A. Novak, M. J. Calhorda, P. J. Costa, S. Woodward
FULL PAPER
stirred at –10 °C for 10 min. A solution of AlMe3 (2 solution in
heptane, 0.5 mL; 1.0 mmol) was added dropwise to the reaction
mixture, which was then warmed to 10 °C. After 24 h at 10 °C the
black reaction mixture was quenched with 2 HCl (2 mL). The
product was extracted into Et2O (2ϫ5 mL), the combined organic
layers were dried with MgSO4. After removal of the solvent the
crude product was purified by flash column chromatography using
mixtures of Et2O/hexane to yield 4[11] as a olourless oil (47 mg;
49%) (63% by GC); Rf = 0.32 (hexane/Et2O, 9:1). 1H NMR
(400 MHz, CDCl3): δ = 7.66 (s, 1 H, =CH), 7.40–7.35 (m, 5 H,
Ar), 3.83 (s, 3 H, OMe), 2.57 (q, J = 7.6 Hz, 2 H, CH2Me), 1.18
(t, J = 7.6 Hz, 3 H, Me) ppm. 13C NMR (100 MHz, CDCl3): δ =
168.8, 138.6, 135.8, 134.8, 129.2, 128.3, 128.0, 51.9, 20.8, 13.9 ppm.
128.2, 113.9, 55.2, 51.8, 20.7, 13.7 ppm. IR (CDCl solution): ν =
˜
3
2952, 2839, 1694 (C=O), 1608, 1514, 1435, 1310, 1258, 1181, 1131,
1035, 833 cm–1. EIMS: m/z (%) = 220 (100) [M+], 189 (18), 160
(53), 145 (46), 115 (11). HR-EIMS: m/z: calcd. for C13H16O3:
220.1099; found 220.1097; elemental analysis: C 70.89, H 7.32
calcd. for C13H16O3; found C 70.73, H 7.37. The HPLC assay: Chi-
ralcel OD-H, isocratic (n-hexane/iPrOH, 99.5:0.5, flow
0.5 mLmin–1), λ = 254 nm, 24.9 min.
(E)-Methyl 2-(4-Fluorobenzylidene)butanoate (22): Prepared analo-
gously to 4 using 0.50 mmol of 12. Colourless oil 74 mg; 71%; Rf
= 0.70 (pentane/Et2O, 9:1). 1H NMR (400 MHz, CDCl3): δ = 7.60
(s, 1 H, =CH), 7.37–7.33 (m, 2 H, Ar), 7.10–7.06 (m, 2 H, Ar), 3.82
(s, 3 H, OMe), 2.52 (q, J = 7.4 Hz, 2 H, CH2Me), 1.16 (t, J =
7.4 Hz, 3 H, CH2Me) ppm. 13C NMR (100 MHz, CDCl3): δ =
IR (CHCl3 solution): ν = 3027, 2952, 2877, 1698 (C=O), 1628,
˜
1495, 1435, 1312, 1284, 1238, 1204, 1130, 1045, 810 cm–1. EIMS:
m/z (%) = 213 (26) [MNa+], 191 (15) [MH+]. HR-EIMS: m/z: calcd.
for C12H14O2Na: 213.0897; found 213.0898. The GC assay: 25 m
(2,6-O-dimethyl,3-O-pentyl)-γ-cyclodextrin silica column, 120 °C
(30 min): 10 °C/min: 200 °C (20 min), 24.9 min.
1
4
168.6, 162.5 (d, JCF = 249.0 Hz), 137.4, 134.5, 131.8 (d, JCF
=
3
2
3.3 Hz), 131.0 (d, JCF = 8.0 Hz), 115.5 (d, JCF = 21.7 Hz), 51.9,
20.7, 13.7 ppm. IR (CHCl solution): ν = 2952, 1609 (C=O), 1600,
˜
3
1511, 1435, 1306, 1233, 1129, 1045, 836 cm–1. EIMS: m/z (%) =
208 (100) [M+], 176 (27), 148 (86), 133 (38). HR-EIMS; m/z: calcd.
for C12H13FO2: 208.0900; found 208.0899.
Partial Resolution of (؎)-Methyl 2-Methylene-3-phenylbutanoate
(3): A sample of (Ϯ)-3 (192 g, 0.92 mmol) was dissolved in THF/
water (3:1, 20 mL), treated with LiOH·H2O (138 mg, 3.29 mmol)
and stirred at ambient temperature (24 h) after which time the reac-
tion mixture was diluted with water (10 mL) and THF was removed
in vacuo. The aqueous phase was extracted with EtOAc in order
to remove any residual starting material and neutralised with 2
HCl (50 mL). The product was extracted with EtOAc, the com-
bined organic layers were dried with Na2SO4 and solvent removed
in vacuo to give a quantitative yield of the derived acid (162.0 mg,
(E)-Methyl 2-(4-Chlorobenzylidene)butanoate (23): Prepared analo-
gously to 4 using 0.50 mmol of 13. Colourless oil (77 mg; 69%); Rf
1
= 0.42 (pentane/EtOAc, 9:1). H NMR (400 MHz, CDCl3): δH
=
7.58 (s, 1 H, =CH), 7.36 (d, J = 8.5 Hz, 2 H, Ar), 7.29 (d, J =
8.5 Hz, 2 H, Ar), 3.82 (s, 3 H, OMe), 2.52 (q, J = 7.5 Hz, 2 H,
CH2Me), 1.16 (t, J = 7.5 Hz, 3 H, CH2Me) ppm. 13C NMR
(100 MHz, CDCl3): δ = 168.5, 137.2, 135.3, 134.2, 134.2, 130.4,
128.7, 52.0, 20.8, 13.7 ppm. IR (CHCl solution): ν = 2902, 1708
˜
3
(C=O), 1243, 1130, 1014 cm–1. EIMS: m/z (%) = 226 (27) [M+,
37Cl], 224 (95) [M+, 35Cl], 193 (32), 165 (56), 139 (100). HRMS:
m/z: calcd. for C12H1335ClO2: 224.0604; found 224.0613.
1
0.92 mmol). H NMR (400 MHz, CDCl3): δ = 7.35–7.30 (m, 2 H,
Ar), 7.26–7.22 (m, 3 H, Ar), 6.48 (s, 1 H, =CH2α), 5.76 (s, 1 H,
=CH2β), 4.05 (q, J = 7.1 Hz, 1 H, CHMe), 1.47 (d, J = 7.1 Hz, 3
H, CHMe) ppm. The latter was dissolved in Et2O (5 mL) and neat
(R)-PhCHMeNH2 (120 µL, 0.95 mmol) added. The resulting white
amine salt was fractionated with CH2Cl2/Et2O. After acidification
(HCl, 2 ), re-extraction (Et2O), drying (Na2SO4) and re-esterifica-
tion (four fold excess TMSCHN2, Et2O, 30 min) the less soluble
amine salt afforded (R)-3 (36.5 mg, 0.19 mmol, 20.7% yield) with
[α]2D1 = –65.6 (c = 0.62, CHCl3) for an 86% ee sample (as deter-
mined by GC as above); ref.[6] [α]2D0 = –47.7 (c = 0.65, CHCl3) for
a 69% ee (R)-3 sample. Similar treatment of the more soluble amine
salt gave (S)-3 (52.2 mg, 0.27 mmol, 30% yield) with [α]2D1 = +51.5
(c = 0.75, CHCl3) for an 66% ee sample (as determined by GC as
above).
(E)-Methyl 2-(4-Methylbenzylidene)butanoate (24): Prepared analo-
gously to 4 using 0.50 mmol of 14. Colourless oil (78 mg; 76%); Rf
= 0.70 (pentane/EtOAc, 9:1). 1H NMR (400 MHz, CDCl3): δ =
7.79 (s, 1 H, =CH), 7.45 (d, J = 8.0 Hz, 2 H, Ar), 7.36 (d, J =
8.0 Hz, 2 H, Ar), 3.98 (s, 3 H, OMe), 2.73 (q, J = 7.4 Hz, 2 H,
CH2), 2.53 (s, 3 H, ArMe), 1.34 (t, J = 7.4 Hz, 3 H, CH2Me) ppm.
13C NMR (100 MHz, CDCl3): δ = 168.9, 138.6, 138.4, 133.8, 132.8,
129.2, 129.1, 51.8, 21.3, 20.8, 13.8 ppm. IR (CHCl solution): ν =
˜
3
2951, 1694 (C=O), 1511, 1435, 1312, 1133, 1045 cm–1. EIMS: m/z
(%) = 204 (100) [M+], 173 (21), 144 (57), 129 (50). HR-EIMS; m/z:
calcd. for C13H16O2: 204.1150; found 204.1147.
(E)-Methyl 2-(4-tert-Butylbenzylidene)butanoate (25): Prepared
analogously to 4 using 0.50 mmol of 15. Colourless oil (93 mg;
76%); Rf = 0.72 (pentane/EtOAc, 9:1). 1H NMR (400 MHz,
CDCl3): δ = 7.64 (s, 1 H, =CH), 7.43 (d, J = 8.4 Hz, 2 H, Ar), 7.35
(d, J = 8.4 Hz, 2 H, Ar), 3.82 (s, 3 H, OMe), 2.59 (q, J = 7.4 Hz,
2 H, CH2Me), 1.34 (s, 9 H, tBu), 1.20 (t, J = 7.4 Hz, 3 H, CH2Me)
ppm. 13C NMR (100 MHz, CDCl3): δ = 168.9, 151.6, 138.5, 133.9,
132.8, 129.2, 125.4, 51.8, 34.7, 31.2, 20.9, 13.8 ppm. IR (CHCl3
(E)-Ethyl 2-Benzylidenebutanoate[12] (20): Prepared analogously to
4 using 0.50 mmol of 10. Colourless oil (69 mg; 68%); Rf = 0.50
(pentane/EtOAc, 9:1). H NMR (400 MHz, CDCl3): δ = 7.65 (s, 1
H, =CH), 7.39–7.37 (m, 5 H, Ar), 4.28 (q, J = 7.1 Hz, 2 H,
CH2Me), 2.55 (q, J = 7.4 Hz, 2 H, OCH2Me), 1.36 (t, J = 7.1 Hz,
3 H, CH2Me), 1.18 (t, J = 7.4 Hz, 3 H, OCH2Me) ppm. 13C NMR
(100 MHz, CDCl3): δ = 168.4, 138.3, 135.9, 135.1, 129.2, 128.5,
1
128.3, 60.7, 20.8, 14.4, 13.9 ppm. IR (CHCl solution): ν = 2970,
˜
solution): ν = 2951, 1694 (C=O), 1626, 1510, 1435, 1314, 1269,
˜
3
1698 (C=O), 1455, 1369, 1311, 1128, 1046 cm–1. EIMS: m/z (%) =
204 (87) [M+], 158 (52), 131 (100), 129 (42), 115 (37), 91 (42). HR-
EIMS: m/z: calcd. for C13H16O: 204.1150; found 204.1163.
1192, 1132, 1045 cm–1. EIMS: m/z (%) = 246 (39) [M+], 231 (100).
HR-EIMS: m/z: for C16H22O2: 246.1620; found 246.1618.
(E)-Methyl 2-(2-Bromobenzylidene)butanoate (26): Prepared analo-
gously to 4 using 0.50 mmol of 16. Colourless oil determined to be
a 9:1 mix of α/γ products (101 mg; 75%); Rf = 0.76 (pentane/
EtOAc, 9:1). 1H NMR (270 MHz, CDCl3): δ = 7.83 (s, 1 H, =CH),
(E)-Methyl 2-(4-Methoxybenzylidene)butanoate (21): Prepared
analogously to 4 using 0.50 mmol of 11. Colourless oil (85 mg;
77%); Rf = 0.35 (pentane/EtOAc, 9:1). 1H NMR (400 MHz,
CDCl3): δ = 7.60 (s, 1 H, =CH), 7.37–7.34 (m, 2 H, Ar), 6.94–6.90 7.82–7.79 (m, 3 H, Ar), 3.85 (s, 3 H, OMe), 2.54 (q, J = 8.1 Hz, 2
(m, 2 H, Ar), 3.82 [s, 3 H, C(O)OMe], 3.80 (s, 3 H, ArOMe), 2.57 H, CH2Me), 1.09 (t, J = 8.1 Hz, 3 H, CH2Me) ppm. 13C NMR
(q, J = 7.4 Hz, 2 H, CH2Me), 1.18 (t, J = 7.4 Hz, 3 H, Me) ppm. (68 MHz, CDCl3): δ = 168.1, 137.9, 136.4, 136.2, 132.7, 129.9,
13C NMR (100 MHz, CDCl3): δ = 169.0, 159.7, 138.2, 132.5, 131.0, 129.5, 127.1, 123.9, 52.0, 20.9, 13.8 ppm. EIMS: m/z (%) = 270 (41)
902
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Eur. J. Org. Chem. 2009, 898–903