A New Synthesis of 3-Substituted Pyrrolidines Using Iron Catalysed Cross-coupling Reactions and Ring Closing Metathesis

Abstract

A series of 3-substituted N-Boc protected pyrrolidines have been prepared via iron catalysed cross-coupling between Boc protected N-allyl-N-(2-bromoallyl)amine 3 and organomagnesium compounds followed by ring closing metathesis and subsequent hydrogenation of the formed pyrrolines.

Key words

pyrrolidines - ring closing metathesis - Grignard reagents - iron catalysed cross-coupling

References

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• 7 Lindsay KB. Tang M. Pyne SG. Synlett  2002,  731 ; for the application of RCM reaction to the synthesis of pyrrolines see references cited therein
• 8 Compound 3 was synthesized in ˜20 g scale from allylamine and 2,3-dibromopropene followed by Boc protection using the procedure described by: Shi L. Narula CK. Mak KT. Kao L. Xu Y. Heck RF. J. Org. Chem.  1983,  48:  3894 
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1

Current address: Novo Nordisk A/S, Medicinal Chemistry Research, 2760 Måløv, Denmark.

15

Typical Procedure: To a stirred solution of allyl-(2-bromoallyl)-carbamic acid tert-butyl ester (3) (1.49 g, 5.4 mmol) and Fe(acac)₃ (38 mg, 2 mol%) in THF (7.5 mL) and NMP (5.4 mL) at 0 °C was added a THF solution of i-PrMgCl (6.0 mL, 1.8 M, 10.8 mmol) drop wise over a period of 30 min. After stirring for 1 h the reaction mixture was quenched with sat. NH₄Cl (20 mL) followed by extraction with CH₂Cl₂ (3 × 20 mL). Drying of the organic layers (Na₂SO₄) and removal of the solvents in vacuo gave crude 5. An analytically sample was purified on silica gel (heptane/EtOAc 20:1). Data for 5: ¹H NMR: δ = 5.84-5.68 (m, 1 H), 5.16-5.03 (m, 2 H), 4.86 (br s, 1 H), 4.73 (br s, 1 H), 3.88-3.68 (m, 4 H), 2.26-2.14 (m, 1 H), 1.46 (s, 9 H), 1.06 (d, J = 7 Hz, 6 H). ¹³C NMR: δ = 151.0 (s), 144.4 (s), 133.9 (d), 116.5 and 116.2 (t), 108.0 and 107.5 (t), 49.4 and 48.3 (t), 31.2 (d), 28.4 (q), 21.7 (q). HRMS calcd for C₁₄H₂₅NO₂: 239.1886. Found: 239.1877. The crude residue was dissolved in degassed CH₂Cl₂ (270 mL) and 2 (229 mg, 5 mol%) were added. After stirring for 24 h at r.t. under nitrogen the solvent was removed in vacuo. The mixture was redissolved in MeOH (20 mL) and 10 wt% Pd/C (400 mg) was added. The mixture was stirred in a hydrogen atmosphere (3 bar) for 24 h and then filtered through celite and gently concentrated in vacuo. Purification on silica gel (heptane/EtOAc 20:1) provided 630 mg (52%) of 11 as a clear oil. Data for 11: ¹H NMR: δ = 3.59-3.44 (m, 2 H), 3.26-3.15 (m, 1 H), 2.91-2.82 (m, 1 H), 2.03-1.92 (m, 1 H), 1.87-1.71 (m, 1 H), 1.54-1.35 (m, 11 H), 0.96-0.89 (m, 6 H). ¹³C NMR: δ = 154.7, 78.7, 50.1, 46.1, 45.9, 31.8, 29.9, 28.3, 21.2, 20.9. HRMS calcd for C₁₂H₂₃NO₂: 213.1729. Found: 213.1724.