Iridium(I)-Catalyzed C?H Borylation in Air by Using Mechanochemistry

Article abstract of DOI:10.1002/chem.201900685

Mechanochemistry has been applied for the first time to an iridium(I)-catalyzed C?H borylation reaction. By using either none or just a catalytic amount of a liquid, the mechanochemical C?H borylation of a series of heteroaromatic compounds proceeded in air to afford the corresponding arylboronates in good-to-excellent yields. A one-pot mechanochemical C?H borylation/Suzuki–Miyaura cross-coupling sequence for the direct synthesis of 2-aryl indole derivatives is also described. The present study constitutes an important milestone towards the development of industrially attractive solvent-free C?H bond functionalization processes in air.

Full text of DOI:10.1002/chem.201900685

A Journal of
Accepted Article
Title: Iridium(I)-Catalyzed C−H Borylation in Air Using
Mechanochemistry
Authors: Yadong Pang, Tatsuo Ishiyama, Koji Kubota, and Hajime Ito
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Iridium(I)-Catalyzed C−H Borylation in Air Using
Mechanochemistry
Yadong Pang,[a] Tatsuo Ishiyama,[a] Koji Kubota,*[a] and Hajime Ito*[a,b]
Abstract: Mechanochemistry has been applied for the first time to an
iridium(I)-catalyzed C−H borylation reaction. Using either none or just
a catalytic amount of a liquid, the mechanochemical C−H borylation
of a series of heteroaromatic compounds proceeded in air to afford
the corresponding arylboronates in good to excellent yield. A one-pot
mechanochemical C−H borylation/Suzuki–Miyaura cross-coupling
sequence for the direct synthesis of 2-aryl indole derivatives is also
described. The present study constitutes an important milestone
toward the development of industrially attractive solvent-free C−H
bond functionalization processes in air.
recently, mechanochemistry has also been applied to the
transition-metal-catalyzed
halogenation,[7b] amination,[7c,f,j]
olefination,[7d] arylation,[7e] allylation,[7g] alkynylation[7h] and
oxidative cyclization[7i] of C−H bonds. However, to the best of our
knowledge, a mechanochemical C−H borylation reaction has not
been reported to date, even if the development of such a catalytic
C−H borylation would be particularly attractive from an industrial
perspective. Herein, we report the first mechanochemical method
for an iridium(I)-catalyzed C−H borylation using a diboron reagent
(Scheme 1b). This reaction was applied to a variety of
heteroaromatic compounds, furnishing the corresponding
arylboronates in good to high yield with excellent regioselectivity.
Notably, this mechanochemical C−H borylation does not require
the use of inert gas and/or harmful organic solvents. To
demonstrate the synthetic utility of this protocol, a one-pot
mechanochemical C−H borylation/Suzuki–Miyaura cross-
coupling sequence was developed.
Organoboronic acids and their derivatives, especially
arylboronate esters, are powerful and versatile reagents in
synthetic chemistry, medicine, and materials science owing to
their high stability, low toxicity, and synthetic utility in various
transformations such as the Suzuki–Miyaura cross-coupling
reaction.[1] C−H borylation reactions have become an especially
important synthetic method since they provide straightforward
access to
a great variety of functionalized organoboron
compounds.[2] In particular, iridium(I)-catalyzed aromatic C−H
borylation reactions have proven to be one of the most efficient
methods, which is widely used in the synthesis of complex
molecules (Scheme 1a).[2c,3] However, despite the significant
progress, the exploration of new concepts and reaction media to
improve the sustainability of such C−H borylation transformations
remains crucial.[2c,3] In this context, the use of significant amounts
of dry and degassed organic solvents and the need to operate
under an atmosphere of inert gas are still important limiting factors.
In recent years, significant progress has been made
concerning organic transformations that are carried out under
mechanochemical conditions.[4,5] Compared to traditional solvent-
based protocols, the advantages of conducting chemical
transformations using mechanochemistry include the avoidance
of harmful organic solvents, shorter reaction times, the absence
of external heating, and the possibility to access different product
compositions.[6] Although chemists have successfully applied
mechanochemical techniques to mechanistically complex organic
reactions, transition-metal-catalyzed C−H bond functionalizations
under solvent-free mechanochemical conditions have remained
underdeveloped.[7] The first of these studies toward the catalytic
mechanochemical C−H bond functionalizations was reported by
Bolm et al. in 2015, where a rhodium(III) complex was used to
catalyze an oxidative Heck-type reaction in a ball mill.[7a] More
Scheme 1. Iridium(I)-catalyzed C−H borylation reactions.
Initially, we applied reaction conditions analogous to those
used by Hartwig and Miyaura[8] for a solution process in the
mechanochemical C−H borylation of indole 1a with
bis(pinacolato)diboron 2 in the presence of [Ir(OMe)cod]2 and
4,4’-di-tert-butyl-2,2’-bipyridine (dtbpy) (Table 1). The reaction
was conducted in a Retsch MM400 mill in a stainless milling jar
using one stainless steel ball. Unfortunately, our first attempt to
perform this mechanochemical reaction in a 1.5 mL milling jar
using a 3.0 mm ball was unsuccessful, and the desired product
(3a) was not detected (entry 1). We found that a careful choice of
the jar and ball dramatically improved the efficiency of the
mechanochemical C−H borylation (entries 2−5). When using a 5.0
mL milling jar and a 7.5 mm ball, 3a was obtained in 74% yield
upon grinding for 99 min (entry 2). Upon increasing the loading of
2 from 0.5 mmol to 0.6 mmol, the yield of 3a improved further
(84%; entry 6), and is comparable to the yield obtained by the
reported solvent-based protocol.[8] In conventional C−H borylation
reactions in solution, one or two of the boryl groups in the diboron
reagent 2 may be introduced into the substrates, depending on
the conditions applied.[2,8] Interestingly, we found that both boryl
[a] Y. Pang, Prof. Dr. T. Ishiyama, Prof. Dr. K. Kubota, Prof. Dr. H. Ito
Division of Applied Chemistry, Graduate School of Engineering,
Hokkaido University, Sapporo, Hokkaido 060-8628, Japan
E-mail: kbt@eng.hokudai.ac.jp, hajito@eng.hokudai.ac.jp
[b] Prof. Dr. H. Ito
Institute for Chemical Reaction Design and Discovery (WPI-ICReDD),
Hokkaido University, Sapporo, Hokkaido 060-8628, Japan
groups in
2 were introduced into 1a under the applied
mechanochemical conditions. Next, we investigated other
transition-metal complexes containing nickel and iron, which are
effective catalysts for aromatic C−H borylation reactions in
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solution (entries 7 and 8).[9] However, no reaction was observed
under the applied mechanochemical conditions.
protonated on silica gel; thus, the isolated yields are generally
lower than the corresponding NMR yields. Methyl-protected
indole 1b also reacted with 2 to afford borylation product 3b in
good yield (65% NMR yield; 37% isolated yield). The reaction of
indoles bearing a methyl group at the 5- or 6-position (1c and 1d)
furnished the corresponding products (3c and 3d) in good to
excellent yield (81% and 74% NMR yield, respectively). In
addition, methoxy (1e) and fluorine (1f) substituents did not
hamper the mechanochemical C−H borylation, providing the
corresponding products (3e and 3f) in 62% and 67% NMR yield,
respectively.
Table 1. Optimization of the mechanochemical C−H borylation reaction
conditions[a]
Entry
Catalyst
Ball
(diameter,
mm)
Milling jar
(mL)
NMR
yield
(%)[b]
Unfortunately, no mechanochemical C−H borylation
occurred when 7-methyl-substituted indole 1g was used as the
substrate (Scheme 2). We speculated that one possible reason
behind the observed reactivity difference could be rheological
changes in the reaction mixture upon mechanical grinding.[10] In
the case of 1a, the reaction mixture dramatically changes from a
solid mixture to a viscous oil (Figure 1a, 1b, and S1). This drastic
change in rheology could improve the mixing efficiency of the
reactants and catalyst, thus facilitating the C−H borylation.[10] In
contrast, the reaction mixture in the case of 1g, which has a higher
melting point (80 C) than 1a (55 C), remained a heterogeneous
solid mixture, even after grinding for 99 min (Figure 1c and 1d).
These results suggest that the low yield of 3g is likely due to poor
mixing of the solid-state reaction mixture in the ball mill.
1
2
[Ir(OMe)cod]2/dtbpy
[Ir(OMe)cod]2/dtbpy
[Ir(OMe)cod]2/dtbpy
[Ir(OMe)cod]2/dtbpy
[Ir(OMe)cod]2/dtbpy
[Ir(OMe)cod]2/dtbpy
Ni(OAc)2/ICy∙HCl
Fe(acac)3
3.0
7.5
7.5
15.0
3.0
7.5
7.5
7.5
1.5
5.0
0
74
0
3
25.0
25.0
5.0
4
0
5
68
84
0
6[c]
7[d]
8[e]
5.0
5.0
5.0
0
[a] Reaction conditions: 1a (1.0 mmol), 2 (0.5 mmol), [Ir(OMe)cod)]2 (0.75
mol%), dtbpy (1.5 mol%), 30 Hz, 99 min. Both jars and balls are made of
stainless steel. [b] Yields are based on the amount of 1a and determined by
1H NMR spectroscopy. [c] 0.6 mmol of 2 were used. [d] Ni(OAc)2 (5 mol%),
1,3-dicyclohexylimidazolium chloride (ICy∙HCl) (5 mol%), and Na(O-t-Bu)
(10 mol%) were used instead of the Ir(I)/dtbpy system. [e] Fe(acac)3 (20
mol%) and K2CO3 (2.0 equiv) were used instead of the Ir(I)/dtbpy system.
Scheme 2. Mechanochemical C−H borylation of 7-methyl-substituted indole 1g.
Table 2. Substrate scope of the mechanochemical C−H borylation of indoles[a]
(c)
(d)
(b)
(a)
Figure 1. Reaction mixtures after grinding in a ball mill. Reaction mixture
containing indole 1a (a) before and (b) after grinding for 99 min, and that of 7-
methyl indole 1g (c) before and (d) after grinding for 99 min.
Therefore, we then attempted grinding in the presence of
abrasive, inert, solid mechanochemical additives such as
lubricants and inorganic salts in order to enhance the mixing
efficiency (Table 3). First, we used common solid lubricants such
as MoS2, graphite, or polytetrafluoroethylene (PTFE) in the
mechanochemical C−H borylation of 1g. However, the desired
product (3g) was not detected under these reaction conditions
(entries 1−3). Reactions in the presence of inert solid auxiliaries
(entries 4−5) or inorganic salts (entries 6−7) were also
investigated, albeit that we did not observe any product formation.
Next, we attempted liquid-assisted-grinding (LAG), which uses
substoichiometric liquid additives, to improve the reactivity
(entries 8−10).[11] These LAG reactions involved 0.25 L of liquid
per mg of reactants. Initially, hexane was tested since it is
frequently employed in solvent-based iridium(I)-catalyzed C−H
borylation reactions. Unfortunately, this reaction did not furnish 3g
[a] Reaction conditions: 1 (1.0 mmol), 2 (0.6 mmol), [Ir(OMe)cod)]2 (0.75 mol%),
dtbpy (1.5 mol%), 30 Hz, 99 min. Yields are based on the amount of 1 and
determined by 1H NMR spectroscopy; isolated yields are shown in parentheses.
With the optimal reaction conditions in hand (Table 1, entry
6), a series of substituted indole substrates was tested in order to
investigate the scope of the present mechanochemical iridium(I)-
catalyzed C−H borylation in a ball mill (Table 2). The C−H
borylation reactions proceeded efficiently to furnish the
corresponding C2-borylated indoles in moderate to good yield.
We found that the purification of the boronate esters without yield
losses was difficult using conventional chromatography
techniques, as these boronate esters are easily hydrolyzed and
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(entry 8). In sharp contrast, the use of tetrahydrofuran (THF)
dramatically improved the reactivity (88% yield; entry 9). The
reaction using CH2Cl2 also proceeded smoothly to afford 3g in
high yield (87% yield; entry 10). We noted that the reaction
mixture containing THF as the LAG additive changed from a solid-
state mixture to a viscous oil.
the LAG additive (33−71%). In the case of 1p, the LAG conditions
improved the yield of 3p to 48%. Interestingly, the
mechanochemical C−H borylation of liquid benzofuran (1r) did not
proceed without a LAG additive, while the desired product 3r was
obtained in high yield under LAG conditions (93%). The results
shown in Tables 3 and 4 suggest that the LAG conditions are
robust and can be applied to a wide range of heteroaryl
compounds, while the borylation of solid substrates with relatively
low melting points (< 70 C) or liquid substrates proceeds
efficiently even in the absence of a LAG additive.[13]
Table 3. Further optimization of the mechanochemical C−H borylation reaction
of 1g[a]
Table 4. Substrate scope of the mechanochemical C−H borylation with the
modified conditions[a]
Entry
Additive
MoS2 (80 mg)
NMR yield (%)[b]
1
2
0
0
Graphite (50 mg)
3
PTFE (50 mg)
0
4
4Å molecular sieves (50 mg)
Sea sand (50 mg)
0
5
0
6
Tetrabutylammonium iodide (50 mg)
NaCl (50 mg)
0
7
0
8
Hexane (0.25 L/mg)
THF (0.25 L/mg)
0
9
88
86
10
CH2Cl2 (0.25 L/mg)
[a] Reaction conditions: 1g (1.0 mmol), 2 (0.6 mmol), [Ir(OMe)cod)]2 (0.75
mol%), dtbpy (1.5 mol%), 30 Hz, 99 min. [b] Yields are based on the amount
of 1g and were determined by 1H NMR spectroscopy.
With the modified conditions in hand, a series of substituted
indoles with relatively high melting points (>70 C) were tested to
investigate the scope of this mechanochemical iridium(I)-
catalyzed C−H borylation enabled by LAG (Table 4a). Substrates
bearing a methyl group at different positions on the aryl ring (1g
and 1h) efficiently reacted with 2 to provide the desired borylation
products (3g and 3h) in moderate to high yield (88% and 32%,
respectively). The relatively low yield of 3h is probably due to
steric hindrance around the reactive C−H bond. Functional groups
such as chlorine (1i), bromine (1j), and ester (1k) were tolerated
and afforded the corresponding products (3i−3k) in good yield
(61−72%). When N-tosyl-protected indole 1l was used as the
substrate, the borylation selectively occurred at the 3-position of
the indole to give 3l as a result of the steric control of the bulky
tosyl group.[12] It should be noted here that the substrates in Table
4a did not react in the absence of the LAG additive THF.
Subsequently, we turned our attention to the scope of the
heteroaryl substrates (Table 4b). Pyrroles bearing ester (1m) and
ketone (1n) moieties, which are solid substrates with melting
points > 70 C, afforded the corresponding borylation products
(3m and 3n) in good yield under LAG conditions (64% and 50%,
respectively). Without LAG additives, no reaction occurred, which
is probably due to poor mixing in the ball mill. Liquid furan
derivatives (1o−1q) were efficiently borylated providing the
corresponding products (3o−3q) in moderate to good yield without
[a] Reaction conditions: 1 (1.0 mmol), 2 (0.6 mmol), [Ir(OMe)cod)]2 (0.75 mol%),
dtbpy (1.5 mol%), THF (0.25 L/mg), 30 Hz, 99 min. Yields are based on the
amount of 1 and were determined by 1H NMR spectroscopy; isolated yields are
shown in parentheses. [b] 0.40 L/mg THF were used as a LAG additive.
To demonstrate the synthetic utility of this method, we
investigated
a
direct one-pot mechanochemical C−H
borylation/Suzuki–Miyaura cross-coupling sequence in air for the
synthesis of 2-aryl indole derivatives from indole 1a (Scheme 3).
The in situ obtained 2-borylated indole 3a was directly subjected
to
a one-pot cross-coupling with aryl iodides using the
Pd/tBuXPhos catalyst originally developed by Buchwald and co-
workers.[14] Pleasingly, we found that the desired 2-aryl indoles
(4a−4e) were successfully obtained via such
a one-pot
mechanochemical strategy in moderate to good yield (37−75%).
This one-pot multi-step transition-metal-catalyzed transformation
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using mechanochemistry represents a more sustainable synthetic
alternative to conventional solution processes.[15]
Scheme 3. Mechanochemical one-pot C−H borylation/Suzuki–Miyaura cross-
coupling sequence[a]
[a] Reaction conditions for the C−H borylation: 1a (1.0 mmol), 2 (0.6 mmol),
[Ir(OMe)cod)]2 (0.75 mol%), dtbpy (1.5 mol%), 30 Hz, 99 min. Reaction
conditions for the Suzuki–Miyaura cross-coupling: Pd(OAc)2 (3 mol%),
tBuXPhos (4.5 mol%), CsF (3.0 mmol), aryl iodide (0.8 mmol), H2O (3.7 mmol),
30 Hz, 99 min. [b] Isolated yields are based on the amount of aryl iodide.
To gain insight into the mechanism of this
mechanochemical C−H borylation reaction, preliminary
mechanistic studies were carried out. First, we determined the
kinetics of the reaction involving the solid indole substrate 1a
under different reaction conditions (Figure 2a). As periodic
sampling of the mechanochemical reaction runs would require
stopping the mill and opening the jar, each data point was
obtained from an individual reaction. Under conventional solution
conditions, the reaction rate is initially high and decreases after
20 min (Figure 2a, orange line). On the other hand, sigmoidal
kinetics were observed under the developed mechanochemical
conditions (Figure 2a, blue line). The reaction did not proceed in
the first 60 min, but was rapidly completed between 60 and 70
min. We noted that the physical state of the reaction mixture
dramatically changed from a solid to a viscous oil after 60–70 min
(Figure 3). This dramatic change in rheology should improve the
mixing efficiency of the reactants and catalyst, which would result
in a rapid increase of the reaction rate.[10] Another possible reason
for such sigmoidal kinetics would be an induction period (60 min)
to generate the catalytically active trisboryl iridium complex from
the iridium precursor under mechanochemical conditions.[16,17]
Subsequently, we investigated the kinetics of the reaction of
the liquid benzofuran 1r (Figure 2b). We found non-reactive
periods of 90 and 50 min before the formation of the desired
borylation product 3r under both conventional solution conditions
and the developed mechanochemical conditions, respectively
(Figure 2b, orange and blue lines). Notably, the
mechanochemical C−H borylation of 1r showed a much shorter
induction period than the reaction in solution. Given that no
rheological changes in the reaction mixture of 1r were observed
under mechanochemical conditions (Figure S3), the main reason
for the sigmoidal kinetics should be attributed to an induction
period of 50 min to form the catalytically active trisboryl iridium
complex from the iridium precursor.[16,17]
Figure 2. Reaction progress of the iridium(I)-catalyzed C−H borylation under
conventional solution conditions or under the developed mechanochemical
conditions: (a) indole 1a (solid) and (b) benzofuran 1r (liquid).
(c)
(b)
(a)
Figure 3. Reaction mixtures containing indole 1a upon grinding after (a) 0, (b)
60, and (c) 70 min.
It should be noted that no reaction occurred when the C−H
borylations were conducted in solution in air (Figure 2a and 2b,
gray lines), while the mechanochemical reactions can be carried
out in air (Figure 2a and 2b, blue lines). This is probably because
the reaction between sensitive iridium species and gaseous
oxygen or water in the ball mill is much slower than that with
dissolved oxygen or water in organic solvents.[18] These results
highlight the synthetic utility of the present C−H borylation protocol
in terms of operational simplicity.
In conclusion, we have described the first application of
mechanochemistry to catalytic C−H borylation reactions. Careful
choice of the reaction milling jar, ball, and LAG additive enabled
the development of a solvent-free C−H borylation reaction that
proceeds efficiently in air. Considering the broad significance of
C−H borylation processes and the industrial demand for
sustainable synthetic methods, the present study constitutes an
important milestone toward the development of industrially
attractive C−H bond functionalization processes. Furthermore, we
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10.1002/chem.201900685
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Brand, D. L. Browne, Angew. Chem., Int. Ed. 2018, 57, 16104−16108;
Angew. Chem. 2018, 130, 16336−16340.
expect that this study will open an unexplored area of C−H
borylation reactions, where reactivity and selectivity different to
those of conventional solution-based reactions may be realized.
We are currently working on a new catalyst design for such
mechanochemical C−H borylations with unique site-selectivity.
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Acknowledgements
This work was supported by MEXT/JSPS KAKENHI: Grant
Numbers JP18H03907 and JP17H06370, as well as the Institute
for Chemical Reaction Design and Discovery (ICReDD), which
was established by the World Premier International Research
Initiative (WPI), MEXT, Japan. Y.P. thanks the Otsuka Toshimi
Scholarship Foundation for a scholarship.
[8]
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Conflict of interest
[10] B. P. Hutchings, D. E. Crawford, L. Gao, P. Hu, S. L. James, Angew.
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The authors declare no conflict of interests.
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Keywords: mechanochemistry • C−H borylation • iridium • boron
• synthetic method
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[3]
[4]
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10.1002/chem.201900685
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Yadong Pang, Tatsuo Ishiyama, Koji
Kubota*, Hajime Ito*
Page No. – Page No.
Iridium(I)-Catalyzed C–H Borylation in
Air Using Mechanochemistry
The first application of mechanochemistry to a catalytic C−H borylation reaction is
described. Using either none or just a catalytic amount of a liquid, a series of
heteroaromatic compounds was efficiently reacted with bis(pinacolato)diboron in the
presence of an iridium(I)/dtbpy catalyst under mechanochemical conditions to afford
the corresponding C−H borylation products in good to excellent yield.
This article is protected by copyright. All rights reserved.