Enantioselective Construction of α-Chiral Silanes by Nickel-Catalyzed C(sp3)?C(sp3) Cross-Coupling

Article abstract of DOI:10.1002/anie.201814340

An enantioselective C(sp³)?C(sp³) cross-coupling of racemic α-silylated alkyl iodides and alkylzinc reagents is reported. The reaction is catalyzed by NiCl₂/(S,S)-Bn-Pybox and yields α-chiral silanes with high enantiocontr

Full text of DOI:10.1002/anie.201814340

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Accepted Article
Title: Enantioselective Construction of alpha-Chiral Silanes by Nickel-
Catalyzed C(sp3)-C(sp3) Cross-Coupling
Authors: Hong Yi, Wenbin Mao, and Martin Oestreich
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201814340
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10.1002/anie.201814340
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Enantioselective Construction of α-Chiral Silanes by Nickel-
Catalyzed C(sp3)–C(sp3) Cross-Coupling
Hong Yi+, Wenbin Mao+, and Martin Oestreich*
Abstract: An enantioselective C(sp3)–C(sp3) cross-coupling of
racemic α-silylated alkyl iodides and alkylzinc reagents is reported.
The reaction is catalyzed by NiCl2/(S,S)-Bn-Pybox and yields α-
chiral silanes with high enantiocontrol. The catalyst system does not
promote the cross-coupling of the corresponding carbon analog,
corroborating the stabilizing effect of the silyl group on the alkyl
radical intermediate (α-silicon effect). Both coupling partners can be,
but do not need to be, functionalized and, hence, even α-chiral
silanes with no functional group in direct proximity of the
asymmetrically substituted carbon atom become accessible. This
distinguishes the new method from established approaches to
synthesize α-chiral silanes.
Methods for catalytic asymmetric formation of C(sp3)–Si bonds
have significantly advanced in recent years. Aside from steady
progress in enantio- and regioselective hydrosilylation of α-
olefins as well as α- or β-substituted styrenes,[1] broadly
applicable conjugate additions[2] and allylic substitutions[3] with
silicon (pro)nucleophiles and even enantioselective C–H
silylation[4] have emerged; carbene insertion into Si–H bonds is
another approach that reliably works with high enantiocontrol.[5]
Conversely, the enantioselective synthesis of α-chiral silicon
compounds by transition-metal-catalyzed C(sp3)–Si cross-
coupling[6] is still elusive although racemic protocols have
recently been developed.[7,8] However, enantioselective C(sp3)–
Scheme 1. Enantioselective C–C bond formation for the construction of α-
chiral silanes. CoPc = cobalt(II) phthalocyanine, NMP = N-methylpyrrolidinone,
glyme = DME = 1,2-dimethoxyethane, DMA = N,N-dimethylacetamide.
C(sp2) cross-coupling reactions of α-silylated reactants are
available as an effective alternative. Three decades ago,
Hayashi and co-workers reported a palladium-catalyzed cross-
coupling of a broad range of racemic α-silylated Grignard
For this purpose, we synthesized a variety of new α-halo
reagents and vinyl bromides (Scheme 1, top).[9] Just recently,
alkylsilanes, mainly by 1,2-addition of silicon nucleophiles to
Reisman and co-workers achieved the same bond formation by
aldehydes followed by halogenation (see the Supporting
Information for details).[14] We began our study with optimizing
the cross-coupling of α-iodo alkylsilane rac-1a and alkylzinc
an elegant reductive cross-coupling of racemic α-silylated benzyl
chlorides and vinyl bromides (Scheme 1, top).[10] The outcome of
these reactions are highly enantioenriched allylsilanes. Of
course, these can be converted into alkylsilanes by
hydrogenation but methods for the direct construction of simple
bromide 2a in the presence of different chiral nickel catalysts
(Table 1). To our delight, this model reaction was promoted by
NiCl2·glyme as the precatalyst and (S,S)-Bn-Pybox[15] (L1) as
the chiral ligand, affording the C(sp3)–C(sp3) coupling product
α-chiral alkylsilanes with no functional group in the proximity of
the asymmetrically substituted carbon atom are rare.[11]
3aa in 89% yield and with a good enantiomeric ratio (e.r.) of 93:7
(entry 1). Other Pybox ligands L2–L5 were investigated as well
Encouraged by the state of the art of enantioselective transition-
metal-catalyzed C(sp3)–C(sp3) couplings of racemic alkyl
(entries 2–5). Both yield and enantioselectivity were sensitive to
electrophiles and carbon nucleophiles,[12,13] we embarked on the
the oxazoline substituent R; moderate yields and good
enantioselectivities were obtained for R = iPr and Cy and trace
amounts were observed for R = Ph and tBu. Ligand types such
as bis(oxazolines) (e.g., L6, entry 6), pyridine-oxazolines, and
elaboration of a procedure that enables enantiocontrolled bond
formation between α-silylated alkyl iodides (= α-iodo
alkylsilanes) and alkylzinc reagents (Scheme 1, bottom).
1,2-diamines (e.g., L7, entry 7) did not promote this
transformation, furnishing only trace amounts of the coupling
product (see Scheme S1 in the Supporting Information). A
screening of nickel(II) salts with L1 did not give better results
than NiCl2·glyme/L1 (entries 8–10). Among the many solvents
screened, DME was the best (e.g., entries 11–13). With the
DME/DMA solvent system, 3aa did form in 91% yield and with
e.r. 96:4. Reaction temperatures lower than 10 °C did not
increase the enantioselectivity but were detrimental to the yield
(not shown). A change from iodide in rac-1a to bromide (entry
[*]
[+]
Dr. Hong Yi,[+] W. Mao,[+] Prof. Dr. M. Oestreich
Institut für Chemie, Technische Universität Berlin
Strasse des 17. Juni 115, 10623 Berlin (Germany)
E-mail: martin.oestreich@tu-berlin.de
Homepage: http://www.organometallics.tu-berlin.de
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201814340
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14) or mesylate (entry 15) resulted in low yield and no product
formation, respectively. Control experiments showed that the
nickel salt and the ligand are necessary for this process (entries
16 and 17).
1a–f with substituents in the ortho-, meta-, and para-positions
were compatible with our catalyst system. Several functional
groups were tolerated, and the coupling of furan-2-yl-containing
rac-1g was also successful. Substrates rac-1h–j with linear
aliphatic substitution participated equally well but required
somewhat higher reaction temperature. An isobutyl group as in
rac-1k led to slight erosion in yield while branching closer to the
reactive site as with the cyclohexyl-substituted iodide completely
shut down the reaction (hydrodeiodination was seen; see the
Supporting Information). We note here that α-iodo benzylsilanes
were not included into this survey due to their chemical
Table 1. Selected examples of the optimization.[a]
instability.
A
robustness test[16] further documented the
functional-group tolerance of this transformation (see Scheme
S2 in the Supporting Information).
Entry
Nickel(II) salt
Solvent
L
Yield
[%][b]
e.r.[c]
1
NiCl2·glyme
NiCl2·glyme
NiCl2·glyme
NiCl2·glyme
NiCl2·glyme
NiCl2·glyme
NiCl2·glyme
NiBr2·glyme
Ni(acac)2
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
L1
L2
L3
L4
L5
L6
L7
L1
L1
L1
L1
L1
L1
L1
L1
L1
—
89
93:7
87:13
—
2
53
3
trace
7
4
50:50
87:13
—
5
58
6
trace
trace
88
7
—
8
91:9
77:23
—
9
68
10
11
12
13
14[e]
15[f]
16
17
NiI2
<5
NiCl2·glyme
NiCl2·glyme
NiCl2·glyme
NiCl2·glyme
NiCl2·glyme
—
90
92:8
96:4
91:9
—
Scheme 2. Scope I: Variation of the alkyl group in the α-iodo alkylsilane. [a] A
reaction on a 1.00 mmol scale afforded 3aa with e.r. 93:7 and in 84% isolated
yield. [b] Run at 20 °C.
DME
92 (91)[d]
86
diglyme
DME
10
Additional (un)functionalized alkylzinc reagents 2b–g were
tested with iodide rac-1a as the coupling partner (Scheme 3).
Functional groups include another acetal (2b), ethers (2c and
2d), an ester (2e) and the cyano group (2f). Yields were
generally high and enantioselectivities moderate to good.
Oxidative degradation of 3ag to (S)-1,5-diphenylpentan-2-ol[17]
allowed for the chemical correlation of the absolute
configuration; S configuration was assigned to 3ag. No desired
product was obtained when using a secondary instead of the
above primary alkylzinc bromides (cyclopentylzinc bromide was
used; see Scheme S3). Likewise, arylzinc reagents did not
engage in the cross-coupling under the standard protocol.
However, 32% yield and e.r. 86:14 were reached in the reaction
of α-iodo alkylsilane rac-1a and 4-anisylzinc chloride with
NiCl2·glyme and a pyridine-oxazoline ligand (see Scheme S4 in
the Supporting Information).
DME
—
—
DME
trace
trace
—
NiCl2·glyme
DME
—
[a] All reactions were performed on a 0.10 mmol scale. [b] Determined by
GLC analysis with tetracosane as an internal standard. [c] Determined by
HPLC analysis on
a chiral stationary phase. [d] Isolated yield after
purification by flash chromatography on silica gel. [e] Br instead of I in rac-
1a. [f] MsO instead of I in rac-1a. acac = acetylacetonate, diglyme = 1-
methoxy-2-(2-methoxyethoxy)ethane, Ms = methanesulfonyl.
With the optimized conditions established, we investigated
the scope of the α-iodo alkylsilanes (Scheme 2). In general,
good yields and enantiomeric ratios were achieved for an array
of substrates (rac-1a–k). The 2-phenylethyl-derived iodides rac-
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R
Radical-Clock Experiment
NiCl2·glyme (10 mol%)
R
I
L1 (15 mol%)
O
NiCl2·glyme (10 mol%)
L1
+
O
O
Ph
I
DME/DMA (5:2)
10 °C for 24 h
Si
(15 mol%)
Ph
O
ZnBr
Ph
+
Si
Si
DME/DMA (5:2)
10 °C for 24 h
Ph
Si
8la: 62%, E:Z > 95:5
rac-1a
2b–g
(2.0 equiv)
3ab–ag
ZnBr
2a
(2.0 equiv)
Ph
Si
rac-1l
O
O
OPh
OBn
Probing the -Silicon Effect
NiCl2·glyme (10 mol%)
O
O
O
O
L1 (15 mol%)
I
Ph
Ph
Si
Ph
+
Si
Si
DME/DMA (5:2)
10 °C for 24 h
3ab: 77%, e.r. 91:9
3ac: 80%, e.r. 90:10
3ad: 82%, e.r. 88:12
ZnBr
rac-9
2a
10: not obtained
(2.0 equiv)
CO2Et
CN
Scheme 5. Control experiments.
Ph
Si
Ph
Si
Ph
Si
3ae: 72%, e.r. 87:13[a]
3af: 74%, e.r. 80:20[a]
3ag: 75%, e.r. 86:14
To summarize, we disclosed here an approach to the
synthesis of α-chiral silanes where the asymmetrically
substituted carbon atom is positioned distant from other
functional groups such as C=O or C=C bonds. This has been
achieved by an enantioselective C(sp3)–C(sp3) cross-coupling of
racemic α-silylated alkyl iodides (= α-iodo alkylsilanes) and
alkylzinc reagents. These coupling partners can contain a broad
range of functional groups, and variation of the substitution
pattern at the silicon atom is also possible, thereby enabling the
flexible synthesis of chiral silicon-containing building blocks. The
reaction is catalyzed by a nickel–Pybox system and was shown
to involve carbon-centered radical intermediates.
(chemically correlated)
Scheme 3. Scope II: Variation of the alkylzinc bromide. [a] Run at 20 °C.
Variation of the substitution pattern at the silicon atom was
also possible (Scheme 4). Replacement of the Me2PhSi group
with the sterically more hindered MePh2Si group had no
influence on the outcome (rac-4a→5aa, top). The simple Me3Si
group could also be installed to result in a fully alkyl-substituted
α-chiral silane with no functional group close to the chiral center
(rac-6j→7jc, bottom).
O
O
NiCl2·glyme (10 mol%)
O
O
I
L1 (15 mol%)
Acknowledgements
+
Si
Ph Ph
DME/DMA (5:2)
10 °C for 24 h
ZnBr
Si
Y.H. gratefully acknowledges the Alexander von Humboldt
Foundation for a postdoctoral fellowship (2017–2019), and W.M.
Ph Ph
5aa: 75%, e.r. 96:4
rac-4a
2a
(2.0 equiv)
thanks the China Scholarship Council for
a predoctoral
fellowship (2017–2021). M.O. is indebted to the Einstein
Foundation Berlin for an endowed professorship.
OPh
NiCl2·glyme (10 mol%)
OPh
L1 (15 mol%)
I
+
DME/DMA (5:2)
20 °C for 48 h
Si
ZnBr
Si
Keywords: cross-coupling • nickel • radical reactions • silicon •
synthetic methods
rac-6j
2c
7jc: 51%, e.r. 91:9
(2.0 equiv)
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Suggestion for the Entry for the Table of Contents
COMMUNICATION
H. Yi, W. Mao, M. Oestreich*
Page No. – Page No.
Enantioselective Construction of α-
Chiral Silanes by Nickel-Catalyzed
C(sp3)–C(sp3) Cross-Coupling
Chiral silicon grease. α-Chiral silanes with no functional group (FG) in direct
proximity of the asymmetrically substituted carbon atom are accessible by an
enantioselective C(sp3)–C(sp3) cross-coupling of racemic α-silylated alkyl iodides
and alkylzinc reagents (see scheme). The coupling partners can be, but do not
need to be, functionalized. By this, α-chiral silanes can be prepared with high
modularity.
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