2-Oxiranyl-pyridines: Synthesis and Regioselective Epoxide Ring Openings with Chiral Amines as a Route to Chiral Ligands

Wosińska-Hrydczuk, Marzena; Skarżewski, Jacek

doi:https://doi.org/10.1155/2019/2381208

Heteroatom Chemistry

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Research Article | Open Access

Volume 2019 | Article ID 2381208 | https://doi.org/10.1155/2019/2381208

2-Oxiranyl-pyridines: Synthesis and Regioselective Epoxide Ring Openings with Chiral Amines as a Route to Chiral Ligands

Marzena Wosińska-Hrydczuk¹and Jacek Skarżewski¹

Academic Editor: Guillaume Berionni

Received15 Jun 2019

Revised31 Jul 2019

Accepted12 Sept 2019

Published09 Oct 2019

Abstract

New epoxides, derivatives of pyridine, 2,2′-bipyridine, and 1,10-phenanthroline, were synthesized from the respective α-methylazaarenes. The obtained racemic 2-oxiranyl-azaarenes along with styrene oxide and trans-stilbene oxide were submitted to the ring opening with chiral primary amines as a chiral auxiliary. The most effective reaction was run in the presence of Sc(OTf)₃/diisopropylethylamine for 7 days at 80°C, affording a good yield of the amino alcohols. Except for styrene oxide which gave both α- and β-amino alcohols, the reactions led regioselectively to the corresponding diastereomeric β-amino alcohols. The resulting diastereomers were separated, and the configurations of their stereogenic centers were established. The obtained enantiomerically pure 2-pyridinyl- and 6-(2,2′-bipyridinyl)-β-amino alcohols were tentatively tested as chiral ligands in the zinc-catalyzed aldol reaction.

1. Introduction

Modular chiral ligands and catalysts attained in a few steps from the well-defined building blocks are considered as a useful tool for asymmetric synthesis [1–4]. Among functional blocks for the modular catalysts, the moieties of pyridine, 2,2′-bipyridine, and 1,10-phenanthroline, forming strong transition metal complexes, belong to the particularly promising ones [5–12]. For this aim, we intended to develop 2-oxiranyl-pyridines that, after epoxide ring openings, would give the desired chiral products.

For this purpose, we synthesize the 2-oxiranyl-azaarenes. Their epoxide ring-opening reactions with chiral amines should lead to the separable diastereomeric β-amino alcohols with the 2-pyridinyl-type substituents. Hence, obtained homochiral complexing amino alcohols would be tested as chiral ligands.

The key synthetic reaction will be carried out using the optimized regioselective epoxide ring opening with chiral primary amines as a chiral auxiliary. This approach has a literature precedent in the synthesis of individual enantiomers of 2-amino cyclohexanol derivatives using chiral 1-phenylethylamine at the epoxide ring-opening step followed by chromatographic separation of the diastereomeric alcohols [13]. Moreover, the method applied to our 2-oxiranyl-pyridines may offer a simple route to the chiral building blocks for important medicinal compounds [14, 15].

Generally, plentiful successful Lewis acid activators for the epoxide ring opening with amines have been developed [16–38]. The regiochemistry of the metal salt-catalyzed aminolysis of styrene oxide depends on the amine nucleophilicity and steric bulkiness as well as the strength of Lewis acid activator (metal ion) [39, 40]. Moreover, an interaction of the metal-ion additives with other complexing functionalities connected to the epoxide often influenced the observed regioselectivity [41–46]. Correspondingly, the metal-complexing pyridine-2-yl substituent demonstrated the regio-steering effect in the epoxide ring-opening reaction in the presence of MgBr₂ [9]. Although the asymmetric aminolysis of meso-epoxides was successful in the presence of chiral metal complexes [24–32], the respective racemic trans-substituted epoxides could hardly be opened stereoselectively with other but aniline-type amine [23, 26].

2. Results and Discussion

2.1. Synthesis of 2-Oxiranyl-pyridines

In order to obtain the required α-azaarene epoxides (Scheme 1), we methylated the parent azaarenes, namely, 2,2′-bipyridine (bpy) and 1,10-phenanthroline (phen) with MeLi followed by the oxidative rearomatization [47, 48]. The α-methyl derivatives 1 (commercial), 2 [47], and 3 [48] were reacted with 1 equiv of benzaldehyde in the presence of a substoichiometric amount of calcium triflate [49]. The products, trans-styryl compounds 4 [50, 51], 5 and 6, were formed in rather moderate yields. However, the unreacted methyl derivatives could be easily recovered. Moreover, when cyclohexyl carbaldehyde was used in the reaction with 3, along with 6b the diene 7 was obtained. Thus, in the next step, 4, 5, and 6 were reacted with NBS in dioxane/water acidified with acetic acid giving the respective bromohydrins 8, 9, and 10 that were smoothly converted into the epoxides 11 [52, 53, 54], 12, and 13 (Scheme 1). Also, rac-2-(oxiranyl)pyridine (14) [55] was prepared analogously from 2-vinylpyridine.

2.2. Selective Epoxide Ring Opening: Model Studies

In order to find the proper conditions for our key reaction, the promising literature method for the Sc(OTf)₃-catalyzed epoxide ring opening [32, 39, 40] was examined. We run the model reaction of racemic epoxides, namely, styrene oxide (15) and trans-stilbene oxide (16) with chiral 1-phenylethylamine in the presence of Sc(OTf)₃/diisopropylethylamine (DIEA) at 80°C (Scheme 2).

The reaction of styrene oxide (15) with (S)-1-phenylethylamine gave both known regioisomers, β-amino alcohol 17 [56–58] and α-amino alcohol 18 [59], as a separable mixture (ca. 1 : 1), and their structures were confirmed by ¹H NMR spectroscopy [56–59]. Then, pure like-17 and unlike-17 diastereomers were separated by recrystallization (CH₂Cl₂/hexane). We ascribed their configurations by comparing the recorded ¹H NMR spectral properties and specific rotations with the reported ones [56, 57, 60]. The configuration of the like-isomer (R,1′R-17) was proved undoubtedly by the X-ray structure [56]. Furthermore, the samples of pure diastereomers 17 and 19 were later used for comparison in the stereochemical assignments of the chiral azaaromatic analogs 20 and 21.

In all cases, the catalyzed reactions were completed within 7 days at 80°C, affording a good yield of the amino alcohols. The reaction mixtures were stirred under argon in a sealed test tube, and the applied reaction time was necessary to reach the maximum conversion (controlled by TLC). The uncatalyzed reaction of 15 with 1-phenylethylamine gave both regioisomers 17 and 18 in 4% yield only. Moreover, the Sc(OTf)₃-catalyzed ring opening in the absence of DIEA resulted in much poorer yield. Interestingly, when we run the reaction of 15 in the presence of Zn(OAc)₂ (weaker Lewis acid), β-amino alcohol 17 was formed regioselectively. The reaction of rac-trans-stilbene oxide (16) with (S)-1-phenylethylamine gave also separable diastereomers (ca. 1 : 1) of amino alcohol 19 [57, 58, 61] in 54% total yield (Scheme 2).

2.3. Selective Epoxide Ring Opening: Pyridine Derivatives

After the model studies, the epoxides with pyridine-type fragments were submitted to the ring-opening reactions. Unlike for styrene oxide (15), the reaction of rac-2-(oxiranyl)pyridine (14) with chiral amines gave only one regioisomer, β-amino alcohol 20, regardless of the catalyst used. However, the better yield was observed for Sc(OTf)₃/DIEA (Scheme 3).

The product 20 consisted of two diastereomers (in ca. 1 : 1 ratio), which were smoothly separated by column chromatography. We ascribed their configuration comparing ¹H NMR spectra between the isolated diastereomers 20 and 17 (see supporting file S1), where similarities between their spectral patterns could be clearly seen.

Other synthesized 2,3-disubstituted trans epoxides with the α-azaaromatic fragments (11–13) were submitted to the ring-opening reactions, and the results are summarized in Scheme 4 and Table 1.

The reaction of 11 and 12 with chiral 1-phenylethylamine carried out in the presence of Sc(OTf)₃/DIEA gave in each case only one regioisomer of the respective β-amino alcohol in good yield. The obtained products 21 and 23 consisted of two diastereomers (ca. 1 : 1), which were separated by column chromatography. Similarly, the reaction of 11 and 12 with (R)-1-cyclohexylethylamine gave regioselectively both amino alcohols 22 and 24. For 22, the diastereoisomers (obtained in nearly 1 : 1 ratio) were separated to give enantiomerically pure compounds (Table 1). For the obtained diastereomeric mixture of 24, only (1R,2R,1′R)-24 could be isolated as a stereochemically pure sample. The reaction of 13b with (R)-1-phenylethylamine was sluggish, and the respective diastereomeric mixture 25 was formed in 8% yield. The reaction of rac-trans-2-(3-phenyloxiranyl)-1,10-phenanthroline (13a) with the same amine gave inseparable mixture, and the corresponding dehydration product could be detected only by ¹H NMR.

It is noteworthy that we observed different outcomes for the scandium-catalyzed ring opening of styrene oxide (15), where both regioisomers were formed (the model reaction, Scheme 2) and 2-oxiranyl-pyridines (Schemes 3 and 4), where only β-amino alcohols were obtained. The observed nucleophilic attack at the benzylic β-position (regioselectivity of aminolysis) can be explained by the specific interaction of scandium ion complexed to the pyridine nitrogen and oxiranyl oxygen atoms, thus supporting the formation of both diastereomers of one regioisomer 21 (Figure 1). This is corroborated by the results of DFT calculations for the simplified models of trans-11 and its Sc³⁺ complex. The calculations indicated an increase of the length of Cβ-epoxide oxygen bond and a substantial rise of the Cβ positive charge as measured by ESP (electrostatic potential charge) (see supporting file S2). It should be noted that the epoxide 11 has already been opened in the MgBr₂-supported reaction with the same regioselectivity. That result was explained by similar Mg²⁺ complexation [52].

In order to confirm the configurations of obtained new ring-opening products, we transformed the amino alcohols into their cyclic urethanes (Scheme 5).

The respective ¹H NMR spectral patterns are very similar for the known (4R,5S,1′S)-26 [58] and new (4R,5R,1′S)-27. Their spectra substantially differ from that for (4S,5S,1′S)-27 (Figure 2) (different configuration descriptors at C5 for (4R,5R,1′S)-27 and (4R,5S,1′S)-26 arise from CIP rules).

The obtained enantiomerically pure pyridine-β-amino alcohols: (S,1′S)-20, (1S,2S,1′R)-21, and (1S,2S,1′S)-21 and bipyridine-β-amino alcohols: (1S,2S,1′S)-23 and (1R,2R,1′S)-23 were preliminarily assessed as chiral catalysts in the asymmetric aldol reaction [62] of p-nitrobenzaldehyde with cyclohexanone. The reaction conditions were optimized by screening chiral ligands and metal salts. The highest selectivity for the anti-aldol (2S,1′R) 55% ee and 38% conversion was obtained with (1R,2R,1′S)-23 and Zn(OAc)₂ + HOAc. For the details, see supporting file S3.

3. Conclusions

Concluding, we have developed an efficient synthesis of 2-oxiranyl-azaarenes designed as precursors of chiral ligands and synthetic building blocks. The regioselective epoxide ring opening with chiral primary amines in the presence of Sc(OTf)₃ and DIEA gave the corresponding β-amino alcohols, derivatives of pyridine and 2,2′-bipyridine. The resulting diastereomeric compounds were separated, and their stereochemical configurations were proved by correlation with the known analogs. The enantiomerically pure pyridine-β-amino alcohol was preliminarily tested as chiral ligands in the asymmetric aldol reaction with up to 55% ee outcome.

4. Experimental

4.1. General Information

Solvents were distilled, and other reagents were used as received. Reactions were monitored by thin-layer chromatography (TLC) on silica gel 60 F-254 or aluminum oxide F-25 (Type E) precoated plates, and spots were visualized with a UV lamp and/or Dragendorff reagent. Separation of products by chromatography was carried out on silica gel 60 (230–400 mesh) or aluminum oxide (neutral). Melting points were determined using an Electrothermal IA 91100 digital melting-point apparatus using the standard open capillary method and are uncorrected. Observed rotations at 589 nm were measured using an Optical Activity Ltd. Model AA-5 automatic polarimeter. ¹H and ¹³C NMR spectra (400, 600 MHz and 100, 151 MHz, respectively) were collected on Jeol 400yh and Bruker Avance II 600 instruments. The spectra were recorded in CDCl₃ referenced to the respective residual signals of the solvent. Chemical shifts are given in parts per million (ppm) downfield from tetramethylsilane as the internal standard in a deuterated solvent and coupling constants (J) are in Hertz (Hz). Infrared spectra (4000–400 cm⁻¹) were collected on a Fourier transform, Bruker VERTEX 70V spectrometer using diamond ATR accessory. High-resolution mass spectra were recorded using electrospray ionization on Waters LCT Premier XE TOF instrument.

4.2. Synthesis of Methyl Derivatives

4.2.1. 6-Methyl-2,2′-bipyridine 2

The methylation was performed according to the literature procedure [47]. Brown oil, 7.6 g, 88% yield, R_f = 0.56 (CHCl₃ : AcOEt : MeOH 1 : 1 : 0.25). ¹H NMR (600 MHz, CDCl₃) δ: 8.59–8.58 (m, 1H), 8.35–8.33 (m, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.69–7.66 (m, 1H), 7.59–7.56 (m, 1H), 7.17–7.15 (m, 1H), 7.04 (d, J = 7.8 Hz, 1H), 2.54 (s, 3H). The NMR data are in agreement with the reported ones [47].

4.2.2. 2-Methyl-1,10-phenanthroline 3

The methylation was performed according to a modified literature procedure [48]. A solution of methyllithium in diethyl ether (1.6 M, 45 mL, 72 mmol) was added dropwise to a solution of 1,10-phenanthroline (10 g, 55 mmol) in toluene (200 mL) at −72°C under Ar atmosphere. The reaction mixture was stirred for 3 h at −72°C and for 2 h at room temperature. Then, ice was added with stirring in an ice-water bath and the resulting solution turned red. The aqueous layer was separated and extracted with diethyl ether (3 × 50 mL). The combined organic phases were washed twice with brine and dried over Na₂SO₄, and ether was removed. The resulting orange toluene solution was treated with MnO₂ (54 g), stirred for 24 h, and then filtered through Celite. The solvent was removed in vacuo to give a crude product. Column chromatography on neutral alumina with t-butyl methyl ether (MTBE) as an eluent gave pure 3 (8.73 g 82%), as yellow crystals, m.p. 76−77°C (lit. [48] m.p. 75−76°C). ¹H NMR (600 MHz, CDCl₃) δ: 9.17 (dd, J = 4.2, 1.8 Hz, 1H), 8.18 (dd, J = 8.0, 1.8 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.69 (q, J = 8.8 Hz, 2H), 7.56 (dd, J = 8.2, 4.6 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 2.92 (s, 3H). The NMR data are in agreement with the reported ones [48].

4.3. General Procedure for the Synthesis of 2-Styryl-azaarenes

The synthesis of 2-styryl-azaarenes was performed according to a modified literature procedure [50]. The mixture of 2-methylazaarene (1 mmol), benzaldehyde (1 mmol), and Ca(OTf)₂ [49] (5 mol%) was heated at 120°C under argon atmosphere for 48 h for α-picoline or 96 h for derivatives of bipyridine and phenanthroline. After the reaction completion (monitored by TLC), the mixture was dissolved in 1 M HCl and extracted with diethyl ether (3 × 15 mL). The remaining aqueous layer was alkalized with NaOH, extracted with diethyl ether (3 × 25 mL), dried over Na₂SO₄, and concentrated in vacuo to give crude product.

4.3.1. 2-[(E)-2-Phenylethenyl]pyridine (4)

White crystals, 88 mg, 48% yield, recrystallized (CH₂Cl₂/hexane), m.p. 89−90°C (lit. [51] m.p. 89−91°C), R_f = 0.67 (CHCl₃ : AcOEt : MeOH 1 : 1 : 0.25). ¹H NMR (600 MHz, CDCl₃) δ: 8.62–8.61 (m, 1H), 7.68–7.63 (m, 1H), 7.59–7.58 (m, 2H), 7.41–7.37 (m, 3H), 7.32–7.29 (m, 1H), 7.20 (s, 1H), 7.17–7.15 (m, 2H). The NMR data are in agreement with the reported ones [51].

4.3.2. 6-[(E)-2-Phenylethenyl]-2,2′-bipyridine (5)

White crystals, 60 mg, 23% yield, recrystallized (CH₂Cl₂/hexane), m.p. 117−118°C, R_f = 0.70 (CHCl₃ : AcOEt : MeOH 1 : 1 : 0.25). ¹H NMR (600 MHz, CDCl₃) δ: 8.71 (d, J = 6.0 Hz, 1H), 8.59 (d, J = 6.0 Hz, 1H), 8.30 (d, J = 7.8 Hz, 1H), 7.89–7.86 (m, 1H), 7.82–7.77 (m, 2H), 7.64 (d, J = 7.2 Hz, 2H), 7.42–7.39 (m, 3H), 7.35–7.30 (m, 2H) 7.28–7.25 (m, 1H); ¹³C NMR (600 MHz, CDCl₃) δ: 156.2, 155.6, 155.0, 148.9, 137.5, 137.1, 136.8, 132.9, 128.7, 128.3, 128.2, 127.2, 123.8, 122.2, 121.4, 119.6; HR-MS (ESI) [C₁₈H₁₄N₂ + H]⁺ requires 259.1230; found 259.1223.

4.3.3. 2-[(E)-2-Phenylethenyl]-1,10-phenanthroline (6a)

Brown oil, 210 mg, 74% yield, purified by column chromatography (SiO_2, CHCl₃ : AcOEt : MeOH 1 : 1 : 0.25), R_f = 0.62 (CHCl₃ : AcOEt : MeOH 1 : 1 : 0.25). ¹H NMR (600 MHz, CDCl₃) δ: 9.28 (dd, J = 4.3, 1.8 Hz, 1H), 8.29 (dd, J = 8.2, 1.8 Hz, 1H), 8.21 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 6.0 Hz, 1H), 7.86–7.78 (m, 3H), 7.76–7.72 (m, 1H), 7.75 (d, J = 6.0 Hz, 2H), 7.67–7.65 (m, 1H), 7.42–7.40 (m, 2H) 7.34–7.31 (m, 1H); ¹³C NMR (600 MHz, CDCl₃) δ: 156.6, 149.9, 145.5, 145.4, 136.8, 136.6, 136.4, 134.8, 129.5, 129.1, 128.8, 128.6, 127.6, 127.4, 126.7, 125.8, 122.9, 120.7; HR-MS (ESI) [C₂₀H₁₄N₂ + H]⁺ requires 283.1230; found 283.1242.

4.3.4. 2-[(E)-2-Cyclohexylethenyl)-1,10-phenanthroline (6b)

Yellow oil, 43 mg, 15% yield, purified by column chromatography (Al₂O₃, 20% AcOEt/hexane). ¹H NMR (400 MHz, CDCl₃) δ: 9.20 (dd, J = 4.6, 1.8 Hz, 1H), 8.22 (dd, J = 8.2, 1.8 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.72 (q, J = 8.9 Hz, 2H), 7.60 (dd, J = 8.2, 4.6 Hz, 1H), 7.01 (dd, J = 16.2, 1.2 Hz, 1H), 6.81 (dd, J = 16.2, 6.4 Hz, 1H), 2.30–2.24 (m, 1H), 1.92–1.88 (m, 2H), 1.82–1.77 (m, 2H), 1.72–1.66 (m, 1H), 1.41–1.16 (m, 5H); ¹³C NMR (400 MHz, CDCl₃) δ: 157.4, 150.3, 146.2, 143.3, 136.3, 136.2, 129.6, 128.9, 127.3, 126.6, 126.5, 125.7, 122.8, 119.9, 41.2, 32.6, 26.3, 26.2; HR-MS (ESI) [C₂₀H₂₀N₂ + H]⁺ requires 289.1699; found 289.1705.

4.3.5. 1-Cyclohexyl-3-cyclohexylidene-2-(1,10-phenonthrolin-2-yl)propene (7)

Yellow oil, 42 mg, 15% yield, purified by column chromatography (Al₂O₃, 20% AcOEt/hexane). ¹H NMR (400 MHz, CDCl₃) δ: 9.17 (dd, J = 4.3, 1.5 Hz, 1H), 8.20 (dd, J = 7.9, 1.8 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.73–7.66 (m, 3H), 7.59 (dd, J = 7.9, 4.3 Hz, 1H), 7.02 (dd, J = 9.8, 1.5 Hz, 1H), 6.05 (s, 1H), 2.46–2.43 (m, 1H), 2.34–2.31 (m, 2H), 1.96–1.93 (m, 2H), 1.77–1.75 (m, 4H), 1.69–1.63 (m, 3H), 1.55–1.50 (m, 2H), 1.40–1.31 (m, 7H); ¹³C NMR (400 MHz, CDCl₃) δ: 159.4, 150.1, 146.4, 145.8, 144.9, 141.4, 136.11, 136.09, 134.6, 129.0, 127.3, 126.6, 125.4, 122.7, 121.9, 118.3, 39.1, 36.9, 32.4, 30.6, 28.8, 27.3, 26.7, 26.3, 26.2; HR-MS (ESI) [C₂₇H₃₀N₂ + H]⁺ requires 383.2482; found 383.2483.

4.4. General Procedure for the Synthesis of Bromohydrins

The synthesis of bromohydrins was performed according to a modified literature procedure [53]. The mixture of 2-styryl-azaarene (3.0 mmol), NBS (587 mg, 3.3 mmol), and acetic acid (0.5 mL) was dissolved in the mixture of dioxane/water (3.5 mL/7 mL) and stirred at room temperature for 24 h. After completion of the reaction, the mixture was extracted with chloroform (3 × 30 mL). The combined organic layers were dried by over Na₂SO₄ filtered and concentrated in vacuo to give the desired product as confirmed by ¹H NMR.

4.4.1. 2-Bromo-1-phenyl-2-(pyridin-2-yl)ethanol (8)

Brown oil, 784 mg, 94% yield; R_f = 0.57 (CHCl₃ : AcOEt : MeOH 1 : 1 : 0.25). ¹H NMR (600 MHz, CDCl₃) δ: 8.57–8.56 (m, 1H), 7.63–7.60 (m, 2H), 7.30–7.27 (m, 2H), 7.27–7.25 (m, 2H), 7.23–7.21 (m, 2H), 5.41 (d, J = 5.4 Hz, 1H), 5.20 (d, J = 5.4 Hz, 1H).

4.4.2. 2-Bromo-1-phenyl-2-(2,2′-bipyridin-6-yl)ethanol (9)

White crystals, 960 mg, 90% yield, purified by column chromatography (SiO₂, CHCl₃ : AcOEt : MeOH 1 : 1 : 0.25), m.p. 117−118°C, R_f = 0.61 (CHCl₃ : AcOEt : MeOH 1 : 1 : 0.25). ¹H NMR (600 MHz, CDCl₃) δ: 8.72 (d, J = 4.8 Hz, 1H), 8.38–8.34 (m, 1H), 7.90 (s, 1H), 7.77–7.74 (t, J = 7.8 Hz, 1H), 7.40–7.38 (m, 1H), 7.32 (d, J = 7.2 Hz, 1H) 7.28–7.24 (m, 4H), 7.24–7.22 (m, 2H), 5.53 (d, J = 5.4 Hz, 1H), 5.28 (d, J = 5.4 Hz, 1H).

4.4.3. 2-Bromo-1-phenyl-2-(1,10-phenanthrolin-2-yl)ethanol (10a)

Brown oil, 1.0 g, 91% yield, purified by column chromatography (SiO₂, CHCl₃ : AcOEt : MeOH 1 : 1 : 0.25), R_f = 0.24 (CHCl₃ : AcOEt : MeOH 1 : 1 : 0.25). ¹H NMR (600 MHz, CDCl₃) δ: 9.31–9.30 (m, 1H), 8.40 (d, J = 7.8 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.87–7.83 (m, 2H), 7.78–7.75 (m, 2H), 7.55 (d, J = 7.2 Hz, 2H), 7.29–7.27 (m, 2H), 7.24–7.21 (m, 1H), 5.79 (d, J = 6.6 Hz, 1H), 5.60 (d, J = 6.6 Hz, 1H).

4.4.4. 2-Bromo-1-cyclohexyl-2-(1,10-phenanthrolin-2-yl)ethanol (10b)

Yellow oil, 520 mg, 45% yield, purified by column chromatography (Al₂O₃, CHCl₃ : AcOEt : hexane 1 : 1 : 2). ¹H NMR (400 MHz, CDCl₃) δ: 9.15 (dd, J = 4.3, 1.8 Hz, 1H), 8.25 (dd, J = 8.2, 1.8 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.81–7.75 (m, 3H), 7.63 (dd, J = 8.2, 4.6 Hz, 1H), 5.17 (d, J = 9.2 Hz, 1H), 4.36 (dd, J = 9.5, 2.4 Hz, 1H), 2.57 (s, 2H), 2.27–2.25 (m, 1H), 2.04–2.02 (m, 1H), 1.82–1.16 (m, 7H).

4.5. General Procedure for the Synthesis of Epoxides

The synthesis of epoxides was performed according to a modified literature procedure [53]. Bromohydrin (2.8 mmol) was dissolved in dioxane (3.5 mL), then 1 M aqueous NaOH (4.5 mL) was added, and the mixture was stirred at room temperature for 24 h. After completion of the reaction, the mixture was extracted with chloroform (3 × 30 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo to give the desired product.

4.5.1. trans-2-(3-Phenyl-2-oxiranyl)pyridine (11)

Brown oil, 375 mg, 68% yield, R_f = 0.63 (CHCl₃ : AcOEt : MeOH 1 : 1 : 0.25). ¹H NMR (600 MHz, CDCl₃) δ: 8.60–8.58 (m, 1H), 7.73–7.69 (m, 1H), 7.38–7.31 (m, 6H), 7.26–7.23 (m, 1H), 4.05 (AB system, 2H). The NMR data are in agreement with the reported ones [52].

4.5.2. trans-6-(3-Phenyl-2-oxiranyl)-2,2′-bipyridine (12)

White crystals, 713 mg, 93% yield, m.p. 117−118°C, R_f = 0.61 (CHCl₃ : AcOEt : MeOH 1 : 1 : 0.25). IR υ_max (Neat) 2960, 2926, 1580, 1563, 775, 760, 746, 694 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ: 8.7 (d, J = 4.2 Hz, 1H), 8.47 (d, J = 7.8 Hz, 1H), 8.4 (d, J = 7.8 Hz, 1H), 7.88–7.84 (m, 2H), 7.40–7.36 (m, 4H), 7.35–7.26 (m, 3H), 4.16 (d, J = 1.8 Hz, 1H), 4.12 (d, J = 1.8 Hz, 1H); ¹³C NMR (600 MHz, CDCl₃) δ: 156.1, 155.8, 155.7, 149.1, 137.8, 137.0, 136.8, 128.6, 128.5, 125.8, 123.9, 121.4, 120.6, 119.7, 63.2, 61.9; HR-MS (ESI) [C₁₈H₁₄N₂O + H]⁺requires 275.1179; found 275.1180.

4.5.3. trans-2-(3-Phenyl-2-oxiranyl)-1,10-phenanthroline (13a)

Brown oil, 784 mg, 94% yield, R_f = 0.44 (CHCl₃ : AcOEt : MeOH 1 : 1 : 0.25). IR υ_max (Neat) 2923, 2853, 1588, 1555, 845, 741, 696 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ: 9.18 (dd, J = 4.3, 1.8 Hz, 1H), 8.31–8.24 (m, 2H), 7.80 (d, J = 1.8 Hz, 2H), 7.63 (dd, J = 8.2, 6.4 Hz, 2H), 7.37–7.33 (m, 5H), 4.69 (d, J = 1.8 Hz, 1H), 4.02 (d, J = 1.8 Hz 1H); ¹³C NMR (600 MHz, CDCl₃) δ: 158.0, 150.6, 146.0, 145.8, 137.5, 136.6, 136.3, 129.2, 128.7, 128.6, 128.1, 126.7, 126.6, 125.9, 123.3, 118.1, 64.0, 63.1; HR-MS (ESI) [C₂₀H₁₄N₂O + H]⁺ requires 299.1135; found 299.1146.

4.5.4. trans-2-(3-Cyclohexyl-2-oxiranyl)-1,10-phenanthroline (13b)

Yellow oil, 811 mg, 95% yield. ¹H NMR (400 MHz, CDCl₃) δ: 9.24 (dd, J = 4.3, 1.5 Hz, 1H), 8.26 (dd, J = 8.2, 1.8 Hz, 1H), 8.22 (d, J = 8.2 Hz, 1H), 7.78 (s, 2H), 7.65 (dd, J = 8.2, 4.6 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 4.47 (d, J = 2.1 Hz, 1H), 2.96 (d, J = 2.1 Hz, 1H), 1.59–1.26 (m, 3H), 1.25–1.24 (m, 6H), 0.86–0.84 (m, 2H); ¹³C NMR (600 MHz, CDCl₃) δ: 159.2, 150.6, 137.1, 136.2, 134.3, 129.6, 129.1, 128.6, 126.6, 126.5, 123.1, 118.3, 38.9, 30.6, 24.1 23.0, 14.1, 11.2; HR-MS (ESI) [C₂₀H₂₀N₂O + H]⁺ requires 305.1648; found 305.1653.

4.6. Procedures for Ring Opening of Epoxides

4.6.1. Method A (Catalyzed by Sc(OTf)₃)

A solution of the epoxide 11, 12, 13b, 14, 15, or 16 (0.5 mmol), 1-phenylethylamine (77 μL, 0.6 mmol), Sc(OTf)₃ (12 mg, 5 mol%), and N-ethyldiisopropylamine (170 μL, 1 mmol) in toluene (2 mL) was stirred under argon in a sealed test tube at 80°C for 7 days. The cooled mixture was directly submitted to the column chromatography on silica gel. In this way, the regioisomers 17 and 18, resulting in the reaction of 15, were separated, and their structures were confirmed by NMR. The isolated diastereoisomers 17, as well as the respective diastereomers formed in the reactions of 11, 12, 14, and 16, were separated by column chromatography. Additionally, the diastereomers 17 could be separated by recrystallization from hexane/CH₂Cl₂.

The reactions of 11 (98 mg, 0.5 mmol) or 12 (137 mg, 0.5 mmol) with (R)-1-cyclohexylethylamine (88 μL, 0.6 mmol), Sc(OTf)₃ (12 mg, 5 mol%), and N-ethyldiisopropylamine (170 μL, 1 mmol) dissolved in toluene (2 mL) were run and then worked up as above. For the epoxide 11, both diastereomers were separated by chromatography and gave pure samples, while for 12, only one diastereomer (1R,2R,1′R)-24 could be isolated in a pure form.

The pure separated products (S,1′S)-17, (R,1′S)-17, (S/R,1′S)-18, (1R,2S,1′S)-19, (1S,2R,1′S)-19, (S,1′S)-20, (R,1′S)-20, (1R,2S,1′S)-21, (1S,2S,1′S)-21, (1S,2R,1′R)-19, (1R,2R,1′R)-21, (1S,2R,1′R)-22, (1R,2R,1′R)-22, (1R,2S,1′S)-23, (1S,2S,1′S)-23, (1R,2R,1′R)-24, and [(1R,2R,1′R)- and (1S,2S,1′R)]-25 were analyzed, and their properties are reported below.

4.6.2. Method B (Catalyzed by Zn(OAc)₂)

The reaction was carried out under the same conditions as in Method A, but instead of Sc(OTf)₃ and N-ethyldiisopropylamine, Zn(OAc)₂ (4.6 mg, 5 mol%) as a catalyst was added. The products (R,1′R)-17, (S,1′R)-17, (S,1′S)-17, (R,1′S)-17, (S,1′S)-20, and (R,1′S)-20 were isolated as in Method A.

4.6.3. Method C (Absence of a catalyst)

The reaction of 14 or 15 (1.0 mmol) with 1-phenylethylamine (154 μL, 1.2 mmol) dissolved in toluene (4 mL) was carried out under argon in a sealed test tube at 80°C for 7 days. After the same workup as in Method A (direct chromatography), the products were analyzed by NMR.

(1) (R,R)-2-(1-Phenylethyl)amino-1-phenyl-ethanol (R,1′R)- 17. White crystals, 41 mg, 34% yield, purified by column chromatography (SiO₂, CHCl₃ : AcOEt : MeOH 1 : 1 : 0.1), m.p. 145–146°C (lit. [60] m.p. 145–148°C), = 26 (c 1.0, CHCl₃), (lit. [60] = 26.5 (c 1.0, CHCl₃)), R_f = 0.20 (CHCl₃ : AcOEt : MeOH 1 : 1 : 0.1). ¹H NMR (400 MHz, CDCl₃) δ: 7.34–7.22 (m, 10H), 4.72 (dd, J = 8.9, 3.7 Hz, 1H), 3.75 (q, J = 6.4 Hz, 1H), 2.64 (dd, J = 12.2, 3.7 Hz, 1H), 2.54 (dd, J = 12.2, 8.9 Hz, 1H), 1.38 (d, J = 6.7 Hz, 3H). The NMR data are in agreement with literature data for (R,1′R)-enantiomer [60].

(2) (S,R)-2-(1-Phenylethyl)amino-1-phenyl-ethanol (S,1′R)- 17. Brown crystals, 41 mg, 34% yield, purified by column chromatography (SiO₂, CHCl₃ : AcOEt : MeOH 1 : 1 : 0.1), R_f = 0.25 (CHCl₃ : AcOEt : MeOH 1 : 1 : 0.1). ¹H NMR (400 MHz, CDCl₃) δ: 7.34–7.22 (m, 10H), 4.55 (dd, J = 8.9, 3.7 Hz, 1H), 3.81 (q, J = 6.4 Hz, 1H), 2.81 (dd, J = 12.2, 3.7 Hz, 1H), 2.54 (dd, J = 12.2, 8.9 Hz, 1H), 1.36 (d, J = 6.7 Hz, 3H). The NMR data are in agreement with literature data for (R,1′S)-enantiomer [60].

(3) (S,S)-2-(1-Phenylethyl)amino-1-phenyl-ethanol (S,1′S)- 17. White crystals, 41 mg, 34% yield, recrystallized (CH₂Cl₂/hexane), R_f = 0.20 (CHCl₃ : AcOEt : MeOH 1 : 1 : 0.1). ¹H NMR (400 MHz, CDCl₃) δ: 7.34–7.22 (m, 10H), 4.60 (dd, J = 8.9, 3.7 Hz, 1H), 3.77 (q, J = 6.4 Hz, 1H), 2.77 (dd, J = 12.2, 3.7 Hz, 1H), 2.63 (dd, J = 12.2, 8.9 Hz, 1H), 1.40 (d, J = 6.7 Hz, 3H). The NMR data are in agreement with literature data for (R,1′R)-enantiomer [60].

(4) (R,S)-2-(1-Phenylethyl)amino-1-phenyl-ethanol (R,1′S)- 17. Brown crystals, 41 mg, 34% yield, recrystallized (CH₂Cl₂/hexane), m.p. 82–83°C (lit. [60] m.p. 80–85°C), = –105 (c 1.0, CHCl₃), (lit. [60] = –110 (c 1.0, CHCl₃)), R_f = 0.25 (CHCl₃ : AcOEt : MeOH 1 : 1 : 0.1). ¹H NMR (400 MHz, CDCl₃) δ: 7.34–7.21 (m, 10H), 4.74 (dd, J = 9.2, 3.4 Hz, 1H), 3.83 (q, J = 6.7 Hz, 1H), 2.79 (dd, J = 12.2, 3.7 Hz, 1H), 2.55 (dd, J = 12.2, 9.2 Hz, 1H), 1.40 (d, J = 6.4 Hz, 3H). The NMR data are in agreement with literature data for (R,1′S)-enantiomer [60].

(5) (R/S,1′S)-2-(1′-Phenylethyl)amino-2-phenyl-ethanol (S,1′S)- 18 and (R,1′S)- 18, (1 : 1). Colorless oil, 46 mg, 38% total yield, purified by column chromatography (SiO₂, CHCl₃ : AcOEt : MeOH 1 : 1 : 0.1). ¹H NMR (400 MHz, CDCl₃) δ: 7.40–7,18 (m, 20H), 3.90–3.88 (m, 1H), 3.77–3.71 (m, 2H), 3.65–3.67 (m, J = 6.7 Hz, 1H), 3.58–3.50 (m, 4H), 1.36 (d, J = 6.4 Hz, 6H); ¹³C NMR (400 MHz, CDCl₃) δ: 129.1, 129.0, 128.9, 128.8, 128.7, 128.6, 128.31, 128.30, 127.90, 127.85, 127.8, 127.7, 127.5, 127.3, 127.2, 126.8, 66.1, 65.9, 62.5, 61.7, 55.5, 55.1, 24.1, 22.2; HR-MS (ESI) [C₁₆H₁₉NO + H]⁺ requires 242.1539; found 242.1545. The NMR data are in agreement with the reported ones [59].

(6) (1R,2R,1′S)-2-(1′-Phenylethyl)amino-1,2-diphenyl-ethanol (1R,2S,1′S)- 19. White crystals, 43 mg, 27% yield, purified by column chromatography (SiO₂, CHCl₃ : AcOEt : MeOH 1 : 1 : 0.1), m.p. 135–136°C, = –63 (c 0.9, CHCl₃), (lit. [58] = –66.1 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ: 7.33–7.13 (m, 11H), 6.98–6.94 (m, 4H), 4.98 (d, J = 4.9 Hz, 1H), 4.0 (d, J = 4.9 Hz, 1H), 3.78 (q, J = 6.4 Hz, 1H), 1.35 (d, J = 6.7 Hz, 3H); ¹³C NMR (400 MHz, CDCl₃) δ: 145.5, 140.5, 139.2, 128.6, 128.2, 128.1, 127.8, 127.5, 127.3, 127.2, 126.6, 126.5, 75.4, 65.6, 54.6, 23.1. The NMR data are in agreement with literature data for (1R,2S,1′S)-enantiomer [58].

(7) (1S,2R,1′S)-2-(1′-Phenylethyl)amino-1,2-diphenyl-ethanol (1S,2R,1′S)- 19. Colorless oil, 43 mg, 27% yield, purified by column chromatography (SiO₂, CHCl₃ : AcOEt : MeOH 1 : 1 : 0.1), = –111 (c 1.0, CHCl₃), (lit. [58] = –112.8 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃); δ: 7.33–7.20 (m, 10H), 7.09–6.95 (m, 5H), 4.64 (d, J = 4.9 Hz, 1H), 3.62 (d, J = 4.9 Hz, 1H), 3.49 (q, J = 6.4 Hz, 1H), 1.23 (d, J = 6.7 Hz, 3H); ¹³C NMR (400 MHz, CDCl₃) δ: 144.9, 140.5, 139.7, 128.5, 128.4, 128.1, 127.8, 127.7, 127.2, 127.1, 126.7, 126.4, 75.6, 65.8, 54.9, 24.8. The NMR data are in agreement with literature data for (1S,2R,1′S-)-enantiomer [58].

(8) (S,S)-2-(1-Phenylethyl)amino-1-(pyridin-2-yl)ethanol (S,1′S)- 20. White crystals, 44 mg, 36% yield, purified by column chromatography (SiO₂, CHCl₃ : AcOEt : MeOH 1 : 1 : 0.1), m.p. 119–120°C, = –42 (c 0.6, CH₂Cl₂). IR υ_max (Neat) 3290, 2971, 1589, 1432, 703 cm¹; ¹H NMR (400 MHz, CDCl₃) δ: 8.50–8.48 (m, 1H), 7.64 (td, J = 7.4, 1.8 Hz, 1H), 7.33–7.22 (m, 6H), 7.17–7.14 (m, 1H), 4.71 (dd, J = 8.1, 3.7 Hz, 1H), 3.75 (q, J = 6.5 Hz, 1H), 2.86 (dd, J = 12.0, 3.7 Hz, 1H), 2.69 (dd, J = 12.0, 8.1 Hz, 1H), 1.36 (d, J = 6.4 Hz, 3H); ¹³C NMR (400 MHz, CDCl₃) δ: 161.0, 148.5, 145.5, 136.7, 128.6, 127.1, 126.7, 122.4, 120.6, 72.3, 58.6, 54.4, 24.4; HR-MS (ESI) [C₁₅H₁₈N₂O + H]⁺ requires 243.1492; found 243.1500.

(9) (R,S)-2-(1-Phenylethyl)amino-1-(pyridin-2-yl)ethanol (R,1′S)- 20. White crystals 44 mg, 36% yield, purified by column chromatography (SiO₂, CHCl₃ : AcOEt : MeOH 1 : 1 : 0.1), m.p. 75–76°C, = –52 (c 0.8, CH₂Cl₂). IR υ_max (Neat) 3081, 2847, 1588, 1433, 702 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ: 8.48–8.46 (m, 1H), 7.63 (td, J = 7.6, 1.8 Hz, 1H), 7.37–7.21 (m, 6H), 7.15 (m, 1H) 4.97 (dd, J = 8.1, 3.7 Hz, 1H), 3.96 (q, J = 6.5 Hz, 1H), 3.08 (dd, J = 12.0, 3.7 Hz, 1H), 2.68 (m, J = 12.0, 8.1 Hz, 1H), 1.50 (d, J = 6.4 Hz, 3H); ¹³C NMR (400 MHz, CDCl₃) δ: 160.4, 148.3, 136.9, 128.8, 127.8, 127.1, 127.0, 122.6, 120.8, 70.9, 58.5, 53.3, 23.3; HR-MS (ESI) [C₁₅H₁₈N₂O + H]⁺ requires 243.1492; found 243.1504.

(10) (1S,2S,1′S)-2-(1′-Phenylethyl)amino-2-phenyl-1-(pyridin-2-yl)ethanol (1S,2S,1′S)- 21. White crystals, 42 mg, 26% yield, purified by column chromatography (SiO₂, AcOEt : CHCl₃ 8 : 2), m.p. 94–95°C, = –78 (c1.0, CH₂Cl₂), R_f = 0.35 (CHCl₃ : AcOEt : MeOH 1 : 1 : 0.1). IR υ_max (Neat) 3147, 3032, 2924, 1592, 1433, 697 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ: 8.36–8.34 (m, 1H), 7.47 (td, J = 7.6, 1.5 Hz, 1H), 7.29–7.24 (m, 4H), 7.24–7.19 (m, 1H), 7.14–7.09 (m, 3H), 7.06–6.94 (m, 4H), 5.12 (d, J = 4.3 Hz, 1H), 4.15 (d, J = 4.3 Hz, 1H), 3.81 (q, J = 6.4 Hz, 1H) 1.35 (d, J = 6.4 Hz, 3H); ¹³C NMR (400 MHz, CDCl₃) δ: 159.6, 148.0, 145.77, 138.9, 136.5, 128.6, 128.2, 127.9, 127.2, 127.1, 126.7, 122.2, 121.5, 74.9, 65.1, 54.8, 23.1; HR-MS (ESI) [C₂₁H₂₂N₂O + H]⁺ requires 319.1805; found 319.1801.

(11) (1R,2R,1′S)-2-(1′-Phenylethyl)amino-2-phenyl-1-(pyridin-2-yl)ethanol(1R,2R,1′S)- 21. Colorless oil, 42 mg, 26% yield, purified by column chromatography (SiO₂, AcOEt : CHCl₃ 8 : 2), = –93 (c 1.0, CH₂Cl₂), R_f = 0.48 (CHCl₃ : AcOEt : MeOH 1 : 1 : 0.1). IR υ_max (Neat) 3324, 3026, 2923, 1592, 1451, 699 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ: 8.39 (d, J = 4.6 Hz, 1H), 7.47 (td, J = 7.6, 1.5 Hz, 1H), 7.26–7.12 (m, 9H), 6.96–6.95 (m, 3H), 4.88 (s, 1H), 4.20 (s, 1H), 3.77 (d, J = 4.9 Hz, 1H), 3.57 (q, J = 6.7 Hz, 1H), 1.30 (d, J = 6.7 Hz, 3H); ¹³C NMR (400 MHz, CDCl₃) δ: 159.5, 148.0, 145.4, 139.2, 136.0, 128.4, 128.3, 128.0, 127.2, 126.90, 126.89, 122.4, 121.8, 76.2, 65.4, 54.9, 25.2; HR-MS (ESI) [C₂₁H₂₂N₂O + H]⁺ requires 319.1805; found 319.1796.

(12) (1R,2R,1′R)-2-(1′-Phenylethyl)amino-2-phenyl-1-(pyridin-2-yl)ethanol (1R,2R,1′R)- 21. White crystals, 46 mg, 29% yield, purified by column chromatography (SiO₂, AcOEt : CHCl₃ 8 : 2), m.p. 94–95°C, = 78 (c 0.9, CH₂Cl₂), R_f = 0.35 (CHCl₃ : AcOEt : MeOH 1 : 1 : 0.1). IR υ_max (Neat) 3133, 3032, 2922, 1592, 1434, 697 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ: 8.37–8.35 (m, 1H), 7.47 (td, J = 7.6, 1.5 Hz, 1H), 7.32–7.20 (m, 5H), 7.25–7.10 (m, 3H), 7.06–7.03 (m, 1H), 6.99–6.93 (m, 3H), 5.10 (d, J = 4.3 Hz, 1H), 4.11 (d, J = 4.3 Hz, 1H), 3.80 (q, J = 6.4 Hz, 1H) 1.34 (d, J = 6.4 Hz, 3H); ¹³C NMR (400 MHz, CDCl₃) δ: 159.6, 148.1, 145.8, 139.9, 136.0, 128.6, 128.1, 127.9, 127.2, 127.1, 126.7, 122.2, 121.5, 74.9, 65.1, 54.7, 23.1; HR-MS (ESI) [C₂₁H₂₂N₂O + H]⁺ requires 319.1805; found 319.1826.

(13) (1S,2S,1′R)-2-(1′-Phenylethyl)amino-2-phenyl-1-(pyridin-2-yl)ethanol(1S,2S,1′R)- 21. Colorless oil, 46 mg, 29% yield, purified by column chromatography (SiO₂, AcOEt : CHCl₃ 8 : 2), = 93 (c 0.8, CH₂Cl₂), R_f = 0.48 (CHCl₃ : AcOEt : MeOH 1 : 1 : 0.1). IR υ_max (Neat) 3322, 3026, 2923, 1593, 1451, 699 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ: 8.39 (d, J = 4.9 Hz, 1H), 7.49 (td, J = 7.2, 1.2 Hz, 1H), 7.28–7.06 (m, 9H), 6.98–6.90 (m, 3H), 4.88 (d, J = 4.9 Hz, 1H), 4.22 (s, 1H), 3.76 (d, J = 4.9 Hz, 1H), 3.57 (q, J = 6.7 Hz, 1H) 1.30 (d, J = 6.7 Hz, 3H); ¹³C NMR (400 MHz, CDCl₃) δ: 159.5, 148.0, 145.3, 139.2, 136.0, 128.4, 128.3, 128.0, 127.2, 126.90, 126.89, 122.4, 121.8, 76.2, 65.4, 54.9, 25.2; HR-MS (ESI) [C₂₁H₂₂N₂O + H]⁺ requires 319.1805; found 319.1811.

(14) (1R,2R,1′S)-2-(1′-Cyclohexylethyl)amino-2-phenyl-1-(pyridin-2-yl)ethanol (1R,2R,1′R)- 22. Brown oil, 53 mg, 33% yield, purified by column chromatography (SiO₂ 20% MTBE/hexane), = –45 (c 0.7, CH₂Cl₂). IR υ_max (Neat) 3139, 3019, 2924, 1435, 696 cm^−-1; ¹H NMR (400 MHz, CDCl₃) δ: 8.46–8.44 (m, 1H), 7.43 (dq, J = 7.6, 1.8 Hz, 1H), 7.14–7.01 (m, 6H), 6.93 (d, J = 7.9 Hz, 1H), 4.95 (d, J = 4.6 Hz, 1H), 4.18 (d, J = 4.6 Hz, 1H), 2.55–2.52 (m, 1H), 1.72–1.63 (m, 8H), 1.28–1.16 (m, 3H), 0.97 (d, J = 6.4 Hz, 3H); ¹³C NMR (400 MHz, CDCl₃) δ: 160.3, 148.2, 140.1, 136.0, 128.0, 127.8, 127.2, 122.1, 121.5, 75.02, 65.25, 55.0, 42.8, 29.8, 28.1, 26.9, 26.8, 26.7, 17.8; HR-MS (ESI) [C₂₁H₂₈N₂O + H]⁺ requires 325.2274; found 325.2280.

(15) (1S,2S,1′R)-2-(1′-Cyclohexylethyl)amino-2-phenyl-1-(pyridin-2-yl)ethanol (1S,2S,1′R)- 22. Brown oil, 53 mg, 33% yield, purified by column chromatography (SiO₂ 20% MTBE/hexane), = 28 (c 0.8, CH₂Cl₂). IR υ_max (Neat) 3062, 3028, 2925, 1434, 699 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ: 8.42–8.40 (m, 1H), 7.48 (dq, J = 7.6, 1.8 Hz, 1H), 7.15–6.97 (m, 7H), 4.97 (d, J = 4.6 Hz, 1H), 4.19 (d, J = 4.6 Hz, 1H), 2.34–2.31 (m, 1H), 1.73–1.70 (m, 7H), 1.40–0.97 (m, 4H), 0.92 (d, J = 6.4 Hz, 3H); ¹³C NMR (400 MHz, CDCl₃) δ: 159.8, 148.1, 138.9, 136.0, 128.4, 127.8, 127.1, 122.2, 121.6, 76.2, 65.0, 54.0, 43.9, 29.6, 28.7, 26.8, 26.7, 26.6, 16.7; HR-MS (ESI) [C₂₁H₂₈N₂O + H]⁺ requires 325.2274; found 325.2289.

(16) (1R,2R,1′S)-2-(1′-Phenylethyl)amino-2-phenyl-1-(2,2′-bipyridin-6-yl)ethanol (1R,2R,1′S)- 23. Colorless oil, 60 mg, 30% yield, purified by column chromatography (Al₂O_3, MTBE), R_f = 0.48 (Al₂O_3, MTBE), = –112 (c 0.9, CH₂Cl₂). IR υ_max (Neat) 3324, 3026, 2924, 1564, 1430, 699 cm⁻¹¹H NMR (400 MHz, CDCl₃) δ: 8.64–8.62 (m, 1H), 8.21 (dd, J = 7.9, 0.9 Hz, 1H), 8.05 (td, J = 7.9, 1.2 Hz, 1H), 7.74 (dd, J = 7.9, 1.8 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.29–7.13 (m, 9H), 7.0–6.98 (m, 3H), 4.95 (s, 1H), 4.22 (br s, 1H), 3.80 (d, J = 4.9 Hz, 1H), 3.59 (q, J = 6.4 Hz, 1H), 1.30 (d, J = 6.7 Hz, 3H); ¹³C NMR (400 MHz, CDCl₃) δ: 158.8, 155.8, 154.5, 149.2, 145.3, 139.3, 137.2, 136.8, 128.4, 128.3, 128.0, 127.2, 126.9, 126.8, 123.8, 121.9, 121.1, 119.7, 76.2, 65.4, 54.8, 25.2; HR-MS (ESI) [C₂₆H₂₅N₃O + H]⁺ requires 396.2070; found 396.2067.

(17) (1S,2S,1′S)-2-(1′-Phenylethyl)amino-2-phenyl-1-(2,2′-bipyridin-6-yl)ethanol (1S,2S,1′S)- 23. Colorless oil, 60 mg, 30% yield, purified by column chromatography (Al₂O_3, MTBE), R_f = 0.39 (Al₂O₃ MTBE), = 7.2 (c 0.6, CH₂Cl₂). IR υ_max (Neat) 3326, 3025, 2923, 1581, 1564, 1453, 1430, 699 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ: 8.62–8.60 (m, 1H), 8.18 (d, J = 6.7 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.67 (td, J = 7.6, 1.8 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.31–7.23 (m, 6H), 7.11–6.94 (m, 3H), 7.01 (d, J = 7.6 Hz, 1H), 6.96–6.94 (m, 2H), 5.14 (d, J = 3.9 Hz, 1H), 4.21 (d, J = 4.3 Hz, 1H), 3.82 (q, J = 6.4 Hz, 1H), 1.35 (d, J = 6.4 Hz, 3H); ¹³C NMR (400 MHz, CDCl₃) δ: 158.9, 155.8, 154.5, 149.1, 145.9, 138.9, 137.2, 136.8, 129.6, 128.1, 127.9, 127.2, 127.1, 126.8, 123.8, 121.7, 121.1, 119.6, 74.9, 65.2, 54.6, 22.8; HR-MS (ESI) [C₂₆H₂₅N₃O + H]⁺ requires 396.2070; found 396.2073.

(18) (1R,2R,1′R)-2-(1′-Cyclohexylethyl)amino-2-phenyl-1-(2,2′-bipyridin-6-yl)ethanol (1R,2R,1′R)- 24. Colorless oil, 64 mg, 32% yield, purified by column chromatography (Al₂O₃, 20% MTBE/hexane). = –37 (c 0.9, CH₂Cl₂). IR υ_max (Neat) 3062, 2925, 2852, 1562, 1428, 773 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ: 8.66–8.64 (m, 1H), 8.25 (td, J = 7.9, 1.2 Hz, 1H), 8.19 (dd, J = 7.6, 0.9 Hz, 1H) 7.79 (td, J = 7.3, 1.8 Hz, 1H), 7.66–7.58 (m, 1H), 7.31–7.27 (m, 1H), 7.15–6.97 (m, 6H), 5.00 (d, J = 4.6 Hz, 1H), 4.22 (d, J = 4.6 Hz, 1H), 2.54–2.51 (m, 1H), 1.71–1.61 (m, 6H), 1.41–1.32 (m, 1H), 1.25–1.21 (m, 1H), 1.16–0.97 (m, 3H), 0,95 (d, J = 6.4 Hz, 3H); ¹³C NMR (400 MHz, CDCl₃) δ: 159.5, 156.1, 154.5, 149.2, 140.3, 137.1, 136.8, 128.1, 127.9, 127.1, 123.7, 121.7, 121.1, 119.5, 76.3, 65.6, 65.0, 55.1, 42.7, 29.9, 27.9, 26.8, 26.7, 17.8; HR-MS (ESI) [C₂₆H₃₁N₃O + H]⁺ requires 402.2540; found 402.2538.

(19) 2-(1′-Phenylethyl)amino-2-cyclohexyl-1-(1,10-phenanthrolin-2-yl)ethanol (1R,2R,1′R)- 25 and (1S,2S,1′R)- 25. Colorless oil, 17 mg, 8% total yield, purified by column chromatography (SiO₂, hexane : AcOEt : CHCl₃ 2 : 1 : 1). ¹H NMR (400 MHz, CDCl₃) δ: 9.16–9.14 (m, 2H), 8.22 (dd, J = 7.9, 1.8 Hz, 2H), 8.17 (d, J = 8.2 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 1.8 Hz, 4H), 7.62–7.58 (m, 2H), 7.52 (d, J = 8.2 Hz, 1H), 7.35–7.14 (m, 11H), 3.96 (d, J = 3.1 Hz, 1H), 3.89 (dd, J = 7.9, 3.4 Hz, 1H), 3.24 (s, 1H), 3.22 (d, J = 2.1 Hz, 1H), 1.79–1.49 (m, 11H), 1.41–1.39 (m, 6H), 1.29–1.19 (m, 9H), 1.10–1.09 (m, 4H); HR-MS (ESI) [C₂₈H₃₁N₃O + H]⁺ requires 426.2540; found 426.2532.

4.7. General Procedure for the Synthesis of Oxazolidinones from Amino Alcohols

The synthesis of oxazolidinones was performed according to the literature procedure [58]. Triphosgene (36 mg, 0.12 mmol) was added to a mixture of the amino alcohol (0.3 mmol) in toluene (3 mL) and potassium carbonate (57 mg, 0.41 mmol) in water (1.3 mL) with vigorous stirring at room temperature. After being stirred for 48 h, the mixture was washed with water and brine, the organic layer was dried over MgSO₄, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/ethyl acetate 7 : 3) to give the corresponding oxazolidinone.

4.7.1. (4R,5S,1′S)-N-(1′-Phenylethyl)-4,5-diphenyl-2-oxazolidinone (4R,5S,1′S)-26

White crystals, 60 mg, 59% yield, m.p. 154–157°C (lit. [58] m.p. 154–156°C), = 19.0 (c 1.0, CHCl₃) (lit. [58] = 19.1 c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ: 7.39–7.32 (m, 6H), 7.07–7.02 (m, 6H), 6.95–6.94 (m, 3H), 5.66 (d, J = 8.2 Hz, 1H), 5.35 (q, J = 7.3 Hz, 1H), 4.56 (d, J = 8.2 Hz, 1H), 1.21 (d, J = 7.3 Hz, 3H); ¹³C NMR (400 MHz, CDCl₃) δ: 158.1, 140.1, 136.6, 134.4, 128.9, 128.3, 128.2, 128.11, 128.07, 127.9, 127.8, 127.5, 126.0, 80.3, 62.8, 53.4, 18.3. The NMR data are in agreement with the literature [58].

4.7.2. (4R,5R,1′S)-N-(1′-Phenylethyl)-5-pyridin-2-yl-4-phenyl-2-oxazolidinone (4R,5R,1′S)-27

White crystals, 47 mg, 46% yield, m.p. 120–122°C, = 21 (c 0.8, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ: 8.24–8.22 (m, 1H), 7.49–7.29 (m, 7H), 7.13 (d, J = 7.6 Hz, 1H), 7.05–7.03 (m, 3H), 6.92–6.89 (m, 2H), 5.71 (d, J = 7.9 Hz, 1H), 5.34 (q, J = 7.0 Hz, 1H), 4.79 (d, J = 8.2 Hz, 1H), 1.20 (d, J = 7.34 Hz, 3H); ¹³C NMR (400 MHz, CDCl₃) δ: 157.7, 154.9, 148.7, 139.9, 136.9, 136.3, 128.9, 128.22, 128.19, 128.1, 127.8, 127.4, 122.4, 120.9, 80.6, 61.9, 53.5, 18.2; HR-MS (ESI) [C₂₂H₂₀N₂O₂ + H]⁺ requires 345.1598; found 345.1618.

4.7.3. (4S,5S,1′S)-N-(1′-Phenylethyl)-5-pyridin-2-yl-4-phenyl-2-oxazolidinone (4S,5S,1′S)-27

White crystals, 47 mg, 46% yield, m.p. 136–137°C, = 16 (c 0.6, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ: 8.23–8.22 (m, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.20–7.12 (m, 6H), 6.93–6.88 (m, 4H), 6.74–6.71 (m, 2H), 5.81 (d, J = 8.2 Hz, 1H), 5.07 (d, J = 8.6 Hz, 1H), 4.62 (q, J = 7.0 Hz, 1H), 1.60 (d, J = 7.0 Hz, 3H); ¹³C NMR (400 MHz, CDCl₃) δ: 157.4, 155.3, 148.6, 140.4, 136.3, 134.9, 128.4, 127.93, 127.91, 127.82, 127.80, 127.5, 122.5, 120.9, 79.8, 64.0, 54.6, 18.9; HR-MS (ESI) [C₂₂H₂₀N₂O₂ + H]⁺ requires 345.1598; found 345.1601.

Data Availability

All the related data are included in the main text and supplementary files.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

This work was supported by a subsidy from the Polish Ministry of Science and Higher Education for the Faculty of Chemistry of Wrocław University of Science and Technology.

Supplementary Materials

This file includes NMR and IR spectra of compounds, a comparison of the ¹H NMR and ¹³C NMR for known and new compounds, DFT computations for ring opening of aryl-heteroaryl-epoxide, and aldol reactions—experimental details and compound characterization. (Supplementary Materials)

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Copyright © 2019 Marzena Wosińska-Hrydczuk and Jacek Skarżewski. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Heteroatom Chemistry

2-Oxiranyl-pyridines: Synthesis and Regioselective Epoxide Ring Openings with Chiral Amines as a Route to Chiral Ligands

Abstract

1. Introduction

2. Results and Discussion

2.1. Synthesis of 2-Oxiranyl-pyridines

2.2. Selective Epoxide Ring Opening: Model Studies

2.3. Selective Epoxide Ring Opening: Pyridine Derivatives

3. Conclusions

4. Experimental

4.1. General Information

4.2. Synthesis of Methyl Derivatives

4.2.1. 6-Methyl-2,2′-bipyridine 2

4.2.2. 2-Methyl-1,10-phenanthroline 3

4.3. General Procedure for the Synthesis of 2-Styryl-azaarenes

4.3.1. 2-[(E)-2-Phenylethenyl]pyridine (4)

4.3.2. 6-[(E)-2-Phenylethenyl]-2,2′-bipyridine (5)

4.3.3. 2-[(E)-2-Phenylethenyl]-1,10-phenanthroline (6a)

4.3.4. 2-[(E)-2-Cyclohexylethenyl)-1,10-phenanthroline (6b)

4.3.5. 1-Cyclohexyl-3-cyclohexylidene-2-(1,10-phenonthrolin-2-yl)propene (7)

4.4. General Procedure for the Synthesis of Bromohydrins

4.4.1. 2-Bromo-1-phenyl-2-(pyridin-2-yl)ethanol (8)

4.4.2. 2-Bromo-1-phenyl-2-(2,2′-bipyridin-6-yl)ethanol (9)

4.4.3. 2-Bromo-1-phenyl-2-(1,10-phenanthrolin-2-yl)ethanol (10a)

4.4.4. 2-Bromo-1-cyclohexyl-2-(1,10-phenanthrolin-2-yl)ethanol (10b)

4.5. General Procedure for the Synthesis of Epoxides

4.5.1. trans-2-(3-Phenyl-2-oxiranyl)pyridine (11)

4.5.2. trans-6-(3-Phenyl-2-oxiranyl)-2,2′-bipyridine (12)

4.5.3. trans-2-(3-Phenyl-2-oxiranyl)-1,10-phenanthroline (13a)

4.5.4. trans-2-(3-Cyclohexyl-2-oxiranyl)-1,10-phenanthroline (13b)

4.6. Procedures for Ring Opening of Epoxides

4.6.1. Method A (Catalyzed by Sc(OTf)3)

4.6.2. Method B (Catalyzed by Zn(OAc)2)

4.6.3. Method C (Absence of a catalyst)

4.7. General Procedure for the Synthesis of Oxazolidinones from Amino Alcohols

4.7.1. (4R,5S,1′S)-N-(1′-Phenylethyl)-4,5-diphenyl-2-oxazolidinone (4R,5S,1′S)-26

4.7.2. (4R,5R,1′S)-N-(1′-Phenylethyl)-5-pyridin-2-yl-4-phenyl-2-oxazolidinone (4R,5R,1′S)-27

4.7.3. (4S,5S,1′S)-N-(1′-Phenylethyl)-5-pyridin-2-yl-4-phenyl-2-oxazolidinone (4S,5S,1′S)-27

Data Availability

Conflicts of Interest

Acknowledgments

Supplementary Materials

References

Copyright

4.6.1. Method A (Catalyzed by Sc(OTf)₃)

4.6.2. Method B (Catalyzed by Zn(OAc)₂)