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,
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studied the least, which is perhaps due to the lack of target
compounds containing this structural scaffold.28 Scattered
examples have been reported for the cross-coupling of isox-
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