Fast and clean borylation of aryl halides under flow using sol-gel entrapped silia cat DPP-Pd

Article abstract of DOI:10.1021/op500008h

The fast and clean synthesis of boronic acid pinacol esters starting from aryl halides and bis(pinacolato)diboron is heterogeneously carried out over the SiliaCat DPP-Pd solid catalyst with largely enhanced reaction rate and catalyst stability. This opens the route to the transfer of cross-coupling borylation in a flow microreactor from the research level to process development.

Full text of DOI:10.1021/op500008h

Communication
pubs.acs.org/OPRD
Fast and Clean Borylation of Aryl Halides Under Flow Using Sol−Gel
Entrapped SiliaCat DPP-Pd
†
†
,†
‡
,‡
Valerica Pandarus, Geneviev
†
̀
e Gingras, Franco
̧
is Bel
́
and,* Rosaria Ciriminna, and Mario Pagliaro*
́ ́
SiliCycle Inc., 2500, Parc-Technologique Boulevard, Quebec, Quebec, Canada G1P 4S6
Istituto per lo Studio dei Materiali Nanostrutturati, CNR, via U. La Malfa 153, 90146 Palermo, Italy
‡
ABSTRACT: The fast and clean synthesis of boronic acid
pinacol esters starting from aryl halides and bis-
(
pinacolato)diboron is heterogeneously carried out over
the SiliaCat DPP-Pd solid catalyst with largely enhanced
reaction rate and catalyst stability. This opens the route to
the transfer of cross-coupling borylation in a flow
microreactor from the research level to process develop-
ment.
Figure 1. Chemical structure of SiliaCat DPP-Pd (A); and chemical
structure of SiliaCat DPP diphenylphosphine heterogeneous ligand
1. INTRODUCTION
(B).
The Miyaura borylation reaction rapidly affords aryl- and
heteroaryl boronates, that are widely used in place of boronic
1
functionalized with diphenylphosphine ligand bound to Pd2+
acids in the Suzuki−Miyaura reaction, when reactive functional
(with typical 0.2−0.3 mmol/g palladium loading, high surface
2
2
groups are present in the electrophilic aryl halides. The
area 300−650 m /g; depending on the applied parameters of
original reaction offering easy and greater access to diverse
borylated species involves the cross-coupling of bis-
the sol−gel synthesis), which is highly active in C−C coupling
9
reactions.
(
pinacolato)diboron (B Pin ) with aryl halides and vinyl
A major advance enabled by these new silica-based materials
made of catalytic species entrapped in mesoporous organosilica
lies in the possibility to carry out solid-phase syntheses under
flow and under automated conditions, nowadays a well-
established organic synthesis technology both in the academia
2
2
halides catalyzed at 80 °C in dioxane or DMSO by 3 mol %
PdCl (dppf) [1,1′-bis(diphenylphosphino)ferrocene
2
dichloropalladium(II)] in the presence of a 3 equiv excess of
base (KOAc). The Miyaura reaction eventually made the
Suzuki−Miyaura C−C coupling reaction the routine method
10
and in the pharmaceutical and fine chemicals industries.
3
used both in industry and in academia, for the synthesis of
Mesoporous, free-flowing organosilica catalytic xerogels indeed
have a number of distinct advantages over traditional polymer
resin beads, including faster kinetics, solvent independence,
diverse biaryls and heterobiaryls, ubiquitous motifs in
pharmaceuticals, natural products, liquid crystals, and many
other valued products used in different industrial sectors.
4
11
ease of use, and pronounced chemical and physical stabilities.
Since the 1995 introduction of the original Miyaura
borylation protocol, other homogeneous palladium catalysts
of enhanced versatility for the cross-coupling of pinacolborane
with aryl halides have been introduced, including palladium
coordinated by (dicyclohexylphosphino)biphenyl-type ligands
such as SPhos and XPhos.
Furthermore, intense research attempts were devoted to
In this report, we show how the catalytic borylation mediated
by SiliaCat DPP-Pd can be carried out under flow with dramatic
enhancement in reaction rate and catalyst stability, compared to
reaction under batch conditions, while retaining the pro-
nounced yield and selectivity observed for the catalytic reaction
under batch conditions. The mesoporous catalyst’s excellent
textural properties, indeed, make it ideally suited for application
in a flow microreactor.
5
efficiently heterogenize palladium catalytic species used in
6
cross-coupling reactions, with the aim to obtain selective and
reusable solid cross-coupling catalysts avoiding contamination
of the product with Pd. In this context, we have recently
described the heterogeneously catalyzed synthesis of boronic
acid pinacol esters using a wide range of aryl chlorides,
bromides and iodides and bis(pinacolato)diboron as borylating
agent over the sol−gel entrapped SiliaCat DPP-Pd catalyst (eq
2. EXPERIMENTAL SECTION
Catalyst and Reagents. The SiliaCat DPP-Pd employed
2
(
0.25 mmol/g palladium loading, 573 m /g BET specific
3
surface area; 1.13 cm /g total pore volume; 7.5 nm BJH
desorption average mesopore diameter; 0.354 g/mL density)
was obtained from SiliCycle, Inc. The flow rate was increased
up to 0.5 mL/min threshold by using particle size of the catalyst
7
8
1
): SiliaCat DPP-Pd (Figure 1) is an organosilica matrix
Special Issue: Continuous Processes 14
Received: January 10, 2014
©
XXXX American Chemical Society
A
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Figure 2. Flow borylation reaction over SiliaCat DPP-Pd.
Table 1. SiliaCat DPP-Pd-catalysed borylation of aryl bromides: batch versus flow
a
Batch reaction. Method A: substrate (5 mmol, 1 equiv), bis(pinacolato)diboron (1 equiv), potassium acetate (2 equiv) in 2-propanol (20 mL, 0.50
b
M), 1 mol % SiliaCat DPP-Pd. Flow reaction: in the solution of the batch reaction, Method A, 40 mL of solvent were used. The solution was
pumped through the catalyst bed preheated at 82 °C at 0.50 mL/min or 0.75 mL/min flow rate. Batch reaction. Method B: substrate (5 mmol, 1
equiv), bis(pinacolato)diboron (1.1 equiv) potassium acetate (2.2 equiv) in 2-propanol (14 mL, 0.75 M, molar concentration). Flow reaction: in the
c
d
solution of the batch reaction, Method B, 50 mL of solvent were used. The solution was pumped through the catalyst bed preheated at 82 °C at 0.25
e
mL/min or 0.50 mL/min flow rate. Column reactor (R1) (0.342 ID × 7 cm, 2.4 mL) was charged with 0.8 g SiliaCat DPP-Pd (0.25 mmol/g Pd
f
g
loading). Column reactor (R2) (0.785 ID × 6.5 cm, 5.1 mL) was charged with 1.76 g SiliaCat DPP-Pd (0.25 mmol/g Pd loading). Scale-up 2 times
h
the conditions of footnote d. Molar concentration with respect to the reagents (substrate + B Pin ). The solution was pumped through the catalyst
bed preheated at 82 °C at 0.25 mL/min or 0.50 mL/min flow rate. All experiments were conducted at 82 °C ± 1 °C. Residence time in the column
reactor charged with the heterogeneous catalyst. The solution of product was collected in a separate vessel for analysis. Conversion/selectivity
2
2
i
j
determined by GC−MS analysis.
B
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Organic Process Research & Development
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Figure 3. Stability of the SiliaCat DPP-Pd supported catalyst in borylation reaction under flow chemistry.
bigger than 200 μm to avoid pressure drop throughout the
catalyst packed in the microreactor (d50 = 224, d90/d10 = 5.9).
All other reagents of pure grade were received from Aldrich (St.
Louis, MI) and were used as such without further purification.
Reaction Set-Up and Conditions. The optimal reaction
conditions developed in the batch reaction over SiliaCat DPP-
Pd for the borylation reaction of 4-bromobenzonitrile (Method
When electronically deactivated 4-bromoanisole was reacted
in batch, the quantitative conversion to the corresponding
arylboronate required 3 h (entry 4). Under flow conditions,
72% conversion was obtained at 0.5 mL/min flow rate, with
2.05 min residence time (entry 5). When the latter time was
increased to 4.1 min, for 0.25 mL/min flow rate, conversion
increased to 83% (entry 5). Eventually, 92% conversion was
obtained under 0.25 mL/min flow rate, in 8.67 min residence
time (entry 6), by replacing the 2.4 mL column reactor (R1)
with a column reactor (R2) with an adjustable end (0.785 ID ×
6.5 cm) charged with twice the original amount of SiliaCat
DPP-Pd (1.76 g).
12
A) and of 4-bromoanisole or 2-bromotoluene (Method B)
were tested under flow in the modular Asia 220 flow chemistry
13
system commercialized by Syrris, using a more diluted
solution to ensure a homogeneous reaction mixture.
The system, whose setup is displayed in Figure 2, allows fast
and reproducible mixing of liquid reactants in the presence of
the solid catalyst. Only one solution was prepared mixing the
substrate, bis(pinacolato)diboron and base (KOAc) in i-PrOH
solvent. The column reactor 2.4 mL (R1) was thus charged
A sterically hindered substrate such as ortho-substituted 2-
bromotoluene that, under batch conditions is quantitatively
converted into the corresponding arylboronates in 2 h (entry
7
), under flow is converted in 82% yield within the 2.4 mL
(
simply packing the column) with 0.8 g SiliaCat DPP-Pd, and
(
R1) column reactor in 2.05 min (entry 8). Using the column
the flow system was initialized during 20 min at room
temperature when only the i-PrOH solvent was processed
using both pump channels directly through the solid-phase
reactor via a T-piece (a tube reactor adaptor enabling up to
three flows of reagents to be combined at the input of the
reactor charged with the solid phase) at 0.50 mL/min or at 0.25
mL/min. After 20 min the solid-phase reactor was heated at 82
reactor (R2) with adjustable end charged with 1.76 g SiliaCat
DPP-Pd brings the conversion after 8.67 min residence time to
9
7% (entry 9). Almost complete conversion (98%) could be
reached when the conditions developed in entry 9 were
repeated for a much longer period of time (7 h, entry 10).
To investigate the stability of the nanoencapsulated catalyst
the reaction using 2-bromotoluene as substrate was carried out,
feeding the reagents continuously into the 5.1 mL R2 reactor
for a much longer period of time (7 h) under the conditions
developed in entry 9. Conversion levels were then checked
every hour. Figure 3 clearly shows that the outcome of the
reaction does not change with time, thus proving the required
long-term stability of solid catalysts needed for practical
synthetic applications.
°
C. The homogeneous regents solution containing 5−10 mmol
substrate kept at room temperature was processed using either
pump channel directly through the solid-phase reactor
preheated at 82 °C.
3. RESULTS AND DISCUSSIONS
First, we tested the borylation of 4-bromobenzonitrile. Results
in Table 1 show the excellent applicability of the mesoporous
SiliaCat DPP-Pd heterogeneous catalyst under flow conditions.
Hence, while under batch conditions complete conversion was
obtained in 1 h (entry 1 in Table 1), under flow at 0.75 mL/
min flow rate the conversion was 90% in 1.37 min residence
time in the column reactor (entry 2). For the quantitative
conversion of 4-bromobenzonitrile into the corresponding
arylboronate, the residence time in the column reactor was
increased to 2.05 min by increasing the flow rate to 0.5 mL/min
Leaching of Pd and Si from the SiliaCat DPP-Pd catalyst
during catalysis was indirectly assessed by analyzing the metals
content in the isolated crude product by ICP-OES (inductively
coupled plasma optical emission spectroscopy) in DMF solvent
14
(100 mg/mL concentration). The low values detected for
both Pd (0.12 mg/kg) and Si (0.28 mg/kg) clearly point to low
metal contamination of the reaction product.
This result markedly differs from that obtained carrying out
the reaction in batch under fast (600 rpm) mechanical stirring,
when considerable mechanical and chemical degradation of the
(
entry 3).
C
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Organic Process Research & Development
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xerogel microparticles comprising the catalyst is observed after
the fourth consecutive reaction run.
(3) (a) Molander, G. A.; Trice, S. L. J.; Dreher, S. D. J. Am. Chem.
Soc. 2010, 132, 17701−17703. Recently, Molander and co-workers
introduced a greener borylating agent, tetrakis(dimethylamino)
diboron; (b) Molander, G. A.; Trice, S. L. J.; Kennedy, S. M. Org.
Lett. 2012, 14, 4814−4817.
OUTLOOK AND CONCLUSIONS
■
In summary, the direct synthesis of boronic acid pinacol esters
starting from different aryl bromides and bis(pinacolato)-
diboron can now be heterogeneously carried out using the
SiliaCat DPP-Pd solid catalyst packed within the microreactor
of a commercial flow chemistry module. In accordance with
(4) Yamaguchi, J.; Itami, K. Biaryl Synthesis through Metal Catalyzed
C-H Arylation. In Metal Catalyzed Cross-Coupling Reactions and More;
de Meijer, A., Bras
013; Vol. 3, pp 1315−1385.
5) (a) Billingsley, K.; Barder, T. E.; Buchwald, S. L. Angew. Chem.,
̈
e, S., Oestreich, M.. Eds.; Wiley-VCH: Weinheim,
2
(
7
Int. Ed. 2007, 46, 5359−5363. (b) Billingsley, K. L.; Buchwald, S. L. J.
results of the reaction in batch, similar excellent results (not
Org. Chem. 2008, 73, 5589−5591.
reported herein) have been obtained also for aryl chloride and
iodide derivatives.
(
6) Pagliaro, M.; Pandarus, V.; Ciriminna, R.; Bel
́
and, F.; Demma
Cara,
̀
P. ChemCatChem 2012, 4, 432−445.
Comparison of reaction under batch and flow chemistry
conditions generally shows that flow chemistry results in a
much enhanced reaction rate with further enhancement in
catalyst stability. This is due to the high reactivity of the silica-
(7) Pandarus, V.; Marion, O.; Gingras, G.; Bel
́
and, F.; Ciriminna, R.;
Pagliaro, M. ChemCatChem, DOI: 10.1002/ cctc.201301035
(8) See also at the URL: www.silicycle.com/eu/applications/
catalysis/use-of-siliacat-dpp-pd (last time accessed, 18 February 2014).
(9) Lemay, M.; Pandarus, V.; Simard, M.; Marion, O.; Tremblay, L.;
15
entrapped Pd catalyst, and to the intrinsic versatility of
chemical processes under flow in which the time of contact
between the catalyst and the reactants can be tuned simply by
varying the reactor volume and/or the flow rate until optimal
conditions are identified.
Bel
10) Yoshida, J-i.; Kim, H.; Nagakining, A. ChemSusChem. 2011, 4,
31−340.
11) For selected examples and further dicussion, see: (a) Pandarus,
V.; Desplantier-Giscard, D.; Gingras, G.; Ciriminna, R.; Demma Cara,
P.; Beland, F.; Pagliaro, M. Tetrahedron Lett. 2013, 54, 4712−4716.
b) Pagliaro, M.; Ciriminna, R.; Beland, F.; Pandarus, V. Eur. J. Org.
́
and, F. Top. Catal. 2010, 53, 1059−1062.
(
3
(
̀
The catalyst is an organosilica xerogel that adsorbs and
concentrates external reactants at the surface of its large
mesoporosity, without shrinking or swelling in any solvent and
withstanding temperatures of over 200 °C. The catalyst is stable
in air, and thus, the method does not require the use of inert
conditions that are common when employing delicate Pd
complexes used in cross-coupling reactions.
The use of anhydrous, non-toxic isopropanol as solvent
coupled to the lack of the catalyst−product separation step
further adds to the environmental benefits of this new method
of broad scope, that opens the route to easier, greater access to
arylboronates via the heterogeneously catalyzed borylation of
readily available aryl halides.
́
(
́
Chem. 2013, 6227−6235.
(12) Batch reaction. Method A: substrate (5 mmol, 1 equiv),
bis(pinacolato)diboron, B Pin (1 equiv), KOAc (2 equiv), 20 mL
2
2
anhydrous i-PrOH (0.5 M molar concentration in respect to aryl
bromide and to bis(pinacolato)diboron) over 1 mol% SiliaCat DPP-
Pd, 82 °C; Method B: substrate (5 mmol, 1 equiv), bis(pinacolato)
diboron, B Pin (1.1 equiv), KOAc (2.2 equiv), 14 mL anhydrous i-
2
2
PrOH (0.75 M molar concentration in respect to aryl bromide and to
bis(pinacolato)diboron) over 2 mol % SiliaCat DPP-Pd, 82 °C.
(
13) Flow reaction. One solution, substrate (1 equiv), B Pin (from 1
2 2
equiv to 1.1 equiv), KOAc (from 2 equiv to 2.2 equiv) in i-PrOH
(0.21M) was prepared. The resulting homogenous solution was
In conclusion, these results provide for the synthetically
relevant cross-coupling borylation reaction, another of those
processed at room temperature using the channels of both pumps (but
a single pump could also be used) directly through the solid-phase
reactor preheated at 82 °C via a T-piece (a tube reactor adaptor
enabling up to three flows of reagents to be combined at the input of
the reactor charged with the solid phase) at 0.50 mL/min or at 0.25
mL/min (0.25 mL/min or 0.125 mL/min each pump). The outcome
solution was collected over water and extracted with ethyl acetate. The
16
“
missing method and technology” required for the transfer of
flow-through processes in flow microreactors from the research
level to process development invoked by Kirschning a decade
ago.
organic layer was separated, dried under MgSO and filtered, and the
4
AUTHOR INFORMATION
Corresponding Authors
E-mail: FrancoisBeland@silicycle.com (F.B.)
E-mail: mario.pagliaro@cnr.it (M.P.)
■
solvents were evaporated under vacuum. For detailed information, see
at the URL: http://syrris.com/flow-products/asia-automated-systems/
asia-220-flow-chemistry (last time accessed, January 10, 2014).
*
(14) Leaching values are given in mg/kg APIs (active pharmaceutical
*
ingredients). Limit of detection: LODPd = 0.01 ppm in solution (100
Notes
mg/mL concentration) or 0.10 mg/kg in the crude product; LOD =
Si
The authors declare no competing financial interest.
0
.005 ppm in solution (100 mg/mL concentration) or 0.05 mg/kg in
the crude product.
ACKNOWLEDGMENTS
(15) (a) Pagliaro, M.; Ciriminna, R.; Palmisano, G. Chem. Soc. Rev.
■
2
007, 36, 932−940. (b) Ciriminna, R.; Demma Cara,
Pagliaro, M. Adv. Synth. Catal. 2011, 353, 677−687.
16) Kirschning, A.; Jas, G. Top. Curr. Chem. 2004, 242, 209−239
̀
P.; Sciortino, M.;
This article is dedicated to the University of Catania’s Prof.
Giovanni Marletta for all he did and is doing for Sicily’s
chemistry undergraduate students. We acknowledge Mr. Maxim
Drobot and Mr. Omar Jina from Syrris (Royston, UK) and Mr.
Simon Bedard and Mr. Pierre-Gilles Vaillancourt from QC
́
Department of SiliCycle Inc. for their valuable contributions.
(
Industrial chemists, interested in using the absolute minimum amount
of Pd, even in an immobilised system, will be able to examine
recirculation of the reaction system through the catalyst bed, that in
itself can lead to very long residence times and catalyst utilisation..
REFERENCES
■
(
7
1) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
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(
1
2) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett.
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dx.doi.org/10.1021/op500008h | Org. Process Res. Dev. XXXX, XXX, XXX−XXX