1,4-Diazabicyclo[2.2.2]octane-Mediated Ring Opening of 1-Acetylcyclopropanecarboxamides and Its Application to the Construction of 3-Alkylated γ-Lactams

Abstract

1,4-Diazabicyclo[2.2.2]octane (DABCO)-mediated ring opening of 1-acetylcyclopropanecarboxamides efficiently gave stable zwitterions that could be formed in situ or readily isolated. An application of this novel type of ring opening was demonstrated in a one-pot efficient construction of biologically interesting 3-alkyl γ-lactams. The Lewis-base protocol provides an opportunity for performing ring opening, cycloaddition, and rearrangement reactions of donor–acceptor cyclopropanes through organocatalysis.

Key words

Lewis bases - ring opening - cyclopropanes - lactams - chirality

• References and Notes


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• 8 (2Z)-3-(Anilinocarbonyl)-5-(4-aza-1-azoniabicyclo-[2.2.2]oct-1-yl)pent-2-en-2-olate (2a); Typical Procedure DABCO (156 mg, 1.05 equiv) was added to a solution of cyclopropane 1a (102 mg, 0.5 mmol) in H₂O (1.0 mL), and the mixture was stirred at 60 °C for 12 h. The mixture was then cooled to r.t., and H₂O was removed under reduced pressure to give a white solid. The crude product was washed with MeOH and EtOAc (×3), and dried under ambient conditions to give a white solid; yield: 150 mg (95%); mp 173–175 °C; ¹H NMR (500 MHz, D₂O): δ = 1.75–1.76 (d, J = 7.5 Hz, 3 H), 2.32–2.35 (t, J = 8.0 Hz, 2 H), 2.72–2.75 (t, J = 8.5 Hz, 2 H), 2.79–2.80 (d, J = 6.5 Hz, 6 H), 3.01–3.02 (d, J = 6.5 Hz, 6 H), 6.83–6.86 (t, J = 7.0 Hz, 1 H), 7.11–7.14 (t, J = 8.0 Hz, 2 H), 7.25–7.26 (d, J = 8.0 Hz, 2 H); ¹³C NMR (125 MHz, D₂O): δ = 20.4, 24.1, 44.2, 51.8, 63.7, 93.2, 119.9, 123.1, 129.5, 139.6, 170.0, 181.4; HRMS (ESI-TOF): m/z [M + H] calcd for C₁₈H₂₆N₃O₂: 316.2025; found: 316.2021.
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• 11 3-Acetyl-3-methyl-1-phenylpyrrolidin-2-one (3a); Typical Procedure DABCO (156 mg, 1.05 equiv) was added to a solution of cyclopropane 1a (102 mg, 0.5 mmol) in MeCN (1.0 mL), and the mixture was stirred at 60 °C for 12 h. The mixture was then cooled to r.t., and MeCN was removed under reduced pressure. A solution of MeI (0.047mL, 1.5 equiv) in DMF (2.0 mL) was added, and the mixture was stirred at r.t. for 30 min. Finally, NaOH (240 mg, 1.2 equiv) was added, and the mixture was stirred for 30 min. The mixture was poured into brine (10 mL) and extracted with EtOAc (3 × 10 mL). The organic phases were combined, washed with H₂O (3 × 10 mL), dried (MgSO₄), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE–Et₂O) to give colorless crystals; yield: 94.5 mg (87%); mp 86–88 °C; ¹H NMR (500 MHz, CDCl₃): δ = 1.55 (s, 3 H), 1.84–1.90 (m, 1 H), 2.33 (s, 3 H), 2.81–2.85 (m, 1 H), 3.71–3.75 (m, 1 H), 3.75–3.87 (m, 1 H), 7.16 (t, J = 7.0 Hz, 1 H), 7.49 (t, J = 7.5 Hz, 2 H), 7.63 (t, J = 7.5 Hz, 2 H); ¹³C NMR (125 MHz, CDCl₃): δ = 21.2, 26.0, 28.6, 45.8, 59.6, 119.8, 124.9, 128.8, 139.1, 172.4, 205.8; HRMS (ESI-TOF): m/z [M + H] calcd for C₁₃H₁₆NO₂: 218.1181; found: 218.1192.

Deacetylation is quite common in the reactions of β-dicarbonyl compounds under either acidic or basic conditions; for selected examples, see:
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