Angewandte
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[8]
atom in the allylic position (Scheme 1, bottom). The silyl
2
group attached to a C(sp ) carbon atom could then be
[
9]
a placeholder for another 18 alkyl group, thereby providing
a two-step regioselective access to exclusively alkyl-substi-
tuted acyclic allylic systems with excellent diastereo- and high
[10]
enantiocontrol (Scheme 2, bottom).
For the optimization of the reaction conditions, we chose
silylated allylic bromide rac-1a as a mixture of regioisomers
[
11]
(
a:g = 53:47) and 2.0 equiv of primary alkylzinc bromide
2
a as model substrates (Table 1). Upon variation of the
[
a]
Table 1: Selected examples of the optimization.
[
c]
Entry Deviation from the standard conditions
Yield
e.r.
[
b]
[%]
[
d]
1
2
3
4
5
6
7
8
None
88 (80)
75
37
64
4
92:8
92:8
93:7
89:11
–
92:8
92:8
91:9
08C instead of RT
À108C instead of RT
Allylic chloride instead of rac-1a
Allylic acetate instead of rac-1a
1.5 equiv of 2a
74
69
Scheme 3. Scope I: Variation of the primary alkylzinc bromide.
1.2 equiv of 2a
5.0 mol% of NiBr ·diglyme and 7.5 mol% of 77
2
L4
allylic bromide (not shown). Functional groups include
another acetal (as in 2b), an ether as well as a silyl ether (as
in 2c and 2j), a phenyl group (as in 2d), a nitrile (as in 2e), an
ester (as in 2 f) and an alkenyl group (as in 2i). Unfunction-
alized alkyl groups (as in 2g and 2h) were also suitable for this
reaction. Yields were generally good, regio- and diastereo-
control excellent, and enantioselectivities moderate to good.
The absolute configuration of product 3ah had already been
[
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.
reaction parameters, we found that NiBr ·diglyme as preca-
talyst and Pybox ligand L4 (R = (S)-sBu; see gray box in
Scheme 1) as the chiral ligand in DMA can afford the C(sp )À the reported value, we were able to establish the absolute
2
[8]
assigned. By comparison of the sign of optical rotation with
3
3
C(sp ) coupling product 3aa regioselectively in 80% yield
with a superb E/Z ratio of > 98:2 and a high enantiomeric
ratio of 92:8 (entry 1). Other nickel precatalysts and Pybox
ligands as well as different solvents were also examined yet
with no improvement (see Table S1 in the Supporting
Information). Temperatures lower than room temperature
had no significant effect on enantioselectivity but resulted in
substantially decreased yields (entries 2 and 3). Changing the
leaving group in rac-1a from bromide to chloride (a:g =
configuration of the obtained cross-coupling products as R.
Variation of the substitution pattern at the silicon atom
was examined next (Scheme 4). Replacement of the Me PhSi
2
group with the more sterically hindered MePh Si and
2
tBuPh Si groups as in rac-4a and rac-5a, respectively was
2
not detrimental to yield and level of enantioselection. The
simplest triorganosilyl group Me Si as in rac-6a could also be
3
installed, and the high enantiomeric ratio was retained. The
same applied to the synthetically valuable BnMe Si group as
2
0
:100) led to lower yield and a slightly lower enantiomeric
in rac-7a (see below for further processing of 11aa). With
ratio (entry 4). The corresponding acetate (a:g = 0:100) did
not react (entry 5). Less alkylzinc reagent 2a decreased the
yield without affecting the enantioselectivity (entries 6 and 7).
A lower catalyst loading can be employed with only a small
loss in yield and enantioselectivity (entry 8).
With the optimized conditions established, we tested
various primary alkylzinc reagents 2b–j with allylic bromides
rac-1a as the coupling partner (Scheme 3). Secondary alkyl-
zinc halides such as cyclohexylzinc bromide and iodide did
not react, only yielding trace amounts of the homocoupled
MePh Si and BnMe Si as silyl groups, we then investigated
2
2
further substituents of the allyl unit. An n-propyl and an n-
1
butyl instead of the methyl group could be installed as R , and
both the yield and the enantioselectivity were high. However,
allylic bromides with a methyl group in the b-position (not
shown) were not chemically stable and could neither be
purified by flash chromatography on silica gel nor isolated
after distillation.
As a consequence thereof, we returned to chemically
more robust silylated allylic chlorides (cf. Table 1, entry 4). To
2
ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 1 – 5
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Kranidiotis-Hisatomi, Nektarios
