# Isocyanide Multicomponent Reactions on Solid Phase: State of the Art and Future Application
## 7 Other Post-Ugi Transformations
### Mediated Transformations  
This section discusses syntheses involving additional step(s) following the Ugi product formation prior to the final cleavage from the resin. The first example in this section utilized a Wang resin-bound isocyanide (cf. Scheme 6) in the Ugi reaction leading to \(\alpha\)-(N-acyl-N-alkylamino)-\(\beta\)-keto amides **177** (cf. Scheme 34) [50]. Immobilized Ugi products **176** underwent cyclization to imidazoles in NH\({}_{4}\)OAc and AcOH at 100 \({}^{\circ}\)C, and simultaneous release from the resin with 10% TFA in DCM led to the target tetrasubstituted imidazoles **337** (Scheme 57). The effects of the BBs on the reaction outcomes were studied. While aniline resulted in low yield (16%), isobutylamine, benzylamine, and even 4-methoxyaniline resulted in moderate yields (35-56%). Aryl glyoxals were tolerated (both unsubstituted and 4-methoxy-substituted) as well as carboxylic acids (aliphatic and aromatic). Finally, the length of the isocyanide linker had no effect on the yield of the imidazoles. Notably, some products were transformed to their methyl esters prior to purification. Direct exposure of Ugi product **176** to 10% TFA in DCM led to the corresponding amides **177** (cf. Scheme 34).  
[PERSON] and his coworker prepared hydantoinimide **344** and tetrazole **346** derivatives by repetitive Ugi reactions using aminomethyl PS resin **38** (Scheme 58) [60], and the hydantoinimides were also synthesized on TentaGel resin **96**. A sequence of two different Ugi 4-CRs was employed. The first Ugi reaction was performed with \(\alpha\)-amino acid (Gly), and the subsequent Ugi reaction was carried out with cyanic acid and trimethylsilyl azide as alternative acid inputs (more details about the alternative acid reagents can be found in Section 9.2).  
Hydantoinimides **344** were obtained in low purities (20-40%) when aromatic aldehyde (benzaldehyde) was used. In contrast, the purity of tetrazole derivative **346** was 88% when benzaldehyde was used. The synthesis sequence was also performed in solution.  
Synthesis of \(\beta\)-turn mimetics of the Freidinger lactam type was also achieved with U-4 CC (Scheme 59) [56]. Acyclic tetrapeptide **350** was then subjected to ring-closing metathesis, including carbon-carbon bond formation and concomitant cyclative cleavage, and yielded lactam ring-containing product **351**. Acid labile protecting groups were cleaved upon TFA treatment (**352**).  
**351**  
**Reagents and conditions: (i) DCMMeOH, rt, 48 h; (ii) (CyCyP)ZQRu=CHPh, DCE, 80 \({}^{\text{\text{\textdegree}}}\)C, 24 h; (iii) TFA/DCM,rt, 16 h. Yield 55%.**  
**Scheme 59. Tandem Ugi 4-CR followed by ring-closing metathesis leading to \(\beta\)-turn mimetics.**An illustrative example of the application of the Ugi reaction to generate structural complexity in synthetic products was demonstrated by [PERSON] et al. [3]. Complex structures were generated via a minimal number of steps: Ugi 4-CR, intramolecular Diels-Alder reaction, and ring-opening-closing olefin metathesis, and all these steps were performed on PS modified with carbon-and-silicon-only extender **354** (Scheme 60). The Ugi reaction with immobilized amine **355**, furfural **356**, benzyl isocyanide **179**, and fumaric acid derivative **357** was carried out in a mixture of MeOH/THF at a ratio of 2:1. Resin-bound Ugi product **358** immediately underwent an intramolecular Diels-Alder reaction, and intermediate **359** was subsequently treated with potassium hexamethyldisilazide (KHMDS) and allyl bromide in THF (**360**). Finally, the metathesis (20 mol% of catalyst **361**, DCM, 40 \({}^{\circ}\)C) was followed by the release of product **362** with HF/pyridine in DCM. The synthesis sequence was initially performed in the solution phase, with a yield of 69%.