Full Paper Ultrasound Assisted Synthesis of 5,9-Dimethylpentadecane and 5,9-Dimethylhexadecane – the Sex Pheromones of Leucoptera coffeella

Racemic 5,9-dimethylpentadecane and 5,9-dimethylhexadecane, the major and minor constituents, respectively, of the sex pheromone of Leucoptera coffeella, have been synthesized from citronellol in 56-58% overall yield through six steps. Ultrasound irradiation efficiently supported tosylation of alcohols (two steps) as well as the subsequent cross coupling reactions with the pertinent Grignard reagents (also two steps).


Introduction
Recent research has shown that several hydrocarbons with a 1,5-dimethyl skeleton are insect pheromones [1].5,9-Dimethylpentadecane (1) and 5,9-dimethylhexadecane (2) are known as the major and minor constituents, respectively, of the sex pheromone of Leucoptera coffeella, a pest of coffee trees [2].Several ways of synthesizing 1 have been described.Stereoisomers of 1 were synthesized starting from (-)-isopulegol by Moreira and Correa [3] and from methyl (R)-and (S)-3-hydroxy-2methylpropanoate by Kuwahara and co-workers [4].Zarbin et al. carried out an unsymmetrical double Wittig olefination as the key reaction to obtain also a stereoisomeric mixture of 1 in a yield of 54% [5].Using citronellol as the starting material, Liang et al. synthesized stereoisomeric mixtures of 1 as well as of 2 in yields of about 25% [6].Using (R)-citronellol as the starting material, Poppe et al. synthesized 1 as a mixture of the (5S,9S) and (5R,9S) stereoisomeric molecules in a related way in an overall yield of 22% [7].However, the stereochemistry of the natural pheromone is still undetermined [5].Zarbin et al. [5] have tested the biological activity of a synthetic stereoisomeric mixture of 1. Their field experiments showed, that it was highly attractive to L. coffeella males [5].
Ultrasonic irradiation has been found useful as support for quite a few organic reactions [8].In this paper, we describe a new six-step synthetic route to 1 and 2 (as a mixture of stereoisomers) from citronellol (3) (see Scheme 1) in which ultrasound irradiation was used to support the tosylation and cross coupling reactions, which were used repeatedly (four out of six steps, see Scheme 1).Scheme 1: Synthesis of 5,9-dimethylpentadecane (1) and 5,9-dimethylhexadecane (2).

Results and Discussion
Citronellol (3), an easily obtainable starting material [9], was tosylated to give the tosylate 4, which subsequently was coupled with either n-butylmagnesium bromide or n-pentylmagnesium bromide to give the alkenes 5a and 5b, respectively.Upon oxidation, 5a and 5b gave the aldehydes 6a and 6b, respectively, which in turn were reduced into the corresponding alcohols 7a and 7b by NaBH 4 .Repeated tosylations and cross coupling reactions converted the alcohols 7a and 7b into the hydrocarbons 1 and 2 via the tosylates 8a and 8b (Scheme 1).
The preparation of the alkyl tosylates 4, 8a and 8b were carried out following a Varma-like procedure [10].According to Kabalka et al. [10], alkyl tosylates can be prepared from alcohols and p-toluenesulfonyl chloride, in the presence of pyridine, by stirring the reactants together in chloroform solution for 2.5-9.0 hours at 0 o C. In our procedure, the reactions were supported by ultrasound irradiation from an ultrasonic processor (steps i and v).The results of a series of experiments are shown in Tables 1 and 2. p-Toluenesulfonyl chloride was added to the reaction solutions within a few minutes, i.e. not over an extended period, as described by Kabalka's group [10], and with the assistance of ultrasound irradiation, the reactions occurred quickly (within 30-45 minutes) to give the tosylates in good yields (Tables 1 and 2).
In 1974 Fouquet and Schlosser [11] reported the formation of a C-C single bonds by a cross coupling reaction of alkyl tosylates with pertinent Grignard reagents in the presence of lithium tetrachlorocuprate at -78 o C after overnight stirring.Adopting the reaction conditions of Fouquet and Schlosser, but using ultrasound to promote the reactivity, we were able to perform the cross coupling reactions between the tosylates and the Grignard reagents (steps ii and vi) within 30-45 minutes, while still obtaining the products in high yields (Table 3).The aldehydes 6a and 6b can be prepared from the alkenes 5a and 5b by ozonolysis [12].In this work, the alkenes 5a and 5b were oxidized by perphthalic acid, then periodic acid [13], to give 6a and 6b, in of 81-82% yields, respectively, The alcohols 7a and 7b were easily prepared from the aldehydes 6a and 6b in yields of 96-97% by reduction of the latter with sodium borohydride in methanol for 15 minutes.Conclusions 5,9-Dimethylpentadecane was prepared from citronellol in the excellent overall yield of 58% through six steps.By the same procedure, 5,9-dimethylhexadecane was prepared in the overall yield of 56%.The use of ultrasound irradiation combined with the use of optimized repetitive synthetic steps (Scheme 1) offer a convenient method for the synthesis of a variety of related branched hydrocarbons.It should be noticed that also the alkyl groups of the Grignard reagent in steps (ii) and (vi) can be varied.

Experimental
General 1 H-and 13 C-NMR spectra were recorded in CDCl 3 with TMS as internal reference standard at frequencies 300 MHz and 75 MHz, respectively, on a Varian Mercury 300 NMR spectrometer, or alternatively, at frequencies 600 MHz and 150 MHz, respectively, on a Varian Inova 600 NMR spectrometer.GC-MS analyses were performed on a Hewlett Packard 5890 Series II apparatus with a Hewlett Packard 5791A MS detector (column: RTX-5MS, 30 m, 0.25 mm, 0.25 µm).A Sonics GE130 ultrasonic processor was used both in the tosylation and the cross coupling reactions.All reagents were purchased from Aldrich, while solvents were from Labscan.The chloroform used in the tosylation reactions was filtered through a plug of alumina to remove ethanol (present as stabilizer) [10].
General procedure for the tosylation of alcohols: 3,7-dimethyl-6-octenyl 4-methylbenzenesulfonate (4) A mixture of citronellol (6.24 g, 40 mmol), pyridine (6.32 g, 80 mmol), and chloroform (20 mL) was placed in a 3-neck round flask and cooled to 0 o C in an ice bath.p-Toluenesulfonyl chloride (11.4 g, 60 mmol) was added to the mixture within a few minutes under irradiation from an ultrasonic processor.The reaction was finished within 30 minutes.After adding water (10 mL), the resulting mixture was extracted with diethyl ether (70 mL).The ethereal layer was washed with 2 M aqueous HCl, aqueous NaHCO 3 , and brine.The solvent was removed by evaporation at reduced pressure, and the residue was chromatographed on a column (24 x 400 mm, 60 g of silica gel, eluent: 2% diethyl ether in hexane) to give 11

Table 1 :
Preparation of the tosylate 4 under ultrasound irradiation.

Table 2 :
Preparation of the tosylates 8a and 8b under ultrasound irradiation.

Table 3 :
Ultrasound assisted cross coupling reactions between tosylates and Grignard reagents.