One-pot Suzuki-Heck relay to prepare industrially valuable intermediates using the Pd-Cy?Phine catalyst system

Article abstract of DOI:10.1039/c7cy01344b

A rare example of a one-pot, palladium-catalyzed Suzuki-Heck sequence has been developed with applicability to APIs and organoelectronic materials. High throughput screening was used to expedite development and survey strategies. Interchangeability of the coupling partners and the avoidance of intermediate isolation gives operational flexibility, which can be used to improve process efficiency and suppress by-product formation.

Full text of DOI:10.1039/c7cy01344b

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One-pot Suzuki–Heck relay to prepare industrially
valuable intermediates using the Pd–Cy*Phine
catalyst system†
Cite this: DOI: 10.1039/c7cy01344b
Received 17th July 2017,
Accepted 23rd August 2017
Uttam K. Das,a Roxanne Clément,a Charles W. Johannes,b Edward G. Robins,c
a
*
DOI: 10.1039/c7cy01344b
Howard Jong b and R. Tom Baker
*
rsc.li/catalysis
A rare example of a one-pot, palladium-catalyzed Suzuki–Heck se-
quence has been developed with applicability to APIs and
organoelectronic materials. High throughput screening was used
to expedite development and survey strategies. Interchangeability
of the coupling partners and the avoidance of intermediate isola-
tion gives operational flexibility, which can be used to improve
process efficiency and suppress by-product formation.
jugated olefin moiety would be first to use a transition metal
catalyzed Suzuki–Miyaura cross-coupling to install a terminal
olefin group,10–18 followed by a Mizoroki–Heck reaction19–21
to attach the other aromatic substrate to the terminal olefin
(Scheme 1). Conceptually, a single pot workflow would im-
prove synthetic efficiency to bypass isolations, as well as alle-
viating the risk of intermediate instability that may arise with
potentially sensitive terminal olefin functional groups.
The installation of conjugated olefin moieties has been
shown to be an important part of the synthetic process to
prepare stilbene-based derivatives as key intermediates of
pharmaceutical intermediates (APIs)1 and materials used in
organic light-emitting diode (OLED) technology2,3 (Fig. 1). As
such, stilbene compounds have numerous applications in ag-
riculture,4 drug discovery5–7 and materials science.8,9
However, despite their usefulness in the synthesis of com-
mercial products, the process by which olefin fragments are
installed is step-wise and often inefficient, largely due to the
complexity of the molecules. Although there are various syn-
thetic routes to assemble these molecules, the process often
requires two distinct reactions due to limited availability of
commercial starting materials. The first involves the installa-
tion of a terminal, unsaturated C–C functional group to an
aromatic substrate while the second involves the attachment
of the unsaturated, terminal fragment to a different aryl
group. In the case where alkynes are the unsaturated C–C
functional group, a selective reduction step would also be
necessary to form the desired olefin motif. A simpler and
more direct approach to performing the assembly of the con-
While a one-pot sequential strategy is not a novel concept,
this combination of transformations has very limited litera-
ture precedent. We are aware of only one reported example of
a one-pot Suzuki/Heck sequence to prepare (E)-stilbenes
using a heterogeneous, recyclable Pd/SiO2 catalyst.22 How-
ever, this sequence is limited by long reaction times, moder-
ate yields and limited substrate scope. To the best of our
knowledge, there are no reports of a homogeneous metal
based catalyst capable of coupling different heteroaryl sub-
strates for both reaction types in a single pot. Thus, there ex-
ists an inherent difficulty in employing a sequential addition
strategy in a single pot, despite the abundant literature prece-
dence for both of these reaction types. To exacerbate the
challenge, substrates used to prepare APIs and performance
a Department of Chemistry and Biomolecular Sciences and Centre for Catalysis
Research and Innovation, University of Ottawa, Ottawa, Ontario K1N 6N5,
Canada. E-mail: rbaker@uottawa.ca
b Organic Chemistry, Institute of Chemical & Engineering Sciences (ICES), Agency
for Science, Technology and Research (A*STAR), 8 Biomedical Grove Neuros #07-
01, Singapore 138665. E-mail: howard_jong@ices.a-star.edu.sg
c Singapore Bioimaging Consortium (SBIC), Agency for Science, Technology and
Research (A*STAR), 11 Biopolis Way, Helios, #02-02, Singapore 138667
† Electronic supplementary information (ESI) available: Experimental procedures
and spectral data. See DOI: 10.1039/c7cy01344b
Fig. 1 Examples of patented commercial molecules that involve the
installation of conjugated olefin moieties in their preparation.
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Rather, it is anticipated that the sequence should begin with
Suzuki first simply due to its higher likelihood of being a
quicker and more efficient transformation, in comparison to
the Heck reaction. Upon literature review of relevant exam-
ples where Suzuki coupling is used as a strategy to install ter-
minal olefin groups, we found that two palladium catalysts,
PdIJPPh3)4 and PdIJdppf)Cl2, are frequently used, with the for-
mer being significantly more popular. It is conceivable that
the lack of other examples could be due to the Suzuki reac-
tion being relative facile, thus obviating the need to use ex-
otic and expensive catalyst alternatives. However, PdIJPPh3)4
and PdIJdppf)Cl2 are not typically suitable for the Heck reac-
tion, where different catalyst systems are favoured to perform
the alkenylation step. Four commercially available vinylic
boron-based reagents are frequently selected as the olefin
source: vinylboronic acid pinacol ester, potassium
vinyltrifluoroborate, vinylboronic acid dibutyl ester, and
vinylboronic anhydride pyridine complex. Furthermore, a va-
riety of solvent and base combinations are suitable for this
transformation; conventional bases such as K2CO3, Na2CO3
and Cs2CO3 are effective when used in combination with sol-
vent systems comprising dimethylformamide, acetonitrile,
and dioxane/H2O mixtures (10–20% H2O v/v). Based on these
findings, we hypothesized that modern catalyst systems that
typically outperform PdIJPPh3)4 and PdIJdppf)Cl2 in traditional
Suzuki coupling reactions should be able to install the vinyl
group onto aryl halide substrates via Suzuki coupling without
significant complications. Furthermore, a favourable combi-
nation of bases and solvents may exist that are applicable for
both the Suzuki transformation and the Heck reaction when
the preferred Heck conditions for the Pd–Cy*Phine system
are applied. In this regard, HTS should readily identify opti-
mal conditions for both the Suzuki and the Suzuki–Heck re-
actions from screening arrays.
We commenced our studies by optimizing the catalytic
conditions for two Suzuki coupling model reactions, HTS 1
using the Pd–Cy*Phine catalyst (Fig. S1 and S2 in ESI†).
Methyl-4-chlorobenzoate (3a) and 5-bromo-1-(tetrahydro-pyran-
2-yl)-1H-indazole (3b) were chosen as model substrates for
HTS 1. These substrates resemble fragments of API interme-
diate 1. Three solvents [DMF, MeCN, and dioxane : H2O (9 :
1)], four commonly used bases [K2CO3, Cs2CO3, NaHCO3, Cy2-
NMe], and four vinylboron reagents were selected for the
study. A total of 96 reactions were set up in HTS 1, consisting
of 48 combinations for each substrate (see product yields in
the ESI†).
In general, the Suzuki coupling of 4-methyl-chloro-
benzoate (3a) using the Pd–Cy*Phine catalyst was fairly
straight forward, giving a broad range of yields of the cou-
pling product, 4a in MeCN, DMF, and dioxane:H2O (Fig.
S1†). The latter combination was the best with the addition
of H2O playing an important role to achieve high conver-
sions, especially with the less soluble inorganic bases. Both
K2CO3 and Cs2CO3 in the dioxane:H2O system afforded vinyl
Scheme 1 Proposed one-pot Suzuki–Heck relay reaction.
materials are considerably more difficult as the functional
groups can interfere with catalysis. As such, only highly capa-
ble catalysts with proven success in transforming a broad
range of functionalized substrates in both reaction types
using similar conditions warrant consideration; these criteria
narrowed the catalyst selection pool substantially.
While the Suzuki reaction is relatively forgiving with a va-
riety of favourable operating conditions, the Mizoroki–Heck
reaction is the opposite, being very sensitive to reaction varia-
tion. In this context, one may be tempted to apply a Heck–
Suzuki coupling strategy. However, one reason why the
Suzuki reaction is so effective is that boronic acids react read-
ily, suggesting they may not be stable under the harsher con-
ditions typically required by the Heck reaction. As a result, it
is more feasible to attempt a Suzuki–Heck strategy and man-
age the complexity of the Heck reaction sensitivity, which is
challenging. For operational ease and practicality, the
Suzuki–Heck sequence employed a single catalyst system as
screening catalyst combinations with multiple reagents, sol-
vents, and conditions exponentially increases the exploration
space.
Several of us previously reported an extremely capable
palladium-based catalyst system that incorporates an evolu-
tionary meta-terarylphosphine ligand, Cy*Phine (Fig. 2). The
Pd–Cy*Phine system has been shown to be very efficient in
both the Suzuki and Heck reactions with notable substrate
tolerability and low catalyst loading.23,24 Recently, we
reported a related PdIJCy*Phine)2Cl2 system which is used in
one-pot multistep reactions including two-step borylation-
Suzuki coupling and three-step borylation-Suzuki-amination
(BSA) sequences.25 Here, we report the development of a one-
pot methodology of
a sequential Pd–Cy*Phine-catalyzed
Suzuki–Heck cross-coupling combination to prepare industri-
ally valuable intermediates via the employment of high-
throughput screening (HTS).
To carry out the one-pot Suzuki–Heck sequence using the
Pd–Cy*Phine catalyst system, we initially set out to identify
complementary conditions required for the Suzuki coupling
step. It should be noted, however, that there is no require-
ment for the Suzuki step to precede the Heck reaction.
product 4a nearly quantitatively with the trend: K2CO3
Cs2CO3 > NaHCO3 > Cy2NMe. In DMF and MeCN, only
≈
Fig. 2 Multi-arylphosphine ligand (Cy*Phine) used in one-pot Suzuki–
Heck relay (SHR) sequence.
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K2CO3 showed good performance (trend: K2CO3 > Cs2CO3 >
NaHCO3 > Cy2NMe) with only three exceptions. Direct activ-
ity comparison of the four boron coupling reagents in the
three solvent systems was not clear since it showed a similar
trend to that observed with the bases.
was added to the reactions, and the plate was heated and
stirred for an additional night. This protocol improved the
consistency across all the reactions for a better comparison
of the results.
The results of the Suzuki–Heck relay (SHR) with 3a (HTS
2) are shown in Fig. 3 (see ESI† for details). A yield of 72% of
the corresponding Suzuki–Heck product was obtained in one
of the reactions, a value that increased to 93% following the
addition of more catalyst – this particular reaction was
conducted in dioxane using K2CO3/Cy2NMe as bases, and
vinylboronic anhydride pyridine complex as the olefin source.
Among the three solvent systems, DMF performed the best,
giving up to 70% yield and 88% after the addition of more
catalyst – the general trend was DMF > MeCN > dioxane,
with MeCN and dioxane becoming more similar after the ad-
dition of more catalyst. The addition of 1 mol% catalyst and
longer reaction times led to significant yield increases,
suggesting that addition of 1 mol% catalyst at the beginning
of the second step, along with the aromatic substrate and
second base, would lead to even better results. Among all
base combinations surveyed, NaHCO3, K2CO3/Cy2NMe, and
NaHCO3/Cy2NMe demonstrated good performance with few
exceptions. The general trend for single bases was NaHCO3 >
K2CO3 > Cy2NMe while that for combined bases was K2CO3/
Cy2NMe ≈ NaHCO3/Cy2NMe > Cs2CO3/Cy2NMe.
The Suzuki coupling with 5-bromo-1-(tetrahydro-pyran-2-yl)-
1H-indazole (3b) was less trivial than with 3a since favourable
combinations were not obvious (Fig. S2†). However, DMF and
dioxane:H2O solvent systems performed slightly better than
MeCN for all boron coupling reagents. The combination of
vinylboronic acid pinacol ester with either K2CO3 or Cs2CO3
gave the best yields, leading to 70–80% of the coupling prod-
uct 4b in all three solvent systems (trend: K2CO3 ≈ Cs2CO3 >
Cy2NMe > NaHCO3). For all coupling reagents, NaHCO3 was
found to be least active in yielding 4b, except in DMF. In con-
trast to the reaction of methyl 4-chlorobenzoate, Cy2NMe pro-
duced higher yields of the coupling product 4b in DMF and
MeCN with all boron coupling reagents. It should be noted
that varying amounts of vinyl boronate ester 4c were observed
using vinylboronic acid pinacol ester.
In light of these results, we set out to design a high-
throughput screen for the Suzuki–Heck relay coupling using
4-methyl-chlorobenzoate and 3-chloropyridine as coupling
partners. Preliminary tests established notable features such
as the addition of tetra-n-butylammonium bromide (TBAB)
that was favourable to the overall two-step reaction, and addi-
tion of Cy2NMe that facilitated the Heck step. Conversely, the
use of excess vinylic boron reagent, or the presence of water
negatively affected the Heck coupling. Thus, the dioxane:H2O
combination was replaced by pure dioxane, which did not
significantly impair either the Suzuki or the Heck reaction.
Finally, all combinations that led to poor yields of the Suzuki
product 4a, as determined in HTS 1, were eliminated, TBAB
was used in all reactions, and the boron coupling reagent
equivalents were limited to 1.01.
The efficacy of the methodology was reinforced by apply-
ing the one-pot Suzuki–Heck sequence to coupling 5-bromo-
Combinations involving the use of a single base (5.0
equivalents added initially) were matched with those in
which Cy2NMe was added at the second step with
3-chloropyridine (2.0 equivalents of base at each step).
Cs2CO3 as a single base was eliminated because it was not a
favourable base for the Heck coupling of substrates investi-
gated previously23 and combinations involving Cs2CO3/
Cy2NMe/vinylboronic dibutyl ester were eliminated due to the
formation of the side-product 4-vinyl-benzoic acid butyl ester;
a series of 58 combinations was thus obtained. Although it
would have been ideal to add the reagents for the Heck as
soon as the Suzuki was completed (observed at times to be as
little as 3 hours), some of the tests revealed that the conver-
sion of 3a to the Suzuki product occasionally required an
overnight reaction time. This incurred the risk that the cata-
lyst's performance could be affected by longer reaction times
in the presence of certain bases, which could potentially af-
fect the second step negatively. To gain more information
about these factors, the Suzuki was run overnight, followed
by the Heck overnight. At this point, aliquots were taken out
for analysis, but an additional 1 mol% of catalyst solution
Fig. 3 Solvent, base and vinylic boron reagent optimization for HTS 2.
Reaction conditions: 3a (0.125 mmol), 3-Cl-pyridine (0.137 mmol),
boron reagent (0.126 mmol), base (0.500 mmol), TBAB (0.025 mmol),
solvent (475 μL). Pd–Cy*Phine catalyst (25 μL). Reactions were
analyzed by GC/FID and quantitation was derived from previously
established calibration curves.
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range of heteroaryl chlorides and bromides to prepare indus-
trially valuable intermediates for APIs and OLED materials
(Table 1). We note that the E-stereoisomers are formed exclu-
sively; none of the Z-isomers could be detected by GC or
NMR spectroscopy. The Pd–Cy*Phine catalyst system demon-
strated good performance, giving average yields of 64–91%
for each step of the one-pot SHR sequence except for com-
pound 8, which afforded 51% average yield. The protocol was
effective for installing the olefin moiety with various chal-
lenging fragments (entries 4, 7 and 8). The key benefit of this
method is the flexibility to interchange the coupling partner
to sidestep undesired homocoupling by-products. The avoid-
ance of intermediate isolation likely improves process effi-
ciency and economics with the absence of costs associated
with workup, purification, isolation, drying, and waste dis-
posal. The need to accommodate changes (i.e. catalysts, con-
ditions, reagents, and solvents) to the subsequent reaction
would further complicate the overall synthetic process.
In summary, a one-pot Suzuki–Heck coupling method was
developed by leveraging high-throughput screening tech-
niques and the capability of the Pd–Cy*Phine catalyst system.
The synthesis of industrially important intermediates for
APIs and organoelectronic materials in moderate to excellent
yields demonstrated the efficacy of the protocol. Since the
single-pot reaction approach is convenient and efficient, this
methodology could be attractive to the synthetic, medicinal,
and fine chemical industries.
Scheme 2 Suzuki–Heck relay reaction using 5-bromo-1-(tetrahydro-
pyran-2-yl)-1H-indazole (3b) and 3-chloropyridine.
1-(tetrahydro-pyran-2-yl)-1H-indazole (3b) and 3-chloropyridine
(Scheme 2) using the best combinations and conditions to af-
ford compound 6. The GC/MS analysis indicated a very prom-
ising 92% conversion to the expected coupling product. In-
trigued by these results, the one-pot SHR sequence was
attempted on a larger scale using substrates 3a and 3b with
3-chloropyridine as coupling partner and the products were
isolated. We were able to achieve 78% isolated yield using 3a
(Table 1, entry 1). However, substrate 3b afforded only 40%
isolated yield (Table 1, entry 2). Careful investigation of this
reaction after the Suzuki step revealed that 3b produced an
undesired homocoupling by-product (4d) along with the
expected Suzuki product as identified by HPLC/MS and 1H
NMR spectroscopy (Fig. S18†). Interestingly, by interchanging
the coupling partners (i.e. using 3-chloropyridine as Suzuki
substrate and 3b as Heck substrate) we achieved 82% of the
coupling product (Table 1, entry 3).
Finally, using the developed protocol, the scope of this
one-pot SHR method was explored by screening a diverse
Table 1 Substrate scope of the one-pot SHR cross-coupling methodologya
Entry
1
Productb,c
Entry
5
Productb,c
2
3
6
7d
4
8
a
Conditions: (Suzuki) 1 mol% PdIJOAc)2/2 mol% Cy*Phine, 2.0 eq. K2CO3, 20 mol% of TBAB, 0.34 eq. vinyl boronic pyridine complex in DMF
b
c
(0.25 M) at 90 °C for 12 h; (Heck) 1.1 eq. substrate, 2.0 eq. Cy2NMe, 1 mol% PdIJOAc)2/Cy*Phine at 110 °C for 12 h. Isolated yield. Bracket
values indicate the average yield of each step. d NMR yield.
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We thank the A*STAR Institute of Chemical and Engineer-
ing Sciences (ICES), the A*STAR Singapore Bio-imaging Con-
sortium (SBIC) and the Canada Research Chairs program for
generous financial support and the University of Ottawa, Can-
ada Foundation for Innovation, and Ontario Ministry of Eco-
nomic Development and Innovation for essential infrastruc-
ture. We appreciate the assistance of Dr. Sharon Curtis for
the analyses using high-resolution mass spectroscopy.
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Conflicts of interest
There are no conflicts to declare.
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