DESC:Technical field:
The present invention relates to an efficient process for synthesis of Navel Orange worm (NOW) Pheromone, (Z,Z)-11,13-Hexadecadienal starting from 10-Bromodecanol.

Background and prior art:
Navel orange worm (NOW) is one of the most damaging pests to California almonds and pistachio crops. Because these worms not only bore into the nut and feed on the nutmeat but also opens the door to Aspergillus molds, which can produce aflatoxin contamination. These aflatoxins possess a serious food safety issue and are regulated throughout the world. Therefore, it is necessary to have an integrated pest management approach to reduce the damage from NOW such as orchard sanitation, biological control, harvest timing, mating disruption, among others. The mating disruption is routinely carried out by dispensing a formulation of the pest’s pheromone in the orchard to disrupt mating patterns thereby leading to reduced damage.

(Z, Z)-11,13-hexadecadienal is female-produced sex pheromone of the navel orange worm (Amyelois transitella), was first isolated, identified and synthesised by Coffelt and his co-workers at U.S. Department of Agriculture (Coffelt et al., J Chem Ecol 5:955-966 (1979). This pheromone is an important semiochemical to monitor the population of the orange worm and thus heavily used in the management of the pest disruption.
(11Z,13Z)-11,13-Hexadecadienal is an organic compound although appears to have simple structure, however, the synthesis of this compound is very difficult due to the presence of both an unstable (Z,Z)-conjugated diene system and a labile formyl group. Moreover, the timing of placing the terminal formyl group is also important, owing to the fact that oxidation in the final step may isomerize the (Z,Z)-conjugated diene system. Therefore, highly selective methods have to be employed for constructing the (Z,Z)-conjugated diene system, which exist in the structure of (11Z,13Z)-hexadecadienal.

There is limited literature available on the synthesis of (11Z,13Z)-11,13-Hexadecadienal, which is discussed herein below.

Kenji MORI et al. reported eight step synthesis of (11Z,13Z)-11,13-Hexadecadienal, starting from Commercially available 10-bromo-1-decanol (Biosci. Biotechnol. Biochem., 73 (12), 2727–2730, 2009). According to the disclosures of this article, 10-bromo-1-decanol was reacted with sodium iodide in acetone to give pure monoiodide 3. PCC oxidation of 3 gave crystalline aldehyde 4. This was treated with triethyl orthoformate and p-toluenesulfonic acid in diethyl ether to give 5. Alkylation of lithiumtrimethylsilylacetylide with 5 in THF/HMPA to furnish 6. Desilylation of 6 with potassium carbonate in methanol to afford 1,1-diethoxy-11-dodecyne 7. Sonogashira-Hagihara coupling of 7 with 8 in benzene/n-propylamine in the presence of tetrakis(triphenylphosphine)- palladium (0) and copper(I) iodide to obtain 9. Z-selective reduction of the triple bond of 9 was carried out with 3–4 equivalents of dicyclohexylborane in THF to effect hydroboration of the triple bond. The borane thus obtained was treated with acetic acid to achieve protonolysis and the mixture was poured into ice-cooled aqueous sodium hydroxide, followed by treatment with hydrogen peroxide to give 10. Compound 10 was dissolved in THF and treated with aqueous oxalic acid to deprotect the acetal moiety and give (11Z, 13Z)-11,13-hexadecadienal 1.

The reaction scheme is shown in scheme 1 below.
Scheme 1

Another article reported (Molecules 2019, 24, 1781; doi:10.3390 /molecules24091781) by Fu Liu et al describes Synthesis of (11Z,13Z)-Hexadecadienal. In this article also, the commercially available 10-bromo-1-decanol was used as the starting material. First, 10-bromo-1-decanol was oxidized using pyrindium chlorochromate in CH2Cl2 at room temperature to obtain aldehyde which was treated with triethylorthoformate and p-toluene sulfonic acid in anhydrous ethanol. Following this, the crude product was refluxed with NaI in anhydrous acetone until the end of the halogen exchange reaction. Alkylation of lithium propargyl alcohol (C3 synthon) with 1,1-diethoxy-10-iododecane 5 in tetrahydrofuran/hexamethyl phosphoryl triamide furnished acetylenic compound. Treatment of the acetylenic compound with excess electrolytic manganese dioxide (30 eq) in hexane at room temperature to obtain alkynal 6. The ylide, prepared from n-propyl triphenylphosphonium bromide via a reaction with potassium bis(trimethylsilyl)amide as the base, in a stoichiometric ratio of reagents, reacted with 6 in THF at -70 °C to give (Z)-16,16-diethoxyhexadec-3-en-5-yne 7. Pure product 7 was isolated from the reaction mixture using column chromatography. 3–4 equivalents of alkylborane in THF was used to complete hydroboration of the triple bond. The reaction system was treated with acetic acid to achieve protonolysis. Oxidation of the resulting dicyclohexyl borinate was achieved via the addition of aqueous sodium hydroxide followed by the dropwise addition of hydrogen peroxide. The crude product contained 1 was liberated in the course of protonolysis with acetic acid. Finally, the mixture was dissolved in THF and treated with aqueous oxalic acid to deprotect the acetal moiety and to yield compound 1.
The synthesis is shown in scheme 2 below.

Scheme 2

Synthesis of navel orangeworm pheromone in a stereo-specific manner via acetylene carbocupration is reported in Tetrahedron Letters, Vo1.26, No.27, pp 3285-3288,1985.

Clyde E. Bishop et all has reported the synthesis of (Z,Z)-11,13-hexadecadienal in J. Org. Chem. 1983, 48, 5, 657–660. According to this article, the 10-undecyn-1-ol 3 obtained by bromination-dehydrobromination of undec-10-enyl alcohol, was treated with methanesulfonyl chloride/pyridine in DMF to yield 11-chloro-l-undecyne 4. Treatment of this compound with ethyl magnesium bromide in THF followed by condensation with acrolein yielded 14-chloro-l-tetradecen-4-yn-3-o1 5, which was treated with acetic anhydride/pyridine to yield the desired acetate 6. The conjugated (2)-enyne moiety was obtained by treatment of the acetate 6 with methylmagnesium bromide in THF and a catalytic amount of Li2Cl4Cu, yielding 15-chloro-(2)-3-pentadecen-5-yne 7, which was treated with dicyclohexylborane to yield the desired 15-chloro-(2,2)-3,5- pentadecadiene 8. This was purified by urea inclusion, converted to a Grignard reagent, and reacted with triethyl orthoformate to give (Z,Z)-11,13-hexadecadienal diethyl acetal 9. Purification and cleavage of the acetal 9 with formic acid yielded the desired (Z,Z)-11,13-hexadecadienal 10. The synthetic scheme reported in this article is shown below as scheme 3.

Scheme 3

Another article by P. E. Sonnet & R. R. Heath published in Journal of Chemical Ecology volume 6, pages 221–228(1980). This article reports the reduction of an unsymmetrical conjugated diyne with dicyclohexylborane to obtain (Z,Z)-11,13-hexadecadienal with good isomeric purity.

US 9181164 B1 discloses a method of making an insect pheromone or pheromone precursor, having one or more Z-alkenyl groups, which comprises treating an alkyne with a copper(I)-nitrogen heterocyclic carbene complex (copper(I)-NHC), which facilitates semireduction of the alkyne to a Z-alkene, a reducing agent containing at least one silicon-hydrogen bond, and a proton donor in an organic solvent, thereby forming the insect pheromone or pheromone precursor having one or more Z-alkenyl groups. Example 1 of this patent specifically describes the synthesis of 16,16-(diethoxy)-(Z,Z)-3,5-hexadecadiene and its further conversion into (Z,Z)-11, 13-hexadecadienal (HDAL) is carried out by treating 16,16-(diethoxy)-(Z,Z)-3,5-hexadecadiene with acid and water.

US 8,115,035 B2 discloses another method for synthesis of (Z,Z)-11, 13-hexadecadienal which method employs 10-chlorodecanol as a starting material. According to this method, 10-chlorodecanol was oxidised in presence of TEMPO to obtain 10-chlorodecanal, which is further treated with triethylorthoformate in presence of p-toluenesulfonic acid monohydrate to obtain 10-chloro-1,1-diethoxydecane, which was further treated with lithium acetylide, ethylenediamine complex and NaI to obtain 12,12-diethoxydodec-1-yne. This was further reacted with 1-bromobut-1-yne to obtain 16, 16-diethoxyhexadeca-3,5-diyne. This compound was further treated with N,N-diethylaniline borane (DEANB), followed by acid hydrolysis to obtain (Z,Z)-11, 13-hexadecadienal.

As is evident from the foregoing, highly selective methods must be employed for constructing the (Z,Z)-conjugated diene system to obtain pure (Z,Z)-11, 13-hexadecadienal. In addition, the timing of placing the terminal formyl group is also important, because oxidation in the final step may damage or isomerize the (Z,Z)-conjugated diene system. Therefore, it is also important to select a mild and cost-effective oxidant so as to retain the configuration.

Accordingly, it is an objective of the present invention to provide an efficient alternate synthetic route for preparation of (Z,Z)-11, 13-hexadecadienal (HDAL), using 10-Bromodecanol, as a starting material.

Summary of the invention:
In accordance with the above, the present invention provides an efficient synthesis for the preparation of (Z,Z)-11, 13-hexadecadienal (HDAL), which comprises;
a) protecting hydroxyl functionality in 10-Bromodecanol using Isobutylene gas under acidic conditions to form 10-Bromodecanyl t-butyl ether;
b) coupling the 10-Bromodecanyl t-butyl ether with 3,3-Diethoxypropyne to form the C-13 Acetal Intermediate;
c) hydrolysing the C-13 Acetal intermediate to its corresponding C-13 Aldehyde Intermediate under acidic conditions;
d) converting the C-13 Aldehyde Intermediate into the C-16 Enyne Intermediate via a Wittig reaction with Triphenyl(propyl)phosphonium bromide;
e) converting the C-16 Enyne Intermediate into C-16 Diene intermediate using hydroboration;
f) deprotecting t-butyl ether group under acidic conditions to yield the C-16 Dienol intermediate; and
g) converting the C-16 dienol into (Z,Z)-11, 13-hexadecadienal by oxidizing the hydroxyl group using copper catalyzed-air oxidation.

Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

In accordance with the above, the present invention provides an efficient synthesis for the preparation of (Z,Z)-11, 13-hexadecadienal (HDAL), which process comprises;
a) protecting hydroxyl functionality in 10-Bromodecanol using Isobutylene gas under acidic conditions to form 10-Bromodecanyl t-butyl ether;
b) coupling the 10-Bromodecanyl t-butyl ether with 3,3-Diethoxypropyne to form the C-13 Acetal Intermediate;
c) hydrolysing the C-13 Acetal intermediate to its corresponding C-13 Aldehyde Intermediate under acidic conditions;
d) converting the C-13 Aldehyde Intermediate into the C-16 Enyne Intermediate via a Wittig reaction with Triphenyl(propyl)phosphonium bromide;
e) converting the C-16 Enyne Intermediate into C-16 Diene intermediate using hydroboration-protodeboronation sequence;
f) deprotecting t-butyl ether group under acidic conditions to yield the C-16 Dienol intermediate; and
g) converting the C-16 dienol into (Z,Z)-11, 13-hexadecadienal by oxidizing the hydroxyl group using copper catalyzed-air oxidation.

Accordingly, in a preferred embodiment, the hydroxyl functionality in 10-Bromodecanol is protected by treating with Isobutylene gas in presence of an acid catalyst, such as Sulphuric acid (under acidic conditions) to form 10-Bromodecanyl t-butyl ether. The 10-Bromodecanyl t-butyl ether thus obtained is coupled with 3,3-Diethoxypropyne in presence of sodium amide/ammonia to form the C-13 Acetal Intermediate, which is further converted into C-13 Aldehyde under acidic conditions. C-13 Aldehyde thus obtained is subjected to Wittig reaction with Triphenyl (propyl)phosphonium bromide in presence of potassium ter. Butoxide to afford C-16 Enyne Intermediate.
The C-16 Enyne Intermediate thus obtained is subjected to hydroboration by reacting with dicyclohexylborane followed by acetic acid mediated protodeboronation to obtain C-16 Diene intermediate. The C-16 Diene intermediate is subjected to deprotection by treating with an acid catalyst such as pTSA to obtain C-16 Dienol intermediate. Finally, the C-16 dienol intermediate is subjected to (bpy) CuI/TEMPO-catalyzed aerobic oxidation in acetonitrile as solvent system to afford (Z,Z)-11, 13-hexadecadienal.
The copper (I) based oxidation catalyst, viz., (bpy) CuI/TEMPO, as used in the present invention is mild and efficiently oxidises C-16 dienol intermediate to afford (Z,Z)-11, 13-hexadecadienal in very good yields.

The synthesis for the preparation of (Z,Z)-11, 13-hexadecadienal (HDAL), is shown in scheme 4.
Scheme 4:

The following examples are presented to further explain the invention with experimental conditions, which are purely illustrative and are not intended to limit the scope of the invention.
Scheme 4 shows the synthesis of (Z,Z)-11, 13-hexadecadienal (HDAL):

Experimental details
Example 1. Synthesis of 10-Bromodecanyl t-butyl ether:
Charge 10-Bromodecanol (100gr) and Hexane (400ml) into the RBF add sulphuric acid (2.0gr) to RM at RT. Pass the isobutylene gas (28.3gr) into the mass. Stir the reaction mixture up to reaction complies. After completion of the Reaction, add Sodium bicarbonate solution (800ml) to the mass, separate both layers, distil off the hexane under vacuum obtain 10-Bromodecanyl t-butyl ether (117gr) analysed by GC with Yield: 95% and > 92 % purity.

Example 2. Synthesis of 13-tertiary butoxy-2-tridecyn-1-al:
Condensed the ammonia(100ml) into the RBF at -60°C, add THF (100ml) and sodamide (19.94gr) to the ammonia at -40°C. Slowly add 3,3-diethoxypropyne(69.8gr) to the mass for 1 hour and followed by the addition of 10-Bromodecanyl t-butyl ether (100gr). Stir for 2 hrs, evaporated ammonia and quench the reaction mass with ammonium chloride solution, extract the compound with hexane, distil off hexane and THF under vacuum to obtain C-13 Acetal Intermediate(58.1gr) analysed by GC with Yield: 50% and > 94 % purity.

Charge C-13 acetal intermediate and MDC (300ml) into the RBF. Add HCl(58.1ml) to the mass at RT, stir the RM for 3hrs at RT Add water(300ml) to the mass. Extract the compound in MDC and wash the MDC layer with sodium bicarbonate solution. distil off MDC under vacuum to obtain 13-tertiary butoxy-2-tridecynal (43.0g) analysed by GC with Yield: 94.9% and > 92 % purity.

Example 3. Synthesis of (Z)-16-tert-butoxyhexadec-3-en-5-yne:
Charge THF (350ml) under N2 atmosphere and add propyl triphenyl phosphonium bromide (173 g), stir followed by the addition of potassium tertiary but oxide (50.4 g) in portion wise to the mixture, stir and cool the mixture to -10°C and slowly added 13-tertiary butoxy-2-tridecynal (100 g), stir for 1hr, check GC. Add water to the mass and separate aqueous and THF layer, extract the aqueous layer with hexane (400 ml), distil off the THF layer under vacuum and distil product under high vacuum to get yield (Z)-16-tert-butoxyhexadec-3-en-5-yne (60 g) analysed by GC with Yield: 55% and > 94 % purity.

Example 4. Synthesis of (3Z,5Z)-16-tert-butoxy hexadecadiene:
Charge THF (250ml) and N,N-diethyl aniline borane complex(150g) into the RBF, cool to 0°C Add cyclohexene(157g) to the mass and stir the mass for 2 hrs at 5-10°C add (Z)-16-tert-butoxyhexadec-3-en-5-yne (100g) compound to the mass at 5-10°C. stir the RM for 16hrs at RT. Add acetic acid (106g) to the RM and raise the temp to 50-55°C. Stir the mass for 2 hrs at 50-55°C. cool the mass to RT. Add 50% of hydrogen peroxide (97.6g) to RM at 25-30°C. Add water (800ml) to the mass. Extract the product with hexane (300ml). Wah the hexane layer with water(1.0Lt). Distil off the hexane under vacuum to get (3Z,5Z)-16-tert-butoxy hexadecadiene (95gr) analysed by GC with yield 95% with 94% purity.

Example 5. Synthesis of (Z,Z) 11,13-hexadecadiene-1-ol:
Charge methanol(400ml) and (3Z,5Z)16-tert-butoxy hexadecadiene (100gr) into the RBF. Add Sulphuric acid(3.3gr) to the mass at RT. Raise the mass to reflux, stir the RM for 8-10hrs reaction monitored by GC, after completion of the reaction, distil off the methanol and add water(400ml) and hexane(300ml), wash the hexane layer with sodium bicarbonate solution(300ml). Distil off the hexane under vacuum to get (Z, Z)11,13-hexadecadiene-1-ol (70g) analysed by GC with yield 86.5% with 94% purity.

Example 6. Synthesis of (Z, Z)11, 13-hexadecadien-1-al
Charge acetonitrile (500ml) and (Z,Z)11,13-hexadecadiene-1-ol (100gr) into the RBF at 25-30?. Add tetrakis acetonitrile copper triflate in ACN (25%) (31.6gr) and followed by 2,2’-bipyridine (3.25g) to the reaction mass at 25-30?. Stir the mass for 5 minutes as the colour turns to dark red. Subsequently add TEMPO (3.25g) to the mass followed by N-Methyl imidazole (3.4g). Stir the reaction mass at 25-30? until completion of reaction. After completion of the reaction, distil off 80% of the acetonitrile under reduced pressure below 50°C.Add water(400ml) and followed by hexane(200ml) to the mass at 25-30?. Extract the product with Hexane(200ml). Distil off the hexane under vacuum to get (Z, Z)11,13-hexadecadiene-1-al (85.0g) analysed by GC with yield 85.9% with 94% purity.
,CLAIMS:1. A Novel process for preparation of a sex attractant pheromone (Z, Z)-11,13-Hexadecadien-1-al using 10-Bromodecanol comprising the steps of:
a) protecting hydroxyl functional group of 10-Bromodecanol using isobutylene gas under acidic conditions to obtain 10-Bromodecanyl t-butyl ether;
b) coupling the 10-Bromodecanyl t-butyl ether with 3,3-diethoxypropyne to obtain the C-13 acetal intermediate;
c) hydrolysing the C-13 acetal intermediate to its corresponding C-13 aldehyde intermediate under acidic conditions;
d) converting the C-13 aldehyde intermediate into the C-16 enyne intermediate via a wittig reaction using triphenyl(propyl)phosphonium bromide;
e) converting the C-16 enyne intermediate into C-16 diene intermediate using hydroboration & protodeboronation sequence;
f) deprotecting t-butyl ether group under acidic conditions to yield the C-16 dienol intermediate; and
g) converting the C-16 dienol into (Z,Z)-11, 13-hexadecadienal by oxidizing the hydroxyl group using copper catalyzed-air oxidation.

2. The process for preparation as claimed in claim 1, wherein the step a), and step f), is carried out under acidic conditions sulphuric acid as a catalyst at room temperature.

3. The process for preparation as claimed in claim 1, wherein the step b, is carried out under in presence of sodamide and ammonia.

4. The process for preparation as claimed in claim 1, wherein the step c, is carried out in presence of hydrochloric acid.

5. The process for preparation as claimed in claim 1, wherein the step d, is wittig reaction carried out under at -10 deg C in presence of THF solvent.

6. The process for preparation as claimed in claim 1, wherein the step g, is Stahl oxidation that is carried out in presence of copper (I) catalyst using solvent acetonitrile at room temperature.

7. The process for preparation as claimed in claim 1, wherein the (Z, Z)-11,13-Hexadecadien-1-al is sex attractant insect pheromone.