Ortho-Selective C-H Borylation of Aromatic Ethers with Pinacol-borane by Organo Rare-Earth Catalysts

Article abstract of DOI:10.1021/acscatal.8b01364

The regioselective C-H borylation of aromatic ethers such as anisoles is of much interest and importance, but has remained a challenge to date. We report herein the catalytic ortho-selective C-H borylation of a wide range of aromatic ethers with pinacolborane (HBpin) by rare-earth metallocene complexes. This protocol offers an efficient and straightforward route for the synthesis of a variety of borylated aromatic ether derivatives. A proper metal/ligand combination for the rare-earth metal catalysts was found to be critically important to promote this transformation.

Full text of DOI:10.1021/acscatal.8b01364

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Letter
Ortho-Selective C–H Borylation of Aromatic Ethers
with Pinacol-borane by Organo Rare-Earth Catalysts
Can Xue, Yong Luo, Huai-Long Teng, Yuanhong Ma, Masayoshi Nishiura, and Zhaomin Hou
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b01364 • Publication Date (Web): 30 Apr 2018
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Ortho-Selective C–H Borylation of Aromatic Ethers with Pina-
col-borane by Organo Rare-Earth Catalysts
Can Xue,† Yong Luo,‡ Huailong Teng,† Yuanhong Ma,‡ Masayoshi Nishiura†,‡ and Zhaomin Hou*,†,‡
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† Advanced Catalysis Research Group, RIKEN Center for Sustainable Resource Science, 2ꢀ1 Hirosawa, Wako, Saitama 351ꢀ
0198, Japan
‡ Organometallic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, 2ꢀ1 Hirosawa, Wako, Saitama 351ꢀ0198,
Japan
ABSTRACT: The regioselective C–H borylation of aromatic ethers such as anisoles is of much interest and importance, but has
remained a challenge to date. We report herein the catalytic orthoꢀselective C–H borylation of a wide range of aromatic ethers with
pinacolborane (HBpin) by rareꢀearth metallocene complexes. This protocol offers an efficient and straightforward route for the synꢀ
thesis of a variety of borylated aromatic ether derivatives. A proper metal/ligand combination for the rareꢀearth metal catalysts was
found to be critically important to promote this transformation.
KEYWORDS: Anisole, orthoꢀborylation, CꢀH activation, rareꢀearth metallocene, anisyl complex, metal hydride, metalꢀligand
combination
The direct C–H borylation of arenes with HBpin or B2pin2
by transition metal catalysts has attracted extensive attention
in recent years, because this transformation offers an efficient
Scheme 1. Catalytic C–H Borylation of Anisole
and straightforward route for the synthesis of aryl boronates
that can serve as useful precursors for diverse chemical transꢀ
formations.1,2 Aromatic ethers such as anisoles are important
structural motifs in a large number of natural products, pharꢀ
maceuticals, and functional materials.3 Therefore, the direct
C–H borylation of aromatic ethers is of great interest and sigꢀ
nificance. However, a big challenge in the catalytic C–H
borylation of aromatic ethers is the control of regioselectivity.
The C–H borylation of anisoles with HBpin and B2pin2 by
several late transition metal catalysts such as Ir, Rh and Co
complexes has been sporadically reported in the literature,
which usually gave a mixture of paraꢀ, metaꢀ, and orthoꢀ
regioisomers of the borylation products (Scheme 1a).4 The
direct orthoꢀselective C–H borylation of anisoles has remained
unknown to date. This is most likely due to steric influence
and a lack of suitable catalysts that can effectively interact
with an ether group to direct orthoꢀselective C–H activation
and borylation without being deactivated by a borylation agent
such as HBpin.
We have recently shown that some organo rareꢀearth (group
3
and
lanthanide)
metal
complexes
such
as
and
Me2Si(C5Me4)(NtBu)Sc(CH2C6H4NMe2ꢀo)
(C5Me5)Sc(CH2C6H4NMe2ꢀo)2 can serve as efficient catalysts
for the orthoꢀselective C–H silylation5 and alkylation6 of aniꢀ
soles. The exclusive orthoꢀselectivity was due to the affinity
(oxophilicity) of rareꢀearth metal ions to an ether oxygen atꢀ
om, which can effectively direct ortho C–H activation of an
anisole unit. In principle, the orthoꢀselective C–H borylation
of anisole could be achieved in a catalytic fashion, if a rare
earth metal hydride species like A regioselectively activates
(deprotonates) an ortho C–H bond of anisole followed by
species like A could also react with HBpin to irreversibly yield
an inactive zwitterion compound like E7 via ringꢀopening of
the pinacolatoboron unit because of the strong oxophilicity of
rare earth metal ions. Obviously, to make the catalytic C–H
borylation operative, it is necessary to search for suitable cataꢀ
lysts that can show much higher activity toward anisole (to
give B and C) than toward HBpin (to give E).
We report herein that the catalytic orthoꢀselective C–H
borylation of a wide range of anisole compounds with HBpin
can be achieved by using organo rareꢀearth metal complexes
with an appropriate metal/ligand combination. This protocol
borylation of the resulting anisyl species like C through
σꢀ
bond metathesis with HBpin (see Scheme 1b). However, the
rareꢀearth metal hydride
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constitutes the first example of orthoꢀselective C–H borylation
of anisoles and offers an efficient route for the synthesis of a
new family of orthoꢀborylated aromatic ether derivatives.
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lyst (Table 1, entry 9). These results demonstrate that the cataꢀ
lytic activity for the present C–H borylation reaction is signifiꢀ
cantly influenced by both the metal ion and the supporting
ligands of the catalysts, and a proper metal/ligand combination
is critically important to promote the C–H borylation reaction.
The use of hexane instead of toluene as a solvent with Y-3 as a
catalyst gave a further higher yield of 2a (85%) under the
same conditions (Table 1, entry 10). The reaction at a lower
temperature (80 ºC) gave a much lower yield (50%) (Table 1,
entry 11).
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Table 1. C–H Borylation of Anisole with HBpin by Rare
Earth Catalysts Bearing Different Ligandsa
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Temp.
(°C)
Yield of 2a
Table 2. Ortho-Selective C–H Borylation of Aromatic
Entry
Solvent
[Ln]
(%)b
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Ethers by a Rare Earth Metallocene Catalyst a
1
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Hexane
Hexane
100
100
100
100
100
100
100
100
100
100
80
N.D.c
Sc-1
Sc-2
Y-2
2
7
3
36
4
11
Lu-2
Nd-2
Pr-2
Y-3
5
2
6
2
7
80
8
80
Lu-3
Y-4
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Trace
85 (83)d
50
10
11
Y-3
Y-3
aReaction conditions: 1a (0.2 mmol), HBpin (0.22 mmol), [Ln]
(10 mol%), solvent (2 mL). Yield determined by H NMR with
b
1
c
CH2Br2 as an internal standard, unless otherwise noted. Not deꢀ
tected. dIsolated yield.
At first, we examined a series of rareꢀearth complexes bearꢀ
ing different Cp ligands for the reaction of anisole (1a) with
HBpin at 100 ºC in toluene. Some representative results are
shown in Table 1. The halfꢀsandwich scandium complex Sc-1
showed no catalytic activity for the C–H borylation of anisole
(Table 1, entry 1), although it was highly active for the C–H
silylation of anisole with PhSiH3 under the similar conditions.5
We presumed that the lack of activity of Sc-1 for the C–H
borylation reaction is probably due to the steric openness
(constrained geometry) around the metal center, which may
allow a hydride species (like A) to react with HBpin to give a
zwitterion compound (like E) (see Scheme 1b and vide infra).
To suppress this possible deactivation process, we then examꢀ
ined a series of rareꢀearth metallocene complexes bearing two
sterically demanding C5Me5 ligands (Table 1, entries 2ꢀ6).
Among these metallocene complexes, the yttrium complex Y-
2 showed the best performance, although it gave only a modꢀ
erate yield (36%) of the target borylation product 2a (Table 1,
entry 3). When the C5Me5 ligands were replaced by two slightꢀ
ly less bulkier C5Me4 ligands (Y-3 and Lu-3), the desired orꢀ
tho C–H borylation product 2a was obtained in a much higher
yield (80%) (Table 1, entries 7 and 8). The use of a further
smaller ligand C5Me2 (Y-4) completely deactivated the cataꢀ
aReaction conditions: 1 (0.2 mmol), HBpin (0.22 mmol), Y-3 (10
mol%), hexane (4 mL), 100 °C, 24 h, isolated yield, unless otherꢀ
wise noted. bLu-3 (10 mol%), NMR yield. cY-3 (5 mol%). dToluꢀ
ene (4 mL).
With the optimized reaction conditions in hand, we next inꢀ
vestigated the scope of aromatic ethers. Some representative
results are summarized in Table 2. The paraꢀmethylꢀ, tertꢀ
butylꢀ, phenylꢀ, and trimethylsilylꢀsubstituted anisoles were all
selectively orthoꢀborylated by Y-3 or Lu-3 in hexane at 100
ºC, giving the desired products 2b-2e in high yields (71–90%).
Halide (F, Cl, Br, I) substituents were compatible with the
catalyst, exclusively affording the corresponding halogenated
anisyl boronate products 2f-2i in excellent yields (87–96%). In
the case of 1,4ꢀdimethoxybenzene, the monoborylated product
2j was obtained as a major product in 50% isolated yield toꢀ
gether with the diborylated product 2j’ (25%). In the cases of
4ꢀtrifluoromethoxyꢀ, 4ꢀmethylthioꢀ, 4ꢀdimethylaminoꢀ, and 4ꢀ
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diphenylaminoꢀsubstituted anisoles, the borylation reaction
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exclusively occurred at an ortho position of the MeO group,
giving the corresponding functionalized anisyl boronate prodꢀ
ucts 2k-2n in 74–89% isolated yields.8 The reaction of 4,4'ꢀ
dimethoxybiphenyl with HBpin afforded the monoborylated
product 2o in 72% yield together with the diborylated product
2o’ as a minor product (13%). In the case of metaꢀsubstituted
anisoles, the C–H borylation reaction took place exclusively at
the less sterically demanding orthoꢀposition albeit with lower
conversion due to steric influence (see 2p–2r). βꢀ
Methoxynaphthalenes could also be efficiently orthoꢀ
borylated (see 2s and 2t). The borylation of 2ꢀmethylanisole
with HBpin did not take place under the same conditions,
probably due to steric influence similar to the case of silylaꢀ
tion.5 However, 2,3ꢀdihydrobenzofuran was efficiently
borylated with HBpin to afford the desired product 2u in 66%
isolated yield, although its silylation reactivity was poor.5 Ethꢀ
oxybenzene (phenetole) was suitable for this reaction, but its
conversion was much lower than that of anisole due to steric
hindrance. Dimethyl acetal could survive the catalytic borylaꢀ
tion conditions, affording the corresponding aldehydeꢀ
substituted anisyl boronate product 2w’ in moderate yield after
silica gel chromatography.
Table 4.C–H Borylation of Aromatic Heterocycles by Y-2a
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aReaction conditions: 3 (0.2 mmol), HBpin (0.22 mmol), Y-2 (5
mol%), octane (2 mL), 80 °C, 24 h, isolated yield, unless otherꢀ
wise noted. bHBpin (0.44 mmol). cNMR yield.
In the case of cyclic aromatic ethers such as furans, the
C5Me4ꢀligated complex Y-3 showed no catalytic activity for
the C–H borylation with HBpin. In sharp contrast, the more
sterically demanding C5Me5ꢀligated analogue Y-2 showed
high activity for the ortho C–H borylation of furans under the
similar conditions (Table 4).11 The reaction of furan with 2.2
equiv. of HBpin in the presence of 5 mol % of Y-2 in octane at
80 ºC afforded the 2,5ꢀdiborylated furan product 4a in 98%
yield. In the case of 2ꢀmethylꢀ, 2ꢀpropylꢀ, and 2,3ꢀdimethylꢀ
substituted furans, the C–H borylation proceeded exclusively
at the 5ꢀposition to give the monoborylation products 4b–4d in
excellent yields (92–95%). The reaction of 3ꢀbromofuran with
HBpin selectively afforded the 2,5ꢀdiborylation product 4e,
with the bromide substituent remaining intact. In the case of
benzofuran, the reaction took place regioselectively at the 2ꢀ
position, affording the 2ꢀborylated benzofuran derivative 4f in
73% isolated yield. Thiophene could also be borylated with
HBpin by Y-2, which gave the corresponding monoborylation
product 4g in 45% yield. NꢀMethylpyrrole was less effective
for the present borylation reaction probably due to steric hinꢀ
drance.
Table 3. Borylation of Aromatic Ethers Bearing Alkene
Substituentsa
aReaction conditions: 1 (0.2 mmol), HBpin (0.44 mmol), Y-3 (10
mol%), hexane (4 mL), 100 °C, 24 h, isolated yield.
Scheme 2. Kinetic Isotope Effect (KIE) Experiments
In the case of anisole derivatives containing an alkene subꢀ
stituent, both the C=C double bond hydroboration and C–H
borylation took place, affording the corresponding unique
diborylation products (such as 2x–2aa) in high yields (Table
3).9,10
The reaction of deuterated anisole 1a-D5 with HBpin cataꢀ
lyzed by Y-3 afforded the C–D borylation product 2a-D4, in
which no DꢀH exchange was observed. The reaction of a 1:1
mixture of 1a and 1a-D5 with HBpin showed a significant
kinetic isotope effect (KIE = 5.7) (Scheme 2a; see also Fig.
S1). The relative ratio of the initial rates of the two sideꢀbyꢀ
side reactions using 1a and 1a-D5, respectively, was deterꢀ
mined to be kH/kD = 7.4 (Scheme 2b,c; see also Fig. S2). These
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results suggest that C–H activation is involved in the rateꢀ
determining step of this transformation.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.
Experimental details and characterization data (PDF).
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Scheme 3. Stoichiometric Reactions of An Yttrium Hy-
dride Complex Y-5 with Anisole and HBpin
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AUTHOR INFORMATION
Corresponding Author
9
*Eꢀmail: houz@riken.jp
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Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported in part by a GrantꢀinꢀAid for Scientific
Research (S) (No. 26220802) and a GrantꢀinꢀAid for Scientific
Research on Innovative Areas (17H06451) from JSPS. We grateꢀ
fully appreciate Mrs. Akiko Karube of Organometallic Chemistry
Laboratory for the measurements of highꢀresolution mass spectra
and elemental analyses.
To gain more information on the mechanistic aspects of the
catalytic ortho C–H borylation, some stoichiometric reactions
were carried out. The reaction of the alkyl complex Y-3 with
HBpin in C6D6 took place rapidly at room temperature, possiꢀ
bly yielding an yttrium hydride species.9,12 However, attempts
to isolate a pure product from this reaction were not successꢀ
ful, possibly due to further reactions with HBpin as shown in
Scheme 1b.7 To confirm if an yttrium hydride species is inꢀ
volved in the present catalytic C–H borylation reaction, we
then synthesized a wellꢀdefined yttrium hydride complex Y-5
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by the reaction of Y-3 with H2 and examined its reactivity
(Scheme 3). The reaction of Y-5 with anisole at 80 °C affordꢀ
ed the orthoꢀmetalated anisyl complex Y-6 in 92% yield,
which was structurally characterized by an Xꢀray crystalloꢀ
graphic study.14 The reaction of Y-6 with HBpin at room temꢀ
perature afforded the orthoꢀborylated anisole derivative 2a in
53% yield. Both the hydride complex Y-5 and the anisyl comꢀ
plex Y-6 afforded 2a in yields comparable to that with Y-3 in
the catalytic reaction of anisole with HBpin. These results
strongly suggest that an yttrium hydride species such as Y-5
(equivalent to A in Scheme 1b), which could be generated by
the reaction of Y-3 with HBpin,9,12 should be a true catalyst
species in the catalytic cycle of the C–H borylation of anisole
with HBpin (see Scheme 1b).
In summary, we have achieved for the first time the catalytꢀ
ic orthoꢀselective C–H borylation of a wide range of aromatic
ethers with HBpin by using rareꢀearth metallocene complexes
bearing an appropriately tuned ligand environment (such as Y-
3). This protocol features high atom efficiency, broad substrate
scope, certain functional group tolerance, and no need for an
H2 acceptor, which constitutes a novel straightforward route
for the synthesis of a new family of borylated aromatic ether
derivatives. The success of this transformation is ascribed to
the adequate oxophilicity of a rareꢀearth metal ion as well as a
proper ligand environment provided by the Cp ligands for the
rareꢀearth metal center, which can effectively suppress possiꢀ
ble deactivation reactions and promote the ortho C–H activaꢀ
tion and borylation of an aromatic ether. Further studies on the
application of the unique features of organo rareꢀearth comꢀ
plexes to the C–H functionalization and other transformations
of related organic substrates are currently in progress.
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around the metal center, which could allow coordination of more than
one molecule of furan (which is less sterically demanding than aniꢀ
sole) and thus hamper the reaction of a metal furyl species with
HBpin. In the case of Y-2, the two sterically demanding C5Me5 ligꢀ
ands may prevent the coordination of excess furan molecules to the
metal center and thus allow the Y−furyl species to react with HBpin
and give the borylation product efficiently. The lower efficiency of
the sterically demanding complex Y-2 for the borylation of anisole
(see Table 1, entry 3) is probably due to the larger steric hindrance of
anisole than that of furan.
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