Easy Access to (E)-β-Ocimene

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.

terpenoids - Grignard reaction - alkenes - hydrocarbons - coupling

References and Notes

1 Knudsen J. Eriksson R. Gershenzon J. Ståhl B. Botan. Rev.  2006,  72:  1 

2 Honda K. Omura H. Hori M. Kainoh Y. In Comprehensive Natural Products II   Vol. 4:  Mander LN. Liu H.-W. Elsevier; Oxford: 2010.  p.563 

3 Kessler D. Baldwin IT. Plant J.  2007,  49:  840 

4a Pare PW. Tumlinson JH. Plant Physiol.  1997,  114:  1161 

4b Navia-Gine WG. Yuan JS. Mauromoustakos A. Murphy JB. Chen F. Korth KL. Plant Physiol. Biochem. (Issy-les-Moulineaux, Fr.)  2009,  47:  416 

5a Kost C. Heil M. J. Ecol.  2006,  94:  619 

5b Piesik D. Lyszczarz A. Tabaka P. Lamparski R. Bocianowski J. Delaney KJ. Ann. Appl. Biol.  2010,  157:  425 

6 Khan ZR. James DG. Midega CAO. Pickett JA. Biol. Control  2008,  45:  210 

7a Du Y. Poppy GM. Powell W. Pickett JA. Wadhams LJ. Woodcock CM. J. Chem. Ecol.  1998,  24:  1355 

7b Mumm R. Dicke M. Can. J. Zool.  2010,  88:  628 

8 Schulz S. Estrada C. Yildizhan S. Boppré ML. Gilbert E. J. Chem. Ecol.  2008,  34:  82 

9 Keegans SJ. Billen J. Morgan ED. Gokcen OA. J. Chem. Ecol.  1993,  19:  2705 

10 Matsushita H. Negishi E. J. Org. Chem.  1982,  47:  4161 

11 Lee PH. Shim E. Lee K. Seomoon D. Sundae K. Bull. Korean Chem. Soc.  2005,  26:  157 

12 Keinan E. Kumar S. Dangur V. Vaya J. J. Am. Chem. Soc.  1994,  116:  11151 

13a Majetich G. Hicks R. Okha F. New J. Chem.  1999,  23:  129 

13b Singh SA. Kabiraj S. Khandare RP. Nalawade SP. Upar KB. Bhat SV. Synth. Commun.  2010,  40:  74 

13c Reddy PV. Bhat SV. J. Indian Chem. Soc.  1998,  75:  10 

14a Tanaka S. Yasuda A. Yamamoto H. Nozaki H.
J. Am. Chem. Soc.  1975,  97:  3252 

14b Yasuda A. Tanaka S. Yamamoto H. Nozaki H. Bull. Chem. Soc. Jpn.  1979,  52:  1752 

15 Wu Z. Wouters J. Poulter CD. J. Am. Chem. Soc.  2005,  127:  17433 

16 Williams CM. Mander LN. Tetrahedron  2001,  57:  425 

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).