Ugi Reaction with Solid-Supported Isonitriles

Different novel resin-bound isonitriles have been prepared in order to perform Ugi multicomponent reactions on the solid phase. Thus, Kennedy et al. [346] prepared a novel resin-bound carbonate convertible isonitrile (CCI) that was applied in the preparation of constrained 2,5-diketopiperazine and l,4-benzodiazepine-2,5-dione libraries in parallel 80-well format The first step of the synthetic strategy was a Ugi reaction with a wide variety of amines, aldehydes, and carboxylic acids. Further manipulations of the Ugi MCR products were achieved after basic cleavage from the resin. 

General procedure for Ugi reaction with support-bound isonitrile [346] A 1.2 m solution of 2-chlorobenzylamine (0.133 mL, 1.1 mmol) and 2-phenylpropio-naldehyde (0.146 mb, 1.1 mmol) in trimethylorthoformate (TMOF) was allowed to react for 30 min. (]3-Isocyano-ethyl)-alkyl-carbonate resin (126 mg, 110 pmol, 0.87 mmol g ) was suspended in 1,2-dichloroethane (1.75 mL) in a 5-mL Bohdan fritted reaction tube and allowed to stand for 15 min. The 1.2 M solution ofimine in trimethylorthoformate was added to the resin, and 

The authors invoked the intermediary formation of an N-acyhminium ion formed from the aldehyde (or its acetal) group and the amide bond created during the Ugi reaction. 

Ugi reaction In a 5-mL glass filter tube, resin-bound isocyanide (0.1 mmol) is suspended in a mixed solvent of CHCI3/CH3OH 1 1 (v/v) (3 mL), ami-noaldehyde diethyl acetal (5 equiv.), and an aliphatic aldehyde (5 equiv.), and the mixture is shaken for 30 min at r. t. Then a carboxylic acid (3-5 equiv.) is added. The resin is shaken for 48 h at r. t. The solvent is drained and the resin is washed as follows  

If the carboxylic component of a Ugi MCR is represented by a suitable nitrogen-protected amino acid, a second Ugi reaction could be performed after the first has been completed, using the free amine of the aforementioned amino acid as the amine component. 

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