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Synlett 2022; 33(05): 401-408
DOI: 10.1055/a-1700-6453
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Radical Fluorosulfonylation: Accessing Alkenylsulfonyl Fluorides from Alkenes and Alkynes

Xingliang Nie
,
Saihu liao  ∗

The National Natural Science Foundation of China (21602028), the Recruitment Program of Global Experts, the Beijing National Laboratory for Molecular Sciences (BNLMS201913), and Fuzhou University are gratefully acknowledged for their financial support.
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Abstract

Sulfonyl fluorides have widespread applications in many fields. In particular, the increasing research interest on the study of sulfonyl fluorides in the context of chemical biology and drug discovery in the past decade has raised a high demand for new and efficient methods for the synthesis of sulfonyl fluorides. Even though many synthetic routes have been developed in recent years, the corresponding radical fluorosulfonylation remains elusive. Here, we report our efforts toward this goal, and the identification of sulfuryl chlorofluoride (FSO2Cl) as an effective fluorosulfonyl radical precursor, as well as the development of radical fluorosulfonylation of alkenes and radical trans-chloro/fluorosulfonylation of alkynes.

1 Introduction

1.1 Functional Group Constructions

1.2 Modular Synthesis with FSO2-Containing Synthetic Blocks

1.3 Direct Fluorosulfonylation

2 Radical Fluorosulfonylation of Alkenes with FSO2Cl

3 Mechanistic Study

4 Radical Chloro/Fluorosulfonylation of Alkynes

5 Summary and Outlook


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Key words

click chemistry - SuFEx - fluorosulfonylation - radical reactions - sulfonyl fluorides
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Xingliang Nie(left) was born in Jiangxi Province, P. R. of China in 1990. He received his BSc degree in chemistry from Nanchang University College of Science and Technology in 2014 and his MSc degree in organic chemistry from Zhejiang Normal University in 2017. He then joined Professor Saihu Liao’s group at the Fuzhou University in 2018, and is currently a fourth-year PhD candidate. His research interest is in the development of novel methods for radical fluorosulfonylation through photoredox/transition-metal catalysis. Saihu Liao was born in Hunan, P. R. of China. After the completion of his bachelor and master studies in Prof. Yuefa Gong’s group at Huazhong University of Science and Technology, he began his study as a doctoral candidate under the guidance of Prof. Benjamin List at the Max-Planck-Institut für Kohlenforschung since 2007. He obtained his PhD degree in organic chemistry in 2011, and then he moved back to China and joined Prof. Yong Tang group at the Shanghai Institute of Organic Chemistry as a research associate. Since September of 2016, he started his independent research at Fuzhou University and promoted to full professor in 2017. His current research interests include organocatalytic polymerization, photoregulated polymerization, and sulfonyl fluoride chemistry.
1

Introduction

In comparison with sulfonyl chlorides, sulfonyl fluorides possess good thermodynamic stability and also show strong resistance to reduction.[1] Nevertheless, the reactivity of sulfonyl fluorides can be switched on by proton or silyl cations to activate the fluoride, which allows for a nucleo­philic substitution exclusively at the sulfur center of sulfonyl fluorides with high efficiency and reliability. By virtue of this unique reactivity, the related sulfur(VI) fluoride exchange (SuFEx) has been classified as the new generation of click chemistry by Sharpless and co-workers in 2014, which has evolved into a powerful tool in ligation chemistry.[1a] In fact, sulfonyl fluorides and the related compounds have drawn considerable research interests from different areas in the past decade, and applications encompass a broad spectrum of fields,[1] including organic synthesis,[2] polymer preparation,[3] chemical biology,[4] drug discovery,[5] etc. In particular, the right balance of stability and reactivity endows the sulfonyl fluoride ‘warheads’ excellent site-specific targeting capability under complex chemical and biological context, which has been employed in various studies, including bioconjugation, activity-based protein profiling, target identification, as well as covalent inhibitor development for drug discovery.[4] [5] [6] Notably, the introduction of a sulfonyl fluoride group could often ring in an enhanced and/or new biological activity, which resembles, to some extent, the beneficial effect of fluorine and trifluoromethyl group in pharmaceuticals.[4] For example, very recently, Dong, Zhang, Sharpless, and co-workers successfully identified fluorosulfonylated resveratrol as a potent agent against resistant bacteria, with 200-fold higher activity than the parent structure.[7] It is of great significance and also highly rewarding to develop novel and effective methods for the synthesis of sulfonyl fluorides.

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Scheme 1 Representative methods and reagents for sulfonyl fluoride synthesis

So far, there are several synthetic routes to access sulfonyl fluorides,[1] , [8] [9] [10] [11] [12] [13] which can be mainly divided into three classes (Scheme [1]).

1.1

Functional Group Constructions

A traditional approach to synthesize sulfonyl fluorides is via chloride–fluoride exchange with the corresponding sulfonyl chlorides, but this method is often limited by the availability and stability of sulfonyl chlorides.[8] In recent years, several alternative methods based on F+ reagents or equivalents have been developed, such as palladium-catalyzed SO2 insertion/fluorination sequence and transformation from thiols with SelectFluor or with potassium fluoride under electrochemical oxidative conditions.[9]


# 1.2

Modular Synthesis with FSO2-Containing Synthetic Blocks

Modular synthesis with FSO2-containing synthetic blocks or hubs could often offer a rapid approach for the construction of sulfonyl fluorides and related compounds with structural diversity.[10] [11] In this regard, ethenesulfonyl fluoride (ESF) could be one of the most widely used synthetic blocks, which can be employed as a Michael acceptor in both polar and radical addition reactions.[10] New building blocks or hubs keep emerging, for example, the Moses group recently disclosed a powerful connective hub, SASF (2-substituted alkynyl-1-sulfonyl fluorides), which can readily participate in various click cycloadditions.[12]


# 1.3

Direct Fluorosulfonylation

Compared with the functional group forging methods via S–F bond formation, direct fluorosulfonylation methods undoubtedly provide a relatively concise and redox economic approach,[1] [13] and direct fluorosulfonylation can become particularly useful in the late-stage modifications of drugs and biomolecules. Sulfuryl fluoride gas (SO2F2)[1] is one of the most extensively used electrophilic reagent, with a preference for the modification of phenols while less reactive toward amines. Recently, two reagents, FDIT and AISF, were disclosed by Sharpless, Dong,[13a] and am Ende,[13b] respectively, which showed high efficiency in the modification of both hydroxyl and amino groups via nucleophilic substitution.

So far, most of the reported fluorosulfonylating reagents are synthetic equivalents of the ‘FSO2 +’ synthons.[1] In contrast, fluorosulfonylation with the corresponding fluorosulfonyl radical (FSO2 •) remains elusive, probably due to the instability and difficulty in generation of this class of radicals.[14] In principle, the reactivity of fluorosulfonyl radicals should be different from that of the FSO2 +-type reagents and favors the radical additions to C–C double or triple bonds. Therefore, the radical approach could afford a complementary approach to the FSO2 +-type reagents in synthesis. Encouraged by this envision, we commenced our study with the search for fluorosulfonyl radical precursors, which finally led to the discovery of sulfuryl chlorofluoride (FSO2Cl) as an effective radical precursor.[15] [16]


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# 2

Radical Fluorosulfonylation of Alkenes with FSO2Cl

In 2013, Zeng and Beckers observed the formation of fluorosulfonyl radical in the flash vacuum pyrolysis of fluorosulfonyl azides,[14b] which encouraged us to initiate this project and seek reagents capable to produce fluorosulfonyl radicals under photoredox conditions. In the beginning, we examined a series of aryl fluorosulfates in the reactions with styrene under various photoredox conditions, but no fluorosulfonylation product was observed. The FDIT salt[13a] was also tested but gave no product formation either. By chance, we found a simple reagent, FSO2Cl, which could afford some fluorosulfonylation products, by 19F NMR analysis, which led to the development of the radical fluorosulfonylation reaction of olefins with an iridium complex as a photosensitizer/photocatalyst in the end (Scheme [2]).[15] This radical fluorosulfonylation reaction of alkenes provides a new method for the synthesis of alkenyl sulfonyl fluorides.

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Scheme 2 Radical fluorosulfonylation of alkenes and modification of natural products

This radical fluorosulfonylation of olefins were compatible with a wide spectrum of alkenes, including both aryl and alkyl olefins, terminal and internal alkenes (Scheme [2]). Notably, the direct radical fluorosulfonylation of di-, trisubstituted, and cyclic olefins could afford multisubstituted alkenylsulfonyl fluorides. In contrast, only the β-monosubstitutions are accessible via Heck-type cross-couplings of ArX with ethenesulfonyl fluoride (ESF).[11] Willis disclosed a synthetic route to alkenylsulfonyl fluorides, based on the couplings of enol triflates with DABSO, followed by fluorination with NFSI, but this method prefers cyclic ketone-derived substrates.[9d] It is worth mentioning that this radical approach can be employed in the direct fluorosulfonylation of the double bonds in natural products and drugs.


# 3

Mechanistic Study

Regarding the reaction mechanism of this radical fluorosulfonylation of alkenes with FSO2Cl, the reaction was found totally inhibited by the radical scavenger TEMPO. A radical clock experiment was also performed under standard reaction conditions, which gave the ring-opened product in 41% yield, suggesting an initial addition of fluorosulfonyl radical to the C–C double bond involved, followed by the ring-opening of the three-membered ring (Scheme [3]A). Accordingly, a possible reaction pathway is proposed in Scheme [3]B. The electron transfers from the excited iridium catalyst to FSO2Cl generates the FSO2 radicals, which subsequently add to the C–C double bond of olefin to give the key intermediate Int-A.[17] This radical intermediate could attack FSO2Cl to give Int-B and initiate a radical-chain pathway. Then, Int-B losing HCl in the presence of base and gives the desired alkenyl fluorides. Even though the redox pathway via the oxidation of Int-A to Int-C by IrIV cannot be excluded, the high quantum yields and also the chlorination products in the radical functionalization of alkynes suggest the redox pathway being involved at a minimum level.

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Scheme 3 Mechanistic study and a mechanistic proposal for the radical fluorosulfonylation of alkenes

# 4

Radical Chlorofluorosulfonylation of Alkynes

To our delight, FSO2Cl can also be employed in the radical functionalization of alkynes, and a series of β-chloro alkenylsulfonyl fluorides (BCASF) became accessible (Scheme [4]).[16] This radical chlorofluorosulfonyl difunctionalization reaction of alkynes showed a very good compatibility with a wide range of functional groups, including ether, halides, aldehyde, ketone, ester, nitrile, and nitro. Of note, due to the highly electrophilic nature of FSO2 radicals, electron-deficient alkynes can also be functionalized. Further, internal alkynes including both aryl and aliphatic ones are also suitable substrates. For example, 1,2-diphenylethyne and 4-octyne could be transformed into the corresponding β-chloro-substituted alkenylsulfonyl fluorides in 83% and 79% yield, respectively. The trans configuration is consistent with a radical-chain mechanism.[16]

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Scheme 4 Radical chlorofluorosulfonylation of alkynes

The introduction of both chloride and the fluorosulfonyl group onto the triple bond affords the chance to develop modular synthetic methods by using BCASF as a synthetic block or hub. As shown in Scheme [5], the BCASF molecules can undergo Suzuki or Sonogashira couplings while keeping the sulfonyl fluoride group intact, and introduce various alkyl, alkenyl, and alkynyl groups to the β-position of BCASF molecules.

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Scheme 5 Examples from the application of BCASF in modular synthesis and modification of peptides and drugs

It is worth mentioning that most of the products are challenging or not possible to synthesize before with the known methods.[1d] [f] Besides the coupling reactions, the chloride of BCASF can be selectively reduced to the cis-alkenylsulfonyl fluorides, which are less stable than the trans isomers and normally challenging to synthesize. Further, the (E)-BCASF molecules can also be isomerized to the corresponding (Z)-BCASF, which could thus offer a different geometry in the Suzuki and Sonogashira couplings. Moreover, also a very important application, BCASF can be employed as a powerful FSO2 carrier for the late-stage modification of peptides and drugs under very mild conditions with a remarkable high selectivity towards the thiol groups (Scheme [5]B).


# 5

Summary and Outlook

In summary, sulfuryl chlorofluoride (FSO2Cl) has been successfully identified as an effective precursor for the generation of fluorosulfonyl radicals (FSO2 •) under photochemical conditions. Its application to the functionalization of alkenes and alkynes has been demonstrated, which enabled the development of a general and facile approach for the synthesis of various alkenyl sulfonyl fluorides that would be otherwise challenging or even not possible to synthesize with known methods. Moreover, this radical fluorosulfonylation method allowed for late-stage modification of drugs and biomolecules. Further, the products (BCASF) of the radical chlorofluorosulfonyl difunctionalization of alkynes can be employed as a new and powerful class of sulfonyl fluoride hubs. Whereas, as FSO2Cl contains a highly electrophilic chloride and a weak S–Cl bond, radical reactions with FSO2Cl prefer a rapid radical-chain pathway and thus make trapping of alkyl radical intermediates difficult by other reagents and restrict the applicable reaction types. In this regard, the development of new radical precursors could be highly rewarding and offer a solution to overcome this limitation. Nevertheless, the first demonstration of the synthetic utility of FSO2 radicals here could serve as an inspiration for the study of FSO2 radicals and radical fluorosulfonylation in both synthetic methodology development and target synthesis of bioactive molecules in future.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank Prof. Jinshuai Song (Zhengzhou University) for the DFT calculations and Dr. Yuhao Hong (Xiamen University) for the peptide analysis.


Publication History

Received: 05 November 2021

Accepted after revision: 18 November 2021

Accepted Manuscript online:
18 November 2021

Article published online:
17 December 2021

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   Permissions and Reprints All articles of this category
Zoom Image
Xingliang Nie(left) was born in Jiangxi Province, P. R. of China in 1990. He received his BSc degree in chemistry from Nanchang University College of Science and Technology in 2014 and his MSc degree in organic chemistry from Zhejiang Normal University in 2017. He then joined Professor Saihu Liao’s group at the Fuzhou University in 2018, and is currently a fourth-year PhD candidate. His research interest is in the development of novel methods for radical fluorosulfonylation through photoredox/transition-metal catalysis. Saihu Liao was born in Hunan, P. R. of China. After the completion of his bachelor and master studies in Prof. Yuefa Gong’s group at Huazhong University of Science and Technology, he began his study as a doctoral candidate under the guidance of Prof. Benjamin List at the Max-Planck-Institut für Kohlenforschung since 2007. He obtained his PhD degree in organic chemistry in 2011, and then he moved back to China and joined Prof. Yong Tang group at the Shanghai Institute of Organic Chemistry as a research associate. Since September of 2016, he started his independent research at Fuzhou University and promoted to full professor in 2017. His current research interests include organocatalytic polymerization, photoregulated polymerization, and sulfonyl fluoride chemistry.
Zoom Image
Scheme 1 Representative methods and reagents for sulfonyl fluoride synthesis
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Scheme 2 Radical fluorosulfonylation of alkenes and modification of natural products
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Scheme 3 Mechanistic study and a mechanistic proposal for the radical fluorosulfonylation of alkenes
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Scheme 4 Radical chlorofluorosulfonylation of alkynes
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Scheme 5 Examples from the application of BCASF in modular synthesis and modification of peptides and drugs