Preparation and Use of PSRs

Polymer-supported reagents [1-3] have been prepared by one of the following methods: (i) formation of a covalent bond between the active/activating moiety and the support, e.g., immobilization of a carbodiimide group to achieve condensation reactions; (ii) polymerization of monomers carrying the active group or precursors thereof; and (iii) ion-exchange enabling the attachment of an ionic active species to immobilized ions, e.g., the quaternary ammonium ions of common anion-exchange resins (Figure 2).

Various types of PSRs will be described in the following sections. However, rather than classify these reagents by the type of support or by functionality, a classification by the way of their preparation will be used here. Furthermore, rather than providing an exhaustive list of all PSRs described in the literature, the aim of this chapter is to provide an understanding of the principles of preparation and application of such reagents, with a special focus on important reactions and on the combination of several PSRs in one synthetic sequence or, if possible, in one pot. The latter aspect is rather novel and highly interesting for combinatorial chemistry applications.

reactive moiety

Solid- phase organic chemistry

XY covalent bond reactive moiety reactive moiety

Polymerization covalent bond reactive moiety

reagent ion exchange chromatography


ionic interaction reagent

Figure 2. General methods for the preparation of PSRs.

4.2.1 Covalent Linkage Between the Active Species and Support PSR Prepared by Solid-Phase Chemistry

A covalent linkage between the active moiety and the support guarantees (under most chemical reaction conditions) a nonleaking reagent, and thus fulfills one of the most important requirements for PSR technology applications. Solid-phase organic chemistry is used for the preparation of reactive functionalities on the support. These moieties are ready to use in the chemical transformation of molecules in solution.

Activators for Amide Couplings

Amides and esters are often formed from activated esters and the corresponding nucle-ophiles. A side product in these coupling reactions is the leaving group of the activated esters, e.g., the pentafluorophenol or hydroxybenzotriazole moiety. The immobilization of these activators on a solid support would remove the most dominant side product from the reaction mixture, and would therefore in most cases obligate further purification steps. This concept was realized with the preparation of polymer-bound active esters of o-nitrophenol, N-hydroxybenzotriazole and 4-hydroxy-3-nitrobenzophenone [13-15]. The first was easily prepared by Friedel-Crafts acylation of polystyrene with 4-hydroxy-3-nitrobenzoyl chloride in the presence of A1C13, but reactions of the active esters with amines were slow [13]. N-hydroxy benzotriazole-derived activated esters were highly reactive but too moisture-sensitive to be useful PSRs. Active esters of 4-hydroxy-3-nitrobenzophenone showed reasonable acylating activities and were stable reagents (Scheme 1). They were prepared via Friedel-Crafts acylation of polystyrene 1 with 4-chloro-3-nitrobenzoyl chloride (2) using A1C13 or FeCl3 as catalyst (Scheme 1). Replacement of fluoride with hydroxide and coupling the resulting phenol 3 to a variety of acids or acid chlorides, e.g., 4 using standard coupling protocols generated the corresponding activated nitro phenyl esters 5. The loading of the polymer was determined by its increase of weight, by titration with benzylamine, or by reaction with excess benzylamine and weighing the resulting amide. Polymeric activated esters with loadings of 0.9-1.2 mmol g 1 of resin were obtained from Boc-phenylalanine, Boc-glycine, and Boc-(0-benzyl)-tyrosine [13]. Coupling of amines, e.g., side chain-protected serine methyl ester (6) with the supported activated ester 5 was performed in chloroform in the presence of triethylamine. Amide 7 was isolated in quantitative yield after 10-15 min. Longer reaction times were required for more hindered amines and activated esters [13].

The polymeric phenols 3 were recyclable. A sample was reactivated for three reaction cycles using benzoyl chloride 2 as acylating agent. Coupling with benzylamine was used to determine the loading, which was found to be virtually identical for all three cycles [13].

Was this article helpful?

0 0

Post a comment