Practical Epoxidation of Olefins Using Air and Ubiquitous Iron-Based Fluorous Salen Complex

The epoxidation of olefins by substituting “air” for potentially harmful oxidants was achieved using an oxidation method that integrated a fluorous iron(III) salen catalyst derived from common metals and pivalaldehyde. Several aromatic disubstituted olefins were converted into their corresponding epoxides with high efficiency and quantitative yields. This reaction represents an environmentally friendly oxidation process that utilizes an abundant source of air and employs a readily available metal, iron, in the form of salen complexes, making it an environmentally conscious oxidation reaction.

In 1992, Kaneda et al. successfully conducted the oxygen epoxidation of olefins under oxygen-bubbling conditions using pivalaldehyde as a co-oxidant [3].This study is significant because of its adoption of an environmentally friendly oxidation method featuring reagents with low explosiveness and no generation of byproducts from the oxidants.However, the continuous bubbling of oxygen, which is the source of oxygen, is required, making the operation cumbersome.Moreover, the use of high-concentration oxygen poses a potential risk of dust explosions.Therefore, the practical application of this method to plant-scale operations in an oxygen atmosphere is challenging.To enhance its applicability to industrial processes as an oxidant, there is a preference for utilizing the more readily available and safer "air directly" in large-scale synthesis.
Furthermore, Mukaiyama et al. presented a method for the asymmetric epoxidation of olefins using oxygen (not air) as the oxidant, combining a manganese salen complex [17,18] with pivalaldehyde [12].However, this oxygen oxidation reaction requires the use of the rare metal manganese.Although there have been a few reports on the epoxidation of olefins using "air" as an oxidant, an efficient epoxidation reaction without using rare metals has rarely been reported.
In our previous study, we developed an asymmetric oxidation catalyst by introducing a fluorous tag at the 3,3 ′ -position of the salen ligand.Using this complex, we achieved the asymmetric epoxidation of olefins under hypervalent iodine conditions for the first time using "iron" [19].However, in this method, the use of oxidants, such as iodosobenzene was essential.If a reaction system using air and a common metal-iron complex can be realized, it has the potential to be applied to industrial processes as a safe and environmentally friendly synthetic method.Fluorous iron salen complexes have been suggested to have a different steric environment than normal salen complexes [19]; therefore, different and unique reactivities are expected.In this paper, we report the air epoxidation of olefins using a novel fluorous iron(III) salen complex with isoaldehyde as a co-oxidant.The reaction system using air directly as the oxidant is fundamentally different from using oxygen molecules, as it eliminates the need for the pre-preparation of oxidants.This enables the construction of an environmentally friendly and energy-efficient reaction system.

Results and Discussions
Two types of iron salen complexes with perfluoroalkyl groups of different lengths were synthesized based on the impact of variations in full-length fluorous-tagged iron salen complexes on catalytic activity.Fluorous iron(III) salen complex 1a with a C 4 F 9 tag at the 3,3 ′ -position of the ligand was prepared using our previously reported procedure [20].Complex 1b with a C 12 F 25 tag at the same position was also synthesized.In other words, perfluoroalkylation reactions were initiated from 5-tert-butylsalicylaldehyde 2 using V-70L [2,2 ′ -azobis(2,4-dimethyl-4-methoxyvaleronitrile)] to obtain the perfluoroalkyl precursors 3a and 3b.Subsequently, each perfluoroalkyl precursor underwent condensation reactions with (1R,2R)-(+)-1,2-diphenylethylenediamine to form a salen ligand.The final step involved coordination exchange with iron(III) chloride to synthesize the desired fluorous iron(III) salen complexes, 1a and 1b (Scheme 1).Non-fluorous catalyst 1c was synthesized using a known synthetic method in which the central metal of the Jacobsen-type Mn salen complex [17], with the R group being the t Bu group, was replaced with iron.The epoxidation of olefins using air as the oxidant was investigated using the synthesized complexes 1a and 1b.The reaction was performed for 5 h at room temperature in acetonitrile using triphenylethylene 4a as a substrate in the presence of an iron(III) salen complex and pivalaldehyde (Table 1) [12].The reaction with complex 1a yielded the desired epoxide 5a; however, the conversion was only 73%.Notably, the reaction with complex 1b yielded 5a quantitatively with significantly better reactivity than that with 1a.Even when the amount of 1b was reduced from 1 to 0.5 mol%, no decrease in the reactivity was observed, and the target product was successfully obtained quantitatively.However, as in a previous report [19], chirality was not induced in this reaction, and the resulting product was racemic.Even when using non-fluorous catalyst 1c under the same conditions, the reaction proceeded; however, its catalytic activity was low.These results showed that 1b is the optimal catalyst for the air oxidation reaction among these catalysts.Next, the aldehyde structure was added as a co-oxidant in the reaction, and complex 1b was optimized (Table 2).Relatively good results were obtained when isovaleraldehyde was used; however, the yield was slightly lower than that when pivalaldehyde was used under the same conditions (Table 2, entries 1 vs. 2).When other aliphatic and alicyclic aldehydes were added, little progress was observed (Table 2, entries 3-5).Similarly, when aromatic aldehydes with nitro, methoxy, or methyl groups at the para-position, 2-naphthalaldehyde or heteroaromatic aldehydes, were used, the reaction did not proceed (Table 2, entries 6-12).These results showed that pivalaldehyde, which is used in combination with salenmanganese complexes, has been reported in the literature [12] and is the most suitable aldehyde as a co-oxidant in this reaction.We then investigated the solvent effect on this reaction (Table 3).In addition to the successful progression observed in dry MeCN, the reaction proceeded smoothly when the protonic polar solvent, t BuOH, was used.However, at the 5-h mark, a thin-layer chromatography (TLC) test showed that the starting material had not disappeared; therefore, the starting material had to be fully consumed for 8 h (Table 3, entry 2).When dry MeOH was used, complex 1b and the substrate did not dissolve in the solvent, leading to a significant reduction in the reaction yield (Table 3, entry 3).For non-protonic polar solvents, dry DMF and dry THF were considered, but neither showed significant progress in the reaction (Table 3, entries 4 and 5).When halogenated solvents, such as dry DCM and 2,3,4,5,6-pentafluorotoluene, were used, longer reaction times were required, but high conversion rates were achieved (Table 3, entries 6 and 7).These results showed that dry MeCN was the optimal solvent for this reaction.Next, the substrate scope of this epoxidation reaction was investigated (Table 4).Quantitatively corresponding epoxides were obtained by extending the reaction time to 6 or 7 h using disubstituted internal olefins 4b and 4c, as well as terminal olefin 4d as substrates (Table 4, entries 2-4).Interestingly, only an isomerized trans-type epoxide was produced in the reaction using cis-β-methylstyrene 4c as the substrate, and no cistype epoxide was observed.When substrates 4e-g with electron-donating or fluorine substituents were used, the reactions proceeded smoothly and quantitatively to produce the corresponding epoxides (Table 4, entries 5-7).However, when (E)-2-styrylnaphthalene 4h was used as the substrate, a decrease in reactivity was observed, and the conversion rate remained at 52% even when the reaction time was extended to 24 h (Table 4, entry 8).When substrate 4i containing both trisubstituted and monosubstituted olefinic moieties was used, only the trisubstituted olefinic site underwent selective epoxidation with perfect regioselectivity, leading to the quantitative formation of monoxide 5i (Table 4, entry 9).
In 2008, Köckritz et al. reported the epoxidation of olefins using aldehydes as cooxidants and highlighted the involvement of radical intermediates in the reaction [5].Notably, in the reaction using salen iron complex 1b, isomerized trans epoxide was observed when cis-β-methylstyrene 4c was used as the substrate (Table 4, entry 3).This observation indicated that the reaction also progressed through the radical species.Therefore, we conducted a control experiment by adding 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as the radical scavenger (Scheme 2).Thus, the reaction did not proceed at all, suggesting that it also proceeds via radical species.Scheme 2. Control experiment using a radical scavenger.It is known that pivalaldehyde forms a peroxyl radical species upon interaction with oxygen molecules [4][5][6].The corresponding trans isomer was also generated in our reaction when cis-olefin was used as the substrate.These observations show that the peroxyl radical species interacts with iron, and the reaction may proceed through an iron(III) complex of radical species, as shown in Scheme 3.

Conclusions
Fluorous salen complex 1b, which features iron as the central metal, was used as a catalyst to achieve the epoxidation reaction of olefins using "air" as the oxidizing agent.This reaction can be applied to various polysubstituted olefins to obtain the corresponding epoxides in high yields.This is an extremely safe reaction system that uses inexhaustible "air" as the oxidant.It is also an environmentally friendly oxidation reaction that uses iron, which is a common metal.In future studies, we aim to expand the catalytic reaction system to recycle and reuse fluorous salen complexes.

Materials and Reagents
All the laboratory chemicals were purchased from Tokyo Chemical Industry Co., Ltd.(Tokyo, Japan), FUJIFILM Wako Pure Chemical Corporation (Richmond, VA, USA), Sigma-Aldrich Co., LLC (St. Louis, MO, USA), and Kanto Chemical Co., Inc. (Tokyo, Japan) and used without further purification unless otherwise stated.Solvents were removed using rotary evaporation under reduced pressure using a water bath at 50 • C. Nonvolatile compounds were dried in vacuo at 0.01 mbar.All reactions were stirred magnetically and monitored using thin-layer chromatography using silica gel plates.Purification by chromatography was performed on silica gel 60 N (spherical, neutral, 63-210 µm, Kanto Chemical Co., Inc.).Fluorous solid phase extraction (FSPE) was performed on FluoroFlash ® SILICA (40 µm, 60 A, Sigma-Aldrich, USA).

Analytical Instruments
Melting points were determined in ATM-01 of AS ONE Corporation and are uncorrected.Nuclear magnetic resonance (NMR) spectra were recorded using JNM-ECZ400S ( 1 H: 400 MHz, 13 C: 101 MHz, 19 F: 376 MHz) spectrometers. 1 H NMR spectral data are reported as follows: chemical shift in ppm referenced to TMS (δ 0.00 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, dd = double doublet, br s = broad signal), coupling constant (J: units in Hz), and integration. 13C NMR spectral data are reported as chemical shifts in ppm referenced to residual solvent (CDCl 3 δ 77.16 ppm). 19F NMR spectral data are reported as follows: chemical shift (uncorrected), integral.High-performance liquid chromatography (HPLC) analyses were performed using DAICEL CHIRALCEL OD-3 column with UV Detector SPD-20A.High-resolution mass spectra were obtained using Exactive TM Plus Orbitrap (Thermo Fisher Scientific, Waltham, MA, USA).The spectra were calibrated with Pierce TM LTQ Velos ESI Positive Ion Calibration Solution before data acquisition.

General Procedure for the Epoxidation of Olefins Using Air
Under air atmosphere (vide Appendix A), pivalaldehyde (109 µL, 1.0 mmol, 5.0 eq.) was added to a suspension of olefin (0.2 mmol, 1.0 eq.) and Fe(III) salen complex (1.0 µmol, 0.5 mol%) in dry-MeCN (2 mL).The mixture was stirred at room temperature.After completion, the reaction mixture was diluted with ethyl acetate, and washed with saturated sodium bicarbonate aq. and brine.The organic layer was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.The conversion was determined by 1 H NMR spectra of the crude product.The ee of the product was determined by HPLC analysis of the epoxides.

a
Determined by 1 H NMR. b Isolated yield.

a
Determined by 1 H NMR. b "MOM" represents the "methoxymethyl group".

Table 3 .
Solvent effects in air-epoxidation reactions.

Entry Solvent Time (h) Conv. (%) a
a Determined by 1 H NMR.