Cyclocondensation of Hydroxylamine with 1,3‐Bis(het)arylmonothio 1,3‐Diketones and 1,3‐Bis(het)aryl‐3‐(methylthio)‐2‐prop­enones: Synthesis of 3,5‐Bis(het)arylisoxazoles with Complementary Regioselectivity

Abstract

Efficient routes for the regioselective synthesis of 3,5-bis-(het)arylisoxazoles with complementary regioselectivity have been developed. The methods involve the cyclocondensation of hydroxylamine hydrochloride with either 1,3-bis(het)arylmonothio-substituted 1,3-diketones 1 or with 3-methylthio-1,3-bis(het)aryl-2-propenones 2 under various reaction conditions. In the first protocol, diketones 1 were treated with hydroxylamine hydrochloride in the presence of sodium acetate/acetic acid (pH 2.2) in refluxing ethanol/benzene to give 3,5-bis(het)arylisoxazoles 5, in which the het(aryl) moiety at-

β‐Cyclodextrin–Glycerol Dimers: Synthesis and NMR Conformational Analysis

“…Of most interest, Singh reported the synthesis of 3‐amino‐5‐substituted isoxazoles via condensation of β‐oxo‐dithioesters, an amine and hydroxylamine (Scheme ) 87. Rangappa and Ila reported the regioselective synthesis of 3,5‐disubstittued isoxazoles from monothio‐β‐diketones and hydroxylamine hydrochloride in the presence of base (Scheme B) 88. Dong developed an efficient synthesis of 5‐amino‐3,4‐disubstituted isoxazoles from cyclopropyl oximes using POCl 3 under mild conditions (Scheme C) 89…”

“… A: 3‐Amino‐5‐substituted isoxazoles from β‐oxo‐dithioesters by Singh 87. B: 3,5‐Disubstituted isoxazoles from monothio‐1,3‐diketones by Ila et al 88. C: 5‐Amino‐3,4‐disubstituted isoxazoles from cyclopropyl oximes by Deng 89…”

General Platform for the Conversion of Isoxazol‐5‐ones to 3,5‐Disubstituted Isoxazoles via Nucleophilic Substitutions and Palladium Catalyzed Cross‐Coupling Strategies

“…Purification by flash column chromatography (SiO 2 , gradient: Hex – 95:5 Hex/AcOEt – 9:1 Hex/AcOEt) affords the title compound as a white solid: 18 mg, 71 %. 1 H (500 MHz, CDCl 3 ) δ: 7.85–7.84 (m, 2H), 7.76–7.75 (m, 2H), 7.46–7.43 (m, 3H), 6.98–6.97 (m, 2H), 6.69 (s, 1H), 3.84 (s, 3H). 13 C (125 MHz, CDCl 3 ) δ: 170.6, 163.1, 161.3, 130.1, 129.5, 129.1, 127.6, 127.0, 120.5, 114.6, 96.3, 55.6.…”

Complementary and Regioselective Synthesis of Isomeric 3-[Isoxazol-3(or 5)-yl]indoles from β-Ethylthio-β-indolyl-α,β-unsaturated Ketones

“…In this context, Ila and co-workers explored the regioselective synthesis of 3-isoxazolylindoles via the cyclocondensation of hydroxylamine hydrochloride with 1-aryl-3-(1-methylindol-3-yl)-3thioxopropan-1-ones and (Z)-1-aryl-3-(1-methylindol-3yl)-3-(methylthio)prop-2-en-1-ones under various conditions. 9 They found that 3-(isoxazol-3-yl)indoles were only obtained in good yields when the cyclocondensation reaction of hydroxylamine hydrochloride with 1-aryl-3-(1-methylindol-3-yl)-3-thioxopropan-1-one was carried out in the presence of NaOAc in a boiling mixture of acetic acid, benzene, ethanol, and water (1:1:0.5:0.1; pH 2.2). while the reaction of hydroxylamine hydrochloride with (Z)-1-aryl-3-(1-methylindol-3-yl)-3-(methylthio)…”

“…prop-2-en-1-one yielded isomeric 3-(isoxazol-5-yl)indoles in the presence of Ba(OH) 2 in refluxing EtOH. 9 Although this method was quite useful to access the target compounds, its limitations are the use of distinct precursors and electrophilic solutions [NaOAc vs Ba(OH) 2 ]. Some other useful methods, including iterative assembly of nitrile oxides with ynamides, 10 electrophilic cyclization of (Z)-O-methyloximes, 11,12 [3+2] cycloaddition of nitrile oxides and arynes, 13,14 iminoxyl radical facilitated regioselective cyclization of -halo-,-and -halo-,-unsaturated ketoximes 15 have also been developed for the regioselective synthesis of 3-(isoxazol-3-yl)indoles.…”