Continuous Flow as Enabling Technology: Synthesis of Heteroaromatic Sulfinates as Bench Stable Cross-Coupling Partners

Article abstract of DOI:10.1021/acs.orglett.0c02155

An enabling continuous flow setup for handling of unstable organolithium intermediates and synthesis of heteroaryl sulfinates on a multigram scale is described. The developed continuous flow process allows for the synthesis and simple isolation of heteroaryl sulfinates which are otherwise challenging to access in classical batch mode. The lithium sulfinate salts prepared by this method were shown to be efficient reaction partners in palladium catalyzed C(sp2)-C(sp2) cross-coupling to access medicinally relevant bis-heteroaryl motifs.

Full text of DOI:10.1021/acs.orglett.0c02155

pubs.acs.org/OrgLett
Letter
Continuous Flow as Enabling Technology: Synthesis of
Heteroaromatic Sulfinates as Bench Stable Cross-Coupling Partners
Fabio Lima,* Jer
ome Andre, Alexander Marziale, Andreas Greb, Susanne Glowienke, Mark Meisenbach,
́ ̂ ́
Berthold Schenkel, Benjamin Martin, and Joerg Sedelmeier*
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sı Supporting Information
ABSTRACT: An enabling continuous flow setup for handling of
unstable organolithium intermediates and synthesis of heteroaryl
sulfinates on a multigram scale is described. The developed
continuous flow process allows for the synthesis and simple
isolation of heteroaryl sulfinates which are otherwise challenging to
access in classical batch mode. The lithium sulfinate salts prepared
by this method were shown to be efficient reaction partners in
2
2
palladium catalyzed C(sp )−C(sp ) cross-coupling to access
medicinally relevant bis-heteroaryl motifs.
iaryls, containing at least one aza-heterocyclic core, are
boronic acids to stabilized boronic esters and boronates such as
B
privileged and recurrent pharmacophoric features in the
triolborates, N-methyl iminodiacetic acid (MIDA) boronates, or
1
−3
9,11,12
small-molecule pharmaceutical landscape. An assessment of
46 WHO-registered kinase inhibitors, a compound class of
N-phenyldiethanolamine boronates.
1
Although these measures can improve the stability of the
coupling partner, they are in contrast to the green chemistry
principals due to reduced atom efficiency as well as generation of
extra organic waste and boron-containing aqueous waste
paramount importance in the pharmaceutical industry, showed
that 33 compounds possess the biaryl motif, of which 18 drugs
embody the heteroaryl−heteroaryl and 15 the heteroaryl−aryl
4
13
motif (see Figure 1). The high recurrence and value of the
streams. An additional aspect relates to preclinical safety and
the high likelihood of boronic acid derivatives to trigger an in
silico alert for mutagenicity, which can require the development
of challenging and time-consuming analytical control and testing
14,15
strategies.
In this context, the substitution of heteroaryl boronic acid
derivatives by their corresponding sulfinate salts opens the
opportunity to circumvent the above-mentioned concerns and
allows access to a complementary cross-coupling strategy.
Recently, Willis et al. described the use of heteroaryl sulfinates
(
especially pyridyl) as alternative nucleophilic partners for
2
2
16−20
2
2
palladium-catalyzed C(sp )−C(sp ) cross-couplings.
These salts are known to be bench-stable and greener compared
to stabilized boronates, with sulfur dioxide (SO ) being one of
Figure 1. C(sp )−C(sp ) in a selection of kinase inhibitors.
21
2
biaryl motif has propelled the development of a vast array of
synthetic protocols to access these scaffolds, with the
the only byproducts of the desulfinative coupling reactions.
Various methodologies for the preparation of aryl (and some
5
palladium-catalyzed Suzuki−Miyaura coupling being acknowl-
heteraryl) sulfinate salts have been described as outlined in
2
2
edged as the most popular method for C(sp )−C(sp ) bond
19,22
Scheme 1.
Aryl and heteroaryl sulfinates are accessible via
6
−8
formation in the pharmaceutical industry.
23
redox or other reactions of prefunctionalized organosulfur
Despite its widespread usage, this catalytic system reveals
limitations when heterocyclic boronic acids need to be cross-
coupled. On the basis of internal experience and also supported
Received: June 29, 2020
9
by a survey performed by Pfizer, this phenomenon becomes
even more pronounced when 2-substituted pyridine boronate
heterocycles are involved as these desirable building blocks show
10
a tendency to rapidely protodeborylate under a wide pH range.
These stability issues can be mitigated by derivatization of the
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c02155
A
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Letter
Scheme 1. Selected Methods for the Synthesis of Aryl (Ar)
and Heteroaryl (Het) Sulfinate Salts
Scheme 2. Metallation−Quench Sequence for the Synthesis
a
of Heteroaryl Sulfinates
compounds (A). Sulfinative approaches (B) occur either via
15,19−21
palladium-catalyzed sulfination of aryl halides
or by
reaction of an organometallic species with electrophilic SO or
2
19,23−26
its surrogate DABSO.
Of note, aryl sulfinates are rarely
described as isolated compounds and are typically used in situ
22
for consecutive reactions.
From an atom economy perspective, the reaction of an
hetero)aryllithium species with SO2 appears the most
(
appealing, however the limited half-life of certain heteroaryl
aryllithium intermediates render this approach challenging in
conventional batch mode. We therefore hypothesized that a
continuous flow “make and consume” approach would allow for
rapid generation and electrophilic quench of an unstable
aryllithium intermediate and thereby extend the scope of this
methodology to access a wide range of advanced heteroaryl
2
4−26
sulfinate species.
Significantly reduced residence times (≤1 s) as well as
enhanced heat- and mass-transfer in flow mode compared to
batch mode operation facilitates the handling of unstable
intermediates and enables chemistries which are highly
challenging or even impossible in conventional batch
2
7−29
reactors.
Here, we describe the synthesis of aryl sulfinates via a
metalation−sulfination sequence in continuous flow mode (C).
On the basis of our previous work in the field of organometallic
reactions, we reverted to our established continuous flow setup
which is a reliable work horse in our process development
a
(
a) Reactions were performed on 4.6 mmol scale in flow (1.0 min
collection at steady-state). (b) Isolated yields are given. Yield is
calculated on nBuLi as limiting reagent. (c) Scale up was realized by
collecting at steady-state for 31 min (2a) and 35 min (2n), amounts
isolated in parentheses.
30,31
laboratory for the synthesis of aryl boronic acids.
The
utilized flow setup integrates precooling loops for all reagent
streams: three Syrdos2 continuous syringe pumps and pressure
sensors for each reagent stream (Scheme 2). The automated
without the requirement of chromatographic purification or
recrystallization.
3
2
flow platform consists of simple PTFE T-pieces (ID = 0.5
mm) as mixing elements, and PFA tubing (ID = 0.8 mm)
providing two tubular reactors. Pleasingly, we realized that only
minimal adjustment to the established boronic acid protocol was
required to establish a flow procedure for the synthesis of aryl
sulfinates. Side-reaction of n-butyllithium (nBuLi) with SO2
leads to the formation of n-butyllithium sulfinate as a major
process impurity, which is difficult to separate from the desired
heteroaryl sulfinate moiety. Therefore, n-butyllithium was
defined as the limiting reagent while sacrificing small amounts
Optimal conversion for the preparation of sulfinates 2a−q was
achieved using a 0.4 M concentration of aryl bromide (1) in
tetrahydrofuran, a commercially available 1.6 M solution of n-
33
butyllithium in hexanes, and a 0.5 M solution of sulfur dioxide
in tetrahydrofuran. The sulfinate immediately precipitates at the
mixing point with sulfur dioxide and consisted of very fine, hard,
and nonsticky particles which did not show a tendency to
accumulate and cause clogging issues under these conditions.
To demonstrate the substrate scope and synthetic value of the
continuous flow process, standard conditions for the conversion
of various aryl bromides to lithium sulfinates were devised. In
total, 17 pharmaceutically relevant heteroaryl sulfinates were
synthesized in moderate to excellent yield. Heteroaromatic
bromides such as pyridines in all three positions (2a−h, 2l−m),
(
10 mol %) of aryl bromide. This comes at a price, however, it
simplifies the workup significantly because all nonsulfinate,
nonpolar impurities can be depleted from the product filter cake
by a washing cycle. High purity compounds are obtained
B
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Letter
and isoquinoline (2i), quininolines (2j,k), pyrimidine (2n), and
benzthioxalzole (2q) were successfully transformed to their
corresponding sulfinate salts.
We considered the scale-ups to be an important proof-of-
concept effort due to the exothermic nature of the two
consecutive reaction steps, and the potential clogging of the
reactor system with sulfinate salts during extended run-time.
Over 35 min, the unit delivered 31 g of the desired sulfinate 2n in
excellent purity and with only neglectable fluctuation in the
back-pressure.
heteroaryl lithium sulfinates) was carried out. These assessments
revealed that 2a, 2b, and 2p showed equivocal results, and the
molecules were not covered in the in silico systems used (Derek
Nexus v 6.0.0, Sarah Nexus v 3.0.0, and Case Ultra v 1.7.0.5).
However, reverse mutation assay Ames tests performed for
theses three heteroaryl sulfinates (2a, 2b, 2p) demonstrated
absence of a mutagenic potential (see Supporting Information
(SI) mutagenicity study data). Hence, they are considered as
nonmutagenic impurities, and no analytical control and testing
strategy would be necessary.
To validate the quality and reactivity of the lithium sulfinates
In concluson, we expanded on an established and reliable
31
continuous flow protocol for boronic acid preparation and
synthesized via the continuous flow procedure, with the
51
16,20
Matterson chemistry to synthesize a broad range of heteroaryl
sulfinates, which serve as valuable building blocks for the
formation of pharmaceutically relevant heterocyclic, biaryl
motifs. This emphasizes the usefulness and scope of this flow
platform and showcases the synthetic utility of organolithium
chemistry. The reported flow setup is equally suitable for the
delivery of small quantities for medicinal chemistry purposes or
for larger quantities for early development phases. We feel that
the straightforward concept will serve to reduce development
times and will generally appeal to the scientific community.
desulfinylative cross-coupling results reported by Willis,
we investigated the reaction of 2 with 3 toward bis-heteroaryls 4
see Scheme 3).
(
Scheme 3. Paladium-Catalyzed Desulfinative Cross-
Couplings of Heteroaromatic Lithium Sulfinates towards bis-
a
Heteroaryls
ASSOCIATED CONTENT
sı Supporting Information
■
*
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02155.
Detailed experimental procedures and spectral data for all
compounds. Computational toxicological report: in silico
prediction of potential mutagenic properties of aryl
sulfinates, bacterial reverse mutation assays of lithium
pyridine-2-sulfinate (2a), lithium 6-methylpyridine-2-
sulfinate (2b) and lithium 2-methylpyridine-4-sulfinate
(2p) (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Joerg Sedelmeier − Chemical and Analytical Development,
Novartis Pharma AG, Basel 4056, Switzerland; orcid.org/
0
000-0002-9683-7918; Email: joerg.sedelmeier.js1@
a
(
a) Reactions were performed using 1.0 mmol of heteroaryl halide 3
roche.com
and 1.5 mmol of heteroaryl sulfinate 2 in a sealed vessel. (b) Isolated
yields after column chromatography are given.
Fabio Lima − Global Discovery Chemistry, Novartis Institutes for
Biomedical Research, Basel 4056, Switzerland; Chemical and
Analytical Development, Novartis Pharma AG, Basel 4056,
Switzerland; orcid.org/0000-0003-2127-9568;
Email: fabio.lima@novartis.com
Under the described palladium-catalyzed cross-coupling
conditions, the lithium sulfinates originating from the
continuous flow procedure gave excellent yield and quality of
the cross-coupled products. In total, 10 pharmaceutically
relevant bis-heteroaryls were synthesized in moderate to
excellent yield following the Willis protocol (4a−j).
Despite the application of heteroaryl sulfinates in palladium-
catalyzed desulfinative cross-coupling reactions, they also
embody versatile building blocks for transition-metal-free
Authors
Jer me Andre
for Biomedical Research, Basel 4056, Switzerland
́
o
̂
́
− Global Discovery Chemistry, Novartis Institutes
Alexander Marziale − Global Discovery Chemistry, Novartis
Institutes for Biomedical Research, Basel 4056, Switzerland
Andreas Greb − Chemical and Analytical Development, Novartis
Pharma AG, Basel 4056, Switzerland
Susanne Glowienke − Preclinical Safety, Novartis Institutes for
Biomedical Research, Novartis Pharma AG, Basel 4056,
Switzerland
34
desulfinative cross-couplings3 or other useful transformations
5,36
37−45
toward sulfonyl fluorides,
sulfones,
and sulfona-
4
6−50
mides.
laboratories.
Investigations in these areas are underway in our
To finally confirm the use of these building blocks as a
replacement to potentially mutagenic boronate species for
pharmaceutical synthesis, in-house in silico assessment for the
presence of structural alerts for mutagenicity of 2a−q (17
Mark Meisenbach − Chemical and Analytical Development,
Novartis Pharma AG, Basel 4056, Switzerland
Berthold Schenkel − Chemical and Analytical Development,
Novartis Pharma AG, Basel 4056, Switzerland
C
https://dx.doi.org/10.1021/acs.orglett.0c02155
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Letter
Benjamin Martin − Chemical and Analytical Development,
Novartis Pharma AG, Basel 4056, Switzerland; orcid.org/
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Microsystems; John Wiley and Sons, 2008.
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0
000-0001-6272-1653
Colacot, T. J., Johansson Seechurn, C. C. C., Eds.; Wiley-VCH, 2020;
pp 61−90.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02155
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(
(
ACKNOWLEDGMENTS
■
We are very thankful for the support of the Novartis Continuous
Manufacturing Unit (Chemical and Analytical Development,
Novartis Pharma AG). In addition, we thank Stephane Schmitt,
Chemical and Analytical Development, Novartis Pharma AG,
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