Arylation of heterocyclic compounds by benzimidazole-based N-heterocyclic carbene-palladium(II) complexes

Article abstract of DOI:10.1016/j.jorganchem.2019.121076

Specific C–H bond can be activated for arylation using aryl halide without the aid of directing the group in the case of electron-rich heteroarenes. The ability to readily generate halo substituted arylated heteroarenes is important in organic chemistry s

Full text of DOI:10.1016/j.jorganchem.2019.121076

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Arylation of heterocyclic compounds by benzimidazole-based N-heterocyclic carbene-
palladium(II) complexes
Neslihan Sahin, Nevin Gürbüz, Hande Karabıyık, Hasan Karabıyık, İsmail Özdemir
PII:
S0022-328X(19)30519-4
DOI:
https://doi.org/10.1016/j.jorganchem.2019.121076
JOM 121076
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 25 October 2019
Revised Date: 12 December 2019
Accepted Date: 13 December 2019
Please cite this article as: N. Sahin, N. Gürbüz, H. Karabıyık, H. Karabıyık, İ. Özdemir, Arylation of
heterocyclic compounds by benzimidazole-based N-heterocyclic carbene-palladium(II) complexes,
Journal of Organometallic Chemistry (2020), doi: https://doi.org/10.1016/j.jorganchem.2019.121076.
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Arylation of Heterocyclic Compounds by Benzimidazole-based N-Heterocyclic Carbene-
Palladium(II) Complexes
Neslihan Sahin1,2,3, Nevin Gürbüz2,3, Hande Karabıyık4, Hasan Karabıyık4, Đsmail
Özdemir2,3,*
1Cumhuriyet University, Faculty of Education, Department of Basic Education, 58040, Sivas, Turkey
2Đnönü University, Faculty of Science and Art, Department of Chemistry, 44280 Malatya, Turkey
3Inönü University, Catalysis Research and Application Center, 44280, Malatya, Turkey
4Dokuz Eylül University, Faculty of Science and Art, Department of Physics, Đzmir, Turkey
Dedicated to 120 years Celebration of Professor Aleksandr Nikolaevich Nesmeyanov.
Abstract
Specific C-H bond can be activated for arylation using aryl halide without the aid of directing
the group in the case of electron-rich heteroarenes. The ability to readily generate halo
substituted arylated heteroarenes is important in organic chemistry since these species are
important building blocks for biochemists. In this manuscript, we report the synthesis of
PEPPSI type-novel benzimidazole-based N-heterocyclic carbene-palladium(II) complexes
1
13
(2a-e). All of the new compounds were fully characterized by H, C{1H} NMR and FT-IR
spectra. The structures of 2c, 2d, and 2e were determined by X-ray crystallography and the
prepared complexes (2a-e) were investigated as catalysts for the direct arylation of 2-n-
propylthiazole, 4,5-dimethylthiazole and 2-acetylthiophene with various aryl bromides. And
showed High catalytic activity for arylation was seen reaction using only 0.5 mol% catalyst
for 1 h.
Keywords: N-heterocyclic carbene, benzimidazole, PEPPSI, direct arylation, thiophenes,
thiazoles.
1. Introduction
Both thiophene and thiazole derivatives have attracted attention due to their important
biological activity. For example, the 2-arylthiophene derivative Canagliflozin is a drug used
in the treatment of type 2 diabetes, and Duloxetine is used against major depressive disorder
diabetes. Motapizone is used in the treatment of against platelet aggregation diabetes and
Tiemonium and Penthienate are antimuscarinics [1-3]. Sulfathiazole is an antimicrobial drug,
1

Ritonavir is used as an antiretroviral drug. Abafungin is used an antifungal drug, and
Bleomycine and Tiazofurin are antineoplastic drugs [4]. Some phenanthrothiazoles display
interesting potential pharmacological activity [5] (Figure 1).
N
R
N
H
N
S
S
S
F
O
O
N
N
H
Motapizone
Canagliflozin
Duloxetine
H3C
H
N
S
N H
O
O
HN
O S O
CH3
N
N
S
H
S
N
HO
O
NH
N
HN
H
H
HO
Thiazofurin
OH
Sülfathiazole
Abafungin
Figure 1. Examples of bioactive thiophene or thiazole derivatives.
Since they have such important biological activity, the discovery of more direct and selective
procedures to synthesize arylated thiophene and thiazole derivatives is an important topic in
synthetic organic chemistry. Classical methods for the synthesis of such compounds are
metal-catalyzed cross-coupling reactions such as Suzuki-, Stille-, Negishi- or Kumada-type
reactions [6-9]. However, such reactions require the pre-synthesis of organometallic
derivatives and they produce stoichiometric amounts of metallic salts as byproducts which
could be harmful in pharmaceutical, agrochemical, and related biological applications [10].
Firstly, In 1985-1992, Ohta et al. first reported the direct arylation of heteroaromatics with
aryl halides using a C−H activation strategy through the cleavage of two C−H bonds, which is
an environmentally and economically more attractive method using in which Pd(PPh3)4 was
used as the catalyst and dimethylacetamide (DMAc) as the solvent [11-13]. Since then,
palladium-catalyzed direct arylation has been successfully applied for the arylation of
heterocycles such as arenes, thiophenes, indoles, indolizines, azoles, pyridines, and furans
[14-19]. Although the heterocyclic compounds are arylated at positions C2, C3, C4 and C5,
both experimental studies and computational studies have shown that predominantly, either
2

C2-arylated product or mixtures of C2- and C5-arylated products have been obtained.
According to computational studies, the reason for this selectivity is the free energy of
activation for C-H bonds [20, 21]. When the C2‐ and C5‐positions are blocked, the C3‐ and
C4‐positions of heterocycles are arylated (Figure 2).
High regioselectivity in favour of C2-, C5-position
X
2
H
H
5
3
4
H
H
If C2, C5-positions are blocked, C3, C4-positions are arlylated.
Figure 2. The most favourable positions of heterocycles for direct arylations.
Palladium complexes containing two halides, an unstable pyridine derivative and a bulky
NHC ligand were defined as "Pyridine Enhanced Precatalyst Preparation Stabilization and
Initiation" (PEPPSI) by Organ [22, 23]. In recent years some studies on the direct arylation
reaction of PEPPSI type palladium-N-heterocyclic carbene (NHC) complexes have been
published [24, 25]. These studies have shown that these complexes exhibit very good catalytic
activity. PEPPSI complexes have gained real practical importance in numerous catalytic
processes because of the ease of handling, and that they are air and moisture stable.
Allyl substituents on such ligand precursors are capable of coordinating to the metal centre
leading to a coordination environment made up of sp2-carbon donors [26, 27]. Inspired by
this, we became interested in the coordination chemistry of N-heterocyclic carbenes bearing
N-methallyl substituents. Herein, synthesis and characterization of methallyl substitued
benzimidazole-based ligand precursors (1a-e) and their PEPPSI-type palladium-NHC
complexes (2a-e) were described. These compounds were characterized using
by
spectroscopic techniques, and the structure of 2c, 2d, and 2e were determined with by single-
crystal X-ray diffraction. The catalytic activities of new Pd(II)-NHC complexes (2a-e) were
also investigated and they showed good activity as catalysts in the direct arylation reaction.
3

2. Experimental
2. 1. Materials and measurements
All experiments were performed under argon in flame-dried glassware using standard Schlenk
techniques. All reagents were purchased from Sigma Aldrich Co. (Dorset, UK). The solvents
used were purified by distillation over the drying agents indicated and were transferred under
argon. Melting points were determined using the Electrothermal 9100 melting point detection
apparatus in capillary tubes and the melting points are reported as uncorrected values. Fourier
transform infrared (FT-IR) spectra were recorded in the range of 400–4000 cm−1 on Perkin
1
13
Elmer Spectrum 100 FT-IR. H NMR and C{1H} NMR spectra were taken using a Bruker
As 400 Mercury spectrometer operating at 400 MHz (1H), 100 MHz (13C{1H}) in CDCl3 with
1
tetramethylsilane as the internal reference. H peaks are labeled as singlet (s), doublet (d),
triplet (t) and multiplet (m). Chemical shifts and coupling constants are reported in ppm and
in Hz, respectively. Catalytic reactions were observed on an Agilent 6890ꢀN GC system by
GC-FID with an HP-5 column of 30ꢀm length, 0.32ꢀmm diameter and 0.25ꢀꢁm film thickness.
Column chromatography was performed using silica gel 60 (70–230 mesh). All the
measurements were taken at room temperature for freshly prepared solutions.
2.2. Synthesis
All the compounds were prepared under argon gas atmosphere. Benzimidazole-based ligand
precursors (1a-e) and their corresponding Pd(II)-NHC complexes (2a-e) were synthesized
according to the literature [28]. Ligand 1a and 1e were published in our previous study [29,
30].
2.3. General procedure for the preparation ligand precursors (1a-e)
Benzimidazole (10 mmol) was added to a solution of NaH (10 mmol) in dry THF (30 mL),
the mixture was stirred for 1 h at room temperature. β-Methallylchloride (10.1 mmol) was
o
added dropwise upon to the obtained solution and heated for 24 h at 60 C. Then, the THF
was removed under the vacuum. Dichloromethane (50 mL) was added upon to the solid. The
mixture was filtered and the obtained clear solution was concentrated under vacuum. Then the
solution was distilled and 1-(β-methallyl)benzimidazole was obtained. The 1-(β-
methallyl)benzimidazole (1 mmol) and alkyl halide (1 mmol) were stirred in DMF (5 mL) for
o
24 h at 80 C. White product was precipitated then after following the completion of the
process, the solution was filtered, the solid was rinsed out with diethyl ether and dried under
vacuum. The crude product was recrystallized from dichloromethane/diethyl ether.
4

2.3.1. 1-(β-Methallyl)-3-(4-methylbenzyl)benzimidazolium chloride, 1a
1
Yield: 82%, mp 195-197 °C; FT-IR ν(CN): 1551 cm-1; H NMR (400 MHz, CDCl3) δ (ppm):
1.72 (s, 3H, NCH2C(CH3)CH2), 2.23 (s, 3H, CH2C6H4-4-CH3), 4.90 (s, 1H,
NCH2C(CH3)CH2), 5.04 (s, 1H, NCH2C(CH3)CH2), 5.21 (s, 2H, NCH2C(CH3)CH2), 5.78 (s,
2H, CH2C6H4-4-CH3), 7.09 (d, 2H, Ar-H, J = 8 Hz), 7.31 (d, 2H, Ar-H, J = 8 Hz), 7.45-7.51,
13
7.53-7.55 and 7.59-7.61 (m, 4H, Ar-H), 11.74 (s, 1H, NCHN). C{1H} NMR (100 MHz,
CDCl3) δ (ppm): 19.7 (NCH2C(CH3)CH2), 21.2 (CH2C6H4-4-CH3), 51.4 (CH2C6H4-4-CH3),
53.6 (NCH2C(CH3)CH2), 116.1 (NCH2C(CH3)CH2), 139.2 (NCH2C(CH3)CH2), 113.7, 113.9,
127.1, 128.2, 128.3, 129.8, 130.0, 131.2, 131.7 and 137.5 (Ar-C), 144.0 (NCHN).
2.3.2. 1-(β-Methallyl)-3-(4-ter-butylbenzyl)benzimidazolium bromide, 1b
1
Yield: 89%, mp 190-192 °C; FT-IR ν(CN): 1553 cm-1; H NMR (400 MHz, CDCl3) δ (ppm):
1.27 (s, 9H, CH2C6H4-4-C(CH3)3), 1.80 (s, 3H, NCH2C(CH3)CH2), 4.99 (s, 1H,
NCH2C(CH3)CH2), 5.13 (s, 1H, NCH2C(CH3)CH2), 5.29 (s, 2H, NCH2C(CH3)CH2), 5.86 (s,
2H, CH2C6H4-4-C(CH3)3), 7.28 (d, 2H, Ar-H, J = 8 Hz), 7.45 (d, 2H, Ar-H, J = 8 Hz), 7.56-
7.58, 7.66-7.71 (m, 4H, Ar-H), 11.60 (s, 1H, NCHN). 13C{1H} NMR (100 MHz, CDCl3) δ
(ppm): 19.9 (NCH2C(CH3)CH2), 31.2 (CH2C6H4-4-C(CH3)3), 34.7 (CH2C6H4-4-C(CH3)3),
51.2 (CH2C6H4-4-C(CH3)3), 53.6 (NCH2C(CH3)CH2), 116.3 (NCH2C(CH3)CH2), 137.4
(NCH2C(CH3)CH2), 113.7, 113.9, 126.4, 127.2, 127.3, 128.0, 129.6, 131.3, 131.6 and 152.5
(Ar-C), 143.2 (NCHN).
2.3.3. 1-(β-Methallyl)-3-(2,4,6-trimethylbenzyl)benzimidazolium chloride, 1c
1
Yield: 87%, mp 226-227 °C; FT-IR ν(CN): 1553 cm-1; H NMR (400 MHz, CDCl3) δ (ppm):
1.77 (s, 3H, NCH2C(CH3)CH2), 2.29 (s, 3H, CH2C6H2-2,4,6-(CH3)3), 2.32 (s, 6H, CH2C6H2-
2,4,6-(CH3)3), 4.89 (s, 1H, NCH2C(CH3)CH2), 5.09 (s, 1H, NCH2C(CH3)CH2), 5.30 (s, 2H,
NCH2C(CH3)CH2), 5.88 (s, 2H, CH2C6H2-2,4,6-(CH3)3), 6.93 (s, 2H, Ar-H), 7.21 (d, 1H, Ar-
H, J = 8 Hz), 7.44 (t, 1H, Ar-H, J = 8 Hz), 7.54 (t, 1H, Ar-H, J = 8 Hz ), 7.66 (d, 1H, Ar-H, J
= 8 Hz), 11.60 (s, 1H, NCHN). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm): 19.7
(NCH2C(CH3)CH2), 20.2 and 21.1 (CH2C6H2-2,4,6-(CH3)3), 47.4 (CH2C6H2-2,4,6-(CH3)3),
53.5 (NCH2C(CH3)CH2), 115.6 (NCH2C(CH3)CH2), 137.6 (NCH2C(CH3)CH2), 113.6, 113.8,
125.0, 127.0, 127.2, 130.2, 131.4, 131.7, 137.9 and 139.8 (Ar-C), 144.4 (NCHN).
2.3.4. 1-(β-Methallyl)-3-(2,3,5,6-tetramethylbenzyl)benzimidazolium chloride, 1d
1
Yield: 88%, mp 235-236 °C; FT-IR ν(CN): 1557 cm-1; H NMR (400 MHz, CDCl3) δ (ppm):
1.69 (s, 3H, NCH2C(CH3)CH2), 2.19 (s, 12H, CH2C6H-2,3,5,6-(CH3)4), 4.80 (s, 1H,
NCH2C(CH3)CH2), 5.01 (s, 1H, NCH2C(CH3)CH2), 5.28 (s, 2H, NCH2C(CH3)CH2), 5.83 (s,
5

2H, CH2C6H-2,3,5,6-(CH3)4), 7.01 (s, 1H, Ar-H), 7.21 (d, 1H, Ar-H, J = 8 Hz), 7.40 (t, 1H,
Ar-H, J = 8 Hz), 7.46 (t, 1H, Ar-H, J = 8 Hz ), 7.60 (d, 1H, Ar-H, J = 8 Hz), 11.29 (s, 1H,
13
NCHN). C{1H} NMR (100 MHz, CDCl3) δ (ppm): 16.1 (CH2C6H-2,3,5,6-(CH3)4), (19.7
(NCH2C(CH3)CH2), 20.6 (CH2C6H-2,3,5,6-(CH3)4), 47.9 (CH2C6H-2,3,5,6-(CH3)4), 53.5
(NCH2C(CH3)CH2), 115.5 (NCH2C(CH3)CH2), 137.7 (NCH2C(CH3)CH2), 113.7, 127.0,
127.2, 127.6, 131.5, 131.7, 133.6, 134.0 and 135.2 (Ar-C), 144.1 (NCHN).
2.3.5. 1-(β-Methallyl)-3-(2,3,4,5,6-pentamethylbenzyl)benzimidazoliumchloride, 1e
o
1
Yield: 84%, mp 201-202 C; ν(CN): 1556 cm-1; H NMR (399.9 MHz, CDCl3) δ (ppm): 1.75
(s, 3H, NCH2C(CH3)CH2), 2.29, 2.27 and 2.24 (s, 15H, CH2C6(CH3)5-2,3,4,5,6), 2.49 (s br,
2H, H2O), 4.85 (s, 1H, NCH2C(CH3)CH2), 5.06 (s, 1H, NCH2C(CH3)CH2), 5.36 (s, 2H,
NCH2C(CH3)CH2), 5.87 (s, 2H, CH2C6(CH3)5-2,3,4,5,6), 7.33-7.29 (m, 2H, NC6H4N), 7.57-
13
7.47 (m, 1H, NC6H4N), 7.84 (d, 1H, NC6H4N, J = 8 Hz), 11.04 (s, 1H, NCHN). C{1H}
NMR (100.5 MHz, CDCl3) δ (ppm): 17.0, 17.1 and 17.3 (CH2C6(CH3)5-2,3,4,5,6), 19.7
NCH2C(CH3)CH2), 48.4
(CH2C6(CH3)5-2,3,4,5,6), 53.5
(NCH2C(CH3)CH2), 115.3
(NCH2C(CH3)CH2), 137.4 (NCH2C(CH3)CH2), 113.7, 124.9, 127.0, 127.1, 131.5, 131.8,
133.6, 134.0 and 137.8 (NC6H4N and CH2C6(CH3)5-2,3,4,5,6), 143.8 (NCHN).
2.4. Preparation of Pd-NHC complex (2a-e)
Ligand precursors (1a-e) (1 mmol), PdCl2 (1 mmol) and K2CO3 (5 mmol and ) (and excess of
KBr for 2b) in pyridine (5 mL) were stirred at 80 0C for 4 h. After the reaction was finished,
pyridine was removed under vacuum. CH2Cl2 (10 mL) was added to the resulting solid
mixture. The solution was filtered through a silica gel and celite layer in order to remove
unreacted PdCl2. The solvent in the reaction medium was removed under vacuum and dried.
The crude product was crystallized in CH2Cl2/pentane and bright yellow Pd-NHC complexes
(2a-e) were obtained.
2.4.1.
Dichloro[1-(β-methallyl)-3-(4-methylbenzylbenzimidazole-2-ylidene]pyridine
palladium(II), 2a
o
1
Yield: 76%, mp 158-160 C; FT-IR ν(CN): 1407 cm-1; H NMR (400 MHz, CDCl3) δ (ppm):
1.55 (s, 3H, NCH2C(CH3)CH2), 2.32 (s, 3H, CH2C6H4-4-CH3), 5.11 (s, 1H,
NCH2C(CH3)CH2), 5.15 (s, 1H, NCH2C(CH3)CH2), 5.58 (s, 2H, NCH2C(CH3)CH2), 6.20 (s,
2H, CH2C6H4-4-CH3), 7.09-7.21 (m, 5H, Ar-H), 7.35 (t, 2H, Ar-H, J = 8 Hz), 7.41 (d, 1H,
Ar-H, J = 8 Hz), 7.47 (d, 2H, Ar-H, J = 8 Hz), 7.77 (t, 1H, Ar-H, J = 8 Hz), 9.0 (tt, 2H,
2
C5H5, J = 4 Hz, J = 4 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm): 20.4
(NCH2C(CH3)CH2),
21.2
(CH2C6H4-4-CH3),
53.0
(CH2C6H4-4-CH3),
55.0
6

(NCH2C(CH3)CH2), 114.7 (NCH2C(CH3)CH2), 137.9 (NCH2C(CH3)CH2), 111.1, 111.5,
123.2, 124.5, 127.9, 129.5, 132.1, 134.9, 138.1, 139.4 and 151.3 (Ar-C), 164.6 (Pd-Ccarb).
2.4.2.
Dibromo[1-(β-methallyl)-3-(4-ter-butylbenzylbenzimidazole-2-ylidene]pyridine
palladium(II), 2b
o
1
Yield: 71%, mp 147-149 C; FT-IR ν(CN): 1403 cm-1, H NMR (400 MHz, CDCl3) δ (ppm):
1.27 (s, 9H, CH2C6H4-4-C(CH3)3), J = 8 Hz), 1.91 (s, 3H, NCH2C(CH3)CH2), 5.14 (s, 1H,
NCH2C(CH3)CH2), 5.15 (s, 1H, NCH2C(CH3)CH2), 5.54 (s, 2H, NCH2C(CH3)CH2), 6.16 (s,
2H, CH2C6H4-4-C(CH3)3), 7.09-7.10 (m, 2H, Ar-H), 7.16-7.20 (m, 1H, Ar-H), 7.31-7.42 (m,
5H, Ar-H), 7.54 (d, 2H, Ar-H, J = 8 Hz), 7.75 (tt, 1H, Ar-H, J = 8 Hz, 2J =4 Hz), 9.04 (tt, 2H,
2
C5H5, J = 4 Hz, J = 4 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm): 20.7
(NCH2C(CH3)CH2), 31.3 (CH2C6H4-4-C(CH3)3), 34.5 (CH2C6H4-4-C(CH3)3), 53.5 (31.3
(CH2C6H4-4-C(CH3)3), 55.5 (NCH2C(CH3)CH2), 115.0 (NCH2C(CH3)CH2), 137.9
(NCH2C(CH3)CH2), 111.1, 111.6, 123.1, 124.5, 125.0, 125.7, 127.8, 131.9, 134.5, 135.1,
137.9, 139.2, 151.1 and 152.6 (Ar-C), 164.1 (Pd-Ccarb).
2.4.3. Dichloro[1-(β-methallyl)-3-(2,4,6-trimethylbenzylbenzimidazole-2-ylidene]pyridine
palladium(II), 2c
o
1
Yield: 76%, mp 206-207 C; FT-IR ν(CN): 1399 cm-1; H NMR (400 MHz, CDCl3) δ (ppm):
1.82 (s, 3H, NCH2C(CH3)CH2), 2.26 (s, 9H, CH2C6H2-2,4,6-(CH3)3), 5.01 (s, 1H,
NCH2C(CH3)CH2), 5.06 (s, 1H, NCH2C(CH3)CH2), 5.52 (s, 2H, NCH2C(CH3)CH2), 6.17 (s,
2H, CH2C6H2-2,4,6-(CH3)3), 6.41 (d, 1H, Ar-H, J = 8 Hz), 6.86-6.91 (m, 3H, Ar-H), 7.06 (t,
2
1H, Ar-H, J = 8 Hz), 7.30 (t, 3H, Ar-H, J = 8 Hz), 7.71 (tt, 1H, Ar-H, J = 8 Hz, J = 4 Hz),
2
13
8.92 (tt, 2H, C5H5, J = 4 Hz, J = 4 Hz). C{1H} NMR (100 MHz, CDCl3) δ (ppm): 20.4
(NCH2C(CH3)CH2), 20.8 (CH2C6H2-2,4,6-(CH3)3), 21.1 (CH2C6H2-2,4,6-(CH3)3), 50.2
(CH2C6H2-2,4,6-(CH3)3), 54.9 (NCH2C(CH3)CH2), 114.6 (NCH2C(CH3)CH2), 138.1
(NCH2C(CH3)CH2), 111.0, 111.5, 122.9, 123.2, 124.5, 127.6, 129.7, 134.6, 134.8, 138.5,
138.7, 139.5 and 151.3 (Ar-C), 164.4 (Pd-Ccarb).
2.4.4.
Dichloro[1-(β-methallyl)-3-(2,3,5,6-tetramethylbenzylbenzimidazole-2-
ylidene]pyridinepalladium(II), 2d
o
1
Yield: 79%, mp 228-230 C; FT-IR ν(CN): 1407 cm-1, H NMR (400 MHz, CDCl3) δ (ppm):
1.90 (s, 3H, NCH2C(CH3)CH2), 2.25 (s, 6H, CH2C6H-2,3,5,6-(CH3)4), 2.25 (d, 6H, CH2C6H-
2,3,5,6-(CH3)4, J = 4 Hz), 5.07 (s, 1H, NCH2C(CH3)CH2), 5.13 (s, 1H, NCH2C(CH3)CH2),
5.59 (s, 2H, NCH2C(CH3)CH2), 6.28 (s, 2H, CH2C6H-2,3,5,6-(CH3)4), 6.44 (d, 1H, Ar-H, J =
7

8 Hz), 6.95 (t, 1H, Ar-H, J = 8 Hz), 7.08 (s, br, 1H, Ar-H), 7.13 (t, 1H, Ar-H, J = 8 Hz), 7.34-
7.37 (m, 3H, Ar-H), 7.77 (tt, 1H, Ar-H, J = 8 Hz, 2J = 4 Hz), 8.95 (tt, 2H, C5H5, J = 4 Hz, 2J
= 4 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm): 16.5 (CH2C6H-2,3,5,6-(CH3)4), 20.4
(NCH2C(CH3)CH2), 20.6 (CH2C6H-2,3,5,6-(CH3)4), 50.7 (CH2C6H-2,3,5,6-(CH3)4), 54.9
(NCH2C(CH3)CH2), 114.5 (NCH2C(CH3)CH2), 138.1 (NCH2C(CH3)CH2), 111.0, 111.4,
122.8, 123.2, 124.5, 130.6, 132.5, 134.3, 134.7, 135.0, 139.4 and 151.2 (Ar-C), 164.4 (Pd-
Ccarb).
2.4.5.
Dichloro[1-(β-methallyl)-3-(2,3,4,5,6-pentamethylbenzylbenzimidazole-2-
ylidene]pyridine palladium(II), 2e
o
1
Yield: 78%, mp 214-215 C; FT-IR ν(CN): 1395 cm-1; H NMR (400 MHz, CDCl3) δ (ppm):
1.90 (s, 3H, NCH2C(CH3)CH2), 2.23 (s, 6H, CH2C6-2,3,4,5,6-(CH3)5), 2.31 (s, 9H, CH2C6-
2,3,4,5,6-(CH3)5), 5.08 (s, 1H, NCH2C(CH3)CH2), 5.13 (s, 1H, NCH2C(CH3)CH2), 5.59 (s,
2H, NCH2C(CH3)CH2), 6.30 (s, 2H, CH2C6-2,3,4,5,6-(CH3)5), 6.42 (d, 1H, Ar-H, J = 8 Hz),
6.93 (t, 1H, Ar-H, J = 8 Hz), 7.11 (t, 1H, Ar-H, J = 8 Hz), 7.34-7.37 (m, 3H, Ar-H), 7.77 (tt,
1H, Ar-H, J = 8 Hz, 2J = 4 Hz), 8.97 (tt, 2H, C5H5, J = 4 Hz, 2J = 4 Hz). 13C{1H} NMR (100
MHz, CDCl3) δ (ppm): 16.9 (CH2C6-2,3,4,5,6-(CH3)5), 17.3 (CH2C6-2,3,4,5,6-(CH3)5), 17.5
(CH2C6-2,3,4,5,6-(CH3)5), 20.4 (NCH2C(CH3)CH2), 51.4 (17.3 (CH2C6-2,3,4,5,6-(CH3)5),
55.0 (NCH2C(CH3)CH2), 114.5 (NCH2C(CH3)CH2), 138.0 (NCH2C(CH3)CH2), 110.9, 111.6,
122.7, 123.1, 124.4, 127.9, 133.1, 134.6, 134.7, 134.8, 135.9, 139.5 and 151.2 (Ar-C), 164.2
(Pd-Ccarb).
2.5. X-ray crystallography
Suitable single crystals of the complexes 2c-e were selected for data collection performed on
an Oxford Xcalibur Eos diffractometer using graphite monochromated MoKα radiation
(λ=0.71073 Å). Details of the data collection conditions and refinement processes are
summarized in Table 1. The collected intensities of three crystals were corrected for Lorentz
and polarization factors. Analytical absorption correction was performed by CrysAlisPro
1.171.38.41 software. Cell parameters were also determined by CrysAlisPro software [31].
Using Olex2 [32], the structures of 2c-e were resolved with the ShelXT structure solution
program using Intrinsic Phasing and refined with the ShelXL [33] refinement package using
Least Squares minimization. All non-hydrogen atoms were refined anisotropically. All H
atoms were positioned geometrically and refined using a riding model, fixing the aromatic
C—H distances at 0.93 Å, methylene C—H distances (except for C16) at 0.97 Å, methyl C—
H distances at 0.96 Å. C—H distances of double-bonded methylene C16 atom were fixed at
8

0.93 Å. Uiso(H) values were set to 1.2Ueq (1.5Ueq for the methyl group) of the parent atom.
Molecular diagrams were created using ORTEP3 [34]. For complex 2c, systematic absences
and intensity statistics indicated non-centrosymmetric P21 space group. However, an
inversion twin has occurred in the crystal structure of 2c. The command TWIN −1 0 0 0 −1 0
0 0 −1 2 was has applied to the data and the crystal structure was refined as a two-component
twin. After the final refinement, the Flack parameter was is 0.50(7).
Table 1. Crystal data and structure refinement parameters for complexes 2c-e
Complex 2c
1883977
C26H29Cl2N3Pd
560.82
294
Monoclinic
P 21
0.21×0.13×0.09
Prism/orange
8.4728(5)
17.0364(10)
17.5407(12)
90
94.232(6)
90
2525.0(3)
4 (Z'=2)
Complex 2d
1883972
C27H31Cl2N3Pd
574.89
304
Triclinic
P -1
0.40×0.35×0.23
Prism/orange
8.5236(6)
11.3683(7)
14.4251(9)
79.636(5)
84.577(5)
70.601(6)
1296.00(15)
2
Complex 2e
1883971
C28H33Cl2N3Pd
588.87
304
Monoclinic
C 2/c
0.60×0.50×0.30
Prism/orange
24.9764(10)
8.4773(3)
25.3075(9)
90
95.110(3)
90
5337.1(3)
8
CCDC number
Chemical formula
Formula weight
Temperature (K)
Crystal system
Space group
Crystal size (mm3)
Crystal shape/color
a (Å)
b (Å)
c (Å)
α (°)
β (°)
γ (°)
Volume (Å3)
Formula Z
Tmin, Tmax
0.872, 0.925
1144
0.762, 0.864
587
1.473
0.696, 0.793
2416
1.466
F(000)
Calc. Density (g cm−3) 1.475
Abs. Coeff. ꢁ (mm−1) 0.97
0.94
0.92
θ range (°)
Index ranges
3.002-2.502
3.194-26.367
−6 ≤ h ≤ 10
−11 ≤ k ≤ 14
−16 ≤ l ≤ 18
6850
5236
4318
303
0.019
3.233-25.681
−30 ≤ h ≤ 20
−9 ≤ k ≤ 10
−24 ≤ l ≤ 30
8848
5031
4086
314
0.019
−9 ≤ h ≤ 10
−20 ≤ k ≤ 20
−20 ≤ l ≤ 20
15662
8868
5979
Measured refls
Independent refls
Observed refls
No. of parameters
Rint
562
0.057
Goodness of Fit on F2 1.01
1.04
1.03
R indices [I>2σ(I)]
R1 = 0.067
R1 = 0.038
wR2 = 0.082
0.52, −0.51
0.0004
R1 = 0.037
wR2 = 0.103
0.55, −0.50
0.002
wR2 = 0.148
2.16, −0.56
<0.0001
ꢂρmax, ꢂρmin (eÅ−3)
(ꢂ/σ)max
9

2.6. General Procedure for the Arylation Reaction
KOAc (1.0 mmol), aryl bromide derivatives (1.0 mmol), heteroaryl derivatives (2-n-
propylthiazole, 4,5-dimethylthiazole and 2-acetylthiophene) (2.0 mmol), and Pd-NHC
complexes 2a-e (0.5 mol% or 1 mol%) were dissolved in N,N-dimethylacetamide (DMAc) (2
mL) in a small Schlenk tube under argon as described in the literature [35]. The reaction
mixture was stirred at the in appropriate temperature for 1 h then was cooled to room
temperature and the solvent was removed under vacuum. The obtained residue was purified
by column chromatography (silica gel 60–120 mesh) by using diethyl ether/n-hexane (1:5) as
eluent to afford the pure product. The purity of the compounds was checked by gas
chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). Conversions
were calculated by taking into account the conversion of aryl bromides to products.
3. Results and Discussion
3.1. Synthesis and characterization of benzimidazole-based ligand precursors and their
corresponding Pd‐NHC complexes
The benzimidazole-based ligand precursors (1a-e) were prepared by reaction of 1-(β-
methallyl)benzimidazole with 4-methylbenzyl chloride, 4-ter-butylbenzyl chloride, 2,4,6-
trimethylbenzyl chloride, 2,3,5,6-tetramethylbenzyl chloride, and 2,3,4,5,6-pentamethyl
chloride. These ligand precursors were prepared according to literature as shown in Scheme 1
[28, 36].
Scheme 1. Synthesis of benzimidazole-based ligand precursors (1a-e)
10

The synthetic route for the synthesis of Pd(II)-NHC complexes is shown in Scheme 2. Pd(II)-
NHC complexes (2a-e) were synthesized from the reaction of PdCl2, corresponding NHC
ligands (1a-e) and K2CO3 in pyridine at 80 oC. The NHC ligands and Pd(II)-NHC complexes
are air and moisture stable in the solid-state. All newly synthesized all compounds were
characterized by FT-IR, 1H NMR and 13C{1H} NMR spectroscopies. Also, For 2c, 2d and 2e
complexes were obtained as appropriate single crystals and the structure of these complexes
were was elucidated in by X-ray diffraction studies.
Scheme 2. Synthesis of benzimidazole-based NHC-palladium(II) complexes (2a-e)
At the FT-IR spectra for all ligand precursors (1a-e), (CN) vibrations of benzimidazolium
salts (1a-e) were assigned at around 1551-1557 cm-1. These vibrations at in the Pd(II)-NHC
complexes (2a-e) have were seen at around 1395-1407 cm-1. The electropositive palladium
center which pulls electron density towards itself and as a result, (CN) vibrations shift to the
11

lesser energy region in the complex by comparison ligand. These results are consistent with
the literature [37, 38].
1
NMR spectra of all the compounds were analyzed in CDCl3. In the H NMR spectra, acidic
protons (NCHN) for benzimidazolium salts (1a-e) were seen at 11.74, 11.60, 11.60, 11.29 and
11.04 ppm, respectively, as a characteristic sharp singlet. This acidic proton is lost when the
complex is formed. It was seen The disappearance of acidic protons was seen in the 1H NMR
spectra of 2a-e and this proves the of complexes formation. Another evidence of complex
formation, the carbene peak of NCN shifts much more to the downfield region compared to
the corresponding the benzimidazolium salt. In the 13C{1H} NMR spectra, NCHN carbon
peaks of ligand precursors (1a-e) were observed at 144.0, 143.2, 144.4, 144.1 and 143.8 ppm,
respectively. After complex formation, NCN carbene resonance on the Pd(II)-NHC
complexes (2a-e) which shifted much more to the downfield region was observed at 164.6,
164.1, 164.4, 164.4 and 164.2 ppm, respectively. These values are in agreement with reported
data for similar PEPPSI type Pd(II)-NHC complexes [28]. Further for more details of
complete NMR and FT-IR studies are given in supplementary information (Figure S1-S18).
3.2. Crystal structure description of 2c, 2d, and 2e complexes
The crystal structures of three similar Pd-NHC complexes, 2c, 2d and 2e, were determined by
using the X-ray single-crystal diffraction technique. There are two symmetry independent
molecules (referred to as mola and molb) in the asymmetric unit of the unit cell of 2c. An
ORTEP3 view of the asymmetric unit of 2c is also given in Figure 3(a). Both the complexes
2d and 2e have one molecule in their asymmetric unit as shown in Figure 3(b)-3(c).
It is expected that Palladium and its four coordination atoms are expected to form a square-
planar geometry. The Pd1/Cl1/Cl2/C1/N1 coordination plane of 2c and 2e are slightly
distorted from planarity. A maximum deviation of −0.028(1) Å for Pd1 atom is observed in 2e
and −0.083(7) Å for C1a in 2c. This distortion is more pronounced in 2d with a maximum
deviation of 0.123(1)Å for Cl2 atom. C1—Pd—N1 and Cl1—Pd—Cl2 bond angles are
expected to be linear. These values are in the range of 174.16(18)°-177.23(13)° for 2c and 2e.
Similar values are observed in the literature [39-41]. A conspicuous deviation from linearity
can be observed for 2d due to Cl2—Pd1—Cl1 angle being of 170.77(3)°. The other bond
angles in the coordination plane are almost perpendicular so as to adopt square geometry and
in the of range 86.3(5)°-92.96(9)° for 2c, 2d, and 2e. Selected bond distances, bond and
torsion angles can be found in Table 2. The main geometric differences in the molecular
structures of 2c, 2d, and 2e are (i) the orientation of methyl-substituted benzene ring and, (ii)
12

the conformation of aliphatic C13/C14/C15/C16 group. As shown in Figure 3(b)-(c), different
orientations of methyl-substituted benzene rings arise from the rotation of the substituted
benzene ring around the single C17—C18 and N3—C17 bonds. Torsion angles τ1 (N3—
C17—C18—C23) are −56.3(4)° for 2d an110.5(4)° for 2e.
(2a)
(2b)
(2c)
Figure 3. The asymmetric unit of (a) complex 2c, (b) complex 2d, (c) complex 2e showing
the atom-labelling scheme. Hydrogen atoms are omitted for clarity. Displacements ellipsoids
are drawn at the 50% probability level. Molb atoms of 2c have not been labeled for clarity.
13

According to Newman projections on the C17—C18 bond, molecule 2d and 2e adapt to –
sc(syn-clinal) conformations and +ac (anti-clinal), respectively. In the asymmetric unit of 2c
as shown in Figure 3(a), mola and molb having very similar bond distances are
conformational isomers. Superimposition of mola and molb including H atoms can be seen in
Figure 4. τ1 torsion angle is 113.0(14)° in mola, while it is 63.8(19)° in molb. They adapt to
+ac and +sc conformations, respectively. Conformational differences of aliphatic substituents
in each complex may predominantly may occur by virtue of rotations of related groups around
the single C13—C14 bond. τ2 (N2—C13—C14—C15) torsion angle is −168.4(4)° in 2d,
whereas it is −47.4(5)° in 2e. The corresponding values are 163.3(15)° and −167.5(15)° for
mola and molb, respectively. Dihedral angles among the mean planes of coordination plane,
benzimidazole, pyridine and C18/C23 rings of each molecule are also given in Table 2. The
Pd—Cl, Pd—N1 and Pd—C1 bond distances given in Table 2 and the other bond distances
are in a good agreement with similar Pd-NHC complexes in the literature [39-41]. In the
absence of classical hydrogen bonds, crystal structures of 2c-e are stabilized by weak
intermolecular interactions. Figures and details of 2c, 2d and 2e are given in the
supplementary information file (Table S1, Figure S19-S21).
Figure 4. An overlay view of conformers mola (green) and molb (red) in the asymmetric unit
of 2c. The root-mean-square fit of atomic positions is 6.052×10−2 Å.
14

Table 2. Selected bond distances (Å), bond, torsion, and dihedral angles (°) of 2c-e
2c-mola
2c-molb
2d
2e
Bond Distances
Pd—Cl1
2.284(5)
2.310(4)
2.120(13)
1.948(14)
2.292(5)
2.302(4)
2.132(15)
1.928(16)
2.317(9)
2.332(9)
2.122(3)
1.946(3)
2.307(9)
2.289(1)
2.108(3)
1.954(3)
Pd—Cl2
Pd—N1
Pd—C1
Bond and Torsion Angles
Cl2—Pd1—Cl1
C1—Pd1—N1
N1—Pd1—Cl1
N1—Pd1—Cl2
C1—N2—C13—C14
C1—N3—C17—C18
N3—C17—C18—C19
N2—C13—C14—C16
Dihedral Angles
A/B
174.16(18) 174.59(19)
170.77(3)
175.62(11)
92.79(8)
92.67(8)
−96.1(4)
−42.3(4)
126.1(3)
12.6(6)
176.32(4)
177.23(13)
92.96(9)
90.07(9)
107.2(4)
141.6(3)
−73.3(4)
137.8(4)
175.0(6)
92.2(4)
175.1(6)
91.2(4)
92.8(4)
93.0(4)
103.8(18)
152.8(14)
−63.2(17)
−20(2)
−106.7(17)
−138.9(15)
−117.9(15)
11(2)
73.7(3)
35.4(6)
71.7(5)
84.2(3)
76.0(3)
37.4(7)
68.0(5)
84.9(3)
72.47(5)
29.65(17)
78.18(12)
77.72(9)
67.64(6)
37.37(17)
75.70(13)
84.20(9)
A/C
B/C
B/D
A, B, C, D in dihedral angles section denote coordination plane, benzimidazole ring, pyridine and C18/C23 rings,
respectively.
3.3. Direct arylation of various heteroaromatic groups with aryl bromides using Pd(II)-
NHC catalysts
Arylation at both C2 and C5 is also fairly common. The selectivity of arylation depends on
the free energy of activation for C-H bonds [42]. Based on previous results on Pd-catalysed
direct arylation, for this study, DMAc (N,N-dimethylacetamide) and KOAc (potassium
acetate) were selected as the solvent and base [15, 35]. However, several attempts were
made with a number of solvents and bases for this study. The reactions were performed at
o
100-150 C under argon in the presence of 2d. The results are summarized in Table 3. At
direct arylation reaction of 2-n-propylthiazole, only C5-arylated product was obtained due
to as it has a blocked C2-position. Coupling reactions of 2-n-propylthiazole with p-
bromobenzaldeyhde were tested in the presence of different bases and solvents using 0.5
mol% or 1 mol% 2d catalyst. The full conversion was obtained using DMAc as solvent
and KOAc as base at 130 0C for 1 h (Table 3, entry 4). In this condition, when temperature
15

o
was reduced to 100 C, the reaction yield was 76% (Table 3, entry 7); when time was
shortened to 0.5 h, reaction yield was 100% (Table 3, entry 8); when the catalyst amount
was decreased to 0.5 mol%, reaction yield was 94% (Table 3, entry 9). It was decided to
reduce the amount of catalyst among the moderating conditions. For coupling of 2-
acetylthiophene with p-bromobenzaldeyhde, the same reaction condition was found to be
optimal (Table 3, entry 13). C5-position of C2-substituted 2-acetylthiophene are is reactive
and mostly C5-arylated product was obtained. When the coupling reaction of 4,5-
dimethylthiazole with p-bromobenzaldeyhde was tested at in the same conditions, only
16% coupling product was obtained (Table 3, entry 10), so the temperature was increased
o
up to 150 C and reaction yield was increased to 77% (Table 3, entry 11). C2-position of
4,5-dimethylthiazole was arylated because of blocked C4- and C5-positions. Although the
amount of catalyst was decided to be 0.5 mol%, in later experiments, with 0.5 mol%
catalyst for p-bromoanisole, it was seen that the reaction yield was seen to be low (Table 3,
entry 14). Consequently, it was found that when the reaction was carried out in DMAc in
the presence of KOAc at 130 °C for 1 h for arylation of 2-n-propylthiazole and 2-
acetylthiophene, for with p-bromotoluene, p-bromobenzaldyehyde and 1-
bromonaphthalene as aryl bromide were used 0.5 mol% Pd(II)-NHC catalyst was used and
for with bromobenzene, p-bromoanisole and p-bromoacetophenone as aryl bromide, were
used 1 mol% Pd(II)-NHC catalyst was used, and for arylation of 4,5-dimethylthiazole, was
used 1 mol% catalyst was used for all aryl bromide. Palladium black formation was
observed at the end of the reaction in all reactions. According to the literature inactive
Pd(0) species is called Pd-black which allows the use of lower catalyst loadings [43, 44].
Table 3. Influence of the reaction conditions for the palladium-catalyzed direct arylation of
heteroaromatic compounds with p-bromobenzaldeyhde.
Entry
Heteroaromatic
Derivatives
Solvent
Base
Cat.
(mol%)
Temp. Yield
(oC)
130
130
130
130
130
130
100
(%)
43
21
0
100
59
47
76
1
2
3
4
5
6
7
2-n-Propylthiazole
2-n-Propylthiazole
2-n-Propylthiazole
2-n-Propylthiazole
2-n-Propylthiazole
2-n-Propylthiazole
2-n-Propylthiazole
DMAc
DMAc
DMAc
DMAc
DMF
NaOAc
K2CO3
Cs2CO3
KOAc
KOAc
KOAc
KOAc
1
1
1
1
1
1
1
Toluene
DMAc
16

8
9
10
11
12
13
2-n-Propylthiazole
2-n-Propylthiazole
4,5-Dimethylthiazole
4,5-Dimethylthiazole
2-Acetylthiophene
2-Acetylthiophene
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
1
0.5
1
1
1
130
130
130
150
130
130
100b
94
16
77
100
90
0.5
aConditions: Heteroaromatic compound (2.0 mmol), p-bromobenzaldehyde (1.0 mmol), base (2 mmol), solvent
(2 mL), 1 h. b) 30 minutes. Product purity was checked by GC, conversions were calculated according to aryl
bromide and the calibrations were based on decane.
Under the optimal conditions, direct arylation of 2-n-propylthiazole with various aryl
bromides was examined and only the C5-arylated thiazole derivatives were obtained with
good yields. When 2-n-propylthiazole was arylated with p-bromotoluene, p-
bromobenzaldeyde and 1-bromonaphthalene, C5-arylated products were obtained by using
only 0.5 mol% Pd(II)-NHC complexes (2a-e) as the catalyst that p-bromotoluene showed
highest conversion in the range of 93-100% (Table 4, entries 6-10) and 1-bromonaphthalene
showed lowest conversion in the range of 62-87% (Table 4, entries 26-30). In reactions using
0.5 mol% catalyst, it can be said that 2a has the highest activity. Of the arylation reactions
with bromobenzene, p-bromoanisole, and p-bromoacetophenone using 1 mol% catalyst, p-
bromoanisole as an electron-rich aryl bromide gave 53% conversion lowest C5-arylated
products with 2d catalyst. (Table 4, entry 14). This is probably, this is because of the
oxidative addition of p-bromoanisole to palladium appears to be slower than the oxidative
addition of 2-n-propylthiazole. Again, 2a showed the highest activity in reactions using 1
mol% catalyst. Although small differences in reactivities were observed for 2a-e catalyst due
to the similar nature of the NHC moieties, it can be said that the most effective catalyst in the
direct arylation of 2-n-propylthiazole with aryl bromide is 2a. 2a catalyst gave 100% yield
with bromobenzene, p-bromotoluene, p-bromoanisole, p-bromobenzaldehyde (Table 4, entries
1, 6, 11 and 16). For arylation reaction of 2-n-propylthiazole in the literature, the reaction
temperature was 150 oC, and the catalyst was 1 mol%. When PEPPSI-type complex was used,
reaction time 1 h [43], and when [PdCl2L2] type complex was used, reaction time was 20 h.
o
[35]. In this study, reaction temperature was decreased to 130 C, the catalyst amount was
decreased to 0.5 mol% and reaction time was 1 h.
17

Table 4. Palladium(II)-NHC-catalyzed direct C5-arylation of 2-n-propylthiazole with aryl
bromides.a
Conv.
(%)
100
100
100
99
Yield
(%)
100
100
100
99
Entry Cat.
Aryl bromide
Product
1
2
3
2a
2b
2c
4
2d
49b
98
49b
98
5
6
7
8
2e
2a
2b
2c
100b
94b
100b
100
93b
100
100b
100
79
100b
94b
100b
100
93b
100
100b
100
79
9
2d
2e
10
11
12
13
14
15
16
17
18
2a
2b
2c
2d
2e
2a
2b
2c
89
53
65
89
53
65
100b
92b
71b
100
94b
100
81b
99
100b
92b
71b
100
94b
100
81b
99
19
20
2d
2e
21
22
23
2a
2b
2c
96
98
96
98
93
93
24
2d
54b
100
87b
80b
62b
100
76b
100
67b
54b
100
87b
80b
62b
100
76b
100
67b
25
26
27
28
2e
2a
2b
2c
Br
29
2d
30
2e
aConditions: 2-n-propylthiazole (2.0 mmol), aryl bromide (1.0 mmol), Pd cat. (1 mol%), KOAc (2 mmol), N,N-
dimethylacetamide (2 mL), 130 oC, 1 h. b) Pd cat. (0.5 mol%). Product purity was checked by GC, conversions
were calculated according to aryl bromide and the calibrations were based on decane.
18

Next, direct arylation of 4,5-dimethylthiazole with various aryl bromides was investigated and
mostly the C2-arylated thiazole derivatives were obtained due to C4- and C5-positions in
blocked methyl groups. For all aryl bromides, were used 1 mol% Pd-NHC catalyst was used
0
and the reaction was performed at 150 C for 1 h. Arylation of p-bromotoluene gave full
conversion with 100% yield with 2a-e (Table 5, entries 6-10), and p-bromobenzene and p-
bromoanisole gave high activities in the range of 60-100% (Table 5, entries 1-5, 11-15). At In
the arylation reactions of p-bromobenzaldeyde, p-bromoacetophenone and 1-
bromonaphthalene were obtained arylated products with the lowest yield in range of 3-57%.
(Table 5, entries 16-30). The electron-deficient aryl groups such as p-bromobenzaldeyde, p-
bromoacetophenone decreased the yield of C2-arylated products. On average, the 2b catalyst
showed the best activity. The 4,5-dimethylthiazole group has been rarely studied in the
literature. As far as is known, while [PdCl2L2] type catalyst was used, PEPPSI type catalyst
was not found for the arylation of 4,5-dimethylthiazole in the reports. Obtained results in this
study are consistent with the literature [15, 45].
Table 5. Palladium(II)-NHC-catalyzed direct C2-arylation of 4,5-dimethylthiazole with aryl
bromides.a
Conv.
(%)
86
94
95
Yield
(%)
86
94
95
100
100
100
100
100
100
83
Entry Cat.
Aryl bromide
Product
1
2
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
2a
2b
2c
3
4
5
6
7
8
9
100
100
100
100
100
100
100
60
100
100
73
100
28
10
11
12
13
14
15
16
17
18
60
100
100
73
100
28
53
24
53
24
19

57
36
12
22
3
18
21
77
39
28
56
34
57
83
12
22
3
18
21
77
39
28
56
88
19
20
21
22
23
24
25
26
27
28
29
30
2d
2e
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
aConditions: 4,5-dimethylthiazole (2.0 mmol), aryl bromide (1.0 mmol), Pd cat. (1 mol%,), KOAc (2 mmol),
N,N-dimethylacetamide (2 mL), 150 C, 1 h. Product purity was checked by GC, conversions were calculated
o
according to aryl bromide and the calibrations were based on decane.
When direct arylation of 2-acetylthiophene with various aryl bromides was investigated,
similar results were obtained with arylation of 2-n-propylthiazole (Table 6). When 2-
acetylthiophene was arylated with p-bromotoluene, p-bromobenzaldeyde and 1-
bromonaphthalene, only 0.5 mol% Pd(II)-NHC complexes (2a-e) were used (Table 6, entries
6-10,16-20, 26-30). These arylbromides gave high conversion in the range of 80-100% with
2b catalyst. 2d catalyst showed lowest activity with 33% converison. When 2-acetylthiophene
was arylated with bromobenzene, p-bromoanisole and p-bromoacetophenone, 1 mol%, Pd(II)-
NHC complexes (2a-e) were used (Table 6, entries 1-5, 11-15, 21-25). 2b catalyst provided
highest conversion with these arylbromides in the range of 67-100%, and 2d catalyst gave
lowest conversion in the range of 49-100%. Also In addition, while from arylation of 2-
acetylthiophene with p-bromotoluene, p-bromoanisole and 1-bromonaphthalene were
obtained only C5-arylated products (Table 6, entries 6-10, 11-15, 26-30), with the other aryl
bromide were obtained mostly C5-arylated product together with a trace of other position
arylated products (Table 6, entries 1-5, 16-20, 21-25). However, with p-bromoanisole, was
obtained the lowest arylated products were obtained (Table 6, entries 11-15). It was seen that
more moderate conditions were presented for this reaction compared to previous studies in the
literature which was used PEPPSI type catalyst [25]. In this study, the reaction temperature
was decreased to 130 0C from 150 0C, the catalyst amount was decreased to 0.5 mol% from 1
mol%, and the reaction time was decreased to 1 h from 2 h compared to literature [25].
.
20

Table 6. Palladium(II)-NHC-catalyzed direct C5-arylation of 2-acetylthiophene with aryl
bromides.a
Conv. Yield
Entry Cat.
Aryl bromide
Product
(%)
(%)
1
2
3
4
5
6
7
8
100
100
95
91
95
89
100
100
91
100
99
92
100
46
67
67
49
39
85
86
88
33
80
80
80
82
86
81
88
80
100
66
79
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
100
100
100b
100b
99b
92b
100b
46
67
67
49
39
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
68b
88b
84b
33b
97b
94
100
94
58
100
88b
80b
100b
66b
79b
Br
aConditions: 2-Acetylthiophene (2.0 mmol), aryl bromide (1.0 mmol), Pd cat. (1 mol%), KOAc (2 mmol), N,N-
dimethylacetamide (2 mL), 130 oC, 1 h. b) Pd cat. (0.5 mol%). Product purity was checked by GC, conversions
were calculated according to aryl bromide and the calibrations were based on decane.
4. Conclusion
In summary, we have prepared a series of benzimidazole-based ligand precursors were
prepared (1a-e). These ligands were metallated with PdCl2 in pyridine to give a new PEPPSI
type palladium-NHC complex series (2a-e). All ligands and palladium complexes were
21

characterized using 1H, 13C{1H} NMR and FT-IR spectroscopies. Crystal structure
determination of 2c, 2d and 2e were was performed by using single-crystal X-ray diffraction
method. Aftermost, PEPPSI-type palladium-NHC complexes were used in the direct arylation
of 2-n-propylthiazole, 4,5-dimethylthiazole and 2-acetylthiophene with various aryl bromides.
These complexes proved to be highly active in the direct arylation reaction of 2-n-
propylthizaole. In addition, it has was seen that he reaction conditions are were more
moderate in terms of reaction temperature, time and quantity of catalyst amount.
Conflicts of interests
The authors have are no conflicts of interests to declare.
Acknowledgments
The authors thank the Scientific and Technological Research Institute of Turkey (TÜBITAK-
BĐDEB) the National Research Fellowship Programme for grants to N. ꢃ. Hande K. and
Hasan K. acknowledge Dokuz Eylul University for the use of the Agilent Xcalibur Eos
diffractometer (purchased under University Research grant No. 2010.KB·FEN.13).
Appendix A. Supplementary data
CCDC: 1883977, 1883971 and 1883972 and contain the supplementary crystallographic data
for complexes 2c, 2d and 2e, respectively. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre by visiting www.ccdc.cam.ac.uk.
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24

Highlights
-Novel N-heterocyclic carbene ligands (NHC) and their PEPPSI type Pd(II)-NHC complexes
have been synthesized.
- Structures of the complexes were determined by NMR, IR and X-ray spectroscopies.
-The complexes have been applied for the direct arylation of thiopene and thiazole derivatives
with aryl bromide as a catalyst.
-Good to excellent coupling products have been obtained.

1
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Hasan K. acknowledge Dokuz Eylul University for the use of the Agilent Xcalibur Eos
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1. Neslihan ꢀahin
25.10.2019
2. Nevin Gürbüz
25.10.2019
3. Hande Karabıyık
25.10.2019
4. Hasan Karabıyık
25.10.2019
5. Đsmail Özdemir
25.10.2019
6. ___________________
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