# Isocyanide Multicomponent Reactions on Solid Phase: State of the Art and Future Application
## 4 Ugi Four-Component Reaction (U-4 CR)
#### 4.1.1 \(\alpha\)-Acylamido carboxamides with Three Diversity Positions  
##### 4.1.1 Amine Resin  
Recently, green solvents with good swelling properties essential for SPS were applied in the Ugi reaction (Scheme 18) [15]. Merrifield and ChemMatrix resins equipped with a Rink amide linker (loadings 1.0 mmol/g and 0.49 mmol/g, respectively) and two green solvents (MeOH and 2-MeTHF) were selected in this study. As expected, 2-MeTHF was a better solvent for the Merrifield resin-supported Ugi reaction, while the reaction carried out on the ChemMatrix resin was effective in both solvents. This fact is explained by the poor swelling properties of Merrifield resin in MeOH, whereas the polar ChemMatrix resin swells well in both solvents. Reactions with all four combinations of resins and solvents were carried out in duplicate to ensure that the results were reproducible. The Ugi reaction was performed in the solution phase first (the overall yield was 38% in MeOH and 50% in 2-MeTHF). Notably, this extensive study described the swelling properties of nine resins in twenty-five green solvents. **Scheme 18. ** Ugi reaction performed in green solvents. The second example in this section is the synthesis of diamide **98** (Scheme 19) on TentaGel S RAM resin **96** under microwave irradiation [37]. An eighteen-membered library was prepared by using three aldehydes, three different carboxylic acids, and two isocyanides. [PERSON] et al. [57] were interested in the synthesis of C-glycoside peptide ligands for cell surface carbohydrate receptors. Prior to synthesizing a library, they carried out a proof-of-concept study focused on a protection strategy (OAc and OBn) of carbohydrates, in which they tested U-4 CC with nine C-glycoside aldehydes 99, nine acids, including three C-glycoside acids, nine isocyanides, and Rink resin **25** as an amino-component (Scheme 20). Debenzylation of the cleaved product was carried out by H\({}_{2}\) with Pd(OH)\({}_{2}\) on carbon, on resin deacetylation with 1 M NaOMe. Chiral acids had practically no effect on the diastereoselectivity, whereas chiral aldehydes showed the biggest influence due to their proximity to the newly formed stereocenter. The diastereomeric ratio was up to 80:20. Then, a library of 96 compounds was prepared using Rink resin and five Rink-resin-supported amino acids **103** serving as the amino components, two isocyanides, eight dicarboxylic acids, and one C-glycoside aldehyde (**99a**, Scheme 21). A second library of 192 compounds was prepared using six resin-bound amines, eight diacids, two isocyanides, and one C-The Ugi reaction also served for the synthesis of peptides used as inhibitors of hematopoietic protein tyrosine phosphatase [69]. The starting compound, carboxylic acid **107** (Scheme 22), was prepared from 4-bromobenzoic acid by reaction with _tert_-butyl acrylate in the presence of Pd(OAc)\({}_{2}\) in a yield greater than 90%. The Ugi reaction was followed by cleavage with 10% TFA in DCM. The purity of the liberated products was above 90%. Derivative **108**, where R\({}^{1}\) = Ph and R\({}^{2}\) = Bn, was the most active tyrosine phosphatase inhibitor, with ahalf maximal inhibitory concentration (IC\({}_{50}\)) = 3.9 \(\upmu\)M.  
Another study aimed at tyrosine phosphatase inhibitors was dedicated to producing \(\alpha\),\(\alpha\)-difluoromethylenphosphonic acids **112** (Scheme 23) [71]. Upon cleavage of the Ugi product from the polymer, the hydrolysis of phosphonate esters with bromotrimethylsilane (TMSBr) was accomplished in the solution phase. Performing the reactions in reverse order was shown to be problematic due to the sensitivity of the Rink resin to acidic conditions. Starting acid **109** was prepared in three steps. Three of the nine tested isocyanides, 1\(H\)-benzotriazol-1-ylymethyl, 2-morpholinoethyl, and toluene-4-sulfonylmethyl isocyanides, did not result in good yields. The yields of the products fluctuated considerably. A library of peptides prepared in 96-well microtiter plates was reported by [PERSON] and coworkers [35].