Flexible Steric Bulky Bis(Imino)acenaphthene (BIAN)-Supported N-Heterocyclic Carbene Palladium Precatalysts: Catalytic Application in Buchwald-Hartwig Amination in Air

Article abstract of DOI:10.1021/acs.joc.6b02867

To achieve efficient palladium-catalyzed cross-coupling reaction under mild reaction conditions with the flexible steric bulk strategy, a series of Pd-PEPPSI (PEPPSI: pyridine-enhanced precatalyst preparation, stabilization, and initiation) complexes C1-C6 were synthesized and characterized, in which unsymmetric flexible steric bulk was introduced on the N-aryl of ancenaphthyl skeleton. These well-defined palladium complexes were found to be excellent precatalysts for Buchwald-Hartwig amination of aryl chlorides with amines in air. The electronic effect of the Pd-PEPPSI complexes and the effect of ancillary pyridine ligands were evaluated, among which complex C3 exhibited the most efficiency. It was demonstrated that the cross-coupling products were obtained in excellent yields in the presence of 0.5-0.1 mol % palladium loading. A wide range of aryl- and heteroaryl chlorides as well as various amines were compatible. The oxidative addition of aryl chlorides is revealed to be the rate-determining step in the catalytic cycle. The catalytic activity can be enhanced by introducing electron-donating groups to the Pd-PEPPSI complexes. This type of Pd-PEPPSI precatalyst showed the most efficiency reported to date for the challenging C-N cross-coupling reactions requiring no anhydrous and inert atmosphere protections, suggesting flexible steric bulk as a promising catalyst design strategy.

Full text of DOI:10.1021/acs.joc.6b02867

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Article
Flexible Steric Bulky Bis(Imino)acenaphthene (BIAN)-
Supported N-Heterocyclic Carbene Palladium Precatalysts:
Catalytic Application in Buchwald-Hartwig Amination in Air
Xiao-Bing Lan, Yinwu Li, Yan-Fang Li, Dong-Sheng Shen, Zhuofeng Ke, and Feng-Shou Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02867 • Publication Date (Web): 28 Feb 2017
Downloaded from http://pubs.acs.org on March 3, 2017
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Flexible Steric Bulky Bis(Imino)acenaphthene (BIAN)-Supported N-Heterocyclic Carbene
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Palladium Precatalysts: Catalytic Application in Buchwald-Hartwig Amination in Air
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＋
＋
Xiao-Bing Lan,†, Yinwu Li, ‡, Yan-Fang Li,† Dong-Sheng Shen,† Zhuofeng Ke,*, ‡ and Feng-Shou
Liu*,†
†School of Chemistry and Chemical Engineering, Guangdong Cosmetics Engineering & Technology
Research Center, Guangdong Pharmaceutical University, Zhongshan, Guangdong, 528458, China
‡School of Materials Science and Engineering, MOE Key Laboratory of Bioinorganic and Synthetic
Chemistry, Sun Yat-sen University, Guangzhou 510275, China
Correspondence authors: Zhuofeng Ke, E-mail: kezhf3@mail.sysu.edu.cn; Feng-Shou Liu, E-mail:
fengshou2004@126.com.
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ABSTRACT:
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To achieve efficient palladium-catalyzed cross-coupling reaction under mild reaction conditions with
the flexible steric bulk strategy, a series of Pd-PEPPSI complexes C1-C6 were synthesized and
characterized, in which unsymmetric flexible steric bulk was introduced on the N-aryl of
ancenaphthyl skeleton. These well-defined palladium complexes were found to be excellent
precatalysts for Buchwald-Hartwig amination of aryl chlorides with amines in air. The electronic
effect of the Pd-PEPPSI complexes and the effect of ancillary pyridine ligands were evaluated,
among which complex C3 exhibited the most efficiency. It was demonstrated that the cross-coupling
products were obtained in excellent yields in the presence of 0.5-0.1 mol% palladium loading. A
wide range of aryl- and heteroaryl chlorides as well as various amines were compatible. The
oxidative addition of aryl chlorides is revealed to be the rate-determining step in the catalytic cycle.
The catalytic activity can be enhanced by introducing electron-donating groups to the Pd-PEPPSI
complexes. This type of Pd-PEPPSI precatalysts showed the most efficiency reported to date for the
challenging C-N cross-coupling reactions requiring no anhydrous and inert atmosphere protections,
suggesting flexible steric bulk as a promising catalyst design strategy.
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Introduction
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Arylamines are frequently found in the synthesis of natural products, pharmaceuticals, as well
as functional materials.1 The palladium-catalyzed Buchwald-Hartwig amination reaction, which
involves the cross-coupling of aryl halide with amines to form arylamines, has emerged as one of the
most valuable synthetic approaches for the construction of C(sp2)-N bonds.2 To achieve a high
efficiency in this C-N cross-coupling reaction, much attention has been paid to the development of
palladium catalysts with new ligands.3
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Since the first isolation of 1,3-diadamantyl-imidazolylidene by Arduengo’s and co-workers in
1991,4 extensive efforts have been directed on the N-heterocyclic carbenes (NHCs) in the past decade,
in light of their strong σ-donation toward metal center and their extraordinary utilities for promoting
organic reactions.5 Recently, an array of well-defined monoligated NHCs-palladium complexes
developed by the groups of Herrmann,6 Nolan,7 Beller,8 Sigman,9 and Organ10 exhibit excellent
catalytic performance in palladium-catalyzed reactions.11 Among these studies, the air-stable,
user-friendly palladium PEPPSI complexes (PEPPSI: Pyridine-Enhanced-Precatalyst Preparation,
Stabilization, and Initiation) developed by Organ and co-workers, turned out to be versatile
precatalysts and can be generally applicable in numerous cross-coupling reactions.12 It revealed that
the increase of steric bulk at the ortho position of N-aryl moiety of the NHCs should benefit the
Buchwald-Hartwig amination.13 For instance, bulky palladium-based PEPPSI complexes, such as
Pd-PEPPSI-IPr [IPr: 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene], Pd-PEPPSI-IPent [IPent:
1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene],10c
Pd-PEPPSI-IPr*
[
IPr*:
1,3-bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazo-2-ylidene]13d, were able to conduct the
most challenging amination reactions at room temperature, even with unactive aryl chlorides and
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amines. In contrast, the less steric of the N-aryl moieties, such as Pd-PEPPSI-IMes [IMes: 1,3-
bis(mesitylene) imidazol-2-ylidene] afforded much less efficiency.10c On the other hand, the
modification on skeletons of the NHCs is another vital strategies to enhance the catalytic
efficiency.14 Tu and co-workers found that bulky acenaphthylene-substituted PEPPSI-IPrAn [IPrAn:
1,3-bis(2,6-diisopropylphenyl)ancenaphthylimidazol-2-ylidene] was highly efficient.14a Recently,
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César and Lavigne developed a new type of palladium complex with PEPPSI-IPr(NMe2)2 [ IPr(NMe2)2
:
1,3-bis(2,6-diisopropylphenyl) (N,N,N’,N’-tetramethyloxalimidamide)imidazol-2- ylidene], wherein
the introduction of the NMe2 groups on the skeleton showed broad applicability and efficiency
towards a wide range of aryl chloride substrates. 14c, 15
Despite significant advances in the NHCs-palladium catalyzed cross-coupling reactions,
operationally simple and generally applicable catalytic systems for cross-coupling aminations are
highly desired.16 For instance, most of these palladium complexes need multiple synthetic steps with
extremely skilful workup.17 It is noteworthy that the NHCs-Pd(II) precatalysts were rather air-stable.
Unexpectedly, the catalytic species of NHCs-Pd(0) were found to be somewhat sensitive to a low
level of dissolved oxygen in commercially available solvent, which could be trapped to form
unreactive peroxo species.12d, 18 To date, rare examples have been successfully achieved in the
amination reactions in air.19 Therefore, we are keenly interested in the development of NHCs
palladium catalysts that do not necessitate the use of air- and moisture-free techniques in both
academic and industrial applications.14f, g
Based on the “flexible steric bulk” strategy proposed by Glorius20 and the extensive works
above, we reasoned that the construction of palladium complexes of PEPPSI-(IPr*IPr)An,
PEPPSI-(IPr(OMe)*IPr)An and PEPPSI-(IPrF*IPr)An (Scheme 1), combined unsymmetric N-aryl
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moieties on the bulky acenaphthyl skeleton, would benefit the cross-coupling amination reactions.
Their catalytic activity for the oxidative addition of aryl chlorides will be accelerated by the strong σ
donating properties of the acenaphthyl,21 meanwhile the bulky steric hindrance can facilitate
reductive elimination and can stabilize the NHCs-Pd(0) species.22 Therefore, at a low palladium
loading, an improvement of catalytic activity could be achieved in air without the need of anhydrous
solvents. In order to further confirm our speculation and gain insights into the relationship between
the structures and catalytic properties, herein, we report the synthesis and characterizations of the
NHCs palladium complexes bearing flexible steric bulk, and describe their catalytic potentials
toward Buchwald-Hartwig amination reaction in air.
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Scheme1. The Design of Pd-PEPPSI Precatalysts with Flexible Bulky Steric
Ph
Ph
Ph
Ph
Ph
Ph
N
N
C
N
N
N
N
R
l
C
l
C
l
C
Pd
N
Ph
Ph
Pd
N
Ph
Ph
Pd
N
Ph
l
l
C
l
C
Ph
s wor
Thi
k
l
C
l
C
X
n
S
- rA
-
- r
Pd PEPP I IP *
ex
Fl ibl
e
er c
t i B lk
u
-
S
Pd PEPP I IP
S
RESULTS AND DISCUSSION
Synthesis and Characterization of Ligands (L1-L3) and Their Palladium Complexes (C1-C6).
The procedures in the synthesis of Pd-PEPPSI complexes were shown in Scheme 2. Initially, the
intermediates of 1-(arylimino)acenaphthylen-2-one (1a-c) were prepared according to the literature
reports.23 Next, the 1-(arylimino)acenaphthylen-2-one derivatives and 2,6-diisopropylaniline were
mixed in toluene in the presence of catalytic amount of para-toluenesulfonic acid (Scheme 2). The
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mixture was refluxed to conduct a routine condensation reaction to form the corresponding
unsymmetric α-diimine compounds (2a-c). Subsequent cyclocondensation with chloromethyl ethyl
ether provided the precipitate of the imidazolium chloride salts. These light green solids were
isolated by filtration and washed with Et2O, giving in moderate to high yields of 87%, 80% and 72%
for L1, L2 and L3, respectively. The spectroscopic properties of the imidazolium salts were
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1
investigated by H NMR, in which the resonance of imidazolium C-H protons (NCHN) was
observed downfield at δ=12.61, 12.69 and 12.71 ppm, respectively. With the imidazolium chloride
salts in hand, the PEPPSI-(IPr*IPr)An, PEPPSI-(IPr(OMe)*IPr)An and PEPPSI-(IPrF*IPr)An complexes
(C1-C6) were conveniently obtained in 68-92% yields with PdCl2 and K2CO3 in neat pyridine or
3-chloropyridine via a one-pot process.
Scheme 2. Synthetic Route for the Pd-PEPPSI Complexes
Ph
Ph
Ph
Ph
PT A
S
+ H2N
N
N
N
O
o uene
T l
R
R
a c
a c
-
-
1
2
Ph
Ph
Ph
Ph
l H Et
C C 2O
Ph
Ph
N
N
R
Ph
Ph
l
C
L
Ph
Ph
Pd l
C 2
,
Pd
N
+
N
l
C
N
K
2CO3
R
l-
C
Ph
Ph
X
:
:
:
= e
R M
=
=
X
:
:
:
=
=
e
=
X H
, ;
:
:
:
= e
R M
;
4
C
C5
L1
L2
L
1
2
C
C
X
l
;
R
M
C
O
,
;
= e
=
=
=
=
e
M
O
;
R M X H
R F X
,
C
l
;
R
,
;
=
C
=
=
e
,
C3 R
M
O
l
;
C
6
R F X H
3 R F
,
;
All these prepared Pd-PEPPSI complexes are air and moisture stable, and can be stored on shelf
for more than a half year without noticeable decomposition or decline in catalytic efficiency. These
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complexes are slightly soluble in Et2O, hexane, and MeOH, while are well soluble in CH2Cl2, CHCl3,
and DMAc. They were fully characterized by NMR spectroscopy, mass spectrometry, and elemental
analysis. The proton signal of NCHN from the imidazolium salts had disappeared in the 1H NMR of
the Pd-PEPPSI complexes, confirming the generation of Pd-Ccarbene bonds. In addition, the 13C NMR
of the palladium complexes revealed the direct evidence of the metalation of carbene carbon, as seen
by the signal in the range of 151.7-159.4 ppm. Single crystals for the solid state structure
determination could be obtained by slow diffusion of hexane into a concentrated CH2Cl2 solution at
ambient temperature. The molecular structures of C1-C4 were determined by means of X-ray
diffraction studies. However, only low-quality crystal was obtained in the case for C2 (seen in
supporting information). As depicted in Figures 1-3, the solid structures of these complexes adopt
slightly distorted square planar coordination geometry with the NHC and “throw away” ligands trans
to each other. Despite bearing steric bulk on the NHC, the Pd-C(1) bond lengths turned out to be
1.960(4), 1.963(2) and 1.971(4) Å, respectively. These lengths are in the range of those observed for
the closely related Pd-PEPPSI analogues for IPr* and IPrAn, for which values of 1.974(6) and
1.960(6) Å have been observed, respectively.13d, 14a Moreover, both of the N-aryl groups are nearly
perpendicular to the plane of the NHC ring. Of particular note is that the bulky steric of the
2,6-dibenzhydryl lies above and below the coordination plane, which are oriented over the axial sites
of the palladium atom. As can be expected, one direction of the axial site would be shielded by the
combination of bulky steric and ancenaphthyl framework. On the other hand, the other N-aryl group
of 2,6-diisopropyl would be much flexible as the existence of the opportunity of the rotation around
the C-N bond. Therefore, these “flexible steric bulk” palladium complexes are expected to exhibit
profound effect on the cross-coupling reactions.
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Figure 1. Molecular structure of C1•CH2Cl2 depicted with 30% thermal ellipsoids. Hydrogen atoms
and uncoordinated CH2Cl2 molecule have been omitted for clarity. Selected bond distances (Å) and
angles (o): Pd(1)-C(1) 1.960(4), Pd(1)-N(3) 2.153(3), Pd(1)-Cl(1) 2.2795(11), Pd(1)-Cl(2) 2.2825(11),
N(3)-Pd(1)-C(1) 178.67(14), N(3)-Pd(1)-Cl(1) 92.14(10), C(1)-Pd(1)-Cl(1) 86.61(10),
N(3)-Pd(1)-Cl(2) 91.31(10), C(1)-Pd(1)-Cl(2) 89.94(10), Cl(1)-Pd(1)-Cl(2) 176.51(4).
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Figure 2. Molecular structure of C3•CH2Cl2 depicted with 30% thermal ellipsoids. Hydrogen atoms
and uncoordinated CH2Cl2 molecule have been omitted for clarity. Selected bond distances (Å) and
angles (o): Pd(1)-C(1) 1.963(2), Pd(1)-N(3) 2.162(2), Pd(1)-Cl(1) 2.2796(8), Pd(1)-Cl(2) 2.2836(8),
N(3)-Pd(1)-C(1) 178.95(9), N(3)-Pd(1)-Cl(1) 92.23(7), C(1)-Pd(1)-Cl(1) 86.72(7), N(3)-Pd(1)-Cl(2)
91.18(7), C(1)-Pd(1)-Cl(2) 89.87(7), Cl(1)-Pd(1)-Cl(2) 176.54(3).
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Figure 3. Molecular structure of C4•CH2Cl2•3H2O depicted with 30% thermal ellipsoids. Hydrogen
atoms and uncoordinated molecules have been omitted for clarity. Selected bond distances (Å) and
angles (o): Pd(1)-C(1) 1.971(4), Pd(1)-N(3) 2.082(4), Pd(1)-Cl(1) 2.2945(12), Pd(1)-Cl(2)
2.2897(12), N(3)-Pd(1)-C(1) 171.15(16), N(3)-Pd(1)-Cl(1) 88.18(11), C(1)-Pd(1)-Cl(1) 91.28(11),
N(3)-Pd(1)-Cl(2) 88.97(11), C(1)-Pd(1)-Cl(2) 92.38(11), Cl(1)-Pd(1)-Cl(2) 173.78(5).
Buchwald-Hartwig Amination Reactions Catalyzed by the Pd-PEPPSI Complexes
To test the efficiency of these designed Pd-PEPPSI complexes towards C-N cross-coupling, our
initial studies about the effect of ligand on the Buchwald-Hartwig reaction were performed. It is
noteworthy that all the solvents for the reactions were used without any further purification and the
reactions were carried out in air. In the presence of 0.5 mol% palladium loading, 2-chloroanisole and
4-fluoroaniline was chosen as a model reaction, using potassium tert-amylate (KOtAm) as base and
o
1,4-dioxane as solvent at 100 C for 2 hours. In these cases, it was found that all these precatalysts
were very efficient and provided almost full conversion of the starting substrates (Runs 1-6, Table 1).
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To better identify the differences in reactivity between these Pd-PEPPSI complexes, the palladium
loading was then decreased to 0.1 mol%. Interestingly, dramatic changes were observed and the
electronic effect of the N-aryl substituents has a noticeable impact on the catalytic performances. On
the other hand, the effect of auxiliary ligands is insignificant (pyridine vs. 3-chloropyridine). As
illustrated in Table 1, bearing a para-Me on N-aryl, the use of C1 and C2 resulted in profound
efficiency, giving the GC yield of 3aa in 86 and 90%, respectively (Runs 7 and 8, Table 1). In
contrast, the introduction of para-OMe group (C3 and C4) delivered the product in nearly
quantitative yields of 100 and 96%, respectively (Runs 9 and 10, Table 1). Under the same reaction
conditions, the C5 and C6 with para-F group, afford a satisfied yield of 87 and 89%, respectively
(Runs 11 and 12, Table 1). To understand the relationship between the structure of the precatalysts
and the active catalysts, the model reactions were monitored by GC in detail. As shown in Figure 4
and Figure S1, the C1-C6 were initiated fast after a short induction period of 5 min. Significantly,
the reaction rates of C3 and C4 were higher than those of other palladium complexes. Considering
the similar steric bulk of these NHC ligands, the enhanced catalytic efficiency derived from OMe
substituent would be resulted from its stronger electron donating character, which facilitates the
oxidative addition of aryl chloride during the cross-coupling process.24 To further evaluate the
catalytic performance on ligand design, control experiments were conducted. As expected, in the
absence of NHC ligand, the use of Pd(OAc)2 as sole precatalyst furnished only trace amount of the
desired product (Run 13, Table 1). This investigation proved the essential role of the NHC ligands
for this cross-coupling. The commercially available Pd-PEPPSI-IPr and the Pd-PEPPSI-IPrAn
previously reported respectively by Organ10c and Tu,14a which exhibited high efficiency in the C-N
amination, were also evaluated under our reaction conditions. However, the results only showed
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moderate yields of 25 and 46%, respectively (Runs 14 and 15, Table 1). The time-course of the
reaction also revealed that the lifetime of Pd-PEPPSI-IPr and Pd-PEPPSI-IPrAn were only 10 min,
which were shorter than those of C1-C6. Moreover, it was noteworthy that the Pd-PEPPSI-IPr had a
long induction period of 45 min. These observations are consistent with previous results that NHCs
catalysts led to much lower yields under air conditions than in inert atmosphere, which suggests the
possibility of rapid capture of the palladium(0) speices by oxygen in these stances.18d, e, g To further
shed light on this point, the reactions were performed under 1 atm of oxygen, whereas the reactions
were completely shut down. Moreover, the reaction was also conducted with the most efficient
precatalyst of bulky steric Pd-PEPPSI-IPr*, which bearing four bulky 2,6-dibenzhydryl groups on
the N-aryl moieties.13c The desired product of 3aa was obtained in excellent yield of 92%. Although
both of the bulky N-aryl moieties are located in the IPr*, a slightly lower reactivity than that of C3
was observed, indicating that both the skeleton of acenaphthyl and the steric bulk of N-aryl played
crucial roles on the overall catalytic activity. Reasonably, the Pd-PEPPSI complex of C3 gave the
best yields as its “flexible steric bulk”, which would stabilize the Pd(0) active species with the
enhancement of the lifetime, and further facilitated the oxidative addition step in this transformation
due to flexible environment.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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Table 1 ．Screening of Precatalysts and Reaction Conditions for the Buchwald−Hartwig
Amination in Aira
e
M
e
O
M
O
H
N
-
NH2
Pd PEPP I
S
l
C
+
so ven n a r
100 o 2h
l
t i
,
i
F
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
F
C
,
a
aa
1
a
2
3
Run Pd complex
T (oC)
100
100
100
100
100
100
100
100
100
100
100
100
100
100
Pd mol% Solvent
1,4-dioxane
Base
Yield (%)
96
98
100
100
97
98
86
1
0.5
0.5
0.5
0.5
0.5
0.5
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.05
0.1
0.1
KOtAm
KOtAm
KOtAm
KOtAm
KOtAm
KOtAm
KOtAm
KOtAm
KOtAm
KOtAm
KOtAm
KOtAm
KOtAm
KOtAm
KOtAm
KOtAm
KOtAm
KOtAm
KOtAm
KOtBu
KOH
C1
2
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
Toluene
C2
3
C3
4
C4
5
C5
6
C6
7
C1
8
90
C2
9
100 (96)b
97
C3
10
C4
11
87
C5
12
89
C6
d
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Pd(OAc)2
-
PEPPSI-IPr
25
46
92
15
12
80
94
8
NR
13
97
88
30
19
PEPPSI-(IPr)An 100
PEPPSI-(IPr)*
100
100
100
100
100
100
100
100
100
100
90
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
DME
THF
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
K2CO3
Cs2CO3
NaOtBu
KOtAm
KOtAm
KOtAm
80
aReagents and conditions: 2-chloroanisole (1 mmol), 4-fluoroaniline (1.2 mmol), palladium source
(0.005-0.0005 mmol), base (1.5 mmol), solvent (3 mL) under aerobic environment. All solvent was
commercial and used as received. Cross-coupling product determined by GC using the
(trifluoromethyl)benzene as internal standard. The cross-coupling yield was given in average twice.
bIsolated yields in parentheses.
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100
90
80
70
60
50
40
30
20
10
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
PEPPSI-IPr
*
An
C1
PEPPSI-IPr
PEPPSI-IPr
C3
C5
0 10 20 30 40 50 60 70 80 90 100 110 120 130
t (min)
Figure 4. Kinetic profiles for Buchwald−Hartwig amination of 2-chloroanisole with 4-fluoroaniline
performing in Table 1.
To investigate promising catalytic reaction conditions, different solvents and bases were
subsequently screened in the amination. It revealed that the 1,4-dioxane gave the best result,
affording the desired product with full conversion and a satisfied isolated yield of 96% was obtained
(Run 9, Table 1). Other solvents, such as toluene, 1,2-dimethoxyethane (DME), and tetrahydrofuran
(THF) afforded inferior values. The examination of bases disclosed that KOtBu and NaOtBu were
very effective, while KOtAm was proved to be the best choice. In contrast, the source of other bases,
such as KOH, K2CO3, and Cs2CO3, gave only poor conversions (Runs 21-23, Table 1). These
observations were in accordance with previous work, whereas better results were obtained using
strong bases.24 To further evaluate the catalytic efficiency, lower palladium of 0.05 mol% was
conducted. To our delight, a satisfied activity of 88% yield was observed (Run 25, Table 1).
o
Moreover, the reactions were also carried out at lower reaction temperature of 80 and 90 C,
respectively. However, a sharp decline of catalytic efficiency was investigated (Run 26 and 27, Table
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1).25
4
5
6
7
8
9
With the optimized reaction conditions in hand, the scope of the reaction was explored using 0.1
mol% of C3 at 100 C, with 1,4-dioxane as solvent and KOtAm as base. As shown in Table 2,
cross-coupling reactions of 2-chloroanisole (3a) with a range of electron-rich anilines were first
examined. Anilines containing methoxyl group at ortho- and para- positions afforded the desired
products in high yields of 97 and 98%, respectively (3ab and 3ac). Bulky anilines bearing
2,6-dimethyl, 2,4,6-trimethyl, 2,6-diethyl, and 2,6-diisopropyl groups were well compatible, and the
corresponding products (3ad-3ag) were isolated in 91-97% yields. In addition, a variety of secondary
and primary amine partners, such as morpholine, N-methylpiperazine, N-methylaniline,
phenylmethanamine, and cyclohexanamine all underwent highly efficient coupling, giving the
products of 3ah-3al in 81-95% yields. Other aryl chlorides with diverse amines were next studied
and excellent results were obtained (Table 3, 3ba-3bh, 3cd-3cj, 3ed). However, the catalytic
performance was found to be less efficient in some cases, when steric hindrance or heteroaryl
chlorides, such as 2,6-dimethyl chloride and 2- and 3-chloropyridines were used. To our delight, high
yields were successfully achieved when coupling aryl chlorides between 2,6-dimethylaniline,
2,6-diisopropylaniline and para-fluoroaniline (3dd, 3fd, 3ga, 3gd, and 3hg) with an increased
palladium loading of 0.5 mol%.
o
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2．Buchwald−Hartwig Amination of 2-Chloroanisole with Amines Catalyzed by C3.a
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9
OMe
R
N
OMe
R
R
C3
0.1
mol%
2
Cl
R
+
H N
100 o
in air
C, h,
1a
2
3aa-3al
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OMe
OMe
OMe
OMe
H
N
H
N
H
N
F
OMe
:
3ac
:
98%
3ab
97%
:
3aa
96%
OMe
OMe
OMe
H
H
N
H
N
N
:
3ad
:
92%
3ae
97%
:
3af
91%
N
OMe
N
OMe
OMe
O
H
N
N
:
3ai
86%
:
3ah
81%
:
92%
N
3ag
OMe
OMe
OMe
H
N
H
N
:
3al
92%
:
:
3ak
93%
85%
3aj
aReagents and conditions: 2-chloroanisole (1 mmol), amine (1.2 mmol), C3 (0.001 mmol), KOtAm
(1.5 mmol), 1,4-dioxane (3 mL) in air. Isolated yields.
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Table 3． Scope of the Buchwald–Hartwig Amination of Aryl Chlorides with Amines Catalyzed
5
6
7
8
by C3.a
R
9
R
R
l
C
. - . mo
l
C
3
0 5 0 1
%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
R
+
r
H N
A
r
A
100 o 2 h i Ai
n
,
r
C
,
2
1
3
e
M
O
H
N
H
H
N
N
e
M
O
F
a
:
3b
95
:
%
c
b
:
3bb
90
%
3
90
%
H
N
O
H
N
N
:
3bd
93
%
:
h
3b
:
g
94
%
3b
85
%
H
H
N
N
N
e
M
O
c
b
:
3
c
3 d
91
:
%
85
:
7
8
%
j
3dd
%
H
N
H
N
H
N
N
F
b
a
:
3
g
99
%
b
:
3fd 7
5
%
e
:
3 d
95
%
H
O
H
N
N
N
N
N
N
F
a
:
h
b
3
86
N
%
:
:
h
9
3 d
3
85
4
%
%
g
g
H
N
H
N
N
N
N
:
b
h
j
3
:
89
%
hd
3
89
%
:
g
h
3
90
%
aReagents and conditions: (Hetero)ArCl (1 mmol), amine (1.2 mmol), C3 (0.001 mmol), KOtAm
b
(1.5 equiv), 1,4-dioxane (3 mL) in air. Isolated yields. Reagents and conditions: (1 mmol), amine
(1.2 mmol), C3 (0.005 mmol), KOtAm (1.5 equiv), 1,4-dioxane (3 mL) in air. Isolated yields.
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DFT Study on the Reaction Mechanism
6
7
8
9
In order to further understand the reaction mechanism and important factors for this
Pd-PEPPSI catalyzed Buchwald-Hartwig amination reactions, DFT studies were carried out with
[Pd(IPrOMe*IPr)An(3-Cl-pyridinyl)Cl2] C3 as a representative model as it has the best reaction
performance. The catalytic cycle involves three mainly stages: 1) oxidative addition, 2)
deprotonation, 3) reductive elimination. The obtained free energy profile and key structures for the
catalytic cycle of C3 are depicted in Figures 5 and 6, respectively. The active species Pd(0) may be
generated from C3 through a reduction elimination process, under the assistance of strong base
KOtAm.26 DFT results (detailed PES is shown in Figure S48) suggested that a di-amido Pd(II)
intermediate can undergo N-N coupling to generate Pd (0) species C3-cat (∆G‡ = 31.0 kcal/mol).
Oxidative Addition. The active Pd0 species with a vacant site would be abstracted by KOtAm
to a resting state intermediate C3-IM1 (-28.8 kcal/mol). By ligand exchange, the reactant aryl
chloride will coordinate with Pd0 center, to form intermediate C3-IM2 (-7.6 kcal/mol). The oxidative
addition of aryl chloride undergoes via transition state C3-TS1 (1.5 kcal/mol), leading to a three
coordinated PdII intermediate C3-IM3 (-12.4 kcal/mol). The activation free energy of this step is
calculated to be 30.3 kcal/mol relative to C3-IM1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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33
34
35
36
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Deprotonation. In the second stage, the unsaturated C3-IM3 would like to further coordinate
with reactant aniline to form a four coordinated intermediate C3-IM4 (-32.6 kcal/mol) with a
square-planar geometry. Then the base KOtAm will abstract the proton of aniline in C3-IM4,
resulting in the deprotonated intermediate C3-IM5 (-48.7 kcal/mol). It is worth noting that the
deprotonation step from C3-IM4 to C3-IM5 drops in free energy by -16.1 kcal/mol without
transition state, indicating a barrierless deprotonation process assisted by strong base.
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Reductive elimination. The reductive elimination step initiates from intermediate C3-IM6,
which is formed by the dissociation of chloride ligand from C3-IM5, uphill in free energy by 7.4
kcal/mol. In this step, C-N coupling via transition state C3-TS2 (-23.9 kcal/mol) furnishes the
PhNHPh as final product, with the regeneration of Pd0 species from PdII center. The activation free
energy of the reductive elimination step is 24.8 kcal/mol relative to intermediate C3-IM5.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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49
50
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53
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56
57
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60
ca mo
l
)
k
l
G
/
(
Ph
Ph
N
N
Ph
Ph
e
M
O
Pd
Ph
Ph
N
N
Ph
Ph
e
M
O
l
C
Pd
Ph
Ph
0 0
e
M
O
N
N
.
1 5
Ph
Ph
.
Ph
Ph
Pd
t
m
A
K
O
-
T 1
S
C3
-
a
- .
7
6
e
M
O
t
C3 C
N
N
HN
-
.
Ph
Ph
12 4
-
IM2
C3
Pd
PhNH2
l
C
Ph
C
l
t
m
A
K
O
-
IM3
C3
Ph
Ph
NH2
-
.
23 9
N
N
-
.
28 8
e
M
O
Ph
Ph
-
T 2
S
C3
Pd
Ph
Ph
-
.
32 6
t
PhNHPh
m
-
A
K
O
IM1
C3
N
N
l
C
-
IM4
C3
e
M
O
-
.
41 3
Pd
Ph
Ph
Ph
Ph
-
.
44 3
l
C
-
IM6
C3
-
.
48 7
Ph
Ph
N
N
-
a
t
C3 C
e
M
O
t
K
l
C
m
A
H
O
-
IM5
C3
Pd
O
e
O
Ph
Ph
M
N
N
t
Ph
Ph
Ph
Ph
m
A
Pd
K
HN
e
M
O
N
N
Ph
Ph
Pd
l
C
HN
K
re uc ve e m na on
ti li ti
e ro ona on
ti
d
i
ox a ve a on
id ti
dditi
t
d
p
Figure 5. Free energy profile for C3-catalyzed Buchwald-Hartwing amination between aniline and
phenyl chloride. Free energies are given in kcal/mol.
Through the DFT results above, the oxidative addition is found to be the rate-determining step
for the C3-catalyzed Buchwald-Hartwing amination between aniline and phenyl chloride. The
activation free energy of the oxidative addition step is 30.3 kcal/mol, which is 5.6 kcal/mol higher
than that of the reductive elimination step. And the deprotonation step is suggested to be barrierless.
To further illustrate the electronic effect of this flexible steric bulky BIAN-Supported NHC-Pd
complexes on the Buchwald-Hartwing amination, DFT studies were performed to compare the
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activities of C1, C3 and C5 complexes with -CH3, -OCH3, and -F substituted groups, respectively.
All these catalysts show accordant mechanism and similar free energy profiles. As shown in Figure 6,
the activation free energies of the rate-determining oxidative addition step are 30.3, 32.3, and 31.5
kcal/mol, for -OCH3, -CH3, and -F substituted NHC-Pd complexes, respectively. And the activation
free energies of the reductive elimination step are 24.8, 20.9, and 13.3 kcal/mol, respectively. The
electron-donating group can enhance the activity of the rate-determining oxidative addition step,
although it may increase the activation free energy of the reductive elimination step. The activation
free energy of the oxidative addition is composed of two parts: the ligand exchange and the C-Cl
cleavage (Figure 5). Interestingly, analysis by separation of these two parts suggests that C-Cl
cleavage contributes majorly to the difference in free energy barriers (Figure 6). The –OCH3
substituted C3 complex has lowest free energy penalty in C-Cl cleavage (9.1 kcal/mol), leading to
the smallest activation free energy, exhibiting the best catalytic performance. Whereas the activities
of C1 and C5 are relatively lower. The calculated results well explain how the electronic effect
influences the catalytic activity, which is in good agreement with experimental observations.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
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52
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7
8
9
Ph
Ph
TS2
TS1
Ph
Ph
R
N
N
N
N
Ph
Ph
R
Pd
Pd
Ph
Ph
Cl
HN
Pd
C
Pd
Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
C
N
Pd-Cl:2.59/2.59/2.57
Pd-C 2.01/2.01/2.01
C-Cl 2.18/2.18/2.18
Pd-N:2.05/2.06/2.05
2.11 2.10
:
:
Pd-C:2.10/
/
:
C-N 1.95/1.92/1.95
≠
32.3
∆
G
31.5
30.3
(kcal/mol)
24.8
20.9
12.4
11.0
9.1
C-Cl
cleavage
13.3
21.2
19.9 20.5
Ligand exchange
C3 C1 C5
C3 C1 C5
reductive elimination
oxidative addition
R=
-F
-OCH3 -CH3
Figure 6. Activation free energies of oxidative addition and reductive elimination steps for NHCs-Pd
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
catalysts with -OCH3, -CH3, and -F groups.
CONCLUSION
We have developed a type of well-defined Pd-PEPPSI-(IPr*IPr)An, Pd-PEPPSI-(IPr(OMe)*IPr)An and
Pd-PEPPSI-(IPrF*IPr)An complexes for Buchwald-Hartwig cross-coupling reactions in air. The
evaluation of the precatalysts confirmed that the “flexible steric bulk” and strong σ-donation nature
are essential in securing high catalytic activity. Under the optimal conditions, the C-N cross-coupling
products were efficiently obtained in excellent yield in the presence of 0.5-0.1 mol% palladium
loading. A wide range of sterically hindered aryl, as well as heteroaryl chlorides, and various amines
were compatible. DFT calculations suggest that the oxidative addition of aryl chlorides is the
rate-determining step in the catalytic cycle. Electron-donating groups would benefit the catalytic
activity. These results highlight a promising strategy to enhance catalytic activities under mild
reaction conditions. Further synthetic program on air-stable Pd-PEPPSI complexes for
cross-couplings is currently underway in our laboratories.
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Physical Measurements and Materials
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2, 6-dibenzhydryl-4-methylaniline and 2, 6-dibenzhydryl-4-methoxyaniline were prepared
according to previous report23. Pd-PEPPSI compounds was synthesized according to literature
methods.10a
The 1D NMR spectra were recorded on a 400 MHz instrument at ambient temperature with the
decoupled nucleus, using TMS as an internal standard and CDCl3 as solvent. The X-ray diffraction
data of single crystals were obtained with the ω-2θ scan mode on a CCD diffractometer with
graphite-monochromated Mo Kα radiation (λ=0.71073Å) at 173K for C1, C2 and C4. Cell
parameters were obtained by global refinement of the positions of all collected reflections. Intensities
were corrected for Lorentz and polarization effects and empirical absorption. The structures were
solved by direct methods and refined by full-matrix least squares on F2. All hydrogen atoms were
placed in calculated positions. Structure solution and refinement were performed by using the
SHELXL-97 package. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were
introduced in calculated positions with the displacement factors of the host carbon atoms.
Computational details.
All the structures were optimized by the density functional theory (DFT)27 at the B3LYP
functional28-30 with basis sets I (BSI, lanl2dz31 for metal atom and 6-31G (d, p) for nonmetal atoms)
in the solvent phase. Frequency analysis calculations for optimized structures were performed to
characterize the structures to be minima (no imaginary frequency) or transition states (one imaginary
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frequency). IRC calculations were taken to confirm the connection between two minima for a
transition state. Based on B3LYP/BSI optimized geometries, the energy results were further refined
by calculating the single point energy at the B3LYP/BSII level of theory (BSII designates SDD32 for
metal atom and 6-311++G**33 for nonmetal atoms). Empirical dispersion correction has been
considered in structure optimization and energy calculation. The bulky solvation effect of
1,4-Dioxane (ε= 2.2) were simulated with SMD32 continuum solvent model at the B3LYP/BSII level
of theory. Reaction temperature was corrected to 373K. All the calculations were performed with the
Gaussian 09 program.34 The 3D optimized structures were displayed by CYLview visualization
program.35
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General Procedures for the Synthesis of α-Ketoimine Compounds
Acenaphthenequinone (5 mmol) was initially suspended in acetonitrile (20 mL). After refluxing
for 1h, 3 mL of acetic acid was injected and keeping refluxing until the acenaphthenequinone was
completely dissolved. To this hot solution, aniline (5 mmol) was added and the reaction was refluxed
for another 8 h under inert atmosphere. When reaching the determined time, the mixture was cooled
and the resulting solid was filtered. The solid was washed with pentane (3 × 20 mL) and dried in air
to afford the desired compound.
[2, 6-(CHPh2)2-4-(CH3)-C6H2-N=C-(An)-(An)-C=O] (1a) was received as bright yellow powder
(2.838 g) in 94% yield. 1H NMR (400 MHz, CDCl3) δ 8.02 (m, Ar-H, 2H), 7.71 (m, Ar-H, 2H), 7.23
(d, J = 7.3 Hz, Ar-H, 4H), 7.18 (d, J = 6.9 Hz, Ar-H, 2H), 7.05 (d, J = 7.5 Hz, Ar-H, 5H), 6.86 (d, J =
7.5 Hz, Ar-H, 4H), 6.78 (s, Ar-H, 2H), 6.60 (m, Ar-H, 4H), 6.43 (m, Ar-H, 2H), 6.13 (d, J = 7.1 Hz,
Ar-H, 1H), 5.43 (s, CH(Ph)2, 2H), 2.26 (s, Ar-CH3, 3H). 13C NMR (101 MHz, CDCl3) δ 189.7, 162.3,
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145.9, 142.9, 141.7, 133.8, 131.8, 131.7, 129.6, 129.4, 128.6, 128.4, 128.1, 127.8, 127.5, 127.2,
126.1, 125.5,123.9, 121.5, 52.1, 21.5.
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[2, 6-(CHPh2)2-4-(CH3O)-C6H2-N=C-(An)-(An)-C=O] (1b) was received as bright red powder
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(2.851 g) in 92% yield. H NMR (400 MHz, CDCl3) δ 8.14 – 7.92 (m, Ar-H, 2H), 7.72 (m, Ar-H,
2H), 7.23 (d, J = 7.5 Hz, Ar-H, 4H), 7.18 (d, J = 7.1 Hz, Ar-H, 2H), 7.06 (d, J = 7.4 Hz, Ar-H, 5H),
6.86 (d, J = 7.4 Hz, Ar-H, 4H), 6.60 (m, Ar-H, 4H), 6.55 (s, Ar-H, 2H), 6.43 (m, Ar-H, 2H), 6.21 (d,
J = 7.1 Hz,Ar-H, 1H), 5.44 (s, CH(Ph)2, 2H), 3.62 (s, Ar-OCH3, 3H).13C NMR (101 MHz, CDCl3) δ
189.7, 162.9, 156.1, 142.5, 141.4, 133.2, 131.8, 129.6, 129.4, 128.5, 128.2, 127.8, 127.5, 127.2,
126.9, 126.3, 125.6, 123.8, 121.5, 113.7, 55.2, 52.2.
[2, 6-(CHPh2)2-4-F-C6H2-N=C-(An)-(An)-C=O] (1c) was received as bright yellow powder (2.674
g) in 88% yield. 1H NMR (400 MHz, CDCl3) δ 8.14 – 7.98 (m, Ar-H, 2H), 7.83 – 7.65 (m, Ar-H, 2H),
7.21 (m, Ar-H, 5H), 7.06 (m, Ar-H, 5H), 6.85 (d, J = 7.5 Hz, Ar-H, 5H), 6.72 (d, J = 9.5 Hz, Ar-H,
2H), 6.61 (m, Ar-H, 4H), 6.44 (m, Ar-H, 2H), 6.16 (d, J = 7.0 Hz, Ar-H, 1H), 5.44 (s, CH(Ph)2, 2H).
13C NMR (101 MHz, CDCl3) δ 189.4, 162.9, 142.5, 142.1, 141.0, 134.1, 131.8, 129.9, 129.6, 129.3,
128.7, 128.3, 127.9, 127.7, 127.2, 126.5, 125.8, 123.8, 121.6, 115.2, 52.2.
General Procedures for the Synthesis of α-Diimine Compounds
α-Ketoimine (5 mmol) and 2,6-diisopropylaniline (5 mmol) were mixed in toluene (20 mL)
with the presence of a catalytic amount of para-toluenesulfonic acid under nitrogen atmosphere, and
o
then the reaction was heated to 110 C for 10 h. When having reached the determined time, the
solution was cooled to room temperature and the solvent was evaporated. The rude material was
crystallized from ethanol or purified by column chromatography as yellow crystals.
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[2, 6-(CHPh2)2-4-(CH3)-C6H2-N=C-(An)-(An)-C=N-(2, 6-(CHCH3)2-C6H3)] (2a) was received as
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bright yellow powder (1.984 g) in 52% yield. H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.2 Hz,
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6.93 (d, J = 7.6 Hz, Ar-H, 4H), 6.81 (s, Ar-H, 2H), 5.64 (s, CH(Ph)2, 2H), 3.17 (m, CH(CH3)2, 2H),
2.28 (s, Ar-CH3, 3H), 1.29 (d, J = 6.7 Hz, CH3, 6H), 1.01 (d, J = 6.8 Hz, CH3, 6H). 13C NMR (101
MHz, CDCl3) δ 162.1, 146.8, 143.6, 142.7, 141.7, 139.6, 135.7, 132.6, 132.3, 129.6, 129.5, 129.2,
129.0, 128.8, 128.4, 128.0, 127.7, 126.8, 126.6, 126.0, 125.4, 124.4, 123.5, 122.8, 52.4, 28.5, 24.3,
23.7, 21.0.
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[2, 6-(CHPh2)2-4-(CH3O)-C6H2-N=C-(An)-(An)-C=N-(2, 6-(CHCH3)2-C6H3)] (2b) was received
as bright yellow powder (1.753 g) in 45% yield. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.2 Hz,
Ar-H, 1H), 7.52 (d, J = 8.3 Hz, Ar-H, 1H), 7.28 (s, Ar-H, 5H), 7.23 (s, Ar-H, 3H), 7.19 (d, J = 7.1
Hz, Ar-H, 2H), 7.12 (d, J = 7.5 Hz, Ar-H, 4H), 6.93 (d, J = 7.3 Hz, Ar-H, 5H), 6.68 – 6.52 (m, Ar-H,
6H), 6.40 (m, Ar-H, 3H), 5.99 (d, J = 7.1 Hz, Ar-H, 1H), 5.64 (s, CH(Ph)2, 2H), 3.64 (s, Ar-OCH3,
3H), 3.15 (m, CH(CH3)2, 2H), 1.28 (d, J = 6.7 Hz, CH3, 6H), 1.01 (d, J = 6.8 Hz, CH3, 6H). 13C
NMR (101 MHz, CDCl3) δ 158.0, 155.7, 145.9, 143.2, 141.3, 140.0, 135.7, 133.7, 129.7, 129.5,
128.6, 128.4, 128.1, 127.8, 127.2, 126.9, 126.8, 126.2, 125.9, 125.6, 124.4, 123.5, 122.9, 113.9, 55.2,
52.2, 28.4, 24.3, 23.7.
[2, 6-(CHPh2)2-4-F-C6H2-N=C-(An)-(An)-C=N-(2, 6-(CHCH3)2-C6H3)] (2c) was received as
bright yellow powder (1.764 g) in 46% yield. 1H NMR (400 MHz, CDCl3) δ 7.69 (m, Ar-H, 1H),
7.51 (d, J = 8.2 Hz, Ar-H, 1H), 7.25 – 7.22 (m, Ar-H, 7H), 7.21 – 7.16 (m, Ar-H, 3H), 7.08 (d, J =
7.5 Hz, Ar-H, 4H), 6.89 (d, J = 7.3 Hz, Ar-H, 5H), 6.72 (d, J = 9.6 Hz, Ar-H, 2H), 6.56 (m, Ar-H,
4H), 6.40 (m, Ar-H, 3H), 5.92 (d, J = 7.1 Hz, Ar-H, 1H), 5.62 (s, CH(Ph)2, 2H), 3.12 (m, CH(CH3)2,
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2H), 1.26 (d, J = 6.7 Hz, CH3,6H), 0.99 (d, J = 6.8 Hz, CH3, 6H). 13C NMR (101 MHz, CDCl3) δ
161.9, 147.0, 142.8, 140.9, 140.0, 135.7, 134.6, 129.7, 129.5, 128.7, 128.6, 128.2, 128.1, 127.9,
127.0, 126.8, 126.4, 125.8, 124.6, 124.2, 123.6, 123.0, 115.3, 115.1, 52.2, 28.5, 24.2, 23.7.
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General Procedures for the Synthesis of Imidazolium Salts
α-Diimine compounds (1 mmol) and chloromethyl ethyl (4 mL) ether were combined under a
nitrogen atmosphere at room temperature, and then the reaction was heated to 100 oC overnight.
When having reached the determined time, the solution was cooled to room temperature, and the
reaction mixture was treated with anhydrous Et2O and stirred for 1 h, causing the formation of a
great deal of precipitate. The solid was isolated by filtration and wash with anhydrous Et2O three
times. The resulting crude was generally obtained in excellent purity and no further purification was
required.
[(IPr*IPrMe)An]+Cl- (L1) was obtained as yellowish powder (0.706 g, 87%). 1H NMR (400 MHz,
CDCl3) δ 12.61 (s, NCHN, 1H), 7.81 (d, J = 8.3 Hz, Ar-H, 1H), 7.64 (d, J = 8.0 Hz, Ar-H, 2H), 7.42
(m, Ar-H, 3H), 7.30 (d, J = 6.1 Hz, Ar-H, 8H), 7.18 (d, J = 6.0 Hz, Ar-H, 2H), 7.02 (m, Ar-H, 2H),
6.91 (s, Ar-H, 2H), 6.81 (d, J = 7.4 Hz, Ar-H, 4H), 6.70 (m, Ar-H, 4H), 6.60 (m, Ar-H, 2H), 6.22 (d,
J = 7.0 Hz, Ar-H, 1H), 5.54 (s, CH(Ph)2, 2H), 2.74 (m, CH(CH3)2, 2H), 2.29 (s, Ar-CH3, 3H), 1.34 (d,
J = 6.7 Hz, CH3, 6H), 1.09 (d, J = 6.7 Hz, CH3, 6H). 13C NMR (101 MHz, CDCl3) δ 152.5, 145.0,
143.9, 141.5, 140.7, 139.0, 136.8, 132.0, 130.6, 129.8, 129.7, 129.5, 129.2, 128.6, 128.2, 127.2,
127.0, 126.7, 126.5, 126.1, 124.9, 124.0, 122.7, 122.1, 121.7, 52.0, 29.4, 24.7, 23.6, 22.0. ESI-MS.
m/z: 775.15, [L1]+.
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[(IPrOMe*IPr)An] +Cl- (L2) was obtained as yellowish powder (0.662 g, 80%). 1H NMR (400 MHz,
CDCl3) δ 12.69 (s, NCHN, 1H), 7.80 (d, J = 8.0 Hz, Ar-H, 1H), 7.64 (m, Ar-H, 2H), 7.44 (d, J = 7.8
Hz, Ar-H, 2H), 7.36 (m, 9.5 Hz, Ar-H, 9H), 7.18 (d, J = 6.1 Hz, Ar-H, 2H), 7.05 (m, Ar-H, 1H), 6.99
(d, J = 6.9 Hz, Ar-H, 1H), 6.84 (d, J = 7.4 Hz, Ar-H, 4H), 6.71 (m, Ar-H, 4H), 6.63 – 6.57 (m, Ar-H,
4H), 6.28 (d, J = 7.0 Hz, Ar-H, 1H), 5.58 (s, CH(Ph)2, 2H), 3.61 (s, Ar-OCH3, 3H), 2.73 (s,
CH(CH3)2, 2H), 1.36 (d, J = 5.3 Hz, CH3, 6H), 1.09 (d, J = 6.1 Hz, CH3, 6H).13C NMR (101 MHz,
CDCl3) δ 161.6, 148.8, 145.1, 143.5, 141.3, 139.3, 134.1, 132.0, 123.0, 129.8, 129.6, 129.4, 129.2,
128.8, 128.7, 128.6, 128.2, 127.6, 127.2, 126.9, 126.5, 124.9, 124.1, 121.7, 115.5, 55.3, 52.2, 29.4,
24.8, 23.7. ESI-MS. m/z: 791.15, [L2]+.
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[(IPrF*IPr)An] Cl- (L3) was obtained as yellowish powder (0.587 g, 72%). H NMR (400 MHz,
CDCl3) δ 12.71 (s, NCHN, 1H), 7.81 (d, J = 8.2 Hz, Ar-H, 1H), 7.65 (d, J = 8.0 Hz, Ar-H, 2H), 7.43
(m, Ar-H, 4H), 7.32 (m, Ar-H, 9H), 6.82 (m, Ar-H, 7H), 6.70 (m, Ar-H, 5H), 6.59 (m, Ar-H, 2H),
6.20 (d, J = 6.9 Hz, Ar-H, 1H), 5.59 (s, CH(Ph)2, 2H), 3.48 (m, CH(CH3)2, 2H), 1.37 (d, J = 6.0 Hz,
CH3, 6H), 1.10 (d, J = 6.2 Hz, CH3, 6H). 13C NMR (101 MHz, CDCl3) δ 145.2, 145.1, 145.0, 140.8,
134.0, 138.2, 136.9, 132.1, 129.8, 129.7, 129.5, 129.1, 128.8, 128.3, 127.2, 127.1, 127.0, 126.7,
125.0, 124.1, 122.5, 122.0, 121.8, 117.4, 117.1, 52.2, 29.5, 24.7, 23.6. ESI-MS. m/z: 779.30, [L3]+.
General Procedures for the Synthesis of Pd-PEPPSI Compounds
In a vial equipped with a stirring bar, the mixture of PdCl2 (177 mg, 1.0 mmol), imidazolium
salt (1.0 mmol), K2CO3 (1382 mg, 10 mmol) and pyridine or 3-chloropyridine (5.0 mL) was stirred
at 80°C during 24 h under a nitrogen atmosphere. After cooling to room temperature, 10 mL
dichloromethane was added, and then the reaction mixture was diluted in CH2Cl2 and passed through
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a pad of silica covered with celite and eluted with CH2Cl2. The solvents were removed under reduced
pressure to furnish the desired product, which was recrystallized in a DCM/pentane mixture to
remove completely the pyridine or 3-chloropyridine. The pure palladium complex was finally
obtained after filtration and drying under high vacuum.
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[Pd(IPr*IPr)An(3-Cl-pyridinyl)Cl2] (C1) was obtained as yellow powder (0.660 g, 62%).1H NMR
(400 MHz, CDCl3) δ 8.98 (s, Ar-H, 1H), 8.84 (d, J = 5.4 Hz, Ar-H, 1H), 7.66 (m, Ar-H, 2H), 7.49 (m,
Ar-H, 3H), 7.30 (d, J = 7.6 Hz, Ar-H, 4H), 7.25 – 7.13 (m, Ar-H, 9H), 7.11 (s, Ar-H, 2H), 6.82 (d, J
= 7.5 Hz, Ar-H, 4H), 6.62 (s, Ar-H, 2H), 6.56 (d, J = 7.0 Hz, Ar-H, 1H), 6.39 (m, 4H), 6.25 (m, Ar-H,
2H), 5.30 (s, CH(Ph)2, 2H), 3.61 (m, CH(CH3)2, 2H), 2.38 (s, Ar-CH3, 3H), 1.47 (d, J = 6.4 Hz, CH3,
6H), 0.98 (d, J = 6.7 Hz, CH3, 6H). 13C NMR (101 MHz, CDCl3) δ 156.5, 150.8, 149.8, 147.2, 144.5,
144.0, 141.6, 140.5, 139.1, 137.6, 135.1, 134.0, 132.0, 130.8, 130.7, 130.4, 129.7, 128.2, 127.9,
127.5, 127.2, 126.2, 125.8, 125.7, 125.4, 124.9, 124.5, 124.0, 122.4, 120.9, 51.1, 29.2, 26.1, 24.4,
21.9.Anal. Calcd for C63H54Cl3N3Pd: C, 70.99; H, 5.11; N, 3.94. Found: C, 70.86 ; H, 5.05; N, 3.97.
ESI-MS. m/z: 914.95, [L1PdCl]+; 775.15, [L1]+.
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MHz, CDCl3) δ 8.91 (d, J = 5.0 Hz, Ar-H, 2H), 7.66 (m, Ar-H, 2H), 7.51 (d, J = 7.7 Hz, Ar-H, 2H),
7.46 (d, J = 8.2 Hz, Ar-H, 1H), 7.32 (d, J = 7.4 Hz, Ar-H, 4H), 7.24 – 7.13 (m, Ar-H, 9H), 7.09 (s,
Ar-H, 2H), 6.83 (d, J = 7.4 Hz, Ar-H, 4H), 6.66 (s, Ar-H, 2H), 6.60 (t, J = 7.6 Hz,s Ar-H, 1H), 6.55
(d, J = 6.9 Hz, Ar-H, 1H), 6.40 (m, Ar-H, 4H), 6.25 (m, Ar-H, 2H), 5.30 (s, CH(Ph)2, 2H), 3.63 (m,
CH(CH3)2, 2H), 2.37 (s, Ar-CH3, 3H), 1.48 (d, J = 6.4 Hz, CH3, 6H), 0.98 (d, J = 6.7 Hz, CH3, 6H).
13C NMR (101 MHz, CDCl3) δ 158.1, 151.7, 147.2, 144.5, 144.0, 141.5, 140.5, 139.0, 137.5, 135.1,
134.1, 130.7, 130.6, 130.4, 129.7, 128.2, 127.9, 127.5, 127.2, 127.1, 126.2, 125.7, 125.6, 125.4,
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124.8, 124.1, 122.4, 120.8, 51.1, 29.1, 26.1, 24.4, 21.9.Calcd for C63H55Cl2N3Pd: C, 73.36; H, 5.37;
N, 4.07. Found: C, 73.24; H, 5.42; N, 4.01. ESI-MS. m/z: 996.85, [L1PdClPy]+; 914.60, [L1PdCl]+;
775.15, [L1]+.
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[Pd(IPrOMe*IPr)An(3-Cl-pyridinyl)Cl2] (C3) was obtained as yellow powder (0.611 g, 56%). H
NMR (400 MHz, CDCl3) δ 8.97 (s, Ar-H, 1H), 8.84 (d, J = 5.3 Hz, Ar-H, 1H), 7.67 (m, Ar-H, 2H),
7.51 (d, J = 7.8 Hz, Ar-H, 2H), 7.46 (d, J = 8.2 Hz, Ar-H, 1H), 7.31 (d, J = 7.5 Hz, Ar-H, 4H), 7.21
(m, Ar-H, 6H), 7.16 (d, J = 6.7 Hz, Ar-H, 2H), 6.89 – 6.78 (m, Ar-H, 6H), 6.65 (s, Ar-H, 2H), 6.64 –
6.57 (m, Ar-H, 1H), 6.55 (d, J = 6.9 Hz, Ar-H, 1H), 6.39 (m, Ar-H, 4H), 6.24 (m, Ar-H, 2H), 5.30 (s,
CH(Ph)2, 2H), 3.69 (s, Ar-OCH3, 3H), 3.60 (m, CH(CH3)2, 2H), 1.46 (d, J = 6.4 Hz, CH3, 6H), 0.97
(d, J = 6.7 Hz, CH3, 6H). 13C NMR (101 MHz, CDCl3) δ 159.4, 156.8, 150.8, 149.8, 147.2, 145.9,
144.1, 141.7, 140.1, 137.6, 134.0, 132.0, 130.7, 130.4, 129.6, 127.9, 127.6, 127.3, 127.1, 126.2,
126.0, 125.8, 125.6, 125.4, 124.9, 124.5, 123.9, 122.6, 120.9, 115.5, 55.2, 51.3, 29.2, 26.1, 24.4.
Calcd for C63H54Cl3N3OPd: C, 69.94; H, 5.03; N, 3.88. Found: C, 69.84; H, 5.07; N, 3.81. ESI-MS.
m/z: 932.40, [L2PdCl]+; 791.15, [L2]+.
[Pd(IPrOMe*IPr)An(pyridinyl)Cl2] (C4) was obtained as yellow powder (0.830 g, 79%). H NMR
1
(400 MHz, CDCl3) δ 8.90 (d, J = 5.0 Hz, Ar-H, 2H), 7.66 (m, Ar-H, 2H), 7.51 (d, J = 7.8 Hz, Ar-H,
2H), 7.45 (d, J = 8.2 Hz, Ar-H, 1H), 7.33 (d, J = 7.6 Hz, Ar-H, 4H), 7.17 (m, Ar-H, 8H), 6.85 (d, J =
7.3 Hz, Ar-H, 4H), 6.80 (s, 2H), 6.69 (s, Ar-H, 2H), 6.66 – 6.57 (m, Ar-H, 1H), 6.55 (d, J = 6.9 Hz,
Ar-H, 1H), 6.40 (m, Ar-H, 4H), 6.24 (m, Ar-H, 2H), 5.36 (s, CH(Ph)2, 2H), 3.69 (s, Ar-OCH3, 3H),
3.62 (m, CH(CH3)2, 2H), 1.48 (d, J = 6.5 Hz, CH3, 6H), 0.98 (d, J = 6.8 Hz, CH3, 6H). 13C NMR
(101 MHz, CDCl3) δ 159.3, 158.5, 151.7, 147.2, 145.9, 144.2, 141.6, 140.2, 138.9, 137.5, 134.1,
130.6, 130.4, 129.7, 127.8, 127.5, 127.3, 127.1, 126.2, 125.9, 125.7, 125.6, 125.4, 124.8, 124.1,
29
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