Enantioselective Organocatalytic Michael Addition and Ring Closure Cascade Reaction of o‐Quinone Methides with Nitriles

Abstract

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 ...

Organocatalytic Enantioselective Cycloaddition of o‐Quinone Methides with Oxazolones: Asymmetric Synthesis of Dihydrocoumarins

“…As part of a continuing research program on the catalytic enantioselctive construction of tetrasubstituted carbon centers, [13] we recently reported the enantioselective conjugate addition and cyclization sequences of o ‐QMs with malononitriles [14] . Herein, we report an enantioselective organocatalytic [4+2] cycloaddition of o ‐QMs with oxazolones promoted by bifunctional organocatalysts (Figure 1).…”

Divergent Reactions of 2‐Aminophenol with α‐Bromoacetate: Asymmetric Synthesis of Two Regioisomeric 1,4‐Benzoxazinones

“…A colorless oil, 59% yield from 5 ; Known compound, ref. 3b,7a; 1 H NMR (400 MHz, CDCl 3 ) 7.47–7.33 (m, 5H), 6.91–6.65 (m, 3H), 5.68 (s, 1H), 2.24 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) 166.9, 140.5, 135.1, 132.5, 129.0, 128.8, 127.1, 125.5, 125.0, 117.0, 116.6, 78.4, 20.8; CSP‐HPLC (Chiralcel OJ‐H column; 40% isopropanol in n ‐hexane; 0.5 mL/min): 93:7 er, t R ( S ‐enantiomer) = 19.8 min; t R ( R‐ enantiomer) = 17.3 min.…”

One-Pot Synthesis of 3,4-Dihydrocoumarins via C-H Oxidation/Conjugate Addition/Cyclization Cascade Reaction

“…Therefore, we envisioned a one-pot synthesis of 3,4-dihydrocoumarin derivatives via C-H oxidation and ring closure cascade of 2-benzyl phenol with oxazolone under Brønsted acid conditions (Scheme 1c). In connection with our work on conjugate addition reactions, [31,32], we reported the Michael-type addition/ring closure sequences of o-QM with dipoles [33]. Herein, we describe the one-pot synthesis of 3,4-dihydrocoumarin derivatives from 2-benzyl phenol via C-H oxidation and acid-catalyzed ring closure cascade.…”