Amide Bond Formation via the Rearrangement of Nitrile Imines Derived from N-2-Nitrophenyl Hydrazonyl Bromides

Abstract

We report how the rearrangement of highly reactive nitrile imines derived from N -2-nitrophenyl hydrazonyl bromides can be harnessed for the facile construction of amide bonds. This amidation reaction was found to be widely applicable to the synthesis of primary, secondary, and tertiary amides and was used as the key step in the synthesis of the lipid-lowering agent bezafibrate. The orthogonality and functional group tolerance of this approach was exemplified by the N -acylation of unprotected amino acids.

Functionalized Tetrazoles as Latent Active Esters in the Synthesis of Amide Bonds

“…Similarly, amide 3c , which features a sterically bulky gem -dimethyl group, was isolated in an excellent 98% yield. This contrasts with our previous procedure utilizing hydrazonyl bromides as NI precursors, in which a gem -dimethyl group severely hindered the reaction and gave the N -acylated product in only 31% yield . Thiophene-2-ethylamine and phenylethylamine were efficiently N -acylated under our conditions to afford amides 3d and 3e in 83% and 94% yield, respectively.…”

“…Disubstituted tetrazole substrates featuring electron-rich aryl rings were well tolerated in the coupling process and afforded benzamides 4a – 4c in excellent yields. It should be noted that these substrates are not compatible with the progenitor process owing to their susceptibility to elemental bromine. Thiocarbamate 4d , a compound isolated from the leaves of Moringa oleifera, was synthesized in 42% yield from the corresponding thioether-substituted tetrazole 1e .…”

“…Moclobemide ( 5a ), a reversible monoamine oxidase inhibitor, and compound 5b , a precursor to the sodium channel blocker procainamide (PCA), were synthesized in 76% and 65% yields, respectively. This represents a considerable improvement over our previous protocol employing the analogous hydrazonyl bromides, which furnished 5a and 5b in 51% and 21% yields, respectively . The thermal activation of electron-rich tetrazole 1o afforded the corresponding active ester which was trapped with the required para -functionalized benzylamine nucleophile, which again would have been incompatible with the original reaction manifold.…”

4-Methoxyphenethyl (E)-3-(o-tolyl)acrylate

“…The synthesis of esters can also be carried out using 1,1 -carbonyldiimidazole (CDI) [11] as a coupling agent; however, the resultant intermediate is less reactive than the acyl chloride intermediate [12]. Hydroxybenzotriazole (HOBt) is usually added to the other coupling reagents, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) [13]; however, concerns have been raised due to its explosive properties [14]. On the other hand, 2-methyl-6-nitrobenzoic anhydride (MNBA) showed great promise in the synthesis of carboxylic esters [15].…”

Untitled

“…Amides are a type of functional group which can be found in both synthetic and natural chemical compounds [1]. It is essential to take life seriously [2]. Amide grouping is a fundamental activity carried out by organic matter seen in common natural compounds such as proteins.…”