Dipolar solid-phase synthesis

Poly(ethylene glycol) supported liquid-phase syntheses by both the reaction of (polyethylene glycol (PEG))-supported imines with nitrile oxides, generated in situ from aldoximes, (300) and 1,3-dipolar cycloadditions of nitrile oxide, generated in situ on soluble polymers with a variety of imines (301, 302) have been described. The solid-phase synthesis of 1,2,4-oxadiazolines via cycloaddition of nitrile oxide generated in situ on solid support with imines has also been elaborated (303). These syntheses of 1,2,4-oxadiazolines provide a library of 1,2,4-oxadiazolines in good yields and purity. 

A solid-phase synthesis of substituted benzopyranoisoxazoles 356 (I R = H, Me, Et, Pr, Ph, CHMe2 R1 =H, Me, decyl, Ph) has been described (414). The six-step synthesis includes a method of generating nitrile oxides on a polymer support, followed by an intramolecular 1,3-dipolar cycloaddition with a tethered alkyne, for assembly of the benzopyranoisoxazole scaffold. 

Scheme 3.22 1,3-Dipolar cydoaddition step for the solid-phase synthesis of isoxazolocyclobuta-nones (171) [110],...

The utility of solid-phase synthesis for rapid generation of libraries of small molecules is unquestionable and this technique is particularly amenable to automation. It is not surprising then that the 1,3-dipolar cycloaddition reactions of nitrones have been applied to solid-phase synthesis, either through a supported... 

Gowravaram and Gallop (169) adapted the rhodium-catalyzed generation of isomiinchnones from diazo imides to the solid-phase synthesis of furans, following a 1,3-dipolar cycloaddition reaction with alkynes. A variety of furans were prepared in this fashion. With unsymmetrical electron-deficient alkynes (e.g., methyl... 

A review on the 1,2,3-triazole formation via 1,3-dipolar cycloaddition of acetylenes with azides under mild conditions has been published <03H(60)1225>. The synthesis of a benzotriazole azo dye phosphoramidite and the subsequent use in solid phase synthesis of oligonucleotides has been reported <03TL1339>. The chemical reactivity of [l,2,3]triazolo[l,5-a]- and [l,5-c]-pyrimidinium salts has been published <03T4297>. A review on the use of benzotriazole as an ideal synthetic auxiliary has been disclosed <03CEJ4586>. 

Dipolar cycloaddition of polyethylene glycol-supported azide with various dipolarophiles followed by acidic cleavage afforded 4- and 5-substituted-1,2,3-triazoles 05T4983>. Trimethylsilyl-directed 1,3-dipolar cycloaddition reactions in the solid-phase synthesis of 1,2,3-triazoles have been developed <05OL1469>. 

A solution phase chiral auxiliary for 1,3-dipolar cycloaddition of isomunchnones with vinyl ethers has been adapted for solid phase synthesis by attaching both enantiomers of the precursor a-hydroxyvaline to benzhydrylamine resin (Scheme 12.12) [13,19]. The auxiliary 22 was then functionalized by acylation and diazotiza-tion to provide diazoimide resin 23. Rhodium(II)-catalyzed nitrogen extrusion and cycloaddition in the presence of different vinyl ethers afforded, after detachment from the polymer, various bicydic molecules (24) in 49-65% yield and provided high degrees of selectivity (93-95% ee). 

Resin-bound nitroalkenes were synthesized via a Knoevenagel condensation of resin-bound nitro acetic acid with aryl and alkyl substituted aldehyde (Scheme 9.29). In this way an extra site of diversity can be introduced into the cycloaddition products of these nitroalkenes. Furthermore, the resin-bound nitroalkenes can serve as activated alkenes in other cycloaddition reactions (Diels-Alder, 1,3-dipolar cycloaddition, [2 + 2] cycloaddition) and therefore lead to the solid phase synthesis of other interesting compoimd classes (see also Scheme 9.3, Sect. 9.2). Formation of the resin-bound nitroalkenes 73a-e was realized in one step via a microwave-assisted condensation of aldehyde 72a-e (10 equiv.) with the resin-bound nitro acetic acid 71, followed by dehydration of the intermediate y -nitroalcohol [6] (Scheme 9.29). THF was used as the solvent in order to obtain optimal diffusion of the aldehyde in the polystyrene resin. 

By using a three component 1,3-dipolar cycloaddition reaction, Hamper et al. developed a solid-phase synthesis of highly substituted pyrrolidines via resin-bound azomethine ylides. 

Scheme 18 Trimethylsilyl-directed 1,3-dipolar cydoaddition reactions in the solid-phase synthesis of 1,2,3-triazoles [57]...

Solid-phase 1,3-dipolar cycloadditions have led to various heterocyclic compounds during recent years. Yedidia and Leznoff ° reported solid-phase synthesis of isoxazoles via 1,3-dipolar cycloaddition in 1980. Alkynes were attached to the resin with an ester linkage... 

Solid-phase synthesis of pyrroles was reported by Mjalli et al. " Pyrroles were prepared via Rink resin-bound mesoionic munchnones (Scheme 11.12). Munchnones behave as azomethine ylides in 1,3-dipolar cycloaddition. Cycloadditions with alkynes give pyrroles after aromatization and spontaneous release of carbon dioxide. A set of compounds was obtained from simple starting materials, aldehyde, amine, carboxylic acid, and isocyanide via the Ugi four-component condensation. Trifluoroacetic acid released highly substituted pyrroles as amides from the Rink resin in high overall yield and purity. A related method via the miinchnone pathway was reported by Strocker et al., and two pyrroles were obtained in 4% and 17% yields. 

Dipolar cycloaddition of azomethine imine or nitrile imine-type dipoles with alkenes or alkynes yields nitrogen heterocycles containing two nitrogen atoms in the ring. MeOPEG resin was applied in the solid-phase synthesis of pyrazolines (Scheme 11.13). Resin-bound... 

K. Hatju, M. Vahermo, I. Mutikainen, J. Yh-Kauhaluoma, Solid-phase synthesis of 1,2,3-triazoles via 1,3-dipolar cycloaddition. J. Comb. Chem. 2003, 5, 826-833. 

W. J. Haap, D. Kaiser, T. B. Walk, G. Jung, Solid phase synthesis of diverse isoxazolidines via 1,3-dipolar cycloaddition. Tetrahedron, 1998, 54, 3705-3724. 

Gowl997 Gowravaram, M.R. and Gallop, M.A., Traceless Solid Phase Synthesis of Furans via 1,3-Dipolar Cycloaddition Reactions of Isomunchnones, Tetrahedron Lett., 38 (1997) 6973-b976. 

---