Camphyl-based α-diimine palladium complexes: Highly efficient precatalysts for direct arylation of thiazoles in open-air

Article abstract of DOI:10.1039/c7ob00856b

Based on the strategy of the development of phosphine-free palladium-catalyzed direct C-H arylation, a series of camphyl-based α-diimine palladium complexes bearing sterically bulky substituents were synthesized and characterized. The palladium complexes

Full text of DOI:10.1039/c7ob00856b

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Camphyl-based α-Diimine Palladium Complexes: Highly Efficient
Precatalysts for Direct Arylation of Thiazoles in Open-Air
Received 00th January 20xx,
Accepted 00th January 20xx
Fu-Min Chen, Dong-Dong Lu, Li-Qun Hu, Ju Huang,* and Feng-Shou Liu*
Based on the strategy in development of phosphine-free palladium-catalyzed direct C-H arylation, a series of camphyl-
based α-diimine palladium complexes bearing bulky steric were synthesized and characterized. The palladium complexes
were applied for the cross-coupling of thiazole derivitives with aryl bromides. The effect of the bulky steric on N-aryl
moiety as well as reaction conditions was screened. Under the optimal protocols, a wide range of aryl bromides can
smoothly coupled with thiazoles in good to excellent yields in the presence of low palladium loading of 0.2 mol% under
open-air condition.
DOI: 10.1039/x0xx00000x
www.rsc.org/
On the other hand, the phosphine-free7 and ligand-free8
catalysts have drawn considerable attention due to their less
toxic, easily available and excellent catalytic properties. For
Introduction
Arylthiazoles and their derivatives represent an important
class of compounds with a wide variety of applications in
chemistry, biology, pharmacy and functional materials.1 Since
the pioneering work by Ohta, the palladium-catalyzed direct
arylation of thiazoles with aryl halides has been recognized as
one of the most attractive approaches to construct these
architectural units, which can overcome the drawbacks
encountered in the traditional palladium-catalyzed cross-
coupling reactions (eg. Suzuki, Kumada, Still etc.), 2 such as the
requirement of multiple synthetic steps and the formation of
the undesired by-product of organometallic salts. Among the
numerous studies on the palladium-catalyzed direct arylation
over the last few decades, sustained efforts have been
devoted to explore highly efficient phosphine-based catalysts
for the cross-coupling reaction and great progresses have been
achieved.3-6 For instance, Miura,3 Mori, 4 Fagnou5 and others6
reported that the cross-coupling reactions would proceeded
more efficiently via using bulky and electron-rich mono- or bi-
dentate phosphine ligands, which make the use of aryl
bromides even chlorides as coupling partners conveniently.
Despite their effectiveness in controlling reactivity and
selectivity, in general, a relatively high concentration of
palladium source (2-10 mol%) associated with a large amount
of phosphine ligands (5-20 mol%) are often needed, owing to
their air and moisture-sensitivity at elevated temperatures.
Therefore, the direct arylation is still considered as a challenge,
especially, be proceeded under mild reaction conditions.
example, Muria and co-workers found that the direct arylation
of thiazoles with aryl iodides promoted by [Pd(Phen)2]PF6 (5
o
mol%) at a temperature of 150 C turned out to be excellent
yields.7a Ozdemir and Doucet employed a more efficient N-
heterocyclic carbene (NHC) palladium complexes (1 mol%) for
this reaction.7b Meanwhile, Doucet and co-workers also
reported a ligand-free palladium catalyzed direct arylation of
thiazoles using Pd(OAc)2 as the sole precatalyst.8c,8d They
demonstrated that the cross-coupling reactions were
performed conveniently in high yields at a low palladium
loading (0.1-0.01 mol%). Nevertheless, the elevated reaction
o
temperature (130-150 C) as well as a strictly air and moisture
free environment were the necessary conditions in the above-
mentioned researches. Therefore, it is highly desirable to
explore efficient catalytic protocols for the direct arylation
under mild reaction conditions.
Recently, it was found that bidentate α-diimine palladium
complexes showed excellent efficiency in Heck,9 Suzuki,10
oxidative cross-coupling11 and olefin polymerization.12
Meanwhile, we have presented a class of α-diimine nickel
complexes with camphyl on backbones that exhibited
excellent reactivities toward ethylene and 1-hexene
polymerization.13 And our subsequent studies further revealed
that the bulky backbones led to a significant improvement in
the thermostability of the metal center, thereby, ensuring a
long-term efficiency of the catalytic species.14 On the basis of
the above observations, we envisioned that the bulky α-
diimine palladium complexes could be used as the promising
precatalysts to promote the direct arylation of thiazoles, in
which both the bulk backbone and N-aryl moieties would be
benifical to stabilize the active palladium(0) intermediate and
eventually allow the catalytic system to overcome the
drawback of the unstable and sensitive nature of the catalytic
School of Chemistry and Chemical Engineering, Guangdong Cosmetics Engineering
and Technology Research Center, Guangdong Pharmaceutical University,
Zhongshan, Guangdong 528458, China. E-mail: xianghuangj@163.com;
fengshou2004@126.com
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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and the ORTEP diagram was shown in Fig. 2. As expected, the
palladium complex features a square-planar geometry in the
solid state. The bond angles and distances in the coordination
plane are close to the values for relative palladium
complexes.13 It is noteworthy that, as a rigid backbone
framework, the gem-dimethyl substituents could effectively
cap the axial sites at the palladium center. Two N-aryl moieties
are nearly perpendicular to the five-membered coordination
plane, giving the dihedral angles of 87.2 and 75.6°,
respectively. Obviously, the bulky substituents exhibited
repulsive interaction between the N-aryl moieties and
backbone group, implying that the catalytic species could be
well protected.
Scheme 1 The structure of camphyl-based α-diimine
palladium complexes
1
Out of our expectation, the H NMR spectra of C1 indicated
that there was existed a mixture of two isomers at ambient
temperature, which implied the rotation around CAr-N bond
can take place in the solution state.14 In contrast, for C2 and
C3, in which the 2, 6-dimethyl group on the N-aryl moieties
was replaced by bulkier 2, 6-diethyl and 2, 6-diisopropyl,
species under aerobic conditions. Herein, we report an
extended study on the use of these palladium complexes as
the efficient precatalysts (Scheme 1) for the direct arylation of
thiazoles with aryl bromides. Moreover, the influence of
various reaction factors such as base, solvent, additive
concentration and the substrate scope of the catalyst system
were also investigated in detail. It is highlighted that in the
presence of a low palladium loading (0.2 mol%), a variety of
cross-coupling products were obtained in moderate to
excellent yields under open-air condition.
respectively, only
a single isomer was detected. This
phenomenon could probably be ascribed to the prohibited
rotation of the CAr-N bond in the presence of bulky N-aryl
moieties at this stage, thus restrain the configuration of the
palladium complexes. Considering the direct C-H arylations
were usually conducted at a high reaction temperature, it
prompted us to further investigate the variable-temperature
1H NMR properties of C3. As shown in Figure 3, according to
the diastereotopic methyl group derived from the backbone,
Results and Discussion
Synthesis of α-Diimine Palladium Complexes
A series of the camphyl-based α-diimine ligands bearing
different N-aryl moieties were synthesized according to a
procedure reported previously (Scheme 1
).12a, 12b Palladium(II)
complexes C1-3 were obtained in high yields from the reaction
of PdCl2 with these α-diimine ligands in refluxing methanol,
and fully characterized by NMR, MS and elemental analyses.
Moreover, single crystal of palladium complex C1 suitable for
X-ray diffraction analysis was grown in hexane/CH2Cl2 solutions
h
g
f
e
d
c
Figure 2 Molecular structure of C1 depicted with 30%
thermal ellipsoids. Hydrogen atoms have been omitted
for clarity. Selected bond distances(Å) and angles (o):
Pd(1)-N(1) 2.058(4), Pd(1)-N(2) 2.054(5), Pd(1)-Cl(1)
2.2803(14), Pd(1)-Cl(2) 2.2776(13), N(1)-Pd(1)-N(2)
80.98(17), N(1)-Pd(1)-Cl(1) 94.29(13), N(1)-Pd(1)-Cl(2)
174.27(13), N(2)-Pd(1)-Cl(1) 174.23(12), N(2)-Pd(1)-Cl(2)
93.30(13), Cl(1)-Pd(1)-Cl(2) 91.39(5)
b
a
ppm
3.50
3.00
2.50
Figure 3 Variable temperature nuclear magnetic spectra of
C3, a: 30 oC, b: 40 oC, c: 50 oC; d: 60 oC; e: 70 oC; f: 80 oC; g:
90 oC; h: 100 oC
.
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the methine protons (H1 and H2) of the isopropyl substituent
on N-aryl moieties gave rise to well-resolved signals at room
temperature, and thus two sets of septets were observed at
3.23-3.28 and 3.32-3.36 ppm, respectively. Significantly, the
signals of H1 and H2 were completely intact in the temperature
Table 1 Conditions optimization in direct palladium-
catalyzed cross-coupling reactiona
o
range of 30 to 100 C, indicating the N-aryl moieties would be
perpendicular to the coordination plane at high temperature.
On the other hand, chemical equivalency was obtained for the
hydrogen pairs of H3 and H4 at room temperature and there
was no obviously change until the tested temperature rose to
Run
Cat.
Solven
t
Additive
Base
Yieldb
(%)
60 C. At a temperature of 70 C, the signals of the H3 and H4
split into two broad sets of septets, which required the N-aryl
moieties to rotate into the square coordination plane.
However, it is deserved to note that the signals were split into
two well-resolved septets other than emerged together at a
o
o
1
2
PdCl2
C1
C2
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
C3
DMAc
DMAc
DMAc
DMAc
DMF
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
-
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
KOAc
73
53
81
89(85)b
51
74
63
32
66
11
17
45
18
55
73
34
48
45
7
3
4
5
o
temperature of 100 C, suggesting the rotation of the CAr-N
6
NMP
bond was still partially retarded at such a high temperature. In
previous report, the α-diimine palladium complexes bearing 1,
2-dimethyl as backbone and 2, 6-diisopropyl on N-aryl
moieties tend to decompose at a temperature of 60 oC.
Reasonably, the incorporation of steric bulk on backbones and
N-aryl moieties on ligand design is therefore expected to make
this process less favorable, and a long life of catalytic species
would be accessed in the process of the cross-coupling
reaction.
7
Dioxa
Xylene
Tolue
DMSO
EtOAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
To explore the effect of these palladium complexes on
direct C-H arylation, we chose the reaction between 4-methyl-
thiazole and 1-(4-bromophenyl) ethanone as the model
substrates under open-air condition. The reaction was
performed by using 0.2 mol% of palladium loading, K2CO3 as
the base, DMAc as the solvent and PivOH as the additive. 13
Initially, PdCl2 was conducted as the precatalyst and we
obtained the desired arylated product in 73% yield (Run 1,
Table 1) at 100 oC. Further screening of the precatalyst
revealed that C3 bearing isopropyl groups gave the highest
yield of 89% (Run 4, Table 1), while C1 bearing methyl groups
gave the lowest yield of 53%. This provided evidence for the
significant impact of steric hindrance of the ligands on the
catalytic reactivities. Reasonably, the result is consistent with
the NMR investigations, which can be ascribed to the increase
in steric hindrance would lead to a restricted rotation of CAr-N
bond and therefore keep the stabilization of the active species.
With these preliminary results in hand, several parameters
were screened to determine the optimal conditions. As
presented in Table 1, among the solvents investigated, DMAc
K3PO4
NaOAc
KF
NaHCO3
LiOH
K2CO3
K2CO3
K2CO3
K2CO3
8
AcOH
77
74
52
DMAc Benzoic acid
DMAc Methanoic
aReaction conditions: 4-methyl thiazole (1 mmol),
parabromoacetophenone (1 mmol), Cat. (0.002 mmol),
additives (0.3 mmol), base (1.5 mmol), solvent (3 mL),
100 °C for 8 h, under aerobic environment. Unless
otherwise specified, commercial solvent was used as
received and anhydrous technology was avoided; cross-
b
coupling product determined by GC. isolated yields in
parentheses.
gave the best result, while other solvents such as DMF, NMP, mol% C3 as precatalyst in combination with DMAc as the
dioxane, xylene, toluene, DMSO and EtOAc resulted in lower solvent, 1.5 equiv K2CO3 as the base and 30 mol% of PivOH as
yields (Runs 5-11, Table 1). Subsequently, a series of different additive.
bases were screened, and it was shown that potassium salts,
Having established the optimized reaction conditions, we
especially K2CO3, was superior to the others (Runs 12-19, Table set out to explore the scope with respect to the aryl bromides,
2). Furthermore, a survey of acid additives was conducted. We as summarized in Table 2. In general, all the investigated aryl
found PivOH was the best choice, while the absence of bromides underwent smooth coupling with 4-methyl-thiazole
additives only gave minor of the desired product (Run 20, to provide the arylated products in moderate to excellent
Table 1), thus demonstrating that the acid played pivotal roles yields (4-15). The electronic effect of substituents on aryl
in the catalytic cycles, which has been shown to function as a bromides was examined. It was found that electron-
proton shuttle in the C-H bond cleavage.15 Therefore, the withdrawing groups such as aldehyde, nitro and ester were
optimized reaction conditions can be concluded that using 0.2 compatible with the catalytic systems, which may be subjected
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Table 3 Palladium catalyzed direct arylation of thiazoles
with aryl bromides
Table 2 Palladium catalyzed direct arylation of 4-
methylthiazole with aryl bromides
R1
0.2 mol% C3
N
N
0.2 mol% C3
N
N
Aryl
Br
Aryl
PivOH, K2CO3
DMAc, 100 oC, 8 h
Br
Aryl
Aryl
S
S
PivOH, K2CO3, DMAc
100 oC, 8 h
R2
S
S
1
O
N
N
F
N
N
N
NO2
F
CHO
CN
OMe
S
S
N
N
S
N
S
N
NO2
CHO
19: 84%
17: 96%
18: 97%
16: 81%
S
S
S
S
O
4: 97%
7: 85%
5: 82%
6: 94%
O
N
S
N
S
N
Cl
F
S
S
OMe
F
CF3
CF3
23:83%
20: 88%
22: 79%
21: 95%
N
N
N
N
F
CF3
F
CF3
S
S
S
S
N
N
S
N
N
CF3
8: 83%
9: 65%
10: 89%
11: 83%
S
S
S
27: 91%
CF3
26: 96%
24: 88%
25: 93%
O
N
N
N
N
O
S
N
S
N
N
N
S
S
S
S
S
S
14: 58%
13: 70%
15: 60%
12: 83%
28: 85%
30: 82%
31: 73%
29: 83%
O
N
N
N
N
N
N
N
Reaction conditions: palladium complex of C3 (0.002
mmol), 4-methylthiazole (1 mmol), aryl bromide (1 mmol),
K2CO3 (1.5 mmol), DMAc, 100 °C, 8 h.
O
S
S
S
S
32: 73%
34: 72%
35: 65%
33: 80%
CF3
CF3
O
N
N
S
CF3
N
S
S
S
OMe
37: 69%
36: 70%
39: 62%
38: 73%
Ph
to further synthetic transformations. Moreover, highly
electron-rich aryl bromides, such as 3-bromoanisole, and 4-
bromoanisole are competent coupling partners, affording the
corresponding product in a moderate yield of 58 and 60%,
respectively. Of particular interest are the products containing
Ph
Ph
N
O
N
N
N
N
CN
CHO
S
S
S
S
43: 92%
40: 57%
42: 89%
41: 68%
Ph
Ph
Ph
CF3
CF3
Ph
N
S
O
N
N
N
CF3
S
S
S
OMe
fluoro-substituent (7-11), which were useful candidates for
47: 51%
44: 76%
45: 74%
46: 93%
pharmaceuticals, could be installed in high yields.
Reaction conditions: palladium complex of C3 (0.002
mmol), thiazole derivatives (1 mmol), aryl bromide (1
mmol), K2CO3 (1.5 mmol), DMAc, 100 °C, 8 h.
The catalytic system offered a significant improvement over
the conventional direct arylation with aryl bromides in such a
mild reaction condition. Inspired by the above result, the
substrate scope was further expanded with thiazole
derivatives. As shown in Table 3, the reaction of 2, 4-dimethyl-
thiazole with aryl bromides, proceeded well under the
optimized conditions. We were pleased that the electron-
withdrawing (such as nitrile and ester) and the electron-
donating substituents (such as methoxy group) on the aryl
bromides were well tolerated and to give the corresponding
products in excellent to almost quantitative yields. And it was
also found that the sterically-hindered substituted1-
bromonaphthalene and 2-methylphenyl bromide did not
influence the reaction significantly, delivering the coupling
product in 91 and 73% (27, 31), respectively. Moreover, the
biologically interesting heteroaryl thiozoles, such as 5-
(isoquinolin-4-yl)-2, 4-dimethylthiazole and 2,4-dimethyl-5-
(pyridin-3-yl)thiazole could be assembled from the relative
heterocyclic bromides using the present method, giving the
products in satisfied yields of 65-72% (34, 35). Furthermore,
other thiozoles substrates, such as 4-methy-thiazole and
sterically 2-phenyl-4-methy-thiazole were investigated. To our
delight, the couplings also proceeded with sufficient
efficiencies.
Physical measurements and materials
2, 6-dimethylaniline, 2, 6-diethylaniline and 2, 6-
diisopropylaniline were purchased from Aldrich Chemical and
were distilled under reduced pressure before being used.
Palladium chloride was purchased from Aldrich Chemical. 2, 6-
diphenylmethyl-4-methyl-aniline,
2,
6-diphenylmethyl-4-
chloroaniline and 2, 6-diphenylmethyl-4-methoxylaniline, were
prepared according to literature methods [12]. The NMR data of
compounds were obtained on a Varian Mercury-Plus 400 MHz
spectrometer with the decoupled nucleus, using CDCl3 as
solvent and referenced versus TMS as standard. Elemental
analyses were determined with a Vario EL Series Elemental
Analyzer from Elementar. The X-ray diffraction data of single
crystals were obtained with the ω-2θ scan mode on a Bruker
SMART 1000 CCD diffractiometer with graphite-
monochromated Mo Kα radiation (λ= 0.71073 Å) at 173 K for
C1. The structure was solved using direct methods, and further
refinement with full-matrix least squares on F2 was obtained
with the SHELXTL program package. All non-hydrogen atoms
were refined anisotropically. Hydrogen atoms were introduced
in calculated positions with the displacement factors of the
host carbon atoms. CCDC 1530593
(C1) contains the
Experimental Sections
supplementary crystallographic data for this paper.
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General procedures for the synthesis of aniline palladium
compounds
24.3, 24.2, 23.9, 23.6, 23.6, 22.7, 21.9, 17.8, 10.9 ppm.
C34H48Cl2N2Pd: C, 61.68; H, 7.31; N, 4.23. Found: C, 61.52; H,
7.40; N, 4.31. LC-MS (m/z,): 680 [C3+Na]+, 657 [C3-Cl+Na]+,
615 [C3-2Cl+Na]+, 526 [L3+Na]+.
Aniline ligand (1.0 mmol), palladium dichloride (0.886 g, 1.1
mmol) and methanol (10 ml) were added into a two-neck flask,
o
the mixture was heated to 80 C and refluxed for 12 h under
N2. The solvent was then evaporated under reduced pressure,
and the dichloromethane (5 ml) was added. After removed the
insoluble part by filtration, n-hexane (20 ml) was added. The
precipitant was then filtered and dried, the palladium complex
was obtained as brown solid.
General procedure for direct arylation promoted by
palladium complexes
The direct arylation reactions were carried out under aerobic
conditions. All solvents were not purified as received. In the
parallel reaction instrument containing tubes were charged
with palladium complexes (0.002 mmol), aryl bromide (1.0
mmol), thiazole derivative (1.0 mmol), K2CO3 (1.5 mmol),
PivOH (0.3 mmol) and 3 mL of DMAc. The tube was then
C1: There are two isomers found in solution sate (the ratio is
1
ca 1.5:1). Isomer 1: H NMR (400 MHz, CDCl3): δ 7.15-7.19 (m,
Ar-H, 2H), 7.03-7.10 (m, Ar-H, 4H), 2.47 (s, CH3, 6H), 2.45 (s,
CH3, 3H), 2.40 (s, CH3, 3H), 2.37 (d, J = 3.6 Hz, CH, 1H), 2.01-
2.04 (m, CH, 1H), 1.92-1.97 (m, CH2, 1H), 1.80-1.86 (m, CH2,
1H), 1.64-1.66 (m, CH2, 1H), 1.24 (s, CH3, 3H), 0.91 (s, CH3, 3H),
0.51 ppm (s, CH3, 3H). 13C NMR (100 MHz, CDCl3): δ 188.1,
187.7, 141.8, 141.4, 130.1, 129.6, 129.1, 128.4, 128.2, 128.1,
127.9, 127.8, 57.7, 52.4 (d, J = 83.9 Hz), 31.6, 23.1(d, J = 33.1
o
heated to 100 C for 8 h with stirring. After completion of the
reaction, the reaction mixture was cooled to room
temperature and 20 mL of water was added, followed by
extraction three times with Et2O. The organic layer was dried
with anhydrous MgSO4, filtered and evaporated under vacuum.
The crude cross-coupling products were purified by silica-gel
1
Hz), 19.2(d, J = 36.0 Hz), 17.5, 10.1 ppm. Isomer 2: H NMR
column
chromatography
ether/dichloromethane (V/V = 20/1) as an eluent. The isolated
corresponding products were characterized by 1H NMR and 13
using
petroleum
(400 MHz, CDCl3): δ 7.15-7.19 (m, Ar-H, 2H), 7.03-7.10 (m, Ar-H,
4H), 2.46 (s, CH3, 3H), 2.46 (s, CH3, 3H), 2.37 (d, J = 3.6 Hz, CH,
1H), 2.01-2.04 (m, CH, 1H), 1.92-1.97 (m, CH2, 1H), 1.80-1.86
(m, CH2, 1H), 1.64-1.66 (m, CH2, 1H), 1.24 (s, CH3, 3H), 0.91 (s,
CH3, 3H), 0.51 ppm (s, CH3, 3H). 13C NMR (100 MHz, CDCl3,
TMS): δ 188.1, 187.7, 141.8, 141.4, 130.1, 129.6, 129.1, 128.4,
128.3, 128.1, 128.0, 127.9, 127.8, 57.7, 52.4 (d, J = 83.9 Hz),
31.6, 23.1 (d, J = 33.1 Hz), 18.8 (d, J = 14.3 Hz), 17.5, 10.1 ppm.
Anal. Calcd for: C26H32Cl2N2Pd: C, 56.79; H, 5.87; N, 5.09. Found:
C
NMR, and the spectrums are reported in Supporting
Information.
Conclusions
In summary, a series of the camphyl-based ligands bearing
different aniline moieties were prepared and employed as the
ligand for palladium-catalyzed direct arylation of several
thiazole derivatives in open-air. Structures of all of the
palladium complexes were characterized by NMR. Moreover,
C1 was characterized by single crystal X-ray diffraction. The
influence of the steric and the electronic effects of the
backbone substitutions on the catalytic activity have been
revealed. It was found that, for the most active precatalyst
C, 56.65; H, 5.90; N, 5.15. LC-MS (m/z): 588 [C1+k]+, 533 [C1
Cl + Na]+, 503 [C1-2Cl+Na]+, 411 [L1+Na]+.
-
C2: 1H NMR (400 MHz, CDCl3): δ 7.27-7.31 (m, Ar-H, 2H), 7.13-
7.19 (m, Ar-H, 4H), 3.11-3.22 (m, CH2CH3, 1H), 3.06-3.09 (m,
CH2CH3, 1H), 2.92-2.99 (m, CH2CH3, 2H), 2.44-2.56 (m, CH2CH3,
4H), 2.37 (d, J = 3.6 Hz, CH, 1H), 1.96-2.02 (m, CH2, 1H), 1.88-
1.94 (m, CH2, 1H), 1.75-1.81 (m, CH2, 1H), 1.60-1.63 (m, CH2,
1H), 1.51 (t, J = 6.0 Hz, CH2CH3, 3H), 1.46 (t, J = 6.0 Hz, CH2CH3,
3H), 1.45 (t, J = 6.0 Hz, CH2CH3, 3H), 1.44 (t, J = 6.0 Hz, CH2CH3,
3H), 1.21 (s, CH3, 3H), 0.88 (s, CH3, 3H), 0.45 ppm (s, CH3, 3H).
13C NMR (100 MHz, CDCl3, TMS): δ 187.9, 187.6, 140.7, 140.3,
135.2, 134.8, 134.4, 134.3, 128.3, 128.2, 125.5, 125.3, 125.1,
124.5, 57.7, 52.5, 51.5, 31.4, 24.4, 24.4, 24.2, 22.9, 22.4, 17.5,
13.7, 13.5, 13.4, 12.8, 10.2 ppm. Anal. Calcd for: C30H40Cl2N2Pd:
C, 59.46; H, 6.65; N, 4.62. Found: C, 59.30; H, 6.70; N, 4.65. LC-
MS (m/z): 628 [C2+Na]+, 597 [C2-Cl+Na]+, 558 [C2-2Cl+Na]+,
453 [L2+Na]+.
(
C3) bearing the bulky 2,6-diisopropylaniline substituents,
when appropriate reaction conditions were employed, high
catalytic performances and substrate tolerance could be
achieved with very low catalyst loading (0.2 mol %) for the
direct C-H arylation of thiazoles and aryl bromides. We hope
that the simple-synthesized, cost-effective, user-friendly, and
air/moisture-stable α-diimine palladium catalyst would be a
valuable alternative choice to traditional catalyst which was
used in the C-H activation reactions.
C3: 1H NMR (400 MHz, CDCl3, TMS): δ 7.30-7.34 (m, Ar-H, 2H),
7.14-7.19 (m, Ar-H, 4H), 3.33-3.36 (m, CH(CH3)2, 1H), 3.23-3.28
(m, CH(CH3)2, 1H), 2.94-3.02 (m, CH(CH3)2, 2H), 2.51 (d, CH, 1H),
2.00-2.11 (m, CH2, 2H), 1.75-1.88 (m, CH2, 2H), 1.60 (d, J = 5.2
Hz, CH(CH3)2, 3H), 1.57 (d, J = 3.2 Hz, CH(CH3)2, 3H), 1.55 (d, J =
5.6 Hz, CH(CH3)2, 6H), 1.37 (d, J = 5.6 Hz, CH(CH3)2, 3H), 1.34
(dd, J1 = 5.6 Hz, J2 = 3.2 Hz, CH(CH3)2, 6H), 1.29 (d, J = 5.6 Hz,
CH(CH3)2, 3H), 1.20 (s, CH3, 3H), 0.91 (s, CH3, 3H), 0.58 ppm (s,
CH3, 3H). 13C NMR (100 MHz, CDCl3, TMS): 187.8, 187.3, 140.3,
140.2, 139.7, 139.4, 138.9, 138.7, 128.9, 128.8, 123.9, 123.6,
123.3, 57.8, 52.4, 51.3, 31.2, 29.3, 29.1, 29.0, 24.9, 24.9, 24.7,
Acknowledgements
This work was supported by the NSFC (No. 51203026) and the
Project
of
Innovation
for
Enhancing
Guangdong
Pharmaceutical University, Provincial Experimental Teaching
Demonstration Center of Chemistry and Chemical Engineering,
and Project Funding of Science and Technology Department,
Guangdong Province (No. 2015A010105030).
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
Journal Name
10 a) G. A. Grasa , A. C. Hillier and S. P. Nolan, Org. Lett., 2001,
, 1077-1080; b) J. Zhou, X. M. Guo, C. Z. Tu, X. Y. Li and H. J.
Notes and references
3
1
a) Y. Katsura, S. Nishino, Y. Inoue, K. Sakane, Y. Matsumoto,
C. Morinaga, H. Ishikawa and H. Takasugi, J. Med. Chem.,
2002, 45, 143-150; b) A. Mori, A. Sekiguchi, K. Masui, T.
Shimada, M. Horie, K. Osakada, M. Kawamoto and T. Ikeda, J.
Am. Chem. Soc., 2003, 125, 1700; c) K. M. Amin, D. E. A.
Sun, J. Organomet. Chem., 2009, 694, 697-702; c) A. O.
Eseola, D. Geibig, H. Görls, W. H. Sun, X. Hao, J. A. O. Woods
and W. Plass, J. Organomet. Chem., 2014, 754, 39-50.
11 A. J. Hickman, M. S. Sanford, ACS Catal., 2011, 1, 170-174.
12 a) L. H. Guo, H. Y. Gao, Q. R. Guan, H. B. Hu, J. Deng, J. Liu, F.
Sh. Liu and Q. Wu, Organometallics, 2012, 31, 6054-6062; b)
F. Sh. Liu, H. Y. Gao, Zh. L. Hu, H. B. Hu, F. M. Zhu and Q. Wu,
J. Polym. Sci. Poly. Chem., 2012, 50, 3859-3866.
13 F. S. Liu, H. B. Hu, Y. Xu, L. H. Guo, Sh. B. Zai, K. M. Song, H. Y.
Gao, L. Zhang, F. M. Zhu and Q. Wu, Macromolecules, 2009,
42, 7789-7796.
14 a) J. S. Ouyang, Y. F. Li, D. S. Shen, Z. F. Ke and F. S. Liu.
Dalton Trans., 2016, 45, 14919-14927. b) B. T. Luo, H. Liu, Z. J.
Lin, J. Jiang, D. S. Shen, R. Z. Liu, Z. F. Ke and F. S. Liu,
Organometallics, 2015, 34, 4881-4894.
15 M. Lafrance, K. Fagnou, J. Am. Chem. Soc. 2006, 128, 16496-
16497.
Rahman and Y. A. Al-Eryani, Bioorg. Med. Chem., 2008, 16
,
5377-5388; d) T. Liu, Y. Huang and B. Shen, J. Am. Chem.
Soc., 2009, 131, 6900-6901; e) H. B. Shi, S. J. Zhang, Q. F. Ge,
D. W. Guo, C. M. Cai and W. X. Hu, Bioorg. Med. Chem. Lett.,
2010, 20, 6555-6559.
2
Y. Aoyagi, A. Inoue, I. Koizumi, R. Hashimoto, K. Tokunaga, K.
Gohma, J. Komatsu, K. Sekine, A. Miyafuji, J. Kunoh, R.
Honma, Y. Akita and A. Ohta, Heterocycles, 1992, 33, 257-
272.
3
4
a) A. Yokooji, T. Okazawa, T. Satoh, M. Miura, M. Nomura,
Tetrahedron, 2003, 59, 5685-5689; b) S. Tabuchi, K. Hirano,
T. Satoh, M. Miura, J. Org. Chem., 2014, 79, 5401-5411.
a) A. Mori, A. Sekiguchi, K. Masui, T. Shimada, M. Horie, K.
Osakada, M. Kawamoto and T. Ikeda, J. Am. Chem. Soc.,
2003, 125, 1700-1701; b) K. Masui, A. Mori, K. Okano, K.
Takamura, M. Kinoshita and T. Ikeda, Org. Lett. 2004,
6,
2011-2014; c) S. Tamba, Y. Okubo, S. Tanaka, D. Monguchi
and A. Mori, J. Org. Chem., 2010, 75, 6998-7001.
5
6
a) L. C. Campeau, M. Bertrand-Laperle, J. P. Leclerc, E.
Villemure, S. Gorelsky, K. Fagnou, J. Am. Chem. Soc., 2008,
130, 3276-3277; b) B. Liegault, I. Petrov, S. I. Gorelsky, K.
Fagnou, J. Org. Chem., 2010, 75, 1047-1060; c) D. Lapointe, T.
Markiewicz, C. J. Whipp, A. Toderian, K. Fagnou, J. Org.
Chem., 2011, 76, 749-759.
a) Y. Kondo, T. Komine and T. Sakamoto, Org. Lett., 2000, 2,
3111-3113; b) G. L. Turner, J. A. Morris, M. F. Greaney,
Angew. Chem. Int. Ed., 2007, 46, 7996-8000; c) T. Martin, C.
Verrier, C. Hoarau and F. Marsais, Org. Lett., 2008, 10, 2909-
2912; d) F. Derridj, A. L. Gottumukkala, S. Djebbar and H.
Doucet, Eur. J. Inorg. Chem., 2008, 16, 2550-2559; e) D. Roy,
S. Mom, M. Beauperin, H. Doucet and J. C. Hierso, Angew.
Chem. Int. Ed., 2010, 49, 6650-6654; f) M. Baghbanzadeh, C.
Pilger and C. O. Kappe, J. Org. Chem., 2011, 76, 8138-8142; g)
K. Beydoun, J. Roger, J. Boixel, H. Le Bozec, V. Guerchais and
H. Doucet, Chem. Commun., 2012, 48, 11951-11953; Pcy3 h)
A. Jakab, Z. Dalicsek and T. Soós, Eur. J. Org. Chem., 2015, 1,
56-59.
7
a) F. Shibahara, E. Yamaguchi and T. Murai, Chem. Commun.,
2010, 46, 2471-2473; b) I. Ozdemir, Y. Gök, Ö. Özeroğlu, M.
Kaloğlu, H. Doucet and C. Bruneau, Eur. J. Inorg. Chem. 2010
,
12, 1798-1805; c) J. K. Huang, J. Chan, Y. Chen, C. J. Borths, K.
D. Baucom, R. D. Larsen and M. M. Faul, Angew. Chem. Int.
Ed. 2011, 50, 2387-2391; d) S. Kirchberg, S. Tani, K. Ueda, J.
Yamaguchi, A. Studer and K. Itami, Angew. Chem. Int. Ed.,
2011, 50, 2387-2391; e) S. Tani, T. N. Uehara, J. Yamaguchi
and K. Itami, Chem. Sci., 2014, 5, 123-135; f) E. Ö. Karaca, N.
Gürbüz, I. Özdemir, H. Doucet, O. Şahin, O. Büyükgüngör and
B. Çetinkaya, Organometallics, 2015, 34, 2487-2493.
8
a) M. Parisien, D. Valette and K. Fagnou, J. Org. Chem. 2005,
70, 7578-7584;; b) F. Bellina, S. Cauteruccio and R. Rossi, Eur.
J. Org. Chem., 2006, 1379-1382; c) F. Požgan, J. Roger and H.
Doucet, Chem. Sus. Chem., 2008, 1, 404-407; d) J. Roger, F.
Požgan and H. Doucet, J. Org. Chem., 2009, 74, 1179-1186; e)
B. Liu, X. R. Qin, K. Z. Li, X. Y. Li, Q. Guo, J. B. Lan and J. S. You,
Chem. Eur. J., 2010, 16, 11836-11839; f) M. Wang, D. K. Li, W.
Zhou and L. Wang, Tetrahedron, 2012, 68, 1926-1930; g) X.
W. Liu, J. L. Shi, J. X. Yan, J. B. Wei, K. Peng, L. Dai, C. G. Li, B.
Q. Wang and Z. J. Shi, Org. Lett., 2013, 515, 774-5777.
9
a) M. Emre Hanhan, Appl. Organometal. Chem., 2008, 22,
270-275; b) Q. Ben, J. Zhang, T. L. Liang, C. Redshaw and W.
H. Sun, J. Organomet. Chem., 2012, 713, 151-156.
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB00856B
Bulky camphyl-based α-diimine palladium complexes have been developed and
exhibited high reactivity for direct arylation of thiazoles in air.