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5.4. SOLUTION-PHASE DERIVATIZATION 159
9ðç 9 h
Solution-phase syntheses employing linking reagents provide an alternative to solid-phase organic synthesis when poor conversions and incomplete reactions yield “deletion intermediates” upon release from resin. Applications are highlighted in various multistep syntheses covered at the end of this chapter.
5.4.2. Byproduct Solution-Phase Linking Reagents
Poorly reactive (poorly sequestrable) byproducts are more frequently encountered than poorly sequestrable reactants. A few reports have appeared describing the use of soluble bifunctional linking reagents to chemically tag
+ NH R4
160 POLYMER-ASSISTED SOLUTION-PHASE METHODS
byproducts to affect their removal. One application featured benzenesul-fonyl isocyanate to sequester an aminothiazole side product 18, formed on hydrolysis of the thioazolyl isocyanate reactant by adventious water. These electron-deficient amines were transformed into acidic acylsulfonimides and then sequestered as ionic adducts.32
5.5. SOLUBLE BIFUNCTIONAL REAGENTS
A + Â
Classical reagents possess inherently reactive functionality; however, the spent reagent byproducts typically exhibit low reactivity and often lack sufficient functionality to enable their sequestration. Bifunctional reagents offer a technique for sequestration of reagents and byproducts. A bifunctional reagent contains a conventional reagent functionality ‘X’ and also contains a remote chemical functional group ‘tag.’ The ‘tag’ functionality does not interfere with the performance of the reagent, but does offer a molecular recognition handle to affect the post-reaction sequestration of excess reagent and byproduct.
5.5.1. Bifunctional Reagents for Condensation Reactions
l-Ethyl-3(3-dimethylaminopropyl)carbodiimide (EDCI) is a commercially available, tertiary-amine-tagged, condensation reagent that has been used in parallel reactions to mediate amide bond formation between carboxylic acids and amines.34 Excess EDCI and the urea byproduct formed from it were removed after the reaction via ion exchange capture. EDCI was also used in a parallel-array format to mediate dichloroacetic acid-catalyzed Moffatt
5.5. SOLUBLE BIFUNCTIONAL REAGENTS
oxidations of hydroxyethylamines.20 A mixed-resin bed containing A-21 tertiary amine resin 19 and Amberlyst A-15 sulfonic acid resin 20 was used to sequester HC1 and the free-base forms of reagent and reagent byproduct. The mixed resin bed of amine and acid functionalities could be used without interfering with each other because the two functional groups were site isolated from each other. Simultaneous acid and base extractions were thereby possible.
alcohol ---------> ketone or aldehyde
HCI «Ã ^N^N=C=N^Me Me Íç
Me u u
HCI • 1 H H
Me Ü^³ç ^
sequestered reagent and byproduct
Bifunctional reagents have recently been used to facilitate separations in the Mitsunobu reaction.39 Mitsunobu products are often hard to separate from excess reagents and byproducts, including phosphines and phosphine oxides. The “tagged” phosphine 21 and azodicarboxylate 22 and the byproducts formed from these are converted to the carboxylic acid forms by treatment with trifluoroacetic acid (TFA) at the end of the reaction. The excess reagents and byproducts could then be captured on an ion exchange resin for convenient removal.
162 POLYMER-ASSISTED SOLUTION-PHASE METHODS
(i) 21,22, THF, 25 gC
RCH2OH + Nu ---------------------> RCH2Nu (5)
5.5.2. Bifunctional Reagents for Removal of Trityl Groups
3-Mercaptopropionic acid has been used as a scavenger in detritylation of protected imidazoles. In the purification, A-21 tertiary amine-functional-ized resin 23 sequestered excess of this acidic reagent, the tritylated byproduct formed from it, and TFA (reaction 6).32
Æ ^ ^CONR2R3