Efficient construction of C–C bonds from aryl halides/aryl esters with arylboronic acids catalysed by palladium(II) thiourea complexes

Article abstract of DOI:10.1002/aoc.5181

A new set of palladium(II) complexes comprising phenyl(thiazolyl)thiourea ligands have been successfully synthesized and characterized with the aid of analytical as well as spectral (IR, UV–visible and NMR) methods. A distorted square-planar geometry with N^S coordination mode of thiourea ligands in the new palladium complexes was corroborated by single-crystal X-ray diffraction methods. Interestingly, the palladium(II) thiourea complexes showed the highest catalytic activity with 0.1 mol% catalyst loading in Suzuki–Miyaura cross-coupling reactions utilizing a range of aryl bromides/unactivated aryl chlorides with arylboronic acids as coupling partners in aqueous–organic media. Syntheses of diaryl ketones using aryl esters and arylboronic acids as coupling partners were also achieved with low catalyst loading within 20 h. The potential of our catalyst was demonstrated by its wide substrate scope, low catalyst loadings and high isolated yield. Moreover, the influences of key parameters like solvent, base, temperature and catalyst loading were also investigated.

Full text of DOI:10.1002/aoc.5181

Received: 23 April 2019
DOI: 10.1002/aoc.5181
Revised: 5 July 2019
Accepted: 25 July 2019
F U L L P A P E R
Efficient construction of C–C bonds from aryl halides/aryl
esters with arylboronic acids catalysed by palladium(II)
thiourea complexes
Manikandan Thimma Sambamoorthy1 | Ramesh Rengan1
| Malecki Jan Grzegorz2
1 Centre for Organometallic Chemistry,
School of Chemistry, Bharathidasan
University, Tiruchirappalli
620 024Tamilnadu, India
2 Department of Crystallography, Institute
of Chemistry, University of Silesia, 40‐006
Katowice, Poland
A new set of palladium(II) complexes comprising phenyl(thiazolyl)thiourea
ligands have been successfully synthesized and characterized with the aid of
analytical as well as spectral (IR, UV–visible and NMR) methods. A distorted
square‐planar geometry with N^S coordination mode of thiourea ligands in
the new palladium complexes was corroborated by single‐crystal X‐ray diffrac-
tion methods. Interestingly, the palladium(II) thiourea complexes showed the
highest catalytic activity with 0.1 mol% catalyst loading in Suzuki–Miyaura
cross‐coupling reactions utilizing a range of aryl bromides/unactivated aryl
chlorides with arylboronic acids as coupling partners in aqueous–organic
media. Syntheses of diaryl ketones using aryl esters and arylboronic acids as
coupling partners were also achieved with low catalyst loading within 20 h.
The potential of our catalyst was demonstrated by its wide substrate scope,
low catalyst loadings and high isolated yield. Moreover, the influences of key
parameters like solvent, base, temperature and catalyst loading were also
investigated.
Correspondence
Ramesh Rengan, Centre for
Organometallic Chemistry, School of
Chemistry, Bharathidasan University,
Tiruchirappalli 620 024, Tamilnadu, India.
Email: ramesh_bdu@yahoo.com
Funding information
Science and Engineering Research Board,
Grant/Award Number: SR/S1/IC‐48/2012;
School of Chemistry, Bharathidasan Uni-
versity, India; DST‐India (FIST
programme)
KEYWORDS
aryl ketone synthesis, biaryl synthesis, carbon–carbon coupling, palladium(II) thiourea complexes,
Suzuki–Miyaura coupling reactions
1 | INTRODUCTION
desirable synthetic target for both commercial as well as
research purposes.
The synthesis of biaryls is an important process owing to
their undeniable applications concerning natural product
synthesis, polymers, dendrimers, nanostructure mate-
rials, molecular switches, motors, agrochemicals and
pharmaceuticals (antifungal, anticancer and antibiotic
agents and anti‐inflammatory treatments)[1] and also in
large‐scale production of industrially important com-
pounds.[2,3] For example, Lipitor (blood cholesterol‐
reducing pharmaceutical drug), boscalid (fungicide) and
biphenomycin (antibiotic drug) containing biaryl moieties
(Scheme 1) are prepared by C–C coupling reactions.
Having such significance, the biaryl moiety is a highly
The aryl ketone moiety is also one of the most indis-
pensable and conventional building blocks existing in a
myriad of pharmaceuticals, fragrances, natural products
and synthetic biologically active molecules.[4] This
privileged skeleton has broad pharmaceutical activities
(Scheme 1), including neuroprotective (Nizofenone), anti-
arrhythmic (Pitofenone), hypolipidemic (Fenofibrate),
antitussive (Morclofone), anxiolytic (Indiplon), anti‐
inflammatory
(Suprofen,
Ketorolac),
antiseptic
(Pyoluteorin), antineoplastic (Nocodazole), anticancer
(ITE) and antitumor (Topsentin) activities. For the past
few decades, biaryl and aryl ketone moieties have been
Appl Organometal Chem. 2019;e5181.
wileyonlinelibrary.com/journal/aoc
© 2019 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.5181

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THIMMA SAMBAMOORTHY ET AL.
SCHEME 1 Selected examples of biaryl
and aryl ketone skeletons in drug
molecules
synthesised by chemists, inspiring us to conduct our stud-
ies of the construction and evaluation of these interesting
motifs.
electrophiles.[14] Utilization of phenyl esters as coupling
partners in SMC reactions has the potential to cleave
bonds either C (aryl)–O bond[15] or C (acyl)–O bond due
to selectivity problems.[16–18] In contrast to C (acyl)–O
Considering the significance of these skeletons, tremen-
dous efforts have been devoted to the synthesis of biaryls
and aryl ketones. A myriad of methodologies such as
Suzuki,[5] Stille,[6] Ullmann,[7] Negishi,[8] Semmelhack,[9]
Kharasch,[10] Meyers[11] and Lipshutz[12] reactions to con-
struct biaryls have been explored. Among these elegant
cross‐coupling reactions, the Suzuki–Miyaura coupling
(SMC) reaction is undoubtedly the most prominent strat-
egy which brought about a revolution in synthetic organic
chemistry. In addition, aryl ketones were achieved by
Friedel–Crafts acylation of aromatic compounds and stoi-
chiometric organometallic compounds with acid chlo-
rides, or Weinreb amides. However, the use of strong
Lewis acids, limited functional group tolerance and strict
handling requirements of the organometallic reagents are
the drawbacks of these methods. For the past decade,
transition‐metal‐catalysed reactions have paved the way
for the synthesis of aryl ketones.[13]
bond, the cleavage of
C
(acyl)–O bond with
decarbonylation ia an alternative pathway.[19] The advan-
tages of this reaction over the other coupling reactions are
the ready availability and easy separation of organoboron
reagents, high stability, inertness to water, functional
group tolerance, low toxicity, high yields as well as high
regio‐ and stereoselectivity. Hence, we were spurred to
the synthesis of aryl ketones from the coupling reaction
of aryl esters with boronic acids in the presence of
palladium–thiourea complexes.
Thiourea is a versatile ligand and can be easily synthe-
sized by reaction of phenylthiocyanate with amines. It has
a diverse range of applications ranging from analytical
chemistry and catalysis to pharmaceutical drugs.[20] The
enormous structural diversity of transition metal com-
plexes having thiourea ligands arises from their interest-
ing coordination behaviour with metal ions.
Generally, palladium‐catalysed SMC reactions take
place through aryl halides and arylboronic acids as cou-
pling partners (Scheme 2). In addition, unactivated aryl
esters are valuable substrates which provide new avenues
for modular coupling processes of common
In continuation of our research endeavour towards the
exploration of eco‐friendly protocols for various organic
reactions[21] and also the synthesis of new bioactive
compounds,[22] herein we report palladium(II) thiourea
complex‐catalysed coupling reactions of aryl halides
SCHEME 2 General reaction for
palladium‐catalysed Suzuki reaction

THIMMA SAMBAMOORTHY ET AL.
3 of 12
and aryl esters with arylboronic acids in aqueous–organic
media.
Pd(L2)Cl(PPh3): Yield: 68%, m.p. 231°C (with
decomposition). Found (%): C, 52.97; H, 3.72; N, 6.18; S,
9.48. Calcd for C29H25ClN3PPdS2 (%): C, 53.38; H, 3.86;
N, 6.44; S, 9.83. FT‐IR (KBr, cm−1): 1579 ν(C&dbond;N),
1258 (m) ν(C&bond;S), 3338 ν(NH), 1461 ν(Pd&bond;
PPh3), 545 (s) ν(Pd&bond;N). 1H NMR (400 MHz, CDCl3,
δ, ppm): 10.56 (s, 1H, NH), 7.70–7.78 (m, 5H, aromatic),
7.39–7.52 (m, 15H, aromatic), 6.77 (d, 1H, aromatic),
2.33 (s, 3H, CH3). 13C NMR (100 MHz, δ, ppm): 159.15,
140.82, 139.87, 135.00, 134.90, 131.22, 128.81, 128.36,
128.24, 124.55, 122.60, 118.60, 12.55. UV–visible (CH3CN,
2 | EXPERIMENTAL
2.1 | General considerations
[PdCl2(PPh3)2], phenylisothiocyanate, 2‐aminothiazole
derivatives and CDCl3 were purchased from Aldrich and
used without further purification. Standard procedures
were employed for distillation of solvents.[23] Melting
points were recorded with a Boetius micro heating table
and are uncorrected. A CHNS Elementar Vario EL III
analyser was used to carry out elemental analysis of car-
bon, hydrogen and nitrogen at the Sophisticated Test
and Instrumentation Centre (STIC), Cochin University
of Science and Technology, Cochin. Fourier transform
λ
max, nm): 441, 281, 229.
Pd(L3)Cl(PPh3): Yield: 61%, m.p. 255°C (with
decomposition). Found (%): C, 48.91; H, 3.01; N, 7.94;
S, 9.12. Calcd for C28H22ClN4O2PPdS2 (%): C, 49.20; H,
3.24; N, 8.20; S, 9.38. FT‐IR (KBr, cm−1): 1581
ν(C&dbond;N), 1269 (m) ν(C&bond;S), 3381 ν(NH),
1
1453 ν(Pd&bond;PPh3), 537 (s) ν(Pd&bond;N). H NMR
infrared (FT‐IR) spectra were acquired with
a
(400 MHz, CDCl3, δ, ppm): 10.65 (s, 1H, NH), 7.66–7.75
(m, 5H, aromatic), 7.39–7.54 (m, 15H, aromatic), 6.98
(s, 1H, aromatic). 13C NMR (100 MHz, δ, ppm): 156.95,
145.44, 142.65, 138.82, 134.48, 133.34, 132.35, 128.61,
128.49, 123.75, 118.85. UV–visible (CH3CN, λmax, nm):
453, 278, 233.
PerkinElmer 597 spectrophotometer in the range 400–
4000 cm−1 using KBr pellets. Electronic spectra were
recorded in acetonitrile solution with a Varian Cary 300
Bio UV–visible spectrophotometer in the range 200–
800 nm at room temperature. The NMR spectral studies
were carried out with a Bruker 400 MHz spectrometer
1
(for H NMR) and a Bruker 100 MHz spectrometer (for
13C NMR) in the presence of CDCl3 as solvent.
2.3 | X‐ray crystallography
Single crystals were grown for complexes 1 and 2 by slow
evaporation of dichloromethane–methanol solvent mix-
ture at room temperature. A Bruker SMART APEX II
four‐circle diffractometer with monochromated Mo ‐Kα
radiation (λ = 0.71073 Å) was used to collect the X‐ray
intensity data at room temperature. Absorption correc-
tions were performed by a multi‐scan method using
SADABS software. The unit cell parameters were deter-
mined by the method of difference vectors using reflec-
tions scanned from three different zones of the reciprocal
lattice. The intensity data were measured using ω and ϕ
scans with a frame width of 0.5°. Frame integration and
data reduction were performed using Bruker SAINT‐Plus
(Version 7.06a) software. Corrections were made for
Lorentz and polarization effects. The crystal structures
were solved and refined using Olex2,[24] SHELXS and
SHELXL[25] programs. The CCDC numbers for complexes
1 and 2 are 1883763 and 1883762, respectively.
2.2 | Synthesis of palladium(II) thiourea
complexes
The palladium(II) thiourea complexes were synthesized
using the following procedure. A methanolic solution of
thiourea ligand (335–399 mg, 1.424 mmol) and a metha-
nolic solution of [PdCl2(PPh3)2] (1 g, 1.424 mmol) were
added into a round‐bottom flask. This reaction mixture
was stirred at room temperature for 24 h. After comple-
tion of the reaction, the yellowish orange‐coloured solid
that was formed was filtered, washed with cold methanol
and dried in air.
Pd(L1)Cl(PPh3): Yield: 71%, m.p. 223°C (with
decomposition). Found (%): C, 52.32; H, 3.36; N, 6.29;
S, 10.44. Calcd for C28H23ClN3PPdS2 (%): C, 52.68; H,
3.63; N, 6.58; S, 10.05. FT‐IR (KBr, cm−1): 1563
ν(C&dbond;N), 1254 (m) ν(C&bond;S), 3345 ν(NH),
1
1465 ν(Pd&bond;PPh3), 540 (s) ν(Pd&bond;N). H NMR
(400 MHz, CDCl3, δ, ppm): 10.62 (s, 1H, NH), 7.73–7.78
(m, 5H, aromatic), 7.39–7.52 (m, 15H, aromatic), 7.06
(d, 1H, aromatic), 6.76 (d, 1H, aromatic). 13C NMR
(100 MHz, δ, ppm): 157.86, 140.65, 139.00, 134.92,
134.86, 131.19, 128.82, 128.34, 128.23, 124.02, 121.25,
111.34. UV–visible (CH3CN, λmax, nm): 435, 283, 225.
2.4 | General method for SMC reaction of
aryl halides/aryl esters with arylboronic
acid
In an oven‐dried round‐bottom flask, a mixture of aryl
halide (1 mmol), arylboronic acid (1.2 mmol), Pd catalyst

4 of 12
THIMMA SAMBAMOORTHY ET AL.
1 (0.5–0.1 mol%) and K2CO3 (2 mmol) was taken in the
presence of isopropanol–water (1:1) as a solvent system
(3 ml). Further, the reaction mixture was refluxed at
80°C for 5–7 h. For the synthesis of diaryl ketones, aryl
ester (1 mmol), arylboronic acid (3 mmol), Pd catalyst 1
(1 mol%) and K2CO3 (4.5 mmol) in tetrahydrofuran
(THF) medium were refluxed at 80°C for 20 h under a
nitrogen atmosphere. After the indicated times in all
the reactions, water (10 ml) was added into the reaction
mixture and the organic layer was extracted with ethyl
acetate. The volume of organic layers was concentrated
in vacuo. The colourless solid formed was purified by
column chromatography using n‐hexane–ethyl acetate
as eluent.
453 nm. The high‐intensity bands of ligand‐based transi-
tions (π–π* and n–π*) were detected at around 225–
283 nm. Relatively intense bands in the region 435–
453 nm are attributed to metal‐to‐ligand charge transfer
transitions in the complexes.
In the 1H NMR spectra, the free ligands showed
&bond;NH proton signals at around 12.2 and 10.6 ppm.
For the complexes, the disappearance of one of the
&bond;NH proton signals (12.2 ppm) in the thiourea unit
indicated that thiolate sulfur is coordinated to the Pd(II)
ion through tautomerism followed by enolization. Fur-
ther, the mode of coordination was confirmed from 13C
NMR spectral data. A notable feature here is that the
downfield shift of thiol sulfur (from 179 to 156–
159 ppm) implied the reduced C&bond;S bond order
upon coordination to the metal centre (Figures S2, S5
and S8, see supporting information). The appearance of
only one sharp singlet in the region 32.45–43.34 ppm for
all the complexes suggested the presence of one PPh3 in
all the complexes (Figures S3, S6 and S9, see supporting
information).
The solid‐state structures of two of the complexes were
derived from single‐crystal X‐ray diffraction (Figures 1
and 2). Complex 1 belongs to the monoclinic system with
the space group P21/n whereas complex 2 belongs to the
triclinic system with space group P‐1. In both complexes,
the thiourea ligands coordinate with palladium metal
centre in a bidentate fashion by way of the thiolate sulfur
and thiazole nitrogen and thus forming a six‐membered
chelate ring. In addition, the triphenylphosphine and
chloride ligands are coordinated to the palladium centre
as co‐ligands and constitute a square‐planar geometry.
Selected bond angles around palladium ion in complex
3 | RESULTS AND DISCUSSION
The reaction of phenylisothiocyanate with substituted 2‐
aminothiazole in dimethylformamide (DMF) medium
afforded the ligands in high yields. Further, these ligands
reacted with [PdCl2(PPh3)2] in methanol medium which
provided the air‐ and moisture‐stable palladium com-
plexes bearing thiourea ligands (Scheme 3). The com-
plexes have good solubility in organic solvents (CH2Cl2,
CHCl3, dimethylsulfoxide and CH3CN) and are analyti-
cally pure as their elemental analysis data confirmed the
proposed molecular formulae.
In the FT‐IR spectra of the free ligands, stretching fre-
quencies were observed at 3357–3420 and 779–826 cm−1
for two νN&bond;H as well as one νC&dbond;S, respectively.
It was noticed that one of the νN&bond;H bands and also
the νC&dbond;S band were found to be absent in the spectra
of the complexes, confirming that the ligands were
tautomerized and coordinated to Pd(II) ion by way of
thiolate form. Further, this was evidenced by the forma-
1
are S(2)–Pd(1)–Cl(1) = 171.92(4)°, S(2)–Pd(1)–P
(1) = 88.74(4)°, P(1)–Pd(1)–Cl(1) = 86.16(4)° and N1–
Pd1–Cl1 = 92.89(10)°. Bond lengths of complex 1 are
2.3576(11) Å for Pd(1)–Cl(1), 2.2572(11) Å for Pd(1)–S
(2), 2.2659(11) Å for Pd(1)–P(1) and 2.0750(3) Å for Pd
(1)–N(1). Similarly, selected bond angles in complex 2
tion of new bands at around 1254–1269 cm−1 for
[25]
νC&bond;S
.
It is worth noting here that the C&dbond;N
stretching vibration of the complexes shifted to lower fre-
quencies (1563–1581 cm−1) compared to the free ligands
which indicated that thiazole nitrogen is one of the coor-
dinating atoms. In addition, the spectra of the complexes
also showed weak bands at 1453 and 537 cm−1 which are
ascribed to PPh3 and nitrogen bonded to the palladium
are S(2)–Pd(1)–Cl(1)
=
174.37(4)°, S(2)–Pd(1)–P
(1) = 89.89(3)°, P(1)–Pd(1)–Cl(1) = 84.72(3)° and N1–
Pd1–Cl1 = 93.02(7)°. Bond lengths of complex 2 are
2.3520(8) Å for Pd(1)–Cl(1), 2.2594(8) Å for Pd(1)–S(2),
2.2692(10) Å for Pd(1)–P(1) and 2.0880(3) Å for Pd(1)–N
(1). It was observed that complex 2 adopts a geometry
similar to that in complex 1 with slight changes in bond
angles and bond lengths.
ion, respectively.[26]
.
In the electronic spectra of the complexes, three
absorption bands were noticed in the region 225–
SCHEME 3 Synthesis of palladium(II)
phenylthiazolylthiourea complexes

THIMMA SAMBAMOORTHY ET AL.
5 of 12
K2CO3 as a base in various solvent systems. To investigate
the effectiveness of the present catalytic system, we chose
different types of solvents including of polar and non‐
polar solvents (Table 1, entries 1–8). Among the solvents,
the isopropanol–water system (1:3) was ascertained to be
the best one which offered a 95% of yield within 5 h at 80°
C in an open atmosphere (Table 1, entry 8). The control
experiment results manifested the essentiality of base
and catalyst in the Suzuki coupling reaction (Table 1,
entries 9 and 10). Further assessment of green solvents
like ethanol and water revealed the formation of homo‐
coupled by‐products in 19–35% yield (Table 1, entries 5
and 6). We also chose a mixture of solvent (dioxane–
water), but it failed to produce the desired products in
high yields (Table 1, entry 7).
We were also interested in studying base‐free organic
reactions. Hence, we performed the base‐free SMC reac-
tion; however, it suppresses the formation of the desired
product. Regarding the influence of various bases, the
best results were noted in terms of reactivity and selectiv-
ity with inorganic bases, which outperformed organic
bases. These results show that this reaction was strongly
reliant on the base used, with K2CO3 providing the best
results (Table 1, entry 9). Further, we probed the impact
of temperature; the best catalytic performance was
obtained at 80°C. Raising the temperature to 100°C did
not significantly affect the reaction (Table 1, entry 18).
On further reducing the reaction temperature to 40°C, a
marked effect was observed on the product yield (Table 1,
entry 17).
FIGURE 1 ORTEP diagram for complex 1 with 30% probability
The results of the effect of low catalyst loading indi-
cated the efficiency of the synthesized Pd(II) thiourea cat-
alysts (Table 2). As anticipated, the reaction showed a
good catalytic performance even at low catalyst loadings.
There is a significant impact on the reaction outcome
when the catalyst loading is reduced to 0.05 mol%
(Table 2, entry 2). Further, a decrease in isolated yields
was obtained when the reaction was performed with a
very low catalyst loading of 0.01or 0.001 mol% (Table 2,
entries 3 and 4). Hence, we chose a catalyst loading of
0.1 mol% for further studies (Table 2, entry 1).
FIGURE 2 ORTEP diagram for complex 2 with 30% probability
3.1 | Suzuki coupling reaction of aryl
Exploring the effect of the catalyst, we probed the SMC
reaction using the synthesized complexes. The results
showed that complex 1 has the potential to produce the
desired product in higher yield with 0.1 mol% catalyst
loading for 5 h (Table 3, entry 1). The catalytic activity
of complex 1 was greater than that of complex 2. Thus,
we chose complex 1 for further studies because of its
excellent catalytic activity. Overall, these optimization
results suggested that the SMC reaction was effective with
iPrOH–H2O (1:3 ratio) as a solvent system in the presence
of K2CO3 as a base with complex 1 (0.1 mol%) at 80°C for
5 h under an open atmospheric condition.
halides/esters with arylboronic acids
The palladium‐catalysed Suzuki coupling reaction is an
important process for building valuable organic com-
pounds because of unique properties as well as variable
oxidation states. The effective catalytic and biological
applications of palladium(II) thiourea complexes
prompted us to the synthesis of biaryl and diaryl ketones
from the Suzuki coupling reaction.
We
commenced
our
studies
with
4‐
bromoacetophenone (1 mmol), phenylboronic acid
(1.2 mmol) and complex 1 (0.1 mol%) in the presence of

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THIMMA SAMBAMOORTHY ET AL.
TABLE 1 Effect of solvent and basea
Entry
Solvent
Base
Temp. (°C)
Yield (%)b
TONac
1
Toluene
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
—
100
100
60
93
62
87
79
65
81
52
95
NR
NR
91
80
75
90
73
51
69
96
930
620
870
790
650
810
520
950
NR
NR
910
800
750
900
730
510
690
960
2
Dioxane
3
THF
4
DMF
120
100
80
5
Water
6
Ethanol
7
Dioxane–water
100
80
8
Isopropanol–water (1:3)
Isopropanol–water (1:3)
Isopropanol–water (1:3)
Isopropanol–water (1:3)
Isopropanol–water (1:3)
Isopropanol–water (1:3)
Isopropanol–water (1:3)
Isopropanol–water (1:3)
Isopropanol–water (1:3)
Isopropanol–water (1:3)
Isopropanol–water (1:3)
9d
10e
11
12
13
14
15
16
17
18
100
100
80
K2CO3
Na2CO3
KOH
80
NaOH
K3PO4
Et3N
80
80
80
Pyridine
K2CO3
K2CO3
80
40
100
aReaction conditions: 4‐bromoacetophenone (1 mmol), phenylboronic acid (1.2 mmol), base (2 mmol), catalyst 1 (0.1 mol%) and solvent (3 ml) for 5 h under air.
bIsolated yield.
cTON = moles of product/moles of catalyst.
dReaction carried out in the absence of base.
eReaction performed in the absence of catalyst.
TABLE 2 Effect of catalyst loadinga
Entry
Catalyst (mol%)
Yield (%)b
TONc
1
2
3
4
0.1
95
83
950
1660
6700
—
0.05
0.01
0.001
67
Trace
aReaction conditions: 4‐bromoacetophenone (1 mmol), phenylboronic acid (1.2 mmol), K2CO3 (2 mmol), catalyst 1 (0.1–0.001 mol%) and iPrOH–H2O (3 ml) for
5 h.
bIsolated yield.
cTON = moles of product/moles of catalyst.

THIMMA SAMBAMOORTHY ET AL.
7 of 12
TABLE 3 Effect of catalyst on Suzuki couplinga
Entry
Pd complex
Yield (%)b
1
2
3
[Pd(L1)Cl(PPh3)]
[Pd(L2)Cl(PPh3)]
[Pd(L3)Cl(PPh3)]
95
89
76
aReaction conditions: 4‐bromoacetophenone (1 mmol), phenylboronic acid (1.2 mmol), K2CO3 (2 mmol), catalyst 1–3 (0.1 mol%) and iPrOH–H2O (3 ml) for 5 h.
bIsolated yield.
electronic effect of substituents on boronic acid derivatives.
p‐Substituted boronic acid derivatives bearing electron‐
rich substituents (&bond;OCH3 and &bond;CH3) gave bet-
ter isolated yields than p‐substituted boronic acid deriva-
tives having electron‐deficient substituents (&bond;Cl
and &bond;F) under optimized conditions (Table 4, prod-
ucts 3ab–3ae). Furthermore, the reaction of 4‐
bromoacetophenone with 6‐bromo‐3‐pyridinylboronic
acid offered the expected arylated coupled product in 85%
isolated yield (Table 4, product 3af).
3.2 | Substrate scope of reaction
3.2.1 | Scope of aryl bromides with
arylboronic acids
With the optimization conditions in hand, we explored the
substrate scope of the Pd(II) thiourea complex‐catalysed
Suzuki reaction with various aryl and heteroaryl halides
and arylboronic acids (Tables 4 and 5). The coupling reac-
tion of 4‐bromoacetophenone with phenylboronic acid
proceeded well to afford the corresponding biaryl in 95%
isolated yield (Table 4, product 3aa). We investigated the
The scope of the reaction was further explored by
employing pharmaceutical active heterocyclic bromides
TABLE 4 Suzuki coupling reaction of aryl bromides with arylboronic acidsa
3aa; 95 %b
3ab; 89 %b
3ac; 90 %b
3ad; 92 %b
3ae; 93 %b
3af; 85 %b
3ba; 91 %b
3bb; 87 %b
3bc; 89 %b
3ca; 93 %b,c
3cb; 83 %b,c
3cc; 87 %b,c
3da; 92 %b,c
3db; 86 %b,c
3dc; 89 %b,c
i
aReaction conditions: aryl bromide (1 mmol), boronic acid derivative (1.2 mmol), K2CO3 (2 mmol), catalyst 1 (0.1 mol%) and PrOH–H2O (3 ml) for 5 h.
bIsolated yield.
cDouble Suzuki coupling reaction (aryl bromide (1 mmol), arylboronic acid (3.2 mmol), K2CO3 (4.2 mmol), catalyst 1 (0.1 mol%) and iPrOH–H2O (4 ml) for 5 h).

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such
as
2‐bromo‐5‐methylpyridine
and
2,6‐
3.2.3 | Scope of aryl esters and arylboronic
acids
dibromopyridine with boronic acid derivatives. Interest-
ingly, the reactions of 2‐bromo‐5‐methylpyridine with
electron‐donating/electron‐withdrawing
substituents
After the successful accomplishment of the SMC reaction
involving aryl halides, we were inspired to explore its
applicability using esters as electrophiles for the synthesis
of aryl ketones.
were efficient and furnished the desired products in high
yields (Table 4, products 3ba–3bd). It is worth noting that
our catalyst works well with the double Suzuki reaction.
The double Suzuki coupling of 2,6‐dibromopyridine with
4‐substituted phenylboronic acids were performed and
afforded the targeted triaryl products in 79–83% isolated
yields (Table 4, products 3ca–3cc). Further, the reaction
With the impressive result of benzophenone in 90%
yield using 1 mol% of catalyst 1 in the test reaction, we
investigated the substrate scope with a variety of
arylboronic acids under the optimal reaction conditions
(Table 6). The influence of electronic effects was studied
in this type of reaction forming ketones. Phenylboronic
acids with electron‐rich substituents outperformed those
with electron‐deficient substituents. The phenylboronic
acids with electron‐rich substituent at p‐position were
rapidly coupled with phenyl benzoate to afford the target
ketone products in 85–88% isolated yields (Table 6, prod-
ucts 5ad and 5ae). Also, the reaction of phenylboronic
acid with an electron‐deficient substituent at p‐position
afforded the respective products in 81–83% yield (Table 6,
products 5ab and 5ac). Further, the catalytic tolerance
was potentially proved by the reaction of 6‐bromo‐3‐
between
1,3‐dibromobenzene
and
substituted
phenylboronic acids furnished the corresponding homo‐
triaryls in good yields (Table 4, products 3da–3dc).
3.2.2 | Scope of aryl chlorides with
arylboronic acids
With impressive results with the range of aryl bromides as
well as boronic acid derivatives, we next sought to explore
a Suzuki coupling reaction with aryl chlorides. In the
SMC reaction, the utilization of aryl chlorides is an attrac-
tive strategy, yet it is difficult to activate the C&bond;Cl
bond. Gratifyingly, we successfully synthesized biaryls
from the coupling reaction of aryl chlorides and
arylboronic acids in good to high yields (Table 5). We also
investigated the electronic effect using aryl chlorides with
boronic acid derivatives as coupling partners (Table 5,
products 4aa–4ae). As expected, arylboronic acid deriva-
tives bearing electron‐rich substituents are better toler-
ated than those bearing electron‐deficient ones. In
addition, 6‐bromo‐3‐pyridinylboronic acid smoothly
reacted with 4‐chloroacetophenone and afforded the tar-
get product in moderate yield even at long reaction times
(Table 5, product 4af).
Given the prevalence and significance of heterocyclic
compounds in industrial production as well as pharma-
ceuticals, we turned our attention to heterocyclic com-
pounds as one of the coupling partners under
optimized conditions. Pleasingly, 2‐chloropyridine
reacted smoothly with substituted phenylboronic acids
and afforded the target products in high yields (Table 5,
products 4ba–4bc). To our delight, the double Suzuki
reaction could also be achieved with aryl chlorides as
electrophiles. Thus, we treated 1,4‐dichlorobenzene with
substituted phenylboronic acid derivatives under opti-
mized conditions which furnished the desired triaryl
products in good yields. Employing 3,6‐dichloropyridine
with boronic acid derivatives resulted in 72–79% yields
of the 2,5‐diphenylpyridine derivatives (Table 5, products
4da–4dc).
pyridinylboronic
acid
and
3,4‐(methylenedioxy)
phenylboronic acid with phenyl benzoate affording the
desired products in good yields (Table 6, products 5af
and 5ag). Further the expanding the substrate scope with
various esters and also the elucidation of the mechanism
are underway in our laboratory.
We also compared the catalytic activity and scope of
the SMC reaction catalysed by our catalyst 1 with that
of other reported palladium(II) complexes. Yang and co‐
workers documented the catalytic activity of palladium–
thiourea complexes (1 mol% of catalyst loading) towards
Suzuki coupling reactions under in situ conditions in
iPrOH–H2O medium.[27] The catalytic performance of
[Pd(dba)2]–bis(thiourea) complex was explored in the
SMC reaction in the presence of N‐methyl‐2‐pyrrolidone
at higher temperature.[28] Further, the self‐supported pal-
ladium–thiourea‐catalysed biaryl synthesis from SMC
reaction at 100°C was reported.[29] Moreover, the Pd(II)
thiocarboxamide (0.1 mol% catalyst loading)‐catalysed
SMC reaction was carried out in toluene medium.[26]
Hence, the present catalysts work well with several
advantages such as high efficiency, ease of synthesis and
air/moisture insensitivity.
3.3 | Mechanism for Suzuki coupling
reaction
Herein, we propose a plausible reaction mechanism for
the SMC reaction according to literature reports.[30–32]

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THIMMA SAMBAMOORTHY ET AL.
TABLE 6 Suzuki coupling reaction of aryl esters with arylboronic acidsa
aReaction conditions: aryl ester (1 mmol), arylboronic acid (3 mmol), K2CO3 (4.5 mmol), catalyst 1 (1 mol%) and THF (3 ml) for 20 h under nitrogen
atmosphere.
bIsolated yield.
In general, the stronger binding nature of chelating
anionic ligands having heteroatoms or carbon with palla-
dium centre prevents bond cleavage during the catalytic
process. These types of ligands show high σ‐donor
strength and the possibility for facilitating the accessibil-
ity of Pd(IV) intermediate by the occurrence of electron
donation through nitrogen lone pairs. Based on the above
considerations, we propose a mechanism which involves
a Pd(IV) species as depicted in Scheme 4 (I and II). In
the initial step, Pd(II) thiourea complex (A) undergoes
oxidative addition with aryl halides/aryl esters to give
Pd(IV) intermediates B and B′. Further, the addition of
a base to B triggers a metathetic process to generate C.
Moreover, D is formed by the transmetalation of
SCHEME 4 Plausible mechanism for SMC reaction

THIMMA SAMBAMOORTHY ET AL.
11 of 12
[4] For reviews, see:a) A. de Meijere, F. Diederich, Metal‐Catalyzed
Cross‐Coupling Reactions, 2nd ed., John Wiley, Weinheim 2004.
b)H. Surburg, J. Panten, Common Fragrance and Flavor Mate-
rials, 5th ed., Wiley‐VCH, Weinheim 2006.
phenylboronic acid, which further undergoes reductive
elimination affording the desired coupled product E.
Likewise, the reaction of B′ with base followed by
transmetalation of B′ furnishes the intermediate C′.
Eventually, D′ is obtained from the reductive elimination
of C′ and regenerates Pd(II) species A.
[5] N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457.
[6] a) J. K. Stille, Angew. Chem. Int. Ed. 1986, 25, 508. b) V. Farina,
V. Krishnamurthy, W. J. Scott, Org. React. 1997, 50, 1.
[7] F. Ullmann, J. Bielecki, Ber. Dtsch. Chem. Ges. 1901, 34, 2147.
4 | CONCLUSIONS
[8] R. Rossi, F. Bellina, A. Carpita, F. Mazzarella, Tetrahedron
1996, 52, 4095.
A simple synthetic route to palladium(II) thiourea com-
plexes and their characterization have been described.
The catalytic performances of the complexes were well
explored for the SMC reaction affording products in good
to excellent yields in aqueous–organic media at low cata-
lyst loadings (0.5–0.1 mol%). Simple and greener SMC
reactions with a broad range of aryl bromides and aryl
chlorides, including aromatic and heteroaromatic ones,
were developed using the palladium(II) thiourea com-
plexes. Further, a successful attempt was also made in
the synthesis of aryl ketone derivatives from aryl esters
and arylboronic acids by exploiting the Pd(II) thiourea
complexes with 1 mol% catalyst loading in 20 h.
[9] M. F. Semmelhack, P. Helquist, L. D. Jones, L. Keller, L.
Mendelson, L. S. Ryono, J. G. Smith, R. D. Stauffer, J. Am.
Chem. Soc. 1981, 103, 6460.
[10] B. M. Trost, T. R. Verhoeven, Comprehensive Organic Chemis-
try, Vol. 8, Pergamon, Oxford 1982 799.
[11] T. G. Gant, A. I. Meyers, Tetrahedron 1994, 50, 2297.
[12] B. H. Lipshutz, F. Kayser, Z. P. Liu, Angew. Chem. 1994, 106,
1962.
[13] Z. Rappoport, The Chemistry of Phenols, John Wiley, Chichester
2003.
[14] a) P. Lei, G. Meng, S. Shi, Y. Ling, J. An, R. Szostak, M. Szostak,
Chem. Sci. 2017, 8, 6525. b) J. Buchspies, M. Szostak, Catalysts
2019, 9, 53.
[15] a) D. A. Shirley, Org. React. 1954, 8, 28. b) S. Nahm, S. M.
Weinreb, Tetrahedron Lett. 1981, 22, 3815.
ACKNOWLEDGEMENTS
[16] For examples containing only 2‐pyridyl esters see: H.
Tatamidani, F. Kakiuchi, N. Chatani, Org. Lett. 2004, 6, 3597.
The authors are grateful to the Science and Engineering
Research Board (SERB) (scheme no. SR/S1/IC‐48/2012)
for providing financial support and for Junior Research
Fellowship to T.S.M. We are also grateful to the
DST‐India (FIST programme) for the use of instrumental
facilities at the School of Chemistry, Bharathidasan Uni-
versity, India.
[17] For examples containing unactivated aryl esters see: a) T.
BenHalima, W. Zhang, I. Yalaoui, X. Hong, Y. –. F. Yang, K.
N. Houk, S. G. Newman, J. Am. Chem. Soc. 2017, 139, 1311.
b) T. BenHalima, J. K. Vandavasi, M. Shkoor, S. G. Newman,
ACS Catal. 2017, 7, 2176. c) C. A. Malapit, D. R. Caldwell, N.
Sassu, S. Milbin, A. R. Howell, Org. Lett. 2017, 19, 1966. d) S.
Shi, P. Lei, M. Szostak, Organometallics 2017, 36, 3784. e) S.
Shi, M. Szostak, Chem. Commun. 2017, 53, 10584.
[18] For examples containing methyl esters see: L. Hie, N. F. Fine
Nathel, X. Hong, Y.‐F. Yang, K. N. Houk, N. K. Garg, Angew.
Chem. Int. Ed. 2016, 55, 2810.
ORCID
Ramesh Rengan https://orcid.org/0000-0001-8358-9583
[19] a) K. Amaike, K. Muto, J. Yamaguchi, K. Itami, J. Am. Chem.
Soc. 2012, 134, 13573. b) K. Muto, J. Yamaguchi, D. G. Musaev,
K. Itami, Nat. Commun. 2015, 6, 7508. c) N. A. LaBerge, J. A.
Love, Eur. J. Org. Chem. 2015, 2015, 5546. d) L. Guo, A.
Chatupheeraphat, M. Rueping, Angew. Chem. Int. Ed. 2016,
55, 11810. e) X. Pu, J. Hu, Y. Zhao, Z. Shi, ACS Catal. 2016,
6, 6692. f) K. Muto, T. Hatakeyama, K. Itami, J. Yamaguchi,
Org. Lett. 2016, 18, 5106. g) X. Liu, J. Jia, M. Rueping, ACS
Catal. 2017, 7, 4491.
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