Nickel-catalyzed insertions of vinylidenes into Si-H bonds

Article abstract of DOI:10.1039/d0cc05970f

A nickel-catalyzed reductive cyclization of 1,1-dichloroalkenyl silanes is reported. The products of this reaction are unsaturated five-or six-membered silacycles. Intermolecular variants are also described, providing access to trisubstituted vinyl silanes that are not accessible by alkyne hydrosilylation or sila-Heck-type processes. A variety of silanes can be utilized, including those that serve as nucleophilic partners in Hiyama cross-coupling reactions. Mechanistic studies using deuterium-labelled silanes are described. This journal is

Full text of DOI:10.1039/d0cc05970f

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Nickel-Catalyzed Insertions of Vinylidenes into Si–H Bonds
Sourish Biswas,‡ Sudipta Pal,‡ and Christopher Uyeda*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A nickel-catalyzed reductive cyclization of 1,1-dichloroalkenyl on myriad factors, such as the tether length, the substitution
silanes is reported. The products of this reaction are unsaturated pattern of the π-bond, steric effects, and the presence of
five- or six-membered silacycles. Intermolecular variants are also functional groups that impart electronic bias.
described, providing access to trisubstituted vinyl silanes that are
not accessible by alkyne hydrosilylation or sila-Heck-type
processes. A variety of silanes can be utilized, including those that
serve as nucleophilic partners in Hiyama cross-coupling reactions.
Mechanistic studies using deuterium-labelled silanes are described.
A. Carbon-to-Silicon Substitutions in Medicinal Chemistry
NMe2
HO
Si
O
HO
N
Cl
Si
OMe
Substitutions of carbon for silicon have attracted the
interest of medicinal chemists as an avenue to optimize the
potency and pharmacokinetic properties of lead compounds
(Figure 1a).1 The larger atomic radius of silicon causes subtle
changes in geometry and conformation, impacting target
binding affinity.2 Silicon substitution generally increases
lipophilicity, which can improve cellular uptake with polar
compounds.3 Finally, the incorporation of silicon into five- and
six-membered rings blocks oxidative aromatization, a common
metabolic liability.4 Despite these potential benefits, the effect
of silicon substitution is often unpredictable, and there are
currently no silicon-containing drugs and only a few silicon-
containing agrochemicals5 that have successfully reached
market. Future investigations of silicon in biologically active
molecules will depend on the availability of robust synthetic
methods that facilitate the construction of Si–C bonds.6
Unsaturated silicon heterocycles are commonly synthesized
using intramolecular C–C bond forming reactions, where silicon
is incorporated into the acyclic precursor as a tethering atom.7
Alternatively, direct intramolecular Si–C coupling can be carried
out using an alkyne hydrosilylation8 or a sila-Heck type process
(Figure 1b).9 In both of these approaches, endo and exo
cyclization modes are possible, and the selectivity is dependent
F
sila-haloperidol
sila-venlafaxine
B. Intramolecular C–Si Coupling Reactions Forming Unsaturated Silacycles
Sila-Heck reaction
Cl
Si
R
R
+
Si
Si
R
R
R
R
Hydrosilylation
exo
endo
H
Si
R
R
C. Catalytic Vinylidene Si–H Insertion
Cl
n
Ni catalyst
reductant
n
H
Cl
H
Si
Si
R
R
R
R
Figure 1. Nickel-catalyzed reductive insertions of 1,1-dichloroalkenes into Si–H bonds as
a route to unsaturated silacycles.
Recently, we have showed that transition metal vinylidene
complexes can be generated from 1,1-dichloroalkenes and a
metal reductant such as Zn.10 We reasoned that the
intramolecular insertion of such M=C=CR2 species into a Si–H
bond11 would yield an unsaturated silacycle without the
regioselectivity issues that arise with additions across alkenes
and alkynes. To that end, we report here a nickel-catalyzed
reductive cyclization of 1,1-dichloroalkenyl silanes to form five-
and six-membered silacycles (Figure 1c). The catalytic reductive
Department of Chemistry, Purdue University, 560 Oval Dr., West Lafayette, IN,
USA.
E-mail: cuyeda@purdue.edu
‡ These authors contributed equally.
Electronic Supplementary Information (ESI) available: experimental procedures,
characterization data, and spectra. See DOI: 10.1039/x0xx00000x
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Si–H insertion can also be carried out in an intermolecular
With optimized conditions in hand, we investigated the
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context to provide trisubstituted vinyl silanes, which are not substrate scope of the reaction (FiguDreOI:21)0..10F3iv9e/D-0CaCn0d59s7i0xF-
accessible by alkyne hydrosilylation.
membered rings could be generated in high yield. Two
examples of seven-membered ring-forming reactions were
demonstrated, providing products 11 and 15 in modest yields
of 29% and 40%, respectively. The substituents on Si could be
alkyl, aryl, or a combination of the two.
Table 1. Catalytic reductive insertions of vinylidenes into Si–H bonds: effect of reaction
parameters.
Cl
Ni(dme)Cl2 (5 mol%)
(±)-t-BuQuinox ( ) (6 mol%)
3
Cl
H
Si
H
Zn (4.0 equiv)
16 h, rt
Ni(dme)Cl2 (5 mol%)
Si
Ph
Ph
(±)-t-BuQuinox ( ) (6 mol%)
Cl
Ph
Ph
3
1:3 DMA/Et2O
1
2
n
H
Cl
H
Si
Zn (4.0 equiv)
16 h, rt
Standard Conditions
n Si
1:3 DMA/Et2O
O
Bn
O
O
O
N
N
Me
N
N
N
N
Si
Si
Si
Si
Ph
Me
Ph
Ph
Bn
Ph
Ph
Ph
Ph
t-Bu
t-Bu
t-Bu
Bn
(±)-t-BuQuinox (
)
Pyrox (
)
9
10
2
11
, 68% Yield
, 93% Yield
Me
, 87% Yield
, 29% Yield
3
4
5
Biox ( )
Ph
NC
Ph
Me
N
i-Pr
O
N
Ph
N
Si
Si
N
N
Si
Si
Ph
Ph
Ph
Ph
N
Ph
Ph
Ph
Ph
i-Pr
a
a
12
13
14
15
, 40% Yield
, 58% Yield
, 92% Yield
, 86% Yield
DIPP
Ph
6
7
8
Phen ( )
BenzoQuinox (
)
IP (
)
PinB
Entry Deviation from Standard Conditionsa
Yield (2)
91%
0%
O
1
2
none
No Zn
Si
Si
3
4
No Ni(dme)Cl2
No (±)-t-BuQuinox (3)
0%
0%
Et
Et
Ph
Ph
Si
Ph
Ph
5
6
7
8
9
10
11
Mn instead of Zn
85%
36%
50%
17%
83%
45%
43%
b
b
16
17
18
, 38% Yield
, 75% Yield
, 52% Yield
DMA only instead of Et2O/DMA
t-BuPyrox (4) instead of 3
BnBiox (5) instead of 3
BenzoQuinox (6) instead of 3
DIPPIP (7) instead of 3
PhPhen (8) instead of 3
BnO
Cl
Si
Si
Ph
Ph
Ph
Ph
Si
Ph
Ph
aReaction conditions: 1 (0.1 mmol, 1.0 equiv), Ni(dme)Cl2 (0.05 equiv), (±)-t-
BuQuinox (0.06 equiv), Zn (4.0 equiv), DMA (0.2 mL), Et2O (0.6 mL), rt, 16 h. Yields
were determined by 1H NMR integration against a mesitylene internal standard.
b
b
b
19
20
21
, 66% Yield
, 32% Yield
, 73% Yield
Figure 2. Substrate scope studies. Reactions were conducted using the standard
conditions shown in Table 1. a10 mol% catalyst loading. b20 mol% catalyst loading; 50 °C
temperature
The dichloroalkenyl silane 1 was selected as a model
substrate for the development of a catalytic reductive
vinylidene Si–H insertion reaction. Under optimized conditions,
Intermolecular variants of the vinylidene Si–H insertion
were also investigated (Figure 3a). In order to obtain high yields,
it was necessary to make minor modifications to the reaction
conditions developed for the intramolecular reaction: the
catalyst loading was increased from 5 mol% to 10 mol%, the co-
solvent was changed from Et2O to THF, and the reaction
temperature and concentration were increased. Under this set
of conditions, vinylsilane 22 was obtained in 75% yield from a
(
t-BuQuinox)NiCl2 (5 mol%) promotes the cyclization of 1 to form
the six-membered unsaturated silacycle 2 in 91% yield (entry 1).
Control experiments indicated that the reductant, metal source,
and supporting ligand are required for the reaction to proceed.
Mn is a viable reductant but is slightly less effective than Zn
(entry 5). A combination of Et2O and a polar amide solvent, such
as DMA, gave the highest yields, and the use of DMA alone
resulted in a significant decrease in product formation (entry 6).
t-BuQuinox (3) proved to be the optimal ligand. However, other
bidentate nitrogen-donor ligands also promoted the formation
of 2, with yields ranging from 17–83% (entry 7-11).
tropinone-derived
1,1-dichloroalkene
and
dimethylphenylsilane. Other tertiary silanes and other ketone-
derived 1,1-dichloroalkenes also proved to be viable as reaction
partners. Benzyldimethylsilane could be used as a substrate,
and the Si–H insertion product can engage in Hiyama cross-
coupling reactions (Figure 3b).12
2 | J. Name., 2012, 00, 1-3
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Sequential C–Si bond-forming reactions were carried out appears to be inconsistent with a concerted insertion of a metal
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DOI: 10.1039/D0CC05970F
using a secondary organosilane. Catalytic hydrosilylation of vinylidene into the Si–H bond, regardless of whether the
methyl eugenol (32) using diphenylsilane yielded a primary insertion is rate-determining or occurs in a fast step following
organosilane,13 which could then be used in an intermolecular rate-determining generation of the metal vinylidene.15,16
Si–H insertion reaction to form 32 in 47% yield over two steps
(Figure 3c).
Interestingly, scrambling was observed when a reaction was
carried out using a 1:1 mixture of PhMe2SiH and Ph2MeSiD
(Figure 4c). The PhMe2Si-substituted product contains 30% D,
and the Ph2MeSi-substituted product is correspondingly
enriched in H. When the PhMe2SiH/Ph2MeSiD mixture was
subjected to the standard catalytic conditions in the absence of
the 1,1-dichloroalkene 34, H/D scrambling was also observed,
indicating that the catalyst is able to activate the Si–H bond
without having to generate a metal vinylidene. One scenario
that would be consistent with both the KIE and scrambling
experiments is a pre-equilibrium Si–H oxidative addition that
occurs prior to the rate-limiting step. This rate-limiting step
could involve activation of the 1,1-dichloroalkene or formation
of the C–Si bond.
A. Intermolecular Vinylidene Si H Insertion Reactions
–
Ni(dme)Cl2 (10 mol%)
Cl
H
(±)-t-BuQuinox ( ) (12 mol%)
3
H
Si
+
Si
Cl
Zn (4.0 equiv)
16 h, 50 °C
(1.0 equiv)
(1.1 equiv)
1:3 DMA/THF
SiPh2Me
O
22
23
24
25
[Si] = SiPhMe2
[Si] = SiPh3
, 75% Yield
, 61% Yield
, 59% Yield
, 72% Yield
EtO
N
[Si] = Si(OEt)2Me
[Si] = SiBnMe2
O
A. Deuterium Labelling Experiment
>99% D
[Si]
26
, 73% Yield
D
SiPh2Me
Cl
Cl
Ni(dme)Cl2 (10 mol%)
SiPh2Me
(±)-t-BuQuinox ( ) (12 mol%)
3
SiPh2Me
Si
F
F
N
O
+
MePh2Si
D
Ph
Ph
O
Zn (4.0 equiv)
16 h, 50 °C
(1.1 equiv)
O
O
O
1:3 DMA/THF
26-d
1, 77% Yield
33
27
28
29
, 34% Yield
, 49% Yield
, 41% Yield
(1.0 equiv)
B. Hiyama Cross-Coupling of the Vinylidene Si H Insertion Product
–
B. Competition Kinetic Isotope Effect Experiment
50% D
O
O
H/D
SiPh2Me
1. TBAF, THF
EtO
EtO
Cl
Cl
N
N
+
+
MePh2Si
H
Ni(dme)Cl2 (10 mol%)
(±)-t-BuQuinox ( ) (12 mol%)
3
2. Pd2(dba)3 (2.5 mol%)
Ar–I (1.5 equiv)
(10.0 equiv)
SiBnMe2
Ar
Zn (4.0 equiv)
16 h, 50 °C
1:3 DMA/THF
KIE = 1.0
O
MePh2Si
D
O
O
Ar =
25
30
, 54% Yield
(10.0 equiv)
26
, 78% Yield
33
Me
(1.0 equiv)
C. Sequential Hydrosilylation and Vinylidene Si H Insertion
–
C. Crossover Experiment
30% D
1. Hydrosilylation with:
Ph
Ph
H/D
SiPhMe2
Si
OMe
OMe
OMe
OMe
Ph2SiH2
Cl
Cl
+
+
Me2PhSi
H
Ni(dme)Cl2 (10 mol%)
2. Si–H Insertion with:
Cl
(±)-t-BuQuinox ( ) (12 mol%)
34
3
(0.55 equiv)
O
N
32
, 47% Yield
over 2 steps
31
Zn (4.0 equiv)
16 h, 50 °C
Cl
+
MePh2Si
D
O
O
OEt
EtO
N
H/D
SiPh2Me
1:3 DMA/THF
(0.55 equiv)
33
O
(1.0 equiv)
70% D
Figure 3. (a) Intermolecular vinylidene Si–H insertion reactions, providing trisubstituted
vinylsilanes. (b) Synthesis of a vinylsilane that can be utilized as a nucleophilic partner in
a Hiyama cross-coupling reaction. (c) Sequential hydrosilylation and vinylidene Si–H
insertion reactions of a secondary organosilane.
26
O
Figure 4. Mechanistic studies using a deuterium-labelled silane.
In summary, (Quinox)Ni catalysts promote reductive
insertions of 1,1-dichloroalkenes into Si–H bonds. One synthetic
application of this transformation is in the synthesis of
unsaturated five- and six-membered silacycles. Additionally,
moderate yields were obtained for the synthesis of seven-
membered silacycles, which have not previously been prepared
by other methods of ring-closure. Ongoing investigations are
aimed at elucidating the mechanism of Si–H insertion and
extending this reactivity to other bond insertion reactions.
Experiments using a deuterium labelled silane were carried
out in order to gain insight into the mechanism of Si–H
insertion.14 As expected, the reaction between 1,1-
dichloroalkene 34 and Ph2MeSiD yielded product 26-d1 with
>99% deuterium incorporation at the vinyl position (Figure 4a).
A kinetic isotope effect (KIE) competition experiment was
carried out using a 1:1 mixture of Ph2MeSiH and Ph2MeSiD
(Figure 4b). The product (26) contained a 1:1 mixture of H and
D at the vinyl position, indicating a kH/KD of 1.0. This result
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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14 E. M. Simmons and J. F. Hartwig, Angew. Chem., VInietw. AErdtic.,le2O0n1lin2e,
This research was supported by the NIH (R35 GM124791).
C.U. acknowledges support from a Camille Dreyfus Teacher–
Scholar award and a Lilly Grantee award. We thank Annah Kalb
and Celia He for helpful discussion and experimental assistance.
51, 3066-3072.
DOI: 10.1039/D0CC05970F
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Conflicts of interest
There are no conflicts to declare.
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DOI: 10.1039/D0CC05970F
Ni Catalyst
Cl
SiR3
H
SiR3
+
reductant
Cl
H
Vinylidene Si–H Insertion
O
H
EtO
N
Ph
Ph
H
Si
SiBnMe2
Intramolecular
Intermolecular
Nickel catalysts promote intramolecular and intermolecular reductive insertions of 1,1-dichloroalkenes
into Si–H bonds.