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. 2023 Mar 8;145(9):4921-4927.
doi: 10.1021/jacs.2c11786. Epub 2023 Feb 21.

Mild Divergent Semireductive Transformations of Secondary and Tertiary Amides via Zirconocene Hydride Catalysis

Rebecca A Kehner  1 , Ge Zhang  1 , Liela Bayeh-Romero  1
Affiliations

Mild Divergent Semireductive Transformations of Secondary and Tertiary Amides via Zirconocene Hydride Catalysis

Rebecca A Kehner et al. J Am Chem Soc. .

Abstract

The mild catalytic partial reduction of amides to imines has proven to be a challenging synthetic transformation, with many transition metals directly reducing these substrates to amines. Herein, we report a mild, catalytic method for the semireduction of both secondary and tertiary amides via zirconocene hydride catalysis. Utilizing just 5 mol % of Cp2ZrCl2, the reductive deoxygenation of secondary amides is demonstrated to furnish a diverse array of imines in up to 94% yield with excellent chemoselectivity and without the need for glovebox handling. Moreover, a novel reductive transamination of tertiary amides is also achievable when the catalytic protocol is carried out in the presence of a primary amine at room temperature, providing access to an expanded assortment of imines in up to 98% yield. Through slight procedural tuning, the single-flask conversion of amides to imines, aldehydes, amines or enamines is feasible, including multicomponent syntheses.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Synthetic potential of amides through semireduction.
Figure 2
Figure 2
Initial inspiration and proposed catalytic manifold.
Scheme 1
Scheme 1. Synthetic Utility of the ZrH-Catalyzed Diversification of Amides
All reactions were carried out under an atmosphere of N2 using Cp2ZrCl2 (5 mol %), HNEt2 (5 mol %), and DMMS (4.0 equiv). Conditions a:2g (0.5 mmol), PhMe (0.5 M), 30 °C, 24 h. Conditions b:2g (0.5 mmol), PhMe (0.5 M), 30 °C, 24 h, followed by aqueous acidic workup. Conditions c:2g (0.5 mmol), PhMe (0.5 M), 30 °C, 19 h, then THF (2.0 mL), allylmagnesium bromide (4.0 equiv), 0 °C – 23 °C, 6 h. Conditions d:6a (0.5 mmol), allylamine (1.05 equiv), THF (0.2 M), 23 °C, 21 h, then allylmagnesium bromide (4.0 equiv), 0 °C – 23 °C, 5 h. Conditions e:6a (0.5 mmol), p-anisidine (1.05 equiv), THF (0.2 M), 23 °C, 19 h, then benzylmagnesium chloride (4.0 equiv), 0 °C – 23 °C, 6 h. Conditions f:6i (0.5 mmol), diethylamine (2.0 equiv), THF (0.5 M), 60 °C, 18 h. Conditions g:6j (0.3 mmol), piperidine (2.0 equiv), THF (0.5 M), 60 °C, 19 h. Yield was determined by 1H NMR spectroscopy of the crude reaction mixture, using mesitylene as an internal standard.
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