Modular Synthesis of 3,6-Disubstituted-1,2,4-triazines via the Cyclodehydration of β-Keto-N-acylsulfonamides with Hydrazine Salts

Abstract

A straightforward method for preparing 3,6-disubstituted-1,2,4-triazines through a redox-efficient cyclodehydration of β-keto- N-acylsulfonamides with hydrazine salts is described. Two approaches for synthesizing the requisite β-keto- N-acylsulfonamides are presented, which allow for the late stage incorporation of either the C3 or C6 substituent in a flexible manner from acid chlorides or α-bromoketones, respectively. The scope of this methodology includes primary and secondary sp-linked substituents at both the C3 and C6 positions, and the mild reaction conditions tolerate a variety of sensitive functionalities.

Triazines: Syntheses and Inverse Electron-demand Diels–Alder Reactions

“…Subsequently, a one-pot hydrohydrazination/cyclodehydration/oxidation sequence was successfully carried out to give the desired 1,2,4-triazines in moderate to good yields. Dowling et al addressed their interesting report for the synthesis of 3,6-disubstituted-1,2,4-triazines (Scheme b) . The key β-keto- N -acylsulfonamides 15 were prepared from acid chlorides or α-bromoketones and then underwent condensation/cyclization with hydrazine salts to give 1,2,4-triazines 16 .…”

“…Dowling et al addressed their interesting report for the synthesis of 3,6-disubstituted-1,2,4-triazines (Scheme 7b). 72 The key βketo-N-acylsulfonamides 15 were prepared from acid chlorides or α-bromoketones and then underwent condensation/ cyclization with hydrazine salts to give 1,2,4-triazines 16. This redox-efficient protocol, avoiding the use of oxidants, was particularly effective for the production of 1,2,4-triazines substituted by alkyl groups at both the C3 and C6 sites such as 16a−16e.…”

A Microwave‐Assisted One‐Pot Three‐Step Metal‐Free [4+2] Annulation for the Sustainable Synthesis of Highly Substituted 1,2,4‐Triazines

“…[13] An alternative approach is represented by the cyclization of β-keto-N-acylsulfonamides with hydrazine salts. [14] In contrast to the more established [4 + 2] annulation method, the [3 + 3] annulation reaction has only recently been designed. In 2017, Ma and colleagues developed a silver-catalyzed 1,3dipolar cycloaddition reaction of reactive diazo compounds with glycine imines.…”

“… [12] The most common synthetic method for creating 3,5‐disubstituted or 3,5,6‐ trisubstituted 1,2,4‐triazines is the [4+2] annulation reaction of α‐dicarbonyl compounds with different nitrogen‐nucleophilic amidrazones [13] . An alternative approach is represented by the cyclization of β‐keto‐N‐acylsulfonamides with hydrazine salts [14] . In contrast to the more established [4+2] annulation method, the [3+3] annulation reaction has only recently been designed.…”

Synthesis of α-Amidoketones through the Cascade Reaction of Carboxylic Acids with Vinyl Azides under Catalyst-Free Conditions

“…α-Amidoketone derivatives have attracted considerable attention because they are not only the essential motifs of a plethora of pharmaceutically active compounds but also the indispensable intermediates that are widely used in organic synthesis. , Due to their importance, a number of methods for the preparation of α-amidoketone derivatives have been developed, which mainly include condensation of ketone-derived nitrones with N -methyl carboximidoyl chloride followed by hydrolytic workup, aza-benzoin condensation of aldehydes with N -acylimines promoted by organocatalysts, − Rh-catalyzed denitrogenative hydration of N -sulfonyl-1,2,3-triazoles, the radical cascade reaction of alkynes with N -fluoroarylsulfonimides and alcohols, the Dakin–West reaction of α-aminoacids with acid anhydrides, Rh-catalyzed hydroformylation of vinyl ester followed by condensation with primary amines and rearrangement, the Ru-catalyzed cascade reaction of 1,2-azidoalcohols, and Cu-catalyzed condensation of N -alkoxylbenzamids with 2 H -azirines. Although these literature methods are generally efficient and reliable, some of them still suffer from the use of expensive transition-metal catalysts, harsh reaction conditions, poor atom economy, and/or limited substrate scope.…”