Advances in radical peroxidation with hydroperoxides

Introduction

Organic peroxides are used in many different areas of human activities. The traditional and most developed field is the use of peroxides as initiators in the polymerization process for the production of a wide range of polymers [1]. They are also applied as curing, hardening and crosslinking agents [2]. Global demand for organic peroxides is expected to increase as the use of engineered plastics increases and production capacity is expanded. In addition, the need for polymers is expected to increase due to growing urbanization, expanding infrastructure projects and industrialization. A wide range of organic peroxide initiators is now available (Scheme 1) and this is continually being expanded to meet the changing requirements of the polymer industry.

Discovery of artemisinin, which was highlighted with the Nobel Prize, initiated a new era in organic peroxide chemistry. A large number of synthetic antimalarial peroxides have been prepared [3,4]. Further intensive research indicated that organic peroxides have antihelmintic, antiprotozoal, fungicidal, antiviral and other activities [5]. Therefore, the development of efficient synthetic approaches to implement organic peroxide functionality in various substrates is a timely task.

From the synthetic point of view, organic peroxides are one of the best sources of oxygen atoms for a variety of oxygenation reactions [6]. Hydroperoxides (especially TBHP), acyl peroxides, oxaziridines, and their derived species are often applied as terminal oxidants [7,8]. The weakness of the O–O bond allows alkoxy radicals to form through homolysis or reduction [9]. The generated alkoxy radicals provide an accessible tool for selective radical cascades, where a variety of functional groups can be functionalized for any synthetic need via HAT or β-scission with subsequent C-centered radical formation [10-13]. Also, peroxy radicals play a key role in the chemistry of the Earth's lower atmosphere [14-16].

The traditional approaches to organic peroxide synthesis mainly include: nucleophilic addition or nucleophilic substitution with H₂O₂ or ROOH [17,18], autoxidation with O₂, pericyclic reactions of unsaturated bonds with O₃ or O₂, and metal-catalyzed peroxidation (Isayama–Mukaiyama hydrosilylperoxidation [19,20], for example) [21-23]. As the topic is broad, the present review mainly focused on radical and metal-catalyzed functionalization of C–H bonds or unsaturated bond with hydroperoxides (Scheme 2). The aim of this review is to cover recent studies in which alkylperoxy radicals have been used for the peroxidation of C(sp³) and C(sp²) sites, either by themselves or with the aid of metal complex catalysis, and to provide an insight into the reactivity of these species. The present work is divided into sections, according to the type of the substrate: C(sp³)–H substrates; aromatic systems; compounds with unsaturated C–C or C–Het bonds.

The pioneer studies devoted to organic peroxide synthesis using radical cascades were reported by Kharasch [24,25]. In recent decades, there has been an intensive growth of publications in this field due to the integration of traditional peroxide chemistry with modern advances in organo-, metal- and photoredox catalysis [26-28]. These methods allow selectivity to be controlled despite the presence of the complex cocktail of radical species generated by hydroperoxides under redox or homolysis conditions.

The main challenge in selective radical peroxidation is the wide range of possible pathways involving radical intermediates from hydroperoxides under redox conditions (Scheme 3). The reactivity of O-centered radicals is less predictable and more diverse depending on radical structure and substrate pattern than the chemistry of C-centered radicals [29,30]. Generally, peroxy radicals have a tendency to recombine with C-centered radicals and add to unsaturated bonds with the formation of new carbon–oxygen bonds. However, alkoxy radicals, which are always present in such systems, are involved not only in the formation of ROO radicals but also in hydrogen atom transfer (HAT) processes and β-scission [31,32], which can lead to side reactions.

Some aspects of the rich metal–peroxide redox chemistry have been discussed in previous reviews [33]. Specifically, the radical functionalization of C–C bonds accessed through the transition metal-mediated reduction of organic peroxides has been covered in Kwon’s review [34]. Cu-catalyzed oxygen atom transfer with TBHP were discussed in the review [35]. The review by Xiao considered visible light-driven C–C bond cleavage enabled with organic peroxides [36]. This comprehensive review summarizes all ever published studies on radical peroxidation with ROOH, but most of them were published after 2010.

Review

C(sp³)–H peroxidation

Allylic C(sp³)–H

The pioneering work on C–H radical peroxidation with hydroperoxides was published by Kharasch in a series of articles entitled "The Chemistry of Hydroperoxides" in the 1950s [24,37,38]. Kharasch with colleagues firstly demonstrated that the decomposition of tert-butyl hydroperoxide (TBHP) by Co(II) naphthenate proceeds via a chain mechanism, leading to the formation of tert-butoxy and tert-butylperoxy radicals (Scheme 4) [24]. When cyclohexene (1) and oct-1-ene (3) were added, the corresponding products of allylic peroxidation 2, 4 and 5 were observed (Scheme 4) [24]. Similar transformations were reported later using CuCl as the catalyst [39]. Later, Gade with coauthors demonstrated the allylic peroxidation of cyclohexane with TBHP using the alkylperoxocobalt(III) complexes [Co(BPI)(OAc)(OO-t-Bu)] [40].

Introduction of the tert-butylperoxy fragment into the allylic position of substituted cyclohexenes 6 was carried out using Pd(OAc)₂ in ambient conditions (Scheme 5) [41]. The corresponding allylic peroxy ethers 7 were synthesized in 62–75% yields, the key intermediate was proposed to be L₂Pd(OO-t-Bu)₂.

Allylic peroxidation of 3-substituted prop-1-ene-1,3-diyldibenzenes 8 was performed with TBHP as the oxidant/peroxidation agent and with Cu₂O as the catalyst [42] (Scheme 6). The proposed mechanism of peroxides 9 formation does not include peroxo–copper complexes and begins with the formation of tert-butoxy and tert-butylperoxy radicals from TBHP as a result of redox reactions with Cu(I)/Cu(II). The tert-butoxy radical abstracts the hydrogen atom from alkene 8 to form the C-centered radical A. The subsequent attack of the tert-butylperoxy radical on intermediate A leads to the formation of peroxide 9.

The enantioselective peroxidation of alkenes 10 with TBHP with the formation of the optically active products 11 was carried out in good yields and low ee by the use of in situ-generated chiral bisoxazoline–copper(I) complexes (Scheme 7) [43].

Studying the oxidation of α-pinene (12) into verbenol and verbenone [44], it was found when using the CuI/TBHP system, the major observed products are peroxides 13 and 14 (Scheme 8).

Carbonyl or cyano-activated C(sp³)–H

In 1959 Kharasch demonstrated the introduction of the tert-butylperoxy fragment into the α-position of cyclohexanone (15) and 2-methylcyclohexanone (17) using the Cu(I)/TBHP system (Scheme 9) [39]. α-Methyl-substituted peroxide 18 was obtained in higher yield (based on consumption of TBHP) than the peroxide from cyclohexanone 16, and was found to be more stable.

Later, the methods for α-peroxidation of β-dicarbonyl compounds (β-diketones, β-ketoesters, and malonic esters) with TBHP via homogeneous and heterogeneous Cu(II)-catalysis were developed (Scheme 10) [45-47]. It was assumed that the reaction pathway includes the formation of diketonate complex A from β-dicarbonyl compound 19 and copper(II) salt, which then reacts with tert-butylperoxy radical B to form the target peroxide 20 and Cu(I). Cu(I) is oxidized by TBHP to form Cu(II) and tert-butoxy radical C, which abstracts a hydrogen atom from TBHP to form tert-butylperoxy radical B. Radical B can also be formed via oxidation of TBHP by complex A or the Cu(II) salt.

The cobalt-catalyzed peroxidation of cyclic compounds 21 by TBHP has been demonstrated (Scheme 11) [48]. There are three possible reaction pathways: the first starts with the oxidation of cobalt(II) by TBHP to form cobalt(III) and the tert-butoxy radical (step A). Next, the formed Co(III) species react with TBHP, resulting in the formation of a peroxocomplex of TBHP with Co(III) (stage B). The oxidation of 4-hydroxy-2(5H)-furanone 21 by Co(III)OO-t-Bu complex generates the target product 22 (step C). A second reaction pathway is also possible, in which the tert-butoxy radical A abstracts the hydrogen atom from TBHP to form the tert-butylperoxy radical (stage D). Next, tert-butylperoxy radical adds to the enol double bond of 4-hydroxy-2(5H)-furanone 21 (step E). Further oxidation of the resulting C-centered radical I into cation II and the proton transfer results in the target product 22 (steps F, G). The third possible pathway involves the abstraction of a hydrogen atom from 4-hydroxy-2(5H)-furanone 21 by the tert-butoxy radical formed in step A to give the alkoxy radical III (step H). Intermolecular hydrogen atom transfer results in the C-centered radical IV (step I). Further recombination of IV with tert-butylperoxy radical provides the target product 22 (step J).

The peroxidation of 2-oxoindoles 23, barbituric acids 25, and 4-hydroxycoumarins 27 by TBHP and α-cumyl hydroperoxide was carried out with the application of catalytic systems based on Co(II) [49], Mn(III) [50], and Fe(II) [51]. The corresponding peroxides 30 are enough stable under the reaction conditions and were isolated in high yields (Scheme 12). Flow-modification of the 2-oxoindole peroxidation method using nanoparticles of iron oxide as the catalyst was proposed [52]. The summarized proposed reaction pathway is presented in Scheme 12. The reaction probably begins with the oxidation of M(II) by TBHP into M(III) to form the tert-butoxy radical A, which abstracts a hydrogen atom from the substrate, generating the C-centered radical B. Peroxocomplex C, which can be formed from M(III)OH and TBHP as a result of ligand exchange, acts as a donor of the tert-butylperoxy radical D. The target peroxide 30 is formed by recombination of the C-centered radical B and tert-butylperoxy radical D.

Peroxidation of barbituric acid derivatives 31 by TBHP were further studied in detail [53]. It was demonstrated that the effective peroxidation of 31 with the formation of products 32 can be achieved as both using Cu-catalysis and in metal-free conditions (Scheme 13). The metal-free peroxidation with TBHP was also demonstrated using 3,4-dihydro-1,4-benzoxazin-2-ones 33 as substrates (Scheme 13) [54]. The assumed mechanism of the target product 32 formation is similar to the metal-catalyzed peroxidation described in Scheme 12 in the case of using the Cu(II)/TBHP oxidation system. Under metal-free conditions the tert-butoxy radical A is probably formed via homolytic thermal decomposition of TBHP.

Recently, the electrochemical generation of a set of tert-butoxy and tert-butylperoxy radicals from TBHP has been demonstrated in an undivided electrochemical cell under constant current conditions (Scheme 14) [55]. Using this approach, the electrochemical peroxidation of cyclic 1,3-dicarbonyl compounds 35 with TBHP was realized to give peroxy derivatives 36 in good yields. Three possible ways were proposed: a) anodic oxidation of TBHP and formation of tert-butylperoxy radical; b) hydrogen reduction of TBHP forming H₂O and the tert-butylperoxy radical; c) anodic oxidation of NO₃ anion to NO₃ radical which act as a mediator to form the tert-butylperoxy radical from TBHP. Intermediate A can be formed by reaction of substrate 35 with the tert-butylperoxy or the NO₃ radical, further recombination with the tert-butylperoxy radical leads to the target product 36. Also, peroxidation of barbituric acids was achieved using TBHP/TiO₂ photocatalytic system under visible light irradiation (443 nm) [56].

Peroxidation of β-ketoesters, cyanoacetic esters, and malonic esters 37 was performed using the TBAI/TBHP system (Scheme 15) [57]. The highest product yields in the TBAI-catalyzed peroxidation were achieved with malonic acid esters, in contrast to the metal-catalyzed methods [45-47]. Two possible reaction pathways were proposed (Scheme 15). Pathway I is based on the generation of tert-butoxy A and tert-butylperoxy B radicals in the TBAI/TBHP system, followed by the formation of the C-centered radical C. The recombination of intermediate C with tert-butylperoxy radical B leads to the target product 38. Pathway II involves the oxidation of TBAI with TBHP to form hypervalent iodine compounds D and E. The reaction of species E with substrate 37 leads to the formation of intermediate F, which interacts with TBHP to yield product 38. There is no consensus on the nature of the iodine species formed in reactions when using iodine-containing agents and their role in the mechanism of peroxidation.

The selective peroxidation of malonodinitriles and cyanoacetic esters 39 with TBHP under Cu-catalysis without oxidative destruction was presented in 2011 (Scheme 16) [58]. The corresponding peroxides 40 were isolated in good yields. Probably, the interaction of dinitrile 39 with Cu(II) salt leads to complex A, which reacts with the tert-butylperoxy radical B to form the target peroxide 40 and Cu(I). TBHP is reduced with Cu(I) into tert-butoxy radical C, which can abstract the hydrogen atom from TBHP to form tert-butylperoxy radical B. The alternative pathway for the formation of radical B is the oxidation of TBHP with complex A.

A manganese-catalyzed radical approach for the remote trifluoromethylation–peroxidation of non-activated alkenes 41 was disclosed (Scheme 17) [59]. The target 6-trifluoromethyl peroxides 42 were synthesized in good yields under mild conditions. The electrophilic CF₃ radical A, generated from CF₃SO₂Na through single-electron oxidation by using Mnⁿ/TBHP system, is captured by the carbon–carbon double bond to generate the nucleophilic carbon radical B. The intramolecular 1,5-HAT of B provided the alkyl radical C, which then cross-coupled with the in situ-generated high-valent Mnⁿ⁺¹OO-t-Bu species to form the 1,6-difunctionalized product 42 via peroxy-ligand transfer.

The remote trifluoromethylthiolation–peroxidation of unsaturated alkenes 43 using AgSCF₃ and TBHP was realized in the presence of the copper catalyst (Scheme 18) [60]. The radical trifluoromethylthiolation of alkenes 43 triggers a 1,5-HAT and further recombination of the generated C-centered radical with the tert-butylperoxy radical to afford the trifluoromethylthiolated organic peroxides 44 in good yields.

Benzyl C(sp³)–H

The direct α-functionalization of alkylaromatic compounds 45 with TBHP with the formation of the mixed peroxides 46 was firstly reported by Minisci using Gif conditions – Fe(NO₃)₃/HOAc/Py (Scheme 19) [61]. Notably, high yields of peroxides 46 were achieved using 1 equiv TBHP. This can be explained by reoxidation of Fe(II) to Fe(III) by oxygen, which is released during thermal decomposition of pyridinium nitrate presented in the system. Later, Mn-catalyzed peroxidation of alkylarenes 47 [50,62] and peroxidation of alkylarenes 49 using Ru-exchanged Montmorillonite K10 [63] were presented (Scheme 19). Chemical and kinetic data confirm that the mechanisms of the described processes are probably of a radical nature with the formation of MOO-t-Bu complexes [61]. The proposed pathway of the peroxidation is shown on the example of 9-substituted fluorenes 51 peroxidation (Scheme 19) [50,62]. Initially, the complex A of 2,2′-bipyridine with manganese(III) acetate is formed. Further oxidation of A by TBHP leads to complex B and tert-butoxy radical C. The later one abstracts an hydrogen atom from fluorene 51 to form C-centered radical F. The reaction of complex B with TBHP gives complex D, which transfers tert-butylperoxy radical E to the C-centered radical F to yield the target peroxide 52 (Scheme 19).

The α-peroxidation of nitriles with hydroperoxides was developed by Kharasch and Sosnovsky in 1958 on the example of the Cu(I)-catalyzed reaction of diphenylacetonitrile (53) with TBHP (Scheme 20) [25]. Peroxide 54 was obtained in a 79% yield using CuBr as the catalyst. The first step of diphenylacetonitrile 53 peroxidation is the oxidation of copper(I) to copper(II) by TBHP, resulting in tert-butoxy radical A, which abstracts the hydrogen atom from substrate 53 to form the C-centered radical B. Copper(II) then oxidizes TBHP to form the tert-butylperoxy radical C and copper(I), closing the catalytic copper cycle. tert-Butylperoxy radical C recombines with radical B to yield the product 54.

The reaction of a mono-substituted nitrile, phenylacetonitrile (55), with TBHP under Cu-catalysis led to a mixture of the oxidation products 56–59 including tert-butyl perbenzoate (57, Scheme 21) [25]. This discovery was later used to develop the synthesis of tert-butyl perbenzoates 61 from phenylacetonitriles 60 and TBHP (Scheme 21) [64]. The process was carried out without solvent and at room temperature, using copper(II) acetate as the catalyst. The reaction pathway of tert-butyl perbenzoate synthesis from benzyl nitriles 60 involves the formation of intermediate D. The Kornblum–DeLaMare rearrangement of peroxide D gives benzoyl cyanide E, which is further attacked by TBHP to give product 61.

Benzyl alcohols 62 were also converted into tert-butyl perbenzoates 63 under the action of the TBAI/TBHP system (Scheme 22) [65,66]. During the process, TBHP oxidizes TBAI into iodine, which reacts with the second TBHP to generate tert-butylperoxy radical B. The oxidation of benzyl alcohol 62 with TBHP results in aldehyde C, HAT from which by tert-butoxy radical A leads to the C-centered radical D. Subsequent recombination of radicals D and B provides the target product 63.

An enantioselective peroxidation method of alkylaromatics with TBHP using chiral in situ-generated Cu(I) complexes was developed (Scheme 23) [43]. 2-Phenylbutane (64) was converted into peroxide 65 in a 70% yield with 4% ee.

A visible light-induced direct decarboxylative peroxidation of carboxylic acids 66 with the formation of peroxides 67 under metal-free conditions using Mes-AcrClO₄ as the photocatalyst has been disclosed (Scheme 24) [67]. According to the authors, the irradiation of the photocatalyst (Acr⁺-Mes) A with a blue LED leads to the excited state (Acr·-Mes·⁺) B. The aliphatic carboxylic acid 66 is converted by deprotonation to the corresponding carboxylate, which is oxidized by the excited photocatalyst to give the benzyl radical D and CO₂. Further, single electron transfer from (Acr·-Mes) C to TBHP results in the ground state photocatalyst (Acr⁺-Mes) A and tert-butoxy radical E, which abstracts the hydrogen atom from TBHP to yield tert-butylperoxy radical F. The recombination of radicals F and D leads to the product 67.

Photochemical peroxidation of isochromans and other benzylic C(sp³)–H substrates 68 with TBHP was developed using Ir(ppy)₃ as the photocatalyst and Bronsted acid as an additive (Scheme 25) [68]. Visible light irradiation of [Ir^III(ppy)₃] to give the excited state [*Ir^III(ppy)₃] is likely to initiate a plausible catalytic cycle. Then TBHP is reduced by [*Ir^III(ppy)₃] through SET, which results in the generation of the tert-butoxy radical. Subsequently, the tert-butoxy radical abstracts a hydrogen atom from substrate 68 to give radical A. Photocatalytic oxidation of radical A with [Ir^IV(ppy)₃] regenerates [Ir^III(ppy)₃] and completes the photoredox catalytic cycle. The Bronsted acid catalyzes the formation of the isochroman oxocarbenium ion B, which is then nucleophilically attacked by TBHP to produce the target peroxide 69.

Heteroatom (N, O)-activated С(sp³)–H

In the pioneering work of Kharasch, N,N-dimethylaniline (70) was peroxidized with TBHP using Cu₂Cl₂ (Scheme 26) [39]. Later, the peroxidation of N-substituted tetrahydroisoquinolines 72 with TBHP was successfully carried out using a similar oxidation system [69,70]. The first step in the proposed mechanism of amine 72 peroxidation is the oxidation of Cu(I) with TBHP, resulting in the formation of tert-butoxy radical A, which abstracts the hydrogen atom from substrate 72 to form the C-centered radical B. The generated Cu(II) oxidizes TBHP to form tert-butylperoxy radical C, which recombines with radical B to form product 73. The mechanism of the transition metal-catalyzed oxidation of amines with TBHP was studied in detail in the work of Doyle and Ratnikov [71]. The scope of the amines 74 that can be functionalized by the tert-butylperoxy fragment was significantly broadened by using a catalytic system based on ruthenium salts [72,73].

The C(sp³)–H bond at the amides 76 was functionalized with the tert-butylperoxy radical under the action of the TBAI/TBHP system (Scheme 27) [74]. The target amido-peroxides 77 were synthesized in high yields. The authors proposed that the process begins with the formation of tert-butoxy A and tert-butylperoxy B radicals as a result of the iodide/iodine redox cycle. Then the tert-butoxy radical A abstracts a hydrogen atom from the substrate 76 to form the C-centered radical C. The target product 77 is formed via recombination of the radical C and the tert-butylperoxy radical В.

Fe(acac)₃-catalyzed oxidation of benzyl, allyl and propargyl ethers 78 with TBHP led to the formation of tert-butylperoxyacetals 79 (Scheme 28) [75]. Probably, in the first step TBHP oxidizes Fe(II) to Fe(III) with the formation of tert-butoxy radical A. Then the second molecule of TBHP is oxidized by Fe(III) into tert-butylperoxy radical B. Radical A abstracts a hydrogen atom from ether 78 to give the C-centered radical C. The authors propose two further pathways for the formation of the target product 79. Pathway I: The C-centered radical C is oxidized to carbocation D, which is captured by TBHP. Pathway II: the recombination of the C-centered radical C and tert-butylperoxy radical B.

The three-component approach to 4-(tert-butylperoxy)-5-phenyloxazol-2(3H)-ones 82 from benzyl alcohols 80 and isocyanates 81 using the Cu(II)/TBHP system was developed (Scheme 29) [76]. The set of tert-butoxy A and tert-butylperoxy B radicals are formed from TBHP during the Cu(I)/Cu(II) redox cycle. The Cu(II)/TBHP system also provides oxidation of benzyl alcohol 80 to the corresponding aldehyde C. The reaction of isocyanate 81 with aldehyde C generates oxazoline D, HAT from D by the action of radical A leads to intermediate E. The recombination of intermediate E with tert-butylperoxy radical B, following elimination of TsH, and oxidation of oxazole G provides the target peroxide 82 formation.

Non-activated С(sp³)–H

A number of studies [77-81] are devoted to the oxidation of cyclohexane 83 with TBHP using mononuclear [77-79] and dinuclear [80] non-porphyrin iron complexes (Scheme 30). Besides the oxygen atom transfer products, cyclohexanol (85) and cyclohexanone (15), the formation of peroxide 84 was observed. Oxidation of cyclohexane (83) was also carried out directly by the Co(lll) complexes with TBHP (Scheme 30) [82]. The key step in the Fe-catalyzed peroxidation mechanism is the generation of the set of tert-butoxy and tert-butylperoxy radicals from TBHP via Fe(II)/Fe(III) cycle. HAT from cyclohexane by tert-butoxy radical and the recombination of the resulting C-centered radical A with tert-butylperoxy radical lead to the tert-butylperoxy cyclohexane 84.

C(sp²)–X peroxidation of arenes

The radical peroxidation of the aromatic core has been realized on the example of the peroxidation of phenols [83-90]. The first studies were carried out as part of the investigation of the enzymatic function of cytochrome P-450 with low valent ruthenium complex catalysts. Various phenols 86 bearing para-substituents were transformed into the corresponding tert-butyldioxy dienones 87 smoothly using RuCl₂(PPh₃)₃ as the catalyst (Scheme 31) [83-85]. The authors rationalized that RuCl₂(PPh₃)₃ reacts with TBHP to give the (alkylperoxido)ruthenium(II) complex, which subsequently undergoes heterolytic cleavage of the O–O bond to form the (oxido)ruthenium(IV) species. HAT from the phenols by Ru(IV)=O intermediate leads to the phenoxyl radical–Ru(III)(OH) intermediate, which provides the cationic intermediate from phenol via electron transfer. The reaction of cation D with TBHP results in the mixed peroxide 87 [84].

However, this mechanism was later doubted based on the experimental data of [Rh₂(cap)₄]-catalyzed peroxidation of phenols 90 with various functional groups tethered to their 4-position afforded 4-(tert-butylperoxy)cyclohexa-2,5-dienones 91 (Scheme 32) [85,87]. The proposed mechanism includes HAT from substrate by tert-butylperoxy radical followed by radical combination between the phenoxy radical and the tert-butylperoxy radical. Peroxidation of β-naphthols 88 with TBHP under an air atmosphere was explored using CuBr as the catalyst resulting in the quaternary peroxide derivatives 89 in good yields (Scheme 32) [86].

An alternative approach to introducing the tert-butylperoxy moiety into phenols is the use of halogen-containing species (Scheme 33) [88,89]. Phenyltrimethylammonium tribromide (PTAB) was applied to the synthesis of peroxy-derivatives 93 of phenols and naphthols 92 in good yields. It was found that the I₂/TBHP system allows selective functionalization of para-substituted phenols 94 with sulfonyl and tert-butylperoxy moiety (Scheme 33) [89]. The mechanism of the process is probably based on the formation of radical species A and B, which disproportionate to form the intermediate C. Sequential addition of sulfonyl and tert-butylperoxy radicals to the double bond of intermediate C leads to intermediate D and on to product 95.

Difunctionalization of unsaturated С–С bonds with ROO fragment

With C-containing second component

Alkyl fragment: The first example of the alkylation–peroxidation of C=C double bonds using TBHP and C–H as partner has been reported in 1995 on the example of Cu-catalyzed functionalization of acrylonitrile (97) (Scheme 34) [91]. Probably as a result of redox reactions of TBHP with Cu(I) or Cu(II) compounds, tert-butoxy radical A or tert-butylperoxy radical B are formed, respectively. The abstraction of an hydrogen atom from R–H 96 by radical A or B generates the C-centered radical C. Then the alkene interacts with the C-centered radical C leads to the formation of radical species D. Finally, recombination of D and B results in the formation of the target difunctionalization product 98.

Related methods were subsequently proposed for the modification of coumarins 99 [92] in the presence of copper(I) oxide as a catalyst (Scheme 35). Probably as a result of redox reactions of TBHP under the action of Cu(I) or Cu(II) compounds, tert-butoxy radical A or tert-butylperoxy radical B are formed, respectively. The formation of tert-butylperoxy radical B can also be led by the abstraction of hydrogen atom from TBHP with radical A. The interaction of hydrogen donors (R–H) with radical A or B generates C-centered radical C. Then two ways of reaction proceeding are possible: the interaction of alkene 99 with C-centered radical C or with tert-butylperoxy radical B leads to the formation of radical particles D and E, respectively. Further, recombination of D and E with radicals B and C results in the formation of the target difunctionalization product 101.

Alkylation–peroxidation of coumarins 102 also was realized without metal catalyst (Scheme 36) [93]. Firstly, the tert-butoxy radical A generated from TBHP abstracts a hydrogen atom from cyclohexane 83 to give a cyclohexyl radical B. Further, tert-butoxy radical reacts with TBHP to give tert-butylperoxy radical C. Coumarin 102 was oxidized by tert-butylperoxy radical C to give C-center radical D. Finally, the radical cross-coupling between cyclohexyl radical B and C-center radical D provides the difunctionalized product 103.

Related methods were subsequently proposed for the modification of indene 104 [42] (Scheme 37). The target peroxides 106 were synthesized in good yields. In the case of indenes 104 a different regioselectivity of attachment to a double bond with a neighboring electron-withdrawing group was found (Scheme 37). The in situ-generated radical species A and B abstract a hydrogen atom from the cycloalkane 105 to generate a cycloalkyl radical species C. The allylic CH₂ of the indene 104 is oxidized to C=O in the presence of Cu/TBHP. The cyclohexyl radical C attacks at the α-carbon of α,β-unsaturated ketone D generating a benzylic radical E. Finally, a radical cross-coupling between B and benzylic radical E furnish the formation of cycloalkyl–peroxy product 106.

The acid-catalyzed radical additions of ketones 108 and TBHP to alkenes 107 (Scheme 38a) [94] and methacrylamides and methacrylates 110 (Scheme 38b) [95] with the formation of γ-peroxyketones 109 and 112 have been demonstrated. The reactions are believed to proceed via thermal decomposition of alkenyl peroxide B, which is formed from geminal hydroxyperoxide A (Scheme 38a). The homolytic bond cleavage in B produces the resonance-stabilized ketone radical C and a tert-butoxyl radical D. Radical D abstracts a hydrogen atom from TBHP, forming the tert-butylperoxy radical E. Addition of the ketone radical C to the starting alkene 107 results in the C-centered radical F, which recombines with the tert-butylperoxy radical E to form product 109.

The various γ-peroxy esters 115 were synthesized from alkenes 113, diazo compounds 114 and TBHP in the presence of Cu(NO₃)₂ (Scheme 39) [96]. The diazo compounds 114 act as the source of the ketone moiety. The formation of tert-butylperoxy A and tert-butoxy B radicals is assumed to be the result of the Cu(I)/Cu(II) catalytic cycle. Diazo compound 114 reacts with Cu(I) giving complex C, which is reduced with isopropanol to intermediate D. The oxidative addition of TBHP to complex D gives intermediate E, which is cleaved to yield the ketone radical F. The subsequent addition of alkene radical F and tert-butylperoxy radical A to alkenes 113 leads to the target product 115.

Cobalt-catalyzed alkylation–peroxidation of alkenes 117 with 1,3-dicarbonyl compounds 116 and TBHP was developed (Scheme 40) [97,98]. Gram-scale syntheses demonstrated that the protocol is practical and useful for preparation of the γ-carbonyl peroxides. The authors propose the following reaction mechanism: initially Co(II) is oxidized by TBHP to form Co(III)OH and the tert-butoxy radical. In result of ligand exchange with TBHP or acetic acid with Co(III)OH, complexes Co(III)OO-t-Bu A and Co(III)OAc B were generated. Complex B reacts with the enolic form of the initial 1,3-dicarbonyl compound 116 to form C, which undergoes single-electron oxidation to form the C-centered radical D. The addition of radical D to the starting alkene 117 provides radical E. tert-Butylperoxy group transfer from Co(III)OO-t-Bu A to E gives the coupling product F, which gives the final three-component product 118 and releases the Co(II) catalyst.

A copper(0)- and cobalt(II)-catalyzed difunctionalization of enynes 119 with the sp³ α-carbon of alcohols 120 and TBHP was developed (Scheme 41) [99]. The reaction proceeds in DMSO at 65 °C, the resulting β-peroxy alcohols 121 were isolated in good yields. It is assumed that in the first step, the reaction of TBHP with a low-valent metal forms tert-butoxy radical A, and that the resulting M⁽ⁿ⁺¹⁾OH species provide the decomposition of the second TBHP molecule to tert-butylperoxy radical B. Further, radical A abstracts a hydrogen atom from the starting alcohol 120 to form the α-hydroxy carbon radical C, which added to enyne 119 to form the C-centered radical D. Recombination of radical D with the tert-butylperoxy radical B provides the target product 121.

The Fe-catalyzed oxidative functionalization of silylallenes 122 with TBHP with the formation of propargylic peroxides 123 was described (Scheme 42) [100]. The authors proposed that tert-butoxy radical A, formed by the reaction of TBHP with Fe(II), abstracts hydrogen atom from silyl allene 122 to form the C-centered propargylic radical B. Fe(III) oxidizes radical B to carbocation C which reacts with Fe(III)OO-t-Bu complex D to yield the target peroxide 123.

Cyclopropanols 124 [101] and their derivatives 128 [102] were used as a source of alkyl moiety in Fe-catalyzed difunctionalization of alkenes with TBHP resulting in δ-peroxy ketones 126 and δ-peroxy esters 129 (Scheme 43a and 43b). In the case of siloxy cyclopropanes 128 the authors used TBAF as the additive to remove the TMS-protecting group. Oxidation of the resulting anion A with TBHP and subsequent β C–C scission of radical B produces the β-keto radical E, driven by strain release. Further alkene 127 adds the β-keto radical E to form the C-centered radical F. The Fe(III)OO-t-Bu complex D resulted from the Fe(II)/Fe(III) catalytic cycle reacts with radical F to yield the target product 129.

A Fe-catalyzed decarbonylative alkylation–peroxidation of alkenes 130 with aliphatic aldehydes 131 and TBHP to provide chain elongated peroxides 132 was developed (Scheme 44a) [103]. Aliphatic aldehyde 131 were used as the sources of 1°, 2°, 3° alkyl moieties via decarbonylation strategy. The proposed mechanism is based on a series of redox reactions of TBHP with Fe(II) catalyst resulting in the formation of tert-butoxy radical A and tert-butylperoxy radical B, respectively (Scheme 44a). Further, hydrogen atom abstraction from the carbonyl group of aldehyde 131 by radical A generates the acyl radical C, which transforms into alkyl radical D via CO elimination. Radical D adds to the double bond of alkene 130, to form the C-centered radical E, which recombines with radical B to yield the target product 132. Later, the same authors reported a four-component radical coupling of two different alkenes 133 and 134 with TBHP and aldehydes as alkyl sources, producing long-chain ketones 136 via intermediate peroxide 135 formation (Scheme 44b) [104].

Acyl fragment: A breakthrough on difunctionalization of C=C double bonds using TBHP and aldehyde has been achieved in 2011 by Li and co-workers (Scheme 45a) [105]. A three-component reaction of alkenes 137, aldehydes 138, and hydroperoxides catalyzed by FeCl₂ to β-peroxy ketones 139 has been realized. The authors proposed the involvement both as acyl and tert-butylperoxy radicals into the reaction pathway. The tert-butoxy radical A and tert-butylperoxy radical B generates via Fe(II)/Fe(III) catalytic cycle. Further, radical A abstracts a hydrogen atom from the aldehyde 138 to form acyl radical C, which adds to the double bond of the alkene 137 generating radical intermediate D (Scheme 45a). Recombination of radical D with tert-butylperoxy radical B leads to the formation of the target product 139. Later, iron-catalyzed three-component reactions of α,β-unsaturated carbonyl compounds 140, aldehydes 141, and TBHP leading to α-ester-β-keto peroxides 142 have been developed (Scheme 45b) [106-108]. Radical coupling of arylaldehydes 144 with α,β-unsaturated esters 143 and TBHP to afford α-peroxy-γ-diketones 145 was also disclosed under the catalysis of dirhodium(II) complex Rh₂(esp)₂ (esp = α,α,α′,α′-tetramethyl-1,3-benzenedipropanoate) (Scheme 45c) [109].

A three-component radical coupling reaction has been established for the assembly of β-peroxyamides 148 with TBHP and formamide derivatives 147 by difunctionalization of 1,3-diene, 1,3-enynes as well as styrenes 146 (Scheme 46) [110]. The iron catalyst is believed to mediate the formation of tert-butoxy and tert-butylperoxy radicals. The former abstracts the hydrogen atom from the formyl C–H bond, revealing the amino acyl radical, which is then added to the double bond.

Tetra-n-butylammonium bromide (TBAB)-catalyzed carbonylation–peroxidation of styrene derivatives 149 with TBHP and aldehydes 150, which allows for the synthesis of β-peroxy ketones 151, was described (Scheme 47) [111]. tert-Butoxy and tert-butylperoxy radicals are generated through the redox reaction of bromine.

Vanadium(IV) oxychloride (VOCl₂) was found to be an efficient catalyst to achieve peroxidation–carbonylation of styrenes 152 with TBHP and aldehydes 153 to give β-peroxy ketones 154 (Scheme 48) [112]. V(IV)OCl₂ is assumed to react with TBHP to form vanadyl(IV) alkyl peroxy complex, which decomposes to vanadyl(V) hydroxide E and tert-butoxy radical A as a result of homolytic O–O bond cleavage with concomitant electron transfer. Vanadyl(V) hydroxide E then reacts with TBHP to provide tert-butylperoxy radical B. A further hydrogen atom transfer from aldehyde 153 to tert-butoxy radical A leads to the formation of the acyl radical C, which adds to the double bond of alkene 152 to form the radical intermediate D. Recombination of radical D with tert-butylperoxy radical B affords the target product 154.

The acylation–peroxidation of alkenes 155 with TBHP and aldehydes 156 through visible-light photocatalysis was developed using fac-Ir(ppy)₃ as the photoredox catalyst (Scheme 49) [113]. Under visible light irradiation, the excited state Ir(III)* is generated, and the single electron transfer of Ir(III)* with TBHP results in tert-butoxy radical A. Generated Ir(IV) can produce tert-butylperoxy radical D from TBHP. Hydrogen atom abstraction from aldehyde 156 with tert-butoxy radical A leads to acyl radical B, which adds to alkene 155 to form the C-centered radical C. Two pathways are then possible for the formation of the final peroxide 157: recombination of radical C with tert-butylperoxy radical D or oxidation of radical C to carbocation E, which is nucleophilically attacked by TBHP.

β-Peroxy ketones 159 were synthesized via oxidative dimerization of styrenes 158 using the Cu(I)/TBHP system (Scheme 50) [42]. The reaction mechanism includes the formation of α-dicarbonyl compound A and elimination of CO which results in aldehyde B. tert-Butoxy E and tert-butylperoxy F radicals are formed during the redox Cu(I)/Cu(II) cycle. The acyl radical C generated via hydrogen atom abstraction with tert-butoxy radical E adds to the double bond of styrene 158 to form the C-centered radical D. Recombination of the tert-butylperoxy radical F and the C-centered radical D leads to the desired product 159.

The iron-catalyzed alkoxycarbonylation–peroxidation of alkenes 161 with carbazates 160 and TBHP to yield β-peroxy esters 162 was demonstrated (Scheme 51) [114]. The generation of the alkoxy radical D from carbazate 160 is assisted by the tert-butoxy radical A formed by the Fe(II)/Fe(III) redox cycle. The step-wise addition of alkoxy radical D and tert-butylperoxy radical B to alkene 161 leads to product 162.

Perfluoroalkyl fragment: In 2016 a radical difunctionalization of styrenes 163 using electrophilic perfluoroalkyl compound 164 and tert-butylperoxy radicals with the formation of (1-(tert-butylperoxy)-2-perfluoroalkyl)ethylbenzene 165 was developed (Scheme 52a) [115]. The proposed mechanism includes the Co(II)/Co(III) cycle and the generation of tert-butylperoxy, tert-butoxy, and perfluoroalkyl radicals [115]. Later, a similar methodology was applied to Co(acac)₂-catalyzed difluoroalkylation−peroxidation of alkenes 166 with difluorohaloacetates 167 and TBHP (Scheme 52b) [116-120]. It is assumed that the Co(III)OO-t-Bu complex is responsible for the key transfer of the tert-butylperoxy group to the C-centered radical generating from alkene 166 and difluoroacetate 167.

Sodium trifluoromethylsulfinate (170) [121] and sodium difluoromethanesulfinate (173) [122] were applied as the second coupling partners in the difunctionalization of alkenes 169 and 172 with hydroperoxides, respectively (Scheme 53a and Scheme 53b). According to the authors [121], the key intermediates are the Co(III)OO-t-Bu and the CF₃ radicals, which are generated from Co(OAc)₂ and CF₃SO₂Na in the presence of TBHP. In the case of copper catalysis the complex Cu(II)OO-t-Bu was proposed [122].

The difunctionalization of styrenes 175 with trifluoromethyl and peroxy groups was carried out using Togni reagent II (176) as a CF₃-group precursor and the metal organic framework Cu₃(BTC)₂ as a heterogeneous catalyst (Scheme 54) [123]. The reaction mechanism was proposed as an anchored ionic type pathway, rather than the free radical one. First, the Togni reagent forms complex A with the dinuclear paddle-wheel copper nodes of Cu₃(BTC)₂. Complex A then adds to styrene 175 to form iodonium cation B, which is converted to intermediate D by transfer of tert-butylperoxy ligand from copper complex C. The target product 177 is formed by cleavage of complex D.

Haloalkyl fragment: In 2018 haloalkylation–peroxidation of alkenes 178 using TBHP and chloroform under metal-free conditions was developed (Scheme 55) [124]. The target α-tert-butylperoxy-β-dichloromethylalkanes 179 were constructed via a radical pathway. First, the oxidation of CHCl₃ by TBHP yields the tert-butoxy radical A and CHCl₂ radical B. The tert-butoxy radical A abstracts hydrogen atom from TBHP to provide tert-butylperoxy radical C. Subsequently, the CHCl₂ radical B reacts with styrene 178 giving a stabilized benzyl radical D, which recombines with tert-butylperoxy radical C to give the target product 179.

Later, this approach was modified and extended to various alkyl halides. Diverse α-peroxy-β-substituted ethylbenzene products 181 were prepared from styrenes 180, TBHP and alkyl halides via radical pathway (Scheme 56) [125]. In the first step, TBHP oxidizes Cu(I) to form tert-butoxy radical A and Cu(II). HAT from TBHP to tert-butoxy radical A gives the tert-butylperoxy radical B, which in turn abstracts a hydrogen atom from the α-position of DIPEA to form the α-amino radical C. Chlorine atom transfer from CHCl₃ to the α-amino radical C results in the formation of the dichloromethyl radical D, which adds to styrene 180 to form the C-centered radical E. The authors further assume three possible pathways of the process. Pathway 1 involves single-electron transfer by Cu(II) to give the benzyl carbocation F, which is intercepted by TBHP. In pathway 2 the formation of 181 occurs through a two-step outer-sphere ligand transfer between Cu(II)OO-t-Bu and the benzyl radical E. Pathway 3 proposes the formation of Cu(III) complex H, followed by reductive elimination and the formation of the target product 181.

With N-containing second fragment

Mn(III)-catalyzed difunctionalization of alkenes 182 with TBHP and tert-butylnitrite to form β-peroxynitroalkanes 183 was developed (Scheme 57) [126]. tert-Butylnitrite was used as the precursor of the nitro group. The reaction proceeds under mild conditions with high yields of β-peroxynitroalkanes 183. The decomposition of t-BuONO produces the NO₂ radical, which adds to alkene 182 to give the C-centered radical B. The tert-butylperoxy radical A or its complex Mn(III)OO-t-Bu reacts with radical B to yield the target product 183.

The same authors reported Mn(II)-catalyzed azidation–peroxidation of alkenes 184 with TMSN₃ and TBHP (Scheme 58) [127]. The proposed mechanism involves the formation of azide radical A and tert-butoxy radical B during the Mn(II)/Mn(III) redox catalytic cycle. Then, radical A adds to the double bond of the alkene 184 to form the C-centered radical D, which reacts with tert-butylperoxy radical C or Mn(OO-t-Bu) to give the target β-peroxy azidoalkanes 185.

With O-containing second fragment

In 1952 Kharasch demonstrated bisperoxidation of butadiene 186 with TBHP under action of cobalt naphthenate (Scheme 59) [24]. 3,4-Di(tert-butylperoxy)but-1-ene (187) and 1,4-di-tert-butylperoxybut-2-ene (188) were obtained in 15% and 14% yield, respectively.

Studies on the bisperoxidation of alkenes 189 and 192 were carried out by Minisci with colleagues (Scheme 60) [128]. The authors demonstrated that the formation of bisperoxide 190 from styrene 189 is favoured under metalloporphyrin catalysis (Mn(III)-tetra(2,6-dichlorophenyl)porphyrin acetate) in basic media over traditional Kharasch copper catalysis (Scheme 60a). Acrylonitrile 192 was converted into bisperoxide 193 in 55% yield under Cu(OAc)₂ catalysis (Scheme 60b) [91].

It was shown that manganese salts in various oxidation states catalyze the peroxidation of styrenes with TBHP [129]. A method was proposed for the synthesis of [1,2-bis(tert-butylperoxy)ethyl]arenes 195 from styrenes 194 under Mn(OAc)₃ catalysis (Scheme 61). The formation of active peroxidising intermediates (tert-butylperoxy radical or Mn(III)(OAc)₂OO-t-Bu) can occur via oxidation of TBHP with Mn(OAc)₃ or via ligand exchange between acetate and TBHP. The Mn(OAc)₃ is regenerated by oxidation of Mn(OAc)₂ with TBHP. The tert-butylperoxy radical reacts with styrene 194 to give the stabilized benzyl radical A, which either recombines with a second t-BuOO• radical or oxidized with Mn(III)(OAc)₂OO-t-Bu accompanied by the transfer of the OO-t-Bu ligand to give the target bisperoxide 195. Also, Mn(IV)(OAc)₂=O can be produced from Mn(III)(OAc)₂OO-t-Bu followed by the reaction of this intermediate with TBHP to form O=Mn(IV)(OAc)₂OO-t-Bu, which can initiate a new catalytic cycle. The use of Co(II)-catalyst allows to synthesize relative 1-aryl-1,2-bis(tert-butylperoxy)ethanes in up to 53% yield [130].

Manganese complexes were applied for the synthesis of bisperoxides 197 and 199 from sterically hindered arylidene-9H-fluorenes 196 and arylideneindolin-2-ones 198 (Scheme 62) [50]. The authors suggest that initially a Mn(III)-2,2'-BPY complex A is formed, which is then oxidized by TBHP to L_n(OH)Mn(IV)(OAc)₃ B and tert-butoxy radical C. Next, ligand transfer results between B and TBHP leads to peroxidizing complex D. The target peroxide 197 is formed via addition of tert-butylperoxy radical E to substrate 196, followed by the reaction of intermediate F with L_nMn(IV)(OAc)₃OO-t-Bu or with tert-butylperoxy radical E.

The oxidation of styrenes 200 with TBHP in the presence of the bipyridylsilylated montmorillonite-supported Ru-catalyst yields mainly vicinal bis(tert-butylperoxy)alkanes 201 in the presence of Et₃N and 2-tert-butylperoxy-1-hydroperoxy-1-phenylethanes 202 without Et₃N (Scheme 63a) [131]. Oxidative cleavage of styrenes 203 by TBHP catalyzed by rhodium(II) caprolactame (Rh₂(cap)₄) was investigated (Scheme 63b) [132]. Vicinal bis-tert-butylperoxides 204 were isolated in low yields among various oxidation products.

Xu and Liu with colleagues demonstrated the influence of the solvent and additives on the chemoselectivity of iodine-catalyzed oxidation of styrenes 206 with TBHP (Scheme 64) [133]. The vicinal diols 208 were preferably obtained in water, but bisperoxides 207 were isolated in high yields using Na₂CO₃ as the additive, and propylene carbonate (PC) as the solvent. The reaction mechanism involves the formation of tert-butylperoxy A and tert-butoxy B radicals during the iodine catalytic cycle.

A Pd-catalyzed synthesis of di-tert-butylperoxyoxoindole derivatives 210 from acrylic acid anilides 209 and TBHP was developed (Scheme 65) [134]. The authors proposed that the initially formed diperoxide A undergoes electrophilic attack by cationic Pd(II) on an aromatic C–H bond with the aid of the ortho-directing group to give the palladium intermediate B, which undergoes reductive elimination to establish the C−C bond.

A Cu-catalyzed difunctionalization of styrenes 211 with TBHP and N-hydroxyphthalimide (NHPI) (212) as sources of O-functional groups was reported (Scheme 66) [135]. The authors assumed that NHPI converts into the PINO radical, which then added to styrene 211 to give radical A. The radical intermediate A can be further transformed into cation intermediate B in the presence of peroxides (the authors did not specify the oxidizing agent). Product 213 was proposed to be generated by nucleophilic attack of the tert-butylperoxy radical to the radical intermediate A or TBHP to the carbocation intermediate B.

Using carboxylic acids 215 and TBHP, the synthesis of β-peroxy-α-acyloxy derivatives 216 was developed via the TBAI-promoted acyloxylation–peroxidation of alkenes 214 (Scheme 67) [136]. Initially, I⁻ promotes the decomposition of TBHP to generate the tert-butyloxy radical and the tert-butylperoxy radical A. The tert-butylperoxy radical A adds preferentially to the electron-deficient alkene 214 to give the electrophilic radical B, which undergoes iodination to generate the iodoperoxidate intermediate C. Finally, nucleophilic addition of anion of carboxylic acid to intermediate C generates the desired product 216.

Based on the iodination/peroxidation strategy the approach to α-hydroxy-β-peroxyethylarenes 219 and α-alkoxy-β-peroxyethylarenes 218 from styrenes 217, oxygen sources (water or alcohol), and TBHP mediated by ammonium iodine has been developed (Scheme 68) [137]. Addition of the tert-butylperoxy radical to alkene 217 followed by S_N2 nucleophilic substitution with O-source was considered as a possible pathway to the formation of products 218 and 219. The authors also considered the transition configuration with the H₂O molecule attacking the α-C atom at the front.

TBAI-catalyzed hydroxyperoxidation of 1,3-butadienes 220 with aqueous hydroperoxides was demonstrated (Scheme 69) [138]. According to the proposed reaction pathway, the redox reaction of iodine and TBHP forms tert-butoxy radical and tert-butylperoxy radical A. Addition of tert-butylperoxy radical A to diene 220 results in the stable allyl radical B, which reacts with iodine radical to form iodoperoxide C. Elimination of iodine anion from C gives carbocation D, which adds water to give the target product 221.

1,2-Peroxyhydroxylation products 222 were obtained from dienes 220 and TBHP in the presence of Na₂CO₃ at 70 °C in CHCl₃ (Scheme 70) [139]. Thermal cleavage of TBHP produces tert-butylperoxy radicals and hydroxy radicals, which are involved in difunctionalization.

With halogens as the second fragment

The synthesis of vicinal iodoperoxyalkanes 225 by the reaction of alkenes 223 with iodine and hydroperoxides 224 was disclosed (Scheme 71) [140]. The high yields of products 225 were achieved by using excess iodine. The reaction is proposed to proceed via 1,2-diiodo intermediate A, which is transformed into iodonium cation B under the action of iodine. The nucleophilic attack of hydroperoxide on intermediate B leads to the target iodo-peroxides 225.

Later, it was shown that monocyclic enol ethers 226 react with I₂/TBHP and I₂/tetrahydropyranyl hydroperoxide systems to afford vicinal iodoperoxides 227 (Scheme 72) [141]. Whereas the reaction of bicyclic enol ethers 228 with I₂/TBHP led to the hydroperoxidation product 229.

The iodination/peroxidation method with the I₂/TBHP system has been extended to various alkenes 230 (Scheme 73) [142]. The corresponding 1-(tert-butylperoxy)-2-iodoethanes 231 were synthesized in high yields at room temperature in toluene.

When the iodine source was changed from I₂ to iodides, the regioselectivity of the difunctionalization of alkenes 232 in the [I]/TBHP system was reversed (Scheme 74) [143]. The radical pathway with the formation of tert-butoxy radicals and tert-butyl peroxy radicals during the I⁻/I₂ redox cycle has been proposed for 1-iodo-2-(tert-butylperoxy)ethanes 233 synthesis.

With P-containing second fragment

The three-component process provides access to β-phosphoryl peroxides 236 by the copper-catalyzed reactions of alkenes 234, P(O)–H compounds 235, and TBHP was firstly reported Li with colleagues (Scheme 75) [144]. Diethyl phosphonate and ethyl phenylphosphinate were applied as P–H components. However, diphenylphosphine oxide failed to result in the phosphorylation–peroxidation product. Cu(II) initially oxidizes phosphonate 235 into P-centered radical A, which adds to alkene 234 to form the C-centered radical B. During the reaction of Cu(I) with two molecules of TBHP, an active peroxy species Cu(II)(OO-t-Bu) is formed. Subsequently, the peroxy group transfers from Cu(II)(OO-t-Bu) to B to give the final product 236.

Later, a cobalt(II) catalyst was used to achieve P(O)-radical-mediated difunctionalization of alkenes 237 with diarylphosphine oxides 238 and hydroperoxides 239 (Scheme 76) [145]. The authors proposed that in the first step the oxidation of Co(II) into Co(III) with hydroperoxide 239 results in the formation of tert-butoxy radical A, while the reaction of Co(III) with hydroperoxide 239 produces tert-butylperoxy radical B. The tert-butoxy radical A abstracts a hydrogen atom from the diarylphosphine oxide 238 to form the P-centered radical C, which adds to the double bond of the alkene 237 to give the C-centered radical D. The recombination of radicals B and D leads to the formation of the target product 240.

With S-containing second fragment

The silver-catalyzed sulfonylation–peroxidation of alkenes 241 with sulfonyl hydrazides 242 and TBHP was disclosed by the Li group (Scheme 77) [146]. A variety of β-sulfonyl peroxides 243 were synthesized by the developed three-component peroxidation strategy. The reaction mechanism involves the formation of Ag(I)OO-t-Bu complex A, which is in equilibrium with the tert-butylperoxy radical B and Ag(0). The oxidation of Ag(0) to Ag(I) with TBHP produces the tert-butoxy radical C, which abstracts a hydrogen atom from arylsulfonyl hydrazide 242 to form the S-centered radical D. Further addition of D to the alkene 241 leads to the formation of the C-centered radical E. The target product 243 is formed via the reaction of the C-centered radical E with Ag(I)OO-t-Bu complex A or tert-butylperoxy radical B.

Sulfonylation–peroxidation of alkenes 244 was also carried out using sulfonylazides 245 and TBHP (Scheme 78) [147]. CoCl₂ was applied as the catalyst to achieve β-sulfonyl peroxides 246.

The difunctionalization of styrenes 247 with TBHP and thiols in the presence of iodine compounds was demonstrated (Scheme 79) [148]. The iodine source – NH₄I or I₂ – and the order of addition of the reagents determined the regioselectivity of the formation of α- or β-peroxysulphides 248 and 249.

The trifluoromethylthiolation–peroxidation of alkenes 250 and allenes 252 using AgSCF₃ and TBHP was realized in the presence of a copper catalyst (Scheme 80) [149]. The β-trifluoromethylthioperoxides 251 and 253 were synthesized in good yields. Probably, the reaction of TBHP with Cu(II) provides Cu(II)OO-t-Bu complex A, which can be a source of tert-butylperoxy radical B. AgSCF₃ is transformed into Ag(II)SCF₃ by oxidation of K₂S₂O₈. The Ag(II)SCF₃ species could produce the SCF₃ radical C through single electron transfer or generates F₃CSSCF₃ D. The addition of intermediates C or D to alkene 250 or 252 leads to the formation of the C-centered radical E, which reacts with Cu(II)OO-t-Bu complex A or tert-butyl peroxy radical B to give the product 251 or 253.

The photocatalytic sulfonyl peroxidation of alkenes 254 via deamination of N-sulfonyl ketimines 255 was demonstrated (Scheme 81) [150]. For this reaction an EnT-mediated pathway is proposed. After irradiation the excited photocatalyst thioxanthone transmits energy to N-sulfonyl ketimine 255 to its excited intermediate A, leading to homolysis of the weak N−S bond to give S-centered sulfonyl radical B and iminyl radical C. S-centered sulfonyl radical B then adds to alkene 254 and generates the C-centered radical D. On the other hand, iminyl radical C provides hydrogen atom abstraction from TBHP to generate the tert-butylperoxy radical. Finally, the cross-coupling of D and the tert-butylperoxy radical delivers the β-peroxyl sulfone product 256.

Photoredox-catalyzed peroxidation/sulfination of enynones 257 using sulfinic acids 258 and TBHP was disclosed in the presence of Eosin Y (Scheme 82) [151]. At first, application of green light generates the photoexcited state that subsequently undergoes a single electron transfer to TBHP to give a tert-butoxy radical A and a hydroxyl anion. The absorption of hydrogen atom from TBHP by radical A leads to tert-butylperoxy radical B which reacts with enynones 257 to give C-centered radical C. Oxidation of sulfinic anion D, generated from sulfinic acid 258, by the charged state of Eosin Y leads to S-centered radical E. The target product 259 is formed via the reaction of the C-centered radical C with the S-centered radical E.

With Si- or the Ge-containing second fragment

Cu-catalyzed silylperoxidation of α,β-unsaturated carbonyl compounds 260 and conjugated enynes 262 to yield silicon-containing peroxy products 261 or 263 was developed (Scheme 83) [152]. The authors proposed that the tert-butoxy radical A is generated from TBHP during Cu(I)/Cu(II) redox transformations. tert-Butoxy radical A abstracts a hydrogen atom from the triethylsilane to form the Si-centered radical B, which adds to the double bond of the α,β-unsaturated compound 260 to give the C-centered radical D. Single electron reduction of radical D with Cu(II)OO-t-Bu leads to intermediate E. The target peroxide 261 is formed by reductive elimination from intermediate E.

The silylperoxidation of alkenes 264 with hydrosilanes 265 and TBHP was also realized using iron or cobalt catalysts (Scheme 84) [153]. β-Silyl peroxides 266 were obtained in good yields and involved in various subsequent transformations.

The germyl peroxidation of a C=C bond with germanium hydrides and TBHP via a copper-catalyzed three-component radical relay strategy was first demonstrated by the Lv and Li group on the example of difunctionalization of alkenes 267 with the formation of germanium-containing peroxy products 268 (Scheme 85) [154]. The key reactive species are the Ge-centered radical and Cu(II)OO-t-Bu complex.

Functionalization of C=N bonds with ROO fragment

In 2016, the Studer group reported the TBAI-catalyzed multistep process for the intramolecular cyclization of diazo compounds 269 with further peroxidation leading to 3-cyano-3-peroxy-disubstituted oxindoles 270 (Scheme 86) [155]. First, carbene C is thermally generated from 269, and then undergoes concerted C–H carbene insertion onto the neighboring arene to give 3-cyanooxindole D. The tert-butylperoxy A and tert-butoxy B radicals are formed in the iodine redox cycle. The tert-butoxy radical B or tert-butylperoxy A abstracts the α-carbonyl H atom of intermediate D forming the C-radical E, which recombined with radical A to give product 270.

A close approach has been demonstrated by Yang, Niu and colleagues in a study of three-component coupling of diazo compounds 272 with benzamides 271 and TBHP using cobalt(II) acetate as a catalyst, yielding the peroxidized spiro-oxindoles 273 (Scheme 87) [156]. According to the authors, Co(II) is oxidized to Co(III) with TBHP. Then the Co(III) species undergoes a concerted metalation/deprotonation to afford intermediate A, which reacts with diazo compound 272 to form a six-membered cyclometalated intermediate B through migratory insertion. The reaction of Co(III) intermediate B with TBHP leads to the Co(IV) intermediate C. The reductive elimination results in Co(II) complex D. Finally, the proto-demetalation of D provides the target product 273.

The esterification–peroxidation of diazo compounds 274 with TBHP and carboxylic acids 275 using Co(ll)-based catalysts was reported (Scheme 88) [157]. The α-peroxy-α-acyloxy esters 276 were synthesized in good yields. The cobalt catalyst is believed to react with TBHP to form t-BuO• A and t-BuOO• B radicals. The diazo compound 274 thermally decomposes into carbene C in the presence of TBHP. The generated carbene C is attacked by carboxylic acid 275 to form ylide D, which transforms into the α-acyloxy ester E. The hydrogen atom abstraction from E with t-BuO• radical A leads to intermediate F, which recombines with t-BuOO• radical B to give the target product 276.

The Cu-catalyzed alkylation–peroxidation of α-carbonylimines 277 and ketones 280 to form α-amino peroxides 279 or α-alkoxyperoxides 281 using TBHP and ethers 278 was developed (Scheme 89) [158]. According to the authors, the catalytic cycle Cu(I)/Cu(II) produces the tert-butoxy radical B and tert-butylperoxy radical A. Then the tert-butylperoxy radical A adds to the C=N or C=O bonds of the initial substrates 277 or 280 to form the radical C. Ether 278 is attacked by tert-butoxy radical B to generate the C-centered radical D. The target peroxides 279 or 281 are formed by recombination of radicals D and C.

Miscellaneous processes

A Mn-catalyzed ring opening peroxidation of cyclobutanols 282 with TBHP to form γ-peroxy ketones 283 was reported (Scheme 90) [159]. The authors proposed that the Mnⁿ⁺/TBHP system oxidizes cyclobutanol 282 into the O-centered radical A, which subsequently undergoes β-scission to generate the γ-keto radical B. The second TBHP molecule reacts with Mn(III)O-t-Bu to give the Mn(III)OO-t-Bu complex, which couples with the γ-keto radical B to deliver the peroxy-ketones 283 via peroxy-ligand transfer.

In 2018 Wu, Zhong with colleagues disclosed the peroxycyclization of tryptophan derivatives 284 into peroxypyrroloindolenines 285 with TBAI/TBHP system (Scheme 91) [160]. The tert-butoxy radical A and tert-butylperoxy radical B are generated during I⁻/I₂ redox catalytic cycle. Furthermore, the tert-butoxy radical A abstracts the hydrogen atom from the substrate 284 to form the N-centered radical C, which is likely to undergo radical coupling with the tert-butylperoxy radical B at the C site of the isomeric C-centered radical D to form intermediate E. Oxidative cyclization of intermediate E under the action of (hypo)iodite species results in intermediate F, which releases iodide to produce product 285. The synthesized peroxypyrroloindolenines 285 exhibit a promising antiproliferation effect against Hela cell lines.

Later, the peroxycyclization of homotryptamine derivatives 286 to peroxytetrahydropyridoindolenines 287 with TBAI/TBHP system was reported (Scheme 92) [161]. The Bu₄N⁺IO⁻ was suggested to be the key active species.

The three-component oxidative coupling of indoles 288, cyanoacetates 289 and TBHP was developed using KI as the catalyst (Scheme 93) [162]. The KI/TBHP system provides the tert-butoxy radical A and tert-butylperoxy radical B. The generated radicals abstract a hydrogen atom from indole 288 to form the N-centered radical C, which turned into the C-centered radical D via an intermolecular electron transfer. The reaction of intermediate D with the tert-butylperoxy radical B leads to the peroxidized intermediate E, which is attacked by the anion of cyanoacetate 289 to form intermediate F. The protonation of F provides the intermediate G, which was oxidized to yield the target product 290.

Conclusion

This review gives a general overview of the radical peroxidation reactions with hydroperoxides, which have been widely explored during the past decades. Radical peroxidation with hydroperoxides has evolved from pioneer Kharasch studies on C–H radical peroxidation using metal/TBHP to cutting-age three-component radical cascade processes, such as those discussed in the sections on C=C bond difunctionalization, that are remarkably selective. The discussed methods of C=C difunctionalization allow the introduction of a wide range of C-, N-, O-, Hal-, S-, Si-, Ge-, and P-containing functional groups in addition to the ROO moiety.

The most popular catalytic system for generating the set of alkoxy and alkylperoxy radicals from hydroperoxides is the metal-containing catalyst. Mechanistic issues which need to be studied concern the structure of catalytically active metal complexes with hydroperoxides. In particular, a deeper systematic investigation of both the nature of the metals themselves and their ligands should allow the design of systems with a better activation of hydroperoxide in synergy with the chemical behavior of the generated alkoxy and alkylperoxy radicals. Most studies postulate that the redox reaction of the metal with hydroperoxides produces free alkoxy and alkylperoxy radicals (Scheme 94a). However, for copper, cobalt, manganese and iron, the reaction pathways via peroxo complexes have been proposed (Scheme 94b). The iodide-assisted processes of hydroperoxide decomposition into alkoxy and alkylperoxy radicals also need to be studied with regard to the types of iodine-containing species formed.

Although only a few examples of metal- and iodine-free processes, such as visible light photoredox catalysis and electrochemistry, have been reported so far, they offer high selectivity, new synthetic routes and appear to be of great interest. For example, using metal-free photoredox catalysts based on organic dyes can help advance the synthetic methods discussed. Electrolysis in an undivided electrochemical cell (where the reaction media are in contact with both the anode and the cathode) appears to be a very promising approach to generating the required set of alkoxy and alkylperoxy radicals from hydroperoxides without additional chemicals.

List of Abbreviations

The abbreviations used in the text and schemes are collected in Table 1.