Concise preparation of the (3E,5Z)-alkadienyl system. New approach to the synthesis of principal insect sex pheromone constituents

Article abstract of DOI:10.1021/jf049406b

A new rapid and low-cost preparation of the (3E,5Z)-3,5-alkadienyl system, encountered in several insect pheromone constituents, was developed. Knoevenagel condensation of (E)-2-alkenals with ethyl hydrogen malonate in dimethyl sulfoxide, in the presence of a catalytic amount of piperidinium acetate, led to a mixture of geometrical isomers of ethyl 3,5-alkadienoates and ethyl 2,4-alkadienoates, from which the (3E,5Z)-3,5-alkadienoate was conveniently separated, by the use of urea inclusion complex formation. The importance of this procedure has been illustrated by the preparation of the (3E,5Z)-3,5-tetradecadienoic acid (megatomoic acid) 1, the (3E,5Z)-3,5- dodecadienyl acetate 2, and the (3E,5Z)-3,5-tetradecadienyl acetate 3. These compounds are the main components of insect sex pheromones and constitute synthetic targets of considerable interest for the semiochemical community.

Full text of DOI:10.1021/jf049406b

J. Agric. Food Chem. 2004, 52, 5047−5051 5047
Concise Preparation of the (3E,5Z)-Alkadienyl System. New
Approach to the Synthesis of Principal Insect Sex Pheromone
Constituents
‡
VALENTINE RAGOUSSIS,*,† MARIA PANOPOULOU,† AND NIKITAS RAGOUSSIS
Department of Chemistry, Laboratory of Organic Chemistry, University of Athens, Panepistimiopolis
Zographou, 157 71 Athens, Greece, and VIORYL S.A., Research Department,
28th Km Athens-Lamia Nat. Road, 19014 Afidnes, Greece
A new rapid and low-cost preparation of the (3E,5Z)-3,5-alkadienyl system, encountered in several
insect pheromone constituents, was developed. Knoevenagel condensation of (E)-2-alkenals with
ethyl hydrogen malonate in dimethyl sulfoxide, in the presence of a catalytic amount of piperidinium
acetate, led to a mixture of geometrical isomers of ethyl 3,5-alkadienoates and ethyl 2,4-alkadienoates,
from which the (3E,5Z)-3,5-alkadienoate was conveniently separated, by the use of urea inclusion
complex formation. The importance of this procedure has been illustrated by the preparation of the
(3E,5Z)-3,5-tetradecadienoic acid (megatomoic acid) 1, the (3E,5Z)-3,5-dodecadienyl acetate 2, and
the (3E,5Z)-3,5-tetradecadienyl acetate 3. These compounds are the main components of insect
sex pheromones and constitute synthetic targets of considerable interest for the semiochemical
community.
KEYWORDS: Knoevenagel condensation; pheromone synthesis; semiochemicals; megatomoic acid;
Attagenus megatoma; Bonagota cranaodes; Recurvaria leucatella
INTRODUCTION
Conjugated diene compounds, with a 3,5-alkadienoic acid or
3,5-alkadienyl ester moiety, are important insect sex attractants.
Among the existing four geometrical isomers, the (3E,5Z)
configuration has already been encountered in certain insect sex
pheromone constituents. For example, the dienoic acid (3E,5Z)-
3,5-tetradecadienoic acid 1 (Figure 1), to which the trivial name
megatomoic acid was assigned, is the principal component of
the sex pheromone of the female black carpet beetle Attagenus
megatoma Fabricius (Coleoptera: Dermestidae) (1). This insect
is a destructive pest in stored grain and flour and also attacks
fabrics in clothing, rugs, and padding of furniture. The (3E,5Z)-
3,5-dodecadienyl acetate 2 is the main female sex pheromone
component of the leafroller moth, Bonagota cranaodes Meyrick
(Lepidoptera: Tortricidae), the most economically important
insect pest on apples in southern Brasil (2). The (3E,5Z)-3,5-
tetradecadienyl acetate 3 is a male sex attractant for orchard
pests of the white-barred groundling moth RecurVaria leucatella
Clerck (Lepidoptera: Gelechidae) (3), found by a screening
process.
Figure 1. Structures of sex pheromone constituents with the (3E,5Z)-
3,5-alkadienyl fragment.
insects (1-3). Therefore, the development of a simple and
efficient synthetic preparation should make possible the ap-
plication of these chemicals on large-scale field investigations.
Different approaches have been reported for the synthesis of
(3E,5Z)-3,5-alkadienoic acids and alkadienoates. Most of these
procedures involve partial reduction or isomerization of acety-
lenes as the steps to introduce the conjugated diene system (1,
4-9). They also use, as starting material, an adequate 2,4-
dienoate, applying a one carbon homologation (10) or a
deconjugative protonation in basic medium (11, 12). None of
the above-reported methods is practical for a routine synthesis
of the conjugated (3E,5Z)-3,5-alkadienoates. They suffer from
insufficient isomeric purity of the final product, or they require
precursors not readily available. Furthermore, very often they
use reaction conditions and chromatographic separations that
The above compounds (Figure 1), synthetically produced,
were found to attract large numbers of insect males in field tests,
and therefore they can be applied in integrated pest management
programs, for the monitoring or the control of the above noxious
* Corresponding author. Telephone: + 30 210 7274497. Fax: + 30
210 7274761. E-mail: ragousi@chem.uoa.gr.
† University of Athens, Greece.
‡ VIORYL S.A.
10.1021/jf049406b CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/20/2004

5048 J. Agric. Food Chem., Vol. 52, No. 16, 2004
Ragoussis et al.
resulting clear solution was allowed to cool slowly to room temperature,
and a fine white precipitate began to separate. Then the mixture was
left overnight at 4 °C. The precipitate was filtered rapidly and washed
with cold hexane. The crystalline urea clathrates were treated as usual
(17), to give a mixture of ethyl (3E,5E)-3,5-tetradecadienoate and ethyl
(2E,4E)-2,4-tetradecadienoate as a pale yellow oil (6.5 g). The washing
hexane and the filtrates were partially concentrated under a vacuum,
and the resulting mixture was treated with hot (50 °C) water (100 mL)
for 15 min. The mixture was cooled to room temperature and extracted
with diethyl ether. The organic phase was washed with water and dried
over anhydrous Na2SO4, and the solvent was removed under a vacuum,
to give a pale yellow oil (4.6 g) enriched in ethyl (3E,5Z)-3,5-
tetradecadienoate.
The obtained product was subjected to urea treatment one more time,
as previously, to give an oil, which was purified by distillation to give
finally pure ethyl (3E,5Z)-3,5-tetradecadienoate 5d (3.2 g, 21% yield
based on the alkenal used): bp 112-115 °C/0.1 mmHg; IR νmax/cm-1
1741, 983, 950; 1H NMR δ 0.87 (3H, t, J ) 6.8 Hz), 1.22-1.30 (15H,
m), 2.15 (2H, q, J ) 6.8 Hz), 3.12 (2H, d, J ) 6.8 Hz), 4.10 (2H, q,
J ) 6.8 Hz), 5.41 (1H, dt, J1 ) 10.8 Hz, J2 ) 7.7 Hz), 5.72 (1H, dt,
J1 ) 15.0 Hz, J2 ) 7.7 Hz), 5.98 (1H, dd, J1 ) 11.0 Hz, J2 ) 10.8
Hz), 6.41 (1H, ddd J1 ) 15.4 Hz, J2 ) 11.2 Hz, J3 ) 1.3 Hz); MS m/z
252 (M+, 12), 178 (8), 164 (15), 95 (20), 79 (68), 67 (100). Anal.
Calcd for C16H28O2: C, 76.14; H, 11.18. Found: C, 76.05; H, 11.10.
The IR spectrum matched that of the literature (12).
are unsuitable for large-scale low-cost preparations. A pre-
requisite for the practical use of these attractants, in pest
management programs, will be the availability of relatively large
quantities of the pure geometric isomers at a reasonable cost.
In our previous work (13), it was well documented that the
reaction of saturated linear aldehydes with malonic acid or its
derivatives in dimethyl sulfoxide (DMSO) leads stereoselectively
to (E)-3-unsaturated acids, with a regio-selectivity higher than
97%. However, this reaction has not been studied with (E)-2-
alkenals, which seemed to be good precursors for the synthesis
of 3,5-unsaturated acids. So, we sought to extend the use of
this reaction to (E)-2-alkenals, anticipating that a problem with
mixtures of geometrical isomers of 3,5-dienoic acids should be
encountered.
Herein, a fast and experimentally simple procedure for the
preparation of (3E,5Z)-3,5-alkadienoates from (E)-2-alkenals is
reported. The method merely involves Knoevenagel condensa-
tion of an (E)-2-alkenal with ethyl hydrogen malonate in DMSO,
in the presence of piperidinium acetate as a catalyst, to give a
mixture of ethyl alkadienoates. The (3E,5Z)-3,5-alkadienoate
was selectively separated from the mixture of isomers, in high
isomeric purity (95-98%), by formation of urea inclusion
complexes.
Ethyl (3E,5Z)-3,5-Dodecadienoate (5c). This compound was ob-
tained from ethyl hydrogen malonate (11.88 g, 0.09 mol) and (E)-2-
decenal (9.24 g, 0.06 mol) by the typical procedure. The distilled
mixture of esters was subjected to the urea inclusion treatment twice,
to give finally pure ethyl (3E,5Z)-3,5-dodecadienoate 5c (3.4 g, 25%)
as a viscous oil: bp 105-108 °C/0.1 mmHg; IR νmax/cm-1 1741, 983,
950; 1H NMR δ 0.88 (3H, t, J ) 6.8), 1.17-1.30 (11H, m), 2.16 (2H,
q, J ) 6.8 Hz), 3.13 (2H, d, J ) 6.8 Hz), 4.10 (2H, q, J ) 6.8 Hz),
5.42 (1H, dt J1 ) 11.0 Hz, J2 ) 7.7 Hz), 5.73 (1H, dt J1 ) 15.0 Hz,
J2 ) 7.7 Hz), 5.98 (1H, dd J1 ) 11.0 Hz, J2 ) 10.8 Hz), 6.42 (1H, ddd
J1 ) 15.2 Hz, J2 ) 11.2 Hz, J3 ) 1.3 Hz); MS m/z 224 (M+, 15), 150
(10), 136 (22), 95 (17), 79 (64), 67 (100). Anal. Calcd for C14H24O2:
C, 74.95; H, 10.78. Found: C, 74.86; H, 10.76.
MATERIALS AND METHODS
Materials. All commercial reagents and solvents were used as
supplied. All (E)-2-alkenals were a gift from Vioryl S.A. (Athens,
Greece) and were distilled before use. Ethyl hydrogen malonate was
prepared according to the literature (14). Red-AL is a solution of sodium
bis(2-methoxyethoxy)aluminum hydride in toluene 65%, from Sigma-
Aldrich Chemie GmbH (Taufkirchen, Germany). Piperidinium acetate
was prepared in situ, by mixing equivalent quantities of piperidine and
acetic acid in 5 mL of DMSO. Thin-layer chromatography (TLC) was
performed on 0.25 mm precoated silica gel 60 F254 aluminum sheets
and column chromatography on silica gel 60 (0.063-0.2 mm), products
of Merck & Co. (Darmstadt, Germany). IR spectra were obtained on a
Perkin-Elmer 7200 spectrophotometer, in 5% CCl4 solutions. 1H NMR
spectra were recorded on a Varian Mercury 200 MHz spectrometer, in
CDCl3 (with TMS as the internal standard). Gas chromatography-
mass spectrometry (GC-MS) analyses were carried out with a GC-
MS system Shimadzu QP 5050 equipped with a 30 m × 0.25 mm i.d.
SPB-1 fused silica capillary column (carrier gas, helium 1 mL/min;
injector temperature, 230 °C; oven temperature, 50 °C (5 min
isothermal) raised at 4 °C/min up to 250 °C; ion source temperature,
220 °C; interface temperature, 250 °C; mass range, 40-500 amu; EI,
70 eV).
Representative Procedure for the Condensation of (E)-2-Alkenals
with Ethyl Hydrogen Malonate: Synthesis of Ethyl (3E,5Z)-3,5-
Tetradecadienoate (5d). In a round-bottom flask, equipped with a
condenser and a bubbler at the exit of the condenser, a solution of
ethyl hydrogen malonate (11.88 g, 0.09 mol) and piperidinium acetate
(85 mg, 0.6 mmol) in DMSO (60 mL) was stirred at room temperature
for 15 min, and (E)-2-dodecenal (10.92 g, 0.06 mol) was added at once.
Stirring was continued for 30 min, and then the reaction mixture was
heated gently at 85 °C, until the evolution of carbon dioxide ceased (3
h). Heating was continued at the same temperature, for 1 more hour.
After cooling to room temperature, the reaction mixture was poured
into cold water (150 mL) and extracted with diethyl ether (3 × 50
mL). The combined extracts were washed with water (50 mL) and dried
over anhydrous Na2SO4, and the solvent was removed under a vacuum.
The crude product (16.8 g) was distilled, to give a mixture of ethyl
(3E,5Z)-3,5-tetradecadienoate 5d, ethyl (3E,5E)-3,5-tetradecadienoate
6d, and ethyl (2E,4E)-2,4-tetradecadienoate 7d (10.58 g, 70%) as a
colorless oil: bp 104-115 °C/0.5 mmHg.
Ethyl (3E,5Z)-3,5-Decadienoate (5b). This compound was obtained
from ethyl hydrogen malonate (11.88 g, 0.09 mol) and (E)-2-octenal
(7.56 g, 0.06 mol) by the typical procedure. The distilled mixture of
esters was subjected to the urea inclusion treatment, three consecutive
times, to give finally pure ethyl (3E,5Z)-3,5-decadienoate 5b (3.3 g,
28%) as a viscous oil: bp 98-101 °C/0.1 mmHg; IR νmax/cm-1 1740,
1
984, 951; H NMR δ 0.89 (3H, t, J ) 6.8 Hz), 1.17-1.43 (7H, m),
2.15 (2H, q, J ) 6.8 Hz), 3.13 (2H, d, J ) 6.8 Hz), 4.10 (2H, q, J )
6.8 Hz), 5.42 (1H, dt J1 ) 11.0 Hz, J2 ) 7.7 Hz), 5.73 (1H, dt J1 )
15.0 Hz, J2 ) 7.7 Hz), 5.98 (1H, dd J1 ) 11.0 Hz, J2 ) 10.8 Hz), 6.42
(1H, ddd J1 ) 15.2 Hz, J2 ) 11.0 Hz, J3 ) 1.3 Hz); MS m/z 196 (M+,
20), 150 (7), 122 (14), 108 (22), 79 (25), 67 (100). Anal. Calcd for
C12H20O2: C, 73.43; H, 10.27. Found: C, 73.54; H, 10.28.
Ethyl (3E,5Z)-3,5-Octadienoate (5a) (Mixture with Ethyl (3E,5E)-
3,5-Octadienoate). This compound was obtained from ethyl hydrogen
malonate (11.88 g, 0.09 mol) and (E)-2-hexenal (5.88 g, 0.06 mol) by
the typical procedure. The distilled mixture of esters was subjected to
the urea inclusion treatment, four consecutive times, to give finally a
product enriched in ethyl (3E,5Z)-3,5-octadienoate as a viscous oil (3.5
g, 35%), containing a mixture of ethyl (3E,5Z)-3,5-octadienoate and
ethyl (3E,5E)-3,5-octadienoate in a ratio of 3/2: bp 76-90 °C/0.1
mmHg; MS m/z less polar compound ethyl (3E,5Z)-3,5-octadienoate
168 (M+, 44), 122 (5), 98 (4), 79 (42), 67 (100), 55(50); more polar
compound ethyl (3E,5E)-3,5-octadienoate 168 (M+, 33), 122 (2), 95
(100), 79 (28), 67 (80), 55 (40).
(3E,5Z)-3,5-Tetradecadienoic Acid (1) (Megatomoic Acid). To a
cold (0-4 °C) stirred solution of aqueous KOH 1 N (5.6 mL, 5.6 mmol),
a solution of ethyl (3E,5Z)-3,5-tetradecadienoate (140 mg, 0.56 mmol)
in ethanol (2 mL) was added. Stirring was continued at the same
temperature for 4 h, and the reaction was monitored by TLC. When
the starting material was exhausted, the mixture was poured into a cold
solution of HCl 1 N (10 mL) and then was extracted with diethyl ether
(3 × 5 mL). The organic phase was dried over anhydrous Na2SO4 and
Separation of Pure Ethyl (3E,5Z)-3,5-Tetradecadienoate (5d) by
Urea Inclusion Complexes. The obtained mixture of ethyl tetradeca-
dienoates (10.5 g) was added, under vigorous stirring, into a hot (50
°C) solution of urea (30.0 g, 0.50 mol) in methanol (150 mL). The

Simple Synthesis of Insect Sex Pheromones
J. Agric. Food Chem., Vol. 52, No. 16, 2004 5049
the solvent was evaporated under a vacuum, to give pure (3E,5Z)-3,5-
tetradecadienoic acid (megatomoic acid) 1 (113 mg, 90%) as a viscous
oil: IR νmax/cm-1 1712, 983, 950, 827; 1H NMR δ 0.88 (3H, t, J ) 6.8
Hz), 1.26-1.43 (12, m), 2.16 (2H, q, J ) 6.8 Hz), 3.18 (2H, d, J )
10.8 Hz), 5.42 (1H, dt J1 ) 10.8 Hz, J2 ) 7.7 Hz), 5.69 (1H, dt J1 )
15.3 Hz, J2 ) 7.7 Hz), 5.94 (1H, dd J1 ) 11.3 Hz, J2 ) 10.8 Hz), 6.46
1
(1H, ddd J1 ) 15.3 Hz, J2 ) 11.0 Hz, J3 ) 1.3 Hz). The IR and H
NMR spectra matched those of the literature (8).
(3E,5Z)-3,5-Tetradecadienyl Acetate (3). (a) To a cold (0-4 °C)
stirred solution of Red-AL (2.1 mL, 6 mmol) in anhydrous diethyl ether
(5 mL), a solution of ethyl (3E,5Z)-3,5-tetradecadienoate (252 mg, 1
mmol) in diethyl ether (2 mL) was added dropwise under nitrogen.
Stirring was continued for 1 h at the same temperature, and then the
solution was left overnight at room temperature. The end of the reaction
was checked by TLC. The reaction mixture was poured carefully into
a cold 5% solution of HCl (20 mL) and then was extracted with diethyl
ether (3 × 5 mL). The organic phase was dried over anhydrous Na2-
SO4, and the solvent was evaporated under a vacuum. The residue was
purified by column chromatography, over silica gel, to give pure
Figure 2. Condensation of (E)-2-alkenals with ethyl hydrogen malonate
in DMSO, at 85 °C, in the presence of piperidinium acetate.
agent instead of malonic acid, to obtain directly the correspond-
ing ethyl ester, which could be easier isolated from the reaction
mixture by distillation. This condensation was performed in
DMSO, for 4 h at 85 °C, in the presence of a catalytic amount
of piperidinium acetate and, as was expected, gave a mixture
of isomers of ethyl decadienoate, along with other byproducts.
Careful distillation, under a vacuum, of the crude reaction
product gave the mixture of isomeric esters in good yield (71%).
Detailed GC-MS analysis showed the presence of three main
components with the same molecular weight (MW ) 196). The
more polar compound gave a dominant fragment m/z 125,
corresponding to ethyl pyrilium, and also the pyrilium fragments
m/z 97 and m/z 81, characteristic of ethyl (2E,4E)-decadienoate
(17). The two less polar compounds have similar mass spectra,
with fragments at m/z 123 and 122 corresponding to [M -
COOCH2CH3]+ and [M - HCOOCH2CH3]+ and m/z 108
corresponding to [M - CH3COOCH2CH3]+, characteristic of
the ethyl 3,5-alkadienoates (6), suggesting that the two com-
pounds are isomeric ethyl 3,5-decadienoates. On the other hand,
study of the 1H NMR spectrum of the obtained mixture showed
a system of two doublets at 3.07-3.11 and 3.11-3.14 ppm,
which can be attributed to the allylic protons on C2 of two
isomers of the ethyl 3,5-decadienoates (1, 5). A distinct multiplet
at the lower fields 7.11-7.33 ppm can be attributed to the
protons on C3 of the ethyl (2E,4E)-decadienoate (17).
(3E,5Z)-3,5-tetradecadienol (186 mg, 88%) as a viscous oil: IR νmax
/
cm-1 3625, 3390, 2990, 985, 952; H NMR δ 0.88 (3H, t, J ) 6.8
Hz), 1.26-1.40 (12H, m), 2.15 (2H, q, J ) 6.8 Hz), 2.37 (2H, q, J )
6.8 Hz), 3.68 (2H, t, J ) 6.8 Hz), 5.39 (1H, dt J1 ) 10.8 Hz, J2 ) 7.7
Hz), 5.62 (1H, dt J1 ) 15.0 Hz, J2 ) 7.7 Hz), 5.96 (1H, dd J1 ) 11.0
Hz, J2 ) 10.8 Hz), 6.42 (1H, ddd J1 ) 15.4 Hz, J2 ) 11.0 Hz, J3 ) 1.3
1
1
Hz). The H NMR spectrum matched that of the literature (8).
(b) To a solution of acetic anhydride (1.0 mL, 10 mmol) in pyridine
(4.0 mL) at 0-4 °C, (3E,5Z)-3,5-tetradecadienol (160 mg, 0.76 mmol)
was added under stirring. The reaction was maintained at the same
temperature for 1 h and then was brought to room temperature and
monitored by TLC. When the reaction was finished (5 h), the mixture
was poured in cold water (20 mL) and was extracted with diethyl ether.
The organic phase was washed by dilute (5%) HCl and then by saturated
NaHCO3 and dried over anhydrous Na2SO4, and the solvent was
removed under a vacuum. The crude product was purified by column
chromatography over silica gel, to give pure (3E,5Z)-3,5-tetradecadienyl
acetate 3 (160 mg, 84%) as a viscous liquid: IR νmax/cm-1 2990, 1744,
1
984, 950; H NMR δ 0.87 (3H, t, J ) 6.8 Hz), 1.27-1.43 (12H, m),
2.05 (3H, s), 2.16 (2H, q, J ) 6.8 Hz), 2.43 (2H, q, J ) 6.8 Hz), 4.10
(2H, t, J ) 6.8 Hz), 5.39 (1H, dt J1 ) 10.8 Hz, J2 ) 7.7 Hz), 5.60 (1H,
dt J1 ) 15.3 Hz, J2 ) 7.7 Hz), 5.96 (1H, dd J1 ) 11.3 Hz, J2 ) 10.8
Hz), 6.38 (1H, ddd J1 ) 15.2 Hz, J2 ) 11.0 Hz, J3 ) 1.3 Hz); MS m/z
192 (M+ - 60, 26), 138 (3), 93 (23), 80 (100), 79 (92), 67 (28). The
1
On the basis of the H NMR spectrum and the GC-MS
analysis of the obtained mixture, the structures that were
attributed to the three main components were ethyl (3E,5Z)-
3,5-decadienoate 5b, ethyl (3E,5E)-3,5-decadienoate 6b, and
ethyl (2E,4E)-2,4-decadienoate 7b. Other isomers of ethyl
decadienoate, if present, were in quantities less than 0.5%. The
overall condensation of the (E)-2-octenal with ethyl hydrogen
malonate, illustrated in Figure 2, gave in 71% yield a mixture
of ethyl (3E,5Z)-3,5-decadienoate 5b, ethyl (3E,5E)-3,5-deca-
dienoate 6b, and ethyl (2E,4E)-2,4-decadienoate 7b, in a ratio
of 44:38:18, according to the GC analysis.
1
IR and H NMR spectra matched those of the literature (4).
(3E,5Z)-3,5-Dodecadienyl Acetate (2). (a) Reduction of ethyl
(3E,5Z)-3,5-dodecadienoate (450 mg, 2 mmol) by Red-AL (3 mL, 8
mmol) in anhydrous diethyl ether (8 mL), as previously described, gave
pure (3E,5Z)-3,5-dodecadienol (332 mg, 91%) as a viscous oil: IR
ν
max/cm-1 3625, 3350, 2990, 985, 949; 1H NMR δ 0.88 (3H, t, J ) 6.8
Hz), 1.28-1.44 (8H, m), 2.17 (2H, q, J ) 6.8 Hz), 2.38 (2H, q, J )
6.8 Hz), 3.72 (2H, t, J ) 6.8 Hz), 5.37 (1H, dt J1 ) 10.8 Hz, J2 ) 7.7
Hz), 5.63 (1H, dt J1 ) 15.3 Hz, J2 ) 7.7 Hz), 5.96 (1H, dd J1 ) 11.0
Hz, J2 ) 10.8 Hz), 6.42 (1H, ddd J1 ) 15.3 Hz, J2 ) 11.2 Hz, J3 ) 1.3
Hz).
Regarding the reaction conditions, prolongation of the reaction
time from 4 to 8 or more hours and increase of the reaction
temperature from 85 to 120 °C gave a somewhat higher yield
of the mixture of ethyl decadienoates, but the ethyl (3E,5Z)-
3,5-decadienoate 5b was less than 10% and the main product
was the ethyl (2E,4E)-2,4-decadienoate 7b (Table 1, entry 3).
The same reaction conditions were applied to the condensation
of the following aldehydes: (E)-2-hexenal 4a, (E)-2-decenal
4c, and (E)-2-dodecenal 4d. Detailed GC-MS analyses of the
distilled reaction products from any of the above aldehydes gave
similar results to the (E)-2-octenal 4b condensation (Table 1).
Separation of geometrical isomers of 3,5-alkadienyl esters
by preparative column chromatography on silver nitrate im-
pregnated silica gel has been already reported (2a, 18). To avoid
this laborious and expensive procedure, the use of urea inclusion
complexes seemed promising. It is known that formation of urea
inclusion complexes is a useful method for preparative scale
(b) Acetylation of (3E,5Z)-3,5-dodecadienol (182 mg, 1.0 mmol)
by acetic anhydride (1.0 mL, 10 mmol) in pyridine (4.0 mL), as
previously described, gave pure (3E,5Z)-3,5-dodecadienyl acetate 2 (192
1
mg, 86%) as a viscous oil: IR νmax/cm-1 2990, 1744, 984, 950; H
NMR δ 0.87 (3H, t, J ) 6.8 Hz), 1.27-1.43 (8H, m), 2.05 (3H, s),
2.16 (2H, q, J ) 6.8 Hz), 2.43 (2H, q, J ) 6.8 Hz), 4.10 (2H, t, J )
6.8 Hz), 5.39 (1H, dt J1 ) 10.8 Hz, J2 ) 7.7 Hz), 5.60 (1H, dt J1 )
15.3 Hz, J2 ) 7.7 Hz), 5.96 (1H, dd J1 ) 11.3 Hz, J2 ) 10.8 Hz), 6.38
(1H, ddd J1 ) 15.2 Hz, J2 ) 11.0 Hz, J3 ) 1.3 Hz); MS m/z 164 (M+
1
- 60, 41), 110 (6), 93 (28), 80 (100), 79 (94), 67 (30). The H NMR
and mass spectra matched those of the literature (2, 15, 16).
RESULTS AND DISCUSSION
In the beginning of this investigation, the condensation of
(E)-2-octenal with ethyl hydrogen malonate was used as a model
study. Ethyl hydrogen malonate was chosen as the condensation

5050 J. Agric. Food Chem., Vol. 52, No. 16, 2004
Ragoussis et al.
Table 1. Condensation of (E)-2-Alkenals with 50% Excess of Ethyl
Hydrogen Malonate, in the Presence of Piperidinium Acetate (1% mol)
as Catalyst, in DMSO
bp (°C,
0.5 mmHg) 6 + 7 (%)
yielda 5 +
ratiob
5:6:7
entry substr
product
1
2
3
4
5
4a
4b
4b
4c
4d
ethyl octadienoatesc
ethyl decadienoatesc
ethyl decadienoatesd
ethyl dodecadienoatesc
60−80
75−90
75−90
85−100
78
71
75
72
70
42:41:17
44:38:18
8:28:64
39:43:18
37:48:15
Figure 3. Synthesis of megatomoic acid 1 and (3E,5Z)-3,5-tetradecadienyl
acetate 3.
ethyl tetradecadienoatesc 104−115
a Yields refer to the distilled mixture of isomers. b Calculated from the integration
of the GC analyses. c The condensation was performed at 85 °C for 4 h. d The
condensation was performed at 120 °C for 8 h.
In conclusion, the one step preparation of the (3E,5Z)-3,5-
alkadienoates, by the herein described method, is experimentally
easy and efficient. The separation of the (3E,5Z) isomer from
the reaction mixture was easily and conveniently accomplished
by elimination of the (3E,5E) and (2E,4E) isomers by formation
of crystalline urea inclusion complexes. This step eliminates
the necessity for chromatographic separations, making the
technique suitable for large-scale preparation of the biologically
active compounds 1, 2, and 3. The simplicity, rapidity, and low
cost of this procedure make it useful for the semiochemical
community.
Table 2. Separation of Ethyl (3E,5Z)-3,5-Alkadienoates by Formation
of Urea Inclusion Complexes
no. of
treat-
ments
yielda
(%)
isomeric
purity
entry
isolated isomer
1
2
3
4
ethyl (3E,5Z)-3,5 octadienoate
ethyl (3E,5Z)-3,5-decadienoate
ethyl (3E,5Z)-3,5-dodecadienoate
ethyl (3E,5Z)-3,5-tetradecadienoate
4
3
2
2
35.0
28.0
25.3
21.1
60
95
97
98
LITERATURE CITED
a Yield based on the quantity of the starting (E)-2-alkenal.
(1) (a) Silverstein, R. M.; Rodin, J. O.; Burkholder, W. E.; Gorman,
J. E. Sex Attractant of the Black Carpet Beetle. Science 1967,
157, 85-87. (b) Burkholder, W. E. Black Carpet Beetle:
Reduction of Mating by Megatomoic Acid, the Sex Pheromone.
J. Econ. Entomol. 1973, 66, 1327-1331.
(2) (a) Unelius, C. R.; Eiras, A.; Witzgall, P.; Bengtsson, M.;
Kovaleski, A.; Vilela, E. F.; Borg-Karlson, A. K. Identification
and Synthesis of the Sex Pheromone of Phtheochroa cranaodes
(Lepidoptera: Tortricidae). Tetrahedron Lett. 1996, 37, 1505-
1508. (b) Coracini, M. D. A.; Bengtsson, M.; Reckziegel, A.;
Lofqvist, J.; Francke, W.; Vilela, E. F.; Eiras, A. E.; Kovaleski,
A.; Witzgall, P. Identification of a Four-Component Sex
Pheromone Blend in Bonagota cranaodes (Lepidoptera: Tor-
tricidae). J. Econ. Entomol. 2001, 94, 911-914.
separation of individual geometrical isomers from their mixtures
(19). Urea inclusion complexes (clathrates) are formed prefer-
entially with E,E isomers (17), which, as guest molecules, are
held in the channel of the helical lattice of hydrogen bonded
urea molecules. Indeed, in the present work, the (2E,4E) and
(3E,5E) isomers are able to form crystalline complexes with
urea, while the (3E,5Z) isomers remained in solution and were
isolated from the mother liquid. The complexation process was
repeated one or more times, to improve the isomeric purity of
the product. The results of the separations are summarized in
Table 2.
(3) Toth, M.; Doolittle, R. E. Sex Attractants for the White-Barred
Groundling Moth (RecurVaria leucatella Clerck) and the Lesser
Bud Moth (R. nagella Hubner) (Lepidoptera: Gelechidae). J.
Chem. Ecol. 1992, 18, 1093-1105.
(4) Doolittle, R. E.; Solomon, J. D. Stereoselective Synthesis of
(Z,E)-3,5-Tetradecadienyl acetate: Sex Attractant for Car-
penterworm Moth Prionoyistus robiniae (Peck) (Lepidoptera:
Cossidae) and effect of Isomers and Monounsaturated acetates
on Its Attractiveness. J. Chem. Ecol. 1986, 12, 619-633.
(5) Rodin, J. O.; Leaffer, M. A.; Silverstein, R. M. Synthesis of
trans-3,cis-5-Tetradecadienoic Acid (Megatomoic Acid), the Sex
Attractant of Black Carpet Beetle and Its Geometric Isomers. J.
Org. Chem. 1970, 35, 3152-3154.
(6) Abrams, S. R. Isomerization of Acetylenic Acids with Sodium
Salt of 1,2-Diaminoethane: a One Step Synthesis of Megatomoic
Acid. Can. J. Chem. 1982, 60, 1238-1243.
(7) DeJarlais, W. J.; Emken, E. A. New Synthesis of cis-3,cis-5 and
trans-3,cis-5-Tetradecadienoic Acid, Pheromone Constituents of
Attagenus elongatulus and A. megatoma. Lipids 1986, 21, 662-
665.
(8) Yadav, J. S.; Reddy, E. J.; Ramalingam, T. Short-Route Synthesis
of (3E,5Z)-Tetradecadienoic Acid (Megatomoic Acid), the Sex
Attractant of the Black Carpet Beetle. New J. Chem. 2001, 25,
223-225.
(9) Chrelashvili, Z. G.; Mavrov, M. V.; Dolidze, A. V.; Chizhov,
A. O.; Serebryakov, E. P. Synthesis of the Grapevine Moth Sex
Pheromone by Grignard-Schlosser Cross-Coupling: The Effect
of the Electrophile Structure on the Stereoisomeric Ration in
the Reaction Products. Russ. Chem. Bull. 1993, 42, 1090-1094.
Taking into account the above results, it is concluded that
the separation of the (3E,5Z)-3,5-alkadienoates, by the urea
complexation, was more efficient for the products with a longer
chain of carbon atoms. The ethyl (3E,5Z)-3,5-dodecadienoate
5c and the (3E,5Z)-3,5-tetradecadienoate 5d were obtained in
high isomeric purity (97-98%), only with two complexations
with urea. The ethyl (3E,5Z)-3,5-decadienoate 5b was obtained
in 95% isomeric purity, after three complexations, and the ethyl
(3E,5Z)-3,5-octadienoate 5a failed to be isolated in acceptable
isomeric purity, even after four urea complexations.
The utility of the herein described preparation of pure ethyl
(3E,5Z)-3,5-alkadienoates was illustrated by their simple trans-
formations to known principal sex pheromone components.
Thus, the ethyl (3E,5Z)-3,5-tetradecadienoate 5d, by simple
hydrolysis in aqueous KOH, gave the corresponding acid, known
as megatomoic acid 1 (Figure 3). Reduction of the same ethyl
ester 5d, by Red-AL in diethyl ether, gave the corresponding
alcohol, which by acetylation gave in 84% yield the (3E,5Z)-
3,5-tetradecadienyl acetate 3, sex attractant of the R. leucatella
Clerck (Figure 3). Starting from the ethyl (3E,5Z)-3,5-dodeca-
dienoate 5c, by the same reduction-acetylation procedure, the
(3E,5Z)-3,5-dodecadienyl acetate 2 was obtained in 86% yield.
From all the reported syntheses of the (3E,5Z)-3,5-dodecadienyl
acetate 2, pheromone of the leafroller B. cranaodes Meyrick
(2, 15, 16, 20), the present synthesis uses the most common
and cheap reagents.

Simple Synthesis of Insect Sex Pheromones
J. Agric. Food Chem., Vol. 52, No. 16, 2004 5051
(10) Tsuboi, S.; Masuda, T.; Takeda, A. A Stereoselective Synthesis
of (3E,5Z)-3,5-Tetradecadienoic Acid (Megatomoic Acid), the
Sex Attractant of the Black Carpet Beetle. Bull. Chem. Soc. Jpn.
1983, 56, 3521-3522.
(11) Tsuboi, S.; Kuroda, A.; Masuda, T.; Takeda, A. Stereoselective
Transformation of 2,4-Alkadienoic Esters to the 3,5-Dienoic
Isomers with Lithium Diisopropylamide. Chem. Lett. 1984,
1541-1542. (b) Tsuboi, S.; Sakamoto, J.; Kuroda, A.; Utaka,
M.; Takeda, A. Stereoselective Synthesis of 3,5-Alkadienoic
Esters from 2,4-Dienoic Isomers. Bull. Chem. Soc. Jpn. 1988,
61, 1410-1412.
Dodecadienyl Acetate, the Sex Pheromone of the Leaf Roller
Moth. Tetrahedron 1999, 55, 14243-14250.
(17) Baeckstrom, P.; Jacobsson, U.; Norin, T.; Unelius, C. K.
Synthesis and Characterization of All Four Isomers of Methyl
2,4-Decadienoate for an Investigation of the Pheromone Com-
ponents of Pityogenes chalcographus. Tetrahedron 1988, 44,
2541-2548.
(18) Heath, R. R.; Tumlinson, J. H.; Doolittle, R. E. Analytical and
Preparative Separation of Geometrical Isomers by High Ef-
ficiency Silver Nitrate Liquid Chromatography. J. Chromatogr.
Sci. 1977, 15, 10-13.
(19) (a) Leadbetter, G.; Plimmer, J. R. An Improved Preparation of
Some Insect Sex Attractants: Synthesis and Separation of
Geometrical Isomers by Formation of Urea Complexes. J. Chem.
Ecol. 1979, 5, 101-108. (b) Fieser, L. F.; Fieser, M. Reagents
for Organic Synthesis; John Wiley and Sons: New York, 1967;
Vol. I, p 1262.
(20) Park, C. P.; Gil, J. M.; Sung, J. W.; Oh, D. Y. A Concise
Synthesis of the Sex Pheromone of Phtheochroa cranaodes
(Lepidoptera: Tortricidae). Tetrahedron Lett. 1998, 39, 2583-
2584.
(12) Ikeda, Y.; Ukai, J.; Ikeda, N.; Yamamoto, H. Selective Proton
Transfer of Unsaturated Esters. Syntheses of a Trail-Following
Pheromone for Subterranean Termites and Megatomoic Acid.
Tetrahedron 1987, 43, 743-753.
(13) Ragoussis, N.; Ragoussis, V. Improvement on the Synthesis of
(E)-alk-3-enoic Acids. J. Chem. Soc., Perkin Trans. 1 1998,
3529-3533.
(14) Strube, R. E. Organic Syntheses; Wiley: New York, 1964;
Collect. Vol. IV, pp 417-419.
(15) Unelius, C. R.; Liblikas, I.; Mozuraitis, R. Synthesis and
Characterization of the Four Isomers of 3,5-Dodecadienyl
Acetate. Acta Chem. Scand. 1998, 52, 930-934.
Received for review April 13, 2004. Revised manuscript received May
23, 2004. Accepted June 5, 2004.
(16) Chong, J. M.; Heuft, M. A. Hydroalumination of 3-Butyn-1-ol:
Application to a Stereoselective Synthesis of (3E,5Z)-3,5-
JF049406B