Pyridazine N-Oxides as Precursors to 2-Aminofurans: Scope and Limitations in Complexity Building Cascade Reactions

Abstract

A method to transform pyridazine N-oxides into 2-aminofurans using a combination of UV light and transition metal catalysis has been developed. These electron-rich species exhibit a surprising range of useful reactivity, including the ability to participate in complexity building cascade processes when reacted with dienophiles. This study also establishes 2-aminofurans as valuable synthons that support modular synthetic entry to the shared heterocyclic core of certain aspidosperma and amaryllidaceae alkaloids.

Synthesis of 2-(1H-Indol-2-yl)acetamides via Brønsted Acid-Assisted Cyclization Cascade

“…It should be pointed out that the conversion of bicyclic intermediate 14 accessed via an alternative route into amide 1 was documented. 20 Acid-mediated cleavage of the furan ring to trigger a cyclization of indoles was also reported. 21 Evidently, successful implementation of this approach would greatly depend on the availability of structurally diverse precursors 4.…”

A Photoinduced Cascade for the Synthesis of 1H‐Indole‐2‐Acetamide Derivatives

“…As shown in Scheme 4, we prepared small library of variants of 1 h via our previously reported two-step protocol. [13] Gratifyingly, all of the substrates we examined (1 h 2 -1 h 12 ) were smoothly transformed to the corresponding 2-indoles. Importantly, electron-donating and electron-withdrawing groups were seamlessly incorporated into the indole scaffold utilizing this method (Scheme 4A).…”

“…[12] A recent follow up study focused on diverting transient species A to 2-aminofurans (2) via the corresponding metallocarbenoid intermediate. [13] This goal was accomplished using Rh 2 (esp) 2 as a catalyst. For example, irradiation (hv = 350 nm) of a solution of 3-aryl-6-pyrrolidinylpyridazine N-oxide 1 (X=H) and 3 mol% Rh 2 (esp) 2 in THF (0.1 M) directly furnished 2-aminofuran 2 (X=H) in 91% yield.…”

“…We began our study by reexamining our previously reported preliminary result shown in Scheme 1. [13] Our goal here was to optimize reaction parameters, this time focusing on the direct conversion of N-oxide 1 a to indole 3 a. As summarized in Table 1, our initially identified conditions employing 1 mol% Rh 2 (esp) 2 proved to be effective, affording 3 a in 93% isolated yield (Table 1, entry 1).…”

“…As shown in Scheme 2, photosubstrates 1 b-q were prepared by reacting 3-(2-aminophenyl)-6-chloropyridzine N-oxide (5 1 ) directly with amines at 85°C. [13,16] Our initial experiments focused on 6-piperdinyl substituted Noxide 1 b. Photolysis of this substrate under the optimized conditions (i. e., Table 1, entry 1) gave a mixture of indole 3 b furan 2 b. This problem was ultimately solved by including CHCl 3 (1% v/v) as a photodegradable co-solvent, which generates HCl over the course of the reaction.…”