Pyridine sulfinates as general nucleophilic coupling partners in palladium-catalyzed cross-coupling reactions with aryl halides

Article abstract of DOI:10.1039/c7sc00675f

Pyridine rings are ubiquitous in drug molecules; however, the pre-eminent reaction used to form carbon-carbon bonds in the pharmaceutical industry, the Suzuki-Miyaura cross-coupling reaction, often fails when applied to these structures. This phenomenon is most pronounced in 2-substituted pyridines, and results from the difficulty in preparing, the poor stability of, and low efficiency in reactions of pyridine-2-boronates. We demonstrate that by replacing these boronates with pyridine-2-sulfinates, a cross-coupling process of unrivalled scope and utility is realized. The corresponding 3-And 4-substituted pyridine variants are also efficient coupling partners. In addition, we apply these sulfinates in a library format to the preparation of medicinally relevant derivatives of the drugs varenicline (Chantix) and mepyramine (Anthisan).

Full text of DOI:10.1039/c7sc00675f

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Pyridine sulfinates as general nucleophilic coupling
partners in palladium-catalyzed cross-coupling
reactions with aryl halides†
Cite this: DOI: 10.1039/c7sc00675f
Tim Markovic,a Benjamin N. Rocke,b David C. Blakemore,b Vincent Mascittib
a
*
and Michael C. Willis
Pyridine rings are ubiquitous in drug molecules; however, the pre-eminent reaction used to form carbon–
carbon bonds in the pharmaceutical industry, the Suzuki–Miyaura cross-coupling reaction, often fails
when applied to these structures. This phenomenon is most pronounced in 2-substituted pyridines, and
results from the difficulty in preparing, the poor stability of, and low efficiency in reactions of pyridine-2-
boronates. We demonstrate that by replacing these boronates with pyridine-2-sulfinates, a cross-coupling
process of unrivalled scope and utility is realized. The corresponding 3- and 4-substituted pyridine variants
are also efficient coupling partners. In addition, we apply these sulfinates in a library format to the
preparation of medicinally relevant derivatives of the drugs varenicline (Chantix) and mepyramine (Anthisan).
Received 13th February 2017
Accepted 11th April 2017
DOI: 10.1039/c7sc00675f
rsc.li/chemical-science
internal electronic laboratory notebook;11 of 358 reactions
attempted using pyridine-2-boronates, including boronic acids,
boronic esters, and stabilized boronates (e.g. MIDA boronates),
Introduction
The Suzuki–Miyaura cross-coupling reaction,1 in which aryl
boronates are combined with aryl halides under the action of
a palladium catalyst, is the mainstay of carbon–carbon bond-
forming transformations employed in the pharmaceutical
industry.2 Factors that have contributed to the success of these
reactions include the wide availability and low toxicity of the
boron-derived substrates, excellent functional group tolerance
and simple experimental protocols, oen resulting in highly
effective transformations. These reactions allow the logical
design of synthetic pathways in which intact ring systems can
be joined together in a predictable, efficient manner.3 Unfor-
tunately, this approach oen becomes unreliable, or fails
completely, when substituted pyridine rings are employed as
nucleophilic substrates. This is most pronounced for 2-
substituted pyridines, and arises from the difficulty in prepa-
ration, poor stability4 and low reaction efficiency of pyridine-2-
boronates (Fig. 1b). Pyridine rings are embedded in a large
number of drug molecules, which are used to tackle a corre-
spondingly broad range of indications, as diverse as HIV,5 lung
cancer6 and arthritis,7 amongst many others (Fig. 1a).8
Substituted pyridine rings are also of importance as ligands in
metal-catalyzed reactions9 and as components of functional
materials.10 The scale of the challenge in using pyridine deriv-
atives in Suzuki chemistry is evident from a survey of the Pzer
aDepartment of Chemistry, University of Oxford, Chemical Research Laboratory,
Manseld Road, Oxford, OX1 3TA, UK. E-mail: michael.willis@chem.ox.ac.uk
bMedicine Design, Pzer Inc., Eastern Point Road, Groton, CT 06340, USA
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c7sc00675f
Fig.
1 (a) Examples of medicinally relevant pyridine containing
molecules; (b) the Suzuki–Miyaura cross-coupling reaction, and (c)
application to pyridine derivatives.
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only 28 experiments, corresponding to <8% of examples, ach- catalyzed desulnylative cross-coupling reactions is docu-
ieved a yield of at least 20%.
mented.15 However, examples of heterocycle-derived substrates
Such is the signicance of this coupling issue that it is are limited, and focus on the use of electron-rich ve-membered
encountered in most pharmaceutical industry projects under- variants.16
taken. Indeed, an internal survey of Pzer's medicinal chemists
The preparation of pyridine sulnates is straightforward
regarding unmet synthetic needs ranked the instability of some with a number of synthetically useful approaches available. For
heterocyclic boronates (in particular the 2-pyridyl boronate) as example, metallation of the parent pyridine followed by trap-
the number one synthetic challenge. The failure of Suzuki- ping with sulfur dioxide or a sulfur dioxide surrogate17 and the
based methods to allow access to these target structures use of Cu-mediated or Pd-catalyzed sulnylative processes are
therefore has serious consequences, potentially halting the both viable routes.13b,18 However, for this study, our preferred
preparation of targeted medicinal agents.
method was the oxidation of the corresponding thiol using
There is of course an alternative disconnection available to sodium hydroxide/hydrogen peroxide mixtures.19 This method
access 2-aryl-substituted pyridines, one in which an aryl boro- exploits commercially available (or readily prepared) thiols and
nate is combined with a 2-halopyridine. This “reverse coupling” is a high yielding, operationally simple process. We began our
approach is feasible for a smaller number of substrate combi- investigation into the cross-coupling reactivity of pyridine sul-
nations, but crucially, from a discovery chemistry perspective, nates by studying the reaction between pyridine-3-sulnate 1a
this approach fails to exploit the vast numbers of commercially and 4-bromotoluene, employing a variety of catalysts and
available bromo- and chloro-substituted arenes (relative to the reaction conditions. The optimized reaction conditions
corresponding boronates), and as such allows only a much involved the use of a catalyst generated from the combination of
narrower region of chemical space to be explored. In addition, palladium acetate and tricyclohexyl phosphine (Table 1).
no such coupling is possible for the synthesis of pyridine– Although the sulnate substrate itself is anionic, the use of an
pyridine (or related) linkages, in which by denition one of the additional inorganic base was crucial to achieve an efficient
coupling partners must be a nucleophilic pyridine. Returning to reaction; potassium carbonate was optimal, delivering the 3-
the use of pyridine 2-boronates, there are a number of reports of arylated pyridine product (2a) in 99% yield. Although some
alternative strategies to achieve efficient Suzuki reactivity for exibility in the metal cation partner of the sulnate was
these substrates, mainly focusing on the use of different boro- possible, with lithium, sodium and potassium sulnates all
nate derivatives.12 However, due to issues of insufficient scope being competent substrates, the identity of the base was more
or the need for substrate-level reaction optimization, no single constrained with only potassium and cesium carbonate being
ꢀ
method has been widely embraced by the chemistry commu- effective. A reaction temperature of 150 C was needed to ach-
nity. Given these considerations, it is evident that there is an ieve complete conversion.
urgent need for an efficient, reliable and operationally simple
methodology to replace pyridine 2-boronates in cross-coupling readily prepared and evaluated in coupling reactions with 4-
chemistry. Desirable features for such method would bromo and 4-chlorotoluene (Table 2). Pleasingly, the simplest
Pyridine-2-sulnates bearing a variety of substituents were
a
include: (i) stable and easy to prepare coupling partners; (ii) unsubstituted pyridine 2-sulnate delivered the expected
efficient reactions with both aryl bromide and chloride coupled product (2b) in excellent yields from both the bromo-
substrates; (iii) the ability to prepare the most challenging and chloro-coupling partners. The ability to routinely employ
products, namely linked pyridine-heterocyclic molecules; (iv) chloro-derivatives has benets from both cost of goods and
tolerance to the use of a single catalyst for all of the various availability perspectives.20 Although the simple unadorned
coupling combinations, involving both aryl- and heteroaryl
substrates. The collaborative research described in this article
delivers chemistry to addresses these issues.
Table 1 Key reaction parameters for the desulfinylative coupling of
pyridine sulfinate 1a and 4-bromotoluenea
Results and discussion
We recently initiated a program exploring the catalytic intro-
duction of sulfur dioxide into organic molecules,13 and during
the development of a palladium-catalyzed sulnylative route to
diaryl sulfones,14 we observed the formation of desulnylated
side-products, resulting in biaryl formation. Signicantly, these
Entry
Variation from (eqn (1))
Yield
side-products were more common when heterocycle-derived
sulnates were implicated as intermediates, relative to the
corresponding carbocyclic variants. Intrigued by the apparent
accelerated loss of sulfur dioxide from the heterocycle deriva-
tives, we instigated the present investigation to determine if we
could exploit desulnylation in the development of a syntheti-
cally useful cross-coupling process for pyridine derivatives. The
use of benzene-derived sulnates as nucleophiles in palladium-
1
2
3
4
5
Cs2CO3 in place of K2CO3
Li2CO3 in place of K2CO3
No base added
90%
0%
0%
77%
29%
K sulnate used in place of 1a
100 ꢀC
a
Reaction conditions: 1a (2.0 equiv.), 4-bromotoluene (1.0 equiv.),
K2CO3 (1.5 equiv.), Pd(OAc)2 (5 mol%), PCy3 (10 mol%). Isolated yields.
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Table 2 Substrate scope for the coupling of pyridine sodium sulfinate
A large selection of substituted benzene-derivatives were
readily employed as coupling partners with the parent pyridine-
2-sulnate (3a–e), 5-triuoromethylpyridine-2-sulnate (3f–l),
pyridine-3-sulnate (3m–o), 6-methoxypyridine-3-sulnate (3p–
x), and pyridine-4-sulnate (3y–aa) (Table 3a), demonstrating
excellent tolerance to the nature and position of substituents.
Notable amongst these examples are substrates bearing steri-
cally demanding ortho-substituents (3a,f,k,q,t,u), as well as
electronically challenging substrates such as the 2,4-dimethoxy-
chlorobenzene substrate used to deliver coupled product
(3k). An alkenyl halide coupling partner was also successfully
used (3x).
derivativesa
More challenging than combining pyridine-sulnates with
benzene-derivatives is to combine them with heteroaromatic
coupling partners to deliver linked bis-heterocyclic products
(Table 3b). Again, product 4a appears deceptively simple, but
the challenge in achieving the union of two unsubstituted
pyridine units in a 2,20-linkage is signicant using conventional
coupling strategies. 2,20-Linked bipyridines featuring a variety
of substituents were also prepared (4b,h,k), and are of interest
as this motif is the most common connection found in bipyr-
idine ligands for metal-mediated catalysis. In addition to
a variety of substituted pyridine coupling partners, heterocycles
such as pyrazines (4d), pyrimidines (4e,l), quinolines (4g,m) and
imidopyridine (4f) could be combined with pyridine-2-
sulnates without incident. Pyridine-3-sulnates (4n–u) and
pyridine-4-sulnate (4v,w) were similarly tolerant, allowing
access to a broad range of linked heterocycles.
The reactions reported in Tables 2 and 3 were routinely
performed on a 0.2 mmol scale in sealed reaction tubes.
Although we have never experienced a pressure event during
these reactions, for larger scale experiments we deemed it
prudent to move to an atmospheric pressure reaction vessel.
Accordingly, 7 grams (20 mmol) of bipyridine 4j were prepared
using a standard round-bottom ask equipped with a reux
condenser. For this larger scale transformation we employed
modied reaction conditions, and required only 1 mol% of
palladium and 2 mol% of phosphine ligand, and only 1.5
equivalents of the sulnate to deliver the coupled product in
92% yield. Dibutyl ether was used as solvent, and the reaction
a
Reaction conditions: pyridine sodium sulnate (2.0 equiv.), aryl halide
(1.0 equiv.), Pd(OAc)2 (5 mol%), PCy3 (10 mol%), K2CO3 (1.5 equiv.), 1,4-
b
dioxane, 150 ꢀC, 3–18 hours. Isolated yields. Pyridine 3-sulnate
employed. c Pyridine 4-sulnate employed.
ꢀ
pyridine-sulnate derivative supercially appears to be the most
straightforward example to employ in coupling chemistry, the
lack of substituents to moderate the basicity and coordinating
ability of the nitrogen atom in fact adds to the challenge of
successfully using this substrate.11 The remainder of the
examples feature substituted 2-pyridyl sulnates (2c–2l) and
show that both electron-donating and electron-withdrawing
substituents can be tolerated in a variety of positions around
the pyridine core, in all cases providing the coupled products in
high yields. The ability to prepare Cl-derivative 2l is particularly
notable, as the Cl-substituent provides a useful functional
group for further manipulation. In addition, pyridine-3-
sulnate itself (2m), as well as derivatives featuring both
electron-donating and -withdrawing substituents performed
well with both the Br- and Cl-coupling partners (2a, 2n), as did
the unsubstituted 4-pyridine derivative (2o).
was heated to 140 C (Scheme 1).
Tables 2 and 3 illustrate the utility of pyridine sulnate
nucleophiles to produce a wide range of structurally varied
coupled products. Further, with a focus on possible applica-
tions in medicinal chemistry we explored this methodology in
the context of library chemistry, a key enabler of rapid Structure
Activity Relationship (SAR) exploration in early drug discovery
programs. The primary goal of library chemistry is to rapidly
synthesize and purify a dened set of analogues using a broad
set of readily available reactants. The analogues prepared are
subsequently tested in vitro to rene the medicinal chemist's
understanding of SAR. In this approach, reaction scope and
synthetic efficiency (speed) are of prime importance over iso-
lated yield, and therefore automated mass-triggered HPLC is
used for rapid isolation of the minimum amount of product
necessary for testing. In this context, we prepared a collection of
pyridyl-coupled derivatives of the smoking cessation treatment
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Table 3 Substrate scope for the coupling of selected pyridine sulfinates with (a) aryl and (b) heteroaryl halidesa
(a) Variation of aryl coupling partners with pyridine sulnates
(b) Variation of heteroaryl coupling partners with pyridine sulnates
a
Reaction conditions: pyridine sodium sulnate (2.0 equiv.), (hetero)aryl halide (1.0 equiv.), Pd(OAc)2 (5 mol%), PCy3 (10 mol%), K2CO3 (1.5 equiv.),
1,4-dioxane, 150 ꢀC, 3–18 hours. Isolated yields. b Lithium sulnate employed.
varenicline.21 Specically, a chlorinated derivative (5) of vare- to produce derivatives of mepyramine, an antihistamine
nicline was combined with eight pyridyl sulnates (Scheme 2). compound that targets the H1-receptor.22 We used a variation of
The sulnates were used aer two months of storage under the optimized reaction conditions for these reactions, employ-
ambient conditions, thus establishing their credentials as ing only 1.2 equivalents of the sulnate, compared to the 2.0
stable, storable building blocks. We also performed an array equivalents used in the standard conditions. This change
experiment in the reverse format. In this case we prepared reects the complexity of the sulnate, and the need to use
a complex lithium 2-pyridyl sulnate (6), which was combined valuable, late-stage sulnates such as 6 in the most economical
with seven pyridine or pyridine-like heteroaryl bromides way possible. For the reasons mentioned above, yields obtained
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in array-type automated syntheses are oen lower than isolated
reactions, and not representative of the robustness of a specic
transformation. In both the mepyramine and varenicline arrays
all of the reactants returned the desired coupling products,
thereby validating the potential of this novel methodology for
library chemistry applications.
Scheme
1 Preparative scale synthesis of bipyridine 4j. Reaction
conditions pyridine sodium sulfinate (1.5 equiv.), aryl halide (1.0 equiv.),
Pd(OAc)2 (1 mol%), PCy3 (2 mol%), K2CO3 (1.5 equiv.), Bu2O, 140 ꢀC, 16
hours.
Conclusions
We have shown that pyridine sulnates are stable and
straightforward to prepare nucleophilic coupling partners for
palladium catalyzed cross-coupling reactions with aryl and
heteroaryl halides. The scope with respect to the halides
coupling partner is considerable, and allows the preparation of
a broad range of linked pyridines. We have shown that appli-
cation of the method to medicinally relevant molecules is
possible, including in the context of library synthesis. As the
ability to employ pyridine derivatives in efficient cross-coupling
processes is essential for medicinal chemistry, we anticipate
that these attributes will lead to brisk exploitation of this
methodology. It is likely that these reagents could also nd
application in related transition metal catalyzed processes for
which aryl and heteroaryl boronates are employed.
Acknowledgements
Financial support for this work was provided by the EPSRC and
Pzer, Inc. In addition, we acknowledge helpful discussions
with Yuan Zhang, and automated purication by Jacob Belval,
Joseph Cantone, and Bhagyashree Khunte, all of Pzer Medic-
inal Sciences. BNR, DCB, and VM are employees of Pzer Inc.
and may own stocks in the company.
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