Organic Letters
Letter
coupling partners hinted at the feasibility of the development
of a chiral variant. A narrow yield range (71−91%) across a
wide range of substrates indicates the robustness of the
method. It is to be noted that the molecules such as 7b, 7f, 7i,
and 7w are amenable for further functional group trans-
formations. On the contrary, the presence of donor−acceptor
groups can make these structures suitable for organic field-
effect transistors (OFETs) or nonlinear optical (NLO)
materials.14
Table 2. Optimization of the Reaction Parameters for the
Atropselective SM Reaction
a
After establishing a practical and efficient method for the
synthesis of unprecedented DAIs, we next focused on
developing a catalytic enantioselective SM coupling to access
chiral DAIs. Although the atropselective synthesis of biaryls has
been achieved by the SM cross-coupling reaction,15 to our
knowledge, a catalytic enantioselective method for axially chiral
styrenes is yet to be established.
After Buchwald’s first report on the atropselective SM cross-
coupling reaction,15a several impressive works followed.15b−f
A
majority of these works pointed to the significant influence of
coordinating groups at the ortho position of the reactive site in
imparting high levels of enantioinduction. Therefore, we have
chosen the enol triflate 5a and the boronic acid 6a (having a
methoxy group at the ortho position) as coupling partners and
subjected them to various combinations of palladium catalysts,
chiral ligands, solvents, and temperature (Table 2).12
The ligands L1−L5 combined with either PdCl2 or
Pd(PPh3)4 provided 8a in good yield but only with poor
enantioselectivity (Table 2, entries 1−6). Interestingly, a
combination of L5 and Pd2(dba)3 showed a marked improve-
ment in the ee (entry 7). With this combination, several
attempts were made to improve the enantioselectivity;
however, it worked only when the reactant was changed to
6q (entry 8). In this stage, a dramatic improvement in the
reaction rate was observed with the addition of water. Thus
several combinations of palladium catalysts and chiral ligands
were evaluated with 5a and 6q as reactants (entries 9−17).
The ligand L14 provided 8b in good yield with high
enantioselectivity (entry 17).16 Interestingly, the O-tert-butoxy
boronic acid 6t with L14 provided 8c with only moderate
enantioselectivity, highlighting the optimum requirement of
the ortho alkoxy group (entry 18).
During the screening, we made some interesting observa-
tions about the substrate and catalyst requirements for an
efficient reaction: (i) A significant difference in the ee with
closely related ligands L13 and L14 indicates the contribution
of phenyl rings to the stabilization of the transition state,
presumably via π−π or C−H−π interactions (Table 2, entries
16 vs 17). (ii) Under the optimal conditions, the boronic acid
possessing a tert-butoxy group at the ortho position (6t) did
not give a better result (entries 17 vs 18), indicating that the
isopropoxy group is an optimal ortho substituent for obtaining
a satisfactory result. (iii) Bisoxazoline (BOX)-type ligands are
found to be superior compared with several other ligand
classes evaluated.
b
c
entry
6/[Pd]/ligand
time (h)
yield (%)
ee (%)
1
2
3
4
5
6
7
6a/PdCl2/L1
6a/PdCl2/L2
6a/PdCl2/L3
6a/PdCl2/L4
6a/Pd(PPh3)4/L4
6a/PdCl2/L5
6a/Pd2(dba)3/L5
6q/Pd2(dba)3/L5
6q/Pd2(dba)3/L6
6q/Pd2(dba)3/L7
6q/Pd2(dba)3/L8
6q/Pd2(dba)3/L9
6q/Pd2(dba)3/L10
6q/Pd2(dba)3/L11
6q/Pd2(dba)3/L12
6q/Pd2(dba)3/L13
6q/Pd2(dba)3/L14
6t/Pd2(dba)3/L14
19
21
16
17
21
16
13
7
7
9
7
8
6
5
4
7
7
7
73
71
72
51
41
80
70
68
65
73
51
57
81
81
73
91
89
81
20
15
10
26
18
30
60
66
40
70
80
10
65
75
60
30
82
64
d
8
9
d
d
10
11
12
13
14
15
16
17
d
d
d
d
d
d
d
d
18
a
b
graphic yields. Determined by the chiral stationary phase HPLC. In
toluene/water (9:1) with 7 mol % Pd2(dba)3.
d
isopropoxy DAI 8b was with 82% ee, whereas the 2,3- and 2,7-
bis(isopropoxy) DAIs 8i and 8k were isolated with 99 and 97%
ee, respectively; however, the 2,7-disubstituted DAI 8l was
realized with relatively less enantioselectivity (72% ee).
Similarly, 8a possessing the monomethoxy naphthalene unit
was obtained with 66% ee, whereas the 2,3-bis(methoxy) DAI
8g was isolated with 85% ee. Similar substituent effects were
observed in a few other cases, for example, 8d vs 8i, 8e vs 8h,
and 8f vs 8j. Interestingly, the 2,6-disubstituted boronic acids
provided the respective DAIs (8m and 8n) with marginally low
enantioselectivities. On the contrary, the reaction did not
The synthesis of various axially chiral DAIs under the
optimized conditions is presented in Scheme 4. The boronic
acids possessing ortho-methoxy, cyclohexyloxy, benzyloxy, and
heptyloxy groups resulted in the formation of the respective
DAIs 8a and 8d−8f with 61−69% ee. Subsequently, a few
other electronically and sterically diverse boronic acids were
evaluated. Among them, boronic acids possessing electron-
donating groups at the 2,3- or 2,7-positions dramatically
influenced the enantioselectivity. For example, the mono-
4911
Org. Lett. 2021, 23, 4909−4914