Angewandte
Communications
Chemie
phosphoramidite ligand, as such ligands have proven efficient
in copper-catalyzed 1,2-addition reactions with 1,1-diborylal-
kanes. Under the reaction conditions, the desired product
was obtained in 97% yield, but a racemic product was
obtained (Table 1, entry 1). The chiral bisphosphine ligand
catalyst and that higher temperatures might be necessary
for an efficient reaction (entry 6). When the temperature was
increased to 608C, the product was obtained in increased
yield without significantly affecting the enantiomeric ratio
(entry 7). We further examined the reaction with various
chiral NHC ligands. Changing the R substituent on the alkyl
tether of the NHC ligand from tert-butyl to phenyl (L5) or
indanol (L6) resulted in lower yields and enantioselectivities
[
17]
[
a]
Table 1: Optimization of the reaction conditions.
(entries 8 and 9). NHC ligand L7 containing a 2,6-isopropyl-
phenyl group was less efficient than L4, resulting in 49% yield
and an enantiomeric ratio of 54:46 (entry 10). Therefore, the
conditions using L4 ligand (entry 7) were selected as optimal
[21]
for the addition reaction. The optimized conditions were
[
b]
[c]
Entry
Ligand [L]
Cu/L ratio
T [8C]
Yield [%]
e.r.
then applied to various a,b-unsaturated acceptors
[22]
1
2
3
4
5
6
7
8
9
L1
L2
–
L3
L4
L4
L4
L5
L6
L7
1:1
1:1
–
1:1
1:1
1:2
1:2
1:2
1:2
1:2
RT
RT
RT
RT
RT
RT
60
60
60
60
97
95
91
95
74
41
86
26
73
49
50:50
50:50
–
50:50
69:31
93:7
(Table 2). A monoester was unreactive, and other diester
and dinitrile compounds exhibited decreased enantioselec-
tivity as compared to diethyl diester compounds (entries 2–4).
[
a]
Table 2: Screening of a,b-unsaturated compounds.
94:6
86:14
53:47
54:46
1
0
[a] General reaction conditions: 1a (0.5 mmol), 2 (0.75 mmol), CuCl
(
0.025 mmol), ligand (0.025 mmol), LiOtBu (1 mmol), THF (1 mL),
1
2
[b]
[c]
Entry
Substrate (Z , Z )
Yield [%]
e.r.
–
room temperature; see the Supporting Information for details. [b] Yield
of the isolated product. [c] The enantiomeric ratio was determined by
HPLC analysis.
1
2
3
4
CO Et, H
0
84
58
77
2
CO Me, CO Me
84:16
87:13
54:46
2
2
CO tBu, CO tBu
2
2
CN, CN
[a] General reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), CuCl
(0.025 mmol), ligand (0.05 mmol), LiOtBu(1 mmol), THF (1 mL), room
temperature. [b] Yield of the isolated product. [c] The enantiomeric ratio
was determined by HPLC analysis.
Next, various a,b-unsaturated diethyl diesters 1 with
[
23]
different b-substituents were examined (Table 3).
The
conjugate addition resulted in the corresponding b-chiral
alkylboronate compounds in good yields with high enantio-
selectivity. Reactions of b-aryl-substituted diesters containing
a halogen or an electron-withdrawing or electron-donating
group yielded the desired products 3b–f and 3h. For the less
electrophilic diester 1g containing a strongly electron donat-
ing p-methoxyphenyl group, decreased yield and enantiose-
lectivity were observed (product 3g). Diesters containing
meta- and ortho-substituted aryl groups and heteroaryl groups
were also tolerated under the optimal reaction conditions
(products 3i–n). Besides aryl substituents, diesters with
primary and secondary alkyl substituents provided enantio-
merically enriched organoboronates 3o and 3p in good yields
(
R,R)-methyl-Duphos (L2) also resulted in a good yield but
with 0% ee (entry 2). We suspected a possible background
reaction for the low ee values and found that a severe
background reaction even occurred in the absence of
a ligand (entry 3). This extremely facile background reaction
inhibited asymmetric conversion in the addition reaction;
therefore, N-heterocyclic carbene (NHC) ligands, which
coordinately tightly to copper, were considered as good
[
19]
ligand candidates.
We examined the reactions using copper catalysts with
chiral NHC ligands L3 and L4 (Table 1, entries 4 and 5), and
with high enantiomeric ratios. We determined the site
[20]
[24]
found that L4 bearing a hydroxy coordinating substituent
yielded promising results with a moderate enantiomeric ratio
69:31). When the molar ratio of copper to ligand was
selectivity (1,4- vs. 1,6-addition)
of the addition with
a,b,g,d-unsaturated dienoates 1q and 1r. Both reactions
afforded only the 1,4-addition product 3q or 3r in good yield
with high enantioselectivity without 1,6-addition. Finally,
when the reaction was carried out on a larger scale
(3 mmol), reduced amounts of catalyst and ligand resulted
in the desired product 3a without reduction in yield or
enantioselectivity.
(
changed to 1:2 to minimize the presence of ligand-free copper
catalyst, the yield of the desired product decreased to 41%,
but the enantiomeric ratio was greatly improved (entry 6).
The results indicated the decreased reactivity of the L4–
copper complex as compared to the ligand-free copper
2
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Angew. Chem. Int. Ed. 2019, 58, 1 – 6
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