Thiourea-Catalyzed Direct Reductive Amination of Aldehydes

Abstract

A hydrogen-bond-catalyzed direct reductive amination of aldehydes is reported. The acid- and metal-free process uses thiourea as organocatalyst and the Hantzsch ester for transfer-hydrogenation and allows for the high-yielding synthesis of diverse amines.

Key words

amines - reductions - organocatalysis - hydrogen bonds - aminations

References and Notes

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• 12a

  Benzene and CH₂Cl₂ are as suitable as toluene, while more polar solvents such as dioxane or THF are less efficient. Protic solvents (e.g. MeOH) are of limited applicability.

• 12b

  Upon extended reaction times, the transformation may also be carried out at r.t.

• 14a

  The catalyst loading may be reduced to 1 mol% upon extended reaction times (>48 h).

• 14b

  Under the same reaction conditions but in the absence of thiourea, the product amine is only obtained in low yields proving the vital influence of the organocatalyst.

• 15 This assumption is supported by previous calculations on related thiourea complexes with aldimines and amines: Vachal P. Jacobsen EN. J. Am. Chem. Soc.  2002,  124:  10012 

13

General Procedure.
A solution of the aldehyde (1a-f, 2.20 mmol) and the amine (2a-g, 2.00 mmol) in toluene (5 mL) is treated with the Hantzsch ester (3, 608 mg, 2.40 mmol), thiourea (4, 15.2 mg, 0.200 mmol) and MS 5 Å (2.0 g). The mixture is stirred 24 h at 70 °C under nitrogen. After filtration over Celite^®, the solvent is evaporated and the residue purified by flash chromatography on silica gel using mixtures of PE and EtOAc as eluants to give the product amines (5a-l) in pure form.

16

All new compounds had spectroscopic data in support of the assigned structures.
Compound 5d: ¹H NMR (300 MHz, CDCl₃): δ = 3.73 (s, 3 H), 4.27 (s, 2 H), 6.56 (d, J = 9.04 Hz, 2 H), 6.76 (d, J = 9.04 Hz, 2 H), 7.12 (d, J = 8.48 Hz, 1 H), 7.60 (d, J = 10.74 Hz, 1 H), 8.10 (d, J = 2.26 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 47.95, 55.80, 114.37, 115.02, 120.26, 123.37, 132.45, 133.56, 136.76, 141.58, 152.66, 154.27. HRMS (ESI): m/z calcd for C₁₄H₁₅N₂O₄ [M + H]⁺: 275.1032. Found: 275,1034.
Compound 5k: ¹H NMR (300 MHz, CDCl₃): δ = 2.54 (s, 3 H), 4.21 (s, 1 H), 4.37 (s, 2 H), 6.71 (d, J = 4.14 Hz, 2 H), 6.82 (d, J = 3.96 Hz 2 H), 7.26-7.36 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 26.73, 48.31, 111.82, 118.01, 127.55, 128.77, 129.40, 138.27, 139.89, 148.29, 198.57. HRMS (ESI): m/z calcd for C₁₅H₁₆NO [M + H]⁺: 226,1232. Found: 226,1233.
Compound 5l: ¹H NMR (400 MHz, CDCl₃): δ = 3.52 (s, 2 H), 4.31 (s, 2 H), 6.60 (d, J = 8.65 Hz, 2 H), 7.07 (d, J = 8.65 Hz, 2 H), 7.26-7.34 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 40.00, 48.47, 113.12, 122.18, 127.54, 128.69, 130.24, 139.24, 139.35, 147.43, 176.85. HRMS (ESI): m/z calcd for C₁₅H₁₆NO₂ [M + H]⁺: 242.1181. Found: 242.1178.