Exercise book on Aromatic Nitrogen Heterocycles Chemistry: How to deal with the synthesis and reactivity of five- and six-membered rings 9782759830824

Table of contents :
Preface
Contents
Abbreviations
Chapter 1 Syntheses
Chapter 2 Reactivity of six-membered heterocycles
Chapter 3 Reactivity of five-membered heterocycles
Chapter 4 Reactivity of polyheterocycles containing both five and six-membered rings
Chapter 5 Answers
Chapter 5 Answers
Appendix Basic notions of nomenclature or how to find out the ring structure from its name

Citation preview

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 sixmembered (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 and N-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 sixmembered 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 Chapter 2 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 heterocycles................................................. 57 3.1 Key-points to remember ...................................................................................... 57 3.2 Typical reactions ................................................................................................. 58 3.3 Applications to heterocycles of interest – Multi-steps syntheses ........................ 68 Chapter 4 Reactivity of polyheterocycles containing both fiveand 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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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

DMA: Dimethylacetamide 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.HBr3: Pyridinium tribromide SEM: [2-(Trimethylsilyl)ethoxy]methylacetal S-Phos: 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl TBAF: Tetrabutylammonium bromide TBAF: Tetrabutylammonium fluoride TBAI: Tetrabutylammonium iodide

Abbreviations

TBAHS: Tetrabutylammonium hydrogen sulfate TEMPO: 2,2,6,6-Tetramethylpiperidine-1-oxyl Tf2O: Trifluromethanesulfonic anhydride TFA: Trifluoroacetic acid TFAA: Trifluoroacetic anhydride Tfp: Trifurylphosphine THP: Tetrahydropyranyl TIPS: Triisopropylsilyl TIPSCl: Triisopropylsilyl chloride TMSOTf: Trimethylsilyl trifluromethanesulfonate TMEDA: N,N,N’,N’-Tetramethylenediamine TMPM: 3,4,5-Trimethoxybenzyl TosMic: N-Tosylmethylisocyanide Tr: Triphenylmethyl Ts: Tosyl Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (bidentate ligand)

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Chapter 1 Syntheses 1.1 Key-points to remember The synthesis of heterocycles requires the formation of C-C and C-N (C-O or C-S) bonds. Except for some specific syntheses, well-known, and mastered reactions of organic chemistry are implemented in the synthesis of heterocycles. The most commonly used reagents have the following features: 1) one or more electrophilic centers, such as ketones, aldehydes, β-diketones, β-ketoesteresters, cyano group, and the α,β-unsaturated analogs; 2) one or more nucleophilic centers such as amines, hydrazines, guanidines, ureas, arylamines, aminothiols, and oamino(thio)phenol; 3) both electrophilic and nucleophilic centers, such as aminoesters, or anthranilic ester. The most frequent reactions include the formation of imines, oximes, amides, and hydrazones for C-N bond formation, and involve imine-enamine and enol-ketone tautomerisms for the formation of C-C bonds. Michael additions are also largely used. For the ring construction, 5- and 6-membered rings are the easiest to form, and C-X bond formation (X = N, S or O) requires the reaction of a nucleophilic heteroatom with an electrophilic carbon. Friedel-Crafts-like reactions lead to benzene- or heterocycle-fused polycycles. More recently developed, the metal-catalyzed syntheses generally involve C-C and/or C-N couplings that are commonly used to modify existing heterocycles, such as direct arylation, Sonogashira, Suzuki or Heck reactions… Also, see the chapters devoted to the chemical reactivities of the different types of heterocycles, for more examples. Through the different exercises, we will come across some of the most conventional methods for the synthesis of heterocycles, from mono-cyclic to benzo- and heterocycle-fused polycycles. We will then exemplify more recent metal-catalyzed approaches through representative syntheses of fused five- and six-membered rings. DOI: 10.1051/978-2-7598-3081-7.c001 © Science Press, EDP Sciences, 2023

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

General reactions and tautomeric equilibrium

1 - Syntheses

13

* Note that a reaction may lead to a mixture of compounds or isomers. * Do not forget that, although it is not indicated, in most reactions, aqueous treatment is needed.

1.2 Non-metal-catalyzed syntheses

________

Exercise 1 ________

Compounds (1.1) to (1.5) are prepared from a mixture of carbonyls containing reagents and amines. Give their structures. Be careful that mixtures of products may be obtained.

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

________

Exercise 2 ________

This exercise highlights the determinant role of the reaction conditions (temperature, solvent, catalyst). The two isomeric methylquinolones (1.6) and (1.7) are obtained from the same two reagents, aromatic amine and ketoester. Give the structures of these reagents and propose the reaction conditions that will selectively give either (1.6) or (1.7).

________

Exercise 3 ________

Quinolines (1.8) and (1.9) are formed by the Skraup reaction, from aniline and acrolein (generated in situ from a glycerol-concentrated sulfuric acid mixture). Give the structures of the two compounds and justify your answer.

1 - Syntheses

15

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Exercise 4 ________

The 2-aminobenzo[b]furane yields (1.10) in the presence of 2-fluorobenzaldehyde in acidic conditions. Give the structure and name of (1.10).

_________

Exercise 5________

Give the structure of the compound (1.11) and indicate the mechanism involved during this synthesis.

________

Exercise 6________

Give the structure of the compound (1.12) and specify the role of pyrrolidine in the first step.

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

________

Exercise 7________

Give the structures of compounds (1.13) – (1.15), indicate the mechanisms involved during these three reactions and justify the regioselectivity.

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Exercise 8________

The isoquinoline ring can be prepared from the four benzene derivatives (1.16) to (1.19) using simple reagents and well-known reactions. Write the different reaction schemes, and specify if the reactions occur under acid or base catalysis.

1 - Syntheses

17

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Exercise 9________

Give the structure and name of (1.20).

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Exercise 10________

Give the structure of (1.21) and detail the mechanism of the reaction.

________

Exercise 11________

Give the structures of (1.22) and (1.23), both having the same empirical formula C15H10N2O3. Detail the mechanism of the reaction and justify possible difference(s) in the reactivity of the two starting pyridine derivatives.

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

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Exercise 12________

Give the structure of (1.24) and detail the mechanism involved in this reaction.

________

Exercise 13________

Give the structure of the bicyclic compound (1.25) and propose a mechanism. Name this bicyclic product.

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Exercise 14________

The compound (1.26) is prepared by the Leimgruber-Batcho reaction (analogous to the Reissert Reaction). Give the structure and propose a reaction mechanism. Note that pyrrolidine is used to activate DMF-DMA.

1 - Syntheses

19

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Exercise 15________

The compound (1.28) is prepared in two reaction steps. The first step is a four-component Ugi-Azide reaction yielding tetrazole (1.27). Give the structure of (1.28), and give the mechanisms of both steps.

________

Exercise 16________

The compound (1.29) is prepared in two-step one-pot procedure. Give the structure of (1.29) and detail the two steps. Name the final molecule.

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

________

Exercise 17________

The compound (1.31) is prepared by using the well-known Fischer reaction. Give the structure of (1.31) and of its intermediate (1.30). Detail the mechanism of formation of (1.31).

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Exercise 18________

The compound (1.32) is prepared in two steps from 2-methylpyridine and 2-bromo-2’nitroacetophenone, and then undergoes a Pictet-Spengler type reaction to give (1.33). Give the structure of (1.32) and (1.33), and detail the mechanisms of each step. Give the name of (1.33).

1 - Syntheses

21

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Exercise 19________

The two reactions proposed here are both related to indole functionalization. Reaction 1: The compound (1.35) is obtained by Pictet-Spengler cyclization of the indolopyrimidine (1.34) with benzaldehyde in acidic conditions. Propose a synthesis of (1.34) from 5-amino-3,6-dichloropyrimidine without using organometallic catalyzed reactions. Give the structure of (1.35).

Reaction 2: The reported synthesis of (1.36) also involves a Pictet-Spengler-type reaction. Propose a schematic pathway and justify your answer.

________

Exercise 20________

The compound (1.37) is a key-intermediate in the synthesis of amlodipine. Describe the reaction involved in the formation of (1.37) and detail the series of steps yielding amlodipine.

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

________

Exercise 21________

Give the structure of the compound (1.37), which is prepared by a three-component reaction. Give the name of this new ring.

________

Exercise 22________

The exercise describes a polymer-supported synthesis of the tri-substituted purine (1.39). Five reactants (Fmoc-protected alanine, 4,6-dichloro-5-nitropyrimidine, benzaldehyde, propylamine and pyrrolidine) are engaged in the different steps, using the reagents indicated below. Describe the different steps that are involved in the preparation of (1.39).

1 - Syntheses

23

________

Exercise 23________

Give the structures of the compound (1.41) and its intermediate (1.40). Note that (1.41) is an example of nitrogen-bridged heterocycles. Name (1.41).

________

Exercise 24________

Propose the synthetic scheme that will give the 4-methyl-3-phenylpyrrolo[1,2-a]pyrazine (1.42), using the reagents given below.

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

________

Exercise 25________

Describe the different steps in the preparation of the indolo[2,3-a]quinolizine (1.44) and its intermediate (1.43).

1.3 Metal-catalyzed syntheses In the following exercises, we will come across synthetic pathways in which metal catalysis is involved in the key-cyclization step and/or in the preparation of reactive intermediates. Despite the fact that a large range of metals has been successfully considered for this purpose, we will mainly focus on palladium and copper, with mention of other recent findings with gold for example. ________

Exercise 26________

Give the structure of the compound (1.45) and the name of this polycyclic ring.

________

Exercise 27________

The compound (1.48) is prepared in a one-pot reaction requiring two reactants, one of them being an aromatic amine. Give the structures of (1.46) and (1.47), and specify the type of reaction(s) involved.

1 - Syntheses

25

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Exercise 28________

The compound (1.50) is prepared in three steps as shown below. Give the structures of (1.49) and (1.50), and specify the type of reaction(s) involved. Pay attention that (1.50) is contaminated by traces of an isomeric by-product.

________

Exercise 29________

This exercise is related to the Hegedus synthesis. Give the structure of (1.51) and propose the mechanism of its formation.

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Exercise 30________

Give the structure of (1.52) and detail the reactions involved. The authors point out that the cyclization does not proceed if the acetamide is replaced by trifluoroacetamide or tosylamide.

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

________

Exercise 31________

The tetrahydrocarbazole is obtained by the reaction shown below. Propose the structure of the reactant (1.53) and detail the mechanism of this reaction.

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Exercise 32________

The isomeric tetracycles (1.57) and (1.58) are prepared from the same dihalogenated quinoline (1.54).

1 - Syntheses

27

1. Knowing that methanesulfonic acid (MSA) is used to promote the acid-mediated cycloisomerization of the 2-aryl-3-alkynyl quinoline intermediates (1.55) and (1.56), give the structures of these two intermediates. 2. The intermediates (1.55) and (1.56) are prepared in two steps from (1.54) using the reaction condition sets, A or B, indicated below. Propose the structure of (1.54), and specify which condition set leads to either (1.55) or (1.56). Justify your answers.

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Exercise 33________

The bicyclic compound (1.60) is prepared in three steps from 2-bromobenzaldehyde. Give the structure of the intermediate (1.59) and bicycle (1.60).

________

Exercise 34________

The compound (1.61) is prepared in a one-pot, two-step process. Give its structure and detail the successive reactions and mechanisms.

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

________

Exercise 35________

This exercise illustrates a solid-supported method for the preparation of azaindoles. The cyclization step is mediated by KOt-Bu.

________

Exercise 36________

The azaindole (1.65) is prepared from the 2-pyridone reactant below. Give the structure of (1.65) and its intermediate (1.64). Justify the regioselectivity of the reactions if necessary.

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Exercise 37________

Propose R1 and R2 substituents for reactant (1.66) that give the following oxoindole. Note that the cyclization-step involves an enolate formation.

1 - Syntheses

29

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Exercise 38________

Propose a structure for the 2-picoline derivative (1.67) that will allow the formation of the indolizine (1.68) precursor of monomorine alkaloid. Give the structure of (1.68) and detail the mechanism.

________

Exercise 39________

The following copper-catalyzed reaction is a route to (1.69). However, starting from the acetamide reactant (R = CH3) an alkylidenebenzoxazine by-product (1.70) is obtained. Give the structures of the two products and propose a mechanism.

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

________

Exercise 40________

The exercise describes a copper-catalyzed one-pot domino reaction. Give the structures of the intermediate (1.71) and the final polycycle (1.72).

________

Exercise 41________

The compound (1.73) is prepared in two steps from 2-bromoanisole. Give the structure of (1.73) and the type of reactions involved.

1 - Syntheses

31

________

Exercise 42________

The dibenzodiazepine (1.74) is prepared in one step. Give the structure of (1.74) and indicate the type(s) of reaction involved in this transformation.

________

Exercise 43________

A one-pot process starting from arylbromide and amidine yields quinazoline (1.75). Describe the products formed at each of the three steps and describe the types of reaction that are involved.

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

________

Exercise 44________

The method described in this exercise allows the preparation of poly-substituted indoles by using solid phase synthesis. Give the structures of (1.76) to (1.78). The key-step in the formation of (1.78) proceeds via the oxidative addition of Pd(0) to vinyl triflate prior to the formation of a π-palladium complex with the alkyne. Propose a mechanism for this step.

________

Exercise 45________

The reaction below involves a pre-complexation of Pd(0) to form an α-acylpalladium intermediate. The methodology has been applied to the synthesis of a non-acidic analog of non-steroidal anti-inflammatory drugs (1.80). Give the structures of (1.80) and its intermediate (1.79), and propose a mechanism.

1 - Syntheses

33

________

Exercise 46________

This synthesis involves alkynyl(phenyl)iodonium salt as electrophilic reagent. Give the structures of (1.81) and (1.82), and propose a mechanism for the cyclization step.

________

Exercise 47________

The indole (1.83) is prepared in one pot from o-propargyl arylamine and a terminal alkyne. Propose the mechanism of this gold-catalyzed transformation.

________

Exercise 48________

The three reactions shown below involve one or more copper-catalyzed oxidative aminations of the C(sp3)-H bond. Give the structures of compounds (1.84) to (1.86), and propose the corresponding reaction mechanisms. Note: When reactions 2) and 3) have been run in the presence of a radical scavenger such as TEMPO, neither (1.85) nor (1.86) have been formed.

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

________

Exercise 49________

Polycyclic phenazine has been obtained in high yield using the conditions indicated below. Give the structure of the starting reagent(s) and specify the type of reaction that is involved.

Chapter 2 Reactivity of six-membered heterocycles 2.1 Key-points to remember Representative types of six-membered heterocycles and benzo-fused analogs

DOI: 10.1051/978-2-7598-3081-7.c002 © Science Press, EDP Sciences, 2023

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

The six-membered ring is a 6π-electron aromatic system. The heteroatom lone pair is not involved in the aromatic sextet. Pyridine is weakly basic, each added nitrogen in the ring decreases basicity. There is a permanent polarization towards nitrogen (electron withdrawing effects by resonance -M and inductive effect -I). The six-membered rings are electron-poor systems: chemistry is dominated by the ease to undergo nucleophilic substitution, and the electrophilicity, at C-2 and C-4, governs regioselectivity. The ease of N-Alkylation and N-oxidation opens up the field of functionalization in six-membered ring chemistry. The chemistry is largely influenced by the existence of tautomeric or zwitterionic forms, especially with the hydroxy-substituted pyridines and analogs. * Note that a reaction may lead to a mixture of compounds or isomers * Do not forget that, although it is not indicated, in most reactions, aqueous treatment is needed

2.2 Typical reactions ________

Exercise 1 ________

In this exercise, we propose a series of reactions involving electrophilic substitutions. The reactions may yield mixtures of compounds.

2 - Reactivity of six-membered heterocycles

37

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

2 - Reactivity of six-membered heterocycles

________

39

Exercise 2 ________

The following synthetic pathway has been optimized to prepare 8-substituted isoquinoline derivatives in a regioselectively controlled manner. Propose the sequence of reactions yielding (2.19). Give the structure of (2.20), and justify the two-step conditions.

________

Exercise 3 ________

How would you regioselectively prepare the 2-, 4- or 3-aminoquinolines (2.21) to (2.23) from simple pyridines, including pyridine itself, hydroxypyridines, or pyridine carboxylic acids.

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

________

Exercise 4 ________

This exercise is related to the easiness of nucleophilic aromatic substitution (SNAr) in sixmembered rings. Order the following chloro-heterocycles from the most reactive to the least ones. Justify your answer.

________

Exercise 5 ________

Give the structures of (2.24) and (2.25), and justify your answers. Note that in both cases, the N-oxide remains in the products.

*Neat means that acid chloride is used as both solvent and reactant

2 - Reactivity of six-membered heterocycles

________

41

Exercise 6 ________

The following reaction implies a halogen-metal exchange. Give the structure of (2.26) and justify your answer.

________

Exercise 7 ________

Write the structure of (2.27) and the mechanism of its formation.

Note that the TFA step removes the t-Bu used as an amine protecting group. ________

Exercise 8 ________

Give the structure of (2.28) and the mechanism of its formation. The mechanism is similar to that in the exercise above.

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

________

Exercise 9 ________

The basic reactivities of pyridine N-oxide are explored in this exercise. Give the structures of (2.29) to (2.32), and detail the mechanism of the reactions.

________

Exercise 10 ________

Give the structures of (2.33) and (2.34) prepared by simple reactions from 4-nitropyridine N-oxide. Justify your answers.

________

Exercise 11 ________

Propose a mechanism to the formation of (2.35) via a three-component reaction.

2 - Reactivity of six-membered heterocycles

________

43

Exercise 12 ________

Propose a one-pot reaction, using simple reagents, to prepare the tri-cyclic (2.36). Note that (2.36) is in equilibrium with a bicyclic minor form.

________

Exercise 13 ________

The two following reactions involve Grignard reagents. Give the structures of (2.37) to (2.39) and discuss the mechanism involved for each reaction.

________

Exercise 14 ________

This one-pot procedure has been optimized to prepare 2-aminoaryl from the corresponding aryl N-oxide. Detail the mechanism of formation of (2.40).

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

________

Exercise 15 ________

The first reaction deals with the formation of the 2-chloro-6-deuteropyridine. The keystep involves an umpolung process. Give the structure of (2.41) and propose a mechanism. Note that the authors postulate the existence of a Lewis pair between a phosphonium salt and DABCO as key-intermediate. The method was applied to the derivatization of quinoxyfen pesticide. Give the structure of (2.42).

________

Exercise 16 ________

The following exercise is also related to quinoxyfen modification. The reaction is made in one pot. Give the structures of the intermediate (2.43) and the final compound (2.44). The chemical formula of (2.44) is C23H22Cl2FN3O2S.

2 - Reactivity of six-membered heterocycles

________

45

Exercise 17 ________

The sequence below is linked to the regioselective iodination of the 3,4dimethoxypyridine. Give the structure of (2.45) and (2.46). Pay attention to the regioselectivity issues of each step and justify your answers.

________

Exercise 18 ________

The following two exercises deal with similar photoinduced reactions. In both cases, the photocatalyst is the acridinium Mes-Acr+ ClO4-. Propose the mechanisms of reactions leading to (2.47) and (2.48).

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

________

Exercise 19 ________

The following reactions are based on the formation of guanidines by the reaction of an amine with the ethoxycarbonyl isothiocyanate followed by EDCI or HgCl2 catalyzed nucleophilic attack by a second amine. Give the structures of compounds (2.49) to (2.53), and justify your answers.

________

Exercise 20________

The 2-chloropyrimidine undergoes a series of reactions to give the tri-substituted pyrimidine (2.54). Give the structures of each intermediate and the final product, indicate the mechanism and justify the regioselectivity of each step.

2 - Reactivity of six-membered heterocycles

________

47

Exercise 21________

Give the structure of (2.55) and (2.56) issued from the reaction pathway described below.

________

Exercise 22________

Give the structure of (2.57) and indicate the type of mechanism involved in this reaction.

________

Exercise 23________

The reaction of the 2,6-diaminopyridine with vinamidinium salt gives the compound (2.58). Give the structure of (2.58) and propose a mechanism for this reaction.

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

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Exercise 24________

The 2-chloro-3,4-diiodopyridine (2.59) is prepared in a one-pot reaction. Propose the mechanism of this synthesis. The tri-substituted pyridine (2.60) is obtained by a series of three palladium cross-coupling reactions. Propose the structures of the aromatic partners and justify the order in which the reactions will take place.

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Exercise 25________

Give the structure of compounds (2.61) and (2.62) resulting from the two-step transformation of the 2,4,5-halogenopyrimidine. Justify the regioselectivity of each reaction.

2 - Reactivity of six-membered heterocycles

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Exercise 26________

Various palladium-catalyzed reactions are used to modify the 2-amino-3,5dibromopyrazine giving (2.63) and (2.65). (2.63) was further transformed into (2.64). Give the structures of each product, indicate the type of reaction used and justify the regioselectivity.

________

Exercise 27________

Give the structures of products (2.66) to (2.68) formed from the three diazine N-oxides.

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

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Exercise 28________

Give the structure of (2.69) and justify your answer. Pay attention to the reaction conditions.

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Exercise 29________

In this exercise, the starting reagent is 1,3-dichloroisoquinoline. Draw the structures of (2.70) to (2.72), and justify the regioselectivity and the type of reaction involved in the transformations.

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Exercise 30________

The following reaction involves easily available pyridine N-oxides. Give the structure of (2.73).

________

Exercise 31________

The Penicolinate C (2.74) has been prepared in three steps from 2,5-dibromopyridine and a diyne, using the reaction conditions indicated below. Propose a synthetic pathway, and justify the order in which the reactions are performed.

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Exercise 32________

Give the structure of (2.75) formed from 3,6-diiodopyridazine. Propose the stoichiometry of the first step, which is not indicated, and justify your answer.

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Exercise 33________

The two-step one-pot reaction of 2-aminopyridazine with 2-chlorobenzene sulfonyl chloride yields the tricyclic (2.76). Detail the two steps, and give the structure and name of the final product.

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Exercise 34________

Give the structure of the final product (2.78), and detail the different steps of the reaction scheme. Propose a method to prepare the 2,4-dimethoxy-6-iodoquinazoline (2.77) from the corresponding quinazoline dione.

2 - Reactivity of six-membered heterocycles

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Exercise 35________

The palladium-catalyzed coupling of uracil and pyridine N-oxide yields (2.79), which further reacts with PCl3 to give (2.80). Give the structures of (2.79) and (2.80) and discuss the mechanism(s) involved.

2.3 Applications to heterocycles of interest – Multi-step syntheses ________

Exercise 36________

Propose a mechanism for this three-component reaction yielding (2.81) and using Lproline as a catalyst.

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Exercise 37________

This multi-step reaction scheme has been designed to prepare the octacycle (2.82) from the commercially available ethacridine and phen-5,6-dione. Propose an efficient pathway to prepare this octacycle involving the key-intermediates (2.83) and (2.84) shown below. Note that several options are possible (justify your choice) and that the entire pathway is metal-free.

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Exercise 38________

The pyridine-pyrimidine heteroaryl (2.85) has been prepared from three aromatic reagents A-C in a multi-step procedure. The conditions used for the different steps are given below the scheme. Give the structures of each intermediate, and justify the order in which the reactions will take place. Note that 1) the synthetic pathway is sequential and may require the preparation of a keyintermediate, and 2) one step involves a Curtius rearrangement (thermal decomposition of an acyl azide to an isocyanate).

2 - Reactivity of six-membered heterocycles

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Exercise 39________

The 2,3-dichloroquinoxaline is the starting point of a series of polycyclic benzo[a]phenazines such as (2.88). The transformation of (2.86) into (2.87) is the keystep of the pathway. The last step, i. e. the formation of (2.88), gives you a clue to find the structure of (2.87). Give the structures of (2.86) and (2.87), and detail the mechanism of formation of (2.87).

Chapter 3 Reactivity of five-membered heterocycles 3.1 Key-points to remember Main types of five-membered heterocycles

The five-membered ring is a 6π-electron aromatic system. The heteroatom lone pair is part of the aromaticity; pyrrole and indole are not basic. There is an electron donation into the ring by resonance +M and an electronwithdrawing effect by inductive -I. The five-membered rings are electron-rich systems: chemistry dominated by the ease to undergo electrophilic substitution. Pyrrole and indole may also undergo N-alkylation under basic catalysis. Lithiation occurs preferentially at the C-2.

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* Note that a reaction may lead to a mixture of compounds or isomers * Do not forget that, although it is not indicated, in most reactions, aqueous treatment is needed

3.2 Typical reactions ________

Exercise 1 ________

Compounds (3.1) and (3.2) are prepared from a common reagent, the 4(5)-ethylimidazole. Give their structures.

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Exercise 2 ________

Propose two strategies to regioselectively prepare either the 5-ethyl-1-methylimidazole (3.3) or the 4-ethyl-1-methylimidazole (3.4) from 4(5)-methylimidazole. You can use the following reagents: ICH3, Boc2O, NaH, and TrCl. Note: You have to play with protecting groups to solve the problem.

3 - Reactivity of five-membered heterocycles

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Exercise 3 ________

Give the structures of (3.5) and (3.6) prepared by acetylation of indole.

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Exercise 4 ________

Propose a mechanism for the formation of (3.7) from 1-methylimidazole.

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Exercise 5 ________

Give the structures of compounds (3.8) and (3.9), and detail the mechanism involved in the reactions.

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

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Exercise 6 ________

Give the structure(s) of (3.10) and justify the regioselectivity.

________

Exercise 7 ________

Give the structure(s) of (3.11) and (3.12), resulting from the nitration of 2-methylindole (R = CH3). Indicate what is happening in the same conditions with indole (R = H). Noting that five-membered rings are prone to polymerization in strongly acidic conditions, consider this side-reaction as well as nitration.

________

Exercise 8 ________

Give the reaction conditions required to prepare (3.13), using I2 and KOH as iodinating reagents.

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Exercise 9 ________

Propose a simple procedure to regioselectively prepare the 3-bromopyrrole (3.14), using NBS as nitrating agent.

________

Exercise 10 ________

Give the reaction conditions and discuss the mechanism used to prepare gramine (3.15) from indole. Detail the reactions yielding tryptophane (3.16).

________

Exercise 11 ________

Give the structures of compounds (3.17) to (3.19) prepared from imidazole, and justify the regioselectivity, if necessary.

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Exercise 12 ________

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Exercise 13 ________

Give the structure of (3.20).

Give the structure of (3.21), which is formed by a radical reaction involving Langlois's trifluoromethylation reagent (CF3SO2Na).

________

Exercise 14 ________

Give the structure of (3.23) prepared in three steps from 1,3-thiazolidine-2,4-dione. Its formula is C4H5NOS. Discuss the mechanism involved in the first step to form (3.22).

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Exercise 15 ________

Starting from 4-methyl[1,3]thiazole, a two-step reaction yields the bicyclic unstable intermediate (3.24) that undergoes a spontaneous rearrangement to form (3.25). Give the

3 - Reactivity of five-membered heterocycles

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structure of (3.24) and (3.25), and detail the mechanisms involved in these transformations.

________

Exercise 16 ________

Give the structure and the name of (3.26), which is formed from 2-amino[1,3]thiazole.

________

Exercise 17 ________

Give the structure and the name of (3.27). Justify your answer.

________

Exercise 18 ________

The procedure described here has been designed to achieve the regioselective alkylation of histidine methyl ester. Write the structures of (3.28) and (3.29). Note that CDI is a coupling agent useful to prepare esters, amides or carbamates.

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Exercise 19 ________

In this exercise, we explore the formation and reactivity of lithiated methoxyindoles. Give the structures of (3.30) to (3.34), and explain the differences of reactivity depending on the conditions and nature of N-group (Me vs SO2Ph). Propose the reaction conditions used to prepare (3.33) from 5-methoxyindole.

________

Exercise 20________

Give the structure of (3.35), and justify your answer.

3 - Reactivity of five-membered heterocycles

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Exercise 21 ________

This example is related to electrophile-controlled regioselectivity. Give the structures of (3.36) and (3.37), and justify your answer.

________

Exercise 22 ________

Propose the structure of (3.38), and detail its preparation from pyrrole.

________

Exercise 23 ________

Propose the structure of the indole reagent (3.39).

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Exercise 24 ________

Give the structures of the different products (3.40) to (3.43). Justify the regioselectivity of the different steps.

________

Exercise 25 ________

How would you regioselectively prepare (3.44) from pyrrole, knowing that direct chlorination of pyrrole leads to a complex mixture? The following reagents are used: NBS (1 eq.), NIS (1 eq.), BuLi (1 eq.), and C2Cl6 (for chlorination). Justify your answer. Then give the structures of the intermediate (3.45) and the final compound (3.46). Justify your answers.

3 - Reactivity of five-membered heterocycles

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Exercise 26 ________

Give the structure of (3.47). Detail the reaction conditions that are generally used to substitute Br or I by RNH2 in five-membered rings and justify the regioselectivity.

________

Exercise 27 ________

The reaction of (3.48) with Pd(0) catalyst may lead to (3.49) and/or (3.50) depending on the reaction conditions. Propose a structure for (3.48) and specify the types of reaction yielding each compound. Note that (3.48) has the formula C23H22INO4.

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Exercise 28 ________

The compound (3.51) is a regioisomer of the starting pyrrole reagent. Explain the mechanism involved in its formation.

3.3 Applications to heterocycles of interest – Multi-steps syntheses

We will now present a few examples of multi-steps chemical modifications of fivemembered rings. Note that exercises 29 to 31 deal with the lamellarin family (general structure (3.52) depicted below), which constitutes an important and broad class of alkaloids, reflected by the large number of publications related to their chemical synthesis. ________

Exercise 29 ________

To start with this first exercise, propose a route to the preparation of pyrrole (3.53) from pyrrole-2-carboxylic acid. Lamellarin (3.52) was prepared in four steps from the set of compounds (3.53) to (3.56). Propose the step sequence. Note that the order in which you will make the different steps is important.

3 - Reactivity of five-membered heterocycles

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Exercise 30 ________

Propose a structure for (3.57), a precursor of the lamellarin structure below, and indicate the type of reactions involved. Note that (3.57) has a tri-substituted pyrrole core and does not bear any halogen.

________

Exercise 31 ________

Propose the structures of the pyrrole derivatives (3.58) and (3.59), and justify the regioselectivity. Pay attention to the bromination conditions and consider the structure of the final lamellarin (3.60). Then suggest the reaction chain that will yield (3.60), using the indicated reactants.

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Exercise 32 ________

Give the structures of compounds (3.61) to (3.63), and indicate the type of reaction involved in the first step. Justify the regioselectivity, if necessary.

3 - Reactivity of five-membered heterocycles

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Exercise 33 ________

In this exercise, a vinyl group is used to protect the imidazole N-H. The synthesis of the final bicyclic (3.65) involves several steps and goes through (3.64) as the key intermediate. This exercise illustrates well differences in reactivity of the three C-H positions of pyrrole. Propose the sequence of reactions that leads to (3.64), then to (3.65) using the reagents given below. Note that a reagent can be used more than once. Give the name of (3.65).

Chapter 4 Reactivity of polyheterocycles containing both five- and six-membered rings 4.1 Key-points to remember

Typical rings that will be studied in this chapter

We will exemplify the chemistry of systems containing both five- and six-membered rings, going from simple pyrrolyl-pyridine (or similar azolyl-azines), in which the two rings are linked through a direct C-C bond or a polymethylenic linker, to different types of fusedheterocycles. Azaindoles, purines, and indolizines were chosen as fused rings. Azaindoles are constituted of a pyrrole fused to a pyridine. The pyridine nitrogen may be found at positions 4 to 7 (7-azaindole or pyrrolo[2,3-b]pyridine is shown here). Azaindoles have both a pyridine-type and a pyrrole-type nitrogen. They belong to a larger family of bicyclic compounds containing several nitrogens, on either ring, such as purines. Indolizine is one of the simplest bicycles having ring-junction nitrogen, it is an isomer of indole.

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Note the very peculiar numbering of the purine ring that does not follow the general nomenclature rules. In a general way, in these bicyclic systems each individual cycle retains its own reactivity: -

Electrophilic substitutions will mainly occur on the pyrrole-type ring, and nucleophilic substitutions on the pyridine-type ring.

-

Alkylation regioselectivity will depend on the presence or absence of base as deprotonation of pyrrole N-H is required for alkylation, unlike pyridine-type nitrogen, which easily reacts with alkylating agents.

* Note that a reaction may lead to a mixture of compounds or isomers * Do not forget that, although it is not indicated, in most reactions, aqueous treatment is needed

4.2 Reactions ________

Exercise 1 ________

Compound (4.2) is prepared from the bicyclic reactant (4.1). Indicate how you would prepare (4.1) from imidazole and pentafluoropyridine. Remember that SEM (trimethylsilylethoxymethyl) is a protecting group. Propose the different steps leading to (4.2) using the reagents indicated below the scheme. Justify the regioselectivity and the mechanisms involved in each step.

4 - Reactivity of polyheterocycles containing both five- and six-membered rings

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Exercise 2 ________

The following synthetic pathway has been designed to prepare 18F radioligand (4.6) from the 7-bromopyrido[4,3-b]indole. 1) Propose the reaction conditions for preparing N-Boc derivative (4.3) from 7bromopyrido[4,3-b]indole. 2) Give the structure of (4.4) to (4.6), and detail the mechanism(s) involved at each step. Justify the regioselectivity if necessary. Note that (4.5) is a salt, and the chemical formula of (4.6) is C16H1018FN3.

3) The unlabeled analog of (4.6) has been transformed in three steps into the cationic (4.7). Describe the different steps, and justify the regioselectivity.

________

Exercise 3 ________

Compound (4.8) is the common intermediate to the synthesis of (4.9) and (4.10). Describe the two synthetic pathways using the indicated reagents, and indicate the type of reaction involved in each step.

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Exercise 4 ________

This exercise exemplifies the reactivity of the 7-azaindole in various reaction conditions. 1) Give the structures of (4.11) to (4.13) and justify the regioselectivity of each reaction.

2) Propose simple reaction conditions (one or two steps) for the regioselective formation of (4.14), and of 7-methyl- or 1-methylazaindole (4.15) and (4.16), respectively.

4 - Reactivity of polyheterocycles containing both five- and six-membered rings

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Exercise 5 ________

In this exercise, the influence of directing group on lithiation regioselectivity is compared. Give the structure of (4.17) to (4.22). Note that a directed metalation-group dance is involved in the reaction leading to (4.21).

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Exercise 6 ________

1,4,5,6-Tetrasubstituted azaindoles (4.23) and (4.24) are prepared in several steps from 7azaindole. Propose the two pathways leading to these compounds using the reagents indicated below the scheme. Note that one or more reagent(s) may be used more than once. Note that both the compounds are prepared from a common intermediate.

________

Exercise 7________

The N-protected 5-methoxy-4-azaindole (4.25) is the starting material to prepare 2- and 5substituted 4-azaindoles. 1) Give the structures of (4.26), (4.28) and the intermediate (4.27).

4 - Reactivity of polyheterocycles containing both five- and six-membered rings

79

2) The same intermediate (4.27) is used for the synthesis of (4.29). Give the structure of the reactant and the type of reaction involved.

________

Exercise 8________

Compound (4.30) is prepared in three steps from 5-azaindole and 2-amino-4chloropyrimidine. Propose a pathway taking into account that there is only one metalcatalyzed Suzuki reaction.

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Exercise 9________

This exercise illustrates the reactivity of the pyrrole ring in azaindoles. 1) 4-Bromo-2-methyl-7-azaindole (4.31) is prepared from 4-bromo-7-azaindole. Propose a synthetic pathway and justify your answer.

2) Give the structure of (4.32), and detail the mechanism(s) if necessary.

________

Exercise 10________

Fused-tetracycle (4.36) is prepared in several steps from the bicyclic 4-bromo-7-methoxy6-azaindole. Detail the different steps of the synthetic pathway, giving the structures of each intermediate and discuss the regioselectivity and the reaction mechanisms.

4 - Reactivity of polyheterocycles containing both five- and six-membered rings

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Exercise 11________

Pentasubstituted 7-azaindoles such as (4.38) may be prepared in several regioselective steps from the trihalogeno azaindole (4.37). 1) Comment on the synthesis of (4.37) from the 5-bromo-7-azaindole, justify the regioselectivity. 2) Give the structure of (4.38), and detail the different steps using the reaction conditions mentioned below the scheme. Pay attention to the reaction conditions to find out in which order the reactions will be done.

________

Exercise 12________

This exercise deals with the regioselectivity of direct arylation of 6- or 7-azaindoles. Reactions of 1-methyl-6- and 1-methyl-7-azaindoles with halogenoaryls give respectively (4.39) and (4.40).

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Compound (4.40) was further modified by treatment with Zn dust in the presence of NH4Cl, and a second arylation step to give (4.42). Give the structures of (4.39) to (4.42). Justify the observed regioselectivity.

________

Exercise 13________

The present exercise describes the synthesis of variously substituted tricyclic pyrido[3’,2’:4,5]pyrrolo[1,2-c]pyrimidine from 7-azaindoles. This fused tricyclic heterocycle is found in alkaloids such as the variolin family.

4 - Reactivity of polyheterocycles containing both five- and six-membered rings

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1) Propose a synthetic pathway to prepare (4.43) from the 7-azaindole, and give the structure of (4.44).

2) The cyclization reaction of (4.44) with either the N-tosylmethylisocyanide (TosMIC) or its N-tosylmethyl dichloroformimide analog gives the third ring but differently substituted, formation of (4.45) and (4.46) respectively. Give the structures of (4.45) and (4.46), and propose the mechanism of their formation.

________

Exercise 14________

The tricyclic pyrido[3’,2’:4,5]pyrrolo[1,2-c]pyrimidine (4.51) may be obtained by the pathway given below. Give the structures of (4.47) to (4.50), and comment on each step.

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Exercise 15________

These two exercises deal with the stability of the purine rings in basic conditions. 1) The ribofuranosylpurine treated in aqueous basic conditions gives the 5,6diaminopurine (4.52) and releases D-ribose. Propose a mechanism to rationalize this reaction.

2) N9-Benzyladenine is treated with hydrogen peroxide and an alkylating agent (bromopropane). The resulting compound (4.53) quickly reacts at pH > 7.6 to give a mixture of two compounds (4.54) and (4.55). Note that heating (4.54) in the presence of deuterated formic acid gives the deuterated (4.55)-D. Give the structure of the four compounds and detail the mechanism(s) involved in the different steps.

4 - Reactivity of polyheterocycles containing both five- and six-membered rings

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Exercise 16________

Heteromines (4.57) and (4.58) are polymethylated guanines prepared from O6methylguanine (4.56). Using the reagents given below the scheme, propose two pathways allowing the formation of each compound with the highest possible regioselectivity. Give the structure of any possible side-product. Note that a reagent may be used more than once.

________

Exercise 17________

The 2,3,5-tri-O-acetylguanosine below is the starting point to access to amino-chloro-, dichloro-, amino-hydroxy- or diamino- purine nucleosides (4.59) to (4.64). 1) Indicate which conditions may be used to prepare the 2-amino-6-chloro purine (4.59) from the protected guanosine.

2) Propose reaction schemes to access (4.60) to (4.64) using the reagents indicated below the scheme. Justify the regioselectivity if necessary. Note that the reactions are metal-free, and that all compounds derive directly from (4.59) or from each other.

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Exercise 18________

The exercise illustrates the importance of the purine substituent pattern on the reactivity. Give the structures of (4.66), (4.68), and (4.70) obtained from (4.65), (4.67), and (4.69), respectively. In the three reactions, the first step is realized in identical conditions. Discuss the mechanism(s) of each reaction. Note: C2Cl6 is used as an electrophilic chlorinating agent.

4 - Reactivity of polyheterocycles containing both five- and six-membered rings

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Exercise 19________

The regioselective alkylation of purine is challenging. This exercise shows an elegant strategy. 6-Chloropurine is transformed in five steps into the mono-alkylated purine (4.71). Describe each step and justify the regioselectivity of each reaction leading.

________

Exercise 20________

The three synthetic pathways below have been designed to regioselectively prepare diazepinopurines. 1) Describe the different steps leading to the diazepinopurine (4.74) from 6chloropurine.

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

2) Give the structure of diazepinopurine (4.76) obtained from (4.75) in two steps. Detail each step.

3) Compound (4.78) is prepared in two steps from the 3-protected adenine (4.77). Give the structure of (4.78) and detail the mechanism(s) of reaction. Note that TMPM is the acid labile 3,4,5-trimethoxyphenylmethyl protecting group.

________

Exercise 21________

The N-9 protected dihalogenopurine (4.79) is transformed via a series of steps into the trisubstituted purine (4.82). Give the structures of (4.82), of the intermediates (4.80) and (4.81), and comment on each step (in terms of regioselectivity, and reaction conditions).

4 - Reactivity of polyheterocycles containing both five- and six-membered rings

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Exercise 22________

The following two reaction pathways illustrate a different type of purine reactivity. Give the structures of the (4.83) to (4.85), and comment on each step (regioselectivity, type of reaction).

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

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Exercise 23________

The preparation of 2,6,8-trisubstituted purines is of major importance in the field of medicinal chemistry. Cross-coupling reactions have opened the way to a wide range of new molecules. The following three-step process gives (4.86). Give the structure of (4.86) and of each intermediate. Justify the regioselectivity. Note, the two first steps are made in one pot.

________

Exercise 24________

The cyclic tetrameric compound (4.94) is prepared from the protected purines (4.87) and (4.88) through a series of regioselective halogenation and Pd-catalyzed reactions. Give the structures of each intermediate, and comment on the regioselectivity and type of reactions involved.

4 - Reactivity of polyheterocycles containing both five- and six-membered rings

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Exercise 25________

The fused-pentacycle (4.95) is prepared in three steps from the 6-methylpurine. Indicate the order in which the different steps will be performed, and specify the type of reaction that is involved.

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

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Exercise 26________

This exercise deals with regioselective palladium-catalyzed N- or CH arylation reactions. The two-steps process leading to (4.98) from protected adenine (4.96) may be realized in one pot as exemplified by the formation of (4.99). Give the structure of (4.97) to (4.99). Pay attention to the nature of the aryl halide and of the reagents used at each step.

________

Exercise 27________

This exercise deals with the reactivity of quinazoline (or pyrrolo[1,2-a]pyridine). Give the structures of (4.100) to (4.105). Justify your answers. The first reaction with acetyl chloride occurs in very mild conditions, indicate what compound will be obtained in harsher conditions.

4 - Reactivity of polyheterocycles containing both five- and six-membered rings

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Exercise 28________

The tri-substituted indolizines (4.106) and (4.108), which differ by the nature of the group at C-7, are modified to give (4.107) and (4.109), respectively. 1) Give the structure of (4.107) and (4.109) by justifying your answers.

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

2) Polysubstituted indolizines are generally prepared by ring synthesis. Propose a synthetic pathway to (4.106) and (4.108) from the reactants shown below.

________

Exercise 29________

Bicyclic reactants (4.110a,b) give in two steps (4.111a,b). However, (4.111a) may also be obtained in only one step in 97% yield. Name the bicyclic initial ring involved in these reactions. Give the structures of (4.111a,b), and detail the mechanisms involved in the two pathways justifying the regioselectivity and the difference in yields observed for the three reactions.

4 - Reactivity of polyheterocycles containing both five- and six-membered rings

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Exercise 30________

The imidazolopyrimidines (4.112) and (4.113) react with morpholine to give the same compound (4.114).

In a separate reaction, the ethyl ester (4.113), treated in basic conditions yields (4.115), which is directly engaged in the last reaction to form (4.116).

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

Give the structures of (4.114) to (4.116), and propose the mechanism of the formation of (4.115) from (4.113). Note that (4.114) and (4.116) have the same molecular formula but neither the same NMR spectra nor the same TLC rf (retention factor). ________

Exercise 31________

This exercise is related to the preparation of fused-tricyclic heterocycles from indolizines. 1) Give the structure of (4.117), and detail the mechanism of formation.

2) The indolizine (4.118) is prepared from the drawn pyridinium salt. Give the mechanism involved in this reaction. Then propose a mechanism to explain the formation of the fused-tricycle (4.119) and detail its further transformations into (4.120).

3) In this third scheme, (4.124) is prepared from the indolizine (4.121) by successive transformations. Give the structure of each intermediate, and explain the different steps.

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Chapter 5 Answers 5.1 Syntheses

________

Exercise 1 ________

The following series correspond to the reactions of carbonyl-containing reagents with amines. A mixture of two isomers is obtained in the case of (1.1). The reaction is driven by the formation of stable hydrazones. Remember that the amino group of hydrazine is highly nucleophilic due to the so-called α-effect.

Note 1: If hydrazine hydrate, NH2NH2.H2O, is used instead of methylhydrazine, two tautomers in equilibrium are obtained. Note 2: If one of the alkyl groups of the diketone is replaced by phenyl or H, the resulting carbonyl will be more electrophilic, and therefore more reactive to the nucleophilic attack, leading to one major isomer.

DOI: 10.1051/978-2-7598-3081-7.c005 © Science Press, EDP Sciences, 2023

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

Note: Thiourea or urea may be used instead of guanidine, thus giving respectively the 2oxo or 2-thione analogues of 2-aminopyrimidine (1.2). To achieve this reaction leading to (1.3), the azeotropic removal of water is required at the first step to form the enamine intermediate.

See Bobbitt J.M. et al. Chem. Commun, 1968, 1429. This reaction mainly gives the six-membered pyridazine (1.4), however, a concurrent PaalKnorr process yields the 1-aminopyrrole as a minor side-product.

Hantzch reaction leads to (1.5). The aldol reaction between the enolate formed in situ and the aldehyde gives an enone. This enone reacts with the second equivalent of enolate via Michael addition. The formed 1,5-diketone then undergoes cyclization with ammonia.

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101

Note: To prepare non-symmetrical pyridines, preformed enamines may be used. ________

Exercise 2 ________

The two isomeric methylquinolones (1.6) and (1.7) are prepared from aniline and βketoester. The 4-quinolone (1.6) is obtained by the Conrad-Limpach reaction, in which the imine (Schiff base) formation at room temperature precedes the 6π-electron cyclization of the keto-enol tautomer at high temperature (over 250°C). Removal of water using azeotropic solvents (toluene, benzene) is often used to favor Schiff base formation. The 2-quinolone (1.7) is prepared using the Knorr reaction. The amide is formed first upon heating, before acid-catalyzed cyclisation.

________

Exercise 3 ________

The Skraup reaction leading to the formation of (1.8) and (1.9) involves 1,4-Michael addition followed by aromatic electrophilic substitution of the benzene ring by the

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carbonyl group. The obtained 1,2-dihydroquinoline is then oxidized by air in presence of nitrobenzene. The regioselectivity is governed by the effect of the nitro or methoxy substituent. Electrondonor group (R = OMe) favors reaction at para position giving (1.9). The deactivating effect of electron-withdrawing substituent (R = NO2) will be less pronounced at the ortho position, thus favoring the formation of (1.8).

________

Exercise 4________

Compound (1.10) is formed by the acid-catalyzed electrophilic substitution at C-3 followed by intramolecular nucleophilic substitution of the fluorine by the amine.

________

Exercise 5________

Compound (1.11) is obtained by a Conrad-Limpach reaction, a two-step procedure as discussed above (exercise 2). The key information for choosing between Conrad-Limpach or Knorr reaction is the high temperature required for the cyclization.

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103

Adapted from Pou S. et al. Org. Process Res. Dev. 2021, 25, 1841. ________

Exercise 6________

In this exercise, pyrrolidine activates the α,β-unsaturated aldehyde by forming a highly reactive iminium salt. Michael nucleophilic attack by the amine forms the enamine that cyclizes to give the dihydroquinoline (note that the iminium intermediate is hydrolyzed in situ by the water molecule released during the cyclization process). The second step is the oxidation to the fully aromatic quinoline (1.12).

See Liu G.-S. et al. Org. Lett. 2008, 10, 5393. ________

Exercise 7________

The three compounds are prepared by the Friedländer reaction, which is very useful for the synthesis of quinolines or in the present case [1,8]naphthyridines. The main advantage of this base-catalyzed synthesis is that it is compatible with acid sensitive substituents, as shown by the formation of (1.15). Its major drawback is probably

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that unsymmetrical ketones give two isomeric products, such as (1.13) and (1.14) in the first illustration. The modification of the starting ketone, by introducing a phosphonate at the α-carbon, allows the control of the enolate formation, and therefore dramatically changes the regioselectivity, with the formation of (1.14) as the sole product. The phosphonate also plays the role of a good leaving group like in the Horner–Wadsworth–Emmons reaction.

See Yasuda N. et al. J. Org. Chem. 2004, 69, 1959 and Hsiao Y. et al. Org. Lett. 2001, 3, 1101. ________

Exercise 8________

The Pomeranz-Fritsch reaction, from benzaldehyde (1.16), requires an amino-containing reagent as the 2-aminoacetaldehyde diethyl acetal, unlike the Schlittler-Muller reaction from (1.18) for which the amine is carried by the aromatic ring, and that necessitates aldehyde containing reagents. For these two reactions, imines are formed as the first step using an azeotropic solvent or drying reagent.

In the Pictet-Spengler from (1.19), formaldehyde is used either as an aqueous solution or under its polymeric form (paraformaldehyde for example). In the reaction designed by Boger et al., starting from benzyl bromide (1.17), a nucleophilic substitution by an aminoacetaldehyde (or its acetal analogue) under basic conditions is required to introduce the amine group. To achieve this step in high yield, the para-toluenesulfonyl-activated amine is used.

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105

For the four reactions, the cyclization into isoquinoline is achieved upon heating in acid solutions. In the Boger reaction, the para-toluenesulfonyl group is cleaved during this step (see Boger D. L. et al. Tetrahedron 1981, 37, 3977). Note that, in the Pictet-Spengler reaction, the cylization of the iminium intermediate requires the presence of an electron-donating group (such as OCH3) at the para-position, and yields the tetrahydroisoquinoline. An oxidation step is then needed to afford the isoquinoline ring.

________

Exercise 9________

The intramolecular cyclization proceeds via the intermediate formation of an oxonium cation.

The name is Ethyl 3‐methylpyrrolo[2,1‐a]isoquinoline‐2‐carboxylate. For more examples, see Leonardi M. et al. J. Org. Chem. 2017, 82, 2570.

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________

Exercise 10________

The intramolecular cyclization proceeds via a Bischler-Napieralski type reaction, in which the electrophilic nitrilium intermediate is generated after the reaction of the amide with triflic anhydride instead of the more common POCl3 activation.

________

Exercise 11________

The formation of (1.22) and (1.23) involves a tandem Michael addition – SNAr basecatalyzed reaction. The intermediate formed during the synthesis of (1.22) is shown below. The temperature required for the formation of (1.23) is higher than that required for (1.22). This may be due to the much lower reactivity of the 3-chloro position against nucleophilic substitution, compared to that of the 2-chloro. Indeed, the 3-chloro position would not react under intermolecular conditions.

________

Exercise 12________

During the first step, the Pictet-Spengler reaction (imine formation then cyclization) yields the tetrahydrocarboline intermediate that is easily aromatized by heating under an oxygen atmosphere.

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107

Note: Remember that nucleophilic substitution is not favored with five-membered rings, and furthermore bromine is not a good leaving group. ________

Exercise 13________

The formation of (1.25) may be explained by the acid-catalyzed imine formation followed by 6-exo-dig cyclization on the triple bond. The 3,4-dihydropyrrolo[1,2-a]pyrazine thus formed isomerizes to the more thermodynamically stable pyrrolo[1,2-a]pyrazine (1.25).

See Alfonsi M. et al. Eur. J. Org. Chem. 2009, 2852. ________

Exercise 14________

The Leimbruger-Batcho reaction is used to prepare indoles from nitro-toluene. In this reaction sequence, the pyrrolidine replaces the dimethylamino group of DMF-DMA to give a more reactive species.

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The deprotonation of the o-nitrotoluene thanks to the release of methylate anion as shown above leads to the enamine intermediate. Reduction of the nitro group initiates the cyclization step giving (1.26).

See Chen J. et al. RSC Adv. 2014, 4, 4672. Note: An analogous reaction has been reported to prepare 4-(1H)quinolone (see Tois J. et al. Tetrahedron 2005, 46, 735). ________

Exercise 15________

A tetrazolo-fused benzodiazepinone (1.28) is formed by a two-step process: a fourcomponent Ugi-azide reaction, followed by cyclization concomitant to amine deprotection.

The mechanism of the four-component reaction is detailed below.

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109

Note: Replacing the ethyl glyoxylate with phenyl glyoxaldehyde yields a mixture of two isomeric benzotetrazolodiazepines as drawn below.

See Gunawan S. et al. Tetrahedron 2012, 68, 5606. ________

Exercise 16________

This procedure starts with the reaction of cyanamide with the pyrrole dithioester to give the N-cyanothioimidate intermediate shown below. The Thorpe-Ziegler type cyclization of the intermediate generates a new 2,4,5-tri-substituted thiazole (1.29) in good yield.

For more examples, see Avadhani A. J. Org. Chem. 2021, 86, 8508.

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________

Exercise 17________

The procedure starts from aniline. The first two steps correspond to the preparation of the hydrazine derivative (1.30) by diazotation and reduction. The reaction of the hydrazine with the aldehyde, formed in situ in acidic conditions, yields indole (1.31).

Note: To avoid the formation of the unstable hydrazine, a procedure involving the more stable oxalylhydrazone, that generates the corresponding hydrazine has been reported (see Ashcroft C. et al. Org. Process Res. Dev. 2011, 15, 98). The general mechanism of the Fischer indole synthesis is described below from an unsymmetrical ketone.

For a general review of indole synthesis, see Inman M. and Moody C. J. Chem. Sci. 2013, 4, 29.

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Exercise 18________

The reaction of 2-methylpyridine with 2-bromoacetophenone is the first step of the preparation of the indolizine (1.32). The pyridinium intermediate, depicted below, easily deprotonates in a mild basic medium thus triggering cyclization. The oxidative Pictet-Spengler transformation of (1.32) into (1.33) involves the reduction of the nitro group, imine formation and acid-catalyzed cyclization. The cyclization is regioselective. Indeed, as with pyrrole itself, the indolizine five-membered ring will preferentially react at the N-ortho position with electrophiles. The new tetracyclic ring thus formed is the fully aromatic indolizino[3,2-c]quinoline (1.33). Note that the dihydro intermediate is not observed under these conditions.

See Park S. ACS Comb. Sci. 2015, 17, 459. ________

Exercise 19________

Compound (1.34) is easily prepared by nucleophilic substitution of dichloropyrimidine with indoline. An oxidation step, with DDQ for example, will give the pyrimidine-indole (1.34).

The reaction of (1.34) with benzaldehyde affords the imine derivative, which then cyclizes to give (1.35).

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See Zheng L. et al. J. Comb. Sci. 2005, 7, 813. The cyclization into (1.35) occurs on the electron-rich pyrrole ring of the indole. On the opposite, in the second reaction, the formation of (1.36), the cyclization must be directed to the phenyl ring. To do this, it is necessary to modify the indole structure to mask its reactivity. The starting indole is thus reduced to the corresponding indoline, in which the nitrogen lone pair of electrons will now delocalize onto the phenyl ring, thus favoring the electrophilic cyclization. An oxidation step will then regenerate the indole ring.

See Magnus N. A. et al. Org. Lett. 2010, 12, 3700. Note: These two examples, formation of (1.35) and (1.36), illustrate well the ability to dramatically modify the regiochemistry by playing with the substituent or modifying the heterocycle itself.

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113

________

Exercise 20________

The reaction used here to prepare the dihydropyridine (1.37) is an aza-Diels-Alder cyclization after imine formation from benzylamine. This approach constitutes an interesting alternative to the Hantzsch reaction. Formation of rac-amlodipine from (1.37) is done by successive de-benzylation, CH3 to CH2Br transformation, the nucleophilic substitution of the bromine giving the ether, and N3 to NH2 reduction.

See Kim S.-C. Bull. Korean Chem. Soc. 2002, 23, 143. ________

Exercise 21________

Compound (1.38) is the 7,8-methylenedioxypyrimido[4,5-b]quinoline- 2,4(1 H ,3 H )dione. The reaction leads to the dihydro analogue of (1.38), which spontaneously oxidizes during heating.

For more examples, see Akin K. et al. Mol. Divers. 2010, 14, 123. Note: Two mechanisms may be involved. The first one starts with the reaction of the aromatic amine with the barbituric acid, and then reaction of the enamine thus formed with the aldehyde and cyclization. In the second pathway, the barbituric acid would react with

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the aldehyde to give a quinone-methide intermediate that then reacts with the amine. The two mechanisms are discussed in the following publication, Tratrat C. et al. Org. Lett. 2002, 4, 3187. ________

Exercise 22________

The steps of the polymer-supported synthesis of the purine (1.39) are detailed below. Note that the presence of the electron-withdrawing NO2 group greatly eases the two aromatic nucleophilic substitutions. Its reduction to amine is necessarily done in a later step.

See Vanda D. et al. ACS Comb. Sci. 2015, 17, 426. ________

Exercise 23________

The compound (1.40) comes from amidation after chlorination with SOCl2. During this step, the tricyclic intermediate drawn below is isolated instead of the expected acyl chloride. Then (1.40) cyclizes by nucleophilic substitution of the fluorine after NHdeprotonation. The next two steps, chlorination and nucleophilic substitution give the pyrazolo[1,5-a]quinoxaline (1.41).

See Karroum N. B. et al. J. Med. Chem. 2019, 62, 7015.

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Exercise 24________

The synthetic scheme yielding the pyrrolo[1,2-a]pyrazine (1.42) starts with the pyrrole Nalkylation. Deprotonation of the resulting benzophenone followed by methylation, precedes the reaction with NH4OAc and cyclization.

See Park S. et al. Tetrahedron 2014, 70, 7534. ________

Exercise 25________

The first step in the preparation of the intermediate (1.43) is the Fischer indole synthesis yielding the 2-pyridylindole, which is then N-protected to give (1.43). The next steps are the lithiation at the β-position of indole, directed by the pyridine nitrogen, and the reaction with bromoacetaldehyde. Both the cyclization and the benzenesulfonyl release occur in the same step. The final tetracycle (1.44) may be written either as a betaine or as a neutral form.

Br

Li N

N

N

N PhO2S

N PhO2S

N PhO2S

(1.43)

intermediates

N

N N (1.44) betaine form

N

OH

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

Note: The compound (1.44) is a model of the zwitterionic sempervirine alkaloid.

See Gribble G. W. Tetrahedron 1988, 44, 3195 and Lipinska T. M. Tetrahedron 2006, 62, 5736. ________

Exercise 26________

The reaction involves the formation of an imine intermediate. A palladium-catalyzed intramolecular direct arylation yields the thieno[3,2-c]quinoline (1.45).

For more details, See Beydoun K. et al. Eur. J. Org. Chem. 2012, 6745. Note: The direct arylation works well with electron-rich 5-membered rings, the organopalladium halide acting as an electrophilic reagent and the mechanism being quite similar to an aromatic electrophilic substitution. ________

Exercise 27________

The formation of the indole (1.48) involves the reaction of the 2-iodo-3nitroaniline (1.46) with the aldehyde (1.47). A first step of imine formation is followed by the cyclization of the corresponding enamine in a palladium-catalyzed intramolecular Heck reaction. This reaction has been optimized as a route to clavicipitic acid.

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117

See Xu Z. et al. J. Org. Chem. 2010, 75, 7626. For more applications of Heck cyclization, see Jia Y. et al. J. Org. Chem. 2006, 71, 7826.

________

Exercise 28________

The first steps yielding (1.49) involve carbodiimide-catalyzed amide formation, followed by N-methylation. An intramolecular Heck cyclization allows the formation of the tetracycle (1.50) by reaction with quinoline C-4, and side-reaction with quinoline C-2 give the isomeric ring.

See Yapi A.-D. et al. Eur. J. Med. Chem. 2010, 45, 2854. ________

Exercise 29________

The formation of (1.51) first involves the amine allylation followed by indole formation via intramolecular Heck reaction. Note that the exo-cyclization is preferred to form the 5membered ring.

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See Odle R. et al J. Org. Chem.1980, 45, 2710. ________

Exercise 30________

The first step of the synthesis of (1.52) is a Stille coupling to form the N-acetyl-2alkynylaniline. The nucleophilic attack by nitrogen on the complexed alkyne followed by cleavage of the Pd-C bond, with the HCl produced, gives the 2-substituted indole (1.52).

See Rudisill D. E. et al. J. Org. Chem. 1989, 54, 5857. ________

Exercise 31________

The tetrahydrocarbazole is prepared from the 4-cyano-2-iodoaniline (1.53) that reacts with the ketone to give the corresponding imine. Its tautomeric enamine then undergoes the palladium-catalyzed intramolecular Heck reaction.

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Exercise 32________

Compounds (1.55) and (1.56) are prepared from the 4-bromo-3-iodoquinoline (1.54), by two successive regioselective palladium-catalyzed cross-coupling (CC) reactions. The nature of the halogen controls the order in which the reactions are done. For palladium-catalyzed CC reactions, iodine is more reactive than bromine, therefore the first coupling will be selectively done at C-3. It is interesting to notice that the Sonogashira reaction seems more sensitive to the nature of the halogen as the substitution of bromine requires heating at 80 °C while that of iodine is realized at room temperature.

For more details and other examples, see Janke S. et al. Eur. J. Org. Chem. 2019, 6177. ________

Exercise 33________

This exercise is another application of the Larock reaction of palladium-catalyzed annulation of alkynes. The intermediate (1.59) is issued from successive Sonogashira reactions and imine formation. The isoquinoline (1.60) is formed by palladium-catalyzed annulation of the iminoalkyne (1.59). However, the authors show that the cyclization can even be more efficiently catalyzed by Cu(I). Note that the initially formed t-Bu-isoquinolinium salt is not isolated, as the t-Butyl group decomposes during the cyclization step.

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

For a detailed study of the reaction conditions, see Roesch K. R. and Larock R.C. J. Org. Chem. 2002, 67, 86. Note 1: The cylization of iminoalkynes can also occur with electrophiles such as iodine or PhSeCl. Note 2: The palladium-catalyzed annulation of alkynes developed is a useful synthetic approach to prepare 2,3-disubstituted indoles from 2-iodoaniline known as ‘Larock indole synthesis’.

For more details about the mechanism and the regioselectivity, see Larock R.C. et al. J. Org. Chem. 1998, 63, 7652. ________

Exercise 34________

This exercise is another illustration of Fischer indole synthesis. The first step is the Buchwald-Hartwig amination, leading to the stable diphenylphenylhydrazone. This intermediate, in equilibrium in the acidic solution with the corresponding phenylhydrazine, may react with the ketone and cyclize to give the indole (1.61) following the Fischer mechanism.

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121

Adapted from: Wagaw S. et al. J. Am. Chem. Soc. 1999, 121, 10251. Note 1: The original aspect of the work lies in the improvement of the synthesis of the hydrazone, with the possibility to N-alkylate or N-arylate the diphenylhydrazone intermediate, thus allowing the synthesis of N-substituted indole after Fischer cyclization. Note 2: Remember that in the palladium-catalyzed amination, bromine is more reactive than chlorine. If an aromatic nucleophilic substitution had taken place, the chlorine would have been substituted. ________

Exercise 35________

The pyridyl carboxylic acid is linked to the resin through amide bond. It is followed by Sonogashira coupling, and base-catalyzed cyclization corresponding to intramolecular addition of the amine to the phenylacetylene. The azaindole (1.63) is released from the solid support by acid treatment.

Note: The rink-MBHA resin is used in peptide synthesis, and cleaved in the presence of TFA, thus releasing the corresponding amide. For more examples on the base-mediated intramolecular cyclization to form indoles or related heterocycles, see Koradin C. et al. Tetrahedron 2003, 59, 1571.

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________

Exercise 36________

The first iodination step occurs at C-3, the least disfavored position for electrophilic substitution in six-membered rings (position activated here, by the presence of the OH donor group at C-2). The two next steps, OH to Cl transformation at C-2, and nucleophilic substitution by the amine regioselectively at C-2, give the o-iodoaminopyridine (1.64). The next two steps are the Sonogashira reaction and the Cu(I) catalyzed Larock type cyclization leading to (1.65). The presence of a by-product indicates that removal of the TMS group may occur either during the cyclization step.

See Kumar V. et al. J. Org. Chem. 1992, 57, 6995. ________

Exercise 37________

The reaction requires the presence of the amide derivative (1.66). The oxindole is obtained after oxidative addition of the phenyl bromide to the palladium complex, formation of the enolate in the basic conditions, cyclization and reductive elimination of the arylpalladium amide enolate intermediate.

For more examples, see Lee S. J. Org. Chem. 2001, 66, 3402.

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________

Exercise 38________

The monomorine alkaloid is prepared by the reduction of the indolizine (1.68). The synthetic pathway starts from the 6-bromo-2-picoline (1.67) and includes a Sonogashira reaction followed by copper-assisted cycloisomerization. In the proposed mechanism, the copper coordinates to the allene intermediate formed by base-induced propargyl-allenyl isomerization inducing the intramolecular nucleophilic attack of ring nitrogen. The zwitterion intermediate formed leads then to the pyrrole motif.

For more details on the mechanism and applications, see Kel'in A. V. et al. J. Am. Chem. Soc. 2001, 123, 2074. ________

Exercise 39________

The formation of (1.69) involves the intramolecular nucleophilic attack of the amide nitrogen on the carbon-carbon triple bond activated by the formation of an η2-alkynecopper complex. This reaction is triggered by the initial deprotonation of the amide. The higher acidity of the trifluoroacetamide (R = CF3) not only eases this deprotonation but also favors the cleavage of this protecting group during the reaction or the work-up. The alkylidenebenzoxazine (1.70) is due to a competing nucleophilic attack by the oxygen of the amide.

Note 1: The authors also report a two-step domino version of this reaction (see Cacchi S. et al. Org. Lett. 2003, 5, 3843).

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Note 2: Similar reactions have been published, see the example below of Hiroya K. et al. Tetrahedron 2005, 61, 10958.

________

Exercise 40________

The first step is the Ullmann-type reaction, i. e. a copper-catalyzed nucleophilic substitution of the aryl-halide by amine or other nucleophiles as here in this exercices. The intramolecular attack of the amine yields the indole intermediate (1.71). The last step is a copper-catalyzed intramolecular C-N bond formation.

See Jiang M. et al. Org. Lett. 2012, 14, 1420. ________

Exercise 41________

The first step is a Buchwald-Hartwig amination of the bromo-anisole. The second step leading to the carbazole (1.73) is a palladium(II)-catalyzed oxidative cyclization.

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125

See Schuster C. et al. Eur. J. Org. Chem. 2014, 4741. Note 1: As already seen in the previous exercise, the metal-catalyzed version of the aromatic nucleophilic substitution makes it possible to carry out on substrates for which it would have been impossible (on electron-rich aromatics). Note 2: The palladium(II)-catalyzed oxidative cyclization works, not only with diarylamines but also with diphenyl ether and benzophenone (see for first examples Akermark B. J. Org. Chem. 1974, 40, 9). In the condition of this exercise, copper acetate is used in a stoichiometric amount to re-oxidize the Pd(0) formed. ________

Exercise 42________

The synthesis starts with a first Buchwald-Hartwig C-N coupling, giving the diphenylamine intermediate, and a second intramolecular Buchwald-Hartwig C-N coupling gives (1.74). The regioselectivity at the first oxidative addition step is due to the stability of the intermediate formed thanks to the tosylimine attractive effect. For the second coupling step leading to (1.74), the tosyl group could be released before the cyclization takes place.

For more detail on the mechanistic study of the reaction, see Peixoto D. et al. RSC Adv. 2015, 5, 99990. ________

Exercise 43________

The three-step synthesis of (1.75) is realized in one pot. The first reaction is a BuchwaldHartwig palladium-catalyzed coupling, forming the arylamidine intermediate. It then reacts with the m-methoxybenzaldehyde to form the imine, and the cyclization into dihydroquinazoline occurs under heating at high temperatures. The last dehydrogenation step gives (1.75).

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For more examples, see McGowan M. A. et al. Org. Lett. 2012, 14, 3800.

________

Exercise 44________

The first step corresponds to the attachment of the starting material via its carboxylate to the solid support. Then (1.76) undergoes a Sonogashira reaction followed by trifluoroacetamide formation to give (1.77).

The next steps corresponding to the indole ring formation start with the oxidative addition of Pd(0) to vinyltriflate containing reagent, formation of the π-palladium complex, intramolecular addition of the nitrogen, and reductive elimination. Note that the trifluoroacetamide is cleaved during the workup. Afterwards, after N-benzylation, the compound (1.78) is released from the support by TFA treatment.

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127

For more applications of the solid-phase synthesis, see Collini M. D. Tetrahedron Lett. 1997, 38, 7963. For a discussion on the mechanism, see Arcadi A. et al. Tetrahedron Lett. 1992, 33, 3915. ________

Exercise 45________

The first step involves the formation of the α-acylpalladium complex from Pd(0), aryl halide and carbone monoxide, otherwise, the mechanism is very similar to that presented in the previous exercise. The reductive elimination of Pd(0) generates (1.79), and the Nalkylation in basic conditions gives (1.80).

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Exercise Book on Aromatic Nitrogen Heterocycles Chemistry

For a discussion on the mechanism involved in the cyclization, see Arcadi A. et al. Tetrahedron 1994, 50, 437. Note: The reaction allows the formation of 2-substituted-3-acylindoles from simple opropargyl arylamines, easily obtained by Sonogashira reaction with the corresponding 2halo arylamines. ________

Exercise 46________

The key-intermediate (1.81) is obtained by the formation of the tosylamide, its deprotonation in presence of a strong base, and the nucleophilic addition to the alkynyl(phenyl)iodonium salt. The elimination of phenyl iodide generates a carbene, which rearranges to the alkyne (1.81).

The palladium-catalyzed cyclization of (1.81) to give the 2-aminoindole (1.82) possibly involves the mechanism shown below.

For more applications and discussion on possible mechanisms, see Witulski B. et al. Angew. Chem. Int. Ed. 2003, 42, 4257. Note: This original method allows the formation of rare 2-amino-substituted indoles.

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________

Exercise 47________

For the formation of (1.83), the proposed mechanism involved a double gold(III)catalyzed hydroamination. The activation of the terminal alkyne with Au(III) and its reaction with the o-propargyl aniline, gives a first imine intermediate. The activation of the remaining triple-bond triggers the nucleophilic addition of the imine/enamine nitrogen.

See Zhang Y. et al. Org. Lett. 2007, 9, 627. Note: This method constitutes one of the few examples of one-pot synthesis of 1,2substituted indoles.

________

Exercise 48 ________

In the three reactions, molecular oxygen has been used for Cu(II)-catalyzed oxidative CH bond activation and C-N bond formation. As indicated by the effect of radical scavenger that prevents the reaction to happen, a radical mechanism is involved in the key-steps. In the three examples, the radical is formed on a benzylic CH2 or CH3. The proposed mechanisms describe the Cu(II)-catalyzed generation of CH or CH2 radicals, and cation formation by single-electron transfer. For the formation of (1.84) and (1.85), the cationic benzylic imine intermediates then undergo intramolecular cyclization.

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For detailed studies of the reaction mechanism and more applications, see Wang H. et al. J. Org. Chem. 2015, 80, 2431; Mohan D. C. et al. Org. Biomol. Chem. 2015, 13, 5602; Li Q. et al. Org. Lett. 2014, 16, 3672. Note 1: This type of direct activation of (hetero)aromatic methyl group is of major interest in the synthesis of polycyclic heterocycles as it makes unnecessary sometimes tricky preparation and use of aldehydes. Note 2: The copper-catalyzed process also avoids the use of dangerous oxidants, such as peroxides, as only air oxidation or clean O2 is used as oxidants. ________

Exercise 49 ________

The phenazine ring can be obtained by copper-catalyzed aerobic oxidative coupling of aminoaromatics. In the present example, the starting reagent is the 3-aminocarbazole (1.87) that gives the desired heptacycle in one step.

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See Meesala R. and Nagarajan R. Synlett 2010, 18, 2808. Note 1: The reaction has also been successfully applied to 2,3-dimethyl-5-aminoindole. Note 2: One common access to the substituted phenazines is the condensation between 1,2-dioxo- and 1,2-diamino reagents.

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5.2 Reactivity of six-membered rings

5.2.1 Important points to keep in mind It is important to write and consider the possible tautomeric and mesomeric forms of the studied molecules. Indeed, the presence of substituents such as hydroxyl, thiol or hydroxylamine, has a pronounced effect on tautomeric equilibrium and therefore on the reactivity. Some of such key equilibriums with pyridine derivatives are depicted below (the most favoured tautomer is written in bold characters).

The figure shown below sums up the reactivity of pyridine in electrophilic/nucleophilic substitution (SEAr vs SNAr), and the key-intermediate in the addition-elimination mechanism involved in SNAr.

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The influence of electron-donating or electron-withdrawing substituents is generally more important at the para position than at ortho position. However, unpredictably, a donor group at C-3 activates C-2 more than C-4 or C-6 against electrophiles in the pyridine ring.

5.2.2 Typical reactions

________

Exercise 1________

This first exercise is related to the regioselectivity of the electrophilic substitution reaction.

Note 1: The compound (2.1) is formed with only 6% yield despite the drastic conditions used (the pyridinium formed is even less reactive than pyridine itself). The nitration occurs at C-3, which is the least disfavored position. Forcing conditions are also needed for preparing 3-bromopyridine (Br2, oleum, 130 °C) but lead to more than 80% of the product. Note 2: Nitronium tetrafluorate used to prepare (2.2) is a mild nitrating agent and the compound (2.2) itself is used as a non-acidic mild nitrating agent.

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Note 3: The compound (2.3) is easily obtained from pyridine N-oxide, which is activated towards SEAr and reacts preferentially at C-4 over C-2.

Note 4: The nitration of free quinoline gives using standard acidic conditions of nitration a mixture of 5- and 8-nitroquinoline (2.4). In the same conditions, quinoline N-oxide is nitrated at C-4 at 90 °C and C-8 at low temperatures (< 20 °C). The 3-nitroquinoline Noxide may be obtained by radical nitration with t-BuONO at 100 °C in CH3CN (see Zhao J. et al. RSC Adv. 2015, 5, 32835). Note 5: In contrast to quinoline, isoquinoline gives under nitration conditions the 5nitroisoquinoline (2.5) as a major product. For both derivatives, the C-5/C-8 ratio is nevertheless very dependent on the reaction conditions and the type of electrophiles.

Note 6: In the synthesis of (2.6), the N-acylpyridinium intermediate is the acylating agent. Note 7: For acetylation of 4-hydropyridine, the N- and O-acylated products (2.7) can be formed in equilibrium and the ratio depends on the nature of the solvent. Remember that 4-hydropyridine prefers the 4-oxopyridine form.

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Note 8: The 4-aminopyridine is methylated on ring nitrogen (compound (2.8) is obtained) as the 2- and 3- derivatives. The three amino-pyridines are all more basic than pyridine itself with a pKa value of 9.1 for the most basic 4-aminopyridine. Note that under this methylation condition, the 2,6-di-t-Bu-pyridine is not N-alkylated due to steric hindrance. Notes 9 and 10: The methylation of 2-hydroxypyridine in the conditions used here gives the N-methylated product (2.9) as a major product. Nevertheless, in the alkylation reaction of 2-hydroxypyridine (also the case for the 4-isomer), electrophiles can attack through either the nitrogen or oxygen atom due to the ambident nucleophile character of the 2pyridone form. In contrast, 3-hydroxypyridine behaves as a typical phenol and the Omethylated (2.10) product is obtained. The ratio of N- versus O-alkylation can be affected by the nature of the electrophile, the base used for deprotonation, the counterion, the solvent and the temperature. For an attempt to rationalize using computational methods, see Breugst M. J. Am. Chem. Soc. 2010, 132, 15380. Note 11: 3-Hydroxyisoquinoline, having the same ambident character as 2-hydropyridine, gives the N-methylated product (2.11).

Note 12: Under these phase transfer catalysis conditions, using Adigen 464 as the catalyst, the O-alkylated product (2.12) is obtained efficiently. Note 13: For the bromination in fuming sulphuric acid, in the formation of (2.13), a complexation of the N-oxide group with sulphur trioxide deactivates positions 2, 4 and 6. Bromination, therefore, occurs preferentially and firstly at C-3. This example highlights the key importance of reaction conditions (temperature, solvents, reagents) for the regioselectivity of electrophilic substitutions in six-membered rings (see Van Ammers M. et al. Tetrahedron 1962, 18, 227).

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Notes 14, 15, and 16: A tentative explanation of the ortho nitration at C-2 yielding (2.14) implies a six-membered chelate complex of the hydroxy group and the nitronium ion. The same regioselectivity is observed in the nitration of 3-hydroxypyridine N-oxide, thus indicating that the directing effect of the 3-OH is more efficient than that of the N-oxide. See Dyumaev K. M. and Smirnov L.D. Russian Chem. Rev. 1975, 44, 83. This preference of 3-hydroxypyridine for the C-2 SEAr is general and the formation of (2.15), which is issued from the Mannich reaction confirms the ortho-directing effect of the 3-OH. The C-6 para position is also activated and the di-alkylated product (2.16) is issued by using an excess of reactants.

Note 17: The first bromination of the 3-hydroxypyridine starts at C-2, but in the presence of an excess of reagent the tri-bromo (2.17) is the only isolated compound. No bromination is observed at C-5, as a new confirmation of the determinant role of the OH group. Note 18: To regioselectively prepare the 4-bromo analogue (2.18), a different approach needs to be used, starting from 3,4-dihydroxypyridine. The reaction of POBr3 with arylOH group, nucleophilic attack of bromine anion and elimination of PO2Br2, is a strategy commonly used to transform OH into Br substituents (or Cl using POCl3). In the present case, the regioselectivity can be explained by the acidity of the reaction medium (HBr released). The reaction occurs on the pyridinium species, which makes C-4 more susceptible to nucleophilic substitution. For more details on the reactivity of hydroxypyridines in electrophilic substitutions, see Dyumaev K. M. and Smirnov L.D. Russian Chem. Rev. 1975, 44, 83; Smirnov L. D. and Dyumaev K. M. Chem. Heterocycl. Compd. 1976, 12, 955 and also Den Hertog H. J. et al. Rec. Trav. Chim. 1950, 69, 1281. ________

Exercise 2 ________

The preparation of (2.19) may be done in three steps as shown below. Isoquinoline reacts first at C-5 with electrophiles in acidic conditions. Therefore, bromination has to be performed before nitration. Note that nitro group has a strong electron-withdrawing effect and would have deactivated the ring against further reaction.

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Partial reduction of the pyridinium ring is realized with sodium cyanoborohydride and it is followed by nitro reduction. In these later conditions (H2, Pd/C, NEt3) de-bromination occurs simultaneously.

Note: Other reduction conditions such as H2 with PtO2 or Zn(OAc)2 selectively reduce the nitro group without touching bromine. For more reaction conditions, see Rey M. et al. Helv. Chim. Acta 1985, 68, 1828. ________

Exercise 3 ________

The 2-aminopyridine (2.21) can be prepared following the two procedures below.

Note that in the Chichibabin reaction, the C-2 regioselectivity towards C-4 is observed (see for more details: Soleymani M. et al. J. Mol. Graph. Model. 2022, 6, 108240). For the second procedure and the chlorination step, remember that 2-hydroxypyridine reacts like an amide (2-oxopyridine is the major tautomeric form). For preparing the 4-aminopyridine (2.22), two approaches can also be proposed.

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Note that in the first approach, a mixture of TiCl4/SnCl2 affords the 4-aminopyridine in one step and high yield from the 4-nitropyridine N-oxide. The regioselectivity of electrophilic attack is in favor of the C4 over C-2 in pyridine N-oxides. The second approach is similar to that applied for preparing 2-aminopyridine, the C-4 as the C-2 position being reactive to SNAr. Access to the 3-aminopyridine (2.23) does not involve the same chemistry as presented above for the 2- and 4- derivatives, as the C-3 position is not activated for SNAr. Two procedures are presented below.

The mechanism of the Hofman rearrangement is shown below (Ar is for 3-pyridyl), but this rearrangement is not restricted to an aromatic amide.

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Note 1: To regioselectively prepared the three aminopyridines (2.21) to (2.23) a common approach is the Ullmann reaction, i. e. the copper-catalyzed amination of the corresponding bromopyridines with protected amines, benzylamine for example, followed by deprotection. For the copper-catalyzed amination, see Neetha M. et al. Chem. Select 2020, 5, 736. Note 2: For more information on aminopyridine chemistry, see Ori K. J. et al. Am. J. Het. Chem. 2021, 7, 11. ________

Exercise 4 ________

The easiness of SNAr in a six-membered ring is related to the ortho/para positions of the leaving group compared to the ring nitrogen. The electron-withdrawing effect of the ring heteroatom is higher at the para than at the ortho position. The addition of nitrogen into the ring increases the electron deficiency and therefore favors nucleophilic substitution. To a lesser extent presence of the fused benzene also have a positive effect, the negatively charged intermediate obtained after the addition of the nucleophile remaining aromatic. In halopyrimidines, the 4/6 positions are generally more reactive than the 2 positions but it is very sensitive to reaction conditions.

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The two rings, in which leaving group is positioned meta to the nitrogen(s), are not reactive:

Note 1: Palladium-catalyzed reactions will be the methods of choice to substitute halogens at the most disfavored meta positions. Note 2: Remember that regioselectivity will be strongly influenced by any substituent (electron-withdrawing or electron-donating effects), and by the reaction conditions (solvent, salt, temperature). ________

Exercise 5 ________

Nucleophilic substitutions (SNAr) are involved in the formation of (2.24) and (2.25). In both starting pyridines, the halogen at C-3 is activated against SNAr thanks to the ortho NO2. The regioselectivity is controlled by the reaction conditions and nature of the leaving groups. The compound (2.24) is formed in acidic conditions, in which the reactive species is the pyridinium. The strong electron-withdrawing effect of the positive nitrogen greatly increases substitution at C-4 (remember that NO2 is a good leaving group). Furthermore, iodine at C-3 is the least reactive halogen against SNAr.

In the second reaction, (2.25) is prepared in basic conditions and from the neutral N-oxide form. The electron-donating effect of N-oxide increases the electron density at C-4, thus disfavoring that position against SNAr. The reaction then occurs at C-3 even if bromine is not as reactive as chlorine or fluorine.

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For more details on the chemistry of aryl N-oxide, see Youssif S. Arkivoc 2001, 242. ________

Exercise 6 ________

Deuterated (2.26) is prepared by halogen-magnesium exchange. The most favored position is at C-2 (complexation of the metal of the base with the negatively charged oxygen enhances the acidity and brings the base closer to the C-2 position).

Note: The reaction may also proceed at other positions than C-2. For more applications, see Duan X.-F. et al. J. Org. Chem. 2009, 74, 939. ________

Exercise 7 ________

The reaction leading to (2.27) is described as an alternative to the Chichibabin synthesis. It proceeds via O-esterification, nucleophilic addition of the amine to C-2 and rearomatization by elimination of TsOH. As indicated in the question, t-Bu is used as an amine protecting group, removed by heating in TFA.

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Note: This example is interesting as the pyridinium salt formed in situ by O-tosylation, also activates the C-Cl bond towards nucleophilic substitution. The reaction conditions (low temperature and short reaction time) are not in favor of the nucleophilic substitution. This example highlights the efficiency of this approach. For more examples, see Yin J. et al. J. Org. Chem. 2007, 72, 4554. ________

Exercise 8 ________

In this illustration, PyBrop, a reagent commonly used in peptide synthesis, activates the N-oxide and allows the addition of the 4-tert-butylphenol.

More applications are described with a wide variety of nucleophiles, see Londregan A. T. Org. Lett. 2011, 13, 1840. ________

Exercise 9 ________

The reactivity of the 3-nitropyridine N-oxide allows the formation of a wide range of compounds. The reductive conditions, H2/PtO2, reduce both the N-oxide and the nitro group to give (2.29). Other conditions, such as PCl3, cleave selectively the N-oxide without affecting the nitro, as for (2.30). These conditions would also modify carboxylic acid or hydroxy groups present in molecules. The reaction starts with the attack of the negatively charged oxygen to PCl3, followed by the elimination of POCl3 as shown below.

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Formations of (2.31) and (2.32) respect similar mechanisms of O-esterification (phosphorylation or acetylation) of the N-oxide followed by addition of the counter-ion (chloride or acetate) at C-2 of the formed salt and then elimination of PO2Cl2 or AcOH.

For (2.32), the ester intermediate is prone to hydrolysis due to the presence of the ortho nitro group. The mechanism is given below:

Note: The nature of the substituent at position 3 and the reaction conditions may influence the ratio between C-2/C-6 regioisomers. See Taylor E.C. and Driscoll J.S. J. Org. Chem. 1960, 25, 1716. ________

Exercise 10 ________

The mechanism of the formation of (2.33) is similar to those of exercises 6 and 7. In the present exercise, the formation of the O-methylpyridinium salt allows the nucleophilic addition at the ortho position. The SNAr reaction of the 4-nitro group by ethanol gives (2.34), the nitro group being a good leaving group in heterocyclic chemistry.

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See Matsumara E. et al. Bull. Chem. Soc. Jpn. 1970, 43, 3210. ________

Exercise 11 ________

The postulation mechanism is written below. O-Acylation of the 3-cyanopyridine N-oxide is followed by C-2 H-abstraction and attack of the carbene formed by THF. Ring opening of the oxonium intermediate by benzoate ultimately yields (2.35).

Electron-deficient pyridine N-oxides are used in this approach, see Jones D. H. et al. Org. Lett. 2017, 19, 3512. ________

Exercise 12 ________

Isoquinoline mainly reacts at C-1, with or without N-oxide. As already discussed with pyridine N-oxide, the introduction of a nucleophilic substituent at the ortho position requires alkylating or esterifying the N-O group. In the present reaction, TsCl and NaN3 are used as reagents. O-tosylation and ortho addition of azide, give 1-azidoisoquinoline,

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which is in equilibrium with the more stable tricyclic form (2.36) resulting from its intramolecular cyclization.

________

Exercise 13 ________

The first reaction is performed at low temperature, to stabilize the aryl magnesium intermediate formed by C-2 deprotonation that then reacts with phenylisocyanate. C-2 versus C-6 regioselectivity is provided by the methoxy group, which is a directed ortho metalation group.

Note: Various electrophiles (I2, ketones, …) can be used. For more examples, see Andersson H. et al. Tetrahedron Lett. 2008, 49, 6901. The second reaction takes place at room temperature and involves the ring opening of the pyridine N-oxide by the addition of Grignard reagent at the C-2 position to form the 2,4dienal oxime (2.38). It further reacts with the Vilsmeier reagent to achieve the oxime to cyanide (2.39) transformation (for this reaction, see Kusurkar R. et al. Indian J. Chem. 2003, 42B, 3148 and for a similar transformation involving BOP as dehydrating agent, see Singh M. K. and Lakshman M. K. J. Org. Chem. 2009, 74, 3079).

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For more examples, see Andersson H. et al. Tetrahedron Lett. 2007, 48, 6941. Note 1: With organolithium reagents, complex mixtures are obtained. Note 2: The ring closure of (2.38) to form the 2-phenylpyridine N-oxide may be achieved by heating in acetic anhydride, see Andersson H. et al. Org. Lett. 2007, 9, 1335. Note 3: The reaction can also afford non-deoxygenative addition dihydroproducts that can be converted to aromatic pyridines following treatment with dehydrating reagents, see Anderson H. et al. Org. Biomol. Chem. 2011, 9, 337. Note 4: In a more recent paper (Larionov O. V. et al. Org. Lett. 2014, 16, 864) it has been reported that performing the reaction of aryl N-oxides with alkyl, aryl or alkenyl Grignard reagents in the presence of a catalytic amount of CuCl at room temperature radically modifies the course of the reaction and gives directly the 2-functionalized aryl compounds as illustrated below.

________

Exercise 14 ________

The reaction proceeds in three steps, N-oxide esterification, pyridine addition at C-2 with the elimination of triflic acid (TfOH), and Zincke ring amination. Note that, in this reaction, the 2-amino group comes from pyridine.

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For more examples of the first arylation step, see Bugaenko D. I. et al. Adv. Synth. Catal. 2020, 362, 5777.

________

Exercise 15 ________

The reaction starts with the N-oxide esterification with trifluoracetic anhydride, and PPh3 addition at C-2 with the elimination of trifluoroacetic acid. Note: The adduct at C-4 is also observed as the minor compound, but pure (2.41) is isolated after counter-ion exchange and crystallization. In the postulated mechanism, a Lewis pair is formed between the phosphonium salt and DABCO, and it dissociates to give an aryl anion in situ. The resulting umpolung (polarity inversion) allows the reaction with electrophiles (here D2O) at C-2 in three steps starting from aryl N-oxides.

For the synthesis of (2.42), the 1-benzoylpyrrole is used as the benzoylating agent.

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For more examples, see Bugaenko D. I. et al. Org. Lett. 2021, 23, 6099.

________

Exercise 16 ________

The following exercise is also related to quinoxyfen functionalization. The two first steps are similar to those described in the precedent exercise, i.e. N-oxidation and esterification. DABCO reacts then at C-2, with the elimination of trifluoroacetic acid to give the highly reactive ammonium salt (2.43) that could react with nucleophile either by SNAr at the quinoline C-2 (and elimination of DABCO) or by ring opening of DABCO cation as shown below.

Note: Ring opening was observed with a variety of nitrogen, sulfur or carbon nucleophiles. For more applications, see Bugaenko D. I. et al. J. Org. Chem. 2017, 82, 2136. ________

Exercise 17 ________

The regioselective synthesis of the 6-iodo-3,4-dimethoxypyridine (2.46) is made from the 2,6-diiodo-3,4-dimethoxypyridine N-oxide (2.45) as a key intermediate.

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It is based on the ortho-directing effect of both the N-oxide and 3-methoxy groups that preferentially direct lithium-halogen exchange at position 2. Peracid N-oxidation followed by lithiation at the nitrogen ortho positions, and iodination with an excess of I2 give the 2,6-diiodo intermediate (2.45). Selective C-2 lithium-iodine exchange and hydrolysis of lithium derivative lead (2.46) after N-oxide cleavage. The sequence steps from (2.45) can be made in the opposite order, N-oxide cleavage first followed by 2-iodine removal. Note that using a short reaction time (5 min) for the first step, the 2-iodo-3,4dimethoxypyridine N-oxide is isolated in 60% yield along with the 2,6-diodo derivative, thus confirming the directing effects mentioned above.

For more details, see Mongin O. et al. J. Chem. Soc. Perkin Trans. 1 1995, 2503.

________

Exercise 18 ________

These two reactions involve photoinduced single electron transfer steps, catalyzed by the acridinium salt Mes-Acr+ ClO4-. The addition of N-oxide to the photoinduced cation radicals allows the intermediate formation of bicyclic radical cations that, upon N-O cleavage yield the 2-alkylpyridine after a second single electron transfer.

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For more applications, see Markham J. et al. Chem. Eur. J. 2019, 25, 6638, and Zhou W. et al. Angew. Chem. Int. Ed. 2018, 57, 5139.

________

Exercise 19 ________

Heating the N-protected thiourea (2.49) (obtained by reaction of 2-aminopyridine with ethoxycarbonyl isothiocyanate) under base catalysis promotes the cyclization into 4-oxo2-thioxopyrido[1,2-a][1,3,5]triazine (2.50) by nucleophilic attack of the carbamate by the pyridine nitrogen. Thioureas are also key intermediates in the formation of N-protected guanidines, by reaction with an amine in the presence of either HgCl2 or a coupling agent such as EDCI. In the formation of (2.51), the cyclization occurs with the pyridine nitrogen, to give the 2propylamino-4-oxo-pyrido[1,2-a][1,3,5]triazine.

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In the second pathway, the starting compound is the 8-aminoquinoline. The reaction also involves the two-step formation of the N-ethoxycarbonyl guanidine (2.52), followed by intramolecular Friedel-Craft’s type cyclization to give the 2-propylaminopyrido[3,2h]quinazolin-4-one (2.53).

For more examples, see Kopp M. et al. J. Heterocyclic. Chem. 2002, 39, 1061, and Zeghida W. et al. J. Org. Chem. 2008, 73, 2473. ________

Exercise 20________

The 2-chloropyridine undergoes a series of reactions yielding (2.54). The first step is the addition of thiophene anion, generated in situ with n-BuLi. The addition occurs at position 4, ortho/para to the two nitrogens, and therefore electron deficient. Dehydrogenation with DDQ regenerates the aromaticity. The second step is the nucleophilic substitution at position 2 by the thiolate anion, and the third step is a second addition-dehydrogenation reaction, the anion being generated by the metal-halogen exchange.

For other examples, see Bello A. M. et al. J. Med. Chem. 2008, 51, 2734.

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________

Exercise 21________

The pathway has been designed to prepare C-4 substituted piperidines from pyridine. After the formation of the N-carbamoyl pyridinium the orgarno-zinc addition is preferentially made at C-4 and is followed by hydrogen-transfer hydrogenation. If position C-4 is already substituted, the addition at C-2 will occur.

For more examples, see Wang X. et al. Eur. J. Org. Chem. 2003, 4586. Note: As illustrated below, a similar BF3.Et2O-mediated addition of Grignard reagents followed by an oxidative aromatization has been reported to prepare C-4 substituted pyridines. See for more examples: Chen Q. et al. J. Am. Chem. Soc. 2013, 135, 4958.

________

Exercise 22________

The polycycle (2.57) is formed by intramolecular inverse electron-demand Diels-Alder reaction. The reaction involves a tetrazine ring and the indole plays the role of electronrich dienophile. The acylation of the amino-substituted tetrazine triggers the reaction by increasing the electron deficiency of the diene part.

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Note: Activation is much more efficient with trifluoroacetylation than with acetylation. For more applications, See Benson S. C. et al. Tetrahedron 2000, 56, 1165. ________

Exercise 23________

The reaction of the 2,6-diaminopyridine with vinamidinium salt gives a 2,6-disubstituted naphthyridine (2.58). The reaction involves the nucleophilic attack of the amine to the vinamidinium salt, and the elimination of dimethylamine gives the iminium intermediate shown below. Cyclization (highly favored by the presence of the iminium group) and elimination of dimethylamine generates the naphthyridine ring.

Note: The reaction is compatible with various R groups on the vinamidinium reagent, such as aryl, pyridine, halogen. For more details, see Jahromi E. B. et al. J. Heterocyclic Chem. 2017, 54, 1210. ________

Exercise 24________

The regioselective iodination of the 2-chloropyridine is made in one pot in the presence of LDA and I2. The mechanism is shown below.

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The first step is the ortho-directed metalation, directed by the chlorine at C-2, leading to the iodination at C-3. A second ortho-directed H-abstraction at C-4 is followed by halogen-dance rearrangement, and gives (2.59).

The three Suzuki-Miyaura reactions are done in the order C-4, C-3 and C-2. The nature of the halogen, I more reactive than Cl, and the electron-deficient character C-4 < C-3, justify this order. The Suzuki-Miyaura reaction involves boronic acids. The three reagents are shown here in the order in which they are used.

For more examples of these iterative cross-couplings, see Daykin L. M. et al. Tetrahedron 2010, 66, 668. ________

Exercise 25________

In both cases, the first step is a nucleophilic substitution by methoxide anion. The most reactive δ+ position is C-4 (in o/p positions to the two nitrogens). The 5-halogeno-2chloro-4-methoxypyridines thus formed react with phenylboronic acid in the presence of palladium catalyst (Suzuki reaction).

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Regioselectivity in palladium-catalyzed cross-coupling reactions is very sensitive to the nature of the halogen (Br is more reactive than Cl). Thus, the presence of bromine at C-5 (X = Br) clearly directs the reaction at that position leading to (2.62). In the case where X = Cl, the reaction occurs at C-2, due to the presence of the methoxy donating group at C4 that disfavors the reaction at C-5 (formation of (2.61)). For more reactions, see Ceide S. C. and Montalban A. G. Tetrahedron Lett. 2006, 47, 4415. ________

Exercise 26________

Regioselectivity in these reactions is directed by the amino group and favors the most electron-deficient C-3 position as the electron-donating effect of the amine is less pronounced at the ortho- compared to the para-position. Possible metal coordination with the amine also favors the C-3 position. In the first reaction, the organozinc reagent is formed in situ from benzylmagnesium chloride. Negishi Pd-catalyzed cross-coupling yields (2.63), whose subsequent modification involving a Suzuki reaction gives the trisubstituted pyrazine (2.64). The compound (2.65) is obtained after the Sonogashira reaction.

See Adamczyk M. et al. Tetrahedron 2003, 59, 8129. ________

Exercise 27________

The reaction illustrated in this exercise is the palladium-catalyzed direct arylation from aryl N-oxides. Remember that direct arylation only occurs in electron-rich systems thus explaining the necessity of the N-oxide. Moreover N-oxide directs the reaction at the o-

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position. Coupling compounds (2.66), (2.67), and (2.68) are then obtained after deoxygenation in presence of Pd/C. The mechanism is quite similar to that of SEAr, the organopalladium halide formed in situ being the electrophile species.

Note 1: The coupling reaction works well with pyrazine and pyridazine N-oxides, even without additives. With pyrimidine N-oxides, CuCN or CuBr is needed. Note 2: With pyrimidine N-oxide, arylation occurs at C-6, para to the free nitrogen, see Krueger A. and Paudler W. W. J. Org. Chem. 1972, 37, 4188. Note 3: As highlighted by several authors, aryl N-oxides are easy to prepare, stable and they allow various transformations. For more examples and details about the reaction optimization, see Leclerc J.-P. and Fagnou K. Angew. Chem. Int. Ed. 2006, 45, 7781. ________

Exercise 28________

The reaction proposed here and leading to (2.69) is a copper-catalyzed N-amination, and not a nucleophilic substitution reaction (o/p electron-withdrawing groups on benzyl chloride would be absolutely needed).

Note: DBO is a powerful ligand for performing Cu-catalyzed couplings of heteroanilines with (hetero)aryl halides, see for more applications: Chen Z. and Ma D. Org. Lett. 2019, 21, 6874.

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________

Exercise 29________

The C-1 of 1,3-dichloroisoquinoline is the most π−deficient position, therefore the Suzuki reaction occurs at that position to give 1-phenyl derivative (2.70). Then regioselective lithiation at position 4 (ortho-directed effect of Cl) with LiN(i-Pr)2 allows the deuterium introduction and gives (2.71). Note that the authors indicate that this regioselectivity remains if the base, LiN(i-Pr)2, is replaced by n-BuLi at -78°C (any transmetalation at C3 occurs). The compound (2.72) is obtained by Kumada coupling at C-3 using the phenyl Grignard reagent. A Suzuki reaction would give the same result.

See Ford A. et al. J. Chem. Soc. Perkin Trans. 1 1997, 927. ________

Exercise 30________

The reaction deals with the C-C bond formation at the ortho position of pyridine N-oxide via the Heck reaction. Pd(II) is here the active species and a palladium complex bound to the N-oxide is involved. The compound (2.73) is obtained after the removal of the N-oxide by reaction with PCl3 and elimination of POCl3.

Note 1: The reaction conditions have also been applied to the Pd-catalyzed direct arylation with unreacted arenes.

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For more applications, see Cho S. H. and al. J. Am. Chem. Soc. 2008, 130, 9254. Note 2: Unexpectedly, CH activation of pyridine N-oxide has also been reported to be successful for coupling of nonactivated secondary alkyl bromide.

See Xiao B. et al. J. Am. Chem. Soc. 2013, 135, 616.

________

Exercise 31________

The first step in the preparation of Penicolinate C is the palladium-catalyzed methoxycarbonylation of the 2,5-dibromopyridine, yielding the 5-bromopicolinic methyl ester shown below.

Double Sonogashira couplings followed by catalytic hydrogenation of the triple bonds give the desired compound (2.74).

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________

Exercise 32________

The first reaction is the nucleophilic substitution of the 3,6-diiodopyridazine by the amine, which is used in large excess, as the introduction of this strong electron-donating substituent prevents a second nucleophilic substitution to occur. The second step is the palladium-catalyzed Sonogashira coupling.

See Draper T. L. and Bailey T. R. J. Org. Chem. 1995, 60, 748. ________

Exercise 33________

The first step is the reaction of the heterocyclic nitrogen with the sulfonyl chloride. The reaction is chemo- and regioselective due to the presence of the o-amino group. The addition of Cu(I) in the solution triggers the Ullmann-type reaction that gives a new tricyclic system (2.76), named benzo[e]pyridazino[1,6-b][1,2,4]thiadiazine 10,10dioxides.

For more applications, See Padmaja R. D. et al. J. Org. Chem. 2019, 84, 11382. ________

Exercise 34________

The formation of (2.77) from the quinazoline dione requires two steps, halogenation and nucleophilic substitution. The direct alkylation with alkyl iodide would lead to a complex mixture of N- and O-alkylation products.

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The key reaction involved in the formation of (2.78) is a Heck-type C-glycosylation. The compound (2.78) is obtained after deprotection of the O-silyl group and reduction of the ketone intermediate (enol form represented below).

The mechanism involves the syn insertion of the aryl palladium iodide (obtained after oxidative addition of Pd(0) in the C-I bond) into the glycal double bond to form the following intermediate. The beta hydride elimination leads then to the enol silyl ether. See Nishikawa T. et al. in Glycoscience, Fraser-Reid B., Tatsuta K. Theim J. (eds). SpringerVerlag Berlin Heidelberg 2008, pp 755-811.

For more applications, see Lee A. H. F. and Kool E. T. J. Org. Chem. 2005, 70, 132 and Yu C.-P. et al. New J. Chem. 2019, 43, 8796. ________

Exercise 35________

The cross-coupling between pyridine N-oxide and 1,3-dibutyluracil gives (2.79).

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Deoxygenation of (2.79) using PCl3 gives (2.80) with the elimination of POCl3. Note that the conditions of this last reaction (2 equivalents of PCl3 and room temperature) would not allow any chlorination of uracil.

The cross-coupling reaction leading (2.79) first involves the palladium C-H activation of uracil at the most electron-rich C-5 position. Coordination to the N-oxide, C-H activation of the ortho position of pyridine N-oxide, and reductive elimination yields (2.79).

For more examples, see Kianmehr E. et al. RSC Adv. 2014, 4, 13764.

5.2.3 Applications to heterocycles of interest – Multistep syntheses

________

Exercise 36________

The formation of (2.81) involves three reactants and proline as the catalyst. Activation of aldehyde I with proline makes easier the Knoevenagel condensation with III (remember that enamine (enaminium salt) formation is a reversible process). Then the

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Michael-type addition of the enaminone II gives an intermediate that may undergo an intramolecular nucleophilic substitution, forming the fused tetracycle (2.81).

For the detailed study of the reaction, see Fu L. et al. ACS Comb. Sci. 2014, 16, 238. ________

Exercise 37________

The first part of this pathway deals with the preparation of the acetal-containing aminoacridine (2.83). The modification of the 9-NH2 requires its transformation into a good leaving group. That was done in three steps: 1) hydrolysis in harsh basic conditions (R = OH), 2) chlorination with POCl3 (R = Cl), and 3) nucleophilic substitution by the aminoacetaldehyde dimethylacetal.

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Note: Remember that the alkylation of p-aminopyridine would only occur at the heterocyclic nitrogen due to the delocalization of the NH2 doublets into the ring, preventing the direct alkylation of the 9-NH2. For the next step towards the formation of the octacycle (2.82), two possible pathways may be proposed. They both involve the formation of the tetracyclic 7H-pyrido[4,3,2kl]acridine ring by Friedel-Craft’s type electrophilic cyclization, and an amination step to give the o-diamino group required to react with the phen-5,6-dione.

As shown above, the amination was done by electrophilic substitution by p-nitrophenyl benzene diazonium salt (step a), and reductive cleavage of the azo-intermediate (step c). The cyclization is acid-catalyzed (step b). The regioselectivity of the cyclization is controlled by the higher directing effect of the o-ethoxy group compared to the m-amino group, however, traces of cyclization on the amino ring cannot be ruled out. The introduction of the p-nitrophenylazo substituent prior to the cyclization prevents any electrophilic reaction on the same ring due to its strong deactivating effect promoting the desired regioisomer. Furthermore, performing the cyclization step before the reductive cleavage of the azo-bond, makes easier the purification steps. For more details, see Bouffier L. et al. Bioorg. Med. Chem. Lett. 2009, 19, 4836.

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________

Exercise 38________

Taking into account the given reactants and reaction conditions, the disconnections required to prepare (2.85) are shown below.

We will first consider reagent B. The conversion from a bromo nicotinic acid into a bromoaminopyridine, involves a Curtius reaction (for the mechanism, see Ninomiya K. et al. Tetrahedron, 1974, 30, 2151). The carbamate (BocNH) thus formed is easily alkylated in the presence of cesium carbonate as base. The next step is the formation of the organostannane required for the C-C bond Stille coupling between rings A and B.

Concerning ring A, the palladium-catalyzed N-arylation allows the introduction of the chloroaniline (ring C). Note that for this step, a nucleophilic aromatic substitution would not have been efficient due to the low nucleophilicity of aromatic amine. Note also that the oxidative addition of Pd(0) occurs regioselectively into the C-Cl bond of the pyrimidine ring due to its low electron density. Before the Stille coupling, the secondary amine is Boc protected (Boc2O, DMAP).

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Ultimately, the Stille coupling (Pd2(dba)3, AsPh3) between the two synthons gives the desired (2.85) after the removal of the N- and O- protecting groups (TFA). For more applications of this strategy, see Kuo G.-H. et al. J. Med. Chem. 2005, 48, 1886. ________

Exercise 39________

The two first steps giving (2.86), i. e. Sonogashira and Suzuki reactions, are performed sequentially in one pot. It is necessary to control and optimize the Sonogashira coupling to avoid the formation of a bis-alkyne side-product. The ring closure of (2.86) is similar to the Larock iodocyclization, and gives the iodosubstituted benzo[a]phenazine (2.87). The presence of the halogen allows further functionalization by Suzuki reaction leading to (2.88). The iodocyclization involves the formation of an iodonium complex by coordination of I2 to the triple-bond, nucleophilic attack of the aromatic ring and deprotonation of the resulting cationic tetracycle.

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For more examples, see Kumar S. et al. Org. Biomol. Chem. 2017, 15, 4686.

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5.3 Reactivity of five-Membered rings

5.3.1 Typical reactions

________

Exercise 1 ________

In presence of an excess of methyl iodide the dialkylated product (3.1) is obtained via the N-alkylated salt as an intermediate. Note that in (3.1) the positive charge is delocalized between the two nitrogens. Basic conditions lead to a mixture of monoalkylated isomers (3.2), N-H imidazole existing under two tautomeric forms.

Note: The reactions of imidazole with acyl chloride or anhydride yield monoacylimidazoles only, as, if formed, acyl-imidazolium salts would hydrolyze during aqueous treatment. ________

Exercise 2 ________

The use of bulky protecting groups directs the reaction to the second nitrogen. In these examples, the trityl group (Tr) is chosen for temporary N1-protection of 4-ethylimidazole, which is the less crowded nitrogen. For the synthesis of (3.3), a second alkylation gives the imidazolium salt, and the trityl group is then removed in mildly acidic conditions. To prepare (3.4), a second temporary group is needed, the Boc group, that resists to trityl removal and that is cleaved in a final step under basic treatment.

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Note: This exercise highlights the possible removal of the N-Boc protecting group of imidazoles under basic aqueous conditions. These cleavage conditions also operate on the Boc group attached to other NH-heteroarenes such as pyrroles, indoles, and carbolines. Aqueous solutions of sodium or potassium carbonate in methanol or dimethoxyethane under reflux are used, see Kazzoudi S. E. Tetrahedron Lett. 2006, 47, 8575, and Chakrabarty M. Synth. Commun 2006, 36, 2069. A catalytic amount of sodium methylate in dry methanol at room temperature can also been used, see Ravinder K. Synth. Commun. 2007, 37, 281. For similar reactions, see Jones J. H. et al. Synthesis 1987, 1110. ________

Exercise 3 ________

The indole N-H is not nucleophilic, therefore to acylate this position and lead to (3.5), its deprotonation is required (AcONa is used here as base). Under acid catalysis, the electrophilic substitution of indole takes place and yields (3.6).

Note: Indole mostly reacts at C-3 with electrophiles, unlike pyrrole which will react at C2 and C-5. However, if the C-3 position is blocked SEAr can occur at C-2 of indoles.

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________

Exercise 4 ________

The formation of 2-acyl-1-alkylimidazole first involves the N-3 acylation, forming an imidazolium salt that upon deprotonation gives the neutral ylide. C-2 benzoylation followed by removal of the N-benzoyl group yields (3.7).

See Regel E. et al. Justus Liebigs Annal. Chem. 1977, 145. ________

Exercise 5________

The reactions involve the Vilsmeier-Haack reagent, i.e. N,N-dimethylchloroiminium cation, which is a highly electrophilic formylating agent formed in situ from DMF and POCl3.

Note 1: Nitrogen-containing five-membered rings (pyrrole, indole) are more reactive toward electrophilic reagents than oxygen- or sulfur-containing rings (furane, thiophene respectively). Note 2: Like pyrrole and thiophene, furane reacts preferentially at C-2 in SEAr.

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________

Exercise 6________

In general, with pyrrole (furan or thiophene) electrophilic α-substitution (positions 2 and 5) is favored over β-substitution (positions 3 and 4). However, the α/β ratio would depend on several factors, including the presence and nature of substituents on the ring. The presence of ester as an electron-withdrawing group, in the present example, favors the 4isomer (3.10) corresponding to the β-substitution. However, the reaction conditions may also dramatically change the α/β ratio from 0/100 to 64/36 by replacing the Lewis acid catalyst AlCl3 with ZnCl2.

Note: In similar conditions, indole mainly reacts at the β-position. See Tani M. et al. Chem. Pharm. Bull. 1996, 44, 48. ________

Exercise 7 ________

Under strongly acidic conditions, 2-methylindole reacts as an indoleninium cation, deactivating the pyrrole ring, and nitration occurs on the benzene ring yielding (3.11) in good yield. Using a mild nitrating agent, (3.12) is obtained by reaction on the most electron-rich pyrrole ring.

In case of R = H, polymerization involving position 2 is mainly observed.

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Note: In similar conditions, nitration occurs at position C-2 of pyrrole, as it is the most reactive towards electrophilic attack. ________

Exercise 8 ________

The conditions for iodination (I2, NaOH) requires the presence of the unsubstituted N-H (indole N-anion intermediate), and must thus be carried out prior to the N-H sulfonation.

________

Exercise 9 ________

Remember that pyrrole preferentially reacts at C-2. To favor reactions at C-3, one solution is to temporarily introduce a bulky protecting group (here the tri-i-propylsilyl group) on N-1.

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Note: 2-Halogeno-pyrroles are rather unstable, they can be prepared using 1 equivalent of the corresponding N-halogeno-succinimide and keeping the reaction mixture at low temperature. ________

Exercise 10 ________

The gramine (3.15) is prepared from the Mannich reaction, which proceeds via the intermediate formation of the highly electrophilic iminium intermediate. The nucleophilic substitution of the N-dimethylamino group of (3.15) occurs via the easy formation of imine-methide or iminium-methide electrophilic intermediate. Formation of (3.16) then involves ester hydrolysis, partial decarboxylation (aq. NaOH) and amide deprotection (H2SO4).

________

Exercise 11 ________

Nitration of imidazole in very acidic conditions involves the much less reactive imidazolium salt as intermediate, and occurs at the least deactivated C-4 position to get (3.17). In neutral mild conditions, the three positions are reactive. It is difficult to limit the reaction at the monobromination in the indicated conditions, and the tri-halogenated compound (3.18) is obtained. However reductive removal of the halogens at C-2 and the C-5 yields (3.19) in good yield.

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Note: The reaction conditions required for the nitration of imidazole are harsher than those used for pyrrole nitration, due to the presence of the electron-withdrawing pyridine-type nitrogen. ________

Exercise 12 ________

The reaction involves a nucleophilic substitution at C-2 only made possible by the presence of the electron-withdrawing benzoyl group at C-4.

Note: Remember that halogens are not the unique class of leaving groups, NO2 or like here SO2Me are also among the good leaving groups. See Franco F. et al. J. Org. Chem. 1982, 47, 1682. ________

Exercise 13 ________

This radical reaction (CF3 radical as reactive species), developed by Baran and coll., involves Langlois's trifluoromethylation reagent, and requires very mild reaction conditions. It allows C-H trifluoromethylation of indole leading to (3.21).

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For more examples and details about the mechanism, see Ji Y. et al. PNAS 2011, 108, 14411. ________

Exercise 14 ________

The first reaction leading to (3.22) involves both Vislmeier-Haack formylation and OH to halogen transformation. Formation of (3.23) is due to the CHO reduction with sodium borohydride, followed by reductive debromination.

________

Exercise 15 ________

Thiazole easily reacts with 2-bromoacetophenone to give the corresponding thiazolium salt. In situ generation of ylide in the presence of NEt3, as shown below, and reaction with the dipolarophile gives (3.24). Cleavage of the C-S bond, triggered by the formation of the pyrrole nucleus, followed by the intramolecular attack to the benzoyl group yields the hemi-thioketal (3.25).

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See Potts K. T. et al. J. Org. Chem. 1976, 41, 187. ________

Exercise 16 ________

The reaction leading to (3.26) involves successive thiazole N-alkylation to form the salt intermediate and then imine formation.

________

Exercise 17 ________

The synthesis of (3.27) involves the acid-catalyzed electrophilic substitution of the most reactive positions of the two reactants (electron-rich indole C-3 and most electrophilic CO-CF3), followed by intramolecular imine formation.

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________

Exercise 18 ________

This strategy allows the regioselective alkylation of histamine at N-1. The first step is the carbonyldiimidazole (CDI) catalyzed cyclic urea formation. N-Methylation, forming the imidazolium cation, makes the urea bond more labile and prone to ring opening.

Note: Ring opening may be achieved with bulkier alcohol, such as tert-butyl alcohol, to provide α-N-Boc derivative, or in aqueous acidic conditions to directly obtain the amine. See Jain R. et al. Tetrahedron 1996, 52, 5363. ________

Exercise 19 ________

These reactions highlight the importance of substituents as directing groups for metalation. The N-Me group is not as efficient as directing group as the OMe group, and the reaction in presence of n-BuLi yields a complex mixture. Compounds (3.30) and (3.31) are isolated with the highest yields and purities, and (3.32) is the minor isomer. Interestingly, switching n-BuLi for t-BuLi and working at a lower temperature drastically modifies the selectivity of the deprotonation, as (3.30) is formed as the sole product. This

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example also draws attention to the sensibility of lithiation to a number of other factors, including the nature of the base, solvent, or temperature.

Replacing the N-Me with N-SO2Ph has a major influence as sulfonyl groups act both as N-electron-withdrawing protecting and ortho-directing groups. In that case, the reaction is fully selective at position 2 giving (3.34).

Preparation of (3.33) from 5-methoxyindole requires N-H deprotonation (typically with NaH), and the reaction of the anionic indole with benzenesulfonyl chloride PhSO2Cl. See Sundberg R. J. et al. J. Org. Chem. 1976, 41, 163. ________

Exercise 20 ________

As for indole, metalation of pyrrole occurs preferentially at the α-position. Here in addition the N-SO2Ph group acts as an ortho-directing group, and (3.35) is obtained after iodination of the Grignard intermediate.

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Note: PhSO2 is a group that plays different roles: N-protection, deactivation of fivemembered rings (due to its strong electron-withdrawing effect), and as a o-directing metalation group. ________

Exercise 21 ________

In the synthesis of (2.37) and (2.38), the first step is the selective lithiation at position 2 directed by the presence of 3-Br. The authors observed that reactive electrophiles (such as aldehyde) would react at C-2 as expected, but less reactive ones (such as TIPSCl) at C-5, probably due to a dynamic equilibrium between C-2 and C-5 lithio intermediates.

For more details, see Fukuda T. et al. Org. Lett. 2010, 12, 2734.

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________

Exercise 22 _______

The 3-phenylsulfonyl indole may be regioselectively prepared from (3.38). As indicated in the reaction scheme, it involves three steps: lithiation upon reaction with n-BuLi (either direct C-H lithiation or halogen-metal exchange), reaction with the electrophilic PhSO2F, and F- catalyzed removal of an acid-labile protecting group. The major issue here is the choice of the protecting group. Indeed, the preparation of (3.38) requires the introduction of a bulky TIPS group, that, by shielding α-positions, will favor bromination at C-3 with 1 equivalent of NBS.

Note: For further lithiation at C-2 of the 3-phenylsulfonyl indole, the TIPS group should be replaced by an ortho-directing group, such as SEM, BOC, or SO2Ph. See Bailey N. et al. Synlett 2008, 185. ________

Exercise 23 ________

This example illustrates that heterocycles can play the roles of either the organo-metallic or the halogenated partners in cross-coupling reactions. The choice will mainly depend on the stability or accessibility of each partner. In the present Stille reaction, the pyrrole ring bears a tributyltin substituent. Therefore, the indole (3.39) should contain halogen, I or Br, at C-3.

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Note: Remember that SEAr is favored at C-3 of indole, and C-2 of pyrrole, and direct lithiation is generally done at C-2 of both indole and pyrrole. Therefore, in the present example, it would be easy to regioselectively prepare both reactants. ________

Exercise 24 ________

In N-substituted imidazoles, the pka of 33.7 of position C-2 allows its regioselective deprotonation in the presence of a stoichiometric amount of organolithium base. The first step is N-protection with tetrahydropyrane (THP). Then lithiation at C-2 and chlorination by hexachloroethane gives (3.40). Chloride is used as a temporary substituent for C-2 as it may be easily removed by reduction (SiMe3 is also routinely used for this purpose). The next stage is the introduction of a pinacol borane group. After C-2, C-5 is the second most acidic position on imidazole. Lithiation and borylation give (3.41). Reductive chloride cleavage at C-2 gives (3.42), which then undergoes the cross-coupling with aryl-iodide. Acid treatment ultimately releases the THP group yielding (3.43).

Note: The reactivity order on imidazole with organolithium base is C2 > C5 >> C4. For more examples of transition metal-catalyzed C-N and C-C bond formation on imidazole, see Bellina F. et al. Adv. Synth. Catal. 2010, 352, 1223. ________

Exercise 25 ________

As previously seen with the formation of (3.38), TIPS-pyrrole is a reactant of choice to regioselectively substitute positions 3 and 4. Here, a sequence of bromination, bromidelithium exchange to introduce the chloride, and then iodination by SEAr yields the Nprotected 3-chloro-4-iodopyrrole (3.44).

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Palladium-catalyzed formation of the imidazole boronic ester (Pin = pinacol) at the most reactive C-I position gives (3.45) and Suzuki coupling yields (3.46) after TIPS removal using TBAF.

Note: Remember the I > Br >> Cl order of reactivity for lithiation exchange or metal crosscoupling reactions. See Morrison M. D. et al. Org Lett. 2009, 11, 1051. ________

Exercise 26 ________

Pyrrole being electron-rich, the aromatic nucleophilic substitution will only occur in presence of strong electron-withdrawing groups such as NO2. In the present example, the amine reacts with the electrophilic trichloromethyl-ketone giving the amide. After aldehyde liberation under acidic conditions, the formation of an intramolecular hemiaminal yields (3.47).

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Note: To achieve the amination of the halogenopyrrole, the palladium-catalyzed Buchwald-Hartwig amination (ex. Pd(OAc)2, Cs2CO3, Xantphos ligand, 1,4-dioxane, Δ) or its copper-catalyzed version (ex. CuI, Cs2CO3, DMF, Δ) can be used. See Dorel R. et al. Angew. Chem. Int. Ed. 2019, 58, 17118. ________

Exercise 27 ________

The compound (3.48) may undergo two different reactions depending on the reaction conditions. As indicated by the formula it contains one iodine.

The compound (3.49) results from the direct arylation of (3.48). After optimization, the reaction conditions are: Pd(OAc)2, PPh3 or DPPP, (n-Bu)4NOAc, DMSO, 60°C. As for (3.50), it results from the Heck reaction, and optimized conditions are Pd(PPh3)4, (n-Bu)4NCl, NaHCO3, CH3CN, 60°C. For more information, see Lage S. et al. Adv. Synth. Catal. 2009, 351, 2460. ________

Exercise 28________

LDA induces lithiation at C-4, which is followed by halogen dance to the most stable C-2 position. The addition of water gives the isomeric dibromo ester (3.51).

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Note: This reaction has been designed in the field of lamellarin synthesis. See Morii K. et al. J. Org. Chem. 2021, 86, 13388.

5.3.2 Applications to heterocycles of interest – Multisteps syntheses

________

Exercise 29 ________

To prepare (3.53) from pyrrole-2-carboxylic acid, the regioselective iodination at C-4 may be done with NIS (1 equivalent) after N-protection with a bulky group such as trityl or TIPS groups. Deprotection will be done either with an acidic treatment or a reaction with F-. Acid chloride can then be prepared by using SOCl2. The synthetic pathway to lamellarin (3.52) starts with the esterification of (3.53) and then its N-alkylation. From the intermediate shown below, three palladium-catalyzed crosscoupling reactions are performed: the Negishi reaction with the zinc chloride (3.55) and then two simultaneous Heck-type reactions. This simple four-step procedure seems attractive, however, the authors report low yield for the last step.

Note: In this Heck-type cyclization, pyrrole acts as the π-system. See Banwell M. G. et al. Aus. J. Chem. 1998, 52, 755, and for a review on the palladiumcatalysed cross-coupling and related reactions involving pyrroles, Banwell M. G. et al. Eur. J. Org. 2006, 3043.

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________

Exercise 30 ________

The double cyclization to lamellarin skeleton is realized by two intramolecular direct oxidative arylations at the C-2 and C-4 positions of the pyrrole ring (copper here is the oxidative agent and Pd(II) the active species).

Note 1: Other oxidants have been reported, such as PIFA, DDQ, CAN… Note 2: With transition-metal-catalyzed oxidative C-H couplings, no pre-functionalization is required. It is widely used to prepare biaryl compounds using two C-H bonds as coupling partners. This exercise illustrates an intramolecular variant of this deshydrogenative coupling. See Ueda K. et al. J. Am. Chem. Soc. 2014, 136, 13226, and for the mechanism proposal, Pintori D. G. and Greaney M. F. J. Am. Chem. Soc. 2011, 133, 1209. ________

Exercise 31 ________

The two-step reaction sequence leading to (3.58) involves a bromination step followed by C-H ring deprotonation to introduce a carboxylic ester. Looking at the structure of the final lamellarin (3.60) makes it possible to conclude that bromine was at C-3 and carboxylic ester at C-2 in the compound (3.58). Despite the fact that bromination of N-substituted pyrroles is known to occur at αpositions, C-2 and C-5 (except in the presence of bulky N-TIPS or N-Tr groups), it has been reported that α-substituted N-benzene sulfonyl pyrroles rearrange at the β position under acidic conditions to give the thermodynamically favored β-adducts (see Zonta C. et al. Org. Lett. 2005, 7, 1003; and for a possible mechanism, see Choi D.-S. et al. J. Org. Chem. 1998, 63, 2646). Then, the lithiation is directed at C-2 by the presence of the halogen at C-3, allowing the regioselective introduction of the ester in (3.58). Remember that C-H lithiation is favored at the α-position of five-membered ring heterocycles.

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As for (3.59), it is obtained after Suzuki-Miyaura coupling at C-3, concomitant deprotection of the MOM group (HCl/MeOH) and the lactone formation (by intramolecular nucleophilic addition of the phenol formed on the ester at C-2), and finally benzene sulfonyl group removal (TBAF).

The next steps to the synthesis of (3.60) are shown below: 1) N-alkylation by Mitsunobu reaction in the presence of diisopropyl azodicarboxylate (DIAD) and PPh3, 2) intramolecular direct arylation in the presence of Pd(PPh3)4, 3) bromination with NBS at C-4, and 4) Suzuki cross-coupling using the boronic ester.

Note: The exercise is adapted from: Ohta T. et al. J. Org. Chem. 2009, 74, 8143.

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________

Exercise 32 ________

In the first step, (3.61) is formed by Cu-catalyzed N-arylation. Note that the phenylsulfonyl group is cleaved under the harsh basic conditions of the N-arylation. The next steps are the selective chlorination of the pyrrole rings leading to (3.62) followed by demethylation of the phenol methyl ethers to finally obtain (3.63).

See Kanakis A. et al. Org. Lett. 2010, 12, 4872. ________

Exercise 33 ________

The eight steps leading to the bicyclic thieno[2,3-d]imidazole (3.65) are detailed below. The N-vinyl protecting group is first introduced by alkylation with 1,2-dibromoethane (it will be easily removed by oxidation of the double bond in the last step). The basic treatment is needed to eliminate the HBr formed. The next steps to (3.64) involve two successive Grignard reactions first at C-2 and then at C-5, both most reactive for metal-halogen exchange compared to C-4 in the imidazole ring. Building the thiophene ring from (3.64) requires the nucleophilic substitution of bromine at C-4 by the thiolate. Remember that this type of reaction is unusual and difficult to realize with five-membered rings. The presence of a strong withdrawing group (usually a nitro group) is required to achieve such SNAr reactions. In the present case, the o-carbonyl group probably plays this role. The intramolecular cyclization is then obtained in basic conditions. Note that ester hydrolysis occurs in these conditions.

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The last two steps are the decarboxylation reaction and the oxidative cleavage of the vinyl group.

See Hartley D. J. and Iddon B., Tetrahedron Lett. 1997, 38, 4647.

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5.4 Reactivity of polyheterocycles containing both five- and six-membered rings

________

Exercise 1 ________

The synthesis of (4.1) requires the N-protection of imidazole with SEM-Cl in basic conditions, then lithiation at the pyrrole C-2 position (the most acidic C-H) followed by nucleophilic substitution at C-4 of pyridine (the most reactive before C-2).

The preparation of (4.2) will involve two Stille cross-coupling reactions to introduce the pyridine and furan rings. To do so, bromination at imidazole C-4 and C-5 is first realized in good yield by treatment with Br2 in AcOH. The next question concerns the sequence of the two Stille reactions. In imidazole, the least favored position is at C-4. Therefore, the first reaction will be done at C-5 with the 4trimethylstannylpyridine, and furan will be introduced next. The resulting tetracyclic compound is shown below. The next two steps are the deprotection of the SEM group in acidic conditions, and then the nucleophilic substitution of fluorine at pyridine C-2 and C-6 by ammonia. Note that these two positions are the most electron-deficient ones, and therefore prone to SNAr reactions. However, the introduction of the first amine makes harder the second substitution.

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Note: For furan coupling, the C-2 stannylated derivative is preferred to the boronic acid, which tends to undergo protodeboronation under the basic conditions of Suzuki-Miyaura reactions. Other C-2 heteroaryl boronic acids exhibit this instability in aqueous base, and particular Suzuky-Miyaura conditions have to be developed (see Kinzel T. et al. J. Am. Chem. Soc. 2010, 132, 14073). For more applications, see Revesz L. et al. Bioorg. Med. Chem. Lett. 2002, 12, 2109. ________

Exercise 2 ________

The synthetic pathway designed to prepare bromopyrido[4,3-b]indole is discussed here.

18

F radioligand (4.6) from the 7-

1) The N-Boc-protected derivative (4.3) is obtained from NaH and Boc2O. Note: N-Alkylation or N-acylation of pyrrole-type nitrogen requires H-abstraction in basic conditions, such as in the presence of NaH or DMAP (dimethylaminopyridine). 2) The preparation of (4.4) involves the formation of pinacol ester followed by the palladium cross-coupling with the 3-bromopyridine N-oxide (Suzuki reaction). Oesterification of (4.4) with p-toluenesulfonic anhydride allows the addition of triethylamine at the ortho-position and elimination of p-toluenesulfonic acid to give (4.5). Nucleophilic substitution by fluoride anion and Boc deprotection in acidic conditions yield the desired compound (4.6).

Note: Synthesis of 2-fluoropyridines may be performed by nucleophilic substitution of either the corresponding 2-halogenopyridines or diazonium salts, however with low yields

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and harsh conditions. As illustrated in this exercise, 2-trialkylammonium pyridines are also efficient precursors despite their tedious preparation. 3) The first step of the preparation of (4.7), see structure below, is the fluorine nucleophilic substitution by dimethylamine. The reaction is highly favored both by the nature of the leaving group (F > Cl >> Br) and the position ortho to the pyridine nitrogen. The next step is the Boc protection of the carbazole-type nitrogen in basic conditions using DMAP. Alkylation with methyltriflate at room temperature regioselectively gives (4.7). The preference for the fused pyridine ring may be due to the electron-donating effect of the pyrrole-type nitrogen (in para position) and to less steric hindrance compared to that of the 2-dimethylaminopyridine ring. See H. Xiong et al. Org. Lett. 2015, 17, 3726. Note: The synthesis of the starting 7-bromopyrido[4,3-b]indole cannot be made by direct bromination of the unsubstituted tricycle. Indeed, bromination of carbazole-type ring mainly occurs at the position para to the heterocyclic nitrogen (or C-8 in the present system). As shown below, efficient methods of reductive cyclization have been reported (see Joule J. A. Science of Synthesis, Knowledge updates 2018, 2, 264, adapted from Limburg W. W. et al. J. Polym. Sci. 1975, 13, 1133).

________

Exercise 3 ________

The first step, common to the two pathways, is the bromination of (4.8) with POBr3. From this bromo-intermediate, (4.9) is prepared by Suzuki reaction with the phenylboronic acid and tetrakis palladium. Formation of the triazole of (4.10) involves a Cu-catalyzed 1,3-dipolar azide-alkyne cycloaddition (CuAAC). The first step is the palladium-catalyzed Sonogashira reaction with trimethylsilylactetylene to introduce the triple bond. The intermediate undergoes a cascade desilylation/CuAAC reaction in presence of 3-azidopyridine using copper sulfate and Na ascorbate (for click reaction) and potassium carbonate to effect in situ desilylation. Finally, tosylate removal in basic conditions leads to (4.10).

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For more details, see Song C. et al. Tetrahedron 2010, 66, 5376, and Yang W. et al. Synth. Commun. 2016, 46, 1118. Note: The initial uncatalyzed azide-alkyne cycloaddition (Huisgen reaction) is not regioselective and gives a mixture of 1,4- and 1,5-disubstituted triazoles. It requires high temperatures. The copper-catalyzed reaction, designed by Sharpless, Fokin, and Meldal only gives the 1,4-isomer. It involves a Cu(I) catalyst, generally formed in situ from Cu(II) reagent and a reducing agent (sodium ascorbate). Interestingly, a ruthenium-catalyzed variant, that only gives the 1,5-isomer, has been reported (see Zhang L. et al. J. Am. Chem. Soc. 2005, 127, 15998). ________

Exercise 4 ________

This exercise exemplifies the reactivity of the 7-azaindole in various reaction conditions. 1) In the three first reactions with electrophiles, the substitutions occur as expected on the electron-rich five-membered ring. Acylation giving (4.11) occurs at N-1 without the need of a base. Mannich reaction gives (4.12), thus following the C-3 indole regioselectivity (and not the C-2 pyrrole regioselectivity). Note the mild conditions (0 °C temperature) for the nitration giving (4.13) due to the high reactivity of indole.

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2) Preparation of the 4-chloroazaindole (4.14) required the activation of the pyridine ring. This can easily be done by N-oxidation with a peracid such as m-CPBA, and reaction with POCl3. Remember that pyrrole or indole do not form N-oxide. The regioselectivity of the chloride attacking at the para position differs from what is generally seen with pyridine (ortho attack), showing the influence of the fused pyrrole. The formation of 1-methyl (4.15) with methyl iodide requires the presence of a base such as NaH to abstract the pyrrole N-H. In the absence of such a base, methyl iodide will react with the pyridine nitrogen to give the corresponding 7-methyl cation that may easily deprotonate during treatment in slightly basic conditions to form the uncharged 7methylazaindole (4.16).

________

Exercise 5 ________

In this exercise, the position of lithiation is directed by the position of the amide substituent. In all the reactions, the chosen electrophile is D+ from CD3OD. For (4.17), the presence of a negative charge on the pyrrole nitrogen shields the ortho C-2 position, therefore the lithiation occurs at the peri position (C-4). This negative effect is suppressed by the presence of a protecting group at N-1 (here a MOM group). The expected ortho-directing effect of the amide at C-2 is thus observed in formation of (4.18).

As for (4.19) and (4.20) in which the ortho-directing group is positioned at N-1 and at N7, respectively, the ortho-directing effect is also observed.

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From (4.20), the addition of a catalytic amount of ClCONi-Pr2 allows the amide migration (directed metalation-group migration) from N-7 to N-1 (probably by N-acylation at N-1 followed by subsequent cleavage of the N-7 cation). The compound (4.21) is then subjected to a second directed lithiation reaction with the introduction of iodine as electrophile at C-2 to give (4.22).

For more applications, see Schneider C. et al. Angew. Chem. Int. Ed. 2012, 51, 2722, and Dalziel M. E. et al. Angew. Chem. Int. Ed. 2019, 58, 7313. ________

Exercise 6________

The preparation of (4.23) and (4.24) from 7-azaindole first involves the formation of 4chloroazaindole, as a common intermediate. Its formation (involving N-oxide formation by m-CPBA and reaction with POCl3) has already been seen in exercise 4. In the present example, methanesulfonyl chloride is used instead of POCl3. For the synthesis of (4.23), after N-protection by the TIPS protecting group, two successive lithiation reactions on the pyridine ring are performed to introduce the electrophiles. Note that the chlorine atom and then the fluorine atom act as directing metalation groups for fluorination at C-5 and carboxylation at C-6, respectively.

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For the synthesis of (4.24), the pathway starts with a second chlorination sequence at C-6 via the N-oxide intermediate. N-protection and then lithiation at C-5 allow the introduction of azide. Finally, the reduction of the azide gives the 5-amino group. Note that TIPS N-protection is used to prevent lithiation at position C-2.

See L’Heureux A. et al. Tetrahedron Lett. 2004, 45, 2317. ________

Exercise 7 ________

1) In the first reaction, lithiation of the N-protected 5-methoxy-4-azaindole (4.25) occurs at C-2 due to the strong ortho-directing effect of the sulfonyl group. Reaction with benzaldehyde gives (4.26).

The action of ISiMe3, prepared in situ from the mixture of ClSiMe3 and NaI, allows the smooth O-demethylation of (4.25). Esterification with trifluoromethanesulfonic anhydride gives the triflate intermediate (4.27) that undergoes Suzuki-Miyaura reaction with pyridine boronic acid to yield (4.28). Note that triflate has quite the same reactivity as bromide in cross-coupling reactions.

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2) The formation of (4.29) from triflate (4.27) involves the Buchwald-Harwig amino coupling reaction with the 4-pyridine carboxamide.

For more examples, see Saab F. et al. Tetrahedron 2010, 66, 102. ________

Exercise 8________

The synthesis of (4.30) requires the introduction of Br or I at C-3 for a Suzuki coupling with phenylboronic acid. In indole, iodination at C-3 can easily be done using I2 and NaOH. The following reaction will be the introduction of the pyrimidine ring at N-1 by aromatic nucleophilic substitution of the corresponding 4-chloropyrimidine, after N-H deprotonation. Finally, Suzuki coupling at C-3 will afford the desired azaindole derivative.

Note: A metal-catalyzed Buchwald-Hartwig reaction (either using palladium or copper catalyst) could have also been used for the N-arylation step. For more examples, see Bryan M. C. et al. Bioorg. Med. Chem. Lett. 2013, 23, 2056.

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________

Exercise 9________

1) To prepare (4.31), the introduction of the methyl group requires a regioselective lithiation at C-2. To do so, it is necessary to protect the pyrrole N-H with an ortho-directing group, such as a sulfonyl group. The presence of bromine on the pyridine ring precludes the use of BuLi (to avoid metal/halogen exchange by-product), therefore lithium amide such as LDA is chosen. The last step of N-deprotection (basic conditions or TBA- induced cleavage) gives (4.31).

Note: The presence of bromine may then be used for further functionalization by crosscoupling reactions. For more examples, see Liddle J. et al. Bioorg. Med. Chem. Lett. 2009, 19, 2504. 2) The compound (4.32) is prepared by a succession of reactions on the pyrrole ring of the 5-bromo-7-azaindole. The first step is the N-protection with POM group (pivaloyloxymethyl chloride). It is followed by the Vielsmeier-Haack electrophilic substitution at C-3, giving the corresponding 3-CHO. The reaction of 2-methoxyphenyl magnesium bromide with this aldehyde yields the corresponding benzylic alcohol, which is then oxidized by MnO2. The final step is acid-catalyzed N-deprotection.

For more examples, see McCoull W. et al. MedChemComm. 2014, 5, 1533; and Mérour J.-Y. et al. Molecules 2014, 19, 19935 (review article).

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________

Exercise 10________

Tetracyclic compound (4.36) is obtained from the 4-bromo-7-methoxy-6-azaindole. The first three steps include tosyl N-protection, O-demethylation in acidic conditions and N-methylation of the pyridone ring to give (4.33). Note: N/O regioselectivity of the alkylation of 2-pyridone remains challenging as most of the time the two regioisomers are formed. This regioselectivity is greatly influenced by the nature of the alkylating agents, and the reaction conditions. Formation of the boronic ester (4.34) is then followed by a Suzuki coupling with the orthoiodoaniline, and then by tosyl deprotection yielding (4.35). The last step is a Mannich-type reaction. The iminium formed in situ reacts at the pyrrole C-3 position to get the fourth ring of (4.36).

For the preparation of the starting 4-bromo-7-methoxy-6-azaindole, See McDaniel K. F. et al. J. Med. Chem. 2017, 60, 8369; for the synthesis of more tetracyclic analogs, see Fidanze S. D. et al. Bioorg. Med. Chem. Lett. 2018, 28, 1804. ________

Exercise 11________

Pentasubstituted 7-azaindole (4.38) is prepared from the trihalogeno azaindole (4.37). 1) The preparation of the 5-bromo-6-chloro-3-iodo-7-azaindole (4.37) starts from the 5bromo-7-azaindole. The first step is the C-3 iodination with NIS (regioselectivity similar to that of indole itself). Oxidation at N-7 with m-CPBA is followed by the formation of the trichloroacetyl ester, and the subsequent attack with chloride anion at the ortho position. This ortho selectivity is less favored than para selectivity as seen in previous exercises. The difference here may be due to the presence of the two bulky halogens at peri and ortho positions of C-4.

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2) To prepare (4.38), there will be four successive palladium-catalyzed cross-coupling reactions. Therefore, the N-methylation of pyrrole-ring is performed first. Note that a labile-protecting group such as p-methoxybenzyl may be used for the preparation of N-H free tetrasubstituted analogs.

Three Suzuki-Miyaura reactions are then involved. The regioselectivity will follow the general reactivity order ArI > ArBr >> ArCl. Looking at the three reaction conditions proposed for the Suzuki-Miyaura, they mainly differ by the temperature and the reaction time. The easiest reaction occurs at C-3 with PhB(OH)2 (60 °C, 30 min), then at C-5 with p-MeOPhB(OH)2 (100 °C, 2 h), and ultimately at the least reactive position C-6 with pMePhB(OH)2 (100 °C > 6 h). Then, functionalization at the crowded C-2 position is achieved through C-H activation and direct arylation with p-MeOPhI and Pd as the catalyst. For more details about this sequential arylation of 7-azaindoles, see Cardoza, S. et al. J. Org. Chem. 2019, 84, 14015. Note: In the C-2 arylation conditions used here, a highly electrophilic palladium catalyst is generated in situ from Pd(OAc)2 and a silver carboxylate (formed from AgOTf and 2nitrobenzoic acid). These conditions were set up from indole derivatives, see Lebrasseur N. and Larrosa I. J. Am. Chem. Soc. 2008, 130, 2926.

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________

Exercise 12________

Direct arylation is known to work well with electron-rich rings, such as azoles, but not with electron-deficient pyridines. N-Oxidation of the pyridine moiety increases the electron density thus offering unique access to its direct arylation. The reaction is directed to the position ortho to the N-oxide. Compounds (4.39) and (4.40) are thus obtained in good yields. Zn dust catalyzed deoxygenation gives (4.41) that is further arylated with iodobenzene at C-2 to afford (4.42).

Note: The C-2/C-3 regioselectivity of the direct arylation is not obvious. A mechanistic study has been done to explain this high C-2 selectivity in the case of indoles. The kinetic isotope effect has been determined for both positions, and the larger value was seen at C3, in favor of an electrophilic palladation of indole. A 1,2-migration of the palladium

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intermediate would explain the observed C-2 selectivity (for a detailed mechanistic study, see Lane B. S. J. Am. Chem. Soc. 2005, 127, 8050).

For more examples of the selective azine/azole selective arylation, see Huestis M. P. and Fagnou K. Org. Lett. 2009, 11, 1357. ________

Exercise 13________

1) The starting compound (4.43) may be prepared in three steps: N-protection after Habstraction, lithiation at C-2 favored by the presence of the ortho-directing protecting group (CO2Me here) and electrophilic bromination at C-3. Radical bromination in the presence of benzoyl peroxide gives the 2-bromomethyl derivative (4.44).

2) The structure of the tricyclic compounds (4.45) and (4.46) is represented below.

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In both cases, the reaction starts with the nucleophilic substitution of 2-bromomethyl by the anion, of TosMIC or its dichloro formimide analog, generated in situ in basic conditions. The phase catalysis conditions are used to avoid the formation of the dialkylated product. Then the two mechanisms of cyclization differ as shown below.

The mechanism involved in the formation of the ester-containing compound (4.45) is supported by the fact that replacing the carboxylate protecting group by tosyl prevents cyclization of the 2-substituted intermediate. For the formation of (4.46), the N-deprotection in basic conditions seems faster than the intramolecular nucleophilic attack. For more details on the reaction and mechanisms, see Mendiola J. et al. J. Org. Chem. 2004, 69, 4974; Baeza A. et al. Eur. J. Org. Chem. 2010, 5607. See also for more applications of TosMIC reagent: Kumar K. ChemistrySelect 2020, 5, 10298. ________

Exercise 14________

Compared to exercise 13, the present reaction scheme shows an alternative pathway to pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine ring from 7-azaindole. The first steps correspond to the temporary protection of the pyrrole N-H by lithiation and in situ reaction with CO2. This intermediate is engaged without purification in a second lithiation, which is ortho-directed to the C-2 position, and reaction with phthalimidoacetaldehyde yields (4.47).

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Protection of the alcohol as tetrahydropyranyl ether and hydrazinolysis of the phthalimide give the amino-substituted product (4.48).

Then, the cyclization is realized by reaction with triphosgene (Cl3CO)2CO. The compound (4.49) is then obtained after acid-catalyzed O-deprotection, ester formation (as mesylate) and aromatization (MsOH elimination). Transformation of the pyrimidinone ring is achieved by O-trimethysilylation by hexamethyldisilazane (HMDSA) followed by substitution by NH3, giving the 9-amino derivative (4.50). The 9-amino position may be further functionalized by a reaction with acetyl chloride or anhydride for example. The next step is the five-membered ring modification. Remember that the C-3 position of indole is highly reactive with electrophiles, such as the iodination with NIS shown here.

See Ahaider, A. et al. J. Org. Chem. 2003, 68, 10020. ________

Exercise 15________

1) This reaction has been studied by liquid chromatography, isotopic labelling and NMR spectroscopy. It involves the nucleophilic attack to C-8 and imidazole ring opening. The existence in solution of the imine shown below leads to ribose cleavage. Then formamide hydrolysis releases the diaminopyrimidine (4.52).

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Note: Remember that five-membered rings are prone to nucleophilic attack and ring opening, unlike six-membered ring. For a detailed study of the mechanism, see Lönnberg H. and Lehikoinen J. Org. Chem. 1984, 49, 4964. 2) N-Oxidation at N-1 and O-alkylation gives (4.53). The N-1 vs N-3 selectivity may be controlled by lower steric hindrance. This compound easily undergoes in slightly basic conditions the nucleophilic attack of hydroxide at C-2 and ring opening. The intermediate is not isolated and immediately reacts to give a mixture of (4.54) (by deformylation) and (4.55) (by ring closure due to the attack of the amino group to the formamide). This later mechanism is confirmed by heating (4.54) with deuterated formic acid, giving the 2-D-(4.55) via intermediate formation of deuterated formamide. This reaction is known as Dimroth rearrangement. The mechanism is one example of ANRORC rearrangement (for Addition of Nucleophile Ring Opening Ring Closure).

For detailed mechanistic studies, see Itaya T. et al Tetrahedron 1972, 28, 535.

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Note: These two examples show that both rings may undergo ring opening after a nucleophilic attack. The presence and nature of the purine substituents and the reaction conditions are determinant factors. ________

Exercise 16________

The first step of the heteromines (4.57) and (4.58) synthesis from (4.56) is the N-9 methylation with ICH3 using K2CO3 or NaH as the base. These conditions yield the N9methylpurine as the major product. The N7-methyl regioisomer is not detectable, however, the N7,N9-bismethylated purine is formed as a side-product, which easily decomposed during basic treatment.

Note 1: N7/N9 alkylation selectivity depends on both the nature of the group at C-6, the reaction conditions (solvent, temperature, stoichiometry) and the nature of the alkylating agent. The N-9 alkylation is preponderant in any case. The use of a bulky group at C-6 increases the N-9 alkylation. Note 2: Selective N-7 alkylation requires set-up a different approach by introducing a protecting group at N-9, followed by alkylation at N-7 and deprotection of N-9. The other strategy will be to build the purine ring from judiciously substituted pyrimidines. The next steps to heteromines require the selective mono- or bis-methylation of the 2-NH2 group.

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Direct methylation with ICH3 will neither be efficient nor selective, and will mainly occur at N-7. Reductive methylation with formaldehyde under acid conditions, using a large excess of reagents, gives the NMe2 group in high yield. To successfully prepare the monomethylated analog, a three-step approach is necessary: NH2 monoprotection with benzoyl chloride, N-alkylation and protecting group removal. Note: the benzoyl group plays two roles: protecting and activating group. The last step is, in both series, the N-7 methylation.

For detailed optimization work, See Roggen H. et al. Tetrahedron 2009, 65, 5199. ________

Exercise 17________

1) Chlorination of the 2,3,5-tri-O-acetylguanosine with POCl3 gives the 6-chloropurine derivative (4.59).

2) Nucleophilic substitution at C-6 of (4.59) by ammonia gives the diaminopurine derivative (4.64). Note the ribose deprotection in these conditions.

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Then, diazotation of (4.64) with sodium nitrite (NaNO2) followed by hydrolysis affords isoguanosine (4.62). The diazonium salt is the intermediate formed during the reaction.

The 2,6-dichloropurine (4.60) is also prepared from (4.59) by a similar diazotation step (with benzyltriethylammonium nitrite) in the presence of acetyl chloride as a chlorine donor.

The last two compounds are prepared by nucleophilic substitution from (4.60). As observed with 2,4-dichloropyrimidine, the most reactive position to nucleophilic substitution is the purine C-6. (4.61) is then obtained from ammonia in ethanol (in the presence of ammonia, the O-acetyl groups are removed). A second SNAr step using NBoc-piperazine affords (4.63).

Note the difference in temperature required for the two reactions. The substitution at C-6 is done at room temperature. The presence of the 6-amino group then increases the electron

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density of the pyrimidine ring and makes much more difficult the second reaction, which requires higher temperature. For more applications, See Bhattarai S. et al. J. Med. Chem. 2020, 63, 2941. ________

Exercise 18________

The three reactions first involve lithiation at the C-8 and 2-amino group. After addition of the chlorinating agent hexachloroethane, (4.65) and (4.69) give the expected 8-chloro analogs (4.66) and (4.70), after THP removal.

In the case of (4.67), the reaction should have also given (4.70), however, the chemical formula of the isolated product (4.68) differs (elimination of HCl). Comparing the structure and reactivity of (4.67) with those of (4.65) and (4.69) points to the importance of the simultaneous presence of a leaving group at C-6 (Cl) and the 2-NH2 group. The mechanism is shown below. It involves the pyrimidine ring opening and formation of bis(cyanamido)pyrrole (4.68).

See Mahajan T. R. and Gundersen L.-L. Tetrahedron Lett. 2015, 56, 5899.

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________

Exercise 19________

The final product of the transformation of the 6-chloropurine is the N7-alkylated-6chloropurine (4.71). Alkylation at purine N-9 is favored in most cases, therefore the first step is the introduction of a protecting group (trityl here) at this position. Direct alkylation of N-7 would yield an unstable N7,N9-bis-alkylated cation. To overcome the problem, a reduction/oxidation pathway is designed. The three steps shown below are the reduction to 7,8-dihydro-purine, alkylation at N-7, trityl deprotection and MnO2 oxidation, thus giving (4.71) in high global yield.

For more examples, see Kotek V. et al. Org. Lett. 2010, 12, 5724. ________

Exercise 20________

In this exercise, regioselective N-7 alkylation is the key-step in the preparation of the diazepinopurines (4.74), (4.76) and (4.78), and different approaches are used. 1) A first Mitsunobu reaction gives the N-9 protection with diphenylmethyl group (DPM), then the chloro nucleophilic substitution by O-benzylhydroxylamine leads to (4.72). Note that (4.72) exists under two tautomeric forms, the oxime being major. Alkylation with bromopropanol and DPM deprotection gives (4.73). Note that the alkylation is realized without the addition of a base, which may have favored the competitive N-alkylation on the pyridine ring. A second Mitsunobu reaction allows the formation of the diazepine ring, giving (4.74) after benzyl removal.

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2) The diazepinonopurine (4.76) is directly prepared from the benzyloxyaminopurine (4.75). Amidation with vinyl acrylate gives the corresponding vinyl amide that then undergoes a Michael-type addition to give the diazepinone ring. Hydrogenolysis of the benzyl group yields (4.76).

3) The presence of the large trimethoxyphenylmethyl (TMPM) group at N-3 hinders the N-9 position thus favoring the alkylation at N-7. The intramolecular cyclization affords (4.78) after TMPM cleavage.

Note: 3-TMPM-protected adenine is prepared from adenine and trimethoxybenzylbromide by heating at 70 °C in DMF for 36 h, in 46% yield.

3,4,5-

For the detailed reaction conditions, see Pappo D. and Kashman Y. Tetrahedron 2003, 59, 6493.

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________

Exercise 21________

The functionalization of purine (4.79) into (4.82) follows the sequence of steps detailed below. Remember that C-6 is the most favored site for nucleophilic substitution, and Cl is a good leaving group (better than I for SNAr). Sonogashira cross-coupling is easily achieved at C2 due to the presence of iodine. To achieve the second SNAr, thiol must be transformed in a good leaving group by oxidation into sulfone.

See Brun V. et al. Tetrahedron Lett. 2001, 42, 8161. ________

Exercise 22________

These two reactions show the interest of a vinyl group in the functionalization of purines. The formation of (4.83) involves the regioselective abstraction of H at C-8 directed by the presence of THP and its iodination. Stille cross-coupling and Michael-type addition of the thiolate afford (4.83).

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The second pathway shows the vinylation at C-2. Catalytic hydrogenation is often used to remove chlorine atoms from heterocycles. Transformation of the amino group by diazotation and iodination give (4.84). Stille coupling and cycloaddition with cyclopentadiene yield (4.85).

See Liu F. et al. Acta Chem. Scandinavica 1999, 53, 269. ________

Exercise 23________

The formation of 2,6,8-trisubstituted purine (4.86) successively involves Fe-catalyzed cross-coupling of Grignard reagent at C-6, Suzuki coupling of phenylboronic acid at C-2, and Pd-catalyzed direct arylation at C-8 in the presence of CuI and Cs2CO3.

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For more details, see Cerna I. et al. Org. Lett. 2006, 8, 5389 (C-H arylation), Hocek M. et al. J. Org. Chem. 2003, 68, 5773 (C-2 and C-6 cross-couplings).

________

Exercise 24________

The preparation of the cyclic tetramer (4.94) from the N9-benzyl-6-chloro-8-iodopurine (4.87) involves a series of iterative Pd-catalyzed coupling reactions and iodination. Note that the choice of the two halogens in the purine reactant is critical to regioselectivity (I more reactive than Cl for Pd-catalyzed reactions). The first two steps correspond to the metalation at C-8 and Negishi cross-coupling of the organozinc intermediate formed with 6-iodopurine (4.88), leading to (4.89). Treatment of (4.89) in aqueous HI smoothy exchanges the Cl for I at the C-6 position with the formation of the dimer (4.90).

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In the next steps, (4.90) is engaged with the organozinc intermediate derived from (4.87) to afford the trimer (4.91), which is also iodinated at C-6 in (4.92).

This trimer (4.92) undergoes a similar procedure starting from (4.87) to access the tetramer (4.93). To achieve the last step of cyclization, the remaining C-8 position of (4.93) is activated by NIS iodination, and then the ring-closure is achieved by hexamethylditin mediated reductive cyclization. The imidazoyl-stannane formed in situ at C-8 is engaged in a Stille reaction (see Hitchcock S. A. et al. Tetrahedron 1995, 36, 9085).

Note: (4.87) may easily be prepared from 6-chloropurine by reaction with NIS thanks to the high reactivity of C-8 with electrophiles. For more details on the synthesis optimization, see Guthmann H. et al. Eur. J. Org. Chem. 2007, 632.

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________

Exercise 25________

The preparation of the pentacycle (4.95) first involves the modification of N-9 by Cu(II)catalyzed N-arylation (conditions b). A Suzuki reaction (conditions c) on the pendant bromo-phenyl substituent and the intramolecular direct C-H arylation (conditions a) allows the ring closure to give (4.95).

For the discussions on different approaches to (4.95), see Cerna I. et al. J. Org. Chem. 2010, 75, 2302. ________

Exercise 26________

The regioselectivity of the two arylation reactions is mainly based on the nature of the arylhalide partner. Chlorine is not a good leaving group for the N-arylation but more acceptable for C-H direct arylation. The presence of the copper catalyst generally used to catalyze C-H direct arylation, is also a good indication that in the first step the reaction will occur at C-8 to give (4.97). The second step, the N-arylation of the 6-NH2 group, is realized in the presence of two equivalents of 2-bromopyridine, thus giving (4.98). Performing the two reactions in one pot yields (4.99).

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Note: Using the iodotoluene in the first reaction conditions gives a mixture of C8-arylation and C8/N-arylations, thus highlighting the importance of the nature of the arylhalide.

For more examples, see Sahnoun S. et al. Org. Biomol. Chem. 2009, 7, 4271. ________

Exercise 27________

Indolizines or pyrrolo[1,2-a]pyridines react with electrophiles on the pyrrole moiety and with nucleophiles on the pyridine moiety. As observed with pyrrole, electrophilic reactions mainly occur at the nitrogen orthoposition, indolizine C-3. Acid-catalyzed Friedel-Crafts type acylation yields 3acylindolizine (4.100), but in harsher conditions (excess acyl chloride, higher temperature and reaction time), additional C-1 acylation will lead to 1,3-diacetylindolizine. Direct arylation, also involving an electrophilic reaction, gives the 3-arylindolizine compound (4.101).

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To achieve the functionalization of the electron-deficient pyridine part, one method of choice is the lithiation (at the nitrogen ortho-position as in pyridine itself) followed by reaction with various electrophiles: iodine or CO2 in the case of (4.102) or (4.104) respectively. Then, the Suzuki-Miyaura coupling reaction can be used for further functionalization from aryl iodide derivative (4.102), as exemplified by the formation of (4.103).

The last reaction is the Pd-catalyzed oxidative homo-coupling, yielding (4.105). Cu(OAc)2 is used as an oxidant, and the reaction occurs at the most electron-rich C-3 position as seen above.

For more applications, see Park C.-H. et al. Org. Lett. 2004, 6, 1159 (Pd-catalyzed arylation); Renard M. and Gubin J. Tetrahedron Lett. 1992, 33, 4433 (metalation and reactivity at C-5); Xia J.-B. eta l. J. Org. Chem. 2009, 74, 456 (C-H/C-H coupling).

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________

Exercise 28________

1) The first reaction involves the Vielsmeier-Haack formylation of (4.106) to give the 3formyl derivative (4.107). Like in pyrrole, the nitrogen ortho position is favored for SEAr. In the second reaction, an aldol condensation happens between the indolizine 7-acetyl group of (4.108) and p-nitrobenzaldehyde, thus giving (4.109).

Note: The reactivity of the substituents that decorate (hetero)aromatics should always be considered. 2) The proposed synthesis of the indolizines involves a base-catalyzed Knoevenagel condensation followed by an intramolecular aldol reaction.

________

Exercise 29________

The starting bicycle is the imidazo[1,2-a]pyrimidine. The calculated electronic structure is in favor of C-3 as the most reactive position for electrophilic substitution (see Paudler W.W. and Kuder J. E. J. Org. Chem. 1966, 31, 809). Writing the different mesomeric forms is also a good tool to predict reactivity. Delocalization of the lone pair of N-4 on the imidazole moiety induces less perturbation of the pyrimidine aromaticity if the negative charge is located at C-3 and not at C-2.

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In the first pathway, (4.110a,b) first undergo iodination at the most reactive C-3 position followed by Suzuki reaction to give (4.111a,b). By lowering the electron density of the ring, the presence of the electron-withdrawing ester at C-2 disfavors the first step and a lower yield for the electrophilic reaction is observed for (4.110b) compared to (4.110a)). On the contrary, the second step, i.e. oxidative palladium addition, will be easier and its yield higher in the presence of the electron-withdrawing group.

The compound (4.111a) is quantitatively obtained in one step by direct arylation, also involving an electrophilic type reaction (with the phenyl-palladium halide intermediate). For more examples, see Enguehard C. et al. J. Org. Chem. 2000, 65, 6572 (two-step approach) and Li W. et al. Org. Lett. 2003, 5, 4835 (direct arylation). ________

Exercise 30________

The amide (4.114) is obtained either by amidation of the acid (4.112) with the HBTU coupling agent, or by transamidation of the ethyl ester (4.113) however with a much lower yield. Aqueous hydrolysis of the ester (4.113) gives (4.115), which happens to be a structural isomer of (4.112). Its amidation yields (4.116), identified as a structural isomer of (4.114).

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Formation of (4.115) from (4.113) in basic conditions involves the ANRORC Dimroth rearrangement already seen in Exercise 15 and shown below.

For a detailed study of the mechanism, see Chatzopoulou M. et al. Tetrahedron 2018, 74, 5280. ________

Exercise 31________

The exercise deals with the preparation of cycl[2,2,3]azines, and more precisely of pyrrolo[2,1,5-cd]indolizines. 1) The first step is the Vielsmeier-Haack formylation of the indolizine (as seen in previous exercises, this electrophilic reaction is regioselective at C-3). Then, hydrogen abstraction at the methyl group in basic conditions and nucleophilic attack of the carbonyl group gives (4.117).

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2) A similar mechanism is involved in the formation of the indolizine (4.118), i.e. easy hydrogen abstraction at CH3 due to the presence of the positive charge on the ring nitrogen, and nucleophilic attack of the benzoyl group giving the five-membered ring. The reaction of (4.118) with the electron-deficient dimethyl acetylenedicarboxylate most probably involves a [8+2] cycloaddition forming the dihydro-tricycle that re-aromatize in the presence of Pd/C to give (4.119). The next sequence of reactions is used for transforming ester groups into cyanide.

Note 1: The dehydrogenation step following cyclization in the formation of (4.119) may also occur spontaneously by air oxidation. Other reagents such as MnO2 have also been used to increase the efficiency of the process. Note 2: The compound (4.119) may also be obtained by a three-component reaction, starting from 2-methylpyridine, bromobenzophenone et dimethyl acetylenedicarboxylate (see Gogoi S. et al. Tetrahedron Lett. 2011, 52, 813).

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3) In this third example, the first step of cycloaddition occurs under air atmosphere to give (4.122) as seen above. Formation of the fused-pentacyclic (4.124) involves the formation of the intermediate (4.123) by methyl bromination with NBS and intramolecular alkylation of the pyridine ring. A second [8+2] cycloaddition step with dimethyl acetylenedicarboxylate, DMAD, affords the fused-hexacyclic compound (4.124).

For a discussion on the cyclization mechanism, see Galbraith. A. et al. J. Amer. Chem. Soc. 1961, 83, 453 and Starokov A. S. et al. Eur. J. Org. Chem. 2020, 5852. For more applications and other synthetic methods, see Babaev E. V. et al. Molecules 2021, 26, 2050.

List of books and reviews

1. Che, Y. X.; Qi, X. N.; Qu, W. J.; Shi, B. B.; Lin, Q.; Yao, H.; Zhang, Y. M.; Wei, T. B., Synthetic strategies of phenazine derivatives: A review. J. Het. Chem. 2022, 59 (6), 969-996. 2. Reeves, E. K.; Entz, E. D.; Neufeldt, S. R., Chemodivergence between Electrophiles in Cross‐Coupling Reactions. Chem. Eur. J. 2021, 27 (20), 6161-6177. 3. Motati, D. R.; Amaradhi, R.; Ganesh, T., Recent developments in the synthesis of azaindoles from pyridine and pyrrole building blocks. Org. Chem. Front. 2021, 8 (3), 466-513. 4. Hunjan, M. K.; Panday, S.; Gupta, A.; Bhaumik, J.; Das, P.; Laha, J. K., Recent advances in functionalization of pyrroles and their translational potential. Chem. Rec. 2021, 21 (4), 715-780. 5. Wang, L.; Zhang, J.; Zhao, J.; Yu, P.; Wang, S.; Hu, H.; Wang, R., Recent synthesis of functionalized s-tetrazines and their application in ligation reactions under physiological conditions: a concise overview. Catal. Rev. 2020, 62 (4), 524-565. 6. Pal, T.; Lahiri, G. K.; Maiti, D., Copper in efficient synthesis of aromatic heterocycles with single heteroatom. Eur. J. Org. Chem. 2020, 2020 (44), 6859-6869. 7. Mekheimer, R. A.; Al-Sheikh, M. A.; Medrasi, H. Y.; Sadek, K. U., Advancements in the synthesis of fused tetracyclic quinoline derivatives. RSC adv. 2020, 10 (34), 19867-19935. 8. Joule, J. A.; Mills, K.; Smith, G. F. Eds., Heterocyclic chemistry. CRC Press, London: 2020. 9. Gujjarappa, R.; Vodnala, N.; Malakar, C. C., Comprehensive Strategies for the Synthesis of Isoquinolines: Progress Since 2008. Adv. Synth. Catal. 2020, 362 (22), 48964990. 10. Fuertes, M.; Masdeu, C.; Martin-Encinas, E.; Selas, A.; Rubiales, G.; Palacios, F.; Alonso, C., Synthetic Strategies, Reactivity and Applications of 1, 5-Naphthyridines. Molecules 2020, 25 (14), 3252. 11. Calcaterra, A.; Mangiardi, L.; Delle Monache, G.; Quaglio, D.; Balducci, S.; Berardozzi, S.; Iazzetti, A.; Franzini, R.; Botta, B.; Ghirga, F., The pictet-spengler reaction updates its habits. Molecules 2020, 25 (2), 414.

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12. Baccalini, A.; Faita, G.; Zanoni, G.; Maiti, D., Transition Metal Promoted Cascade Heterocycle Synthesis through C− H Functionalization. Chem. Eur. J. 2020, 26 (44), 9749-9783. 13. Joule, J. A.; Álvarez, M., Pyridoacridines in the 21st Century. Eur. J. Org. Chem. 2019, 2019 (31-32), 5043-5072. 14. Dorel, R.; Grugel, C. P.; Haydl, A. M., The Buchwald–Hartwig amination after 25 years. Angew. Chem. Int. Ed. 2019, 58 (48), 17118-17129. 15. Bugaenko, D. I.; Karchava, A. V.; Yurovskaya, M. A., Synthesis of indoles: recent advances. Russ. Chem. Rev. 2019, 88 (2), 99. 16. Sinha, A. K.; Equbal, D.; Uttam, M. R., Metal-catalyzed privileged 2-and 3functionalized indole synthesis. Chem. Heterocycl. Compd. 2018, 54 (3), 292-301. 17. Heravi, M. M.; Kheilkordi, Z.; Zadsirjan, V.; Heydari, M.; Malmir, M., Buchwald-Hartwig reaction: an overview. J. Organomet. Chem. 2018, 861, 17-104. 18. Plodek, A.; Bracher, F., New perspectives in the chemistry of marine pyridoacridine alkaloids. Marine drugs 2016, 14 (2), 26. 19. Laha, J. K.; Bhimpuria, R. A.; Prajapati, D. V.; Dayal, N.; Sharma, S., Palladium-catalyzed regioselective C-2 arylation of 7-azaindoles, indoles, and pyrroles with arenes. Chem. Commun. 2016, 52 (23), 4329-4332. 20. Bheeter, C. B.; Chen, L.; Soulé, J.-F.; Doucet, H., Regioselectivity in palladiumcatalysed direct arylation of 5-membered ring heteroaromatics. Catal. Sci. Technol. 2016, 6 (7), 2005-2049. 21. Liang, Y.; Wnuk, S. F., Modification of purine and pyrimidine nucleosides by direct CH bond activation. Molecules 2015, 20 (3), 4874-4901. 22. Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C., Cross‐Coupling of Heteroarenes by C- H Functionalization: Recent Progress towards Direct Arylation and Heteroarylation Reactions Involving Heteroarenes Containing One Heteroatom. Adv. Synth. Catal. 2014, 356 (1), 17-117. 23. Prajapati, S. M.; Patel, K. D.; Vekariya, R. H.; Panchal, S. N.; Patel, H. D., Recent advances in the synthesis of quinolines: a review. Rsc Advances 2014, 4 (47), 24463-24476. 24. Khan, I.; Ibrar, A.; Abbas, N.; Saeed, A., Recent advances in the structural library of functionalized quinazoline and quinazolinone scaffolds: Synthetic approaches and multifarious applications. Eur. J. Med. Chem. 2014, 76, 193-244. 25. Zhao, L.; Bruneau, C.; Doucet, H., Palladium‐catalysed direct polyarylation of pyrrole derivatives. ChemCatChem 2013, 5 (1), 255-262. 26. Wang, D.; Gao, F., Quinazoline derivatives: synthesis and bioactivities. Chem. Cent. J. 2013, 7 (1), 1-15. 27. Liu, C.; Luo, J.; Xu, L.; Huo, Z., Synthesis of 2-substituted pyridines from pyridine N-oxides. Arkivoc 2013, 1, 154-174. 28. Li, J. J., Heterocyclic chemistry in drug discovery. John Wiley & Sons, Hoboken: 2013. 29. Inman, M.; Moody, C. J., Indole synthesis–something old, something new. Chem. Sci. 2013, 4 (1), 29-41. 30. Rossi, R.; Bellina, F.; Lessi, M., Selective Palladium‐Catalyzed Suzuki–Miyaura Reactions of Polyhalogenated Heteroarenes. Adv. Synth. Catal. 2012, 354 (7), 1181-1255.

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31. Gribble, G. W., Metalation of Azoles and Related Five-Membered Ring Heterocycles. Vol. 29. Topics in Heterocyclic Chemistry, Maes B. U. W. Series Ed. Springer: 2012 32. Zhao, D.; You, J.; Hu, C., Recent progress in coupling of two heteroarenes. Chem. Eur. J. 2011, 17 (20), 5466-5492. 33. Tyrell, J. A.; Quin, L. D. Eds., Fundamentals of heterocyclic chemistry: importance in nature and in the synthesis of pharmaceuticals. John Wiley & Sons, Hoboken: 2010. 34. Roger, J.; Gottumukkala, A. L.; Doucet, H., Palladium-catalysed C3 or C4 direct arylation of heteroaromatics via a CH bond activation using aryl halides. ChemCatChem 2010, 2, 20-40. 35. Getmanenko, Y. A.; Tongwa, P.; Timofeeva, T. V.; Marder, S. R., Basecatalyzed halogen dance reaction and oxidative coupling sequence as a convenient method for the preparation of dihalo-bisheteroarenes. Org. Lett. 2010, 12 (9), 2136-2139. 36. Clavier, G.; Audebert, P., s-Tetrazines as building blocks for new functional molecules and molecular materials. Chem. Rev. 2010, 110 (6), 3299-3314. 37. Bellina, F.; Rossi, R., Regioselective Functionalization of the Imidazole Ring via Transition Metal‐Catalyzed C-N and C-C Bond Forming Reactions. Adv. Synth. Catal. 2010, 352 (8), 1223-1276. 38. Joule; J. A. and Mills K. Eds. Heterocyclic Chemistry, Wiley, New-York 2010. 39. Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F., Lamellarins and related pyrrolederived alkaloids from marine organisms. Chem. Rev. 2008, 108 (1), 264-287. 40. Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.; Senanayake, C. H., Organometallic methods for the synthesis and functionalization of azaindoles. Chem. Soc. Rev. 2007, 36 (7), 1120-1132. 41. Seregin, I. V.; Gevorgyan, V., Direct transition metal-catalyzed functionalization of heteroaromatic compounds. Chem. Soc. Rev. 2007, 36 (7), 1173-1193. 42. Schnürch, M.; Spina, M.; Khan, A. F.; Mihovilovic, M. D.; Stanetty, P., Halogen dance reactions—A review. Chem. Soc. Rev. 2007, 36 (7), 1046-1057. 43. Campeau, L.-C.; Fagnou, K., Applications of and alternatives to π-electrondeficient azine organometallics in metal catalyzed cross-coupling reactions. Chem. Soc. Rev. 2007, 36 (7), 1058-1068. 44. Banwell, M. G.; Goodwin, T. E.; Ng, S.; Smith, J. A.; Wong, D. J., Palladium‐ Catalysed Cross‐Coupling and Related Reactions Involving Pyrroles. Eur. J. Org. Chem. 2006, 2006 (14), 3043-3060. 45. Lane, B. S.; Brown, M. A.; Sames, D., Direct palladium-catalyzed C-2 and C-3 arylation of indoles: a mechanistic rationale for regioselectivity. J. Amer. Chem. Soc. 2005, 127 (22), 8050-8057. 46. Duan, X.-F.; Zhang, Z.-B., Recent progress of halogen-dance reactions in heterocycles. Heterocycles 2005, 65 (8), 2005-2012. 47. Kirsch, G.; Hesse, S.; Comel, A., Synthesis of five-and six-membered heterocycles through palladium-catalyzed reactions. Curr. Org. Synth. 2004, 1 (1), 47-63. 48. Littke, A. F.; Fu, G. C., Palladium‐catalyzed coupling reactions of aryl chlorides. Angew. Chem. Int. Ed. 2002, 41 (22), 4176-4211. 49. Battistuzzi, G.; Cacchi, S.; Fabrizi, G., The aminopalladation/reductive elimination domino reaction in the construction of functionalized indole rings. Eur. J. Org. Chem. 2002, 2002 (16), 2671-2681.

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50. Youssif, S., Recent trends in the chemistry of pyridine N-oxides. Arkivoc 2001, 1, 242-268. 51. Molinski, T. F., Marine pyridoacridine alkaloids: structure, synthesis, and biological chemistry. Chem. Rev. 1993, 93 (5), 1825-1838 Apple Interactive book: The portable chemist’s consultant. A survival guide for discovery, process and radiolabeling. Ishihara Y., Montero A. and P. Baran. First published 2013.

Appendix Basic notions of nomenclature or how to find out the ring structure from its name It is generally easier to find a structure from its name than the other way around. We will limit this short overview of the basic principles of nomenclature through the study of a few examples of “name to structure” determination of unsaturated heterocycles. The first point to remember is the definition of a heterocycle: a ring that contains at least one heteroatom (other than carbon), in most cases nitrogen, oxygen, or sulfur. The standard method used here follows the Hantzsch-Widman rules. A large number of heterocycles has a trivial name (such as pyridine, pyrrole, carbazole, purine…), which will be chosen preferably when establishing the name. Lists of trivial names can be easily found on the internet. If there is no trivial name, to define the heterocycle you need: -

The prefix that gives the type and number of heteroatoms and their relative positions into the ring (oxa for O, thia for sulfur and aza for N). The atoms are cited in their order of importance: O > S > N.

Note: in the case where two vowels are found side by side, the first one is deleted (oxaaza will be oxaza). -

The suffix that indicates the size of the ring and the degree of unsaturation (-ine for an unsaturated 6-membered ring, and -ole for a 5-membered ring).

Note: the suffix is different for saturated rings (-ane or -inane for a 6-membered ring, and -olane for a 5-membered ring). -

The position of the common bond in fused heterocycles

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1) Mono-cyclic heterocycles: In this first example, the suffix -ine indicates a 6membered heterocycle. The prefix oxathiaz(a) (for oxa-thia-aza) designates the presence of three heteroatoms: O, S, N, and the numbers 1,4,2 correspond to their relative positions. Numbering starts at the most important atom, O in the present case. The heteroatoms have the lowest possible numbers. In this second example, the suffix -ole indicates a 5membered heterocycle. The prefix triaza implies the presence of three N, and the numbers 1,2,4 correspond to their relative positions. Numbering starts at N-H (pyrrole-type nitrogen). Note: The smallest possible numbers are given at the heteroatoms (1, 2, 4- is better than 1,3,5-)

2) Benzo-fused heterocycles. For the benzo-fused heterocycles without a trivial name, the name is in the form: benzo[letter]heterocycle.

Appendix - Basic notions of nomenclature or how to find out the ring structure from its name

229

The bonds of the main ring, the heterocycle, are identified with letters (“a” for a bond between positions 1 and 2, “b” for the C2-C3 bond and so on…). The bond shared by the two cycles is written in brackets in italics.

3) Fused-heterocycles For fused heterocycles without a trivial name, the name is in the form: minor ring[number,number-letter]main ring. The name is composed of the prefix, derived from the minor heterocycle name (pyrrolo for pyrrole, pyrido for pyridine, furo for furane…), and of the suffix corresponding to the major ring name. The numbers in brackets refer to the atoms of the minor ring involved in the common bond, and the letter refers to the bond of the major ring. The black arrow indicates the numbering direction of the main ring.

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Note: the numbering direction of the main ring is used to differentiate regioisomers as illustrated below.

Note: To do the opposite task, i.e. structure to name determination, other rules are to be known, in particular for the selection of the main cycle and the re-numbering of the newly named heterocycle. This is not the purpose of the present book to detail all these rules. Nomenclature courses and IUPAC recommendations may be found on different internet websites.