Helena Lundberg

Catalytic amide formation from non-activated carboxylic acids and amines

The amide functionality is found in a wide variety of biological and synthetic structures such as proteins, polymers, pesticides and pharmaceuticals. Due to the fact that synthetic amides are still mainly produced by the aid of coupling reagents with poor atom-economy, the direct catalytic formation of amides from carboxylic acids and amines has become a field of emerging importance. A general, efficient and selective catalytic method for this transformation would meet well with the increasing demands for green chemistry procedures. This review covers catalytic and synthetically relevant methods for direct condensation of carboxylic acids and amines. A comprehensive overview of homogeneous and heterogeneous catalytic methods is presented, covering biocatalysts, Lewis acid catalysts based on boron and metals as well an assortment of other types of catalysts.

Direct Amide Coupling of Non-activated Carboxylic Acids and Amines Catalysed by Zirconium(IV) Chloride

Direct Amide Coupling of Non-activated Carboxylic Acids and Amines Catalysed by Zirconium(IV) Chloride

Metal-Free N-Arylation of Secondary Amides at Room Temperature

The arylation of secondary acyclic amides has been achieved with diaryliodonium salts under mild and metal-free conditions. The methodology has a wide scope, allows synthesis of tertiary amides with highly congested aryl moieties, and avoids the regioselectivity problems observed in reactions with (diacetoxyiodo)benzene.

High Throughput Screening of a Catalyst Library for the Asymmetric Transfer Hydrogenation of Heteroaromatic Ketones : Formal Syntheses of (R)-Fluoxetine and (S)-Duloxetine

A total of 21 amino acid based ligands including hydroxy amide, thioamide, and hydroxamic acid functionalities, respectively, were combined with [Ru(p‐cymene)Cl2]2 and [RhCp*Cl2]2, and used as catalysts for the asymmetric transfer hydrogenation of four different heteroaromatic ketones in 2‐propanol. The reactions were performed on a Chemspeed automated high‐throughput screening robotic platform. Optimal catalysts were identified for the individual heterocyclic substrate classes. Based on these results, the formal syntheses of the antidepressant drugs (R)‐fluoxetine and (S)‐duloxetine were conducted by using the found catalysts in the key reaction step, which results in high isolated yields (94 %) and excellent product enantioselectivities (>99 % ee) of the formed 1,3‐amino alcohols.

Single Site Supported Cationic Rhodium(I) Complexes for the Selective Redox Isomerization of Allylic Alcohols

The isomerization of allylic alcohols to carbonyl compounds by a heterogeneous rhodium complex is reported. Different silica material supports and catalyst/ligand systems were evaluated. The most efficient catalyst in terms of catalytic activity and stability was found to be a cationic rhodium(I) complex with sulfonated phosphine ligands anchored on a mesoporous aluminosilica AlSBA‐15. The heterogeneous complex catalyzed the isomerization of a variety of allylic alcohols in excellent yields with very low catalyst loadings (0.5 mol %). The catalyst could be recycled without significant loss of activity or selectivity. The optimized catalyst was characterized by N2 sorption, powder X‐ray diffraction, transmission electron microscopy, as well as solution and solid‐state nuclear magnetic resonance, and Fourier Transform infrared spectroscopies.

Ruthenium-catalyzed tandem-isomerization/asymmetric transfer hydrogenation of allylic alcohols.

A one-pot procedure for the direct conversion of racemic allylic alcohols to enantiomerically enriched saturated alcohols is presented. The tandem-isomerization/asymmetric transfer hydrogenation process is efficiently catalyzed by [{Ru(p-cymene)Cl2 }2 ] in combination with the α-amino acid hydroxyamide ligand 1, and performed under mild conditions in a mixture of ethanol and THF. The saturated alcohol products are isolated in good to excellent chemical yields and in enantiomeric excess up to 93 %.

Mechanistic Elucidation of Zirconium-Catalyzed Direct Amidation

The mechanism of the zirconium-catalyzed condensation of carboxylic acids and amines for direct formation of amides was studied using kinetics, NMR spectroscopy, and DFT calculations. The reaction is found to be first order with respect to the catalyst and has a positive rate dependence on amine concentration. A negative rate dependence on carboxylic acid concentration is observed along with S-shaped kinetic profiles under certain conditions, which is consistent with the formation of reversible off-cycle species. Kinetic experiments using reaction progress kinetic analysis protocols demonstrate that inhibition of the catalyst by the amide product can be avoided using a high amine concentration. These insights led to the design of a reaction protocol with improved yields and a decrease in catalyst loading. NMR spectroscopy provides important details of the nature of the zirconium catalyst and serves as the starting point for a theoretical study of the catalytic cycle using DFT calculations. These studies indicate that a dinuclear zirconium species can catalyze the reaction with feasible energy barriers. The amine is proposed to perform a nucleophilic attack at a terminal η2-carboxylate ligand of the zirconium catalyst, followed by a C-O bond cleavage step, with an intermediate proton transfer from nitrogen to oxygen facilitated by an additional equivalent of amine. In addition, the DFT calculations reproduce experimentally observed effects on reaction rate, induced by electronically different substituents on the carboxylic acid.

Ruthenium‐Catalyzed Asymmetric Transfer Hydrogenation of Propargylic Ketones

The asymmetric transfer hydrogenation of α,β‐propargyl ketones catalyzed by an in situ formed ruthenium–hydroxyamide complex was explored. The acetylenic alcohols were isolated in good to excellent yields with excellent ee values (typically >90 %) after short reaction times at room temperature.