Iterative Synthesis of Pluripotent Thioethers through Controlled Redox Fluctuation of Sulfur

Article abstract of DOI:10.1055/s-0036-1591864

Target- and diversity-oriented syntheses are based on diverse building blocks, whose preparation requires discrete design and constructive alignment of different chemistries. To enable future automation of the synthesis of small molecules, we have devised a unified strategy that serves the divergent synthesis of unrelated scaffolds such as carbonyls, olefins, organometallics, halides, and boronic esters. It is based on iterations of a nonelectrophilic Pummerer-type C-C coupling enabled by turbo -organomagnesium amides that we have recently reported. The pluripotency of sulfur allows the central building blocks to be obtained by regulating C-C bond formation through control of its redox state.

Full text of DOI:10.1055/s-0036-1591864

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
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K. Colas, A. Mendoza
Letter
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Iterative Synthesis of Pluripotent Thioethers through Controlled
Redox Fluctuation of Sulfur
Kilian Colas
Abraham Mendoza*
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Department of Organic Chemistry and Berzelii EXSELENT
Center for Porous Materials Stockholm University, Arrhenius
Laboratory, 106 91 Stockholm, Sweden
abraham.mendoza@su.se
Dedicated to Prof. Kazuhiro Kobayashi
Published as part of the Special Section 9th EuCheMS Organic
Division Young Investigator Workshop
Received: 27.10.2017
Accepted after revision: 16.11.2017
Published online: 29.01.2017
DOI: 10.1055/s-0036-1591864; Art ID: st-2017-d0792-l
Abstract Target- and diversity-oriented syntheses are based on di-
verse building blocks, whose preparation requires discrete design and
constructive alignment of different chemistries. To enable future auto-
mation of the synthesis of small molecules, we have devised a unified
strategy that serves the divergent synthesis of unrelated scaffolds such
as carbonyls, olefins, organometallics, halides, and boronic esters. It is
based on iterations of a nonelectrophilic Pummerer-type C–C coupling
enabled by turbo-organomagnesium amides that we have recently re-
ported. The pluripotency of sulfur allows the central building blocks to
be obtained by regulating C–C bond formation through control of its
redox state.
Dr. Abraham Mendoza was born and raised in Gijón, a city in the
beautiful coast of Asturias (Spain). He obtained his BSc and PhD de-
grees in Chemistry (2009) at the University of Oviedo with Profs. J. Bar-
luenga, F. J. Fañanás, and F. Rodríguez. He was awarded a Fulbright
Fellowship (2010–2012) to join Prof. P. S. Baran at The Scripps Research
Institute and then returned to Europe as a Marie Curie Fellow (2012–
2013) at the University of Cambridge with Prof. M. J. Gaunt. In late
2013, he started his independent career at Stockholm University as a
Junior Researcher of the Swedish Research Council and became ERC and
Wallenberg Academy Fellow in 2017. His group is currently pursuing
scalable and automatic synthetic methods involving C–H functionaliza-
tion, oxidative coupling, and main-group organometallic photochemis-
try.
Kilian Colas received his MSc degree in Organic Chemistry from the
University of Rouen (France) and his Engineer’s degree in Fine Chemis-
try and Process from the INSA of Rouen in 2013. After spending a year
in Actelion Pharmaceuticals Ltd. in Basel (Switzerland) he has been un-
dertaking his PhD studies in the Department of Organic Chemistry at
Stockholm University on C–C coupling reactions mediated by main-
group organometallics.
Key words sulfur, Pummerer coupling, iterative synthesis, Grignard
reagents
One of the biggest challenges of modern organic synthe-
sis is the acceleration of its own development.1 Today, auto-
matic synthesizers deliver large libraries of compounds in
predictable time scales with minimal human input, thus
enabling research campaigns in chemistry, medicine, and
biology that would have been impossible otherwise.2 The
success of automatic synthesizers is inspired by the same
principles of iterative activation and coupling that domi-
nate in Nature.3 Despite their power to create C–N, C–O, and
P–O bonds in peptides,2a oligosaccharides,2c and oligonucle-
otides,2b the automatic synthesis of ubiquitous C–C bonds is
still an ongoing endeavor.1a,2d,3e In this regard, recent cut-
ting-edge technologies have emerged to enable iterative ac-
tivation/coupling strategies towards complex molecules
(Scheme 1, A), albeit only valid for some types of C–C
bonds. Metal-catalyzed cross-couplings dominate C(sp2)-
containing bonds;2d,3b,e while carbenoid–organoboron cou-
pling excels at creating C(sp3)–C(sp3) bonds.4 All these strat-
egies are aimed at growing carbon skeletons in each itera-
tion. To the best of our knowledge, a strategy to decorate a
single carbon atom (ipso functionalization) iteratively with
diverse C(sp3), C(sp2), and C(sp) fragments is yet to be real-
ized (Scheme 1, B). Unlike homologation strategies, the
number of iterations possible for the ipso decoration of a
single carbon atom is fundamentally restricted by its bond-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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K. Colas, A. Mendoza
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ing possibilities (3–4 iterations in a sp3-hybridized carbon).
Far from undermining the potential of this approach, this
characteristic is complementary in the classes of molecules
that it targets. We envisage that such technology could
transform how building blocks are sourced, and thus how
plan conventional or automatic approaches to both target-1b,2e
and diversity-oriented syntheses are planned.5
tors.11 In connection with our activity in unusual C–C cou-
pling reactions promoted by main-group organometallics,12
our group has contributed to widen the chemical space
available to the Pummerer coupling by providing a prelimi-
nary solution to the above-mentioned incompatibility.13
Namely, we have reported a nonelectrophilic system based
on a specific magnesium base (iPr2NMgCl·LiCl) that enables
productive coupling with a wide range of aryl, alkyl,
alkenyl, and alkynyl Grignard nucleophiles (Scheme 2, A).
The resulting thioether products 1′ could in principle be S-
oxidized to initiate a second round of iterative coupling, but
the need for two separate reactions (S-oxidation and Pum-
merer) hindered the implementation of a practical iterative
protocol. In this contribution, we disclose a procedure to
perform S-oxidation followed by Pummerer C–C coupling
without isolating the intermediate sulfoxide product.
Scheme 1 Contrast between iterative homologation (A) and ipso-cou-
pling (B) strategies
This technology requires a critically important chemical
handle (grey circle; Scheme 1, B), which needs to be easily
and orthogonally activated; sufficiently stable to be trans-
ported over several iterations and ideally primed for inte-
gration with solid-phase techniques.2a–c Once the carbon
framework is assembled, it needs to be replaced by distinct
nucleophilic and electrophilic functional groups to deliver
relevant building blocks, such as boronic esters, carbonyls,
organometallics, halides, ketones, or olefins. In this regard,
thioethers 1 (Scheme 2, A) attracted our attention for their
innate synthetic potential to suit this purpose. Specifically,
thioethers can be selectively activated through mild S-oxi-
dation (favored over most functional groups), they can be
used as substrates in cross-coupling methods6 and are plu-
ripotent precursors of various functional groups.7 Addition-
ally, they have a balanced reactivity-stability profile that
has been extensively exploited in total synthesis,8 and are
primed for immobilization.9 Taking advantage of these fea-
tures, we envisioned an iterative C–C coupling strategy that
would be enabled by controlled modification of the redox
state of sulfur (Scheme 2, A). This way, a given thioether 1
would be oxidized to the corresponding sulfoxide 2 and
then reductively coupled with a C-nucleophile to provide
thioether 1′ with concomitant transfer of the redox state
from sulfur to the adjacent carbon. Thioether 1′ could thus
be a substrate for a new iteration, or be transformed into a
different functional group, as desired.
Scheme 2 Iteration design based on nonelectrophilic Pummerer C–C
coupling and the discovery of its implementation in one-pot. a Isolated
yield. b Yield determined after workup by 1H NMR using 1,1,2,2-tetra-
chloroethane as internal standard.
Among the various procedures to oxidize thioethers to
sulfoxides,14 we found that the conditions developed by
Kakarla and co-workers14a were instrumental to obtain
sulfoxides with minimal overoxidation to their sulfones. For
example, thioether 1a is efficiently oxidized to obtain the
sulfoxide 2a, which can be isolated in 92% yield after liquid
extraction workup and chromatographic purification. As
we reported earlier,13 2a engages in Pummerer coupling in
nucleophilic media, producing the thioether 1b. Using the
purified sulfoxide 2a, the Pummerer coupling produces 1b
in 73% yield (Scheme 2, B; entry 1). At first glance, the
aqueous conditions of the oxidation reaction and its work-
up seemed reasonably challenging to be telescoped in com-
bination with an organometallic reaction. To our surprise,
Despite intense and creative research dedicated to inter-
molecular reductive coupling reactions between sulfoxides
and C-nucleophiles (Pummerer processes),8,10 there were
fundamental limitations that prevented the use of organo-
metallic nucleophiles with traditional electrophilic activa-
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K. Colas, A. Mendoza
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the chromatographic purification of the sulfoxide was only
marginally relevant for our Pummerer coupling (Scheme 2,
B, entry 2). Moreover, we found that the reductive coupling
was less sensitive than we initially anticipated, and simple
high-vacuum treatment was sufficient to remove moisture
permit subsequent Pummerer coupling with similar effi-
ciency (Scheme 2, B, entry 3). This result is remarkable, tak-
ing into account that only 1.05 equiv of Grignard reagent
were used in the C–C coupling reaction. Overall, the yield
obtained for both telescoped operations compares well
with the efficiency of the stepwise synthesis (Scheme 2, B;
right column). From an engineering perspective, this result
is particularly important as implementation of the vacuum
operation would be relatively easy (as opposed to alterna-
tive workups and/or purification procedures) in a future
automatic synthesizer.
products submitted to a second round of C–C coupling with
secondary and tertiary alkyl Grignards. In this way, the
products 1d–g that arise from all four possible combina-
tions in this sequence were seamlessly obtained in 50–56%
yield. Despite the current moderate yields, the versatility of
the concept allows the synthesis of four difunctionalized
derivatives using only four different Grignard reagents. The
efficiencies obtained in this telescoped procedure16 are
similar to those observed using the stepwise protocol that
required the isolation of the intermediate sulfoxide.13 Un-
fortunately, attempts to perform two iterations in a single
flask or a third iterative coupling to create quaternary thio-
ethers were not successful and will require further develop-
ments of this chemistry, which we are currently pursuing.
The versatility of the current protocol is well illustrated
by 1e, which can be used to deliver different small mole-
cules bearing central functional groups. We have illustrated
recently13 that 1e can be oxidatively hydrolyzed into the
corresponding ketone or reduced to a specifically deuterat-
ed alkane.7e The olefin manifold can be accessed using the
method reported by Marek, thus opening the door for epox-
ides, aziridines, and cross-metathesis products.7d Oxidative
chlorination7c and fluorination allow the preparation of
electrophiles and organofluorine products, respectively.
Reductive lithiation pioneered by Screttas,7a,f provides ac-
cess to organometallic reagents that give rise, for example,
to aldehydes or boronic esters for further manipulation, in-
cluding the latest iterative carbenoid homologations.4 Thus,
To illustrate the viability of this telescoped protocol in
the synthesis of pluripotent thioether intermediates, we se-
lected thioanisole (1a) as a simple commercial substrate
that, in this context, behaves as a single carbon (C1) donor
(Scheme 3). After S-oxidation, the crude sulfoxide was
cross-coupled in situ with two different aryl sources: com-
mercial PhMgBr and 2-naphthyl bromide. The latter exem-
plifies the capacity of our nonelectrophilic Pummerer pro-
tocol to integrate with Knochel’s magnesium–halogen ex-
i
change (treating the bromide in situ with PrMgCl·LiCl).15
Both one-pot experiments yielded thioethers 1b and 1c in
64% and 52% yield over the two telescoped steps, respec-
tively. These products were again S-oxidized and the crude
Scheme 3 Iterative synthesis of diverse building blocks by controlled fluctuation of the redox state of sulfur. Reagents and conditions: H2O2, Ac2O, SiO2,
DCM, rt, followed by vacuum evaporation, followed by DIPAMgCl·LiCl, RMgX (or ArX, iPrMgCl·LiCl), THF, rt (to 65 °C). Derivatization conditions:13 (a)
Olah’s reagent, DBH, H2O, DCM, rt; (b) NiCl2·6H2O, NaBD4, THF, CD3OD, rt; (c) H2O2, Ac2O, SiO2, DCM, rt, followed by LDA, THF, –78 °C to –40 °C,
followed by nBuLi, THF, –78 °C to –50 °C, followed by Zn(CH2I)2, THF, –50 °C to rt; (d) PhICl2, DCM, rt; (e) NiCl2·6H2O, Olah’s reagent, DBH, DCM, 0 °C to
rt; (f) LiNp, THF, –78 °C to –20 °C, followed by DMF; (g) LiNp, THF, –78 °C to 0 °C followed by (iPrO)BPin. 2-Np = 2-naphthyl; DBH = 1,3-dibromo-5,5-
dimethylhydantoin; LiNp = lithium naphthalenide.
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the versatile chemistry of the C–S bond17 is primed to max-
imize the utility of the iterative C–C coupling strategy that
we have introduced herein.
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In summary, the iterative construction of complex car-
bon frameworks using sulfur compounds has been enabled
by a one-pot S-oxidation/reductive-coupling protocol. This
strategy is based on an intermolecular reductive C–C cou-
pling between sulfoxides and sp3-, sp2-, and sp-Grignard
nucleophiles that our group has recently developed.13 Here-
in we have introduced the sulfur moiety as control unit for
C–C coupling through iterative fluctuation of its redox state.
The choice of sulfur benefits from its rich chemistry, which
can deliver unrelated scaffolds such as carbonyls, olefins,
halides, organometallics and boronic esters, among others.
Despite these features, important challenges remain to be
solved to reach the goal of assembling in solid-phase qua-
ternary carbon centers in an enantiospecific fashion. Our
group is actively pursuing fundamental solutions to these
challenges, thus aiming to complement current approaches
towards iterative C–C assembly and to inspire further re-
search in downstream sulfur manipulations.
Funding Information
Financial support for this work has been received from the Knut and
Alice Wallenberg Foundation (KAW2016.0153), the ERC (StG-
714737), the Swedish Research Council (Vetenskapsrådet, 2012-
2969), the Swedish Innovation Agency (VINNOVA) through the Ber-
zelii Center EXSELENT, the Marie Curie Actions (631159), and Astra-
Zeneca AB.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591864 and for download from
Zenodo (https://doi.org/10.5281/zenodo.1033411); see Table S1 in
the Supporting Information for details.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E