tailor-made solutions for scalable processes - Chemistry Today

ANDREAS MEUDT
SVEN NERDINGER
BERND LEHNEMANN
Suzuki Coupling at Clariant:
tailor-made solutions for
scalable processes
ABSTRACT
Clariant, the first chemical company to develop an industrial-scale Suzuki process in the early 1990s, offers
a broad portfolio of customized solutions for catalytic C-C coupling processes from gram to ton scale. This
article highlights latest industrial developments in this area, with a special emphasis on the production of the
required boronic acids. Latest development in this area is a new synthesis method for aliphatic boronic
acids, using a newly developed hydroboration-based method. Furthermore, alternative syntheses of biaryls
are discussed which sometimes are more economic than Suzuki couplings.
The Suzuki coupling reaction - the transition-metal catalyzed C-C bond formation between an
organoboronic derivative and an organohalide or sulfonate - is a valuable tool for the organic chemist.
It is - although still constantly being improved 1 - widely employed for construction of biaryl and heterobiaryl
structures in the laboratory and - within the last ten years - has found its way into industrial manufacture of
fine and specialty chemicals, too.
HISTORY: THE OTBN STORY
When in the early 1990s the sartanes family of angiotensin converting enzyme inhibitors emerged from the
initially introduced Losartan 2 , O-tolylbenzonitrile (OTBN) was chosen as a starting material for the industrial
production of one of these compounds (Scheme 1). The first syntheses being lenghty and expensive (5 steps),
about ten companies tried to find a more economic production route to this biphenyl structure, among them
the part of former Hoechst AG which is now part of Clariant’s Pharmaceutical Fine Chemical Business.
They decided to investigate a C-C coupling pathway, leading to one of the first industrial-scale applications
of a Suzuki protocol ten years ago.
To fit the needs of a large-scale Suzuki process, it was necessary to find a catalyst system which could be
easily recycled and would provide the product in high yields with high selectivity at low palladium loadings.
Furthermore, the reaction conditions had to allow easy separation of the product from the reaction mixture.
Clariant’s approach (shown in Scheme 1) was based on the water-soluble ligand tris(3-sulfonatophenyl)
phosphine (TPPTS) which is commercially
available and - when used in a biphasic
reaction medium - allows for easy reuse of
the aqueous phase carrying the catalyst
while the product is isolated from the
organic phase 3 . Several hundred tons of
OTBN have been produced using this
process.
Scheme 1: The sartanes, their precursor OTBN and Clariant’s Suzuki approach
6
COUPLING OF
NON-ACTIVATED AND
DEACTIVATED SUBSTRATES
In the meantime, Suzuki coupling has
emerged as the most common tool for
C-C coupling in the fine chemicals area
due the usually mild reaction conditions,
good yields and high functional group
tolerance. Although the palladium-TPPTS
system is still successfully applied to many
Suzuki couplings and often shows far
superior reactivity compared to other
early-generation catalyst systems like
CHIRAL CATALYSIS - Oxidation and C-C Coupling supplement to chimica oggi • Chemistry Today

tetrakis(triphenylphosphine)palladium,
especially with aryl and heteroaryl
bromides, new synthetic and economic
challenges involving heteroaromatic
coupling partners and cheap but less
reactive non-activated chloroaromatics
lead to the discovery of new, highly active
catalyst systems. Due to the excellent
backwards integration with Clariant’s
know-how in boronic acid production und
aromatic halogenation, Clariant offers
tailor-made solutions for all the
pharmaceutical industry’s needs for
coupling products. For example, a highly
versatile catalyst system developed by Fu
and co-workers, palladium/tri-tert-butyl
phosphine (Scheme 2), shows excellent
results in the coupling of deactivated aryl
chlorides at low catalyst loads4 and is not
patent protected, thus being a system of
choice for the outsourcing needs of pharmaceutical companies who do not want to depend on a single
source or complicated intellectual property situations. In many cases even tricyclohexylphosphine is a
sufficiently active ligand - not only for palladium, but also for nickel which can often be used as a substitute.
With Clariant’s experience in organometallic chemistry, we are able to make customized phosphine ligands
as well. For instance, the reaction of 2-hydroxybiphenyl with phosphorus trichloride and then with a
Grignard compound leads to high yields of 2-dialkylphosphino-2’-hydroxybiphenyls5 Scheme 2: Suzuki coupling of deactivated aryl chlorides using Fu’s catalyst systems
which show very high
activities in challenging couplings.
SUZUKI COUPLING OF HETEROAROMATIC SUBSTRATES
Heteroarylphenyl and biheteroaryl derivatives are becoming more and more important as pharmaceutical
building blocks, especially those involving pyridine- and furane-derived structures. Both heteroarylboronic
acids and heteroaryl halides can be used to assemble these structures. With six-membered nitrogen
heterocycles palladium on charcoal has
been shown to be an efficient and costeffective
catalyst
(Scheme 3a). Although the literature states
that addition of a phosphine ligand is
essential for these couplings 6 , we have
found a way to conduct the reaction under
ligand-free conditions in high yields.
This allows for easy isolation and
purification of the product.
Most heteroarylboronic acids and halides
can be coupled under Suzuki conditions,
including those derived from electron-rich
heterocycles, i.e. furans and thiophenes
(Scheme 3b).
Additionally, Clariant has developed a
copper-mediated method for the assembly
of 4-arylpyridines from arylgrignard
reagents and pyridines (Scheme 3c).
1,4-Addition of the Grignard reagent leads
to a 1,4-dihydropyridine which is easily
reoxidized to the pyridine. The main
advantage of this method is that normal
pyridines can be used which are usually
ten to fifty times cheaper than the
corresponding halopyridines.
C-C-COUPLING
Scheme 3: Heteroaryl couplings using a) heteroaryl halides,
b) heteroaryl boronic acids and c) halide-free pyridines
ALIPHATIC COUPLINGS
So far most alkyl boronic acids could not be coupled with satisfying yields under standard Suzuki conditions
because of predominant beta-hydrogen elimination which seriously constrains the utility of the Suzuki
reaction. Clariant is currently developing a process for Suzuki coupling of vinylic and especially alkyl
boronic compounds 7 . Together with the new hydroboration-based pathway to functionalized alkyl and
CHIRAL CATALYSIS - Oxidation and C-C Coupling supplement to chimica oggi • Chemistry Today
7

8
C-C-COUPLING
alkenylboronic acids described below, this new method provides a convenient way to assemble structures
that haven’t been accessible by the Suzuki method before.
INDUSTRIAL MANUFACTURE OF BORONIC ACIDS
Most boronic acids are produced by reacting an organometallic species - usually an organolithium or a
Grignard compound - with a trialkylborate, followed by aqueous workup. The organometallic species is
usually formed by Grignard reaction or halogen-metal exchange using an aryl halide as starting material.
But many aryl chlorides fail to undergo the Grignard reaction, and in general chlorides are not suitable for
halogen-metal exchange so that the
expensive bromides have to be used. For
this purpose Clariant has developed its
lithium technology - the chloroarene
precursor is metalated using solid lithium
metal, and the resulting organolithium
species is then reacted with a trialkyl
borate (Scheme 4a). Apart from obviating
the need to use expensive bromo
compounds for direct metalations of
haloarenes, this new methodology
additionally gives rise to tailor-made
organolithium bases that are made in situ
from chlorinated precursors and can be
used for metalation of C-H acidic
substrates like furanes or indoles
(Scheme 4b).
Aliphatic boronic acids are not as readily
available as aromatic and heteroaromatic
ones. Recently a broadly applicable
method for the production of
functionalized alkyl and alkenyl boronic
acids has been devoloped by Prof. Victor
Snieckus’ group in collaboration with
Clariant 8 .
When 2,5-dimethylhexa-2,4-diene is
reacted with borane or a borane source,
diisopropylprenylborane (iPP 2 BH) is
formed almost exclusively. This reagent
which can be generated and used in situ
combines properties of both
disiamylborane and allyl boranes. It can
be used to hydroborate alkenes and
alkynes, and the hydroboration products can be transformed into boronic acids and esters under mild
conditions (Scheme 4c). Finally these boronic ester can be either isolated or used directly for Suzuki
coupling reactions.
Another method currently evolving from the university laboratories is the Pd-catalyzed coupling of
haloarenes with bis(pinacolato)diboron to yield boronic pinacolate esters. Using this method
hydrolysis-sensitive boronic compounds can be prepared.
In some cases even C-H-functionalization is possible using Rh or Ir catalysts. The main drawback of this
reaction is the high price of the boron reagent and the bad atom economy of the reaction (one equivalent of
boron is discarded) which precludes its use for large-scale processes (Scheme 4d).
Scheme 4: Manufacture of boronic acids using Clariant’s lithium technology
(a) direct metalation, b) proton abstraction by an in situ made custom base),
c) diisopropylprenylborane and d) bis(pinacolato)diboron
OTHER ISSUES
For pharmaceutical use it is very important to achieve very low residual palladium contents in the final
product. Usually these strict specifications can not be met by standard workup procedures. Even with
heterogenous catalysts the amount of heavy metals leaching from the substrate is too high to be acceptable
for pharmaceutical building blocks, especially in later stages of the synthesis. Apart from standard
procedures like distillation, adsorption and complexation which are routinely employed to lower palladium
contents 9 Clariant has developed their own proprietary technology to reach residual heavy metal contents
as low as 1-2 ppm, employing readily available and cheap materials.
It is often an option to use nickel instead of palladium since most of the residual nickel can be easily
separated during work-up simply by proper pH adjustment, too. Besides this advantage, nickel is also
traded about 50-fold cheaper than palladium and not subject to daily price changes. For activated aryl
halides Pd can often be substituted by Ni. Even tosylates are amenable to nickel-catalyzed Suzuki coupling,
and when no sensitive functional groups are present, Kumada coupling employing Grignard reagents
CHIRAL CATALYSIS - Oxidation and C-C Coupling supplement to chimica oggi • Chemistry Today

C-C-COUPLING
instead of boronic acids can be used where Ni catalysts often show superior selectivity in terms of less
homocoupling-derived byproducts. At Clariant, Kumada couplings using either Pd or Ni catalysts have been
performed on a several hundred kilogram scale, too.
Another important issue when it comes to industrial-scale processes are intellectual property rights.
For kilo-lab and piloting campaigns for early-stage pharmaceutical intermediates whose clinical success
probabality is naturally limited it is often too circumstantial to negotiate about licencing issues, and
pharmaceutical companies often do not want to rely on a single source. For this reason, Clariant tries to use
proprietary technologies and methods or catalysts which are available without the necessity of preliminary
intellectual property agreements whenever possible to achieve a maximum of flexibility and independence
from third parties for the customer.
Clariant has gained experience in cross-couplings from pilot plant up to several hundred ton scale for more
than ten years now, having manufactured more than 25 different carbocyclic and heterocyclic boronic acids
and more than 20 different biaryls, heterobiaryls and oligophenyls on an industrial scale. Backed up by this
know-how, Clariant is well prepared for future challenges: The trend towards ever increasing substrate
complexity as well as heteroatom and functional group diversity at increasing economic efficiency is clearly
visible.
ANDREAS MEUDT*, SVEN NERDINGER
BERND LEHNEMANN
* Corresponding author:
Clariant GmbH
Industriepark Höchst, Building D569
D-65926 Frankfurt - Germany
REFERENCES
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C. Yang, D.R. Lieberman, R.A. Reamer, D.M. Tschaen, T.R. Verhoeven,
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J.F. Arnett, J. Org. Chem. 1994, 59, 6391.
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5. H.-J. Kleiner, D. Regnat, EP 0748811 (Hoechst AG), 1996.
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7. To be published soon.
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3399.
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CHIRAL CATALYSIS - Oxidation and C-C Coupling supplement to chimica oggi • Chemistry Today