Anomalous reactivity of silylborane: Transition-metal-free boryl substitution of aryl, alkenyl, and alkyl halides with silylborane/alkoxy base systems

Article abstract of DOI:10.1021/ja309578k

An unexpected borylation of organic halides with a silyborane in the presence of an alkoxy base has been observed. This formal nucleophilic boryl substitution can be applied to a broad range of substrates with high functional group compatibility. Even sterically hindered aryl bromides afforded the corresponding boryl compounds in high yields. Preliminary mechanistic studies indicated that this boryl substitution is promoted by neither transition-metal contamination nor a radical-mediated process.

Full text of DOI:10.1021/ja309578k

Communication
pubs.acs.org/JACS
Anomalous Reactivity of Silylborane: Transition-Metal-Free Boryl
Substitution of Aryl, Alkenyl, and Alkyl Halides with Silylborane/
Alkoxy Base Systems
Eiji Yamamoto, Kiyotaka Izumi, Yuko Horita, and Hajime Ito*
Division of Chemical Process Engineering and Frontier Chemistry Center, Faculty of Engineering, Hokkaido University, Sapporo
060-8628, Japan
S
* Supporting Information
Scheme 1. Boryl Substitution in the Silylborane/Alkoxy Base
System
ABSTRACT: An unexpected borylation of organic
halides with a silyborane in the presence of an alkoxy
base has been observed. This formal nucleophilic boryl
substitution can be applied to a broad range of substrates
with high functional group compatibility. Even sterically
hindered aryl bromides afforded the corresponding boryl
compounds in high yields. Preliminary mechanistic studies
indicated that this boryl substitution is promoted by
neither transition-metal contamination nor a radical-
mediated process.
that silylborane compounds generate the silyl nucleophile
rather than the boryl nucleophile when a base or nucleophilic
catalyst is used.12,13 Herein we describe a novel, transition-
metal-free boryl substitution of aryl, alkenyl, and alkyl halides
with silylborane/base reagents. The reaction affords the desired
borylation products in high yields with high borylation/
silylation ratios.
rylboronates are recognized as essential synthetic building
A
blocks because of their wide applicability to C−X (X = C,
N, O) bond-forming reactions and ease of handling.1 Reacting a
carbon nucleophile such as an aryl Grignard or aryllithium
reagent with a trialkylboronate is a common synthetic method
for arylboronates.1b,d,2 However, these reactions generally have
low functional group compatibility because of the strong
basicity and nucleophilicity of the reagents. Over the past two
decades, transition-metal-catalyzed boryl substitution of aryl
halides and arene C−H borylation with high functional group
tolerance have been developed as complementary synthetic
methods.3 However, the high process cost and heavy-metal
impurities in the products often make them unsuitable for
pharmaceutical production.4 To overcome this, several
transition-metal-free borylation reactions such as the Sand-
meyer-type borylation5 and electrophilic arene C−H boryla-
tions6 have been developed recently, but there are still
limitations in terms of both the substrate scope and
regioselectivity. Recently, we reported base-mediated silabora-
tion of aromatic alkenes.7,8 While studying the silaboration
reaction, we found that the silylborane PhMe2Si−B(pin) (1)
showed unexpected reactivity in combination with an alkoxy
base: the formal nucleophilic borylation of aryl, alkenyl, and
alkyl halides (Scheme 1).
First, we explored the reactions of p-bromoanisole (2a) with
silylborane 1 under a variety of conditions (Table 1). No
reaction occurred without a promoter (entry 1). Using KOMe
in the reaction of 1 with 2a afforded the counterintuitive boryl
substitution product in high yield with an excellent borylation/
silylation ratio (borylation product 3a, 87% GC yield; isolated
3a, 77%; total, 92% GC yield; B/Si = 95:5; entry 2). This
reaction proceeded very rapidly, requiring only 15 min to reach
completion at 30 °C, while comparable transition-metal-
catalyzed borylations require several hours at 80−100
°C.3b,c,e,f Ethereal solvents are suitable for this boryl
substitution (entries 2−7). The use of tetrahydrofuran
(THF) afforded results similar to those for 1,2-dimethoxy-
ethane (DME) (85% yield, B/Si = 94:6; entry 3), while both
toluene and CH2Cl2 provided the product in lower yields
(entries 4 and 5, respectively). When N,N-dimethylformamide
(DMF) or MeOH was used, silylborane 1 was consumed
completely, but no desired product was detected (entries 6 and
7). Next, the effects of reaction temperature were examined
(entries 8 and 9). The reaction at a higher temperature of 50
°C gave results similar to those at 30 °C (87% yield, B/Si =
95:5; entry 8), whereas lowering the reaction temperature to 0
°C resulted in unfavorable B/Si selectivity in comparison with
the reactions at 30 and 50 °C (83% yield, B/Si = 86:14; entry
9). The reaction performed at high concentration gave only
This boryl substitution reaction is counterintuitive, as silyl
substitution should be anticipated on the basis of the general
reactivity of silylboranes. Kawachi, Tamao, and co-workers have
reported that reacting a silylborane with a stoichiometric
amount of strong base such as RLi, MeMgBr, or KOtBu affords
the silyl nucleophilic species.9,10 Hoveyda and co-workers
reported that a chiral N-heterocyclic carbene (NHC) can also
activate silylboranes, enabling catalytic enantioselective silyla-
tion of α,β-unsaturated compounds.11 These examples suggest
Received: September 27, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja309578k | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 1. Optimization of the Reaction Conditions for Boryl
Substitution of Aryl Halides with PhMe2Si−B(pin)/Base
Table 2. Substrate Scope of Boryl Substitution of Aryl
a
a
Bromides Using the PhMe2Si−B(pin)/KOMe System
b
c
entry
1
X
solvent
base
none
temp. (°C) yield (%)
B/Si
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
I
DME
DME
THF
30
30
30
30
30
30
30
50
0
0
d
2
KOMe
KOMe
KOMe
KOMe
KOMe
KOMe
KOMe
KOMe
KOMe
LiOMe
NaOMe
KOtBu
KOAc
K2CO3
KF
92 (77)
85
20
10
0
95:5
94:6
95:5
3
4
5
6
7
8
9
toluene
CH2Cl2
DMF
MeOH
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
50:50
0
87
83
87
0
95:5
86:14
92:8
e
10
30
30
30
30
30
30
30
30
30
30
11
12
13
14
15
16
17
18
19
81
66
0
80:20
73:27
0
0
DBU
0
KOMe
KOMe
27
81
85:15
96:4
a
Reaction conditions: A mixture of 1 (0.75 mmol) and a base (0.6
mmol) in a solvent (5 mL) was stirred for 10 min at 30 °C, after which
aryl halide 2 (0.5 mmol) was added. The resultant mixture was stirred
b
c
for 1 h. Total GC yield of 3a and 4a. Ratio of borylated product to
d
silylated product. The isolated yield of 3a is shown in parentheses.
The reaction was conducted under high-concentration conditions
e
(0.5 mL of DME solvent).
a
Reaction conditions: A mixture of silylborane 1 (0.75 mmol) and
KOMe (0.6 mmol) in DME (5 mL) was stirred for 10 min at 30 °C,
after which aryl halide 2 (0.5 mmol). was added. The resultant mixture
slightly inferior results (87% yield, B/Si = 92:8; entry 10). Bases
other than KOMe proved to be inferior (entries 11−17).
LiOMe provided no product (entry 11), and NaOMe resulted
in a lower B/Si ratio (entry 12). Using KOtBu resulted in a
significant decrease in the product yield and B/Si ratio (66%,
B/Si = 73:27; entry 13). No reaction occurred with weaker
bases such as KOAc, K2CO3, and KF (entries 14−16). The
reaction with a strong organic base, 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU), also resulted in no reaction (entry 17).
Finally, we investigated the effects of the halogen group. p-
Chloroanisole (2a′) gave the product 3a in lower yield, while p-
iodoanisole (2a″) afforded the product with a yield and B/Si
ratio comparable to those for 2a (entries 18 and 19).
With the optimized conditions in hand, we examined the
scope of the boryl substitution with various aryl bromides
(Table 2). Neutral or electron-rich aryl bromides (2b−e)
underwent the reaction to give 3b−e in high yields. The
substitution position of the methyl group in 2b−d had no
significant effect on the yield. Reactions with electron-deficient
substrates 2f and 2g also gave the desired products (3f and 3g,
respectively) in good yields. Additionally, electron-deficient
substrates containing an ester group (2h and 2i) were also
tolerated in this reaction, and no transesterified byproduct was
detected. Reactions with nitrogen-containing aryl bromides 2j−
l afforded the desired borylation products 3j−l in high yields
b
c
d
was stirred for 1 h at 30 °C. Isolated yield. GC yield. NMR yield.
(68−78%). Boryl substitution of alkenyl bromide 2m also
proceeded in 58% yield without any silaborated byproduct.
Furthermore, sterically congested 1-bromo-2,6-dimethylben-
zene (2n) and 9-bromoanthracene (2o) gave the correspond-
ing borylated products 3n and 3o in high yields (85 and 72%,
respectively). In addition, sterically demanding 1-bromo-2,4,6-
triisopropylbenzene (2p) also reacted to give the borylation
product 3p in excellent yield (92% yield). It is noteworthy that
boryl substitution of 2p has been reported to be difficult even
using diboron and transition-metal catalysts.14 This boryl
substitution system was also successfully applied to the reaction
of alkyl bromide 2q to give the corresponding product 3q in
good yield with high B/Si selectivity (3q, 75%; total, 82%; B/Si
= 91:9; Scheme 2).
Scheme 2. Boryl Substitution Reaction with Alkyl Halide 2q
B
dx.doi.org/10.1021/ja309578k | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
The usefulness of this boryl substitution reaction was further
confirmed by the reaction of aryl halide 2r containing an
allyloxy group, which is sensitive to the palladium-catalyzed
reaction (Scheme 3). Generally, Pd(0) species react with any
Scheme 5. Mechanistic Investigations of an Aryl-Radical-
Mediated Mechanism
Scheme 3. Chemoselective Boryl Substitution of 4-
Allyloxyphenyl Bromide (2r)
acyclic borylated product 3s in 91% yield, and no cyclic
borylated product 6s was detected. In addition, the reaction of
4-bromoanisole 2a in the presence of 1,9-dihydroanthracene
(7), a known radical scavenger, was conducted. No significant
retardation in the reaction rate was observed (Scheme 6).
allyloxy group to generate π-allylpalladium species, leading to
the removal of the allyloxy group. In fact, the reaction of 2r
under typical palladium-catalyzed borylation conditions15
resulted in the decomposition of the substrate, whereas our
boryl substitution method gave the desired product 3r in 90%
yield. We also examined a sequential boryl substitution/
Suzuki−Miyaura coupling procedure to demonstrate the
practical utility of our reaction. Conventional Suzuki−Miyaura
coupling conditions could be applied after workup of the
borylation without chromatographic purification of the
arylboronate intermediates and gave the corresponding cross-
coupling products in high yields. (Scheme 4).
Scheme 6. Mechanistic Investigations with Radical
Scavenger 7
Scheme 4. Sequential Boryl Substitution and Suzuki−
a
Miyaura Coupling
These results indicate that the boryl substitution reaction
involves neither a transition-metal- nor radical-mediated
mechanism. As a possible alternative mechanism, we speculate
that the reaction could be triggered by nucleophilic attack of
the silyl nucleophile on the bromo group of the substrate
followed by C−B bond formation (see the Supporting
Information).18 Further mechanistic studies will be required
in order to verify this counterintuitive reactivity.
In summary, we have demonstrated the first transition-metal-
free boryl substitution of aryl, alkenyl, and alkyl halides using
silylborane 1 and an alkoxy base. This reaction tolerates a
variety of functional groups, including esters, which are fragile
in the presence of strong nucleophiles and basic reagents. This
reaction is fast, as the borylation of unhindered substrates
finished within 30 min. For more challenging, sterically
hindered aryl bromides, the reaction reached completion
within 1 h at room temperature, giving the corresponding
boronates in high yields. As for the reaction mechanism, the
results of the preliminary investigations discounted catalysis due
to transition-metal contamination and any radical-mediated
process. We are now trying to apply this borylation reaction to
the synthesis of various organoboron compounds bearing a
variety of substituents on the boron atom, including a
diarylboryl moiety. Further investigations of the mechanism
and synthetic applications of this reaction are also in progress.
a
Isolated yields are shown.
Finally, to investigate the reaction mechanism, we first
assumed that there was some contamination by transition-metal
impurities in the base. However, no significant amount of any
transition metal (Ni, Pd, Pt, Rh, Au, Ag, Ir, Ru, or Co) was
detected in the KOMe reagent.16 In addition, repeating the
borylation reaction in the presence of a transition-metal (Ni,
Pd, Cu, Pt, Rh, Ag, Ir, Ru, Fe, or Co) salt showed no
acceleration in the reaction (see the Supporting Information).
Control experiments with virgin reagents and new labware
conducted by another research group showed almost the same
results (3a in THF: 82% total GC yield; B/Si = 95:5). We next
explored the possibility of a radical-mediated mechanism by
performing the reaction on o-(3-butenyl)bromobenzene (2s)
(Scheme 5). The corresponding aryl radical has been reported
to undergo 5-exo-trig cyclization with a rate constant of 108 s−1
to form 1-methylindane after hydrogen atom abstraction.17 The
reaction of 2s under the standard conditions afforded the
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization of all new com-
pounds, and the data assessing the effect of adding a transition-
metal salt on the boryl substation reaction. This material is
available free of charge via the Internet at http://pubs.acs.org.
C
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Journal of the American Chemical Society
Communication
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AUTHOR INFORMATION
Corresponding Author
hajito@eng.hokudai.ac.jp
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. T. Ohkuma and Prof. N. Kurono (Hokkaido
University) for conducting the independent control experi-
ments. The Funding Program for Next Generation World-
Leading Researchers (NEXT Program, GR002) is gratefully
acknowledged. We thank the Open Facility (Sousei Hall,
Hokkaido University) for allowing us to perform ICPE-9000
measurements on the ICP-AES and especially N. Takeda for
her great technical assistance and helpful suggestions.
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