Nucleophilic Substitution on 2-Monosubstituted Quinoxalines Giving 2,3-Disubstituted Quinoxalines: Investigating the Effect of the 2-Substituent

Abstract

An investigation on the effect of substituent at the 2-position of mono-substituted quinoxalines in the synthesis of di-substituted quinoxaline derivatives via nucleophilic substitution reactions, is reported. Di-substituted quinoxalines bearing aryl-alky, aryl-aryl, aryl-heteroaryl, aryl-alkynyl, and amino-alkyl substituents were prepared in moderate to good yields. 2-Monosubstituted quinoxalines bearing a phenyl and butyl substituent reacted readily with alkyl-, aryl-, heteroaryl-and alkynyl-nucluephiles, giving di-substituted quinoxalines. 2-Monosubstituted quinoxalines bearing an amine and alkynyl substituent only reacted with alkyl nucleophiles. Oxidative rearomatization to give 2,3-disubstituted quinoxaline products occurred in atmospheric O 2 .

A REP-FAMSEC Method as a Tool in Explaining Reaction Mechanisms: A Nucleophilic Substitution of 2-Phenylquinoxaline as a DFT Case Study

“…According to the experimental report by Ndlovu et al [ 16 ], this reaction occurs at the position occupied by a hydrogen atom in the electron deficient ring (C3 in 1 ) to form the so called σ H -adduct. However, from the generated molecular graph of 1 , three other sites, namely C2, C5, and C10, were identified as potential competing sites for the reaction being studied.…”

“…It is commonly accepted that the mechanism shown in Scheme 1 is well understood. However, following the general and applicable protocols, Ndlovu et al [ 16 ] reported yields of widely varying degrees when 2-substitued quinoxalines reacted with different carbon-based nucleophiles. Not entirely surprisingly, the steric hindrance was proposed as the contributing factor affecting the yields of these reactions.…”

“…The reaction of quinoxaline derivatives with aryl and alkyl nucleophiles has been investigated extensively and mechanisms have been proposed [10][11][12][13][14][15][16]. This reaction is assumed to follow the oxidative nucleophilic substitution of hydrogen (ONSH) reaction mechanism shown in Scheme 1.…”

Recent Advances in the Transition-Metal-Free Arylation of Hetero­arenes

“…Nxumalo and Ndlovu investigated the substituent effect on arylation of 2-substituted quinoxalines with aryl-metal compounds (Scheme 37). 46 2,3-Diaryl or 2-alkyl-3-aryl quinoxalines can be easily obtained from the reaction of aryl nucleophiles (Li-or Mg-aryls) with mono-substituted quinoxalines. The reaction uses air oxygen as an oxidant.…”

Transition Metal-Free Heteroarylation of Quinoxaline: Construction of Heteroaryl-Fused Phenazines by Oxidative Coupling

“…Therefore, there has been great interest in the development of efficient protocols for HFPs and HQs. Generally, the condensation reaction of 1,2-diketone derivatives with o -phenylenediamine has been used for the preparation of HFPs (Scheme a) − and HQs (Scheme b). , The Suzuki–Miyaura cross-coupling reaction has been carried out for the synthesis of some HQs as well. − However, direct (Scheme c) (and via its halogenated derivative) heteroarylation of quinoxaline with heteroaromatic Grignard reagents and lithioheteroaromatics has been reported. − Recently, an effective method has been reported for the synthesis of mono- and 2,3-disubstituted quinoxalines by AlCl 3 -mediated (hetero)­arylation of 2,3-dichloroquinoxaline. , The limitation of these methods is the necessity of preparation of suitable 1,2-diketones, halogen-containing heteroaryls, and arylboronic acids. Some phenazine derivatives can be successfully obtained by cyclization of 3-alkynyl-2-arylquinoxalines. − However, it is not possible to synthesize the derivatives in the present study by that method.…”