Synthesis of five- and six-membered cyclic organic peroxides: Key transformations into peroxide ring-retaining products Alexander O. Terent'ev*1,§, Dmitry A. Borisov1, Vera A. Vil’1 and Valery M. Dembitsky1,2 Review Open Access Address: Beilstein J. Org. Chem. 2014, 10, 34–114. 1N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of doi:10.3762/bjoc.10.6 Sciences, Leninsky Prospect 47, Moscow, 119991, Russia and 2Institute for Drug Research, P.O. Box 12065, Hebrew University, Received: 17 August 2013 Jerusalem 91120, Israel Accepted: 16 November 2013 Published: 08 January 2014 Email: Alexander O. Terent'ev* - [email protected] Associate Editor: T. P. Yoon * Corresponding author © 2014 Terent'ev et al; licensee Beilstein-Institut. § Tel +7-916-385-4080 License and terms: see end of document. Keywords: cyclic peroxides; 1,2-dioxanes; 1,2-dioxenes; 1,2-dioxolanes; ozonides; 1,2,4,5-tetraoxanes; 1,2,4-trioxanes; 1,2,4-trioxolanes Abstract The present review describes the current status of synthetic five and six-membered cyclic peroxides such as 1,2-dioxolanes, 1,2,4- trioxolanes (ozonides), 1,2-dioxanes, 1,2-dioxenes, 1,2,4-trioxanes, and 1,2,4,5-tetraoxanes. The literature from 2000 onwards is surveyed to provide an update on synthesis of cyclic peroxides. The indicated period of time is, on the whole, characterized by the development of new efficient and scale-up methods for the preparation of these cyclic compounds. It was shown that cyclic perox- ides remain unchanged throughout the course of a wide range of fundamental organic reactions. Due to these properties, the molec- ular structures can be greatly modified to give peroxide ring-retaining products. The chemistry of cyclic peroxides has attracted considerable attention, because these compounds are used in medicine for the design of antimalarial, antihelminthic, and antitumor agents. Introduction Approaches to the synthesis of five and six-membered cyclic In the last decade, two reviews on this rapidly progressing field peroxides, such as 1,2-dioxolanes I, 1,2,4-trioxolanes were published by McCullough and Nojima [1] and Korshin (ozonides) II, 1,2-dioxanes III, 1,2-dioxenes IV, 1,2,4-triox- and Bachi [2] covering earlier studies. There are several review anes V, and 1,2,4,5-tetraoxanes VI, published from 2000 to articles on medicinal chemistry of peroxides, where the prob- present are reviewed. These compounds are widely used in syn- lems of their synthesis are briefly considered. In addition to thetic and medicinal chemistry (Figure 1). these reviews other publications dealing with this subject 3344 Beilstein J. Org. Chem. 2014, 10, 34–114. the number of oxygen atoms and the ring size. In the individual sections, the data are arranged mainly according to the common key step in the synthesis of the cyclic peroxides. Examples of the synthesis of peroxide derivatives via modifications of func- tional groups, with the peroxide bond remaining unbroken, are given in the end of each chapter. In most cases, the syntheses of compounds having high biological activity are considered. Currently, the rapid progress in chemistry of organic peroxides is to a large degree determined by their high biological activity. In medicinal chemistry of peroxides, particular emphasis is given to the design of compounds having activity against Figure 1: Five and six-membered cyclic peroxides. causative agents of malaria and helminth infections. The World Health Organization (WHO) considers malaria as one of the appeared: Tang et al. [3], O’Neill, Posner and colleagues [4,5], most dangerous social diseases. Worldwide, 300–500 million Masuyama et al. [6], Van Ornum et al. [7], Jefford [8,9], cases of malaria occur each year, and 2 million people die from Dembitsky et al. [10-15], Opsenica and Šolaja [16], Muraleed- it [47,48]. haran and Avery [17], and other [18-27] including dissertations [28-32]. Due to a high degree of resistance in malaria to traditional drugs as quinine, chloroquine, and mefloquine, an active search for Reviews published earlier on the chemistry of ozone [33-36] other classes of new drugs is performed. In this respect, organic and on the chemistry and biological activity of natural perox- peroxides play a considerable role. In medicinal chemistry of ides, and cyclic peroxides [37-46] are closely related to this peroxides, artemisinin a natural peroxide exhibiting high anti- review. Generally speaking, state-of-the-art approaches to the malarial activity, is the most important drug in use for approxi- synthesis of cyclic peroxides are based on three key reagents: mately 30 years. Artemisinin was isolated in 1971 from leaves oxygen, ozone, and hydrogen peroxide. These reagents and of annual wormwood (Artemesia annua) [49-51]; the 1,2,4- their derivatives are used in the main methods for the introduc- trioxane ring V is the key pharmacophore of these drugs. A tion of the peroxide group, such as the singlet-oxygen ene reac- series of semi-synthetic derivatives of artemisinin were synthe- tion with alkenes, the [4 + 2]-cycloaddition of singlet oxygen to sized: artesunate, artemether, and artemisone (Figure 2). dienes, the Mukaiyama–Isayama peroxysilylation of unsatu- Currently, drugs based on these compounds are considered as rated compounds, the Kobayashi cyclization, the nucleophilic the most efficacious for the treatment of malaria [52-76]. addition of hydrogen peroxide to carbonyl compounds, the ozonolysis, and reactions with the involvement of peroxycarbe- The discovery of arterolane, a synthetic 1,2,4-trioxolane, is a nium ions. considerable success in the search for easily available synthetic peroxides capable of replacing artemisinin and its derivatives in Each part of the review deals with a particular class of the medical practice. Currently, this compound is currently in phase above-mentioned peroxides in accordance with an increase in III clinical trials [77-81]. Figure 2: Artemisinin and semi-synthetic derivatives. 35 Beilstein J. Org. Chem. 2014, 10, 34–114. The mechanism of antimalarial action of peroxides is unusual compounds containing the 1,2-dioxene ring possess fungicidal for pharmaceutical chemistry. According to the commonly [210,213-224] and antimycobacterial activities [128-131,225- accepted mechanism, peroxides diffuse into Plasmodium- 228]. The present review covers literature relating to 5- and infected erythrocytes, and the heme iron ion of the latter 6-membered cyclic peroxide chemistry published between 2000 reduces the peroxide bond to form a separated oxygen-centered and 2013. radical anion, which rearranges to the C-centered radical having Review a toxic effect on Plasmodium [82-87]. 1. Synthesis of 1,2-dioxolanes In the course of the large-scale search for synthetically acces- The modern approaches to the synthesis of 1,2-dioxolanes are sible and cheap antimalarial peroxides (compared with natural based on the use of oxygen and ozone for the formation of the and semi-synthetic structures), it was found that structures peroxide moiety, the Isayama–Mukaiyama peroxysilylation, containing 1,2-dioxolane [88-90], 1,2,4-trioxolane [91-101], and reactions involving peroxycarbenium ions. Syntheses 1,2-dioxane [102-112], 1,2-dioxene [113-119], 1,2,4-trioxane employing hydrogen peroxide and the intramolecular [120-127] or 1,2,4,5-tetraoxane rings [128-146] exhibit Kobayashi cyclization are less frequently used. pronounced activity, and in some cases, even superior to that of artemisinin. 1.1. Use of oxygen for the peroxide ring formation The singlet-oxygen ene reaction with alkenes provides an effi- Another important field of medicinal chemistry of organic cient tool for introducing the hydroperoxide function. The reac- peroxides includes the search for antihelminthic drugs. For tion starts with the coordination of oxygen to the double bond example, compounds containing 1,2-dioxolane [147], 1,2,4- followed by the formation of hydroperoxides presumably by a trioxolane [148-152], 1,2,4-trioxane [153-158] or bridged stepwise or concerted mechanism [229,230]. The oxidation of 1,2,4,5-tetraoxane [159] moieties show activity against Schisto- α,β-unsaturated ketones 1a–c by singlet oxygen affords soma. Schistosomiasis is one of the most widespread helminthic 3-hydroxy-1,2-dioxolanes 3a–c via the formation of diseases; 800 million people are at risk of acquiring this infec- β-hydroperoxy ketones 2a–c (Scheme 1) [231]. tion [160-174]. Dioxolane 6 was synthesized in 36% yield by the reaction of Additionally, based on synthetic peroxides, several compounds oxygen with hydroperoxide 4 in the presence of di-tert-butyl exhibiting antitumor activity were synthesized. These com- peroxalate (DTBPO) followed by the treatment of the reaction pounds contain 1,2-dioxolane [10-15,175-178], 1,2-dioxane mixture with acetic anhydride and pyridine at room tempera- [10-15,112,178-181], 1,2-dioxene [114,182-185] or 1,2,4- ture (Scheme 2). trioxane [10-15,175,176] rings. More than 300 peroxides are known to have a toxic effect on cancer cells [10-15,73,186- It should be emphasized that a mixture of dioxolanes 5 and 6 in 206]. a ratio of 7:3 is formed already in the first step [232]. Synthetic peroxides exhibit also other activities. For example, The photooxygenation of oxazolidines 7a–d through the forma- compounds containing the 1,2,4-trioxane ring are active against tion of hydroperoxides 8a–d gives spiro-fused oxazolidine- Trichomonas [207], compounds with the 1,2-dioxane ring show containing dioxolanes 9a–d in low yields (12–30%) (Scheme 3) antitrypanosomal and antileishmanial activities [208-212], and [233]. Scheme 1: Synthesis of 3-hydroxy-1,2-dioxolanes 3a–c. 36 Beilstein J. Org. Chem. 2014, 10, 34–114. Scheme 2: Synthesis of dioxolane 6. Scheme 3: Photooxygenation of oxazolidines 7a–d with formation of spiro-fused oxazolidine-containing dioxolanes 9a–d. The reaction was performed in a temperature range from −10 to transition-metal salts as the catalysts. The reactions of bicy- −5 °С. The conversion of oxazolidines 7 and the yields of diox- cloalkanols 10a–e with singlet oxygen in the presence of olanes 9 were determined by 1H NMR spectroscopy. catalytic amounts of Fe(III) acetylacetonate produce peroxides 12a–e, which can also be synthesized starting from silylated An efficient method for the synthesis of 1,2-dioxolanes is based bicycloalkanols 11a–e with the use of Cu(II) acetylacetonate on the oxidation of cyclopropanes by oxygen in the presence of (Scheme 4, Table 1) [234]. Scheme 4: Oxidation of cyclopropanes 10a–e and 11a–e with preparation of 1,2-dioxolanes 12a–e. Table 1: Structures and yields of dioxolanes 12a–e. Bicycloalkanol 10a–e, 1,2-Dioxolane 12a–e silylated bicycloalkanol 11a–e Method Aa Method Bb R n Reaction time, h Yield, % Reaction time, h Yield, % a CH3 1 3 35 5 54 b C4H9 1 3 55 3.5 84 c C6H13 1 3 68 – – d CH2Ph 1 3 50 5 78 e CH3 2 36 54 6 80 aEt2O, O2, hν, silica gel, Fe(acac)3 (4 mol %). bEtOH, O2, hν, Cu(acac)2 (4 mol %). 37 Beilstein J. Org. Chem. 2014, 10, 34–114. Similarly, the reactions of silylated bicycloalkanols 13a–c with This reaction gives β-hydroxyketones as by-products that are oxygen in the presence of the catalyst VO(acac) yielded diox- formed as a result of the decomposition of dioxolanes 14. 2 olanes 14a–c, which made it possible to perform the oxidation without irradiation (Scheme 5, Table 2) [235]. Cyclopropanols 15a–g are readily oxidized by molecular oxygen in the presence of Mn(II) abietate or acetylacetonate (Scheme 6) [236]. Presumably, the reaction proceeds via the intermediate forma- tion of О- and С-centered radicals 16a–g and 17a–g, respective- ly. According to this method, dioxolanes 18a–g (exist in equi- librium with the open form 19a–g) were synthesized in 60–80% Scheme 5: VO(acac)2-catalyzed oxidation of silylated bicycloalkanols yields. 13a–c. Like hydroxycyclopropanes, aminocyclopropanes are trans- formed into 1,2-dioxolanes. For example, N-cyclopropyl-N- Table 2: Structures and yields of dioxolanes 14a–c. phenylamines 20a–c form dioxolanes 21a–c in the presence of Silylated bicycloalkanol atmospheric oxygen (Table 3). It was found that the reaction 13a–c rate substantially increases in the presence of catalytic amounts Yield of [(phen)3Fe(III)(PF6)3] or equimolar amounts of benzoyl R1 R2 Solvent 14a–c, peroxide or di-tert-butyl peroxide. The possible mechanism of % the oxidation is shown in Scheme 7 [237]. EtOH 45 a H Me CF3CH2OH 86 According to the 1H NMR data, dioxolanes 21a–c are formed b H Bn CF3CH2OH 43 under the above-mentioned conditions in almost quantitative c Me Me CF3CH2OH 43 yields; the yields based on the isolated product were not higher than 80% [237]. Scheme 6: Mn(II)-catalyzed oxidation of cyclopropanols 15a–g. Table 3: Peroxidation of N-cyclopropyl-N-phenylamines 20a–c to form 3-(1,2-dioxalanyl)-N-phenylamines 21a–c. Dioxolane 21a–c R1 R2 Reaction conditions a H H 1. (BzO)2 (1 mol/1 mol 20a), CHCl3, dark, −20 °C, 3 days. 2. (t-BuO)2 (1 mol/1 mol 20a), CHCl3, UV (254 nm), ambient temperature, aerobic, 2 h. 3. [(phen)3Fe(III)(PF6)3] (0.6 % mol), CHCl3, ambient temperature, aerobic, 1 h. b Me H 1. (t-BuO)2 (1 mol/1 mol 20b), CHCl3, UV (254 nm), ambient temperature, aerobic, 2 h. c H Me 1. (t-BuO)2 (1 mol/1 mol 20c), CHCl3, UV (254 nm), ambient temperature, aerobic, 2 h. 2. [(phen)3Fe(III)(PF6)3] (0.6 % mol), CHCl3, ambient temperature, aerobic, 1 h. 38 Beilstein J. Org. Chem. 2014, 10, 34–114. Scheme 7: Oxidation of aminocyclopropanes 20a–c. Structurally similar 3-ethyl-6a-methyl-6-(4-phenoxy- phenyl)hexahydro[1,2]dioxolo[3,4-b]pyrroles 24a and 24b were synthesized from (Z)-N-(hex-3-enyl)-N-(4-phenoxy- phenyl)acetamide (22). It was suggested that aminocyclo- propane 23 is formed in situ, which is subsequently oxidized in air on silica gel (Scheme 8) [238]. The total yield of both isomers 24 was 31%. Trifluoromethyl-containing dioxolane 25 (Figure 3) was synthe- Figure 3: Trifluoromethyl-containing dioxolane 25. sized according to this method in 40% yield [239]. A series of 1,2-dioxolanes 27a–e containing various functional The reaction was performed in the presence of Ph Se 2 2 groups R were prepared by the oxidation of cyclopropanes (10 mol %) and azobisisobutyronitrile (AIBN, 8 mol %) in air 26a–e (Scheme 9, Table 4). under irradiation for two days. The product was purified by Scheme 8: Synthesis of aminodioxolanes 24. 39 Beilstein J. Org. Chem. 2014, 10, 34–114. Scheme 9: Synthesis of 1,2-dioxolanes 27a–e by the oxidation of cyclopropanes 26a–e. The reaction was performed in acetonitrile or in a mixture of Table 4: Structures and yields of dioxolanes 27a–e. toluene and acetonitrile with the use of 9,10-dicyanoanthracene (DCA), 1,2,4,5-tetracyanobenzene (TCNB), or N-methyl-quino- Yield Dioxolane R (cis + Ratio linium tetrafluoroborate (NMQ+BF4−) as sensitizers. Under 27a–e trans), (cis/trans) these conditions, dioxolane 29a was obtained in quantitative % yield (1H NMR data), the yield of 29b was not reported [241]. a 88 1/7 Under irradiation in the presence of oxygen, 1,5-bis(4- methoxyphenyl)bicyclo[3.1.0]hexane (30) and 1,5-bis(4- trans b 100 methoxyphenyl)-6,7-diazabicyclo[3.2.1]oct-6-ene (31) were isomer transformed into bicyclic dioxolane 33. It was suggested that both reactions proceed via the formation of 1,3-radical cation 32 c 75 1/22 (Scheme 11). d 100 1/13 e 82 1/2.8 flash chromatography to obtain a mixture of cis and trans isomers, whose ratio depends primarily on the nature of the substituent in cyclopropanes 26a–e [240]. The oxidation of methylenecyclopropanes 28a and 28b under Scheme 11: Irradiation-mediated oxidation. photoinduced electron-transfer conditions is described by a similar scheme (Scheme 10). Dioxolane 33 was synthesized in the highest yields (91% from 30 and 100% from 31) in acetonitrile with the use of 9,10- dicyanoanthracene (DCA) as the sensitizer [242]. After irradiation of diazene 34 in an argon matrix at 10 K, biradical 35 was detected by IR spectroscopy and the reaction of the latter with oxygen at 10 K proceeded regioselectively to give dioxolane 36 (Scheme 12) [243]. Bicyclic peroxide 2-heptyl-3,4-dioxabicyclo[3.3.0]oct-1(8)-ene was prepared by a similar process [244]. The oxidation of arylacetylenes 37a–h with atmospheric Scheme 10: Photoinduced oxidation of methylenecyclopropanes 28. oxygen in the presence of catalytic amounts of Mn(OAc) in an 3 40 Beilstein J. Org. Chem. 2014, 10, 34–114. by a peroxide radical, are able to undergo intramolecular cyclization to form the 1,2-dioxolane ring. For example, the Co(modp) -catalyzed peroxysilylation (modp = 2 1-morpholino-5,5-dimethyl-1,2,4-hexanetrionate) of (2-vinylcy- clopropyl)benzene (40) affords triethyl(1-(5-phenyl-1,2-diox- olan-3-yl)ethylperoxy)silane (41) in 37% yield (Scheme 14). Scheme 12: Application of diazene 34 for dioxolane synthesis. excess of acetylacetone afforded dioxolanes 38a–h in moderate yields (34–64%) (Scheme 13, Table 5) [245]. Scheme 13: Mn(OAc)3-catalyzed cooxidation of arylacetylenes 37a–h and acetylacetone with atmospheric oxygen. Table 5: Structures and yields of dioxolanes 38a–h and epoxides 39a–h. Yield 38a–h, Yield 39a–h, 37a–h R1 % % a Ph 45 5 b 4-MeC6H4 52 7 c 4-MeOC6H4 64 2 Scheme 14: Peroxidation of (2-vinylcyclopropyl)benzene (40). d 4-ClC6H4 38 2 e 4-FC6H4 41 6 The reaction was carried out in 1,2-dichloroethane at room F 1-naphthyl 54 6 temperature, and the reaction products were separated by g 2-naphthyl 52 8 column chromatography. 1-Hydroxy-1-phenylpentan-3-one (42) h 3,4-(MeO)2C6H3 34 11 was isolated as a by-product in 16% yield [248]. The reaction was performed at 23 °С in glacial acetic acid in The peroxidation of 1,4-dienes 43a,b with the Co(modp) / 2 air; the 37/acetylacetone/Mn(OAc) molar ratio was 1/10/10. Et SiH/O system according to a similar reaction scheme gave 3 3 2 The reaction gave oxiranes 39 as by-products, which can also dioxolanes 44a,b. Acetophenone (45) was obtained as the be synthesized in quantitative yields by the treatment of diox- by-product (Scheme 15, Table 6) [249]. olanes 38 with silica gel in methanol [245]. 1.2. Peroxidation of alkenes with the Co(II)/Et SiH/ 3 O system (Isayama–Mukaiyama reaction) 2 Peroxysilylation of alkenes with molecular oxygen in the pres- ence of triethylsilane catalyzed by cobalt(II) diketonates was described for the first time by S. Isayama and T. Mukaiyama in Scheme 15: Peroxidation of 1,4-dienes 43a,b. 1989 [246,247]. Currently, this approach is one of the main methods for the preparation of peroxides from alkenes. The desilylation of the initially formed silicon peroxide fol- Compounds (oxidized by the Isayama–Mukaiyama reaction) lowed by cyclization of the hydroperoxide accompanied by the containing a reaction center that can be subjected to the attack attack on the electrophilic center is another example of the use 41 Beilstein J. Org. Chem. 2014, 10, 34–114. to give the unsaturated hydroperoxides 50 (Scheme 16, Table 7) Table 6: Synthesis of dioxolanes 44a,b. [249]. Reaction 1,4-Diene Conversion, R time, Yield, % 43 % 1,2-Dioxolanes can be produced from oxetanes 53a,b h containing a double bond in the side chain according to a 44 45 similar scheme. The first step afforded peroxysilanes 54a,b, which upon treatment with aqueous HF gave the target diox- a H 4.5 47 27 49 olanes 55a,b (Scheme 17) [250]. b COOEt 2 44 56 22 A similar way to 1,2-dioxolanes used an oxirane cycle for the stages of ring opening followed by 1,2-dioxolane ring closing of the Isayama–Mukaiyama reaction for the synthesis of cyclic [251]. peroxides. In some cases, the reaction with 1,5-dienes 46a–d produces, along with 1,2-dioxanes 51 (desilylation products of The synthesis of spirodioxolane 59 involved the peroxysilyla- the corresponding 1,2-dioxanes 48), 1,2-dioxolanes (52b,d) as a tion of 1,3-dicyclohexenylpropan-2-yl acetate (56) catalyzed by result of cyclization of the corresponding peroxysilyl epoxides cobalt complexed with 2,2,6,6-tetramethylheptane-3,5-dione 49. In these reactions, unsaturated triethylsilyl peroxides 47 are (Co(THD) ) as the first step giving 1,3-bis(1-(triethylsi- 2 formed as by-products, which are desilylated during hydrolysis lylperoxy)cyclohexyl)propan-2-yl acetate (57) that was subse- Scheme 16: Peroxidation of 1,5-dienes 46. Table 7: Peroxidation of 1,5-dienes 46. Yielda, % Diene 46 R1 R2 Reaction time, h Conversion, % 45 49 50 51 52 a H H 6 82 4 – 13 31 – b H Me 2.5 83 36 – 12 13 33 c H Ph 3.5 75 57 38 7 27 – d Me Me 3 84 51 – – 31 26 aThe yields are given based on the converted dienes 46a–d. 42 Beilstein J. Org. Chem. 2014, 10, 34–114. Scheme 17: Peroxidation of oxetanes 53a,b. quently transformed into the carbonyl-containing diperoxide are formed immediately in the reaction mixture rather than in (1,3-bis(1-(triethylsilylperoxy)cyclohexyl)propan-2-one) (58) in the course of the treatment or purification of the reaction prod- two steps. The latter was treated with p-TsOH to give the target ucts. It was suggested that the reaction proceeds via the forma- peroxide 59 (Scheme 18) [252]. tion of hydroperoxy acetals 61a,b (Scheme 19) [250]. 1.3. The use of ozone. Peroxycarbenium ions in the The ozonolysis of 9-methyleneheptadecane-7,11-diyl- 1,2-dioxolanes synthesis bis(methanesulfonate) (63) gave 9-oxoheptadecane-7,11-diyl- The ozonolysis of unsaturated compounds is a reliable and bis(methanesulfonate) (64). The latter reacted with H O in the 2 2 facile method for the introduction of the peroxide functional presence of sulfuric acid (or iodine) as the catalyst to form 9,9- group. As in the above-considered studies, the intramolecular dihydroperoxyheptadecane-7,11-diyl-bis(methanesulfonate) 65, cyclization of ozonolysis products can be performed with the and the replacement of the mesyl groups in the latter compound use of the hydroperoxide group provided that there is an appro- afforded 3,8-dihexyl-1,2,6,7-tetraoxaspiro[4.4]nonane (66, priate electrophilic center. Scheme 20). The yield of dioxolane 66 was 36% based on 63 [252]. The reaction of oxetanes 60a,b with ozone in methanol produced 3-alkoxy-1,2-dioxolanes 62a,b. The analysis of the The treatment of 3,3'-(cyclohexa-3,6-diene-1,3-diyl)dipropan-1- reaction mixture (TLC, NMR) confirmed that cyclic peroxides ol (67) and 4,4'-(cyclohexa-3,6-diene-1,3-diyl)dibutan-2-ol (69) Scheme 18: Peroxidation of 1,6-diene 56. Scheme 19: Synthesis of 3-alkoxy-1,2-dioxolanes 62a,b. 43