Exercise book on Aromatic Nitrogen Heterocycles Chemistry

Martine Demeunynck, Sabine Chierici

Description

Heterocyclic chemistry is one of the largest branches of chemistry. Heterocycles play major roles in important fields such as medicinal and pharmaceutical chemistries, agrochemicals or polymers. A good understanding of the comparative reactivity of simple five- and six-membered rings, i.e. pyrrole vs pyridine type rings, makes it possible to approach or predict the reactivity of more complex heterocycles.
This book is a compilation of exercises, mostly adapted from published works. For more clarity we have chosen to limit ourselves to nitrogen containing heterocycles. The book is mainly aimed to Master students, but it will also be of interest for anyone who wants to train in this important field of synthetic chemistry. The book is organized in five sections. In the first chapter, typical syntheses along with metal catalyzed pathways are presented. The two following chapters are devoted to the chemical reactivity of the six-membered (pyridine, quinoline, azines) and five-membered rings (pyrrole, indole, azoles). In these two chapters, the exercises of increasing difficulties focus on the main types of reactions, including electrophilic and nucleophilic aromatic substitutions, N-alkylation and N-arylation, lithiation and other organometallic reactions, and metal catalyzed cross-coupling reactions. In the fourth chapter, the principles discussed in the previous chapters will be applied to the chemistry of complex polycyclic heterocycles containing both five and six membered rings (pyrrolyl-pyridine, aza-indole, indolizine, purine).
The exercise solutions are commented in a separate chapter at the end of the book. Basic notions of nomenclature are given in a short appendix, allowing students to find out a ring structure from its name.

Abréviations.................................................................. .................................................. ...............7

Chapitre 1 Synthèses ................................................................ .................................................. ....11

1.1Les points-clés à retenir.................................................. .......................................11

1.2 Synthèses non catalysées par des métaux ....................................................... 13

1.3 Synthèses catalysées par des métaux ........................................................................24

Chapitre 2 Réactivité des hétérocycles à six chaînons...................................................... 35

2.1Points-clés à retenir ........................................................................................35

2.2 Réactions typiques......................................................................................36

2.3 Applications aux hétérocycles d'intérêt – Synthèses multi-étapes......................... 53

Chapitre 3 Réactivité des hétérocycles à cinq chaînons......................................... ...... 57

3.1Points-clés à retenir..............................................................................................57

3.2 Réactions typiques............................................................................................58

3.3 Applications aux hétérocycles d'intérêt – Synthèses multi-étapes............................ 68

Chapitre 4 Réactivité des polyhétérocycles contenant à la fois des cycles à cinq [1] et à six chaînons.................................73

4.1Points-clés à retenir.................................................................................73

4.2 Réactions...................................................................74

Chapitre 5 Réponses ..................................................................................99

5.1Synthèses........................................................................................................99

5.2 Réactivité des cycles à six chaînons................................................................ 132

5.2.1Points importants à garder à l'esprit .............................................................. 132

5.2.2 Réactions typiques..............................................................................133

5.2.3 Applications aux hétérocycles d'intérêt – Synthèses multi-étapes.............. 161

5.3 Réactivité des anneaux à cinq membres .......................................................167

5.3.1 Réactions typiques ................................................................................167

5.3.2 Applications aux hétérocycles d'intérêt – Synthèses multi-étapes ......................183

5.4 Réactivité des polyhétérocycles contenant à la fois des cycles à cinq et à six chaînons .188

Liste des livres et critiques .................................................. .............................................223

Annexe Notions de base de nomenclature ou comment trouver la bague structure de son nom .................................227

Sujets

• Chimie
• Science
• Chemistry
• Organic
• Sciences et techniques

Informations

• Publié par: EDP Sciences
• Date de parution: 09 mars 2023
• Nombre de lectures: 0
• EAN13: 9782759830824
• Langue: English
• Poids de l'ouvrage: 10 Mo

Extrait

Current Natural Sciences _____________

Sabine CHIERICI and Martine DEMEUNYNCK

Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

How to deal with the synthesis and reactivity of five- and six-membered rings

Printed in France

EDP Sciences – ISBN(print): 978-2-7598-3081-7 – ISBN(ebook): 978-2-7598-3082-4 DOI: 10.1051/978-2-7598-3081-7

All rights relative to translation, adaptation and reproduction by any means whatsoever are reserved, worldwide. In accordance with the terms of paragraphs 2 and 3 of Article 41 of the French Act dated March 11, 1957, “copies or reproductions reserved strictly for private use and not intended for collective use” and, on the other hand, analyses and short quotations for example or illustrative purposes, are allowed. Otherwise, “any representation or reproduction – whether in full or in part – without the consent of the author or of his successors or assigns, is unlawful” (Article 40, paragraph 1). Any representation or reproduction, by any means whatsoever, will therefore be deemed an infringement of copyright punishable under Articles 425 and following of the French Penal Code.

© Science Press, EDP Sciences, 2023

Preface

Heterocyclic chemistry is one of the largest branches of chemistry. Heterocycles play a major role in important fields such as medicinal and pharmaceutical chemistries, agrochemicals and polymers.

A combination of heterocycles from different classes, ring size and heteroatom type, gives a high degree of molecular and geometrical diversities, and therefore of biological, chemical and physical properties. However, from a chemical point of view, it appears that a good understanding of the comparative reactivity of simple five- and six-membered rings, i.e. pyrrole vs pyridine, makes it possible to approach or predict the reactivity of more complex heterocycles.

There is a number of excellent books dedicated to heterocyclic chemistry, but surprisingly very few specific exercise textbooks or e-books are available.

This book is mainly aimed at Master class students who want to apply their knowledge in heterocyclic aromatic chemistry, but it will also be of interest to chemists who want to train in this specific field of organic chemistry. The present book, mostly based on our Master courses, is a compilation of exercises. For more understanding, we have chosen to limit ourselves to nitrogen-containing heterocycles. The exercises of increasing difficulties cover a large range of reaction types.

The book is organized into five chapters. Examples of commonly used and well-known syntheses along with illustrations of metal-catalyzed reactions are presented in the first chapter. The two following chapters are devoted to the chemical reactivity of six- membered (pyridine, quinoline, azines) and five-membered rings (pyrrole, indole, azoles). The reactions are presented in the following order: electrophilic and nucleophilic aromatic substitutions,N-alkylation andN-arylation, lithiation and other organometallic reactions, to conclude with metal-catalyzed cross-coupling reactions and recent green approaches such as light-induced reactions. In the fourth section, the notions discussed in the previous chapters will be applied to complex polycyclic heterocycles containing both five- and six- membered rings (pyrrolyl-pyridines, azaindoles, indolizines, and purines).

DOI: 10.1051/978-2-7598-3081-7.c901 © Science Press, EDP Sciences, 2023

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

The solutions to the exercises are given in a separate section at the end of the book. If necessary, some comments underlying the observed reactivities are highlighted to help students.

Most of the exercises are adapted from published works, and we strongly suggest that students have a glance at the references given for deeper information. The books and review articles used to prepare this work are referenced in a separate list. As a bonus, basic notions of nomenclature are given in a short appendix, allowing students to find out a ring structure from its name.

Contents

Abbreviations.................................................................................................................. 7 Chapter 1 Syntheses...................................................................................................... 11 1.1 Key-points to remember ...................................................................................... 11 1.2 Non-metal-catalyzed syntheses ........................................................................... 13 1.3 Metal-catalyzed syntheses ................................................................................... 24 Chapter2 Reactivity of six-membered heterocycles.................................................. 35 2.1 Key-points to remember ...................................................................................... 35 2.2 Typical reactions ................................................................................................. 36 2.3 Applications to heterocycles of interest – Multi-step syntheses .......................... 53 Chapter 3 Reactivity of five-membered heterocycles7..................5............................... 3.1 Key-points to remember ...................................................................................... 57 3.2 Typical reactions ................................................................................................. 58 3.3 Applications to heterocycles of interest – Multi-steps syntheses ........................ 68 Chapter4 Reactivity of polyheterocycles containing both five- and six-membered rings............................................................................................... 73 4.1 Key-points to remember ...................................................................................... 73 4.2 Reactions ............................................................................................................. 74 Chapter 5 Answers........................................................................................................ 99 5.1 Syntheses ............................................................................................................. 99 5.2 Reactivity of six-membered rings...................................................................... 132 5.2.1 Important points to keep in mind.................................................................... 132 5.2.2 Typical reactions ............................................................................................ 133 5.2.3 Applications to heterocycles of interest – Multi-step syntheses ..................... 161 5.3 Reactivity of five-Membered rings.................................................................... 167

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

5.3.1 Typical reactions ............................................................................................ 167 5.3.2 Applications to heterocycles of interest – Multi-steps syntheses ................... 183 5.4 Reactivity of polyheterocycles containing both five- and six-membered rings. 188 List of books and reviews........................................................................................... 223 Appendix Basic notions of nomenclature or how to find out the ring structure from its name.............................................................................................. 227

Abbreviations

Acac: Acetylacetonate Adogen 464: Methyltrialkyl(C8-C10)ammonium chloride APTS: Para-toluenesulfonic acid BINAP: 2,2’-Bis(diphenylphosphino)-1,1’-binaphtyl

Bn: Benzyl Boc:tert-Butoxycarbonyl Bz: Benzoyl CAN: Ceric ammonium nitrate dba: dibenzylideneacetone CDI: 1,1’-Carbonyldiimidazole CHDA: 1,2-Diaminocyclohexane m-CPBA: meta-Chloroperbenzoic acid DABCO: 1,4-Diazabicyclo[2.2.2]octane DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE: 1,2-Dichloroethane DCI: 1,1'-Carbonyl diimidazole DDQ: 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DHP: Dihydropyran DIAD: Diisopropyl azodicarboxylate DIBAL-H: Diisobutylaluminium hydride DIPEA:N,N-Diisopropylethylamine

DIC:N,N-Di-Isopropylcarbodiimide

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DMA: Dimethylacetamide

Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

DMAD: Dimethyl acetylenedicarboxylate

DMAP: 4-(Dimethylamino)pyridine

DMF:N,N-Dimethylformamide

DMF-DMA:N,N-Dimethylformamide dimethyl acetal

Dppb: 1,4-Bis(diphenylphosphino)butane

Dppf: 1,1-Bis(diphenylphosphino)ferrocene EDCI:N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride HBTU: 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

HMDSA: Hexamethyldisilazane

HOBt:N-Hydroxybenzotriazole

KHMDS: Potassium bis(trimethylsilyl)amide

LDA: Lithium diisopropylamide

LiTMP: Lithium 2,2,6,6-tetramethylpiperidine

MSA: Methanesulfonic acid

NaHDMS: Sodium bis(trimethylsilyl)amide

NBS:N-Bromosuccinimide

NFSI:N-Fluorobenzenesulfonimide

NIS:N-Iodosuccinimide

NMP:N-Methylpyrrolidine

PIFA: Phenyl iodonium ditrifluoroacetate

Pin or Pinacol: 2,3-Dimethyl-2,3-butanediol

Piv-OH: Pivalic acid or trimethylacetic acid

POMCl: Pivaloyloxymethyl chloride

PyBrop: Bromo-tris-(pyrrolidino)-phosphonium hexafluorophosphate

Pyr.HBr 3 : Pyridinium tribromide

SEM: [2-(Trimethylsilyl)ethoxy]methylacetal

S-Phos: 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl

TBAF: Tetrabutylammonium bromide

TBAF: Tetrabutylammonium fluoride

TBAI: Tetrabutylammonium iodide