Phosphine-Free Suzuki Cross-Coupling Reaction Using an Efficient and Reusable Pd Catalyst in an Aqueous Medium under Microwave Irradiation

Article abstract of DOI:10.1080/00397911.2015.1057289

We report here an improved, highly efficient, and general method for the ligand-free Suzuki cross-coupling reaction to the synthesis of biaryls, bipyridyls, thienylpyridine, and allylphenols. Microwave irradiation of (het)aryl halides and (hetaryl, allyl)arylboronic acid N-methyl-iminodiacetic acid (MIDA) ester, using polyurea microencapsulated palladium catalyst (Pd EnCat 30), gave the coupling adducts 1a-x in excellent yields in just 10-18 min.

Full text of DOI:10.1080/00397911.2015.1057289

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Phosphine-Free Suzuki Cross-Coupling Reaction Using
an Efficient and Reusable Pd Catalyst in an Aqueous
Medium Under Microwave Irradiation
Joaquim F. M. da Silvaa, Andres F. Yepes Perezab & Natália P. de Almeidaa
a Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
b Facultad de Ciencias Físicas Exactas y Naturales, Universidad de Santander (UDES),
Bucaramanga, Colombia
Accepted author version posted online: 11 Jun 2015.
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To cite this article: Joaquim F. M. da Silva, Andres F. Yepes Perez & Natália P. de Almeida (2015): Phosphine-Free Suzuki
Cross-Coupling Reaction Using an Efficient and Reusable Pd Catalyst in an Aqueous Medium Under Microwave Irradiation,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry
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Phosphine-free Suzuki cross-coupling reaction using an efficient and reusable Pd
catalyst in an aqueous medium under microwave irradiation
Joaquim F. M. da Silva1, Andres F. Yepes Perez1,2, Natália P. de Almeida1
1Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
2Facultad de Ciencias Físicas Exactas y Naturales, Universidad de Santander (UDES),
Bucaramanga, Colombia
Corresponding author E-mail: joaquim@iq.ufrj.br
Abstract
We report here an improved, highly efficient and general method for the ligand-free
Suzuki cross-coupling reaction to the synthesis of biaryls, bipyridyls, thienylpyridine and
allylphenols. Microwave irradiation of (het)aryl halides and (hetaryl, allyl)arylboronic
acid N-methyl-iminodiacetic acid (MIDA) ester, using polyurea microencapsulated
palladium catalyst (Pd EnCat 30) gave the coupling adducts 1a-x in excellent yields in
just 10-18 min.
KEYWORDS: Suzuki coupling, microwave irradiation Pd EnCat30, phosphine-free
reactions, organoboronic acid MIDA ester
INTRODUCTION
The Suzuki reaction is the coupling of an aryl or alkyl boronic acid with an aryl or alkyl
halide in the presence of a palladium catalyst. It is a powerful cross-coupling method that
allows for the synthesis of conjugated olefins, styrenes and biphenyls.[1] Suzuki coupling
1

reaction occurs for both aryl iodide and bromide systems in a very efficient way under
phosphine-free conditions, what is very important from environmental and economic
points of view. Because of the potential advantages of using heterogeneous catalysts for
fine chemical synthesis, recently polyurea-encapsulated palladium-catalyzed
[PdEnCat™] coupling has been reported. The scope and utility of Pd(OAc)2 encapsulated
in polyurea was investigated in a range of synthetically significant applications, including
Suzuki-type reactions involving the cross-coupling of aryl boronic acids with aryl
bromides. Pd EnCat™ could also be applied to other reactions such as carbonylation
reactions, Heck reactions, Stille couplings and hydrogenation reactions.[2-4] We recently
reported the Sonogashira coupling for the preparation of arylalkynes using Pd EnCat as
catalyst.[5] These transformations are often mediated by Pd species in the presence of
phosphine ligands, and this may result in difficulties associated with the removal of
homogeneous material from reaction mixtures. In preliminary results[6] we reported the
use of Pd EnCat 30 as catalyst in Suzuki coupling reactions using conventional heating
(oil bath), and although yields were good, longer reaction times were required, and some
yields were not satisfactory. Further, we also wanted to extend our strategy to the
preparation of substituted phenols.
Here, we explore, under microwave heating conditions, the catalyst charge, the volume
ratio of aqueous medium and the use of different bases, in order to find optimal reaction
conditions to obtain higher yields. Furthermore, we explored if with this new heating
condition, it is possible to recycle the catalyst without losing its activity. The strategy was
also extended to use halophenols as precursors and allyl MIDA ester as organoboronic
2

reagent, in order to evaluate if these phenolic precursors coupled effectively using water
as solvent.
We used our methodology that involves phosphine-free, supported Pd catalyst entrapped
in a polyurea matrix and microwave as heating source, with potential for both economic
and environmental advantages. Pd EnCat™ 30 has proven to be effective as recyclable
catalysts for use in Suzuki type cross-coupling reactions and do not require expensive and
toxic phosphines as co-ligands.[7-9] Secondly, microwave irradiation has emerged as a
powerful technique for promoting a variety of chemical reactions.[10] Reactions performed
under microwave irradiation conditions benefit from significant enhancements in rate and
product yields. In recent years, we have developed some new methods for the efficient
synthesis of heterocyclic compounds under microwave irradiation.[5,11,12]
Our continued interest in PdEnCat chemistry have led us to investigate the catalytic
activity of PdEnCat30 towards C–C cross-coupling reaction. Herein we report the
PdEnCat-catalyzed Suzuki cross-coupling reaction between organoboronic MIDA ester
and (hetaryl)aryl halides, under microwave irradiation in the absence of ligands, and
under mild and environmentally friendly conditions.
RESULTS AND DISCUSSION
C–C Cross-Coupling Reaction
In a first approach, to develop an optimal catalytic system for the Suzuki cross-coupling
reactions, various parameters such as temperature, % catalyst, solvent, base and reaction
3

time were studied, always under microwave irradiation and without using any ligand. As
a part of our ongoing research programme in the development of new ecofriendly
protocols, the coupling reaction was studied initially using only ethanol as solvent,
K2CO3 (3 mmol) as base and PdEnCat30™ (10 mol%) as the catalyst, under microwave
irradiation (10-20 min at 100 °C to 140 °C). We isolated the Suzuki product in very low
yields, the majors products being the homocoupling and the dehalogenation products,
alongside with the formation of black palladium. However, yields increased substantially
when significant volumes of water were added to the reaction.
Then, for the optimization of our conditions we selected as model the reaction of 4-
bromoacetophenone with 2-formylphenylboronic acid MIDA (1.5 mmol). Table 1 shows
the effect of different volumetric ratios of solvent and loadings of the catalyst used on the
Suzuki coupling between 2-formylphenylboronic acid MIDA and 4-bromoacetophenone.
We have used some EtOH:H2O mixtures (1:1, 2:1, 3:1, 4:1, 6:1, 8:1) and different
decreasing amounts of Pd EnCat30™ (1, 2.5, 6, 8 and 10%mol, respectively) with an
irradiation time of 10 min, at 120 °C.
In Table 1 it is possible to see that the highest conversion to 1a was observed using
EtOH:H2O in a 4:1 ratio, probably because it better dissolves both organic reagents and
the inorganic base, and 6 mol% catalyst, together with the lowest occurrence of the
debrominated or homocoupling side products, while the formation of black palladium
was not observed. The isolated yield of Suzuki-product 1a was 95%. In the other ratios
tested, the coupling reactions were accompanied by different extents of
4

hydrodehalogenation or homocoupling, and in some these cases the formation of black
palladium was observed. In order to investigate the role of the base and using the model
selected, four bases were investigated, namely KF, K3PO4, NaHCO3 and K2CO3. The
results show that K2CO3 was the optimum base under microwave irradiation at 120°C.
(Table 2)
Recycling investigations (Table 3) were carried out using PdEnCat30™ 6 mol% in the
reaction between 2-formylphenylboronic acid MIDA and 4-bromoacetophenone. The
heterogeneous catalyst allows efficient recycling by filtration. Indeed, the catalyst was
reused for three cycles, and after each run the reaction mixture was centrifuged and the
liquid mixture was decanted. The residual solid catalyst was employed again with fresh
solvent, substrates and base. The results showed that when the catalyst was recycled 3
times at the reaction conditions established no significant loss of activity or yield
occurred. During these reactions, the formation of black palladium was not observed
(Table 3).
Microwave heating has been reported to increase reaction rates as well as often to avoid
by-products formation as compared with conventional heating.[13–15] Therefore, Suzuki
cross-coupling reactions were also attempted under microwave irradiation using other
(orto- meta- para-)-aryl halides and heteroaryl halides in the ethanol/H2O (4:1) mixture.
A comparative analysis of the results in Table 1 and 4, allows to conclude that microwave
heating dramatically improves the rate of reaction for all reactions performed,
5

corresponding sometimes even to a 54-fold increase in reaction rate, compared with
conventional heating. Interestingly, microwave heating appears to be particularly
beneficial in the cross-coupling of p-bromoacetophenone and p-iodoanisol with
significantly improved conversions as compared with 1-bromo-4-methylbenzene (p-
bromotoluene). (Table 4, entries: 1, 4, 5).
Our studies on the Suzuki reaction coupling were performed using aryl halides bearing
both electron-donating and electron-withdrawing groups and the results were comparable.
Therefore, under the defined conditions, reactions did not show any sensitivity to
electronic effects; for example, 4-iodoanisole or 4-chloro-3-methylphenol has a
comparable result to 4-bromobenzaldehyde or 1-iodo-4-nitrobenzene (Table 4, entries: 2,
3, 4, 10).
In Table 4 are shown the data obtained using the catalytic system for Suzuki cross-
coupling reaction of different types of aryl bromides, iodides and less reactive aryl
chlorides, using three different boronic acid MIDA esters under microwave irradiation at
120 °C.
Our protocol showed that the reaction successfully occurred without any phosphine
ligand to give the corresponding Suzuki coupling products 1a–x in good to excellent
yields. Also, the Suzuki coupling reaction of aryl halides with 2-formylphenylboronic
acid MIDA ester and 6-methoxy-2-pyridylboronic acid MIDA ester or allylboronic acid
MIDA ester, respectively, occurred efficiently to provide the corresponding products. For
6

example, 2-bromobenzaldehyde and 4-chloro-3-methylphenol reacted with 2-
formylphenylboronic acid MIDA ester to yield in 88% (1i) and 84% (1j), respectively. 1-
Iodo-4-nitrobenzene and 4-bromobenzaldehyde reacted with 6-methoxy-2-pyridylboronic
acid MIDA ester to yield in 84% (1m) and 90% (1o), respectively, and 4-chlorophenol
reacted with allylboronic acid MIDA ester to yield in 75% (1w).
With the optimized reaction conditions in hand, the coupling reactions of a variety of
hetaryl halides and 2-formylphenylboronic acid MIDA ester or 6-methoxy-2-
piridylboronic acid MIDA ester were carried out. As shown in Table 4, significant
structural variations in the (hetero)aryl halides components were well tolerated and
afforded the corresponding heteroaromatic functionalized compounds (1f-h, 1q-v) in
good yields.
Bipyridines have been extensively used.[16]. Hosseini et al. and Sadimenko’s showed their
use as organometallic ligands.[17,18] In particular, the 2,4-, 2,2-, and 2,3-bipyridyl such as
collismycins and cytosine, have been used as antibiotics and to help with smoking
cessation, and 4,6-diaryl-2,4'-bipyridines for cancer treatment.[19] (Scheme 1)
Typically, the 2-pyridyl–boron bond is exquisitely sensitive to protodeborylation, making
most 2-pyridyl boranes unstable. In contrast, 2-pyridyl N-methyliminodiacetic acid
(MIDA) boronate (Table 4) is the first 2-pyridylborane derivative that is both air stable
and commercially available.[20]
7

The coupling reactions of representative heteroaromatic halides (Entry 17-22) with 6-
methoxypiridylboronic acid MIDA ester proved to be effective with our new protocol
using microwave. It was also observed that the chemical yields of bipyridines and 2-
thienyl-pyridine systems from the Suzuki-Miyaura coupling reaction were 77-87% after
10-min when the microwave irradiation were used. Furthermore, in a first approach to
produce allyl-substituted phenolic, allylphenols 1w and 1x were prepared by reaction of
4-chlorophenol or 2-iodo-4-nitrophenol and allylboronate acid MIDA ester respectively.
The results showed that the Suzuki products were obtained in good yields (75% and 70%
respectively). It is important to note that our methodology opens a new possibility for the
preparation of allylphenols without using excessive heating and excessive reaction times
via the well-known Claisen-rearrangement, and can be used in the synthesis of
allylphenols for pharmaceutical industry such as alprenolol, and the Eugenol-Niacin
hybrids[21,22]. (Figure 1)
Moreover, further experiments conducted in our laboratory showed that the reaction can
be scaled up without compromising the yield. The reaction of 4-bromoacetophenone, 4-
iodoanisol, 4-bromotoluene, 4-bromopyridine and 2-bromothiophene, respectively, with
2-formylphenylboronic acid MIDA and 6-methoxy-2-piridylboronic acid MIDA ester
(1.5 mmol) were repeated on a 3 mmol scale (Table 4, entry: 1,4,5,6,8,14,16,20,22) using
microwave irradiation. The isolated yield of products were 1a (93%), 1d (81%), 1e
(79%), 1f (92%), 1h (84%), 1n (77%), 1p (85%), 1t (80%) and 1v (73%), respectively,
almost identical to that when the reactions were performed on a 1 mmol scale.
8

CONCLUSIONS
In summary, we have developed a general, rapid and eco-friendly method for the
synthesis of functionalized biaryls (1a-e, 1i-l), (hetaryl)aryls (1f-h, 1m-p),
(hetaryl)pyridines (1q-v) and allylphenols (1w, 1x) from (heteroaryl)aryl halides and
three N-methyliminodiacetic acid (MIDA) boronates by using microwave-assisted Suzuki
cross-coupling reactions mediated by the Pd-encapsulated PdEnCatTM 30. The reactions
are applicable to a wide range of substrates, avoiding the use of toxic eco-unfriendly
solvents. Furthermore, most of the reactions involved are efficient, giving the desired
compounds in high yields within short reaction time. Our new protocol could be directed
to the synthesis of compounds with potential biological activity. In general, our
methodology has the advantage of low catalyst loadings, rapid reaction times, ease of
reaction (no need for anaerobic conditions), and the most important, the reactions occur
without presence any phosphine-ligand and in aqueous medium or in water.
EXPERIMENTAL
General Procedure For The Microwave-Assisted Suzuki Reactions.
In a 10 mL glass tube were placed halide (1.0 mmol), 2-formylphenyl or 2-pyridyl MIDA
boronate (1.5 mmol) or allyl MIDA boronate, K2CO3 (3.0 mmol), Pd EnCat30 (6 mol %)
and ethanol:H2O (4:1 v/v) or water, and a magnetic stir bar. The vessel was sealed with a
septum and placed into the microwave cavity. The temperature being ramped from rt to
120 °C or 135°C. Once the reaction temperature was reached, the reaction mixture was
held at this temperature for 10-18 min. After the mixture was allowed to cool to room
temperature, the reaction vessel was opened and the contents were poured into a
9

separating funnel. Water and ethyl acetate (3 x10 mL) were added. The combined
organics were dried over Na2SO4, filtered and concentrated in vacuo. The organic residue
was adsorbed onto silica gel, and then purified by column flash chromatography
(hexane/ethyl acetate as eluent) to afford the desired product 1a-x. The biaryls,
bipyridines or allylphenols prepared are known compounds.[23-45] The products were
confirmed by comparing the 1H NMR and mass spectral data with authentic samples
reported in the literature.
SUPPLEMENTAL MATERIAL
Full experimental procedures and characterization data for all synthesized compounds for
this article can be accessed on the publisher’s website.
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Table 1. Optimization of solvent and catalyst loading for Suzuki cross-coupling reaction
under microwave irradiation.a
Entry Volumetric ratios
EtOH:H2O
Catalyst Loading
(mol%)
Suzuki-coupling product (1a)
% yieldb
60
1
2
3
4
5
6
7
8
9
10
1:1
2:1
3.1
4:1
4:1
4:1
4:1
4:1
6:1
8:1
10 %mol
10 %mol
10 %mol
10 %mol
8 %mol
68
72
82
89
6 %mol
95
2.5 %mol
1 %mol
77
74
10 %mol
10 %mol
70
67
a 3.0 equiv of K2CO3 were used, microwave 120°C.
b isolated yield
15

Table 2. Optimization of base for Suzuki cross-coupling reaction.a
Entry Base
Suzuki-coupling product (1a) % yieldb
1
2
3
4
KF
83
80
K3PO4
NaHCO3 70
K2CO3 95
a Reaction conditions: 1a (1.0 mmol), phenylboronic acid MIDA (1.5 mmol),
base (3.0 mmol), EtOH:H2O (4:1).
b microwave, 10 min, 120°C
16

Table 3. Recycling investigations.a
Entry Cycle % yieldb (1a)
1
2
3
1
2
3
92
87
81
a Reaction conditions: 1a (1.0 mmol), phenylboronic acid MIDA (1.5 mmol),
K2CO3 (3.0 mmol), EtOH:H2O (4:1).
b
microwave, 10 min, 120°C
17

Table 4. Suzuki coupling reaction between (het)aryl halides and 2-formylphenylboronic
MIDA ester.a
Entryc R1X
R-MIDA boronate
Reaction time Yieldb (%)
1
4-bromoacetophenone
2-formylphenyl-MIDA 10 min.
1a (95)
1b (89)
1c (97)
1d (83)
1e (80)
1f (95)
1g (95)
1h (90)
1i (88)
1j (84)f
1k (75)f
2
1-iodo-4-nitrobenzene
4-bromobenzaldehyde
4-iodoanisole
=
=
=
=
=
=
=
=
=
=
10 min.
10 min.
10 min.
10 min.
10 min.
10 min.
10 min.
10 min.
16 min.
16 min.
3
4
5
1-bromo-4-methylbenzene
4-bromopyridine
6d
7
3-bromopyridine
8
2-bromothiophene
2-bromobenzaldehyde
4-chloro-3-methylphenol
2-bromo-5-
9
10e
11e
hydroxybenzaldehyde
2-iodo-4-nitrophenol
1-iodo-4-nitrobenzene
12e
13
=
16 min.
10 min.
1l (70)f
6-methoxypiridyl-
1m (84)
MIDA
14
15
4-bromoacetophenone
4-bromobenzaldehyde
=
=
10 min.
10 min.
1n (81)
1o (90)
18

16
17
18
19
20d
21
22
23
24
4-iodoanisole
=
10 min.
10 min.
10 min.
10 min.
10 min.
10 min.
10 min.
18 min.
18 min.
1p (87)
1q (80)
1r (78)
1s (87)
1t (81)
1u (84)
1v (77)
1w (75)f
1x (70)f
2-bromopyridine
2-chloro-5-nitropyridine
3-bromopyridine
4-bromopyridine
2-bromoquinoline
2-bromothiophene
4-chlorophenol
=
=
=
=
=
=
allyl-MIDA
=
2-iodo-4-nitrophenol
a Reaction conditions: halide (1.0 mmol), 1.5 equiv of MIDA boronate, 6 mol % Pd
EnCat30, 3.0 equiv of K2CO3, 0.1 M in 4:1 ethanol/H2O.
b isolated yield.
c Cross-couplings were run at 120°C.
d 4-bromopyridine hydrochloride was used.
e pure water as solvent was used.
f cross-couplings were run at 135°C.
19

Scheme 1. Structure of some bipyridines of biological interest that can be prepared using
our protocol.
20

Figure 1. Some allyl-substituted phenolic compounds of medicinal interest that can be
prepared using our protocol.
21