The 4H-chromene core exist in a number of natural products with various biological activities. 1 Among the 4Hchromene derivatives, the 2-amino-4H-chromenes have attracted substantial attention in medicinal chemistry due to their diverse range of pharmacological activities mediated via anti-inflammatory, antimicrobial, antiviral, and anticancer effects. 2 The ortho-quinone methides (o-QMs) are viable intermediates in synthetic organic chemistry, chemical biology, and material chemistry. 3 Substantial progress has been made in the conjugate addition to o-QMs with Michael donors in organocatalysis, 4 and transition-metal catalysis. 5 Further, o-QMs have emerged as formal 1,4-dipoles that react with various two-carbon reaction partners to afford six-membered oxacyclic compounds. Recently, the Han group reported organocatalytic asymmetric annulation of o-QMs with malonitrile to obtain 2-amino-4H-chromene derivatives with high enantioselectivity. 6 Nonetheless, a more efficient approach for the enantioselective synthesis of 2-amino-4H-chromenes is still highly desired.In connection with our research program investigating asymmetric catalysis, 7 we have reported the decarboxylative alkylation of β-keto acids to o-QMs derived from o-hydroxy benzylic alcohols. 8 Herein, we present the enantioselective organocatalytic conjugate addition and cyclization sequences of nitriles to o-QMs.To determine the optimized reaction conditions for the enantioselective organocatalytic conjugate addition and cyclization cascade of nitriles to o-QMs, we investigated a reaction system with o-QM 1a and malonitrile (2a) in the presence of 5 mol % of organocatalyst. We first surveyed the efficiency of binaphthyl-based bifunctional organocatalysts I-VI ( Figure 1) in dichloromethane (Table 1, entries 1-6). Catalyst III was the best catalyst for the enantioselective conjugate addition and cyclization cascade (94% ee, Table 1, entry 3). Next, we screened several common solvents including dichloromethane, 1,2-dichloroethane (DCE), chloroform, toluene, ethyl acetate, ethanol, acetonitrile, and acetone (Table 1, entries 3 and 7-13). Chloroform was found to be the optimal solvent in this reaction (Table 1, entry 8). Finally, we lowered the amount of catalyst III to 1 mol %, which compromised the yield and enantioselectivity of the desired product 3a (Table 1, entries 8 and 14-16). However, a further decrease in the amount of catalyst to 0.5 mol % decreased the yield and selectivity (Table 1, entry 17).After determining the optimal reaction conditions, we investigated the substrate scope of of o-QMs 1 with malonitrile 2a in the presence of 1 mol % of catalyst III in dichloromethane at room temperature ( Table 2). The reactions of o-QMs 1a-1e with various substituents in the aryl group yielded the corresponding products 3a-3e in high yields and excellent enantioselectivities (76-88% yields and 89-95% ee). The heteroaryl-substituted o-QM 1f provided desired products 3f with high selectivity (84% yields and 89% ee). To further examine the scope of this ...

An efficient asymmetric synthesis of pyranonaphthoquinones via Michael addition and oxo‐Michael cyclization sequence of 2‐hydroxy‐1,4‐naphthoquinone with (E)‐2‐nitroallylic acetates has been developed. The synthetically useful chiral pyranonaphthoquinone derivatives were obtained in moderate to high yields and high enantioselectivities. This approach offers a facile way to prepare chiral pyranonaphthoquinone derivatives with a wide range of functional group tolerance.