GB2104061A - 2,3-Dihydropyrans and methods for combatting insects therewith - Google Patents

Description

1 GB 2 104 061 A 1

SPECIFICATION

2,3-Dihydropyrans, processes for their preparation, and methods for combating insects therewith The present invention is directed to a class of compounds which can be described generally as 2,3-dihydropyrans. The invention is also directed to processes for the preparation of these compounds and to methods for the use of the compounds in the control of insects such as tobacco beetles.

4,6-dimethyi-7-hydroxynonane-3-one (Serricornin) is a known pheromone component of the female tobacco beetle Lasioderma serricorne R; see Tetrahedron Letters 25, 2361 (1979).

The present invention is based on the discovery that 2,6-diethyi-3,5dimethyi-2,3-dihydroxy-4Hpyran (anhydroserricornin) is a further, hitherto unknown, pheromone component of the female tobacco beetle Lasioderma serricorne. The concentration of anhydroserricornin in the sexual lure of the tobacco beetle is about 10 times smaller than that of the serricornin; however, with respect to its sexual luring action and mating inducing action, anhydroserricomin has, surprisingly, been found to be about 1,000 times more powerful than serricornin.

Accordingly, the invention is directed to 2,3- dihydropyrans of the general formula R 4 R 3 1 R:0., a_R2 1 0 (1) RI, R21 R,, and R4 denote alkyl groups having one to four carbon atoms. Alternatively either one or two of the R groups may be hydrogen atoms.

Compounds of the general formula (1) have several asymmetric centres and the various optical isomers of the compounds are within the scope of the present invention.

Although the 2,6-diethyi-3,5-dimethyi-2,3- dihydroxy-4H-pyran occurs naturally as a pheromone component of the female tobacco beetle Lasiderma serricorne, it is of no practical value due to its low concentration therein, and the 100 difficulties of separating it into a pure form which then may be used to combat insects as will be disclosed below.

The compounds of the present invention may be prepared by the reaction of a hetetocyclic nitrogen compound with a ketone in the presence of a condensing agent to yield an enamine. The enamine is then reacted with a vinyinitrile; the resulting intermediate is hydrogenated and then reacted with an alkyl magnesium bromide and hydrolized to yield a hydroxy ketone. The hydroxy ketone is then cyclized to yield the 2,3-dihydropyran.

Alternatively the compounds of the present invention may be prepared starting with a cyclo- 105 with n being 1 or 2, or alkyl amine of 5 to 6 carbons which is reacted with a ketone to yield an azomethine. The azomethine is reacted with an alkyl Grignard reagent having 1 to 5 carbons to give an enaminium salt which is then converted by reaction with a vinyinitrile and subsequent hydrolysis and hydrogenation to a hydroxy alkyl nitrile. This intermediate is then reacted with an alkyl magnesium bromide having from 1 to 4 carbons and hydrolized to yield a hydroxy ketone which is then cyclized to yield the 2,3-dihydro- pyran.

The 2,3-dihydropyrans are used as synthetic lures in a method to detect insects comprising applying the compounds of the present invention to a suitable carrier to act as a baited trap. Alternatively the insects may be combated directly by administering an overdose of the compounds or by combining the compounds with an insecticide or other insect control agent.

The compounds of the present invention have the general formula X 4 R3 1 R.141 n^ 1 0 'R2 (1) One or two of the groups, RV R21 R3, and R,, may be hydrogen atoms. At least two and preferably all four of the R groups are alkyl radicals having from one to four carbon atoms. The alkyl groups may be methyl, ethyl, n-propyl, ipropy], n-butyl, sec.-butyl or tert.-butyl groups.

Compounds of the invention according to the general formula (1), wherein the groups Rj, R2, R3 and R4 denote alkyl groups having 1 to 2, carbon atoms, are preferred. The abovementioned anhydroserricornin corresponding to the general formula (1), wherein the groups IR, and R2 denote ethyl radicals and the groups R3 and R4 denote methyl radicals, is particularly preferred.

The compounds of the invention can be obtained by a process in which pyrrolidine, piperidine or morpholine is reacted with a ketone of the general formula 0 it 1 111 C112-R4 in the presence of a condensing agent, for example titanium tetrachloride or a carbodflmide, to give an enamine of the general formula c (CH 2) n N) ..lk4 2 GB 2 104 061 A 2 The azomethine IX is then reacted with a Grignard reagent of the general formula (111b) 30 R-MgX (X) R 4 R 1 The compounds (ilia and b) are reacted with a vinyinitrile of the general formula where R is an alkyl group having from 1 to 5 carbon atoms and X is a halogen atom. The resulting reaction product is an enamium salt of the general formula.

3 (C R M9X 0--- CH-R (Xl) Y OV) n-C CN 35 to give a compound of the general formula R 4 P13 4:: Tr-IN the compound (V) is hydrogenated to give a compound of the general formula "4 np-3 R 1 H the compound (V1) is reacted with an alkyimagnesium bromide of the general formula Rj-1V1g13r and the resulting intermediate is hydrolysed to give a compound of the general formula (V) (V1) (VIO 55 3'411 f"" "3 R 1 013 R2 (V] 11) The compound (VIII) thus obtained is cyclized to give a 2,3-dihydropyran (1). In these formulae, the groups Rj, R 21 R 3 and R 4 have the meanings given above.

Alternatively the 2,3-dihydropyran may be prepared starting with cyclopentylamine or cyclo hexylamine which is reacted with a ketone of the general formula 11 to give an azomethine of the general formula (C] 1 2) " 7 OX) CH -R 2 4 in which m=1 or 2 and R1 and R4 are defined as above.

Compound (M) is then reacted with a vinylnitrile of the general formula (IV) and is then subsequently hydrolized to yield a compound of the general formula (V). Compound (V) is hydrogenated to yield (V1), reacted with an alkylmagnesium bromide (VII) and hydrolysed to yield (VII0 which is then cyclized to yield the 2, 3dihydropyran (1).

The invention is further directed to the use of 2,3-dihydropyrans of the general formula (1) for the early detection, localisation and combating of insect pests, particularly Lasioderma serricorne F. The compound of the present invention may be used in methods to detect infestations, to delineate infestations and to estimate insect populations. In addition, the present invention provides a means for interferring with and confusing mating communication of insects. Alternatively, insects may be trapped using the compounds as an attractant or directly destroyed using the compounds in conjunction with insecticides.

For these purposes, the compounds of the invention, which are synthetically-prepared lures, can be applied in tobacco store rooms or other infested areas in an amount sufficient to attract the insects to a specific location. For example the compounds may be used in baited traps with customary solid or liquid carriers, insecticides and/or insect control agents. Examples of suitable carrier materials are paper, corrugated board, plastics, rubber and the like. In this manner, even a trivial attack by tobacco beetles can be detected, so that suitable measures for combating them can be taken in time. The insects can also be directly combated, for example, by administering an overdose of the sexual lure and thereby interferring with the mating communication or by administering a combination of this substance with insecticides or insect control agents.

In the accompanying drawing, the sole Figure, Fig. 1, is a graph comparing the relative attractive powers of the known pheromone, Serricornin, and the preferred 2,3-dihydropyran of the present invention, Anhydroserricornin, at different concentrations.

3 Example

Preparation of Anhydroserricornin The preparation of 2,6-diethyi-3,5-d im ethyl- 2,3-dihydroxy-4H-pyran (anhydroserricornin) is 65 described below.

A. N-(1-Ethyi-l-propenyi)-pyrrolidine A solution of 104.35 g of titanium tetra- chloride (0.55 mol) in 100 mi of pentane was added dropwise to a mixture of 86.15 g of pentan-3-one (1 mol), 213.36 g of pyrrolidine (3 mols) and 1.8 1. of pentane, under dry nitrogen.

During this process, the temperature of the reaction mixture was kept between OOC and 1 OIC by cooling with ice. The mixture was then stirred for a few more hours at room temperature and was left to stand overnight. The pentane was decanted off from the precipitate, and the latter was carefully hydrolyzed with ice. The aqueous phase was rendered alkaline with dilute KOH and 80 was extracted with ether.

The combined organic phases were dried over sodium sulphate, the solvent was removed and the residue was distilled.

Yield: 74.8 g=53.7%; bp.=71-73 IC/1 5 mm Literature reference: analogously to W. A.

White, H. Weingargen, J. Org. Chem. 32,213 (1967).

B. 5-Oxo-2,4-dimethyiheptanitrile A solution of 63 g (0.425 mol) of A as prepared above and 30.3 g (0.425 mol) of methacrylonitrile is heated under reflux to a boil for 20 hours in 500 mi of absolute ethanol. 120 m] of water are then added to the mixture, and the latter is again boiled 95 for 90 minutes. The bulk of the solvent is then removed; 300 mi of water are added to the mixture; and the mixture is extracted several times with ether. The ether phase is washed several times with dilute FICI, dried over sodium sulphate, 100 concentrated and distilled in vacuo.

Yield: 32.3 g=46.6%; bp.=1 07-113 IC/1 5 mm Literature reference: analogously to G. Storck et al., J.A.C.S. 85,207 (1967).

C. 5-Hydroxy-2,4-dimethyiheptanitrile 32.3 g (0.211 mol) of B are carefully added dropwise to a solution of 5. 15 g (0. 136 mol) of sodium borohydride in 500 mi of absolute ethanol and the mixture is then stirred for two days. The hydrolysis is effected with approximately 100 mi of dilute HCI. The solvent is then stripped off, and the residue is taken up with ether, washed with water and dried over sodium sulphate. After the solvent has been removed, the residue is distilled in vacuo.

Yield: 25.! g=77%; bp.=1 300C/1 5 mm Literature reference: analogously to Organikum D. 4,6-Dimethy]-7-hydroxy-3-nonanone 25.5 g (0.164 mol) of C in 50 m] of absolute ether are carefully added dropwise to a solution of GB 2 104 061 A 0.41 mol of ethyl-magnesium bromide (obtained from 44.8 g of ethyl bromide and 10 g of magnesium chips) in 660 mi of absolute ether, and the solution is heated under reflux to the boil for 3 hours. The mixture is thereafter hydrolyzed overnight with saturated ammonium chloride solution, the ether phase is separated off, the aqueous phase is extracted several times with ether and the combined organic phases are dried over magnesium sulphate.

The crude product is not isolated, but is immediately further processed.

Serricornin can also be isolated from the crude product after removal of the solvent (in a neutral medium). The process according to the stages A to D thus also represents an excellent process for the preparation of serricornin.

E. 2,6-Diethyi-3,5-dimethyl-2,3-dihydro-4Hpyran The ether phase contained D is stirred for approximately 1 hour over 10% strength hydrochloric acid and separated off, and the aqueous phase is extracted several times with ether. The combined ether extracts are dried over a mixture of sodium sulphate and sodium carbonate, the solvent is removed and the residue is distilled in vacuo.

Yield: 7.3 g=26.5%; bp.=89-930C/20 mm The anhydroserricomin obtained according to the procedure above is identical with natural anhydroserricornin in the sexual lure of the female tobacco beetle Lasioderma serricorne. By means of a gas chromatographic examination of a pheromone extract from female tobacco beetles which had not mated, natural anhydroserricomin was first detected and isolated. A gas chromatograph Fractovap 2101 of Messrs. Carlo Erba, with a glass capillary (WCOT [wall coated open tube] coated with Superox as the separating phase), length 25 m, diameter 0.2 mm, was used for this purpose. Helium (3 mVmin) was used as the carrier gas; the split was 1:20; the temperature program was established as f61lows:

Temperature program: 601 to 1801C at 3.30C/min.

The anhydroserricornin peak appeared after about 4 minutes; the peak of the serricornin appeared after about 20 minutes.

The structure of anhydroserricornin was determined by mass spectroscopy and was finally confirmed by an independent synthesis according to the example above.

Pheromone activity Tests for comparing the pheromone activities of serricornin and anhydroserricornin are reported below.

Lasioderma serricome, which also attack the tissue of plant species other than Nicotiana tabacum, were bred from crushed corn with an additive of 5% of dried beer yeast, at 26+11 OC and at 55+5% relative atmospheric humidity, and 4 GB 2 104 061 A 4 with a photoperiod of 14 hours light and 10 hours darkness. Male and female beetles were recognized either by external distinguishing characteristics of the pupae, or by microscopic 5 examination of the sex organs of the imagines.

For the comparison of the pheromone activities of serricornin and anhydroserricornin, tests were carried out using laboratory-bred populations of tobacco beetles. 50 male and 50 female tobacco beetles, at an age of 5 to 10 days after the emergence from the pupal state, were conditioned for 24 hours in a 2 1. glass vessel, covered with perforated aluminium foil which has a central slit. Rectangular strips of filter paper (12 x 3 cm), impregnated with increasing quantities of serricomin or anhydroserricornin, were hung from the covering of the glass vessels. Soon thereafter, the male beetles were observed to fly in the direction of the small region (diameter about 8 mm) which contains one or other of the abovementioned components. After landing, the beetles travel in a circular and zigzag-like pattern to the pheromone source, where they aggregate for varying lengths of time. The number and duration of the visits and copulation attempts prove to be dependent on the component present and the dosage (observation time 30 minj. A comparison of these parameters shows that the activity of anhydroserricornin is about 1,000 times greater than that of the serricornin. Within a range of 10-6-10-2 micrograms, the increase in the attractive action in the case of anhydroserricomin is conpiderably greater than for serricornin. For a dose of 10-1 micrograms and more, an adaptation to both components is shown (cf. Fig. 1). In the presence of 101 up to 100 micrograms of anhydroserricornin, male tobacco beetles gather in great numbers on both sides of the treated section of paper and attempt to copulate with one another. Serricornin applied in the same quantity merely causes a few beetles to perform this gathering and copulation.

Claims (12)

Claims

1. A 2,3-dihydropyran of the general formula:

X 4 R 3 1 R 1 0 R2 wherein Rj, R2 and R 3 and R. are hydrogen or alkyl groups having from 1 to 4 carbon atoms; and where at least two of the groups Rj, R2, R3 and R. are said alkyl groups; including all optical isomers thereof.

2. A 2,3-dihydropyran as claimed in claim 1, wherein RP R2, R3 and R4 are alkyl groups having from 1 to 4 carbon atoms. 55

3. A 2, 3-dihydropyran as claimed in claim 2, wherein F1p F12, R3 and R,, are alkyl groups having 1 or 2 carbon atoms.

4. A 2,3-dihydropyran of the formula:

CH 3 CH3 0 c H5 Z including all optical isomers thereof.

5. A process for the preparation of a 2,3- dihydropyran as claimed in claim 1 comprising:

reacting a heterocyclic nitrogen compound chosen from pyrrolidone, piperidine, or 65 morpholine with a ketone of the general formula 0 R 1..1,- ([,, CH2-R 4 (11) in the presence of a condensing agent to yield an enamine having a general formula c (CH 2)n N) R 1.I4 with n=l, or 2, or c) R 4 R 1 (ilia) Ollb) reacting said enamine with a vinyinitrile of the general formula Y R3 CN OV) to yield an intermediate V having the general formula R 4 'R XX YCN.3 (V) hydrogenating said intermediate V to yield an intermediate VI having the general formula N 3 H Ct; P-3 R 1 reacting said intermediate VI with an alkyl magnesium bromide of the general formula (V1) Ri --- MgBr (V11) to yield an intermediate and then hydrolyzing said intermediate to yield an intermediate Vill having the general formula R4 C 'S R 1 OH -R2 and cyclizing said intermediate Vill to yield the 2,3-dihydropyran.

6. A process for the preparation of a 2,3dihydropyran as claimed in claim 1 comprising:

reacting cyclopentylamine or cyclohexylamine with a ketone of the general formula 0 it 1 1_ f, C1U2-R4 to yield an azomethine having the general formula IX (C 2)3n R 101 1 N==C CH2-R4 GB 2 104 061 A 5 hydrogenating compound V to yield a compound of the general formula R4 3 R 1 nNCN reacting compound V1 with an alkyl magnesium bromide of the general formula R--MgBr (V1) (V11) to yield an intermediate and then hydrolyzing said intermediate to yield a compound having the 35 general formula (1x) where m=l or 2; reacting the azomethine with a Grignard reagent having an alkyl group of from 1 to 5 40 carbon atoms to yield an enamium salt; reacting the enamium salt with a vinyinitrile of the general formula Y R 3 CN fiv) 45 to yield a reaction product and then hydrolyzing said reaction product to yield a 50 compound of the general formula R4 P, 3 R CIR R4 R 3 R 1 foR C R2 (V) 55 (V111) and cyclizing said compound Vill to yield the 2,3-dihydropyran.

7. A 2,3-dihydropyran as claimed in claim 1 substantially as hereinbefore described.

8. A method of combating insects comprising subjecting the insects to a 2, 3-dihydropyran as claimed in any one of claims 1 to 4 or claim 7 in an amount sufficient to attract the insects to a specific location.

9. A method as claimed in claim 7 wherein the 2,3-dihydropyran is applied in conjunction with a solid or liquid carrier.

10. A method as claimed in claim 8 or claim 9 wherein the 2,3dihydropyran is placed in insect traps.

11. A method as claimed in any one of claims 8 to 10 wherein the insect to be combated is the tobacco beetle Lasioderma serricorne F.

12. A method as claimed in claim 8 substantially as hereinbefore described.

Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1983. Published by the Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained