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

Marzena Wosińska-Hrydczuk; Jacek Skarżewski

doi:10.1155/2019/2381208

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

Wosińska-Hrydczuk, Marzena;Skarżewski, Jacek 2019-10-09 00:00:00 Hindawi Heteroatom Chemistry Volume 2019, Article ID 2381208, 12 pages https://doi.org/10.1155/2019/2381208 Research Article 2-Oxiranyl-pyridines: Synthesis and Regioselective Epoxide Ring Openings with Chiral Amines as a Route to Chiral Ligands Marzena Wosin´ ska-Hrydczuk and Jacek Skarz˙ewski Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wyb Wyspian´skiego 27, 50-370 Wrocław, Poland Correspondence should be addressed to Jacek Skarzewski; jacek.skarzewski@pwr.edu.pl Received 15 June 2019; Revised 31 July 2019; Accepted 12 September 2019; Published 9 October 2019 Academic Editor: Guillaume Berionni Copyright © 2019 Marzena Wosin´ska-Hrydczuk and Jacek Skarz˙ewski. †is 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. New epoxides, derivatives of pyridine, 2,2′-bipyridine, and 1,10-phenanthroline, were synthesized from the respective α-methylazaarenes. †e 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. †e most eŽective reaction was run in the presence of Sc(OTf) /diisopropylethylamine for 7 days at 80 C, aŽording 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. †e resulting diastereomers were separated, and the conšgurations of their stereogenic centers were established. †e 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. enantiomers of 2-amino cyclohexanol derivatives using 1. Introduction chiral 1-phenylethylamine at the epoxide ring-opening step Modular chiral ligands and catalysts attained in a few steps followed by chromatographic separation of the di- from the well-dešned building blocks are considered as a astereomeric alcohols [13]. Moreover, the method applied to useful tool for asymmetric synthesis [1–4]. Among func- our 2-oxiranyl-pyridines may oŽer a simple route to the chiral building blocks for important medicinal compounds tional blocks for the modular catalysts, the moieties of pyridine, 2,2′-bipyridine, and 1,10-phenanthroline, forming [14, 15]. strong transition metal complexes, belong to the particularly Generally, plentiful successful Lewis acid activators for promising ones [5–12]. For this aim, we intended to develop the epoxide ring opening with amines have been developed 2-oxiranyl-pyridines that, after epoxide ring openings, [16–38]. †e regiochemistry of the metal salt-catalyzed would give the desired chiral products. aminolysis of styrene oxide depends on the amine nucleo- For this purpose, we synthesize the 2-oxiranyl-azaarenes. philicity and steric bulkiness as well as the strength of Lewis †eir epoxide ring-opening reactions with chiral amines acid activator (metal ion) [39, 40]. Moreover, an interaction should lead to the separable diastereomeric β-amino alco- of the metal-ion additives with other complexing func- hols with the 2-pyridinyl-type substituents. Hence, obtained tionalities connected to the epoxide often in¤uenced the homochiral complexing amino alcohols would be tested as observed regioselectivity [41–46]. Correspondingly, the metal-complexing pyridine-2-yl substituent demonstrated chiral ligands. †e key synthetic reaction will be carried out using the the regio-steering eŽect in the epoxide ring-opening reaction optimized regioselective epoxide ring opening with chiral in the presence of MgBr [9]. Although the asymmetric primary amines as a chiral auxiliary. †is approach has a aminolysis of meso-epoxides was successful in the presence literature precedent in the synthesis of individual of chiral metal complexes [24–32], the respective racemic 2 Heteroatom Chemistry trans-substituted epoxides could hardly be opened stereo- phenylethylamine gave also separable diastereomers (ca. 1 : selectively with other but aniline-type amine [23, 26]. 1) of amino alcohol 19 [57, 58, 61] in 54% total yield (Scheme 2). 2. Results and Discussion 2.3. Selective Epoxide Ring Opening: Pyridine Derivatives. 2.1. Synthesis of 2-Oxiranyl-pyridines. In order to obtain the After the model studies, the epoxides with pyridine-type required α-azaarene epoxides (Scheme 1), we methylated the fragments were submitted to the ring-opening reactions. parent azaarenes, namely, 2,2′-bipyridine (bpy) and 1,10- Unlike for styrene oxide (15), the reaction of rac-2-(oxir- phenanthroline (phen) with MeLi followed by the oxidative anyl)pyridine (14) with chiral amines gave only one rearomatization [47, 48]. 1e α-methyl derivatives 1 regioisomer, β-amino alcohol 20, regardless of the catalyst (commercial), 2 [47], and 3 [48] were reacted with 1 equiv of used. However, the better yield was observed for Sc(OTf) / benzaldehyde in the presence of a substoichiometric amount 3 DIEA (Scheme 3). of calcium triﬂate [49]. 1e products, trans-styryl com- 1e product 20 consisted of two diastereomers (in ca. pounds 4 [50, 51], 5 and 6, were formed in rather moderate 1 : 1 ratio), which were smoothly separated by column yields. However, the unreacted methyl derivatives could be chromatography. We ascribed their conﬁguration com- easily recovered. Moreover, when cyclohexyl carbaldehyde paring H NMR spectra between the isolated di- was used in the reaction with 3, along with 6b the diene 7 astereomers 20 and 17 (see supporting ﬁle S1), where was obtained. 1us, in the next step, 4, 5, and 6 were reacted similarities between their spectral patterns could be clearly with NBS in dioxane/water acidiﬁed with acetic acid giving seen. the respective bromohydrins 8, 9, and 10 that were smoothly Other synthesized 2,3-disubstituted trans epoxides with converted into the epoxides 11 [52, 53, 54], 12, and 13 the α-azaaromatic fragments (11–13) were submitted to the (Scheme 1). Also, rac-2-(oxiranyl)pyridine (14) [55] was ring-opening reactions, and the results are summarized in prepared analogously from 2-vinylpyridine. Scheme 4 and Table 1. 1e reaction of 11 and 12 with chiral 1-phenylethyl- 2.2. Selective Epoxide Ring Opening: Model Studies. In order amine carried out in the presence of Sc(OTf) /DIEA gave to ﬁnd the proper conditions for our key reaction, the in each case only one regioisomer of the respective promising literature method for the Sc(OTf) -catalyzed β-amino alcohol in good yield. 1e obtained products 12 epoxide ring opening [32, 39, 40] was examined. We run the and 23 consisted of two diastereomers (ca. 1 : 1), which were separated by column chromatography. Similarly, the model reaction of racemic epoxides, namely, styrene oxide (15) and trans-stilbene oxide (16) with chiral 1-phenyleth- reaction of 11 and 12 with (R)-1-cyclohexylethylamine gave regioselectively both amino alcohols 22 and 24. For ylamine in the presence of Sc(OTf) /diisopropylethylamine (DIEA) at 80 C (Scheme 2). 22, the diastereoisomers (obtained in nearly 1 : 1 ratio) were separated to give enantiomerically pure compounds 1e reaction of styrene oxide ( 15) with (S)-1-phenyl- ethylamine gave both known regioisomers, β-amino alcohol (Table 1). For the obtained diastereomeric mixture of 24, only (1R,2R,1′R)-24 could be isolated as a stereochemically 17 [56–58] and α-amino alcohol 18 [59], as a separable mixture (ca. 1 :1), and their structures were conﬁrmed by H pure sample. 1e reaction of 13b with (R)-1-phenyleth- ylamine was sluggish, and the respective diastereomeric NMR spectroscopy [56–59]. 1en, pure like-17 and unlike- 17 diastereomers were separated by recrystallization mixture 25 was formed in 8% yield. 1e reaction of rac- trans-2-(3-phenyloxiranyl)-1,10-phenanthroline (13a) (CH Cl /hexane). We ascribed their conﬁgurations by 2 2 with the same amine gave inseparable mixture, and the comparing the recorded H NMR spectral properties and speciﬁc rotations with the reported ones [56, 57, 60]. 1e corresponding dehydration product could be detected only by H NMR. conﬁguration of the like-isomer (R,1′R-17) was proved undoubtedly by the X-ray structure [56]. Furthermore, the It is noteworthy that we observed diﬀerent outcomes for the scandium-catalyzed ring opening of styrene oxide (15), samples of pure diastereomers 17 and 19 were later used for comparison in the stereochemical assignments of the chiral where both regioisomers were formed (the model reaction, Scheme 2) and 2-oxiranyl-pyridines (Schemes 3 and 4), azaaromatic analogs 20 and 1.2 In all cases, the catalyzed reactions were completed where only β-amino alcohols were obtained. 1e observed nucleophilic attack at the benzylic β-position (regiose- within 7 days at 80 C, aﬀording a good yield of the amino alcohols. 1e reaction mixtures were stirred under argon in a lectivity of aminolysis) can be explained by the speciﬁc interaction of scandium ion complexed to the pyridine sealed test tube, and the applied reaction time was necessary nitrogen and oxiranyl oxygen atoms, thus supporting the to reach the maximum conversion (controlled by TLC). 1e uncatalyzed reaction of 15 with 1-phenylethylamine gave formation of both diastereomers of one regioisomer 12 (Figure 1). 1is is corroborated by the results of DFT cal- both regioisomers 17 and 18 in 4% yield only. Moreover, the 3+ Sc(OTf) -catalyzed ring opening in the absence of DIEA culations for the simpliﬁed models of trans-11 and its Sc complex. 1e calculations indicated an increase of the length resulted in much poorer yield. Interestingly, when we run the reaction of 15 in the presence of Zn(OAc) (weaker of Cβ-epoxide oxygen bond and a substantial rise of the Cβ positive charge as measured by ESP (electrostatic potential Lewis acid), β-amino alcohol 17 was formed regioselectively. 1e reaction of rac-trans-stilbene oxide (16) with (S)-1- charge) (see supporting ﬁle S2). It should be noted that the Heteroatom Chemistry 3 11, py, R′ = Ph, 68% 12, bpy, R′ = Ph, 93% 13a, phen, R′ = Ph, 94% 13b, phen, R′ = cyclohexyl, 95% N R 7, 15%, along with 6b NaOH 1. MeLi Br R′-CHO NBS, acetic acid 2. KMnO /acetone Ca(OTf) dioxane/water 4 2 N R′ R′ N N 1, py, commercial 4, py, R′ = Ph, 48% OH 5, bpy, R′ = Ph, 23% 2, bpy, 88% 8, py, R′ = Ph, 94% 6a, phen, R′ = Ph, 74% 9, bpy, R′ = Ph, 90% 3, phen, 82% 6b, phen, R′ = cyclohexyl, 15% 10a, phen, R′ = Ph, 91% 10b, phen, R′ = cyclohexyl, 45% Scheme 1: Preparation of the α-azaarene epoxides. O R R —NH R + OH Catalyst, toluene 80°C, 7d NH OH R = H, 15 R = H, 17 R = Ph, 16 R =Ph, 19 R -NH2 Epoxide Catalyst Product, isolated yield (%) (S)-1-Phenylethylamine 15 Sc(OTf) , DIEA (S,1′S)-17, 19 (R,1′S)-17, 19 (R/S,1′S)-18, 38 (S)-1-Phenylethylamine 16 Sc(OTf) , DIEA (1S,2R,1′S)-19, 27 (1R,2S,1′S)-19, 27 (R)-1-Phenylethylamine 15 Zn(OAc) (R,1′R)-17, 34 (S,1′R)-17, 34 (S)-1-Phenylethylamine 15 Zn(OAc) (S,1′S)-17, 34 (R,1′S)-17, 34 (S)-1-Phenylethylamine 15 No catalyst (S,1′S)-17 and (R,1′S)-17 and (R/S,1′S)-18 (total 4%) Scheme 2: Ring opening of styrene and stilbene oxides with chiral 1-phenylethylamine. CH CH 3 3 (S)-1-Phenylethylamine HN (S) Ph HN (S) Ph Catalyst, (5% mol) (R) (S) toluene, 80°C,7d N N OH OH Catalyst Product, isolated yield (%) Zn(OAc) (S,1′S)-20, 17 (R,1′S)-20, 17 (total 34) Sc(OTf) , DIEA (S,1′S)-20, 36 (R,1′S)-20, 36 (total 72) No catalyst (S,1′S)-20 and (R,1′S)-2 (1:1 by NMR, total 5) Scheme 3: Ring opening of 2-(oxiranyl)pyridine with (S)-1-phenylethylamine. epoxide 11 has already been opened in the MgBr -supported (Figure 2) (diﬀerent conﬁguration descriptors at C5 for reaction with the same regioselectivity. 1at result was (4R,5R,1′S)-27 and (4R,5S,1′S)-26 arise from CIP rules). 2+ explained by similar Mg complexation [52]. 1e obtained enantiomerically pure pyridine-β-amino al- In order to conﬁrm the conﬁgurations of obtained new cohols: (S,1′S)-20, (1S,2S,1′R)-,12 and (1S,2S,1′S)-12 and ring-opening products, we transformed the amino alcohols bipyridine-β-amino alcohols: (1S,2S,1′S)- and (1R,2R,1′S)- into their cyclic urethanes (Scheme 5). were preliminarily assessed as chiral catalysts in the asymmetric 1e respective H NMR spectral patterns are very similar aldol reaction [62] of p-nitrobenzaldehyde with cyclohexanone. for the known (4R,5S,1′S)-26 [58] and new (4R,5R,1′S)-27. 1e reaction conditions were optimized by screening chiral 1eir spectra substantially diﬀer from that for (4S,5S,1′S)-27 ligands and metal salts. 1e highest selectivity for the anti-aldol 23 23 4 Heteroatom Chemistry NHR R NH 1 2 1 R R Sc(OTf) , DIEA, toluene, 80°C, 7d OH R R 11-13 21-25 Epoxide Chiral amine Product 1 2 R = pyrid-2-yl, R = Ph, 11 R = 1-phenylethyl 21 1 2 R = pyrid-2-yl, R = Ph, 11 R = 1-cyclohexylethyl 22 1 2 R = 2,2′-bipyrid-6-yl R = Ph, R = 1-phenylethyl 23 1 2 R = 2,2′-bipyrid-6-yl, R = Ph, R = 1-cyclohexylethyl 24 1 2 R = 1,10-phenanthrolin-2-yl, R = cyclohexyl, 13b R = 1-phenylethyl 25 Scheme 4: Ring opening of 2-oxiranyl-azaarenes with chiral amines. Table 1: Ring opening of 2-oxiranyl-azaarenes with chiral amines. Epoxide Amine Product, yield (%) Total yield (%) 11 (S)-1-Phenylethylamine (1S,2S,1′S)-21, 26 (1R,2R,1′S)-21, 26 52 11 (R)-1-Phenylethylamine (1R,2R,1′R)-21, 29 (1S,2S,1′R)-21, 29 58 11 (R)-1-Cyclohexylethylamine (1R,2R,1′R)-22, 33 (1S,2S,1′R)-22, 33 66 12 (S)-1-Phenylethylamine (1S,2S,1′S)-23, 30 (1R,2R,1′S)-23, 30 60 12 (R)-1-Cyclohexylethylamine (1R,2R,1′R)-24, 32 (1S,2S,1′R)-24 64 13b (R)-1-Phenylethylamine (1R,2R,1′R)-25, (1S,2S,1′R)-25 8 a b c †e yield of each isolated diastereomer. Pure (1S,2S,1′R)-24 could not be isolated (remained in a mixture). †e isolated 1 :1 diastereomeric mixture was identišed by HR-MS and H NMR. O O (S) 4.62 5.34 (S) 5.35 (S) (S) (S) H H H N N O O N O H N NH (S) 2 (S) (S) CH H C (R) (R) (R) H H H C 3 3 α H H H H H H 1.80 1.20 1.21 (R) (R) (S) (S) H H N O O N N Sc Sc 4S,5S,1′S-27 4R,5R,1′S-27 4R,5S,1′S-26 Figure 1: Models for regioselective aminolysis of rac-trans-11. Figure 2: Structures and selected H NMR (400 MHz, CDCl ) resonances of oxazolidinones 26 and 27. Me O Me 1′ 3. Conclusions 2 1′ HN Ph Cl CO OCCl 3 3 Ph Concluding, we have developed an e¨cient synthesis of 2- K CO /H O 2 3 2 5 4 Ph oxiranyl-azaarenes designed as precursors of chiral ligands toluene, 48h, RT R Ph OH and synthetic building blocks. †e regioselective epoxide (1S,2R,1′S)-19 R = Ph (4R,5S,1′S)-26 59% ring opening with chiral primary amines in the presence of (1S,2S,1′S)-21 R = pyridin-2-yl (4S,5S,1′S)-27 46% Sc(OTf) and DIEA gave the corresponding β-amino al- (1R,2R,1′S)-21 R = pyridin-2-yl (4R,5R,1′S)-27 46% cohols, derivatives of pyridine and 2,2′-bipyridine. †e resulting diastereomeric compounds were separated, and Scheme 5: Synthesis of oxazolidinones from β-amino alcohols. their stereochemical conšgurations were proved by corre- lation with the known analogs. †e enantiomerically pure pyridine-β-amino alcohol was preliminarily tested as chiral (2S,1′R) 55% ee and 38% conversion was obtained with ligands in the asymmetric aldol reaction with up to 55% ee (1R,2R,1′S)-23 and Zn(OAc) + HOAc. For the details, see outcome. supporting šle S3. NO Heteroatom Chemistry 5 7.56 (dd, J � 8.2, 4.6 Hz, 1H), 7.47 (d, J � 8.2 Hz, 1H), 2.92 4. Experimental (s, 3H). 1e NMR data are in agreement with the reported 4.1. General Information. Solvents were distilled, and other ones [48]. reagents were used as received. Reactions were monitored by thin-layer chromatography (TLC) on silica gel 60 F-254 or 4.3. General Procedure for the Synthesis of 2-Styryl-azaarenes. aluminum oxide F-25 (Type E) precoated plates, and spots 1e synthesis of 2-styryl-azaarenes was performed according were visualized with a UV lamp and/or Dragendorﬀ reagent. to a modiﬁed literature procedure [50]. 1e mixture of 2- Separation of products by chromatography was carried out methylazaarene (1 mmol), benzaldehyde (1 mmol), and on silica gel 60 (230–400 mesh) or aluminum oxide (neu- Ca(OTf) [49] (5 mol%) was heated at 120 C under argon tral). Melting points were determined using an Electro- atmosphere for 48 h for α-picoline or 96 h for derivatives of thermal IA 91100 digital melting-point apparatus using the bipyridine and phenanthroline. After the reaction comple- standard open capillary method and are uncorrected. Ob- tion (monitored by TLC), the mixture was dissolved in 1 M served rotations at 589 nm were measured using an Optical 1 13 HCl and extracted with diethyl ether (3 ×15 mL). 1e Activity Ltd. Model AA-5 automatic polarimeter. H and C remaining aqueous layer was alkalized with NaOH, NMR spectra (400, 600 MHz and 100, 151 MHz, re- extracted with diethyl ether (3 × 25 mL), dried over Na SO , 2 4 spectively) were collected on Jeol 400yh and Bruker Avance and concentrated in vacuo to give crude product. II 600 instruments. 1e spectra were recorded in CDCl referenced to the respective residual signals of the solvent. Chemical shifts are given in parts per million (ppm) 4.3.1. 2-[(E)-2-Phenylethenyl]pyridine (4). White crystals, downﬁeld from tetramethylsilane as the internal standard in 88 mg, 48% yield, recrystallized (CH Cl /hexane), m.p. 2 2 a deuterated solvent and coupling constants (J) are in Hertz ° ° 89− 90 C (lit. [51] m.p. 89− 91 C), R � 0.67 (CHCl : AcOEt : f 3 − 1 (Hz). Infrared spectra (4000–400 cm ) were collected on a MeOH 1 :1 : 0.25). H NMR (600 MHz, CDCl ) δ: 8.62–8.61 Fourier transform, Bruker VERTEX 70V spectrometer using (m, 1H), 7.68–7.63 (m, 1H), 7.59–7.58 (m, 2H), 7.41–7.37 diamond ATR accessory. High-resolution mass spectra were (m, 3H), 7.32–7.29 (m, 1H), 7.20 (s, 1H), 7.17–7.15 (m, 2H). recorded using electrospray ionization on Waters LCT 1e NMR data are in agreement with the reported ones [51]. Premier XE TOF instrument. 4.3.2. 6-[(E)-2-Phenylethenyl]-2,2′-bipyridine (5). White 4.2. Synthesis of Methyl Derivatives crystals, 60 mg, 23% yield, recrystallized (CH Cl /hexane), 2 2 m.p. 117− 118 C, R � 0.70 (CHCl : AcOEt : MeOH 1 :1 : f 3 4.2.1. 6-Methyl-2,2′-bipyridine 2. 1e methylation was 0.25). H NMR (600 MHz, CDCl ) δ: 8.71 (d, J � 6.0 Hz, 1H), performed according to the literature procedure [47]. Brown 8.59 (d, J � 6.0 Hz, 1H), 8.30 (d, J � 7.8 Hz, 1H), 7.89–7.86 (m, oil, 7.6 g, 88% yield, R � 0.56 (CHCl : AcOEt : MeOH 1 :1 : f 3 1H), 7.82–7.77 (m, 2H), 7.64 (d, J � 7.2 Hz, 2H), 7.42–7.39 0.25). H NMR (600 MHz, CDCl ) δ: 8.59–8.58 (m, 1H), 3 13 (m, 3H), 7.35–7.30 (m, 2H) 7.28–7.25 (m, 1H); C NMR 8.35–8.33 (m, 1H), 8.12 (d, J � 7.8 Hz, 1H), 7.69–7.66 (m, (600 MHz, CDCl ) δ: 156.2, 155.6, 155.0, 148.9, 137.5, 137.1, 1H), 7.59–7.56 (m, 1H), 7.17–7.15 (m, 1H), 7.04 (d, 136.8, 132.9, 128.7, 128.3, 128.2, 127.2, 123.8, 122.2, 121.4, J � 7.8 Hz, 1H), 2.54 (s, 3H). 1e NMR data are in agreement 119.6; HR-MS (ESI) [C H N + H] requires 259.1230; 18 14 2 with the reported ones [47]. found 259.1223. 4.2.2. 2-Methyl-1,10-phenanthroline 3. 1e methylation was 4.3.3. 2-[(E)-2-Phenylethenyl]-1,10-phenanthroline (6a). performed according to a modiﬁed literature procedure [48]. Brown oil, 210 mg, 74% yield, puriﬁed by column chro- A solution of methyllithium in diethyl ether (1.6 M, 45 mL, matography (SiO CHCl : AcOEt : MeOH 1 :1 : 0.25), 2, 3 72 mmol) was added dropwise to a solution of 1,10-phe- 1 R � 0.62 (CHCl : AcOEt : MeOH 1 :1 : 0.25). H NMR f 3 nanthroline (10 g, 55 mmol) in toluene (200 mL) at − 72 C (600 MHz, CDCl ) δ: 9.28 (dd, J � 4.3, 1.8 Hz, 1H), 8.29 (dd, under Ar atmosphere. 1e reaction mixture was stirred for J � 8.2, 1.8 Hz, 1H), 8.21 (d, J � 8.2 Hz, 1H), 7.95 (d, 3 h at − 72 C and for 2 h at room temperature. 1en, ice was J � 6.0 Hz, 1H), 7.86–7.78 (m, 3H), 7.76–7.72 (m, 1H), 7.75 added with stirring in an ice-water bath and the resulting (d, J � 6.0 Hz, 2H), 7.67–7.65 (m, 1H), 7.42–7.40 (m, 2H) solution turned red. 1e aqueous layer was separated and 13 7.34–7.31 (m, 1H); C NMR (600 MHz, CDCl ) δ: 156.6, extracted with diethyl ether (3 × 50 mL). 1e combined 149.9, 145.5, 145.4, 136.8, 136.6, 136.4, 134.8, 129.5, 129.1, organic phases were washed twice with brine and dried over 128.8, 128.6, 127.6, 127.4, 126.7, 125.8, 122.9, 120.7; HR-MS Na SO , and ether was removed. 1e resulting orange tol- + 2 4 (ESI) [C H N + H] requires 283.1230; found 283.1242. 20 14 2 uene solution was treated with MnO (54 g), stirred for 24 h, and then ﬁltered through Celite. 1e solvent was removed in vacuo to give a crude product. Column chromatography on 4.3.4. 2-[(E)-2-Cyclohexylethenyl)-1,10-phenanthroline (6b). neutral alumina with t-butyl methyl ether (MTBE) as an Yellow oil, 43 mg, 15% yield, puriﬁed by column chroma- eluent gave pure 3 (8.73 g 82%), as yellow crystals, m.p. tography (Al O , 20% AcOEt/hexane). H NMR (400 MHz, 2 3 ° ° 76− 77 C (lit. [48] m.p. 75− 76 C). H NMR (600 MHz, CDCl ) δ: 9.20 (dd, J � 4.6, 1.8 Hz, 1H), 8.22 (dd, J � 8.2, CDCl ) δ: 9.17 (dd, J � 4.2, 1.8 Hz, 1H), 8.18 (dd, J � 8.0, 1.8 Hz, 1H), 8.13 (d, J � 8.2 Hz, 1H), 7.80 (d, J � 8.2 Hz, 1H), 1.8 Hz, 1H), 8.08 (d, J � 8.2 Hz, 1H), 7.69 (q, J � 8.8 Hz, 2H), 7.72 (q, J � 8.9 Hz, 2H), 7.60 (dd, J � 8.2, 4.6 Hz, 1H), 7.01 6 Heteroatom Chemistry (dd, J � 16.2, 1.2 Hz, 1H), 6.81 (dd, J � 16.2, 6.4 Hz, 1H), 1H), 8.24 (d, J � 8.4 Hz, 1H), 7.87–7.83 (m, 2H), 7.78–7.75 2.30–2.24 (m, 1H), 1.92–1.88 (m, 2H), 1.82–1.77 (m, 2H), (m, 2H), 7.55 (d, J � 7.2 Hz, 2H), 7.29–7.27 (m, 2H), 7.24– 1.72–1.66 (m, 1H), 1.41–1.16 (m, 5H); C NMR (400 MHz, 7.21 (m, 1H), 5.79 (d, J � 6.6 Hz, 1H), 5.60 (d, J � 6.6 Hz, 1H). CDCl ) 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, 4.4.4. 2-Bromo-1-cyclohexyl-2-(1,10-phenanthrolin-2-yl)eth- 26.2; HR-MS (ESI) [C H N + H] requires 289.1699; 20 20 2 anol (10b). Yellow oil, 520 mg, 45% yield, puriﬁed by col- found 289.1705. umn chromatography (Al O , CHCl : AcOEt : hexane 1 :1 : 2 3 3 2). H NMR (400 MHz, CDCl ) 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), 4.3.5. 1-Cyclohexyl-3-cyclohexylidene-2-(1,10-phenonthrolin- 7.81–7.75 (m, 3H), 7.63 (dd, J � 8.2, 4.6 Hz, 1H), 5.17 (d, 2-yl)propene (7). Yellow oil, 42 mg, 15% yield, puriﬁed by J � 9.2 Hz, 1H), 4.36 (dd, J � 9.5, 2.4 Hz, 1H), 2.57 (s, 2H), column chromatography (Al O , 20% AcOEt/hexane). H 2 3 2.27–2.25 (m, 1H), 2.04–2.02 (m, 1H), 1.82–1.16 (m, 7H). NMR (400 MHz, CDCl ) 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, 4.5. General Procedure for the Synthesis of Epoxides. 1e 1.5 Hz, 1H), 6.05 (s, 1H), 2.46–2.43 (m, 1H), 2.34–2.31 (m, synthesis of epoxides was performed according to a modiﬁed 2H), 1.96–1.93 (m, 2H), 1.77–1.75 (m, 4H), 1.69–1.63 (m, literature procedure [53]. Bromohydrin (2.8 mmol) was 3H), 1.55–1.50 (m, 2H), 1.40–1.31 (m, 7H); C NMR dissolved in dioxane (3.5 mL), then 1 M aqueous NaOH (400 MHz, CDCl ) δ: 159.4, 150.1, 146.4, 145.8, 144.9, 141.4, (4.5 mL) was added, and the mixture was stirred at room 136.11, 136.09, 134.6, 129.0, 127.3, 126.6, 125.4, 122.7, 121.9, temperature for 24 h. After completion of the reaction, the 118.3, 39.1, 36.9, 32.4, 30.6, 28.8, 27.3, 26.7, 26.3, 26.2; HR- mixture was extracted with chloroform (3 × 30 mL). 1e MS (ESI) [C H N + H] requires 383.2482; found 27 30 2 combined organic layers were dried over Na SO , ﬁltered, 2 4 383.2483. and concentrated in vacuo to give the desired product. 4.4. General Procedure for the Synthesis of Bromohydrins. 4.5.1. trans-2-(3-Phenyl-2-oxiranyl)pyridine (11). Brown oil, 1e synthesis of bromohydrins was performed according to 375 mg, 68% yield, R � 0.63 (CHCl : AcOEt : MeOH 1 :1 : f 3 a modiﬁed literature procedure [53]. 1e mixture of 2-styryl- 0.25). H NMR (600 MHz, CDCl ) δ: 8.60–8.58 (m, 1H), azaarene (3.0 mmol), NBS (587 mg, 3.3 mmol), and acetic 7.73–7.69 (m, 1H), 7.38–7.31 (m, 6H), 7.26–7.23 (m, 1H), acid (0.5 mL) was dissolved in the mixture of dioxane/water 4.05 (AB system, 2H). 1e NMR data are in agreement with (3.5 mL/7 mL) and stirred at room temperature for 24 h. the reported ones [52]. After completion of the reaction, the mixture was extracted with chloroform (3 × 30 mL). 1e combined organic layers 4.5.2. trans-6-(3-Phenyl-2-oxiranyl)-2,2′-bipyridine (12). were dried by over Na SO ﬁltered and concentrated in 2 4 White crystals, 713 mg, 93% yield, m.p. 117− 118 C, R � 0.61 vacuo to give the desired product as conﬁrmed by H NMR. (CHCl : AcOEt : MeOH 1 :1 : 0.25). IR υ (Neat) 2960, 3 max − 1 1 2926, 1580, 1563, 775, 760, 746, 694 cm ; H NMR 4.4.1. 2-Bromo-1-phenyl-2-(pyridin-2-yl)ethanol (8). Brown (600 MHz, CDCl ) δ: 8.7 (d, J � 4.2 Hz, 1H), 8.47 (d, oil, 784 mg, 94% yield; R � 0.57 (CHCl : AcOEt : MeOH 1 : f 3 J � 7.8 Hz, 1H), 8.4 (d, J � 7.8 Hz, 1H), 7.88–7.84 (m, 2H), 1 : 0.25). H NMR (600 MHz, CDCl ) δ: 8.57–8.56 (m, 1H), 7.40–7.36 (m, 4H), 7.35–7.26 (m, 3H), 4.16 (d, J � 1.8 Hz, 7.63–7.60 (m, 2H), 7.30–7.27 (m, 2H), 7.27–7.25 (m, 2H), 1H), 4.12 (d, J � 1.8 Hz, 1H); C NMR (600 MHz, CDCl ) δ: 7.23–7.21 (m, 2H), 5.41 (d, J � 5.4 Hz, 1H), 5.20 (d, J � 5.4 Hz, 156.1, 155.8, 155.7, 149.1, 137.8, 137.0, 136.8, 128.6, 128.5, 1H). 125.8, 123.9, 121.4, 120.6, 119.7, 63.2, 61.9; HR-MS (ESI) [C H N O + H] requires 275.1179; found 275.1180. 18 14 2 4.4.2. 2-Bromo-1-phenyl-2-(2,2′-bipyridin-6-yl)ethanol (9). White crystals, 960 mg, 90% yield, puriﬁed by column 4.5.3. trans-2-(3-Phenyl-2-oxiranyl)-1,10-phenanthroline chromatography (SiO , CHCl : AcOEt : MeOH 1 :1 : 0.25), 2 3 (13a). Brown oil, 784 mg, 94% yield, R � 0.44 (CHCl : f 3 m.p. 117− 118 C, R � 0.61 (CHCl : AcOEt : MeOH 1 :1 : AcOEt : MeOH 1 :1 : 0.25). IR υ (Neat) 2923, 2853, 1588, f 3 max − 1 1 0.25). H NMR (600 MHz, CDCl ) δ: 8.72 (d, J � 4.8 Hz, 1H), 3 1555, 845, 741, 696 cm ; H NMR (600 MHz, CDCl ) δ: 9.18 8.38–8.34 (m, 1H), 7.90 (s, 1H), 7.77–7.74 (t, J � 7.8 Hz, 1H), (dd, J � 4.3, 1.8 Hz, 1H), 8.31–8.24 (m, 2H), 7.80 (d, 7.40–7.38 (m, 1H), 7.32 (d, J � 7.2 Hz, 1H) 7.28–7.24 (m, J � 1.8 Hz, 2H), 7.63 (dd, J � 8.2, 6.4 Hz, 2H), 7.37–7.33 (m, 4H), 7.24–7.22 (m, 2H), 5.53 (d, J � 5.4 Hz, 1H), 5.28 (d, 5H), 4.69 (d, J � 1.8 Hz, 1H), 4.02 (d, J � 1.8 Hz 1H); C J � 5.4 Hz, 1H). NMR (600 MHz, CDCl ) 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) [C H N O + H] 20 14 2 4.4.3. 2-Bromo-1-phenyl-2-(1,10-phenanthrolin-2-yl)ethanol requires 299.1135; found 299.1146. (10a). Brown oil, 1.0 g, 91% yield, puriﬁed by column chromatography (SiO , CHCl : AcOEt : MeOH 1 :1 : 0.25), 2 3 R � 0.24 (CHCl : AcOEt : MeOH 1 :1 : 0.25). H NMR 4.5.4. trans-2-(3-Cyclohexyl-2-oxiranyl)-1,10-phenanthroline f 3 (600 MHz, CDCl ) δ: 9.31–9.30 (m, 1H), 8.40 (d, J � 7.8 Hz, (13b). Yellow oil, 811 mg, 95% yield. H NMR (400 MHz, 3 Heteroatom Chemistry 7 CDCl ) δ: 9.24 (dd, J � 4.3, 1.5 Hz, 1H), 8.26 (dd, J � 8.2, chromatography (SiO , CHCl : AcOEt : MeOH 1 :1 : 0.1), 3 2 3 ° ° 1.8 Hz, 1H), 8.22 (d, J � 8.2 Hz, 1H), 7.78 (s, 2H), 7.65 (dd, m.p. 145–146 C (lit. [60] m.p. 145–148 C), [α] � 26 (c 1.0, J � 8.2, 4.6 Hz, 1H), 7.45 (d, J � 8.2 Hz, 1H), 4.47 (d, CHCl ), (lit. [60] [α] � 26.5 (c 1.0, CHCl )), R � 0.20 3 3 f J � 2.1 Hz, 1H), 2.96 (d, J � 2.1 Hz, 1H), 1.59–1.26 (m, 3H), (CHCl : AcOEt : MeOH 1 :1 : 0.1). H NMR (400 MHz, 1.25–1.24 (m, 6H), 0.86–0.84 (m, 2H); C NMR (600 MHz, CDCl ) δ: 7.34–7.22 (m, 10H), 4.72 (dd, J � 8.9, 3.7 Hz, 1H), CDCl ) δ: 159.2, 150.6, 137.1, 136.2, 134.3, 129.6, 129.1, 3.75 (q, J � 6.4 Hz, 1H), 2.64 (dd, J � 12.2, 3.7 Hz, 1H), 2.54 128.6, 126.6, 126.5, 123.1, 118.3, 38.9, 30.6, 24.1 23.0, 14.1, (dd, J � 12.2, 8.9 Hz, 1H), 1.38 (d, J � 6.7 Hz, 3H). 1e NMR 11.2; HR-MS (ESI) [C H N O + H] requires 305.1648; data are in agreement with literature data for (R,1′R)-en- 20 20 2 found 305.1653. antiomer [60]. (2) (S,R)-2-(1-Phenylethyl)amino-1-phenyl-ethanol (S,1′R)- 4.6. Procedures for Ring Opening of Epoxides 17. Brown crystals, 41 mg, 34% yield, puriﬁed by column chromatography (SiO , CHCl : AcOEt : MeOH 1 :1 : 0.1), 2 3 4.6.1. Method A (Catalyzed by Sc(OTf ) ). A solution of the 3 1 R � 0.25 (CHCl : AcOEt : MeOH 1 :1 : 0.1). H NMR f 3 epoxide 11, 12, 13b, 14, 15, or 16 (0.5 mmol), 1-phenyl- (400 MHz, CDCl ) δ: 7.34–7.22 (m, 10H), 4.55 (dd, J � 8.9, ethylamine (77 μL, 0.6 mmol), Sc(OTf) (12 mg, 5 mol%), 3.7 Hz, 1H), 3.81 (q, J � 6.4 Hz, 1H), 2.81 (dd, J � 12.2, 3.7 Hz, and N-ethyldiisopropylamine (170 μL, 1 mmol) in toluene 1H), 2.54 (dd, J � 12.2, 8.9 Hz, 1H), 1.36 (d, J � 6.7 Hz, 3H). (2 mL) was stirred under argon in a sealed test tube at 80 C 1e NMR data are in agreement with literature data for for 7 days. 1e cooled mixture was directly submitted to the (R,1′S)-enantiomer [60]. column chromatography on silica gel. In this way, the regioisomers 17 and 18, resulting in the reaction of 15, were (3) (S,S)-2-(1-Phenylethyl)amino-1-phenyl-ethanol (S,1′S)- separated, and their structures were conﬁrmed by NMR. 1e 17. White crystals, 41 mg, 34% yield, recrystallized (CH Cl / 2 2 isolated diastereoisomers 17, as well as the respective di- hexane), R � 0.20 (CHCl : AcOEt : MeOH 1 :1 : 0.1). H f 3 astereomers formed in the reactions of 11, 12, 14, and 16, NMR (400 MHz, CDCl ) δ: 7.34–7.22 (m, 10H), 4.60 (dd, were separated by column chromatography. Additionally, J � 8.9, 3.7 Hz, 1H), 3.77 (q, J � 6.4 Hz, 1H), 2.77 (dd, J � 12.2, the diastereomers 17 could be separated by recrystallization 3.7 Hz, 1H), 2.63 (dd, J � 12.2, 8.9 Hz, 1H), 1.40 (d, J � 6.7 Hz, from hexane/CH Cl . 2 2 3H). 1e NMR data are in agreement with literature data for 1e reactions of (98 mg, 0.5 mmol) or (137 mg, (R,1′R)-enantiomer [60]. 0.5 mmol) with (R)-1-cyclohexylethylamine (88 μL, 0.6 mmol), Sc(OTf) (12 mg, 5 mol%), and N-ethyldiisopropylamine (4) (R,S)-2-(1-Phenylethyl)amino-1-phenyl-ethanol (R,1′S)- (170 μL, 1 mmol) dissolved in toluene (2 mL) were run and then 17. Brown crystals, 41 mg, 34% yield, recrystallized (CH Cl / 2 2 worked up as above. For the epoxide , both diastereomers ° ° hexane), m.p. 82–83 C (lit. [60] m.p. 80–85 C), [α] � –105 were separated by chromatography and gave pure samples, (c 1.0, CHCl ), (lit. [60] [α] � –110 (c 1.0, CHCl )), 3 3 while for , only one diastereomer (1R,2R,1′R)- could be R � 0.25 (CHCl : AcOEt : MeOH 1 :1 : 0.1). H NMR f 3 isolated in a pure form. (400 MHz, CDCl ) δ: 7.34–7.21 (m, 10H), 4.74 (dd, J � 9.2, 1e pure separated products (S,1′S)-17, (R,1′S)-17, (S/ 3.4 Hz, 1H), 3.83 (q, J � 6.7 Hz, 1H), 2.79 (dd, J � 12.2, 3.7 Hz, R,1′S)-18, ( 1R,2S,1′S)-19, (1S,2R,1′S)-19, (S,1′S)-20, (R,1′S)- 1H), 2.55 (dd, J � 12.2, 9.2 Hz, 1H), 1.40 (d, J � 6.4 Hz, 3H). 20, (1R,2S,1′S)-,12 (1S,2S,1′S)-,12 (1S,2R,1′R)-19, (1R,2R,1′R)- 1e NMR data are in agreement with literature data for ,12 (1S,2R,1′R)-, (1R,2R,1′R)-, (1R,2S,1′S)-, (1S,2S,1′S)- (R,1′S)-enantiomer [60]. , (1R,2R,1′R)-, and [(1R,2R,1′R)- and (1S,2S,1′R)]- were analyzed, and their properties are reported below. (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 (SiO , CHCl : AcOEt : 2 3 4.6.2. Method B (Catalyzed by Zn(OAc) ). 1e reaction was MeOH 1 :1 : 0.1). H NMR (400 MHz, CDCl ) δ: 7.40–7,18 carried out under the same conditions as in Method A, but (m, 20H), 3.90–3.88 (m, 1H), 3.77–3.71 (m, 2H), 3.65–3.67 instead of Sc(OTf) and N-ethyldiisopropylamine, Zn(OAc) 3 2 (m, J � 6.7 Hz, 1H), 3.58–3.50 (m, 4H), 1.36 (d, J � 6.4 Hz, (4.6 mg, 5 mol%) as a catalyst was added. 1e products 6H); C NMR (400 MHz, CDCl ) δ: 129.1, 129.0, 128.9, (R,1′R)-17, (S,1′R)-17, (S,1′S)-17, (R,1′S)-17, (S,1′S)-20, and 128.8, 128.7, 128.6, 128.31, 128.30, 127.90, 127.85, 127.8, (R,1′S)-20 were isolated as in Method A. 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) [C H NO + H] requires 16 19 242.1539; found 242.1545. 1e NMR data are in agreement 4.6.3. Method C (Absence of a catalyst). 1e reaction of 14 or 15 (1.0 mmol) with 1-phenylethylamine (154 μL, 1.2 mmol) with the reported ones [59]. 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 (6) (1R,2R,1′S)-2-(1′-Phenylethyl)amino-1,2-diphenyl-etha- in Method A (direct chromatography), the products were nol (1R,2S,1′S)- 19. White crystals, 43 mg, 27% yield, puriﬁed analyzed by NMR. by column chromatography (SiO , CHCl : AcOEt : MeOH 2 3 1 :1 : 0.1), m.p. 135–136 C, [α] � –63 (c 0.9, CHCl ), (lit. 20 1 (1) (R,R)-2-(1-Phenylethyl)amino-1-phenyl-ethanol (R,1′R)- [58] [α] � –66.1 (c 1.0, CHCl ). H NMR (400 MHz, 17. White crystals, 41 mg, 34% yield, puriﬁed by column CDCl ) δ: 7.33–7.13 (m, 11H), 6.98–6.94 (m, 4H), 4.98 (d, 25 24 23 23 22 22 24 12 12 11 8 Heteroatom Chemistry J � 4.9 Hz, 1H), 4.0 (d, J � 4.9 Hz, 1H), 3.78 (q, J � 6.4 Hz, 65.1, 54.8, 23.1; HR-MS (ESI) [C H N O + H] requires 21 22 2 1H), 1.35 (d, J � 6.7 Hz, 3H); C NMR (400 MHz, CDCl ) δ: 319.1805; found 319.1801. 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. 1e NMR data are (11) (1R,2R,1′S)-2-(1′-Phenylethyl)amino-2-phenyl-1-(pyr- in agreement with literature data for (1R,2S,1′S)-enantiomer idin-2-yl)ethanol(1R,2R,1′S)- 1.2 Colorless oil, 42 mg, 26% [58]. yield, puriﬁed by column chromatography (SiO , AcOEt : CHCl 8 : 2), [α] � –93 (c 1.0, CH Cl ), R � 0.48 (CHCl : 3 2 2 f 3 (7) (1S,2R,1′S)-2-(1′-Phenylethyl)amino-1,2-diphenyl-etha- AcOEt : MeOH 1 :1 : 0.1). IR υ (Neat) 3324, 3026, 2923, max − 1 1 nol (1S,2R,1′S)- 19. Colorless oil, 43 mg, 27% yield, puriﬁed 1592, 1451, 699 cm ; H NMR (400 MHz, CDCl ) δ: 8.39 (d, by column chromatography (SiO , CHCl : AcOEt : MeOH J � 4.6 Hz, 1H), 7.47 (td, J � 7.6, 1.5 Hz, 1H), 7.26–7.12 (m, 2 3 20 20 1 :1 : 0.1), [α] � –111 (c 1.0, CHCl ), (lit. [58] [α] � – 9H), 6.96–6.95 (m, 3H), 4.88 (s, 1H), 4.20 (s, 1H), 3.77 (d, D D 112.8 (c 1.0, CHCl ). H NMR (400 MHz, CDCl ); δ: J � 4.9 Hz, 1H), 3.57 (q, J � 6.7 Hz, 1H), 1.30 (d, J � 6.7 Hz, 3 3 7.33–7.20 (m, 10H), 7.09–6.95 (m, 5H), 4.64 (d, J � 4.9 Hz, 3H); C NMR (400 MHz, CDCl ) δ: 159.5, 148.0, 145.4, 1H), 3.62 (d, J � 4.9 Hz, 1H), 3.49 (q, J � 6.4 Hz, 1H), 1.23 (d, 139.2, 136.0, 128.4, 128.3, 128.0, 127.2, 126.90, 126.89, 122.4, 13 + J � 6.7 Hz, 3H); C NMR (400 MHz, CDCl ) δ: 144.9, 140.5, 121.8, 76.2, 65.4, 54.9, 25.2; HR-MS (ESI) [C H N O + H] 3 21 22 2 139.7, 128.5, 128.4, 128.1, 127.8, 127.7, 127.2, 127.1, 126.7, requires 319.1805; found 319.1796. 126.4, 75.6, 65.8, 54.9, 24.8. 1e NMR data are in agreement with literature data for (1S,2R,1′S-)-enantiomer [58]. (12) (1R,2R,1′R)-2-(1′-Phenylethyl)amino-2-phenyl-1-(pyr- idin-2-yl)ethanol (1R,2R,1′R)- 1.2 White crystals, 46 mg, 29% (8) (S,S)-2-(1-Phenylethyl)amino-1-(pyridin-2-yl)ethanol yield, puriﬁed by column chromatography (SiO , AcOEt : (S,1′S)- 20. White crystals, 44 mg, 36% yield, puriﬁed by CHCl 8 : 2), m.p. 94–95 C, [α] � 78 (c 0.9, CH Cl ), 3 2 2 column chromatography (SiO , CHCl : AcOEt : MeOH 1 : R � 0.35 (CHCl : AcOEt : MeOH 1 :1 : 0.1). IR υ (Neat) 2 3 f 3 max 20 − 1 1 1 : 0.1), m.p. 119–120 C, [α] � –42 (c 0.6, CH Cl ). IR υ 3133, 3032, 2922, 1592, 1434, 697 cm ; H NMR (400 MHz, 2 2 max 1 1 (Neat) 3290, 2971, 1589, 1432, 703 cm ; H NMR (400 MHz, CDCl ) δ: 8.37–8.35 (m, 1H), 7.47 (td, J � 7.6, 1.5 Hz, 1H), CDCl ) δ: 8.50–8.48 (m, 1H), 7.64 (td, J � 7.4, 1.8 Hz, 1H), 7.32–7.20 (m, 5H), 7.25–7.10 (m, 3H), 7.06–7.03 (m, 1H), 7.33–7.22 (m, 6H), 7.17–7.14 (m, 1H), 4.71 (dd, J � 8.1, 6.99–6.93 (m, 3H), 5.10 (d, J � 4.3 Hz, 1H), 4.11 (d, J � 4.3 Hz, 3.7 Hz, 1H), 3.75 (q, J � 6.5 Hz, 1H), 2.86 (dd, J � 12.0, 3.7 Hz, 1H), 3.80 (q, J � 6.4 Hz, 1H) 1.34 (d, J � 6.4 Hz, 3H); C 1H), 2.69 (dd, J � 12.0, 8.1 Hz, 1H), 1.36 (d, J � 6.4 Hz, 3H); NMR (400 MHz, CDCl ) δ: 159.6, 148.1, 145.8, 139.9, 136.0, C NMR (400 MHz, CDCl ) δ: 161.0, 148.5, 145.5, 136.7, 128.6, 128.1, 127.9, 127.2, 127.1, 126.7, 122.2, 121.5, 74.9, 128.6, 127.1, 126.7, 122.4, 120.6, 72.3, 58.6, 54.4, 24.4; HR- 65.1, 54.7, 23.1; HR-MS (ESI) [C H N O + H] requires 21 22 2 MS (ESI) [C H N O + H] requires 243.1492; found 319.1805; found 319.1826. 15 18 2 243.1500. (13) (1S,2S,1′R)-2-(1′-Phenylethyl)amino-2-phenyl-1-(pyridin- (9) (R,S)-2-(1-Phenylethyl)amino-1-(pyridin-2-yl)ethanol 2-yl)ethanol(1S,2S,1′R)- 21. Colorless oil, 46 mg, 29% yield, (R,1′S)- 20. White crystals 44 mg, 36% yield, puriﬁed by puriﬁed by column chromatography (SiO , AcOEt : CHCl 2 3 column chromatography (SiO , CHCl : AcOEt : MeOH 1 : 8 : 2), [α] � 93 (c 0.8, CH Cl ), R � 0.48 (CHCl : AcOEt : 2 3 2 2 f 3 1 : 0.1), m.p. 75–76 C, [α] � –52 (c 0.8, CH Cl ). IR υ MeOH 1 :1 : 0.1). IR υ (Neat) 3322, 3026, 2923, 1593, 2 2 max max − 1 1 − 1 1 (Neat) 3081, 2847, 1588, 1433, 702 cm ; H NMR 1451, 699 cm ; H NMR (400 MHz, CDCl ) δ: 8.39 (d, (400 MHz, CDCl ) δ: 8.48–8.46 (m, 1H), 7.63 (td, J � 7.6, J � 4.9 Hz, 1H), 7.49 (td, J � 7.2, 1.2 Hz, 1H), 7.28–7.06 (m, 1.8 Hz, 1H), 7.37–7.21 (m, 6H), 7.15 (m, 1H) 4.97 (dd, J � 8.1, 9H), 6.98–6.90 (m, 3H), 4.88 (d, J � 4.9 Hz, 1H), 4.22 (s, 1H), 3.7 Hz, 1H), 3.96 (q, J � 6.5 Hz, 1H), 3.08 (dd, J � 12.0, 3.7 Hz, 3.76 (d, J � 4.9 Hz, 1H), 3.57 (q, J � 6.7 Hz, 1H) 1.30 (d, 1H), 2.68 (m, J � 12.0, 8.1 Hz, 1H), 1.50 (d, J � 6.4 Hz, 3H); J � 6.7 Hz, 3H); C NMR (400 MHz, CDCl ) δ: 159.5, 148.0, C NMR (400 MHz, CDCl ) δ: 160.4, 148.3, 136.9, 128.8, 145.3, 139.2, 136.0, 128.4, 128.3, 128.0, 127.2, 126.90, 126.89, 127.8, 127.1, 127.0, 122.6, 120.8, 70.9, 58.5, 53.3, 23.3; HR- 122.4, 121.8, 76.2, 65.4, 54.9, 25.2; HR-MS (ESI) + + MS (ESI) [C H N O + H] requires 243.1492; found [C H N O + H] requires 319.1805; found 319.1811. 15 18 2 21 22 2 243.1504. (14) (1R,2R,1′S)-2-(1′-Cyclohexylethyl)amino-2-phenyl-1- (10) (1S,2S,1′S)-2-(1′-Phenylethyl)amino-2-phenyl-1-(pyr- (pyridin-2-yl)ethanol (1R,2R,1′R)- 22. Brown oil, 53 mg, 33% idin-2-yl)ethanol (1S,2S,1′S)- 1.2 White crystals, 42 mg, 26% yield, puriﬁed by column chromatography (SiO 20% yield, puriﬁed by column chromatography (SiO , AcOEt : MTBE/hexane), [α] � –45 (c 0.7, CH Cl ). IR υ (Neat) 2 2 2 max 20 − -1 1 CHCl 8 : 2), m.p. 94–95 C, [α] � –78 (c1.0, CH Cl ), 3139, 3019, 2924, 1435, 696 cm ; H NMR (400 MHz, 3 2 2 R � 0.35 (CHCl : AcOEt : MeOH 1 :1 : 0.1). IR υ (Neat) CDCl ) δ: 8.46–8.44 (m, 1H), 7.43 (dq, J � 7.6, 1.8 Hz, 1H), f 3 max 3 − 1 1 3147, 3032, 2924, 1592, 1433, 697 cm ; H NMR (400 MHz, 7.14–7.01 (m, 6H), 6.93 (d, J � 7.9 Hz, 1H), 4.95 (d, J � 4.6 Hz, CDCl ) δ: 8.36–8.34 (m, 1H), 7.47 (td, J � 7.6, 1.5 Hz, 1H), 1H), 4.18 (d, J � 4.6 Hz, 1H), 2.55–2.52 (m, 1H), 1.72–1.63 7.29–7.24 (m, 4H), 7.24–7.19 (m, 1H), 7.14–7.09 (m, 3H), (m, 8H), 1.28–1.16 (m, 3H), 0.97 (d, J � 6.4 Hz, 3H); C 7.06–6.94 (m, 4H), 5.12 (d, J � 4.3 Hz, 1H), 4.15 (d, J � 4.3 Hz, NMR (400 MHz, CDCl ) δ: 160.3, 148.2, 140.1, 136.0, 128.0, 1H), 3.81 (q, J � 6.4 Hz, 1H) 1.35 (d, J � 6.4 Hz, 3H); C 127.8, 127.2, 122.1, 121.5, 75.02, 65.25, 55.0, 42.8, 29.8, 28.1, NMR (400 MHz, CDCl ) δ: 159.6, 148.0, 145.77, 138.9, 136.5, 26.9, 26.8, 26.7, 17.8; HR-MS (ESI) [C H N O + H] re- 3 21 28 2 128.6, 128.2, 127.9, 127.2, 127.1, 126.7, 122.2, 121.5, 74.9, quires 325.2274; found 325.2280. Heteroatom Chemistry 9 (15) (1S,2S,1′R)-2-(1′-Cyclohexylethyl)amino-2-phenyl-1- (19) 2-(1′-Phenylethyl)amino-2-cyclohexyl-1-(1,10-phenan- (pyridin-2-yl)ethanol (1S,2S,1′R)- 22. Brown oil, 53 mg, 33% throlin-2-yl)ethanol (1R,2R,1′R)- 25 and (1S,2S,1′R)- 25. yield, puriﬁed by column chromatography (SiO 20% Colorless oil, 17 mg, 8% total yield, puriﬁed by column 20 1 MTBE/hexane), [α] � 28 (c 0.8, CH Cl ). IR υ (Neat) chromatography (SiO , hexane : AcOEt : CHCl 2 :1 :1). H 2 2 max 2 3 − 1 1 3062, 3028, 2925, 1434, 699 cm ; H NMR (400 MHz, NMR (400 MHz, CDCl ) δ: 9.16–9.14 (m, 2H), 8.22 (dd, CDCl ) δ: 8.42–8.40 (m, 1H), 7.48 (dq, J � 7.6, 1.8 Hz, 1H), J � 7.9, 1.8 Hz, 2H), 8.17 (d, J � 8.2 Hz, 1H), 8.13 (d, 7.15–6.97 (m, 7H), 4.97 (d, J � 4.6 Hz, 1H), 4.19 (d, J � 4.6 Hz, J � 8.2 Hz, 1H), 7.75 (d, J � 1.8 Hz, 4H), 7.62–7.58 (m, 2H), 1H), 2.34–2.31 (m, 1H), 1.73–1.70 (m, 7H), 1.40–0.97 (m, 7.52 (d, J � 8.2 Hz, 1H), 7.35–7.14 (m, 11H), 3.96 (d, 4H), 0.92 (d, J � 6.4 Hz, 3H); C NMR (400 MHz, CDCl ) δ: J � 3.1 Hz, 1H), 3.89 (dd, J � 7.9, 3.4 Hz, 1H), 3.24 (s, 1H), 159.8, 148.1, 138.9, 136.0, 128.4, 127.8, 127.1, 122.2, 121.6, 3.22 (d, J � 2.1 Hz, 1H), 1.79–1.49 (m, 11H), 1.41–1.39 (m, 76.2, 65.0, 54.0, 43.9, 29.6, 28.7, 26.8, 26.7, 26.6, 16.7; HR-MS 6H), 1.29–1.19 (m, 9H), 1.10–1.09 (m, 4H); HR-MS (ESI) + + (ESI) [C H N O + H] requires 325.2274; found 325.2289. [C H N O + H] requires 426.2540; found 426.2532. 21 28 2 28 31 3 (16) (1R,2R,1′S)-2-(1′-Phenylethyl)amino-2-phenyl-1-(2,2′- 4.7. General Procedure for the Synthesis of Oxazolidinones bipyridin-6-yl)ethanol (1R,2R,1′S)- . Colorless oil, 60 mg, from Amino Alcohols. 1e synthesis of oxazolidinones was 30% yield, puriﬁed by column chromatography (Al O MTBE), 2 3, performed according to the literature procedure [58]. Tri- R � 0.48 (Al O MTBE), [α] � –112 (c 0.9, CH Cl ). IR υ f 2 3, 2 2 max phosgene (36 mg, 0.12 mmol) was added to a mixture of the − 11 (Neat) 3324, 3026, 2924, 1564, 1430, 699 cm H NMR amino alcohol (0.3 mmol) in toluene (3 mL) and potassium (400 MHz, CDCl ) δ: 8.64–8.62 (m, 1H), 8.21 (dd, J � 7.9, carbonate (57 mg, 0.41 mmol) in water (1.3 mL) with vigorous 0.9 Hz, 1H), 8.05 (td, J � 7.9, 1.2 Hz, 1H), 7.74 (dd, J � 7.9, stirring at room temperature. After being stirred for 48 h, the 1.8 Hz, 1H), 7.65 (t, J � 7.6 Hz, 1H), 7.29–7.13 (m, 9H), 7.0–6.98 mixture was washed with water and brine, the organic layer was (m, 3H), 4.95 (s, 1H), 4.22 (br s, 1H), 3.80 (d, J � 4.9 Hz, 1H), dried over MgSO , ﬁltered, and concentrated in vacuo. 1e 13 4 3.59 (q, J � 6.4 Hz, 1H), 1.30 (d, J � 6.7 Hz, 3H); C NMR residue was chromatographed on silica gel (hexane/ethyl acetate (400 MHz, CDCl ) δ: 158.8, 155.8, 154.5, 149.2, 145.3, 139.3, 7 : 3) to give the corresponding oxazolidinone. 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) + 4.7.1. (4R,5S,1′S)-N-(1′-Phenylethyl)-4,5-diphenyl-2-oxazoli- [C H N O + H] requires 396.2070; found 396.2067. 26 25 3 dinone (4R,5S,1′S)-26. White crystals, 60 mg, 59% yield, ° ° m.p. 154–157 C (lit. [58] m.p. 154–156 C), [α] � 19.0 (c 1.0, (17) (1S,2S,1′S)-2-(1′-Phenylethyl)amino-2-phenyl-1-(2,2′- 20 1 CHCl ) (lit. [58] [α] � 19.1 c 1.0, CHCl ). H NMR 3 3 bipyridin-6-yl)ethanol (1S,2S,1′S)- 23. Colorless oil, 60 mg, (400 MHz, CDCl ) δ: 7.39–7.32 (m, 6H), 7.07–7.02 (m, 6H), 30% yield, puriﬁed by column chromatography (Al O 2 3, 20 6.95–6.94 (m, 3H), 5.66 (d, J � 8.2 Hz, 1H), 5.35 (q, J � 7.3 Hz, MTBE), R � 0.39 (Al O MTBE), [α] � 7.2 (c 0.6, CH Cl ). f 2 3 2 2 D 13 1H), 4.56 (d, J � 8.2 Hz, 1H), 1.21 (d, J � 7.3 Hz, 3H); C IR υ (Neat) 3326, 3025, 2923, 1581, 1564, 1453, 1430, max − 1 1 NMR (400 MHz, CDCl ) δ: 158.1, 140.1, 136.6, 134.4, 128.9, 699 cm ; H NMR (400 MHz, CDCl ) δ: 8.62–8.60 (m, 1H), 128.3, 128.2, 128.11, 128.07, 127.9, 127.8, 127.5, 126.0, 80.3, 8.18 (d, J � 6.7 Hz, 1H), 7.97 (d, J � 7.9 Hz, 1H), 7.67 (td, 62.8, 53.4, 18.3. 1e NMR data are in agreement with the J � 7.6, 1.8 Hz, 1H), 7.63 (t, J � 7.6 Hz, 1H), 7.31–7.23 (m, literature [58]. 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 4.7.2. (4R,5R,1′S)-N-(1′-Phenylethyl)-5-pyridin-2-yl-4-phe- (q, J � 6.4 Hz, 1H), 1.35 (d, J � 6.4 Hz, 3H); C NMR nyl-2-oxazolidinone (4R,5R,1′S)-27. White crystals, 47 mg, (400 MHz, CDCl ) δ: 158.9, 155.8, 154.5, 149.1, 145.9, 138.9, 46% yield, m.p. 120–122 C, [α] � 21 (c 0.8, CHCl ). H 137.2, 136.8, 129.6, 128.1, 127.9, 127.2, 127.1, 126.8, 123.8, 3 NMR (400 MHz, CDCl ) δ: 8.24–8.22 (m, 1H), 7.49–7.29 (m, 121.7, 121.1, 119.6, 74.9, 65.2, 54.6, 22.8; HR-MS (ESI) 3 7H), 7.13 (d, J � 7.6 Hz, 1H), 7.05–7.03 (m, 3H), 6.92–6.89 [C H N O + H] requires 396.2070; found 396.2073. 26 25 3 (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); C NMR (18) (1R,2R,1′R)-2-(1′-Cyclohexylethyl)amino-2-phenyl-1-(2,2′- (400 MHz, CDCl ) δ: 157.7, 154.9, 148.7, 139.9, 136.9, 136.3, bipyridin-6-yl)ethanol (1R,2R,1′R)- . Colorless oil, 64 mg, 3 128.9, 128.22, 128.19, 128.1, 127.8, 127.4, 122.4, 120.9, 80.6, 32% yield, puriﬁed by column chromatography (Al O , 20% 2 3 61.9, 53.5, 18.2; HR-MS (ESI) [C H N O + H] requires MTBE/hexane). [α] � –37 (c 0.9, CH Cl ). IR υ (Neat) 22 20 2 2 2 2 max − 1 1 345.1598; found 345.1618. 3062, 2925, 2852, 1562, 1428, 773 cm ; H NMR (400 MHz, CDCl ) 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), 4.7.3. (4S,5S,1′S)-N-(1′-Phenylethyl)-5-pyridin-2-yl-4-phenyl-2- 7.66–7.58 (m, 1H), 7.31–7.27 (m, 1H), 7.15–6.97 (m, 6H), oxazolidinone (4S,5S,1′S)-27. White crystals, 47 mg, 46% 20 1 5.00 (d, J � 4.6 Hz, 1H), 4.22 (d, J � 4.6 Hz, 1H), 2.54–2.51 (m, yield, m.p. 136–137 C, [α] � 16 (c 0.6, CHCl ). H NMR 1H), 1.71–1.61 (m, 6H), 1.41–1.32 (m, 1H), 1.25–1.21 (m, (400 MHz, CDCl ) δ: 8.23–8.22 (m, 1H), 7.39 (t, J � 7.9 Hz, 1H), 1.16–0.97 (m, 3H), 0,95 (d, J � 6.4 Hz, 3H); C NMR 1H), 7.20–7.12 (m, 6H), 6.93–6.88 (m, 4H), 6.74–6.71 (m, (400 MHz, CDCl ) δ: 159.5, 156.1, 154.5, 149.2, 140.3, 137.1, 2H), 5.81 (d, J � 8.2 Hz, 1H), 5.07 (d, J � 8.6 Hz, 1H), 4.62 (q, 136.8, 128.1, 127.9, 127.1, 123.7, 121.7, 121.1, 119.5, 76.3, J � 7.0 Hz, 1H), 1.60 (d, J � 7.0 Hz, 3H); C NMR (400 MHz, 65.6, 65.0, 55.1, 42.7, 29.9, 27.9, 26.8, 26.7, 17.8; HR-MS (ESI) CDCl ) δ: 157.4, 155.3, 148.6, 140.4, 136.3, 134.9, 128.4, [C H N O + H] requires 402.2540; found 402.2538. 127.93, 127.91, 127.82, 127.80, 127.5, 122.5, 120.9, 79.8, 64.0, 26 31 3 23 10 Heteroatom Chemistry [10] M. Liu, S. Ma, Z. 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Y. Nishikawa, Hisashi Yamamoto (2011)
Iron-catalyzed asymmetric epoxidation of β,β-disubstituted enones.
Journal of the American Chemical Society, 133 22

Publisher: Hindawi Publishing Corporation
Copyright: 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.
ISSN: 1098-1071
eISSN: 1042-7163
DOI: 10.1155/2019/2381208
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Abstract

Hindawi Heteroatom Chemistry Volume 2019, Article ID 2381208, 12 pages https://doi.org/10.1155/2019/2381208 Research Article 2-Oxiranyl-pyridines: Synthesis and Regioselective Epoxide Ring Openings with Chiral Amines as a Route to Chiral Ligands Marzena Wosin´ ska-Hrydczuk and Jacek Skarz˙ewski Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wyb Wyspian´skiego 27, 50-370 Wrocław, Poland Correspondence should be addressed to Jacek Skarzewski; jacek.skarzewski@pwr.edu.pl Received 15 June 2019; Revised 31 July 2019; Accepted 12 September 2019; Published 9 October 2019 Academic Editor: Guillaume Berionni Copyright © 2019 Marzena Wosin´ska-Hrydczuk and Jacek Skarz˙ewski. †is 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. New epoxides, derivatives of pyridine, 2,2′-bipyridine, and 1,10-phenanthroline, were synthesized from the respective α-methylazaarenes. †e 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. †e most eŽective reaction was run in the presence of Sc(OTf) /diisopropylethylamine for 7 days at 80 C, aŽording 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. †e resulting diastereomers were separated, and the conšgurations of their stereogenic centers were established. †e 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. enantiomers of 2-amino cyclohexanol derivatives using 1. Introduction chiral 1-phenylethylamine at the epoxide ring-opening step Modular chiral ligands and catalysts attained in a few steps followed by chromatographic separation of the di- from the well-dešned building blocks are considered as a astereomeric alcohols [13]. Moreover, the method applied to useful tool for asymmetric synthesis [1–4]. Among func- our 2-oxiranyl-pyridines may oŽer a simple route to the chiral building blocks for important medicinal compounds tional blocks for the modular catalysts, the moieties of pyridine, 2,2′-bipyridine, and 1,10-phenanthroline, forming [14, 15]. strong transition metal complexes, belong to the particularly Generally, plentiful successful Lewis acid activators for promising ones [5–12]. For this aim, we intended to develop the epoxide ring opening with amines have been developed 2-oxiranyl-pyridines that, after epoxide ring openings, [16–38]. †e regiochemistry of the metal salt-catalyzed would give the desired chiral products. aminolysis of styrene oxide depends on the amine nucleo- For this purpose, we synthesize the 2-oxiranyl-azaarenes. philicity and steric bulkiness as well as the strength of Lewis †eir epoxide ring-opening reactions with chiral amines acid activator (metal ion) [39, 40]. Moreover, an interaction should lead to the separable diastereomeric β-amino alco- of the metal-ion additives with other complexing func- hols with the 2-pyridinyl-type substituents. Hence, obtained tionalities connected to the epoxide often in¤uenced the homochiral complexing amino alcohols would be tested as observed regioselectivity [41–46]. Correspondingly, the metal-complexing pyridine-2-yl substituent demonstrated chiral ligands. †e key synthetic reaction will be carried out using the the regio-steering eŽect in the epoxide ring-opening reaction optimized regioselective epoxide ring opening with chiral in the presence of MgBr [9]. Although the asymmetric primary amines as a chiral auxiliary. †is approach has a aminolysis of meso-epoxides was successful in the presence literature precedent in the synthesis of individual of chiral metal complexes [24–32], the respective racemic 2 Heteroatom Chemistry trans-substituted epoxides could hardly be opened stereo- phenylethylamine gave also separable diastereomers (ca. 1 : selectively with other but aniline-type amine [23, 26]. 1) of amino alcohol 19 [57, 58, 61] in 54% total yield (Scheme 2). 2. Results and Discussion 2.3. Selective Epoxide Ring Opening: Pyridine Derivatives. 2.1. Synthesis of 2-Oxiranyl-pyridines. In order to obtain the After the model studies, the epoxides with pyridine-type required α-azaarene epoxides (Scheme 1), we methylated the fragments were submitted to the ring-opening reactions. parent azaarenes, namely, 2,2′-bipyridine (bpy) and 1,10- Unlike for styrene oxide (15), the reaction of rac-2-(oxir- phenanthroline (phen) with MeLi followed by the oxidative anyl)pyridine (14) with chiral amines gave only one rearomatization [47, 48]. 1e α-methyl derivatives 1 regioisomer, β-amino alcohol 20, regardless of the catalyst (commercial), 2 [47], and 3 [48] were reacted with 1 equiv of used. However, the better yield was observed for Sc(OTf) / benzaldehyde in the presence of a substoichiometric amount 3 DIEA (Scheme 3). of calcium triﬂate [49]. 1e products, trans-styryl com- 1e product 20 consisted of two diastereomers (in ca. pounds 4 [50, 51], 5 and 6, were formed in rather moderate 1 : 1 ratio), which were smoothly separated by column yields. However, the unreacted methyl derivatives could be chromatography. We ascribed their conﬁguration com- easily recovered. Moreover, when cyclohexyl carbaldehyde paring H NMR spectra between the isolated di- was used in the reaction with 3, along with 6b the diene 7 astereomers 20 and 17 (see supporting ﬁle S1), where was obtained. 1us, in the next step, 4, 5, and 6 were reacted similarities between their spectral patterns could be clearly with NBS in dioxane/water acidiﬁed with acetic acid giving seen. the respective bromohydrins 8, 9, and 10 that were smoothly Other synthesized 2,3-disubstituted trans epoxides with converted into the epoxides 11 [52, 53, 54], 12, and 13 the α-azaaromatic fragments (11–13) were submitted to the (Scheme 1). Also, rac-2-(oxiranyl)pyridine (14) [55] was ring-opening reactions, and the results are summarized in prepared analogously from 2-vinylpyridine. Scheme 4 and Table 1. 1e reaction of 11 and 12 with chiral 1-phenylethyl- 2.2. Selective Epoxide Ring Opening: Model Studies. In order amine carried out in the presence of Sc(OTf) /DIEA gave to ﬁnd the proper conditions for our key reaction, the in each case only one regioisomer of the respective promising literature method for the Sc(OTf) -catalyzed β-amino alcohol in good yield. 1e obtained products 12 epoxide ring opening [32, 39, 40] was examined. We run the and 23 consisted of two diastereomers (ca. 1 : 1), which were separated by column chromatography. Similarly, the model reaction of racemic epoxides, namely, styrene oxide (15) and trans-stilbene oxide (16) with chiral 1-phenyleth- reaction of 11 and 12 with (R)-1-cyclohexylethylamine gave regioselectively both amino alcohols 22 and 24. For ylamine in the presence of Sc(OTf) /diisopropylethylamine (DIEA) at 80 C (Scheme 2). 22, the diastereoisomers (obtained in nearly 1 : 1 ratio) were separated to give enantiomerically pure compounds 1e reaction of styrene oxide ( 15) with (S)-1-phenyl- ethylamine gave both known regioisomers, β-amino alcohol (Table 1). For the obtained diastereomeric mixture of 24, only (1R,2R,1′R)-24 could be isolated as a stereochemically 17 [56–58] and α-amino alcohol 18 [59], as a separable mixture (ca. 1 :1), and their structures were conﬁrmed by H pure sample. 1e reaction of 13b with (R)-1-phenyleth- ylamine was sluggish, and the respective diastereomeric NMR spectroscopy [56–59]. 1en, pure like-17 and unlike- 17 diastereomers were separated by recrystallization mixture 25 was formed in 8% yield. 1e reaction of rac- trans-2-(3-phenyloxiranyl)-1,10-phenanthroline (13a) (CH Cl /hexane). We ascribed their conﬁgurations by 2 2 with the same amine gave inseparable mixture, and the comparing the recorded H NMR spectral properties and speciﬁc rotations with the reported ones [56, 57, 60]. 1e corresponding dehydration product could be detected only by H NMR. conﬁguration of the like-isomer (R,1′R-17) was proved undoubtedly by the X-ray structure [56]. Furthermore, the It is noteworthy that we observed diﬀerent outcomes for the scandium-catalyzed ring opening of styrene oxide (15), samples of pure diastereomers 17 and 19 were later used for comparison in the stereochemical assignments of the chiral where both regioisomers were formed (the model reaction, Scheme 2) and 2-oxiranyl-pyridines (Schemes 3 and 4), azaaromatic analogs 20 and 1.2 In all cases, the catalyzed reactions were completed where only β-amino alcohols were obtained. 1e observed nucleophilic attack at the benzylic β-position (regiose- within 7 days at 80 C, aﬀording a good yield of the amino alcohols. 1e reaction mixtures were stirred under argon in a lectivity of aminolysis) can be explained by the speciﬁc interaction of scandium ion complexed to the pyridine sealed test tube, and the applied reaction time was necessary nitrogen and oxiranyl oxygen atoms, thus supporting the to reach the maximum conversion (controlled by TLC). 1e uncatalyzed reaction of 15 with 1-phenylethylamine gave formation of both diastereomers of one regioisomer 12 (Figure 1). 1is is corroborated by the results of DFT cal- both regioisomers 17 and 18 in 4% yield only. Moreover, the 3+ Sc(OTf) -catalyzed ring opening in the absence of DIEA culations for the simpliﬁed models of trans-11 and its Sc complex. 1e calculations indicated an increase of the length resulted in much poorer yield. Interestingly, when we run the reaction of 15 in the presence of Zn(OAc) (weaker of Cβ-epoxide oxygen bond and a substantial rise of the Cβ positive charge as measured by ESP (electrostatic potential Lewis acid), β-amino alcohol 17 was formed regioselectively. 1e reaction of rac-trans-stilbene oxide (16) with (S)-1- charge) (see supporting ﬁle S2). It should be noted that the Heteroatom Chemistry 3 11, py, R′ = Ph, 68% 12, bpy, R′ = Ph, 93% 13a, phen, R′ = Ph, 94% 13b, phen, R′ = cyclohexyl, 95% N R 7, 15%, along with 6b NaOH 1. MeLi Br R′-CHO NBS, acetic acid 2. KMnO /acetone Ca(OTf) dioxane/water 4 2 N R′ R′ N N 1, py, commercial 4, py, R′ = Ph, 48% OH 5, bpy, R′ = Ph, 23% 2, bpy, 88% 8, py, R′ = Ph, 94% 6a, phen, R′ = Ph, 74% 9, bpy, R′ = Ph, 90% 3, phen, 82% 6b, phen, R′ = cyclohexyl, 15% 10a, phen, R′ = Ph, 91% 10b, phen, R′ = cyclohexyl, 45% Scheme 1: Preparation of the α-azaarene epoxides. O R R —NH R + OH Catalyst, toluene 80°C, 7d NH OH R = H, 15 R = H, 17 R = Ph, 16 R =Ph, 19 R -NH2 Epoxide Catalyst Product, isolated yield (%) (S)-1-Phenylethylamine 15 Sc(OTf) , DIEA (S,1′S)-17, 19 (R,1′S)-17, 19 (R/S,1′S)-18, 38 (S)-1-Phenylethylamine 16 Sc(OTf) , DIEA (1S,2R,1′S)-19, 27 (1R,2S,1′S)-19, 27 (R)-1-Phenylethylamine 15 Zn(OAc) (R,1′R)-17, 34 (S,1′R)-17, 34 (S)-1-Phenylethylamine 15 Zn(OAc) (S,1′S)-17, 34 (R,1′S)-17, 34 (S)-1-Phenylethylamine 15 No catalyst (S,1′S)-17 and (R,1′S)-17 and (R/S,1′S)-18 (total 4%) Scheme 2: Ring opening of styrene and stilbene oxides with chiral 1-phenylethylamine. CH CH 3 3 (S)-1-Phenylethylamine HN (S) Ph HN (S) Ph Catalyst, (5% mol) (R) (S) toluene, 80°C,7d N N OH OH Catalyst Product, isolated yield (%) Zn(OAc) (S,1′S)-20, 17 (R,1′S)-20, 17 (total 34) Sc(OTf) , DIEA (S,1′S)-20, 36 (R,1′S)-20, 36 (total 72) No catalyst (S,1′S)-20 and (R,1′S)-2 (1:1 by NMR, total 5) Scheme 3: Ring opening of 2-(oxiranyl)pyridine with (S)-1-phenylethylamine. epoxide 11 has already been opened in the MgBr -supported (Figure 2) (diﬀerent conﬁguration descriptors at C5 for reaction with the same regioselectivity. 1at result was (4R,5R,1′S)-27 and (4R,5S,1′S)-26 arise from CIP rules). 2+ explained by similar Mg complexation [52]. 1e obtained enantiomerically pure pyridine-β-amino al- In order to conﬁrm the conﬁgurations of obtained new cohols: (S,1′S)-20, (1S,2S,1′R)-,12 and (1S,2S,1′S)-12 and ring-opening products, we transformed the amino alcohols bipyridine-β-amino alcohols: (1S,2S,1′S)- and (1R,2R,1′S)- into their cyclic urethanes (Scheme 5). were preliminarily assessed as chiral catalysts in the asymmetric 1e respective H NMR spectral patterns are very similar aldol reaction [62] of p-nitrobenzaldehyde with cyclohexanone. for the known (4R,5S,1′S)-26 [58] and new (4R,5R,1′S)-27. 1e reaction conditions were optimized by screening chiral 1eir spectra substantially diﬀer from that for (4S,5S,1′S)-27 ligands and metal salts. 1e highest selectivity for the anti-aldol 23 23 4 Heteroatom Chemistry NHR R NH 1 2 1 R R Sc(OTf) , DIEA, toluene, 80°C, 7d OH R R 11-13 21-25 Epoxide Chiral amine Product 1 2 R = pyrid-2-yl, R = Ph, 11 R = 1-phenylethyl 21 1 2 R = pyrid-2-yl, R = Ph, 11 R = 1-cyclohexylethyl 22 1 2 R = 2,2′-bipyrid-6-yl R = Ph, R = 1-phenylethyl 23 1 2 R = 2,2′-bipyrid-6-yl, R = Ph, R = 1-cyclohexylethyl 24 1 2 R = 1,10-phenanthrolin-2-yl, R = cyclohexyl, 13b R = 1-phenylethyl 25 Scheme 4: Ring opening of 2-oxiranyl-azaarenes with chiral amines. Table 1: Ring opening of 2-oxiranyl-azaarenes with chiral amines. Epoxide Amine Product, yield (%) Total yield (%) 11 (S)-1-Phenylethylamine (1S,2S,1′S)-21, 26 (1R,2R,1′S)-21, 26 52 11 (R)-1-Phenylethylamine (1R,2R,1′R)-21, 29 (1S,2S,1′R)-21, 29 58 11 (R)-1-Cyclohexylethylamine (1R,2R,1′R)-22, 33 (1S,2S,1′R)-22, 33 66 12 (S)-1-Phenylethylamine (1S,2S,1′S)-23, 30 (1R,2R,1′S)-23, 30 60 12 (R)-1-Cyclohexylethylamine (1R,2R,1′R)-24, 32 (1S,2S,1′R)-24 64 13b (R)-1-Phenylethylamine (1R,2R,1′R)-25, (1S,2S,1′R)-25 8 a b c †e yield of each isolated diastereomer. Pure (1S,2S,1′R)-24 could not be isolated (remained in a mixture). †e isolated 1 :1 diastereomeric mixture was identišed by HR-MS and H NMR. O O (S) 4.62 5.34 (S) 5.35 (S) (S) (S) H H H N N O O N O H N NH (S) 2 (S) (S) CH H C (R) (R) (R) H H H C 3 3 α H H H H H H 1.80 1.20 1.21 (R) (R) (S) (S) H H N O O N N Sc Sc 4S,5S,1′S-27 4R,5R,1′S-27 4R,5S,1′S-26 Figure 1: Models for regioselective aminolysis of rac-trans-11. Figure 2: Structures and selected H NMR (400 MHz, CDCl ) resonances of oxazolidinones 26 and 27. Me O Me 1′ 3. Conclusions 2 1′ HN Ph Cl CO OCCl 3 3 Ph Concluding, we have developed an e¨cient synthesis of 2- K CO /H O 2 3 2 5 4 Ph oxiranyl-azaarenes designed as precursors of chiral ligands toluene, 48h, RT R Ph OH and synthetic building blocks. †e regioselective epoxide (1S,2R,1′S)-19 R = Ph (4R,5S,1′S)-26 59% ring opening with chiral primary amines in the presence of (1S,2S,1′S)-21 R = pyridin-2-yl (4S,5S,1′S)-27 46% Sc(OTf) and DIEA gave the corresponding β-amino al- (1R,2R,1′S)-21 R = pyridin-2-yl (4R,5R,1′S)-27 46% cohols, derivatives of pyridine and 2,2′-bipyridine. †e resulting diastereomeric compounds were separated, and Scheme 5: Synthesis of oxazolidinones from β-amino alcohols. their stereochemical conšgurations were proved by corre- lation with the known analogs. †e enantiomerically pure pyridine-β-amino alcohol was preliminarily tested as chiral (2S,1′R) 55% ee and 38% conversion was obtained with ligands in the asymmetric aldol reaction with up to 55% ee (1R,2R,1′S)-23 and Zn(OAc) + HOAc. For the details, see outcome. supporting šle S3. NO Heteroatom Chemistry 5 7.56 (dd, J � 8.2, 4.6 Hz, 1H), 7.47 (d, J � 8.2 Hz, 1H), 2.92 4. Experimental (s, 3H). 1e NMR data are in agreement with the reported 4.1. General Information. Solvents were distilled, and other ones [48]. reagents were used as received. Reactions were monitored by thin-layer chromatography (TLC) on silica gel 60 F-254 or 4.3. General Procedure for the Synthesis of 2-Styryl-azaarenes. aluminum oxide F-25 (Type E) precoated plates, and spots 1e synthesis of 2-styryl-azaarenes was performed according were visualized with a UV lamp and/or Dragendorﬀ reagent. to a modiﬁed literature procedure [50]. 1e mixture of 2- Separation of products by chromatography was carried out methylazaarene (1 mmol), benzaldehyde (1 mmol), and on silica gel 60 (230–400 mesh) or aluminum oxide (neu- Ca(OTf) [49] (5 mol%) was heated at 120 C under argon tral). Melting points were determined using an Electro- atmosphere for 48 h for α-picoline or 96 h for derivatives of thermal IA 91100 digital melting-point apparatus using the bipyridine and phenanthroline. After the reaction comple- standard open capillary method and are uncorrected. Ob- tion (monitored by TLC), the mixture was dissolved in 1 M served rotations at 589 nm were measured using an Optical 1 13 HCl and extracted with diethyl ether (3 ×15 mL). 1e Activity Ltd. Model AA-5 automatic polarimeter. H and C remaining aqueous layer was alkalized with NaOH, NMR spectra (400, 600 MHz and 100, 151 MHz, re- extracted with diethyl ether (3 × 25 mL), dried over Na SO , 2 4 spectively) were collected on Jeol 400yh and Bruker Avance and concentrated in vacuo to give crude product. II 600 instruments. 1e spectra were recorded in CDCl referenced to the respective residual signals of the solvent. Chemical shifts are given in parts per million (ppm) 4.3.1. 2-[(E)-2-Phenylethenyl]pyridine (4). White crystals, downﬁeld from tetramethylsilane as the internal standard in 88 mg, 48% yield, recrystallized (CH Cl /hexane), m.p. 2 2 a deuterated solvent and coupling constants (J) are in Hertz ° ° 89− 90 C (lit. [51] m.p. 89− 91 C), R � 0.67 (CHCl : AcOEt : f 3 − 1 (Hz). Infrared spectra (4000–400 cm ) were collected on a MeOH 1 :1 : 0.25). H NMR (600 MHz, CDCl ) δ: 8.62–8.61 Fourier transform, Bruker VERTEX 70V spectrometer using (m, 1H), 7.68–7.63 (m, 1H), 7.59–7.58 (m, 2H), 7.41–7.37 diamond ATR accessory. High-resolution mass spectra were (m, 3H), 7.32–7.29 (m, 1H), 7.20 (s, 1H), 7.17–7.15 (m, 2H). recorded using electrospray ionization on Waters LCT 1e NMR data are in agreement with the reported ones [51]. Premier XE TOF instrument. 4.3.2. 6-[(E)-2-Phenylethenyl]-2,2′-bipyridine (5). White 4.2. Synthesis of Methyl Derivatives crystals, 60 mg, 23% yield, recrystallized (CH Cl /hexane), 2 2 m.p. 117− 118 C, R � 0.70 (CHCl : AcOEt : MeOH 1 :1 : f 3 4.2.1. 6-Methyl-2,2′-bipyridine 2. 1e methylation was 0.25). H NMR (600 MHz, CDCl ) δ: 8.71 (d, J � 6.0 Hz, 1H), performed according to the literature procedure [47]. Brown 8.59 (d, J � 6.0 Hz, 1H), 8.30 (d, J � 7.8 Hz, 1H), 7.89–7.86 (m, oil, 7.6 g, 88% yield, R � 0.56 (CHCl : AcOEt : MeOH 1 :1 : f 3 1H), 7.82–7.77 (m, 2H), 7.64 (d, J � 7.2 Hz, 2H), 7.42–7.39 0.25). H NMR (600 MHz, CDCl ) δ: 8.59–8.58 (m, 1H), 3 13 (m, 3H), 7.35–7.30 (m, 2H) 7.28–7.25 (m, 1H); C NMR 8.35–8.33 (m, 1H), 8.12 (d, J � 7.8 Hz, 1H), 7.69–7.66 (m, (600 MHz, CDCl ) δ: 156.2, 155.6, 155.0, 148.9, 137.5, 137.1, 1H), 7.59–7.56 (m, 1H), 7.17–7.15 (m, 1H), 7.04 (d, 136.8, 132.9, 128.7, 128.3, 128.2, 127.2, 123.8, 122.2, 121.4, J � 7.8 Hz, 1H), 2.54 (s, 3H). 1e NMR data are in agreement 119.6; HR-MS (ESI) [C H N + H] requires 259.1230; 18 14 2 with the reported ones [47]. found 259.1223. 4.2.2. 2-Methyl-1,10-phenanthroline 3. 1e methylation was 4.3.3. 2-[(E)-2-Phenylethenyl]-1,10-phenanthroline (6a). performed according to a modiﬁed literature procedure [48]. Brown oil, 210 mg, 74% yield, puriﬁed by column chro- A solution of methyllithium in diethyl ether (1.6 M, 45 mL, matography (SiO CHCl : AcOEt : MeOH 1 :1 : 0.25), 2, 3 72 mmol) was added dropwise to a solution of 1,10-phe- 1 R � 0.62 (CHCl : AcOEt : MeOH 1 :1 : 0.25). H NMR f 3 nanthroline (10 g, 55 mmol) in toluene (200 mL) at − 72 C (600 MHz, CDCl ) δ: 9.28 (dd, J � 4.3, 1.8 Hz, 1H), 8.29 (dd, under Ar atmosphere. 1e reaction mixture was stirred for J � 8.2, 1.8 Hz, 1H), 8.21 (d, J � 8.2 Hz, 1H), 7.95 (d, 3 h at − 72 C and for 2 h at room temperature. 1en, ice was J � 6.0 Hz, 1H), 7.86–7.78 (m, 3H), 7.76–7.72 (m, 1H), 7.75 added with stirring in an ice-water bath and the resulting (d, J � 6.0 Hz, 2H), 7.67–7.65 (m, 1H), 7.42–7.40 (m, 2H) solution turned red. 1e aqueous layer was separated and 13 7.34–7.31 (m, 1H); C NMR (600 MHz, CDCl ) δ: 156.6, extracted with diethyl ether (3 × 50 mL). 1e combined 149.9, 145.5, 145.4, 136.8, 136.6, 136.4, 134.8, 129.5, 129.1, organic phases were washed twice with brine and dried over 128.8, 128.6, 127.6, 127.4, 126.7, 125.8, 122.9, 120.7; HR-MS Na SO , and ether was removed. 1e resulting orange tol- + 2 4 (ESI) [C H N + H] requires 283.1230; found 283.1242. 20 14 2 uene solution was treated with MnO (54 g), stirred for 24 h, and then ﬁltered through Celite. 1e solvent was removed in vacuo to give a crude product. Column chromatography on 4.3.4. 2-[(E)-2-Cyclohexylethenyl)-1,10-phenanthroline (6b). neutral alumina with t-butyl methyl ether (MTBE) as an Yellow oil, 43 mg, 15% yield, puriﬁed by column chroma- eluent gave pure 3 (8.73 g 82%), as yellow crystals, m.p. tography (Al O , 20% AcOEt/hexane). H NMR (400 MHz, 2 3 ° ° 76− 77 C (lit. [48] m.p. 75− 76 C). H NMR (600 MHz, CDCl ) δ: 9.20 (dd, J � 4.6, 1.8 Hz, 1H), 8.22 (dd, J � 8.2, CDCl ) δ: 9.17 (dd, J � 4.2, 1.8 Hz, 1H), 8.18 (dd, J � 8.0, 1.8 Hz, 1H), 8.13 (d, J � 8.2 Hz, 1H), 7.80 (d, J � 8.2 Hz, 1H), 1.8 Hz, 1H), 8.08 (d, J � 8.2 Hz, 1H), 7.69 (q, J � 8.8 Hz, 2H), 7.72 (q, J � 8.9 Hz, 2H), 7.60 (dd, J � 8.2, 4.6 Hz, 1H), 7.01 6 Heteroatom Chemistry (dd, J � 16.2, 1.2 Hz, 1H), 6.81 (dd, J � 16.2, 6.4 Hz, 1H), 1H), 8.24 (d, J � 8.4 Hz, 1H), 7.87–7.83 (m, 2H), 7.78–7.75 2.30–2.24 (m, 1H), 1.92–1.88 (m, 2H), 1.82–1.77 (m, 2H), (m, 2H), 7.55 (d, J � 7.2 Hz, 2H), 7.29–7.27 (m, 2H), 7.24– 1.72–1.66 (m, 1H), 1.41–1.16 (m, 5H); C NMR (400 MHz, 7.21 (m, 1H), 5.79 (d, J � 6.6 Hz, 1H), 5.60 (d, J � 6.6 Hz, 1H). CDCl ) 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, 4.4.4. 2-Bromo-1-cyclohexyl-2-(1,10-phenanthrolin-2-yl)eth- 26.2; HR-MS (ESI) [C H N + H] requires 289.1699; 20 20 2 anol (10b). Yellow oil, 520 mg, 45% yield, puriﬁed by col- found 289.1705. umn chromatography (Al O , CHCl : AcOEt : hexane 1 :1 : 2 3 3 2). H NMR (400 MHz, CDCl ) 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), 4.3.5. 1-Cyclohexyl-3-cyclohexylidene-2-(1,10-phenonthrolin- 7.81–7.75 (m, 3H), 7.63 (dd, J � 8.2, 4.6 Hz, 1H), 5.17 (d, 2-yl)propene (7). Yellow oil, 42 mg, 15% yield, puriﬁed by J � 9.2 Hz, 1H), 4.36 (dd, J � 9.5, 2.4 Hz, 1H), 2.57 (s, 2H), column chromatography (Al O , 20% AcOEt/hexane). H 2 3 2.27–2.25 (m, 1H), 2.04–2.02 (m, 1H), 1.82–1.16 (m, 7H). NMR (400 MHz, CDCl ) 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, 4.5. General Procedure for the Synthesis of Epoxides. 1e 1.5 Hz, 1H), 6.05 (s, 1H), 2.46–2.43 (m, 1H), 2.34–2.31 (m, synthesis of epoxides was performed according to a modiﬁed 2H), 1.96–1.93 (m, 2H), 1.77–1.75 (m, 4H), 1.69–1.63 (m, literature procedure [53]. Bromohydrin (2.8 mmol) was 3H), 1.55–1.50 (m, 2H), 1.40–1.31 (m, 7H); C NMR dissolved in dioxane (3.5 mL), then 1 M aqueous NaOH (400 MHz, CDCl ) δ: 159.4, 150.1, 146.4, 145.8, 144.9, 141.4, (4.5 mL) was added, and the mixture was stirred at room 136.11, 136.09, 134.6, 129.0, 127.3, 126.6, 125.4, 122.7, 121.9, temperature for 24 h. After completion of the reaction, the 118.3, 39.1, 36.9, 32.4, 30.6, 28.8, 27.3, 26.7, 26.3, 26.2; HR- mixture was extracted with chloroform (3 × 30 mL). 1e MS (ESI) [C H N + H] requires 383.2482; found 27 30 2 combined organic layers were dried over Na SO , ﬁltered, 2 4 383.2483. and concentrated in vacuo to give the desired product. 4.4. General Procedure for the Synthesis of Bromohydrins. 4.5.1. trans-2-(3-Phenyl-2-oxiranyl)pyridine (11). Brown oil, 1e synthesis of bromohydrins was performed according to 375 mg, 68% yield, R � 0.63 (CHCl : AcOEt : MeOH 1 :1 : f 3 a modiﬁed literature procedure [53]. 1e mixture of 2-styryl- 0.25). H NMR (600 MHz, CDCl ) δ: 8.60–8.58 (m, 1H), azaarene (3.0 mmol), NBS (587 mg, 3.3 mmol), and acetic 7.73–7.69 (m, 1H), 7.38–7.31 (m, 6H), 7.26–7.23 (m, 1H), acid (0.5 mL) was dissolved in the mixture of dioxane/water 4.05 (AB system, 2H). 1e NMR data are in agreement with (3.5 mL/7 mL) and stirred at room temperature for 24 h. the reported ones [52]. After completion of the reaction, the mixture was extracted with chloroform (3 × 30 mL). 1e combined organic layers 4.5.2. trans-6-(3-Phenyl-2-oxiranyl)-2,2′-bipyridine (12). were dried by over Na SO ﬁltered and concentrated in 2 4 White crystals, 713 mg, 93% yield, m.p. 117− 118 C, R � 0.61 vacuo to give the desired product as conﬁrmed by H NMR. (CHCl : AcOEt : MeOH 1 :1 : 0.25). IR υ (Neat) 2960, 3 max − 1 1 2926, 1580, 1563, 775, 760, 746, 694 cm ; H NMR 4.4.1. 2-Bromo-1-phenyl-2-(pyridin-2-yl)ethanol (8). Brown (600 MHz, CDCl ) δ: 8.7 (d, J � 4.2 Hz, 1H), 8.47 (d, oil, 784 mg, 94% yield; R � 0.57 (CHCl : AcOEt : MeOH 1 : f 3 J � 7.8 Hz, 1H), 8.4 (d, J � 7.8 Hz, 1H), 7.88–7.84 (m, 2H), 1 : 0.25). H NMR (600 MHz, CDCl ) δ: 8.57–8.56 (m, 1H), 7.40–7.36 (m, 4H), 7.35–7.26 (m, 3H), 4.16 (d, J � 1.8 Hz, 7.63–7.60 (m, 2H), 7.30–7.27 (m, 2H), 7.27–7.25 (m, 2H), 1H), 4.12 (d, J � 1.8 Hz, 1H); C NMR (600 MHz, CDCl ) δ: 7.23–7.21 (m, 2H), 5.41 (d, J � 5.4 Hz, 1H), 5.20 (d, J � 5.4 Hz, 156.1, 155.8, 155.7, 149.1, 137.8, 137.0, 136.8, 128.6, 128.5, 1H). 125.8, 123.9, 121.4, 120.6, 119.7, 63.2, 61.9; HR-MS (ESI) [C H N O + H] requires 275.1179; found 275.1180. 18 14 2 4.4.2. 2-Bromo-1-phenyl-2-(2,2′-bipyridin-6-yl)ethanol (9). White crystals, 960 mg, 90% yield, puriﬁed by column 4.5.3. trans-2-(3-Phenyl-2-oxiranyl)-1,10-phenanthroline chromatography (SiO , CHCl : AcOEt : MeOH 1 :1 : 0.25), 2 3 (13a). Brown oil, 784 mg, 94% yield, R � 0.44 (CHCl : f 3 m.p. 117− 118 C, R � 0.61 (CHCl : AcOEt : MeOH 1 :1 : AcOEt : MeOH 1 :1 : 0.25). IR υ (Neat) 2923, 2853, 1588, f 3 max − 1 1 0.25). H NMR (600 MHz, CDCl ) δ: 8.72 (d, J � 4.8 Hz, 1H), 3 1555, 845, 741, 696 cm ; H NMR (600 MHz, CDCl ) δ: 9.18 8.38–8.34 (m, 1H), 7.90 (s, 1H), 7.77–7.74 (t, J � 7.8 Hz, 1H), (dd, J � 4.3, 1.8 Hz, 1H), 8.31–8.24 (m, 2H), 7.80 (d, 7.40–7.38 (m, 1H), 7.32 (d, J � 7.2 Hz, 1H) 7.28–7.24 (m, J � 1.8 Hz, 2H), 7.63 (dd, J � 8.2, 6.4 Hz, 2H), 7.37–7.33 (m, 4H), 7.24–7.22 (m, 2H), 5.53 (d, J � 5.4 Hz, 1H), 5.28 (d, 5H), 4.69 (d, J � 1.8 Hz, 1H), 4.02 (d, J � 1.8 Hz 1H); C J � 5.4 Hz, 1H). NMR (600 MHz, CDCl ) 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) [C H N O + H] 20 14 2 4.4.3. 2-Bromo-1-phenyl-2-(1,10-phenanthrolin-2-yl)ethanol requires 299.1135; found 299.1146. (10a). Brown oil, 1.0 g, 91% yield, puriﬁed by column chromatography (SiO , CHCl : AcOEt : MeOH 1 :1 : 0.25), 2 3 R � 0.24 (CHCl : AcOEt : MeOH 1 :1 : 0.25). H NMR 4.5.4. trans-2-(3-Cyclohexyl-2-oxiranyl)-1,10-phenanthroline f 3 (600 MHz, CDCl ) δ: 9.31–9.30 (m, 1H), 8.40 (d, J � 7.8 Hz, (13b). Yellow oil, 811 mg, 95% yield. H NMR (400 MHz, 3 Heteroatom Chemistry 7 CDCl ) δ: 9.24 (dd, J � 4.3, 1.5 Hz, 1H), 8.26 (dd, J � 8.2, chromatography (SiO , CHCl : AcOEt : MeOH 1 :1 : 0.1), 3 2 3 ° ° 1.8 Hz, 1H), 8.22 (d, J � 8.2 Hz, 1H), 7.78 (s, 2H), 7.65 (dd, m.p. 145–146 C (lit. [60] m.p. 145–148 C), [α] � 26 (c 1.0, J � 8.2, 4.6 Hz, 1H), 7.45 (d, J � 8.2 Hz, 1H), 4.47 (d, CHCl ), (lit. [60] [α] � 26.5 (c 1.0, CHCl )), R � 0.20 3 3 f J � 2.1 Hz, 1H), 2.96 (d, J � 2.1 Hz, 1H), 1.59–1.26 (m, 3H), (CHCl : AcOEt : MeOH 1 :1 : 0.1). H NMR (400 MHz, 1.25–1.24 (m, 6H), 0.86–0.84 (m, 2H); C NMR (600 MHz, CDCl ) δ: 7.34–7.22 (m, 10H), 4.72 (dd, J � 8.9, 3.7 Hz, 1H), CDCl ) δ: 159.2, 150.6, 137.1, 136.2, 134.3, 129.6, 129.1, 3.75 (q, J � 6.4 Hz, 1H), 2.64 (dd, J � 12.2, 3.7 Hz, 1H), 2.54 128.6, 126.6, 126.5, 123.1, 118.3, 38.9, 30.6, 24.1 23.0, 14.1, (dd, J � 12.2, 8.9 Hz, 1H), 1.38 (d, J � 6.7 Hz, 3H). 1e NMR 11.2; HR-MS (ESI) [C H N O + H] requires 305.1648; data are in agreement with literature data for (R,1′R)-en- 20 20 2 found 305.1653. antiomer [60]. (2) (S,R)-2-(1-Phenylethyl)amino-1-phenyl-ethanol (S,1′R)- 4.6. Procedures for Ring Opening of Epoxides 17. Brown crystals, 41 mg, 34% yield, puriﬁed by column chromatography (SiO , CHCl : AcOEt : MeOH 1 :1 : 0.1), 2 3 4.6.1. Method A (Catalyzed by Sc(OTf ) ). A solution of the 3 1 R � 0.25 (CHCl : AcOEt : MeOH 1 :1 : 0.1). H NMR f 3 epoxide 11, 12, 13b, 14, 15, or 16 (0.5 mmol), 1-phenyl- (400 MHz, CDCl ) δ: 7.34–7.22 (m, 10H), 4.55 (dd, J � 8.9, ethylamine (77 μL, 0.6 mmol), Sc(OTf) (12 mg, 5 mol%), 3.7 Hz, 1H), 3.81 (q, J � 6.4 Hz, 1H), 2.81 (dd, J � 12.2, 3.7 Hz, and N-ethyldiisopropylamine (170 μL, 1 mmol) in toluene 1H), 2.54 (dd, J � 12.2, 8.9 Hz, 1H), 1.36 (d, J � 6.7 Hz, 3H). (2 mL) was stirred under argon in a sealed test tube at 80 C 1e NMR data are in agreement with literature data for for 7 days. 1e cooled mixture was directly submitted to the (R,1′S)-enantiomer [60]. column chromatography on silica gel. In this way, the regioisomers 17 and 18, resulting in the reaction of 15, were (3) (S,S)-2-(1-Phenylethyl)amino-1-phenyl-ethanol (S,1′S)- separated, and their structures were conﬁrmed by NMR. 1e 17. White crystals, 41 mg, 34% yield, recrystallized (CH Cl / 2 2 isolated diastereoisomers 17, as well as the respective di- hexane), R � 0.20 (CHCl : AcOEt : MeOH 1 :1 : 0.1). H f 3 astereomers formed in the reactions of 11, 12, 14, and 16, NMR (400 MHz, CDCl ) δ: 7.34–7.22 (m, 10H), 4.60 (dd, were separated by column chromatography. Additionally, J � 8.9, 3.7 Hz, 1H), 3.77 (q, J � 6.4 Hz, 1H), 2.77 (dd, J � 12.2, the diastereomers 17 could be separated by recrystallization 3.7 Hz, 1H), 2.63 (dd, J � 12.2, 8.9 Hz, 1H), 1.40 (d, J � 6.7 Hz, from hexane/CH Cl . 2 2 3H). 1e NMR data are in agreement with literature data for 1e reactions of (98 mg, 0.5 mmol) or (137 mg, (R,1′R)-enantiomer [60]. 0.5 mmol) with (R)-1-cyclohexylethylamine (88 μL, 0.6 mmol), Sc(OTf) (12 mg, 5 mol%), and N-ethyldiisopropylamine (4) (R,S)-2-(1-Phenylethyl)amino-1-phenyl-ethanol (R,1′S)- (170 μL, 1 mmol) dissolved in toluene (2 mL) were run and then 17. Brown crystals, 41 mg, 34% yield, recrystallized (CH Cl / 2 2 worked up as above. For the epoxide , both diastereomers ° ° hexane), m.p. 82–83 C (lit. [60] m.p. 80–85 C), [α] � –105 were separated by chromatography and gave pure samples, (c 1.0, CHCl ), (lit. [60] [α] � –110 (c 1.0, CHCl )), 3 3 while for , only one diastereomer (1R,2R,1′R)- could be R � 0.25 (CHCl : AcOEt : MeOH 1 :1 : 0.1). H NMR f 3 isolated in a pure form. (400 MHz, CDCl ) δ: 7.34–7.21 (m, 10H), 4.74 (dd, J � 9.2, 1e pure separated products (S,1′S)-17, (R,1′S)-17, (S/ 3.4 Hz, 1H), 3.83 (q, J � 6.7 Hz, 1H), 2.79 (dd, J � 12.2, 3.7 Hz, R,1′S)-18, ( 1R,2S,1′S)-19, (1S,2R,1′S)-19, (S,1′S)-20, (R,1′S)- 1H), 2.55 (dd, J � 12.2, 9.2 Hz, 1H), 1.40 (d, J � 6.4 Hz, 3H). 20, (1R,2S,1′S)-,12 (1S,2S,1′S)-,12 (1S,2R,1′R)-19, (1R,2R,1′R)- 1e NMR data are in agreement with literature data for ,12 (1S,2R,1′R)-, (1R,2R,1′R)-, (1R,2S,1′S)-, (1S,2S,1′S)- (R,1′S)-enantiomer [60]. , (1R,2R,1′R)-, and [(1R,2R,1′R)- and (1S,2S,1′R)]- were analyzed, and their properties are reported below. (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 (SiO , CHCl : AcOEt : 2 3 4.6.2. Method B (Catalyzed by Zn(OAc) ). 1e reaction was MeOH 1 :1 : 0.1). H NMR (400 MHz, CDCl ) δ: 7.40–7,18 carried out under the same conditions as in Method A, but (m, 20H), 3.90–3.88 (m, 1H), 3.77–3.71 (m, 2H), 3.65–3.67 instead of Sc(OTf) and N-ethyldiisopropylamine, Zn(OAc) 3 2 (m, J � 6.7 Hz, 1H), 3.58–3.50 (m, 4H), 1.36 (d, J � 6.4 Hz, (4.6 mg, 5 mol%) as a catalyst was added. 1e products 6H); C NMR (400 MHz, CDCl ) δ: 129.1, 129.0, 128.9, (R,1′R)-17, (S,1′R)-17, (S,1′S)-17, (R,1′S)-17, (S,1′S)-20, and 128.8, 128.7, 128.6, 128.31, 128.30, 127.90, 127.85, 127.8, (R,1′S)-20 were isolated as in Method A. 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) [C H NO + H] requires 16 19 242.1539; found 242.1545. 1e NMR data are in agreement 4.6.3. Method C (Absence of a catalyst). 1e reaction of 14 or 15 (1.0 mmol) with 1-phenylethylamine (154 μL, 1.2 mmol) with the reported ones [59]. 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 (6) (1R,2R,1′S)-2-(1′-Phenylethyl)amino-1,2-diphenyl-etha- in Method A (direct chromatography), the products were nol (1R,2S,1′S)- 19. White crystals, 43 mg, 27% yield, puriﬁed analyzed by NMR. by column chromatography (SiO , CHCl : AcOEt : MeOH 2 3 1 :1 : 0.1), m.p. 135–136 C, [α] � –63 (c 0.9, CHCl ), (lit. 20 1 (1) (R,R)-2-(1-Phenylethyl)amino-1-phenyl-ethanol (R,1′R)- [58] [α] � –66.1 (c 1.0, CHCl ). H NMR (400 MHz, 17. White crystals, 41 mg, 34% yield, puriﬁed by column CDCl ) δ: 7.33–7.13 (m, 11H), 6.98–6.94 (m, 4H), 4.98 (d, 25 24 23 23 22 22 24 12 12 11 8 Heteroatom Chemistry J � 4.9 Hz, 1H), 4.0 (d, J � 4.9 Hz, 1H), 3.78 (q, J � 6.4 Hz, 65.1, 54.8, 23.1; HR-MS (ESI) [C H N O + H] requires 21 22 2 1H), 1.35 (d, J � 6.7 Hz, 3H); C NMR (400 MHz, CDCl ) δ: 319.1805; found 319.1801. 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. 1e NMR data are (11) (1R,2R,1′S)-2-(1′-Phenylethyl)amino-2-phenyl-1-(pyr- in agreement with literature data for (1R,2S,1′S)-enantiomer idin-2-yl)ethanol(1R,2R,1′S)- 1.2 Colorless oil, 42 mg, 26% [58]. yield, puriﬁed by column chromatography (SiO , AcOEt : CHCl 8 : 2), [α] � –93 (c 1.0, CH Cl ), R � 0.48 (CHCl : 3 2 2 f 3 (7) (1S,2R,1′S)-2-(1′-Phenylethyl)amino-1,2-diphenyl-etha- AcOEt : MeOH 1 :1 : 0.1). IR υ (Neat) 3324, 3026, 2923, max − 1 1 nol (1S,2R,1′S)- 19. Colorless oil, 43 mg, 27% yield, puriﬁed 1592, 1451, 699 cm ; H NMR (400 MHz, CDCl ) δ: 8.39 (d, by column chromatography (SiO , CHCl : AcOEt : MeOH J � 4.6 Hz, 1H), 7.47 (td, J � 7.6, 1.5 Hz, 1H), 7.26–7.12 (m, 2 3 20 20 1 :1 : 0.1), [α] � –111 (c 1.0, CHCl ), (lit. [58] [α] � – 9H), 6.96–6.95 (m, 3H), 4.88 (s, 1H), 4.20 (s, 1H), 3.77 (d, D D 112.8 (c 1.0, CHCl ). H NMR (400 MHz, CDCl ); δ: J � 4.9 Hz, 1H), 3.57 (q, J � 6.7 Hz, 1H), 1.30 (d, J � 6.7 Hz, 3 3 7.33–7.20 (m, 10H), 7.09–6.95 (m, 5H), 4.64 (d, J � 4.9 Hz, 3H); C NMR (400 MHz, CDCl ) δ: 159.5, 148.0, 145.4, 1H), 3.62 (d, J � 4.9 Hz, 1H), 3.49 (q, J � 6.4 Hz, 1H), 1.23 (d, 139.2, 136.0, 128.4, 128.3, 128.0, 127.2, 126.90, 126.89, 122.4, 13 + J � 6.7 Hz, 3H); C NMR (400 MHz, CDCl ) δ: 144.9, 140.5, 121.8, 76.2, 65.4, 54.9, 25.2; HR-MS (ESI) [C H N O + H] 3 21 22 2 139.7, 128.5, 128.4, 128.1, 127.8, 127.7, 127.2, 127.1, 126.7, requires 319.1805; found 319.1796. 126.4, 75.6, 65.8, 54.9, 24.8. 1e NMR data are in agreement with literature data for (1S,2R,1′S-)-enantiomer [58]. (12) (1R,2R,1′R)-2-(1′-Phenylethyl)amino-2-phenyl-1-(pyr- idin-2-yl)ethanol (1R,2R,1′R)- 1.2 White crystals, 46 mg, 29% (8) (S,S)-2-(1-Phenylethyl)amino-1-(pyridin-2-yl)ethanol yield, puriﬁed by column chromatography (SiO , AcOEt : (S,1′S)- 20. White crystals, 44 mg, 36% yield, puriﬁed by CHCl 8 : 2), m.p. 94–95 C, [α] � 78 (c 0.9, CH Cl ), 3 2 2 column chromatography (SiO , CHCl : AcOEt : MeOH 1 : R � 0.35 (CHCl : AcOEt : MeOH 1 :1 : 0.1). IR υ (Neat) 2 3 f 3 max 20 − 1 1 1 : 0.1), m.p. 119–120 C, [α] � –42 (c 0.6, CH Cl ). IR υ 3133, 3032, 2922, 1592, 1434, 697 cm ; H NMR (400 MHz, 2 2 max 1 1 (Neat) 3290, 2971, 1589, 1432, 703 cm ; H NMR (400 MHz, CDCl ) δ: 8.37–8.35 (m, 1H), 7.47 (td, J � 7.6, 1.5 Hz, 1H), CDCl ) δ: 8.50–8.48 (m, 1H), 7.64 (td, J � 7.4, 1.8 Hz, 1H), 7.32–7.20 (m, 5H), 7.25–7.10 (m, 3H), 7.06–7.03 (m, 1H), 7.33–7.22 (m, 6H), 7.17–7.14 (m, 1H), 4.71 (dd, J � 8.1, 6.99–6.93 (m, 3H), 5.10 (d, J � 4.3 Hz, 1H), 4.11 (d, J � 4.3 Hz, 3.7 Hz, 1H), 3.75 (q, J � 6.5 Hz, 1H), 2.86 (dd, J � 12.0, 3.7 Hz, 1H), 3.80 (q, J � 6.4 Hz, 1H) 1.34 (d, J � 6.4 Hz, 3H); C 1H), 2.69 (dd, J � 12.0, 8.1 Hz, 1H), 1.36 (d, J � 6.4 Hz, 3H); NMR (400 MHz, CDCl ) δ: 159.6, 148.1, 145.8, 139.9, 136.0, C NMR (400 MHz, CDCl ) δ: 161.0, 148.5, 145.5, 136.7, 128.6, 128.1, 127.9, 127.2, 127.1, 126.7, 122.2, 121.5, 74.9, 128.6, 127.1, 126.7, 122.4, 120.6, 72.3, 58.6, 54.4, 24.4; HR- 65.1, 54.7, 23.1; HR-MS (ESI) [C H N O + H] requires 21 22 2 MS (ESI) [C H N O + H] requires 243.1492; found 319.1805; found 319.1826. 15 18 2 243.1500. (13) (1S,2S,1′R)-2-(1′-Phenylethyl)amino-2-phenyl-1-(pyridin- (9) (R,S)-2-(1-Phenylethyl)amino-1-(pyridin-2-yl)ethanol 2-yl)ethanol(1S,2S,1′R)- 21. Colorless oil, 46 mg, 29% yield, (R,1′S)- 20. White crystals 44 mg, 36% yield, puriﬁed by puriﬁed by column chromatography (SiO , AcOEt : CHCl 2 3 column chromatography (SiO , CHCl : AcOEt : MeOH 1 : 8 : 2), [α] � 93 (c 0.8, CH Cl ), R � 0.48 (CHCl : AcOEt : 2 3 2 2 f 3 1 : 0.1), m.p. 75–76 C, [α] � –52 (c 0.8, CH Cl ). IR υ MeOH 1 :1 : 0.1). IR υ (Neat) 3322, 3026, 2923, 1593, 2 2 max max − 1 1 − 1 1 (Neat) 3081, 2847, 1588, 1433, 702 cm ; H NMR 1451, 699 cm ; H NMR (400 MHz, CDCl ) δ: 8.39 (d, (400 MHz, CDCl ) δ: 8.48–8.46 (m, 1H), 7.63 (td, J � 7.6, J � 4.9 Hz, 1H), 7.49 (td, J � 7.2, 1.2 Hz, 1H), 7.28–7.06 (m, 1.8 Hz, 1H), 7.37–7.21 (m, 6H), 7.15 (m, 1H) 4.97 (dd, J � 8.1, 9H), 6.98–6.90 (m, 3H), 4.88 (d, J � 4.9 Hz, 1H), 4.22 (s, 1H), 3.7 Hz, 1H), 3.96 (q, J � 6.5 Hz, 1H), 3.08 (dd, J � 12.0, 3.7 Hz, 3.76 (d, J � 4.9 Hz, 1H), 3.57 (q, J � 6.7 Hz, 1H) 1.30 (d, 1H), 2.68 (m, J � 12.0, 8.1 Hz, 1H), 1.50 (d, J � 6.4 Hz, 3H); J � 6.7 Hz, 3H); C NMR (400 MHz, CDCl ) δ: 159.5, 148.0, C NMR (400 MHz, CDCl ) δ: 160.4, 148.3, 136.9, 128.8, 145.3, 139.2, 136.0, 128.4, 128.3, 128.0, 127.2, 126.90, 126.89, 127.8, 127.1, 127.0, 122.6, 120.8, 70.9, 58.5, 53.3, 23.3; HR- 122.4, 121.8, 76.2, 65.4, 54.9, 25.2; HR-MS (ESI) + + MS (ESI) [C H N O + H] requires 243.1492; found [C H N O + H] requires 319.1805; found 319.1811. 15 18 2 21 22 2 243.1504. (14) (1R,2R,1′S)-2-(1′-Cyclohexylethyl)amino-2-phenyl-1- (10) (1S,2S,1′S)-2-(1′-Phenylethyl)amino-2-phenyl-1-(pyr- (pyridin-2-yl)ethanol (1R,2R,1′R)- 22. Brown oil, 53 mg, 33% idin-2-yl)ethanol (1S,2S,1′S)- 1.2 White crystals, 42 mg, 26% yield, puriﬁed by column chromatography (SiO 20% yield, puriﬁed by column chromatography (SiO , AcOEt : MTBE/hexane), [α] � –45 (c 0.7, CH Cl ). IR υ (Neat) 2 2 2 max 20 − -1 1 CHCl 8 : 2), m.p. 94–95 C, [α] � –78 (c1.0, CH Cl ), 3139, 3019, 2924, 1435, 696 cm ; H NMR (400 MHz, 3 2 2 R � 0.35 (CHCl : AcOEt : MeOH 1 :1 : 0.1). IR υ (Neat) CDCl ) δ: 8.46–8.44 (m, 1H), 7.43 (dq, J � 7.6, 1.8 Hz, 1H), f 3 max 3 − 1 1 3147, 3032, 2924, 1592, 1433, 697 cm ; H NMR (400 MHz, 7.14–7.01 (m, 6H), 6.93 (d, J � 7.9 Hz, 1H), 4.95 (d, J � 4.6 Hz, CDCl ) δ: 8.36–8.34 (m, 1H), 7.47 (td, J � 7.6, 1.5 Hz, 1H), 1H), 4.18 (d, J � 4.6 Hz, 1H), 2.55–2.52 (m, 1H), 1.72–1.63 7.29–7.24 (m, 4H), 7.24–7.19 (m, 1H), 7.14–7.09 (m, 3H), (m, 8H), 1.28–1.16 (m, 3H), 0.97 (d, J � 6.4 Hz, 3H); C 7.06–6.94 (m, 4H), 5.12 (d, J � 4.3 Hz, 1H), 4.15 (d, J � 4.3 Hz, NMR (400 MHz, CDCl ) δ: 160.3, 148.2, 140.1, 136.0, 128.0, 1H), 3.81 (q, J � 6.4 Hz, 1H) 1.35 (d, J � 6.4 Hz, 3H); C 127.8, 127.2, 122.1, 121.5, 75.02, 65.25, 55.0, 42.8, 29.8, 28.1, NMR (400 MHz, CDCl ) δ: 159.6, 148.0, 145.77, 138.9, 136.5, 26.9, 26.8, 26.7, 17.8; HR-MS (ESI) [C H N O + H] re- 3 21 28 2 128.6, 128.2, 127.9, 127.2, 127.1, 126.7, 122.2, 121.5, 74.9, quires 325.2274; found 325.2280. Heteroatom Chemistry 9 (15) (1S,2S,1′R)-2-(1′-Cyclohexylethyl)amino-2-phenyl-1- (19) 2-(1′-Phenylethyl)amino-2-cyclohexyl-1-(1,10-phenan- (pyridin-2-yl)ethanol (1S,2S,1′R)- 22. Brown oil, 53 mg, 33% throlin-2-yl)ethanol (1R,2R,1′R)- 25 and (1S,2S,1′R)- 25. yield, puriﬁed by column chromatography (SiO 20% Colorless oil, 17 mg, 8% total yield, puriﬁed by column 20 1 MTBE/hexane), [α] � 28 (c 0.8, CH Cl ). IR υ (Neat) chromatography (SiO , hexane : AcOEt : CHCl 2 :1 :1). H 2 2 max 2 3 − 1 1 3062, 3028, 2925, 1434, 699 cm ; H NMR (400 MHz, NMR (400 MHz, CDCl ) δ: 9.16–9.14 (m, 2H), 8.22 (dd, CDCl ) δ: 8.42–8.40 (m, 1H), 7.48 (dq, J � 7.6, 1.8 Hz, 1H), J � 7.9, 1.8 Hz, 2H), 8.17 (d, J � 8.2 Hz, 1H), 8.13 (d, 7.15–6.97 (m, 7H), 4.97 (d, J � 4.6 Hz, 1H), 4.19 (d, J � 4.6 Hz, J � 8.2 Hz, 1H), 7.75 (d, J � 1.8 Hz, 4H), 7.62–7.58 (m, 2H), 1H), 2.34–2.31 (m, 1H), 1.73–1.70 (m, 7H), 1.40–0.97 (m, 7.52 (d, J � 8.2 Hz, 1H), 7.35–7.14 (m, 11H), 3.96 (d, 4H), 0.92 (d, J � 6.4 Hz, 3H); C NMR (400 MHz, CDCl ) δ: J � 3.1 Hz, 1H), 3.89 (dd, J � 7.9, 3.4 Hz, 1H), 3.24 (s, 1H), 159.8, 148.1, 138.9, 136.0, 128.4, 127.8, 127.1, 122.2, 121.6, 3.22 (d, J � 2.1 Hz, 1H), 1.79–1.49 (m, 11H), 1.41–1.39 (m, 76.2, 65.0, 54.0, 43.9, 29.6, 28.7, 26.8, 26.7, 26.6, 16.7; HR-MS 6H), 1.29–1.19 (m, 9H), 1.10–1.09 (m, 4H); HR-MS (ESI) + + (ESI) [C H N O + H] requires 325.2274; found 325.2289. [C H N O + H] requires 426.2540; found 426.2532. 21 28 2 28 31 3 (16) (1R,2R,1′S)-2-(1′-Phenylethyl)amino-2-phenyl-1-(2,2′- 4.7. General Procedure for the Synthesis of Oxazolidinones bipyridin-6-yl)ethanol (1R,2R,1′S)- . Colorless oil, 60 mg, from Amino Alcohols. 1e synthesis of oxazolidinones was 30% yield, puriﬁed by column chromatography (Al O MTBE), 2 3, performed according to the literature procedure [58]. Tri- R � 0.48 (Al O MTBE), [α] � –112 (c 0.9, CH Cl ). IR υ f 2 3, 2 2 max phosgene (36 mg, 0.12 mmol) was added to a mixture of the − 11 (Neat) 3324, 3026, 2924, 1564, 1430, 699 cm H NMR amino alcohol (0.3 mmol) in toluene (3 mL) and potassium (400 MHz, CDCl ) δ: 8.64–8.62 (m, 1H), 8.21 (dd, J � 7.9, carbonate (57 mg, 0.41 mmol) in water (1.3 mL) with vigorous 0.9 Hz, 1H), 8.05 (td, J � 7.9, 1.2 Hz, 1H), 7.74 (dd, J � 7.9, stirring at room temperature. After being stirred for 48 h, the 1.8 Hz, 1H), 7.65 (t, J � 7.6 Hz, 1H), 7.29–7.13 (m, 9H), 7.0–6.98 mixture was washed with water and brine, the organic layer was (m, 3H), 4.95 (s, 1H), 4.22 (br s, 1H), 3.80 (d, J � 4.9 Hz, 1H), dried over MgSO , ﬁltered, and concentrated in vacuo. 1e 13 4 3.59 (q, J � 6.4 Hz, 1H), 1.30 (d, J � 6.7 Hz, 3H); C NMR residue was chromatographed on silica gel (hexane/ethyl acetate (400 MHz, CDCl ) δ: 158.8, 155.8, 154.5, 149.2, 145.3, 139.3, 7 : 3) to give the corresponding oxazolidinone. 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) + 4.7.1. (4R,5S,1′S)-N-(1′-Phenylethyl)-4,5-diphenyl-2-oxazoli- [C H N O + H] requires 396.2070; found 396.2067. 26 25 3 dinone (4R,5S,1′S)-26. White crystals, 60 mg, 59% yield, ° ° m.p. 154–157 C (lit. [58] m.p. 154–156 C), [α] � 19.0 (c 1.0, (17) (1S,2S,1′S)-2-(1′-Phenylethyl)amino-2-phenyl-1-(2,2′- 20 1 CHCl ) (lit. [58] [α] � 19.1 c 1.0, CHCl ). H NMR 3 3 bipyridin-6-yl)ethanol (1S,2S,1′S)- 23. Colorless oil, 60 mg, (400 MHz, CDCl ) δ: 7.39–7.32 (m, 6H), 7.07–7.02 (m, 6H), 30% yield, puriﬁed by column chromatography (Al O 2 3, 20 6.95–6.94 (m, 3H), 5.66 (d, J � 8.2 Hz, 1H), 5.35 (q, J � 7.3 Hz, MTBE), R � 0.39 (Al O MTBE), [α] � 7.2 (c 0.6, CH Cl ). f 2 3 2 2 D 13 1H), 4.56 (d, J � 8.2 Hz, 1H), 1.21 (d, J � 7.3 Hz, 3H); C IR υ (Neat) 3326, 3025, 2923, 1581, 1564, 1453, 1430, max − 1 1 NMR (400 MHz, CDCl ) δ: 158.1, 140.1, 136.6, 134.4, 128.9, 699 cm ; H NMR (400 MHz, CDCl ) δ: 8.62–8.60 (m, 1H), 128.3, 128.2, 128.11, 128.07, 127.9, 127.8, 127.5, 126.0, 80.3, 8.18 (d, J � 6.7 Hz, 1H), 7.97 (d, J � 7.9 Hz, 1H), 7.67 (td, 62.8, 53.4, 18.3. 1e NMR data are in agreement with the J � 7.6, 1.8 Hz, 1H), 7.63 (t, J � 7.6 Hz, 1H), 7.31–7.23 (m, literature [58]. 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 4.7.2. (4R,5R,1′S)-N-(1′-Phenylethyl)-5-pyridin-2-yl-4-phe- (q, J � 6.4 Hz, 1H), 1.35 (d, J � 6.4 Hz, 3H); C NMR nyl-2-oxazolidinone (4R,5R,1′S)-27. White crystals, 47 mg, (400 MHz, CDCl ) δ: 158.9, 155.8, 154.5, 149.1, 145.9, 138.9, 46% yield, m.p. 120–122 C, [α] � 21 (c 0.8, CHCl ). H 137.2, 136.8, 129.6, 128.1, 127.9, 127.2, 127.1, 126.8, 123.8, 3 NMR (400 MHz, CDCl ) δ: 8.24–8.22 (m, 1H), 7.49–7.29 (m, 121.7, 121.1, 119.6, 74.9, 65.2, 54.6, 22.8; HR-MS (ESI) 3 7H), 7.13 (d, J � 7.6 Hz, 1H), 7.05–7.03 (m, 3H), 6.92–6.89 [C H N O + H] requires 396.2070; found 396.2073. 26 25 3 (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); C NMR (18) (1R,2R,1′R)-2-(1′-Cyclohexylethyl)amino-2-phenyl-1-(2,2′- (400 MHz, CDCl ) δ: 157.7, 154.9, 148.7, 139.9, 136.9, 136.3, bipyridin-6-yl)ethanol (1R,2R,1′R)- . Colorless oil, 64 mg, 3 128.9, 128.22, 128.19, 128.1, 127.8, 127.4, 122.4, 120.9, 80.6, 32% yield, puriﬁed by column chromatography (Al O , 20% 2 3 61.9, 53.5, 18.2; HR-MS (ESI) [C H N O + H] requires MTBE/hexane). [α] � –37 (c 0.9, CH Cl ). IR υ (Neat) 22 20 2 2 2 2 max − 1 1 345.1598; found 345.1618. 3062, 2925, 2852, 1562, 1428, 773 cm ; H NMR (400 MHz, CDCl ) 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), 4.7.3. (4S,5S,1′S)-N-(1′-Phenylethyl)-5-pyridin-2-yl-4-phenyl-2- 7.66–7.58 (m, 1H), 7.31–7.27 (m, 1H), 7.15–6.97 (m, 6H), oxazolidinone (4S,5S,1′S)-27. White crystals, 47 mg, 46% 20 1 5.00 (d, J � 4.6 Hz, 1H), 4.22 (d, J � 4.6 Hz, 1H), 2.54–2.51 (m, yield, m.p. 136–137 C, [α] � 16 (c 0.6, CHCl ). H NMR 1H), 1.71–1.61 (m, 6H), 1.41–1.32 (m, 1H), 1.25–1.21 (m, (400 MHz, CDCl ) δ: 8.23–8.22 (m, 1H), 7.39 (t, J � 7.9 Hz, 1H), 1.16–0.97 (m, 3H), 0,95 (d, J � 6.4 Hz, 3H); C NMR 1H), 7.20–7.12 (m, 6H), 6.93–6.88 (m, 4H), 6.74–6.71 (m, (400 MHz, CDCl ) δ: 159.5, 156.1, 154.5, 149.2, 140.3, 137.1, 2H), 5.81 (d, J � 8.2 Hz, 1H), 5.07 (d, J � 8.6 Hz, 1H), 4.62 (q, 136.8, 128.1, 127.9, 127.1, 123.7, 121.7, 121.1, 119.5, 76.3, J � 7.0 Hz, 1H), 1.60 (d, J � 7.0 Hz, 3H); C NMR (400 MHz, 65.6, 65.0, 55.1, 42.7, 29.9, 27.9, 26.8, 26.7, 17.8; HR-MS (ESI) CDCl ) δ: 157.4, 155.3, 148.6, 140.4, 136.3, 134.9, 128.4, [C H N O + H] requires 402.2540; found 402.2538. 127.93, 127.91, 127.82, 127.80, 127.5, 122.5, 120.9, 79.8, 64.0, 26 31 3 23 10 Heteroatom Chemistry [10] M. Liu, S. Ma, Z. 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2-Oxiranyl-pyridines: Synthesis and Regioselective Epoxide Ring Openings with Chiral Amines as a Route to Chiral Ligands

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

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

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

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