Continuous flow palladium(II)-catalyzed oxidative heck reactions with arylboronic acids

Article abstract of DOI:10.1002/ejoc.201000063

Palladium(II)-catalyzed oxidative Heck reactions were investigated under continuous flow conditions. Selective, fast and convenient protocols for the coupling of arylboronic acids with electron-rich and electron-poor olefins were developed by using a commercially available flow reactor.

Full text of DOI:10.1002/ejoc.201000063

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000063
Continuous Flow Palladium(II)-Catalyzed Oxidative Heck Reactions with
Arylboronic Acids
Luke R. Odell,[a] Jonas Lindh,[a] Tomas Gustafsson,[b] and Mats Larhed*[a]
Keywords: Continuous flow / Cross-coupling / Boron / Palladium / Homogeneous catalysis
Palladium(II)-catalyzed oxidative Heck reactions were inves-
tigated under continuous flow conditions. Selective, fast and
convenient protocols for the coupling of arylboronic acids
with electron-rich and electron-poor olefins were developed
by using a commercially available flow reactor.
dium(0)-catalyzed coupling reactions, efficient processing
protocols must be developed. In this short article, we pres-
ent the successful continuous flow development, using a
commercially available reactor, of various palladium(II)-
catalyzed Heck reactions with arylboronic acids.
Introduction
The synthetic chemists of today are increasingly being
expected to quickly deliver target products, at different
scales, in good yield and high purity. Hence, new synthetic
methods and purification strategies are urgently required to
reach quality and productivity goals.[1,2] Within the phar-
maceutical and fine chemistry communities, the use of
emerging synthetic technologies such as microwave heat-
ing[3,4] and continuous flow processing[5–14] have attracted
Results and Discussion
The first aim of this investigation was to develop a fast
considerable interest. Key advantages associated with con- and convenient continuous flow method for the vinylation
tinuous flow protocols in comparison with traditional batch of arylboronic acids. Our previously employed vinylation
techniques include the ability to independently control, and conditions [2 mol-% Pd(OAc)2 and 2.2 mol-% 1,3-bis(di-
directly evaluate, reaction parameters such as stoichiometry, phenylphosphanyl)propane, dppp] with the use of 4-acet-
temperature, pressure and flow rate.[15,16] In addition, flow ylboronic acid (1j, Table 1) were used as a starting point
techniques provide unique possibilities for facilitated and for reaction parameter optimization.[30] In our straightfor-
straightforward scale-up.[5,17]
ward experimental set-up, the two reactor sample loops
Palladium(II)-catalyzed reactions with arylboronic acids were loaded with a reactant solution containing 1j (0.5 )
constitute a group of recently developed synthetic methods and vinyl acetate (VA, 5 ) in DMF and a catalytic solution
that, in batch mode, typically afford high yields and selec- consisting of Pd(OAc)2 (0.01 ) and dppp (0.011 ) in
tivities, provided an efficient palladium(II) regeneration DMF. The solutions were then simultaneously pumped
takes place after each catalytic turnover.[18–23] We are cur- through a T-inlet and into a preheated PFTE reaction
rently developing new oxidative palladium(II)-catalyzed chamber (2 mL, 1 mm inner diameter). Optimization of re-
coupling reactions to increase the number of available sidence time and reaction temperature revealed that full
transformations starting from arylboron substrates.[24] conversion of 1j was reliably achieved after only 2 min of
Whereas related palladium(0)-catalyzed coupling reactions heating at 150 °C, providing desired styrene 2j in 86% iso-
with organohalides (or halide surrogates) have been pre- lated yield (Table 1, Entry 10).[31] Furthermore, no trace
viously investigated under continuous flow conditions,[25–29] amounts of acetophenone, resulting from deborylation of
the palladium(II)-catalyzed counterparts remain unex- 1j, or the corresponding stilbene were detected, suggesting
plored. Consequently, for the mild palladium(II)-catalyzed that a continuous flow reaction format may provide ad-
methodologies to become an industrial alternative to palla- ditional benefits over comparable batch techniques.[32]
Next, to investigate the generality of this protocol, the
vinylation of a range of arylboronic acids (Table 1) was con-
ducted. As can be seen from Table 1, all the reactions pro-
ceeded smoothly, providing moderate to good isolated
yields (42–86%) of the desired styrenes. Electron-rich
(Table 1, Entries 1–7) and electron-poor arylating agents
(Table 1, Entries 8–13) were all well tolerated. Marginally
lower yields were observed upon the introduction of an or-
[a] Organic Pharmaceutical Chemistry, Department of Medicinal
Chemistry, Uppsala Biomedical Centre, Uppsala University,
Box 574, 75123 Uppsala, Sweden
Fax: +46-18-4714474
E-mail: mats@orgfarm.uu.se
[b] AstraZeneca R&D Mölndal,
SE43183 Mölndal, Sweden
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000063.
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Continuous Flow PdII-Catalyzed Oxidative Heck Reactions
Table 1. Continuous flow vinylation of arylboronic acids 1.[a]
formed well, providing styrene 2b, an intermediate in the
synthesis of naproxen, in good yield (71%; Table 1, En-
try 2). The modest yield afforded by 3,5-dimethylphenyl-
boronic acid (1g) can be attributed to the volatile nature of
the styrene product (42%; Table 1, Entry 7). Rewardingly,
the potentially labile Cbz and Boc amino protecting groups
both remained intact (Table 1, Entries 5 and 12) despite the
presence of the palladium catalyst and the relatively high
reaction temperature. Finally, a successful 10 mmol scale-
out reaction on 1d was performed, affording 2d in 77% iso-
lated yield after only 20 min of flow processing.
Having demonstrated the wide substrate scope and func-
tional group compatibility of our continuous flow vinyl-
ation protocol, we next turned our attention to the oxidative
Heck arylation of electron-poor and electron-rich olefins.
Again, we used batch conditions previously developed in
our laboratory [2 mol-% Pd(OAc)2, 2.2 mol-% 2,9-dimethyl-
1,10-phenanthroline, dmphen][33] and p-benzoquinone (BQ,
1 equiv.) together with 1j and n-butyl acrylate (3a) as a
point of departure for our investigation.[34] Encouraged by
the modest amounts of deborylation observed in the vinyl-
ation reactions, we decided to use the boronic acid as the
limiting reactant. This is in contrast to our previously re-
ported oxidative Heck protocols, where the boronic acid (or
equivalent) has been used in excess.[30,34] Thus, a secondary
aim of our investigation became the development of a more
economical and process friendly protocol. Initially, the two
sample loops were loaded with a reactant solution contain-
ing 1j (0.25 ) and 3a (0.5 ) in DMF and a catalytic solu-
tion consisting of Pd(OAc)2 (0.005 ), dmphen (0.0055 )
and BQ (0.25 ) in DMF. Test reactions at 150 °C and a
residence time of 5 min revealed a working protocol; how-
ever, the stock catalytic solution was unstable and could not
be stored for more than a few hours at room temperature.
To our delight, exchanging dmphen for dppp provided a
stable catalytic system capable of promoting the arylation
of 3a. A time/temperature optimization showed that full
conversion of 1j was accomplished after only 5 min of heat-
ing at 130 °C, affording desired acrylate 4j in 85% yield
(Table 2, Entry 8).
To further enhance the scope of this methodology, 3a
was arylated with a variety of arylboronic acids under the
optimized continuous flow reaction conditions (Table 2).
Rewardingly, the reactions performed well with both elec-
tron-rich (Table 2, Entries 1–5) and electron-poor (Table 2,
Entries 6–9) boronic acids, furnishing E products 4 in mod-
erate to good yields. Full chemoselectivity was observed in
the reaction between bromine-containing 1p and 3a, with
no trace amounts of side products resulting from bromine
activation detected by LC–MS (Table 2, Entry 7). Once
again, palladium(0)-labile, Cbz-protected aniline 1e proved
to be a useful substrate, providing 81% of the desired
acrylate product (Table 2, Entry 3).
[a] Reaction conditions: Boronic acid (1 mmol, 0.5 ), VA
(10 mmol, 5 ), Pd(OAc)2 (0.02 mmol, 0.01 ), dppp (0.022 mmol,
0.011 ) in DMF, 150 °C, residence time 2 min. [b] Isolated yields
with purity Ͼ95% (LC–MS and H NMR spectroscopy). [c] Reac-
tion carried out on a 10-mmol scale.
1
Next, the electron-rich olefin n-butyl vinyl ether (3b) and
a small number of arylboronic acids were coupled under
tho substituent (Table 1, Entries 1, 6 and 12) presumably our continuous flow conditions (Table 3). As expected,
due to unfavourable steric interactions and/or palladium these reactions were highly regiospecific, providing the in-
chelation. 6-Methoxy-2-naphthylboronic acid also per- ternally arylated products, which were hydrolyzed and iso-
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L. R. Odell, J. Lindh, T. Gustafsson, M. Larhed
SHORT COMMUNICATION
Table 2. Continuous flow arylation of n-butyl acrylate (3a) with lated as the corresponding methyl ketones 5.[20,34–37] Most
arylboronic acids 1.[a]
of the reactions proceeded smoothly, delivering modest to
good yields of the desired products. Unfortunately, the reac-
tion between 1p and 3b (Table 3, Entry 4) was extremely
sluggish and doubling the residence time gave only a slight
improvement in isolated yield (31 vs. 43%).
Table 3. Continuous flow arylation of n-butyl vinyl ether (3b) with
arylboronic acids 1.[a]
[a] Reaction conditions: Boronic acid (0.5 mmol, 0.25 ), 3b
(1 mmol, 0.5 ), BQ (0.5 mmol, 0.25 ), Pd(OAc)2 (0.01 mmol,
0.005 ), dppp (0.011 mmol, 0.055 ) in DMF, 130 °C, residence
time 5 min. Then hydrolysis with 1  HCl (aq.). [b] Isolated yields
1
with purity Ͼ95% (LC–MS and H NMR spectroscopy). [c] Resi-
dence time 10 min.
Finally, we were intrigued by the prospect of synthesizing
disubstituted styrenes, from arylboronic acids, by a sequen-
tial two-step vinylation–arylation continuous flow process.
To this end, two different reaction schemes were designed,
[a] Reaction conditions: Boronic acid (0.5 mmol, 0.25 ), 3a
(1 mmol, 0.5 ), BQ (0.5 mmol, 0.25 ), Pd(OAc)2 (0.01 mmol,
0.005 ), dppp (0.011 mmol, 0.055 ) in DMF, 130 °C, residence
time 5 min. [b] Isolated yields with purity Ͼ95% (LC–MS and H
NMR spectroscopy).
1
Scheme 1. Two-step vinylation/arylation process.
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Continuous Flow PdII-Catalyzed Oxidative Heck Reactions
(0.5 mmol, 0.25 ) and 3a or 3b (1 mmol, 0.5 ) and a catalytic
solution containing Pd(OAc)2 (0.01 mmol, 0.005 ), dppp
(0.0011 mmol, 0.0055 ) and BQ (0.5 mmol, 0.25 ) in DMF.
These solutions were loaded into separate 2-mL sample loops and
simultaneously pumped through a T-inlet and into a PFTE reac-
tion chamber (volume 2 mL) preheated to 130 °C at a constant
flow rate of 0.4 mLmin–1 (residence time 5 min). The output of the
reaction was collected and diluted with EtOAc filtered through a
syringe filter and washed with NaOH (0.1  aq.) and if 3b was used
HCl (1 , aq.) and then with a 1:1 mixture of NH4Cl (10% aq.)
incorporating both an electron-rich and an electron-poor
intermediate styrene (Scheme 1). We reasoned that the ex-
cess amount of VA, present after the vinylation step, may
compete with the styrene during the subsequent arylation
step. Thus, the vinylation protocol was tuned and it was
found that full conversion of 1k was achieved, at 150 °C,
when 4 equivalents of VA were employed with a residence
time of 4 min. In the two-step protocol, Pd(OAc)2 (2 mol-
%), BQ (1 equiv.) and 1d (1 equiv.) were added to the out-
put of this reaction, and the solution passed through a sec- and NaCl (30% aq.). The organic phase was dried (phase separa-
tor) and concentrated in vacuo. The crude mixture was purified by
silica chromatography (10 g silica, 0–20% EtOAc in heptane) to
afford 4 or 5.
ond 10-mL PFTE reaction chamber at 130 °C for 5 min.
This reaction gave a 1:9 mixture of α/β regioisomers and
terminal E β-product 6 was isolated in 35% yield. When
the process was reversed (i.e., vinylation of 1d and arylation
with 1k) a decrease in β-selectivity was observed (α/β, 1:1)
and internal α-arylated styrene 7 could be isolated in 40%
yield. These results are in good agreement with the expected
regioselectivity for styrene arylation under cationic condi-
tions.[35,38]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization details for com-
pounds 2g, 2l, 4a, 4e and 6 as well as 1H and 13C NMR spectra
for all products.
Acknowledgments
We gratefully acknowledge financial support from the Swedish Re-
search Council and Knut and Alice Wallenberg’s Foundation. We
would also like to thank AstraZeneca R&D, Mölndal, Sweden for
use of their continuous flow equipment.
Conclusions
We have developed the first continuous flow methods for
the palladium(II)-catalyzed vinylation of arylboronic acids
and the oxidative Heck arylation of electron-rich and elec-
tron-poor olefins. Compared to the previously reported [1] A. Kirschning, W. Solodenko, K. Mennecke, Chem. Eur. J.
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veloped and an investigation into the scope of this method-
ology is currently underway in our laboratory. In view of
the large number of commercially available boronic acids,
we anticipate that our work will increase the utilization of
continuous flow palladium(II)-catalyzed transformations in
various applications related to fine and pharmaceutical
chemistry.
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Typical Procedure for the Preparation of Styrenes 2: Two stock solu-
tions were prepared. A reagent solution containing the boronic acid
(1 mmol, 0.5 ) and vinyl acetate (10 mmol, 5 ) and a catalytic
solution containing Pd(OAc)2 (0.02 mmol, 0.01 ) and dppp
(0.022 mmol, 0.011 ) in DMF. These solutions were loaded into
separate 2-mL sample loops and simultaneously pumped through
a T-inlet and into a PFTE reaction chamber (volume 2 mL) pre-
heated to 150 °C at a constant flow rate of 1 mLmin–1 (residence
time 2 min). The output of the reaction was collected and diluted
with EtOAc, filtered through a syringe filter and washed with
NaOH (0.1  aq.) and then with a 1:1 mixture of NH4Cl (10% aq.)
and NaCl (30% aq.). The organic phase was dried (phase separa-
tor) and concentrated in vacuo. The crude mixture was purified by
silica chromatography (10 g silica, 0–20% EtOAc in heptane) to
afford 2.
Typical Procedure for the Preparation of 4 and 5: Two stock solu-
tions were prepared. A reagent solution containing the boronic acid
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SHORT COMMUNICATION
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[32]
Previous studies have indicated that a Pd -catalyzed mecha-
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Received: January 18, 2010
Published Online: March 11, 2010
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