New synthetic methodologies to functionalize 3,4-dihydroquinoxalin-2-ones and 3,4-dihydro-1,4-benzoxazin-2-ones using visible-light photocatalysis

En aquesta tesi, es presenten diversos enfocaments sintètics per a la funcionalització en C-3 de 3,4-dihidroquinoxalin-2-ones i 3,4-dihidro-1,4-benzoxazin-2-ones mitjançant catàlisi fotoredox amb llum visible. La tesi es divideix en tres parts diferenciades, sent la primera una introducció general i els objectius principals. A continuació, en la segona part, es descriuen els esforços en la funcionalització nucleòfila de 3,4-dihidroquinoxalina-2-ones i 3,4-dihidro-1,4-benzoxazin-2-ones. Concretament, hem desenvolupat protocols sintètics per a la reacció de Friedel-Crafts entre 3,4-dihidroquinoxalin-2-ones i 3,4-dihidro-1,4-benzoxazin-2-ones amb indols i altres arenes rics en electrons (capítol 1). A més a més, vam identificar les condicions de reacció per a la reacció oxidativa asimètrica de Mannich mitjançant una combinació de catàlisi fotoredox i organocatàlisi (capítol 2). Així doncs, vam obtindre les condicions òptimes per a desenvolupar una estratègia per reaccionar 3,4-dihidroquinoxalin-2-ones amb pirazol-3-ones (capítol 3). L'última aportació en la part de funcionalització nucleòfila va ser l'alquinilació catalitzada per coure de 3,4-dihidroquinoxalin-2-ones amb alquins terminals (capítol 4). La tercera part d'aquesta tesi engloba la funcionalització electròfila de 3,4-dihidroquinoxalin-2-ones i 3,4-dihidro-1,4-benzoxazin-2-ones. Inicialment, vam desenvolupar un sistema catalític dual basat en la catàlisi fotoredox per a la reacció de Giese entre 3,4-dihidroquinoxalin-2-ones i alquens pobres en electrons (capítol 5). A continuació, vam presentar el nostre enfocament sobre l'aminació de 3,4-dihidroquinoxalin-2-ones i 3,4-dihidro-1,4-benzoxazin-2-ones amb azodicarboxilats de dialquil (capítol 6). Després, vam desenvolupar una reacció d'addició 1,2 de 3,4-dihidroquinoxalin-2-ones a trifluorometil cetones mitjançant catàlisi fotoredox a la llum visible (capítol 7). Finalment, es presenta una reacció d'addició 1,6 catalitzada per un catalitzador fotoredox orgànic de 3,4-dihidroquinoxalin-2-ones a p-quinona metins (capítol 8).In this thesis, several synthetic approaches for the C-3 functionalization of 3,4-dihydroquinoxalin-2-ones and 3,4-dihydro-1,4-benzoxazin-2-ones using visible-light photoredox catalysis are presented. The thesis is divided into three different parts, being the first one a general introduction and the main objectives. Then, in the second part, the efforts on the nucleophilic functionalization of 3,4-dihydroquinoxalin-2-ones and 3,4-dihydro-1,4-benzoxazin-2-ones with are presented. Specifically, we developed synthetic protocols for the Friedel-Crafts reaction between 3,4-dihydroquinoxalin-2-ones and 3,4-dihydro-1,4-benzoxazin-2-ones with indoles and other electron-rich arenes (chapter 1). Besides, we identified reaction conditions for the asymmetric oxidative Mannich reaction using a combination of photoredox catalysis and organocatalysis (chapter 2). Additionally, we could develop a strategy to react 3,4-dihydroquinoxalin-2-ones with pyrazol-3-ones (chapter 3). The last contribution in the nucleophilic functionalization part was the copper-catalyzed alkynylation of 3,4-dihydroquinoxalin-2-ones with terminal alkynes (chapter 4). The third part of this thesis encompasses the electrophilic functionalization of 3,4-dihydroquinoxalin-2-ones and 3,4-dihydro-1,4-benzoxazin-2-ones. Initially, we developed a dual catalytic system based on photoredox catalysis for the Giese reaction between 3,4-dihydroquinoxalin-2-ones and electron-poor alkenes (chapter 5). Thereafter, we presented our approach on the amination of 3,4-dihydroquinoxalin-2-ones and 3,4-dihydro-1,4-benzoxazin-2-ones with dialkyl azodicarboxylates (chapter 6). Then, we developed a 1,2-addition reaction of 3,4-dihydroquinoxalin-2-ones to trifluoromethyl ketones through visible-light photoredox catalysis (chapter 7). Lastly, an organophotoredox-catalyzed 1,6-addition reaction of 3,4-dihydroquinoxalin-2-ones to p-quinone methides is presented (chapter 8)

Recent Advances in Photocatalytic Functionalization of Quinoxalin-2-ones

Quinoxalin‐2(1H)‐one is an important class of nitrogen heterocycle in medicinal and pharmaceutical industry, which became a synthetic target in organic chemistry in recent years. This review covers the recent advances in the functionalization of this particular nitrogen heterocycle through photocatalysis

Copper-Catalyzed Aerobic Oxidative Alkynylation of 3,4-Dihydroquinoxalin-2-ones

Herein, we described a ligand-free copper-catalyzed aerobic oxidative functionalization of 3,4-dihydroquinoxalin-2(1H)-ones with terminal alkynes using visible-light and oxygen as terminal oxidant to give 3-ethynyl-3,4-dihydroquinoxalin-2(1H)-one, cyclic propargylic amines, in moderate to good yields. Moreover, we demonstrate the versatility of the 3-ethynyl-3,4-dihydroquinoxalin-2(1H)-ones obtained by preparing several 3,4-dihydroquinoxalin-2-one derivatives

Asymmetric Oxidative Mannich Reactions

The asymmetric Mannich reaction is one of the most straightforward methodologies for the enantioselective synthesis of chiral amines. In general, asymmetric Mannich reactions involve the use of imines as electrophiles. However, in recent years, several asymmetric oxidative Mannich reactions have been reported using amines as electrophiles. This review provides an overview of these recent publications, including the different oxidants used and the scope and limitations of the different catalytic systems

Catalytic Nucleophilic and Electrophilic Functionalization of Dihydroquinoxalin-2-ones

The functionalization at the C-3 position of 3,4-dihydroquinoxalin-2-one core has been significantly targeted over the last years. Several nucleophilic, electrophilic as well as radical catalytic functionalization of these nitrogen heterocycles have been reported. Usually, the more convenient methods are the direct photoredox functionalizations which use mild, green and sustainable conditions

Photocatalytic Giese Addition of 1,4-Dihydroquinoxalin-2-ones to Electron-Poor Alkenes Using Visible Light

The visible-light photoredox-catalyzed coupling of 1,4-dihydroquinoxalin-2-ones and Michael acceptors was achieved using Ru(bpy)3Cl2 as the photocatalyst and (PhO)2PO2H as an additive. The optimized reaction conditions provide a good yield for the radical conjugate addition products (44 examples) with a wide range of structurally different Michael acceptors. A gram scale reaction using sunlight irradiation is also described. Furthermore, several transformations were carried out with the Giese addition products

9,10-Phenanthrenedione as Visible-Light Photoredox Catalyst: A Green Methodology for the Functionalization of 3,4-Dihydro-1,4-Benzoxazin-2- Ones through a Friedel-Crafts Reaction

A visible-light photoredox functionalization of 3,4-dihydro-1,4-benzoxazin-2-ones through a Friedel-Crafts reaction with indoles using an inexpensive organophotoredox catalyst is described. The reaction uses a dual catalytic system that is formed by a photocatalyst simple and cheap, 9,10-phenanthrenedione, and a Lewis acid, Zn(OTf)2. 5W white LEDs are used as visible-light source and oxygen from air as a terminal oxidant, obtaining the corresponding products with good yields. The reaction can be extended to other electron-rich arenes. Our methodology represents one of the most valuable and sustainable approach for the functionalization of 3,4-dihydro-1,4-benzoxazin-2-ones, as compared to the reported procedures. Furthermore, several transformations were carried out, such as the synthesis of the natural product cephalandole A and a tryptophol derivative

Radical Addition of Dihydroquinoxalin-2-ones to Trifluoromethyl Ketones under Visible-Light Photoredox Catalysis

A visible-light photocatalytic radical addition reaction of dihydroquinoxalin-2-ones to trifluoromethyl ketones has been established using Ru(bpy)3Cl2 as photocatalyst, acetonitrile as solvent, and HP Single Blue LED as the source of light. The reaction provides a straightforward approach to the synthesis of dihydroquinoxalin-2-ones bearing a trifluoromethyl-substituted tertiary alcohol moiety in moderate to good yields under mild conditions

Organophotoredox 1,6-Addition of 3,4-Dihydroquinoxalin-2-ones to para-Quinone Methides Using Visible Light.

An organophotoredox 1,6-radical addition of 3,4-dihidroquinoxalin-2-ones to para-quinone methides catalyzed by Fukuzumi's photocatalyst is described under the irradiation of a HP Single LED (455 nm). The corresponding 1,1-diaryl compounds bearing a dihydroquinoxalin-2-one moiety (20 examples) are obtained with good to excellent yields under mild reaction conditions. Several experiments have been carried out in order to propose a reaction mechanism

A Combination of Visible-Light Organophotoredox Catalysis and Asymmetric Organocatalysis for the Enantioselective Mannich Reaction of Dihydroquinoxalinones with Ketones

An enantioselective photooxidative Mannich reaction of dihydroquinoxalinones with ketones by the merger of organophotoredox and asymmetric organocatalysis is described. This protocol features very mild reaction conditions using simple and cheap catalysts (Eosin Y and (S)-Proline) for the synthesis of chiral quinoxaline derivatives with good to high yields (up to 94%) and excellent enantioselectivities (up to 99% ee)