Boryl substitution of functionalized aryl-, heteroaryl- and alkenyl halides with silylborane and an alkoxy base: expanded scope and mechanistic studies

Article abstract of DOI:10.1039/c5sc00384a

A transition-metal-free method has been developed for the boryl substitution of functionalized aryl-, heteroaryl- and alkenyl halides with a silylborane in the presence of an alkali-metal alkoxide. The base-mediated boryl substitution of organohalides with a silylborane was recently reported to provide the corresponding borylated products in good to high yields, and exhibit good functional group compatibility and high tolerance to steric hindrance. In this study, the scope of this transformation has been extended significantly to include a wide variety of functionalized aryl-, heteroaryl- and alkenyl halides. In particular, the boryl substitution of (E)- and (Z)-alkenyl halides proceeded smoothly to afford the corresponding alkenyl boronates in good to high yields with retention of the configuration using modified reaction conditions. The results of the mechanistic studies suggest that this boryl substitution proceeds via a carbanion-mediated mechanism.

Full text of DOI:10.1039/c5sc00384a

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Boryl substitution of functionalized aryl-,
heteroaryl- and alkenyl halides with silylborane and
an alkoxy base: expanded scope and mechanistic
studies†
Cite this: Chem. Sci., 2015, 6, 2943
*
Eiji Yamamoto, Satoshi Ukigai and Hajime Ito
A transition-metal-free method has been developed for the boryl substitution of functionalized aryl-,
heteroaryl- and alkenyl halides with a silylborane in the presence of an alkali-metal alkoxide. The base-
mediated boryl substitution of organohalides with a silylborane was recently reported to provide the
corresponding borylated products in good to high yields, and exhibit good functional group
compatibility and high tolerance to steric hindrance. In this study, the scope of this transformation has
been extended significantly to include a wide variety of functionalized aryl-, heteroaryl- and alkenyl
halides. In particular, the boryl substitution of (E)- and (Z)-alkenyl halides proceeded smoothly to afford
the corresponding alkenyl boronates in good to high yields with retention of the configuration using
modified reaction conditions. The results of the mechanistic studies suggest that this boryl substitution
proceeds via a carbanion-mediated mechanism.
Received 1st February 2015
Accepted 2nd March 2015
DOI: 10.1039/c5sc00384a
www.rsc.org/chemicalscience
show a broad functional group compatibility. However, the
application of these methods to the preparation of pharma-
Introduction
ceuticals has been limited by the costs associated with the use
of expensive transition-metal catalysts and the potential for
contamination of the product with residual transition-metal
impurities.8,9 Furthermore, many transition-metal-catalyzed
borylation reactions are susceptible to steric constraints
imposed by the substrate. For example, reaction of bulky 2,4,6-
triisopropylbromobenzene requires exquisite catalysts.4e–g
Based on these limitations, the development of functional
group and steric-bulk tolerant, transition-metal-free synthetic
Functionalized aryl-, heteroaryl- and alkenyl boronate esters are
incredibly useful and versatile building blocks in organic
synthesis because they can be readily converted into a wide
variety of different functional groups. Heteroaryl boronates are
especially important for pharmaceutical applications because
heteroaryl moieties such as oxazole, carbazole, pyridine, pyr-
azole and pyrimidine groups are oen found in a large number
of pharmaceuticals and natural products, as shown in Fig. 1.1
Considerable research effort has been devoted to the devel-
opment of versatile methods for the preparation of organo-
boronate esters.2 Despite considerable progress in this area, the
existing synthetic methods are still in need of further
improvement. One of the most conventional procedures for the
synthesis of organoboronate esters involves the reaction of
organolithium or Grignard reagents with boron electrophiles.3
However, these methods are limited by the availability of the
organolithium or Grignard reagents, which have low functional
group compatibility and require additional preparation steps.
Several transition-metal-catalyzed methods have been
developed during the course of the past two decades for the
borylation of aryl and alkenyl halides,4,5 C(sp2)–H borylation6
and the hydroboration of alkynes,7 and all of these methods
Division of Chemical Process Engineering and Frontier Chemistry Center, Faculty of
Engineering, Hokkaido University, Sapporo 060-8628, Japan. E-mail: hajito@eng.
hokudai.ac.jp
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5sc00384a
Fig. 1 Natural products and pharmaceuticals containing five- and six-
membered heterocyclic rings.
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routes for the construction of organoboronates is strongly to afford the corresponding alkenyl boronates in good to high
desired. Several transition-metal-free borylation methods have yields with retention of the conguration, under modied
been developed, including radical-mediated and electrophilic reaction conditions. The results of our mechanistic experi-
borylation10,11 reactions. However, these reactions still have ments supported the existence of a carbanion-mediated
issues in terms of their reactivity, regioselectivity and functional mechanism and discounted the possibility of a radical anion-
group compatibility. Furthermore, to the best of our knowledge, mediated mechanism.
there are currently no transition-metal-free boryl substitution
reactions available for the synthesis of disubstituted (Z)-alkenyl
boronates, which are important building blocks in organic
Results and discussion
chemistry.
We previously reported that the BBS method tolerates various
We previously reported the boryl substitution of organo- functional groups, including chloro, uoro, ester, amide, ether
halides with a commercially available silylborane, PhMe2Si– and dialkyl amino groups.12 In this study, we initially examine
B(pin) (1), in the presence of an alkoxide base [i.e., base-medi- extending the functional group compatibility of the boryl
ated borylation with silylborane (BBS method), Fig. 2].12 This substrate to include various aryl bromides, using our previously
reaction proceeds smoothly in the absence of transition-metal reported borylation conditions12 to investigate the scope of the
catalysts and shows good functional group compatibility as well method (Table 1). An aryl bromide bearing an epoxy group
as high tolerance toward sterically hindered substrates. Most underwent the borylation reaction to give the desired product
notably, the silylborane reagent used in this reaction performs a 3a in 84% yield. p-Methylthiophenyl boronate 3b was also
formal nucleophilic boryl substitution reaction with halide formed in good yield (78%). Pleasingly, aryl bromides bearing
electrophiles. This boryl substitution is a counterintuitive an aromatic alkene moiety reacted smoothly to afford the
reaction, in that the silylborane substrate should react with the desired products in high yields (3c: 85%, 3d: 87%). Unfortu-
base to generate the corresponding silyl nucleophile, as seen in nately, p-nitrobromobenzene (2e) performed poorly as
the base-mediated activation of B–Si13,14 bonds in the absence of substrate and provided the desired product 3e in low yield (8%).
a transition-metal. p-Bromophenylacetylene (2f) and p-bromobenzophenone (2g)
a
In our previous study,12 aryl-, alkenyl- and alkyl halide were even less effective as substrates and gave complex
substrates were investigated. However, the substrate scope and mixtures. The failure of these substrates was attributed to
limitations of the reaction were not thoroughly investigated, nucleophilic attack of the silyl moiety on the keto group or the
with a heteroaryl bromide bearing a 1-methylindol moiety and a abstraction of a proton from the terminal alkyne of the
tetrasubstituted alkenyl bromide being shown as the only substrate. The borylation of heteroaryl bromides was also
examples of heteroaryl and alkenyl substrates, respectively. investigated, and the reactions of 4-bromodibenzofuran (2h), 3-
With regard to the reaction mechanism, the results of several bromo-9-ethylcarbazole (2i), 2-bromodibenzothiophene (2j) and
experimental studies12 and a DFT-based theoretical study15 led 5-bromobenzothiophene (2k) all proceeded smoothly to give the
to the proposal of a carbanion-mediated mechanism. However, desired products in good to high yields (3h: 77%, 3i: 85%, 3j:
further mechanistic studies are still necessary to assess the 75%, 3k: 51%). Substrates containing a 5-membered hetero-
validity of the proposed mechanism.
cycle, such as a thiophene, pyrazole, isoxazole, oxazole or thia-
Herein, we report the results of our recent efforts towards zole group, also reacted efficiently to provide the corresponding
expanding the substrate scope of this transition-metal-free heteroaryl boronates in good yields (3l–q: 87, 68, 67, 74, 63 and
boryl substitution reaction to functionalized aryl-, heteroaryl- 68% yields, respectively). The application of the reaction
and alkenyl halides, and our mechanistic investigation of the conditions to 5-bromopyrimidine (2r) did not afford any of the
BBS method. Notably, extensive investigation of the substrate borylated product 3r. However, 5-bromopyrimidine derivatives
scope revealed that a variety of functionalized aryl-, hetero- bearing a methoxy or piperidyl group at their 2-position
aryl- and alkenyl halides could be successfully applied to this successfully underwent the borylation reaction, to give the
borylation. Furthermore, (E)- and (Z)-alkenyl iodides reacted desired products in moderate to good yield (3s: 38%, 3t: 71%).
This difference in the reactivity of these substrates could be
attributed to the reactivity of their 2-positions towards the silyl
nucleophile. 3-Bromopyridine (2u) and 3-bromoquinoline (2v)
both reacted smoothly under the standard conditions to afford
the borylated products in moderate to good yields (68 and 58%,
respectively). Disappointingly, however, the products 3u and 3v
could not be isolated because they decomposed during puri-
cation by silica-gel column chromatography.
We then conducted sequential boryl substitution/Suzuki–
Miyaura coupling procedures to demonstrate the utility of this
borylation reaction (Table 2). Aer being quenched with TBAF
to allow for the decomposition of any unreacted silylborane, the
reaction mixture was subjected to an aqueous work-up proce-
dure to give the crude borylation product, which was progressed
Fig. 2 Boryl substitution of organohalides with silylborane and an
alkoxy base.
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Table 1 Boryl substitution of aryl- and heteroaryl bromides with the Table 2 Sequential boryl substitution/Suzuki–Miyaura couplinga
PhMe2Si–B(pin)/base reagenta,b
a
b
Isolated yields. 1-Iodo-4-nitrobenzene, K2CO3 (2.0 equiv.) and
Pd(PPh3)4 (10 mol%) were used in a 10 : 1 (v/v) mixture of DMF and
c
H2O at 100 ꢀC. Iodobenzene, K2CO3 (2.0 equiv.) and Pd(PPh3)4 (10
mol%) were used in a 10 : 1 (v/v) mixture of DMF and H2O at 100 ꢀC.
d
4-Iodoanisole, K3PO4 (2.55 equiv.), PCy3 (3.6 mol%) and
Pd2(dba)3$CHCl3 (1.5 mol%) were used in a 3 : 1 (v/v) mixture of 1,4-
dioxane and H2O at 100 ꢀC.
of the products during the work-up process. In both cases, the
sequential reaction process proceeded smoothly to afford the
corresponding coupled products 4u and 4v in moderate to good
yields (64 and 58%, respectively).
The overall utility of this borylation process was further
demonstrated through the synthesis of key precursors in the
production of Crizotinib16 and a GPR119 agonist17 (Scheme 1).
The borylation of pyrazolyl bromide 2y proceeded smoothly to
give the corresponding borylated product 3y in good yield.
Borylation of the 5-bromopyrimidine derivative 2z followed by
oxidation of the resulting product gave 5z, which is a precursor
of the GPR 119 agonist, in good yield (71% yield, over 2 steps).
Results obtained during the course of our investigation into
the substrate scope of the borylation reaction with heteroaryl
halides indicated that quinoline (6) undergoes silyl addition
under the conditions used in the BBS method to give 2-silylated
quinoline 7 in an isolated yield of 19% (Scheme 2). It is note-
worthy that reports pertaining to silyl substitution reactions
with quinolines or pyridines using a silyl nucleophile via a
transition-metal-free dearomatization are scarce.18–20 This sily-
lation reaction therefore represents a possible pathway for the
formation of by-products when heteroaryl halides are used as
substrates in the borylation reaction. These results also suggest
that a silyl nucleophile is formed under the conditions used in
the BBS method.
a
Reaction conditions: a mixture of PhMe2Si–B(pin) (0.75 mmol) and
KOMe (0.6 mmol) in DME (5 mL) was stirred for 10 min at 30 ꢀC. Aryl
bromide 2 (0.5 mmol) was then added, and the resulting mixture was
stirred for 1 h. Isolated yields of product 3, yields of 3 based on 1H
b
c
NMR analysis are shown in parentheses. Isolated yield of product 3n
containing a small amount of the corresponding silylated by-product
d
(total yield: 82%; B/Si ¼ 81 : 19). Isolated yield of the borylated
product 3o containing a small amount of the corresponding silylated
e
by-product (total yield: 57%; B/Si
(1.5 mmol) and KOMe (1.2 mmol) were used.
¼
90 : 10).
PhMe2Si–B(pin)
directly into a cross-coupling reaction under conventional
conditions. This reaction sequence provided facile access to
compounds 4h, 4t and 4w in high yields (84, 78 and 74%,
respectively). However, substrate 2x containing a nitrile group
afforded the corresponding coupled product 4x in a much lower
yield (36%), which was attributed to a low yield during the
initial borylation step. For substrates 2u and 2v, the sequential
boryl substitution/Suzuki–Miyaura coupling procedure was
performed in one pot without an aqueous work-up, to avoid loss
With regard to the preparation of alkenyl boronates, the
thermal hydroboration of alkynes is a common and straight-
forward method for the synthesis of (E)-alkenyl borates.21 In
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B/Si ¼ 97 : 3). Finally, increasing the amount of silylborane 1 to
2.0 equivalents relative to the substrate afforded the highest
yield of the product boronate observed during this optimization
process (Table 3, entry 4, 89%, Z/E ¼ 97 : 3, B/Si ¼ 96 : 4). Several
other bases were also investigated (Table 3, entries 5–8). No
reaction occurred when LiOMe was used as the base (Table 3,
entry 5), and the use of bulky alkoxide bases, such as K(O-t-Bu)
and Na(O-t-Bu), afforded much lower yields of the product than
NaOEt, as well as lower selectivities (Table 3, entries 6 and 7). The
use of a weaker base (i.e., NaOTMS) did not lead to signicant
improvements in the yield or selectivity of the reaction (Table 3,
entry 8). The reaction also proceeded when THF or 1,4-dioxane
was used instead of DME, although the products were formed in
lower yields in both cases (Table 3, entries 9 and 10). The use of
CH2Cl2 or toluene as the solvent afforded only trace amounts of
the borylated product (Table 3, entries 11 and 12).
With the optimized conditions in hand (Table 3, entry 4), we
proceeded to investigate the substrate scope for various alkenyl
halide substrates (Table 4). In most cases, the Z/E ratios of the
substrates employed for investigating the substrate scope were
>98.5 : 1.5 (for details, see the ESI†), and only less than trace
amounts of geometric isomers (<5%) were detected in the
borylated products based on GC and 1H NMR analysis. The
reaction of alkenyl iodide (E)-8a proceeded in high yield with
retention of the conguration [(E)-9a, 86%]. Several other (Z)-
alkenyl iodides bearing n-pentyl or phenethyl groups also
reacted smoothly under these conditions, to provide the corre-
sponding borylated products (Z)-9b and (Z)-9c in 83 and 80%
yields, respectively. The boryl substitution reactions of a,a-
disubstituted alkenyl bromide 8d and trisubstituted alkenyl
iodide (Z)-8e proceeded as anticipated to give the corresponding
borylated products in moderate to good yields [9d: 43%, (E)-9e:
64%]. The tetrasubstituted alkenyl bromide 8f also reacted
effectively, albeit under modied conditions, to provide the
corresponding alkenyl boronate 9f, although the yield was
similar to that achieved under the previously reported condi-
tions [i.e., 1 (1.5 equiv.) and KOMe (1.2 equiv.) in DME at 30 ꢀC
for 1 h, 58%].12 Functionalized (Z)-alkenyl iodides containing a
benzoyl or acetal group also successfully underwent the boryl
substitution reaction to afford the desired products in good
yields [(Z)-9g: 70%, (Z)-9h: 74%]. A cyclic alkenyl boronate
containing a MOM group 9i was also formed in good yield under
the optimized conditions (58%). For cyclic alkenyl iodides and
pseudohalides containing a dihydropyranyl moiety, the C]C
double bond can undergo positional isomerisation under the
Pd-catalyzed borylation conditions, which can lead to a decrease
in the yield of the desired alkenyl boronate.5a,23 However, under
the current borylation conditions, substrate 8j bearing a dihy-
dropyranyl moiety gave the desired oxacyclic alkenyl boronate 9j
in good yield (71%). The sterically hindered cyclic alkenyl
bromide 8k bearing a butyl ester moiety also provided the
desired borylated product 9k in good yield (53%).
Scheme 1 Synthetic application of the borylation reaction to the
synthesis of precursors of Crizotinib and a GPR 119 agonist. aIsolated
yield of the derivatized product obtained from sequential borylation/
NaBO3$4H2O oxidation of 2y over two steps. For details, see the ESI.†
Yield of 3y based on 1H NMR analysis is shown in parentheses. bIsolated
yield of product 5z.
Scheme
2 Reaction of quinoline under the boryl substitution
conditions.
contrast, (Z)-alkenyl boronates are usually prepared via an
indirect trans-hydroboration reaction using alkynyl bromides,
which requires highly reactive nucleophilic reagents such as
alkenyl lithium compounds.22 With this in mind, we proceeded
to investigate the borylation of (Z)-alkenyl iodide 8a under a
variety of different conditions (Table 3). Our initial efforts in
this area focused on applying our previously determined
optimum conditions for the boryl substitution of aryl bromides
to an alkenyl halide substrate.12 The reaction of (Z)-8a with
PhMe2Si–B(pin) (1.5 equiv.) in the presence of KOMe (1.2 equiv.)
in DME at 30 ꢀC afforded the (Z)-product in moderate yield and
with high levels of both (Z)- and borylation/silylation (B/Si)
selectivity (Table 3, entry 1, 53%, Z/E ¼ 92 : 8, B/Si ¼ 95 : 5). In
addition, vinylcyclohexane, which is a protonated product of 8a,
was observed as the major by-product under these reaction
conditions. The use of NaOMe instead of KOMe successfully
suppressed the formation of the by-product and led to an
improvement in the yield, as well as in the Z/E and B/Si selec-
tivities (Table 3, entry 2, 72%, Z/E ¼ 96 : 4, B/Si ¼ 96 : 4).
Furthermore, the use of NaOEt as the base led to a further
increase in the yield of the desired (Z)-borylated product
compared with NaOMe (Table 3, entry 3, 79%, Z/E ¼ 97 : 3,
Mechanistic studies
It was initially assumed that the boryl substitution reaction
could proceed according to one of four possible reaction
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Table 3 Boryl substitution of (Z)-alkenyl iodide with the PhMe2Si–B(pin)/base reagenta
Entry
Base
Si–B (equiv.)
Solvent
Yield of 9ab (%)
Z/E of 9ac (%)
B/Sid
1
2
3
4
5
6
7
8
KOMe
NaOMe
NaOEt
1.5
1.5
1.5
2.0
1.5
1.5
1.5
1.5
2.0
2.0
2.0
2.0
DME
DME
DME
DME
DME
DME
DME
DME
53
72
79
89(71)
0
27
41
65
81
73
2
92 : 8
96 : 4
97 : 3
97 : 3
95 : 5
96 : 4
97 : 3
96 : 4
NaOEt
LiOMe
K(O-t-Bu)
Na(O-t-Bu)
NaOTMS
NaOEt
NaOEt
NaOEt
NaOEt
83 : 17
95 : 5
89 : 11
96 : 4
98 : 2
68 : 32
74 : 26
92 : 8
97 : 3
99 : 1
9
THF
10
11
12
1,4-Dioxane
CH2Cl2
Toluene
0
a
Reaction conditions: a mixture of PhMe2Si–B(pin) and base (0.6 mmol) in solvent (5 mL) was stirred for 10 min at 30 ꢀC. (Z)-(2-Iodovinyl)
b
cyclohexane 8a (Z/E ¼ 98 : 2, 0.5 mmol) was then added to the reaction, and the resulting mixture was stirred for 1 h. GC yields. Isolated
yields are shown in parentheses. c Z/E ratios were determined based on GC analysis. d Ratios of the borylated (9a) and silylated (10a) products.
pathways, including: (1) trace-transition-metal catalysis, (2) a mechanism was involved in the silyl substitution reaction of
radical-mediated mechanism, (3) a radical-anion-mediated aryl iodides with an a-aminosilyllithium reagent. Further
mechanism or (4) a carbanion-mediated mechanism (Scheme 3). investigation of the borylation of (Z)-alkenyl halides revealed
Several experiments were conducted in our previous paper to that the reaction proceeded in a perfectly stereoretentive
investigate the reaction mechanism.12 The possibility of trace- manner, as shown in Tables 3 and 4. It was therefore envisaged
transition-metal catalysis was investigated by analyzing the that the generation of a corresponding vinyl radical species
alkoxide base for the presence of various transition-metals (i.e., would lead to the E/Z-isomerization of the intermediate, which
Ni, Pd, Pt, Rh, Au, Ag, Ir, Ru and Co) using ICP-AES. The results would subsequently lead to a lower E/Z ratio of the product (eqn
of this analysis revealed that the contamination resulting from (1)).25 These experimental results therefore suggest that a
trace-transition metals was signicantly low (e.g., 3.0 ppm for carbanion-mediated mechanism is more likely than a radical-
Co, Ni, Ir and Pd, and 2.0 ppm for Ag, Pt, Rh, Ru and Au). mediated mechanism.
Furthermore, the borylation reaction was repeated in the pres-
ence of transition-metal salts, which showed no acceleration in
the yield or selectivity of the reaction. Several experiments were
also conducted to probe the possibility of a radical-mediated
mechanism, such as reaction of o-butenylbromobenzene under
(1)
the optimized conditions and a borylation in the presence of a
radical scavenger. The results of our previous study12 suggested
that the borylation reaction does not involve trace-transition-
metal catalysis or a radical-mediated mechanism. However,
Several competition experiments were conducted to develop
the possibility of a radical-mediated mechanism was not
further mechanistic insight into this transformation. We
completely ruled out by the results of our previous study.
initially performed a competition reaction with two different
Furthermore, the possibility of the reaction occurring via a
aryl bromides to investigate the involvement of a radical- or
radical-anion- or carbanion-mediated mechanism has still not
radical-anion-mediated mechanism (Scheme 4a). (E)-p-Bro-
mostilbene (2d) has a lower reduction potential than 4-bro-
mo(triuoromethyl)benzene (2a0), and the carbon atom bound
to the bromine in the latter of these two substrates is much
more electrophilic than that of the former.26 The competition
reaction with these two halides afforded the borylated products
been investigated. Thus, further mechanistic studies were
needed to elucidate the mechanism of this reaction.
The occurrence of a radical-mediated mechanism can be
discounted based on the results of the stereoretentive bor-
ylation of (Z)-alkenyl halides. This borylation reaction could
proceed via a radical mechanism if a radical species can be
3d and 3a0 in a ratio of 12 : 88. A further competition reaction
generated from an organohalide via a SET process involving a
was performed using three aryl bromides (2b0–d0) with different
silylborane/alkoxy-base ate complex under basic conditions. For
example, Strohmann et al.24 reported that a radical-mediated
levels of electrophilicity (Scheme 4b). The borylation of 4-
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Table 4 Substrate scope of the boryl substitution reaction with the
PhMe2Si–B(pin)/base reagenta,b
Scheme 4 Competition reactions between aryl bromides.
halogenophilic attack by the silyl nucleophile would be the key
reaction in the borylation process. It is noteworthy, however,
that this reaction has not yet been studied in great detail.27,28
With this in mind, we performed the silyl substitution reaction
of an aryl bromide with (dimethylphenylsilyl)lithium, which is a
common silyllithium reagent (Scheme 5). The silyl substitution
of p-bromoanisole (2d0) with the (dimethylphenyl)silyl lithium
proceeded smoothly to provide the corresponding silylated
product 11 in 51% yield. This reaction most probably involved
an initial halogenophilic attack by the silyl nucleophile on the
bromine atom, followed by reaction of the resultant silyl
bromide with the aryl lithium species to provide the silyl
substitution product 11. This result provides further evidence in
support of the formation of an aryl anion intermediate from the
reaction of aryl halides with the silyl nucleophile generated by
the reaction between PhMe2Si–B(pin) and an alkoxide base.
Based on the experimental ndings presented above, we
have proposed a plausible carbanion-mediated mechanism for
the BBS method, involving a halogenophilic attack by the silyl
anion on the bromine atom of the substrate (Scheme 6).12,15
PhMe2Si–B(pin) would initially react with the alkoxide base to
a
Reaction conditions: a mixture of PhMe2Si–B(pin) (1.0 mmol) and base
(0.6 mmol) in solvent (5 mL) was stirred for 10 min at 30 ꢀC. Alkenyl
halide 8 (0.5 mmol) was then added to the reaction, and the resulting
b
c
mixture was stirred for 1 h. Isolated yields. Yield based on GC
analysis is shown in parentheses. d Yield based on H NMR analysis is
1
e
shown in parentheses. Substrate 8e had a Z/E ratio of 6 : 94, and no
signicant amount of (Z)-9e was contained in the isolated product
based on NMR analysis. Isolated yield was determined aer Suzuki–
Miyaura cross coupling. Details are described in the ESI.
f
Scheme 3 Four possible reaction pathways for the BBS method.
bromo(uoro)benzene (2b0) proceeded much more rapidly than
for the other two substrates, which were less electrophilic.
These observations therefore support the existence of a carb-
anion-mediated mechanism rather than a radical- or radical-
anion-mediated mechanism, and are also in good agreement
with the results of the DFT study reported in our other paper.15
We then proceeded to investigate the possibility of a carb-
anion-mediated mechanism using a silyl nucleophile. Consid-
eration of the carbanion-mediated mechanism revealed that the
Scheme 5 Reaction of p-bromoanisole with a silyl nucleophile.
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reaction. Furthermore, the results of competition experiments
and the reaction of a silyllithium reagent with an aryl bromide
support the occurrence of a carbanion-mediated mechanism,
rather than a radical- or radical-anion-mediated mechanism. It
is envisaged that the results of this study will lead to the
development of new strategies for the preparation of organo-
boron and organosilane compounds, as well as to a deeper
understanding of boron and silicon chemistry.
Acknowledgements
The Funding Program for Next Generation World-Leading
Researchers (NEXT Program, GR002) is gratefully acknowl-
edged. This work was supported by JSPS KAKENHI Grant
number 262447. E.Y. was supported by Grant-in-Aid for JSPS
Fellows. Some of the PhMe2Si–B(pin) used in this study was
provided by Frontier Scientic, Inc.
Scheme 6 Plausible reaction mechanism.
give the silylborane/alkoxy-base complex A. Subsequent nucle-
ophilic attack by the nucleophilic silyl moiety of complex A on
the bromine atom of an organobromine substrate would lead to
the formation of complex B, which contains a carbanion
species. The carbanion species would then attack the boron
electrophile rather than the PhMe2SiBr generated in situ to give
the corresponding organoborate intermediate C, which would
then react with the silyl bromide to give the corresponding
organoboronate ester together with ROSiMe2Ph and a bromide
salt, which would be formed as by-products. Based on this
mechanism, the nature of the counter cation and the bulkiness
of the base activator would be expected to have a signicant
impact on the yield and B/Si selectivity. For the alkenyl halide
substrate 8a, sodium alkoxides such as NaOEt and NaOMe were
found to be more suitable as base activators than KOMe, which
afforded the best results when aryl bromides were used as
substrates. Furthermore, the use of KOMe resulted in the
production of vinylcyclohexane as a major by-product. These
results could be attributable to the basicity of the carbanion29 in
complex B: the high basicity of the vinyl potassium species in
complex B would lead to the formation of the by-product
through the abstraction of a proton. With regard to the effect of
the bulkiness of the base, the results of the reactions presented
in Table 3 with a t-butoxide base indicate that the presence of a
bulky substituent on the base lowers the B/Si selectivity by
increasing the kinetic stability of the boron electrophile in
complex B, which would prevent this complex from being
attacked by the carbanion species.
Notes and references
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Conclusions
In summary, we have successfully expanded the scope of our
borylation reaction using silylborane and an alkoxide base to a
variety of functionalized aryl-, heteroaryl- and alkenyl halides. It
is noteworthy that the reactions of the (Z)-alkenyl halides also
proceeded in a stereoretentive manner. Furthermore, we have
demonstrated the overall utility of this reaction for the bor-
ylation of heteroaryl substrates by synthesizing the precursors
involved in the preparation of Crizotinib and a GPR119 antag-
onist. This reaction has also been applied to the development
of a sequential boryl substitution/Suzuki–Miyaura coupling
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´
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This journal is © The Royal Society of Chemistry 2015
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