Pyrrolate-Catalyzed Conjugate Addition of Pyrrole to Electron-Deficient Alkenes

Robert D. Richardson; Felix A. Hernandez-Juan; Darren J. Dixon

doi:10.1055/s-2005-922777

LETTER

Pyrrolate-Catalyzed Conjugate Addition of Pyrrole to Electron-Deficient Alkenes

Robert D. Richardson^a, Felix A. Hernandez-Juan^a, Darren J. Dixon*^b
^a Cambridge University Chemical Laboratories, Lensfield Road, Cambridge, CB2 1EW, UK
^b School of Chemistry, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK
Fax: +44(161)2754939; e-Mail: darren.dixon@manchester.ac.uk;

Abstract

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Abstract

The conjugate addition of pyrrole as a nitrogen nucleophile can be catalyzed by potassium pyrrolate in coordinating solvents or by lithium pyrrolate in the presence of coordinating ligands offering an efficient route to protected β-amino carbonyl compounds.

Key words

conjugate addition - pyrrole - pyrrolate - catalysis - ligand acceleration

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References

References and Notes

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General Method for Potassium Pyrrolate Catalyzed Conjugate Addition.
Pyrrole 1 was added to a suspension of potassium (1.95 g,
50 mmol, hexane-washed) in THF (50 mL) and the mixture was warmed to 40 °C until effervescence ceased. The resulting solution was cooled to r.t. and made up to 250 mL with further THF. An aliquot of this solution (5 mL, 19 mmol of 1, 1 mmol of 4) was added to a solution of electrophile (10 mmol) in THF (5 mL) and the mixture was stirred at 0 °C for 18 h. Then, sat. aq NH₄Cl (5 mL) was added and the aqueous layer was extracted with CH₂Cl₂ (2 × 5 mL). The combined organic extracts were dried (MgSO₄) and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, EtOAc-hexane). NMR data for compound 5a: ¹H NMR (400 MHz, CDCl₃): δ = 6.70 (2 H, t, J = 2.0 Hz), 6.13 (2 H, t, J = 2.0 Hz), 4.53 (1 H, sext, J = 7.0 Hz), 2.69 (1 H, dd, J = 13.0, 7.0 Hz), 2.60 (1 H, dd, J = 13.0, 7.0 Hz), 1.49 (3 H, d, J = 7.0 Hz), 1.39 (9 H, s); matches that previously reported.⁸

Use of lithium pyrrolate in place of potassium pyrrolate led to no catalytic turnover - the reaction stopped at 10% conversion independent of reaction time when using tert-butyl crotonate.

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General Procedure for Ligated Lithium Pyrrolate Acceleration Studies.
n-BuLi (10 mmol, 2.5 mol dm^-3 in hexane) and ligand (10 mmol) were added to a solution of pyrrole 1 (20 mmol) in toluene (5 mL) at 0 °C and the mixture was stirred at 0 °C for 15 min. Compound 13 (10 mmol) was added and the solution was stirred for 2 h at 0 °C before quenching with sat. aq NH₄Cl (5 mL). The aqueous layer was extracted with Et₂O (3 mL) and the combined organic extracts were dried (MgSO₄) and concentrated under reduced pressure. The conversion of 13 to 5c was determined by ¹H NMR analysis of the crude reaction mixture.

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