The [2+2] Photocycloaddition of Uracil Derivatives with Ethylene as a General Route to cis-Cyclobutane β-Amino Acids

Abstract

A three-step procedure, based on the [2+2]-photochemical reaction of uracils with ethylene followed by controlled degradation of the heterocyclic ring, has been developed for the synthesis of a range of C1- and C2-substituted cis-cyclobutane β-amino acids, in good overall yield.

β-amino acids - cyclobutane - uracils - [2+2]-photo­cycloaddition - substituent effects

References and Notes

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Representative Procedure for Photocycloaddition. Compound 1j (0.250 g, 1.76 mmol) was introduced into a cylindrical water-cooled reactor containing a 1:1 mixture of acetone-H₂O (160 mL), which was vented under a fume hood. The mixture was stirred at r.t. and degassed with argon for 30 min, then sat. with ethylene for 30 min. Then, whilst ethylene bubbling continued, the mixture was irradiated with a 400 W medium-pressure mercury lamp fitted with a Pyrex filter for 4 h. The solution was evaporated and the solid residue was washed with cyclohexane then acetone. The cyclobutane adduct 2j was obtained as a white solid in 86% yield (0.257 g, 1.51 mmol). Mp 146-148 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.78-1.88 (m, 3 H), 2.06-2.13 (m, 1 H), 3.43 (dd, J = 10.8, 5.3 Hz, 1 H), 3.60 (dd, J = 10.8, 6.0 Hz, 1 H), 3.79 (td, J = 7.1, 4.2 Hz, 1 H), 5.08 (br t, J = 5.4 Hz, 1 H), 7.69 (br s, 1 H), 10.03 (br s, 1 H) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 22.8, 27.5, 46.9, 48.8, 63.9, 152.4, 174.7 ppm. MS (ES⁺): m/z = 193 [MNa]⁺. HRMS (ES⁺): m/z calcd for C₇H₁₀N₂O₃Na: 193.0589; found: 193.0597.
Representative Procedure for Heterocyclic Ring-Opening. Compound 2j (0.245 g, 1.44 mmol) was dissolved in 0.5 M NaOH solution (17.6 mL) and stirred overnight at r.t. Cation exchange resin (Bio-Rad AG 50W-X8, H⁺, 20-50 mesh) was then added until pH was about 4. Filtration and then evaporation of H₂O left the desired compound 3j as a white paste in 87% yield (0.236 g, 1.25 mmol). ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.62-1.74 (m, 1 H), 1.85-1.98 (m, 2 H), 2.04-2.15 (m, 1 H), 3.49 (d, J = 10.8 Hz, 1 H), 3.61 (d, J = 10.8 Hz, 1 H), 4.13 (q, J = 8.9 Hz, 1 H), 4.80 (br s, 1 H), 5.56 (s, 2 H), 6.16 (d, J = 8.9 Hz, 1 H), 12.25 (br s, 1 H) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 20.5, 25.6, 47.5, 57.6, 64.6, 157.8, 174.7 ppm. MS (ES⁺): m/z = 189 [MH]⁺, 211 [MNa]⁺. HRMS (ES⁺): m/z calcd for C₇H₁₂N₂O₄Na: 211.0695; found: 211.0691.
Representative Procedure for Diazotization. Compound 3j (0.180 g, 0.96 mmol) was dissolved in 3.5 M HCl solution (22 mL). Then, 1 equiv of NaNO₂ (0.066 g; 0.96 mmol) was added and the mixture was stirred overnight at r.t. The solution was deposited on a cation-exchange column (Dowex 5 × 8 W, H⁺, 50-100 mesh). The column was washed with H₂O until the eluent was neutral, then the amino acid was eluted with 1 M NH₄OH. Pure product 4j was recovered after evaporation of appropriate fractions as a white solid in 70% yield (0.097 g, 0.67 mmol). Mp 91-94 °C. ¹H NMR (400 MHz, D₂O): δ = 1.77-1.89 (m, 1 H), 1.92-2.18 (m, 2 H), 2.13-2.25 (m, 1 H), 3.55 (d, J = 11.4 Hz, 1 H), 3.72 (d, J = 11.4 Hz, 1 H), 3.68-3.72 (m, 1 H) ppm. ¹³C NMR (100 MHz, D₂O): δ = 22.5, 23.3, 47.9, 52.7, 65.9, 180.7 ppm. MS (ES⁺): m/z = 146 [MH]⁺, 168 [MNa]⁺. HRMS (ES⁺): m/z calcd for C₆H₁₂NO₃: 146.0817; found: 146.0822.