The reactivity of 2-trichloromethylbenzoxazoles toward various nucleophiles, under metal-free or iron-catalyzed conditions, for the synthesis of substituted benzoxazoles is described. These methods allow for selective substitution at either the 2-or 2′-position of the benzoxazoles using the same starting materials/reagents. This approach allows for the controlled synthesis of a variety of key derivatives from a single 2-trichloromethylbenzoxazole starting material.
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I. General Experimental InformationUnless otherwise stated, all commercially available reagents and solvents were used without further purification.THF and DCM were dried over sodium/benzophenone and calcium hydride respectively, and purified by distillation prior to use. Toluene was dried by distillation. All anhydrous experiments were carried out in flamedried glassware. The solvents used for flash column chromatography were technical grade. For purification procedures using column chromatography, silica gel (60-120) mesh was used. Thin layer chromatography was carried out using Merck Kieselgel silica gel 60 F254 plates (0.2 mm) and visualisation was achieved using UV light followed by dipping in a potassium permanganate solution and heating. 1 H NMR and 13 C NMR were recorded on a JEOL 270 Mhz spectrometer at ambient temperature using CDCl 3 (7.27 ppm). Chemical shift values are expressed as parts per million (ppm) and coupling constants and are expressed in Hertz, followed by multiplicity indicated as s: singlet, d: doublet, t: triplet, q: quartet or combination, br.s broad singlet or m: multiplet. Solution IR spectra were recorded on a Perkin Elmer 1600 series FTIR-spectrophotometer.Microwave reactions were run in a Biotage Initiator 2.0 microwave and the reaction temperature was monitored by IR. Mass spectra were determined using a Bruker MicroTOF mass spectrometer.
II. Synthesis of trichlorobenzoxazoles 2a-lGeneral procedure 1: To a stirred suspension of PtCl 4 (10 mol %) and 2-aminophenol (1 equiv.) in n-hexane (1 M) at rt was added trichloroacetonitrile (2.2 equiv.). The resultant mixture was stirred at 80 °C for 19 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (3% ethyl acetate in petroleum ether) to afford the benzoxazole.General procedure 2: To a solution of 2-aminophenol (1 equiv.) in methanol (1M) at rt was added trichloroacetonitrile (1.1 equiv.). The resultant mixture was stirred at 40 °C for 19 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (3% ethyl acetate in petroleum ether) to afford the trichlorobenzoxazole.
2-(Trichloromethyl)benzo[d]oxazole (2a) 1General procedure 1: PtCl 4 (18 mg, 0.05 mmol), 2-aminophenol (1a, 58 mg, 0.53 mmol), trichloroacetonitrile (117 µL, 1.17 mmol) in n-hexane (0.53 mL), afforded 2-(trichloromethyl)benzo[d]oxazole (2a, 102 mg, 82% yield) as a white solid. General procedure 2: 2-Aminophenol (1a, 233 mg, 2.14 mmol), trichloroacetonitrile (236 µL, 2.35 mmol) in methanol (2.14 mL), afforded 2-(trichloromethyl)benzo[d]oxazole (2a, 499 mg, 99% yield) as a white solid. N O CCl 3 2a S3
Allyl amides were synthesised from the reaction of allyl alcohols and halogenated nitriles using a platinum multifaceted catalysis approach in which both the nucleophilic addition and subsequent [3,3]-sigmatropic rearrangement steps of the process were catalysed by the same complex. Additionally, (1)H/(13)C{(1)H} NMR and GC studies provided the first insights into the mechanism of this transformation.
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