Visible-Light-Driven Transition-Metal-Free Thiol-Free Cascade Synthesis of S-2-Pyridyl Phosphorodithioates from Malononitriles, P4S10, Alcohols: Broad Scope and HepG2 Anticancer Activity

Visible-light photoredox-catalyzed method has been developed for the synthesis of quinoxalin-2(1H)-one-containing vinyl phosphorodithioates via direct difunctionalization of alkynes with quinoxalin-2(1H)-ones, P4S10 and alcohols. This four-component reaction could be carried out under metal-free and mild conditions, affording a number of quinoxalin-2(1H)-one-containing vinyl phosphorodithioates in moderate to good yields with Z-isomers as the major products. Photocatalytic radical mechanism is proposed based on the results of radical trapping and fluorescence quenching experiments.

Organophosphorothioates are organic molecules containing sulfur and phosphorus, with significant biological activity and physicochemical properties, widely used in organic synthesis, medicinal chemistry, and the agrochemical industry. In particular, many phosphorothioates display a variety of biological activities, such as antifungal, antibacterial, anti‐parasite, anticancer, and so on. Traditionally, the synthesis of phosphorothioates has mainly relied on indirect methods involving the construction of S‐P bond. In recent years, direct phosphorothiolation has gained attention as a reliable and rapid method for introducing the ‐S‐P(O)(OR)2 group into parent molecules. This article reviews the latest advances in direct phosphorothiolation reactions, categorized based on the different sources of the ‐S‐P(O)(OR)2 group.

Recent innovations in metal‐free phosphorothioate synthesis have underscored increased utility as a sustainable alternative to metal‐catalyzed procedures. Green approaches, such as metal‐free coupling reactions and oxidations, radical‐induced methods, electrochemical processes, and multicomponent reactions, were reported from 2020 to 2025 for the successful development of S‐aryl phosphorothioates and S‐heterocyclic phosphorothioates. These methods involve high atom economy, broad functional group tolerance, and mechanistic studies, positioning metal‐free phosphorothiolation as an emergent tool of power and sustainability in modern organic synthesis under a green system.

… , and organic synthesis. In this review, the synthesis of phosphorothioate, phosphonothioate and … [ Citation 54 ] reported a transition-metal-free, one-pot strategy for the synthesis of …

… for the synthesis of β-oximino phosphorodithioates via TEMPO radical mediated four-component cascade … In 2023, Tang reported a transition-metal-free, one-pot direct synthesis of …

In recent years, transition‐metal‐ and external photocatalyst‐free photochemical reactions have garnered significant attention as environmentally friendly and sustainable approaches to organic synthesis. These reactions rely on either direct photoexcitation of substrates or photoexcitation of electron donor–acceptor complexes to enable diverse transformations. This review summarizes representative advances reported in the recent years, organized by the construction of C–C and C–heteroatom bonds, and highlights key mechanistic features. This review aims to provide guidance and inspiration for reaction design and mechanistic exploration in this field.

An environmentally friendly and resourceful modular protocol for the synthesis of phosphorochalcogenoates, phosphorochalcogenothioates, and phosphinothioates under blue light-emitting diode irradiation is described. The blue LED-promoted P-S, P-Se, and P-Te bond constructions occurred under metal-free, ligand-free, oxidant-free, and photocatalyst-free conditions with minimum chemical waste generation and high atom economy providing the resulting phosphorochalcogenoates, phosphorochalcogenothioates, and phosphinothioates in good to excellent yields.

An efficient and facile method has been developed for the construction of novel P-S-C and P-Se-C bonds by facilitating the three-component cross-coupling reaction of P-H bonds with elemental sulfur/selenium and vinylsulfonium salts, utilizing sodium bicarbonate as a base. This approach eliminates the need for the use of toxic and odorous active sulfur/selenium reagents and noble metals, thereby offering a new pathway for synthesizing S-phosphinothioates and Se-phosphinoselenoates via the organic conversion of inorganic sources. The reaction has showcased remarkable versatility in terms of substrate applicability, particularly for organophosphorus compounds containing P-H bonds and vinylsulfonium salt derivatives. The resulting phosphinothioation/phosphinoselenoation products can be obtained with high yield and regioselectivity. Additionally, a plausible reaction mechanism for this transformation has been proposed based on step-by-step control experiments and 31P NMR tracking analysis.

Two operationally simple visible-light protocols for tribromomethyl-/aryseleno-phosphorothiolation of alkenes are reported. Both methods feature broad scope, excellent functional-group tolerance, and gram-scale practicality.

A novel visible‐light‐driven protocol has been established for the direct difunctionalization of unactivated alkenes using arylhydrazines and H‐phosphine oxides as dual‐function reagents. Through visible‐light photocatalysis, phosphonyl radicals are generated as key intermediates, which undergo a cascade process involving radical addition, single‐electron oxidation, and dehydration coupling to achieve the in‐situ construction of C–P and C=N–N bonds. The method demonstrates broad substrate compatibility with excellent functional group tolerance, delivering β‐phosphinoyl hydrazones in moderate to good yields. Notably, several synthesized compounds exhibit potent anti‐proliferative activity against HepG2 cells. Mechanistic investigations through radical trapping experiments and kinetic studies confirm a radical chain pathway, with photocatalysis crucially mediating the initial radical generation and subsequent electron transfer processes.

A novel catalyst-free, three-component strategy for the synthesis of phosphinothioic/phosphinoselenoic anhydrides has been developed, employing elemental sulfur or selenium, acyl chlorides (or anhydrides), and H-phosphine oxides. This protocol operates under...

… decasulfide (P4S10) or the Lawesson’s reagent (LR), it was the topic of recent reviews [3]. … The reaction was performed under photochemical conditions (UV light). A wide range of …

BACKGROUND A wide variety of biological activities are exhibited by N, O and S containing heterocycles and recently, many reports appeared for the synthesis of these heterocycles. The synthesis of heterocycles with the help of metal and non-metal catalyst has become a highly rewarding and important method in organic synthesis. This review article concentrated on the synthesis of S-heterocylces in the presence of metal and non-metal catalyst. The synthesis of five-membered S-heterocycles is described here. OBJECTIVE There is a need for the development of rapid, efficient and versatile strategy for the synthesis of heterocyclic rings. Metal, non-metal and organocatalysis involving methods have gained prominence because traditional conditions have disadvantages such as long reaction times, harsh conditions and limited substrate scope. CONCLUSION The metal-, non-metal-, and organocatalyst assisted organic synthesis is a highly dynamic research field. For ßthe chemoselective and efficient synthesis of heterocyclic molecules, this protocol has emerged as a powerful route. Various methodologies in the past few years have been pointed out to pursue more sustainable, efficient and environmentally benign procedures and products. Among these processes, the development of new protocols (catalysis), which avoided the use of toxic reagents, are the focus of intense research.

In recent years, with the rapid development of photocatalytic and electrocatalytic technologies, multicomponent reaction systems employing carbon disulfide (CS2) or elemental sulfur (S8) as key reagents have emerged as a burgeoning research frontier in synthetic chemistry. This review systematically summarizes recent advances in the development of photocatalytic and electrocatalytic multicomponent reaction systems employing carbon disulfide or elemental sulfur as key sulfur‐containing reagents, with particular emphasis on mechanistic insights, catalytic innovation, and sustainable synthetic applications.

A simple and efficient strategy has been developed to access β-oximino phosphorodithioate through additive-free four-component reactions of sodium nitrite, aromatic alkenes, P4S10, and alcohols. The present reaction was carried out under mild conditions through a positive ion process. A series of β-oximino phosphorodithioates could be obtained in moderate to good yields by employing sodium nitrite as a promoter and an oxime source.

A visible-light-induced protocol for the synthesis of phosphorothioates is developed by employing the Ir-catalyzed decarboxylative phosphorothiolation of N-hydroxyphthalimide esters. This novel synthesis method utilizes carboxylic acids as raw material, which is stable, cheap, and commercially available. Scope studies show that this reaction has good compatibility of functional groups. Notably, both the synthesis of steric hindrance phosphorothioates and the later modification of some bioactive compounds are successfully achieved.

… , we further assessed their antitumor activity and imaged the … this area including transition-metal-free protocols to construct … via an S-phenyl phosphorothioate intermediate. This …

Organophosphorus compounds, especially phosphorylated heterocycles, are gaining increasing attention in the fields of materials science, pharmaceuticals, and agrochemistry due to their excellent biological activities. Consequently, the exploration of green and efficient methods for the synthesis of phosphorylated heterocycles has garnered significant interest from organic chemists. In recent years, visible light‐induced photoredox‐catalyzed organic synthesis has made substantial progress in the field of phosphorylation reaction since its eco‐friendly and mild conditions. This review summarizes the advance of the past five years in the visible‐light‐mediated synthesis of phosphorylated heterocycles using phosphine oxides as precursors through P‐centered radical addition, cross‐couping, and cyclization reactions.

… A metal-free synthesis of such compounds via visible light-mediated phosphonylation of 2H-indazoles with diarylphosphine oxides has been disclosed by the group of Hajra.44a The …

… synthesis of organic phosphorus compounds in recent years. On the other hand, visible-light-induced … synthesis of functionalized heterocycles [2]. For the synthesis of phosphorylated …

… generation of phosphorus radicals has been less explored.[7] With the aim of mildly generating phosphorus-based radicals, we anticipated that the use of a visible-light photocatalyst in …

Organophosphorus heterocycles have long been acknowledged for their significant potential across diverse fields, including catalysis, material science, and drug development. Incorporating phosphorus functionalities into organic compounds offers a means to effectively tailor their medicinal properties, augment biological responses, and enhance selectivity and bioavailability. The distinctive physical and photoelectric characteristics of phosphorus‐containing conjugated compounds have garnered considerable interest as promising materials for organic optoelectronics. These compounds find extensive utility in various applications such as light‐emitting diodes, photovoltaic cells, phosphole‐based fluorophores, and semiconductors.

An efficient and highly regioselective C6-phosphorylation protocol for pyrrolo[2,3-d]pyrimidine (7-DAP) derivatives with various H-phosphine oxides induced by visible light at room temperature is described for the first time. This protocol has been successfully achieved by the combination of Na2-eosin Y as a photocatalyst and LPO as an oxidant under transition metal- and additive-free conditions. The broad substrate scope, good functional group tolerance, excellent regioselectivity, and air tolerant conditions make this process favorable for the functional modification of pyrrolo[2,3-d]pyrimidine scaffold and enrich the phosphorylated 7-DAP compounds for further biological evaluation.

Heterocycles functionalized with pentavalent phosphorus are of great importance since they include a great variety of biologically active compounds and pharmaceuticals, advanced materials, and valuable reactive intermediates for organic synthesis. Significant progress in synthesis of P(O)R2-substituted six-membered heterocycles has been made in the past decade. This review covers the synthetic strategies towards aromatic monocyclic six-membered N-heterocycles, such as pyridines, pyridazines, pyrimidines, and pyrazines bearing phosphonates and phosphine oxides, which were reported from 2012 to 2022.

Metal-free, visible-light-induced denitrogenative phosphorylation of 1,2,3-benzotriazinones was achieved. With the use of eosin Y as a photoredox catalyst, N,N-diisopropylethylamine as a base, CH3CN-H2O as a solvent and sunlight or blue LED as a light source, a variety of aryl-phosphonates, -phosphinates, and -phosphine oxides were efficiently prepared. In addition, B2pin2 instead of P-nucleophiles as a radical acceptor was also demonstrated. The key advantages of this newly developed method are the clean reaction profile, use of low-cost organic-dye catalyst, energy-efficiency, broad substrate scope, good to excellent yields and large-scale synthetic applicability. The gram-scale synthesised compounds could be isolated pure just upon extraction, followed by re-crystallisation; no tedious chromatographic purification was required.