Xantphos-ligated palladium dithiolates: An unprecedented and convenient catalyst for the carbonylative Suzuki–Miyaura cross-coupling reaction with high turnover number and turnover frequency

Article abstract of DOI:10.1002/aoc.5255

Xantphos- and dithiolate-ligated macrocyclic palladium complexes as an efficient and stable catalyst for the carbonylative Suzuki–Miyaura cross-coupling reaction have been synthesized. The catalysts were characterized by ¹H-nuclear magnetic resonance (NMR), CHNS (carbon, hydrogen, nitrogen, and sulfur) analysis, melting point analysis, and ³¹P-NMR spectroscopy. Several sensitive functional groups (e.g., –NO₂, –F, –Cl, –Br, –NH₂, and –CN) on the aromatic ring were well tolerated in the carbonylative Suzuki–Miyaura coupling reaction. The present palladium complexes produce six times higher turnover number (TON) and five times higher turnover frequency (TOF) compared with conventional homogeneous palladium precursors. Maximum TONs in the range of 10⁵ to 10⁶ and TOF in the range of 10⁴ to 10⁵ could be generated by a very low amount of catalyst loading (10^–5?mol%).

Full text of DOI:10.1002/aoc.5255

Received: 12 February 2019
DOI: 10.1002/aoc.5255
Revised: 26 August 2019
Accepted: 1 September 2019
F U L L P A P E R
Xantphos‐ligated palladium dithiolates: An unprecedented
and convenient catalyst for the carbonylative Suzuki–
Miyaura cross‐coupling reaction with high turnover
number and turnover frequency
1
2
2,3
Vinayak V. Gaikwad
| Pravin A. Mane | Sandip Dey
|
1
Bhalchandra M. Bhanage
1
Department of Chemistry, Institute of
Xantphos‐ and dithiolate‐ligated macrocyclic palladium complexes as an effi-
cient and stable catalyst for the carbonylative Suzuki–Miyaura cross‐coupling
Chemical Technology, Nathalal Parekh
Marg, Matunga, Mumbai 400019, India
2
Chemistry Division, Bhabha Atomic
1
reaction have been synthesized. The catalysts were characterized by H‐nuclear
Research Centre, Mumbai 400085, India
magnetic resonance (NMR), CHNS (carbon, hydrogen, nitrogen, and sulfur)
3
Training School Complex, Homi Bhabha
31
analysis, melting point analysis, and P‐NMR spectroscopy. Several sensitive
functional groups (e.g., –NO , –F, –Cl, –Br, –NH , and –CN) on the aromatic
National Institute, Mumbai 400094, India
2
2
Correspondence
ring were well tolerated in the carbonylative Suzuki–Miyaura coupling reac-
tion. The present palladium complexes produce six times higher turnover
number (TON) and five times higher turnover frequency (TOF) compared with
conventional homogeneous palladium precursors. Maximum TONs in the
Sandip Dey Chemistry Division, Bhabha
Atomic Research Centre, Mumbai 400085,
India.
Email: dsandip@barc.gov.in
Bhalchandra M. Bhanage, Department of
Chemistry, Institute of Chemical
5
6
4
5
range of 10 to 10 and TOF in the range of 10 to 10 could be generated by
a very low amount of catalyst loading (10– mol%).
5
Technology, Nathalal Parekh Marg,
Matunga, Mumbai 400019, Maharashtra
(
India).
KEYWORDS
Email: bm.bhanage@gmail.com;
bm.bhanage@ictmumbai.edu.in
biaryl ketone, carbonylation, homogeneous catalyst, palladium dithiolate, xantphos
Funding information
Board of Research in Nuclear Sciences of
the Department of Atomic Energy, Grant/
Award Number: No. 37(2)/14/32/2018‐
BRNS/37238
1
| INTRODUCTION
The most convenient and traditional method for the
synthesis of biaryl ketones involves Friedel–Crafts acyla-
Biaryl ketones are recognized as an important synthetic
target because of their participation in a variety of useful
organic transformations. Formation of these ketones is an
important structural building block in the synthesis of
natural products, pharmaceuticals, pesticides, photosensi-
tion reaction. However, this method requires an over‐
stoichiometric amount of Lewis acid and suffers from
compatibility issues with many substrates containing
deactivating groups. It also generates waste such as alu-
minum salts, leading to poor atom economy. By contrast,
carbonylative Suzuki–Miyaura cross‐coupling of an aryl
halide and organoboron aryl compounds over a Pd cata-
lyst in the presence of a suitable base offers an alternative
[1–5]
tizers, and advanced organic materials (Figure 1).
The
synthesis of biaryl ketones by noncarbonylative
[6–13]
approaches is well documented in the literature.
Appl Organometal Chem. 2019;e5255.
wileyonlinelibrary.com/journal/aoc
© 2019 John Wiley & Sons, Ltd.
0 of 8
https://doi.org/10.1002/aoc.5255

1
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GAIKWAD ET AL.
to provided high TON and TOF. In 2003, Grigg and co‐
[
47]
workers
successfully synthesized isoindolinone using
in situ palladium nanoparticles generated from
palladacycle complex in the presence of CO. Fairlamb
[
31]
and co‐workers
used Bedford catalyst along with Bis
(
diphenylphosphino)ferrocene (dppf) to study alkoxy
and aminocarbonylation reaction in 2007. Others
employed Herrmann palladacycle as the catalyst in car-
[
48]
[49]
bonylation
and aminocarbonylation
reactions
using solid Mo(CO)6 as a CO surrogate. Buchwald
FIGURE 1 Examples of pharmaceutically active biaryl ketone
[50]
et al.
employed xantphos‐ligated Pd catalyst at low
temperatures for the aminocarbonylation (hetero) of
[51–53]
aryl bromide in 2014. Bhanage and co‐workers
route for the synthesis of biaryl ketones, and hence is
widely applied. The aforementioned reaction has unique
features such as readily accessible and stable substrates,
functional groups tolerance, broad substrate scope, and
the phenyl boronic acids (provide nucleophilic source
for this reaction) are easy to handle, nontoxic, and mois-
ture, air and thermally stable. Recently, Fe‐ and Ni‐
catalyzed carbonylative cross‐coupling between aryl
halides and phenyl boronic acid with carbon monoxide
reported carbonylative Suzuki reaction with palladium
chalcogenolate complexes and Bedford catalyst and
carbonylative Sonogashira reaction with oxime
palladacycle in 2014, 2015, and 2016, respectively. We
have recently developed supramolecular co‐ordination
complexes of palladium(II) made from bridging
[54]
dithiolates with two cis positions blocked by dppe
[
55]
and xantphos ligands.
These sulfur‐based ligands
were little explored due to their propensity to form
insoluble polymeric products and the misbelief as cata-
lyst poison. It is noteworthy that the new macrocyclic
complexes are easy to synthesize and highly stable,
[
14–
has been reported for the synthesis of biaryl ketones.
1
7]
Several studies have used homogeneous and heteroge-
[18–28]
neous palladium catalysts in this reaction.
However,
[
54,55]
many of these catalytic systems require high catalyst
loading, with some even using active aryl iodides, thus
limiting their large‐scale application. By contrast, the
presence of excess amounts of π‐acidic CO as compared
with the catalytic quantities of palladium lowers the rate
of oxidative addition of metal with aryl halide. Some-
times, CO aggregation of palladium also leads to catalyti-
cally inactive species. Hence, to resolve this issue, it is
necessary to design a new catalyst that can minimize
the aforesaid drawbacks and provide good catalytic activ-
ity in the carbonylation reaction; however, designing
such a catalyst remains a challenging task.
and showed excellent catalytic activity in Suzuki
and Heck
[
56]
C–C coupling reactions at very low con-
centrations. Encouraged by these results, in this work,
we used xantphos‐ligated Pd dithiolate complexes as cat-
alysts to investigate carbonylative Suzuki–Miyaura reac-
tions. Catalyst 1 {[Pd (xantphos) (4,4′‐SC H S)] (OTf)
2
2
12
8
2
4
(II)} and catalyst 2 {[Pd(xantphos)(1,4‐SC H SH)] (OTf)
6
4
2
(I) and [Pd (xantphos) (1,4‐SC H S)] (OTf) (II)}
2
2
2
6
4
2
4
[
55]
(Figure 2)
were chosen for the coupling reaction of
aryl iodides with phenyl boronic acids in the presence
of gaseous CO. The optimization studies with respect
to various reaction parameters, the synthesis of biaryl
ketones by coupling different aryl iodides with boronic
acids, low catalyst loading, activity of present palladium
macrocycles compared with traditional Pd catalysts, and
Recently, there has been an increasing interest in the
development of palladacycle chemistry and significant
advances have been made, especially on their applica-
[29–33]
tion as an organometallic catalyst.
This was attrib-
uted to the ability of palladacycle complexes to achieve
high activity at parts per million (ppm) level, remain
thermally stable in various catalytic applications, and
remain recyclable with a proper solvent system. Herr-
[34]
mann et al.
developed tri(o‐tolyl)phosphine cyclo‐
palladacycles and employed them in the study of Heck
and Suzuki reaction way back in 1995. Afterwards, sev-
eral research work into this field has been rapidly
progressed for the development of series of nitro-
[35–38]
[39–43]
[44,45]
[46]
gen,
phosphorous,
sulfur,
and oxygen
derived palladium catalysts which were used for the car-
ried out C‐C and C‐heteroatom bond forming a reaction
FIGURE 2 Structures of palladium catalysts 1 and 2

GAIKWAD ET AL.
2 of 8
gram scale‐up synthesis of benzophenone, etc. will be
discussed herein.
added. A wine‐red solution mixture results which was
stirred for 4 hr. The solvent was then evaporated in vac-
uum, and the red residue was washed with diethyl ether
and extracted with acetone (3 × 5 ml). Finally, diethyl
ether (10 ml) was added to yield a red colored solid of
catalyst 2 (48.1 mg, 0.024 mmol, 65%) with melting
point > 230 °C (dec). Analytical calculation for
I·(H O)2 C H F O P Pd S (H O) : C, 55.64; H, 3.96;
2
2
| EXPERIMENTAL
.1 | Materials
2
92 74
6
8
4
2 6
2
2
All the chemicals and solvents were purchased from dif-
ferent reputed commercial sources (Sigma Aldrich, Alfa
Aesar, Lobha Chemicals and S.D. fine chemicals) and
were used without further purification. Carbon monox-
ide (cylinder) was purchased from Rakhangi Gas Services
S,
9.67%;
calculation
for
II·(H O)
2 4
C172H136F O P Pd S (H O) : C, 56.00; H, 3.93; S,
12
16
8
4 8
2
4
1
6
.95%; found: C, 55.11; H, 3.75; S, 9.98%. H‐NMR
(
300 MHz, acetone‐d ): δ 1.50 (s, 6H, CH ), 1.97 (s,
6
3
6
H, CH ), 5.60 (br s, 4H, C H ), 6.88 (br s, 12H, p‐H
3
6
4
(Mumbai) with 99.99% purity. The Pd catalysts 1 and 2
of PPh2 + CHCHCH), 7.39 (m, 20H, m‐H of PPh +
2
were prepared according to the literature method and
CPCHCH), 7.66 (br s, 16H, o‐H of PPh ), 7.92 (br s,
[55]
2
are provided in main manuscript.
the reaction was monitored by gas chromatography
GC) and GC–mass spectrometry (MS) and thin‐layer
The progress of
1
4
H, CHCHCC), H‐NMR (500 MHz, CD OD): δ 1.50
3
(
s, 6H, CH ), 1.97 (s, 6H, CH ), 5.53 (br s, 8H, C H ),
3 3 6 4
(
6
.84 (br s, 12H, p‐H of PPh + CHCHCH), 7.29 (m,
2
chromatography using Merck silica gel 60 F254 plates.
The products were visualized with a 254‐nm UV lamp.
2
0H, m‐H of PPh + CPCHCH), 7.59 (br s, 16H, o‐H
2
31
1
of PPh ), 7.90 (br s, 4H, CHCHCC),
P{ H}‐NMR
2
The
GC–MS‐QP
2010
instrument
[Rtx‐17,
(
1
121 MHz, acetone‐d ): δ 4.3 (br, s), 7.9 (br, s) in about
:1 ratio. The P‐NMR spectrum of catalyst is shown in
6
3
0 m × 25 mm inner diameter, film thickness
31
−
1
(
df) = 0.25 μm; column flow 2 ml min , 100 to 240 °C
Figure S1.
−
1
at 10 °C min rise] was used for the mass analysis of
the products. The products were purified by
column chromatography using 100–200‐mesh silica gel.
Elemental analysis for C, H, N, and S (CHNS analysis)
was performed on a Carlo Erba EA‐1110 CHNS
Catalyst
1
{[Pd (xantphos) (4,4′‐SC H S)] (OTf)
2
2
12
8
2
4
(II)} was prepared similar to catalyst 2, using [Pd
(
xantphos)(OTf) ] (75.1 mg, 0.076 mmol) and 4,4′‐
2
biphenyldithiol (8.3 mg, 0.038 mmol) to yield the title
complex as a red solid (50.3 mg, 0.013 mmol, 70%) with
melting point > 230 °C (dec). Analytical calculation for
Catalyst 1 C184H144F O P Pd S : C, 58.63; H, 3.85; S,
1
Analyser. The H‐nuclear magnetic resonance (NMR)
spectra were recorded at 500 MHz in CDCl3 using
12
16
8
4 8
tetramethylsilane (TMS) as an internal standard. The
1
6
.81; found: C, 58.60; H, 3.82; S, 6.94%. H‐NMR
13
C‐NMR spectra were recorded at 125 MHz in CDCl3.
(
300 MHz, acetone‐d ): δ 1.62 (s, 6H, CH ; another peak
6
3
Chemical shift was detected in parts per million (ppm)
due to the methyl group merged with the solvent peak
using TMS as an internal standard, with J (coupling con-
3
at δ 2.05 ppm), 5.89 (d, J
= 7.8 Hz, 4H, o‐H, C H ),
1
HH
12
8
stant) value recorded in Hertz. The H‐NMR spectra of
3
6.32 (d, J
= 7.8 Hz, 4H, m‐H, C H ), 7.09 (br s, 4H,
HH
12
8
the catalysts were recorded on Bruker and Varian NMR
spectrometers operating at 300 and 500 MHz, respec-
tively, with chemical shifts relative to internal
CHCHCH), 7.22 (br s, 8H, p‐H of PPh ), 7.30–7.49 (m,
2
3
2
1
0H, m‐H of PPh + CPCHCH), 7.53 (t, J
= 6.9 Hz,
2
HH
3
6H, o‐H of PPh ), 7.97 (d, J = 7.8 Hz, 4H, CHCHCC),
1
9
2
HH
acetone‐d and methanol‐d peak (δ 2.05 and 3.31).
{
F
6
4
1
H‐NMR (500 MHz, CD OD): δ 1.56 (s, 6H, CH ), 2.01 (s,
1
31
1
3
3
H} and P{ H}‐NMR spectra were recorded on a
3
6
H, CH ), 5.84 (d, J = 8.0 Hz, 4H, o‐H, C H ), 6.22 (d,
3
HH
12
8
Bruker NMR spectrometer operating at 376 and
3
JHH = 8.0 Hz, 4H, m‐H, C H ), 7.01 (br s, 4H,
13
1
12
8
1
21 MHz, respectively, and C{ H}‐NMR spectra were
recorded on a Varian NMR spectrometer operating at
01 MHz.
CHCHCH), 7.14 (br s, 8H, p‐H of PPh ), 7.31–7.44 (m,
2
3
2
0H, m‐H of PPh + CPCHCH), 7.53 (t, J
= 7.5 Hz,
2
HH
2
3
1
6H, o‐H of PPh ), 7.89 (d, J = 7.5 Hz, 4H, CHCHCC),
2
HH
13
1
C{ H}‐NMR (201 MHz, acetone‐d ): δ 23.4 (s, CH ), 38.7
6
3
1
2.2 | Catalyst preparation and its
(s, CCH
3
), 117.6 (d, JPC = 45.1 Hz, CP of C15
), 127.9 (s, CH of C15
of C H ), 130.5 (s, CH of C H O), 130.8 (s, m‐C of
H
12O), 127.4
characterization
(s, o‐C of C12
H
8
H12O), 130.3 (s, m‐C
1
2
8
15 12
1
Catalyst 2 {[Pd(xantphos)(1,4‐SC H SH)] (OTf) (I) and
C H ), 131.8 (s, CS of C H ), 132.9 (d, J = 71.6 Hz,
6
4
2
2
6 5 12 8 PC
[
Pd (xantphos) (1,4‐SC H S)] (OTf) (II)} was prepared
CP of C H ), 134.2 (s, o−/p‐C of C H ), 134.7 (s, CH of
2
2
6
4
2
4
6
5
6
5
as follows: To a 5 ml acetone solution of 1,4‐
benzenedithiol (5.4 mg, 0.038 mmol), 5 ml acetone solu-
C H O), 137.6 (s, CC of C H ), 139.0 [s, CCC (CH )
15 12 12 8 3
1
19
of C H O], 157.4 (s, CO of C H O), F{ H}‐NMR
1
5
12
15 12
31
1
tion of [Pd(xantphos)(OTf) ] (75.2 mg, 0.076 mmol) was
(376 MHz, acetone‐d ): δ −78.7 (s),
P{ H}‐NMR
2
6

3
of 8
GAIKWAD ET AL.
(
121 MHz, acetone‐d ): δ 9.1 (s). Figure 2 shows struc-
2.4 | General procedure for synthesis of
biaryl ketone by carbonylative Suzuki–
Miyaura reaction
6
tures of catalysts 1 and 2.
In a typical procedure, 100‐ml autoclave was charged
with iodobenzene (0.5 mmol), aryl boronic acid
2
.3 | Preparation of stock solution of the
(
0.75 mmol), and K CO (1.5 mmol) with 10 ml anisole
2 3
catalyst
as a solvent. Then, 0.1 mol% of Pd “2” (catalyst) was
added and the autoclave was closed tightly with a
clamp. Next, the autoclave was flushed with nitrogen
gas three times. The autoclave was then pressurized
with CO (0.3 MPa) and heated at 100 °C for 8 hr. The
reaction mixture was stirred with a mechanical stirrer
at 500 rpm. After completion of the reaction, the auto-
clave was cooled down to room temperature and the
remaining CO was vented carefully and the reactor
was opened. The reaction mixture was quenched with
water and the product extracted with ethyl acetate
(3 × 15 ml). The organic solvent was evaporated by a
Initially, we prepared the stock solution of the catalyst by
dissolving the complex in acetonitrile solvent, and vari-
−
1
−5
ous catalyst concentrations (10 to 10 mol%) were
prepared. First, to prepare 1 mol% of catalyst, 9.75 mg
complex was weighed and dissolved into 1 ml acetoni-
–2
–3
–4
trile (solvent). Afterward, we prepared 10 , 10 , 10 ,
and 10– mol% solutions by successive dilution from
stock solution using acetonitrile. No special precautions
were taken for the preparation of stock solution, and
the catalyst was weighed and handled in air as it is air
stable.
5
a
TABLE 1 Screening of optimal reaction condition
b
b
Entry number Pd precursor Base
Solvent
CO pressure (bar) Time (hr) Conversion (%) Selectivity 5:6
1
2
3
4
5
6
8
9
1
1
1
1
1
1
1
Pd (1)
Pd (2)
Pd (2)
Pd (2)
Pd (2)
Pd (2)
Pd (2)
Pd (2)
Pd (2)
Pd (2)
Pd (2)
Pd (2)
Pd (2)
Pd (2)
Pd (2)
K
K
2
2
CO
3
Anisole
5
5
5
5
5
5
5
5
3
1
3
3
3
3
3
8
8
8
8
8
8
8
8
8
8
6
4
8
8
8
85
96
80
83
73
60
66
45
97
70
83
66
98
85
50
85:15
94:6
CO
3
Anisole
Na
2
CO
3
Anisole
87:13
89:11
80:20
85:15
65:35
49:51
96:4
K
3
PO
4
Anisole
Cs
2
CO
3
Anisole
K
K
K
2
2
2
CO
CO
CO
3
3
3
Toluene
Dimethylformamide
3
CH CN
0
1
2
3
4
5
6
K
2
CO
3
Anisole
Anisole
Anisole
Anisole
Anisole
Anisole
Anisole
K
K
K
K
K
K
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
3
88:12
83:17
69:31
95:5
3
3
3
3
3
c
d
e
90:10
80:20
a
Optimized reaction condition: 3 (0.5 mmol), 4 (0.7 mmol), catalyst (0.1 mol%), base (1 mmol), solvent (10 ml), 100°C.
b
c
Conversion and selectivity based on iodobenzene and calculated by GC and GC–MS.
20 °C.
1
d
80 °C.
e
60 °C.
GC, gas chromatography; MS, mass spectrometry.

GAIKWAD ET AL.
4 of 8
a
rotary evaporator to obtain the crude product, which
was further purified by column chromatography (silica
gel, 100–200‐mesh size), with petroleum ether–ethyl
acetate as the eluent to afford a pure product. The prod-
ucts were confirmed by GC–MS and H‐ and C‐NMR
spectroscopic analysis.
TABLE 2 Effect of catalyst loading on the reaction
b
Entry
number
Yield
(%)
TOF
−1
Pd (2) mol%
TON
(hr )
−
−
−
−
1
2
3
4
2
3
4
2
3
4
1
13
1
2
3
4
10
10
10
10
10
10
97
97
95
45
50
10
9.70 × 10
9.70 × 10
1.21 × 10
1.21 × 10
9.50 × 10
1.18 × 10
5
4
4.50 × 10
5.00 × 10
1.00 × 10
5.62 × 10
6.25 × 10
1.25 × 10
3
| RESULTS AND DISCUSSION
c
−4
5
6
4
5
5
−
5
6
To achieve our goal, iodobenzene (3) and phenyl boronic
acid (4) were chosen as model substrates as shown in
Table 1. Initially, we have investigated the use of palla-
dium catalysts 1 and 2 in the synthesis of biaryl ketone.
It is noteworthy that catalyst 1 exists exclusively as a
tetranuclear (II) macrocyclic Pd complex, whereas cata-
lyst 2 is composed of both dinuclear (I) and tetranuclear
a
2 3
Optimized palladium loading: 3 (0.5 mmol), 4 (0.7 mmol), K CO (1
mmol), anisole (10 ml), 100 °C, 8 hr, CO (0.3 MPa).
b
Yield determined by GC and GC‐MS.
c
1
20 °C.
GC, gas chromatography; MS, mass spectrometry; TOF, turnover frequency;
TON, turnover number.
[55]
(
II) Pd complexes in solution.
In the experimental
study, first, iodobenzene (0.5 mmol) was reacted with
phenyl boronic acid (0.7 mmol) using the Pd catalysts 1
and 2 (0.1 mol%), respectively, with K CO (1 mmol) as
Only 66% conversion of iodobenzene was observed for
4‐hr reaction time (Table 1, Entry 13). Thus, based on this
result, 8 hr was found to be sufficient for reaction comple-
tion with good conversion and selectivity. Finally, varia-
tion of temperature revealed that conversion and
selectivity remained the same when the temperature
was raised from 100 to 120 °C (Table 1, Entry 14). How-
ever, upon decreasing the temperature from 80 °C or
60 °C, conversion of iodobenzene also reduced (Table 1,
Entries 15 and 16). Thus, the temperature study indicated
that 100 °C was optimum for the complete conversion of
iodobenzene.
2
3
the base under a CO atmosphere in 10 ml anisole at
00 °C for 8 hr. The results showed that Pd catalyst 2
1
was more active than Pd catalyst 1 (Table 1, Entry 1);
thus, further optimization was performed using only the
former (Table 1, Entry 2). Second, the base study was per-
formed using Na CO , K PO , and Cs CO as inorganic
2
3
3
4
2
3
bases (Table 1, Entries 3–5), which resulted in 80%, 83%,
and 73% conversion of iodobenzene, respectively, with
good selectivity. It was observed that replacing of K CO3
2
the conversion of the iodobenzene was brought down.
However, K CO3 acted as an effective base, which
We then aimed to achieve high TON and TOF by
reducing the catalyst loading (Table 2). We started the
experiment by initially loading 10 mol% of palladium,
which gave a product yield of 97% with TON and TOF
2
enabled efficient conversion of iodobenzene (97%) as well
as good selectivity (Table 1, Entry 10). Furthermore, we
studied the influence of various solvents on the model
reaction. The effect of different solvents, such as toluene
−
1
2
2
of 9.70 × 10 and 1.21 × 10 , respectively (Table 2, Entry
−
2
−3
(
60%), dimethylformamide (66%), CH CN (45%), and
1). Although catalyst loading of 10 mol% and 10 mol
% did not present any significant changes in the product
yields, both TON and TOF were amplified to 9.70 × 10
and 9.50 × 10 for the former and 1.21 × 10 and
1.18 × 10 for the latter, respectively (Table 2, Entries 2
3
anisole (97%) was screened (Table 1, Entries 6–10).
Among these, anisole was found to be an excellent sol-
vent for the proposed protocol and thus further optimiza-
tion was performed only using anisole (Table 1, Entry 10).
We then investigated the effect of CO (gas) pressure on
the model reaction (Table 1, Entries 10–11). When CO
pressure decreases from 0.5 to 0.3 MPa, no significant
conversion of iodobenzene was observed; however, upon
further lowering the CO pressure from 0.3 to 0.1 MPa,
both conversion of iodobenzene and selectivity decreased.
Thus, the study of CO pressure indicates that 0.3 MPa is
enough to ensure effective reaction progress. The reaction
time was optimized by performing the reaction for differ-
ent periods, ranging between 4 and 8 hr (Table 1, Entries
3
4
3
4
and 3). Inspired by this result, we further decreased the
−
4
catalyst loading to 10 mol%. Although the yield of
product was 45% in this case, the TON increased to
5
4.50 × 10 (Table 2, Entry 4). With the aim of increasing
the yield of product, we performed the reaction with
−
4
10 mol% catalyst loading at 120 °C for 8 hr; however,
this reaction yielded only 50% of ketone, with TON and
5
4
TOF estimated as 5.00 × 10 and 6.25 × 10 , respectively
(Table 2, Entry 5). Finally, the reactor was charged with
−
5
10 mol% of catalyst, but this gave only 10% yield of
the expected product, although the TON was very high
1
8
0, 12, and 13). When we reduced the reaction time from
to 6 hr, conversion was also reduced from 97% to 83%.
6
(1.00 × 10 ; Table 2, Entry 6).

5
of 8
GAIKWAD ET AL.
a
TABLE 3 Scope of the palladium catalyst for the synthesis of biaryl ketone
a
−3
Reaction condition: 3a (0.5 mmol), 4a (0.7 mmol), catalyst (10 mol%), K
2
CO
3
(1 mmol), anisole (10 ml), 100 °C, 8 hr, CO (0.3 MPa).
GC, gas chromatography; MS, mass spectrometry; TOF, turnover frequency; TON, turnover number.
Under optimized reaction conditions, we next applied
the developed protocol for the synthesis of substituted
benzophenone by carbonylative coupling of a range of aryl
iodides with phenyl boronic acid (Table 3). Overall, the
reactions progressed smoothly and tolerated a wide variety
of functional groups. Simple iodobenzene and phenyl
boronic acid coupled smoothly under the developed proto-
col and produced excellent yield (95%) of the desired prod-
disubstituted iodobenzene such as o‐NH and p‐Cl were
2
also coupled with phenyl boronic acid to yield ketone 6f
4
with TON of 7.5 × 10 . Next, electron‐withdrawing func-
tionalities such as p‐CN and m‐NO also produced ketones
2
4
4
6g and 6h in good yield with TONs of 9 × 10 and 8 × 10 ,
respectively. Likewise, a fused‐ring 1‐iodonaphthalene
was smoothly reacted with phenyl boronic acid and 4‐F‐
phenyl boronic acid to yield the corresponding ketones 6i
4
4
4
uct (6a) with TON of 9.50 × 10 . The electron‐donating
and 6j, with TONs of 8.2 × 10 and 8.5 × 10 , respectively.
Next, we explore the current protocol could be work by
using substituted phenyl boronic acid. Electron‐donating
groups such as p‐OMe, p‐Me, m‐OMe, m‐Me, and m‐N
(Me)2 could be successfully coupled with aryl iodide,
which gave corresponding ketones 6k, 6l, 6m, 6n, and 6o
substituent bearing aryl iodide was then smoothly con-
verted into the corresponding ketone. Donating groups
such as p‐Me, p‐OMe, p‐NH , and o‐NH on iodobenzene
2
2
were successfully transformed into respective ketones
4
4
6
b–6e with TON ranging from 9.3 × 10 to 7.8 × 10 and
3
3
4
4
TOF from 1.16 × 10 to 9.7 × 10 . Furthermore,
with high TONs (range 9.10 × 10 to 7.30 × 10 ) and TOFs

GAIKWAD ET AL.
6 of 8
TABLE 4 Comparative study of palladium catalysts 1 and 2 with
a
conventional palladium precursors
b
Entry number Pd precursor Yield TON
TOF (hr)
4
1
2
3
4
5
Pd(OAc)
2
21
13
18
83
95
2.10 × 10 2625
4
PdCl
PdCl
Pd 1
Pd 2
2
2
1.30 × 10 1625
4
(PPh
3
)
2
1.80 × 10 2250
4
8.30 × 10 10,375
4
9.50 × 10 11,875
a
−3
Reaction condition: 3 (0.5 mmol), 4 (0.7 mmol), catalyst (10 mol%), base
(
1 mmol), anisole (10 ml), 100 °C, 8 hr, CO (0.3 MPa).
b
Yield calculated by GC and GC‐MS.
GC, gas chromatography; MS, mass spectrometry; TOF, turnover frequency;
TON, turnover number.
SCHEME 1 Plausible reaction mechanism of palladium thiolate‐
catalyzed carbonylative Suzuki–Miyaura cross‐coupling reaction
4
3
(
range 1.13 × 10 to 9.12 × 10 ). Further, 3,4‐
[
55]
(methylenedioxy)phenylboronic acid was also reacted
reactions.
The thermal stability of the catalysts was
with aryl iodide to produce ketone 6p with TON
evaluated by thermogravimetric analysis. The thermo-
gravimetric curves indicated that both catalysts are sta-
ble enough in solid state, and the decomposition phase
4
6
.30×10 . Next, oxybenzone (6q) was successfully synthe-
sized, an important molecule in medicinal chemistry,
which can be used as a sunscreen agent as it protects the
starts after 320 and 305 °C, respectively, for catalyst
[57,58]
[55]
skin from harmful effects of the sun.
Moreover, halo-
1
and 2 (Figures S2 and S3 in electronic supplemen-
genated biaryl ketones (6r–6t) were synthesized using the
aforesaid protocol with yield range of 69%–71% and TONs
from 6.9 × 10 to 7.1 × 10 .
tary information (ESI)). Overall, the palladium com-
plexes provided an excellent yield of the expected
products with TONs of up to 8.30 × 10 to 9.50 × 10
4
4
4
4
Furthermore, we tested the efficiency of catalyst 2 for
the gram scale‐up synthesis of benzophenone. The cata-
lytic activity of catalyst 2 was slightly reduced for gram
scale‐up to 5 mmol (1.02 g) with 87% benzophenone yield
achieved.
achieved (Table 4, Entries 4 and 5). Based on these
results, it can be concluded that catalyst 2 exhibits
superior activity in terms of TON and TOF, which are
sixfold and fivefold more than conventional palladium
precursors, respectively.
Next, we compared various conventional palladium
precursors with the present palladium thiolate com-
plexes 1 and 2 with respect to TON and TOF (Table 4).
Iodobenzene (3) and phenyl boronic acid (4) were cho-
sen as reacting substrates for the synthesis of biaryl
ketone. In the comparative study, both catalysts 1 and
The mechanism of carbonylative Suzuki–Miyaura
cross‐coupling reaction with palladium complexes is
shown in Scheme 1. Initially, aryl iodide (A) is sub-
jected to oxidative addition with palladium (0) species
to form intermediate B. Then, CO (gas) co‐ordinates
with palladium to form species C. Next, in the presence
of a base (K CO ), phenyl boronic acid undergoes
2
demonstrated superior catalytic activity than conven-
2
3
tional palladium precursors. Commercially available Pd
precursors such as Pd(OAc) , PdCl , and PdCl (PPh )
3 2
transmetalation with palladium species to give species
D. Subsequently, reductive elimination of palladium
occurs for the synthesis of benzophenone. The high
2
2
2
gave very poor yield and generated low TONs
4
4
(
2.10 × 10 to 1.80 × 10 ; Table 4, Entries 1–3). However,
a
TABLE 5 Recycled study of the catalyst
catalyst 2 showed slightly higher activity in comparison
to catalyst 1, which is attributed to the higher stability
of the latter. Catalyst 2 comprises both tetranuclear (II)
and dinuclear (I) complexes in solution in almost equal
b
Entry number
Recycle run
Yield (%)
1
2
3
4
Fresh catalyst
First recycle
95
93
92
65
31
proportions, as demonstrated by
P‐NMR spectra,
whereas catalyst 1 only exists as II. In a previous work,
we have estimated the stability of II (−870 kcal/mol),
Second recycle
Third recycle
which is −435 kcal/mol higher than that of
I
a
This catalyst shows better activity than other one: 3 (0.5 mmol), 4
0.7 mmol), catalyst (1 mol%), base (1 mmol), anisole (9 ml), water(1 ml),
(
−435 kcal/mol), as evaluated by density functional the-
(
[55]
ory calculation.
Similarly, the stability of II in 1 was
100 °C, 8 hr, CO (0.3 MPa).
b
found to be −872 kcal/mol. The same trend was also
observed in the case of Suzuki–Miyaura C–C coupling
Yield calculated by GC and GC‐MS.
GC, gas chromatography; MS, mass spectrometry.

7
of 8
GAIKWAD ET AL.
activity of Pd complexes can be attributed to the wide
bite angle (110°) and flexible coordination behavior
ACKNOWLEDGMENTS
V.V.G. and P.A.M. are thankful to Council of Scientific
and Industrial Research (CSIR), New Delhi, Government
of India, and Department of Atomic Energy–Mumbai
University Collaborative Scheme, respectively, for provid-
ing a Senior Research Fellowship (SRF). We are also
thankful to the Board of Research in Nuclear Sciences
of the Department of Atomic Energy for funding this
work (Sanction No. 37(2)/14/32/2018‐BRNS/37238).
[59]
(97°–133°) of xantphos.
As the cycle produces the
intermediate Ph–Pd–COPh before the production of
the benzophenone Ph CO, the increase in bite angle
2
(i.e., P–Pd–P) can diminish the Ph–Pd–COPh angle,
thus speeding up the reductive elimination process, as
[60]
observed in C–C coupling reactions.
We next evaluated the recycle ability of the catalyst. For
this purpose, we used iodobenzene and phenyl boronic
acid as model substrates for the synthesis of benzophe-
none. Initially, the reactor was charged with the starting
materials and catalyst, and then solvent (9 ml) and water
ORCID
Vinayak V. Gaikwad
531
Sandip Dey https://orcid.org/0000-0001-9198-8808
Bhalchandra M. Bhanage https://orcid.org/0000-0001-
538-3339
https://orcid.org/0000-0003-4152-
(1 ml) were added. The reactor was then pressurized with
0
0
.3 MPa of CO and stirred at 450 rpm for 8 hr. After com-
pletion of the reaction, the reactor was cooled down to
room temperature and the remaining CO was vented care-
fully. The reaction mixture was quenched with water and
the product was extracted with ethyl acetate. The collected
water was then evaporated under vacuum and the product
dried in an oven. The dried catalyst was used for next recy-
cle by charging of reactor with starting material. The
results showed that up to the second run no significant dif-
ference was observed in the yield of benzophenone
9
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