Supporting ligand-assisted N-heterocyclic carbene palladium complexes: Characterization, computation, and catalytic activity in Suzuki-Miyaura cross coupling between aryl and heteroaromatic chlorides and various boronic acids

Article abstract of DOI:10.1016/j.tetlet.2016.03.086

A new series of imine-Pd-(N-heterocyclic carbene) complexes have been developed as efficient catalysts for Pd-catalyzed Suzuki-Miyaura coupling reaction. Based on the performance of supporting ligands, correlation of structure and catalytic activity has been demonstrated via experimental and computational modeling. A broad reaction scope of aryl and heteroaromatic chlorides could proceed at extremely low catalyst loading (minimum 0.005 mol %).

Full text of DOI:10.1016/j.tetlet.2016.03.086

Accepted Manuscript
Supporting Ligand-assisted N-Heterocyclic Carbene Palladium Complexes:
Characterization, Computation and Catalytic Activity in Suzuki-Miyaura Cross
Coupling between aryl and heteroaromatic chlorides and various boronic acid
An Shen, Yu-Cai Hu, Ting-Ting Liu, Chen Ni, Yong Luo, Yu-Cai Cao
PII:
S0040-4039(16)30313-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.03.086
TETL 47474
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
22 February 2016
25 March 2016
28 March 2016
Please cite this article as: Shen, A., Hu, Y-C., Liu, T-T., Ni, C., Luo, Y., Cao, Y-C., Supporting Ligand-assisted N-
Heterocyclic Carbene Palladium Complexes: Characterization, Computation and Catalytic Activity in Suzuki-
Miyaura Cross Coupling between aryl and heteroaromatic chlorides and various boronic acid, Tetrahedron
Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.03.086
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Tetrahedron Letters
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Supporting Ligand-assisted N-Heterocyclic Carbene Palladium Complexes:
Characterization, Computation and Catalytic Activity in Suzuki-Miyaura Cross
Coupling between aryl and heteroaromatic chlorides and various boronic acid
An Shen , Yu-Cai Hu , Ting-Ting Liu , Chen Ni , Yong Luo , Yu-Cai Cao a,b,
a,b
a,b
a
a,b
a,b
a
State Key Laboratory of Polyolefins and Catalysis (Shanghai Research Institute of Chemical Industry), 345 East Yunling Road, Shanghai 200062, China.
Shanghai Key Laboratory of Catalysis Technology for Polyolefins (Shanghai Research Institute of Chemical Industry), 345 East Yunling Road, Shanghai
b
2
00062, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new series of imine-Pd-(N-Heterocyclic Carbene) complexes have been developed as efficient
catalysts for Pd-catalyzed Suzuki-Miyaura coupling reaction. Based on the performance of
supporting ligands, correlation of structure and catalytic activity has been demonstrated via
experimental and computational modeling. A broad reaction scope of aryl and heteroaromatic
chlorides could proceed at extremely low catalyst loading (minimum 0.005 mol%).
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
N-heterocyclic carbene
Suzuki-Miyaura coupling
Aryl chlorides
Heteroaromatic chlorides
DFT computation
—
——

Corresponding author. Tel.: +86-021-52817942; fax: +86-021-52800850; e-mail: caoyc@srici.cn (Y.-C. Cao)

2
Transition-metal-catalyzed cross-coupling processes, for
example, the Suzuki-Miyaura reactions, are powerful and
valuable methods for the construction of carbon-carbon
condition was fixed by choosing 2-chlorotoluene and
phenylboronic acid as a model system (Table 1). Considering
the excellent activities of the catalysts, catalyst loading was
decreased to extremely low level (0.01 mol%). Through tests
it was found that in many solvents the desired cross-coupling
reaction didn’t proceed well (Table 1, entries 1-3). Isopropanol
mixed with water was proved to be an effective solvent,
wherein the reaction taken place readily (Table 1, entry 5,
yield=94%). One key point needs to be underlined was that
appropriate basicity is beneficial to this reaction. Within
1
bonds. Since the discovery of the Suzuki-Miyaura reaction,
various boronic acids and aryl halides have been employed as
2
indispensable reagents. Particularly, aryl chlorides are more
attractive electrophiles due to their low cost, wide availability,
and good stability. Many novel ligands and catalysts are
designed to realize the efficient coupling. In addition to
classical phosphine palladium complexes, N-heterocyclic
carbene (NHC) palladium complexes have also been
established and applied successfully in this coupling reaction
2 3
expectation, only 6% yield was achieved when using K CO
as base (Table 1, entry 6). It’s worthy to note that modification
of supporting ligands, even change of substitutes on them,
indeed influenced the activities of this type of catalysts.
Compared with oxime supporting ligands (cat 1), aryl imines
supporting ligands (cat 2 and 3) were much more effective
obviously (Table 1, entry 5 and entries 8-9). Electron-
withdrawing groups on aryl imines seemed to afford the best
3,4
as effective catalyst package. Furthermore, several research
groups have well recognized the significance of supporting
ligands in the complexes, which could influence the catalytic
4
activity obviously. Therefore, besides developing novel NHC
ligands, to find out appropriate natures and great diversity of
supporting ligands is also a big challenge in this research field
2
yield of 96%. However, using 0.01 mol% PdCl without any
(Figure 1).
ligand as catalyst could not work in this reaction condition.
Decreasing of the catalyst loading to 0.005 mol% gave a
slightly lower yield of 91% (Table 1, entry 11), which was
quite satisfactory in consideration of ultra-low catalyst loading.
However, the reaction couldn’t proceed normally when the
amount of catalyst was reduced further (Table 1, entry 12).
Table 1. Various reaction parameters for Suzuki-Miyaura
a
coupling
Figure 1. Some representative examples of supporting ligands
In previous work, our group developed novel imine-Pd-
NHC complexes (Figure 1, R=OH or OMe), which proved to
be quite effective as pre-catalysts in Suzuki-Miyarua cross-
yield
entry
cat.
base
solvent
b
(%)
c
5
1
2
3
4
5
6
7
8
9
2 (0.01 mol%)
2 (0.01 mol%)
2 (0.01 mol%)
2 (0.01 mol%)
2 (0.01 mol%)
2 (0.01 mol%)
2 (0.01 mol%)
1 (0.01 mol%)
3 (0.01 mol%)
KOH
KOH
KOH
KOH
KOH
K CO
Dixoane
DMA
-
coupling reaction of aryl chlorides. Our observation of close
c
-
relationship between catalytic activity and the structure of
imine supporting ligands clearly indicated the importance and
effect of supporting ligands. Thus, in this work, we turned our
interest into developing/optimizing supporting ligands and
c
Toluene
-
i
PrOH
76
94
6
i
i
i
i
i
i
i
i
d
d
d
d
d
d
d
d
PrOH
PrOH
PrOH
PrOH
PrOH
PrOH
PrOH
PrOH
building up know-how in the mechanism.
A
few
representative imine-Pd-NHC complexes (cat.2 and 3) have
2
3
5-7
been easily obtained by similar synthetic method, whose
structures were determined by NMR and X-ray
crystallographic study (Figure 2).
t
KO Bu
KOH
KOH
KOH
KOH
KOH
90
80
96
c
1
1
1
0
1
2
PdCl
2
(0.01 mol%)
-
3 (0.005 mol%)
3 (0.002 mol%)
91
32
a
Reaction conditions: 2-chlorotoluene (3.0 mmol, 1 equiv),
phenylboronic acid 6a (3.15 mmol, 1.05 equiv), base (4.5 mmol,
1
.5 equiv), solvent (5 mL).
GC yield of coupling product, average of two runs.
b
c
Not determined.
Mixed with water ( PrOH/H
d
i
2
O=10:1).
To confirm the function of supporting ligands or even the
substitutes on them, some more substrates were employed
under the same reaction condition with 0.005 mol% catalyst
loading (Table 2).
Figure 2. Imine-Pd-NHC complexes and their X-ray structures
Table 2. Activities of different catalysts for Suzuki-
Miyaura coupling of several aryl chlorides
In order to get more efficient catalytic system, we replaced
original oxime functional group with aryl imines to optimize
the structure of supporting ligands. Optimized reaction
a

b
GC yield of coupling product, average of two runs.
The above results revealed the significant variation of
catalytic activity among these catalysts with different
supporting ligands, which definitely demonstrated our
speculation for the supporting ligands. Aryl substitute with
electron-withdrawing groups on N atom of supporting ligand
would be beneficial to improve catalytic activity. Given that
there was a lack of mechanistic details about imine-Pd-NHC
complexes catalyzed Suzuki cross-couplings reaction, we
carried out DFT computations to have an insight into the
mechanism of this catalytic cycle and the function of
supporting ligands. What needs to be emphasized was that the
bulk 2, 6-diisopropyl groups in NHC structure were replaced
b
b
b
entry
1
product
cat.1
cat.2
cat.3
80%
56%
43%
94%
95%
64%
96%
>99%
96%
2
3
4
8
by methyl groups for simplicity. Analogous activation
mechanism of Pd(0)-NHC species from initial Pd(II)-NHC
9
complexes has been reported. For imine-Pd(0)-NHC species,
the reasonable pathway should be clarified as follows: simple
substitution of the chloride with iso-propoxide at the Pd center
followed by β-H elimination and reductive elimination lead to
the formation of imine-Pd(0)-NHC species I0. So, we stated
from imine-Pd(0)-NHC (I0) species. The overall computed
89%
96%
96%
a
Reaction conditions: 2-chlorotoluene (3.0 mmol, 1 equiv),
phenylboronic acid 6a (3.15 mmol, 1.05 equiv), KOH (4.5 mmol,
10
profile of this model catalytic cycle is displayed in Figure 3.
i
1
0
.5 equiv), solvent ( PrOH/H
.005 mol%.
2
O=10:1, 5 mL), catalyst loading:
Figure 3. Proposed mechanism for imine-Pd-NHC complexes catalyzed cross-couplings reaction. All the structures were calculated at
M06 level, with LANL2DZ basis set for Pd and 6-31G(d) basis set for the rest. The prefixes I and TS stand for intermediates and transition
states, respectively.

4
Tetrahedron
It was evident from Figure 3 that there were three main
stages in the considered Suzuki catalytic cycle: oxidative addition,
transmetalation and reductive elimination. First, the reactant I0
directly separates into monocoordinated palladium(0) species,
which is still coordinated by supporting ligand imine (I1). I1
activates the chlorobenzene through TS1 to produce a three-
coordinate Pd(II) intermediate I3, with an energy barrier of
5
6
7
8
7i
7j
99
98
86
+
17.04 kcal/mol. In the second stage, based on the interaction
between B-OH and Pd atom, the phenyl group of arylboronic
acids bond to Pd atom in I4 through TS2. The energy barrier for
this step is +6.00 kcal/mol. Tetracoordinated intermediate I6 is
formed, containing two phenyl groups. Finally, I6 undergoes
TS3 to form the biaryl product and NHC-Pd(0) species. The
energy barrier of this stage is only 1.14 kcal/mol. It is worth
mentioning that during the optimizing search in the last stage, we
7k
7l
c
99
a
11
Reaction conditions: aryl chloride 5 (3.0 mmol, 1 equiv), boronic
acids 6 (3.15 mmol, 1.05 equiv), KOH (4.5 mmol, 1.5 equiv), solvent
PrOH/H O=10:1, 5 mL), catalyst loading: 0.005 mol%.
2
GC yield of coupling product, average of two runs.
catalyst loading: 0.05 mol%.
Gratifyingly, all of the coupling proceeded rapidly and
found negative TS many times. It could be considered as a
theoretical transition state, this process may convert directly
without transition state in actual reactions. It’s clearly showing
that oxidative addition is the rate-determining step of the overall
reaction mechanism. As shown in Figure 3, the energetic
difference between products and reactants is −42.67 kcal/mol, it
is a quite exoergic chemical process.
i
(
b
c
efficiently to afford the desired biphenyls in remarkable yields
up to 99% yield, table 3, entry 5). Both electron-donating and -
(
Three kinds of catalysts (1, 2 and 3) with different supporting
ligands were all taken into consideration. From the kinetic point
of view, the energy barriers in the rate-determining step were
nearly equal for these three systems. However, there’s significant
difference in thermodynamics analysis. The order of relative
Gibbs free energy of any intermediate or any transition state was
withdrawing groups on the phenyl ring of aryl chlorides did not
seem to affect the product yields apparently. Reactions involving
different arylboronic acids were also achieved. (table 3, entries 1-
6
). Polycyclic aromatic chlorides were also tolerant in the system,
although more catalyst loadings were required in some cases
table 3, entries 7 and 8). Despite above substrates, the coupling
(
1
> 2 > 3(details in SI Table 1). We can find that aryl imine are
reactions of most heteroaromatic chlorides still remain a
better supporting ligands especially with electron-withdrawing
groups on it. This kind of supporting ligands lead to more
exothermic steps among the catalytic cycle, which is in
agreement with the experimental observations.
challenge, because of the potential bind to palladium though
12
sulfur and nitrogen atom. The new developed imine-Pd-NHC
complexes should be a good choice for sulfur and nitrogen
containing heteroaromatic chlorides. Inspiring results were
shown in Scheme 1. All products could be obtained in high yield
at 0.05 mol% catalyst loading.
The function of catalysts, especially of the supporting ligands
could be comprehended profoundly from both experimental and
computational side. Thus, with catalyst 3 in hand, which should
be an ideal catalyst with extremely high activity, we set out to
explore the scope of the cross coupling of aryl chlorides and
arylboronic acids. As summarized in Table 3, a series of aryl
Scheme 1. Suzuki-Miyaura coupling of heteroaromatic
chlorides and phenylboronic acids in the presence of catalyst
a
3
chlorides 5 and arylboronic acids 6 were investigated in
i
PrOH/H O in the presence of 0.005 mol % catalyst 3 and 1.5
2
o
equiv KOH at 80 C.
Table 3. Suzuki-Miyaura coupling of various aryl chlorides
a
and arylboronic acids in the presence of catalyst 3
boronic acids
6
yield
aryl chlorides
entry
1
product
7e
b
5
(%)
97
a
Reaction conditions: heteroaromatic chloride 8 (3.0 mmol, 1 equiv),
phenyl boronic acid 6a (3.15 mmol, 1.05 equiv), KOH (4.5 mmol,
i
2
3
4
7f
7g
7h
94
1.5 equiv), solvent ( PrOH/H
2
O=10:1, 5 mL), catalyst loading: 0.05
mol%. Both GC yield and (isolated yield) of coupling product were
tested.
In conclusion, a new series of imine-Pd-NHC complexes have
been developed, which could enable a broad reaction scope of
aryl and heteroaromatic chlorides in Pd-catalyzed Suzuki
coupling reaction at quite low catalyst loading. Imine supporting
ligand should be crucial in catalytic cycle due to the experimental
results and DFT computations. Aryl substitute with electron-
withdrawing groups on N atom of supporting ligand would be
94
91

beneficial to improve catalytic activity. This study of imine
supporting ligand might offer a novel solution to improve the
effectiveness of catalyst. In consideration of the remarkable
activity of the catalysts, the application in other types of coupling
reaction is still in exploring.
G. C. Angew. Chem. Int. Ed. 2006, 45, 1282; (c) Feuerstein, M.;
Doucet, H.; Santelli, M. J. Organomet. Chem. 2003, 687, 327.
Supplementary Material
All experimental procedures, computational details,
spectroscopic data and crystallographic data of CCDC 1417436,
and CCDC 1417438 associated with this article can be found, in
the online version.
Acknowledgments
Financial supports from Science and Technology Commission
of Shanghai Municipality (15QB1701700) is gratefully
acknowledged.
References and notes
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7
.
2
General Procedures: LiCl (4 mmol 170 mg) and PdCl (2 mmol
3
54 mg) were mixed with MeOH and then stirred at rt for 8 hours
4
to generate LiPdCl -MeOH solution. The solution was injected
into the mixture of NaOAc (2 mmol 164 mg) and acetophenone,
which could be stirred at rt for 3 days to afford palladacycle
t
dimmer. KO Bu (1.3 mmol 146 mg), palladacycle complex (0.5
mmol 290 mg), NHC•HCl (1.25 mmol 531 mg) were mixed with
THF and stirred at rt for 2 days. N-heterocyclic carbene palladium
complex should be purified by flash column chromatography
using hexane-EtOAc=5:1.
8
9
.
.
For analogous strategies, see: Guest, D.; Silva, V. H. M. D.;
Batista, A. P. D. L.; Roe, S. M.; Braga, A. A. C.; Navarro, O.
Organometallics 2015, 34, 2463.
(a) Kantchev, E. A. B.; O'Brien, C. J.; Organ, M. G. Angew.
Chem. Int. Ed. 2007, 46, 2768; (b) Viciu, M. S.; Germaneau, R.
F.; Navarro-Fernandez, O.; Stevens, E. D.; Nolan, S. P.
Organometallics 2002, 21, 5470.
-
1
1
0. We take I0, PhCl and PhB(OH)
2
as reactants. Details of all the
computed geometries are given as Supporting Information.
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Robert, H.; Beyer, M. K.; Joachim, S.; Helmut, S. Angew. Chem.,
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S. G.; Ding, X. L. J. Phys. Chem. C, 2010, 114, 12271.
1
2. (a) Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig, J. F. Angew.
Chem. Int. Ed. 2005, 44, 1371; (b) Kudo, N.; Persighini, M.; Fu,

Graphical Abstract
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Supporting Ligand-assisted N-Heterocyclic
Carbene Palladium Complexes:
Characterization, Computation and
Catalytic Activity in Suzuki-Miyaura Cross
Coupling of Aryl and Heteroaromatic
Chlorides
An Shen, Yu-Cai Hu, Ting-Ting Liu, Chen Ni, Yong Luo, Yu-Cai Cao

Highlights



A new series of imine-Pd-(N-Heterocyclic Carbene) complexes have
been developed as efficient catalysts.
The mechanism have been illustrated though DFT computations, based
on the function of supporting ligands.
Aryl and heteroaromatic chlorides could be synthesized efficiently by
using the new catalysts.