Primary Vinyl Ethers as Acetylene Surrogate: A Flexible Tool for Deuterium‐Labeled Pyrazole Synthesis

Abstract

A novel synthetic path to 1,3‐disubstituted pyrazoles and their deuterated derivatives was developed. It is based on the reaction of vinyl ethers with hydrazonoyl chlorides in the presence of triethylamine. The reaction mechanism, clarified by the joint experimental and computational study, involves 1,3‐dipolar cycloaddition of the in situ generated nitrile imines to vinyl ethers and subsequent cleavage of alcohol from the formed alkoxypyrazoline. The results highlight the possibility of using vinyl ethers as acetylene surrogate and provide a novel access to pyrazoles, 4,5‐dideuteropyrazoles and their regioselectively labeled derivatives, 5‐deuteropyrazoles.

One‐Pot and Two‐Chamber Methodologies for Using Acetylene Surrogates in the Synthesis of Pyridazines and Their D‐Labeled Derivatives

“…Summarizing the results of the experiments including calcium carbide usage as a surrogate of acetylene, one can propose that the CaC 2 −H 2 O mixture should be replaced with a neutral analog to avoid 1,2,4,5‐tetrazine decomposition at elevated temperatures (most of the tetrazines decomposed in the presence of Ca(OH) 2 ). Recently, we demonstrated that benzyl vinyl ether can be used as an acetylene surrogate in 1,3‐dipolar cycloaddition reactions [20] . In this way, pyrazoles were obtained in up to quantitative yields in a one‐pot manner.…”

“…The second way to perform water‐ and base‐sensitive reactions with acetylene is to replace it with vinyl ethers [20] . Vinyl ethers are readily available and relatively nontoxic compounds with well‐known physical characteristics that can be used as safe and easily dosed acetylene surrogates [20–21] . From a certain point of view, vinyl ethers can be described as simple and safe reagents compared to acetylene itself.…”

“…Using vinyl ethers entirely excludes intermediate gas formation and excessive pressure in the reaction vessel. Previously, we successfully demonstrated that primary vinyl ethers can be used as acetylene surrogates in the synthesis of pyrazoles [20] …”

“…In this way, 1,2,4,5‐tetrazine 1 a and its electron withdrawing group‐containing derivatives 1 b – e reacted with calcium carbide and D 2 O in a two‐chamber reactor, giving desired 4,5‐dideuteropyridazines 3 a – e in quantitative yields and excellent deuterium incorporation values (98–99%, Table 2, entries 1–5). The reaction was performed in 1,4‐dioxane to prevent undesirable deuterium‐hydrogen exchange [20,25] …”

Pyrazole Scaffold Synthesis, Functionalization, and Applications in Alzheimer’s Disease and Parkinson’s Disease Treatment (2011–2020)

“…Ledovskaya et al reported that the weak organic base trimethylamine (TEA) could promote the 1,3-dipolar cycloaddition of vinyl ethers and hydrazonoyl chlorides to produce 1,3-disubstituted pyrazoles with absolute regioselectivity [ 28 ] ( Scheme 23 ).…”