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

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.


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 N 4 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 H 2 O 2 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.

Results and Discussion
The commercial bleaching agent sodium percarbonate (Na 2 CO 3 1.5H 2 O 2 ) 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 nonenantioselective 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).

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, 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).  The epoxidations with H 2 O 2 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, 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). Table 1. Asymmetric epoxidation of chalcone with sodium percarbonate in the presence of catalyst 1 1 .

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, 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). 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).

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 (Na 2 CO 3 1.5H 2 O 2 ) 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].

Instrumentation
1 H 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 CDCl 3 (7.26 ppm) for 1 H 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].

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 CH 3 CN (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 Na 2 CO 3, and the products were extracted with Et 2 O (3 × 4 mL). The solvent was evaporated, and the residue was analyzed by 1 H 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].

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.
Supplementary Materials: The following supporting information (SI) can be downloaded at: https: //www.mdpi.com/article/10.3390/molecules27082538/s1, Table S1: 1 H NMR data for the epoxides; Table S2: HPLC data for the epoxides; Figure S1: Selected examples of 1 H NMR spectra of reaction mixtures; Figure