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/\/C02H t Q/^co2H
The role of bifunctional (tagged) reagents in the transformations described above is similar to that of polymer-immobilized reagents. However, they exhibit more reliable reaction kinetics because they react in the solution phase. Moreover, manipulation of these reagents is more easily automated since transfer of solutions is much easier than transfer of solids.
5.6. POLYMER-SUPPORTED SUBSTRATES
A + Â ---------------> product + O-c
Polymer-supported reactants are most useful for cases where reactant byproducts would otherwise be difficult to sequester. Recycling of the
5.6. POLYMER-SUPPORTED SUBSTRATES 163
support is possible in the frequently encountered case where the byproduct is a polymer-supported leaving group. A recent example illustrates a process in which a mixture of 10 phenolic compounds was immobilized on Amber-lite IRA-900, giving reagent 24 (reaction 7). This polymer-supported mixture was reacted with butyl bromide to give the product aryl ethers and a supported quaternary ammonium bromide as an easily removed byproduct.25
Several polymeric acyl-transfer reactants have been used to give amide/ester products in the solution phase. The excess polymer-bound acyl-transfer reactants and polymer-bound nucleofuge byproducts are easily removed after completion of the reactions. One such application involved the activated nitrophenyl esters 25 (reaction 8).40 A mixture of 10 acid chlorides was converted to an equimolar mixture of 10 amide products; a potent preemergent herbicide was discovered using this parallel synthetic approach.41
Polymer-bound active esters 26 were prepared from a 1-hydroxyben-zotriazole (HOBt) functionalized polymer and carboxylic acids in the presence of tripyrrolidinyl-bromophosphonium hexafluorophosphate (Py-
164 POLYMER-ASSISTED SOLUTION-PHASE METHODS
BrOP). These active esters react smoothly with amines at room temperature (reaction 9).42 Similarly, supported oximino esters 2743 and hydroxamic esters 2844 undergo facile acyl transfer reactions with amines at room temperature (reaction 10). The spent activating agent can be regenerated many times (by acylation with the appropriate acid chloride) without appreciable loss in activity.
» vCc> * R"N^R
R1 = Me, Ph, 4-N02C6H4
A novel thiophenoxy 4-nitrophenylcarbonate-linked resin has been used to generate isocyanates in solution phase through the intermediacy of a resin-bound carbamate 29. The released isocyanates could be trapped with amines to form substituted ureas.45
5.7. POLYMER-SUPPORTED REAGENTS 165
5.7. POLYMER-SUPPORTED REAGENTS
Polymer-supported reagents differ from polymer-supported substrates in that the former mediate a reaction rather than becoming an integral part of the product. A major attribute of tethered reagents is that both the reagent and the reagent byproduct can be directly filtered away from solution-phase products.
5.7.1. New Polymeric Bases
The polymer-supported superbase 30 was developed and used for the deprotonation and alkylation of weakly acidic nitrogen heterocycles such as indoles, phthalazinones, and pyrazoles.46 The diagram below illustrates the use of superbase 30 to alkylate a weakly basic pyrazole NH after acylation or alkylation of the more nucleophilic piperidine NH. Ami-nomethyl resin 1 was added after each step to sequester excess alkyl and/or acyl halide from the solution phase.
166 POLYMER-ASSISTED SOLUTION-PHASE METHODS
A polymer-bound guanidine base 31 has been used for the formation of aryl ethers from suitable phenols and alkyl halides. In addition to serving as a base to affect deprotonation, reagent 31 also acts as a sequestering agent for excess starting phenol (reaction 11).26
5.7.2. Polymeric Reagents that Mediate Condensation Reactions
A polyethylene glycol (PEG 2000) linked Burgess reagent 32 was prepared and used to mediate cyclodehydration of (3-hydroxy amides and thioamides (equation 12).47 Filtration through a silica gel plug afforded the desired oxazolines and thiazolines in high yields and purities. Interestingly, in some cases the yields of products were superior to yields obtained using the classical Burgess reagent.
H Et3+N^NA0^-PEG0Me |i
R'i:r —-—- jr#
X p3 OH R X H
The PEG3400-linked triarylphosphine 33 was developed as a liquid-phase polymeric reagent for use in Staudinger and Mitsunobu reactions.48 Precipitation of the PEG polymer with cold diethyl ether, filtration, and evaporation afforded the purified products.
5.7. POLYMER-SUPPORTED REAGENTS 167