Recent Advances in the Synthesis and Reactivity of Isothiazoles

Abstract

Isothiazoles represent an important class of five‐membered sulfur heterocycles that are widely utilized in medicinal chemistry and organic synthesis due to the unique properties of two electronegative heteroatoms in a 1,2‐relationship. However, in contrast to other 1,2‐azoles, the facile assembly of isothiazoles has always been considered a substantial challenge. In the last decade, major advances have taken place in the fields of synthesis and functionalization of isothiazoles that make them accessible to a wide range of interested chemists through unprecedented pathways. New condensation methods have emerged that address the challenges posed by unstable thiohydroxylamine. New metal‐catalyzed approaches have been reported that deliver densely decorated isothiazoles bearing various sensitive functional groups. New functionalization strategies have been developed through both cross‐coupling and direct C−H activation chemistry. Finally, the emergence of novel heterocyclic architectures based on isothiazole opens the door for future investigations of this versatile heterocyclic scaffold. This review covers the period from January 2004 to December 2018 and is intended as a sequel to the review on isoxazoles, which represent another class of synthetically‐important 1,2‐azoles (see Adv. Synth. Catal. 2015, 357, 2583–2614).

Stereoselective Synthesis of 4,5‐Dihydroisoxazole Derivatives from 1,1‐Dicyanocyclopropanes and Hydroxylamine Hydrochloride

“…Numerous isoxazoline derivatives have been developed as pharmaceuticals, veterinary drug and agrochemicals, [11–16] such as human leukocyte elastase inhibitors, [17] papaya ringspot virus inhibitors ( 6 ), [18] glyceraldehyde‐3‐phosphate dehydrogenase inhibitors ( 5 ), [19] antifungal agents ( 3 ), [20] anti‐HIV agents, [21] anticancer agents ( 4 ), [22,23] herbicides ( 2 ), [24] and insecticides ( 1 ; Figure 1 ) [25–27] . Additionally, polysubstituted isoxazolines as versatile intermediates exhibit superior applications in organic synthesis [28–40] . Accordingly, not surprisingly, numerous synthetic approaches leading to an isoxazoline nucleus have been developed, principally consisting of the cycloaddition from 1,3‐dicarbonyl intermediates and hydroxylamine or from modified three‐carbon 1,3‐electrophilic intermediates of 1,3‐dicarbonyl compounds, including β‐alkylthioenones, enamino ketones, ynones, and α,β‐unsaturated ketones [41–46] .…”

Et3N/DMSO-supported one-pot synthesis of highly fluorescent β-carboline-linked benzothiophenones via sulfur insertion and estimation of the photophysical properties

“…Sulfur-containing organic compounds are broadly associated with numerous bioactive natural products and pharmaceutical drugs [ 20 – 22 ]. Thioaurones (2-benzylidene benzo[ b ]thiophen-3(2 H )-one) are sulfur-containing heterocyclic compounds, an important subclass of flavonoids which were first introduced by O’Sullivan in 1977 [ 23 ].…”

Ruthenium(II) Complexes of Isothiazole Ligands: Crystal Structure, HSA/DNA Interactions, Cytotoxic Activity and Molecular Docking Simulations

“…Isothiazoles, on the other hand, represent an important class of aromatic organic ligands with nitrogen and sulfur in the adjacent position (Figure ). These two electronegative heteroatoms allow very easy coordination of the five‐membered aromatic heterocycle for different metal ions . Isothiazole was first synthesized in 1956 and since then its chemical and physical properties have been extensively studied, as well as its derivatives .…”