Angewandte
Communications
Chemie
Table 1: Optimization of the reaction conditions.[a]
Entry
L
Solvent[b]
Base
T [8C]
Yield [%]
ee [%]
1[c]
2[c]
L1
L2
L3
L4
L5
L6
L7
L8
L9
L4
L4
A
A
B
B
B
B
B
B
B
C
D
Na2CO3
Na2CO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
KOH
100
100
80
80
80
80
80
80
80
65
65
20
10
99
91
33
45
61
65
97
49
94
9(+)
13(À)
43(À)
79(À)
69(À)
75(À)
71(À)
73(À)
74(À)
91(À)
91(À)
3[d]
4[d]
5[d]
6[d]
7[d]
8[d]
9[d]
Scheme 2. Planned strategy based on “platform molecules”.
10[d]
11[d]
[a] The reaction was conducted with 1a (0.10 mmol), 2a (0.15 mmol), Pd
(5 mol%), and the ligand (10 mol% for monodentate ligands; 7.5 mol%
for bidentate ligands) in a Schlenk tube with a screw cap. [b] A: toluene/
EtOH/H2O (3:1:2); B: toluene/EtOH/H2O (3:1:1); C: DCE/H2O (3:1);
D: DCE/H2O (1:1). [c] [Pd2(dba)3] (2.5 mol%) was used. [d] [Pd(acac)2]
was used. The R configuration was tentatively assigned by comparison
with compound 3n in Table 2. acac=acetylacetonate, dba=dibenzyli-
deneacetone, DCE=1,2-dichloroethane.
be a class of “platform molecules” for the synthesis of biaryl
axially chiral compounds (Scheme 2). We reasoned that the
ketone moiety could be conveniently transformed into other
functionalities, and groups could be readily introduced at the
À
a’-position to the ketone. The allylic C H bonds (g-position)
are also potential sites for further elaboration. An additional
advantage of this strategy is that the starting 2-halo cyclohex-
2-enones are readily prepared. Thus, it avoids the tedious
preparation of different polyfunctionalized aryl halides, and
the reoptimization of reaction conditions for other substrates,
in particular for those with ortho substituents. However,
challenges included the lack of precedent for enone-based
axial chirality and the possibility that the three sp3-hybridized
carbon atoms in 2-hexenone could lead to increased ring
flexibility as compared to the corresponding aromatic rings,
which could lead to lower rotational barriers for the 2-
hexenone-based atropisomers. Thus, relatively mild reaction
conditions, in particular a low reaction temperature, are
crucial for this type of cross-coupling reaction.
improved the yield at 808C (entry 3). By the use of BoPhoz
ligand L4, the ee value of the product was increased to 79%
(entry 4).[13] Further optimization focused on modification of
the BoPhoz ligand. Both electronic and steric effects of the
ligand were investigated. However, the introduction of p-
methyl, p-trifluoromethyl, and m-methoxy groups into the
phosphinamine moiety (ligands L5–L7) did not give better
selectivity (entries 5–7). Use of the bulkier ligand L8 and
electron-rich ligand L9 led to a slight decrease in the
enantioselectivity (entries 8 and 9). We found that the
ee value of the product could be increased to 91% by removal
of the cosolvent ethanol and lowering of the reaction
temperature, although the yield dropped (entry 10). Finally,
when KOH was used as a base, the chemical yield of 3a was
improved to over 90% without the loss of selectivity (Table 1,
entry 11).
With these considerations in mind, we selected iodide 1a
and boronic acid 2a as model substrates to optimize the
reaction conditions (Table 1). The reactions with phosphor-
amidite ligands L1 and L2 gave poor yields and enantiose-
lectivity (Figure 1 and Table 1, entries 1 and 2). Bidentate
ligand L3 in combination with [Pd(acac)2] significantly
Studies on thermal racemization demonstrated that the
half-life of enantiopure 3a was about 17 h at 1008C in toluene
(Figure 2a), whereas the ee value of the corresponding more
rigid phenol 4a dropped only very slightly from 99.5 to 98.5%
over 48 h at the same temperature. We monitored the ee value
over time at three different temperatures and concluded that
the activation energy (Ea) for the thermal racemization of 3a
was around 27 kcalmolÀ1 (Figure 2b; see the Supporting
Information for details). Notably, by analysis of the crystal
structure (Figure 2c),[14] we found that the configurationally
less rigid C(sp3)-atom chain in the cyclohexenone moiety
À
=
leads to a C1 C2/C6 O1 torsion angle of 20.68 (see the
Supporting Information for details), which might account for
the lower stability of axial chirality as compared to that of the
corresponding biaryl compounds.
Figure 1. Some typical ligands used.
2
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
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