Facile synthesis of NC(sp3)O pincer palladium complexes and their use as efficient catalysts for Suzuki-Miyaura reaction of aryl bromides in aqueous medium

Article abstract of DOI:10.1016/j.jorganchem.2020.121645

Two NC(sp³)O pincer palladium(II) complexes 3a-3b were readily prepared in high yields in only two steps. Of the first step, catalytic hydrophosphination of 2-alkenoylpyridines and subsequent in situ phosphine oxidation produced the NC(sp³)O pincer preligands 2a-2b. The second step is palladation of the preligands 2a-2b where PdCl₂ was used as the Pd source to afford the desired Pd pincers 3a-3b via C(sp³)-H bond activation. Single crystal X-ray diffraction analysis of complex 3a unambiguously confirmed the NCO tridentate coordination mode of the complexes. The two complexes 3a-3b were applied to catalyze the Suzuki-Miyaura reaction. Complex 3b was found to be more efficient and exhibited very high activity in the Suzuki reaction of structurally diverse aryl bromides with arylboronic acids in aqueous ethanol under air. At a reaction temperature of 70 °C, a TON of up to 1.9 × 10⁵ and a TOF of up to 9800 h^?1 were achieved. At lower temperatures 3b was still very active, giving a TON of up to 9.5 × 10³ and a TOF of up to 3900 h^?1 at room temperature.

Full text of DOI:10.1016/j.jorganchem.2020.121645

Journal of Organometallic Chemistry 932 (2021) 121645
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Facile synthesis of NC(sp3)O pincer palladium complexes and their use
as efficient catalysts for Suzuki-Miyaura reaction of aryl bromides in
aqueous medium
Ya-Ping Pan, Nan Li, Jing-Jing Yang, Zhi-Wu Zhu, Jun-Fang Gong∗, Mao-Ping Song
College of Chemistry, Green Catalysis Center, Zhengzhou University, Zhengzhou 450001, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Two NC(sp3)O pincer palladium(II) complexes 3a-3b were readily prepared in high yields in only two
steps. Of the first step, catalytic hydrophosphination of 2-alkenoylpyridines and subsequent in situ phos-
phine oxidation produced the NC(sp3)O pincer preligands 2a-2b. The second step is palladation of the
preligands 2a-2b where PdCl2 was used as the Pd source to afford the desired Pd pincers 3a-3b via
C(sp3)-H bond activation. Single crystal X-ray diffraction analysis of complex 3a unambiguously confirmed
the NCO tridentate coordination mode of the complexes. The two complexes 3a-3b were applied to cat-
alyze the Suzuki-Miyaura reaction. Complex 3b was found to be more efficient and exhibited very high
activity in the Suzuki reaction of structurally diverse aryl bromides with arylboronic acids in aqueous
ethanol under air. At a reaction temperature of 70 °C, a TON of up to 1.9 × 105 and a TOF of up to 9800
h−1 were achieved. At lower temperatures 3b was still very active, giving a TON of up to 9.5 × 103 and
a TOF of up to 3900 h−1 at room temperature.
Article history:
Received 8 July 2020
Revised 16 October 2020
Accepted 1 December 2020
Available online 2 December 2020
Keywords:
NC(sp3)O pincer palladium(II) complex
Catalytic hydrophosphination
C(sp3)-H activation
Room temperature Suzuki-Miyaura reaction
Aryl bromide
Aqueous medium
© 2020 Elsevier B.V. All rights reserved.
1 Introduction
nite)(imine) H [27] and (aminophosphine)(pyrazole) I [28] as well
as (imine)(thiophosphinite) NCS pincers J [29] were all success-
Palladium(II) pincer complexes with monoanionic tridentate lig-
ands have been extensively investigated and widely used as cat-
alysts in organic transformations [1–13], ever since the indepen-
dent pioneering works of Moulton and Shaw [14], van Koten
and Noltes [15] in the late 1970s. Of particular significance, a
broad variety of these complexes have been developed as ef-
fective catalysts for the Suzuki-Miyaura (SM) coupling reaction
of aryl halides with arylboronic acids, providing a powerful tool
for the construction of important biaryl compounds [13]. The
first example of pincer Pd complex catalyzed SM coupling ap-
peared in 2000 where Bedford and co-workers demonstrated that
aryl-based bis(phosphinite) PCP pincer Pd complex A (X = TFA,
Fig. 1) exhibited high activity with a turnover number (TON) of
up to 1.9 × 105 in the reactions of aryl bromides [16]. This
work inspired the subsequent development of many more pin-
fully applied to the SM reaction. Among the reported pincer Pd
catalysts, complex C showed extremely high activity with a TON
of up to 106 and a turnover frequency (TOF) of up to 1.5 × 106
h−1 in the couplings of aryl bromides [20]. Furthermore, with a
catalyst loading of 0.1 mol% of complex C, the coupling of non-
activated chlorides such as chlorobenzene proceeded efficiently
and afforded the desired coupled product in a reaction time as
short as 1.5 h. Complex B was also able to accomplish the coupling
of non-activated aryl chlorides, albeit with a relatively high cata-
lyst loading (1 mol%) [19]. Importantly, complexes C [21], D [23],
E [25] and I [28] performed very well when the reactions of aryl
bromides were conducted in aqueous medium or in neat water.
In contrast to the wide applications of aryl-based pincer Pd
complexes in catalysis such as in Suzuki reaction as described
above, researches on the aliphatic pincer Pd complexes with
C(sp3)-Pd bonds are far less common [30–32]. In particular, those
cer Pd catalysts (Fig. 1). As
PCP pincers [16–18] and
a
result, besides bis(phosphinite)
[19], bis(aminophosphine) PCP
ꢀ
A
B
on unsymmetrical EC(sp3)E Pd pincers remain scarce. This is
pincers [20–22] such as C, NCN pincers [23–26] such as
bis(pyrazole) D, bis(thiazole) E and (oxazoline)(pyrazole) F, hy-
brid PCN pincers such as (phosphinite)(pyrazole) G [18], (phosphi-
partly because the synthesis of these complexes via C(sp3)-H acti-
vation has been a considerable challenge. Additionally, unlike aro-
matic ligands, the appropriate aliphatic pincer preligands are usu-
ally difficult to obtain. To the best of our knowledge, there are
only two reports on the use of EC(sp3)E Pd pincers as catalysts
for Suzuki reaction (Fig. 2). One is from Olsson and Wendt who
∗
Corresponding authors.
E-mail address: gongjf@zzu.edu.cn (J.-F. Gong).
https://doi.org/10.1016/j.jorganchem.2020.121645
0022-328X/© 2020 Elsevier B.V. All rights reserved.

Y.-P. Pan, N. Li, J.-J. Yang et al.
Journal of Organometallic Chemistry 932 (2021) 121645
ꢀ
Fig. 1. Selected examples of aryl-based EC(sp2)E and EC(sp2)E pincer Pd catalysts for the Suzuki-Miyaura reaction.
a chiral NC(sp3)O pincer Pd complex (Scheme 1) [46]. This pro-
cedure provides a direct and convenient method for the synthesis
ꢀ
of rare and unsymmetrical EC(sp3)E Pd pincers [47–49]. Unfortu-
nately, the yield of the obtained chiral Pd pincer was rather mod-
est. To further expand the chemistry and practical applications of
aliphatic sp3-carbometalated pincer Pd complexes, herein we re-
port the synthesis of achiral NC(sp3)O pincer Pd complexes 3a-3b
(Scheme 2) by modifying the procedure for the preparation of chi-
ral NC(sp3)O Pd pincer. The obtained Pd complexes 3 were applied
to the Suzuki reaction of aryl bromides with arylboronic acids.
Fig. 2. Reported aliphatic PC(sp3)P pincer Pd catalysts for the Suzuki-Miyaura reac-
tion.
found that with the cyclohexyl-based PC(sp3)P Pd pincer K as the
catalyst a temperature as high as 160 °C was needed to achieve ac-
ceptable results [33]. The other report is by Frech and co-workers
showing an adamantyl-based PC(sp3)P Pd pincer L to be a more
efficient catalyst, which worked well under much milder reaction
conditions (in water/NaOH or toluene/K3PO4 at 100 °C) with a TON
of up to 104 and a TOF of up to 4 × 104 h−1 for the coupling of
various aryl bromides [34].
2. Results and discussion
2.1. Synthesis and characterization
As shown in Scheme 2, bis(phosphinite) PCP pincer Pd complex
A (X = Cl) catalyzed hydrophosphination of 2-alkenoylpyridines
1a-1b with diphenylphosphine was carried out in toluene at room
temperature. Upon completion of the catalytic hydrophosphination,
aqueous H2O2 was added directly to the reaction mixture to enable
in situ phosphine oxidation and the pyridine-functionalized phos-
phine oxides 2a-2b were thus obtained in 78 and 87% yields, re-
spectively. Subsequently, the resulting NC(sp3)O pincer preligands
2 reacted with PdCl2 in the presence of Et3N in CH2Cl2 at 50 °C
In our previously reported studies, we synthesized a wide vari-
ety of achiral and chiral pincer Pd complexes and explored their
potentials in Pd-catalyzed organic transformations [18,26,27,35–
ꢀ
45]. It was found that the achiral PCP complexes A (X = Cl), NCN
complexes F as well as PCN complexes G and H were all effec-
tive catalysts for the Suzuki reaction of both aryl bromides and ac-
tivated aryl chlorides even at a temperature as low as 40–50 °C
[18,26,27,43]. In a more recent study on the chiral PCN pincer Pd
catalyzed asymmetric hydrophosphination of 2-alkenoylpyridines,
we discovered that phosphine oxide of the catalysis product was
able to react with PdCl2 in CH2Cl2 at room temperature to give
–
where the desired C H palladation of the preligands occurred ef-
ficiently to afford the NC(sp3)O pincer Pd(II) complexes 3a-3b in
89 and 83% yields, respectively. The overall yields of the two com-
plexes reached ~70%. It is worthy to point out that all the materi-
als and reagents employed in above synthetic procedure are either
commercially available or can be easily synthesized. For example,
Scheme 1. Synthesis of a chiral NC(sp3)O pincer Pd complex.
2

Y.-P. Pan, N. Li, J.-J. Yang et al.
Journal of Organometallic Chemistry 932 (2021) 121645
Scheme 2. Synthesis of achiral NC(sp3)O pincer Pd complexes.
Table 1
˚
Selected bond lengths (A) and angles
(deg) for complex 3a.
Complex
3a
Pd(1)-C(7)
2.030(4)
Pd(1)-N(1)
2.020(4)
Pd(1)-O(2)
2.063(3)
Pd(1)-Cl(1)
2.4034(12)
83.52(15)
86.39(13)
177.28(11)
169.83(13)
95.94(10)
94.09(8)
C(7)-Pd(1)-N(1)
C(7)-Pd(1)-O(2)
C(7)-Pd(1)-Cl(1)
N(1)-Pd(1)-O(2)
N(1)-Pd(1)-Cl(1)
O(2)-Pd(1)-Cl(1)
Table 2
Summary of crystal structure determination for complex 3a.
Fig. 3. Molecular structure of complex 3a with ellipsoids drawn at the 50% proba-
bility level (hydrogen atoms are omitted for clarity).
Complex
3a
Formula
Mr
C
26H21ClNO2PPd
552.26
temp [K]
291(2)
the Pd pincer catalyst A (X = Cl) for hydrophosphination was con-
veniently prepared via a one-pot phosphorylation/palladation re-
action, that is, by simply mixing resorcinol, Ph2PCl and PdCl2 in
the presence of Et3N in refluxing toluene [18]. It is also interesting
to note that through a pincer Pd complex catalyzed hydrophosphi-
nation reaction and the ensuing in situ phosphine oxidation, the
pincer preligands 2 were produced in just one step with high ef-
ficiency. In the synthesis of pincer Pd complexes that are either
sp2-carbometalated or sp3-carbometalated, preparation of the re-
quired pincer preligands via a catalyzed reaction is not very com-
mon. In addition, despite the fact that in the literature Pd(OAc)2,
[PdCl2(RCN)2] (R = Ph or Me) and [PdCl2(COD)] are more often
˚
wavelength [A]
cryst syst
0.71073
orthorhombic
space group
cryst size [mm]
Pbca
0.2 × 0.16 × 0.16
˚
a [A]
11.528(3)
˚
b [A]
17.256(5)
˚
c [A]
23.198(4)
α [deg]
β [deg]
90.00
90.00
γ [deg]
90.00
3
˚
V [A ]
4615.0(19)
Z
8
Dcalcd [g cm−3
μ [mm−1
]
1.590
]
1.013
–
used as palladation reagent in the C H activation step for the con-
θ range [deg]
2.942 to 26.369
index range
−14 ≤ h ≤ 6, -21 ≤ k ≤ 13, -28 ≤ l ≤ 26
–
struction of Pd pincers, we have shown above that the desired C H
no. of data collected
no. of unique data
12,691
bond even a C(sp3)-H bond activation can also be readily accom-
plished by using PdCl2 as the Pd source. Taken together, the syn-
thesis of complexes 3a-3b is facile, convenient and high-yielding,
which provides additional examples of rare and unsymmetrical
4710
final R indices [I >2σ(I)]
R1 = 0.0427
wR2 = 0.0922
R1 = 0.0629
wR2 = 0.1047
2224
R indices [all data]
ꢀ
EC(sp3)E pincer Pd complexes.
F(000)
The molecular structure of complex 3a was unambiguously de-
termined by single crystal X-ray diffraction analysis. The molecule
is illustrated in Fig. 3. Selected bond lengths and bond angles
are listed in Table 1. Details of crystal structure determination for
complex 3a are given in Table 2. Fig. 3 shows clearly that the
pyridine-functionalized phosphine oxide 2a acts as a NC(sp3)O tri-
dentate ligand when complexed with palladium, leading to the
formation of the pincer Pd complex 3a. The palladium atom fea-
tures a distorted-square-planar geometry with tridentate coordina-
tion of the ligand 2a via pyridine-N, the sp3-C adjacent to carbonyl
group and the phosphine oxide-O to the Pd(II) center and the chlo-
−3
˚
Largest diff. peak/hole [e A
]
1.410/−0.441
ride occupying the fourth coordination site. The two fused five-
membered palladacycles are thus formed in which the two pal-
ladacycles both adopt envelope conformation. The Pd-C and Pd-O
˚
bond lengths in complex 3a are 2.030(4) and 2.063(3) A, respec-
tively, which are slightly shorter than those in the related chiral
NC(sp3)O Pd complex [46]. While the Pd-N and Pd-Cl distances are
slightly longer than those in the chiral complex [46]. All of the
3

Y.-P. Pan, N. Li, J.-J. Yang et al.
Journal of Organometallic Chemistry 932 (2021) 121645
Table 3
Suzuki coupling of 2-bromotoluene with phenylboronic acid catalyzed by the NC(sp3)O pincer Pd(II) complexes 3a.
Entry
Cat. (mol%)
Solvent
Base
Temp. ( °C)
Time (h)
Yieldb (%)
1
3b (0.1)
EtOH
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
70
70
110
110
70
70
70
70
70
70
70
70
70
12
12
12
12
12
12
24
12
6
65
56
47
26
98
80
79
98
98
98
85
81
92
2
3b (0.1)
MeOH
Toluene
DMF
3
3b (0.1)
4
3b (0.1)
c
c
c
c
c
c
c
c
c
–
EtOH H2O
5
3b (0.1)
–
EtOH H2O
6
3b (0.01)
3b (0.01)
3b (0.01)
3b (0.01)
3b (0.01)
3a (0.01)
3b (0.001)
3b (0.001)
–
EtOH H2O
7
–
EtOH H2O
8
–
EtOH H2O
9
–
10
11
12
13
EtOH H2O
2
–
EtOH H2O
2
–
EtOH H2O
12
24
–
EtOH H2O
a
Reaction conditions: 2-bromotoluene (0.5 mmol), PhB(OH)2 (0.6 mmol), pincer Pd cat. 3, base (1.0 mmol), sol-
c
vent (3.0 mL), under air. bIsolated yield. EtOH H2O (v/v = 1:1, 3.0 mL).
–
bond angles around the Pd(II) center are comparable to those in
the chiral complex [46] with the C-Pd-Cl and N-Pd-O angles be-
ing177.28(11)° and 169.83(13)°, respectively.
4–OCH3- and 3–OCH3-substituted aryl bromides, the activated 4-
NO2- bromide and the non-activated 4-CH3- bromide as well as
sterically hindered 2-CH3-substituted aryl bromide all proceeded
very well, affording the corresponding products in excellent yields
after 24 h (entries 3,4,7,8 and also Table 3, entry 13). By contrast,
in the case of 2-bromoanisole, a reactant both electronically deacti-
vated and sterically hindered, a higher catalyst loading than 0.001
mol% was needed to achieve an excellent yield within 24 h (en-
tries 5 and 6). On the other hand, for the 4-CH3- and 4-CHO- aryl
bromides, a catalyst loading as low as 0.0005 mol% was sufficient
to ensure highly efficient couplings (entries 9 and 10). In compari-
son with aryl bromides, heteroaryl bromides were much less reac-
tive. When 3-bromopyridine was subjected to the reaction with a
catalyst loading of 0.01 mol%, the expected 3-phenylpyridine was
obtained in only 63% yield after 24 h (entry 11).
2.2. Catalytic properties of Pd complexes
At the outset the coupling of sterically hindered 2-
bromotoluene with phenylboronic acid was chosen as a model to
evaluate the catalytic potential of the obtained NC(sp3)O pincer Pd
complexes in the Suzuki reaction (Table 3). The desired coupled
product was obtained in 65% yield after 12 h when the reaction
was carried out with 0.1 mol% of complex 3b as the catalyst in
the presence of K3PO4 base in EtOH under air at 70 °C (entry
1). Changing the solvent from EtOH to MeOH, toluene or DMF
(and also elevating the reaction temperature to 110 °C in the
latter two solvents) did not afford better results (26–56% yields,
The above data indicate that pincer Pd complex 3b is a very
efficient catalyst for the Suzuki couplings of aryl bromides with
phenylboronic acid at 70 °C. This finding prompted us to inves-
tigate how well complex 3b would perform catalytically at lower
reaction temperature such as 50 °C and particularly at room tem-
perature. In the literature the related such reports remain very
few [26–28,43] and pincer Pd catalysts often exhibited low ac-
tivity when the reactions were conducted at lower temperatures.
For example, with 1 mol% of complex B (Fig. 1) as the catalyst
the reaction of 2-bromotoluene with 4-tolylboronic acid in diox-
ane at 50 °C gave the coupled product in merely 45% yield after
20 h [19]. When 0.01 mol% of aliphatic adamantyl-based PC(sp3)P
Pd pincer L (Fig. 2) was used to catalyze the coupling of phenyl
bromide with phenylboronic acid in water at 50 °C, 86% conver-
sion into biphenyl could be achieved after 6 h. However, for the
same reaction at room temperature only 2% conversion was ob-
served after 6 h [34]. Therefore, development of effective pincer
Pd catalysts for the Suzuki-Miyaura reaction at lower temperature
is highly desirable. Thus, we conducted the following series of cou-
pling reactions between aryl bromides and arylboronic acids, us-
ing complex 3b as the catalyst at a reaction temperature of 50
°C (Table 5). We were pleased to find that complex 3b also ex-
hibited high activity at 50 °C with a TON of up to 9.9 × 103
and a TOF of up to 9900 h−1. With a catalyst loading as low as
0.01 mol%, 2–bromo and 4-bromotoluene, 4–bromo, 3–bromo and
2-bromoanisole, 4-bromobenzaldehyde, 4-bromobenzonitrile, 1,3-
dibromobenzene were all successfully coupled with phenylboronic
acid or substituted phenylboronic acids to deliver the correspond-
–
entries 2–4). Pleasingly, the use of EtOH H2O mixture (1:1) as the
solvent gave an excellent yield of 98% (entry 5). We then tried to
reduce the loading of complex 3b. When the catalyst loading was
reduced to 0.01 mol%, the yields decreased dramatically to ~80%
(entries 6 and 7). However, by replacing K3PO4 base with K2CO3,
excellent yield (98%) was achieved again (entry 8). Furthermore,
with K2CO3 as the base excellent yields were still obtained in a
shorter reaction time such as in a time as short as 2 h (entries 9
and 10). Under the same conditions, complex 3a showed a lower
activity than complex 3b (85%, entry 11 vs 98% yield, entry 10).
Further reducing the catalyst loading of complex 3b to 0.001
mol% resulted in an obviously decreased yield of 81% (entry 12 vs
8). Fortunately, prolonging the reaction time from 12 h to 24 h
provided an excellent yield of 92% at this level of catalyst loading
of 0.001 mol% (entry 13).
Based on the above results, the Suzuki coupling reactions of a
variety of electronically and structurally diverse aryl bromides with
phenylboronic acid were investigated with complex 3b as the cat-
–
alyst in the presence of K2CO3 base in EtOH H2O under air at 70
°C (Table 4). As shown in Table 4, complex 3b exhibited very high
activity with the TON value reached up to 1.9 × 105 and the TOF
value up to 9800 h−1 in these couplings. With a catalyst loading of
0.01 mol%, both sterically hindered 2-bromotoluene and electron-
ically deactivated 4-bromoanisole reacted smoothly with phenyl-
boronic acid to deliver the desired products in excellent yields af-
ter only one hour (entries 1 and 2). When the catalyst loading was
decreased to 0.001 mol%, the reactions of electronically deactivated
4

Y.-P. Pan, N. Li, J.-J. Yang et al.
Journal of Organometallic Chemistry 932 (2021) 121645
Table 4
Suzuki couplings of aryl bromides with phenylboronic acid at 70 °C catalyzed by the NC(sp3)O pincer Pd(II) complex 3ba.
Entry
Cat. (mol%)
R
Time (h)
Yieldb (%)
TONc
TOFd (h−1
)
1
0.01
2-CH3
4–OCH3
4–OCH3
3–OCH3
2–OCH3
2–OCH3
4-NO2
4-CH3
4-CH3
4-CHO
–
1
95
98
99
99
76
95
99
98
96
92
63
9500
9500
9800
4125
4125
3167
1583
4125
4083
8000
7667
263
2
0.01
1
9800
3
0.001
0.001
0.001
0.005
0.001
0.001
0.0005
0.0005
0.01
24
24
24
12
24
24
24
24
24
99,000
99,000
76,000
19,000
99,000
98,000
192,000
184,000
6300
4
5
6
7
8
9
10
11e
a
–
Reaction conditions: ArBr (0.5 mmol), PhB(OH)2 (0.6 mmol), pincer Pd cat. 3b, K2CO3 (1.0 mmol), EtOH H2O (v/v = 1:1, 3.0 mL),
70 °C, under air. bIsolated yield. cTON: Turnover number. Defined as moles of product per mole of catalyst. dTOF: Turnover fre-
quency. Defined as moles of product per mole of catalyst per hour. e3-bromopyridine was used as the substrate.
Table 5
Suzuki couplings of aryl bromides with arylboronic acids at 50 °C catalyzed by the NC(sp3)O pincer Pd(II) complex 3ba.
Entry
R1
R2
Time (h)
Yieldb (%)
TONc
TOFd (h−1
)
1
2-CH3
4–OCH3
3–OCH3
2–OCH3
4-CH3
4-CHO
4-CN
H
1
1
1
4
1
1
1
7
5
3
2
4
94
93
98
95
99
99
99
94
96
96
98
98
9400
9300
9800
9500
9900
9900
9900
9400
9600
9600
9800
9800
9400
9300
9800
2375
9900
9900
9900
1343
1920
3200
4900
2450
2
H
3
H
4
H
5
H
6
H
7
8e
H
3-Br
H
9
2-CH3
4-CH3
4-CH3
4–OCH3
4–OCH3
4–OCH3
2–OCH3
3-Cl
10
11
12
a
–
Reaction conditions: ArBr (0.5 mmol), ArB(OH)2 (0.6 mmol), pincer Pd cat. 3b (0.01 mol%), K2CO3 (1.0 mmol), EtOH H2O (v/v = 1:1,
3.0 mL), 50 °C, under air. bIsolated yield. cDefined as moles of product per mole of catalyst. dDefined as moles of product per mole of
catalyst per hour. e1,3-dibromobenzene (0.5 mmol), PhB(OH)2 (1.2 mmol), K2CO3 (2.0 mmol).
ing biaryl products in 93–99% yields within several hours. In most
cases, excellent yields were achieved after only 1–2 h. Particularly,
the reactions of electronically deactivated and/or sterically hin-
dered 2-bromoanisole and 2-bromotoluene also proceeded quite
well in a short reaction time (entries 1,4 and 9). Furthermore, for
the reactions of 2-bromotoluene and 4-bromoanisole with phenyl-
boronic acid, decreasing the temperature from 70 °C to 50 °C did
not result in any appreciable loss of the activity of complex 3b
(Table 4, entries 1 and 2 vs Table 5, entries 1 and 2).
and/or sterically hindered 2-bromoanisole and 2-bromotoluene re-
acted very well with arylboronic acids at room temperature, fur-
nishing the corresponding biaryls in excellent yields (entries 8–
11). Overall, complex 3b was a quite effective catalyst for the
Suzuki reaction of aryl bromides with arylboronic acids. Espe-
cially, the complex maintained high activity in the room temper-
ature reactions. But unfortunately, employment of complex 3b as
catalyst for the Suzuki reaction of 4-chlorotoluene with phenyl-
boronic acid proved to be unsuccessful. The desired coupled prod-
uct was obtained in rather low yields (5–17%) with a catalyst load-
ing of 0.1–1.0 mol% (for details see Table S1 in the Supporting
Information).
Considering the high activity of complex 3b at 50 °C, we next
explored its performance at room temperature (Table 6). The re-
action of 4-bromoanisole with phenylboronic acid was first tested
(entries 1 and 2). In the presence of 0.01 mol% complex 3b as
the catalyst, a promising yield of 39% was obtained after 1 h
even though the yield was much lower than that at 50 °C (39%
vs 93%). By extending the reaction time to 12 h, a good yield
of 79% was achieved (entry 2). Under these conditions, reactions
of the more reactive 4-bromotoluene and 4-bromobenzaldehyde
with phenylboronic acid provided the coupled products in excel-
lent yields as expected (95%, entries 3 and 4). When the catalyst
loading was increased to 0.1 mol%, good to excellent yields (86–
98%) could be achieved within several hours for the reactions of
some representative aryl bromides with arylboronic acids (entries
5–11). Of particular significance is that electronically deactivated
To further explore the practical potential of complex 3b-
catalyzed Suzuki reaction, we conducted the reactions of 3,5-
dibromophenol with arylboronic acids catalyzed by 3b for the syn-
thesis of 3,5-diarylphenols 4a-b, which are the key precursors to
the inhibitors of the luteinizing hormone (LH) receptor [50]. With
a catalyst loading of 0.01 mol% the reaction on a 0.5 mmol scale
proceeded well, delivering the desired product 4a in a 92% yield
(Scheme 3). However, the yield dropped dramatically to 76% when
the same reaction was scaled up to 5 mmol level. Gratifyingly,
upon increasing the catalyst loading to 0.05 mol%, the gram-scale
syntheses of 4a and 4b were successfully accomplished with 98%
and 95% yields, respectively (Scheme 3).
5

Y.-P. Pan, N. Li, J.-J. Yang et al.
Journal of Organometallic Chemistry 932 (2021) 121645
Table 6
Suzuki couplings of aryl bromides with arylboronic acids at room temperature catalyzed by the NC(sp3)O pincer Pd(II) complex 3ba.
Entry
Cat. (mol%)
R1
R2
Time (h)
Yieldb (%)
TONc
TOFd (h−1
)
1
0.01
0.01
0.01
0.01
0.1
4–OCH3
4–OCH3
4-CH3
H
1
39
79
95
95
94
96
86
97
97
90
98
3900
7900
9500
9500
940
3900
658
792
792
313
384
143
323
121
150
327
2
H
12
12
12
3
3
H
4
4-CHO
4–OCH3
4-CH3
H
5
H
6
0.1
H
2.5
6
960
7
0.1
4-NO2
2-CH3
H
860
8
0.1
H
3
970
9
0.1
2–OCH3
2-CH3
H
8
970
10
11
0.1
4–OCH3
3-Cl
6
900
0.1
2-CH3
3
980
a
–
Reaction conditions: ArBr (0.5 mmol), ArB(OH)2 (0.6 mmol), pincer Pd cat. 3b, K2CO3 (1.0 mmol), EtOH H2O (v/v = 1:1, 3.0 mL),
room temperature, under air. bIsolated yield. cDefined as moles of product per mole of catalyst. dDefined as moles of product per mole
of catalyst per hour.
Scheme 3. Application of complex 3b in the synthesis of 3,5-diarylphenols.
In order to gain some insights into the mechanism of the
complex 3b-catalyzed Suzuki reaction, the mercury drop exper-
iments were performed. Specifically, the coupling reaction of 4-
bromobenzaldehyde with phenylboronic acid catalyzed by 0.0005
the yield but did not inhibit the reaction (81% vs 94% in entry 5,
Table 6). The result indicated that the room temperature reactions
likely occurred through a mechanism different from that of the re-
actions at 70 °C.
–
mol% of 3b was carried out in EtOH H2O (1:1) at 70 °C and with
addition of one drop of elemental mercury. It turned out that the
reaction was almost completely inhibited by the presence of mer-
cury and the desired coupled product was obtained in only 3%
yield after 24 h (3% vs 92% in entry 10, Table 4). The result sug-
gested that at 70 °C palladium nanoparticles were probably the
catalytically active form of complex 3b and the reactions likely
proceeded via a classical Pd(0)/Pd(II) catalytic cycle consisting of
oxidative addition, transmetalation and reductive elimination steps.
For the pincer Pd(II)-catalyzed Suzuki reaction, it was reported that
in many cases pincer Pd(II) complexes acted as precursors for the
release of palladium nanoparticles as the active catalytic species
[19,21,29]. On the other hand, the addition of one drop of mercury
to the room temperature reaction of 4-bromoanisole with phenyl-
boronic acid catalyzed by 0.1 mol% of 3b led to some decrease in
2.3. Conclusions
In summary, we have synthesized two NC(sp3)O pincer palla-
dium(II) complexes in a facile, convenient and high-yielding fash-
ion. Complex 3b was found to be a highly efficient catalyst for the
Suzuki reaction of aryl bromides with arylboronic acids in aqueous
ethanol under air. In particular, this complex still exhibited high
activity even at room temperature, which is rare for the Pd pin-
cer catalysts suggested for this reaction. Mercury drop experiments
indicate that palladium nanoparticles may be the actual catalytic
species for reactions at 70 °C while for reactions at room temper-
ature other catalytically active form of complex 3b is responsible
for the high activity.
6

Y.-P. Pan, N. Li, J.-J. Yang et al.
3. Experimental
3.1. General
Journal of Organometallic Chemistry 932 (2021) 121645
was purified by column chromatography on silica gel with EtOAc-
petroleum ether as the eluent to give the biaryl products. All the
products are known compounds and identified by 1H NMR spec-
troscopy.
Solvents were dried with standard methods and freshly distilled
prior to usage if needed. 2-alkenoylpyridines 1a-1b [51] and Pd
pincer catalyst A (X = Cl) [18] were prepared according to the liter-
ature methods. All other chemicals were used as purchased. Melt-
ing points were measured on a WC-1 microscopic apparatus and
were uncorrected. 1H NMR, 13C{1H} NMR and 31P{1H} NMR spectra
were recorded on a Bruker DPX-400 spectrometer in CDCl3 with
TMS as an internal standard for 1H, 13C{1H} NMR and 85% H3PO4
as the external standard for 31P{1H} NMR.
3.4. X-ray diffraction studies
Crystals of 3a (CCDC 1999573) were obtained by recrystalliza-
tion from acetone/n-hexane at ambient temperature. The data were
collected on an Oxford diffraction Gemini E diffractometer with
˚
graphite-monochromated Mo Kα radiation (λ = 0.71073 A). The
structure was solved by direct methods using the SHELXS-97 pro-
gram, and all non-hydrogen atoms were refined anisotropically on
F2 by the full-matrix least-squares technique, using the SHELXL-97
crystallographic software package [52]. The hydrogen atoms were
included but not refined.
3.2. Synthesis of the NC(sp3)O pincer Pd complexes 3a-3b
In a 10 mL Schlenk tube a mixture of PCP pincer Pd cata-
lyst A (12.4 mg, 5 mol%) and KOAc (3.9 mg, 10 mol%) in toluene
(4 mL) was stirred at room temperature for 0.5 h under Ar atmo-
sphere. Upon addition of diphenylphosphine (74.5 mg, 0.4 mmol),
the mixture was stirred for additional 0.5 h. Subsequently, 2-
alkenoylpyridine 1 (0.6 mmol) was added and the resulting mix-
ture was stirred at room temperature for 12 h. Then, H2O2 aqueous
solution (30%, 120 μL) was added to oxidize the catalysis product.
Once being stirred at room temperature for 2 h, the reaction mix-
ture was purified directly by chromatography on silica gel plates
with CH2Cl2/acetone (5/1 or 10/1) as eluent to afford the pyridine-
functionalized phosphine oxides 2.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
Acknowledgments
This research was supported by a grant from the National Nat-
ural Science Foundation of China (21472176).
To a stirred solution of 2 (0.5 mmol) in CH2Cl2 (4 mL) was
added Et3N (84 μL, 0.6 mmol) and PdCl2 (106.4 mg, 0.6 mmol, 1.2
equiv) under Ar atmosphere. After being stirred at 50 °C for 12 h,
the reaction mixture was filtered through Celite. Evaporation of the
solvent gave a residue, which was purified by column chromatog-
raphy on silica gel with CH2Cl2/acetone (5/1) as eluent to give the
NC(sp3)O pincer Pd(II) complexes 3.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.jorganchem.2020.
121645.
References
Complex 3a: pale yellow solids, M.p. 208–209 °C. 1H NMR
(400 MHz, CDCl3): δ 9.08 (d, JHH = 5.3 Hz, 1H), 7.96–7.83 (m, 3H),
7.64–7.52 (m, 7H), 7.46–7.40 (m, 3H), 7.21–7.15 (m, 3H), 6.99–6.97
(m, 2H), 5.20 (dd, JHH = 9.6 Hz, JHP = 4.1 Hz, 1H, PCHCH), 4.92
(dd, JHH = 9.6 Hz, JHP = 16.4 Hz, 1H, PCHCH). 13C NMR (100 MHz,
CDCl3): δ 192.8 (d, JCP = 13.2 Hz), 157.4, 151.5, 139.4, 133.70, 133.65
(d, JCP = 2.5 Hz), 133.2 (d, JCP = 2.6 Hz), 132.9 (d, JCP = 8.9 Hz),
131.8 (d, JCP = 10.0 Hz), 129.0 (d, JCP = 12.0 Hz), 128.9 (d,
JCP = 98.0 Hz), 128.7 (d, JCP = 5.3 Hz), 128.6 (d, JCP = 2.3 Hz),
128.4 (d, JCP = 11.8 Hz), 127.8 (d, JCP = 3.1 Hz), 127.2, 125.0 (d,
JCP = 94.1 Hz), 122.6, 56.0, 48.6 (d, JCP = 72.0 Hz). 31P{1H} NMR
(162 MHz, CDCl3): δ 73.5. Anal. Calcd for C26H21ClNO2PPd.H2O: C,
54.76; H, 4.07; N, 2.46. Found: C, 54.29; H, 4.43; N, 2.15.
Complex 3b [46]: pale yellow solids, M.p. 173–174 °C. 1H NMR
(400 MHz, CDCl3): δ 9.09 (d, JHH = 5.4 Hz, 1H), 7.95–7.91 (m, 1H),
7.85–7.80 (m, 2H), 7.64–7.58 (m, 5H), 7.55–7.50 (m, 2H), 7.46–7.43
(m, 3H), 6.87 (dd, J = 8.6 and 1.9 Hz, 2H), 6.70 (d, JHH = 8.6 Hz,
2H), 5.14 (dd, JHH = 10.0 Hz, JHP = 4.0 Hz, 1H, PCHCH), 4.87 (dd,
JHH = 10.0 Hz, JHP = 16.8 Hz, 1H, PCHCH), 3.75 (s, 3H).
[1] M. Albrecht, G. van Koten, Angew. Chem. Int. Ed. 40 (2001) 3750–3781.
[2] M.E. van der Boom, D. Milstein, Chem. Rev. 103 (2003) 1759–1792.
[3] J.T. Singleton, Tetrahedron 59 (2003) 1837–1857.
[4] R.B. Bedford, Chem. Commun. (2003) 1787–1796.
[5] E. Peris, R.H. Crabtree, Coord. Chem. Rev. 248 (2004) 2239–2246.
[6] D. Pugh, A.A. Danopoulos, Coord. Chem. Rev. 251 (2007) 610–641.
[7] D. Morales-Morales, Mini-Rev. Org. Chem. 5 (2008) 141–152.
[8] J.M. Serrano-Becerra, D. Morales-Morales, Curr. Org. Synth 6 (2009) 169–192.
[9] I. Moreno, R. SanMartin, B. Inés, M.T. Herrero, E. Domínguez, Curr. Org. Chem
13 (2009) 878–895.
[10] N. Selander, K.J. Szabó, Dalton Trans. (2009) 6267–6279.
[11] N. Selander, K.J. Szabó, Chem. Rev. 111 (2011) 2048–2076.
[12] H. Valdés, M.A. García-Eleno, D. Canseco-Gonzalez, D. Morales-Morales, Chem-
CatChem 10 (2018) 3136–3172.
[13] L. González-Sebastián, D. Morales-Morales, J. Organomet. Chem. 893 (2019)
39–51.
[14] C.J. Moulton, B.L. Shaw, J. Chem. Soc., Dalton Trans. (1976) 1020–1024.
[15] G. van Koten, K. Timmer, J.G. Noltes, A.L. Spek, J. Chem. Soc., Chem. Comun.
(1978) 250–252.
[16] R.B. Bedford, S.M. Draper, P.N. Scully, S.L. Welch, New J. Chem 24 (2000)
745–747.
[17] T. Kimura, Y. Uozumi, Organometallics 25 (2006) 4883–4887.
[18] J.-F. Gong, Y.-H. Zhang, M.-P. Song, C. Xu, Organometallics 26 (2007)
6487–6492.
[19] M.C. Lipke, R.A. Woloszynek, L. Ma, J.D. Protasiewicz, Organometallics 28
(2009) 188–196.
3.3. General procedure for Suzuki-Miyaura cross-coupling reactions
[20] J.L. Bolliger, O. Blacque, C.M. Frech, Angew. Chem. Int. Ed. 46 (2007) 6514–6517.
[21] J.L. Bolliger, C.M. Frech, Adv. Synth. Catal 352 (2010) 1075–1080.
[22] D. Benito-Garagorri, V. Bocokic´, K. Mereiter, K. Kirchner, Organometallics 25
(2006) 3817–3823.
[23] F. Churruca, R. SanMartin, I. Tellitu, E. Domínguez, Synlett (2005) 3116–3120.
[24] T. Takemoto, S. Iwasa, H. Hamada, K. Shibatomi, M. Kameyama, Y. Motoyama,
H. Nishiyama, Tetrahedron Lett. 48 (2007) 3397–3401.
[25] Q.-L. Luo, J.-P. Tan, Z.-F. Li, W.-H. Nan, D.-R. Xiao, J. Org. Chem. 77 (2012)
8332–8337.
[26] X.-Q. Hao, Y.-N. Wang, J.-R. Liu, K.-L. Wang, J.-F. Gong, M.-P. Song, J. Organomet.
Chem. 695 (2010) 82–89.
[27] B.-S. Zhang, C. Wang, J.-F. Gong, M.-P. Song, J. Organomet. Chem. 694 (2009)
2555–2561.
A 10 mL Schlenk tube was charged with complex 3b, ArBr
(0.5 mmol), ArB(OH)2 (0.6 mmol), K2CO3 (138.2 mg, 1.0 mmol),
and solvent (3 mL). The mixture was stirred at specified temper-
ature under air for a certain time (monitored by TLC). Upon com-
pletion of the reaction, the mixture was let to cool down (for the
reaction being conducted at room temperature this cooling step
was unnecessary) and quenched with saturated brine, and then
extracted with ethyl acetate (EtOAc) and dried over Na2SO4. Af-
ter filtration and evaporation of the solvent, the resulting residue
7

Y.-P. Pan, N. Li, J.-J. Yang et al.
Journal of Organometallic Chemistry 932 (2021) 121645
[28] B. Inés, R. SanMartin, F. Churruca, E. Domínguez, M.K. Urtiaga, M.I. Arriortua,
Organometallics 27 (2008) 2833–2839.
[41] X.-Q. Hao, Y.-W. Zhao, J.-J. Yang, J.-L. Niu, J.-F. Gong, M.-P. Song,
Organometallics 33 (2014) 1801–1811.
[29] V.A. Kozlov, D.V. Aleksanyan, Y.V. Nelyubina, K.A. Lyssenko, A.A. Vasil’ev,
P.V. Petrovskii, I.L. Odinets, Organometallics 29 (2010) 2054–2062.
[30] D. Gelman, R. Romm, Top. Organomet. Chem. 40 (2013) 289–318.
[31] K.J. Jonasson, O.F. Wendt, Chapter 8, 213-227, in: K.J. Szabó, O.F. Wendt (Eds.),
Pincer and Pincer-Type Complexes: Applications in Organic Synthesis and
Catalysis, Wiley-VCH, Weinheim, 2014.
[42] C. Wang, Y. Li, B. Lu, X.-Q. Hao, J.-F. Gong, M.-P. Song, Polyhedron 143 (2018)
184–192.
[43] J.-L. Niu, X.-Q. Hao, J.-F. Gong, M.-P. Song, Dalton Trans. 40 (2011) 5135–5150.
[44] X.-Q. Hao, J.-L. Niu, X.-M. Zhao, J.-F. Gong, M.-P. Song, Chin. J. Org. Chem. 33
(2013) 663–674.
[45] J.-K. Liu, J.-F. Gong, M.-P. Song, Org. Biomol. Chem. 17 (2019) 6069–6098.
[46] X.-Q. Hao, J.-J. Huang, T. Wang, J. Lv, J.-F. Gong, M.-P. Song, J. Org. Chem. 79
(2014) 9512–9530.
[32] G.C. Dickmu, I.P. Smoliakova, Coord. Chem. Rev. 409 (2020) 213203.
[33] D. Olsson, O.F. Wendt, J. Organomet. Chem. 694 (2009) 3112–3115.
[34] R. Gerber, O. Blacque, C.M. Frech, ChemCatChem 1 (2009) 393–400.
[35] B.-S. Zhang, W. Wang, D.-D. Shao, X.-Q. Hao, J.-F. Gong, M.-P. Song,
Organometallics 29 (2010) 2579–2587.
[47] X.-Y. Yang, W.S. Tay, Y. Li, S.A. Pullarkat, P.-H. Leung, Chem. Commun. 52 (2016)
4211–4214.
[48] W.S. Tay, X.-Y. Yang, Y. Li, S.A. Pullarkat, P.-H. Leung, RSC Adv
75951–75959.
6 (2016)
[36] J.-L. Niu, Q.-T. Chen, X.-Q. Hao, Q.-X. Zhao, J.-F. Gong, M.-P. Song,
Organometallics 29 (2010) 2148–2156.
[49] L.B. Balázs, W.S. Tay, Y. Li, S.A. Pullarkat, P.-H. Leung, Organometallics 37 (2018)
2272–2285.
[37] A.-T. Hou, Y.-J. Liu, X.-Q. Hao, J.-F. Gong, M.-P. Song, J. Organomet. Chem. 696
(2011) 2857–2862.
[38] T. Wang, X.-Q. Hao, X.-X. Zhang, J.-F. Gong, M.-P. Song, Dalton Trans. 40 (2011)
8964–8976.
[39] M.-J. Yang, Y.-J. Liu, J.-F. Gong, M.-P. Song, Organometallics 30 (2011)
3793–3803.
[40] T. Wang, X.-Q. Hao, J.-J. Huang, K. Wang, J.-F. Gong, M.-P. Song, Organometallics
33 (2014) 194–205.
[50] L.H. Heitman, R. Narlawar, H. de Vries, M.N. Willemsen, D. Wolfram, J. Brussee,
A.P. IJzerman, J. Med. Chem. 52 (2009) 2036–2042.
[51] P.K. Singh, V.K. Singh, Org. Lett. 10 (2008) 4121–4124.
[52] (a) G.M. Sheldrick, SHELXS-97, Program for Crystal Structure Solution, Univer-
sity of Göttingen, Göttingen, Germany, 1997; (b) G.M. Sheldrick, SHELXL-97,
Program for Crystal Structure Refinement, University of Göttingen, Göttingen,
Germany, 1997.
8