Study of the Structure-Activity Relationship in a Heterogeneous Copper-Palladium Catalysed Suzuki-Miyaura Coupling

Article abstract of DOI:10.1007/s10562-015-1490-y

Abstract Copper-palladium bimetallic catalyst supported on 4 ? molecular sieve prepared with two-step wet impregnation was successfully applied in the Suzuki-Miyaura reaction. The reaction took place with a variety of substituted boronic acids as well as with a collection of iodo- and bromobenzene derivatives. In some cases steric effects had influence on the reaction, ortho-substituted iodo- or bromobenzenes gave lower yield independently from the substituent. But most m- and p-substituted iodo- and bromobenzenes showed good to excellent activity. Several biphenyls were obtained by two or even three pathways: either the boronic acid or the respective iodo- or bromobenzene was functionalised.

Full text of DOI:10.1007/s10562-015-1490-y

Catal Lett
DOI 10.1007/s10562-015-1490-y
Study of the Structure–Activity Relationship in a Heterogeneous
Copper–Palladium Catalysed Suzuki–Miyaura Coupling
´
Anna Fodor Agnes Magyar Dora Barczikai
•
•
•
´
Laurence Pirault-Roy Zoltan Hell
•
´
Received: 14 January 2015 / Accepted: 23 January 2015
Ó Springer Science+Business Media New York 2015
Abstract Copper–palladium bimetallic catalyst sup-
˚
ported on 4 A molecular sieve prepared with two-step wet
Keywords Cu–Pd bimetallic catalyst Á Heterogeneous
˚
catalysis Á 4 A molecular sieve Á Structure–activity
impregnation was successfully applied in the Suzuki–Mi-
yaura reaction. The reaction took place with a variety of
substituted boronic acids as well as with a collection of
iodo- and bromobenzene derivatives. In some cases steric
effects had influence on the reaction, ortho-substituted
iodo- or bromobenzenes gave lower yield independently
from the substituent. But most m- and p-substituted iodo-
and bromobenzenes showed good to excellent activity.
Several biphenyls were obtained by two or even three
pathways: either the boronic acid or the respective iodo- or
bromobenzene was functionalised.
relationship Á Suzuki–Miyaura reaction
1 Introduction
Suzuki–Miyaura coupling is known as one of the most
important tools for palladium catalysed carbon–carbon
bond formation (Fig. 1).
The starting materials (aryl halides and boronic acids)
are easily available in stable and widely functionalised
form. Short reaction time, easy work up and wide range of
products is representative. Since the first publications [1, 2]
several methods were elaborated and a great number of
publications and reviews were released reporting homo-
geneous [3–6] and heterogeneous [7–10] pathways to
perform this coupling. Suzuki coupling was also the subject
of several reviews providing extensive knowledge on cer-
tain fields as heterogeneous palladium catalysis [11]; large
scale application for pharmaceutical production [12] and
efficient, selective and recyclable palladium catalysts [13],
etc. Furthermore, studies were also made on the isomer
effects in this reaction. Schmidt and Riemer [14] examined
the Suzuki reaction of halophenols and phenol boronic
acids and revealed that certain combinations of boron-
ophenols and halophenols are disfavoured. Zou et al. [15]
found o-substitution effect as a reason of low activity
caused by steric hindrance and absorption associated with
heterogeneous Pd/C.
Graphical Abstract
´
A. Fodor Á A. Magyar Á D. Barczikai Á Z. Hell (&)
Department of Organic Chemistry and Technology, Budapest
University of Technology and Economics, M}uegyetem rkp, 3,
Budapest 1111, Hungary
Ligand-free heterogeneous catalysts are well reported to
carry out coupling reactions, for example mesoporous sil-
ica-supported Pd catalysed Suzuki–Miyaura and Heck
reactions [16], Pd supported on a polyionic resin was also
applicable in these reactions as well as in Sonogashira-
e-mail: zhell@mail.bme.hu
A. Fodor Á L. Pirault-Roy
Institute of Chemistry of Poitiers: Materials and Natural
Resources (IC2MP) UMR-CNRS 7285, University of Poitiers, 4,
ˆ
rue Michel Brunet (Bat B27), 86073 Poitiers Cedex, France
123

A. Fodor et al.
method described in [22]. The catalyst was treated at
120 °C for 1 h before the reaction. Boronic acid (1.5 mmol
or 1.2 mmol), aryl halide (1 mmol), potassium carbonate
(3 mmol) and the pretreated catalyst Cu–Pd-4A-TSI (0.1 g;
2.26 mol% Pd and 9.86 mol% Cu) were stirred in 5 ml
refluxing ethanol for 1 or 1.5 h. Then the solid was filtered
out, and washed with ethanol. The filtrate was evaporated.
The residue was extracted three times with dichlorometh-
ane and with water. The organic phase was dried over
anhydrous sodium sulphate, filtered and the solvent was
evaporated. The product was subjected to either GC–MS
analysis and/or 1H NMR. If required, the product was
recrystallized.
Fig. 1 General scheme of the Suzuki–Miyaura coupling
reaction [17]. Besides these materials monometallic cata-
lytic Pd/Cu bimetallic catalysts attract also great attention.
Several publications described nano-Pd/Cu systems as
efficient catalysts for the Sonogashira-reaction [18–20] or
electrochemical reaction such as electrooxidation of formic
acid [21]. It is well reported, that these catalysts possess an
increased catalytic activity compared to their monometallic
counterparts and a positive synergistic effect of Pd and Cu
has also been described [18, 21].
All products have satisfactory spectral data (1H NMR,
MS). The spectral data of the known compounds were
identical with those reported in the literature. Representa-
tive physical and spectroscopic data of some products:
3-Methyl-biphenyl (Table 1, entry 2; Table 3, entry 1
In our previous paper [22] the characteristics of the Cu–
˚
Pd bimetallic catalyst—supported on 4A molecular sieve
prepared with two-step wet impregnation (Cu–Pd-4A-
TSI)—were presented and discussed. This catalyst contains
6.2 wt% Cu and 2.4 wt% Pd, possesses with a BET surface
area of 310 m2/g and its average particle size is 2.5 nm
thus it is a nano-structured catalyst. It was used six times in
the coupling of iodobenzene with phenylboronic acid
without any loss of activity. The used catalyst surface
analysis showed the presence of Cu/Pd 1/1 alloy which has
been proven to be the catalytically active species in this
reaction. According to these results we concluded that the
role of Cu in our reactions was stabilizing palladium due to
a Pd:Cu interaction, thus Pd could keep its active form.
This observation is in accordance with the literature
reporting the synergistic effects of these two metals [18,
21]. As in our former article a full study on the catalyst’s
properties was provided, herein, the wide range of substi-
tuted aryl halides and substituted boronic acids, which
undergo the Suzuki-coupling in the presence of our cop-
per–palladium bimetallic catalyst, is presented. The steric
and electronic effects of the substituents were examined
according to the yield of desired product formation.
1
and Table 4, entry 7): white solid, H NMR (300 MHz,
CDCl3) d (ppm): 2.4 (s, 3H, CH3), 7.28–7.41 (m, 7H, Ph),
7.55–7.58 (m, 2H, Ph). MS m/z (%): 168 (M?, 100), 152
(35), 128 (8), 115 (10), 83 (15).
4-Methyl-biphenyl (Table 1, entry 3; Table 3, entry 2
and Table 4, entry 8): white solid, mp: 43–45 °C (literature
1
44–46 °C [23] ). H NMR (300 MHz, CDCl3) d (ppm):
2.38 (s, 3H, CH3), 7.24 (d, 2H, Ph), 7.31–7.34 (m, 1H, Ph),
7.42 (t, 2H, Ph), 7.48 (d, 2H, Ph), 7.56 (d, 2H, Ph). MS m/z
(%): 168 (M?, 100), 152 (25), 115 (12), 83 (15).
4-Trifluoromethyl-biphenyl (Table 1, entry
4 and
Table 4, entry 11): white solid, mp: 64–66 °C (literature
1
65–67 °C [24] ). H NMR (300 MHz, CDCl3) d (ppm):
7.40–7.50 (m, 3H, Ph), 7.59 (d, 2H, Ph), 7.69 (s, 4H, Ph);
13C NMR (75 MHz, CDCl3): 125.8 (qua), 127.4, 127.5,
128.3, 129.0, 139.9, 144.8.
3-Nitro-biphenyl (Table 3, entry 3): 1H NMR
(300 MHz, CDCl3) d (ppm): 7.43–7.52 (m, 3H, Ph),
7.58–7.63 (m, 3H, Ph), 7.91 (d, 1H), 8.2 (d, 1H), 8.45 (s,
1H); 13C NMR (75 MHz, CDCl3): 122.2, 122.3, 127.4,
128.8, 129.4, 129.9, 133.3, 138.9, 143.1.
4-Nitro-biphenyl (Table 3, entry 4): 1H NMR
(300 MHz, CDCl3) d (ppm): 7.45–7.53 (m, 3H, Ph), 7.62
(d, 2H, Ph), 7.74 (d, 2H), 8.3 (d, 2H); 13C NMR (75 MHz,
CDCl3): 124.2, 127.5, 127.9, 129.0, 129.3, 138.9, 147.7.
4-Methoxy-biphenyl (Table 3, entry 5): 1H NMR
(300 MHz, CDCl3) d (ppm): 3.85 (s, 1H CH3O), 6.97 (d,
2H, Ph), 7.3 (m, 1H, Ph), 7.41 (t, 1H, Ph), 7.54 (m, 4H, Ph);
13C NMR (75 MHz, CDCl3): 55.4, 114.3, 126.7, 126.8,
128.2, 128.8, 133.9, 159.2.
Biphenyl-4-carboxylic acid (Table 3, entry 6): 1H NMR
(300 MHz, CDCl3) d (ppm): 7.41–7.51 (m, 3H, Ph), 7.64
(d, 2H, Ph), 7.71 (d, 2H), 8.19 (d, 2H); 13C NMR (75 MHz,
CDCl3 ? DMSO-d6) d (ppm): 127.0, 127.3, 128.1, 128.9,
130.4, 137.6, 140.1, 145.4.
2 Experimental
GC–MS measurements were performed on an Agilent
6890N-GC-5973N-MSD
chromatograph,
using
a
30 m 9 0.25 mm Restek, Rtx-5SILMS column with a film
layer of 0.25 lm. The initial temperature of column was
45 °C for 1 min, followed by programming at 10 °C/min
up to 310 °C and a final period at 310 °C (isothermal) for
17 min. The temperature of the injector was 250 °C. The
carrier gas was He and the operation mode was splitless. 1H
NMR spectra were made on BRUKER Avance-300
instrument using TMS as an internal standard in CDCl3.
Typical procedure for the Suzuki–Miyaura-coupling:
The catalyst Cu–Pd-4A-TSI was prepared according to the
123

Cu–Pd Catalysed Suzuki–Miyaura Coupling
Table 1 Reaction of iodobenzene with boronic acid derivatives
Entry
Boronic acid
Product
Yield (%)a
Fig. 2 Suzuki–Miyaura coupling in the presence of Cu–Pd-4A-TSI
catalyst
1
92
3 Results and Discussion
2
3
91
72
The reaction of boronic acid with aryl halides was per-
formed in the presence of Cu–Pd-4A-TSI as a catalyst,
K2CO3 as a base, in boiling ethanol. The reaction of iodo-
and bromobenzene with boronic acid derivatives and the
reaction of phenylboronic acid with substituted aryl iodides
and -bromides (Fig. 2) were examined.
4
98
Table 1 summarizes the results obtained in the coupling
of iodobenzene with different substituted boronic acids.
The reaction of iodobenzene with 4-trifluoromethyl-phe-
nylboronic acid (Table 1, entry 4) and tolylboronic acids
(Table 1, entries 1–3) gave excellent yield, in the case of
2-naphthylboronic acid (Table 1, entry 6) good yield was
observed. In the reaction of tolylboronic acids small
amount of the corresponding dimethyl-biphenyls, yielding
from the homocoupling of the boronic acids, were also
obtained. In the reaction of 2-acetylphenylboronic acid
with iodobenzene (Table 1, entry 5) the expected product
was formed only in negligible amount, in the GC–MS
spectra a compound with 220 Da molar mass was found as
main product. Earlier we have observed that in the Pd-
catalysed reaction of acetophenone derivatives in basic
alcohol a transfer hydrogenation reaction could also occur,
where ethanol would oxidise to acetaldehyde. [25] In this
case a similar reaction might be assumed, and the acetal-
dehyde formed can react with the acetyl group in an aldol
type reaction.
5
6
<5
80
7
~30
~60
8
9
Heteroaryl boronic acids showed less activity (Table 1,
entries 7–11). Indoleboronic acids gave the corresponding
products with moderate to poor yield (Table 1, entries
7–8), moreover, 1-(tert-butoxycarbonyl)-indole-2-boronic
acid (Table 1, entry 9) failed to react. According to the
GC–MS analysis of the reaction mixture, in this case 1-tert-
butoxycarbonyl indole was formed as a result of boronic
acid function loss. This weak reactivity can be explained
by two facts. These indoleboronic acids proved to be quite
unstable. In addition, copper and palladium on the catalyst
might form a complex with the amine function of the
starting material, and this complex is inactive in the reac-
tion. This hypothesis was verified by XRF examination of
the product. Considerable amount of copper as well as
some palladium was detectable, while in the products
obtained from the reaction of homoaromatic boronic acids
no metal contamination of the product was found. The lack
b
–
b
10
11
–
b
–
Reaction conditions: boronic acid (1.5 mmol), iodobenzene (1 mmol),
potassium carbonate (3 mmol), 0.1 g catalyst Cu–Pd-4A-TSI
(2.26 mol% Pd and 9.76 mol% Cu) in EtOH, 78 °C, 1 h
a
1
Isolated yield, the purity was verified by H NMR spectroscopy
b
No reaction was observed
123

A. Fodor et al.
Table 2 Reaction of iodobenzene with aliphatic boronic acids
Entry
Boronic acid
Reacꢀon ꢀme (h)
Product
Yield (%)a
1
<15
1
3
<10
b
1
6
–
2
b
–
Reaction conditions: boronic acid (1.5 mmol), iodobenzene (1 mmol), potassium carbonate (3 mmol), 0.1 g catalyst Cu–Pd-4A-TSI (2.26 mol%
Pd and 9.76 mol% Cu) in EtOH, 78 °C
a
1
Yield estimated from the H NMR spectra of the product
b
No reaction was observed
of reactivity of pyridineboronic acids can also be explained
by this complex formation, as none of the expected pro-
ducts were isolated in these cases either (Table 1, entries
10–11).
Table 3 Reaction of phenylboronic acid with substituted
iodobenzenes
Entry
Aryl iodide
Product
Yield (%)a
The reaction of iodobenzene with aliphatic boronic acids
was also performed. The results obtained are summarized
in Table 2. As in these cases after 1 h reaction time sig-
nificant amount of starting material was detected by TLC,
longer reaction times were used. Nevertheless, no better
results were obtained. In case of trans-1-penten-1-ylbo-
ronic acid (Table 2, entry 1) after 3 h reaction time the
yield was lower. Butyl-1-boronic acid (Table 2, entry 2)
failed to react in the presence of Cu–Pd-4A-TSI irrespec-
tively of the reaction time. The aliphatic boronic acids are
known as less active in the coupling reactions, thus the use
of a ligand and/or stronger base might have been needed to
perform the coupling [26, 27].
1
77
2
3
89
91
4
5
96
87
Substituted iodobenzenes showed excellent activity
(Table 3 entries 1–6) except 2-iodobenzoic acid (Table 3,
entry 7) which can be explained by steric effects.
Performing the reaction with bromobenzene after 1 h
biphenyl was formed with 80 % yield [22]. As aryl bro-
mides are generally less active in the Suzuki–Miyura
reaction, the reaction time was increased to 1.5 h which
resulted in the product formation with good to excellent
yield (Table 4). In case of certain o-, and m-substituents the
yield dropped (Table 4, entries 1, 4, 7).
6
7
94b
The results obtained show that functional groups in
the o-position of the aryl halide can hinder the desired
product formation. No electronic effect can be found, as
the yields are similar with both electron withdrawing
groups (EWG) and electron donating groups (EDG) in
ortho-position.
b, c
–
Reaction conditions: boronic acid (1.2 mmol), iodobenzene
(1 mmol), potassium carbonate (3 mmol), 0.1 g catalyst Cu–Pd-4A-
TSI (2.26 mol% Pd and 9.76 mol% Cu) in EtOH, 78 °C, 1 h
Comparing the experiments yielding o-, m-, and p-tol-
ylbiphenyls from substituted boronic acids (Table 1.
entries 1–3), iodobenzenes (Table 3, entries 1–2) and
bromobenzenes (Table 4, entries 6–8) it can be concluded
a
b
c
1
Isolated yield, the purity was verified by H NMR spectroscopy
4 mmol potassium carbonate was used
Unidentified by-product was formed
123

Cu–Pd Catalysed Suzuki–Miyaura Coupling
that the position of the functional group has an importance.
The ortho- and meta-substituents should be favourably on
the boronic acid moiety, as in this case excellent yields
were obtained. But better results were obtained with para-
substituted aryl halides. However, from economic consid-
erations, in large scales the iodo- or bromobenzene deriv-
ative might be favoured as their application results still in
good yield. The place of the functional group had no
importance in case of p-trifluoromethyl-biphenyl as
excellent yields were achieved in both cases (Table 1,
entry 4; Table 4, entry 11). p-Methoxybiphenyl can be
formed from p-bromoanisole with excellent yield (Table 3,
entry 5), with good yield from p-iodoanisole (Table 4,
entry 2). Comparing iodo- (Table 3, entries 1–2) and
bromobenzenes (Table 4, entries 6–8) one can conclude
that higher yields were achieved with the application of
bromobenzenes during a slightly elevated reaction time.
Table 4 Reaction of phenylboronic acid with substituted
bromobenzene
Bromobenzene
derivaꢀve
Entry
Product
Yield (%)a
1
59
2
3
4
5
97
92
<45b,c
88b
4 Conclusions
In summary, a series of substituted biphenyls were syn-
thesized starting from substituted boronic acids and iodo-
benzene or bromobenzene derivatives in the presence of
the bimetallic Cu–Pd-4A-TSI catalyst. The m- and p-
substituted derivatives gave excellent yield, while o-
substituted aryl halide derivatives sometimes gave weaker
results because of steric effects. No significant electronic
effect was observed. Substituted biphenyls from two or
three pathways were achieved at least with good yields.
Excellent yields were resulted in ortho-, meta-position with
substituted boronic acid, while in para-position with aryl
halides. Aliphatic boronic acids didn’t undergo the
coupling.
6
7
8
9
80
65
>99
72
Acknowledgments The authors would like to thank the French
Government for the scholarship that made the cooperation between
the two research groups possible.
10
11
90
95
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Reaction conditions: boronic acid (1.2 mmol), iodobenzene (1 mmol),
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Isolated yield, the purity was verified by H NMR spectroscopy
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Unidentified by-product was formed
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