Easy access to (E) β-ocimene

Article abstract of DOI:10.1055/s-0031-1289869

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. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289869

LETTER
2831
Easy Access to (E)-b-Ocimene
E
asyAccess to
e
(
E
)-b-Oci
l
mene ma 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
Received 23 September 2011
mixtures of products.13 A synthesis developed by Nozaki
et al. converts protected geraniol into a diol via an ep-
oxide, and finally furnishes 5 by elimination.14
Abstract: b-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 in-
volving 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.
Because we needed 5 for several experiments and had re-
ceived requests from other research groups, we developed
a simple procedure to obtain gram quantities of pure (E)-
b-ocimene, which is useful for further research, especially
in chemical ecology.
Key words: terpenoids, Grignard reaction, alkenes, hydrocarbons,
coupling
Initial attempts at the synthesis of 5 via 2,6-dimethyl-2,5-
heptadienal and Wittig methenylation were not satisfacto-
ry because of low E/Z selectivity and/or low yields. There-
fore, we decided to introduce the conjugated double bond
system early in the synthesis (Scheme 1). The terpene
building block 1 is commercially available in stereochem-
ically pure form. Wittig reaction with methyltriphe-
nylphosphonium bromide furnishes the diene ester 2. The
ester can be quantitatively reduced with LiAlH4 and con-
verted into bromide 4 by treatment with PBr3. This proce-
dure is more convenient than the reported Appel
bromination15 because both column chromatography and
Kugelrohr distillation of this sensitive bromide can be
avoided. Finally, cross-coupling of 3 with commercially
available 2-methyl-1-propenylmagnesium bromide under
catalysis of Li2CuCl4 furnished (E)-b-ocimene (5) in good
yield. The E/Z ratio was determined to be 96:4 by GC
analysis. Careful analysis by GC showed that slight
isomerization can take place during the bromination and
cross-coupling steps, leading to the observed isomer ratio.
The stereochemical purity of 5 can be further enhanced by
argentation chromatography.16 An extension of the meth-
odology to the synthesis of (2E,6E)-a-farnesene failed be-
cause we could not obtain a Grignard reagent from 1-
(E)-b-Ocimene (5) is an acyclic monoterpene that is a
widespread component of many essential oils. It is one of
the most common flower volatiles known, occurring in
more than 70% of plant families investigated.1,2 In this
context, it often functions as a pollination attractant of in-
sects, together with other compounds.2,3 Ocimene also
plays important roles in chemical communication and
trophic interactions. Several herbivores induce (E)-b-
ocimene production in the host plant when feeding,4
neighboring undamaged plants can thus be stimulated to
enhance their own emission of volatiles.5 These volatile
signals indicating presence of herbivores can be exploited
by parasitoids of the herbivores.2,6,7 Male Heliconius mel-
pomene butterflies use 5 as an antiaphrodisiac pheromone
during courtship,8 and it is also produced by other insects,9
but no function has been described in these cases.
Pure and easily available compounds are a prerequisite for
biological testing and are needed as analytical reference
material. Unfortunately, 5 is only commercially available
as a mixture of isomers, and not in pure form. (E)-b-
Ocimene has been synthesized repeatedly, but a short, re-
liable and easy to reproduce synthesis is missing. An early
metal-organic synthesis developed by Huo and Negishi,
starting from geranyl acetate,10 furnished ocimene in one
step by treatment with propargyl zinc bromide. However,
instead of the reported 75:25 E/Z mixture, the opposite,
29:71 E/Z ratio, was obtained in moderate yield in our
hands. A related reaction using an allylindium reagent and
palladium catalysis furnished 5 in good yield from ethyl
geranyl carbonate, but no data on the E/Z ratio were re-
ported.11 Several substrates were tested for elimination re-
actions with allylpalladium reagents, but, again, mixtures
of stereo- and regioisomers were formed.12 Various proce-
dures using thermal or other elimination protocols starting
from linalool, pinene, or geraniol usually furnished only
O
O
MePPh3Br, n-BuLi
O
O
O
83%
1
2
LiAlH4
100%
PBr3
OH
Br
100%
3
4
Li2CuCl4
68%
MgBr
5
SYNLETT 2011, No. 19, pp 2831–2833
Advanced online publication: 11.11.2011
x
x
.x
x
.2
0
1
1
E/Z 96:4
DOI: 10.1055/s-0031-1289869; Art ID: B08311ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

2832
S. Yildizan, S. Schulz
LETTER
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: Rf = 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):
d = 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).
bromo-2,6-dimethylhept-1-ene, which was needed as a
precursor.
In essence, the described synthesis17 can be easily handled
even in less experienced laboratories and opens the way
for more investigations into the effects of this terpene in
Nature.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank the State of Lower Saxony for funding and Marin
Stürminger for technical assistance.
(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
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, L. N.;
Liu, H.-W., Eds.; Elsevier: Oxford, 2010, 563.
(3) Kessler, D.; Baldwin, I. T. Plant J. 2007, 49, 840.
(4) (a) Pare, P. W.; Tumlinson, J. H. Plant Physiol. 1997, 114,
1161. (b) Navia-Gine, W. G.; Yuan, J. S.; Mauromoustakos,
A.; Murphy, J. B.; Chen, F.; Korth, K. L. Plant Physiol.
Biochem. (Issy-les-Moulineaux, Fr.) 2009, 47, 416.
(5) (a) Kost, C.; Heil, M. J. Ecol. 2006, 94, 619. (b) Piesik, D.;
Lyszczarz, A.; Tabaka, P.; Lamparski, R.; Bocianowski, J.;
Delaney, K. J. Ann. Appl. Biol. 2010, 157, 425.
sufficiently pure for use in the next step. 1H NMR (400
MHz, CDCl3): d = 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): d = 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).
(6) Khan, Z. R.; James, D. G.; Midega, C. A. O.; Pickett, J. A.
Biol. Control 2008, 45, 210.
(E)-5-Bromo-3-methylpenta-1,3-diene (4):
(7) (a) Du, Y.; Poppy, G. M.; Powell, W.; Pickett, J. A.;
Wadhams, L. J.; Woodcock, C. M. J. Chem. Ecol. 1998, 24,
1355. (b) Mumm, R.; Dicke, M. Can. J. Zool. 2010, 88, 628.
(8) Schulz, S.; Estrada, C.; Yildizhan, S.; Boppré, M. L.;
Gilbert, E. J. Chem. Ecol. 2008, 34, 82.
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):
d = 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):
d = 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).
(9) Keegans, S. J.; Billen, J.; Morgan, E. D.; Gokcen, O. A.
J. Chem. Ecol. 1993, 19, 2705.
(10) Matsushita, H.; Negishi, E. J. Org. Chem. 1982, 47, 4161.
(11) Lee, P. H.; 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.
(13) (a) Majetich, G.; Hicks, R.; Okha, F. New J. Chem. 1999, 23,
129. (b) Singh, S. A.; Kabiraj, S.; Khandare, R. P.;
Nalawade, S. P.; Upar, K. B.; Bhat, S. V. Synth. Commun.
2010, 40, 74. (c) Reddy, P. V.; Bhat, S. V. J. Indian Chem.
Soc. 1998, 75, 10.
(14) (a) Tanaka, S.; Yasuda, A.; Yamamoto, H.; Nozaki, H.
J. Am. Chem. Soc. 1975, 97, 3252. (b) Yasuda, A.; Tanaka,
S.; Yamamoto, H.; Nozaki, H. Bull. Chem. Soc. Jpn. 1979,
52, 1752.
(15) Wu, Z.; Wouters, J.; Poulter, C. D. J. Am. Chem. Soc. 2005,
127, 17433.
(E)-b-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
(16) Williams, C. M.; Mander, L. N. 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
Synlett 2011, No. 19, 2831–2833 © Thieme Stuttgart · New York

LETTER
was extracted three times with pentane. The combined
Easy Access to (E)-b-Ocimene
2833
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):
d = 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).
organic phases were dried with MgSO4 and the solvent was
removed. The product was purified by flash chromatography
on silica(pentane). Pure (E)-b-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: Rf = 0.75 (pentane); 1H NMR
(400 MHz, CDCl3): d = 6.42–6.31 (m, 1 H, CH), 5.45 (t, J =
Synlett 2011, No. 19, 2831–2833 © Thieme Stuttgart · New York

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