Isoxazole library

The first demonstration of fluorous synthesis was in the preparation of small (8-12 members) isoxazo-line and isoxazole libraries by the three-step procedure outlined in Figure 8.1461 All reactions were purified by three-phase liquid-liquid extraction. The starting substrates were simple allylic alcohols which were tagged with the fluorous silyl halide 5 to make substrates 6 for an ensuing dipolar cycloaddition. This was conducted by the Mukaiyama method with a large excess of nitro compound and... 

Savant MM, Pansuriya AM, Bhuva CV, Kapuriya N, Patel AS, Audichya VB, Pipaliya PV, NaliparaN (2010) Water mediated construction of trisubstituted pyrazoles/isoxazoles library using ketene dithioacetals. J Comb Chem 12(1) 176-180... 

As for the solid support, several polymer-supported amines were tested (Fig. 2). For either the pyrazole and isoxazole synthesis, the best results were given by aniline-functionalized cellulose, which has also the advantage of a relatively low cost. For the 2-aminopyrimidine library, polystyrene-based piperazine and piperidine gave products with a much higher purity compared with other secondary non-cyclic or primary amines, hi both cases, the resins could be reused for up to four times before degradation in their behavior was observed. This reusability could be further enhanced (up to 10 cycles for cellulose-based aniline) when the microwave-assisted protocols were used. 

A solid-phase synthesis of pyrroloindolizines has been developed using this cycloaddition methodology, whereby an isoxazolopyrroloindolizine can be removed from the polymeric resin upon treatment with trifluoroacetic acid (TFA). This also results in ring opening of the isoxazole to give the isolated compound 210 (Scheme 58). A library of 96 such derivatives has been prepared in this way <1998TL5869>. 

A small library of isoxazole fused azepines 39 was synthesised by the acid catalysed conjugate addition of 3,5-dimethyl-4-nitroisoxoazole 36 to a,p-unsaturated ketones 37 yielding the adduct 38 followed by tin(II) chloride reduction of the nitro group and imine formation <07ARK266>. 

Pellegrino G, Leonetti F et al (2010) Solid phase synthesis of a molecular library of pyrimidines, pyrazoles, and isoxazoles with biological potential. Tetrahedron Lett 51 1702-1705... 

In a search for new isoxazole-based liquid crystalline compounds, a 22-member library of 3,5-diaryl isoxazoles 628 was prepared by parallel synthesis on solid phase (Rink resin) through 1,3-dipolar cycloaddition of supported phenylacetylene units with suitable aryl nitrile oxides generated in situ from hydroxyiminoyl chlorides. Cleavage from the resin under acidic conditions allowed the generation of the cyano moiety <2004TL2277>. 

Solid-supported nitrile oxides have the main advantage over those prepared in solution that formation of dimers is avoided. Thus, a 96-member library of 3-hydroxymethyl isoxazoles (265) [298] has been prepared from nitroethanol on a modified tetrahydropyranyl linker (263) as nitrile oxide precursor. The cycloaddition step was then performed by generating the nitrile oxide under the Mukaiyama conditions in the presence of alkynes (Scheme 59). As expected, the presence of dimer furoxane was never detected. 

The search of the in-house virtual library identified more than 1,000 compounds containing the resorcinol substructure that were assessed for fit to the Nt-Hsp90 active site. Some 225 compounds were selected, of which 170 were delivered and assayed. Some of these compounds are shown in Table 1. Not only did this approach retrieve the same resorcinol 7 found by virtual and experimental screening [31] and encouraged us to generate additional SAR around the resorcinol-pyr-azole template (compounds 21-25), it also identified isoxazole (26-28) replacements for the pyrazole, which were explored in lead optimisation. 

An 18-member library of 5-isoxazol-4-yl-[l,2,4]oxadiazoles 14 was prepared on solid-phase through nitrile oxide 1,3-DC to resin-bound alkynoate ester 10 <04JOC1470>. 

The first report of the use of cellulose beads as support for microwave-assisted SPOS was published in 2003 and described the generation of a library of pyrazoles and isoxazoles [49]. The synthesis was performed using commercially available amino cellulose (Perloza VT-100) containing aminoaryl ethyl sulfone groups in flexible chains (Scheme 16.27). Initially, the solid support was treated with excess formyl imidazole and the corresponding yS-keto compounds to generate cellulose-bound enaminones in a one-pot Bredereck-type condensation. The reaction was catalyzed by (+)-camphor-10-sulfonic acid (CSA) and performed under microwave-irradiation conditions in an open vessel to enable the methanol formed to be removed from the reaction equilibrium [49]. 

Electron-rich isoxazoles are also known to undergo electrophilic substitution under similar conditions. The bromination of 5-aminoisoxazole provided the 4-bromo derivative that was utilized as part of a synthesis of a library of compounds screened for their ability to act as bradykinin B2 receptor antagonists. ... 

Substituted-phenyl-5-isoxazolecarboxaldehydes have been identified as activated aldehydes for the generation of isoxazole-based combinatorial libraries in the solid (Scheme 3.206) and solution phase (Scheme 3.207). The highly functionalized isoxazole-based libraries have been synthesized in parallel format using the MBH reaction and Michael addition. With an objective of lead generation, the libraries have been evaluated for their biological activities in vivo. 

A small library of alkyl, sulfone, and carboxamide-functionalized pyrazoles and isoxazoles has been developed via a rapid sequential condensation of various R-acylketene dithioacetals with hydrazine hydrate or hydroxylamine hydrochloride, followed by oxidation of sulfide to sulfone using water as the reaction medium [3] (Scheme 8.3). An efficient and safe oxidation of sulfides to the corresponding sul-fones using sodium per borate system in aqueous medium has also been reported. The concise and two-step synthesis of trisubstituted pyrazoles and isoxazoles was investigated under a variety of reaction conditions. The newly developed methodology has the advantage of excellent yield and chemical purity with short reaction time using water as a solvent. 

A tetrahydropyranyl linker is an acid-sensitive linker for alcohols. Nitrile oxides were generated in situ from tetrahydropyranyl-linked nitro alkanes and phenyl isocyanate under Mukaiyama conditions, and reactions with various alkynes gave resin-bound isoxazoles (Scheme 11.39). Cleavage with diluted trifluoroacetic acid gave isoxazoles as primary alcohols in a traceless manner. A library of 3-hydroxymethyl-4,5-disubstituted isoxazoles was prepared in a parallel and automated fashion by a 96-well plate synthesizer with an average yield of 60%. 

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