Organic Letters
Letter
2
e
synthesize ketones; following this result, we investigated an
array of Pd-catalyzed cross-coupling reactions on aryl bromides
and iodides prefunctionalized with KATs to explore the
possibility of rapid diversification.
derivative 11f in 83% yield. It is worth mentioning that 2-
pyridyl KATs are shown to enhance the ligation kinetics in
5b
protein conjugation reactions.
Subsequently, Buchwald−Hartwig amination was explored
2
At the outset of the study, we investigated the Suzuki−
Miyaura coupling of commercially available potassium 4-
bromobenzoyltrifluoroborate (1a) with 4-chlorophenylboronic
acid (Scheme 1). A series of conditions were screened to
determine the optimal reaction conditions in which the C−B
bond on KAT 1a (Figure 1b) remained intact while the C−B
group of the 4-chlorophenylboronic acid participated in the
S1). Pd(dppf)Cl ·CH Cl was identified as a suitable catalyst,
using the KAT building blocks to establish a C(sp )−NHAr or
2
C(sp )−N(Me)Ar linkage (Scheme 2). A 2 mol % XPhos Pd
Scheme 2. Buchwald−Hartwig Cross-Coupling Reaction on
c
KATs
2
2
2
but XPhos Pd G3 performed even better for a greater range of
substrates. The reaction proceeded smoothly in 1,2-dimethoxy-
ethane (DME) and in the presence of water as a co-solvent.
K CO was chosen as the base. Having optimized the reaction
2
3
conditions, we chose a diverse array of boronic acid substrates
to make biaryl KATs upon reaction with KATs 1a−1f (Figure
1
b).
The first set of aryl boronic acid substrates possessed a
variety of functional groups with different electronic effects,
including CN, CF , NO , OCF , SCF , F, and Cl. All of these
3
2
3
3
functionalities were well tolerated in the coupling, and the
corresponding biaryl KATs (7a−7k) were isolated in 63−96%
yields. The next set of substrates for the Suzuki coupling was
selected to deliver bifunctional KATs, which could be
potentially used to incorporate KATs into complex bio-
molecules and chemical probes via chemoselective reactions.
KATs (8a−8j) bearing reactive functional groups, including
CN, alkene, ketone, ester, trimethylsilyl, OH, and CH OH
2
groups that are amenable to chemoselective modifications in
the presence of the KAT functionality, were successfully
synthesized in 64−99% yields. These results further demon-
strated the simplicity of our approach in introducing
orthogonal reactive handles into KATs in a single step, thus
expanding the repertoire of bifunctional KAT reagents.
Next, we investigated the boronic acid derivatives of
privileged heterocycles, including pyridine, quinoline, thio-
phene, and benzothiophene, as coupling partners with arenes
a
b
Potassium 4-bromobenzoyltrifluoroborate 1a was used. Potassium
c
3
-iodobenzoyltrifluoroborate 1d was used. Reaction conditions: KAT
building block 1a or 1d (0.15 mmol), anilines 12a−12i (1.5 equiv),
XPhos Pd G3 (2 mol %), potassium tert-butoxide (3.0 equiv), 1.4-
dioxane (2 mL), 60 °C, 18−24 h.
2
G3 precatalyst was successfully able to catalyze C(sp )−N
bond formation between KAT building block 1a or 1d and
various primary and secondary anilines 12a−12j to afford
KATs 13a−13j, respectively, in high yields. K(OtBu) was
found to be compatible with the KAT functionality (see Table
S2 for optimization of reaction conditions). It was noted that
the KAT functionality remained intact during the amination
reaction and the formation of TIM derivatives did not occur
with the anilines. However, the use of aliphatic amines, such as
cyclohexylamine, morpholine, and n-butylamine, did not afford
the desired products or the corresponding TIMs, and the
recovery of the KAT starting material was unsuccessful.
1
a, 1c, and 1d. The desired heterocyclic frameworks bearing
KATs 9a−9f were successfully obtained in 60−99% yields.
Pyrene, fluorene, and other conjugated π-arenes, such as
naphthalene, are useful structural motifs in organic materials.
Functionalizing these scaffolds with KATs can broaden the
application of KAT chemistry in the area of materials science.
Hence, we investigated π-arenes functionalized with boronic
acid 5a−5e and carried out the Suzuki coupling with KAT 1a
or 1d. Substrates 5a−5d smoothly underwent the Suzuki
coupling to furnish KAT derivatives 10a−10d, respectively, in
Next, we explored the compatibility of KAT building blocks
1c and 1d under Sonogashira coupling conditions. The
standard coupling conditions, which use a copper co-catalyst
and organic base, did not work in our hands, and the KAT
starting material was decomposed to an unidentified impurity.
Hence, we screened a number of reaction conditions (see
Table S3) and identified a copper-free version of the reaction
to be optimal in effecting the transformation while keeping the
KAT functionality intact. The optimized conditions used the
XPhos Pd G3 catalyst and K CO as the base. The use of water
as a co-solvent increased the reaction yield. Under the
optimized conditions, phenyl acetylenes 14a−14d were
successfully coupled to KAT building block 1c and/or 1d to
furnish the corresponding products (15a−15d, respectively) in
6
3−99% yields. Pyrene-1-boronic acid 5e afforded the desired
KAT 10e in 43% yield. We were also pleased to observe that
the boronic acid derivatives of natural products, such as
estrone 6a and sugar 6b, underwent Suzuki coupling with KAT
building block 1d to afford the respective KAT derivatives 11a
and 11b in 50% and 53% yields, respectively, demonstrating
the application of this method to complex molecule
modification. Following this, thiophene KAT 1e was treated
with three different aryl boronic acids. We were impressed to
see this heteroaryl KAT reacted smoothly with these boronic
acids to furnish the respective thiophene-based biaryl KATs
2
3
1
1c−11e in 95−98% yields. Finally, 2-pyridyl KAT 1f was
treated with 4-tolylboronic acid to afford 2-pyridyl KAT
1
888
Org. Lett. 2021, 23, 1886−1890
Deng, Xingwang
