The Role of Flow Chemistry on the Synthesis of Pyrazoles, Pyrazolines and Pyrazole-Fused Scaffolds

Abstract

Nitrogen-containing heterocycles are fundamental scaffolds in organic chemistry, particularly due to their prevalence in pharmaceuticals, agrochemicals and materials science. Among them, five-membered rings, containing two nitrogen atoms in adjacent positions-such as pyrazoles, pyrazolines and indazoles-are especially significant due to their versatile biological activities and structural properties, which led to the search for greener, faster and more efficient methods for their synthesis. Conventional batch synthesis methods, while effective, often face challenges related to reaction efficiency, scalability and safety. Flow chemistry has emerged as a powerful alternative, offering enhanced control over reaction parameters, improved safety profiles and opportunities for scaling up synthesis processes efficiently. This review explores the impact of flow chemistry on the synthesis of these pivotal heterocycles, highlighting its advantages over the conventional batch methods. Although indazoles have a five-membered ring fused with a benzene ring, they will also be considered in this review due to their biological relevance.

Keywords: flow chemistry; green chemistry; indazoles; pyrazoles; pyrazolines; synthesis.

Figure 1

Chemical structures and numbering of pyrazole 1, dihydropyrazole (pyrazoline) tautomers 2–4 and pyrazolidine 5.

Figure 2

Chemical structures of indazole 6, pyrazolopyrimidinone 7 and pyrazolopyridine 8 scaffolds.

Scheme 1

Cyclocondensation of carbonyl compounds 9–12 with hydrazine derivatives 13.

Scheme 2

Multicomponent synthesis of pyrazoles.

Scheme 3

1,3-Dipolar cycloaddition of sydnones with carbonyl compounds.

Scheme 4

1,3-Dipolar cycloaddition of nitrilimines with terminal alkynes.

Scheme 5

1,3-Dipolar cycloaddition of diazo compounds with terminal alkynes.

Scheme 6

Common strategies for the synthesis of N-aryl-1H-indazoles 32.

Figure 3

Principles, advantages and limitations of flow chemistry.

Scheme 7

Flow synthesis of pyrazole-4-carboxylate derivatives 34.

Scheme 8

Continuous-flow 1,3-dipolar cycloaddition of alkynes with trimethylsilyldiazomethane to give pyrazoles 36a,b.

Scheme 9

Synthesis of 3,5-disubstituted pyrazoles 37 under flow conditions.

Scheme 10

Flow synthesis of pentafluorosulfanylpyrazoles 39 and 39′.

Scheme 11

Transition metal-free continuous-flow process for the synthesis of 3,5-di- and 1,3,5-trisubstituted pyrazoles 41 and 16, respectively.

Scheme 12

Photochemical synthesis of pyrazolines 14 and pyrazoles 16 from tetrazoles in flow conditions.

Scheme 13

Expansion and/or rearrangement and cyclization of pyridinium salts and subsequent carbon deletion for the synthesis of pyrazoles 47, under flow conditions.

Scheme 14

Continuous-flow synthesis of pyrazole 50 based on the Knorr cyclocondensation.

Scheme 15

Four-stage multistep setup for continuous-flow production of pyrazoles 53 from anilines.

Scheme 16

Continuous-flow–microwave hybrid approach for the synthesis of pyrazoles 53.

Scheme 17

Continuous-flow synthesis of N-aryl-5-methylpyrazole 55.

Scheme 18

Continuous-flow process for the synthesis of celecoxib 58.

Scheme 19

Copper-catalyzed cycloaddition of sydnones with terminal alkynes to produce pyrazoles 22 under flow conditions.

Scheme 20

Synthesis of diazoalkanes in flow followed by cycloaddition in batch conditions to afford pyrazoles 63 and pyrazolines 64.

Scheme 21

Continuous-flow setup for the in situ generation of diazo compounds and further cycloaddition with alkynes and alkenes to achieve pyrazoles 63 and pyrazolines 64, respectively.

Scheme 22

Thermal synthesis of N-arylindazoles 66 from nitroaromatic imines via Cadogan reaction, in flow conditions.

Scheme 23

Cadogan reaction mechanism for the synthesis of N-substituted indazoles.

Scheme 24

Continuous-flow synthesis of N-arylindazoles 66 by photochemical generation of benzynes and subsequent trapping with sydnones.

Scheme 25

Three-step-flow procedure for the synthesis of indazole derivatives 66.

Scheme 26

Synthesis of pyrazolopyrimidinones 72 under flow conditions.

Scheme 27

Synthesis of pyrazolo[1,5-a]pyridine 74 by thermolysis of azidoacrylates, under flow conditions.

Scheme 28

Microwave–flow hybrid approach for the synthesis of pyrazolo[3,4-b]pyridin-4-ols 78a–c and pyrazolo[3,4-b]pyridin-4-amines 81a,b.