Reactions of mono- and bicyclic enol ethers with the I₂–hydroperoxide system

Abstract

Reactions of mono- and bicyclic enol ethers with I₂–H₂O₂, I₂–Bu^tOOH, and I₂–tetrahydropyranyl hydroperoxide systems have been studied. It was shown that the reaction pathway depends on the nature of peroxide and the ring size. The reaction of 2,3-dihydrofuran and 3,4-dihydro-2H-pyran with the I₂–hydroperoxide system affords iodoperoxides, α-iodolactones, and α-iodohemiacetals. Bicyclic enol ethers are transformed into vicinal iodoperoxides only in the reaction with the I₂–H₂O₂ system, whereas the reaction with I₂–Bu^tOOH gives the hydroperoxidation product.

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Introduction

In the last few decades an extensive development of methods for the synthesis of organic peroxides has been observed, for example, catalysts in combination with hydroperoxides are used such as H₂WO₄,¹ phosphomolybdic and phosphotungstic acids,² methyltrioxorhenium (MeReO₃) in trifluoroethanol,³ trifluroacetic acid with cinchona alkaloids,⁴ Re₂O₇,⁵ BF₃·Et₂O,⁶ CAN,⁷ silicon-supported sodium hydrogen sulfate,⁸ camphorsulfonic acid,⁹ SrCl₂·6H₂O,¹⁰ and also salts of ruthenium,¹¹ copper,¹² cobalt,¹³ and iron,¹⁴ including Gif¹⁵ and metalloporphyrin¹⁶ systems. This development is associated with the fact that many compounds of this class exhibit pronounced antimalarial and anthelmintic activities.¹⁷ Some synthesized compounds show antiparasitic activity comparable to or higher than that of the natural peroxide artemisinin commonly used in medical practice.¹⁸ The search for natural substances and the synthesis of new compounds with antitumor activity is a relatively new and fast-developing field of application of this class of compounds.¹⁹ Peroxides are widely used in the polymer chemistry as radical polymerization initiators and cross-linking reagents.²⁰ These aspects of the application of compounds containing the –O–O– moiety stimulated the development of new approaches to their synthesis.

However, despite the more than a hundred year history of the development of this field of chemistry, the selective synthesis and the controlled transformation of peroxides, as well as their analysis, still present difficulties due to low stability of these compounds (compared to other classes) and the fact that they easily undergo decomposition by a homolytic or heterolytic mechanism.

The present study is in the line with the current trends of using the I₂–H₂O₂ system for the peroxidation and halogenation of organic compounds. This system shows unique and unpredictable reactivity, which is manifested in the fact that the reactions with this system afford a great variety of products. An idea of the combination of iodine or its compounds with peroxides was successfully implemented for the introduction of the peroxide moiety into carbonyl compounds²¹ and alkenes,²² in the synthesis of monoperoxyacetal-containing compounds²³ and cyclic triperoxides,²⁴ for the activation and introduction of iodine in the iodoalkoxylation of alkenes,²⁵ the iodination of arenes,²⁶ ketones,²⁷ and alkynes.²⁸ Besides, this system was used for the Baeyer–Villiger oxidation of ketones to lactones,²⁹ the ring contraction of 1,2-quinones to form cyclopentenones,³⁰ the oxidative C–N³¹ and C–O³² coupling, and the oxidative cyclization to form heterocyclic compounds.³³

The results of investigations covering the iodination of organic compounds or iodine-catalyzed transformations, including peroxides, are summarized in reviews.^34–36

In our previous study we showed that the reaction of enol ethers 1 (containing an exocyclic oxygen atom) with the I₂–H₂O₂ system in Et₂O produces 2-iodo-1-methoxyhydroperoxides 2 and 2-iodoketones 3. Depending on the reaction conditions, either compounds 2 or 3 can be synthesized in preparative yield (Scheme 1).³⁷

Scheme 1 Synthesis of 2-iodo-1-methoxyhydroperoxides 2 and 2-iodo ketones 3.

In the present study, we focused our attention on another type of enol ethers, featuring an endocyclic oxygen atom (4a,b and 10a–c). Contrary to expectations, cyclic enol ethers 4a,b and 10a–c show substantially different behaviour in the reaction with the iodine–hydroperoxide system compared to their acyclic analogues 1 (Scheme 2).

Scheme 2 Reactions of cyclic enol ethers 4a,b, and 10a–c with the iodine–hydroperoxide system.

We studied two groups of enol ethers–monocyclic enol ethers, such as 2,3-dihydrofuran 4a and 3,4-dihydro-2H-pyran 4b, and more complex compounds, such as bicyclic enol ethers, in which a five-membered 10a, six-membered 10b, or seven-membered 10c carbocycle is fused with the dihydropyran ring.

Reactions of 2,3-dihydrofuran 4a and 3,4-dihydro-2H-pyran 4b with the iodine–H₂O₂ system

The reaction of dihydrofuran 4a with the iodine–H₂O₂ system at 0 °C affords a complex mixture of products consisting of iodohydroperoxide 7a (yield 65%), α-iodolactone 9a (yield 15%), and hemiacetal 8a (yield 15%). The reaction of dihydropyran 4b with the iodine–H₂O₂ system produced a mixture of iodohydroperoxide 7b (yield 74%) and hemiacetal 8b (yield 12%), the expected iodovalerolactone was not detected. Apparently, this is associated with the fact that δ-valerolactone, unlike γ-butyrolactone, easily polymerizes.³⁸

Reactions of 2,3-dihydrofuran 4a and 3,4-dihydro-2H-pyran 4b with the iodine–tert-butyl (TBHP) and iodine–tetrahydropyranyl hydroperoxide (THPHP) systems

The iodoperoxidation of 2,3-dihydrofuran (Table 1, entries 1–7) 4a and 3,4-dihydropyran 4b (Table 1, entries 8–14) was performed in Et₂O, CH₃CN, or CH₃CN–Et₂O using a two- or fourfold molar excess of TBHP (Table 1, entries 1–5 and 8–11) or a fourfold molar excess of THPHP (Table 1, entries 6–7 and 12–14) and iodine (0.5–2 mole per mole of 4). To suppress the oxidative side reactions, the synthesis was performed at 0 °C (Scheme 3 and Table 1).

Table 1 Reactions of 2,3-dihydrofuran 4a and 3,4-dihydro-2H-pyran 4b with the I₂–TBHP and I₂–THPHP systems; synthesis of peroxides 5a,b and 6a,b

Entry^a	Solvent	ROOH	Molar ratio: I2/4a,b	Reaction time, min	Yield of 5a,b and 6a,b, %
a Molar ratio: ROOH/4a,b = 4 (entries 1–3, 5–14) and 2 (entry 4).b At 20–25 °C.
1	Et2O	TBHP	0.5 (4a)	30	28 (5a)
2	Et2O	TBHP	1 (4a)	30	76 (5a)
3	Et2O	TBHP	2 (4a)	30	56 (5a)
4	Et2O	TBHP	2 (4a)	30	77 (5a)
5	CH3CN–Et2O	TBHP	2 (4a)	30	52 (5a)
6	Et2O	THPHP	1 (4a)	120	78 (6a)
7	CH3CN	THPHP	1 (4a)	120	35 (6a)
8	Et2O	TBHP	1 (4b)	30	91 (5b)
9	Et2O	TBHP	1 (4b)	120	88 (5b)
10	CH3CN–Et2O	TBHP	1 (4b)	30	56 (5b)
11^b	Et2O	TBHP	1 (4b)	30	17 (5b)
12	Et2O	THPHP	1 (4b)	120	86 (6b)
13	Et2O	THPHP	1 (4b)	30	42 (6b)
14	CH3CN	THPHP	1 (4b)	120	46 (6b)

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Scheme 3 Reactions of 2,3-dihydrofuran 4a and 3,4-dihydro-2H-pyran 4b with the I₂–TBHP and I₂–THPHP systems.

The highest yield of products 5a (76%) and 5b (91%) was achieved when the reaction was performed for 30 min (Table 1, entries 2 and 8) in the presence of an equivalent amount of iodine. An increase in the reaction time to 2 h had no substantial effect of the yield of 5b (Table 1, entry 9). The use of a twofold excess of iodine led to a decrease in the yield of 5a to 56% (Table 1, entry 3). A decrease in the amount of TBHP (Table 1, entry 4) compared to entry 2 had no effect on the yield of the product. The replacement of Et₂O (the reaction medium) by more polar solvent CH₃CN or a CH₃CN–Et₂O mixture led to a sharp decrease in the yield of 5a,b and 6a,b (entries 5, 7, 10, and 14). The reaction with the use of THPHP requires 2 h for the synthesis of 6a,b to be efficient (Table 1, entries 6 and 12). On the whole, the yields of dihydrofuran derivatives 5a and 6a (Table 1, entries 1–7) are lower compared to their dihydropyran homologs 5b and 6b (Table 1, entries 8–14). At room temperature, dihydropyran polymerizes under the action of the reaction system used, which leads to a decrease in the yield of 5b (Table 1, entry 11).

Reaction of bicyclic enol ethers 10b,c with the I₂–H₂O₂ system

One important feature to consider when comparing mono- and bicyclic enol ethers is the absence of hydrogen atoms near double bond in the later systems. Usually peroxides containing R₂(R′O)COOH fragment are more stable than R₂HCOOH peroxides, since they have no easily oxidizable CH fragment. This difference in stability is observed in acid-catalyzed peroxidation of aldehydes and ketones or their acetals⁶ with hydrogen peroxide. It is common knowledge that aldehydes can be easily oxidated by H₂O₂ in carboxylic acids, in contrast more rigid conditions are needed for oxidation of ketones by H₂O₂ with the same result.³⁹ In the case of base-catalyzed processes, R₂HCOOH peroxides can be rearranged in ketones by means of Kornblun–DeLaMare reaction.⁴⁰

Apparently, this is the reason why iodohydroperoxides of bicyclic enol ethers 10b,c are formed more selectively than analogous peroxides of monocyclic enol ethers 4a,b, which undergo further transformations (Scheme 4).

Scheme 4 Reaction of bicyclic enol ethers 10b,c with the I₂–H₂O₂ system.

The conditions of the peroxidation of bicyclic ethers 10b,c (Table 2, entries 15–20) were optimized taking into account the conditions of entry 2 (Table 1). The most significant parameters, viz., the temperature and the reaction medium, were varied. As the temperature was lowered from room temperature to −40 °C, the yield of target product 11b increased from trace amounts to 82% (Table 2, entries 15–17) due, apparently, to the reduction of the effect of polymerization with the participation of enol ether. The reaction in CH₃CN (Table 2, entries 18 and 19) produces virtually no iodohydroperoxide 11b.

Table 2 Reaction of bicyclic enol ethers 10b,c with the I₂–H₂O₂ system; synthesis of iodohydroperoxides 11b,c

Entry	Bicyclic enol ethers 10b,c	Solvent	Onset temperature of the reaction, °C	Yield of 11b,c, %
15	10b	Et2O	20	11b, 10
16	10b	Et2O	0	11b, 43
17	10b	Et2O	−40	11b, 82
18	10b	CH3CN	20	11b, traces
19	10b	CH3CN	−40	11b, traces
20	10c	Et2O	−40	11c, 40

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Iodohydroperoxides 11b,c are unstable compounds and they decompose during isolation and storage.

Reaction of bicyclic enol ethers 10a–c with the I₂–Bu^tOOH system

TBHP is much more bulky than hydrogen peroxide, which has a decisive effect on the structure of the reaction products. Thus, tert-butyl hydroperoxide adds at the double bond, whereas iodine is not involved in the final product.

The reactions of bicyclic ethers 10a–c with the I₂–Bu^tOOH system were performed using a fourfold molar excess of TBHP and an equimolar amount of iodine, with the resulting formation of peroxidated oxabicycloalkanes 12a–c (Scheme 5 and Table 3).

Scheme 5 Reaction of bicyclic enol ethers 10a–c with the I₂–Bu^tOOH system.

Table 3 Reaction of bicyclic ethers 10a–c with the I₂–Bu^tOOH system; synthesis of peroxides 12a–c

Entry	Bicyclic enol ethers 10b,c	Solvent	Onset temperature of the reaction, °C	Yield of 12a–c, %
21	10a	Et2O	−70	12a, 89
22	10b	Et2O	20	12b, 43
23	10b	Et2O	0	12b, 51
24	10b	Et2O	−40	12b, 70
25	10b	Et2O	−70	12b, 75
26	10b	CH3CN	−70	12b, traces
27	10c	Et2O	−70	12c, 66

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In the reaction with the I₂–Bu^tOOH system, like in the reaction with I₂–H₂O₂, the temperature and the nature of the solvent (Table 3, entries 21–27) play a key role in the synthesis of target peroxide 12. In entries 22–25 (Table 3), the yield of the target peroxide increased from 43 to 75% as the reaction temperature was lowered from 20 to −70 °C. Acetonitrile (Table 3, entry 26) proved to be unsuitable as a solvent for the synthesis of 12b. Products 12a–c are more stable compared to 11a–c; however, these compounds substantially decompose during storage even at 0 °C for one week.

Summary from the Tables 1–3 about influence of type of mono- and bicyclic enol ether, hydroperoxide, and solvent on the structure of the products

It is known that particles with positively charged iodine and protons are formed in the iodine–hydroperoxide system.^28a,41 Both these positively charged particles, as well as iodine add at the double bond of enol ether thus initiating the peroxidation. The reactions with dihydrofuran and dihydropyran are accompanied by the iodoperoxidation. In the case of bicylic compounds, the iodoperoxidation is observed only in the reactions with hydrogen peroxide. The reactions with more bulky TBHP involve the addition of only this compound, whereas iodine is not involved in the resulting peroxide. In the reactions with THPHP, no peroxidation of bicyclic compounds is observed.

In addition to the formation of iodohydroperoxide 7a, the reaction of dihydrofuran with the I₂–H₂O₂ system involves the reduction of the hydroperoxide group with HI giving iodo alcohol 8a (ref. 42) and the oxidation of 8a with iodine or particles containing positively charged iodine producing iodolactone 9a.⁴³

Diethyl ether proved to be a much more efficient solvent compared to acetonitrile, because it is a good base, an acceptor of a proton or positively charged iodine, due to which the synthesis can be performed in a relatively milder acidic medium. The reaction in acetonitrile yields mainly resinification products due, apparently, to the acid-catalyzed polymerization characteristic of enol ethers.⁴⁴

Establishment of the structures of the synthesized compounds

The structures of products 5, 6, 11, and 12 were established by ¹H and ¹³C NMR spectroscopy. The ¹H NMR spectra of products 5 and 6 show characteristic signals of the CHI group and the peroxyacetal moiety at δ 3.7–4.15 and 4.9–5.7, respectively. The signal of the CH₂O group is observed at δ 3.5–4.0. Signals of other CH₂ groups are present in the characteristic region at δ 1.2–2.5.

In the ¹³C NMR spectra, the signal of the monoperoxyacetal moiety is observed at δ 103–113, which is consistent with the known data.⁴⁵ The spectra of peroxides 5 show the signal of the tertiary carbon atom of the tert-butylperoxide group at δ 79–81. The spectra of peroxides 6 display several signals of the peroxiacetal moiety due to the formation of different steteroisomers. The ¹³C NMR spectra show signals of the CH₂O group at δ 60–67 ppm and signals of other CH₂ groups at δ 24–36. The chemical shifts of the CHI group in the ¹³C NMR spectra substantially depend on the environment of the carbon atom. In the spectra of products 5 and 6, the signals of this group are observed at δ 19–23, whereas the signals for products 11 containing the tertiary carbon atom are shifted downfield (to δ 65–76).

The structures of compounds 7a, 8a, 9a, and 7b, 8b, which were not isolated in the individual state, were unambiguously established by ¹H and ¹³C NMR spectroscopy using 2D correlation spectroscopic techniques (COSY, NOESY, editing-HSQC, HSQC-TOCSY, and HMBC). The molecular skeleton was established based on heteronuclear correlations. The O–CH–OOH and O–CH–OH groups in cyclic compounds 7a, 8a, and 7b, 8b differ by the chemical shifts in the ¹³C NMR spectra. It is known⁴⁶ that the replacement of one alkoxy group in acetal by the peroxide group leads to a shift of the signal of the carbon atom in the O–C–O group to lower field. The same dependence was observed in the present study. Based on the HSQC NMR data, the chemical shifts for hydroperoxides are 105 ppm (7a) and 98 ppm (7b), whereas the chemical shifts for hemiacetals are observed at lower field (98 ppm for 8a and 93 ppm for 8b). The similar dependence is observed in the ¹H NMR spectra; for hydroperoxides, the chemical shifts are 5.6 ppm (7a) and 4.9 ppm (7b); for hemiacetal, the corresponding values are lower (4.8 ppm for 8a and 4.1 ppm for 8b).

The IR spectra of peroxides 5, 6, and 11 show characteristic CH–I stretching bands in the region of 500–800 cm⁻¹ and CH–O stretching bands of the peroxyketal moiety in the region of 1020–1300 cm⁻¹.

The compositions of the synthesized compounds were established also using HRMS data. The mass spectra of 5, 6, and 12 have peaks corresponding to the molecular ions. According to the mass-spectrometric data, the ES ionization of 11 leads to the elimination of the peroxide moiety 11b or iodine atom and peroxide moiety 11c.

Conclusions

The reactions of mono- and bicyclic enol ethers with the I₂–H₂O₂, I₂–Bu^tOOH, and I₂–tetrahydropyranyl hydroperoxide systems were studied. We succeeded in synthesizing and characterizing difficult-to-synthesize unstable oxacyclic peroxides and iodoperoxides. It was shown that the reaction pathway depends on the nature of peroxide and the ring size. The reaction of monocyclic enol ethers with the I₂–H₂O₂ system produces iodoperoxides, α-iodohemiacetals, and α-iodolactones, whereas the reaction with I₂–Bu^tOOH gives only iodoperoxidation products. Bicylic enol ethers are transformed into vicinal iodoperoxides in 40–82% yields only in the reactions with the I₂–H₂O₂ system, whereas the reaction with I₂–Bu^tOOH affords hydroperoxidation products in 66–89% yields, iodine being not involved in the target product.

Experimental

¹H and ¹³C NMR spectra were recorded on Bruker AMX-III 400 (400.1 and 100.6 MHz, respectively) and Bruker AVANCE II 300 (300.1 and 75.5 MHz, respectively) spectrometers in CDCl₃. Assignments of ¹H and ¹³C signals were made and the structures of the compounds were determined with the aid of 2D COSY, NOESY, editing-HSQC, HSQC-TOCSY, and HMBC spectra in the case of studying mixtures 7a, 8a, 9a and 7b, 8b.

MeCN (HPLC grade) for ESI-HRMS experiments was ordered from Merck and used as supplied. All samples for ESI-HRMS experiments were prepared in 1.5 mL Eppendorf tubes. All plastic disposables (Eppendorf tubes and tips) used in sample preparation were washed with MeCN before use.

High resolution mass spectra were recorded on a Bruker maXis instrument equipped with electrospray ionization (ESI) ion source.^47,48 The all measurements were performed in a positive (+MS) ion mode (interface capillary voltage: 4500 V) with scan range m/z: 50–3000. External calibration of the mass spectrometer was performed with Electrospray Calibrant Solution (Fluka). A direct syringe injection was used for the all analyzed solutions in MeCN (flow rate: 3 μL min⁻¹). Nitrogen was used as nebulizer gas (0.4 bar) and dry gas (4.0 L min⁻¹); interface temperature was set at 180 °C. The all spectra were processed by using Bruker DataAnalysis 4.0 software package.

The TLC analysis was carried out on standard silica gel chromatography plates. The melting points were determined on a Kofler hot-stage apparatus. Chromatography was performed on silica gel (0.060–0.200 mm, 60 A, CAS 7631-86-9).

Petroleum ether 40–70 (PE), Et₂O, CH₃CN, CH₂Cl₂, and ethyl acetate (EA) were distilled before use over the corresponding drying agents. The reagents I₂, Na₂S₂O₃·5H₂O, and Na₂SO₄ were of chemical purity grade. tert-Butyl hydroperoxide (70% solution in water), 3,4-dihydro-2H-pyran and 2,3-dihydrofuran were purchased from Acros. Bicyclic enol ethers 10a–c were synthesized according to known procedures.^49,50

A solution of H₂O₂ was prepared by the extraction with diethyl ether from a 37% aqueous H₂O₂ solution followed by drying over MgSO₄.²² A 51% ethereal solution of tert-butyl hydroperoxide was prepared by a similar procedure using tert-butyl hydroperoxide (70% solution in water).

2,3,4,5,6,7-Hexahydrocyclopenta[b]pyran (10a)⁴⁹

Colorless oil. δ_H (300 MHz, CDCl₃): 1.52–2.29 (10H, m, C(CH₂)₃C, C(CH₂)₂CH₂O), 3.96 (2H, m, CH₂O).

δ_C (50 MHz, CDCl₃): 19.3, 21.8 (CCH₂CH₂CH₂C), 22.7 (OCH₂CH₂CH₂C), 30.9 (CCH₂(CH₂)₂C), 32.3 (OCCH₂(CH₂)₂C), 69.8 (OCH₂), 106.8 (CH₂CCH₂), 151.0 (OCCH₂).

Calculated (%): C 77.38; H, 9.74%; found (%): C, 77.45; H, 9.73. C₈H₁₂O%.

3,4,5,6,7,8-Hexahydro-2H-chromene (10b)⁵⁰

Colorless oil. δ_H (300 MHz, CDCl₃): 1.45–2.34 (12H, m, C(CH₂)₄C, (CH₂)₂CH₂O), 3.91 (2H, m, CH₂O).

δ_C (50 MHz, CDCl₃): 22.9 (OCH₂CH₂), 23.1 (CH₂CCH₂CH₂), 23.26 (C(CH₂)₂CH₂CH₂C), 25.2 (OCH₂CH₂CH₂), 27.2 (CCH₂(CH₂)₃C), 28.9 (OCCH₂), 65.5 (OCH₂), 104.3 (CH₂CCH₂), 146.7 (OCCH₂).

Calculated (%): C, 78.21; H, 10.21; found (%): C, 78.25; H, 10.18. C₉H₁₄O%.

2,3,4,5,6,7,8,9-Octahydrocyclohepta[b]pyran (10c)

Colorless oil. δ_H (300 MHz, CDCl₃): 1.33–2.45 (14H, m, (CH₂)₅, (CH₂)₂CH₂O), 3.83 (2H, m, CH₂O).

δ_C (75 MHz, CDCl₃): 23.4 (CH₂CH₂O), 25.8 ((CH₂)₂CH₂(CH₂)₂), 27.0 (CH₂CH₂(CH₂)₃), 27.2 (O(CH₂)₂CH₂), 31.0 (CH₂CCH₂), 32.5 (OCCH₂CH₂), 33.2 (OCCH₂), 65.4 (OCH₂), 108.3 (CH₂CCH₂), 152.2 (OCCH₂).

Calculated (%): C, 78.90; H, 10.59; found (%): C, 78.96; H, 10.52; C₁₀H₁₆O%.

Reaction of monocyclic enol ethers 4a,b with the I₂–H₂O₂ system. Synthesis of 7a, 8a, 9a and 7b, 8b

Iodine (0.256–1.024 g, 1–4 mmol) was dissolved in Et₂O or CH₃CN (10 mL), a 2.53 M ethereal solution of H₂O₂ (3.16 mL, 8 mmol) was added, and then a solution of 4a or 4b (0.140 or 0.160 g, 2 mmol) in Et₂O (2 mL) was added dropwise with stirring at 0 °C. The mixture was stirred for 30 min at 0 °C. Petroleum ether (20 mL) and finely dispersed Na₂S₂O₃·5H₂O (1.5 g) were added, and the mixture was stirred until the it became colorless. The solid residue and possible polymeric resins were separated using a silica gel layer. The solvents were rotary evaporated at 10–15 mmHg and 15–20 °C. The resulting oil (0.420 g for 7–9a or 0.462 g for 7–8b) was studied by NMR spectroscopy, including homo- and heteronuclear correlation spectroscopic techniques (COSY, NOESY, editing-HSQC, HSQC-TOCSY and HMBC); the structures of the compounds and their yields were determined from the NMR data.

Experiment to Table 1. Reactions of 3,4-dihydro-2H-pyran 4a and 2,3-dihydrofuran 4b with the I₂–tert-butyl hydroperoxide and I₂–tetrahydropyranyl hydroperoxide systems; synthesis of peroxides 5a,b and 6a,b

Iodine (0.256–1.024 g, 1–4 mmol) was dissolved in Et₂O or CH₃CN (10 mL), a 51% ethereal solution of tert-butyl hydroperoxide (0.693 g, 4 mmol or 1.386 g, 8 mmol) or tetrahydropyranyl hydroperoxide (0.945 g, 8 mmol) was added, and then a solution of 4a or 4b (0.14 or 0.16 g, 2 mmol) in Et₂O (2 mL) was added dropwise with stirring at 0 °C. The mixture was stirred for 30 or 120 min at 0 °C (in entry 11, at 20–25 °C). Then petroleum ether (20 mL) and finely dispersed Na₂S₂O₃·5H₂O (1.5 g) were added, and the mixture was stirred until it became colorless. The solid residue was filtered off. The solvents were rotary evaporated at 10–15 mmHg and 15–20 °C. Peroxides 5a,b and 6a,b were isolated from the residue by column chromatography on silica gel. Eluent EA–PE = 1 : 30.

Experiment to Table 2. Reaction of bicyclic enol ethers 10b,c with the I₂–H₂O₂ system to form iodohydroperoxides 11b,c

Iodine (0.508 g, 2 mmol) was dissolved in Et₂O or CH₃CN (10 mL), a 2.53 M ethereal solution of H₂O₂ (3.16 mL, 8 mmol) was added, and then a solution of enol ether 10 (10b, 0.280 g, 2 mmol; 10c, 0.304 g, 2 mmol) in Et₂O (2 mL) was added dropwise with stirring at 20, 0, or −40 °C. The mixture was stirred for 1 h; in the experiments using cooling, the temperature was gradually raised to 20–25 °C. Then petroleum ether (20 mL) and finely dispersed Na₂S₂O₃·5H₂O (1.5 g) were added, and the mixture was stirred until it became colorless. The solid residue was filtered off. The solvents were rotary evaporated at 10–15 mmHg and 15–20 °C. Iodohydroperoxides 11b,c were isolated from the residue by column chromatography on silica gel. Eluent EA–PE = 1 : 5.

Experiment to Table 3. Reaction of bicyclic enol ethers 10a–c with the I₂–Bu^tOOH system to form peroxides 12a–c

Iodine (0.508 g, 2 mmol) was dissolved in Et₂O or CH₃CN (10 mL), a 51% ethereal solution of tert-butyl hydroperoxide (1.386 g, 8 mmol) was added, and then a solution of enol ether 10 (10a, 0.248 g, 2 mmol; 10b, 0.280 g, 2 mmol; 10c, 0.304 g, 2 mmol) in Et₂O (2 mL) was added dropwise with stirring at 20, 0, −40, or −70 °C. The mixture was stirred for 1 h with the temperature being gradually raised to 20–25 °C. Then petroleum ether (20 mL) and finely dispersed Na₂S₂O₃·5H₂O (1.5 g) were added, and the mixture was stirred until it became colorless. The solid residue was filtered off. The solvents were rotary evaporated at 10–15 mmHg and 15–20 °C. Iodohydroperoxides 12a–c were isolated from the residue by column chromatography on silica gel. Eluent EA–PE = 1 : 30.

2-(tert-Butylperoxy)-3-iodotetrahydrofuran (5a).
Yellow oil. Rf = 0.84 (EA : PE = 1 : 10). δ_H (200 MHz, CDCl₃): 1.21 (9H, s, (CH₃)₃C), 2.15–2.19 (1H, m, HCHCHI), 2.47–2.54 (1H, m, HCHCHI), 4.02–4.22 (3H, m, CH₂O, CHI), 5.74 (1H, m, CHO).

δ_C (75 MHz, CDCl₃): 19.6 (CHI), 26.3 (CH₃), 36.5 (CH₂CH₂O), 67.9 (CH₂O), 81.3 (C(CH₃)₃), 113.4 (CHO).

IR (KBr): 2979 (vs), 2933 (s), 2897 (s), 1475 (m), 1455 (m), 1439 (m), 1387 (m), 1364 (vs), 1309 (m), 1286 (m), 1245 (s), 1194 (vs), 1151 (m), 1123 (s), 1087 (vs), 1069 (vs), 1036 (s), 996 (vs), 953 9 (s), 920 (s), 860 (s), 773 (m), 754 (m) cm⁻¹.

HRMS (ESI) m/z [M + Na]⁺: calculated for [C₈H₁₅IO₃Na]⁺: 308.9958. Found: 308.9948.

2-(tert-Butylperoxy)-3-iodotetrahydro-2H-pyran (5b).
Yellow oil. Rf = 0.15 (EA : PE = 1 : 20). δ_H (300 MHz, CDCl₃): 1.28 (9H, s, (CH₃)₃C), 1.60–1.66 (2H, m, (CH₂CHI)), 2.04–2.07 (1H, m, HCHCH₂O), 2.31–2.33 (1H, m, HCHCH₂O), 3.62 (1H, m, HCHO), 3.99–4.2 (2H, m, HCHO, CHI), 5.02 (1H, m, CHO).

δ_C (75 MHz, CDCl₃): 23.4 (CHI), 26.4 (CH₂CH₂O), 26.5 (CH₃), 34.6 (CH₂CHI), 64.5 (CH₂O), 81.7 (C(CH₃)₃), 104.6 (CHO).

IR (KBr): 2977 (vs), (vs), 2865 (s), 1467 (m), 1439 (m), 1387 (m), 1364 (vs), 1259 (m), 1244 (m), 1196 (vs), 1170 (m), 1120 (vs), 1097 (s), 1076 (vs), 1038 (s), 1026 (s), 965 (s), 902 (m), 867 (m), 696 (m), 466 (m) cm⁻¹.

HRMS (ESI) m/z [M + Na]⁺: calculated for: [C₉H₁₇IO₃Na]⁺: 323.0115. Found: 323.0120.

2-[(3-Iodotetrahydrofuran-2-yl)peroxy]tetrahydro-2H-pyran (6a).
Colorless oil. Rf = 0.6 (EA : PE = 1 : 5). δ_H (300 MHz, CDCl₃): 1.45–2.59 (8H, m, CHICH₂, (CH₂)₃CH(O)OO), 3.50–3.65, 3.96–4.25, 5.1–5.25, 5.84–5.91 (7H, m, 2CH₂O, CHI, 2CH).

δ_C (75 MHz, CDCl₃): 19.0, 19.2, 19.3, 19.9 (CHI, CH₂(CH₂)₂O), 25.0 (CH₂CH₂O), 27.5, 27.7, 27.8 (CH₂CH(O)OO), 36.1, 36.3 (CHICH₂), 62.0, 62.3, 62.4, (CH₂)₃CH₂O, 67.8, 68.1 (CHICH₂CH₂), 100.2, 100.9, 101.8 (CH₂CH(O)OO), 113.2, 113.9 (CHICH(O)OO).

IR (KBr): 2944 (vs), 2895 (s), 2872 (s), 2852 (s), 1469 (m), 1454 (m), 1441 (m), 1352 (m), 1260 (m), 1204 (s), 1186 (m), 1107 (vs), 1085 (s), 1040 (vs), 1017 (s), 983 (s), 955 (vs), 903 (vs), 874 (s), 817 (m), 430 (m) cm⁻¹.

HRMS (ESI) m/z [M + Na]⁺: calculated for [C₉H₁₅IO₄Na]⁺: 336.9907. Found: 336.9905.

3-Iodo-2-(tetrahydro-2H-pyran-2-ylperoxy)tetrahydro-2H-pyran (6b).
Colorless oil. Rf = 0.6 (EA : PE = 1 : 5). δ_H (300 MHz, CDCl₃): 1.52–2.29 (10H, m, CHICH₂, (CH₂)₃CH(O)OO), 3.50–3.65, 3.88–4.18, 5.19–5.33 (7H, m, 2CH₂O, CHI, 2CH).

δ_C (75 MHz, CDCl₃): 19.1, 19.3, 19.5 (CHI, CH₂CH₂(CH₂)₂O), 24.8, 25.0, 25.1 (CHICH₂CH₂CH₂O, CHOO(CH₂)₂CH₂), 27.5, 27.6, 27.8 (CH₂CH(O)OO), 32.5, 32.7 (CHOOCH₂, CHICH₂), 62.0, 62.3, 63.5 ((CH₂)₃CH₂O, CHI(CH₂)₂CH₂O, (CH₂)₃CH₂O), 100.1, 100.3, 101.9 (CH₂CH(O)OO), 101.7, 102.0 (CHICH(O)OO).

IR (KBr): 2942 (vs), 2872 (vs), 2852 (vs), 2740 (m), 1737 (m), 1468 (s), 1454 (s), 1441 (vs), 1388 (s), 1352 (vs), 1310 (s), 1283 (s), 1261 (s), 1204 (vs), 1186 (vs), 1106 (vs), 1078 (vs), 1040 (vs), 1017 (vs), 953 (vs), 903 (vs), 874 (vs), 817 (s), 697 (m), 589 (m), 567 (m), 532 (m), 505 (w), 430 (s) cm⁻¹.

HRMS (ESI) m/z [M + Na]⁺: calculated for [C₁₀H₁₇IO₄Na]⁺: 351.0064. Found: 351.0062.

4a-Iodooctahydro-8aH-chromen-8a-yl hydroperoxide (11b).
White crystals; mp 79–81 °C. Rf = 0.55 (EA : PE = 1 : 5). δ_H (300 MHz, CDCl₃): 1.15–2.70 (12H, m, (CH₂)₄, (CH₂)₂CH₂O), 3.61–4.05 (2H, m, CH₂O), 7.60 (1H, br. s, OOH).

δ_C (50 MHz, CDCl₃): 22.0, 24.0, 24.6, 30.8, 36.6, 41.1 ((CH₂)₄, (CH₂)₂CH₂O), 61.5 (CH₂O), 65.1 (C–I), 103.8 (COOH).

IR (KBr): 3459 (vs), 3264 (vs), 2955 (vs), 2938 (vs), 2887 (s), 2863 (s), 1712 (m), 1460 (s), 1367 (s), 1289 (s), 1217 (vs), 1190 (vs), 1165 (s), 1094 (s), 1054 (vs), 987 (vs), 902 (s), 869 (s), 842 (m), 799 (m), 727 (m), 604 (m), 550 (s), 476 (m) cm⁻¹.

HRMS (ESI) m/z [M − OOH]⁺: calculated for [C₉H₁₄IO]⁺: 265.0084. Found: 265.0093.

4a-Iodooctahydrocyclohepta[b]pyran-9a(2H)-yl hydroperoxide (11c).
Yellow oil. Rf = 0.39 (EA : PE = 1 : 5). δ_H (300 MHz, CDCl₃): 1.15–2.50 (14H, m, (CH₂)₅, (CH₂)₂CH₂O), 3.50–3.80 (2H, m, CH₂O).

δ_C (75 MHz, CDCl₃): 20.7, 21.0, 25.8, 27.6, 33.8, 36.4, 44.9 ((CH₂)₅, (CH₂)₂CH₂O), 61.1 (CH₂O), 61.5 (CI), 106.3 (COOH).

IR (KBr): 3355 (m), 2930 (vs), 2860 (s), 1705 (m), 1450 (m), 1359 (m), 1212 (m), 1074 (s), 996 (m), 892 (m), 732 (m) cm⁻¹.

HRMS (ESI) m/z [M + Na − HI]⁺: calculated for [C₁₀H₁₆O₃]⁺: 207.0992. Found: 207.1009.

7a-(tert-Butylperoxy)octahydrocyclopenta[b]pyran (12a).
Yellow oil. Rf = 0.12 (EA : PE = 1 : 10). δ_H (300 MHz, CDCl₃): 1.23–2.14 (20H, m, (CH₂)₃COO, (CH₂)₂CH(CH₂)₃, CH), 3.66–3.87 (2H, m, CH₂O).

δ_C (50 MHz, CDCl₃): 21.0 (CHCH₂CH₂CH₂C), 22.8 (CH₂CH₂O), 26.7 (C(CH₃)₃), 28.5, 31.2 (CHCH₂CH₂, CH₂CH₂CH), 36.0 (CCH₂), 39.5 (CH), 61.0 (CH₂O), 79.0 (OOC(CH₃)₃), 110.1 (OCOO).

IR (KBr): 3424 (m), 2944 (vs), 2878 (s), 1738 (s), 1464 (m), 1446 (m), 1067 (s), 993 (s), 915 (m), 900 (m) cm⁻¹.

HRMS (ESI) m/z [M]⁺: calculated for [C₁₂H₂₁O₃]⁺: 213.1485. Found: 213.1492.

8a-(tert-Butylperoxy)octahydro-2H-chromene (12b).
Yellow oil. Rf = 0.11 (EA : PE = 1 : 10). δ_H (300 MHz, CDCl₃): 1.21–1.54 (22H, m, C(CH₂)₄C, (CH₃)₃C, OCH₂(CH₂)₂CH, CH), 3.64–3.98 (2H, m, CH₂O).

δ_C (50 MHz, CDCl₃): 22.5, 25.9 (CCH₂CH₂(CH₂)₂CH, OCH₂CH₂), 26.3, 26.6 (CHCH₂CH₂(CH₂)₂C, CH(CH₂)₂CH₂CH₂CH), 26.8 (C(CH₃)₃) 29.8 (CHCH₂), 32.3 (OOCCH₂) 44.6 (CH), 60.9 (CH₂O), 78.8 (OOC(CH₃)₃), 101.3 (OCOO).

IR (KBr): 2977 (vs), 2936 (vs), 2883 (s), 2860 (s), 1447 (m), 1362 (s), 1254 (m), 1243 (m), 1214 (m), 1200 (s), 1107 (m), 1091 (vs), 1025 (m), 994 (m), 969 (m), 957 (m), 931 (s), 892 (m), 867 (m), cm⁻¹.

HRMS (ESI) m/z [M + Na]⁺: calculated for [C₁₃H₂₄O₃Na]⁺: 251.1618. Found: 251.1619.

9a-(tert-Butylperoxy)decahydrocyclohepta[b]pyran (12c).
Yellow oil. Rf = 0.14 (EA : PE = 1 : 10). δ_H (300 MHz, CDCl₃): 1.20–2.01 (24H, m, C(CH₂)₅C, (CH₃)₃C, OCH₂(CH₂)₂C, CH), 3.59–4.10 (2H, m, CH₂O).

δ_C (50 MHz, CDCl₃): 20.7, 21.5, 23.4, 26.1 (C(CH₂)₂CH₂(CH₂)₂C, CH₂CH₂(CH₂)₃, OCCH₂CH₂(CH₂)₃C, OCH₂CH₂), 26.7 (C(CH₃)₃) 29.8 (CHCH₂), 31.4 (O(CH₂)₂CH₂CH), 34.4 (OCCH₂), 38.3 (CH), 62.4 (CH₂O), 78.7 (OOC(CH₃)₃), 105.7 (OCOO).

IR (KBr): 3400 (m), 2974 (vs), 2934 (vs), 2864 (s), 1735 (s), 1704 (vs), 1456 (m), 1363 (s), 1243 (s), 1197 (s), 1170 (m), 1154 (m), 1052 (m), 910 (m) cm⁻¹.

HRMS (ESI) m/z [M + Na]⁺: calculated for [C₁₄H₂₆O₃Na]⁺: 265.1774. Found: 265.1773.

Acknowledgements

This work was supported by the Russian Foundation for Basic Research (Grant 14-03-00237-a), the Program for Basic Research of the Presidium of the Russian Academy of Sciences, and the Ministry of Education and Science of the Russian Federation. High resolution mass spectra were recorded in the Department of Structural Studies of Zelinsky Institute of Organic Chemistry, Moscow.

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H, ¹³C NMR, IR and HRMS spectra. See DOI: 10.1039/c3ra46462h

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