# Isocyanide Multicomponent Reactions on Solid Phase: State of the Art and Future Application
## 6 Post-Ugi Transformations of Convertible Isocyanides
### Polymer-Supported Convertible Isocyanides  
[PERSON] et al. applied convertible isocyanides to synthesize \(\gamma\)-lactam analogs [1]. The synthesis utilized a UDC strategy and was performed in solution as well as on the solid phase. U-4 CR was carried out on versatile safety-catch linker **56**[80] (Route A, Scheme 47) and on resin-bound cyclohexenyl isocyanide **55** (Route B), with N-Boc-\(\beta\)-amino-aldehydes **266** (easily prepared from the carboxylic acid via the Weinreb amide formation and subsequent reduction with LiAlH\({}_{4}\)) [94], amines, and carboxylic acids.  
Route A involves the reaction of polymer-supported Ugi product **269** with Boc\({}_{2}\)O (resin **270**) to activate the isocyanide-derived carboxamide for a nucleophilic attack by NaOMe. Liberated methyl esters **271** were treated with 10% TFA in DCE (linear intermediate **272**) and yielded the target lactams **273**. The cyclization was promoted by solvent evaporation at 65 \({}^{\circ}\)C in a SAVANT\({}^{\text{TM}}\) evaporator. Alternatively, the Ugi product bound to the cyclohexenyl resin (intermediate **274**) was converted to methyl ester **275** and subsequently cyclized to product **273** (Route B). The partial cyclization was completed by a proton scavenger. This route suffered from the formation of a side product, carboxamide **276**. The purities were analyzed by ELSD and UV absorption analysis at 220 nm.  
Figure 46: Transformations of convertible isocyanide.  
Both isocyanide resins were stable at \(-20\)\({}^{\circ}\)C and odorless. In contrast, the stability of the \(N\)-Boc-\(\beta\)-amino-aldehydes was limited (it is necessary to use freshly prepared batches). In this paper, the synthesis of bicyclic \(\gamma\)-lactams was carried out (cf. Scheme 64).  
In 2002, [PERSON] et al. discovered a novel CCI resin **58** (cf. Scheme 12) and demonstrated its applicability to the synthesis of 2,5-diketopiperazines **284** and 1,4-benzodiazepepine-2,5-diones **286** (Scheme 48) [81]. The synthesis sequence comprised U-4 CC followed by a two-step, one-pot procedure (including base-activation of the resin-bound Ugi product **280** resulting in cleavage via formation of a \(N\)-acyloxazolidone **281**, which was then converted to methyl ester **282**). Final post-cleavage cyclization in a mixture of HFIP (1,1,1,3,3,3-hexafluoropropan-2-ol) and TFA led to the desired 2,5-diketopiperazines **284**. The crude product was treated with silica-based scavengers to remove impurities. Similarly, 1,4-benzodiazepepine-2,5-diones **286** were prepared (in the Ugi reaction, \(N\)-R\({}^{3}\)-anthranilic acids were used).  
The use of safety-catch linker **56** (cf. Scheme 10) allows for cleavage of the product upon Boc activation with a nucleophile (methoxide or hydroxide) and was reported by [PERSON] and coworkers [80]. The UDC strategy was applied to the preparation of carboxylic acids **291**, 1,4-benzodiazepepine-2,5-diones **292**, diketopiperazines **293**, ketopiperazines **294**, and dihydroquinoxalinones **295** (Scheme 49). The Ugi reaction of the Wang resin-bound isocyanide **56**, which was prepared via four steps (cf. Scheme 10), aldehyde, amine, and carboxylic acid yielded \(\alpha\)-acylamido carboxamides, which needed to be activated by Boc\({}_{2}\)O prior to cleavage (resin **290**). Four different internal N-nucleophiles were tested, namely, \(N\)-Boc anthranilic acid, \(N\)-Boc \(\alpha\)-amino acids, and two \(N\)-Boc diamines. Cleavage of the Boc group with AcCl in MeOH and evaporation at 65 \({}^{\circ}\)C in a SAVANT\({}^{\rm TM}\) evaporator afforded the target bicycles **292** and **295**. Partial cyclization to **293** and **294** was facilitated by a base. The purities were analyzed by ELSD and UV absorption analysis at 220 nm.  
**Scheme 49.** Synthesis of nitrogen-containing heterocycles on Wang resin-bound isocyanide.