Aerobic Cu and amine free Sonogashira and Stille couplings of aryl bromides/chlorides with a magnetically recoverable Fe3O4@SiO2 immobilized Pd(II)-thioether containing NHC

Article abstract of DOI:10.1016/j.tetlet.2021.152844

Two value added C–C cross coupling reactions; Sonogashira and Stille couplings were achieved at milder conditions in the catalytic presence of a magnetically recoverable heterogeneous catalyst Fe₃O₄@SiO₂@NHC^SPh-Pd(II). The catalyst was earlier reported for Suzuki-Miyaura reaction, and as an extension of its catalytic efficiency, the Stille and Sonogashira cross coupling reactions under aerobic condition has been explored in present report. The Sonogashira coupling of aryl bromides and terminal alkynes produced an excellent yield (~96% at 0.25 mol% Pd) of the desired coupling product under copper and amines free conditions. Moreover, an excellent Stille coupling of readily available and more latent aryl chlorides and trialkylstannane was obtained (yields up to 95% at 0.25 mol% Pd) in absence of toxic fluorides additives. The broad substrate scope of the catalyst for both the coupling reactions and the magnetically recoverable feature of catalyst make this reaction highly desirable for industrial applications of present heterogeneous catalysis.

Full text of DOI:10.1016/j.tetlet.2021.152844

Tetrahedron Letters 67 (2021) 152844
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Tetrahedron Letters
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Aerobic Cu and amine free Sonogashira and Stille couplings of aryl
bromides/chlorides with a magnetically recoverable Fe3O4@SiO2
immobilized Pd(II)-thioether containing NHC
a,
Himanshu Khandaka a, Kamal Nayan Sharma b, , Raj Kumar Joshi
⇑
⇑
a Department of Chemistry, Malaviya National Institute of Technology, Jaipur 302017, Rajasthan, India
b Department of Chemistry, Amity School of Applied Sciences (ASAS), Amity University Haryana, Manesar, Gurugram 122413, Haryana, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Two value added CAC cross coupling reactions; Sonogashira and Stille couplings were achieved at milder
Received 30 October 2020
Revised 6 January 2021
Accepted 10 January 2021
Available online 2 February 2021
conditions in the catalytic presence of
a magnetically recoverable heterogeneous catalyst
Fe3O4@SiO2@NHC^SPh-Pd(II). The catalyst was earlier reported for Suzuki-Miyaura reaction, and as an
extension of its catalytic efficiency, the Stille and Sonogashira cross coupling reactions under aerobic con-
dition has been explored in present report. The Sonogashira coupling of aryl bromides and terminal alky-
nes produced an excellent yield (~96% at 0.25 mol% Pd) of the desired coupling product under copper and
amines free conditions. Moreover, an excellent Stille coupling of readily available and more latent aryl
chlorides and trialkylstannane was obtained (yields up to 95% at 0.25 mol% Pd) in absence of toxic fluo-
rides additives. The broad substrate scope of the catalyst for both the coupling reactions and the magnet-
ically recoverable feature of catalyst make this reaction highly desirable for industrial applications of
present heterogeneous catalysis.
Keywords:
Thioether-NHC
Pd-catalyst
Copper free Sonogashira coupling
Stille coupling
Heterogeneous catalysis
Ó 2021 Elsevier Ltd. All rights reserved.
The CAC bond forming reactions catalyzed by palladium based
catalysts [1] are currently rank amongst most versatile and straight
forward protocols in laboratory as well as industrial organic syn-
thesis of pharmaceuticals, agrochemicals, natural products, thera-
peutic agents and many other value added organic materials [2].
The Pd and Cu (as co-catalyst) catalyzed Sonogashira coupling of
terminal alkynes and aryl/vinyl halide/triflate is of utmost impor-
tance among the Pd catalyzed coupling reactions [3]. The Sono-
gashira cross coupling has shown outstanding applications in the
synthesis of biaryl derivatives of acetylene which are key interme-
diates in the multistep synthesis of several naturally occurring
compounds, pharmaceutical, organic-LEDs, sensing of carbohy-
drates, new carbon allotropes and carbon rich materials [4]. How-
ever, the certain limitations of Sonogashira coupling which are
quiet predominant are the use of amine and co-catalyst copper
salt. In presence of co-catalyst copper salt, the copper acetylide
undergo Glaser-Hay homo coupling under aerobic conditions [5].
Moreover, the use of amines for deprotonation in such cross cou-
pling reactions is not environmental benign. Therefore, the devel-
opment of new catalytic system is required, which can avoid the
use of copper and amine in coupling reactions. For biaryl forma-
tion, the Stille coupling is an important Pd catalyzed cross coupling
reaction which coupled the organostannanes and organic halides/
triflate in the presence of metal fluorides activators [6,7]. However,
the toxicity of organostannane compounds which are used in sto-
ichiometric amount is still a prime drawback of the reaction, but
some reports indicate the isolation of toxic tin residue from the
desired product [8].
A broad spectrum of Pd based homogeneous catalysts contain-
ing sterically hindered phosphanes [9], PEPPSI based Pd catalyst
[10], palladacycles [9b,11] and NHC-Pd catalyst [12] have been
envisioned for Pd activated cross coupling reactions. The catalytic
systems reported for Sonogashira reaction required high Pd load-
ing (generally 1.0 mol% or more), and high working temperature
[13,14]. Furthermore, the recovery and reusability of the catalyst
is also a major issue associated with homogeneous catalytic sys-
tems. The removal of the catalyst from the reaction is highly essen-
tial to avoid the metal contaminations especially in the
pharmaceutical and drugs molecules [15]. Therefore, given the cur-
rent scenario of catalysis, the main focus is to develop a catalyst
which can fulfill both the criteria of (i) good activity as homoge-
neous catalyst (ii) and good recoverability to avoid the wastage
of non-renewable precious metals. Solid supported metal catalysts
offer a combination of both the properties, and also make them
⇑
Corresponding authors.
E-mail address: rkjoshi.chy@mnit.ac.in (R.K. Joshi).
https://doi.org/10.1016/j.tetlet.2021.152844
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

H. Khandaka, Kamal Nayan Sharma and Raj Kumar Joshi
Tetrahedron Letters 67 (2021) 152844
economically viable and applicable to a broad range of essential
catalytic conversions [16]. In this context, the NHCs have gained
wide applications in organometallic chemistry and serve as better
alternative of toxic, expensive, difficult to handle and sterically
hindered phosphines [13c,17]. Owing to the availability of two
transformation of respective coupling products was recorded
(Scheme 2).
To find the optimum conditions for the significant transforma-
tions, the optimization of various reaction parameters was initi-
ated and summarized in Table 1. It was begin with the solvent
optimization, and a range of polar and non-polar solvents were
screened, the first trial was carried out in neat water at 90 °C,
but no product formation observed (Table 1, entry 1). The reaction
was again repeated in water along with the addition of a phase
transfer catalyst tetra-n-butylammonium bromide (TBAB) to
enhance the catalyst activity in water, reaction initiated but only
the trace of coupling product was obtained (Table 1, entry 2). Var-
ious other solvents including the DMSO, toluene, 1,4-dioxane and
acetonitrile were also investigated but all together failed to
improve the yield of product (Table 1, entries 3–8). However, an
excellent yield of the product (96%) was exclusively obtained in
DMF solvent, hence, DMF was found to be ideal solvent for the pre-
sent reaction.
Traditionally, the Sonogashira reactions essentially desire the
presence of copper as a co-catalyst and a significant amount of
amines. In the present method, Sonogashira coupling performed
well in the absenteeism of both copper and amines. However, it
is observed that base is essentially required for the reaction, as
reaction does not work in the absence of base (Table 1, entry 9).
Various strong and weak bases such as potassium carbonate,
cesium carbonate, sodium acetate, sodium hydroxide and potas-
sium hydroxide were investigated (Table 1, entries 3 and 10–13).
It was observed that reaction is selectively works in presence of
K2CO3 (up to 96% yield), while other base failed to mimic the reac-
tions The amount of catalyst was also examined and it was found
that 15 mg of the catalyst (contains 0.25 mol% of Pd, determined
by ICP-AES analysis) significantly bring the optimum transforma-
tions (Table 1, entry 3). Reducing the catalyst amount, drastically
reduces the product yield (Table 1, entries 14–17). During the opti-
electrons stronger
r
-donor and very weak
p-accepting
coordination behavior of NHC ligands, their NHC-metal
complexes have gained a unique balance of stability versus
reactivity, which is highly desired in catalysis [13c,17,18]. The
NHC ligands are strongly coordinated to the metal center and
thereby contribute the much needed stability of the catalytic
system and also prevent leaching of metal during the catalytic
process. Apart of that, NHC ligands also favor the metal center
more electron-rich and provide affluence in the important
oxidative addition process of reaction. In contrast to phosphines,
the organochalcogen containing complexes are robustly works in
air/moisture and aqueous system with greater efficiency [19].
Therefore, having a mindset of a unique combinations of NHC
and thioether donors, both had mixed and a heterogeneous cata-
lyst Fe3O4@SiO2@NHC^SPh-Pd(II) was crafted [19e]. The catalyst
is fully explored for the Sonogashira and Stille cross coupling
reactions. The catalyst have showen an excellent activity, and
emerged as an efficient recoverable Pd catalyst for Sonogashira
coupling under aerobic condition, and Stille cross coupling
reactions of highly desirable, readily available and inexpensive
chloroarenes.
The solid supported Pd catalyst; Fe3O4@SiO2@NHC^SPh-Pd(II)
was synthesized by reported method (Scheme 1) [19e]. The
quantity of the palladium bonded to the surface of Fe3O4@SiO2
nanoparticles was determined by ICP-AES analysis of Fe3O4@SiO2
supported Pd(II)-thioether-NHC complex. The concentration of Pd
was estimated to be 0.167 mmol of Pd/g.
Activity of Fe3O4@SiO2@NHC^SPh-Pd(II) in catalysis for
Sonogashira Cross Coupling
Table 1
To elucidate the catalytic potential of Fe3O4@SiO2@NHC^SPh-Pd
(II) for various cross coupling reactions, the Sonogashira cross-cou-
pling reaction of the acetylene and aryl bromide in DMF solvent
under open air conditions was investigated, and good to excellent
Reaction parameters optimizations for Sonogashira cross coupling catalyzed with
Fe3O4@SiO2 supported Pd(II)-thioether-NHC catalyst.a
Entry No.
Pd catalyst
(in mg)
Base
used
Temp. (°C)
Solvent
(2.0 mL)
Yield (%)
1
15
15
15
15
15
15
15
15
15
15
15
15
15
12
10
8
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
No base
Cs2CO3
NaOAc
NaOH
KOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
60
70
80
100
Water
Waterb
DMF
Toluene
1,4-Dioxane
THF
DMSO
Acetonitrile
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Nd
Trace
96
2b
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Nd
Nd
Nd
Nd
Nd
Nd
Nd
Nd
Nd
Nd
85
Scheme 1. Synthesis of Fe3O4@SiO2 supported Pd(II)-thioether-NHC catalyst.
70
Trace
Nd
Nd
49
80
96
5
15
15
15
15
15 examples
a
Conditions: bromobenzene (0.157 g, 1.0 mmol), phenyl acetylene (0.122 g,
1.2 mmol), 15 mg Pd catalyst contains 0.25 mol% Pd, time (12 h), isolated yield after
column chromatography, solvent (2.0 mL), base (1.4 mmol).
Scheme 2. Copper and amine free Sonogashira cross coupling catalyzed with Fe3-
O4@SiO2 supported Pd(II)-thioether-NHC heterogeneous catalyst.
b
TBAB (0.161 g, 0.5 mmol) used; Nd (not detected).
2

H. Khandaka, Kamal Nayan Sharma and Raj Kumar Joshi
Tetrahedron Letters 67 (2021) 152844
mization of reaction temperature, the reaction was screened from
room temperature but no product was obtained up to 60 °C, how-
ever, a trace of the product was observed at 70 °C. Moving towards
the higher temperature, significantly increased the yield of product
(Table 1, entries 18–21) and a maximum 90% yield was obtained at
90 °C. Among all screened conditions, 1.0 mmol of aryl bromide,
1.2 mmol of phenylacetylene, 1.4 mmol of K2CO3, 0.25 mol%
(15 mg) of catalyst in 2 mL of DMF at 90 °C under aerobic condi-
tions furnished the optimum yields of cross-coupled product in
12 h. The product yield was significantly affected by the duration
of reaction. The time profile of a representative Sonogashira cou-
pling reaction of bromobenzene with phenyl acetylene was studied
and shown in Fig. 1. The formation of the desire cross-coupled pro-
duct was detected just after 1 h of the reaction. The % conversion of
the substrate consistently increases with time and the highest
yield was achieved in 12 h. Further stirring the reaction mixture
does not produce any significant changes in the yield of the
product.
high level of reactivity in the Sonogashira coupling of bromoben-
zene and electron accepting group (R = CN, CHO, COCH3, NO2,
CF3) substituted aryl bromides such as 4-bromobenzonitrile, 1-
bromo-4-nitrobenzene, 1-acetyl-4-bromobenzene, 4-bromoben-
zaldehyde and 1-bromo-4-(trifluoromethyl)benzene with phenyl
acetylene was observed (Table 2, entries 1b-1f). A series of linear
p-conjugated systems having a strong electron accepting group
at an end (electron pull system) were successfully synthesized.
Outstanding results in the coupling of electron donating group
(–OCH3) substituted aryl bromide with phenyl acetylene was also
observed and one end electron push linear
p-conjugated system
was synthesized in good yield (Table 2, entry 1g). The reaction
scope for terminal alkyne derivatives was investigated in and sev-
eral substituted aryl acetylene substrates including the ones with
the electron donating groups as well as the electron withdrawing
groups were used and good yields of desire cross coupling products
was obtained (Table 2, entries 1h-1m). Here, it is worth mention-
ing that by using the combinations of substituted aryl bromides
and aryl acetylene, some pull-pull (Table 2, compound 1j and 1k)
and push–pull (Table 2, compounds 1i, 1l and 1m) systems were
successfully prepared in good yields. Moreover, reaction also works
well for heteroaryl bromides, as the coupling of 3-(phenylethynyl)
quinoline and 3-(phenylethynyl)pyridine with phenylacetylene
resulted 69% and 75% yield of the desired products (1m and 1n).
A typical Sonogashira cross coupling reaction require an inert
atmosphere under strict air and moisture free dry conditions
[3,20], while present Sonogashira reaction is performed in a reac-
tion tube in an open air conditions.
With the optimized conditions in hand, the present coupling
reaction was further generalized for a vast substrate scope of both
the reactants; the aryl bromide and terminal alkynes (Table 2). A
A comparison of the catalytic activity of Fe3O4@SiO2@NHC^SPh-
Pd(II) with previously reported Pd catalyst for copper and amine
free Sonogashira coupling reaction has been made. A recyclable
heterogeneous Pd catalyst supported on zeolite was reported for
copper free Sonogashira coupling of aryl bromides but the catalyst
needed 1 mol% of Pd along with 10 mmol of Et3N under inert atmo-
sphere to achieve maximum conversions [21]. PdCl2(PPh3)2 com-
plex with tetra-n-butylammonium fluoride (TBAF) as activator
[22] reported as efficient homogeneous catalyst for copper, amine
and solvent free Sonogashira coupling of ArI, Br and Cl under dry
reaction conditions, however, reaction demands a high catalyst
loading (3.0 mol% Pd) [23].
Fig. 1. Time profile of the Sonogashira coupling of bromobenzene and phenyl
acetylene catalyzed with Pd(II)-thioether-NHC catalyst.
A nonsymmetrical PCN pincer Pd complex was also reported to
catalyze Sonogashira coupling under copper free condition but it
was only applicable for aryl iodide substrates and needs amine
base and larger catalyst loading (2 mol%) [24]. The palladacycle
(40 °C, 0.5 mol% Pd, Et3N) [25] and Pd(NH3)2Cl2 complex with
2,20-dipyridylamine ligand (rt, 0.1 mol%, aryl iodide substrate)
[26] are also found a bit less efficient to present recyclable Pd-cat-
alyst under copper free, amine free and inert atmosphere free
Sonogashira coupling. Elhage et al. reported [27] TiO2 (Pd@TiO2),
CND (Pd@CND) or Nb2O5 (Pd@Nb2O5) supported Pd NPs as efficient
air/moisture tolerant catalysts for the copper/amine free Sono-
gashira coupling reaction of aryl iodides. Their catalytic studies
demonstrated that direct visible excitation of the Pd NP is required
and the catalyst can be reused a couple of times but lost activity
due to a reductive photochemical reaction. Furthermore, the cata-
lyst activated the Sonogashira coupling of aryl iodides substrates
only. The chalcogen containing palladacycles were also reported
as air, moisture insensitive and efficient catalyst for copper/amine
free Sonogashira coupling under aerobic conditions [28]. These
chalcogen containing palladacycles were comparable with the pre-
sent catalyst in terms of air/moisture insensitivity, Pd catalyst
loading, copper or amine free condition, temperature, recyclability
but the nature of the catalysis is of cocktail type between homoge-
neous and heterogeneous [28]. The present catalyst is undoubtedly
an efficient recyclable heterogeneous Pd(II) catalyst with having
additional filtration-free, magnetically retrievable features for the
Table 2
Substrate scope of aryl bromides and terminal alkynes used for Sonogashira cross
coupling catalyzed with Fe3O4@SiO2@NHC^SPh-Pd(II) catalyst.a
a
Optimized Conditions: aryl or heteroaryl bromide (1.0 mmol), acetylene
derivative (1.2 mmol), Cat. [Pd]: Fe3O4@SiO2@NHC^SPh-Pd(II) (0.015 g, 0.25 mol%
Pd), temp (90 °C), time (12 h), isolated yields are given, DMF (2.0 mL), K2CO3
(0.200 g, 1.4 mmol), EWG (electron withdrawing groups) and EDG (electron
donating groups).
3

H. Khandaka, Kamal Nayan Sharma and Raj Kumar Joshi
Tetrahedron Letters 67 (2021) 152844
catalysis of copper and amine free Sonogashira coupling reaction
under aerobic conditions and also this is for the first time when
the organochalcogen functionalized NHC-Pd(II) complex is studied
in the catalysis of Sonogashira coupling reaction.
(inorganic species) in organic solvent as well as the solvation of
organic substrates in water during catalysis. In order to further
improve the yield, the reaction was investigated with various sol-
vent trials (Table 3, entry 2–6). The yield was improved satisfacto-
rily when DMF-Water solvent mixture was used (Table 3, entry 2).
The best result in terms of product yield was obtained when dry
DMF was used for the reaction (Table 3, entry 3). It was observed
that the base is an essential requisite for the successful completion
and best output of the reaction. Hence, different bases including
K2CO3, Cs2CO3, CH3COONa, NaOH, and KOH were investigated for
the reaction (Table 2, entry 7–10), of these, the sodium acetate
and potassium carbonate was found to be efficient for the present
coupling reaction and gave 90% and 95% yield of the desired prod-
ucts respectively. In all the optimization reactions, 15 mg of cata-
lyst was used, it works well for all reactions. Decreasing the
amount of catalyst from 15 mg, drastically reduced the product
yield (Table 3, entry 11–15). In all the optimization reactions the
working temperature was 90 °C. A diminished yield of the cross
coupled product was observed on lowering the reaction tempera-
ture. Hence, after all the optimizations, aryl bromide (1.0 mmol),
tributylphenylstannane (1.0 mmol), K2CO3 (1.5 mmol), catalyst
(0.015 g) in 2 mL of DMF at 90 °C under aerobic conditions resulted
the maximum yields of the desired product in 6 h.
Activity of Fe3O4@SiO2@NHC^SPh-Pd(II) catalyst for Stille cross
coupling reaction
Encouraged by the outstanding catalytic potential of the Fe3-
O4@SiO2 supported Pd(II)-thioether-NHC catalyst for Suzuki-
Miyaura coupling [19e], copper/amine free Sonogashira coupling,
the catalyst was also investigated for Stille cross coupling
reaction. The Pd-catalyst work efficiently and it also activates the
readily available and more latent aryl chlorides to produce the
desire coupling product under aerobic reaction conditions
(Scheme 3).
The reaction conditions were optimized using the representa-
tive substrate combination for Stille coupling reaction (Table 3).
The reaction of tributylphenylstannane and chlorobenzene was
initially performed in water and TBAB, a considerable yield was
observed (Table 3, entry 1). The ionic species formed with the
phase transfer catalyst (TBAB) during the course of coupling reac-
tion are soluble in both organic as well as aqueous phases, and con-
tinuously transfer between both the phases facilitating coupling
reaction [29]. Therefore, TBAB plays important role to accelerate
the cross coupling reaction by facilitating the solvation of the base
After having the best possible combinations of reaction param-
eters, the general scope of Stille coupling for a variety of aryl bro-
mides/chlorides and organostannes compounds in presence of
Fe3O4@SiO2 supported Pd(II)-thioether-NHC catalyst at 90 °C under
aerobic conditions was investigated. It was noted, that the tradi-
tional Stille cross coupling reaction require fluoride reagents, those
are toxic but essential to activate the organotin compounds for
transmetallation. The present reaction was performed in complete
absence of toxic fluoride additive.
Moreover, after the completion of reaction, the Bu3SnX salt was
easily removed by passing it through silica (with 2–5% triethy-
lamine in the eluent) or immediately purifying by standard column
chromatography. Coupling of electron withdrawing substituent at
para position of aryl chlorides e.g. 4-chloro- benzaldehyde, 4-
chlorobenzonitrile, 4-chloronitrobenzene, 4-chloroaceophenone
and 4-chlorobenzoic acid gave good yield of cross coupling prod-
ucts (Table 4, entries 2b-2f). The present coupling reaction does
not work with the aryl chlorides containing an electron donating
group. The Stille coupling of activated bromoarenes with
tributylphenylstannane was completed in optimum time of 6 h.
The deactivated para substituted aryl bromides were also found
to provide the high yield of biaryl cross coupled products (Table 4,
entries 2g and 2h). Both 4-bromoanisole and 4-bromotoluene with
tributylphenylstannane gave unambiguously results in the form of
90% and 93% yield of cross coupled product, respectively. The N-
heterocyclic aromatic halides for Stille coupling reactions were
also tested in present catalytic investigations (Table 4, entries 2i-
2k). The catalyst worked efficiently in case of heteroaryl bromide
substrates as the yield up to 92% was obtained with 5-bromopy-
rimidine (Table 4, entry 2k). Some Stille coupling reactions by
using a thiophene containing organotin compound; 2-(tributyl-
stannyl)thiophene with aryl bromides/chloride were also explored
to test the catalytic efficiency of present Pd catalyst (Table 4,
entries 2m-2o) and a decent yields of respective cross coupled pro-
duct was obtained.
15 examples
Scheme 3. Stille cross coupling catalyzed with Fe3O4@SiO2 supported Pd(II)-
thioether-NHC heterogeneous catalyst.
Table 3
Reaction parameters optimizations for Stille cross coupling catalyzed with Fe3O4@-
SiO2 supported Pd(II)-thioether-NHC catalyst.a
Entry No.
Pd Cat.
(in mg)
Base used
Temp.
(°C)
Solvent
Yield
(%)
1
2
3
4
5
6
7
8
15
15
15
15
15
15
15
15
15
15
15
14
12
10
8
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
NaOAc
NaOH
KOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
Water, TBAB
DMF-Water
DMF
Toluene
1,4-Dioxane
THF
58
75
95
Nd
Nd
Nd
Nd
90
Nd
Nd
95
89
60
50
Nd
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
9
10
11
12
13
14
15
In contrast to previous reports on Stille cross couplings, com-
parisons have been made between the previous catalysts and the
current recyclable palladium catalyst. Su et al., reported Pd2(dba)3,
and proazaphosphatrane (supporting ligand), as an efficient sys-
tem for homogeneous catalysis of Stille cross couplings of aryl
chloride. But higher Pd-catalyst loading (1.5 mol%), use of toxic flu-
oride additive (CsF), longer reaction time (24–48 h) and require-
ment of argon atmospheres increase the overall cost of the
DMF
a
Reaction conditions: Chlorobenzene (0.157 g, 1.0 mmol), tributylphenylstan-
nane (0.367 g, 1.0 mmol), Cat. [Pd]: Fe3O4@SiO2@NHC^SPh-Pd(II) (0.015 g, 0.25 mol
% Pd), time (6 h), isolated yield after column chromatography, solvent (2.0 mL), Nd
(not detected).
4

H. Khandaka, Kamal Nayan Sharma and Raj Kumar Joshi
Tetrahedron Letters 67 (2021) 152844
Table 4
and heteroaryl substrates. It should be noted that the Pd(II) com-
plex of organochalcogen ligands and any chalcogenated NHC have
not been applied yet for the catalysis of Stille cross coupling reac-
tion and therefore, this is the first example of the organochalcogen
functionalized NHC-Pd(II) complex studied for the catalysis of
Stille cross coupling reaction so far.
Substrate scope of Stille cross coupling reaction catalyzed with Fe3O4@SiO2 supported
Pd(II)-thioether-NHC catalyst.a
The reusability of Pd catalyst; Fe3O4@SiO2@NHC^SPh-Pd(II) was
studied for both the Sonogashira and Stille coupling reactions by
using the representative reactions of bromobenzene with pheny-
lacetylene and tributylphenylstannane, respectively (see details
in experimental section). After completion of reaction, the catalyst
was magnetically retrieved (as shown in Figure 2) and the cross
coupling product was decanted out by mixing with organic solvent
thereof.
In each recycling run, new batch of bromobenzene, pheny-
lacetylene (Sonogashira coupling), tributylphenylstannane (Stille
coupling), K2CO3 and DMF were added to the reaction tube and
the reaction mixture was subjected to continuous stir under opti-
mized reaction conditions. The present Pd catalyst exhibited
appreciable recyclability up to three cycles with very less decrease
in efficiency but after third run a larger decrease (~10% decrease in
yield) in efficiency was observed. The results of all recycling exper-
iments is depicted in Figure 3, which shows the yields observed in
five cycles for both the coupling reactions catalyzed by the solid
supported Pd catalyst. The approximate 10% decrease in yield of
cross coupled product after 2–3 run may be due to the leaching
of discrete Pd from the silica coated Fe3O4 NPs. The Pd content in
the Fe3O4@SiO2 supported Pd catalyst was determined by ICP-
AES analysis of the sample, before and after three catalytic cycles.
bYield isolated ArCl substrates, solvent (2.0 mL), EWG (electron withdrawing group)
and EDG (electron donating group).
a
Reaction conditions: ArBr/Cl (1.0 mmol), tributylphenylstannane (0.367 g,
1.0 mmol), Pd catalyst (0.015 g, 0.0025 mmol, 0.5 mol% Pd), K2CO3 (0.200 g,
1.4 mmol), temp (90 °C), time (6 h), isolated yield after column chromatography.
synthesis [30]. Pd nanoparticles were also reported as efficient
recyclable catalyst for Stille coupling reaction of aryl bromide
and chloride but requirement of higher Pd loading (2.5 mol%) for
good conversions is again a major drawback of the reaction [31].
A heterogeneous approach has been developed for chloro deriva-
tives with 0.05 mol% palladium, however, use of CsF additive was
an essential requisite of the reaction [32]. A organosilica anchored
Pd(II) complex was found to work as a recyclable and efficient cat-
alyst for the Stille coupling reaction but reaction is sensitive and
only works in argon atmosphere [33], moreover, good conversion
demands a CsF additive, more reaction time and a relatively higher
temperature than the present method. Pd catalyst based on Pd NPs
supported on magnetite (magnetically retrievable) has also been
employed for Stille coupling [34], it was established as a phos-
phine-free heterogeneous Pd catalyst, it worked efficiently, stable
and recyclable but it was found to be selective only for aryl bro-
mides [34]. Pd nanoparticles supported on mesoporous graphitic
carbon nitride were also found highly effective and can be reused
further for Stille coupling of aryl bromide/iodides under mild con-
ditions but at high catalyst loading (3.28 mol%) [35]. In 2017, Gha-
simi et al. reported a Pd- free Stille coupling reaction catalyzed by
conjugated microporous polymer based photo-catalyst under visi-
ble light irradiation at room temperature, however, the scope of
reaction was limited up to aryl iodide, while only one product of
each aryl bromide/chloride has been explored [36]. Thus, the pre-
sent thioether-NHC Pd(II) complex immobilized on SiO2@Fe3O4
NPs may be labeled as highly efficient, reusable catalyst as the
yields up to 96% (ArBr) and 82% (ArCl) without any fluoride addi-
tive. The catalytic process is also simple, much more effective in
terms of reaction time, does not demand fluorides salts, catalyst
recyclability and gives biaryls in good amount for a range of aryl
Fig. 2. Magnetic removal of the catalyst after catalytic run (a) after catalyzing
reaction (b) separation of the catalyst using an external magnet.
Fig. 3. Recycling of the Pd catalyst for Sonogashira and Stille coupling reactions
under optimized reaction parameters.
5

H. Khandaka, Kamal Nayan Sharma and Raj Kumar Joshi
Tetrahedron Letters 67 (2021) 152844
For fresh sample of the catalyst, the wt% of Pd was measured to
1.78% and after three cycles it was reduced to 1.42% due to the
leaching of Pd from the surface of Fe3O4@SiO2 supported Pd cata-
lyst. The leached Pd content is probably the amide/amine coordi-
nated Pd which decomposed in the first and second run of the
catalysis. It is possible that some amide/amine groups might left
intact during the immobilization of thioether functionalized benz-
imidazole moiety on to the surface of Fe3O4@SiO2–NH2 or Fe3O4@-
SiO2-amide-NH2 NPs. The disruption of the silica coating due to the
mechanical stirring stress may also be another possible reason for
the observed decrease in the catalyst efficiency during its reuse.
evaporator and the desired cross coupled product was obtained
after column chromatographic purifications on silica gel.
General procedure for Stille cross coupling reaction
A mixture of organostannes (1.0 mmol) and aryl/heteroaryl
chloride/bromide (1.0 mmol), K2CO3 (0.200 g, 1.4 mmol) and cata-
lyst (15 mg) in DMF (2.0 mL) was stirred at 90 °C in reaction tube.
The reaction was continuously monitored on TLC until the maxi-
mum conversion of the desired product obtained. On completion,
the product was extracted in diethyl ether (20 ꢀ 2 mL). The solvent
was removed with a rotary evaporator, and then subjected to chro-
matographic separation to get the purified cross coupling products.
Heterogeneous nature of catalysis
The heterogeneous nature of this Fe3O4@SiO2 supported Pd cat-
alyst has been established in earlier report for the catalysis of
Suzuki-Miyaura coupling reaction in which the Pd leaching was
analyzed through ICP-AES measurement and hot-filtration test.
Present study also includes a hot filtration test for the typical Sono-
gashira coupling of 4-bromobenzaldehyde with phenylacetylene
for to ascertain the heterogeneous or homogeneous nature of catal-
ysis. After the initial 3 h of Sonogashira coupling, the yield of the
cross coupled product was measured (~40%, NMR yield) and Pd-
nanoparticles were magnetically separated from the reaction. The
reaction mixture was then split in two equal halves; one half
was transferred in another reaction tube and let the reaction run
without catalyst, while the isolated Pd-catalyst NPs were added
into another half reaction mixture. Both reactions tube were
allowed to stir under optimized reaction conditions for another
12 h and product yield was measured through 1H NMR. Reaction
without any added catalyst shows ~48% NMR yield, while reaction
with added catalyst shows ~94% yield of the desire coupling prod-
uct. These results supports the heterogeneous nature of the catal-
ysis, here, the strong binding interaction of the Pd(II)–NHC-
thioether on the surface of Fe3O4@SiO2 NPs prevent the leaching
of discrete palladium into the solution. It also has been supported
through the poor conversion of 48% observed in 12 h of the reac-
tion, whereas the 40% transformation was observed in initial 3 h
of reaction before magnetically isolation of the catalyst.
Procedure for recyclability of the catalyst
In a reaction tube, bromobenzene (1.0 mmol), phenyl acetylene/
organostannes (1.0 mmol), Pd catalyst (15 mg), K2CO3 (1.4 mmol),
were mixed in DMF (2 mL). The mixture was then stirred at opti-
mized temperature on oil bath. After 3 h, the mixture was cooled
to room temperature and 50 lL from the reaction mixture was pip-
ette out to analyze the conversion% by proton NMR. The solution
was decanted and the catalyst was washed and dried with suitable
solvent (diethyl ether or ethyl acetate) by putting an external mag-
net on outer wall of the reaction tube. Thereafter, a new lot of sub-
strate and base was added without new catalyst loading and the
reaction mixture was again allowed to run again for maximum
standardized reaction time under similar reaction conditions. The
procedure was keep on repeating for further catalytic cycles.
Hot-filtration test
In order to ascertain the nature of catalysis, homogeneous or
heterogeneous, a typical Sonogashira coupling of 4-bromoben-
zaldehyde and phenylacetylene in presence of Fe3O4@SiO2 immo-
bilized Pd catalyst was investigated in detail under the optimized
reaction conditions. 4-bromobenzaldehyde (0.185 g, 1.0 mmol),
phenylacetylene (0.122 g, 1.2 mmol), K2CO3 (0.207 g, 1.5 mmol),
catalyst (15 mg, 0.25 mol%) and DMF (2.0 mL) were taken in a reac-
tion tube and stirred at 90 °C. After 1 h, the catalyst was removed
magnetically by using an external magnet and the reaction mixture
was decanted off and also filtered with G4-crucible. The liquid fil-
trate was then divided in two halves; one half was transferred into
another reaction tube and further run the reaction without addi-
tion of catalyst, while the isolated Pd-catalyst NPs were added into
the remaining half. Both reaction tubes were allowed to stir under
optimized similar reaction conditions for next 12 h and yield of
expected product was analyzed through 1H NMR.
Conclusion
In conclusion, the magnetically recoverable Fe3O4@SiO2 sup-
ported Pd(II)-thioether-NHC heterogeneous catalyst is efficiently
work for Sonogashira and Stille cross coupling reactions under aer-
obic conditions. The catalyst found to be highly efficient and recy-
clable for Sonogashira coupling reactions and it coupled a wide
varieties of aryl bromides with terminal alkynes in copper and
amine free conditions. The present catalyst is an ideal example of
highly desirable, efficient and recyclable heterogeneous Pd-cata-
lysts, which efficiently works for Stille cross coupling under aero-
bic conditions, and smoothly coupled aryl chlorides and aryl
bromides. The catalyst can be easily separated and reused up to
three catalytic cycles without much loss in its catalytic efficiency.
Conflict of Interest
No conflict of interest exists.
Funding
Experimental
All of the sources of funding for the work described in this pub-
lication are acknowledged below: Council of Scientific and Indus-
trial Research (CSIR) (Grant No. 01(2996)/19/EMR-II). SERB,
Department of Science and Technology (SERB, DST New Delhi).
Procedure for Sonogashira coupling reaction
A mixture of terminal alkyne (1.5 mmol), K2CO3 (1.4 mmol,
0.200 g), aryl bromides (1.0 mmol) and catalyst (0.015 g) in DMF
(2.0 mL) was stirred at 90 °C. Reaction was monitored on TLC until
the optimum conversion of the cross coupled product was
obtained. After the completion of the reaction, the crude product
was extracted in diethyl ether. The solvent was removed by rotary
Research Ethics
We further confirm that any aspect of the work covered in this
manuscript does not involved any human patients or studies.
6

H. Khandaka, Kamal Nayan Sharma and Raj Kumar Joshi
Tetrahedron Letters 67 (2021) 152844
1164;
Declaration of Competing Interest
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