Highly functionalized biaryls via Suzuki-Miyaura cross-coupling catalyzed by Pd@MOF under batch and continuous flow regimes

Article abstract of DOI:10.1002/cssc.201402858

A diverse set of more than 40 highly functionalized biaryls was synthesized successfully through the Suzuki-Miyaura cross-coupling reaction catalyzed by Pd nanoparticles supported in a functionalized mesoporous MOF (8 wt% Pd@MIL-101(Cr)-NH₂). This could be achieved under some of the mildest conditions reported to date and a strong control over the leaching of metallic species could be maintained, despite the presence of diverse functional groups and/or several heteroatoms. Some of the targeted molecules are important intermediates in the synthesis of pharmaceuticals and we clearly exemplify the versatility of this catalytic system, which affords better yields than currently existing commercial procedures. Most importantly, Pd@MIL-101-NH₂ was packed in a micro-flow reactor, which represents the first report of metallic nanoparticles supported on MOFs employed in flow chemistry for catalytic applications. A small library of 11 isolated compounds was created in a continuous experiment without replacing the catalyst, demonstrating the potential of the catalyst for large-scale applications.

Full text of DOI:10.1002/cssc.201402858

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DOI: 10.1002/cssc.201402858
Highly Functionalized Biaryls via Suzuki–Miyaura Cross-
Coupling Catalyzed by Pd@MOF under Batch and
Continuous Flow Regimes
Vlad Pascanu,[a] Peter R. Hansen,[b] Antonio Bermejo Gꢀmez,[a] Carles Ayats,[c] Ana E. Platero-
Prats,[a, d] Magnus J. Johansson,[e] Miquel ꢁ. Pericꢂs,[c, f] and Belꢃn Martꢄn-Matute*[a]
A diverse set of more than 40 highly functionalized biaryls was
synthesized successfully through the Suzuki–Miyaura cross-
coupling reaction catalyzed by Pd nanoparticles supported in
a functionalized mesoporous MOF (8 wt% Pd@MIL-101(Cr)-
NH2). This could be achieved under some of the mildest condi-
tions reported to date and a strong control over the leaching
of metallic species could be maintained, despite the presence
of diverse functional groups and/or several heteroatoms. Some
of the targeted molecules are important intermediates in the
synthesis of pharmaceuticals and we clearly exemplify the ver-
satility of this catalytic system, which affords better yields than
currently existing commercial procedures. Most importantly,
Pd@MIL-101-NH2 was packed in a micro-flow reactor, which
represents the first report of metallic nanoparticles supported
on MOFs employed in flow chemistry for catalytic applications.
A small library of 11 isolated compounds was created in a con-
tinuous experiment without replacing the catalyst, demonstrat-
ing the potential of the catalyst for large-scale applications.
Introduction
At the center of the rapidly evolving green revolution in
chemistry,[1] catalysis plays a pivotal role.[2] Without catalytic
processes, it would be unconceivable to aim for a sustainable
chemical industry.[3] When it comes to organometallic catalysis,
special attention is dedicated to the recycling of metallic spe-
cies.[4] Aside from the obvious health hazards associated with
exposure to heavy metals, resources of palladium or ruthenium
are scarce and likely to become increasingly expensive in the
future.[5] Solid supports facilitate the recovery of these species
and have been used for the immobilization of catalysts as
either discrete species[6] or nanometer-scale metal clusters.[7]
Still, a common limitation in heterogeneous transformations is
the narrow substrate scope, which often addresses model sub-
strates that do not reflect the challenges of practical applica-
tions. Relevant substrates with multiple heteroatoms and com-
peting functional groups are more challenging, so they should
be addressed when new heterogeneous catalysts are devel-
oped.
Metal–organic frameworks (MOFs),[8] porous crystalline mate-
rials with extremely high surface areas, have the potential to
fill in this area because they are highly versatile compared to
other materials.[9] Since their properties can easily be modulat-
ed,[10] they could be applied in advanced organic processes
such as tandem and cascade reactions.[11]
Microscale flow chemistry[12] has diffused slowly into aca-
demic laboratories, provoking synthetic chemists to face issues
traditionally reserved for process chemists and engineers to
deal with.[13] The symbiosis between heterogeneous catalysis
and flow chemistry became a natural direction of progress in
the field, leading to a new generation of packed-bed micro-
reactors.[14] Surprisingly, despite all recent reports on MOF-type
catalysts, they have not yet been developed into flow applica-
tions. To the best of our knowledge, Galarneau and co-work-
ers[15] were the only ones so far to develop a successful catalyt-
ic process at the intersection of flow chemistry and MOFs,
using Cu-HKUST-1.[16]
[a] V. Pascanu, Dr. A. Bermejo Gꢀmez, Dr. A. E. Platero-Prats,
Prof. B. Martꢁn-Matute
Department of Organic Chemistry and Berzelii Center EXSELENT
Arrhenius Laboratory
Stockholm University
Stockholm, 106 91 (Sweden)
E-mail: belen@organ.su.se
[b] P. R. Hansen
RIA IMed, Medicinal Chemistry, Innovative Medicines Unit
AstraZeneca R&D, Mçlndal, 431 83 (Sweden)
[c] Dr. C. Ayats, Prof. M. ꢂ. Pericꢃs
Institute of Chemical Research of Catalonia
Av. Pa¨ısos Catalans, 16, Tarragona, 43007 (Spain)
[d] Dr. A. E. Platero-Prats
Department of Materials and Environmental Chemistry
Arrhenius Laboratory, Stockholm University, Stockholm, 106 91 (Sweden)
[e] Dr. M. J. Johansson
CVMD IMed, Medicinal Chemistry, Innovative Medicines Unit
AstraZeneca R&D, Mçlndal, 431 83 (Sweden)
Herein, we report the synthesis of heteroatom-functionalized
biaryls through Suzuki–Miyaura cross-couplings catalyzed by
[f] Prof. M. ꢂ. Pericꢃs
[17]
Pd nanoparticles supported on MIL-101-NH2 under very mild
Department of Organic Chemistry
University of Barcelona, 08028 Barcelona (Spain)
reaction conditions. The coupling products are potential build-
ing blocks of biologically active molecules. Besides a significant
expansion of the substrate scope, we discuss in detail some of
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201402858.
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the particularities of performing this reaction under heteroge-
neous conditions. We also show the first example of a nanoca-
talyst supported on a MOF and employed in a packed-bed
micro-flow reactor. Pd@MIL-101-NH2 displays good stability
under a continuous flow regime, with barely detectable levels
of leached metallic species.
alized (hetero)aromatic iodides reacted in excellent yields at
mild temperatures (20 or 508C) and in very short reaction
times (0.5–4 h), leading to the facile synthesis of 3a–f despite
the presence of one or several heteroatoms. Even hindered
aryl iodides (2b) and lengthy substrates (2 f) afforded the cou-
pling products 3b and 3 f, important building blocks in the
synthesis of pharmaceutically active intermediates,[20] in high
yields (85% and 82%, respectively) after short reaction times
(1 and 4 h, respectively). We then proceeded to the coupling
of less reactive aryl bromides (2g–2m) while also testing the
reactivity of different types of boronates (Scheme 1b). A quan-
titative yield was obtained in the synthesis of 3g from p-anisyl-
boronic acid (R=OCH3, BY=B(OH)2), even when the catalyst
loading was decreased 10 times (0.1 mol% Pd), as well as from
the analogous trifluoroborate and MIDA (N-methyliminodiace-
tic acid) ester. The latter, more complex MIDA-boronate gave
to our delight an excellent yield, however showed no rate en-
hancement relative to the other boron derivatives and was
therefore not considered further. The same product, 3g, was
also obtained in less than 30 min at 208C when ethyl 4-bromo-
benzoate (2g) was replaced with the corresponding triflate. 2-
Bromobenzonitrile (2h) could also be coupled with p-tolylbor-
onic acid at ambient temperature in only 30 min, affording
a quantitative yield of 3h, an intermediate in the synthesis of
the cardiovascular drug Valsartan.[21]
A summary of relevant homogeneous Pd catalysts for diffi-
cult Suzuki–Miyaura cross-couplings and a comparison of our
catalyst with recently developed heterogeneous systems are
included in the Supporting Information (Section I). Although
the majority of aryl chlorides are still out of reach, the Pd
nanocatalyst reported herein has the highest activity amongst
the existing heterogeneous systems for this type of applica-
tions.
Results and Discussion
We started by investigating the coupling of boronic acids [1,
Y=(OH)2] or pinacolate esters (1, Y=pinacolate=pin) with
heteroaryl iodides (2a–f) using K2CO3 as base (2 equiv) in a mix-
ture of H2O/EtOH (1:1) as solvent and a catalyst loading of only
1 mol% Pd (Scheme 1a). The material of choice was 8 wt%
Pd@MIL-101-NH2, which we recently reported to have the opti-
mal amount of palladium impregnated in MIL-101-NH2 for this
type of applications.[18,19] The large majority of these function-
Scheme 1. Couplings of (hetero)aromatic aryl iodides and bromides. [a] Unless otherwise noted, 0.1 mmol of aryl halide and 1.1 equiv of transmetallating
agent were used. Conversion determined by LC-MS. Isolated yields in parenthesis. [b] 80% conversion in 4 h from 2-bromothiophene. [c] 0.1 mol% Pd was
used. [d] Equimolar amounts of boronic acid were used (1.02 equiv) [e] Low isolated yield due to the hydrolysis of the ester. Pin=pinacolate. MIDA=N-meth-
yliminodiacetate.
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Methyl 5-bromo-1H-pyrrole-2-carboxylate (2k), 6-bromoin-
dole (2l), and 3-bromoquinoline (2m) were all well tolerated
reaction partners despite their coordinating properties and the
bulky nature of 2l and 2m, and afforded 3k–3m in good-to-
excellent yields. The catalytic system displayed very good com-
patibility under microwave (MW) irradiation conditions
(Scheme 1b, 3j), as further exemplified in the following sec-
tions, which helped to speed up the reaction significantly.
The extent to which functional groups can exert a steric hin-
drance was further examined in more detail (Scheme 2). In the
series of trifluoromethylphenylboronic acids (Scheme 2a), the
ortho substituted starting material completely inhibited the re-
action even at 508C (Scheme 2a, 4c). In contrast, the para and
meta analogues afforded 4a–b in excellent yields. This surpris-
conditions than the meta and para ethyl analogues. Conse-
quently, although a significant rate deceleration is observed,
this problem can be, in most cases, circumvented at higher
temperatures and the catalyst is capable to return an excellent
conversion.
Even though the catalytic tests performed so far were re-
warding, superior results were obtained when the heterocyclic
moiety was located on the boron transmetallating partners. As
a general trend, it was observed that this arrangement of reac-
tive groups (boron located on the more functionalized frag-
ment) leads to a better tolerance towards multiple coordinat-
ing heteroatoms. A large variety of interesting (hetero)aromatic
or vinylboronic acids (6a–6n) were coupled with aryl iodides
(Scheme 3a, 7a–j) and aryl bromides (Scheme 3b, 7k–n) and
afforded biaryls 8a–j and 8k–n, respectively, encountering
very little difficulties. Notably, 8c and 8d, containing a sophisti-
cated motif present in patented antagonists of P2X purinergic
receptors,[22] reached full conversion at low temperatures in
30 min and in 2 h, respectively. It was especially interesting to
observe that a complex aryl halide such as 7d could be easily
coupled with isoprene-2-yl boronic acid pinacolate ester (6d),
which contains a vinylic substituent. Furthermore, boronic
acids of pyridines, indoles, furans and thiophenes were well
tolerated. The use of MW irradiation was proven once again to
be highly effective and led to the isolation of 8e and the steri-
cally hindered 8 f in excellent yields, after merely 10 min of re-
action time. More sophisticated products like 8m and 8n
could also be synthesized and successfully isolated in very
good yields from the corresponding aryl bromides at 508C.
In our efforts to determine the tolerance limit that Pd@MIL-
101-NH2 has for complex substrates, it was found that certain
classes of heterocycles do not react readily. Halides of pyra-
zoles, indazoles and benzimidazoles stood out as very chal-
lenging substrates. Their poisoning effect was recently dis-
cussed in detail by Buchwald and co-workers,[23] who provided
evidence for the formation of bridged Pd complexes, which in-
hibit the Suzuki coupling. A strong influence over the outcome
was also attributed to the pKa values of the heterocycles em-
ployed. In this context, it was interesting to examine the inhibi-
tory properties of these substrates. In a robustness assessment,
as proposed by Glorius et al.,[24] when this type of heterocycles
(benzimidazole or 1-methylimidazole) were used as additives
in the cross-coupling of two standard substrates, the reaction
was completely suppressed and no product formation could
be detected (Scheme 4). In contrast, when indole was used as
an additive, almost no inhibition could be detected.
Scheme 2. Influence of steric effects. [a] 0.1 mmol of aryl halide and
1.1 equiv of transmetallating agent were used. Conversion determined by
LC–MS. Isolated yields in parenthesis.
ing interference prompted us to examine other ortho-substitut-
ed phenylboronic acids. When a less bulky chloride replaced
the trifluoromethyl functionality at the ortho position, the reac-
tivity returned to normal and 4d could be obtained in a very
good yield. Furthermore, a range of other hindered products
were synthesized and isolated successfully (4e–g) proving
a good tolerance of our catalyst to different ortho substituents
(i.e.; OMe, CH2OH and OH). However, 2-formylphenylboronic
acid (4h) reacted at a slightly reduced rate, while the o-methyl-
carboxylate function (4i), inhibited the reaction. This set of ex-
periments indicates that formation of the desired products is
suppressed when the boronic acid contains electron-withdraw-
ing groups in addition to bulky ortho substituents.
Gratifyingly, this problem was partially bypassed using the
heterocycles as transmetallating agents under mild conven-
tional heating (Scheme 5, 9a and b) or MW irradiation condi-
tions. This strategy enabled the synthesis of several aryl substi-
tuted pyrazoles and oxazoles in good to excellent yields (9a–
d).
Although previous reports provide limited evidence that cat-
alysis can occur on the surface of the nanoparticles and inside
the pores,[25] homogeneous contributions from leached metal-
lic species must be considered, while the debate on the true
nature of the active Pd species is still fiercely active.[26] We con-
This effect proved to be less pronounced when the bulky,
electro-withdrawing functionality was switched to the aryl
halide (Scheme 2b). In this case, methyl o-iodobenzoate react-
ed with (5-formylfuran-2-yl)boronic acid using slightly harsher
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Scheme 3. Couplings of (hetero)aromatic boronic acids. [a] Unless otherwise noted, 0.1 mmol of aryl halide and 1.1 equiv of transmetallating agent were
used. Conversion determined by LC-MS. Isolated yields in parenthesis. [b] Using isoprene-2-yl boronic acid pinacolate ester. [c] Using 2-bromofuran.
Scheme 4. Inhibitory effects of heterocycles. [a] 0.1 mmol scale. 1.2 equiv of transmetallating agent and 1 equiv of additive were used. Composition of the re-
1
action mixture after 30 min determined by H NMR spectroscopy using 1,2,4,5-tetrachloro-3-nitrobenzene as internal standard. Pin=pinacolate.
sider the character of the dominant mechanism (heterogene-
ous or homogeneous) to be strongly dependent on the reac-
tion conditions but these two possible pathways can operate
simultaneously.[24b] Taking advantage of the good scavenging
properties of the MOF, products free of contamination can still
be obtained.
most cases below the detection limit of the inductively cou-
pled plasma–optical emission spectrometry (ICP-OES) method
(<0.1 ppm). Our attempts to measure precise kinetic profiles
of the reaction over several runs were hampered by the insuffi-
cient solubility of the starting materials in the solvents mixture
and the precipitation of the biaryl product at high concentra-
tions. However, even when the catalyst loading was decreased
to 0.1 mol%, the reaction between p-bromobenzaldehyde and
phenylboronic acid was completed in less than 10 min, over at
least 5 recycling runs. The rate in this case was mainly influ-
enced by the rate of solvation of the aryl halide. After repeated
Several reactions presented above were repeated in order to
assess the extent of Pd leaching and to investigate its depend-
ence on the nature of the substrates and the reaction condi-
tions. When model substrates with no heteroatoms were used,
the Pd content in solution after filtration of the catalyst was in
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affects the stability of the nanoparticles even more than the
harsh conditions employed.
In order to further demonstrate the applicability of our cata-
lyst, the Pd loading was decreased to 0.01 mol% and 1-(4’-bro-
mophenyl)ethanone was reacted in a 7.5-gram-scale using only
an equimolar amount of p-tolylboronic acid as transmetallating
agent (Scheme 7). The conversion was measured at regular in-
tervals by LC–MS and determined to be complete after
280 min. A simple extraction with EtOAc led to the isolation of
the desired biaryl (10) in 99% yield (turnover number TON=
1
10000) with remarkable purity as proven by the H NMR spec-
trum of the crude mixture (Figure S6). Without further purifica-
tion, 4-(4’-methylphenyl) acetophenone (10) was reacted for
3 h with commercially available alloxan hydrate to obtain com-
pound 11 in a 96% yield after just filtration and washing with
water, with no need for chromatographic purification or recrys-
tallization (Scheme 7). This is a drastic improvement on the
previously reported synthesis of 11 by Nicolotti et al.[27] (50%
overall yield), which has been proposed as an inhibitor for
matrix metalloproteinases involved in inflammatory diseases.
Scheme 5. Coupling of pyrazole and oxazole derived boronic acids.
[a] Unless otherwise noted, 0.1 mmol of aryl halide and 1.1 equiv of transme-
tallating agent were used. Conversion determined by LC–MS. Isolated yields
in parenthesis [b] 50% conversion at 508C, conventional heating. Pin=pina-
colate.
recycling runs, some Pd agglomeration becomes evident
under TEM.[18] These results suggest that even if Pd leaching
occurs, the redeposition process is extremely efficient and
products completely free of contamination can be obtained.
However, when one N atom is present in the aryl halide,
leached Pd can be detected in very small amounts (2.8–
5.0 ppm) which appear to also be dependent on the reaction
time and temperature (Scheme 1 and 6, 3i, 3l and 3m). At ele-
vated temperatures and under MW irradiation (Scheme 3 and
6, 8e), even higher levels of Pd can be detected (12–14 ppm),
Scheme 7. Synthesis of MMP inhibitor 11.
Encouraged by the results presented above and the facile
recyclability of this catalyst under batch conditions, previously
demonstrated by our group,[18] we proceeded to investigate
the behavior of Pd@MIL-101-NH2 under continuous-flow condi-
tions.[28]
The catalyst was packed in an Omnifit glass column (d=
10 mm; 70 mm max adjustable bed height). For evaluating its
performance under flow conditions, an “endurance test” was
set up. Thus, 350 mg of catalyst (7.29 wt% Pd@MIL-101-NH2)
was packed as described in the Supporting Information. A vig-
orously stirred mixture of starting materials (10 mmol of p-bro-
mobenzaldehyde, 12 mmol of phenylboronic acid pinacolate
ester, and 20 mmol of K2CO3, in a mixture of 30 mL H2O and
120 mL EtOH) was passed through the column at an optimized
flow rate of 75 mLminÀ1. After stabilization of the system, regu-
Scheme 6. Pd leaching measured for various N-containing substrates.
although the MOF keeps the leaching at very reasonable levels
for such drastic conditions. The only case where the leaching
of Pd was severe was that of pyrazole (Scheme 5 and 6, 9c).
51 ppm of Pd were detected after 10 min at 808C under MW
irradiation, conditions which were required to achieve a com-
plete conversion. When the same set of substrates were react-
ed for 1 h at 308C, the level of Pd in solution was measured to
be only 5.9 ppm but no desired product was observed. This in-
dicates that the presence of a second N atom in the substrate
1
larly collected samples were analyzed by H NMR spectroscopy
for measuring the conversion and by ICP-OES for determining
the level of leached metallic species. The catalyst displayed
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a remarkable stability for a considerable period of 54 h, during
which the aryl halide was fully converted to the desired prod-
uct, at a turnover frequency of 1.25 hÀ1 (0.91 hÀ1 calculated
from isolated yield), with no formation of by-products and
barely detectable levels of metallic species in solution (max.
0.2 ppm of Pd and max. 0.1 ppm of Cr; see Table S1).
After 66 h, it was observed that the outflowing solution had
turned from colorless to strongly yellow. This correlated with
increased leaching (up to 1.2 ppm of Pd and 0.2 ppm of Cr)
while significant amounts of dehalogenated by-product (ben-
zaldehyde) were detected. The experiment was stopped after
70 h and the catalyst was recovered, washed and dried. The
XRPD analysis showed a complete amorphization of the recy-
cled material (Figure S4a). The increased leaching and loss of
selectivity are not surprising considering that after the
amorphization of the framework, Pd nanoparticles are no
longer protected by the MOF pores. In this case, they will ag-
glomerate, forming conglomerates of uncontrolled size and
morphology, with inferior catalytic properties.
Satisfied with the determined stability timeframe, we plan-
ned to synthesize a small library of more challenging com-
pounds in a single continuous flow experiment. This is an in-
teresting application of flow processes with immobilized cata-
lytic systems in pharmaceutical research. In this manner, fo-
cused libraries of drug candidates or drug intermediates can
be readily prepared in a sequential procedure, free of contami-
nation by the metal catalyst, through a process easily amena-
ble to automation.[29]
Mixtures of similar concentration (0.3 mmol of aryl halide in
6 mL of solvent, see the Supporting Information) were pre-
pared and passed through an identically packed catalyst
column at a reduced flow rate of 50 mLminÀ1 (see the Support-
ing Information for detailed procedure). To our delight, 11 cou-
pling products (Scheme 8, 14a–l), several of which were
known to be problematic, could be synthesized before catalyt-
ic activity of the system was compromised.
Scheme 8. Synthesis of a mini-library of coupling products in one continu-
ous flow experiment. [a] Products listed in the order they were synthesized.
1
Left: Isolated yields reported. Right: by-products determined by H NMR
spectroscopy from crude reaction mixtures. [b] Outflowing solution slightly
yellow. [c] Outflowing solution strongly yellow. [d] Product not isolated.
Pin=pinacolate.
By running the reaction under non-equilibrium conditions
specific to continuous flow regimes, some slightly lower yields
were obtained compared to batch reactions. Also a minor de-
crease in activity and selectivity is gradually observed as the
column starts to degrade under the stress produced by pass-
ing more bulky and heteroaromatic substrates. However, it is
not until the 12th product that the operation of the flow
column becomes unproductive.[30] As previously observed,
a yellow coloration of the outflowing solution started to mark
the steep decline in catalytic activity. The recovered catalyst
was found to be partially crystalline (Figure S4b) with a remain-
ing Pd content of 6.81 wt% (initially 7.29 wt%).
matic and highly functionalized biaryls (more than 40 exam-
ples). The substrate scope includes motifs frequently encoun-
tered in drug molecules and we illustrate the potential to im-
prove existing synthetic routes for commercially relevant
products. By adapting this system to operation under continu-
ous flow, we have developed what will hopefully become the
first in a rich family of catalysts based on metallic nanoparticles
supported on MOFs and applied in packed-bed flow reactors.
After successfully synthesizing a small library of 11 isolated
products in a single experiment, we are confident that the set
up exemplified in this work demonstrates the potential of
Pd@MIL-101-NH2 to be employed in automated processes
under a continuous-flow regime. Fulfilling the main directives
of green chemistry through catalysis, efficiency, selectivity and
recyclability, we hope that the arguments presented in this
report make Pd@MIL-101-NH2 an attractive solution for large-
scale applications.
Conclusions
We propose a robust heterogeneous catalytic system for the
Suzuki–Miyaura cross-coupling reaction. The system consists of
palladium nanoparticles immobilized on the metal–organic
framework MIL-101-NH2, and employs some of the mildest re-
action conditions reported to date. Its applicability is demon-
strated in the synthesis of a large number of diverse heteroaro-
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Experimental Section
General procedure for the Suzuki–Miyaura cross-coupling
reactions
8 wt% Pd@MIL-101-NH2 was prepared according to the reported
procedure.[18] Unless otherwise stated, in a 20 mL regular vial or Bi-
otage microwave vial, the arylboronic acid (0.83 mmol), the aryl
halide (0.158 g, 0.75 mmol), K2CO3 (0.207 g, 1.5 mmol), and 8 wt%
Pd@MIL-101Cr-NH2 (10 mg, 7.5 mmol, 1 mol% Pd) were added to-
gether with a magnetic stirring bar. EtOH (5 mL) and H2O (5 mL)
were added. The mixture was stirred in a sealed vial at the given
temperature under conventional heating or microwave irradiation.
The compound was extracted with EtOAc or CH2Cl2 (5 mL), the or-
ganic phase was separated and the volatile solvents were evapo-
rated to yield the crude product. The product was purified by flash
chromatography (see the Supporting Information).
Procedure for experiments under flow regime
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For the mini-library experiment, 12 mixtures of starting materials
were prepared: consisting of aryl halide (0.3 mmol), boronic acid/
ester (0.45 mmol) and K2CO3 (0.6 mmol) in a mixture of H2O
(1.5 mL) and EtOH (4.5 mL). Due to the low solubility of some of
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the loading process. Increasing the excess of transmetallating re-
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nation by-products. Each freshly prepared mixture was passed
through the column at 50 mLminÀ1 corresponding to a residence
time of 35–40 min. The column was then flushed with a clean sol-
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at 500 mLminÀ1 for another 30 min. The outflowing solution was
checked by TLC to verify that no residual product is left in the
column before switching the inlet needle to the next reaction mix-
ture. For each run, the outflowing solution was collected together
with the flushing solvent and extracted with EtOAc. The organic
phase was separated, the volatiles were evaporated and the resi-
due was purified by column chromatography (see the Supporting
Information).
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Acknowledgements
This project was supported by the Swedish Governmental Agency
for Innovation Systems (VINNOVA) and AstraZeneca through the
Berzelii Center EXSELENT, by the Swedish Research Council (VR)
through a project grant to B.M.-M and for the MATsynCELL proj-
ect through the Rçntgen ꢄngstrçm Cluster, and by the Knut and
Alice Wallenberg Foundation (Catalysis in selective organic syn-
thesis). The work on flow chemistry was funded by MINECO
(grant CTQ2012-38594-C02-01), DEC (grant 2009SGR623) and the
ICIQ Foundation. ICIQ authors also thank EU-ITN network Mag(-
net)icFun (PITN-GA-2012-290248) for financial support. B.M.-M.
was supported by VINNOVA through a VINNMER grant. V.P. is
grateful to the EU-ITN network Mag(net)icFun (PITN-GA-2012-
290248) for a secondment at ICIQ. C.A. thanks MICINN for a Juan
de la Cierva postdoctoral fellowship.
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Keywords: flow chemistry · heterocycles · MOF catalysis ·
suzuki–miyaura
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FULL PAPERS
www.chemsuschem.org
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Received: August 19, 2014
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Published online on && &&, 0000
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FULL PAPERS
MOFember: A robust heterogeneous
catalytic system is proposed for the
Suzuki–Miyaura cross-coupling reaction,
and consists of palladium nanoparticles
immobilized on the metal–organic
framework MIL-101-NH2. A set of highly
functionalized biaryls is synthesized
under mild reaction conditions. By pack-
ing Pd@MIL-101-NH2 in a micro-flow re-
actor, the system can be successfully
adapted for operation under continu-
ous-flow conditions.
V. Pascanu, P. R. Hansen,
A. Bermejo Gꢀmez, C. Ayats,
A. E. Platero-Prats, M. J. Johansson,
M. ꢂ. Pericꢃs, B. Martꢁn-Matute*
&& – &&
Highly Functionalized Biaryls via
Suzuki–Miyaura Cross-Coupling
Catalyzed by Pd@MOF under Batch
and Continuous Flow Regimes
ꢅ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 0000, 00, 1 – 9
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These are not the final page numbers!