Multicomponent Reductive Cross-Coupling of an Inorganic Sulfur Dioxide Surrogate: Straightforward Construction of Diversely Functionalized Sulfones

Article abstract of DOI:10.1002/anie.201911449

Conventionally, sulfones are prepared by oxidation of sulfides with strong oxidants. Now, a multicomponent reductive cross-coupling involving an inorganic salt (sodium metabisulfite) for the straightforward construction of sulfones is disclosed. Both intramolecular and intermolecular reductive cross-couplings were comprehensively explored, and diverse sulfones were accessible from the corresponding alkyl and aryl halides. Intramolecular cyclic sulfones were systematically obtained from five- to twelve-membered rings. Naturally occurring aliphatic systems, such as steroids, saccharides, and amino acids, were highly compatible with the SO₂-insertion reductive cross-coupling. Four clinically applied drug molecules, which include multiple heteroatoms and functional groups with active hydrogens, were successfully prepared via a late-stage SO₂ insertion. Mechanistic studies show that alkyl radicals and sulfonyl radicals were both involved as intermediates in this transformation.

Full text of DOI:10.1002/anie.201911449

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Inorganic Sulfur Dioxide Surrogate-Involved Multicomponent
Reductive Cross-Coupling: A Straightforward Functional Sulfone
Construction and Linkage
Authors: Yingying Meng, Ming Wang, and Xuefeng Jiang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201911449
Angew. Chem. 10.1002/ange.201911449
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10.1002/anie.201911449
Angewandte Chemie International Edition
RESEARCH ARTICLE
Multicomponent Reductive Cross-Coupling of an Inorganic Sulfur
Dioxide Surrogate: Straightforward Construction of Diversely
Functionalized Sulfones
Yingying Meng1, Ming Wang*,1 & Xuefeng Jiang*,1,2
oxidation economy.[9] For example, the transition metal-
Abstract: Sulfone motifs have attracted considerable interest due to
their extensive applications in pharmaceuticals and organic
photoconducting materials. Conventionally, sulfones are prepared
via the oxidation of sulfides with strong oxidants, which has low
functional group compatibility. Herein, a multicomponent reductive
cross-coupling involving an inorganic salt (sodium metabisulfite) for
the straightforward construction of sulfones is disclosed. Both
intramolecular and intermolecular reductive cross-couplings were
comprehensively explored, and diverse sulfones were accessible
from the corresponding alkyl and aryl halides. Intramolecular cyclic
sulfones were systematically obtained from five- to twelve-
membered rings. Naturally occurring aliphatic systems, such as
steroids, saccharides and amino acids, were highly compatible with
the SO2-insertion reductive cross-coupling. Four clinically applied
drug molecules, which include multiple heteroatoms and functional
groups with active hydrogens, were successfully prepared via a late-
stage SO2 insertion. Mechanistic studies demonstrated that alkyl
radicals and sulfonyl radicals were both involved as intermediates in
this transformation.
catalyzed syntheses of sulfones and sulfonamidesfrom boronic
acids [RB(OH)2][10], organolithium reagents (RLi)[11], Grignard
reagents (RMgBr)[12] and organosilanes [RSi(OEt)3][13] have
been well established by the groups of Toste, Shavnya, Willis,
Wu and Tu, and these processes involve elegant couplings of
organometallic reagents with organohalides.[14] Over the past
few decades, direct reductive cross-couplings of distinct halides
without a pre-formed organometallic reagent have been studied
extensively (Scheme 2a-1).[15] We envisioned that the lone pair
of sulfur dioxide can be activated for diradical generation and
subsequent coupling with two distinct electrophilic partners,
which would offer a convenient and practical synthesis of
multifunctional sulfones from readily available organic halides
(Scheme 2a-2). The selectivity of the cross-coupling along with
the activation of the sulfur dioxide make this concept extremely
challenging, as compatible activation mode for distinguishing the
electrophiles and avoiding the homo-coupling by-products is
required. Recently, our research showed that sodium
metabisulfite (Na2S2O5) could be used to introduce hypervalent
sulfur especially in multicomponent tandem assembly
processes.[16] When sulfur dioxide, which has a lone pair in a p
orbital in the ground state, is excited to the active state, one
electron will move to a d orbital. Based on the transformation of
inorganic sulfur to organic sulfides,[17] we disclosed a palladium-
catalysed multicomponent reductive cross-coupling of aryl
halides, alkyl halides and sodium metabisulfite to construct
sulfones through a radical process (Scheme 2b).
Introduction
Sulfone motifs are widely present in modern pharmaceutical
molecules since they balance and control the rate of drug
metabolism and biotransformation[1]. A selection of well-known
sulfone-containing molecules that are clinically applied drugs are
shown in Scheme 1.[2-7] Conventionally, sulfones are prepared
via the oxidation of sulfides with strong oxidants, resulting in low
functional group compatibility.[8] Strategies for sulfone
construction through the introduction of sulfur dioxide into
organic frameworks is of great interest due to its atom, step and
Results
Optimization of the multicomponent reductive cross-coupling:
We commenced the multicomponent reductive coupling with
sodium metabisulfite (Na2S2O5), 4-iodotoluene, and n-butyl
bromide in the presence of the catalyst and potassium hydrogen
phosphate in dimethyl sulfoxide. Diverse nickel and cobalt
catalysts were tested first since they have exhibited impressive
catalytic activities in reductive cross-couplings. However,
desired sulfone 3a was only detected in 29% yield in the
[1]
Y. Meng, Dr. M. Wang, Prof. Dr. X. Jiang
Shanghai Key Laboratory of Green Chemistry and Chemical
Process, School of Chemistry and Molecular Engineering, East
China Normal University, 3663 North Zhongshan Rd., Shanghai
200062 (P. R. China).
E-mail: xfjiang@chem.ecnu.edu.cn; wangming@chem.ecnu.edu.cn.
Prof. Dr. X. Jiang
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, Shanghai (P. R. China)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
.
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Scheme 1. Important sulfone-containing molecules.
Scheme 2. The reductive cross-coupling reaction.
presence of NiCl2(dppf), and this was the best reaction outcome
(Table 1, entries 1-5). Delightfully, sulfone formation was
achieved in 73% yield when PdCl2(dppf) was employed (Table 1,
entries 6-7). Further evaluation of ligands revealed that 1,3-
bis(diphenylphosphino)propane (dppp), triphenylphosphine and
Xantphos
furnished
lower
yields
than
1,1'-
ferrocenebis(diphenylphosphine) (dppf) (Table 1, entries 8-10).
Using tin instead of zinc as a reductant dramatically increases
the efficiency of the formation of sulfone 3a (96% yield, Table 1,
entries 11-14).
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Table 1. Optimization of the multicomponent reductive cross-coupling.[a]
diverse aryl halides smoothly underwent the reaction with
sodium metabisulfite to afford the corresponding five-membered
(3ak-3am) and six-membered (3an-3as) cyclic sulfones.
Remarkably, medium-sized rings (3at and 3au (seven-
membered), 3av and 3aw (eight-membered), and 3ax (nine-
membered)) were efficiently generated via this transformation.
Even macrocyclic compounds (3ay-3ba, ten- to twelve-
membered rings) can be established through the current
strategy with promising efficiency.
Entry
1
Catalyst
-
Ligand
dppf
Reductant Yields (%)b
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Mn
Mg
Fe
Sn
0
9
2
NiCl2
dppf
3
NiCl2(dppf)
Ni(COD)2
CoCl2
dppf
29
4
dppf
trace
trace
64
To highlight the great applicability of this multicomponent
reductive cross-coupling protocol suitable for a broad array of
aryl and alkyl halide electrophiles, its efficacy with naturally
occurring biomolecules and pharmaceutical systems was
investigated (Scheme 4). Sulfone-containing estrone (3bb),
borneol (3bc) and lenalidomide (3bd) derivatives were obtained
in high yields from the corresponding aryl and alkyl halide
precursors. The structure of 3bb was confirmed through X-ray
diffraction analysis.[18] Saccharides, such as fructose and
glucose derivatives, were also compatible and provided the
corresponding sulfone derivatives (3be and 3bf). Amino acids,
including L-phenylalanine and L-leucine, were coupled with alkyl
bromides using SO2 as the connector via the current strategy
(3bg-3bj). Specifically, L-phenylalanine and L-valine could be
coupled with cholesterol via the current multicomponent
reductive cross-coupling protocol (3bk and 3bl).
5
dppf
6
7c
Pd(OAc)2
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
dppf
dppf
73
8
dppp
PPh3
Xantphos
dppf
54
9
45
10
11
12
13
14
11
30
dppf
50
dppf
53
dppf
96
[a]Reaction conditions: 1a (0.1 mmol), Na2S2O5 (0.2 mmol), 2a (0.3 mmol),
catalyst (0.01 mmol), ligand (0.02 mmol), reductant (0.3 mmol), K2HPO4·3H2O
(0.2 mmol), TBAB (0.15 mmol), DMSO (1.0 mL), 100 °C, 10 h, [b]isolated yields.
With the optimized conditions in hand, the reductive cross-
coupling was systemically studied (Scheme 3), and
a
comprehensive library of functionalized sulfones was
established. Substituents at the meta or even ortho positions of
the aromatic ring of the aryl halide substrates were well tolerated.
A broad range of aryl halides bearing electron-donating (3e-3h)
or electron-withdrawing (3i-3n) groups were coupled in good to
excellent yields. Aryl iodides with fused ring systems were
converted to the desired sulfones in good yields (3q). This
reaction was generally quite efficient for heteroaryliodide
substrates, namely, indolyl, pyridinyl and thiophene-derived
substrates (3r-3t).
To further demonstrate the practicality and applicability of the
multicomponent reductive cross-coupling protocol, clinically
applied pharmaceutical molecules were synthesized via the
current cross-coupling strategy with sulfone installation as the
last stage, highlighting the attractiveness of this protocol
particularly in the pharmaceutical industry (Scheme 5). The
antipsychotic drug amisulpride, which has free amide and amine
groups, was efficiently prepared using the developed
transformation (61% yield, 4a). Late-stage modifications of
amisulpride were then conducted by employing different alkyl
halide precursors to afford diverse amisulpride analogues (4b
and 4c). The SO2 motif was incorporated into a series of
Furthermore, a variety of alkyl electrophiles, including ethyl
bromides and strained four-membered alkyl bromides (3u-3aa),
suitable for the reaction. A large range of functional groups,
including methylthio (3ad), vinyl (3ae, 3af), and perhaps most
notably, alkynyl (3ag), are readily tolerated in this process.
Following the successful establishment of a sulfone library from
the intermolecular variant, sulfones generated from the
intramolecular variant, the structures of which were confirmed
via X-ray diffraction analysis of compound 3at,[18] were further
studied to highlight the efficiency of this method for the
preparation of cyclic sulfones. A broad range of electronically
pharmaceuticals
bearing
multiple
heteroatom-containing
functional groups. The COX-2 inhibitor rofecoxib (4d), the small
molecule utrophin modulator ezutromid (4e) and the first
Hedgehog signalling pathway-targeting agent vismodegib (4f)
were successfully obtained from the corresponding aryl and alkyl
halides through the current strategy.
To determine the mechanism of the multicomponent reductive
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10.1002/anie.201911449
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Scheme 3. The reductive cross-coupling of aryl halides, Na2S2O5 and alkyl halides.[a] [a]Reaction conditions: 1 (0.1 mmol), Na2S2O5 (0.2 mmol), 2 (0.3 mmol),
PdCl2(dppf) (0.01 mmol), dppf (0.02 mmol), Sn (0.3 mmol), K2HPO4·3H2O (0.2 mmol), TBAB (0.15 mmol), DMSO (1.0 mL), 100 °C, 10 h, isolated yields. [b]dppp
instead of dppf. [c]90 °C instead of 100 °C. [d]AlCl3 instead of K2HPO4·3H2O. [e]LiCl instead of K2HPO4·3H2O.
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Scheme 4. Three-component reductive cross-coupling of functional molecules.[a] [a]Reaction conditions: 1 (0.1 mmol), Na2S2O5 (0.2 mmol), 2 (0.3 mmol),
PdCl2(dppf) (0.01 mmol), dppf (0.02 mmol), Sn (0.3 mmol), K2HPO4·3H2O (0.2 mmol), TBAB (0.15 mmol), DMSO (1.0 mL), 100 °C, 10 h, isolated yields.
Scheme 5. Late-stage modification and synthesis of pharmaceuticals.
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-5.8
-6.2
-6
y = 1.0082x - 3.8178
R2 = 0.9800
y = 0.1882x - 4.995
-5.6
R2 = 0.9958
-5.8
-5.6
-5.4
-5.2
-5
-5.4
-5.2
-5
-4.8
-1.3
-1.8
-2.3
-2.8
-0.5
-1
-1.5
-2
-5.4
-5.2
-5
-5.6
-5.4
-5.2
-5
y = 0.1269x - 4.3217
y = 0.1732x - 4.9382
R2 = 0.9947
-4.8
-6.2 -6.4 -6.6 -6.8
-7
-7.2 -7.4 -7.6
-1.3
-1.5
-1.7
-1.9
-2.1
-2.3
-2.5
Scheme 6. Mechanistic study.
cross-coupling reaction, 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) was added in the standard conditions, and the desired
product 3a was provided in trace (Scheme 6a-1). Subsequently,
(bromomethyl)cyclopropane
5
was conducted under the
standard conditions (Scheme 6a-2). Ring-opened product 3ae
was obtained in 38% yield, which provided strong evidences for
an alkyl radical intermediate being involved in this transformation.
a
radical clock experiment involving aryl halide 1a and
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Sulfonyl iodide 7, which furnished desired product 3a in only
14% yield, indicated that the intermediate was not involved in
the current reaction (Scheme 6b-1). In the absence of
PdCl2(dppf) and the ligand, desired product 3a was not detected,
but homo-coupling product 8 was obtained in 75% yield,
indicating that the palladium and ligand were necessary to
activate the aryl halide (Scheme 6b-2). Kinetic studies were
used to further elucidate the mechanism, as shown in (Scheme
6c.) The concentration of aryl halide had a significant effect on
the rate of product formation (Scheme 6c, II), and the reaction
rate shows 1.00th-order dependence on the aryl halide, 0.188th-
order in the alkyl halide (Scheme 6c, I), 0.173th-order in
Na2S2O5 (Scheme 6c, III) and 0.127th-order in PdCl2(dppf)
(Scheme 6c, IV). These results demonstrated that the oxidative
addition of the aryl halide was the rate-determining step, and the
formations of both the alkyl radical and alkyl radical with sodium
metabisulfite are rapid.
Based on these experimental results, a reaction pathway was
predicted as shown in (Scheme, 7). Alkyl radical intermediate 9
was generated via a single-electron transfer process between
alkyl halide 2a and tin. The reaction of intermediate 9 and
sodium metabisulfite provides sulfonyl radical 10, which could be
reduced by tin to afford sulfonyl anion 11. Intermediate 12, which
was formed via the oxidative addition of aryl halide to Pd0,
reacted with intermediate 11, leading to the precipitation of
intermediate 13. Reductive elimination from 13 afforded desired
product 3 and regenerated the Pd0 catalyst.
Scheme 7. Plausible mechanism.
demonstrated that alkyl radicals and sulfonyl radicals were
involved as intermediates in this transformation. Remarkably,
this broadly applicable method shows good step economy and a
Conclusion
In conclusion, an efficient and practical multicomponent
reductive cross-coupling involving an inorganic salt (sodium
metabisulfite) for the synthesis of sulfones through a simple
combination of alkyl and aryl halides is reported. Both the
intermolecular and intramolecular reductive cross-couplings
were fully explored and provided facile access to a wide range of
sulfones from the corresponding alkyl and aryl halides. Using the
intramolecular variant, five- to twelve-membered cyclic sulfones
were systematically generated. Naturally occurring biomolecules,
such as steroids, saccharides, and amino acids, were highly
compatible with this multicomponent reductive cross-coupling
protocol. Four drug molecules bearing multiple heteroatoms and
active hydrogen-containing functional groups were efficiently
prepared via late-stage SO2 insertion. Mechanistic studies
high tolerance for
a
wide range of functionalities by
circumventing the use of pre-prepared organometallic species.
Further drug discovery studies with this protocol are underway in
our laboratory.
Acknowledgements
The authors are grateful for the financial support provided by
The National Key Research and Development Program of China
(2017YFD0200500), NSFC (21971065, 21722202, 21672069
and 21871089 for M.W.), S&TCSM of Shanghai (Grant
18JC1415600), Professor of Special Appointment (Eastern
Scholar) at Shanghai Institutions of Higher Learning, and the
National Program for Support of Top-notch Young Professionals.
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Keywords: sulfone • sulfur dioxide • sodium metabisulfite •
radical • reductive cross-coupling
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Angewandte Chemie International Edition
RESEARCH ARTICLE
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RESEARCH ARTICLE
Yingying Meng, Ming Wang*, and
Xuefeng Jiang*
Page No. – Page No.
Multicomponent Reductive Cross-
Coupling of an Inorganic Sulfur
Dioxide Surrogate: Straightforward
Construction of Diversely
Functionalized Sulfones
A multicomponent reductive cross-coupling involving an inorganic salt for the
straightforward construction of sulfones is disclosed. Both intramolecular and
intermolecular reductive cross-couplings were comprehensively explored, and
diverse sulfones were accessible from the corresponding alkyl and aryl halides.
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