Journal of the American Chemical Society
Article
directing group (2q), which resulted in 91% yield of the
product with ortho-selectivity of 99/1.
observed that these substrates (3a, 3b, and 3c) undergo
regioselective C5 borylation with excellent yields. In this
context, it deserves mentioning that the ester, ketone, and
cyano groups attached with the five-membered heterocycles
completely failed to show their directing effect as compared to
the arenes bearing these groups. We did not observe any
borylated products next to the ester, ketone, and cyano groups
of these heterocycles. Importantly, this is also in sharp contrast
to the results with the silica-supported phosphine ligands
(Silica-SMAP-Ir),88 which delivered the Bpin group at the
position adjacent to the ester group. We then focused on
borylations of C3-substituted thiophenes (3d−3g) that are
known to give nonselective borylations.94 To our delight, our
developed conditions resulted in borylation exclusively at the
C5 position (4d−4g). Moreover, we saw that benzothiophene
(3h) afforded C2-selective borylation with high yield.
Similarly, the borylation of the 2-substituted furans (3i and
3j) and pyrrole (3l) occurred at the C5 position as the major
products regardless of the existence of the ester and ketone
directing groups. Similar to benzothiophene (3h), benzofuran
(3k) undergoes borylation to deliver the corresponding C5
borylated products in good yields. Importantly, whereas
traditional Ir-catalyzed borylation of simple indole (3m) and
N-methylindole (3n) are known to undergo borylation at the
C2 and C3 position, respectively, our method did not
differentiate whether the indole N-atom is free or protected:
Both resulted exclusively the C2 borylated products.
Accordingly, other indoles with various substitutions (3o−
3s) produce the C2-borylated products. The method is also
compatible for the carbazole (3t) borylation. Notably, while
arene-bearing amide directing groups direct borylation at the
ortho-position (for example, 2a-I−2d), a five-membered
heteroarene having an amide directing group did not show
any directing effect to give the borylation product next to the
amide group. Instead, borylation occurred at the 5-position of
the pyrrole ring via inherently directed fashion (Figure 6A,
4u).95
Late-Stage Borylation. We next turned our attention
toward the late-stage C−H bond borylation96 of pharmaceuti-
cally and medicinally important molecules. While late-stage
modification and functionalization are always important97 for
the discovery of new drugs and drug-like molecules, it is also
difficult to selectively functionalize a particular C−H bond of a
complex molecule. Delightfully, our developed catalytic system
demonstrated that it could be successfully applied for the late
stage borylation of various important molecules, and some of
them are listed in Figure 6B. For example, even in the presence
of so many similar C−H bonds, sertraline (3v, antidepressant
agent), clopidogrel (3w, drug used for heart disease at high
risk), cannabinoid core (3x, psychoactive drug), fendiline (3y,
drug for calcium channel blocker, used as antihypertensive
drug), and naproxen (3z, NSAIDs) are selectively borylated,
which exclusively yielded one isomer with good yields.
While an unsubstituted arene with a NHBoc directing group
is known to give nonselective borylation via an outer-sphere50
mechanism (although substituted arenes with an NHBoc
directing group afforded excellent ortho-selectivity), our
developed conditions exhibited promising outcomes that
afforded 49/1 ortho-selectivity (2r), but when the directing
group of arene was changed from NHBoc to NHCOCF3 (2s),
the ortho-selectivity went down to 9/1, although the yield was
comparable. The reason for the relatively low ortho-selectivity
might be due to the different electronic nature of the directing
groups. Importantly, these electronic differences were not
observed for the arenes featuring the directing groups NHAc
(2t), NHPiv (2u), and NHMe (2v). Both the substrate classes
afforded the same ortho-selectivity (99/1) and yield of the pure
isolated borylated products. The less reactive arenes having
thiomethyl (2w) and benzylthiomethyl (2x) are also borylated
selectively using this catalytic system, underlining the robust-
ness of the method. Notably, despite of the different electronic
nature of these two different directing groups, both the
substrate classes resulted in complete ortho-selectivity (99/1),
although, the benzyl thioanisole gave ortho-,ortho-diboryla-
tions. The efficiency of the catalytic system is also highlighted
with the arenes bearing dimethyl acetal (2y), OMe-benzyl
(2z), MOM-benzyl (2aa), and OMOM (2bb) functionalities,
where the borylation occurred via coordination with the sp3
oxygen atom. Moreover, arenes containing electron-deficient
and electron-rich benzylamine functionalities (2cc, 2dd, 2ee,
and 2ff) appeared to be very general for the preparation of the
synthetically useful borylation products in moderate to good
yields. In sharp contrast, increasing the chain length from
benzyl (2dd) to homobenzyl (2gg), the borylation also
proceeded smoothly giving a high yield of the borylated
product. The borylation of 2-phenylpyridine (2hh) and 8-
phenylquinoline (2ii) also proceeded smoothly affording a
single isomer. The borylation of arene featuring a cyclic amine
as the directing group (2jj) also delivered the directed ortho-
product with excellent selectivity (99/1). Thus, it is evident
that arenes featuring numerous types of functionalities with
different electronics and steric properties (2a-I−2jj) could
successfully be borylated with high ortho-selectivity and yield
using a single catalytic conditions.
Apart from these directed C−H borylation methods, we
became interested in seeing what would happen for non-
directed C−H borylation, especially for those substrates that
do not have good directing groups. For that reason, we first
performed a borylation of benzene and observed that
borylation proceed smoothly and gave a monoborylated
product (2kk) in 90% isolated yield (based on B2pin2 as
limiting agent).
Site-Selective C−H Borylation of Heterocyclic Mole-
cules. We then investigated various heterocyclic molecules
under our developed conditions. Needless to mention,
heterocyclic aromatics are commonly found in drug candidates
because of their inherent properties to improve solubility and
lower lipophilicity of drug molecules.85 One of the key
challenges86−93 in the application of C−H borylation is
realizing a method for controlling the positional selectivity of
heterocyclic molecules. Thus, we focused on the positionally
selective C−H borylation of the heterocyclic molecules using
our developed catalytic system (Figure 6A). First, we tested
the C−H borylation of various 2-substituted thiophenes and
Directed C(sp3)−H Borylation. Next, we became
interested to determine the efficiency of our developed
catalytic system for the borylation of strong C(sp3)−H
bonds (Figure 7). Thus, when a reaction was performed
with the substrate (5a) under the developed catalytic
conditions, it afforded the corresponding C(sp3)−H borylated
product (6a) in 84% isolated yield. Employing the same set of
reaction conditions, a number of six-membered nitrogen
heterocycles were borylated that afforded the C(sp3)−H
borylated products with high isolated yield (entries 6b−6d).
5029
J. Am. Chem. Soc. 2021, 143, 5022−5037