Organocatalytic Synthesis Of Chiral 2-Amino-4H-Chromene And 2-Amino-4H-Pyran Derivatives

Chromenes, known as the benzopyrans, are an important class of heterocyclic compounds, widely distributed in natural products. Chromenes and its derivatives have unique biological and pharmacological activities. Among various chromene family members, polysubstituted 2-amino-4H-chromenes and polysubstituted 2-amino-4H-pyrans are especially important for medicinal applications, and they are versatile and useful building blocks for the preparation of bioactive molecules and natural products. Therefore, the synthesis of 2-amino-4H-chromene and 2-amino-4H-pyran derivatives has attracted considerable attention. Despite the fact that racemic synthesis has been studied, the asymmetric synthesis of chiral 2-amino-4H-chromenes and 2-amino-4H-pyran derivatives have not yet been explored much. In this dissertation, we have designed and synthesized a series of bifunctional chiral thiourea and squaramide organocatalysts, and applied them in various asymmetric synthesis of chiral 2-amino-4H-chromene and 2-amino-4H-pyran derivatives. The main work is as follows:With the bifunctional chiral organocatalysts, an efficient highly enantioslective Michael addition/cyclization of malononitrile to(E)-2-(2-nitrovinyl)phenol was developed, and chiral 2-amino-4-(nitromethyl)-4H-chromene-3-carbonitrile derivatives were obtained. Through the optimization of organocatalysts and reaction conditions, the reactions were performed well with 10 mol% quinine-derived thiourea as the catalyst at 60 oC, affording the desired 2-amino-4-(nitromethyl)-4H-chromene-3-carbonitrile derivatives in high yields with good enantioselectivities(up to 91% ee). A catalytic activation mode for this catalytic system was hypothesized. The chiral thiourea activated the(E)-2-(2-nitrovinyl)phenol through double hydrogen bonding and the malononitrile was activated by the tertiary nitrogen of the quinuclidine.An efficient highly enantioselective Michael addition/cyclization of cyclohexane-1,3-diones to benzylidenemalononitriles was investigated by using the bifunctional chiral organocatalysts. The chiral 2-amino-5,6,7,8-tetrahydro-5-oxo-4H-chromene-3-carbonitrile derivatives were obtained. Through the optimization of organocatalysts and reaction conditions, the reactions finished within 5h at 0 oC using chiral squaramide as the catalyst, and affording the desired(R)-2-amino-4-aryl-5,6,7,8-tetrahydro-5-oxo-4H-chromene-3-carbonitrile derivatives in high yields with good enantioselectives.With the bifunctional chiral organocatalysts, an efficient enantioselective Friedel-Crafts alkylation of indoles with iminochromenes was developed to construct 2-amino-4-(1H-indol-3-yl)-4H-chromene-3-carbonitrile skeleton and achieved good yield and moderate enantioselectivity. Through the optimization of organocatalysts, additives, and solvents, the reactions were performed well with quinine-derived thiourea as the catalyst and 2-methylbenzoic acid as the additive at room temperature. Twelve chiral 2-amino-4-(1H-indol-3-yl)-4H-chromene-3-carbonitrile derivatives were obtained.With the bifunctional chiral organocatalysts, an efficient enantioselective Michael addition/cyclization of malononitrile to 2,5-dibenzylidenecyclopentanones was developed. The chiral 2-amino-4-phenyl-4H-pyran-3-carbonitrile derivatives were obtained. Through the optimization of organocatalysts and reaction conditions, the reactions were performed well with quinine-derived squaramide as the catalyst at room temperature, and affording the desired 2-amino-4-aryl-4H-pyran-3-carbonitrile derivatives in high yields with excellent enantioselectivities(up to 98% ee). A catalytic activation mode for the catalytic system was hypothesized. The chiral thiourea activated the 2,5-dibenzylidenecyclopentanone through double hydrogen bonding and the malononitrile was activated by the tertiary nitrogen of the quinuclidine.