The Synthesis Of Fluorine-Containing Oxazole Heterocyclic Compounds

Oxazole heterocyclic compounds present a common type of cyclic compounds containing oxygen, nitrogen, widely used in medicine, materials and organic synthesis. The introduction of fluorine atom into organic compouds may greatly change their biological activities and physical, chemical properties. This dissertation is focused on the synthesis of fluorine-containing oxazole compounds, including the following three parts.1. The synthesis of3-aryl-4-fluoroalkyl-2-oxazolidinones is investigated. The aryl amine reacted with chloroformate allyl ester in THF in the presence of K2CO3at room temperature to give allyl arylcarbamates1-5in95.9%-99.5%yields. The allyl arylcarbamates1-5reacted with fluoroalkyl iodides a-c initiated by sodium dithionite in aqueous acetonitrile at room temperature to give the corresponding adducts6a-10c in29.3%-84.9%yields. The intramolecular N-cyclization of adducts6a-10c was carried out under sodium hydride in THF at room temperature to afforded corresponding3-aryl-4-fluoralkyoxazolidin-2-ones10a-15c in29.3%-58.5%yields. Through the study, an efficient and convenient protocol for synthesis of3-aryl-4-fluoroalkyl-2-oxazolidinones is provided.2. The synthesis of3-aryl/alkyl-5-fluoroalkyl-oxazolidin-2-ones is investigated. At room temperature, aryl/alkyl amines reacted with benzyl chloroformate (CbzCl) to give the corresponding benzyl aryl/alkylcarbamates17-22in57.8%-99.7%yields in the presence of K2CO3, which were then treated with allyl bromide in the presence of NaH and TBAI to afford the corresponding benzyl allyl (aryl/alkyl) carbamates23-28in96.3%-99.9%yields. The benzyl allyl (aryl/alkyl) carbamates23-28reacted with fluoroalkyl iodides a, d initiated by sodium dithionite in aqueous acetonitrile at room temperature to give the corresponding adducts29a-34d in44.9%-62.0%yields. The intramolecular O-cyclization reaction failed to give the target products under acidic, alkaline conditions, in the presence of zinc or at high temperature. However, the intramolecular O-cyclization of adducts29a-34d was realized under microwave irradiation with a power of250W in2min in DMF to afforded corresponding3-aryl/alkyl-5-fluoralkyoxazolidin-2-ones35a-40d in61.1%-90.4%yields. Notably. the3-aryl/alkyl-5-fluoralkyoxazolidin-2-ones35e-40e can also be obtained from benzyl allyl (aryl/alkyl) carbamates23-28and fluoroalkyl iodide e with high boiling point by a one-pot sequential addition-cyclization reaction using AIBN as an initiator in71.6%-82.3%yields. Through the study, an efficient and convenient protocol for the synthesis of3-aryl/alkyl-5-fluoroalkyl-2-oxazolidinones is provided.3. The synthesis of N-aryl-5-fluoroalkyl-oxazoline-2-amine is investigated. The1-allyl-3-arylureas41,42were obtained by the reaction of isocyanate with allyl amine in methylene chloride at room temperature in56.4%-99.1%yields. The Nt-allyl-N2-aryl-oxalamides43-45were conveniently obtained by condensation of arylamine with oxalylchloride under refluxing in methylene chloride, then treated with allyl amine at room temperature in47.6%-52.3%yields. The1-allyl-3-arylureas41,42/N-1-allyl-N2-aryl-oxalamides43-45reacted with fluoroalkyl iodides a, b initiated by sodium dithionite in aqueous acetonitile at room temperature to give the corresponding adducts46a-50b in48.6%-63.9%yields. The reaction of adduct46b in the presence of weak alkali (K2CO3) gave the ternary cyclic amine53b and in the presence of strong alkali (NaH) gave a mixture of ternary cyclic amine53b and two eliminate products54b,55b. The intramolecular O-cyclization of adducts46a-47b was realized by heating in water or DMF for30-60minutes to afford corresponding N-aryl-5-fluoroalkyl-oxazoline-2-amine51a-52b in51.0%-69.0%yields. However. by heating in DMF, N1-phenyl-N2-(3-fluoroalkyl-2-iodopropyl)oxalamides were hydrolized to give N1-aryl-N2-(3-fluoroalkyl-2-hydroxypropyl)oxalamides56a-58b in74.9%-83.4%yields.. Notably, the N-aryl-5-fluoroalkyl-oxazoline-2-amine51e-52e can also be obtained from1-allyl-3-arylureas41,42and fluoroalkyl iodide e with high boiling point by a sequential addition-cyclization reaction using AIBN as an initiator in39.3%-53.4%yields. Through the study, an efficient and convenient protocol for synthesis of N-aryl-5-fluoroalkyl-oxazoline-2-amine is provided.In conclusion, through the invesigation on the syntheis of fluorine-containing oxazole heterocyclic compounds, an efficient and convenient protocol for synthesis of fluorine-containing oxazole heterocyclic compounds is provided.