Remote C-H Bond Functionalizations E-Book

• Herausgeber: Wiley-VCH GmbH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 591

Veröffentlichungsjahr: 2021

Beschreibung

Presenting a systematic compilation of distal C-H functionalizations which belongs to the most important topics in present day organic synthesis. Essential for every synthetic chemist.

Leseprobe

Table of Contents

Cover

Title Page

Copyright

1 Introduction

2 Transition Metal‐Catalyzed Remote

meta

‐C–H Functionalization of Arenes Assisted by

meta

‐Directing Templates

2.1 Introduction

2.2 Template‐Assisted meta‐C–H Functionalization

2.3 Mechanistic Considerations

2.4 Conclusion

References

3 C–H Functionalization of Arenes Under Palladium/Norbornene Catalysis

3.1 Introduction

3.2 Pd(0)‐Catalyzed C–H Functionalization of Aryl (Pseudo)Halides

3.3 Pd(II)‐Catalyzed C–H Functionalization of Arenes

3.4 Conclusions and Outlook

Acknowledgments

References

4 Directing Group Assisted

meta

‐C–H Functionalization of Arenes Aided by Norbornene as Transient Mediator

4.1 Introduction

4.2 meta‐C–H Alkylation of Arenes

4.3

meta

‐C–H Arylation of Arenes

4.4

meta

‐C–H Chlorination of Arenes

4.5

meta

‐C–H Amination of Arenes

4.6

meta

‐C–H Alkynylation of Arenes

4.7 Enantioselective meta‐C–H Functionalization

4.8 Conclusion

References

5 Ruthenium‐Catalyzed Remote C–H Functionalizations

5.1 Introduction

5.2

meta

‐C–H Functionalizations

5.3

para

‐C–H Functionalizations

5.4

meta‐/ortho

‐C–H Difunctionalizations

5.5 Conclusions

Acknowledgments

References

6 Harnessing Non‐covalent Interactions for Distal C(sp

2

)–H Functionalization of Arenes

6.1 Introduction

6.2 Non‐covalent Interactions in Metal Catalyzed CH Bond Functionalization

6.3 Overview of Iridium‐Catalyzed Borylation

6.4 Non‐covalent Interactions in Ir‐Catalyzed Borylation

6.5

meta

‐Selective Borylation using Non‐covalent Interactions

6.6

para

‐Selective Borylation using Non‐covalent Interactions

6.7 Conclusions

References

7 The Non‐directed Distal C(sp

2

)–H Functionalization of Arenes

7.1 Introduction

7.2 C–Het Formation

7.3 CC Bond Forming Reactions

7.4 Outlook

References

Note

8 Transition Metal Catalyzed Distal

para

‐Selective C–H Functionalization

8.1 Introduction

8.2 Template Assisted para‐Selective C–H Functionalization

8.3 Steric Controlled and Lewis Acid‐Transition Metal Cooperative Catalysis

8.4 Non‐covalent Interaction Induced para‐C–H Functionalization

8.5 Conclusion and the Prospect

Acknowledgments

References

9 Regioselective C–H Functionalization of Heteroaromatics at Unusual Positions

9.1 Introduction

9.2 Indole

9.3 (Benzo)Thiophene

9.4 Pyrrole

9.5 Pyridine

9.6 Miscellaneous Heteroarenes

9.7 Conclusion

References

10 Directing Group Assisted Distal C(sp

3

)–H Functionalization of Aliphatic Substrates

10.1 Introduction

10.2 γ‐C(sp3)–H Functionalization of Aliphatic Acids

10.3 δ‐/ɛ‐C(sp3)H Bond Functionalization of Aliphatic Amines

10.4 γ‐C(sp3)H Bond Functionalization of Aliphatic Ketones or Aldehydes

10.5 γ‐/δ‐C(sp3)H Bond Functionalization of Aliphatic Alcohols

10.6 Conclusions and Outlook

References

11 Radically Initiated Distal C(sp

3

)–H Functionalization

11.1 Introduction

11.2 Distal C(sp3)–H Functionalization Promoted by Carbon‐Centered Radicals

11.3 Distal C(sp

3

)–H Functionalization Promoted by Nitrogen‐Centered Radicals

11.4 Oxygen‐Centered Radicals Initiate Distal C(sp3)–H Functionalization

11.5 Summary and Outlook

References

12 Non‐Directed Functionalization of Distal C(sp

3

)H Bonds

12.1 Introduction

12.2 Reactions Occurring Without Formation of Metal–Carbon Bonds

12.3 Reactions Occurring via Formation of Metal–Carbon Bonds

12.4 Altering Innate Reactivity by Polarity Reversal Strategies

Acknowledgments

References

13 Remote Oxidation of Aliphatic CH Bonds with Biologically Inspired Catalysts

13.1 Introduction

13.2 Innate Substrate Based Aspects Governing Site Selectivity in C–H Oxidations

13.3 Remote Oxidations by Reversal of Polarity

13.4 Remote Oxidations Guided by Supramolecular Recognition

13.5 Selective Aliphatic C–H Oxidation at Dicopper Complexes

13.6 Conclusions

References

Index

End User License Agreement

List of Tables

Chapter 3

Table 3.1 Bisfunctionalization of aryl (pseudo)halides under Pd(0)/NBE cataly...

Chapter 12

Table 12.1 Examples of BDEs of aliphatic CH bonds [5].

Chapter 13

Table 13.1 Catalyst dependent selective oxidation of the androstanediol deriv...

Table 13.2 C9 hydroxylation of the androstanediol derivative

S2

R

.

Table 13.3 Oxidation of ibuprofen with the

Mn

2

(terpy

–

COOH)

catalyst.

Table 13.4 Evidence on favor of a recognition‐driven selectivity.

List of Illustrations

Chapter 2

Scheme 2.1 Directing template assisted

meta

‐CH bond functionalization. Rela...

Scheme 2.2 Three categories of chelating functionality (CF). (a)

N‐Based

...

Scheme 2.3

meta‐

C–H activation of toluene derivatives.

Scheme 2.4

meta‐

C–H olefination of hydrocinnamic acid derivatives.

Scheme 2.5 (a) 2‐hydroxybenzonitrile template assisted mono

meta

‐selective o...

Scheme 2.6 (a) Proposed remote‐selective C‐H activation via κ2 coordination ...

Scheme 2.7 (a) Rh(III)‐catalyzed directing template assisted remote

meta

‐C–H...

Scheme 2.8

meta‐

C–H arylation of hydrocinnamic acids with arylboronic ...

Scheme 2.9

meta‐

C–H arylation of hydrocinnamic acids with aryl iodides...

Scheme 2.10

meta‐

C–H olefination of phenylacetate.

Scheme 2.11

meta‐

C–H olefination of phenylacetic acid derivatives. Sou...

Scheme 2.12 Rh‐catalyzed

meta‐

C–H olefination of phenylacetic acid der...

Scheme 2.13 Pyridine‐based template assisted

meta‐

C–H olefination of p...

Scheme 2.14 (a)

meta

‐C‐H perfluoroalkenylation of phenylacetic acid derivati...

Scheme 2.15 Pyridine‐based template assisted

meta‐

C–H arylation and io...

Scheme 2.16 (a)

meta‐

C–H deuteration of phenylacetic acid derivatives ...

Scheme 2.17 (a)

meta

‐C–H olefination of benzoic acids. (b) Removal of direct...

Scheme 2.18 (a)

meta

‐C–H acetoxylation of benzoic acids. (b) Elaboration of

Scheme 2.19

meta‐

C–H olefination of benzoic acid derivatives with conf...

Scheme 2.20

meta‐

C–H olefination of aniline derivatives.

Scheme 2.21 (a) synthesis of substrate from CO

2

for

meta‐

C–H activatio...

Scheme 2.22

meta‐

C–H olefination of tertiary anilines.

Scheme 2.23 (a)

meta‐

C–H acetoxylation of aniline amides. (b)

meta‐

...

Scheme 2.24

meta‐

C–H acetoxylation of benzylamine derivatives.

Scheme 2.25

meta‐

C–H olefination of tertiary benzylamines and distal a...

Scheme 2.26

meta‐

C–H olefination of phenylethylamine derivatives.

Scheme 2.27 Sequential remote‐selective regiodivergent C–H olefination of 2‐...

Scheme 2.28 (a) Conformation promoted

meta

‐selective activation. (b)

meta‐

...

Scheme 2.29 (a)

meta‐

C–H olefination of indoline derivatives. (b) Remo...

Scheme 2.30

meta‐

C–H arylation of indoline derivatives.

Scheme 2.31

meta‐

C–H acetoxylation of indoline derivatives.

Scheme 2.32

meta‐

C–H olefination of

N

‐heterocycles.

Scheme 2.33

meta‐

C–H olefination of 3‐phenylpyridines.

Scheme 2.34

meta‐

C–H olefination of 3‐phenylpyridines using nitrile‐ba...

Scheme 2.35 (a)

meta‐

C–H olefination of benzylsulfonic acid derivative...

Scheme 2.36 (a)

meta‐

C–H olefination of 2‐phenethylsulfonic acid deriv...

Scheme 2.37

meta‐

C–H olefination and alkylation of benzylsulfonyl and ...

Scheme 2.38

meta‐

C–H olefination and acetoxylation of benzylsulfonyl e...

Scheme 2.39 Rh‐catalyzed

meta‐

C–H olefination of benzylsulfonyl esters...

Scheme 2.40

meta‐

C–H perfluoroalkenylation of benzylsulfonyl esters....

Scheme 2.41

meta‐

C–H allylation of benzylsulfonyl esters.

Scheme 2.42

meta‐

C–H oxygenation of benzylsulfonyl esters.

Scheme 2.43

meta‐

C–H cyanation of benzylsulfonyl and 2‐phenethylsulfon...

Scheme 2.44

meta‐

C–H deuteration of benzylsulfonyl esters.

Scheme 2.45

meta‐

C–H silylation and germanylation.

Scheme 2.46

meta‐

C–H olefination of phenol derivatives.

Scheme 2.47 Organosilicon template assisted

meta‐

C–H olefination of ph...

Scheme 2.48 Rh(III)‐catalyzed

meta‐

C–H olefination of phenol derivativ...

Scheme 2.49 (a)

meta

‐selective C–H olefination of phenols. (b) Nickel‐cataly...

Scheme 2.50

meta

‐C–H olefination of 2‐phenyl phenol derivatives.

Scheme 2.51

meta

‐C–H olefination of benzyl alcohols.

Scheme 2.52

meta

‐C–H olefination of benzyl and phenyl ethyl alcohols.

Scheme 2.53

meta

‐C–H iodination of benzyl and phenylethyl alcohols.

Scheme 2.54

meta

‐C–H olefination of distal arene‐tethered alcohols.

Scheme 2.55

meta

‐C–H functionalizations of arenes with different linker leng...

Scheme 2.56 Removal of the pyrimidine‐based template.

Scheme 2.57

meta

‐C–H allylation of alcohol derivatives.

Scheme 2.58

meta

‐C–H olefination of arene‐tethered diols.

Scheme 2.59

meta

‐C–H deuteration of alcohols.

Scheme 2.60

meta

‐C–H olefination of benzyl silanes.

Scheme 2.61 (a)

meta

‐C–H cyanation of benzyl silanes. (b) Application of

met

...

Scheme 2.62

meta

‐C–H functionalizations of phosphonates.

Scheme 2.63

meta

‐C–H alkylation of phosphonates.

Scheme 2.64

meta

‐C–H deuteration of phosphonates.

Scheme 2.65 Proposed catalytic cycle for

meta‐

C–H olefination.

Scheme 2.66 Proposed transition state through computational study.

Chapter 3

Scheme 3.1 Catellani's initial report on C–H functionalization of iodoarenes...

Scheme 3.2 Proposed catalytic cycle for the

ortho

‐C–H alkylation of aryl iod...

Scheme 3.3

ortho

‐C–H alkylation of

ortho

‐substituted iodoarenes under Pd/NBE...

Scheme 3.4 Lautens' modified reaction conditions for

ortho

‐C–H alkylation of...

Scheme 3.5 Pd(II)‐initiated C–H functionalization of arenes under Pd/NBE cat...

Scheme 3.6

ortho

‐Alkylation of

ortho

‐unsubstituted iodoarenes with two diffe...

Scheme 3.7

ortho

‐C–H trifluoroethylation iodoarenes with trifluoroethyl iodi...

Scheme 3.8

ortho

‐Alkylation with racemic secondary alkyl iodides.

Scheme 3.9

ortho

‐Alkylation with enantioenriched secondary alkyl iodides.

Scheme 3.10 Asymmetric

ortho

‐alkylation of iodoarenes under Pd/NBE catalysis...

Scheme 3.11 Recent work on

ortho

‐alkylation reactions using various terminat...

Scheme 3.12

ortho

‐Alkylation/

ipso

‐alkynylation reactions using terminal alky...

Scheme 3.13 Total synthesis of (+)‐linoxepin using

ortho

‐alkylation/

ipso

‐Hec...

Scheme 3.14

ortho

‐Alkylation/

ipso

‐heteroarylation of iodoarenes with heteroa...

Scheme 3.15

ortho

‐Alkylation using bifunctional alkylating reagents under Pd...

Scheme 3.16

ortho

‐Alkylation of iodoarenes containing terminating functional...

Scheme 3.17

ortho

‐Alkylation of simple iodoarenes with alkyne‐tethered alkyl...

Scheme 3.18 Pd/NBE‐catalyzed reactions of iodoarenes with aryl‐substituted 2

Scheme 3.19 Pd/NBE‐catalyzed reactions of iodoarenes with aziridines.

Scheme 3.20 Pd/NBE‐catalyzed reactions of iodoarenes with epoxides.

Scheme 3.21 Pd/NBE‐catalyzed homocoupling of 4‐fluorobromobenzene.

Scheme 3.22 Pd/NBE‐catalyzed homocoupling of

ortho

‐substituted iodoarenes....

Scheme 3.23 Pd/NBE‐catalyzed cross‐coupling of iodoarenes with electron‐poor...

Scheme 3.24

ortho

‐Arylation of iodoarenes using

o

‐bromophenols and 1‐bromo‐2...

Scheme 3.25

ortho

‐Arylation of iodoarenes using bromoarenes with

N

‐containin...

Scheme 3.26

ortho

‐Arylation of iodoarenes using bifunctional aryl halides.

Scheme 3.27

ortho

‐Arylation of iodoarenes using

o

‐bromophenols.

Scheme 3.28

ortho

‐Arylation of bifunctional iodoarenes under Pd/NBE catalysi...

Scheme 3.29 Theoretical investigation on the origin of the “

ortho

effect.”...

Scheme 3.30 Deviation from the “

ortho effect

.”

Scheme 3.31 Overcoming the “

ortho effect

” in

ortho

‐arylation reactions by us...

Scheme 3.32

ortho

‐Acylation of aryl iodides using pre‐formed or in situ gene...

Scheme 3.33

ortho

‐Acylation of aryl iodides using norbornene derivatives as ...

Scheme 3.34

ortho

‐Acylation of aryl iodides using other types of terminating...

Scheme 3.35

ortho

‐Acylation of aryl iodides using bifunctional acylation rea...

Scheme 3.36 Synthesis of benzo‐fused cyclic ketones and natural products usi...

Scheme 3.37

ortho

‐Alkoxycarbonylation of aryl iodides under Pd/NBE catalysis...

Scheme 3.38 Dong's initial report on

ortho

‐amination of iodoarenes with

N

‐be...

Scheme 3.39

ortho

‐Amination of iodoarenes using

N

‐benzoyloxyamines in the pr...

Scheme 3.40

ortho

‐Amination of aryl bromides using

N

‐benzoyloxyamines.

Scheme 3.41

ortho

‐Amination of iodoarenes containing a terminating functiona...

Scheme 3.42

ortho

‐Amination of

ortho

‐unsubstituted iodoarenes using bridgehe...

Scheme 3.43 Application of

ortho

‐amination/

ipso

‐alkynylation of iodoarenes i...

Scheme 3.44

ortho

‐Thiolation of iodoarenes using thiosulfonates as the thiol...

Scheme 3.45 Pd(II)‐catalyzed C2‐functionalization of indoles.

Scheme 3.46 Proposed mechanism for the Pd(II)‐catalyzed C2‐functionalization...

Scheme 3.47 Synthetic applications of the Pd(II)‐catalyzed 2‐alkylation of i...

Scheme 3.48 Pd(II)‐catalyzed 2‐alkylation of pyrroles.

Scheme 3.49 Pd(II)‐catalyzed 2‐trifluoroethylation of indoles.

Scheme 3.50 Pd(II)‐catalyzed

meta

‐C–H alkylation and arylation of arenes bea...

Scheme 3.51 Pd(II)‐catalyzed

meta

‐C–H functionalization of arenes bearing an...

Scheme 3.52 Pd(II)‐catalyzed enantioselective

meta

‐C–H functionalization of ...

Scheme 3.53 Pd(II)‐catalyzed

ortho

alkylation of arylboronic acids or esters...

Scheme 3.54 Pd(II)‐catalyzed

ortho

arylation of arylboronic esters.

Scheme 3.55 Pd(II)‐catalyzed

ortho

acylation and amination of aryl boroxines...

Chapter 4

Scheme 4.1 Directing group assisted site‐selective C–H functionalization of ...

Scheme 4.2 Proposed catalytic cycle of directing group assisted

meta

‐C–H fun...

Scheme 4.3

meta

‐C–H alkylation of phenylacetic amide derivatives with NBE....

Scheme 4.4

meta

‐C–H alkylation of phenylacetic amide derivatives with Yu‐med...

Scheme 4.5

meta

‐C–H alkylation of benzylsulfonamide derivatives.

Scheme 4.6

meta

‐C–H alkylation of nosyl‐protected methyl ester of phenylalan...

Scheme 4.7

meta

‐C–H arylation of phenylacetic amide derivatives with NBE....

Scheme 4.8

meta

‐C–H arylation of phenylacetic amide derivatives with Yu‐medi...

Scheme 4.9

meta

‐C–H arylation of β‐arylethylamine derivatives.

Scheme 4.10

meta

‐C–H arylation of biaryl‐2‐trifluoroacetamide derivatives....

Scheme 4.11

meta

‐C–H arylation of nosyl‐protected aryl ethylamine, phenylgly...

Scheme 4.12

meta

‐C–H arylation of benzylsulfonamide derivatives.

Scheme 4.13

meta

‐C–H arylation of benzyl amine derivatives.

Scheme 4.14

meta

‐C–H arylation of aniline, heterocyclic aromatic amine, phen...

Scheme 4.15 (a)

meta

‐C–H arylation of benzylamine derivatives. (b) Synthetic...

Scheme 4.16

meta

‐C–H arylation of masked aromatic aldehyde derivatives.

Scheme 4.17 (a)

meta

‐C–H arylation of benzyl alcohol derivatives. (b) Cleava...

Scheme 4.18

meta

‐C–H arylation of free phenylacetic acids.

Scheme 4.19 (a)

meta

‐C–H chlorination of aniline and phenol derivatives. (b)...

Scheme 4.20

meta

‐C–H chlorination of benzylamine derivative.

Scheme 4.21

meta

‐C–H amination of aniline and phenol derivatives.

Scheme 4.22

meta

‐C–H amination of benzylamine and masked aromatic aldehyde d...

Scheme 4.23

meta

‐C–H alkynylation of aniline derivatives.

Scheme 4.24 (a) Enantioselective

meta

‐C–H activation. (b) Enantioselective

m

...

Chapter 5

Figure 5.1 Strategies for remote

meta

‐/

para

‐selective C–H activation. (a) St...

Scheme 5.1 Ruthenium catalysis for C–H alkylation with

n

‐hexyl bromide. (a) ...

Scheme 5.2 Remote

meta

‐C–H alkylations with secondary alkyl halides. (a) Sco...

Scheme 5.3

meta

‐C–H Alkylations with tertiary alkyl halides. (a) Reactions o...

Scheme 5.4 Proposed catalytic cycle for remote C–H alkylations via

ortho

‐rut...

Scheme 5.5 Remote

meta

‐C–H alkylation with transformable/removable directing...

Scheme 5.6 Remote

meta

‐C–H alkylation with removable directing groups. (a)

m

...

Scheme 5.7 Ruthenium‐catalyzed

meta

‐C–H mono‐ and difluoromethylations. (a) ...

Scheme 5.8 Remote C–H alkylations with α‐bromocarbonyl compounds. (a) Ruthen...

Scheme 5.9 Proposed catalytic cycle for the synergistic ruthenium‐phosphine ...

Scheme 5.10 Remote C–H alkylations using an arene‐ligand‐free ruthenium comp...

Scheme 5.11 Photo‐induced ruthenium‐catalyzed

meta

‐C–H alkylations with alky...

Scheme 5.12 Remote

meta

‐C–H alkylations under visible light irradiation.

Scheme 5.13 Oxidative ruthenium‐catalyzed

meta

‐benzylation with toluene deri...

Scheme 5.14 Site‐selectivity switch for ruthenium‐catalyzed C–H benzylation....

Scheme 5.15 Proposed catalytic cycle for remote

meta

‐C–H benzylations. Sourc...

Scheme 5.16 Ruthenium‐catalyzed remote C–H carboxylation.

Scheme 5.17 Remote C–H acylation via oxidative decarboxylation.

Scheme 5.18

meta

‐C–H Sulfonylations of phenylpyridines

1

with sulfonyl chlor...

Scheme 5.19 Proposed catalytic cycle for

meta

‐sulfonylation. Source: Modifie...

Scheme 5.20 Azoarene‐directed

meta

‐sulfonation.

Scheme 5.21 Ruthenium‐catalyzed

meta

‐bromination. (a)

meta

‐Bromination with ...

Scheme 5.22 Homogeneous or heterogeneous ruthenium catalysts for

meta

‐bromin...

Scheme 5.23 Ruthenium‐catalyzed

meta

‐halogenation. (a)

meta

‐Halogenation wit...

Scheme 5.24 Ruthenium‐catalyzed

meta

‐nitration.

Scheme 5.25 Proposed catalytic cycle for ruthenium‐catalyzed

meta

‐nitration....

Scheme 5.26 Ruthenium‐catalyzed remote C–H nitration. (a)

meta

‐C–H Nitration...

Scheme 5.27 Oxidative C–H/C–H activation for

para

‐selective alkylations.

Scheme 5.28

para

‐C–H Oxygenations of anisoles

85

under ruthenium catalysis....

Scheme 5.29 Ruthenium‐catalyzed

para

‐C–H alkylations with α‐bromo esters. (a...

Scheme 5.30 Ruthenium‐catalyzed

para

‐C–H mono‐ and difluoroalkylations. (a) ...

Scheme 5.31

para

‐C–H Sulfonylations of pyridines

96

under ruthenium catalysi...

Scheme 5.32 Sequential

meta

‐C–H alkylation/

ortho

‐C–H functionalizations in a...

Scheme 5.33

meta

‐C–H Sulfonylation/

ortho

‐C–H chlorination of phenoxypyridine...

Chapter 6

Figure 6.1 Site‐selective sp

3

CH bond oxidation using Mn‐based catalysts: (...

Figure 6.2 Development progression of iridium‐catalyzed borylation of arenes...

Figure 6.3 Mechanism of iridium‐catalyzed borylation of arenes, as proposed ...

Figure 6.4 Considerations concerning the regioselectivity of iridium‐catalyz...

Figure 6.5 Examples of

ortho

‐selective borylation using non‐covalent interac...

Figure 6.6 Kuninobu, Kanai, and coworkers'

meta

‐selective borylation using b...

Figure 6.7 Kuninobu, Kanai, and coworkers' urea containing ligand modificati...

Figure 6.8 Sulfonated bipyridine ligands developed within the Phipps group, ...

Figure 6.9 Extending the chain length between the arene and ammonium groups ...

Figure 6.10 Use of sulfonated bipyridine ligand to engage in hydrogen bond d...

Figure 6.11 Substrates that present a competition between ion pair and hydro...

Figure 6.12 Chattopadhyay's

meta

C–H borylation of amides: (a) reaction over...

Figure 6.13

para

C–H borylation by using an L‐shaped ligand: (a) reaction ov...

Figure 6.14 Use of a bulky cation to disfavor borylation at the

meta

positio...

Figure 6.15 Phipps and coworkers' “steric shield” strategy to controlling

pa

...

Figure 6.16 Stepwise increase of cation size across the benzylsulfonate subs...

Figure 6.17 Maleczka, Smith, and coworkers' strategy to controlling

para

‐sel...

Chapter 7

Scheme 7.1 The iridium‐catalyzed borylation developed by Maleczka, Smith, an...

Scheme 7.2 The para‐selective Ir‐catalyzed borylation by Saito et al. [34]....

Scheme 7.3 The Rh‐catalyzed silylation developed by Cheng and Hartwig [48]....

Scheme 7.4 The Pd‐catalyzed imidation and aryl‐piperazine formation develope...

Scheme 7.5 The arene C–H amination developed by Nicewicz and coworkers [10]....

Scheme 7.6 Arene C–H aminations to form primary anilines by Togni, Carreira,...

Scheme 7.7 The dirhodium catalyzed arene C–H amination by Falck and coworker...

Scheme 7.8 The synthesis of primary anilines through Fe‐catalyzed aminations...

Scheme 7.9 Oxidative aromatic oxygenation by Ritter and coworkers [69].

a

Re...

Scheme 7.10 Electrophilic aromatic fluorination by Ritter and coworkers [73]...

Scheme 7.11 Nucleophilic

18

F‐fluorination by Nicewicz, Li, and coworkers [74...

Scheme 7.12 The non‐directed chlorination by Fuchs, Nagib, and coworkers [77...

Scheme 7.13 The thiofluoromethylation of unactivated arenes by Iskra, Yi, an...

Scheme 7.14 The C–H thianthrenation of arenes developed by Ritter and cowork...

Scheme 7.15 The Au‐catalyzed oxidative arylation developed by Ball, Lloyd‐Jo...

Scheme 7.16 First arene‐limited olefination developed by Yu and coworkers us...

Scheme 7.17 Pd‐catalyzed arene‐limited olefinations with a 2‐pyridone ligand...

Scheme 7.18 Direct C–H cyanation of arenes by Wang, Nicewicz, Gooßen, and co...

Scheme 7.19 Pd‐catalyzed arene‐limited cyanations by Ritter, van Gemmeren, Y...

Chapter 8

Scheme 8.1 Approaches for distal

para

‐C–H functionalizations. (a) DG assiste...

Scheme 8.2

para

‐Selective alkenylation of toluene scaffolds using D‐shaped t...

Scheme 8.3

para

‐Selective acetoxylation of toluene scaffolds using D‐shaped ...

Scheme 8.4

para

‐Selective alkenylation of phenols using D‐shaped template....

Scheme 8.5 DG removal from

para

‐alkenylated product.

Scheme 8.6 Optimization of DG and silylating reagent.

Scheme 8.7 Scope of

para

‐silylation.

Scheme 8.8 Plausible catalytic cycle for

para

‐silylation.

Scheme 8.9 Scope of

para

‐ketonization.

Scheme 8.10 Plausible catalytic cycle for

para

‐ketonization reaction.

Scheme 8.11 Plausible hydrolysis pathways of

para

‐alkenylated ether (

E

).

Scheme 8.12

para

‐Selective acetoxylation of benzoic acid derivative.

Scheme 8.13 Scope of

para

‐selective cyanation.

Scheme 8.14 Rhodium catalyzed

para

‐selective alkenylation.

Scheme 8.15 C4‐alkylation of pyridine in Ni/Al cooperative catalysis.

Scheme 8.16 Plausible mechanism for C4‐alkylation of pyridine in Ni/Al coope...

Scheme 8.17 Labeling experiment in C4‐alkylation of pyridine in Ni/Al cooper...

Scheme 8.18 C4‐alkenylation of pyridine in Ni/Al cooperative catalysis.

Scheme 8.19 Ni–Al bimetallic intermediate bridged by pyridine.

Scheme 8.20 Plausible mechanism for C4‐alkenylation of pyridine in Ni/Al coo...

Scheme 8.21 Scope of C4‐alkylation of benzamide and aromatic ketone in Ni/Al...

Scheme 8.22 Labelling experiment for C4‐alkylation of benzamide in Ni/Al coo...

Scheme 8.23 Plausible mechanism for C4‐alkylation of benzamide in Ni/Al coop...

Scheme 8.24

para

‐C–H alkylation of sulfonamides by Ni–Al co‐operative cataly...

Scheme 8.25

para

‐Borylation of amide in Ir/Al co‐operative catalysis.

Scheme 8.26 C4‐borylation of pyridine in Ir/Al co‐operative catalysis.

Scheme 8.27 Catalyst controlled

para

‐borylation of arenes.

Scheme 8.28 Proposed L‐shaped template.

Scheme 8.29 Scope of

para

‐borylation using L‐shaped template.

Scheme 8.30

para

‐C–H borylation using ion‐pair interaction by Smith's protoc...

Scheme 8.31

para

‐C–H borylation using ion‐pair interaction by Phipps protoco...

Chapter 9

Scheme 9.1 Innate electronic bias of indole based on resonance of pyrrole mo...

Scheme 9.2 Seminal example of C–H functionalization of indole at unusual C4 ...

Scheme 9.3 Palladium‐catalyzed highly C4‐selective C–H alkenylation of trypt...

Scheme 9.4 Ruthenium‐catalyzed C4‐selective C–H alkenylation of 3‐formylindo...

Scheme 9.5 Directing‐group‐controlled C4‐ and C2‐selective C–H alkenylation ...

Scheme 9.6 Iridium‐catalyzed C4‐selective C–H amidation of 3‐carbonylindoles...

Scheme 9.7 Palladium‐catalyzed C4‐selective C–H arylation of 3‐pivaloylindol...

Scheme 9.8 Palladium‐catalyzed C4‐selective C–H trifluoroethylation of 3‐ace...

Scheme 9.9 Rhodium‐catalyzed, coupling‐partner‐dependent C4‐ and C2‐selectiv...

Scheme 9.10 Rhodium‐catalyzed C4‐selective C–H alkenylation of 3‐mercaptoind...

Scheme 9.11 Site selectivity controlled by directing group on nitrogen: C2 v...

Scheme 9.12 Iridium‐catalyzed C–H borylation of NH indoles.

cod

,

1,5‐cyclooc

...

Scheme 9.13 Iridium‐catalyzed C7‐selective C–H borylation of indoles.

Scheme 9.14 Cp

*

Rh(III)‐catalyzed, pivaloyl‐directed C7‐selective C–H alk...

Scheme 9.15 Iridium‐catalyzed, pivaloyl‐directed C7‐selective C–H amidation ...

Scheme 9.16 Palladium‐catalyzed C7‐selective C–H arylation and alkenylation ...

Scheme 9.17 Rhodium‐catalyzed C7‐selective C–H arylation, alkenylation, acyl...

Scheme 9.18 Copper‐catalyzed C5‐selective C–H arylation of 3‐pivaloylindoles...

Scheme 9.19 Copper‐catalyzed, P(O)(

t

Bu)

2

‐directed C6‐selective C–H arylation...

Scheme 9.20 Ruthenium‐catalyzed C6‐selective C–H alkylation of indoles with ...

Scheme 9.21 Resonance, theoretical p

K

a

values, and early examples of α‐selec...

Scheme 9.22 Palladium‐catalyzed β‐selective C–H arylation of thiophenes with...

Scheme 9.23 Palladium‐catalyzed β‐selective C–H arylation of thiophenes with...

Scheme 9.24 Palladium‐catalyzed β‐selective C–H arylation of (benzo)thiophen...

Scheme 9.25 Directed C4‐selective C–H functionalization of benzothiophenes....

Scheme 9.26 Rhodium‐ and iridium‐catalyzed β‐selective C–H borylation of

N

‐T...

Scheme 9.27 Palladium‐catalyzed β‐selective C–H alkenylation of

N

‐TIPS pyrro...

Scheme 9.28 Rhodium‐catalyzed β‐selective C–H arylation of pyrroles with ary...

Scheme 9.29 Early examples of C2‐selective C–H functionalization of pyridine...

Scheme 9.30 Palladium‐catalyzed C3‐selective C–H arylation of pyridines with...

Scheme 9.31 Palladium‐catalyzed C3‐selective C–H alkenylation of pyridines w...

Scheme 9.32 Palladium‐catalyzed directed C3‐selective C–H arylation of pyrid...

Scheme 9.33 Palladium‐catalyzed, oxidant‐controlled C3‐ and C2‐selective deh...

Scheme 9.34 Palladium‐catalyzed directed C4‐selective C–H arylation of pyrid...

Scheme 9.35 Nickel/aluminum‐catalyzed C4‐selective C–H alkylation of pyridin...

Scheme 9.36 Nickel/aluminum‐catalyzed C4‐selective C–H alkenylation of pyrid...

Scheme 9.37 Iridium‐/aluminum‐catalyzed C4‐selective C–H borylation of pyrid...

Scheme 9.38 Metal hydride‐catalyzed C4‐selective C–H alkylation of pyridines...

Scheme 9.39 Early examples of C–H arylation of thiazoles at the C2 and/or C5...

Scheme 9.40 Palladium‐catalyzed C4‐selective C–H arylation of thiazoles with...

Scheme 9.41 Rhodium‐catalyzed C8‐selective C–H arylation of quinolines with ...

Scheme 9.42 Iridium‐catalyzed C8‐selective C–H silylation of quinolines with...

Chapter 10

Scheme 10.1 Directing group assisted transition metal‐catalyzed C–H function...

Scheme 10.2 Directed metal‐catalyzed site‐selective C(sp

3

)–H functionalizati...

Scheme 10.3 Palladium‐catalyzed γ‐C(sp

3

)–H arylation of amino acids.

Scheme 10.4 Palladium‐catalyzed γ‐C(sp

3

)–H arylation of aliphatic carboxamid...

Scheme 10.5 Quinoline‐ligand enabled palladium‐catalyzed arylation of γ‐C(sp

Scheme 10.6 Palladium‐catalyzed γ‐C(sp

3

)–H alkynylation of 3,3‐dimethylbutyi...

Scheme 10.7 Palladium‐catalyzed γ‐C(sp

3

)–H alkylation of

L

‐valine derivative...

Scheme 10.8 Ligand‐enabled palladium‐catalyzed γ‐C(sp

3

)–H olefination and ca...

Scheme 10.9 Sequential γ‐C(sp

3

)–H olefination and carboxylation.

Scheme 10.10 Palladium‐catalyzed γ‐C(sp

3

)–H alkenylation of carboxylic acids...

Scheme 10.11 Palladium‐catalyzed γ‐C(sp

3

)–H silylation and germanylation of ...

Scheme 10.12 Palladium‐catalyzed γ‐C(sp

3

)–H chalcogenation of carboxylic aci...

Scheme 10.13 Palladium‐catalyzed γ‐C(sp

3

)–H intramolecula amination.

Scheme 10.14 Cobalt‐catalyzed γ‐benzyl C(sp

3

)–H dehydrogenative amination....

Scheme 10.15 Ligand‐enabled palladium‐catalyzed γ‐C(sp

3

)–H arylation of

N

‐Ph...

Scheme 10.16 Palladium‐catalyzed γ‐C(sp

3

)–H arylation of free aliphatic acid...

Scheme 10.17 Palladium‐catalyzed γ‐C(sp

3

)–H arylation of

N

‐protected

tert

-le...

Scheme 10.18 Palladium‐catalyzed intramolecular amination of C(sp

3

)H bonds ...

Scheme 10.19 Construction of polycyclic nitrogen-containing heterocycles vi...

Scheme 10.20 Palladium‐catalyzed oxalyl amide directed δ‐C–H amination of al...

Scheme 10.21 Palladium‐catalyzed methylation of bicyclic amine with bidentat...

Scheme 10.22 Palladium‐catalyzed remote arylation of anti‐influenza virus A ...

Scheme 10.23 Arylation of alkyl picolinamides via Pd‐catalyzed remote C–H ac...

Scheme 10.24 Palladium‐catalyzed remote δ‐arylation of various amines with d...

Scheme 10.25 Iterative (hetero)arylation of aliphatic amines.

Scheme 10.26 Palladium‐catalyzed remote ɛ‐C(sp

3

)–H alkynylation of alkyl ami...

Scheme 10.27 Palladium‐catalyzed remote δ‐arylation of anilines assisted by ...

Scheme 10.28 Stoichiometric formation and isolation of C–H cyclopalladation ...

Scheme 10.29 Palladium‐catalyzed native directed remote δ‐arylation of free ...

Scheme 10.30 Palladium‐catalyzed δ‐C(sp

3

)–H of alkyl amines via transient di...

Scheme 10.31 Site‐selective alkenylation of δ‐C(sp

3

)H bonds with alkynes vi...

Scheme 10.32 Mechanistic experiments and proposed catalytic cycle.

Scheme 10.33 Site‐selective δ‐C(sp

3

)–H alkylation of amino acids and oligope...

Scheme 10.34 Palladium‐catalyzed γ‐C(sp

3

)–H arylation of a ketone enabled by...

Scheme 10.35 Ligand‐enabled γ‐C(sp

3

)–H arylation of aliphatic ketones [71]....

Scheme 10.36 Ligand‐promoted γ‐C(sp

3

)–H arylation of aliphatic aldehydes [35...

Scheme 10.37 Site‐selective γ‐C(sp

3

)–H arylation of alcohols with full sp

2

c...

Scheme 10.38 Synthesis of six‐membered palladacycles via competition experim...

Scheme 10.39 Design of the tridentate directing group for remote C–H activat...

Scheme 10.40 Proposed catalytic cycle for C(sp

3

)–H carbonylation.

Scheme 10.41 Hemilabile benzyl ether directed distal C(sp

3

)–H carbonylation ...

Chapter 11

Scheme 11.1 Radical‐mediated distal C(sp

3

)–H functionalization.

Scheme 11.2 Selected milestones in radical‐mediated distal C(sp

3

)–H function...

Scheme 11.3 sp

2

carbon radical promoted hydrogen transfer.

Scheme 11.4 Aryl radical guided desaturation of remote aliphatic CH bond wi...

Scheme 11.5 Visible‐light photoredox catalyzed remote hydroxylation of aliph...

Scheme 11.6 Aryl diazonium initiated remote C(sp

3

)–H functionalization.

Scheme 11.7 Photoinduced Pd‐catalyzed desaturation of C(sp

3

)H bonds.

Scheme 11.8 Radical arylation of inactive secondary/tertiary C(sp

3

)H bonds ...

Scheme 11.9 (a) KO

t

Bu promoted carbon–carbon coupling of remote tertiary C(s...

Scheme 11.10 Hydrogen‐atom transfer of hybrid vinyl palladium radical interm...

Scheme 11.11 Regioselective vinylation of remote unactivated C(sp

3

)H bonds....

Scheme 11.12 Total synthesis of Leuconoxine, Melodinine E, and Mersicarpine ...

Scheme 11.13 Enantioselective C(sp

3

)H bond functionalization via 1,5‐HAT....

Scheme 11.14 Alkyl radical guided C–H desaturation of aliphatic alcohols.

Scheme 11.15 Catalytic iodine‐mediated Hofmann–Loffler reaction.

Scheme 11.16 Catalytic bromine‐mediated Hofmann–Loffler reaction.

Scheme 11.17 Triiodide‐mediated δ‐amination of inert CH bonds.

Scheme 11.18 Visible‐light‐induced photoredox catalyzed Hofmann–Loffler reac...

Scheme 11.19 Generation of nitrogen radical by reductive cleavage of CF bon...

Scheme 11.20 Metal‐catalyzed C–H amination with organic azides.

Scheme 11.21 Remote C(sp

3

)–H functionalization via radical initiated decompo...

Scheme 11.22 Copper‐catalyzed remote C(sp

3

)–H azidation of benzohydrazides....

Scheme 11.23 Photoredox 1,5‐H transfer of iminyl radicals.

Scheme 11.24 Oxidative cleavage of α‐imino‐oxy acid based oxime to generate ...

Scheme 11.25 Generation of nitrogen radicals by oxidation of NH bonds. (a) ...

Scheme 11.26 Generation of nitrogen radicals by abstraction of hydrogen.

Scheme 11.27 Electrochemical mediated generation of nitrogen radical.

Scheme 11.28 Generation of oxygen radicals from

N

‐alkoxyphthalimides by phot...

Scheme 11.29 Enantioselective functionalization of remote C(sp

3

)H bonds....

Scheme 11.30 Photoredox catalyzed radical translocation of

N

‐alkoxypyridiniu...

Scheme 11.31 Dual copper/photoredox catalyzed remote C(sp

3

)–H functionalizat...

Scheme 11.32 Generation of oxygen radicals by Fe(II) catalyzed reduction of ...

Scheme 11.33 Cascade of 1,5‐HAT and 1,4‐heteroaryl migration.

Scheme 11.34 Oxygen radical directed heteroarylation of remote C(sp

3

)H bond...

Scheme 11.35 Redox neutral remote C(sp

3

)H bond animation.

Chapter 12

Scheme 12.1 Examples of TFDO oxidations at tertiary and secondary C–H positi...

Scheme 12.2 Selectivity of dioxirane C–H oxidation in steroid derivatives.

Scheme 12.3 Basic mechanisms of decatungstate photocatalysis, and representa...

Scheme 12.4 TBADT‐catalyzed remote C–H fluorination of aliphatic esters with...

Scheme 12.5 Decatungstate‐catalyzed C–H fluorination and

18

F‐fluorination of...

Scheme 12.6 Comparison of selectivity for different C–H fluorination methods...

Scheme 12.7 Decatungstate‐catalyzed CC bond formation in aliphatic nitriles...

Scheme 12.8 Decatungstate‐catalyzed CC bond formation in aliphatic ketones ...

Scheme 12.9 Influence of steric and electronic effects on the regioselectivi...

Scheme 12.10 Electrochemical aerobic oxidation of remote CH bonds.

Scheme 12.11 Electrochemical fluorination of remote CH bonds.

Scheme 12.12 General mechanism of the metal‐catalyzed carbene insertion.

Scheme 12.13 Examples of catalyst‐dependent site selectivity in the insertio...

Scheme 12.14 Examples of catalysts employed for the insertion of carbenes in...

Scheme 12.15 Examples of selective carbene insertion into unactivated second...

Scheme 12.16 Examples of selective carbene insertion into unactivated tertia...

Scheme 12.17 Examples of selective carbene insertion into unactivated primar...

Scheme 12.18 RhCp*‐catalyzed selective borylation of primary, non‐hindered C...

Scheme 12.19 General mechanism for the Rh‐catalyzed C–H borylation of alkane...

Scheme 12.20 Selectivity among different primary CH bonds in Rh‐ and Ir‐cat...

Scheme 12.21 Selective borylation of secondary β CH bonds in cyclic ethers....

Scheme 12.22 Ir‐catalyzed borylation of secondary CH bonds in cyclopropanes...

Scheme 12.23 Activation and deactivation of CH bonds via polarity reversal ...

Scheme 12.24 Comparison of BDE values and/or Δ

G

values for HAT of CH bonds ...

Scheme 12.25 Example of selectivity of C–H oxidation in aliphatic amines und...

Scheme 12.26 Oxidation of remote tertiary and secondary CH bonds in aliphat...

Scheme 12.27 Oxidation of remote primary CH bonds in aliphatic amines via P...

Scheme 12.28 Oxidation of remote benzylic CH bonds in aliphatic amines usin...

Scheme 12.29 Remote C–H oxidation of aliphatic amines using Fe(PDP) complexe...

Scheme 12.30 Oxidation of remote tertiary and secondary CH bonds in aliphat...

Scheme 12.31 Supramolecular interaction between Mn(PDP–BC) and long‐chain al...

Scheme 12.32 Photochemical decatungstate‐catalyzed oxidation of remote secon...

Scheme 12.33 CC bond formation via amine protonation and radical addition‐t...

Scheme 12.34 Effect of hydrogen bond donor HFIP on the selectivity of oxidat...

Scheme 12.35 Effect of hydrogen bond donor HFIP on the selectivity of oxidat...

Chapter 13

Scheme 13.1 Representative selective C–H oxidations taking place in nature....

Scheme 13.2 Basic mechanistic scheme of C–H oxidation by mononuclear iron en...

Scheme 13.3 Basic typology of C–H oxidation catalysts discussed in this chap...

Scheme 13.4 Relative reactivity of CH bonds against HAT agents on the basis...

Scheme 13.5 (a) Effect of EWGs on site‐selectivity in the oxidation tertiary...

Scheme 13.6 Catalyst dependent selectivity based in sterics. (a) Oxidation o...

Scheme 13.7 Carboxylic acid directed C–H oxidation compared with oxidation o...

Scheme 13.8 Stereoelectronic effects in C–H oxidation reactions. (a) Catalyt...

Scheme 13.9 (a) Strain release in C–H oxidations of 1,2‐dimethyl substituted...

Scheme 13.10 Chirality dependent site selectivity in the oxidation of

trans

‐...

Scheme 13.11 Protonation or complexation driven remote CH bond oxidation of...

Scheme 13.12 Remote oxidation in amide and imide containing substrates.

Scheme 13.13 Schematic representation of the HAT reaction of a methylenic si...

Scheme 13.14 Catalytic hydroxylation of methylenes in HFIP. Values in italic...

Scheme 13.15 Comparative chemoselective C–H oxidation in alcohol and ether c...

Scheme 13.16 Comparative chemoselective C–H oxidation in amide and amine con...

Scheme 13.17 Oxidation of cholesterol governed by lipophilic interactions.

Scheme 13.18 Geometry control in the oxidation of an androstenediol derivati...

Scheme 13.19 Control of selectivity by metal to ligand binding. (a) Metallop...

Scheme 13.20 Kemps triacid appended supramolecular catalyst and envisioned i...

Scheme 13.21 Competitive oxidation of a

cis

/

trans

mixture of

S7

.

Scheme 13.22 Stereoselective C–H oxidation driven by recognition: enantiotop...

Scheme 13.23 Distribution of ketone products formed upon oxidation of linear...

Scheme 13.24 Selective oxidation of diamines by a supramolecular porphyrin c...

Scheme 13.25 Schematic diagram of the selective oxidation of steroidal molec...

Guide

Cover Page

Title Page

Copyright

Table of Contents

Begin Reading

Index

WILEY END USER LICENSE AGREEMENT

Pages

iv

1

2

3

4

5

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

412

413

414

415

416

417

418

419

420

421

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

Remote CH Bond Functionalizations

Methods and Strategies in Organic Synthesis

Edited by

Debabrata MaitiSrimanta Guin

Editors

Debabrata Maiti

Indian Institute of Technology Bombay

Department of Chemistry

Main Gate Rd, IIT Area

400076 Powai, Mumbai

India

Srimanta Guin

Indian Institute of Technology Bombay

Department of Chemistry

Main Gate Rd, IIT Area

400076 Powai, Mumbai

India

Cover

Cover Image: © selvanegra / Getty Images

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.

Library of Congress Card No.:

applied for

British Library Cataloguing‐in‐Publication Data

A catalogue record for this book is available from the British Library.

Bibliographic information published by the Deutsche Nationalbibliothek

The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at <http://dnb.d-nb.de>.

© 2021 WILEY‐VCH GmbH, Boschstr. 12, 69469 Weinheim, Germany

All rights reserved (including those of translation into other languages). 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: 978‐3‐527‐34667‐7

ePDF ISBN: 978‐3‐527‐82412‐0

ePub ISBN: 978‐3‐527‐82414‐4

oBook ISBN: 978‐3‐527‐82413‐7

1Introduction

Uttam Dutta, Srimanta Guin, and Debabrata Maiti

Indian Institute of Technology Bombay, Department of Chemistry, Powai, Mumbai, 400076, India

Innovation and implementation of science and technology is a defining parameter to determine the progress of a civilization. Inquisitive minds are constantly devoted in empowering the human civilization by elegant discoveries and their subsequent applications in practical life. Organic chemistry, being a prime component of modern science, has served the human society in a way that has pronounced to be a boon for the present era. In one hand organic chemistry has unfolded the mechanistic intricacies of biorelevant reactivity, while on the other hand it has uncovered the methods to synthesize the molecular architecture that can either mimic the biological activity or can alter the same. Additionally, organic chemistry has profound industrial application including agrochemicals, food industry, dyes industry, polymer industry, and so on. As a whole, organic chemistry has become an inseparable component in our daily life. However, the genesis of these applications and large scale synthesis used to be initiated at synthetic laboratory. The ground breaking discoveries by erudite chemist have thus proved the intellectual supremacy of human race. However, the efficacy of synthetic methods is dependent on the step economy, atom economy, and environment benignity. Never ending aspiration to search such fruitful methods continues to challenge the chemist and inspire new chemical transformations. Accounting these existing literature precedents in the form of a concise summary, which would be the tutorial resources for future generation to accomplish successive progress, is undeniably one of the best efforts to intensify the expansion of chemical synthesis.

CH bond being the fundamental backbone of organic compounds, the potential of a C–H functionalization to amend a molecule overrides traditional routes on grounds of step and atom economy. This has triggered the development of various strategies with the aim to alter the physicochemical properties of specific compounds or add on molecular complexity. Irrespective of aliphatic or aromatic setup, the CH bonds, vicinal to a functional group, are relatively easier to functionalize either by exploiting its acidity or by taking the advantage of its coordinating ability to the metal. Moving further toward distal positions, C–H functionalization is engrossed with several issues including the intrinsic inertness as well as regioselectivity due to the overabundance of multiple CH bonds with subtle reactivity differences. Therefore, a curious quest was always followed to execute distal C–H functionalization with precise site selectivity. In its itinerary thus far, a number of elegant approaches have been conceived to install functional group at distal location with precise and predictable selectivity. In this book, an attempt is made to provide a broad overview on contemporary advancements in the field of distal C–H functionalization. Eminent researchers, who are known for their significant contributions in distinguished research areas, have penned down their collective efforts to outline a coherent and comprehensive discussion about different strategies for distal C–H functionalization.

Chapter 2 introduces to the realm of directing group (DG) assisted distal arene meta‐functionalization. Precise control on regioselectivity is one of the most important aspects in arene C–H functionalization. Arenes bearing heteroatom containing functionality, which is famously known as directing group (DG), were extensively exploited for proximal ortho‐C–H activation. Extending such DG‐assisted distal meta‐functionalization strategy required proper template engineering that would ensure the meta‐selective C–H activation. In this context, Yu and coworkers disclosed a “U”‐shaped template for meta‐selective alkenylation. Thereafter, Yu, Maiti, Tan, Li, and others embarked on exploring the scope of meta‐functionalizations employing several templates. Gao and Li have collectively penned down in delineating a monograph on recent development of transition metal‐catalyzed, template assisted distal meta‐C–H functionalization.

Chapter 3 deals with the involvement of the Catellani reaction for distal functionalization of (pseudo)halo arenes. Transition metal‐catalyzed cross‐coupling reactions have revolutionized the art of modern synthesis. While aryl halides or pseudohalides produced ipso‐functionalized compounds, a new class of reactivity of aryl (pseudo)halide was developed by Catellani utilizing the combination of strained bicyclic olefin, norbornene (NBE), and palladium. A phenylnorbornylpalladium(II) (PNP) dimeric Pd‐catalyst was successfully employed to furnish o,o′‐disubstituted vinylarenes starting from aryl iodides, alkyl iodide, and olefin in a regioselective manner. This Pd–NBE cooperative catalysis was expanded further for a diverse class of substrates including NH‐indoles and NH‐pyrroles, arenes bearing directing group (DG), and arylboron compounds by several eminent scientists. Several electrophiles were utilized for ortho‐functionalization, and various nucleophiles were used as terminating reagent for ipso‐functionalization. In Chapter 3, Juntao Ye and Mark Lautens have provided a vivid description about the development of arene C–H functionalization relying on Pd–NBE catalysis. The discussion was initially focused on the processes initiated with Pd(0) and subsequent discussion was made on the protocols initiated with Pd(II). However, a large part of Chapter 3 was devoted in portraying synthetic applicability of the Pd–NBE cooperative catalysis.

The seminal work by Catellani on di‐functionalization of aryl (pseudo)halides evolved in 1997. In later years, enormous efforts have been devoted in expanding the scope of this Pd–NBE cooperative catalysis in a relayed C–H activation process. In this context, Dong and Yu independently pioneered a directing group assisted meta‐C–H functionalization utilizing the concept of Catellani reaction. An ortho‐directing group was employed for initial ortho‐C–H activation and subsequent palladium relay was realized in presence of NBE to accomplish meta‐selective arene‐C–H functionalizations. While the directing group (DG) assisted C–H functionalization was extensively studied for ortho‐functionalization, aforementioned seminal reports opened up a new horizon in distal meta‐C–H functionalization. Cheng and Zhou discussed about the recent advancements on directing group assisted meta‐selective functionalization of arenes relying on NBE mediated Catellani type reaction. A detailed discussion was made on various functionalizations including alkylation, arylation, alkynylation, chlorination, and amination, which were achieved by anchoring different ortho‐directing groups such as amides, amines, pyridine, or even free carboxylic acid.

In Chapter 5, a comprehensive summary on ruthenium catalyzed distal meta‐ and para‐C–H functionalization was provided by Ackermann and coworkers. In last decades a number of handful synthetic protocols were developed to accomplish remote arene C–H functionalization by Ru‐catalysis. Ru‐catalyzed ortho‐C–H ruthenation and subsequent ortho‐functionalization were known in literature over few decades. In a sharp contrast, a unique catalytic reactivity to furnish meta‐functionalized product from such ortho‐ruthenated arenes was first observed by Frost and Ackermann in 2011 and 2013, respectively. In later years, Ackermann, Frost, Greaney, Zhang, and others successfully demonstrated a number of useful meta‐functionalization methods relying on similar strategy. Ru‐catalyzed para‐selective functionalization was also included in Chapter 5 to retrospect the entire spectrum of Ru‐catalyzed remote C–H functionalization.

While Chapters 2–5 of this book were focused on discussing various approaches for distal arene C(sp2)–H functionalization based on directing group assisted protocols, Catellani reactions, or via arene cyclo‐ruthenation methods, in Chapter 6 Phipps and coworkers devoted their efforts in summarizing a complementary strategy for remote arene functionalization harnessing the non‐covalent interactions. Although non‐covalent interactions are prevalent in enzymatic reactions but translating such interaction in regioselective functionalization of small molecule in synthetic scale is rare. Despite the several challenges associated in controlling the site selectivity of arene functionalization, in recent years a number of elegant methods were developed by Smith, Kanai, Phipps, Chattopadhyay, and others. Phipps and his co‐authors illuminated about the emergence of non‐covalent interaction in distal arene‐C–H functionalization in Chapter 6.

Although use of directing group, transient mediator or non‐covalent interactions have been popularized in recent years to harness the regioselective transformation of arenes. However, transition metal‐catalyzed functionalization governed by the steric and/or electronic factors was cultivated over the century to mitigate the issues pertaining to the site‐selectivity. Intrinsic biasness derived from the substituted functionality present in arenes or heteroarenes is considered to be the key component in defining the selectivity. While such strategy, precludes preinstallation of directing group or circumvent the complicated catalytic path involved in NBE mediated process, but were largely limited by the nature of substrate as well as usage of excess amount of arenes. However, prudent combination of catalyst, ligand, and reagent designing has been realized in recent years to enable regioselective functionalization of arenes or heteroarene with broad functional group tolerance. An exemplified discussion of such non‐directed distal arene functionalization is made by van Gemmeren et al. in Chapter 7. The prime attention was paid in depicting the recent progresses on non‐directed distal arene functionalization, where arenes were used as limiting reagent.

In Chapter 8, Dutta and Maiti discussed about the recent progresses in the realm of distal arene para‐C–H functionalizations. Distinction of energetically comparable CH bonds to achieve regioselective C–H functionalization is one of prime focus of modern synthesis. In this regard, a number of strategies are known in the literature to perpetrate para‐selective functionalization. Although electronic controlled Friedel–Crafts reaction being the early examples to promote para‐C–H functionalization but this strategy is severely restricted with certain substrates and produced ortho‐functionalized product as an unavoidable side product. Thus, the propulsive thrust in establishing strategies exists, which are not dependent on the electronic properties of the targeted substrate. The use of directing group, steric governance, non‐covalent interactions, and radical initiation is cultivated to expand the scope of arene para‐C–H functionalization. Chapter 8 is aimed to provide a comprehensive and exemplified discussion on directing group assisted, steric controlled, and non‐covalent interactions promoted para‐functionalizations to enlighten the scope of para‐selective functionalizations beyond electronic control.

Chapter 9 deals with heterocycle functionalizations at unusual positions. Heterocycles are prevalent structural core in pharmaceuticals, natural products, and agrochemicals. Regioselective C–H functionalization of heterocycles is of paramount importance as the derivatization of these heterocyclic cores can alter their inherent properties. However, C–H functionalizations of hetero‐arenes are predominantly achieved at electronically biased positions. Therefore, standing against the innate inertness to attain selective C–H functionalization at unusual positions is of paramount importance in order to enrich the repertoire of heterocyclic compounds. The ever‐expanding inquisitive minds have dedicated their efforts in finding and devising suitable methodology to promote site selective C–H functionalization of apparently inert CH bonds present in heteroarenes. Hirano and Miura have elucidated these recent reports in Chapter 9. Recent progress on C–H functionalization of important heterocycles, namely, indole, (benzo)thiazole, pyrrole, pyridine, quinoline, and others is concisely recapitulated in Chapter 9.

Unlike arene C(sp2)–H functionalization, aliphatic C(sp3)–H functionalization is relatively challenging due to its inherent inertness, low acidity, and overabundance with flexible long chain. Additionally, control over stereoselectivity is another important aspect to take care. Although functionalization of acidic CH bonds adjacent to electron‐withdrawing functional group or allylic and benzylic CH bonds was exploited with electrophile, reciprocating such reactivity is impossible for remote C–H functionalization of long chain aliphatic substrates. However, the assistance from directing group enabled the delivery of functional groups at a desired position with uncompromised yield and selectivity. A vivid exemplification about the recent reports on directing group assisted remote functionalization of aliphatic substrates was presented by Li, Zhang, and Shi in Chapter 10.

Chapter 11 by Li and Zhu articulates the recent progresses on radical initiated distal C(sp3)–H functionalizations. Intramolecular hydrogen atom transfer process has provided a synthetically useful tool to promote regioselective functionalization of aliphatic substrates. Hofmann–Loffler–Freytag (HLF) reaction was considered as the pioneering invention in this realm. Although the potential of this strategy was realized lately in 2010, when a rapid growth was witnessed to promote radical initiated distal aliphatic functionalization via hydrogen atom transfer. In Chapter 11, comprehensive summary on different methods, synthetic applicability, and mechanistic intricacies are discussed from 2010 onwards.

Chapter 12 is devoted in discussing non‐directed functionalizations of aliphatic compounds, governed by innate reactivity. Although several challenges associated with the site selective functionalization of aliphatic substrates, constant up‐search in finding suitable protocols either by tuning the innate reactivity of particular CH bond present in the substrate or by controlling the reagent and catalyst has led to revolutionize the modern era of aliphatic C–H functionalization. Sambiagio and Maes have summarized the recent progress on non‐directed aliphatic C–H functionalization at the remote position. Although a major part of aliphatic C–H activation was accomplished by directing group assisted strategy, Chapter 12 includes only non‐directed aspect of aliphatic distal C–H functionalization. Chapter 12 was broadly divided into two parts: (i) the reaction involving distinct formation of metal–carbon bond and (ii) the reactions occurring without the metal–carbon bond formation.

While the sojourn through transition metal‐catalyzed distal C–H functionalization goes on in Chapters 2–12, in Chapter 13, Costas introduces to the territory of remote aliphatic C–H oxidation by bioinspired catalysis. Selective C–H oxidation is a routine task in biological system. The selectivity in enzymatic process is governed by the virtue of several interactions that enable the proper substrate trajectory and geometric orientation. Imitating such reactivity in laboratory synthesis is relatively challenging yet worthy to explore. Therefore, a persistent attempt to comprehend the mechanistic insight of biological reactivity and catalyst or ligand design was pronounced to furnish site selective functionalization of aliphatic substrate. A comprehensive survey on aliphatic C–H oxidation imparted by the bio‐inspired catalysis is outlined by Costas in Chapter 13.

The endless curiosities of human mind are the key to the technological advancements and evolution. This eternal truth has remained the essence for every piece of advancement since ancient times and will continue to remain persistent till times eternity. Modernization of scientific research in organic chemistry genre has shaped up in the form of C–H activation based protocols that has fostered a novel dimension in synthetic prospects and restructured the temperament of the scientific fraternity accordingly. This book besides providing a comprehensive scenario on the field of distal C–H activation also aims to inculcate cognizance among researchers of present and future generations to streamline and channelize their scientific understanding for the welfare of human civilization.

2Transition Metal‐Catalyzed Remote meta‐C–H Functionalization of Arenes Assisted by meta‐Directing Templates

Yuzhen Gaoand Gang Li

State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences (CAS), 155 West Yang‐Qiao Road, Fuzhou, Fujian, 350002, China

2.1 Introduction

Site‐selective C–H functionalization has emerged as an important synthetic methodology in organic synthesis in the past two decades [1–10]. For such synthetic methodology to be synthetically useful, precise control of the site‐selectivity of C–H functionalization reactions is one of the most important issues required to be resolved due to the presence of several CH bonds with similar reactivity in an organic molecule. Notably, meta‐selectivity in C–H functionalization of arenes is one of the intriguing site selectivities that have been intensely studied in recent years [1–10]. Although thousands of methods for ortho‐C–H functionalizations of arenes via proximity‐induced cyclometallation have been reported, only a limited number of approaches have been disclosed in meta‐C–H functionalizations of arenes. One of the representative approaches of meta‐C–H functionalization of arenes is the directing template assisted remote meta‐C–H functionalizations of arenes via geometry‐induced metalation (Scheme 2.1a) [5–10].

ortho‐C–H functionalization has been usually promoted by σ‐chelation of the directing template. However, applying this chelation to meta‐C–H functionalization is much more challenging since a strained cyclophane‐like metallacycle might be involved in this transformation [11]. In 2012, the group of Yu and coworkers disclosed the first geometry‐induced remote meta‐C–H activation of toluenes and hydrocinnamic acids with a Pd(II) catalyst, which is assisted by two types of rationally designed nitrile‐based templates that are covalently linked with toluenes or hydrocinnamic acids through an ether or amide bond (Scheme 2.1b) [11]. The presumable linear coordination mode of the nitrile‐based chelating functionality (CF) in the U‐shaped template that weakly coordinates to the palladium center in an end‐on fashion is important for securing a possible less strained cyclophane‐like pre‐transition state. However, a more likely catalytic scenario is the weakly chelating template may “catch and release” the Pd(II) catalyst closely to the target meta‐CH bond, leading to a high effective concentration of the Pd(II) catalyst at the target meta‐CH bond without forming an 11‐ or 12‐membered cyclophane‐like palladacycle.

Scheme 2.1 Directing template assisted meta‐CH bond functionalization. Related reviews:

(a) Li et al. [5], Yang [6], Chattopadhyay and Bisht [7], Dey et al. [8], Ghosh and De Sarkar [9], and Dey et al. [10]; Source: (b) Modified from Leow et al. [11].

Inspired by this pioneering work, a series of directing template assisted remote meta‐C–H activation reactions have been realized for a list of substrates including acids, amines, sulfonic acids, and so on (Scheme 2.1c). Notably, one of the key features of these reactions is the target CH bond is usually 10–12 atoms away from the chelating atom of the template (Scheme 2.1b,d), although longer length was also possible. To date, three categories of CFs have been engineered including two nitrogen‐based CN‐containing (Scheme 2.2a) or heteroarene‐containing (Scheme 2.2b) CFs and one oxygen‐based CO2H‐containing CF (Scheme 2.2c). It should be noted that besides these three CFs that covalently attached to the substrate, two catalytic bifunctional templates that reversibly coordinate to the substrate were also reported recently and they are not classified in these categories [12,13]. Another key feature of these reactions is that hexafluoroisopropanol (HFIP), which could also be used as an additive, appears to be the privileged solvent. Finally, N‐acetyl glycine (Ac‐Gly‐OH), a mono‐N‐protected amino acid (MPAA), is often the ligand of choice for many of these reactions, although other MPAA ligands could also be utilized in some cases.

Herein, we summarize important achievements that were disclosed until October 2019 in the field of directing template assisted meta‐C–H functionalization of arenes with Pd or Rh catalysts since 2012. Different aspects of this type of methodology will be covered while discussing the works that are categorized by the substrate type. Important mechanistic studies on this methodology will also be included. It is hoped that the reader will learn the key points, especially structural features, for rationally designing a feasible template for new substrates as well as developing new types of meta‐C–H transformation after reading this chapter.

Scheme 2.2 Three categories of chelating functionality (CF). (a) N‐Based CN‐containing CF; (b) N‐based heteroarene‐containing CF; (c) O‐based CO2H‐containing CF.

2.2 Template‐Assisted meta‐C–H Functionalization

2.2.1 Toluene Derivatives

In 2012, Yu and coworkers devised the first effective U‐shaped nitrile‐based directing template that was covalently linked to the toluene derivatives via a removable benzyl ether linkage (Scheme 2.3) [11]. Notably, the directing ability of the template was improved by installing two isobutyl templates at the α‐position adjacent to the linearly chelating nitrile template due to the Thorpe–Ingold effect. This directing template efficiently enabled the meta‐C–H olefination of a broad range of toluene derivatives using Pd(OPiv)2 as the catalyst and AgOPiv as the oxidant. It is worth mentioning that such remote C–H activation that possibly demanded a cyclophane‐like 11‐membered palladacycle was first ever disclosed. Remarkably, the intrinsic electronic and steric biases of the substrates were successfully overridden. Finally, the directing template was readily cleaved through hydrogenolysis with a Pd/C catalyst.

Scheme 2.3meta‐C–H activation of toluene derivatives.

Source: Modified from Leow et al. [11].

2.2.2 Acid Derivatives

2.2.2.1 Hydrocinnamic Acid Derivatives

In Yu's seminal report, meta‐C–H olefination of hydrocinnamic acid derivatives was also achieved using an easily synthesized and recyclable 2,2′‐azanediyldibenzonitrile directing template, which is now available from Sigma–Aldrich as the Yu–Li auxiliary [11]. This template was attached to several hydrocinnamic acids via a readily cleavable amide linkage (Scheme 2.4). It is worth mentioning that hydrocinnamic acids are core motifs of many drug molecules such as Baclofen. Notably, it was discovered that the MPAA ligand Ac‐Gly‐OH from the simplest amino acid significantly improved the yield of the reaction and improved the selectivity as well with the optimal HFIP solvent that was crucial for the full conversion of the substrate. It was found in subsequent reports that this set of novel reaction conditions was also highly effective for many of the directing templated assisted meta‐C–H transformations. In this transformation, not only the intrinsic electronic biases of the substrate were overridden (9, 10), but also challenging steric hindrance was overcome by the template (11). Intriguingly, biaryl acid substrate that has the same length between the chelating nitrile group and the target meta‐CH bond as hydrocinnamic acid could also undergo meta‐selective C–H olefination of the remote aryl ring (12