Enantioselective quaternization of 4-substituted oxazol-5-(4H)-ones using recoverable Cinchona-derived dimeric ammonium salts as phase-transfer organocatalysts

Tetrahedron: Asymmetry 23 (2012) 176–180

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Enantioselective quaternization of 4-substituted oxazol-5-(4H)-ones using recoverable Cinchona-derived dimeric ammonium salts as phase-transfer organocatalysts Silvia Tarí, Angel Avila, Rafael Chinchilla ⇑, Carmen Nájera ⇑ Departamento de Química Orgánica, Facultad de Ciencias, Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo 99, 03080 Alicante, Spain

a r t i c l e

i n f o

Article history: Received 16 January 2012 Accepted 19 January 2012 Available online 17 February 2012

a b s t r a c t Dimeric anthracenyldimethyl-derived Cinchona ammonium salts are used as chiral organocatalysts (5 mol %) for the enantioselective 4-alkylation of 4-substituted azlactones. The corresponding adducts bearing a new quaternary center were obtained with up to 80% ee when using a dimeric ammonium salt derived from cinchonidine, and are precursors of a,a-disubstituted a-amino acids. The catalysts can be recovered almost quantitatively by precipitation in ether and reused without loss of activity. Ó 2012 Elsevier Ltd. All rights reserved.

1. Introduction The development of strategies for the preparation of enantiomerically enriched non-proteinogenic a,a-disubstituted a-amino acids has received considerable attention in recent years.1 These quaternized a-amino acids show interesting properties in biological and medicinal chemistry; the additional a-substituent often helps to sterically constrain free rotation of the residue’s side chain leading to unique folding when incorporated into peptides.1d,2 In addition, peptides containing quaternary a-amino acids present increased hydrophobicity, as well as a higher stability toward both chemical3 and metabolic4 decomposition. Moreover, quaternary a-amino acid derivatives can be found in Nature either in their free form, or within the structures of biologically interesting heterocyclic natural compounds.1c,5 Oxazol-5-(4H)-ones, also known as azlactones, are well known starting materials suitable for the synthesis of different amino acids due to their diverse chemistry.6 In particular, 4-substituted oxazol-5-(4H)-ones are appropriate substrates for synthesizing enantiomerically enriched quaternary substituted a-amino acids.7 Thus, 4-substituted oxazol-5-(4H)-ones are readily available and configurationally labile a-amino acid derivatives due to the acidity of the a-hydrogen (pKa  9, H2O, 25 °C),8 and have been 4-alkylated enantioselectively mainly by catalytic procedures involving chiral transition metal complexes.7 Recently, this transformation has also been achieved using chiral organocatalysts, after enantioselective addition to conjugated systems9 or Mannich reactions.10 However, although the direct 4-alkylation of 4-substituted oxazol-5-(4H)-ones using alkyl halides has been shown to be feasible ⇑ Corresponding authors. Tel.: +34 96 5903728; fax: +34 96 5903549. E-mail addresses: [email protected] (R. Chinchilla), [email protected] (C. Nájera). 0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2012.01.012

under simple and convenient phase-transfer conditions,11 the enantioselective version of this process has remained almost unexplored. Thus, recently, azlactones from a-substituted a-amino acids have been alkylated with activated alkyl halides under biphasic conditions using a P-spiro chiral tetraaminophosphonium salt as a phase-transfer organocatalyst;12 this salt has also been employed as a catalyst for the 4-akylation of azlactones on a terminal peptide backbone.13 Surprisingly, in spite of being very commonly employed as chiral organocatalysts, especially when dealing to phase-transfer processes,14 Cinchona alkaloid-derived ammonium salts have never been used in this transformation. In the last few years, our group has developed recoverable unsupported15–18 and supported19 Cinchona alkaloid-derived ammonium salts for use in organocatalyzed enantioselective reactions. Particularly interesting has been the preparation of a series of dimeric anthracenyldimethyl-derived ammonium salts from Cinchona alkaloids, which have been employed as recoverable organocatalysts in enantioselective transformations such as asymmetric alkylation15 and Michael addition16 reactions of glycinate Schiff bases for the enantioselective synthesis of a-amino acids under phase-transfer conditions. Recently, they have also been employed in the enantioselective quaternization of cyclic b-keto esters18 and in the enantioselective cyanoformylation of aldehydes.17 Herein we report the use of these dimeric ammonium salts as recoverable organocatalysts in the 4-alkylation of 4-substituted oxazol-5-(4H)ones for the enantioselective generation of quaternary stereocenters of a,a-disubstituted a-amino acid derivatives. 2. Results and discussion As a model starting material for the first screening reactions, we employed 4-benzylated oxazol-5-(4H)-one (S)-4a, available in a

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important for the enantioselectivity of the reaction. Thus, the allylation of (S)-4a was carried out under the same reaction conditions but using the commercially available Lygo’s monomeric cinchonidine ammonium salt 221 (10 mol %) as the phase-transfer catalyst (Table 1, entry 4). The resulting azlactone (S)-5aa was obtained in a shorter reaction time, but with only 14% ee.

78% yield via cyclization of N-benzoyl-L-phenylalanine promoted by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI).20 The dimeric cinchonidine-derived ammonium salt 1a15,16 was used as an organocatalyst (5 mol %) in the reaction of (S)-4a with allyl bromide in the presence of solid K3PO4H2O (5 equiv) as base and a mixture of toluene/chloroform (7/3 v/v), usually effective in enantioselective phase-transfer reactions involving dimeric ammonium salts,15 as solvent at room temperature (Table 1, entry 1). Under these conditions, the resulting 4-allylated azlactone 5aa was obtained as the (S)-enantiomer in 73% ee. The use of an O-allylated cinchonidine-derived ammonium salt 1b15,16 under the same reaction conditions caused a considerable decrease in enantioselectivity (Table 1, entry 2), but when the Ofree quinine-derived dimeric ammonium salt 1c18 was employed as the catalyst, the enantioselectivity for (S)-5aa increased slightly to 33% (Table 1, entry 3).

-

Cl

N + OH N 2

R1

Other bases were then tested in order to improve the enantioselectivity of this process. Thus, the use of K2HPO4 gave rise to a much longer reaction time and 59% ee for (S)-5aa (Table 1, entry 5), whereas the use of K2CO3 showed an increase in the enantioselectivity of the process up to 70% ee (Table 1, entry 6). The use of other carbonates as bases, such as Na2CO2, afforded 67% ee for (S)-5aa (Table 1, entry 7), whereas Cs2CO3 yielded only 17% ee (Table 1, entry 8). In addition, the use of liquid–liquid phase-transfer conditions was attempted by employing saturated aq K2CO3, but the enantioselectivity decreased to 54% ee (Table 1, entry 9). After solid K2CO3 was established as the most convenient base, other solvents were tested. The use of tert-butyl methyl ether (TBME) gave no enantioselection (Table 1, entry 10), while dichloromethane gave 58% ee for (S)-5aa in a rather rapid reaction (Table 1, entry 11). The effect of the reaction temperature was subsequently explored using solid K2CO3 as the base and a mixture of PhMe/CHCl3

2 X-

N + 2

OR

R1

+N

N 2

R O 1

2

N

1a, R = H, R = H, X = Cl 1 2 1b, R = H, R = allyl, X = Br 1 2 1c, R = OMe, R = H, X = Cl

Since the O-free cinchonidine-derived dimeric ammonium salt 1a proved more effective than the related quinine-derived salt 1c, we decided to clarify whether the dimeric structure of 1a was

Table 1 Screening and optimization of the reaction conditions for the enantioselective allylation reaction

O Ph N

O

O

Ph

Br cat., base

* N

solvent, T

Ph

Ph (S)-4a

a b

O

5aa

Ent.

Cat. (mol %)

Base

Solvent

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

1a (5) 1b (5) 1c (5) 2 (10) 1a (5) 1a (5) 1a (5) 1a (5) 1a (5) 1a (5) 1a (5) 1a (5) 1a (5) 1a (5) 1a (5) 1a (10) 3 (5)

K3PO4H2O K3PO4H2O K3PO4H2O K3PO4H2O K2HPO4 K2CO3 Na2CO3 Cs2CO3 K2CO3 (aq) K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3

PhMe/CHCl3 PhMe/CHCl3 PhMe/CHCl3 PhMe/CHCl3 PhMe/CHCl3 PhMe/CHCl3 PhMe/CHCl3 PhMe/CHCl3 PhMe/CHCl3 TBME CH2Cl2 PhMe/CHCl3 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2

Determined by 1H NMR (300 MHz) using diphenylmethane as the internal standard. The enantioselectivities and absolute stereochemistry were determined by chiral HPLC.12

T (°C) 25 25 25 25 25 25 25 25 25 25 25 0 0 20 30 20 20

t (d)

Yielda (%)

eeb (%)

0.6 0.2 0.7 0.1 2 0.2 0.2 0.2 0.3 1 0.1 2 0.3 2 3 2 5

73 53 84 74 61 72 39 48 65 34 78 64 66 49 39 54 43

63 (S) 11 (S) 33 (S) 14 (S) 59 (S) 70 (S) 67 (S) 17 (S) 54 (S) 0 58 (S) 70 (S) 73 (S) 80 (S) 70 (S) 64 (S) 10 (R)

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Table 2 Enantioselective 4-alkylation of 4-substituted oxazol-5-(4H)-ones 4 organocatalyzed by cinchonidine-derived dimeric ammonium salt 1a under phase-transfer conditions

R1

O O

N 4 R1

Entry 1 2 3 4 5 6 7 8 9 10 a b c

Ar

PhCH2 PhCH2 PhCH2 PhCH2 PhCH2 PhCH2 PhCH2 Me Et iBu

+

1a (5 mol%)

2

R Br

R2

K2CO3 (s, 5eq)

O

N

CH2Cl2, -20 ºC

Ar

5 R2Br

No.

Ph Ph Ph Ph 4-MeOC6H4 4-F3CC6H4 4-ClC6H4 Ph Ph Ph

O

R1

*

t (d)

CH2@CHCH2Br CH2@C(Me)CH2Br (Me)2C@CHCH2Br HC„CCH2Br CH2@CHCH2Br CH2@CHCH2Br CH2@CHCH2Br CH2@CHCH2Br CH2@CHCH2Br CH2@CHCH2Br

(S)-4a (S)-4a (S)-4a (S)-4a (S)-4b (S)-4c (S)-4d (S)-4e rac-4f (S)-4g

2 3 3 1 3 2 3 3 5 3

Ar Yielda (%)

No. c

(S)-5aa (S)-5ab rac-5ac (S)-5ad (S)-5ba (S)-5ca (S)-5da (R)-5ea (R)-5fa (R)-5ga

49 32 81 23 18 90 90 65 35 35

eeb (%) 80 59 0 25 42 55 52 62 53 57

Determined by 1H NMR (300 MHz) using diphenylmethane as an internal standard. Enantioselectivities determined by chiral HPLC. The absolute configuration was determined by the order of elution of the enantiomers in chiral HPLC.12

(7/3 v/v) as the solvent. Lowering the temperature to 0 °C did not increase the enantioselection for (S)-5aa compared to when room temperature was used, but the reaction rate decreased dramatically (Table 1, compare entries 6 and 12). However, when dichloromethane was used as the solvent, lowering the reaction temperature to 0 °C raised the enantioselectivity for (S)-5aa up to 73% ee with a short reaction time (Table 1, entry 13). Therefore, dichloromethane was used as the solvent when the temperature was diminished to 20 °C, affording (S)-5aa in 80% ee (Table 1, entry 14). Lowering the temperature down to 30 °C did not give better results (Table 1, entry 15). In addition, an increase in the loading of catalyst 1a up to 10 mol % at 20 °C gave a lower enantioselection for (S)-5aa (Table 1, entry 16). Expecting to achieve an opposite enantioselection, we performed this enantioselective allylation reaction using the cinchonine-derived dimeric ammonium salt 3, which can be considered a pseudoenantiomer of the cinchonidine-derived counterpart 1a.15 This was confirmed by the isolation of the corresponding opposite allylated azlactone (R)-5aa, but only in poor 10% ee (Table 1, entry 17).

-

2 Cl + N HO

N+

N OH N

3

With the most appropriate ammonium salt 1a and convenient reaction conditions (solid K2CO3 as base, dichloromethane as solvent, 20 °C reaction temperature) established, we proceeded to extend the procedure to other 4-substituted oxazol-5-(4H)-ones, as well as other halides (Table 2).

Initially, the behaviors of allylic bromides, other than allyl bromide, were investigated (Table 2). Thus, when the oxazol-5(4H)-one from L-phenylalanine (S)-4a was reacted with methallyl bromide, the corresponding quaternized azlactone 5ab was obtained in 59% ee (Table 2, entry 2); the use of prenyl bromide gave rise to the corresponding azlactone 5ac but as a racemic mixture (Table 2, entry 3). When propargyl bromide was employed as an electrophile for the alkylation of 4a, the quaternized adduct (S)4a was obtained in only 25% ee (Table 2, entry 4). The absolute configuration of these and other alkylated azlactones was tentatively assigned assuming the same sense in enantioselectivity was achieved with 1a than when using substrate (S)-4a. The possible effect on the enantioselectivity of the process of the presence of electron-withdrawing or electron-releasing groups on the aryl group at the 2-position of the oxazol-5-(4H)-one was investigated by preparing L-phenylalanine-derived azlactones 4a,b,c bearing methoxylated, trifluoromethylated, and chlorinated aryl groups respectively, and performing the alkylation reaction with allyl bromide. Thus, the methoxylated azlactone (S)-4b gave rise to the corresponding allylated product 5ba in 42% ee and low yield, whereas the azlactone (S)-4c, bearing a trifluoromethyl group, afforded the corresponding product 5ca in 55% ee and very good yield (Table 2, entries 5 and 6), similar results being obtained when the chlorinated oxazolone (S)-4d was allylated (Table 2, entry 7). Other oxazol-5-(4H)-ones, obtained from a-amino acids other than L-phenylalanine, were also prepared and employed in the allylation with allyl bromide. Thus, oxazolone (S)-4e from L-alanine was obtained and allylated under the optimized reaction conditions, affording the 4-allylated oxazolone 5ea in 62% ee (Table 2, entry 8). The oxazolone derived from racemic 2-aminobutyric acid gave rise to the corresponding allylated product 5fa in 53% ee, thus discarding a possible ‘memory of chirality’ effect in the origin of the enantioselectivities achieved in this process (Table 2, entry 9). In addition, the allylation of L-leucine-derived azlactone (S)-4g afforded adduct 5ga in 57% ee (Table 2, entry 10). It is interesting to note that the ammonium salt 1a can be recovered in 93% yield once the reaction is complete after removing the base by filtration, evaporation of the dichloromethane, addition of ethyl ether and filtration of the precipitate. The recovered ammonium salt can be reused up to three times in the model

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reaction (Table 2, entry 1) giving rise to almost identical yields and enantioselectivities. 3. Conclusions It can be concluded that quaternized oxazol-5-(4H)-ones, precursors of a,a-disubstituted a-amino acids can be generated enantioselectively by a direct alkylation reaction between oxazol5-(4H)-ones from a-amino acids and activated bromides, using Cinchona-derived dimeric ammonium salts as chiral organocatalysts under solid–liquid phase-transfer conditions. The best results were obtained with a cinchonidine-derived dimeric species. This organocatalyst can be separated from the reaction medium by precipitation in ether and filtration, and reused without a loss of activity. 4. Experimental 4.1. General All reagents and solvents employed were of the best grade available and were used without further purification. Melting points are uncorrected. Specific rotations were measured using a Perkin-Elmer 341 polarimeter. IR data were collected on a Nicolet Impact 400D-FT spectrometer. The 1H and 13C NMR spectra were recorded at 25 °C on a Bruker AC-300 at 300 MHz and 75 MHz, respectively, using CDCl3 as the solvent and TMS as the internal standard. MS (EI, 70 eV) were performed on a HP MS-GC-5973A. HRMS analyses were carried out on a Finnigan MAT 95S. Enantioselectivities were determined by chiral HPLC using Chiralcel columns and n-hexane/2-propanol mixtures as eluent. Ammonium salts 1a,17b 1b,15a 1c18 and 318 have been prepared following reported procedures. The absolute configuration of adduct 5aa was determined according to the described order of elution of their enantiomers in chiral HPLC.12 The absolute configuration of the other adducts was assigned by analogy. Reference racemic samples of adducts 5 were obtained by performing the enantioselective reaction using tetra-n-butylammonium bromide as the phase-transfer organocatalyst. 4.2. Preparation of the oxazol-5-(4H)-ones 4a–d 4.2.1. General procedure20 A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.5 mmol, 1.05 g) in dry CH2Cl2 (10 mL) was added to a solution of the corresponding N-aroyl-a-amino acid22 in dry CH2Cl2 (40 mL). The mixture was stirred for 1 h at 0 °C, diluted with CH2Cl2 (50 mL) and washed with water (25 mL), saturated NaHCO3 (25 mL) and water (25 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo (15 Torr). The synthesis of oxazol-5-(4H)-ones 4a23 and 4b24 has already been described. New compounds 4c and 4d were obtained in 72% and 28% yields, respectively, and their analytical and spectroscopic data are as follows. 4.2.2. (S)-4-Benzyl-2-(4-(trifluoromethyl)phenyl)oxazol-5(4H)one 4c White solid; mp 84 °C (CH2Cl2/Et2O). ½a25 D ¼ 0:5 (c 1, MeOH); IR (KBr): m 2931, 2855, 1830, 1786, 1647, 1325, 1065, 863, 694 cm1; 1H NMR: d 8.03 (d, J = 8.2 Hz, 2H, Ar-CF3), 7.71 (d, J = 8.3 Hz, 2H, Ar-CF3), 7.32–7.17 (m, 5H, Ph), 4.74 (dd, J = 6.3, 5.1 Hz, 1H, PhCH2CH), 3.40 (dd, J = 14.0, 4.9 Hz, 1H, PhCHAHBCH), 3.21 (dd, J = 14.0, 6.6 Hz, 1H, PhCHAHBCH); 13C NMR: d 176.9, 160.7, 134.9, 130.9, 130.6, 129.5, 128.5, 128.3, 127.4, 125.8, 125.7, 66.6, 37.2; MS (EI, 70 eV): m/z (%) 319 (M+, 2), 91 (100); HRMS (EI): m/z calcd for C17H12F3NO2 (M+) 319.0820, found 319.0826.

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4.2.3. 4-Benzyl-2-(4-chlorophenyl)oxazol-5(4H)-one 4d White solid; mp 120 °C (CH2Cl2/Et2O). ½a25 D ¼ 4:7 (c 1, MeOH); IR(KBr): m 2359, 2340, 1820, 1653, 1489, 1044, 731 cm1; 1H NMR: d 7.85 (d, J = 8.5 Hz, 2H, Ar-Cl), 7.43 (d, J = 8.5. 2H, Ar-Cl), 7.31 (m, 5H, Ph), 4.69 (dd, J = 6.5, 5.0 Hz, 1H, PhCH2CH), 3.37 (dd, J = 13.9, 4.9 Hz, 1H, PhCHAHBCH), 3.19 (dd, J = 13.9, 6.7 Hz, 1H, PhCHAHBCH); 13C NMR: d 177.3, 161.0, 139.2, 135.2, 132.0, 129.6, 129.3, 128.5, 127.4, 124.3, 66.6, 37.4; MS (EI, 70 eV): m/z (%) 285 (M+, 7), 91 (100); HRMS (EI): m/z calcd for C16H12ClNO2 (M+) 285.0557, found 285.0527. 4.3. Preparation of the oxazol-5-(4H)-ones 4e–g 4.3.1. General procedure26 A solution of the N-benzoyl-a-amino acid22 (2.5 mmol) and trifluoroacetic anhydride (2.5 mmol, 348 lL) in anhydrous CH2Cl2 (125 mL) was stirred at room temperature overnight under an argon atmosphere. The mixture was washed with a saturated solution of NaHCO3 (65 mL) and a saturated solution of NaCl (65 mL). The organic phase was dried (MgSO4) and evaporated (15 Torr). The synthesis of oxazol-5-(4H)-ones 4e–g has already been described.25 4.4. Enantioselective alkylation reaction 4.4.1. Typical procedure To a solution of 1a (0.05 mmol, 43 mg), (S)-4a (1 mmol, 251 mg) and allyl bromide (1.2 mmol, 104 lL) in CH2Cl2 (6 mL) was added solid K2CO3 (5 mmol, 691 mg) at 20 °C. The reaction mixture was stirred vigorously at 20 °C for 2 d (TLC), and the base was filtered. The filtrate was evaporated (15 Torr) and Et2O (6 mL) was added, recovering the precipitated catalyst 1a by filtration (40 mg, 93%). The filtrate was diluted with water (20 mL) and extracted with AcOEt (3  5 mL). The organics were dried (MgSO4), filtered and evaporated (15 Torr), leading to adduct 5aa. The synthesis of the adducts 5aa,12 5ab,20 5ac,27 5ad,12 5ea11 and 5ga12 have already been described. Retention times observed in chiral HPLC for both enantiomers and chromatographic separation conditions for all adducts described, as well as full analytical and spectroscopic data for the newly prepared compounds 5ba,ca,da,fa are as follows. 4.4.2. (S)-4-Allyl-4-benzyl-2-phenyloxazol-5(4H)-one 5aa HPLC: Chiralcel OD-H, k = 210 nm, n-hexane/2-propanol, 1000:1, 0.5 mL/min, tr (minor) = 36.3 min, tr (major) = 39.1 min. 4.4.3. (S)-4-Benzyl-4-(2-methylallyl)-2-phenyloxazol-5(4H)-one 5ab HPLC: Chiralcel OJ, k = 210 nm, n-hexane/2-propanol, 999:1, 1 mL/min, tr (minor) = 14.1 min, tr (major) = 29.6 min. 4.4.4. rac-4-Benzyl-4-(3-methylbut-2-en-1-yl)-2-phenyloxazol5(4H)-one 5ac HPLC: Chiralcel OJ, k = 210 nm, n-hexane/2-propanol, 97:3, 1.0 mL/min, tr1 = 5.5 min, tr2 = 7.2 min. 4.4.5. (S)-4-Benzyl-2-phenyl-4-(prop-2-yn-1-yl)oxazol-5(4H)one 5ad HPLC: Chiralcel OD-H, k = 210 nm, n-hexane/2-propanol, 98:2, 0.5 mL/min, tr (minor) = 18.9 min, tr (major) = 20.3 min. 4.4.6. (S)-4-Allyl-4-benzyl-2-(4-methoxyphenyl)oxazol-5(4H)one 5ba Colorless oil; IR (film): m 2922, 1814, 1652, 1608, 1512, 1456, 1305, 1258, 1171, 1090, 1030, 977, 890, 840, 700 cm1; 1H NMR:

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d 7.79 (d, J = 8.8 Hz, 2H, Ar-OMe), 7.17 (m, 5 H, Ph), 6.91 (d, J = 8.8 Hz, 2H, Ar-OCH3), 5.75–5.60 (m, 1H, CH2CH@CH2), 5.20 (dd, J = 16.8, 1.1 Hz, 1H, CH2CH@CHAHB), 5.11 (dd, J = 9.9, 1.1 Hz, 1H, CH2CH=CHACHB), 3.85 (s, 3H, OCH3), 3.21 (d, J = 13.4 Hz, 1H, CHACHBPh), 3.14 (d, J = 13.3 Hz, 1H, CHAHBPh), 2.79–2.64 (m, 2H, CH2CH=CH2); 13C NMR: d 179.4, 163.2, 159.7, 134.6, 130.4, 130.0, 129.3, 128.6, 127.9, 126.9, 117.9, 113.6, 74.9, 55.2, 43.4, 41.8; MS (EI, 70 eV): m/z (%) 321 (M+, 1), 135 (100); HRMS (EI): m/z calcd for C20H19NO3 (M+) 321.1365, found 321.1364; HPLC: Chiralcel OJ, k = 210 nm, n-hexane/2-propanol, 90:10, 1.0 mL/min, tr (minor) = 8.0 min, tr (major) = 11.7 min. 4.4.7. (S)-4-Allyl-4-benzyl-2-(4-(trifluoromethyl)phenyl)oxazol5(4H)-one 5ca Colorless oil; IR (film): m 2358, 1820, 1652, 1416, 1324, 1175, 1132, 1066, 698, 619 cm1; 1H NMR: d 7.96 (d, J = 8.2Hz, 2H, ArCF3), 7.69 (d, J = 8.2 Hz, 2H, Ar-CF3), 7.17 (m, 5H, Ph), 5.67 (m, 1H, CH2CH=CH2), 5.18 (dd, J = 15.4, 1.0 Hz, 1H, CH2CH=CHAHB), 5.14 (dd, J = 10.1, 1.0 Hz, 1H, CH2CH=CHAHB), 3.25 (d, J = 13.5 Hz, 1H, CHACHBPh), 3.18 (d, J = 13.5 Hz, 1H, CHACHBPh), 2.82–2.69 (m, 2H, CH2CH@CH2); 13C NMR: d 178.6, 158.9, 134.1, 130.5, 130.2, 128.3, 128.3, 127.4, 125.8, 125.8, 121.0, 75.2, 43.2, 41.5; MS (EI, 70 eV): m/z (%) 359 (M+, 3), 91 (100); HRMS (EI): m/z calcd for C20H16NO2F3 (M+) 359.1133, found 359.1129; HPLC: Chiralcel OJ, k = 210 nm, n-hexane/2-propanol, 97:3, 1.0 mL/min, tr (minor) = 7.3 min, tr (major) = 8.6 min. 4.4.8. (S)-4-Allyl-4-benzyl-2-(4-chlorophenyl)oxazol-5(4H)-one 5da Colorless oil; IR (film): m 2922, 2852, 2359, 2341, 1816, 1652, 1598, 1489, 1310, 1294, 1088, 972, 699 cm1; 1H NMR: d 7.77 (d, J = 8.5 Hz, 2H, Ar-Cl), 7.41 (d, J = 8.5 Hz, 2H, Ar-Cl), 7.16 (m, 5H, Ph), 5.68 (m, 1H, CH2CH@CH2), 5.21 (dd, J = 16.1, 1.0 Hz, 1H, CH2CH@CHAHB), 5.13 (dd, J = 10.1, 1.0 Hz, 1H, CH2CH@CHAHB), 3.22 (d, J = 13.4 Hz, 1H, CHACHBPh), 3.16 (d, J = 13.4 Hz, 1H, CHACHBPh), 2.81–2.64 (m, 2H, CH2CH=CH2); 13C NMR: d 178.9, 159.2, 139.0, 134.3, 130.7, 130.2, 129.2, 128.5, 128.3, 127.4, 124.2, 120.8, 75.1, 43.3, 41.5; MS (EI, 70 eV): m/z (%) 325 (M+, 12), 139 (100); HRMS (EI): m/z calcd for C19H16NClO2 (M+) 325.0870, found 325.0860; HPLC: Chiralcel OJ, k = 254 nm, n-hexane/2-propanol, 90:10, 1.0 mL/min, tr (minor) = 5.9 min, tr (major) = 8.5 min. 4.4.9. (R)-4-Allyl-4-methyl-2-phenyloxazol-5(4H)-one 5ea HPLC: Chiralcel OD-H, k = 210 nm, n-hexane/2-propanol, 99:1, 1.0 mL/min, tr (major) = 5.0 min, tr (minor) = 6.2 min. 4.4.10. (R)-4-Allyl-4-ethyl-2-phenyloxazol-5(4H)-one 5fa Colorless oil; IR (film): m 2924, 1818, 1655, 1451, 1322, 1290, 1260, 1036, 1019, 887, 799, 699 cm1; 1H NMR: d 8.01 (d, J = 7.1 Hz, 2H, Ph), 7.58 (t, J = 7.4 Hz, 1H, Ph), 7.49 (t, J = 7.7 Hz, 2H, Ph), 5.65 (m, 1H, CH2CH=CH2), 5.17 (dd, J = 17.1, 1.4 Hz, 1H, CH2CH@CHAHB), 5.10 (dd, J = 10.2, 0.9 Hz, 1H, CH2CH@CHACHB), 2.69–2.64 (m, 1H, CHAHBCH@CH2), 2.61–2.55 (m, 1H, CHAHBCH@CH2), 1.96 (q, J = 7.3 Hz, 2H, CH2CH3), 0.86 (t, J = 7.4 Hz, 3H, CH2CH3); 13C NMR: d 180.0, 160.2, 132.8, 131.0, 128.9, 128.1, 125.9, 120.5, 74.3, 41.5, 30.3, 8.3; MS (EI, 70 eV): m/z (%) 229 (M+, 1), 105 (100); HRMS (EI): m/z calcd for C14H15NO2 (M+) 229.1103, found 229.1131; HPLC: Chiralcel OD-H, k = 210 nm, n-hexane/2-propanol, 995:5, 1.0 mL/min, tr (major) = 7.8 min, tr (minor) = 12.4 min.

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