Ruthenium-catalyzed CH silylation of methylboronic acid using a removable α-directing modifier on the boron atom

Article abstract of DOI:10.1246/cl.2011.916

Ruthenium-catalyzed CH silylation of methylboronic acid was achieved by use of 2-(1H-pyrazol-3-yl)aniline as a removable α-directing modifier on the boron atom. Crosscoupling of the product, i.e., (phenyldimethylsilyl) methylpinacolborane, with aryl halides proceeded in the presence of a [PdCl ₂(dppf)] catalyst and CsOH as a base.

Full text of DOI:10.1246/cl.2011.916

doi:10.1246/cl.2011.916
916
Published on the web September 5, 2011
Ruthenium-catalyzed C-H Silylation of Methylboronic Acid
Using a Removable ¡-Directing Modifier on the Boron Atom
Hideki Ihara,1,# Akinori Ueda,1 and Michinori Suginome*1,2
1Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering,
Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510
2JST, CREST, Katsura, Nishikyo-ku, Kyoto 615-8510
(Received March 14, 2011; CL-110216; E-mail: suginome@sbchem.kyoto-u.ac.jp)
Ruthenium-catalyzed C-H silylation of methylboronic acid
esters.10 It should be noted that, in spite of its potential
was achieved by use of 2-(1H-pyrazol-3-yl)aniline as a
removable ¡-directing modifier on the boron atom. Cross-
coupling of the product, i.e., (phenyldimethylsilyl)methylpina-
colborane, with aryl halides proceeded in the presence of a
[PdCl2(dppf)] catalyst and CsOH as a base.
usefulness, no catalytic C-H-functionalization at the ¡-hydrogen
of alkylboronic acids has been reported. Herein, we describe
¡-C-H silylation of methylboronic acid using an ¡-directing
modifier that is attached to the boron atom.
Methylboronic acid was condensed with 2-(1H-pyrazol-
3-yl)aniline and anthranilamide, giving MeB(pza) (1) and
MeB(aam) (2), respectively, in high yields (eqs 1 and 2). A
phenol analog MeB(pzp) (3) of 1 was also prepared by the
reaction with commercially available 2-(1H-pyrazol-3-yl)phenol
in high yield (eq 1).
Directed catalytic functionalization of the sp3-C-H bond is
an attractive strategy for the synthesis of functionalized alkanes
in organic synthesis.1 Functional groups such as pyridyl,
quinolinyl, oxazolinyl, carboxyl, aminocarbonyl, and imino
groups are attached to alkanes as directing groups for C-H
functionalization through arylation,2 amination,3 silylation,4
acetoxylation,5 halogenation,6 etc. Despite the remarkable
acceleration of the catalytic reaction by the directing groups,
the need for their installation in the substrates significantly limits
the scope of the reaction. It is likely that the development of
“traceless” or “convertible” directing groups will make directed
C-H activation really useful and applicable to organic syn-
thesis.7
We have developed removable o-directing groups, which
are attached to the boron atoms of arylboronic acids, for
Ru-catalyzed o-C-H silylation at their sp2-carbon atoms. 2-(1H-
Pyrazol-3-yl)aniline and anthranilamide form six-membered
diazaborine structures 1 and 2 containing N-B-N linkages upon
condensation with arylboronic acids.8,9 The nitrogen atoms in
the attached directing group coordinate to the transition-metal
catalysts and enable the C-H functionalization at the ortho-
positions. It would be highly attractive if the strategy could be
extended to activation of alkylboronic acids. In particular, such
a synthetic strategy is most attractive for the synthesis of
¡-functionalized methylboronic acids (Figure 1), because they
are not accessible by hydroboration unlike the higher alkyl-
boronic acids. It has been shown that even strong bases are
not able to abstract ¡-hydrogen atoms of methylboronic acid
CH3B(OH)2
+
ð1Þ
X
N
toluene
reflux, 1h
N
B
XH HN
N
CH3
MeB(pza) (1) (X = NH: 89%)
MeB(pzp) (3) (X = O: 87%)
O
CH3B(OH)2
+
ð2Þ
O
toluene
reflux, 1h
HN
NH
B
NH2 NH2
CH3
MeB(aam) (2) (80%)
The modified methylboronic acids 1-3 were subjected to
Ru-catalyzed reaction with triorganosilanes in the presence
of norbornene as a hydrogen scavenger (Table 1).11 With
the [RhCl(cod)]2 catalyst, a trace amount of the expected
¡-silylation product was detected by 1H NMR (Entry 1).
Ruthenium catalysts were found to be more effective for
¡-silylation. The [RuH2(CO)(PPh3)3] catalyst, which served as
the best catalyst in the o-C-H silylation of PZA- and AAM-
modified arylboronic acids, afforded the ¡-silylation product in
high yield after 12 h under reflux in toluene (Entry 3). Attempts
at lowering the catalyst loading resulted in a decrease in the
product yields (Entries 4 and 5). It should be remarked that the
AAM-modified methylboronic acid 2 completely failed to give
the ¡-silylation product (Entry 6). It is presumed that a four-
membered metallacyclic intermediate or transition state, in
which the AAM group assists the activation of the ¡-C-H bond,
is not favorable, in contrast to the favorable formation of a five-
membered metallacycle in the PZA-assisted reactions. It should
also be noted that 3, a phenol analog of 1, was found to be
totally unreactive in the ¡-silylation reaction despite our
expectation of forming a favorable five-memberd metallacycle,
which is quite similar to that formed in the PZA-assisted
reaction (Entry 7). The contrasting reactivity can be rationalized
by the observed difference in the 11B chemical shifts between 1
and 3. The phenol analog 3 showed its 11B signal at 4.2 ppm in
RO
OR
RO
OR
FG
DG
α
-functionalization
B
C
H
B
C
H
H
H
H
DG
—
DG
DG
FG-H
B
C
H
B
C
H
catalyst
H
FG
H
H
Figure 1. ¡-C-H functionalization of methylboronic acid via
introduction of a directing group (DG) to the boron atom.
Chem. Lett. 2011, 40, 916-918
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

917
Table 1. Reaction of methylboronic acid derivatives 1-3 with
dimethylphenylsilane in the presence of transition-metal cata-
lystsa
corresponding product in good yield (Entry 2). Silyl hydride
having a benzyl group, which is easily convertible to a fluorine
group for further transformation,12 also provided the corre-
sponding product in high yield (Entry 3). In the reaction of
Ph2MeSiH, a slight decrease in yield was encountered, presum-
ably because of steric hindrance (Entry 4). With a more bulky
silyl hydride such as t-BuMe2SiH, the silylated product was
obtained only in low yield (Entry 5). Neither (EtO)3SiH nor
(Me3Si)Me2SiH gave the silylated product at all under these
reaction conditions.
We attempted the reaction of PZA-derivatives of ethyl-
boronic acid and cyclohexylboronic acid under the same
reaction conditions. In the reaction of EtB(pza) (5), two silylated
products 6a and 6b via ¡- and ¢-silylation were obtained,
although the consumption of EtB(pza) was sluggish and
incomplete (eq 3). Reaction of CyB(pza) was found to be
extremely slow under the standard reaction conditions. Use of
20 mol % catalyst without solvent resulted in C-H silylation
at the pyrazolyl group (eq 4). After treatment with pinacol,
silylated pyrazolylaniline 8 was isolated in 36% yield. No
product formed via silylation at the cyclohexane ring was found
in the reaction mixture.
catalyst
PhMe2SiH (5 equiv)
norbornene (5 equiv)
X
Y
X
Y
B
B
toluene, 135 °C, 12 h
H2C
CH3
SiMe2Ph
Entry Substrate Catalyst (mol % metal) NMR yield/%
1
2
3
4
5
6
7
1
1
1
1
1
2
3
[RhCl(cod)]2 (6)
[Ru3(CO)12] (6)
trace
37
97
58
52
0
[RuH2(CO)(PPh3)3] (6)
[RuH2(CO)(PPh3)3] (3)
[RuH2(CO)(PPh3)3] (1)
[RuH2(CO)(PPh3)3] (6)
[RuH2(CO)(PPh3)3] (6)
0
a1-3 (0.25 mmol), a catalyst (15 ¯mol), norbornene (120 mg,
1.3 mmol), PhMe2SiH (1.3 mmol), and anisole (13.6 ¯L,
internal standard) in toluene (0.13 mL) were heated at 135 °C
for 12 h.
Table 2. Ru-catalyzed ¡-silylation of MeB(pza) (1) with silyl
hydridesa
1) [RuH2(CO)(PPh3)3]
PhMe2SiH
norbornene
(pin)B
SiMe2Ph
1) [RuH2(CO)(PPh3)3]
R1R2R3SiH
(pza)B
ð3Þ
(pin)B
toluene, 135 °C
36 h
2) pinacol, TsOH
THF, rt
PhMe2Si
norbornene
(pin)B
SiR1R2R3
4a-e
5
6a (21%)
6b (21%)
HN
N
N
toluene, 135 °C
2) pinacol, TsOH
THF, rt
B
CH3
MeB(pza) (1)
1) [RuH2(CO)(PPh3)3]
(20 mol%)
PhMe2SiH
norbornene
B(pin)
B(pza)
Entry
Silane
NMR yield/% Isolated yield/%
ð4Þ
+
neat, 160 °C, 24 h
(76% conv)
2) pinacol, TsOH
THF, rt
1
2
3
4
5
PhMe2SiH
Et3SiH
BnMe2SiH
Ph2MeSiH
t-BuMe2SiH
97
95
94
73
29
85 (4a)
81 (4b)
86 (4c)
67 (4d)
28 (4e)
SiMe2Ph
NH2
N
N
H
7
8 (36%)
We then tried to optimize the Suzuki-Miyaura coupling
of the pinacol ester of ¡-silylmethylboronic acid with aryl
halides.13 We found that the coupling of 4a with 1-naphthyl
bromide proceeded in good yield in the presence of
[PdCl2(dppf)] as a catalyst and CsOH as a base (eq 5). Use of
Cs2CO3 as a base or [PdCl2(PPh3)2] as a catalyst lowered the
yields significantly. These reaction conditions could be applied
to the coupling of 3-bromoacetophenone with 4a, which
afforded the products in 61% yield (eq 6). Although use of
an excess amount of Ag(I) salt14 or use of the corresponding
trifluoroborates15 has been recommended for cross-coupling of
alkylboronic acid derivatives because of their low reactivity, we
found that the coupling of silylmethylboronic ester 4a proceeded
without applying such modified reaction conditions.16,17
a1 (46 mg, 0.25 mmol), [RuH2(CO)(PPh3)3] (14 mg, 15 ¯mol),
norbornene (120 mg, 1.3 mmol), silane (1.3 mmol), and anisole
(13.6 ¯L, internal standard) in toluene (0.13 mL) were heated
at 135 °C for 12 h. The reaction mixture was treated with
pinacol (59 mg, 0.5 mmol) and TsOH¢H2O (95 mg, 0.5 mmol)
at rt for 1 h.
chloroform-d, which is unusually higher than typical three-
coordinating organoboronic acid derivatives, including
MeB(pza) (1, 32.7 ppm) and MeB(aam) (2, 32.3 ppm). The
high-field shift of the 11B signal can be ascribed to the formation
of a four-coordinating species, in which the pyrazolyl nitrogen
atoms coordinate to the boron atoms. Presumably, the lower
donating ability of oxygen compared with nitrogen makes the
boron atom of 3 more acidic than 1, allowing the coordination of
the pyrazolyl nitrogen to the boron atom.
Under the optimized reaction conditions, ¡-C-H silylation
with various hydrosilanes was carried out (Table 2). For these
examinations, the primary silylation products were treated with
pinacol in the presence of TsOH and isolated as pinacol esters.
In the reactions with PhMe2SiH, the one-pot procedure afforded
the pinacol ester of (phenyldimethylsilyl)methylboronic acid in
85% isolated yield (Entry 1). Likewise, Et3SiH afforded the
Br
SiMe2Ph
[PdCl2(dppf)] (10 mol%)
CsOH•H2O (3 equiv)
(pin)B
SiMe2Ph
ð5Þ
ð6Þ
+
THF, H2O (10/1)
80 °C, 24 h
4a
4a
9 (78%)
SiMe2Ph
Br
[PdCl2(dppf)] (10 mol%)
CsOH•H2O (3 equiv)
(pin)B
SiMe2Ph
+
THF, H2O (10/1)
80 °C, 24 h
O
O
10 (61%)
Chem. Lett. 2011, 40, 916-918
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

918
In summary, we have established that use of 2-(1H-pyrazol-
Reddy, E. J. Corey, Org. Lett. 2006, 8, 3391.
3-yl)aniline as a modifier on the boron atom of methylboronic
acid allows ¡-silylation with silyl hydrides in the presence of
a ruthenium catalyst. The corresponding reaction of EtB(pza)
afforded a mixture of ¡- and ¢-silylated products. In the
silylation of PZA-modified cyclohexylboronic acid, silylation
takes place at the PZA group rather than at the methyl group.
Cross-coupling of the ¡-silylated products with aryl halides has
been achieved with a [PdCl2(dppf)] catalyst and CsOH as a base.
Exploration of more efficient and selective C-H functionaliza-
tion of alkylboronic acids is now being undertaken in this
laboratory.
6
7
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8
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References and Notes
#
A temporary graduate student from Sumitomo Chemical Co.,
Ltd.
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Chem. Lett. 2011, 40, 916-918
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/