SiliaCat diphenylphosphine palladium(II) catalyzed borylation of aryl halides

Article abstract of DOI:10.1002/cctc.201301035

We investigate the heterogeneously catalyzed direct synthesis of boronic acid pinacol esters using a wide range of aryl chlorides, bromides, and iodides, and bis(pinacolato)diboron as the borylating agent over the sol-gel entrapped SiliaCat diphenylphosphine palladium(II) catalyst. Optimization of the reaction conditions, scale-up of the optimized process, and analysis of palladium leaching enabled us to establish a new selective route for direct access to a diverse set of boronic acid pinacol esters. Clean borylation for scale-up: With the easy access and broad availability of diverse borylated species, the Suzuki-Miyaura reaction has become routine in industry and in research labs. We report a new selective route for direct access to a diverse set of boronic acid pinacol esters over the sol-gel entrapped SiliaCat diphenylphosphine palladium(II) catalyst that can be easily scaled-up.

Full text of DOI:10.1002/cctc.201301035

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DOI: 10.1002/cctc.201301035
SiliaCat Diphenylphosphine Palladium(II) Catalyzed
Borylation of Aryl Halides
Valerica Pandarus,[a] Olivier Marion,[a] Geneviꢀve Gingras,[a] FranÅois Bꢁland,*[a]
Rosaria Ciriminna,[b] and Mario Pagliaro*[b]
We investigate the heterogeneously catalyzed direct synthesis
of boronic acid pinacol esters using a wide range of aryl chlor-
ides, bromides, and iodides, and bis(pinacolato)diboron as the
borylating agent over the sol–gel entrapped SiliaCat diphenyl-
phosphine palladium(II) catalyst. Optimization of the reaction
conditions, scale-up of the optimized process, and analysis of
palladium leaching enabled us to establish a new selective
route for direct access to a diverse set of boronic acid pinacol
esters.
Introduction
The Suzuki–Miyaura reaction[1] is perhaps the single most im-
portant cross-coupling synthetic methodology to prepare di-
verse biaryls and heterobiaryls, ubiquitous motifs in pharma-
ceuticals, natural products, and organic chemistry needed in
many industrial sectors.[2] The palladium-catalyzed Suzuki–
Miyaura cross-coupling involves a boron-containing nucleo-
metallic compounds that are easily turned into boronic
esters.[6]
In 1995, Miyaura pioneered the palladium-catalyzed boryla-
tion of aryl halides.[7] The report described the first synthesis of
numerous aryl- and heteroaryl boron derivatives bearing sensi-
tive functional groups through cross-coupling of bis(pinacola-
phile (a variety of aryl and heteroarylboronic acids, esters, ArÀ to)diboron (B2Pin2) with aryl halides or vinyl halides, without
BBN, trifluoroborates, as well as other boron species) and vinyl
or aryl halides (the electrophilic species). Besides crucial high
functional-group tolerance, its significant benefits include high
efficiency, low toxicity, mild reaction conditions, as well the rel-
ative stability of boronic acid to heat, oxygen, and water, as
well as ease of handling and separation of boron-containing
byproducts.[2]
the use of toxic organometallic reagents. With easy and great-
er access to diverse borylated species, the use of the Suzuki–
Miyaura reaction became routine both in industry and in re-
search laboratories.[8] Borylated pinacol esters derived from
B2Pin2, for example are suitable synthetic coupling partners in
cross-coupling reactions because they survive the normal
product work-up procedures including chromatographic purifi-
cation, and are stable towards oxidation by oxygen in air.[9]
Since then, considerable attention has been devoted to cata-
lytic borylation. Beyond Pd, new Cu,[10] Rh,[11] Ni,[12] and Ir[13] cat-
alysts have been identified.
The typical preparation of arylboronic acids or esters used in
the Suzuki–Miyaura coupling involves the reaction between an
organoborate and alkyl- or aryllithium compounds or Grignard
reagents.[3] However, the method is difficult to apply to aryl
chlorides or to substrates bearing functional groups that are
not compatible with organolithium reagents.[4] Also, some aryl-
lithium intermediates are intrinsically unstable, as in the case
of many aromatic heterocycles.[5]
The most versatile catalyst systems reported to date employ
(dicyclohexylphosphino) biphenyl-type ligands such as SPhos
and XPhos.[14] The use of Pd0 complexes coordinated to these
ligands allows the borylation of sterically or electronically chal-
lenging aryl chlorides (2 mol% Pd/SPhos, room temperature,
86%) and 4-chloroanisole (0.1 mol% Pd/XPhos, 1108C, 94%).
Another efficient and selective catalyst suitable for the cross-
coupling of pinacolborane with aryl bromides enabling the
synthesis of ortho-, meta-, and para-substituted electron-rich
and electron-deficient arylboronates results from the combina-
tion of bis(dibenzylideneacetone)palladium (Pd(dba)2) and
bis(2-di-tert-butylphosphinophenyl)ether.[15]
The use of boronic esters in place of boronic acids in the
Suzuki–Miyaura coupling is desirable if reactive functional
groups are present in the electrophilic aryl halides. One effec-
tive methodology to prepare highly functionalized boronic
esters makes use of the magnesiation of iodoaryl and iodohe-
teroaryl boronic esters with iPrMgCl·LiCl leading to mixed bi-
All the above reactions are homogeneously performed in
the presence of Pd species in solution. Intense research at-
tempts are devoted to efficiently heterogenize the palladium
catalytic species,[16] with the aim to obtain selective and reusa-
ble solid cross-coupling catalysts avoiding product contamina-
tion associated with the use of expensive and nonreusable ho-
[a] V. Pandarus, O. Marion, G. Gingras, Dr. F. Bꢀland
SiliCycle Inc.
2500, Parc-Technologique Blvd, Quꢀbec, Quꢀbec, G1P 4S6 (Canada)
E-mail: FrancoisBeland@silicycle.com
[b] R. Ciriminna, Dr. M. Pagliaro
Istituto per lo Studio dei Materiali Nanostrutturati, CNR
via U. La Malfa 153, 90146 Palermo (Italy)
E-mail: mario.pagliaro@cnr.it
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mogeneous Pd catalysts, and their undesired tendency to
remain in the final products.
amount of dimer (36–60% yield). Milder KOAc base was unex-
pectedly the best basic species. Best results in terms of conver-
sion (the yield of the product) and selectivity were obtained by
performing the reaction in alcohol (iPrOH, nBuOH, 2-BuOH)
and alcohol mixtures such as nPrOH/MeOH.
In this work, we report the successful heterogeneous palladi-
um-catalyzed coupling reaction of B2Pin2 and aryl iodide, bro-
mide, and chloride over SiliaCat diphenylphosphine palladi-
um(II) (DPP–Pd) [Eq. (1)].
For example, entry 1 in Table 1 demonstrates that with
DMSO as the solvent, 88% conversion and 83% se-
lectivity were obtained in 16 h by using 1.5 equiva-
lents of B2Pin2 and 3 equivalents of KOAc. The con-
version in nPrOH/MeOH (v/v=3/1) was instead com-
plete in 2 h reaction time in 80% selectivity (entry 2).
Further attempts to increase selectivity in arylboronic
esters and reducing formation of the dimer below
20% by varying different reaction parameters were
unsuccessful (entries 3–9).
SiliaCat DPP–Pd (Figure 1) is an organosilica matrix function-
alized with diphenylphosphine ligand bound to Pd2+ with
a typical palladium loading of 0.2–0.3 mmolgÀ1, high surface
area (300–650 m2 gÀ1), and large accessible mesoporosity.[17] Ac-
cordingly, this sol–gel catalyst is highly active in CÀC coupling
reactions.[18]
Table 1. SiliaCat DPP–Pd catalyzed coupling reaction of B2Pin2 and 4-bro-
mobenzonitrile in DMSO and in nPrOH/MeOH.[a]
Entry
B2Pin2
Base
Solvent
t
Conv. (Select.)[b]
[%]
[equiv.]
[equiv.]
[h]
1
2
3
1.50
1.50
1.25
KOAc (3)
KOAc (3)
KOAc (3)
DMSO
n-PrOH/MeOH
n-PrOH/MeOH
16
2
0.5
1
2
0.5
1
1
1
1
88 (83)
100 (80)
81 (83)
88 (83)
93 (84)
88 (75)
100 (71)
100 (78)
96.5 (72)
86 (45)
84 (72)
90 (69)
78 (79)
86 (78)
4
1.10
KOAc (3)
n-PrOH/MeOH
5
6
7
8
1.05
1.00
0.75
1.05
KOAc (3)
KOAc (3)
KOAc (3)
KOAc (2)
n-PrOH/MeOH
n-PrOH/MeOH
n-PrOH/MeOH
n-PrOH/MeOH
Figure 1. Chemical structure of A) commercially available SiliaCat DPP–Pd
and B) the heterogenized diphenylphosphine ligand in SiliaCat DPP.
1
2
1
2
9
1.00
KOAc (2)
n-PrOH/MeOH
The reaction is heterogeneous in nature. There is no induc-
tion period, and no further conversion is observed in the reac-
tion filtrate obtained after filtering the catalyst at 50% sub-
strate conversion. We have recently discussed how to distin-
guish between homogeneous and heterogeneous palladium-
catalyzed cross-coupling reactions,[16] almost concomitantly to
Crabtree who published a similar study[19] of broader scope,
addressing this central issue of modern research in catalysis,
which is of great important in practical catalyst development
and the object of the present study.
[a] Experimental conditions: Substrate (5 mmol, 1 equiv.), B2Pin2 (from 1.0
to 1.5 equiv.), KOAc (from
2 to 3 equiv.), nPrOH/MeOH HPLC grade
(20 mL, 3/1 v/v), SiliaCat DPP–Pd (0.5 mol%, Pd loading 0.25 mmolgÀ1),
808C. [b] Conversion/selectivity evaluated by GC–MS.
Results in Table 2, however, demonstrate that with the anhy-
drous iPrOH used as solvent, the selectivity increases to more
than 90%. Complete conversions with 99% (entry 5) or 98%
(entry 6) selectivity were obtained in 1 h over 1 mol% of the
SiliaCat DPP–Pd catalyst by using 1 equivalent of B2Pin2 in the
presence of 2 equivalents of KOAc in 0.5m and 0.75m solvent
with respect to the reagents.
Following optimization of the reaction conditions, we inves-
tigate the scale-up of the process along with stability and reus-
ability of the solid catalyst in several consecutive reaction runs.
The catalyst is truly broad in scope and can be conveniently
used in air without the need to exclude oxygen. The limited
leaching in valued Pd and the excellent mechanical properties
of organosilica make the case for practical application.
The amount of catalyst was then decreased from 1 to
0.25 mol%. If 0.5 mol% catalyst was used, the complete con-
version required 2 h (entry 8), whereas over 0.25 mol% catalyst
a maximum 85% conversion was obtained in 4 h (entry 9).
The solvent also plays an important role. The reaction is gen-
erally accelerated in polar solvents (DMSOꢀDMF>dioxane>
toluene). However, in the seminal 1995 report, Miyaura per-
formed the borylation in dioxane (the exact solvent), and tolu-
ene is generally the best solvent for nickel-catalyzed boryla-
tion. In Table 3 it is shown that for different solvents (EtOH,
nBuOH, 2-BuOH, DMF, DMSO), complete conversion was in
Results and Discussion
The reaction conditions were optimized by using 4-bromoben-
zonitrile as a substrate. Stronger bases, such as K3PO4 or K2CO3,
promoted further reactions of the arylboronic esters formed
with the haloarenes resulting in contamination by a substantial
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KOAc were used (entry 4). Over-
all, entry 5 in Table 4 reveals that
the complete conversion of 4-
bromoanisole in 97% selectivity
(and 95% isolated yield) was ob-
tained (method B) if 1.1 equiva-
lents of B2Pin2 were reacted with
the substrate over 2 mol% cata-
lyst in the presence of 2.2 equiv-
alents of KOAc in 0.75m iPrOH
alcohol with respect to substrate
and B2Pin2.
Table 2. SiliaCat DPP–Pd catalyzed coupling reaction of B2Pin2 and 4-bromobenzonitrile in anhydrous iPrOH
(method A).[a]
[d]
Entry B2Pin2
Catalyst Base
Solvent
[m][b]
t
Conv. (Select.)[c] Yield[c] Leaching [mgkgÀ1
]
[equiv.] [mol%] [equiv.]
[h] [%]
[%]
Pd
Si
1
2
3
4
5
6
7
8
1.25
1.1
1
1
1
1
1
1
1
1
1
1
1
1
1
0.5
KOAc (3)
KOAc (3)
KOAc (3)
iPrOH (0.56)
iPrOH (0.52)
iPrOH (0.50)
1
1
1
1
1
1
1
1
2
1
2
4
100 (90)
80
88
92
94
97
96
93
–
<0.50
<0.50
0.50
<0.50
1.57
0.68
<0.50
<0.50
1.40
0.96
0.89
0.98
1.12
1.20
0.56
0.30
100 (94)
100 (95)
100 (97)
100 (99)
100 (98)
100 (94)
94
100 (89)
59
63
KOAc (2.5) iPrOH (0.50)
KOAc (2)
KOAc (2)
KOAc (2)
KOAc (2)
iPrOH (0.50)
iPrOH (0.75)
iPrOH (1.00)
iPrOH (0.50)
Further attempts to decrease
the amount of the catalyst by
using anhydrous iPrOH as sol-
vent revealed that the conver-
sion obtained in 3 h decreased
to 96% over 1.5 mol% (Table 4,
entry 6) and to 93% (entry 7)
over 1 mol% Pd catalyst (with
0.75m solvent). Conversion,
however, rose again to 96% by
using a more concentrated 1m
solution (entry 8).
9
1
0.25
KOAc (2)
iPrOH (0.50)
–
2.50
1.46
85 (96)
[a] Experimental conditions: Substrate (5 mmol, 1 equiv.), B2Pin2 (from 1.25 to 1 equiv.), KOAc (from 3 to
2 equiv.), anhydrous iPrOH (from 0.5 to 1.0m, molar concentration with respect to the reagents), SiliaCat DPP–
Pd (from 0.25 to 1 mol%, Pd loading 0.25 mmolgÀ1), 828C. [b] Molar concentration with respect to the re-
agents. [c] Conversion/selectivity evaluated by GC–MS. Isolated yield. [d] The leaching in Pd and Si was as-
sessed by ICP–OES analysis of the isolated crude product in DMF solvent (concentration 100 mgmLÀ1) and re-
ported as mgkgÀ1 API. LODPd =0.05 ppm in solution (100 mgmLÀ1 concentration) or 0.50 mgkgÀ1 in the crude
product; LODSi =0.02 ppm in solution (100 mgmLÀ1 concentration) or 0.20 mgkgÀ1 in the crude product.
Heating should improve the conversion, so iPrOH was re-
placed by an alcohol solvent with a higher boiling point (2-
BuOH) and the reaction mixture was heated from 828C to
928C. Under these harsher conditions, complete conversion
over 1 mol% Pd catalyst was obtained in 3 h (Table 4, entry 9),
and good 96% conversion could also be reached in 5 h over
0.5 mol% Pd (entry 10). If the amount of the catalyst was fur-
ther decreased to 0.25 mol%, the complete conversion re-
quired 16 h reaction time (entry 11).
Table 3. SiliaCat DPP–Pd catalyzed coupling reaction of B2Pin2 and 4-bro-
mobenzonitrile over 1 mol% SiliaCat DPP–Pd in different solvents
(method A).[a]
Entry
Solvent
t
[h]
Conv. (Select.)[b]
[%]
1[b]
2
3
4
5
6
7
8
EtOH anh.
n-PrOH HPLC
anhydrous n-PrOH
iPrOH HPLC
anhydrous iPrOH
nBuOH HPLC
1
1
1
1
1
1
1
1
2
1
1
2
100 (82)
97 (63)
99 (90)
100 (80)
100 (99)
96 (62)
100 (85)
94
anhydrous 2-BuOH
anhydrous DMF
Scale-up and stirring effects
100 (85)
100 (84)
69
9
10
anhydrous DMF/iPrOH
anhydrous DMSO
In Table 5 the results of the borylation reaction of 4-bromoani-
sole over 2 mol% SiliaCat DPP–Pd are shown on scaling-up the
reaction from 10 mmol to 200 mmol substrate. Leaching
values in terms of mgkgÀ1 of both Si and Pd in the product
[active pharmaceutical ingredients (APIs)] are included. In gen-
eral, two methods (A and B) are used for the results in
Tables 5–7. Method A (Table 2, entry 5) was used for substrates
bearing electron-withdrawing groups (ÀNO2 or ÀCN); whereas
method B (Table 4, entry 5) was applied to the conversion of
substrates containing electron-donating groups (ÀOCH3, ÀCH3,
ÀOH in ortho, meta, and para positions), and to the heteroa-
tom substrates.
71 (84)
[a] Experimental conditions: Substrate (5 mmol, 1 equiv.), B2Pin2 (1 equiv.),
KOAc (2 equiv.), solvent (20 mL; 0.5m, molar concentration with respect
to the reagents), SiliaCat DPP–Pd (0.2 g, Pd loading 0.25 mmolgÀ1), 1 h at
828C. [b] Conversion/selectivity evaluated by GC–MS.
general obtained in 1 h or 2 h. The best selectivity was none-
theless obtained in anhydrous iPrOH (99%, Table 3, entry 5).
The conditions (method A) developed for 4-bromobenzoni-
trile borylation over 1 mol% SiliaCat DPP–Pd (Table 2, entry 5)
were then applied to 4-bromoanisole, namely to a bromoben-
zene derivative functionalized with an electron-withdrawing
group (Table 4, entry 1).
Early kinetic data (Table 5, entries 1–3) reveal that there is no
induction period. More than 70% of 4-bromoanisole was con-
verted in the borylation product within the first 30 min of reac-
tion and nearly all (98–99%) substrate was converted in
90 min, except for the reaction with 10 mmol substrate in
which the complete conversion required approximately 3 h
(entry 1). Thus, the reaction rate increased by scaling up the
conversion (Figure 2).
Now, only 66% conversion could be obtained in 2 h. Conver-
sion increased first to 75% if the catalyst amount was doubled
to 2 mol% (entry 2 in Table 4); and further increased to 80% if
the concentration of the reaction mixture was increased from
0.5 to 0.71m (entry 3), or if 10% higher amounts of B2Pin2 and
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In Figure 3 the kinetics of the reaction on 40 mmol
substrate scale is shown if magnetic stirring
(700 rpm) was replaced by mechanical stirring either
with a normal stirrer (blade PTFE 19 mm/76 mm,
width/length, for 10 mm shafts in a 500 mL three-
necks flask) or with an oval stirrer (blades in PTFE
19 mm/60 mm, width/length, for 10 mm shafts). Only
89% and 95% conversion degrees, respectively, were
achieved in 3 h.
Table 4. SiliaCat DPP–Pd catalyzed coupling reaction of B2Pin2 and 4-bromoanisole.
Optimization of the reaction conditions.[a]
Entry
1
B2Pin2
[equiv.]
Catalyst
[mol%]
KOAc
[equiv.]
Solvents[b]
[m]
t
[h]
Conv. (Select)[c]
[%]
1
1
2
iPrOH
(0.50)
1
2
3
1
3
1
3
1
3
1
2
3
1
3
1
3
1
3
1
2
3
1
3
5
1
5
16
60
66
71 (92)
75
90 (94)
80
95 (96)
85
95 (99)
84
94
100 (97)
81
96 (94)
75
93 (96)
81
96 (97)
85
95
100 (95)
75
83
96 (98)
54
76
2
3
4
5
1
2
2
2
2
2
iPrOH
(0.50)
iPrOH
(0.71)
iPrOH
(0.50)
iPrOH
(0.75)
1
2
The plot in Figure 3 also reveal that complete con-
version in 90 min requires the use of a perforated
banana-type stirrer (blades in PTFE 21 mm/87 mm,
width/length, for 10 mm shafts). Stirring at 600 rpm
rate was enough to ensure complete conversion of
the entire substrate in 1.5 h.
1.1
1.1
2.2
2.2
6
7
8
9
1.1
1.1
1.1
1.1
1.5
1
2.2
2.2
2.2
2.2
iPrOH
(0.75)
iPrOH
(0.75)
iPrOH
(1.00)
2-BuOH
(1.00)
The efficiency of the latter perforated banana-type
stirrer is further shown in Figure 4. Under 40 mmol
scale, complete conversion in 98% selectivity in
90 min requires either 700 rpm magnetic stirring
(Table 5, entry 3) or 600 rpm mechanical stirring
(entry 4). The use of perforated banana-type stirrer in
the scaled-up conversion of 200 mmol substrate in
a 1000 mL three-necks flask (50 g borylation product
synthesis) enables full conversion at 550 rpm
(entry 5).
1
1
10
11
1.1
1.1
0.5
2.2
2.2
2-BuOH
(1.00)
0.25
2-BuOH
(1.00)
The results in Table 5 show that the values of palla-
dium leached in the isolated crude product were
<10 mgkgÀ1, and that the values of leached Si were
<10 mgkgÀ1 even after the conversion of 200 mmol
starting product.
100 (94)
[a] Experimental conditions: Substrate (from 5 to 10 mmol, 1 equiv.), B2Pin2 (from 1 to
1.1 equiv.), KOAc (from 2 to 2.2 equiv.), anhydrous 2-PrOH from 0.5 to 1.0m, SiliaCat
DPP–Pd (from 1 to 2 mol% Pd, Pd loading 0.25 mmolgÀ1), at 828C. [b] Molar concen-
tration with respect to the reagents. [c] Conversion/selectivity evaluated by GC–MS.
Scope of the heterogeneous reaction
To explore the scope of the SiliaCat DPP–Pd hetero-
geneously catalyzed reaction we extended its appli-
cation to various aryl bromides, chlorides, and io-
dides carrying electron-withdrawing or electron-do-
nating groups, and to heteroatom substrates such as
pyridine, indole, and quinoline.
Table 5. SiliaCat DPP–Pd catalyzed coupling reaction of B2Pin2 and 4-Bromoanisole in
iPrOH (method B). Scale-up to 200 mmol starting product.[a]
Entry Substrate
t
Conv. (Select.)[d] Yield[d] Leaching[e] [mgkgÀ1 API]
[mmol]/[equiv.] [h] [%]
[%]
Pd
Si
1[b]
2[b]
3[b]
4[c]
5[c]
10/1
20/1
0.5 77
95
5.45
2.65
The results obtained with bromide substrates by
using method A (for substrates bearing electron-with-
drawing groups) or method B (for substrates contain-
ing electron-donating groups and heteroatoms) are
listed in Table 6. In general, borylation proceeded in
good to excellent yields, achieving the desired bor-
onic ester in 3 h. Only the indole derivative (entry 11)
required 20 h to afford maximum 80% conversion
(with 81% selectivity).
2
3
92
100 (97)
0.5 77
1.5 98
97
8.12
8.84
8.17
8.22
5.78
5.25
5.84
4.89
2
100 (98)
40/1
0.5 77
1.5 99
97.2
97.5
97
2
100 (98)
40/1
0.5 78
1.5 98
2
100 (98)
200/1
0.5 79
1.5 99
The results in Table 7 reveal that different aryl chlo-
ride substrates bearing electron-withdrawing groups
or electron-donating groups can be coupled with
B2Pin2 to selectively form boronate esters in the pres-
ence of SiliaCat DPP–Pd under the conditions of
method B (Table 4, entry 5).
2
100 (98)
[a] Experimental conditions: Method B: Substrate (from 10 to 200 mmol, 1 equiv.),
B2Pin2 (1.1 equiv.), KOAc (2.2 equiv.), iPrOH (0.75m, molar concentration with respect
to substrate and to B2Pin2, over SiliaCat DPP–Pd (2 mol%), 828C. [b] Magnetic stirring
(700 rpm). [c] Mechanical stirring (550–600 rpm). [d] Conversion/selectivity evaluated
by GC–MS. Isolated yield. [e] The leaching in Pd and Si was assessed by ICP–OES anal-
ysis of the isolated crude product in DMF solvent (concentration 100 mgmLÀ1) and re-
ported as mgkgÀ1 API.
Complete conversions in high yield were obtained
for 4-chloracetophenone in 0.5 h (Table 7, entry 2)
and for 4-chlorotoluene in 2 h (entry 3). Coupling of
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ever, revealed the opposite:
namely 4-iodoanisole was less
reactive than 4-bromoanisole
and 4-chloroanisole (Table 8). In
detail, the 4-iodoanisole boryla-
tion catalyzed by SiliaCat DPP–
Pd, according to both method A
and method B afforded 47%
(Table 8, entry 1) and 74%
(entry 2) conversion, respectively,
in 3 h reaction time. This finding
is in contrast to what is normally
obtained in the Suzuki–Miyaura
conversion of aryl halides, and
points to a likely hindering effect
of the matrix mesoporosity in
the presence of the larger I con-
taining substrates.
Table 6. SiliaCat DPP–Pd catalyzed coupling reaction of B2Pin2 and different aryl bromide substrates.[a]
Entry Substrate
Method Product
t
Conv. (Select.)[b] Yield[c]
[h] [%]
[%]
1
2
A
A
1
1
100 (97)
93.5
100 (99)
94
–
1
2
51
74 (81)
3
4
A
B
1
2
77
99 (87)
86[d]
1
2
3
84
94
100 (97)
5
6
B
B
95
98
To increase the conversion to
more than 80%, 1.5 equivalents
of B2Pin2 and 3 equivalents of
KOAc were needed (Table 8,
entry 3, method C), with excel-
lent conversion and selectivity
obtained also for 3-iodoanisole
(entry 4).
2
3
90
100 (99)
7
B
1
100 (98)
96
1
2
95
100 (98)
8
9
B
B
96
96
Leaching and catalyst stability
2
3
89
100 (98)
To investigate leaching of both
Pd and Si from the SiliaCat DPP–
Pd catalyst during catalysis, we
analyzed the crude solid prod-
ucts by inductively coupled
plasma optically emission spec-
troscopy (ICP–OES, Table 9). In
general, values of leached Pd
and Si in isolated crude product
were <5 ppm, except for the 3-
bromopyridine (entry 9), 3-bro-
moquinoline (entry 10), 3-chloro-
pyridine (entry 13), and 2-chloro-
quinoline (entry 14) substrates.
This clearly points to coordina-
tion of the nitrogen atoms in
these aryl halides with the orga-
nosilica-tethered Pd.
1
2
95
100 (88)
10
11
B
B
85[d]
1
2
48
58
72[d]
20 89 (81)
12
B
3
100 (97)
87
[a] Experimental conditions: Method A: Substrate (5 mmol, 1 equiv.), B2Pin2 (1 equiv.), KOAc (2 equiv.), anhy-
drous 2-PrOH (20 mL, 0.5m, molar concentration with respect to aryl bromide and to B2Pin2) over SiliaCat DPP–
Pd (1 mol%), 828C; Method B: Substrate (10 mmol, 1 equiv.), B2Pin2 (1.1 equiv.), KOAc (2.2 equiv.), anhydrous 2-
PrOH (28 mL, 0.75m, molar concentration with respect to aryl bromide and to B2Pin2) over SiliaCat DPP–Pd
(2 mol%), 828C. [b] Conversion/selectivity evaluated by GC–MS. [c] Isolated yield. [d] Yield evaluated by GC–MS.
The catalyst employed in the
72 mmol (12.5 g) substrate con-
version in the 1st run was fil-
3-chloropyridine (90% isolated yield) occurred with 98% con-
version in 3 h. Complete conversion of 4-chloroaniline and 2-
chloroquinoline was obtained in 2 h, but with lesser selectivity
(yields less than 80%, entries 5 and 6).
tered after reaction completion, washed extensively (ꢃ2 with
EtOAc, ꢃ3 with EtOH/H2O v/v=1/1, ꢃ2 with EtOH), dried at
room temperature, and reused in a subsequent run. Overall,
six consecutive runs were performed with recovering and
washing the catalyst each time as described above (Table 10).
In the 1st and 2nd run complete conversion could be ob-
tained in 2 h. Then, a rapid decrease in activity was observed,
Under homogeneous conditions, the coupling of halide sub-
strates with the CÀI bond is faster than with the CÀBr or CÀCl
bonds. The heterogeneous reaction over SiliaCat DPP–Pd, how-
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offset by increasing the reaction time. Hence, in
3rd run, complete conversion in 92% isolated yield
required 4 h; whereas complete conversion in the
4th and 5th runs required 20 h, that is, ten times the
original reaction time. Clearly, the tethered catalyst
decomposes upon reuse, even if in general four cata-
lytic cycles can be performed with the same catalyst
affording the desired product in almost quantitative
yield.
Table 7. SiliaCat DPP–Pd catalyzed coupling reaction of B2Pin2 and different aryl chlo-
ride substrates.[a]
Entry Substrate
Product
t
Conv. (Select.)[b] Yield[c]
[h]
[%]
[%]
1
24
21 (98)
48 (66)
1
31[d]
2
3
4
5
0.5 100 (98)
95
Conclusions
1
2
95
100 (97)
94
The heterogeneously catalyzed direct synthesis of
boronic acid pinacol esters can now be performed
with a wide range of aryl chlorides, bromides, and io-
dides, and bis(pinacolato)diboron as the borylating
agent over the sol–gel entrapped SiliaCat diphenyl-
phosphine palladium(II) catalyst. The use of anhy-
drous nontoxic iPrOH as a reaction solvent avoids ho-
mocoupling and increases the selectivity.
1
2
3
75
90
98 (96)
90
2
100 (75)
100 (70)
75[d]
6
2
70[d]
The method tolerates a wide range of functional
groups and allows easy, direct access to a diverse set
of boronic acid pinacol esters. Excellent yields and se-
lectivities are achieved with very low (<5 ppm)
leaching of valued Pd during catalysis.
[a] Experimental conditions: Method B: Substrate (10 mmol, 1 equiv.), B2Pin2
(1.1 equiv.), KOAc (2.2 equiv.), anhydrous 2-PrOH (28 mL, 0.75m, molar concentration
with respect to aryl bromide and to B2Pin2) over SiliaCat DPP–Pd (2 mol%), 828C.
[b] Conversion/selectivity evaluated by GC–MS. [c] Isolated yield. [d] Yield evaluated
by GC–MS.
All the reagents utilized are stable in air. Hence,
the process does not require the use of a glovebox
or inert conditions, with relevant practical advantages over ex-
isting methods that often require the exclusion of air and hu-
midity from the reaction system.
The method could by easily
Table 8. SiliaCat DPP–Pd catalyzed coupling reaction of B2Pin2 and different aryl iodides.[a]
scaled up from 10 to 200 mmol
of starting product with noticea-
ble increase in reaction rate and
consistent low leaching upon
scale-up, a clearly beneficial fea-
ture for practical applications of
this commercial catalytic materi-
al in synthetic organic and me-
dicinal chemistry. Further studies
using this sol–gel catalyst under
flow and in consecutive reac-
tions performed in one pot are
in course.
Entry
Substrates
Method
Solvent
[m][b]
Products
t
[h]
Conv. (select.)[c]
[%]
Yield[d]
[%]
iPrOH
(0.50)
3
20
47
57 (100)
1
2
3
A
B
C
74
57
81
iPrOH
(0.75)
1
3
31
74 (100)
iPrOH
(1.25)
1
3
71
82 (98)
iPrOH
(1.25)
4
C
3
100 (98)
94[e]
Experimental Section
iPrOH
(0.75)
3
20
45
68 (70)
5
6
B
C
48
75
Materials and analyses
All reactions were run in oven-
dried flasks using anhydrous sol-
vents. Inert conditions were not re-
quired. Unless otherwise noted, re-
agents were commercially avail-
able and used without purification.
The substrate used in Table 5,
entry 12, was synthesized by fol-
lowing the literature procedure.[20]
iPrOH
(1.25)
3
5
65
82 (92)
[a] Experimental conditions: Method A: See the experimental conditions in Table 6; Method B: See the experi-
mental conditions in Table 6; Method C: Substrate (10 mmol, 1 equiv.), B2Pin2 (1.5 equiv.), KOAc (3 equiv.), anhy-
drous 2-PrOH (20 mL, 1.25m, molar concentration), 2 mol% SiliaCat DPP–Pd, 828C. [b] Molar concentration
with respect to substrate and to B2Pin2. [c] Conversion/selectivity evaluated by GC–MS. [d] Yield evaluated by
GC–MS. [e] Isolated yield.
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Figure 4. Performance of the SiliaCat DPP–Pd in the scale-up borylation reac-
tion under magnetic stirring (700 rpm) and mechanical stirring (550–
600 rpm).
in the crude product; LODSi =0.02 ppm in solution (100 mgmLÀ1
concentration) or 0.20 mgkgÀ1 in the crude product.
Synthetic method A
A 100 mL two-necked flask containing a magnetic stir bar and
a condenser was charged with KOAc (10 mmol, 2 equiv.), pinacol
B2Pin2 (5 mmol, 1 equiv.), anhydrous iPrOH (20 mL, 0.5m, molar
concentration with respect to the reagents). After 5 min stirring,
the substrate (5 mmol, 1 equiv.) was added to the resulting mix-
ture. Then the reaction mixture was heated at 808C and SiliaCat
DPP–Pd (1 mol%, Pd loading 0.25 mmolgÀ1) was added. The reac-
tion was monitored by GC–MS. After completion of the reaction,
the reaction mixture was cooled to RT and ethyl acetate (50 mL)
was added. The mixture was filtered by using a 70 mL Bꢄchner
funnel equipped with paper glass (microfiber filter 961). The heter-
ogeneous catalyst was collected and rinsed with ethyl acetate
(3ꢃ50 mL).
Figure 2. A) Performance of the SiliaCat DPP–Pd in the scale-up borylation
reaction from 10 to 40 mmol starting product. B) Zoom from 0 to 65 min.
The filtrate was evaporated under vacuum. The solid residue was
dissolved in EtOAc (50 mL), washed with brine (3ꢃ50 mL), and
dried over magnesium sulfate. After filtration, the solvent was re-
moved to obtain a crude product, purified by flash chromatogra-
phy if needed. The catalyst recovered by filtration was washed
again with EtOH/H2O (1:1, v/v, 3ꢃ25 mL), EtOH (2ꢃ25 mL), and
THF (2ꢃ25 mL), and dried at RT by simply letting the solvent to
evaporate under ambient conditions. The catalyst stored in an
open vessel was then reused in a subsequent reaction run as de-
scribed above.
Figure 3. Performance of the SiliaCat DPP–Pd in the 40 mmol scale-up 4-bro-
moanisole borylation reaction under mechanical stirring. Influence of the
stirrer blade type on the reaction.
Synthetic method B
A 100 mL two-necked flask containing a magnetic stir bar and
a condenser was charged with KOAc (22 mmol, 2.2 equiv.), pinacol
B2Pin2 (11 mmol, 1.1 equiv.), and anhydrous iPrO (28 mL, 0.75m,
molar concentration with respect to the reagents). After 5 min stir-
ring, the substrate (10 mmol, 1 equiv.) was added to the resulting
mixture. Then the reaction mixture was heated to reflux (828C)
and SiliaCat DPP–Pd (2 mol%, Pd loading 0.25 mmolgÀ1) was
added. The reaction was monitored by GC–MS. After completion of
the reaction, the reaction mixture was cooled to RT and ethyl ace-
GC–MS was used to assess conversion and selectivity. The yields
were also measured by isolating the reaction products. The leach-
ing in Pd and Si was assessed by ICP–OES analysis of the isolated
crude product in DMF solvent (concentration 100 mgmLÀ1). Leach-
ing values are given in mgkgÀ1 API. Limit of detection: LODPd
=
0.05 ppm in solution (100 mgmLÀ1 concentration) or 0.50 mgkgÀ1
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tration, the solvent was removed
to obtain a crude product, purified
by flash chromatography when
needed. If a heteroatom aryl sub-
strate was converted, the ethyl
acetate was replaced by THF. The
catalyst recovered by filtration was
washed again with EtOH/H2O (1:1,
v/v, 3ꢃ25 mL), EtOH (2ꢃ25 mL),
and THF (2ꢃ25 mL), and dried at
RT by simply letting the solvent to
evaporate under ambient condi-
tions. The catalyst stored in an
open vessel was then reused in
a subsequent reaction run as de-
scribed above.
Table 9. SiliaCat DPP–Pd catalyzed coupling reaction of B2Pin2 and different aryl halides. Leaching test.
Entry Substrate
B2Pin2 Catalyst KOAc
Solvent
t
Conv.
Yield[e] Leaching[f]
[mgkgÀ1 API]
(select.)[e]
[equiv.] [mol%] [equiv.] [m][d]
iPrOH
[h] [%]
[%]
Pd
Si
1[a]
2[a]
1
1
2
1
1
100 (99) 94
1.57 1.12
1.16 0.82
(0.50)
iPrOH
(0.50)
1
1
2
100 (97) 94.5
iPrOH
(0.75)
3[a]
1.1
2
2.2
2
99 (82)
96 (94)
–
–
4.60 3.07
iPrOH
(0.75)
4
1.1
1.1
1.5
2
2.2
2.2
3
3
1.93 2.07
5.45 2.65
iPrOH
(0.75)
5[a]
100 (97) 95
100 (99) 98
iPrOH
(0.75)
6[a]
1.1
1.1
2
2
2.2
2.2
3
1
0.56 3.05
5.76 2.70
Method C
A 100 mL two-necked flask con-
taining a magnetic stir bar and
iPrOH
(0.75)
7[a]
100 (98) 96
100 (98) 96
a
condenser was charged with
KOAc (30 mmol, 3 equiv.), pinacol
B2Pin2 (15 mmol, 1.5 equiv.), anhy-
drous iPrOH (20 mL, 1.25m, molar
concentration with respect to the
reagents). After 5 min stirring, the
substrate (10 mmol, 1 equiv.) was
added to the resulting mixture.
Then the reaction mixture was
heated to reflux (828C) and hetero-
geneous SiliaCat DPP–Pd (2 mol%,
iPrOH
(0.75)
8[a]
1.1
2
2.2
2
3.93 4.09
iPrOH
(0.75)
9[a]
1.1
1.1
1.1
2
2
2
2.2
2.2
2.2
3
2
100 (98) 96
100 (88) 85
14.5
3.85
11.77 3.80
<0.50 4.28
iPrOH
(0.75)
10[a]
11[b]
iPrOH
(0.75)
0.5 100 (98) 95
Pd loading 0.25 mmolgÀ1
) was
added. The reaction was moni-
tored by GC–MS. After completion
of the reaction, the reaction mix-
ture was cooled to RT, and ethyl
acetate (100 mL) was added. The
mixture was filtrated by using
a 70 mL Bꢄchner funnel equipped
with paper glass microfiber filter
961. The heterogeneous catalyst
was collected and rinsed with
ethyl acetate (3ꢃ50 mL). The or-
ganic solvent was evaporated
under vacuum. The solid residue
was dissolved in EtOAc (100 mL),
washed with brine (3ꢃ100 mL),
and dried over magnesium sulfate.
After filtration, the solvent was re-
moved to obtain a crude product,
purified by flash chromatography
when needed. The catalyst recov-
ered by filtration was washed
again with EtOH/H2O (1:1, v/v, 3ꢃ
25 mL), EtOH (2ꢃ25 mL), and THF
iPrOH
(0.75)
12[b]
1.1
2
2.2
2
100 (97) 94
98 (96) 90
3.16 5.56
iPrOH
(0.75)
13[b]
14[b]
1.1
1.1
2
2
2.2
2.2
3
2
13.87 2.61
18.81 1.53
iPrOH
(0.75)
100
70
iPrOH
(1.25)
15[c]
16[c]
1.5
1.5
2
2
3
3
5
3
82 (92) 75
100 (98) 92
1.38 2.77
1.25 6.06
iPrOH
(1.25)
For experimental conditions, see [a] Table 5, [b] Table 6, [c] Table 7. [d] Molar concentration with respect to the
reagents. [e] Conversion/selectivity evaluated by GC–MS. Isolated yield. [f] The leaching in Pd and Si was as-
sessed by ICP–OES analysis of the isolated crude product in DMF solvent (concentration 100 mgmLÀ1) and re-
ported as mgkgÀ1 API. LODPd =0.05 ppm in solution (concentration 100 mgmLÀ1) or 0.50 mgkgÀ1 in the crude
product; LODSi =0.02 ppm in solution (concentration 100 mgmLÀ1) or 0.20 mgkgÀ1 in the crude product.
(2ꢃ25 mL), and dried at RT by simply letting the solvent to evapo-
rate under ambient conditions. The catalyst stored in an open
vessel was then reused in a subsequent reaction run as described
above.
tate (50 mL) was added. The mixture was filtered by using a 70 mL
Bꢄchner funnel equipped with paper glass (microfiber filter 961).
The heterogeneous catalyst was collected and rinsed with ethyl
acetate (3ꢃ50 mL). The organic solvent was evaporated under
vacuum. The solid residue was dissolved in 100 mL EtOAc, washed
with brine (3ꢃ100 mL), and dried over magnesium sulfate. After fil-
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Acknowledgements
Table 10. Reusability of the SiliaCat DPP–Pd catalyst in the borylation of
4-bromobenzonitrile with B2Pin2.[a]
This article is dedicated to to Prof. Franck Dumeignil (University
of Lille) for his elegant work on glycerol catalytic upgrading. We
acknowledge the valued assistance of Mr. Simon Bꢀdard and Mr.
Pierre-Gilles Vaillancourt from QC Department of SiliCycle Inc.
t
[h]
Conv. (Select.)[b]
[%]
Yield[b]
[%]
Leaching[c] [mgkgÀ1 API]
Pd Si
Run 1
Run 2
Run 3
1
2
1
2
2
96.5
100 (95)
87
100 (96)
90
94
95
92
4.93 1.99
1.37
4.28
1.65
2.20
Keywords: boron
· halides · heterogeneous catalysis ·
palladium · sol–gel processes
3
95
4
2
99 (97)
72
Run 4
Run 5
Run 6
93
4.10
9.57
2.14
6.56
4
20
2
4
20
2
83
100 (95)
67
82
100 (98)
35
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1 equiv.), B2Pin2 (1 equiv.), KOAc (2 equiv.), anhydrous 2-PrOH (0.5m, molar
concentration with respect to the reagents), SiliaCat DPP–Pd (1 mol%, Pd
loading 0.25 mmolgÀ1). [b] Conversion/selectivity evaluated by GC–MS.
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Scale-up of 200 mmol
4-bromoanisole conversion
A 1000 mL three-necked flask (center neck 45/50, side necks 24/40)
containing a perforated banana-type stirrer blade PTFE (21 mm/
87 mm, width/length, for 10 mm shafts) and a condenser was
charged KOAc (43.19 g, 440 mmol, 2.2 equiv.), B2Pin2 (55.87 g,
220 mmol, 1.1 equiv.), 560 mL HPLC grade iPrOH (0.75m, molar
concentration with respect to reagents). After 5 min mechanical
stirring, the 4-bromoanisole (37.41 g, 25.05 mL, 200 mmol, 1 equiv.)
was added to the resulting mixture. Then, the reaction mixture
was heated to reflux (828C) under 300 rpm mechanical stirring and
SiliaCat DPP–Pd (2 mol%, Pd loading 0.25 mmolgÀ1) was added.
The mechanical stirring was increased to 550 rpm. The reaction
was monitored by GC–MS. When reaction was complete, the reac-
tion mixture was cooled to RT, and distillated water (200 mL) was
added, followed by diethyl ether (100 mL). The mixture was filtered
by using a 200 mL Bꢄchner funnel equipped with paper glass mi-
crofiber filter 961. The heterogeneous catalyst was collected and
rinsed with diethyl ether (3ꢃ100 mL) and with distillated water
(2ꢃ100 mL). The two layers were separated. The aqueous layer
was extracted again with diethyl ether (200 mL).
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Received: December 5, 2013
Revised: December 23, 2013
Published online on March 3, 2014
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 2014, 6, 1340 – 1348 1348