Synthesis of Aza/Oxaspiro-γ-lactams by Radical Translocation Cyclization ­Reactions

Abstract

A cascade radical translocation cyclization of the N-­allyl-N-(2′-bromophenyl)amide moiety of heterocyclic carboxylic acids and its N-propynyl analogues were investigated. It provides a convenient method for the preparation of aza/oxaspiro-γ-lactams that are useful γ-turn mimetics in drug discovery.

radical translocation - [1,5]-hydrogen transfer - spiro-γ-lactams

References

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Genenal procedure: To a stirred solution of 5 (2 mmol) in degassed toluene (50 mL), Bu₃SnH (0.688 mL, 2.4 mmol) and AIBN (33 mg, 0.2 mmol) in toluene (20 mL) were added dropwise over 7 h using a syringe pump under reflux. After addition, the solution was heated at reflux for a further 2 h. The solvent was removed, and the residue was purified by flash chromatography on silica gel (petroleum ether-EtOAc, 5:1-1:1) to give products 12, 13, and 14 (order of elution).
Compound 12f: 7%; light yellowish oil. ¹H NMR (300 MHz, CDCl₃): δ = 1.10 (d, 3 H, J = 7.2 Hz, 1.79-1.89 (m, 2 H), 1.92-2.04 (m, 2 H), 2.21-2.26 (m, 1 H), 2.87-2.95 (m, 1 H), 3.22-3.30 (m, 1 H), 3.34-3.38 (dd, 1 H, J = 3.6 Hz, J = 9.6 Hz), 3.80 (s, 3 H), 3.81-3.86 (dd, 1 H, J = 6.3 Hz, J = 9.8 Hz), 4.79 (br s, 1 H, D₂O exchangeable), 6.89 (d, 2 H, J = 9.0 Hz), 7.53 (d, 2 H, J = 9.0 Hz); ¹³C NMR (75 MHz, CDCl₃): δ = 14.22, 26.10, 35.32, 37.67, 47.47, 52.97, 55.44, 71.07, 114.02, 121.26, 132.95, 156.49, 176.39; MS (ESI): m/z = 261.1 [M + H⁺]; Anal. Calcd for C₁₅H₂₀N₂O₂: C, 69.20; H, 7.74; N, 10.76. Found: C, 68.02; H, 7.65; N, 10.83.
Compound 13f: 66%; light yellowish solid; mp 82.4-83.6 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.15 (d, 3 H, J = 7.2 Hz), 1.59-1.69 (m, 1 H), 1.76-1.86 (m, 1 H), 1.91-2.03 (m, 2 H), 2.31-2.39 (m, 1 H), 2.97-3.04 (m, 1 H), 3.23-3.30 (m, 2 H), 3.68-3.73 (m, 1 H, J = 7.5 Hz, J = 9.6 Hz), 3.80 (s, 3 H), 4.78 (br s, 1 H, D₂O exchangeable), 6.90 (d, 2 H, J = 9.0 Hz), 7.53 (d, 2 H, J = 9.0 Hz); ¹³C NMR (75 MHz, CDCl₃): δ = 11.89, 26.26, 28.78, 39.34, 47.62, 52.08, 55.44, 70.64, 114.02, 121.09, 132.80, 156.47, 177.70; MS (ESI): m/z = 261.1 [M + H⁺]; Anal. Calcd for C₁₅H₂₀N₂O₂: C, 69.20; H, 7.74; N, 10.76. Found: C, 68.97; H, 7.62; N, 10.51.
Compound 14f: 8%; light yellowish oil. ¹H NMR (300 MHz, CDCl₃): δ = 1.35 (d, 3 H, J = 6.9), 1.78-1.89 (m, 2 H), 2.17-2.25 (m, 1 H), 2.88-2.91 (m, 1 H), 3.20-3.25 (m, 1 H), 3.44-3.58 (m, 2 H), 3.64-3.70 (m, 1 H), 3.80 (s, 3 H), 3.91-3.93 (m, 1 H), 4.18-4.32 (m, 1 H), 4.76 (br s, 1 H, D₂O exchangeable), 6.73 (d, 2 H), 8.10 (m, 1 H); MS (ESI):
m/z = 261.1 [M + H⁺].

<A NAME="RU06105ST-9">9</A>

To a solution of 13b (180 mg, 0.5 mmol) in EtOAc (4 mL) at r.t. was added a saturated solution of HCl in EtOAc (5 mL). After stirring for 2 h, the reaction was quenched with 30 % aq NaOH, and extracted with EtOAc (3 × 15 mL).The organic layer was washed with brine (2 × 10 mL), dried over MgSO₄, and concentrated in vacuo to give 13f (113 mg, 87%) as a light yellowish solid (mp 82.1-84.0 °C).