Aza-Reformatsky Reaction Promoted by Catalytic Samarium Diiodide: Synthesis of β-Amino Esters or Amides

Abstract

The synthesis of β-amino esters or amides has been achieved from moderate to high yields from the reaction of imines and α-halo esters or amides promoted by catalytic amounts of ­samarium diiodide in the presence of magnesium turnings as co-­reductant. A mechanism is proposed to explain this catalytic samarium(II)-promoted aza-Reformatsky reaction.

Key words

amino esters - catalytic reactions - enolates - ­Reformatsky reaction - samarium

• References and Notes


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• 19 Procedure for the Synthesis of N-Tosyloctan-1-imine (1a) A mixture of n-octanal (10 mmol), p-toluenesulfonamide (10 mmol), sodium p-toluenesulfinate (10 mmol) in H₂O (15 mL), and formic acid (15 mL) was stirred for 24 h at r.t. The resulting white precipitate was collected by filtration, washed with H₂O (3 × 10 mL) and hexane (2 × 10 mL), then dissolved in CH₂Cl₂ (100 mL), followed by addition of H₂O (35 mL) and sat. aq NaHCO₃ (35 mL). The solution was well stirred for 10 min at r.t. The organic phase was collected, the aqueous phase was extracted with CH₂Cl₂ (3 × 70 mL). The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo to yield N-tosyloctan-1-imine (1a) as a colorless oil (1.84 g, 65%). This material was used without further purification. ¹H NMR (300 MHz, CDCl₃): δ = 8.60 (t, J = 4.6 Hz, 1 H), 7.81 (d, J = 8.2 Hz, 2 H), 7.34 (d, J = 8.2 Hz, 2 H), 2.51 (dt, J = 7.4, 4.6 Hz, 2 H), 2.40 (s, 3 H), 1.66–1.57 (m, 2 H), 1.39–1.14 (m, 8 H), 0.86 (t, J = 6.8 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 178.4 (CH), 144.4 (C), 134.4 (C), 129.5 (2 × CH), 127.8 (2 × CH), 35.6 (CH₂), 31.2 (CH₂), 28.7 (CH₂), 28.5 (CH₂), 24.3 (CH₂), 22.2 (CH₂), 21.3 (CH₃), 13.7 (CH₃). IR (neat): ν = 3292, 1629, 1020, 737 cm^–1.
• 20 Please note that a minimum of 2.0 equiv of SmI₂ are required to carry out this transformation in a stoichiometric manner.
• 21 Since magnesium is normally coated with a layer of MgO, we have previously treated the magnesium turnings with a few crystals of iodine to activate its surface.
• 22 Procedure for the Synthesis of Ethyl 3-(Tosylamino)-decanoate (3a) A solution of N-tosyloctan-1-imine (1a, 0.2 mmol) and ethyl bromoacetate (2a, 0.2 mmol) in THF (2.5 mL) was added dropwise at r.t. and vigorous stirring to a mixture of SmI₂ (0.1 M in THF, 0.8 mL) and activated Mg (1.2 mmol) with iodine and ZnCl₂ (1.2 mmol) in THF (2.5 mL). After stirring at the same temperature 3.5 h, the mixture was hydrolyzed with an aq solution of HCl (0.1 M, 10 mL). The aqueous phase was filtered through a pad of Celite^® and extracted with CH₂Cl₂ (3 × 10 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated in vacuo. Flash column chromatography on silica gel (hexane–EtOAc, 5:1) provided pure ethyl 3-(tosylamino)decanoate (3a) as a yellow oil (62 mg, 83%). ¹H NMR (300 MHz, CDCl₃): δ = 7.69 (d, J = 8.0 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 2 H), 5.22 (d, J = 9.0 Hz, 1 H), 4.09–3.92 (m, 2 H), 3.50–3.38 (m, 1 H), 2.51 (ddd, J = 3.0, 15.0, 30.0 Hz, 2 H), 2.35 (s, 3 H), 1.47–1.06 (m, 12 H), 1.15 (t, J = 7.0 Hz, 3 H), 0.79 (t, J = 7.0 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 171.3 (C), 143.1 (C), 138.1 (C), 129.5 (2 × CH), 126.8 (2 × CH), 60.5 (CH₂), 50.6 (CH), 41.2 (CH₂), 38.8 (CH₂), 34.6 (CH₂), 31.6 (CH₂), 29.1 (CH₂), 28.9 (CH₂), 25.6 (CH₂), 22.5 (CH₃), 21.4 (CH₃), 13.9 (CH₃). IR (neat): ν = 1747, 1331, 1160, 1094 cm^–1. HRMS: m/z calcd for C₁₉H₃₂NO₄S [M + H]⁺: 370.2052; found: 370.2049.
• 23 For the synthesis of N-Boc imine 1g, see: Wenzel AG, Jacobsen EN. J. Am. Chem. Soc. 2002; 124: 12964
• 24 Molander GA, Stengel PJ. J. Org. Chem. 1995; 60: 6660
• 25 Spectroscopic Data of Compound 3e ¹H NMR (300 MHz, CDCl₃): δ = 7.54 (d, J = 8.2 Hz, 2 H), 7.14–7.10 (m, 5 H), 6.93 (d, J = 8.2 Hz, 2 H), 5.21 (d, J = 8.2 Hz, 1 H), 4.08–3.92 (m, 2 H), 3.74–3.63 (m, 1 H), 2.72 ( d, J = 6.0 Hz, 1 H), 2.71 (d, J = 6.0 Hz, 1 H), 2.37 (d, J = 5.2 Hz, 2 H), 2.32 (s, 3 H), 1.15 (t, J = 7.1 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 171.6 (C), 143.5 (C), 137.8 (C), 137.1 (C), 129.9 (2 × CH), 129.6 (2 × CH), 128.9 (2 × CH), 127.3 (2 × CH), 127.0 (CH), 61.0 (CH₂), 52.2 (CH), 41.0 (CH₂), 38.3 (CH₂), 21.8 (CH₃), 14.4 (CH₃). IR (neat): ν = 2929, 1740, 1265, 1160, 738 cm^–1. HRMS: m/z calcd for C₁₉H₂₄NO₄S [M + H]⁺: 362.1426; found: 362.1428.