Anchored Pd(0) Nanoparticles on Synthetic Talc for the Synthesis of Biaryls and a Precursor of Angiotensin II Inhibitors

Article abstract of DOI:10.1055/s-0040-1705989

The palladium-catalyzed Suzuki-Miyaura cross-coupling reaction is one of the most important and efficient reactions to prepare a variety of organic compounds, including biaryls. Despite the overwhelming number of reports related to this topic, some methodological difficulties persist in terms of catalyst handling, recovery, and reuse, as well as the reaction media. This work reports the rational design of new, efficient, cost-effective, and reusable palladium catalysts supported on synthetic talc for the Suzuki-Miyaura reaction. From the results, key points were identified: both designed catalysts accelerated the reaction in EtOH and an open-flask setup, affording moderate to excellent yields within a short time (e.g., 30 min) even for deactivated aryl halides; the protocol can be applied to a great number of both cross-coupling partners, showing an excellent functional group tolerance; the catalysts can be recovered and reused without significant loss of activity. This protocol was used for the synthesis of a precursor of angiotensin II inhibitors such as valsartan, losartan, irbesartan, and telmisartan.

Full text of DOI:10.1055/s-0040-1705989

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, 933–942
paper
933
en
B. F. dos Santos et al.
Paper
Synthesis
Anchored Pd(0) Nanoparticles on Synthetic Talc for the Synthesis
of Biaryls and a Precursor of Angiotensin II Inhibitors
Beatriz F. dos Santosa
X
Beatriz A. L. da Silvaa
Aline R. de Oliveirab
Maria H. Sarragiottob
0
0
0
0
-
0
0
0
3
-1
6
8
5
-
6
3
1
6
O
H
N
Pd
Si
O
O
R'
O
R'
Nelson Luís C. Domingues*a
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+
Y
a Organic Catalysis and Biocatalysis Laboratory – LACOB,
Federal University of Grande Dourados – UFGD, Dourados,
MS, Brazil
R
R
27 examples
X = I, Br
Y = B(OH)2, Bpin
- new and recyclable Pd catalysts
- mild conditions and excellent yields
- drug precursor
nelsondomingues@ufgd.edu.br
b State University of Maringá – UEM, Maringá, PR, Brazil
Corresponding Author
Received: 22.09.2020
Accepted after revision: 05.11.2020
Published online: 15.12.2020
ance.5 These characteristics of boronic acids result in excel-
lent structural diversity in the corresponding products and
render them safe,5 thus making them the ideal starting ma-
terials. Furthermore, boronic acids are highly stable to heat,
oxygen, and water, and are easily separated from byprod-
ucts.6 Over the last few years, some important advances
have been made in the Suzuki–Miyaura reaction, including
the use of aryl chlorides, low catalyst loading, and room-
temperature reactions.7 However, the major drawback of
the Suzuki–Miyaura coupling lies in the use of palladium
salts and expensive ligands.8 Despite its disadvantages of
high cost and low abundance, palladium is still the most
widely used metal for designing new catalysts and is often
applied in reactions aiming at the formation of C–C bonds.9
DOI: 10.1055/s-0040-1705989; Art ID: ss-2020-m0500-op
Abstract The palladium-catalyzed Suzuki–Miyaura cross-coupling re-
action is one of the most important and efficient reactions to prepare a
variety of organic compounds, including biaryls. Despite the over-
whelming number of reports related to this topic, some methodologi-
cal difficulties persist in terms of catalyst handling, recovery, and reuse,
as well as the reaction media. This work reports the rational design of
new, efficient, cost-effective, and reusable palladium catalysts support-
ed on synthetic talc for the Suzuki–Miyaura reaction. From the results,
key points were identified: both designed catalysts accelerated the re-
action in EtOH and an open-flask setup, affording moderate to excellent
yields within a short time (e.g., 30 min) even for deactivated aryl ha-
lides; the protocol can be applied to a great number of both cross-cou-
pling partners, showing an excellent functional group tolerance; the
catalysts can be recovered and reused without significant loss of activi-
ty. This protocol was used for the synthesis of a precursor of angioten-
sin II inhibitors such as valsartan, losartan, irbesartan, and telmisartan.
Cl
HO
OH
O
H
N
Cl
O
OH
N
H2N
N
H
Key words cross-coupling, palladium, supported catalysts, Suzuki–
Miyaura reaction, synthetic talc
H
N
O
NH2
O
OH
Biphenomycin B
Boscalid
Cross-coupling reactions, specifically the Suzuki–
Miyaura reaction, are a powerful method for the formation
of C–C bonds.1 This reaction is performed by using a palla-
dium catalyst, organoborons, and organic halide or triflate
reagents, and produces a variety of compounds, including
biaryls. The biaryl moiety is found in a range of compounds
as it is an important building block for polymers2 and li-
gands,3 as well as in a wide variety of natural products (bi-
phenomycin B) and biologically active target molecules
(boscalid) and pharmaceuticals1,4 (e.g., diflunisal and flurbi-
profen) (Figure 1).4 Unlike other types of C–C cross-cou-
pling reactions involving organometallic reagents, the
Suzuki–Miyaura reaction can be performed under mild
conditions using boronic acids, which are simple to use,
easily accessible, and show good functional group toler-
O
OH
HO
F
HO
O
F
F
Diflunisal
Flurbiprofen
Figure 1 Bioactive molecules containing a biaryl nucleus
As a result, many researchers have developed heteroge-
neous and reusable palladium catalysts,10 as homogeneous
palladium catalysts are expensive and difficult to separate
from the reaction, meaning they are not recoverable; fur-
ther, the final product can be contaminated by the metal,
which poses an issue for the pharmaceutical industry.11 In
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 933–942
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

934
B. F. dos Santos et al.
Paper
Synthesis
most cases, a heterogeneous catalyst consists of the metal
encapsulated in a polymeric shell12 or adsorbed on different
organic13 or inorganic14 supports.
not obtain the product, implying that the catalyst is essen-
tial for the reaction (entry 6). We also performed studies re-
garding catalyst loading (entries 7 and 8). For this, we used
the standard reaction but decreased the catalyst loading to
2.5% w/w (entry 7) and 1.5% w/w (entry 8), and the yields
dropped to 94% and 76%, respectively. However, the data
obtained for entry 7, with a similar yield as the standard re-
action, led us to assess the influence of the reaction time on
the yield. Thus, we performed a further standard reaction
(entry 9); however, decreasing the reaction time to 2 hours
drastically reduced the yield (67%), as expected. Finally, we
carried out the reaction with 3% w/w catalyst for 3 hours
(entry 10) but observed no increase in the yield. Thus, the
optimized reaction conditions were determined as follows:
boronic acid (2.0 mmol), iodoarene (1.0 mmol), catalyst (5%
w/w), 3 h reaction time.
The development of improved heterogeneous palladium
catalysts is crucial for their application on an industrial
scale so that considerable cost savings can be achieved ow-
ing to their ease of removal and reuse.12 However, the cata-
lytic activity of immobilized palladium catalysts is some-
times low due to the presence of the support,12 which ne-
cessitates higher catalyst loading. In this sense, synthetic
talc (magnesium organosilicates) has become an important
and efficient tool in catalytic organic synthesis due to its
physicochemical properties.15 Despite magnesium organo-
silicates having very attractive characteristics, such as low
cost and adsorption capacity of organic substances,15 there
are limited studies on the applications of this material in
organic reactions.
With this goal, our group has been investigating cross-
coupling reactions, and we have previously described pro-
tocols for C–S cross-coupling by using a heterogeneous pal-
ladium catalyst.16,17 As a continuation of this research, we
herein introduce synthetic talc as an efficient, inexpensive,
and eco-friendly heterogeneous support for immobilized
palladium catalyst synthesis – LACOB-Pd1 and LACOB-Pd4.
The difference between these two catalysts lies in the labels
1 and 4 which refer to the initial loading of the palladium
salt added to synthetic talc (see the Supporting Informa-
tion). Initially, we chose this support because it is insoluble
and stable in many organic solvents as well as easy and in-
expensive to synthesize.
We initially prepared the LACOB-Pd1 catalyst as de-
scribed in the experimental section. Next, we evaluated the
catalytic activity of the supported palladium catalyst. We
selected phenylboronic acid (1a) and iodobenzene (2a) as
starting materials in the standard reaction for optimizing
the reaction conditions (Table 1). Then, the effect of palladi-
um catalyst loading on the yield was assessed, as well as the
effect of the stoichiometric amount of phenylboronic acid,
solvent, and reaction time. First, the standard reaction was
carried out with 5% w/w (in relation to the theoretical
weight of the product) of catalyst in water due to our inter-
est in establishing a ‘greener’ procedure18 (entry 1), but this
afforded the product in only a moderate yield (67%). When
the same reaction was carried out in EtOH, the yield in-
creased (entry 2, 88% yield). As EtOH is also a ‘green’ sol-
vent, we chose this as the solvent for the subsequent reac-
tions. Aiming to improve the yield, we changed the amount
of phenylboronic acid; however, there was no improvement
in the yield when using a decreased amount of phenylbo-
ronic acid (entries 3 and 4) in comparison to that in entry 1.
Gratifyingly, when the stoichiometric amount was in-
creased to 2.0 equivalents, the Suzuki–Miyaura cross-cou-
pled product 3a was obtained in 97% yield (entry 5). We
also carried out a blank reaction (without catalyst) but did
Table 1 Optimization of the Reaction Conditions
B(OH)2
I
catalyst
+
solvent, base, time
3a
1a
2a
Entry Phenylboronic LACOB-Pd1 (% w/w)
acid (mmol)
Time Solvent Yielda
(h)
(%)
1
1.5
1.5
1.0
1.3
2.0
2.0
2.0
2.0
2.0
2.0
5.0
5.0
5.0
5.0
5.0
–
3
3
3
3
3
3
3
3
2
3
water
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
67
2
88
67
50
97
–
3
4
5
6
7
2.5
1.5
5.0
3.0
94
76
67
90
8
9
10
a Reaction conditions: iodobenzene (1.0 mmol), K2CO3 (1.0 mmol), solvent
(3 mL), 80 °C.
b Isolated (column chromatography) yields.
The characteristics of the synthesized catalyst were de-
termined by X-ray diffraction (XRD), scanning electron mi-
croscopy (SEM), and energy-dispersive spectroscopy (EDS)
analyses. As shown in Figure 2, all the reflection planes for
the modified materials (Figure 2a) changed compared with
the magnesium chloride salt (Figure 2b). Besides, two new
reflections appeared at 2θ = 40.32° and 46.44° for the palla-
dium catalyst, corresponding to the reflection planes (111)
and (200), which are characteristic of the face-centered cu-
bic (fcc) structure of Pd nanoparticles.19 These data indicate
that the Pd element exists in the form of Pd0 and not Pd2+.20
Based on the half-width of the (111) reflection, the average
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 933–942

935
B. F. dos Santos et al.
Paper
Synthesis
crystallite size (1.3 nm) of the synthesized Pd nanoparticles
was estimated through the Scherrer equation. The elemen-
tal composition of the palladium catalyst was also deter-
mined by EDS, which is shown in Figure 3a. The presence of
palladium is clearly indicated in the figure, along with other
elements including oxygen, nitrogen, and magnesium. Fur-
thermore, the morphology of the palladium catalyst was in-
vestigated by using SEM analysis (Figure 3b).
were obtained when electron-donating groups were pres-
ent on the phenylboronic acid (3b, 3g, 3l, 3m, and 3x). An
electronic effect for the iodoarene can also be observed (en-
tries 3a–3y), with iodoarenes bearing an electron-deficient
group affording high yields. Even when we carried out the
reaction by using an ortho-nitro, the electron-deficient
property has a greater influence than the stereo effect from
the nitro group in the ortho position (3x and 3z). Products
3f, 3g, 3h, and 3i, derived from disubstituted phenylboronic
acids, were obtained in moderate to excellent yields.
R'
B(OH)2
I
+
R
R'
R
1
2
3
Figure 2 (a) XRD patterns of the main components of the LACOB-Pd1
MeO
Me
catalyst; (b) XRD pattern of the magnesium chloride salt
3a
97%
3b
>99%
3c
83%
3d
63%
3e
83%
3f
67%
Cl
F
F3C
Me
3g
>99%
3h
77%
3i
Me
75%
MeO
Me
F
Me
Cl
OMe
OMe
NO2
3j
3k
3l
>99%
Me
MeO
MeO
NO2
no product
no product
NO2
NO2
3m
>99%
3n
89%
3o
77%
F3C
NO2
Cl
Me
F
NO2
NO2
Me
Me
Me
3p
83%
3q
92%
3r
Cl
F
83%
Me
Me
Me
3s
76%
3t
85%
3u
63%
MeO
Me
Me
Cl
NO2
NO2
3z
97%
MeO
F
F
3v
60%
3x
>99%
Me
N3
O
Me
Figure 3 (a) EDS analysis of the LACOB-Pd1 catalyst; (b) SEM analysis
of the LACOB-Pd1 catalyst
Me
3w
94%
3y
11%
Having established the optimized reaction conditions,
we performed the reaction with different boronic acids and
iodoarenes (Scheme 1). Regarding the phenylboronic acids,
the electronic nature of the functional groups, as expected,
has a great effect on the reaction (3a–3i). The best results
F
F
Me
Me
Scheme 1 Substrate scope for the Suzuki–Miyaura cross-coupling
reaction using LACOB-Pd1. Reagents and conditions: arylboronic acid
(2 mmol), iodoarene (1 mmol), LACOB-Pd1 (5% w/w), K2CO3 (1 mmol),
EtOH (3 mL), 80 °C, 3 h; isolated yields.
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 933–942

936
B. F. dos Santos et al.
Paper
Synthesis
Unexpected results were obtained for 3r and 3i (83%
and 75% yield, respectively) obtained from 2,3-disubstitut-
ed boronic acids. However, from the literature, we conclud-
ed that for these compounds there is an important stereo-
electronic effect, mainly from the ortho-substituted group,
in the transition state for the reductive elimination step,
which affords the best geometry for the orbital overlap.21
This is very clear when analyzing the similar compounds of
3r and 3i, in other words compounds 3p and 3f, respective-
ly. Both similar compounds 3p and 3f present disubstituted
groups like 3r and 3i, but now at positions 3 and 4. For com-
pound 3f, the yield decreased, which proves the role of the
stereoelectronic effect on the transition state. Additionally,
when we observe the yield for compound 3z which is ob-
tained from the 3,4-disubstituted boronic acid, but now us-
ing as a cross-coupling partner the ortho-substituted (nitro
group) iodoarene, it is clear that ortho-substitution posi-
tively affects the yields for this reaction. It is worth men-
tioning that 4-iodoacetophenone was also a suitable sub-
strate for this transformation, giving the desired product
3w in 94% yield. Additionally, product 3y was obtained in a
small amount when an azide group was present on the io-
dobenzene.
under similar conditions (Scheme 4). Specifically for this
precursor, the reaction was performed using 2-bromoben-
zonitrile, 4-formylphenylboronic acid pinacol ester, LACOB-
Pd4, and NMP as the solvent. It is worth mentioning that
here the reaction time was increased to 4 hours. The reason
for that is twofold: (a) the significant hindrance increasing
on the boronic group, now used as the pinacol instead of
hydroxide group, and (b) the leaving group at arene was
R'
B(OH)2
I
+
R
R'
R
1
2
3
MeO
Me
3a
90%
3b
>99%
3c
>99%
3d
93%
3e
>99%
3f
96%
Cl
F
F3C
Me
These results from the use of LACOB-Pd1 were a great
delight for us, but aiming to increase the yields, and having
the goal to produce the cross-coupling compounds from de-
activated iodoarenes (3j and 3k), we tried to enhance the
efficiency of the catalyst. In this sense, we assessed the cat-
alyst synthesized by using 0.4 g of palladium acetate, from
now on named as LACOB-Pd4. The results for the Suzuki–
Miyaura cross-coupling reaction using LACOB-Pd4 are pre-
sented in Scheme 2. To our delight, we observed that for al-
most all the reactions, even for deactivated iodoarenes,
there was a significant increase in the yields. Allied to this,
there was a deeply decreased reaction time.
Thus, with LACOB-Pd4 (synthesized by using an initial
fourfold increased palladium loading), the Suzuki–Miyaura
cross-coupling reaction time decreased sixfold compared
with the same reactions performed with LACOB-Pd1, which
we concluded relates to the increased palladium loading on
LACOB-Pd4. To verify this possibility, we performed EDS
and SEM analyses for LACOB-Pd4, which confirmed that
LACOB-Pd4 presents twice the palladium loading than
LACOB-Pd1 and a very high degree of morphological homo-
geneity (Figure 4).
It is important to note that nitrobiphenyls can be re-
duced to aminobiphenyl compounds which are key mole-
cules in organic chemistry. These amino compounds and
derivatives have been widely used in the chemical industry
and many examples have known antitumor activity
(Scheme 3).22
To demonstrate a direct application of LACOB-Pd4 in the
Suzuki–Miyaura cross-coupling reaction, we performed the
synthesis of an intermediate of angiotensin II inhibitors
3g
>99%
3h
>99%
3i
>99%
Me
MeO
Me
F
Me
Cl
OMe
OMe
NO2
3j
56%
3k
50%
3l
>99%
Me
MeO
MeO
NO2
NO2
NO2
3m
>99%
3n
>99%
3o
>99%
F3C
NO2
Cl
Me
F
NO2
NO2
Me
Me
Me
3p
>99%
3q
>99%
3r
>99%
Cl
F
Me
Me
Me
3s
>99%
3t
3u
75%
MeO
Me
Me
Cl
>99%
NO2
NO2
3z
>99%
N3
MeO
F
F
3v
3x
Me
O
Me
89%
>99%
Me
3w
3y
20%
F
F
>99%
Me
Me
Scheme 2 Substrate scope for the Suzuki–Miyaura cross-coupling
reaction using LACOB-Pd4. Reagents and conditions: arylboronic acid
(2 mmol), iodoarene (1 mmol), LACOB-Pd4 (5% w/w), K2CO3 (1 mmol),
EtOH (3 mL), 80 °C, 30 min; isolated yields.
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 933–942

937
B. F. dos Santos et al.
Paper
Synthesis
O
O
CN
CN
H
Br
H
10% w/w LACOB-Pd4
+
Me
Me
O
B
K2CO3 (0.5 mmol)
NMP (3 mL)
110 °C, 4 h
4
75%
O
0.5 mmol
0.5 mmol
Me
Me
Me Me
N N
HN
N
N
CO2H
Me
N N
O
OH
Cl
Valsartan
HN
N
N
O
N
CN
H
Losartan
Me
precursor
N N
HN
O
N
N
N
Irbesartan
Me
N
Me
N
O
OH
N
Me
N
Me
Telmisartan
Scheme 4 Precursor and angiotensin II inhibitors
as DMF, DCM, chloroform, and toluene. To recover and reuse
the used catalysts, the standard reaction was first per-
formed [1a (2.0 mmol), 2a (1.0 mmol), catalyst (5% w/w),
EtOH, 3 h or 30 min depending on the catalyst]. After the
initial run was finished, the catalyst was separated from the
reaction crude by centrifugation followed by washing with
distilled water, and left to dry in air for 24 hours. The cata-
lyst weight was then measured, which indicated that there
was no loss of the catalysts. Further, the catalysts were
Figure 4 (a) EDS analysis of the LACOB-Pd4 catalyst; (b) SEM analysis
of the LACOB-Pd4 catalyst
bromide, known to be a worse leaving group than iodine.
However, even with these structural modifications, the
drug precursor 4 was obtained in 75% yield.
Finally, we focused on the catalyst recycling process.
Notably, we realized that the immobilized palladium cata-
lysts are insoluble in EtOH and other organic solvents such
H
N
NH2
S
O
O
IC50 = 18 nM
F3C
NO2
NH2
reduction
antitumor activity
F3C
F3C
3n
IC50 = 1649 nM
F
H
N
NH2
S
O
O
IC50 = 5 nM
F3C
Scheme 3 Biologically active aminobiphenyl compounds
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 933–942

938
B. F. dos Santos et al.
Paper
Synthesis
reused in the subsequent reaction. This methodology was
performed five times. The results for catalyst recycling in
the Suzuki–Miyaura reaction demonstrated the possibility
of reusing the catalysts in up to five successive cycles, as
shown in Figure 5. Moreover, the high catalytic activity of
the recovered catalysts implies that the Pd nanoparticles
were not leached into the solvent during the reaction cy-
cles. To prove this statement, we performed a hot filtration
test. Firstly, a standard reaction of 1a with 2a was carried
out under the conditions described in Scheme 2. After 30
minutes, the LACOB-Pd4 catalyst was removed by filtration,
and then the starting materials 1a and 2a, as well as base,
were added again to the supernatant liquid. The reaction
mixture was heated at 80 °C for another 30 minutes and the
product was isolated by column chromatography. After all,
compound 3a was obtained in 96% yield indicating that the
second step coupling product was obtained in only a 6%
yield. These data testify that LACOB-Pd4 plays a crucial role
in the efficiency of the Suzuki–Miyaura reaction.
Table 2 Results Comparison of Compound 3a Synthesized Using
LACOB-Pd4 with Reported Catalysts
Entry
1 (this
Catalyst and conditions
Halide
I
Yield (%)
90
LACOB-Pd4 (5% w/w, 0.007 g), K2CO3,
EtOH, 30 min, 80 °C
work)
223a
Fe3O4@SiO2@SePh@Pd(0) (0.01
mol%), K2CO3, water, 2 h, 80 °C
I
I
I
I
90
90
90
91
323b
423c
523d
Pd NP/THH-CO2H@CoFe2O4 (0.08 g),
K2CO3, PEG, 45 min, 120 °C
Pd(0)–pDAB (0.14 mol%), K2CO3, tolu-
ene, 8 h, 90 °C
PANI-Pd (0.06 g), K2CO3, dioxane/wa-
ter, 4 h, 95 °C
oped here also tolerates a variety of groups in both counter-
partners for the Suzuki–Miyaura reaction. Thus, several bi-
aryl compounds were successfully synthesized in good to
excellent yields under mild reaction conditions and by us-
ing low catalyst loading in short reaction times, reaching 30
minutes for LACOB-Pd4. Further, this protocol presents an
eco-friendly approach that uses EtOH as the solvent in an
open-flask procedure. All those reaction parameters led us
to apply this protocol in the synthesis of a precursor to
drugs such as valsartan, losartan, irbesartan, and telmisar-
tan, affording high yield (75%). Even products obtained
from deactivated iodoarenes can be achieved by changing
the catalyst used in the process, which makes this protocol
highly applicable in organic synthesis. In terms of the reus-
ability of the catalysts, they can be easily recovered and re-
used without any significant loss of catalytic activity for at
least five cycles. Additionally, these data proved that the
catalysts are not leached during the recycling runs.
Figure 5 Reusability of the palladium catalysts in the Suzuki–Miyaura
reaction between phenylboronic acid (1a) and iodobenzene (2a) with
5% w/w catalyst for 3 hours or 30 minutes
All reactions were carried out using chemical reagents and solvents
without any specific treatment. The respective reactions were moni-
tored by TLC (MACHEREY-NAGEL, SIL G/UV254) and were visualized by
fluorescence quenching with UV light at 254 nm. Purification of com-
pounds was performed by column chromatography using hexane. 1H
and 13C NMR spectra were recorded in CDCl3 on Bruker 300 MHz or
500 MHz spectrometers. 1H NMR data are reported as follows: chemi-
cal shift (, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m =
multiplet), coupling constant(s) (J, Hz), integration. IR spectra were
recorded on a Jasco FT/IR 4100 type A spectrophotometer.
To compare the efficiency of our catalyst (LACOB-Pd4)
with some reported heterogeneous palladium catalysts in
the Suzuki–Miyaura reaction,23 we have tabulated the re-
sults of these catalysts for the synthesis of compound 3a. As
shown in Table 2, our catalyst is superior to some of the
previously reported catalysts in terms of reaction condi-
tions and reaction time. This comparison revealed that the
present protocol with LACOB-Pd4 presents better efficiency
in terms of catalytic loading used (7 mg) and regarding the
reaction time (30 min). Besides, the other advantage lies in
the support; in other words, synthetic talc is inexpensive,
stable, and easily prepared.
In summary, we have demonstrated new, efficient, and
recyclable immobilized palladium catalysts for the Suzuki–
Miyaura reaction based on a simple and inexpensive MgCl2
support. We have designed LACOB-Pd1 and LACOB-Pd4,
and both catalysts showed efficiency in the optimization
protocol developed in that study. The methodology devel-
MgCl2 Support
The MgCl2 support synthesis was performed by following the report
by Jasra and co-workers.24 MgCl2 (8.36 g) was dissolved in a beaker
containing MeOH (200 mL) and the solution was stirred at 25 °C for
10 min. In another beaker, APTES (9.8 g, 10.35 mL) was dissolved in
MeOH (50 mL). This solution was added dropwise to the MgCl2 solu-
tion, with the resulting mixture forming a white suspension. Then,
0.5 M NaOH solution was slowly added until the pH reached 10.5 un-
der stirring at 25 °C. The suspension obtained was aged for 1 week at
25 °C and the gel formed was centrifuged, washed with distilled wa-
ter, and dried at 65 °C.
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Synthesis
LACOB-Pd1 and LACOB-Pd4 Immobilized Catalysts
1H NMR (500 MHz, CDCl3):  = 7.70 (s, 4 H), 7.62–7.60 (dd, J1 = 8.1 Hz,
J2 = 1.0 Hz, 2 H), 7.50–7.47 (m, 2 H), 7.43–7.40 (m, 1 H).
13C NMR (125 MHz, CDCl3):  = 144.73, 139.76, 128.97, 128.17,
In a flask, the MgCl2 support (0.1 g) and KOH (0.1 g, dissolved in dis-
tilled water) were added to EtOH (5 mL) and stirred for 10 min at 25
°C. Next, salicylaldehyde (0.1 g, 94 L) was added and the mixture was
stirred at 25 °C for 2 h. Then, NaBH4 was added until the solution be-
came white and turbid. The reaction mixture was stirred overnight.
After this period, the white solid was centrifuged and washed with
distilled water. For the synthesis of the immobilized catalysts, the li-
gand was stirred with NaOH (0.1 g) in EtOH for 15 min. Then,
Pd(OAc)2 (0.1 g for LACOB-Pd1 or 0.4 g for LACOB-Pd4) was added,
and the mixture was stirred at 25 °C for 2 h. The black solid formed
was centrifuged and washed with chloroform.
127.41, 127.27, 125.70, 125.67.
4-Chloro-1,1′-biphenyl (3e)25
White solid; yield: 157 mg (83%) for LACOB-Pd1, 187 mg (>99%) for
LACOB-Pd4; mp 78 °C.
IR (KBr): 1477, 1398, 1097, 832, 757 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.57–7.51 (m, 4 H), 7.46–7.35 (m, 5 H).
13C NMR (125 MHz, CDCl3):  = 140.01, 139.68, 133.39, 128.92,
128.90, 128.40, 127.60, 127.00.
Suzuki–Miyaura Cross-Coupling Reaction; General Procedure
4-Fluoro-3-methyl-1,1′-biphenyl (3f)26
In a 5 mL round-bottom flask, the palladium catalyst (5% w/w, in rela-
tion to the theoretical weight of product), arylboronic acid (2 mmol),
iodoarene (1 mmol), and K2CO3 (1 mmol) were stirred in EtOH (3 mL)
at 80 °C (using an oil bath) for 3 h or 30 min. The progress of the reac-
tion was monitored by TLC (EtOAc/hexane, 10:90). After this time, the
solution was cooled to room temperature, diluted with EtOAc (20 mL),
and washed with water (3 × 20 mL). The organic phase was separated,
dried with Na2SO4, and concentrated under vacuum. The obtained
product was purified by column chromatography (hexane).
Colorless oil; yield: 125 mg (67%) for LACOB-Pd1, 179 mg (96%) for
LACOB-Pd4.
IR (KBr): 3031, 2924, 1511, 1484, 1232, 1119, 697 cm–1
1H NMR (300 MHz, CDCl3):  = 7.80–7.78 (d, J = 7.3 Hz, 2 H), 7.70–7.56
(m, 5 H), 7.35–7.29 (t, J = 8.9 Hz, 1 H), 2.60 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 162.92, 159.68, 140.71, 137.34, 137.28,
130.51, 130.45, 129.00, 127.37, 127.25, 126.26, 126.15, 125.37,
125.14, 115.63, 115.33, 14.96, 14.91.
.
1,1′-Biphenyl (3a)23a
4-Methoxy-3-methyl-1,1′-biphenyl (3g)27
White solid; yield: 149 mg (97%) for LACOB-Pd1, 139 mg (90%) for
LACOB-Pd4; mp 69 °C.
White solid; yield: 196 mg (>99%) for LACOB-Pd1, 196 mg (>99%) for
LACOB-Pd4; mp 74 °C.
IR (KBr): 3031, 1478, 1427, 729, 695 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.65–7.63 (m, 4 H), 7.50–7.47 (m, 4 H),
IR (KBr): 2971, 1604, 1511, 1240, 1133, 699 cm–1
.
7.41–7.37 (m, 2 H).
13C NMR (125 MHz, CDCl3):  = 141.21, 128.72, 127.22, 127.14.
1H NMR (300 MHz, CDCl3):  = 7.70–7.66 (m, 2 H), 7.55–7.50 (m, 4 H),
7.44–7.38 (m, 1 H), 7.00–6.97 (m, 1 H), 3.95 (s, 3 H), 2.43 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 157.70, 141.37, 133.64, 129.79, 129.00,
127.19, 127.07, 126.85, 125.71, 110.47, 55.66, 16.73.
4-Methoxy-1,1′-biphenyl (3b)23a
White solid; yield: 182 mg (>99%) for LACOB-Pd1, 182 mg (>99%) for
LACOB-Pd4; mp 92 °C.
3-Chloro-4-methyl-1,1′-biphenyl (3h)28
IR (KBr): 2961, 1606, 1522, 1488, 835, 759 cm–1
.
Colorless oil; yield: 156 mg (77%) for LACOB-Pd1, 201 mg (>99%) for
LACOB-Pd4.
1H NMR (500 MHz, CDCl3):  = 7.59–7.54 (ddt, J = 11.9, 5.2, 2.1 Hz, 4
H), 7.46–7.42 (m, 2 H), 7.34–7.31 (m, 1 H), 7.02–6.99 (m, 2 H), 3.87 (s,
3 H).
IR (KBr): 2923, 1553, 1480, 1052, 758, 695 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.64–7.57 (ddd, J = 8.2, 5.3, 2.0 Hz, 3 H),
7.50–7.30 (m, 5 H), 2.46 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 159.18, 140.86, 133.81, 128.75,
128.18, 126.77, 126.69, 114.23, 55.36.
13C NMR (75 MHz, CDCl3):  = 140.68, 140.00, 135.11, 135.00, 131.48,
129.10, 127.83, 127.80, 127.16, 125.49, 19.96.
4-Methyl-1,1′-biphenyl (3c)23a
3-Fluoro-2-methyl-1,1′-biphenyl (3i)29
White solid; yield: 139 mg (83%) for LACOB-Pd1, 167 mg (>99%) for
LACOB-Pd4; mp 43 °C.
Colorless oil; yield: 140 mg (75%) for LACOB-Pd1, 184 mg (>99%) for
LACOB-Pd4.
IR (KBr): 2915, 2855, 1485, 823, 754, 689 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.65–7.64 (dd, J = 5.0, 3.3 Hz, 2 H),
7.57–7.55 (m, 2 H), 7.50–7.47 (m, 2 H), 7.40–7.37 (dd, J = 8.2, 6.6 Hz, 1
H), 7.32–7.30 (d, J = 8.5 Hz, 2 H), 2.46 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 141.23, 138.43, 137.07, 129.55,
128.78, 127.06, 127.04, 21.16.
IR (KBr): 2927, 1575, 1464, 1238, 759 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.47–7.30 (m, 5 H), 7.24–7.17 (m, 1 H),
7.06–7.01 (dd, J = 11.8, 4.7 Hz, 2 H), 2.20–2.19 (d, J = 2.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 163.38, 160.15, 129.40, 128.37, 127.38,
126.72, 126.60, 125.52, 125.47, 114.12, 113.82, 12.38, 12.31.
4-(Trifluoromethyl)-1,1′-biphenyl (3d)25
4,4′-Dimethoxy-1,1′-biphenyl (3j)30
White solid; yield: 139 mg (63%) for LACOB-Pd1, 207 mg (93%) for
LACOB-Pd4; mp 70 °C.
White solid; yield: 120 mg (56%) for LACOB-Pd4, mp 178 °C.
1H NMR (500 MHz, CDCl3):  = 7.51–7.47 (m, 4 H), 7.00–6.95 (m, 4 H),
3.85 (s, 6 H).
IR (KBr): 2925, 1613, 842, 769 cm–1
.
13C NMR (125 MHz, CDCl3):  = 158.73, 133.52, 127.75, 114.19, 55.37.
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Synthesis
4-Methoxy-4′-nitro-1,1′-biphenyl (3l)27
3-Fluoro-2-methyl-4′-nitro-1,1′-biphenyl (3r)
Yellow solid; yield: 227 mg (>99%) for LACOB-Pd1, 227 mg (>99%) for
LACOB-Pd4; mp 124 °C.
Yellow solid; yield: 192 mg (83%) for LACOB-Pd1, 229 mg (>99%) for
LACOB-Pd4; mp 125 °C.
IR (KBr): 2928, 2835, 1596, 1509, 1343, 756 cm–1
.
IR (KBr): 3107, 2932, 1597, 1514, 1348, 792 cm–1
.
1H NMR (300 MHz, CDCl3):  = 8.29–8.24 (m, 2 H), 7.71–7.66 (m, 2 H),
7.61–7.56 (m, 2 H), 7.05–7.00 (m, 2 H), 3.88 (s, 3 H).
1H NMR (300 MHz, CDCl3):  = 8.32–8.27 (m, 2 H), 7.52–7.47 (m, 2 H),
7.29–7.22 (m, 1 H), 7.12–7.02 (m, 2 H), 2.18 (d, J = 2.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 160.66, 147.40, 146.74, 131.25, 128.77,
127.26, 124.34, 114.82, 55.63.
13C NMR (75 MHz, CDCl3):  = 163.40, 160.16, 147.56, 147.52, 147.32,
142.03, 141.97, 130.37, 127.29, 127.17, 125.21, 125.16, 123.71,
123.06, 122.83, 115.40, 115.09, 12.35, 12.28.
4-Methyl-4′-nitro-1,1′-biphenyl (3m)31
4-Methoxy-4′-methyl-1,1′-biphenyl (3s)27
Yellow solid; yield: 211 mg (>99%) for LACOB-Pd1, 211 mg (>99%) for
LACOB-Pd4; mp 170 °C.
IR (KBr): 3079, 2924, 1593, 1511, 1341, 1105, 823 cm–1
1H NMR (300 MHz, CDCl3):  = 8.30–8.26 (m, 2 H), 7.74–7.70 (m, 2 H),
7.55–7.52 (m, 2 H), 7.33–7.30 (m, 2 H), 2.43 (s, 3 H).
White solid; yield: 151 mg (76%) for LACOB-Pd1, 196 mg (>99%) for
LACOB-Pd4; mp 129 °C.
IR (KBr): 2913, 1607, 1498, 1250, 1038, 807 cm–1
.
.
1H NMR (300 MHz, CDCl3):  = 7.57–7.46 (m, 4 H), 7.27–7.24 (m, 2 H),
7.02–6.97 (m, 2 H), 3.87 (s, 3 H), 2.41 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 159.16, 138.19, 136.57, 133.97, 129.67,
13C NMR (75 MHz, CDCl3):  = 147.78, 147.05, 139.31, 136.04, 130.10,
127.67, 127.43, 124.30, 21.42.
128.18, 127.96, 126.81, 114.39, 55.56, 21.28.
4-Nitro-4′-(trifluoromethyl)-1,1′-biphenyl (3n)32
4,4′-Dimethyl-1,1′-biphenyl (3t)35
Yellow solid; yield: 238 mg (89%) for LACOB-Pd1, 265 mg (>99%) for
LACOB-Pd4; mp 140 °C.
IR (KBr): 3077, 1599, 1519, 1346, 1323, 1069, 829 cm–1
1H NMR (300 MHz, CDCl3):  = 8.35–8.32 (m, 2 H), 7.79–7.72 (m, 6 H).
13C NMR (75 MHz, CDCl3):  = 147.89, 146.23, 142.49, 128.34, 128.01,
White solid; yield: 155 mg (85%) for LACOB-Pd1, 180 mg (>99%) for
LACOB-Pd4; mp 148 °C.
IR (KBr): 3022, 2915, 1502, 804 cm–1
1H NMR (300 MHz, CDCl3):  = 7.60–7.56 (m, 4 H), 7.34–7.31 (dd, J =
8.4, 0.6 Hz, 4 H), 2.48 (s, 6 H).
.
.
126.40, 126.34, 126.29, 126.25, 124.47.
13C NMR (75 MHz, CDCl3):  = 138.58, 136.96, 129.73, 127.10, 21.37.
4-Chloro-4′-nitro-1,1′-biphenyl (3o)33
4-Chloro-4′-methyl-1,1′-biphenyl (3u)25
Yellow solid; yield: 180 mg (77%) for LACOB-Pd1, 231 mg (>99%) for
LACOB-Pd4; mp 174 °C.
IR (KBr): 3072, 1595, 1511, 1343, 815, 753 cm–1
1H NMR (300 MHz, CDCl3):  = 8.32–8.27 (m, 2 H), 7.73–7.68 (m, 2 H),
7.59–7.54 (m, 2 H), 7.49–7.45 (m, 2 H).
White solid; yield: 128 mg (63%) for LACOB-Pd1, 152 mg (75%) for
LACOB-Pd4; mp 152 °C.
IR (KBr): 3026, 2922, 1479, 1089, 808 cm–1
.
.
1H NMR (300 MHz, CDCl3):  = 7.55–7.39 (m, 6 H), 7.29–7.26 (m, 2 H),
2.42 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 147.46, 146.52, 137.39, 135.46, 129.58,
128.84, 127.88, 124.42.
13C NMR (75 MHz, CDCl3):  = 139.82, 137.66, 137.33, 133.25, 129.82,
129.07, 128.41, 127.04, 21.33.
4-Fluoro-3-methyl-4′-nitro-1,1′-biphenyl (3p)34
4-Fluoro-3,4′-dimethyl-1,1′-biphenyl (3v)36
Yellow solid; yield: 192 mg (83%) for LACOB-Pd1, 229 mg (>99%) for
LACOB-Pd4; mp 68 °C.
White solid; yield: 120 mg (60%) for LACOB-Pd1, 178 mg (89%) for
LACOB-Pd4; mp 38 °C.
IR (KBr): 3029, 2921, 1593, 1495, 1238, 808, 757 cm–1
IR (KBr): 2925, 1597, 1509, 1340, 1232, 753 cm–1
.
.
1H NMR (300 MHz, CDCl3):  = 8.30–8.25 (m, 2 H), 7.70–7.66 (m, 2 H),
7.46–7.38 (m, 2 H), 7.15–7.09 (m, 1 H), 2.36 (d, J = 1.7 Hz, 3 H).
1H NMR (300 MHz, CDCl3):  = 7.48–7.34 (m, 4 H), 7.28–7.24 (m, 2 H),
7.10–7.04 (m, 1 H), 2.42 (s, 3 H), 2.37–2.36 (m, 3 H).
13C NMR (75 MHz, CDCl3):  = 163.81, 160.52, 147.16, 147.01, 134.83,
134.78, 130.82, 130.74, 127.79, 126.66, 126.56, 126.11, 125.87,
124.32, 116.13, 115.82, 14.93, 14.88.
13C NMR (75 MHz, CDCl3):  = 162.73, 159.49, 137.82, 137.23, 137.19,
137.09, 130.27, 130.21, 129.70, 127.05, 126.02, 125.91, 125.26,
125.03, 115.54, 115.25, 21.29, 14.94, 14.90.
3-Chloro-4-methyl-4′-nitro-1,1′-biphenyl (3q)
1-(4′-Fluoro-3′-methyl-[1,1′-biphenyl]-4-yl)ethanone (3w)37
Yellow solid; yield: 228 mg (92%) for LACOB-Pd1, 245 mg (>99%) for
LACOB-Pd4; mp 109 °C.
IR (KBr): 3079, 2922, 1599, 1509, 1340, 828, 753 cm–1
1H NMR (300 MHz, CDCl3):  = 8.31–8.26 (m, 2 H), 7.72–7.67 (m, 2 H),
7.61–7.60 (d, J = 1.9 Hz, 1 H), 7.44–7.33 (m, 2 H), 2.44 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 147.41, 146.27, 138.06, 137.15, 135.43,
White solid; yield: 215 mg (94%) for LACOB-Pd1, 226 mg (>99%) for
LACOB-Pd4; mp 87 °C.
.
IR (KBr): 2924, 1681, 1600, 1491, 1267, 1235, 815 cm–1
.
1H NMR (300 MHz, CDCl3):  = 8.04–8.00 (m, 2 H), 7.65–7.61 (m, 2 H),
7.46–7.38 (dtdd, J = 4.8, 2.9, 2.4, 0.5 Hz, 2 H), 7.12–7.06 (m, 1 H), 2.64
(s, 3 H), 2.36–2.35 (d, J = 1.9 Hz, 3 H).
131.84, 128.01, 127.77, 125.66, 124.39, 20.07.
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 933–942

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Synthesis
13C NMR (75 MHz, CDCl3):  = 197.90, 163.43, 160.15, 145.17, 135.92,
130.64, 130.57, 129.13, 127.23, 126.45, 126.34, 125.73, 125.50,
115.87, 115.57, 26.85, 14.93, 14.88.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1705989.
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o
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4′-Methoxy-2-nitro-1,1′-biphenyl (3x)38
Yellow solid; yield: 227 mg (>99%) for LACOB-Pd1, 227 mg (>99%) for
LACOB-Pd4; mp 59 °C.
References
IR (KBr): 3019, 2927, 1610, 1516, 1357, 1177, 751 cm–1
.
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1H NMR (300 MHz, CDCl3):  = 7.82–7.79 (m, 1 H), 7.62–7.56 (m, 1 H),
7.47–7.42 (tt, J = 7.1, 1.5 Hz, 2 H), 7.29–7.24 (m, 2 H), 6.99–6.94 (m, 2
H), 3.85 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 159.91, 149.62, 136.06, 132.37, 132.14,
129.70, 129.34, 127.95, 124.21, 114.44, 55.52.
4′-Azido-4-fluoro-3-methyl-1,1′-biphenyl (3y)
Brown solid; yield: 25 mg (11%) for LACOB-Pd1, 45 mg (20%) for
LACOB-Pd4.
(5) Stanforth, S. P. Tetrahedron 1998, 54, 263.
1H NMR (300 MHz, CDCl3):  = 7.55–7.50 (m, 2 H), 7.38–7.30 (ddd, J =
7.2, 6.7, 2.2 Hz, 2 H), 7.11–7.04 (m, 3 H), 2.35–2.34 (d, J = 1.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 162.90, 159.64, 139.22, 137.46, 136.23,
136.18, 130.20, 130.12, 128.49, 125.95, 125.85, 125.51, 125.28,
119.59, 115.71, 115.41, 14.93, 14.88.
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Adv. 2018, 8, 17176.
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ChemistrySelect 2018, 3, 535. (b) Zim, D.; Gruber, A. S.; Ebeling,
G.; Dupont, J.; Monteiro, A. L. Org. Lett. 2000, 2, 2881.
(10) (a) Leadbeater, N. E.; Marco, M. Chem. Rev. 2002, 102, 3217.
(b) Yin, L.; Liebscher, J. Chem. Rev. 2007, 107, 133.
(11) (a) Diallo, A. K.; Ornelas, C.; Salmon, L.; Aranzaes, J. R.; Astruc, D.
Angew. Chem. Int. Ed. 2007, 46, 8644. (b) Herrmann, W. A.; Öfele,
K.; Schneider, S. K.; Herdtweck, E.; Hoffmann, S. D. Angew.
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4′-Fluoro-3′-methyl-2-nitro-1,1′-biphenyl (3z)
Yellow solid; yield: 224 mg (97%) for LACOB-Pd1, 229 mg (>99%) for
LACOB-Pd4; mp 54 °C.
IR (KBr): 3070, 2926, 1604, 1572, 1519, 1357, 1227, 1122, 896, 851
cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.86–7.83 (dd, J = 8.1, 1.0 Hz, 1 H),
7.64–7.58 (td, J = 7.6, 1.3 Hz, 1 H), 7.51–7.40 (m, 2 H), 7.17–7.02 (m, 3
H), 2.32–2.31 (d, J = 1.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 163.19, 159.93, 149.49, 135.70, 133.34,
133.28, 132.50, 132.16, 131.28, 131.21, 128.42, 127.20, 127.09,
125.67, 125.43, 124.29, 115.69, 115.39, 14.82, 14.77.
4′-Formyl-[1,1′-biphenyl]-2-carbonitrile (4)39
Light yellow solid; yield: 78 mg (75%) for LACOB-Pd4; mp 181 °C.
1H NMR (300 MHz, CDCl3):  = 10.10 (s, 1 H), 8.03–8.01 (m, 2 H), 7.83–
7.80 (d, J = 8.2 Hz, 1 H), 7.78–7.68 (ddd, J = 8.5, 5.9, 1.4 Hz, 3 H), 7.57–
7.50 (ddd, J = 13.0, 6.5, 2.7 Hz, 2 H).
(13) Liang, L.; Nie, L.; Jiang, M.; Bie, F.; Shao, L.; Qi, C.; Zhang, X. M.;
Liu, X. New J. Chem. 2018, 42, 11023.
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2012, 68, 3577.
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N.L.C.D. thanks Fundação de Apoio ao Desenvolvimento do Ensino,
Ciência e Tecnologia do Estado de Mato Grosso do Sul (FUNDECT/Brazil -
Chamada FUNDECT/CNPq Nº 15/2014 - PRONEM - MS) and Conselho
Nacional de Desenvolvimento Científico e Tecnológico (Chamada
CNPq Nº 12/2017 - Bolsas de Produtividade em Pesquisa - PQ) for fi-
nancial support and a fellowship. Furthermore, B.F.S. thanks Coorde-
nação de Aperfeiçoamento de Pessoal de Nível Superior
(CAPES/Brazil) for her scholarship.
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