Biomol. Chem. 2003, 1, 1447–1449.
(12) For reviews on potassium organotrifluoroborates, see: (a) Darses, S.;
Genˆet, J.-P. Eur. J. Org. Chem. 2003, 4313–4327. (b) Molander, G. A.; Figueroa,
R. Aldrichim. Acta 2005, 38, 49–56. (c) Molander, G. A.; Ellis, N. Acc. Chem.
Res. 2007, 40, 275–286. (d) Stefani, H. A.; Cella, R.; Adriano, S. Tetrahedron
2007, 63, 3623–3658. (e) Darses, S.; Genˆet, J.-P. Chem. ReV. 2008, 108, 288–
305.
(13) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302–4314.
(14) See the Supporting Information for the preparation of isoquinolin-4-
yltrifluoroborate from the corresponding 4-bromoisoquinoline.
974 J. Org. Chem. Vol. 74, No. 3, 2009

Reactions of Potassium Heteroaryltrifluoroborates
TABLE 1. Preparation of Diverse Potassium Heteroaryltrifluoro-
boratesa
mobenzonitrile as the electrophilic partner, 1 mol % of
Pd(OAc)2, 2 mol % of RuPhos,16 and 2 equiv of Na2CO3 in
ethanol at 85 °C were determined to be the most effective
coupling conditions.17
Among the five-membered heterocycles, furan is one of the
most extensively studied because numerous natural products,
pharmaceutically active compounds, flavors, and fragrances
incorporate this motif.18 Even though the furan moiety is an
important scaffold, the low stability19 of the boronic acid
derivatives toward protodeboronation limits their use in
Suzuki-Miyaura reactions. Nonetheless, a few research groups
have reported the cross-coupling of furanboronic acid deriv-
atives.4b,6,7a,20 Recently, Plenio and Fleckstein demonstrated the
efficient cross-coupling of furan-3-ylboronic acid with a broad
range of activated N-heteroaryl chlorides using Na2PdCl4 and
disulfonated dicyclohexylfluorenylphosphine ligand at elevated
temperature (100 °C), but the cross-coupling of furan-2-
ylboronic acid was not reported.7a
Using the reaction conditions developed herein, furan-2-
yltrifluoroborate (2a) was efficiently coupled with a variety of
aryl halides. Initially, 2a was cross-coupled with various aryl
bromides (Table 2, entries 1-8). As shown in Table 2, the
reaction conditions worked equally well for electron-withdraw-
ing (Table 2, entries 1, 3, 4, 6, and 8), electron-donating (Table
2, entries 2, 5, 7, 9, and 10), and sterically hindered bromides
(Table 2, entry 5). Next, attention was turned to other electro-
philes, including aryl chlorides, iodides, and triflates. All classes
of electrophiles studied provided the products in good yields
(Table 2, entry 1). Because aryl chlorides are more readily
available and inexpensive compared to other electrophiles, these
substrates were examined in some detail with 2a. As was the
case with bromides, electron-withdrawing (Table 2, entries 1
and 3), electron-donating (Table 2, entries 2, 5, and 10), and
sterically hindered chlorides (Table 2, entries 5 and 9) all reacted
smoothly, affording the products in good to excellent yields.
We also demonstrated that the reaction could be scaled to 5
mmol, while at the same time reducing the catalyst/ligand ratio
by half [0.5 mol % of Pd(OAc)2 and 1 mol % of RuPhos,
respectively]. In this case the cross-coupled product was isolated
in 91% yield (Table 2, entry 1).
To expand the scope of the general reaction conditions further,
attention was turned to the cross-coupling of various heteroaryl-
trifluoroborates with 4-halobenzonitriles.
Five-Membered Ring Heterocycles. As previously men-
tioned, furan-2-ylboronic acid is a challenging coupling
partner,4b and using the protocols developed herein, 2a was
efficiently cross-coupled to aryl bromides and chlorides. The
conditions established were utilized to examine the coupling
of substituted furan-2-yltrifluoroborate derivatives. Toward this
end, 5-methylfuran-2-yltrifluoroborate (2b) was coupled with
a Commerically available heteroarylboronic acids were used.
b 4-Methylthiophen-2-ylboronic acid was recrystallized from CHCl3
immediately prior to use. c The isoquinolin-4-yltrifluoroborate was
prepared directly from 4-bromoisoquinoline.
With the requisite heteroaryltrifluoroborates in hand, general
conditions were sought to accomplish their cross-coupling. The
cross-coupling of a few heteroaryltrifluoroborates using condi-
tions reported in the literature gave the cross-coupled products
in modest yields,13,15 and therefore, additional screening was
undertaken to obtain more effective reaction conditions. We
chose furan-2-yltrifluoroborate (2a) as a model nucleophilic
partner because the corresponding furan-2-ylboronic acid is
known to protodeboronate rapidly during cross-coupling
events.4b,7a After an extensive screening process with 4-bro-
(16) RuPhos, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl.
(17) Variables changed in coupling optimization included catalyst/ligand
ratios (5/10 mol % and 3/6 mol %], solvents (DME, n-butanol, sec-butanol and
tert-amyl alcohol), bases (Cs2CO3, K2CO3, K3PO4, and Et3N), and base
equivalents (3, 1, and 0).
(18) (a) Liu, Y.; Zhang, S.; Abreu, P. J. M. Nat. Prod. Rep. 2006, 23, 630–
651. (b) Zviely, M. Perfum. FlaVor. 2006, 31, 20–35. (c) Sanz, C.; Czerny, M.;
Cid, C.; Schieberle, P. Eur. Food Res. Technol. 2002, 214, 299–302.
(19) Florentin, D.; Fournie-Zaluski, M. C.; Callanquin, M.; Roques, B. P.
J. Heterocycl. Chem. 1976, 13, 1265–1272.
(20) (a) Li, J.-H.; Zhu, Q.-M.; Xie, Y.-X. Tetrahedron 2006, 62, 10888–
10895. (b) Li, J.-H.; Deng, C.-L.; Xie, Y.-X. Synth. Commun. 2007, 37, 2433–
2448.
(21) (a) Heterocyclic Chemistry; Joule, J. A., Mills, K., Eds.; Blackwell
Science: Malden, MA, 2000. (b) Press, J. B. In Thiophene and its DeriVatiVes;
Gronowitz, S., Ed.; Wiley: New York, 1985; pp 345-677.
(15) (a) Barder, T. E.; Buchwald, S. L. Org. Lett. 2004, 6, 2649–2652. (b)
Molander, G. A.; Fumagalli, T. J. Org. Chem. 2006, 71, 5743–5747. (c) Pagano,
N.; Maksimoska, J.; Bregman, H.; Williams, D. S.; Webster, R. D.; Xue, F.;
Meggers, E. Org. Biomol. Chem. 2007, 5, 1218–1227.
J. Org. Chem. Vol. 74, No. 3, 2009 975

Molander et al.
TABLE 2. Cross-Coupling of Potassium Furan-2-yltrifluoroborate
with Diverse Aryl Halidesa
TABLE 3. Cross-Coupling of Five-Membered Potassium
Heteroaryltrifluoroborates with 4-Halobenzonitrilea
a All reactions were carried out using 0.25 mmol of aryl halide and
0.26 mmol of heteroaryltrifluoroborate. b Used 3 mol % of Pd(OAc)2
and 6 mol % of RuPhos. c Recovered 45% of deprotected product.
d Heated reaction for 48 h. e Used 5 mol % of Pd(OAc)2, 10 mol % of
RuPhos, and 3 equiv of Na2CO3, 48 h.
tion than thiophen-3-ylboronic acid.22 Until recently, few
examples had been reported for the cross-coupling of thiophe-
nylboronic acid derivatives.4b,6,7a,20 Doucet and Santelli reported
the cross-coupling of thiophen-3- and thiophen-2-ylboronic acids
witharylhalides6a andheteroarylbromides6b usingthe[Pd(C3H5)Cl]2/
Tedicyp23 catalytic system. These cross-coupling reactions were
performed at elevated temperatures (130 °C) using excess
boronic acids.
a All reactions were carried out using 0.25 mmol of aryl halide and
0.26 mmol of furan-2-yltrifluoroborate. b 1 mmol scale. c 5 mmol scale;
reduced catalyst/ligand loading to 0.5 mol % of Pd(OAc)2 and 1 mol %
of RuPhos.
Given the differential sensitivity of isomeric thiophenylbo-
ronic acids to protodeboronation, we were pleased that the
position of the trifluoroborate moiety (at the 3- or 2-position)
did not influence the coupling with 4-bromobenzonitrile, as the
desired products 4c,d were obtained in comparable yields, 93%
and 98%, respectively (Table 3, entries 3 and 4). However, for
the coupling of 4-chlorobenzonitrile, differences were observed
wherein thiophen-3-yltrifluoroborate (2d) was coupled in 96%
yield, while thiophen-2-yltrifluoroborate (2e) coupled in a
4-bromobenzonitrile, providing the product 4a in excellent yield
(Table 3, entry 1). However, the coupling of 2b with 4-chlo-
robenzonitrile afforded the product 4a in moderate yield (Table
3, entry 1). Additionally, the coupling of 5-formylfuran-2-
yltrifluoroborate (2c) with 4-bromobenzonitrile gave the desired
product 4b in only 39% yield (Table 3, entry 2).
Thiophenes find extensive use in materials science and in
medicinal chemistry.21 Although thiophenylboronic acids are
more stable than furanylboronic acids,7a they themselves also
suffer from protodeboronation under protic conditions, with
thiophen-2-ylboronic acid being more prone to protodeborona-
(22) Brown, R. D.; Buchanan, A. S.; Humffray, A. Aust. J. Chem. 1965, 18,
1521–1525.
(23) Tedicyp: cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane.
976 J. Org. Chem. Vol. 74, No. 3, 2009

Reactions of Potassium Heteroaryltrifluoroborates
slightly lower 83% yield. These conditions also proved to be
effective for the coupling of 4-methylthiophen-2-yltrifluorobo-
rate (2f) with 4-chlorobenzonitrile, affording the product 4e in
74% yield (Table 3, entry 5).
azoleboronic acid derivatives with aryl bromides, and the
couplings typically required 5-10 mol % of catalyst loading.29
The unified conditions developed herein proved to be effective
for the coupling of the 3,5-dimethylisoxazol-4-yltrifluoroborate
(2j) with 4-chlorobenzonitrile, affording the product 4i in 71%
yield (Table 3, entry 9).
Pyrroles receive significant attention because they are fre-
quently found in natural products and have use in pharmaceu-
ticals, molecular recognition, and materials science.24 Several
conditions for the cross-coupling of pyrroleboronic acid deriva-
tives have been reported in the literature.4a,b,5,25 The relatively
limited number of citations might be attributed to difficulties
associated with protodeboronation, as well as the propensity of
the boronic acids to homocouple.3 The homocoupling can be
avoided by protection of the nitrogen with either tert-butoxy-
carbonyl (Boc), triisopropylsilyl (TIPS), or phenysulfonyl
groups. Buchwald and co-workers recently reported that N-
protected pyrroleboronate esters serve as a better alternative than
the corresponding boronic acids for the cross-coupling
reactions.4a
Six-Membered-Ring Heterocycles and Benzannulated
Heterocycles. Pyridines are prevalent heterocycles found in
natural products and bioactive compounds, and therefore, their
efficient incorporation onto organic molecules as building blocks
is highly desirable.30 However, the installation of pyridyl
derivatives via the Suzuki-Miyaura reaction has been chal-
lenging owing to their low stability, electron-deficiency, and
the resulting reduced nucleophilicity of the organoboron spe-
cies.31 Recently, important progress has been made in the use
of pyridinyl derivatives for cross-coupling reactions. 4,5,7b,13,15a,32
For the cross-coupling of pyridinyltrifluoroborates, the catalyst/
ligand loading was increased to 3 mol % of Pd(OAc)2 and 6
mol % of RuPhos because the original reaction conditions
developed required a longer reaction time (>24 h) for the cross-
coupling. The increase in catalyst/ligand loading is not surpris-
ing; as mentioned above, pyridinyl derivatives are electron-
deficient and less nucleophilic and therefore transmetalate more
slowly.31
The cross-coupling of pyridin-4-yltrifluoroborate (2k) with
4-bromo- and 4-chlorobenzonitrile was examined. The desired
product, 5a, was obtained in excellent yields (Table 4, entry
1). We observed a slight decrease in yields with the coupling
of pyridin-3-yltrifluoroborate (2l) with 4-bromo- and 4-chlo-
robenzonitrile (Table 4, entry 2). Next, we examined the
coupling of substituted pyridyl derivatives, 2-fluoropyridin-3-
and 6-fluoropyridin-3-yltrifluoroborate (Table 4, entries 3 and
4). The coupling of 2-fluoropyridin-3-yltrifluoroborate (2m) with
4-bromobenzonitrile afforded the product 5c in 73% yield, while
the coupling with 4-chlorobenzonitrile afforded the product 5c
in only 49% yield (Table 4, entry 3). Surprisingly, for the cross-
coupling of 6-fluoropyridin-3-yltrifluoroborate (2n), the opposite
trend was observed, wherein the coupling with 4-chloroben-
zonitrile provided the product 5d in a higher yield than
4-bromobenzonitrile (Table 4, entry 4). Of particular note, the
coupling of pyridin-2-yltrifluoroborate with 4-chlorobenzonitrile
was attempted, but unfortunately none of the cross-coupled
product was obtained.
To avoid homocoupling, we examined the couplings of
N-Boc-pyrrol-2-yltrifluoroborate (2g). When 4-bromobenzoni-
trile was used as the electrophile, the desired product 4f was
isolated in 90% yield (Table 3, entry 6). However, when
4-chlorobenzonitrile was used as the electrophile, the cross-
coupled product 4f was obtained in 52% yield along with the
corresponding deprotected product in 45% yield (Table 3, entry
6). The removal of the Boc group under cross-coupling
conditions is not unusual and has been previously reported.5
Pyrazoles have extensive use in the pharmaceutical26 and
agrochemical industries as heterocyclic building blocks. As with
the case of pyrroleboronic acid derivatives, the cross-coupling
of pyrazoleboronic acid derivatives is also difficult without
protecting groups.5,27 Fu and co-workers recently attempted the
cross-coupling of unprotected 1H-pyrazol-4- and 1H-pyrazol-
5-ylboronic acid, but the products were obtained in <21%
yields. Not surprisingly, the protection of pyrazol-4- and pyrazol-
5-ylboronic acid improved the yields dramatically.5
The cross-coupling of unprotected 1H-pyrazol-4- and 1H-
pyrazol-5-yltrifluoroborate under conditions developed herein
provided the desired heterobiaryls 4g,h in low yields (20% and
26%) after 48 h (Table 3, entries 7 and 8). Upon increasing the
catalyst/ligand loading to 5 mol % of Pd(OAc)2 and 10 mol %
of RuPhos using 3 equiv of Na2CO3 and heating the reaction
for 48 h, the cross-coupling of 1H-pyrazol-5-yltrifluoroborate
(2i) gave the product 4h in 84% yield (Table 3, entry 8).
Disappointingly, the cross-coupling of 1H-pyrazol-4-yltrifluo-
roborate (2h) only improved slightly to give the cross-coupled
product 4g in 37% yield (Table 3, entry 7).
Pyrimidine derivatives, including the nucleobase uracil, have
extensive use in the pharmaceutical industry.33 In particular,
(29) (a) Goh, W. K.; Black, D. S.; Kumar, N. Tetrahedron Lett. 2007, 48,
9008–9011. (b) Kumar, J. S. D.; Ho, M. M.; Leung, J. M.; Toyokumi, T. AdV.
Synth. Catal. 2002, 344, 1146–1151. (c) Davies, M. W.; Wybrow, R. A. J.;
Johnson, C. N.; Harrity, J. P. A. Chem. Commun. 2001, 1558–1559. (d) Moore,
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Among the five-membered heterocycles, isoxazoles have been
studied the least, which is perhaps due to the lack of target
compounds containing this structural scaffold.28 Scattered
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J. Org. Chem. Vol. 74, No. 3, 2009 977

Molander et al.
TABLE 4. Cross-Coupling of Six-Membered Potassium
Heteroaryltrifluoroborates with 4-Halobenzonitrilea
TABLE 5. Cross-Coupling of Benzannulated Potassium
Heteroaryltrifluoroborates with 4-Halobenzonitrilea
a All reactions were carried out using 0.25 mmol of aryl halide and
0.26 mmol of heteroaryltrifluoroborate.
a All reactions were carried out using 0.25 mmol of aryl halide and
0.26 mmol of heteroaryltrifluoroborate. b Used 3 mol % of Pd(OAc)2
and 6 mol % of RuPhos.
5-substituted uracil derivatives are potential antiviral agents, and
one possible method for their preparation is by Suzuki-Miyaura
cross-coupling followed by a reduction.34 In 2005, Seley and
co-workers reported the preparation of a 5-substituted uracil
derivative via cross-coupling of 2,4-dibenzyloxypyrimidin-5-
ylboronic acid with an appropriate electrophile in the presence
of 5.5 mol % of Pd(PPh3)4, followed by a reduction with
ammonia in butanol. The desired product was isolated in 78%
yield over two steps.35
Using the conditions developed herein, the efficient cross-
coupling of 2,4-dimethoxypyrimidin-5-yltrifluoroborate (2o) was
demonstrated with 4-bromo- and 4-chlorobenzonitrile in 88%
and 86% yields, respectively (Table 4, entry 5). Additionally,
2-methoxypyrimidin-4-yltrifluoroborate (2p) was successfully
coupled to 4-chlorobenzonitrile in excellent yield (Table 4, entry
6).
into organic molecules have been developed. As with pyrrolyl-
and pyrazinylboronic acid derivatives, indolylboronic acid
derivatives usually necessitate protection for an efficient cross-
coupling. The Suzuki-Miyaura cross-coupling of substituted
indolylboronic acid derivatives with aryl and heteroaryl halides
has been reported in the literature.4a,b,5,7b,37 Recently, indolyl-
trifluoroborates have been shown to be better nucleophilic
partners for the cross-coupling reactions, as they provided the
products in higher yields.15c,38
To expand the utility of the general reaction conditions to
indoles, we cross-coupled 1H-indol-6- and 1H-indol-5-yltrif-
luoroborate, obtaining the products 6a,b in excellent yields
(Table 5, entries 1 and 2). During the cross-coupling of N-Boc-
indol-2-yltrifluoroborate (2s), the Boc group was cleaved under
the reaction conditions, and the deprotected product 6c was
obtained in 81% yield (Table 5, entry 3).
Indoles are among the most important heterocycles because
they are found in myriad natural products, pharmaceutical
agents, and polymers.36 Because they are highly desirable
targets, numerous methods to incorporate this heterocyclic core
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A.; Bryce, M. R.; Tarbit, B. Eur. J. Org. Chem. 2007, 5712–5716, and references
cited therein.
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978 J. Org. Chem. Vol. 74, No. 3, 2009

Reactions of Potassium Heteroaryltrifluoroborates
TABLE 6. Cross-Coupling of Various Potassium
Although benzothiophenes and benzofurans are less common
heterocycles than indoles, they still have use in the pharmaceuti-
cal industry.39 The cross-coupling of benzothiophenyl- and
benzofuranylboronic acid derivatives has been reported, gener-
ally with aryl bromides.40 We demonstrated that 4-chloroben-
zonitrile smoothly cross-coupled to benzothiophen-2-yltrifluo-
roborate (2t) and benzofuran-2-yltrifluoroborate (2u) in 82%
and 92% yields, respectively (Table 5, entries 4 and 5).
Benzopyridine derivatives, including quinoline and isoquino-
line, are most often found in naturally occurring alkaloids and
other pharmacologically active compounds. Even though the
first synthesis of quinolin-3-ylboronic acid dates back to 1959,3
only a few examples have been reported in the literature of their
incorporation into an organic molecule by means of the
Suzuki-Miyaura cross-coupling reaction.11a,41
Heteroaryltrifluoroborates with Various Heteroaryl Chloridesa
The cross-coupling of quinolin-3-yltrifluoroborate (2v) with
4-bromo- and 4-chlorobenzonitrile afforded the heterobiaryl
product 6f in comparable yields (Table 5, entry 6). The cross-
coupling of isoquinolin-4-yltrifluroborate (1) with 4-chloroben-
zonitrile provided the product 6g in 85% yield (Table 5, entry
7).
Heterobiaryls. One of the biggest challenges in cross-
coupling reactions occurs when both coupling partners are
heterocycles. Until recently, no general conditions had been
developed to enable this useful C-C bond formation.4a,5,6b,7
To expand the scope of the general reaction conditions further,
attention was turned to the coupling of heterobiaryls. Because
these are difficult couplings, 3 mol % of Pd(OAc)2 and 6 mol
% of RuPhos were employed. Initially, we examined the cross-
coupling of 2-chloropyridine with 2a, because both are known
to be demanding coupling partners.7a We were able to achieve
coupling, albeit in modest yield (Table 6, entry 1). Subsequently,
the coupling of 2-chloropyridine with 2j and 2l was successful,
affording the desired coupled products 7b,c in 95% and 82%
yield, respectively (Table 6, entries 2 and 3). The coupling of
3-chloropyridine with 2q afforded the product 7d in excellent
yield (Table 6, entry 4), but the coupling of 2s provided the
deprotected product 7e in only moderate yield (Table 6, entry
5). Additionally, 2a coupled to 2-chloropyrimidine, 2-acetyl-
5-chlorothiophene, 2-formyl-5-chlorothiophene, and 2-formyl-
5-chlorofuran in moderate to excellent yields (Table 6, entries
6-10).
a All reactions were carried out using 0.25 mmol of heteroaryl halide
and 0.26 mmol of heteroaryltrifluoroborate. b Yield of Boc-deprotected
cross-coupled product.
In conclusion, over twenty structurally diverse five-membered,
six-membered, and benzannulated heteroaryltrifluoroborate de-
rivatives were prepared from commercially available boronic
acids. We determined that these organotrifluoroborates are much
less prone to protodeboronation when compared to their
heteroarylboronic acid counterparts, and thus they can be stored
indefinitely at ambient temperatures. By combining the electron-
rich, monodentate ligand, RuPhos, with heteroaryltrifluorobo-
rates as the nucleophilic coupling partners, general, mild, and
efficient reaction conditions for cross-coupling were developed.
Of note, essentially stoichiometric ratios of the heteroaryltri-
fluoroborates can be employed in these reactions, which take
place at lower temperatures than previously developed protocols
when using comparable catalyst loading (as low as 0.5 mol %).
Using a unified set of reaction conditions, a broad range of aryl
and heteroaryl halides were cross-coupled in good to excellent
yields. Furthermore, the reaction conditions developed are
scalable and economically viable because inexpensive aryl
chlorides, Na2CO3, and ethanol are utilized in the cross-coupling
reactions.
Experimental Section
General Experimental Procedure for the Preparation of Potas-
sium Heteroaryltrifluoroborates. Preparation of Potassium Furan-
2-yltrifluoroborate (2a).42 To a solution of furan-2-ylboronic acid
(1.0 g, 8.93 mmol) in MeOH (2.6 mL, 3.5 M or enough MeOH to
give a free flowing suspension) under N2 was added KHF2 (2.09 g,
26.8 mmol) in one portion at 0 °C. To the suspension was added
H2O dropwise (5.95 mL, 4.5M) at 0 °C. The ice-water bath was
(39) Arzel, E.; Swahn, B.; Wensbo, D. WO 2008108730, September 12, 2008;
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Monguchi, Y.; Sajiki, H. Chem. Commun. 2007, 5069–5071. (b) DiMauro, E. F.;
Vitullo, J. R. J. Org. Chem. 2006, 71, 3959–3962. (c) Wang, Z.; Elokdah, H.;
McFarlene, G.; Pan, S.; Antane, M. Tetrahedron Lett. 2006, 47, 3365–3369. (d)
Kumar, S.; Kim, T.-Y. J. Org. Chem. 2000, 65, 3883–3884.
(41) Rewinkel, J.; Enthoven, M.; Golstein, I.; van der Rijst, M.; Scholten,
A; van Tilborg, M.; de Weys, D.; Wisse, J.; Hamersma, H. Bioorg. Med. Chem.
2008, 16, 2753–2763.
(42) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R. J.
Org. Chem. 1995, 60, 3020–3027.
J. Org. Chem. Vol. 74, No. 3, 2009 979

Molander et al.
removed, and the reaction was stirred at rt until 11B NMR indicated
completion of the reaction (∼2 min). The crude mixture was
concentrated and dried overnight in vacuo. The crude solid was
purified using continuous Soxhlet extraction (4 h) with acetone (60
mL) (unless otherwise specified). The collected solvent was
concentrated and then redissolved in a minimal amount of acetone
(5 mL). The addition of ether (30 mL) led to the precipitation of
the product. The product was filtered, concentrated, and dried in
vacuo to afford the pure compound in 90% yield (1.08 g, 8.03
mmol) as a light orange solid: mp >200 °C; 1H NMR (500 MHz,
DMSO-d6) δ 7.40 (m, 1H), 6.18 (m, 1H), 6.06 (d, 1H, J ) 2.6
evacuated, and purged with nitrogen (×3). Ethanol (0.18 M, 1.4
mL) was added via syringe, and the reaction was heated at 85 °C
for 12 h. The reaction mixture was allowed to cool to rt and filtered
through a thin pad of silica gel (elution with 25% methanol in
EtOAc). The solvent was removed in vacuo, and the crude product
was purified by silica gel column chromatography (elution with
hexane/EtOAc 7:1) to yield the pure product in 91% yield (38.49
1
mg, 0.23 mmol) as a white solid: H NMR (500 MHz, CDCl3) δ
7.72 (d, 1H, J ) 8.5 Hz), 7.63 (d, 1H, J ) 8.5 Hz), 7.52 (m, 1H),
6.80 (d, 1H, J ) 3.5 Hz), 6.52 (dd, 1H, J ) 1.8, 3.4 Hz); 13C NMR
(125.8 MHz, CDCl3) δ 152.1, 143.8, 134.8, 132.7, 124.1, 119.0,
112.3, 110.4, 108.3.
Hz); 13C NMR (125.8 MHz, DMSO-d6) δ 141.0, 110.2, 108.5; 19
F
NMR (470.8 MHz, DMSO-d6) δ -139.1; 11B NMR (128.4 MHz,
DMSO-d6) δ 0.3; FT-IR (KBr) 3428, 3022, 2921, 2822, 1496, 1126,
1088, 1066, 1002 cm-1; HRMS (ESI) m/z calcd for C4H3BF3O (M
- K) 135.0235, found 135.0234.
General Experimental Procedure for Suzuki-Miyaura Cross-
Coupling Reaction of Aryl and Heteroaryl Electrophiles with
Heteroaryltrifluoroborates. Preparation of 4-(Furan-2-yl)benzoni-
trile (3a).43 A Biotage microwave vial was charged with Pd(OAc)2
(3.4 mg, 0.015 mmol), RuPhos (14 mg, 0.03 mmol), 4-bromoben-
zonitrile (46.0 mg, 0.25 mmol), potassium furan-2-yltrifluoroborate
(46.0 mg, 0.26 mmol), and Na2CO3(53.0 mg, 0.5 mmol). The test
tube was sealed with a cap lined with a disposable Teflon septum,
Acknowledgment. This work was generously supported by
the National Institutes of Health (General Medical Sciences)
and Merck Research Laboratories. We also acknowledge
Aldrich, BoroChem, and Frontier Scientific for their donation
of the heteroarylboronic acids.
Supporting Information Available: Experimental proce-
dures, spectral characterization, and copies of 1H, 13C, 11B, and
19F spectra for all compounds prepared by the method described.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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JO802590B
980 J. Org. Chem. Vol. 74, No. 3, 2009