Radical Fluorosulfonylation: Accessing Alkenyl Sulfonyl Fluorides from Alkenes

Article abstract of DOI:10.1002/anie.202012229

Sulfonyl fluorides have widespread applications in many fields. In particular, their unique biological activity has drawn considerable research interest in the context of chemical biology and drug discovery in the past years. Therefore, new and efficient methods for the synthesis of sulfonyl fluorides are highly in demand. In contrast to extensive studies on FSO₂⁺-type reagents, a radical fluorosulfonylation reaction with a fluorosulfonyl radical (FSO₂^.) remains elusive so far, probably owing to its instability and difficulty in generation. Herein, the development of the first radical fluorosulfonylation of alkenes based on FSO₂ radicals generated under photoredox conditions is reported. This radical approach provides a new and general access to alkenyl sulfonyl fluorides, including structures that would otherwise be challenging to synthesize with previously established cross-coupling methods. Moreover, extension to the late-stage fluorosulfonylation of natural products is also demonstrated.

Full text of DOI:10.1002/anie.202012229

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Radical Fluorosulfonylation: Accessing Alkenyl Sulfonyl Fluorides
from Alkenes
Authors: Saihu Liao, Xingliang Nie, Tianxiao Xu, Jinshuai Song,
Anandkumar Devaraj, Bolun Zhang, and Yong Chen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202012229
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Radical Fluorosulfonylation: Accessing Alkenyl Sulfonyl
Fluorides from Alkenes
Xingliang Nie,[a] Tianxiao Xu,[a] Jinshuai Song,[b] Anandkumar Devaraj,[a] Bolun Zhang,[a] Yong Chen,[a]
and Saihu Liao*[a,c]
[a]
X. Nie, T. Xu, Dr. A. Devaraj, B. Zhang, Dr. Y. Chen, Prof. Dr. S. Liao
Key Laboratory of Molecule Synthesis and Function Discovery (Fujian Province University), State Key Laboratory of Photocatalysis on Energy and
Environment, College of Chemistry, Fuzhou University
Fuzhou 350108, China
E-mail: shliao@fzu.edu.cn
[b]
[c]
Prof. Dr. J. Song
College of Chemistry and Molecular Engineering, Zhengzhou University
Zhengzhou 450001, China
Prof. Dr. S. Liao
Beijing National Laboratory of Molecular Science (BNLMS)
Beijing 100190, China
Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under https://xxxxxxxxxx..
Abstract: Sulfonyl fluorides have widespread applications in many
fields. In particular, their unique biological activity has drawn
considerable research interest in the context of chemical biology and
drug discovery in the past years. Therefore, new and efficient
methods for the synthesis of sulfonyl fluorides is highly in demand. In
contrast to extensive studies on FSO2+ type reagents, a radical
fluorosulfonylation reaction with fluorosulfonyl radical (FSO2•) remains
elusive so far, probably due to its instability and difficulty in generation.
Here, we report the development of the first radical fluorosulfonylation
of alkenes based on FSO2 radicals generated under photoredox
conditions. This radical approach provides a new and general access
to alkenyl sulfonyl fluorides, including structures that would otherwise
be challenging to synthesize with previously established cross
coupling methods. Moreover, further extention to the late-stage
fluorosulfonylation of natural products is also demonstrated.
The development of effective methods for the introduction of
functional groups or moieties is of central importance in modern
organic synthesis. In the past decade, sulfonyl fluorides have
drawn considerable research interests from different fields,[1]
encompassing organic synthesis, materials science, drug
discovery, etc.[2-6] Recently, Sulfur(VI) Fluoride Exchange
(SuFEx) has been identified by Sharpless[1a] as the new
generation of click chemistry. In particular, their unique proton-
mediated reactivity-switch-on mechanism endows sulfonyl
fluorides excellent site-specific targeting ability under complex
biological contexts.[1,4-6] In fact, the past few years have witnessed
a fast-growing research interest on the study of sulfonyl fluorides
as selective warhead in chemical biology and drug discovery.[4-6]
Consequently, the development of new and efficient synthetic
methods to expand the scope of available sulfonyl fluorides is of
great significance and highly desirable.[4,6,7]
Direct introduction of the FSO2 group by using FSO2-containing
reagents[1,8,9] represents a concise and redox economic approach,
in comparison with the conventional synthetic routes via chloride-
fluoride exchange from sulfonyl chlorides which are often limited
by their low stability and availability.[1] The known
fluorosulfonylating reagents such as the widely used sulfuryl
fluoride gas (SO2F2) and two newly developed reagents (FDIT[8a]
and AISF[8b]) can be regarded as synthetic equivalents of the
Figure 1. (A) Examples of known FSO2- reagents and FSO2 synthons in organic
synthesis. (B) Methods for the synthesis of alkenyl sulfonyl fluorides. DABSO =
1,4-diazabicyclo[2.2.2]octane-bis(sulfur dioxide).
“FSO2+” synthons. In contrast, fluorosulfonylation reaction with
fluorosulfonyl radicals (FSO2•), to the best of our known, remains
elusive so far (Figure 1A). We thus questioned whether
fluorosulfonyl radical (FSO2•) can be readily generated and
utilized in organic synthesis. In particular,
a
reactivity
fundamentally different from its cationic counterpart (FSO2+) can
be expected, which could probably bring in the opportunity to
overcome the challenging issues in sulfonyl fluoride synthesis.
Due to its instability and difficulty in generation, the FSO2• has
been regarded as a long-sought sulfur-centered radical.[11]
Nonetheless, recently Zeng and Beckers observed the formation
of this radical in the flash vacuum pyrolysis of fluorosulfonyl
azides,[11a] which encouraged us to seek appropriate FSO2•
precursors to establish a radical fluorosulfonylation reaction. Here,
1
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Table 2. The Scope of Radical Fluorosulfonylation of Terminal Olefins.[a]
we report our efforts toward this goal, and the finding that FSO2
radicals can be readily generated under photoredox conditions,
which allowed for the development of the first radical
fluorosulfonylation of alkenes. The significance and attractive
biological properties of alkenyl sulfonyl fluorides have attracted
considerable efforts to develop effective approaches to construct
this class of molecules.[1,6,9,10] These methods work well, but are
often fundamentally limited to certain type of substitutions.[9,10] For
example, only β-mono-substitutions are accessible via the cross
couplings of ArX with ethenesulfonyl fluoride (ESF) (Figure 1B).[9]
Whereas, the present radical method represents a new approach
for the synthesis of alkenyl sulfonyl fluorides, accessible to
various substitution patterns, including structures (e.g. β-alkyl, tri-
substituted ones) that would otherwise be challenging to
synthesize with the known cross coupling methods.
Table 1. Reaction Conditions for Radical Fluorosulfonylation of Styrene.[a]
Entry
Deviation from the standard conditions
none
Yield[b]
96%
20%
85%
97%
0%
1
2
3
4
5
6
solvent: PhCF3 instead of Et2O
5 mol% of Rhodamine 6G instead of [Ir]
with 1 mol% [Ir]
[a] On 0.2 mmol-scale. [b] With 5 mol% Rhodamine 6G as the photocatalyst. Ts
= 4-toluenesulfonyl.
alkenes (Table 2). Remarkably, the reaction conditions are
compatible with a wide range of functional groups such as
aldehyde (3ah), ketone (3ai), ester (3aj), and nitro (3am). Further,
multi-substituted ones (3aq-3at) also reacted well. Notably, bulky
aryl (3as) can be well introduced to the β-position of product. The
advantage of this radical method became manifested when
applied to the synthesis of β-alkyl vinyl sulfonyl fluorides (3aw-
3bb), which are challenging to synthesize via the Heck-type
couplings with ESF, due to the potential β-H elimination in cases
of alkyl substrates.[9a-c] Moreover, allylic arene (3ay), indole (3az),
alcohol (3ba) and amine (3bb) can all be smoothly
fluorosulfonylated with FSO2 radicals.
The most prominent feature of this radical method could be that
it allows for direct fluorosulfonylation of cyclic, di- and tri-
substituted olefins to access multi-substituted vinyl sulfonyl
fluorides, which are impossible to synthesize via cross couplings
with ESF.[1d,9] As shown in Table 3A, α,β- and β,β-di-substituted,
and also α,β,β-tri-substituted vinyl sulfonyl fluorides (5a-5l) can all
be synthesized via this radical approach from the corresponding
substituted olefins. Cyclic alkenyl sulfonyl fluorides (5b-5g) can
be prepared from the corresponding cyclic alkenes (4b-f). It is
worth mentioning that, for the synthesis of 5b, no product was
no photocatalyst
in dark
<1%
[a] On 0.2 mmol-scale. [b] Determined by 19F NMR analysis.
We commenced our study with the screening of suitable FSO2
radical precursors in the form of FSO2–X that might be able to
generate the FSO2 radical under photoredox conditions.[12] Even
though no desired product was observed in the reactions of
styrene with a number of possible precursors including FDIT and
fluorosulfates, we finally found sulfuryl chlorofluoride (FSO2Cl),[13]
could afford the desired radical fluorosulfonylation product, albeit
in low yield. Surprisingly, a large amount of chlorinated by-
products were detected by GC-MS analysis (for details, see Table
S1). This may be ascribed to the strong electronegativity of
fluorine, which make the chloride in FSO2Cl very electrophilic and
its reactivity significant different from the corresponding alkyl or
aryl sulfonyl chlorides (RSO2Cl).[14] Nevertheless, upon further
optimization (Table S1-3), we could finally achieve 96% 19F NMR
yield by using Ir[dF(CF3)ppy]2(dtbbpy)PF6 ([Ir]) as photocatalyst
under blue LEDs irradiation (product 3aa, Table 1, entry 1). In
addition, Rhodamine 6G, a cheap organic dye, can also promote
the reaction (entry 3). Control experiments indicate that both the
photocatalyst and light are crucial to the reaction (entry 5 & 6).
Having the optimized reaction conditions in hand, we next
examined the generality of this transformation with different
obtained
via
the
palladium-catalyzed
sulfur
dioxide
insertion/fluorination sequence from the corresponding alkenyl
triflate.[10] The superiority of this radical approach was further
demonstrated in the direct fluorosulfonylation of natural products.
The C-C double bonds of different electronic nature in oleic ester
(4m), cinnamate (4n), and chromene (4o) can all be
2
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10.1002/anie.202012229
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functionalized to give the corresponding sulfonyl fluoride 5m-5o
in good to high yields. Moreover, direct fluorosulfonylation of
Estrone-derived olefin (4p), Pregnenolone (4q), and Cholesterol
(4r) is also feasible via this radical approach. The Z/E-
configurations of 5a, 5i, 5k and 5n were assigned based on NMR
analysis and density functional theory (DFT) calculation. The E-
configuration of 5k was further confirmed by its X-ray crystal
structure (see SI for details).
fluorosulfonyl radicals, which subsequently add to the C-C double
bond of olefin and form the key intermediate Int-1. This radical
intermediate could attack FSO2Cl to give Int-2 and initiate the
chain pathway,[16] which is in line with the formation of chlorinated
product 7 in the radical clock experiment (Eq. 2). Then, Int-2 loses
HCl, giving the desired conjugated product 3.[17] Alternatively, a
redox pathway via the oxidation of Int-1 to Int-1’ by IrIV (C),
followed by deprotonation, may be also involved to some extent.
Table 3. Extension to di-, tri-, Cyclic Olefins, and Late-stage Functionalization.[a]
Figure 2. Mechanistic Study and Proposal.
In summary, fluorosulfonyl radical (FSO2•) has been
demonstrated as a feasible and useful synthon for introducing the
sulfonyl fluoride group. Its addition activity toward C–C double
enables the development of a general and facile approach for the
synthesis of alkenyl sulfonyl fluorides. In particular, this radical
fluorosulfonylation method allows for a convenient access to
multi-substituted vinyl sulfonyl fluorides, which are challenging to
synthesize via the known cross coupling methods with ESF. We
anticipate that the first demonstration of the synthetic utility of
FSO2• here will encourage the engagement in the study of radical
fluorosulfonylation in both synthetic methodology development
and target synthesis of bioactive molecules in future.
[a] On 0.2 mmol scale. [b] With 5 mol% Rhodamine 6G as the photocatalyst.
Regarding
the
reaction
mechanism,
this
radical
fluorosulfonylation was found totally inhibited by the radical
scavenger 2,2,6,6-tetramethylpiperidinooxy (TEMPO, Figure 2A,
Eq. 1). A radical clock experiment was also performed with radical
probe 6 under standard reaction conditions, which gave the ring-
opened product 7 in 41% yield, suggesting an initial radical
addition to the C-C double bond happened, followed by the ring-
opening of the three-membered ring (Eq. 2). We also performed
a DFT calculation on FSO2• and compared its properties with the
known radical of trifluoromethylsulfonyl (CF3SO2•). The FSO2•
has not only a more planar conformation but also a more positive
sulfur center (NPA charge 1.930 vs 1.579 by natural bond orbital
analysis) than CF3SO2• (Figure 2, B),[15] in consistence with the
strong electronegativity of fluorine and the highly electrophilic
nature of the chloride in FSO2Cl that led to the formation of
chloride sideproducts. Accordingly, a possible reaction pathway
is proposed in Figure 2B. The electron transfer from the excited
iridium catalyst to chlorosulfonyl fluoride generates the
Acknowledgements
We gratefully acknowledge National Natural Science Foundation
of China (Nr. 21602028), Beijing National Laboratory of Molecular
Science (BNLMS), and Fuzhou University for the financial support.
Keywords: SuFEx • Sulfonyl Fluorides • Alkenes • Radical
Reactions • Visible Light
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4
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Entry for the Table of Contents
Insert graphic for Table of Contents here.
Here demonstrates the generation of FSO2 radicals under photoredox conditions, which led to the realization of radical
fluorosulfonylation of alkenes. This method provides a new method for the synthesis of alkenyl sulfonyl fluorides, and allows for access
to many structures that would otherwise be challenging to synthesize with known methods. Late-stage functionalization of natural
products is also demonstrated.
5
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