Facile synthesis of mill moth's sex pheromone components

Article abstract of DOI:10.1080/00397910801929341

An improved method for the preparation of mill moth's sex pheromone components in high diastereomeric purity is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910801929341

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Facile Synthesis of Mill Moth's Sex Pheromone
Components
Gábor Hornyánszky a , János Rohály a & Lajos Novák a
a Department of Organic Chemistry and Technology and Research Group for
Alkaloid Chemistry of the Hungarian Academy of Sciences , University of
Technology and Economics , Budapest, Hungary
Published online: 24 Apr 2008.
To cite this article: Gábor Hornyánszky , János Rohály & Lajos Novák (2008) Facile Synthesis of Mill Moth's Sex
Pheromone Components, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 38:10, 1533-1540, DOI: 10.1080/00397910801929341
To link to this article: http://dx.doi.org/10.1080/00397910801929341
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Synthetic Communicationsw, 38: 1533–1540, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801929341
Facile Synthesis of Mill Moth’s Sex
Pheromone Components
´ ´ ´ ´ ´
Gabor Hornyanszky, Janos Rohaly, and Lajos Novak
Department of Organic Chemistry and Technology and Research Group
for Alkaloid Chemistry of the Hungarian Academy of Sciences,
University of Technology and Economics, Budapest, Hungary
Abstract: An improved method for the preparation of mill moth’s sex pheromone
components in high diastereomeric purity is described.
Keywords: Mill moth, pheromone, Wittig reaction
INTRODUCTION
Mediterranean flour or mill moth (Ephestia kuehniella, Zeller) is a worldwide
pest, particularly of flour, stored grain, and fruit. Together with the grain moth
(Ephestia elutella, Hu¨bner) and Indian meal moth (Plodia interpunctella,
Hu¨bner) it is the main moth pest of cereal storage, flour and groutmills, and
bakeries and shops.[1–6] Most stored foods may be attacked by these insects
and contaminated by the faecal material and bodies of them. Among the
various strategies suggested to control the population of these harmful
insects, the use of their sex pheromone components seems most promising.
The natural pheromone may be useful to trap the pests and control their
population.
Received in Poland September 27, 2007
´
Address correspondence to Lajos Novak, Department of Organic Chemistry and
Technology and Research Group for Alkaloid Chemistry of the Hungarian Academy
of Sciences, University of Technology and Economics, Budapest, Hungary. E-mail:
lnovak@mail.bme.hu
1533

´ ´ ´
G. Hornyanszky, J. Rohaly, and L. Novak
1534
RESULTS AND DISCUSSION
The sex pheromone extracts of these insects consist of (Z,E)-tetradeca-9,
12-dien-1-yl acetate (1a) and (Z,E)-tetradeca-9,12-dien-1-ol (1b). An approxi-
mately 4:1 mixture of compounds 1a and 1b showed the strongest attractive
effect on the males of these insects.[2–5]
During our studies in the field using pheromones as moth control agents,
we required larger amounts of compounds 1a and b. We now report an
improved method for the synthesis of pheromone components (1a, b),
which is efficient and applicable for large-scale preparation.
Numerous methods had been elaborated for the preparation of compounds
1a,b.[7–13] For our purpose, the most appropriate was the one elaborated by
Bestmann’s group,[8] with some modification (Scheme 1).
However, Bestmann’s method suffered from a serious limitation. Namely,
one of the methylene-interrupted conjugated double bonds was formed by
Julia’s cyclopropane cleavage reaction. This ring-opening process generally
showed high stereoselectivity except for the preparation of (E)-homoallylic
Scheme 1.

Mill Moth’s Sex Pheromone
1535
bromide (4). Here, an isomeric composition of E/Z ¼ 90/10 was formed, and
its separation required preparative HPLC.[14]
We found that the commercially available (E)-pent-3-enoic acid methyl
ester (2) can be cleanly and almost quantitatively transformed into the corre-
sponding alcohol 3 by LiAlH4 reduction. The latter was then reacted with in
situ prepared PPh3 Br2 reagent in CH2Cl2 to afford compound 4 in acceptable
yield. Treatment of bromide 4 with PPh3 in acetonitrile gave stereochemically
pure phosphonium salt 5 in excellent yield.
The key intermediate of the synthesis, the oxo ester 8, was prepared by a
known procedure. Acetylation of diol 6 with AcOH afforded hydroxy ester 7,
which was then treated with PCC in CH2Cl2 to afford compound 8 in good
yield.[15]
The second double bond of target compounds 1a,b, could be generated in
Wittig reaction with the aldehyde 8 and the phosporane formed from the phos-
phonium salt 5 with base. We screened four bases, LiN(iPr)2, [(H2)3Si]2NNa,
BuLi, and tert-BuOK, to optimize the reaction conditions. In our hands,
LiN(iPr)2 proved to be the best base for this coupling reaction. The major
component of pheromone 1a was isolated in acceptable yield and in high dia-
stereochemical purity (more than 96%).
The minor compound 1b was then prepared by the hydrolysis of 1a with
NaOH in CH3OH.
EXPERIMENTAL SECTION
Starting materials and reagents were purchased from Aldrich or Fluka and
used without further purfication. Thin-layer chromatography (TLC) was
performed on precoated silica-gel plates (60 F254) and visualized by UV
irradiation or spraying with phosphomolybdic acid stains followed by
charring on a hot plate. 1H and 13C NMR spectra were obtained on a
Bruker DRX/500 spectrometer. All NMR spectra are reported in parts per
million (ppm) relative to TMS. Gas chromatography (GC) measurements
were taken on an Agilent 4890 D instrument. The column was an HP-
INNOWAX (30 m ꢀ 0.32 mm).
(E)-Pent-3-en-1-ol (3)
A solution of methyl (E)-pent-3-enoate (2: 20 g, 0.175 mol) in dry ether
(100 mL) was added dropwise to a stirred suspension of LiAlH4 (8.4 g,
0.22 mol) in dry ether (100 mL) at 0 8C. The resulting mixture was stirred
at rt for 4 h. After cooling to 0–5 8C, the reaction mixture was successively
treated with water and 2N NaOH (80 mL each), and the precipitated solid
was collected and washed with ether. The combined filtrate and washing
were dried (anhydrous MgSO4) and concentrated, and the crude residue was

´ ´ ´
G. Hornyanszky, J. Rohaly, and L. Novak
1536
purified by vacuum distillation to yield the title compound as a colorless oil
(12.5 g, 83%). Bp: 88–90 8C/120 mm [lit. bp: 78–79 8C/88 mm[16]]. GC:
1
Rt ¼ 3.99 min (60–90 8C, 2 8C/min, 10 psi). H NMR [CDCl3]: 1.65 [1H,
s (br), OH], 1.69 (3H, d, J ¼ 6.4 Hz, CH3), 2.25 (2H, q, J ¼ 6.4 Hz, CH2),
3.62 (2H, t, J ¼ 6.3 Hz, OCH2), 5.40 (1H, m, 55CH), 5.58 (1H, m, 55CH).
13C NMR (CDCl3): 17.98 (CH3), 35.91 (CH2), 61.88 (OCH2), 126.78
(CH55), 128.12 (CH55).
(E)-5-Bromopent-2-ene (4)
Bromine (6.6 mL, 0.13 mol) was added dropwise to a stirred solution of
triphenylphosphine (36.8 g, 0.14 mol) in dry dichloromethane (200 mL) at
0 8C. The resulting mixture was stirred for some minutes, and then a
solution of (E)-pent-3-en-1-ol (3: 7.0 g, 81 mmol) in dichloromethane
(30 mL) was added in small portions. The resultant slurry was stirred at
room temperature for 12 h and then diluted with pentane (200 mL). The
solid was filtered off; the filtrate was successively washed with 10% sodium
hydrocarbonate solution and brine (100 mL each) and then dried (anhydrous
MgSO4). The solvent was evaporated, and the residue was purified by
vacuum distillation to afford compound 4 as a colorless oil (8 g, 66%). Bp:
78–82 8C/120 mm [lit. bp: 68–69 8C/102 mm[17]]. GC: Rt ¼ 1.79 min
1
(60–90 8C, 2 8C/min, 10 psi). H NMR (CDCl3): 1.67 (3H, d, J ¼ 6.5 Hz,
CH3), 2.53 (2H, q, J ¼ 7.0 Hz, CH2), 3.36 (2H, t, J ¼ 7.5 Hz, CH2Br), 5.44
(1H, m, CH55), 5.57 (1H, m, CH55). 13C NMR (CDCl3): 17.87 (CH3),
32.77 (CH2Br), 35.96 (CH2), 127.34 (CH55), 127.98 (CH55).
(E)-Pent-3-enyltriphenylphosphonium Bromide (5)
Triphenylphosphine (21 g, 80 mmol) was added to a solution of (E)-5-
bromopent-2-ene (4: 11.7 g, 79 mmol) in dry acetonitrile (60 mL), and the
resulting mixture was refluxed for 80 h. The solvent was evaporated in
vacuo; the residue was triturated with ether and filtrated. Yield: 31.5 g
1
(97%). Mp.: 123–124 8C [lit.[8]: 124 8C]. H-NMR (CDCl3): 1.47 (3H, d,
J ¼ 6.0 Hz, CH3), 2.34 (2H, m, CH2), 3.71 (2H, m, CH2P), 5.39 (1H, m,
CH55), 5.47 (1H, m, CH55), 7.66 (6H, m, aromatic protons), 7.76 (9H, m,
aromatic protons). 13C NMR (CDCl3): 17.62 (CH3), 22.72 (CH2), 25.54
(CH2), 117.50, 118.18, 127.10 (CH55), 127.94 (CH55), 130.12, 130.22,
133.26, 133.33, 134.76.
9-Hydroxynon-1-yl Acetate (7)
A solution of nona-1,9-diol (6: 8.8 g, 55 mmol) in acetic acid (100 mL) was
added to a solution of sulfuric acid (15 mL) in water (800 mL), and the

Mill Moth’s Sex Pheromone
1537
resulting mixture was continuously extracted with hexane for 44 h. The
organic layer was separated and dried (MgSO4), and the solvent was evapor-
ated in vacuo. The residue (a 7:1 mixture of compound 7 and the correspond-
ing diester) was separated by vacuum chromatography (hexane–EtOAc 1:1 as
eluent) to afford the title compound 7 (8 g, 72%) as an oil.[15] TLC: 0.44. 1H
NMR (CDCl3): 1.30 (10H, m, 5CH2), 1.53–1.62 (4H, m, 2CH2), 1.73 (1H, s,
OH), 2.04 (3H, s, CH3), 3.63 (2H, t, J ¼ 6.6 Hz, OCH2), 4.04 (2H, t, J ¼ 6.8
Hz, OCH2). 13C NMR (CDCl3): 20.95 (CH3), 25.65 (CH2), 26.81 (CH2), 28.52
(CH2), 29.08 (CH2), 29.24 (CH2), 29.37 (CH2), 32.66 (CH2), 62.83 (OCH2),
64.46 (OCH2), 170.78 (CO).
1,9-Diacetoxynonane:[18] yield 1.8 g (7%). TLC: 0.74. 1H NMR (CDCl3):
1.30 (10H, m, 5CH2), 1.61 (4H, m, 2CH2), 2.04 (6H, s, 2CH3), 4.05 (4H, t,
J ¼ 6.8 Hz, 2OCH2). 13C NMR (CDCl3): 20.95 (2CH3), 25.82 (CH2), 26.81
(2CH2), 28.52 (2CH2), 29.08 (2CH2), 29.29 (CH2), 64.42 (2OCH2), 170.71
(2CO).
9-Oxonon-1-yl Acetate (8)
Pyridinium chlorochromate (30.5 g, 0.14 mol) was added portionwise to a
stirred solution of compound 7 (14 g, 69 mmol) in dry dicloromethane
(600 mL), and the mixture was stirred at rt for 3 h. The reaction mixture
was diluted with ether (300 mL), and then MgSO4 (30 g) was added. The
resultant mixture was filtered through a short silica-gel column (200 g) and
washed with dichloromethane, and the solvent was evaporated in vacuo.
The residue was purified by column chromatography (hexane–EtOAc 7:3)
1
to yield title compound 8 (11.2 g, 81%).[15] TLC: 0.4. H NMR (CDCl3):
1.32 (8H, m, 4CH2), 1.61 (4H, m, 2CH2), 2.05 (3H, s, CH3), 2.42 (2H, t,
J ¼ 7.1 Hz, CH2), 4.05 (2H, t, J ¼ 6.8 Hz, OCH2), 9.76 (1H, s, CHO). 13C
NMR (CDCl3): 20.94 (CH3), 21.98 (CH2), 25.77 (CH2), 28.50 (CH2), 28.98
(CH2), 29.08 (CH2), 29.29 (CH2), 43.76 (CH2), 64.38 (OCH2), 170.74
(CO), 202.20 (CHO).
(Z,E)-Tetradeca-9,12-dien-1-yl Acetate (1a)
Method A
n-BuLi (1.77 M in hexane, 12 mL, 21.3 mmol) was added to a cooled (25 8C)
and stirred solution of diisopropylamine (2.15 g, 3 mL, 21.5 mmol) in dry
THF (25 mL). After stirring for 30 min at 25 8C, this solution was added
dropwise into a cold (270 8C) and stirred suspension of phosphonium salt 5
(8.5 g, 20.7 mmol) in dry THF (200 mL), and the resulting mixture was
stirred at 220 8C for 1 h. The mixture was then cooled to 278 8C, and a
solution of aldehyde 8 (4.1 g, 20.4 mmol) in dry THF (40 mL) was added

´ ´ ´
G. Hornyanszky, J. Rohaly, and L. Novak
1538
dropwise. The reaction mixture was stirred at 260 8C for 1 h and then at rt
overnight. The solvent was evaporated in vacuo, the residue was trituated
with ether (150 mL each) three times and filtered, and the solvent was evap-
orated in vacuo. The residue was purified by column chromatography
(hexane–EtOAc 9:1) to afford pheromone component 1a (2.8 g, 54%) as a
colorless oil. Isomeric purity was more than 96%. GC: Rt ¼ 7.65 min
[(E,E)-diastereomer Rt ¼ 7.97 min] (150–180 8C, 2 8C/min, 10 psi). 1H
NMR (CDCl3): 1.30 (10H, m, 5CH2), 1.62 (2H, t, J ¼ 7.0 Hz, CH2), 1.66
(3H, d, J ¼ 5.0 Hz, CH3), 2.02 (2H, m, CH2), 2.05 (3H, s, CH3), 2.72 (2H,
m, CH2), 4.06 (2H, t, J ¼ 6.7 Hz, OCH2), 5.39 (4H, m, 4CH55). 13C NMR
(CDCl3): 17.84 (CH3), 20.95 (CH3), 25.84 (CH2), 27.00 (CH2), 28.53
(CH2), 29.11 (CH2), 29.14 (CH2), 29.30 (CH2), 29.53 (CH2), 30.35 (CH2),
64.46 (OCH2), 124.73 (CH55), 127.33 (CH55), 129.25 (CH55), 129.99
(CH55), 170.73 (CO).
Method B
n-BuLi (2.5 M in hexane, 14.6 mL, 36.5 mmol) was added dropwise to a
stirred suspension of phosphonium salt 5 (15 g, 36.5 mmol) in dry THF
(150 mL) at 270 8C. After stirring at 270 8C for 0.5 h, a solution of
aldehyde 8 (8.2 g, 36.5 mmol) in dry THF (50 mL) was added dropwise,
and the mixture was stirred at 270 8C for 1 h and then at rt for overnight.
The reaction mixture was diluted with ether and filtered, and the solvent
was evaporated in vacuo. The residue was purified by column chromatography
(hexane–EtOAc 20:1 as eluent) to give sex pheromone component 1a (5.6 g,
61%) consisting of 85% (Z,E)- and 15% (E,E)-stereoisomers.
(Z,E)-Tetraeca-9,12-dien-1-ol (1b)
Aq NaOH (2N, 30 mL), was added to a stirred solution of compound 1a (3.5 g,
13.8 mmol) in methanol (30 mL) and the resulting mixture was stirred at rt for
3 h. The methanol was evaporated in vacuo, the residue was extracted three
times with ether (50 mL each), and the combined ethereal solutions were
dried over MgSO4. The solvent was evaporated, and the residue was
purified by column chromatography (hexane–EtOAc 7:3) to afford
pheromone component 1b (2.5 g, 87%) as a colorless oil. The isomeric
purity was more than 96%. GC: Rt ¼ 9.48 min [(E,E)-diastereomer
1
Rt ¼ 9.85 min] (150–180 8C, 2 8C/min, 10 psi). H NMR (CDCl3): 1.30
(10H, m, 5CH2), 1.49 (1H, b, OH), 1.55 (2H, t, J ¼ 6.5 Hz, CH2), 1.65 (3H,
d, J ¼ 5.0 Hz, CH3), 2.02 (2H, q, J ¼ 7.0 Hz, CH2), 2.71 (2H, m, CH2),
3.63 (2H, t, J ¼ 6.6 Hz, OCH2), 5.39 (4H, m, 4CH55). 13C NMR (CDCl3):
18.27 (CH3), 26.09 (CH2), 27.44 (CH2), 29.55 (CH2), 29.74 (CH2), 29.82
(CH2), 29.98 (CH2), 30.78 (CH2), 33.14 (CH2), 63.32 (OCH2), 125.15
(CH55), 127.73 (CH55), 129.68 (CH55), 130.45 (CH55).

Mill Moth’s Sex Pheromone
ACKNOWLEDGMENT
1539
Generous support by NKFP program contract 3–35-2002 (Hungarian
Ministry of Education) is gratefully acknowledged.
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