# Isocyanide Multicomponent Reactions on Solid Phase: State of the Art and Future Application
## 3 Resins
### Isocyanide Resin  
Unlike amines, carboxylic acids, and aldehydes, structurally varied isocyanides are not commercially available. The synthesis of isocyanides suffers from several drawbacks, including multistep synthesis and unpleasant odor. However, the polymer-supported isocyanides are completely odor-free, which is an advantage of the IMCRs performed on the solid phase. Two different strategies for the preparation of isocyanide resins were developed: (i) the isocyanide-containing reagent was prepared in solution and then attached to the resin, or (ii) the isocyanide was formed on the resin, typically from a resin-bound amine by formylation followed by dehydration [8; 29; 50]. Analogous to the amine resins, the isocyanide was either directly linked to a resin-bound linker (typically Rink amide linker, **29**, Scenario A, Scheme 4) or a diversity element \(\mathbb{R}^{4}\) was introduced between the isocyanide and the linker (**31**, Scenario B) [73]. Accordingly, three or four diversity position products were formed. First, we discuss the most common route to polymer-supported isocyanide by dehydration of formyl amides. In 1981, isocyanide resin in U-4 CC was reported for the first time by [PERSON] and [PERSON] [29]. Their original work [29] focused on peptide synthesis by ligation of a C-terminal fragment with an N-terminal fragment. Dedicated PS and polyacrylamide polymers crosslinked with bisacrylamide were prepared and evaluated. Copolymerization included 2,4,5-trichlorophenoxylyacrylate **33** (Scheme 5), which introduced a functional group for subsequent reaction with diamine and formylation (resins **34**). Both formamide polymers were subsequently dehydrated with an excess of _p_-TsCl in pyridine (resins **35**) and afforded comparable results. The authors selected the polar polyacrylamide polymer to carry out the scope and limitation experiments described in Section 4.1.2. On-resin dehydration was used very frequently. [PERSON] et al. reported the preparation of Wang resin-bound isocyanide **37** (Scheme 6) and its usage for the synthesis of imidazoles (cf. Scheme 57) [50]. It was further utilized for syntheses of other heterocycles, such as 2-thiohydantoin 4-imides, hydantoin 4-imides, tetrazoles, and lactams (cf. Sections 8.2 and 9.2.2) [53; 54]. The synthetic strategy was based on formylation and dehydration. Formylated resin-bound amino acids, prepared by reaction with HCOOEt or HCOOH in the presence of Ac\({}_{2}\)O, were attached to Wang resin **24**, and precursor **36** was subjected to dehydration with PPh\({}_{3}\) and CCl\({}_{4}\) in DCM in the presence of triethylamine (TEA) to produce target resin **37**. The resin was reportedly stable for up to 6 months at 23 \({}^{\circ}\)C, when kept in a vacuum desiccator. However, the usage of carcinogenic CCl\({}_{4}\) makes this method less desirable. The synthesis of isocyanides was also evaluated on various resins, including aminomethyl PS, TentaGel-NH\({}_{2}\), polydimethylacrylamide, copolymersrene-acrylamide, copolymersrene-acrylamide, and copolydimethylacrylamide-acrylate, via formylation with HCOOH/Ac\({}_{2}\)O and dehydration with TsCl in pyridine [74]. Figure 4: Preparation of the resin-bound isocyanides. Less hazardous dehydration conditions were applied by another research group [49]. Inexpensive aminomethyl PS resin was functionalized with an isocyano group, which was either directly generated on the resin (**40**, Scheme 7) or attached via a spacer (**43**). The spacer unit (Gly, \(\beta\)-Ala, \(\gamma\)-aminobutyric acid (GABA)) decreased the steric hindrance at the isocyanide functional group and thereby facilitated the Ugi reaction. The preparation of both isocyanide resins is outlined in Scheme 7 (Route A, Route B). Oxyma (ethyl cyano(hydroxymethyl)acetate) was added to facilitate the coupling reaction of formylated \(\beta\)-Ala **41b** and GABA **41c** with aminomethyl resin **38**. Formylated amino acids **41a-41c** were prepared by reaction of amino acid with HCOOH in the presence of acetic anhydride.