A sustainable heterogenized palladium catalyst for Suzuki-Miyaura cross coupling reaction of azaheteroaryl halides in aqueous media

Article abstract of DOI:10.1016/j.jorganchem.2018.02.030

A unique recyclable Pd catalyst (‘SiO₂’-NH₂-Pd) for Suzuki-Miyaura coupling reaction of azaheteroaryl halides is developed. The catalytic system is working under mild aqueous condition with low Pd loading and without the use of phosphine ligand. The plausible mechanism is proposed based on the formation of undesired symmetrical biaryl from the coupling reaction of azaheteroaryl chlorides due to the oxidative homocoupling of nucleophilic arylboronic acid. This catalytic system represents an attractive and promising approach for the synthesis of azaheterobiaryls with high product yields. The catalyst has demonstrated an excellent recyclability.

Full text of DOI:10.1016/j.jorganchem.2018.02.030

Accepted Manuscript
A sustainable heterogenized palladium catalyst for Suzuki-Miyaura cross coupling
reaction of azaheteroaryl halides in aqueous media
S. Ganesamoorthy, M. Muthu Tamizh, K. Shanmugasundaram, R. Karvembu
PII:
S0022-328X(18)30129-3
10.1016/j.jorganchem.2018.02.030
JOM 20329
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 11 September 2017
Revised Date: 10 February 2018
Accepted Date: 21 February 2018
Please cite this article as: S. Ganesamoorthy, M. Muthu Tamizh, K. Shanmugasundaram, R. Karvembu,
A sustainable heterogenized palladium catalyst for Suzuki-Miyaura cross coupling reaction of
azaheteroaryl halides in aqueous media, Journal of Organometallic Chemistry (2018), doi: 10.1016/
j.jorganchem.2018.02.030.
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ACCEPTED MANUSCRIPT
A sustainable heterogenized palladium catalyst for Suzuki-Miyaura cross
coupling reaction of azaheteroaryl halides in aqueous media
S. Ganesamoorthya,b, M. Muthu Tamizhc, K. Shanmugasundaramb and R. Karvembu*a
aDepartment of Chemistry, National Institute of Technology, Tiruchirappalli 620015, India
bDiscovery Chemistry, Syngene International Ltd., Biocon Park, Bommasandra Industrial Area, Bommasandra-
Jigani Link Road, Bangalore 560099, India
cDepartment of Chemistry, Siddha Central Research Institute, Central Council for Research in Siddha,
Arumbakkam, Chennai 600106, India
ABSTRACT
A unique recyclable Pd catalyst (‘SiO2’-NH2-Pd) for Suzuki-Miyaura coupling reaction of
azaheteroaryl halides is developed. The catalytic system is working under mild aqueous
condition with low Pd loading and without the use of phosphine ligand. The plausible
mechanism is proposed based on the formation of undesired symmetrical biaryl from the
coupling reaction of azaheteroaryl chlorides due to the oxidative homocoupling of
nucleophilic arylboronic acid. This catalytic system represents an attractive and promising
approach for the synthesis of azaheterobiaryls with high product yields. The catalyst has
demonstrated an excellent recyclability.
Keywords: Palladium catalyst; Suzuki-Miyaura coupling reaction; Azaheteroaryl halides
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1. Introduction
The azaheteroaryl units are integral parts of many active motifs; mostly
pharmaceuticals and herbicides are utilizing these units as bioisosteres. These units are
functional group alternates, which mimic the nature by ‘fooling’ it in a very subtle way [1,2].
In the field of charge transport materials, fused azaheterocycles exhibit excellent
photophysical properties due to their strong skeletal rigidity and large π-conjugation system
[3-6]. Latest research advancements hint the huge commercialization demands for
azaheteroaryl analogues. For instance, dual P13K/mTOR inhibitors BEZ235, GDC-0980 [7-
9], ATP-competitive mTOR inhibitors Torin 2, AZD8055 [10-14] and semiconducting
polymers PDTFTh-BT, PDTFPy-BT [15] are reported with sufficient promise in life style
applications (Fig. 1).
O
N
OH
H2N
N
CF3
NC
N
N
N
O
O
N
H2N
N
N
N
N
N
S
N
N
O
N
Torin 2
GDC-0980
BEZ235
CnH2n+1
S
H2n+1Cn
S
O
O
N
S
S
N
N
OH
S
N
N
N
Ar
Ar
Ar
S
n
N
O
and
N
AZD8055
PDTFTh-BT and PDTFPy-BT
Fig. 1. Commercially important molecules prepared via Suzuki-Miyaura cross coupling
reaction of azaheteroaryl halides.
Furthermore, functionalization of these molecules can be achieved via Suzuki-
Miyaura cross coupling reaction to induce structural diversity [16]. However, the potential
binding ability of the azaheteroaryl substrates to the metal center imposes certain limitations
on cross coupling reactions [17-19]. Therefore, Suzuki-Miyaura cross coupling reaction of
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azaheteroaryl substrates demands extra precaution to overcome such kind of interventions. In
many instances, Pd-catalyzed reactions of these moieties are suffering from undesired Pd-
traces in the final active ingredients, phosphine contamination, use of expensive ligands,
rigorous inert conditions and excess heating with hydrocarbon solvents [20-22]. Moreover,
allowed limit for traces of Pd left in the desired compound is very low (<10 ppm) in many
applications. In particular, minimizing the residual palladium in a pharmaceutical substance
to its tolerable concentration limit involves costly purification techniques [23]. In contrast,
extremely low loading of palladium led to agglomeration of active Pd(0) and consequently,
terminate the reaction in the halfway. Thus, aligning the environmental and economic
rewards to the large scale manufacturing processes and very importantly to manage
sustainable advancements, the inherent approach is to develop an appropriate reusable
catalytic system in green solvent. Although many reports are available on solid supported
heterogenized catalytic systems for Suzuki-Miyaura reaction [20-22, 24-27], only very few
dealt with coupling of azaheteroaryl substrates in aqueous medium [28]. In this context, we
report here a newly developed efficient heterogenized Pd catalyst (‘SiO2’-NH2-Pd) prepared
by replacing one of the coordinated CH3CN ligands in [PdCl2(CH3CN)2] with amine present
in functionalized silica (‘SiO2’-NH2). It was deduced that the grafting of the catalyst onto the
functionalized silica creates a steric congestion around the active Pd centre. This, in turn,
retards the displacement of second acetonitrile ligand. Moreover, silica is composed of
submicron-sized spheres. These spheres possess uniform pore size, large surface area, large
number of silanol groups, and a high chemical and thermal stability. Thus, it is considered as
a very promising candidate for catalyst support. This reusable catalyst mediates the Suzuki-
Miyaura coupling reaction of azaheteroaryl chlorides as well as bromides in aqueous
medium, with Na2CO3 as a base, affording excellent conversions. Advantageous feature of
this new catalyst is that it does not require typical deaerated and harsh reaction conditions,
and expensive ligands for stabilizing the catalyst in aqueous medium. Often these parameters
are perceived as critical for Suzuki-Miyaura coupling reactions using Pd catalyst.
2. Experimental section
2.1. Materials
All the reagents used were of chemically pure and analar grade. Commercial grade
solvents were distilled according to normal procedures and dried over molecular sieves
before use. Silica fumed (0.014 µm, surface area 225 m2/g) and 3-aminopropyltriethoxysilane
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were purchased from Sigma Aldrich and used without further purification. [PdCl2(CH3CN)2]
was prepared according to the literature method [29]. Amine functionalized silica
(‘SiO2’−NH2) was prepared according to the procedure as given below.
Fumed silica (1 g) was dispersed in dry toluene under N2 atmosphere. To this 3-
aminopropyl-1-triethoxysilane (12 mL) was added slowly and refluxed overnight under
stirring. The reaction mixture was cooled down to room temperature, 1.5 N HCl was added
slowly and stirred for an hour. The mixture was filtered and the resulting solid was washed
with acetone several times. The solid was dried at 100°C under vacuum for 6 h to get
‘SiO2’−NH2.
2.2. Immobilization of [PdCl2(CH3CN)2] on to amine functionalized silica (‘SiO2’−NH2−Pd)
[PdCl2(CH3CN)2] (200 mg) and ‘SiO2’−NH2 (1 g) were stirred at room temperature in
dry dichloromethane (20 mL) for 120 h. The mixture was filtered and washed several times
with dichloromethane. The obtained solid was subjected to Soxhlet extraction using
dichloromethane for two days to ensure leaching out of all unbound Pd complex. The solid
was dried at 100°C under vacuum for 6 h to give a pale yellow powder (1.1 g, 0.061 wt% of
Pd).
2.3. Catalyst characterization
The morphology and Pd content of the catalyst were analyzed by JEOL, JSM-6701F
field emission scanning electron microscope (FE-SEM). FT-IR spectra were obtained on a
Perkin Elmer Spectrum 100 FT-IR spectrophotometer as KBr pellet in the frequency range of
400-4000 cm-1. The BET surface area was measured using ASAP 2020 surface area analyzer.
The Pd content in the catalyst was measured by Perkin Elmer Optima 5300 DV inductively
coupled plasma optical emission spectrometer (ICP-OES). 13C CP-MAS solid state NMR was
recorded using Bruker AVANCE III-500 WB solid state NMR spectrometer equipped with
3.2 mm triple resonance (HXY) solid state probe. Shimadzu GC-2010 gas chromatograph
was used to monitor Pd-catalyzed Suzuki-Miyaura cross coupling reaction.
2.4. Procedure for Suzuki-Miyaura cross-coupling reaction
Azaheteroaryl halide (1 mmol), catalyst (0.005 – 0.05 mol %) and 1 M aq. Na2CO3
(1.1 mL) were stirred in a mixture of H2O-EtOH (1:2, 5 mL). The arylboronic acid (1.1
mmol) was added to the above mixture and stirring was continued for required time at 60°C.
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After the requisite time, reaction mixture was diluted with ethyl acetate and the catalyst was
separated by centrifugation. The centrifugate was dried over anhydrous sodium sulphate and
evaporated. Then the product was analyzed by GC-MS or LC-MS. The solution was
concentrated and chromatographed on a silica gel column with n-hexane-ethyl acetate (4:1)
as the eluting solvent to give the coupled product. The product was confirmed by 1H and 13C
NMR spectral analysis. The used catalyst was washed with water, ethanol and
dichloromethane, and dried under vacuum before reuse.
3. Results and discussion
3.1. Catalyst preparation
[PdCl2(CH3CN)2] was prepared according to the literature method [12]. Amine
functionalized silica (‘SiO2’−NH2) was prepared according to the procedure as given below.
Fumed silica (1 g) was dispersed in dry toluene under N2 atmosphere. To this 3-aminopropyl-
1-triethoxysilane (12 mL) was added slowly and refluxed overnight under stirring. The
reaction mixture was cooled down to room temperature, 1.5 N HCl was added slowly and
stirred for an hour. The mixture was filtered and the resulting solid was washed with acetone
several times. The solid was dried at 100°C under vacuum for 6 h to get ‘SiO2’–NH2.
[PdCl2(CH3CN)2] (200 mg) and ‘SiO2’−NH2 (1 g) were stirred at room temperature in dry
dichloromethane (20 mL) for 120 h. The mixture was filtered and washed several times with
dichloromethane. The obtained solid was subjected to Soxhlet extraction using
dichloromethane for two days to ensure leaching out of all unbound Pd complex. The solid
was dried at 100°C under vacuum for 6 h to give a catalyst as pale yellow powder (1.1 g,
0.061 wt% of Pd). (Fig. 2).
Fig. 2. Preparation of ‘SiO2’–NH2–Pd.
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3.2. Catalyst characterization
The newly prepared heterogenized catalyst was characterized by using different
analytical techniques. SEM images and SEM-EDX data are shown in the Fig. S1 and S2
respectively. The morphological changes during the grafting process were evident from SEM
images. ICP-OES confirms that the Pd loading is approximately 0.06 % per weight of the
total silica (5.8 × 10-5 mol/g of Pd on silica). A BET surface area of unfunctionalised silica
was 225 m2/g; while Pd anchored silica catalyst showed a surface area of 179 m2/g. The
expected decrease in the surface area is due to the attachment of Pd complex on to silica via
silyloxy linkage. The 13C CP-MAS NMR spectrum showed four peaks that reveal the
presence of four different aliphatic carbons (Fig. S3). The peak at 13.16 ppm is the
characteristic of methyl carbon in acetonitrile. The intense signals at 25.90, 27.16, 45.10 and
49.83 ppm were assigned to three carbons of the silyloxy amino propyl moiety. The observed
split in the peak at 25.90 ppm indicated that the carbons were attached to two different forms
of silicon i.e. Q type [Si(O−)4] and T-type [R1-Si-(O−)3]. During the grafting process, there
might be unreacted ethoxy groups in 3-aminopropyl-1-triethoxysilane [30]. The peaks at
45.10 and 49.83 ppm were assigned to the middle and terminal (attached to amino group)
carbons respectively. This confirms that the amino propyl group was bound to the support.
The FT-IR spectrum indicated the heterogenization of Pd complex on to the silica support
(Fig. S4). XPS analysis was carried out for the immobilized heterogenized catalyst to
understand the chemical states of surface elements (Fig. S5). The over-all XPS survey
spectrum showed peaks at 101, 152, 283, 336 and 530 eV which correspond to Si2p, Si2s,
C1s, Pd3d and O1s states [Fig. S5 (a)]. Gaussian−Lorentzian peak shape curve fitting was
used to find the shift in the peak. Prior to this, a Shirley baseline correction was made [31].
The binding energy values of O1s and Pd3p are very close to each other and thereby a
merged peak was observed ca. 531 eV. Gaussian−Lorentzian curve fitting of this spectrum
gave two peaks at 530.4 and 532.8 eV which were due to O1s and Pd3p respectively [32].
The broad Si2p spectrum was deconvoluted into two peaks with the binding energies of 101.1
and 103.8 eV which respectively confirmed the presence of Si−O and Si−C bonds [33,34].
Similarly, deconvolution of Pd3d spectrum furnished four peaks. The deconvoluted peaks
with binding energy values at 336.4 and 341.6 eV clearly authenticated the presence of Pd2+
[35]. In addition, a less intense Pd0 peaks were also identified at 334.2 and 339.1 eV [36].
TEM analysis was carried out to have clear vision on the particle size of Pd catalyst. The
magnified image showed that the Pd complexes were well dispersed and uniformly decorated
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all over the surface of SiO2 solid support. The ultrafine Pd particles with narrow size range
were recognized by the 20 and 10 nm bar scale images and particle size distribution graph
(Fig. 3). The particle size distribution was ranging from 1.2 to 2.0 nm and the mean diameter
of Pd particle was found to be ca. 1.6 nm. Interestingly, no free Pd was identified in the
background. It evidenced the strong and complete attachment of nano Pd complex onto the
SiO2 surface. The powder XRD pattern of the catalyst showed a broad peak at 2ꢀ = 22°,
which indicated low crystalline or amorphous nature of the catalyst (Fig. S5).
(a)
(b)
(c)
Fig. 3. TEM images of ‘SiO2’–NH2–Pd with (a) 20 nm, (b) 10 nm magnifications and (c) the
corresponding crystallite size distribution of Pd nano complex.
3.3. Optimization of Suzuki-Miyaura cross coupling reaction of azaheteroaryl halides
To attain the flawless experimental conditions, the impact of various bases, quantity
of catalyst and suitable solvent has been studied utilizing 5-bromopyrimidine and
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naphthalenen-2-boronic acid. Water has been opted as solvent from the economic and green
chemistry point of view. Since most of the azaheteroaryl halides possess poor solubility in
water, we decided to introduce water-organic solvent mixture to improve the solubility of
these substrates. Initially, we screened different combination of solvent mixtures to identify
the suitable solvent for optimal catalyst reactivity. Of different solvent mixtures screened,
aqueous mixtures of ethanol, DMF and DMSO showed good conversion. The role of water is
thought to be of two fold. Firstly, water in the reaction medium is suppose to accelerate the
coupling reaction via solvolytic transformation of ‘SiO2’-NH2-PdII into a more active catalyst
‘SiO2’-NH2-Pd-OH2 [37]. Secondly, it facilitates the solubility of base and boronic acid.
Thus, water helps the reaction to proceed smoothly even under mild conditions. Initially the
common bases like Na2CO3, K2CO3, NaOH, NaOMe, Et3N, Cs2CO3, K3PO4 and CsF were
screened using 0.01 mol% of heterogenized catalyst at 60°C. The NaOH and NaOMe have
shown lower conversion under the same reaction conditions as it is prone to compete for
aromatic nucleophilic substitution reaction. Noticeably 1.5 equiv. of Na2CO3 or K2CO3 was
found to be more persuasive as it showed good conversion within short span of time.
However counter ions were of not much influential, while the amount of base is important.
The economic concerns justified the use of Na2CO3 as base for all the further studies. We
observed homocoupling of boronic acid (~ 10 %) when we used 0.01 mol% of catalyst and
1.5 equiv. of base. The highest level of conversion was realized, when 1.1:1.1:0.005 equiv. of
boronic acid, base and catalyst were used at slightly elevated temperature (60°C) (Table 1,
entry 14). The 1:2 ratio of water and ethanol mixture has given promising conversion rates. It
has been noted that the presence of water in the reaction medium is most important.
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Table 1
Optimization of reaction conditionsa
'SiO2'-NH2-Pd
N
N
HO
HO
N
N
+
Br
B
Base, aq. Solvent
60°C
NBA
Base
Catalyst
(mol%)
0.01
Time Conv.b
(h) (%)
60
Entry
Solvent
Base
(equiv.)
(equiv.)
1
H2O-CH3CN
H2O-THF
1.5
Na2CO3 1.5
Na2CO3 1.5
Na2CO3 1.5
Na2CO3 1.5
Na2CO3 1.5
Na2CO3 1.5
K2CO3 1.5
2
2
2
2
2
2
2
4
5
4
3
5
2
2
1.5
1.5
1.5
1.5
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.005
60
65
75
79
89
85
80
84
81
75
80
90
3
H2O-Dioxane
H2O-DMF
4
5
H2O-DMSO
6
H2O-C2H5OH 1.5
H2O-C2H5OH 1.5
H2O-C2H5OH 1.5
H2O-C2H5OH 1.5
H2O-C2H5OH 1.5
H2O-C2H5OH 1.5
H2O-C2H5OH 1.5
H2O-C2H5OH 1.1
7
8
NaOH
1.5
9
Cs2CO3 1.5
K3PO4 1.5
NaOMe 1.5
10
11
13
14
CsF
1.5
Na2CO3 1.1
a5-Bromopyrimidine (1 mmol), ‘SiO2’-NH2-Pd, aq. solvent (5 mL), 60°C, NBA =
Naphthalenen-2-boronic acid. bDetermined by LC-MS.
3.4. Suzuki-Miyaura cross coupling reaction of azaheteroaryl bromides
The scope and limitations of this catalytic system for various azaheteroaryl bromides
were investigated (Table 2). The previous reports indicated that the position of bromide on
the azaheteroaromatic ring influences the efficiency of the coupling reaction [38-40]. It is
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worth to mention that coupling of 5-bromo-2-nitro pyridine with naphthalene-2-boronic acid
led to desired product in good yield (80%) after 8 h at 60°C (Table 2, entry 1). 5-
Bromonicotinic acid afforded coupled product in excellent yield (84%) with the use of 3
equiv. of base (Table 2, entry 2). The C−C coupling reaction of 2-bromonicotinic acid with
phenylboronic acid formed the desired heterobiaryl product in good conversion (Table 2,
entry 3) which is superior to that of two step cobalt-catalyzed arylation of nicotinic acid
[40,41]. 2-Bromo pyridine reacted with phenylboronic acid or 4-methylphenylboronic acid to
afford corresponding coupled product with significant conversion (Table 2, entries 4 and 5).
The conversion is better than that obtained from Pd-catalyzed Suzuki reaction of heteroaryl
fluorosulfates [42-46]. Generally, o-amino group in the azaheteroaryl halides is protected
prior to the Pd-catalyzed coupling reaction in order to deactivate the nitrogen atom towards
complexation process with Pd [47]. In this regard, 5-bromo-3-methoxypyrazin-2-amine was
examined as a substrate, the conversion was essentially quantitative (92%), suggesting that
oxidative addition is favored over complexation (Table 2, entry 6). The reaction of 5-bromo-
2-chloropyrimidine with aryl or heteroarylboronic acids produced corresponding biaryl
products without undergoing coupling at chloro position (Table 2, entries 7, 8 and 9). This
clearly indicates the chemoselective nature of ‘SiO2’-NH2-Pd. Coupling of 5-bromo-2-amino
pyrimidine was expected to be problematic, nonetheless underwent complete conversion
under optimized reaction conditions (Table 2, entry 10). The catalyst was tested for the
coupling of sulphur and oxygen containing heteroaromatic bromides. Notoriously, sulphur
atom in the substrates was known to poison the catalyst [48]. But, in the present case, 2-
bromobenzothiophene and 2-bromothiophene demonstrated high conversion (Table 2, entries
11 and 12); delightfully, the present catalyst is better than palladacycles derived from
phosphinamide [49-58]. Electron rich 5-bromobenzofuran readily reacted with 3-
(methoxycarbonyl)pheylboronic acid to produce the corresponding heterocyclic biaryl
product in good conversion (Table 2, entry 13). The reaction performed slightly on larger
scale (2 g) proved that this reaction can be scaled up without compromising the yield, which
revealed the possibility of application of ‘SiO2’-NH2-Pd in industries.
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Table 2
Suzuki-Miyaura cross coupling reaction of azaheteroaryl bromidesa
HO
HO
'SiO2'-NH2-Pd (0.005 mol%)
Azahetero
Ar/
Ar
Azahetero
Ar/
AzH
+
Br
B
AzH
Na2CO3 (1.1 equiv.)
H2O-EtOH, 60°C
Azahetero = pyridine, pyrazine,
pyrimidine, thiophene,
benzothiophene or
benzofuran
Ar = napthalene, benzene, toluene or
3-methoxycarbonyl benzene
AzH = 2,4-dimethoxy pyrimidine or
2-fluoro pyridine,
Conv. (Yieldb)
(%)
Entry
1
Ar−Br
Ar'−B(OH)2
Ar−Ar'
Time (h)
TON TOF (h-1)
8
5
87 (80)
90 (84)
17400
18000
2175
3600
2c
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3[54,55]
6
5
87
17400
17200
2900
3440
4[56,57]
86 (77)
5[58-60]
8
6
74 (69)
92 (81)
14800
18400
1850
3067
6
7
8
5
9
96
19200
18400
3840
2044
92 (87)
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9
10
9
10
7
90 (78)
66 (62)
92
18000
13200
18400
2000
1320
2629
11[61-68]
12[69,70]
12
9
82 (80)
93
16400
18600
1367
2067
13
aReaction conditions: Azaheteroaryl bromide (1 equiv.), arylboronic acid (1.1 equiv.), ‘SiO2’-NH2-Pd (0.005 mol%), Na2CO3 (1.1 equiv.), H2O-
C2H5OH (1:2) mixture (5 mL). bIsolated yield. cNa2CO3. (3 equiv.).
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3.5. Suzuki-Miyaura cross coupling reaction of azaheteroaryl chlorides
The plethora of commercially available azaheteroaryl chlorides deserved to be
forerunner starting material for Suzuki-Miyaura coupling partners. The high C−Cl bond
strength makes their activation difficult. In the recent past, more efficient coupling reactions
involving azaheterocyclic substrates were performed in water or in water-containing solvent
mixtures [59-65]. Most of the prominent catalysts display significant reactivity for the
coupling of deactivated azaheteroaryl chlorides, while a relatively high catalyst loading and
high temperature are often required to attain satisfactory results [66]. Such harsh reaction
conditions leading a way to change in stereo chemistry, functional group intolerance,
competitive homocoupling of boronic acid, trimerization of boronic acid, undesired aromatic
nucleophilic substitution, protodeboronation and protodehalogenation [67]. Considering these
facts in mind, reaction conditions were optimized for the coupling of azaheteroaryl chlorides
in the presence of ‘SiO2’-NH2-Pd. When 0.05 mol % of the catalyst was introduced, the
reaction was completed in 10 h at 120°C. The black particles were witnessed, which might be
due to the leaching out of reduced Pd. The above observation suggests that new catalyst has
limited stability at high temperature. When the reaction temperature was reduced to 60°C,
complete conversion was achieved in 15 h; advantageously no black particles were observed.
The scope was extended to study the generality of the new catalyst for cross coupling of
azaheteroaryl chlorides under optimized conditions. The chlorides of pyridine, pyrazine and
pyrimidine moieties were tested. 4-chloro-3-nitro pyridine was coupled with naphthalene-2-
boronic acid to obtain coupled product with 84% conversion in 11 h (Table 3, entry 1). It is
evident that electron withdrawing group in the ortho position to chloride enhances the C−Cl
bond polarization and helps the oxidative addition to proceed smoothly. Nicotinic acids
having chloride at different positions were tested using different boronic acids as coupling
partners. Coupling reaction of 4-chloro nicotinic acid with phenylboronic acid gave the best
conversion of 90% using 3 equiv. of base (Table 3, entry 2) [68]. The electron withdrawing
groups on boronic acid led to lower conversion even after prolonged reaction time (Table 3,
entries 3-5) [69-71]. This lower conversion can be ascribed to a lower nucleophilicity of the
coupling partner due to the presence of the electron withdrawing group that deactivates the
polarization of C–B bond and retards transmetalation of the arylboronic acid. Whereas
boronic acid containing ethoxy group afforded the coupled product in moderate yield (68%)
(Table 3, entry 6). The coupling reaction of 3-chloropyridine with phenylboronic acid showed
lower conversion of 15% and remaining 80% was identified as undesired symmetrical biaryl
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resulted from homocoupling of boronic acid (Table 3, entry 7) [72-78]. To address this issue,
one equiv. of tetrabutylammonium bromide (TBAB) was introduced to form a stable complex
[ArB(OH)2X]-[Bu4N]+ between boronic acid and the quaternary ammonium salt [79], which
led to the desired coupled product formation after extended reaction hours. However, cross
coupling reaction of 3-chloropyridine with phenylboronic acid was not satisfactory even in
the presence of TBAB. In presence of TBAB and the heterogenized catalyst, highly electron-
deficient 2-chloropyrazine gave cheering conversion (Table 3, entry 8) which is higher than
that observed in the palladium-catalyzed ligand-free cross coupling reaction of heteroaryl
chlorides with N-methyliminodiacetic acid (MIDA) boronates [80,81]. Usually, biologically
important pyrimidines are detrimental to the catalytic activity of Pd. In contrary, 2,4-dichloro
pyrimidine selectively underwent coupling reaction smoothly to give 4-coupled product
(Table 3, entries 10 and 11) [82,83]. The present catalytic system is compatible to functional
groups such as ester, ether and nitro.
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Table 3
Suzuki-Miyaura cross coupling reaction of azaheteroaryl chloridesa
Time Conv. / (Yieldb)
Entry
1
Ar−Cl
Ar'−B(OH)2
Ar−Ar'
TON
1680
TOF (h-1)
153
(h)
(%)
Cl
NO2
11
84 (78)
N
2[68]
8
90 (85)
1800
225
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3[37,69]
13
12
75 (69)
34 (31)
1500
680
115
57
4
5[70,71]
15
14 (12)
72 (68)
280
19
6
10
13
1440
144
7[72-78]
15 (13)
90
300
23
8c[79,80]
7
1800
257
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9c
10
10
88
1760
1840
176
184
Cl
Cl
N
N
Cl
Cl
10c
[81,82]
N
N
92 (87)
11c
8
87
1740
218
aReaction conditions: Azaheteroaryl chloride (1 equiv.), arylboronic acid (1.1 equiv.), ‘SiO2’-NH2-Pd (0.05 mol%), Na2CO3 (1.1 equiv.), H2O-
C2H5OH (1:2) mixture (5 mL), 70°C. bIsolated yield. cTBAB (1 equiv.) used.
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3.6. Proposed mechanism
The plausible mechanism is proposed based on the formation of undesired
symmetrical biaryl from the Suzuki-Miyaura reaction of azaheteroaryl chlorides due to the
oxidative homocoupling of nucleophilic arylboronic acid (Fig. 4).
Fig. 4. Proposed mechanism for Suzuki-Miyaura cross coupling reaction of azaheteroaryl
chlorides.
To illustrate the theoretical possibilities, a rational mechanism was proposed. Initially
the catalyst is converted into an aqua complex under basic aqueous medium. While the high
degree of C−Cl bond strength restricts the rapid oxidative addition into azaheteroaryl
chloride, Pd aqua species is transformed into peroxo complex in situ by availing oxygen from
19

ACCEPTED MANUSCRIPT
the air [84]. Then one of the oxygen atoms in the Pd peroxo complex interacts with the
oxophilic boron atom of the arylboronic acid, which provides a way to impetuous reaction
under stoichiometric concentration of ArB(OH)2. A subsequent transmetalation by a second
molecule of ArB(OH)2, followed by reductive elimination generates undesired symmetrical
biaryl product. To bypass this anomaly, at first the arylboronic acid was treated with TBAB
to form an adduct. This would make the boron atom less oxophilic and allowed to react with
less reactive azaheteroaryl chlorides. Secondly, prior to the catalyst addition, the argon gas
was bubbled into the reaction mixture to drive out dissolved oxygen from the medium. This
action favors the Pd insertion (oxidative addition) into azaheteroaryl chloride over peroxo
11
complex formation. A shift in the peak in the B NMR spectrum proved the formation of
boronic acid adduct with TBAB (Fig. S7).
3.7. Heterogeneous nature of the catalyst
The split test was performed during the coupling of 2-chloro-5-bromo pyrimidine
with phenylboronic acid to prove the durability of the heterogenized catalyst (Fig. 5). The
portion of reaction mixture at approximately 50% conversion was filtered and the filtrate was
allowed to react further without the catalyst. After extended period, both the reactions were
monitored. The filtrate showed no further conversion whereas original reaction mixture
proceeded to completion, which showed that no traces of Pd metal leach out from the support
into the reaction medium. Further to confirm these results, half of the filtrate was again
treated with recovered Pd catalyst and the reaction was monitored. The reaction started to
proceed as soon as the recovered catalyst was added, which clearly indicates that the
recovered Pd catalyst is active.
Fig. 5. Split test for coupling reaction of 2-chloro-5-bromo pyrimidine with phenylboronic
acid.
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3.8. Reusability
The catalyst was reused five times for the coupling reaction of 5-bromo pyrimidine
with 2-naphthalene boronic acid without significant loss of catalytic activity (Fig. 6). At 5th
run the conversion remained at 90%, indicating that the ‘SiO2’-NH2-Pd has an ability to
consider as a reusable catalyst. Even though reusability test showed a decrease in activity
after the first run, the activity remains good. The ICP-OES of recovered catalyst confirmed
that there was no much variation in the Pd content. The IR spectrum of recovered catalyst
was recorded and compared with the fresh catalyst. It demonstrated that the IR spectrum of
the recovered catalyst matched well with the fresh catalyst except C≡N stretching frequency
(Fig. S8).
Fig. 6. Reusability of ‘SiO2’-NH2-Pd for the coupling reaction of 5-bromopyrimidine with
phenylboronic acid.
4. Conclusion
In conclusion, we have demonstrated that a new recyclable ‘SiO2’-NH2-Pd catalyst for
Suzuki-Miyaura coupling reaction of heteroaryl halides can be synthesized from
[PdCl2(CH3CN)2]. This is an efficient and mild protocol for the Suzuki-Miyaura cross
coupling reaction of azaheteroaryl bromides and azaheteroaryl chlorides with a diverse range
of arylboronic acids. It also offers an efficient system for mediating the reaction in aqueous
medium under mild conditions with low Pd loading; a reaction of appreciable interest in the
present scenario. The catalyst was reused up to five runs without any substantial lack in the
reactivity. High product yields (89-99% isolated yields) were observed. Undoubtedly, these
21

ACCEPTED MANUSCRIPT
results will advance the scope of the Suzuki-Miyaura cross coupling reactions in the
industrial arena and add tremendous value to the process research.
Acknowledgments
S. G. gratefully acknowledges Syngene International Limited for the support. We thank Dr.
S. Ganesh Babu and Dr. M. Gopiraman for their technical support. R. K. thanks DAE-BRNS
for financial support.
Appendix A. Supplementary data
Supplementary data associated with this article can be found,in the online version, at
http://dx.doi.org/10.1016/j.jorganchem.2018.xx.xx
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Highlights
‹ An efficient and reusable heterogenized Pd catalyst has been prepared for Suzuki
coupling reaction of azaheteroaryl halides in aqueous medium.
13
‹ This catalyst was characterised by FT-IR, SEM-EDAX, TEM-EDAX, solid state C
CP-MAS NMR, XPS and ICP-OES.
‹ The plausible mechanism was explained.
‹ The Pd catalyst showed a better recyclability and excellent efficacy in Suzuki
coupling reaction.