Enantioconvergent and Regioselective Synthesis of Allenylsilanes by Nickel-Catalyzed C(sp2)-C(sp3) Cross-Coupling Starting from Racemic α-Silylated Propargylic Bromides

Article abstract of DOI:10.1021/acs.organomet.1c00112

A direct synthesis of enantioenriched allenylsilanes from racemic α-silylated propargylic bromides by an enantioconvergent nickel-catalyzed cross-coupling is reported. The high regioselectivity is governed by the bulky silyl group, and the C(sp²)-C(sp³) bond formation occurs exclusively at the γ-position of the propargyl electrophile. The level of enantioselection induced by a chiral Pybox ligand is moderate.

Full text of DOI:10.1021/acs.organomet.1c00112

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Enantioconvergent and Regioselective Synthesis of Allenylsilanes
by Nickel-Catalyzed C(sp2)−C(sp3) Cross-Coupling Starting from
Racemic α‑Silylated Propargylic Bromides
Yan Xu, Hong Yi, and Martin Oestreich*
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ABSTRACT: A direct synthesis of enantioenriched allenylsilanes
from racemic α-silylated propargylic bromides by an enantiocon-
vergent nickel-catalyzed cross-coupling is reported. The high
regioselectivity is governed by the bulky silyl group, and the
C(sp2)−C(sp3) bond formation occurs exclusively at the γ-position
of the propargyl electrophile. The level of enantioselection induced
by a chiral Pybox ligand is moderate.
ethods for the enantioconvergent cross-coupling of
racemic electrophiles with various zinc- and magne-
group steers the coupling toward the sterically less hindered
position.4 A related application of this directing effect to
propargylic substitution is not known. We anticipated that,
with α-silylated propargyl electrophiles as starting materials,
the formation of the allenylsilane would therefore be favored
(Scheme 1, bottom). Nickel-catalyzed cross-coupling reactions
of propargylic halides usually yield the propargylic coupling
M
sium-based carbon nucleophiles have significantly advanced,
especially with chiral Pybox-nickel complexes as catalysts.1
One recent facet is the C(sp3)−C(sp3) cross-coupling of α-
silylated alkyl halides and primary alkylzinc reagents to form α-
chiral alkylsilanes with high levels of enantiocontrol (Scheme
1, top).2 When a silyl group is installed in either the α- or γ-
position of an allyl electrophile, the enantioconvergent cross-
coupling also becomes regioconvergent to arrive at vinylsilanes
with an allylic stereocenter (Scheme 1, middle).3 The silyl
product,5 with one noteworthy exception being reported by
6
́
Cardenas and co-workers. The silyl group will secure high γ-
selectivity, thereby providing the direct preparation of
enantioenriched allenylsilanes from racemic precursors.7
Examples for this are still rare,8 as the vast majority of their
syntheses relies on enantioselective or -specific SN′ displace-
ments of propargylic acceptors with or without a silyl
substituent at the alkyne terminus when carbon9 or silicon10
nucleophiles are employed, respectively.
Scheme 1. Racemic Silylated Electrophiles in Nickel-
Catalyzed Enantioconvergent Cross-Coupling with Zinc
Nucleophiles (R2 = Alkyl)
We began our study with testing different (R,R)-Pybox
ligands L2−L6 in a model reaction employing the setup
previously established for the aforementioned C(sp3)−C(sp3)
cross-coupling (Table 1, entries 1−5). The reaction of α-
silylated propargylic bromide rac-1a and primary alkylzinc
bromide 2a did proceed in all cases, affording the desired
allenylsilane (R)-3aa in moderate yields. However, no
enantioinduction was obtained with (R,R)-Bn-Pybox (L2) as
the chiral ligand (entry 1). Ligands with L3−L5 bearing 2°
alkyl residues as R groups resulted in promising ee values
(entries 2−4). (R,R)-Ph-Pybox (L6) was inferior in terms of
yield and enantioselectivity (entry 5). Other ligands such as L7
Special Issue: Organometallic Solutions to Challenges
in Cross-Coupling
Received: February 25, 2021
© XXXX The Authors. Published by
American Chemical Society
https://doi.org/10.1021/acs.organomet.1c00112
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A

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a
Table 1. Selected Examples of the Optimization
b
c
entry
ligand L
nickel catalyst
solvent
T (°C)
yield of 3aa (%)
ee of 3aa (%)
1
2
3
4
5
6
7
8
L2
L3
L4
L5
L6
L7
L4
L4
L4
L4
L4
L4
L4
L4
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
Ni(acac)2
DMA
DMA
DMA
DMA
DMA
DMA
Et2O
THF
DMF
NMP
THF
THF
THF
THF
THF
THF
10
10
10
10
10
10
10
10
10
10
0
−20
10
10
10
10
56
65
63
43
59
25
69
68
70
62
43
25
53
<10
trace
0
60
70
74
21
0
65
82
72
70
81
0
9
10
11
12
13
14
15
16
0
Ni(OTf)2
NiBr2·diglyme
L4
trace
a
b
c
All reactions were performed on a 0.10 mmol scale. Isolated yield after flash chromatography on silica gel. Determined by HPLC analysis on a
chiral stationary phase.
were less effective (entry 6; see the Supporting Information for
the complete ligand screening). We continued with (R,R)-iPr-
Pybox (L4) to further optimize the procedure. Out of several
solvents used, THF was superior to DMA, Et2O, DMF, and
NMP (entries 7−10). The formation of (R)-3aa in 68%
isolated yield with 82% ee was the best result (entry 8), which
did not further improve at lower temperatures (entries 11 and
12). A reaction temperature of 10 °C appeared to be crucial, as
the yield and eventually enantioinduction collapsed at 0 and
−20 °C, respectively. Other nickel salts such as Ni(acac)2 and
Ni(OTf)2 were not suitable (entries 13 and 14). Control
experiments showed that both (R,R)-iPr-Pybox (L4) and
NiBr2·diglyme are needed (entries 15 and 16).
Scheme 2. Enantioselective Cross-Coupling of α-Silylated
Aryl-Substituted Propargylic Bromides: Variation of the
a
Aryl and Silyl Groups
To assess the generality of the optimized procedure (see
Table 1, entry 8), a broad range of aryl-substituted11 α-
silylated propargylic bromides was subjected to the reaction
conditions with alkylzinc reagent 2a as the coupling partner
(Scheme 2).12 Electron-donating groups as in rac-1b−d,i as
well as electron-withdrawing groups as in rac-1e−h,j on the
phenyl ring were compatible, furnishing the corresponding
cross-coupling products (R)-3 in yields of up to 81% with
moderate enantiomeric excesses of around 71%. Similar results
were obtained for substrates rac-1b−d containing a methyl
group in the ortho, meta, or para position of the phenyl ring.
Functional groups such as halo as in rac-1e−g and cyano as in
rac-1j were also tolerated. Variation of the substitution pattern
at the silicon atom was possible. Propargylic bromides rac-1k−
m with a SiMe2Ph, SiMePh2, and SitBuPh2 group in the α-
position, respectively, reacted equally well with (R)-3la
(SiMePh2; 72%, 82% ee) reaching the result obtained with
model system (R)-3aa (SitBuMe2; 68%, 82% ee). It must be
noted here that allenylsilanes 3 were generally sensitive
compounds in our hands, decomposing on exposure to air
and on storage at −20 °C for longer periods of time. The tert-
butyl-substituted derivatives (SitBuMe2 and SitBuPh2) are
a
Unless specified otherwise, all reactions were performed on a 0.20
b
mmol scale. 72% yield and 81% ee were obtained on a 1.0 mmol
scale.
relatively stable, while those with SiMe2Ph and SiMePh2 as silyl
groups are particularly unstable.
We then evaluated the scope of the functionalized primary
alkylzinc reagents (2b−e; Scheme 3). Secondary alkylzinc
halides such as cyclohexylzinc bromide did not react as
B
https://doi.org/10.1021/acs.organomet.1c00112
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Communication
Scheme 3. Enantioselective Cross-Coupling of α-Silylated
Scheme 4. Control Experiments
Aryl-Substituted Propargylic Bromides: Variation of the
a
Primary Alkylzinc Reagent
a
All reactions were performed on a 0.20 mmol scale.
planned, affording the hydrodebrominated products in
significant quantities (not shown). As is typical for these
nickel-catalyzed cross-coupling reactions,1−3 the functional-
group tolerance was excellent. Yields and ee values were largely
unaffected by the nucleophilic coupling partner. As no single
crystals suitable for X-ray diffraction were obtained, we decided
to assign the absolute configuration of 3 by a comparison with
known allenylsilanes. However, the structural motif with the
SitBuMe2 group is new. For this reason, we coupled
propargylic bromide 1k decorated with the conventional
SiMe2Ph group and methylzinc bromide (2f) to yield the
previously reported allenylsilane 3kf9b (Scheme 3, gray box).
On the basis of the optical rotation,9b its absolute configuration
is R. Arylzinc reagents failed to give the desired products.
The effect of the silyl substituent was probed in the reaction
of the secondary propargylic bromides rac-4a and rac-4b under
the optimized conditions (Scheme 4, top). The cross-coupling
of unhindered rac-4a with alkylzinc reagent 2b led to a mixture
of the allene 5ab (10%) and alkyne 6ab (82%), clearly favoring
the propargylic coupling product.5 Conversely, rac-4b with a
tert-butyl group in the α-position converted selectively into
allene 5bb (76%). This corresponds with the outcome
obtained with the α-silylated substrates rac-1, where no
propargylsilane was detected in any of the above reactions.
We therefore ascribe the high regioselectivity to the steric
demand of the propargylic substitutent. The potential radical
nature of this nickel-catalyzed cross-coupling was demon-
strated by the addition of 2.0 equiv of TEMPO to the cross-
coupling of rac-1a and 2b (Scheme 4, bottom).6 The amount
of the desired product (R)-3ab was diminished (32% versus
72%), and the TEMPO adduct 7ab or 8ab was detected by
GC-MS analysis (gray box). This result verifies the known
involvement of radical intermediates.1,13
enantioinduction is only moderate, the method is one of the
few examples of a catalytic asymmetric synthesis of
allenylsilanes directly starting from a racemic precursor.8−10
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.1c00112.
General procedures, experimental details, and character-
ization and spectral data for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Martin Oestreich − Institut fur Chemie, Technische
̈
Universität Berlin, 10623 Berlin, Germany; orcid.org/
0000-0002-1487-9218; Email: martin.oestreich@tu-
berlin.de
Authors
Yan Xu − Institut fur Chemie, Technische Universität Berlin,
̈
10623 Berlin, Germany; orcid.org/0000-0003-4171-
5056
̈
Hong Yi − Institut fur Chemie, Technische Universität Berlin,
10623 Berlin, Germany; orcid.org/0000-0002-3337-
1452
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.1c00112
In summary, an enantioconvergent and regioselective nickel-
catalyzed cross-coupling of α-silylated propargylic bromides
and primary alkylzinc reagents has been developed. Allenylsi-
lanes were obtained as single regioisomers, which is attributed
to a steering effect of the bulky silyl group.4 While the
Notes
The authors declare no competing financial interest.
C
https://doi.org/10.1021/acs.organomet.1c00112
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Communication
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ACKNOWLEDGMENTS
■
Y.X. thanks the China Scholarship Council for a predoctoral
fellowship (2018−2022), and Y.H. gratefully acknowledges the
Alexander von Humboldt Foundation for a postdoctoral
fellowship (2017−2019). M.O. is indebted to the Einstein
Foundation Berlin for an endowed professorship.
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