TBAI/K₂S₂O₈-Promoted [4 + 2] Annulation of Ketene N,S-Acetals and N-Tosylhydrazones toward Pyridazines

Abstract

A TBAI/K2S2O8-promoted [4 + 2] annulation of ketene N,S-acetals, and N-tosylhydrazones was efficiently developed, enabling straightforward access to a variety of trisubstituted pyridazines in reasonable to good yields. The synthetic methodology features a broad substrate scope and a good functional group tolerance. Control experiments demonstrated the indispensability of the alkylthio functionality in the enaminone substrates.

Synthesis of Pyridazine Derivatives via Aza-Diels–Alder Reactions of 1,2,3-Triazine Derivatives and 1-Propynylamines

“…We began our research by taking methyl 6-phenyl-1,2,3-triazin-4-carboxylate (10a) and N,N-dibenzyl-1-propyn-1-amine (11) in CHCl 3 at room temperature (Table 1, entry 1). Under these conditions, pyridazine 13 was obtained in 50% yield, together with 37% yield of pyridine 12a, with moderate regioselectivity.…”

“…A wide array of interesting applications has facilitated the development of synthetic methods for pyridazines with different substituents . Therefore, extensive efforts have been directed toward developing new strategies for the construction of these nitrogen heterocycles including [4 + 2] annulation of alkoxyallenes with 1,2-diaza-1,3-dienes, [4 + 2] annulation of hydrazines with 1,4-bifunctional compounds, [4 + 2] annulation of ketene N , S -acetals and N -tosylhydrazones, formal [3 + 3] cycloaddition of cyclopropene derivatives and hydrazones, [3 + 3] annulation of aldehyde hydrazones and α,β-unsaturated nitrile, catalytic three-component annulations in one-step procedures, and multistep synthesis involving a diaza-Wittig reaction . Despite these achievements, a more efficient metal-free synthesis of pyridazines under neutral conditions is highly desirable to expand the library of substituted pyridazines.…”

Emerging Trends in N‐Tosylhydrazone Mediated Transition‐Metal‐Free Reactions

“…Xiao and his group [84] explored [4+2] annulation of N ‐tosylhydrazones 3 and ketene N, S ‐ acetals 55 promoted by TBAl / K 2 SO 8 to give Pyridazines 56 . Iodine catalyst somewhat decreases the reaction output, although NIS (N‐Iodosuccinimide) adequately declines the reaction productivity and KI could not speed up the reaction to give the desired product.…”

“…Tang and his colleagues developed an important electrosynthesis process that produces thiadiazoles in 2019 [11] . The use of tosylhydrazone continues with [4+2] annulation by Liu et al [12] . (Figure 1).…”

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

“…Recently, a number of 3,6‐disubstituted pyridazines demonstrated antitumor activities, [6] what forces us to admit a high potency of the pyridazine cycle in the construction of new pharmaceuticals. The pyridazine ring was specifically ranked by pharmaceutical companies as one of the best potential heterocycles for the design of new drugs [7] …”