# Isocyanide Multicomponent Reactions on Solid Phase: State of the Art and Future Application
## 2 Isocyanide-Based Multicomponent Reactions (IMCRs)
### Practical Assessments  
From a practical point of view, a single synthetic transformation instead of traditional follow-up synthesis is one of the advantages of IMCRs, which is reflected in the large interest in MCRs. The feasibility of the synthesis involving the Ugi reaction in comparison to the standard stepwise synthetic protocol is illustrated in the following example (Scheme 2). While the conventional synthesis of linear precursor **15** involved 3 steps [33], analogous intermediate **21** was formed by U-4 CR in only one step [34]. Acidic treatment initiated a cleavage of the protecting groups as well as simultaneous cleavage of the intermediate from the resin and cyclization to the target 3,4-dihydropyrazin-2(1\(H\))-one **16** and **22**. A reduction in the synthetic steps is one of several advantages of IMCRs. Other advantages are high atom-efficiency (when only one molecule of water is lost) and usually high yields of product. The yields of the products are primarily sensitive to the nature of the aldehyde [35]. The aliphatic aldehydes and aromatic aldehydes bearing electron-donating groups (EDGs) afforded good yields in comparison to the aldehydes containing electron-withdrawing groups (EWGs, e.g., References [35; 36; 37; 38]). Even larger excess reagents or repeated addition of fresh reagents often did not improve the yield [35; 38], although the opposite observation was also described [39]. In addition to the poor reactivity of aromatic aldehydes in the Ugi reaction, aromatic isocyanides were also reported to be less reactive [40]. Since a limited number of commercially available isocyanides greatly reduces the structural diversity of a library [35], convertible isocyanides play an important role in the achievement of diverse products. Another important aspect of IMCRs is the unpleasant odor of most isocyanides. This odor can be circumvented by immobilization of isocyanides onto a polymer support, which is an advantage of solid-phase synthesis (SPS) over solution-phase synthesis. The other option to avoid the odor is the preparation of the isocyanide in situ, which has been applied so far only in the solution phase [41; 42]. The scope of the reaction components is not limited to amine, aldehyde, carboxylic acid, and isocyanide--alternative reagents were successfully examined. For example, sulfonamide was used as an amine reagent [43], imine was directly bound to the Rink resin [44], or ketones were applied to replace the aldehydes despite their lower reactivity [45; 46; 47; 48; 49]. Alternatively, glyoxal was used as the aldehyde component in U-4 CR, and the second carbonyl functionality was employed for the imidazole ring formation [50]. Alcohol was used as an acid component [39], or application of thiocarboxylic [51; 52], cyanic [53; 54], thiocyanic, or hydrazoic acid [54] was reported in the literature. Alternatively, one starting component can bear two functional groups, e.g., ketoacid, thus serving as both ketone and carboxylic acid [1; 54]. A list of resin-bound starting materials of IMCRs was shown by [PERSON] [55]. Regarding the solvents, the Ugi reaction is typically performed in methanol (MeOH) in the case of solution-phase synthesis. In solid-phase chemistry, it is essential to consider the swelling propertiesof the respective resin. Typical SPS is carried out using hydrophobic polystyrene (PS)-based resin, which shrinks in MeOH. Therefore, mixtures of solvents are used, including MeOH/tetrahydrorofuran (THF) and MeOH/dichloromethane (DCM) in various ratios (e.g., References [3; 56; 57; 58; 35]), while the usage of MeOH/CHCl\({}_{3}\)[36; 59], MeOH/CHCl\({}_{3}\)/H\({}_{2}\)O [53; 54; 60], or DCM/DMF [37] was reported much less frequently. In addition, polar TentaGel resin, composed of PEG-grafted PS, was successfully used in MCR [37; 39; 46; 60]. U-4 CR was even successful when H\({}_{2}\)O was used (in the case of filter paper used as solid support) [38; 61; 62], and 2-methyltetrahydrorofuran (2-MeTHF) [15] was described recently as a green solvent in the Ugi reaction.