An Efficient Method for Reductive Amination of Carbonyl Compounds under Nonacidic Conditions

Julian A. Hudson; J. B. Sweeney

doi:10.1055/s-0032-1316683

Synlett, Table of Contents

Synlett 2012; 23(15): 2176-2178
DOI: 10.1055/s-0032-1316683

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An Efficient Method for Reductive Amination of Carbonyl Compounds under Nonacidic Conditions

Julian A. Hudson*

^aCardiovascular & Gastrointestinal Innovative Medicines Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK, Fax: +44(1625)516667 Email: Julian.Hudson@astrazeneca.com

,

J. B. Sweeney*

^bDepartment of Chemistry, University of Huddersfield, Queensgate, Huddersfield West Yorkshire, HD1 3DH, UK, Email: j.b.sweeney@hud.ac.uk

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Abstract

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Abstract

A high yielding reductive amination procedure for ketones and aldehydes under neutral conditions is described. The key advantage for the method is the applicability to acid-sensitive substrates, and the procedure is applicable to a wide range of primary and secondary amines, on a multigram scale.

Key words

reductive amination - nonacidic conditions - carbonyl compounds - amines - imine formation - reduction

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References

References

For reviews, see:

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3 Key data for 2: ¹H NMR (400 MHz, DMSO): δ = 8.61 (s, 1 H), 8.11–8.26 (m, 2 H), 7.88 (d, J = 7.6 Hz, 1 H), 7.60–7.79 (m, 2 H), 4.12–4.36 (m, 1 H), 3.77–4.03 (m, 4 H), 3.32 (t, J = 11.2 Hz, 2 H), 2.74 (dt, J = 8.0, 25.5 Hz, 2 H), 2.41–2.49 (m, 2 H), 2.30 (t, J = 10.2 Hz, 1 H), 2.00–2.18 (m, 1 H), 1.74 (d, J = 12.1 Hz, 2 H), 1.62 (dd, J = 12.8, 6.5 Hz, 1 H), 1.31–1.55 (m, 2 H). MS (ES+): m/z = 400.30 [M + H]⁺.
4 General Procedure: MgSO₄ (0.75 mmol) was added to a solution of the primary or secondary amine (1.28 mmol), the carbonyl compound (1.28 mmol) and N,N-di-isopropylethylamine (3.83 mmol) in THF (30 mL). The resulting suspension was stirred at r.t. for 5 min. NaBH(OAc)₃ (2.55 mmol) was added and stirring was continued overnight. The solvent was removed in vacuo, and the residue was dissolved in CH₂Cl₂ (150 mL). The solution was washed with sat. aq NaHCO₃ (50 mL), dried (Na₂SO₄) and concentrated in vacuo to yield the desired product.
5 See, for instance: Righi M, Bedini A, Piersanti G, Romagnoli F, Spadoni G. J. Org. Chem. 2011; 76: 704