Solids supported reagents

In addition to demonstrating the synthesis of dipeptides, the authors also reported the preparation of a tripeptide (59% yield, 95% purity), with an overall processing time of 6-7 h compared with batch protocols which take 24h to complete. The authors noted that an additional advantage associated with the use of a continuous flow process is that the reagents spend very little time in contact with the supported reagents, hence racemization is negligible. 

Furthermore, the authors demonstrated the ability to protect, and react, several bifunctional compounds, obtaining esters and ethers in quantitative yield and 

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R. J. Booth and J.C. Hodges, Solid-supported reagent strategies for rapid purification of combinatorial synthesis products, Acc Chem Res 32 18-26 1999. 

S. V. Ley, l.R. Baxendale, G. Brusotti, M. Caldarelli, A. Massi and M. Nesi, Solid-supported Reagents for Multi-step Organic Synthesis Preparation and Application, II Farmaco 57 321-330 2002. 

Viewed in conjunction with the solid-like, nonvolatile nature of ionic liquids, it is apparent that TSILs can be thought of as liquid versions of solid-supported reagents. Unlike solid-supported reagents, however, TSILs possess the added advantages of kinetic mobility of the grafted functionality and an enormous operational surface area (Figure 2.3-1). It is this combination of features that makes TSILs an aspect of ionic liquids chemistry that is poised for explosive growth. 

Figure 2.3-1 Substrate interactions with (I to r) solid-supported reagent, polymer gel support-...

Baxendale, I.R., Brusotti, G., Matsuoka, M., Ley, S.V. (2002) Synthesis of Nornicotine, Nicotine, and Other Functionalised Derivatives Using Solid-supported Reagents and Scavengers. Journal of the Chemical Society Perkin Transactions 1, 143-154. 

Apart from examples where the inorganic support merely acts as a catalyst, there are many instances where a solid-supported reagent can be used very effectively in... 

Scheme 7.110 Synthesis of a novel solid-supported reagent and its use in acylation.

The quest for a solvent-free deprotection procedure has led to the use of relatively benign reagent, ammonium persulfate on silica, for regeneration of carbonyl compounds (Scheme 6.10) [48]. Neat oximes are simply mixed with solid supported reagent and the contents are irradiated in a MW oven to regenerate free aldehydes or ketones in a process that is applicable to both, aldoximes and ketoximes. The critical role of surface needs to be emphasized since the same reagent supported on clay surface delivers predominantly the Beckmann rearrangement products, the amides [49]. 

Recently, a novel method for the synthesis of a library of substituted prolines with microwave technology [95] has been described. In the first step, 1 equivalent of an amine is added to 1.1 equivalents of an aldehyde in 1,2-dichloroethane (DCE), with subsequent irradiation at 180 °C for 2 min. In the second step, 0.85 equivalents of the maleimide are added and the resulting solution is heated at 180 °C for an additional 5 min. This methodology allowed the production of a solution-phase library of 800 compounds with a crude purity between 65 and 82% (Scheme 9.45). The compounds were purified by solid-supported reagent scavenging to afford the final products with a purity between 90 and 98% and in 79-85 % yield [96]. 

Solid Supported Reagents in Multi-Step Flow Synthesis... 

Fig. 3. Natural products and derivatives accessed through solid supported reagent technology...

Fig. 4. Assembly of columns using solid supported reagents...

Baxendale IR, Lee A-L, Ley SV (2001) A concise synthesis of the natural product carpanone using solid-supported reagents and scavengers. Synlett 482-484... 

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