Efficient synthesis of (±)-4-methyloctanoic acid, aggregation pheromone of rhinoceros beetles of the genus oryctes (Coleoptera: Dynastidae, Scarabaeidae)

Article abstract of DOI:10.1021/jf0704662

(±)-4-Methyloctanoic acid and its ethyl ester are aggregation pheromones of many rhinoceros beetles of the genus Oryctes and are investigated for the control of these pests by olfactory trapping. A simple, economical, and high-yield (>50%) synthesis of (±)-4-methyloctanoic acid and its ethyl ester is presented starting from n-hexanal. The key step in this sequence is an orthoester Claisen rearrangement for the elongation of the carbon chain by two.

Full text of DOI:10.1021/jf0704662

5050 J. Agric. Food Chem. 2007, 55, 5050−5052
Efficient Synthesis of (
Pheromone of Rhinoceros Beetles of the Genus Oryctes
Coleoptera: Dynastidae, Scarabaeidae)
±)-4-Methyloctanoic Acid, Aggregation
(
VALENTINE RAGOUSSIS,* ALEXANDROS GIANNIKOPOULOS, EFTHYMIA SKOKA, AND
PANAGIOTIS GRIVAS
Department of Chemistry, Laboratory of Organic Chemistry, University of Athens,
Panepistimiopolis Zographou, 157 71 Athens, Greece
(()-4-Methyloctanoic acid and its ethyl ester are aggregation pheromones of many rhinoceros beetles
of the genus Oryctes and are investigated for the control of these pests by olfactory trapping. A
simple, economical, and high-yield (>50%) synthesis of (()-4-methyloctanoic acid and its ethyl ester
is presented starting from n-hexanal. The key step in this sequence is an orthoester Claisen
rearrangement for the elongation of the carbon chain by two.
KEYWORDS: Pheromone synthesis; rhinoceros beetles; Oryctes elegans; Oryctes rhinoceros; Oryctes
monoceros; 4-methyloctanoic acid; ethyl-4-methyloctanoate; Claisen rearrangement
INTRODUCTION
Rhinoceros beetles of the genus Oryctes are the main pests
of coconut and date palm plantations in Southeast Asia, North
Africa, and some Pacific islands (1-3). Adult beetles burrow
galleries in the fresh and growing point of palms for feeding.
The damage is particularly severe when apical buds in young
trees or the fruit stalks in producing trees are attacked. Despite
the use of high doses of insecticides (e.g., carbofuran and
cypermethrin) against most rhinoceros beetles (4), efficient and
acceptable methods of controlling these insects are still lacking,
because adults spend more of their life hidden in galleries and
rapidly colonize new feeding and breeding sites, flying easily
away from the initial colony. The idea to manipulate adult
populations by luring beetles into traps with specific attractants
was investigated in the 1970s (5). The attractant chosen at that
time, ethyl chrysanthemate, was rapidly abandoned because of
insufficient catches. More recently, it was reported (1-3) that
the main male pheromone emitted from most of the Oryctes
species is a blend of 4-methyloctanoic acid (1) and its ethyl
ester (2) (Figure 1) and that these species appear to use 1 and
Figure 1. Aggregation pheromones of rhinoceros beetles.
various foods (9-11). However, no information about the
absolute configuration of this naturally occurring substance is
available.
Field experiments revealed that synthetic pheromones 1 and
2
in their racemic forms are very efficient attractants, indicating
that chirality is not a critical point in the pheromone activity of
Oryctes species (1, 3, 9-11).
A prerequisite for the application of aggregation pheromones
in large trapping areas is the availability of cheap 4-methyloc-
tanoic acid (1) of high purity in sufficient quantities. To date,
different approaches have been reported for the synthesis of
racemic 4-methyloctanoic acid and its esters. Among the most
general ones are (a) reaction of 4-ketopentanoic acid or its ethyl
ester with the appropriate Grignard reagent for the elongation
of the chain (12); (b) reductive desulfurization of bithienyl
carboxylic acids (13); (c) methylation of N-tert-butylimine
derivative of hexanal, condensation with malonic acid, and
hydrogenation (14); (d) conjugate addition of organocuprates
to ethyl acrylate (1, 6) or Ni-catalyzed coupling of alkyliodides
with ethyl acrylate (7); and, finally, (e) chain elongation of
2
differently and modulate the released amounts under certain
circumstances. Furthermore, it has been demonstrated that the
ethyl 4-methyloctanoate (2) is the aggregation pheromone of
the tropical Oryctes rhinoceros (1, 2) and of Oryctes monoceros
(6-8), whereas 4-methyloctanoic acid (1) is the aggregation
pheromone of Oryctes elegans (3). Both substances have been
studied (1-3) in adequate traps and proved to be powerful
attractants in operational programs to control the major pest in
oil palm plantations.
2
-methylhexanoic acid via malonic ester synthesis (15) or via
reduction and elongation of the chain by the Wittig reaction
16). Concerning the optically active 4-methyloctanoic acid, one
Besides its activity as a pheromone, 4-methyloctanoic acid
is also cited in the literature for its contribution to the aroma of
(
asymmetric synthesis has been reported (16), and two others
used enantiopure 2-alkyl-branched acids (17) or natural cit-
ronellol (1) as starting material. Resolution of the racemic acid
*
Corresponding author (telephone + 30 210 7274497; fax + 30 210
7
274761; e-mail ragousi@chem.uoa.gr).
1
0.1021/jf0704662 CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/27/2007

Efficient Synthesis of 4-Methyloctanoic Acid
J. Agric. Food Chem., Vol. 55, No. 13, 2007 5051
with brine, dried with anhydrous Na SO , and concentrated under
Scheme 1a
2
4
reduced pressure to leave a clear oily product. The product was purified
by column chromatography on silica gel (1:1 petroleum ether/diethyl
ether) to give the allyl alcohol 5 (7.35 g, 90%; purity by GC ) 97%)
-
1
1
as a colorless oil: IR, cm 3624; H NMR δ 0.88 (t, 3H, J ) 7.2 Hz),
1
2
2
.14-1.49 (m, 4H), 2.03 (t, 2H, J ) 7.2 Hz), 2.37 (s, 1H), 4.04 (s,
13
H), 4.82-4.85 (m, 1H), 4.97-4.98 (m, 1H); C NMR δ 13.87, 22.43,
1
13
9.89, 32.63, 65.77, 108.85, 149.17; H NMR and C NMR values
are in accordance with the literature data (22).
Ethyl 4-Methyleneoctanoate (6). A mixture of the 2-methylene-
hexanol 5 (6.50 g, 0.057 mol), triethyl orthoacetate (55 mL, 0.29 mol),
and a catalytic amount of propionic acid (4 drops) was heated at 138
°
C for 5 h with continuous removal of the ethanol formed during the
reaction. The reaction mixture was cooled to room temperature, poured
into ice water (150 mL) containing NaHCO (1.0 g), and extracted
with diethyl ether (3 × 50 mL). The organic phase was washed with
water, dried with Na SO , and concentrated under reduced pressure.
3
a
2
4
Reagents and conditions: (a) (CH
C, 24 h; (b) NaBH , 5% NaHCO
CH COOH, 138 C, 5 h; (d) H , 10% Pd/C, EtOH, 3 h; (e) KOH/EtOH/
O, reflux 2.5 h.
3
)
2
NH·
Η
Cl, 37% aqueous formaldehyde,
The crude product was purified by column chromatography on silica
7
0
°
3
4
3
, MeOH, 5
°
C, 1 h; (c) CH C(OC
3
2 5 3
H ) ,
gel (8:1 petroleum ether/diethyl ether) to give 6 (7.94 g, 76%; purity
CH
2
°
2
-
1
1
H
2
by GC ) 98%), as a colorless oil: IR, cm 1736, 1645; H NMR δ
0
.80-0.91 (m, 3H), 1.19-1.26 (t, 3H, J ) 7,2 Hz), 1.05-1.48 (m,
H,), 1.96-2.06 (m, 2H), 2.30-2.47 (m, 4H), 4.10 (q, 2H, J ) 7.2
Hz), 4.67 (s, 1H), 4.71 (s, 1H); C NMR δ 13.90, 14.18, 22.36, 29.88,
4
by a lipase-mediated enantioselective esterification has also been
described (18-20).
The above presented methods involve not readily available
substrates (13, 14), starting materials already lacking the methyl
group (15, 16), or the use of organometallic syntheses (1, 6, 7,
13
3
0.81, 32.74, 35.92, 60.24, 109.0, 148.22, 173.31; EI-MS, m/z (%) 184
+
(M , 3), 142 (21), 110 (19), 96 (70), 69 (100), 41 (98), 55 (97). Anal.
20 2
Calcd for C11H O : C, 71.69; H, 10.94. Found: C, 71.54; H, 10.85.
Ethyl 4-Methyloctanoate (2). A mixture of pure ethyl 4-methyl-
eneoctanoate 6 (3.00 g, 16.3 mmol) in ethanol (15 mL) and 10% Pd/C
1
2) unsuitable for large-scale preparations.
Addressing the drawbacks of the existing methods, we were
2
(10 mg) was stirred under H at room temperature. The reaction was
looking for an alternative synthesis of racemic 4-methyloctanoic
acid (1), which should be simple, low cost, and workable
on large scale. The proposed synthetic route is outlined in
Scheme 1.
completed in 3 h, and the catalyst was filtered through Celite and
washed with diethyl ether. The combined filtrates were concentrated
under reduced pressure to give almost pure 2 (2.78 g, 92%; purity by
-
1
1
GC ) 97%) as a colorless oil: IR, cm 1735; H NMR δ 0.86-0.92
(
m, 6H), 1.26 (t, 3H, J) 7.2 Hz), 1.16-1.75 (m, 9H), 2.25-2.34 (m,
2
2
H), 4.12 (q, 2H, J ) 7.2 Hz); 13C NMR δ 14.07, 14.20, 19.26, 22.9,
MATERIALS AND METHODS
9.12, 31.88, 32.13, 32.34, 36.30, 60.13, 174.14; All spectroscopic data
are in accordance with the literature data (1).
-Methyloctanoic Acid (1). The ethyl ester 2 (2.65 g, 14.2 mmol)
All reagents and solvents were purchased from Sigma-Aldrich and
were used as supplied. Thin-layer chromatography (TLC) was per-
formed on 0.25 mm precoated silica gel 60 F254 aluminum sheets and
column chromatography on silica gel 60 (0.063-0.2 mm) as well as
silica gel 60 (<0.063 mm), products of Merck & Co. (Darmstadt,
4
was saponified by refluxing with alcoholic potassium hydroxide (1.6
g of KOH, 12 mL of water and 35 mL of ethanol) for 2.5 h. The reaction
mixture, after cooling, was added into water (60 mL) and was extracted
with diethyl ether (2 × 25 mL) to remove any remaining ester 2 and
neutral impurities as well. The aqueous phase was acidified to pH 2
by the addition of 10% HCl (5 mL) and was extracted with diethyl
ether (3 × 20 mL). The organic phase was washed with water, dried
4
Germany). IR spectra were obtained in CCl solutions (5%) on a Perkin-
1
13
Elmer 247 spectrophotometer. H NMR and C NMR spectra were
recorded in CDCl on a Varian Mercury 200 MHz spectrometer, with
3
TMS as an internal standard. Gas chromatography-mass sprectrometry
analyses were carried out with a GC-MS Hewlett-Packard 5890-5970
system, equipped with a 30 m × 0.25 mm i.d. SPB-1 fused silica
capillary column: carrier gas, helium, 1 mL/min; injector temperature,
2 4
with anhydrous Na SO , and concentrated under reduced pressure to
give pure acid 1 (2.14 g, 95%; purity by GC ) 98%) as a colorless
-
1
1
oil: IR, cm 1710; H NMR δ 0.84-0.90 (m, 6H), 1.10-1.52 (m,
1
3
8
H), 1.56-1.80 (m, 1H), 2.29-2.38 (m, 2H), 11.45 (s, 1H); C NMR
δ 14.07, 19.21, 22.91, 29.09, 31.59, 31.88, 32.27, 36.27, 180.58; EI-
MS, m/z (%) 129 (M - 29, 3), 101 (27), 99 (32), 83 (17), 73 (60), 60
30), 57 (100), 55 (55), 43 (77), 41 (50). The mass spectrum is in
2
30 °C; oven temperature, 50 °C (5 min isothermal) raised at 4 °C/
min to 250 °C; ion source temperature, 220 °C; interface temperature,
50 °C; mass range, 40-500 amu; EI, 70 eV.
-Methylenehexanal (4). A mixture of hexanal 3 (10.00 g, 0.10
+
2
(
2
accordance with the literature data (3).
mol), dimethylamine hydrochloride (9.85 g, 0.12 mol), and 37%
aqueous formaldehyde (9.73 g, 0.12mol) was stirred at 70 °C for 24 h.
The aqueous phase was separated and extracted with diethyl ether (3
RESULTS AND DISCUSSION
×
20 mL). The combined organic phases were dried with anhydrous
SO , and the solvent was evaporated under reduced pressure. The
Hexanal, a common cheap aldehyde, was the starting material
of our synthesis. Mannich reaction (23) of hexanal (3) with
formaldehyde and dimethylammonium chloride gave 2-meth-
ylenehexanal (4) (88%). This was subsequently reduced by
sodium borohydride in methanol, to give the allylic alcohol 5
in high yield (90%). The Claisen rearrangement (24) of the
intermediate formed by heating alcohol 5 with triethyl orthoac-
etate in the presence of propionic acid gave the ethyl 4-meth-
yleneoctanoate (6) (76%). This new compound, identified by
its spectroscopic data, is the key element of the present approach.
Finally, hydrogenation of an ethanolic solution of 6 in the
presence of 10% Pd/C gave ethyl 4-methyloctanoate (2) in high
yield (92%). Saponification of the ethyl ester 2 gave 4-methy-
loctanoic acid (1) almost quantitatively and in high purity.
Na
2
4
product was purified by distillation to afford pure 4 (9.87 g, 88%; purity
by GC ) 95%) as a colorless oil: bp 60-64 °C/40 mmHg [lit. (21)
-
1
1
4
6-48 °C/15 mmHg]; IR, cm 1696, 1627; H NMR δ 0.91 (t, 3H,
J ) 7.2 Hz), 1.22-1.51 (m, 4H), 2.25 (t, 2H, J ) 7.2 Hz), 5.98 (s,
1
1
3
H), 6.24 (s, 1H), 9.54 (s, 1H); C NMR δ 13.73, 22.3, 27.4, 29.83,
1
133.75, 150.41, 194.65; IR and H NMR values are in accordance with
the literature data (21, 22).
-Methylenehexanol (5). To a cold (5 °C) suspension of NaBH
2.75 g, 0.072 mol) in H O (20 mL) and 5% NaHCO (6.8 mL) was
added a cold solution of aldehyde 4 (8.00 g, 0.072 mol) in methanol
100 mL). The final solution was stirred for 1 h at 5 °C. The reaction
2
4
(
2
3
(
mixture was then poured into ice water (220 mL), followed by the
addition of 10% HCl (35 mL). The aqueous layer was extracted with
diethyl ether (3 × 100 mL); the combined organic layers were washed

5052 J. Agric. Food Chem., Vol. 55, No. 13, 2007
Ragoussis et al.
Although no efforts have been made to optimize the yields, the
above reactions gave sufficient quantities of products that can
be easily purified either by distillation or by a rapid column
chromatography.
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Received for review February 16, 2007. Revised manuscript received
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