# Isocyanide Multicomponent Reactions on Solid Phase: State of the Art and Future Application
## 6 Post-Ugi Transformations of Convertible Isocyanides
### Convertible Isocyanides in Solution  
The planar cellulose support, previously described for the synthesis of peptides (cf. Scheme **29**) [38], was also utilized for the preparation of diketopiperazine macro-arrays [61]. This synthesis was inspired by reports on syntheses carried out in solution [77], and on the solid phase (cf. Scheme 37) [46]. Solid-supported Ugi product **298** (Scheme 50) was converted into methyl ester **299** [78], which, upon cleavage of the Fmoc group, underwent spontaneous cyclization to immobilized diketopiperazines **301** (Route A). Subsequent treatment with Ac\({}_{2}\)O in the presence of DIEA and photocleavage afforded the target diketopiperazines **302**. When intermediate **298** was directly subjected (after cleavage of the Fmoc group) to cyclization with 10% TFA in DCM, as reported by [PERSON] [77], the anticipated product was not obtained (Route B). Only primary amide hydrolysis product **304** and other by-products were formed. The Ugi reaction was performed with three aldehydes and eight amino acids. The U-4 CC of resin-bound carboxylic acids **77** and **78** (cf. Scheme 16), amine, aldehyde, and 1-isocyanocyclohexene, resulted in cyclohexenamides **307** (Scheme 51) [83]. They were subsequently transformed into carboxylic acids **308**, esters **309**, or pyrroles **310**, which, upon acidic cleavage, resulted in the desired products **311-313**. The synthetic strategy was based on 1-isocyanocyclohexene as a convertible isocyanide which afforded unrelated products. **Scheme 50. ** Synthesis of diketopiperazines via Ugi 4-CR and subsequent cyclization. **Scheme 51. ** Conversion of the Ugi product to carboxylic acids, esters, and pyrroles via m\(\ddot{\text{u}}\)mchnones. It is important to note that the intermediate formed in each route was munchnone **315**, which was formed by cycloelimination of protonated cyclohexenamide **314**. The munchnone then underwent a nucleophilic attack by water or alcohol, leading to carboxylic acid **311** or ester **312** (Route A and Route B), or proton cleavage, causing the formation of a 1,3-dipole, which is capable of cycloaddition with acetylene (product **313**, Route C). The transformation of munchones with respect to the formation of carboxylic acids and pyrroles was also described by another research group [93]. [PERSON] et al. carried out U-4 CC of polymer-supported amine **316**, aldehyde, carboxylic acid, and isocyanides **51** and **52**, which afforded \(N\)-acyl-\(N\)-alkyl-\(\alpha\)-amino amides **319** (Scheme 52). The reaction was carried out in a mixture of CHCl\({}_{3}\)/MeOH/pyridine (1:1:1), in which the pyridine buffered the reaction mixture and stabilized the isocyanide. Following hydrolysis of Ugi product **319a** (X = CH) to the corresponding acids, **320** proceeded in two steps (Route A). The target pyrroles **321** were achieved by a 1,3-dipolar cycloaddition of the alkynes with the resin-bound munchones. Alternatively, polymer-supported amide **319b** (X = N, Route B) was cyclized directly to munchnone, which was trapped in situ with different alkynes to yield **321**. Route B produced the pyrroles in lower yields; on the other hand, it proceeded via a single step. [PERSON] et al. reported the Ugi four-component synthesis of diamide backbone **324** followed by derivatization through displacement of a Weinreb amide [95] with a Grignard reagent (Scheme 53) [2]. Acidic cleavage led to the target \(\alpha\)-oxodipeptides **325**. A 96-membered library was prepared by using twelve carboxylic acids and eight aldehydes. The effect of these components on the yields of the target products was studied. Aliphatic aldehydes or aldehydes bearing EDG afforded the products in good yields in comparison to those derived from EWG-containing aldehydes. While carboxylic acids with phenolic moieties resulted in low yields, the others led to products in good yields. The larger scale did not significantly influence the yields. The Weinreb amide was prepared from glycine via six steps in solution. **Scheme 53.