Table of Contents

Cover

Title Page

List of Contributors

Preface

Chapter 1: Click Chemistry: Mechanistic and Synthetic Perspectives

1.1 Cycloaddition Click Reactions
1.2 Thiol-Based Click Reactions
1.3 Miscellaneous Click Reactions
References

Chapter 2: Applications of Click Chemistry in Drug Discovery and Development

2.1 Introduction
2.2 Part A: Application of Click Chemistry to Drug Discovery and Development
2.3 Part B: Synthesis of Triazole-Based Drugs Currently in use
References

Chapter 3: Green Chemical Synthesis and Click Reactions

3.1 Introduction
3.2 Huisgen 1,3-Dipolar Cycloaddition
3.3 Other 1,3-Dipolar Cycloadditions
3.4 Atom Economy and Simplicity of Procedures in Multicomponent Reactions
3.5 Summary and Conclusions
References

Chapter 4: Synthesis of Substituted 1,2,3-Triazoles through Organocatalysis

4.1 Introduction
4.2 Preformed-Enolate-Based Synthesis of Substituted 1,2,3-Triazoles
4.3 Preformed-Enamine-Based Synthesis of Substituted 1,2,3-Triazoles
4.4 Synthesis of Substituted 1,2,3-Triazoles via Catalytic Enolate Intermediates
4.5 General Mechanistic Aspects of Enolate Route
4.6 Synthesis of Substituted 1,2,3-Triazoles via Enamine Intermediates
4.7 General Mechanistic Aspects of Enamine Route
4.8 Synthesis of Substituted 1,2,3-Triazoles via Iminium Intermediate
4.9 Miscellaneous Routes for the Synthesis of 1,2,3-Triazoles
4.10 Conclusions
Acknowledgments
References

Chapter 5: Applications of the Cu-Catalyzed Azide–Alkyne Cycloaddition (CuAAC) in Peptides

5.1 Introduction
5.2 CuAAC-Mediated Peptide Conjugation Strategies
5.3 CuAAC-Mediated Peptide Backbone Modification Strategies
5.4 Conclusions
References

Chapter 6: Synthesis of Diverse Carbohydrate-Based Molecules using Click Chemistry

6.1 Introduction
6.2 Cu-Catalyzed Click Chemistry in the Synthesis of Diverse Glycoconjugates
6.3 Synthesis of Carbohydrate-Based Simple to Complex Macrocycles
6.4 Click-Inspired Synthesis of Diverse Neoglycoconjugates
6.5 Conclusion and Future Perspective
Acknowledgment
References

Chapter 7: Azide–Alkyne Click Reaction in Polymer Science

7.1 Introduction
7.2 Linear, Dendritic, and Hyperbranched Polymers
7.3 Telechelic and Block Copolymers
7.4 Star and Star-Block Polymers
7.5 Cyclic Polymers
7.6 Side-Chain Clickable Polymers
7.7 Cross-linked Polymeric Systems
7.8 Porous Organic Polymers
7.9 Surface Modification using CuAAC Reaction
7.10 Strain-Promoted Click Reaction
7.11 Topochemical Azide–Alkyne Cycloaddition (TAAC) Reactions
7.12 Summary and Outlook
References

Chapter 8: Thiol-Based “Click” Chemistry for Macromolecular Architecture Design

8.1 Introduction
8.2 Thiol Chemistry for Macromolecular Architecture Design
8.3 Conclusion
Acknowledgments
References

Chapter 9: Synthesis of Macrocycles and Click Chemistry

9.1 Introduction
9.2 Summary and Conclusions
References

Chapter 10: Modifications of Nucleosides, Nucleotides, and Nucleic Acids using Huisgen's [3+2] Azide–Alkyne Cycloaddition: Opening Pandora's Box

10.1 Introduction
10.2 Nucleotide and Nucleic Acid Modifications
10.3 Conclusion
Acknowledgments
References

Index

End User License Agreement

List of Illustrations

Chapter 1: Click Chemistry: Mechanistic and Synthetic Perspectives

Scheme 1.1 Huisgen 1,3-dipolar cycloaddition between alkynes and azides.
Scheme 1.2 CuAAC click reaction.
Figure 1.1 Sialic-acid-based neuraminidase inhibitors; a disaccharide mimic A and a dendrimer B.
Figure 1.2 Triazole-containing macrocycles used for the detection of anions.
Scheme 1.3 Mechanism of the CuAAC reaction as proposed by Jan H. van Maarseveen [15].
Figure 1.3 Ligands used in CuAAC click reactions.
Scheme 1.4 Formation of 1,5-disubstituted or 1,4,5-trisubstituted triazoles via Ru-catalyzed 1,3-dipolar cycloaddition reaction between azides and alkynes.
Scheme 1.5 Proposed mechanism of RuAAC click reactions.
Scheme 1.6 An example for SPAAC click reaction.
Scheme 1.7 Proline-catalyzed synthesis of fused triazole from Hagemann's ester and tosyl azide.
Scheme 1.8 Mechanism for amine-catalyzed 1,3-dipolar cycloaddition between aldehydes and azides.
Scheme 1.9 The hydrothiolation of a CC bond in the presence of hν or a radical initiator.
Scheme 1.10 The mechanism for the hydrothiolation of a CC bond in the presence of a photoinitiator and light.
Scheme 1.11 The reaction mechanism of thiol–yne addition reaction.
Scheme 1.12 Multistep thiol–yne mediated synthesis of a highly functional dendrimer.
Scheme 1.13 Base catalyzed thiol–epoxy ring-opening click reaction.
Scheme 1.14 Tertiary-amine-catalyzed thiol–isocyanate click reaction.
Scheme 1.15 The base-catalyzed mechanism for the hydrothiolation of an activated CC bond.
Scheme 1.16 Nucleophilic catalysis of thiol–Michael addition reactions.
Scheme 1.17 Staudinger and traceless Staudinger ligation click reactions.

Chapter 2: Applications of Click Chemistry in Drug Discovery and Development

Scheme 2.1
Scheme 2.2
Figure 2.1 Triazole bioisostere of Resveratrol.
Figure 2.2 Triazole as a non-classical bioisostere of labile esters.
Figure 2.3 Role of triazole in improving intrinsic potency and bioavailability.
Figure 2.4 Application of in situ click chemistry in the discovery of new ligands.
Figure 2.5 Enzyme- directed fragment- based lead discovery of Huprin-based inhibitors.
Figure 2.6 Huprin moiety as a catalytic site binder for in situ click chemistry.
Scheme 2.3
Scheme 2.4
Figure 2.7 Conjugation strategy for combating bacterial resistance.
Figure 2.8 Triazole variant of podophyllotoxin as antimicrotubule agents.
Figure 2.9 Triazolylmethyl analogue of podophyllotoxin for improved anticancer activity.
Figure 2.10 Traizole NSC746457 as a novel HDAC-1 inhibitor.
Figure 2.11 Optimisation of NSC746457 as potent HDAC inhibitors.
Figure 2.12 Triazole moiety as selective HDAC-8 inhibitor.
Figure 2.13 Triazole linked Ematinib analog as potent Src Kinase inhibitor.
Figure 2.14 Substituted triazoles as novel microtubule agents.
Figure 2.15 Functionalised triazoles as HSP-90 inhibitors.
Scheme 2.5
Figure 2.16 Galactoside-derived triazoles as novel anticancer agents.
Figure 2.17 Oleanolic acid-coupled triazoles as novel anticancer agents.
Figure 2.18 1,2,3-Triazole variants of TSAO nucleosides.
Figure 2.19 1,2,3-Triazole carbanucleoside analogue of Neplanocin A.
Figure 2.20 Cidofovir as a reference standard for antiviral agent.
Scheme 2.6
Figure 2.21 1,2,3-Triazole linked carbazole analogues as anti tubercular agents.
Scheme 2.7
Figure 2.22 Diaryltriazole carbinols as antitubercular agents.
Figure 2.23 Diaryltriazoles as follow up antitubercular agents.
Figure 2.24 Evaluation of aminoaryl and its acyl derivatives as antitubercular agents.
Figure 2.25 1,2,3-Triazole-admantyl acetamide hybrids as antitubercular agents.
Figure 2.26 Improved variants of L-708906 as non-nucleoside HIV integrase inhibitors.
Scheme 2.8
Figure 2.27 1,2,3-Triazole as a bioisotere of amide leading to Dopamine 3 receptor selective ligands.
Figure 2.28 1,2,3-Triazole- based drugs currently in use.
Figure 2.29 1,2,3-Triazole-based pharmaceuticals in clinical trials.
Scheme 2.9
Scheme 2.10
Figure 2.30 Impurities formed during the synthesis of tazobactam [131a].
Scheme 2.11
Scheme 2.12
Scheme 2.13
Scheme 2.14
Scheme 2.15
Scheme 2.16
Scheme 2.17
Scheme 2.18
Scheme 2.19
Scheme 2.20
Scheme 2.21
Scheme 2.22

Chapter 3: Green Chemical Synthesis and Click Reactions

Scheme 3.1 General 1,3-dipolar cycloaddition of azides and alkynes.
Figure 3.1 Phosphinite and phosphonite copper complexes.
Scheme 3.2 Reaction of N,N′-bis[2,6-diisopropylphenyl]imidazolin-2-ylidene with propargyl alcohol.
Scheme 3.3 Synthesis of 5-substituted-1,2,3-triazoles.
Scheme 3.4 Regioselective 1,3-dipolar cycloaddition on a terminal alkyne.
Scheme 3.5 Sinthesis of a fluerescent chemosensor by a CuAAc.
Scheme 3.6 1,3-Dipolar cycloaddition of an azomethine imine with a terminal alkyne.

Chapter 4: Synthesis of Substituted 1,2,3-Triazoles through Organocatalysis

Scheme 4.1 Thermal-, metal-, and strain-promoted 1,2,3-triazole synthesis.
Scheme 4.2 Synthesis of 5-amino-1,2,3-triazoles.
Scheme 4.3 Potassium tert-butoxide mediated synthesis of 5-amino-1,2,3-triazoles.
Scheme 4.4 Synthesis of 1-vinyl-1,2,3-triazoles.
Scheme 4.5 Synthesis of 5-methyl-1,4-diphenyl-1,2,3-triazole.
Scheme 4.6 Base-promoted 1,3-dipolar cycloaddition of cyanoacetamide and 2,3,5-tri-O-benzoyl-β-D-ribofuranosyl azide.
Scheme 4.7 Synthesis of 5-amino-1-benzyl-1H-1,2,3-triazoles.
Scheme 4.8 1H-1,2,3-Triazole synthesis from heterocyclic CH-active compounds.
Figure 4.9 1H-1,2,3-Triazole synthesis from 2-benzothiazolylacetone.
Scheme 4.10 Synthesis of aryl-1H-1,2,3-triazol-4-yl sulfones.
Scheme 4.11 Synthesis of aryl 1,2,3-triazoles in a continuous-flow reactor.
Scheme 4.12 One-pot, three-component synthesis of 1,4,5-trisubstituted 1,2,3-triazoles starting from primary alcohols.
Scheme 4.13 Regioselective synthesis of 5-trifluoromethyl-1,2,3-triazoles via CF₃-directed cyclization.
Scheme 4.14 Reaction of dienamines with aryl azides.
Scheme 4.15 Reaction of cyclic dienamine with aryl azides.
Scheme 4.16 Reaction of enamines with aryl azides.
Scheme 4.17 Synthesis of 1-aryl-4,5-dihydro-5-morpholinotriazoles.
Scheme 4.18 1,3-Dipolar cycloaddition reactions of 2-alkylidenedihydroquinolines and phenyl azide.
Scheme 4.19 1,3-Dipolar cycloaddition reactions of organic azides with morpholinobuta-1,3-dienes.
Scheme 4.20 Reactions of β-azolylenamines with sulfonyl azides for the synthesis of N-unsubstituted 1,2,3-triazoles.
Scheme 4.21 TMG (1,1,3,3-tetramethylguanidine)-catalyzed synthesis of 1,2,3-triazoles.
Scheme 4.22 Recyclable DBU-H₂O catalytic system for synthesis of 1,4,5-trisubstituted 1,2,3-triazoles.
Scheme 4.23 Organocatalytic azide–aldehyde [3+2]-cycloaddition for regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles.
Scheme 4.24 Organocatalytic azide–ketone [3+2]-cycloaddition for regioselective synthesis of fully decorated 1,2,3-triazoles.
Scheme 4.25 Carbonate-catalyzed synthesis of 5-amino-1,2,3-triazoles.
Scheme 4.26 General mechanism for base-catalyzed 1,2,3-triazole synthesis.
Scheme 4.27 Synthesis of NH-1,2,3-triazoles via push–pull dienamine intermediate.
Scheme 4.28 Organocatalytic enamide–azide cycloaddition for regiospecific synthesis of 1,4,5-trisubstituted 1,2,3-triazoles.
Scheme 4.29 Organocatalytic synthesis of 1,2,3-triazoles from unactivated ketones and aryl azides.
Scheme 4.30 Pyrrolidine-catalyzed synthesis of highly substituted 1,2,3-triazoles.
Scheme 4.31 Synthesis of arylselanyl-1H-1,2,3-triazole-4-carboxylates by organocatalytic cycloaddition.
Scheme 4.32 Diethylamine-catalyzed cycloaddition of azides to unsaturated aldehydes for the synthesis of 1,4-disubstituted 1,2,3-triazoles.
Scheme 4.33 Synthesis of 1,4,5-trisubstituted 1,2,3-triazoles via dienamine intermediate.
Scheme 4.34 Organocatalytic 1,3-dipolar cycloaddition reactions of ketones and azides with water as a solvent.
Scheme 4.35 Organocatalytic synthesis of (arylselanyl)phenyl-1H-1,2,3-triazole-4-carboxamides by cycloaddition of azidophenyl arylselenides and β-oxo-amides.
Scheme 4.36 Organocatalytic 1,3-dipolar cycloaddition reaction of allyl ketones with azides for the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles.
Scheme 4.37 One-pot synthesis of 1,4-disubstituted 1,2,3-triazoles.
Scheme 4.38 General mechanism for enamine-mediated 1,2,3-triazole synthesis.
Scheme 4.39 Organocatalytic 1,3-dipolar cycloaddition of α,β-unsaturated ketones with azides for the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles.
Scheme 4.40 Mechanism of 1,2,3-triazole formation via iminium intermediate.
Scheme 4.41 Tetramethylammonium-hydroxide-catalyzed synthesis of 1,5-disubstituted 1,2,3-triazole.
Scheme 4.42 Synthesis of 1,5-disubstituted 4-(trimethylsilyl)-1H-1,2,3-triazoles.
Scheme 4.43 One-pot, two-step synthesis of 1,5-fused-1,2,3-triazoles.
Scheme 4.44 Multicomponent cascade reaction for regiospecific synthesis of 1,5-disubstituted 1,2,3-triazoles.
Scheme 4.45 Synthesis of 1,5-disubstituted 1,2,3-triazolylated carbohydrates.
Scheme 4.46 Propargyl-cation-mediated rapid synthesis of fully substituted 1,2,3-triazoles.
Scheme 4.47 Synthesis of 1,4,5-trisubstituted 1,2,3-triazoles via three-component reaction.
Scheme 4.48 Lewis-base-catalyzed synthesis of 1,4,5-trisubstituted 1,2,3-triazoles via azide–zwitterion cycloaddition.
Scheme 4.49 Mechanism for 1,2,3-triazole synthesis via azide–zwitterion cycloaddition.
Scheme 4.50 One-pot strategy for synthesis of 1,4-disubstituted 1,2,3-triazoles.
Scheme 4.51 Synthesis of 1,4-disubstituted 1,2,3-triazoles in one pot from ketones, N-tosylhydrazines, and amines.
Scheme 4.52 Mechanism for I₂ mediated 1,2,3-triazole synthesis from ketones, N-tosylhydrazines, and amines.
Scheme 4.53 I₂/TBPB-mediated synthesis of 1,4-disubstituted 1,2,3-triazoles.
Scheme 4.54 p-TsOH-mediated synthesis of 4-aryl-NH-1,2,3-triazoles.
Scheme 4.55 Synthesis of 4-trifluoromethanesulfonyl-1,2,3-triazoles.
Scheme 4.56 Silver-catalyzed access to synthesis of 1,5-fused-1,2,3-triazoles.
Scheme 4.57 Synthesis of 1,4-disubstituted and 1,5-disubstituted 1,2,3-triazoles via cycloaddition of α-chlorotosylhydrazones with arylamines.
Scheme 4.58 Mechanism for the synthesis of 1,4-disubstituted and 1,5-disubstituted 1,2,3-triazoles from α-chlorotosylhydrazones.

Chapter 5: Applications of the Cu-Catalyzed Azide–Alkyne Cycloaddition (CuAAC) in Peptides

Figure 5.1 The CuAAC or click reaction.
Figure 5.2 Examples of clickable amino acids and tags.
Figure 5.3 Clickable fluorescent coumarins.
Figure 5.4 A PEGylated peptide.
Figure 5.5 A polymer–peptide hybrid.
Figure 5.6 Triazole-linked glycopeptide structures.
Figure 5.7 Triazole-linked glycopeptides derived from C34.
Figure 5.8 Glycoamino acids and cyclic peptides synthesized by Kuijpers et al. [18].
Figure 5.9 Late-stage fluorination through the click reaction.
Figure 5.10 Late-stage fluorination click reaction of an RGD derivative.
Figure 5.11 Azide-functionalized ¹⁸F-label for conjugation with alkyne-containing peptides.
Figure 5.12 Backbone-modified analog of a cyclic RGD peptide.
Figure 5.13 Triazole-containing backbone-modified analogs of PSmac-21 (23).
Figure 5.14 Triazole-containing peptides self-assembling to nanotubes.
Figure 5.15 Cyclopeptides and triazole-backbone modifications.
Figure 5.16 Leu-enkephalin (33) and a triazole-modified mimic.
Figure 5.17 A radiolabeled triazole-containing bombesin peptidomimetic.
Figure 5.18 Examples of triazolamers.
Figure 5.19 (a) Native dipeptide and the triazole derivative. (b) Sequences of pLI-GCN4 (43) and modified peptides 44–46.
Figure 5.20 Triazole-based β-turn mimetics.
Figure 5.21 β-Turn mimetics containing a 1,4-triazole.
Figure 5.22 Triazole-mimetics to study β-turn cis/trans-isomerization.
Figure 5.23 Triazole-containing locked conformations of SFTI-1.

Chapter 6: Synthesis of Diverse Carbohydrate-Based Molecules using Click Chemistry

Scheme 6.1 Regioselectivity in azide–alkyne [3+2] cycloaddition reaction.
Scheme 6.2 Synthesis of triazole-linked disaccharide analog 7.
Scheme 6.3 Click-inspired synthesis of morpholine-fused triazolyl glycoconjugates.
Scheme 6.4 Synthesis of ethisterone glycoconjugates via Cu-catalyzed click chemistry.
Scheme 6.5 Click-inspired synthesis of noscapine glycoconjugates.
Scheme 6.6 Synthesis of triazolyl glycoconjugates.
Scheme 6.7 Synthesis of ferrocene-containing triazolyl glycoconjugates.
Scheme 6.8 Synthesis of glycosyl triazoles as potential insecticidal activity.
Scheme 6.9 Synthesis of antileishmanial triazolyl O-benzylquercetin glycoconjugates.
Scheme 6.10 Click-inspired synthesis of dual HIV-1 PR/HIV-1 RT inhibitor.
Scheme 6.11 Synthesis of glycopeptide hybrid lactam mimetics using CuAAC.
Scheme 6.12 Click-inspired synthesis of α- and β-D-glucopyranosyl triazoles.
Scheme 6.13 Synthesis of galactose-derived TcTs inhibitors using CuAAC reaction.
Figure 6.1 Structure of triazolyl glycoconjugates as TcTS inhibitory activity.
Scheme 6.14 Synthetic multivalent iminosugars prepared by click reaction.
Scheme 6.15 Triazolyl glycoconjugates as selective PTP1B inhibitors.
Figure 6.2 Diverse triazolyl glycoconjugates as glycogen phosphorylase inhibitors.
Scheme 6.16 Synthesis of triazolyl glycoconjugate as antiproliferative activity.
Scheme 6.17 Synthesis of glycosyl triazoles as anticancer agents.
Figure 6.3 Chemical structures of anticancer agent created via triazole linkage.
Scheme 6.18 Synthesis of triazole-linked divalent glycoamino acid mimics.
Scheme 6.19 Multicomponent synthesis of Triazolyl N-carboxamides.
Figure 6.4 Chemical structures of carbonic anhydrase inhibitors explored via click chemistry.
Scheme 6.20 Synthesis of zanamivir-based anti-AIV agent.
Figure 6.5 Neuraminidase inhibition activity of developed glycosyl triazoles.
Scheme 6.21 Triazole-linked sialic-acid-based neuraminidase inhibitors.
Figure 6.6 Triazolyl glycoconjugates as antifungal and antibacterial agents.
Scheme 6.22 Triazole-linked glycoconjugate against ManT activity.
Scheme 6.23 Synthesis of α-tocopherol-based triazolyl glycoconjugate.
Scheme 6.24 Click-inspired synthesis of rapamycin triazolyl glycoconjugate.
Scheme 6.25 ¹⁸F-glycosylation of sugar azide and subsequent clicking with peptide moieties.
Scheme 6.26 Synthesis of diarylpyrazole glycoconjugate.
Scheme 6.27 Synthesis of ¹⁸F-fluoroglycosylation of alkyne-bearing RGD peptides.
Scheme 6.28 Click-to-chelate procedure for a regular click ligand.
Scheme 6.29 Synthesis of pyridine–tetraacetic acid glycoconjugates.
Scheme 6.30 Synthesis of triazolyl glycoconjugate 119 as suitable ligand.
Scheme 6.31 Synthesis of Michael addition catalyst 121 via click reaction.
Scheme 6.32 Preparation of glucose-linked 1,2,3-triazolium ionic liquids.
Scheme 6.33 Click-inspired synthesis of D-glucose-derived chemosensor for Cu²⁺ ions.
Scheme 6.34 Synthesis of sugar-based fluorescent-labeled biomolecules.
Scheme 6.35 Click-inspired synthesis of triazole-containing glycolipids.
Scheme 6.36 Synthesis of 1,2,3-triazole-linked α-GalCer analogs.
Scheme 6.37 Functionalization of alkyne-grafted analog of monophosphoryl lipid A.
Scheme 6.38 Click-inspired synthesis of C-2 and C-3 symmetric glyco-macrocyles.
Scheme 6.39 Cu(I)-catalyzed cyclooligomerization of azidoalkyne-functionalized furanosides.
Scheme 6.40 Synthesis of macrocyclic carbohydrate/amino acid hybrids via CuAAC reaction.
Scheme 6.41 Synthesis of C_n-symmetric triazole-linked cycloglucopyranosides.
Scheme 6.42 Amino-acid-templated macrocyclization to access sucrose-derived macrocycles.
Scheme 6.43 Synthesis of monomeric triazolophane from furanoside-tethered azido–alkyne.
Scheme 6.44 Synthesis of carbohydrate-based macrocycle.
Scheme 6.45 Chemoenzymatic synthesis of sialic-acid-containing macrocycle.
Scheme 6.46 Intramolecular glycosidation through click-generated triazole as rigid spacer.
Scheme 6.47 Click-inspired synthesis of cyclic arginine–glycine–aspartate-containing macrocycle.
Scheme 6.48 Click-inspired synthesis of cyclopeptide-based fucosylated glycodendrimers 180.
Scheme 6.49 Click-inspired synthesis of neoglycopeptides.
Scheme 6.50 Synthesis of glycopolymer by combining click reaction with CCCTP technique.
Scheme 6.51 4-Vinyl-traizole monomer by combining CuAAC and RAFT technique.
Scheme 6.52 Click-inspired synthesis of porphyrin core glycodendrimer.
Scheme 6.53 Multivalent C-sialoside monomers via Click reaction.
Scheme 6.54 Synthesis of biologically active mannose-centered tetragalactose clusters.
Scheme 6.55 Click-inspired synthesis of virus glycoconjugates.
Scheme 6.56 Crown-like tetra-fucosylated glycocluster-based on a mannose core.
Scheme 6.57 Synthesis of calix[4]arene glycocluster.
Scheme 6.58 Click-inspired synthesis of calix[4]arene glycocluster using calix[4]arene platform.
Scheme 6.59 Synthesis of glycosylated calixarene using CuAAC.
Figure 6.7 A link-spacer-controlled supramolecular chirality based on self-assembly of the perylene bisimide glycoconjugates.

Chapter 7: Azide–Alkyne Click Reaction in Polymer Science

Scheme 7.1 The azide–alkyne click reaction.
Scheme 7.2 Schematic representation of the various types of polymers.
Scheme 7.3 Types of step-growth polymerization processes.
Scheme 7.4 CuAAC-reaction-mediated synthesis of linear polymers; examples of trialkynes and triazides used for the preparation of cross-linked polymers.
Scheme 7.5 Examples of linear conjugated polymers and conjugated foldamers via CuAAC.
Scheme 7.6 Tetraphenyl ethylene containing polymer via CuAAC; the polymer exhibits AIE.
Scheme 7.7 Biocompatible trehalose–oligoethyleneimine containing polymers for potential use as DNA delivery vehicles.
Scheme 7.8 CuAAC reaction of preassembled organogelators – a case of pseudo-topotactic polymerization.
Scheme 7.9 Convergent synthesis of dendron via CuAAC reaction.
Scheme 7.10 Synthesis of unsymmetrical dendrimer via CuAAC reaction of azide and alkyne containing dendrons.
Scheme 7.11 Synthesis of diblock dendrimer via CuAAC reaction (a) and a dendrinized linear polymer via CuAAC reaction of azido dendron with poly(vinylacetylene) (b).
Scheme 7.12 Convergent synthesis of hydrophilic dendrimer via iterative CuAAC reaction.
Scheme 7.13 Direct synthesis of a hyperbranched polymer via CuAAC reaction of an AB₂ monomer.
Scheme 7.14 Synthesis of hyperbranched polymer via CuAAC reaction of trialkyne and diazide.
Scheme 7.15 Unusual synthesis of a HBP with low PDI and high DB via pseudo-chain-growth CuAAC polymerization of an AB₂ monomer carrying two azides and one alkyne group.
Scheme 7.16 Synthesis of clickable hyperbranched polyesters and their postpolymerization modification to generate core–shell-type and Janus-type structures.
Scheme 7.17 Anionic polymerization (a), ATRP process (b).
Scheme 7.18 Synthesis of PS-PMMA diblock copolymer via CuAAC reaction.
Scheme 7.19 Synthesis of polystyrene-block-polyvinyl acetate copolymer via using RAFT polymerization in conjunction with CuAAC reaction.
Scheme 7.20 Synthesis of ABC triblock copolymer using a combination of CuAAC and Diels–Alder reaction.
Scheme 7.21 Synthesis of rod–coil block copolymers by a combination of ROP, ATRP, and CuAAC reaction.
Scheme 7.22 Synthesis of ABA triblock copolymer containing P3HT central block via CuAAC reaction of a dialkyne derivative of P3HT and azide-terminated polystyrene.
Scheme 7.23 CuAAC-reaction-mediated synthesis of alternating multiblock copolymer poly(Ph2TPh-OEG).
Scheme 7.24 Synthesis of four-arm PS-star polymer via CuAAC reaction of PS-azide with a core bearing multiple propargyl groups.
Scheme 7.25 Synthesis of three-arm PS-PEO star-block copolymer grown from a trifunctional ATRP initiator by combination of ATRP and CuAAC reaction.
Scheme 7.26 Single-step in situ formation of star-block copolymer using a combination of CuAAC and Diels–Alder reaction; three components, namely a heterotelechelic polystyrene bearing anthracene and azide end groups, maleimide-terminated PMMA, and a tris(propargyl ether) core, were used.
Scheme 7.27 Synthesis of star-like diblock copolymer via CuAAC reaction using solvent-assisted collocation of the azide and an alkyne groups placed at the same end of the polymer chain; the bottom panel depicts the aggregation of PDMA-block-PNIPAM in water at 50 °C, which is above the LCST of PNIPAM.
Scheme 7.28 Synthesis of cyclic-PS from a heterotelechelic propargyl-PS-azide via CuAAC reaction.
Scheme 7.29 Synthesis of cyclic diblock copolymer of PMA and PS by a combination of ATRP and CuAAC reaction.
Scheme 7.30 Synthesis of cyclic diblock copolymer of PS and PEO by intermolecular CuAAC reaction between a PS-diazide and dipropargylated PEO.
Scheme 7.31 Preparation of heterotelechelic PNIPAM via CuAAC reaction.
Scheme 7.32 Preparation of different cyclic polymer topologies using a combination of time-regulated dosing of an alkyne-bearing comonomer during CRP and CuAAC reaction for generation of the ring.
Scheme 7.33 Iterative flow synthesis of precise oligomers from a TIPS-protected ω-bromoalkyne.
Scheme 7.34 Synthesis of glycopolymers by a combination of ATRP and CuAAC reaction.
Scheme 7.35 Synthesis of azide-containing clickable polymer by ATRP and subsequent postpolymerization modification with various alkynes via CuAAC reaction.
Scheme 7.36 Synthesis of a series of periodically clickable polyesters and their postpolymerization modification with MPEG-350 azide via CuAAC reaction.
Scheme 7.37 Synthesis of cross-linked hydrogels using the CuAAC reaction between a dialkyne and a tetraazide.
Scheme 7.38 Synthesis of PVA-based hydrogels via CuAAC reaction between azide- and alkyne-functionalized PVA.
Scheme 7.39 Synthesis of hydrogels via CuAAC reaction between a PEG-diazide and a dendronized triblock copolymer carrying propargyl ester terminal groups and a central PEG segment.
Scheme 7.40 Synthesis of liquid-crystalline elastomers via CuAAC reaction between a diazide liquid crystalline block and tripropargyl amine.
Scheme 7.41 Synthesis of porous organic polymers by CuAAC reaction between tetrakis(4-azidophenyl)methane and tetrakis(4-ethynylphenyl)methane.
Scheme 7.42 Porous organic polymers bearing BTP ligands for efficient anchoring of Pd nanoparticles.
Scheme 7.43 Surface modification via a combination of SAM, ATRP and CuAAC reaction.
Scheme 7.44 Modification of CVD-coated surface via CuAAC reaction.
Scheme 7.45 Formation of a cross-linked polymer coating on an alkyne-functionalized substrate using strain-promoted click reaction.
Scheme 7.46 Synthesis of PEGylated polyamido dendrimers via SPAAC.
Scheme 7.47 Topochemical azide–alkyne click reaction for the synthesis of a polynucleoside from its monomer in the crystalline solid state.

Chapter 8: Thiol-Based “Click” Chemistry for Macromolecular Architecture Design

Figure 8.1 Example of reactions carried out in thiol-based “click” for the fabrication of polymeric materials.
Figure 8.2 Synthesis of linear polymers by polymerizing dithiol and molecules with two thiol-reactive functionalities.
Figure 8.3 Synthesis of linear polymers by thiol–epoxy “click” polymerization.
Figure 8.4 Synthesis of linear polymers by polyhydrothiolation of diynes with dithiols.
Figure 8.5 Synthesis of linear polymers by polymerization of monoalkyne and a dithiol compound.
Figure 8.6 Synthesis of the graft or comb polymers by thiol-based click reactions.
Figure 8.7 Synthetic strategies for the preparation of glucose-functionalized polymers [20].
Figure 8.8 Synthesis of graft polymers by the photo-triggered deprotection of the 2-nitrobenzyl thioether moiety on a polymer backbone, followed by the highly efficient thiol–maleimide chemistry.
Figure 8.9 Visible light photocatalytic thiol–ene reaction [25].
Figure 8.10 The “arm-first” technique used to fabricate star polymers via thiol-based “click” reaction.
Figure 8.11 Synthesis of three-arm star polymers via a thiol–vinyl Michael “click” reaction.
Figure 8.12 Synthesis of cyclodextrin-centered star polymers via thiol-based “click” reaction.
Figure 8.13 Cyclization of linear polymers by thiol-based click reaction to form cyclic polymer.
Figure 8.14 Synthesis of cyclic poly(lactide) by thiol-based click reaction.
Figure 8.15 Synthesis of cyclic PNIPAM via thiol–ene in combination with CuAAc chemistry [32].
Figure 8.16 Schematic illustration of the syntheses of cyclic polymer template, functionalized cationic and thermoresponsive cyclic polymers.
Figure 8.17 Synthesis of dendrimers by thiol–ene.
Figure 8.18 Synthesis of dendrimers via thiol–yne chemistry and esterification reactions.
Figure 8.19 Synthesis of hyperbranched polymer by polymerization of a molecule bearing an alkyne and a thiol.
Figure 8.20 Synthesis of hyperbranched polymer by sequential thiol–ene and thiol–ene click chemistry.
Figure 8.21 Synthesis of hyperbranched polymer by sequential thiol–halogen and thiol–yne chemistry.
Figure 8.22 One-pot preparation of multiblock and hyperbranched polymers.
Figure 8.23 Synthesis of protein–polymer conjugate via thiol–ene chemistry.
Figure 8.24 Polymer synthesis and protein conjugation [42].
Figure 8.25 Synthesis of bioactive Janus particles by SEP and thiol–halogen chemistry.
Figure 8.26 Modified inorganic nanoparticles via thiol–ene chemistry.
Figure 8.27 Preparation of multimodal latex particles by composite miniemulsion polymerization, followed by attachment of PEG chains to the surface of composite particles using thiol–ene chemistry.
Figure 8.28 Overall synthetic approach for the surface modification of TiO₂ nanoparticles with POEGMA.
Figure 8.29 Synthesis of glycopolymer-coated iron oxide nanoparticles.

Chapter 9: Synthesis of Macrocycles and Click Chemistry

Scheme 9.1 Prototypical conditions for: the Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction, (a) 1,3-dipolar cycloaddition and (b) the thiol–ene click reaction.
Figure 9.1 Strategy for the modular synthesis of macrocyclic organopeptide hybrids 4. The starting linear polypeptides comprise an N-terminal tail (light gray), O-propargyl tyrosine, a target sequence (AA₁…AA_n), and a GyrA intein segment. Macrocyclization occurs upon coupling of this protein to a synthetic precursor (SP) by concomitant CuAAC and thioester–hydrazide coupling [33].
Figure 9.2 Synthetic route to on-resin peptide macrocyclization using thiol–ene photochemistry [38].
Figure 9.3 Cyclic peptides obtained by CuAAC or RuAAC click chemistries incorporating 1,4- or 1,5-disubtituted triazole linkages as trypsin inhibitors analog of 9 [39].
Figure 9.4 Regioisomeric triazole-containing cyclic peptides composed of cis-β-furanoids and β-alanines [51].
Figure 9.5 Synthesis of click macrocycles through the cyclization of oligosaccharide linear monomers of varying lengths [61].
Figure 9.6 Structures of BODIPY-based sugar-containing macrocycles [62].
Figure 9.7 Triazole- and triazolium-containing macrocycles for the binding of anions. In gray: triazole or triazolium amide surrogates as the key functionalities responsible for binding [65–68].
Figure 9.8 Structures of macrocycle 23 and control compound 24, and (bottom) operating principles of the macrocyclic chiroptical sensor 23 in which the variation of the CD response of the Binol unit is the key sensing output.
Figure 9.9 High-yielding synthesis of “Sauvage-type” symmetrical catenane 26 [89].
Figure 9.10 Synthesis of trefoil knot 29 by Leigh and coworkers [92].
Figure 9.11 Terminal insertion of azide and “Click” cyclization of polystyrene prepared via ATRP [105].
Figure 9.12 The synthetic routes of the linear and cyclic polymers [108].

Chapter 10: Modifications of Nucleosides, Nucleotides, and Nucleic Acids using Huisgen's [3+2] Azide–Alkyne Cycloaddition: Opening Pandora's Box

Figure 10.1 Base-modified nucleosides 1–4.
Figure 10.2 Base-modified nucleoside analogs.
Figure 10.3 Structures of sugar-modified nucleosides 15–23.
Figure 10.4 Nucleoside bioconjugates bearing carboranes and closo-dodecarborane.
Figure 10.5 Structures of nucleoside bioconjugates 27–30.
Figure 10.6 Structure of bioconjugates nucleosides 31–33.
Figure 10.7 Fucosyltransferase inhibitor 34.
Figure 10.8 Structures of bioconjugate nucleosides 35.
Figure 10.9 Structures of nucleoside bioconjugates 36–41.
Figure 10.10 Structure of nucleoside bioconjugates 42.
Figure 10.11 Structure of radiolabeled bioconjugate 43 and cavitand 44.
Figure 10.12 Examples of “artificial” DNAs.
Figure 10.13 Pyrene-containing nucleosides 50 and 51.
Figure 10.14 Structures of boronic-acid-modified thymidine-5′-triphosphate 52 and lipid–oligonucleotide conjugates 53.
Figure 10.15 Synthesis of fluorophore gamma-labeled nucleoside 5′-triphosphates.
Figure 10.16 Preparation of the nile-red-modified DNA1.
Figure 10.17 Internal DNA labeling between 8-aza-7-deaza-2′-deoxyadenosine, 5′-modified dU alkyne precursors and azide-labeled fluorogenic dyes.
Figure 10.18 Labeling of the 5-position of uridine analog with 3-azido-7-hydroxycoumarins.
Figure 10.19 Sequential modification of DNA by three consecutive CuAAC reactions.
Figure 10.20 Preparation of DNA–peptide hybrids via CuAAC.
Figure 10.21 Selective functionality transfer and click reaction on O⁶-Me-dG with FAM-N₃.
Figure 10.22 Dye labeling at the 2-position of ribose in ODNs using CuAAC.
Figure 10.23 Xanthene- and cyanine-labeled probe prepared by postsynthetic CuAAC reactions.
Figure 10.24 (a) bs-TO and bs-TR as two base surrogates allow excitionic interactions that interfere with energy transfer (ET). (b) U-TO clicked at 2′-position of uridine, U-A base pairing block undesired excitonic interactions.
Figure 10.25 Synthesis of the polymer-escorted siRNA.
Figure 10.26 Click reaction between DNA-bounded picazoplatin and a dansyl fluorophore.
Figure 10.27 Synthesis of catenated DNA by click chemistry.
Figure 10.28 Construction of branched DNA structures using CuAAC.
Figure 10.29 Stepwise click reactions on DNA using a chelating and a nonchelating azido group containing linker.
Figure 10.30 Site-specific click reaction.
Figure 10.31 Postsynthetic CuAAC click reactions with a 5′-bisalkyne ODN.
Figure 10.32 Immobilization of azide-modified gold nanoparticles to alkyne-modified DNA.
Figure 10.33 SPAAC click between DIBO and Texas red tag for terminal labeling of DNA.
Figure 10.34 DNA cross-linking using copper-free SPAAC click reactions with DIBO and BCN (R = DNA).
Figure 10.35 SPAAC click product obtained by reaction between 5-azidomethyl dU and BCN-labeled fluorophore.
Figure 10.36 Selective SPAAC-mediated biotin labeling of mismatched 5hmU.

List of Tables

Chapter 2: Applications of Click Chemistry in Drug Discovery and Development

Table 2.1 m-AChE-directed synthesis of huprine-based heterodimers
Table 2.2 IC₅₀ of OvCHT1 inhibition
Table 2.3 IC₅₀ values (μM)
Table 2.4 Cytotoxicity data
Table 2.5 IC₅₀ values (nM)
Table 2.6 IC₅₀ values (μM)
Table 2.7 IC₅₀ values (μM)
Table 2.8 IC₅₀ values (nM)
Table 2.9 In vitro anticancer activity (IC₅₀ μM) of compound 52
Table 2.10 IC₅₀ value of compound 54 against human cancer cell lines
Table 2.11 EC₅₀ values (μM)
Table 2.12 EC₅₀ values (μM)
Table 2.13 K_i (μM) value of compound 46 and reference compounds 67 and 68
Table 2.14 K_i values ±SEM
Table 2.15 Effect of solvents on yield

Chapter 5: Applications of the Cu-Catalyzed Azide–Alkyne Cycloaddition (CuAAC) in Peptides

Table 5.1 Stability tests for 13a and 13b, respectively

Chapter 8: Thiol-Based “Click” Chemistry for Macromolecular Architecture Design

Table 8.1 Example of polymers synthesized via thiol-based click chemistry

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List of Contributors

Franck Amblard

Emory University School of Medicine

Center for AIDS Research

and Department of Pediatrics

Atlanta, GA 30322

USA

Kengadarane Anebouselvy

University of Hyderabad, Central University (P.O.)

Catalysis Laboratory

School of Chemistry

Prof. CR Rao Road

Gachibowli

500 046 Hyderabad

India

Maria José Arévalo

Universidad de Extremadura

Escuela Politécnica

Departamento de Química Orgánica e Inorgánica

Avenida de la Universidad

s/n, 10004 Cáceres

Spain

Kalpattu Kuppusamy Balasubramanian

INSA Senior Scientist

Department of Biotechnology

Indian Institute of Technology

Madras

Chennai 600036

India

Sebastien Boucle

Emory University School of Medicine

Center for AIDS Research

and Department of Pediatrics

Atlanta, GA 30322

USA

Poonam Chauhan

Indian Institute of Technology

Department of Chemistry

208016 Kanpur

India

Gaojian Chen

Soochow University

Center for Soft Condensed Matter Physics and Interdisciplinary Research

1 ShiZi Street

Jiangsu Province

Suzhou 215006

P. R. China

Kui Chen

Soochow University

Center for Soft Condensed Matter Physics and Interdisciplinary Research

1 ShiZi Street

Jiangsu Province

Suzhou 215006

P. R. China

Maria Victoria Gil

Universidad de Extremadura

Departamento de Química Orgánica e Inorgánica

Facultad de Ciencias

Avda. de Elvas

s/n, 06071 Badajoz

Spain

Balasubramanian Gopalan

Orchid Chemicals and Pharmaceuticals Limited

Drug Discovery Research

Plot #476/14

Old Mahabalipuram Road

Sholinganallur

600119 Chennai

India

Freek A. B. M. Hoogstede

Radboud University

Institute for Molecules and Materials

Department of Synthetic Organic Chemistry

Heyendaalseweg 135

6525 AJ Nijmegen

The Netherlands

Ahmed Khalil

Emory University School of Medicine

Center for AIDS Research

and Department of Pediatrics

Atlanta, GA 30322

USA

Óscar López

Universidad de Sevilla

Departamento de Química Orgánica

Facultad de Químicas

c/Profesor García González

s/n, 41012 Seville

Spain

Joydeb Mandal

Indian Institute of Science

Department of Inorganic and Physical Chemistry

560012 Bangalore

India

Amrita Mishra

Banaras Hindu University

Department of Chemistry

Faculty of Science

221005 Varanasi, UP

India

Kunj B. Mishra

Banaras Hindu University

Department of Chemistry

Faculty of Science

221005 Varanasi, UP

India

Dario Pasini

University of Pavia

Department of Chemistry and INSTM Research Unit

Viale Taramelli

10-27100 Pavia

Italy

Dhevalapally B. Ramachary

University of Hyderabad

Central University (P.O.)

Catalysis Laboratory

School of Chemistry

Prof. CR Rao Road

Gachibowli

500 046 Hyderabad

India

S. Ramakrishnan

Indian Institute of Science

Department of Inorganic and Physical Chemistry

560012 Bangalore

India

Ramesh Ramapanicker

Indian Institute of Technology

Department of Chemistry

208016 Kanpur

India

Floris P. J. T. Rutjes

Radboud University

Institute for Molecules and Materials

Department of Synthetic Organic Chemistry

Heyendaalseweg 135

6525 AJ Nijmegen

The Netherlands

Ozkan Sari

Emory University School

of Medicine

Center for AIDS Research

and Department of Pediatrics

Atlanta, GA 30322

USA

Raymond F. Schinazi

Emory University School

of Medicine

Center for AIDS Research

and Department of Pediatrics

Veterans Affairs Medical Center

Atlanta, GA 30322

USA

Anoop S. Singh

Banaras Hindu University

Department of Chemistry

Faculty of Science

221005 Varanasi, UP

India

Vinod K. Tiwari

Banaras Hindu University

Institute of Science

Department of Chemistry

Centre of Advanced Study

221005 Varanasi, UP

India

Weidong Zhang

Soochow University

Center for Soft Condensed Matter Physics and Interdisciplinary Research

1 ShiZi Street

Jiangsu Province

Suzhou 215006

P. R. China

Preface

Organic chemists are generally familiar with “Name Reactions” and many of these have had profound influence over the way we practice organic chemistry. However, there are a few reactions without a name that changed the course of history (science) and are unparalleled in terms of their impact over a wide range of scientific disciplines. “Olefin metathesis” is one such reaction that led to the award of Nobel Prize to the pioneers who contributed to the development of this reaction. In a similar vein, we have a group of reactions without a proper name that have taken the scientific community by storm in less than fifteen years, that is, “Click Reactions.”

Click chemistry is a chemical concept enunciated by Barry Sharpless, Scripps Research Institute, USA, in 2001, which highlights the importance of using a set of powerful, highly reliable, selective reactions under simple reaction conditions to join small molecular units together quickly for the rapid synthesis of new compounds via heteroatom links and create molecular diversity. Several types of reactions have been identified that fulfill the criteria- thermodynamically favored reactions that lead specifically to one product such as nucleophilic ring opening reactions of epoxides and aziridines, nonaldol type carbonyl reactions, additions to carbon–carbon multiple bonds, Michael additions, and cycloaddition reactions. The best-known click reactions are the copper-catalyzed reaction of azides and alkynes or the so-called CuAAC reaction and the thiol-ene reaction.

After the advent of click chemistry, the synthesis of molecules with outstanding, multifaceted properties has become very popular and easier simply by conjugating two or more molecules that possess remarkable individual properties. Over the past fifteen years, developments in the area of click chemistry have been extraordinary, and these reactions have been explored to their limits in various fields.

Who would have imagined that this simple set of reactions referred to as “click reactions” would revolutionize the approach to science cutting across disciplines such as drug discovery, polymer synthesis, materials science, chemical biology, supramolecular chemistry, and cosmetic chemistry in a short span of time. The tenth anniversary of the discovery of this concept of click reactions was celebrated with a lot of fanfare in the scientific community in 2011.

A number of review articles appeared in leading scientific journals covering the impact of this simple but elegant set of reactions in the design and synthesis of novel molecular architectures. While there are a couple of books that have been published dealing with click chemistry and its application to biology and material science, no book has been published so far that highlights the “click concept” and its far-reaching implications in various facets of organic synthesis. Hopefully, this book would fulfill this need and would also serve as a ready reckoner for accessing all information in pursuit of newer vistas in scientific research.

This book Click Reactions in Organic Synthesis covers ten different topics that would illustrate the scope of click reactions in various facets of organic synthesis. Leading experts who are active in this field have contributed to this venture. In the introductory chapter, Ramapanicker and Chauhan provide the mechanistic and synthetic perspectives of click reactions. Gopalan and Balasubramanian discuss the applications of click reactions in the synthesis of pharmaceuticals and drug discovery/development in Chapter 2. In Chapter 3, Gil and coworkers present the perspectives of green chemical synthesis. Ramachary and Anebouselvy have focused the attention on metal-free click reactions in organic synthesis in Chapter 4. Rutjes and Hoogstede have provided details on the use of click chemistry to peptide synthesis in Chapter 5. In Chapter 6, work related to the application of click chemistry to the synthesis of carbohydrate derivatives is discussed by Tiwari and coworkers. Synthesis of polymers and modifications using CuAAC click reactions are enunciated by Ramakrishnan and Mandal in Chapter 7. Chemistry related to thiol-ene (click) reactions in polymer synthesis and modifications are presented by Chen and coworkers in Chapter 8. Pasini highlights the importance of click chemistry in the synthesis of macrocycles in Chapter 9. In the last chapter, Schinazi and coworkers discuss the importance of click chemistry in DNA synthesis and modifications. I feel honored by the excellent contributions that the authors have delivered, and I owe my special thanks to all these scientists. I would also like to thank publishing editors /staff of Wiley-VCH for their fruitful collaboration.

Finally, I would like to place on record my sincere thanks to the pioneer of this area of work, Professor Barry Sharpless on the occasion of the 15^th anniversary of “Click Reactions.”

Srinivasan Chandrasekaran

Bangalore
April 2, 2016