A Simple and Cost Effective Synthesis of 3 , 11-Dimethyl-nonacosan-2one , A Female Sex Pheromone of the German Cockroach

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.


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 femaleproduced 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 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-2one (1) are linear synthetic approaches involving expensive reagents and inconvenient handling [5ab,5f].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).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 CBr 4 /PPh 3 method proved to be relatively low yielding (80%) [12].Compound 12 was treated with Et 3 SiH in the presence of BF 3 •OEt in CH 2 Cl 2 to afford the product 13 [5a] in 95% yield.Chain-elongation of 13 with ethyl 2methylacetoacetate 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].

Conclusions
In summary, we have demonstrated a new and practical large scale route to 3,11-dimethylnonacosan-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].

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 silica gel 60 [Scientific Adsorbents Incorporated (SAI), particle size 32-63 µm, pore size 60 Å]. 1 H-NMR, 13 C-NMR, and 2D-NMR spectra were recorded in CDCl 3 on a Bruker DPX 400 instrument operating at 400 MHz ( 1 H) and 100 MHz ( 13 C), 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].

9-Bromononan-2-one (8)
A stirred solution of acid 7 (45.0g, 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 reaction mixture was allowed to warm to 0 ºC for 1 h, and quenched with sat'd aqueous NH 4 Cl solution (250 mL), followed by extraction with ether (3×300 mL).The organic layer was separated, dried over anhydrous MgSO 4 , 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.R f = 0. 1-Bromomethylhexacosan-8-ol (12) Anhydrous ether (150 mL) was placed in a three-necked flask equipped with a dropping funnel, a N 2 gas inlet and a septum.After the apparatus was swept with dry N 2 , 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 NH 4 Cl 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 MgSO 4 , 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.R f = 0.3 (20% hexane in ethyl acetates); IR (neat, NaCl) 3520-2916, 2848 cm -1 ; 1 H-NMR δ 3.64 (t, J = 6.8 Hz, 2H, CH 2 Br), 1.65-1.48(m, 6H, 3×CH 2 ), 1.32-1.20 (m, 44H, 22×CH 2 ), 0.88 (t, J = 7.2 Hz, 3H, CH 3 ); HRMS calcd.for C 27 H 56 OBr: 475.3515 [M+H] + , found: 475.3521.

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 K 2 CO 3 (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 NH 4 Cl 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 MgSO 4 , 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.R f = 0.