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

Abstract

We report the use of N-2,4-dinitrophenyltetrazoles as latent active esters (LAEs) in the synthesis of amide bonds. Activating the tetrazole generates an HOBt-type active ester without the requirement for exogenous coupling agents. The methodology was widely applicable to a range of substrates, with up to quantitative yields obtained. The versatility and functional group tolerance were exemplified with the one-step synthesis of various pharmaceutical agents and the N-acylation of resin-bound peptides.

One-Pot Oxidative Amidation of Aldehydes via the Generation of Nitrile Imine Intermediates

“…Purification by flash column chromatography (15% ethyl acetate in petroleum ether) followed by trituration in hexane afforded N -(2-methoxybenzyl)-4-methylbenzamide ( 2b ) (52.3 mg, 41%) as an off-white solid. Spectroscopic data were consistent with the literature …”

“…Aldehydes featuring electron-withdrawing groups in the para -position gave the corresponding amides 2s – 2u in 41–58% yield. In relation to the nitrobenzene-derived substrate 2u , the yield obtained (40%) compares very favorably with our progenitor process which used a 2,5-diaryl tetrazole precursor to furnish the amide product in 39% isolated yield . Substrates bearing electron-donating groups were generally less efficient under the strongly oxidative conditions; however, mono- and dimethoxy analogues 2v and 2w were isolated in 41 and 25%, respectively.…”

“…After condensation of the aldehyde and hydrazine, the resulting hydrazone is converted to the highly reactive NI intermediate via KBr/Oxone-mediated bromination and subsequent hydrodehalogenation in the presence of potassium carbonate. Before the NI 1,3-dipole can engage in a 1,7-electrocyclization with the ortho -nitro motif to form an HOBt-type active ester, under the strongly oxidizing conditions of the reaction that differ from our progenitor processes which utilized only base promotion, the acyl diazene 3 is formed, likely through the intermediacy of a hydrazide species 4 . This mechanistic proposal is similar to that described previously by Müller and Waldmann, where activated acyl diazene intermediates are generated via enzyme-mediated oxidative cleavage of phenyl hydrazides with mushroom tyrosinase under an oxygen atmosphere before hydrolysis to provide carboxylic acids …”

Efficient preparation of cyclic polymers via pre-stacking of photo-cycloaddition capable end groups and a continuous-flow technique

“…20,40 In addition, the signal at 3.5 ppm (H b″ ) for the proton of the CH group adjacent to the terminal polystyrene amino group (NH 2 -PSt 26 -NH 2 ) shifted downfield significantly to 5.0 ppm (H b′′′ ) after amidation (SP-PSt 26 -SP). 41 Note that the proton peak of the amide is around 7.2 ppm, 40 which overlaps with the peaks of the aromatic protons of SP, so it cannot be distinguished in the spectrum. The degree of terminal functionalization can also be quantified using the integral area ratio of H a (the methyl group) and H p (the pyrene group).…”

Acid‐Catalyzed Ring Opening Reaction of Cyclopropyl Carbinols with Acetonitrile to Synthesize Amides

“…Beckmann rearrangement, [9] Schmidt rearrangement, [10] and Overman rearrangement [11] are also commonly used to synthesize amides while there are some less common reactions, such as the Passerini reaction, [12] Ugi reaction, [13] Schotten‐Baumann reaction, [14] etc. Recently, Craig's group reported the use of N ‐2,4‐dinitrophenyltetrazoles as latent active esters (LAEs) in the synthesis of amide bonds (scheme 1b) [15] . Activating the tetrazole generates an HOBt‐type active ester without the requirement for exogenous coupling agents.…”