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.

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.

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.

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 

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.