Pd-N-heterocyclic carbene complex catalysed C-H bond activation of 2-isobutylthiazole at the C5 position with aryl bromides

Article abstract of DOI:10.1039/d1nj00514f

An effective and efficient catalytic system has been reported for the synthesis of C5-arylated 2-isobutylthiazoles. Pd-N-heterocyclic carbene complexes like [Pd(μ-Cl)Cl(SIPr)]₂(2) and (LCl₂Pd-SIPr) (3:L= PPh₃,4:L= Py;5:L= 3-CHO-Py) were synthesized and characterized by¹H,¹³C,³¹P NMR, LC-MS/MS, elemental analysis, and FTIR spectroscopy. These Pd-N-heterocyclic carbene complexes were assessed for the first time as catalysts for the C-H arylation reaction of 2-isobutylthiazole at the C5 position with different (hetero)aryl bromides. The catalytic system showed a low catalyst loading (1 mol%) and did not require the use of additional additives such as pivalic acid. The catalytic system developed with these catalysts enables the synthesis of fine chemicals in high yields under aerobic or anaerobic conditions. All complexes showed moderate to good yields in the C5 direct arylation of 2-isobutylthiazole, while complex2exhibited higher catalytic activity than the other complexes.

Full text of DOI:10.1039/d1nj00514f

NJC
View Article Online
View Journal | View Issue
PAPER
Pd-N-heterocyclic carbene complex catalysed
C–H bond activation of 2-isobutylthiazole
at the C5 position with aryl bromides†‡
b
Cite this: New J. Chem., 2021,
45, 6281
Siraj Khan,a Nesrin Bugday,
˘
Sedat Yas-ar, *b Naseem Ullaha and
b
˙Ismail O¨ zdemir
An effective and efficient catalytic system has been reported for the synthesis of C5-arylated
2-isobutylthiazoles. Pd-N-heterocyclic carbene complexes like [Pd(m-Cl)Cl(SIPr)]2 (2) and (LCl2Pd-SIPr)
(3: L = PPh3, 4: L = Py; 5: L = 3-CHO-Py) were synthesized and characterized by 1H, 13C, 31P NMR,
LC-MS/MS, elemental analysis, and FTIR spectroscopy. These Pd-N-heterocyclic carbene complexes
were assessed for the first time as catalysts for the C–H arylation reaction of 2-isobutylthiazole at the
C5 position with different (hetero)aryl bromides. The catalytic system showed a low catalyst loading
(1 mol%) and did not require the use of additional additives such as pivalic acid. The catalytic system
developed with these catalysts enables the synthesis of fine chemicals in high yields under aerobic
or anaerobic conditions. All complexes showed moderate to good yields in the C5 direct arylation of
2-isobutylthiazole, while complex 2 exhibited higher catalytic activity than the other complexes.
Received 31st January 2021,
Accepted 22nd February 2021
DOI: 10.1039/d1nj00514f
rsc.li/njc
ideal routes for the formation of bi-heteroaryl compound linkages
to avoid the problem associated with conventional ArX/ArM
Introduction
Heteroaromatic molecules represent an important research coupling reactions.12 Ohta et al. reported the direct C2 or
field in organic synthesis, used in natural and synthetic C5-arylation of many heteroaromatics with aryl halides and
compounds, as well as in biologically active compounds, and obtained the product in moderate to good yields by using the
as intermediates in the preparation of several bioactive commercially available catalyst Pd(PPh3)4 and N,N-dimethyl-
compounds.1,2 Among heteroaromatic molecules, the five- acetamide (DMAc) as the solvent.13 After Ohta’s work, direct
membered heterocycles have shown remarkable biological arylation reactions have become a key research area. Since, the
activity, including antihypertensive, cholecystokinin antagonist, use of palladium as a catalyst has proved to be an efficient,
antibacterial, antifungal, anti-asthmatic, and lipoxygenase environment-friendly and atom economical route for the
inhibition activities.3,4 Thiazoles are one of the most well-
known heteroaromatic compounds with many applications.
Thiazole or thiazole-containing compounds are known to play
a vital role in biologically active molecules, organic materials,
agrochemicals, and pharmaceuticals. Some selected examples of
thiazole-containing compounds are Meloxicam, Cefotaxime,
Thiamin (vitamin B12), Ethaboxam and Thiamethoxam as shown
in Scheme 1.5–11 From the atom economy and synthetic simplicity
points of view, the C–H activation reaction will be one of the most
a Quaid-i-Azam University, Faculty of Biological Sciences, Department of Pharmacy,
Islamabad, 45320, Pakistan
b
˙
¨ ¨
Inonu University, Faculty of Science and art, Department of Chemistry, 44210,
Malatya, Turkey. E-mail: sedat.yasar@inonu.edu.tr; Fax: +90 4223410212;
Tel: +90 4223413737
† Dedicated to Prof. Christian Bruneau for his outstanding contribution to
catalysis.
Scheme 1 Examples of bioactive thiazole derivatives containing thiazole
groups.
‡ Electronic supplementary information (ESI) available: NMR, FTIR and LC-
MSMS spectra of compounds. See DOI: 10.1039/d1nj00514f
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem., 2021, 45, 6281–6292
| 6281

View Article Online
Paper
NJC
synthesis of arylated heteroaromatic compounds.1,14,15 Indeed, Results and discussion
the majority of the byproducts obtained during the reaction are
Synthesis and characterization of Pd–NHC complexes (2–5)
bases associated with HX (X = Cl, Br, I), instead of metallic salts
formed under classical procedures.16 In addition, the C–H
activation/functionalization avoids the preparation of the
preliminary organometallic compounds, thus reducing the number
of steps required during the preparation of these compounds.
In spite of this, mostly these reactions are carried out in
relatively toxic solvents, such as DMAc, DMF, dioxane N-methyl-
pyrrolidone (NMP) or xylene. Successful work has been reported
by Douce et al. in a solvent-free environment.17a A large number
of these C–H activation reactions catalyzed by different transition
metal catalysts like Ni,17b,c Pd,17d Cu,17e–h and Rh17i have been
reported. However, these reactions have limitations such as
substrate scope, sensitivity, the requirement of additional ligands
and additives, a high catalyst loading, elevated temperature and
the complexity of purification. Hence, researchers are working
intensively to perform this reaction under mild and non-toxic
reaction conditions.
N-heterocyclic carbenes (NHCs) are very important ligands
to transition metals due to their strong s-donating with weak
p-accepting capability and structure versatility.18 Additionally,
they can be endowed with stereo-electronic properties by fine-
tuning either the NHC backbone or the wingtip substitutions.19
As further vital features, Pd–NHC complexes are air and moisture
stable, which are convenient to handle.20 Mononuclear, dinuclear,
trinuclear and expanded cycles bearing Pd–NHC complexes have
been synthesized by various research groups so as to use as
catalysts for various organic transformations.21 Among these
Pd–NHC complexes, Pd-PEPPSI (Pyridine-Enhanced Precatalyst
Preparation Stabilization and Initiation) type complexes have
attracted great attention due to their high catalytic activity and
stability against air and moisture. The Pd-PEPPSI complex
synthesized by Organ22 is used in many organic transformations
Complexes 2–5 were synthesized according to already published
procedures with modifications.25,26 The reaction of N,N0-bis(2,6-
diisopropylphenyl)amidine with 1,2-dibromoethane carried out
in the presence of 0.5 (eq) K2CO3 in CH3CN produces 1 in good
yield (Scheme 2). The [Pd(m-Cl)Cl(SIMes)]2 (2) was synthesized in
high yield (90%) as a result of the straightforward reaction of
1 with PdCl2 in the presence of KtOBu in freshly-distilled THF
(on the Na/K alloy) at 80 1C.
Complex 3 was synthesized via the addition of 2 eq. of PPh3
to a solution of 2 in 10 mL DCM in 82% yield. Also, Pd-PEPPSI
complexes 4–5 (PEPPSI = Pyridine-Enhanced Precatalyst Pre-
paration, Stabilization, Initiation) were synthesized in 79% and
81% yields, respectively, by the addition of 2 eq. of the
corresponding pyridine or 3-carboxaldehydepyridine to
a
solution of 2 in 10 mL DCM.26 The disappearance of the NCHN
1
signal in the H NMR spectra of 2 indicates that synthesis of 2
took place. However, the shift of the carbon signal (NCHN)
from 160.5 to 180.1 ppm in the 13C NMR spectrum of 1
confirmed the formation of complex 2. Similarly, the NCN 13C
signals of 3, 4 and 5 were observed at 199.4, 186.1 and 188.9
ppm, respectively. The 31P NMR signal observed at 18.86 ppm
confirmed the formation of complex 3. The LC-MS/MS
and elemental analyses of the synthesized Pd–NHC complexes
confirm the proposed structures of the complexes.
The Pd–NHC catalyzed direct C5 arylation reaction of
2-isobutylthiazole
To determine the suitability of these Pd–NHC complexes as catalysts
in the C5 direct C–H activation reactions of 2-isobutylthiazoles with
¨
as a pre-catalyst successfully. Ozdemir et al. synthesized and used
Pd-PEPPSI type complexes as catalysts in C–C bond formation and
C–H activation reactions.23 However, many researchers have
synthesized Pd-PEPPSI complexes and applied them to the C–H
bond activation reaction as a catalyst.24
To the best of our knowledge, when looking at the studies
reported in the literature, there is no published study that
investigates or compares the catalytic activities of the most
commonly synthesized Pd–NHC type complexes in C–H
activation reactions. Therefore, in this study, the synthesis of
LnPd–NHC complexes (Ln = pyridine, 3-formylpyridine, and
PPh3) was carried out and the catalytic activities of their on the
C–H bond activation reaction of 2-isobutylthiazole were investigated.
The catalytic system described here led to the formation of
C5-arylated-2-isobutylthiazole heteroaromatics with aryl
bromide derivatives successfully. Fortunately, all Pd–NHC
complexes reported here are highly effective and show good to
excellent catalytic activities in the C5-direct arylation reactions of
2-isobutylthiazole with different (hetero)aryl bromides. All
catalytic products were characterized by 1H NMR, 13C NMR,
31P NMR, GC-MS and FTIR analyses for the support of the
proposed structures.
Scheme 2 Synthesized Pd–NHC complexes.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
6282
| New J. Chem., 2021, 45, 6281–6292

View Article Online
NJC
Paper
(hetero)aryl bromides, we performed a set of reactions under conditions. For this reason, we examine the effects of the
optimized conditions (Table 1). The reactions were performed catalyst loading, solvent, base, reaction temperature and
under an argon atmosphere, using Pd–NHC (1 mol%) as the reaction time on the reaction yield. First, the effect of catalyst
catalyst, KOAc as the base, and DMA as the solvent at a loading was examined. As expected, a decrease in the catalyst
temperature of 120 1C (Table 1, entries 1–4). Various types of amount leads to a significant decrease in the reaction yield. For
catalysts are used in the model reaction to determine the more this reason, the most effective amount of catalyst for the
active catalyst. The result indicates that catalyst 2 exhibits reaction was determined to be 1 mol% (Table 1, entries 5 and 6).
better catalytic activity in almost all cases. Complex 3 is more Then, different polar solvents were tested. Among them, DMA
stable than other complexes, which can make more difficult the gives the best result, while other solvents or neat conditions
oxidative addition of aryl halides. This may cause a decrease in give lower yields or no yield at all (Table 1, entries 7–9).
catalytic activity of complex 3. In the catalytic cycle, the pyridine Although the efficiency of a solvent-free catalytic system is
ligand may easily get displaced from the metal centre, while the lower than the system with a solvent, it is very important in
substrate remains firmly bound, a behaviour which has been terms of saving energy, reducing solvent waste and non-use of
found to increase the reactivity of catalysts by generating an toxic chemicals. After defining the solvent, a series of bases
extra coordination space when compared to the use of more were tested, and KOAc was found to be the most efficient base
traditional ligands. Likewise, an extra coordination space may for this catalytic system (Table 1, entries 10–14). Another
occur in the metal center by easily breaking the bridging bonds. important thing is the determination of optimum reaction
Thus, catalyst 2 was used to define the optimum reaction temperature and time. Preliminary results showed that low
Table 1 Optimization of the C5 direct arylation of 2-isobutylthiazolea
Entry
Cat.
Catalyst (mol%)
Solvent
Base
T/1C
Yieldb (%)
1
2
3
4
5
6
7
8
2
3
4
5
2
2
2
2
2
2
2
2
2
2
2
2
1
1
1
1
0.5
0.25
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
DMA
DMA
DMA
DMA
DMA
DMA
NMP
DMSO
—
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
150
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
91
69
40
41
50
18
65
3
30
5
2
32
0
2
45
88
54
55
40
52
62
66
60
40
Nr
Nr
Nr
Nr
Nr
Nr
Nr
Nr
Nr
Nr
9
10
11
12
13
14
15
16
17c
18d
19
20
24
25
26
28
29e
30e
31e
32e
33e
34e
35e
36e
37e
38e
DMA
DMSO
NMP
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
2
2
PdCl2
Pd(OAc)2
Pd(OAc)2/1
PdCl2(PPh3)2
Pd(OAc)2/PPh3
PdCl2(CH3CN)2
2
3
4
5
PdCl2
Pd(OAc)2
Pd(OAc)2/PPh3
PdCl2(PPh3)2
Pd(OAc)2/1
PdCl2(CH3CN)2
1
a
b
Reaction conditions: 2-isobutylthiazole (1.0 mmol), 4-bromobenzene (1.0 mmol), base (2.0 mmol), solvent (2 ml), 1 h. GC yield using
c
d
e
(trifluoromethyl)benzene as an internal standard. 30 min. Under air. Chlorobenzene used as the aryl halide, Nr: No reaction.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem., 2021, 45, 6281–6292
| 6283

View Article Online
Paper
NJC
Table 2 Pd–NHC catalyzed C5-direct coupling of 2-isobutylthiazole with (hetero)aryl bromidesa
Entry
Catalyst
ArX
Product
Conversion-Yielda (%)
1
2
3
4
2
3
4
5
91% (90%)
94% (94%)b
95% (95%)c
94% (94%)c
5
2
40% (40%)
6
7
8
3
4
5
35% (35%)
37% (37%)
35% (35%)
9
2
80% (80%)
10
11
12
3
4
5
87% (87%)b
55% (55%)
57% (57%)
13
3
0% (0%)b
14
2
72% (72%)
15
16
17
3
4
5
69% (69%)b
70% (70%)b
79% (79%)b
18
2
97% (97%)b
19
20
21
3
4
5
68% (68%)b
97% (97%)c
98% (97%)c
22
5
0% (0%)c
23
2
100% (99%)
24
25
26
3
4
5
65% (65%)d
92% (92%)c
93% (93%)c
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
6284
| New J. Chem., 2021, 45, 6281–6292

View Article Online
NJC
Paper
Table 2 (continued)
Entry
27
Catalyst
ArX
Product
Conversion-Yielda (%)
100% (99%)
2
28
29
30
3
4
5
99% (98%)c
100% (99%)c
99% (99%)c
31
2
100% (88%)c
32
33
34
3
4
5
78% (62%)c
93% (77%)c
90% (75%)c
35
2
100% (99%)
36
3
88% (88%)c
59% (59%)f
100% (99%)c
99% (99%)c
37
38
4
5
39
2
100% (99%)
40
41
42
3
4
5
90% (65%)c
100% (99%)c
100% (99%)c
43
2
90% (90%)c
44
45
46
3
4
5
92% (92%)c
73% (73%)c
71% (71%)c
47
2
38% (38%)e
48
49
50
3
4
5
29% (26%)d
40% (40%)e
41% (40%)e
51
2
96% (93%)c
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem., 2021, 45, 6281–6292
| 6285

View Article Online
Paper
NJC
Table 2 (continued)
Entry
Catalyst
ArX
Product
Conversion-Yielda (%)
52
53
54
3
4
5
65% (63%)c
100% (98%)c
99% (98%)c
55
2
100% (99%)
56
57
58
3
4
5
100% (98%)
99% (98%)c
98% (98%)c
59
2
97% (97%)c
60
61
62
3
4
5
69% (69%)c
91% (91%)c
92% (92%)c
100% (90%)
100% (90%)f
100% (93%)c
100% (93%)c
100% (90%)c
63
2
64
65
66
3
4
5
67
68
69
70
2
3
4
5
100% (99%)
96% (85%)c
99% (98%)c
98% (97%)c
71
72
73
74
2
3
4
5
99% (93%)c
100% (73%)c
61% (54%)d
63% (58%)d
75
76
77
78
2
3
4
5
100% (95%)
100% (98%)d
100% (97%)c
100% (95%)c
a
Reaction conditions: Pd–NHC (1 mol%), 2-isobutylthiazole (1.0 mmol), aryl halides (1.0 mmol, for 6h, 6p, 6r 0.5 mmol), KOAc (2.0 mmol), DMA
b
c
(2 ml), 1 h; the values within parentheses indicate GC yields and are defined using (trifluoromethyl)benzene as an internal standard. 2 h. 3 h.
d
e
f
6 h. 12 h. In air, 3 h.
temperature and a short reaction time led to a dramatic complex showed the best catalytic activity when compared to
decrease in yields (Table 1, entries 15–17). Also, reactions in other palladium complexes (Table 1, entries 19–28). Besides, we
open-air give lower yields than the reactions carried out under determined that the catalyst formed with Pd(OAc)2/PPh3 under
an argon atmosphere (Table 1, entry 18). In addition, we in situ conditions showed lower activity than the PdCl2(PPh3)2
investigated the activity of some commercially available catalyst (Table 1, entry 35). Likewise, the same situation was
palladium complexes and palladium salts under the same observed in the in situ reaction with Pd (OAc)2/NHC (Table 1,
reaction conditions. We determined that the PdCl2(PPh3)2 entry 37). All the aforementioned palladium complexes were
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
6286
| New J. Chem., 2021, 45, 6281–6292

View Article Online
NJC
Paper
studied in the C5 direct arylation of 2-isobutylthiazole with
chlorobenzene and it was observed that no catalysts showed
activity in this reaction (Table 1, entries 29–38). After these
reactions, we defined the reaction conditions as follows:
2-isobutylthiazole (1 mmol), (hetero)aryl bromides (1 mmol),
Pd–NHC 1 mol%, 1 mmol KOAc, 2 mL DMAc, 120 1C for 1 hour
under an argon atmosphere. Unlike the studies in the
literature,33,35,36 there is no need to use an excessive amount
of 2-isobutylthiazole because the catalysts work selectively and
prevent the formation of homo-coupling by-products.
Following the determination of optimal reaction conditions,
we examined the extent of a well-known set of p-substituted aryl
bromides (Table 2). As shown in Table 2, employing
2-isobutylthiazole and p-substituted aryl bromides as the
coupling partners in this catalytic system gave C5 arylated
2-isobutylthiazoles in excellent yields in a short time. We should
specify that no formation of 4-arylated or 4,5-diaraylated
2-isobutylthiazoles was detected. The contribution of the
electron-withdrawing substituted group bearing aryl bromides
(NO2, CF3, acetyl, CN) or the electron-donating substituted group
bearing aryl bromides (methoxy, methyl) limited the product
yields in the catalytic system. Both situations are fairly well
tolerated by the catalytic system and gave the desired product
in high yields. Notably, the arylated thiazoles bearing NO2, F and
CN groups are important for the synthesis of natural and
biologically important compounds by further chemical transfor-
mations. As shown in Table 2, the o-substituted (hetero)aryl
bromides were also arylated (6h and 6j) in excellent yields. The
results showed that the steric effect of the o-substituent did not
negatively affect the efficiency of the catalyst. Next, the reactivity
of two o-substituted aryl bromides was examined. Due to the
high steric effect of 2,6-dimethoxy groups, a moderate yield (6k)
was observed for the direct-arylation of 2,6-dimetoxyphenyl-
bromide. Because of the encouraging results of this catalytic
system, we attempted to perform di-arylation of 3,5-dibromo-
pyridine, 2,5-dibromotiyophene and 1,4-dibromobenzene with
2-isobutylthiazole. We show that these reactions took place
successfully and afforded di-arylated products in high yields
(6p, 6r, 6s). In these reactions, the selectivity of the catalysts in
the formation of di-heteroarylated products is quite satisfactory
because monoheteroarylated products were not observed at all.
These diarylated products might be more considerable compounds
for medical applications.
Scheme 3 Proposed catalytic mechanism for the direct C5 arylation of
isobutylthiazole catalyzed by Pd–NHC complexes.
In previous works,17,27–36 similar substrates were employed
with the use of a higher catalyst loading (2 mol%) and
additives33–36 (Table 3) and require a longer reaction time for
the direct arylation of isobutylthiazole. However, similar
studies were performed with lower catalyst loadings, and the
substrates used in these studies are different from
2-isobutylthiazole.37,38 The difference of the used substrate prevents
us from making a clear comparison of our catalysts with those
reported in the literature.37,38 Here, in the present work, the catalyst
loading is 1 mol%, the reaction time shortened to 1 h for aryl
bromides and PivOH is not required for the direct arylation
reactions.
As a result, this catalytic system has the following advantages:
(i) (hetero)aryl bromide tolerance, (ii) no need for additives, and
(iii) a high yield, a low catalyst loading and a short reaction time.
Therefore, we proposed that these catalysts could be used for
other C–H catalytic transformation reactions. However, the
system we present here provides low yields or no product with
aryl chloride.
In the present study, the dimeric palladium complex 2
exhibited better catalytic performance in the C5 direct arylation
of 2-isobutylthiazole with heteroaryl bromides than the
other catalysts derived from 2 in many cases. The proposed
catalytic mechanism for the C5 direct arylation reaction of
Experimental
Materials and methods
2-isobutylthiazole is presented in Scheme 3, and it is seen All synthesis and catalytic experiments were carried out under
that the key step, which determines the reaction rate, is the an argon atmosphere using Schlenk techniques. The reagents
oxidative addition. Palladium metal center with high electron were purchased directly from Sigma-Aldrich and used as
density facilitates oxidative addition of aryl halides. We received. The solvents were used as purchased or purified using
attributed the catalytic difference of complex 2 to its dimeric an MBraun SPS 800 solvent purification system. For NMR
structure which may have a higher electron density metal analysis, a Bruker Avance III 400 MHz NMR spectrometer was
center, making the oxidative addition of the heteroaryl used at room temperature with the decoupled nucleus using
bromides easier.
CDCl3 and DMSO-d6 as solvents and referenced to TMS as the
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem., 2021, 45, 6281–6292
| 6287

View Article Online
Paper
NJC
Table 3 Pd-catalyzed direct C–H bond arylation of thiazoles
Thiazole
Ar-X
Product
Catalyst
Additive
PivOH
Base
Solvent
Yield (%)
Ref.
33
Pd(OAc)2 1 mol%
K2CO3
DMF (Ar)
55–80
PCy3, 2 mol%
PdCl(C3H5) (dppb) 1 mol%
—
Cs2CO3
DMC (Ar)
73–87
76–86
47–78
34
35
Pd-phosphine 0.5–2 mol%
PivOH
K2CO3
DMA
54
Pd-diimine 0.2 mol%
Pd–NHC 1 mol%
PivOH
K2CO3
DMAc (Air)
51–97
57–72
36
—
KOAc
DMA (Ar or Air)
28–99
49–99
This work
standard. The coupling constants ( J values) are given in hertz. The remaining oily sticky substance was washed with diethyl
NMR multiplicities are abbreviated as follows: s = singlet, ether (5 ꢀ 5 mL). The white solid was dissolved in 10 mL DCM,
d = doublet, t = triplet, m = multiplet signal. All reactions were to which 20 mL of diethyl ether was added, and the product was
monitored on a Shimadzu GC2010 Plus system by GC-FID with precipitated in the form of a white crystalline solid with a
an HP-5 column of 30 m length, 0.32 mm diameter, and yield of 89%. The NMR spectra were compared to previously
0.25 mm film thickness. Some of the products of C–H direct published data.25
arylation reactions were previously reported. New compounds
Yield 89%, mp 282–284 1C, 1H NMR (400 MHz, DMSO-d6): d
were characterized by different spectroscopic techniques. 9.47 (s,1H, NCHN), 7.56 (t, 2H, Ar-H, J = 8 Hz), 7.44 (d, 4H, Ar-H,
LC-MS/MS analyses were performed in the ESI positive mode J = 8 Hz), 4.56 (s, 4H, NCH2CH2N), 3.09 (sept, 4H, CH(CH3)3, J =
using a Shimadzu 8040 instrument after the samples were 6.7 Hz), 1.37 (d, 12H, CH(CH3)3, J = 4 Hz), 1.21 (d, 12H,
dissolved in acetonitrile. The GCMS analysis of compounds CH(CH3)3, J = 4 Hz). 13C{1H} NMR (101 MHz, DMSO-d6): d
was performed using a Shimadzu GC-MS 2010 Plus using a 160.5 (NCHN), 146.6, 131.6, 130.3, 125.3 (Ar-C), 54.2
TRX-5 column in the positive ESI mode. The FTIR data were (NCH2CH2N), 28.8 (CH(CH3)3), 25.5 (CH(CH3)3), 23.8
analysed using a PerkinElmer Spectrum 100 GladiATR FT/IR (CH(CH3)3). IR (cmꢁ1): 2964, 2930, 1473, 1255.
spectrometer. The melting points of the complexes and NHC
precursors were determined using Stuart automatic melting
point apparatus (SMP-40) (see the ESI‡).
Synthesis of [Pd(l-Cl)Cl(SIMes)]2 (2)
The [(SIPr)PdCl2]2 complex has been synthesized according to a
published procedure with modifications.25 1 (1 mmol) and
KtOBu (1 mmol) were put into a well-flame-dried Schlenk tube
Synthesis of 1,3-bis-(2,6-diisopropylphenyl)-4,5-dihydro-3H-
imidazol-1-ium bromide (1)
and left under high vacuum for 30 minutes. Freshly dried THF
The synthesis of 1 has been done as reported previously with (20 mL) was added to the Schlenk tube and stirred for 1 hour at
modifications.25 A solution of N,N0-bis(2,6-diisopropylphenyl) room temperature. The solution was filtered through Celite, to
amidine (1 equiv.), 1,2-dibromoethane (1 equiv.) and potassium which PdCl2 (1 mmol) was added, and the mixture was stirred at
carbonate (0.5 equiv.) in acetonitrile was refluxed for 1 day, room temperature for 24 hours. THF was removed under high
and then solid impurities were removed via filtration. vacuum and the residue was washed with hexane (2 ꢀ 10 mL).
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
6288
| New J. Chem., 2021, 45, 6281–6292

View Article Online
NJC
Paper
Yellow solid crystals were obtained with DCM/hexane in 90% CH(CH3)3, J = 6.7 Hz), 1.56 (d, 12H, CH(CH3)3, J = 8 Hz), 1.27
yield. The NMR spectra were compared to previously published (d, 12H, CH(CH3)3, J = 8 Hz). 13C{1H} NMR (101 MHz, DMSO-d6):
data.25
d 188.9 (CHO), 184.7 (NCN), 156.0, 154.2, 147.6, 136.2, 135.2,
[(SIPr)PdCl2]2 (2). Yield 90%, mp 296–298 1C 1H NMR 131.8, 129.6, 124.5 (Ar-C), 53.9 (NCH2CH2N), 28.8 (CH(CH3)3), 26.8
(400 MHz, CDCl3): d 7.38-7.34 (m, 4H, Ar-H), 7.21–7.12 (CH(CH3)3), 24.2 (CH(CH3)3). MS(m/z, LC-MS/MS (ESI)): 694.20
(m, 8H, Ar-H), 3.81 (s, 4H, NCH2CH2N), 3.80 (s, 4H, NCH2CH2N), [M+ ꢁ 2H + Na], 676.20 [M+ + H] 576.20 [M+ ꢁ CHOCl2 + H].
3.29–3.16 (m, 4H, CH(CH3)3), 3.00–2.88 (m, 4H, CH(CH3)3), 1.36– Elemental analysis calcd. (%) for C33H43Cl2N3OPd (673.18);
1.24 (m, 24H, CH(CH3)3), 1.11–1.02 (m, 24H, CH(CH3)3). 13C{1H} C: 58.72, H: 6.42, N: 6.22; found; C: 58.00, H: 6.61, N: 6.26.
NMR (101 MHz, CDCl3): d 180.1 (NCN), 147.4, 147.0, 146.6,
134.5, 129.6, 124.6 (Ar-C), 53.7 (NCH2CH2N), 28.7 and 28.6
(CH(CH3)3), 26.7, 24.3 and 24.2 (CH(CH3)3). IR (cmꢁ1): 2964,
General procedure for Pd–NHC catalyzed direct C5 C–H
arylation of 2-isobutylthiazole (6a–s)
1591, 1482, 1454, 1270. MS(m/z, LC-MS/MS (ESI)): 1154.35 [M+ ꢁ
H + Na], 1065.40 [M+ ꢁ 2Cl + H]. Elemental analysis calcd. (%) (Hetero)aryl bromides (1.0 mmol), 2-isobutylthiazole (1.0 mmol),
for C54H78Cl4N4Pd2 (1132.29): C: 57.10, H: 6.74, N: 4.93; found: KOAc (2.0 mmol), Pd–NHC catalysts (1 mol%), and DMA (4 mL)
C: 57.00, H: 6.41, N: 4.78.
were placed in an argon-filled Schlenk tube and heated for a
specific time at 120 1C. A specified quantity was taken from the
reaction mixture and cooled to room temperature, and GC was
General protocol for the synthesis of 3–5
Complexes 3, 4, and 5 were synthesized as previously reported performed with this sample to determine the conversion and GC
with modifications.27 A mixture of the dimeric complex 2 yields. Then, 5 ml of water and 5 ml of ethyl acetate were added
(1 equiv.) and the ligand (2 equiv.) was dissolved in 10 mL of to the solution and the organic layer was separated by extraction.
DCM and stirred at room temperature for 3 days. The reaction The organic layer was dried with MgSO4 and filtered. After all
mixture was filtered through silica and then n-hexane was volatiles were removed under vacuum, the crude product was
added to the solution, which led to the formation of a yellow obtained. The crude product was purified by silica-gel column
solid. Then, the solid was filtered off, washed with diethyl ether chromatography using ethyl acetate–hexane (1 : 50) as the eluent
(2 ꢀ 5 mL), and dried under vacuum to yield the pure product and the new compounds were characterized by 1H NMR, 13C
as a yellow powder. The complexes were used directly as NMR, 31P NMR, GC-MS, and FTIR spectroscopic techniques and
catalysts without further purification.
the spectra are presented in the ESI.‡
(SIPr)Pd(PPh3)Cl2 (3). Yield 77%, mp 261–263 1C 1H NMR
2-Isobutyl-5-phenylthiazole (6a). 1H NMR (400 MHz, CDCl3):
(400 MHz, CDCl3): d 7.40 (t, 2H, Ar-H, J = 8 Hz), 7.25–7.14 (m, d 7.83 (s, 1H, NCHCS), 7.53 (d, 2H, Ar-H, J = 8 Hz), 7.37 (t, 2H,
13H, Ar-H), 7.09–7.05 (m, 6H, Ar-H), 4.01 (s, 4H, NCH2CH2N), Ar-H, J = 6 Hz), 7.31-7.29 (m, 1H, Ar-H), 2.88 (d, 2H,
3.52 (sept, 4H, CH(CH3)3, J = 7.3 Hz), 1.29 (d, 12H, CH(CH3)3, J = CH2CH(CH3)2, J = 4 Hz), 2.14 (sept, 1H, CH2CH(CH3)2, J = 6.7 Hz),
4 Hz), 1.15 (d, 12H, CH(CH3)3, J = 4 Hz). 13C{1H} NMR (101 MHz, 1.02 (d, 6H, CH2CH(CH3)2, J = 8 Hz). 13C{1H} NMR (101 MHz,
CDCl3): d 146.6, 134.4, 130.1, 124.7 (Ar-C), 54.0, 53.9 (NCH2CH2N), CDCl3): d 169.7 (NCS), 138.5, 137.6, 131.7, 129.0, 128.0, 126.6 (Ar-C),
28.9 (CH(CH3)3), 25.5 (CH(CH3)3), 24.1 (CH(CH3)3). IR (cmꢁ1): 42.5 (CH2CH(CH3)2), 29.8 (CH2CH(CH3)2), 22.3 (CH2CH(CH3)2).
2960, 1589, 1477, 1454, 1269, 1092. 31P NMR (400 MHz, CDCl3):
2-Isobutyl-5-(p-tolyl)thiazole (6b). 1H NMR (400 MHz,
d 18.86. MS(m/z, LC-MS/MS (ESI)): 793.30 [M+ ꢁ Cl], 759.30 [M+ ꢁ CDCl3): d 7.78 (s, 1H, NCHCS), 7.42 (d, 2H, Ar-H, J = 8 Hz),
2Cl + H], 848.25 [M+ ꢁ 3H + Na]. Elemental analysis calcd. (%) for 7.19 (d, 2H, Ar-H, J = 8 Hz), 2.87 (d, 2H, CH2CH(CH3)2, J = 8 Hz),
C45H53Cl2N2PPd (828.24); C: 65.10, H: 6.43, N: 3.37; found; C: 2.36 (s, 3H, CH3), 2.13 (sept, 1H, CH2CH(CH3)2, J = 6.7 Hz), 1.02
65.53, H: 6.75, N: 3.10.
(d, 6H, CH2CH(CH3)2, J = 8 Hz). 13C{1H} NMR (101 MHz, CDCl3):
(SIPr)Pd(Pyr)Cl2 (4). Yield 86%, mp 217–219 1C 1H NMR d 169.2 (NCS), 138.6, 137.9, 137.1, 129.7, 128.8, 126.5 (Ar-C),
(400 MHz, CDCl3): d 8.55–8.53 (m, 2H, Ar-H), 7.56–7.52 (m, 1H, 42.5 (CH2CH(CH3)2), 29.8 (CH2CH(CH3)2), 22.3 (CH2CH(CH3)2),
Ar-H), 7.45–7.42 (m, 2H, Ar-H), 7.33 (s, 2H, Ar-H), 7.31 (s, 2H, 21.2 (CH3).
Ar-H), 7.12–7.08 (m, 2H, Ar-H), 4.08 (s, 4H, NCH2CH2N), 3.62
2-Isobutyl-5-(4-methoxyphenyl)thiazole (6c). 1H NMR
(sept, 4H, CH(CH3)3, J = 7.3 Hz), 1.59 (d, 12H, CH(CH3)3, J = (400 MHz, CDCl3): d 7.72 (s, 1H, NCHCS), 7.46 (d, 2H, Ar-H,
4 Hz), 1.29 (d, 12H, CH(CH3)3, J = 4 Hz). 13C{1H} NMR (101 MHz, J = 12 Hz), 6.92 (d, 2H, Ar-H, J = 12 Hz), 3.83 (s, 3H, CH3), 2.86
DMSO-d6): d 186.1 (NCN), 151.3, 147.6, 137.3, 135.4, 129.4, (d, 2H, CH2CH(CH3)2, J = 8 Hz), 2.13 (sept, 1H, CH2CH(CH3)2,
124.4, 124.0 (Ar-C), 53.9 (NCH2CH2N), 28.8 (CH(CH3)3), 26.8 J = 6.7 Hz), 1.02 (d, 6H, CH2CH(CH3)2, J = 8 Hz). 13C{1H} NMR
(CH(CH3)3), 24.3 (CH(CH3)3). IR (cmꢁ1): 2960, 1604, 1477, 1444, (101 MHz, CDCl3): d 168.8 (NCS), 159.5, 138.3, 136.6, 127.9,
1267. MS(m/z, LC-MS/MS (ESI)): 646.20 [M+ + H], 669.15 [M+ + 124.3, 114.4 (Ar-C), 55.4 (OCH3), 42.5 (CH2CH(CH3)2), 29.8
H + Na], 620.15 [M+ ꢁ 2Cl ꢁ H + 2Na], 576.15 [M+ + H ꢁ 2Cl]. (CH2CH(CH3)2), 22.3 (CH2CH(CH3)2).
Elemental analysis calcd. (%) for C32H43Cl2N3Pd (645.19); C:
59.40, H: 6.70, N: 6.49; found; C: 59.61, H: 6.46, N: 6.30.
1-(4-(2-Isobutylthiazol-5-yl)phenyl)ethan-1-one (6d). 1H NMR
(400 MHz, CDCl3): d 7.99–7.95 (m, 3H, Ar-H + NCHCS), 7.63
(SIPr)Pd(Pyr-COH)Cl2 (5). 1H NMR (400 MHz, CDCl3): d 9.89 (d, 2H, Ar-H, J = 12 Hz), 2.91 (d, 2H, CH2CH(CH3)2, J = 4 Hz),
(s,1H, CHO), 9.06 (d, 1H, Ar-H, J = 4 Hz), 8.83 (d, 1H, Ar-H, J = 2.62 (s, 3H, CH3), 2.15 (sept, 1H, CH2CH(CH3)2, J = 7.3 Hz), 1.03
8 Hz), 8.04 (d, 1H, Ar-H, J = 8 Hz), 7.44-7.40 (m, 2H, Ar-H), 7.31– (d, 6H, CH2CH(CH3)2, J = 8 Hz). 13C{1H} NMR (101 MHz, CDCl3):
7.27 (m, 5H, Ar-H), 4.08 (s, 4H, NCH2CH2N), 3.59 (sept, 4H, d 197.2 (CO), 171.2 (NCS), 166.5 ((CO)OCH3), 139.0, 137.3,
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem., 2021, 45, 6281–6292
| 6289

View Article Online
Paper
NJC
3
136.2, 136.2, 129.2, 126.4 (Ar-C), 42.6 (CH2CH(CH3)2), 29.9 140.4, 135.6 (Ar-C), 139.07, 138.99 (d, JCF = 8 Hz), 132.3, 132.2
3
4
(CH2CH(CH3)2), 26.6 ((CO)CH3), 22.3 (CH2CH(CH3)2).
(d, JCF = 9 Hz), 126.93, 126.90 (d, JCF = 3 Hz), 117.48, 117.27,
4-(2-Isobutylthiazol-5-yl)benzonitrile (6e). 1H NMR (400 MHz, 113.05, 112.84 (dd, JCF = 21 Hz), 42.4 (CH2CH(CH3)2), 29.8
CDCl3): d 7.87 (s, 1H, NCHCS), 7.58 (q, 4H, Ar-H, J = 9.3 Hz), 2.84 (CH2CH(CH3)2), 22.4 (CH2CH(CH3)2), 21.2 (CH3). d ꢁ114.0 (CF).
(d, 2H, CH2CH(CH3)2, J = 8 Hz), 2.08 (sept, 1H, CH2CH(CH3)2, IR (cmꢁ1): 2960, 1585, 1490, 1226, 1154. GC-MS (ESI), m/z = 249
J = 6.7 Hz), 0.96 (d, 6H, CH2CH(CH3)2, J = 8 Hz). 13C{1H} NMR [M] (calculated for C14H16FNS: 249.1).
2
(101 MHz, CDCl3): d 171.8 (NCS), 139.4, 136.5, 136.1, 132.9,
126.8, 118.6, 111.3 (Ar-C), 42.6 (CH2CH(CH3)2), 29.9 CDCl3): d 8.05–8.03 (m,1H, Ar-H), 7.81–7.76 (m, 2H, Ar-H), 7.67
(CH2CH(CH3)2), 22.3 (CH2CH(CH3)2). (s, 1H, NCHCS), 7.45–7.36 (m, 4H, Ar-H), 2.86 (d, 2H,
2-Isobutyl-5-(naphthalen-1-yl)thiazole (6l). 1H NMR (400 MHz,
1
2-Isobutyl-5-(4-(trifluoromethyl)phenyl)thiazole (6f). H NMR CH2CH(CH3)2, J = 8 Hz), 2.11 (sept, 1H, CH2CH(CH3)2, J =
(400 MHz, CDCl3): d 7.82 (s, 1H, NCHCS), 7.53 (s, 4H, Ar-H), 2.81 6.7 Hz), 0.98 (d, 6H, CH2CH(CH3)2, J = 8 Hz). 13C{1H} NMR
(d, 2H, CH2CH(CH3)2, J = 4 Hz), 2.06 (sept, 1H, CH2CH(CH3)2, J = (101 MHz, CDCl3): d 170.8 (NCS), 141.0, 135.5, 133.8, 131.9,
6.7 Hz), 0.94 (d, 6H, CH2CH(CH3)2, J = 8 Hz). 13C{1H} NMR 129.0, 128.9, 128.6, 128.5, 126.8, 126.2, 125.3, 125.3 (Ar-C), 42.5
(101 MHz, CDCl3): d 171.0 (NCS), 138.9, 136.9, 135.2 (Ar-C), 130.3, (CH2CH(CH3)2), 29.9 (CH2CH(CH3)2), 22.5 (CH2CH(CH3)2).
2
129.9, 129.6, 129.3 (q, JCF = 32 Hz), 128.0, 125.3, 122.6, 119.9
2-Isobutyl-5-(4-(methyl)naphthalen-1-yl)thiazole (6m). Liquid,
(q, 1JCF = 270 Hz) 126.1, 126.0, 125.98, 125.94 (q, 4JCF = 3 Hz), 42.6 1H NMR (400 MHz, CDCl3): d 8.04 (d,1H, Ar-H, J = 8 Hz), 7.95
(CH2CH(CH3)2), 29.8 (CH2CH(CH3)2), 22.3 (CH2CH(CH3)2). 19F NMR (d,1H, Ar-H, J = 8 Hz), 7.63 (s, 1H, NCHCS), 7.48-7.40 (m, 2H,
(376.1 MHz, CDCl3): d -62.7 (CF3).
Ar-H), 7.34 (d,1H, Ar-H, J = 4 Hz), 7.23 (d,1H, Ar-H, J = 8 Hz), 2.85
Methyl 4-(2-isobutylthiazol-5-yl)benzoate (6g). mp 66–68 1C, (d, 2H, CH2CH(CH3)2, J = 8 Hz), 2.62 (s, 3H, CH3), 2.10 (sept, 1H,
1H NMR (400 MHz, CDCl3): d 7.98 (d, 2H, Ar-H, J = 8 Hz), 7.87 (s, CH2CH(CH3)2, J = 7.3 Hz), 0.98 (d, 6H, CH2CH(CH3)2, J = 8 Hz).
1H, NCHCS), 7.53 (d, 2H, Ar-H, J = 12 Hz), 3.86 (s, 3H, CH3), 2.84 13C{1H} NMR (101 MHz, CDCl3): d 170.6 (NCS), 141.0, 135.5,
(d, 2H, CH2CH(CH3)2, J = 8 Hz), 2.08 (sept, 1H, CH2CH(CH3)2, 132.9, 132.0, 128.4, 127.2, 126.4, 126.1, 126.1, 126.0, 124.6 (Ar-C),
J = 7.3 Hz), 0.96 (d, 6H, CH2CH(CH3)2, J = 8 Hz). 13C{1H} NMR 42.5 (CH2CH(CH3)2), 29.9 (CH2CH(CH3)2), 22.5 (CH2CH(CH3)2),
(101 MHz, CDCl3): d 171.2 (NCS), 166.5 ((CO)OCH3), 138.5, 19.7 (CH3). IR (cmꢁ1): 2956, 1590, 1463, 1384. GC-MS (ESI), m/z =
137.5, 135.9, 130.4, 129.5, 127.3, 126.3 (Ar-C), 52.2 ((CO)OCH3), 281.0 [M] (calculated for C18H19NS: 281.1)
42.5 (CH2CH(CH3)2), 29.9 (CH2CH(CH3)2), 22.3 (CH2CH(CH3)2).
IR (cmꢁ1): 2956, 1718, 1605, 1435. GC-MS (ESI), m/z = 275 [M] 1H NMR (400 MHz, CDCl3): d 7.52 (s, 1H, NCHCS), 7.46 (d,
(calculated for C15H17NO2S: 275.1) 1H, Ar-H, J = 4 Hz), 6.96 (d, 1H, Ar-H, J = 8 Hz), 2.83 (d, 2H,
5-(2,6-Dimethylpyridin-3-yl)-2-isobutylthiazole (6n). Liquid,
2-Isobutyl-5-(2-methyl-4-nitrophenyl)thiazole (6h). mp 55– CH2CH(CH3)2, J = 8 Hz), 2.53 (s, 3H, CH3), 2.49 (s, 3H, CH3), 2.08
57 1C, 1H NMR (400 MHz, CDCl3): d 8.09 (d,1H, Ar-H, J = (sept, 1H, CH2CH(CH3)2, J = 6.7 Hz), 0.96 (d, 6H, CH2CH(CH3)2,
4 Hz), 8.01 (dd, 1H, Ar-H, J = 4 Hz), 7.65 (s, 1H, NCHCS), 7.47 J = 8 Hz). 13C{1H} NMR (101 MHz, CDCl3): d 170.8 (NCS), 141.0,
(d, 1H, Ar-H, J = 8 Hz), 2.87 (d, 2H, CH2CH(CH3)2, J = 8 Hz), 2.46 135.4, 133.8, 131.9, 129.0, 129.0, 128.6, 128.5, 126.8, 126.2,
(s, 3H, CH3), 2.10 (sept, 1H, CH2CH(CH3)2, J = 6.7 Hz), 0.98 (d, 125.3, 125.3 (Ar-C), 42.5 (CH2CH(CH3)2), 29.9 (CH2CH(CH3)2),
6H, CH2CH(CH3)2, J = 4 Hz). 13C{1H} NMR (101 MHz, CDCl3): d 22.5 (CH2CH(CH3)2). IR (cmꢁ1): 2956, 1738, 1465, 1369. GC-MS
172.0 (NCS), 147.3, 141.4, 137.8, 137.6, 134.5, 131.2, 125.8, (ESI), m/z = 246.0 [M] (calculated for C14H18N2S: 246.1)
121.2 (Ar-C), 42.3 (CH2CH(CH3)2), 29.9 (CH2CH(CH3)2), 22.3
(CH2CH(CH3)2), 21.5 (CH3). IR (cmꢁ1): 2956, 1577, 1511, 1340. 1H NMR (400 MHz, CDCl3): d 9.56 (s,1H, Ar-H, CHO), 7.97 (s,
GC-MS (ESI), m/z = 276 [M] (calculated for C14H16N2O2S: 276). 1H, NCHCS), 7.23 (d,1H, Ar-H, J = 4 Hz), 6.61 (d,1H, Ar-H, J =
5-(2-Isobutylthiazol-5-yl)furan-2-carbaldehyde (6o). Liquid,
2-Isobutyl-5-(4-nitro-3-(trifluoromethyl)phenyl)thiazole (6i). 4 Hz), 2.84 (d, 2H, CH2CH(CH3)2, J = 4 Hz), 2.07 (sept, 1H,
1
mp 57–59 1C, H NMR (400 MHz, CDCl3): d 7.94 (s,1H, Ar-H), CH2CH(CH3)2, J = 6.7 Hz), 0.94 (d, 6H, CH2CH(CH3)2, J = 8 Hz).
7.92–7.89 (m, 1H, Ar-H), 7.86 (s, 1H, NCHCS), 7.77 (dd, 1H, 13C{1H} NMR (101 MHz, CDCl3): d 177.0 (CHO), 172.0 (NCS),
Ar-H, J = 4 Hz), 2.88 (d, 2H, CH2CH(CH3)2, J = 4 Hz), 2.10 (sept, 152.2, 152.0, 140.7, 126.4, 109.0 (Ar-C), 42.4 (CH2CH(CH3)2),
1H, CH2CH(CH3)2, J = 6.7 Hz), 0.97 (d, 6H, CH2CH(CH3)2, J = 29.9 (CH2CH(CH3)2), 22.2 (CH2CH(CH3)2). IR (cmꢁ1): 2956,
8 Hz). 13C{1H} NMR (101 MHz, CDCl3): d 173.2 (NCS), 140.2, 1670, 1533, 1386. GC-MS (ESI), m/z = 235.0 [M] (calculated for
136.6, 134.9, 130.0, 128.4, 128.3 (Ar-C), 125.6, 125.58, 125.52,
C
12H13NO2S: 235.1)
3
2
125.47 (q, JCF = 6 Hz), 125.5, 125.2, 124.8, 124.5 (q, JCF
=
1,4-Bis(2-isobutylthiazol-5-yl)benzene (6p). 1H NMR (400 MHz,
34 Hz), 42.6 (CH2CH(CH3)2), 29.9 (CH2CH(CH3)2), 22.3 CDCl3): d 7.79 (s, 2H, NCHCS), 7.47 (s,4H, Ar-H), 2.83 (d, 4H,
(CH2CH(CH3)2). d ꢁ60.1 (CF3). IR (cmꢁ1): 2963, 1590, 1528, CH2CH(CH3)2, J = 4 Hz), 2.08 (sept, 1H, CH2CH(CH3)2, J = 6.7 Hz),
1319, 1141. GC-MS (ESI), m/z = 330 [M] (calculated for 0.96 (d, 6H, CH2CH(CH3)2, J = 8 Hz). 13C{1H} NMR (101 MHz,
C
14H13F3N2O2S: 330.1).
5-(4-Fluoro-2-methylphenyl)-2-isobutylthiazole (6j). Liquid, (CH2CH(CH3)2), 29.9 (CH2CH(CH3)2), 22.3 (CH2CH(CH3)2).
1H NMR (400 MHz, CDCl3): d 7.46 (s,1H, Ar-H), 7.25–7.19 (m,
2,5-Bis(2-isobutylthiazol-5-yl)thiophene (6r). mp 73–76 1C,
CDCl3): d 170.1 (NCS), 137.8, 137.7, 131.3, 127.1 (Ar-C), 42.6
1H, Ar-H), 6.92–6.81 (m, 2H, Ar-H and NCHCS), 2.82 (d, 2H, 1H NMR (400 MHz, CDCl3): d 7.66 (s,2H, Ar-H), 6.98 (s, 2H,
CH2CH(CH3)2, J = 8 Hz), 2.29 (s, 3H, CH3), 2.07 (sept, 1H, NCHCS), 2.81 (d, 4H, CH2CH(CH3)2, J = 8 Hz), 2.06 (sept, 1H,
CH2CH(CH3)2, J = 6.7 Hz), 0.96 (d, 6H, CH2CH(CH3)2, J = 8 Hz). CH2CH(CH3)2, J = 6.7 Hz), 0.95 (d, 6H, CH2CH(CH3)2, J = 8 Hz).
13C{1H} NMR (101 MHz, CDCl3): d 170.4 (NCS), 163.8, 161.3, 13C{1H} NMR (101 MHz, CDCl3): d 169.8 (NCS), 137.9, 133.1,
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
6290
| New J. Chem., 2021, 45, 6281–6292

View Article Online
NJC
Paper
12 J. Dong, Y. Huang, X. Qin, Y. Cheng, J. Hao, D. Wan, W. Li,
X. Liu and J. You, Chem. – Eur. J., 2012, 18, 6158–6162.
13 A. Ohta, Y. Akita, T. Ohkuwa, M. Chiba and R. Fukunaga,
Heterocycles, 1990, 31, 1951–1958.
14 A. L. Gottumukkala and H. Doucet, Eur. J. Inorg. Chem.,
2007, 3629–3632.
131.2, 125.9 (Ar-C), 42.4 (CH2CH(CH3)2), 29.9 (CH2CH(CH3)2),
22.3 (CH2CH(CH3)2). IR (cmꢁ1): 2956, 1691, 1464, 1384. GC-MS
(ESI), m/z = 362.0 [M] (calculated for C18H22N2S3:362.1)
3,5-Bis(2-isobutylthiazol-5-yl)pyridine (6s). mp 92–94 1C,
1H NMR (400 MHz, CDCl3): d 8.65 (s,2H, Ar-H), 7.87 (s, 2H,
NCHCS), 7.84 (t,1H, Ar-H, J = 4 Hz), 2.86 (d, 4H, CH2CH(CH3)2,
J = 8 Hz), 2.10 (sept, 1H, CH2CH(CH3)2, J = 6.7 Hz), 0.97 (d, 6H,
CH2CH(CH3)2, J = 8 Hz). 13C{1H} NMR (101 MHz, CDCl3): d
171.5 (NCS), 146.2, 139.3, 133.8, 131.3, 128.3 (Ar-C), 42.6
(CH2CH(CH3)2), 29.9 (CH2CH(CH3)2), 22.3 (CH2CH(CH3)2). IR
(cmꢁ1): 2956, 1522, 1463, 1384. GC-MS (ESI), m/z = 357.0 [M]
(calculated for C19H23N3S2:357.1).
15 T. Wakaki, T. Togo, D. Yoshidome, Y. Kuninobu and
M. Kanai, ACS Catal., 2018, 8, 3123–3128.
´
16 J. Hassan, M. Sevignon, C. Gozzi, E. Schulz and M. Lemaire,
Chem. Rev., 2002, 102, 1359–1470.
17 (a) S. Bensaid and H. Doucet, ChemSusChem, 2012, 5,
1559–1567; (b) H. Hachiya, K. Hirano, T. Satoh and
M. Miura, Org. Lett., 2009, 11, 1737–1740; (c) P. Y. Xin,
H. Y. Niu, G.-R. Qu, R.-F. Ding and H. M. Guo, Chem.
Commun., 2012, 48, 6717–6719; (d) F. Bellina,
S. Cauteruccio and R. Rossi, Eur. J. Org. Chem., 2006,
1379–1382; (e) M. Zakeri, M. Moghadam, V. Mirkhani,
S. Tangestaninejad, I. M. Baltork and Z. Pahlevanneshan,
Appl. Organomet. Chem., 2018, 32(1), 3937; ( f ) T. Yoshizumi,
H. Tsurugi, T. Satoh and M. Miura, Tetrahedron Lett., 2008,
49, 1598–1600; (g) W. Zhang, Q. Zeng, X. Zhang, Y. Tian,
Y. Yue, Y. Guo and Z. Wang, J. Org. Chem., 2011, 76,
4741–4745; (h) W. Zhang, Y. Tian, N. Zhao, Y. Wang, J. Li
and Z. Wang, Tetrahedron, 2014, 70, 6120–6126;
(i) J. C. Lewis, A. M. Berman, R. G. Bergman and
J. A. Ellman, J. Am. Chem. Soc., 2008, 130, 2493–2500.
18 M. N. Hopkinson, C. Richter, M. Schedler and F. Glorius,
Nature, 2014, 510, 485–496.
Conclusions
Herein, we have synthesized and characterized four different
types of Pd–NHC complexes and examined the catalytic activity
of these complexes in the C–H bond activation reaction of
2-isobutylthiazole with different (hetero)aryl bromides. The
results show that complexes 2–5 exhibit high catalytic activity
and high selectivity at a low catalyst loading without any acid
additive. Complexes 2, 4 and 5 have shown better catalytic
activity in almost all cases than complex 3.
Conflicts of interest
There are no conflicts to declare.
19 A. Gautam, C. Shahini, A. P. Siddappa, M. J. Grzegorz,
B. Hemavathi, T. Ahipa and B. Srinivasa, J. Organomet.
Chem., 2021, 934, 121540.
20 S. Shi, S. P. Nolan and M. Szostak, Acc. Chem. Res., 2018, 51,
2589–2599.
21 (a) Z.-S. Gu, W.-X. Chen and L.-X. Shao, J. Org. Chem., 2014, 79,
5806–5811; (b) R. F. Alamdaari, M. S. Saeedi and F. Panahi,
Appl. Organomet. Chem., 2017, 31, 3870; (c) M. Ibrahim,
I. Malik, W. Mansour, M. Sharif, M. Fettouhi and B. E. I. Ali,
Appl. Organomet. Chem., 2018, 32(1), 4280.
Acknowledgements
˙
¨
This work was supported by the Inonu¨ University (BAP Project
No: FBG-2019-1789) and we would like to thank the ‘‘Turkiye
Bursları’’ for grand S. Khan.
Notes and references
22 J. Nasielski, N. Hadei, G. Achonduh, E. A. B. Kantchev,
C. J. O’Brien, A. Lough and M. G. Organ, Chem. – Eur. J.,
2010, 16(35), 10844.
1 N. Kaur, Catal. Rev., 2015, 57, 1–78.
2 J. Roger, F. Pozgan and H. Doucet, J. Org. Chem., 2009, 74,
1179–1186.
¨
˙
23 (a) M. Kaloglu, S. D. Du¨s-u¨nceli and I. Ozdemir,
3 R. V. Orru and M. de Greef, Synthesis, 2003, 1471–1499.
˘
J. Organomet. Chem., 2020, 915, 121236; (b) M. Kaloglu
¨
4 A. Domling, Chem. Rev., 2006, 106, 17–89.
¨
˙
and I. Ozdemir, Tetrahedron, 2018, 74, 2837–2845;
5 X. W. Liu, J. L. Shi, J. X. Yan, J. B. Wei, K. Peng, L. Dai,
C. G. Li, B. Q. Wang and Z. Shi, Org. Lett., 2013, 15,
5774–5777.
¨
˙
(c) L. Boubakri, K. Dridi, A. S. Al-Ayed, I. Ozdemir, S. Yas-ar
and N. Hamdi, J. Coord. Chem., 2019, 72, 516–527;
¨
˙
(d) F. Imik, S. Yas-ar and I. Ozdemir, J. Organomet. Chem.,
6 W. Lee, C. Shin, S. E. Park and J. M. Joo, J. Org. Chem., 2019,
84, 12913–12924.
¨
˙
2019, 896, 162–167; (e) F. Imik, S. Yas-ar and I. Ozdemir,
Inorg. Chim. Acta, 2019, 495, 118969; ( f ) N. Touj, N. Gu
¨rbu¨z,
7 T. K. Achar, J. P. Biswas, S. Porey, T. Pal, K. Ramakrishna,
S. Maiti and D. Maiti, J. Org. Chem., 2019, 84, 8315–8321.
8 F. Zhu, J. L. Tao and Z. X. Wang, Org. Lett., 2015, 17,
4926–4929.
¨
˙
N. Hamdi, S. Yas-ar and I. Ozdemir, Inorg. Chim. Acta, 2018,
478, 187–194; (g) N. Touj, S. Yas-ar, N. Gu¨rbu¨z, N. Hamdi
and I. Ozdemir, J. Organomet. Chem., 2018, 860, 59–71;
¨
˙
¨
˙
9 A. Struengmann, B. Freudensprung and K. Klokkers, 2001.
(h) Z. I. Dehimat, S. Yas-ar, D. Tebbani and I. Ozdemir,
Inorg. Chim. Acta, 2018, 469, 325–334.
˘
10 M. Kaloglu and I. Ozdemir, Tetrahedron, 2018, 74,
2837–2845.
24 (a) S. Yadav, A. Singh, I. Mishra, S. Ray, S. M. Mobin and
C. Dash, Appl. Organomet. Chem., 2019, 33, e4936;
11 Z. Jin, Nat. Prod. Rep., 2006, 23, 464–496.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem., 2021, 45, 6281–6292
| 6291

View Article Online
Paper
NJC
(b) V. A. Glushkov, M. S. Denisov, A. A. Gorbunov, 30 L. Chen, C. Bruneau, P. H. Dixneuf and H. Doucet, Chem-
Y. A. Myalitzin, M. V. Dmitriev and P. A. Slepukhin, Chem. CatChem, 2013, 5, 1956–1963.
Heterocyclic Compounds, 2019, 55(3), 217–228; (c) A.-X. Song, 31 M. Baloch, R. J. Roy, D. Roy, K. Beydoun and H. Doucet, RSC
X.-X. Zeng, B.-B. Ma, C. Xu and F.-S. Liu, Organometallics, Adv., 2011, 1, 1527–1536.
2020, 39, 3524–3534; (d) A. Kumar, M. Kumar and 32 A. Beladhria, K. Beydoun, H. B. Ammar, R. B. Salem and
A. K. Verma, J. Org. Chem., 2020, 85, 13983–13996; H. Doucet, Synthesis, 2012, 2264–2276.
(e) A. Gokanapalli, V. K. R. Motakatla and 33 M. Baghbanzadeh, C. Pilger and C. O. Kappe, J. Org. Chem.,
V. G. R. Peddiahgari, Appl. Organometal. Chem., 2020, 2011, 76, 8138–8142.
34, e5869; ( f ) F. Tu¨rker, I. Bereket, D. Barut Celepci, 34 J. J. Dong, J. Roger, C. Verrier, T. Martin, R. Le Goff,
¨
A. Aktas- and Y. Gok, J. Mol. Struct., 2020, 1205, 127608.
C. Hoarau and H. Doucet, Green Chem., 2010, 12,
25 D. R. Jensen and M. S. Sigman, Org. Lett., 2003, 5, 63–65.
2053–2063.
´
26 L. Boubakri, S. Yas-ar, V. Dorcet, T. Roisnel, C. Bruneau, 35 A. Jakab, Z. Dalicsek and T. Soos, Eur. J. Org. Chem., 2015,
¨
˙
N. Hamdi and I. Ozdemir, New. J. Chem., 2017, 41,
5105–5113.
56–59.
36 F. M. Chen, D. D. Lu, L. Q. Hu, J. Huang and F. S. Liu, Org.
Biomol. Chem., 2017, 15, 5731–5736.
27 H. A. Chiong and O. Daugulis, Org. Lett., 2007, 9, 1449–1451.
´
28 S. Chikhi, S. Djebbar, J. F. SoulU and H. Doucet, 37 A.-X. Song, X.-X. Zeng, B.-B. Ma, C. Xu and F.-S. Liu,
J. Organomet. Chem., 2017, 831, 55–63. Organometallics, 2020, 39, 3524–3534.
29 J. Laroche, K. Beydoun, V. Guerchais and H. Doucet, Catal. 38 B.-B. Ma, X.-B. Lan, D.-D. Shen, F.-S. Liu and C. Xu,
Sci. Technol., 2013, 3, 2072–2080.
J. Organomet. Chem., 2019, 897, 13–22.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
6292
| New J. Chem., 2021, 45, 6281–6292