Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

Abstract

Pyrazoles are rarely found in nature but are traditionally used in the agrochemical and pharmaceutical industries, while other areas of use are also actively developing. However, they have also found numerous other applications. The search for new and efficient syntheses of these heterocycles is therefore highly relevant. The modular concept of multicomponent reactions (MCR) has paved a broad alley to heteroaromatics. The advantages over traditional methods are the broader scope and increased efficiency of these reactions. In particular, traditional multistep syntheses of pyrazoles have considerably been extended by MCR. Progress has been made in the cyclocondensation of 1,3-dielectrophiles that are generated in situ. Limitations in the regioselectivity of cyclocondensation with 1,3-dicarbonyls were overcome by the addition-cyclocondensation of α,β-unsaturated ketones. Embedding 1,3-dipolar cycloadditions into a one-pot process has additionally been developed for concise syntheses of pyrazoles. The MCR strategy also allows for concatenating classical condensation-based methodology with modern cross-coupling and radical chemistry, as well as providing versatile synthetic approaches to pyrazoles. This overview summarizes the most important MCR syntheses of pyrazoles based on ring-forming sequences in a flashlight fashion.

Keywords: cycloaddition; cyclocondensation; multicomponent reaction; one-pot reactions; pyrazole.

Scheme 1

Consecutive three-component synthesis of pyrazoles 1 via in situ-formed 1,3-diketones 2 [44].

Scheme 2

Consecutive three-component synthesis of 4-ethoxycarbonylpyrazoles 5 via SmCl₃-catalyzed acylation of ethyl acetoacetate [45].

Scheme 3

Consecutive four-component synthesis of 1-(thiazol-2-yl)pyrazole-3-carboxylates 8 [51].

Scheme 4

Three-component synthesis of thiazolylpyrazoles 17 via in situ formation of acetoacetylcoumarins 18 [52].

Scheme 5

Consecutive pseudo-four-component and four-component synthesis of pyrazoles 21 from sodium acetylacetonate (20), isothiocyanates 19, and hydrazine [53].

Scheme 6

Consecutive three-component synthesis of 1-substituted pyrazoles 24 from boronic acids, di(Boc)diimide 23, and 1,3-dicarbonyl compounds [54].

Scheme 7

Consecutive three-component synthesis of N-arylpyrazoles 25 via in situ formation of aryl-di(Boc)hydrazines 26 [56].

Scheme 8

Consecutive three-component synthesis of 1,3,4-substituted pyrazoles 27 and 28 from methylhydrazine, ethyl formate, and β-ketoesters, β-ketoamides or 3-aminocrotonitrile [58].

Scheme 9

Consecutive three-component synthesis of 4-allylpyrazoles 32 via oxidative allylation of 1,3-dicarbonyl compounds [59].

Scheme 10

Pseudo-five-component synthesis of tris(pyrazolyl)methanes 35 [61].

Scheme 11

Pseudo-three-component synthesis of 5-(indol-3-yl)pyrazoles 39 from 1,3,5-triketones 38 [64].

Scheme 12

Three-component synthesis of thiazolylpyrazoles 43 [65].

Scheme 13

Three-component synthesis of triazolo[3,4-b]-1,3,4-thiadiazin-3-yl substituted 5-aminopyrazoles 47 [67].

Scheme 14

Consecutive three-component synthesis of 5-aminopyrazoles 49 via formation of β-oxothioamides 50 [68].

Scheme 15

Synthesis of 3,4-biarylpyrazoles 52 from aryl halides, α-bromocinnamaldehyde, and tosylhydrazine via MBSC/cyclocondensation-elimination sequence [70].

Scheme 16

Consecutive three-component synthesis of 3,4-substituted pyrazoles 57 from iodochromones 55 by Suzuki coupling and subsequent ring opening-ring closing cyclocondensation with hydrazine [72].

Scheme 17

Pseudo-four-component synthesis of pyrazolyl-2-pyrazolines 59 by ring opening/ring closing cyclocondensation with hydrazine [76].

Scheme 18

Consecutive three-component synthesis of pyrazoles 61 [77].

Scheme 19

Three-component synthesis of pyrazoles 62 from malononitrile, aldehydes, and hydrazines [–90].

Scheme 20

Four-component synthesis of pyrano[2,3-c]pyrazoles 63 [91].

Scheme 21

Three-component synthesis of persubstituted pyrazoles 65 from aldehydes, β-ketoesters, and hydrazines [95].

Scheme 22

Three-component synthesis of pyrazol-4-carbodithioates 67 [100].

Scheme 23

Regioselective three-component synthesis of persubstituted pyrazoles 68 catalyzed by ionic liquid [bmim][InCl₄] [101].

Scheme 24

Consecutive three-component synthesis of 4-halopyrazoles 69 and anellated pyrazoles 70 [102].

Scheme 25

Three-component synthesis of 2,2,2-trifluoroethyl pyrazole-5-carboxylates 72 [103].

Scheme 26

Synthesis of pyrazoles 75 in a one-pot process via carbonylative Heck coupling and subsequent cyclization with hydrazines [104].

Scheme 27

Copper-catalyzed three-component synthesis of 1,3-substituted pyrazoles 76 [105].

Scheme 28

Pseudo-three-component synthesis of bis(pyrazolyl)methanes 78 by ring opening-ring closing cyclocondensation with hydrazine [106].

Scheme 29

Three-component synthesis of 1,4,5-substituted pyrazoles 80 [107].

Scheme 30

Consecutive three-component synthesis of 3,5-bis(fluoroalkyl)pyrazoles 83 [111].

Scheme 31

Consecutive three-component synthesis of difluoromethanesulfonyl-functionalized pyrazole 88 [114].

Scheme 32

Consecutive three-component synthesis of perfluoroalkyl-substituted fluoropyrazoles 91 [115].

Scheme 33

Regioselective consecutive three-component synthesis of 1,3,5-substituted pyrazoles 93 [116].

Scheme 34

Three-component synthesis of pyrazoles 96 mediated by trimethyl phosphite [117].

Scheme 35

One-pot synthesis of pyrazoles 99 via Liebeskind–Srogl cross-coupling/cyclocondensation [118].

Scheme 36

Synthesis of 1,3,5-substituted pyrazoles 101 via domino condensation/Suzuki–Miyaura cross-coupling of β,β-dibromenones 100 and 1,1-dimethylhydrazine [119].

Scheme 37

Consecutive three-component synthesis of 1,3,5-trisubstituted pyrazoles 102 and 103 by Sonogashira alkynylation–cyclocondensation sequences from alkynes, (hetero)aroyl chlorides, and hydrazines [127].

Scheme 38

Polymer analogous consecutive three-component synthesis of pyrazole-based polymers 107 [132].

Scheme 39

Synthesis of 1,3,5-substituted pyrazoles 108 by sequentially Pd-catalyzed Kumada–Sonogashira cyclocondensation sequence [136].

Scheme 40

Consecutive four-step one-pot synthesis of 1,3,4,5-substituted pyrazoles 110 [137].

Scheme 41

Four-component synthesis of pyrazoles 113, 115, and 117 via Sonogashira coupling and subsequent Suzuki coupling [138].

Scheme 42

Consecutive four- or five-component synthesis for the preparation of 4-pyrazoly-1,2,3-triazoles 119 and 120 [139].

Scheme 43

Four-component synthesis of pyrazoles 121 via alkynone formation by carbonylative Pd-catalyzed coupling [140]. ^a5.00 mol % PdCl₂(PPh₃)₂, 2.00 mol % CuI.

Scheme 44

Preparation of 3-azulenyl pyrazoles 124 by glyoxylation, decarbonylative Sonogashira coupling, and subsequent cyclization [146].

Scheme 45

Four-component synthesis of a 3-indoloylpyrazole 128 [147].

Scheme 46

Two-step synthesis of 5-acylpyrazoles 132 via glyoxylation-Stephen–Castro sequence and subsequent cyclization with Boc hydrazine [–149].

Scheme 47

Copper on iron mediated consecutive three-component synthesis of 3,5-substituted pyrazoles 136 [150].

Scheme 48

Consecutive three-component synthesis of 3-substituted pyrazoles 141 by Sonogashira coupling and subsequent cyclization with hydrazine hydrate [151].

Scheme 49

Consecutive three-component synthesis of pyrazoles 143 initiated by Cu(I)-catalyzed carboxylation of terminal alkynes [152].

Scheme 50

Consecutive three-component synthesis of benzamide-substituted pyrazoles 146 starting from N-phthalimides and lithiated alkynes [–154].

Scheme 51

Consecutive three-component synthesis of 1,3,5-substituted pyrazoles 148 [156].

Scheme 52

Three-component synthesis of 4-ninhydrin-substituted pyrazoles 151 [158].

Scheme 53

Consecutive four-component synthesis of 4-(oxoindol)-1-phenylpyrazole-3-carboxylates 155 [159].

Scheme 54

Three-component synthesis of pyrazoles 160 [160].

Scheme 55

Consecutive three-component synthesis of pyrazoles 165 [162].

Scheme 56

Consecutive three-component synthesis of 3,5-disubstituted and 3-substituted pyrazoles 168 and 169 from in situ formed diazo compounds [172].

Scheme 57

Three-component synthesis of 3,4,5-substituted pyrazoles 171 via 1,3-dipolar cycloaddition of vinylazides and in situ formed diazo compounds [174].

Scheme 58

Three-component synthesis of pyrazoles 173 and 174 from aldehydes, tosylhydrazine, and vinylidene cyclopropane diesters 172 [176].

Scheme 59

Three-component synthesis of pyrazoles 175 from glyoxyl hydrates, tosylhydrazine, and electron-deficient alkenes [177].

Scheme 60

Pseudo-four-component synthesis of pyrazoles 177 from glyoxyl hydrates, tosylhydrazine, and aldehydes [178].

Scheme 61

Consecutive three-component synthesis of pyrazoles 179 via Knoevenagel-cycloaddition sequence [179].

Scheme 62

Three-component synthesis of 5-dimethylphosphonate substituted pyrazoles 182 from aldehydes, the Bestmann–Ohira reagent (181), and nitriles [180].

Scheme 63

Consecutive three-component synthesis of 5-(dimethyl phosphonate)-substituted pyrazoles 185 from aldehydes, methyl ketones, and the Bestmann–Ohira reagent (181) via Claisen–Schmidt/1,3-dipolar cycloaddition/oxidation sequence [181].

Scheme 64

Three-component synthesis of 5-(dimethyl phosphonate)-substituted pyrazoles 187 from aldehydes, the Bestmann–Ohira reagent (181), and β-keto phosphonates 186 [182].

Scheme 65

Three-component synthesis of 5-diethylphosphonate/5-phenylsulfonyl substituted pyrazoles 189 from aldehydes, Bestmann–Ohira reagent (181), and α-diazo-β-keto esters [184].

Scheme 66

Pseudo-three-component synthesis of 3-(dimethyl phosphonate)-substituted pyrazoles 190 [185].

Scheme 67

Three-component synthesis of 3-trifluoromethylpyrazoles 193 [186].

Scheme 68

Consecutive three-component synthesis of 5-stannyl-substituted 4-fluoropyrazole 197 [–192].

Scheme 69

Pseudo-three-component synthesis of 3,5-diacyl-4-arylpyrazoles 199 [195].

Scheme 70

Three-component synthesis of pyrazoles 204 via nitrilimines [196].

Scheme 71

Three-component synthesis of 1,3,5-substituted pyrazoles 206 via formation of nitrilimines and salicylate elimination [197].

Scheme 72

Pseudo four-component synthesis of pyrazoles 209 from acetylene dicarboxylates 147, hydrazonyl chloride, and 2-aminothiophenol (208) [198].

Scheme 73

Consecutive three-component synthesis of pyrazoles 213 via syndnones 214 [200].

Scheme 74

Consecutive three-component synthesis of pyrazoles 216 via in situ-formed diazomethinimines 217 [201].

Scheme 75

Consecutive three-component synthesis of 3-methylthiopyrazoles 219 from aldehydes, hydrazine, and 1,1-bis(methylsulfanyl)-2-nitroethene (218) [203].

Scheme 76

Three-component synthesis of 1,3,5-substituted pyrazoles 220 from aldehydes, hydrazines, and terminal alkynes [–207].

Scheme 77

Three-component synthesis of 1,3,4,5-substituted pyrazoles 222 from aldehydes, hydrazines, and DMAD [208].

Scheme 78

Pseudo three-component synthesis of pyrazoles 224 from sulfonyl hydrazone and benzyl acrylate under transition-metal-free conditions [210].

Scheme 79

Titanium-catalyzed consecutive four-component synthesis of pyrazoles 225 via enamino imines 226 [211]. ^a10 mol% Ti(NMe₂)₂(dpma); ^b20 mol % Ti(dpm)(NMe₂)₂.

Scheme 80

Titanium-catalyzed three-component synthesis of pyrazoles 227 via enhydrazino imine complex intermediates [212].

Scheme 81

Pseudo-three-component synthesis of pyrazoles 229 via Glaser coupling of terminal alkynes and photocatalytic cyclization with hydrazines [214].

Scheme 82

Copper(II)acetate-mediated three-component synthesis of pyrazoles 232 [216].

Scheme 83

Copper-catalyzed three-component synthesis of 1,3,4-substituted pyrazole 234 from oxime acetates, anilines, and paraformaldehyde [217].

Scheme 84

Three-component synthesis of 3-trifluoroethylpyrazoles 239 [218].

Scheme 85

Pseudo-three-component synthesis of 1,4-bisulfonyl-substituted pyrazoles 242 [219].

Scheme 86

Three-component synthesis of 4-hydroxypyrazole 246 [221].