Transition Metal Catalysis
Nickel-Catalyzed, Reductive C(sp3)Si Cross-Coupling of a-Cyano
Alkyl Electrophiles and Chlorosilanes
Liangliang Zhang and Martin Oestreich*
Abstract: A nickel/zinc-catalyzed cross-electrophile coupling
of alkyl electrophiles activated by an a-cyano group and
chlorosilanes is reported. Elemental zinc is the stoichiometric
reductant in this reductive coupling process. By this, a C(sp3)
Si bond can be formed starting from two electrophilic reactants
whereas previous methods rely on the combination of carbon
nucleophiles and silicon electrophiles or vice versa.
Transition-metal-catalyzed C(sp3)Si bond formation[1] by
cross-coupling of either carbon nucleophile/silicon electro-
phile[2] or carbon electrophile/silicon (pro)nucleophile[3–5]
combinations has seen substantial progress in recent years
but several challenges remain (Scheme 1, top). For example,
asymmetric versions are currently limited to copper-cata-
lyzed, SN2-type reactions of activated alkyl electrophiles with
boron-based silicon pronucleophiles[4] or uncatalyzed dis-
placements of unactivated alkyl electrophiles with metalated
silicon reagents.[6] Another open task is to combine carbon
and silicon electrophiles in reductive coupling reactions not
requiring any preceding metalation of either coupling part-
ner. Last year, such a reductive process was described for
C(sp2)Si bond formation starting from vinyl and aryl
triflates/halides by Shu and co-workers (Scheme 1,
bottom).[7,8] Shus procedures rely on nickel(II) bipyridine
complexes as precatalysts and elemental manganese as the
stoichiometric reductant. A requirement of this broadly
applicable method is that the chlorosilane must be substituted
with a vinyl group to enhance its coordination ability to the
nickel catalyst. A related C(sp3)Si bond-forming reaction is
not known to date. We disclose here a nickel-catalyzed cross-
electrophile coupling[9] of an activated alkyl electrophile[4a,10]
and various chlorosilanes (Scheme 1, bottom).
We started with the reaction of a-triflyloxy nitrile 1aand
vinyl-substituted chlorosilane 2a(Table 1). Extensive exami-
nation of the reaction parameters revealed that the combi-
nation of (Ph3P)2NiCl2/L3 and elemental zinc in DMA is
optimal (see Tables S1–S4 in the Supporting Information for
details). The a-silyl nitrile 3aawas obtained in 76% isolated
yield at room temperature (entry 1). Control experiments
showed that the stoichiometric reductant zinc and the nickel
catalyst are needed; with no additional ligand the yield was
lower (entries 2–4). Other bipyridine ligands such as L1 and
L2 as well as terpyridine L4 did not give any improvement
over L3 (entries 5–7); the yield collapsed when using 1,10-
phenanthroline (L5; entry 8). Replacing zinc by manganese
resulted in a lower yield (entry 9). Related a-cyano alkyl
electrophiles with chloride and bromide leaving groups
afforded 3aa also in good yields (entries 10 and 11). The
reactions were routinely run at room temperature, and no
significant effect was seen at higher or lower reaction
temperature (entries 12 and 13). Of note, the attempted
reductive coupling of unactivated alkyl electrophiles such as
3-phenylpropyl trifluoromethanesulfonate and cyclohexyl
bromide did not lead to the formation of the desired product
(not shown).
With the optimized setup in hand, we tested other
chlorosilanes (Scheme 2). Consistent with Shus results,[7]
trivinylchlorosilane (2b) brought about an isolated yield in
the range of that obtained with 2a. However, trialkylchloro-
silanes 2c and 2d devoid of the nickel-coordinating vinyl
group also participated in this reductive cross-coupling; 3ac
Scheme 1. Methods of transition-metal-catalyzed CSi bond forma-
tion. DMF=N,N-dimethylformamide, Tf=trifluoromethanesulfonyl.
[*] L. Zhang, Prof. Dr. M. Oestreich
Institut fr Chemie, Technische Universitt Berlin
Strasse des 17. Juni 115, 10623 Berlin (Germany)
E-mail: martin.oest[email protected]
Homepage: http://www.organometallics.tu-berlin.de
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202107492.
2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
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How to cite: Angew. Chem. Int. Ed. 2021,60, 18587–18590
International Edition: doi.org/10.1002/anie.202107492
German Edition: doi.org/10.1002/ange.202107492
18587Angew. Chem. Int. Ed. 2021,60, 18587 –18590 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
and 3ad did form in 33% and 40% yield, respectively. This
stands in contrast to Shus report[7] and is remarkable in the
sense that especially Me3SiCl (2d) is an often-used additive in
nickel-catalyzed, reductive cross-coupling reactions but with-
out any C-Si coupling products being observed.[11] Chlorosi-
lanes bearing a phenyl ring or a tert-butyl group on the silicon
atom did not lead to the a-cyano silane but instead converted
into the corresponding disilane and disiloxane (not shown).
Proceeding with vinylchlorosilane 2a as the electrophilic
silicon reactant, we subjected various a-triflyloxy nitriles 1b–r
to the general procedure (Scheme 3). Derivatives of model
substrate 1a with halogenation at the aryl group reacted in
good yields (1b,c!3ba,ca); no cross-electrophile coupling of
the aryl bromide in 1cto form a C(sp2)Si bond was observed.
Substrate 1dcontaining a furyl unit instead of the aryl group
converted equally well into the desired product 3da. Sub-
strate 1e with a longer alkyl tether than in 1a–dled to
a similar result (1e!3ea). Further substrates with different
kinds of functional groups such as a primary alkyl bromide as
in 1f, various esters as in 1g–i, an ether as in 1j, and
unsaturation as in 1k,lwere tolerated in moderate to good
yields. Conversely, a linear alkyl residue resulted in a lower
yield (1m!3ma) while substrates with 2
8
and 3
8
alkyl groups
generally displayed better reactivity to the reductive coupling
(1n–r!3na–ra).
To learn whether this reductive coupling proceeds
through a radical intermediate, we added excess 2,2,6,6-
tetramethylpiperidin-1-oxyl (TEMPO) to the model reaction
(1a!3aa; Scheme 4, top); there was hardly any effect on the
Table 1: Selected examples of the optimization.[a]
Entry Variation Yield [%][b]
1 None 90 (76)[c]
2 w/o Zn 0
3 w/o (Ph3P)2NiCl20
4 w/o L3 70
5L1 instead of L3 85
6L2 instead of L3 80
7L4 instead of L3 76
8L5 instead of L3 5
9 Mn instead of Zn 54
10 Cl instead of OTf 80
11 Br instead of OTf 75
12 0
8
C instead of RT 83
13 40
8
C instead of RT 81
[a] All reactions were performed on a 0.20 mmol scale. [b] Determined by
GLC analysis with tetracosane as an internal standard. [c] Isolated yield
after purification by flash chromatography on silica gel. DMA=N,N-
dimethylacetamide.
Scheme 2. Scope I: Variation of the chlorosilane. All reactions were
performed on a 0.20 mmol scale with the isolated yield determined
after flash chromatography on silica gel. [a] Value in parentheses for
reaction on a 1.0 mmol scale.
Scheme 3. Scope II: Variation of the a-triflyloxy nitrile. All reactions
were performed on a 0.20 mmol scale with the isolated yield deter-
mined after flash chromatography on silica gel. Boc=tert-butoxycar-
bonyl, Bz=benzoyl, Piv=pivaloyl.
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yield. A radical-probe experiment was done with cyclopropyl-
substituted 1s (middle). While the yield of 3sa was low, no
ring-opening product was detected (gray box). The corre-
sponding a-bromo nitrile led to the same outcome, furnishing
3sain 21% yield (see the Supporting Information for details).
Also, there was no competing radical cyclization seen in the
cross-electrophile coupling of 1k and 2a (see Scheme 3). In
turn, the reaction of (R)-1a (99% ee)[4a] under the standard
reaction conditions led to complete racemization (bottom),
proving that the reductive coupling reaction is not stereospe-
cific (cf. Ref. [4a]). The involvement of silyl radicals seems
unlikely as no disilane was detected by GC-MS analysis when
using vinyl-substituted chlorosilane 2a. Moreover, trapping of
the possible silyl radical with added alkenes was unsuccessful
(not shown).
On the basis of the above results and previously reported
mechanistic proposals,[12] we envision the Ni0!NiII!NiI!
NiIII!NiI!Ni0catalytic cycle outlined in Scheme 5. Oxida-
tive addition of the C(sp3)X bond in 1to an in situ-generated
nickel(0) complex results in the formation of an alkylnickel-
(II) intermediate. This is the step where racemization could
occur despite lack of evidence for radical intermediates (cf.
Scheme 4).[11a,12a] One-electron reduction by zinc metal gives
an alkylnickel(I) intermediate to which the SiCl bond of 2
oxidatively adds. The resulting alkyl(silyl)nickel(III) complex
undergoes reductive elimination with formation of the C-
(sp3)Si bond in 3. The released nickel(I) complex will be
eventually reduced to nickel(0) by the zinc reductant. An
alternative order of events, that is oxidative addition of the
chlorosilane 2prior to that of the activated alkyl triflate 1,
cannot be ruled out at this stage.
To summarize, we introduced herein a nickel/zinc-cata-
lyzed cross-electrophile coupling of a-cyano alkyl electro-
philes and chlorosilanes to construct C(sp3)Si bonds. It is the
first example of a reductive cross-coupling of an sp3-hybrid-
ized carbon and a silicon electrophile. The method provides
access to a range of a-silylated nitriles which can, for example,
be further employed in Hiyama cross-coupling reactions.[13]
The extension to unactivated alkyl electrophiles and the
development of asymmetric version are currently under
investigation in our laboratory.
Acknowledgements
L.Z. thanks the China Scholarship Council for a predoctoral
fellowship (2017–2021), and M.O. is indebted to the Einstein
Foundation Berlin for an endowed professorship. Open
access funding enabled and organized by Projekt DEAL.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: cross-coupling · nickel · silicon · synthetic methods ·
zinc
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Manuscript received: June 5, 2021
Accepted manuscript online: July 2, 2021
Version of record online: July 16, 2021
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