CA1086734A

CA1086734A - Morpholine derivatives

Info

Publication number: CA1086734A
Application number: CA291,886A
Authority: CA
Inventors: Walter Himmele; Ernst-Heinrich Pommer; Norbert Goetz
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 1976-12-15
Filing date: 1977-11-28
Publication date: 1980-09-30
Also published as: AT356455B; DE2656747A1; MY8500333A; JPS5377070A; NO146026B; FI781117A; NO781229L; SU667101A3; NL190012B; LU79385A1; FR2374315A1; KE3165A; NL190012C; SE7804074L; CS195346B2; BE861828A; AU3556578A; BR7708252A; HU178175B; NL7713685A

Abstract

ABSTRACT OF THE DISCLOSURE: New and valuable morpholine deriva-tives and salts thereof, having a good fungicidal action, fungi-cides containing these compounds as active ingredients, and processes for combatting fungi with these compounds.

Description

~ V 516734 The present invention relates to new and valuable morpholine derivatives and their salts and molecular compounds and adducts, having a good fungicidal actionl Eungicides containing these compounds, and processes for combatting fungi with these compounds.
The use of N-tridecyl-2,6-dimethylmorpholine and its salts, molecular compounds and adducts as fungicides has been disclosed (German 1,164,152, German 1,173,722, German -Laid-Open Application DOS 2,461,513).
We have now found that morpholine derivatives of the ~ :
formula R3 Rl CH -C ~ CH2-CH-CH2-N O

R2 :.
where Rl, R2, R3 and R4 denote hydrogen, methyl or ethyl, and their salts, moleeular compounds and~adduets have a good fungieidal aetion which is superior to the aetion o prior art morpholine derivatives.
~ Examples of salts are those wi~th inorganic or organic aeids, e.g., ehlorides, fluorides, bromides, iodides, sulfates, nitrates, phosphates, aeetates, propionates~and fumarates.
Moleeular eompounds and adduc~ts are formed for i-nstanee with aeids o~f surfaetants, e.g., dodecylbenzenesulfonie acid.
.. . .. ,, ': .
I~ the~new~eompounds are 2,6-dimethyl derivatives, they may ~e isolated as Ci6 and trans isomers.
The morpholine derivatives of the invention are . .
prepared by reaeting 3-p-tert-butylphenyl-2-methylpropanal of the formula~

~ CH3 CH3 ~ O
~ ~ ; CH3-C ~ CH2-CH-C
CH3 ~ H

:: : ; - 1 - .::

`: :,' is reacted with a morpholine of the Eormula R Rl ~/
H - N b R2 ~ R4 whère Rl, R , R3 and R4 have the above meanings, in ~he presence of formic acid, with or without a diIuent, at temperatures of from 50 to 110C.
The preparation of the new compounds is illustrated by the following examples. ~-~

Synthesis of N-(3-p-tert-butylphenvl-2-methyl-1-propyl)-cis-

2,6-dimethvlmorpholine ~ , .
2,6-Dimethylmorpholine which has been obtained by suIfuric acid-catalyzed cyclization of diisopropanolamine is separated into the cis and trans forms by fractlonal distillation in a column packed with steel mesh coils. About 75 wt% of~the 2,6-dimethylmorpholine is in the cis configuration, the remainder in the trans form. The isomers are separated by fractional distillatlon i.n a column having about 40 theoretical plates. The cis form dis~ils as a 99~ product at 80 to 81C and a pressure of 100 mm Hg. ~The trans-form of 2,6-dimethylmorpholine may be obtained under the same conditions at 88 to 89C/100 mm Hg as~ a more than 95~ product.
575 g of 98% formic acid is placed in a stirred apparatu8 equipped with reflux condenser, thermometer and dropping funnel.~ While stirring and cooling 345 g of 99% 2,6-cis-; dimethylmorpholine is then dripped in. ~he~mix*ure issubsequently slowly heated on a water bath to 70C. Over a ~period of~4~ho~urs,~ 612 g of 3-p-tert-butylphenyl-2-methylpropanal 30~ ~ is dripped lnto the reaction mixture, a temperature of approx. -100C being~maintained. Condensation proceeds with marked ;~evolu~tion of~CO2. Upon conclusion of the reactlon the mixture : : L~ :: : 2 -.~. .~,.: :. : . :
: . . . .

.
is kep~ for 2 hours at 100C while s~irriny.
.
The excess formic acid is then d.istilled o~f undex reduced pressure. Substantial separation of the formic acid ~is achieved under a water pump vacuum at 100C.
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,. ~ ~ : ~ - . . ' ' -,: ' :
, :. : : . , :, : .: ~ ' ' .

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' ' ~ ~ ' , ,,, :.

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, . : .. ' ' :.:

2à --- .

~lO~ Ei734 ~ O.Z. 32,325 The base is liberated from the formate by dripping in 500 g o~ 40% aqueous caustic soda solutionO The caustic soda solution is advantageously added at from 80 to 100C to facilitate ad-mixture of the amine phase which forms with the caustic phase.
200 g of toluene is added to depress the viscosity. After separation of the caustic phase, the organic phase is washed twice with water, each time with 250 g.
For further purification, the amine is fractionally distil-led at 0. 2 mm Hg in a distillation column having 5 trays. In addition to a small amount of first runnings (up to 143C/0.2 mm Hg;
50 g), there is obtained 865 g of N-(3~tert-bu~ylphenyl)-2-methyl 1-propyl)-2~6-cis-dimethylmorpholineg which distils at 0.2 mm Hg between 14~ and 146C. According to gas-chromatographic analysis~
the amine is more than 98% pure. With reference to aldehyde~ the yield was 84.5%.
To convert the compound to the hydrochloride, 30 g of the pure product is dissolved in 50 g of ethanol which has been saturated with hydrogen chloride at room temperatureO After cooling, there is obtained 23 g of the hydrochloride (m.p. 220C) in very pure form.

Synthesis of N-(3-p-tert-butylphenyl-2-methyl-1-propyl )-?~-trans-dimethylmorpholine While cooling with ice, 29 g o~ 2,6-trans-dimethylmorpholine is introduced into 70 g of 98% formic acîd, While stirring, 41 g o~ 3-p-tert-butylphenyl-2-methylpropanal is then added. The reaction mixture is heated for 6 hours at 100C. IJpon commencement Or the reaction~ very strong C02 e~olution takes place which drops noticeably a~er about an hour. Further working up is effected :
as disclosed in more~detail in Example 1,

3 N-(3-p-tert-butylphenyl-2-methyl-1-propyl)-2,6-trans-di-methylmorpholine dist~lls at 168-169C (5 mm Hg). The yield is ~ 3~

~ 734 o.z. 32,325 52 g (86% of theory, with reference to aldehyde). 11 g of the amine is dissolved in 20 g o~ ethyl acetate which has been saturated with anhydrous hydro~en chloride. The hydrochloride crystallizes out upon cooling; m.p.: 165C.
The other compounds are obtained analogously.
Examples of compounds accordin~ to the invention are ~iven below:
CH CH
3 , ~ CH2-CH-CH2-Compound no.
1 R-N ~ b.p.: 123C/0.01 mm 2R-N ~ 0 ,H25C12 ~ m.p.: 108C

~~ ~ CH3 3 R-~ 0 ~b.p.: 143-146C/0.2 mm \~

cis form nT~
~ 3

4 R-~ 0 b.p.: 168-169Ci5 mm trans form R-N ~ .HCl m.p.: 220C

; cis ~orm ~ 3S73~
O.Z. 32,32 ~ CH3 6 R-N O .HCl m.p.: 165C
CH
trans form 3 10R-N ~ b.p.: 128C/0.02 mm 11R-N ~ b.p.: 133C/0.05 mm 3 .
CH ~
12R-N ~ ~ b.p.: 125C/0.02 mm , . .
13 R-N~_~0 b.p.: 170C/5.0 mm 14 R-N ~ . HCl m.p.: 206C

15R-N O b.p.: 145C/0.3 mm H3C . :
16R-N ~ O . HCl m.p.: 172C

2 5 .
17R-N ~ b.p.: 148C/0.3 mm ~ 2 5 18R- ~ O b~p.: 146-148C~0.3 mm ~ CH3 19R-N ~ .HBr m.p.: 228C

cis ~orm ~ CH3 R-N 0 .HOOC ~ CH m.p.: 174C
~ CH3 HC COOH
cis form _ 5 -, - - -- - .: - - . . .. -:

~ 34 ~). z. 32,~25 The active ingredients according to the invention and the fungicides containing them are partlcularly suitable for combatting plant diseases such as Erysiphe ~raminis in cereals, Erysiphe cichoriacearum in Cucurbitaceae, Podosphaera leucotricha in apples, Uncinula necator in grapes,Erysiphe ~olygoni in beans, Sphaerotheca annosa in roses, r~icrosphaera querci in oaks, Botrytis cinerea in strawberries and grapes,r~ycos~haerella musicola in bananas, Puccinia species (rusts) in cereals, IJromyces appendiculatus and U. phaseoli in beans, Hemileia vastatrix in coffee, and Rhizoctonia solani. They have a systemic action; they are not only taken up by - the roots but also absorbed by the leaves, and are translocated in the plant tissue.
Application is effected for instance by watering, spra~ing, dusting, or disinfecting the plants or treating the seed wlth the active ingredients.
When the new active ingredients are used to protect plants against fungus infec~ion, the application rates are from 0.025 to

5 kg of active in~redient per hectare. For the surface protection of trees or fruit, the active ingredients may also be used in combinatioh with plastics dispersions in amounts of from 0.25 to 5%, based on the weight of the dispersion. In general, the fungi-cides contain from 0.1 to 95, preferably from 0.5 to 90, wt~ of active ingredient.
The active ingredients may also be mixed with other, prior art, fungicides. In many instances, the spectrum of fungicidal action is increased; with a number of fungicidal compositions in the weight ratio range of 1:10 to 10:1 synergistic effects also occur, i.e.~ the fungicidal action of the combination product is greater than the effect of the individual components added together.
Exam~les Or fungicides which may be combined with the compounds of the invention are dithiocarbamates and derivatives thereof, e.g1, zinc dimethyldithiocarbamate ~''.

- 6 -4 o.z. 32,325 manganese ethyleneb isdithiocarbamat zinc ethylenebisdithiocarbamate tetramethylthiuram disul~ide ammonia co iex o~ zinc-(N,N'-ethylene-bisdithiocarbamate) and N,N'-polyethylene-bis-(thiocarbamoyl)-disul~ide ammonia complex of zinc-(N,N'-propylene-bisdithiocarbamate) and N,N'-polypropylene-bis-(thiocarbamoyl)-disulfide heterocyclic structures, such as N-trichloromethylthiotetrahydrophthalimide N-trichloromethylthiophthalimide N-(1,1,2,2-tetrachloroethylthio)-tetrahydrophthalimide methyl 1-(butylcarbamoyl)-2-benzimidazole carbamate 2-methoxycarbonylaminobenzImidazole . .
2,3-dihydro-5-carboxanilido-6-methyl-1~4-oxathiin-~,4-dioxide 2~3-dihydro-5-carboxanilido-6-methyl-194-oxathiin 5-butyl-2-dimethylamino-4-hydroxy-6-methylpyrimidine 1~2-bis-(3-ethoxycarbonyl-2-thioureido)-benzene 1,2-Ois-~3-methoxycarbonyl)-2-thioureido)-benzene and various fungicides, such as dodecylguanidine aoetate N-dichlorofluoromethylthio-N'9N'-dimethyl-N-phenylsulfuric acid diamide 2,5-dimethylfuran-3-carboxylic acid anilide 2,5-dimethylfuran-3-carboxylic acid cyclohexyl amide 2-iodobenzoic acid anilide 2-bromobenzoic acid anilide 3-nitroisophthalic acid diisopropyl ester 30 ~ 1,2~4-triazolyl-1') Ll- ( 4'-chloropheno~y)]-3,3-dimethyl-butan-2-one imidazolyl)-2-allylo~J-2-(2,4-dichlorophenyl)-ethane .
~ ~ ~ ~ 7 ~ ~ -6,734 O.Z. 32,325 piperazine-1,4-diyl-bis-1-(2,2,2-trichloroethyl)-formamide 2~4,5,6-tetrachloroisophthalonitrile 1,2-dimethyl-3,5-diphenylpyrazoliniummethylsulfate.
Application may be effected for instance in the form of directly sprayable solutions, powders, suspensions, dispersions, emulsions, oil dispersionsS pastes, dusts, broadcasting agents, or granules by spraying~atomizing, dusting, broadcasting or ~atering.
The rorms o~ application depend entirely on the purpose for which the agents are being used; in any case they should ensure a fine distribution of the active ingredient.
For the preparation of solutions, emulsions, pastes and oil dispersions to be sprayed direct, mineral oil fractions of medium to high boiling point, such as kerosene or diesel oil, further coal-tar oils, etc. and oils of vegetable or animal origin, aliphatic, oyclic and aromatic hydrocarbons such as benzene, toluene, xylene, paraffin, tetrahydronaphthalene, alkyl-ated naphthalenes and their derivatives such as methanol, ethanol, propanol, butanol, chloroform, carbon tetrachloride, cyclohexanol, cyclohexanone, chlorobenzene, isophorone, etc., and strongly polar solvents such as dimethylformamide, dimethyl sulfoxide, N-methyl-pyrrolidone, water, etc. are suitable.
A~ueous formulations may be prepared from emulsion con-centrates, pastes, oil dispersions or wettable powders by adding water. To prepare emulsions, past s and oil dispersions the in~redients as sUch or dissolved in an oil or solvent may be homo~enized in water by means of wetting or dispersing agents, adherents or emulsifiers. Concentrates which are suitable ~or dilution with water may be prepared from active ingredient, wetting;agent, adherent, emulsifying~or dispersing agent and -~
possib~ly 901vent or oil. -. .
:

~cF3~ 7 3 4 ^ O.Z. 32,325 ~xamples of surfactants are: allcali metal, alkaline earth metal and ammonium salts Or ligninsulfonic acid, naphthalene-sulfonic acids, phenolsulfonic acids~ alkylaryl sulfonates, alkyl sulfates, and alkyl sulfonates3 alkali metal and alkaline earth metal sal~s of dibutylnaphthalenesulfonic acid, lauryl ether sulfate, fatty alcohol sulfates, alkali metal and alkaline earth metal salts of ~atty acids, salts of sulfated hexadecanols, heptadecanols, and octadecanols, salts of sulfated fatty alcohol glycol ethers, condensation products of sul~onated naphthalene and naphthalene derivatives with formaldehyde, condensation pro-ducts o~ naphthalene or naphthalenesulfonic acids with phenol and formaldehyde, polyoxyethylene octylphenol ethers, ethoxylated isooctylphenol, ethoxylated octylphenol and ethoxylated nonyl-phenol, alkylphenol polyglycol ethers, tributylphenol polyglycol ethers, alkylaryl polyester alcohols, isotridecyl alcohols, fatty alcohol ethylene oxide condensates, ethoxylated cas~or oil, poly-oxyethylene alkyl ethers, ethoxylated polyoxypropylene, lauryl alcobol polyglycol ether acetalg sorbitol esters, lignin, sulfite waste liquors and methyl cellulose.
Powders, dusts and broadcasting agents may be prepared by mixing or grinding the active ingredients with a solid carrier.
Granules, e.g., coated, impregnated or homogeneous granules, may be prepared by bonding the active in~redients to solid carriers.
Examples of solid carriers are mineral earths such as silicic acid, silica gels? silicates, talc, kaolin, Attaclay, limestone, lime, chalk, bole, loess, clay, dolomite, diatomaceous earth, calcium sulfate, magnesium sul~ate, magnesium oxide, ~round plastics,~fertilizers such as ammonium sulfate, ammonium phos~
phate, ammonium nitrate, and ureas, and vegetable products such as 3 grain flours, bark meal, wood meal, and nutshell meal, cellulosic powders, etc.

~ 9 ' ~ .
:::

i734 O,Z. 32,325 There may be added to the CompoSitions or individual active ingredients oils of various types, herbicides, f~glcides, nema-tocides, insecticides, bactericides, trace elements~ fertilizers, antifoams (e.g., silicones), growth regulators, antidotes and other herbicidally effective compounds.
The the following experiments, the following prior art com-pounds were used for comparison purposes:

Compound no.

~~~\~ CH3

7 C13H27 N ~

C~3 (prior art) ~ CH3

8 C13~27 ~ .CH3COOH

(prior art)

9 C13H2 - ~ .C12~25 ~ 3 (prior art) 3 ~.

Leaves of what seedlings o~ the "Jubilar" variety grown in pots are treated with aqueous emulsions consisting of 80% (wt%) of

10 active ingredient and 20% emulsifier and dusted, after the sprayed-on layer has dried, with spores of wheat mildew (Erysi~he graminis ~ar._tritici). The plants are then placed in a greenhouse at from 20 ~o 22C and 75 to 80% relative humidity. The extent the fungus has spread is determined after 10 days.

.
''" ' ' , . . . . .. . .. .. .. ..

~ 11~6734 -:` 0,Z. 32,325 Active ingredient Leaf attack after spraying with liquors con-taining active ingredients in amounts of 0 006%0.012% 0.025% 0.05%

4 1 0 0 0 ~-0 0 0 0 :
6 1 0 0 0 ~ .
19 0 0 0 0 '. -7 ) 3-4 3 2 8 ) prior art 4 4 2 9 ) 2 1 1 0 Control (untreated) 4 : ;
0 = no attack~ graduated down to 5 = surface of leaves completely covered by fungus.
~ EXAMPLE 4 :
: .
Leaves of barley seedlings of the "Firlbecks Union" variety -~
grown in pots are tre~ated as described in Example 3, and dusted with ~-spores of barley~mildew (Erysiphe Qraminis var. hordei). ~ : .
Active ingredient~; Leaf attack after spraying with :liquors con-taining:active ingredient in amounts of 0:.o06% ~ 0.012% 0.025%
~O: O
2 ~ 0 0 0 ~ `.
:-, ~ o O
4 . :0 0 0 6 ~ ~ 0 0 0 :
19 ~ ~ ~ 0 ~ ~ ~ 0 O
:~20 ~ 0~ : 0 0 ~ prior~art ~ 2~ ; 1 0-1 : Control::(untreated) _ _ 4 _ :
O~ no:~ attack3 ~gràduated down to 5 - surface of leaves completely covered~:by~ungusO ~

r 1~3~734 O.Z. 32,325 Leaves of wheat plants grown in pots are artificially in-fected with spores of lea~ rust (Puccinia recondita) and placed for 48 hours in a steam-saturated chamber kept at 20 to 25C.
The plants are then sprayed with aqueous liquors containing a mixture, dissolved or emulsified in water, of 80% o~ the active ingredient and 20% o~ sodium lignin sulfonate, and placed in a greenhouse at ~rom 20 to 22C and 75 to 80% relative humidity.
The extent the fungus has spread is assessed after 10 days.

Active ingredient Leaf attack after spraying with liquor con- -taining active ingredient in amounts o~
0.025 0.05 0.1 ... ... _ .

o o 0 19 O O O - ' 7 ) 4 3 2 8 ) prior art 4 4 3 9 ) ll 3 3 Control untreated) 4 0 = no damage, graduated down to 5 = surface of leaves completely covered by fungus.
~ ~ EXAMPLE 6 90 parts by weight of compound 3 is mixed with 10 parts by wei~ht o~ N-methyl~-pyrrolidone. A mixture is obtained which is .
suitable for~application~in the form of very fine drops.

20 parts by weight of compound 4 is dissolved in a mixture ~consisting~of 80 parts by weight of xylene, 10 parts by weight of the~adduct of 8 to 10 moles of ethylene oxide to 1 mole o~

~: :
.. . . ..... . ..

673~
~ .Z, 32,~25 oleic acid ~-monoethanolamide, 5 parts by weight of the calcium salt of dodecylbenzenesulfonic acid, and 5 parts by weight o~
the adduct of 40 moles o~ ethylene oxide to 1 mole of castor oil. By pouring the solution into 100,000 parts by weight of water and uniformly distributing it therein, an aqueous dispersion is obtained con~aining 0. 02% by wei~ht of the active ingredient.

20 parts by weight o~ compound 3.is dissolved in a mixture consisting of 40 parts by weight of cyclohexanone, 30 parts by weight o~ isobutanol, 20 parts by weight of the adduct of 7 moles of ethylene oxide to 1 mole of isooctylphenol, and 10 parts by weight of the adduct of 40 moles o~ ethylene oxide to 1 mole of castor oil. By pouring the solution into 100,000 parts by weight of water and uniformly distributing it therein, an aqueous dis persion is obtained containing 0002% by weight of the active ingredient.

20 parts by weight of compound 4 is dissolved in a mixture consisting o~ 25 parts by weight of cyclohexanol, 65 parts by weight of a mineral oil fraction having a boiling point between 210 and 280C, and 10 parts by weight of the adduct of 40 moles of ethylene oxide to 1 mole of castor oil. By pouring the solution into 100,000 parts by weight of water and uniformly distributing it therein, an aqueous dispersion is obtained containing .?~ by :-~
weight o~ the active ingredient. ::

20 parts by weight of compound 5 is well mixed with 3 parts by weight of the sodium salt of diisobutylnaphthalene-~,-sulfonic acid, 17 parts by weight of the sodium salt of a ligninsulfonic acid obtained from a sulfite waste liquor~ and 60 parts by weight .:
,, .

~ , .

73~
o.z. 32,325 of powdered silica gel, and triturated,in a hammer mill. By uniformly distributing the mixture in 20,000 partS by weight of water, a spray liauid is obtained containing 0. l~o by weight of the active ingredient.

3 parts by weight of compound 3 is intimately mixed with 97 parts by weight of particulate kaolin. A dust is obtained con-taining 3% by weight o~ the active ingredient.
~XAMPLE 12 -30 parts by weight of compound 4 is intimately mixed wikh a mixture consisting of 92 parts by weight of powdered silica gel and 8 parts by weight of paraffin oil which has been sprayed onto the surface of this silica gel. A formulation of the active ingredient is obtained having good adherence.

40 parts by weight of compound 3 is intimately mixed with ~0 parts of the sodium salt of a phenolsulfonic acid-urea-formalde hyde condensatej 2 parts of silica gel and 48 parts of water to ', give a stable aqueous dispersion. Dilution in 100,000 parts by weight of water ~ives an aqueous dispersion containing 0.04 wt% of active ingredient.

20 parts of compound 4 is intimately mixed with 2 parts of the calcium salt of dodecylbenzenesulfonic acid, 8 parts of a fatty aloohol polyglycol ~ether, 2 parts of the sodium salt of a phenolsulfonic acid-urea-~ormaldehyde condensate and 68 parts of a paraffinic mineral oil. A stable oily dispersion is obtained. ' . .

.

..
: '

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. Morpholine derivatives of the formula , where R1, R2, R3 and R4 denote hydrogen, methyl or ethyl, and their addition salts with inorganic or organic acids.

2. A process for combatting fungi, wherein the plants, or their seed, to be protected against fungus attack are treated with a morpholine derivative of the formula , where R1, R2, R3 and R4 denote hydrogen, methyl or ethyl, or an acid addition salt thereof.

3. A process for preparing a morpholine derivative of the formula , where R1, R2, R3 and R4 denote hydrogen, methyl or ethyl, wherein 3-p-tert-butylphenyl-2-methylpropanal of the formula is reacted with a morpholine of the formula , where R1, R2, R3 and R4 have the above meanings, in the presence of formic acid, with or without a diluent, at temperatures of from 50° to 110°C.