Meta Selective C-H Borylation of Sterically Biased and Unbiased Substrates Directed by Electrostatic Interaction

Article abstract of DOI:10.1021/jacs.1c01770

An electrostatically directed meta borylation of sterically biased and unbiased substrates is described. The borylation follows an electrostatic interaction between the partially positive and negative charges between the ligand and substrate. With this strategy, it has been demonstrated that a wide number of challenging substrates, especially 4-substituted substrates, can selectively be borylated at the meta position. Moreover, unsubstituted substrates also displayed excellent meta selectivity. The reaction employs a bench-stable ligand and proceeds at a milder temperature, precluding the need to synthesize a bulky and sophisticated ligand/template.

Full text of DOI:10.1021/jacs.1c01770

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Meta Selective C−H Borylation of Sterically Biased and Unbiased
Substrates Directed by Electrostatic Interaction
Jagriti Chaturvedi, Chabush Haldar, Ranjana Bisht, Gajanan Pandey, and Buddhadeb Chattopadhyay*
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ABSTRACT: An electrostatically directed meta borylation of sterically biased and unbiased substrates is described. The borylation
follows an electrostatic interaction between the partially positive and negative charges between the ligand and substrate. With this
strategy, it has been demonstrated that a wide number of challenging substrates, especially 4-substituted substrates, can selectively be
borylated at the meta position. Moreover, unsubstituted substrates also displayed excellent meta selectivity. The reaction employs a
bench-stable ligand and proceeds at a milder temperature, precluding the need to synthesize a bulky and sophisticated ligand/
template.
ver time, transition-metal-catalyzed C−H bond func-
possible for 4-substituted substrates. The reason behind this
is solely the steric effects that hamper the noncovalent
interaction next to the borylation site. Second, the require-
ment of customized ligands or catalysts bestows a barrier to
those looking to use “standard reagents” for a practical
application.28 Herein we report a concept based on the
electrostatic interaction for the meta borylation of arenes
bearing −SO2CF3, −SO2CH3, −COCF3, −COCH3, and
−COtBu at mild reaction conditions. Moreover, we
demonstrate that, with the developed concept, meta
borylation can be possible with those arenes featuring a
substitution at the para position with a high meta selectivity.
The inspiration of this meta borylation concept is based on
the recently developed electrostatically directed ortho
borylation of phenols developed by Smith, Maleczka, and
Singleton (Chart 1B, TS-1).44 Thus, with this inspiring
concept, we questioned if this strategy could be further
extended toward the meta borylation of arenes.
The working hypothesis of this present work is based on
the following key considerations: (i) generation of the
tris(boryl)(Ir) complex from Ir-precatalyst and diborane
reagent, (ii) examination of commercially available bidentate
nitrogen ligands instead of the customized ligands for the in
situ formation of the pentacoordinated Ir complex that would
likely be the partially positive charge in nature, (iii) use of
such type of functionalities attached with arenes, which by
virtue of resonance could develop a partial negative charge at
any given heteroatom, and (iv) an appropriate electrostatic
interaction between the ligand and substrate (Chart 1B, TS-
2).
O
tionalization1−5 has been recognized as one of the most
important methods to construct carbon−carbon and carbon−
heteroatom bonds for the synthesis of a complex molecular
architecture. But, the key challenge lies in a site-selective6−10
functionalization owing to the presence of multiple C−H
bonds in organic molecules. In this context, while the last few
decades have seen numerous developments in ortho selective
functionalization,11−14 the developments of meta and para
functionalization15,16 are much less compared to the ortho
functionalization. Achieving the remote meta and para
selectivity in an arene C−H functionalization by overcoming
the steric demands is a major challenge. Consequently, the
functionalization of a remote C−H bond often necessitates
the attachment and detachment of a bulky directing template,
which limits the practicability of this method.
In this context, among various C−H bond functionaliza-
tions, an iridium-catalyzed borylation17−20 has been demon-
strated as one of the most important synthetic tools due to
the versatility of the C−B bonds.21−24 While there are many
useful methods that are now available for the ortho selective
C−H borylation including the directed ortho metalations
(DoM),25,26 meta and para selective C−H borylations are still
difficult to realize. Earlier only one type of meta borylation
was possible via iridium catalysis from 1,3-disubstituted
arenesa seminal contribution by Smith, Maleczka, and
Hartwig.27−30 Apart from other directed meta boryla-
tions,31,32 recently, one new paradigm of meta selective
borylation has been developed by means of various
noncovalent interactions33−39 (Chart 1A). Moreover, the
use of a noncovalent interaction and Lewis acid−base
interaction has also been seen for para C−H borylations.40−43
However, despite the ingenuity of the noncovalent
interaction in C−H borylation, several aspects limit its wide
application. First, because of the weak nature of this
interaction, a big competition is encountered for those
substrates having a substituent next to the C−H borylation
site. For example, the meta C−H borylation is still not
Received: February 15, 2021
Published: May 14, 2021
https://doi.org/10.1021/jacs.1c01770
J. Am. Chem. Soc. 2021, 143, 7604−7611
© 2021 American Chemical Society
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Chart 1. Noncovalent Catalysis for Meta Borylation: Previous and Present Work
We began our studies using arene (1a) bearing an (Et)N−
SO2CF3 group with the commercially available ligands (Chart
2). As per our hypothesis for an electrostatic interaction, the
borylation was performed in cyclohexane using bipyridine
(L1) at 40 °C with 1.0 equiv of bis(pinacolato)diboron
(B2pin2) (entry 1). We observed that, while the borylation
gave promising meta selectivity, it also produced significant
diborylated products. Thus, to minimize the diborylation,
subsequent optimizations were conducted with 0.5 equiv of
the boron source (i.e., B2pin2). The selectivity is based on a
gas chromatography/mass spectrometry (GC/MS) analysis of
the reaction.
Accordingly, when the borylations were performed with
bipyridine ligands (L1, L2, & L3) with the reduced amount
of B2pin2 a clear trend in the enhancement of the meta
selectivity was observed as the bipyridine ligands were made
electron-deficient. For example, whereas bipyridine ligand
(L1) and electron-rich bipyridine ligand (L2) resulted in 5.6/
01 (entry 2) and 4.8/01 (entry 3) meta-to-para selectivities,
respectively, an electron-deficient bipyridine ligand (L3)
produced a much higher proportion of meta selectively
(10.1/01), although with poor conversion (entry 4). From
this selectivity pattern with electronically different bipyridine
ligands, it may be stated that the electron-withdrawing bis-
CF3 groups attached with the bipyridine ligand (L3) pull the
electron from the ligand system, making it more electro-
positive after coordination with the iridium that interacts well
with the partial negatively charged oxygen atom of the
functional group of the arene via an electrostatic interaction.
Next, we considered electronically different 1,10-phenanthro-
line ligands that are not much explored in C−H
borylations.45,46 The 1,10-phenanthroline is a rigid, planar,
electron-poor heteroaromatic chelating ligand. Moreover, the
two N-donor atoms point inward and are juxtaposed to each
other in contrast to the bipyridine ligand. The inward
inclination of N donor atoms can be disrupted by a free
rotation along the single bond. Another distinctive property
of the phenanthroline ligand is its π-electron deficiency,
which makes it a suitable π-acceptor.47 Thus, considering
these important special properties of the phenanthroline
framework, we conducted a reaction using ligand (L4) (entry
5). To our delight, a high meta selectivity was achieved
(meta/para = 32/01) with 91% isolated borylated product
(2a). Modification of the 1,10-phenanthroline ligand by
introducing an electron-withdrawing group (L5) also
appeared to be comparable (entry 6), although the
conversion was sacrificed largely. Notably, the use of an
electron-donating 3,4,7,8-tetramethylphenanthroline ligand
(L8) and 5-amino phenanthroline ligand (L7) exhibited
poor meta selectivity (entries 9 and 8). Moreover, we found
that, while the ligand (L6) showed moderate meta selectivity
(entry 7), the ligand (L9) failed completely for the borylation
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Chart 2. Reaction Optimization
Chart 3. Meta Borylation of Monosubstituted Arenes
borylated product. The substrate (3c-V) bearing a benzyl
group instead of an alkyl group also selectively underwent
meta borylation without disturbing the C−H bonds of the
benzyl group. Importantly, conducting the borylation under
the same conditions with the (3aa) and (3bb) that do not
have any noncovalent interacting sites failed to undergo
borylations, which demonstrates the necessity of the above-
mentioned functional groups for the successful electrostati-
cally directed meta borylation.
(entry 10). For this failure, we reasoned that the bulky
phenyl substitution at the C6 position of the ligand (L9)
creates steric crowding that inhibited the borylation.
At this point, we were curious whether benzylamines
(3cc−3ff) would be suitable substrates or not considering the
greater distance compared to the anilines. Accordingly,
borylation was performed with these substrates, and we
found that, while unsubstituted substrate (3cc) and 4-fluoro
substrate (3ee) gave good meta selectivity, 2-chloro (3dd)
and 4-methoxy (3ff) provided moderate meta selectivity. This
indicates that the electrostatic interaction is not strong
enough for benzylamine substrates to give a high meta
selectivity especially for those benzylamines bearing a
substituent at the ortho or para position. For further
elaboration, we attempted meta borylations with arenes
bearing other functionalities. We observed that, while an
arene with sulfonamide (3gg) exhibited good meta selectivity
(m/p = 72/28), benzamide (3hh) and phosphonate ester
(3ii) failed to undergo borylationindicating the lack of an
appropriate electrostatic interaction. To see the effect of
other ligands (L1 and L2) borylation was performed with a
4-substituted arene (3a-II) using (L1 & L2). We found that,
while (L4) gave a quantitative conversion, ligands (L1) and
(L2) also afforded meta borylation, although with a poor
conversion (49% and 53%, respectively), which suggests a
significant substrate effect with the ligand (L4) affording
With these promising results, we then intended to test if
the electrostatic interaction will be validated for other
functionalities, such as Et(N)−SO2CF3, Et(N)−SO2CH3,
Et(N)−COCF3, and Et(N)−COCH3. We found that all
these functionalities exhibited a high meta selectivity (Chart
3, 2a−2d). Thus, borylations were conducted with several
alkyl groups containing substrates,48 for example, methyl (1a-
I), propyl (1a-II), isopropyl (1a-III), butyl (1a-IV), pentyl
(1a-V), hexyl (1a-VI), heptyl (1a-VII), and found that an
increase in chain length does not hamper the meta selectivity.
Next, we examined the scope of the meta borylation of
those substrates featuring a substituent at the para position
(Chart 4). To our delight, testing numerous 4-substituted
substrates with five different functional groups, we found that
almost all the substrates produced meta borylation products
exclusively. For example, the functional groups like R(N)−
SO2CF3, R(N)−SO2Me, R(N)−COCF3, R(N)−COMe, and
R(N)−COtBu with electronically and sterically different
substituents smoothly underwent meta borylations. The
bulky tert-butyl group at the 4-position also afforded the
meta borylation (meta/para = 90/10) (entry 4c-IV), but it
was isolated via cross-coupling due to a stability issue of the
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Chart 4. Substrate Scope for 4-Substituted Arenes
higher efficiency. This may be attributed to the unique
properties47 of the phenanthroline ligand (L4).
(6a-VI). Notably, while the 4-F and 4-CN substrates (Chart
4) afforded a complete meta borylation (which usually gives
borylation next to the F and CN group), 3-F and 3-CN
substrates (Chart 5) did not give borylation completely next
to these groups but, instead, resulted in a meta borylated
product as the major product. This result is a further
indication of an electrostatic interaction as per the proposed
The scope of the developed method was then evaluated for
the substrates bearing substitution at the different positions of
the arene (Chart 5). In all cases, a high meta selectivity was
obtained with high isolated yields of the borylated products
(entries 6a-I to 6a-VIII) including the 2,5-difluoro substrate
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a
Chart 5. Substrate Scope for Substituted Arenes
Chart 6. Synthetic Transformations
a
Conditions: (i) 1.2 equiv of oxone, (3/1) acetone/water, 0 °C to rt,
2 h. (ii) 1.0 mol % [Ir(cyclooctadiene)OMe]2, (4/1) (tetrahydrofur-
an/D2O), 80 °C, 12 h. (iii) 2.5 mol % Pd(PPh3)4. 2.0 equiv of K2CO3,
1.1 equiv of 5-bromo-m-xylene, (1/1) dimethoxyethane/H2O, 100
°C, 12 h. (iv) 10 mol % Cu(OAc)2, 1.5 equiv of NaN3, MeOH, 55 °C,
under air, 24 h. (v) 1.2 equiv of phenylacetylene, 3.0 mol % sodium
ascorbate, H2 O, MeOH, rt, 24 h. (vi) 1.0 mol
%
Pd2(dibenzylideneacetone)3.CHCl3, 4.0 mol % PPh3, 4.0 equiv of
K2CO3, 1.2 equiv of BnBr, (10/1) tetrahydrofuran/H2O, 100 °C, 24
h. (vii) 4.0 equiv of TFA, 2.0 equiv of Cu(OTf)2, CH3CN, 60 °C, 20
h. (viii) 3.0 equiv of CuCl2, (1/1) MeOH/H2O, 80 °C, 12 h. (ix) 3.0
equiv of CuBr2, (1/1) MeOH/H2O, 80 °C, 12 h.
hypothesis. Interestingly, we also found that the heterocyclic
substrate (5a-IX) proceeded with the C−H borylation
affording a high meta borylation.
To demonstrate the synthetic utility, we showed that the
borylated compound (2a) can be transformed to many useful
synthons employing known transformations, such as hydrox-
ylation,17 fluorination,49 chlorination,50 bromination,50 deut-
eration,51 arylation,21 benzylation,52 and azidation followed
by cycloaddition53 (Chart 6).
The standard reaction mechanism of the C−H borylation
of arene was reported54 earlier, and the present meta
borylation possibly follows the same mechanism. But, to get
an understanding of the proposed electrostatic model (Chart
7A, TS-2), we first analyzed the electronic effects of ligands.
Earlier it has been demonstrated that, for electrostatically
directed ortho borylation (TS-1),44 an electronic alteration of
the ligand framework affects the ortho selectivity.
Analyzing the electronic effects of the various 1,10-
phenanthroline ligands,47 we observed that the meta
borylation follows the same trend (Chart 7B) that is
consistent with the previous electrostatic model. For a
further understanding, several control experiments were
performed. As per our hypothesis, the lone-pair electrons of
the nitrogen atom will be delocalized through the
trifluoromethanesulfonyl group rather than the arene ring
(Chart 7A) due to its strong electron-withdrawing nature,
and thus the substrate (1) will develop a partial negative
charge at the oxygen atom (1A) instead of the arene ring
(1B), which would interact with the partial positive charge of
the ligand. We envision that, if this hypothesis is correct, then
a functional group alteration of the nitrogen atom should
affect the meta selectivity. Following this hypothesis, we
performed a borylation with substrates bearing several
functional groups (Chart 7C) and found that substrates
without suitable functional groups (9, 10, & 11) resulted in
either no reaction or a nonselective borylation. Next,
borylation was performed with the substrates (12a, R =
triflate (Tf)) having a free NH unit, and it was found that the
conversion was poor indicating that protection is necessary to
augment the electron delocalization into the −SO2CF3 group
by restricting the chelation with the catalyst. Moreover, when
the R group is altered from Tf to either acetyl (Ac) (12b) or
trifluoroacetic acid (TFA) (12c), almost the same trend is
observed. Moreover, protection of both the H atoms of
aniline (13) with the −SO2CF3 group afforded a regioiso-
meric mixture of the meta and para borylation products in
statistical ratios with a moderate conversion. Thus, this
finding indicates the necessity of an alkyl group as the lone
pairs of N atom are delocalized over two −SO2CF3 groups
and diminish the negative charge density on the carbonyl O
atom. Collectively, all these control experiments are
suggestive of an electrostatic model for the meta borylation.55
In conclusion, we have developed a method for the meta
borylation of arenes via an electrostatic model. The method
shows a broad substrate scope, especially for those substrates
bearing a substituent adjacent to the borylation site, which
was an utmost challenge. While the most iridium-catalyzed
remote C−H borylations require minimum 1.0 equiv of
diborane (B2pin2), our method requires only half of the
B2pin2 (0.5 equiv), demonstrating the practicality of the
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Babasaheb Bhimrao Ambedkar University, Lucknow
226025, Uttar Pradesh, India
Chart 7. Validation of Proposed Electrostatic Model
Chabush Haldar − Division of Molecular Synthesis & Drug
Discovery, Center of Biomedical Research, Lucknow 226014,
Uttar Pradesh, India
Ranjana Bisht − Division of Molecular Synthesis & Drug
Discovery, Center of Biomedical Research, Lucknow 226014,
Uttar Pradesh, India
Gajanan Pandey − Department of Applied Chemistry,
Babasaheb Bhimrao Ambedkar University, Lucknow
226025, Uttar Pradesh, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c01770
Notes
The authors declare the following competing financial
interest(s): We have filed a patent based on this work.
ACKNOWLEDGMENTS
■
This work was supported by SERB-STAR AWARD grant
(STR/2019/000045), SERB-CRG grant (CRG/2018/
000133), and SERB-SUPRA grant (SPR/2019/000158).
J.C. thanks UGC for SRF, C.H. thanks CSIR for SRF, and
R.B. thanks SERB-SUPRA for RA fellowship. B.C. thanks the
SERB for the Science and Technology Award for Research.
We also thank CBMR for research facilities.
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ASSOCIATED CONTENT
* Supporting Information
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AUTHOR INFORMATION
Corresponding Author
Buddhadeb Chattopadhyay − Division of Molecular
Synthesis & Drug Discovery, Center of Biomedical Research,
Lucknow 226014, Uttar Pradesh, India; orcid.org/0000-
0001-8473-2695; Email: buddhadeb.c@cbmr.res.in,
buddhachem12@gmail.com
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Jagriti Chaturvedi − Division of Molecular Synthesis & Drug
Discovery, Center of Biomedical Research, Lucknow 226014,
Uttar Pradesh, India; Department of Applied Chemistry,
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