Solid-phase organic synthesis 2+2 cycloaddition reactions

The Diels-Alder reaction is a [4-1-2]-cycloaddition to synthesize six-membered rings. It is a well-known reaction in combinatorial chemistry and there have been many examples in which this reaction has been described in solid-phase synthesis [266]. In solid-phase organic synthesis it is possible to immobilize the diene (Scheme 3.21) [267] or the dienophile [268]. 

The most widely used, and often most convenient reagents for such one-pot reactions are sodium hypochlorite (45) or hypobromite (16). These reactions are performed in the presence of an organic base (generally triethylamine) that normally enhances the yield of cycloaddition products (45). This method was employed for many intermolecular reactions (71) and also seems especially suited for intramolecular ones (72-77) as well as for the solid-phase synthesis (78) of 2-isoxazolines. Hypohalite can also be replaced by sodium broruite in combination with a catalytic amount of tri-u-butyltin chloride (79). In a related method, O-tributylstannyl oximes were treated with tert-butyl hypochlorite to produce nitrile oxides that were trapped with aUcenes or alkynes to afford the corresponding isoxazolines or isoxazoles in moderate to good yield (80). 

The utility of the Huisgen 1,3-dipolar cycloaddition was discovered when it was realized that copper not only catalyzes the reaction but also promotes the regiospecificity, with exclusive production of the 1,4-triazole regioisomer (Figure 14.8) [64]. The first publication by Meldal et al., in 2002, outlined the use of copper in the cycloaddition reaction for triazole synthesis on a solid phase [66]. This was an organic-solvent-based... 

Over the last 10 years, a burst of publications and reviews has been focused on the translation of different types of organic reactions towards the solid phase. The difficulty of transferring certain key reactions to the solid phase has stimulated solution phase library synthesis approaches which may be more effective. Cycloaddition reactions allow straightforward and often stereoselective construction of cyclic systems, which can serve as templates for further derivatization. Therefore, cycloaddition reactions play a key role in combinational chemistry sequences. The translation of cycloaddition reactions, especially 1,3-dipolar- [2] and Diels-Alder reactions [3] to the solid phase has been extensively studied. Although the benefits of high pressure for all type of cycloaddition reactions (e.g. [4 + 2] 1,3-dipolar, [2 + 2]) have been very well illustrated in past decades, the application of high pressure to solid phase cycloaddition reactions is still in its infancy. 

Solid-phase Cu(l) catalyzed azide-alkyne cycloadditions have also proven to be a rehable and highly robust procedure [6,25-27]. Both the azide and the alkyne functions have been incorporated into different resins. These functionaUzed supports have been appUed to the synthesis of triazole- and non-triazole-containing products by using, in the latter case, the triazole functionaUty as a hnker. The cycloadditions proceed easily on the solid phase showing more sensitivity to steric factors than in solution phase and little sensitivity to reaction conditions, resin type, or subsequent transformations. The Cu(II) reduction protocol, as well as the use of Cu(I) salts, work with equal efficiency in various organic solvents (THF, DMF, acetonitrile, DMSO). 

Preparation of Heterocycles. BSA has been used in the solid-phase synthesis of 1,2,3-triazoles via trimethylsilyl-directed 1,3-dipolar cycloaddition reactions of 1-trimethylsilylacetylenes with organic azides (eq 48). When resin 56 was allowed to react with trimethylsilylpropynoic acid in the presence of BSA, high regioselectivity was observed and the trisubstituted triazole 57a was obtained in near quantitative yield that is greater than 98% purity. 

Yedl980 Yedidia, V. and Leznoff, C.C., The Use of Polymer Supports in Organic Synthesis. Part XXII. Regioselectivity in Cycloaddition Reactions on Solid Phases, Can. J. Chem., 58 (1980) 1144-1150. 

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