Transition‐Metal‐Free Reductive Functionalization of Tertiary Carboxamides and Lactams for α‐Branched Amine Synthesis

Abstract

A new method for the synthesis of a-branched amines by reductive functionalization of tertiary carboxamides and lactams is described. The process relies on the efficient and controlled reduction of tertiary amides by a sodium hydride/ sodium iodide composite, in situ treatment of the resulting anionic hemiaminal with trimethylsilyl chloride and subsequent coupling with nucleophilic reagents including Grignard reagents and tetrabutylammonium cyanide. The new method exhibits broad functional-group compatibility, operates under transition-metal-free reaction conditions, and is suitable for various synthetic applications on both sub-millimole and on multigram scales. Recently, the Chiba group disclosed a controlled hydride reduction of tertiary carboxamides for the synthesis of aldehydes using a combination of NaH and NaI in THF. [15] Key to the success of this chemistry was the stability (prior to aqueous work-up) of the anionic hemiaminal intermediates formed through single hydride transfer from the activated NaH to the carboxamides. [16] Building on this discovery, we Scheme 1. Selected a-branched amines currently used in the clinic.

Asymmetric Spirocyclization Enabled by Iridium and Brønsted Acid-Catalyzed Formal Reductive Cycloaddition

“…23,24 In this context, owing to the stability of the amide group, the two-step process of amide reduction-activation and nucleophilic substitution or nucleophilic addition are generally involved. Therefore, stoichiometric activating agents or reductants, including triflic anhydride (Tf 2 O), [25][26][27] DIBAL-H, 28,29 Schwartz's reagent (Cp 2 ZrHCl), 30,31 and NaH 32 have been used to successfully motivate the reaction (Scheme 1b). And Tf 2 O-mediated formal reductive cycloadditions of amides with alkynes or alkenes in a one-pot manner to give azaheterocycles have been reported.…”

Reductive Functionalization of Amides in Synthesis and for Modification of Bioactive Compounds

“…Very recently, Chiba and Dixon again utilized Grignard reagents as nucleophiles. However, this time the unique sodium hydride-sodium iodide composite was used as the reducing system (Ong et al, 2020). The developed methodology was applied for the late-stage functionalization of napropamide (Figure 3H), a soil-applied herbicide for pre-emergence control of weeds in a range of crops.…”

“…Very recently, surprisingly, sodium hydride joined this group because of the specific enhancement of its reducing activity by the formation of a composite with other inorganic components (Figure 1E) (Hong et al, 2016). This methodology can be applied to the exhaustive reduction of amides (Ong et al, 2019), as well as their reductive functionalization (Ong et al, 2020).…”

Reductive Functionalization of Carboxamides: A Recent Update

“…26 Thus, subsequent silylation of the anionic hemi-aminals with trimethylsilyl chloride (TMSCl) followed by addition of carbon-based nucleophiles allowed for overall production of α-branched amines from tertiary carboxamides under a transition-metal free manner. 60 In this context, a series of Grignard reagents were found amenable to the downstream C-C bond formation ( Figure 25B). In this process, MgBr 2 present in the Grignard reagents (due to the Schlenk equilibrium) likely functions as a Lewis acid to assist generation of the iminium ion.…”