Communication
chiral auxiliary for the development of a diastereoselective
Suzuki–Miyaura cross-coupling reaction. Herein we report the
use of asymmetric Suzuki–Miyaura coupling reactions for the
first time to synthesize chiral biaryl compounds with the
menthyl phenylphosphinate group as a chiral auxiliary under
mild reaction conditions. A series of functionalized chiral bi-
aryls is obtained in excellent yields and with good diastereose-
lectivities (up to> 95:5 d.r.; Scheme 1).
such as [Pd(PPh3)2Cl2], Pd(OAc)2, Pd(acac)2, and PdCl2 could
also catalyze this reaction, albeit with lower yields (Table 1, en-
tries 7–11). Different phosphorus ligands were also tested and
we found that 1,3-bis(diphenylphosphino)propane (dppp) and
2’-dicyclohexylphosphino-N,N-dimethylbiphenyl-2-amine
(L)
were also suitable for the reaction (Table 1, entries 14 and 15).
Finally, other bases, such as K2CO3, KF, Cs2CO3, and tBuOLi,
were also effective in the reaction (Table 1, entries 16–19).
Better diastereoselectivity (89:11 d.r.) was achieved when the
temperature was reduced to 608C (Table 1, entries 20 and 21),
although a further reduction in the reaction temperature to
408C caused the reaction to become too sluggish (Table 1,
entry 22).
The asymmetric Suzuki–Miyaura cross-coupling between RP-
(+)-menthyl 1-bromonaphthalen-2-yl(phenyl)phosphinate (1a),
which was synthesized by the cross-coupling of SP-(+)-menthyl
phenylphosphinate[16] with 1-bromonaphthalen-2-yl trifluoro-
methanesulfonate (see the Supporting Information for de-
tails),[17] and o-tolylboronic acid (2a) was chosen as the model
reaction (Table 1). In the presence of 2.0 mol% of [Pd2(dba)3]
(dba=dibenzylideneacetone), 4.8 mol% of 2-dicyclohexylphos-
phino-2’,6’-dimethoxybiphenyl (SPhos), and 3.0 equivalents of
K3PO4, several conventional solvents were tested. Whereas vari-
ous solvents were suitable for this reaction, toluene provided
the desired product 3aa in 85% yield and a promising diaste-
reomeric ratio of 84:16 and therefore we considered it the op-
timal choice (Table 1, entries 1–6). Other Pd catalyst precursors,
Having established standard conditions, we applied a series
of arylboronic acids and substituted 1-bromonaphthalen-2-yl-
(phenyl)phosphinates to the reaction system, in order to ex-
plore the reaction scope (Table 2). To our delight, o-phenyl-
and o-formyl-substituted phenylboronic acids provided good
yields of the coupling products (3ab, 3ac) with high diastereo-
selectivities (Table 2, entries 2 and 3). The successful coupling
of 2-formylphenylboronic acid demonstrates a promising func-
tional group tolerance of the reaction (Table 2, entry 3). Fur-
thermore, the absolute configu-
ration of the product 3ab was
confirmed by single-crystal X-ray
Table 1. Screening for reaction conditions.[a,b]
crystallography (see the Sup-
porting Information). Various
other o-substituted phenylbor-
onic acids were tested as sub-
strates to construct axially chiral
biaryl compounds containing
phosphinate moieties (Table 2,
entries 4–7). In general, all reac-
tions of arylboronic acids with
Entry
[Pd]
Base
Ligand
Solvent
T [oC]
Yield [%][b]
d.r.[c]
an electron-donating group af-
forded satisfactory yields and
diastereomeric ratios from 84:16
to over 95:5. We speculate that
the effects of steric hindrance
and the electronic effect may be
responsible for this result. Small
groups such as methyl and me-
thoxy at the ortho position of
phenylboronic acid gave diaste-
reomeric ratios of only 89:11
and 84:16, respectively (Table 2,
entries 1 and 6). In contrast,
phenylboronic acids with large
groups at the ortho position,
such as o-isopropyl phenylbor-
onic acid, provided higher dia-
stereoselectivity, and we ob-
tained the product 3ae with an
excellent d.r. value of >95:5
(Table 2, entry 5). Naphthylbor-
onic acids were also examined
and gave good yields with mod-
1
2
3
4
5
6
7
8
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd(PPh3)4]
[Pd(PPh3)2Cl2]
Pd(OAc)2
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
KF
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
PPh3
BINAP
dppp
L
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
toluene
THF
DME
MeOH
DMF
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
85
75
66
81
73
84
trace
15
26
56
84:16
79:21
84:16
70:30
75:25
84:16
–
84:16
84:16
84:16
84:16
–
DME+H2O
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Pd(acac)2
PdCl2
54
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
trace
trace
55
84
75
61
75
81
85
–
84:16
84:16
84:16
84:16
84:16
84:16
84:16
89:11
91:9
Cs2CO3
tBuOLi
K3PO4
K3PO4
K3PO4
60
40
85
72
[a] Conditions: Aryl bromide 1a (1.0 mmol), arylboronic acid 2a (2.0 mmol), Pd (4.0 mol%) , ligand (4.8 mol%),
base (3.0 mmol), solvent (5.0 mL), 1008C, 24 h under argon atmosphere unless otherwise noted; [b] yield of iso-
lated product; [c] determined by 1H NMR and 31P NMR spectroscopy of the crude mixture; [d] t=40 h; [e] t=
72 h.
&
&
Chem. Eur. J. 2015, 21, 1 – 6
2
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