Synthesis of 3,5-Disubstituted Isoxazoles and Isoxazolines in Deep Eutectic Solvents

Abstract

The synthesis of different 3,5-disubstituted isoxazoles and related isoxazolines using choline chloride:urea as deep eutectic solvent (DES) in a one-pot three step reaction has been accomplished successfully. The use of highly nucleophilic functionalized DES did not affect the process where highly electrophilic reagents or intermediates are involved. The presence of DES showed to be essential since the reaction in absence of this media did not proceed. The DES media could be reused up to five times without a detrimental effect on the yield of the reaction. To exemplify the synthetic potential of this methodology, the reaction was scaled up to gram scale without any noticeable problem. Finally, different isoxazoles were easily transformed into β-aminoenones.

Deep Eutectic Solvents: The Organic Reaction Medium of the Century

“…[140] The nucleophilic mixture allowed the initial condensation, followed by chlorination to give the corresponding imidoyl chloride. Surprisingly, the DES did not react with the high electrophilic intermediates.…”

Thermal azide–alkene cycloaddition reactions: straightforward multi-gram access to Δ2-1,2,3-triazolines in deep eutectic solvents

“…21 In particular, DESs have been applied to several cycloaddition reactions such as Lewis acid-catalysed Diels-Alder reactions, 22 formation of pyrrolidines from the corresponding azomethine ylides, 23 and isoxazoles from nitrile oxides. 24 From azides, either tetrazoles 25 or triazoles 26 have been prepared in DES. In many of these examples the beneficial effect of DES as reaction media was rationalised either through the Lewis acidity of one of the components, or the formation of hydrogen bonds between either of the components and the cycloaddition partners.…”

The synthetic and therapeutic expedition of isoxazole and its analogs

“…2) from aldehydes and alkynes using choline chloride (ChCl): urea as a biorenewable deep eutectic solvent (DES). DES are an environmentally benign alternative to hazardous (Majewsky et al 2014) 2 Sulfisoxazole Antibacterial (Genc et al 2008) 3 Acetyl sulfisoxazole Antibacterial (Cronin et al 2002) 4 Cycloserine Antitubercular, Antileprotic (Desjardins et al 2016) 5 Acivicin Antitumour, Antileishmania (Conti et al 2003) 6 Broxaterol Bronchodilatory agent (Giustina et al 1995) 7 Oxacillin Antibacterial (Lainson et al 2017) (Zhao et al 2017a) 10 Zonisamide Anticonvulsant (Buoli et al 2017), Antiobesity (Shin et al 2014) 11 Risperidone Antpsychotic (Schoretsanitis et al 2017) 12 Valdecoxib COX-2 inhibitor (Bartzatt 2014) 13 Danazol Androgenic (McKinney et al 2013) (organic) solvents that can be recycled (Pérez and Ramón 2015). Jadhav et al synthesized highly pure 3,5-disubstituted isoxazoles (Route d, Fig.…”