Resin functionalisation

The functionalisation of commercially available standard solid supports is of common interest for combinatorial applications to enable a broad range of reactions to be studied. Since these transformations usually require long reaction times under conventional thermal conditions, it was obvious to combine microwave chemistry with the art of resin functionalisation. 

The benzoic acid was quantitatively coupled within 5 min via its cesium salt by using a dedicated multi-mode batch reactor, carried out in standard glassware under atmospheric reflux conditions. In a more extended study, various substituted carboxylic acids (Fig. 7.7) were coupled to chlorinated Wang resin, employing an identical reaction protocol. In a majority of cases, the microwave-mediated conversion reached at least 85% after 3-15 min. These microwave conditions represented a significant rate enhancement, in contrast to the conventional protocol, which took 24-48 h. The microwave protocol has additional benefits in comparison to the conventional method, as the amounts of acid and base equivalents can be reduced and potassium iodide as an additive can be eliminated from the reaction mixture27. 

In general, the reasons for rate-enhancements in microwave-assisted transformations in comparison to conventional heating are not always fully understood. Some authors have postulated a specific non-thermal microwave effect for those effects that could not be rationalised as a simple consequence of superheated solvents and higher reaction temperatures. Stadler and Kappe therefore carried out a kinetic comparison of the thermal coupling of benzoic acid to chloro-Wang resin at 80° C, with the microwave-assisted coupling at the identical temperature of 80°C and otherwise identical reaction parameters. However, the reaction rates for the two runs were quite similar and the small observed differences could not be attributed to non-thermal effects. In order to confirm this hypothesis, the authors also carried out coupling experiments with 

The isourea protocol was carried out in a 9 1 dichloromethane/N,N-dimethylf-ormamide (DCM/DMF) solvent mixture in sealed vessels, whereas the anhydride reactions were carried out in 1 -methyl-2-pyrrolidinone (NMP) under atmospheric pressure. In all experiments, the loading was estimated by on-bead Fourier transform infrared spectroscopy (FTIR) analysis and determined by cleavage from the PS Wang resin with 50% TFA in DCM. 

Surprisingly, the isourea protocol showed some deficiencies, as complete conversion could not be obtained due to unexpected side reactions at higher temperatures. The anhydride protocol was superior to this method, as it could be carried out in simple glassware (open vessels in a dedicated multi-mode cavity) without the need for high pressure vessels. Quantitative coupling to the resin could be obtained with the anhydrides within 10 min, employing microwave heating at 200° C. 

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Figure 6.36 Epoxidation of cyclohexene with tBHP catalysed by Mo(VI) immobilised on polystyrene resin functionalised with a 2-aminomethylpyridine ligand.

Figure 6.37 Thermogravimetric analysis curves for polystyrene resin functionalised with 2-aminomethylpyridine ligands (A) and the Mo(VI) complex of the latter (Q).

Despite the relative infancy in the development of solid phase reactions, a wide range of functionalised resins are commercially available. The main uses of these functionalised resins can be roughly classified as follows ... 

The ability to downgauge, decrease part weight, improve barrier properties and reach new levels of product performance are propelling polyolefins into new markets previously dominated by other plastics. The high growth rate in PP production capacity is mainly being driven by the ability of PP to replace other resins on a cost/performance basis. For example, functionalisation of PP by incorporation of acrylic functionality has extended its weatherability performance. Interpolymer competition will have a significant impact on the amount and type of additives used. 

Solid-phase combinatorial synthesis of AT-acyl-L-HSL has also been reported. The procedure entails the DIC/HOBt catalysed acylation of methionine functionalised resin with a carboxylic acid followed by BrCN-mediated cyclisation process to produce HSL libraries with retention of stereochemistry (Scheme 5) [55]. 

An alternative strategy towards benzimidazole synthesis relies on the palladium-catalysed cyclisation of (2-bromophenyl)amidines. This chemistry has been reported to take place under aqueous reaction conditions, in the presence of sodium hydroxide in sealed microwave vials. The products were isolated by a catch and release method using a strongly acidic ion exchange resin, thereby avoiding conventional chromatographic purification (Scheme 3.14)23. Selectively, N-functionalised benzimidazoles were conveniently prepared by this method. 

They produced an 18-member library of a-acylamino amides, in acceptable to high yields and purity, from a variety of isocyanides, aldehydes and carboxylic acids by using an amino-functionalised TentaGel resin (TentaGel S RAM). The developed procedure represents a rapid and efficient way of synthesising a-acylamino amides, simplifying the tedious purifications, which can usually accompany multi-component reactions. 

Due to their mode of preparation, polymeric resin beads consist of a macroporous internal structure and of highly cross linked areas (>5%), respectively. The latter renders rigidity to the resin, whereas the porous areas provide a large internal surface for functionalisation, even in the dry state. These macroporous polystyrene-based resins are subsequently modified in various manners, which renders the accessibility to numerous... 

Scheme 7.9 Microwave-promoted preparation of functionalised resins.

In a more recent study, Westman and Lundin described the solid-phase synthesis of aminopropenones and aminopropenoates, respectively30 as intermediates for heterocyclic synthesis. Two different three-step methods for the preparation of heterocycles have been developed. The first method involved formation of a polymer-bound ester from a IV-protected glycine derivative and Merrifield resin (Scheme 7.10a), while the second method employed an interesting approach utilising simple aqueous methy-lamine solution for functionalisation of the solid support (Scheme 7.10b). In this latter approach, a variety of hetero cycles were readily synthesised from the generated polymer-bound benzylamine using a two-step protocol (see Section 5.3.3). 

The versatility of cyclohexane- 1,3-dione functionalised resins has been illustrated by their syntiietic application as both capture and release reagents and resin scavengers. In addition, CHD resins show considerable potential for further use as linkers in several other solid-phase applications. 

An interesting and recently published study presented the functionalisation of insoluble polystyrene resin with soluble polyethylenglycol (PEG) (Scheme 7.46) to produce hybrid polymers that combine the advantages of both PEG and polystyrene as polymeric supports52. 

Bradley described the first solid-phase synthesis of PAMAM dendrimers in 1997 [220]. To this end, phthaloyl-protected norspermidine was coupled to aminomethyl functionalised polystyrene-polyethylene-glycol resin ((PS-PEG)-NH2) through an acid-labile linker (see Fig. 23). PAMAM dendrons were assembled by treating deprotected scaffold-bound resin 24 first with an excess of methyl acrylate... 

PAMAM-bound resins can be functionalised with peptide sequences, being synthesised either separately and then coupled onto the resin immobilised PAMAM, or residue by residue on the dendrimer using standard Fmoc solid-phase peptide chemistry [221],... 

The resin fractions of organic sulfur-rich bitumens are for a substantial part composed of monomers with linear, isoprenoid, steroid, hopanoid and carotenoid carbon skeletons connected to each other by (poly)sulfide linkages. These structural units may contain additional intramolecular sulfur linkages. This sulfur-rich geopolymer is also formed by sulfur incorporation into functionalised lipids in an intermolecular fashion during early diagenesis. 

Of particular interest to combinatorial chemistry is the use of immobilised functionalised boronic acid templates which are capable of further transformations [20]. For instance, an aryl carboxylic acid 50 can be converted into the corresponding amide 51 (Scheme 12), whilst still being attached to the resin. Benzyl amine and butylamine were coupled efficiently to afford (after cleavage) the corresponding amides 52 in high yield (Scheme 12). 

Solid supported isoxazolines 40 were prepared starting from a sulfmate-functionalised resin 38. Oxidation of the resin linked cyclobutanols 40, with concomitant cleavage of the sulfone linker, produced isoxazolinocyclobutenones 41 in 34-38% overall yield (4 steps) <02OL741>. A five-step solid phase synthesis of isoxazolino-pyrrole-2-carboxylates that employing the same traceless sulfone linker strategy has also been reported <02JOC6564>. 

Functionalised polystyrenes, initially used as ion-exchange resins and supports for solid phase peptide synthesis, have progressively expanded in importance as insoluble supports for catalysts and organic reagents1. Currently, most of these reactive polymers are prepared from polychloromethylstyrene, the so-called Merrifield resin, by a nucleophilic attack onto the chlorine atom. However, these supports present two main drawbacks ... 

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