Ligand-Enabled, Iridium-Catalyzed ortho-Borylation of Fluoroarenes

Article abstract of DOI:10.1021/acscatal.1c01206

A terpyridine derivative and an iridium complex catalyze the C-H borylation of a stoichiometric amount of a fluoroarene with high ortho-selectivity and tolerance of functional groups such as bromide, chloride, ester, ketone, amine, and in situ-borylated hydroxyl. Complex drug molecules such as haloperidol can be selectively borylated ortho to the F atom. The terpyridine ligand undergoes rollover cyclometalation to produce an N,N,C-coordinated iridium complex, which may either selectively borylate the fluoroarene by itself or undergo reductive elimination to produce a borylated ligand.

Full text of DOI:10.1021/acscatal.1c01206

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Letter
Ligand-Enabled, Iridium-Catalyzed ortho-Borylation of Fluoroarenes
Olena Kuleshova, Sobi Asako, and Laurean Ilies*
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ABSTRACT: A terpyridine derivative and an iridium complex
catalyze the C−H borylation of a stoichiometric amount of a
fluoroarene with high ortho-selectivity and tolerance of functional
groups such as bromide, chloride, ester, ketone, amine, and in situ-
borylated hydroxyl. Complex drug molecules such as haloperidol can
be selectively borylated ortho to the F atom. The terpyridine ligand
undergoes rollover cyclometalation to produce an N,N,C-coordinated iridium complex, which may either selectively borylate the
fluoroarene by itself or undergo reductive elimination to produce a borylated ligand.
KEYWORDS: iridium catalysis, terpyridine ligand, fluoroarene, borylation, rollover cyclometalation
luoroarenes are ubiquitous molecular motifs for drug
is the most commonly used ligand,11 but regioselectivity is
1
Fdiscovery, and they have recently also received attention largely controlled by steric factors, and for substrates such as
as optoelectronic molecules for materials science.2 Late-stage
fluorobenzene, a mixture of isomers is produced. A tridentate
diversification3 of these compounds4 is of paramount
ligand has the potential to modify the coordination sphere of
the metal catalyst and impart selectivity, but this feature has
rarely been investigated for iridium-catalyzed borylation,12
probably because of the perceived crowded environment of the
Ir(III) active species.13 Terpyridine derivatives have often been
used as tridentate ligands for catalysis,14 including for C−H
borylation.15 These compounds act mostly through the N,N,N-
coordination mode, and, despite numerous studies on rollover
cyclometalation16 and suggestions of potentially enhanced
reactivity of the resulting metal complexes,17 the N,N,C-
coordination mode18 has remained underexplored for
catalysis,19 including C−H activation.20 Introduction of
appropriate substituents on a terpyridine compound (such as
R-OleTpy) may promote rollover cyclometalation21,22 to
produce an N,N,C-ligated iridium complex (such as A in
Scheme 1b), and we were intrigued by the possibility of
selective interaction between such catalytic species unsym-
metrically biased by strong σ-donation, and a fluoroarene
substrate. When we performed the reaction of 0.60 mmol of
fluorobenzene (1a) with B2pin2 (100 mol %) in the presence of
[IrOMe(cod)]2 (1.5 mol %) and Ph-OleTpy (3 mol %) in
dioxane at 80 °C for 44 h, we obtained the borylated product
2a in 47% yield and 93:7 regioselectivity (ortho/meta + para),
together with diborylated compound (16% based on 1a, and
32% based on B2Pin2; a mixture of 2,6-/2,5-/2,4-/3,5-isomers
in 36:56:8:<1 ratio). We note that control experiments
importance for both fine-tuning of properties and introducing
drastic changes to compounds, for example, to create more
potent and less cytotoxic drug molecules. Synthetic methods
that are tailored toward this end must functionalize
fluoroarenes in a regioselective manner,5 must tolerate
sensitive functional groups so that they can be used at a late
stage, and must allow incorporation of broad functionality.
Transition-metal-catalyzed C−H borylation of arenes6 is an
attractive approach because the resulting boron compounds
can be further elaborated easily,7 and iridium-,8 cobalt-,9 or
platinum-catalyzed10 ortho-selective borylation of fluoroarenes
have been reported, with various degrees of success in
controlling regioselectivity and chemoselectivity (see Scheme
1a). Here, we report that a terpyridine derivative, in
combination with an iridium complex, catalyzes the stoichio-
metric borylation of a range of fluoroarenes with high ortho-
selectivity to fluorine (Scheme 1b). The catalytic system
tolerates functional groups such as bromide, chloride, ester,
ketone, amine, and in situ-borylated hydroxyl, and the C−H
bond ortho to fluorine is selectively borylated in the presence
of other potential directing groups. The synthetic potential of
the method is illustrated by the selective borylation of the
complex drug molecule haloperidol. Preliminary mechanistic
studies suggest that the terpyridine ligand undergoes rollover
cyclometalation to generate an N,N,C-coordinated iridium
complex (A), which enables ortho-selective reaction either by
itself or after undergoing reductive elimination to produce a
borylated ligand (B) that can also selectively borylate a
fluoroarene.
Received: March 16, 2021
Revised: April 22, 2021
Iridium-catalyzed borylation of arenes has become a
benchmark reaction in C−H activation chemistry.6 The
bipyridine derivative 4,4′-di-tert-butyl-2,2′-bipyridine (dtbpy)
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a
Scheme 1. ortho-Selective Borylation of Fluoroarenes
Scheme 2. Effect of the Ligand on the Borylation of
a
Fluorobenzene (1a)
a
Yields in parentheses and selectivity determined by 19F NMR
spectroscopic analysis. The term “ortho” refers to the site vicinal to
fluorine. Diborylated product was also obtained; for details, see
Scheme 3 (presented later in this work) and the Supporting
b
Information (SI). B2pin2 (50 mol %), [IrOMe(cod)]2 (0.75 mol
c
%), and dtbpy (1.5 mol %). Conditions are the same as those for
footnote (b), 50 °C.
a
Reaction conditions: fluorobenzene (1a, 0.20 mmol), B2pin2 (100
mol %), [IrOMe(cod)]2 (1.5 mol %), and ligand (3 mol %) in dioxane
(0.8 mol/L), 80 °C, 24 h. The yield and selectivity (reported as ortho/
meta/para) were estimated by GC using tridecane or hexadecane as
internal standard. The yield of the diborylated product is shown in
(Supporting Information (SI)) showed that HBin, which forms
from the reaction of B2pin2 with the fluoroarene, reacts much
slower than B2pin2 under these conditions. Under the same
reaction conditions (shorter reaction time: 24 h), 2-
bromofluorobenzene (1c) reacted with high yield (81%
determined by NMR analysis, 68% after isolation) and
selectivity (ortho/others = 94:6), together with a small amount
(5% based on 1c) of diborylated compound, and recovery of
the starting material was 6%. We note that, in some cases,
isolation by column chromatography resulted in a decreased
yield, because of the overadsorption of pinacol boronic esters
on silica gel,23 and we report both the yield based on NMR
analysis and that obtained after isolation. The bromide group
was tolerated under the reaction conditions, and no
debrominated product was observed. When the same reaction
was conducted using dtbpy as a ligand at 50 °C, a mixture of
regioisomers was obtained.
The key structural elements of the R-OleTpy ligand that
enable high ortho selectivity are illustrated in Scheme 2: a
terpyridine backbone having a 2-substituent on the peripheral
pyridine ring, and a tert-butyl group on the central pyridine
ring. Under the optimized reaction conditions (1.5 mol %
catalyst, 100 mol % B2pin2, and 0.8 mol/L substrate
concentration), the conversion of the starting material 1a
was high, but a significant amount of diborylation also
proceeded. We confirmed that diborylation does not
significantly affect the selectivity, as demonstrated by perform-
b
parentheses. For details, see the SI. B2pin2 (50 mol %) in dioxane
c
(0.2 mol/L). Fluorobenzene (0.40 mmol), B2pin2 (50 mol %),
[IrOMe(cod)]2 (0.75 mol %), ligand (1.5 mol %), and dioxane (0.4
d
mol/L), 80 °C, 24 h. Conditions are the same as those for footnote
(c), 15 °C, 12 h.
ing the reaction using the Ph-OleTpy ligand under standard
conditions for 24 h (ortho/meta/para = 93:6:1, 12%
diborylation), and at lower concentration with 50 mol %
B2pin2 to minimize diborylation (ortho/meta/para = 91:8:1,
2% diborylation). Under the latter, low-conversion conditions
and at 15 °C, the standard dtbpy ligand was largely unselective
(57:38:5). The presence of a 2-substituent on the pyridine ring
(R) was crucial; its absence ( H-OleTpy and L1) led to a
decrease in both yield and selectivity. The size and electronic
nature of R did not significantly impact either reactivity or
selectivity (L2−L6). We speculate that this ligand accelerates
rollover metalation by sterically destabilizing the N,N,N-
coordination mode; accordingly, the reaction using a
terpyridine ligand (L10), in which rollover metalation is
sterically blocked, was unselective. Changing the nitrogen
group on the peripheral pyridine to carbon (L8 and L9)
greatly reduced the selectivity, possibly because of slower
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a
rollover metalation of the phenyl ring as compared with the
electron-deficient pyridine. The tert-butyl group on the
peripheral pyridine ring was not important for selectivity
(Ph-OleTpy vs L2), but substantial influence of the tert-butyl
group on the central ring was clear (L12), possibly by
increasing the coordination ability of the sterically hindered
pyridine, and kinetically preventing borylation of this ring.20 By
introducing a trimethylsilyl group at the site of rollover
metalation (L7), borylation proceeded with low selectivity,
suggesting the importance of rollover metalation. In the
absence of a ligand, the borylated product was obtained in a
trace amount (2% (SI)). We chose Ph-OleTpy as the optimal
ligand with respect to both reactivity and selectivity. Details of
the optimization studies, such as the nature of the iridium
precursor and the borylating reagent, are described in the SI.
We then investigated the reaction scope and found that a
variety of fluoroarenes can be regioselectively borylated ortho
to fluorine (Scheme 3). As shown in Scheme 1, fluorobenzene
(1a) reacted with high regioselectivity, but a significant
amount of diborylated product was also obtained. 2-
Chlorofluorobenzene (1b) and 2-bromofluorobenzene (1c)
reacted with high yield and regioselectivity, and we did not
observe dehalogenation. The reaction of 2-iodofluorobenzene
(1d) was also regioselective, but this substrate was much less
reactive and was mostly recovered (80%), together with a small
amount (2%) of deiodinated product (fluorobenzene). We
speculate that unproductive oxidative addition of the C−I
bond may have inactivated the iridium catalytic species. 1,2-
Difluorobenzene (1e) was regioselectively diborylated in good
yield. An ester group ortho to fluorine was tolerated (1f), but
the regioselectivity decreased (isomer ratio 3-/4- = 65:33),
probably because the electron-withdrawing nature of the ester
group activated the 4-position toward oxidative addition.
Accordingly, when the ester group was placed meta to fluorine
(1o), the regioselectivity was high. An electron-donating
methoxy group ortho to fluorine (1h) did not significantly
decrease the yield, and the borylated product was obtained
with high regioselectivity. A substrate bearing a protected
piperazine group ortho to fluorine (1i) also reacted well, albeit
with slightly decreased selectivity. 1-Fluoronaphthalene (1j)
reacted in good yield but with lower regioselectivity,
presumably because of the activating effect of the fused
benzene ring, similar to that of the 2-ester group. The reaction
was also regioselective for meta-substituted fluorobenzenes
(1k−1o). While a meta trifluoromethyl-substituted substrate
reacted with high selectivity (1m), the presence of a meta
bromide decreased the selectivity (1n), presumably because of
increased electron density at the C−H site proximal to
fluorine. In the reaction of 3-fluorobiphenyl (1k), the phenyl
ring bearing the F atom was borylated selectively. A hydroxyl
group was protected in situ by borylation with HBpin, the
phenyl ring bearing the F atom reacted selectively over the
electron-rich phenol ring (1l), and the regioselectivity was
high. 2-Bromo-1,3-difluorobenzene (1p) was regioselectively
diborylated in high yield. The regioselectivity is unique to
fluoroarene substrates; for chlorobenzene (3) or trifluoroto-
luene (4), the ortho-borylation was sterically retarded, and a
mixture of meta- and para-isomers was obtained. Unsubstituted
benzene (5) was largely unreactive under these conditions.
Other unsuccessful substrates are described in the SI. A nitrile
group retarded the reaction, possibly because of unproductive
coordination to the iridium species; in agreement with this
hypothesis, benzonitrile itself was unreactive, and adding 50
Scheme 3. Reaction Scope
a
Reaction conditions: fluoroarene (1, 0.40 mmol), B2pin2 (100
mol %), [IrOMe(cod)]2 (1.5 mol %), and Ph-OleTpy (3 mol %) in
dioxane (0.8 mol/L), 80 °C, 24 h. The yield of the isolated
monoborylated product (2) is reported, unless otherwise noted; the
yield in parentheses was determined by 19F NMR analysis using
trifluorotoluene as internal standard. The isomer ratio is reported as
ortho-to-fluorine/others and was based on GC, 19F, or 1H NMR
analysis. For details, see the SI. Substrate (0.60 mmol), 44 h;
regioisomers of the diborylated product: 2,6-/2,5-/2,4-/3,5- =
36:56:8:<1. Estimated by GC using tridecane as internal standard.
B2pin2 (50 mol %), [IrOMe(cod)]2 (0.75 mol %), and dtbpy (1.5
b
c
d
mol %) in dioxane (0.4 mol/L); regioisomers of the diborylated
product: 2,6-/2,5-/2,4-/3,5- = 7:50:19:24. Substrate (0.20 mmol)
e
f
and B2pin2 (50 mol %) in dioxane (0.2 mol/L), 50 °C, 15 h. B2pin2
g
h
(150 mol %); 3,6-/3,5-regioisomer ratio. 67 h. Substrate (0.20
i
j
mmol), 65 h. B2pin2 (200 mol %). Determined by 1H NMR analysis
using 1,1,2,2-c-tetrachloroethane as internal standard.
mol % of benzonitrile to the reaction of fluorobenzene under
standard conditions completely shut down the reaction.
Pyridine compounds reacted with low yield and selectivity;
the discussion on the reaction of these compounds is
complicated by the decomposition of α-borylated pyridines
under iridium catalysis.24 Fluoroarene derivatives bearing a
methyl group (for example, 3-fluorotoluene) reacted regiose-
lectively, but the reaction was complicated by competing
benzylic borylation.25
The reaction could be applied for the selective functionaliza-
tion of complex molecules such as haloperidol, one of the most
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commonly used antipsychotic drugs.26 Synthesis and evalua-
tion of derivatives of haloperidol is of much interest for
medicinal chemistry, but chemical modification of the carbon
framework is tedious.27 Late-stage functionalization of this
molecule via C−H bond activation is attractive, but has been
less investigated,28 possibly because of difficulties associated
with controlling regioselectivity and the required tolerance of
functionality such as carbonyl, amino, hydroxy, and chloro
groups. After protection with HBpin in situ, we subjected
haloperidol to our optimized reaction conditions, and we
observed 50% conversion into the desired ortho-to-fluorine
monoborylated product, together with 12% of diborylated
product and 8% of an unidentified product (Scheme 4). After
Scheme 5. Mechanistic Considerations
a
Scheme 4. Selective Borylation of Haloperidol
a
b
Determined by 19F NMR analysis. Stoichiometry based on the
c
estimated amount of borylated product. Determined after isolation
using silica gel column chromatography.
removing the solvent in vacuo, the borylated haloperidol was
reacted in one pot with an aromatic bromide under palladium
catalysis, to obtain the corresponding haloperidol derivative in
32% yield as a single isomer, after isolation by silica gel column
chromatography.
a
Estimated by 1H NMR analysis using mesitylene as internal
b
standard. Conversion of fluorobenzene and isomer ratio determined
c
by 19F NMR analysis. Relative Gibbs energies calculated at the M06/
Finally, we investigated the origins of the high ortho
selectivity induced by the R-OleTpy ligands. The mechanism
of iridium-catalyzed arene borylation has been much
investigated, and it is generally accepted that the oxidative
addition of an Ir(III) species to the arene C−H bond is the
turnover-limiting and regioselectivity-determining step.29 The
regioselectivity in the reaction of mono- or disubstituted
benzenes is typically controlled by sterics, and electronic effects
are more complex; for example, factors such as the acidity of
the C−H bond and the energy of the forming C−Ir bond have
been proposed to govern regioselectivity.30 However, these
studies on iridium catalysis have largely ignored the reaction of
fluoroarene derivatives; Chirik31 proposed that the regiose-
lectivity in the cobalt-catalyzed borylation of fluoroarenes is
dictated by the “ortho fluorine effect”,32 the strengthening of
the newly forming C−Co bond by the neighboring F atom.
To gain insight into the reaction mechanism, we investigated
by NMR analysis and mass spectroscopy the reaction of a
stoichiometric amount of Me-OleTpy and iridium precursor
with an excess of B2pin2, to observe the formation of a
borylated ligand as the main product (Scheme 5a). This
borylated ligand could not be isolated because of fast
protodeborylation,24 but the addition of fluorobenzene (1a)
to the reaction mixture resulted in ortho-selective borylation,
matching the selectivity profile of the catalytic reaction.
Computational analysis using a simplified ligand model
(Scheme 5b; for structures of the transition states (TS) and
SDD:6-311+G(d,p)1,4‑dioxane(SMD)//B3LYP-D3/SDD:6-31G(d,p) level
d
of theory. The length of the cleaving ortho C−H bond of 1a at the
e
transition state. The length of the forming ortho C−Ir bond of 1a at
the transition state.
details of the computational study, see the SI) showed that an
iridium complex bearing the borylated ligand (B′) oxidatively
adds the ortho C−H bond of fluorobenzene selectively,
although the energy difference of ortho and meta transition
states is low (0.2 kcal/mol) and comparable to that of a
bipyridine ligand (0.3 kcal/mol). The presence of the B atom
may indicate potential B−F interaction with the substrate33
(B−F distance in ortho TS from B′ is 3.776 Å); however, a
detailed investigation showed that oxidative addition proceeds
more readily from isomer B″ (activation energy 29.3 kcal/mol
vs 32.4 kcal/mol for B′), where the Bpin on the pyridyl group
is turned away from the substrate and B−F interaction is not
possible. The transition state is late (C−H bond length at TS
from B″: 1.643 Å), and we propose that the strengthening of
the C−Ir bond by the ortho fluorine effect is important for
selectivity (energy difference of ortho TS vs meta TS: 1.3 kcal/
mol),31 and this effect may be enhanced by the strong donating
N,N,C-ligand.32
The regioselective formation of the borylated ligand strongly
suggests initial rollover cyclometalation to generate the N,N,C-
iridium complex (A in Scheme 1b), which undergoes reductive
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elimination in the presence of B2pin2 to give B. However, we
should note that the borylated ligand, despite being the major
product in the NMR spectrum, accounted for only ∼60% of
the material balance. This suggests the presence of other
undetected species, possibly including A. Computations
showed that N,N,C-iridium complex A′ is also ortho-selective
(energy difference of ortho TS vs meta TS: 1.1 kcal/mol).
Moreover, a surrogate of the borylated ligand, silylated L7, was
poorly selective, suggesting the importance of a cyclometalated
intermediate. Thus, at present, we cannot conclusively
establish whether the N,N,C-iridium complex (A) or the
borylated ligand complex B is the active species responsible for
ortho-selective C−H activation of fluoroarenes.
In summary, we found that a terpyridine derivative enables
iridium-catalyzed selective ortho-borylation of fluoroarenes.
The reaction conditions tolerate several sensitive functional
groups (bromide, chloride, ester, ketone, amine, and in situ-
borylated hydroxyl) and allow functionalization of complex
drug molecules such as haloperidol. Preliminary mechanistic
studies suggest that the ligand undergoes rollover cyclo-
metalation to generate an N,N,C-iridium complex, which may
undergo reductive elimination in the presence of B2pin2 to
produce a borylated ligand; computations showed that both of
these intermediates can cleave the ortho C−H bond of
fluorobenzene selectively. We hope that these findings will
stimulate interest in the reactivity of N,N,C-coordinated metal
complexes and their use for catalysis, a topic that is under
investigation in our laboratory.
ACKNOWLEDGMENTS
■
This work was supported by the Japan Society for the
Promotion of Science (JSPS) KAKENHI (No. JP20H04830)
(L.I.) (Hybrid Catalysis). O.K. was an international research
fellow of the JSPS (Postdoctoral Fellowships for Research in
Japan (Standard)). Computational time provided by the
RIKEN HOKUSAI BigWaterfall is gratefully acknowledged.
We thank Dr. Zhaomin Hou and Dr. Masanori Takimoto for
generously allowing us to use the mass spectrometer.
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.1c01206.
Experimental procedures, compound data, NMR spectra
(PDF)
Coordinates of the optimized structures (TXT)
AUTHOR INFORMATION
■
Corresponding Author
Laurean Ilies − RIKEN Center for Sustainable Resource
Science, Wako, Saitama 351-0198, Japan; orcid.org/
0000-0002-0514-2740; Email: laurean.ilies@riken.jp
Authors
Olena Kuleshova − RIKEN Center for Sustainable Resource
Science, Wako, Saitama 351-0198, Japan
Sobi Asako − RIKEN Center for Sustainable Resource Science,
Wako, Saitama 351-0198, Japan; orcid.org/0000-0003-
4525-5317
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.1c01206
Author Contributions
The manuscript was written through contributions of all
authors. O.K. performed the experiments, and S.A. conducted
the mechanistic study. All authors have given approval to the
final version of the manuscript.
Notes
The authors declare no competing financial interest.
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ACS Catal. 2021, 11, 5968−5973

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
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5973
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ACS Catal. 2021, 11, 5968−5973