Synlett 2011(19): 2831-2833  
DOI: 10.1055/s-0031-1289869
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Easy Access to (E)-β-Ocimene

Selma Yildizhan, Stefan Schulz*
Institut für Organische Chemie, TU Braunschweig, Hagenring 30, 38106 Braunschweig, Germany
Fax: +49(531)3915272; e-Mail: stefan.schulz@tu-bs.de;
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Publikationsverlauf

Received 23 September 2011
Publikationsdatum:
14. November 2011 (online)

Abstract

β-Ocimene is one of the most common monoterpenes found in Nature, but a simple and reliable synthesis of the pure E-isomer has been missing. Here, we report a simple procedure involving a Grignard coupling as the key step that allows its synthesis on gram scales. The configuration of the double bond is fixed in the starting material.

    References and Notes

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17

Ethyl ( E )-3-Methylpenta-2,4-dienoate(2): A solution of
n-butyllithium (1.6 M in hexane, 14.4 mL, 23 mmol) was added dropwise at -78 ˚C to a solution of methyltriphenyl-phosphonium bromide (8.1 g, 22.7 mmol) in absolute THF (75 mL). The mixture was brought to 0 ˚C and stirred for 1 h. After cooling to -78 ˚C, ethyl (E)-3-methyl-4-oxo-2-butenoate (1; 3 g, 21.1 mmol) dissolved in absolute THF (30 mL) was added slowly. The mixture was stirred for 24 h at r.t., hydrolyzed with water, and extracted three times with Et2O. The combined organic phases were dried with MgSO4 and the solvent was removed. The residue was purified by flash chromatography (pentane-Et2O, 40:1) to give 2 (83% yield, 2.43 g, 17.3 mmol). TLC: R f  = 0.24 (pentane-Et2O, 40:1); ¹H NMR (400 MHz, CDCl3):  = 6.30-6.37 (ddd, J = 17.4, 10.6, 0.8 Hz, 1 H, CH), 5.74-5.71 (m, 1 H, CH), 5.54 (d, J = 17.4 Hz, 1 H, CH), 5.31 (d, J = 10.6 Hz, 1 H, CH), 4.11 (q, J = 7.2 Hz, 2 H, CH2), 2.20 (d, J = 1.3 Hz, 3 H, CH3), 1.22 (t, J = 7.1 Hz, 3 H, CH3); ¹³C NMR (100 MHz, CDCl3): δ = 167.0 (s), 151.9 (s), 140.2 (d), 120.0 (d), 119.3 (t), 59.8 (t), 14.3 (q), 13.1 (q); MS (EI, 70 eV): m/z (%) = 140 (54)[M+], 112 (78), 111 (76), 97 (41), 96 (12), 95 (100), 83 (10), 69 (17), 67 (91), 66 (27), 65 (35), 56 (12), 55 (13), 51 (13), 41 (60), 40 (13), 39 (57).
( E )-3-Methylpenta-2,4-dien-1-ol (3): Ethyl (E)-3-methylpenta-2,4-dienoate (2; 2.18 g, 15.57 mmol) was added to a suspension of LiAlH4 (913 mg, 24 mmol) in absolute Et2O (45 mL) under a N2 atmosphere. The mixture was heated to reflux for 1 h and quenched by the addition of ice-cooled H2O. The residue formed was dissolved by addition of 10% H2SO4. The phases were separated and the aqueous phase was washed with Et2O. The combined organic phases were dried with MgSO4 and the solvent was removed in vacuo. The residue of (E)-3-methylpenta-2,4-dien-1-ol (3; 1.53 g, 15.57 mmol, 100% yield) was sufficiently pure for use in the next step. ¹H NMR (400 MHz, CDCl3): δ = 6.45-6.33 (m, 1 H, CH), 5.73-5.63 (m, 1 H, CH), 5.22 (d, J = 16.9 Hz, 1 H, CH), 5.07 (d, J = 10.6 Hz, 1 H, CH), 4.29 (d, J = 6.8 Hz, 2 H, CH2), 1.82-1.77 (m, 3 H, CH3), 1.45 (br. s., 1 H, OH); ¹³C NMR (100 MHz, CDCl3): δ = 140.7 (d), 136.4 (s), 130.4 (d), 113.2 (t), 59.4 (t), 11.8 (q); MS (EI, 70 eV): m/z (%) = 98 (30)[M+], 97 (11), 83 (83), 80 (23), 79 (44), 70 (37), 69 (85), 65 (17), 55 (100), 53 (47), 51 (27), 43 (35), 41 (81), 39 (70).
( E )-5-Bromo-3-methylpenta-1,3-diene (4): Tribromophosphine (1.5 mL, 4.2 g, 15 mmol) was added dropwise at 0 ˚C to a solution of (E)-3-methylpenta-2,4-dien-1-ol (3; 2.67 g, 27.2 mmol) in absolute Et2O (100 mL) under a N2 atmosphere. An additional identical portion of tribromophosphine was added after 30 min if starting material was still present (TLC). After 30 min, the mixture was diluted by addition of Et2O (50 mL) and hydrolyzed by addition of brine (100 mL). The organic phase was separated and dried with MgSO4. The resulting (E)-5-bromo-3-methylpenta-1,3-diene (4; 4.38 g, 27.2 mmol, 10.2 mmol, 100% yield) was sufficiently pure for use in the next step. Because of its instability during purification, the compound was directly used in the following coupling reaction. The
E/Z ratio was 97:3 (GC). ¹H NMR (400 MHz, CDCl3): δ = 6.37 (ddd, J = 17.4, 10.7, 0.8 Hz, 1 H, CH), 5.78 (t, J = 8.8 Hz, 1 H, CH), 5.30 (d, J = 17.4 Hz, 1 H, CH), 5.12 (d, J = 10.6 Hz, 1 H, CH), 4.13 (d, J = 8.8 Hz, 2 H, CH2), 1.84 (d, J = 1.3 Hz, 3 H, CH3); ¹³C NMR (100 MHz, CDCl3): δ = 140.1 (d), 139.8 (s), 126.7 (d), 114.8 (t), 28.9 (t), 11.4 (q); MS (EI, 70 eV): m/z (%) = 162 (5), 160 (5), 82 (7), 81 (100), 80 (11), 79 (33), 77 (9), 66 (9), 65 (8), 55 (5), 53 (27), 52 (7), 51 (11), 50 (8), 41 (21), 39 (18).
( E )-β-Ocimene (5): A solution of (E)-5-bromo-3-methyl-penta-1,3-diene (4; 4.38 g, 27.2 mmol) in absolute 1,2-dimethoxyethane (8 mL) was treated with dilithium tetrachlorocuprate(II) (0.1 M in THF, 10.8 mL, 1.08 mmol). A solution of 2-methyl-1-propenylmagnesium bromide (0.5 M in THF, 70 mL, 35 mmol) was added at 0 ˚C and the mixture was stirred for 45 min. After an additional stirring period of 18 h at r.t., ice-cooled H2O was added. The organic phase was washed with sat. NH4Cl, and the aqueous phase was extracted three times with pentane. The combined organic phases were dried with MgSO4 and the solvent was removed. The product was purified by flash chromatography on silica(pentane). Pure (E)-β-ocimene (2.53 g, 18.6 mmol, 68% yield) was obtained in an E/Z ratio of 96:4 (GC). If needed, the E/Z ratio can be further enhanced by using argentation chromatography (5% AgNO3 on silica in the dark) with pentane as solvent, but significant loss of material has to be considered. TLC: R f  = 0.75 (pentane); ¹H NMR (400 MHz, CDCl3): δ = 6.42-6.31 (m, 1 H, CH), 5.45 (t, J = 7.5 Hz, 1 H, CH), 5.15-5.05 (m, 2 H, 2 × CH), 4.93 (d, J = 10.9 Hz, 1 H, CH), 2.82 (t, J = 7.2 Hz, 2 H, CH2), 1.78-1.74 (m, 3 H, CH3), 1.70 (d, J = 1.3 Hz, 3 H, CH3), 1.64 (d, J = 0.6 Hz, 3 H, CH3); ¹³C NMR (100 MHz, CDCl3, TMS): δ = 141.5 (d), 133.7 (s), 132.2 (s), 131.8  (d), 122.2 (d), 110.6 (t), 27.3 (t), 25.7 (q), 17.7 (q), 11.6 (q); MS (EI, 70 eV): m/z (%) = 136 (6), 121 (17), 107 (8), 105 (21), 93 (100), 92 (25), 91 (55), 80 (33), 79 (51), 77 (42), 67 (13), 65 (12), 53 (20), 51 (11), 41 (32), 39 (32).