[Pd(IPr*R)(acac)Cl]: Efficient bulky Pd-NHC catalyst for Buchwald-Hartwig C-N cross-coupling reaction

Article abstract of DOI:10.1016/j.jorganchem.2018.02.035

A series of bulky palladium catalysts based on N-heterocyclic carbene, (Pd(NHC)(acac)Cl: NHC = IPr*me = N,N′-bis(2,6-bis(di-p-tolylmethyl)-4-methylphenyl)-imidazol-2 -ylidene, Pd(IPr*me)(acac)Cl; NHC = IPr*ipr = N,N′-bis(2,6-bis(di-4-isopropylphenyl)-4-methylphenyl)-imidazol-2 -ylidene, Pd(IPr*ipr)(acac)Cl; and NHC = IPr*tBu = N,N′-bis(2,6-bis(di-4-(tert-butyl)phenyl)- 4-methylphenyl)- imidazol-2-ylidene, Pd(IPr*tBu)(acac)Cl; acac = acetylacetonate), have been designed and synthesized. These three new catalysts showed much better catalytic activity in the Buchwald?Hartwig arylamination coupling reaction as compare to the earlier congener (IPr*)Pd(acac)Cl (IPr* = N,N′-bis(2,6-diphenylmethyl)-4-methylphenylimidazol-2-ylidene). The highly active Pd^II precatalyst [Pd(IPr*me)(acac)Cl] has been fully explored by using a wide range of substrates with different electronic and steric demands of coupling partners, for which up to 99% isolated yields were obtained. Remarkably, the moderate isolated yield was obtained for the challenging coupling of the amine bearing very bulky groups.

Full text of DOI:10.1016/j.jorganchem.2018.02.035

Accepted Manuscript
[Pd(IPr*R)(acac)Cl]: Efficient bulky Pd-NHC catalyst for Buchwald-Hartwig C-N cross-
coupling reaction
Xiabing Tian, Jing Lin, Sheng Zou, Junwei Lv, Qingfei Huang, Jin Zhu, Shuping
Huang, Qiwei Wang
PII:
S0022-328X(18)30134-7
10.1016/j.jorganchem.2018.02.035
JOM 20334
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 8 January 2018
Revised Date: 6 February 2018
Accepted Date: 21 February 2018
Please cite this article as: X. Tian, J. Lin, S. Zou, J. Lv, Q. Huang, J. Zhu, S. Huang, Q. Wang,
[Pd(IPr*R)(acac)Cl]: Efficient bulky Pd-NHC catalyst for Buchwald-Hartwig C-N cross-coupling reaction,
Journal of Organometallic Chemistry (2018), doi: 10.1016/j.jorganchem.2018.02.035.
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ACCEPTED MANUSCRIPT
[Pd(IPr*R)(acac)Cl]: Efficient Bulky Pd-NHC catalyst for Buchwald-Hartwig
C-N cross-coupling reaction
，
，
Xiabing Tian1 2, Jing Lin,3 Sheng Zou1, Junwei Lv4，Qingfei Huang1 *, Jin Zhu1,
，
，
*
Shuping Huang3 * and Qiwei Wang1
1Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu
610041, China. E-mail: qfhuang@cioc.ac.cn wqw@cioc.ac.cn
；
2University of Chinese Academy of Sciences, Beijing 100049, China
3College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, P. R. China.
E-mail: huangshp@gmail.com
4Department of Materials Science and Engineering, Southwest Petroleum University,
Chengdu 610500, China
ABSTRACT:
A series of bulky palladium catalysts based on N-heterocyclic carbene,
(Pd(NHC)(acac)Cl:
NHC = IPr*me = N,N’-bis(2,6-bis(di-p-tolylmethyl)-4-methylphenyl)-imidazol-2
-ylidene, Pd(IPr*me)(acac)Cl;
NHC = IPr*ipr = N,N’-bis(2,6-bis(di-4-isopropylphenyl)-4-methylphenyl)-imidazol-2
-ylidene, Pd(IPr*ipr)(acac)Cl;
and NHC = IPr*tBu = N,N’-bis(2,6-bis(di-4-(tert-butyl)phenyl)- 4-methylphenyl)-
imidazol-2-ylidene, Pd(IPr*tBu)(acac)Cl;
acac = acetylacetonate), have been designed and synthesized. These three new
catalysts showed much better catalytic activity in the Buchwald−Hartwig
arylamination coupling reaction as compare to the earlier congener (IPr*)Pd(acac)Cl
(IPr*
=
N,N’-bis(2,6-diphenylmethyl)-4-methylphenylimidazol-2-ylidene). The
highly active PdII precatalyst [Pd(IPr*me)(acac)Cl] has been fully explored by using a
wide range of substrates with different electronic and steric demands of coupling
partners, for which up to 99% isolated yields were obtained. Remarkably, the

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moderate isolated yield was obtained for the challenging coupling of the amine
bearing very bulky groups.
1. Introduction
Palladium-catalyzed cross-coupling reactions have been extensively studied over
the past 30 years[1]. In particular, palladium-catalyzed arylamination has become an
important and widely employed method for the formation of C−N bonds[2]. Unlike
phosphine-based ligands[3], palladium N-heterocyclic carbene (Pd-NHC) complexes
feature significant air and moisture stability and strong σ-donating properties, which
make them very user friendly and benefit for the oxidative addition of aryl halides
during the catalytic cycle[4]. However, reports of Pd-NHC catalysts used in C-N
coupling reactions are still relatively rare[5]. Recent years, the improvement in the
design of catalysts, especially the design of ligands’ sterical hindrance, promote the
development of this field. Sterically demanding ancillary ligands can kinetically
stabilize highly reactive low-valent transition metals and permit high catalytic
activity[6].
Nolan group have done a systematic work in this filed. They developed the
(IPr)Pd(acac)Cl (IPr = N,N′-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) complex
and successfully applied it in Buchwald-Hartwig C-N cross-coupling reactions,
achieving desired results in 2006 [5a]. Afterwards, they developed a bulkier catalyst
(IPr*)Pd(acac)Cl featuring better stability and excellent catalytic activity, in which the
carbene center located in center of a bowl-shaped cavity [4]. The properties of NHCs
ligands have a great influence on the performance of Pd- NHC catalysts. The steric
hindrance facilitated reductive elimination and stabilization of a low-valent active

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intermediate [7]. Therefore, the exploration of even bulkier NHC ligands and study of
their catalytic performance to further develop highly active Pd-NHC catalyst would
be of great significance. We reasoned that the catalytic activity of Pd-NHC catalyst
based on (IPr*)Pd(acac)Cl can be enhanced by simply introducing a bulky substituent
group, such as methyl, isopropyl or tert-butyl.
To evaluate this concept, we designed and synthesized a series of
Pd(NHC)(acac)Cl catalysts incorporating the bulkier methyl, isopropyl or tert-butyl
substituent group in the IPr* units (Figure 1). Subsequently, they were applied in
Buchwald-Hartwig C-N cross-coupling reactions and gave rise to much better
catalytic activity as expected. Furthermore, the catalytic activity was tunable, and
significantly enhance by increasing the steric hindrance of the ligand. Additionally,
the theoretical calculations further confirmed that the energy of Pd-C bond in
Pd-NHC was reduced with the increasing of the steric hindrance of the NHC ligand,
thus resulted in the enhancement of the catalytic activity.
Figure 1. The chemical structure of Pd(NHC)(acac)Cl
2. Results and discussion
Multigram quantities of NHC ligands (IPr*R·HCl: IPr*·HCl, IPr*me·HCl、
IPr*ipr·HCl and IPr*tBu·HCl) were successfully prepared (SI scheme 1) using the
method reported in the previous literature [8]. Ultimately, the desired palladium
N-heterocyclic carbene complexes (Pd-NHC) were obtained through a facile ligand
exchange between Pd(acac)2 and the corresponding NHC ligands.

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Figure 2. Synthesis of Pd(NHC)(acac)Cl
All the Pd(NHC)(acac)Cl complexes are found to be both air and moisture stable.
And the crystal of Pd(IPr*me)(acac)Cl suitable for X-ray diffraction were
successfully grown by slow diffusion of hexane into a saturated benzene solution of
the complex (Figure 2). The Pd(II) atom adopted a square planar geometry,
coordinated to the Cl, two O from acac ligand, and the C from imidazol ring of NHC
ligand.
Figure 3. Molecular structure of Pd(IPr*me)(acac)Cl .
Selected bond lengths (Å) and angles (deg): Pd1−C43, 1.965(4); Pd1−O1, 2.026(7);
Pd1−O2, 2.022(7); Pd1−Cl1, 2.284(3); C1−Pd1−O1, 86.5(3); O1−Pd1−O2, 93.4(3);
C43− Pd1−Cl1, 87.5(3); O2−Pd1−Cl1, 179.59(2).

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Figure 4. First Screening of Catalysts Performance.
aReagents and conditions: 1-bromo-4-methylbenzene (1 mmol), morpholine (1.2 mmol), Pd precatalyst
(0.2-0.4 mol %), solvent (1 mL), base (1.2 mmol), 110℃, 3 h. Conversion of the coupling product
based on starting aryl halide determined by NMR.
To evaluate the catalytic activities, we examined the performance of these new
catalysts by using the Pd(IPr*)(acac)Cl as the control in the identical condition
reported by Nolan[4]. The results clearly indicated that the catalyst incorporated
bulkier ligand exhibited a relatively higher catalytic activity as shown in Figure 3. All
the three new catalysts exhibited higher activities than Pd(IPr*)(acac)Cl with over
10% increasing of the conversion yield. Considering the easier preparation of
IPr*me·HCl, the Pd(IPr*me)(acac)Cl was selected to further expand the substrate
scope of C-N cross-coupling reaction.
The optimal base/solvent systems for the Buchwald-Hartwig C-N cross-coupling
reaction were of 4-Bromotoluene with N-morpholine then carefully explored under
various conditions listed in Table 1. The preliminary data clearly demonstrated that
the catalytic arylamination displayed the best performance in the system of LiHMDS
as base and 1,4-dioxane as solvent.

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Table 1. Further Screening of Base/Solvent System for Amination with
[Pd(IPr*me)(acac)Cl]a
Entry
Solvent
dimethoxyethane
dimethoxyethane
toluene
Base
Yield (%)
1
2
3
4
5
6
LiHMDS
KOtBu
88
86
90
83
98
97
LiHMDS
KOtBu
toluene
1,4-dioxane
1,4-dioxane
LiHMDS
KOtBu
aReagents and conditions: 1-bromo-4-methylbenzene (1 mmol), morpholine (1.2 mmol), Pd precatalyst
1 (0.40 mol %), solvent (1 mL), base (1.2 mmol), 110℃, 3 h. Conversion to coupling product based on
starting aryl halide determined by NMR.
The optimized condition, 0.4 mol % of catalyst loading at 110 °C in
1,4-dioxane with LiHMDS for 3h, was established, which was the same as the
condition reported by Nolan[4]. Under the optimized base/solvent system, we
screened the coupling of different aryl halides with N-morpholine. As listed in Table
2, excellent catalytic activities were successfully achieved with good isolated yields
up to 99%. The yield of the hindered aryl bromide (entries 3, 5 and 10) in the
coupling reaction was also satisfactory. The inactive aryl chloride also could provide
a good yield of 91% (entry 1). The aryl bromides bearing weakly steric groups
(entries 9, 11 and 13) and heterocyclic aryl bromides (entries 6,7 and 8) also proved to
be suitable partners. Aryl bromides bearing electron-donating groups (entries 14, 15
and 16) showed high activity in the reaction. Aryl bromides bearing
electron-withdrawing substituents, including trifluoromethyl group, were
well-tolerated, affording the coupled products in a good yield (entry 17), but aryl

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bromides bearing nitro substituent coupled with aniline proceeded with only moderate
yields (entry 18). According to the relevant literature，we speculated that the catalyst
may form a (nitroso)Pd(II) species and lose its activity [9].
Table 2. Arylamination Screening of Various Aryl halides with N-morpholinea
Pd(IPr*me)(acac)Cl (0.4 mol%)
X
N
O
HN
O
LiHMDS,1,4-dioxane
R
R
110
h
℃，3
(X = Cl or Br)
N
O
N
O
N
O
O
N
O
1. 98%, 91%b
2. 99%
3. 95%
4. 75%
O
S
N
N
H3CO
N
N
N
O
O
N
7. 89%
5. 85%
6. 81%
8. 96%
N
O
N
O
N
O
N
O
9. 99%
11. 97%
OCH3
12. 98%
10. 95%
H3CO
N
O
N
MeO
N
O
N
O
N
O
13. 98%
14. 85%
15. 99%
16. 99%
F
F
O
O2N
N
O
F
17. 90%
18. 41%
aReagents and conditions: aryl bromide (1 mmol), morpholine (1.2 mmol), Pd precatalyst 1 (0.40
mol %), solvent (1 mL), base (1.2 mmol), 110 ℃, 3 h. Isolated yield after chromatography on silica
gel.
bAr-Cl as material

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The selected optimized conditions were also generally applied to a wide number
of amine substrates. The good to excellent isolated yields were obtained (Table 3).
The p-toluidine and aniline were successfully coupled with 4-Bromotoluene under
these conditions (entries 1 and 5), affording the coupled products in excellent yields.
N-methylaniline also proved to be suitable partners, successfully coupled with aryl
chloride (entry 7), aryl bromide (entries 4 and 10) and heterocyclic (entry 8),
affording the coupled products in excellent yields. Aniline with electron- donating
groups has a higher activity in reaction than that with electron-withdrawing
substituents (entry 2 vs entry 3). In addition, piperidine and 4-Bromotoluene (entry 6)
were successfully coupled and excellent isolated yields were obtained.
The Buchwald−Hartwig arylamination is a very powerful synthetic tool for the
preparation of a wide range of biologically active molecules[10]. However, there was
few satisfied results obtained in the C-N cross-coupling reaction based on the
substrates with very bulky group[6]. Therefore, we proposed examining the reactivity
of several aryl groups bearing hindered substituents, excellent yields were obtained
(entries 9, 11, 12 and 13). Surprisingly, a moderate isolated yield could be obtained
for the challenging coupling of both sterically and electronically disfavored amine
with 4-Bromotoluene (entry 14). Meanwhile, the Buchwald−Hartwig arylamination is
also been applicated in small-molecule organic light emitting diodes (OLEDs)
component synthesis[11]. And this system is more efficient, obtained an good yield
product of 92% (entry 15).

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Table 3. Arylamination Screening of Various Aamines with Aryl halidesa
R'
R
R'
R
Pd(IPr*me)(acac)Cl (0.4 mol%)
LiHMDS,1,4-dioxane
X
N
HN
R
R
110
h
℃，3
(X = Cl or Br)
H
N
H
H
F
N
OMe
N
3. 70%
N
1. 99%
2. 99%
H
N
N
4. 99%
5. 99%
6. 97%
H
N
N
N
N
7b. 99%
8. 99%
9. 99%
H
N
MeO
N
10. 97%
11. 98%
H
N
H
N
12. 98%
13. 98%
14. 52%, 68%c
N
H
15. 92%
a Reagents and conditions: aryl halides (1 mmol), amines (1.2 mmol), Pd precatalyst 1 (0.40 mol %),

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solvent (1 mL), base (1.2 mmol), 110℃, 3 h. Isolated yield after chromatography on silica gel.
bAr-Cl as material.
c 12 h.
Besides the experiment, we also used theoretical calculations to verify our
assumptions about the subject. All the theoretical calculations were carried out using
Gaussian 09 [12]. The density functional theory (DFT) [13] at the gradient-corrected
correlation functional PBE1PBE [14] was used to optimize molecular geometries
without symmetry constraint. During the optimization processes, the convergent
values of maximum force, root-mean-square (RMS) force, maximum displacement,
and RMS displacement are set by default. The 6-31G(d，p) [15] basis set was used for
C, H, N, O, and Cl, while the Stuttgart–Dresden (SDD) [16] basis set and the effective
core potentials (ECP) were employed for Pd. The optimized geometries were
confirmed with all real frequencies.
The calculated bond lengths of Pd-Cl and Pd-C of Pd(IPr*me)(acac)Cl by the
PBE1PBE functional are 2.30 and 1.97 Å, which are close to the corresponding bond
lengths (2.28 and 1.96 Å) in its X-ray structure. The calculated bond energies of the
Pd-C bonds for Pd(IPr*)(acac)Cl, Pd(IPr*me)(acac)Cl, Pd(IPr*ipr)(acac)Cl, and
Pd(IPr*tBu)(acac)Cl by the PBE1PBE functional are 1.96, 1.88, 1.69, 1.47 eV,
respectively, indicating that the increasing steric bulk of the NHCs leads to a decrease
of the Pd-C bond energy. The better activity of Pd(IPr*me)(acac)Cl would be related
to its lower Pd-C bond energy.
3. Summary
Three new well-designed bulky catalysts Pd(NHC)(acac)Cl (Pd(IPr*me)(acac)Cl,
Pd(IPr*ipr)(acac)Cl, and Pd(IPr*tBu)(acac)Cl) were successfully synthesized and
applied in the Pd catalyzed C-N cross-coupling reaction. They show better activities
than its earlier generation [Pd(IPr*)(acac)Cl] congener, which is attributed to the
improving of the sterical hindrance in NHC ligand. [Pd(IPr*me)(acac)Cl] showed
excellent performance in C-N bond formation between the aryl-chlorides/bromides

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and amines, including sterically hindered and deactivated substrate. Our strategy of
simple ligand modification successfully leads to the remarkable promotion of catalyst
activity further verify the theory proposed by Nolan and provide the guideline for
further exploitation and application of palladium N-heterocyclic carbene catalysts.
Further investigations are ongoing in our laboratory to extend its use to other
reactions.
4. Experimental section
4.1. Materials and instruments
All aryl halides and amines were used as purchased without further purification.
1H NMR and 13C NMR spectra were recorded on Bruker at 300 and 75 MHz,
respectively, in CDCl3 with tetramethylsilane as internal reference standard or
DMSO-d6. High resolution mass spectra (HRMS) were recorded in positive ion mode
by Electrospray Ionization (ESI) using time of flight mass spectrometer. Column
chromatography was performed using 300-400 mesh silica gel and technical grade
solvents.
4.2 General Procedure for the Synthesis of [Pd(NHC)(acac)Cl]
In a Schlenk flask equipped with a magnetic stirring bar, IPr*R·HCl (1.4 eq) and
Pd(acac)2 (1 eq) were dissolved in dry 1,4-dioxane (15 mL) under an atmosphere of
nitrogen. The reaction mixture was then refluxed at 110℃ for 12 h. After removal of
the dioxane solvent, the residue was re-dissolved in CH2Cl2, filtered on a pad of silica
covered with Celite. The crude product was obtained after evaporating the CH2Cl2
solvent. After chromatography on silica gel, the pure complex was obtained as a
yellow powder.
4.3. Buchwald−Hartwig Cross-Coupling of Aryl Halides with Primary or Secondary
Amines: General Procedure.
A glass vial was charged with [Pd(IPr*me)(acac)Cl] (1) , neat amine (1.1 mmol),
and the aryl halide (1 mmol) in dry 1,4-dioxane (1 mL) under an atmosphere of
argon，and sealed with a screw cap fitted with a septum. LiHMDS (1.1 mmol) was
subsequently injected at room temperature under argon, the reaction mixture was then

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refluxed at 110 ℃ for 3 h, After this time, dioxane was evaporated, the crude product
was dissolved in CH2Cl2. The solution was filtered on a pad of silica covered with
Celite, and the pad was eluted with CH2Cl2. After chromatography on silica gel, the
pure complex was obtained.
Acknowledgments
We are grateful for financial support from Chengdu Xiling Lab Co., Ltd of this
research. We would also like to thank Dr. Jinkun Huang for help comments. Dr.
Shuping Huang acknowledges the financial support from the National Natural Science
Foundation of China No. 21703036.

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ACCEPTED MANUSCRIPT
Highlights
1) We have design and synthesis a series of bulky palladium catalysts based on
N-heterocyclic carbine for C-N cross-coupling reaction.
2) .They all show better activities than its earlier generation [Pd(IPr*)(acac)Cl]
congener, which is attributed to the improving of the sterical hindrance in NHC
ligand.
3) This strategy of simple ligand modification successfully leads to the remarkable
promotion of catalyst activity further verify the theory proposed by Nolan and
provide the guideline for further exploitation and application of palladium
N-heterocyclic carbine catalysts.