Mechanistic Insights on Reduction of Carboxamides by Diisobutylaluminum Hydride and Sodium Hydride−Iodide Composite

Abstract

Dedicated to Professor Philippe Renaud in celebration of his 60th birthdayThe reaction mechanisms on reduction of tertiary carboxamides by diisobutylaluminum hydride (DIBAL) and sodium hydride (NaH)-sodium iodide (NaI) composite were elucidated by the computational and experimental approaches. Reduction of N,N-dimethyl carboxamides with DIBAL provides the corresponding amines, whereas that with the NaHÀ NaI composite exclusively forms aldehyde even at high reaction temperature. DFT calculations revealed that dimeric structural nature of DIBAL and Lewis acidity on its Al center play crucial role to decompose the tetrahedral anionic carbinol amine intermediate through CÀ O bond cleavage. On the other hand, in the reduction with the NaHÀ NaI composite, the resulting tetrahedral anionic carbinol amine intermediate could be kept stable, thus providing aldehydes as a sole product by the aqueous workup Scheme 2. Controlled reduction of amides into aldehydes by NaHÀ NaI. Scheme 3. Reduction of amide 1a. Scheme 4. Reduction of amide 1b.[a] The reactions were conducted using 0.5 mmol of amide 1a.[b] 1 H-NMR yields based on the internal standard.

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

“…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 . 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 . Building on this discovery, we were keen to leverage further synthetic value from these intermediates, in particular for the synthesis of α‐branched amines.…”