Synthesis of five- and six-membered cyclic organic peroxides: Key transformations into peroxide ring-retaining products

Abstract

The present review describes the current status of synthetic five and six-membered cyclic peroxides such as 1,2-dioxolanes, 1,2,4-trioxolanes (ozonides), 1,2-dioxanes, 1,2-dioxenes, 1,2,4-trioxanes, and 1,2,4,5-tetraoxanes. The literature from 2000 onwards is surveyed to provide an update on synthesis of cyclic peroxides. The indicated period of time is, on the whole, characterized by the development of new efficient and scale-up methods for the preparation of these cyclic compounds. It was shown that cyclic peroxides remain unchanged throughout the course of a wide range of fundamental organic reactions. Due to these properties, the molecular structures can be greatly modified to give peroxide ring-retaining products. The chemistry of cyclic peroxides has attracted considerable attention, because these compounds are used in medicine for the design of antimalarial, antihelminthic, and antitumor agents.

Keywords: 1,2,4,5-tetraoxanes; 1,2,4-trioxanes; 1,2,4-trioxolanes; 1,2-dioxanes; 1,2-dioxenes; 1,2-dioxolanes; cyclic peroxides; ozonides.

Figure 1

Five and six-membered cyclic peroxides.

Figure 2

Artemisinin and semi-synthetic derivatives.

Scheme 1

Synthesis of 3-hydroxy-1,2-dioxolanes 3a–c.

Scheme 2

Synthesis of dioxolane 6.

Scheme 3

Photooxygenation of oxazolidines 7a–d with formation of spiro-fused oxazolidine-containing dioxolanes 9a–d.

Scheme 4

Oxidation of cyclopropanes 10a–e and 11a–e with preparation of 1,2-dioxolanes 12a–e.

Scheme 5

VO(acac)₂-catalyzed oxidation of silylated bicycloalkanols 13a–c.

Scheme 6

Mn(II)-catalyzed oxidation of cyclopropanols 15a–g.

Scheme 7

Oxidation of aminocyclopropanes 20a–c.

Scheme 8

Synthesis of aminodioxolanes 24.

Figure 3

Trifluoromethyl-containing dioxolane 25.

Scheme 9

Synthesis of 1,2-dioxolanes 27a–e by the oxidation of cyclopropanes 26a–e.

Scheme 10

Photoinduced oxidation of methylenecyclopropanes 28.

Scheme 11

Irradiation-mediated oxidation.

Scheme 12

Application of diazene 34 for dioxolane synthesis.

Scheme 13

Mn(OAc)₃-catalyzed cooxidation of arylacetylenes 37a–h and acetylacetone with atmospheric oxygen.

Scheme 14

Peroxidation of (2-vinylcyclopropyl)benzene (40).

Scheme 15

Peroxidation of 1,4-dienes 43a,b.

Scheme 16

Peroxidation of 1,5-dienes 46.

Scheme 17

Peroxidation of oxetanes 53a,b.

Scheme 18

Peroxidation of 1,6-diene 56.

Scheme 19

Synthesis of 3-alkoxy-1,2-dioxolanes 62a,b.

Scheme 20

Synthesis of spiro-bis(1,2-dioxolane) 66.

Scheme 21

Synthesis of dispiro-1,2-dioxolanes 68, 70, 71.

Scheme 22

Synthesis of spirohydroperoxydioxolanes 75a,b.

Scheme 23

Synthesis of spirohydroperoxydioxolane 77 and dihydroperoxydioxolane 79.

Scheme 24

Ozonolysis of azepino[4,5-b]indole 80.

Scheme 25

SnCl₄-mediated fragmentation of ozonides 84a–l in the presence of allyltrimethylsilane.

Scheme 26

SnCl₄-mediated fragmentation of bicyclic ozonide 84m in the presence of allyltrimethylsilane.

Scheme 27

MCl₄-mediated fragmentation of alkoxyhydroperoxides 96 in the presence of allyltrimethylsilane.

Scheme 28

SnCl₄-catalyzed reaction of monotriethylsilylperoxyacetal 108 with alkene 109.

Scheme 29

SnCl₄-catalyzed reaction of triethylsilylperoxyacetals 111 with alkenes.

Scheme 30

Desilylation of tert-butyldimethylsilylperoxy ketones 131a,b followed by cyclization.

Scheme 31

Deprotection of peroxide 133 followed by cyclization.

Scheme 32

Asymmetric peroxidation of methyl vinyl ketones 137a–e.

Scheme 33

Et₂NH-catalyzed intramolecular cyclization.

Scheme 34

Synthesis of oxodioxolanes 143a–j.

Scheme 35

Haloperoxidation accompanied by intramolecular ring closure.

Scheme 36

Oxidation of triterpenes 149a–d with Na₂Cr₂O₇/N-hydroxysuccinimide.

Scheme 37

Curtius and Wolff rearrangements to form 1,2-dioxolane ring-retaining products.

Scheme 38

Oxidative desilylation of peroxide 124.

Scheme 39

Synthesis of dioxolane 158, a compound containing the aminoquinoline antimalarial pharmacophore.

Scheme 40

Diastereomers of plakinic acid A, 162a and 162b.

Scheme 41

Ozonolysis of alkenes.

Scheme 42

Cross-ozonolysis of alkenes 166 with carbonyl compounds.

Scheme 43

Ozonolysis of the bicyclic cyclohexenone 168.

Scheme 44

Cross-ozonolysis of enol ethers 172a,b with cyclohexanone.

Scheme 45

Griesbaum co-ozonolysis.

Scheme 46

Reactions of aryloxiranes 177a,b with oxygen.

Scheme 47

Intramolecular formation of 1,2,4-trioxolane 180.

Scheme 48

Formation of 1,2,4-trioxolane 180 by the reaction of 1,5-ketoacetal 181 with H₂O₂.

Scheme 49

1,2,4-Trioxolane 186 with tetrazole fragment.

Scheme 50

1,2,4-Trioxolane 188 with a pyridine fragment.

Scheme 51

1,2,4-Trioxolane 189 with pyrimidine fragment.

Scheme 52

Synthesis of aminoquinoline-containing 1,2,4-trioxalane 191.

Scheme 53

Synthesis of arterolane.

Scheme 54

Oxidation of diarylheptadienes 197a–c with singlet oxygen.

Scheme 55

Synthesis of hexacyclinol peroxide 200.

Scheme 56

Oxidation of enone 201 and enenitrile 203 with singlet oxygen.

Scheme 57

Synthesis of 1,2-dioxanes 207 by oxidative coupling of carbonyl compounds 206 and alkenes 205.

Scheme 58

1,2-Dioxanes 209 synthesis by co-oxidation of 1,5-dienes 208 and thiols.

Scheme 59

Synthesis of bicyclic 1,2-dioxanes 212 with aryl substituents.

Scheme 60

Isayama–Mukaiyama peroxysilylation of 1,5-dienes 213 followed by desilylation under acidic conditions.

Scheme 61

Synthesis of bicycle 218 with an 1,2-dioxane ring.

Scheme 62

Intramolecular cyclization with an oxirane-ring opening.

Scheme 63

Inramolecular cyclization with the oxetane-ring opening.

Scheme 64

Intramolecular cyclization with the attack on a keto group.

Scheme 65

Peroxidation of the carbonyl group in unsaturated ketones 228 followed by cyclization of hydroperoxy acetals 229.

Scheme 66

CsOH and Et₂NH-catalyzed cyclization.

Scheme 67

Preparation of peroxyplakoric acid methyl ethers A and D.

Scheme 68

Hg(OAc)₂ in 1,2-dioxane synthesis.

Scheme 69

Reaction of 1,4-diketones 242 with hydrogen peroxide.

Scheme 70

Inramolecular cyclization with oxetane-ring opening.

Scheme 71

Inramolecular cyclization with MsO fragment substitution.

Scheme 72

Synthesis of 1,2-dioxane 255a, a structurally similar compound to natural peroxyplakoric acids.

Scheme 73

Synthesis of 1,2-dioxanes based on the intramolecular cyclization of hydroperoxides containing C=C groups.

Scheme 74

Use of BCIH in the intramolecular cyclization.

Scheme 75

Palladium-catalyzed cyclization of δ-unsaturated hydroperoxides 271a–e.

Scheme 76

Intramolecular cyclization of unsaturated peroxyacetals 273a–d.

Scheme 77

Allyltrimethylsilane in the synthesis of 1,2-dioxanes 276a–d.

Scheme 78

Intramolecular cyclization using the electrophilic center of the peroxycarbenium ion 279.

Scheme 79

Synthesis of bicyclic 1,2-dioxanes.

Scheme 80

Preparation of 1,2-dioxane 286.

Scheme 81

Di(tert-butyl)peroxalate-initiated radical cyclization of unsaturated hydroperoxide 287.

Scheme 82

Oxidation of 1,4-betaines 291a–d.

Scheme 83

Synthesis of aminoquinoline-containing 1,2-dioxane 294.

Scheme 84

Synthesis of the sulfonyl-containing 1,2-dioxane.

Scheme 85

Synthesis of the amido-containing 1,2-dioxane 301.

Scheme 86

Reaction of singlet oxygen with the 1,3-diene system 302.

Scheme 87

Synthesis of (+)-premnalane А and 8-epi-premnalane A.

Scheme 88

Synthesis of the diazo group containing 1,2-dioxenes 309a–e.

Figure 4

Plakortolide Е.

Scheme 89

Synthesis of 6-epiplakortolide Е.

Scheme 90

Application of Bu₃SnH for the preparation of tetrahydrofuran-containing bicyclic peroxides 318a,b.

Scheme 91

Application of Bu₃SnH for the preparation of lactone-containing bicyclic peroxides 320a–f.

Scheme 92

Dihydroxylation of the double bond in the 1,2-dioxene ring 321 with OsO₄.

Scheme 93

Epoxidation of 1,2-dioxenes 324.

Scheme 94

Cyclopropanation of the double bond in endoperoxides 327.

Scheme 95

Preparation of pyridazine-containing bicyclic endoperoxides 334a–c.

Scheme 96

Synthesis of 1,2,4-trioxanes 337 by the hydroperoxidation of unsaturated alcohols 335 with ¹O₂ and the condensation of the hydroxy hydroperoxides 336 with carbonyl compounds.

Scheme 97

Synthesis of sulfur-containing 1,2,4-trioxanes 339.

Scheme 98

BF₃·Et₂O-catalyzed synthesis of the 1,2,4-trioxanes 342a–g.

Scheme 99

Photooxidation of enol ethers or vinyl sulfides 343.

Scheme 100

Synthesis of tricyclic peroxide 346.

Scheme 101

Reaction of endoperoxides 348a,b derived from cyclohexadienes 347a,b with 1,4-cyclohexanedione.

Scheme 102

[4 + 2]-Cycloaddition of singlet oxygen to 2Н-pyrans 350.

Scheme 103

Synthesis of 1,2,4-trioxanes 354 using peroxysilylation stage.

Scheme 104

Epoxide-ring opening in 355 with H₂O₂ followed by the condensation of hydroxy hydroperoxides 356 with ketones.

Scheme 105

Peroxidation of unsaturated ketones 358 with the H₂O₂/CF₃COOH/H₂SO₄ system.

Scheme 106

Synthesis of 1,2,4-trioxanes 362 through Et₂NH-catalyzed intramolecular cyclization.

Scheme 107

Reduction of the double bond in tricyclic peroxides 363.

Scheme 108

Horner–Wadsworth–Emmons reaction in the presence of peroxide group.

Scheme 109

Reduction of ester group by LiBH₄ in the presence of 1,2,4-trioxane moiety.

Scheme 110

Reductive amination of keto-containing 1,2,4-trioxane 370.

Scheme 111

Reductive amination of keto-containing 1,2,4-trioxane and a Fe-containing moiety.

Scheme 112

Acid-catalyzed reactions of Н₂О₂ with ketones and aldehydes 374.

Scheme 113

Cyclocondensation of carbonyl compounds 376a–d using Me₃SiOOSiMe₃/CF₃SO₃SiMe₃.

Scheme 114

Peroxidation of 4-methylcyclohexanone (378).

Scheme 115

Synthesis of symmetrical tetraoxanes 382a,b from aldehydes 381a,b.

Scheme 116

Synthesis of unsymmetrical tetraoxanes using of MeReO₃.

Scheme 117

Synthesis of symmetrical tetraoxanes using of MeReO₃.

Scheme 118

Synthesis of symmetrical tetraoxanes using of MeReO₃.

Scheme 119

MeReO₃ in the synthesis of symmetrical tetraoxanes with the use of aldehydes.

Scheme 120

Preparation of unsymmmetrical 1,2,4,5-tetraoxanes with high antimalarial activity.

Scheme 121

Re₂O₇-Catalyzed synthesis of tetraoxanes 398.

Scheme 122

H₂SO₄-Catalyzed synthesis of steroidal tetraoxanes 401.

Scheme 123

HBF₄-Catalyzed condensation of bishydroperoxide 402 with 1,4-cyclohexanedione.

Scheme 124

BF₃·Et₂O-Catalyzed reaction of gem-bishydroperoxides 404 with enol ethers 405 and acetals 406.

Scheme 125

HBF₄-Catalyzed cyclocondensation of bishydroperoxide 410 with ketones.

Scheme 126

Synthesis of symmetrical and unsymmetrical tetraoxanes 413 from benzaldehydes 412.

Scheme 127

Synthesis of bridged 1,2,4,5-tetraoxanes 415a–l from β-diketones 414a–l and H₂O₂.

Scheme 128

Dimerization of zwitterions 417.

Scheme 129

Ozonolysis of verbenone 419.

Scheme 130

Ozonolysis of O-methyl oxime 424.

Scheme 131

Peroxidation of 1,1,1-trifluorododecan-2-one 426 with oxone.

Scheme 132

Intramolecular cyclization of dialdehyde 428 with H₂O₂.

Scheme 133

Tetraoxanes 433–435 as by-products in peroxidation of ketals 430–432.

Scheme 134

Transformation of triperoxide 436 in diperoxide 437.

Scheme 135

Preparation and structural modifications of tetraoxanes.

Scheme 136

Structural modifications of steroidal tetraoxanes.

Scheme 137

Synthesis of 1,2,4,5-tetraoxane 454 containing the fluorescent moiety.

Scheme 138

Synthesis of tetraoxane 458 (RKA182).