Resins scavenger

The major impetus for the development of solid phase synthesis centers on appUcations in combinatorial chemistry. The notion that new drag leads and catalysts can be discovered in a high throughput fashion has been demonstrated many times over as is evidenced from the number of publications that have arisen (see references at the end of this chapter). A number of approaches to combinatorial chemistry exist. These include the split-mix method, serial techniques and parallel methods to generate libraries of compotmds. The advances in combinatorial chemistry are also accompanied by sophisticated methods in deconvolution and identification of compounds from libraries. In a number of cases, iimovative hardware and software have been developed for these purposes. 

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In a detailed investigation, Turner and coworkers have described the preparation and application of solid-supported cyclohexane-1,3-dione as a so-called capture and release reagent for amide synthesis, as well as its use as a novel scavenger resin [125]. Their report included a three-step synthesis of polymer-bound cyclohexane-1,3-dione (CHD resin, Scheme 7.104) from inexpensive and readily available starting materials. The key step in this reaction was microwave-assisted complete hydrolysis of 3-methoxy-cyclohexen-l-one resin to the desired CHD resin. 

Scheme 7.106 Preparation of high-loading cyclohexane-1,3-dione scavenger resin (CHD-SR).

In order to explore the potential of CHD resins as scavenger materials, 1-ethyl-3,5-dimethoxycydohexa-2,5-dienecarboxylic acid was anchored to a commercially available trisamine resin (Scheme 7.106), which yielded a high-loading cyclohexane-1,3-dione scavenger resin (CHD-SR) [125]. 

Scheme 7.107 Palladium-catalyzed deprotection of O-alloc benzyl alcohol employing the scavenging resin CHD-SR.

Humphrey CE, Easson MAM, Tierney JP, Turner N (2003) Capture and release reagent for the synthesis of amides and novel scavenger resin. J Org Lett 5 849-852... 

FIGURE 1.57 Scavenging of excess reagent with scavenger resin. (Reproduced with permission from Biotage AB.)... 

Solution-phase library Resin scavenging Resin capture Split and mix... 

The combinatorial library synthesis of a diverse set of trisubstituted ureas has been described [64]. The synthetic pathway involves the prehminary preparation of various nitrophenylcarbamates from commercially available nitrophenyl chlorofor-mate and a selection of amines allowing for wide scope in the divergence of the final urea products. In a further reaction of the nitrophenylcarbamates with a second amine, the urea was generated. Simultaneous addition of an electrophilic and basic scavenger resin removed all by-products, again allowing rapid isolation of the products in excellent yield and purity (Scheme 2.43). 

The acylation of benzylamine with 4-chlorobenzoyl chloride served as a model reaction to evaluate the efficacy of both of these resins. After removal of both protons and amines the corresponding amide was obtained in 77% yield contaminated with less than 1% benzylamine and acid chloride. The transformation was also performed with commercially available scavenger resins PS-NCO and/or PS-NMM to obtain comparable results, but only approximately half the mass and volume of dendronized resin was required to achieve similar scavenging efficiency. 

Both resins were also examined in a second test reaction, the tosylation of a primary amine, to receive analogous results compared with the commercially available resins. The authors did not report on the re-isolation, regeneration, and reuse of their dendronized scavenger resins. 

To appreciate the way a scavenger resin works, refer again to the simple reaction between a primary amine and an alkyl halide ... 

The use of scavenger resins in solution-phase synthesis illustrates a type of procedure that is actually a hybrid between solution-phase and solid-phase methods. The first step of this procedure is clearly a form of solution-phase synthesis since the reactions take place totally within a dissolved state with no solid support provided for any of the reactants. The separation stage of the process occurs only after products have become attached to solid supports—the scavenger resins—from which they may or may not then be removed. 

The assembly consists of three fritted jacketed columns (each 2 cm wide) including two top columns (type A) for reagent synthesis a catalytic column (type B) into which the reagent columns feed and a scavenger resin column (type C) below the catalytic column. (Adapted from Hafez et ah, 2001)... 

Table 4 Use of a electrophilic scavenger resin to improve yields in the heteroatom Diels-Alder reaction (Equation 34)...

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