Remarkable [3+2] Annulations of Electron-Rich Olefins with Unstabilized Azomethine Ylides

Abstract

Herein we would like to communicate that an unstabilized azomethine ylide generated from commercial trimethylamine N-oxide will undergo a remarkable 1,3-dipolar cycloaddition in good yield with electron-rich and unpolarized olefins. A broad range of substituents on the alkenes are tolerated provided they are compatible with excess LDA. This demonstration of novel reaction scope should encourage others to try trimethylamine N-oxide as an azomethine ylide precursor in the synthesis of challenging 3,4-di­substituted pyrrolidines.

Key words

3,4-disubstituted pyrrolidine - cycloaddition - unstabilized azomethine ylide

References and Notes

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9

Representative Procedure
Commercial LDA (2.5 M in THF, 3.1 mL, 4.7 mmol, 4.5 equiv) was added to a solution of (E)-1,2-dimethoxy-4-styrylbenzene (250 mg, 1.0 mmol, 1 equiv) and trimethyl-amine N-oxide 4 (117 mg, 1.6 mmol, 1.5 equiv) in anhyd THF (10 mL) at 0 ˚C. After 1 h, the reaction was quenched with H₂O and extracted with EtOAc. The combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. The crude residue was purified by flash chroma-tography eluting with CH₂Cl₂-MeOH (95:5) to give 285 mg (92%) of trans-3,4-disubstituted pyrrolidine 8 as a yellow oil: ^¹H NMR (400 MHz, CDCl₃): δ = 7.26-7.12 (m, 5 H), 6.75-6.70 (m, 2 H), 6.68 (s, 1 H), 3.81 (s, 3 H), 3.78 (s, 3 H), 3.36-3.26 (m, 2 H), 3.12-3.06 (m, 2 H), 2.87-2.80 (m, 2 H), 2.44 (s, 3 H) ppm. LC-MS: m/z = 298.1 [M + 1].

12

Representative Procedure
A solution of N-methylpyrrolidine 8 (255 mg, 0.9 mmol) in neat ACE-Cl (3 mL) was irradiated in a microwave reactor at 170 ˚C for 30 min. MeOH (3 mL) was added to the mixture and thermally refluxed for an additional 1 h. The crude reaction mixture was purified by ion exchange on a MP-TsOH column to give 51 mg (21%) of pyrrolidine 11 as a pale yellow oil: ^¹H NMR (400 MHz, CDCl₃): δ = 7.26-7.20 (m, 2 H), 7.18-7.12 (m, 3 H), 6.73-6.70 (m, 1 H), 6.70-6.66 (m, 1 H), 6.62 (d, J = 2.0 Hz, 1 H), 3.79 (s, 3 H), 3.75 (s, 3 H), 3.66-3.54 (m, 2 H), 3.35-3.25 (m, 2 H), 3.24-3.14 (m, 2 H), 2.62 (br s, 1 H) ppm. LC-MS: m/z = 284.0 [M + 1].