N-heterocyclic carbene-palladium-imine complex catalyzed α-arylation of ketones with aryl and heteroaryl chlorides under air atmosphere

Article abstract of DOI:10.1016/j.tetlet.2020.152124

A new structure of saturated ring skeleton monoligated NHC-Pd-Imine complex was easily synthesized and unambiguously confirmed by X-ray single crystal diffraction. It was found to be an efficient and air-stable catalyst for the α-arylation of ketones. The reaction could be operated in air without any negative effect. Non-activated aryl and heteroaryl chlorides have been successfully applied in the reaction with only 0.5 mol% catalyst loadings under air atmosphere. Excellent to good product yields were afforded.

Full text of DOI:10.1016/j.tetlet.2020.152124

Tetrahedron Letters xxx (xxxx) xxx
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N-heterocyclic carbene-palladium-imine complex catalyzed
a-arylation
of ketones with aryl and heteroaryl chlorides under air atmosphere
⇑
⇑
Hui-Yang Lu, An Shen , Yong-Qing Li, Yu-Cai Hu, Chen Ni, Yu-Cai Cao
State Key Laboratory of Polyolefins and Catalysis, Shanghai Key Laboratory of Catalysis Technology for Polyolefins, Shanghai Research Institute of Chemical Industry Co Ltd, 345
East Yunling Road, Shanghai 200062, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new structure of saturated ring skeleton monoligated NHC-Pd-Imine complex was easily synthesized
and unambiguously confirmed by X-ray single crystal diffraction. It was found to be an efficient and
air-stable catalyst for the a-arylation of ketones. The reaction could be operated in air without any neg-
ative effect. Non-activated aryl and heteroaryl chlorides have been successfully applied in the reaction
with only 0.5 mol% catalyst loadings under air atmosphere. Excellent to good product yields were
afforded.
Received 24 March 2020
Revised 1 June 2020
Accepted 5 June 2020
Available online xxxx
Keywords:
N-heterocyclic carbene
Ó 2020 Elsevier Ltd. All rights reserved.
a-Arylation
Palladium catalyzed coupling
Ketones
Aryl chlorides
Introduction
could be acted as suitable electrophiles in a-arylation of ketones.
However, only Nolan [5b] and Shi group [9b] were able to reduce
the amount of catalyst to below 1 mol%, while much fewer
reaction could be operated in air. Therefore, it is necessary to
explore efficient catalytic system with extra low catalyst loadings
for non-activated aryl and heteroaryl chlorides in air.
In previous work, we have developed a series of novel NHC-Pd-
Imine complexes 1 (Fig. 1a), which can be easily synthesized from
commercially available imidazolium salts (IPrꢀHCl) and different
imines in a few steps [10]. Without regard to the influence of
NHC ligands, It has been confirmed that the structure of ancillary
imine ligands could affect catalytic cycle based on the experimen-
tal results and DFT computations [10b,11]. However, modification
Palladium catalyzed
a-arylation of carbonyl compounds has
emerged as one of the most attractive methodologies for the for-
mation of CSP2-CSP3 bonds to obtain valuable
a-aryl substituted
carbonyl moiety, which could be commonly found in natural prod-
ucts and pharmaceutical molecules [1]. Many efforts have been
made to improve the ligands and precatalysts [2]. Compared with
hindered phosphine ligands, N-heterocyclic carbenes (NHC) are
better ligands with higher air, moisture and thermal stability
[2b,3]. Additionally, both of the bulky and strong donating NHC
skeletons as well as diverse ancillary ligands might be conducive
to palladium-catalyzed reactions [4]. Except for the great demands
of fairly stable, easily available and less expensive NHC-Pd com-
plexes, there are still three aspects need to be considered meticu-
lously: a) high efficient catalysts with low catalyst loadings should
be employed due to the high cost of palladium compounds, b) the
starting materials, especially the electrophiles, should be readily
available and economically attractive and c) the reaction process
could be operated as conveniently as possible.
of imine ligands only might be insufficient to catalyze a-arylation
reaction efficiently and be worked in air as well [12]. Consequently,
change of NHC skeletons should be taken into consideration.
Herein, due to the ongoing interest of NHC-Pd-Imine complexes,
we reported our progress in
a-arylation of ketones with an air-
stable catalyst under air atmosphere.
In order to investigate the difference in activity of NHC-Pd-
During the past years, lots of well-defined NHC-Pd complexes
have been developed by Nolan [5], Organ [6], Tu [7], Shao [8],
and others [9]. Various kinds of NHC ligands and ancillary ligands
have been evaluated, and in most cases, inactive aryl chlorides
Imine complexes, a precatalyst 2 containing saturated NHC
skeleton (SIPr) had been synthesized. It could be easily obtained
by a slightly modified method on the basis of complexes 1 [13].
The structure of 2 was unambiguously determined by NMR and
X-ray crystallographic study (Fig. 1c) [14]. To evaluate the cat-
alytic properties of two NHC-Pd-Imine complexes, acetophenone
and chlorobenzene were chosen as the model reaction
(Table 1).
⇑
Corresponding author. Tel.: +86 021 52817942; Fax.: +86 021 52800850
(An Shen). Tel.: +86 021 52817942; Fax.: +86 021 52800850 (Yu-Cai Cao).
E-mail addresses: shenan@srici.cn (A. Shen), caoyc@srici.cn (Y.-C. Cao).
https://doi.org/10.1016/j.tetlet.2020.152124
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: H.-Y. Lu, A. Shen, Y. Q. Li et al., N-heterocyclic carbene-palladium-imine complex catalyzed
heteroaryl chlorides under air atmosphere, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152124
a-arylation of ketones with aryl and

2
H.-Y. Lu et al. / Tetrahedron Letters xxx (xxxx) xxx
this reaction. It is worth noting that complex 2 seems to be a more
effective catalyst in -arylation of ketones, because of the higher
yields in same reaction condition (Table 1, Entries 5 and 6, 11
and 12, 13 and 14). The difference could be explained by Vbur
a
%
[15] to some extent. Since Vbur % of SIPr is larger than IPr [16], it
means that in most cases the catalytic activity of SIPr-Pd com-
plexes might be superior to IPr-Pd complexes [17]. One step fur-
ther, the catalyst loading was also investigated. When 0.1 mol%
catalyst was used, only 55% yield of 6a could be achieved within
a prolonged reaction time (Table 1, Entry 15). When less sodium
tert-butoxide had been used, the yield of product would obviously
decrease (Table 1, Entry 16). While using a little more amount of
bases would be benefit for the reaction [18]. It seems to be that
2.2 equivalent of base is quite enough. Some more bases added
(2.5 equiv.) might be workless (Table 1, Entries 17 and 18). At last,
Fig. 1. a) NHC-Pd-Imine complexes 1. b) NHC-Pd-Imine complexe 2. c) X-ray
structure of complexe 2.
Based on the high-activities of NHC-Pd-Imine complexes, we
tried to reduce the amount of catalyst as far as possible. Using
complex 1a (0.5 mol%) as the catalyst, different bases were firstly
evaluated. No product was detected when either potassium car-
bonate or potassium phosphate was acted as the base (Table 1,
Entries 1 and 2). Only trace of product could be found when
sodium ethoxide was used (Table 1, Entry 3), whereas better
results were observed with both of potassium tert-butoxide and
sodium tert-butoxide (Table 1, Entries 4 and 5). In the view of
the significant influence of solvent, a variety of solvents were then
tested with sodium tert-butoxide as the base (Table 1, Entries 6–
14). Dioxane might be the most suitable solvent for Complex 2 in
we tried to operate the a-arylation reaction without the protection
of nitrogen. Fortunately, almost the same yield was observed
(Table 1, Entry 19). It means the modification of NHC complex
might be contributed to improve in activity and stability [19]. On
the other hand, over-arylation product was not detected under this
condition, while a portion of unreacted chlorobenzene could be
observed. When increased the amount of chlorobenzene to
4.8 mmol, over-arylation was still not occurred (Table 1, Entries
20–22). Thus, as summarized from Table 1, the optimum reaction
condition for the NHC-Pd-Imine catalyzed
a-arylation of ketones
Table 1
Optimization for the NHC-Pd-Imine complexes-catalyed
a
-arylation of acetophenone 3a.
Entrya
Cat.
Base
Solvent
Temp. (℃)
6a Yield (%)b
6a’ Yield (%)b
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
2
2
2
2
2
2
1a
2
1a
2
2
2
2
2
2
K2CO3
K3PO4
THF
THF
THF
THF
70
70
70
70
70
70
80
80
NRk
NRk
Trace
20
38
43
Trace
36
30
49
62
35
83
70
55
49
88
88
80
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
NaOEt
KOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBud
NaOtBue
NaOtBuf
NaOtBue
NaOtBue
NaOtBue
NaOtBue
THF
THF
iPrOH
MeCN
DIPE
DMF
9
65
10
11
12
13
14
15c
16
17
18
19g
20h
21i
22j
120
100
100
100
100
100
100
100
100
100
100
100
100
Toluene
Toluene
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
NDl
NDl
NDl
NDl
NDl
NDl
80
80
80
2
2
a
Reaction conditions: acetophenone 3a (2.4 mmol, 1.2 equiv), chlorobenzene 5a (2.0 mmol, 1.0 equiv), base (4.0 mmol, 2.0 equiv), catalyst loading: 0.5 mol%, reaction
time: 4 h.
b
GC yield of coupling product, average of two runs.
c
d
e
f
Catalyst loading: 0.1 mol%, reaction time: 8 h.
2.0 mmol base (1.0 equiv) was used.
4.4 mmol base (2.2 equiv) was used.
5.0 mmol base (2.5 equiv) was used.
Operated in air.
Operated in air and 2.4 mmol chlorobenzene 5a was used.
Operated in air and 3.6 mmol chlorobenzene 5a was used.
Operated in air and 4.8 mmol chlorobenzene 5a was used.
No reaction.
g
h
i
j
k
l
Not detected.
Please cite this article as: H.-Y. Lu, A. Shen, Y. Q. Li et al., N-heterocyclic carbene-palladium-imine complex catalyzed
heteroaryl chlorides under air atmosphere, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152124
a-arylation of ketones with aryl and

H.-Y. Lu et al. / Tetrahedron Letters xxx (xxxx) xxx
3
were conducted in dioxane and with sodium tert-butoxide as the
base in the presence of 0.5 mol% 2 at 100 ℃ for 4 h without the pro-
tection of nitrogen [20].
the reaction was still worked well. Even if increased the amount
of acetophenone to 2 equiv, arylation product of 6j was not
detected (Table 2, Entries 10 to 11). Heteroaryl chlorides might
not be a suitable substrate, only 67% and 30% yield could be
observed respectively (Table 2, Entries 12 to 13). Similarly,
4-chlorobenzaldehyde was also unsatisfactory.
Because of more difficult self-condensation, the amount of
phenylacetone could be reduced to 1.1 equiv without any negative
effects [5a]. In most cases, propiophenone with an electron-
donating group(-OMe) or an electron-withdrawing group(-F)
could be performed well and excellent yield could be reached.
On the other hand, electronic effect of chlorinated substrates was
also taken into consideration. There was no significant difference
between the aryl chlorides with methyl, methoxy and N-methyl
substituents (Table 3, Entries 1 to 11). The disparity of yields
might be contrubuted to the effect of steric hindrance as
mentioned above. However, when trifluoromethyl substituent
was employed, the reaction yields were decreased sharply, unless
To probe the substrate scope of the reaction, a series of (hetero)
aryl chlorides and aryl/alkyl ketones were used to test the general-
ity and limitation of the reactions. As shown in Table 2–4, almost
all reactions proceeded smoothly to give the corresponding prod-
ucts in good to excellent yields under the optimized conditions.
In consideration of dimerization, 1.2 equiv acetophenone 3 was
used in the reaction. It was found that increasing the steric
hindrance of aryl chlorides not only has not affected the yields of
a-ketone arylation reactions, but has promoted them (Table 2,
Entries to 4). Acetophenone with an electron-donating
1
group(-OMe) (Table 2, Entries 5 to 8) could also be performed well
under air atmosphere. About 77% yield could be achieved when
using 1-chloronaphthalene as substrate. If the reaction proceeded
under nitrogen atmosphere, reaction yield could be increased to
93% (Table 2, Entry 9). When 1,4-dichlorobenzene was employed,
Table 2
a
-Arylation of acetophenone 3 with various aryl and heteroaryl chlorides in the presence of catalyst 2.
a
Entry
1
Ketone
Aryl chloride
Product
6
Yield (%)b
80
6a
2
3
6b
6c
>99
96
4
5
6
6d
6e
6f
99
90
>99
7
8
6g
6h
85
93
9
6i
6j
77
93c
10
82
84
11d
6j
12
13
6k
6l
67e
30e
14
6m
11e
Reaction conditions: acetophenone 3 (2.4 mmol, 1.2 equiv), chlorobenzene 5 (2.0 mmol, 1.0 equiv), NaOtBu (4.4 mmol, 2.2 equiv), dioxane 8 mL, catalyst loading: 0.5 mol
a
%, reaction time: 4 h.
b
Isolated yield of coupling product, average of two runs.
With nitrogen protection.
4.0 mmol acetophenone 3 (2.0 equiv) was used.
GC yield of coupling product, average of two runs.
c
d
e
Please cite this article as: H.-Y. Lu, A. Shen, Y. Q. Li et al., N-heterocyclic carbene-palladium-imine complex catalyzed
heteroaryl chlorides under air atmosphere, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152124
a-arylation of ketones with aryl and

4
H.-Y. Lu et al. / Tetrahedron Letters xxx (xxxx) xxx
Table 3
a
-Arylation of acetophenone 4 with various aryl and heteroaryl chlorides in the presence of catalyst 2.
Entrya
1
Ketone
Aryl chloride
Product
7
Yield (%)b
>99
7a
2
3
4
5
6
7b
7c
7d
7e
7f
93
92
83
93
90
7
7g
7h
7i
96
82
70
81
8
9
10
7j
11
12
7k
7l
91
61
96c
13
14
15
16
17
7m
7n
7o
7p
7q
67
95c
97
90
77
80
94c
18
19
20
7r
7s
7t
47
88c
83
87c
27
90c
21
7u
47
>99c
a
Reaction conditions: acetophenone 4 (2.2 mmol, 1.1 equiv), chlorobenzene 5 (2.0 mmol, 1.0 equiv), NaOtBu (4.4 mmol, 2.2 equiv), dioxane 8 mL, catalyst loading: 0.5 mol
%, reaction time: 4 h.
b
Isolated yield of coupling product, average of two runs.
With nitrogen protection.
c
the reaction were operated under the N2 (Table 3, Entries 12 and
13). It might be elucidated from the catalytic mechanism. Firstly,
the presence of sterically hindering moiety in substrates could
increase the steric bulk around the palladium center, which
promoted the reductive elimination during the catalytic cycle
[21]. Secondly, the oxidative addition might be not the rate deter-
mining step based on the results of selected substrates. Non-
involvement of oxidative addition in dictating the rate of a reaction
is not unprecedented, but the exact mechanism is still not entirely
clear [22]. When polycyclic aryl chlorides or heteroaryl chlorides
got involved in the reaction, much lower yield might be found at
the same reaction condition. However, the situation was improved
Please cite this article as: H.-Y. Lu, A. Shen, Y. Q. Li et al., N-heterocyclic carbene-palladium-imine complex catalyzed
heteroaryl chlorides under air atmosphere, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152124
a-arylation of ketones with aryl and

H.-Y. Lu et al. / Tetrahedron Letters xxx (xxxx) xxx
5
Table 4
-Arylation of chlorobenzene 5a with various di-alkyl substituted ketones in the
presence of catalyst 2.
data to this article can be found online at https://doi.org/10.1016/j.
tetlet.2020.152124.
a
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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
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Please cite this article as: H.-Y. Lu, A. Shen, Y. Q. Li et al., N-heterocyclic carbene-palladium-imine complex catalyzed
heteroaryl chlorides under air atmosphere, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152124
a-arylation of ketones with aryl and

6
H.-Y. Lu et al. / Tetrahedron Letters xxx (xxxx) xxx
(b) M.S. Viciu, O. Navarro, R.F. Germaneau, R.A. Kelly, W. Sommer, N. Marion,
needed, purged three times with nitrogen. Then, ketones (2.4 mmol, 1.2 equiv.
or 2.2 mmol, 1.1 equiv.) and aryl chlorides (2.0 mmol, 1.0 equiv.) were
successively added followed by the 8 mL stock solution in every vial. Finally,
the mixtures were stirred at 100 °C for 4 h, after which time the turbid liquids
were cooled and extracted with CH2Cl2. Organic phases were collected and
dried over anhydrous Na2SO4. The solvent was evaporated in vacuum. The
crude was purified by flash chromatography on silica gel (300-400 mesh) to
afford the desired product (typically hexane: ethyl acetate 40:1).
E.D. Stevens, L. Cavallo, S.P. Nolan, Organometallics 23 (2004) 1629–1635;
(c) A. Gómez-Suárez, D.J. Nelson, S.P. Nolan, Chem. Commun. 53 (2017) 2650–
2660.
[18] M.S. Viciu, R.F. Germaneau, S.P. Nolan, Organic Lett. 4 (2002) 4053–4056.
[19] V. Paradiso, C. Costabile, F. Grisi, Molecules 2016, 21.
[20] General procedure for the
mg NHC-Pd-Imine complex was dissolve in 50 mL anhydrous dioxane to
prepare catalyst stock solution (1.25 mmol/L). In typical run, vial
containing a stir bar was charged with NaOtBu (4.4 mmol, 2.2 equiv.), and if
a-arylation of ketones Under air atmosphere, 45.4
a
a
[21] D.A. Culkin, J.F. Hartwig, Acc. Chem. Res. 36 (2003) 234–245.
[22] B.S. Lane, M.A. Brown, D. Sames, J. Am. Chem. Soc. 127 (2005) 8050–8057.
Please cite this article as: H.-Y. Lu, A. Shen, Y. Q. Li et al., N-heterocyclic carbene-palladium-imine complex catalyzed
heteroaryl chlorides under air atmosphere, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152124
a-arylation of ketones with aryl and