A convenient phosphine-free palladium-catalyzed direct arylation of thiazole under mild aerobic conditions

Article abstract of DOI:10.1016/j.jorganchem.2015.12.009

A series of bulky amine palladium complexes {[(Ar-NH₂)₂PdCl₂]} were synthesized and characterized. The catalytic activity of the palladium complexes was evaluated via the direct C-H arylation of thiazoles with aryl bromide

Full text of DOI:10.1016/j.jorganchem.2015.12.009

Accepted Manuscript
A Convenient Phosphine-Free Palladium-Catalyzed Direct Arylation of Thiazole under
Mild Aerobic Conditions
Xiao-Xi He, Yan-Fang Li, Ju Huang, Dong-Sheng Shen, Feng-Shou Liu
PII:
S0022-328X(15)30227-8
10.1016/j.jorganchem.2015.12.009
JOM 19315
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 15 September 2015
Revised Date: 19 November 2015
Accepted Date: 4 December 2015
Please cite this article as: X.-X. He, Y.-F. Li, J. Huang, D.-S. Shen, F.-S. Liu, A Convenient Phosphine-
Free Palladium-Catalyzed Direct Arylation of Thiazole under Mild Aerobic Conditions, Journal of
Organometallic Chemistry (2016), doi: 10.1016/j.jorganchem.2015.12.009.
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ACCEPTED MANUSCRIPT
Graphics
A series of bulky aniline palladium complexes were synthesized and characterized,
which exhibited significantly activities for direct arylation of thiazoles with aryl
bromides.

ACCEPTED MANUSCRIPT
A Convenient Phosphine-Free Palladium-Catalyzed Direct Arylation of Thiazole
under Mild Aerobic Conditions
Xiao-Xi He, Yan-Fang Li, Ju Huang*, Dong-Sheng Shen, Feng-Shou Liu*
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical
University
Corresponding authors: Ju Huang, email: xianghuangj@163.com; Feng-Shou Liu,
email: fengshou2004@126.com;

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Abstract: A series of bulky amine palladium complexes {[(Ar-NH2)2PdCl2]} were
synthesized and characterized. The catalytic activity of the palladium complexes was
evaluated via the direct C-H arylation of thiazoles with aryl bromides in aerobic
conditions at 80-100 °C. Under the optimal conditions, 0.5-0.05 mol% of the bulky
palladium complexes were found to be very efficient and produced the desired
cross-coupling products in high yields.
Keywords: bulky aniline; palladium complex; thiazole; direct arylation; aerobic
condition
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1 Introduction
With broad functional group tolerance and without the need for synthesis
of organometallic coupling partners, palladium-catalyzed direct C-H bond
arylation has become an important method for the formation of carbon-carbon
bonds during the past decade [1]. Particularly, the direct arylation of thiazoles
has received much attention [2-4] because such structural units are frequently
found in pharmaceuticals, natural products, and functional organic materials [5].
The efficiency of this cross-coupling is greatly influenced by the choice of
ligand, base, solvent and additives [6]. The ligand, which binds to the palladium
to stabilize the catalytic intermediates, plays a pivotal role in the transformation
process. Thus, considerable efforts have been directed toward the development
of efficient ligands [7]. Noticeable advances have been achieved with bulky and
electron-rich phosphine ligands, which have significantly enlarged the scope of
direct arylation [2g,h,n,o]. However, except some well-known air-stable
phosphine developed by Buchwald, most of these phosphine-based ligands are
not readily available, and they are air-sensitive and toxic [8].
In contrast, the recent development of phosphine-free and ligand-free
catalysts has shown promise because they have the potential to overcome the
disadvantages of catalytic instability and environmental concerns [7a-c]. Itami
and coworkers were the first to report the palladium-catalyzed C4-selective
arylation of thiazoles with arylboronic acids using 2,2’-bipyridyl (bipy) or
1,10-phenanthroline (phen) as the ligand [3h,r,s]. Subsequently, the Pd/bipy
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was successfully applied for the C5-selective arylation of thiazole with aryl
iodides [3g]. Murai and coworkers highlighted that commercial
[Pd(phen)2](PF6)2 can promote the one-pot multiple direct arylation of thiazole
with aryl halides in the presence of 5 mol% catalyst loading [3f,i]. Recently,
Doucet and Gök demonstrated the
N-heterocyclic carbenes (NHCs) palladium
catalysts have excellent performance in the preparation of arylthioazoles, even
using the aryl bromides and chlorides as the coupling partners in a high reaction
temperature (>130°C) [3e,3p]. However, there are still much room to explore
an efficient phosphine-free palladium catalyst for the direct C-H arylation,
especially with respect to the palladium loading (<0.1 mol%), the substrate
scope of the method, and mild reaction temperature. Therefore, there is a need
for readily available and efficient catalysts that can mediate the transformation
under mild conditions.
Simple amines are highly efficient ligands for the Suzuki-Miyaura
cross-coupling reaction, and they have a broad substrate scope [9]. Very
recently, the use of dual Pd/Cu catalysts in conjunction with amine ligands
enabled the direct arylation of 2’-deoxyadenosines with both aryl iodides and
bromides [10]. Moreover, Bulky substituted pyridine developed by Tsuji also
exhibited highly efficient in air oxidation of alcohols [11]. Inspired by the
promising performance of the nitrogen based ligands, we hypothesized that
sterically bulky primary anilines, which can stabilize the palladium active
species, would be beneficial for the direct arylation. Herein, we report a general
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method for the synthesis of 5-arylthiazoles using aniline palladium complexes
under mildly aerobic reaction conditions.
2 Results and discussion
2.1 Synthesis and characterization of aniline palladium complexes
L2-L5 can be readily synthesized via the ortho-alkylation of anilines with
diphenylmethanol in one-step, according to the procedure proposed by Markó
and Nolan [12]. Moreover, the reaction of substituted anilines with palladium
chloride in DMAc produced the corresponding C1-C5 in high yields (Scheme
1). These palladium complexes were characterized using NMR, MS, and
elemental analysis. An advantage of these palladium complexes is that they are
stable toward air and moisture, so that the preparation, purification and
crystallization of the palladium complexes can be conveniently operated in
open-air.
<Insert Scheme 1
>
Crystals of C2-C5 that were suitable for X-ray diffraction were grown from a
solution of dichloromethane and methanol in aerobic conditions. As shown in Figure
1-4, a slightly distorted square-planar coordination geometry was observed, in which
the two aniline ligands are oriented trans to each other in the C2-5. The nitrogens,
N(1) and N(2), and chlorines, Cl(1) and Cl(2) that are attached to palladium are all in
the same plane. The solid state structure of these four palladium complexes revealed
similar bond lengths. Nevertheless, it is deserved to note that the Pd-N bond lengths
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(
2.056(3) Å) in C2 were shorter than that of the typical Pd–N(sp3) single bond length
(2.07-2.10 Å) and that of C2-5, indicating a slightly stronger interaction between the
coordinated atoms and the palladium in C2 [9b,i,13].
<Insert Figure 1
<Insert Figure 2
<Insert Figure 3
<Insert Figure 4
>
>
>
>
2.2 Direct arylation catalyzed by aniline palladium complexes
Initially, we chose 4-methylthiazole (1a) and 4-bromobenzonitrile (2a) as
the model substrates in the presence of 0.5 mol% of the palladium complex
(Table 1). To establish mild reaction conditions, the heteroarene and the aryl
bromides were employed in equimolar quantities. The experiments were
performed at a temperature of 80 °C for 24 h, using K2CO3 as the base, DMAc
as the solvent, and pivalic acid (PivOH) as the additive. As shown in Table 1,
the precatalysts critically affected the efficiency of this reaction. Cy2NH/PdCl2,
which was proved highly efficient in the Suzuki-Miyaura coupling [9a, b],
showed promising results, and it provided the direct arylation product, 3aa, in a
86% GC yield (Entry 1, Table 1). Meanwhile, C1, with 2,6-diisopropyl
substituents on the aniline moiety, provided the coupling product, 3aa, with
almost the same efficiency as the Cy2NH/PdCl2. In contrast, the bulky
benzhydryl group on the aniline moiety exhibited a profound effect on the
activities. For example, C2
-
C5 exhibited superior reactivity than C1 and
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Cy2NH/PdCl2 (Entries 3-6, Table 1). Reasonably, the use of bulky steric of the
ligand, which can stabilize the palladium center and further facilitate the
elimination rate, is essential for the direct arylation process [2i, 14]. However,
quite out of our expectation, in these aniline palladium complexes screened, C2
,
which is less bulky than C3-C5, was found to be the most active catalyst in the
direct arylation. For example, the coupling reaction that employed C2 as the
precatalyst afforded the corresponding product, 3aa, in an almost quantifiable
conversion, and an isolated yield of 92% was obtained (Entry 3, Table 1).
Probably, bearing the 2,6-benzhydryl group on aniline moiety, the most bulky
precatalysts C3-C5 was too crowed. In contrast, with mono benzhydryl group
on C2, it was sufficient for stabilizing the palladium center and the less bulky
steric would facilitate the rate of oxidative addition process.
<Insert Table 1
>
Based on the above promising results, other reaction conditions for the
direct C-H arylation were then investigated. As shown in Table 2, the base,
solvent, and acid additives were all crucial to the efficiency of this reaction.
Among the bases such as K2CO3, Na2CO3, NaHCO3, C6H5CO2Na, NaOAc,
K3PO4 and KOAc examined, the use of K2CO3 as a base led to best yield
(Entries 1-7, Table 2). However, the bases, such as NaOH and Cs2CO3, were
much less effective and produced a minor yield of 6% and 5%, respectively
(Entries 8 and 9, Table 2). Furthermore, no products were observed when KOH,
KOtBu and NaOtBu, were used (Entries 10-12, Table 2). A number of solvents
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were then screened, and the solvents, such as DMF, dioxane, toluene, xylene
and N-methyl-2-pyrrolidone (NMP), all led to the formation of the product in
moderate to good yields (Entries 13-17, Table 2), whereas DMAc produced the
best yield (Entry 1, Table 2). The acid additives were also evaluated and it was
found that only a 9% product yield was observed when there was no acid
additive under the standard conditions (Entry 20, Table 2). In contrast, there
was a significant acceleration effect when introducing the carboxylic acid
additive to the reaction. For example, acetic acid and propanoic acid produce
moderate yields of 65 and 64%, respectively (Entries 21-22, Table 2).
Moreover, among the screened acid additives, PivOH provided the best yield
for the coupling reaction product (Entry1, Table 2). The indispensable of the
acid additives is in accordance with a concerted metalation-deprotonation
(CMD) pathway [15]. Thus, the optimization results were obtained by using a
mixture of thiazole (1.0 equiv), aryl bromide (1.0 equiv), C2 as the precatalyst,
K2CO3 as the base, and PivOH as the acid additive in DMAc. Under our
reaction conditions, only a trace amount of side products, such as
homocoupling biaryl products that were derived from the aryl bromides and
C-2 arylation of the thiazoles, were observed during the course of this reaction.
<Insert Table 2
>
After the reaction conditions were optimized, the scope of the direct
arylation between a variety of aryl bromides and 4-methylthiazole was explored.
As shown in Table 3, in the presence of 0.5 mol% of C2, the cross-coupling
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reagents smoothly reacted to afford the desired products at 80 °C. Moreover, a
wide range of functional groups on the aryl bromides were tolerated well during
this process, allowing further transformations or modifications. For example,
the electron-deficient aryl bromides, such as 4-bromobenzonitrile,
1-bromo-4-chlorobenzene,
4-bromobenzaldehyde,
and
methyl
4-bromobenzoate, provided the corresponding products, 3aa
-
3ac and 3aj, in
excellent yields (86-94%). The electron-deficient substrates bearing the fluoro-
and trifluoro-methyl heteroatoms, which are important motifs in
pharmaceuticals, were produced in high yields (76-97%). Additionally, some
electron-deficient substrate partners, which bear the nitro (-NO2) and acetyl
(-COMe) groups, commonly produced low yields in previous reports.2k It
provided the corresponding products, 3ad and 3ai, in high yields of 88%.
Regarding the electron-neutral and electron-rich aryl bromides, such as
1-bromobenzene, 4-bromotoluene, 3-bromotoluene, 3-bromoanisole, and
1-bromonaphthalene, they were also well tolerated and yielded the biaryl
products, 3al, 3am, 3an, 3ap and 3ar, in satisfactory yields (55-92%).
However, the sterically hindered substrates and less active substrates, such as
1-bromo-2-methylbenzene and 4- bromoanisole, produced 3ao and 3aq in
much lower yields of 31% and 39%, respectively.
<Insert Table 3
>
Decreasing the amount of the palladium to catalyze the reaction process is
desirable not only because of cost, but also in order to facilitate metal removal
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once the reaction is complete. The outstanding performance of C2 naturally led
us to examine the effect of reducing the catalyst loading. Remarkably, both the
electron-deficient and electron-rich aryl bromides were easily reacted with
thiazole to produce the corresponding products using a lower palladium loading
of 0.1 mol% in moderate to excellent yields, if the temperature was raised to
100°C (Table 4). When the amount of catalyst was further reduced to 0.05
mmol%,
1-bromo-4-chlorobenzene, 4-bromobenzonitrile, and 4-bromobenzaldehyde,
also can provide the corresponding products (3aa 3ab and 3ac) in moderate to
the
electron-deficient
aryl
bromides,
such
as
-
high yields (71-82%). Moreover, a highly efficient direct C5-arylation was also
achieved when 2,4-dimethylthiazole was introduced. The methyl group on the
C-2 position of the thiazole did not cause obvious steric inhibition, and it
provided the desired products, 3bb
<Insert Table 4
-3bl, in good to excellent yields.
>
By probing the aggregation state of the catalytic species and the
mechanism of the palladium-catalyzed direct arylation, important insight into
the C-H bond functionality can be provided. Generally, the transformations via
ligand-based catalytic systems have been recognized as homogenous catalytic
processes [16]. In these cases, the ligands, which could stabilize the palladium,
played a critical role in the catalytic efficiency and regioselectivity under mild
reaction conditions. However, the ligand-free palladium catalysts could also
successfully achieve the direct arylation under carefully controlled conditions,
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such as at elevated temperature (>130 °C) and in polar solvent [3d,17]. In the
latter case, the heterogeneous palladium nanoparticles (PdNPs) were generated
in situ, and the cross-coupling reaction occurred via the interaction of the
substrates with the palladium on the outer rim of the nanoparticles [18].
Nevertheless, the species involved in the palladium-catalyzed cross-coupling is
still not clear, and the possible aggregation states of the palladium require
further research. Very recently, Fairlamb et al. demonstrated that in the
piperidine-activated palladium/copper direct arylation, the monodentate
nitrogen atoms are prone to decoordination from the palladium center even
when a homogenous palladium precursor was used [10c]. Moreover, the
transmission electron microscopy (TEM) suggested that the PdNPs were
generated under a mild reaction temperature of 80 °C.
To determine if the PdNPs are involved in the catalytic cycle, we first
performed poisoning experiments with the aniline-based palladium precatalyst.
Quantitative poisons, such as PPh3 and CS2 (< 1 equiv relative to the palladium
loading), can effectively terminate the reaction activity, thus confirming the
heterogeneous nature of the Pd(0) catalyst in the cross-coupling reaction[19].
Considering the low boiling point of CS2, we first checked the PPh3 poisoning
method. The reaction was performed using 4-bromobenzonitrile (1 mmol),
4-methylthiazole (1 mmol), K2CO3 (1.5 mmol), PivOH (0.3 mmol), and C2
(0.001 mmol) in DMAc (3 mL) at 100 °C for 24 h. An excess (100 equiv
relative to the palladium) of PPh3 was added at the beginning of the reaction,
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and the catalytic activity of C2 showed a high GC yield of 86%, indicating a
negative effect. Moreover, a Hg(0) poison test (300 equiv relative to the
palladium) was also conducted, and the catalytic activity was not quenched, but
it produced a lower GC yield of 48%. Furthermore, submitting the samples of
the reaction mixtures to TEM imaging after the reaction did not produce any
aggregated nanoparticles, indicating the homogenous nature of the catalytic
system. Thus, we conclude that the excellent catalytic performance of the
aniline palladium catalyst is attributed to the ligand structure.
In order to obtain further information on the mechanism of the cross-coupling,
we conducted the stoichiometric reaction of PivOH/K2CO3 with precatalyst C2 in
DMAc solution at a temperature of 80°C. The preliminary investigation involved
tracing the catalytic species with ESI-MS (seen in Figure S6). The result showed a
peak at m/z = 570.1, which could be formed from [L2Pd(PivO)Cl]K+. Moreover, the
13C NMR analysis of the obtained compound showed a resonance at 161.7 and 160.6
ppm, which suggested the ligand exchange between halide with the pivalic anion
(seen in Figure S7). Subsequently, we investigated the direct arylation between
4-bromobenzonitrile and 4-methylthiazole in the presence of a 10 mol% amount of
o
C2 at 80 C for 2 h. The reaction proceeded in 52% GC yield and the mixture was
determined by ESI-MS (seen in Figure S8). It was found the peaks at m/z = 963.7 and
696.6, which could be formed from [2L2Pd(4-methylthiazole)(C6H4CN)Br]+ and
[L1Pd(4-methylthiazole)(C6H4CN)(PivO)]+. These result suggested that an oxidative
addition of Pd(0) with 4-bromobenzonitrile and subsequently a smooth ligand
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exchange would be involved in the process of the direct arylation.
On the basis of the above observations, we propose plausible catalytic cycles
[20]. As can be seen in Scheme 2, when aniline palladium complex was used, the
reduction of Pd(II) to Pd(0) (A) would be taken in situ. Then, the oxidative of aryl
bromide with Pd(0) to afford the aryl Pd(II) species (B). Subsequently, an exchange of
the bromide ligand with pivalic anion allowed for a related CMD type transition state
(C) to afford the diaryl-Pd(II) intermediate (D). After the reductive elimination
rendering the target arylated product, the release Pd(0) species can enter the next
catalytic cycle.
3 Conclusions
We developed a class of aniline palladium complexes for the direct
arylation of thiazoles by incorporating the bulky ortho-CH2Ph2 framework. These
aniline ligands, which contain a protected palladium center, have provided a highly
versatile strategy for direct C-H bond functionality reactions. In addition to a broad
substrate scope, including electron-rich and deficient aryl bromides, the simple
precatalyst, C2, also demonstrated its catalytic ability under mild reaction conditions
for low palladium loading. Our investigation into the mechanism revealed that a
homogenous process is involved in the cross-coupling reaction.
4 Experimental
4.1 Physical Measurements and Materials
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2,6-Diisopropylaniline was purchased from Aldrich Chemical and were distilled
under reduced pressure before being used. Palladium chloride was purchased from
Aldrich Chemical. 2,6-diphenylmethyl-4-methylaniline, 2,6-diphenylmethyl-4-chloro-
aniline 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 at ambient temperature 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=0.71073Å) at 173K for C2, C3 and C4, Cu Kα radiation
(λ=1.54178Å) at 173K for C5. 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 1401361-1401364 (C2-C5) contain the
supplementary crystallographic data for this paper.
4.2 General procedures for the synthesis of aniline palladium compounds
Aniline ligand (10.0 mmol) and palladium dichloride (0.886 g, 5.0 mmol) were
dissolved in 15 mL of DMAc at room temperature. After the mixture was stirred for
o
0.5 h at 80 C, the methanol (50 mL) was added and the precipitation was formed.
The precipitate of palladium complexes was then dissolved in 5 mL dichloromethane,
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then 20 mL hexane was added. After crystallized from the mixture of ethanol and
dichloromethylene, the palladium complex was obtained as light yellow crystals.
4.2.1 Synthesis of [2,6-(iPr)2C6H3NH]2PdCl2 (C1)
1H NMR (400 MHz, CDCl3): δ (ppm) 7.23 (t, JHH=7.6 Hz, Ar-H, 2H), 7.12 (t, JHH=7.6
Hz, Ar-H, 4H), 4.69 (s, NH2, 4H), 3.57 (m, CH(CH3)2, 4H), 1.36 (m, CH(CH3)2, 24H).
13C NMR (100 MHz, CDCl3): δ (ppm) 139.8, 133.4, 126.5, 123.6, 28.2, 23.5. ESI-MS.
m/z: 497, [2L1PdCl] +; 461, [2L2Pd] 2+; Anal. Calcd for: C24H38Cl2N2Pd: C, 54.19; H,
7.20; N, 5.27. Found: C, 54.01; H, 7.28; N, 5.16. Tm: 230.5oC.
4.2.2 Synthesis of [2-(CHPh2)-4,6-(CH3)2C6H2NH]2PdCl2(C2)
1H NMR (400 MHz, CDCl3): δ (ppm) 7.32 (m, Ar-H, 20H), 6.80 (s, Ar-H, 2H), 6.80
(s, Ar-H, 2H), 6.48 (s, Ar-H, 2H), 6.37 (s, CHPh2, 2H), 4.17 (s, NH2, 4H), 2.44 (s,
13
CH3, 6H), 2.08 (s, CH3, 6H). C NMR (100 MHz, CDCl3): δ (ppm) 141.6, 135.8,
135.1, 133.8, 130.1, 129.8, 129.2, 128.9, 128.7, 127.0, 51.6, 21.2, 18.9. ESI-MS. m/z:
715, [2L2PdCl] +; 681, [2L2Pd] 2+; 288, [L2]+. Anal. Calcd for: C42H42Cl2N2Pd: C,
67.07; H, 5.63; N, 3.72. Found: C, 66.78; H, 5.71; N, 3.65. Tm: 248.0 oC.
4.2.3 Synthesis of [2,6-(CHPh2)2-4-(CH3) C6H2NH]2PdCl2 (C3)
1H NMR (400 MHz, CDCl3): δ (ppm) 7.24 (m, Ar-H, 40H), 6.45 (s, Ar-H, 4H), 6.44
(s, CHPh2, 4H), 4.11 (s, NH2, 4H), 2.03 (s, CH3, 6H). 13C NMR (100 MHz, CDCl3): δ
(ppm) 141.4, 136.1, 134.9, 133.6, 129.7, 129.6, 128.6, 127.1, 51.7, 21.5. ESI-MS. m/z:
584, [L3PdCl] +; 440, [L3]+. Anal. Calcd for: C66H58Cl2N2Pd: C, 75.03; H, 5.53; N,
2.65. Found: C, 74.96; H, 5.60; N, 2.61. Tm: 280.6 oC.
4.2.4 Synthesis of [2,6-(CHPh2)2-4-(OCH3) C6H2NH]2PdCl2 (C4)
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1H NMR (400 MHz, CDCl3): δ (ppm) 7.24 (m, Ar-H, 40H), 6.45 (s, Ar-H, 4H), 6.19
(s, CHPh2, 4H), 4.04 (s, NH2, 4H), 3.42 (s, CH3, 6H). 13C NMR (100 MHz, CDCl3): δ
(ppm) 156.6, 141.1, 137.8, 129.7, 129.2, 128.7, 127.2, 114.5, 54.8, 51.8. ESI-MS. m/z:
456, [L4]+. Anal. Calcd for: C66H58Cl2N2O2Pd: C, 72.83; H, 5.37; N, 2.57. Found: C,
72.67; H, 5.41; N, 2.51. Tm: 282.4 oC.
4.2.5 Synthesis of [2,6-(CHPh2)2-4-(Cl) C6H2NH]2PdCl2 (C5)
1H NMR (400 MHz, CDCl3): δ (ppm) 7.29 (m, Ar-H, 7H), 7.25 (m, Ar-H, 33H), 6.63
(s, Ar-H, 4H), 6.40 (s, CHPh2, 4H), 4.15 (s, NH2, 4H). 13C NMR (100 MHz, CDCl3):
δ (ppm) 140.4, 138.3, 134.9, 131.4, 129.6, 129.0, 128.9, 127.6, 51.8. ESI-MS. m/z:
460, [L5]+. Anal. Calcd for: C64H52Cl4N2Pd: C, 70.05; H, 4.78; N, 2.55. Found: C,
69.88; H, 4.86; N, 2.51. Tm: 283.2 oC.
4.3 General Procedure for Direct Arylation promoted by palladium complexes
Unless otherwise noted, the direct arylation reactions were carried out under
aerobic conditions. Reaction temperatures are reported as the temperature of the
heating the vessel unless otherwise stated. All solvents were not purified as received.
In the parallel reaction instrument containing tubes were charged with palladium
complexes, aryl bromide (1.0 mmol), heteroarene (1.0 mmol), K2CO3 (1.5 mmol),
PivOH (0.3 mmol) and 3 mL of DMAc. The reaction mixture was carried out at 100
oC for 24h. After completion of the reaction, the reaction mixture was cooled to room
temperature and 20 mL of water was added. The mixture was diluted with Et2O (5
mL), followed by extraction three times (3 × 5 mL) with Et2O. The organic layer was
dried with anhydrous MgSO4, filtered and evaporated under vacuum. The crude
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products were purified by silica-gel column chromatography using petroleum
ether-ethyl acetate (20/1, V/V) as an eluent, and the isolated yield was then calculated
based on the feeding of the aryl halide. The isolated corresponding products were
1
characterized by H NMR and 13C NMR, and the spectrums are reported in
Supporting Information.
4.3.1 4-(4-methylthiazol-5-yl)benzonitrile 3aa [3d]
1H NMR (400 MHz, CDCl3), δ (ppm): 8.76 (s, Ar-H, 1H), 7.74 (d, J=8.7 Hz, Ar-H,
2H), 7.58 (d, J=8.7 Hz, Ar-H, 2H), 2.58 (s, CH3, 3H). 13C NMR (100 MHz, CDCl3), δ
(ppm): 151.5, 150.0, 136.8, 132.5, 130.0, 129.7, 118.4, 111.5, 16.3.
4.3.2 5-(4-chlorophenyl)-4-methylthiazole 3ab [2k]
1H NMR (400 MHz, CDCl3), δ (ppm): 8.69 (s, Ar-H, 1H), 7.42 (m, Ar-H, 4H), 2.53 (s,
13
CH3, 3H). C NMR (100 MHz, CDCl3), δ (ppm): 150.4, 148.8, 133.9, 130.6, 130.4,
130.4, 129.1, 16.0.
4.3.3 4-(4-methylthiazol-5-yl)benzaldehyde3ac [2r]
1H NMR (400 MHz, CDCl3), δ (ppm): 10.03 (s, CHO, 1H), 8.74 (s, Ar-H, 1H), 7.94
(m, Ar-H, 2H), 7.62 (m, Ar-H, 2H), 2.58 (s, CH3, 3H). 13C NMR (100 MHz, CDCl3),
δ (ppm): 191.4, 151.4, 149.8, 138.2, 135.3, 130.7, 130.0, 129.6, 16.4.
4.3.4 4-methyl-5-(4-nitrophenyl)thiazole 3ad [3m]
1H NMR (400 MHz, CDCl3): δ (ppm) 8.78 (s, Ar-H, 1H), 8.30 (m, Ar-H, 2H), 7.63
(m, Ar-H, 2H), 2.59 (s, CH3, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 151.8, 150.4,
147.0, 138.8, 129.9, 129.8, 124.0, 16.4.
4.3.5 5-(2-fluorophenyl)-4-methylthiazole 3ae [3m]
17

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1H NMR (400 MHz, CDCl3): δ (ppm) 8.77 (s, Ar-H, 1H), 7.38 (m, Ar-H, 2H), 7.21
(m, Ar-H, 2H), 2.43 (s, CH3, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 160.9, 158.4,
151.7, 150.8, 132.1, 130.2 (d, J=8.2 Hz), 124.2 (d, J=3.7 Hz), 119.4 (d, J=15.2 Hz),
116.1(d, J=21.9 Hz), 15.9 (d, J=2.8 Hz).
4.3.6 5-(3-fluorophenyl)-4-methylthiazole 3af [3m]
1H NMR (400 MHz, CDCl3): δ (ppm) 8.71 (s, Ar-H, 1H), 7.41 (m, Ar-H, 1H), 7.22
(m, Ar-H, 1H), 7.16 (m, Ar-H, 1H), 7.08 (m, Ar-H, 1H), 2.54 (s, CH3, 3H). 13C NMR
(100 MHz, CDCl3): δ (ppm) 163.9, 161.4, 150.7, 149.1, 134.0 (d, J=8.2 Hz), 130.2 (d,
J=8.5 Hz), 125.0 (d, J=2.9 Hz), 116.1 (d, J=12.2 Hz), 114.8 (d, J=20.9 Hz), 16.1.
4.3.7 5-(4-fluorophenyl)-4-methylthiazole 3ag [3m]
1H NMR (400 MHz, CDCl3): δ (ppm) 8.67 (s, Ar-H, 1H), 7.41 (t, J=7.2 Hz, Ar-H,
2H), 7.13 (m, J=8.0 Hz, Ar-H, 2H), 2.50 (s, CH3, 3H). 13C NMR (100 MHz, CDCl3):
δ (ppm) 163.6, 161.1, 150.3, 148.5, 131.0 (d, J=8.1 Hz), 127.8 (d, J=3.4 Hz), 115.7 (d,
J=21.6 Hz), 15.9.
4.3.8 5-(3,5-bis(trifluoromethyl)phenyl)-4-methylthiazole 3ah [21]
1H NMR (400 MHz, CDCl3): δ (ppm) 8.78 (s, Ar-H, 1H), 7.87 (s, Ar-H, 3H) 2.55 (s,
CH3, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 151.7, 150.4, 134.3, 132.2 (q,
J=33.4 Hz), 129.2, 128.7, 123.0 (q, J=271.2 Hz), 121.6 (q, J=3.7 Hz), 16.0.
4.3.9 1-(4-(4-methylthiazol-5-yl)phenyl)ethanone 3ai [2x]
1H NMR (400 MHz, CDCl3): δ (ppm) 8.66 (m, Ar-H, 1H), 7.94 (m, Ar-H, 2H), 7.48
(m, Ar-H, 2H), 2.56 (m, CH3, 3H), 2.49 (m, CH3, 3H). 13C NMR (100 MHz, CDCl3):
δ (ppm) 197.1, 151.0, 149.3, 136.5, 135.9, 130.6, 129.0, 128.5, 26.4, 16.1.
18

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4.3.10 methyl 4-(4-methylthiazol-5-yl)benzoate 3aj [3m]
1H NMR (400 MHz, CDCl3): δ (ppm) 8.71 (s, Ar-H, 1H), 8.09 (m, Ar-H, 2H), 7.52
(m, Ar-H, 2H), 3.93 (s, CH3, 3H), 2.55 (s, CH3, 3H). 13C NMR (100 MHz, CDCl3): δ
(ppm) 166.5, 151.0, 149.4, 136.6, 130.9, 129.9, 129.3, 129.0, 52.2, 16.3.
4.3.11 4-methyl-5-(4-(trifluoromethyl)phenyl)thiazole 3ak [3m]
1H NMR (400 MHz, CDCl3): δ (ppm) 8.70 (s, Ar-H, 1H), 7.66 (m, Ar-H, 2H), 7.53
(m, Ar-H, 2H), 2.52 (s, CH3, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 151.0, 149.4,
135.6, 130.3, 129.8 (q, J=32.5 Hz), 129.4, 125.6 (q, J=3.6 Hz), 123.9 (q, J=270.4 Hz),
16.0.
4.3.12 4-methyl-5-phenylthiazole 3al [3m]
1H NMR (400 MHz, CDCl3), δ (ppm): 8.69 (s, Ar-H, 1H), 7.45 (m, Ar-H, 4H), 7.38
13
(m, Ar-H, 1H), 2.54 (s, CH3, 3H). C NMR (100 MHz, CDCl3), δ (ppm): 150.2,
148.4, 131.9, 131.9, 129.3, 128.7, 127.9, 16.0.
4.3.13 4-methyl-5-(p-tolyl)thiazole3am [2k]
1H NMR (400 MHz, CDCl3), δ (ppm): 8.70 (s, Ar-H, 1H), 7.39 (d, J=8.1 Hz, Ar-H,
13
2H), 7.30 (d, J=8.1 Hz, Ar-H, 2H), 2.58(s, CH3, 3H), 2.45 (s, CH3, 3H). C NMR
(100 MHz, CDCl3), δ (ppm): 150.0, 148.2, 137.9, 132.0, 129.4, 129.2, 129.0, 21.2,
16.0.
4.3.14 4-methyl-5-(m-tolyl)thiazole 3an [3m]
1H NMR (400 MHz, CDCl3): δ (ppm) 8.53 (s, Ar-H, 1H), 7.20 (m, Ar-H, 3H), 7.05
(m, Ar-H, 1H), 2.42 (s, CH3, 3H), 2.27 (s, CH3, 3H). 13C NMR (100 MHz, CDCl3): δ
(ppm) 150.0, 148.2, 138.2, 131.9, 131.6, 129.8, 128.5, 128.4, 126.2, 21.2, 15.9.
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4.3.15 4-methyl-5-(o-tolyl)thiazole 3ao [3m]
1H NMR (400 MHz, CDCl3), δ (ppm): 8.74 (s, Ar-H, 1H), 7.32 (m, Ar-H, 2H), 7.25
(m, Ar-H, 2H), 2.30 (s, CH3, 3H), 2.21 (s, CH3, 3H). 13C NMR (100 MHz, CDCl3), δ
(ppm): 151.0, 151.0, 149.7, 137.9, 131.3, 130.8, 130.3, 128.7, 125.7, 20.1, 15.4.
4.3.16 4-methyl-5-(naphthalen-1-yl)thiazole 3ap [3m]
1H NMR (400 MHz, CDCl3): δ (ppm) 8.67 (s, Ar-H, 1H), 7.75 (m, Ar-H, 2H), 7.55
(m, Ar-H, 1H), 7.36 (m, Ar-H, 4H), 2.14 (s, CH3, 3H). 13C NMR (100 MHz, CDCl3):
δ (ppm) 151.4, 150.6, 133.5, 132.3, 129.2, 129.0, 128.9, 128.6, 128.3, 126.5, 126.0,
125.4, 125.0, 15.6.
4.3.17 5-(4-methoxyphenyl)-4-methylthiazole 3aq [2k]
1H NMR (400 MHz, CDCl3): δ (ppm) 8.52 (s, Ar-H, 1H), 7.26 (m, Ar-H, 2H) 6.85 (m,
13
Ar-H, 2H), 3.72 (s, CH3, 3H), 2.41 (s, CH3, 3H). C NMR (100 MHz, CDCl3): δ
(ppm) 159.2, 149.5, 147.7, 131.6, 130.3, 123.9, 114.0, 55.1, 15.8.
4.3.18 5-(3-methoxyphenyl)-4-methylthiazole 3ar [2k]
1H NMR (400 MHz, CDCl3): δ (ppm) 8.64 (m, Ar-H, 1H), 7.32 (m, Ar-H, 1H), 7.00
13
(m, Ar-H, 2H), 6.89 (m, Ar-H, 1H), 3.80 (s, CH3, 3H), 2.52 (s, CH3, 3H). C NMR
(100 MHz, CDCl3): δ (ppm) 159.5, 150.1, 148.4, 133.0, 131.6, 129.6, 121.6, 114.9,
113.1, 55.1, 16.0.
4.3.19 4-(2, 4-dimethylthiazol-5-yl)benzonitrile 3ba [22]
1H NMR (400 MHz, CDCl3), δ (ppm): 7.68 (m, Ar-H, 2H), 7.50 (m, Ar-H, 2H), 2.68
(s, CH3, 3H), 2.46 (s, CH3, 3H). 13C NMR (100 MHz, CDCl3), δ (ppm): 164.7, 148.7,
137.1, 132.3, 129.4, 129.3, 118.5, 110.9, 19.1, 16.3.
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4.3.20 5-(4-chlorophenyl)-2, 4-dimethylthiazole 3bb
1H NMR (400 MHz, CDCl3), δ (ppm): 7.35 (m, Ar-H, 4H), 2.65 (s, CH3, 3H), 2.41 (s,
13
CH3, 3H). C NMR (100 MHz, CDCl3), δ (ppm): 163.5, 147.3, 133.5, 130.7, 130.2,
130.0, 128.7, 19.0, 15.9. ESI-MS. m/z: 224 [M+]
4.3.21 4-(2, 4-dimethylthiazol-5-yl)benzaldehyde 3bc
1H NMR (400 MHz, CDCl3), δ (ppm): 10.01 (s, CHO, 1H), 7.91 (m, Ar-H, 2H), 7.57
(m, Ar-H, 2H), 2.69 (s, CH3, 3H), 2.49 (s, CH3, 3H). 13C NMR (100 MHz, CDCl3), δ
(ppm): 191.4, 164.6, 148.5, 138.6, 135.0, 130.1, 130.0, 129.3, 19.1, 16.4. ESI-MS.
m/z: 218 [M+]
4.3.22 methyl 4-(2, 4-dimethylthiazol-5-yl)benzoate 3bj
1H NMR (400 MHz, CDCl3), δ (ppm): 8.05 (m, Ar-H, 2H), 7.46 (m, Ar-H, 2H), 3.91
(m, CH3, 3H), 2.67 (s, CH3, 3H), 2.47 (m, CH3, 3H). 13C NMR (100 MHz, CDCl3), δ
(ppm): 166.5, 164.1, 148.1, 137.0, 130.3, 129.8, 128.9, 128.7, 52.1, 19.1, 16.3.
ESI-MS. m/z: 248 [M+]
4.3.23 2, 4-dimethyl-5-phenylthiazole 3bl [2g]
1H NMR (400 MHz, CDCl3), δ (ppm): 7.38 (m, Ar-H, 4H), 7.31 (m, Ar-H, 1H), 2.65
(s, CH3, 3H), 2.44 (s, CH3, 3H). 13C NMR (100 MHz, CDCl3), δ (ppm): 163.1, 146.9,
132.2, 131.2, 129.0, 128.5, 127.4, 18.9, 15.9.
4.3.24 2, 4-dimethyl-5-(p-tolyl)thiazole 3bm [23]
1H NMR (400 MHz, CDCl3), δ (ppm): 7.29 (m, Ar-H, 2H), 7.20 (m, Ar-H, 2H), 2.65
13
(s, CH3, 3H), 2.44 (s, CH3, 3H), 2.36 (s, CH3, 3H). C NMR (100 MHz, CDCl3), δ
(ppm): 162.7, 146.5, 137.2, 131.2, 129.2, 129.2, 128.8, 21.0, 18.9, 15.8.
21

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Acknowledgements
The authors gratefully thank the Foundation for Distinguished Young Talents in
Higher Education of Guangdong and National Science Foundation of China (No.
Yq2013101, No. 51203026, No. 2012-LYM0080) for the financial support.
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