Organic/inorganic salting-in/salting-out agents as promoters of Pd-catalysed ligand free synthesis of biaryls in water

Article abstract of DOI:10.1016/j.jorganchem.2015.12.025

Biaryls were synthesized using Pd-catalyzed Suzuki-Miyaura cross coupling reactions of aryl halides with aryl boronic acids in water in the presence of organic/inorganic additives as promoters. The coupling reactions, carried out in absence of ligand, proceed in good to excellent yields with easy product isolation and in relatively shorter reaction time.

Full text of DOI:10.1016/j.jorganchem.2015.12.025

Journal of Organometallic Chemistry 804 (2016) 26e29
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Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Communication
Organic/inorganic salting-in/salting-out agents as promoters of Pd-
catalysed ligand free synthesis of biaryls in water
a
a
b
a, *
Preeti Rekha Boruah , Sankar Jyoti Bora , Prakash J. Saikia , Diganta Sarma
a
Department of Chemistry, Dibrugarh University, Dibrugarh, 786004, Assam, India
Analytical Chemistry Division, CSIR-North East Institute of Science & Technology, Jorhat, 785006, Assam, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 October 2015
Received in revised form
Biaryls were synthesized using Pd-catalyzed SuzukieMiyaura cross coupling reactions of aryl halides
with aryl boronic acids in water in the presence of organic/inorganic additives as promoters. The
coupling reactions, carried out in absence of ligand, proceed in good to excellent yields with easy product
isolation and in relatively shorter reaction time.
4
December 2015
Accepted 20 December 2015
Available online 23 December 2015
©
2015 Elsevier B.V. All rights reserved.
Keywords:
Suzuki coupling
Green chemistry
Salting-out agent
Palladium
1
. Introduction
environmentally benign solvents. In this regard water, the nature's
gift, is undoubtedly the best substitute for several organic solvents
[3].
Biaryls are important structural moieties in many kinds of
compounds like polymers, natural products, agrochemicals and
pharmaceuticals. Developing methods to construct biaryl unit,
therefore, is of great interest to scientific community. Palladium
catalyzed SuzukieMiyaura cross coupling reaction is one of the
most important and efficient strategies for the construction of
biaryl compounds [1]. This method finds several advantages over
other CeC bond forming reactions like (i) mild reaction conditions
and commercial availability of diversed boronic acids, (ii) better
compatibility of organoboron compounds than organozinc or
Grignard reagents, (iii) low toxicity and high thermal stability of
boron compounds, (iv) easy handling and removal of the boron
containing byproducts etc.
The promoting activity of salts in organic transformations is
reported from time to time [4]. Salting-out agents usually enhance
reaction rate whereas salting-in agents inhibit the reaction prog-
ress. The phrases “salting-out” and “salting-in” are generally used
to denote, respectively, an increase and a decrease in the solubility
of the nonelectrolyte with increasing concentration of electrolyte
[4]. Herein, we present the results of SuzukieMiyaura cross
coupling reactions carried out in different organic/inorganic
salting-in and salting-out agents.
2. Results and discussion
SuzukieMiyaura reaction is
a palladium-catalyzed cross
In this work, biaryls were synthesized by palladium catalyzed
coupling between organoboronic acids and halides or triflates [2].
The couplings, which involve a base and a ligand, are generally
carried out in THF and diethyl ether in the presence of Pd (II) or Pd
0) catalysts which are soluble in these solvents. In view of the
environmental pollution caused by the use of the volatile organic
solvents, there has been an increasing interest to replace them by
Suzuki couplings in aqueous solutions of different organic and
inorganic salting-out (Inorganic- LiCl, NaCl, NaBr, CaCl , Na SO
and KCl; Organic- [EMIM][Br]) and salting-in agents (Inorganic-
Urea, Guanidium chloride and LiClO ; Organic- [OMIM][Br]) (Fig. 1).
The reaction of phenyl boronic acid with 4-bromotoluene
catalyzed by 2 mol% PdCl in water gave 90% yield of the desired
2
2
4
,
(
4
2
product in 4 h (Table 1, Entry 1). The same reaction in the presence
of 0.05 M LiCl solution afforded biaryl in 92% yields after 1.5 h
(Table 1, Entry 2). Slightly better results were observed when the
*
Corresponding author.
E-mail addresses: dsarma22@gmail.com, dsarma22@dibru.ac.in (D. Sarma).
salt concentration was increased up to 2 M (Table 1, entries 3e4),
http://dx.doi.org/10.1016/j.jorganchem.2015.12.025
022-328X/© 2015 Elsevier B.V. All rights reserved.
0

P.R. Boruah et al. / Journal of Organometallic Chemistry 804 (2016) 26e29
27
9
0e96% yields (Table 1, Entries 5e7). For the same reaction, while
carried out in aqueous solutions of MgCl and CaCl , no promoting
effect was observed (Table 1, Entries 8e9).
Imidazolium derived organic salts containing short alkyl chain
behave as salting-out agents whereas organic salts containing long
alkyl chain length behave as salting-in agents [8]. [EMIM][Br], a
salting-out agent enhances the SuzukieMiyaura reaction rate
2
2
Salting-out
Inorganic Organic
Salting-in
Inorganic Organic
Urea,
N
LiCl, NaCl,
[Br]
guanidium
hydrochlorid
e, tetrabutyl
ammonium
bromide and
( )
7
N
N
NaBr, CaCl
MgCl2,
2
,
[Br]
(Table 1, Entry 10), affording 92% yields in 2 h. The use of b-cyclo-
N
[
EMIM][Br],
dextrin, a 7-membered sugar ring molecule, enhances the rate of
SuzukieMiyaura coupling reaction in water. The reaction of phenyl
2
Na SO
4
, and
KCl
β-cyclodextrin
[OMIM][Br]
LiClO
4
boronic acid with 4-bromotoluene in 2 mol%
ded 90% yields in 1.5 h (Table 1, Entry 11). This promoting effect of
cyclodextrin could be due to the inclusion complexes formed by
b-cyclodextrin affor-
Fig. 1. Organic/Inorganic additives used in this study.
b
-
cyclodextrin simultaneously with aryl halide and aryl boronic acid,
thereby increasing the solubility of the compounds in water. Our
results were well supported by the earlier literature report. Chris-
tophe Len et al. observed dramatic acceleration of SuzukieMiyaura
Table 1
a
Effect of additives on Suzuki couplings.
coupling reactions carried out in the presence of
The reaction of 4-bromo acetophenone with phenyl boronic acid
catalyzed by palladium acetate in the presence of 0.5 mol%
cyclodextrin at room temperature afforded the biaryl adduct in 94%
b-cyclodextrin [9].
Br
B(OH)
2
2 2 3
PdCl , K CO
Additives, r.t.
b
-
Entry
Solvent
Time (h)
% Yieldsb
yields in 24 h. Whereas the same reaction, in absence of
dextrin gave 63% yields.
b-cyclo-
1
2
3
4
5
6
7
8
9
Water
4.0
1.5
1.5
1.0
2.0
3.0
3.0
4.0
4.0
2.0
1.5
4.0
3.0
2.5
2.5
2.0
90
92
95
95
90
94
96
88
85
92
90
60
94
90
88
92
0.05 M LiCl
1.0 M LiCl
2.0 M LiCl
0.05 M Na SO
2 4
0.05 M NaCl
0.1 M KCl
We then next examined the effect of salting-in agents on the
course of SuzukieMiyaura cross coupling. The reaction of phenyl
boronic acid with 4-bromotoluene in 1 M urea solution was
inhibited, affording 60% yields in 4 h (Table 1, Entry 12). But, other
salting-in agents like guanidine chloride, [OMIM][Br], tetrabutyl
ammonium bromide and lithium perchlorate promoted the prog-
ress of SuzukieMiyaura couplings in water (Table 1, Entries 13e16).
Urea, a non-ionic species, is believed to inhibit the SuzukieMiyaura
coupling by chelating the palladium catalyst.
To extend the promoting effect of ionic additive on Suzuki-
Miaura couplings, different electron rich and electron deficient
aryl bromides and boronic acid derivatives were used to construct
biaryls (Table 2, Entries 1e10). Under the reaction condition,
various aryl bromides bearing electron-withdrawing groups such
as nitro, nitrile and aldehyde moieties and electron-releasing
groups such as methyl and methoxy moieties react with aryl
boronic acids to afford biaryls in high yields along with trace
amount of homocoupling products of aryl boronic acids (2e5%).
Intriguing by the promoting effect of ionic additives on the
Suzuki couplings of aryl bromides with aryl boronic acids, we next
0.1 M MgCl
0.1 M CaCl
0.05 M [EMIM][Br]
2 mol% -cyclodextrin
0.1 M Urea
0.1 M Guanidium hydrochloride
0.1 M [OMIM][Br]
2 mol% Tetrabutyl ammonium bromide
2
2
10
11
12
13
14
15
16
b
0.1 M LiClO
4
a
Reaction conditions: Aryl halide (1 mmol), arylboronic acid (1.2 mmol), PdCl
CO (2 mmol), aqueous salt (organic or inorganic) solutions (2 mL), r.t.
Isolated yields.
2
(
2 mol%), K
2
3
b
but beyond 2 M salt concentration catalyst decomposition was
observed which was evidenced by the precipitation of black
residues.
Lithium chloride, a salting-out agent, was found to accelerate
DielseAlder reaction [5]. Kumar et al. showed dramatic accelera-
tion of DielseAlder reaction rate in the presence of 5 M LiCl solution
Table 2
a
Effect of substituents on SuzukieMiyaura reactions.
[5d]. The effect of salts on kinetics of DielseAlder reactions has
been discussed in terms of several parameters like hydrophobic
packing, solvent pressure, hydrogen bonding, hydrophobic hydra-
tion etc. [5] To the best of our knowledge, no such observations are
reported in literature for SuzukieMiyaura cross coupling reactions.
Br
B(OH)2
2 2 3
PdCl , K CO
R1
R2
0.05 M LiCl
R1
R2
aq. solutions, r.t.
Bora et al. recently reported the accelerating effect of Na
Suzuki reactions performed in water [6]. The reaction of 4-nitro
bromobenzene with phenyl boronic acid in the presence of PdCl
and Na SO afforded 90% yields in 5 h whereas the same reaction
without Na SO gave very poor yield, 20% yields in 10 h. They
suggested that the promoting effect in the presence of Na SO
could be due to the in situ formation of a water soluble ate complex
Na PdCl (SO which catalyzed the SuzukieMiyaura reactions.
2 4
SO in
R1
R2
% Yieldsb
Entry
Time (h)
2
1
2
3
4
5
6
7
8
9
4-Me
4-OMe
3-OMe
H
4-Me
4-CN
H
H
H
1.5
3.0
3.5
2.0
3.0
2.5
3.0
3.0
4.0
4.0
92
96
95
96
99
80
90
95
70
65
2
4
2
4
2
4
4-OMe
4-OMe
H
H
H
H
H
2
2
4 2
)
4-NO
2
Sarma et al. recently reported a base free and ligand free protocol
for Suzuki coupling reactions carried out in ionic liquid with
lithium chloride as promoter [7].
4-CHO
3-CHO
2-CHO
10
The reaction of phenyl boronic acid with 4-bromotoluene in
a
Reaction conditions: Aryl bromide (1 mmol), arylboronic acid (1.2 mmol), PdCl
CO (2 mmol), 1 M LiCl solutions (2 mL), r.t.
Isolated yields.
2
aqueous solution of NaCl, Na
2
SO
4
and KCl afforded biaryls in
(2 mol%), K
2
3
b

28
P.R. Boruah et al. / Journal of Organometallic Chemistry 804 (2016) 26e29
proceeded to the SuzukieMiyaura couplings of chloro aryl de-
rivatives. Among the halogens, iodide and bromide derivatives
show excellent activity towards the biaryl synthesis by Suzu-
kieMiyaura couplings. Aryl chlorides show very poor reactivity
towards the boronic acid derivatives. Aryl chlorides are more
difficult to be activated because of high CeCl bond strength. The
Suzuki coupling of chloro derivatives are reported in literature from
time to time either using some harsh reaction conditions or using
some ligands [11]. Thus, a major challenge still remains in Suzu-
kieMiyaura reaction is to develop a catalyst system that can acti-
vate aryl chlorides easily. Suzuki coupling reactions with various
electron and electron deficient chloroaryls and boronic acid de-
rivatives were carried out to construct biaryl adducts. Under this
reaction condition, aryl chlorides were not very reactive towards
aryl boronic acids, very low yields (<10%) were observed. But, in the
presence of ethylene glycol, aryl chlorides bearing electron-
withdrawing groups such as nitro, carbomethoxy and aldehyde
moieties and electron-releasing groups such as methyl react with
aryl boronic acids to afford biaryls in comparatively higher yields
synthesis in water in a ligand free environment. Organic/Inorganic
ionic additives show excellent promoting activity towards biaryl
synthesis. The methodology is quick, versatile and highly efficient.
Under this reaction condition, aryl bromides and chlorides reacted
efficiently with aryl boronic acids to afford the biaryl adducts. This
simple protocol provides a wide scope for the synthesis of desired
biaryls in excellent yields in a relatively shorter period of time.
4. Experimental
4.1. Preparation of organic salts
Organic salts N-Ethyl-N-methyl imidazolium bromide, ([EMIM]
[Br]) and N-Methyl-N-Octyl imidazolium bromide, ([OMIM][Br])
were prepared according to a literature procedure [10]. For
example, under vigorous stirring 1-bromoethane (15.24 g,
121.95 mmol) was added to 1-methylimidazole (5 g, 60.98 mmol).
ꢀ
The reaction mixture was stirred at 80 C until two phases were
formed. The top phase, containing the unreacted starting material,
was decanted and ethyl acetate was added to the vessel. The
product [EMIM][Br] was washed with ethyl acetate thrice and dried
(Table 3, Entries 1e7). In absence of ionic additives, Suzu-
kieMiyaura cross coupling of aryl chlorides with aryl boronic acids
in ethylene glycol alone afforded biaryls in comparatively lower
yields. This clearly indicates the promoting activity of additives
towards biaryl synthesis.
ꢀ
under vacuum at 70 C for 6 h 1H NMR (200 MHz, CDCl ): d 10.05 (s,
3
1H), 7.54 (d, 2H), 4.21 (q, 2H), 3.95 (s, 3H), 1.43 (t, 3H). The same
procedure was followed for the synthesis of [OMIM][Br].
The Suzuki reaction of 4-nitro chloro benzene and phenyl
boronic acid in the presence of lithium chloride proceeded
comparatively well, affording 45% yields of the desired biphenyl
adducts in 6 h as compared to the very poor yields (<10%) obtained
in water alone (Table 3, Entry 1). Identical results were obtained
with other chloro aryls also (Table 3, Entries 2e6). The reaction of 4-
cloro toluene with 4-methoxy phenyl boronic acid afforded the best
result (70% yields, Entry 6, Table 3) under this reaction condition.
The role of ionic additives and other agents on the promoting
4
.2. General experimental procedure for Suzuki cross coupling
reactions in salt solutions
In a 50 mL round buttom flask, a mixture of aryl halide (1 mmol),
2
phenyl boronic acid (1.2 mmol), PdCl (2 mol%), potassium car-
bonate (2 mmol) and salts solution (organic or inorganic) (2 mL)
was stirred at room temperature for a time period as mentioned in
Table 1. The progress of the reaction was monitored by TLC. The
resulting mixture was extracted with diethyl ether (3 Â 5 mL). The
(
for all the additives except urea) or inhibiting effect (in case of
urea) during the course of Suzuki couplings is not well understood.
It could be due to the combination of several parameters such as
polarity of solvent media, hydrogen bonding, hydrophobic effect
etc. Also the ionic additive, by coordination to the Pd(II) adducts, is
believed to play significant role in the oxidative addition of aryl
halides to palladium species favouring the formation of thermo-
dynamically more stable trans isomer.
2 4
ether layer was separated and dried over anhydrous Na SO . The
product was purified by column chromatography over silica gel
using n-hexane/ethyl acetate (9:1 v/v) to get the desired coupling
product. The products were characterized by H-NMR and GCeMS.
1
Acknowledgements
DS is thankful to UGC, New Delhi for a start-up grant [No. F.20-
3(2)/2012(BSR)]. The authors also acknowledge the Department of
Science and Technology for financial assistance under DST-FIST
programme and UGC, New Delhi for Special Assistance Pro-
gramme (UGC-SAP) to the Department of Chemistry, Dibrugarh
University.
3
. Conclusion
In summary, we have developed a novel protocol for biaryl
Table 3
a
Effect of organic/inorganic salts on Suzuki couplings.
References
Cl
B(OH)2
PdCl
2 2 3
, K CO
[
1] (a) N. Miyaura, A. Suzuki, Chem. Rev. 95 (1995) 2457;
(b) N. Miyaura, T. Yanagi, A. Suzuki, Synth. Commun 11 (1981) 513;
(c) A. Suzuki, Angew. Chem. Intl. Ed. 50 (2011) 6722;
R1
R2
0
.1 M LiCl aq.
solutions, EG,
r.t., 6 h
R1
R2
(
d) A. Suzuki, Heterocycles 80 (2010) 15.
2] (a) S. Kotha, K. Lahiri, D. Kashinath, Tetrahedron 58 (2002) 9633;
b) P. Das, U. Bora, A. Tairai, C. Sharma, Tetrahedron Lett. 51 (2010) 1479;
(c) P. Das, C. Sharma, A. Tairai, U. Bora, Appl. Organomet. Chem. 25 (2011) 283;
d) T. Maegawa, Y. Kitamura, S. Sako, T. Udzu, A. Sakurai, A. Tanaka,
[
(
Entry
R1
4-NO
R2
% Yieldsb
(
1
2
3
4
5
6
7
2
H
H
45
60
65
55
60
70
65
Y. Kobayashi, K. Endo, U. Bora, T. Kurita, A. Kozaki, Y. Monguchi, H. Sajiki,
Chem. Eur. J. 13 (2007) 5937;
(e) C. Amatore, G.L. Duc, A. Jutand, Chem. Eur. J. 19 (2013) 10082;
(f) C. Amatore, A. Jutand, G.L. Duc, Chem. Eur. J 18 (2012) 6616.
4-CHO
H
H
4-OMe
4-CF
H
4-OMe
H
3
4-COCH
3
[3] (a) V. Polshettiwar, A. Decottignies, C. Len, A. Fihri, ChemSusChem 5 (2010)
502;
4-CH
4-OMe
3
(b) A. Fihri, D. Luart, C. Len, A. Solhy, C. Chevrin, V. Polshettiwar, Dalton Trans.
40 (2011) 3116;
a
Reaction conditions: Aryl chloride (1 mmol), arylboronic acid (1.2 mmol), PdCl
CO (2 mmol), 0.1 M LiCl solutions (1 mL), Ethylene Glycol (EG) 1 mL, r.t.
Isolated yields.
2
(c) G. Sartori, G. Enderlin, G. Herve, C. Len, Synthesis 44 (2012) 767;
(d) A. Hassine, S. Sebti, A. Solhy, A. Zahouily, C. Len, A.S. Hedhili, A. Fihri, Appl.
Catal. A General 450 (2013) 13;
(
2 mol%), K
2
3
b

P.R. Boruah et al. / Journal of Organometallic Chemistry 804 (2016) 26e29
e) G. Sartori, G. Herve, G. Enderlin, C. Len, Synthesis 45 (2013) 330; 32 (2013) 101.
29
(
(
(
(
f) S. Gallagher-Duval, G. Herv eꢀ , G. Sartori, G. Enderlin, C. Len, New J. Chem. 37
[10] (a) D.R. McFarlane, J.M. Pringle, K.M. Johansson, S.A. Forsyth, M. Forsyth,
Chem. Commun (2006) 1905;
2013) 1989;
g) G. Herv eꢀ , G. Sartori, G. Enderlin, G. Mackenzie, C. Len, RSC Adv. 4 (2014)
(b) A.R. Hajipour, F. Rafiee, J. Iran, Chem. Soc. 6 (2009) 647;
(c) L.D.S. Yadav, S. Singh, V.K. Rai, Tetrahedron Lett. 50 (2009) 2208;
(d) C. Chiappe, B. Melai, A. Sanzone, G. Valentini, Pure Appl. Chem. 81 (2009)
2035;
(e) R. Wang, J.C. Xiao, B. Twamley, J.M. Shreeve, Org. Biomol. Chem. 5 (2007)
671;
1
8558.
4] (a) J. Dupont, R.F. de Souza, P.A.Z. Suarez, Chem. Rev 102 (2002) 3667;
b) M. Lamblin, L. Nassar-Hardy, J. Hierso, E. Fouquet, F. Felpin, Adv. Synth.
Catal. 352 (2010) 33;
c) R. Breslow, Acc. Chem. Res. 24 (1991) 159.
5] (a) D. Sarma, A. Kumar, Org. Lett. 8 (2006) 2199;
[
[
(
(
(f) C. Ye, J.C. Xiao, B. Twamley, A.D. LaLonde, M.G. Norton, J.M. Shreeve, Eur. J.
Org. Chem. (2007) 5095.
(
(
(
(
b) D. Sarma, S.S. Pawar, S.S. Deshpande, A. Kumar, Tetrahedron Lett. 47
2006) 3957;
[11] (a) R. Martin, S.L. Buchwald, Acc. Chem. Res. 41 (2008) 1461;
(b) T.E. Barder, S.D. Walker, J.R. Martinelli, S.L. Buchwald, J. Am. Chem. Soc. 127
(2005) 4685;
c) D. Sarma, A. Kumar, Appl. Catal. A General 335 (2008) 1;
d) A. Kumar, Chem. Rev. 101 (2001) 1.
[
[
[
[
6] M. Mondal, U. Bora, Green Chem. 14 (2012) 1873.
(c) G.A. Molander, D. Ryu, M. Hosseini-Sarvari, R. Devulapally, D.G. Seapy,
J. Org. Chem. 78 (2013) 6648;
(d) X. Yang, Z. Fei, D. Zhao, W.H. Ang, Y. Li, P.J. Dyson, Inorg. Chem. 47 (2008)
3292.
7] P.R. Boruah, M.J. Koiri, U. Bora, D. Sarma, Tetrahedron Lett. 55 (2014) 2423.
8] Z.P. Visak, J.N.C. Lopes, L.P.N. Rebelo, Monatsh. fur Chem. 138 (2007) 1153.
9] A. Decottignies, A. Fihri, G. Azemar, F. Djedaini-Pilard, C. Len, Catal. Commun