A Study of the Effect of Unsaturated Aliphatic Groups in Barbituric Acids¹

Palladium-Catalyzed Asymmetric Allylic Alkylation of Barbituric Acid Derivatives: Enantioselective Syntheses of Cyclopentobarbital and Pentobarbital

“…The ( R )-enantiomer has been synthesized from a chiral starting material, ( R )-pulegone; however, the ( S )-enantiomer has proven much more difficult to make in high optical purity . We began our studies by applying the reaction conditions developed for cyclopentobarbital to the reaction of barbiturate 6 with allylic carbonate 7 using ligand L1 to give barbituric acid derivative 8 (eq 4). The reaction was found to be much slower than the previous case, and gentle heating was required to achieve complete conversion (Table , entry 2).…”

“…5-Ethyl-5-(1-methyl-2-butenyl)barbituric Acid (8). A test tube was charged with barbiturate 6 10 (15 mg, 0.096 mmol), flushed with nitrogen, and then charged with CH 2 Cl 2 (0.3 mL). The resulting mixture was sonicated for 1 min.…”

“…A prestirred solution (15 min) of tris(dibenzylidineacetone)dipalladium(0) chloroform complex (1.0 mg, 0.96 μmol), ( R,R )- L1 (1.3 mg, 0.0019 mmol), pent-2-enyl methyl carbonate 7 (15 mg, 0.11 mmol), and TBAT (5.2 mg, 0.0096 mmol) in CH 2 Cl 2 (0.6 mL) was added. The heterogeneous reaction was stirred under nitrogen at room temperature for 3 h. The resulting homogeneous solution was purified by flash chromatography on silica gel (40% ether/petroleum ether) to give 20.7 mg of 8 (96%) as a white solid: R f = 0.20 (20% ethyl acetate/petroleum ether); mp = 108−110 °C (lit . mp 114.5−116 °C); [α] 23 D = 2.4° ( c 2.8, dichloromethane); HPLC (Chiralcel AS column, 90:10 heptane/2-propanol, flow = 1.00 mL/min, λ = 254) t R (major) = 10.42 min, t R (minor) = 13.41 min; 1 H NMR (CDCl 3 , 300 MHz) δ 8.76 (s, 1H), 8.68 (s, 1H), 5.47−5.59 (m, 1H), 5.31 (ddd, J = 15.2, 9.3, 1.5 Hz, 1H), 2.70−2.80 (m, 1H), 1.97−2.07 (m, 2H), 1.64 (dd, J = 6.3, 1.2 Hz, 3H), 1.07 (d, J = 6.9 Hz, 3H), 0.82 (t, J = 7.5 Hz, 3H).…”