C-O Functionalization of α-Oxyboronates: A Deoxygenative gem-Diborylation and gem-Silylborylation of Aldehydes and Ketones

Article abstract of DOI:10.1021/jacs.7b02518

A deoxygenative gem-diborylation and gem-silylborylation of aldehydes and ketones is described. The key for the success of this transformation is the base-promoted C-O bond borylation or silylation of the generated α-oxyboronates. Experimental and theoret

Full text of DOI:10.1021/jacs.7b02518

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Article
C-O Functionalization of #-Oxyboronates: A Deoxygenative gem-
Diborylation and gem-Silylborylation of Aldehydes and Ketones
Lu Wang, Tao Zhang, Wei Sun, Zeyu He, Chungu Xia, Yu Lan, and Chao Liu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 17 Mar 2017
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C-O Functionalization of α-Oxyboronates: A Deoxygenative gem-
Diborylation and gem-Silylborylation of Aldehydes and Ketones
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‡
†
Lu Wang,† Tao Zhang,†,‡ Wei Sun,† Zeyu He,† Chungu Xia,† Yu Lan,*, and Chao Liu*,
† State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Lanzhou Insti-
tute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, P. R. China
‡ School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400030, P. R. China
Supporting Information Placeholder
ABSTRACT: A deoxygenative gem-diborylation and gem-silylborylation of aldehydes and ketones is described. The key for the
success of this transformation is the base-promoted C-O bond borylation or silylation of the generated α-oxyboronates. Experi-
mental and theoretical studies exhibit that the C-O bond functionalization proceeds via an intramolecular five-membered tran-
sition-state (9-ts) boryl migration followed by a 1,2-metallate rearrangement with OBpin as a leaving group. The transformation
occurs with an inversion on the carbon center. Direct conversion of aldehydes and ketones to gem-diboron compounds was
achieved by combining copper catalysis with this base-promoted C-OBpin borylation. Various aldehydes and ketones were de-
oxygenatively gem-diborylated. gem-Silylborylation of aldehydes and ketones were achieved by a stepwise operation, in which
B2pin2 initially react with those carbonyls followed by a silylation with Bpin-SiMe2Ph.
INTRODUCTION
Scheme 1. Approaches for Tetracoordinated Boron Spe-
cies in Boron-Mediated 1,2-Metallate Rearrangements
Organoboron compounds are powerful reagents in chemical
sciences.1 Among various boron-involved organic transfor-
mations, the tetracoordinated boron-mediated 1,2-metallate
rearrangement is one of the most versatile strategies for con-
structing many complex molecules, and efforts are continual-
ly devoted in this area.2 The key for such transformation is
the formation of a four-coordinated boron species A with a
migrating group (Nu) and a leaving group (LG) bound to a
linker group (L) (Scheme 1). Up to date, Approach I domi-
nates the formation of species A, in which a tricoordinated
boron species interacts with a nucleophilic L-LG. Many clas-
sic transformations follow this approach,2d such as the oxida-
tion of organoboranes with peroxides,3 amination with hy-
droxylamine derivatives,4 homologation with diazo com-
pounds,2c lithiated carbamates,2a,5 and lithiated alkyl chlo-
rides,2e etc. In the other approach (Approach II), an ampho-
teric nucleophile attacks to the tricoordinated boron center
(RR’B-L-LG) to form A (Scheme 1). The latter approach main-
ly relies on the reaction of (α-haloalkyl)boronic esters (LG =
halides).2e,2f,6 Those (α-haloalkyl)boronic esters have been
applied in plentiful of synthetic strategies.2b,7 However, other
α-functionalized boronic esters, especially α-oxyboronic es-
ters (O-type leaving group) have not been disclosed in such
approach to date. The α-oxyboronic esters are conveniently
accessed via the catalytic borylation of widely available alde-
hydes or ketones, including the enantioselective version of
borylation.8 synthetic application of such type of compounds,
however, still remains limited.8b,8g,9 Therefore, applying α-
oxyboronic esters in Approach II would not only significantly
diversify such boron chemistry but also expand the applica-
tion of α-oxyboronic esters in synthetic chemistry.
α-OBpin (or OH) boronates are usually produced from the
borylation of aldehydes and ketones.8 It has been demon-
strated that the boryl group could activate its gem-chemical
bond.10 As a result, the α-C-O bond is activated in α-OBpin
boronates, and the OBpin group may act as a leaving group.
If an amphoteric boryl or silyl nucleophile could be intro-
duced on the Bpin-C group of 2, a B-B-C or Si-B-C intermedi-
ate 2’ might be formed (Scheme 2). The 1,2-metallate rear-
rangement gem-diborylation and gem-silylborylation with
OBpin as the leaving group then might be achieved to form
the gem-diboryl or gem-silylboryl compounds (Scheme 2). It
is noteworthy to emphasize the migrating ability of boryl or
silyl group in intermediate 2’. To our knowledge, the 1,2-
metallate rearrangement of such type of intermediates has
been demonstrated (Approach I type), either with OCb as
the leaving group in the gem-silylborylation of lithiated car-
bamates by Aggarwal et al,11 or with N2 as the leaving group
in the gem-diborylation or gem-silylborylation of N-
tosylhydrazone by Wang et al,12 or with halide as the leaving
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o
o
group in the gem-silylborylation of lithiated alkyl halides by
Shimizu et al.13 Therefore, it is possible to realize the hypoth-
esis shown in Scheme 2. Herein, we demonstrate the first
borylation and silylation of α-oxyboronic esters, accordingly
ture to 80 C or 60 C resulted in low yields of 3aa. No 3aa
was observed at 25 oC.
1
2
3
Scheme 3. The Effect of NaOtBu Amount and Tempera-
ture a
achieving
a deoxygenative gem-diborylation and gem-
4
5
6
7
8
9
NaOtBu (x equiv)
Bpin
silylborylation of aldehydes and ketones (Scheme 2), in
which various gem-diboryl and gem-silylboryl compounds
were synthesized. These gem-bimetallic compounds have
attracted increasing attentions in synthetic applications, due
to their potential for selective mono- or di-
functionalization.10c,14 Synthetically, in addition to those re-
ported methods including borylation of diazoalkanes,15
deprotonation/alkylation of 1,1-diborylmethane,16 and boryla-
tion of terminal alkynes,17 N-tosylhydrodrazones,12a gem-
dihaloalkanes,18 alkenylboron,19 benzylic alkanes,10a,20 the
direct deoxygenative gem-diborylation of carbonyls would
provide an intriguing alternative for the practical and diverse
synthesis of gem-bis(boronates).
OBpin
+
B2pin2
Temperature
Toluene, 6 h
Cy
Bpin
3aa
Cy
Bpin
2aa
1.1 equiv
80
3aa (100 oC)
3aa (80 oC)
3aa (60 oC)
3aa (25 oC)
(72%)
70
60
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20
10
0
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(33%)
(25%)
(x = 1.2)
(0)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
The amount of NaOtBu (x equivalent)
Scheme 2. Deoxygenative gem-Diborylation and gem-
Silylborylation of Aldehydes and Ketones
a
Reaction conditions: 2aa (0.2 mmol), B2pin2 (0.22 mmol), toluene (1.0
mL), NaOtBu (0.2x mmol), 6 hours. b Yields were determined by GC anal-
ysis with biphenyl as an internal standard. Cy = cyclohexyl.
The above results evinced that the introduction of a nucle-
ophilic Bpin group is realizable with OBpin as a leaving
group. This promising result encouraged us to further test
other nucleophilic boryl or silyl groups for the synthesis of
gem-diboryl compounds with two different boryl groups or
gem-silylboryl compounds. Consequently, Bpin-Bdan, Bpin-
SiEt3 and Bpin-SiMe2Ph were applied to react with 2aa
(Scheme 4).21 As a result, the lower nucleophilic Bpin-Bdan22
23
and the less reactive Bpin-SiEt3 failed to give any desired
RESULTS AND DISCUSSION
product 3ba or 3ca, while Bpin-SiMe2Ph afforded the desired
gem-silylboronate 3da in 82% isolated yield, indicating Bpin-
SiMe2Ph is an approapriate reagent for the synthesis of gem-
silylboryl compounds.
Borylation of α-OBpin boronic esters. According to the
hypothesis shown in Scheme 2, the key challenge would be
the introduction of a boryl group to the α-OBpin boronates 2
followed by an 1,2-metallate rearrangement to form the final
product 3, as the addition of B2pin2 to aldehydes has been
shown to easily take place under NHC-Cu catalytic system at
ambient temperature (NHC = N-Heterocyclic Carbene).8 The
transformation of 2 (LG = OBpin) to 3 has thus far been elu-
sive. For that reason, in our initial attempt, we focused on
realizing this essential step. 2aa was prepared from cyclohex-
anecarbaldehyde (1aa) by using the reported copper catalytic
system.8e Moreover, alkali metal alkoxides have been exten-
sively used to activate B2pin2 in many borylative transfor-
mations. During our investigation, we noticed that 1.2
Scheme 4. Reaction of 2aa with Different Boryl or Silyl
Nucleophiles
o
equivalents of NaOtBu in toluene at 100 C was sufficient for
Furthermore, different OY group of 2a was screened to in-
vestigate the reactivity of different leaving groups (Scheme 5).
When Y = H (2ea), the hydroxyl group was successfully sub-
stituted by boryl group to generate 3aa in 56% yield under
the reaction condition of B2pin2/NaOtBu system.24 It is rather
interesting to find that when the OH group was protected by
COCH3 (Ac, 2fa), the yield of the desired borylation product
3aa dropped to 11%. When the OH group was protected by
COCF3 (TFA, 2ga) group or CONiPr2 (Cb, 2ha) group, only
trace or none of 3aa was observed. Generally, OAc, OTFA
and OCb are known as better leaving groups than free OH
group. However, in our study the OH substrate 2ea afforded
the best yield of 3aa. These interesting results encouraged us
to further investigate the mechanism of this alkoxide-
converting 2aa with B2pin2 (1.1 equiv) to the desired gem-
diboryl compound 3aa (Scheme 3). The amount of NaOtBu
and the reaction temperature were found to be crucial for
this transformation. Catalytic amounts of NaOtBu (10 mol%)
resulted in trace amount of the desired 3aa formation. Along
with the increase of NaOtBu, the yield of 3aa increased ac-
cordingly. When 1.2 equivalents of NaOtBu was used, the
yield of 3aa reached maximum at 72% (x = 1.2). Further in-
creasing the amount of NaOtBu resulted in quick decrease of
3aa. When 3.0 equivalents of NaOtBu were used, only less
than 5% of 3aa was observed together with remaining of 2aa
(observed as α-OH boronate 2ea, 75%) and B2pin2 (70%),
indicating that excess amount of NaOtBu is detrimental to
the conversion of 2aa to 3aa. Lowering the reaction tempera-
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promoted C-OBpin bond borylation and silylation before
expanding the substrate scope.
SiMe2Ph was applied to react with 2aa in the presence of 1.2
equivalents of NaOtBu (eq. 1). As a result, no 10B-labeled 3da
was observed. The normal 3da was isolated in an 80% yield.
From those three pathways discussed above, A and B would
result in non-10B-labeled 3da (with silyl as the migration
group), while Pathway C will generate 10B-labeled 3da. Thus,
Pathway C was ruled out.
1
2
3
4
5
6
7
8
Scheme 5. Reactivity of Different O-Type Leaving
Groups a
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We then utilized Density functional theory (DFT) calcula-
tion to further reveal Pathways A and B (Pathway C has also
been revealed for comparison, see details in the supporting
information). Density function M11-L with a standard 6-
311+G(d) basis set were employed in the calculation. It can be
derived from Scheme 6 that 2-Z is the same intermediate for
all these three pathways. As shown in Figure 1, the free ener-
gy of α-OBpin boronate 2 was set to the relative zero value.
In Pathway A, the interaction of tert-butoxide with B2pin2
generates intermediate Z.25-26 Then a direct transfer of a boryl
Bpin to 2 takes place via a transition state 4-ts to afford the
intermediate 2-Z. The computed activation free energy for
this step is 60.4 kcal/mol, indicating that Pathway A is less
possible. In pathway B, the coordination of tert-butoxide to
2-Z reversibly affords a boronate intermediate 6 via the tran-
sition state 5-ts with a barrier of 16.1 kcal/mol. The following
a
Reaction conditions: 2a (0.2 mmol), B2pin2 (0.22 mmol), toluene (2.0
mL), NaOtBu (0.24 mmol), 100 oC, 6 hours. Yields were determined by GC
analysis with biphenyl as an internal standard. b 0.9 equivalents of NaOt-
Bu was used.
Mechanistic study for the borylation of α-OBpin bo-
ronic esters. Three possible reaction pathways were pro-
posed based on the initially possible interaction of NaOtBu
with three types of Bpin group (Bpin-B, Bpin-O and Bpin-C)
in the reaction mixture (Scheme 6). The activation of B2pin2
(Bpin-B) with alkoxide has been previously proven to gener-
ate an adduct Z which could provide a nucleophilic Bpin
group.25 Accordingly, Z may transfer its boryl group to 2 to
form an ‘ate’ complex 2-Z followed by 1,2-metallate rear-
rangement with OBpin as leaving group, generating the de-
sired product 3 (Scheme 6, Pathway A). Furthermore, the
reaction between 2 and NaOtBu may occur via two possible
routes. First, the Bpin-O group exchanges with NaOtBu to
generate 2’ followed by the reaction with B2pin2 to afford an
adduct 2-O-Z. An intramolecular transfer of the boryl Bpin
group also generate 2-Z, which undergoes a similar process
as Pathway A to generate 3 (Pathway B). It is also possible
that NaOtBu interacts with the Bpin-C group of 2 to generate
a carbanion 2’’ followed by the reaction with B2pin2 to afford
2-Z, then to generate 3 (Pathway C).
t
dissociation of BuOBpin from 6 could occur via transition
state 7-ts. In this case, a three-membered spiro-boronate
intermediate 2’ was generated. The free energy span of this
step is 23.7 kcal/mol. Subsequently, intermediate 2’ could
readily react with B2pin2 by the cleavage of the three-
membered ring to give a more stable boronate intermediate
2-O-Z via transition state 8-ts. The energy barrier of this step
is only 5.6 kcal/mol. Then, the intermediate 2-Z is formed
irreversibly by a concerted boryl transfer via
a five-
membered ring type transition state 9-ts with an energy bar-
Scheme 6. Proposed Reaction Pathways
rier of 14.0 kcal/mol.27 The computational results implied
t
that the dissociation of BuOBpin from intermediate 6 via
transition state 7-ts is the rate-determining step in pathway
B. The calculated apparent activation free energy is 23.7
kcal/mol, indicating that this transformation could take
place under mild conditions through Pathway B (Compara-
bly, the calculated apparent activation free energy of Path-
way C is 29.4 kcal/mol, which is 5.7 kcal/mol higher than
that of Pathway B, see details in the supporting information).
Later on, the generation of gem-diboron product 3 from in-
termediate 2-Z was also studied theoretically. A concerted
boron-shift and C-O bond cleavage transition state is located
as 14-ts. In geometry information of transition state 14-ts, the
bond lengths of B1-B2, B2-C, and C-O are 1.91, 2.21, and 2.21 Å,
respectively, indicating that when the B2-C bond is forming,
the B1-B2 and C-O bonds are partly broken. The angle of B2-
C-O is 160.6°, which reveals an intramolecular nucleophilic
substitution from the back of C-O bond (See details in the
supporting information). The calculated activation free ener-
gy of this step is 20.6 kcal/mol, suggesting a facile process.
The calculated highest occupied molecular orbital (HOMO)
of intermediate 2-Z (Figure 1) showed that this orbital major-
ly located between the B-B bond, further demonstrating the
nucleophilicity of the migrating boron atom. Therefore, the
subsequent nucleophilic substitution would occur. Overall,
To verify these possible mechanisms, a 10B-labeling exper-
iment was initially carried out. The synthesized 10Bpin-
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the DFT calculations exhibit that Pathway B is the most plau-
sible pathway for the borylation of α-OBpin boronate.
Moreover, Pathway B could explain why α-OH boronate
2ea is reactive in the borylation process (Scheme 5), as the
deprotonation of 2ea with NaOtBu would generate 2’ fol-
lowed by a facile generation of 2-O-Z. When the OH group
was protected (2fa, 2ga, 2ha), the generation of 2-O-Z was
blocked as a result to shut the borylation down. The OAc
(2fa) substrate afforded 11% of the desired 3aa might due to
the trans-esterification of 2fa with NaOtBu to release inter-
mediate 2’ to initiate the reaction. Therefore, both theoreti-
cal studies and experimental results support Pathway B as
the reaction mechanism for the borylation of α-OBpin boro-
nates.
tion was confirmed by comparing with the reported result11),
1
2
3
4
5
6
7
8
indicating an inversion on the carbon center and the silyla-
tion indeed took place with a stereospecific manner. The
stereochemical course further confirms the proposed trans-
formation of 2-Z to the final product 3.
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Selected substrate scope for the borylation and silyla-
tion of α-OBpin boronic esters. With the insightful under-
standing of this transformation, several α-OBpin boronic
esters 2 were synthesized and were subjected to react with
B2pin2 or Bpin-SiMe2Ph (Table 1).28 Compounds 2 generated
from aldehydes, such as 2aa, 2al, and 2ap were successfully
borylated with B2pin2 and silylated with Bpin-SiMe2Ph in the
presence of NaOtBu. The corresponding gem-diboryl com-
pounds 3aa, 3af and 3ag, gem-silylboryl compounds 3da, 3df
and 3dg were obtained in good to excellent yields. Those
products are stable for isolation. Compound 2kg generated
from cyclohexanone afforded its corresponding gem-diboryl
compound 3kg and gem-silylboryl compound 3dg in 51% and
56% yields, respectively.
GM11-L/toluene
(kcal/mol)
OtBu
pin
B
pin
B
Bpin
Bpin
O
pin
B
O
nPr
OtBu
Bpin
Bpin
nPr
O
O
O
nPr
pin
OtBu
pin
B
B
pinB
nPr
nPr
Bpin
Bpin
8-ts
Bpin
5-ts
B
pin
4-ts
7-ts
9-ts
Bpin
O
60.4
4-ts
nPr
pin
Pathway B
Pathway A
B
Bpin
17.2
7-ts
16.1
14-ts
tBuOBpin
OtBu
5-ts
tBuOBpin
Z
3.2
(17.5)
B2pin2
4.6
9-ts
3.7
8-ts
0.0
14-ts
Table 1. Borylation and Silylation of α-OBpin Boronic
-1.9
2
B
Bpin
2'
Esters 2 a
pin
-6.5
6
OBpin
OtBu
Z
-9.4
2-O-Z
-17.4
(-3.1)
O
O
nPr
nPr
Bpin
OtBu
nPr
Bpin
2-Z
O
Bpin
-69.9
Bpin
Bpin
(-55.7)
2
6
2'
3
O
nPr
Bpin
O
Bpin
Bpin
nPr
Bpin
Bpin
nPr
pinB Bpin
Bpin
2-Z
2-O-Z
3
HOMO (-1.54 ev)
Figure 1. Free energy profiles of Pathways A and B. Energy values are
given in kcal/mol and represent the relative free energies that were
calculated using the M11-L method in toluene. Energy values of 2-Z
to 3 in Pathway A are in parentheses.
According to the transformation of intermediate 2-Z to the
final product 3 in Pathway B, the boryl group attacks the
carbon center from the back side and will result in an inver-
sion on the carbon center. In order to testify the inversion
process (eq. 2), an enantioenriched α-OH boronate (S)-2p-H
(94% ee of the corresponding silyl protected product) was
synthesized from aldehyde 1p according to the Ito proce-
dure9a and subjected to the silylation with Bpin-SiMe2Ph to
confirm the inversion process (eq. 2). Since (S)-2p-H is un-
stable to be purified by column chromatography over silica
gel, we used it only after a fast filtration through a silica plug
followed by removing the solvent (See details in the support-
ing information). The obtained (S)-2p-H was subjected to
the silylation with PhMe2Ph-Bpin in the presence of NaOtBu.
Consequently, we observed the desired (R)-3dp in 38% yield
(based on aldehyde 1p) with 96% ee (The absolute configura-
a
Reaction conditions: 2 (0.3 mmol), B2pin2 (0.33 mmol) or Bpin-
SiMe2Ph (0.33 mmol), toluene (2.0 mL), NaOtBu (0.36 mmol), 100 oC, 6
hours. Isolated yields. b 0.5 mmol scale in 2.0 mL toluene.
Exploring the direct deoxygenative gem-diborylation
of aldehyde and ketones. Compounds 2 are usually not
easy to isolate and suffer from instability in air, which makes
the method impractical for the synthesis of gem-diboryl or
gem-silylboryl compounds. Directly utilizing aldehydes or
ketones would be more straightforward and practical. In-
spired by the pioneering work on NHC-Cu catalyzed addition
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of B2pin2 to aldehydes or ketones,8b,8e,8f our next effort is to
Substrate scope of deoxygenative gem-diborylation of
1
2
3
4
5
6
7
8
explore the integrated use of Cu catalytic system with the
above base-promoted C-OBpin borylation to figure out the
direct gem-diborylation of aldehydes and ketones.
aldehydes and ketones. Following the standard condition,
a series of aliphatic aldehydes were examined in this trans-
formation (Table 2). The R group of 1 can be various second-
ary alkyl groups, including cyclopentyl, cyclopropyl and i-
pentyl, all affording the corresponding products 3ab-3ah in
moderate to excellent isolated yields. Especially, lily aldehyde
and helional were well gem-diborylated to generate their
corresponding products 3af and 3ag in high yields. Both 2-
phenylpropionaldehyde and phenylacetaldehyde were shown
to be suitable substrates and the desired product 3ah and 3ai
were obtained in 68% and 50% yields, respectively. Simple
long chain aliphatic aldehydes proceeded smoothly and gave
the corresponding gem-diboron compound in a moderate
yields (3aj-3al). 7-Methoxy-3,7-dimethyl-octanal afforded the
corresponding product 3am in a 77% isolated yield. gem-
Diborylation product 3an of citronellal was isolated in 58%
yield, indicating that the olefinic bond could be tolerated.
Aromatic trifluoromethyl group could also kept intact (3ao).
With cyclohexanecarbaldehyde 1aa and B2pin2 (2.2 equiv)
as substrates, the amount of NaOtBu was investigated in tol-
o
uene at 100 C (Scheme 7) by using ICyCuCl as the catalyst
(ICy = 1,3-dicyclohexylimidazol-2-ylidene, the optimizations
of other reaction parameters were listed in the supporting
information). As 2aa is easily hydrolyzed to give 2ea during
aqueous workup, the amount of 2ea was quantified instead
of 2aa. It can be seen from Scheme 7 that less than 20% of
2ea was obtained and no 3aa was observed in the absence of
NaOtBu. When 10 mol% of NaOtBu was added, there was still
no observation of 3aa, while the yield of 2ea increased to
over 60%. This may due to the generation of more active
catalyst ICyCuOtBu from ICyCuCl and NaOtBu, for the addi-
tion of B2pin2 to aldehyde carbonyl.8f Whereafter, along with
the increase of NaOtBu, the yield of 2ea decreased together
with the yield of 3aa increased. When 1.3 equivalents of
NaOtBu was applied, the yield of 3aa maximized at 79%
without any observation of 2ea. These results are consistent
with the previous study on the conversion of 2aa to 3aa, in-
dicating that 2aa is the intermediate for the gem-
diborylation of 1aa to 3aa. Interestingly, further increasing
the amount of NaOtBu resulted in a quick decrease of 3aa
with the re-observation of 2ea. To rationalize this phenome-
non, mechanistic study (Pathway B in Scheme 6) exhibited
that the exchange between α-OBpin boronate 2 and one
equivalent of NaOtBu will generate 2’ which is also an alkox-
ide analog. Excess NaOtBu will compete with 2’ to interact
with B2pin2. This may slow down the conversion of 2’ to 2-O-
Z. Furthermore, even if 2-O-Z is formed, the coordination of
excess amount of tert-butoxide to either C-Bpin or the mi-
grating Bpin group may block the migration step. Hence,
excess amount of NaOtBu is detrimental to the conversion of
2aa to 3aa. Finally, a single-operation gem-diborylation of
aldehyde with B2pin2 was achieved under copper catalysis in
the presence of 1.3 equivalents of NaOtBu.
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t
When R is a bulky Bu group, the reaction became sluggish
and a prolonged reaction time was required to reach a good
yield for pivalaldehyde (3aq). It was interesting to find that
paraformaldehyde (CH2O)n also worked under the reaction
condition and afforded the desired product 3ar albeit in a
relatively low yield (37%).
Table 2. Deoxygenative gem-Diborylation of Aldehydes a
Scheme 7. The Effect of NaOtBu for the Conversion of
Aldehyde
80
60
40
20
a
Reaction conditions: 1 (0.5 mmol), B2pin2 (1.1 mmol), ICyCuCl (0.025
mmol), NaOtBu (0.65 mmol), toluene (2.0 mL), 100 C, 6 hours. Isolated
o
0
yields. b 24 hours. c paraformaldehyde was used.
0.0 0.5 1.0 1.5 2.0 2.5 3.0
Next, deoxygenative gem-diborylation of ketones was also
examined under the standard condition (Table 3). Acetone,
2-pentanone and 3-pentanone were well gem-diborylated to
t
The amount of NaO Bu (x equivalent)
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afford their products 3ka-3kc in good yields. Cyclic ketones
tempted one-step reaction for this gem-silylborylation by
1
2
3
4
5
6
7
8
with five-membered ring, six-membered ring and seven-
membered ring were all suitable for this deoxygenative gem-
diborylation and gave their corresponding products 3kd-3ki
in moderate to good yields. Arylacetones were also applied
and the aromatic methoxyl and C-F groups were well tolerat-
ed (3kj, 3kk). Benzyl ethyl ketone afforded the desired prod-
uct 3kl in a 77% yield.
initially adding all materials (eq. 5). Unfortunately, no de-
sired 3da was observed in this case. The α-silyl alcohol 2da-
H was obtained as the major product (73%) together with the
observation of 3aa (26%). 2da-H was generated from the
addition of Bpin-SiMe2Ph to 1aa, followed by hydrolysis.29
The products distribution suggested that Bpin-SiMe2Ph is
more reactive than Bpin-Bpin in the addition to aldehyde 1aa
under the reaction conditions and 2da could not be convert-
ed to the desired gem-silylboryl compound 3da in the pres-
ence of B2pin2 and NaOtBu.
Table 3. Deoxygenative gem-Diborylation of Ketones a
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Following the above result, several aldehydes and ketones
were selected to test the substrate scope under the stepwise
strategy (Table 4). Both aliphatic and aromatic aldehydes
afforded their corresponding gem-silylboryl compounds 3db-
3dd in moderate yields. Acyclic and cyclic ketones were silyl-
borylated in moderate yields (3de, 3dg). It is worthy to note
that acetophenone was also suitable substrate and gave the
desired gem-silylboryl compound 3df in a 57% yield.
a
Reaction conditions: 1 (0.5 mmol), B2pin2 (1.1 mmol), ICyCuCl (0.025
mmol), NaOtBu (0.65 mmol), toluene (2.0 mL), 100 C, 6 hours. Isolated
yields. b 1.0 mmol scale in 2.0 mL toluene.
o
To demonstrate the practicability of this transformation, a
1o mmol scale reaction was carried out using helional (1af) as
substrate while lowering the catalyst loading to 2 mol% (eq.
3). Subsequently, 3.01 grams (70% yield) of the desired prod-
uct 3af was isolated, indicating the possibility to scale up this
procedure.
Table 4. gem-Silylborylation of Aldehydes and Ketones
Exploring deoxygenative gem-silylborylation of alde-
hydes and ketones. The silylation of α-OBpin boronic es-
ters with Bpin-SiMe2Ph in Table 1 encouraged us to further
investigate the deoxygenative gem-silylborylaton of alde-
hydes and ketones. Since α-OBpin boronic esters 2 can be
generated from aldehydes or ketones with B2pin2 and can be
silylated with Bpin-SiMe2Ph, the stepwise addition of B2pin2
and Bpin-SiMe2Ph was carried out to achieve deoxygenative
gem-silylborylation of 1aa (eq. 4). First, the reaction between
1aa and Bpin-Bpin proceeded initially in the presence of 5
mol% ICyCuCl and 0.1 equivalents of NaOtBu in toluene at
a Reaction conditions: 1 (0.6 mmol), B2pin2 (0.5 mmol), ICyCuCl (0.025
mmol), NaOtBu (0.05 mmol), toluene (2.0 mL), 50 oC, 6 hours, then
NaOtBu (0.6 mmol), Bpin-SiMe2Ph (0.6 mmol), 100 oC, 6 h. Isolated
yields. b 1.0 mmol scale in 2.0 mL toluene.
CONCLUSION
o
60 C. After 6 hours, 1.2 equivalents of Bpin-SiMe2Ph and 1.2
equivalents of NaOtBu were added into the reaction mixture.
In summary, we have demonstrated a deoxygenative gem-
diborylation and gem-silylborylation of aldehydes and ke-
tones for the first time. The key for the success of this trans-
formation is the base-promoted C-O bond borylation or si-
lylation of the generated α-oxyboronates. Experimental and
theoretical studies exhibit that the C-O bond functionaliza-
tion proceeds via an intramolecular five-membered transi-
o
Then, the reaction was heated at 100 C for another 6 hours.
To our delight, the desired gem-silylborylation product 3da
was obtained in 71% yield (eq. 4). The yield was quantified
based on B2pin2. 1.2 equivalents of 1aa was used to make sure
the full conversion of B2pin2 in the first step. We also at-
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Journal of the American Chemical Society
Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2011;
tion-state boryl migration followed by a 1,2-metallate rear-
Vol. 1 and 2.
1
2
3
4
5
6
7
8
rangement with OBpin as a leaving group. The transfor-
mation occurs with an inversion on the carbon center. Direct
conversion of aldehydes and ketones to gem-diboron com-
pounds was achieved by combining copper catalysis with this
base-promoted C-OBpin borylation. Various aldehydes and
ketones were deoxygenatively gem-diborylated. gem-
Silylborylation of aldehydes and ketones were achieved by a
stepwise operation, in which B2pin2 must react with those
carbonyls first followed by a silylation with Bpin-SiMe2Ph.
Further exploring other nucleophiles in the reaction with α-
oxyboronates is currently ongoing in our laboratory.
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ASSOCIATED CONTENT
Supporting Information
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: lanyu@cqu.edu.cn
*E-mail: chaoliu@licp.cas.cn
ORCID
Yu Lan: 0000-0002-2328-0020
Chao Liu: 0000-0002-2521-924X
Notes
The authors declare no competing financial interests.
(11) Aggarwal, V. K.; Binanzer, M.; de Ceglie, M. C.; Gallanti, M.;
Glasspoole, B. W.; Kendrick, S. J. F.; Sonawane, R. P.; Vázquez-
Romero, A.; Webster, M. P. Org. Lett. 2011, 13, 1490.
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J. Org. Lett. 2014, 16, 448; (b) Li, H.; Wang, L.; Zhang, Y.; Wang, J.
Angew. Chem., Int. Ed. 2012, 51, 2943.
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Kitagawa, H.; Kurahashi, T.; Hiyama, T. Angew. Chem., Int. Ed. 2001,
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ACKNOWLEDGMENT
This work was supported by the National Natural Science
Foundation of China (21673261, 21603245, 21633013, and
21372266). We also gratefully thank the State Key Laboratory
for Oxo Synthesis and Selective Oxidation (OSSO), Lanzhou
Institute of Chemical Physics (LICP), Chinese Academy of
Sciences for generous financial support. Support from CAS
Interdisciplinary Innovation Team was also acknowledged.
We are also thankful for computing resources and time on
the Supercomputing Center, Big Data Center of Gold and
Arid Region Environment and Engineering Research Insti-
tute, Chinese Academy of Sciences.
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(27) The direct attack of boryl group to the carbon center (2-O-Z) via
a four-membered transition state has been considered by DFT
calculation. Although we have tried many times to locate the
transition state, no stable structure could be found. The required C-
B bond could not be formed when the C-O bond cleaves during the
structure optimization, which might due to the less possible four-
membered intramolecular attack.
1
2
3
4
5
6
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8
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n
(21) Other nucleophiles such as PhBpin, hexyl-Bpin and BuLi were
also tested to react with 2aa, in which nBuLi afforded the desired
alkylation product in a 33% yield, suggesting that the alkylation of α-
OBpin boronates could also be achieved with OBpin as the leaving
group. See details in the supporting information.
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from hexane.
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(24) The base effect was re-investigated, see details in the supporting
information.
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O
Nu
Bpin
R'
Nu
Bpin-Bpin / Bpin-
1
R
R'
R
3
1
2
3
4
Deoxygenative gem-diborylation
Deoxygenative gem-silylborylation
B2pin2
LG
5
6
7
8
LG
LG
Nu
Bpin
R
Bpin
Nu
2'
R
R'
R'
Nu
= Bpin
or
SiMe2Ph
2
9
LG
= OBpin
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