Asymmetric Epoxidation of Olefins with Sodium Percarbonate Catalyzed by Bis-amino-bis-pyridine Manganese Complexes

Abstract

Asymmetric epoxidation of a series of olefinic substrates with sodium percarbonate oxidant in the presence of homogeneous catalysts based on Mn complexes with bis-amino-bis-pyridine ligands is reported. Sodium percarbonate is a readily available and environmentally benign oxidant that is studied in these reactions for the first time. The epoxidation proceeded with good to high yields (up to 100%) and high enantioselectivities (up to 99% ee) using as low as 0.2 mol. % catalyst loadings. The epoxidation protocol is suitable for various types of substrates, including unfunctionalized alkenes, α,β-unsaturated ketones, esters (cis- and trans-), and amides (cis- and trans-). The reaction mechanism is discussed.

1. Introduction

Chiral epoxides are useful building blocks in organic synthesis and essential synthetic targets [1,2,3]. The demand for synthetic methodologies of chiral epoxides preparation has been nourished by the biological activities exhibited by various natural products containing an epoxide unit and their applications as convenient (stable yet readily reactive) precursors to more complex chiral molecules [4,5,6]. The production of epoxides from the corresponding olefins by asymmetric epoxidation reaction in the presence of transition metal catalysts is considered the most efficient and versatile method [7,8,9,10,11]. In this realm, manganese(II) complexes with chiral N₄ bis-amino-bis-pyridine and related ligands were established as highly enantioselective and efficient catalysts of olefins epoxidation with the environmentally benign oxidant hydrogen peroxide [12,13,14,15]. In the recent decade, the topic has been extensively studied by groups of Sun [16,17,18,19,20,21,22,23], Costas [24,25,26,27], Bryliakov [12,28,29,30,31,32], and others [33,34,35]. Using hydrogen peroxide in these reactions is considered beneficial for several reasons: aqueous H₂O₂ is a safe, easy-to-handle oxidant with high active oxygen content (47%), which produces water as the only by-product. Nonetheless, it is known that hydrogen peroxide is prone to disproportionation in solutions containing transition metals like iron or manganese, which may significantly deteriorate the oxidant efficiency. Typically, this is partially sorted out via slow, syringe-pump oxidant addition. Other oxidants, including peracids, alkylhydroperoxides, and iodosylarenes, have also been utilized in bis-amino-bis-pyridine manganese complexes catalyzed epoxidation [31,36]. We present the use of sodium percarbonate as a convenient and environmentally benign solid oxidant for manganese catalyzed enantioselective epoxidation, which is added to the reaction mixture in portions. The corresponding epoxides of various olefins were obtained in good to quantitative yields with up to 99% ee.

2. Results and Discussion

The commercial bleaching agent sodium percarbonate (Na₂CO₃ 1.5H₂O₂) is a white powder stable at room temperature [37]. It has no shock sensitivity and contains 15% of active oxygen. Previously, sodium percarbonate was utilized in various oxidation reactions, including oxidations of sulfides to sulfones, anilines to nitroarenes, and non-enantioselective epoxidations [37,38]. In order to find appropriate conditions for employing sodium percarbonate in manganese-catalyzed asymmetric epoxidation, we initially tested it in reaction with chalcone in the presence of catalyst 1 [30] (Figure 1).

The epoxidations with H₂O₂ in the presence of bis-amino-bis-pyridine manganese complexes usually require adding carboxylic acid as a co-catalytic additive [28,29]. Herewith, using acetic acid, AcOH, as an additive (14 equiv. vs. chalcone) and sodium percarbonate (2 equiv. vs. chalcone, added in one portion) as an oxidant resulted in a nearly quantitative formation of chalcone epoxide having 82% ee (

Table 1. Asymmetric epoxidation of chalcone with sodium percarbonate in the presence of catalyst 1 ¹.

Entry	Oxidant Equiv.	Additive	Conversion/Yield, %	ee, %
1	2.0	AcOH	99/97	82
2	2.0	EBA	83/81	94
3	2.5	EBA	94/92	94
4	2.0 2	EBA	100/97	94

¹ Reaction conditions: −40 °C, [Mn]/[oxidant]/[chalcone]/[additive] = 0.2 μmol:200 μmol:100 μmol:1.4 mmol in CH₃CN (0.4 mL), oxidant was added in one portion. ² Oxidant was added in 3 portions within 30 min intervals.

, entry 1). To improve the enantioselectivity of the reaction, a more sterically demanding 2-ethylbuthanoic acid (EBA) [20,29] was probed (Table 1, entry 2). Indeed, the enantioselectivity increased up to 94% ee, albeit with a reduced conversion of 83%. Raising the amount of oxidant to 2.5 equiv. vs. substrate led to only a minor increase in epoxide yield (92%, Table 1, entry 3). Adding sodium percarbonate in three portions within 30 min intervals was revealed as the most practical protocol, furnishing nearly quantitative conversion of chalcone to the epoxide having 94% ee (Table 1, entry 4).

Having these optimized conditions in hand, we carried out the asymmetric epoxidation of a series of substrates (Figure 2) in the presence of Mn complex 1 (

Table 2. Asymmetric epoxidation of olefins with sodium percarbonate in the presence of 1 ¹.

Entry	Substrate	Cat. Loadings, %	Conversion/Yield, %	ee, %
1	3b	0.2	100/100	62
2	3c	0.2	100/99	79
3	3d	0.2	95/95	63
4	3e	0.2	98/84	51
5	3f	0.2	99/99	95
6 2	3g	0.2	47/47	87
7	3h	0.2	83/83	80
8	3i	0.2	83/83	87
9 3	3j	0.5	60/60	99
10	3k	0.2	100/100	86
11	3l	0.2	96/96	94
12	3m	0.5	86/69	79

¹ Reaction conditions: −40 °C, [Mn]/[oxidant]/[substrate]/[additive] = 0.2 μmol:200 μmol:100 μmol:1.4 mmol in CH₃CN (0.4 mL), oxidant was added in 3 portions within 30 min intervals. ² Mixed CH₃CN/CH₂Cl₂ (0.4 mL/0.4 mL) solvent was used. ³ Mixed CH₃CN/CH₂Cl₂ (0.4 mL/0.6 mL) solvent was used.

). The epoxidation of unfunctionalized alkenes 3b–e (Table 2, entries 1–4) afforded the corresponding epoxides with high yields (95–100%) and moderate to good enantioselectivity (51–79% ee). The epoxidation of 2,2-dimethyl-2H-chromene-6-carbonitrile 3f to the corresponding epoxide (a precursor for the antihypertensive agent levcromakalim [39]) was accomplished in 99% yield and 95% ee (Table 2, entry 5). Substrate 3g, bearing α,β-unsaturated ketone functionality, was epoxidized with moderate conversion under these conditions (47% yield, Table 2, entry 6). Nonetheless, the enantioselectivity was high (87% ee). The epoxidation of trans-α,β-unsaturated esters 3h and 3i demonstrated the dependence of asymmetric induction on the steric demand of alkyl substituents in the ester group (cf. 87% ee for –OiPr vs. 80% ee for –OMe, Table 2, entries 7,8), in full accordance with previous observations [30]. Highly enantioselective epoxidation (99% ee) of trans-enamide 3j was documented (Table 2, entry 9), although it required increased catalyst loading of 0.5 mol. % and was accomplished in moderate yield (60%). The same amount of the catalyst was enough to mediate the asymmetric epoxidation of cis-enamide 3m with 81% yield and 79% ee (Table 2, entry 12). The esters of cis-cinnamic acid 3k and 3l were converted to corresponding epoxides with high yields (100 and 96%, respectively); the enantioselectivity was higher for the bulkier –OiPr ester (94% ee, Table 2, entry 11), cf. 86% ee for the–OEt ester (Table 2, entry 10).

Based on earlier data [32], one could expect that increasing the electron-donating ability of the ligands of the Mn-based catalysts should enhance the epoxidation enantioselectivity. Indeed, catalyst 2 [30], bearing stronger electron-donating NMe₂ groups at the pyridylmethyl moieties of the ligand (Figure 1), in all cases but 3j, showed higher enantioselectivities (

Table 3. Asymmetric epoxidation of olefins with sodium percarbonate in the presence of 2 ¹.

Entry	Substrate	Cat. Loadings, %	Conversion/Yield, %	ee, %
1	3a	0.2	99/96	96
2	3b	0.2	75/75	67
3	3c	0.2	71/71	82
4	3d	0.2	100/98	71
5	3e	0.2	100/100	60
6	3f	0.2	100/100	95
7 2	3g	0.2	77/77	82
8	3h	0.2	61/61	86
9	3i	0.2	46/46	87
10 3	3j	0.5	100/100	97
11	3k	0.2	98/98	84
12	3l	0.2	84/84	95
13	3m	0.5	90/90	82

¹ Reaction conditions: −40 °C, [Mn]/[oxidant]/[substrate]/[additive] = 0.2 μmol:200 μmol:100 μmol:1.4 mmol in CH₃CN (0.4 mL), oxidant was added in 3 portions within 30 min intervals. ² Mixed CH₃CN/CH₂Cl₂ (0.4 mL/0.4 mL) solvent was used. ³ Mixed CH₃CN/CH₂Cl₂ (0.4 mL/0.6 mL) solvent was used.

), which improvement was most significant in the case of unfunctionalized alkenes 3b–e (Table 3, entries 2–5). For the epoxidation of trans-α,β-unsaturated esters 3h and 3i, the steric hindrance did not affect the asymmetric induction (86 and 87% ee, respectively, Table 3, entries 8, 9; cf. entries 6, 7 of Table 2). cis-Cinnamic acid derivatives 3k-m were epoxidized in high yields (84–98%) and enantioselectivities (82–95% ee, Table 3, entries 11–13). Olefins 3a, 3f, and 3j were converted to the corresponding epoxides almost quantitatively, with excellent enantioselectivity (95–97% ee, Table 3, entries 1, 6, 10).

It was reported previously [38] that sodium percarbonate is prone to deliver hydrogen peroxide in the reaction medium. The intermediate formation of peroxycarboxylic acid can be ruled out as far as under near-anhydrous conditions it is possible only from carboxylic acid anhydrides or chloroanhydrides rather than the acid itself [37]. Therefore, one can suggest that the slowly liberated H₂O₂ acts as a true oxidant. We have established that for bis-amino-bis-pyridine manganese complexes-catalyzed asymmetric epoxidation with H₂O₂, the addition of carboxylic acid is required to achieve reasonable conversions [29,30]. The latter is assumed to promote the heterolytic cleavage of the O-O bond in the (L)Mn^IIIOOH intermediate to generate the (L)Mn^V = O active species, responsible for the enantioselective oxygen transfer [30,31].

3. Materials and Methods

3.1. Materials

All chemicals and solvents were purchased from Aldrich, Acros Organics, or Alfa Aesar and were used without additional purification unless noted otherwise. For catalytic epoxidation experiments, technical grade sodium percarbonate (Na₂CO₃ 1.5H₂O₂) was used. Chiral Mn catalysts 1 and 2 were prepared as described [30] and were recrystallized from acetonitrile/diethyl ether. Substrates 3a–f were purchased and used without further purification; others were prepared as described [12,32].

3.2. Instrumentation

¹H NMR spectra were measured on Bruker Avance 400 spectrometer at 400.13 MHz and on Bruker DPX-250 spectrometer at 250.13 MHz, respectively. Chemical shifts were internally referenced to the residual proton signal of CDCl₃ (7.26 ppm) for ¹H NMR spectra. The enantiomeric excess values of chiral epoxides were measured by HPLC (Shimadzu LC-20 chromatograph,) equipped with a set of chiral columns (Daicel) as described [12,30,32].

3.3. General Procedure for the Catalytic Epoxidation of Olefins with Sodium Percarbonate

In a typical experiment, substrate (100 μmol) and carboxylic acid (1.4 mmol) were added to the solution of the manganese catalyst (0.2 μmol) in CH₃CN (0.4 mL), and the mixture was thermostated at −40 °C. Then, 200 μmol of mortar-grounded sodium percarbonate was added to the reaction mixture in 3 roughly equal portions, with 30 min intervals between the additions (66.7 μmol in each portion). The resulting mixture was stirred for 2 h at −40 °C (total reaction time: 3 h). The reaction was quenched with a saturated aqueous solution of Na₂CO_3, and the products were extracted with Et₂O (3 × 4 mL). The solvent was evaporated, and the residue was analyzed by ¹H NMR spectroscopy (Table S1, Figure S1, SI) to determine conversions and yields and by HPLC on chiral stationary phases (Table S2, Figure S2, SI) to measure the enantiomeric excess values of the chiral epoxides as previously described [12,30,32].

4. Conclusions

In conclusion, we have demonstrated that sodium percarbonate can be a convenient oxidant in the asymmetric epoxidation of olefins catalyzed by bis-amino-bis-pyridine manganese complexes. The epoxidation of various types of substrates, including unfunctionalized alkenes, α,β-unsaturated ketones, esters (cis- and trans-), and amides (cis- and trans-), proceeded with good to high yields (up to 100%) and high enantioselectivities (up to 99% ee) using as low as 0.2 mol. % of catalyst loadings. It is assumed that sodium percarbonate releases hydrogen peroxide in the catalytic epoxidation leading to the formation of the reputed manganese(V)-oxo oxygen transferring species. The advantage of the designed epoxidation protocol is the absence of necessity for syringe pump addition of the oxidant. We foresee further studies involving sodium percarbonate oxidant in other manganese catalyzed chemo- and stereoselective oxidations.