Catalytic Cleavage of Amide C−N Bond: Scandium,Manganese, and Zinc Catalysts for Esterification of Amides

Amide C?N bonds are thermodynamically stable and their fission, such as by hydrolysis and alcoholysis, is considered a long‐challenging organic reaction. In general, stoichiometric chemical transformations of amides into the corresponding esters and acids require harsh conditions, such as strong acids/bases at a high reaction temperature. Accordingly, the development of catalytic reactions that cleave not only primary and secondary amides, but also tertiary amides in mild conditions, is in high demand. Herein, we surveyed typical stoichiometric transformations of amides, and highlight our recent achievements in the catalytic esterification of amides using scandium, manganese, and zinc catalysts, together with some recent catalyst systems using late‐transition metal reported by other groups.     

Cross‐Coupling of Secondary Amides with Tertiary Amides: The Use of Tertiary Amides as Surrogates of Alkyl Carbanions for Ketone Synthesis

In recent years, exciting progress has been made in the field of direct transformation of amides, nevertheless, the condensation between two amides remains rare and restricted to homo‐coupling reactions. Herein, we report the cross‐coupling of secondary amides with tertiary amides, which provides a synthesis of ketones under mild conditions, and features the use of tertiary amides as surrogates of alkyl carbanions. The method relies on the coupling of enamines, generated from tertiary amides by catalytic partial reduction of tertiary amides with Vaska's catalyst, with nitrilium ions, formed in situ from secondary amides via activation with trifluoromethanesulfonic anhydride, and on the subsequent deformylation.     

The selective reaction of primary amines with carbonyl imidazole containing compounds: selective amide and carbamate synthesis

A new highly selective synthesis of amides and carbamates is described. In both cases the syntheses involve the formation of carbonyl imidazole intermediates which subsequently undergo previously unreported selective reactions with primary amines. Acid imidazolides with sufficient chain length will exclusively react with primary amines even in the presence of secondary and tertiary functionality. The imidazole carboxylic esters of secondary or tertiary alcohols also react selectively with primary amines, forming controlled carbamate structures.     

Novel Synthesis of Optically Active 2‐Ethylhexanoic Acid, 2‐Ethylhexanol,and 2‐Ethylhexylamine via the Asymmetric Favorskii Rearrangement

The asymmetric Favorskii rearrangement of optically active α‐haloketones, which are easily prepared from chiral menthyl‐4‐toluenesulfoxide in several steps using primary or secondary amines, yields their corresponding secondary or tertiary chiral amides. The secondary chiral amides were converted to acids or amines using acylation followed by hydrolysis or reduction. In addition, the tertiary amides were directly reduced to alcohol with Super‐Hydride^®.     

Influence of structural changes on the ion selectivities of magnesium ionophores based on malonic acid diamides

In an investigation of octamethylene bis(malonic acid diamides) and their selectivities for magnesium, it was found that presence of secondary amides within the particular ionophore played a considerable role in the enhancement of magnesium selectivity. Similar effects in other ionophores, i.e. tris(malonic acid diamides), were thus systematically looked at with the help of selectivity measurements with the hope of optimizing the number of secondary and tertiary amides so as to improve the magnesium selectivity. The syntheses of several investigated tris(malonic acid diamide) isologues are equally reported.Deceased in November 1992     

Mild and selective hydrozirconation of amides to aldehydes using Cp2Zr(H)Cl: scope and mechanistic insight

An investigation of the use of Cp2Zr(H)Cl (Schwartz's reagent) to reduce a variety of amides to the corresponding aldehydes under very mild reaction conditions and in high yields is reported. A range of tertiary amides, including Weinreb's amides, can be converted directly to the corresponding aldehydes with remarkable chemoselectivity. Primary and secondary amides proved to be viable substrates for reduction as well, although the yields were somewhat diminished as compared to the corresponding tertiary amides. Results from NMR experiments suggested the presence of a stable, 18-electron zirconacycle intermediate that presumably affords the aldehyde upon water or silica gel workup. A series of competition experiments revealed a preference of the reagent for substrates in which the lone pair of the nitrogen is electron releasing and thus more delocalized across the amide bond by resonance. This trend accounts for the observed excellent selectivity for tertiary amides versus esters. Experiments regarding the solvent dependence of the reaction suggested a kinetic profile similar to that postulated for the hydrozirconation of alkenes and alkynes. Addition of p-anisidine to the reaction intermediate resulted in the formation of the corresponding imine mimicking the addition of water that forms the aldehyde.     

Structural and thermodynamic characteristics of amide solvents

The structural and thermodynamic characteristics of amide solvents are calculated with different types of molecular self-assembly through hydrogen bonding. Under a model-based approach, the specific and nonspecific components of the total energy of intermolecular interactions are identified for primary, secondary, and tertiary amides of carboxylic acids. It is found that similarly to water, primary amides have a network of hydrogen bonds and belong to the class of liquids characterized by an increase in nonspecific interactions with temperature. In secondary amides with the chain self-assembly, the contribution of these interactions is practically independent of temperature, and in tertiary amides it decreases with an increase in temperature. The molar values of the specific and nonspecific components are used to analyze the intermolecular interactions and the structural properties of amides with different degrees of N-substitution.     

Efficient transamidation of primary carboxamides by in situ activation with N,N-dialkylformamide dimethyl acetals

Two protocols for the transamidation of primary amides with primary and secondary amines, forming secondary and tertiary amides, respectively, are described. Both processes employ N,N-dialkylformamide dimethyl acetals for primary amide activation, producing N'-acyl-N,N-dialkylformamidines as intermediates, as widely documented in the literature. Although the latter intermediates react irreversibly with amines by amidinyl transfer, we show that in the presence of certain Lewis acid additives efficient acyl transfer occurs, providing new and useful methods for amide exchange. In one protocol for transamidation, the N'-acyl-N,N-dialkylformamidine intermediates are purified by flash-column chromatography and the purified intermediates are then treated with an amine (typically, 2.5 equiv) in the presence of scandium triflate (10 mol %) in ether to form in high yields the products of transamidation. In a second procedure, N'-acyl-N,N-dialkylformamidines are generated in situ and, without isolation, are subjected to transamidation in the presence of zirconium chloride (0.5 equiv) and an amine (typically 2 equiv). A variety of different primary amides and amines are found to undergo efficient transamidation using the methods described.     

Palladium catalyzed alkoxy- and aminocarbonylation of vinyl tosylates

The palladium catalyzed alkoxycarbonylation and aminocarbonylation of vinyl tosylates are described. A variety of ketone and aldehyde derived vinyl tosylates may be carbonylated in the presence of primary, secondary, and tertiary alcohols, or primary and secondary amines, to provide the corresponding esters and amides in good yields. The alkoxycarbonylation was applied to a short synthesis of isoguvacine.     

Construction of macrocyclic structure using conformational properties of secondary and tertiary aromatic amides

A large macrocyclic compound with six para-phenylene rings and six amide moieties, which are alternately secondary and tertiary, was synthesized. In a stepwise synthesis, the final cyclization step was successful because a combination of three tertiary amides, which prefer a cis conformation, and two linear secondary amides would arrange both amino and carboxyl ends close to each other, while various sizes of macrocyclic compounds including the target cyclic trimer were generated in one-pot synthesis where three secondary amide bonds were formed.     

A General and Efficient CuBr2‐Catalyzed N‐Arylation of Secondary Acyclic Amides

A general and efficient Cu(II)‐catalyzed cross‐coupling method is reported for the preparation of acyclic tertiary amides. Generally moderate to excellent yields and functional group tolerance were obtained with secondary acyclic amides and aryl halides as substrates in toluene.     

Carbamoylimidazolium salts as diversification reagents: an application to the synthesis of tertiary amides from carboxylic acids

An efficient method for the preparation of tertiary amides from carbamoylimidazolium salts and carboxylic acids is described. The transformation occurs at room temperature and under relatively mild conditions. The carbamoylimidazolium salts are obtained from the reaction of secondary amines with N,N′-carbonyldiimidazole, followed by methylation with methyl iodide. The utility of this reaction was demonstrated in the formation of Weinreb amides and in a short synthesis of fused bicyclic amides. The introduction of this reaction now permits carbamoylimidazolium salts to be utilized in the formation of tertiary amides, ureas, carbamates and thiocarbamates under a single set of conditions.     

Development of carbohydrate-based scaffolds for restricted presentation of recognition groups. Extension to divalent ligands and implications for the structure of dimerized receptors

The solution structure of glycosyl amides has been studied by using NMR. A strong preference is displayed by tertiary aromatic glycosyl amides for E-anti structures in contrast with secondary aromatic glycosyl amides where Z-anti structures predominate. The structural diversity displayed by these classes of molecules would seem to be important as the directional properties of the aromatic ring, or groups attached to the aromatic ring, would be determined by choosing to have either a secondary or tertiary amide at the anomeric center and could be considered when designing bioactive molecules with carbohydrate scaffolds. The structural analysis was also carried out for related divalent secondary and tertiary glycosyl amides and these compounds display preferences similar to that of the monovalent compounds. The constrained divalent compounds have potential for promoting formation of clusters that will have restricted structure and thus have potential for novel studies of mechanisms of action of multivalent ligands. Possible applications of such compounds would be as scaffolds for the design and synthesis of ligands that will facilitate protein-protein or other receptor-receptor interactions. The affinity of restricted divalent (or higher order) ligands, designed to bind to proteins that recognize carbohydrates which would facilitate clustering and concomitantly promote protein-protein interactions, may be significantly higher than monovalent counterparts or multivalent ligands without these properties. This may be useful as a new approach in the development of therapeutics based on carbohydrates.     

Direct chemoselective allylation of inert amide carbonyls

Direct allylation of inert amide carbonyls utilizing the Schwartz reagent afforded either substituted tertiary or secondary amines. A preactivation step was successfully avoided, which is generally a requisite to increase the electrophilicity of amides. The reaction exhibited remarkable functional group tolerance and proceeded even in the presence of methyl esters and nitro groups.     

Highly enantioselective synthesis of glycidic amides using camphor-derived sulfonium salts. Mechanism and applications in synthesis

The reactions of a range of amide-stabilized sulfur ylides derived from readily available camphor-derived sulfonium salts for the synthesis of glycidic amides have been studied. Primary, secondary, and tertiary amides were tested, and it was found that the highest enantioselectivities were observed with tertiary amides, which provided glycidic amides in good to excellent yields, exclusive trans selectivity, and excellent enantioselectivities. The reaction was general for aromatic aldehydes, but aliphatic aldehydes gave more variable enantioselectivities. The epoxy amides could be converted cleanly into epoxy ketones by treatment with organolithium reagents. We were also able to effect selective ring opening of the epoxy amides with a variety of nucleophiles, followed by hydrolysis of the amide to yield the corresponding carboxylic acid. This methodology was applied to the total synthesis of the target compound SK&F 104353. A combination of crossover experiments and theoretical calculations has revealed that the rate- and selectivity-determining step is ring closure, not betaine formation as was the case for phenyl-stabilized ylides.     

N-Acylbenzotriazoles: neutral acylating reagents for the preparation of primary, secondary, and tertiary amides

Readily available N-acylbenzotriazoles 2a-q efficiently acylate aqueous ammonia and primary and secondary amines to give primary, secondary, and tertiary amides in good to excellent yields. The wide applicability of the procedure is illustrated by the preparation of (i) alpha-hydroxyamides from alpha-hydroxy acids and of (ii) perfluoroalkylated amides.     

A mild titanium-based system for the reduction of amides to aldehydes

A mild method for the reduction of amides to aldehydes using 1,1,3,3-tetramethyldisiloxane/titanium(IV) isopropoxide reducing system is described. The reaction occurs under mild conditions and allows the reduction of aromatic as well as aliphatic, tertiary amides to the corresponding aldehydes, in good yields. This methodology was extended to the reduction of aromatic secondary and primary amides to the corresponding aldehydes.     

Palladium-catalyzed decarboxylative aminocarbonylation with alkynoic acid and tertiary amine for the synthesis of alkynyl amide

We developed a method for the synthesis of alkynyl amides via the carbonylation of alkynoic acids and C-N activation of tertiary amines. The reaction of alkynoic acid and tertiary amine with carbon monoxide using a palladium catalyst in the presence of oxygen, KI, and K₃PO₄, gave the desired alkynyl amides in good yields.     

Effect of the Temperature on the Stoichiometry of Borane Dimethyl Sulfide Reduction of Secondary and Tertiary Amides

A simple procedure has been described for the reduction of secondary and tertiary amides to amines using borane-dimethyl sulfide in theoretical amounts.     

Investigation of the synthetic and mechanistic aspects of the highly stereoselective transformation of alpha-thioamides to alpha-thio-beta-chloroacrylamides

Treatment of a series of alpha-thioamides with N-chlorosuccinimide results in efficient transformation to the analogous alpha-thio-beta-chloroacrylamides. The mechanistic pathway has been established through isolation and characterisation of intermediate compounds. The scope of the transformation has been explored-aryl and alkylthio substituents, primary, secondary and tertiary amides can be employed. In most instances, the chloroacrylamides are formed exclusively as the Z-stereoisomer; however, with tertiary propanamides or with amides derived from butanoic or pentanoic acid a mixture of E- and Z-stereoisomers is formed.