Chemoselective Reduction of Tertiary Amides to Amines Catalyzed by Triphenylborane

Triphenylborane (BPh₃) was found to catalyze the reduction of tertiary amides with hydrosilanes to give amines under mild condition with high chemoselectivity in the presence of ketones, esters, and imines. N,N‐Dimethylacrylamide was reduced to provide the α‐silyl amide. Preliminary studies indicate that the hydrosilylation catalyzed by BPh₃ may be mechanistically different from that catalyzed by the more electrophilic B(C₆F₅)₃.     

Chemoselective Reductive Nucleophilic Addition to Tertiary Amides,Secondary Amides,and N‐Methoxyamides

As the complexity of targeted molecules increases in modern organic synthesis, chemoselectivity is recognized as an important factor in the development of new methodologies. Chemoselective nucleophilic addition to amide carbonyl centers is a challenge because classical methods require harsh reaction conditions to overcome the poor electrophilicity of the amide carbonyl group. We have successfully developed a reductive nucleophilic addition of mild nucleophiles to tertiary amides, secondary amides, and N‐methoxyamides that uses the Schwartz reagent [Cp₂ZrHCl]. The reaction took place in a highly chemoselective fashion in the presence of a variety of sensitive functional groups, such as methyl esters, which conventionally require protection prior to nucleophilic addition. The reaction will be applicable to the concise synthesis of complex natural alkaloids from readily available amide groups.     

Additive-Free Chemoselective Acylation of Amines

Aliphatic and aromatic amines are efficiently acylated by acetic, pivalic, benzoic, phthalic, or maleic anhydrides in ethyl acetate at room temperature. Under the same experimental conditions, amino alcohols are chemoselectively acylated at the amino group.     

Highly Efficient Dehydrogenative Coupling of Hydrosilanes with Amines or Amides Using Supported Gold Nanoparticles

Hydroxyapatite‐supported gold nanoparticles (Au/HAP) can act as a highly active and reusable catalyst for the coupling of hydrosilanes with amines under mild conditions. Various silylamines can be selectively obtained from diverse combinations of equimolar amounts of hydrosilanes with amines including less reactive bulky hydrosilanes. This study also highlights the applicability of Au/HAP to the selective synthesis of silylamides through the coupling of hydrosilanes with amides, demonstrating the first example of an efficient heterogeneous catalyst. Moreover, Au/HAP shows high reusability and applicability for gram‐scale synthesis.     

Chemoselective Intermolecular α‐Arylation of Amides

A new approach for the fully chemoselective α‐arylation of amides is presented. By means of electrophilic amide activation, aryl groups can be regioselectively introduced α‐ to amides, even in the presence of esters and alkyl ketones. Mechanistic studies reveal key reaction intermediates and emphasize a remarkably subtle base effect in this transformation.     

A Manganese Pre‐Catalyst: Mild Reduction of Amides,Ketones, Aldehydes,and Esters

A new (N ‐phosphinoamidinate)manganese complex is shown to be a useful pre‐catalyst for the hydrosilative reduction of carbonyl compounds, and in most cases at room temperature. The Mn‐catalyzed reduction of tertiary amides to tertiary amines, with a useful scope, is demonstrated for the first time by use of this catalyst, and is competitive with the most effective transition‐metal catalysts known for such transformations. Ketones, aldehydes, and esters were also successfully reduced under mild conditions by using this new Mn catalyst.     

Enantioselective Synthesis of α‐Hydroxy Amides and β‐Amino Alcohols from α‐Keto Amides

Synthesis of enantiomerically enriched α‐hydroxy amides and β‐amino alcohols has been accomplished by enantioselective reduction of α‐keto amides with hydrosilanes. A series of α‐keto amides were reduced in the presence of chiral Cu^II/(S)‐DTBM‐SEGPHOS catalyst to give the corresponding optically active α‐hydroxy amides with excellent enantioselectivities by using (EtO)₃SiH as a reducing agent. Furthermore, a one‐pot complete reduction of both ketone and amide groups of α‐keto amides has been achieved using the same chiral copper catalyst followed by tetra‐n‐butylammonium fluoride (TBAF) catalyst in presence of (EtO)₃SiH to afford the corresponding chiral β‐amino alcohol derivatives.     

Chemoselective Reduction of Aldehydes using Decaborane in Aqueous Solution

Reduction of aldehydes using decaborane (B₁₀H₁₄) in an aqueous solution gave the corresponding alcohol chemoselectively in good to high yields.     

A Fast and General Route to Ketones from Amides and Organolithium Compounds under Aerobic Conditions: Synthetic and Mechanistic Aspects

We report that the nucleophilic acyl substitution reaction of aliphatic and (hetero)aromatic amides by organolithium reagents proceeds quickly (20 s reaction time), efficiently, and chemoselectively with a broad substrate scope in the environmentally responsible cyclopentyl methyl ether, at ambient temperature and under air, to provide ketones in up to 93 % yield with an effective suppression of the notorious over-addition reaction. Detailed DFT calculations and NMR investigations support the experimental results. The described methodology was proven to be amenable to scale-up and recyclability protocols. Contrasting classical procedures carried out under inert atmospheres, this work lays the foundation for a profound paradigm shift of the reactivity of carboxylic acid amides with organolithiums, with ketones being straightforwardly obtained by simply combining the reagents under aerobic conditions and with no need of using previously modified or pre-activated amides, as recommended.     

Intensification of Double Kinetic Resolution of Chiral Amines and Alcohols via Chemoselective Formation of a Carbonate–Enzyme Intermediate

Chiral amines and alcohols are synthons of numerous pharmaceutically-relevant compounds. The previously developed enzymatic kinetic resolution approaches utilize a chiral racemic molecule and achiral acyl donor (or acyl acceptor). Thus, only one enantiodivergent step of the catalytic cycle is engaged, which does not fully exploit the enzyme’s abilities. The first carbonate-mediated example of simultaneous double chemoselective kinetic resolution of chiral amines and alcohols is described. Herein, we established a biocatalytic approach towards four optically-pure compounds (>99% ee, Enantioselectivity: E > 200) via double enzymatic kinetic resolution, engaging chiral organic carbonates as acyl donors. High enantioselectivity was ensured by extraordinary chemoselectivity in lipase-catalyzed formation of unsymmetrical organic carbonates and engaged in a process applicable for the synthesis of enantiopure organic precursors of valuable compounds. This study focused not only on preparative synthesis, but additionally the catalytic mechanism was discussed and the clear impact of this rarely observed carbonate-derived acyl enzyme was shown. The presented protocol is characterized by atom efficiency, acyl donor sustainability, easy acyl group removal, mild reaction conditions, and biocatalyst recyclability, which significantly decreases the cost of the reported process.     

Formation of Secondary or Tertiary Aliphatic Amines in Aqueous Media

Secondary and tertiary amines can be easily obtained from primary and secondary amines, respectively, in completely aqueous media, in the presence of a bicatalytic system formed of cheap commercial aluminum (Al) powder and 5% rhodium (Rh) or ruthenium (Ru) deposed on charcoal.     

Reduction of N,N‐Dimethylcarboxamides to Aldehydes by Sodium Hydride–Iodide Composite

A new and concise protocol for selective reduction of N,N‐dimethylamides into aldehydes was established using sodium hydride (NaH) in the presence of sodium iodide (NaI) under mild reaction conditions. The present protocol with the NaH‐NaI composite allows for reduction of not only aromatic and heteroaromatic but also aliphatic N,N‐dimethylamides with wide substituent compatibility. Retention of α‐chirality in the reduction of α‐enantioriched amides was accomplished. Use of sodium deuteride (NaD) offers a new step‐economical alternative to prepare deuterated aldehydes with high deuterium incorporation rate. The NaH‐NaI composite exhibits unique chemoselectivity for reduction of N,N‐dimethylamides over ketones.     

Supported Gold Nanoparticles for Efficient α‐Oxygenation of Secondary and Tertiary Amines into Amides

Although the α‐oxygenation of amines is a highly attractive method for the synthesis of amides, efficient catalysts suited to a wide range of secondary and tertiary alkyl amines using O₂ as the terminal oxidant have no precedent. This report describes a novel, green α‐oxygenation of a wide range of linear and cyclic secondary and tertiary amines mediated by gold nanoparticles supported on alumina (Au/Al₂O₃). The observed catalysis was truly heterogeneous, and the catalyst could be reused. The present α‐oxygenation utilizes O₂ as the terminal oxidant and water as the oxygen atom source of amides. The method generates water as the only theoretical by‐product, which highlights the environmentally benign nature of the present reaction. Additionally, the present α‐oxygenation provides a convenient method for the synthesis of ¹⁸O‐labeled amides using H₂¹⁸O as the oxygen source.