Lewis Acids and Heteropoly Acids in the Synthesis of Organic Peroxides

Organic peroxides are an important class of compounds for organic synthesis, pharmacological chemistry, materials science, and the polymer industry. Here, for the first time, we summarize the main achievements in the synthesis of organic peroxides by the action of Lewis acids and heteropoly acids. This review consists of three parts: (1) metal-based Lewis acids in the synthesis of organic peroxides; (2) the synthesis of organic peroxides promoted by non-metal-based Lewis acids; and (3) the application of heteropoly acids in the synthesis of organic peroxides. The information covered in this review will be useful for specialists in the field of organic synthesis, reactions and processes of oxygen-containing compounds, catalysis, pharmaceuticals, and materials engineering.


Introduction
Organic peroxides, due to their unique ability to form O-centered radicals via cleavage of the O-O bond, are widely used in polymer chemistry. In particular, dicumyl peroxide, dibenzoyl peroxide, 1,1-di-tert-butyl hydroperoxy cyclohexane, tert-butyl hydroperoxide, which are convenient in handling, have found application as initiators for low-temperature polymerization of styrene, butadiene, vinyl chloride, acrylates, ethylene [1,2], and as reagents for vulcanization of rubbers [3,4]. According to the latest research, the global organic peroxide market size was around US $2 billion in 2020 [5]. Despite the successful application of peroxides in the polymer industry, it was believed for a long time that the application of organic peroxides as drugs was not possible due to their low stability and the generation of hazardous reactive oxygen species, which can quickly and nonspecifically interact with biomolecules. Discovery of the natural peroxide Artemisinin (Qinghaosu) and its outstanding antimalarial activity [6,7] in 1972, showed that cyclic peroxides can be used in medicine as drugs. In 2015, Youyou Tu was awarded the Nobel Prize "for her discoveries regarding a new therapy for malaria" [8,9].
This review, which covers the major achievements in the synthesis of organic peroxides ( Figure 2) using Lewis acids and heteropoly acids, consists of three parts: (1) metal-based Lewis acids in the synthesis of organic peroxides; (2) synthesis of organic peroxides promoted by non-metal-based Lewis acids; (3) application of heteropoly acids in the synthesis of organic peroxides. This review provides information that will be useful to specialists in the field of organic synthesis, catalysis, pharmaceuticals, and the polymer industry. thesis of organic peroxides. This review provides information that will be useful to specialists in the field of organic synthesis, catalysis, pharmaceuticals, and the polymer industry.

Metal-Based Lewis Acids as Catalysts in the Synthesis of Organic Peroxides
Traditionally, strong Bronsted acids play the role of a catalyst in the synthesis of organic peroxides. The use of metal-based Lewis acids for the synthesis of peroxides is a surprising phenomenon. Generally, peroxides decompose or rearrange under the action of transition metal salts [93,94]. However, some metal-based Lewis acids, on the contrary, promote the assembly of peroxides. In this section, we summarized the approaches on the synthesis of 1,2-dioxolanes, 1,2-dioxanes, 1,2-dioxepanes, 1,2-dioxocanes, 1,2,4,5-tetraoxanes, 1,2,4,5,7,8-hexaoxonanes, and acyclic peroxides under the action of metal-based Lewis acids.

Synthesis of Organic Peroxides Catalyzed by SnCl4, Me2SnCl2, SnCl2, and TiCl4
The first example of selective synthesis of organic peroxide using a metal-based Lewis acid SnCl4 as a catalyst goes back to 1950 [95]. Bartlett

Metal-Based Lewis Acids as Catalysts in the Synthesis of Organic Peroxides
Traditionally, strong Bronsted acids play the role of a catalyst in the synthesis of organic peroxides. The use of metal-based Lewis acids for the synthesis of peroxides is a surprising phenomenon. Generally, peroxides decompose or rearrange under the action of transition metal salts [93,94]. However, some metal-based Lewis acids, on the contrary, promote the assembly of peroxides. In this section, we summarized the approaches on the synthesis of 1,2-dioxolanes, 1,2-dioxanes, 1,2-dioxepanes, 1,2-dioxocanes, 1,2,4,5-tetraoxanes, 1,2,4,5,7,8hexaoxonanes, and acyclic peroxides under the action of metal-based Lewis acids.

Synthesis of Organic Peroxides Catalyzed by SnCl 4 , Me 2 SnCl 2 , SnCl 2 , and TiCl 4
The first example of selective synthesis of organic peroxide using a metal-based Lewis acid SnCl 4 as a catalyst goes back to 1950 [95]. Bartlett  In 1959, R. Huttel et al. found that benzyl hydroperoxide 4 is formed by treating benzyl chloride 3 with an excess of hydrogen peroxide (90% aq. solution) in the presence of tin (IV) chloride as a catalyst [96]. The yield of benzyl hydroperoxide 4 was 23% (Scheme 2). In 1959, R. Huttel et al. found that benzyl hydroperoxide 4 is formed by treating benzyl chloride 3 with an excess of hydrogen peroxide (90% aq. solution) in the presence of tin (IV) chloride as a catalyst [96]. The yield of benzyl hydroperoxide 4 was 23% (Scheme 2). Scheme 1. Synthesis of hydroperoxide 2.
In 1959, R. Huttel et al. found that benzyl hydroperoxide 4 is formed by treating benzyl chloride 3 with an excess of hydrogen peroxide (90% aq. solution) in the presence of tin (IV) chloride as a catalyst [96]. The yield of benzyl hydroperoxide 4 was 23% (Scheme 2).

Scheme 7. Synthesis of alkyl peroxides 18.
Allylation of monoperoxyacetals 19, 20 makes it possible to obtain peroxides 21, 22 in good yield at −78 °C in methylene chloride. The reaction is catalyzed by TiCl4 and SnCl4 (Scheme 8) [100]. The transformation of alkyl peroxides under the action of Lewis acids has been described, where 1,2-dioxanes, 1,2-dioxepanes, and 1,2-dioxocanes are formed as target products [87]. Thus, intramolecular cyclization of peroxyacetals 23, 25, and 27, containing an electron-rich double bond, occurs with the formation of cyclic peroxides 24, 26, and 28, respectively, under action of 1 equiv. of TiCl 4 or SnCl 4 at −78 • C in CH 2 Cl 2 at the N 2 atmosphere (Scheme 9). The size of the peroxide ring depends on the position of the double bond in the starting alkyl peroxide.
The reaction mechanism of the formation of 1,2-dioxolane 30 includes the formation of hydroperoxycarbenium ion A peroxyacetal 29 under the action of SnCl 4 or TiCl 4 at the first step. Then hydroperoxycarbenium ion A undergoes nucleophilic attack by allyltrimethylsilane to form cation B, the cyclization of which leads to the 1,2-dioxolane 30 (Scheme 11) [101]. scribed, where 1,2-dioxanes, 1,2-dioxepanes, and 1,2-dioxocanes are formed as target products [87]. Thus, intramolecular cyclization of peroxyacetals 23, 25, and 27, containing an electron-rich double bond, occurs with the formation of cyclic peroxides 24, 26, and 28, respectively, under action of 1 equiv. of TiCl4 or SnCl4 at −78 °C in CH2Cl2 at the N2 atmosphere (Scheme 9). The size of the peroxide ring depends on the position of the double bond in the starting alkyl peroxide. The interaction of allyltrimethylsilane with α-alkoxyhydroperoxides 29, promoted by SnCl4 and TiCl4, afforded with the formation of substituted 1,2-dioxolanes 30 (Scheme 10) [101].  The reaction mechanism of the formation of 1,2-dioxolane 30 includes the formation of hydroperoxycarbenium ion A peroxyacetal 29 under the action of SnCl4 or TiCl4 at the first step. Then hydroperoxycarbenium ion A undergoes nucleophilic attack by allyltrimethylsilane to form cation B, the cyclization of which leads to the 1,2-dioxolane 30 (Scheme 11) [101]. The reaction mechanism of the formation of 1,2-dioxolane 30 includes the formation of hydroperoxycarbenium ion A peroxyacetal 29 under the action of SnCl4 or TiCl4 at the first step. Then hydroperoxycarbenium ion A undergoes nucleophilic attack by allyltrimethylsilane to form cation B, the cyclization of which leads to the 1,2-dioxolane 30 (Scheme 11) [101]. Scheme 11. Probable mechanism of 1,2-dioxolane 30 formation.
The above-mentioned approach was used to transform ozonides 31 into 1,2-dioxolanes 32. This reaction proceeds under the action of SnCl4/AllylTMS system in a nitrogen atmosphere at the temperature range from −78 °C to 0 °C (Scheme 12) [103]. In the absence of allyltrimethylsilane, TiCl4 or SnCl4 can catalyze the heterolysis of the O-O-bond in ozonides. This reaction proceeds with the formation of the corresponding lactones and ketones (Scheme 13). The transformation of ozonides 31 into 1,2-dioxolanes Scheme 11. Probable mechanism of 1,2-dioxolane 30 formation.
The above-mentioned approach was used to transform ozonides 31 into 1,2-dioxolanes 32. This reaction proceeds under the action of SnCl 4 /AllylTMS system in a nitrogen atmosphere at the temperature range from −78 • C to 0 • C (Scheme 12) [103]. The reaction mechanism of the formation of 1,2-dioxolane 30 includes the formation of hydroperoxycarbenium ion A peroxyacetal 29 under the action of SnCl4 or TiCl4 at the first step. Then hydroperoxycarbenium ion A undergoes nucleophilic attack by allyltrimethylsilane to form cation B, the cyclization of which leads to the 1,2-dioxolane 30 (Scheme 11) [101]. Scheme 11. Probable mechanism of 1,2-dioxolane 30 formation.
The above-mentioned approach was used to transform ozonides 31 into 1,2-dioxolanes 32. This reaction proceeds under the action of SnCl4/AllylTMS system in a nitrogen atmosphere at the temperature range from −78 °C to 0 °C (Scheme 12) [103]. In the absence of allyltrimethylsilane, TiCl 4 or SnCl 4 can catalyze the heterolysis of the O-O-bond in ozonides. This reaction proceeds with the formation of the corresponding lactones and ketones (Scheme 13). The transformation of ozonides 31 into 1,2-dioxolanes 32 under the action of SnCl 4 in the presence of allyltrimethylsilane proceeds through Path A and Path B, including the ionization of both C-O and C-OO bonds [104].
The interaction of silylperoxyacetals 35 with alkenes 36 promoted by SnCl 4 leads to in the formation of substituted 1,2-dioxolanes 37. This process proceeds through the formation of the trimethylsilyl peroxycarbenium ion (Scheme 15) [82,106,107]. It was found that 1,2-dioxolanes 37a and 37b have a high antimalarial activity against P. falciparum [108].
This approach was used for the synthesis of 1,2-dioxalane (OZ78) 40, which exhibits high activity against Fasciola hepatica (Scheme 16) [109]. The SnCl4 or TiCl4-mediated reaction between peroxyacetals 33 and electron-rich kenes results in the formation of functionalized 3,5-disubstituted 1,2-dioxolanes through the formation of a peroxycarbenium ion, which is attacked by the nucleophi (Scheme 14) [105]. The interaction of silylperoxyacetals 35 with alkenes 36 promoted by SnCl4 leads in the formation of substituted 1,2-dioxolanes 37. This process proceeds through the fo mation of the trimethylsilyl peroxycarbenium ion (Scheme 15) [82, 106,107]. It was foun that 1,2-dioxolanes 37a and 37b have a high antimalarial activity against P. falciparu [108]. A and Path B, including the ionization of both C-O and C-OO bonds [104]. The SnCl4 or TiCl4-mediated reaction between peroxyacetals 33 and electron-rich a kenes results in the formation of functionalized 3,5-disubstituted 1,2-dioxolanes 3 through the formation of a peroxycarbenium ion, which is attacked by the nucleophil (Scheme 14) [105]. The interaction of silylperoxyacetals 35 with alkenes 36 promoted by SnCl4 leads in the formation of substituted 1,2-dioxolanes 37. This process proceeds through the fo mation of the trimethylsilyl peroxycarbenium ion (Scheme 15) [82,106,107]. It was foun that 1,2-dioxolanes 37a and 37b have a high antimalarial activity against P. falciparu [108]. Natural compounds with antitumor activity, such as stereoisomers of plakinic acids 47a,b, were synthesized from peroxide 44 in three steps (Scheme 18). The key 1,2-dioxolane 46 in this sequence was synthesized from α-alkoxydioxolane 44 and O,S-ketene acetal 45 promoted by TiCl4 in 82% yield (Scheme 18). Both isomers of acid 47a,b were isolated in individual form [111]. Also it was found that plakinic acids 47 inhibit the growth of the fungi Saccharomyces cerevisiae and Penicillium atrounenetum [39].

Scheme 18. Synthesis of plakinic acid A 47a,b.
It was found that the type of peroxidation product of allylic alcohols containing a lactam ring 48 depends on the amount of Lewis acid. Thus, peroxidation of alcohol 48 with the use of 0.9 eq. of SnCl4 leads to the formation of both mono-and diperoxides 49 and 50. Increasing the amount of acid to 2.5 eq. with respect to 48 leads to the formation of epoxyalkyl peroxide 51 (Scheme 19) [112]. Anchimeric assistance of the hydroxyl group facilitates the addition of tert-butyl hydroperoxide to the double bond. Under the action of SnCl4, through the formation of a carbocation, the nucleophilic substitution of the hydroxyl group for tert-butyl peroxide occurs. It was found that the type of peroxidation product of allylic alcohols containing a lactam ring 48 depends on the amount of Lewis acid. Thus, peroxidation of alcohol 48 with the use of 0.9 eq. of SnCl 4 leads to the formation of both mono-and diperoxides 49 and 50. Increasing the amount of acid to 2.5 eq. with respect to 48 leads to the formation of epoxyalkyl peroxide 51 (Scheme 19) [112]. Anchimeric assistance of the hydroxyl group facilitates the addition of tert-butyl hydroperoxide to the double bond. Under the action of SnCl 4 , through the formation of a carbocation, the nucleophilic substitution of the hydroxyl group for tert-butyl peroxide occurs.
Catalysis of the peroxidation reaction of acetylacetone 52 by strong protic acids (H 2 SO 4 , HClO 4 , HCl) leads to a complex mixture of cyclic and acyclic peroxides. However, with the use of SnCl 2 ·2H 2 O and AlCl 3 ·6H 2 O as a catalyst, the peroxidation of acetylacetone 52 proceeds selectively with the formation of dihydroperoxo-1,2-dioxolane 53 (Scheme 20) [113,114]. The reaction was carried out at a room temperature with 5-25 molar excess of 30% aq. solution of H 2 O 2 and 10-20 mol% LA with respect to 52.
The SnCl 2 ·2H 2 O/H 2 O 2 system was used in the peroxidation of 2,5-heptadione 54. In this case, the reaction proceeds with the formation of hydroxyhydroperoxy 1,2-dioxane 55, but in a low yield of target compound of 15% (Scheme 21) [115]. The reaction was carried out at a room temperature with 5-fold molar excess of 50% aq. solution of H 2 O 2 and 20 mol. % SnCl 2 ·2H 2 O with respect to 54.

Peroxidation of Ketones and Aldehydes in the Presence of MeReO 3
The proposed mechanism of ketone peroxidation by the H 2 O 2 /MeReO 3 system is based on the coordination of hydrogen peroxide with rhenium, which acts as a Lewis acid with the formation of peroxocomplex 61 (Scheme 23) [116][117][118]. The resulting peroxocomplex 61 interacts with a carbonyl compound with the transfer of a peroxo group. Furthermore, MeReO 3 can react with a carbonyl group, as a Lewis acid to activate the carbonyl carbon atom. Scheme 21. Synthesis of hydroxyhydroperoxy 1,2-dioxane 55 from 2,5-heptadione 54.

Sc(OTf)3, Yb(OTf)3, InCl3 and In(OTf)3 in the Synthesis of Organic Peroxides
In     The interaction of Donor-Acceptor cyclopropane 88 with t BuOOH and N-halosuccinimides 89, which acts as a source of halogen, provides haloperoxides 90 in moderate to good yields (Scheme 31) [92].
It is noteworthy that the interaction of cyclopropanes 91 containing one acceptor substituent with tert-butyl hydroperoxide under the action of 0.5 eq. Sc(OTf) 3 leads to bis-tert-butyl peroxides 92 in 56-72% yields (Scheme 32) [92]. The interaction of Donor-Acceptor cyclopropane 88 with t BuOOH and N-halosuccinimides 89, which acts as a source of halogen, provides haloperoxides 90 in moderate to good yields (Scheme 31) [92]. The interaction of Donor-Acceptor cyclopropane 88 with t BuOOH and N-halosuccinimides 89, which acts as a source of halogen, provides haloperoxides 90 in moderate to good yields (Scheme 31) [92].  It is noteworthy that the interaction of cyclopropanes 91 containing one acceptor substituent with tert-butyl hydroperoxide under the action of 0.5 eq. Sc(OTf)3 leads to bis-tertbutyl peroxides 92 in 56-72% yields (Scheme 32) [92]. The use of the H2O2 or TBHP/Sc(OTf)3 system for ring opening of donor-acceptor aziridines 92 leads to α-sulfanilamido peroxides 93 and 94 in good yield (Scheme 33) [126]. The reaction can be scaled up to the grams in 70% yield.  The use of the H 2 O 2 or TBHP/Sc(OTf) 3 system for ring opening of donor-acceptor aziridines 92 leads to α-sulfanilamido peroxides 93 and 94 in good yield (Scheme 33) [126]. The reaction can be scaled up to the grams in 70% yield. It is noteworthy that the interaction of cyclopropanes 91 containing one acceptor substituent with tert-butyl hydroperoxide under the action of 0.5 eq. Sc(OTf)3 leads to bis-tertbutyl peroxides 92 in 56-72% yields (Scheme 32) [92]. The use of the H2O2 or TBHP/Sc(OTf)3 system for ring opening of donor-acceptor aziridines 92 leads to α-sulfanilamido peroxides 93 and 94 in good yield (Scheme 33) [126]. The reaction can be scaled up to the grams in 70% yield.  Hydroperoxyoxetane 98 rearranged into endoperoxide 99 in 12% yield and exoperoxide 100 in 33% yield under the action of Yb(OTf) 3 in methylene chloride (Scheme 35) [74].
The use of catalytic amounts of Sc(OTf) 3 or InCl 3 in the reaction of endoperoxyacetals 101 with allyltrimethylsilane (AllylTMS) and its derivatives (Nu-TMS) makes it possible to obtain 3,5-disubstituted-1,2-dioxolanes 102 and 103 by the Sakurai reaction. Sc(OTf) 3 or InCl 3 allow the reaction to be carried out under milder conditions than when using SnCl 4 and TiCl 4 (Scheme 36) [128,129]. The use of catalytic amounts of Sc(OTf)3 or InCl3 in the reaction of endoperoxyacetals 101 with allyltrimethylsilane (AllylTMS) and its derivatives (Nu-TMS) makes it possible to obtain 3,5-disubstituted-1,2-dioxolanes 102 and 103 by the Sakurai reaction. Sc(OTf)3 or InCl3 allow the reaction to be carried out under milder conditions than when using SnCl4 and TiCl4 (Scheme 36) [128,129]. The use of catalytic amounts of Sc(OTf)3 or InCl3 in the reaction of endoperoxyacetals 101 with allyltrimethylsilane (AllylTMS) and its derivatives (Nu-TMS) makes it possible to obtain 3,5-disubstituted-1,2-dioxolanes 102 and 103 by the Sakurai reaction. Sc(OTf)3 or InCl3 allow the reaction to be carried out under milder conditions than when using SnCl4 and TiCl4 (Scheme 36) [128,129].

Mercury Salts in the Synthesis of Peroxides
In a process known as peroxymercuration, alkyl peroxides D, E can be prepared from alkenes A and alkyl hydroperoxide B in the presence of a suitable mercury (II) salt (Scheme 38). In this case, mercury salts act as a mild electrophilic reagent. The interaction of mercury (II) salt with an alkene leads to cationic species, which reacts with alkyl hydroperoxide to form mercurylalkyl peroxides C. The obtained mercurylalkyl peroxides C can be demercurated using sodium borohydride or by bromonolysis. Both peroxymercuration and demercuration occur rapidly under mild conditions. Cyclic peroxides such as spiro 1,2,4-trioxepanes 106 were obtained from hydroperoxides 104 and ketones 105 by using Indium (III) triflate as a catalyst (Scheme 37) [130].

Mercury Salts in the Synthesis of Peroxides
In a process known as peroxymercuration, alkyl peroxides D, E can be prepared from alkenes A and alkyl hydroperoxide B in the presence of a suitable mercury (II) salt (Scheme 38). In this case, mercury salts act as a mild electrophilic reagent. The interaction of mercury (II) salt with an alkene leads to cationic species, which reacts with alkyl hydroperoxide to form mercurylalkyl peroxides C. The obtained mercurylalkyl peroxides C can be demercurated using sodium borohydride or by bromonolysis. Both peroxymercuration and demercuration occur rapidly under mild conditions. Bloodworth A.J. demonstrated a two-stage approach to halogeno-alkyl peroxides 108, 109 (Scheme 39) [131]. At the first stage, peroxymercuration of such unsaturated ketones 107 was carried out with the use of t BuOOH/Hg(OAc)2 system then demercuration of peroxymercurated product afforded with the formation of target peroxides 108, 109 in 32-84% and 45-79% yields, respectively.

Mercury Salts in the Synthesis of Peroxides
In a process known as peroxymercuration, alkyl peroxides D, E can be prepared from alkenes A and alkyl hydroperoxide B in the presence of a suitable mercury (II) salt (Scheme 38). In this case, mercury salts act as a mild electrophilic reagent. The interaction of mercury (II) salt with an alkene leads to cationic species, which reacts with alkyl hydroperoxide to form mercurylalkyl peroxides C. The obtained mercurylalkyl peroxides C can be demercurated using sodium borohydride or by bromonolysis. Both peroxymercuration and demercuration occur rapidly under mild conditions. Scheme 38. Synthesis of acyclic peroxides D and E.

Mercury Salts in the Synthesis of Peroxides
In a process known as peroxymercuration, alkyl peroxides D, E can be prepared from alkenes A and alkyl hydroperoxide B in the presence of a suitable mercury (II) salt (Scheme 38). In this case, mercury salts act as a mild electrophilic reagent. The interaction of mercury (II) salt with an alkene leads to cationic species, which reacts with alkyl hydroperoxide to form mercurylalkyl peroxides C. The obtained mercurylalkyl peroxides C can be demercurated using sodium borohydride or by bromonolysis. Both peroxymercuration and demercuration occur rapidly under mild conditions.

Scheme 38. Synthesis of acyclic peroxides D and E.
Bloodworth A.J. demonstrated a two-stage approach to halogeno-alkyl peroxides 108, 109 (Scheme 39) [131]. At the first stage, peroxymercuration of such unsaturated ketones 107 was carried out with the use of t BuOOH/Hg(OAc)2 system then demercuration of peroxymercurated product afforded with the formation of target peroxides 108, 109 in 32-84% and 45-79% yields, respectively. Phenyl cyclopropane 110 undergoes ring opening under the action of the t BuOOH/Hg(CF3COO)2 system with the formation of mercurylalkyl peroxide 111 in a 47% yield. Further reduction 111 leads to alkyl peroxide 112 in a 19% yield [132]. yield. Further reduction 111 leads to alkyl peroxide 112 in a 19% yield [132]. T system was applied for the synthesis of peroxide 115 from styrene 113 (Scheme 4 Adam W. et al. presented a method for the regioselective synthesis of bicyclic peroxide 120 by the peroxymercuration of non-conjugated cyclic dienes 119 (Scheme 42) [134]. Organo-mercury trifluoroacetates were separated by dissolving their mixture in benzene. The peroxide 120 did not dissolve in benzene and precipitated as white crystals. Reductive demercuration of 120 proceeded under mild conditions with the formation of bridged 1,2-dioxepane 124. Bromination of peroxide 120 followed by demercuration led to dibromocycloperoxide 123. The peroxymercuration and demercuration of 1,4-cyclooctadiene 125 proceeded in a similar way with the formation of peroxides 126 and 127 (Scheme 43). Peroxides 126 and 127 were obtained in 38% and 28% yield respectively [135]. The peroxymercuration and demercuration of 1,4-cyclooctadiene 125 proceeded in a similar way with the formation of peroxides 126 and 127 (Scheme 43). Peroxides 126 and 127 were obtained in 38% and 28% yield respectively [135]. The peroxymercuration and demercuration of 1,4-cyclooctadiene 125 proceeded in a similar way with the formation of peroxides 126 and 127 (Scheme 43). Peroxides 126 and 127 were obtained in 38% and 28% yield respectively [135]. The peroxymercuration and demercuration of 1,4-cyclooctadiene 125 proceeded in a similar way with the formation of peroxides 126 and 127 (Scheme 43). Peroxides 126 and 127 were obtained in 38% and 28% yield respectively [135]. Direct demercuration of peroxides 134 is not possible because the hydroperoxide group is reduced under the action of sodium borohydride. However, the subsequent protection of hydroperoxy group by 2-methoxypropene, borohydride reduction, and deprotection of peroxy group led to peroxides 135 in 30-54% yield (Scheme 46) [138]. Hydroperoxycyclopropanes 136 under the action of Hg(OAc)2 in the presence of perchloric acid were transformed into 1,2-dioxolanes 137, the bromodemercuration of which led to 1,2-dioxolanes 138 (Scheme 47) [139]. Cyclic peroxides were isolated by column chromatography on SiO2 at 0 °C. The target peroxides 138 were obtained in 52-60% yield. The first example of the synthesis of diastereomeric saturated analogs of plakinic acids A, C and D 142 was described in 1996 by Bloodworth A. J. and colleagues [140]. Peroxides 142 were obtained in four stages from ketones 139. At one stage of this synthetic route, the peroxymercuration of esters 140 was used with the formation of 1,2-dioxolanes Direct demercuration of peroxides 134 is not possible because the hydroperoxide group is reduced under the action of sodium borohydride. However, the subsequent protection of hydroperoxy group by 2-methoxypropene, borohydride reduction, and deprotection of peroxy group led to peroxides 135 in 30-54% yield (Scheme 46) [138]. Direct demercuration of peroxides 134 is not possible because the hydroperoxide group is reduced under the action of sodium borohydride. However, the subsequent protection of hydroperoxy group by 2-methoxypropene, borohydride reduction, and deprotection of peroxy group led to peroxides 135 in 30-54% yield (Scheme 46) [138]. Hydroperoxycyclopropanes 136 under the action of Hg(OAc)2 in the presence of perchloric acid were transformed into 1,2-dioxolanes 137, the bromodemercuration of which led to 1,2-dioxolanes 138 (Scheme 47) [139]. Cyclic peroxides were isolated by column chromatography on SiO2 at 0 °C. The target peroxides 138 were obtained in 52-60% yield. The first example of the synthesis of diastereomeric saturated analogs of plakinic acids A, C and D 142 was described in 1996 by Bloodworth A. J. and colleagues [140]. Peroxides 142 were obtained in four stages from ketones 139. At one stage of this synthetic route, the peroxymercuration of esters 140 was used with the formation of 1,2-dioxolanes Hydroperoxycyclopropanes 136 under the action of Hg(OAc) 2 in the presence of perchloric acid were transformed into 1,2-dioxolanes 137, the bromodemercuration of which led to 1,2-dioxolanes 138 (Scheme 47) [139]. Cyclic peroxides were isolated by column chromatography on SiO 2 at 0 • C. The target peroxides 138 were obtained in 52-60% yield. Hydroperoxymercuration of alkenes 130 with the use of aq. H2O2 proceeds with the formation of hydroperoxide 131 and alcohol 132. The resulting peroxides 131 were obtained in yield up to 86% (Scheme 45) [137,138]. Direct demercuration of peroxides 134 is not possible because the hydroperoxide group is reduced under the action of sodium borohydride. However, the subsequent protection of hydroperoxy group by 2-methoxypropene, borohydride reduction, and deprotection of peroxy group led to peroxides 135 in 30-54% yield (Scheme 46) [138]. Hydroperoxycyclopropanes 136 under the action of Hg(OAc)2 in the presence of perchloric acid were transformed into 1,2-dioxolanes 137, the bromodemercuration of which led to 1,2-dioxolanes 138 (Scheme 47) [139]. Cyclic peroxides were isolated by column chromatography on SiO2 at 0 °C. The target peroxides 138 were obtained in 52-60% yield. The first example of the synthesis of diastereomeric saturated analogs of plakinic acids A, C and D 142 was described in 1996 by Bloodworth A. J. and colleagues [140]. Peroxides 142 were obtained in four stages from ketones 139. At one stage of this synthetic route, the peroxymercuration of esters 140 was used with the formation of 1,2-dioxolanes Scheme 47. Synthesis of 1,2-dioxolane 138.
The first example of the synthesis of diastereomeric saturated analogs of plakinic acids A, C and D 142 was described in 1996 by Bloodworth A. J. and colleagues [140]. Peroxides 142 were obtained in four stages from ketones 139. At one stage of this synthetic route, the peroxymercuration of esters 140 was used with the formation of 1,2-dioxolanes 141. Saponification of which led to 1,2-dioxolanes 142 with a free carboxyl group (Scheme 48).

Other Metal-Based Lewis Acids
Zhang and Li reported the synthesis of β-hydroperoxy alcohols 144 by the reaction of epoxides 143 with H2O2, catalyzed by silica-supported antimony trichloride (SbCl3/SiO2) (Scheme 49) [141]. Interestingly, the authors demonstrated that SbCl3/SiO2 is more active than unsupported-SbCl3. Under the best conditions, a range of β-hydroxy hydroperoxides 144 was obtained in 72-86% isolated yields.

Other Metal-Based Lewis Acids
Zhang and Li reported the synthesis of β-hydroperoxy alcohols 144 by the reaction of epoxides 143 with H 2 O 2 , catalyzed by silica-supported antimony trichloride (SbCl 3 /SiO 2 ) (Scheme 49) [141]. Interestingly, the authors demonstrated that SbCl 3 /SiO 2 is more active than unsupported-SbCl 3 . Under the best conditions, a range of β-hydroxy hydroperoxides 144 was obtained in 72-86% isolated yields.

Other Metal-Based Lewis Acids
Zhang and Li reported the synthesis of β-hydroperoxy alcohols 144 by the reaction of epoxides 143 with H2O2, catalyzed by silica-supported antimony trichloride (SbCl3/SiO2) (Scheme 49) [141]. Interestingly, the authors demonstrated that SbCl3/SiO2 is more active than unsupported-SbCl3. Under the best conditions, a range of β-hydroxy hydroperoxides 144 was obtained in 72-86% isolated yields.  Lewis acids such as SrCl3·6H2O [142], cerium ammonium nitrate (CAN) [143], Bi(OTf)3 [144], and AlCl3·6H2O [114] are effective catalysts for the synthesis of bishydroperoxides 149-152 from cyclic and acyclic ketones and aldehydes 148. Peroxidation proceeds under mild conditions at room temperature with the formation of target peroxides in a good yield. All Lewis acids demonstrated approximately equal efficiency in the peroxidation reaction. The main advantage of these methods is the use of Lewis acids in catalytic amounts and an inexpensive 30% aqueous H2O2 (Scheme 51 Lewis acids such as SrCl3·6H2O [142], cerium ammonium nitrate (CAN) [143], Bi(OTf)3 [144], and AlCl3·6H2O [114] are effective catalysts for the synthesis of bishydroperoxides 149-152 from cyclic and acyclic ketones and aldehydes 148. Peroxidation proceeds under mild conditions at room temperature with the formation of target peroxides in a good yield. All Lewis acids demonstrated approximately equal efficiency in the peroxidation reaction. The main advantage of these methods is the use of Lewis acids in catalytic amounts and an inexpensive 30% aqueous H2O2 (Scheme 51 Also, bismuth (III) triflate is a good catalyst for the synthesis of 1,2,4,5-tetraoxanes 155. In this case, the target peroxides 152 were obtained in a yield up to 94%. Synthetic 1,2,4,5-tetraoxane 155a exhibits high activity against helminths Fasciola hepatica and in rats in vivo (Scheme 52) [144,145]. Also, bismuth (III) triflate is a good catalyst for the synthesis of 1,2,4,5-tetraoxanes 155. In this case, the target peroxides 152 were obtained in a yield up to 94%. Synthetic 1,2,4,5-tetraoxane 155a exhibits high activity against helminths Fasciola hepatica and in rats in vivo (Scheme 52) [144,145]. The palladium-catalyzed cyclization of unsaturated hydroperoxides 158 afforded with the formation of 1,2-dioxanes 159 (Scheme 54) [147]. The reaction was carried out in toluene, 1,4-dioxane, or 1,2-dichloroethane at 80 °C for 3h. To oxidize Pd(0), which is formed in the catalytic cycle, p-benzoquinone (BQ) or silver carbonate were used. The interaction of 1,2,4-trioxolanes (ozonides) 156 with Lewis acid SbCl 5 in methylene chloride led to 1,2,4,5-tetraoxanes 157 (Scheme 53) [146]. Also, bismuth (III) triflate is a good catalyst for the synthesis of 1,2,4,5-tetraoxanes 155. In this case, the target peroxides 152 were obtained in a yield up to 94%. Synthetic 1,2,4,5-tetraoxane 155a exhibits high activity against helminths Fasciola hepatica and in rats in vivo (Scheme 52) [144,145]. The palladium-catalyzed cyclization of unsaturated hydroperoxides 158 afforded with the formation of 1,2-dioxanes 159 (Scheme 54) [147]. The reaction was carried out in toluene, 1,4-dioxane, or 1,2-dichloroethane at 80 °C for 3h. To oxidize Pd(0), which is formed in the catalytic cycle, p-benzoquinone (BQ) or silver carbonate were used. The palladium-catalyzed cyclization of unsaturated hydroperoxides 158 afforded with the formation of 1,2-dioxanes 159 (Scheme 54) [147]. The reaction was carried out in toluene, 1,4-dioxane, or 1,2-dichloroethane at 80 • C for 3h. To oxidize Pd(0), which is formed in the catalytic cycle, p-benzoquinone (BQ) or silver carbonate were used. Also, bismuth (III) triflate is a good catalyst for the synthesis of 1,2,4,5-tetraoxanes 155. In this case, the target peroxides 152 were obtained in a yield up to 94%. Synthetic 1,2,4,5-tetraoxane 155a exhibits high activity against helminths Fasciola hepatica and in rats in vivo (Scheme 52) [144,145]. The palladium-catalyzed cyclization of unsaturated hydroperoxides 158 afforded with the formation of 1,2-dioxanes 159 (Scheme 54) [147]. The reaction was carried out in toluene, 1,4-dioxane, or 1,2-dichloroethane at 80 °C for 3h. To oxidize Pd(0), which is formed in the catalytic cycle, p-benzoquinone (BQ) or silver carbonate were used. Such a Lewis acid as Cu(OTf)2 turned out to be the most effective catalyst for the synthesis of peroxides 162 by the ring opening reaction of activated aziridines 160 under the action of various hydroperoxides 161. It was found that electron-neutral or halogenated substrates 160 provide better results in comparison with substrates containing electron-withdrawing substituents in an aromatic ring (Scheme 56) [126]. Such a Lewis acid as Cu(OTf) 2 turned out to be the most effective catalyst for the synthesis of peroxides 162 by the ring opening reaction of activated aziridines 160 under the action of various hydroperoxides 161. It was found that electron-neutral or halogenated substrates 160 provide better results in comparison with substrates containing electronwithdrawing substituents in an aromatic ring (Scheme 56) [126].

Application of BF 3 ·Et 2 O in the Synthesis of Organic Peroxides
The first mentions of the formation of peroxides under the action of boron trifluoride goes back to the 1950s. A US patent 2,630,456 [148] from 1953 describes a selective method for producing tert-butyl hydroperoxide 164 from the corresponding alcohol 163 [149]. The reaction was carried out at room temperature using an equimolar amount of a 50% aqueous solution of hydrogen peroxide with 0.3 eq. of boron trifluoride etherate (Scheme 57). Since BF 3 can form BF 3 ·H 2 O complex [150][151][152][153][154][155], this makes it possible to use BF 3 ·Et 2 O in the presence of water.

Application of BF3·Et2O in the Synthesis of Organic Peroxides
The first mentions of the formation of peroxides under the action of boron trifluoride goes back to the 1950s. A US patent 2,630,456 [148] from 1953 describes a selective method for producing tert-butyl hydroperoxide 164 from the corresponding alcohol 163 [149]. The reaction was carried out at room temperature using an equimolar amount of a 50% aque ous solution of hydrogen peroxide with 0.3 eq. of boron trifluoride etherate (Scheme 57) Since BF3 can form BF3·H2O complex [150][151][152][153][154][155], this makes it possible to use BF3·Et2O in the presence of water.   The reaction of vinyl esters 167 and hydroperoxides 168 in the presence of gaseous boron trifluoride leads to the formation of monoperoxyketals 169. The reaction was carried out in benzene or hexane at temperatures from 0 to 30 °C (Scheme 59) [157]. The reaction proceeds within 5-10 min with a yield of 80-96%. This method is the first way to obtain monoperoxyacetals in high yields. The reaction of vinyl esters 167 and hydroperoxides 168 in the presence of gaseous boron trifluoride leads to the formation of monoperoxyketals 169. The reaction was carried out in benzene or hexane at temperatures from 0 to 30 • C (Scheme 59) [157]. The reaction proceeds within 5-10 min with a yield of 80-96%. This method is the first way to obtain monoperoxyacetals in high yields. The reaction of vinyl esters 167 and hydroperoxides 168 in the presence of gaseous boron trifluoride leads to the formation of monoperoxyketals 169. The reaction was carried out in benzene or hexane at temperatures from 0 to 30 °C (Scheme 59) [157]. The reaction proceeds within 5-10 min with a yield of 80-96%. This method is the first way to obtain monoperoxyacetals in high yields. The synthesis of alkyl peroxides 171 was carried out by the reaction of tertiary alkyltrichloroacetimides 170 with tert-butyl hydroperoxide in the presence of boron trifluoride etherate (Scheme 60) [158]. A wide range of bishydroperoxides 175 was obtained from acetals 173, enol ethers 174 and hydrogen peroxide in the presence of boron trifluoride etherate (Scheme 61) [159,160]. The developed method allows one to obtain peroxides of various structures. The advantages of these reactions are the rapidity and ease of its implementation, and among the disadvantages can be noted the formation of by-products, as well as the impossibility of synthesizing bishydroperoxides from acetals or enol ethers obtained from aryl-substituted ketones. of these reactions are the rapidity and ease of its implementation, and among the disadvantages can be noted the formation of by-products, as well as the impossibility of synthesizing bishydroperoxides from acetals or enol ethers obtained from aryl-substituted ketones.
A wide range of bishydroperoxides 175 was obtained from acetals 173, enol ethers 174 and hydrogen peroxide in the presence of boron trifluoride etherate (Scheme 61) [159,160]. The developed method allows one to obtain peroxides of various structures. The advantages of these reactions are the rapidity and ease of its implementation, and among the disadvantages can be noted the formation of by-products, as well as the impossibility of synthesizing bishydroperoxides from acetals or enol ethers obtained from aryl-substituted ketones. The possibility to obtain geminal bis(tert-butyl)peroxides 178 of both cyclic and acyclic structures with a yield of 13% to 89%, respectively, was described from acetals 176 and enol ethers 177 (Scheme 63) [161]. The reaction of the enol esters 177 with tert-butyl hydroperoxide, catalyzed by boron trifluoride etherate, is a general approach for the preparation of geminal bishydroperoxides. 1,2-Dioxane 180 was obtained by the reaction of the corresponding acetal 179 with urea hydrogen peroxide, catalyzed by boron trifluoride etherate (Scheme 64) [162]. Under these conditions, only one of the two methoxyl groups is exchanged for the hydroperoxide one, and the intermediate hydroperoxyketal undergoes intramolecular cyclization (according to Michael) due to the attack of the hydroperoxide group on the double bond activated by the nitro group with the formation of 1,2-dioxane in 51% yield. The possibility to obtain geminal bis(tert-butyl)peroxides 178 of both cyclic and acyclic structures with a yield of 13% to 89%, respectively, was described from acetals 176 and enol ethers 177 (Scheme 63) [161]. The reaction of the enol esters 177 with tert-butyl hydroperoxide, catalyzed by boron trifluoride etherate, is a general approach for the preparation of geminal bishydroperoxides. The possibility to obtain geminal bis(tert-butyl)peroxides 178 of both cyclic and acyclic structures with a yield of 13% to 89%, respectively, was described from acetals 176 and enol ethers 177 (Scheme 63) [161]. The reaction of the enol esters 177 with tert-butyl hydroperoxide, catalyzed by boron trifluoride etherate, is a general approach for the preparation of geminal bishydroperoxides. 1,2-Dioxane 180 was obtained by the reaction of the corresponding acetal 179 with urea hydrogen peroxide, catalyzed by boron trifluoride etherate (Scheme 64) [162]. Under these conditions, only one of the two methoxyl groups is exchanged for the hydroperoxide one, and the intermediate hydroperoxyketal undergoes intramolecular cyclization (according to Michael) due to the attack of the hydroperoxide group on the double bond activated by the nitro group with the formation of 1,2-dioxane in 51% yield. 1,2-Dioxane 180 was obtained by the reaction of the corresponding acetal 179 with urea hydrogen peroxide, catalyzed by boron trifluoride etherate (Scheme 64) [162]. Under these conditions, only one of the two methoxyl groups is exchanged for the hydroperoxide one, and the intermediate hydroperoxyketal undergoes intramolecular cyclization (according to Michael) due to the attack of the hydroperoxide group on the double bond activated by the nitro group with the formation of 1,2-dioxane in 51% yield. However, when NO2 was replaced by C(O)OEt, the reaction proceeded with the formation of bisperoxide 182 (Scheme 65) [163]. This is probably due to the fact that the ester group has lower electron-withdrawing properties. However, when NO 2 was replaced by C(O)OEt, the reaction proceeded with the formation of bisperoxide 182 (Scheme 65) [163]. This is probably due to the fact that the ester group has lower electron-withdrawing properties.      Presumably, the reaction proceeds along the following route: the first stage of the reaction involves the opening of the ozonide cycle in 188 under the action of BF3·Et2O with Presumably, the reaction proceeds along the following route: the first stage of the reaction involves the opening of the ozonide cycle in 188 under the action of BF 3 ·Et 2 O with the formation of a BF 3 -coordinated intermediate A, containing a peroxide fragment. The attack of intermediate A at the alkene 189 is accompanied by the formation of two intermediates, B and C, which, in turn, leads to ring closure and gives 1,2-dioxolane. However, the rate of ring closure is much slower than the rotation of the C-C bond, so the formation of four isomeric products occurs. The mechanism in Scheme 68 illustrates that the ratio of (190d + 190e) to (190f + 190g) corresponds to the ratio of the two approaches of BF 3 -coordinated intermediate A to alkene.  Also, boron trifluoride etherate is efficient for the synthesis of 1,2,4,5-tetraoxanes 201 from gem-bisperoxides 199 and orthoformates 200 (Scheme 72) [170]. The trans-isomer 201 was the major product in all cases as determined by NMR, while the cis-isomer was found only in trace amounts. The reaction was carried out in dichloromethane at room temperature. This approach was the first method for the preparation of tetraoxanes cis-201 and trans-201 with an alkoxy substituent. In the study on the synthesis of pharmacologically important endoperoxides, peroxide 204 was synthesized from substituted aldehydes 202; boron trifluoride etherate was used as a catalyst in this reaction. Condensation of peroxide 203 with betulin aldehydes 202 in the presence of BF3·Et2O led to the assembly of peroxides 204. The yield of the target peroxide was low, and the resulting diastereoisomers could not be separated. Unfortunately, mixtures of isomers did not show significant anticancer activity (Scheme 73) [171]. Also, boron trifluoride etherate is efficient for the synthesis of 1,2,4,5-tetraoxanes 201 from gem-bisperoxides 199 and orthoformates 200 (Scheme 72) [170]. The trans-isomer 201 was the major product in all cases as determined by NMR, while the cis-isomer was found only in trace amounts. The reaction was carried out in dichloromethane at room temperature. This approach was the first method for the preparation of tetraoxanes cis-201 and trans-201 with an alkoxy substituent. In the study on the synthesis of pharmacologically important endoperoxides, peroxide 204 was synthesized from substituted aldehydes 202; boron trifluoride etherate was used as a catalyst in this reaction. Condensation of peroxide 203 with betulin aldehydes 202 in the presence of BF3·Et2O led to the assembly of peroxides 204. The yield of the target peroxide was low, and the resulting diastereoisomers could not be separated. Unfortunately, mixtures of isomers did not show significant anticancer activity (Scheme 73) [171]. Also, boron trifluoride etherate is efficient for the synthesis of 1,2,4,5-tetraoxanes 201 from gem-bisperoxides 199 and orthoformates 200 (Scheme 72) [170]. The trans-isomer 201 was the major product in all cases as determined by NMR, while the cis-isomer was found only in trace amounts. The reaction was carried out in dichloromethane at room temperature. This approach was the first method for the preparation of tetraoxanes cis-201 and trans-201 with an alkoxy substituent. Also, boron trifluoride etherate is efficient for the synthesis of 1,2,4,5-tetraoxanes 201 from gem-bisperoxides 199 and orthoformates 200 (Scheme 72) [170]. The trans-isomer 201 was the major product in all cases as determined by NMR, while the cis-isomer was found only in trace amounts. The reaction was carried out in dichloromethane at room temperature. This approach was the first method for the preparation of tetraoxanes cis-201 and trans-201 with an alkoxy substituent. In the study on the synthesis of pharmacologically important endoperoxides, peroxide 204 was synthesized from substituted aldehydes 202; boron trifluoride etherate was used as a catalyst in this reaction. Condensation of peroxide 203 with betulin aldehydes 202 in the presence of BF3·Et2O led to the assembly of peroxides 204. The yield of the target peroxide was low, and the resulting diastereoisomers could not be separated. Unfortunately, mixtures of isomers did not show significant anticancer activity (Scheme 73) [171]. Cyclic peroxides 207 can be obtained from hydroperoxides 205 and ketones 206 in the presence of boron trifluoride etherate in up to 17% yield (Scheme 74) [130]. The yield of the target peroxides 207 was in the same range as when using In(OTf)3 as a catalyst (see Scheme 33). However, BF3·Et2O is less expensive than In(OTf)3.

Scheme 74. Synthesis of macrocyclic peroxides 207.
The reaction of 1,1′-bishydroperoxy(cycloalkyl)peroxides 209 with ketals 208 in the presence of BF3·Et2O afforded 1,2,4,5,7,8-hexaoxonanes 210 in up to 94% yields (Scheme 75) [172]. This approach is convenient and simple for the synthesis of 1,2,4,5,7,8-hexaoxonanes, which significantly expands the structural diversity of these compounds and, in most cases, allows them to be synthesized in high yield. Cyclic peroxides 207 can be obtained from hydroperoxides 205 and ketones 206 in the presence of boron trifluoride etherate in up to 17% yield (Scheme 74) [130]. The yield of the target peroxides 207 was in the same range as when using In(OTf) 3 as a catalyst (see Scheme 33). However, BF 3 ·Et 2 O is less expensive than In(OTf) 3 . Cyclic peroxides 207 can be obtained from hydroperoxides 205 and ketones 206 in the presence of boron trifluoride etherate in up to 17% yield (Scheme 74) [130]. The yield of the target peroxides 207 was in the same range as when using In(OTf)3 as a catalyst (see Scheme 33). However, BF3·Et2O is less expensive than In(OTf)3.
Tricyclic monoperoxides 227 were obtained by the peroxidation of β,δ -triketones 226 with the H 2 O 2 /BF 3 ·Et 2 O system (Scheme 82) [81,86]. Peroxidation was carried out under mild conditions at room temperature for 1 h. Despite the presence of three carbonyl groups, peroxidation proceeded selectively with the formation of cyclic product 227. The yield of target peroxides 227 was 48-93%. It was found that the tricyclic monoperoxide exhibits a high in vitro and in vivo anthelmintic activity against S. mansoni. Scheme 80. Synthesis of β-alkoxy-β-peroxylactones 223.
In continuation of studies in this direction, the BF3·Et2O/H2O2 system was applied to the γ-ketoesters 224. Peroxidation proceeded with the formation of cyclic γ-hydroperoxyγ-peroxylactones 225 in 44-83% yields (Scheme 81) [179]. Tricyclic monoperoxides 227 were obtained by the peroxidation of β,δ′-triketones 226 with the H2O2/BF3·Et2O system (Scheme 82) [81,86]. Peroxidation was carried out under mild conditions at room temperature for 1 h. Despite the presence of three carbonyl groups, peroxidation proceeded selectively with the formation of cyclic product 227. The yield of target peroxides 227 was 48-93%. It was found that the tricyclic monoperoxide exhibits a high in vitro and in vivo anthelmintic activity against S. mansoni. The first total synthesis of natural bioactive azaperoxides Verruculogen 230a and Fumitremorgin A 230b was developed in 2015 by the Baran group [180]. The final step included the catalyzed by BF3·Et2O condensation of aldehyde 229 with peroxide 228 (Scheme 83).

Iodine in the Synthesis of Organic Peroxides
Iodine in the synthesis of organic peroxides can act as both a catalyst and a reagent. The presence of iodine can activate substrates via halogen bonding (acts as Lewis acid), iodonium(I) species or formation of "hidden" HI Broensted acid [181][182][183][184][185][186][187]. The interaction of alkenes 231 with hydroperoxide in the presence of molecular iodine makes it possible to obtain vicinal iodoperoxyalkanes 232 (Scheme 84) [188]. This reaction was carried out Tricyclic monoperoxides 227 were obtained by the peroxidation of β,δ′-triketones 226 with the H2O2/BF3·Et2O system (Scheme 82) [81,86]. Peroxidation was carried out under mild conditions at room temperature for 1 h. Despite the presence of three carbonyl groups, peroxidation proceeded selectively with the formation of cyclic product 227. The yield of target peroxides 227 was 48-93%. It was found that the tricyclic monoperoxide exhibits a high in vitro and in vivo anthelmintic activity against S. mansoni. The first total synthesis of natural bioactive azaperoxides Verruculogen 230a and Fumitremorgin A 230b was developed in 2015 by the Baran group [180]. The final step included the catalyzed by BF3·Et2O condensation of aldehyde 229 with peroxide 228 (Scheme 83).

Iodine in the Synthesis of Organic Peroxides
Iodine in the synthesis of organic peroxides can act as both a catalyst and a reagent. The presence of iodine can activate substrates via halogen bonding (acts as Lewis acid), iodonium(I) species or formation of "hidden" HI Broensted acid [181][182][183][184][185][186][187]. The interaction

Iodine in the Synthesis of Organic Peroxides
Iodine in the synthesis of organic peroxides can act as both a catalyst and a reagent. The presence of iodine can activate substrates via halogen bonding (acts as Lewis acid), iodonium(I) species or formation of "hidden" HI Broensted acid [181][182][183][184][185][186][187]. The interaction of alkenes 231 with hydroperoxide in the presence of molecular iodine makes it possible to obtain vicinal iodoperoxyalkanes 232 (Scheme 84) [188]. This reaction was carried out with 0.7 eq. iodine and 4 eq. hydroperoxide in diethyl ether or dichloromethane at room temperature. Depending on the reactivity of the hydroperoxide, the reaction time was from 5 to 72 h. The mechanism of the formation of iodoperoxyalkanes and iodoalkanols is shown in Scheme 85. Presumably, the formation of iodoperoxyalkane can proceed along path A or B. Path A corresponds to the classical scheme of sequential addition of electrophilic iodine and nucleophilic hydroperoxide to the double bond. Path B is based on experimental data according to which an increase in the amount of iodine (a nucleophile competing with tert-butyl hydroperoxide) leads to an increase in the yield of 1-(tert-butylperoxy)-2-iodocyclohexane, while the expected 1,2-diiodocyclohexane is formed in trace amounts. Iodoperoxide appears to be formed by pathway B through a previously unknown process. Initially, the reaction forms 1,2-diiodocyclohexane, which is converted by iodine to intermediate Y, which contains a partially positive charge on the carbon atoms. The latter reacts with hydroperoxide. The cyclization of unsaturated hydroperoxyacetal 234 was performed using systems such as pyridine/I2 or t-BuOK/I2. The use of the latter made it possible to obtain 1,2-dioxanes 235 in a yield up to 85% (Scheme 86) [189]. The mechanism of the formation of iodoperoxyalkanes and iodoalkanols is shown in Scheme 85. Presumably, the formation of iodoperoxyalkane can proceed along path A or B. Path A corresponds to the classical scheme of sequential addition of electrophilic iodine and nucleophilic hydroperoxide to the double bond. Path B is based on experimental data according to which an increase in the amount of iodine (a nucleophile competing with tert-butyl hydroperoxide) leads to an increase in the yield of 1-(tert-butylperoxy)-2iodocyclohexane, while the expected 1,2-diiodocyclohexane is formed in trace amounts. Iodoperoxide appears to be formed by pathway B through a previously unknown process. Initially, the reaction forms 1,2-diiodocyclohexane, which is converted by iodine to intermediate Y, which contains a partially positive charge on the carbon atoms. The latter reacts with hydroperoxide. The mechanism of the formation of iodoperoxyalkanes and iodoalkanols is shown in Scheme 85. Presumably, the formation of iodoperoxyalkane can proceed along path A or B. Path A corresponds to the classical scheme of sequential addition of electrophilic iodine and nucleophilic hydroperoxide to the double bond. Path B is based on experimental data according to which an increase in the amount of iodine (a nucleophile competing with tert-butyl hydroperoxide) leads to an increase in the yield of 1-(tert-butylperoxy)-2-iodocyclohexane, while the expected 1,2-diiodocyclohexane is formed in trace amounts. Iodoperoxide appears to be formed by pathway B through a previously unknown process. Initially, the reaction forms 1,2-diiodocyclohexane, which is converted by iodine to intermediate Y, which contains a partially positive charge on the carbon atoms. The latter reacts with hydroperoxide. The cyclization of unsaturated hydroperoxyacetal 234 was performed using systems such as pyridine/I2 or t-BuOK/I2. The use of the latter made it possible to obtain 1,2-dioxanes 235 in a yield up to 85% (Scheme 86) [189]. The cyclization of unsaturated hydroperoxyacetal 234 was performed using systems such as pyridine/I 2 or t-BuOK/I 2 . The use of the latter made it possible to obtain 1,2dioxanes 235 in a yield up to 85% (Scheme 86) [189]. However, the use of the pyridine/I2 system for unsaturated hydroperoxyacetal 236 did not provide the assembly of 1,2,4-trioxane 237. The t-BuOK/I2 system, which performed well in the assembly of 1,2-dioxalane 235 (Scheme 87), led to peroxide 237, but in low yield. Cyclization 236 under the action of the KH/I2 system also proceeded in a low yield (Scheme 87) [189]. Using 30% aq. H2O2 and iodine as a catalyst, geminal bishydroperoxides 239 were obtained from cyclic and acyclic ketones 238 in a yield of 50 to 98% (Scheme 88). All geminal bishydroperoxides 239 exhibit pronounced in vitro antimicrobial and antifungal activity against B. cereus, E. coli, P. aeruginosa, S. aureus, C. albicans, and A. niger [190]. However, the use of the pyridine/I 2 system for unsaturated hydroperoxyacetal 236 did not provide the assembly of 1,2,4-trioxane 237. The t-BuOK/I 2 system, which performed well in the assembly of 1,2-dioxalane 235 (Scheme 87), led to peroxide 237, but in low yield. Cyclization 236 under the action of the KH/I 2 system also proceeded in a low yield (Scheme 87) [189]. However, the use of the pyridine/I2 system for unsaturated hydroperoxyacetal 236 did not provide the assembly of 1,2,4-trioxane 237. The t-BuOK/I2 system, which performed well in the assembly of 1,2-dioxalane 235 (Scheme 87), led to peroxide 237, but in low yield. Cyclization 236 under the action of the KH/I2 system also proceeded in a low yield (Scheme 87) [189]. Using 30% aq. H2O2 and iodine as a catalyst, geminal bishydroperoxides 239 were obtained from cyclic and acyclic ketones 238 in a yield of 50 to 98% (Scheme 88). All geminal bishydroperoxides 239 exhibit pronounced in vitro antimicrobial and antifungal activity against B. cereus, E. coli, P. aeruginosa, S. aureus, C. albicans, and A. niger [190]. Using 30% aq. H 2 O 2 and iodine as a catalyst, geminal bishydroperoxides 239 were obtained from cyclic and acyclic ketones 238 in a yield of 50 to 98% (Scheme 88). All geminal bishydroperoxides 239 exhibit pronounced in vitro antimicrobial and antifungal activity against B. cereus, E. coli, P. aeruginosa, S. aureus, C. albicans, and A. niger [190]. However, the use of the pyridine/I2 system for unsaturated hydroperoxyacetal 236 did not provide the assembly of 1,2,4-trioxane 237. The t-BuOK/I2 system, which performed well in the assembly of 1,2-dioxalane 235 (Scheme 87), led to peroxide 237, but in low yield. Cyclization 236 under the action of the KH/I2 system also proceeded in a low yield (Scheme 87) [189]. Using 30% aq. H2O2 and iodine as a catalyst, geminal bishydroperoxides 239 were obtained from cyclic and acyclic ketones 238 in a yield of 50 to 98% (Scheme 88). All geminal bishydroperoxides 239 exhibit pronounced in vitro antimicrobial and antifungal activity against B. cereus, E. coli, P. aeruginosa, S. aureus, C. albicans, and A. niger [190].
This approach was also used in the synthesis of bishydroxyperoxides 241 from acetophenone and benzaldehydes 240. Unfortunately, peroxidation of compounds containing an electron-withdrawing substituent in the ring did not lead to the target geminal bishydroxyperoxides (Scheme 89) [190]. This approach was also used in the synthesis of bishydroxyperoxides 241 from acetophenone and benzaldehydes 240. Unfortunately, peroxidation of compounds containing an electron-withdrawing substituent in the ring did not lead to the target geminal bishydroxyperoxides (Scheme 89) [190]. The action of iodine as a Lewis acid is based on its interaction with the oxygen atom of the carbonyl group of 240, which facilitates the nucleophilic attack of hydrogen peroxide on the neighboring carbon atom. Iodine then eliminates the hydroxy group from the sp 3 -carbon atom of intermediate A and the peroxycarbenium ion B is formed, which is attacked by the second hydrogen peroxide molecule to form the final product 241. The last stage of this mechanism is irreversible (Scheme 90). The action of iodine as a Lewis acid is based on its interaction with the oxygen atom of the carbonyl group of 240, which facilitates the nucleophilic attack of hydrogen peroxide on the neighboring carbon atom. Iodine then eliminates the hydroxy group from the sp 3 -carbon atom of intermediate A and the peroxycarbenium ion B is formed, which is attacked by the second hydrogen peroxide molecule to form the final product 241. The last stage of this mechanism is irreversible (Scheme 90). This approach was also used in the synthesis of bishydroxyperoxides 241 from acetophenone and benzaldehydes 240. Unfortunately, peroxidation of compounds containing an electron-withdrawing substituent in the ring did not lead to the target geminal bishydroxyperoxides (Scheme 89) [190]. The action of iodine as a Lewis acid is based on its interaction with the oxygen atom of the carbonyl group of 240, which facilitates the nucleophilic attack of hydrogen peroxide on the neighboring carbon atom. Iodine then eliminates the hydroxy group from the sp 3 -carbon atom of intermediate A and the peroxycarbenium ion B is formed, which is attacked by the second hydrogen peroxide molecule to form the final product 241. The last stage of this mechanism is irreversible (Scheme 90). The iodine-catalyzed peroxidation of carbonyl compounds 242 (acyclic and cyclic ketones and aromatic aldehydes), is a simple and effective approach to obtain geminal hydroperoxides 244 and geminal tert-butyl peroxides 246. A similar reaction in methanol led to hydroperoxyacetals 243 and tert-butylperoxyacetals 245 (Scheme 91) [90].
The previously unknown 1-hydroperoxy-1′-alkoxyperoxides 265 were synthesized in 45-64% yield by iodine-catalyzed reaction of geminal bishydroperoxides 263 with acetals 264 (Scheme 96) [193]. The nature of the solvent has a decisive influence on the yield of the target peroxides. Good results were obtained in such solvents as Et2O and THF. The formation of cyclic peroxides was not observed. 1-Hydroperoxy-1′-alkoxyperoxides 265 were readily isolated from the reaction mixture by column chromatography. Also, 1-hydroperoxy-1 -alkoxyperoxides 265 are formed by the interaction of bishydroperoxides 263 with enol ethers 266 in the presence of molecular iodine (Scheme 97) [193].
The previously unknown 1-hydroperoxy-1′-alkoxyperoxides 265 were synthesized in 45-64% yield by iodine-catalyzed reaction of geminal bishydroperoxides 263 with acetals 264 (Scheme 96) [193]. The nature of the solvent has a decisive influence on the yield of the target peroxides. Good results were obtained in such solvents as Et2O and THF. The formation of cyclic peroxides was not observed. 1-Hydroperoxy-1′-alkoxyperoxides 265 were readily isolated from the reaction mixture by column chromatography. Peroxidation of 2-allyl-1,3-diketones 267 under the action of the I2/H2O2 led to the formation of diastreoisomeric bicyclic peroxides 269 and 270 (Scheme 99) [194]. The reaction was carried out under mild conditions in dichloromethane at 20-25 °C with the use of a five-fold molar excess of H2O2 and a two-fold excess of I2 with respect to the starting diketone. It should be noted that the expected bridged tetraoxanes were not found during the peroxidation of 1,3-diketones 267. Diastereomeric iodine peroxides 269 and 270 were obtained as a mixture of diastereoisomers with a yield of 50 to 81%. The interaction of ketones 267 containing an aromatic ring adjacent to the carbonyl group with the I2/H2O2 system led to the formation of iodides 268 with a yield of 11-24%, but not to the bicyclic peroxides 269 and 270. Scheme 98. The proposed mechanism for the assembly of 1-hydroperoxy-1 -alkoxyperoxides 265.
Peroxidation of 2-allyl-1,3-diketones 267 under the action of the I 2 /H 2 O 2 led to the formation of diastreoisomeric bicyclic peroxides 269 and 270 (Scheme 99) [194]. The reaction was carried out under mild conditions in dichloromethane at 20-25 • C with the use of a five-fold molar excess of H 2 O 2 and a two-fold excess of I 2 with respect to the starting diketone. It should be noted that the expected bridged tetraoxanes were not found during the peroxidation of 1,3-diketones 267. Diastereomeric iodine peroxides 269 and 270 were obtained as a mixture of diastereoisomers with a yield of 50 to 81%. The interaction of ketones 267 containing an aromatic ring adjacent to the carbonyl group with the I 2 /H 2 O 2 system led to the formation of iodides 268 with a yield of 11-24%, but not to the bicyclic peroxides 269 and 270. of a five-fold molar excess of H2O2 and a two-fold excess of I2 with respect to the starting diketone. It should be noted that the expected bridged tetraoxanes were not found during the peroxidation of 1,3-diketones 267. Diastereomeric iodine peroxides 269 and 270 were obtained as a mixture of diastereoisomers with a yield of 50 to 81%. The interaction of ketones 267 containing an aromatic ring adjacent to the carbonyl group with the I2/H2O2 system led to the formation of iodides 268 with a yield of 11-24%, but not to the bicyclic peroxides 269 and 270. Scheme 99. Synthesis of diastereomeric bicyclic peroxides 269 and 270.
The first stage involves the interaction of iodine with a double bond to form the iodonium cation A, which undergoes cyclization to the intermediate tetrahydrofuran B, stabilized by the anomeric effect [66][67][68] (Scheme 100). Then H2O2 attacks B with the formation of iodoperoxide C, which undergoes cyclization with the formation of 269 + 270. In the case of compounds containing an aryl substituent at the carbonyl group, peroxide C is protonated with the formation of D, which undergoes Baeyer-Villiger rearrangement to form cation E, which is iodinated by HI to form 268.  [195]. This method allows for the obtaining of cyclic triperoxides in good yields from 51 to 82%. Scheme 100. The proposed mechanism for the assembly of bicyclic peroxides 269 and 270.

Synthesis of Peroxides Promoted by TMSOTf and TBDMSOTf
A convenient method has been developed for the synthesis of symmetric 1,2,4,5tetraoxanes 276 from carbonyl compounds 274 and peroxidizing agent bis(trimethylsilyl) peroxide 275 in the presence of 1 equiv. of TMSOTf. The reaction was carried out at 0 °C in acetonitrile or at −70 °C in CH2Cl2 (Scheme 102) [196]. The in vitro and in vivo studies demonstrated that these types of cyclic peroxides are active against P. falciparum [197].

Synthesis of Peroxides Promoted by TMSOTf and TBDMSOTf
A convenient method has been developed for the synthesis of symmetric 1,2,4,5tetraoxanes 276 from carbonyl compounds 274 and peroxidizing agent bis(trimethylsilyl) peroxide 275 in the presence of 1 equiv. of TMSOTf. The reaction was carried out at 0 • C in acetonitrile or at −70 • C in CH 2 Cl 2 (Scheme 102) [196]. The in vitro and in vivo studies demonstrated that these types of cyclic peroxides are active against P. falciparum [197]. Peroxidation of carbonyl compounds with the use of Me3SiOOSiMe3/TMSOTf system allows one to obtain steroidal tetraoxanes 278 (Scheme 103) [198]. The reaction was carried out at 0 °C in acetonitrile using a 1.5-fold molar excess of Me3SiOOSiMe3 and TMSOTf with respect to ketone 277. Peroxidation of carbonyl compounds with the use of Me 3 SiOOSiMe 3 /TMSOTf system allows one to obtain steroidal tetraoxanes 278 (Scheme 103) [198]. The reaction was carried out at 0 • C in acetonitrile using a 1.5-fold molar excess of Me 3 SiOOSiMe 3 and TMSOTf with respect to ketone 277.
Cyclic peroxolactones (1,2,4-trioxan-5-ones) 295 were obtained by the reaction of carbonyl compounds 293 with silyl peroxides 294 under the action of TfOSiMe 3 . This reaction does not proceed in the absence of TfOSiMe 3 . The synthesis was carried out in methylene chloride at a temperature of −78 • C (Scheme 108) [200,201].
1,2,4-Trioxanes 304 were obtained by the reaction of diketone 303 with containing alkyl substituents endoperoxides 302 (Scheme 110) [205]. Unfortunately, the yield of target peroxides did not exceed 10%. 1,2,4-Trioxanes 304 were obtained by the reaction of diketone 303 with containing alkyl substituents endoperoxides 302 (Scheme 110) [205]. Unfortunately, the yield of target peroxides did not exceed 10%. The use of TMSOTf in the reaction of endoperoxide 308 with cyclic diene 309 opened access to tetrasubstituted 1,2-dioxanes 310 (Scheme 112) [207]. At the first step, the interaction of endoperoxide 308 with TMSOTf leads to the formation of carbocation A. The subsequent attack of 1,4-diphenyl-1,3-cyclodiene B on carbocation A occurs in a regio-and diastereospecific manner. The intramolecular attack of the peroxysilyl function on the carbocation in C leads to product 310 (Scheme 113). At the first step, the interaction of endoperoxide 308 with TMSOTf leads to the formation of carbocation A. The subsequent attack of 1,4-diphenyl-1,3-cyclodiene B on carbocation A occurs in a regio-and diastereospecific manner. The intramolecular attack of the peroxysilyl function on the carbocation in C leads to product 310 (Scheme 113).
The use of TMSOTf/Et 3 SiH system in the reaction with bicyclic peroxides 314 and 316 led to unusual results. Substituted 1,2-dioxane 314 was transformed into 1,2-dioxane 315. But in the case of a 7-membered cyclic peroxide 316, the main product was bicyclic peroxide containing ozonide cycle 317 (Scheme 115) [209]. At the first step, the interaction of endoperoxide 308 with TMSOTf leads to the formation of carbocation A. The subsequent attack of 1,4-diphenyl-1,3-cyclodiene B on carbocation A occurs in a regio-and diastereospecific manner. The intramolecular attack of the peroxysilyl function on the carbocation in C leads to product 310 (Scheme 113). Scheme 113. The proposed mechanism for the assembly of tetrasubstituted 1,2-dioxanes 310.
The reaction of allyltrimethylsilane 312 with endoperoxides 311 in the presence of catalytic amounts of TMSOTf resulted in bicyclic 1,2-dioxanes 313 with a yield of 10% to 60% (Scheme 114) [208]. At the first step, the interaction of endoperoxide 308 with TMSOTf leads to the formation of carbocation A. The subsequent attack of 1,4-diphenyl-1,3-cyclodiene B on carbocation A occurs in a regio-and diastereospecific manner. The intramolecular attack of the peroxysilyl function on the carbocation in C leads to product 310 (Scheme 113).   REVIEW 53 But in the case of a 7-membered cyclic peroxide 316, the main product was bicyclic pe ide containing ozonide cycle 317 (Scheme 115) [209]. It has been shown that triethylsilyl hydrotrioxide 319 (Et3SiOOOH), obtained in from ozone and triethylsilane, is a mild and effective dioxetane-forming reagent from nyl ethers and vinyl thioethers on a relatively small (50-100 mg) scale. A number of s ies have demonstrated that the interaction of TBDMSOTf with dioxetane A leads t rearrangement into 1,2,4-trioxanes 320. Such peroxides exhibit in vitro antimalarial a ity, which is not inferior to peroxides like Artemisinin (Scheme 116) [210][211][212]. It has been shown that triethylsilyl hydrotrioxide 319 (Et 3 SiOOOH), obtained in situ from ozone and triethylsilane, is a mild and effective dioxetane-forming reagent from vinyl ethers and vinyl thioethers on a relatively small (50-100 mg) scale. A number of studies have demonstrated that the interaction of TBDMSOTf with dioxetane A leads to its rearrangement into 1,2,4-trioxanes 320. Such peroxides exhibit in vitro antimalarial activity, which is not inferior to peroxides like Artemisinin (Scheme 116) [210][211][212].
It has been shown that triethylsilyl hydrotrioxide 319 (Et3SiOOOH), obtained in situ from ozone and triethylsilane, is a mild and effective dioxetane-forming reagent from vinyl ethers and vinyl thioethers on a relatively small (50-100 mg) scale. A number of studies have demonstrated that the interaction of TBDMSOTf with dioxetane A leads to its rearrangement into 1,2,4-trioxanes 320. Such peroxides exhibit in vitro antimalarial activity, which is not inferior to peroxides like Artemisinin (Scheme 116) [210][211][212]. In a study [213] on the synthesis of cyclic peroxides 322 and 323 with high antimalarial activity, TMSOTf was used as a catalyst at the stage of peroxide cycle assembly (Scheme 117). Peroxoacetals 322 and 323 were obtained from substrate 321 in 41% yield. The antimalarial activity of peroxides 322 and 323 is comparable to the antimalarial activity of Artemisinin. In a study [213] on the synthesis of cyclic peroxides 322 and 323 with high antimalarial activity, TMSOTf was used as a catalyst at the stage of peroxide cycle assembly (Scheme 117). Peroxoacetals 322 and 323 were obtained from substrate 321 in 41% yield. The antimalarial activity of peroxides 322 and 323 is comparable to the antimalarial activity of Artemisinin.
It has been shown that triethylsilyl hydrotrioxide 319 (Et3SiOOOH), obtained in situ from ozone and triethylsilane, is a mild and effective dioxetane-forming reagent from vinyl ethers and vinyl thioethers on a relatively small (50-100 mg) scale. A number of studies have demonstrated that the interaction of TBDMSOTf with dioxetane A leads to its rearrangement into 1,2,4-trioxanes 320. Such peroxides exhibit in vitro antimalarial activity, which is not inferior to peroxides like Artemisinin (Scheme 116) [210][211][212]. In a study [213] on the synthesis of cyclic peroxides 322 and 323 with high antimalarial activity, TMSOTf was used as a catalyst at the stage of peroxide cycle assembly (Scheme 117). Peroxoacetals 322 and 323 were obtained from substrate 321 in 41% yield. The antimalarial activity of peroxides 322 and 323 is comparable to the antimalarial activity of Artemisinin.

Heteropoly Acids in the Synthesis of Organic Peroxides
In recent years, great interest has been paid to heteropoly acids as catalysts in the synthesis of organic peroxides. Heteropoly acids such as phosphomolybdic (PMA) and phosphotungstic (PTA) acids have a unique ability to form peroxo complexes with hydrogen peroxide and transfer the peroxide function to the substrate [37,[214][215][216]. The deposition of heteropoly acids on a support allows them to be reused after regeneration [37,216]. This section covers approaches on the synthesis of bisperoxides, 1,2,4-trioxolanes, 1,2,4,5tetraoxanes, and tricyclic monoperoxides with the use of heteropoly acids.
The use of the t BuOOH/H 6 P 2 W 18 O 62 system allows one to obtain dialkyl peroxides 325 from alcohols 324 in good yield (Scheme 118) [217]. In the case of secondary alcohols, the formation of an ether was observed in the reaction, which led to a decrease in the yield of the target peroxide. No by-product formation was observed in the case of tertiary alcohols.

Heteropoly Acids in the Synthesis of Organic Peroxides
In recent years, great interest has been paid to heteropoly acids as catalysts in the synthesis of organic peroxides. Heteropoly acids such as phosphomolybdic (PMA) and phosphotungstic (PTA) acids have a unique ability to form peroxo complexes with hydrogen peroxide and transfer the peroxide function to the substrate [37,[214][215][216]. The deposition of heteropoly acids on a support allows them to be reused after regeneration [37,216]. This section covers approaches on the synthesis of bisperoxides, 1,2,4-trioxolanes, 1,2,4,5-tetraoxanes, and tricyclic monoperoxides with the use of heteropoly acids.
The use of the t BuOOH/H6P2W18O62 system allows one to obtain dialkyl peroxides 325 from alcohols 324 in good yield (Scheme 118) [217]. In the case of secondary alcohols, the formation of an ether was observed in the reaction, which led to a decrease in the yield of the target peroxide. No by-product formation was observed in the case of tertiary alcohols.

Scheme 118. Synthesis of peroxides 325.
Supported phosphotungstic acid (PTA) on zeolite (NaY) allows the synthesis of a wide range of geminal bisperoxides 327 under heterogeneous conditions with a yield of 8 to 97% (Scheme 119) [216]. Such a system (H2O2, PTA/NaY) is effective for the synthesis of 1,2,4,5-tetraoxanes 329. Target products 329 were obtained in 71% to 92% yield. Supported phosphotungstic acid (PTA) on zeolite (NaY) allows the synthesis of a wide range of geminal bisperoxides 327 under heterogeneous conditions with a yield of 8 to 97% (Scheme 119) [216]. Such a system (H 2 O 2 , PTA/NaY) is effective for the synthesis of 1,2,4,5-tetraoxanes 329. Target products 329 were obtained in 71% to 92% yield. Supported phosphotungstic acid (PTA) on zeolite (NaY) allows the synthesis of a wide range of geminal bisperoxides 327 under heterogeneous conditions with a yield of 8 to 97% (Scheme 119) [216]. Such a system (H2O2, PTA/NaY) is effective for the synthesis of 1,2,4,5-tetraoxanes 329. Target products 329 were obtained in 71% to 92% yield. In 2009, the group of Wu et. al. reported the application phosphomolybdic acid (PMA) as a catalyst for the ring-opening of epoxides with H2O2. This method gives the opportunity to obtain β-hydroperoxy alcohols 331 at ambient temperature (Scheme 120) [218]. For all tested substrates the ring-opening of epoxides 330 is highly regioselective to give the hydroperoxyl group at the quaternary carbon. In 2009, the group of Wu et. al. reported the application phosphomolybdic acid (PMA) as a catalyst for the ring-opening of epoxides with H 2 O 2 . This method gives the opportunity to obtain β-hydroperoxy alcohols 331 at ambient temperature (Scheme 120) [218]. For all tested substrates the ring-opening of epoxides 330 is highly regioselective to give the hydroperoxyl group at the quaternary carbon. The ability of heteropoly acids to form peroxo complexes and coordinate with the carbonyl group allows the peroxidation of ketones and their derivatives under milder conditions. For example, peroxidation of 1-aryl-2-allylalkane-1,3-diones 335 with I2/H2O2 system proceeds with the formation of iodinated ketoesters 336. The addition of catalytic amounts of PMA to the I2/H2O2 system facilitates the assembly of bicyclic peroxides 337 The ability of heteropoly acids to form peroxo complexes and coordinate with the carbonyl group allows the peroxidation of ketones and their derivatives under milder conditions. For example, peroxidation of 1-aryl-2-allylalkane-1,3-diones 335 with I2/H2O2 system proceeds with the formation of iodinated ketoesters 336. The addition of catalytic The ability of heteropoly acids to form peroxo complexes and coordinate with the carbonyl group allows the peroxidation of ketones and their derivatives under milder conditions. For example, peroxidation of 1-aryl-2-allylalkane-1,3-diones 335 with I 2 /H 2 O 2 system proceeds with the formation of iodinated ketoesters 336. The addition of catalytic amounts of PMA to the I 2 /H 2 O 2 system facilitates the assembly of bicyclic peroxides 337 and 338 (Scheme 122) [220]. Ozonide 340 was obtained in one step by peroxidation of ketoacetal 339 with a yield of 74%. Phosphoromolybdic acid (PMA) was used as a catalyst in the amount of 0.02 equiv. with respect to 339. (Scheme 123) [218]. Phosphomolybdic (PMA) and phosphotungstic (PTA) acids efficiently catalyze the peroxidation reaction of β-diketones 341, including easily oxidized diketones, with the formation of bridged 1,2,4,5-tetraoxanes 342 (Scheme 124) [214]. Peroxides can be obtained in grams. The bridged 1,2,4,5-tetraoxane 342 containing an adamantane substituent in its composition exhibit a high activity (IC50: 0.3 μM) in vitro and in vivo (worm burden reduction was 75%) against S. mansoni [16]. Ozonide 340 was obtained in one step by peroxidation of ketoacetal 339 with a yield of 74%. Phosphoromolybdic acid (PMA) was used as a catalyst in the amount of 0.02 equiv. with respect to 339. (Scheme 123) [218]. Ozonide 340 was obtained in one step by peroxidation of ketoacetal 339 with of 74%. Phosphoromolybdic acid (PMA) was used as a catalyst in the amount equiv. with respect to 339. (Scheme 123) [218]. Phosphomolybdic (PMA) and phosphotungstic (PTA) acids efficiently catal peroxidation reaction of β-diketones 341, including easily oxidized diketones, w formation of bridged 1,2,4,5-tetraoxanes 342 (Scheme 124) [214]. Peroxides can be o in grams. The bridged 1,2,4,5-tetraoxane 342 containing an adamantane substitue composition exhibit a high activity (IC50: 0.3 μM) in vitro and in vivo (worm bur duction was 75%) against S. mansoni [16]. Phosphomolybdic (PMA) and phosphotungstic (PTA) acids efficiently catalyze the peroxidation reaction of β-diketones 341, including easily oxidized diketones, with the formation of bridged 1,2,4,5-tetraoxanes 342 (Scheme 124) [214]. Peroxides can be obtained in grams. The bridged 1,2,4,5-tetraoxane 342 containing an adamantane substituent in its composition exhibit a high activity (IC 50 : 0.3 µM) in vitro and in vivo (worm burden reduction was 75%) against S. mansoni [16].
The reaction of β,δ'-triketones 343, containing a benzyl substituent in the α-position, with an ethereal solution of H 2 O 2 , catalyzed by heteropoly acids (PMA, PTA) in a polar aprotic solvent, proceeds along three paths with the formation of three classes of peroxides: tricyclic monoperoxides 344, bridged tetraoxanes 345 and a pair of stereoisomeric ozonides 346 and 347 (Scheme 125) [215,221]. The reaction is unusual in that bridged tetraoxanes and ozonides with a free carbonyl group were formed. The synthesis of ozonides from ketones and H 2 O 2 is a unique process in which ozonide is formed with the participation of two carbonyl groups. Bridged ozonides exhibit high in vitro cytotoxicity against androgen dependent prostate cancer cell lines DU145 and PC3. In some cases the anticancer activity of ozonides is higher than that of doxorubicin, cisplatin, and etoposide [222]. Phosphomolybdic (PMA) and phosphotungstic (PTA) acids efficiently catalyze the peroxidation reaction of β-diketones 341, including easily oxidized diketones, with the formation of bridged 1,2,4,5-tetraoxanes 342 (Scheme 124) [214]. Peroxides can be obtained in grams. The bridged 1,2,4,5-tetraoxane 342 containing an adamantane substituent in its composition exhibit a high activity (IC50: 0.3 μM) in vitro and in vivo (worm burden reduction was 75%) against S. mansoni [16]. The reaction of β,δ'-triketones 343, containing a benzyl substituent in the α-position, with an ethereal solution of H2O2, catalyzed by heteropoly acids (PMA, PTA) in a polar aprotic solvent, proceeds along three paths with the formation of three classes of peroxides: tricyclic monoperoxides 344, bridged tetraoxanes 345 and a pair of stereoisomeric ozonides 346 and 347 (Scheme 125) [215,221]. The reaction is unusual in that bridged tetraoxanes and ozonides with a free carbonyl group were formed. The synthesis of ozonides from ketones and H2O2 is a unique process in which ozonide is formed with the participation of two carbonyl groups. Bridged ozonides exhibit high in vitro cytotoxicity against androgen dependent prostate cancer cell lines DU145 and PC3. In some cases the anticancer activity of ozonides is higher than that of doxorubicin, cisplatin, and etoposide [222]. More recently, an efficient catalyst H3+xPMo12-x 6+ Mox 5+ O40/SiO2 was developed for the synthesis of bridged ozonides 349, 350 and 1,2,4,5-tetraoxanes 352 under heterogeneous conditions (Scheme 126) [37] The synthesis of peroxides under heterogeneous conditions is a rare process and presents a challenge in this area of chemistry, as peroxides tend to decompose on the catalyst surface. The yield of diastereoisomeric bridged ozonides 349, 350 was up to 90%, and of bridged 1,2,4,5-tetraoxanes 352 wasup to 86%. More recently, an efficient catalyst H 3+x PMo 12-x 6+ Mo x 5+ O 40 /SiO 2 was developed for the synthesis of bridged ozonides 349, 350 and 1,2,4,5-tetraoxanes 352 under heterogeneous conditions (Scheme 126) [37] The synthesis of peroxides under heterogeneous conditions is a rare process and presents a challenge in this area of chemistry, as peroxides tend to decompose on the catalyst surface. The yield of diastereoisomeric bridged ozonides 349, 350 was up to 90%, and of bridged 1,2,4,5-tetraoxanes 352 wasup to 86%. The reaction of β,δ'-triketones 343, containing a benzyl substituent in the α-position, with an ethereal solution of H2O2, catalyzed by heteropoly acids (PMA, PTA) in a polar aprotic solvent, proceeds along three paths with the formation of three classes of peroxides: tricyclic monoperoxides 344, bridged tetraoxanes 345 and a pair of stereoisomeric ozonides 346 and 347 (Scheme 125) [215,221]. The reaction is unusual in that bridged tetraoxanes and ozonides with a free carbonyl group were formed. The synthesis of ozonides from ketones and H2O2 is a unique process in which ozonide is formed with the participation of two carbonyl groups. Bridged ozonides exhibit high in vitro cytotoxicity against androgen dependent prostate cancer cell lines DU145 and PC3. In some cases the anticancer activity of ozonides is higher than that of doxorubicin, cisplatin, and etoposide [222]. More recently, an efficient catalyst H3+xPMo12-x 6+ Mox 5+ O40/SiO2 was developed for the synthesis of bridged ozonides 349, 350 and 1,2,4,5-tetraoxanes 352 under heterogeneous conditions (Scheme 126) [37] The synthesis of peroxides under heterogeneous conditions is a rare process and presents a challenge in this area of chemistry, as peroxides tend to decompose on the catalyst surface. The yield of diastereoisomeric bridged ozonides 349, 350 was up to 90%, and of bridged 1,2,4,5-tetraoxanes 352 wasup to 86%.

Summary and Outlook
This review summarizes approaches to the synthesis of organic peroxides under the action of Lewis acids and heteropoly acids. The possibility of Lewis acids to coordinate with the oxygen atom of the carbonyl group, as well as to generate a peroxycarbenium ion in the starting compounds, allows for the expansion of the potential of the peroxidation reaction of carbonyl compounds.
The possibility of metal-containing compounds such as PMA, PTA, and MeReO 3 to form peroxo complexes with hydrogen peroxide makes it possible to transfer the peroxide function to the substrate. This transfer of peroxide groups, mediated by metal complexes, makes it possible to obtain organic peroxides under heterogeneous conditions. Analysis of the literature allows us to conclude that in the next decade the vector in peroxide chemistry will shift towards the use of the Lewis acid/peroxidizing agent system. This system is promising and its use will open up new horizons in peroxide chemistry for the chemical and medical industries.