Polymer-supported reagents reductive aminations

Solid-phase scavenger methods are employed with increasing frequency as a prehminary reaction cleanup step in combinatorial chemistry, and have recently become commercially available (Argonaut, Calbiochem-Novabiochem, Varian, Alltech). lilly researchers first reported on this approach, employing sohd supported electrophiles and nucleophiles for reaction purification in acylation and alkylation reactions. Yield and purity values reported were 90-95% and 50-99%, respectively, for a library generated by reductive amination. Parke-Davis researchers achieved the removal of known reaction product impurities by the application of custom synthesized polymer supported reagents, specifically polystyrene-divinylbenzene supported derivatives of methylisocyanate and tm(2-aminomethyl)amine for cleanup of by-products resulting from urea, thiourea,sulfonamide,amide, and pyrazole libraries. 

Various polymer-supported hydrides have been applied successfully to reductions of both carbonyl and olefin groups. Rajasree and Devaky13 describe a cross-linked polystyrene-supported ethylenediamine borane reagent for the selective reduction of aldehydes in the presence of ketones (entry 9). This borane reagent is easily prepared and can be recycled after completion of the reaction. This is a practical alternative to standard borane reagents such as diborane, borane-amine, or borane-sulfide complexes. 

Scheme 40 presents a synthetic route to polymer-supported Weinreb amides starting from commercially available BAL-linker [216]. Whilst most approaches to Weinreb linkers start with the conversion of alcohol functionalities (and following Mitsunobu approach), the BAL linker 260 has to be reacted via reductive amination into the desired methoxyamines 261. Afterwards resin 261 is treated with carboxylic acids 262 in the presence of coupling reagents to give amides 263 containing the target structure. 

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