Dehydrogenative amidation

Biosynthesis of the polypeptide chain is realised by a complicated process called translation. The basic polypeptide chain is subsequently chemically modified by the so-called posttranslational modifications. During this sequence of events the peptide chain can be cleaved by directed proteolysis, some of the amino acids can be covalently modified (hydroxylated, dehydrogenated, amidated, etc.) or different so-called prosthetic groups such as haem (haemoproteins), phosphate residues (phosphoproteins), metal ions (metal-loproteins) or (oligo)saccharide chains (glycoproteins) can be attached to the molecule by covalent bonds. Naturally, one protein molecule can be modified by more means. 

Secondary amines do not react under these conditions. Thus, heating dibenzylamine with 1-hexanol under the experimental conditions resulted in a quantitative yield of hexyl hexanoate (entry 6, Table 1.8). The scope of this method was extended to the bis-acylation processes with diamines. Upon refluxing a slight excess of a primary alcohol and catalyst 1 with diamines (500 equivalent relative to 1) in toluene under argon, bis-amides were produced in high yields (Table 1.9). The high selectivity of the dehydrogenative amidation reaction to primary amine functionalities enabled the direct bis-acylation of diethylenetriamine with 1-hexanol to provide the bis-amide in 88% yield without the need to protect the secondary amine functionality [14]. 

Nova A, Crabtree RH, Eisenstein O et al (2010) An experimental-theoretical study of the factors that affect the switch between ruthenium-catalyzed dehydrogenative amide formation versus amine alkylation. Organometallics 29(23) 6548-6558... 

Keywords Amide-bond formation Dehydrogenative amidation Hydrolytic amidation Nitrile hydration Rearrangements Ruthenium catalysts... 

Scheme 19 Dehydrogenative amidation of primary alcohols and ctnnpeting processes...

On the other hand, the dehydrogenative amidation proved to be also sensitive to the electronic properties of the amines. Thus, with electron-poor amines, which display a low nucleophilic character, the formation of the hemiaminal intermediate is disfavored. As a consequence, substrates like anilines usually lead to low or moderate conversions, even at elevated temperatures or after long reaction periods, and large amounts of the corresponding esters by-products are formed. In this context, the ruthenium catalysts have conduced, in general, to quite disappointing results [114, 115, 117, 124], In fact, only gold nanoparticles have proven to be useful with this type of amines [132]. 

Scheme 26 Proposed mechanism for the dehydrogenative amidation of alcohols with azides...

Scheme 28 Dehydrogenative amidation of aldehydes promoted by [RuH2(PPh3)4]...

Scheme 32 Proposed mechanism for the ruthenium-catalyzed dehydrogenative amidation of...

Fu Z, Lee J, Kang B, Hong SH (2012) Dehydrogenative amide synthesis azide as a nitrogen source. Org Lett 14 6028... 

Chen C, Verpoort F, Wu Q (2016) Atom-eeonomie dehydrogenative amide synthesis via ruthenium catalysis. RSC Adv 6(60) 55599-55607... 

Scheme 17.24 Dehydrogenative amide formation using Milstein s Ru-PNN catalyst.

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