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

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

• References


For reviews, see:
• 1a Margaretha P In Science of Synthesis, Knowledge Updates . Vol. 2010/4, Section 40.1.1.1.2. Procter DJ, Molander GA. Thieme; Stuttgart: 2011: 405-442
• 1b Tripathi RP, Verma SS, Pandey J, Tiwari VK. Curr. Org. Chem. 2008; 12: 1093
• 1c Baxter EW, Reitz AB. Org. React. (N. Y.) 2002; 59: 1
• 1d Hutchins RO, Hutchins MK In Comprehensive Organic Synthesis . Vol. 8. Trost BM, Fleming I. Pergamon Press; Oxford: 1991: 25-78
• 1e Lane CF. Synthesis 1975; 135
• 1f Emerson WS. Org. React. (N. Y.) 1948; 4: 174
• 2a Abdel-Magid AF, Carson KG, Harris BD, Maryanoff CA, Shah RD. J. Org. Chem. 1996; 61: 3849
• 2b Abdel-Magid AF, Mehrman SJ. Org. Process Res. Dev. 2006; 10: 971
• 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