Synthesis of Pyridylsulfonium Salts and Their Application in the Formation of Functionalized Bipyridines

Article abstract of DOI:10.1021/acs.orglett.0c03048

An S-selective arylation of pyridylsulfides with good functional group tolerance was developed. To demonstrate synthetic utility, the resulting pyridylsulfonium salts were used in a scalable transition-metal-free coupling protocol, yielding functionalized bipyridines with extensive functional group tolerance. This modular methodology permits selective introduction of functional groups from commercially available pyridyl halides, furnishing symmetrical and unsymmetrical 2,2′- A nd 2,3′-bipyridines. Iterative application of the methodology enabled the synthesis of a functionalized terpyridine with three different pyridine components.

Full text of DOI:10.1021/acs.orglett.0c03048

pubs.acs.org/OrgLett
Letter
Synthesis of Pyridylsulfonium Salts and Their Application in the
Formation of Functionalized Bipyridines
Vincent K. Duong, Alexandra M. Horan, and Eoghan M. McGarrigle*
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ABSTRACT: An S-selective arylation of pyridylsulfides with good functional group tolerance was developed. To demonstrate
synthetic utility, the resulting pyridylsulfonium salts were used in a scalable transition-metal-free coupling protocol, yielding
functionalized bipyridines with extensive functional group tolerance. This modular methodology permits selective introduction of
functional groups from commercially available pyridyl halides, furnishing symmetrical and unsymmetrical 2,2′- and 2,3′-bipyridines.
Iterative application of the methodology enabled the synthesis of a functionalized terpyridine with three different pyridine
components.
ulfur-mediated organic synthesis continues to be a rich
area for exploration.1 Sulfonium salts have garnered
considerable attention of late in organic synthesis, especially
for their utility in mediating C−C bond formation (Scheme
1).2,3 Examples using sulfonium salts bearing sp2-hybridized
ligand-coupling reactions. Triarylsulfonium salts have pre-
viously demonstrated utility in transition-metal-free ligand-
coupling reactions,8 forming aryl−aryl products. However,
limited examples of heteroaryl−aryl bond formations have
been demonstrated8f,9 and, to the best of our knowledge, no
heteroaryl−heteroaryl bond formations resulting from the use
of sulfonium salts in ligand-coupling reactions have been
reported (in contrast ligand coupling via heteroarylsulfoxides
has precedent).8f,10,11 The lack of routes to access diary-
lpyridylsulfonium salts may be one reason for this. We
postulated that a general route to diarylpyridylsulfonium salts
would enable their subsequent reaction with lithiated pyridines
in a transition-metal-free coupling protocol to access function-
alized bipyridines. Bis-heteroaryls are common motifs in
organic synthesis and drug targets, especially the bipyridine
core. Bipyridines are highly sought after within the fields of
synthetic chemistry, photochemistry, material sciences, and
drug development.12 This common structural motif can be
found in biologically active natural products13 (e.g., Caer-
ulomycin F, Figure 1), but arguably, their most prevalent use is
as ligands for transition metals, in both catalysts and
photosensitizers.12
S
Scheme 1. Recent Reactions of Triarylsulfonium Salts2,3b,6
carbon substituents include reactions of vinylsulfonium salts to
generate pharmaceutically relevant heterocycles,4 cross-cou-
plings,5 and transformations using the extremely versatile
thianthrenium and benzothiophenium salts.2 Triarylsulfonium
salts have been demonstrated to be particularly versatile
reagents, capable of forming C−C bonds via various different
methods.2,3,6
Methods of accessing synthetically useful arylsulfonium salts
are limited in the literature;3 this is especially true for 2- and 4-
pyridylsulfonium salts,5,7 and consequently their applications in
organic chemistry remain underexplored. One such application
of pyridylsulfonium salts which would be beneficial to the
synthetic community involves their use in sulfur-mediated
Received: September 14, 2020
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© XXXX American Chemical Society
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further demonstrates the synthetic capabilities of sulfonium
salts as versatile functional handles in organic synthesis.
The first challenge was to develop a synthetic route to the
rare diarylpyridylsulfonium salts.7d,e Pyridylsulfides 1 were
accessed easily through SNAr reactions between the corre-
sponding thiol and halopyridines. We focused on using p-
methylthiophenol, as it is a solid with relatively low odor. The
corresponding sulfonium salts 2 were obtained by copper-
catalyzed S-selective arylation with Ph2IOTf (Tables 1 and
Figure 1. Exemplar molecules containing a bipyridine core.
Table 1. Optimization of S-Selective Arylation of
a
Pyridylsulfides
When we started this project, existing methods for making
bipyridines had limitations. They are commonly accessed using
transition-metal-catalyzed methods (Scheme 2a); however,
these processes have a significant number of constraints.
Accessibility of cross-coupling precursors, high cost of
transition metals, toxicity, and poor stability of reagents are
examples of limitations. An analysis of Pfizer e-notebooks
revealed that <8% of Suzuki−Miyaura cross-couplings with
pyridyl boronic acids/esters gave >20% yield.14 Willis and co-
workers recently reported pyridyl sulfinates as improved
coupling partners; however, this still requires costly transition
metals.14,15 The availability of transition-metal-free routes for
the synthesis of bipyridines are limited, with contributions by
McNally and co-workers being a notable advance.16 Their
phosphorane-mediated route provides access to an extensive
range of bipyridines; however, there are still limitations such as
poor EDG tolerance, limited access to fluorinated bipyridines,
and no access to 2,3′-bipyridines. Examples of the analogous
sulfur-mediated ligand-coupling processes are limited in the
literature, especially for pyridine−pyridine coupling. A route
with pyridylsulfoxides as the pyridine surrogate10 was
expanded upon significantly in a recent publication as we
finalized this manuscript.17 Qin and co-workers described
using diisopropyldisulfide to mediate the coupling of
heteroaryl Grignard reagents in good-to-excellent yield
(Scheme 2c). They focused on 2-pyridyl-heteroaryl couplings
e.g., 2,2′-bipyridines, but showed that 2,4′- and 2,3′-bipyridines
could be accessed in moderate yields in several cases; it has
been previously noted that ligand exchange processes can lead
to undesired mixtures of coupling products with 3- and 4-
pyridylsulfoxides.8f,11 We envisioned that we could develop a
simple method of accessing the synthetically useful pyridylsul-
fonium salts and apply them in effective ligand-coupling
reactions to synthesize valuable functionalized bipyridines.
This approach would involve the synthesis of diarylpyridylsul-
fonium salts, followed by reaction with lithiated pyridines
forming a sulfurane intermediate, which would undergo
heteroaryl−heteroaryl ligand-coupling to form the targeted
bipyridines (Scheme 2d). The methodology reported herein
b
Entry
Cu source
Solvent
Ratio of S/N-arylation Yield (%)
1
2
3
4
5
6
Cu, CuCl
CuCl
CuI
Cu(TC)
Cu(OTf)2
None
DCE
Toluene
DCE
DCE
DCE
DCE
4:1
40
18
67
15
69
0
3:1
14:1
10:1
>20:1
No reaction
a
Using: 1a (1.1 equiv), Ph2IOTf (1 equiv), copper source (5 mol %)
and solvent (0.6 M). Isolated yield; Cu(TC) = Copper(I) 2-
b
thiophene-2-carboxylate.
Table 2. Scope of S-Selective Arylation for the Synthesis of
Substituted 2-Pyridyldiarylsulfonium Salts (Isolated Yields,
0.4−2.9 g)
Scheme 2. Current Bis-heteroaryl Syntheses and the System Reported Herein14−17
B
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2).18 The problem of competing S- vs N-arylation had been
previously noted as a limitation.7e We discovered that the
choice of copper source was important; e.g., an initial screening
showed that the Cu/CuCl system used by Krief and co-
workers19 (Table 1, entry 1) gave the corresponding sulfonium
salt in 40% yield along with N-arylated product, which proved
to be difficult to remove by chromatography. Use of toluene as
solvent gave some product but was less effective than DCE
(entry 2). CuI gave S-selective arylation in Maruoka’s
sulfoximine synthesis20 and also gave high levels of selectivity
in our system (entry 3). Cu(TC) gave slightly reduced levels of
selectivity compared to CuI, with isolation of 2a again proving
problematic (entry 4). Optimization of the copper source
revealed that Cu(OTf)2 produced the desired sulfonium salt 2a
in 69% yield with negligible amounts of competing N-arylation
(entry 5). Using a modification of the copper-free method
developed by Olofsson and co-workers for S-arylation of
thioamides,21 there was no reaction (entry 6). The factors
influencing S- vs N-arylation remain a topic of investigation in
our laboratory.
Using this new S-selective arylation method, various novel
functionalized sulfonium salts 2b−2i were furnished on
multigram scale (Table 2) with no further optimization
required. While the S-arylation of hindered sulfides (1b,c)
was slightly lower yielding, it was pleasing to see that a range of
electronically varied salts 2d−h could be obtained in good-to-
excellent yields. Bromo-substituted salt 2i demonstrated the
potential complementarity of the proposed ligand-coupling
system. Sulfonium salts were bench-stable with no sign of
degradation over a full year.
bipyridines (Table 4). Both electron-rich and electron-poor
systems were well tolerated in different substitution patterns.
Dihalogenated pyridines were competent reaction partners (8,
13, 17, 29, 30). Functional groups such as amines, alkenes,
alkynes, sulfides and acetals were also well tolerated. Thus, a
wide range of further functionalization of the product
bipyridines is possible. Ligand-coupling also proceeded
efficiently in the presence of trifluoromethyl and fluoro groups,
two functionalities that are prevalent in medicinal chemistry.
Another noteworthy feature of the methodology is that it
enables access to underexplored 2,3′-bipyridines which have
potential in medicinal chemistry,23 as ligands,24 and have been
proposed as scaffolds for N2-fixation recently.25 No mod-
ification of conditions was required, and the method did not
seem to suffer from the problem of ligand exchange leading to
undesired 2,2′-bipyridines that had been reported for coupling
with some 3-pyridylsulfoxides8f,11 (it is unclear if Qin’s
sulfoxide method17 suffers from this problem, they report
two examples of 2,3′-bipyridines). The method is comple-
mentary to previously reported methods, and as with any
method there are limitations. In particular, to-date we have
been unable to make 2,4′-bipyridines (whereas Qin17 reports
several successful examples) and certain functional groups are
incompatible with organolithiums (see SI for further details).
Although the method is not “pot-efficient”, we note that the
single set of arylation and coupling conditions will be useful for
library synthesis. By contrast, Qin’s method17 is more “pot-
efficient” but requires different conditions for different
products.
Next, we explored the synthesis of bipyridines through
variation of sulfonium salt coupling partner (Table 4).
Substituted pyridylsulfonium salts 2b−2i were reacted with
various lithiated pyridines. A diverse range of symmetrical and
unsymmetrical bipyridines were synthesized via this method-
ology. Electron-deficient and electron-rich bipyridines could be
accessed successfully with various substitution patterns.
Sterically hindered substituted bipyridines 23−26 could be
accessed with no deleterious effect on yield, demonstrating the
tolerance of sterically hindered ligands in the carbon−carbon
bond formation step. Halogenated bipyridines were also
synthesized, providing functional handles for further derivati-
zation, highlighting the orthogonality of this process. A
limitation was that reactions with nitro-substituted sulfonium
salt 2e gave complex mixtures of products that were difficult to
separate.
With respect to the mechanism, the coupling reaction is
proposed to proceed through the formation of a sulfurane
intermediate: attack of the organolithium species at the
electropositive sulfur center, followed by subsequent ligand-
coupling of the two pyridine units forms the bipyridine
product and phenyltolylsulfide (Scheme 3).8 Sulfuranes
bearing solely carbon substituents have been proposed and
detected previously.2,8 Recently they have been invoked in
aryl−aryl, aryl−vinyl, and vinyl−vinyl couplings.2b,d In our
case, the selectivity for bipyridine formation over pyridyl−aryl
or phenyl−tolyl couplings can be rationalized as follows: the
incoming nucleophile would be expected to occupy an apical
position and ligand coupling with an equatorial pyridine would
be favored over phenyl or tolyl groups.10,11,16 The reaction
pathway may involve pseudorotations if both pyridines occupy
the apical positions in the initially formed intermediate.
Direct SNAr attack could also lead to the formation of the
bipyridine products. An initial probe of this possibility was
With a robust route to pyridylsulfonium salts in hand, we
began investigating the ligand-coupling reaction (Table 3).
Table 3. Ligand-Coupling Optimization
a
Entry
Deviation from standard conditions
Yield (%)
b
1
2
3
4
5
none
90
3-bromopyridine in place of ArI
0.05 M
0.2 M
65
67
69
48
2 equiv of halopyridine
a
b
Spectroscopic yield. Isolated yield.
Reaction conditions were screened using sulfonium salt 2a as
the model substrate and 3-iodopyridine as the coupling
partner. Under the best conditions found, lithiation at −78
°C with n-BuLi22 was followed by the addition of sulfonium
salt 2a and the reaction was left to stir at −78 °C for 2 h. The
corresponding 2,3′-bipyridine 3 was obtained in 90% yield.
Changing to 3-bromopyridine gave a yield of 65% (entry 2).
Varying the concentration from 0.1 to 0.05 or 0.2 M gave
lower yields (entries 3 and 4). Use of two equivalents of
iodopyridine also gave lower yields (entry 5).
Having identified suitable reaction conditions, we began to
explore the functional group tolerance of our system.
Sulfonium salt 2a was subjected to reaction with various
lithiated pyridines to produce a range of 2,2′- and 2,3′-
C
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a
Table 4. Variation of Organolithium and Sulfonium Salt Coupling Partners
a
b
Lithiations were performed using bromopyridine starting materials except where stated. Iodopyridine starting material was used. *Reaction
performed at 0.1 mmol scale.
The coupling method can be scaled up, as demonstrated by
the synthesis of 0.91 g of bisisoquinoline 25 without further
optimization (Scheme 5a). With methodology in hand, we
Scheme 3. Proposed Reaction Mechanism
Scheme 5. (a) Gram-Scale Synthesis of 25; (b) Modular
Synthesis of an Unsymmetrical Terpyridine 43
conducted by reacting n-BuLi and sulfonium salt 2a. The
expected product from SNAr would be 2-butylpyridine.
However, the formation of 2-phenylpyridine 42 was
observed. This outcome is consistent with formation of a
sulfurane intermediate 41 from reaction of the organolithium
and 2a, followed by ligand coupling to form the biaryl species
42 (Scheme 4).
Scheme 4. Testing the Possibility of Direct SNAr
proceeded to apply it to the synthesis of a privileged class of
ligands, terpyridines (Scheme 5b).26 Using our standard
conditions, with no optimization, a novel unsymmetrically
substituted terpyridine 43 was accessed through two sequential
ligand coupling reactions starting from readily available 2,6-
dibromopyridine. Different pyridine cores were integrated
through iterative use of our methodology, exhibiting its
synthetic potential.
D
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by Sulfur-Lithium Exchange. Chem. Soc. Rev. 2008, 37 (12), 2620−
In summary, we have developed a transition-metal-free
strategy for the synthesis of bipyridines using pyridylsulfonium
salts.27 We have also developed an S-selective arylation
methodology to furnish these synthetically useful diary-
lpyridylsulfonium salts. The combination of these methods
enables access to a wide range of symmetrical and unsym-
metrical bipyridines in a modular fashion, offering a new
complementary method to existing procedures, which we
believe will be an attractive strategy for medicinal and catalysis
chemists.
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
Corresponding Author
A.; Ball, M.; Pulis, A. P.; Procter, D. J. An Interrupted Pummerer/
Nickel-Catalysed Cross-Coupling Sequence. Angew. Angew. Chem.
2018, 130 (31), 9933−9937.
■
Eoghan M. McGarrigle − SSPC, the SFI Research Centre for
Pharmaceuticals, Centre for Synthesis & Chemical Biology,
UCD School of Chemistry, University College Dublin, Dublin,
Ireland; orcid.org/0000-0001-8160-6431;
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Email: eoghan.mcgarrigle@ucd.ie
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Sons, Ltd., Chichester, UK, pp 313−385;. (d) Peter, A.; Perry, G. J.
P.; Procter, D. J. Radical C−C Bond Formation Using Sulfonium Salts
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(e) Kozhushkov, S. I.; Alcarazo, M. Synthetic Applications of
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Vinyl Sulfonium Salts in the Stereo-Controlled Asymmetric Synthesis
of Epoxide- and Aziridine-Fused Heterocycles: Application to the
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Org. Chem. 2014, 79 (21), 10226−10239. (c) Wang, Z. H.; Shen, L.
W.; Xie, K. X.; You, Y.; Zhao, J. Q.; Yuan, W. C. Diastereoselective
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Vincent K. Duong − SSPC, the SFI Research Centre for
Pharmaceuticals, Centre for Synthesis & Chemical Biology,
UCD School of Chemistry, University College Dublin, Dublin,
Ireland
Alexandra M. Horan − SSPC, the SFI Research Centre for
Pharmaceuticals, Centre for Synthesis & Chemical Biology,
UCD School of Chemistry, University College Dublin, Dublin,
Ireland
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03048
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
V.K.D. thanks the National University of Ireland for a
Travelling Studentship. A.M.H. thanks the Irish Research
Council for a Postgraduate Scholarship (GOIPG/2017/1306).
We thank SFI (12/RC/2275_p2) and (18/RI/5702) for MS
infrastructure.
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