Practical and scalable synthesis of (Z)-9-Tricosene, the housefly sex pheromone

Article abstract of DOI:10.2174/157017812803521199

A practical and scalable synthesis of (Z)-9-tricosene, the sex pheromone of the housefly, has been achieved by the addition of one-carbon unit from the readily available (Z)-erucic acid. The synthesis is composed of three consecutive steps, lithium aluminium hydride reduction of erucic acid, tosylation of the resulting alcohol, and copper-catalyzed Kumada- type cross-coupling of the tosylate with methylmagnesium bromide as the key step. This approach is quite straightforward and capable of scale-up synthesis.

Full text of DOI:10.2174/157017812803521199

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628
Letters in Organic Chemistry, 2012, 9, 628-631
Practical and Scalable Synthesis of (Z)-9-Tricosene, the Housefly Sex
Pheromone
Miri Kim,a,b Arigala Pitchaiah,a No-Joong Park,a In Taek Hwanga and Kee-In Leea,b*
aGreen Chemistry Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong, Taejon 305-600,
Korea
bGreen Chemistry and Environmental Biotechnology Major, University of Science & Technology, Taejon 305-333,
Korea
Received February 29, 2012: Revised August 09, 2012: Accepted August 10, 2012
Abstract: A practical and scalable synthesis of (Z)-9-tricosene, the sex pheromone of the housefly, has been achieved by
the addition of one-carbon unit from the readily available (Z)-erucic acid. The synthesis is composed of three consecutive
steps, lithium aluminium hydride reduction of erucic acid, tosylation of the resulting alcohol, and copper-catalyzed Ku-
mada-type cross-coupling of the tosylate with methylmagnesium bromide as the key step. This approach is quite straight-
forward and capable of scale-up synthesis.
Keywords: (Z)-9-Tricosene, biochemical pesticide, erucic acid, housefly, kumada cross-coupling, sex pheromone.
INTRODUCTION
was identified as (Z)-9-tricosene [2]. Later several sex-
related pheromones in the housefly were also identified and
the structures are depicted in Fig. (1). A number of studies
have figured out that (Z)-9-tricosene 1 serves as a major
component in the sex pheromones, and it can be modified to
the corresponding oxygenated congeners (2 and 3) and ho-
mologated to the chain isomers (4 and 5) during hydrocarbon
biosynthesis [3]. In addition, field evaluations have proved
that (Z)-9-tricosene is the most active component [4]. The
attractant (Z)-9-tricosene, commonly called muscalure, is
Biochemical pesticides are naturally occurring substances
that control pests by non-toxic mechanisms and can substan-
tially decrease the use of conventional pesticides. The bio-
chemical pesticides such as insect sex pheromones are effec-
tive against only the target pest and closely related organ-
isms in very small quantities, thereby resulting in lower ex-
posures and largely avoiding the pollution problems caused
by the conventional pesticides [1].
H
H
(Z)-9-tricosene 1 (muscalure)
H
H
O
O
(Z)-14-tricosen-10-one 3
cis-9,10-epoxytricosane 2
H
H
H
H
(Z)-9-pentacosene 4
(Z)-9-heptacosene 5
Fig. (1). Common female housefly sex pheromones.
The hydrocarbon sex pheromone of the female housefly
Musca domestica was isolated by Carlson et al. in 1971 and
currently registered as a biochemical pest control agent for
use to get rid of houseflies, stable flies, eye gnats, and horse
flies [5]. Owing to the substantial importance of muscalure
in ecology-based pest management, an adequate supply from
an economical synthesis is desirable.
*Address correspondence to this author at the Green Chemistry Division,
Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong,
Taejon 305-600, Korea; Tel: +82 42 860 7186; Fax: +82 42 860 7034;
E-mail: kilee@krict.re.kr
The synthesis of (Z)-9-tricosene as a mixture of 85% of
(Z)- and 15% of (E)-isomer was firstly reported by Carlson,
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

Practical and Scalable Synthesis of (Z)-9-tricosene
Letters in Organic Chemistry, 2012, Vol. 9, No. 9
629
H
H
H
H
MeLi, o-phenanthroline, Et2O
N2H2, KOH, diethylene glycol
H3C(H2C)7C C(CH2)11COOH
H3C(H2C)7C C(CH2)11COCH3
1
200 oC, 4 h
rt, 30 min
(Z)-erucic acid 6
7
Scheme 1. Previous synthesis of (Z)-9-tricosene from (Z)-erucic acid via Wolf-Kishner reduction of ketone 7 [11a].
H
H
H
H
LiAlH4
H3C(H2C)7C C(CH2)11CH2OH
H3C(H2C)7C C(CH2)11COOH
Et2O, rt, 2h
8 (96%)
6
CuI (5 mol%)
MeMgBr
H
H
H
H
TsCl, pyridine
CH2Cl2, rt, 12h
H3C(H2C)7C C(CH2)11CH2CH3
H3C(H2C)7C C(CH2)11CH2OTs
THF, rt, 2h
1 (90%)
9 (94%)
Scheme 2. Synthesis of (Z)-9-tricosene 1.
utilizing a Wittig reaction of 1-bromotetradecane and
nonanal [2a]. Until now, several efficient methods have been
published for the stereoselective synthesis of the pheromone.
These mainly include Wittig-type olefination of aldehydes
and phosphorane derivatives [2a, 6], alkylation of alkynes
followed by partial hydrogenation [7], and metathesis of
olefins [8]. However, the methods are not likely to be scal-
able because they use expensive materials, require a more
sophisticated reaction control, and sometimes suffer from
E/Z-selectivity. In turn, there have been reports on the syn-
thesis through utilization of biologically available materials
such as jojoba wax [9], oleic acid derivatives [10], and erucic
acid [11].
Reduction of (Z)-erucic acid 6 with lithium aluminium
hydride in diethyl ether at room temperature gave erucyl
alcohol in 96% yield. Then, alcohol 8 was smoothly con-
verted to erucyl p-toluenesulfonate 9 in 94% yield, by the
treatment with tosyl chloride and pyridine in methylene chlo-
ride at ambient temperature. The final installation could be
efficiently achieved via copper-catalyzed Kumada-type
cross-coupling reaction of the tosylate with methyl Grignard
[16]. After considerable experimentation, we found that cop-
per(I) iodide is the catalyst of choice and 5 mol% of the cata-
lyst is sufficient for the coupling reaction of 9 with methyl-
magnesium bromide to afford (Z)-9-tricosene 1 in 90% yield
(Scheme 2). The whole synthesis was double checked and
the spectroscopic data were exactly matched with those of an
authentic sample in all regards.
In order to secure a substantial amount, we need a
greener, cheaper, and more reliable method for the synthesis
of muscalure. Herein we report a practical and scalable syn-
thesis of (Z)-9-tricosene from the bio-origin material (Z)-
erucic acid as a greener way.
In conclusion, we have developed a convenient and prac-
tical synthesis of the sex pheromone of the female housefly,
(Z)-9-tricosene with quite a straightforward way. The syn-
thesis is based on chain-elongation of (Z)-erucic acid by the
one-carbon addition, employing copper-catalyzed Kumada-
type cross coupling reaction of erucyl tosylate with methyl-
magnesium bromide. The use of bio-origin and the one-
carbon strategy renders our approach green and competitive.
Thus, this approach should obviously be adaptable to a large
scale preparation.
RESULTS AND DISCUSSION
Previously, Cargill et al. reported a very efficient synthe-
sis of (Z)-9-tricosene [11a], where (Z)-erucic acid 6 was
converted into ketone 7 by the treatment of 2 equiv of meth-
yllithium followed by Wolf-Kishner reduction [10a] using
85% hydrazine hydrate with potassium hydroxide in diethyl-
ene glycol (200 °C, 4 h) to give 1 in 82% overall yield
(Scheme 1). The (Z)-erucic acid is produced naturally across
a great range of green plants [12] and is available commer-
cially at low prices [13]. Thus, the choice of the acid made
the synthesis simple and straightforward, because it already
possesses a Z-geometry in the appropriate position. Keeping
in mind the above view, we adopted the second sequence
since it is easy in handling and manipulation. Indeed, many
pheromonal hydrocarbons [9, 10b, 11b, 14] have been fre-
quently synthesized by way of Grignard addition into the
appropriate alkyl halides in the presence of Li2CuCl4 as the
catalyst [15]. We thus ambitioned that copper-catalyzed cou-
pling of halide or tosylate with one-carbon unit would offer
the most reliable synthetic route to 1 as depicted in Scheme 2,
without the use of any dangerous material.
EXPERIMENTAL SECTION
(Z)-Erucic acid (99+% for GC) was obtained from a
commercial supplier. All analytic grade chemicals and anhy-
drous solvents were purchased and used without further puri-
fication. The reactions were monitored by TLC with Merck
silica gel 60 F254 TLC glass plates. All reactions were con-
1
ducted under argon atmosphere. H and 13C NMR spectra
were recorded at 300 MHz and 75 MHz respectively on a
Jeol Eclipse FT 300 MHz Spectrometer in CDCl3 as solvent
using TMS as internal standard and chemical shifts are ex-
pressed as ꢀ ppm. Mass spectra were detected by electronic
impact (EI) and obtained on an Agilent 1100 Series VLL or
JEOL the MStation JMS 700 mass Spectrometer. The E/Z
ratio was determined by GC analysis using HP 5890

630 Letters in Organic Chemistry, 2012, Vol. 9, No. 9
Kim et al.
0
equipped with a FID detector on a 50 m ꢀ 0.2 mm ID, BP-20
capillary column.
carbonate (20 mL) at 0 C. The organic layer was separated
and the aqueous layer was extracted with diethyl ether (2 x
30 mL). The combined organic layer was dried over anhy-
drous magnesium sulfate and concentrated under reduced
pressure to give crude residue. The residue was purified by
passing through a pad of silica gel with hexane to afford 1 as
Synthesis of (Z)-docos-13-en-1-ol (8)
To a suspension of LiAlH4 (1.68 g, 44.3 mmol) in diethyl
1
ether (20 mL) was added (Z)-erucic acid 6 (10.0 g, 29.5
a colorless oil (7.26 g, 90.0%): H NMR (300 MHz, CDCl3)
0
mmol) in diethyl ether (80 mL) dropwise for 15 min at 0 C
ꢁ 5.35 (t, J = 5.7 Hz, 2H), 2.01 (d, J = 4.9 Hz, 4H), 1.58 (d, J
= 1.9 Hz, 2H), 1.39-1.14 (m, 32H), 0.93-0.81 (m, 6H); 13C
NMR (75 MHz, CDCl3) ꢁ 130.05, 32.10, 32.08, 29.95,
29.87, 29.83, 29.74, 29.70, 29.54, 29.50, 27.37, 22.86, 14.26;
EI-HRMS calcd for C23H46: 322.3600, found: 322.3596.
Anal. Calcd for C23H46: C, 85.63; H, 14.37. Found: C, 85.55;
H, 14.79.
under argon atmosphere. The reaction mixture was stirred
vigorously for 2 h at room temperature. Then, the reaction
0
was quenched with ethyl acetate (40 mL) at 0 C and 0.1N
HCl (60 mL). The reaction mass was filtered through a pad
of Celite and washed with ethyl acetate (2 x 20 mL). The
organic layer was separated and the aqueous layer was ex-
tracted with ethyl acetate (2 x 30 mL). The combined organic
layer was washed with brine (2 x 30 mL) and dried over an-
hydrous magnesium sulfate, and concentrated under reduced
CONFLICT OF INTEREST
1
pressure to give 8 as an oil (9.21 g, 96.2%): H NMR (300
The author(s) confirm that this article content has no con-
flicts of interest.
MHz, CDCl3) ꢁ 5.35 (t, J = 4.8 Hz, 2H), 3.63 (t, J = 6.6 Hz,
2H), 2.02 (t, J = 7.4 Hz, 5H), 1.68-1.45 (m, 3H), 1.26 (m,
29H), 0.88 (t, J = 5.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) ꢁ
171.50, 130.10, 64.89, 63.25, 33.0, 32.11, 29.98, 29.90,
29.85, 29.82, 29.77, 29.73, 29.65, 29.52, 29.47, 29.38, 28.80,
27.41, 26.1, 25.95, 22.88, 14.30; EI-HRMS calcd for
C22H44O: 324.3392, found: 324.3389.
ACKNOWLEDGEMENTS
This study was supported by grants from the Ministry for
Food,
Agriculture,
Forestry
and
Fisheries
(109192031CG000) and from the Ministry of Knowledge
Economy (10035574), Republic of Korea. The authors are
deeply indebted to Hyundai Biotech Co., Ltd. for its concern
and support for this study.
Synthesis of (Z)-docos-13-enyl 4-methylbenzenesulfonate
(9)
To a solution of 8 (9.20 g, 28.3 mmol) in dichloro-
methane (120 mL) was added pyridine (6.15 mL, 29.5 mmol)
REFERENCES
0
at 0 C under argon atmosphere. To this solution was added
[1]
(a) Carlson, P.; Luscher, M. Pheromones: a new term for a class of
biologically active substances. Nature 1959, 183, 55-56. (b) Casida,
J.E.; Quistad, G.B. Golden Age of Insecticide Research: Past, Pre-
sent, or Future? Annu. Rev. Entomol., 1998, 43, 1-16.
0
TsCl (8.26g, 43.3 mmol) in dichloromethane (70 mL) at 0 C
and the resulting mixture was allowed to stir vigorously for
12 h at room temperature. To this mixture was introduced
0
[2]
(a) Carlson, D.A.; Mayer, M.S.; Sihacek, D.Z.; James, J.D.;
Beroza, M.; Bierl, B.A. Sex attractant pheromone of the house fly:
Isolation, identification and synthesis. Science, 1971, 174, 76-78.
(b) Carlson, D.A.; Beroza, M. Field evaluations of (Z)-9-tricosene,
a sex attractant pheromone of the house fly. Environ. Entomol.,
1973, 2, 555-559.
6N HCl (120 mL) at 0 C. The organic layer was separated
and the aqueous layer was extracted with dichloromethane (2
x 30 mL). The combined organic layer was washed with
water (2 x 30 mL) and dried over anhydrous magnesium
sulfate, and evaporated under reduced pressure to afford 9 as
oil (12.8 g, 94.5%): 1H NMR (300 MHz, CDCl3) ꢁ 7.78 (d, J
= 7.7 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 5.35 (t, J = 5.2 Hz,
2H), 4.01 (t, J = 6.4 Hz, 2H), 2.45 (s, 3H), 2.01 (m, 4H),
1.68-1.57 (m, 4H), 1.39-1.14 (m, 28H), 0.93-0.82 (m, 3H);
13C NMR (75 MHz, CDCl3) ꢁ 144.81, 133.46, 130.42,
130.12, 130.08, 129.99, 128.09, 70.91, 32.11, 29.98, 29.82,
29.80, 29.76, 29.73, 29.71, 29.59, 29.52, 29.14, 29.02, 27.41,
25.53, 22.89, 21.83, 14.32; EI-HRMS calcd for C29H50O3S:
478.3481, found: 478.3480.
[3]
(a) Dillwith, J.W.; Blomquist, G.J. Experientia 1982, 38, 471-473;
(b) La-France, D.; Shani, A.; Margalit, J. J. Chem. Ecol., 1989, 15,
1475-1490; (c) Mpuru, S.; Blomquist, G.J.; Schal, C.; Roux, M.;
Kuenzli, M.; Dusticier, G.; Clément, J.-L.; Bagnères, A.-G. Insect.
Biochem. Mol. Biol., 2001, 31, 139-155; (d) Hanley, M.E.; Dunn,
D.W.; Abolins, S.R.; Goulson, D. JEN, 2004, 128, 478-482.
Veal, L.; Bath, C.; Hutcheson, D. A comparison of the attractive-
ness towards house flies of two lamps used in insect electrocuting
traps. Int. J. Environm. Health. Res., 1995, 5, 247-254.
[4]
[5]
[6]
[7]
U.S.
EPA
Product
Reg
No;
7319-5;
Access
/day/government/shared/11454630/-Z-9- Tricosene-103201-Fact-
Sheet-Pesticides-US-EPA.
Bestmann, H.J.; Vostrowsky, O.; Platz, H. Eine stereoselektive
synthese des sexuallockstoffes der stubenfliege (Musca domestica).
Chem. Unserer Zeit, 1974, 98, 161-162.
(a) Eiter, K. Neue synthese des tricosen-(9-cis) ("muscalure"), eines
attraktivstoffes der hausfliege. Naturwissenschaften, 1972, 59, 468-
469. (b) Kovalev, B.G.; Stan, V.V.; Antoch, T.K.; Konyukhov,
V.P.; Nedopekina, S.F. Synthetic studies of attracting substances
(sexual attractants) of insects. III. Convenient method of preparing
higher dialkylacetylenes. Synthesis of muscalure, the attractant of
the housefly Musca domestica. Zh. Org. Khim., 1977, 13, 2049-
2052.
Synthesis of (Z)-tricos-9-ene (1)
In a 250 mL flame-dried flask, copper(I) iodide (0.23 g,
1.20 mmol) was activated by flame under argon atmosphere.
0
The resulting solid was dissolved in THF (30 mL) at 0 C.
To this cooled solution, 3M MeMgBr in diethyl ether (33.4
mL, 100.2 mmol) was added dropwise over 10 min. During
the addition, the yellow color of the solution changed to col-
orless. After 10 min, 9 (12.0 g, 25.0 mmol) in THF (80 mL)
[8]
(a) Küpper, F.W.; Streck, R. Synthesis of insect attractants by
metathesis catalysts. Z. Naturforsch., 1976, 31b, 1256-1264. (b)
Nakamura, R.; Echigoya, E. Metathesis of oleyl chloride. Chem.
Lett., 1977, 1227-1230.
0
was added to the solution at 0 C. The reaction mixture was
stirred for 2 h at room temperature. Then, the reaction mix-
ture was quenched with 5% aqueous solution of sodium bi-

Practical and Scalable Synthesis of (Z)-9-tricosene
Letters in Organic Chemistry, 2012, Vol. 9, No. 9
631
[9]
(a) Shani, A. An efficient synthesis of muscalure from jojoba oil or
oleyl alcohol. J. Chem. Ecol. 1979, 5, 557-564. (b) La-France, D.;
Shani, A.; Margalit, J. Biological activity of synthetic hydrocarbon
mixtures of cuticular components of the female housefly (Musca
domestica L). J. Chem. Ecol., 1989, 15, 1475-1490.
(a) Ho, T.-L.; Wong, C. M. A synthesis of muscalure, the housefly
sex attractant. Can. J. Chem., 1974, 52, 1923-1924. (b) Verba,
G.G.; Abdukakharov, V.S.; Abduvakhabov, A.A. Synthesis of
muscalure - the pheromone of Musca domestica. Chem. Nat. Comp.,
1985, 21, 655-675.
[12]
[13]
[14]
Sahasrabudhe, M. R. Crismer values and erucic acid contents of
rapeseed oils. J. Am. Oil Chem. Soc., 1977, 54, 323-324.
1Kg costs $191 form SigmaAldrich; http://www.sigmaaldrich.
com/catalog/product/aldrich/45630?lang=en&region=US).
Odinokov, V.N.; Tolstikov, G.A.; Galeyeva, R.I. Kargapol'tseva
T.A. A novel stereospecific synthesis of muscalure, the sex phero-
mone of house fly (Musca Domestica). Tetrahedron Lett., 1982, 23,
1371-1372.
[10]
[11]
[15]
[16]
Tamura, M.; Kochi, J. Coupling of grignard reagents with organic
halides. Synthesis, 1971, 303-305.
(a) Cargill, R.L.; Rosenblum, M.G. Synthesis of the housefly sex
attractant. J. Org. Chem., 1972, 37, 3971. (b) Kang, S.-K.; Lee, D.-
H. A convenient synthesis of (Z)-9-tricosene (muscalure), the
housefly sex pheromone. J. Korean Chem. Soc., 1988, 32, 609-612.
(a) Cahiez, G.; Chaboche, C; Jezequel, M. Cu-catalyzed alkylation
of grignard reagents: a new effcient procedure. Tetrahedron, 2000,
56, 2733-2737. (b) Frisch, A.C.; Beller, M. Catalysts for cross-
coupling reactions with non-activated alkyl halides. Angew. Chem.,
Int. Ed., 2005, 44, 674-688.