Cobalt-Catalyzed Asymmetric Synthesis of gem-Bis(silyl)alkanes by Double Hydrosilylation of Aliphatic Terminal Alkynes

Article abstract of DOI:10.1016/j.chempr.2019.02.001

Chiral organosilanes are of great value in asymmetric synthesis, functional materials, and medicinal chemistry. Compared with single-silyl compounds, bis(silyl) ones are understudied because of the lack of the efficient synthetic protocols. The development of efficient synthetic approaches to access bis(silyl) compounds is highly desirable for studying their basic properties and potential utilities. Here, a cobalt-catalyzed sequential double hydrosilylation of aliphatic alkynes was developed to synthesize highly enantioenriched gem-bis(silyl)alkanes. This protocol used simple aliphatic alkynes and silanes to construct valuable chiral gem-bis(silyl)alkanes. The control experiments, isotopic labeling experiments, kinetic studies, and density functional theory calculations were conducted to elucidate the reaction mechanism. The synthetic versatility of gem-bis(silyl)alkanes was demonstrated by the synthesis of chiral organosilanols, α-hydroxysilanes through selective C–Si bond transformation and hydrosilylation of alkynes to construct chiral silanes containing adjacent C-stereocenter and Si-stereocenter. Chiral organosilanes are important synthetic intermediates for chiral catalysts, functional materials, and silasubstitution in medicinal chemistry. Because of the absence of highly efficient catalytic synthetic methods, enantiopure polysilyl-substituted compounds are rare and their applications are not well explored. Our methodology enables double hydrosilylation of aliphatic alkynes for the construction of unique chiral gem-bis(silyl)alkanes via cobalt catalysis with excellent chemo-, regio-, and enantioselectivity. We anticipate that this strategy will be a useful tool for synthesis of diverse chiral organosilanes. Furthermore, we also expect the unique gem-bis(silyl)alkanes will be employed not only in stereoselective organic synthesis but also in chiral catalyst and functional materials. A cobalt-catalyzed sequential highly enantioselective double hydrosilylation of aliphatic alkynes for the precise synthesis of chiral gem-bis(silyl)alkanes was achieved. This protocol used relatively simple and available starting materials to construct more valuable products with excellent chemo-, regio- and enantioselectivities. Synthetic versatility of gem-bis(silyl)alkanes was demonstrated by the synthesis of chiral organosilanols and α-hydroxysilanes and hydrosilylation of alkynes to construct chiral silanes. The control experiments, isotopic labeling experiments, kinetic studies, and density functional theory calculations were conducted to elucidate the reaction mechanism.

Full text of DOI:10.1016/j.chempr.2019.02.001

Article
Cobalt-Catalyzed Asymmetric Synthesis of
gem-Bis(silyl)alkanes by Double
Hydrosilylation of Aliphatic Terminal Alkynes
Jun Guo, Hongliang Wang,
Shipei Xing, Xin Hong, Zhan Lu
hxchem@zju.edu.cn (X.H.)
luzhan@zju.edu.cn (Z.L.)
HIGHLIGHTS
Precise synthesis of chiral gem-
bis(silyl)alkanes with dihydro- and
trihydrosilane
Dual cobalt catalysis for
sequential double hydrosilylation
of alkynes
Readily available starting
materials under mild reaction
conditions
The proposed mechanism is
supported by kinetic studies and
DFT calculations
A cobalt-catalyzed sequential highly enantioselective double hydrosilylation of
aliphatic alkynes for the precise synthesis of chiral gem-bis(silyl)alkanes was
achieved. This protocol used relatively simple and available starting materials to
construct more valuable products with excellent chemo-, regio- and
enantioselectivities. Synthetic versatility of gem-bis(silyl)alkanes was
demonstrated by the synthesis of chiral organosilanols and a-hydroxysilanes and
hydrosilylation of alkynes to construct chiral silanes. The control experiments,
isotopic labeling experiments, kinetic studies, and density functional theory
calculations were conducted to elucidate the reaction mechanism.
Guo et al., Chem 5, 1–15
April 11, 2019 ª 2019 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2019.02.001

Please cite this article in press as: Guo et al., Cobalt-Catalyzed Asymmetric Synthesis of gem-Bis(silyl)alkanes by Double Hydrosilylation of
Aliphatic Terminal Alkynes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.02.001
Article
Cobalt-Catalyzed Asymmetric Synthesis
of gem-Bis(silyl)alkanes by Double
Hydrosilylation of Aliphatic Terminal Alkynes
Jun Guo,1,2 Hongliang Wang,1,2 Shipei Xing, Xin Hong, * and Zhan Lu1,3,*
1
1,
SUMMARY
The Bigger Picture
Chiral organosilanes are of great value in asymmetric synthesis, functional
materials, and medicinal chemistry. Compared with single-silyl compounds,
bis(silyl) ones are understudied because of the lack of the efficient synthetic pro-
tocols. The development of efficient synthetic approaches to access bis(silyl)
compounds is highly desirable for studying their basic properties and potential
utilities. Here, a cobalt-catalyzed sequential double hydrosilylation of aliphatic
alkynes was developed to synthesize highly enantioenriched gem-bis(silyl)al-
kanes. This protocol used simple aliphatic alkynes and silanes to construct
valuable chiral gem-bis(silyl)alkanes. The control experiments, isotopic labeling
experiments, kinetic studies, and density functional theory calculations were
conducted to elucidate the reaction mechanism. The synthetic versatility of
gem-bis(silyl)alkanes was demonstrated by the synthesis of chiral organosila-
nols, a-hydroxysilanes through selective C–Si bond transformation and hydrosi-
lylation of alkynes to construct chiral silanes containing adjacent C-stereocenter
and Si-stereocenter.
Chiral organosilanes are
important synthetic intermediates
for chiral catalysts, functional
materials, and silasubstitution in
medicinal chemistry. Because of
the absence of highly efficient
catalytic synthetic methods,
enantiopure polysilyl-substituted
compounds are rare and their
applications are not well
explored. Our methodology
enables double hydrosilylation of
aliphatic alkynes for the
construction of unique chiral gem-
bis(silyl)alkanes via cobalt
catalysis with excellent chemo-,
regio-, and enantioselectivity. We
anticipate that this strategy will be
a useful tool for synthesis of
diverse chiral organosilanes.
Furthermore, we also expect the
unique gem-bis(silyl)alkanes will
be employed not only in
INTRODUCTION
1
–6
Chiral organosilanes are of great value in asymmetric synthesis
and functional
7
–9
materials.
be employed as silicon-containing drugs.
Furthermore, many organosilicon compounds are bioactive and can
1
0–12
To date, several protocols have
been developed to efficiently synthesize chiral organosilanes with carbon-stereo-
genic centers or silicon-stereogenic centers, such as asymmetric hydrosilylation of
1
3–24
25–31
unsaturated bonds,
silicon-hydrogen bond insertions.
bis(silyl) ones are understudied because of the lack of efficient synthetic proto-
desymmetrization of prochiral silanes,
and asymmetric
stereoselective organic synthesis
but also in chiral catalyst and
functional materials.
3
2–34
Compared with single-silyl compounds,
3
5–38
cols.
The development of efficient synthetic processes to access various
bis(silyl) compounds is highly desirable for studying their basic properties and
exploring their potential utilities.
Although sequential double hydrosilylation of alkynes enabled by hydrosilylation of
alkenyl silanes as the key step was considered one of the most ideal methods for syn-
thesizing bis(silyl) compounds because of the challenge of controlling the chemo-,
regio-, and enantioselectivities from multicomponents, double hydrosilylations of
alkynes have been rare. In 2002, Hayashi reported a successive platinum and palla-
dium-cocatalyzed double 1,2-hydrosilylation of arylacetylenes for the synthesis of
1
,2-diols with excellent enantioselectivity; however, the reaction of aliphatic alkynes
1
5
has not been reported (Scheme 1A). Therefore, the development of highly enan-
tioselective double hydrosilylation of aliphatic alkynes is highly desirable.
Chem 5, 1–15, April 11, 2019 ª 2019 Elsevier Inc.
1

Please cite this article in press as: Guo et al., Cobalt-Catalyzed Asymmetric Synthesis of gem-Bis(silyl)alkanes by Double Hydrosilylation of
Aliphatic Terminal Alkynes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.02.001
Scheme 1. Asymmetric Double Hydrosilylation of Alkynes
Because of the low cost, abundance, and low toxicity of cobalt, as well as good func-
3
9–55
tional-group tolerance, cobalt-catalyzed transformation
hot topic in organic chemistry. In 2017, our group reported an example on
CoBr ,Xantphos-catalyzed anti-Markovnikov hydrosilylation of phenylacetylene to
has emerged as a
2
2
0
afford (E)-alkenyl silane. Most recently, during the preparation of our paper, the
Ge group described a cobalt-catalyzed (E)-selective anti-Markovnikov hydrosilyla-
5
6
tion of terminal alkynes. Inspired by the previous works on cobalt-catalyzed
hydrosilylation of alkynes and enantioselective hydrosilylation of unsaturated
2
0–22,24
bonds,
silyl)alkanes enabled by CoBr
here, we developed a highly enantioselective synthesis of gem-bis
(
2
,Xantphos- and CoBr ,OIP (OIP = oxazoline-imino-
2
pyridine)-catalyzed sequential asymmetric double 1,1-hydrosilylation of aliphatic al-
kynes by using a combination of dihydrosilanes and trihydrosilanes as the silyl source
(
Scheme 1B). To realize the above transformation, there lie several challenges: (1)
how to control the reactivity of two different silanes in which dihydrosilanes have a
5
7
similar silicon-hydrogen bond dissociation free energy with trihydrosilanes, (2)
how to control the complicated regioselectivities in the sequential reaction (1,1-
5
8
versus 1,2- versus 2,1- versus 2,2-bis(silyl)alkanes), and (3) how to achieve the
high enantioselectivity in hydrosilylation of 1,2-disubstituted aliphatic alkenes.
RESULTS AND DISCUSSION
Initially, we chose but-3-yn-1-ylbenzene 1a as a simple model substrate, diphenylsi-
lane and phenylsilane as two different silanes. The reaction of 1a with Ph
PhSiH in the presence of 1.0 mol % of CoBr ,Xantphos, 5.0 mol % of cobalt preca-
talyst L1,CoCl2, and 18 mol % of NaBHEt in a solution of toluene (0.5 M) at room
2 2
SiH and
3
2
3
temperature for 24 h was carried out to afford the designed product 2a (Figures
S11 and S92) in 82% yield but with only 9.1% ee and without 1,2-dihydrosilylation
isomer (entry 1, Table 1). With the increased steric hindrance of the group on oxazo-
line (Bn, iPr, and tBu), yields of 2a were decreased from 74% to 27%; however, enan-
tioselectivities were sharply increased from 43.0% to 99.9% (entries 2–4). When
1Department of Chemistry, Zhejiang University,
Hangzhou, Zhejiang 310058, China
2These authors contributed equally
3Lead Contact
2
,4,6-trimethyl-aniline-derived ligand L5 (Figure S10) was used, the yield of 2a
increased slightly (entry 5). When the more hindered 2,6-diisopropyl-aniline-derived
ligand L6 was used, the only product of single hydrosilylation with Ph SiH alkenyl
*
Correspondence: hxchem@zju.edu.cn (X.H.),
luzhan@zju.edu.cn (Z.L.)
https://doi.org/10.1016/j.chempr.2019.02.001
2
2
2
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Aliphatic Terminal Alkynes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.02.001
Table 1. Optimizations
a
b
Entry
[Co]
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Yield of 2a (%)
ee of 2a (%)
9.1
1
2
3
4
5
6
7
8
9
L1,CoCl
L2,CoCl
L3,CoCl
L4,CoCl
L5,CoCl
L6,CoCl
L5,CoBr
L5,CoBr
L5,CoBr
L5,CoBr
L5,CoBr
L5,CoBr
L5,CoBr
L5,CoBr
2
2
2
2
2
2
2
2
2
2
2
2
2
2
82
74
72
27
32
<3
46
17
10
33
26
72
43.0
80.3
99.9
99.9
ꢀ
99.9
99.9
ꢀ
2
Et O
THF
10
11
12
13
14
1,4-dioxane
n-hexane
toluene
toluene
toluene
99.9
99.9
99.9
99.9
ꢀ
c
c,d
d,f
e
84
<1
a
1
Yields were determined by H NMR with TMSPh as an internal standard.
b
ee values were determined by chiral HPLC.
,Xantphos (1 mol %) and L5,CoBr (10 mol %).
c
CoBr
2
2
d
48 h.
e
Isolated yield.
f
3
Without NaBHEt .
silane 3a was observed in 94% yield (entry 6). The yield of 2a was increased to 46%
when cobalt bromide complex was used instead of cobalt chloride complex (entry 7).
After screening a series of solvents, no better results were obtained (entries 8–11).
After the catalyst loading was increased to 10 mol %, the yield of 2a was increased
to 72% (entry 12). The reaction for 48 h afforded 2a in 84% isolated yield (entry 13).
The control reaction without NaBHEt
mediate of alkyne hydrosilylation with PhSiH
However, no designed product was observed (entry 14). The standard conditions are
identified as 0.5 mmol of alkyne, 0.5 mmol of Ph SiH , 0.6 mmol of PhSiH , 1 mol %
of CoBr ,Xantphos, 10 mol % of L5,CoBr (see Data S1), and 33 mol % of NaBHEt in
.0 mL of toluene for 48 h.
3
was also conducted to afford 3a and an inter-
3
3b in 10% and 22% yield, respectively.
2
2
3
2
2
3
1
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Aliphatic Terminal Alkynes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.02.001
Scheme 2. Scope of Chiral Bis(silyl)alkanes
a
Alkynes (0.5 mmol), Ph
2
SiH
2 3 2 2
(0.5 mmol), PhSiH (0.5 mmol), CoBr ,Xantphos (1mol %), and L5,CoBr (10 mol %), 48 h.
b
L
3
,CoBr
2
instead of L5,CoBr .
2
With the optimal reaction conditions in hand, the substrate scope was illustrated
in Scheme 2. First, the scope of silanes was investigated. Various dihydrosilanes
or trihydrosilanes containing electron-donating or withdrawing groups on the phenyl
ring were investigated to afford the corresponding chiral gem-bis(silyl)alkanes
2
b–2g (Figures S13–S23 and S93–S98) in 51%–85% yield with 98% to >99% ee. Inter-
estingly, alkyl silane could also be transformed to chiral silane 2h (Figures S24–S26
and S99) in 78% yield with 98% ee. As far as we know, it is the first time that highly
enantioselective hydrosilylation has been achieved with alkyl trihydrosilane.
4
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Aliphatic Terminal Alkynes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.02.001
Scheme 3. Gram-Scale Reactions
Next, the scope of aliphatic alkynes was also examined. The reactions of substrates
bearing withdrawing substituents 1i and 1j could afford 2i (Figures S26–S27 and
S100) and 2j (Figures S28–S30 and S101) in 76% yield with >99% ee and 61% yield
with 98% ee, respectively. When substrates contained para-, meta-, or ortho-methyl
substituents on the phenyl ring, all of them could be delivered to the corresponding
products 2k–2n (Figures S31–S38 and S102–S105) in 41%–68% yields with 98%
to >99% ee. The polycycle 1-naphthyl (1o) and heterocycle 2-thienyl (1p) could be toler-
ated well to afford 2o (Figures S39, S40, and S106) and 2p (Figures S41, S42, and S107)
in 73% and 58% yield with 99% ee, respectively. Prop-2-yn-1-ylbenzene (1q) reacted
smoothly to afford 2q (Figures S43, S44, and S108) in 82% yield and 96% ee. The influ-
ence of different carbon chain length of aliphatic alkynes was studied to afford 2r–2u
(
Figures S45–S52 and S109–S112) and 2w (Figures S55, S56, and S114) in 50%–82%
yields with 96% to >99% ee. The reaction of substrate bearing cyclopropyl 1v was car-
ried out to give 2v (Figures S53, S54, and S113) in 56% yield and >99% ee with
C
12
H
25SiH
3
instead of PhSiH
3
and with more reactive and less hindered ligand L3
25SiH as a trihydrosilane was that, for
instead of L5. The reason for choosing C12
H
3
some substrates, alkyl trihydrosilane was more reactive than the aryl one under these
catalytic conditions. Substrates bearing various functional groups, such as amide (1x),
ester (1y), free alcohol (1z), halide (1aa), and ethers (1ab and 1ac), were also suitable
to yield the corresponding chiral silanes 2x–2ac (Figures S57–S67 and S115–S120) in
2
5%–84% yields with 98% to >99% ee. There are six examples of which the yields are
around or below 50% (three examples for yield below 50% and three examples for yield
around 50%). For these cases, there are actually around 20% of hydrogenation byprod-
ucts of alkenyl silanes in this transformation (density functional theory [DFT] calculation;
see Figures S7 and S9). It had been reported that the cobalt complex could also pro-
59
mote both hydrogenation and hydrosilylation reaction of alkene with silanes. It might
be the reason why, in these cases, isolated yields of products are around or below 50%.
When phenylacetylene was used, only alkyne hydrosilylation product with Ph
2 2
SiH , i.e.,
(
E)-alkenyl silane, was obtained in 97% yield. We also tried to employ this catalytic sys-
tem to the general internal alkenes. Unfortunately, when pent-3-en-1-ylbenzene was
subjected to this system, no reaction occurred (for details, see Figures S6 and S8 and
Scheme S1). The absolute configuration was verified by X-ray diffraction of the corre-
sponding dihydroxyl silanol 5e (Figure S20; Data S2) of product 2e, and the other prod-
ucts were then assigned by analogy.
To demonstrate the synthetic utility, we conducted gram-scale reactions smoothly
by using 0.5 mol % of CoBr
2
,Xantphos with 2.0 mol % of L
,Xantphos with 0.5 mol % of L ,CoBr for 90 h to afford 2h in
6% yield with 98% ee or 66% yield with 93% ee, respectively (Scheme 3, equation 1).
3 2
,CoBr for 24 h or
0
8
.25 mol % of CoBr
2
3
2
Additionally, the piperidine derivative 1ad and desloratadine derivative 1ae could
also be transformed smoothly under standard conditions to 2ad (Figure S68)
and 2ae (Figure S69) in 65% and 75% yields, respectively (see Supplemental
Information).
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Scheme 4. Derivatizations
2 2
Reaction conditions: (a) catalytic Pd/C (20 wt %), Et O/H O = 10/1, v/v, room temperature (RT),
overnight; (b) KHCO
3
(0.5 equiv), H
2
O
2
(30% aq., 2.0 equiv), MeOH/THF = 1/1, v/v, RT, 5 min; (c)
5
ꢁ
[
(
Ru(h -Cp*)(CH
3
CN)
ꢁ
3
]Cl
2
(4 mol %), DCM, 20 C, 40 h; (d) LiCl (5.0 equiv), 4-OMeC
6
H
4
MgBr
5.0 equiv), THF, 80 C, 41 h; (e) CH
2
I
2
(50 equiv), ZnEt
2
(30 equiv), 1,2-dichloroethane, RT, 40 h; (f)
ꢁ
BF
3
.2AcOH (10 equiv), CHCl
3
, 65 C, 16 h; (g) KF (4.0 equiv), KHCO
3
(4.0 equiv), H
2
O
2
(30% aq.,
ꢁ
2
3 equiv), MeOH/THF = 1/1, v/v, 65 C, 12 h.
6
0
Organosilanols have important applications in various fields, such as in polymetric
materials science, organic synthesis, and medicinal chemistry. The chiral bis(silyl)
6
1
alkane 2a could be completely oxidized to chiral silanols 4a (Figures S12 and
6
2
S122) or selectively oxidized to 5a (Figures S70 and S121) in 76% or 81% yield,
respectively (Scheme 4). The 2a could also undergo ruthenium-catalyzed hydrosily-
lation of alkyne to afford vinyl silane 6 (Figure S71) in 99% yield with a diastereomeric
6
3
ratio (d.r.) of 2.8:1. The reaction of 2a with Grignard reagent gave 7 (Figure S72) in
6
4
24
9
2% yield with a d.r. of 1:1. Interestingly, after being methylated, product 2h
6
5
66
could undergo Fleming-Tamao oxidation to afford chiral a-hydroxysilanes (9)
Figures S74 and S123), which have been utilized for stereocontrolled C–C bond
(
formation.
Because of their unique properties, chiral organosilanes containing a Si-stereocen-
ter have attracted increasing attention in medicinal chemistry and material sci-
2
4,67
ences.
of the most challenging aspects of organosilicon chemistry. Here, using the ob-
tained chiral silanes 2, a CoBr ,Xantphos-catalyzed hydrosilylation of alkynes to
construct chiral silanes containing adjacent C-stereocenter and Si-stereocenter
10) was presented (Scheme 5). A variety of substrates containing functional
However, the synthesis of Si-stereogenic silanes is undoubtedly one
6
8
2
(
groups, such as halogen, ether, ester, amide, alkene, and free alcohol, were toler-
ated well to afford the corresponding products 10a–10l (Figures S75–S86) in 84%–
9
6% yields.
Several control experiments were conducted to elucidate the possible reaction
pathway (Scheme 6). The competitive reaction of 1a with Ph SiH and PhSiH using
mol % of CoBr ,Xantphos as precatalyst and 3 mol % of NaBHEt as reductant in
toluene (0.5 M) for 5 min was carried out to give (E)-b-alkenyl silane 3a in 93% yield
2
2
3
1
2
3
6
9
and (E)-b-alkenyl phenyl silane 3b in trace yield (equation 2, Scheme 6). 3a could
react with PhSiH smoothly to afford 2a in 74% yield with >99% ee under standard
conditions without CoBr ,Xantphos; however, only hydrogenation product 11 was
obtained when 3b reacted with Ph SiH . These two experiments indicated that 3a
might be the reaction intermediate (equations 3 and 4, Scheme 6). Two control
3
2
2
2
6
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Scheme 5. Synthesis of Chiral Silanes Containing Adjacent C- and Si-Stereocenters
The diastereomeric excess of all the substrates is about 11:1.
experiments omitting CoBr
CoBr ,Xantphos, a mixture of product 2a (12% yield), 11 (18% yield), 3a (12%
yield), and a-alkenyl silane 12 (30% yield) was observed (equation 5, Scheme 6);
without L5,CoBr , 2a and 3a were obtained in 13% and 70% yield, respectively
equation 6, Scheme 6). Equations 5 and 6 underscore the challenges in achieving
2 2
,Xantphos or L5,CoBr were conducted: without
2
2
(
the high regio- and enantioselectivities observed in our catalytic system. These
control experiments indicated that the reaction might mainly undergo
CoBr
2
,Xantphos-catalyzed hydrosilylation of aliphatic alkynes with dihydrosilanes
-catalyzed asymmetric hydrosilylation of alkenyl silanes
followed by OIP,CoBr
2
with the trihydrosilanes pathway. Isotopic labeling experiments were also con-
ducted to figure out the possible mechanism (see Supplemental Information for
details).
2 2 2
The hydrosilylation reaction of alkynes and Ph SiH catalyzed by CoBr ,Xantphos is
so fast that the rate-determining step (RDS) is less likely to be involved in this proced-
ure. In order to simplify the complexity, we finally conducted quantitative kinetic
studies of the reaction of 3a with PhSiH
3
to determine the roles of 3a, PhSiH3, and
catalyst at the RDS. Measurements of the initial rates (kin) for the reaction of PhSiH
3
with different concentration of vinyl silane (3a) and catalyst showed a rise in the rates
of the reactions. Plots of kin versus the concentration of vinyl silane (Figures 1A and
S2; Tables S2 and S3) and catalyst (Figures 1B and S4; Tables S6 and S7) gave two
À4
À1
À2
À1
linear curves (slope = 1.59 3 10 Ms ; 4.35 3 10 Ms ), which suggested a
first-order rate dependence on vinyl silane and catalyst (Figures 1A and 1B). Similar
3
kinetic studies on PhSiH showed no change in kin (Figures 1C and S3; Tables S4 and
S5), indicating a zero-order rate dependence on trihydrosilanes. These quantitative
kinetic studies indicate that the vinyl silane coordination and insertion process is the
RDS. Qualitative kinetic studies were also conducted. Measurement of reaction
progress with different additives showed that CoBr
2
,Xantphos had no effect on
this transformation, and the reaction rates were slightly affected negatively by the
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Scheme 6. Control Experiments
addition of 0.4 equiv of 2a into the system, which indicated that there might be a
competition between product and trihydrosilane to form the silyl cobalt species (Fig-
ures 1D and S1; Table S1).
According to the control experiments, deuterium experiments, qualitative and
quantitative kinetic studies, and previous reports on cobalt-catalyzed hydrosilylation
6
2,70–72
of unsaturated bond,
the most likely reaction mechanisms are proposed in
,Xantphos reacts with NaBHEt to form cobalt
Scheme 7. First, the precatalyst CoBr
2
3
hydride species A. Then alkyne undergoes coordination with species A followed
by insertion into a Co–H bond to generate vinyl cobalt species B, which goes
through s-bond metathesis with Ph
balt hydride species A. Vinyl silane 3 can react with silyl cobalt species C, which is
generated by the reaction of OIP,CoBr with PhSiH and NaBHEt , to deliver alkyl
cobalt species D. The vinyl silane coordination and insertion process is the RDS. Spe-
2 2
SiH to afford vinyl silane 3 and regenerate co-
2
3
3
cies D goes through s-bond metathesis with PhSiH
release product 2.
3
to reproduce species C and
The proposed mechanism is supported by DFT calculations. The free-energy
changes of the most favorable pathway of Co-catalyzed sequential hydrosilylations
of but-3-yn-1-ylbenzene are shown in Figure 2. The possible closed-shell singlet,
open-shell singlet, and triplet-spin states were all explored, and the most stable
singlet and triplet state energies are presented. The detailed energies of all spin
states for each stationary point are included in Table S9. From the (Xantphos)CoH
cat1, alkyne coordination leads to the (Xantphos)CoH(alkyne) species int1.
Subsequent hydrometallation via TS1 is facile and irreversible, generating the
alkenylcobalt species int2. This alkenylcobalt species is not stable and un-
dergoes facile s-bond metathesis via TS2 to produce the vinyl silane 3a and
regenerate the active (Xantphos)CoH catalyst. The vinyl silane 3a coordinates to
the (OIP)Co(SiH
2
Ph) cat2, leading to int4. int4 then undergoes the insertion of 3a
via TS3, and subsequent s-bond metathesis of alkylcobalt species int5 produces
8
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Aliphatic Terminal Alkynes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.02.001
Figure 1. Qualitative and Quantitative Kinetic Studies
(
(
(
(
A) A plot of kin versus vinyl silane (3a) concentrations.
B) A plot of kin versus OIP.Co catalyst concentrations.
C) A plot of kin versus phenyl silane concentrations.
D) Time course study of 2a.
the final disilylation product 2a and regenerates cat2. According to the free-energy
changes of the sequential catalytic cycles, the first hydrosilylation with (Xantphos)
CoH is very efficient, and the hydrometalation step vis TS1 determines the rate of
the first hydrosilylation. The secondary hydrosilylation with (OIP)Co(SiH
has the alkene insertion via TS3 and determines the overall rate, with a barrier of
0.1 kcal/mol from int4 to TS3. Comparing the two catalytic cycles, the alkene inser-
2
Ph) cat2
2
tion via TS3 is the rate-limiting step of the dihydrosilylation, which is consistent with
the above kinetic studies.
On the basis of the reaction mechanism, we next explored the regioselectivity of
2
alkene insertion with the (OIP)Co(SiH Ph) catalyst. The competing regioisomeric in-
sertions can occur via TS3 or TS5, leading to the observed regioselectivity (Fig-
ure 3). TS3 is 8.9 kcal/mol more favorable than TS5 in terms of free energy, which
is consistent with the experimental results showing that disilylation exclusively oc-
curs at the same carbon center. The free-energy diagram of the corresponding cat-
alytic cycle involving TS5 is included in Figure S5. The origins of regioselectivity
7
3
were further elucidated by distortion and interaction analysis. The transition-
state structure was separated into two distorted fragments, (OIP)Co(SiH Ph) and
2
vinyl silane. DEdist-cat refers to the energy penalty associated with the geometric
change of the cat2 fragment from the triplet int4 to the corresponding geometry
in TS3 or TS5. DEdist-sub refers to energy required for the geometric change of vinyl
silane in the same process. The interaction energy DEint reflects the stabilizing
interaction between the two distorted fragments in the transition state. From the
distortion and interaction analysis (Figure 3), we found that the interaction energy
Chem 5, 1–15, April 11, 2019
9

Please cite this article in press as: Guo et al., Cobalt-Catalyzed Asymmetric Synthesis of gem-Bis(silyl)alkanes by Double Hydrosilylation of
Aliphatic Terminal Alkynes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.02.001
Scheme 7. The Proposed Mechanisms
is the leading contribution to the preference of TS3. The distortion energies are
similar between the two transition states, suggesting that steric effects play a
limited role in determining the regioselectivity. Therefore, the existing silyl group
of vinyl silane directs the secondary silyl insertion and results in the exclusive dis-
ilylation at the same carbon center.
Conclusions
In summary, a cobalt-catalyzed sequential double hydrosilylation of aliphatic alkynes
was developed to synthesize highly enantioenriched gem-bis(silyl)alkanes. To the
best of our knowledge, this is the first time that this transformation has been
achieved. The protocol used simple aliphatic alkynes and silanes, which were readily
available from large-scale industrial processes or easily synthesized by a variety of
efficient strategies, to construct the more valuable chiral gem-bis(silyl)alkanes. The
synthetic versatility of gem-bis(silyl)alkanes was demonstrated by the synthesis of
chiral organosilanols, a-hydroxysilanes, and hydrosilylation of alkynes to construct
chiral silanes containing adjacent C- and Si-stereocenters. The control experiments,
isotopic labeling experiments, and qualitative and quantitative kinetic studies were
conducted to figure out the primary mechanism. DFT calculations were performed
to elucidate the reaction mechanism and the origins of the regioselectivities. The pri-
mary mechanistic studies illustrated that the reaction might mainly undergo
CoBr
2
,Xantphos-catalyzed hydrosilylation of aliphatic alkynes with dihydrosilanes
-catalyzed asymmetric hydrosilylation of (E)-b-alkenyl silanes
followed by OIP,CoBr
2
within the trihydrosilane pathway. Further studies will focus on exploring the poten-
tial utility of this unique chiral gem-bis(silyl)alkanes in materials science and
pharmaceuticals.
EXPERIMENTAL PROCEDURES
Full experimental procedures are provided in the Supplemental Information.
Computational Details
7
4
All DFT calculations were performed with the Gaussian 09 program. Geometry
7
5–77
optimizations were carried out with the B3LYP
-D3 (Becke-Johnson damping
7
8,79
80
function)
functional and def2-SVP basis sets for all elements. The vibrational
frequency was calculated at the same level of theory to identify each optimized
stationary point as an energy minimum or a transition state and to evaluate the
zero-point vibrational energy and thermal corrections at 298 K. On the basis of
the gas-phase optimized structures, the single-point energies and solvent effects
10
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Aliphatic Terminal Alkynes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.02.001
Figure 2. Free-Energy Diagram for the Most Favorable Reaction Pathways of Sequential Hydrosilylations of But-3-yn-1-ylbenzene
Spin states are shown in parentheses. OSS refers to open-shell singlet, and CSS refers to closed-shell singlet.
8
1
of toluene were calculated with the B3LYP-D3 functional and def2-TZVP basis sets
8
2
for all elements in the SMD solvent model. The 3D diagrams of computed species
8
3
were generated by CYLView. Stability of wavefunction was confirmed for all orga-
nocobalt species.
Because the thermal corrections are based on the ideal gas model, this approach
ignores the solvent suppression on the rotational and translational freedoms of
solutes, resulting in overestimation of entropy contributions to the reaction free
8
4,85
energies in solution.
To correct the entropy change in solution, we applied
8
6
an empirical approach proposed by Martin and co-workers because there is
currently no widely accepted quantum-mechanics-based approach to correct en-
tropy in solution. For each component change in a reaction at 298 K and 1 atm,
a correction of 4.3 kcal/mol is applied to the reaction free energy (i.e., a reaction
from m- to n-components has an additional free-energy correction for (n À m) 3
4
.3 kcal/mol). This approach has been validated through a number of computa-
tional and experimental studies. Yu and co-workers have found that the entropy
corrections are overestimated by about half in several cyclo-addition reac-
8
7–89
tions.
free-energy changes in a number of metal-catalyzed reactions by using the empir-
Wang and co-workers have discovered the improved description of
9
0–93
ical approach from Martin.
In order to adjust the Gibbs free energies from 1
atm to 1 mol/L, a correction of RTln(cs/cg) (1.9 kcal/mol) is added to energies of
all species. cs is the standard molar concentration in solution (1 mol/L), cg is the
standard molar concentration in the gas phase (0.0446 mol/L), and R is the gas
constant. Data from the zero-point correction (ZPE), thermal correction to enthalpy
(
TCH), thermal correction to Gibbs free energy (TCG), energies (E), enthalpies (H),
and Gibbs free energies (G) (in Hartree) of the structures for all the figures calcu-
lated are shown in Table S8. Cartesian coordinates of the calculated species are
shown in Table S10.
DATA AND SOFTWARE AVAILABILITY
The crystallography data have been deposited at the Cambridge Crystallographic
2
Data Center (CCDC) under accession numbers CCDC: 1435434 (L5,CoBr ) and
Chem 5, 1–15, April 11, 2019
11

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Aliphatic Terminal Alkynes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.02.001
Figure 3. Optimized Structures, Energies, and Distortion and Interaction Analysis of the Regioisomeric Insertion Transition States with Vinyl Silane
Energy barriers in kcal/mol are compared to those of triplet int4. All hydrogens are omitted for clarity.
CCDC: 1845310 (5e) and can be obtained free of charge from http://www.ccdc.cam.
ac.uk/getstructures.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found with this article online at https://doi.org/10.
1
016/j.chempr.2019.02.001.
ACKNOWLEDGMENTS
We are grateful for financial support from National Natural Science Foundation of
China (21772171 and 21472162 to Z.L.; 21702182 and 21873081 to X.H.), the Nat-
ural Science Foundation of Zhejiang Province (LR19B020001 to Z.L.), the National
9
73 Program (2015CB856600 to Z.L.), the Fundamental Research Funds for the Cen-
tral Universities (2018QNA3009 to Z.L.), and Zhejiang University K.P. Chao’s High
Technology Development Foundation (to Z.L.) and the Chinese ‘‘Thousand Youth
Talents Plan’’ (to X.H.). Calculations were performed on the high-performance
computing system at the Zhejiang University Department of Chemistry. We thank
Mr. Jiyong Liu at Zhejiang University for helping with X-ray diffraction analysis and
reviewers for their constructive suggestions.
AUTHOR CONTRIBUTIONS
Conceptualization, Z.L. and J.G.; Methodology, Z.L., J.G., and H.W.; Investigation,
J.G., H.W., and S.X.; Writing - original draft, J.G. and H.W.; Writing - review & edit-
ing, Z.L., X.H., J.G., and H.W.; Funding Acquisition, Z.L. and X.H.; Supervision, Z.L.
and X.H.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: August 22, 2018
Revised: November 18, 2018
Accepted: January 31, 2019
Published: February 28, 2019
12
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Aliphatic Terminal Alkynes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.02.001
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Please cite this article in press as: Guo et al., Cobalt-Catalyzed Asymmetric Synthesis of gem-Bis(silyl)alkanes by Double Hydrosilylation of
Aliphatic Terminal Alkynes, Chem (2019), https://doi.org/10.1016/j.chempr.2019.02.001
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