Direct C-H bond (Hetero)arylation of thiazole derivatives at 5-position catalyzed by N-heterocyclic carbene palladium complexes at low catalyst loadings under aerobic conditions

Article abstract of DOI:10.1016/j.jorganchem.2019.06.016

A highly efficient and practical protocol has been developed for the synthesis of 5-(hetero)arylated thiazole derivatives via an N-heterocyclic carbene palladium (Pd-NHC) complex catalyzed direct C-H arylation reaction. Utilization of this methodology, th

Full text of DOI:10.1016/j.jorganchem.2019.06.016

Accepted Manuscript
Direct C-H bond (Hetero)arylation of thiazole derivatives at 5-position catalyzed by
N-heterocyclic carbene palladium complexes at low catalyst loadings under aerobic
conditions
Bei-Bei Ma, Xiao-Bing Lan, Dong-Sheng Shen, Feng-Shou Liu, Chang Xu
PII:
S0022-328X(19)30255-4
DOI:
https://doi.org/10.1016/j.jorganchem.2019.06.016
JOM 20828
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 24 February 2019
Revised Date: 5 June 2019
Accepted Date: 14 June 2019
Please cite this article as: B.-B. Ma, X.-B. Lan, D.-S. Shen, F.-S. Liu, C. Xu, Direct C-H bond
(Hetero)arylation of thiazole derivatives at 5-position catalyzed by N-heterocyclic carbene palladium
complexes at low catalyst loadings under aerobic conditions, Journal of Organometallic Chemistry
(2019), doi: https://doi.org/10.1016/j.jorganchem.2019.06.016.
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ACCEPTED MANUSCRIPT
Direct C-H Bond (Hetero)arylation of Thiazole Derivatives at 5-Position
Catalyzed by N-heterocyclic Carbene Palladium Complexes at Low Catalyst
Loadings Under Aerobic Conditions
Bei-Bei Ma#, Xiao-Bing Lan#, Dong-Sheng Shen, Feng-Shou Liu and Chang Xu*
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical
University, Zhongshan, Guangdong 528458, China.
#Author Contributions
These authors contributed equally to this work.
*To whom correspondence should be addressed. E-mail: xcpanda9@163.com.
Keywords: N-heterocyclic carbene palladium complex; Direct C-H arylation reaction;
Aryl bromide; Thiazole Derivative
Abstract
A highly efficient and practical protocol has been developed for the synthesis of
5-(hetero)arylated thiazole derivatives via an N-heterocyclic carbene palladium
(Pd-NHC) complex catalyzed direct C-H arylation reaction. Utilization of this
methodology, the arylation of substituted thiazoles with (hetero)aryl bromides
efficiently proceeded at low catalyst loading (0.1-0.05 mol%) and under aerobic
conditions. A variety of (hetero)aryl bromides, even some strongly deactivated or
highly congested (hetero)aryl bromides, with a broad range of functional groups were
compatible under the optimal reaction conditions. In all cases, the target products
were afforded in moderate to quantitative yields.
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1. Introduction
The 5-(hetero)aryl substituted thiazoles represent a class of privileged structural
units, which are frequently found in organic electronic materials and biologically
active compounds as well as pharmaceuticals (Figure 1) [1-6]. Owing to their
widespread applications, the development of practical and versatile synthetic methods
has received considerable attention and remains an essential research topic in organic
synthesis [7-12].
F
N
F3C
S
S
N
CF3
N
S
N
SO2Me
p38 MAP kinase inhibitor
n-Type OFET
O
N
N
OMe
MeO
MeO
NH2
S
NH
N
N
HN
S
N
N
NH2
S
N
EtO
O
aurora kinase inhibitor
tubulin polymerization inhibitor
potential p38 MAP kinase inhibitor
Figure 1. Selected examples of functional 5-(hetero)aryl thiazoles.
Since the publication of Ohta’s reports [13], the palladium-catalyzed direct C-H
bond (hetero)arylation reactions of thiazoles with (hetero)aryl halides has undergone
rapid development [14-27]. It has been considered as an environmentally and
economically more attractive method compared to the classical palladium-catalyzed
cross-coupling reactions with organometallic reagents. In this context, a variety of
elegant palladium/ligand catalytic systems have been developed to date (Table 1)
[19-22, 25-29]. Despite their promising utility in research and industrial applications,
in most cases, these catalytic systems still suffered from the extreme susceptibility of
the catalytic LPd(0) species toward moisture and oxygen. Therefore, in general, a
relatively high concentration of palladium source ligated with ancillary ligands and
the strict air- and moisture-free reaction conditions were indispensable [22, 30]. Given
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the above information, the development of more readily available and effective
catalytic systems for the direct coupling of thiazole derivatives, especially reducing
the amount of the catalyst and easy-of-use manipulation under aerobic conditions, is
still challenging.
Table 1. Pd-catalyzed direct C-H bond (hetero)arylation reactions of thiazoles.
The N-heterocyclic carbenes (NHCs) recently have become ubiquitous ancillary
ligands for metal-catalyzed transformations because of their thermal and oxidative
stability, adjustability as electronically and sterically and excellent catalytic activities
[31-42]. So far, numerous examples of Pd-NHC complexes catalyzed direct arylations
of heteroaromatics have been described by the research groups of Doucet, Shao and
ours [43-54]. Notably, it has been disclosed that increasing the steric hindrance of the
NHC ligands, including the incorporation of bulky substituents into the nitrogen
atoms and the backbones of ligands, is vital to promote catalytic abilities of the
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Pd-NHC complexes [51-52, 55-56]. More importantly, since the elegant publication
of Organ in 2006, it has been proved that the PEPPSI (pyridine enhanced precatalyst
preparation, stabilization and initiation) type precatalysts, which mix the coordination
of NHCs with monodentate pyridine ligand, exhibit higher air-stability and reactivity
than that of the NHCs/phosphine ligands in the Pd-catalyzed cross-coupling reactions
[57-62]. For example, Lee and co-workers reported the Pd-PEPPSI-type NHC
complexes as efficient catalysts for the C5 arylation of heteroaromatics, which
demonstrated higher catalytic activities than that of Pd ligated with NHCs/phosphine
ligands [62]. Recently, we have also developed a series of Pd-PEPPSI-type NHC
complexes, which exhibited extremely high catalytic abilities for direct arylation of
azoles with aryl bromides in the presence of 0.5-0.05 mol% palladium and under
aerobic conditions [56].
Although great advance has been made in Pd-PEPPSI-type NHC complexes
catalyzed direct arylation reactions, the structural design of catalysts on N-moieties is
still mainly restricted to properly adjust the steric environment at ortho-positions to
facilitate the reductive elimination process and stabilize the active LPd(0) species
[57-62]. Moreover, in light of the experimental evidence of Holland’s and ours [52,
63], a remote substitution at para-position on N-aryl moieties could further promote
the palladium-catalyzed cross-coupling reactions. Thus, it is reasonable to assume that
the NHCs bearing with bulky substitution at the ortho positions and substituents at the
para position on N-aryl moieties should be advantageous, which may also provide us
with another insight into the key catalyst design features that are of consequence in
the catalytic cycle.
Herein, we wish to present the synthesis of a new type of Pd-PEPPSI-type NHC
complexes, describe their structural characterizations and evaluate their potential
catalytic performances for direct arylation of a set of thiazoles with a variety of
heteroaryl or aryl bromides under aerobic conditions.
2. Result and discussion
2.1 Synthesis and characterization of palladium complexes C1-2
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R
R
R
NH2
O O
Ar N
N Ar
NH2
conc. HCl, ZnCl2
160oC
HC CH
HCO2H,EtOH,60oC
B1: R=Me;
B2: R=H;
OH
OMe
R
R
100oC
ClCH2OEt
OMe
R
A1: R=Me;
A2: R=H;
R
R
R
R
R
R
OMe
R
R
R
PdCl2
+
MeO
R
N
N
MeO
R
N
Cl
N
OMe
R
Py, 80oC
Cl-
Pd
Cl
Py
R
R
R
R
C1: R=Me;
C2: R=H;
L1: R=Me;
L2: R=H;
Scheme 1. Synthesis of N-heterocyclic Carbene Palladium Precatalysts.
The N-heterocyclic carbene palladium complexes C1-2 were synthesized
according to procedures similar to those reported previously for other imidazolium
carbene Pd-PEPPSI complexes [61]. As can be seen in Scheme 1, p-anisidine reacted
with di-phenylmethanol under solvent-free conditions in the presence of
stoichiometric amounts of conc. HCl and ZnCl2 led to the formation of A1-2. With the
aid of formic acid, A1-2 underwent a condensation reaction with glyoxal to give
α-diimine compounds B1-2. Cyclization of B1-2 with chloromethyl ethyl ether
yielded the imidazolinium salts L1-2 as grey solids in moderate yields. Subsequently,
the imidazolinium salts L1-2 were treated with PdCl2 in the presence of K2CO3 in
pyridine at 80oC readily furnished the crude palladium complexes. After purification
by chromatograph using silica gel, desired carbene Pd-PEPPSI compounds C1-2 were
obtained in moderate yields as yellowish solids. The C1-2 complexes, which are
highly moisture- and air-stable both in solution and solid state against air, light and
moisture, could be stored at room temperature for months without an obvious decline
in catalytic efficiency.
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The compounds C1-2 were characterized by 1H and 13C NMR spectroscopy. The
structure of complex C1 was further confirmed by X-ray single-crystal analysis and
illustrated in Figure 2. The complex C1 crystallizes in a triclinic system with space
group P-1 and adopts the expected slightly distorted square-planar geometry around
palladium centre. The carbene and the pyridine ligand are in trans-position with
respective distances to the Pd centre of 1.973(4) Å and 2.122(4) Å, which are well
within the expected range of reported values [57-62]. The N-phenyl rings were found
to be approximately perpendicular to the NHC ring with dihedral angles of 70.43o and
68.41o. It is worthy to note that the bulky steric of the 2,6-bis(di-p-tolylmethyl)phenyl
is in the position of above and below the palladium coordination plane, which is
oriented over the axial sites of the palladium atom. Reasonably, this direction of the
axial sites could be effectively shielded and is expected to make a long life of the
catalytic species.
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)-C(1)
1.9730(38), Pd(1)-N(3) 2.1216(38), Pd(1)-Cl(1) 2.3041(13), Pd(1)-Cl(2) 2.2937(13),
N(3)-Pd(1)-C(1) 179.44(17), N(3)-Pd(1)-Cl(1) 91.40(11), N(3)-Pd(1)-Cl(2) 91.52(11),
C(1)-Pd(1)-Cl(1) 88.70(12), C(1)-Pd(1)-Cl(2) 88.39(12), Cl(1)-Pd(1)-Cl(2) 177.07(4)
2.2 The Pd-catalyzed direct C–H arylation reaction
The direct C-H arylation of heteroarenes with heteroaryl bromides remains
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challenging due to the low reactivity of substrates and the strong metal coordination
ability of heteroatoms, which could cause the poisoning of palladium species. To test
the efficiency of these synthesized palladium complexes on the direct C–H arylation
reaction, we chose 4-methylthiazole and 3-pyridyl bromide as the model substrates to
start our catalytic investigation. The reaction was performed in the open air by using
0.5 mol% of palladium loading, K2CO3 as the base, DMAc as the solvent and PivOH
as the additive, under the conditions that have been established from our previous
studies on palladium-catalyzed C-H arylation (Table 2, entry 1) [61]. We were pleased
to obtain the highly regioselective 5-arylated product in quantitative yield. It
demonstrates that complex C1 is extraordinarily effective for this coupling reaction.
Because of our continuous interest in developing more efficient Pd-catalyzed systems
for direct arylation reactions, the effect of catalyst loading was initially investigated.
To our delight, decreasing the catalyst loading from 0.5 to 0.05 mol% did not
significantly affect the yields of the desired product (Table 2, entries 1, 2, and 4).
However, when the catalyst loading was further declined to 0.01 mol%, much lower
activity was observed and the coupled product was afforded in 55% yield (Table 2,
entry 5). Additionally, a comparison of the reactivity of C1 with C2 and previously
reported complex C3 [64] (Scheme 2) revealed that complexes C2-C3 were all
inferior to C1 (Table 2, entries 5-7). This result can be attributed to the fact that more
steric repulsion of the bulkier substitution on N- aryl moieties causes more axial
shielding on the palladium centre, which provides more protection for the metal
center to prolong the lifetimes of catalytic species. Thus, C1 was selected as the
standard catalyst for the following screening. With all these preliminary results in
hand, the effects of temperature, reaction time, base, solvent and the amount effect of
PivOH additive were screened to further optimize the reaction conditions. Different
reaction temperatures were examined, and the analysis (Table 2, entries 2, 3) revealed
that the use of lower reaction temperature led to a decrease in reactivity. A survey of
reaction time was also conducted, and the results showed that there was no significant
improvement in the product yield with the prolonged reaction time (Table 2, entries 5,
8). Subsequently, a series of different bases were screened, and it was shown that
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K2CO3 were superior to the others (Table 2, entries 5, 9-11). Among the solvents
investigated, DMAc gave the best result, while other solvents such as dioxane,
toluene, xylene, NMP and DMSO resulted in lower yields or even completely shut
down the reaction (Table 2, entries 5, 12-16). Lastly, the amount effect of PivOH was
investigated. In the absence of PivOH, the reaction did not work (Table 2, entry 17).
Upon increasing the amount of PivOH, enhanced reaction efficiencies were observed
(Table 2, entries 5, 17-19). The yield of product was raised to 55% when employing
0.3 mmol of PivOH (Table 2, entry 5). No more improvement was found when further
increasing the amount of PivOH (Table 2, entry 20). Thus, the optimized reaction
conditions were established by using 4-methylthiazole (2.0 equiv.), 3-bromopyridine
(1.0 equiv.), C1 (0.05 mol%) as the precatalyst, K2CO3 as the base, PivOH (30 mol%)
as the acid additive and DMAc as the solvent in an aerobic environment.
Scheme 2. The structure of the complex C3.
Table 2. Optimization of the reaction conditionsa
Run
1
Cat
Base
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOAc
K3PO4
Cs2CO3
Solvent
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
T/oC
130
130
110
130
130
130
130
130
130
130
130
t/h
4
Yield(%)b
C1 0.5%
C1 0.1%
C1 0.1%
C1 0.05%
C1 0.01%
C2 0.01%
C3 0.01%
C1 0.01%
C1 0.01%
C1 0.01%
C1 0.01%
100
100
72
99
55
48
51
55
33
0
2
4
3
4
4
4
5
4
6
4
7
4
8
24
4
9
10
11
4
4
0
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12
13
C1 0.01%
C1 0.01%
C1 0.01%
C1 0.01%
C1 0.01%
C1 0.01%
C1 0.01%
C1 0.01%
C1 0.01%
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Dioxane
Toluene
Xylene
NMP
130
130
130
130
130
130
130
130
130
4
4
4
4
4
4
4
4
4
0
0
14
15
0
15
16
DMSO
DMAc
DMAc
DMAc
DMAc
0
17c
18d
19e
20f
0
32
47
55
aReaction conditions: 4-methylthiazole (2 mmol), 3-bromopyridine (1 mmol), palladium
source (0.01−0.1 mol %), PivOH (0.3 mmol), K2CO3 (2 mmol), DMAc (3 mL), 130 °C, 4
b
h, in an aerobic atmosphere. GC yield using (trifluoromethyl)benzene as an internal
c
d
e
standard. No PivOH was added. 0.1 mmol PivOH was used instead of 0.3 mmol. 0.2
f
mmol PivOH was used instead of 0.3 mmol. 0.4 mmol PivOH was used instead of 0.3
mmol.
With the optimal reaction conditions in hand, we set out to explore the substrate
scope of this transformation. To begin with, we evaluated various substituted
heteroaryl bromides (Table 3). As shown in Table 3, this reaction applies to a variety
of substituted heteroaryl bromides, affording the corresponding products in moderate
to excellent yields. For example, a wide range of π-electron deficient heteroaryl
bromides, such as pyridine, quinoline, isoquinoline, pyrimidine, reacted efficiently to
afford the corresponding products in excellent yields. On the other hand, it was noted
that highly π-electron excessive heteroaryl bromides, such as thiophenes and furans,
afforded the coupled products in relative lower yields (42 to 56%). However, with
those kinds of substrates, significant improvement of the yields (69 to 90%) could be
obtained in the presence of slightly higher catalyst loading of 0.1 mol%. In addition, a
variety of diverse functional groups on heteroaryl bromides were also examined. It
was shown that the electronic properties of the substituents on heteroaryl bromides
has limited effect on the reaction efficiency. Both the electron-withdrawing (such as
chloro and ester) and the electron-donating substituents (such as methoxy group) on
the heteroaryl bromides were all well-tolerated and furnished the corresponding
products in excellent yields. Furthermore, 2-methylthiazole and sterically hindered
2-methyl-4-methythiazole were also investigated to determine the influence of a
2-substitution on thiazole on the reaction efficiency. The results demonstrated that
thiazoles bearing 2-and/or 4-substituents could feasibly afford the desired product in
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high yields. It is worthy to point out that the corresponding products, such as
5-(isoquinolin-4-yl)-2,4-dimethylthiazole and 2,4-dimethyl-5-(pyridin-3-yl)thiazole,
are biologically interesting heteroaryl thiazoles and could be obtained in almost
quantitative yields (94–97%) using the present method. Encouraged by these results,
we proceeded to diheteroarylation of 4-methythiazole with 3,5-dibromopyridine. To
our delight, the coupling reaction successfully took place and afforded the desired
diheteroarylated product in an excellent yield of 97%, which could provide a potential
method for the effective direct diheteroarylation reaction to furnish some functional
materials.
To further expand the substrate generality of this reaction, we were intrigued to
explore the substrate scope with respect to the aryl bromides and the results were
summarized in Table 4. In general, all the investigated aryl bromides reacted
efficiently with substituted thiazoles to afford the arylated products in moderate to
excellent yields. Concerning the electronic properties of the aryl bromides,
electron-withdrawing and electron-donating groups were all well tolerated and gave
the desired products in high yields. Notably, the presence of the substituents, such as
Cl, F and so on, on the arylated thiazole derivatives is very important, which may be
subjected to further synthetic transformations for the synthesis of diverse natural and
biologically active compounds. And it was also found that the sterically-hindered
1-bromonaphthalene could also be employed successfully and similar yields of the
desired coupling products were obtained (20a, 92% yield). Moreover, other thiazole
substrates,
such
as
4-methyl-thiazole
and
sterically
hindered
2-methyl-4-methythiazole were also explored with 1-bromonaphthalene. Consistently,
the corresponding coupling reactions successfully proceeded again and comparable
yields were obtained (20b and 20c, 90 and 92% yield, respectively).
Table 3. Palladium-catalyzed Direct Arylation of thiazole derivatives with heteroaryl
bromides.
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C1
R1
R1
PivOH 0.3mmol
N
N
+
HetAr
Br
K2CO3 2mmol
DMAc 3mL
130 oC/ 4 h
HetAr
H
S
S
R2
R2
2mmol
1mmol
N
S
N
N
N
N
Cl
F
OMe
S
S
S
N
N
N
S
N
2a:91a
1a:98a
4a:78a 92b
N
3a:99a
N
S
N
N
N
S
N
N
O
S
N
7a:93a
6a:96a
8a:48a 87b
5a:97a
O
N
N
N
N
S
OMe
S
O
S
S
S
N
COOMe
10a:56a 90b
9a:42a 69b
11a:95a
1b:88a
N
N
N
N
N
Cl
F
N
S
N
N
S
N
S
N
N
S
3b:68a
2b:73a
4b:75a
6b:80a
N
N
N
OMe
F
S
S
N
S
S
N
2c:97a
7b:83a
4c:95a
1c:98a
N
N
S
N
S
N
N
N
S
N
S
N
S
N
6c:99a
5c:94a
7c:96a
12aa:97a
aC1 0.05 mol%. bC1 0.1 mol%.
Table 4. Palladium-catalyzed Direct Arylation of thiazole derivatives with aryl
bromides.
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3. Conclusions
In summary, we have developed a well-defined and air-stable Pd-PEPPSI-type
NHC complex C1 and tested its potential catalytic activity in the direct
(hetero)arylation of thiazole derivatives at 5-position. The results showed that the
complex C1 is extraordinarily efficient at low catalyst loading and under aerobic
conditions. Furthermore, the outstanding performance of C1 revealed that the
combination of bulky substitutions at the ortho and para position on N-moieties led to
significant improvements in the catalytic efficiency. This complex thus has the
potential to act as an efficient catalyst in other synthetic scenarios especially in
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scenarios involving arene C-H functionalization. Further studies focused on its
applicability to other reactions are currently underway in our laboratory.
4. Experimental section
Physical Measurements and Materials. All thiazole compounds and bromides
were purchased from Aldrich Chemical. p-methoxyaniline, di-phenylmethanol,
chloromethyl ethyl ether, palladium chloride, inorganic bases, and Glyoxal were also
purchased from Aldrich Chemical. Pyridine, 3-chloropyridine, and other solvents
were purchased from Guangzhou Chemical Reagent Factory and were used as
received. The compounds 2,6-bis(di-p-tolylmethyl)-4-methoxyaniline (A1) [65], the
imidazolium salt L2 [66] and palladium complex C3 [64] were synthesized according
to literature methods.
The NMR data of compounds were obtained on a Varian Mercury-Plus 400 MHz
spectrometer at ambient temperature with the decoupled nucleus, using CDCl3 as
solvent and referenced versus TMS as standard. The X-ray diffraction data of single
crystals were obtained with the ω-2θ scan mode on a Bruker SMART 1000 CCD
diffractometer 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
[67-68]. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were
introduced in calculated positions with the displacement factors of the host carbon
atoms. CCDC 1883738 (C1) contains the supplementary crystallographic data for this
paper.
Synthesis of the N,N’-bis(2,6-bis(di-p-tolylmethyl)-4-methylphenyl)
diazabutadiene (B1)
The titled compound was synthesized according to a modified literature
procedure [61]. An aqueous solution of glyoxal (1.82 mg, 13.0 mmol, 40 % aq.
solution)
was
added
slowly
to
a
pre-made
mixture
of
2,6-bis(di-p-tolylmethyl)-4-methoxyaniline (A1) (5.00g, 10.0 mmol)，ethanol (125
mL) and a catalytic amount of formic acid (4 mL). The reaction mixture was stirred at
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60 ºC for 24h, resulting a suspension of light yellow solids in the solution. The titled
compound B1 solids were collected by filtration and washed with EtOH to remove
impurities, then dried under high vacuum. No further purification was required (74%
1
isolated yield). H NMR (400 MHz, CDCl3) δ 7.23 (s, N=C-H, 2H), 6.96 (d, J = 8.0
Hz, Ar-H, 16H), 6.83 (d, J = 8.0 Hz, Ar-H, 16H), 6.39 (s, Ar-H, 4H), 5.15 (s, CH-H,
13
4H), 3.49 (s, OCH3-H, 6H), 2.23 (s, CH3-H, 24H). C NMR (101 MHz, CDCl3) δ
164.2, 156.1, 142.8, 140.8, 135.7, 134.0, 129.3, 128.9, 113.8, 55.0, 50.4, 21.0.
Synthesis of imidazolium Salts（L1）
The titled compound was synthesized according to a modified literature
procedure [61]. α-Diimine compounds (B1, 1mmol) and chloromethyl ethyl ether (6
mL) were combined under a nitrogen atmosphere at room temperature, and the
resulting mixture was heated at 100 °C overnight. After cooling to room temperature,
the reaction mixture was triturated with anhydrous Et2O, resulting a great deal of light
yellow precipitate. The precipitate was collected by filtration and washed three times
with anhydrous Et2O. The titled product was then obtained as a yellowish white
powder in excellent purity, and no further purification was required (60% isolated
1
yield). H NMR (400 MHz, CDCl3) δ 11.98 (s, N-CH=N, 1H), 7.05 (s, Ar-H, 16H),
6.92 (d, J = 7.6 Hz, Ar-H, 8H), 6.68 (d, J = 7.7 Hz, Ar-H, 8H), 6.46 (s, Ar-H, 4H),
5.63 (s, C=CH-H, 2H), 5.13 (s, CH-H, 4H), 3.53 (s, OCH3-H, 6H), 2.27 (s, CH3-H,
13
24H). C NMR (101 MHz, CDCl3) δ 160.66 (s), 142.73 (s), 139.41 (s), 138.93 (s),
136.45 (s), 136.28 (s), 129.70 (s), 129.29 (s), 129.20 (s), 128.93 (s), 125.12 (s),
123.88 (s), 115.43 (s), 55.21 (s), 50.74 (s), 21.02 (s).
General Procedure for the Synthesis of Pd-PEPPSI Compounds (C1-2)
The titled compounds were synthesized according to a modified literature
procedure [61]. A mixture of imidazolium salt (1 mmol), PdCl2 (0.177 g, 1 mmol),
and K2CO3 (0.690 g, 10 mmol) in pyridine (4 mL) was stirred at 80 °C for 24 h. After
cooling to room temperature, the reaction mixture was added with 20 mL of
dichloromethane. The resulting reaction solution was then loaded onto a short
silica-gel column (5 cm x 1 cm). After elution with substantial dichloromethane, the
14

ACCEPTED MANUSCRIPT
filtrate was evaporated to dryness under reduced pressure. The solid residue was
stirred with hexane (15 mL), resulting a great deal of precipitate. The precipitate was
collected by filtration, and recrystallized from dichloromethane and diethyl ether to
give the titled compounds.
The complex C1 was obtained as a yellowish powder (73% isolated yield). Single
crystals of C1 suitable for X-ray diffraction studies were obtained by layering their
1
dichloromethane solution with hexane at ambient temperature. H NMR (400 MHz,
CDCl3) δ 9.18–8.92 (m, Ar-H
6.5 Hz, Ar-H 2H), 7.30 (d, J = 8.1 Hz, Ar-H
(d, J = 7.9 Hz, Ar-H 8H), 6.65 (d, J = 8.0 Hz, Ar-H
Ar-H CH-H4H), 5.03 (s, CH-H, 2H), 3.53 (s, OCH3-H, 6H), 2.26 (d, J = 11.8 Hz,
,
2H), 7.78 (t, J = 7.6 Hz, Ar-H
8H), 6.98 (d, J = 7.9 Hz, Ar-H
8H), 6.50 (s, Ar-H 4H), 6.27 (s,
,
1H), 7.34 (dd, J = 7.6,
,
,
,
8H), 6.82
,
,
,
,
CH3-H, 24H). 13C NMR (101 MHz, CDCl3) δ 158.5, 151.9, 143.6, 141.6, 141.2, 135.2,
130.9, 130.3, 129.1, 128.8, 128.5, 124.2, 115.2, 54.9, 50.2, 21.0.
1
The complex C2 was obtained as a yellowish powder (80% isolated yield). H
NMR (400 MHz, CDCl3) δ 9.11–9.06 (m, Ar-H，2H), 7.79 (td, J = 7.6, 1.3 Hz, Ar-H，
1H), 7.45 (d, J = 7.5 Hz, Ar-H，8H), 7.39 – 7.33 (m, Ar-H, 2H), 7.24 – 7.13 (m, Ar-H,
12H), 7.09 – 6.98 (m, Ar-H, 12H), 6.77 (d, J = 7.5 Hz, Ar-H, 8H), 6.49 (s, Ar-H, 4H),
6.36 (s, CH-H, 4H), 4.82 (s, C=C-H，2H), 3.52 (s, OMe-H，6H). 13C NMR (101 MHz,
CDCl3) δ 158.7, 151.8, 151.6, 144.3, 143.8, 143.6, 137.9, 130.9, 130.5, 129.3, 128.1,
127.8, 126.2, 126.1, 124.3, 124.0, 115.4, 54.8, 51.1.
General Procedure for Direct Arylation Promoted by Palladium Complexes.
Typically, (hetero)aryl bromide (1.0 mmol), thiazole derivatives (2.0 mmol),
Pd-PEPPSI complexes (0.01−0.5 mol%), base (2 mmol), acid additive (0.3 mmol),
and 3 mL of DMAc solvent were added into a parallel reactor. After heating at 130 °C
for 4 h, the resulting mixture was cooled to room temperature. Subsequently, 25 mL
of water and 20 mL of dichloromethane were added into the reactor, and the mixture
was stirred for another several minutes, followed by extraction three times with
dichloromethane (3 × 5 mL). The organic layer was then combined, dried over
anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the
15

ACCEPTED MANUSCRIPT
crude products. The crude products were then purified by silica-gel column
chromatography using petroleum ether–dichloromethane (15/1) as the eluent. The
1
13
obtained pure products were characterized by H NMR and C NMR spectroscopy,
and the spectra can be found in the Supporting Information. And the isolated yields of
products were obtained based on the amounts of (hetero)aryl bromides.
General Information for NMR Data. The NMR data of compounds were obtained
on a Varian Mercury-Plus 400 MHz spectrometer at ambient temperature, using
CDCl3 as solvent and referenced versus TMS as standard. Chemical shifts are
reported in ppm, and coupling constants are reported in Hz.
5-(6-methoxypyridin-3-yl)-4-methylthiazole (1a). 1H NMR (400 MHz, CDCl3) δ 8.66
(s, Ar-H, 1H), 8.20 (dd, J = 2.5, 0.6 Hz, Ar-H, 1H), 7.58 (dd, J = 8.6, 2.5 Hz, Ar-H,
1H), 6.77 (dd, J = 8.6, 0.7 Hz, Ar-H, 1H), 3.93 (s, Ar-OCH3, 3H), 2.46 (s, Ar-CH3,
3H). 13C NMR (101 MHz, CDCl3) δ 163.6, 150.4, 148.9, 146.8, 139.3, 128.2, 121.0 ,
110.8 , 77.3 , 77.0 , 76.7, 53.5 , 15.7 .
4-methyl-5-(6-methylpyridin-3-yl)thiazole (2a). 1H NMR (400 MHz, CDCl3) δ 8.69 (s,
Ar-H, 1H), 8.56 (d, J = 1.3 Hz, Ar-H, 1H), 7.61 (dd, J = 8.0, 2.0 Hz, Ar-H, 1H), 7.20
(d, J = 8.0 Hz, Ar-H, 1H), 2.57 (s, Ar-CH3, 3H), 2.50 (s, Ar-CH3, 3H).13C NMR (101
MHz, CDCl3) δ 157.9, 150.8, 149.4, 148.9, 136.7, 128.2, 125.1, 123.0, 24.1, 15.9.
5-(6-chloropyridin-3-yl)-4-methylthiazole (3a). 1H NMR (400 MHz, CDCl3) δ 8.75 (s,
Ar-H,1H), 8.47 (s, Ar-H, 1H), 7.70 (dd, J = 8.2, 2.1 Hz, Ar-H, 1H), 7.40 (d, J = 8.2 Hz,
Ar-H, 1H), 2.52 (s, Ar-CH3, 3H). 13C NMR (101 MHz, CDCl3) δ 151.5, 150.8, 150.2,
149.4, 139.0, 127.2, 126.7, 124.2, 16.0.
5-(6-fluoropyridin-3-yl)-4-methylthiazole (4a). 1H NMR (400 MHz, CDCl3) δ 8.74 (s,
Ar-H, 1H), 8.29 (dd, J = 1.7, 0.8 Hz, Ar-H, 1H), 7.84 (ddd, J = 8.4, 7.5, 2.6 Hz, Ar-H,
1H), 7.01 (ddd, J = 8.5, 3.1, 0.6 Hz, Ar-H, 1H), 2.51 (s, Ar-CH3, 3H). 13C NMR (101
MHz, CDCl3) δ 164.2, 161.8, 151.3, 145.0, 147.8, 147.6, 141.8, 141.7, 126.7, 126.2,
126.1, 109.8, 109.4, 15.8.
1
5-(isoquinolin-4-yl)-4-methylthiazole (5a). H NMR (400 MHz, CDCl3) δ 9.22 (s,
Ar-H, 1H), 8.82 (s, Ar-H, 1H), 8.45 (s, Ar-H, 1H), 7.97 (d, J = 7.9 Hz, Ar-H, 1H),
7.67–7.50 (m, Ar-H, 3H), 2.24 (s, Ar-CH3, 3H). 13C NMR (101 MHz, CDCl3) δ 153.0,
152.1, 151.6, 144.6, 134.7, 131.0, 128.0, 127.8, 127.4, 125.1, 124.1, 122.7, 15.6.
1
4-methyl-5-(quinolin-4-yl)thiazole (6a). H NMR (400 MHz, CDCl3) δ 8.91 (d, J =
4.4 Hz, Ar-H, 1H), 8.85 (s, Ar-H, 1H), 8.15 (d, J = 8.4 Hz, Ar-H, 1H), 7.72–7.66 (m,
16

ACCEPTED MANUSCRIPT
Ar-H, 2H), 7.50 (ddd, J = 8.3, 6.8, 1.2 Hz, Ar-H, 1H), 7.33 (d, J = 4.4 Hz, Ar-H, 1H),
2.27 (s, Ar-CH3, 3H).13C NMR (101 MHz, CDCl3) δ 152.3, 151.4, 149.5, 148.4, 138.1,
129.9, 129.7, 127.1 , 126.0, 125.2, 123.2, 15.8.
1
4-methyl-5-(quinolin-3-yl)thiazole (7a). H NMR (400 MHz, CDCl3) δ 8.98 (d, J =
2.3 Hz, Ar-H , 1H), 8.78 (s, Ar-H , 1H), 8.18 (d, J = 2.1 Hz, Ar-H , 1H), 8.12 (d, J =
8.5 Hz, Ar-H , 1H), 7.86–7.81 (m, Ar-H , 1H), 7.74 (ddd, J = 8.4, 6.9, 1.4 Hz, Ar-H ,
1H), 7.58 (ddd, J = 8.1, 7.0, 1.1 Hz, Ar-H , 1H), 2.59 (s, Ar-CH3 , 3H). 13C NMR (101
MHz, CDCl3) δ 151.3, 150.5, 150.0, 147.2, 135.6, 130.0, 129.3, 128.2, 127.8, 127.4,
125.3, 16.1.
1
4-methyl-5-(pyrimidin-5-yl)thiazole (8a). H NMR (400 MHz, CDCl3) δ 9.21 (s,
Ar-H , 1H), 8.85 (s, Ar-H , 3H), 2.58 (s, Ar-CH3 , 3H). 13C NMR (101 MHz, CDCl3) δ
157.7, 156.3, 152.2, 151.0, 126.9, 124.2, 16.0.
4-methyl-5-(thiophen-2-yl)thiazole (9a). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, Ar-H ,
1H), 7.35 (dd, J = 5.1, 1.2 Hz, Ar-H , 1H), 7.14 (dd, J = 3.6, 1.2 Hz, Ar-H , 1H), 7.08
(dd, J = 5.1, 3.6 Hz, Ar-H , 1H), 2.61 (s, Ar-CH3 , 3H). 13C NMR (101 MHz, CDCl3) δ
149.9, 149.0, 133.2, 127.6, 127.1, 126.2, 125.5, 16.5.
1
4-methyl 5-(4-methylthiazol-5-yl)furan-2-carboxylate (10a). H NMR (400 MHz,
CDCl3) δ 7.95 (s, Ar-H , 1H), 7.21 (d, J = 3.4 Hz, Ar-H , 1H), 6.56 (d, J = 3.4 Hz,
Ar-H , 1H), 3.91 (s, Ar-CH3, 3H), 2.74 (s, Ar-CH3 , 3H). 13C NMR (101 MHz, CDCl3)
δ 158.9, 151.4, 151.2, 150.6, 143.8, 1213, 119.8, 109.5, 52.0, 17.00.
1
3-(4-methylthiazol-5-yl)-2H-chromen-2-one (11a). H NMR (400 MHz, CDCl3) δ
8.81 (s, Ar-H, 1H), 7.85 (s, Ar-H, 1H), 7.57 (t, J = 4.5 Hz, Ar-H, 2H), 7.41–7.33 (m,
Ar-H, 2H), 2.61 (s, Ar-CH3, 3H).13C NMR (101 MHz, CDCl3) δ 160.1, 153.2, 152.8,
152.1, 141.2, 132.1, 128.0, 124.9, 124.0, 120.4, 118.9, 116.7, 17.2.
4-methyl-5-(pyridin-3-yl)thiazole (12a). 1H NMR (400 MHz, CDCl3) δ 8.74 (s, Ar-H,
1H), 8.70 (s, Ar-H, 1H), 8.59 (d, J = 4.1 Hz, Ar-H, 1H), 7.78–7.72 (m, Ar-H, 1H),
13
7.37 (dd, J = 7.8, 4.9 Hz, Ar-H, 1H), 2.53 (s, Ar-CH3, 3H). C NMR (101 MHz,
CDCl3) δ 151.2, 149.7, 149.6, 148.8, 136.3, 128.2, 128.0, 123.4, 15.9.
5-(6-methoxypyridin-3-yl)-2-methylthiazole (1b). 1H NMR (400 MHz, CDCl3) δ 8.30
(d, J = 2.1 Hz, Ar-H, 1H), 7.68 (dd, J = 8.8, 2.4 Hz, Ar-H, 2H), 6.76 (dd, J = 8.6, 0.5
Hz, Ar-H, 1H), 3.95 (s, Ar-OCH3, 3H), 2.72 (s, Ar-CH3, 3H).13C NMR (101 MHz,
CDCl3) δ 165.0, 163.7, 144.4, 137.3, 136.6, 135. 121.0, 111.0, 53.5, 19.2.
1
2-methyl-5-(6-methylpyridin-3-yl)thiazole (2b). H NMR (400 MHz, CDCl3) δ 8.66
(s, Ar-H, 1H), 7.82–7.65 (m, Ar-H, 2H), 7.18 (d, J = 7.7 Hz, Ar-H, 1H), 2.75 (d, J =
2.7 Hz, Ar-CH3 3H), 2.58 (s, Ar-CH3 3H).13C NMR (101 MHz, CDCl3) δ 165.8, 158.0,
146.7, 138.2, 135.2, 133.9, 124.9, 123.2, 24.2, 19.4.
17

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1
5-(6-chloropyridin-3-yl)-2-methylthiazole (3b). H NMR (400 MHz, CDCl3) δ
8.55–8.53 (m, Ar-H, 1H), 7.83 (s, Ar-H, 1H), 7.76 (dd, J = 8.3, 2.6 Hz, Ar-H, 1H),
7.36 (dd, J = 8.3, 0.6 Hz, Ar-H, 1H), 2.75 (s, Ar-CH3, 3H).13C NMR (101 MHz,
CDCl3) δ 166.9, 150.6, 147.0, 139.1, 136.2, 133.6, 126.8, 124.5, 19.5.
1
5-(6-fluoropyridin-3-yl)-2-methylthiazole (4b). H NMR (400 MHz, CDCl3) δ 8.32
(dd, J = 1.7, 0.8 Hz, Ar-H, 1H), 7.86 (ddd, J = 8.5, 7.4, 2.6 Hz, Ar-H, 1H), 7.74 (s,
Ar-H, 1H), 6.94 (ddd, J = 8.5, 3.1, 0.6 Hz, Ar-H, 1H), 2.70 (s, Ar-CH3, 3H). 13C NMR
(101 MHz, CDCl3) δ 166.4, 164.1, 161.8, 145.1, 145.0, 139.0, 138.9, 138.7, 138.7,
133.5, 125.9, 125.8, 110.0, 109.6, 19.3.
2-methyl-5-(quinolin-4-yl)thiazole (6b). 1H NMR (400 MHz, CDCl3) δ 8.89 (d, J =
4.4 Hz, Ar-H, 1H), 8.17 (dd, J = 8.4, 0.8 Hz, Ar-H, 2H), 7.85 (s, Ar-H, 1H), 7.74 (ddd,
J = 8.5, 6.9, 1.3 Hz, Ar-H, 1H), 7.56 (ddd, J = 8.2, 6.9, 1.3 Hz, Ar-H, 1H), 7.38 (d, J =
4.4 Hz, Ar-H, 1H), 2.81 (s, Ar-CH3, 3H).13C NMR (101 MHz, CDCl3) δ 167.5, 149.6,
148.5, 142.0, 137.4, 132.9, 129.9, 129.6, 127.1, 126.1, 124.8, 121.8, 19.1.
1
2-methyl-5-(quinolin-3-yl)thiazole (7b). H NMR (400 MHz, CDCl3) δ 9.09 (d, J =
2.3 Hz, Ar-H, 1H), 8.18 (d, J = 2.2 Hz, Ar-H, 1H), 8.11–8.08 (m, Ar-H, 1H), 7.97 (s,
Ar-H, 1H), 7.83–7.80 (m, Ar-H, 1H), 7.70 (ddd, J = 8.4, 6.9, 1.5 Hz, Ar-H, 1H), 7.56
(ddd, J = 8.1, 6.9, 1.2 Hz, Ar-H, 1H), 2.77 (s, Ar-CH3, 3H).13C NMR (101 MHz,
CDCl3) δ 166.4, 148.6, 147.4, 138.9, 135.4, 132.4, 129.7,127.4, 129.3, 127.8, 127.4,
124.9, 19.5.
1
5-(6-methoxypyridin-3-yl)-2,4-dimethylthiazole (1c). H NMR (400 MHz, CDCl3) δ
8.18 (s, Ar-H, 1H), 7.56 (d, J = 8.5 Hz, Ar-H, 1H), 6.76 (d, J = 8.5 Hz, Ar-H, 1H),
3.94 (s, Ar-OCH3, 3H), 2.66 (s, Ar-CH3, 3H), 2.39 (s, Ar-CH3, 3H).13C NMR (101
MHz, CDCl3) δ 163.4, 147.5, 146.7, 139.2, 127.6, 121.4, 110.8, 53.5, 19.1, 15.7.
1
2,4-dimethyl-5-(6-methylpyridin-3-yl)thiazole (2c). H NMR (400 MHz, CDCl3) δ
8.51 (d, J = 2.0 Hz, Ar-H, 1H), 7.56 (dd, J = 8.0, 2.4 Hz, Ar-H, 1H), 7.17 (d, J = 8.0
13
Hz, Ar-H, 1H), 2.66 (s, 3H), 2.56 (s, Ar-CH3, 3H), 2.41 (s, Ar-CH3, 3H). C NMR
(101 MHz, CDCl3) δ 163.9, 157.5, 148.8, 145.0, 136.5, 127.5, 125.5, 122.9, 24.1, 19.1,
15.8.
1
5-(6-fluoropyridin-3-yl)-2,4-dimethylthiazole (4c). H NMR (400 MHz, CDCl3) δ
8.20 (d, J = 2.4 Hz, Ar-H, 1H), 7.76 (ddd, J = 8.4, 7.6, 2.6 Hz, Ar-H, 1H), 6.99–6.90
13
(m, Ar-H, 1H), 2.65 (s, Ar-CH3, 3H), 2.37 (s, Ar-CH3, 3H). C NMR (101 MHz,
CDCl3) δ 164.3, 163.9, 161.5, 148.4, 147.4, 147.3, 141.5, 141.4, 126.4, 126.4, 126.0,
125.9, 109.6, 109.2, 19.0, 15.7.
5-(isoquinolin-4-yl)-2,4-dimethylthiazole (5c). 1H NMR (400 MHz, CDCl3) δ 9.27 (s,
Ar-H, 1H), 8.49 (s, Ar-H, 1H), 8.04 (d, J = 8.1 Hz, Ar-H, 1H), 7.83–7.57 (m, Ar-H,
18

ACCEPTED MANUSCRIPT
3H), 2.76 (s, Ar-CH3, 3H), 2.22 (s, Ar-CH3, 3H).13C NMR (101 MHz, CDCl3) δ 165.4,
153.0, 150.4, 144.7, 135.0, 131.1, 128.3, 128.0, 127.6, 124.6, 124.5, 123.3, 19.2, 15.7.
1
2,4-dimethyl-5-(quinolin-4-yl)thiazole (6c). H NMR (400 MHz, CDCl3) δ 8.90 (d, J
= 4.4 Hz, Ar-H, 1H), 8.16 (d, J = 8.4 Hz, Ar-H, 1H), 7.80 (dd, J = 8.4, 0.8 Hz, Ar-H,
1H), 7.73 (ddd, J = 8.4, 6.9, 1.4 Hz, Ar-H, 1H), 7.54 (ddd, J = 8.3, 6.9, 1.2 Hz, Ar-H,
13
1H), 7.34 (d, J = 4.4 Hz, Ar-H, 1H), 2.81 (s, Ar-CH3,3H), 2.22 (s, Ar-CH3,3H). C
NMR (101 MHz, CDCl3) δ 167.5, 149.6, 148.5, 142.0, 137.4, 132.9, 129.9, 129.5,
127.1, 126.1, 124.8, 121.8, 19.1, 15.9.
1
2,4-dimethyl-5-(quinolin-3-yl)thiazole (7c). H NMR (400 MHz, CDCl3) δ 8.91 (d, J
= 2.3 Hz, Ar-H, 1H), 8.09–8.04 (m, Ar-H, 2H), 7.77 (dd, J = 8.2, 1.1 Hz, Ar-H, 1H),
7.67 (ddd, J = 8.3, 7.0, 1.4 Hz, Ar-H, 1H), 7.54–7.46 (m, Ar-H, 1H), 2.67 (s, Ar-CH3,
3H), 2.47 (s, Ar-CH3, 3H). 13C NMR (101 MHz, CDCl3) δ 164.4, 150.4, 148.5, 146.8,
135.0, 129.7, 129.1, 127.6, 127.5, 127.4, 127.2, 125.6, 19.1, 15.9.
1
3,5-bis(4-methylthiazol-5-yl)pyridine (12aa). H NMR (400 MHz, CDCl3) δ 8.79 (s,
Ar-H, 2H), 8.70 (d, J = 2.1 Hz, Ar-H, 2H), 7.80 (t, J = 2.2 Hz, Ar-H, 1H), 2.59 (s,
Ar-CH3, 6H).13C NMR (101 MHz, CDCl3) δ 151.6, 150.3, 148.8, 136.5, 128.3, 127.4,
16.1.
1
4-methyl-5-(4-(trifluoromethyl)phenyl)thiazole (13a). H NMR (400 MHz, CDCl3) δ
8.70 (s, Ar-H, 1H), 7.65 (d, J = 7.4 Hz, Ar-H, 2H), 7.52 (d, J = 7.6 Hz, Ar-H, 2H),
2.52 (s, Ar-CH3, 3H).13C NMR (101 MHz, CDCl3) δ 151.0, 149.4, 135.6, 130.3, 129.4,
125.6, 125.6, 125.5, 125.5, 125.2, 122.5, 119.8, 16.0.
4-methyl-5-(4-nitrophenyl)thiazole (14a). 1H NMR (400 MHz, CDCl3) δ 8.79–8.74
(m, Ar-H, 1H), 8.27 (t, J = 10.3 Hz, Ar-H, 2H), 7.61 (dd, J = 10.1, 5.8 Hz, Ar-H, 2H),
2.59 (s, Ar-CH3, 3H).13C NMR (101 MHz, CDCl3) δ 151.8, 150.4, 147.0, 138.8, 129.8,
124.0, 113.9, 16.4.
4-(4-methylthiazol-5-yl)benzonitrile (15a). 1H NMR (400 MHz, CDCl3) δ 8.75 (s,
Ar-H, 1H), 7.73 (d, J = 1.9 Hz, Ar-H, 1H), 7.71 (d, J = 2.0 Hz, Ar-H, 1H), 7.57 (d, J =
2.0 Hz, Ar-H, 1H), 7.55 (d, J = 1.9 Hz, Ar-H, 1H), 2.56 (s, Ar-CH3, 3H). 13C NMR
(101 MHz, CDCl3) δ 151.6, 150.0, 136.8, 132.5, 130.1, 129.7, 118.4, 111.5, 16.3.
1
5-(4-fluorophenyl)-4-methylthiazole (16a). H NMR (400 MHz, CDCl3) δ 8.67 (s,
Ar-H, 1H), 7.42–7.35 (m, Ar-H, 2H), 7.11 (t, J = 8.1 Hz, Ar-H, 2H), 2.50 (s, Ar-CH3,
3H).13C NMR (101 MHz, CDCl3) δ 163.6, 161.1, 150.3, 148.54, 131.0, 131.0, 115.8,
115.6, 15.9.
1
5-(4-chlorophenyl)-4-methylthiazole (17a). H NMR (400 MHz, CDCl3) δ 8.68 (s,
13
Ar-H, 1H), 7.41–7.33 (m, Ar-H, 4H), 2.51 (s, Ar-CH3, 3H). C NMR (101 MHz,
CDCl3) δ 150.5, 148.8, 133.9, 130.6, 130.5, 130.4, 128.9, 16.0.
19

ACCEPTED MANUSCRIPT
1
4-methyl-5-phenylthiazole (18a). H NMR (400 MHz, CDCl3) δ 8.68 (s, Ar-H, 1H),
13
7.46–7.42 (m, Ar-H, 4H), 7.38–7.34 (m, Ar-H, 1H), 2.54 (s, Ar-CH3, 3H). C NMR
(101 MHz, CDCl3) δ 150.3, 148.5, 131.9, 131.9, 129.3, 128.7, 127.9, 16.1.
4-methyl-5-(p-tolyl)thiazole (19a). 1H NMR (400 MHz, CDCl3) δ 8.66 (s, Ar-H, 1H),
7.34 (d, J = 8.1 Hz, Ar-H, 2H), 7.23 (dd, J = 8.4, 0.6 Hz, Ar-H, 2H), 2.53 (s, Ar-CH3,
3H), 2.39 (s, Ar-CH3, 3H). 13C NMR (101 MHz, CDCl3) δ 150.0, 148.2, 137.8, 132.0,
129.4, 129.2, 128.9, 21.2, 16.0.
1
4-methyl-5-(naphthalen-1-yl)thiazole (20a). H NMR (400 MHz, CDCl3) δ 8.83 (s,
Ar-H, 1H), 7.90 (d, J = 7.8 Hz, Ar-H, 2H), 7.70 (d, J = 8.1 Hz, Ar-H, 1H), 7.52–7.44
13
(m, Ar-H, 4H), 2.30 (s, Ar-CH3, 3H). C NMR (101 MHz, CDCl3) δ 151.4, 150.6,
133.5, 132.3, 129.2, 129.0, 1289, 128.6, 128.3, 126.54, 126.0, 125.4, 125.0, 15.6.
1
5-(4-methoxyphenyl)-4-methylthiazole (21a). H NMR (400 MHz, CDCl3) δ 8.60 (s,
Ar-H, 1H), 7.34–7.30 (m, Ar-H, 2H), 6.93–6.89 (m, Ar-H, 2H), 3.79 (s, Ar-OCH3, 3H),
2.48 (s, Ar-CH3, 3H). 13C NMR (101 MHz, CDCl3) δ 159.2, 149.5, 147.7, 131.5, 130.3,
123.9, 114,0, 55.1, 15.8.
1
4-(4-methylthiazol-5-yl)benzaldehyde (22a). H NMR (400 MHz, CDCl3) δ 10.03
(s,CHO-H 1H), 8.74 (s, Ar-H, 1H), 7.93 (d, J = 8.1 Hz, Ar-H, 2H), 7.61 (d, J = 8.1 Hz,
Ar-H, 2H), 2.58 (s, Ar-CH3, 3H). 13C NMR (101 MHz, CDCl3) δ 191.4, 151.4, 149.8,
138.2, 135.3, 130.7, 130.0, 129.6, 16.4.
1
4-methyl -(4-methylthiazol-5-yl)benzoate (23a). H NMR (400 MHz, CDCl3) δ 8.71
(s, Ar-H, 1H), 8.07 (d, J = 8.5 Hz, Ar-H, 2H), 7.50 (d, J = 8.5 Hz, Ar-H, 2H), 3.92 (s,
Ar-COOCH3, 3H), 2.55 (s, Ar-CH3, 3H). 13C NMR (101 MHz, CDCl3) δ 166.5, 151.0,
149.4, 136.6, 130.9, 129.9, 129.3, 129.0, 52.2, 16.3.
2-methyl-5-(4-(trifluoromethyl)phenyl)thiazole (24b). 1H NMR (400 MHz, CDCl3) δ
13
7.86 (s, Ar-H, 1H), 7.61 (d, J = 2.0 Hz, Ar-H, 4H), 2.74 (s, Ar-CH3, 3H). C NMR
(101 MHz, CDCl3) δ 166.6, 138.9, 137.2, 135.1, 130.3, 129.9, 129.6, 129.3, 128.0,
126.6, 126.0, 126.0, 126.0, 125.9, 125.3, 122.6, 119.9, 19.4.
1
5-(4-chlorophenyl)-2-methylthiazole (17b). H NMR (400 MHz, CDCl3) δ 7.76 (d, J
= 1.0 Hz, Ar-H, 1H), 7.45–7.40 (m, Ar-H, 2H), 7.34 (dd, J = 7.9, 1.3 Hz, Ar-H, 2H),
2.71 (s, Ar-CH3, 3H).13C NMR (101 MHz, CDCl3) δ 165.6, 137.9, 137.6, 133.8, 130.1,
129.2, 127.7, 19.3.
2-methyl-5-phenylthiazole (18b). 1H NMR (400 MHz, CDCl3) δ 7.71 (s, Ar-H, 1H),
7.44 (t, J = 1.7 Hz, Ar-H, 1H), 7.42–7.41 (m, Ar-H, 1H), 7.31–7.27 (m, Ar-H, 2H),
7.24–7.20 (m, Ar-H, 1H), 2.63 (s, Ar-CH3, 3H). 13C NMR (101 MHz, CDCl3) δ 165.2,
138.8, 137.6, 131.5, 128.9, 127.9, 126.5, 19.3.
20

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2-methyl-5-(naphthalen-1-yl)thiazole (20b). 1H NMR (400 MHz, CDCl3) δ 8.16–8.12
(m, Ar-H, 1H), 7.91–7.85 (m, Ar-H, 2H), 7.74 (s, Ar-H, 1H), 7.55–7.45 (m, Ar-H,
4H), 2.80 (s, Ar-CH3, 3H).13C NMR (101 MHz, CDCl3) δ 166.3, 141.1, 135.7, 133.7,
131.9, 129.0, 128.8, 128.5, 128.4, 126.7, 126.1, 125.2, 125.2, 19.2.
4-(2-methylthiazol-5-yl)benzaldehyde (22b). 1H NMR (400 MHz, CDCl3) δ 10.00 (s,
CHO-H,1H), 7.93 (s, Ar-H, 1H), 7.90–7.87 (m, Ar-H, 2H), 7.68–7.65 (m, Ar-H, 2H),
13
2.75 (s, Ar-CH3, 3H). C NMR (101 MHz, CDCl3) δ 191.3, 167.1, 139.5, 137.5,
137.4, 135.5, 130.5, 126.8, 19.5.
methyl 4-(2-methylthiazol-5-yl)benzoate (23b). 1H NMR (400 MHz, CDCl3) δ 8.02 (d,
J = 8.6 Hz, Ar-H, 2H), 7.87 (s, Ar-H, 1H), 7.55 (d, J = 8.6 Hz, Ar-H, 2H), 3.91 (s,
13
Ar-OCH3, 3H), 2.72 (s, Ar-CH3, 3H). C NMR (101 MHz, CDCl3) δ 166.5, 166.4,
138.9, 137.7, 135.9, 130.3, 129.3, 126.2, 52.1, 19.4.
2,4-dimethyl-5-(4-(trifluoromethyl)phenyl)thiazole (24c). 1H NMR (400 MHz, CDCl3)
δ 7.61 (d, J = 8.2 Hz, Ar-H, 2H), 7.47 (d, J = 8.1 Hz, Ar-H, 2H), 2.65 (s, Ar-CH3, 3H),
2.43 (s, Ar-CH3, 3H).13C NMR (101 MHz, CDCl3) δ 164.1, 148.1, 136.0, 129.7, 129.1,
125.5, 125. 4, 125.4, 122.5, 119.9, 18.9, 16.0.
4-(2,4-dimethylthiazol-5-yl)benzonitrile (15c). 1H NMR (400 MHz, CDCl3) δ 7.67 (d,
J = 8.5 Hz, Ar-H, 2H), 7.49 (d, J = 8.5 Hz, Ar-H, 2H), 2.67 (s, Ar-CH3, 3H), 2.46 (s,
Ar-CH3, 3H). 13C NMR (101 MHz, CDCl3) δ 164.7, 148.7, 137.1, 132.3, 129.4, 129.3,
118.5, 110.9, 19.1, 16.3.
1
5-(4-fluorophenyl)-2,4-dimethylthiazole (16c). H NMR (400 MHz, CDCl3) δ 7.31
(dd, J = 8.6, 5.4 Hz, Ar-H, 2H), 7.04 (t, J = 8.7 Hz, Ar-H, 2H), 2.63 (s, Ar-CH3, 3H),
2.38 (s, Ar-CH3, 3H). 13C NMR (101 MHz, CDCl3) δ 163.20 (d, J = 16.2 Hz), 160.8,
147.0, 130.7, 130.1, 128.2, 115.6 115.4, 18.9, 15.7.
1
2,4-dimethyl-5-phenylthiazole (18c). H NMR (400 MHz, CDCl3) δ 7.40–7.34 (m,
Ar-H, 4H), 7.32–7.27 (m, Ar-H, 1H), 2.65 (s, Ar-CH3, 3H), 2.44 (s, Ar-CH3, 3H). 13C
NMR (101 MHz, CDCl3) δ 163.1, 146.9, 132.2, 131.2, 129.0, 128.5, 127.4, 77.3, 77.0,
76.7, 18.9, 15.9.
1
2,4-dimethyl-5-(naphthalen-1-yl)thiazole (20c). H NMR (400 MHz, CDCl3) δ
7.91–7.87 (m, Ar-H, 2H), 7.79–7.75 (m, Ar-H, 1H), 7.53–7.45 (m, Ar-H, 4H), 2.76 (s,
Ar-CH3, 3H), 2.21 (s, Ar-CH3, 3H). 13C NMR (101 MHz, CDCl3) δ 164.4, 149.3,
133.6, 132.4, 129.2, 129.2, 128.9, 128.3, 128.3, 126.5, 126.0, 125.6, 125.1, 19.1, 15.6.
4-(2,4-dimethylthiazol-5-yl)benzaldehyde (22c). 1H NMR (400 MHz, CDCl3) δ 10.01
(s, Ar-H, 1H), 7.90 (d, J = 8.2 Hz, Ar-H, 2H), 7.56 (d, J = 8.2 Hz, Ar-H, 2H), 2.69 (s,
Ar-CH3, 3H), 2.49 (s, Ar-CH3, 3H). 13C NMR (101 MHz, CDCl3) δ 191.4, 164.6,
21

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148.5, 138.6, 135.0, 130.0, 129.3, 19.1, 16.4.
1
methyl 4-(2,4-dimethylthiazol-5-yl)benzoate (23c). H NMR (400 MHz, CDCl3) δ
8.04 (d, J = 8.0 Hz, Ar-H, 2H), 7.45 (d, J = 8.0 Hz, Ar-H, 2H), 3.91 (s, Ar-OCH3, 3H),
2.67 (s, Ar-CH3, 3H), 2.47 (s, Ar-CH3, 3H). 13C NMR (101 MHz, CDCl3) δ 166.5,
164.1, 148.1, 137.0, 130.3, 129.8, 128.9, 128.7, 52.1, 19.1, 16.3.
Appendix A. Supplementary material
CCDC 1883738 (C1) contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Declarations of interest. None.
Acknowledgements. The authors acknowledge with thanks the support from the
Guangdong Pharmaceutical University.
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Highlights:
•
This work is for better understanding of catalyst design for direct C-H
arylation.
•
•
Reactions efficiently proceeded under aerobic conditions with low
catalyst loading.
Good yields were achieved in most cases.