A Conceptually New and Straightforward Method for the One-pot Transformation of Alcohols into Amines

Abstract

A conceptually new amination method of alcohols has been developed using α-hydroxy esters as substrates and N-phenyl bis-trifluoromethanesulfonimide (PhNTf₂) as a test reagent. Playing two roles at once, PhNTf₂ activates the hydroxyl group as a highly reactive triflate intermediate and introduces the amino functionality through an in situ nucleophilic substitution by the anionic residue PhTfN^-. Two complementary procedures (methods A and B herein) have been developed, the latter permitting reaction of substrates with unstable alcoxides.

amination - amino esters - nucleophilic substitution - triflate - one-pot

References

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4 For a recent article wherein the drawbacks associated with the Mitsunobu reaction were discussed, see: Kiankarimi M. Lowe R. McCarthy JR. Whitten JP. Tetrahedron Lett.  1999,  40:  4497 

The stability of triflates of alcohols is marginal and closely depends on the nature of the starting material. For some related descriptions, see:

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5c

See also ref. [3a-d] .

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13

Typical Procedure (Method A): A tetrahydrofuran (1 mL) solution of methyl mandelate (100 mg, 0.6 mmol) was added under argon at 0 °C to a suspension of sodium hydride (29 mg, 60% in oil, 0.72 mmol) in tetrahydrofuran (1 mL). After stirring 15 min, this alkoxide solution was added dropwise at -20 °C to a tetrahydrofuran (1 mL) solution of triflimide (236 mg, 0.66 mmol). After 15 min, the solution was hydrolyzed with water (5 mL) and extracted with diethyl ether (3 × 5 mL). Combined organic layer was dried over magnesium sulfate and concentrated under vacuum to give the desired amine which was purified from side-products by flash-chromatography on a silica gel column (eluant: cyclohexane-ethyl acetate (9-1 to 7-3).

14

Typical Procedure for the Amination of 3-[3-Nitrophenyl]-2-hydroxy-methyl Propanoate (Method B) A tetrahydrofuran (1 mL) solution of α-hydroxy ester (100 mg, 0.43 mmol) and triflimide (167 mg, 0.47 mmol) was added dropwise under argon at -20 °C to a suspension of NaH (20 mg, 60% in oil, 0.51 mmol) in tetrahydrofuran (1 mL). After 15 min the solution was hydrolyzed with water (5 mL) and extracted with diethyl ether (3 × 5 mL). Combined organic layer was dried over magnesium sulfate and concentrated under vacuum to give the desired amine which was purified by flash-chromatography on a silica gel column (eluant: cyclohexane-ethyl acetate (9-1 to 7-3).