Polymer-bound isonitrile

Polymer-bound isonitrile (423), obtained from TentaGel-NH2 through treatment of the resin with formic acid and acetic anhydride, followed by dehydration of the resulting formamide with tosyl chloride and pyridine, has been employed in the preparation of N-substituted amino add ester [349]. Thus, Ugi MCR, performed in the presence of an alcohol instead of the carboxylic component, gave rise to an imino-ether spedes (426). Several Lewis acids were tested in searching for optimal reaction conditions. Boron trifluoride etherate displayed the better yields in term of desired product of the Ugi-type reaction. Amino acid methyl esters (427) were thus obtained when using methanol as the alcohol component, after deavage from the resin of the intermediate imino-ethers by an acetone/water mixture (Scheme 87). 

Scheme 7.120 Palladium-catalyzed isonitrile formation utilizing polymer-bound triphenylphosphine.

Multicomponent reactions have been described for several syntheses of imidazoles. Highly efficient methods for the syntheses of spiroimidazolinones via microwave-assisted three-component one-pot sequential reactions or one-pot domino reactions have been described <06JOC3137>. Multicomponent reactions between 2-aminopyrimidine, aldehydes and isonitriles afforded imidazo[l,2-a]pyrimidines <06TL947>. Two novel one-step microwave mediated syntheses of arrays of 3-iminoaryl-imidazo[l,2-a]pyridines and imidazo[l,2-a]pyridyn-3-ylamino-2-acetonitriles were synthesized by multicomponent reactions under microwave condition in methanol by simply mixing a-aminopyridines, aldehydes, and trimethylsilylcyanide catalyzed by polymer-bound scandium triflate <06TL2989>. 3-Aminoimidazo[l,2-a]pyridines have been synthesized via the multicomponent reaction of aldehydes, isocyanides and 2-aminopyridines in the presence of the ionic liquid l-butyl-3-methylimidazolium bromide [bmim]Br<06TL3031>. 

Microwave-assisted heterocycle synthesis has also been used to prepare a small set of pharmaceutically important imidazole derivatives [54]. The procedure utilized an initially prepared polymer-bound 3-N,N-(dimethylamino) isocyanoacrylate. The best results in imidazole synthesis were obtained by microwave-assisted reaction of an eightfold excess of the polymer-supported isonitrile suspended in 1,2-dimethoxyethane (DME) with the corresponding amines (Scheme 16.31). Cleavage with 50% trifluoroacetic acid in dichloromethane afforded the desired heterocyclic scaffolds in moderate yields. 

One limitation encountered so far was the well known lack of reactivity of aromatic aldehydes and isonitriles under the Ugi conditions. The scope of this method was further extended by introduction of a third substituent at the 2-position of the pyrimidines. Thus, polymer-bound sulfones 348 were subjected to multidirectional cleavage with one equivalent of different nucleophiles affording compounds 350 in good yields and high puritiesl (Scheme 4.6.7). 

Very recently, a polymer-supported construct for quantifying the reactivity of monomers involving multicomponent Ugi strategies was reported [53]. The authors investigated the Ugi four-component condensation of a set of aldehydes, acids, and isonitriles. The amine compound used was bound to a specially modified Rink amide polystyrene resin bearing an ionization leveler and bromine functionality as a mass splitter for accurate analysis by positive electrospray ionization mass spectrometry. The microwave-assisted experiment was performed with a set of ten carboxylic acids, hydrocinnamaldehyde, and cyclohexyl isonitrile in DCM-... 

---