In the world of organic chemistry, a quiet revolution is underway, turning once-stable chemical groups into versatile tools for building complex molecules.
Imagine a molecular transformation where a stable chemical group, once considered merely a protective shield or a passive spectator, can be strategically removed to create highly reactive intermediates that build complex molecular architectures. This is the reality of radical desulfonylation—an advanced synthetic technique that has emerged as a powerful tool in modern organic chemistry.
Sulfonyl-containing compounds have earned the nickname "chemical chameleons" due to their incredible reactive flexibility. Recently, chemists have discovered how to harness these compounds in radical transformations, where the sulfonyl group acts as a leaving group through selective cleavage of C-S, N-S, O-S, S-S, and Se-S bonds. These methods provide complementary strategies to classical two-electron cross-couplings that rely on organometallic or ionic intermediates 1 .
The development of radical-mediated desulfonylation has unlocked new possibilities for constructing carbon-carbon bonds, the fundamental framework of organic molecules, particularly under mild, environmentally benign conditions such as visible light irradiation 3 . This approach has proven especially valuable in pharmaceutical sciences, where it enables the modification of biologically active compounds without the need for protecting groups, streamlining the drug discovery process.
Sulfonyl compounds are organic molecules characterized by the presence of a sulfonyl group (SOâ‚‚) attached to two carbon atoms or a carbon and another atom. Traditionally used as sulfonylation reagents or protecting groups in organic synthesis, these compounds have recently revealed their potential as radical precursors when subjected to the appropriate conditions 3 .
Classical synthetic methods typically involve two-electron processes with ionic intermediates. In contrast, radical desulfonylation operates through single-electron transfer (SET) mechanisms, generating highly reactive radical species with unpaired electrons 1 3 .
The key advantage of radical approaches lies in their ability to forge new bonds through mechanisms that often complement traditional methods, accessing molecular architectures that might be challenging to construct via ionic pathways.
The transformation of stable sulfonyl compounds into reactive radicals follows several distinct pathways, depending on the specific sulfonyl precursor and reaction conditions:
In this mechanism, a photocatalyst excited by visible light transfers an electron to the sulfonyl compound, generating a radical anion intermediate. This intermediate then undergoes fragmentation, releasing the sulfonyl group as sulfur dioxide and generating a carbon-centered radical that can participate in various bond-forming reactions 3 .
In some cases, the excited photocatalyst transfers energy rather than an electron to the substrate, leading to homolytic bond cleavage and radical formation. This pathway has been implicated in reactions involving sulfonamides, where energy transfer facilitates N-O bond cleavage, followed by decarboxylation and desulfonylative Smiles rearrangement 3 .
Certain sulfonyl compounds, such as sulfinates, can form EDA complexes with reaction partners. These complexes can undergo direct photoexcitation to generate radicals without the need for an external photocatalyst, providing a simplified reaction setup 3 .
Electron transfer leads to fragmentation
Energy transfer enables bond cleavage
Direct photoexcitation without catalysts
One particularly innovative application of radical desulfonylation addresses the long-standing challenge of modular gem-difluoride synthesis. gem-Difluorides (molecules containing a CFâ‚‚ group) are important in pharmaceutical chemistry because the difluoromethylene moiety often serves as a bioisostere for oxygen, improving metabolic stability and lipophilicity of drug candidates 5 .
Before this breakthrough, synthetic approaches to gem-difluorides faced significant limitations. The conventional route relying on direct fluorination required pre-functionalized molecular frameworks and suffered from functional group incompatibility.
The ideal solution—a difluoromethylene radical anion synthon (diFRAS) that could sequentially incorporate both an electrophile and a radical acceptor—remained elusive due to the intrinsic dilemma between carbanion stability and radical reactivity.
A research team devised an elegant solution using readily available difluoromethyl phenyl sulfone (PhSOâ‚‚CFâ‚‚H) as a novel diFRAS. Their approach involved two distinct steps 5 :
The carbanion derived from PhSOâ‚‚CFâ‚‚H was reacted with various electrophiles including alkyl halides, aldehydes, ketones, and imines to form functionalized phenyl sulfones (PhSOâ‚‚CFâ‚‚R).
The synthesized phenyl sulfones were then subjected to visible light-promoted desulfonylalkylation, generating difluoroalkyl radicals (•CF₂R) that coupled with radical acceptors, particularly alkenes.
The key innovation was identifying conditions for the radical cleavage of the stubborn S-C bond in PhSOâ‚‚CFâ‚‚R derivatives. After extensive optimization, the team discovered that 2-naphthalenethiol (2-NpSH) served as both photocatalyst and hydrogen atom transfer (HAT) catalyst when combined with potassium formate in DMSO under white light irradiation 5 .
The methodology demonstrated remarkable breadth and versatility, successfully incorporating diverse structural motifs including 5 :
| Starting Material | Electrophile | Radical Acceptor | Product | Yield |
|---|---|---|---|---|
| PhSOâ‚‚CFâ‚‚H | Propionaldehyde | Vinylphenyldimethylsilane | 3a | Moderate to high |
| PhSOâ‚‚CFâ‚‚H | Cyclic sulfate | Vinylphenyldimethylsilane | 4a-4c | Moderate to high |
| PhSOâ‚‚CFâ‚‚H | Alkyl halides | Vinylphenyldimethylsilane | 4d-4i | Moderate to high |
| PhSOâ‚‚CFâ‚‚H | Estrone derivative | Vinylphenyldimethylsilane | 3r | Moderate |
Table 1: Selected Examples from the difluoromethylene Radical Anion Synthon Study 5
This breakthrough represents the first successful implementation of a double intermolecular diFRAS strategy, enabling the annexation of two additional molecules to forge gem-difluorides (Râ‚-CFâ‚‚-Râ‚‚) in a modular fashion. The method overcomes previous limitations by separating the nucleophilic and radical steps, leveraging the unique properties of the phenylsulfonyl group to stabilize the carbanion intermediate while remaining amenable to radical cleavage under mild photochemical conditions 5 .
The field of radical desulfonylation employs a diverse array of sulfonyl precursors, each offering distinct advantages and applications:
| Reagent | Chemical Structure | Function in Desulfonylation | Key Applications |
|---|---|---|---|
| Sulfonyl Chlorides | R-SO₂Cl | Source of R• radicals after SO₂ and Cl⻠loss | Trifluoromethylation of heteroarenes; alkene difunctionalization |
| Sulfinates | R-SO₂M | Alkyl radical precursors under photoredox conditions | Alkylation of heteroarenes; Csp²-Csp³ cross-coupling |
| Sulfonamides | R-NH-SOâ‚‚R' | Generate radicals via Smiles rearrangement | C-C bond construction via decarboxylation/desulfonylation |
| Difluoromethyl Phenyl Sulfone | PhSOâ‚‚CFâ‚‚H | difluoromethylene radical anion synthon (diFRAS) | Modular synthesis of gem-difluorides |
| Arenethiol Catalysts | Ar-SH | Dual photocatalyst/HAT catalyst | Enables S-C bond cleavage without expensive photocatalysts |
Table 2: Essential Reagents in Radical Desulfonylation Chemistry 1 3 5
The utility of radical desulfonylation continues to expand across various domains of synthetic chemistry:
Recent advances have demonstrated the effectiveness of radical desulfonylation in multicomponent tandem reactions. For instance, researchers have developed an additive-free four-component selenosulfonylation of alkenes that simultaneously constructs C-S and C-Se bonds under mild conditions 7 .
The merger of photoredox catalysis with radical desulfonylation has been particularly fruitful, enabling reactions under mild, environmentally benign conditions 3 . The development of metal-free photocatalytic systems using arenethiols represents an important step toward sustainable methodology development 5 .
The mild conditions and excellent functional group tolerance of radical desulfonylation have enabled its application in the late-stage modification of pharmaceuticals and biologically active compounds 3 . This capability is invaluable in medicinal chemistry for rapidly generating analog libraries.
| Biologically Active Compound | Desulfonylation Method | Modification | Significance |
|---|---|---|---|
| Fasudil | Alkyl sulfinate desulfonylation | Heteroarene alkylation | Demonstrates tolerance of unprotected amide groups |
| Rotenone | Chlorotrifluoromethylation | Alkene difunctionalization | Introduces trifluoromethyl group with 1:1 diastereoselectivity |
| Quinine | diFRAS strategy | Incorporation into gem-difluorides | Highlights potential for natural product derivatization |
| Estrone | diFRAS strategy | Incorporation into gem-difluorides | Enables steroid functionalization |
Table 3: Selected Applications in Biologically Active Molecule Modification 3 5
The development of radical desulfonylation represents a paradigm shift in how chemists approach molecular construction. By transforming stable sulfonyl groups from protective entities into versatile radical precursors, researchers have unlocked powerful new strategies for building complex molecular architectures.
As the field advances, we can anticipate several developing trends: the discovery of increasingly efficient photocatalytic systems, expansion of the substrate scope to encompass more challenging molecular frameworks, development of enantioselective desulfonylative transformations, and greater integration with other emerging technologies such as electrochemistry and flow chemistry.
The ongoing exploration of radical desulfonylation exemplifies how reimagining the role of traditional functional groups continues to drive innovation in synthetic chemistry, providing increasingly powerful tools for drug discovery, materials science, and chemical biology.
References will be added here in the final publication.
Growth in publications on radical desulfonylation (2010-2023)