Recent Strategies in Transition-Metal-Catalyzed Sequential C-H Activation/Annulation for One-Step Construction of Functionalized Indazole Derivatives

Abstract

Designing new synthetic strategies for indazoles is a prominent topic in contemporary research. The transition-metal-catalyzed C-H activation/annulation sequence has arisen as a favorable tool to construct functionalized indazole derivatives with improved tolerance in medicinal applications, functional flexibility, and structural complexity. In the current review article, we aim to outline and summarize the most common synthetic protocols to use in the synthesis of target indazoles via a transition-metal-catalyzed C-H activation/annulation sequence for the one-step synthesis of functionalized indazole derivatives. We categorized the text according to the metal salts used in the reactions. Some metal salts were used as catalysts, and others may have been used as oxidants and/or for the activation of precatalysts. The roles of some metal salts in the corresponding reaction mechanisms have not been identified. It can be expected that the current synopsis will provide accessible practical guidance to colleagues interested in the subject.

Keywords: C–H functionalization; cyclization; indazole products; transition metals catalysis.

Figure 1

(i) Indazole derivatives with biological activity; (ii) Natural products of indazole alkaloids.

Scheme 1

A synthetic route for the preparation of 1H-indazole derivatives 3 from the reaction between imidates 1 and nitrosobenzenes 2 in the presence of a rhodium/copper catalyst.

Scheme 2

A rational mechanism for the synthesis of 1H-indazole derivatives 3 from the reaction between imidates 1 and nitrosobenzenes 2 in the presence of a rhodium/copper catalyst.

Scheme 3

A synthetic route for the transformation of azobenzene substrates 10 to indazole derivatives 11 in the presence of a Rh(III) catalyst.

Scheme 4

A possible mechanism for the transformation of azobenzene substrates 10 to indazole derivatives 12 in the presence of a Rh(III) catalyst.

Scheme 5

A synthetic route for the preparation of 2,3-dihydro-1H-indazole derivatives 19 from the reaction between 1,2-disubstituted arylhydrazines 18 and electron-poor alkenes 11 in the presence of a Rh(III) catalyst.

Scheme 6

A synthetic route for the preparation of 2,3-dihydro-1H-indazoles 19 via the C–H cleavage of arylhydrazines 18 in the presence of a Rh(III) catalyst.

Scheme 7

A synthetic route for the preparation of pyrazolo[1,2-a] indazoles 22 containing a quaternary carbon in the presence of a Rh(III) catalyst.

Scheme 8

A synthetic route for the preparation of indazolo[1,2-b]phthalazine-trione derivatives 25 from the reaction between 2-aryl-2,3-dihydrophthalazine-1,4-diones 23 and isocyanates 24 under ruthenium catalysis.

Scheme 9

A rational mechanism for the synthesis of indazolo[1,2-b]phthalazine-trione derivatives 25 from the reaction between 2-aryl-2,3-dihydrophthalazine-1,4-diones 23 and isocyanates 24 under ruthenium catalysis.

Scheme 10

A synthetic route for the preparation of 2H-indazoles derivatives 33 via the regio- and chemoselective [4 + 1] annulation of azoxy compounds 31 with diazoesters 32 under rhodium catalysis.

Scheme 11

A synthetic route for the preparation of indazoles derivatives 36 via the oxidative annulation of ketoxime methyl ethers 34 with sulfonamide 35a–b under rhodium catalysis.

Scheme 12

A possible mechanism for the synthesis of indazole derivatives 36 via the oxidative annulation of ketoxime ethers 34 with sulfonamide 35 under rhodium catalysis.

Scheme 13

A synthetic route for the preparation of 1H-indazole derivatives 43 and 45 from azobenzenes 10 using paraformaldehyde 42 as a one-carbon synthon or trifluoroacetaldehyde ethyl hemiacetal 44.

Scheme 14

A synthetic route for the preparation of indazole derivatives 48 through the C–H activation of phthalazinones 23 or pyridazinones 46 and allenes 47 under Rh(III) catalysis.

Scheme 15

A synthetic route for the preparation of 2H-indazole derivatives 50 via the annulation of azobenzenes 10 with vinylene carbonate 49 under Rh(III) catalysis.

Scheme 16

A possible mechanism for the synthesis of 2H-indazole derivatives 50 via the annulation of azobenzenes 10 with vinylene carbonate 49 under Rh(III) catalysis.

Scheme 17

A synthetic route for the preparation of 1H-indazoles 59 via hydrazine-directed C−H functionalization with 1-alkynylcyclobutanols 21.

Scheme 18

A plausible mechanism for the synthesis of 1H-indazoles 59 via hydrazine-directed C−H functionalization with 1-alkynylcyclobutanols 58.

Scheme 19

A synthetic route for the preparation of indazole derivatives 71 via C−H bond functionalization and cyclative capture.

Scheme 20

A synthetic route for the preparation of indazole derivatives 72, 73, and 74 via an alkenylation–annulation approach.

Scheme 21

A plausible mechanism for the synthesis of indazole derivatives 72 or 73 via an alkenylation–annulation approach.

Scheme 22

A synthetic route for the preparation of 1H-indazole derivatives 80 via C−H amidation and N−N bond formation.

Scheme 23

A rational mechanism for the synthesis of 1H-indazole derivatives 80 via C−H amidation and N−N bond formation.

Scheme 24

A synthetic route for the preparation of 3-Acyl-(2H)-indazoles 90 via the [4 + 1] annulation of azobenzenes 10 with α-carbonyl sulfoxonium ylides 89.

Scheme 25

A plausible mechanism for the synthesis of 3-acyl-(2H)-indazoles 90 via the [4 + 1] annulation of azobenzenes 10 with α-carbonyl sulfoxonium ylides 89.

Scheme 26

A synthetic route for the preparation of 2H-indazoles 90 through the annulation reaction of azobenzenes 10 with sulfoxonium ylides 89.

Scheme 27

A possible mechanism for the synthesis of 2H-indazoles 90 through the annulation reaction of azobenzenes 10 with sulfoxonium ylides 89.

Scheme 28

A synthetic route for the preparation of substituted indazole N-oxides 101 via the tandem acylmethylation/annulation of N-nitrosoanilines 100 with sulfoxonium ylides 89.

Scheme 29

A rational mechanism for the synthesis of substituted indazole N-oxides 101 via the tandem acylmethylation/annulation of N-nitrosoanilines 100 with sulfoxonium ylides 89.

Scheme 30

A synthetic route for the preparation of 3-acyl-2-H-indazoles 90 via the annulation of azobenzenes 10 with α-Cl ketones 109.

Scheme 31

A rational mechanism for the synthesis of 3-acyl-2-H-indazoles 90 via the annulation of azobenzenes 10 with α-Cl ketones 109.

Scheme 32

A synthetic route for the preparation of functionalized 1H-indazole 113 via the double C−H activation of aldehyde hydrazones 112.

Scheme 33

A synthetic route for the preparation of 2H-indazole derivatives 115 via the [4 + 1] annulation of azoxy compounds 31 with alkynes 114.

Scheme 34

A synthetic route for the preparation of H-indazoles 117 via the C−N/N−N coupling of imidates 1 with anthranils 116.

Scheme 35

A rational mechanism for the synthesis of H-indazoles 117 via the C−N/N−N coupling of imidates 1 with anthranils 116.

Scheme 36

A synthetic route for the preparation of 3-aminoindazoles 128 from tertiary amides 127.

Scheme 37

A synthetic route for the preparation of 3-nitro-1-(phenylsulfonyl)-1H-indazole derivatives 130 via the direct C−H nitration and intramolecular C−H functionalization of 129.

Scheme 38

A rational mechanism for the synthesis of 3-nitro-1-(phenylsulfonyl)-1H-indazole derivatives 130 via the direct C−H nitration and intramolecular C−H functionalization of 129.

Scheme 39

A synthetic route for the preparation of pyrido[1,2-b]indazoles 140 via the tandem C−H azidation and N-N bond formation of arylpyridines 139.

Scheme 40

A synthetic route for the preparation of 3-aryl/alkylindazoles 142 via the C−H activation/intramolecular amination reaction.

Scheme 41

A synthetic route for the preparation of indazoles 71 via C–H bond functionalization/addition/cyclization cascades.

Scheme 42

A synthetic route for the preparation of indazole derivatives 71 via the [4 + 1] annulation of azobenzenes 10 with aldehydes 70.

Scheme 43

A rational mechanism for the synthesis of indazole derivatives 71 via the [4 + 1] annulation of azobenzenes 10 with aldehydes 70.

Scheme 44

A synthetic route for the preparation of indazole derivatives 151 via C(sp²)−H amidation 149 with azides 150 as amino sources.

Scheme 45

A synthetic route for the preparation of indazole derivatives 153 via aerobic C(sp²)−H functionalization/C−N bond formation.

Scheme 46

A rational mechanism for the synthesis of indazole derivatives 153 via aerobic C(sp²)−H functionalization/C−N bond formation.