A One-Pot, Solid-Phase Synthesis of Secondary Amines from Reactive Alkyl Halides and an Alkyl Azide

Abstract

A one-pot, two-step, polymer-bound, triphenylphosphine-supported synthesis of secondary amines from the corresponding azide and a reactive alkyl halide is described.

secondary amines - azides - phosphinimine - polymer-supported triphenylphosphine - alkylation

References and Notes

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9

Reagent purchased from Argonaut Technologies, P/N 800379.

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The compounds (Table 1, entries 1, 2, and 4) gave spectral data consistent with the assigned structures and in close agreement to the literature values. For recent examples, see:

11a Entry 1: Cho BT. Kang SK. Tetrahedron  2005,  61:  5732 

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12

General Procedure for the Synthesis of Secondary Amines 6
Anhyd THF (5 mL) was added to polymer-supported Ph₃P⁹ (2.15 mmol/g, 200 mg, 0.43 mmol). The mixture was left to stand for 5 min, whereupon a solution of the azide (0.215 mmol) in anhyd THF (1 mL) was added. The suspension was agitated at r.t. for 4 h. To the mixture was added a solution of the alkylating reagent (0.645 mmol) in anhyd THF (500 µL). The mixture was agitated at r.t. for 16 h, filtered and the resin washed with anhyd THF (5 × 10 mL) and anhyds CH₂Cl₂ (5 × 10 mL). The resin was suspended in MeOH (2 mL) and transferred to a 4 mL screw-lock vial, and a solution of KOH (2% in MeOH, 2.15 mmol) was added. The suspension was agitated at 65 °C for 4 h, cooled to r.t., filtered and the resin washed with CH₂Cl₂ (4 × 3 mL) and MeOH (2 × 3 mL). The filtrate and washings were combined and concentrated to dryness. The crude product was partitioned between CH₂Cl₂ and 10% aq NaHCO₃, and the aqueous layer extracted with EtOAc. The combined organic extracts were dried over anhyd Na₂SO₄, filtered, and concentrated to give the amine. Yields and purities of isolated amines are shown in Table [1] .

13

Spectral Data for Table 1 Entry 3: ¹H NMR (400 MHz, CDCl₃): δ = 1.25 (s, 9 H), 1.55 (br s, 1 H), 3.78 (s, 2 H), 3.83 (s, 2H), 7.25-7.39 (m, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 31.1, 34.6, 49.5, 49.8, 126.0, 127.3, 128.9, 129.3, 129.7, 129.9, 130.5, 152.5. MS (ES⁺): m/z = 254.39 [H + M]⁺. HRMS (ES⁺): m/z calcd for C₁₈H₂₃N: 254.1903; found: 254.1904 [H + M]⁺.
Entry 5: ¹H NMR (400 MHz, CDCl₃): δ = 1.32 (s, 9 H), 3.84 (s, 3 H), 4.34 (s, 2 H), 4.44 (br s, 1 H), 6.50 (d, J = 8.7 Hz, 2 H), 7.28 (d, J = 7.6 Hz, 2 H), 7.38 (d, J = 7.6 Hz, 2 H), 7.84 (d, J = 8.7 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 31.4, 34.6, 47.5, 51.5, 111.6, 118.6, 125.7, 127.3, 131.6, 135.3, 150.6, 151.8, 167.3. MS (ES⁺): m/z = 298.23 [H + M]⁺. HRMS (ES⁺): m/z calcd for C₁₉H₂₃NO₂: 298.1801; found: 298.1802 [H + M]⁺.
Entry 6: ¹H NMR (400 MHz, CDCl₃): δ = 0.88-0.94 (m, 6 H), 1.20-1.30 (m, 1 H), 1.41 (s, 9 H), 1.58-1.70 (m, 2 H), 2.70 (s, 3 H), 2.96-3.10 (m, 2 H), 3.90-4.00 (m, 1 H), 5.20-5.28 (br s, 1 H), 5.48-5.50 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 21.8, 22.8, 28.2, 33.2, 41.9, 46.2, 50.8, 80.1, 156.2. MS (ES⁺): m/z = 231.35 [H + M]⁺. HRMS (ES⁺): m/z calcd for C₁₂H₂₆N₂O₂: 231.2073; found: 231.2074 [H + M]⁺.
Entry 7: ¹H NMR (400 MHz, CDCl₃): δ = 0.84-0.86 (m, 6 H), 1.21-1.23 (m, 1 H), 1.25 (s, 9 H), 1.43 (s, 9 H), 1.58-1.63 (m, 2 H), 3.85-3.90 (m, 2 H), 3.84-4.03 (m, 3 H), 5.65 (br s, 1 H), 5.80 (br s, 1 H), 7.31 (d, J = 7.6 Hz, 2 H), 7.36 (d, J = 7.6 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 21.9, 22.7, 28.3, 31.1, 34.6, 41.9, 46.1, 50.0, 50.4, 79.7, 125.9, 129.4, 152.1, 156.3, 168.6. MS (ES⁺): m/z = 363.56 [H + M]⁺. HRMS (ES⁺): m/z calcd for C₂₂H₃₈N₂O₂: 363.3006; found: 363.3007 [H + M]⁺.

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