Synthesis of zwitterionic palladium complexes and their application as catalysts in cross-coupling reactions of aryl, heteroaryl and benzyl bromides with organoboron reagents in neat water

Article abstract of DOI:10.1039/c7dt01433c

N-(3-Chloro-2-quinoxalinyl)-N′-arylimidazolium salts (aryl = 2,6-diisopropylphenyl [HL1Cl]Cl, aryl = mesityl [HL2Cl]Cl) have been synthesized by treating 2,3-dichloroquinoxaline with the corresponding N′-arylimidazole in neat water. Facile reactions of these imidazolium salts with Pd(PPh₃)₄ and Pd₂(dba)₃/PPh₃ (dba = dibenzyledene acetone) at 50 °C have afforded zwitterionic palladium(ii) complexes [Pd(HL1)(PPh₃)Cl₂] (I) and [Pd(HL2)(PPh₃)Cl₂] (II) in excellent yields. I and II have been tested for their ability to catalyze Suzuki-Miyaura cross coupling (SMC) reactions in neat water/K₂CO₃ and are found to be highly active for carrying out these reactions between aryl bromides and organoboron reagents. Furthermore, the scope of the catalyst I was also examined by employing (hetero)aryl bromides, hydrophilic aryl bromides, benzyl bromides and various organoboron reagents. More than 80 aryl/benzyl bromide-arylboronic acid combinations were screened in neat water/K₂CO₃ and it was found that I was a versatile catalyst, which produced biaryls/diarylmethanes in excellent yields. A TON of 82 000 was achieved by using I. Studies on the mechanism have also been carried out to investigate the involvement of carbene complexes in the catalytic path. Poison tests and a two-phase test were also conducted and the results are reported.

Full text of DOI:10.1039/c7dt01433c

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Synthesis of Zwitterionic PalladiumComplexes and
Their Application as Catalysts in CrossꢀCoupling
Reactions of Aryl, Heteroaryl and Benzyl Bromides
with Organoboron Reagents in Neat Water
V. Ramakrishna and N. Dastagiri Reddy*
Department of Chemistry, Pondicherry University, Pondicherry 605014, India
*Corresponding author. E–mail: ndreddy.che@pondiuni.edu.in
Abstract: Nꢀ(3ꢀChloroꢀ2ꢀquinoxalinyl)ꢀN′ꢀarylimidazolium salts (aryl = 2,6ꢀdiisopropylphenyl
[HL1Cl]Cl, aryl
=
mesityl [HL2Cl]Cl) have been synthesized by treating 2,3ꢀ
dichloroquinoxaline with corresponding N'ꢀarylimidazole in neat. Facile reactions of these
o
imidazolium salts with Pd(PPh3)4 and Pd2(dba)3/PPh3 (dba = dibenzyledene acetone) at 50 C
have afforded zwitterionic palladium(II) complexes [Pd(HL1)(PPh3)Cl2] (I) and
[Pd(HL2)(PPh3)Cl2] (II) in excellent yields. I and II have been tested for their ability to catalyze
SuzukiꢀMiyaura cross coupling (SMC) reactions in neat water/K2CO3 and are found to be highly
active for carrying out these reactions between aryl bromides and organoboron reagents. Further,
the scope of the catalyst I was also examined by employing (hetero)aryl bromides, hydrophilic
aryl bromides, benzyl bromides and various organoboron reagents. More than 80 aryl/benzyl

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bromideꢀarylboronic acid combinations were screened in neat water/K2CO3 and found that I is a
versatile catalyst, which produced the biaryls/diarylmethanes in excellent yields. A TON of
82,000 was achieved by using I. Studies on the mechanism have also been carried out to
investigate the involvement of carbene complexes in the catalytic path. Poison tests and two
phase test were also conducted and the results are reported.
Key words: 2,3ꢀdichloroquinoxaline; Nꢀheterocyclic carbene; PdꢀNHC; SuzukiꢀMiyaura
coupling; zwitterion
Introduction
Palladium–catalyzed SuzukiꢀMiyaura crossꢀcoupling (SMC) reaction of aryl and benzyl
halides with nucleophilic organoboron reagents has been extensively utilized in the construction
of unsymmetrical biaryl and diarylmethane derivatives.1 These structural units are widely found
in biologically active compounds, herbicides, natural products, conducting polymers and liquid
crystalline materials.2 In 1979, Suzuki reported Pd catalyzed sp2(C)–sp2(C) cross coupling
reactions and several years later in 1994, Keay demonstrated sp3(C)–sp2(C) coupling.3 The SMC
crossꢀcoupling has emerged as an efficient methodology over Kumada,4 Hiyama,5 Stille6 and
Negishi7 coupling reactions owing to the advantages of the organoboron reagents, which are
used in SMC reactions. Organoboron reagents are less toxic, commercially available, thermally
stable, not sensitive to air/moisture, and have high tolerance toward the functional groups in
substrates.8 In the literature, a variety of methods have been developed for the SMC reactions
such as microwaveꢀheating,9 ultrasonicꢀirradiation,10 ligandꢀfree methodology,11 waterꢀsoluble
catalysis,12 nano catalysis,13 and the addition of organic coꢀsolvents,14 surfactants or phaseꢀ
transfer reagents.15 Over the past few years, there has been a growing interest to exploit water as

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a solvent for the SMC reactions.16 Water being an ideal solvent from a green chemistry
perspective has a greater scope as an alternative to organic solvent as it is inexpensive, readily
available, renewable, nonꢀflammable and nonꢀtoxic. Moreover, if water is used as a solvent, the
desiccation of the substrates is not required and the products can easily be separated.17
Traditionally, sulfonate, carboxylate, and ammonium groups have been incorporated into
ligands in order to improve the water solubility of metal complexes.18 In this context,
zwitterionic metal complexes have received considerable attention. The most common among
the zwitterionic metal complexes are of two types. One is with a formal cationic charge on the
metal center and an associated anionic ancillary ligand. The other type is with a formal anionic
charge on the metal center and an associated cationic ancillary ligand.19 Though several
zwitterionic complexes of Pd are known in the literature, only a few of them have been studied
for their catalytic activity.18c,h,20 Recently, a few such complexes with a formal negative charge
on Pd have been reported in the literature (Figure 1, a ꢀ e). However, except for c, catalytic
activity of these complexes has not been explored.20aꢀf Lee and his coꢀworkers have reported that
c is highly active in carrying out the SMC reactions in aqueous medium (4:1 dioxane/water).20f
Hence, we became interested in synthesizing zwitterionic Pd(II) complexes with formal anionic
charge on the metal. Herein, we report the facile synthesis of zwitterionic palladium(II)
complexes (Figure 1) and their efficiency as catalysts in water mediated sp2(C)–sp2(C) and
sp3(C)–sp2(C) carbon coupling reactions.

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Figure 1 Examples of zwitterionic anionic Pd(II) complexes derived from imidazole or triazole
derivatives
Results and Discussion
Nꢀ(3ꢀChloroꢀ2ꢀquinoxalinyl)ꢀN′ꢀarylimidazolium salts [HL1Cl]Cl (aryl
=
2,6ꢀ
diisopropylphenyl) and [HL2Cl]Cl (aryl = mesityl) were prepared as ligand precursors from
inexpensive reactants 2,3ꢀdichloroquinoxaline and the corresponding N'ꢀarylimidazoles in a
single step in very high yields (Scheme 1). These salts were characterized by NMR spectroscopy.
The 1H NMR spectrum in DMSOꢀd6 displayed a singlet in downfield region (∼10.60 and ∼10.80
ppm), characteristic to the acidic NCHN proton. Further, the solid state structure of the
imidazolium salt [HL2Cl]PF6 was confirmed from single crystal Xꢀray diffraction analysis and

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an ORTEP diagram of the molecular structure is shown in Figure S1 (see Electronic
Supplementary Information).
Scheme 1 Synthesis of imidazolium salts
Path A
R1
N
N R1
N
N
N
N
N
Pd(PPh3)4, 6 h
THF, 50 oC
Cl
Cl
N
Cl
Pd
Cl
Ph3P
R1 = 2,6-Diisopropylphenyl [Pd(HL1)(PPh3)Cl2] (I)
Mesityl
[Pd(HL2)(PPh3)Cl2] (II)
Path B
R1
N
N R1
Cl
N
N
N
N
N
Pd2(dba)3, 6 h
PPh3, THF, 50 oC
Cl
Cl
N
Cl
Pd
Ph3P
R1 = 2,6-Diisopropylphenyl
Mesityl
[Pd(HL1)(PPh3)Cl2] (I)
[Pd(HL2)(PPh3)Cl2] (II)
Scheme 2 Synthesis of zwitterionic Pd(II) complexes
The Pd(II) complexes were synthesized by the reaction of the imidazolium salts with
commercially available Pd(PPh3)4 or Pd2(dba)3/PPh3 in THF at 50 °C (Scheme 2). The C−Cl
bond is oxidatively added to Pd(0) to afford pale/bright yellow zwitterionic Pd(II) complexes
[Pd(HL1)(PPh3)Cl2] (I) and [Pd(HL2)(PPh3)Cl2] (II), which were characterized using NMR
spectroscopy and elemental analysis. While the presence of the imidazolium group and PPh3 was

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1
31
evident from the H NMR spectra, the P NMR spectra confirmed the coordination of PPh3 to
Pd. In order to explore the structural features of these complexes, single crystal Xꢀray diffraction
analysis was performed on single crystals grown from saturated solutions of the complexes in
acetonitrile at 0 °C. The ORTEP diagrams depicting the molecular structures of I and II are
given in Figure 2 and the selected bond parameters are listed in Table 1. The structures reveal
that the metal in both the complexes is in slightly distorted square planar geometry and
coordinated by an orthoꢀheteroaryl carbon of the quinoxaline ring, triphenyl phosphine and two
chloride ions. The quinoxaline ring is almost orthogonal to the coordination plane of the metal
with a dihedral angle of 87.50o in I and 81.46o & 86.55o in II. The imidazolium ring is also not
coplanar with the quinoxaline ring and the dihedral angle between the planes is 23.33o in I and
32.59o & 32.66o in II. The structure further reveals that both I and II are cis complexes. The
Pd−C bond length was found to be 1.988(2) Å in I and 2.003(5) Å & 1.997(5) Å in II, which is
in accordance with the reports in the literature.20c,f
a)
b)

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Figure 2 a) Molecular structure of I, b) molecular structure of II. All hydrogen atoms and
solvent molecules have been removed for clarity. Thermal ellipsoids are drawn at 50%
probability level.
Table 1 Selected bond parameters of [Pd(HL1)(PPh3)Cl2] (I) and [Pd(HL2)(PPh3)Cl2] (II).
Bond lengths [Å]
Bong angles [o]
I
II
II*
I
II
II*
Pd1−P1
Pd1−C5
2.2454(6) 2.2588(14)
2.2626(14)
C5−Pd1−Cl1
88.93(6)
86.38(14)
87.50(14)
1.988(2) 2.003(5)
1.997(5)
C5−Pd1−P1
Cl1−Pd1−Cl2
P1−Pd1−Cl2
P1−Pd1−Cl1
89.61(6)
93.40(2)
88.03(2)
177.37(2)
90.98(14)
92.07(5)
90.58(5)
177.33(5)
91.36(14)
91.05(5)
90.09(5)
178.83(5)
Pd1−Cl1 2.3771(5) 2.3796(13)
Pd1−Cl2 2.3981(5) 2.3942(12)
2.3838(13)
2.3918(12)
1.440(6)
N2−C4
C4−C5
N4−C4
N3−C5
N1−C3
1.442(3)
1.438(3)
1.300(0)
1.316(3)
1.332(3)
1.441(7)
1.431(7)
1.305(6)
1.307(6)
1.334(7)
1.432(7)
1.304(7)
1.311(6)
1.332(7)
C5−C4−N2
N4−C4−N2
C5−Pd1−Cl2
N3−C5−Pd1
121.57(18) 122.3(4)
112.93(18) 112.5(4)
120.8(4)
114.2(4)
178.47(14)
115.6(4)
177.47(6)
177.65(15)
116.78(15) 116.5(3)
* Two molecules are present in the asymmetric unit of II
Table 2 Optimization of reaction conditionsa
Entry
1
Base
Solvent
1,4ꢀdioxane
Time (h)
5
bYield (%)
K2CO3
81
2
3
K2CO3
K2CO3
1,4ꢀdioxane/water (2:1)
1,4ꢀdioxane/water (1:2)
8
5
92
95
DMF/water (1:2)
4
5
6
K2CO3
K2CO3
K2CO3
5
5
5
94
95
85
Isopropanol/water (1:2)
DMSO/water (1:2)
7
8
9
10
11
K2CO3 or Na2CO3 water
3
3
3
3
3
96
61
55
28
21
NaOAc
KOAc
NaOH
KOH
water
water
water
water

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aReaction conditions: 4ꢀbromoacetophenone (1.0 mmol), phenylboronic acid (1.2 mmol), K2CO3
b
(2.0 mmol), solvent (3 mL), [Pd] (0.5 mol%), at room temperature, in air. Isolated yield after
column chromatography.
As the main aim of designing and synthesizing I and II is to use them as catalysts for the
SMC reactions in aqueous medium, a number of experiments were carried out using them as
catalysts under various conditions. It has been well established that the combination of the
solvent and the base play a significant role in SMC reactions.21 Therefore, the probe began with
optimizing a model reaction between 4ꢀbromoacetophenone and phenylboronic acid in various
solvent/base combinations in the presence of 0.5 mol% of the catalysts at rt. The results of the
reactions using I have been illustrated in Table 2. II also showed similar activity. It was observed
that all the reactions, wherever there was a combination of water and K2CO3, afforded the cross
coupling product in excellent yields (Table 2, entries 2ꢀ7). The best combination was found to be
neat water and K2CO3 (or Na2CO3) with yields reaching near quantitative in 3 h (Table 2, entry
7). The catalysts could not perform well with the combination of strong bases and H2O, which is
reflected in low yields of the product. Organotrifluoroborates, which can easily be prepared by
the treatment of a boronic acid with potassium hydrogen fluoride, have advantages over boronic
acid such as greater stability to air and moisture, easy isolation and no trimer formation.22 To the
best of our knowledge, there are only a few articles reported in the literature, which describe the
SMC reactions in aqueous medium utilizing organotrifluoroborates in place of boronic acids.23
Hence, we further investigated the aforementioned optimized SMC reaction using potassium
phenyltrifluoroborate in place of phenylboronic acid. Though at room temperature the reaction in
water with K2CO3 as base yielded only 80% of the cross coupled product, when the reaction was
conducted at 70 °C the yield was quantitative in 3 h. All these probe reactions were conducted

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using both the catalysts I and II separately and found that they are equally efficient. The fact that
none of these reactions produced homocoupling byꢀproducts make these palladium complexes
highly efficient catalyst precursors for the SMC reactions.
Table 3 SuzukiꢀMiyaura crossꢀcoupling reaction of substituted aryl bromides with
phenylboronic acid and potassium phenyltrifluoroborate in neat watera
Entry
1
Aryl bromide 1
Organoboron
reagent
Biaryl 4
bYield (%)
2a
3a
98 (2a)c
98 (3a)
97 (2a)c
95 (3a)
98 (2a)c
97 (3a)
2
3
2a
3a
2a
3a
4
5
96 (2a)c
98 (3a)
95 (2a)
2a
3a
2a
3a
94 (3a)
6
2a
3a
95 (2a)
96 (3a)

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7
8
2a
95 (2a)
93 (3a)
95 (2a)
3a
2a
93 (3a)
3a
3a
9
96
10
11
12
3a
97
97 (2a)
2a
95 (3a)
96 (2a)
3a
2a
94 (3a)
95 (2a)
3a
2a
13
14
93 (3a)
93 (2a)
3a
2a
92 (3a)
3a
15
2a
3a
95 (2a)
93 (3a)
16
17
94
3a
91c,d
3a

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18
19
2a
95 (2a)
93 (3a)
3a
2a
94 (2a)c,d
92 (3a)c,d
3a
20
2a
3a
95 (2a)
94 (3a)
aReaction conditions: 1/n mmol of aryl bromide (n = number of bromine atoms on aryl ring),
organoboron reagent (2a or 3a) (1.2 mmol), K2CO3 (2.0 mmol), H2O (3 mL), [Pd] (0.5 mol%),
b
1
reaction time of 3 h, in air. Isolated yield (purity of the isolated product was confirmed by H
d
NMR), cat rt. Isolated yields after column chromatography.
To expand the scope of the catalyst I, we further studied the SMC reactions of the
organoboron reagents [phenylboronic acid (2a) and potassium phenyltrifluoroborate (3a)] with
the aryl bromides containing various substituents including diverse functional groups. The
products were separated by simply filtering the reaction mixture if they are solids and in case of
semiꢀsolids and oily substances they were extracted with diethyl ether. However, in few cases
column chromatography was needed to purify the products. It was observed that the products
that were separated by filtering the reaction mixture were found to contain traces of Pd black,
which was removed by dissolving them in ethyl acetate and filtering the solution through a plug
of silica or celite. The results of these coupling reactions are furnished in Table 3. All the
substituted aryl bromides, irrespective of the nature of the substituent, afforded the desired
products in excellent yields. When phenylboronic acid was employed, except in four cases
o
(Table 3, entries 1–4), all the 20 aryl bromides screened required higher temperature (70 C) for

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the completion of the reaction in 3 h. However, all the reactions involving potassium
o
phenyltrifluoroborate took place only at 70 C to afford the cross coupled products in excellent
yields. Moderately hindered aryl bromides also underwent quantitative coupling with 2a and 3a
(Table 3, entries 13–17). Two terphenyls and one quarterphenyl were synthesized successfully
using dibromoꢀ and tribromobenzene in high yields respectively (Table 3, entries 18–20).
Table 4 SuzukiꢀMiyaura coupling of substituted phenylboronic acids with aryl bromides in neat
watera
Entry
1
Aryl halide 1
Boronic acid
Biaryl 4
bYield
(%)
98
2
95
3
4
5
6
7
95
96
91c
98
93

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8
96
9
95
96
10
11
95
12
13
14
93
92c
96
15
55

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16
Nil
aReaction conditions: 1/n mmol of aryl bromide (n = number of bromine atoms on aryl ring),
arylboronic acid (1.2 mmol), K2CO3 (2.0 mmol), H2O (3 mL), [Pd] (0.5 mol%), at 70 ºC,
b
1
reaction time of 3 h, in air. Isolated yield (purity of the isolated product was confirmed by H
NMR). cIsolated yield after column chromatography.
The SMC reactions were also conducted on a wide variety of arylboronic acids using I to
examine the scope of the catalyst. In most of these reactions (Table 4 entries 1–9), 4ꢀ
bromoacetophenone (1a) was employed, but a few other substituted aryl bromides (Table 4,
entries 10–14) were also used to crosscheck the applicability of the catalyst for various boronic
o
acidꢀbromobenzene combinations. In all the cases, the reaction was completed in 3 h at 70 C
and excellent yields of the cross coupled products were obtained. However, when the reactions
were conducted at room temperature the yields were low (50 ꢀ 70%). Further, when the
moderately hindered boronic acid 2,4ꢀdifluorophenylboronic acid (Table 4, entry 15) was used
with 4ꢀbromoacetophenone, the yield was drastically reduced to 55%. Sterically demanding 2,6ꢀ
dimethylphenylboronic acid (Table 4, entry 16) afforded no cross coupled product. These results
and also entry 17 in Table 4 suggest that the catalytic efficiency of the complex I does not
depend on the steric crowd on the aryl bromide, but is highly sensitive to the bulkiness of the
boronic acid. In some of the cases (Table 4, entries 9, 10, 11 and 14), formation of <10% of
homoꢀcoupled products of boronic acid was also observed and hence the crossꢀcoupled products
were purified by column chromatography.
Table 5 Synthesis of biaryls containing heteroaromatic ring catalyzed by Ia

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Entry
1
Aryl bromide 5
Organoboron
Biaryl 6
bYield (%)
92 (2a)
95 (3a)
92 (2a)
90 (3a)
reagent
2a
3a
2
2a
3a
3
4
5
2a
3a
92 (2a)
93 (3a)
2a
3a
95 (2a)
93 (3a)
95 (2a)
96 (3a)
96
2a
3a
6
7
8
3a
92
2a
94c

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9
2a
93c
10
11
12
95
96
93
13
14
15
96
92c
88c
16
17
65c
85c

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aReaction conditions: aryl bromide (1.0 mmol), organoboron reagent (1.2 mmol), K2CO3 (2.0
mmol), H2O (3 mL), [Pd] (0.5 mol%), at 70 ºC, reaction time of 3 h, in air. bIsolated yield (purity
of the isolated product was confirmed by 1H NMR). cIsolated yield after column
chromatography
.
Arylꢀheteroaryl and heteroarylꢀheteroaryl moieties are commonly present in drugs and
bioactive natural products.1 Synthesis of such systems through the SMC reaction is quite
challenging owing to the ligating ability of the heteroatoms, which can lead to the catalyst
deactivation by forming stable Pd(II) complexes. Hence the literature on their synthesis is limited
to only a few articles. Reports on such reactions in water are even less.24 In the present
investigation, we also examined the ability of I to bring about the coupling between heteroaryl
bromides and organoboron reagents and in few cases between aryl bromides and
heteroarylboronic acids under the said optimized reaction conditions (Table 5). Except the
reaction between 4ꢀbromobenzaldehyde and benzothiopheneꢀ2ꢀboronic acid (Table 5, entry 16),
which gave the corresponding cross coupled product in moderate yield, all the reactions yielded
the biaryls in excellent yields. It is noteworthy that indoleꢀ5ꢀboronic acid, without any protection
of NH group, also underwent coupling with 4ꢀbromobenzonitrile in water and produced the
corresponding biaryl in very good yield (Table 5, entry 17).
Table 6. SuzukiꢀMiyaura sp3(C)−sp2(C) crossꢀcoupling of benzyl bromides with aryl boronic
acids and potassium phenyltrifluoroboratea

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Entry Benzyl bromide 5
Organoboron
reagent
Methylene bridged biaryl bYield (%)
6
1
3a
98
96
2
3
3a
3a
92
4
5
6
3a
3a
3a
91
94
93
7
8
3a
3a
94
97
9
92
95
10
11
92c

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12
13
92
93
14d
2a
3a
95 (2a)
94 (3a)
15
16
93
91c
17
85c
aReaction conditions: benzyl bromide (1.0 mmol), organoboron reagent (2 or 3a, 1.2 mmol),
K2CO3 (2.0 mmol), H2O (3 mL), [Pd] (0.5 mol%), at 70 ºC, reaction time of 3 h, in air. bIsolated
1
yield (Purity of the isolated product was confirmed by H NMR). cIsolated yield after column
chromatography.
dOrganoboron reagent (2 or 3a, 2.4 mmol)
Further, the catalyst I was also probed to carry out sp3(C)−sp2(C) coupling between a
series of benzyl bromides and organoboron reagents 2 and 3a (Table 6). The resultant
diarylmethane derivatives constitute an important class of building blocks in the synthesis of
supramolecules and bioꢀactive organic molecules. A thorough literature search revealed that only

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a few examples of aqueousꢀphase SMC reactions of benzyl halides have been reported so far.25
In this study, a series of eight benzyl bromides were studied for their coupling reaction with
potassium phenyltrifluoroborate 3a and few arylboronic acids including heteroarylboronic acids
o
using I as a catalyst in water at 70 C. All the reactions produced diarylmethanes in very good
yields, which can be seen in Table 6. Initially, selected benzyl bromides were screened with 3a
(Table 6, entries 1−8). Upon successful applicability of I in carrying out sp3(C)−sp2(C) coupling
in these substrates, the catalyst was tested further for its ability to catalyze the reactions between
various combinations of benzyl bromides and arylboronic acids (Table 6, entries 9−13). Even the
heteroaryl boronic acids employed in this study also produced very good yields (Table 6, entries
15−17). In case of 2ꢀbromobenzyl bromide both sp3(C)−sp2(C) and sp2(C) sp2(C) couplings took
place when slightly more than two equivalents of organoboron reagent (2a or 3a) were used
under similar conditions (Table 6, entry 14).
Table 7 SuzukiꢀMiyaura coupling of hydrophilic aryl bromides with arylboronic acidsa
Entry
1
Aryl halide 5
Boronic acid 2
Biaryl 6
bYield
(%)
2a
98
97
98
2
3
2a
2a

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4
5
2a
2a
97
98
6
7
95c
98
8
9
2a
2a
98
98
10
11
97
98
aReaction conditions: aryl bromide (1.0 mmol), arylboronic acid (2) (1.2 mmol), K2CO3 (2.0
b
mmol), H2O (3 mL), [Pd] (0.5 mol%), at 70 ºC, reaction time of 3 h, in air. Isolated yield (the

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1
c
purity of the isolated product was confirmed by H NMR). Isolated yield after column
chromatography
.
Biaryls containing hydrophilic functional groups are intermediates in many
pharmaceutical compounds and liquid crystal materials. Due to the low solubility of these
hydrophilic bromides in common organic solvents, high polar solvents like DMF, dimethyl
acetamide and DMSO are frequently used for constructing hydrophilic biaryls via the SMC
route.26 The major problem in using these solvents lies in difficulty in extracting and purifying
the products. Whereas, when water is used as solvent, the biaryls can easily be separated in pure
form without any loss especially when the conversion is quantitative. So far there is only one
report available in the literature, which describes the synthesis of hydrophilic functionalized
biaryls through water mediated SMC reactions. The authors demonstrated that
[PdCl2(NH2CH2COOH)2]/K2CO3 system showed excellent activity in catalyzing the SMC
reactions of a wide variety of water soluble aryl bromides with boronic acids at room
temperature.27 In the present work, I was also tested for its ability to catalyze the SMC reactions
between hydrophilic aryl bromides and arylboronic acids in neat water and found that it was a
highly efficient catalyst, which produced the biaryls in almost quantitative yields (Table 7). Out
of the 11 biaryls synthesized only one compound required purification by column
chromatography and all the other biaryls were obtained in pure form by neutralizing the reaction
mixture with 4N HCl followed by filtration. The antiꢀinflammatory drug felbinac (Table 7, entry
1
8) was synthesized with >98% purity (as per H NMR analysis) just by neutralization and
filtration. Most of the synthetic procedures currently used for making this drug require column
chromatography or other purification methods.28 Several arylboronic acid/hydrophilic aryl
bromide combinations were screened and found that the biaryls were produced in almost

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quantitative yields. Identical conditions were also explored for coupling 2ꢀ(bromomethyl)ꢀ3ꢀ
phenylacrylonitrile with aryl or heteroarylboronic acids, as depicted in Scheme 3. The
corresponding cross coupled products 7a, 7b and 7c were obtained in excellent yields.
Scheme 3 SuzukiꢀMiyaura coupling of 2ꢀ(bromomethyl)ꢀ3ꢀphenylacrylonitrile
For an economically viable synthesis of fine chemicals, a low loading catalyst is
needed.29 In this regard, we probed I and II for their ability to execute the SMC reaction between
4ꢀbromoacetophenone and phenylboronic acid at various catalyst loadings at rt and also at 70 °C.
The results, which are given in Table S1 (see electronic supplementary information (ESI))
indicate that the catalysts I and II are equally efficient and even with the loading as low as 0.001
mol% (500 times lower than the optimized loading), afforded the cross coupled product in 82%
yield at 70 °C in 24 h with excellent TONs (82,000 with I and 80,000 with II).
Insights into mechanism
In order to understand the mechanistic path of these reactions, an NMR tube reaction was
conducted between the imidazolium complex I and K2CO3 in D2O at rt under ultraꢀsonication.
The 1H NMR recorded after 10 minutes showed no signals due to the insolubility of the contents
of the reaction mixture in water. The water was syringed out and the residue was dissolved in
CDCl3 to obtain a 1H NMR spectrum, which showed full conversion of the imidazolium complex
to a carbene complex [Pd(L1)(PPh3)Cl] (III). Later, the carbene complexes III and
[Pd(L2)(PPh3)Cl] (IV) were synthesized from I and II respectively using DMAP as a base in

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acetonitrile at rt (Scheme 4). III and IV were isolated and characterized by using NMR
spectroscopy and elemental analysis.
Scheme 4 Synthesis of orthoꢀpalladatedꢀNHCꢀphosphine complexes
The solid state structure of III was determined by single crystal Xꢀray analysis. An
ORTEP diagram along with the selected bond parameters is given in Figure 3. The molecular
structure of the carbene complex shows the ligand is ortho chelated to palladium forming a
palladacycle. Triphenylphosphine occupies the position trans to the carbene carbon. The
geometry around the metal is a distorted square planar with the maximum deviation from the
ideal bond angle occurring within the chelate ring (C3−Pd1−C5 = 80.34o).

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Figure 3 Molecular structure of [Pd(L1)(PPh3)Cl] (III). All hydrogen atoms have been
omitted for clarity. Thermal ellipsoids are drawn at 50% probability level. Selected bond lengths
[Å]: Pd1−P1 2.3216(11), Pd1−Cl1 2.3454(12), Pd1−C5 2.006(4), Pd1−C3 2.044(4), C5−C4
1.457(6), C5−N3 1.308(5), N2−C3 1.354(5), N1−C3 1.342(5), N4−C4 1.282(5), N2−C4
1.413(5). Selected bond angles [o]: P1−Pd1−Cl1 91.64(4), C5−Pd1−P1 92.70(11), C3−Pd1−Cl1
95.32(11), C5−Pd1−C3 80.34(15), C5−C4−Pd1 114.6(3), N2−C3−Pd1 114.1(3), , C3−N2−C4
118.2(3), N2−C4−C5 112.4(3), N3−C5−Pd1 128.6(3), N1−C3−Pd1 141.3(3).
At first, it was felt that these carbene complexes were involved in the reaction path.
Therefore, III was employed in the SMC reaction (with or without base) under similar
conditions used for the reactions catalyzed by the imidazolium complexes I and II. However, the
carbene complex catalyzed reactions took much longer time (26 h) for the completion of the
reaction compared to those catalyzed by the imidazolium complexes (3 h). This observation rules
out the involvement of a carbene complex in the mechanistic path. To confirm further, two

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zwitterionic complexes of Pd(II) (complexes V and VI) in which there is no possibility of
formation of a carbene complex were designed and synthesized (Scheme 5). In complex V, C3
position of imidazolium ring is blocked by a methyl group. Imidazolium ring in the complex I is
replaced with N,Nꢀdimethylꢀ4ꢀaminopyridinium ring to obtain complex VI. The ligand precursor
of VI has been structurally characterized and an ORTEP diagram is given in the electronic
supplementary information. Both the complexes were well characterized by using NMR
technique before employing them as catalysts for the SMC reactions. In case of V, the structure
was further confirmed by single crystal Xꢀray analysis and an ORTEP diagram along with the
selected bond parameters is given in Figure 4. It was found that these zwitterionic complexes
were as active as I and II, and took much less time than the carbene complexes for the
completion of the SMC reactions under similar conditions. These results further confirm that the
SMC reactions catalyzed by I do not depend on the formation of a carbene complex.
Scheme 5 Synthesis of zwitterionic Pd(II) complexes V and VI

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Figure 4 Molecular structure of [Pd(L3)(PPh3)Cl2] (V). All hydrogen atoms and solvent
molecules have been removed for clarity. Thermal ellipsoids are drawn at 50% probability level.
Selected bond lengths [Å]: Pd1−P1 2.243(2), Pd1−C5 1.985(7), Pd1−Cl1 2.394(2), Pd1−Cl2
2.417(2), N2−C4 1.445(9), C4−C5 1.446(10), N4−C4 1.286(9), N3−C5 1.303(9), N1−C3
1.358(10). Selected bond angles [o]: C5−Pd1−Cl1 83.1(2), C5−Pd1−P1 91.7(2), Cl1−Pd1−Cl2
94.83(8), P1−Pd1−Cl2 90.39(8), P1−Pd1−Cl1 174.78(8), C5−C4−N2 120.3(6), N4−C4−N2
114.3(6), C5−Pd1−Cl2 175.2(2), N3−C5−Pd1 117.4(5).
It has been reported in the literature that the most likely active species in SMC reactions
is a Pd(0) species.30 Recently, Braga, Navarro and their coꢀworkers carried out computational
studies on the plausible pathway in Heck coupling reactions catalyzed by an ionic complex
[TBA][(NHC)PdCl3] and suggested in situ formation of [(NHC)Pd(0)Cl]−, which is the active
species in the reaction.31 Lee et al. observed the formation of two and three coordinated Pd(II)
species in ESꢀMS spectra of catalyst precursors, and speculated that these species could generate
LnPd(0), which plays a key role in the catalytic cycle.20f Similar to their observation, we also

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noticed that all the imidazoium complexes and the dimethylaminopyridinium complex showed
corresponding three coordinated species [PdL(PPh3)Cl]+ [m/z = 761.16 (I–Cl), 719.11(II–Cl),
705.10 (V–Cl) and 655.08 (VI–Cl)] when they were subjected to ESꢀMS. In addition, the ESꢀMS
spectra also showed peaks corresponding to [M–2Cl–H]+, presumably due to the formation of a
two coordinated species [Pd(L–H+)(PPh3)]+ with the loss of two Cl– ions and an acidic proton on
the imidazolium/pyridinium ion. As with the literature report, these results also suggest the
possibility of in situ formation of two/three coordinated Pd(II), which have the potential to
generate the active species L(PPh3)Pd(0).
In order to probe the nature of the catalysis (homogeneous vs heterogeneous) in these
reactions, poisoning tests and a two phase test were carried out. The details of these experiments
are given in the ESI. Though the poisoning tests conducted on I and VI with the addition of Hg
and the addition of PPh3 at room temperature adversely affected the reactions, the reactions
conducted at 70 oC afforded excellent yields. In a two phase test, a mixture of 4ꢀ
bromoacetophenone and freshly prepared immobilized aryl bromide were treated with an excess
1
of phenylboronic acid in the presence of I as a catalyst and K2CO3 in water at 70 ºC. The H
NMR analysis of the products after hydrolyzing the immobilized phase indicated that the
immobilized aryl bromide was also converted to the cross coupled product to the extent of 52%.
These results indicate that the catalysis is largely homogeneous.
In most of the reactions reported in this article, formation of Pd black was observed
during the course of the reaction. In order to find out if the Pd black is involved in catalysis, it
was isolated from the reaction mixture by filtering on a 0.2 ꢁm filter paper followed by washing
the precipitate with ethyl acetate and used as a catalyst under the optimized conditions. The Pd
black was unable to initiate the SuzukiꢀMiyaura reaction. It is noteworthy that the filtrate from

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the reaction mixture too was found to be catalytically inactive, which indicates that neither the
active catalyst nor the precatalyst are present in the reaction medium at the end of the reaction.
Conclusion
In summary, two imidazolium substituted quinoxaline based organopalladium complexes
I and II were synthesized and structurally characterized. These complexes are found to be
excellent catalysts for carrying out SuzukiꢀMiyaura crossꢀcoupling reactions in neat water. The
results of a series of experiments conducted using I clearly indicate that it has the advantages of
i) being highly efficient in neat water medium, which enables easy separation of products (just
filtration is enough in most cases), ii) needing no organic base (only a cheap inorganic base
K2CO3 is required), iii) demanding no phase transfer catalyst, iv) requiring only low catalyst
loading resulting in high turnover number (82,000), v) producing crossꢀcoupled products in
almost quantitative yields and no homoꢀcoupled products in most cases, vi) being versatile: as
demonstrated in the synthesis of biaryls with variety of functional groups, heterobiaryls and
hydrophilic biaryls. Though initially it appeared that these catalysts may form carbene
complexes as active catalysts, subsequent experiments conducted using carbene complexes
obtained from these catalysts showed that they were less efficient than the imidazolium
complexes and thus rule out their involvement in the catalytic cycle. PPh3 and mercury poisoning
tests on I and VI, and a two phase test involving an immobilized aryl bromide using I suggest
that the catalysis is largely homogeneous. Currently, we are examining the complexes, which are
reported in this article, for their catalytic activity in the SMC reactions of aryl chlorides. The
preliminary reactions carried out on I showed positive results and the details will be discussed
elsewhere. Studies are ongoing on the synthesis of water soluble catalysts for cross coupling
reactions.