Palladium and Norbornene Cooperative Catalysis E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 385

Veröffentlichungsjahr: 2025

Beschreibung

A comprehensive exploration of Pd/Norbornene (NBE) catalysis

In Palladium and Norbornene Cooperative Catalysis: Fundamentals and Applications, renowned researcher Professor Guangbin Dong delivers a systematic and comprehensive discussion of Pd/NBE catalysis, including its mechanisms, scopes, applications, and current limitations. The book provides readers with the fundamental knowledge they will need to use this type of catalysis in their own research, as well as how to choose the best reaction conditions and catalyst combinations.

Each of the eight chapters are written by leading experts in the Pd/NBE catalysis field. They cover topics ranging from the mechanistic foundation of Pd/NBE catalysis to the scope of the ipso and ortho functionalization, asymmetric development, a review of the Pd/NBE-catalyzed heteroarene functionalization, and more.

Readers will also find:

• A thorough introduction to intramolecular and intermolecular cyclizations
• Comprehensive explorations of the annulation chemistry
• Practical discussions of Pd(II)-initiated reactions
• A complete summary of a variety of applications in the synthesis of complex molecules and organic materials using Pd/NBE catalysis

Perfect for chemistry students with an interest in transition-metal catalysis and organic synthesis. This book will also benefit academic researchers and practicing chemists.

Leseprobe

Table of Contents

Cover

Table of Contents

Title Page

Copyright

Dedication

Preface

1 The Palladium/Norbornene‐Catalyzed Annulation Chemistry: Rapid Access to Diverse Ring Structures

1.1 Introduction

1.2 Intramolecular Cyclizations

1.3 Intermolecular Cyclizations Following Intermolecular

Ortho

Functionalization

1.4 Cyclizations with Three‐Membered Heterocycles as Both the Electrophile and Terminating Reagent

1.5 Norbornene/Norbornadiene‐Integrated Cyclizations

1.6 One‐Pot Postcatalytic Intramolecular Cyclizations

1.7 Summary

References

2 Diverse

Ipso

Arene Functionalization by the Palladium/Norbornene Cooperative Catalysis

2.1 Introduction

2.2

Ipso

Functionalization Reaction in the Pd/NBE Catalytic Cycle

2.3 Type of

Ipso

Functionalization Reactions

2.4 Prospects and Challenges of

Ipso

Functionalization

References

3 Diverse

Ortho

C–H Functionalization by the Palladium/Norbornene Cooperative Catalysis

3.1 Introduction

3.2 Carbon‐Electrophile

3.3 Nitrogen‐Electrophile

3.4 Sulfur‐Electrophile

3.5 Oxygen‐Electrophile

3.6 Conclusion and Outlook

References

4 Asymmetric Palladium/Norbornene Cooperative Catalysis

4.1 Introduction

4.2 Stereochemistry Controlled by the Substrate

4.3 Catalytic Asymmetric Transformations Controlled by Chiral Ligands

4.4 Catalytic Asymmetric Transformation Controlled by Chiral Norbornenes

4.5 Summary and Outlook

References

5 Pd(II)‐Initiated Palladium/Norbornene Cooperative Catalysis

5.1 Introduction

5.2 Pd/NBE‐catalyzed C–H Functionalization of NH‐containing Heteroarenes

5.3 Directing Group‐Enabled

meta

‐C–H Functionalization of Arenes

5.4 Directing Group‐Free Mono‐ and Difunctionalization of (Hetero)Arenes

5.5 Template‐Enabled Remote C–H Functionalization

5.6 Enantioselective Remote C–H Functionalization

5.7 Borono‐Catellani Reactions

5.8 Conclusion and Outlook

References

6 Functionalization of Heteroarenes by the Palladium/Norbornene Cooperative Catalysis

6.1 Introduction

6.2 Pd/NBE Reactions of Five‐Membered Haloheteroarenes

6.3 Pd/NBE Reactions of Six‐Membered Haloheteroarenes

6.4 Pd/NBE Reactions of Parent Heteroarenes

6.5 Conclusion

List of Abbreviations

Acknowledgments

References

7 Addressing the Substrate Limitation in the Palladium/Norbornene Cooperative Catalysis

7.1 Introduction

7.2

Ortho

Constraint

7.3

Meta

Constraint

7.4 Aryl Iodide Constraint

7.5 Beyond Aromatic Substrates

7.6 Conclusions and Outlook

Acknowledgments

References

8 Application of the Palladium/Norbornene Cooperative Catalysis to Synthesis of Natural Products and Materials

8.1 Applications in Synthesis of Natural Products and Drugs

8.2 Applications in Synthesis of Organic Aromatic Materials

8.3 Summary

References

Index

End User License Agreement

List of Tables

Chapter 7

Table 7.1 Summary of bis

ortho

C—H functionalization reactions.

Table 7.2 NBE effect for the mono

ortho

C—H amination of 3‐iodotoluene.

Table 7.3 Selected substrate scope for mono

ortho

functionalization of

meta

...

Table 7.4 NBE effect in Pd(II)‐initiated C—H arylation.

Table 7.5 Sequential unsymmetrical C—H diarylation of anisole.

Table 7.6 The NBE effect for the annulation reaction.

Table 7.7 Selected substrate scope for THBAs syntheses.

Table 7.8 Selected substrate scope for mono

ortho

alkylation.

Table 7.9 Annulation to form fused tricyclic compounds.

Table 7.10 NBE examination for

meta

constraint.

Table 7.11 Selected substrate scope for addressing the

meta

constraint.

Table 7.12 Selected substrate scope for aryl triflate annulation.

Table 7.13 Comparison of the leaving groups.

Table 7.14

Ortho

‐amination/

ipso

‐Heck reaction of aryl triflates.

Table 7.15 Ligand effect for the

ortho

‐amination/

ipso

‐hydrogenation of aryl ...

Table 7.16 Selected substrate scope for Catellani‐type reactions of aryl bro...

Table 7.17 Selected substrate scope for

ortho

‐oxygenation of aryl bromides....

Table 7.18 Selected substrate scope for difunctionalization of iodopyridones...

Table 7.19 NBE effect for alkenyl bromide difunctionalization.

Table 7.20 Representative scope of tetrasubstituted alkene products.

Table 7.21 Examination of H/N reagents and NBEs.

Table 7.22 Representative examples for the carbonyl 1,2‐transposition.

Table 7.23 NBE effect for

α‐

carbamoylation of alkenyl triflates....

Table 7.24 Representative examples of forming multisubstituted acrylamide pr...

Table 7.25 Distal alkenyl C—H arylation.

Chapter 8

Table 8.1 Summary of natural product/drug synthesis using Pd/NBE cooperative...

List of Illustrations

Chapter 1

Scheme 1.1 The general Catellani reaction.

Scheme 1.2 The general mechanism of the Catellani reaction.

Scheme 1.3 First annulative Catellani methodology.

Scheme 1.4 Examples of

ortho

‐alkylation/

ipso

‐Heck‐termination annulative met...

Scheme 1.5 Macrocycle formation using an epoxide as an alkylating reagent.

Scheme 1.6 First methodology using (homo)allylic alcohols as the Heck accept...

Scheme 1.7 Examples of

ortho

‐alkylation/

ipso

‐redox‐relay Heck annulative met...

Scheme 1.8 Synthesis of annulated indoles via

ipso

C–H arylation.

Scheme 1.9 Examples of

ortho

‐alkylation/

ipso

‐C–H arylation annulative method...

Scheme 1.10

Ipso

‐alkyne insertion followed by C–H activation to form (a) tet...

Scheme 1.11 Syntheses of tetrasubstituted helical alkenes (a) initial report...

Scheme 1.12

Ipso

‐alkyne insertion followed by dearomatization of (a) indoles...

Scheme 1.13 Synthesis of spiroindolenines.

Scheme 1.14 Harnessing

in situ

generated enolates to synthesize (a) tetralin...

Scheme 1.15 Synthesis of carbocycles using alkyl carbagermatranes.

Scheme 1.16 Synthesis of (a) indolines and (b) tetrahydroquinolines via

orth

...

Scheme 1.17 Synthesis of 6‐phenanthridinones.

Scheme 1.18 Subsequent examples of

ortho

‐arylation/

ipso

‐C–N termination annu...

Scheme 1.19 Examples of

ortho

‐arylation/

ipso

‐C–O termination annulative meth...

Scheme 1.20

Ortho

‐arylation/

ipso

‐C=X termination methodologies for the synth...

Scheme 1.21 Enantioselective synthesis of fluorenols.

Scheme 1.22 Synthesis of fluorenes via denitrogenation.

Scheme 1.23 Synthesis of phenanthren‐9‐ols.

Scheme 1.24 Macrocycle formation via

ortho

‐acylation and

ipso

‐Heck terminati...

Scheme 1.25 Subsequent examples of

ortho

‐acylation/

ipso

‐Heck termination ann...

Scheme 1.26 First use of carbamoyl chlorides in Pd/NBE chemistry.

Scheme 1.27 Subsequent examples of

ortho

‐acylation/

ipso

‐C–H arylation annula...

Scheme 1.28 Synthesis of N‐containing bridged scaffolds via

ortho

‐amination/

Scheme 1.29 Synthesis of C3,C4‐disubstituted indoles via

ortho

‐amination/

ips

...

Scheme 1.30 Synthesis of tetrahydrobenzo[b]azepines using (a) C7‐ and (b) C2...

Scheme 1.31 Br on a modified NBE's C7 acting as an L ligand coordinating to ...

Scheme 1.32 Indole formation via reversal of traditional regioselectivity of...

Scheme 1.33 Pd(II)‐initiated annulative methodologies using (a) boronic acid...

Scheme 1.34 First methodology of

ortho

‐functionalization with an external re...

Scheme 1.35 Subsequent examples of

ortho

‐functionalization with an external ...

Scheme 1.36 First methodology of ortho‐functionalization with a tethered ele...

Scheme 1.37 Combining an iodoarene tethered to an electrophile with an elect...

Scheme 1.38 Subsequent examples of intramolecular

ortho

‐functionalization fo...

Scheme 1.39 Intramolecular

ortho

‐alkylation followed by intramolecular (a)

i

...

Scheme 1.40 Study on the erosion of enantiomeric excess using enantioenriche...

Scheme 1.41 Synthesis of phenanthrenes from an alkyne and (a) two identical ...

Scheme 1.42 Synthesis of triphenylenes from an aryl iodide and two

ortho

‐bro...

Scheme 1.43 Synthesis of spirocarbocycles from aryl iodides, bromonaphthols,...

Scheme 1.44 Synthesis of indoles from aryl iodides,

O

‐benzoylhydroxylamines,...

Scheme 1.45 Synthesis of (a) indoles and (b) dihydroimidazoles from aryl iod...

Scheme 1.46 Proposed mechanism for the formation of indoles and dihydroimida...

Scheme 1.47 Synthesis of indolines from aryl iodides and (a) 2‐unsubstituted...

Scheme 1.48 Synthesis of 2,3‐dihydrobenzofurans from aryl iodides and epoxid...

Scheme 1.49 Synthesis of NBE‐containing adducts due to a coordinating amide‐...

Scheme 1.50 Synthesis of NBE‐containing azacycles following C(sp

2

)–C(sp

3

) re...

Scheme 1.51 Synthesis of NBE‐ and sulfoximine‐containing adducts using (a) o...

Scheme 1.52 Subsequent examples of NBE‐containing adducts.

Scheme 1.53 Structural comparison between NBE and norbornadiene.

Scheme 1.54 Synthesis of norbornadiene‐fused spirocarbocycles via phenol dea...

Scheme 1.55 Synthesis of dibenzoazepines following C(sp

2

)–C(sp

3

) reductive e...

Scheme 1.56 Synthesis of C4‐functionalized indoles via (a)

ortho

‐amination (...

Scheme 1.57 Synthesis of aminated phenanthrenes.

Scheme 1.58 Synthesis of (a) phenanthrene derivatives and (b) heptagon‐embed...

Scheme 1.59 Synthesis of N‐heterocycles via a postcatalytic aza‐Michael addi...

Scheme 1.60 Synthesis of O‐ and N‐heterocycles via postcatalytic oxa‐ and az...

Scheme 1.61 Synthesis of dibenzocycles using (a)

ortho

‐bromophenols, (b)

ort

...

Scheme 1.62 Postcatalytic retro‐Mannich reactions using MVK as the

ipso

‐term...

Scheme 1.63 Postcatalytic intramolecular Michael addition onto an NBE moiety...

Chapter 2

Scheme 2.1 Catalytic cycle.

Scheme 2.2

Ipso

functionalization and NBE insertion.

Scheme 2.3 Alkenylation and NBE insertion.

Scheme 2.4 Electrophile reagents and

ipso

functionalization reagents.

Scheme 2.5 Amines as the nucleophile.

Scheme 2.6 NBE extrusion and

ipso

functionalization.

Scheme 2.7 Effect of phosphine ligands.

Scheme 2.8 Dehalogenation reaction and

ipso

functionalization. Hydrogen sour...

Scheme 2.9 First case of Pd/NBE cooperative catalysis reaction.

Scheme 2.10 The substrate scope of olefins.

Scheme 2.11

Ortho

C–H alkylation and

ipso

alkenylation.

Scheme 2.12

Ortho

C–H arylation and

ipso

alkenylation. (a) C–H self‐arylatio...

Scheme 2.13 Fluoroiodobenzene as the substrate.

Scheme 2.14

Ortho

C–H amination and

ipso

alkenylation.

Scheme 2.15 Different

ortho

C–H functionalization.

Scheme 2.16 Carbene coupling reaction.

Scheme 2.17

Ortho

C–H alkylation and

ipso

carbene coupling reaction.

Scheme 2.18

Ortho

C–H amination and carbene.

Scheme 2.19

Ortho

arylation

ipso

allenylation.

Scheme 2.20

Ortho

C–H amination and

ipso

allenylation.

Scheme 2.21

Ipso

alkynylation reactions.

Scheme 2.22 Application to the synthesis of polymers.

Scheme 2.23 Suzuki coupling and Pd/NBE chemistry.

Scheme 2.24

Ipso

Suzuki coupling reaction.

Scheme 2.25

Ipso

C–H arylation. of various heterocycles.

Scheme 2.26

Ipso

C–H arylation of polyfluoroaromatic hydrocarbons.

Scheme 2.27 Coupling reaction of boron reagents: (a)

ipso

allylation; (b)

ip

...

Scheme 2.28 Coupling reaction of germanium reagents.

Scheme 2.29

Ipso

ketone α‐arylation.

Scheme 2.30

Ortho

‐C–H functionalization.

Scheme 2.31 C–H activation of inert alkyl groups.

Scheme 2.32 The C—C bond cleavage reaction: (a) The C—C bond cleavage reacti...

Scheme 2.33

Ipso

allylation.

Scheme 2.34 The 1,4‐Pd shift.

Scheme 2.35 Hydrogenation reaction.

Scheme 2.36

Ortho

C–H functionalization.

Scheme 2.37 Cyanation reaction.

Scheme 2.38

Ipso

cyanation with various

ortho

C–H functionalization.

Scheme 2.39 Borylation reaction.

Scheme 2.40

Ortho

C–H acylation.

Scheme 2.41 The construction of

ipso

C–S or C–Se bonds: (a)

ortho

C–H carbon...

Scheme 2.42 Decarbonylative

ipso

thiolation reaction.

Scheme 2.43

Ipso

iodination.

Chapter 3

Scheme 3.1 The Pd/NBE catalysis and the development of electrophiles.

Scheme 3.2 Possible mechanisms for the reaction between ANP and the electrop...

Scheme 3.3 First

ortho

alkylation reaction.

Scheme 3.4

Ortho

alkylation using alkyl halides.

Scheme 3.5

Ortho

alkylation of aryl bromides using alkyl halides.

Scheme 3.6

Ortho

alkylation with enantioenriched substrates.

Scheme 3.7 Proposed mechanism for the oxidative addition with ANP.

Scheme 3.8

Ortho

methylation using methyl sulfonates and trimethylammonium s...

Scheme 3.9

Ortho

methylation using 4‐methyl tosylate and trimethylphosphate....

Scheme 3.10

Ortho

alkenylation using 2

H

‐azirines.

Scheme 3.11

Ortho

alkylation reactions using epoxides.

Scheme 3.12

Ortho

alkylation reaction using aziridines.

Scheme 3.13

Ortho

alkylation reaction using ethers and TMSI.

Scheme 3.14 The importance of

ortho

substitution in

ortho

arylation.

Scheme 3.15 Reaction and mechanism study for norbornene involved cyclization...

Scheme 3.16 “

Ortho

effect” in the

ortho

arylation.

Scheme 3.17 Seminal work on the

ortho

arylation reaction.

Scheme 3.18 Homo

ortho

arylation.

Scheme 3.19 Development of the cross‐coupling type

ortho

arylation.

Scheme 3.20 Cross‐coupling type

ortho

arylation.

Scheme 3.21 Cross

ortho

arylation using aryl chlorides as the electrophile....

Scheme 3.22

Ortho

arylation using aryl diazonium salts.

Scheme 3.23

Ortho

acylation using symmetrical anhydrides.

Scheme 3.24

Ortho

acylation reaction using carbonate‐based anhydrides.

Scheme 3.25

Ortho

acylation using acyl chlorides.

Scheme 3.26 Further development of the

ortho

acylation reactions.

Scheme 3.27

Ortho

acylation using thioesters and selenides.

Scheme 3.28

Ortho

alkoxycarbonylation and aminocarbonylation reactions.

Scheme 3.29

Ortho

aminocarbonylation reaction using aryl carbamic chlorides....

Scheme 3.30

Ortho

alkoxycarbonylation

ipso

selenation.

Scheme 3.31

Ortho

aminocarbonylation of alkenyl sulfonates.

Scheme 3.32 First

ortho

amination of aryl iodides.

Scheme 3.33

Ortho

amination of aryl iodides.

Scheme 3.34 Introducing secondary and primary amines by the

ortho

amination....

Scheme 3.35 Carbonyl 1,2‐transposition via

ortho

amination of alkenyl sulfon...

Scheme 3.36

Ortho

thiolation using aryl or alkyl thiosulfonates.

Scheme 3.37

Ortho

thiolation using aryl or alkyl sulfenamides.

Scheme 3.38 The design of the polarity‐reversed N–O reagents for the

ortho

a...

Scheme 3.39

Ortho

methoxylation of aryl halides.

Scheme 3.40 Computational study for the

ortho

alkoxylation.

Chapter 4

Scheme 4.1 Mechanism and stereoselective step of Catellani‐type reactions: (...

Scheme 4.2 Intramolecular chirality transfer to synthesize chiral heterocycl...

Scheme 4.3 Intermolecular chirality transfer in different solvents.

Scheme 4.4 Synthesis of helical alkenes.

Scheme 4.5 Chiral helical alkenes constructed via domino‐Catellani reaction....

Scheme 4.6 Total synthesis of (+)‐linoxepin via Catellani reaction as the ke...

Scheme 4.7 Catalytic cycle of epoxide‐ or aziridine involved Catellani react...

Scheme 4.8 Synthesis of dihydrobenzofurans using chiral epoxides

Scheme 4.9 Synthesis of benzo‐fused heterocycles: (a) olefins as electrophil...

Scheme 4.10 Synthesis of tetrahydroisoquinolines: (a) chiral aziridines as a...

Scheme 4.11 Synthesis of enantio‐enriched rhazinilam family natural products...

Scheme 4.12 Construction of tetrahydronaphthalenes with quaternary stereogen...

Scheme 4.13 Construction of axially chiral biaryls and the plausible mechani...

Scheme 4.14 Desymmetrization of N‐containing ketones using chiral amino acid...

Scheme 4.15 Synthesis of chiral C‐ and N‐containing bridged scaffolds.

Scheme 4.16 Proposed reaction pathway for the construction of benzo‐fused br...

Scheme 4.17 Synthesis of 1,3‐substituted planar chiral molecular.

Scheme 4.18 Pd/Chiral NBE catalyzed

meta

‐C(sp

2

)–H alkylation: (a) new approa...

Scheme 4.19 Synthesis of chiral DHBFs through kinetic resolution: (a) kineti...

Scheme 4.20 Construction of chiral benzo[c]chromenes via kinetic resolution....

Scheme 4.21 Synthesis of biaryl atropisomers and chiral fluorenes: (a) diffe...

Scheme 4.22 Construction of chiral biaryls monophosphine oxides.

Scheme 4.23 Mechanism for the construction of biaryls monophosphine oxides....

Scheme 4.24 Synthesis of chiral pyridone derivatives.

Scheme 4.25 Synthesis of biaryl pyridone derivatives via axial chirality tra...

Scheme 4.26 Synthesis of atropisomeric

o

‐terphenyls with diaxes: (a) atropis...

Scheme 4.27 Construction of ferrocene derivatives bearing axial and planar c...

Chapter 5

Scheme 5.1 Conventional Pd(0)‐initiated Catellani‐type reaction and the sugg...

Scheme 5.2 C2 Alkylation of NH‐indoles.

Scheme 5.3 (a) Control experiments and (b) isolated intermediates; (c) propo...

Scheme 5.4 C2 Alkylation of an NH‐tryptophan derivative.

Scheme 5.5 (a) C2 Trifluoroethylation of NH‐indoles; (b) late‐stage trifluor...

Scheme 5.6 (a) C2 Methylenephosphorylation of NH‐indoles; (b) synthetic appl...

Scheme 5.7 (a) C2/N‐alkylation of NH‐indoles; (b) C2/C3‐alkylation of NH‐ind...

Scheme 5.8 C2 Glycosylation of NH‐indoles and tryptophan.

Scheme 5.9 Application of Pd(II)/NBE‐catalyzed C2 alkylation of NH‐indoles a...

Scheme 5.10 C2 Alkylation of NH‐pyrroles.

Scheme 5.11 C2/N‐alkylation of electron‐deficient pyrrole.

Scheme 5.12 C1 alkylation of NH‐carbazoles.

Scheme 5.13 C2 Arylation of NH‐indoles.

Scheme 5.14 Speculated catalytic cycle of Pd(II)/NBE cocatalyzed

meta

‐C−H fu...

Scheme 5.15

Meta

‐selective C−H alkylations of arenes with a directing group....

Scheme 5.16

Meta

‐selective C−H arylations of phenylacetic amides.

Scheme 5.17 (a)

Meta

‐selective C−H arylations of β‐arylethylamine derivative...

Scheme 5.18

Meta

‐selective C−H arylations of biaryl‐2‐trifluoroacetamides.

Scheme 5.19

Meta

‐selective C−H arylations of benzyl amines.

Scheme 5.20

Meta

‐selective C−H arylations of nosyl‐protected aryl ethylamine...

Scheme 5.21

Meta

‐selective C−H arylations of benylsulfonamides.

Scheme 5.22 (a)

Meta

‐C−H arylation of aniline, heterocyclic aromatic amine, ...

Scheme 5.23 (a)

Meta

‐C−H arylation of benzylamine derivatives; (b) synthetic...

Scheme 5.24

Meta

‐C−H arylation of masked aromatic aldehyde derivatives.

Scheme 5.25

Meta

‐C−H arylation of benzyl alcohol derivatives.

Scheme 5.26

Meta

‐C−H arylation of free phenylacetic acids.

Scheme 5.27

Meta

‐C−H chlorination of (a) aniline, phenol, and (b) benzylamin...

Scheme 5.28

Meta

‐C−H arylation of amination of (a) phenols, anilines, (b) be...

Scheme 5.29

Meta

‐C−H alkynylation of aniline derivatives.

Scheme 5.30 Distal C–H functionalization of

Z

‐alkenes with a directing group...

Scheme 5.31

Meta

‐C−H arylation of (a) electron‐rich arenes; (b) fluoroarenes...

Scheme 5.32 (a)

Meta

‐C−H arylation of anisole derivatives; (b) nondirected u...

Scheme 5.33 Vicinal difunctionalization of (a) thiophenes, furans; and (b) i...

Scheme 5.34 (a) Vicinal difunctionalization of five‐membered heteroarenes wi...

Scheme 5.35 (a) Remote site‐selective C–H arylation of benzoazines; (b) remo...

Scheme 5.36 (a)

para

‐C–H arylation of arenes; (b) synthetic application.

Scheme 5.37 Enantioselective

meta

‐C−H arylation and alkylation.

Scheme 5.38 (a) Atroposelective remote

meta

‐C–H arylation and alkenylation o...

Scheme 5.39 (a) Enantioselective synthesis of 1,3‐disubstituted planar chira...

Scheme 5.40 Speculated catalytic cycle of the borono‐Catellani reaction.

Scheme 5.41 The Pd(II)‐initiated borono‐Catellani reactions.

Scheme 5.42 Redox‐neutral

ortho

acylation and amination of aryl boronic acid...

Scheme 5.43 Orthogonal reactivity between aryl iodides and aryl boron specie...

Chapter 6

Figure 6.1 Mono‐functionalization of heteroarenes represented as thiophenes ...

Scheme 6.1 Catellani reactions of (a) 3‐iodothiophene, (b) 3‐iodobenzothioph...

Scheme 6.2 (a) Proposed mechanism of the Catellani reactions of 3‐iodothioph...

Scheme 6.3 Catellani reactions of (a) 5‐iodo‐1‐methylpyrazole and (b) 4‐iodo...

Scheme 6.4 Catellani reactions of (a) an iodoindole and (b) indolyl thioeste...

Scheme 6.5 Pd‐catalyzed 1:2 annulation of iodopyrazoles and NBD.

Scheme 6.6 Pd‐catalyzed 1:2 annulation of (a) 2‐bromothiophene and (b) 3‐bro...

Scheme 6.7 Pd‐catalyzed three‐component coupling and 2:1 annulation of (a) 4...

Scheme 6.8 Catellani reactions of (a) 3‐iodopyridine and (b) 3‐iodoquinoline...

Scheme 6.9 Catellani reaction of 3‐iodo‐9‐methylcarbazole

Scheme 6.10 Catellani reaction of (a) 4‐bromoquinoline and (b) 4‐bromo‐3‐met...

Scheme 6.11

Ortho

‐methoxylation and

ipso

‐Heck reactions of iodoheteroarenes....

Scheme 6.12 Pd/NBE cooperative catalysis of 3‐halo‐2‐methoxypyridines.

Scheme 6.13 Catellani reaction of 4‐iodo‐2‐quinolones.

Scheme 6.14 Catellani reactions of (a) 2‐pyridone and (b) uracil derivatives...

Scheme 6.15 Catellani reactions of 3‐iodochromone for (a) difunctionalizatio...

Scheme 6.16 Pd‐catalyzed three‐component annulation of 3‐iodochromone/NBE/α‐...

Scheme 6.17 Pd‐catalyzed three‐component coupling of 3‐iodochromone involvin...

Scheme 6.18 [2 + 2 + 1] annulation of 3‐iodochromone with (a) CO and (b) vin...

Scheme 6.19 (a) Annulation of 3‐iodochromone with NBD and aryl iodides and (...

Scheme 6.20 Annulation with 8‐bromo‐1‐naphthoic acid: (a) 3‐iodochromone and...

Scheme 6.21 (a)

Ortho

‐arylation and

ipso

‐Heck reactions of thiophenes and (b...

Scheme 6.22

Ortho

‐arylation of electron‐deficient thiophenes, pyrroles, and ...

Scheme 6.23 (a)

Ortho

‐arylation and

ipso

‐alkynylation reactions of pyrroles ...

Scheme 6.24

Ortho

‐arylation and

ipso

‐alkynylation reactions of (a) 2‐chlorot...

Scheme 6.25 (a)

Ortho

‐arylation and

ipso

‐Heck reactions of indoles and (b) t...

Scheme 6.26 C1‐alkylation and acylation of carbazoles.

Chapter 7

Scheme 7.1 First catalytic example of Pd/NBE cooperative catalysis.

Scheme 7.2 Generic catalytic cycle of the Pd/NBE cooperative catalysis.

Scheme 7.3 Unselective arylation with 4‐fluorobromobenzene.

Scheme 7.4 The origin of the “ortho effect.”

Scheme 7.5 Addressing the “

ortho effect

” with C2‐ester‐substituted NBE‐2.

Scheme 7.6

Ortho

constraint: selective mono

ortho

C—H functionalization.

Scheme 7.7 Mechanistic considerations for addressing the

ortho

constraint.

Scheme 7.8 Mono C—H amination for

para

‐substituted aryl iodides.

Scheme 7.9 Mechanistic studies.

Scheme 7.10 Catalytic reactivity for isolated complexes.

Scheme 7.11 DFT calculation results. All energies are in kcal/mol. Calculati...

Scheme 7.12 (a) Cyclopentene as the ligand. (b) Generic good arene substrate...

Scheme 7.13 Annulation of aryl iodides with

meta

‐substituents.

Scheme 7.14

Ortho

‐bisalkylation of aryl iodides with

meta

‐substituents.

Scheme 7.15

Ortho

arylation with

meta

‐substituents.

Scheme 7.16

Ortho

trifluoroethylation of an aryl iodide with a

meta

‐fluoro s...

Scheme 7.17 Annulation of aryl iodides containing

meta

‐electrophiles.

Scheme 7.18 Annulation to form fused bicyclic compounds.

Scheme 7.19

Meta

constraint.

Scheme 7.20 All energies are with respect to Int 7–126 in kcal/mol. Calculat...

Scheme 7.21 Orthogonal reactivity requirement for Catellani reactions.

Scheme 7.22 Typical aryl substrates for Catellani‐type reactions.

Scheme 7.23

Ortho

‐alkylation/

ipso

‐Heck reaction of an aryl triflate substrat...

Scheme 7.24 One‐pot fluorosulfation‐Catellani cascade. PMP:

p

‐methoxyphenyl....

Scheme 7.25

Ortho

‐amination/

ipso

‐hydrogenation of an aryl bromide substrate....

Scheme 7.26 Annulation of two aryl bromides.

Scheme 7.27 Miscellaneous examples utilizing aryl bromides.

Scheme 7.28 Alkenyl Catellani reactions.

Scheme 7.29 Reductive coupling of an alkenyl bromide and NBE.

Scheme 7.30 Iodo‐uracil as the substrate for the Catellani‐type difunctional...

Scheme 7.31 Annulations of iodoquinolones and iodocoumarins.

Scheme 7.32 Mechanism of the Pd/NBE‐catalyzed distal C—H functionalization. ...

Scheme 7.33 Distal alkenyl C—H alkylation.

Chapter 8

Figure 8.1 Four types of transformations commonly employed in the key reacti...

Figure 8.2 Total synthesis of (+)‐linoxepin.

Figure 8.3 Synthesis of (±)‐fufenozide.

Figure 8.4 Total synthesis of (±)‐eptazocine.

Figure 8.5 Total synthesis of (±)‐ramelteon

Figure 8.6 Formal synthesis of psymberin.

Figure 8.7 Total synthesis of dalesconol A.

Figure 8.8 Total synthesis of (−)‐berkelic acid

Figure 8.9 Total synthesis of (±)‐stepharine and (±)‐pronuciferine.

Figure 8.10 Total synthesis of michellamines B

Figure 8.11 Total synthesis of cularine and dactyllactone A.

Figure 8.12 Synthesis of carbazomycin A, nitidine, assoanine, and pratosine....

Figure 8.13 Total synthesis of (+)‐rhazinal, (+)‐kopsiyunnanine C3, and (+)‐...

Figure 8.14 Synthesis of Abilify and Flunixin.

Figure 8.15 Synthesis of Tolvaptan.

Figure 8.16 Synthesis of (±)‐ketoprofen.

Figure 8.17 Synthesis of (±)‐pauciflorol F and (±)‐acredinone A.

Figure 8.18 Total syntheses of (±)‐aspidospermidine and (±)‐goniomitine.

Figure 8.19 Total synthesis of (+)‐kopsihainanine A.

Figure 8.20 Total synthesis of (−)‐aspidophylline A.

Figure 8.21 Formal synthesis of (+)‐strictamine.

Figure 8.22 Total synthesis of (−)‐deoxoapodine.

Figure 8.23 Total synthesis of (−)‐tryprostatin A.

Figure 8.24 Total synthesis of (+)‐cochlearol B.

Figure 8.25 Synthesis of (±)‐pallescensin A.

Figure 8.26 Synthesis of ladder polymers using catalytic arene‐NBE annulatio...

Figure 8.27 Synthesis of CBD‐containing polycyclic conjugated hydrocarbons....

Figure 8.28 Multicomponent “

in situ

‐functionalization” polymerization.

Figure 8.29 Synthesis of the water‐soluble PPE.

Guide

Cover

Table of Contents

Title Page

Copyright

Dedication

Preface

Begin Reading

Index

End User License Agreement

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Palladium and Norbornene Cooperative Catalysis

Fundamentals and Applications

Edited by Guangbin Dong

Editor

Prof. Guangbin DongUniversity of Chicago5735 S. Ellis Ave.Chicago 60637IL, USA

Cover Image: © Sergey Tarasov/Alamy Stock Photo

All books published by WILEY‐VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

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© 2025 WILEY‐VCH GmbH, Boschstraße 12, 69469 Weinheim, Germany

The manufacturer's authorized representative according to the EU General Product Safety Regulation is Wiley‐VCH GmbH, Boschstr. 12, 69469 Weinheim, Germany, e-mail: [email protected].

All rights reserved (including those of translation into other languages, text and data mining and training of artificial technologies or similar technologies). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.

Print ISBN: 978‐3‐527‐35238‐8ePDF ISBN: 978‐3‐527‐84295‐7ePub ISBN: 978‐3‐527‐84296‐4oBook ISBN: 978‐3‐527‐84297‐1

To my prior mentors: Professors Zhen Yang, Barry M. Trost, and Bob Grubbs

Preface

Poly‐substituted arenes, heteroarenes, and alkenes are commonly found in bioactive compounds and organic materials. Devising efficient methods for constructing these structural motifs has been of long‐standing interest in the synthetic community. While numerous arene‐functionalization and alkene‐synthesis approaches exist, those that can simultaneously introduce two or more different functional groups to arenes or alkenes in a regio‐ and site‐selective manner are still rare. For example, the use of aryne chemistry for arene functionalization is generally constrained by substrate specificity and/or complexed by strongly basic conditions; the strategy of preparing tri‐ or tetra‐substituted alkenes from internal alkynes often suffers from poor regioselectivity control and limits to linear substrates. So, does an alternative strategy allowing general, rapid, site‐selective functionalizations of arenes, heteroarenes, and alkenes exist? I trust you can find answers in this book.

This book provides a comprehensive overview of the palladium/norbornene (Pd/NBE) cooperative catalysis, which represents a unique approach to enable site‐selective vicinal difunctionalization of aryl and alkenyl substrates. Through forming the key aryl (alkenyl) norbornyl palladacycle (ANP) intermediate, the difunctionalization is typically realized through coupling a nucleophile at the ipso position and an electrophile at the ortho position, which represents the unique feature of the Pd/NBE catalysis. One can imagine that numerous coupling combinations and variations could stem from this distinctive reactivity mode, resulting in enormous opportunities for developing powerful synthetic methods. For example, using aryl halide substrates, termination with hydrogen at the ipso position can lead to functionalization of conventionally less reactive positions. In addition, as a multi‐component reaction, the tethering of any reaction components in the Pd/NBE catalysis can deliver interesting, polycyclic scaffolds. Moreover, the merge of the Pd/NBE catalysis, electrophilic arene halogenation, and cross couplings can allow access to challenging benzenoid substitution patterns. Furthermore, the application of the ortho C—H amination to the enol system can result in carbonyl 1,2‐transposition.

Since the landmark discovery of the ortho C—H alkylation by Professor Marta Catellani in 1997, the field of the Pd/NBE cooperative catalysis has evolved enormously. Especially in the past decade, a number of longstanding constraints and limitations have been overcome to enable more general and diverse transformations. New related reaction modes have also been uncovered, leading to exciting applications. However, compared to the concurrently developed Buchwald−Hartwig couplings (i.e. amination, oxygenation, etc.), the Pd/NBE catalysis has received much less attention outside this field, particularly in the pharmaceutical industries. One possible reason could be due to the relatively complex reaction mechanism and catalyst system, making many people feel intimidated from trying this type of reactions. Thus, one main purpose of this book is to provide readers a systematic understanding of the Pd/NBE catalysis, including the mechanisms, scopes, and current limitations. It is our hope that this book will not only offer fundamental knowledge to students or entry‐level researchers in the organic synthesis field, but also provide guidance to advance researchers about how to use this type of catalysis (e.g., how to choose the best reaction conditions or catalyst combination) to help their research.

This book contains eight chapters, each written by leading experts in the Pd/NBE catalysis field. It starts with the annulation chemistry by Abel‐Snape and Lautens, given the importance of diverse ring structures in organic synthesis, which also sets the mechanistic foundation of the Pd/NBE catalysis. The following two chapters cover the scope of the ipso and ortho functionalization by the Liang group and my own group, respectively. Chapter 4 is centered on the asymmetric development, contributed by Professor Gu. Then, the book shifts to the discussion of the Pd(II)‐initiated reactions by a team effort of Zhou and Yu, followed by a wonderful review of the Pd/NBE‐catalyzed heteroarene functionalization from Professor Joo. Chapter 7 written by Professor Wu is centered on newly developed approaches to address various constraints in the Pd/NBE catalysis. The book closes with the summary of various applications in synthesis of complex molecules and organic materials by Professor Wang.

As the editor, I am very grateful to a large number of kind and outstanding people. First of all, I would like to thank all the chapter authors for their incredible passions and dedications. Note that they have made impressive contributions not only to the writing of the book but also to the field of the Pd/NBE catalysis. It is certainly my honor to work with all of them. In addition, Dr. Xin Liu is highly acknowledged for his kind help in proofreading all the chapters, and his insightful inputs are greatly appreciated. Moreover, Ms. Alia McDaniel is thanked for her dedicated administrative assistance during this process. Needless to mention, I am indebted to all my current and former students and postdocs who worked in the Pd/NBE catalysis projects for their exceptional creativity and persistence. Special gratitude to my former graduate student Dr. Zhe Dong—now a professor at SUSTech—who initiated and popularized the Pd/NBE catalysis project in my lab. Furthermore, I have to express my deepest appreciation to Professor Marta Catellani for her original and inspiring seminal works of the Pd/NBE chemistry, as well as her generous support!

Finally, I would like to thank my family, especially my wife and two daughters, for their unconditional love and support. This book would not have existed without them.

May 2024

Guangbin Dong

University of ChicagoChicago, IL, USA

1The Palladium/Norbornene‐Catalyzed Annulation Chemistry: Rapid Access to Diverse Ring Structures

Mark Lautens and Xavier Abel‐Snape

Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto, Ontario, M5S 3H6, Canada

1.1 Introduction

Palladium–norbornene (NBE) cooperative catalysis, commonly known as the Catellani reaction, constitutes a general and straightforward method to sequentially difunctionalize a haloarene at the ortho and ipso positions, with two different reagents [1–6]. These reagents are typically opposite in reactivity, as the first to react does so as an electrophile (E), which will functionalize the ortho site, while the second serves as a terminating reagent, which is often a nucleophile in character (Nu), which will add at the ipso position (Scheme 1.1). This sequence is made possible due to a unique combination of characteristics, including NBE's exceptional reactivity due to the strain, the resulting rigid framework that creates a transient directing group, and lack of accessible β‐hydrogens, that prevent side reactions.

Scheme 1.1 The general Catellani reaction.

The mechanism has been investigated in detail. Following oxidative addition into the C—X bond, the initial arylpalladium(II) species preferentially reacts with NBE via carbopalladation in order to release its ring strain rather than with the terminating reagent (Scheme 1.2). Every Catellani reaction subsequently generates a key intermediate, known as the arylnorbornyl palladacycle (ANP), which is typically formed after concerted metalation deprotonation (CMD) occurs at the ortho position in the presence of a base. The electrophile is then installed via one of two possible pathways: (i) oxidative addition to form a Pd(IV) intermediate followed by reductive elimination or (ii) dinuclear transmetalation [7–9]. Due to the steric congestion, NBE is then extruded via β–C elimination, giving rise to a new ortho‐functionalized arylpalladium(II) species that can now react with the terminating reagent.

Scheme 1.2 The general mechanism of the Catellani reaction.

In most cases, the aryl group bears one ortho‐substituent to avoid di‐ortho‐functionalization with the electrophile or NBE‐integrated side‐products and ultimately, a lower yield of desired product [9]. This requirement is known as the ortho constraint. To tackle this issue, various modified NBE scaffolds have been developed to successfully employ ortho‐unsubstituted aryl halides as substrates that give good to excellent yields [10–12].

Chapter 1 presents various cyclization methodologies harnessing Pd‐NBE cooperative catalysis. The first section describes the most common way of forming rings, i.e. intramolecular cyclization, where two or all three out of the aryl halide, electrophile or terminating reagent are tethered to one another. The second section reports annulations involving sequential intermolecular ortho‐functionalization and ring closure steps with external reagents. Three‐membered rings constitute the focus of section three, where their innate strain turns them into valuable electrophiles and terminating reagents upon ring opening, thereby forming five‐membered rings. Reactions where NBE and its analog norbornadiene find themselves incorporated in the final annulated product instead of solely being used as transient directing groups are included in section four. The final section is comprised of reactions where the annulation step occurs after the catalytic cycle.

1.2 Intramolecular Cyclizations

1.2.1 Electrophile Tethered to Terminating Reagent

1.2.1.1 Ortho Alkylation

Ipso Heck Termination The original 1997 report by Catellani described a reaction between an unsubstituted or para substituted aryl iodide, an alkyl halide, and a Heck acceptor [1]. The catalyst, known as the PNP complex, was a phenyl norbornyl palladium halide dimer prepared from phenyl mercuric chloride, NBE, and palladium chloride. In 1999, Pd(OAc)2 in DMF was shown to be a suitable combination for reacting ortho‐substituted aryl iodides [13]. In 2000, Lautens developed an annulative process and reported what have become the most widely used conditions, namely Pd(OAc)2, phosphines, acetonitrile, and cesium carbonate (Scheme 1.3). In this example, the electrophile, i.e. the alkyl bromide, is tethered to the Heck acceptor providing access to fused ring systems [14].

Scheme 1.3 First annulative Catellani methodology.

This set of conditions paved the way for subsequent ring‐forming processes, generating a variety of benzofused carbo‐ and heterocycles via ortho‐alkylation and ipso‐Heck termination under identical or modified conditions (Scheme 1.4) [15–19]. Some of these examples illustrate that heterocycles are tolerated, which was not possible until Lautens' report in 2006 [18].

Scheme 1.4 Examples of ortho‐alkylation/ipso‐Heck‐termination annulative methodologies.

Alkyl bromides were generally preferred over the analogous iodides likely due to potential side reactions, namely oxidative addition of Pd(0) into the C(sp3)–I bond followed by β–H elimination and reductive elimination to give the corresponding olefin and HI [13]. However, the iodides were ideal electrophiles in a β‐fluoroalkylation process [20]. Alkyl tosylates were also found to be compatible electrophiles in the Catellani reaction [21].

The Zhou group identified epoxides as alkylating reagents in a macrocyclization event using the potassium salt of 5‐NBE‐2‐carboxylic acid N1 (Scheme 1.5) [22].

Scheme 1.5 Macrocycle formation using an epoxide as an alkylating reagent.

(Homo)allylic alcohols were suitable as the Heck acceptor, furnishing the corresponding carbonyl compounds via a redox‐relay Heck cyclization (Scheme 1.6) [23].

Scheme 1.6 First methodology using (homo)allylic alcohols as the Heck acceptor.

Zhou was able to generate ring sizes ranging from five to seven [19, 24, 25]. Dong was also able to provide aldehyde‐tethered rings using modified procedures (Scheme 1.7) [26, 27].

Scheme 1.7 Examples of ortho‐alkylation/ipso‐redox‐relay Heck annulative methodologies.

Ipso C–H ArylationThe first examples of annulative C–H arylation were reported by Lautens in 2005. The use of an unfunctionalized arene offers an attractive alternative to cross‐coupling reactions where both arenes typically need a compatible functional group. Lautens showcased the power of C–H arylation by generating annulated indoles (Scheme 1.8) [28].

Scheme 1.8 Synthesis of annulated indoles via ipso C–H arylation.

This concept was generalized to include the synthesis of related hetero‐ and carbocycles (Scheme 1.9) [29–36].

Scheme 1.9 Examples of ortho‐alkylation/ipso‐C–H arylation annulative methodologies.

Ipso Alkyne Insertion Following ortho‐alkylation and NBE extrusion, the resulting arylpalladium(II) species may undergo a migratory insertion relay step, followed by subsequent annulation reactions that increase molecular complexity.

Lautens reported reactions of alkyne‐substituted alkyl halides that lead to ipso‐alkyne insertion and C–H functionalization, leading to tetracyclic‐fused pyrrole and indole derivatives. Carbopalladation of the alkyne precedes the C–H activation (Scheme 1.10a,b) [37, 38]. A related approach was reported a few years later to furnish tetrasubstituted helical alkenes (Scheme 1.10c) [39].

Scheme 1.10Ipso‐alkyne insertion followed by C–H activation to form (a) tetracyclic‐fused pyrrole derivatives (b) tetracyclic‐fused indole derivatives (c) tetrasubstituted helical alkenes.

The vinyl‐Pd(II) species can undergo an exo‐migratory insertion across NBE or norbornadiene followed by C–H activation to incorporate the bicycle in the final product. This method provided a different kind of tetrasubstituted helical alkenes as a single diastereomer (Scheme 1.11a) [40]. Interestingly, using chiral bromoalkyl aryl alkynes resulted in moderate diastereoselectivities (Scheme 1.11b) [41]. It was proposed the R4 substituent induces helical chirality upon ipso‐alkyne insertion and the resulting major vinylpalladium(II) species is favored over the minor due to 1,3‐allylic strain between the pseudoequatorial R4 substituent and R3‐aryl ring [42, 43]. In both cases, NBE undergoes exo‐insertion into the C–Pd(II) bond with its methylene group facing away from R1. Subsequently, C–H activation onto the alkyne‐tethered arene occurs, followed by reductive elimination.

Scheme 1.11 Syntheses of tetrasubstituted helical alkenes (a) initial report (b) subsequent work using enantiomerically pure bromoalkyl aryl alkynes.

Nucleophilic attack on the vinyl‐Pd(II) species can also occur. The Luan group reported two methodologies involving the dearomatization of indole and a phenol system, respectively, thereby forming a spiro palladacycle upon nucleophilic substitution (Scheme 1.12) [44, 45]. In a related report, Zhang, Liang, Li, and Quan synthesized indoles via a concerted C–N bond forming and N–S bond cleaving process following ipso‐alkyne insertion [46].

Scheme 1.12Ipso‐alkyne insertion followed by dearomatization of (a) indoles (b) phenols.

Ipso Dearomatization Using a similar bromoalkyl‐tethered indoles with a free N–H group, a dearomatization step can occur in the presence of a base. The ortho‐functionalized arylpalladium(II) intermediate undergoes a ligand substitution with the deprotonated indole at its 3‐position to subsequently provide spiroindolenines (Scheme 1.13) [47].

Scheme 1.13 Synthesis of spiroindolenines.

Ipso Enolate Termination A related carbon‐based nucleophile can be generated as a metal‐enolate. Zhou developed a three‐component synthesis of 1,8‐disubstituted tetralines from 2‐substituted aryl iodides, aryl methyl ketones and 1‐bromo‐3‐chloropropane (Scheme 1.14a). It was proposed the aryl methyl ketones reacted with 1‐bromo‐3‐chloropropane under the basic conditions via an SN2 reaction to form a bromoalkyl‐tethered ketone prior to entering the catalytic cycle [48]. Liang synthesized spirodihydroindenones using a bromoalkyl‐tethered cyclopentanone bearing an acidic α‐proton (Scheme 1.14b) [49]. Zhou reported an enantioselective annulative process using a bromomethyl‐tethered cyclohexanone that formed an enamine in situ with a chiral amino acid catalyst (Scheme 1.14c) [50].

Scheme 1.14 Harnessing in situ generated enolates to synthesize (a) tetralines (b) spirodihydroindenones (c) bridged ketones.

Ipso C–Alkyl Termination Alkyl nucleophiles using organometallic reagents are generally considered to be less successful in transition‐metal‐catalyzed reactions compared to aryl or vinyl nucleophiles due to the increased number of possible side‐reactions that may occur, for instance β–H elimination and the more difficult transmetallation processes. As such, using an alkyl carbagermatrane as a fine‐tuned organogermanium reagent, Xiao was able to construct carbocycles with ring sizes ranging from six to eight (Scheme 1.15) [51].

Scheme 1.15 Synthesis of carbocycles using alkyl carbagermatranes.

Ipso C–N TerminationA nucleophilic heteroatom can also be employed as a compatible ipso terminating reagent. Using brominated alkylamines, Lautens was able to furnish indolines and tetrahydroquinolines depending on the alkyl chain's length (Scheme 1.16) [52, 53]. It was established that a para‐nitrophenyl group as R4 was the optimal nitrogen‐protecting group for the synthesis of indolines. Phenyl and ethoxycarbonyl were the only other groups that were found to be compatible.

Scheme 1.16 Synthesis of (a) indolines and (b) tetrahydroquinolines via ortho‐alkylation and ipso‐Buchwald–Hartwig coupling.

1.2.1.2 Ortho Arylation

Ipso C–N TerminationOrtho‐arylation is usually conducted with a less reactive haloarene than the one meant to undergo sequential ortho‐ and ipso‐functionalizations. Typically, the former is an aryl bromide and the latter, an aryl iodide. The careful choice of different haloarenes ensures Pd(0) oxidatively adds into the more reactive C–I bond preferentially and that the ANP then reacts with the less reactive aryl bromide. Lautens showed aryl triflates can be used instead of aryl iodides [54], while aryl chlorides can also constitute the ortho‐arylating reagent [54–56]. Two bromoarenes can also be used as coupling partners, although significant electronic differences make one more reactive than the other [57].

Catellani applied this reasoning in her synthesis of 6‐phenanthridinones by reacting iodoarenes with 2‐bromobenzamides (Scheme 1.17) [58]. Once ortho‐arylation and NBE extrusion occurred, an ipso‐C–N coupling took place to furnish the desired azacycles.

Scheme 1.17 Synthesis of 6‐phenanthridinones.

Various N‐heterocycles of different ring sizes were synthesized based on this method (Scheme 1.18) [54, 55, 57, 59–66].

Scheme 1.18 Subsequent examples of ortho‐arylation/ipso‐C–N termination annulative methodologies.

Ipso C–O TerminationSimilarly, C—O bond formation can occur using the appropriate terminating reagents (Scheme 1.19 [67–70].

Scheme 1.19 Examples of ortho‐arylation/ipso‐C–O termination annulative methodologies.

Various C=X Bonds as Ipso Heck Terminating Reagents Carbonyls can serve as ipso‐terminating reagents, although their reactivity differs significantly depending on the functional group to which they belong and on the reaction conditions. Lautens was able to synthesize 9H‐fluoren‐9‐ols from ketones as well as 9H‐fluoren‐9‐ones from esters and aldehydes via direct addition to the carbonyl (Scheme 1.20) [56].

Scheme 1.20Ortho‐arylation/ipso‐C=X termination methodologies for the synthesis of (a) 9H‐fluoren‐9‐ols from ketones (b) 9H‐fluoren‐9‐ones from esters (c) 9H‐fluoren‐9‐ones from aldehydes.

Using a chiral NBE derivative, Zhou was able to generate fluorenols enantioselectively (Scheme 1.21) [71].

Scheme 1.21 Enantioselective synthesis of fluorenols.

2‐Bromoarylaldehyde hydrazones were used in a denitrogenative synthesis of fluorenes (Scheme 1.22) [72]. It was determined the reaction pathway does not proceed via carbene insertion.

Scheme 1.22 Synthesis of fluorenes via denitrogenation.

Ipso Enolate Termination The Lautens group included three examples of enolates as terminating reagents in their work on carbonyls as ipso terminating reagents (Scheme 1.23) [56]. Tweaking the conditions by removing water and changing the solvent from DME to acetonitrile modulated the system's reactivity and favored enolate formation rather than the direct addition of the arylpalladium(II) intermediate to the ketone.

Scheme 1.23 Synthesis of phenanthren‐9‐ols.

1.2.1.3 Ortho Acylation

Ipso Heck TerminationUsing a mixed anhydride, Dong discovered how to ortho‐acylate aryl iodides [73]. Subsequently, an extension of this method was developed to generate macrocycles via an ipso‐Heck termination step (Scheme 1.24) [74].

Scheme 1.24 Macrocycle formation via ortho‐acylation and ipso‐Heck termination.

Smaller ring systems were also accessible using an analogous reagent (Scheme 1.25) [11]. A mixed anhydride could also be generated in situ from the corresponding carboxylic acid and the Yamaguchi reagent [75]. Carbamoyl chlorides were developed as alternative ortho‐acylating reagents, giving access to related carbocycles [76, 77].

Scheme 1.25 Subsequent examples of ortho‐acylation/ipso‐Heck termination annulative methodologies.

Ipso C–H Arylation Jiao was the first to use carbamoyl chlorides as ortho‐acylating reagents in Pd/NBE chemistry. These reagents were tethered to aryl rings, thereby leading to an intramolecular ipso C–H arylation termination, which furnished the corresponding phenanthridinones (Schemes 1.26, 1.27) [77].

Scheme 1.26 First use of carbamoyl chlorides in Pd/NBE chemistry.

Scheme 1.27 Subsequent examples of ortho‐acylation/ipso‐C–H arylation annulative methodologies.