C-N Formation Reactions Controlled By Lewis Acid Promoters

Lewis-acids catalysis in modern organic synthesis has grown by leaps and bounds in the past few decades. Although lewis-acids have been demonstrated as efficient promoters for many carbon-carbon bond formation reactions, there are only few kinds of carbon-nitrogen bond formation reactions. Most reports of carbon-nitrogen bond formation reactions with Lewis-acids as catalysts are Aza-Michael, Aza-Diels-Alder, and Aza-Baylis–Hillman reactions. It is interesting to explore the potential of Lewis-acids for new organic reactions.During our ongoing research program on carbon-nitrogen bond formation reactions of azaheterocyclic skeletons with different Lewis-acids as catalysts, 2-thiohydantoins, 4,4-dimethyl-3-isoxazolidinone, 3-Methyl-2-pyrazolin-5-one, 2-imidazolidone, 2-imidazolidimethione, caprolactam were surveyed.Thiohydantoins and their derivatives exist in many fungicides, herbicides, medicines, and natural products. Great efforts have been devoted to introducing thiohydantoins and their derivatives into desirable substrates such as pharmacophores and synthetic intermediates in the past decades. We have developed two novel kinds of carbon-nitrogen bond formation reactions of 2-thiohydantoins promoted by TiCl4 and BF3·Et2O, FeCl3 or AlCl3. Promoted by TiCl4, a three-component reaction of aromatic aldehydes, acetonitrile and 2-thiohydantoins occurs, and a different N-C-N bond-forming reaction yielding bis (2-thiohydantoin) derivatives took place with FeCl3, AlCl3 or BF3·Et2O as promoters.4,4-Dimethyl-3-isoxazolidinone is the heterocyclic part of Clomazone. Two kinds of reactions took place in the solution of aromatic aldehydes and 4,4-dimethyl-3-isoxazolidinone with different Lewis-acids as catalysts. Through TiCl4 catalyzed ring opening reactions and BF3?OEt2 catalyzed N-C-N bond-forming reactions, aminooxypropionic acid derivatives and bis (4,4-dimethyl-3-isoxazolidinone) derivatives were prepared in excellent yields respectively, and bis (4,4-dimethyl-3-isoxazolidinone) derivatives can be also transformed into corresponding aminooxypropionic acid derivatives in high yields with plentiful amount of TiCl4. Those aminooxypropionic acid and their derivatives were found to exhibit antimicrobial and antiinflammatory activity.To extend the applied range, 3-Methyl-2-pyrazolin-5-one, 2-imidazolidone, 2-imidazolidimethione, caprolactam as other types of substrates were tested using TiCl4 as promoter. Similar three-component reaction as 2-thiohydantoin only occurred in low yields using 2-imidazolidimethione with acetonitrile and propionitrile as reagent and solvent, and did not occurred in phenylacetonitrile. The NH group may be activated by the C=S moiety in 2-imidazolidimethione and thiohydantoins comparing to NH group of amide.All results described above indicate that TiCl4 and BF3·Et2O play different roles as Lewis acid promoters. Not only the lewis acidity and/or ability of forming coordination intermediate, but also the par.t.icularity of azaheterocyclic skeletons controlled the types and efficiency of the reactions.The mechanism of those carbon-nitrogen bond formation reactions of azaheterocyclic skeletons with different Lewis-acids as catalysts, and fur.t.her investigations on application of the protocol using the other type of substrates including different azaheterocyclic skeletons, the other aldehydes, ketones, aldehyde acetals and cyano derivatives are in progress.