Green Synthetic Approach for the Construction of 3,5‐Disubstituted 1,2,4‐Oxadiazoles and Ataluren Analogues from Dithioesters Using Water

Abstract

An innovative green synthesis of 3,5‐disubstituted 1,2,4‐oxadiazoles from dithioesters using water as a solvent. This approach becomes more interesting because it undergoes nucleophilic substitution–dehydration–intramolecular cyclization in a single step to give 3,5‐disubstituted 1,2,4‐oxadiazoles in good to excellent yields under transition‐metal free conditions and allows wide functional group tolerance. This green protocol leads to synthesis of a drug lead molecule, Ataluren and their analogues.

Thiol-promoted intermolecular cyclization to synthesize 1,2,4-oxadiazoles including tioxazafen under transition metal-free conditions

“…It is noteworthy that when CH 3 CN was used as the solvent, a yield as high as 96% was obtained (entry 14). Other solvents such as 1,4-dioxane, DMF, and C 2 H 5 OH were used as the reaction solvent, and the yields of 3aa were decreased to an appreciable extent (Table 1, entries [15][16][17], whereas no reaction took place in THF or H 2 O (Table 1, entries 18 and 19). Next, the effects of the equivalent of BnSH on the reaction yield were also explored by using CH 3 CN as the solvent and Cs 2 CO 3 as the base at 80 °C.…”

“…1,3-Dipolar cycloaddition of nitriles to nitrile oxide 13 is also considered a good choice (Scheme 1c), although some metal catalysts (PtCl 4 and ZnCl 2 ) need to be used. Moreover, the reactions of other coupling partners such as iodobenzene, 14 dithioesters, 15 or gem -dibromomethylarenes 16 with amidoximes have also been realized to fulfill the incessant research leading to 1,2,4-oxadiazoles.…”

TFA-Mediated Synthesis of 1,2,4-Oxadiazoles from Carbamates and Nitriles

“…White solid (1.30 g, 57% yield; eluent, 1/10 ethyl acetate/petroleum ether); 1 H NMR (400 MHz, CDCl 3 ) δ 8.07 (s, 1 H), 7.67−7.66 (m, 1 H), 7.38− 7.37 (m, 1 H), 6.58−6.56 (m, 1 H), 1.51 (s, 9 H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 158.0, 155. 4,147.7,141.4,120.3,112.2,83.5,oxy]carbamate (1u). White solid (1.35 g, 51% yield; eluent, 1/10 ethyl acetate/petroleum ether); 1 H NMR (400 MHz, CDCl 3 ) δ 7.92 (s, 1 H), 7.31−7.27 (m, 2 H), 7.23− 7.19 (m, 3 H), 3.03−2.99 (m, 2 H), 2.79−2.75 (m, 2 H), 1.48 (s, 9 H); 13 C{ 1 H} NMR (100 MHz,CDCl 3 ) 172.1,155.4,139.6,128.6,128.2,126.5,83.2,33.4,30.5,.…”

“…White solid (1.66 g, 62% yield; eluent, 1/4 ethyl acetate/petroleum ether); 1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (s, 1 H), 7.87−7.85 (m, 1 H), 7.49− 7.45 (m, 1 H), 6.96−6.92 (m, 2 H), 3.85 (s, 3 H), 1.44 (s, 9 H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 165. 4,159.7,155.7,134.8,132.2,120.5,116.4,112.2,83.1,56.1,oxy]carbamate (1h). White solid (2.00 g, 75% yield; eluent, 1/4 ethyl acetate/petroleum ether); 1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (s, 1 H), 7.99−7.97 (m, 2 H), 6.89− 6.86 (m, 2 H), 3.82 (s, 3 H), 1.44 (s, 9 H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 165.8, 164.…”

“…Among them, the most widely applied method is the [4+1] assembly reaction of amidoximes. Over the past several decades, carboxylic derivatives, dithioesters, and benzyl thiols have been utilized in the synthesis of 1,2,4-oxadiazoles (Scheme a). Another common approach involves the 1,3-dipolar cycloaddition of nitrile oxides to nitriles or azetine derivatives .…”