A simple and cost effective synthesis of 3,11-dimethylnonacosan-2-one, a female sex pheromone of the German cockroach

Article abstract of DOI:10.3390/11100751

A convenient synthesis of 3,11-dimethylnonacosan-2-one (1) is described. Our strategy involves the use of well known C-alkylation and ethyl acetoacetate synthesis reactions as key steps. We expect that this method will prove to be useful for large scale preparation of 1 and modification of dimethylnonacosanones.

Full text of DOI:10.3390/11100751

Molecules 2006, 11, 751-757
molecules
ISSN 1420-3049
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Full Paper
A Simple and Cost Effective Synthesis of 3,11-Dimethyl-
nonacosan-2-one, A Female Sex Pheromone of the German
Cockroach
Kwang–Chan Ahn 1, Jae–Chul Jung 2 and Oee–Sook Park 1,*
1 Department of Chemistry, Institute for Basic Sciences, College of Natural Sciences, Chungbuk
National University, Cheongju 361–763, Chungbuk, South Korea.
2 Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, P.O. Box 1848,
University, Mississippi 38677–1848, USA. E-mail: jcjung@olemiss.edu
* To whom correspondence should be addressed; E-mail: ospark@chungbuk.ac.kr
Received: 27 September 2006; in revised form: 10 October 2006 / Accepted: 10 October 2006 /
Published: 12 October 2006
Abstract: A convenient synthesis of 3,11-dimethylnonacosan-2-one (1) is described. Our
strategy involves the use of well known C–alkylation and ethyl acetoacetate synthesis
reactions as key steps. We expect that this method will prove to be useful for large scale
preparation of 1 and modification of dimethylnonacosanones.
Keywords: 3,11-Dimethylnonacosan-2-one, C–alkylation, Ethyl acetoacetate synthesis,
Large scale preparation.
Introduction
Many insects emit precise chemical odors to attract their mates (sex pheromones). Pheromones are
naturally occurring, environmentally friendly and species specific compounds that do not result in the
development of insecticide resistance [1]. The Nishida group [2] reported the isolation of the female–
produced sex pheromone of the German cockroach, Blattella germanica, from its cuticular waxes in
1974. The compound, which elicited typical courting behavior in males including wing–raising [3,4],
was identified as 3,11-dimethylnonacosan-2-one (1, Figure. 1). Since the synthesis of the mixture of
diastereomers of 1 was first achieved by Nishida et al. [3], a number of syntheses yielding a

Molecules 2006, 11
752
diastereomeric mixture of 1 were reported [5]. Bioassay of these four stereoisomers of 1 showed that
they were equally active [6]. Most of these methods for the generation of 3,11-dimethylnonacosan-2-
one (1) are linear synthetic approaches involving expensive reagents and inconvenient handling [5a-
b,5f].
Figure 1. Structure of 3,11-dimethylnonacosan-2-one (1)
O
11
3
n-C17H35
Our research required large quantities of 1 and key fragments 2–4 to serve as potential scaffolds
for modification of 1. We therefore became interested in studying a synthesis of 1 suitable for large
scale production. We wish to report herein a convenient new approach to the synthesis of this target
molecule via C–alkylation–ionic hydrogenation and C–alkylation–decarboxylation reactions starting
from 1,8-octane-diol (5) and 1-octadecanol (9).
Results and Discussion
The retrosynthetic analysis for 3,11-dimethylnonacosan-2-one (1) is summarized in Scheme 1. The
synthetic key strategies involve C–alkylation–decarboxylation reaction of unit 3 with acetate anion 4
in order to form the C3–C4 bond, and C–alkylation–ionic hydrogenation of alkyl anion 2 with unit 3
for generation of the C11–C12 bond. Units 2 and 4 can be smoothly derived from freshly prepared
bromide 10 [7] and commercially available ethyl 2-methylacetoacetate in the presence of base. The
electrophilic unit 3 was generated via bromination, oxidation, and methylation of 1,8-octanediol (5).
Scheme 1. Retrosynthetic analysis of 3,11-dimethylnonacosan-2-one (1).
C-Alkylation and ionic hydrogenation
O
n-C17H35
11
3
1
C-Alkylation and decarboxylation
O
n-C17H35
+
+
11
3
2
3
4

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753
The synthesis of key fragments 8 and 11 was accomplished as depicted in Scheme 2.
Commercially available 5 underwent bromination with aqueous hydrogen bromide (48%) in benzene
using a Dean–Stark apparatus to afford a 6:1 ratio (by G.L.C. analysis) of monobromo alkanol 6 and
dibromo alkane [8]. Compound 6 was oxidized by Jones reagent at 0 °C in acetone to generate acid 7
in 80% yield [9], which was then treated with methyllithium (1.4 M solution in ether) in THF to give
9-bromononan-2-one (8) in 64% yield [10]. Bromination of alcohol 9 was performed with phosphorus
tribromide in ether to produce a 95% yield of bromide 10, which was treated with Li metal in dry THF
to yield anion 11, which was coupled in situ with bromide 8 [11] in DMF to generate tertiary alcohol
12 in 60% yield for two steps. In this bromination reaction the alternate CBr4/PPh3 method proved to
be relatively low yielding (80%) [12]. Compound 12 was treated with Et3SiH in the presence of
BF3·OEt in CH2Cl2 to afford the product 13 [5a] in 95% yield. Chain–elongation of 13 with ethyl 2-
methylacetoacetate was executed employing potassium carbonate as the base to give 14 in 93% yield.
Hydrolysis of 14 with concomitant decarboxylation of the resulting acid furnished the final product,
3,11-dimethylnonacosan-2-one (1) in 73% yield [5].
Scheme 2. Synthesis of 3,11-dimethylnonacosan-2-one (1).
O
O
b
c
HO
R
6
Br
Br
HO
5
5
5 R = OH
6 R = Br
7
8
a
f
e
d
CH3(CH2)16CH2 Li
CH3(CH2)16CH2Br
CH3(CH2)16CH2OH
11
10
9
CH3(CH2)17
HO
(CH2)6
g
CH3(CH2)17
h
(CH2)6
Br
Br
12
13
O
O
CH3(CH2)17
(CH2)7
i
n-C17H35
CO2Et
1
14
(a) HBr (48% aq)/benzene, reflux, 18 h, (72%); (b) Jones reagent, acetone, 0 ºC to rt, 1 h, (80%);
(c) CH3Li (2 equiv)/THF, –78 ºC to 0 ºC, 1 h, (64%); (d) PBr3/ether, reflux, 2 h, (95%);
PPh3,CBr4/CCl4, rt, 3 h, (80%); (e) Li/ether, rt, 30 min; (f) 8 + 11, ether, 0 ºC, 3 h, (60%, two
steps); (g) Et3SiH, BF3·OEt/CH2Cl2, 0 ºC, 2 h, (95%); (h) ethyl-2-methyl acetoacetate, K2CO3,
KI/acetone, reflux, 20 h, (93%); (i) 15% NaOH, (n-Bu)4NOH/THF, rt, 2 h, (73%).

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Conclusions
In summary, we have demonstrated a new and practical large scale route to 3,11-dimethyl-
nonacosan-2-one (1) using readily available inexpensive reagents and simple reaction conditions that
do not require any special equipment or techniques. We expect that this method will prove to be useful
for the large scale preparation of 1 and for modification of dimethylnonacosanones. All physical and
spectral data for the synthetically prepared 1 were identical to those reported [3,5].
Experimental
General
Reactions requiring anhydrous conditions were performed following the usual precautions for
rigorous exclusion of air and moisture. Tetrahydrofuran was distilled from sodium benzophenone ketyl
prior to use. Thin layer chromatography (TLC) was performed on precoated silica gel G and GP
uniplates (Analtech) and visualized with 254–nm UV light. Flash chromatography was carried out on
1
silica gel 60 [Scientific Adsorbents Incorporated (SAI), particle size 32–63 µm, pore size 60 Å]. H-
13
NMR, C-NMR, and 2D-NMR spectra were recorded in CDCl3 on a Bruker DPX 400 instrument
operating at 400 MHz (1H) and 100 MHz (13C), respectively. The chemical shifts are reported in parts
per million (ppm) downfield from tetramethylsilane. Infrared (IR) spectra were obtained on an ATI
Mattson FT/IR spectrometer. Mass spectra were recorded with a Waters Micromass ZQ LC–Mass
system and high resolution mass spectra (HRMS) were measured with a Bruker BioApex FTMS
system by direct injection using an electrospray interface (ESI). When necessary, chemicals were
purified according to the reported procedures [13].
8-Bromooctan-1-ol (6)
To a stirred solution of 1,8-octanediol (5, 31.2 g, 213.5 mmol) in benzene (500 mL) was added
48% aqueous HBr (37.5 mL) and the mixture was refluxed for 18 h, while the water formed was
trapped using a Dean–Stark water separator. The reaction mixture was washed successively with 6N
aqueous NaOH solution (200 mL), 10% HCl aqueous solution (250 mL), water (300 mL) and brine
(300 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by Kugelrohr distillation (b.p. 66–70 ºC/3 torr, lit.
[8c] b.p. 110–120 ºC/2 torr) to give 6 (32.0 g, 72%) as a colorless oil. IR (neat, NaCl) 3455, 2984,
1
2875, 1142, 1048, 852 cm-1; H-NMR δ 3.72 (t, J = 6.8 Hz, 2H, CH2Br), 3.45 (t, J = 7.0 Hz, 2H,
CH2OH), 1.25–1.15 (m, 12H, 6×CH2); HRMS calcd. for C8H18OBr: 209.0541 [M+H]+, found:
209.0547.
9-Bromononan-2-one (8)
A stirred solution of acid 7 (45.0 g, 201.0 mmol) in dry THF (1.4 L) was cooled to –78 ºC and
methyllithium (287.5 mL, 402.0 mmol, 1.4 M solution in ether) was added dropwise over 20 min. The

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reaction mixture was allowed to warm to 0 ºC for 1 h, and quenched with sat’d aqueous NH4Cl
solution (250 mL), followed by extraction with ether (3×300 mL). The organic layer was separated,
dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 15% ethyl acetate in hexanes) to give 8 (28.5 g,
64%) as a colorless oil. Rf = 0.4 (20% ethyl acetate in hexanes); IR (neat, NaCl) 2977, 2876, 1712,
1518, 1452, 1250, 1068, 781 cm-1; 1H-NMR δ 3.38 (t, J = 6.8 Hz, 2H, CH2Br), 2.40 (t, J = 7.6 Hz, 2H,
CH2CO), 2.11 (s, 3H, CH3), 1.87–1.77 (m, 2H, CH2), 1.58–1.49 (m, 2H, CH2), 1.44–1.36 (m, 2H,
13
CH2), 1.35–1.18 (m, 4H, 2×CH2); C-NMR δ 208.9 (CO), 43.5 (CH2CO), 33.8 (CH2Br), 31.9 (CH3),
30.2 (CH2), 28.5 (CH2), 28.1 (CH2), 26.8 (CH2), 23.4 (CH2); HRMS calcd. for C5H10OBr: 164.9915
[M+H]+, found: 164.9908.
1-Bromomethylhexacosan-8-ol (12)
Anhydrous ether (150 mL) was placed in a three–necked flask equipped with a dropping funnel, a
N2 gas inlet and a septum. After the apparatus was swept with dry N2, lithium wire (1.5 g, 216.0 mmol)
was cut into small pieces, which were allowed to fall into the reaction flask. With stirring, a solution of
1-bromooctadecane (10, 30.0 g, 90.0 mmol) in anhydrous ether (150 mL) was added. After a period of
1 h, the mixture became slightly cloudy. The reaction mixture then was cooled to –10 ºC. The
remainder of the 1-bromooctadecane solution was added over a period of 3 h at the same temperature.
After addition was completed, the reaction mixture was kept at the same temperature for additional 1 h
and then was allowed to warm up to 10 ºC with stirring. Over a period of 30 min, the reaction mixture
was cannulated to a two–necked flask in which bromide 8 (15.0 g, 60.0 mmol) in ether (75 mL) at 0 ºC
was placed and the resulting reaction mixture was stirred at 0 ºC for 3 h. The reaction mixture was
quenched by addition of 50% aqueous NH4Cl solution (150 mL) and aqueous phase was extracted with
ether (180 mL). The combined organic phases were washed with brine (150 mL), dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column
chromatography (silica gel, 20% hexane in ethyl acetates) to give alcohol 12 (25.5 g, 60%) as a
colorless oil. Rf = 0.3 (20% hexane in ethyl acetates); IR (neat, NaCl) 3520–2916, 2848 cm-1; 1H-NMR
δ 3.64 (t, J = 6.8 Hz, 2H, CH2Br), 1.65–1.48 (m, 6H, 3×CH2), 1.32–1.20 (m, 44H, 22×CH2), 0.88 (t, J
= 7.2 Hz, 3H, CH3); HRMS calcd. for C27H56OBr: 475.3515 [M+H]+, found: 475.3521.
1-Bromo-8-methylhexacosane (13)
To a stirred solution of 1-bromo-8-methylhexacosan-8-ol (12, 24.0 g, 50.0 mmol) in
dichloromethane (600 mL) was added triethylsilane (12.0 g, 120.0 mmol), followed by addition of
BF3·OEt (20.0 g, 150.0 mmol) at 0 ºC and the mixture was stirred for 2 h. The reaction mixture was
diluted with CH2Cl2 (400 mL) and washed with sat’d aqueous NH4Cl solution (500 mL) and brine
(500 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash column chromatography (silica gel, 5%
ethyl acetate in hexanes) to give bromide 13 (22.0 g, 95%) as a colorless oil. Rf = 0.5 (5% ethyl acetate
in hexanes); IR (neat, NaCl) 2978, 1446, 1062, 838 cm-1; 1H-NMR δ 3.43 (t, J = 6.8 Hz, 2H, CH2Br),

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1.61–1.39 (m, 7H), 1.35–1.21 (m, 43H), 0.89 (t, J = 7.0 Hz, 3H, CH3); HRMS calcd. for C27H56Br:
459.3565 [M+H]+, found: 459.3573.
3,11-Dimethyl 3-ethoxycarbonylnonacosan-2-one (14)
To a stirred solution of ethyl 2-methylacetoacetate (9.0 g, 63.0 mmol) in acetone (150 mL) was
added K2CO3 (18.6 g, 135.0 mmol) and KI (3.0 g, 18.0 mmol) at room temperature. After 10 min, a
solution of bromide 13 (27.6 g, 60.0 mmol) in acetone (60 mL) was added and the reaction mixture
was rapidly brought to reflux by heating in oil bath. After 20 h, the resultant mixture was cooled to
room temperature, diluted with ether (300 mL) and filtered. The residue was washed with sat’d
aqueous NH4Cl solution (150 mL) and brine (150 mL). The organic layer was separated, and the
aqueous phase was extracted with ether (150 mL). The combined organic phases were dried over
anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by
flash column chromatography (silica gel, 10% ethyl acetate in hexanes) to give acetate 14 (28.5 g,
93%) as a colorless oil. Rf = 0.3 (10% ethyl acetate in hexanes); IR (neat, NaCl) 2924, 2853, 1735
1
(CO), 1716 (COO), 1458, 1265, 1120 cm-1; H-NMR δ 4.18 (t, J = 7.0 Hz, 2H, CH2), 2.03 (s, 3H,
CH3), 1.86–1.72 (m, 2H, CH2), 1.48–1.21 (m, 51H, CH, 25×CH2), 0.85–1.02 (m, 6H, 2×CH3); HRMS
calcd. for C33H65O3: 509.4934 [M+H]+, found: 509.4922.
3,11-Dimethylnonacosan-2-one (1)
To a stirred solution of 3,11-dimethyl-3-ethoxycarbonylnonacosan-2-one (14, 15.2 g, 30.0 mmol)
in THF (500 mL) was added 15% aqueous NaOH solution (300 mL), followed by addition of
tetrabutylammonium hydroxide solution (38.0 g, 150.0 mmol, 1.0 M sol. in water) and the mixture was
stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate (600 mL) and
washed with sat’d aqueous NH4Cl solution (600 mL) and brine (400 mL). The organic layer was
separated, and the aqueous phase was extracted with ethyl acetate (300 mL). The combined organic
phases were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash column chromatography (silica gel, 10% ethyl acetate in hexanes) to give
1 (9.8 g, 73%) as a colorless oil. Rf = 0.3 (10% ethyl acetate in hexanes); IR (neat, NaCl) 2957, 1729
1
(CO), 1446, 1285, 1024, 837 cm-1; H-NMR δ 2.55–1.41 (m, 1H, CH), 2.06 (s, 3H, CH3), 1.72–1.22
(m, 55H), 0.84 (t, J = 7.0 Hz, 3H, CH3); HRMS calcd. for C31H63O: 451.4879 [M+H]+, found:
451.4887.
Acknowledgements
This work was supported by Chungbuk National University Grant in 2004.
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Sample Availability: Samples of the compounds are available from authors.
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