The direct C4-arylation of 3,5-dimethylisoxazole with aryl bromides catalyzed by imidazolidin-2-ylidene based palladium-PEPPSI complexes

Article abstract of DOI:10.1016/j.ica.2020.119454

In this study, the synthesis and characterization of four new imidazolinium salts as carbene precursors and their corresponding four new PEPPSI-type (PEPPSI = .Pyridine Enhanced Precatalyst Preparation Stabilization and Initiation) palladium complexes wer

Full text of DOI:10.1016/j.ica.2020.119454

InorganicaChimicaActa504(2020)119454
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Research paper
The direct C4-arylation of 3,5-dimethylisoxazole with aryl bromides
catalyzed by imidazolidin-2-ylidene based palladium-PEPPSI complexes
⁎
Murat Kaloğlua,b, İsmail Özdemira,b,
a İnönü University, Faculty of Science and Arts, Department of Chemistry, 44280 Malatya, Turkey
b İnönü University, Catalysis Research and Application Center, 44280 Malatya, Turkey
A R T I C L E I N F O
A B S T R A C T
Keywords:
In this study, the synthesis and characterization of four new imidazolinium salts as carbene precursors and their
corresponding four new PEPPSI-type (PEPPSI = Pyridine Enhanced Precatalyst Preparation Stabilization and
Initiation) palladium complexes were reported. The structures of these new compounds were characterized by
spectroscopic and analytical techniques. The catalytic activities of all palladium complexes were evaluated in the
direct C4-arylation of 3,5-dimethylisoxazole with para-substituted aryl bromides, ortho-substituted aryl bromides
and heteroaryl bromides. A range of functional groups such as methoxy, acetyl, formyl, fluoro, trifluoromethyl,
nitrile or tert-butyl on the aryl bromide were succesfully tolerated, and good yields were generally obtained in
presence of 1 mol% catalyst loading at 120 °C.
N-heterocyclic carbene
Imidazolidin-2-ylidene
Palladium
PEPPSI
Direct arylation
Isoxazole
1. Introduction
aryl halides and organometallic derivatives of isoxazole, and also be-
tween haloisoxazoles and arylmetal derivatives are some of the most
Arylated isoxazoles are very important structural motifs in organic
chemistry because they are components of a wide number of pharma-
ceutical products and biologically active molecules [1,2]. Many herbi-
cides, hypoglycemics, antibiotics, anti-inflammatory, and analgesic
agents contain the isoxazole ring. As selected examples, Valdecoxib
(marketed as Bextra®) is a non-steroidal anti-inflammatory drug used in
the treatment of osteoarthritis, rheumatoid arthritis, and painful men-
struation and menstrual symptoms [3], Parecoxib (marketed as Dyna-
stat®) is a water-soluble and injectable prodrug of Valdecoxib, with
anti-inflammatory, analgesic, and antipyretic activities [3], Oxacillin
(marketed as Bactocill®) is a penicillin beta-lactam antibiotic used in
the treatment of bacterial infections caused by susceptible, usually
gram-positive organisms [4], and Mofezolac (marketed as Disopain®) is
a non-steroidal anti-inflammatory drug, which acts via the cycloox-
ygenase enzyme [5]. Due to the industrial importance of arylated iso-
xazoles, the discovery of simple and easier procedures allowing the easy
access to these compounds is important research area in modern or-
ganic chemistry Fig. 1
important methods for the synthesis of such compounds. In 2001,
Krogsgaar-Larsen et al. reported the synthesis of 4-arylisoxazoles by
Suzuki reaction in presence of Pd(PPh3)2Cl2 catalyst between 4-iodoi-
soxazoles and arylboronic acids [7a]. Then, Shafiee et al. also reported
the synthesis of 5-alkylthio-3,4-diarylisoxazoles by palladium-catalyzed
Suzuki cross-coupling reactions between 5-alkylthio-3-aryl-4-iodoisox-
azoles and arylboronic acids (Scheme 1, a) [7e]. But, this reaction re-
quire the preliminary preparation of an organometallic derivative and
provide an organometallic salt as a by-product.
The direct arylation process represent an ideal alternative to con-
ventional cross-coupling reactions in the synthesis of arylated iso-
xazoles. This process not only minimizes by-product formation, but also
has a great advantage as it makes organic synthesis easier [9]. How-
ever, to date, only a few examples of C4-arylation of isoxazoles have
been reported [10]. In 2009, the ligand-free palladium-catalyzed direct
C4-arylation of 3,5-disubstituted isoxazoles with (hetero)aryl bromides
was described by the group of Doucet and Santelli [11], (Scheme 1, b).
By employing 0.1–0.5 mol% of the air-stable PdCl2 complex as a cata-
lyst, a wide variety of 4-arylisoxazole derivatives were prepared by the
direct 4-arylation of 3,5-disubstituted isoxazoles between 44 and 95%
yields. Following these pioneering studies, palladium-catalyzed direct
arylation process has been demonstrated to be one of the most powerful
Transition-metal-catalyzed cross-coupling reactions are one of the
most important synthetic tools for the synthesis of isoxazoles. In this
context, a variety of elegant transition-metal-catalyzed systems have
been developed to date [6]. Suzuki [7] or Stille [8] reactions between
⁎ Corresponding author at: İnönü University, Faculty of Science and Arts, Department of Chemistry, 44280 Malatya, Turkey.
E-mail address: ismail.ozdemir@inonu.edu.tr (İ. Özdemir).
URL: https://www.inonu.edu.tr/ (İ. Özdemir).
https://doi.org/10.1016/j.ica.2020.119454
Received 3 December 2019; Received in revised form 16 January 2020; Accepted 16 January 2020
Availableonline23January2020
0020-1693/©2020ElsevierB.V.Allrightsreserved.

M. Kaloğlu and İ. Özdemir
InorganicaChimicaActa504(2020)119454
and steric properties by replacing the N-substituents [13]. Thus NHCs
have played an important role in homogeneous catalysis and co-
ordination chemistry, partially replacing the well-known tertiary
phosphine ligands. Palladium-complexes of NHCs are the most pow-
erful and widely used catalysts in homogeneous catalysis [14]. Among
the various palladium-NHC complexes, PEPPSI-type (PEPPSI is an ac-
ronym for Pyridine Enhanced Precatalyst Preparation Stabilization and
Initiation) palladium-NHC complexes have shown remarkable catalytic
activities towards various carbon-carbon and carbon-heteroatom cross-
coupling reactions [15]. The high success of PEPPSI-type palladium
complexes in catalysis has been attributed to the presence of a loosely
bound “throwaway” pyridine ligand that makes way for the incoming
substrate [15b].
To date, a wide variety of PEPPSI-type palladium-NHC complexes
were synthesized, and their catalytic activities in the direct arylation of
heteroaromatics were described [16]. Recently, we have also developed
benzimidazolin-2-ylidene based PEPPSI-type palladium complexes,
which exhibited extremely high catalytic abilities for the direct aryla-
tion of heteroarenes with aryl halides [17]. Though a large number of
PEPPSI-type palladium catalysts of unsaturated NHC systems like that
of the (benz)imidazol-2-ylidene and triazole-2-ylidene based ones have
been reported, such analogs of the saturated ones such as imidazolidin-
2-ylidenes are surprisingly scarce. Thus, there are only a few examples
of the imidazolidin-2-ylidene based PEPPSI-type palladium-catalyzed
direct arylation reactions [18]. To our knowledge, this study is the first
report of imidazolidin-2-ylidene based PEPPSI-type palladium-cata-
lyzed direct C4-arylation of 3,5-dimethylisoxazole with (hetero)aryl
bromides. In this work, we now report the successful synthesis of four
new imidazolinium salts as carbene precursors (1a-1d) and their cor-
responding four new PEPPSI-type palladium complexes (2a-2d). Their
characterization were made by different techniques such as 1H NMR,
13C NMR, FT-IR spectroscopy and elemental analysis. In the present
study, the catalytic application of all palladium complexes have been
evaluated in the direct C4-arylation of 3,5-dimethylisoxazole with para-
substituted aryl bromides, ortho-substituted aryl bromides and hetero-
aryl bromides in presence of 1 mol% catalyst loading (Scheme 1). A
range of functional groups such as methoxy, acetyl, formyl, fluoro,
trifluoromethyl, nitrile or tert-butyl on the aryl bromide were tolerated.
Fig. 1. Examples of pharmacologically active arylated isoxazole moieties.
2. Results and discussion
2.1. Synthesis
The general procedure for the imidazolinium salts (1a-1d) and their
corresponding PEPPSI-type palladium complexes (2a-2d) are shown in
Scheme 2. Some physical and spectroscopic data of the new compounds
are summarized in Table 1.
2.2. Preparation of imidazolinium salts as carbene precursors
The four new imidazolinium salts 1a-1d were synthesized as car-
bene precursors by the interaction of imidazoline with substituted
benzyl group on nitrogen atom and 4-phenoxybutyl bromide. The re-
actions were carried out in dimethylformamide (DMF) at 80 °C for 16 h,
and the target salts were obtained 67–80% yields. The structures of the
imidazolinium salts were established by the 1H NMR, 13C NMR, FT-IR
spectroscopy and elemental analysis techniques. In 1H NMR spectra,
C(2)-H proton downfield resonance of 1a-1d salts were observed as
sharp singlets at δ = 9.96, 9.57, 9.19 and 10.01 ppm, respectively. In
13C NMR spectra, C(2)-carbon resonance of 1a-1d salts appeared at
δ = 157.90, 157.71, 157.16 and 158.17 ppm, respectively as single
signal. These downfield signals of the acidic C(2)-H proton and C(2)-
carbon support the formation of imidazolinium salts. Also, the FT-IR
data clearly indicated that the 1a-1d salts exhibit a characteristic
Scheme 1. Palladium-catalyzed C4-arylation of 3,5-disubstituted isoxazoles.
methods for the synthesis of C4-arylated isoxazoles.
N-Heterocyclic carbenes (NHCs) are neutral two-electron donors
and they are known to be strong Lewis bases and excellent nucleophiles
that bind metals better than phosphines [12]. One of the key features of
NHCs compared to other classes of ligands is their stability. The strong
σ-donating but poor π-accepting ability of NHC ligands lead to the
formation of many stable metal-NHC complexes. Another feature of
NHCs is that it allows to obtain complexes having the desired electronic
ν(C] vibration band typically at 1650, 1651, 1653 and 1662 cm−1
,
N)
respectively. These spectroscopic values are in line with those found for
2

M. Kaloğlu and İ. Özdemir
InorganicaChimicaActa504(2020)119454
Scheme 2. The general synthesis of imidazolinium salts (1a-1d) and their PEPPSI-type palladium complexes (2a-2d).
observed as singlet at δ = 180.79, 181.56, 180.17 and 180.75 ppm,
respectively. Also, characteristic signals of the aromatic carbons of
Table 1
Some physical and spectroscopic data of 1a-1d and 2a-2d compounds.
pyridine ring between
δ = 123.44–124.49, 136.70–137.79 and
Compound Formula
Isolated
yield
(%)
M.p. (oC) FT-IR
v(CN)
C(2)-
1H
NMR
C(2)
13C
NMR
151.43–152.46 ppm, support the formation of PEPPSI-type palladium
complex. FT-IR data clearly indicated that the 2a-2d palladium com-
plexes exhibit a characteristic ν(CN) band typically 1602, 1601, 1601
and 1600 cm−1, respectively. Due to the flow of electrons from the
carbene ligand to the palladium centre, the C]N bond is weakened,
and as a result, a decreasing in v(CN) stretching frequency is expected.
These complexes show typical spectroscopic signatures, which are in
line with those reported for other similar type palladium complexes
[16b,18a]. (For the 1H NMR, 13C NMR and FT-IR spectrum of the 2a-2d
complexes, see SI file, pages S9-S16).
H
(cm−1
)
(ppm) (ppm)
1a
1b
1c
1d
2a
2b
2c
2d
C
C
C
C
C
C
C
C
21H27BrN2O
23H31BrN2O
25H35BrN2O
24H33BrN2O
26H31Br2N3OPd 44
28H36Br2N3OPd 61
30H39Br2N3OPd 64
29H37Br2N3OPd 57
80
71
78
67
111–112 1650
116–117 1651
157–158 1653
100–101 1662
117–118 1602
9.96
9.57
9.19
10.01
─
─
─
─
157.90
157.71
157.16
158.17
180.79
181.56
180.17
180.75
147.148
1601
266–267 1601
116–117 1600
other imidazolinium salts of the literature [19]. (For the 1H NMR, 13C
2.4. Optimization of the reaction conditions for the direct arylation
NMR and FT-IR spectrum of the 1a-1d salts, see SI file, pages S1-S8).
First, in order to determine the most suitable reaction conditions in
the direct C4-arylation of 3,5-dimethylisoxazole, we selected the 3-
bromoquinoline as model coupling partner. The effect of the catalysts,
bases, solvents, temperature and reaction time were examined. The
chemical characterization of the C4-arylated product was made by 1H
NMR spectrometry. The yields were based on the 3-bromoquinoline by
GC results. The selected results from our experiments are summarized
in Table 2.
2.3. Preparation of imidazolidin-2-ylidene based palladium-PEPPSI
complexes
The imidazolidin-2-ylidene based four new palladium-PEPPSI
complexes (2a-2c) were synthesized by the interaction of imidazoli-
nium salts (1a-1d) with PdCl2 and pyridine in the presence of po-
tassium bromide. The reactions were carried out in acetonitrile at 80 °C
for 16 h. The palladium complexes, which are highly moisture- and air-
stable both in solution and solid state against air, light and moisture,
could be stored at room temperature for months without an obvious
decline in catalytic efficiency. They are soluble in most organic sol-
vents, such as dichloromethane, chloroform, ethyl acetate and di-
methylsulfoxide, with the exception of non-polar ones, such as pentane
and hexane. All palladium complexes were characterized by different
spectroscopic and analytical techniques such as 1H NMR, 13C NMR, FT-
IR and elemental analysis. In 1H NMR spectra of palladium complexes,
the absence of the characteristic signals of the acidic C(2)-H proton of
the imidazolinium salts, suggests the formation of carbene ligands.
Also, the characteristic signals of aromatic hydrogens of pyridine ring
were observed as downfield resonances in 1H NMR spectra between
δ = 7.24–8.96 ppm. These signals suggest that the pyridine ring co-
ordinated to the palladium centre to form a PEPPSI-type palladium
complex. In 13C NMR spectra of palladium complexes, characteristic
signal of C(2)-carbon of corresponding 1a-1d salts between
δ = 157.16–158.17 ppm were completely disappeared, and the char-
acteristic palladium-C(2) carbene signals of 2a-2d complexes were
In order to examine the effect of the catalyst on the reaction, the
reaction of 3,5-dimethylisoxazole with 3-bromoquinoline was carried
out in presence of KOAc as the base and dimethylacetamide (DMA) as
the solvent. But, no product was formed without the addition of Pd-
catalyst at 150 °C and 4 h (Table 2, entry 1). Under these conditions,
when 1 mol% of Pd(OAc)2 or PdCl2 were used as catalyst, 82% and 90%
yields were observed, respectively (Table 2, entries 2,3). To identify the
most active catalyst, reactions were carried out in presence of 1 mol%
2a-2d loading. Under these conditions, the target C4-arylated product
formed in almost quantitative yield (Table 2, entries 4–7). We observed
relatively similar yields with these four catalysts (95–99%), but again,
as a result of these preliminary studies, it was observed that the most
active catalyst was 2c complex with 99% yield (Table 2, entry 6). When
in situ generated catalytic system with 2 equiv. of 1c salt and 1 equiv. of
PdCl2 was used, 72% yield was observed (Table 3, entry 8). We then
t
studied this reaction using various bases such as NaOAc, BuOK and
Cs2CO3 in the presence of only 1 mol% 2c complex. When NaOAc was
used as the base in presence of 2a catalyst, the yield dropped to 75%
(Table 2, entry 9). We obtained 26% and 53% yields in the presence of
tBuOK or Cs2CO3 bases, respectively (Table 2, entries 10,11). The yield
3

M. Kaloğlu and İ. Özdemir
InorganicaChimicaActa504(2020)119454
Table 2
Palladium-catalyzed direct C4-arylation of 3,5-dimethylisoxazole with 3-bromoquinoline.a
.
a
Conditions: 3,5-dimethylisoxazole (2 equiv.), 3-bromoquinoline (1 equiv.), KOAc (2 equiv.), DMA (2 mL).
Yields were calculated with respect to 3-bromoquinoline from the results of GC spectrometry.
In situ generated catalytic system with 1c salt as carbene precursor (2 equiv.) and PdCl2 (1 equiv.) was used.
b
c
was almost quantitative by using KOAc as the base in presence of 2a
catalyst, whereas NaOAc, BuOK or Cs2CO3 gave much lower yields.
yield was observed to decrease significantly (Table 2, entry 23). After
these preliminary trials, it was concluded that the best conditions for 2c
catalyst in this reaction were achieved in presence of KOAc as the base
in DMA as the solvent at 120 °C, 30 min (Table 2, entry 21).
In light of the information summarized in Table 2, we investigated
the scope and limitations of this reaction using other (hetero)aryl
bromides in presence of 2a-2d catalyst. The reaction worked well for a
wide variety of para-substituted aryl bromides such as 4-bromotoluene,
4-bromoanisole, 4-bromobenzaldehyde, 4-bromoacetophenone, 1-
bromo-4-fluorobenzene, 4-bromobenzotrifluoride and 1-bromo-4-tert-
butylbenzene (Table 3). We also tried ortho-substituted aryl bromides
such as 2-bromotoluene and 2-bromobenzonitrile (Table 4), and het-
eroaryl bromides such as 3-bromoquinoline and 2-bromothiophene
(Table 5).
First, we studied the reactivity of bromobenzene and para-sub-
stituted aryl bromides (Table 3). We performed these reactions using
DMA, KOAc, 120 °C and 1 mol% of 2a-2d catalysts as reaction condi-
tions. Under the given reaction condition, the direct C4-arylation of 3,5-
dimethylisoxazole with aryl bromides were examined and the C4-ary-
lated isoxazoles were obtained with moderate to high yield. Although a
high yielding coupling product was obtained with 3-bromoquinoline for
30 min (Table 2, entry 21), lower yields were obtained with para-sub-
stituted aryl bromides under similar conditions. For this reason, para-
substituted aryl bromides were tested at optimum reaction times, in
which the best yields were observed.
t
Therefore, KOAc proved to be the best base in this reaction. Next, we
also investigated the effects of N-methyl-2-pyrrolidone (NMP) as the
solvent on the reaction. When NMP was used as the solvent at 150 °C
for 4 h, 87% yield was observed (Table 2, entry 12). Diethyl carbonate
(DEC) and water, which were considered as “green solvents” were also
evaluated on the reaction. Before, Doucet employed carbonates as the
solvent for the arylation of some five-membered ring heterocycles [20],
whereas, Greaney and Djakovitch employed water as the solvent for the
direct arylation of heterocycles [21]. When DEC was used as the green
solvent at 150 °C for 4 h, only 54% yield was observed (Table 2, entry
13). When DMA/DEC (1:1) or DMA/water (1:1) solvent mixtures were
used under same conditions, 78% and 64% yields were observed, re-
spectively (Table 2, entries 14,15). Thus, it was found that DMA was the
best solvent among other solvents under the conditions tested (Table 2,
entry 6). Then, we examined the effect of reaction temperature on yield.
When the reaction temperature was reduced from 150 °C to 120 °C in
presence of 2c catalyst, no noticeable effect on the yield was also ob-
served (Table 2, entry 16). The yield was still almost quantitative at
120 °C, whereas when the reaction temperature was reduced to 90 °C,
the yield dropped to 80% (Table 2, entry 17). When the reaction times
were regularly reduced from 4 h to 1 h at 120 °C, no noticeable effect on
the yield was observed (Table 2, entries 18–20). Surprisingly, when the
reaction time is reduced from 1 h to 30 min, we observed that the re-
action still worked well, and we obtained C4-arylated 3,5-dimethyli-
soxazole in very good yield (Table 2, entry 21). This was a very sur-
prising result, since the reaction of 3,5-dimethylisoxazole with 3-
bromoquinoline was known with longer reaction times in the literature
[11]. However, when the reaction time was reduced from 30 min to
15 min, the yield dropped to 66% (Table 2, entry 22). When the catalyst
loading was decreased from 1 mol% to 0.5 mol% at 120 °C for 30 min,
When 3,5-dimethylisoxazole was arylated with bromobenzene, de-
sired product 3,5-dimethyl-4-phenylisoxazole [22], was obtained with
65–84% yields for 1 h by using only 1 mol% 2a-2d complexes as cat-
alysts (Table 3, entries 1–4). The reaction of 3,5-dimethylisoxazole with
4-bromotoluene generated the 3,5-dimethyl-4-(p-tolyl)isoxazole [23],
in 88% yield in the presence of 2c catalyst for 2 h, but with the same
catalyst, 13% yield was observed for 30 min (Table 3, entry 7). The 4-
4

M. Kaloğlu and İ. Özdemir
InorganicaChimicaActa504(2020)119454
Table 3
Table 4
Palladium-catalyzed direct C4-arylation of 3,5-dimethylisoxazole with para-
Palladium-catalyzed direct C4-arylation of 3,5-dimethylisoxazole with ortho-
substituted aryl bromides.a
substituted aryl bromides.a
.
.
Yield (%)b,c
Entry Aryl bromide
[Pd] Product
Time (h) Yield
(%)b,c
Entry
Aryl bromide
[Pd]
Product
Time (h)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2a
2b
2c
2d
8
8
8
8
2
2
2
2
36
57
74 (< 5)
65
65
82
88 (28)
75
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2a
2b
2c
2d
1
1
1
1
2
2
2
2
68
74
84 (56)
65
57
70
88 (13)
66
9
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
4
4
4
4
1
1
1
1
1
1
1
1
70
75
87 (< 5)
68
76
88
96 (57)
64
71
80
a
Conditions: [Pd] 2a-2d (0.01 equiv.,
1 mol%), 3,5-dimethylisoxazole
10
11
12
13
14
15
16
17
18
19
20
(2 equiv.), aryl bromide (1 equiv.), KOAc (2 equiv.), DMA (2 mL), 120 °C.
b
Yields were calculated with respect to aryl bromide from the results of GC
spectrometry.
c
Yields obtained after 30 min were shown in parentheses.
Table 5
Palladium-catalyzed direct C4-arylation of 3,5-dimethylisoxazole with hetero-
aryl bromides.a
94 (47)
69
21
22
23
24
2a
2b
2c
2d
1
1
1
1
72
75
88 (39)
73
25
26
27
28
29
30
31
32
2a
2b
2c
2d
2a
2b
2c
2d
1
1
1
1
8
8
8
8
84
81
94 (55)
77
70
71
82 (< 5)
57
.
Entry
Aryl bromide
[Pd]
Product
Time (h)
Yield (%)b,c
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2a
2b
2c
2d
0.5
0.5
0.5
0.5
1
1
1
1
70
81
98
77
63
68
87 (46)
59
a
Conditions: [Pd] 2a-2d (0.01 equiv.,
1 mol%), 3,5-dimethylisoxazole
(2 equiv.), aryl bromide (1 equiv.), KOAc (2 equiv.), DMA (2 mL), 120 °C.
b
Yields were calculated with respect to aryl bromide from the results of GC
spectrometry.
a
Conditions: [Pd] 2a-2d (0.01 equiv.,
1 mol%), 3,5-dimethylisoxazole
c
Yields obtained after 30 min were shown in parentheses.
(2 equiv.), heteroaryl bromide (1 equiv.), KOAc (2 equiv.), DMA (2 mL), 120 °C.
b
Yields were calculated with respect to heteroaryl bromide from the results
bromoanisole, which an electron-rich aryl bromide, was also led to 3,5-
dimethyl-4-(4-methoxyphenyl)isoxazole [24], with 68–87% yield in
presence of 2a-2d catalysts for 4 h (Table 3, entries 9–12). The same
reaction took place in less than 5% yield in the presence of 2c catalyst
for 30 min (Table 3, entry 11). The reaction of 3,5-dimethylisoxazole
with 4-bromobenzaldehyde gave almost quantitative amount of desired
product 4-(3,5-dimethylisoxazol-4-yl)benzaldehyde [25], in the pre-
sence of 2c catalyst for 1 h, whereas the reaction gave much lower
yields in 30 min (Table 3, entry 15). When 3,5-dimethylisoxazole was
used with 4-bromoacetophenone in presence of 2c catalyst for 1 h, we
obtained to high yields of 4-(3,5-dimethylisoxazol-4-yl)acetophenone
[11], (Table 3, entry 19). 1-Bromo-4-fluorobenzene which was a
slightly activated aryl bromide gave the expected product 3,5-dimethyl-
4-(4-fluorophenyl)isoxazole [11], in moderate to high yields in the
presence of 2a-2d catalysts (Table 3, entries 21–24). However, when 2c
catalyst was used for 30 min, only 39% yield was observed (Table 3,
entry 23). The reaction of 3,5-dimethylisoxazole with 4-bromobenzo-
trifluoride gave the 3,5-dimethyl-4-(4-(trifluoromethyl)phenyl)iso-
xazole [11], in 94% and 84% yields in the presence of 2c and 2a cat-
alysts, respectively (Table 3, entries 27 and 25). When 1-Bromo-4-tert-
butylbenzene which was deactivated aryl bromide was used, we
of GC spectrometry.
c
Yields obtained after 30 min were shown in parentheses.
obtained 3,5-dimethyl-4-(4-tert-butylphenyl)isoxazole [24], in 82%
yield in the presence of 2c catalyst after 8 h. Even in the presence of the
2c complex which was the most active catalyst, this substrate was not
susceptible to reaction, therefore we obtained a yield of less than 5% in
30 min (Table 3, entry 31).
Next, we examined the reactivity of 2-bromotoluene and 2-bromo-
benzonitrile which were ortho-substituted aryl bromides with 3,5-di-
methylisoxazole (Table 4). ortho-Substituents on the aryl bromides
generally have a more important effect on the yields of most palladium-
catalyzed reactions due to their steric and/or coordination properties.
The reaction of 3,5-dimethylisoxazole with 2-bromotoluene gave the
3,5-dimethyl-4-(o-tolyl)isoxazole [23], in 74% yield in the presence of
2c catalyst, but it took 8 h to achieve this yield. The same reaction took
place in less than 5% yield in the presence of 2c catalyst in 30 min
(Table 4, entry 3). However, when 2-bromobenzonitrile was used, we
obtained good yields of coupling products 2-(3,5-dimethylisoxazol-4-yl)
benzonitrile [11], in presence of 2b and 2c catalysts in lower reaction
time such as 2 h (Table 4, entry 6 and 7).
5

M. Kaloğlu and İ. Özdemir
InorganicaChimicaActa504(2020)119454
Then, we examined the reactivities of heteroaryl bromides such as
3-bromoquinoline and 2-bromothiophene with 3,5-dimethylisoxazole
(Table 5). Pyridine derivatives such as quinolines are known π-electron-
deficient heterocycles. Therefore, reactivity of these type compounds is
quite similar to electron-deficient aryl bromides such as 4-bromoace-
tophenone or 1-bromo-4-fluorobenzene. As expected, using 3-bromo-
quinoline, we obtained the coupling product 3-(3,5-dimethylisoxazol-4-
yl)quinoline [11], in very high yield with only 1 mol% of 2a-2d cata-
lysts for 30 min (Table 5, entries 1–4). 2-Bromothiophene gave also the
expected 3,5-dimethyl-4-(thiophene-2-yl)isoxazole [26], in very good
yields in presence of 2c catalyst. But, when reaction time was reduced
to 30 min, the yield dropped to 46% (Table 5, entry 7).
available transition-metal catalyts [7–11]. But, to our knowledge, this
study is the first report of the direct C4-arylation of 3,5-dimethylisox-
azole with (hetero)aryl bromides catalyzed by imidazolidin-2-ylidene
based PEPPSI-type palladium complexes. Moreover, further studies fo-
cused on the sythesis of new imidazolidin-2-ylidene based palladium
complexes and their applicability to other heteroaromatics by using via
CeH activation process are currently underway in our laboratory.
4. Experimental
4.1. General remarks
Finally, in the present work, 1 mol% catalyst loading was used, and
the reaction time was shortened to 0.5–8 h. Moreover, 3,5-dimethyli-
soxazole was efficiently arylated at the C4-position, and satisfactory
results were obtained as compared to previously reported similar stu-
dies [7–11].
All manipulations were carried out under argon atmosphere using
standard Schlenk line techniques. PdCl2, pyridine, 4-phenoxybutyl
bromide, 3,5-dimethylisoxazole, all (hetero)arylbromides, all bases,
and all solvents were commercially providedand used without further
purification. Melting points were measures in open capillary tubes with
an Electrothermal-9200 melting points apparatus. The C, H and N
elemental analyses were determined by LECO CHNS-932 elemental
analyser. FT-IR spectra were recorded on GladiATR unit (Attenuated
Total Reflection) in range of 450–4000 cm−1 with a Perkin Elmer
Spectrum 100 Spectrometer. The 1H NMR and 13C NMR spectra were
recorded with a Bruker Ascend™ 400 Avance III HD NMR spectrometer
with sample solutions prepared in CDCl3. The NMR studies were carried
out in high-quality 5 mm NMR tubes. The chemical shifts (δ) were re-
ported in ppm relative to CDCl3. Coupling constants (J values) were
given in hertz. NMR multiplicities were abbreviated as follows:
s = singlet, d = doublet, t = triplet, dd = doublet of doublets,
tt = triplet of triplets, ddd = doublet of doublet of doublets,
m = multiplet. 1H NMR spectra were referenced to residual protiated
solvents (δ = 7.28 ppm for CDCl3), 13C NMR chemical shifts were re-
ported relative to deuterated solvents (δ = 77.16 ppm for CDCl3). All
catalytic reactions were determined by using Shimadzu GC 2025 with
GC-FID sensor and RX-5 ms column of 30 m length, 0.25 mm diameter
and 0.25 μm film thickness.
For the last two decades, the role of the steric and electronic effects
on the catalytic activity has been researched for the NHC ligands using
a variety of techniques in the literature [15b,15d,27]. But still, under-
standing of the role of these effects on the catalytic activity are highly
limited. In this study, we preferred saturated imidazolidin-2-ylidene
ligands bearing 4-phenoxybutyl with O- donor, and sterically bulky
benzyl substituents. We known that, when saturated imidazolidin-2-
ylidene ligands were compared with imidazolin-2-ylidenes which were
unsaturated analogues in terms of both steric bulk and electron donor
ability, imidazolidin-2-ylidenes were a better donor ligands than their
unsaturated analogue [27b]. Also, altering the N-substituent on the
NHC ligand would allow the topography around the metal to be tuned
to ensure the required steric bulk for reductive elimination is in place.
Of the palladium complexes 2a-2c, progressively better results were
seen as the number of methyl groups of the N-benzyl rings were in-
creased from mono-methyl to tri-methyl, and from tri-methyl to penta-
methyl. Therefore, steric factors are likely much more at work in the
improved performance of 2c complex. Electronic effects are as im-
portant as steric effects. Therefore, the presence of NHC ligands bearing
a different second donating group such as ether side chains on the metal
may radically increase the catalytic performance of the catalyst. The
chelating nature of these ligands promotes production of highly stable
complexes. The hemilabile part of such ligands is capable of reversible
dissociation to produce vacant coordination sites, allowing complexa-
tion of substrates during the catalytic cycle. At the same time the strong
donor-carbene moiety remains connected to the metal centre [27b].
Therefore, we believe that such substituents on the NHC ligands pro-
vides the synergetic steric and electronic effects to confer the metal
center the appropriate properties to make optimum to key steps of the
catalytic cycles.
4.2. General procedure for the preparation of imidazolinium salts as
carbene precursors (1a-1d)
1-(Substitutedbenzyl)-imidazoline (5 mmol) was dissolved in de-
gassed DMF (5 mL) and 4-phenoxybutyl bromide (1.145 g, 5 mmol) was
added under argon atmosphere. The solution was stirred at 80 °C for
16 h. After completion of the reaction, diethyl ether (15 mL) was added
to obtain a white crystalline solid, which was filtered off. The solid was
washed with diethyl ether (3 × 10 mL), and dried under vacuum. The
crude product was recrystallized from EtOH/Et2O mixture (1:5, v/v) at
room temperature, and completely dried under vacuum. The imidazo-
linium salts 1a-1c were isolated as air- and moisture-stable white solids
in 67–80% yields.
3. Conclusion
In summary, we prepared four new imidazolinium salts as carbene
precursors and their corresponding four new PEPPSI-type palladium
complexes. The catalytic properties of these complexes were evaluated
in the direct C4-arylation of 3,5-dimethylisoxazole with a wide variety
of (hetero)aryl bromides by using 1 mol% of palladium catalyst. In
presence of low catalyst loading, the direct arylation process provided
an economically and environmentally attractive procedure for the
preparation of a variety of 4-aryl-3,5-dimethylisoxazoles. This process
using commercially available substrates was very simple, and the air
stability of the catalysts we prepared also made this procedure very
convenient. Also, only AcOH and HBr were formed as by-products, thus
the by-product formation was minimized compared to the multi-step
conventional transition metal-catalyzed reactions such as Suzuki or
Stille reactions. We would like to mention that all of the 4-aryl-3,5-
dimethylisoxazole products we prepared in these catalytic studies have
been described in the literature before in presence of commercially
4.2.1. 1-(4-Phenoxybutyl)-3-(4-methylbenzyl)imidazolinium bromide (1a)
Yield 80%, 1.163 g (white solid); mp: 111–112 °C; FT-IR (vC(2)-N):
1650 cm−1
.
1H NMR (400 MHz, CDCl3, 25 °C, TMS):
δ
(ppm) = 1.78–1.83 (m, 2H, NCH2CH2CH2CH2OC6H5); 1.85–1.90 (m,
2H, NCH2CH2CH2CH2OC6H5); 2.30 (s, 3H, NCH2C6H4(CH3)-4); 3.68 (t,
J = 7.1 Hz, 2H, NCH2CH2CH2CH2OC6H5); 3.75–3.80 and 3.91–3.93
(m, 4H, NCH2CH2N); 3.96 (t, J = 6.0 Hz, 2H, NCH2CH2CH2CH2OC6H5);
4.77 (s, 2H, NCH2C6H4(CH3)-4); 6.83 (d, J = 7.9 Hz, 2H, arom. Hs of
NCH2CH2CH2CH2OC6H5); 6.90 (t, J = 7.3 Hz, 1H, arom. H of
NCH2CH2CH2CH2OC6H5); 7.13 (d, J = 7.9 Hz, 2H, arom. Hs of
NCH2CH2CH2CH2OC6H5); 7.22 (d, J = 8.0 Hz, 2H, arom. Hs of
NCH2C6H4(CH3)-4); 7.26 (d,
NCH2C6H4(CH3)-4); 9.96 (s, 1H, NCHN). 13C NMR (101 MHz, CDCl3,
25 °C, TMS): (ppm) 21.19 (NCH2C6H4(CH3)-4); 24.17
J = 8.0 Hz, 2H, arom. Hs of
δ
=
(NCH2CH2CH2CH2OC6H5); 26.09 (NCH2CH2CH2CH2OC6H5); 47.67
(NCH2CH2CH2CH2OC6H5); 48.16 and 48.46 (NCH2CH2N); 51.79
6

M. Kaloğlu and İ. Özdemir
InorganicaChimicaActa504(2020)119454
(NCH2C6H4(CH3)-4); 66.76 (NCH2CH2CH2CH2OC6H5); 114.41, 120.78,
128.88, 129.44, 129.49, 129.86, 138.95 and 158.58 (arom. Cs of
NCH2CH2CH2CH2OC6H5 and CH2C6H4(CH3)-4); 157.90 (NCHN).
J
=
8.3 Hz, 2H, arom. Hs of NCH2C6H4(C(CH3)3)-4); 7.39 (d,
J = 8.3 Hz, 2H, arom. Hs of NCH2C6H4(C(CH3)3)-4); 10.01 (s, 1H,
NCHN). 13C NMR (101 MHz, CDCl3, 25 °C, TMS): δ (ppm) = 24.20
(NCH2CH2CH2CH2OC6H5); 26.12 (NCH2CH2CH2CH2OC6H5); 31.25
(NCH2C6H4(C(CH3)3)-4); 34.67 (NCH2C6H4(C(CH3)3)-4); 47.70
(NCH2CH2CH2CH2OC6H5); 48.25 and 48.36 (NCH2CH2N); 51.87
(NCH2C6H4(C(CH3)3)-4); 66.78 (NCH2CH2CH2CH2OC6H5); 114.43,
120.82, 126.18, 128.67, 129.41, 129.53, 152.18 and 158.59 (arom. Cs
of NCH2CH2CH2CH2OC6H5 and NCH2C6H4(C(CH3)3)-4); 158.17
(NCHN). Elemental analysis calcd. (%) for C24H33BrN2O
(M.w. = 445.45 g.mol−1): C 64.71, H 7.47, N 6.29; found (%): C 64.86,
H 7.56, N 6.35.
Elemental
analysis
calcd.
(%)
for
C21H27BrN2O
(M.w. = 403.36 g.mol−1): C 62.53, H 6.75, N 6.95; found (%): C 62.74,
H 6.85, N 7.04.
4.2.2. 1-(4-Phenoxybutyl)-3-(2,4,6-trimethylbenzyl)imidazolinium
bromide (1b)
Yield 71%, 1.531 g (white solid); mp: 116–117 °C; FT-IR (vC(2)-N):
1651 cm−1
(ppm)
.
1H NMR (400 MHz, CDCl3, 25 °C, TMS):
1.85–1.94 (m, 4H, NCH2CH2CH2CH2OC6H5 and
δ
=
NCH2CH2CH2CH2OC6H5);
NCH2C6H2(CH3)3–2,4,6);
2.27
3.75
and
J
2.36
7.1
(s,
Hz,
9H,
2H,
(t,
=
4.3. General procedure for the preparation of imidazolidin-2-ylidene based
NCH2CH2CH2CH2OC6H5); 3.79–3.81 and 3.96–3.98 (m, 4H,
NCH2CH2N); 4.02 (t, J = 5.6 Hz, 2H, NCH2CH2CH2CH2OC6H5); 4.86 (s,
2H, NCH2C6H2(CH3)3–2,4,6); 6.86 (dd, J = 8.7, 0.9 Hz, 2H, arom. Hs of
palladium-PEPPSI complexes (2a-2d)
A solution of imidazolinium salts, 1a-1c (1 mmol), PdCl2 (0.177 g,
1 mmol), K2CO3 (0.691 g, 5 mmol), KBr (1.190 g, 10 mmol) and pyr-
idine (0.119 g, 1.5 mmol) in 10 mL of acetonitrile was stirred at 80 °C
for 16 h. Then, all volatiles were removed under vacuum, and the solid
residue was washed with n-pentane (2 × 5 mL). The crude product was
dissolved in CH2Cl2 (5 mL), then filtered through a pad of celite and
silica gel (70–230 mesh) to remove the unreacted imidazolinium salt,
PdCl2 and pyridine. The crude complex was crystallized from CH2Cl2/n-
pentane mixture (1:5, v/v) at room temperature and, completely dried
under vacuum. Imidazolidin-2-ylidene based palladium-PEPPSI com-
plexes were isolated as air- and moisture-stable yellow solids in 44–64%
yields.
NCH2CH2CH2CH2OC6H5);
6.89
(s,
2H,
arom.
Hs
of
NCH2C6H2(CH3)3–2,4,6); 6.95 (dt, J = 10.6, 4.1 Hz, 1H, arom. H of
NCH2CH2CH2CH2OC6H5); 7.26 (dd, J = 7.0, 1.6 Hz, 2H, arom. Hs of
NCH2CH2CH2CH2OC6H5); 9.57 (s, 1H, NCHN). 13C NMR (101 MHz,
CDCl3, 25 °C, TMS):
δ
(ppm)
=
20.25 and 20.98
(NCH2C6H2(CH3)3–2,4,6); 24.23 (NCH2CH2CH2CH2OC6H5); 26.03
(NCH2CH2CH2CH2OC6H5); 46.32 (NCH2CH2CH2CH2OC6H5); 47.84
(NCH2C6H2(CH3)3–2,4,6); 48.26 and 48.32 (NCH2CH2N); 66.84
(NCH2CH2CH2CH2OC6H5); 114.41, 120.87, 125.34, 129.54, 129.86,
137.89, 139.12 and 158.55 (arom. Cs of NCH2CH2CH2CH2OC6H5 and
CH2C6H2(CH3)3–2,4,6); 157.71 (NCHN). Elemental analysis calcd. (%)
for C23H31BrN2O (M.w. = 431.47 g.mol−1): C 64.03, H 7.24, N 6.49;
found (%): C 64.42, H 7.87, N 6.67.
4.3.1. Dibromo-[1-(4-phenoxybutyl)-3-(4-methylbenzyl)imidazolidin-2-
ylidene](pyridine)palladium(II) (2a)
4.2.3. 1-(4-Phenoxybutyl)-3-(2,3,4,5,6-pentamethylbenzyl)imidazolinium
bromide (1c)
Yield 44%, 0.293 g (yellow solid); mp: 117–118 °C; FT-IR (vC(2)-N):
1602 cm−1
.
1H NMR (400 MHz, CDCl3, 25 °C, TMS):
δ
Yield 78%, 1.791 g (white solid); mp: 157–158 °C; FT-IR (vC(2)-N):
(ppm) = 1.89–1.94 (m, 2H, NCH2CH2CH2CH2OC6H5); 1.96–2.01 (m,
2H, NCH2CH2CH2CH2OC6H5); 2.27 (s, 3H, NCH2C6H4(CH3)-4);
3.32–3.37 and 3.55–3.60 (m, 4H, NCH2CH2N); 4.03 (t, J = 5.8 Hz, 2H,
1653 cm−1
(ppm)
.
1H NMR (400 MHz, CDCl3, 25 °C, TMS):
1.84–1.93 (m, 4H, NCH2CH2CH2CH2OC6H5 and
δ
=
NCH2CH2CH2CH2OC6H5);
NCH2C6(CH3)5–2,3,4,5,6);
NCH2CH2CH2CH2OC6H5); 3.87–3.91 and 3.98–4.02 (m, 4H,
NCH2CH2N); 4.03 (t, J = 5.4 Hz, 2H, NCH2CH2CH2CH2OC6H5); 4.90 (s,
2H, NCH2C6(CH3)5–2,3,4,5,6); 6.83 (d, J = 7.9 Hz, 2H, arom. Hs of
NCH2CH2CH2CH2OC6H5); 6.94 (t, J = 7.3 Hz, 1H, arom. H of
NCH2CH2CH2CH2OC6H5); 7.26 (d,
NCH2CH2CH2CH2OC6H5); 9.19 (s, 1H, NCHN). 13C NMR (101 MHz,
CDCl3, 25 °C, TMS): (ppm) 16.92, 17.14 and 17.21
(NCH2C6(CH3)5–2,3,4,5,6); 24.30 (NCH2CH2CH2CH2OC6H5); 25.95
(NCH2CH2CH2CH2OC6H5); 47.43 (NCH2CH2CH2CH2OC6H5); 48.27 and
48.28 (NCH2CH2N); 48.42 (NCH2C6H(CH3)4–2,3,5,6); 66.94
(NCH2CH2CH2CH2OC6H5); 114.34, 120.87, 125.48, 129.53, 133.38,
133.63, 136.62 and 158.52 (arom. Cs of NCH2CH2CH2CH2OC6H5 and
CH2C6(CH3)5–2,3,4,5,6); 157.16 (NCHN). Elemental analysis calcd. (%)
for C25H35BrN2O (M.w. = 459.47 g.mol−1): C 65.35, H 7.68, N 6.10;
found (%): C 65.49, H 7.81, N 6.22.
2.21,
3.74
2.24
(t,
and 2.31
6.7
(s,
Hz,
12H,
2H,
NCH2CH2CH2CH2OC6H5);
4.13
(t,
J
=
7.2
Hz,
2H,
J
=
NCH2CH2CH2CH2OC6H5); 5.23 (s, 2H, NCH2C6H4(CH3)-4); 6.83–6.87
(m, 2H, arom. Hs of NCH2CH2CH2CH2OC6H5); 7.10 (d, J = 7.8 Hz, 2H,
arom. Hs of NCH2C6H4(CH3)-4); 7.16–7.22 (m, 4H, arom. Hs of
NCH2CH2CH2CH2OC6H5 and NCH2C6H4(CH3)-4); 7.38 (ddd, J = 7.9,
5.2, 1.4 Hz, 2H, arom. Hs of pyridine); 7.65 (tt, J = 7.4, 1.5 Hz, 1H,
arom. H of pyridine); 8.88 (dd, J = 6.3, 1.4 Hz, 2H, arom. CHs of
pyridine). 13C NMR (101 MHz, CDCl3, 25 °C, TMS): δ (ppm) = 21.22
J = 7.5 Hz, 2H, arom. CHs,
δ
=
(NCH2C6H4(CH3)-4);
(NCH2CH2CH2CH2OC6H5); 47.58 (NCH2CH2CH2CH2OC6H5); 48.42 and
50.34 (NCH2CH2N); 54.71 (NCH2C6H4(CH3)-4); 67.28
24.30
(NCH2CH2CH2CH2OC6H5);
26.50
(NCH2CH2CH2CH2OC6H5); 114.58, 120.60, 128.85, 129.42, 129.45,
132.18 and 158.99 (arom. Cs of NCH2CH2CH2CH2OC6H5 and
CH2C6H4(CH3)-4); 124.49, 137.79 and 152.44 (arom. Cs of pyridine);
180.79 (Pd-Ccarbene). Elemental analysis calcd. (%) for C26H31Br2N3OPd
(M.w. = 667.78 g.mol−1): C 46.76, H 4.68, N 6.29; found (%): C 47.00,
H 4.75, N 6.58.
4.2.4. 1-(4-Phenoxybutyl)-3-(4-tert-butylbenzyl)imidazolinium
(1d)
bromide
4.3.2. Dibromo-[1-(4-phenoxybutyl)-3-(2,4,6-trimethylbenzyl)
imidazolidin-2-ylidene](pyridine)palladium(II) (2b)
Yield 67%, 1.492 g (white solid); mp: 100–101 °C; FT-IR (vC(2)-N):
Yield 61%, 0.425 g (yellow solid); mp: 147–148 °C; FT-IR (vC(2)-N):
1662 cm−1. 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ (ppm) = 1.30 (s,
1601 cm−1
(ppm)
NCH2CH2CH2CH2OC6H5);
.
1H NMR (400 MHz, CDCl3, 25 °C, TMS):
δ
9H,
NCH2C6H4(C(CH3)3)-4);
1.85–1.89
(m,
2H,
=
1.87–1.99 (m, 4H, NCH2CH2CH2CH2OC6H5 and
2.20 and 2.34 (s, 9H,
NCH2CH2CH2CH2OC6H5); 1.91–1.94 (m, 2H, NCH2CH2CH2CH2OC6H5);
3.75 (t, J = 7.0 Hz, 2H, NCH2CH2CH2CH2OC6H5); 3.78–3.82 and
NCH2C6H2(CH3)3–2,4,6); 3.07–3.12 and 3.45–3.50 (m, 4H,
NCH2CH2N); 4.03 (t, J = 5.8 Hz, 2H, NCH2CH2CH2CH2OC6H5); 4.13 (t,
3.92–3.97 (m, 4H, NCH2CH2N); 4.01 (t,
J = 5.7 Hz, 2H,
NCH2CH2CH2CH2OC6H5); 4.81 (s, 2H, NCH2C6H4(C(CH3)3)-4); 6.87 (d,
J = 7.9 Hz, 2H, arom. Hs of NCH2CH2CH2CH2OC6H5); 6.93 (t,
J = 7.3 Hz, 1H, arom. H of NCH2CH2CH2CH2OC6H5); 7.25 (d,
J = 7.4 Hz, 2H, arom. Hs of NCH2CH2CH2CH2OC6H5); 7.33 (d,
J
=
7.2 Hz, 2H, NCH2CH2CH2CH2OC6H5); 5.22 (s, 2H,
NCH2C6H2(CH3)3–2,4,6); 6.80–6.85 (m, 5H, arom. Hs of
NCH2CH2CH2CH2OC6H5 and NCH2C6H2(CH3)3–2,4,6); 7.16–7.24 (m,
4H, arom. Hs of NCH2CH2CH2CH2OC6H5 and pyridine); 7.66 (tt,
7

M. Kaloğlu and İ. Özdemir
InorganicaChimicaActa504(2020)119454
J = 7.7, 1.6 Hz, 1H, arom. H of pyridine); 8.91 (dd, J = 6.5, 1.5 Hz,
2H, arom. Hs of pyridine). 13C NMR (101 MHz, CDCl3, 25 °C, TMS): δ
4.4. General procedure for the direct C4-arylation of 3,5-dimethylisoxazole
with (hetero)aryl bromides
(ppm)
=
20.82 and 20.99 (NCH2C6H2(CH3)3–2,4,6); 24.39
(NCH2CH2CH2CH2OC6H5); 26.50 (NCH2CH2CH2CH2OC6H5); 47.69
(NCH2CH2CH2CH2OC6H5); 47.93 and 48.87 (NCH2CH2N); 50.61
(NCH2C6H2(CH3)3–2,4,6); 67.28 (NCH2CH2CH2CH2OC6H5); 114.57,
120.99, 128.24, 129.20, 129.44, 137.90, 138.48 and 158.99 (arom. Cs
of NCH2CH2CH2CH2OC6H5 and CH2C6H(CH3)4–2,3,5,6); 124.49,
137.77 and 152.46 (arom. Cs of pyridine); 181.56 (Pd-Ccarbene).
3,5-Dimethylisoxazole (0.049 g, 0.5 mmol, 2 equiv.), aryl bromide
derivative (0.25 mmol, 1 equiv.), KOAc (0.049 g, 0.5 mmol, 2 equiv.),
and DMA (2 mL) were added to an oven dried Schlenk tube under argon
atmosphere.
Subsequently,
the
palladium-catalyst
(2a-2c)
(0.005 mmol, 0.01 equiv., 1 mol%) was added to stirred solution in a
Schlenk tube, and the closed Schlenk tube was stirred at 120 °C. Then,
this solution was stirred for different durations, as given in Tables 3–5.
End of the reaction, the solution was cooled to room temperature and
CH2Cl2 (1 mL) was then added to the crude mixture. This solution was
used for GC analysis and yields (%) were calculated according to
(hetero)aryl bromide. The chemical characterization of the C4-arylated
product was made by 1H NMR spectrometry.
Elemental
analysis
calcd.
(%)
for
C28H36Br2N3OPd
(M.w. = 696.84 g.mol−1): C 48.26, H 5.21, N 6.03; found (%): C 48.45,
H 5.38, N 6.14.
4.3.3. Dibromo-[1-(4-phenoxybutyl)-3-(2,3,4,5,6-pentamethylbenzyl)
imidazolidin-2-ylidene](pyridine) palladium(II) (2c)
Yield 64%, 0.463 g (yellow solid); mp: 266–267 °C; FT-IR (vC(2)-N):
CRediT authorship contribution statement
1601 cm−1
(ppm)
NCH2CH2CH2CH2OC6H5);
.
1H NMR (400 MHz, CDCl3, 25 °C, TMS):
δ
=
1.89–1.98 (m, 4H, NCH2CH2CH2CH2OC6H5 and
2.16, 2.18 and 2.30 (s, 15H,
Murat Kaloğlu: Conceptualization, Methodology, Investigation,
Writing - original draft, Writing - review & editing, Funding acquisition.
NCH2C6(CH3)5–2,3,4,5,6); 3.08–3.13 and 3.44–3.49 (m, 4H,
NCH2CH2N); 4.03 (t, J = 5.7 Hz, 2H, NCH2CH2CH2CH2OC6H5); 4.13 (t,
İsmail Özdemir: Conceptualization, Writing
Supervision.
-
original draft,
J
=
7.1 Hz, 2H, NCH2CH2CH2CH2OC6H5); 5.32 (s, 2H,
NCH2C6(CH3)5–2,3,4,5,6); 6.83–6.87 (m, 3H, arom. Hs of
NCH2CH2CH2CH2OC6H5); 7.17–7.24 (m, 4H, arom. Hs of
NCH2CH2CH2CH2OC6H5 and pyridine); 7.66 (tt, J = 7.6, 1.5 Hz, 1H,
arom. H of pyridine); 8.92 (dd, J = 6.4, 1.4 Hz, 2H, arom. Hs of pyr-
idine). 13C NMR (101 MHz, CDCl3, 25 °C, TMS): δ (ppm) = 16.81,
Acknowledgements
This study was supported by the Technological and Scientific
Research Council of Turkey TÜBİTAK (Project No: 119R003).
16.06
(NCH2CH2CH2CH2OC6H5); 25.48 (NCH2CH2CH2CH2OC6H5); 46.79
(NCH2CH2CH2CH2OC6H5); 48.63 (NCH2CH2N); 49.54
and
16.47
(NCH2C6(CH3)5–2,3,4,5,6);
23.36
Declaration of Competing Interest
The authors declare no conflict of interest.
Appendix A. Supplementary data
(NCH2C6(CH3)5–2,3,4,5,6); 66.25 (NCH2CH2CH2CH2OC6H5); 113.53,
119.53, 127.41, 128.39, 131.81, 133.08, 134.26 and 157.96 (arom. Cs
of NCH2CH2CH2CH2OC6H5 and CH2C6(CH3)5–2,3,4,5,6); 123.44,
136.70 and 151.43 (arom. Cs of pyridine); 180.17 (Pd-Ccarbene).
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.ica.2020.119454.
Elemental
analysis
calcd.
(%)
for
C30H39Br2N3OPd
(M.w. = 723.89 g.mol−1): C 49.78, H 5.43, N 5.80; found (%): C 49.99,
H 5.55, N 5.95.
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