Reactions on solid phase

Scheme 7 Microwave-assisted Ugi reaction on solid phase...

Abstract Current microwave-assisted protocols for reaction on solid-phase and soluble supports are critically reviewed. The compatibility of commercially available polymer supports with the relatively harsh conditions of microwave heating and the possibilities for reaction monitoring are discussed. Instrmnentation available for microwave-assisted solid-phase chemistry is presented. This review also summarizes the recent applications of controlled microwave heating to sohd-phase and SPOT-chemistry, as well as to synthesis on soluble polymers, fluorous phases and functional ionic liquid supports. The presented examples indicate that the combination of microwave dielectric heating with solid- or soluble-polymer supported chemistry techniques provides significant enhancements both at the level of reaction rate and ease of purification compared to conventional procedures. 

To perform Diels-Alder reactions on solid phase, the 2(lH)-pyrazinone scaffold is linked to a suitable support via its amide nitrogen atom. While N-l-substituted pyrazinones are readily accessible by the choice of an appropriate amine, it is not possible to prepare N-l-unsubstituted pyrazinones using the general strategy as previously outlined in the introduction. How-... 

As the first multi-component domino reaction on solid phase the above mentioned domino-Knoevenagel-hetero-Diels-Alder reaction was performed using a 1,3-dicarbonyl compound bound to a modified Merrifield resin.171... 

Combinatorial chemistry and solid-phase synthesis have evolved in the last decade to become one of the most important techniques to save time for drug discovery. To reach its full potential, the solid-phase synthesis has to incorporate many versatile organometallic reactions developed over recent several decades. The first example of the Nicholas reaction on solid phase was reported by Kann and his co-workers in 2002, which involves the reaction of polymer-bound cobalt complexes 51 with various carbon-centered nucleophiles in the presence of a Lewis acid to... 

One of the most striking demonstrations of the Heck reaction on solid phase was an efficient macrocyclization reaction by Hauske et al. They cyclized the resin-bound species 19 under mild conditions and obtained products with high post-cleavage purity (Scheme 19).49 The efficiency of these reactions for a variety of structural modifications in the ring seems to suggest that the pseudodifution effects of site isoiation on resin are important. 

Bray, A. M. Chiefari, D. S. Valerio, R. M. Maeji, N. J. Rapid Optimization of Organic Reactions on Solid Phase Using the Multipin Approach Synthesis of 4-Aminoproline Analogs by Reductive Animation, Tetrahedron Lett. 1995,36, 5081. 

General reactions on solid phase are described in a review Br... 

Support-bound primary or secondary aliphatic alcohols can be acylated under conditions similar to those used in solution, provided that these conditions are compatible with the chosen linker. For instance, acids can be activated with a carbodiimide either as symmetric anhydrides or as O-acylisoureas, which quickly react with alcohols in the presence of a catalyst, such as DMAP or another base, to yield esters (Table 13.12). Further acid derivatives suitable for esterification reactions on solid phase include acyl halides and imidazolides. HOBt esters react only slowly with alcohols, but enable the selective acylation of primary alcohols in the presence of secondary alcohols (Entry 5, Table 13.12). 

Thiophenes have been prepared on insoluble supports mainly by arylation or viny-lation of halothiophenes and thienylstannanes (Table 15.10). Heck, Suzuki, and Stille couplings with thiophenes usually proceed as smoothly as those with substituted benzenes, and arylations or vinylations of thiophenes have often been used as examples to illustrate new conditions for the realization of these coupling reactions on solid phase. 

A De Kok, M Hiemstra, CP Vreeter. Optimization of the postcolumn hydrolysis reaction on solid phases for the routine high-performance liquid chromatographic of N-methylcarbamate pesticides in food products. J Chromatogr 507 459-472, 1990. 

The famous Ugi reaction, the one-pot condensation of a carboxylic acid, an amine, an aldehyde or ketone and an isocyanide to yield an a-acylaminoamide, have recently been used as an efficient method for the synthesis of diverse libraries of small organic molecules such as benzodiazepines, pyrroles, lactams and diketopiperazines2. Even though some solution-phase Ugi reactions proceed rapidly, such reactions on solid phase have been found to take between one and several days. In 1999, Hoel and Nielsen17 performed the first microwave assisted, solid phase Ugi four-component condensation (see Scheme 5.5). 

Scheme 7.14 Microwave-promoted cycloaddition reactions on solid-phase.

Microwave-assisted rearrangement reactions on solid-phase have not been discussed in the literature very often. At the time when this chapter was being written only... 

The first array-based technique was designed specifically to study reactions on solid phase catalysts as IR thermography.9,19 This approach utilizes IR sensitive FPA detectors to measure the temperature of catalysts under reaction conditions. This approach has the advantages of a theoretical high thermal sensitivity, typically several tens of millikelvin, and the ability to study both endothermic and exothermic reactions. The main disadvantage of this approach, however, is the lack of chemical information. It must be assumed that the temperature change is associated entirely with the desired reaction pathway. The presence of unexpected side reactions will not be detected in this approach, as long as they have similar thermal behavior as the reaction under study. 

Solid-phase synthesis is of importance in combinatorial chemistry. As already mentioned RuH2(PPh3)4 catalyst can be used as an alternative to the conventional Lewis acid or base catalyst. When one uses polymer-supported cyanoacetate 37, which can be readily obtained from the commercially available polystyrene Wang resin and cyanoacetic acid, the ruthenium-catalyzed Knoevenagel and Michael reactions can be performed successively [27]. The effectiveness of this reaction is demonstrated by the sequential four-component reaction on solid phase as shown in Scheme 11 [27]. The ruthenium-catalyzed condensation of 37 with propanal and subsequent addition of diethyl malonate and methyl vinyl ketone in TH F at 50 °C gave the adduct 40 diastereoselectively in 40 % yield (de= 90 10). 

Reaction on solid phase (9.93) Fj = no fluorescence, F2 = weak fluorescence, F3 = strong fluorescence. Reaction in solution (soluble aryl bromide). 

Wisen S, Androsavich J, Evans CG et al (2008) Chemical modulators of heat shock protein 70 (Hsp70) by sequential, microwave-accelerated reactions on solid phase. Bioorg Med Chem Lett 18 60-65... 

Solid-supported a-bromoketone 148 was condensed with various 2-aminopyridines or 2-aminopyrimidine derivatives to give imidazo[l,2-a]pyridines or imidazo[l,2-fl]pyriniidine derivatives 149 after cleavage with acid <03TL6265>. An abnormal aza-Wittig reaction on solid-phase parallel synthesis of 3-aryl-2,4-dioxo-l,3,5-triazino[l,2-a]benzimidazoles was observed <03TL3705>. New spiroimidazolidinone derivatives 151 were prepared Irom SynPhase lanterns from dipeptides anchored on the solid-supports 150 <03JCO356>. 

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