General and Facile Synthesis of 1,2-Amino Alcohols

Abstract

Facile preparation of 1,2-amino alcohols has been achieved by the reaction of benzyloxymethyl lithium with imines, which are generated from α-amido sulfones and benzyloxymethyl lithium in situ at -78 °C in THF.

amino alcohol - α-amidoalkyl phenylsulfone - benzyl­oxymethyl lithium - nucleophilic addition - activated imine

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14

Representative Experimental Procedure for Addition of Benzyloxymethyl Lithium Reagent to α-Amidoalkyl Phenylsulfones (Table 2, Entry 6).
Benzyloxymethyltributylstannane (2.5 mmol), prepared according to ref.¹³, was dissolved in THF (5 mL) and charged with argon. This solution was cooled to -78 °C and n-BuLi (1.24 mL, 2.48 mmol, 2.0 M solution in cyclohexane) was added dropwise to this cooled solution. After stirring for 10 min, the solution became yellowish, and the solution of α-amidoalkyl phenylsulfone 1 g (1 mmol) in 2 mL of THF was added in one portion. The mixture was stirred for 1.5 h. The reaction mixture was quenched with sat. aq solution of NH₄Cl, diluted and extracted with Et₂O, dried over MgSO₄ and evaporated to give crude 4g, which was purified by silica gel chromatography, (eluent: EtOAc-n-hexane, 1:10) to give pure 4g in 81% yield. ¹H NMR (300 MHz, CDCl₃): δ = 0.88 (d, 3 H), 0.91 (d, 3 H), 1.42 (s, 9 H), 1.87 (m, 1 H), 3.46 (m, 3 H), 4.46 (q, 2 H), 4.71 (d, 1 H), 7.28 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 18.5, 19.5, 28.4, 29.7, 55.7, 70.6, 73.2, 78.9, 127.4, 127.6, 128.3, 138.3, 155.9. MS (EI): Anal. Calcd for C₁₇H₂₇NO₃: 293.1991. Found: 292.21.

15

Experimental Procedure for Addition of Benzyloxymethyl Lithium Reagent to in situ-Generated Imine 3 (Table 1, Entry 8).
To a suspension of 40 mg of NaH in 2 mL of THF under argon, 1 mmol of 1a in 1 mL of THF was added and the resulting mixture was stirred for 30 min. The solution was added to the cold (-78 °C) benzyloxymethyl lithium solution containing 1.5 mmol of benzyloxymethyl lithium.¹⁴ After stirring for 30 min, the reaction mixture was quenched with sat. aq solution of NH₄Cl, diluted and extracted with Et₂O, dried over MgSO₄ and evaporated to give crude 4a, which was purified by silica gel chromatography, (eluent: EtOAc-n-hexane, 1:10) to give 4a in 83% yield. ¹H NMR (300 MHz, CDCl₃): δ = 1.25 (s, 9 H), 3.61 (q, 2 H), 3.70 (q, 2 H), 4.48 (q, 2 H), 4.84 (br, 1 H), 5.25 (br, 1 H), 7.28 (m, 10 H). ¹³C NMR (75 MHz, CDCl₃): δ = 28.3, 54.7, 70.3, 73.1, 79.5, 126.7, 127.2, 127.5, 127.6, 127.8, 137.9, 140.6, 155.3. MS (EI): Anal. Calcd for C₂₀H₂₅NO₃: 327.1834. Found: 326.41.

16

Representative Procedure for Acidic Deprotection of Boc Group (compound 5). To 4a (50 mg) in MeOH (2 mL) was added 2 mL of 4 N HCl/1,4-dioxane. The solution was stirred for 3 h at 25 °C. After TLC analysis of the completion of the reaction, the solution was concentrated in vacuo. The resulting crude 5 was recrystallized from CHCl₃-Et₂O to give pure 5 in 92% yield. ¹H NMR (300 MHz, CDCl₃): δ = 3.73 (m, 2 H), 4.33 (br, 1 H), 4.50 (q, 2 H), 7.25 (m, 10 H), 8.96 (br, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 52.6, 74.9, 76.1, 125.7, 126.6, 127.1, 127.3, 128.1, 129.5, 137.2, 141.3.