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• do not compromise diversity introduced by obligatory linking functionality;
• need no additional steps for attachment and release from a polymer support;
• often involve reaction incubation in a homogeneous medium with predictable and reliable reaction kinetics;
• provide a strategy for purification after reactions that do not proceed to completion, reducing the need for high stringency validation;
• allow use of conventional analytical tools for assessing reaction progress and chemical purities; and
• accommodate convergent as well as linear synthetic strategies.
This chapter categorizes major approaches to polymer-assisted solution-phase syntheses. It highlights recent reports describing multistep chemical library synthesis using only polymer-assisted purifications, so disproving the assertion that solution-phase syntheses of libraries is limited only to
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one- or two-step campaigns. Examples are provided wherein both solid-phase organic synthesis and polymer-assisted solution-phase strategies are used in the same library synthesis campaign. Indeed, polymer-assisted technologies are increasingly applied by practitioners of solid-phase organic synthesis during “resin-release” reactions, and solid-phase organic syntheses are being used in polymer-assisted schemes, especially for “resin-capture” of solution-phase intermediates or products.
5.2. REACTANT SEQUESTRATION
Reactant sequestration provides a rapid method for removing an excess of solution-phase reactants, as shown below. Excess A or Â is used to drive a bimolecular reaction to completion and, after the transformation is complete or has reached equilibrium, a resin bearing an organic functionality (cA) complementary to that of A is added to sequester excess A. Conversely, a resin expressing cB functionality could also be used to sequester remaining B. Filtration and concentration affords purified product. Reactant-sequestering resins were independently reported by various research groups and have been called “solid-phase scavenging agents,”19 “complementary molecular reactivity sequestrants,”20 and “polymer-supported quenching reagents.”21
A + Â ------------> product + excess A + excess Â
Several resins have been used frequently in reactant sequestration. Ami-nomethylpolystyrene 1 and the more highly functionalized polyamine resins 2 and 3 have been reported to sequester excesses of solution-phase electrophiles, including isocyanates, isothiocyanates, sulfonyl chlorides, acid chlorides, anhydrides, aldehydes, and imines. Cross-site reactivity is not an issue with the more densely functionalized sequestering resins so their use in an automated laboratory environment offers a significant resin and volume economy compared to less densely functionalized resins.
5.2. REACTANT SEQUESTRATION 153
electrophile + nucleophilic resin
resin capture product
electrophiles = RNCO, RN'CS, RS02CI, RCOCI, RCHO,RCH=NR
nucleophilic resin =
Appropriately functionalized resins can sequester excess nucleophiles from solution-phase reactions. Thus the calcium sulfonate resin 4 captures tetra-rc-butylammonium fluoride (TBAF) from a variety of desilylation reactions.22,24 Polymer-bound tetra-n-butylammonium sulfonate and insoluble calcium fluoride are formed. The applicability of this strategy was illustrated for deprotection of p-trimethylsilylethyl esters as well as silyl ethers.
nucleophile + electrophilic resin ------------------> resin capture
A quaternary ammonium hydroxide ion exchange resin 6 was shown to sequester phenols, hydroxypyrazoles, and other weakly acidic heterocycles.25 The sequestered nucleophiles could also be used as polymer-supported reactants. Similarly, the guanidine-functionalized resin 7 was also shown to be a useful capture agent for weakly acidic nucleophiles, including phenols and cyclic iV-acyl sulfonamides.26
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A methyl isocyanate-functionalized resin 8 has been used to sequester excesses of amines or hydrazines from solution phase when these reactants were used in urea-forming reactions or pyrazole-forming reactions.19,21 Finally, the a-bromoketone resin 9 was shown to efficiently sequester thioureas from solution in Hantzsch aminothiazole-forming reactions.27
nucleophile + electrophilic resin -------> resin capture product
H2N N H
Resin capture can be faster and more efficient than classical methods of purification (e.g., chromatography). Chemoselective sequestration requires minimal amounts of solvent for separating reactants from solution-phase products. Gradient elution techniques, common in chromatographic separations, are avoided, saving time and solvent. Additionally, concurrent use
5.2. REACTANT SEQUESTRATION 155
of resins containing otherwise incompatible functionality is possible, allowing two different reagents to be captured simultaneously. Equation 1 illustrates this concept for the amine-functionalized support 3 and the isocyanate-functionalized resin 8.21 Cross-resin reactions do not occur because of site isolation on the supports.