POPd/TBAB co-catalyzed Suzuki cross-coupling reaction of heteroaryl chlorides/bromides with 4-fluorophenylboronic acid in water

Article abstract of DOI:10.1007/s13738-015-0775-9

An organic solvent free and efficient heterogeneous synthesis for bridging heteroaryl halides and 4-fluorophenylboronic acid was studied in aqueous media according to the Suzuki cross-coupling protocol. High yields of heteroaryl-aryl fluorides were successfully obtained with: chloro-/bromo-substituted pyridine, thiophene, indole, and inzole in neat water using palladium phosphinous acid complexes (POPd)/tetrabutylammonium bromide (TBAB) as co-catalysts. A possible mechanism for the heterogeneous coupling reaction is proposed and discussed according to the function of the TBAB interphases. The notable properties of the reported method are highly co-catalytic activity, hetero-atom tolerance, simple separating procedure and little environmental disposal impact.

Full text of DOI:10.1007/s13738-015-0775-9

J IRAN CHEM SOC (2016) 13:637–644
DOI 10.1007/s13738-015-0775-9
ORIGINAL PAPER
POPd/TBAB co‑catalyzed Suzuki cross‑coupling reaction
of heteroaryl chlorides/bromides with 4‑fluorophenylboronic acid
in water
Ben Li1 · Zhiqiang Zhang1
Received: 6 May 2015 / Accepted: 2 November 2015 / Published online: 16 November 2015
© Iranian Chemical Society 2015
Abstract An organic solvent free and efficient heteroge-
neous synthesis for bridging heteroaryl halides and 4-fluo-
rophenylboronic acid was studied in aqueous media accord-
ing to the Suzuki cross-coupling protocol. High yields of
heteroaryl-aryl fluorides were successfully obtained with:
chloro-/bromo-substituted pyridine, thiophene, indole, and
inzole in neat water using palladium phosphinous acid
complexes (POPd)/tetrabutylammonium bromide (TBAB)
as co-catalysts. A possible mechanism for the heterogene-
ous coupling reaction is proposed and discussed according
to the function of the TBAB interphases. The notable prop-
erties of the reported method are highly co-catalytic activ-
ity, hetero-atom tolerance, simple separating procedure and
little environmental disposal impact.
the manufacture of pharmaceutical [3–6] and agrochemi-
cal products [7–9]. Advantageously, fluorine substituents
can enhance the lifetime and activity of pharmaceutical
and agrochemical chemicals in a multitude of approaches
[10]. The introduction of fluorine into heteroaryl-aryl
molecules can significantly improve molecular properties
and electronic stabilities [5, 11, 12], but the synthesis of
C–F bond within heteroaromatic compounds still remains
challenging. Since fluorinated polycyclic aromatic hydro-
carbons (FPAHs) are not naturally occurring, these com-
pounds are synthesized according to the specific synthetic
routes such as Balz–Schiemann reaction [7, 13, 14] or
transition-metal-mediated fluorination [9, 15], which is
still a significant challenge for aryl C–F bond formation
[8, 16, 17].
Keywords POPd/TBAB co-catalysis · Heterogeneous
Suzuki cross-coupling reaction · Heteroaryl-aryl fluorides ·
Green chemistry
In an alternative approach, Pd-catalyzed Suzuki cross-
coupling reactions [18, 19] of heteroaryl halides and
fluorinated arylboronic acid leading to the coupling of
heteroaryl-aryl compounds is another proposed efficient
indirect synthetic route for C–F aromatic compound
formation. It has also been demonstrated that with this
approach, Suzuki cross-coupling reactions can be per-
formed using environmentally friendly aqueous sol-
vent systems [20]. The formation of the C(sp2)–C(sp2),
C(sp2)–C(sp3) and C(sp3)–C(sp3) bonds involves the
nucleophilic aromatic substitution reactions between
electron-deficient organic halides and organoboronic rea-
gents [21, 22]. Both coupling components must be func-
tionalized on the noble metal sites following oxidative-
transmetallic-reductive cycling steps, and the required
organometallic nucleophilic reagents should be highly
efficient. The use of water provides an environmentally
and economically more attractive method compared with
the use of traditional organic reaction solvents. Water
is generally regarded as the ultimate green solvent for
Introduction
Fluorinated aromatic compounds are of increasing inter-
est due to their ability to provide functional synthetic
intermediates, medicinal agents, and organic materials,
e.g., the fluorinated heteroaryl-aryl group is found in
many natural products that exhibit remarkable biological
activities [1, 2]. Fluorinated heteroaryl-aryl compounds
are also deemed as the effective structural moieties for
* Zhiqiang Zhang
zhangzhiqiang@ustl.edu.cn
1
School of Chemical Engineering, University of Science
and Technology Liaoning, Anshan 114051, China
1 3

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J IRAN CHEM SOC (2016) 13:637–644
organic synthesis. Hence, water based heterogeneous
Suzuki cross-coupling reactions represent an attractive,
simple, flexible, and robust alternative to the traditional
organic solvent-catalyzed route especially when used to
synthesize FPAHs.
Phosphinous acid complex [(t-Bu)2P(OH)]2PdCl2
(POPd) was reported as a highly effective and environ-
mental friendly Pd-catalyst for Suzuki cross-coupling
reaction of (hetero) aryl halides and arylboronic acids
[23–25]. POPd and its family derivatives [[(t-Bu)2P-(OH)
(t-Bu)2PO)]PdCl]2 (POPd1) and [(t-Bu)2P(OH)PdCl2]2
(POPd2) are typically characterized as air-stable, with good
water solubility, high reactivity, and easy separation from
the organic mixtures, their steric molecular frameworks are
depicted in Fig. 1 [23].
The properties of the heteroaryl-aryl structural unit in
biologically and synthetically important molecules have
attracted considerable attention in the development of
novel methods for CAr–CAr bond formation. Traditional
methods [26, 27] for making fluoro-aromatics, use expen-
sive reagents and produce a large amount of undesired by-
products. In contrast, the synthetic procedure described
in this report using inexpensive water as the liquid phase
allows the production of fluoroaromatics by an efficient,
cost-effective, and environmentally friendly heterogene-
ous process. This study describes the further development
of the efficient synthetic procedures to prepare biologi-
cally relevant heterocyclic compounds. In particular, these
recent studies have been directed towards the heterogene-
ous preparative synthesis of a diverse range of heteroaryl-
aryl fluorides using POPd/TBAB co-catalyzed Suzuki
cross-coupling reactions in a water based solvent system.
The TBAB served to function as a phase transfer catalyst
(PTC) in these reactions.
Experimental
General remarks
Synthesis of heteroaryl-aryl fluorides was performed in a
Schlenk glass tube under nitrogen atmosphere. Flash col-
umn chromatography was performed using silica gel (pore
size 60 Å, standard grade) and 0.65–0.85 mm particle size
sand. Analytical thin-layer chromatography was performed
using glass plates pre-coated with 0.25 mm 200–300 mesh
silica gel impregnated with a fluorescent indicator (silica
gel 60 F254, Sinopharm Chemical Reagent Co., Ltd). Thin
layer chromatography plates were illuminated at 254nm
by exposure to UV light to monitor the coupling reaction
process. Organic solutions were concentrated using a rotary
evaporator operated at low vacuum conditions at the temper-
ature below 40 °C. Commercial A.R. grade reagents (Sinop-
harm Chemical Reagent Co., Ltd.) and solvents were used
1
as received. H NMR (500 MHz) spectra were recorded
using CDCl3 as solvent on a Bruker Avance (AV500) spec-
trometer with tetramethylsilane (TMS) acting as the internal
standard substance. Mass spectra were obtained using an
Agilent 1100 LC–MS system equipped with electrospray
and atmospheric pressure chemical ionization sources.
A general procedure for CAr–CAr Suzuki cross-coupling
reaction of 4-fluoro-phenyl boronic acid with heteroaryl
halides is demonstrated in Scheme 1.
With reference to Scheme 1: in a 15 ml Schlenk bottle
pre-filled with nitrogen, a mixture of 4-fluorophenylboronic
acid 1a (1.2 mmol), heteroaryl bromides 2a (1.0 mmol, 1.0
equiv), KOH (3.0 mmol, 3.0 equiv), TBAB (0.3 mmol)
and POPd (0.005 mmol) in water (2 ml) was magneti-
cally stirred and refluxed for 1-24 h. After completion of
the reaction as indicated by TLC analysis, the mixture was
Fig. 1 Highly active and air-stable (di)palladium phosphinous acid complexes, steric framework of POPd, POPd1 and POPd2
POPd/TBAB
base, water
reflux, N2
F
B(OH)2
+
Heteroaryl halides
2a
F
Heteroaryl
F
F
+
1a
3a
4a
Scheme 1 Typically performed heterogenous Suzuki cross-coupling reaction in water
1 3

J IRAN CHEM SOC (2016) 13:637–644
639
gradually cooled to room temperature. The resulting mix-
ture was extracted with ethyl acetate (3×20 ml aliquots)
and dried using magnesium sulfate powder. The combined
ethyl acetate extracts were then subjected to evaporation
under vacuum resulting in the isolation of a dense oily liq-
uid. This oil was purified by flash column chromatography
using petroleum ether and ethyl acetate as the eluting phase
to isolate the corresponding product 3a and by-product 4a
(4,4′-difluorobiphenyl).
J = 5.92 Hz, 2H); MS (ESI): m/z [M+H]+ calculated for
C13H9FN2: 213.0; found: 213.0.
5-(4-fluorophenyl)-1H-indole: white powder; mp 81.8–
1
82.5 °C; H NMR (500 MHz, CDCl3) δ 2.96 (s, 1H), 6.42
(s, 1H), 7.19 (s, 2H), 7.37 (d, J = 3.25 Hz, 2H), 7.67 (s,
1H), 7.69 (d, J = 5.47 Hz, 2H), 7.81 (s, 1H); MS (ESI):
m/z [M+H]+ calculated for C14H10FN: 212.0; found:
212.0 m/z.
Summary of structural analysis results
Results and discussion
2-(4-fluorophenyl)-thiophene: yellow powder; mp 48.2–
49.1 °C; 1H NMR (500 MHz, CDCl3) δ 7.05 (m, 3H), 7.36
(s, 1H), 7.44 (s, 1H), 7.72 (t, J = 7.80 Hz, 2H); MS (ESI):
m/z [M+H]+ calculated for C10H7FS: 179.0; found: 179.1.
2-(4-fluorophenyl)-pyridine: white powder; mp 39.9–
40.7 °C; 1H NMR (500 MHz, CDCl3) δ 7.24 (m, 2H), 7.33
(m, 1H), 7.87 (m, 1H), 7.92 (d, J = 7.90 Hz, 1H), 8.17 (m,
2H), 8.66 (d, J = 4.61 Hz, 1H); MS (ESI): m/z [M+H]+
calculated for C11H8FN: 174.0; found: 173.9 m/z.
Initially, to optimize the experimental conditions for the
heterogeneous Suzuki coupling reaction in water, the reac-
tion shown in Scheme 1 was studied. In the presence of
POPd/TBAB the heterogeneous Suzuki cross-coupling of
4-fluorophenylboronic acid (1a) with 2-bromopyridine (2a)
occurred to afford (3a) in an aqueous reaction mixture. The
effects of different Pd-catalysts, phase transfer catalysts,
alkalis, and solvents were experimentally investigated.
Experimental cross-coupling results in both water and other
different organic solvents were initially compared using the
same experimental conditions.
The results are summarized in Table 1, entries 1–8. With
respect to the seven organic solvents, the 3a yield of 55 %
obtained in neat water compared to: (1) a corresponding
54 % yield in DMSO and, (2) between the highest yield in
toluene and the lowest yield in THF. The yield of 2-phe-
nylpyridine in water is moderate compared with other
organic solvents. Therefore, it was established that water
provides considerable potential to act as a highly effective
reaction solvent for Suzuki cross-coupling reaction of aro-
matic halides.
4-(4-fluorophenyl)-pyridine:
white
powder;
mp
47.1–48.0 °C; 1H NMR (500 MHz, CDCl3) δ 7.15 (t,
J = 7.23 Hz, 2H), 7.26 (s, 1H), 7.57 (dd, J1 = 4.37 Hz,
J2 = 5.42 Hz, 2H), 7.65 (d, J = 4.68 Hz, 2H), 7.92 (s,
1H), 8.20 (s, 1H); MS (ESI): m/z [M+H]+ calculated for
C11H8FN: 174.0; found: 173.9.
2-amino-5-(4-fluorophenyl)-pyridine: light yellow pow-
1
der; mp 126.8–127.7 °C; H NMR (500 MHz, CDCl3)
4.77 (d, J = 6.50 Hz, 2H), 6.61 (d, J = 6.50 Hz, 1H), 7.09
(t, J = 7.36 Hz, 2H), 7.44 (t, J = 7.80 Hz, 2H), 7.65 (d,
J = 4.40 Hz, 1H), 8.37 (s, 1H); MS (ESI): m/z [M+H]+
calculated for C11H9FN2: 189.0; found: 188.9.
2-fluoro-5-(4-fluorophenyl)-pyridine: white powder; mp
99.1–100.3 °C; H NMR (500 MHz, CDCl3) δ 7.17 (m,
In comparison, using Pd2(dba)3 and Pd(PPh3)4 as Pd-
catalyst results in 49 and 11 % respective yields of the tar-
get 3a 2-(4-fluorophenyl-pyridine) in water, and a trace of
4,4′-difluorobyphenyl 4a via the inter-coupling reaction of
1a. In contrast POPd serials afforded 3a in an encouraging
82–85 % yield (Table 1, entries 11, 17, 18). A further study
demonstrated that increasing the amount of POPd from
0.25 to 2.0 % mmol led to a faster coupling rate, but the
coupling yield of 3a still remained less than 90 %. Exami-
nation of the amount of phase transfer catalysts revealed
that the yield was found to increase with increasing PTC/
POPd ratio. A lower yield was obtained using the combina-
tion of POPd with TMAB acting as the PTC (Table 1, entry
21). No reaction occurred in the absence of Pd-catalysts or
PTCs.
1
1H), 7.20 (m, 2H), 7.74 (m, 2H), 8.21 (m, 1H), 8.48 (d,
J = 2.33 Hz, 1H); MS (ESI): m/z [M+H]+ calculated for
C11H7F2N: 192.0; found: 191.9.
3-fluoro-4-(4-fluorophenyl)-pyridine: white powder; mp
89.1–90.0 °C; 1H NMR (500 MHz, CDCl3) δ 7.34 (m, 2H),
7.61 (m, 1H), 7.77 (m, 2H), 8.51 (d, J = 4.94 Hz, 1H), 8.59
(d, J = 2.61 Hz, 1H); MS (ESI): m/z [M+H]+ calculated
for C11H7F2N: 192.0; found: 191.9.
2,5-di-(4-fluorophenyl)-pyridine: white powder; mp
1
188.4–189.2 °C; H NMR (500 MHz, CDCl3) δ 2.97 (s,
1H), 7.41 (m, 4H), 7.79 (t, J = 7.36 Hz, 2H), 7.94 (s, 1H),
8.21 (d, J = 5.40 Hz, 1H), 8.47 (m, 2H), 8.89 (s, 1H);
MS (ESI): m/z [M+H]+ calculated for C17H11F2N: 268.0;
found: 267.9.
The results shown in Table 1 indicate an “alkaline
effect” whereby the strong bases give rise to the high
yields, whereas the low yields were obtained using the
weak bases (Table 1, entries 8–16). When weak inorganic
bases were exchanged for the weak organic bases such as
5-(4-fluorophenyl)-inzole: white powder; mp 237.8–
1
238.7 °C; H NMR (500 MHz, CDCl3) δ 2.99 (s, 1H),
7.29 (dd, J1 = 8.86 Hz, J2 = 6.93 Hz, 2H), 7.65 (dd,
J1 = 1.66 Hz, J2 = 1.56 Hz, 2H), 7.84 (m, 2H), 8.63 (d,
1 3

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J IRAN CHEM SOC (2016) 13:637–644
Table 1 Optimization of
reaction conditions for the
reaction shown in Scheme 1
Entry
Time (h)
Pd catalyst
Solvent
Base
PTC
Yield (%)b
1
6
POPd
POPd
POPd
POPd
POPd
POPd
POPd
POPd
POPd
POPd
POPd
POPd
POPd
POPd
POPd
POPd
POPd1
POPd2
Pd2(dba)3
Pd(PPh3)4
POPd
Toluene
DMF
C2H5OH
Dioxane
THF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOtBu
NaOtBu
KOH
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TMABc
67
66
63
63
37
54
48
55
87
86
85
65
48
11
6
2
4
3
4
4
5
5
6
6
3
DMSO
2-Propanol
H2O
7
6
8
5
9
2.5
2.5
2.5
2.5
4
H2O
10
11
12
13
14
15
16
17
18
19
20
21
H2O
H2O
H2O
NaOH
Na2CO3
NaHCO3
Et3N
H2O
6
H2O
8
H2O
2.5
2.5
2.5
2.5
2.5
2.5
H2O
NaOAc
KOH
4
H2O
85
82
49
11
66
H2O
KOH
H2O
KOH
H2O
KOH
H2O
KOH
a
Reaction conditions: 2-bromopyridine 2a (1.0 mmol), 4-fluorophenylboronic acid 1a (1.2 mmol, 1.2
equiv), base (3.0 mmol), PTC (0.3 mmol), water 3 ml, 4 h
b
Isolated yield based of 2-bromopyridine 1a
c
Tetramethylamine bromide
Et3N or NaOAc, only trace levels of the desired product
were synthesized (Table 1, entries 15 and 16). However,
using the strong bases NaOtBu, KOtBu or KOH, the cor-
responding yields of 3a are between 85 and 87 %. Hence,
under optimized conditions [using: POPd (0.5 mmol %),
TBAB (3.0 equiv), KOH, water], the 2-(4-fluorophenyl-
pyridine) product 3a, was obtained in 85 % isolated yield
by flash column chromatography as well as 5.0 % yield of
4,4′-difluorobyphenyl (4a).
After obtaining the results summarized in Table 1, the
study involving the use of water as reaction solvent was
extended to a second series of synthetic reactions. This
involved the CAr–CAr bond coupling formation/arylation of
4-fluorophenylboronic acid 1a with hetero-aryl bromides
and chlorides according to Table 2. Using the optimized
conditions established for the reactions shown in Table 1, a
range of various substrates were subjected to Suzuki cross-
coupling reactions as summarized in Table 2.
arylated products in moderate to good yields in water using
POPd/TBAB as co-catalyst.
It has been previously established that the POPd/TBAB
catalytic complex can tolerate a wide range of functional
groups, such as NO2, OMe, CN, OH, Cl, and NH2 [22]. As
shown in Table 2, a series of heteroaryl halides underwent
efficient Suzuki cross-coupling reaction with p-fluorophe-
nylboronic acid when the reaction was performed in water
with POPd/TBAB. Heteroaryl halides containing electron-
withdrawing groups afforded higher yields than those con-
taining electron-donating groups, especially for pyridine
chlorides (Table 2, Entries 1–3 & 7–8). Pyridine halides
also afforded moderate yields between 39 and 79 %. It
was observed that the coupling yield of 3-chloropyridine
(77 %) is almost twice compared with 2-chloropyridine
(39 %), indicating the pronounced steric hindrance of the
chloride atom with the nitrogen atom during the coupling
reaction. Unexpected high yield (98 %) of 4-fluoro-5-phe-
nylindole and low yield (10 %) of 4-fluoro-5-phenylinda-
zole was, respectively obtained (Entries 4 & 5 in Table 2).
The enormous cross-coupling divergence for these two aza-
polycyclic compounds in water could be plausibly caused
by the neighbour nitrogen atoms conjugating interaction
and electron pair overlapping each other to strengthen the
The results of the second series of synthetic experiments
are provided in Table 2, bromide or chloride directed CAr–
CAr Suzuki cross-coupling formation can be further applied
to a wide variety of substrates. Thus, 4-fluorophenylboronic
acid 1a/phenylboronic acid 1b coupled with a range of het-
eroaryl bromides or chlorides to give the corresponding
1 3

J IRAN CHEM SOC (2016) 13:637–644
641
Table 2 CAr–CAr bond coupling formation/arylation of 4-fluorophenylboronic acid 1a and phenylboronic acid 1b with heteroaryl bromides and
chlorides
POPd/TBAB
KOH, water
relux, N2
F
heteroaryl
X
B(OH)2
F
F
+
2a-2j
+
1a X: F
1b X: H
4a
3a-3j
Br
Br
N
N
Cl
Cl
Cl
N
N
H
N
H
Br
Br
N
2a
2b
2c
2d
2e
NH2
Cl
Br
N
Br
N
F
N
F
Br
N
S
2i
2f
2g
2h
2j
Entry Boronic acid 1a/1b
2
Time [h]
3
Yield (%)a
F
1
2
3
1a
1a
1a
2a
6
55.0
N
3a
F
N
2b
2c
6.5
7.5
77.0
39.0
3b
3a
F
N
F
F
4
5
1a
1a
2d
2e
8
98.0
10.0
N
N
N
H
3d
21
N
N
H
3e
3f
F
6
7
1a
1a
2f
2
4
79.0
79.0
S
F
F
2g
N
3g
F
8
1a
1a
2h
2i
6
2
F
N
73.0
57.0
3h
F
NH2
9
N
3i
1 3

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J IRAN CHEM SOC (2016) 13:637–644
Table 2 continued
F
F
10
1a
2j
6.5
18.5
N
3j
11
12
13
14
15
1b
1b
1b
1b
1b
2a
2b
2c
2f
6.0
8
32.0
N
3k
N
-
3l
8
-
N
3k
3.5
8
82.4
35.2
S
3m
NH2
2i
N
3n
N
16
1b
2j
6.5
35.5
3o
Reaction conditions: 4-fluorophenylboronic acid 1a (1.2 mmol), heteroaryl bromides 2a–2j (1.0 mmol), PTC (0.3 mmol), base (3 mmol), water
(3 ml), reflux, 2–21 h
a
Isolated yield based on heteroaryl bromides
electrovalent bond with bromine atom which is deemed as
an electrostatic hindrance for the CAr–Br oxidative addition
with POPd in water.
pair imposed on the CAr–CAr bond formation. For 2c, the
chlorine atom is in the para-position to the nitrogen atom
leading to a low hindrance for bond formation. In contrast,
for 2b the chlorine atom is in close vicinity to the nitrogen,
and part of electron cloud on these two atoms would be
overlaid and could cause interference to disturb new bond
formation of the CAr–CAr. Improved results were obtained
when heteroaryl chlorides containing a moderately elec-
tron-withdrawing group 2 g/2 h or electron-neutral group
(H atom) 2a/2f were employed.
Based on known metal-catalyzed directing-group-
assisted C–C bond coupling reactions [28–32] and an
analogy for the reaction of 4-fluorophenylboronic acid, a
proposed reaction scheme for the Suzuki cross-coupling
for arylboronic acid and heteroaryl haloride (2a–2j) is
provided in Scheme 2. As reported in literature [16], the
roles of TBAB are categorized as facilitating solvation
of the organic substrates in aqueous mixture and activat-
ing the arylboronic acid via the intermediate formation
To investigate the real influence of the fluorine atom for
the coupling reaction of arylboronic acid and heteroaryl
halides, phenylboronic acid was chosen as a reference to
reaction with 2a–2c, 2f, 2i and 2j under the same experi-
mental conditions (Table 2, Entries 11–16). It was found
that the C–X (X: Br or Cl) bond strength and steric hin-
drance of the nitrogen lone electron pair determined the
reactivity of the substrates. Pyridine bromide substrates
could tolerate several functional groups such as NH2 or
F atom (actually F atom is not a group but is the strong-
est electron withdrawing atom). 2-bromopyridine (2a)
was experimentally determined to provide a higher yield
than 2-chloropyridine (2c), but for the isomer of 3-chloro-
pyridine (2b), 2b gives even higher yield (77 %) than its
counterpart bromide 2a (55 %), which could be explained
according to the steric effect of the nitrogen single electron
1 3

J IRAN CHEM SOC (2016) 13:637–644
643
of [ArB(OH)3]−[Bu4N]+. Additionally, TBAB molecules
simultaneously form an interface between arylboronic
acid/POPd and heteroaryl haloride in the liquid mixture,
resulting in the POPd active sites becoming associated
with the heteroaryl haloride in the organic phase, that
returns after oxidation to the aqueous phase, with sub-
sequent transfer of the target coupling products to the
organic phase.
reductive elimination of Pd atom affords the cross-coupling
product and returns to the organic phase with respect to the
transportation of TBAB. The fluoro-substituted biphenyl
product was formed during the decomposition of 4-fluoro-
phenylboronic acid becoming self-coupled together to form
the corresponding biphenyl fluoride compound (4a).
The proposed catalytic coupling process involves
the following steps: (1)–(2), the cyclo-palladation of
heteroaryl haloride via CAr-haloride bond activation
(TBAB→POPd→2a). The Pd atom is temporarily oxi-
dized by the addition of 2a; (3)–(4), the TBAB transports
[POPd→2a] oxidative complex back to the alkaline aque-
ous mixture, and the [TBAB→ POPd→2a] transition
complex continues to undergo transmetallation with 4-fluo-
rophenylboronic acid, cross-coupling of these two mol-
ecules by switching halide atom with borates; (5)–(6), the
Conclusions
In a summary, we have described a combined and efficient
method for the arylation of heteroaryl halides via CAr–CAr
Suzuki coupling method using POPd/TBAB in water. A
combination of POPd and TBAB, greatly accelerated the
rate of the coupling reaction and effectively bridged the
gap between two immiscible phases by binary activity at
the interphases. The desired CAr–CAr bond formation pro-
ceeded efficiently with good functional-group tolerance
Scheme 2 Proposed mecha-
nism for POPd/TBAB co-
catalyzed heterogeneous Suzuki
cross-coupling reaction in water
1 3

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and high selectivity. The proposed mechanism for the
arylation of heteroaryl bromides and chlorides is consistent
with the experimental results that have been obtained. We
are currently conducting a series of further studies involv-
ing the application of the heterogeneous couplings in water
between C atom and hetero-atoms such as N or S to synthe-
size CAr-heteroatom bonds.
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Acknowledgments We are grateful for financial support from
the Program for Liaoning Excellent Talents in University (No.
LR2014009), (No.L2015258) and the kind donation of Pd-catalysts
from Combiphos Catalysts.
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