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Synlett 2008(1): 97-99  
DOI: 10.1055/s-2007-990927
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Susana Ayesa, Bertil Samuelsson, Björn Classon*
Medivir AB, P.O. Box 1088, 141 22 Huddinge, Sweden
Fax: +46(8)54683199; e-Mail: bjorn.classon@medivir.se;
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Publikationsverlauf

Received 28 August 2007
Publikationsdatum:
03. Dezember 2007 (online)

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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.

Key words

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

9

Reagent purchased from Argonaut Technologies, P/N 800379.

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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] .

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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]+.