Organoselenium (OSe) compounds have recently gained considerable interest as a potential class of organic motifs due to their outstanding applications in synthetic organic and medicinal chemistry and their possible properties in materials science [1,2,3,4]. These are attributed to the exceptional properties of the selenium (Se) element. The latter is a non-metal present in almost living organisms as part of selenoproteins (e.g., thioredoxin reductases and glutathione peroxidase antioxidants enzymes) [5,6,7,8,9]. Accordingly, Se is crucial for protecting human cells from oxidative damage and the immune system’s normal function [10,11,12]. Compared to sulfur (S), Se has a larger atomic radius (S: 1.02 Å vs. Se: 1.17 Å), lower electronegativity (S: 2.58 vs. Se: 2.55), higher polarizability (S: 2.9 Å vs. Se: 3.8 Å), and therefore Se is a likely better nucleophile than the S [5,8,13]. Accordingly, OSe compounds are known for their ability to react with O₂-free radicals and thus prevent the progression of oxidative stress-related diseases [3,6,10,14]. Furthermore, OSe compounds were also used in material science due to their semiconductor potential and therefore used in sodium-ion batteries, solar cells, and H₂ evolution catalysts [2,15,16,17]. Moreover, the Se center is present in many naturally occurring and bioactive interesting OSe compounds (Figure 1), such as the selenoaminoacids (e.g., selenocysteine (I), selenomethionine (II), and selenocystine (III)) [18,19,20]. Furthermore, ebselen (IV) is the most investigated Se compound with exciting GPX-like activity and has recently reached clinical phase III trials as a possible drug for Meniere’s disease [11,21,22] (Figure 1). Moreover, ethaselen (V) entered trial phase II for non-small lung cancer treatment [23,24,25,26]. On the other hand, different OSe compounds have also manifested efficient catalytic activity for various organic reactions, such as the palladium-based OSe complex VI for the Heck reaction (Figure 1) [27].

Given the exciting activities and the diverse applications of the OSe compounds, sustainable and efficient approaches for their preparation are in high demand. The synthesis of OSe compounds depends on their chemical structures (e.g., selenides, selenocyanates, diselenides) [26,28,29]. Standard methods include direct selenylation via reaction with proper Se reagents such as Na₂Se₂ and KSeCN. On the other hand, indirect selenylations include rearrangement of Se-containing precursors (e.g., isoselenocyanates) or multistep synthetic procedures using elemental Se together with organolithium or Grignard reagents and [2,13,24,30,31,32,33,34,35]. Despite being efficient, these classical strategies are relatively limited due to the challenges associated with the complicated synthetic procedure, regioselectivity, or harsh reaction conditions issues. Recently, various alternative reactions were developed as efficient and milder synthetic protocols within combinatorial chemistry (CC) [36,37,38,39,40,41,42,43]. The latter has emerged as a robust tool in medicinal chemistry [44,45]. It is now widely and consecutive covalent bonds formed between different building blocks [46]. Concurrently, drug candidates are discovered and selected by the screening of small molecule libraries for particular biological targets [47]. Despite the various strategies used in CC, multicomponent reactions (MCRs) are amongst the most investigated techniques for the efficient synthesis of chemical libraries [43,45]. MCRs have been known for over a century. They include generating skeletally diverse and complex molecular entities from more than two starting materials by straightforward chemical transformations employing comparatively mild conditions [37,48,49,50].

From an economical step and atom viewpoint, the MCR one-pot strategy would offer more robust access to OSe compounds. Though the MCRs have emerged as an efficient tool for constructing C-S bonds, similar approaches for synthesizing C-Se bonds have recently attracted more attention.

2. Metal-Catalyzed Synthesis of the OSe Compounds