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Synlett 2008(3): 333-338  
DOI: 10.1055/s-2008-1032068
LETTER
© Georg Thieme Verlag Stuttgart · New York

Parallel Kinetic Resolution of 1-Phenylethanol Using Quasi-Enantiomeric Active Esters

Elliot Coulbeck, Jason Eames*
Department of Chemistry, University of Hull, Cottingham Road, Kingston upon Hull HU6 7RX, UK
Fax: +44(1482)466410; e-Mail: j.eames@hull.ac.uk;
Further Information

Publication History

Received 13 November 2007
Publication Date:
23 January 2008 (online)

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Abstract

The parallel kinetic resolution of racemic 1-phenylethanol using an equimolar combination of quasi-enantiomeric pentafluorophenyl esters is discussed. The levels of diastereoselectivity were excellent (>88% de) leading to separable quasi-enantiomeric esters in good yields.

Key words

chiral auxiliaries - chiral resolution - kinetic resolution - molecular recognition - stereoselectivity

8

Alternatively, n-BuLi (in hexanes) and PhLi (in dibutyl ether) could be used but they contained traces of lithium butoxide which can lead to the formation of an inseparable by-product, butyl 2-phenylpropionate (in 16% and 5% yields for n-BuLi and PhLi, respectively). Characterisation data for butyl 2-phenylpropionate; R f [light PE (40-60 °C)-Et2O, 1:1] 0.80. IR (film): 1674 (C=O) cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.15-7.28 (m, 5 H, 5 × CH, Ph), 3.99 (td, J = 1.5, 6.8 Hz, 2 H, OCH2), 3.63 (q, J = 7.2 Hz, 1 H, CHMe), 1.43-1.52 (m, 2 H, CH2), 1.42 (d, J = 7.2 Hz, 3 H, CHMe), 1.18-1.28 (m, 2 H, CH2), 0.79 (t, J = 7.5 Hz, 3 H, Me). 13C NMR (100 MHz, CDCl3): δ = 174 (C=O), 140.6 (i-C, Ph), 128.4, 127.4, 126.9 (3 × CH, Ph), 64.5 (OCH2), 45.5 (PhCH), 30.4, 18.9 (2 × CH2), 18.4 (MeCH), 13.6 (MeCH2). HRMS: m/z [M+] calcd for C13H18O2: 206.1299; found: 206.1301.

9

Using racemic lithium 1-(4-methoxyphenyl)ethoxide, epimerisation of esters such as (S,S)-anti-24 and (S,R)-syn-24, has been shown to occur at a significantly faster rate than simple transesterification.

11

Measured by 1H NMR (400 MHz) spectroscopy; for rac,anti-17, the methyl doublets appear at δ = 1.43 (d, J = 7.2 Hz, 3 H, MeCH) and 1.42 (d, J = 6.6 Hz, 3 H, MeCH), whereas for rac,syn-17, the methyl doublets appear at δ = 1.41 (d, J = 7.2 Hz, 3 H, MeCH) and 1.35 (d, J = 6.6 Hz, 3 H, MeCH).

12

For active esters: R f [light PE (40-60 °C)-Et2O, 9:1] 0.69 [for (R)-11] and 0.50 [for (S)-12]. For further information see ref. 10.

13

For a representative procedure, see ref. 7d.

17

Experimental Procedure for 1-Phenylethyl 2-Phenylpropionate [( R , R )- anti -17] and 1-Phenylethyl 2-(6-Methoxynaphthalen-2-yl)propionate [( S , S )- anti -24] Derived from the Parallel Kinetic Resolution of 1-Phenylethanol ( rac -16) Using Active Esters ( R )-11 and ( S )-12: t-BuLi (1.81 mL, 1.7 M in pentane, 3.07 mmol) was added to a stirred solution of 1-phenylethanol (rac-16; 1.25 g, 1.24 mL, 10.25 mmol) in THF at -78 °C. A solution of ZnCl2 (3.07 mL, 1 M in Et2O, 3.07 mmol) was added and the resulting solution was stirred for 2 min. An equimolar combination of pentafluorophenyl 2-phenylpropionate [(R)-11; 0.16 g, 0.51 mmol] and pentafluorophenyl 2-(6-methoxynaphthalen-2-yl)propionate [(S)-12; 0.203 g, 0.51 mmol] in THF (20 mL) was added, and the resulting solution was stirred for 12 h. The reaction was quenched by the addition of sat. aq NH4Cl (5 mL) and H2O (10 mL). The organic layer was extracted with CH2Cl2 (3 × 50 mL), washed with H2O (10 mL), dried (over MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with light PE (40-60 °C)-Et2O (9:1) to give a pair of inseparable diastereomers (anti/syn, 93:7) of 1-phenylethyl 2-phenylpropionates (R,R)-anti-17 and (R,S)-syn-17 (0.10 g, 77%) as an oil {R F [light PE (40-60 °C)-Et2O (1:1)] 0.80} and a pair of inseparable diastereomers (anti/syn, 94:6) of 1-phenylethyl 2-(6-methoxynaphthalen-2-yl)propionates (S,S)-anti-24 and (S,R)-syn-24 (0.13 g, 76%) as an oil {R f [light PE (40-60 °C)-Et2O (1:1)] 0.62}. Pentafluorophenol, if present, can be removed by an aq NaOH extraction. All compounds synthesised had satisfactory 1H and 13C NMR, IR and HRM spectra with >95% purity.
Characterisation data for:
1-Phenylethyl 2-Phenylpropionate [(R,R)-anti-17]: transparent solid; mp 81-83 °C; R f [light PE (40-60 °C)-Et2O, 1:1] 0.80; [α]D 20 +10.53 (c = 3.0, CHCl3) {lit.19 [α]D 20 +9.9 (c = 0.87, CHCl3)}. IR (CHCl3): 1730 (C=O) cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.14-7.30 (m, 8 H, 8 × CH, PhA and PhB), 7.00-7.05 (m, 2 H, 2 × CH, PhA or PhB), 5.78 (q, J = 6.6 Hz, 1 H, PhCHMeO), 3.68 (q, J = 7.2 Hz, 1 H, PhCHMe), 1.43 (d, J = 7.2 Hz, 3 H, PhCHMe), 1.42 (d, J = 6.6 Hz, 3 H, PhCHMeO). 13C NMR (100 MHz, CDCl3): δ = 173.5 (C=O), 141.6 (i-C, PhCHMeO), 140.4 (i-C, PhCHMe), 128.5,2 128.3,2 127.6,2 127.5,1 127.0,1 125.6,2 (10 × CH, PhA, PhB), 72.4 (PhCHMeO), 45.7 (PhCHMe), 22.3 (PhCHMeO), 18.3 (PhCHMe). HRMS: m/z [MNH4 +] calcd for C17H22NO2: 272.1645; found: 272.1648. MS: m/z (%) = 254 (10) [M+], 105 (100) [PhCHMe+].
1-Phenylethyl 2-(6-Methoxynaphthalene-2-yl)propionate [(S,S)-anti-24]: white solid; mp 94-96 °C; R f [light PE (40-60 °C)-Et2O (1:1)] 0.62; [α]D 20 +26.6 (c = 3.2, CHCl3). IR (CHCl3): 1723 (C=O) cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 8.4 Hz, 1 H, CH, Ar), 7.63 (d, J = 8.4 Hz, 1 H, CH, Ar), 7.55 (br s, 1 H, CH, Ar), 7.33 (dd, J = 1.8, 8.3 Hz, 1 H, CH, Ar), 7.08-7.19 (m, 7 H, 7 × CH, Ar, Ph), 5.86 (q, J = 6.6 Hz, 1 H, PhCHMeO), 3.90 (s, 3 H, OMe, Ar), 3.88 (q, J = 7.2 Hz, 1 H, ArCHMe), 1.56 (d, J = 7.2 Hz, 3 H, ArCHMe), 1.50 (d, J = 6.6 Hz, 3 H, PhCHCMeO). 13C NMR (100 MHz, CDCl3): δ = 173.7 (C=O), 147.5 (i-CO, Ar), 141.6 (i-C, Ph), 135.6 (i-C, Ar), 133.6, 128.9 (2 × i-C, Ar), 129.3,1 127.0,1 126.4,1 126.0,1 118.8,1 105.51 (6 × CH, Ar), 128.2,2 127.5,1 125.7,2 (5 × CH, Ph), 72.5 (PhCHMeO), 55.3 (OMe), 45.6 (ArCHMe), 22.3 (PhCHMeO), 18.4 (ArCHMe). HRMS: m/z [MNH4 +] calcd for C22H26NO3: 352.1907; found: 352.1907. MS: m/z (%) = 334 (20) [M+], 185 (100) [ArCHMe+], 105 (60) [PhCHMe+].