A meta-selective C-H borylation directed by a secondary interaction between ligand and substrate

Article abstract of DOI:10.1038/nchem.2322

Regioselective C-H bond transformations are potentially the most efficient method for the synthesis of organic molecules. However, the presence of many C-H bonds in organic molecules and the high activation barrier for these reactions make these transformations difficult. Directing groups in the reaction substrate are often used to control regioselectivity, which has been especially successful for the ortho-selective functionalization of aromatic substrates. Here, we describe an iridium-catalysed meta-selective C-H borylation of aromatic compounds using a newly designed catalytic system. The bipyridine-derived ligand that binds iridium contains a pendant urea moiety. A secondary interaction between this urea and a hydrogen-bond acceptor in the substrate places the iridium in close proximity to the meta-C-H bond and thus controls the regioselectivity. 1 H NMR studies and control experiments support the participation of hydrogen bonds in inducing regioselectivity. Reversible direction of the catalyst through hydrogen bonds is a versatile concept for regioselective C-H transformations.

Full text of DOI:10.1038/nchem.2322

ARTICLES
PUBLISHED ONLINE: 17 AUGUST 2015 | DOI: 10.1038/NCHEM.2322
A meta-selective C–H borylation directed
by a secondary interaction between ligand
and substrate
Yoichiro Kuninobu1,2 , Haruka Ida1, Mitsumi Nishi1,2 and Motomu Kanai1,2
*
*
Regioselective C–H bond transformations are potentially the most efficient method for the synthesis of organic molecules.
However, the presence of many C–H bonds in organic molecules and the high activation barrier for these reactions make
these transformations difficult. Directing groups in the reaction substrate are often used to control regioselectivity, which
has been especially successful for the ortho-selective functionalization of aromatic substrates. Here, we describe an
iridium-catalysed meta-selective C–H borylation of aromatic compounds using a newly designed catalytic system. The
bipyridine-derived ligand that binds iridium contains a pendant urea moiety. A secondary interaction between this urea
and a hydrogen-bond acceptor in the substrate places the iridium in close proximity to the meta-C–H bond and thus
1
controls the regioselectivity. H NMR studies and control experiments support the participation of hydrogen bonds in
inducing regioselectivity. Reversible direction of the catalyst through hydrogen bonds is a versatile concept for
regioselective C–H transformations.
egioselective transformations are important for efficient synth- effects. Fifth, palladium-catalysed oxidative alkenylation provides
eses. Regioselectivity can be achieved by introducing activated meta-selective alkenylated products (Fig. 1e)22–24. Regioselectivity
R
functional groups such as halogens and triflates, but bypassing is thus controlled by a well-designed directing group connected to
this step would be attractive. For this reason, C–H transformations the aromatic ring through a special long linker. Here, we report
have recently received increasing attention as efficient and ideal an iridium-catalysed meta-selective C–H borylation of aromatic
alternative reactions. C–H transformations require fewer reaction amides, esters, phosphonates, phosphonic diamide and phosphine
steps to attain the target molecule and generate less waste than con- oxides controlled by hydrogen bonds, in which the hydrogen-
ventional methods involving preactivation processes. However, it is bonding donor site of the ligand recognizes the hydrogen-
usually difficult to realize regioselective C–H transformations except bonding acceptor site of the substrate and orients the meta-C–H
with special substrates bearing only one possible reaction site and/or bond of the substrates to the catalytic site (Fig. 2)25. The directing
a directing group. In the case of C(sp2)–H transformations of aro- group-controlled reaction (Fig. 1e) and the present hydrogen-
matic rings, the use of directing groups generally produces only bond-controlled reaction (Fig. 2b) are related: the directing group
ortho-selective reactions1–6. The development of meta-selective is covalently bound to the substrate in Fig. 1e, whereas the
transformations is very difficult, but synthetically useful7. Several hydrogen-bonding ligand, required only in a catalytic amount,
pioneering examples of meta-selective transformations have been interacts reversibly with the substrate in Fig. 2b.
reported recently. First, iridium-catalysed C(sp2)–H borylation
and silylation afford a mixture of meta- and para-borylated and sily-
lated products, respectively (Fig. 1a shows borylation)8–14. In the
case of 1,3-disubstituted aromatic compounds, only meta-borylated
(or silylated) products are obtained. In these reactions, the steric
effects of substituents at the 1 and 3 positions control regioselectiv-
ity. Second, palladium-catalysed oxidative C(sp2)–H alkenylation
produces meta-alkenylated products (Fig. 1b)15–17. The regioselec-
tivity is controlled by electronic effects, and aromatic compounds
with electron-withdrawing group(s) and pyridines are used as sub-
strates. Third, ruthenium-catalysed meta-selective C(sp2)–H sulfo-
nation18 and alkylation19 have been reported (Fig. 1c shows
alkylation). These reactions proceed via the formation of an
ortho-arylruthenium intermediate directed by the pyridyl group,
followed by remote electrophilic aromatic substitution assisted by
a strong para-directing effect from the ruthenium centre. Fourth,
hypervalent iodine-mediated arylation affords meta-arylated pro-
ducts from aromatic amides and α-aryl carbonyl compounds
(Fig. 1d)20,21. In Fig. 1b–d, regioselectivity is controlled by electronic
Results and discussion
To overcome the problems described above (Fig. 1a–e), we designed
a new catalytic system in which a hydrogen-bond donor was
appended to a metal-binding ligand such that a secondary inter-
action between this donor and a suitable hydrogen-bond acceptor
in the substrate would place the metal centre of the catalyst in
close proximity to the desired C–H group (Fig. 2b). We hypoth-
esized that hydrogen bonding would be suitable for controlling
the relative positions of the catalyst and the reaction site of the
substrates because it has both the appropriate strength (not so
strong that it would prevent catalyst turnover) and the
directionality required.
To validate the catalytic system, we selected iridium-catalysed C
(sp2)–H borylation9. We used a bipyridine core as a ligand for C–H
borylation9 and a urea moiety as a hydrogen-bonding donor for
the carbonyl groups26 (Fig. 2b). To achieve high meta-selectivity,
selection of the appropriate linker between the ligand for the tran-
sition metal and hydrogen-bonding site is important. Molecular
1Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. 2ERATO, Japan Science and
Technology Agency (JST), Kanai Life Science Catalysis Project, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. e-mail: kuninobu@mol.f.u-tokyo.ac.jp;
*
kanai@mol.f.u-tokyo.ac.jp
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2322
ARTICLES
Cl
Cl
Cl
did not improve the meta/para ratio (entries 4–8). The borylation
reaction did not proceed using ligand 3g (bearing a thiourea
moiety, entry 9). When ligand 3a in p-xylene solvent was used,
the meta/para ratio increased to 27, whereas the yield of 6a slightly
decreased (entry 10). The ortho-phenylene linker is important for
high meta-selectivity. When using a methylene or phenylethynylene
linker (ligands 4 and 5), the meta/para ratio was low or the boryla-
tion reaction did not proceed (entries 11 and 12). When the
amounts of diboron 2a, [Ir(OMe)(cod)]2 and 3a were increased,
the yield of 6a also increased, but the meta/para ratio decreased
(entry 13). The borylation reaction did not proceed in the
absence of 3a.
a
Cat. [IrCl(cod)]2
Bpin
+
HBpin
Cl
O
OEt
O
OEt
b
Cat. Pd(OAc)2
oxidant
O
+
OEt
OEt
O
Major product
We then investigated the substrate scope of the borylation reac-
tion (Table 2). In all cases of ortho-mono-substituted aromatic
amides 1b–1j, regioselectivity was greatly improved by 3a (con-
dition A; upper row) compared with dtbpy (condition B; lower
row) and the corresponding meta-mono-borylated products 6b–6j
were obtained in moderate to excellent yields. The borylation reac-
tion exhibited high functional group tolerance with methoxy,
bromo, chloro, fluoro, trifluoromethyl, trifluoromethoxy and meth-
oxycarbonyl groups, which remained unchanged during the reac-
tion. The meta-selective borylation reaction also proceeded when
the substituents on the amide nitrogen atom were changed
(1k–1n). Interestingly, the yield of product 6m was drastically
increased by 3a compared with dtbpy. Although product 6o was
obtained when bis(hexylene glycolato)diboron (2b) was used as a
borylation reagent, the yield and regioselectivity were decreased
compared to when 2a was used. In the case of meta-mono-substi-
tuted aromatic amides 1p–1s and ortho- and meta-disubstituted
aromatic amides 1t–1u, only single products 6p–6u were formed
with both ligands 3a and dtbpy. The borylation of heteroaromatic
amides 1v–1z proceeded regioselectively to afford 6v–6z and, in
some cases, 3a improved regioselectivity compared with dtbpy.
Because regioselective borylation proceeded from both six- and
c
MesCO2
Me
N
Ru
N
N
H
iPr
Remote σ-activation
+
Cat. [RuCl2(p-cymene)]2
MesCO2H
Br
nC6H13
nC6H13
base
d
e
tBu
tBu
Cat. Cu(OTf)2 (70 °C)
or
without Cu(OTf)2 (90 °C)
H
N
O
H
N
O
Ph2IOTf
+
Ph
tBu
tBu
tBu
O
tBu
Cat. Pd(OPiv)2
oxidant
O
N
iBu
iBu
iBu
iBu
a
Linker
C
C
N
Ligand
Receptor
+
(hydrogen-bonding site)
CO2Et
Metal
C–H transformation
only at this position
Hydrogen bond(s)
CO2Et
H
C
Major product
FG
H
C
C
FG = functional group
Figure 1 | meta-Selective C–H transformations. Regioselectivity is controlled
by: a, steric effects; b, electronic effects; c, a strong para-directing effect
from the ruthenium centre (electronic effects); d, electronic effects in
hypervalent iodine-mediated arylation; e, a directing group.
H
C
C
H
H
Cat. [Ir(OMe)(cod)]2
Cat. ligand
O
O
b
modelling studies suggested that ortho-phenylene was a suitable
linker. Based on this design, the catalytically active iridium
centre should be placed in close proximity to a C–H bond at the
meta-position of aromatic substrates.
pinB
B2pin2
NR2
+
NR2
Major product
O
We first investigated several known and designed ligands for
iridium-catalysed C–H borylation (Table 1). Treatment of aromatic
amide 1a with bis(pinacolato)diboron (B2pin2, 2a) in the presence
of catalytic amounts of [Ir(OMe)(cod)]2 (cod = cyclooctadiene)
and a reported ligand (4,4′-di-tert-butyl-2,2′-bipyridine [dtbpy] or
(MeO)2bpy) gave a mixture of meta- and para-borylated products
6a in moderate yield with low regioselectivity (meta/para = 1.9
and 1.4, entries 1 and 2). In a previous study, an iridium-catalysed
reaction using N,N-diethylbenzamide as a substrate afforded a
mixture of ortho-, meta- and para-borylated products with the
ortho-borylated form as the major product27. The meta-selectivity
via
O
O
B
N
H
N
H
B2pin2
=
B
O
O
Hydrogen
bonds
O
N
[Ir]
NR2
N
was markedly higher when designed ligand 3a was used (50% Figure 2 | Concept of regioselective C–H transformations controlled by a
yield, meta/para = 8.3, entry 3). In this case, however, the hydrogen-bonding secondary interaction between ligand and substrate.
ortho-borylated product was not detected by 1H NMR and gas a, Design of catalytic systems for regioselective C–H transformations.
chromatography (GC) analyses of a crude mixture. Compared b, Hydrogen-bond-controlled meta-selective C–H borylation as a possible
with 3a, other substituents on the urea moiety (ligands 3b–3f) proof of concept (this work).
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2322
Table 1 | Structures of new ligands for meta-selective C–H transformations and their application to iridium-catalysed borylation.
ARTICLES
O
3a R = Cy
[Ir(OMe)(cod)]2 (0.75 mol%)
Ligand (1.5 mol%)
O
3b R = hex
m
N(hex)2
3c R = 4-(MeO)C6H4
3d R = 4-(CF3)C6H4
3e R = 4-(nBu)C6H4
3f R = 2,6-Me2C6H3
pinB
N(hex)2
+
B2pin2
N
H
O
R
Hexane, 25 °C, 16 h
p
N
H
6a
1a
2a
N
N
Entry
Ligand
Yield (%)*
(mono)
Ratio of
meta to para*
Yield (%)*
(di)†
Recovery of
1a (%)*
1‡
2
3
4
5
6
7
8
9
dtbpy§
(MeO)2bpy||
67
52
1.9
3
30
44
47
69
77
N
H
S
N
H
1.4
4
N
N
3a
3b
3c
3d
3e
3f
3g
3a
4
3
50
31
8.3
7.4
1.4
3g
0
O
1
22
N
N
H
1
31
7.2
3.9
3.6
−
66
56
H
N
4
40
32
4
N
0
68
>99
45
50
>99
27
0
0
10‡
11‡
44
47
0
27
10
N
H
O
H
3
2.0
−
N
N
12‡
13‡,¶
5
N
0
5
3a
51 (48)#
17 (19)**
22 (17)#
2a (0.75 equiv). *Determined by 1H NMR using 1,1,2,2-tetrachloroethane as an internal standard. †N,N-Dihexyl-3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide. ‡p-Xylene was used as a
§
solvent. dtbpy = 4,4′-di-tert-butyl-2,2′-bipyridine. ꢀ(MeO)2bpy = 4,4′-dimethoxy-2,2′-bipyridine. ¶2a (1.0 equiv), [lr(OMe)(cod)]2 (1.5 mol%), 3a (3.0 mol%). #Isolated yield. **Ratio of meta to para in the
isolated product.
five-membered (hetero)aromatic amides, ligand 3a must have the 3h, which has the urea moiety at the para-position of the phenylene
flexibility to accept several substrate types. Regioselective borylation linker (Fig. 3b). This result indicates that the spatial arrangement of
also proceeded using aromatic esters 1A and 1B. In these reactions, the bipyridine and urea moieties is crucial to furnish the high meta-
the CF3 group-substituted ligand 3d led to higher regioselectivity selectivity. In addition, covalently connecting the bipyridine and
than 3a (6A, 98% yield [meta/para = 3.7]; 6B, 94% yield [meta/ urea moieties is indispensable for the high meta-selectivity. Thus,
para = 0.59]). C–H borylation also proceeded using aromatic phos- when a mixture of cyclohexylphenylurea and 2,2′-bipyridine was
phorus compounds, such as aryl phosphonates 1C–1G, phosphonic used, the meta/para ratio was comparable to that when using
diamide 1H and phosphine oxides 1I–1K, and the corresponding dtbpy (Fig. 3b, 2,2′-bipyridine + urea). This finding indicates that
borylated products 6C–6K were obtained with high meta-selectivity. the intramolecularity of the bipyridine and urea moieties is impor-
In most entries, the total percentages of the yields of borylated pro- tant to bring the position of the iridium centre close to the meta-
ducts and recovered starting materials were almost quantitative. N, position of the substrate. Third, a high meta/para ratio was observed
N-Dihexyl-2-naphthamide, N,N-dihexyl-2-(methylthio)benzamide in nonpolar solvents (hexane, 60% yield, meta/para = 6.9; cyclo-
and N,N-dihexyl-4-(trifluoromethyl)benzamide did not give the hexane, 43% yield, meta/para = 29; p-xylene, 42% yield, meta/
borylated products. In addition, the borylated products were not para ≥ 30; THF, 27% yield, meta/para = 3.5; N-methylpyrrolidone,
obtained using benzaldehyde, acetophenone and nitrobenzene.
15% yield, meta/para = 2.8 for reactions of 1a using 3a), at a
The reaction mechanism of the iridium-catalysed borylation has lower reaction temperature and under a higher concentration.
been reported previously28 and the present reaction probably pro- These findings are consistent with the notion that hydrogen
ceeds via the same pathway. To confirm the importance of hydrogen bonds between the amide group of substrates and the urea moiety
bonding between the substrates and the urea moiety of ligand 3a for of the ligand are key to controlling regioselectivity.
the high regioselectivity, we conducted the following experiments.
To demonstrate the utility of this reaction, we performed two
First, significant lower field shifts of the urea N–H protons of experiments. The first involved a reaction that is practical and can
1
ligand 3a were observed by H NMR in the presence of substrate be performed on a gram scale. Treatment of 1.00 g 1f with 2a pro-
1a (Fig. 3a, entries 1–3)29,30. This finding strongly supports our duced 1.23 g 6f in 90% yield (meta/para ≥ 30). The yield of 6f in
notion that a hydrogen-bonding interaction occurs between 3a the gram-scale reaction was comparable to that shown in Table 2
and amide substrates. Second, borylation reactions were carried (1f: 89.4 mg scale). In the second experiment, we performed a
out using control ligands 3a-Me1 and 3a-Me2, with the nitrogen competition reaction between an amide and an ester using ligand
atom(s) of the urea moiety protected by methyl group(s) (Fig. 3b). 3a or dtbpy. Treatment of a 1:1 mixture of amide 1k and methyl ben-
As a result, the meta/para ratio of the borylated products dramati- zoate and 2a (1.5 equiv.) with catalytic amounts of [Ir(OMe)(cod)]2
cally decreased compared with the use of 3a and the ratio was (1.5 mol%) and 3a (3.0 mol%) in p-xylene at 25 °C for 16 h gave
almost the same as when using the dtbpy ligand. Consistent with borylated-amide (6k) and -ester in 44% yield (meta/para = 21) and
1
this result, H NMR revealed no significant chemical shift changes 16% yield (meta/para = 1.0), respectively. On the other hand, when cat-
of the N–H proton of 3a-Me1 in the presence of 1a (Fig. 3a, alytic amounts of [Ir(OMe)(cod)]2 (1.5 mol%) and dtbpy (3.0 mol%)
entries 4–6). The regioselectivity was also low (meta/para = 1.0) were used, borylated-amide (6k) and -ester were obtained in
when the reaction was carried out using another control ligand 7% yield (meta/para = 2.5) and 45% yield (meta/para = 1.0),
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2322
ARTICLES
Table 2 | Regioselective aromatic C–H borylation controlled by hydrogen bonding.
[Ir(OMe)(cod)]2 (1.5 mol%)
O
O
Ligand (3.0 mol%)
NR2
NR2
+
B2pin2
2
2
Ar
pinB
Ar
p-Xylene, 25 °C, 16 h
2a
R1
R1
6
1
O
O
O
O
O
O
N(hex)2
CF3
N(hex)2
OCF3
N(hex)2
OMe
N(hex)2
N(hex)2
N(hex)2
pinB
pinB
pinB
pinB
pinB
pinB
Me
Br
Cl
6b
6c
A: 35% (12)
B: 39% (0.72)
6d
6e
A: >99% (13)
B: >99% (0.61)
6f
6g
A: 59% (7.8)
B: 40% (0.46)
A: 96% (7.5)
B: 97% (0.46)
A: >99% (>30)
B: >99% (0.86)
A: >99% (6.9)
B: >99% (0.25)
O
O
O
O
O
O
N
N(hex)2
CO2Me
N(hex)2
NMe2
N
N
pinB
Me
pinB
pinB
pinB
pinB
pinB
O
Ph
Br
6k†
6l†
6h
6i
6j*
6m
A: >99% (>30)
B: >99% (2.1)
A: 26% (>30)
B: 32% (3.9)
A: 51% (3.3)
B: 54% (1.1)
A: 44% (27)
B: 49% (1.5)
A: 46% (>30)
B: 40% (1.5)
A: 95% (3.3)
B: 5% (0.67)
O
O
O
O
O
O
pinB
pinB
N(hex)2
N(hex)2
O
O
N(hex)2
N(hex)2
N
N(hex)2
CF3
pinB
pinB
pinB
B
Ph
CN
F
Br
6n†
6o‡
6p
6q
6r
6s
A: 46% (17)
B: 45% (2.3)
A: 77% (5.0)
B: 56% (1.1)
A: >99% (9.1)
B: >99% (1.0)
A: 85%
B: >99%
A: >99%
B: >99%
A: 92% (20)
B: 75% (12)
O
O
O
4
pinB
pinB
pinB
N(hex)2
N(hex)2
O
O
N(hex)2
pinB
pinB
O
5
S
N
H
N
N(hex)2
N
H
F
Cl
N(hex)2
pinB
N(hex)2
Me
CF3
Cl
6x§
6y||
6t
6u
6v
6w
A: >99%
B: >99%
A: >99%
B: >99%
A: 86%
B: 90%
A: 94%
B: 96%
A: 84% (6.6)
B: 95% (2.3)
A: 86% (>30)
B: 89% (>30)
O
P
O
P
O
O
O
O
4
P
4
4
OEt
OEt
OEt
OEt
OEt
OEt
NMe2
OEt
pinB
pinB
pinB
pinB
pinB
pinB
N
OEt
5
N
N
5
5
OMe
Me
6z¶
6aa§,#
6bb§,#
6cc**
6dd††
6ee††
A: 86% (6.4)
B: 88% (1.9)
A: >99% (4.3)
B: 92% (1.3)
A: 99% (1.5)
B: 89% (0.48)
A: 52% (16)
B: 61% (1.5)
A: 82% (0.52)
B: >99% (0.28)
A: 85% (7.5)
B: >99% (0.59)
O
P
O
P
O
P
O
P
O
P
O
P
OEt
OEt
OEt
OEt
Cy
Cy
Cy
Cy
NEt2
NEt2
Cy
Cy
pinB
pinB
pinB
pinB
pinB
pinB
CF3
Br
OMe
Cl
6ff††
A: 99% (13)
B: >99% (0.32)
6gg††
6hh**
6ii**
6jj
6kk
A: 44% (>30)
B: 99% (0.55)
A: 46% (>30)
B: 61% (1.3)
A: 44% (>30)
B: 53% (1.9)
A: >99% (>30)
B: 86% (0.42)
A: >99% (>30)
B: >99% (0.14)
2a (1.5equiv.)wasusedunlessotherwisenoted. A:1HNMRyieldofmono-borylatedproducts (as a mixture of meta-andpara-products) using 3a asaligandwiththemeta/pararatiodescribedinparentheses. B: 1H NMR
yield of mono-borylated products using dtbpy as a ligand with the meta/para ratio described in parentheses. See Supplementary Fig. 1 for details. *35 °C, 24 h. †2a (1.0 equiv). ‡Bis(hexylene glycolato)diboron
(2b) was used as a borylation reagent. §Ratio of 5-position/4-position. ||[Ir(OMe)(cod)]2 (2.0 mol%), 3a (4.0 mol%), 24 h. ¶Ratio of 4-position/5-position. #3d was used as a ligand. **2a (1.0 equiv.), 40 °C,
6 h. ††40 °C.
respectively. The contrasting substrate preference using either 3a or a bipyridine moiety, with a pendant hydrogen-bond donor. This is
dtbpy is probably due to hydrogen bonding between 3a and 1k, the first reported catalyst-controlled regioselective C–H borylation
whereas the inherent substrate reactivity (that is, electronic factor) of aromatic compounds. The important aspect of this reaction is
underlies the ester preference when using dtbpy. These findings that hydrogen bonding between the substrates and the catalyst con-
indicate that both regio- and chemoselectivity can be controlled trols the regioselectivity of a C–H bond transformation. The present
by the use of ligand 3a with its hydrogen-bonding ability.
catalytic system has the following merits: (1) it has a wide substrate
In summary, we have successfully developed a regioselective aro- scope; (2) common functional groups are used for catalyst direction;
matic C–H borylation using a designed iridium catalyst comprising and (3) the ligands are easily accessed. We believe that the present
4
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2322
ARTICLES
a
b
[Ir(OMe)(cod)]2 (1.5 mol%)
Ligand (3.0 mol%)
O
O
N
O
N(hex)2
+
B2pin2
N(hex)2
Ha
N
pinB
Hc
p-Xylene, 25 °C, 16 h
N
N
CF3
1f
CF3
Hb
2a
6f
(1.5 equiv.)
3a
Ligand
meta/para
Yield (%)
3a
1a
Entry
3a/1a
H
a (ppm)
Hb (ppm) Hc (ppm)
3a
95
90
18
(mM) (mM)
1.6
3a-Me1
90
99
98
0.84
1.0
3a-Me2
3h
1
2
3
2.5
2.5
0
1/0
1/1
5.65
5.78
3.60
3.74
5.88
3.63
3.65
3.89
2.5
N
H
O
N
dtbpy
0.96
*
1/64 7.00–7.50
2.5 160
N
N
bpy +
99
1.1
1H NMR spectra were measured using benzene-d6.
Me
Cy
N-Ph,N´-Cy-urea
3a-Me1
O
N
Cy
N
H
N
O
N
O
N
Me
N
N
H
Hd
N
He
N
N
N
N
3h
Me
Cy
Me
3a-Me1
3a-Me2
tBu
O
3a-Me1
(mM)
1a
(mM)
Entry
3a-Me1/1a
Hd (ppm) He (ppm)
Cy
tBu
N
N
H
N
H
N
N
4
5
6
2.5
2.5
2.5
0
1/0
6.26
6.26
6.37
3.91
3.91
3.92
N
2.5
1/1
bpy
N-Ph-N´-Cy-urea
dtbpy
160
1/64
1H NMR spectra were measured using benzene-d6.
Figure 3 | Mechanistic support for the importance of hydrogen bonding between the catalyst and substrates in controlling regioselectivity. a, 1H NMR
chemical shift changes caused by interaction between ligand 3a and amide 1a or 3a-Me1 and 1a. b, Comparison of product meta/para ratios using 3a,
3a-Me1, 3a-Me2, 3h, dtbpy and a mixture of bpy and a urea derivative. *Because the signal overlapped with aromatic signals, the value of the chemical shift
could not be determined.
7. Truong, T. & Daugulis, O. Directed functionalization of C–H bonds: now also
meta selective. Angew. Chem. Int. Ed. 51, 11677–11679 (2012).
8. Cho, J.-Y., Tse, M. K., Holmes, D., Maleczka, R. E. Jr & Smith, M. R. III.
concept will give a general solution for controlling the regioselectiv-
ity of C–H bond transformations and other reactions, without the
need for directing groups.
Remarkably selective iridium catalysts for the elaboration of aromatic C–H
bonds. Science 295, 305–308 (2002).
9. Ishiyama, T. et al. Mild iridium-catalyzed borylation of arenes. High turnover
Methods
Full experimental details and characterization of the compounds can be found in the
numbers, room temperature reactions, and isolation of a potential intermediate.
J. Am. Chem. Soc. 124, 390–391 (2002).
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Supplementary Information.
General procedure for meta-selective C(sp2)–H borylation. A mixture of
[Ir(OMe)(cod)]2 (2.5 mg, 3.8 μmol, 1.5 mol%), ligand 3a (2.8 mg, 7.5 μmol, 3.0 mol%)
and bis(pinacolato)diboron (2a) (95.2 mg, 0.375 mmol, 1.50 equiv.) was added to a
solution of a benzamide derivative (0.250 mmol, 1.0 equiv.) in p-xylene (1.5 ml).
The mixture was then stirred at 25 °C for 16 h. The product was isolated by recycling
preparative HPLC to give a meta/para mixture of borylated products (or only a
meta-borylated product).
Received 31 January 2015; accepted 8 July 2015;
published online 17 August 2015
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metalation: complementary borylation of aromatics and heteroaromatics. Chem.
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2322
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Additional information
Supplementary information and chemical compound information are available in the
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Competing financial interests
The authors declare no competing financial interests.
6
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