A straightforward synthesis of N-monosubstituted α-keto amides via aerobic benzylic oxidation of amides

An efficient sodium bicarbonate promoted aerobic oxidation reaction to prepare N-monosubstituted α-keto amides in the presence of n-tetrabutylammonium hydrogensulfate (TBAHS) was described. This reaction provides a very simple and convenient synthetic route to N-monosubstituted α-keto amides from easily available aryl- or heteroarylacetamides in good to high yields without using toxic reagents and harsh conditions.     

Hydrogen-bond-assisted transition-metal-free catalytic transformation of amides to esters

The amide C-N cleavage has drawn a broad interest in synthetic chemistry,biological process and pharmaceutical industry.Transition-metal,luxury ligand or excess base were always vital to the transformation.Here,we developed a transition-metalfree hydrogen-bond-assisted esterification of amides with only catalytic amount of base.The proposed crucial role of hydrogen bonding for assisting esterification was control experiments,density functional theory(DFT)calculations and kinetic studies.Besides broad substrate scopes and excellent functional groups tolerance,this base-catalyzed protocol complements the conventional transition-metal-catalyzed esterification of amides and provides a new pathway to catalytic cleavage of amide C–N bonds for organic synthesis and pharmaceutical industry.     

Catalytic, asymmetric synthesis of α-acetoxy amides

Non-racemic cyanohydrin acetates are readily available from aldehydes and potassium cyanide/acetic anhydride by use of bimetallic titanium (salen) catalyst 1. Treatment of the cyanohydrin acetates with a platinum(II) phosphinito catalyst 3 under neutral conditions results in chemoselective hydrolysis to the corresponding α-acetoxy amides in a racemization free process.     

Ru-catalyzed highly enantioselective hydrogenation of α-keto Weinreb amides

Asymmetric hydrogenation of α-keto Weinreb amides has been realized with [Ru((S)-Sunphos)(benzene)Cl]Cl as the catalyst and CeCl 3·7H2O as the additive.A series of enantiopure α-hydroxy Weinreb amides(up to 97% ee) have been obtained.Catalytic amount of CeCl3·7H2O is essential for the high reactivity and enantioselectivity and the ratio of CeCl3·7H2O to [Ru((S)-Sunphos)(benzene)Cl]Cl plays an important role in the hydrogenation reaction.     

Palladium-catalyzed arylation of α,β-unsaturated Weinreb amides

Palladium-catalyzed arylation of α,β-unsaturated Weinreb amides has been examined to obtain β-aryl-α,β-unsaturated Weinreb amides. The chelation between the palladium center of an alkylpalladium intermediate and Weinreb amide moiety facilitated both coordination and insertion steps.     

Synthesis and reactions of α-fluoro-α-amino amides

N-((S)-1-Phenylethyl)halofluoroethanamides have been investigated as precursors to N-protected α-fluoro-α-amino amides by nucleophilic displacement of halide with nitrogen nucleophiles such as potassium phthalimide, sodium succinimide, sodium glutarimide, trimethylamine and sodium azide. With single diastereoisomers of the iodofluoroethanamide, clean inversion of configuration occurs at room temperature, but subsequent epimerisation may occur as a result of the liberated iodide. The α-fluoro-α-amino amides made underwent a wide variety of reactions depending on conditions, but in many cases the carbon-fluorine bond was compromised. However, reacting trimethylamine and N-((S)-1-phenylethyl)iodofluoroethanamide gave the corresponding α-fluorobetaine amide, and subsequent acidic hydrolysis led to α-fluorobetaine as the first example of an ‘unprotected’ α-fluoroamino acid.     

Can we predict the conformational preference of amides?

To what extent, if any, is the conformation of secondary amides revealed by theory? This question has now been addressed by computational methods using calculations at the B3LYP/6-31G level of theory and (1)H NMR spectroscopy. Both gas-phase and solvent studies predict a Z-anti conformation to be the lowest in energy for an evaluated series of acetamides. Moreover, Z-anti conformations may also be inferred from the chemical shifts of the N-CH alpha protons determined by NMR spectroscopy. Thus, a proton situated anti to the N-H proton consistently appears approximately 0.8 ppm further downfield than a proton situated gauche to the N-H proton. This finding, which could only be derived by using the DFT calculations of conformational preference as a guide to interpret the NMR data, might prove to be useful as a simple and convenient methodology for establishing amide conformation experimentally.     

Tribromogermyl monochelates — derivatives of N,N-disubstituted 2-hydroxycarboxylic amides

Reactions of GeBr₄ with N,N-dimethyl-2-trimethylsiloxypropionamide (2a), (S)-2-trime-thylsiloxypropionpyrrolidide ((S)-2b), and N,N-dimethyl-O-(trimethylsilyl)mandelamide (2c) afforded pentacoordinated neutral (O,O)-monochelates, viz., N,N-dimethyl-2-tribromoger-myloxypropionamide (3a), (S)-2-tribromogermyloxypropionpyrrolidide ((S)-3b), and N,N-dimethyl-O-(tribromogermyl)mandelamide (3c), respectively. X-ray diffraction study was performed for tribromides 3a, (S)-3b, and 3c, as well as for the N,N-dimethylmandelamide (1c) described earlier. According to the X-ray diffraction data, the Ge atom in tribromides 3a, (S)-3b, and 3c is pentacoordinated and has trigonal bipyramidal configuration with two halogen atoms and oxygen atom of the ether group in the equatorial positions and the halogen atom and the amide oxygen atom in the axial fragment, the bonds in which are somewhat longer as compared to the analogous bonds in tetracoordinated Ge compounds.     

Enzymatic and chiral HPLC resolution of α-azido acids and amides

For the first time, enzymatic resolution of α-azido acid amides has been successfully demonstrated with high yields and enantiomeric excess. In one case dynamic kinetic resolution was achieved leading to more than 50% yield of the enantiomerically pure azido acid. Chiral HPLC was also used to separate racemic α-azido acids and the separation process was automated. Two routes to enantiopure α-azido acid building blocks for solid-phase peptide synthesis have, therefore, been established.     

Ni-mediated C–N activation of amides and derived catalytic transformations

Amide, as a ubiquitous functional group, is essential in various aspects of chemistry and biology. Although the history of studying amide is rich and fruitful, the synthetic application of amide is very limited due to the inertness of amide C–N bond. Recently,significant advances have been achieved towards the nickel-mediated C–N activation of amides. This approach allows a facile generation of acyl-nickel intermediates, and a number of unique transformations have been designed and realized based on the amide C–N bond activation. Focused on the catalytic transformation, this review summarizes and categorizes the recent advances on the synthetic applications of Ni-mediated C–N bond activation of amides.     

Oligomers of β-amino acid bearing non-planar amides form ordered structures

In this report, we explore the feasibility of using bicyclic chiral β-amino acids, (1R,2R,4S)- and (1S,2S,4R)-7-azabicyclo[2.2.1]heptane-2-carboxylic acid (R-Ah2c and S-Ah2c, respectively), to prepare novel peptides with unique properties. Facile cis-trans isomerization of the non-planar amide bonds of these β-amino acids should result in great flexibility of the backbone structure of β-peptides containing them. Indeed, oligomers of these amino acids showed thermostability and characteristic CD absorptions, which were not concentration-dependent, suggesting that the oligomers remained monomeric. The results indicated the formation of self-organized monomeric structures with chain-length-dependent stabilization. Energy calculations suggested that the peptides can take helical structures in which the energy barriers to cis-trans isomerization are greater for the central amide bonds than for the terminal amides.     

Are the enolates of amides and esters stabilized by electrostatics?

The fact that amides and esters form less stable enolates than ketones might be seen as evidence that electrostatic stabilization is unimportant in these anions. However, ab initio molecular orbital calculations show that electrostatic stabilization does in fact lie beneath the competing resonance effect that causes the decrease in acidity. The electrostatic contribution is revealed by examining torsionally twisted amide and ester structures in which the pi resonance interactions are largely inhibited. These twisted amides and esters have greater enolate acidity than the corresponding ketones. Qualitatively similar behavior is observed with respect to protonation, such that twisted amides and esters are generally less basic than the reference ketones, in striking contrast to their behavior in the normal geometries.     

An efficient synthesis of substituted alkyl acrylates using α-keto amides

The addition of α-keto amides as a NH-acid to alkyl propiolates and dialkyl acetylenedicarboxylates in the presence of a catalytic amount of triphenylphosphine gives the corresponding substituted alkyl acrylates.     

Five- and six-membered N-H?S hydrogen bonding in aromatic amides

The capacity of sulfur to form intramolecular five- or six-membered S?H-N hydrogen bonding in aromatic amides is assessed. The five-membered S?H-N hydrogen bonding is observed in crystal structures of five compounds, whereas the six-membered S?H-N hydrogen bonding is revealed in crystal structures of three compounds. The trityl group has been used to promote formation of the weak hydrogen bonding because it efficiently inhibits the competition of the intermolecular CO?H-N hydrogen bonding. (2D) ¹H NMR experiments indicate that both patterns also exist in chloroform.     

Iron-mediated remote C–H bond benzylation of 8-aminoquinoline amides

An efficient and convenient method for C5-benzylation of quinoline frameworks is developed with the using of inexpensive FeCl₃ catalyst. A range of N-bisbenzylic and N-monobenzylic sulfonamides smoothly react with aliphatic amides and aromatic amides, giving the corresponding products in moderate to excellent yields.     

Synthesis of functional derivatives ofN-carboxamidomethyl- andN-phthalimidomethyl-a-amino acids and peptides by reaction of amides and nitriles of α-amino acids with formaldehyde and primary amides or phthalimide

A direct method for the synthesis of functional derivatives ofN-carboxatnidomethyl- and N-phthalimidomethyl-a-amino acids by the reaction of nitriles and amides of -amino acids (including peptides) with formaldehyde and NH-compounds (amides and imides) in DMF in the presence of TsOH was developed. The reactions of the compounds synthesized with acetic anhydride, tosyl chloride, and phcnylalanine benzylamide in the presence of dicyclohexylcarbodiimide affording the corresponding N-acyl and N-sulfonyl derivatives or peptides containing carboxamido- and phthalimidomethyl substituents at the terminal N-atom of the peptide chain, were studied.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1480–1488, June, 1996.