Table 1. Sterically hindered Suzuki–Miyaura cross-coupling: Ligand and
base effect.
ed biaryl phosphine oxide for the first time through a
Suzuki–Miyaura coupling reaction (entry 18).
Sterically demanding Suzuki–Miyaura couplings to con-
struct functionalized tetra-ortho-substituted biaryls are par-
ticularly important for the syntheses of biaryl natural prod-
[1a]
ucts or ligands. However, few efficient catalysts are availa-
ble in terms of high yield, broad substrate scope, and low
catalyst loadings. The strong basic reaction conditions with
NaOtBu as the base were incompatible for substrates with
functionalities such as aldehydes, nitriles, phosphonate, or
nitro groups. Furthermore, the protodeboronation of func-
tionalized arylboronic acids is significantly accelerated
under strong basic conditions. For example, the half-life of
2,6-dimethoxyphenylboronic acid in the presence of
[
a]
[b]
Entry
Ligand
Base
Yield [%]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
NaHCO
KF
CsF
3
<1
<1
33
20
47
60
56
97
<1
1
K
2
CO
Cs CO
PO
NaOH
3
2
3
K
3
4
[15]
NaOtBu in toluene at 1008C is about 2 h. To address this
issue, a mild base such as potassium phosphate must be em-
NaOtBu
TEA
DBU
1
1
1
ployed for these substrates. Although the catalyst Pd/1 with
10
11
12
13
14
15
16
17
18
[16]
DABCO
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
<1
4
5
K PO as the base proved to be less effective, we were
3 4
S-Phos
Ru-Phos
X-Phos
DPPF
[17]
pleased that ligand
2 with an anthracenyl moiety
(
Scheme 1) was efficient for various functionalized sub-
3
strates at only 1 mol% Pd loading (Table 3). Functionalities
such as aldehyde, ketone, phosphonate, cyano, nitro, or
fluoro groups were well tolerable. Arylboronic acids with
ortho-methoxy groups were also suitable substrates, provid-
ing the corresponding biaryls in good to excellent yields (en-
tries 1–3). A quinoline-phosphonate biaryl (entry 12) was
also synthesized in 90% yield. The coupling of 2-iodophe-
nyldiphenylphosphine oxide and 9-anthracenylboronic acid
was also successful (entry 13). Notably, the Pd/2 catalyst was
effective for the cross-coupling between a sterically hindered
aryl iodide and 2,4,6-triisopropylphenylboronic acid to pro-
vide a bulky monophosphorus ligand precursor in a moder-
ate yield (entry 14).
22
10
<1
3
PCy
PtBu
PPh
3
3
3
[
a] The reactions were carried out at 1108C in toluene (2 mL) for 12 h
with 2-bromo-1,3-dimethoxybenzene (3, 1 mmol), 2,4,6-triisopropylphe-
nylboronic acid (4, 1.5 mmol), and base (3 mmol) in the presence of Pd-
ACHTUNGTRENNUNG( OAc) (1 mol%) and ligand (2 mol%). [b] HPLC assay yields were
2
averaged from two runs.
We then looked into the substrate scope of the catalyst
Pd/1 for extremely sterically demanding Suzuki–Miyaura
coupling reactions. As can be seen in Table 2, the Pd/1 cata-
lyst in combination with NaOtBu as the base allowed for
the first time the syntheses of a series of tetra-ortho-substi-
tuted biaryls bearing ortho-isopropyl substituents in excel-
lent yields (entries 1–14). A biaryl product containing two
ortho-ethyl and two ortho-isopropyl groups was also pre-
pared in a high yield (entry 8). Substituents such as methoxy
To understand the unique reactivity of the Pd/BI-DIME
catalyst for sterically hindered Suzuki–Miyaura coupling re-
0
actions, a [Pd ((S)-BI-DIME) ] complex was prepared by
2
[18]
mixing [Pd
at room temperature. Its X-ray structure (Figure 1)
showed a larger P-Pd-P angle (167.98) to those observed in
A
H
U
G
R
N
U
G
with 2 equiv of (S)-BI-DIME
2
[19]
0
[6c]
0
[20]
(
(
(
entries 4, 7, 12), benzyloxy (entry 9), and phosphine oxide
entry 18) were well-tolerated. Heteroaryls, such as pyrazole
entry 5), quinoline (entries 16,17), and acridine (entry 6)
[Pd
A
H
U
T
E
N
N
(S-Phos) ]
(164.58) and [Pd
A
H
U
G
R
N
U
G
(154.88)
2
2
complexes, indicating the bulkier size of BI-DIME ligand.
We believed the bulkiness of BI-DIME ligand would facili-
tate the formation of its active monoligated palladium spe-
were all compatible. Sterically hindered aryl chlorides could
also be employed (entries 10–12). Notably, this catalytic
system was also applicable for the synthesis of a biaryl with
four ortho-isopropyl substituents (entry 14), which has sig-
nificantly expanded the scope of Suzuki–Miyaura coupling
reactions on steric tolerance. A tri-ortho-substituted biaryl
with a tert-butyl ortho substituent can also be synthesized in
an excellent yield (entry 15). Syntheses of sterically bulky
biaryl phosphine oxides through a sterically demanding
Suzuki–Miyaura coupling would be a valuable addition to
[6d,21]
cies.
A strong bulky base such as NaOtBu would further
facilitate the formation of an active monomeric arylpallad-
[6c]
the known method through a benzyne mechanism. How-
ever, such strategy has not been successfully explored.
Gratifyingly, the Pd/1 catalyst enabled the cross-coupling be-
tween 2-iodophenyldiphenylphosphine oxide and 2,4,6-tri-
[
14]
0
0
Figure 1. The X-ray structure of a) [Pd ((S)-BI-DIME)
2
] and b) [Pd ((R)-
2)
2
]. Hydrogen atoms are omitted for clarity. Selected bond lengths and
angles: a) P Pd 2.267, 2.263 ꢁ; <P-Pd-P 167.98. b) P Pd 2.300, 2.311, C
Pd 2.195, 2.264 ꢁ.
À
À
À
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
isopropylphenylboronic acid to provide a sterically congest-
&
2
&
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Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
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