An efficient indenyl-derived phosphine ligand for the Suzuki-Miyaura coupling of sterically hindered aryl halides

Article abstract of DOI:10.1039/c6ob00096g

An air-stable aryl substituted indenyl phosphine used in combination with Pd(OAc)₂ provides a highly efficient catalyst for the Suzuki-Miyaura cross-coupling reaction of sterically hindered aryl halides with aryl boronic acids.

Full text of DOI:10.1039/c6ob00096g

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An efficient indenyl-derived phosphine ligand for the
Suzuki-Miyaura coupling of sterically hindered aryl halides
Yan Liu, Hui Peng, Jia Yuan, Meng-Qi Yan, Xue Luo, Qing-Guo Wu, Sheng-Hua Liu,
Jian Chen*, and Guang-Ao Yu*
a Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, Wuhan 430079, People’s Republic of
China.
* Corresponding authors: E-mail address, jianc@mail.ccnu.edu.cn;
yuguang@mail.ccnu.edu.cn.
Abstract
An air-stable aryl substituted indenyl phosphine used in combination with Pd(OAc)2
provides a highly efficient catalyst for the Suzuki-Miyaura cross-coupling reaction of
sterically hindered aryl halides with aryl boronic acids. In addition, a catalyst loading
down to 0.025 mol% can be achieved.
Introduction
Sterically hindered biaryl structures exist in many biologically important natural
products and also serve as pivotal frameworks for efficient ligands in homogenous
catalysis.1,2 Their synthesis has attracted a great deal of interest. The use of the
palladium-catalyzed Suzuki-Miyaura cross-coupling reaction to construct biaryl
compounds is particularly attractive owing to its versatility and compatibility with
various functional groups.3,4 However, the Suzuki–Miyaura coupling reaction of
sterically demanding substrates remains a synthetic challenge. Only a limited number
of methods are available for the synthesis of tetra-ortho-substituted biaryl compounds.
An efficient catalyst for the synthesis of highly sterically hindered biaryls was
reported by Buchwald and co-workers in 2002.5 Since then, the groups of Snieckus,6
Kwong,7 Hagiwara,8 Ackermann,9 Tang,10 and others have reported their progress
(Figure 1).11 N-heterocyclic carbene ligands have also shown efficiency in the
1

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Suzuki-Miyaura coupling reaction of sterically hindered substrates.12 Despite these
advances, limitations remain. For example, previously reported catalyst loadings for
this transformation were often higher (>1mol%) than those required to make the
large-scale synthesis of pharmaceutical intermediates or other bulk fine chemicals
economical.13 These factors have limited the use of the Suzuki-Miyaura coupling
reaction of arylboronic acids with aryl halides to produce low cost, sterically hindered
biaryls and commodity building blocks. Therefore, the development of efficient
catalytic system towards the synthesis of sterically hindered biaryls using lower
catalyst loadings remains
a
very challenging and important goal. The
cyclopentadienyl phosphine ligand developed by Plenio have demonstrated a broad
substrate scope in Suzuki-Miyaura, Sonogashira, and Buchwald-Hartwig
cross-coupling reaction.14 In addition, the indenyl phosphine ligands developed by our
group have been widely used in cross-coupling reaction (Figure 2).15 Herein, we
report a novel aryl substituted indenyl monophosphine ligand, We expected that this
ligand would afford excellent reactivity for the syntheses of sterically hindered biaryls
using the Suzuki-Miyaura coupling reaction with low-catalyst loadings and therefore
be complementary to existing catalytic system.
Results and discussion
The Synthesis of ligand 2 was accomplished in two steps, which could be prepared on
a gram scale from 2-bromoindene. A palladium-catalyzed Suzuki-Miyaura coupling
reaction of 2-bromoindene and 2, 6-dimethoxyphenyl boronic acid provided 1 in 90%
yield. Straightforward deprotonation of 1 using nBuLi followed by reaction of the
lithiated intermediate with dicyclohexyl phosphine chloride (Cy2PCl) gave the
air-stable monophosphine ligand 2 in 70% yield (Scheme 1).
We initially investigated the reaction of 2-bromomesityl with naphthenylboronic
acid to establish the performance of ligand 2 in the Suzuki-Miyaura coupling reaction
and to optimize the reaction conditions (Table 1). First, the reaction was conducted
without any base and/or phosphine ligand and no product was obtained (Table 1,
entries 1–3). Then, 2.0 mol% of phosphine ligand 2 and 3.0 equivalent tBuONa were
2

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used to give the coupling product in 81% yield (Table 1, entry 4). Whereas low
conversions were generally observed in this challenging cross-coupling reaction with
indenyl phosphine ligands such 13, 14 and 15 (Table 1, entries 5–7). The use of base
was found to be crucial for a high yield in the reaction. While strong bases (such as
tBuOK) provided almost no desired product (Table 1, entry 8), the use of weak bases
(such as Cs2CO3 and CsF) gave excellent yields (Table 1, entries 9, 10). Among the
various bases employed, K3PO4 proved to be most efficient and provided the desired
coupling product in 99% yield (Table 1, entry 11). Studies to determine the efficiency
of the catalyst showed that the reaction occurred to completion after 3 h at 110 ºC in
99% yield with 0.1 mol% of catalyst (Table 1, entry 12). The reaction conducted with
0.05 mol% of Pd(OAc)2 and 0.10 mol% of ligand 2 gave 98% conversion at 110 ºC
after 3 h (Table 1, entry 13). Also, the reaction occur to almost full completion in 98%
yield after 3 h at 110 ºC with 0.025 mol% of catalyst (Table 1, entry 14) and to 36%
conversion with only 0.01 mol% catalyst (Table 1, entry 15). For comparison, several
commercially available phosphine ligands, such as CyJohnPhos, RuPhos and
BrettPhos provided low to moderate conversions (Table 1, entries 16–18). To further
expand the application of ligand 2, the optimized reaction conditions were established
using Pd(OAc)2 (0.05 mol%)/2 (0.10 mol%) as the catalyst, K3PO4 as the base and
toluene (2.0 mL) as the solvent at 110 ºC for 3 h.
Using the optimized reaction conditions, we then looked into the substrate scope of
the catalytic system using Pd(OAc)2/2 in the Suzuki-Miyaura coupling reaction of
sterically demanding substrates. As illustrated in Table 2, aryl bromides bearing
electron-donating substituents such as –CH3 and –OCH3 in the ortho position were
coupled with 1-naphthylboronic acid to afford the corresponding biaryl products in
very high yield (Table 2, entries 1, 2). Various di-ortho-substituted aryl halides such
as 2, 6-dimethoxyiodobenzene and 9-bromoanthracene were coupled with
1-naphthylboronic acid to provide tri-ortho-substituted biaryl products in excellent
yield (Table 2, entries 3, 4). Extremely hindered 1-bromo-2, 4, 6-triisopropylbenzene
also gave the desired coupling product in 83% yield (Table 2, entry 5). To further
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extend the scope of the reaction using our catalytic system, we investigated the
cross-coupling reaction of aryl chlorides. For example, the reaction of
1-naphthylboronic acid with 2-chlorotoluene gave the desired product in 71% yield
(Table 2, entry 6). Aryl chlorides bearing electron-withdrawing groups such as –CHO,
–NO2, –Cl in the ortho position were also tolerated in the cross-coupling reaction with
1-naphthylboronic acid and gave the desired products in moderate to high yield (Table
2, entries 7-9). Heteroaryl substrates, such as quinolone was compatible (Table 2,
entry 10).
Besides its excellent reactivity in the coupling reaction of sterically hindered
1-naphthylboronic acid, ligand 2 was also used for the coupling of sterically
congested aryl halides (Table 3). For example, 2-methoxyphenylboronic acid
underwent coupling reactions with 2-bromomesitylene in excellent yield under the
optimized conditions (Table 3, entries 1). In addition, sterically demanding
2,6-dimethoxyphenylboronic acid could also react efficiently with 2-bromomesitylene
to afford the corresponding tetra-ortho-substituted biaryl products in good yield
(Table 3, entry 2). The reaction of 2,6-dimethylphenylboronic acid with
1-iodo-2,6-dimethoxybenzene also gave the tetra-ortho-substituted biaryl product in
90% yield (Table 3, entry 3). Moreover, we investigated the coupling reaction of
9-bromoanthracene with ortho-substituted phenylboronic acids with high yields being
obtained in the case of 2-methylphenylboronic acid and 2-methoxyphenylboronic acid
(Table 3, entries 4, 5).
The catalytic system using Pd(OAc)2/2 was also applicable for the coupling of
sterically congested 2-chloro-2,6-m-xylene (Table 4). For example, the reaction of
2-chloro-2, 6-m-xylene with 1-naphthylboronic acid gave the desired product in
almost quantitative yield (Table 4, entry 1). The reaction of 2-chloro-2, 6-m-xylene
with aryl boronic acids bearing electron-donating substituents such as –OCH3 and –
CH3 in the para position gave the corresponding tri-ortho-substituted biaryl products
in moderate yield (Table 4, entries 2, 3). Phenyl boronic acid bearing the
electron-withdrawing group –CF3 in the ortho position was also tolerated in the
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reaction with 2-chloro-2, 6-m-xylene and gave the desired product in 66% yield
(Table 4, entry 4).
Conclusion
In summary, we have demonstrated a highly efficient method to perform the
Suzuki-Miyaura coupling reaction of sterically demanding substrates using
Pd(OAc)2/2. The Pd(OAc)2/2 catalyst system is efficient for the synthesis of
functionalized tri- and tetra-ortho-substituted biaryls using a low catalyst loading.
This catalytic system has also enabled the synthesis of sterically hindered heteroaryls
using the Suzuki-Miyaura coupling reaction. Work on further applications of this
catalyst system is currently ongoing in our laboratory.
Acknowledgements
The authors would like to thank the National Natural Science Foundation of China
(Nos. 21472060, 21072071 and 21272088), self-determined research funds of CCNU
from the colleges’ basic research and operation of MOE (Nos. CCNU15KFY001,
CCNU15A02012).
Notes and references
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Figure Legends
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Figure 1 Some effective ligands for the Suzuki-Miyaura cross-coupling reaction.
PCy2
PCy2
PCy2
PCy2
10
11
12
13
PCy2
PCy2 Cy2P
N
PCy2
N
15
16
14
Figure 2 Some indenyl phosphine ligands for the cross-coupling reaction.
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2-bromo-1H-indene
K2CO3 (2 M)
B(OH)2
MeO
OMe toluene/H2O (15:1)
Pd(PPh3)4
90 C, 4h
rt, 30 min
OMe
1) n-BuLi, -78 C, 30 min
2) rt, 6 h
OMe
1
OMe
OMe
1) Cy2PCl, -78 C, 30min
2) rt, 6 h
PCy2
2
Scheme 1 Syntheses of Phosphine ligand 2.
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Table 1 Initial screening of Suzuki-Miyaura cross-coupling of 2-bromomesityl with
naphthenylboronic acida
Pd(OAc)2
(mol%)
yield
(%)b
entry
Ligand (mol%)
base
1
2
1.0
1.0
-
-
-
0
tBuONa
-
0
3
1.0
2 (2.00)
0
4
1.0
2 (2.00)
tBuONa
tBuONa
tBuONa
tBuONa
tBuOK
CsF
81
<5
15
15
<5
97
96
99
99
98
98
36
68
75
0
5
1.0
13 (2.00)
14 (2.00)
15 (2.00)
2 (2.00)
6
1.0
7
1.0
8
1.0
9
1.0
2 (2.00)
10
11
12
13
14
15
16
17
18
1.0
2 (2.00)
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
1.0
2 (2.00)
0.1
2 (0.20)
0.05
0.025
0.01
0.025
0.025
0.025
2 (0.10)
2 (0.05)
2 (0.02)
CyJohnPhos (0.05)
RuPhos (0.05)
BrettPhos (0.05)
aReaction conditions: naphthenylboronic acid (1.5 mmol),
2-bromomesityl (1.0 mmol), Pd(OAc)2, ligand 2, base (3.0 equiv),
toluene (1.5 mL), 110 °C, 3 h. bIsolated yield.
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Table 2 Suzuki-Miyaura cross-coupling reactions of naphthenyl boronic acid with aryl
halidesa
yield
entry
1
Ar
product
(%)b
97
2
3
95
92
4
5
94
83
71
85
95
94
86
6
7
8
9
10
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aReaction conditions: naphthenylboronic acid (1.5
mmol), 2-bromomesityl (1.0 mmol), Pd(OAc)2 (0.05
mol %), ligand 2 (0.10 mol %), K3PO4 (3.0 equiv),
toluene (1.5 mL), 110 °C, 3 h. bIsolated yield.
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Table 3 Suzuki-Miyaura cross-coupling reactions of sterically hindered aryl bromides and
aryl iodidesa
yield (%)b
entry
1
ArX
Ar’B(OH)2
product
98
81
90
2
3
OMe
OMe
94
88
4
5
aReaction conditions: arylboronic acid (1.5 mmol), aryl bromides
or aryl iodies (1.0 mmol), Pd(OAc)2 (0.05 mol %), ligand 2 (0.10
b
mol %), K3PO4 (3.0 mmol), toluene (1.5 mL), 110 °C, 3 h. Isolated
yield.
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Table 4 Suzuki-Miyaura cross-coupling reactions of 2-chloro-2, 6-m-xylene with aryl
boronic acidsa
yield
entry
1
Ar
product
(%)b
99
2
3
4
65
82
66
aReaction
conditions:
2-chloro-1,3-dimethyl
benzene(1.0 mmol), arylboronic acid (1.5 mmol),
Pd(OAc)2 (1.0 mol %), ligand 2 (2.0 mol %), K3PO4
(3.0 equiv) in toluene at 110 °C for 24 h.bIsolated
yields.
14