Recent Advances in Synthetic Strategies and Biological Properties of Indazole Scaffolds: A Review

Abstract

Research on heterocyclic compounds is an area of continuous focus, capturing the interest of both synthetic and natural product chemists. Indazoles are one of the rare heterocycles that are available in nature. Indazole and its derivatives are one of the most important classes of heterocycles in pharmacological molecules. The structurally different indazole motifs, with impressive bioactivity, have drawn increasing attention from medicinal chemists in recent years for the continuous development of novel drug moieties. Thus, knowledge of the biological activities and synthetic pathways of indazole scaffolds is essential to enhancing further developments in the number of indazole-based lead molecules. The goal of the present review is to highlight information on the biological properties of some existing indazole-based drugs and activities of novel bioactive indazole compounds in clinical trails, with specific attention to the most recent advances in various synthetic strategies towards indazole and its derivatives over the past 7 years (2017-2024). Moreover, we discuss the substrate tolerance and mechanistic insights for most of the summarized synthetic protocols.

Keywords: Biological activities; Clinical trails; Heterocycles; Indazole; Mechanistic insights; Synthetic routes.

Fig. 1

Tautomeric forms of indazoles

Fig. 2

Significant bioactive indazole scaffolds

Fig. 3

Bioactive indazole compounds in clinical trails

Scheme 1

The first report of the creation of indazole

Scheme 2

Previously reported techniques for the construction of indazoles [–75]

Scheme 3

Synthesis of indazole scaffolds 3a–v

Scheme 4

Substrate scope for the Rh(III)-promoted C–H activation of phthalazinones and allenes

Scheme 5

Possible mechanism for indazole 3a formation

Scheme 6

Synthesis of indazole N-oxides

Scheme 7

Scope of sulfonium ylides for the construction of indazole N-oxides

Scheme 8

Possible mechanism for the formation of inazole N-oxide

Scheme 9

Construction of 2H-indazol-3-yl-methanolderivatives

Scheme 10

Substrate scope for the generation of 2H-indazol-3-yl-methanol derivatives

Scheme 11

Substrate scope for unsymmetrical 2H-indazol-3-yl-methanol scaffolds

Scheme 12

Plausible mechanism of 2H-indazol-3-yl-methanol synthesis

Scheme 13

Synthesis of CF₃-tethered indazoles

Scheme 14

Substrate scope for preparation of CF₃-tethered indazoles

Scheme 15

Scope of CF₃-ynones

Scheme 16

Plausible mechanism for CF₃-tethered indazole 12a

Scheme 17

Rh(III)-catalyzed synthesis of 3-acyl-2H-indazoles

Scheme 18

Scope of symmetrical azobenzenes

Scheme 19

Scope of unsymmetrical azobenzenes

Scheme 20

Scope of sulfoxonium ylides

Scheme 21

Plausible reaction mechanism for 3-acyl-2H-indazole16a

Scheme 22

Pd-mediated construction of N-methyl-3-aryl indazoles

Scheme 23

Synthesis of title compounds 21a–j

Scheme 24

Ag(I)-catalyzed synthesis of 1,3-substituted indazoles

Scheme 25

Substrate scope for 1,3-substituted indazole

Scheme 26

Substrate scope for 1-aryl substituents

Scheme 27

Plausible reaction mechanism 1,3-substituted indazole

Scheme 28

Synthesis of 2-aryl-2H-indazole-3-phosphonates

Scheme 29

Substrate scope for 2-aryl-2H-indazole-3-phosphonates

Scheme 30

A possible mechanism for the construction of 2-aryl-2H-indazole-3-phosphonates

Scheme 31

Construction of tetraaryl indazoles using Pd catalyst

Scheme 32

Substrate scope for the synthesis of tetraaryl indazoles

Scheme 33

Construction of substituted 1H-indazoles using Cu catalyst

Scheme 34

Synthesis of substituted 1H-indazoles 33a–k

Scheme 35

A possible mechanism for substituted 1H-indazoles 33a

Scheme 36

Synthetic route for indazole carboxylic acids

Scheme 37

Synthesis of E-hydrazone esters 35a–h

Scheme 38

Substrate scope for indazole carboxylic acids

Scheme 39

Synthetic path for 2-aryl-2H-indazoles

Fig. 4

Synthetic route for Cu(I) complexes

Scheme 40

Synthesis of 2-aryl-2H-indazoles 39a–o

Scheme 41

Possible mechanism for 2-aryl-2H-indazole formation

Scheme 42

Synthetic route for 2-aryl-2H-indazoles 42a–l

Scheme 43

Synthesis of 2-aryl-2H-indazoles 42a–l

Scheme 44

Plausible mechanism for construction of 2-phenyl-2H-indazole 42a

Scheme 45

One-pot synthesis of N-phenyl-1H-indazoles

Scheme 46

Substrate scope for N-phenyl-1H-indazoles

Scheme 47

Substrate scope forN-thiazolyl-1H-indazoles

Scheme 48

Route for the synthesis of fluorinated indazoles

Scheme 49

Substrate scope for fluorinated indazoles. ^a Chromatographicisolated yields; compounds 49e and 49f are purchased commercially available materials

Scheme 50

Presumptive Ullmann mechanism for fluorinated indazole (51)

Scheme 51

Cu-mediated construction of 3-aryl-1H-indazoles

Scheme 52

Substrate scope for 3-aryl-1H-indazoles

Scheme 53

Possible mechanism for 3-phenyl indazole 53a

Scheme 54

Cu(OAc)₂ promoted construction of 1N-alkoxycarbonyl indazoles

Scheme 55

Scope of boronic acids 54 in the reaction with diazadicarboxylate tert-butyl-2-acetylhydrazine-1-carboxylate (55)

Scheme 56

Scope of boronic acid 54 in the reaction with diisopropyl (E)-diazene-1,2-dicarboxylate(57)

Scheme 57

Proposed mechanism for 1N-alkoxycarbonyl indazole

Scheme 58

Base-catalyzed cyclization of 2-nitrobenzylamines

Scheme 59

Microwave-assisted synthesis of hydroxy- and alkoxyindazole acetic acids (60a–h)

Scheme 60.

Plausible mechanism for alkoxyindazole acetic acid 60a

Scheme 61

Synthetic route for bis-indazoles

Scheme 62

Substrate scope of the one-pot sequential cascade reaction of annulated bis-indazoles

Scheme 63

Substrate scope of the one-pot sequential cascade reaction of annulated indazoles

Scheme 64

Proposed mechanism for the one-pot sequential cascade reaction

Scheme 65

Synthesis of indazole using conventional and ultrasound sonication method using H₃PMo₁₂O₄₀ and H₃PW₁₂O₄₀

Scheme 66

Ultrasound method for preparation of indazole derivatives (68a–f) by using H₃PMo₁₂O₄₀

Scheme 67

Ultrasound method for preparation of indazole derivatives 63g–l by using H₃PW₁₂O₄₀

Scheme 68

Possible mechanism using H₃PMo₁₂O₄₀ and H₃PW₁₂O₄₀ for synthesis of 68a–l

Scheme 69

Ultrasound-assisted synthesis of 2-phenyl-2H-indazole derivatives

Scheme 70

Substrate scope for 2-phenyl-2H-indazoles 71a-l.^a The reaction mixture was ultrasonicated for four cycles for 1 h at 40 °C

Scheme 71

Ultrasonic-promoted synthesis of 2-aryl indazoles75a–o

Scheme 72

A plausible mechanism for the construction of 2-phenyl-2H-indazole 75a

Scheme 73

Metal-free synthesis of 2H-indazoles in photochemical/thermal conditions

Scheme 74

Synthesis of N,N-diethyl-3-(sufonyl)-2H-indazol-2-amines

Scheme 75

Synthesis of 2H-indazole-3-carbaldehydes

Scheme 76

Plausible mechanism for 3-((arylsulfonyl)methyl)-N,N-diethyl-2H-indazol-2-amine

Scheme 77

Possible mechanism2-(diethylamino)-2H-indazole-3-carbaldehyde 79a

Scheme 78

Synthetic route for 3-alkyl/aryl-3H-indazole-3-phosphonates and 3-alkyl/aryl-1H-indazoles

Scheme 79

Substrate scope for 3-alkyl/aryl-3H-indazole-3-phosphonates and 3-alkyl/aryl-1H-indazoles

Scheme 80

Plausible mechanism for 3-alkyl/aryl-3H-indazole-3-phosphonate (82) and 3-alkyl/aryl-1H-indazole (83)

Scheme 81

Synthesis of indazoles 85a–l by diazo activation strategy

Scheme 82

Substrate scope for methyl 1-(aryl)-1H-indazole-3-carboxylate

Scheme 83

Diazo activation by diazonium and formation of diazenium intermediate

Scheme 84

Cadogan synthesis of 2-aryl indazoles

Scheme 85

Potassium methoxide-promoted synthesis of 2-aryl-2H-indazoles

Scheme 86

Substrate scope for 2-aryl-2H-indazoles

Scheme 87

Plausible mechanism for 2-phenyl-2H-indazole 89a

Scheme 88

Reaction pathway for the synthesis of indazole derivatives 1a–d and 2a–d

Scheme 89

Indazole derivatives 94a–d and 95a–d

Scheme 90

Reaction path for the synthesis of different 1,3-substituted 1H-indazoles

Scheme 91

Synthesis of N,1-diaryl-1H-indazol-3-amines

Scheme 92

Possible mechanism for 1-phenyl-1H-indazol-3-amine (98a)

Scheme 93

Synthetic pathway for 3-methyl-1-phenyl-1H-indazole motifs (102a–c)