Multicomponent Reactions towards Heterocycles E-Book

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

Seitenzahl: 713

Veröffentlichungsjahr: 2021

Beschreibung

Presents a wide-ranging overview of essential topics and recent advances in MCR chemistry

Heterocycles are a central component in natural product chemistry, pharmaceuticals, agrochemicals, and material science. New synthetic methodologies integrating the sequencing of multicomponent reactions (MCRs) are today being used for the rapid synthesis of diversified heterocycles in just one step. Multicomponent Reactions towards Heterocycles presents an up-to-date summary MCR chemistry with a focus on the conjugation between modern synthetic methodologies and MCRs.

Featuring contributions by leaders in the field, this comprehensive resource highlights applications of MCRs in natural products and intermediate synthesis, discusses current trends and future prospects in MCR chemistry, outlines novel multicomponent procedures, and more. The authors provide the practical information required for designing new reaction strategies and mechanisms, covering topics including MCR-based green synthetic methods, cyclization and cycloaddition reactions, heterocycle multicomponent syntheses in a continuous flow, catalytic alkynoyl generation, MCR synthesis of saturated heterocycles, and C–H functionalization and multicomponent reactions.

• Provides a thorough overview of heterocycles as input in multicomponent reactions
• Discusses recent advances in the field of MCR chemistry and progress in the synthesis and functionalization of heterocycles
• Demonstrates the use of MCRs to simplify synthetic design and achieve complexity and diversity in novel bioactive molecules
• Highlights examples of multicomponent polymerizations, target-oriented synthesis, and applications of MCR in medicinal chemistry
• Explains the methodology of using on-resin MCRs to produce heterocycle compounds

Illustrating the key role of MCRs towards heterocycles in natural product synthesis, drug discovery, organic synthesis, and other applications, Multicomponent Reactions towards Heterocycles is required reading for synthetic chemists in academia and industry alike.

Leseprobe

Table of Contents

Cover

Title Page

Copyright

Preface

1 Heterocycles as Inputs in MCRs: An Update

1.1 Introduction

1.2 Concerted MCRs

1.3 Radical MCRs

1.4 Metal-catalyzed MCRs

1.5 Carbonyl/Imine Polar MCRs

1.6 Isocyanide-based MCRs

1.7 Miscellany Processes

1.8 Conclusion

Acknowledgment

References

2 Heterocycles and Multicomponent Polymerizations

2.1 Introduction

2.2 Ugi-type Multicomponent Polymerizations

2.3 Mannich-type Multicomponent Polymerizations

2.4 Biginelli-type Multicomponent Polymerizations

2.5 Hantzsch-type Multicomponent Polymerizations

2.6 Debus–Radziszewski-type Multicomponent Polymerizations

2.7 Other Multicomponent Polymerizations

2.8 Conclusions and Outlook

References

3 Multicomponent Reactions in Medicinal Chemistry

3.1 Introduction

3.2 Scaffolds and the Chemical Space of MCR

3.3 Some Biopharmaceutical Application of MCR

3.4 Conclusion

References

4 Solid-Phase Heterocycle Synthesis Using Multicomponent Reactions

4.1 Introduction

4.2 Synthesis of Five-Membered Ring Heterocycles

4.3 Synthesis of Six-Membered Ring Heterocycles

4.4 Synthesis of Fused Heterocyclic Ring Systems

4.5 Synthesis of Heterocycles on Solid-Supported Amino Acids

4.6 Solid-Phase Multicomponent Construction of DNA-Encoded Heterocycle Libraries

4.7 Miscellaneous Supports for Multicomponent Synthesis of Heterocycles

4.8 Conclusions

References

5 Green Synthesis of Heterocycles Via MCRs

5.1 Introduction

5.2 High-Order MCRs

5.3 Consecutive MCRs

5.4 MCRs Followed by Cyclization Reactions

5.5 MCRs Followed by Cycloaddition or Annulation Reactions

5.6 Conclusion and Outlook

References

6 The Use of Flow Chemistry in the Multicomponent Synthesis of Heterocycles

6.1 Introduction

6.2 Multicomponent Reactions Under Standard Flow Conditions

6.3 Multicomponent Reactions with Hazardous Reagents

6.4 Multicomponent Reactions Under Special Conditions

6.5 Telescoped Reactions

6.6 Conclusions

References

7 C–H Functionalization as an Imperative Tool Toward Multicomponent Synthesis and Modification of Heterocycles

7.1 Introduction

7.2 Transition-metal-involved C–H Functionalization

7.3 Transition-metal-involved C–H Functionalization

7.4 Transition-metal-free C–H Functionalization

References

8 Multicomponent-Switched Reactions in Synthesis of Heterocycles

References

9 Recent Applications of Multicomponent Reactions Toward Heterocyclic Drug Discovery

9.1 Introduction

9.2 Multicomponent Reactions

9.3 The Ugi Reaction

9.4 The Passerini Reaction

9.5 Groebke–Blackburn–Bienaymé (GBB-3CR) MCR

9.6 Gewald (G-3CR) Reaction

9.7 The Hantzsch Dihydropyridine (DHP) Synthesis

9.8 The Biginelli Reaction

9.9 van Leusen Reaction

References

10 Multicomponent Syntheses of Heterocycles by Catalytic Generation of Alkynoyl Intermediates

10.1 Introduction

10.2 Catalytic Generation of Alkynones

10.3 Multicomponent Syntheses of Five-membered Heterocycles

10.4 Multicomponent Syntheses of Six-membered Heterocycles

10.5 Conclusion and Outlook

References

11 Synthesis of Saturated Heterocycles via Multicomponent Reactions

11.1 Introduction

11.2 Three-membered Ring Heterocycles

11.3 Four-membered Ring Heterocycles

11.4 Five-membered Ring Heterocycles

11.5 Six-membered Ring Heterocycles

11.6 Seven-membered Ring Heterocycles

11.7 Macrocycles

11.8 Fused Heterocycles

11.9 Spiro Heterocycles

References

12 Multicomponent Reactions and Asymmetric Catalysis

12.1 Introduction

12.2 Imine-based MCRs

12.3 Michael Addition-based MCRs

12.4 Isocyanide-Based MCRs

12.5 Conclusion

References

13 Recent Trends in Metal-catalyzed MCRs Toward Heterocycles

13.1 Introduction

13.2 Five-membered Heterocycles with One Heteroatom

13.3 Five-membered Systems with Two Heteroatoms

13.4 Five-membered Systems with Three Heteroatoms

13.5 Six-membered Heterocycles with One Heteroatom and Their Benzo-fused Derivatives

13.6 Six-membered O-heterocycles and their Benzofused Derivatives

13.7 Four-membered N-heterocycles and Seven-membered Benzofused N-heterocycles

13.8 Conclusion

References

Index

End User License Agreement

List of Tables

Chapter 2

Table 2.1 Different MCRs utilized for MCPs.

Table 2.2 Synthesis of polyamides

4

.

Table 2.3 Synthesis of polyamide

7

.

Table 2.4 Synthesis of polyamides

9

.

Table 2.5 Synthesis of benzoxazine

12

and subsequent ring-opening polymerizat...

Table 2.6 Synthesis of benzoxazine

15

and subsequent ring-opening polymerizat...

Table 2.7 Synthesis of PBA precursors

18

and subsequent ring-opening polymeri...

Table 2.8 Synthesis of PBA precursor

21a–c

and ring-opening polymerizat...

Table 2.9 Synthesis of PBAs

23

.

Table 2.10 Synthesis of poly(DHPM(T))

26

.

Table 2.11 Synthesis of poly(DHMPs)

30

.

Table 2.12 Synthesis of poly(DHPM(T))

30

.

Table 2.13 Synthesis of poly(3,4-DHMP(T))

26/27

, poly(1,4-DHP)

35a

, and poly(...

Table 2.14 Synthesis of polyimidzaoles

37

.Source: Chauveau et al. [68]; Cha...

Table 2.15 Synthesis of polyimidzaoles

39

.

Table 2.16 Synthesis of the selected polymers

39

,

40

, and

42

.

Table 2.17 Synthesis of selected polymers

50

.

Table 2.18 Synthesis of polymer

53

.

Table 2.19 Synthesis of polymer

55

.

List of Illustrations

Chapter 1

Scheme 1.1 Heterocycles as inputs in MCRs.

Scheme 1.2 Access to julolidines via double Povarov MCRs.

Scheme 1.3 Indoles as inputs in Povarov MCRs.

Scheme 1.4 Aminoheterocycles in Povarov MCRs.

Scheme 1.5 Mechanistic variations of the Povarov-type processes.

Scheme 1.6 Cycloaddition-type MCRs.

Scheme 1.7 [3 + 2] Dipolar cycloaddition MCRs.

Scheme 1.8 Azines and isatins in dipolar MCRs.

Scheme 1.9 Azine-aryne MCRs.

Scheme 1.10 3/4-Membered heterocycles in aryne MCRs.

Scheme 1.11 Minisci-type radical MCRs.

Scheme 1.12 Site-selective azine-based radical MCRs.

Scheme 1.13 SO

2

photoredox MCR.

Scheme 1.14 Heterocycle dearomatization in radical MCRs.

Scheme 1.15 Maleamides as inputs in radical MCRs.

Scheme 1.16 C–H activation MCRs.

Scheme 1.17 A3-type MCRs.

Scheme 1.18 Carbonylative transition-metal catalyzed MCRs.

Scheme 1.19 Au(Ag)-catalyzed MCR post-transformations.

Scheme 1.20 Mannich-type MCRs.

Scheme 1.21 Petasis MCR.

Scheme 1.22 Dicarbonyl derivatives in Biginelli- and Hantzsch-type MCRs.

Scheme 1.23 Coumarins and isatins in MCRs.

Scheme 1.24 Aminoazoles in conjugated addition-type MCRs.

Scheme 1.25 Reissert-type reactions.

Scheme 1.26 Ugi-type MCRs. Mechanistic variations.

Scheme 1.27 Ugi-type MCRs. Substrate variations.

Scheme 1.28 Joullié-type MCRs. Substrate variations.

Scheme 1.29 GBB-type MCRs. Mechanistic variations.

Scheme 1.30 GBB-type MCRs: post-transformations.

Scheme 1.31 Isocyanide MCRs based on cycloadditions and insertions.

Scheme 1.32 MCRs featuring BODIPYs.

Scheme 1.33 Azole and azine nucleophilic MCRs.

Scheme 1.34 MCRs based on nitro derivatives and AI reaction discovery.

Chapter 2

Figure 2.1 MCP strategies toward polymers with heterocyclic fragments.

Figure 2.2 Synthesis of polyamide

4

via the Ugi reaction of levulinic acid

1

Figure 2.3 Synthesis of polyamide

7

via the Ugi reaction of

5

,

6a

,

2a10

, and...

Figure 2.4 Synthesis of polyamides

9

via the Ugi reaction of S-PEGs

8

, aldeh...

Figure 2.5 Synthesis of polybenzoxazine

13

from

12

, using a MCP of

10a

,

11

, ...

Figure 2.6 Reaction mechanism of the synthesis of benzoxazine

12

[31]. Reacti...

Figure 2.7 Synthesis of benzoxazine

15

from bisphenol-A

14

, aniline

11

, and for...

Figure 2.8 (a) Synthesis of PBA precursors

18

via the Mannich reaction of bi...

Figure 2.9 Synthesis of PBA precursor

21a-c

via the Mannich reaction of

20a

...

Figure 2.10 Synthesis of PBA

23

via the Mannich reaction of phenol

10

, piper...

Figure 2.11 Synthesis of poly(DHPM(T))

26

via the Biginelli reaction of

24

a...

Figure 2.12 Synthesis of poly(DHMPs)

29

via the MCP Biginelli reaction of

27

Figure 2.13 Synthesis poly(DHPM(T))

30

via the Biginelli HTP–MCP of

31

,

32

, ...

Figure 2.14 Synthesis of poly(3,4-DHMP(T))

26

/

27

via the Biginelli reaction ...

Figure 2.15 Synthesis of polyimidazoles

37

via the Debus–Radziszewski reactio...

Figure 2.16 Synthesis of polyimidazoliniums

39

via the Debus–Radziszewski re...

Figure 2.17 Cu-catalyzed MCP-synthesis of polymers

43

(or

46

) with

40

,

41

, a...

Figure 2.18 Pd-catalyzed synthesis of

50

reacting

47

,

48

, and

49

.

Figure 2.19 Pd-catalyzed synthesis of

53

reacting

51

,

52

, and

49a

.

Figure 2.20 Synthesis of polymer

55

via the MALI reaction of

28a

,

2a6

, and

5

...

Chapter 3

Figure 3.1 Major MCRs associated with their inventors (name reactions). The ...

Figure 3.2 Word cloud with the major attributes of MCR chemistry.

Figure 3.3 Timeline of p53/MDM2 antagonist discoveries in the Dömling labora...

Figure 3.4 The protein–protein interaction between the negative regulator MD...

Figure 3.5 The van Leusen trisubstituted imidazole scaffold to antagonize p5...

Scheme 3.1 Benzodiazepinediones as potent p53/MDM2 antagonists: 2-Step MCR s...

Scheme 3.2 Synthesis of benzimidazolones as p53 MDM2 antagonists.

Scheme 3.3 Ugi-4CR for synthesis of potent p53/MDM2 antagonists.

Scheme 3.4 U-4CR synthesis of fluorinated indole-based MDM2 antagonist.

Scheme 3.5 One-pot Orru-3CR reaction followed by amidation for the synthesis...

Scheme 3.6 β-Lactams as p53/MDM2 antagonists.

Scheme 3.7 Macrocyclic p53/MDM2 antagonists synthesized by U-4CR followed by...

Scheme 3.8 G-3CR product as 53/MDM2 antagonist.

Scheme 3.9 Gewald thienodiazepine-2,5-dione synthesis.

Figure 3.6 MCR peptide stapling. (a) Solid-phase synthesis of stapled peptid...

Scheme 3.10 NITD688 as a potent Dengue virus inhibitor and the Gewald chemis...

Scheme 3.11 Phenserine synthesis by MCR.

Scheme 3.12 U-4CR for Tadalafil synthesis.

Scheme 3.13 MCR synthesis for Bestatin.

Scheme 3.14 Racemic penicillamine can be synthesized by an Asinger-3CR follo...

Scheme 3.15 MCR synthesis of ivosidenib.

Scheme 3.16 HCV inhibitors Telaprevir and Boceprevir and MCR synthesis of Te...

Scheme 3.17 MCR synthesis of Praziquantel.

Scheme 3.18 MCR route to Atorvastatin.

Scheme 3.19 A MCR synthesis of carfentanil.

Scheme 3.20 Two MCR syntheses of racemic clopidogrel.

Scheme 3.21 Synthesis of xylocaine by U-3CR.

Scheme 3.22 U-3CR synthesis of quinapril.

Scheme 3.23 MCR synthesis of piracetam and structure of other synthesized ra...

Scheme 3.24 2-Step (

R)

-lacosamide synthesis via Ugi MCR.

Scheme 3.25 Olanzapine synthesis involving a Gewald MCR fragment.

Scheme 3.26 Nifedipine synthesis using the Hantzsch MCR and structures of ot...

Scheme 3.27 Almorexant synthesis via the U-3CR.

Scheme 3.28 Ugi reaction synthesis of antiviral Amenamevir.

Scheme 3.29 Synthesis of antibody drug conjugates (ADC) using the U-4CR.

Figure 3.7 IMCR protein conjugation.

Scheme 3.30 Stereoselective, convergent, low step, and high yielding N

14

-des...

Figure 3.8 The ANCHOR.QUERY VS platform to screen >31 million MCR molecules....

Chapter 4

Scheme 4.1 Applications of solid-phase 1,3-dipolar cycloadditions in the syn...

Scheme 4.2 Solid-phase synthesis of sulfur-containing five-membered ring het...

Scheme 4.3 Solid-phase syntheses of DHPM derivatives by the Biginelli-3CR fr...

Scheme 4.4 Synthesis of furo[3,4-

d

]pyrimidines, pyrrolo[3,4-

d

]-pyrimidines, ...

Scheme 4.5 Synthesis of functionalized 1,4-dihydropyridine by the Hantzsch 3...

Scheme 4.6 SPS of 2,3-dihydro-4-pyridones (a) and tetrahydropyridines (b) by...

Scheme 4.7 SPS of tetrahydroquinoline derivatives by the Grieco-3CR with a r...

Scheme 4.8 SPS of pyrido-fused tetrahydroquinolines by an aza-Diels–Alder re...

Scheme 4.9 Synthesis of zwitterionic tricyclic compounds by solid-phase Tsug...

Scheme 4.10 Synthesis of polysubstituted fused heterocycles from resin-ancho...

Scheme 4.11 Synthesis of quinoline derivatives by the Grieco-3CR with

p

-amin...

Scheme 4.12 Synthesis of tetrazoles and hydantoinimides by two consecutive o...

Scheme 4.13 Synthesis of six-membered heterocycle such as thiomorpholinones ...

Scheme 4.14 Synthesis of tetrazole-peptidomimetics as M1-aminopeptidase inhi...

Scheme 4.15 On-resin construction of DNA-encoded heterocycle libraries by MC...

Scheme 4.16 On-cellulose synthesis of DKP libraries by Ugi/cyclization strat...

Scheme 4.17 Synthesis of heterocycles by the Biginelli-3CR (a) and the Gewal...

Chapter 5

Scheme 5.1 Conceptual figures for representative 5CRs.

Scheme 5.2 5CRs for triazole-tethered spirochromenocarbazoles.

Scheme 5.3 5CR for dihydropyrazolopyridines.

Scheme 5.4 Pseudo-5CR for spiro-piperidines bearing Meldrum's acid.

Scheme 5.5 Pseudo-5CR for polyheterocycles.

Scheme 5.6 Pseudo-5CR for pyrazole- and pyrazolone-fused dihydrooxepines....

Scheme 5.7 Pseudo-5CR for pyrrolidine-based polycyclic compounds.

Scheme 5.8 Pseudo-5CR for heterocycles bearing oxoindoline, quinoline, and p...

Scheme 5.9 Pseudo-5CR for bicyclo[2.2.2]octane-centered polycycles.

Scheme 5.10 5C4CR for pyridopyrimidines.

Scheme 5.11 5C3CR for polyheterocycles.

Scheme 5.12 7CR for heterocycles involving Knoevenagel/Ugi/click reactions....

Scheme 5.13 Pseudo-6CR for rhodanine- and furan-containing compounds.

Scheme 5.14 Pseudo-6CR for bistetrazole-containing cyclic amines.

Scheme 5.15 Pseudo-6CR for highly condensed heterocycles.

Scheme 5.16 Pseudo-7CR for C

2

-symmetric heterocycles.

Scheme 5.17 Conceptual figure of consecutive MCR.

Scheme 5.18 Double GBB reactions for diimidazopyrimidines.

Scheme 5.19 Biginelli and Ugi-4CR reactions for tetrahydropyrimidinone amide...

Scheme 5.20 Double inter- and intramolecular Huisgen reactions for polyheter...

Scheme 5.21 3CR and GBB reactions for imidazotriazoles.

Scheme 5.22 Ugi-4C4CR and Ugi-4C3CR reactions for tetrazolopiperazinones....

Scheme 5.23 Ugi-4C3CR and Pictet–Spengler reactions for polycyclic indole al...

Scheme 5.24 Two Ugi-4CRs and a Ugi-4C3CR reactions for cyclopeptoid.

Scheme 5.25 Sequential Ugi-4CR, Passerini, and Ugi-4C3CR reactions for penta...

Scheme 5.26 Conceptual figure of MCR and cyclization.

Scheme 5.27 Huisgen reaction and post-condensation modifications for three d...

Scheme 5.28 Intramolecular [3 + 2] and post-condensation modifications.

Scheme 5.29 Huisgen and cyclization reactions for heterocycles.

Scheme 5.30 Huisgen and radical reactions for CF

3

-substituted heterocycles....

Scheme 5.31 Huisgen and Staudinger/aza-Wittig reactions for tetrahydropyrrol...

Scheme 5.32 Huisgen and Heck reactions for hexahydropyrroloisoquinolines....

Scheme 5.33 Ugi-4CR and cyclization for spiroindolines.

Scheme 5.34 Ugi-4CR and Au-catalyzed cyclization for polycyclic azepinoindol...

Scheme 5.35 Ugi-4CR and 6-

exo

-dig cyclization for morpholinone glycoconjugat...

Scheme 5.36 Asinger, Ugi-4C3CR, and cyclization reactions for heterocycles....

Scheme 5.37 Asinger and Ugi-4C3CR reactions for benzodiazepinediones.

Scheme 5.38 Conceptual figure for MCR and cycloaddition.

Scheme 5.39 Huisgen and Diels–Alder reactions for polyheterocycles.

Scheme 5.40 One-pot Huisgen and click reactions for heterocycles.

Scheme 5.41 Huisgen and [5 + 

n

] annulation reactions for heterocycles.

Scheme 5.42 4CR and [5 + 1] annulation for oxazinanones.

Scheme 5.43 Pictet–Spengler and Diels–Alder reactions pentacyclic alkaloids....

Scheme 5.44 Ugi-4CR and post modifications for polyheterocycles.

Chapter 6

Scheme 6.1 Synthesis of tetrasubstituted imidazoles

5

using a modified Radzis...

Scheme 6.2 Hantzsch synthesis of 1,4-dihydropyridines

9

under superheated con...

Scheme 6.3 Regioselective synthesis of aminoimidazo[1,2-

a

]pyrimidines via th...

Scheme 6.4 Flow synthesis of substituted tetrahydropentaazaphenalene-1,3-dio...

Scheme 6.5 Highly selective Huisgen 1,4-dipolar cycloaddition.

Scheme 6.6 Multicomponent synthesis of 2-aminochromenes

26–27

.

Scheme 6.7 Sequential Hantzsch/Biginelli continuous flow synthesis of

33

.

Scheme 6.8 Radical multicomponent selenosulfonation for the synthesis of

37

....

Scheme 6.9 Highly automated setup for the synthesis and purification of dias...

Scheme 6.10 High-throughput reaction optimization and catalyst screening by ...

Scheme 6.11 Safe handling of HCN in a modified Strecker reaction.

Scheme 6.12 The Bucherer–Bergs reaction for the synthesis of hydanthoins.

Scheme 6.13 Continuous flow synthesis of 1,4-disubstituted triazoles by CuAA...

Scheme 6.14 Three component synthesis of

N

-unsubstituted 4-aryl-1

H

-1,2,3-tri...

Scheme 6.15 Synthesis of quinolinones

64

through a three component reaction ...

Scheme 6.16 Synthesis of isoindolin-1-one-3-phosphonates

68

with a continuous...

Scheme 6.17 Synthesis of spiro-oxindole dihydroquinazolinones

72

using a SiC...

Scheme 6.18 Synthesis of propargylated cyclic amines

76

with a copper or gol...

Scheme 6.19 High temperature/high pressure synthesis of dihydropyridine

80

i...

Scheme 6.20 In-line synthesis of pyrrolidines

84

and pyrroles

85

with the ai...

Scheme 6.21 Synthesis of pyrrolidin-2-one

89

using a packed-bed reactor fill...

Scheme 6.22 Continuous flow Biginelli reaction using a Zn-based coordination...

Scheme 6.23 Multicomponent functionalization of cyclic amines with haloalkan...

Scheme 6.24 Synthesis of imidazo[2,1-

b

]thiazoles with Cu-based catalytically...

Scheme 6.25 Synthesis of benzoxazepinone

109

via a photoredox multicomponent...

Scheme 6.26 Synthesis of stannylated lactam

111

via a three component reacti...

Scheme 6.27 Three component synthesis of

115

using an aminopropylated monoli...

Scheme 6.28 Selective synthesis of highly substituted tetrahydrofurans

119

....

Scheme 6.29 Synthesis of 2,3-dihydro-1,5-benzothiazepine

124

through a teles...

Scheme 6.30 Continuous flow synthesis of 3-thio-1,2,4-triazole derivatives

1

...

Scheme 6.31 Telescoped synthesis of oxadiazoles

136

using a liquid–liquid mi...

Scheme 6.32 Telescoped synthesis of Ciprofloxacin

145

in a sequence of six c...

Chapter 7

Scheme 7.1 Sequential three-component synthesis of oxindoles.

Scheme 7.2 Mechanistic proposal for oxindole synthesis.

Scheme 7.3 Copper-catalyzed three-component synthesis of indoles.

Scheme 7.4 Transformations of N-sulfonyl ketoimines.

Scheme 7.5 Rh-catalyzed multicomponent reactions of 2-phenylpyridines.

Scheme 7.6 TEMPO oxoammonium salt-mediated three-component synthesis of quin...

Scheme 7.7 Rh-catalyzed synthesis of quinolines from anilines, alkynes and p...

Scheme 7.8 Multicomponent reactions of O-methyl oximes.

Scheme 7.9 Synthesis of isoquinolinones from oxazolines, diazomalonates and ...

Scheme 7.10 Divergent reactivity of N-acetyloxy amides towards methyleneoxet...

Scheme 7.11 A carbonylative interaction of anilines with benzynes.

Scheme 7.12 Rh-catalyzed synthesis of polycyclic azinium salts.

Scheme 7.13 Pseudo-four-component synthesis of pyrimidines.

Scheme 7.14 A consecutive Pd-catalyzed thee-component synthesis of pyrazoles...

Scheme 7.15 A four-component synthesis of fluorinated isoxazoles.

Scheme 7.16 Synthesis of isoxazolylazides employing Togni's reagent as a C1-...

Scheme 7.17 Three-component reactions of alkynes, bromides and 2-amino-subst...

Scheme 7.18 Multicomponent Pd-catalyzed reactions of isatins and benzoisatin...

Scheme 7.19 Proposed mechanism for the synthesis of annulated benzazepines....

Scheme 7.20 Copper-catalyzed reaction of bis(2-bromophenyl)methanone, alkyne...

Scheme 7.21 Rh-catalyzed preparation of polyannulated heterocycles.

Scheme 7.22 Proposed mechanism for polyannulation of alkynes to benzamidines...

Scheme 7.23 Multicomponent synthesis of triazolobenzazepines.

Scheme 7.24 Three-component reaction of cyclic N-sulfonyl ketimines, aldehyd...

Scheme 7.25 Proposed mechanism for a three-component reaction of cyclic N-su...

Scheme 7.26 Three-component synthesis of indolines.

Scheme 7.27 Four-component synthesis of 2-alkoxytetrahydroquinolines.

Scheme 7.28 Catellani reaction in the synthesis of oxygen-containing heteroc...

Scheme 7.29 Three-component reaction of isatins, alkynes and carboxylic acid...

Scheme 7.30 Proposed mechanism for a three-component reaction of isatins, al...

Scheme 7.31 Rh-catalyzed synthesis of iminocoumarins.

Scheme 7.32 Three-component synthesis of benzo[b]thiophenes.

Scheme 7.33 Three-component functionalization of indoles with aryldiazoaceta...

Scheme 7.34 Three-component functionalization of indoles with aryldiazoaceta...

Scheme 7.35 Three-component interaction of indoles, aryldiazoacetates and un...

Scheme 7.36 A carbonylative functionalization of pyridyl-substituted heteroc...

Scheme 7.37 Aminocarbonylation of pyridyl-substituted heterocycles.

Scheme 7.38 Three-component reaction of 8-aminoquinoline, benzoyl chlorides,...

Scheme 7.39 Three-component reaction of 8-aminoquinoline, anhydrides of alip...

Scheme 7.40 Ru-catalyzed synthesis of difluoromethyl-substituted aminoquinol...

Scheme 7.41 Three-component 1,4-carboamination of conjugated dienes.

Scheme 7.42 Friedel–Crafts alkylation of π-excessive heterocycles.

Scheme 7.43 Co(III)-catalyzed three-component functionalization of isoquinol...

Scheme 7.44 A pseudo three-component arylation of benzobisthiazoles.

Scheme 7.45 Catellani reaction in functionalization of thiophene.

Scheme 7.46 Three-component functionalization of 1,3-azoles.

Scheme 7.47 Synthesis of polycylic pyrazole-containing molecules.

Scheme 7.48 Functionalization of tetrahydroisoquinolines with alkynes, dialk...

Scheme 7.49 Ugi-type reaction of tetrahydroisoquinolines.

Scheme 7.50 Three-component reaction of cyclic ethers with N-tosylhydrazones...

Scheme 7.51 Functionalization of dioxanes and dioxolanes.

Scheme 7.52 Multicomponent synthesis of indolizines, mediated by TBHP.

Scheme 7.53 Synthesis of polysubstituted pyrroles from 2-imidazolines.

Scheme 7.54 Synthesis of imidazo[1,2-a]pyridines from 2-aminopyridines, acet...

Scheme 7.55 Visible-light-promoted three-component synthesis of 3-aminoimida...

Scheme 7.56 An electrochemical preparation of imidazoles.

Scheme 7.57 Multicomponent synthesis of condensed triazines.

Scheme 7.58 Synthesis of 1,3-oxazines under aerobic conditions.

Scheme 7.59 Transition-metal-free functionalizations of pyridine-N-oxides.

Scheme 7.60 Functionalization of azines with alkanes.

Scheme 7.61 Transition-metal-free functionalization of tetrahydroisoquinolin...

Scheme 7.62 Visible-light-promoted functionalization of pyrroles and thiophe...

Scheme 7.63 Functionalization of pyridine with benzyne.

Scheme 7.64 Three-component functionalization of quinoxalinones with alkenes...

Scheme 7.65 Three-component functionalization of quinoxalinones with ketones...

Chapter 8

Scheme 8.1 Multicomponent switching effect.

Scheme 8.2 The first example of the multicomponent-switched reaction.

Scheme 8.3 Multicomponent-switched reaction of 3-amino-1,2,4-triazoles with ...

Scheme 8.4 Multicomponent-switched reaction of 5-amino-3-methylpyrazole with...

Scheme 8.5 MCR switching effect does not work.

Scheme 8.6 Multicomponent-switched reaction leading to non-isomeric compound...

Scheme 8.7 Multicomponent-switched reaction as a side process.

Scheme 8.8 More functions, more direction: the use of arylidene pyruvic acid...

Scheme 8.9 Switched reaction pathways of arylidene pyruvic acid esters or th...

Scheme 8.10 Multicomponent-switched reaction of 3-amino-5-methylisoxazole an...

Scheme 8.11 Tuning the selectivity of MCR by a variation of solvent.

Scheme 8.12 Tuning the selectivity of MCR by a variation of solvent/catalyst...

Scheme 8.13 Tuning the selectivity of MCR of Meldrum's acid by a variation o...

Scheme 8.14 Influence of binucleophile structure on the direction of MCR.

Scheme 8.15 Switching of MCR between 5-amino-3-methylisoxazole, aldehydes, a...

Scheme 8.16 Tuning the selectivity of MCR by a variation of solvent and acti...

Scheme 8.17 Switching of MCR of arylglyoxals, cyclohexanediones, and 5-amino...

Scheme 8.18 Other examples of switching of MCR involving arylglyoxals.

Scheme 8.19 Tuning the selectivity of MCR involving pyruvic acids.

Scheme 8.20 Influence of binucleophile structure on the direction of MCR inv...

Scheme 8.21 Kinetic control

vs

thermodynamic control in MCRs of 5-amino-1,2,...

Scheme 8.22 Kinetic control

vs

thermodynamic control in MCRs involving aceto...

Scheme 8.23 Unproven pathway of MCRs involving acetoacetamides, aldehydes, a...

Scheme 8.24 Kinetic control

vs

thermodynamic control in three-component reac...

Scheme 8.25 From one set of the starting materials to three different final ...

Scheme 8.26 Switching of MCR of 5-aminopyrazoles, aromatic aldehydes, and 1,...

Scheme 8.27 Switching of MCR involving salicylic aldehydes with post-cycliza...

Scheme 8.28 Switching of MCR involving salicylic aldehydes, pyruvic acids, a...

Scheme 8.29 Diverse directions of MCRs involving salicylic aldehydes and ace...

Scheme 8.30 Stereochemical features of MCRs involving some aminoazoles and s...

Scheme 8.31 Formation of polycondensed chromenes in MCRs involving salicylic...

Scheme 8.32 Tuning the selectivity of MCR of salicylaldehyde, 5-amino-3-meth...

Scheme 8.33 Switching of MCR 5-amino-3-methylisoxazole, salicylic aldehydes,...

Scheme 8.34 Examples of modular reaction sequences

via

stabilized enolates....

Scheme 8.35 Modular reaction sequences are impossible for unstabilized inter...

Chapter 9

Scheme 9.1 The Ugi reaction.

Scheme 9.2 Proposed mechanism for an Ugi 4CR.

Scheme 9.3 Alternative mechanism for an Ugi 4CR.

Figure 9.1 Manipulation of the acid component in Ugi 4CR.

Scheme 9.4 Post-Ugi cascade to tetracyclic spiroindolines.

Scheme 9.5 5-endo-trig oxidative radical cyclization of benzylamine-derived ...

Scheme 9.6 Synthesis of ustiloxin D utilizing an Ugi 4CR.

Scheme 9.7 A two-step synthesis of Carfentanil via an Ugi 4CR.

Figure 9.2 (a) Sensitivity of

7

to opioid antagonist: groups of mice (

n

 = 10...

Scheme 9.8 A four-step synthesis of Lipitor utilizing Ugi 4CR methodology....

Scheme 9.9 A two-step synthesis of Ivosidenib utilizing Ugi 4CR methodology....

Scheme 9.10 Exploring the SAR of IDH1 inhibitors toward the lead compound, I...

Scheme 9.11 The three-component Passerini reaction.

Scheme 9.12 Proposed mechanism of the Passerini reaction.

Scheme 9.13 Synthesis of

N

14

-desacetoxytubulysin H via a diastereoselective ...

Scheme 9.14 General GBB-3CR reaction.

Scheme 9.15 Synthesis of highly selective uPA inhibitor

17

.

Figure 9.3 Reference compounds and their inhibitory effect against uPA.

Scheme 9.16 Synthesis of the proposed inhibitor of 5-lipoxygenase.

Scheme 9.17 Synthesis of oxadiazole-quinoline derivative

29

.

Figure 9.4 Reference compounds and their inhibitory effect against 5-LO and ...

Figure 9.5 Reference antibiotics used in comparison with synthesized compoun...

Scheme 9.18 General G-3CR reaction.

Figure 9.6 Investigated drugs containing 2-aminothiophene scaffold based on ...

Scheme 9.19 One-pot synthesis of thieno[3,2-

e

]pyrrolo[1,2-

a

]pyrimidine analo...

Figure 9.7 Marketed drug for CF.

Scheme 9.20 Synthesis of GLPG1837.

Scheme 9.21 Hantzsch dihydropyridine synthesis.

Scheme 9.22 Nonsymmetrical Hantzsch dihydropyridine synthesis.

Figure 9.8 FDA-approved DHP drugs by year.

Figure 9.9 Zone of inhibition (ZOI) of DHPs at 100 μg/ml DMSO (disk diameter...

Figure 9.10 Anti-tuberculosis 1,4-dihydropyridines.

Figure 9.11 Comparison of DPPH radical scavenging activity of DHPs and ascor...

Scheme 9.23 Biginelli reaction.

Scheme 9.24 Retrosynthetic synthesis of (+)-Ptilomycalin A. with tethered Bi...

Scheme 9.25 Retrosynthetic Synthesis of (+/−)-Crambescin A via tethered Bigi...

Scheme 9.26 Retrosynthetic synthesis of (+)-Crambescin A via enantioselectiv...

Figure 9.12 Structural similarities between barbituric acid DHPMs.

Figure 9.13 Biginelli products antitumor properties for blood cancer.

Figure 9.14 Biginelli products antitumor properties for breast cancer.

Figure 9.15 Biginelli products antitumor properties for brain cancer.

Figure 9.16 Biginelli products antitumor properties for cervical cancer.

Figure 9.17 Biginelli products antitumor properties for colorectal cancer.

Figure 9.18 Biginelli products antitumor properties for kidney cancer.

Figure 9.19 Biginelli products antitumor properties for liver cancer.

Figure 9.20 Biginelli products antitumor properties for lung cancer.

Scheme 9.27 TosMIC-mediated cyclization to construct heterocyclic chemotypes...

Figure 9.21 Biginelli products antitumor properties for lymphoma cancer.

Figure 9.22 Biginelli products antitumor properties for ovarian cancer.

Figure 9.23 Biginelli products antitumor properties for pancreas cancer.

Figure 9.24 Biginelli products antitumor properties for prostate cancer.

Scheme 9.28 Proposed mechanism of 3C-van Leusen reaction.

Figure 9.25 Biginelli products antitumor properties for skin cancer.

Scheme 9.29 Synthesis of imidazole[1,5-

a

]quinoxaline

104

through van Leusen ...

Scheme 9.30 Post-modifications of van Leusen reaction toward imidazoquinolin...

Scheme 9.31 DNA-conjugated one-pot three-component van Leusen reaction.

Figure 9.26 Selected imidazole-containing clinical drugs.

Scheme 9.32 Structural modification of PX27R antagonists via van Leusen reac...

Scheme 9.33 Structure-based scaffold-hopping approach to synthesize IDO1 inh...

Scheme 9.34 Synthesis of

129

as a disruptor of p53/MDM2 interaction via van ...

Scheme 9.35 Repetitive 3C-van Leusen reaction/formylation cycle to construct...

Scheme 9.36 Hit-to-lead optimization of TGFβR inhibitors.

Scheme 9.37 Synthesis of imidazole

140

(

BMS-986260

) through van Leusen react...

Chapter 10

Scheme 10.1 Alkynones, alkyl propiolates, and alkyne-1,2-diones as alkynoyl ...

Scheme 10.2 Six Sonogashira cross-coupling-based protocols for the synthesis...

Scheme 10.3 Sonogashira coupling to ynones via C—N bond cleavage of

N

-acylsa...

Scheme 10.4 Sonogashira synthesis of 3-aryl propiolates from ethyl propiolat...

Scheme 10.5 Copper-catalyzed aerobic oxidative coupling to ynediones.

Scheme 10.6 Three-component activation-alkynylation-cyclocondensation synthe...

Scheme 10.7 Four-component coupling–coupling-cyclocondensation syntheses of ...

Scheme 10.8 Three-component alkynylation-cyclocondensation synthesis of 3-hy...

Scheme 10.9 Four-component alkynylation-cyclocondensation-desilylation-CuAAC...

Scheme 10.10 Three-componentalkynylation-cyclocondensation synthesis of pyra...

Scheme 10.11 Three-component alkynylation-cyclocondensation syntheses of sub...

Scheme 10.12 Three-component alkynylation-cyclocondensation synthesis of 3,5...

Scheme 10.13 Copper-catalyzed azidation-alkyne-azide cycloaddition synthesis...

Scheme 10.14 Five-component carboxylation-propargylation-CuAAC-Michael addit...

Scheme 10.15 Pseudo five-component coupling-cyclocondensation synthesis of d...

Scheme 10.16 Domino insertion-alkynylation synthesis of propynylidene indolo...

Scheme 10.17 Mechanistic proposal for the domino insertion-alkynylation synt...

Scheme 10.18 Consecutive three-component insertion-alkynylation-Michael addi...

Scheme 10.19 One-pot three-component synthesis of 3-piperazinyl propenyliden...

Scheme 10.20 Consecutive four-component insertion-alkynylation-Michael addit...

Scheme 10.21 Three-component coupling-cyclocondensation synthesis of α-pyrid...

Scheme 10.22 Consecutive three- and four-component coupling-cyclocondensatio...

Scheme 10.23 Three-component coupling-(3+3)-anellation synthesis of tricycli...

Scheme 10.24 Two-step coupling-cyclocondensation synthesis of alkaloid funct...

Scheme 10.25 Four-component coupling-addition-borylation synthesis of difluo...

Scheme 10.26 Three-component alkynylation-addition synthesis of coumarin-bas...

Scheme 10.27 Synthesis of 3-hydroxyisoquinolines by sequential Ugi four-comp...

Scheme 10.28 Consecutive five-component Ugi-insertion-alkynylation-deprotect...

Scheme 10.29 Consecutive four- and five-component syntheses of 3-(2-aminovin...

Scheme 10.30 Three-component activation-alkynylation-cyclocondensation synth...

Scheme 10.31 Synthesis of expanded 5-(hetero)aryl-thien-2-yl substituted 3-e...

Scheme 10.32 Sequentially Cu-catalyzed five-component glyoxylation-alkynylat...

Chapter 11

Scheme 11.1 Aza–Darzens three-component synthesis of aziridines.

Scheme 11.2 MCR synthesis of aziridines.

Scheme 11.3 MCR asymmetric synthesis of α-thiofunctional β-lactams.

Scheme 11.4 MCR synthesis of oxazolidine-2,4-diones.

Scheme 11.5 MCR syntheses of oxazolidin-2-ones. (a) Cu-catalyzed three-compo...

Scheme 11.6 Pd-catalyzed MCR synthesis of cyclic carbonates.

Scheme 11.7 Ugi five-center four-component reaction in the synthesis of γ-la...

Scheme 11.8 Synthesis of isocotinine analogs via Ugi reactions. (a) Synthesi...

Scheme 11.9 MCR synthesis of steroidal thiazolidinones.

Scheme 11.10 MCR synthesis of novel thiazolidinone derivatives. (a) MCR synt...

Scheme 11.11 MCR synthesis of isoxazolidines.

Scheme 11.12 Flow set-up for the synthesis of 3-nitropyrrolidines

Scheme 11.13 Synthesis of hydantoins via the Bucherer–Bergs reaction in flow...

Scheme 11.14 Synthesis of the oxazine-tetrazole scaffold via the Asinger-Ugi...

Scheme 11.15 Synthesis of organophosphorus heterocycles via MCR.

Scheme 11.16 (a) Synthesis of 4-benzyl-3-phenylmorpholin-2-ol from the Petas...

Scheme 11.17 Synthesis of hexahydropyrimidine-4-carboxylates via the modifie...

Scheme 11.18 Solvent-free syntheses of trifluoromethyl-hexahydropyrimidines ...

Scheme 11.19 (a) Synthesis of novel (1,5,3-dithiazepan-3-yl)alkanoic acids v...

Scheme 11.20 Synthesis of

N

-alkyl-2-(2-oxoazepan-1-yl)-2-arylacetamide deriv...

Scheme 11.21 Bidirectional multiple multicomponent macrocyclization procedur...

Scheme 11.22 Synthesis of cyclic pentadepsipeptoids through consecutive MCRs...

Scheme 11.23 Microwave-mediated synthesis of a cyclic pentadepsipeptoid thro...

Scheme 11.24 MCR synthesis of fused azaspiro tricycles and azaspiro tetracyc...

Scheme 11.25 MCR synthesis of imidazoindoles by Ulmann-type reaction.

Scheme 11.26 Ugi-mediated synthesis of tricyclic compounds.

Scheme 11.27 Stereoselective synthesis of hydrotiazole fused rings by a mult...

Scheme 11.28 Multicatalytic MCR synthesis of furo[2,3-b]pyrrole derivatives....

Scheme 11.29 Synthetic pathway using the modified A-4CR and U-3CR to obtain ...

Scheme 11.30 Synthesis of fused heteropolycycles by CH–MCR with substituted ...

Scheme 11.31 Synthesis of fused polycyclic bispiroindolines containing two c...

Scheme 11.32 MCR synthesis of a novel heptacyclic ring system.

Scheme 11.33 Stereoselective MCR synthesis of hetero-tetracycles.

Scheme 11.34 Stereoselective MCR synthesis of hetero-tetracycles. (a) Synthe...

Scheme 11.35 (a) MCR synthesis of tropane derivatives. (b) MCR synthesis of ...

Scheme 11.36 MCR approach to furanobenzodihydropyran-fused polycyclic hetero...

Scheme 11.37 A three-component/Diels–Alder process to obtain hydroepoxyisoch...

Scheme 11.38 Integrated flow chemistry set up for the synthesis of tricyclic...

Scheme 11.39 Integrated flow chemistry set up for the synthesis of chiral te...

Scheme 11.40 MCR synthesis of spiro-fused heterocycles from isatin.

Scheme 11.41 MCRs between isatin, chalcones and aminoacids. (a) Synthesis of...

Scheme 11.42 MCR synthesis of polycyclic 3,3′-pyrrolidinyl-dispirooxindoles....

Scheme 11.43 MCR synthesis of spirooxindolo derivatives with antimicrobial a...

Scheme 11.44 MCR synthesis of oxindole pyrrolidine 8-nitroquinolone hybrids....

Scheme 11.45 Flow mode for the Griesbaum co-ozonolysis.

Chapter 12

Scheme 12.1 Scope of the Strecker reaction of

4

catalyzed by

CU1

.

Scheme 12.2 Scope of the Mannich reaction toward

8

. (

S

)-enantiomers (

8a-h

) c...

Scheme 12.3 Potassium

L

-prolinate -catalyzed (

P1

) synthesis of propargyl ami...

Scheme 12.4 ACDC three-component Mannich reaction toward

16

catalyzed by

TPA

...

Scheme 12.5 Scope of the aza-Henry reaction toward

18

catalyzed by

SQ1

.

Scheme 12.6 Scope of the Petasis reaction toward

20

catalyzed by

B1

.

Scheme 12.7 Scope of aza-Diels–Alder reaction of

21

catalyzed by

CPA1

.

Scheme 12.8 Scope of the Povarov reaction toward

25

catalyzed by (

S

)-

P2

.

Scheme 12.9 Scope of the [2 + 2 + 2]-cycloaddition toward

29

catalyzed by Cu...

Scheme 12.10 Plausible mechanism for the formation of

29

through a formal [2...

Scheme 12.11 Scope of the Hantzsch reaction toward

36

catalyzed by (

R

)-

P2

....

Scheme 12.12 Plausible mechanism of the Hantzsch reaction toward

36

.

Scheme 12.13 Scope of the Biginelli reaction toward

43

catalyzed by the self...

Scheme 12.14 Scope of the Biginelli reaction toward

46

catalyzed by

CPA.IS

....

Scheme 12.15 Oxa-Michael/Michael/Michael/aldol condensation sequence followe...

Scheme 12.16 Proposed mechanism of the oxa-Michael/Michael/Michael/aldol/inv...

Scheme 12.17 Scope of the Knoevenagel/Michael/lactonization cascade synthesi...

Scheme 12.18 Proposed mechanism of the Knoevenagel/Michael/lactonization cas...

Scheme 12.19 Scope Michael/Michael/Henry cascade synthesis of

67

catalyzed b...

Scheme 12.20 Proposed mechanism of the Michael/Michael/Henry cascade reactio...

Scheme 12.21 Concerted mechanism of the Passerini reaction.

Scheme 12.22 Mechanism of the Ugi reaction through the ionic intermediate

76

Scheme 12.23 Substrate scope of aliphatic carboxylic acids, aliphatic aldehy...

Scheme 12.24 Substrate scope of asymmetric three-component synthesis of tetr...

Scheme 12.25 Proposed mechanism of the Passerini-type reaction with TMSN

3

....

Scheme 12.26 Substrate scope of the asymmetric synthesis of 1,2-dihydroisoqu...

Scheme 12.27 Multicomponent synthesis of oxadiazines catalyzed by

CDA1

.

Scheme 12.28 Multicomponent synthesis of benzoxazoles catalyzed by

CDA1

.

Scheme 12.29 Substrate scope of aromatic aldehydes for the catalytic asymmet...

Scheme 12.30 Scope of the Ugi-type three-component reaction catalyzed by

CPA

...

Scheme 12.31 Chemical structure of

CPA4

and

CPA5

and the chiral pocket of th...

Scheme 12.32 Substrate scope of the Ugi four-component reaction with

CPA4

to...

Scheme 12.33 Substrate scope of the Ugi four-component reaction with

CPA5

to...

Chapter 13

Scheme 13.1 Multicomponent synthesis of pyrroles catalyzed by a [Cu(NHC)].

Scheme 13.2 Palladium-catalyzed multicomponent synthesis of multisubstituted...

Scheme 13.3 Pd-Catalyzed multicomponent synthesis of fused pyrroles.

Scheme 13.4 Synthesis of pyrroles via catalytic formal [2 + 2 + 1] reaction ...

Scheme 13.5 Synthesis of pyrroles by means of MCR between propargylic carbon...

Scheme 13.6 Synthesis of 5-iminopyrrolones via [2 + 2 + 1] cycloaddition cat...

Scheme 13.7 Palladium-catalyzed synthesis of

N

-substituted phthalimides.

Scheme 13.8 Cu-catalyzed synthesis of γ-alkylidenebutenolides via a Sonogash...

Scheme 13.9 Pd-catalyzed five-component synthesis of substituted 2-(furan-3-...

Scheme 13.10 Pd-catalyzed three-component reaction to prepare substituted fu...

Scheme 13.11 Pd-catalyzed five-component coupling for the synthesis of imida...

Scheme 13.12 Synthesis of imidazolidines via a Pd-catalyzed three-component ...

Scheme 13.13 Synthesis of imidazolones by dual-catalyzed, three-component pr...

Scheme 13.14 Synthesis of 1,2,3-triazole tethered benzimidazo[1,2-a]quinolin...

Scheme 13.15 Interrupted click reaction by action of suitable electrophiles....

Scheme 13.16 Three-component reaction for the synthesis of trisubstituted tr...

Scheme 13.17 Multicomponent, multicatalyst reaction for the synthesis of sub...

Scheme 13.18 Synthesis of triazolopyrimidines catalyzed by copper through co...

Scheme 13.19 One-pot combinatorial synthesis of fused 1,2,3-triazolo-1,3,6-t...

Scheme 13.20 Three-component dual-metal-catalyzed reaction for the synthesis...

Scheme 13.21 Cu-catalyzed synthesis of fully substituted triazoles by oxidat...

Scheme 13.22 Cu-catalyzed [2 + 2 + 2] alkenylation of nitriles with vinyliod...

Scheme 13.23 Synthesis of 2,4-diarylsubstituted-pyridines through a Ru-catal...

Scheme 13.24 Synthesis of pyridinium salts through a Rh(III)-catalyzed vinyl...

Scheme 13.25 Four-component cascade C−H functionalization/cyclization/nucleo...

Scheme 13.26 Synthesis of 3-diaryl 2,4-quinolinediones via a Pd-catalyzed mu...

Scheme 13.27 Multicomponent synthesis of trifluoroethyl isoquinolines from a...

Scheme 13.28 Microwave assisted four-component synthesis of 3-

N

-sulfonylamid...

Scheme 13.29 Synthesis of 4-amino iminocoumarines and 4-aminoquinolines via ...

Scheme 13.30 Kemp elimination in the Cu-catalyzed multicomponent synthesis o...

Scheme 13.31 Cu-catalyzed three-component synthesis of iminolactones via 6π-...

Scheme 13.32 Pd-catalyzed multicomponent synthesis of β-lactams through Münc...

Scheme 13.33 Rh-catalyzed [5 + 2] cycloadditions of quinolinium ylides with ...

Scheme 13.34 Rh-catalyzed three-component [3 + 2]/[5 + 2] annulation for the...

Guide

Cover

Table of Contents

Title Page

Copyrigt

Preface

Begin Reading

Index

End User License Agreement

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Multicomponent Reactions towards Heterocycles

Concepts and Applications

Edited by

Erik V. Van der Eycken

Upendra K. Sharma

Editors

Prof. Dr. Erik V. Van der EyckenKatholieke Universiteit LeuvenDepartment of ChemistryCelestijnenlaan 200F3001 HeverleeBelgium

Dr. Upendra K. SharmaKatholieke Universiteit LeuvenDepartment of ChemistryCelestijnenlaan 200F3001 LeuvenBelgium

Cover Image: DenisKot (globe)

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Print ISBN: 978-3-527-34908-1ePDF ISBN: 978-3-527-83242-2ePub ISBN: 978-3-527-83244-6oBook ISBN: 978-3-527-83243-9

Cover Design: Adam-Design, Weinheim, Germany

Preface

Owing to the countless plausible combinations of carbon, hydrogen, and various heteroatoms, heterocyclic chemistry has remained as the foundation of novel chemical compounds in the sphere of natural product chemistry, pharmaceuticals, agrochemicals, and material sciences. They can serve as useful tools to facilitate tunable interactions with biological targets, thereby providing improved pharmacological and physicochemical properties of biomolecules as well as drug candidates. Recently, heightened cognizance of environmental issues is directing our society toward more sustainable solutions. Ever since the 12 principles of Green Chemistry were articulated, chemists answered the call to play their part in generating more sustainable syntheses. Multicomponent reactions (MCRs) appear as an obvious solution since most of the reactants' atoms are often incorporated in the final product. Moreover, a vast literature has been produced showing the power of MCRs as well as post-MCRs, in simplifying the synthetic design and yet obtaining high complexity and diversity in the construction of privileged structures. This is crucial in the development of novel bioactive molecules, wherein the production of libraries of compounds is necessary for the search of optimal drug candidates. Given the broad applications of heterocycles in the plethora of scientific fields, the current book title “Multicomponent Reactions towards Heterocycles. Concepts and Applications” is well warranted. In addition, recent advances in the field of MCR chemistry along with the plausible scope toward the synthesis and functionalization of biologically relevant heterocycles has encouraged us to compile this volume.

As the vast majority of small molecule drugs are of heterocyclic nature, the interplay of heterocycles with MCRs becomes therefore significant. The first chapter focuses on the recent progress made in the area according to the main reactivity mode involved in the transformation: concerted, radical, metal-catalyzed, carbonyl/imine, and isocyanide-based processes. The chapter itself provides an overview of heterocycles as input in MCRs. The next chapter “Heterocycles and Multi-Component Polymerizations” highlights some of the latest examples in this emerging field. The third chapter highlights examples from the viewpoint of target-oriented synthesis, the use of MCR in medicinal chemistry, from drug discovery, synthesis of drugs, to screening libraries, and biopharmaceutical applications. Further, heterocyclic chemistry has traditionally relied on solution-phase synthesis as technological platform to discover and produce bioactive scaffolds. The next chapter “Solid-phase Heterocycle Synthesis using Multicomponent Reactions” highlights methodological aspects of the implementation of on-resin MCRs to produce heterocycle compounds. Different name reactions, synthetic strategies, and solid-supports are analyzed critically in this chapter.

In the synthesis of heterocyclic compounds, MCRs have inherent advantage on pot, atom, and step economy (PASE) and are simple in operation, consume less energy, and release a reduced amount of waste. The fifth chapter discusses MCR-based green synthetic methods, including high-order MCRs, consecutive MCRs, MCRs followed by cyclization, and cycloaddition reactions, for the synthesis of heterocycles. Further, the use of enabling methods viz. continuous flow approaches has been beneficial in terms of yield, selectivity, reaction time, real-time monitoring. The next chapter is focused on different methodologies that can be used to perform heterocycle multicomponent syntheses in a continuous flow, to highlight the advantages over batch synthesis. Similarly, the next chapter analyzes a merging of C–H functionalization and MCRs approaches toward synthesis and modification of heterocyclic compounds.

MCRs have demonstrated their reliability and effectiveness as a synthetic approach that provides rapid access to chemical complexity. Among the many factors that bring this about, the MCR effect stands out, based on the fact that a changed number of reagents becomes the main differentiating factor of the reaction direction, that enables multicomponent-switched heterocyclizations, the topic of the next chapter in the book. Alkynoyl functionalities are densely substituted bifunctional electrophiles and prerequisite in many heterocycle syntheses via cyclocondenzations or cycloadditions. The 10th chapter of the book summarizes, explains, and highlights recent endeavors in the catalytic alkynoyl generation and their application to diversity-oriented multicomponent syntheses of heterocycles. The next chapter of the book is focused on the MCR synthesis of saturated heterocycles, encompassing the synthesis of small ring size (from 3 to 7) heterocycles, macroheterocycles, fused rings, and spirocyclic compounds. This is followed by the topic asymmetric MCRs where the development of enantioselective versions of these reactions have led to optimized reaction conditions, broader scopes, and increased chemo- and enantioselectivities. At last, the final chapter focuses on the recent advances made in MCRs built upon transition metal-catalysis directed toward the synthesis of heterocycles. In conclusion, this volume offers a versatile overview of the topic alongside discussing the recent progress in the flourishing area of MCR chemistry. This would, in turn, provide a platform for future innovations toward the designing of novel green transformations for heterocyclic synthesis.

Finally, we are extremely grateful to all authors for their excellent contributions to this volume. We are also thankful to the Wiley editors in particular Dr. Elke Maase and Ms. Katherine Wong for their professional support and assistance during this endeavor.

University of Leuven (KU Leuven)

Dr. Upendra K. Sharma

Belgium

Prof. Dr. Erik V. Van der Eycken

21 June 2021

1Heterocycles as Inputs in MCRs: An Update

Ouldouz Ghashghaei, Marina Pedrola, Carmen Escolano, and Rodolfo Lavilla

University of Barcelona, Laboratory of Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine IBUB, Av. de Joan XXIII, 27-31, Barcelona 08028, Spain

1.1 Introduction

Multicomponent reactions (MCRs) hold a privileged position in organic synthesis and are currently gaining momentum in the fields where a fast access to high levels of structural diversity is needed. This is especially important in medicinal chemistry and key to drug discovery. In this endeavor, as the vast majority of small-molecule drugs are of heterocyclic nature, the interplay of heterocycles with MCRs becomes significant [1]. Although the majority of work has been devoted to the synthesis of heterocyclic adducts from non-heterocyclic reactants [2, 3], we will focus, however, on the intrinsic reactivity of basic heterocycles as a source of synthetically useful MCRs (Scheme 1.1). This approach, still quite unexplored in the MCR context, is arguably a rich source of novel, complex scaffolds. There is a wide choice of commercially available heterocyclic inputs, which together with their often-exclusive reactivity make this perspective simple, conceptually attractive, and synthetically productive. In this chapter, we describe a representative selection of relevant results in the last six years, as the field has experienced impressive growth since our last revision [4], and an exhaustive account is out of scope. This update groups the highlighted processes according to the main reactivity modes defining the MCRs: concerted, radical, metal-catalyzed, carbonyl/imine, and isocyanide-based processes. Finally, a miscellany section is included to cluster those MCRs that do not clearly fit in the classification. Occasionally, some significant post-transformations and applications have been detailed.

1.2 Concerted MCRs

The impact of heterocycle-based concerted MCRs in organic synthesis is quite relevant, with recent contributions arising from Povarov reactions, hetero Diels–Alder processes, and dipolar cycloadditions. The Povarov MCR, the interaction of an aromatic amine, an aldehyde, and an activated alkene, remains one of the best synthetic approaches to access tetrahydroquinolines (THQs) [5] and is especially productive in medicinal chemistry [6]. Although the concerted cycloaddition is a well-founded hypothesis for the reaction mechanism, there is evidence on polar stepwise processes in some cases, and both pathways are considered here.

Scheme 1.1 Heterocycles as inputs in MCRs.

For instance, a double Povarov process led to julolidine derivatives: the first MCR generates a secondary amine, which under calixarene-based polysulfonic acid catalysis spontaneously triggers a second MCR, leading to the final five-component adducts with good yields and modest stereoselectivity (Scheme 1.2) [7].

Indole derivatives participate in Povarov MCRs not only as aldehyde or olefin inputs, but also as aniline surrogates. Their specific structural arrangement, and the catalytic conditions used, determines the outcome. In this way, while indole-3-carbaldehyde gives the expected Povarov adduct [8], indole-7-carbaldehyde reacts in a different way, leading to fused adduct where the indole nitrogen closes a six-membered ring [9]. Interestingly, indole-2-carbaldehyde, depending on the catalysts used, may lead to the normal Povarov adduct or to a different scaffold, with a distinct connectivity through an alternative [3 + 2] cycloaddition mode (Scheme 1.3) [10].

As olefin inputs, indoles unsubstituted at C2 and C3 yield the THQ adduct, losing the aromaticity at the pyrrole ring [11]. In this respect, 2-vinylindoles react exclusively at the olefin moiety to yield the expected THQ adduct [12]. However, the isomeric 3-vinyl derivatives react quite differently, leading to bisindole-piperidines in a stereo- and enantio-controlled fashion, using chiral catalysts (Scheme 1.3) [13].

Regarding heterocyclic inputs, the interaction of aldehydes, 1,4-dhydropyridines as activated olefins, and aminocoumarin, as aniline surrogate, leads to complex functionalized chromenonaphthyridines [14]. Relevantly, 3-aminopyridine imines react with alkynes (terminal or internal) to regioselectively afford the naphthyridine scaffold [15]. Similarly, 3-aminopyridones also lead to oxidized Povarov adducts (Scheme 1.4) [16].

Scheme 1.2 Access to julolidines via double Povarov MCRs.

Scheme 1.3 Indoles as inputs in Povarov MCRs.

There are mechanistic variations that dramatically modify the connectivity pattern of standard Povarov MCRs. For instance, a Ferrier rearrangement was promoted during a Povarov process involving glycals [17]. An interesting example of interrupted Povarov process with salicylaldehydes, anilines, and dihydrofurans, instead of yielding the expected THQ adduct, follows a Mannich-type process with the enol ether, and the resulting intermediate is trapped by the phenolic hydroxyl, yielding the MCR adduct in a stereoselective fashion (Scheme 1.5) [18].

In a remarkable photoredox-catalyzed process, aldimines, dihydrofurans and trimethylsilyl azide, afforded azidotetrahydrofurans. The observed polarity reversal can be explained through a mechanism involving an azido radical, which adds on the β-position of the enol ether to promote the imine addition (Scheme 1.5) [19].

Finally, the Povarov MCR has enabled the selective tagging of benzaldehyde-functionalized DNA chains through the reaction with anilines and an N-protected dihydropyrrole [20].

Isochromenylium ions react with dienophiles in a [4 + 2] cycloaddition to yield adducts, which go through a Ritter-type domino process with acetonitrile to afford complex tetracyclic compounds [21]. Also, a formal concerted MCR connects in situ generated isoquinolinium salts with unsaturated aldehydes and alcohols in a process promoted by N-heterocyclic carbenes to give bridged azaheterocycles [22]. A [4 + 3] cycloaddition process is triggered by the condensation of an iminoindole with aldehydes to give an azadiene that reacts in situ with a sulfur ylide to yield azepinoindoles (Scheme 1.6) [23].

MCRs involving [3 + 2] cycloadditions have produced a substantial number of new transformations. The processes involving azinium ions have been reviewed [24]. The interaction of heterocyclic secondary amines with carbonyl inputs to generate dipoles is a common motif in the field. For instance, THQs, aldehydes, and ketomalonate afford the corresponding oxazolidine adducts [25].

Azomethine ylides, mostly generated by condensation or decarboxylation of α-amino acids, have been thoroughly used in MCRs in the presence of suitable dipolarophiles, often with applications in drug discovery [26]. The synthesis of pyrrolizidines and indolizidines through this MCR methodology has been reviewed [27]. A remarkable five-component interaction based on a double [3 + 2] cycloaddition of azomethine ylides has led to tetracyclic adducts in high yields in a stereoselective manner (Scheme 1.7) [28].

Azines are also present in this reactivity. α-Methylquinolines, aldehydes and alkynoates yield a fused adduct in a domino process starting with the formation of the dehydrated aldol-like intermediate [29]. Moreover, quinoline and pyridine dipoles react with azomethine ylides in an unprecedented fashion to yield complex fused pyrrolidine cycloadducts [30]. Finally, isatin undergoes a series of complex transformations triggered by the initial [3 + 2] cycloadduct generated through its interaction with proline and alkynoates (Scheme 1.8) [31].

Scheme 1.4 Aminoheterocycles in Povarov MCRs.

Scheme 1.5 Mechanistic variations of the Povarov-type processes.

Scheme 1.6 Cycloaddition-type MCRs.

Scheme 1.7 [3 + 2] Dipolar cycloaddition MCRs.

Scheme 1.8 Azines and isatins in dipolar MCRs.

Arynes yield dipoles through interaction with nucleophilic species. Their participation in MCRs has been recently reviewed [32]. Azines are N-arylated, and the resulting dipole interacts with carbonyl groups in an addition/cyclization mode or through proton transfer to generate second nucleophiles that trap the azinium intermediate. Also, the azine dipoles react with the aryne in [3 + 2] dipolar cycloaddition MCRs (Scheme 1.9).

In a series of related processes, epoxides, aziridines, and also four-membered cyclic amines and (thio)ethers react with arynes and protonucleophiles leading to the corresponding adduct featuring a substituted chain originated in the heterocycle (Scheme 1.10) [32].

1.3 Radical MCRs

The incorporation of radical chemistry into MCRs has unlocked access to new synthetic pathways unavailable through conventional polar reactions. Radical MCRs generally consist of a proradical, a relay reagent, and a trapping component [33]. Novel radical MCRs exploiting photochemical approaches have experienced rapid growth in recent years [34]. However, their pairing with heterocyclic inputs has been mainly restricted to the functionalization of the heterocyclic component. In this regard, the multicomponent versions of Minisci reaction stand out [35]. In these processes pyridine-type heterocycles get alkylated in the presence of a suitable alkene and an initiator amenable to produce the radical species [36]. β-Dicarbonyl radicals [37] as well as heteroatomic radicals including azido [38], sulfonyl, and phosphonyl [39] species have been reported to yield Minisci adducts in a similar fashion. As for the alkene components, N-vinylacetamide has been coupled with suitable azines and the proradical, to enantioselecitvely afford γ-aminoesters in the presence of a chiral phosphoric acid (Scheme 1.11) [40].

The scope of the heterocycic inputs in Minisci MCRs is mainly restricted to pyridine-type systems, usually substituted at some reactive positions (C2/C4) to block undesired regioisomer formation. In an alternative approach, the use of 4-cyanopyridine allows the γ-selective functionalization under a variety of conditions, involving the favored generation of pyridyl radicals [41, 42]. Interestingly, the use of Tf2O as the azine activator and a CF3 radical source results in the regioselective p-trifluoromethyl-alkylation of pyridines and quinolines [43]. In a related process, the use of pyridyl halides directs the functionalization upon the C4 position in a Ni-catalized radical process. It also features an interesting [1,5]-H shift that enables the heteroatom addition upon the β position of the initiating carbon radical (Scheme 1.12) [44].

Other heterocyclic systems have also been functionalized through radical MCRs. For instance, the C-sulfonylation of imidazoles has been reported in an Eosin-catalyzed photoredox transformation (Scheme 1.13) [45].

Dearomatization of indoles and related heterocycles has also been achieved through radical MCRs. In a remarkable approach, C3-spiro trifluoromethylindolines have been assembled in a copper-catalyzed radical MCR with β-aminomethylindoles, carbon dioxide, and a trifluoromethyl radical source. The CF3-indole radical is intramolecularly trapped by the copper carbamate, which is formed in situ, through the condensation of amine and CO2. Furans with similar side chains have successfully afforded the corresponding spiro adducts (Scheme 1.14) [46].

Scheme 1.9 Azine-aryne MCRs.

Scheme 1.10 3/4-Membered heterocycles in aryne MCRs.

Scheme 1.11 Minisci-type radical MCRs.

Scheme 1.12 Site-selective azine-based radical MCRs.

Scheme 1.13 SO2 photoredox MCR.

Scheme 1.14 Heterocycle dearomatization in radical MCRs.

Finally, maleimides have been involved in a remarkable Minisci-type MCR, in which the initiating alkyl radical was generated through a novel mild process [47]. Moreover, the assembly of fused quinolines through the condensation of 3-arylaminoacrylates, maleimides, and an electrophilic radical source has been achieved, matching the radical affinities in a domino process (Scheme 1.15) [48].

1.4 Metal-catalyzed MCRs

Transition metal-catalyzed MCRs featuring heterocyclic inputs have also experienced immense progress in recent years. Regarding the C–H activation processes, the direct functionalization of azoles through the insertion of an isocyanide, followed by the attack of a heterocycle, has been reported for the synthesis of di(hetero)aryl-ketones and-alkylamines [49]. The methodology involves the reaction of azoles, haloarenes, and isocyanides resulting in the formation of an imine, which can be hydrolyzed or reduced to yield the final adducts. Other examples of C—H bond functionalization include the preparation of fused imidazo-heterocycles starting from methyl ketones, o-tosylhydroxylamine and 2-pyridinone or thiazo/benzo[d]thiazol-2(3H)-ones [50]. This MCR consists of the copper catalyst coordination, the formation of the C–H functionalized intermediate, followed by a tandem addition-cyclization process. A relevant C–H glycosylation via a Catellani-type arylation allows the synthesis of C-aryl glycosides, which can undergo further transformations, such as Heck, Suzuki, and Sonogashira cross-couplings (Scheme 1.16) [51].

Scheme 1.15 Maleamides as inputs in radical MCRs.

Scheme 1.16 C–H activation MCRs.

Progress in the A3-related MCRs, the interaction of aldehydes, amines, and alkynes, includes the use of isoquinolines, suitably activated by a chloroformate as amine inputs through an enantioselective copper-catalyzed protocol [52]. Remarkably, the interaction of azine-2-carbaldehydes with secondary amines and terminal alkynes starts via the A3 MCR, and the adduct undergoes a formal Cu-catalyzed hydroamination to yield indolizines [53, 54]. Terminal alkynes are also useful inputs in the MCR coupling of N-heteroaromatics (quinolines) with alkyl halides. The tandem process is catalyzed by CuI and allows the formation of 1,2-difunctionalized quinoline-type derivatives (Scheme 1.17) [55].

Some carbonylative MCR processes dealing with heterocyclic inputs have also been disclosed: a Pd-catalyzed four-component coupling involving tryptamine leads to alkaloid-like compounds featuring the quinazolinone core [56]. Divergent PdI2/KI-catalyzed aminocarbonylation-cyclization pathways starting from alkynylthioimidazoles yield functionalized imidazo-thiazinones and -thiazoles (Scheme 1.18) [57].