Green chem.: non enantioselective synthesis of trifluoromethyloxazine quinoline in aqueous phase

Fluorine-containing molecules have unique physical, chemical and biological characteristics, which make organic fluorine compounds have been widely used as building materials, liquid crystal components, pesticides and drugs It is not fully estimated that about 20-25% of drugs and agricultural chemicals currently used contain at least one fluorine atom On the other hand, the molecule with 1,3-oxazine skeleton has many activities, which can be used as anticoagulant, analgesic, antispasmodic, antidepressant, antituberculotic, antibacterial and fungicide In recent years, FDA has approved many drugs containing 1,3-oxazine skeleton, and they have been sold on the market, such as efavirenz, dolutegravir and biocegravir, which can be used to treat HIV patients Etifoxine is an antianxiety and anticonvulsant drug, which can enhance the function of GABAA receptor Dirithromycin is a macrolide glycopeptide antibiotic used to treat many different types of bacterial infections, such as bronchitis, pneumonia, tonsillitis and even skin infections Recently, the research group of Valentine g nenajdenko, Professor of Moscow State University, reported the green method of synthesizing trifluoromethyloxazine quinoline by the reaction of trifluoromethylalkynone and quinoline in the aqueous phase The reaction is rapid, efficient and environmentally friendly Relevant research results were published in green chem (DOI: 10.1039/c9gc03044a) (source: Green chem.) recently, the author reported a three-component reaction (chem Commun., 2018, 54, 2268) between zine, trifluoromethylalkyne and water molecules, which was carried out in MeCN at room temperature, and the corresponding trifluoromethyloxazine quinoline was obtained by non enantioselectivity However, when the product is separated by column chromatography or acid solvent, it will lead to the rapid occurrence of epimerization, and then get the mixture of non enantiomers Therefore, the author hopes to improve the above methods from the perspective of sustainable chemistry A series of solvents (such as DMF, et 2O, PhMe, DCM, EtOAc, H 2O, etc.) were screened It was found that although the raw materials are difficult to dissolve in water, the reaction of ketone 2A (1 equivalent) and quinoline (0.95 equivalent) in water phase was completed by stirring for 1 h to form a solid (scheme 1) Compared with MeCN solvent, the reaction speed of the substrate in the aqueous phase is 20 times faster, and the reaction only forms a single (3R *, 4A R *) - diastereomer trifluoromethyloxazine quinoline After simple recrystallization, the target product 3A can be obtained in 93% yield (source: Green chem.) the author speculates that the reaction mechanism is the addition of quinoline and trifluoroacetylene to form the key intermediate, zwitterion a Obviously, polar media can promote the formation of such highly polar intermediates, so water may be the best choice Subsequently, the intermediate a and H 2O were added to form the target product 3a (source: Green chem.) under the best reaction conditions, the author investigated the universality of the reaction (scheme 3) A variety of ketones and quinoline can react smoothly, and the corresponding trifluoromethyloxazine quinoline 3 can be obtained with a yield of up to 99% The ketones containing a variety of electron donor or halogen substituent groups in benzene ring can obtain the corresponding product 3B - 3j in excellent yield In addition, quinoline with halogen or cyano group can also be compatible with the reaction, and the yield of trifluoromethyloxazine quinoline 3K - 3P is 92% - 99% In addition, 1,8-naphthopyridine reacts with ketone 2a to form derivative 3q in 94% yield In order to prove the practicability of this method, the author synthesized the compound 3A on the scale of gram, and the yield did not decrease obviously (source: Green chem.) Summary: Based on the reaction of trifluoromethylketone and quinoline in aqueous phase, a green and non enantioselective method for the preparation of trifluoromethyloxazine quinoline was developed The reaction is rapid and the yield of heterocyclic product is as high as 99% In addition, the reaction can be prepared in gram scale, which further proves the practicability of the reaction.