# Isocyanide Multicomponent Reactions on Solid Phase: State of the Art and Future Application
## 3 Resins
### Isocyanide Resin
While the reaction worked well for Gly and \(\beta\)-Ala (**41a** and **41b**), the formylation of GABA afforded a lower yield of 41c due to internal cyclization and formation of pyrrolidin-2-one. Regarding the stability of the resins, the authors reported that formylated resins **42** were stable for months; in contrast, isocyanide resins **43** decomposed in a few weeks. The resins were used for the synthesis of \(\alpha\),\(\alpha\)-dialkylglycines as highly hindered C-tetrasubstituted amino acids (cf. Scheme 27). The next example shows the immobilization of isocyanide prepared in solution. This new method for the synthesis of resin-bound isocyancarboxylic acids was described by [PERSON] and coworkers (Scheme 8) [73]. They developed a direct coupling method of four different potassium isocyanacarboxylates **44** (prepared from the corresponding acids by ethanolic KOH) onto two brominated resins **45** and **48**. The ester bond cleavage of the Ugi product with 3-methylbutylamine yielded amides, and treatment with LiOH provided acids (cf. Scheme 33). The lack of commercially available isocyanides prompted the design and synthesis of dedicated linkers for the attachment of isocyanide to the resin. These resins are referred to in the literature as universal (also named versatile or convertible) isocyanide resins and enable post-Ugi conversion of the amide to other functional groups. They allow for the release of the Ugi products from the resin through cleavage of the secondary amide bond and yielding the final products as amides, acids, or esters. The first reported convertible isocyanide was 1-isocyanocyclohexene **50** (Figure 2), which was discovered by [PERSON] and [PERSON] in 1963 [75], and referred to as Armstrong isocyanide [76,77]. Other convertible isocyanides are isocyanobenzene **51**, 2-isocyanopyridine **52**, Weinreb-type amide **53**, and 3-\(N\),\(N\)-(dimethylamino)-2-isocyanoacrylate **54**. Regarding the resin-bound, cyclohexenyl isocyanide resin (Armstrong-type isocyanide) **55**, safety-catch linker isocyanide resin **56**, universal Rink isocyanide resin **57**, carbonate convertible isocyanide (CCI) resin **58**, and 3-\(N\),\(N\)-(dimethylamino)-2-isocyanoacrylate resin **59** were developed for MCRs. The application of those isocyanides is covered in Sections 6 and 9.2.1. The Armstrong cyclohexenyl isocyanide **50** was originally prepared from \(N\)-(1-cyanocyclohexyl) formamide **61** by dehydration with phosphorus oxychloride by [PERSON] and [PERSON] [75]. Subsequently, the yields were improved by using a different dehydrating agent, triphosphate, and by purifying **61** prior to dehydration (Scheme 9) [78]. The Armstrong-type isocyanide was also prepared on the solid phase by [PERSON] and coworkers (resin **55**, Figure 2) [79]. Convertible safety-catch linker **56** was prepared from resin-bound aniline **63** via formylation and subsequent dehydration (Scheme 10) [80]. After the U-4 CC, the secondary amide linkage was stable and needed to be activated for nucleophile cleavage by \(N\)-Bocylation (safety-catch principle, cf. Scheme 49). Typical nucleophilic reagents included LiOH and NaOMe. The isocyanide resin **56** was stable for more than six months at low temperature. Figure 2: Solution-phase and resin-bound convertible isocyanides. In 2001, [PERSON] et al. first reported the preparation of convertible Rink-isocyanide resin and its usage for the traceless synthesis of 3-acylamido imidazo[1,2-\(a\)]pyridines [8]. Rink-isocyanide resin **57** (Scheme 11) was prepared via two steps from commercially available Rink resin. The primary amino group of the Rink linker underwent formylation with HCOOH via activation with DIC in the presence of pyridine in DCM, which was followed by dehydration with POCI\({}_{3}\) in the presence of \(N\),_N_-disopropylethyllamine (DIEA) under ice cooling and in an argon atmosphere. The progress of the reaction was monitored by infrared (IR) spectroscopy.