Catalyst-controlled regiodivergent C-H borylation of multifunctionalized heteroarenes by using iridium complexes

Article abstract of DOI:10.1002/chem.201500658

The regiodivergent C-H borylation of 2,5-disubstituted heteroarenes with bis(pinacolato)diboron was achieved by using iridium catalysts formed in situ from [Ir(OMe)(cod)]₂/dtbpy (cod=1,5-cyclooctadiene, dtbpy: 4,4′-di-tert-butyl-2,2′-bipyridine) or [Ir(OMe)(cod)]₂/2 AsPh₃. When [Ir(OMe)(cod)]₂/dtbpy was used as the catalyst, borylation at the 4-position proceeded selectively to afford 4-borylated products in high yields (dtbpy system A). The regioselectivity changed when the [Ir(OMe)(cod)]₂/2 AsPh₃ catalyst was used; 3-borylated products were obtained in high yields with high regioselectivity (AsPh₃ system B). The regioselectivity of borylation was easily controlled by changing the ligands. This reaction was used in the syntheses of two different bioactive compound analogues by using the same starting material. Minor adjustments, major differences: The regiodivergent C-H borylation of 2,5-disubstituted heteroarenes with bis(pinacolato)diboron was achieved by using iridium catalysts formed in situ from [Ir(OMe)(cod)]₂/dtbpy (cod=1,5-cyclooctadiene, dtbpy: 4,4'-di-tert-butyl-2,2'-bipyridine) or [Ir(OMe)(cod)]₂/2 AsPh₃ (see scheme).

Full text of DOI:10.1002/chem.201500658

DOI: 10.1002/chem.201500658
Full Paper
&
Homogeneous Catalysis
Catalyst-Controlled Regiodivergent CÀH Borylation of
Multifunctionalized Heteroarenes by Using Iridium Complexes
Ikuo Sasaki, Jumpei Taguchi, Shotaro Hiraki, Hajime Ito,* and Tatsuo Ishiyama*[a]
Abstract: The regiodivergent CÀH borylation of 2,5-disubsti-
tuted heteroarenes with bis(pinacolato)diboron was ach-
ieved by using iridium catalysts formed in situ from [Ir(O-
Me)(cod)]2/dtbpy (cod=1,5-cyclooctadiene, dtbpy: 4,4’-di-
tert-butyl-2,2’-bipyridine) or [Ir(OMe)(cod)]2/2AsPh3. When
[Ir(OMe)(cod)]2/dtbpy was used as the catalyst, borylation at
the 4-position proceeded selectively to afford 4-borylated
products in high yields (dtbpy system A). The regioselectivity
changed when the [Ir(OMe)(cod)]2/2AsPh3 catalyst was used;
3-borylated products were obtained in high yields with high
regioselectivity (AsPh3 system B). The regioselectivity of bor-
ylation was easily controlled by changing the ligands. This
reaction was used in the syntheses of two different bioactive
compound analogues by using the same starting material.
search groups, including our group, in recent years.[8,9] The se-
lectivity arises from the interaction between the coordinating
heteroatom in the carbonyl group and the iridium metal
center.
Introduction
Multisubstituted heteroarenes are important structural motifs;
they are found in many naturally occurring compounds and
biologically active agents.[1] Regioselective CÀH borylation of
mono- or disubstituted heteroarenes containing functional
groups, in combination with further derivatization of the resul-
tant heteroaryl boronic acid esters, offers a convenient and re-
liable synthetic method for multisubstituted heteroarenes, in
combination with various known derivatization reactions of
CÀB bonds.[2–4]
In contrast, catalyst-controlled regiodivergent CÀH boryla-
tion provides a powerful method for the rapid derivatization of
starting heteroarenes. However, only a few examples of cata-
lyst-controlled CÀH borylation with transition-metal catalysts
have been reported. One example of heteroarene borylation
was published by Sawamura and co-workers; they used 4,4’-di-
tert-butyl-2,2’-bipyridine (dtbpy) and silica-SMAP (silica-sup-
ported silicon-constrained monodentate trialkylphosphine) as
the ligands.[10] The reaction took place in high yield with good
regioselectivity. Herein, we report the catalyst-controlled regio-
divergent CÀH borylation of multifunctionalized heteroarenes,
such as furans, thiophenes, and pyrroles, by using two differ-
ent iridium catalyst systems. The borylation of various hetero-
arenes 1 with bis(pinacolato)diboron (B2pin2; 2) proceeded re-
gioselectively at the 3-position under catalysis with an [Ir(O-
Me)(cod)]2/dtbpy complex (Scheme 1, dtbpy system A); the [Ir-
Because CÀH bonds are ubiquitous in organic compounds,
the most important requirement for CÀH borylation is control
of the site selectivity. Initial studies of selective iridium-cata-
lyzed CÀH borylations at the meta positions of various sub-
stituents were reported by us and the groups of Smith and
Hartwig.[5–7] The regioselectivity of borylation was driven by
steric repulsion between the iridium catalysts and various func-
tional groups, namely, alkyl, aryl, halide, or carbonyl groups.
Steric hindrance of the substrates can control the selectivity to
some extent. For example, 1,3-disubstituted arenes gave the
meta-borylated product exclusively in the iridium-catalyzed
borylation. However, other monosubstituted substrates gave
a product mixture of meta and para CÀH borylation.[5–7] Iridi-
um-catalyzed CÀH borylation at the ortho position of the coor-
dinating functionalities has also been reported by many re-
[a] Dr. I. Sasaki, J. Taguchi, S. Hiraki, Prof. Dr. H. Ito, Dr. T. Ishiyama
Division of Chemical Process Engineering and
Frontier Chemistry Center (FCC)
Graduate School of Engineering, Hokkaido University
Kita 13 Nishi 8 Kita-ku, Sapporo, Hokkaido 060-8628 (Japan)
Fax: (+81)117066562
E-mail: hajito@eng.hokudai.ac.jp
ishiyama@eng.hokudai.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500658.
Scheme 1. Regiodivergent CÀH borylation of various heteroarenes.
Chem. Eur. J. 2015, 21, 9236 – 9241
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(OMe)(cod)]2/2AsPh3 complex afforded the 4-borylated product
Table 2. Scope of heteroarenes with a methyl group at the 5-position.[a]
4 (Scheme 1, AsPh3 system B).
Results and Discussion
We first examined the borylation of furan derivative 1a, which
had a carbonyl group and a methyl group at the 2- and 5-posi-
tions, respectively, with [Ir(OMe)(cod)]2 and a series of ligands
(Table 1, entries 1–7). The reaction of 1a with 2 (1.1 equiv) in
Entry
X
R
System
Yield [%][b,c] (3/4)
1
2
3
4
5
6
7
8
O
Me (1b)
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
36 (21)[d] (>99:<1)
92 (<1:>99)
Table 1. Optimization of reaction conditions.[a]
O
OMe (1c)
NMe2 (1d)
N(iPr)2 (1e)
Et (1 f)
99 (86)[d] (>99:<1)
51 (<1:>99)
O
93 (78)[d] (>99:<1)
99 (<1:>99)
O
97 (93)[d] (>99:<1)
99 (<1:>99)
Entry Ligand ([mol%])
T [8C] Solvent
Yield [%][b,c]
(3a/4a)
9
S
84 (79)[d] (>99:<1)
86 (<1:>99)
10
11
12
13
14
15
16
17
18
19
20
21
22
24 (19)[d] (>99:<1)
96 (<1:>99)
1
2
3
4
5
6
7
8
dtbpy (3)
3,4,7,8-Me4Phen[e] (3) RT
RT
octane
octane
octane
octane
octane
octane
octane
octane
DMF
92 (76)[d] (>99:<1)
82 (>99:<1)
74(43)[d,f] (<1:>99)
0 (–:–)
31 (<1:>99)
22 (<1:>99)
18 (<1:>99)
28 (<1:>99)
0 (–:–)
S
Me (1g)
99 (78)[d] (>99:<1)
81 (<1:>99)
AsPh3 (6)
P[3,5-(CF3)2C6H3]3 (6)
P(C6F5)3 (6)
PPh3 (6)
120
S
OMe (1h)
NMe2 (1i)
N(iPr)2 (1j)
Et (1k)
120
120
120
120
120
120
120
120
S
81 (80)[d] (>99:<1)
99 (<1:>99)
77 (61)[d] (>99:<1)
81 (<1:>99)
PCy3 (6)
S
–
90 (91)[d] (>99:<1)
92 (<1:>99)
9
10
11
AsPh3 (6)
AsPh3 (6)
AsPh3 (6)
NCO2Me
NCO2Me
diglyme
mesitylene 72 (<1:>99)
69 (<1:>99)
OMe (1l)
81 (75)[d] (>99:<1)
43 (<1:>99)
[a] Reaction conditions: 1a (0.5 mmol),
2
(0.55 mmol), [Ir(OMe)(cod)]2
(1.5 mol%), ligand (3.0–6.0 mol%) in solvent (3 mL). [b] Yields were deter-
mined by GC analysis (internal standard: dodecane). [c] Ratios of isomers
in the crude reaction mixture were determined by 1H NMR spectroscopy
analysis. [d] Yield of product isolated. [e] 3,4,7,8-Me4Phen=3,4,7,8-tetra-
methyl-1,10-phenanthroline. [f] The yield of borylated product 4a signifi-
cantly decreased during the isolation step.
[a] dtbpy system A:
1
(0.5 mmol),
2
(0.55 mmol), [Ir(OMe)(cod)]2
(1.5 mol%), and dtbpy (3.0 mol%) in octane (3 mL) at room temperature
for 16 h. AsPh3 system B: 1 (0.5 mmol), 2 (0.55 mmol), [Ir(OMe)(cod)]2
(1.5 mol%), and AsPh3 (6.0 mol%) in octane (3 mL) at 1208C for 16 h.
[b] Yields were determined by GC analysis (internal standard: dodecane).
[c] Ratios of isomers in the crude reaction mixture were determined by
1H NMR spectroscopy analysis. [d] Yield of product isolated.
the presence of [Ir(OMe)(cod)]2 (1.5 mol%) and dtbpy
(3.0 mol%) in octane at room temperature afforded the 4-bor-
ylated product 3a in 92% yield after 16 h (Table 1, entry 1).
The yield of 3a decreased to 82% when 3,4,7,8-tetramethyl-
1,10-phenanthroline (3,4,7,8-Me4Phen) was used as the ligand
(Table 1, entry 2). In contrast, the borylation of 1a with AsPh3
as the catalyst ligand gave the 3-borylated product 4a in 74%
yield after 16 h (Table 1, entry 3). Use of phosphorous-contain-
ing ligands resulted in significant decreases in the yields (4a:
0–31% after 16 h, Table 1, entries 4–7). This borylation took
place in the absence of a ligand to afford 4a in 28% yield
(Table 1, entry 8). Although no reaction occurred in DMF as the
solvent, other solvents such as diglyme and mesitylene could
be successfully used (diglyme: 69%, mesitylene: 72%; Table 1,
entries 10 and 11). These results clearly show that the boryla-
tion regioselectivity was switched by changing the ligands in
the iridium catalyst.
s A or B (Table 2). The yields of 3-borylated products signifi-
cantly decreased during the isolation step; thus, we deter-
mined the regioselectivities and yields of the products by GC
1
and H NMR spectroscopy analysis of the crude mixture. The
reaction of 1b, which had a acetyl group at the 2-position,
proceeded regioselectively, whereas the 4-borylated product
3b was obtained in low yield under dtbpy system A (36%, 3b/
4b= >99:<1, Table 2, entry 1). In contrast, 3-borylated prod-
uct 4b was produced in high yield with excellent regioselectiv-
ity (92%, 3b/4b= <1:>99, Table 2, entry 2). Furans substitut-
ed with methoxycarbonyl (1c) or aminocarbonyl (1d and 1e)
groups reacted with 2 to afford the corresponding products in
moderate to high yields under both systems (Table 2, en-
tries 3–8). Other heteroarenes, such as thiophenes or N-meth-
oxycarbonyl-protected pyrroles, with functional groups at the
2-position could also be used as substrates for borylation with
high selectivity (dtbpy system A: 77–99%, >99:<1; AsPh3 sys-
tem B: 43–99%, <1:>99; Table 2, entries 9–22), except for
acetyl-substituted thiophene 1g (Table 2, entry 11). These re-
sults suggested that different R groups on the carbonyl func-
With the optimal conditions in hand, we next examined the
scope of heteroarenes with a methyl group at the 5-position
and various functional groups at the 2-position, under system-
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tionality at the 2-position did not affect the regioselectivity of
borylation under either system.
stituent (Table 3, entries 3 and 4). The regioselectivity was com-
pletely reversed compared with those for Table 3, entries 1 and
3, when tert-butyl derivative 1o was used as the substrate
under dtbpy system A; only the 3-borylated product 4o was
obtained in good yield (75%, 3o/4o= <1:>99, Table 3,
entry 5). This result suggests that the tert-butyl moiety may act
as a more bulky substituent than the propionyl group. AsPh3
system B also led to 3-borylated furan 4o in 67% yield
(Table 3, entry 6). The reactivity and selectivity of the TMS de-
rivative 1p were similar to those of 5-tert-butyl furan 1o, and
the 3-borylated product 4p was produced in 58 and 48%
yields under dtbpy system A and AsPh3 system B, respectively
(Table 3, entries 7 and 8).
The regioselectivity of this borylation under dtbpy system A
was affected by the steric properties of the 2- or 5-substituents
because the selectivity originated from steric repulsion be-
tween the 2- or 5-substitutents and the iridium catalyst. The
use of heteroarenes with various substituents other than
a methyl group at the 5-position changed the isomer ratios
(Scheme 2).
Next, we examined the scope of thiophenes containing
functional groups other than alkyl groups at the 5-position
(Table 4). The CF3 group behaved as a larger substituent than
Scheme 2. Schematic illustration of steric and coordinating effects on the re-
activity and regioselectivity in reactions with dtbpy system A.
Table 4. Scope of heteroarenes with functional groups other than alkyl
groups at the 5-position.[a]
We therefore investigated the steric effect of the substituent
at the 5-position on the borylation regioselectivity by using
furan substrates with various alkyl or trimethylsilyl (TMS)
groups at the 5-position and a propionyl group at the 2-posi-
tion (Table 3). 5-Ethylfuran derivative 1m reacted smoothly
with 2 to afford the 4-borylated product 3m in high yield,
with high regioselectivity (dtbpy system A, 81%, 3m/4m=
97:3; Table 3, entry 1). Under AsPh3 system B, the selectivity of
borylation changed completely; only the 3-borylated product
was obtained in good yield (68%, 3m/4m= <1:>99; Table 3,
entry 2). Similar trends in terms of reactivity and selectivity
were observed with substrate 1n, which contained a 5-Cy sub-
Entry
R1
System
t [h]
Yield [%][b] (3/4)
1
2
3
4
5
6
7
8
CF3 (1q)
A[c]
B[d]
A
B
A
B
A
B
20
20
16
30
16
16
1
80 (56:44)
75 (<1:>99)
82 (77)[e] (>99:<1)
0 (–:–)
82 (63)[e] (>99:<1)
46 (26:74)
OMe (1r)
Cl (1s)
Table 3. Steric effects on the regioselectivity of borylation.[a]
Br (1t)
53 (>99:<1)
0 (–:–)
48
[a] dtbpy system A:
1
(0.5 mmol),
2
(0.55 mmol), [Ir(OMe)(cod)]2
(1.5 mol%), and dtbpy (3.0 mol%) in octane (3 mL) at room temperature.
AsPh3 system B: 1 (0.5 mmol), 2 (0.55 mmol), [Ir(OMe)(cod)]2 (1.5 mol%),
and AsPh3 (6.0 mol%) in octane (3 mL) at 1208C. [b] Combined yields and
ratios of isomers in the crude reaction mixture were determined by
1H NMR spectroscopy analysis (internal standard: dibromomethane).
[c] 2.5 mol% of [Ir(OMe)(cod)]2 and 5.0 mol% of dtbpy were used.
[d] 2.5 mol% of [Ir(OMe)(cod)]2 and 10 mol% of AsPh3 were used. [e] Yield
of product isolated.
Entry
R1
System
t [h]
Yield [%][b] (3/4)
1
2
3
4
5[e]
6
7[e]
8[f]
Et (1m)
A
B
A
B
A
B
A
B
24
3
8
4
4
3
3
30
81 (62)[c] (97:3)
68 (<1:>99)
86 (94:6)
94 (<1:>99)
75 (66)[e] (<1:>99)
67 (<1:>99)
58 (<1:>99)
48 (<1:>99)
Cy[d] (1n)
tBu (1o)
TMS (1p)
that of a Cy group in this borylation.[2e,11] Borylation of the 5-
CF3-substituted thiophene 1q produced a 1:1 mixture of iso-
mers when the dtbpy ligand was used (dtbpy system A;
Table 4, entry 1). In contrast, the 3-borylated product 4q was
obtained selectively under AsPh3 system B (Table 4, entry 2). Al-
though the methoxy-substituted thiophene 1r reacted with 2
under dtbpy system A to afford the 4-borylated product 3r in
high yield (82%, 3r/4r= >99:<1; Table 4, entry 3), no reac-
tion occurred under AsPh3 system B (Table 4, entry 4). A chloro
group did not interfere with the formation of 4-borylated
product 3s (dtbpy system A, 82%, 3s/4s= >99:<1; Table 4,
entry 5). Low reactivity and regioselectivity were observed
[a] dtbpy system A:
1
(0.5 mmol),
2
(0.55 mmol), [Ir(OMe)(cod)]2
(1.5 mol%), and dtbpy (3.0 mol%) in octane (3 mL) at room temperature.
AsPh3 system B: 1 (0.5 mmol), 2 (0.55 mmol), [Ir(OMe)(cod)]2 (1.5 mol%),
and AsPh3 (6.0 mol%) in octane (3 mL) at 1208C. [b] Combined yields and
ratios of isomers in the crude reaction mixture were determined by
1H NMR spectroscopy analysis (internal standard: dibromomethane).
[c] Yield of product isolated. [d] Cy=cyclohexyl. [e] This reaction was car-
ried out at 608C. [f] This reaction was carried out at 808C.
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when AsPh3 was used as the ligand (AsPh3 system B: 46%, 3s/
4s=26:74; Table 4, entry 6). This result suggests that the
chloro group might weakly coordinate with the iridium cen-
ter.[9f] The borylation of substrate 1t, which had a bromo
group, proceeded regioselectively at the 4-position to give 3t
in 53% yield under dtbpy system A (Table 4, entry 7), but the
3-borylated product 4t was not obtained (AsPh3 system B;
Table 4, entry 8).[12] These results show that 1r or 1t cannot be
used as substrates under AsPh3 system B.
Table 5. Scope of heteroarenes with a dimethylamide group at the 2-po-
sition[a]
In the borylation of 1r or 1t under AsPh3 system B, the
methoxy or bromo groups may inhibit coordination between
the oxygen atom of the carbonyl group and the iridium center
(Scheme 3a). Selective borylation was therefore achieved by
changing the propionyl group to more strongly coordinating
carbonyl groups (Scheme 3b).
Entry
X
R1
System
t [h]
Yield [%][b] (3/4)
1
2
3
4
5
6[c]
O
Br (1w)
A
B
A
B
A
B
2
9
4
4
1
6
99 (95:<5)
56 (<1:>99)
98 (>99:<1)
74 (13:87)
94 (78)[d] (>99:<1)
93 (<1:>99)
S
S
Cl (1x)
OMe (1y)
[a] dtbpy system A:
1
(0.5 mmol),
2
(0.55 mmol), [Ir(OMe)(cod)]2
(1.5 mol%), and dtbpy (3.0 mol%) in octane (3 mL) at 808C. AsPh3 sys-
tem B: 1 (0.5 mmol), 2 (0.55 mmol), [Ir(OMe)(cod)]2 (5.0 mol%), and AsPh3
(20 mol%) in octane (3 mL) at 1208C. [b] Combined yields and ratios of
isomers in the crude reaction mixture were determined by 1H NMR spec-
troscopy analysis (internal standard: dibromomethane). [c] 1.5 mol% of
[Ir(OMe)(cod)]2 and 6.0 mol% of AsPh3 were used. [d] Yield of product iso-
lated.
Scheme 3. Schematic illustration of steric and coordinating effects on the re-
activity and regioselectivity in reactions with AsPh3 system B.
We have performed the borylations of 5-bromothiophenes
with methoxycarbonyl 1u or dimethylaminocarbonyl 1v
groups under both systems because heteroarenes containing
both bromo and boryl substituents are important intermedi-
ates, which can be used in stepwise cross-coupling procedures
(Scheme 4). The use of 2-methoxycarbonyl thiophene 1u sig-
nificantly increased the reactivity and regioselectivity of boryla-
tion, compared with the reaction of 2-propionyl thiophene 1t,
under both systems. Furthermore, the borylation of 2-dimethyl-
aminocarbonyl-substituted thiophene 1v afforded the 3-bor-
ylated product 4v in 40% yield. These results indicate that
substituting an amide group for an ester group at the 2-posi-
tion improves the reactivity of this borylation.
at the 5-position proceeded regioselectively to give the 4-bory-
lated product 3w in high yield under dtbpy system A (2 h,
99%, 3w/4w=95:<5; Table 5, entry 1). AsPh3 system B also
led to 3-borylated 4w in good yield (9 h, 56%, 3w/4w=
<1:>99; Table 5, entry 2). The yields and regioselectivities in-
creased when chloro-functionalized thiophene 1x was used in-
stead of the 2-propionyl derivative 1s (dtbpy system A: 4 h,
98%, 3x/4x= >99:<1; AsPh3 system B: 4 h, 74%, 3x/4x=
13:87; Table 5, entries 3 and 4). The methoxy-substituted thio-
phene 1y reacted smoothly to afford both isomers in high
yields and with excellent regioselectivities (dtbpy system A:
1 h, 94%, 3y/4y= >99:<1; AsPh3 system B: 6 h, 93%, 3y/
4y= <1:>99; Table 5, entries 5 and 6). These results show
that the regiodivergent borylation tolerated various functional
groups at the 5-position when dimethylamide-substituted het-
eroarenes were used.
To confirm the utility of the dimethylamide group as a coor-
dinating group, borylations of other heteroarenes were investi-
gated (Table 5). The reaction of furan 1w with a bromo group
To further demonstrate the synthetic utility of this regiodi-
vergent borylation, we synthesized two different biologically
active compound analogues by using borylated furans derived
from 1w (Scheme 5).[1b,g] The one-pot synthesis of 6 was ach-
ieved by using a stepwise cross-coupling strategy without iso-
lation of unstable boron intermediates. After borylation of 1w
under dtbpy system A, the solvent was removed under re-
duced pressure; and then the cross-coupling reaction of crude
3w with 1-chloro-3-iodobenzene (1.1 equiv) took place at
room temperature. After completion of the reaction, (4-fluoro-
phenyl)boronic acid (2.0 equiv) was added to the reaction mix-
ture. The mixture was stirred for 0.5 h, NRT inhibitor analogue
6 was obtained in 47% yield (one pot, three steps). NHE-1 in-
hibitor analogue 8 was obtained in 30% yield (one pot, three
steps) by regioselective borylation of 1w under AsPh3 sys-
tem B, followed by a stepwise cross-coupling procedure by
Scheme 4. Borylation of 5-bromothiophene with ester or amide groups at
the 2-position. [a] dtbpy system A: 1 (0.5 mmol), 2 (0.55 mmol), [Ir(OMe)-
(cod)]2 (1.5 mol%), and dtbpy (3.0 mol%) in octane (3 mL). AsPh3 system B:
1 (0.5 mmol), 2 (0.55 mmol), [Ir(OMe)(cod)]2 (5.0 mol%), and AsPh3
(20 mol%) in octane (3 mL). [b] Combined yields and ratios of isomers in the
1
crude reaction mixture were determined by H NMR spectroscopy analysis
(internal standard: dibromomethane).
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Scheme 6. Proposed mechanisms for the catalytic systems.
through the same mechanism as that in the reaction of com-
plex G with 2.
Conclusion
We developed regiodivergent CÀH borylation of multifunction-
alized heteroarenes with 2 by using iridium catalysts generated
from [Ir(OMe)(cod)]2/dtbpy or [Ir(OMe)(cod)]2/2AsPh3. The bor-
ylation proceeded regioselectively to afford the products in
high yields. The use of the [Ir(OMe)(cod)]2/dtbpy catalyst pro-
duced 4-borylated products in high yields (dtbpy system A).
The regioselectivity changed when the [Ir(OMe)(cod)]2/2AsPh3
catalyst (AsPh3 system B) was used; 3-borylated products were
obtained in high yields and with high regioselectivities. Addi-
tionally, the syntheses of two different bioactive compound an-
alogues from one starting material were achieved by using this
regiodivergent borylation.
Scheme 5. Regiodivergent synthesis of biologically active furan derivatives
from 1w. DME=dimethoxyethane, dppf=1,1’-bis(diphenylphosphino)ferro-
cene.
using iodobenzene (1.1 equiv) and (3-chlorophenyl)boronic
acid (2.0 equiv).
Two proposed catalytic cycles are shown in Scheme 6.[13] In
Pathway 1 (dtbpy system A), tris(boryl)iridium complex A is
first produced by reaction of an iridium/dtbpy complex with 2.
Oxidative addition of the CÀH bond at the 4-position to A pro-
duces complex B. This regioselectivity is probably caused by
bulkiness around the iridium center, at which the coordinative
carbonyl group only acts as a sterically congesting group. Re-
ductive elimination of 3 produces the iridium–hydride complex
C. Finally, oxidative addition of 2 to C, followed by reductive
elimination of HBpin, regenerates A. In Pathway 2 (AsPh3 sys-
tem B), the mono- (n=1) or tris- (n=3) boryliridium complex
D is first produced by reactions of iridium(I) complexes con-
taining AsPh3 with 2. Next, the oxygen atom in the carbonyl
group coordinates with the iridium center (complex E), and
then oxidative addition of the CÀH bond neighboring the di-
recting group to E produces the pseudo-metallacycle F. Reduc-
tive elimination produces the iridium–hydride complex G and
the 3-borylated product 4. Finally, regeneration of D proceeds
Experimental Section
General procedure for the [Ir(OMe)(cod)]2/dtbpy-catalyzed
CÀH borylation of heteroarenes (dtbpy system A)
[Ir(OMe)(cod)]2 (5.0 mg, 7.5 mmol), 2 (139 mg, 0.55 mmol), and
dtbpy (4.0 mg, 15 mmol) were placed in an oven-dried, two-necked
flask. The flask was connected to a vacuum/nitrogen manifold
through a rubber tube. It was evacuated and then backfilled with
nitrogen. This cycle was repeated three times. Octane (3.0 mL) was
then added to the flask through a rubber septum by using a sy-
ringe, and stirred at room temperature for 15 min. Heteroarene
(0.50 mmol) was then added to the reaction mixture by using a sy-
ringe, and stirred at room temperature. After the reaction was
complete, the reaction mixture was concentrated and purified by
Chem. Eur. J. 2015, 21, 9236 – 9241
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9240
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Full Paper
Cheung, A. C. Maxwell, L. Shukla, B. Roberts, D. C. Blakemore, Org.
Biomol. Chem. 2014, 12, 7318–7327; b) S. M. Preshlock, D. L. Plattner,
P. E. Maligres, S. W. Krska, R. E. Maleczka, M. R. Smith III, Angew. Chem.
Int. Ed. 2013, 52, 12915–12919; Angew. Chem. 2013, 125, 13153–13157;
c) H. Tajuddin, P. Harrisson, B. Bitterlich, J. C. Collings, N. Sim, A. S. Batsa-
nov, M. S. Cheung, S. Kawamorita, A. C. Maxwell, L. Shukla, Chem. Sci.
2012, 3, 3505–3515.
Kugelrohr distillation to give the corresponding heteroarylboro-
nates.
General procedure for the [Ir(OMe)(cod)]2/AsPh3-catalyzed
CÀH borylation of heteroarenes (AsPh3 system B)
[Ir(OMe)(cod)]2 (5.0 mg, 7.5 mmol), 2 (139 mg, 0.55 mmol), and
AsPh3 (9.2 mg, 30 mmol) were placed in an oven-dried, two-necked
flask. The flask was connected to a vacuum/nitrogen manifold
through a rubber tube. It was evacuated and then backfilled with
nitrogen. This cycle was repeated three times. Octane (3.0 mL) was
then added to the flask through a rubber septum by using a sy-
ringe, and stirred at room temperature for 15 min. Heteroarene
(0.50 mmol) was then added to the reaction mixture by using a sy-
ringe, and stirred at 1208C. After the reaction was complete, the
reaction mixture was concentrated and purified by Kugelrohr distil-
lation to give the corresponding heteroarylboronates.
[4] For the application of borylated heteroarenes to total syntheses of nat-
ural products, see: a) S. Zhou, Y. Jia, Org. Lett. 2014, 16, 3416–3418;
b) S. Han, K. C. Morrison, P. J. Hergenrother, M. Movassaghi, J. Org.
Chem. 2014, 79, 473–486; c) L. McMurray, F. O’Hara, M. J. Gaunt, Chem.
Soc. Rev. 2011, 40, 1885–1898; d) S. Han, M. Movassaghi, J. Am. Chem.
Soc. 2011, 133, 10768–10771; e) E. M. Beck, R. Hatley, M. J. Gaunt,
Angew. Chem. Int. Ed. 2008, 47, 3004–3007; Angew. Chem. 2008, 120,
3046–3049.
[5] a) T. Ishiyama, J. Takagi, K. Ishida, N. Miyaura, N. R. Anastasi, J. F. Hartwig,
J. Am. Chem. Soc. 2002, 124, 390–391; b) T. Ishiyama, J. Takagi, J. F. Hart-
wig, N. Miyaura, Angew. Chem. Int. Ed. 2002, 41, 3056–3058; Angew.
Chem. 2002, 114, 3182–3184; c) J. Y. Cho, M. K. Tse, D. Holmes, R. E. Mal-
eczka, M. R. Smith III, Science 2002, 295, 305–308.
[6] For regioselective CÀH borylation of arenes at the meta position by
using bidentate ligands, see: a) J. F. Hartwig, Chem. Soc. Rev. 2011, 40,
1992–2002; b) J. M. Murphy, X. Liao, J. F. Hartwig, J. Am. Chem. Soc.
2007, 129, 15434–15435; c) C. C. Tzschucke, J. M. Murphy, J. F. Hartwig,
Org. Lett. 2007, 9, 761–764; d) S. Paul, G. A. Chotana, D. Holmes, R. C.
Reichle, R. E. Maleczka, M. R. Smith III, J. Am. Chem. Soc. 2006, 128,
15552–15553; e) T. Ishiyama, N. Miyaura, Pure Appl. Chem. 2009, 78,
1369–1375; f) T. Ishiyama, Y. Nobuta, J. F. Hartwig, N. Miyaura, Chem.
Commun. 2003, 2924–2925; g) T. Ishiyama, N. Miyaura, J. Organomet.
Chem. 2003, 680, 3–11; h) J. Takagi, K. Sato, J. F. Hartwig, T. Ishiyama, N.
Miyaura, Tetrahedron Lett. 2002, 43, 5649–5651.
[7] For regioselective CÀH borylation of polycyclic aromatics, see: a) L. Ji, K.
Fucke, S. K. Bose, T. B. Marder, J. Org. Chem. 2015, 80, 661–665; b) Z.
Liu, Y. Wang, Y. Chen, J. Liu, Q. Fang, C. Kleeberg, T. B. Marder, J. Org.
Chem. 2012, 77, 7124–7128; c) A. G. Crawford, Z. Liu, I. A. Mkhalid,
M. H. Thibault, N. Schwarz, G. Alcaraz, A. Steffen, J. C. Collings, A. S. Bat-
sanov, J. A. Howard, Chem. Eur. J. 2012, 18, 5022–5035; d) D. N. Coven-
try, A. S. Batsanov, A. E. Goeta, J. A. Howard, T. B. Marder, R. N. Perutz,
Chem. Commun. 2005, 2172–2174.
Acknowledgements
This work was financially supported by the Funding Program
for Next Generation World-Leading Researchers (NEXT Pro-
gram, no. G002) from the Japan Society for the Promotion of
Science (JSPS), a Grant-in-Aid for Scientific Research (B) (no.
21350049) from the Ministry of Education, Culture, Sports, Sci-
ence, and Technology, Japan and the MEXT (Japan) program
“Strategic Molecular and Materials Chemistry through Innova-
tive Coupling Reactions” of Hokkaido University.
Keywords: borylation
iridium · regioselectivity
·
CÀH activation
· heterocycles ·
[1] a) D. Bosc, S. Lethu, E. Mouray, P. Grellier, J. Dubois, Med. Chem.
Commun. 2012, 3, 1512–1517; b) K. Thede, S. Greschat, S. Wildum, D.
Paulsen, (AICURIS GmbH & Co. KG), WO2010075957A1, 2010; c) H.
Yang, R. T. Hendricks, N. Arora, D. Nitzan, C. Yee, M. C. Lucas, Y. Yang, A.
Fung, S. Rajyaguru, S. F. Harris, Bioorg. Med. Chem. Lett. 2010, 20, 4614–
4619; d) N. A. McGrath, M. Brichacek, J. T. Njardarson, J. Chem. Educ.
2010, 87, 1348–1349; e) M. Menichincheri, C. Albanese, C. Alli, D. Balli-
nari, A. Bargiotti, M. Caldarelli, A. Ciavolella, A. Cirla, M. Colombo, F. Co-
lotta, V. Croci, R. D’Alessio, M. D’Anello, A. Ermoli, F. Fiorentini, B. Forte,
A. Galvani, P. Giordano, A. Isacchi, K. Martina, A. Molinari, J. K. Moll, A.
Montagnoli, P. Orsini, F. Orzi, E. Pesenti, A. Pillan, F. Roletto, A. Scolaro,
M. Tató, M. Tibolla, B. Valsasina, M. Varasi, P. Vianello, D. Volpi, C. Santo-
canales, E. Vanotti, J. Med. Chem. 2010, 53, 7296–7315; f) E. Yasui, M.
Wada, N. Takamura, Tetrahedron Lett. 2009, 50, 4762–4765; g) S. Lee, T.
Kim, B. H. Lee, S.-e. Yoo, K. Lee, K. Y. Yi, Bioorg. Med. Chem. Lett. 2007,
17, 1291–1295; h) M. Fujita, T. Hirayama, N. Ikeda, Bioorg. Med. Chem.
2002, 10, 3113–3122.
[2] For regioselective CÀH borylation of five-membered heteroarenes, see:
a) A. G. Green, P. Liu, C. A. Merlic, K. N. Houk, J. Am. Chem. Soc. 2014,
136, 4575–4583; b) I. A. Mkhalid, J. H. Barnard, T. B. Marder, J. M.
Murphy, J. F. Hartwig, Chem. Rev. 2010, 110, 890–931; c) V. A. Kallepalli,
F. Shi, S. Paul, E. N. Onyeozili, R. E. Maleczka, Jr., M. R. Smith III, J. Org.
Chem. 2009, 74, 9199–9201; d) I. A. I. Mkhalid, D. N. Coventry, D.
Albesa-Jove, A. S. Batsanov, J. A. Howard, R. N. Perutz, T. B. Marder,
Angew. Chem. Int. Ed. 2006, 45, 489–491; Angew. Chem. 2006, 118, 503–
505; e) G. A. Chotana, M. A. Rak, M. R. Smith III, J. Am. Chem. Soc. 2005,
127, 10539–10544; f) T. Ishiyama, J. Takagi, Y. Yonekawa, J. F. Hartwig, N.
Miyaura, Adv. Synth. Catal. 2003, 345, 1103–1106; g) S. Konishi, S. Kawa-
morita, T. Iwai, P. G. Steel, T. B. Marder, M. Sawamura, Chem. Asian J.
2014, 9, 434–438.
[8] Our group has reported ortho borylations of functionalized arenes, see:
a) H. Itoh, T. Kikuchi, T. Ishiyama, N. Miyaura, Chem. Lett. 2011, 40, 1007–
1008; b) T. Ishiyama, H. Isou, T. Kikuchi, N. Miyaura, Chem. Commun.
2010, 46, 159–161.
[9] Other groups have reported ortho borylations of functionalized arenes,
see: a) A. Ros, R. Fernµndez, J. M. Lassaletta, Chem. Soc. Rev. 2014, 43,
3229–3243; b) B. Xiao, Y.-M. Li, Z.-J. Liu, H.-Y. Yang, Y. Fu, Chem.
Commun. 2012, 48, 4854–4856; c) H.-X. Dai, J.-Q. Yu, J. Am. Chem. Soc.
2012, 134, 134–137; d) T. E. Hurst, T. K. Macklin, M. Becker, E. Hartmann,
W. Kügel, P. L. Salle, A. S. Batsanov, T. B. Marder, V. Snieckus, Chem. Eur. J.
2010, 16, 8155–8161; e) K. Yamazaki, S. Kawamorita, H. Ohmiya, M. Sa-
wamura, Org. Lett. 2010, 12, 3978–3981; f) S. Kawamorita, H. Ohmiya, K.
Hara, A. Fukuoka, M. Sawamura, J. Am. Chem. Soc. 2009, 131, 5058–
5059.
[10] S. Kawamorita, H. Ohmiya, M. Sawamura, J. Org. Chem. 2010, 75, 3855–
3858.
[11] a) F. Leroux, ChemBioChem 2004, 5, 644–649; b) T. Nagai, G. Nishioka,
M. Koyama, A. Ando, T. Miki, I. Kumadaki, J. Fluorine Chem. 1992, 57,
229–237.
[12] Smith and co-workers reported that the borylation of 5-bromo-2-cyano-
thiophene was unsuccessful in the presence of Ir/dtbpy/HBpin/THF cat-
alysis (ref. [2e]), which is similar to our dtbpy system A (Ir/dtbpy/2/
octane).
[13] a) M. A. Larsen, J. F. Hartwig, J. Am. Chem. Soc. 2014, 136, 4287–4299;
b) T. M. Boller, J. M. Murphy, M. Hapke, T. Ishiyama, N. Miyaura, J. F. Hart-
wig, J. Am. Chem. Soc. 2005, 127, 14263–14278; c) H. Tamura, H. Yama-
zaki, H. Sato, S. Sakaki, J. Am. Chem. Soc. 2003, 125, 16114–16126.
Received: February 16, 2015
[3] For regioselective CÀH borylation of other heteroarenes, see: a) S. A.
Sadler, H. Tajuddin, I. A. Mkhalid, A. S. Batsanov, D. Albesa-Jove, M. S.
Published online on May 12, 2015
Chem. Eur. J. 2015, 21, 9236 – 9241
www.chemeurj.org
9241
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim