Regio- and Diastereoselective 1,3-Dipolar Cycloadditions of 1,2,4-Triazin-1-ium Ylides: a Straightforward Synthetic Route to Polysubstituted Pyrrolo[2,1-f][1,2,4]triazines

Abstract

A synthetic strategy to pyrrolo[2,1- f ][1,2,4]triazines is reported. We show that various synthetically easily accessible 1,2,4-triazines can be efficiently alkylated under mild conditions to provide the corresponding 1-alkyl-1,2,4-triazinium salts. These bench-stable salts serve as precursors to triazinium ylides, which react in 1,3-dipolar cycloadditions with electron-poor dipolarophiles to yield polysubstituted pyrrolotriazines in a single step.

Synthesis of C3-Substituted N1-tert-Butyl 1,2,4-Triazinium Salts via the Liebeskind–Srogl Reaction for Fluorogenic Labeling of Live Cells

“…29 Our initial experiments revealed that N1-methylated and N1-ethylated triazinium salts were not compatible with the previously applied conditions. 29 However, the N1-tert-butyl triazinium was well tolerated, and the desired C 3 -phenyl-substituted triazinium Trz + 2a formed in 74% yield (Table 1, entry 1). To explore the impact of various parameters on the reaction outcome, we systematically varied the composition of the catalytic system, nucleophiles, ligands, mediators, temperature, and solvents (Table 1 and Table S1).…”

“…Moreover, overalkylation can pose a problem for compounds containing additional reactive nucleophilic sites. To overcome these limitations, we sought to develop a late-stage modification strategy based on the L–S cross-coupling reaction, which we previously used for the modification of 1,2,4-triazines at position C 3 . Our initial experiments revealed that N 1-methylated and N 1-ethylated triazinium salts were not compatible with the previously applied conditions .…”

Triazinium Ligation: Bioorthogonal Reaction of N1‐Alkyl 1,2,4‐Triazinium Salts**

“…Based on these preliminary data, we next investigated how the different alkyl groups would affect the reactivity, solubility, and stability of the triazinium ions. Methylated and ethylated derivatives are synthetically accessible via alkylation by commercial methyl‐ and ethyl‐trifluoromethanesulfonates [19b] . For preparation of iso ‐propyl ( i Pr) and tert ‐butyl ( t Bu) analogs, we generated the corresponding triflates in situ from the respective alcohols and triflic acid anhydride in the presence of pyridine (SI).…”

Triazinium Ligation: Bioorthogonal Reaction of N1-alkyl 1,2,4-Triazinium Salts

“…These dipoles react in 1,3-dipolar cycloadditions with electron poor dipolarophiles to yield pyrrolotriazines. [37][38] Alternatively, an intramolecular cycloaddition of triazinium salts leading to substituted pyridines has been described. 39 In this context, we sought to exploit triazinium salts as chemoselective reaction partners in bioorthogonal cycloadditions with strained dienophiles.…”

“…Methylated and ethylated derivatives are synthetically accessible via alkylation by commercial methyl-and ethyltrifluoromethanesulfonates. 38 For preparation of iso-propyl (iPr) and tert-butyl (tBu) analogs, we generated the corresponding triflates in situ from the respective alcohols and triflic acid anhydride in the presence of pyridine (SI).…”