Frustrated Lewis Pair Catalyzed Hydrogenation of Amides: Halides as Active Lewis Base in the Metal-Free Hydrogen Activation

Abstract

A method for the metal-free reduction of carboxylic amides using oxalyl chloride as an activating agent and hydrogen as the final reductant is introduced. The reaction proceeds via the hydrogen splitting by B­(2,6-F2-C6H3)3 in combination with chloride as the Lewis base. Density functional theory calculations support the unprecedented role of halides as active Lewis base components in the frustrated Lewis pair mediated hydrogen activation. The reaction displays broad substrate scope for tertiary benzoic acid amides and α-branched carboxamides.

Borane‐Catalyzed Hydrogenation of Tertiary Amides Activated by Oxalyl Chloride: DFT Mechanistic Insights

“…A similar two‐step mechanism was also found in our recent DFT calculations for the activation of Ph 3 P=O with (COCl) 2 but with a lower overall barrier of 17.5 kcal/mol for the initial electrophilic attack step instead, suggesting the wide applicability of such electrophilic activating method. Obviously, the electrophilic amide activation with (COCl) 2 does benefit from the strong electron donation from nitrogen lone pair, consistent with the observed tolerance of ester functional groups that usually are more susceptible to nucleophilic attack at the carbonyl carbon site. The addition of Cl – to 3 + is 12.4 kcal/mol endergonic to form the neutral complex PhCCl 2 N(CH 2 ) 5 ( 3 ‐Cl) in solution, indicating the low Lewis acidity at the iminium carbon center.…”

“…Recently, chemo‐selective reduction of tertiary and secondary amides activated by triflic anhydride has been reported using either Hantzsch esters or silanes as reducing reagent. More recently, mild one‐pot reduction of tertiary amides with H 2 is advanced by using oxalyl chloride (COCl) 2 as cleaner amide activation reagent and catalytic amount of borane BAr 3 (Ar = 2,6‐F 2 C 6 H 3 ) as Lewis acid catalyst, affording hydrochloride salts of tertiary amines that can be conveniently isolated by filtration. Experimentally, it is known that chlorination reagents such as (COCl) 2 and phosgene O=CCl 2 may react with the amide C=O group to form ionic chloroiminium chloride in solution, while the combination of borane BAr 3 and halides may act as frustrated Lewis pair (FLP) catalyst, for H 2 ‐cleavage.…”

“…More recently, mild one‐pot reduction of tertiary amides with H 2 is advanced by using oxalyl chloride (COCl) 2 as cleaner amide activation reagent and catalytic amount of borane BAr 3 (Ar = 2,6‐F 2 C 6 H 3 ) as Lewis acid catalyst, affording hydrochloride salts of tertiary amines that can be conveniently isolated by filtration. Experimentally, it is known that chlorination reagents such as (COCl) 2 and phosgene O=CCl 2 may react with the amide C=O group to form ionic chloroiminium chloride in solution, while the combination of borane BAr 3 and halides may act as frustrated Lewis pair (FLP) catalyst, for H 2 ‐cleavage. However, the detailed mechanism and energetics for the amide activation and reduction reactions, which is crucial for finding better catalysts and reaction conditions, still remains unclear and this will be the central topic of the present DFT study.…”

Controlled Reduction of Carboxamides to Alcohols or Amines by Zinc Hydrides

“…In contrast, alcohols or amines could be formed when I fragments through either CÀNo rC ÀOb ond scission, respectively,a nd the resulting aldehydes or imine/iminium intermediates are reduced by the second hydride.Atpresent, the state-of-the-art approaches for reduction of amides to alcohols are catalytic hydrogenation by well-defined pincer complexes,b ased on Ru, Fe,a nd Mn, under ah ighly pressurized H 2 atmosphere, [4] whereas those for the production of amines are facilitated by either hydrosilylation [5] with various metals [6] or organoboranes [7] as catalysts or electrophilic activation of amides with triflic anhydride. [8,9] Methodologies leveraging means of single-electron-reduction have recently emerged, enabling controlled reduction of amides. [10] Nonetheless,i mplementation of the amide reduction with precise and predictable control of the CÀN/CÀOcleavage for the formation of alcohol/amine still remains achallenge,and requires the sophisticated design of the reaction settings.…”

Controlled Reduction of Carboxamides to Alcohols or Amines by Zinc Hydrides

“…[2,3] Aldehydes are synthesized when the tetrahedral anionic carbinol amine intermediates I,f ormed by the first hydride transfer, are kept intact prior to the aqueous quench. [8,9] Methodologies leveraging means of single-electron-reduction have recently emerged, enabling controlled reduction of amides. [8,9] Methodologies leveraging means of single-electron-reduction have recently emerged, enabling controlled reduction of amides.…”