Desulfinylative Pd-catalyzed coupling reaction of arenediazonium salt with aryl sulfinates to give unsymmetrical biaryls

Article abstract of DOI:10.1016/j.tetlet.2017.06.045

An efficient route for the synthesis of unsymmetrical biaryls was developed via palladium catalyzed reaction of arenediazonium salts and aryl sulfinates under inert atmosphere. This synthesis involves cascade processes. Tetrabutylammonium iodide was used as an iodide source for in situ formation of aryl iodide, followed by desulfinylative cross-coupling reaction between aryl sulfinates and aryl iodides. A wide range of biaryls were selectively prepared in one pot from simple substrates in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2017.06.045

Accepted Manuscript
Desulfinylative Pd-catalyzed coupling reaction of arenediazonium salt with aryl
sulfinates to give unsymmetrical biaryls
Sitaram Haribhau Gund, Kishor Eknath Balsane, Jayashree Milind Nagarkar
PII:
S0040-4039(17)30776-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.045
TETL 49037
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
9 May 2017
12 June 2017
13 June 2017
Please cite this article as: Gund, S.H., Balsane, K.E., Nagarkar, J.M., Desulfinylative Pd-catalyzed coupling reaction
of arenediazonium salt with aryl sulfinates to give unsymmetrical biaryls, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.06.045
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Desulfinylative Pd-catalyzed coupling
reaction of arenediazonium salt with aryl
sulfinates to give unsymmetrical biaryls
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Sitaram Haribhau Gunda, Kishor Eknath Balsanea and Jayashree Milind Nagarkara*

1
Tetrahedron Letters
Desulfinylative Pd-catalyzed coupling reaction of arenediazonium salt with aryl
sulfinates to give unsymmetrical biaryls
Sitaram Haribhau Gunda, Kishor Eknath Balsanea and Jayashree Milind Nagarkara*
a
Department of Chemistry, Institute of Chemical Technology, Matunga, Mumbai – 400019, India. Fax: +91 22 33611020; Tel.: +91 22-33611111/2222;
E-mail: jm.nagarkar@ictmumbai.edu.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient route for the synthesis of unsymmetrical biaryls was developed via palladium
catalyzed reaction of arenediazonium salts and aryl sulfinates under inert atmosphere. This
synthesis involves cascade processes. Tetrabutylammonium iodide was used as an iodide source
for in situ formation of aryl iodide, followed by desulfinylative cross-coupling reaction between
aryl sulfinates and aryl iodides. A wide range of biaryls were selectively prepared in one pot
from simple substrates in good to excellent yields.
Available online
Keywords:
Palladium
Cross-coupling
Aryl sulfinate
2009 Elsevier Ltd. All rights reserved.
Arenediazonium salt
Tetrabutylammonium iodide
Introduction
biaryls by using transition metal-catalyzed homocoupling
reactions are presented below (Fig. 2).
A palladium-catalysed cross-coupling reaction is one of the most
applied synthetic methods for the construction of carbon-carbon
(C-C) bonds.1 The importance of biaryls, especially for their
applications in the synthesis of natural products, organic
semiconductors, nonlinear optics, synthesis of herbicides,
medicinal chemistry and conducting polymers2 is well known. The
most common approaches to prepare biaryls include traditional
cross-coupling reactions such as Suzuki,3 Stille4 and Hiyama.5
The examples of few top selling drug molecules, highlighting the
biaryl core present in these molecules are given below6 (Fig. 1).
Fig. 2 Synthesis of biaryls by using metal catalyzed coupling
methods.
Palladium-catalyzed desulfitative cross-coupling of arylsulfinates
with arylboronic acids7a (Fig. 2, route a), palladium catalyzed
desulfinylative couplings between aryl sulfinates and aryl iodide
for the synthesis of biaryls7b (Fig. 2, route b), catalytic
desulfitative homocoupling of sodium arylsulfinates in water
7c
using PdCl2 as the recyclable catalyst and O2 (Fig. 2, route c),
palladium-catalyzed Hiyama type cross coupling reactions of
arenesulfinates with organosilanes7d (Fig. 2, route d), Ni- or Co-
catalyzed cross-coupling of arylsulfonic acid salts with RMgX7e
(Fig. 2, route e) and Pd/C catalyzed coupling of arenediazonium
salts with potassium aryltrifluoroborates7f (Fig. 2, route f) are
Fig. 1 Drug molecules containing the biaryl core.
Some of the previous reported methods for the synthesis of

2
previous reported methods for the synthesis of biaryls.
arenediazonium salts21 are also reported. Therefore, in this work,
we describe the alternative path for the synthesis of biaryls using
arenediazonium salts and sodium arylsulfinates as starting
materials, Pd(dppf)Cl2 as catalyst, P(OPh)3 as ligand and TBAI
as iodine source. The reaction proceeds in DMF at 150 °C under
inert atmosphere (Scheme 1).
Aromatic diazonium salts are highly attractive synthetic
alternatives to the corresponding aromatic halides, which exhibit
higher reactivity. They are also good arylating agents. They are
easy to handle, stable and can be conveniently prepared from
anilines.8 Several groups have reported the synthesis of organic
compounds by using arenediazonium salts in various coupling
reactions,9 such as Suzuki-Miyaura,10 Stille,11 Sonogashira12 and
Mizoroki-Heck reactions.13
In the past few decades, aryl sulfinates have been shown to
be more reactive substrates for the synthesis of various aromatic
compounds.14 Cu- or Pd-catalyzed cross-coupling reactions of
sulfinate salts with disulfides,15 phenylacetylene,16 aryl halide,17
Scheme 1. Reaction between 4-Methoxybenzenediazonium
tetrafluoroborate and sodium aryl sulfinate.
aryl boronic acid,18 azoles,19
phenylethylene20 and
Results and discussion
Table 1. Optimization of reaction parameters.a
Entry
Catalyst (mol%)
Ligand (mol%)
Base (mmol)
Additive (mmol)
Yieldb (%)
1
2
PdCl2
P(OPh)3
P(OPh)3
-
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
CS2CO3
NaHCO3
K2CO3
K2CO3
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
KI
61
59
Pd(OAc)2
3
Pd(PPh3)4
35
4
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
P(OPh)3
81
5
Tri(o-
tolyl)phosphine
P(Ph)3
73
6
54
7
-
49
8
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
58
9
55
10
11
12
13
14
63
72
TBAB
TBAI
TBAI
Trace
81c
75d
K2CO3
K2CO3
a Reaction condition: 4-Methoxybenzenediazonium tetrafluoroborate (0.8 mmol), sodium aryl sulfinates (0.5 mmol), TBAI (0.8 mmol) Palladium source (2.5
mol%), ligand source (5 mol%), Base (1.0 mmol), DMF (2 mL), 150 °C, under N2, bIsolated yields, c160 °C, d140 °C.
The reaction conditions were optimised by carrying out the
coupling reaction of 4-Methoxybenzenediazonium
tetrafluoroborate with sodium arylsulfinates.
homogeneous palladium catalysis. Here we screened various
ligands such as triphenyl phosphite [P(OPh)3], Tri(o-
tolyl)phosphine and triphenyl phosphine [P(Ph)3] (Table 1,
entries 4-6) and the best results were obtained when the reaction
was carried out with Pd(dppf)Cl2 as a catalyst and triphenyl
phosphite as the ligand. We also examined the effect of various
bases by employing K2CO3, Na2CO3, CS2CO3 and NaHCO3
(Table 1, entries 4, 8, 9&10). Potassium carbonate was found to
be the most effective base in the model reaction.
Initially we screened various palladium sources as a
catalyst for model reaction by employing PdCl2, Pd(OAc)2,
Pd(PPh3)4 and Pd(dppf)Cl2 as catalyst (Table 1, entries 1-4). In
the course of this study, it was found that Pd(dppf)Cl2 is the best
catalyst as it afforded maximum yield (81%) of the desired
product. Phosphine ligand plays a very crucial role in

3
We also performed model reaction with various halogen
sources (to form the aryl halide in situ) such as TBAI
(Tetrabutylammonium iodide), KI ( Potassium iodide) and TBAB
(Tetrabutylammonium bromide) (Table 1, entries 4, 11&12). The
results clearly show that TBAI is the most suitable halogen
source giving maximum product yield. The optimum temperature
was found to be 150 °C for the model reaction. Increase in
temperature to 160 °C, did not improve the product yield,
whereas significant decrease in the product yield was observed
when the temperature was decreased to 140 °C (Table 1, entries
4, 13&14). All above experiments reveal that the optimized
12
13
14
78
74
79
reaction
conditions
are
4-Methoxybenzenediazonium
a
Reaction condition: arenediazonium salts (0.8 mmol), aryl sulfinates (0.5
tetrafluoroborate (0.8 mmol), sodium arylsulfinates (0.5 mmol),
Pd(dppf)Cl2 (2.5 mol%), P(OPh)3 (5 mol%), TBAI (0.8 mmol),
K2CO3 (1.0 mmol), DMF (2 mL), 150 °C temperature and 24h
reaction time under inert atmosphere.
mmol), TBAI (0.8 mmol), Pd(dppf)Cl2 (2.5 mol%), P(OPh)3 (5 mol%),
K2CO3 (1.0 mmol), DMF (2 mL), 150 °C, 24h under N2. bIsolated yield.
After optimizing all parameters such as catalyst, ligand, base,
additive and reaction temperature, we further investigated the
catalytic activity for the coupling of structurally different
arenediazonium salts and aryl sulfinates as substrates under the
optimized reaction conditions. The results are shown in Table 2.
Arenediazonium salts with many valuable functional groups
present on aromatic ring such as -OCH3, -CH3, -Cl and -F groups
were screened to give the desired unsymmetrical biaryl (Table 2,
entries 1–14). Aryl sulfinates coupled smoothly with
arenediazonium salts bearing both electron-deficient and
electron-rich substituents, to afford the corresponding products in
good to excellent yields. It was observed that substrates
containing electron donating group deliver excellent products as
compared to substrates containing withdrawing groups. It was
also observed that the substituent at para-position exhibits greater
reactivity than ortho- or meta-position, which might be due to
steric factors.
Table 2. Reaction between arenediazonium salts and aryl
sulfinates.a
Entry Ar-N2BF4
Ar-SO2Na
Yieldb (%)
1
84
81
80
76
77
73
78
80
81
82
75
2
3
The proposed reaction mechanism for synthesis of biaryls is
illustrated in Fig.3.
The reaction proceeds in three sequential steps as oxidative
addition, transmetalation and reductive elimination.
The palladium(0) compound required in this cycle is
generally prepared in situ from a Pd(dppf)Cl2(II) precursor,
which is reduced by triphenylphosphite to Pd(0). Further,
arenediazonium salt in presence of TBAI form aryl iodide, which
immediately undergoes oxidative addition with the Pd(0) species
to give the aryl–Pd complex.
4
5
A weakly coordinated halide ion, is replaced by sulfinate to
produce sulfinato-complex. Then the reaction proceeds via the
direct extrusion of SO2 to yield bis-arylated species. Finally,
reductive elimination of the complex facilitates the catalytic
cycle by regenerating the active Pd(0) species and producing the
cross coupled product.
6
7
8
9
10
11
Fig. 3 The proposed mechanism for the synthesis of biaryls.

4
Tetrahedron
2199-2204; (f) Varnedoe, L. S.; Angel, B. D.; McClellan, J. L.;
Hanna, J. M. Jr. Letters in organic chemistry 2010, 7, 1-6.
Conclusions
In conclusion, we have developed a novel, simple and efficient
method for the desulfinylative cross-coupling reaction between
aryl sulfinates and arenediazonium salt. Arenediazonium salts
proved to be good alternatives to other environmentally
hazardous or costly arylating agents. This protocol is applicable
to a variety of diazonium salts, giving good to excellent yields.
The catalyst Pd(dppf)Cl2 is the highlight of this protocol with low
palladium loadings.
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Acknowledgment
The author S. H. Gund is greatly thankful to the university grant
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5
 Developed a novel method for the desulfinylative cross-
coupling reaction.
 Diazonium salts proved to be good alternatives to other
costly arylating agents.
 Low palladium loading the catalyst Pd(dppf)Cl2.

6
Tetrahedron
Desulfinylative Pd-catalyzed coupling
reaction of arenediazonium salt with
aryl sulfinates to give unsymmetrical
biaryls
Sitaram Haribhau Gunda, Kishor Eknath Balsanea and
Jayashree Milind Nagarkara*
aDepartment of Chemistry, Institute of Chemical Technology,
Matunga, Mumbai – 400019, India.
*Corresponding author. Tel.: +91 22
33611111/2222; fax: +91 22 33611020.
Email: jm.nagarkar@ictmumbai.edu.in
_________________________________________
__________________________________
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