Rapid Microwave-Assisted Reductive Amination of Ketones with Anilines

Abstract

Using microwave technology, a new protocol has been developed that improves the reaction rate and overall efficiency of the direct reductive amination of ketones with anilines. When using sodium triacetoxyborohydride as the reducing agent, high product yields and increased reaction rates are achieved for a variety of electronically different anilines. Furthermore, we have found that this protocol can also be applied to aldehydes.

Key words

reductive amination - anilines - ketones - microwave synthesis - aldehydes

References and Notes

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7

Indeed, laboured and inefficient reactions are often encountered in reductive aminations with anilines, see reference 3 for examples.

13

CEM Microwave Technology Ltd., 2 Middle Slade, Buckingham Industrial Park, MK18 1WA, UK; http://www.cem.com

15

Commercially available from Biotage.

16

The acetic acid is believed to protonate the intermediate imine which assists in its reduction, see reference 6.

17

Representative experimental procedure for the reductive amination of ketones: To a solution of aniline (100 mg, 1.07 mmol) and cyclohexanone (210 mg, 2.14 mmol) in DCE (2.1 mL) in a microwave vial, was added NaBH(OAc)₃ (567 mg, 2.68 mmol) and AcOH (193 mg, 3.21 mmol). The vial was capped and the resulting solution was heated in a CEM Discover^® microwave for ten minutes (fixed hold time) at 140 °C. The reaction was quenched with NaHCO₃ (10 mL, sat. aq) and then extracted with CH₂Cl₂ (3 × 20 mL). The combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. Purification by flash column chromatography (eluting with CH₂Cl₂) gave cyclohexylphenylamine as a viscous oil (177 mg, 94%).¹⁹

18

It should be noted that in these cases the starting aniline was not isolated.

19

All known compounds exhibited spectroscopic data consistent with that reported in the chemical literature.

20

All new compounds exhibited the expected NMR, HPLC, LCMS and IR data which will be reported in a full publication in due course.

21

Representative experimental procedure for the reductive amination of aldehydes: To a solution of aniline (200 mg, 2.2 mmol) and cyclohexanecarbaldehyde (123 mg, 1.1 mmol) in DCE (2.1 mL) in a microwave vial, was added NaBH(OAc)₃ (567 mg, 2.68 mmol) and AcOH (193 mg, 3.21 mmol). The reaction was then subjected to the same procedure described in reference 17. Purification gave cyclohexylmethylphenyl-amine as a viscous oil (185 mg, 91%).¹⁹