Continuous-Flow C-H borylation of arene derivatives

Article abstract of DOI:10.1002/adsc.201000160

A new continuous-flow system for C-H borylation has been developed. An insoluble catalyst prepared from chloro(1,5-cyclooctadien)iridium(I) dimer and 2,2′-bipyridine-4,4′-dicarboxylic acid in the presence of bis(pinacolato)diboron exhibited high reactivity under continuous-flow processing without the loss of expensive iridium metal.

Full text of DOI:10.1002/adsc.201000160

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DOI: 10.1002/adsc.201000160
À
Continuous-Flow C H Borylation of Arene Derivatives
a,b
b
a,
Tsuyoshi Tagata, Mayumi Nishida, and Atsushi Nishida *
a
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Fax : (+81)-43-290-2929; phone: (+81)-43-290-2907; e-mail: nishida@p.chiba-u.ac.jp
Koei Chemical Company, Ltd., 25, Kitasode, Sodegaura, Chiba 299-0266, Japan
b
Received: March 1, 2010; Published online: June 30, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000160.
Abstract: A new continuous-flow system for CÀH
borylation has been developed. An insoluble cata-
lyst prepared from chloro(1,5-cyclooctadien)iridi-
it has high atom efficiency and can be conducted
under milder reaction conditions compared with tra-
ditional halogen-metal exchange reactions.
[
9,10]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
um(I) dimer and 2,2’-bipyridine-4,4’-dicarboxylic
Recently, we reported the preparation of a recycla-
acid in the presence of bis(pinacolato)diboron ex-
hibited high reactivity under continuous-flow proc-
essing without the loss of expensive iridium metal.
ble iridium catalyst for the CÀH borylation reac-
[
11]
tion.
The iridium catalyst, which can be prepared
from an iridium precursor, 2,2’-bipyridine-4,4’-dicar-
boxylic acid (BPDCA) and bis(pinacolato)diboron
(Pin B , 1), could be reused at least ten times in the
Keywords: 2,2’-bipyridine-4,4’-dicarboxylic acid; CÀ
2
2
H borylation; continuous-flow system; iridium
borylation of benzene. This iridium catalyst has low
solubility in organic media, but does not have support
materials, such as resins, silica gels or charcoals. Fur-
thermore, this non-supported catalyst also offers the
further advantages of robustness and solvent-inde-
Flow chemistry is a well-established technology for in- pendent behaviour, such as swelling. We next studied
[
1]
dustrial processes as well as laboratory experiments.
the application of this iridium catalyst to continuous-
Compared with reactions under standard batch condi- flow processes. In this paper, we report the first con-
tions, flow chemistry has been reported to offer many tinuous-flow CÀH borylation system using our new
advantages, such as 1) operational simplicity, 2) rapid recyclable catalyst.
and efficient heat dispersion, 3) ability to handle a
First, we synthesized a recyclable iridium catalyst
[
2]
[11]
multi-step reaction in a continuous sequence, and 4) according to our procedure (Scheme 1). A mixture
rapid scale-up with little or no process development of iridium precursor [IrCl(COD)] (1.2 mmol) with
by either changing the reactor volume or by running 2,2’-bipyridine-4,4’-dicarboxylic acid (2.4 mmol) in
several reactors in parallel. benzene (21.4 mL, 240 mmol) was heated at 808C for
Arylboronates are synthetic intermediates that are 4 h in the presence of Pin B 1 (8.0 mmol). During the
AHCTUNGTRENNUNG
2
2
2
[
3–5]
used in the synthesis of drugs
rials.
and functional mate- reaction, the reaction mixture turned black with the
[6–8]
Therefore, arylboronates are synthesized in evolution of hydrogen gas. After the reaction, the re-
quantities ranging from bulk chemicals to fine chemi- action mixture was filtered off in a glove-box and the
cals. Among the methods used for their preparation, iridium complex (BPDCA-cat) was obtained in quan-
[
12]
CÀH borylation is one of the most promising because titive yield (1.58 g) based on iridium metal. The cat-
Scheme 1. Preparation of BPDCA-cat.
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Adv. Synth. Catal. 2010, 352, 1662 – 1666

Continuous-Flow CÀH Borylation of Arene Derivatives
alyst had to be handled in a glove-box, because it is system used is shown in Figure 1. A stainless steel re-
ignitable under air.
actor was constructed using Swagelock components, a
We checked the activity of BPDCA-cat in CÀH sintered metal filter, and a stainless tube, which were
borylation using various arenes and 1 in the presence commercially available for columns in liquid chroma-
of 3 mol% of isolated catalyst under batch conditions. tography. No special equipment is necessary. This re-
The results are shown in Table 1. After the reaction, actor has a bed size of 30 mmꢁ4 mm and is packed
the catalyst could be separated by filtering through a with 145 mg of BPDCA-cat in a glove-box. The reac-
disk filter (0.45 mm mesh). In the case of benzene, the tor was heated by an aluminum block heating system.
catalyst had sufficient activity and gave the product in The results of CÀH borylation under continuous-flow
excellent yields as checked by both GC and isolation. conditions are shown in Table 2. In the first run, a
In the case of benzofuran, a 17 mol% of catalyst load- benzene solution of 1 (0.18M) was passed through
ing was necessary to obtain the borylated product in the column packed with catalyst at 808C at different
good yield.
flow rates: 0.1 mmol/h, 0.2 mmol/h, and 0.3 mmol/h.
Next, CÀH borylation under continuous-flow condi- As the substrate solution flowed, hydrogen gas was
tions using BPDCA-cat was studied, and the flow evolved. The reactions proceeded smoothly, and the
Table 1. Evaluation of reactivity of BPDCA-cat under batch conditions.
[a]
[b,c]
Entry
Substrate
Product
Yield
[
d]
1
2
93% (88%)
82% (78%)
3
4
5
87% (83%)
87% (83%)
77% (71%)
87% (83%)
6
7
[e]
[f]
59% (43% )
[
[
a]
Reactions were carried out in a methylcyclohexane solution of the substrates (0.72M) and 1 (0.36M) unless otherwise
noted.
Yields were determined by GC using 4-ethylbiphenyl as an internal standard, except that tetralin was used as an internal
standard in entry 3.
Yields in parentheses are the isolated yield.
Reaction was carried out in a benzene solution of 1 (0.18M).
Reaction was carried out using 0.36M of 1 (0.18 mmol) and 0.72M of benzofuran (0.36 mmol) in the presence of
b]
[
[
[
c]
d]
e]
1
7 mol% of catalyst.
[
f]
1
Product contained ca. 5% of 3-borylated isomer as observed by H NMR.
Adv. Synth. Catal. 2010, 352, 1662 – 1666
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asc.wiley-vch.de
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Tsuyoshi Tagata et al.
COMMUNICATIONS
Figure 1. Continuous-flow system.
Table 2. CÀH borylation under continuous-flow conditions.
[a]
[b,c]
[d]
Entry
Substrate
Concentration (mol/L)
Flow rate
[mmol/h]
Yield
[%]
Ir leaching
ACHTUNGTNERNUNG[ ppm]
Substrate
1
A
H
U
G
R
N
U
G
1
2
3
4
5
6
7
8
9
0.1
0.2
0.3
0.1
0.2
0.3
0.1
0.2
0.3
0.1
0.2
0.3
85 (80)
83 (79)
85
53 (49)
43
36
89
83
70
<0.1
<0.1
<0.1
–
0.18
0.18
0.36
<0.1
[e]
0.36
0.72
N.A.[
N.A.
0.4
e]
0.2
0.1
10
11
12
88 (82)
73
63
<0.1
[
e]
N.A.[
0
0
.72
.72
0.36
0.36
0.36
e]
N.A.
13
14
15
0.1
0.2
0.3
93 (87)
80
76
0.4
0.6
0.6
[
f]
f]
f]
16
17
18
0.1[
0.2[
0.3
75 (71)
65
54
17
7.9
6.7
0
0
.72
.72
1
2
9
0
0.1
0.1
78 (75)
85 (78)
1.5
2.7
0.36
0.36
[f]
[g]
21
0.72
0.1
67 (62)
0.6
[
[
a]
In the case of benzene (entries 1–3), benzene was used as a substrate as well as a solvent.
Yields based on boron atoms of 1 were determined by GC analysis using 4-ethylbiphenyl as an internal standard, except
b]
that in the reaction of 1,3-dichlorobenzene the yield was determined by GC analysis using tetralin as an internal stan-
dard.
[
[
[
[
[
c]
d]
e]
f]
Yields in parentheses are isolated yields.
The contents of iridium in the reaction mixture were analyzed by ICP.
Not analyzed.
Cyclopentyl methyl ether was used as a solvent.
Product contained ca. 5% of 3-borylated isomer as observed by H NMR. The structures of the products are shown in
g]
1
Table 1.
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Adv. Synth. Catal. 2010, 352, 1662 – 1666

Continuous-Flow CÀH Borylation of Arene Derivatives
desired borylated product 2 was obtained in respec- stirred at 808C for 4 h. In a glove-box, the reaction mixture
was filtered through a filter paper (Kiriyama No. 5C) and
tive yields of 85%, 83%, and 85%. Between reactions
the black solid obtained was washed twice with 10 mL ben-
with different substrates, the catalyst was washed with
zene. The black solid was dried under vacuum. The com-
methylcyclohexane (10 mL, flow rate 0.2 mL/min) to
bined filtrate and washings were analyzed by GC to deter-
avoid contamination of the products. Indeed, the pre-
mine the yield of 2 (33% yield based on boron atom of 1)
vious substrate and product could be removed by
using 4-ethylbiphenyl as an internal standard. Iridium and
washing to less than 0.1% as detected by GC analysis.
boron contents in the catalyst were calculated to be 31%
For substrates other than benzene, methylcyclohex-
(
w/w) for iridium and 3.7% (w/w) for boron by ICP analysis.
ane or cyclopentyl methyl ether (CPME) was used as BPDCA-cat (1.58 g) was obtained in quantitive yield based
an inert solvent. Compared with the reaction of ben- on iridium metal. Caution: The catalyst is ignitable under
zene, the reaction of 1,2-dichlorobenzene proceeded air.
slowly with 1 at a concentration of 0.18M. On the
other hand, the reaction rate increased at a higher
CÀH Borylation of Benzene using BPDCA-cat under
concentration. Furthermore, as the flow rate in- Batch Conditions
creased, the yield of product decreased. In the case of
A 20-mL test tube equipped with a magnetic stirring bar
and a three-way cock with a septum inlet was charged with
BPDCA-cat (19 mg) in a glove-box. A benzene solution
2,6-dichloropyridine, CPME was used as a solvent be-
cause of its low solubility in methylcyclohexane to
make a 0.72M solution. Notably, benzofuran was (0.18M) of 1 (5.56 mL, 1.0 mmol) was added and the mix-
borylated under these flow conditions (entry 21), the ture was stirred at 808C for 12 h. The reaction mixture was
same as in the batch condition using 17 mol% of cata- filtered through a disc filter (0.45 mm mesh) and the black
solid obtained was washed twice with 5 mL benzene. The
lyst, although the reaction was slower than with other
combined filtrate and washings (11.68 g) were divided into
substrates. The best result was achieved using a flow
two portions. One portion was used for GC and ICP analy-
rate of 0.1 mmol/h with substrates other than benzene.
sis. The GC yield was determined using 4-ethylbiphenyl as
an internal standard (93%). The remaining portion (3.613 g)
was evaporated and distilled using a Kꢂgelrohr apparatus
Less than 10 ppm of iridium leaching was observed in
the reaction mixture. All reactions (Table 2) were car-
ried out using a single column under heating at 808C
for more than one month. No significant deactivation
(
oven temperature; 80–1008C, pressure; 1–2 mmHg) to give
analytically pure (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
of the catalyst was observed. Furthermore, this flow yl)benzene as
colorless oil; yield: 111 mg (88%).
H NMR: d=1.35 (s, 12H), 7.37 (t, 2H, J=7.4 Hz), 7.46 (t,
a
1
system can be readily performed even outside of a
1
3
glove box because the catalyst is hardly exposed to 1H, J=7.3 Hz), 7.81 (d, 2H, J=7.3 Hz); C NMR: d=
2
4.86, 83.74, 127.69, 131.24, 134.74.
air and moisture in a column reactor. This is the most
important advantage of this flow system.
CÀH Borylation of Benzene using BPDCA-cat under
In conclusion, we have developed a continuous-
flow CÀH borylation system using an insoluble iridi-
Continuous-Flow Conditions
um catalyst which we developed. This catalyst exhibit-
ed high reactivity and also high stability toward heat-
A benzene solution (0.18M) of 1 was passed through the re-
actor packed with catalyst at 808C at 0.1 mmol/h for ca. 18 h
ing. Although this catalyst is sensitive to air and mois- (8.7 mL) using a syringe pump. The reaction mixture was
ture, it could be easily handled as a packed stainless transferred to another bottle from a product stock bottle.
steel column. This continuous-flow system, which has The product stock bottle was washed with 10 mL benzene.
The combined filtrate and washings (15.35 g) were divided
many advantages, such as easy separation of the cata-
into two potions. One portion was used for GC and ICP
lyst from the reaction mixture, simple operation, and
analysis. The GC yield was determined using 4-ethylbiphen-
application to a variety of substrates, can be applied
yl as an internal standard (85%). The remaining portion
to the industrial-scale production of aromatic borates
(
4.832 g) was evaporated and distilled using a Kꢂgelrohr ap-
without the loss of expensive iridium metal. Further
studies to apply this flow system to other substrates
are now in progress.
paratus (oven temperature; 80–1008C, pressure; 1–2 mmHg)
to give analytically pure (4,4,5,5-tetramethyl-1,3,2-dioxabor-
olan-2-yl)benzene as a colorless oil; yield: 161 mg (80%).
CÀH Borylation of 1,3-bis[trifluoromethyl]benzene
Experimental Section
using BPDCA-cat under Continuous-Flow Conditions
A methylcyclohexane solution of 1 (0.36M) and 1,3-ditri-
fluoromethylbenzene (0.72M) was passed through the reac-
tor packed with catalyst at 808C at 0.1 mmol/h for ca. 13 h
(4.0 mL) using a syringe pump. The reaction mixture was
transferred to another bottle from a product stock bottle.
The product stock bottle was washed with 10 mL methylcy-
clohexane. The combined filtrate and washings (10.29 g)
were divided into two portions. One portion was used for
Synthesis of BPDCA-cat
A 100-mL flask equipped with a magnetic stirring bar and a
three-way cock with a septum inlet was charged with [IrCl-
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(COD)] (806 mg, 1.2 mmol), 2,2’-bipyridine-4,4’-dicarboxyl-
2
ic acid (586 mg, 2.4 mmol) and bis(pinacolato)diboron
(
2.03 g, 8.0 mmol). After the flask had been flushed with ni-
trogen, benzene (21.4 mL) was added and the mixture was
Adv. Synth. Catal. 2010, 352, 1662 – 1666
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asc.wiley-vch.de
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Tsuyoshi Tagata et al.
COMMUNICATIONS
GC and ICP analysis. The GC yield was determined using 4-
ethylbiphenyl as an internal standard (93%). The remaining
portion (3.112 g) was evaporated and distilled using a Kꢂgel-
rohr apparatus (oven temperature; 80–1008C, pressure; 2–
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3
mmHg) to give analytically pure 1,3-ditrifluoromethyl-5-
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(
4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene as
a
1
white solid; yield: 258 mg (87%). H NMR: d=1.37 (s,
1
3
1
1
2H), 7.95 (s, 1H), 8.24 (s, 2H); C NMR: d=24.83, 84.84,
23.49 (q, JC,F =273 Hz), 124.72 (q, JC,F =3.3 Hz), 130.88 (q,
JC,F =33 Hz), 134.65 (d, JC,F =3.3 Hz).
[
[
[
[
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Acknowledgements
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We thank Mr. Matsuo (Koei Chemical Company, Ltd.) and
Mr. Mizoguchi (Koei Chemical Company, Ltd.) for the ICP
analysis and Mr. Ishikawa (Koei Chemical Company, Ltd.)
for the GC-MS analysis. Financial support from Koei Chemi-
cal Company, Ltd. is gratefully acknowledged. This research
was conducted as part of Research for Promoting Technolog-
ical Seeds and was supported by JST Innovation Satellite
Ibaraki.
4
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based on the boron atoms of 1. BPDCA-cat contains
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1662 – 1666