Ammonia-Promoted One-Pot Tetrazolopiperidinone Synthesis by Ugi Reaction

Abstract

Ammonia in the tetrazole Ugi variation together with α-amino acid methyl ester-derived isocyanides provides tetrazolopiperidinones in good to high yields in one pot. The scope and limitations of this reaction were investigated by performing >70 reactions. The scaffold is useful to fill high-throughput screening decks and in structure-based drug design.

Tetrazoles via Multicomponent Reactions

“…Dömling et al. 358 replaced the amine component with ammonia which provided tetrazolopyrazinones 210 in good to high yields in one-pot fashion. After quite some optimization, ammonium chloride proved to be the best ammonia source followed by treatment with catalytic amount (0.1 equiv) of ammonium hydroxide as a base at 50 °C for 18 h, giving the cyclized adducts (Scheme 93, Figure 42).…”

Synthesis of a novel category of pseudo-peptides using an Ugi three-component reaction of levulinic acid as bifunctional substrate, amines, and amino acid-based isocyanides

“…In continuation of our interest on the synthesis of novel pseudo-peptides [27–29] via multicomponent reactions, herein we investigate the Ugi-4C-3CR of levulinic acid, aromatic and aliphatic amines and amino acid-based isocyanides. First of all, racemic α-amino acids such as DL-tryptophan, DL-phenylalanine and DL-leucine were used as amine source for the synthesis of isocyanide esters 3 through three sequential reactions [30–31]. The first reaction is esterification of the α-amino acid using thionyl chloride in methanol as reagent and solvent.…”

One-Pot Parallel Synthesis of 5-(Dialkylamino)tetrazoles

“…According to the recent reports, tetrazole is the third most frequently occurring azole system in the structures of FDA approved drugs. , A broad range of biological activities of tetrazole derivatives, including antimicrobial, antiviral, antifungal, antitumor, anticonvulsant, and antihypertensive properties are extensively reviewed in the literature. − However, the availability of diversely substituted tetrazoles for their application in medicinal and other industries is highly dependent on the capability of the currently used synthetic methods for both multigram preparation and microgram-scale parallel synthesis. ,, To date, the reported combinatorial approaches to tetrazole ring construction were limited to a small set of reactions. The most commonly utilized method involves Ugi–azide four-component reaction leading to (1 H -tetrazol-5-yl)­methanamines. − Other less commonly used methods include azide cycloaddition with electron-poor nitriles and reaction of peptide N -terminal amino group with arylisothiocyanates …”